Phosgene chemistry: A concise history

qui peut tout aussi bien chlorure d'oxidede carbone, offre une composition si simple et si remarquable que, s'il
r\177alisait toutes les r\177actions que I'on a droit d'en esp\177rer,

\177tre consid\177r\177
L'acidechloroxicarbonique,
comme
un
on parviendrait reproduire, les plus curieuses de la chimie

\177
\177
Acad\177mie
desSciences on december 6 1 and

\177
son aide, les combinaisons organique... (Read to the french

\177
31, 833). 1
Die Chlorkohlens\177ure als das ChlorLir

besitzt
setzung, man die Recht davon erwarten gen

wL\177rde,
w (Phosgen), elche eben so gut des Kohlenoxyds betrachtet werden kann, eine so einfache und merkwLirdige Zusammendab wenn es allen Reaktionen entspr\177che, die
k6nnte, man damn gelandie merkwLidigsten Zusammensetzungen der organischen Chemiewieder hervorzubringen....(Translation published in Annalen der Chemie
\177
\177).
acid (phosgene)which can also be Chloroxycarbonic consideredas a carbon oxide chloride, offers a composition which is simple and yet remarkable. If it producesall the reactions we expectof it, we will be able to reproduce some of the most fascinating combinations in organic chemistry.
lean Baplisle
Dumas
Jean Baptiste Dumas
Canne, France), French chemist and politician. Tutor at the EcolePolytechnique (Paris one of the founders of the EcolePolytechnique (Paris ), one of the founders of the Ecole Centrale des Arts et Planufactures (Paris Professorof Chemistry at the facult\177 desSciences de Paris, at the facult\177 de Pl\177decine, Lecturer at the desSciences Coll\177ge de france, Member of the Acad\177mie electedat the Acad\177mie Fran(::aise (1875).)))
(b.1800 1821), 1821

Al\177s,
France
- d.1884
1829),
(1832),
Prefa(e
At the early beginnings, organic chemistry was taken by the scientific community as the chemistry of living matter. After the discovery of the synthesis of urea by W\177hler in organic chemistry was defined as the chemistry of carbon-containing compounds. Almost the entire amount of the carbon available on the earth surfaceexists in the form of carbonic acid (free or as calcium salts) and in fossil fuels obviously originated from living matter. It is well known that carbon dioxide is the necessaryingredient in the life cycle of animal and
1828,
as Therefore, rganic chemistry must be considered o relatedto the chemistry of carbon dioxide and its strongly
plants.
derivatives.
\177{
Carbonic acid dichloride called discovered by John Davy in still nowadays the only appears efficient simple activated form of carbon dioxide, and despite intensive researchdone to replace it with less noxious starting material, phosgeneremains a substitute for carbon dioxide, l\177oreover, becauseof the presenceof acid chloridefunctions, phosgeneexhibits a large range of other chemical reactionswhich make it a very useful multipurpose tool in organic chemistry. The first chemical studies on phosgenechemistry have been associatedwith the development of organic chemisIn the period e try during its classical ra
\177,
1812,
\177
(18201940).
after world war two,
a tremendous growth
phosgenechemistry has experienced and wide interest. Vast numbers)))
Preface
of scientific papers and patents have been published by several thousands of organic chemists working in academic
and industrial
By now,
I
Preface
wish to express y gratitude to all my Furthermore, m from SNPE group and from the US and French colleagues Universities who have participated along these last 25 in the development of news aspects of phosgene years chemistry.
Finally,
I
researchlaboratories. although phosgene chemistry

with well
as is established
books, chemistry and reviews, it seemsthat truly important monographs facets of new and unusual aspects are somewhat neglected. In this book, have tried to provide an essentially complete survey of the work done for a quarter century at
documented text
I
a fully-grown
would
particularly
like
to acknowledge Pro-
fessorRoy Olofson(The Pennsylvania
of phosgeneand related compounds, with specialemphasis on unusual, unexpected and new reactionsor applications. Phosgene is widely used in organic chemistry as a = building block providing the C O such as in carbamates, carbonates,isocyanates, reas, heterocycles tc., or as a e u reagent for chlorination, dehydration, alkylation, de-alkylaSNPE group
in the
chemistry
State University) for his unfailing enthusiastic support during our more than ten years collaboration on the development of new synthetic reagentsand preparative methods in phosgeneand related compounds chemistry. am deeply grateful to him for his
I
patience,wisdom and kidness scientist and a teacher.
and for being
a model as a
tion, protection Consequently,
and activation etc. have chosento divide this

I
book in
two Buthiers,
volumes :
Volume on physical
some considerations introduction, propertiesand chemical reactivity, and four

includes derivatives
Jean-Pierre SENET G. France Seine-ebMarne,

August
1997)))
chapters devoted to phosgeneand
as building
blocks.
Volume vatives
2 presentsapplicalEions of phosgeneand derias reagents and the general conclusion. Of course,selectionof topics to be included in these
I
two volumes is undoubtedly influenced by the author's interest. So would like to make here my apolopersonal who may found their own gies to any of my colleagues work discussed inadequately.
because nothing comes from nothing\177 in other becauseeverything has predecessors,is important it to note that if .John Davy discoveredphosgene,Jeanits chemistry and may be theBaptiste Dumas invented reforeconsideredas the true pioneerin the chemistry of T phosgene. o take stock of this question, have included in the first volume one sectiondedicatedto the history of phosgenechemistry.
Also\177
terms
\177
\177
Contents first volume

(ll\177pter Introduction
Section Section Section
Section1-4 Classification of phosgenereactions
(hapter
\177
o Characteristics f phosgene
Section2-1 Physical properties Section2-2 Chemical reactivity of phosgene
(hapter
\"\177
Phosgeneand derivatives as building blocks Section3-1 Reaction at a carbon center
Section3-2 Reactionsat an oxygen or sulfur center 3-2-1Highlights of some particular chloroformates

starting
from
3-2-2Reaction
of phosgene at oxygen center of unconventional substrates

of of of
3-2-2-1eaction R 3-2-2-2eaction R 3-2-2-3eaction R

3
................................ 1-1 ............ 1-2 10 .................... 1-3 .................. 11 ... 1 1 15 ........................ 15 ..................... 16 .......... ............. ................ 31 ........................ .................. ..................... ......................
7
History
of phosgenechemistry
Toxicity
of phosgene Breakdown of consumption
of
phosgenein
the industry
27
27
alcohols or phenols
34
phosgene with glycerol phosgene with epoxides phosgene with aldehydes
....................
and
48 48
224
ketones.novel c\177-chlorinated and related reagents
Vinylicchloroformates, carbamates
53 ...................................... carbonates 81 ............................................

and
chloroformates
Section3-3 : Reactions at a nitrogen center 3-3-1 Highlights of some reactions of phosgene

with amines, imines, oxazolines
3-3-2 Reaction
of 1-chloroalkyl chloroformates with amines, synthesis and useful applications of 1-chloroethyl carbamates 3-3-3 1-Chloroalkyl carbonates as acylating agents for the synthesis of carbamates
......... 105 105 .................. 115 .................... ..................

129)))
Contentsirst volume f
3-3-4 Reaction 3-3-5 Reaction
of phosgene and its derivatives ureas and amides
D
132
Introduction
with carbamates,
of phosgene with sulfonamides, preparation of sulfonyl isocyanates formation
Section3-4 : Ring 3-4-1Cyclisation
3+2
between two oxygen atoms Cyclisation between an oxygen and a nitrogen atoms
3-4-3Cyclisation 3-4-4Cyclisation
atoms
................. ................. .................. 143 ........... .............................................. 151 ......... ................................................................1)

141
reactions 143
between two nitrogen atoms between a nitrogen and a sulfur
167
173
lllslory of
\177hemislry
The story of phosgenediscovery (Ref.
phosgene
(\177ontents
second volume
Phosgeneand derivatives as reagents Section4-I Chlorination
(Acid chlorides, Imidoyl and Chloroiminium chlorides, Alkyl Chlorides, Chlorinated Phosphorous compounds chlorination of heterocycles, etc.)
In the early beginning of the 19th century, chlorine gas was still uniformly considered a combination of muriatic as acid (hydrochloric acid) and oxygen called oxymuriatic
Chapter4
acid
\177.
Davy, Sir Humphry Davy's the opinion that oxymuriatic younger brother, expressed acid was, as a matter of fact, an elementary substance. in
However,
Dr. 1810, John
Section4-2 Section4-3
Dehydration
This opinion was not at all acceptedand several scientists, in order to refute the arguments of Dr. Davy, tried therefore to remove oxygen content of oxymuriatic acid by treatment
with
(Nitriles and Isonitriles) Alkylation
charcoal at a
white
of phenols and amines

activation
monoxide
M
Muriat\177c
[Scheme
+
1].
heat or
with
carbon
MO
Section4-4 Protection and

functional
of
0
Oxygen
\177
groups (Amino acids protection and activation, protection of hydroxyl groups, activation of carboxylic acids, etc.)
acid
Oxymuriat\177c
acid
CO
Carbon monoxide
De-oxygenation
=.
M
Murlatlc
+
acid
CO2
Section4-5
N and
O- dealkylation
Scheme 1 This versy
\177
Expected
de- oxygenation opening

official
of oxymuriatic
\177
acid
(chlorine).
Chapter
Conclusion
Is any conceivable nontoxic option to overcome phosgene in its industrial applications ?
was the
between Dr. John
of the so called chlorine controDavy and Dr. Murray, fervent
supporter of the
theory. This
debate took
the form
7)))
Introduction
to Nicholson's Journal >), both from their own experiments. arguing In an experiment of fundamental importance, after a mixture of one volume of carbonic oxide having exposed and one volume of oxymuriatic acid to bright sunshine, Dr. Davy noticed that the color of the chlorine has entirely disappeared,and that the remaining gas occupiedthe of space one volume. After addition of ammonia, he found no tracesof carbonic oxide and observed effervescence an
<<
Introduction
contributed
of letters
authors
The infancy
of the phosgenechemistry
of
the ammoniacal salt formed with
nitric
acid. He also
spite of his neat discovery, Dr. Davy has not foreas prolific potentiality of phosgene an outstanding block and reagent in chemistry. However, while building with ammonia, he was very closeto anotreating phosgene ther discovery of extreme importance, that of the elucidation of the nature of urea. Dr. Davy noticed that phosgene dissolvesin alcohol,
In
seenthe
gas resulting from the evident action of oxymuriatic acid and carbonic oxide did not fume when thrown into atmosphereand that it had a most intolerable
suffocating
noticed that the new
but without
In
1833,
mentioning any reaction. French chemist Jean-Baptiste umas while D
odor and that water absorbedit very slowly. These results were however again contestedby Dr.
Murray who, to support his opinion that oxymuriatic acid and carbon monoxide do not react, quoted unsuccessful trials from French chemists Gay-Lussac Thenard : and
<<
alcohol in a flask containing phosgene, first synthetic derivative (Ref. He noticed a strong and instant heating, and after work-up and analysis, he identified the resulting compound as a new chloroxicarbonic ether (ethyl chloroformate). adding
absolute ethyl
discovered its
2).
muriatique
r\177 \177t\177
sec,et/egaz oxide de carbonepr\177paavecle fer et le carbonatede barite, quelque forte qu'ait la lumisre laquelle on les a exposes, enfin quelque
oxl\177n\177
\177 \177t\177 \177.
...mais
Dumas
<(
immediately
\177
quelque
dosequ'on
air
m\177l\177
le gaz acide
of phosgenechemistry
\177tre consid\177r\177
had an inkling of the with this prediction
importance
le contact, il n'y a point eu d'action long qu'ait At last, in an important and well-argued letter read to the Royal Society on February Dr. Davy refuted all the arguments of Dr. Murray and, on the basis of careful and indisputable experiments, proved the reality of the new gas [Scheme
6, 1812,
qui peut tout aussi bien comme un chlorure d'oxide carbone,offre de une composition si simple et si remarquable que, r)alisait routes les r\177actions que I'on adroit d'en esp)rer, on parviendrait son aide,les combinaisons reproduire,
\177 \177
L'acidechloroxicarbonique,
les plus curieusesde la chimie organique Translation Phosgeneexhibits such a simple

\177.
\177
and
2].
remarkable composition that, should
CI2
Chlorine
\"
+
(1 vol.)
acid
\"
CO
Carbon monoxide of phosgene.
Light
realizeall the reactions one is entitled to hopefor, one could reproduce,

it
\177
)
vol.)
COCI 2
Phosgene ( 1
vol)
thanks to it, the strangest combinations

in organic chemistry All investigations clearly fulfilled
\177.
(1
Oxymurlat\177c
Scheme 2
1-he discovery
the
since then have expectation of
To designateit, he suggesteda simple name,
that
of
Phosgene (or phosphene), , and to produce

light
)\177 \177
from
ancient Greek roots
Dumas who may be thereforeconsideredas the pioneerin the chemistry of phosgene.

Jean-Baptiste DUMAS (1800IB84) Pioneer in the Chemistry of Phosgene
\177.
9)))
Tntrod uction
uction Tntrod
highly
Phosgene is a
toxic gas which was
used as a
13
ol phosgene
\177nSlllnplion
chemical weapon during World War I.

At high concentration, it causessevere pulmonary irritation and can induce delayed pulmonary edema.It is the reasonwhy all personswho have been exposedto phosgene,even in very low concentration, must see a physician
Breakdown
in this field is generally Although information kept confidential, worldwide phosgeneproduction is estimated to range from 6 to 8 millions tons/year. The breakdown of phosgeneconsumption is the following
ihe industry
immediately.
concentrations in
Some relationships between phosgene

air and physiological
are summarized in table The table son betweensome toxic gases.

Perception of odor Recognition of odor
Irritation in
1-1.
effectson
1-2 gives
humans
compari-
-: -
Di and polyisocyanates (TDI, THDI) for polyurethanes Aromatic polycarbonates
Hanufacture
of fine chemicals
Beginning of lung damage Clinical pulmonary edema
L(CT)0 L(CT)50
lbble
(\177et
L(CT)100
I 1
\177).
.............................................. ............................................1.5 ......... ................................... ................................... ................................................................. ............................................................... .............................................................

eyes,nose,throat,
and bronchi
30 1.50 ~ 300 .500 ~ 1300
> > > > >
0.4 ppm
ppm ppm
The consumption of phosgenefor fine chemicals, about 300,000 T/year is roughly divided into : used as poly50% for perestersand percarbonates
merization initiators,
........................... ........................ .....................

85% 10%
and dyestuffs.
ppm-min ppm-min
25 % for agrochemicals, 25 % for pharmaceuticals
ppm-min ppm-min
ppm-min
Con\177enttatiot\177
effect
relattonshtps
of
phosqene exposure tn
hamcms
14
exp.
Gas
Phosgene
Chlorine
Odoridentification
ppm
min L(CT)0-30
ppm
Since the pioneering study by Dumas, phosgene devoted to fine chemicals, has grown chemistry, especially
and still remains in an active field of investitremendously gation with papersand patents published eachyear. can be diviAlmost all the chemical reactions phosgene of ded into two classes,epending on wether the structural d unit remains in the final product or not.
1.5
1
No
10
873 4 000 30 000
phosgene
real:lioll s
2500
Carbon monoxide
Ammonia
5
between some toxic gases,
Table 1-2 Comparison :
First
Due to these high toxicity properties, the presenceof on large quantities of phosgene a site must be strictly treated as major hazard. The regulatory requirements in transportation and safety know-how in the handling and storage of phosgene, have restricted its uses to specialized companies. Custom synthesis is a common practice in this field, because the transportation of raw materials to phosgene producers is preferredto the transportation of phosgeneitself.
introduce
as class: Reaction of phosgene a building block to Someexamples the structural unit carbonyl
\177
\177.
are given
in
table
1-3.
10
11)))
Tntroduction
Substrate Aromatic Product Ar-C-CI
Acid chloride
Tntroduction
class Second : Phosgeneand
Su bstrate
Carboxylic
derivatives
as reagents
: Ar-H
Product
O
Ar-C-Ar
Aromatic
II
ketone
acid
: R-COOH
(+
n-C-Cl
Acidchlorlde
O
Alcohol or
II
O
Chloroformate
II
phenol: R-OH
R-O-C-CI
II
R1OCOCI)
Esler R-C-O'Rlll
R-O-C- O-R
II
Carbonate
Alcohol : R-OH
R- CI
Alkyl
chloride
Primary amine
: RNH2
R-
=C= O
socyanate
N,N-Disubstituted
: R 1R2NCHO
R\177\\
Cl\"
formamide
RI\\
R2
N---CHCI
Vilsrneier
sail
Secondary or tertiary R 1 R 2 R3N (R
amine
:
R
\"
N-C-CI chlonde
II
Carbamoyl
Primary amide
: R-CONH 2 : R-OCOH
R-C\177N
Nitrile
O
1
3- = H or alkyl)
RI\\ R 2\"
N-C-N
/R 2
Urea
Alkyl
formate
R- O-CHCl2
t ,1-D\177chloromethyl
elher
II
\\R
Phenol
: At-OH : H2N-CHR-COOH
At- OMe
Aryl
methyl
ether
O
cz-Amino acids H2N-CHR-COOH
R\177N..
\177
Amino acid
N-Carboxy
RO-
C-NH-CH-COOH
II I
N-
Protected
amino acid
Anhydride
(NCA)
Tertiary
CI
I
amine:
R 1R2R3N
RI\\ R
3= (R alkyl)
c\177
2z
NH
N-Dealkylated
amine
Aldehydes
: RCHO
R- CH-O-C-CI
II
-Chloro
alkyl
Chloroformate
Aryl methyl ether
: Ar-O-He
(+ PhCOCI
+ catalyst)
Ar-O-\177
\177-\177 Phenol
Aryl
benzoate
Sulfonamide
: FLSO2NH
RSO2-
N----
C=O
At-OH
Sulfonyl
Isocyanate Table
Table I-3
I-4
,\"
Examples
of phosgene and derivatives
as reagents,
Examples
of phosgene reactions to introduce
the group
>C=O.
12
13)))
of Characteristics phosgene
Physical
properlies
At ambient temperature and pressure,phosgeneis a colorlessgas which exhibits an irritating and suffocating odonAt low concentrations, it has a characteristic odor like moldy hay. However, the odor threshold of phosgeneis higher than its toxic limit and one must remember that the senseof smell fails to detect small concentrations in air. Somephysical properties phosgeneare presentedin of
table
2-1.
CAS number Molecular weight Structure
98.92 +
75-44 - 5
= : C-O = C-Cl
nm 0.128 nm 0.168
Planar molecule Inter atomic distances
Melting point Boiling point
130\302\260C
8.2\302\260C
Vapor pressure Vapor density

Liquid density
1.6 atm.
3.42
I
(20\302\260C)
3.99 atm.
(50\302\260C)
(50\302\260C)
1.43
ppm
(O\302\260C)
1.275
Conversion factor
= 4.043 3 m\177/m
of moldy hay
Odor
Table 2-1 Principal
Reminiscent
physical
properties of phosgene,
15)))
Characteristics phosgene of
Chemi(al
rea(\177i\177i\177y
be accounted
T gene reactions. wo
of
A large part of phosgenereactivity may for on the basisof two main mechanisms :
phosgene
a)
Nucleophilic attack on carbonyl function
nucleophilicity
-phosgene
substrate
;
catalytic by
paths
are obviously possible

of the
activation
means of an increasing of its

<<
character,, of chloride
activation by improvement anion.
leaving
Concerning phosgene reactions with active hydrogen strates [Scheme.5]
sub-
+Ci\"
Nu--H Scheme 3.
COCI 2
Catalyst
\177
Nu--C--CI o
II
+ HCl
Scheme 5.
b) Electrophilic
related reactions COCl 2

+ MCl Lewis acid
Friedel & Crafts reactions,especially
mechanistic
University in
studies performed with France (Ref. 4) resulted
the help of Nantes in the revelation of
activation based on nucleophilicity of chloride anion in the case of Q+ CI- type catalyst (quaternary ammonium chloride for example).The mechanism of nucleosubstrate
O
+
\\\\
of as an philic assistance these catalysts can be understood increaseof the nucleophilicity of the substrate by proton abstraction followed by the condensation the promoted of anion on the electrophilephosgene) [Scheme6] : (
1/2
Scheme 4.
Becausesome important aspectsof the mechanism of the nucleophilic reactionswith phosgeneseemed somewhat neglectedor unknown in the previous art, SNPE teams have focused their efforts in terms of basic and applied research on the catalysis of such reactions.The
main
Nu--H
Gcr
Nu
..... ......
1/2-
CI
o
+
Q\321\207
goal of
improve industrial
the range of substrates able to reactwith phosgene. As a consequence,his investigation succeeded devet in and lopment of many improved processes the discovery of several previously unknown reactions which are discussed
in this
this active and long investigation was to a phosgenation processesnd to extend
CI-
+ HCI
Cl,\177Nu
Scheme 5. This mechanism has been confirmed by reacting a series of onium chloridesalts with phenol using 3sCI NI\"IR determination as physical probe as shown in table
book.
the 16
The principal obstacleto progress this field has been in difficulty of establishing the catalytic mechanism of phos-
2-2.
17)))
of Characteristics phosgene
Range of
of Characterislics phosgene Line width
Q + CI
(a)
TMCA (b)
1/2
Q+
phosgenation
efficiency HIGH
(Hz) (c)
240
Tetra hexyl ammonium chloride

Benzyl tributyl
MEDIUM
220.5 145.5
141
58
o The success f this
new synthetic route
ammonium
chloride
Tetrabutyl ammonium
to
o\321\236-chodnated
chloride
LOW Benzyl trimethyl ammonium
chloroformates which are very useful intermediates (seechapter 3,section3-2) is strongly dependenton the nucleophilic power of the chloride anion as shown in table
chloride
Catalyst
2-3:
%)
(a)
Phosgenation
of phenol
into phenyl chloroformate

chloride
or
carboxylic GI
acids into
Me
Nucleophilicity
lIChloro ethyl chloroformate

Yield %
acid chlorides
(5 mol.
(Hz)
(b) Tetramethyl
chloroformamidinium
Me N\177
Me\"
I
Me
GI
Benzyl tributyl ammonium

chloride
145.5
95
(c)
Line width of the chloride (solvent
anion
resonance
;n the system onium
chloride
Benzyl trimethyl ammonium
salt/phenol
: CH3CN)
efficiency
Table 2-2.'General correlation between catalyst chloride anion. Study by35CI NMR.
and nucleophilidty
of
58
0
(No reaction)
and
chloride
out that the C-nucleophilicity of chloride anion is also acting. In the courseof our researchrelated with carbonyl compounds, we to the reaction of phosgene
We pointed
between nucleophilicity determined by 35CI NMR Table 2-3 Correlation results obtained in phosgenation of acetaldehyde.
The role of the
nucleophilicity
of the
chloride anion is
chloroformates when treated with phosgenein the presence of a Q+ Cl- catalyst (Ref. 5). The assumed mechanism involves the nucleophilic attack of the chloride of anion on the aldehyde followed by the acylation the intermediate chloroalkoxideanion by phosgene
roalkyl
KCI/18crown 6 as catalysts for the phosgenation of

aldehydes. Tracesof HCl (moisture) inhibit the reaction because than Cl-. HCl 2- anion exhibits much less nucleophilicity such as little toluene Including hydrochloric acid scavenger diisocyanate in the mixture generally solvesthe problem.
[Scheme7]
18
19)))
of arac;eris;icsphosgene
The nucleophilicity of the chloride anion is of coursea of the nature of the counterion To increase the nucleophilicity, one can either or both increase the bulkiness and the dispersal of the positive charge of the counterion. We discoveredthat hexaalkyl guanidinium chlorides are very efficient and powerful phosgenation
function
(\177+.
of Charac;eris;icsphosgene
R
NH
COCI2
/ \177 / N--C--N
R\\ R
COCI 2
II
\\ R R
CIR\\ +
catalysts
R R
[Scheme8]
/CI
2 R2NH
\177-
R \\
NIl
-/ CI+ R
I
R/N\177'N__ R
R,\\
+ R,,,NH
/ R
N/C\177N/
I
R
N
\177-
COCI2 4\1771
+
N
CI-.HCI
X X-
= CI or HCI2 = Me '
HBGCI\"
\"
90oc
Scheme 9
R \\
N
II /C\177
Fi
P%\"
/ N-C-CI
O
-torr) (0.2
' HCl
R/N\177R
Scheme 8
.\"
R=n Bu :
R
chlorides.
HMGCI\"
.\"
R
Preparation
R chlorides
Hexaalkyl
guanidinium
of hexa
alkyl guanidinium
This industrial
these guanidinium salts in a 198_5 on the conversion of carboxylic acids to patent (Ref. 6) acid chlorides with phosgene.In this process,nly o mol. % of HBGCl was required, two orders of magnitude less than the quantities of other catalysts typically used. reactions Many new other applications including phosgene with phenols, thiols, aldehydes, epoxides O-demethylaor
We introduced
tion methods have in this book.
0.02
chloride hydrochloride (HBGCI.HCl)which, as above mentioned, failed as a catalyst in the reaction requiring high C-nucleophilicity of chloride anion. Pure HBGCl may be
leads to process
hexabutylguanidinium
obtained
a solution of HBGCI.HCl with excess The dried (HgSO4)rganic layer is concen10% NaOH. o
by shaking
trated and then nitrogen.
treated at
100\302\260C
under vacuum
for 24 h. The off-white
powder obtained is stored under
been developed later
and
arediscussed
Moreover, these new catalysts may be considered themselves as phosgene derivatives becausethey are made from phosgene and secondary amines by the scheme
depictedbelow [Schemec)]
of The decomposition methyl chloroformate is a very convenient method to establish a nucleophilicity power scale of the chloride anion in onium chlorides, allowing thus to easily comparea priori the catalytic efficiency of different I candidates.t is known that the decarboxylation of methyl Cl- type compounds chloroformate is catalyzed by thus producing only methyl chloride and carbon dioxide accordingto a pure SN 2 reaction (Ref. 7) [Scheme :
(\177+
10]
Q+ Cl\"
CH3--O--C--
\177
CH3Cl
CO2+
Cl\"
Scheme 10 Decomposition of methyl
O
chloroformate
21)))
II
20
of Characlerisli(sphosgene
We used this specific reaction on IR analysis as kinet chemical probe (Ref. 8). Among the various oniuf chlorides commonly encountered,hexabutyl guanidiniuf chloride (HI3GCl) exhibits the highest activity as shown table 2-4
.-
of Chara(terisli(s phosgene
Catalyst HBGCI HHGCI Tetrahexyl ammonium
Relative rate constant
100
47
chloride chloride chloride
42
27
Benzyl tributyl
ammonium
Trioctyl methyl ammonium

Table formate
14
chlo\177
Relative rate constant values of SN 2 decomposition of methyl at in the presencef onium chloride catalysts o For HBGEI, the k value is 12.52in. m 8).
70\302\260E
\1771
24
Scheme 11 Molecular model of hexabutyl Although
guanidinium
chloride
(1%).
(Re\320\210
As
nium
expectedconsidering table 2-4, hexabutyl

chloride
displays higher
catalytic activity
chloride (HMGCI) is hexamethyl guanidinium i its hexabutyl congener,t is very useful in several industrial applications, becauseof its good water solubility, and alsobecauseits hydrochloride is often inso-
lessactive than
guanid than it
analogue. However, HMGCl offers sore becauseof its solubility in water which make advantages easier elimination by aqueous washings and because precipitates in several phosgenation media after removal c phosgeneexcess.
hexamethyl
\177
allow easy luble in organic mediums. Thesetwo properties removal of the catalyst after reaction. of octane thiol proceeds For example, phosgenation to give octyl of in presence HMGCI, even at rapidly thiochloroformate [Scheme
: 12]
n
30\302\260C
HMGOI n
To sum
up, hexabutyl
guanidinium
chloride
exhibit
Oct-S-H + OOOI 2
30\302\260O
\177
Oct-$--O--OI
\321\207
HMGOI.HOI
some particularities
due to its extraordinary bulkiness an, the hydrophobicity of the the n-butyl substituent: the dispersal f the positive charge is somewha o However, counterbalancedy the out of plane distortion of the bulk b
substituents as suggestedby molecular modeling calcul\177 tions on HBGCl using the CSC Chem 3D program (Ref. Due to this kind of geometry and for reasonsof symmetr\177 it is assumed that the chloride anion will be locatedalon the central axis and will interact weakly with the positiv
Scheme 12 Synthesis of n octyl
o
II
thiochloroformate
in presence of HMGCI.
After completion
9'
H gene excess, MGCI.HCIwhich
center[Scheme
: 11]
filtrated thus Another insoluble in all media and thereforeeasily removable by filc S reusable. uch heterogeneous atatration and indefinitely offersmany advantages, particularly in the caseof prolyst ducts difficult to purify by distillation becauseof thermal instability
of the reaction and removal of phosprecipitates completely is giving very pure product (Ref. approach is to have a catalytic system strictly
10).
or too high
boiling point.
23)))
22
reported the preparation of silicasupported guanidinium salts, especially pentabutyl propylchloride grafted on silica beads,and their uses guanidinium as phosgenation heterogeneouscatalysts (Ref. For example, starting from macroporous silica glass beads
We have recently
t /
11).
having
- diameter :1 characteristics: - specificsurface: 78 m2/g - porous : 0.9cm3/g - OH content :4.8 mol./m 2

the following
salts was supported guanidinium alsowell established reactions sensitive to reversal while in that treatment of aldehydes heating. Thus, we discovered with oxalyl chloride in the presence a naked of catalyst (e.g., BGCI)produces 1-chloroalkyl oxalyl chloridesin H 60-97%yields (Ref. 12)[Scheme
utility
The
of
silica
{{
\177
mm
: 14]
R
O
R...jk.H
+
O
CI\177L.\177CI
volume
FI
we obtained at pilot scalea catalytic of meq./g active sites.
system bearing
0.085
Scheme 14 Reaction
.\"
\177-
HBGCI
.......
\"CI-\" CI
O.\177 O
56-58\302\260C/20mm
= CH : bp 3
The synthesisroute we developedis depictedon scheme13
97% yield
ofexcessxalyl o
with
chloride with aldehydes.
Bu
CI\\ +
I \\
(MeO)3-Si-(CH2)3-NHBu+
N=C--=N
CI
Bu
Bu
(MeO)3Si(CH2) 3
Bu
However,
Bu
aromatic aldehydes or
Bu/
--\177
\177
Bu
/1\"4.
Bu
CA)
(A)
Silica
beads
/
\\
\177 i\177+
N
1\"4\177
heating resulted
in the in
presenceof the catalyst reversion to the aldehyde

fatty
chloral, during distillation and attempts to
with
cr
entirely remove the trituration
HBGCI catalyst, for example by
\\Bu
OH
Final treatment OH with Me3SiCI
\177
OSiMe 3
Si(CH2) 3 r,l.
Bu/\"
\177,,'+
Silica
beads
Bu
\177N
\\Bu
CI-
to the partial solubility of pentane this salt in the non-polar medium. This problem was overcome utilizing the supported by In catalyst above described. a typical example, distilled 1,2,2,2-tetrachloroethyl oxalyl chloride was thus obtained from chloral in 95% yield after 4 h reaction.
failed due
Bu/N\\Bu Scheme 13 Synthesis route to silica-supported

.\"
guanidinium
chloride catalyst.
Sincethis supported catalyst

diameter,
it
is
stable, insoluble
and
can be easily recovered by filtration and be and activity of silica supported stability salts, along with the ability to reusethe solid guanidinium catalyst were demonstrated on repetitive batch phosgenations of carboxylic acids.
composedof mechanically strong particles of 1 reused. he high T
mm
24
25)))
and derivatives as buildin blocks
Phos[lene
,i{eactions
,I (\177rl)on
(\177lll\177r
In the course of several studies, we demonstrated that with aromatics reaction of phosgene the Friedel-Crafts dependscritically on the purity of catalyst, the presenceof water and on the ratio catalyst/substrate. of with aromatics in Generally, condensation phosgene presence of Lewis acids affords benzophenonesas the main products, unless a specialmean is employed to remove : the intermediate complex [Scheme
15]
R
AICI
+ COCI 2
3
\177
\342\200\242
AICI3
O
R R
AICI
\342\200\242
\177
Scheme 15:Friede\177Craftsreacdon
ofphosgene with aromatics.
that the adduct ketone/AlCl stablethan the adduct acid chlofide/AlCl
Note
3 is
much
more
3.
an w developed improved processhich leadsto a very pure product with low content of xanthone [Scheme16]
ether with For example, condensation of diphenyl phosgeneunder Friedel-Crafts conditions gives 4,4'-dipheWe as noxy benzophenone the major product (Ref.
13).
27)))
a as b Phosgenend derivalives building locks

O \177\177 COCl
+
as b a Phosgenend derivalives building locks

Me
AICI
CICH2CH2CI
\177.
Me, 3
\177
Me Me
AlCl 3
2 O
[\177Me
COCI 2
Me
o Xylene
\177\177_ \177O\177
Yield
:85%
143\302\260C
M.P.:
Yield
> 80% Purity > 99.9%

of high
purity
Traces
( < O.1%)
Oxidation
==
O
BTDA
Scheme 15: Preparation
4,4;diphenoxy
benzophenone,
j\177\177\177
dianhydride
High purity ring material
i 4,4'-diphenoxy benzophenones a key star-
Scheme 18.'Synthesis of benzophenone tetracarboxylic
ether-etherketones(PEEK) scheme17
for the production of high molecular weight with terephtaloyl polymers. Thus, its polycondensation chloride in presence of FriedeI-Crafts catalyst gives poly-
Friedel-Crafts reaction of phosgenewith heterocyclic aromatic compounds is also difficult to stop at the acid
chloride
with the structure
depictedon
stage.However,
under chloride
selectedconditions, hetero[Scheme19]
\177,-
aromatics such as thiophene

give thiophenecarbonyl
can be
directly
acylated to (Ref. 1.5)
\1770\177 \1770
Scheme 17, Structural unit of thermoplastic
poly ether ether
'\177\"
Ol /n
COCI 2
CH2CI2
+ AICI 3 +
\177
\177S
ketones
Addition of thiophene at -20c'C the mixture in Phosgene + AICI 3 chloride
S\177 O
Yield
No
CI
: 96%
ether ether ketonesare usedas high performance engineering thermoplastics which offer an unique range of
Poly
Scheme 19
3-isomer
Preparation
of 2-thiophenecarbonyl
propertiesamong
continuous
them
working temperature ; high chemical resistance
of
250\302\260C
hours at temperature
-hydrolysis resistance on service of thousands of in excess f o in steam under

250\302\260C
pressure;
easily processible. Another example is the Friedel-Crafts
chloride is used as intermediate of many pharmaceuticals. For example, its condensation with protected L-4-hydroxyproline followed gives a product claimed as antiinflammaby deprotection tory and antidystrophic agent (Ref. 2-Thiophenecarbonyl
in the synthesis
16).
phosgene reaction
in o.xylene giving 3,3',4,4'-tetramethylbenzophenone and free of isomers(Ref. 14). his substituted T is t benzophenone easily oxidized into benzophenoneetraacid dianhydride (BTDA) widely used for the carboxylic manufacture of polyimides [Scheme with high yield
Nucleophilic addition efficient synthetic route
of vinyl ethers to phosgeneis an to valuable 3-alkoxy and 3-phe-
W noxy acryloyl chlorides. e studied an improved process under specialcatalytic based on literature data (Ref.
conditions
: 18]
[Scherne20]
17)
28
29)))
a a Phosgenend derivatives s building
blo\321\236ks
as a Phosgenendderivatives building
RO
blo\321\236ks
+ RO
Cl Cl
----\"
R.T.
LRO\" \"Cl
c,
HCl
Scheme 20 Phosgenation of vinyl ethers to give
Cl
o \"\177:= CI
Et-O-C-NHSiMe3 -\177-\177.
RO\177
\"\177
O
of Ethyl
II
Me3SiCI
HN o\177OEt
( E- configuration)
3 alkoxyacryloyl
chlorides
Scheme 23 . Preparation
N-alkoxyacryloyl
carbamate
E-3-alkoxyacryloyl chlorides are high potential intermefor organic synthesis, especially the preparation of various heterocycles, such as coumarins [Scheme
diates in
: 21]
OH
offer an interesting option carbamates N-alkoxyacryloyl to avoid the use of toxic and expensive alkoxyacryloyl isocyanates in the synthesis of uracil derivatives with antiviral activity [Scheme24] : HO. O
NH2
Et-O-CH\177CH-C-CI
\177
Yield
O
Scheme 21 P/epu/ulion of Ayapin
II
o
M.p. : 223-4{'C
0 MeON\177= o
HO
: 60%
(R\177L
uMng
3 ethoxyauyloyl :
chloHd\177
18) 1) Cyclisation
O MeOH
\177,
HO
NH
OMe
or quinolines [Scheme
NH
22]
',-.2HO\177N\177O
HO
2) 12 / HNO 3
2
0
II
87%
Scheme 24.'Preparation
of uracil derivatives
as antivirals
(ReL
20)
H2SO4
90%
F\177
O
POCl 3 87.5%
Scheme 22 Synthesis of quinoline of herbicides paration 19)

(Re\320\210
F\177,-\177 Cl
intermediates for the pre
Reactions
an
derivatives,
valuable
or sulfur center
oxyp\177en
Another valuable application of 3-alkoxyacryloyl chlorides is the preparation of N-alkoxyacryloyl carbamates to an original process eveloped SNPE Group at according d
[Scheme23]
mona or poly with aliphatic compounds at room temperature or below to afford corresponding aliphatic chloroformates in good yields. In contrast, phenols are quite inert toward phosgeReaction of ne, even at temperatures as high as s phosgenewith phenols requires an acid scavengeruch as tertiary amine or a mineral base (room temperature or below) or a catalyst (seesection2-2) such as HBGCI.HCl
Phosgenereacts easily
hydroxy
150\302\260C.
(temperature higher than
90\302\260C)
[Scheme25].
30
31)))

R1-OH R-OH +
COC\177 \177
blocks a as Phosgenend derivalives building
1 R-O-C-O-R
\177\177 R-O-C-Cl
- HCI O
II
HCI
II
...
B.P. Structure R.N.

\302\260C/mm
chloroformate
Applications
\177Scavenger
Ar-OH
\177\"
Chloromethyl
\177.or catalyst
no reaction
R-OH Ar-OH +
R-O-C- -Ar O o R-O-C-O-Ar

II
\177\"
22128-62-7 106/760 CI-CH20-C-CI O

II
Pharmaceuticals Agrochemicals Photo resists
Trichloromethyl
CI3C-O-C-CI503-38-8 125/748 o
II
\"
Phosgene{{
diphosgene(als\302\260 calledSUbstitute,,)
COC! 2 scavenger,
or catalyst,
Ar-O-C-CI
o
II T<20\302\260C
90\302\260C
\177Scavenger
1-Chloroethyl
CI
OH3-C HIO
^.1 nu'\177 Ar -OH
'\177r
catalyst
II
T>
Ar-O-C- -At O o
1,2,2,2-Tetrachloro ethyl
50893-53-3 117/760 Antibiotics (pro N-dealkylation (+) 95597t. amines 56-1
drugs)
of
0
CI
\177I'CI
Pharmaceuticals
Scheme 25 Reactions of phosgene with alcohols and
98015-53-3
80/14
Peptide
chemistry,
phenols
pharmaceuticals
Cl3C-CHIO-C-CI
0
Aliphatic and aromatic chloroformates can reac further, easily with aliphatic hydroxy compounds to yiel of bases o carbonate diesters and only in
Vinyl
II
CH2=CH-O-C-CI 5130-24-5
89
presence
O
Isopropenyl H3
II
760
90/
Polymers
Contact lenses
Pharmaceuticals
N-dealkylation
catalysts with
chemistry of chloroformates has been alread reviewed in depth (Ref. ) and this section3-2 is limite to unusual or unexpectedproducts or reactions,mostl in developed SNPE Group.Table gives someexample
phenols.
The
57933-83-2
94.5/
747
Pharmaceuticals Peptide chemistry
21
CH2=C-O-C-CI
O
2.2-Dichloro
vinyl
It
3-1
of non
conventional
chloroformates.
CI2C=CH_O_C_CI
113421-96-8
O
2,2,2-Fluorodinitro ethyl
I
II
82-85/ 120 58/2
Polymers
(optical
fibers) Agrochemicals
?
\177
\302\2602
31841-79-9
Explosives Propellants
F__C_CH2_O_C.CI
NO
O
24608-52-4
II
t-Butyl
(CH3)3C-O-C-CI
3-4/0.9- Peptide
1.7
Dec.
\177s
chemistry
O
2-Oxo-1 3-dioxolan 4-yl methyl /\177/
CH
II
(this chloroformate very unstable)
20-C-Cl 23385-72-0
Dec.
UV
curable
acrylic
resins Hydro Blowing

plastic
gels foams
0
Table
agents for
Foods additives
3-1
:Some
unusual aliphatic chloroformates.
32
33)))
as b a Phosgenend derivatives building locks

the course of previous studiesdevoted to new substituted chloroformates,we were interested in the chloroformates. synthesis of nitro and aminoalkyl a in explosives and propellants, Thus, for application of 2,2,2-fluorodinitroethyl for safe process the preparation chloroformate was developedstarting from fiuorodinitrotable ethanol (Ref. 22).See The case of aminoalkyl chloroformates is more complicated becauseof the instability of chloroformates in presence of amines. It is well known (Ref. 21)that aliphatic
In
b as a Phosgenendderivatives building locks

cardiovascular agents for the acylation of
zinone
some parli(ular (hloroformales and (arbonales

of
Highlighls
(Ref. 24) [Scheme27] : OMe
quinolylthiadia-
S\177/Me
\177
o
Et
slarlingfrom al(oholsor phenols
3-1.
OI\177__N,
Scheme
27
chloroformatesdecompose by scheme 26:

(a)
\177
Et
agent.
New cardiovascular
two
paths
depicted in
of aromatic chloroformates bearing electrons withdrawing groups is posing a problem. For example, the phosgenation of p-nitrophenol in presenceof a catalyst to afford p-nitrophenyl chloroformate is equilibrated.The balanceis easily tipped towards starting mateAs excess. a consequence, rials by elimination of phosgene attempts of purification by distillation give rise to the forcarbonateand, more hazarmation of 4,4'-dinitrodiphenyl dous, phosgeneaccording to the mechanism depictedon The
manufacture
H--C--C--CI 2 + CO
I I I I
H--C--C--O-C-CI
I I
o
II
\177
(b)
Scheme 26: Decomposition paths of aliphatic
\177
chloroformates
+ HCl +
CO 2
scheme28
Temperature of decomposition varies widely depending : on the structure of the aliphatic radical ; on the presenceand nature of other compounds, espeammonium salts (SNi or SN2 cially amines or quaternary mechanisms).
Catalyst
o
O2N
O,
Therefore,the preparation of aminoalkyl chloroformates conditions (Ref. 23) requires carefully selected Low temperatures (below+ ; solutions ; into phosgene Addition of amino alcohols to have a completeprecipiselectedin order -Solvents tation of the hydrochlorides ; carried out away from any trace of moisture. Filtration Amino chloroformates are generally isolatedas their hydrochlorides and stored under dry nitrogen at low They are interesting potent intertemperature (< mediates for pharmaceuticals. Thus, 2-(N,N-dieth\177/lamino) ethyl chloroformateis used in the preparation of new
\177
O2N\177-O
p-nitrophenyl
Q+ +
COCI 2
10\302\260C)
Q+
c,O
Q+
chloroformate
\177)2N\177-'\177OI
O2 N
--\177--
CO + O+CI2
Scheme 28: The problem
of p-nitrophenyl
chloroformate
synthesis.
+5\302\260C).
elimiby Again, this difficulty was overcome complete nation of the catalyst from the mixture before distillation thus giving a pure and stablechloroformate.
34
35)))
b a a Phosgenend derivatives s building locks

p-Nitrophenyl chemistry, substitute

of
hexabutylguanidinium
chloroformate is widely
agent
of urethanes. For example, a new amine photogenerator was preparedfrom p-nitrophenyl chloroformate (Ref. 2,5)accordingto the scheme
in the synthesis
NO2 NO
especiallyas a protecting
usedin industrial or as a phosgene
chloride
hydrochloride
(HBGCl.
29.
to 3,5-dichloro-2-pyridinyl HCl) beads quantitatively On further heating, in presence chloroformate (Ref. 28). this slowly of HBGCI.HCl, new chloroformate decomposes to afford starting material and phosgenealmost quantitatively
). (reversereaction, seescheme31
p.Nitrophenyl chloroformate CH2-OH

\177
MeO
MeO
\177_
=\177
O MeO\177-\177k
MeO
NO
O==\177o\177N02
Me
2,6-dimethyl piperidine
MeO
- p. Nitrophenol
MeO
\177O
O==\177
\177N.\177.
]
T
COCI2
CAT. : HBGCI.HCl
80\302\260C
5\177herne
29
.'
Preparation
of
a new
amine photogenerator.
1
II II
\177
110\302\260C
another example, p-nitrophenyl chloroformate was required to introduce a sophisticated carbamate function in a multi-steps synthesis of retroviral protease inhibiting The structure of the intermediate compounds (Ref.
In
carbonateis given
p.Nitroph
chlor\302\260formate
\177
26).
in
scheme30. /F-S
enyl
STRUCTURAL
\177 N'Y
.\"
/f--S
PROOF
NO2
'OH
yield
: 78%
of
N\177 O
intermediate
i-PrOH
Et3N
_\1770\177 O
for the synthesis
Scheme 30 Preparation protease inhibitors.
a key
of retroviral
H +
ClAq.
with certain The final result of the reaction of phosgene hydroxy compounds may dependdrastically on the catalyst used. For example, the phosgenation of 3,5-dichloro-2in toluene, in presence of DMF, gives hydroxy pyridine in good yields. This compound is a 2,3,5-trichloropyridine valuable intermediate for producing herbicides (.Ref. 27). in presence Surprisingly, we found that the phosgenation
NH3
CI
\177
\177
CI
87%
OVERALL
YIELD 3,5-dichloro-2-pyridone.
\"N
\"CI
Scheme 31.'Unusual reaction of phosgene with
36
37)))
as a Phosgenend derivalives buildinblocks

reactswith Phosgenein excess
catalyst
trial
as a Phosgenend derivalives buildinblocks

The propertiesof chloromethyl chloroformate which been made alsoby phosgenation of monomeric formalfurther in section dehyde (Ref. 29),are discussed Someinteresting relationships between Diphosgene phosgene(Ref. 30)and the dismutation of phosgeneinto carbon tetrachloride and carbon dioxide (Ref. 31) are
has
{{
thiols in
presenceof a
in indus-
to
afford
it
disulfides and thiocarbonates. side products, especially in As already discussed section 2-2, use of HMGCI.HCI
catalyst,
processes,
thiochloroformates. However, is often difficult to avoid formation
of
3-2-2.
soluble during the reaction, insoluble
affcer
completion
and removed by simple filtration, gives high quality products. useful intermediate For example, n-octyl thiochloroformate, scheme is obtaifor the manufacture of herbicides ned in quantitative yield, without any tracesof sideproducts. the filtered catalyst is indefinitely reusable. Moreover,
depictedin scheme34
Charcoal
+
Lewis acid
[See
32]
Pressure
\"
2 COCl 2
\177
Cl3C-O-C-Cl
Q+ Cl
0
II
,,\177-- CCl4
Lewis acid + pressure
(FeCI3)
CO 2
type catalyst
CI--,,,\177N, N
Scheme 34.'Reverse dismutation of phosgene.

Foliar active herbicide
n-Oct-Scheme
\177,SyI
I1\177
PYRIDATE
Trade
introduced by Chemie-Linz AG mark Lentagran

\"
32.
from n Octyl thiochloroformate.
Chlorination
of methyl chloroformate
bonate affords
chloroformate
\177
also [11] [I], trichloromethyl carbonate called Diphosgene and bis(trichloromethyl) scheme33] known as Triphosgene [see [111]
chloroformate
\177 \177 \177
substitutes useful phosgene
and dimethyl carchloromethyl
The reversibility of the decomposition of carbon tetrachloride and carbon dioxide is still a controversial topic. However, the production of phosgene and carbon dioxide by reaction of carbon tetrachloride Lewis acidswas recently claimed in over catalysts such as The reaction is assumed to proRussian patents (Ref. 32). ceedthrough the formation of trichloromethyl chloroforcarbonate. mate or bis(trichloromethyl) At the presenttime, one crucial question still remains : what is the industrial value of Diphosgene and Triphosinto
\177 \177 \177
CH3-O-C-CI -
0
II
\177
Cl 2 , hv
HC\177
Cl2,hv
CICH2-O-C-CI -
[I] bp. 106oC

h C[2,v
II
HCI
CI2CH-O-C-CI
II
\177-
CI3C-O-C'CI ] [ II
O
II
\"Diphosgene\"
HC\177
bp. :
Vapor
128\302\260C
10mm
pressure/
/
20\302\260C
\342\200\242
gene as liquid and solid substitutes for phosgene? Are ? the two reagentsreally saferthan phosgene Both reagentshave proved to be useful substitutes for phosgenein all its main applications.Indeed,they are sold commercially as the efficient equivalents of 2 and 3 phosy gene moleculesrespectively in processesielding chloroformates, carbonates,carbamates,ureas and isocyanates, as well as in chlorinations, carboxylations and dehydrations use in organic syn(For a recentreview of Triphosgene
\177
{{
\177
O CH3- _C.O_CH 3
Cl 2
o
II
20\302\260C,
28 h\" - 6 HCI
from
thesis, seeRef. 33).

Accurate amounts
3 Cl3C_O.C.O--CCl
can be easily
weighed,
limiting
II
r [111
blems due to
80\302\260C
excesseagent.It is possiblealsoto increase r

industrial
pro-
\"Triphosgene\"
: bp. :
rnp.
206\302\260(\177
(dec.)
with phosgene itself. reagent concentrations compared However, there is little prospectthat either reagent will
Scheme 33: hlorination C
products
methyl chloroformate
and dimethyl carbonate.
be utilized
in significant
processes.
39)))
38

Both reagents decomposeto phosgene on heating, in preslowly when pure, very rapidly and quantitatively senceof a nucleophile such as a naked ,, chloride anion
\177
a a b Phosgenend derivatives s building locks

Table 3-2 gives a
Catalyst
cornparison
betweensome catalysts
Time for 100% conversion
Temperature
[Scheme35]:
HBGCI.HCl
HMGCI.HCI
160175 160170
guanidinium guanidinium
\302\260C
165 170
7.75H
\302\260C
IHIDAZOLE
\302\260C
5.25 H 2.50 H
\177,
2 COCI 2
HBGCI.HCI
+ Cl
HP1GCI.HCI
= Hexa n-butyl = Hexarnethyl
chloride hydrochloride. chloride hydrochloride.
lbble
3-2
c\177
cI
/0
\177,\177
F c*0
dlphenyl
c\177
Comparison of the efficiency of some catalysts in the synthesis of carbonate in bulk (3% Mol. Catalyst/phenol)
.'
CI3C-cI
O--\177:---CI
3 COCl 2
+
O+C;I
2
,\177
ClTriphosgene
carboAmong the numerous applications of diphenyl nate, the preparation and chemistry of dichlorodiphenoxy methane appears somewhat neglected.This phosgene derivative can be preparedin good yield by treatment of
diphenyl
Scheme 35 .'Decomposition of ,, Diphosgene ,, and
carbonatewith
phosphorus
pentachloride at
As noted by 5. Damle (Ref.34), the toxicity of both and triphosgene is exactly the same of phosdiphosgene on gene sinceboth decompose heating and upon reaction with any nucleophile. Even a trace of moisture leadsto formation of phosgene. or handling accident,both Thus, in any transportation compounds are phosgene. The manufacture of symmetrical or mixed carbonates or by reaction of chloroformates with alcohols phenols is I well documented. n the courseof different studies devoted to the manufacture of aromatic carbonates,we have designeda one-stepprocedurethat affords diphenyl carbonatein excellentield and purity using simple equipment y and no solvent [Scheme36]
temperature (Ref. 35)according to PCl5
scheme37
high
180-
CI
200'\177c
- POCI 3
bp
cI
: 183-187 / 12mm \"C mp : 42-44 80% yield
\302\260C
\177
heine
37
Preparation
of dichlorodiphenoxy
key starting
methane.
Besideseing a b
tion
material for the
of polyorthocarbonates, methane dichlorodiphenoxy is a versatile synthon for the construction of heterocyclic systems of medicinal interest (Ref. 36).Its condensation with cyanamide affords diphenyl cyanocarbonimidate in high yield (Ref. 35)as shown in scheme
prepara-
38:
OH
Neat
CI
\177
2
mp
+ COCI 2
bp
O--\177-O
+2H
: :
41\302\260C
Catalyst (1-5% tool.)
O\177 -O__\177
\177
+ NH2CN
\177
80\302\260C
AcOet
-CN
Cl
\177__
mp:
...[\177.
_\177
diphe41)))
182\302\260C
mp
bp
79.5\302\260C
315\302\260C
Scheme 36
91%yield
156-8\302\260C
Improved
diphenyl
carbonate synthesis.
\177cheme
38
.\"
Preparation
of diphenyl
cyanocarbonimidate
from dichloro
noxy methane.
4o

provides cyanocarbonimidate to N-cyanoguanidines a simple, low cost, high yield access which are active as histamine H2 antagonists. Kline &,'French For example, researchersfrom Smith a new facile synthesis has described (Ref.

of aromatic carbonatessubstituted by electronwithdrawing groups is an efficient method to get substituted diphenyl ethers.We found that pentaalare superior catalysts for the synthesis of kyl guanidines ether from 4,4'-dinitro diphenyl carbo4,4'-dinitrodiphenyl The generally acceptedmechanism involves nate (Ref. 37). nucleophilic attack by the substituted guanidine at the carbonyl of the carbonateto form an acylated guanidinium phenoxide salt. In a second step, the p.nitro phenoxide anion attacks the aromatic ring of the a\177lated guanidinium cation (SNAr reaction) to leadto the expectedether after lossof CO [Scheme 2 The decarboxylation
The availability of diphenyl
Laboratories
of the
36)
(\177{
scheme39: f--S
NH
anti-ulcer drug, Cimetidine
Tagamet
\177)
depictedon
Me
HN
x,\177,
\177 /\177 ' \177 \177

OPh
Me'NH2
N'CN
Room temp.
Yield
> 90%
NHMe H
Me
'k/_\177,'
f--S
\177
H
-Ue\177
41].
S\177__\177
N-CN
Yield
>90%
from diphenyl
cyanocarbonim\177da\177
N-CN
Scheme 39
Preparation
of Cimetidine
in
heterocydic chemistry (Ref. 3.5).

i-PrOH
Scheme40 shows someother examplesof applications

N
\177-
H2
[I
\"'-\177
/
/J
Ar
OAr + CO 2
R
N N
R AF=
/REFLUX lh
NH
'
MP.
278\302\260C
Scheme 41 Mechanism of the
decarboxylation
of 4,4'-dinitrodiphenyl
carbonate
catalyzed by pentaalkyl guanidines
i-PrOH, RT,
1h
74%
'
MP. : 175\"C
of the guanidine must be, carefully Nucleophilicity controlled,to avoid arylation of the catalyst ' itself. This could be easily accomplished through a proper choiceof Note also that delocalization of charge the substituents. over the three nitrogens in the assumed intermediate guathe nucleophilicity of its counter nidinium cation enhances
the p.nitro phenoxide anion. anion, With 2-methyl-l,l,3,3-tetrabutyl guanidine as catalyst, at temperature lower than the decarboxylation proceeds those described with conventional base catalysts. The result
lamina
N/CN
i-PrOH
'
,
e.g.
RT, 2h
HN
\177
\177
NH2NH2
H
N
\177-\177/NH2
15min
-2\177C MP. : 190
MP.
86% :
160-1\302\260C
is even better comparedwith

pyridine
using 4-N,N-dimethy-
Scheme 40
Examples
of diphenyl
cyanocarbonimidate
(I) applicatio, ns.
(DfIAP) as shown
in
scheme42.
43)))
42
a as Phosgenend derivatives buildin\177 blocks

ether can be easily hydrogenated 4,4'-Dinitro diphenyl suitable for the to 4,4'-diamino ether especially diphenyl manufacture of polymers such as polyimides.
through The required pentaalkyl guanidines were easily prepared of the appropriate urea to give the phosgenation salt which reactswith corresponding chloroformamidinium an excessf amine to yield the expected o guanidine (Ref.
a a Phosgenend derivatives s buildin\177 blocks

The course of the decomposition the mixed anhyof drides [Scheme which leadsto the formation of expec44] ted esters(path A) or to a mixture of symmetrical carbonates and anhydrides (path B) strongly depends on the structures of the chloroformate and the carboxylic acid but also on the choiceof the catalyst.. Becauseselectiveproduction of estersif of great interest, we have studied the thermal instability of the mixed anhydrides and developed a new efficient and selectiveesterification reaction with chloroformates using a silica supportedguanidinium in catalyst (Ref. 39).This method will be discussed vol. 2
37).
160\"C
\177
section4-4.
+ 002 O2N\177--O--\177--NO2
R\177O-C-R
\177
4,5H
Catayst
DMAP
: :
H2
77% yield 88% yield
O
2 R10-C-O-C-R O O 2
\177
(5 Mol. %)
Bu2N\177NMe Bu2N
1/2
R\177O-C-OR
Pressure Scheme 42
diphenyl
Scheme 44 Decomposition paths

ether and 4-4'-diamino
O
o\177
mixed carboxfliocarbonic
Improved
synthesis of 4,4'-dinitro diphenyl
ether
lhe use of the

also a
\177owerful
mixed
carboxglic-carboaic anhgdrides
for
One of the most convenient esterification methods developedearlier was based on the decarboxylation of unstable mixed carboxylic-carbonicnhydrides preparedby a reaction of chloroformates with carboxylic acids(Ref. 38) according to scheme43.
+ R]O-C-Cl O
II
the formation
method of carboxglic acidsactivatioa of amide bounds in \177e\177tide chemistrg

with
vol.
2, section4-4). 8eaction of chloroformates
(see
sodium
alkgl
carbo-
through reactioaof carbon dioxide with sodium alkoxides, affords dicarbonatesalso called \177grocarbonates as shown ia scheme
nates, easilg available
45.
2 CH2CI
R2-C-Cl O
II
\177
Etsa
O\177C
2 R]O-C-O-C-R O O
II II
Examples
Et-O-C-O-C-CH 3
Et-O--C-O-C\177-\177NO
1 R-O-C-CI R]-O-C-O-Na + R-O-C-O-C-O-R - NaCl O O O O Scheme 45: Preparation of dicarbonates from chloroformates.
II II II II
\177
0 o
Scheme 43 44
o 0
/
bp
64-7\302\260C
20mm
mp
56-7\302\260C
Preparation
of mixed
carboxylic-carbonic
anhydrides.
45)))
ne
a_nd
derivatives s buildinblocks a
Pyrocarbonatesfind
a as Phosgenend derivatives buildinblocks

several
reagents, Z20 and (AIIoc)20, conveniently supthe known chloroformates for the protection of amines. plement Cyanoformate esters may be prepared through reaction of alkyl chloroformates with cyanides salts by procedures
using phase-transfer ternary
fields, such as
useful
applications
in
These two
Preservatives for wines, soft drinks, fruit juices, specially e -- 1 = Ethyl. in the case of diethyl pyrocarbonate R R
Blowing
agents
for
plastics,
methyl,
Freon
\177'
substitutes. For
=
polyurethane example, t.butyl

Rt
foams as
methyl
pyrocarbonate
to achieve a cellular structure by liberation of carbon dioxide (Ref. 40). Protection of amino groups.Di-t.butyl dicarbonate called (Boc)20(which is not made from the very unstable t.butyl chloroformate) is well known as the most popular
reagent for the preparation
(R as a foaming agent
= t.
butyl)was
claimed
catalysis with 18-crown-6 43)or qua(Ref. ammonium salts (Ref.44) according to scheme
46.
of added during processing polymers
R-O-C-CI + or O
II
NaCN KCN
\177'
Phase transfer
catalysis
R-O-C-CN+ or O
II
NaCI KCI
Sideproduct :
Scheme
46:
RO-C-OR O
II
Preparation
of cyanofom\177ate
esters from
chloroformates.
of t.Bocprotectedamines,
especiallyt.Boc-amino acidsin peptide chemistry. We reported the synthesis (data on table 3-3)and some applications of dibenzyl dicarbonate (Ref. 41) and diallyl dicarbonate (Ref. 42).
Dicarbonate
Dibenzyl dicarbonate
Diallyl
Although convenient tities of cyanoformate
for the preparation
of small
quan-
esterssuch as ethyl
cyanoformate,
Yield
mp or bp
79 %
mp. 28
\302\260C
dicarbonate
82 % (60 %
distilled)
useful
bp. 65
\302\260C/0.05
Torr
Table3-3 Synthesis of new

Dibenzyl
dicarbonates.
we found the method to be unsatisfactory for the production on a larger scalebecauseof the formation of carbonate estersreducing the yield. In the courseof our studies devoted to the scaling up of ethyl cyanoformate preparation, we noticed that the sidereaction is strongly related to the nucleophilicity of the o cyanide anion which depends n the structure of the counter cation of the catalyst. Ouite goodresults can be achieved of by a proper choice the catalyst as depicted in scheme47.
CH2CI / H20 2
preparation red to the
preparation is easily achieved under standard pH-stat conditions if the pH is carefully regulated. was used for the allyloxycarbonyl Diallyl dicarbonate amino compounds including amino acids, protection of Except for the reaction with amino sugars and nucleosides. does not require an additional amino acids,the reagent and the only by-products, allyl alcohol and carbon
dicarbonate offers some advantages in the of N-benzyloxycarbonyl amino-acids, compawidely used benzyl chloroformate. For example, of dipeptide-free -benzyloxycarbonyl glycine N
EtO-C-CI+ O
II
NaCN
EtO--C-CN
+ NaCI
T:<
Catalyst:
20\302\260C
HM='CIG
Side
reactio\177n
:
NaCN
bp. : Yield
II
35\302\260C
/ 30 mm 83-6% distilled
Q+CI+
EtO--C-CN
+
Q+CN- +
NaCI
\321\207
Q+CN-
\177.__
O + EtOQ
EtO-C-CN
\177
: with
HMGCI
For example, N-allyloxycarbonyl dioxide are both volatile. obtained analytically was pure by simple glucosamine
evaporation
base,
O
Diethyl carbonate formed
II
NC-C-CN + EtO-Q O EtO-C-OEt+ Q+CNO

II
of the reaction
mixture.
Scheme 47
with HBGCI
preparation
: < 1% : 10%
47)))
Improved
of ethyl
cyanoformate.
46

Ethyl

under-
cyanoformate is an effective dipolarophile
can be easily obtained through

glycerol and diethyl
transesterification
between
a going 1,3-dipolarddition
to azides, or examplewith ethyl f azidoacetate to afford tetrazoleaceticacid derivatives acid (Ref. 45).Tetrazoleacetic is a key starting material for the preparation of pharmaceuticals such as the antibiotic
<<
carbonateunder basicconditions. OCOCI
Cefazolin
>>
The chemistry of cyanoformate esters has been the subject of a recent review (Ref. 46).
[Scheme48].
OH
OH
OH
Excess COCi \177\" CICOO OCOCI 2 OCOCI

/\177/-(i)
Quantitative yield
EtO-C-CN EtO-CCH2N3 + 98% O O

II II
\177
110\302\260c
COOEt
N\177
I<1.-
,N-CH2COOEt
- 2 EtOH Basiccatalyst
\177-
Et2CO3
OH
OyO O
160\302\260C
/\177-0 0 (11)
1 N
HCI
\177
N\177
N..I
65%
-CH2COOH a
,N-CH2-C-NH
\177
Scheme 49
glycerol,
y O
bp.
/ 0.8mm
through phosgenation
Preparation
of chloroformate-carbonate
of
N\177
\177.--
S
\177
\"Cefazolin\"
\"\177[\177..,,,
N
I\1771
O/j- \177CH2S
COOH
Scheme 48 Preparation
.'
\177\"
\177oa3
and use of tetrazoleacetic acid starting
The chloroformate (I) and the corresponding alcohol (11) are very interesting intermediates for numerous applications Blowing agents adapted to the production of cellulated or expandedpolymers (Ref. 47),for example by reaction
from ethyl
cyanoformate.
of (11)with maleic
anhydride
[Scheme.50]. O-C
o,;,,
3-\177-\177
Reactionof
OyU
O
Scheme 50
\177
O
of a foaming
'--<\302\260\302\260\302\260\"
OyO O
mp.
Dec.' 150<'C (pure)

112'\177C
112-4\302\260C
al phosgene
oxygen \177enter
of uncon
1%aazco3)
agent for expanded polymers.
(with
Preparation
substrates
The
ventional
- Leavening systems for preparing baked goodsto (Ref. 48). - carbon metals. for
supply Extractants dioxide required
Reaction of phosgene
with
\177lycerol
doesnot
reaction of large excessphosgenewith glycerol afford the corresponding trischloroformate but a

five
For example, compounds obtained through reaction of chloroformate (I) with trimethylol propaneand with polyethylene
monochloroformate bearing a
nate function
membered
cyclic
carbo-
methyl (2-oxo-l,3-dioxolan-4-yl
(I) as shown on
T scheme49. he corresponding alcohol (11)
chloroformate
table
from
glycol are highly in hydro-metallurgy
aqueoussolutions
effective chelating agents suito recovervaluable metals ions (Ref. 49) [Scheme
51].
48
49)))

The study of light-induced polymerization of the new CL demonstrated the outcompounds, especially of acrylic monomers containing five standing reactivity membered cyclic carbonatefunction (Ref. _52). Photopo-
\302\260
ococI
EtC(CH2OH)3
1042,
/\177--
Pyridine
o
Et
\177_.\177
o
o--LL-
oyO(I) O
Acetone
88% Yield
mp,
O
o-\177
\320\205
\"j\"
120\302\260C
0%
83% yield
Mn
even occurswithout any added photoinitiator. These new monomers combine high reactivity and intensive cure to give hard but still flexiblematerials. CL 1042as used in _50% amount as reactive diluent in w
lymerization
with
formulation
HO(CH2CH20)n-H
+2
polyurethane oligomers bearing pendant was also employed to acrylate groups (Ref. _53). CL with synthesize cyclic carbonate copolymers pendant
1042
CH2Cl2 o.,.[r-
= 900
from
ox[i/O
groups.Their chemical modification
by
ring
opening
Soluble in toluene
Scheme 51 solutions.
reaction provided a convenient method for preparing functional polymers (Ref. 54), as shown on scheme_53 :
Cyclic
carbonates suitable for the extraction of metals
aqueous
--CH2-ca
-o
60\302\260C
-- -CH2CH
-- Paint
duct
of methacryloyl
-Ultraviolet-curable acrylic resins.
powders for automotive, for example the reaction prochloride and the alcohol (11) Ref. _50). (
The reaction of chloroformate (I) with acrylic acid followed by the decarboxylation of the unstable mixed carboxylic-carbonic anhydride
formed, gives the
2-oxo-l,3Scheme 53 Chemical bonate functions.
dioxolan-4-yl methyl acrylate in good yield (Ref. _51 ). The reaction of (I) with 2-hydroxyethyl acrylate in the presence of a baseaffords a new acrylic monomer, SNPE code num-
ber CL
in 1042, excellentield y
(Ref. 51 [Scheme )
52].
modification
of copolfmers containing pendant cfclic car-
00001
O,\177]/O
//
\177
of
\302\260 \302\260
72 Ojo
Yield
_Et3\"o
Pyridine
Reaction of
0,.\1770
0
93 %
42\302\2600
with phosgene
0
II
CL1042
Yield
chloroformote-
epoxides
The reaction of phosgenewith an epoxidecatalyzed by to afford \177-chloro chloroformates is well known pyridine U (Ref. 5.5). nfortunately, this reaction often leadsto non ring regio-specific opening of the epoxidesand produces bis-\177-chlorocarbonates as side products in yield up to
Scheme 52 carbonate.
Preparotion
UV-curable
mp, monomers from glycerol
20-30% [Scheme54].
50
51)))
a a Phosgenend derivatives s buildinblocks

Pyridine R
CI
a a Phosgenend derivatives s buildinblocks t /

In
Cl o..r_ O
+o
Cl
chloroformate was easily
(A)
(B)
+ [:\177-chloro
carbonate., Scheme 54 General react/on of epoxides with phosgene.

.\"
another example, 1-chloromethyl-2-chloroethyl preparedby catalyzed addition of This to epichlorhydrin using the sameprocedure. phosgene chloroformate is an useful intermediate for a simple carbamates route to new fluoroisopropenyl preparative in scheme_56 (Ref. 57) depicted
reactionsof monoalkyl epoxideswith phosw gene were conducted, ithin 2-6 h, using HBGCI or silicachloride as catalyst, neat or in supported guanidinium toluene solution, the results are strikingly different. The
When the
ring opening reaction gave single products with C-CI bond formation at the carbon that lacks the substituent. I'loreover, the reaction did not produceany of the symmetrical T carbonate. he \177}-chloro chloroformate (A) (seescheme_54) are thus isolated in nearly quantitative yields (Ref. _56). For example, the phosgenation of n-butylglycidyl ether in toluene, in presenceof 0._5 tool.% HBGCI, at within 2 h, gave the corresponding 1-chloromethyl-2n.butoxy ethyl chloroformate in 96% yield. This chloroformate is the key starting material for the preparation of an intermediate carbamateused in the Febarbamate
30\302\260C ((
\177
CI k_7,.,/'--
CI
COCI 2
\177
Cat. : HBGCI
/ Ci.--
\"--k.)_O-C-el 95% Yield
II
distilled
bp.
R1
93\302\260C
20 mm
C'---xkr__
c\177
THF
O-C-Cl4
R\\
NH
II
R 2\"
Base \177
R1
C,\177_._ Cl
O-C IIN\177/R2 O
Bu4N,
3e q.
\177_
F\177_
O\177I.N/R2
65\"C,8 h
\177ctyenye
72% yield with : 2 1 R = Pr ; R = cyclohexyl

i
56: New isopropenyl
carbamates
from
phosgene and
epichlorhydrine,
manufacture
n.BuO
as shown 00012
in
scheme5_5. Reaclion of
\177'
--/ O
NH
Toluene
2H n.BuO--\177
Cat. : HBGCI
50\302\260C
n.BuO\177_
CI--'96%Yield
( hexane )
OCOCI
3 / H20
\177
Cl\177/0
II I
)__O.C_NH
90%Yield
rap,
35.3\302\260C
aldehydesand ketones : novel chlorinated

\177\321\236
w phosgene ith
of alkyl chloroformates, generally Photochlorination limited to the case of methyl chloroformate and ethyl chloroformate, was the only method for the preparation of 1-chloroalkyl chloroformates before the work done at
SNPE
[Scheme57].
CI2, UV CI
\177
chloroformates
and
OCONH 2
'\"\"'\"\"-- Oin. Bu
related
RCH2- O-C-CI
reagents
Et2CO
\177
II
- HO
UV
\177-
RCH- O-C-CI
\"
eL...4
E
\"
NH
Febarbamate
\"
CI2, - HO
CI
O O
II
II
+ large amounts of
other (poly)chlorinated compounds
CH3CH-O--C-OEt
chloroformates
( Tranquilizer )
Scheme 57 Photochlorination
.\"
of alkyl useful
and diethyl carbonate.
Scheme 55
facture.
Preparation
of intermediate carbamate
for
a pharmaceutical
This method
manu-
synthesis
chloromethyl gives poor yields and bad quality
for
chloroformate
in
the
caseof
53)))
52

1-chloroethyl chloroformate, and completely fails with higher chloroformates, becauseof the lack of selectivity of the radical chlorination. Eighteen attempts to dine,
as b a Phosgenendderivalives building locks

reactor already
that containing the catalyst reacts immediately, formaldehyde and phosgene,so thus avoiding its However, in this last case, we
years ago,
in
the
course of
unsuccessful
repolymerisation (Ref. found the procedure difficult technical that the
preparevinyl chloroformate by phosgenation of aldehydes in presenceof tertiary amines, especiallyyrip

we discovered a
new
route to
formate (Ref. 58)as presentedin
scheme58
H2C\177
e\177-chloroalkyl
chloro-CI
to scale up, becauseof problems of formaldehyde polymerization. Note reaction doesnot work with the polymeric forms of formaldehyde, either trioxane or paraformaldehyde. .Some results are gathered in table 3-4 (Ref. 5, 58, 60).
Catalyst Yield % Boiling point
\302\260C/mm
60).
CH3CHO+ OOOI+ 2
Pyridine
\177
CHoClo
/7\177
CH-O--\177
(mol. %/aldehyde) CI
I
( Catalytic amount)
\177
\"\177
Scheme 58 The origin of the route.
CH3-CH-O-C-CI 63% O
II
Me Me
Et
discovery
of the new u-chlorinated
chloroformates
CI3C
i-Pr
The value of this new route immediately was recognized because1-chloroethyl ethyl carbonatewhich could be obtained from 1-chloroethyl chloroformate and ethanol already was on the market as an alkylating agent to prepare coworkersat aldehydes are readiconverted to 1-chloroalkyl chloroformates when treated ly with phosgenein the presenceof a naked Cl\" catalyst The reaction has been found to proceedcleanly in (Ref. 5). good to excellentyields and to be quite general with almost all aldehydes, but not with most ketones (Ref. 59). On a laboratory scale,one of the favored catalyst is the benzyl tri-n-butyl ammonium chloride (BTBAC). The most
Penn the orally active antibiotic Bacampicillin Not long after, together with OIofson and
{{ \177.
CH2 = CH
Cyclohexyl
(1.8) (3.0) 18-Crown-6(5.7) KCI (35.2) BTBAC(9.0) BTBAC(10.7) BTBAC(12.5) Pyridine (10) Pyridine (10)
BTBAC BTBAC BTAC
42 (a) 96
78
106/760 77/180 117/760

62-3/52
89 65
87
75-9/19 58-9/28
54
87 87
38/10 90-3/10 81-3/1

70/0.4
(10.3) (10)
State University, we found
that
Phenyl
Pyridine
68
(a) With respect to the phosgene used CI

R-CHO + Catalyst
\177{
\177
COCI 2
R-CH-O-C-CI O
II
Table3-4
Preparation
of some
l-chloroalkyl
chloroformates.
important
reagent, (z-chloroethyl chloroformate
(\177
ACE-Cl
\177),
is isolatedin 96% yield by stirring acetaldehyde typically with phosgene eq.)neat for an hour in the presence of 3 mol. % BTBAC.Even chloromethyl chloroformate can be prepared using this process,but it is essential to
(1.1
introduce 54
the monomeric
gaseousformaldehyde
into the
The yields and recoveriespresentedin this table are those for isolatedmaterials (purity > 99%). Phosgenecan be replacedwith either diphosgeneor triphosgene in the same conditions to give the correspon). ding 1-alkyl chloroformates in very good yields (Ref.
61
55)))
and derivalives building locks as b
b as a Phosgenend derivalives building locks

mate previously prepared through chlorination of chloroformate in direct sunlight (Ref. 62). The addition of 1-chloroalkyl chloroformates to hols or phenols is a quite general method and gives
Phosgene
For safety
the reaction between suspected,we thoroughly
reasons,because a possiblereversibility of phosgeneand aldehydes was

studied the thermal
stability
I I
ethyl
of
are much more stable than the aralkyl compounds which at begin to decompose 60 C or below.It is important to note that the only products of thermal decompositionre a the derived 1,1-dichlorides and carbon dioxide [Scheme
\302\260
This stability greatly depends 1-chloroalkyl chloroformates. on the structure of the R radical. Simple alkyl compounds
alcogood
are to excellent ields. 5ome examples given y

R R1
in
table
3-5.
Method
Yield
bp.
\302\260C/mm
Ref.
(%)
H Et Pyridine
mp.
\302\260C
contrast, the chloroformate from chloral reverts to the aldehyde and phosgenewhen heated. This easily is decomposition catalyzed by naked Cl- and particular must be taken in the handling of tetrahaloethyl precaution
In
\177
\177
59].
76
bp. 53/14 bp. 67/22

bp.
63 64 64
5NPE
Me
Et Et
i-Pr
Pyridine Heating
(70\302\260C)
chloroformates, and more generally

roalkyl
in the
case of 1-chlo-
containing strong electron withdrawing groups (with regard to the mechanism of the see decomposition, farther on in this section).
chloroformates
He He He He He He
80
62
77
97
Pyridine Pyridine Heating Pyridine
t-Bu Cyclohexyl Benzyl

o\177CH2
90
94
160/760 5 bp. 57-9/10 65
bp. bp. 77/1 bp.
88/20
100/0.564
64 64 66
67
CI
I
Pyridine Pyridine
88
94
bp. 95/0.2
bp. rap. mp. rap.
Heating
-\177 II
CH3CH-O-C-CI O
T >>
CH3CHCI 2
CO 2
Me Me
Phenyl
Me
117/0.564
98-100 68-70
108\302\260C
100\302\260C
\177
I
\177\177 CH-O-C-CI CI
Heating
\177-
Cl3C
\1770
Me
Pyridine Pyridine
98
87
t-Bu
0
II II
>\177
60\302\260C
\177
CHCI 2
\321\207
CO 2
o Cl3C
\177,_
Triethylamine
83
CI
I
Heating
Q\321\207
CI3C-CH-O-C-CI or O
Schema 59
.\"
cr
\177
+ CI3C-CHO COOl 2
chloroformates. Table
CI
I
Base (pyridine) or heating

+ R1-OH
CI
I
R-CH-O-(\177-CI
Thermal
stability of l-chloroalkyl
- HCI
\177-
R-CH-O-(\177-
1 O-R
3-5
Preparation
of l-chloroMkyl
trialkyl
carbonates.
conventional chloro1-Chloroalkyl formates react easily with alcohols, ither in the presence e of or simply by heating to give the chloralkyl carbonates.1-Chloroalkylchloroformates reactalsowith phenols, but only in presenceof a base to afford 1-chloroalkyl aryl carbonates.
chloroformates like
The use of a
1-
base
amine, for example triethyl
amine,
expected
because1-chloroalkyl i as a scavengers not recommended

chloroformates react very easily with tertiary alkyl amines to afford N,N-disubsituted carbamates (Ref. 68)as discus-
sed in section3-3.
in the
1-Chloroethyl
by
M\177iller
ethyl
carbonateitself was first prepared

with
by heating
ethanol
1-chloroethyl
chlorofor-
Although pyridine process using
appearsas one of the bestscavengers must be avoided base,any excess

57)))
56
Phosgene /
s
,\177ecause
buildinblocks
scheme60:
formation
a as Phosgenend derivalives buildinblocks

salt
\177)--OH
of the
of a
quaternary
ammonium
on as depicted
x
+
1 R-CHO-C-OR
I
Base
R
I
O.
OEt
o
II
= CI Br, A.I. = Active ingredient

X
\342\200\242
(\177\177
functions (from carboxylic
O-CH-O'C-OR\177
\302\251o Scheme 60 Ouaternary ammonium salt carbonate.

.\"
from pyridine
and 1-choroethyl ethyl the development ton lots of 1-chlo-
Scheme 62 .' Modification of-OH using (z-chloroalkyl carbonates. This kind Bacampicillin,
H2 H
N N
II
acids or phenols)
In
the
courseof our
work
t processo manufacture roethyI ethyl carbonate,we studied the main side reaction which is the transesterification of the desiredproduct with ethanol [Scheme
industrial
of an
devoted to
of application was a prodrug from
initially
Ampicillin
to developed produce [Scheme63].
Me
61].
\177O\177 o
Scheme
\177-\177'Me
O O
Et
O
Me\177--
+ El-OH
CH3-CH-O-\177-O-EI
\177.\177. EI2CO3
CH3CHO+
HCI
2 CH3CHO
Aldo sation, dehydration
63 Semi-synthetic antibiotic l-iodoethyl ethyl carbonate.

Current
penicillins
Bocampicillin
from Ampicilhn
and
\177-
H20
\177.
O CH3ICH\177CH.CH
_
\177_
H20
n
CH3-(CH\177CH-)n-CHO
Scheme
61
max absorption
preparation
increasesith w
Main
side reactions in the
of
l-chloroethyl
ethyl carbonate.
or cephalosporins clinically used for suitable for oral administration becauseof their low absorption from the gastro-intestinal tract. The prodrug approach by chemical modification into bio-labile derivatives with improved physicochemical properties lipophiliciinjection
are not
Experimentally, the rate of formation of diethyl carbonate was found to be proportional to the concentration of both 1-chloroethyl ethyl carbonateand ethanol, so that the reaction rate in may be expressed term of following equation with an assumedfirst order with respectto both
ty) that
better transport enables
(i.e.
a powerful mean for improving such approach requires a latentiating group stable in both gastric acidic and basicintestinal conditions, and easily removable
by enzymatic hydrolysis. The modification of carboxylic acid function or phenolic function by the alkyloxycarbonyloxyalkyl estergroup is especially suitable as shown in scheme
through biological barriers, is o drug delivery. The successf
reactants
d At
carbonatesto mask acid or hydroxy functions 1-haloalkyl of certain types of active compounds such as parmaceuticalsor pesticides ccording to the scheme62. a
58
cations
[EtOH]/dt = k [EtOH][MeCHCIOCOOEt] the k value was determined at 7.2 x -`5 10 tool. -1.i.min-1. heat of activation was calculated at 25 The kcal. mol.-1. In the past 2_5 years,there have been numerous publi75\302\260C,
64.
R
I
Chemical
modification
1
\177
R 1 Drug--C-O-CH-O-C-OR O O
II II I
Drug--C-OH+
and
patents
0
II
X-CH-O-C-OR - HX O
II
claiming
applications
of
Drug delivery
Esterase Scheme 54.' The prodrug
Drug--C-OH+ O
II
R-CHO +
F\177-OH
CO 2
function.
concept apphed to drug with
a carboxyh'c
59)))
a as Phosgenend derivalives buildin\177 blocks

Tomeet all requirements needed,t is possible select i to radicals R and R for example : R = H or methyl R 1 = Et, isopropyl, even derivatives

N,OMeH
I
the
1,
S/\"\177NNr--\177S\"h
\177N\177s\\
\177J\"
N=\177
Nxx/N\177x
Me
cyclohe\320\247yl,
sugar
(seefarther Besides mpicillin, A
on in this
section).
Me
0 0
\177j\177
\"\1771\"
Me
CEFOTIAM
\177\"
Me HEXETIL
1-chloroalkyl alkyl carbonatesand particularly 1-chloroethyl ethyl carbonate(CEEC),1-chloroethyl isopropyl carbonate (CEIC), 1-chloroethyl cycloand chloromethyl ethyl carbonate hexyl carbonate(CECC) (CEMC), have been proposed to modify numerous com-
0 0 0
\177
\177j\177j
CEFPODOXIME
PROXETIL
(CS-807}
( SCE-2174)
/\177
.S,
Me
H
pounds.
which
Among the many types of prodrugs patented of require this method, there are examples : Antibiotics such as Cefpodoximeroxetil from Sankyo P
0
Me,\177O O0\1771\177
N,\177
F
O\177M\177)_..
Et
DIFLUNISAL
0\177._
(\177Et
of (Ref. 73) example Chem. (Ref. 74) - Herbicides(Ref. 75).

derivative
Diflunisal
Co.,Ltd.(Ref.69),Cefotiam Hexetil from Takeda Chem. Indust., Ltd (Ref. TO,71) Antiflammatories and analgesics such as Ampiroxicam from Pfizer and Toyama Chem. Co. (Ref. 65,72)or a
TCV
AMPIRQXlCAM
Der\177vatwe
for Antihypertensives, Indust., Ltd
116 from
Takeda
Scheme 65
,\"
Examples
of Prodrugs
from
1-chloroalkyl
alkyl
carbonates.
given in
Some structures of these pro-active scheme65.
ingredients
are
of insecticides F (Ref. 76). or example, Carbosulfan active systemic herbicide derived from Carbovery furan and much lesstoxic for mammalians than its parent compound. In order to improve transport through biological barriers of the plants, we thought that the chemical modification of known pesticides with 1-chloroalkyl alkyl carbonates containing sugar or glycerol moiety should be of some interest. For this purpose\177 we synthesized at laboracarbonates(Ref. 77). tory scaleseveral new o\177-chlorinated The products preparedand results obtained are depicted
field
\177 \177
Chemical modification of agrochemicals, to improve their pesticidal properties and to reduce toxicity toward nontarget organisms, has been the object of intensive researchin both academiaand industry, especially the in
\177
is a
\177
on
scheme66.
60
61)))
and b Phosgene derivatives building locks

as\177
1
O-C-CI
II
CH2CI , Pyridine 2 93%

bp
O : Dec. O
OyO
Diacetone-D-Glucose
Cl
\177_
0,)
\177--\177
CH2012,Pydine ri
pO
\1770\177
O\177\177o
O\177\"
Scheme 55 Some new 1-chloroolkyl alkyl carbonates, for the preporotion of prodrugs end propesticides.
99.7% useful
\177
starting moteriols
The 1-Chloroalkyl carbonate(11),obtained through the of 1-chloroalkyl chloroformate with glycerol carbonate was used for the preparation of a proherbicide derived from Acifluorfen scheme67]. (Ref. 77) [See
reaction
\177
acid or phenolic functions. However, these o(-iodocarbonates exhibit severeinstability (Ref. 78) and are generally preparedin-situ or just beforeuse (Ref. 79,80, ). Thus, researchefforts in different industrial laboratories have been directedtoward the preparation of 1-bromoalkyl alkyl carbonatesassumed to be more stable than the 1-iododerivatives, and more reactive than the parent chloro compounds.For example, 1-bromoethyl ethyl carbonate was made by the halide exchange of 1-chloroethyl ethyl carbonatewith LiBr or NaBr, or by a radical type bromination of diethyl carbonate(Ref. 82).However, in the caseof halide exchange,he conversion is low and a mixt ture results. Even with a large excess f bromide o salt, this problem remains. Radical bromination was found to give results for the same reasonsthan the chlounsatisfactory rination, and failed in the case of unsymmetrical dialkyl carbonatesbecauseof its non-regioselectivity. We reported a new method consisting of using a volatile bromine containing reagent (E- Br), especially HBr, and a catalyst to accomplish the exchange(Ref. 84).The equilibrium is driven to the desiredproduct by removal of the more volatile E-Cl formed as shown in table This table gathers some results thus obtained.
Sincein terms of leaving group ability in SN 2 reactions > Br > Cl, oeiodoalkyl alkyl carbonatesare the reagents of choicefor the chemical modification of either carboxylic
I
81
83, 3-6.
\302\260C/0.4
CI
1)DMF / Nail
F3C
O __\177
\177
NO 2
\177,.
COOH 2)(11)
CI
,\177:Nal
F3C--\177 O-\177NO20
920/0 Scheme 57 62
Proherbic/de from Acifluorfen.
phenyl carbonate (bp.72-7 ram) preparedin 91% yield from THS-Brand 1-chloroethyl phenyl carbonateusing this technic. It should be noted that 1-bromoalkyl carbonatescan be alsoeasily obtained through HBr addition to the double bond of vinyl alkyl or vinyl aryl carbonates (Ref. 8.5)This will process be describedin section3-2-2-4 devoted to
1-Bromoethyl
was
vinylic
f\"\"
chloroformates and derivatives.
/\177--0, >q o
0
\302\260
.\"
63)))
a and Phosgene derivatives s buildin\177 blocks

R1 Catalyst

bp.
Temp.
\302\260C
Eq. Me
Pie Et
Time Hours
Besides the
Yield %
synthesis
of
method is general enough to
1-chloroalkyl carbonates,this be used for the preparation
\302\260C/mm
none HgBr2
80 65 85 85
of 1-fluoroalkyl, 1-bromoalkyl or 1-iodoalkylcarbonates as shown in table 3-7. However, the method gives poor results or even failed when the haloformate is too unstable
in
Et
0.038 0.014 0.019
24 6
7
80 82 69
gas into the
' 0210/18
presence of the
catalyst
Me
n-Bu
iipr
TBAB(a)
B0-3/18
He
added
BTBAC(b)
60-2/2
R
medium
example, attempts to prepare1-chloroethyl ethyl carbonate dichloroethane at with (CEEC)itself in equ. almost total decomposition of ethyl chloropyridine, gave formate.
For (see section 3-2-1).

60\302\260C
1,2
0.05
R1
HBr was
(a)TBAB : (b) BTBAC : benzyl CI

I
continuously by bubbling the anhydrous tetra n-butyl ammonium bromide tri-n-butyl ammonium
Catalyst
Temp.
\302\260C
Time Hours
Yield
bp
\302\260C/Torr
mp
[\302\260C]
chloride
CH3 CH3
1
Ph
CI CI CI Br
I
Pyridine Pyridine Pyridine Pyridine Pyridine
80
60
1 + HBr
RCH-O-(\177-O-R
\177 \177
Br
I
CHCI-CH3 CH=CCI2
Ph Ph
5 4
HCI
RCH-O-(\177-O-R
CH3 CH3 CH3
80 83
70
1.5
1
Table
36
Preparation
of some l-bromoalkyl
1.5
5 4 24 2 20 20
alkyl carbonates.
67-8/0.15 67-72/9 83 44-5/0.1 82 74-9/0.03 80 93-7/0.45

71
49
[.59-61 ]
CCI3 CH2CI
CHCI-CCI3 CI CI Pyridine Pyridine
In order to complement the usual 1-chloroalkyl carbonates synthesis, we decidedto find a new route to a broader classof these compounds.More particularly, we tried to open accesso carbonatesin which the alcohol(R1-OH) t doesn'texist and to the previously unknown 1-fluoro-alkyl
CCI3 CCI3
H
80 80
82 65 65 83
76
60-1/11
82-6/0.03 82-5/2.5
77-8/5
88 90-5/0.05
32
76 72 67
Ph
DHAP KF/
(CH2)7CH3
Et
18-C-6
ICCI3
Ph
Table
carbonates. in Our efforts succeeded the discovery of a different based on the reaction of an aldemethod of preparation hyde with a halogenoformate in presence of a catalyst 8 (Ref. 86, 7), as depictedin scheme68.
Catalyst X
I
\177\"
KF/
18-C-6
C(CH3)=CH2
CI Pyridine
92-6/0.2
3-7
Preparation
of 1-haloalkyl of
carbonates.
None
R-CHO
R1-O-C-X
0
II
6o- 10ooc 32- 90%
salts,
the catalysts N,N-dimethylamino
tested : quaternary
pyridine
ammonium
imi-
1 R-CH-O-C-OR
(DHAP), 1-methyl
0
II
x =
F,
Cl, Br,
Scheme 68 New route to
l-haloalkyl
carbonates.
dazole, tertiary amines, Michler's ketone, quinoline etc. performed as well as pyridine. For the preparation of system found 1-fluoroalkyl carbonate, the best catalytic was the KF/18-crown-6omplex. o avoid side reactions, T c only aldehydes without hydrogen at 02should be used in
this
case.
64
65)))
a as Phosgenendderivatives buildin\177 blocks

Fluoroformates

attacked
ways
by
(Ref.
(Ref. 89)usedhere were preparedaccordingto literature procedure (see also farther on in this section). The preparation of isopropenyl chloroformate,as well as chloroformate will be presented in 2,2-dichlorovinyl section 3-2-2-4. At the beginning of our work devotedto new potential applications of 1-chloroalkyl chloroformates and 1-chloroalkyl carbonates,available literature data as well as our
preliminary
88) and
phenyl
iodoformate
as shown
nucleophiles following three in schemeTO
different
path-
Nu-C-Z
II
R-CliO + C[
A1
A\177
O
\177
R--CH-O--C--Z
R-CH-O-C-Z Cl+
I
Nu
O
II
Scheme69
products
strong variations in the distribution resulting from nucleophilic attacks. gives some examplesdemonstrating that the the nature
derivatives.
experiments indicated
R-CH-O-C-Nu
I
+z
types of obtained products strongly dependon of reactant.
Scheme 70 Possible types of nucleophilic attacks to
Cl
1-chloroalkyl-oxycarbonyl
EtO-C-F
3
EtO-\177-O-CH-CH
o
II I I II
Ethyl
fluoroformate
EtO--C-O-CH-CH 3 O 1-Iodoethyl ethyl

CI
carbonate
RO-C-N
,R
RO-C-O-CH-CH Base 3 _
R1R\177 O
II
'R
20
1 O-C-R
II
RO
-C-O-CH-CH 3
Cl
o
\177
o
II
CH3-CH-O-C-CI O CI
I II
CH3-CHCI2
1-chlo-
Research our laboratories the last fifteen years in over has beendirectedto understanding the mechanisms which are operative in nucleophilic attacks of 1-chloroalkyloxycarbonyl compounds, in order to be able to further predict new potential reactionsas well as to improve existing methods. The reactionsfactors assumed to affect the products distribution and the kinetics of the reactions are the : following Strength of nucleophilicity of the nucleophile. Strength of electrophilicity of centerA and B. Nucleofugacities of 1-chloroalkoxide anions and Z anions.
Solvent and temperature
effects.
in the framework
Stericeffects. Our approachwas
outlined
CI3C-CH-O-C-Cl
Scheme 69
roalkyl Examples chloroformates
+
C\177\177,
Hard-Soft Acid-Basetheory (HSAB,

+ 2 CI3C-CHO COCl
of variations of nucleophilic attacks pathways to and carbonates.
1-chloroalkyl chloroformates and derivatives very interesting mechanistic problem, since they present two reactive electrophilic centers which may be
In fact,
pose a
66
react with hard electrophilesnd a philes prefer to react with soft electrophiles. There are two electrophiliccentersin the 1-chloroalkyA Ioxycarbonyl derivatives (designated and B in scheme 70).Center B is a carbon sp3 hybridized and is softer than the carbonyl group, centerA. The factors that influence the degreeof hardness work
definition, prefer to
the HSAB theory
Ref. states that hard
90). In
of the a short nucleophiles soft nucleo-
67)))

for both centersA and B in the same way. That is electron withdrawing groups (in R or Z) increasethe hardness of
both
-\177
as a Phosgenendderivalives buildin\177 blocks

One of the first representative reaction with hard was the reaction of 1-chloroalnucleophileswe developed
with fluorides anion. This reaction proceeds kyl carbonates through A1 attack mechanism, which is in accordto the HSAB theory, thus converting 1-chloroalkyl carbonatesto fluoroformates in good yields (Ref. In the preferredliterature, most fluoroformates are prepared from their analogous chloroformates through KF using excess activated by a little halogen exchange
centers
In
term of the
R group
The following orderof hardness is proposedfor centers B > R = CCI3 Aryl > Alkyl > H Note that is also the same order for nudeofugacity (leaving group capability) in a A1,2type reaction In term of the Z group Electron withdrawing groups in the R radical will make centersA and B both harder. The orderchosenin our work was based on the Infra-Red carbonyl stretch. Assuming that electronwithdrawing Z groups will give a higher C=O the order of decreasing hardness stretch, we established
A and
91 ).
18-
\177
Crown-6. owever, H
this method proved
to be impractical
presentedin table 3-8.

OAr
for tertiary alkyl fluoroformates and/or benzyl fluoroformates, either because the corresponding chloroformates are not stable or because of the lack of selectivity of the alcoholswith fluoride attack. Acylation of the respective COF or COFClequires complexequipment not accessible r 2 to standard laboratories and/or multipurpose plants.
the easily available 1-chloroethyl ;R (RCHCI-OCO2R1= CH3)are heated,neat When
carbonates
or in
solution
O
-NI
\177
R
N'
\177
OR 1
SAr
II
-P(OR1)2
'R
C=O
stretch
1840 1780 1780 1775 O R-CH-O-C-Z

I II
1765 1745
1740 1729
presenceof to aldehydes and fluoro18-Crown-6, fragment they formates in good to excellent ields (Ref. 92)as shown in y table
with KF in
(benzonitrile or diglyme)
the
3-9.
Catalyst
Cl
R1 R
Solvent
Temp/press
\302\260C/mm
Time h
Yield
bp
\302\260C/ram
= Alkyl
t- Butyl t.
Amyl 1-Adamantyl Benzyl Cholesteryl Phenyl
(18-06)
mole/%
[rap.
None
\302\260C]
Table3-8 Decreasing hardness order of centers A and B asa function
of Z group.
The nucleophiles we three categories
studied
can be placedin one of
- Soft
-\177
\177 \177
Hard nucleophiles F-, Borderline nucleophiles

\177 \177 \177
nucleophiles
CN-. (RO)3P, The reaction.s of

amines,
: R-COOH, R 1R2NH, -OCN. ROH, : ArO-, ArNH2, Imidazole, Br-, CI-. :I-, -SCN,RS-, ArS-, (R10)R2p(=x)s-,
this
6 5 4 5 9 5
.Cl
None None None

Ph-CN
30 34 36 120/1.2
70/37
84
83
76
70/14
55/1.2
40/3 75/20
4 31
60 82
70
None
1.5
40-2/175 35-6/36 [30-2] 44-6/1 [114-7] 60-3/20
as well as ducts are not dicussed here in for section3-3.

68
1-chloroalkyl chloroformates with further reactionsof the resulting pro-
CH
KF 3-CH-'O=\177-OR\177+/...
\177
R1-O-\177-F
CH3\"CHO+
KCI
sectionand are reserved
Table
3-9.'Fluoroformates
prepared
from
1-chloroethyl
carbonates.
69)))

be noted that this new methodology exempliunusual conversion of an ester to an acid halide. Because radical R = CCl3 inductively increasesthe the hardness of the electropholicenterA and makes c
It should
as a Phosgenendderivatives buildin\177 blocks

as reactants.While chloroformates react explosively with DM50(Pummerer reaction) and exothermically with DMF (Vilsmeier-Haack reaction), Olofson and coworkers (Ref. 9:5) have found that fluoroformates are stable in this solvents below 100
carboalkoxylating
Fluoroformates offer alsosomedecisive advantages
fies an
reagentsfor
polar
tetrachloroethoxideanion a better
1,2,2,2than
leaving
group
carbonate is a more reactive acylating agent than the analogous carbonatefrom acetaldehyde = CH3)and (R doesn'trequire a catalyst. Thus, heating 1,2,2,2tetrachlocarbonateat for 8 h with KF in the roethyl tert-butyl polar solvent DMF under vacuum of 20 mm, with a simultaneous treatment of the distillate with ethylene glycol, pure t.butyl fluoroformate (BOC-F)was isolated in 75-79%yield [.Scheme 1]. 7
50\302\260C
1-chloroethoxide, 1,2,2,2-tetrachloroethyl tert-butyl
\302\260C.
.Severalimportant ning compounds
classesof
only
and amino-contaihydroxyl soluble in polar solvents such as and efficiently carboalkoxy-
DP150and
DP1F
can be easily
lated with fluoroformates. For example,percarboethoxylation of glucosewas readily achieved in good yield with
ethyl OH
fluoroformate
in
DP150as shown
in
scheme72.
.
OH OH
OCO2Et
20mm press. t.Bu-O-O-O-OH-OCI 3 + KF t.Bu-O--O-F CI30-OHO + 1.5 eq. DMF O ca80% yield Scheme 71 Economics for commercial synthesis of 800-F NO
II I
\177
O CI
50\302\2600
ETOCO2
\177
H
I\177-D-GLUCOSE
DMSO KF,1 Oh, 60\"C

In
CO2Et EtOCO2---\177-\177
\177 \177O.
UL'U21:[
II
Scheme 72
89% yield mp : 100
Efficient
synthesis of penta-O-(ethoxycarbonyl)-D-glucose.
CATALYS\177
since t. butyl fluoroformate (BOC- ) has been highly recommendedy F b $chnabel (Ref. 93) and Carpino (94) as a substitute for the expensive di-tert.butyl dicarbonatecalled (BOC)20. Indeed,BOC F is an extremely cleanand efficient reagent
particular interest
These results are of
Under tions
selectedconditions,
with
fluoroformates
included
react easily BOC-F

to
afford result proved
products containing
aromatic
carbonates in
phenolic funchigh yields. This
for the amino
protection of amino-acids into BOC-AA. However, the reagent is not stableenough to be shipmore ped safely becauseit decomposes or lessrapidly into
isobutene, carbon dioxide and HF, thus developing autogenous pressurein containers.This has led SNPE and its to and react BOC-F on subsidiary I.SOCHEH manufacture thus offering low cost protectedamino compounds. site, we succeeded the preparation of in Furthermore, FI\"IOC-F (c)-fluorenylmethyl fluoroformate) as a crystalline solid (mp. 41 This reagent exhibits the samestability as FI\"IOC-ONSu and can be easily shipped.Compared with FHOC-F FHOC-ONSu, gives similar to superior results in the protection of amines in peptidessynthesis.
\302\260C).
to be suitable for the production of valuable monomers used in resist materials for microelectronic. Recentprogresshas been made in microelectronic devicefabrication, particularly in microlithography used to the high-resolution circuit elementsof intemanufacture based grated circuit (Ref. 96).Deep-UVphotolithography on chemically amplified resist is likely to be the first technology that met the severe performance criteria required. The best known chemically amplified resist is basedon poly styrene) or copolymers(Ref. c)7). (4-t-butoxycarbonyloxy As shown in scheme 73, irradiation of the resist of results in the decomposition an added photoactive acid thus liberating a Br6nsted's acid, generator(Crivello's salt) of which upon heating leadsto cleavage the t-BOC protecting group. The irradiated regions are soluble in basicwater
71)))
70

and insoluble in organic solvents. Image development can be achieved either with aqueousbaseaffording a positivetone image or with an organic solvent to give negative-tone
O- -CH3 O
BOC-F
\177,
O-K +
BOC-oxystyrene
t-BuOK
image.
Ph3S+ SbF6 Photoactive acid generator
av
\177
Ph2S
H+SbF6
RN : 87188-51-0 80%overall yield
distilled
bp.
NaOH H
+
90-3 0.06mm /
95% yield after workup
Diglyme
\"\177n
OH
Mn
BOC-F
in
\177,
excess
25\177'C
'\177n
= 1100-1500
O
Scheme 73 .'Photocatalyzed
oxystyrene). removal
Scheme 74 of the BOC protecting group ofpoly
0
of 4-t-butoxycarbonyloxy
styrene and its polymer using
Preparation
(80C-
BOE F.
Similar the
to
The required monomer, 4-t-butoxycarbonyloxystyrene, is widely described the literature. Because in 4-hydroxy styrene is difficult to isolatedue to its rapid polymerization, BOC-oxystyrene is generally prepared by treatment of 4with strong basethus giving the corresponacetoxystyrene followed by addition of ding phenoxide, immediately in THF solution (Ref. 98). (BOC)20 At SNPE Group, we developed s processesuitable for the manufacture of either BOC-oxystyrenefrom 4-aceor toxystyrene and BOC-F directly poly (BOC-oxystyrene) reaction of BOC-Fwith poly (4-vinyl phenol), through
I'dARUKA Lyncur in
I'd
soft nates is
reaction
nucleophile
in
case of fluoride attack, the reaction of iodideanion with 1-chloroalkyl carbogood accordancewith the HSAB theory. The
the
proceedselectively through B mechanism to give s

carbonates[Scheme75].
1-iodoalkyl
The poor stability of such compounds has been already mentioned in this section.Caubereand coworkers (Ref. 78) reportedthat when 1-iodoethylalkyl carbonateswere heated in toluene at 75-105 they decomposerapidely to form the corresponding alkyl iodides.
\302\260C,
from
I'dARUZEN
Petro-chemical
Co.
+ R-CH-O-C-O-R
\177
scheme 74, these processes re quite a simple and afford good yields (Ref. c29). Researchersfrom Nippon Telegraph and Telephone with Corp. disclosedpositive-working resists developable alkali aqueoussolutions, consisting of a novolak resin, an
Ltd. As shown acid-generating
\177
II
Na+l
Acetone
\177
1 + R-CH-O-C-O-R
II
NaCI
Toluene
CI
O
Nal R
1
+ R-CH-O-C-CI R1-OH+
\177
\177
R 1-1
agent
and
In our laboratories, the latter phenyl] propane(Ref. was readily prepared in good yield through reaction of bisphenol A with BOC-F, using usual procedure.
100).
2,2-[p-(t-butoxycarbonyloxy)
- OH = n-C12H25-OH
81%
\177
Isolated
yields
Scheme 75 New
= 1-Adamantyl -\177 = Ph-CH2CH2-OH \177

preparation
76 %
I 81%
of alkyl iodides.
73)))
72
a Phosgenend derivatives s building locks a b

Becauseduring the reaction the
transient authors
a Phosgenend derivatives building locks as b

discovered in acetone,in the that absenceof alkali thiocyanate, thiocyanates (I) were readily isomerized under mild conditions to the correspondingisothiocyanates as (11)
However, the authors
back formation
R1-OH,hey t formed one-potfrom

and Nal, thus
of the correspondingfree alcohol demonstrated that the reaction can be

1-chloroethyl chloroformate, discovering a new preparation
in
observedthe
pep
presenceof Bu4PBr
table
but in the
iodidesas shown
scheme7.5.
alcohol of alkyl
R
shown in
3-11.
72
of the reaction was thoroughly studied in order to understand the origin of the N-bounded compounds (Ref. Someexamples f the reaction are o given in table
corresponding1-thiocyanoand/or1-isothiocyano ethyl carbonatesin good yields (Ref.101 ). Because the interest of compounds of containing both carbonateand isothiocyano groups in chemistry, the mechanism phytosanitary
Another example of soft nucleophile attack according to the HSAB theory was given by the reaction of thiocyanate salts with 1-chloroethylcarbonates affording the
Time hours
Yield, isolated
(II)
Et t-Bu
n-C8H17
Ph-CH2 SCN
I
13 26 48
Acetone
\177--
81 81 56 82
N=C=S
CH3-CH
(11)
O-li\177-OR
102). 3-10.
Solvent
I\"leOH I\"leO H
CH3-CH
(I) Table
O-li\177-OR
Bu4PBr
56 C
3-11Isomen\177ation
.\"
carbon ates.
R Et
,'
of 1-thiocyanoethyl carbonates to
1-[\177othiocyanoethyl
H
K
Time h.
(I)+(II)
%
(I) +
(I)/
(11)
(II)/ (I)+ (11)
23
76
58
78
76
, Et
Et
\177'
NH4
K
HCONH2 HCONH2 HCONH2

PleOH
, Et
t-Bu
,'
NH4 NH4
K
4.75
, n-CSH17
\177
17
73 72
SCN
86 89
70 51
Ph
NH4
0.93
1
CH3-C
0.85 0.15 0.79 0.21

0.07
0
N=C=S
.\"
0.83 0.17
1 1
0 0
The authors proposedthe mechanism 76 (Ref. 101).

SCN
I
given
in
scheme
Bu4PBr
SH3-CH-O-C-OR
I
L
+
II
\177 CH3-CH-O-C-OR
O
carbonate
\177omerization.
II
N:C=S
--\177,-ICH3-CH-O--\177-OF
Bu\177PSCN
Scheme 76 Proposed mechanism

It could
HCONH2
of 1-thiocyanoethyl
L I I I I
CI
I
' CH3-CHO-F-OR+
,
Table
4MSCN
\177 R.T.
Solvent
CH3_CHO_\177.OR+
(I)
HO-\177.OR (II)
0
at
3-10: Reaction
give a more marked cationic like transition state.Therefore according to the HSAB theory, the substrate would be attacked by the harder side of thiocyanate anion. t predicted,he soft nucleophile cyanide 1-chloroalkyl carbonates to afford carbonates in good yields as shown with depictedin scheme77. As
with
be suggestedthat
the bromine
atom would
of
1-
chloroethyl
carbonates
with
MSCN
\177
protic solvent
anion
20\302\260C
reacts
-N=C=S harder nudeophile than is

thiocyanate anion
From this study, the authors concluded that most isothiocyanates (11)must be due to a N-condensation of the thiocyanate anion rather than an isomerization. Because
1-cyanoalkyl the example
to
decomposition.
74
\"SCN, attack of the isothe carbonyl will explain the observed
O
\"
KCN,
18-C-6
\177
O
,I
CICH2-O-C-O
Scheme 77
_\177
of
Me
Et20
25\177'C,
4 days
carbonate
N\177-C-CH2-O-C-O
90 %
preparation.
Me _\177
Example
1-cyanoalkyl
75)))
and derivatives buildin\177 blocks as

Scheme78 gives
the preparation dialkyldithiophosphate two examples[reactiona and c] of of insecticidal phosphoric acid estersfrom
tPhos\177ene

1
bonate claimed
in
a
II
anions and 1-chloroethyl patent (Ref.
S
(EtO)2-P-SNH4*
\177-
103).
ethyl
car-
a
CI
/\177\"
CH3CN,70\302\260C,
7h
\177
74%
reaction with triethyl phosphite appearsto be a violation of the HSAB theory. As already developedin the start of this section,the reaction of carboxylate anions with 1-chloroethyl carbonates is widely used for the preparation of commercial prodrugs. The hard nucleophile RlCOO attacks selectively the soft center B, that is apparently contrary to the HSAB theory. favour
The last
O-C-OEt
O
II
S
S(EtO)2-p. NH4 +
\177
2 s.P(OEt)
(a_)
However, the required
use of added
Nal
O-C-OEt
\\
Nal, THF, reflux,

PrS\177
\177.O
_
3h
N+
II
78% (b )
cation-like transition state, the cationic intermediate having thereforetwo hard electrophilic centersand B attack would not be in violation of the rule [Scheme
may
80].
H2Me2 c\177. EtO/P'-.S H20 , DMF,

70\302\260C,
% /SPr
Cl
O O-C-OR+
II I-
7h
\177-
\177
s.P\\ OEt
II
85%
\177
DMF
[t /\"O-C-OR\177
I-
O
II
R\177COO
1 \177-C-R
Scheme
78
Reaction
of dialkyldithiophosphate
-O-C-OEt O
carbonate.
\177
B
Scheme 80:Assumed mechanism carbonates. 1-chloroethyl
//\"'O-C-OR O
II
of the
reaction
of carboxylate
anion with
anions
with l <hloroethyl
Reaction b in
tories.In
reaction
scheme78 was performed in our laborac, the thiophosphate anion is an ambident
estersfor subsequentpeptidecoupling
the tetrachloroethyl
N-protected amino acidshave been converted to active

by treatment with
are gathered in scheme79 (Ref. 104). O

II
nudeophile and can attack with either the oxygen or the sulfur. As found, attack with sulfur is in accord with the HSAB theory. Some other examples attack of of chloroethyl ethyl carbonatewith soft nucleophile phosphorous compounds
1-
(EtO)2--P- Na+
THF,0\302\260C,1
O\177p(OEt)2
/\177O-C-OEt
77%
O
\"\177
O-C-OEt
Bu3P
\177\"
+PBu3
\"\177O-C-OEt
67%
R-C-O-C-O-Act + CI3C-CHO
0
II
o o
\" \"
J
A1
.\"
The reaction proceedsy initial attack of the carboxyb late on the carbonyl and releaseof either chloral and chloride anion (A1 mechanism) or N-oxysuccinimide
RCOO-
carbonate of N-hydroxysuccinimide, 2,4,5-trichloro penol,pentafluoro phenol, etc. (Ref. 67).
noxide) anion (A2 mechanism)

O-Act Cl3C-CH- O-;-C-\177'Cll
(or pheas depictedon scheme81.
\177
\177IO1\177
ActO-
\177 % O--C-R-C-O--CH-CCI
3
\177A2
( \177to)ap
\177-
00
h
eth\177l
Scheme
79
(\177tO)\177-P-C-O\177t
5g% phosphorous Scheme
R-C-O-Act
Cl- +
\17750\302\260C,
\1778
Cl3C-CHO
using
fxamples
of reactions of
compounds.
1-chloroeth.gl
carbonate
with
O 81
tetrachloroethyl
II
76
Assumed mechanism carbonates.
of active esters synthesis
1,2,2,277)))
as a Phosgenend derivatives buildin\177 blocks

l\"]ixed aryl and oximido tetrachloroethyl
as a Phosgenendderivatives buildin\177 blocks

carbonate. The method section4-4.
Again,
will
crystalline tion of tetrachloroethyl
and
carbonatesare stable compounds easily obtained by reacchloroformate imides as shown in

with
be developedin
volume
2,
phenols or N-hydroxy
Yield %
table 3-12.
Crystn solv.
substituted
Act-
mp bp
the HSAB theory, secondaryand 1-chloroalkyl carbonatesas hard through A 1 attack mechanism to afford carnucleophiles bamatesin high yields.This reaction has been shown to be primary amines
according to
reactwith
(\302\260C)
very
(\302\260C/mm)
general under different reaction conditions utilizing differents types of amines including amino acids(Ref. 64, Scheme below displays the gene-
66,105, 106,107). 82
ral picture
83 66
2
108 121-122
150-5/0.02
Pet. ether
CI
I
of the reaction.
R2
K2CO3/THF/H20
20\302\260C \177
O2N
\177'-\177
NO
Pet. ether
R-CH-O-C-OR +HN\" 'R 3 O

1
II
50 - 95 %
'2 R10-C-N
R
+ R-CHO
II
'R3
Cl
Cl--\177 Cl F\177-F F
(31
92 91 98 85
= H, CH , CCI 3 3 1 R = alkyl, aryl

R
Scheme 82 : ma tes.
1-Chloroalkyl
carbonates
as reagents
for the synthesis
of carba-
80/0.05 120
145-147
CI
Pyridine
I
In
terms of the rate of the reaction and the yield, the
following trends
Ethyl
are observed
CI
I
:
II
\177
OI
\177
acetate
CI
I
O
II
(31
NNN
O
CI
i I
Dichloromethane
O
II
O
II
+ Act-OH CI3C-CH-O-C-CI
--\177- I3C-CH-O-C-O-Act C or
triethylamine
L
Table
3-12Preparation
1 -O-C-ORt Cl3C-CH-O-C-OR 1\177 CH3-CH-O-C-OR CICH2 The releaseof an aldehyde can be a severelimitation in the use of this reaction since the aldehyde formed can react with the starting amine to lead to a considerable o decreasef the yield of the expectedcarbamate.However, this difficulty can be simply overcome depending on the and the structure of the carbonate choiceof the respective
>
II
ofsome aryl
and oximido
tetrachloroethyl
carbonates.
The easy preparation protectedamino acid active ester derivatives using cheap reagents, in a reaction where the by product is water
new method provides an N-
of
soluble and easily eliminated from the reaction mixture. The processs illustrated by the isolation of the N-succini imidyl ester of BOC-Alanine in 94 % yield from activation of BOC-Ala with 1,2,2-2-tetrachloro-ethyl N-succinimidyl
78
have been proposed Therefore, 1-chloroalkyl carbonates to as new acylating agents and thus are valuable precursors ureas as thiocarbamates and unsymmetrical carbamates, outlined in section3-3, this volume. carbonate(BOC-OTCE) 1,2,2,2-Tetrachloroethyl-t.butyl as was especiallydevelopped a crystalline, nontoxic reagent for the N-BOC protection of amino acids (Ref. 66) [see section3-3].
79)))
amine, and on the reaction conditions (Ref. 64).
as blocks Phosgeneand derivalives buildin

In
a as Phosgenendderivalives buildinblocks
In
related chemistry,
the Arbusov
1-chloroethyl chloroformate and easily converted into amino alkyl
reaction products of trialkyl phosphites were
another
case,we
of
have
observed and
chloroformate
studied
the
rearrangement
ted cI
in
scheme83(Ref. 108).
phosphonatesas depicCI
chloroformate (Ref. 110) chloro-l-propenyl [Scheme8.5].
1-chloroallyl
to E,Z-3-
Neat
ZnCI
90\302\260C,
CIH2C\177 2h
bp :
82-41\302\260C
cI O
II
e 2 , 0.012q.
+ CH3-CH-O-C-CI
@NH
CH2CI 2
,0\302\260C,
(i.PrO)3P-\177 CH3-CH-O-C-P(Oi.Pr)2 100% OO OO

II II
\177
93%
(i'PrO)2P-C-Nx.\177/\177
Scheme 85 Rearrangement
81%yield
of 1-chloroallyl
While studying the mechanism, of the rearrangement in
E/Z=3.1/1
chloroformate.
32mm
Scheme 83.'Acylation
ofphosphonate
compound.
reversibility
we demonstrated the presenceof TiCI4.
Some interesting miscellaneous reactionshave been also explored.For example, 1,2,2,2-tetrachloroethyl chloroformate reacts with carboxylic acids at without solvent to afford acid chlorides cyclic anhydrides in high or
110\302\260C
3-Z-Z 4
Vinylic
The
interest
yields
Since the reaction doesn'trequire any catalyst, such result cannot be explained by the decomposition of the chloroformate to phosgene and chloral. The assumed mechanism is given in scheme84.
CI
I
(Ref.
109).
\177:hloroformales,
rarbonatesand
(arbama\177es
\\
have been areas of major research species [Scheme86]

in
synthesis
and chemistry
of
1-alkenyloxycarbonyl
academiclaboratoriesas well
especiallyat
in the industry, the early beginnings for polymers applications.
/
1-Alkenyloxycarbonyl group
C\177O_C
?\177
R-COOH +
CI3C-CH-O-C-CI O
II
\177 '2
Neat
110\302\260C
O
+
II
R-COCI
80- 90% distilled
+ 2 CI3C-CHO CO + HCI
CH-O-C-CVinyl chloroformate CH2=

I
= Ph,
etc. cyclohexyl, 017H35,CH3-CH=CH,

\177,
CH3
I
O
chloroformate
II
OH2=C-O-C-CI Isopropenyl
90%
HOOC\177-\177COOH
Proposed mechanism:
\177 O
\177
O
CI2CzCH_O-C_CI 2,2-Dichlorovinyl
chloroformate
II
O
R-COCI CH2\177_CH-O-C.O-R Vinyl carbonate
II
R-COOH-\177
Scheme 84
.\"
Preparation
1,2,2,2-tetrachloroethyl
chloroformate
of acid chlorides or anhydrides through reaction of with carboxylic acids.
O4
Scheme 86
O O
E
II
- Butadienyl
carbonate
fxamples
of vinylic
oxycarbonyl
species.
81)))
8O

Huch of the early work describedin the literature was centered around vinyl chloroformate classically made by the gas phase pyrolysis of ethylene glycol bis-chloroforma-
a as b Phosgenendderivatives building locks
te at
However, this route (Ref. to be industrially and economically impracticable proved and because of low yields (11-44%) formation of large amount of chlorinated side products and tars. Scheme87 presents the decomposition pathways of ethylene glycol bis-chloroformate.
460-480\302\260C
111,112,113).
CI_C_O.CH_CH2_O_C.CI
0
Scheme 88
0
CI
.\"
bp : 104-6 arm. pressure

\302\260C
Pyrolysis
of the
bis-chloroformate
of propylene
glycol.
In
an
114),
viously king
Hatuszak
obscure short paper published in 1934 (Ref. reported the first preparation of the preisopropenyl
unknown
chloroformate. While
wor-
- CO 2
co 2
HCI
as a physical chemist at the US Bureau of Hines, he isolatedthis compound by microfractionation from a reaction mixture of 70 ml of acetoneand 7 ml of liquid phosgene after half an hour at room temperature. Several chemists teams in the world, as well as researchersin our laboratories this exciattempted to reproduce whatever ting simple and cheap process. nfortunately, U the conditions and catalysts used, all the carried out trials
failed and the only products isolated were mesityl oxide and various chlorinated compounds.The conclusion of
o
- CO 2
cI
- CO 2
__\177,c\177
cI
most investigators was that Platuszak did not isolate isopropenyl chloroformate but a mixture of chlorinated products. However, as shown in table the properties Matuszak closelycorrespond those of the isoto given by
3-13,
propenyl chloroformate made farther on in this section).

glycol at
450-480\302\260C
by
the mercury
processsee (
index
Scheme 87
.\"
Pyrolysis
of the
bis-chloroformate
of ethylene
Isopropenyl chloroformate
Boiling point
\302\260C/mm
Density
Refractive
\302\260C
20
\302\260C/20
20\302\260C
Besides severedifficulties encounteredin the scathe was stymied by tile impossibility of this process ling up,
generalization 1-alkenyl chloroformates.For the same conditions, pyrolysis of the bischloroexample in formate of propylene glycol affords selectively the 1-propenyl chloroformate instead of the desired isopropenyl chloroformate as shown in scheme (Ref.
Phosgenation of
to other
acetone
Phosgenation of chloro-mercuri
93/746
94.5/747
1.103 1.121
made by the mercury
1.4138
by Matuszak
88
111).
acetone
Table
3-13 Comparison
properties of the 82
of properties of the product obtained

chlororoformate
and
isopropenyl
process.
83)))
a a Phosgenend derivatives s building locks b

spite of numerous failures to preparevinyl chloroformate and isopropenyl chloroformate by direct phosgenation of either acetaldehyde acetone,we or the chalIn
a as b Phosgenend derivatives building locks

The
zable aldehydes could react with chloroformates to

vinyl
r lenge to find economical outes to vinylic chloroformates and their derivatives, vinylic carbonatesand carbamates. We have shown in investigations that easily enoli-
accepted
of enol silanes was studied in a phosgenation secondstageof our investigations. Severalilyl enol ethers s from acetaldehyde, cetone, cyclohexanone were prepaa red accordingto general procedures given in the literature.
197.5
carbonatesin goodyields as illustrated

O
in
scheme89.
afford
However, again, all the attempts failed, the only products isolated resulted from C-acylation of the enols.For example, phosgenation of the enol silane of acetonein presenceof amount of mercury (11)chloride afforded 2,4,6catalytic
heptanetrione
O
(EtO)2P-CH2-CHO +
as the
Et3N
major product
as depictedin scheme
91.
RO-C-Cl
O
II
\177 (EtO)2PCH=CH.O.C_OR
II
Scheme
89 Reaction
O R=Me bp : 128-9/1.5 63% mm; R=Et bp:138/1.5mm ; 70%

with diethyl (2-oxoethy/phosphonate).
y
O \177
+ Me3SiCI
Et3N
. HCI
OSiMe3
of alkyl
chloroformates
+00012
Olofsonand coworkers (Ref. 115) found that reaction of ketoneswith LiTHP producedenolateswhich were spewith chloroformates when cifically O-acylated hexamethyl phosphorotriamide (HP1PT) was added in the reaction mixture thus giving alkenyl carbonatesin 49-90% yield. Therefore,our first idea was to O-acylateimple enolates s with phosgene.n a first courseof I attempts, we investigated the reaction of phosgene with alkaline metals enolates. For example we preparedlithium enolateof acetaldehyde through cleavageof tetrahydrofuran by n- butyllithium and (Ref. 116) reactedwith phosgeneunder various conditions. Unfortunately, no trace of vinyl chloroformate was found in all experiments performed [Scheme 90].
+ n-BuLi O\177
\177
from
20\302\260C)
O-C-CI
0 0 0
=\177/
Scheme 91 Phosgenation of the enol silane
OSiMe 3
acetone.
led The phosgenation of the tributyltin enolateof acetone the same results although some trials performed at low showed the possibility to obtain temperature (below small amounts of isopropenyl chloroformate. It is noteworthy to
new synthesis of retinal A aldehyde), Bienaym& from Rh6ne-Poulenc (Ref. (Vitamin in low yield obtained isopropen-l-yl chloroformate of the reaction product of tributyltin through phosgenation that, in
a recent work devoted to a
117),
methoxide with
92. as 1-acetoxy isoprene depictedin scheme

0\302\260
--.-\177H2C\177CH_
II
O- Li +
+ n-C4Hlo + CH2=CH 2
COCI 2
\177
COCl2
OAc
+ Bu3SnOMe
H2C=CH-O-C-CI o
Scheme
\177
90.'Reaction
of phosgene with the
lithium
enolate of acetaldehyde.
CH2CI / Toluene 2
\177 \177 \177

C
CH2Cl2
OSnBu3
+ AcOMe
OiC-CI
+ Bu3SnCl
28% yield
Scheme 92.'Prepara
rio
o
te.
85)))
II
unstable product n of isopren- 1-yl chloroforma
84

,\177t
b a as Phosgenend derivatives building locks

precautions and efficient cleaning up methods used. To circumvent the difficulty, we attempted to start from keto compounds. hus, we prepared other c\177-C-metallated T the reaction of disodium by acetonyltetracarbonylferrate tetracarbonylferrate (Caution : pyrophoric !)with chloroacetone in THF according to literature data (Ref. chloroformate in situ afforded isopropenyl Phosgenation
safety but in very variable and non-reproducible yields not % as depictedin scheme94 (Ref. ding
this point
of our
investigations,
we thought
that the
work,
were later to provide the basis for a long collaboration in new areasof chloroformate chemistry between SNPE and Penn State University. In the first step of the SNPE process, chloromercury
contact\177
good way to synthesize enol chloroformates may be the reaction of phosgenewith c\177-C-metallated aldehydes and ketones.With this new courseof action, we were able for the first time to obtain the desiredcompounds by treating with chloromercury acetaldehydeor chloromercury acetone phosgenein polar solvent. about the same time, Olofson and coworkers turned a similar conceptnto a practicable laboratory route to enol chloi roformates (Ref. 118). When we became acquainted with this
,\177t
121).
excee-
50
122).
were initiated
which
Na2Fe(CO)
4+
ClCH2-\177I-CH
THF
20o\177CH3-\177I-CH2Fe(CO)4-Na+
-NaCI
cOQ2
\177'
CH3
I
a acetaldehydend chloromercury red by reaction in water of vinyl
acetate respectively
oxide and
In
mercury
a mixture of (11)chloride (Ref.

with
80\302\260C
1:1
acetoneare easily prepaacetate and isopropenyl
< 50%
Scheme 94
H2C\177C-O-C-CI
NaCI
\"
Fe3(CO)12\"
O
Isopropenyl chloroformate
II
through phosgenation
of acetonyltetra-
second step, the dried chloromercurials comin nitrobenzepounds are treated with phosgeneat ne as the key solvent (Ref.120). chloroformate and Vinyl isopropenyl chloroformate are isolated by simple distillation in 75-85 yield rseescheme93]. %
the
119).
mercury
(ll)
carbonylferrate.
The studies
However,
it
in this
area were
not further
pursued.
possibilities still remain untapped. To give lust one example, the phosgenation of the reaction product of zirconium tetrachloride with acetone CI3ZrCH2COCH by 3 described Joseph and
seemsthat several high-potential
J 1/2 HgCI 2 H2C\177CO-CCH3+ 1/2 HgO

I
II
\177
H20
\177,
CIHgCH2--C-R + CH3COOH
mp:134\302\260C,97%yield R = Me, mp 105\302\260C, 90% yield
R=H,
0
:
R
I
II
should yield, under selectedconditions, isopropenyl chloroformate. In the course of other studies related to dehalogenation methods through electrosynthesis with sacrificial Blumenthal
(Ref.
123),
Nitro
benzene
\302\260c
CIHgCH2-C-R + COCI 2
0
Scheme 93 process.
II
80
H2C\177C-O-C-CI
of 1,2-dihathought that the dehalogenation chloroformates should provide with an interesting Ioalkyl route to vinylic chloroformates.ln orderto checkthe feasiw bility of such process, e carried out a set of exploratory
anode, we
75-85%
R R
0
= H ; bp :89-90 = CH3 ; bp : 94.5
chloroformates
\302\260C/760 \302\260C/747
II
mm mm
experiments under aprotic conditions using 1,2-dibromoechloroformathyl chloroformate and 1,2-dibromoisopropyl t te as starting materials (Ref. 124),hese materials having
bromination of vinyl and isopropenyl chlowas performed in an roformates. The electroreduction undivided cell equippedwith a stainless steelcathodeand a consumable zinc anode using acetonitrile as the solvent and Bu4N+BF4 as the electolytic salt.The promising resulLs
Preparation
of vinyl
and
isopropenyl
by the mercury
been made by
The system was designed recycle HgCI 2 in nitro to the benzenewithout removal from the reactor.However, the w process as severely handicapped by of
86 mercury
compounds
whatever
the bad reputation the strictly controlled
obtained
are given
in
schemec)5.
87)))

R
Br B/\177\"r

high
O
O/jL'CI
e
CH3CN , Bu4N+BF4
\177-
Zn
anode
C\302\260nstantcurrent(l'lA/dm2)
Temperature Scheme 95
dibromoalkyl
2.1Faraday
:30'-C
mole
chloroformates
O o/JL'cI R=H; 54% yield

R
/'\177\"
commercial interest of vinylic chloroformates derivatives
(seefarther
efforts nates
on
by
on in this the synthesis

which
section), we decidedto focus our of alkenyl carbamates and carbo-
methods
do
not require
vinylic
chlorofor-
R= Me ; 76% yield
by electroreduction
mates.
of 1,2-
Preparation chlo rofo rma
of vinylic tes.
made
1-Chloroalkyl carbonates and carbamatesare easily from reaction of 1-chloroalkyl chloroformates with
Thesepretty good results prompted us to find a practical route to 1,2-dihaloalkyl chloroformates.

1,2-Dichloroethylchloroformate is a known product made by classicalhlorination of vinyl chloroformate with c a 2. We have developed new, easily practicable route by treatment of 4-chloroethylene carbonate with PCI5 at which gives a mixture of the desiredchloroformate and the dichloro isomer in a 95 : 5 ratio as depictedin scheme Careful fractional distillation afforded the dichloroethyl chloroformate in 65% pure yield (Ref.
alcohols amines through standard processes secand tion 3-2-2-3,this volume) or original methods developed teams (section If a simple method by SNPE research
(see
for the
]\177-elimination
could be devised, the
3-3).
ready availabili-
and carbonates would seem ty of 1-chloroalkyl carbamates to make these compounds attractive precursors vinylic to
carbamatesand carbonates. Olofsonand coworkersdiscovered a

o process f thermal
chloroethyl high yields carbonyl)
refluxing
110\302\260C
relatively
simple
elimination
In
of hydrochloric acid from example, N-(vinyloxyin
1-
96.
1,2125).
o
carbamatesto produce vinyl carbamates in

(Ref.
126). a typical
[see
%o__.%o__.
O
CCI4
\177
CI2 , hv
PCI
CI
110
\"C
CI
% yield just by piperidine for 3 h in N-(1-chloroethyloxycarbonyl) o.dichlorobenzene containing eq. recyclable2,4,6-collidine as an acid scavenger scheme
piperidine
was obtained
89
1.2
97].
CI
58% dist.
107\302\260C/10
Distill.
mm
91-2\302\260C
90mm
CI
O--\177
95:5
CI
cI
H
3C_C\177
o.Dichlorobenzene\177, H.O.\177I.
CI
N\177_/\177
Collidine,
Reflux,
3h
1.2 eq_
H2C
Scheme
9\177
Scheme 97 of
1,2-dichloroethy! chloroformate.
O 89% distilled bp. 123-8 / 47 mm

\"C
=CH-O-\177-
N\177__\177
Preparation
of VOC-piperidine
from ACE-piperidine.
Novel preparation
The starting material, was preparedby standard

ethylene Unfortunately,
4-chloroethylene carbonate of the cheap photo-chlorination carbonateas describedin the literature.

the
the dechlorination of 1,2-dichloroethyl the electroreduction method afforded by only very bad yields of vinyl chloroformate, whatever the conditions selected. Moreover, all the attempts to prepare the 1,2-dibromoethyl chloroformate failed.
Without collidine, the reaction has been proved to work but is much slower. When the methyl of the 1-chloroethyloxycarbonyl group is substituted by alkyls, the elimination is easier,probably due to inductive stabilization of the carbocation intermediate.
chloroformate
At this point
88
of our
investigations,
and on
accountof the
The effectsof various conditions such as added mineral or organic salts (to catalyse the EI elimination), temperature and solvents were carefully studied by Wooden (Ref. 127). Some representative examples of the method are gathered in table
3-14.
89)))

RI

bp.
R2
-NR3R4
Base
Solvent
Yield
cI
H3C-CH-OoC-N
(%)
H H H Pie
(\302\260C/mm)
--N\177
Collidine Collidine
o.DCB
Tetrachloro
ethylene
82 134-6/49 84 86-90/0.5
78
II
\177
o. DCB
\177,
\177
H2C\177---CH-O-C-N
150\321\236C,
vacuum
Catalyst
Catalyst
:0.055 eq. : - TBAB,9 h.

non isolated,
il
\177
-N\177
20% decomposition. - CHBG.HCI, h, 100%completion 7

Scheme 98
bonyl)
100%completion 80 % by NMR
--'\177'\177
N
Collidine
/
Collidine
Bromo benzene Bromo benzene 1,2-Dichloro

ethane
81-5/0.2
100%yield of two
E1
NMR,
85 % isolated.
Comparison
promoters in the synthesis of N-(vinyloxy-car-
morpholine.
R'
\177
Zo-V
Me +
86 125-7/0.6
97
Light
tion red
Pie
l\"le
c[
3
_N(CH2)aNMe
None
gum
the carbamate chemistry, thermal eliminahydrochloric acid from 1-chloroalkyl carbonates much higher temperature and is accompanied by requires major yield destructive sidereactions.The key to an economiIn
contrast
to
of
CI
R\177\\
3 4
R R
CH-CH-O-C-N'
'R3
CH_O_C_
II
\\C\177
O
of
II
'R
'R 4
Table
3-14 Preparation
and w to vinylic carbonates as discoveredby Olofson o This discovery was the consequencef coworkers (Ref. a beautiful observation made by Dang, Olofson'student, on s the formation of neopentyl fluoroformate and, unexpectably
cal route
129).
1-alkenyl
carbamates
from
1-chloroalkyl
carbamates.
of
extra functionnalities are t\177lera\177edl Somemoieties even catalyze the elimination by last example in the table). increasing salt concentration The value of hexabutylguanidinium chloride or
As illustrated
in
table 3-14,many
(see
heating 1-chloroethyl neopentyl carbonate with KF in benzonitrile (Ref. Treatment of enolizablealdehydes with fluoroformates and KF in DP1SO for 15-24 afforded 1-alkenyl h) (55-100\302\260C stu% yield. According to Olofson's carbonatesin
vinyl
neopentyl
carbonatewhile
130).
72-92
acylation catalyst has been already outlined in section2-2 of this volume. In a later study devoted to the evaluation of potential facilitation of E elimination 1 in sensitive systems by including HBGCI, Kreutzberger (Ref. proposed a modification of the Wooden method basedof the use of a salt promoter
as HBGCI.HCI) an
(HBGCI
dies,the
nares the
activated
fluoride anion acting
as a basedeproto-
aldehyde to yield an enolatewhich reacts rapidto give the desiredvinylic carboly with the fluoroformate Excess neutraKF nate as shown in scheme99 (Ref.
131 ).
128)
lisesthe o
nl\\
HF which
is liberated
RI\\
\342\200\242
in the
reaction as KHF 2.
+ KHF 2
\177
\177.
of comparisons experiments without collidine in o.dichlorobenzeneunder vacuum demonstrated a decisive advantage of HBGCI.HCIover TBAB as shown in scheme98.
allows to avoid the use of collidine combined with its thermal stability at tempera,fores exceeding 200\302\260C made this salt a prime candidate as salt promoter in this process.
\177 \177
with collidine tetrachloroethylene as the acid scavenger,the guanidinium salts are superior to ammonium bromide (TBAB). Moreover, the tetrabutyl
\302\260C),
In refluxing
(121
CH-CH
II
DMSO + KF
C=C-O
R 2/
RI\\
R 2/ DMSO
RO-C-F / R2 O Scheme 99 Mechanism of the

C\177-C-O-
\177
R\177\\
C=C-O-C-OR F +
O
fluoroformates
II
II
n 2/
The efficiency of HBGCIwhich
presence of KF in
reaction of
with aldehydes
in
DMSO.
Note that the reaction tonitrile

if
also can be carried out in aceis 18-crown-6 used as a catalyst. In this latter
9|)))
9o
a b Phosgenend derivatives building locks as

case, chloroformates
mates if
method
n may

in a work carried out to assess the kinetics of radical polymerization of somevinyl alkyl carbonates, bdon and coworE kers showed that contrary to the conclusions of the previous
be
substituted
for fluoroforin the
two equivalents
of KF are included
medium.
Some results obtained using the fluoroformates are presentedin table 3-15.
R RI
R2
Temp., Time, h
\302\260C
Yield
bp.
\302\260C/mm
studies, the compounds can be polymerized readily polymers of high molecular weight with conventional initiators such as benzoyl peroxide(Ref.
to
give
radical
Hg
1 Et H 1 C6HS-CH2H 1 i-Pr H - CH2CH2CH22 H 2 CH2CH2-O-CH2CH2 H 1 Et Ple 1 CF3-CH2H
H H H H H Pie H
55/20 70/15
80/5 80/24
73 87
43-5/45
112-5/4
90/8
90/24
86 44-6/33 92 130-2/O.5 80 123-30/O.7

74
45-7/16
43-4/2..5
80/20 /n
81
R1XC=CH_O_C_O/R R2'
\177
Table
3 15.reparation P
KF
The chemical modification of poly (vinyl chloroformate) and its copolymers has been also studied. Treatment of such polymers with amines, alcohols and phenols affords the corresponding poly (vinyl urethanes) and poly (vinyl carbonates) (Ref. Poly (mixed anhydrides) have been also preparedby chemical modification of poly (vinyl chloroformate) by carboxylic acids under various conditions (Ref. The materials obtained from polymerization of vinyl carbonates and carbamates hard (but not brittle) cleartherare with high decomposition temperatures, excellent moplastics chemical resistanceand varying glasstransition temperatures.
137).
138, 39). 1
140, 142). 141,
of
1-alkenyl
carbonates
flora aldehydes,
fluoroformale\177
and
in
DMSO.
is notable, because the 2,2,2-trifluoroethyl vinyl carbonate has beenproposed useful monomer in optical fibers as applications (Ref. 1-Alkenyl chloroformates, especially vinyl and isopropenyl
3-15
The good yield
obtained
in the last experiment
of table
that the heretoforenot accessible at cost diethyleneglycol bis-vinyl carbonatecalled acceptable CVD [see scheme100] made in 80% yield using the is fluoroformate as depictedin table 3-15. process
It is noteworthy
\177 \177
o
,CH2CH2-O'C-O-CH\177CH
o
2
132).
o,
CH2C H2-O-C'O'CH\177CH2
=CH ,CH2CH2-O-C-O-CH2-CH 2
CH2CH
2-O-\1771
a chloroformates, as well as vinylic carbonatesnd carbamates have found number of valuable applications in various fields.
o
II
-O\" CH2\"CH
\177
CH2
considerableotential of these p vinylic compounds in organic syntheses, selectedtypes of applications are presentedin the following pages. The use of vinyl chloroformate and its derivatives as
In
orderto illustrate
the
CVD
CR
o-
Scheme 100 Compared structures of two calplastic lenses. CVD is known
39
for the fabrication
monomers
of opti-
to
monomers
in the manufacture
of thermoplastic
or crosslin-
polymerize
an
order of
magnitude
ked polymers is the oldestapplication developed. of vinyl chloroforPolymerization and copolymerization mate (Ref. carbonatesand carbavinyl
more easily (Ref. 143)than the analogous bis-allyl nate marketed under the designation CR-39which
leading material
carbois the
133, 34, 35), 1 1 mates (135, using standard 136)

yield high oxydicarbonates) and random copolymers is well
for
radical initiators
to
p (e.g. er-
molecular weight polymers documented. More recently,
crosslinked homopolymer of CVD exhibits similar propertiesbut with the advantages of much better scratch resistance and higher hardness and modulus.
Hethacryloxyethyl vinyl
decades. he T
casting
prescription
eyewear since
carbonateprepared from
hydro93)))
92
and derivatives s building locks a b
a a Phosgenend derivatives s building

enolates generatedin
the
hosgene
blocks
and vinyl chloroformate [Scheme ] was claimed as an UV curable crosslinking agent useful in the formulation of hydrogels for contact lenses manufacture (Ref.
xyethyl
101
methacrylate
144).
of presence N,N,N',N'-tetramethydiamine (TP1EDA) as depicted in scheme 103. lethylene In our continuing trials to extent the scopeof the vinylic carbonatessynthesis through the fluoroformate process,
vinyl menthyl
o\177Ok__/O
paration
+ \177
0--\177
0
CI
--'\177\" 0--/< =\177\177 0

O\\
0 '
carbonate was
menthyl
(80%)from
obtained in excellent yield fluoroformate. The polymer of vinyl men-
thyl carbonate was
Scheme 101 Synthesis of methacryloyloxyethyl
of biomedical
0%
vinyl
carbonate used in the pre-
as alsoproposed menthol-release agent. It is noteworthy that this polymer can be easily prepared by reaction of menthyl fluoroformate with poly(vinyl alcohol) in DP1SO.
1)Nail (
articles,
1.1 eq.)
reflux of
Aromatic product
bis-vinylcarbonates,
for example the

with
reaction
bisphenoI-A [Scheme are recommended the preparation of highly senfor sitive, high-contrast positive working resists (Ref.
102],
o
\177
of vinyl chloroformate
Y
O
r\177
+ L'v\177
--
TMEDA
THF,
( 1 eq.)
enol\177t
145).
\177
o.-JC- 2) Addition ci
formate
solution to chloro-
\177 i
\177
O..J[\177
O.\177
(-)-Menthyl
chloroformate
; THF,
0\302\260C
79 % yield
Me
Scheme 103 Effident synthesis of isopropenyl facture of polymeric menthol-release agents.
menthyl carbonate for the manu-
Scheme 102 Aromatic mance photoresists,
o
his-vinyl
Vinylic
for the manufacture
carbonate
of high
not limited
perfor-
the New N-vinyloxycarbonyl leucine alkyl estershave been synthesized from vinyl chloroformate and polymerized to
yield polymers and copolymers optically and physiologically active with liquid crystals properties(Ref.
chloroformates, as well as their derivatives are to rolesas monomers. Initial Olofson'spublications outlined (Ref. use of vinyl chloroformate (VOC-Cl) as a reagent for
150, 151)
in especially peptide synthesis, via the electrophile-labilecarbamate.Amino acidsare converted
amine protection,
to
carbonatesand carbamatescontaining chromophore groups have been prepared and claimed as useful polymerisablephotoinitiators for photoreticulable polymers (Ref. 147). and carPolymers and copolymersof vinylic carbonates bamates may find interesting applications as aroma and flayours releasing agents. For example, isopropenyl menthyl carbonate has beenpatented (Ref. 148) s an useful monomer a for the manufacture of a smoking composition comprising an admixture of tobaccoand a menthol-release agent. Recently, Harwood et al (Ref. 149) have published a new preparation of enol carbonates including especially isopropenyl menthyl carbonate by selective O-acylation of ketones sodium
Vinyl
146).
cedure.The most significant advantage of the VOC-group is associated with its removal which is facilited by the high of the C=C bound toward electrophiles. cidA reactivity induced hydrolysis with HCI or HBr in Ac-OHor with HCI gas through
wed by
their N-vinyloxycarbonyl derivatives by standard acylation with VOC-CI, for example by Schnabel's pH-stat pro-
an inert solvent containing the peptidefollowarming the hydrohalide adduct in ethanol affords the deblocked peptidesalt in excellent yield. The value of the methodology was underscored an efficient process in for the construction of the heptapeptide sequence, H-Ser-
(all L) (Ref. ). chloroformate (IPCF) has no value in amine protection but appears to be the most versatile chloroformate for acid activation. Thus, IPCF was proved
Phe-Leu-Pro-VaI-Asn-Leu-OH Isopropenyl
95)))
151
94

in
(z-Amino
\"r
H2
to be an excellent eagent for the amino acid activation r
esters
Yields
peptideamide bound formation via the mixed anhydride intermediate as depictedin scheme104 (Ref. 152).
(%)
mp
(\302\260C)
[(z]D, Cl, i\"leOH
.o
+
Z-Ala-OCH2-pNO2C6H4 Boc-Phe-OBzl
78
N\"T\"'COOMe R2
I\177\"
w
Boc..\177
R2
N.\177J,,.COOMe
Scheme 104 Amino acid activation

propenyl chloroformate.
\177H R
1
CO + 2
y
O
formation
.]
by
Cl2C6H3 Boc-VaI-OCH2-o,p Fm ooTrp-O-[2.3-O-(isopro pylidene glyceryl]

Boc-VaI-O(+) Z-Phe-O-t.Bu Z-Pro-O-t.Bu Z-Trp-O-t.Bu Table Bornyl
92 85 65 60
99-100 64-5 110-1 61-2

54-7 B1-2
- 16.3 - 6.3 - 10.5 - 12 - 75 - 9.9 - 51 - 5.2

(z-amino
88
90 60
70-1
of N-protected
3- 16 cz-Amino
It
for
peptide amide bound
iso-
esters by
IPCF activation
acids.
by isosecondaryand terin as tiary alcohols presenceof 4-dimethylamino pyridine catalyst affords the corresponding estersin good yield as shown in scheme105 (Ref. 153).
Reaction
of N-protected amino acidsactivated

with
propenyl
chloroformate
primary,
coworkers (Ref. 154) made from recently proposedallyl isopropenyl dicarbonate isopropenyl chloroformate and sodium allyl carbonateas a convenient reagent for the preparation of allyl estersof
that Takeda and carboxylic acids.Allyl isopropenyl dicarbonatereacts with carboxylic acidsin the presenceof DP1AP under mild neutral conditions to give allyl esters in high yields. Allyl esters
which
is noteworthy
could
p --N.\177COOH
H DMAP
RI\"oH
\177
===\177/
Et3N
-oo2 /P-NH Acetone

L
Scheme
105 IPCF activation
. :
/
O-C-CI O
II
especiallyuseful in the caseof unstable compounds under acid or basic conditions, for example O-glycopeptides,
penicillin
be deprotected by
palladium
catalysts
are
derivatives,
etc.
/L.
\";1\"
.DMAP + ' R10
\177
in
p_N
O-R1
O
for
-J'\177 H
The condensationof a chiral N-protected amino acid with Pleldrum's acid in the presence isopropenyl chloroof formate and DI\"IAP is the key for a stereospecific synthesis of N-protected Statine (Ref. The novel route to
Statine is
depictedin scheme106.
155).
one-pot esterification
of N-protected
amino
adds.
Someexamples are given
table
3-10.
Boc__N\177COOH H
\177\"
BocNH
O.\177
\177
O\177:
IPCF
DMAP
AcOEt
OH
BOC--
(I)
O\177O
_\177 - Acetone
NHBoc
\177
O
88% from (I)
H2
Adam's catalyst\177
\177UH Boo--N: J
\177 \177 \177
\177,
\177cheme
\17705
2) HQ
\177 \177COOH 1)aaoH

I \177H
Acetone
N-Boc-Statine
\177tereospecific
synthesis of \177t\177tine
#ore
IPEE
96
97)))

strategy was utilized acylation of Pleldrum's In this work, isopropenyl ester chloroformate was found to give the best results of several mixed carbonic anhydrides derived from the required starting carboxylic acid when used in the presenceof 5 molar equivalents of

reactive than the commonly
Plore recently, a similar to prepare the Dolastatin
15via
synthetic
used reagents.
Me,.
(150).
o Me.,s,.O
\177.\177O..\177Ci
Me,.s,O. O ]
1
.CO 2
DI\177IAP.
Dolastatin
proved to
exhibit promising
remarkable
Scheme 108 Pummerer rearrangement With penicillin
._o
the
\177-
./..L..__CI
with vinyl chloroformate.
anticancer properties.
J]-sulfoxide, VOC-CIinduces a novel
Olofsonand coworkers alsointroduced vinyl chloroformate as a reagent for the N-dealkylation of tertiary amines 1 159). (Ref. 157, 58, Comparedwith commonly utilized reain N-dealkylation procedures, the use of VOC.-CI eads l gents
to significantly improved yields under milder conditions combined with greater discrimination between alkyl groups in is unsymmetrical amines. The procedure illustrated by the selective N-deethylation of N-ethyl piperidine to afford piperidine.HCI in 90% yield (Ref. 159) depictedin scheme 107. as The N-dealkylation selectivities follow the order : benzyl; allyl; t.butyl >> s.alkyl n.alkyl >> piperidine scission. The methodolo\177 was subsequently applied to the pre_>
rearrangement
depictedin
H
involving cleavageof scheme109,

ZNH_
C-5-C bound as
O 56%
S. /
O\177 O
Scheme
formate.
109
CO2Me
Novel rearrangement
from penicilfin
l\177-sulfoxide
and
vinyl chloro-
Alkenyl kyl
carbonatesreadily add HBr to give 1-bromoalcarbonateswhich are better alkylating agents for the
of carboxylic acid functions
in
modification
than 1-chloroalkyl
paration of the potent analgesic Nalbuphine and the potent narcotic antagonists Naloxone and Naltrexone (Ref.
100).
carbonates as already mentioned

(Ref.
nate
yield
example, 1-bromoethyl tisopropyl (BEIC) was preparedat pilot scale in 92 %

by bubbling
85). For
section 3-2-2-3 carbo

distilled
_/N 1
1,2-DCE
\177
Et VOC-CI
0\302\260C
'Et
L
CI-
-\177
90%
O
N--\177
HBr through
vinyl isopropyl
neat,
O\177,
at
20-25\302\260C
Br
) HCI
2) EtOH
100%
Scheme 107
\177\"
1.1 eq. 20-25oc

HBr,
Neat
\177NH.HCI
tion of N-ethyl pipefidine with vinyl chloroformate.
7h
/-4 /-04-0
O
92%
110.
carbonate,
(98% pure)
mm
N-Deethyla
bp:
78\302\260C/100
However, vinyl chloroformate largely has been replaced for N-dealkylation by 1-chloroethyl chloroformate which shows similar dealkylation selectivities and equally easyreplacement of N-alkyl by the carbamate group (seesection3-3).
in Vinyl chloroformate might find interesting applications Pummerer related rearrangements. Thus, VOC-CI reacts
d of
1-bromoethyl isopropyl
2\302\260
: 1.34
(BEIE).
carbonate
mates,
with
me
98
108 161 (Ref. ).
sulfoxides
to
yield
In
o\177-chlorosulfides
as shown
in
sche-
this type
of reaction, VOC-CIis more
Besidesthe synthesis of vinylic carbonatesand carbaOlofson coworkers reported a simple synthesis of and and carbamates 1-(1,3butadienyl)carbonates (Ref. 162). and its congeners are easily and often Crotonaldehyde converted to trans-butadienyl carbonates stereospecifically and carbamates treatment with potassium tert.butoxide by
99)))
a blo(ks a Phosgenend derivatives s building

followed chloride
given Y in with
a as b Phosgenend derivatives building lo(ks

to reospecifically form
(IV) which, after LAH reduction and (+) - Hernandulcin (V) as depicted in
addition
of a chloroformate or
table 3-17.
THF
KOt.Bu
111. examplesare Some

0
Et\177
Y,N/__\177O
carbamoyl
scheme112, o
N\177L-
oxidation
affords
0
+
HsC/_\177H
H
Z-C-el
0
II
- 78 oc
,
H
--/k/z
O
H +
o
II
Y = H, Me, CI 2 Z = OR or NF\177R
(I)
I\177,\177 Me
k
OH
Me
TiC'4
-\177
(Et)2N-C\177 v
Me\"
Me
\177MgBr
(111)
Scheme 111 Alkyl dienyl carbonates and carbamates dehydes with KOt.Bu and acyl chlorides.
Y H H H Z
(ll)
from reaction
of crotonal-
o
II
OH
Yield
(%)
bp
(\302\260C/mrn)
2) Pyridinium
M\177v)V
Me\"
O-Et
O-Allyl
O-CH2CCI3
O-Et O-Et N(Et)2
He
CI
83 58 68 78 32
75
48-51/0.6 .5 58-61/I
74-84/I
carbamates and carbonates.
55/0.8 99/0.7
42/3
Scheme 112 Novel

In
.\177
preparation
chlorochromate
v.\177
(V)
of the sweet sesquiterpene Hernandulcin,
Table 3-17 Preparation
of trans-
1-(1,3-butadienyl)
course of several investigations devotedto the of new halogen substituted carbamates and phosphonato esters for agricultural screening, we were interested in the compounds containing the 2,2-dichlorovithe synthesis
nyloxycarbonyl
unit.
The alkyldienyl carbamates were utilized both at Pennstate University and at 5NPE in parallel studies to - Hernandulcin developa stereospecific synthesis of (_+) and congeners (Ref. The intensely sweet sesquiterpene, ernandulcin, was H isolated from a plant known to the Aztecs as Tzonpelic Xihuilt or sweet herb (Lippia dulcis). Hernandulcin which could be considered the prototype of a new classof times sweedietary sucrosesubstitutes is said over ter than sucrose. owever to a human panel at SNPE, H while tasting synthetic Hernandulcin made by the new some aftertaste and a slight bitterness was methodology, perceived 50% of the persons. by
163).
in the world continue to take advantage of the toxicity to insects of particular patterns of halogens in the molecule. be more accepTo
Various
insecticides sed extensively u
table than
gically
many
sensitive
other agricultural agents in today's ecolosociety, they must contain functionalities
c\177
1000
guaranteeing ready degradation by environmental agents. A report published thirty years ago (Ref. outlined the potential insecticidal activity of 2,2-dichlorovinyl carbamates and carbonates.However, progressin this area has been stifled because 2,2-dihalovinyl chloroformates were unknown. For the preparation of the phosphonato
164)
In our method, the N,N-diethyl butadienyl carbamates reacts both regio and stereospecifically methyl vinyl to (I) ketone to give the cyclohexene in 89% yield, which in (11) turn adds the Grignard's reagent (111), gain and stea
re\177io
ester (A) assumedto exhibit interesting insecticidal properties as compared to the well known insecticide unknown 2,2-dichloDichlorvos, we neededthe heretofore scheme rovinyl chloroformate [see
113].
100
101)))
a as Phosgenend derivatives buildin\177 blocks o

CI2C =CH-O-P(OMe)2
Dichlorvos
from
II

avoid any uncontrollable exotherm. No induction period found in the same reaction from 1-chloro-2,2,2-tribromoethyl chloroformate but the yield of 2,2-dibromovinyl
o
CI2C \177CH-O-C-P(OMe)2
(A)
was
Arbuzov reaction of
chloroformate was only
dichlorovinyl chloroformate Scheme 113 Comparedstructures ofthe insecticide Dichlorvos and a parent comunit. pound containing the 2,2-dichlorovinyloxycarbonyl
33% [Scheme115]. o
Br2C\177CH-O.C-CI
CI2C---CH-O-C-CI
Yield
75 %
33%
describedin section 3-2-2-3. thought that if this We chloroformate could be induced to undergo a Boord elimination of chlorine, the desired2,2-dichlorovinyl chloroformate would be easily available as shown in scheme114.
dy
chlopreparation of 1,2,2,2-tetrachloroethyl roformate by treatment of chloral with phosgenein the of n presence a reusable, aked CI-, catalyst has beenalrea-
The facile
82-5 / 120mm bp. Scheme 115 2,2-dihalovinyl chloroformates.
\302\260C
68-3
\302\260C/12
mm
Both chloroformates are stable for at least several months at room temperature if all tracesof the byproducts zinc salts are carefully removed by distillation. Even more surprising, we discoveredthat 2,2-dichloroviis isolated in 50% distilled yield when nyl chloroformate and zinc dust in methyl acechloral is treated with phosgene tate (Ref. Efforts were made to generalize this process and o\177-bromo by extending the reaction to other oechloro
CI
I
O
II
O
Dechlorination
\177,
II
CI3C-CH-O-C-CI
CI2C__--CH-O-C-CI
chloroformate.
167).
Scheme 114 Expected route to 2,2-dichlorovinyl .'
However, several precedents in the literature would seem to negate a favourable outcomefor such a scheme. For example, the treatment of 2,2,2-trichloroethyl acetate with zinc leads to 1,1-dichloroethylene a dramatically in exothermic process. Sincechloroformate anion is a better than acetate,it should compete with chloride leaving group for that role. Chloroformate ion also should be lost in an anticipated subsequentzinc-mediated elimination to yield the explosive chloroacetylene. Horeover,the well-known of chloroformate in presenceof zinc salts decomposition
(Ref. 167). aldehydes and ketones as shown in table When Z is hydrogen, alkyl or aryl, the chloroformate is obtained only when A and B are halogen or alkyl but not hydrogen.
A
CI
3-18
B
CI
Yield
(%)
bp.
(\302\260C/mm)
Ph Ph
CN
Me
Me
I\"1e
66 54
67
86-8/0.4
57-74/0.5
He He
CI
80-3/10
He He
P(O)(OHe)2
H H
provides another
problem.
-(CH2)5He O
+ x-C--C-Z COCI 2
,A
II
Despitethese strong omensof failure, the reaction was successfully performed (Ref. 165, 66). 1 When zinc dust was added in small portions to a solution of 1,2,2,2-tetrachloroethyl
dichlorovinyl yield. Initiation
-(CH2)4Zn
\177-
83 56 59 68
\"CA/k-\177-('O-/k/'
68-71/52 48-50/0.7 80-2/8

O
I
chloroformate in THF at room temperature, chloroformate was isolatedin 75% distilled
reaction after addition of the first portion of zinc is variable in time and no more zinc should be added until the first portion has been consumed to
of the
Table nyl
3 18.'Preparation
of substituted
vinylic chloroformates
from u-halo
carbo-
cpds.
102
103)))

that the reaction applied to 2,2-dichlodione leadsto the previously unknown ro-l,3-cyclohexane through a clean decomposition dichlorocyclohexenone of the intermediate enol chloroformate as depictedin scheIt

Entry
is noteworthy
IHonomer
bp.
(\302\260C/ram)
ND20
Density
20
me
116.
I 2 3
Table
CI2C=CH-OC(O)OC6F5 CI2C=CH-OC(O)OCD3 56/15 C12 2CC13 142/760 C=CH-OC(O)OCH
115/151.4663 1.658
1.4590 1.420 1.5005 1.604
fibers
0 CI
FO
00012Zn
CI
3-19 New vinylic

.\"
carbonates
as monomers for
optical
applications,
\177)
.\"
IYW__0
I
- 002
CI
Their polymerization
and copolymerization
with
vinyl
Scheme 115Preparation
of 2,3-dicbloro-2-cyclobexen-1-one.
carbonate was also studied. vinyl methyl Whatever the radical initiator used (AIBN, benzoyl peroxit de,dicyclohexyl percarbonate)he monomers are too hinderedto self-polymerize. phosphoMonomer
acetate or
The value of being able to

nato groups among allowed
include cyano and
is of particular interest. Severalmodel experiments were carried out to guarantee the efficiency of these enol chloroformates as
Z substituents acylating
(I) and (2)polymerize
give alternating tail structure and
1:1 copolymers
Tg
95\302\260C
with
vinyl
acetate to
head to
with
an unusual
and
75-90\302\260C
respectively.
agents. Thus,
many
carbonates, carbamates,
new chloroformates with
phosphonato
estershave been obtained in good to excelreaction of the
alcohols phenols, amines, trialkyl phosphites (Ref. 168). or carbonates and carba1,2-dichlorovinyl Significantly, mates may have an interesting future as specialty monomers, for example as core materials in all-plastic optical fibers.
known that the optical absorption which is the drawback of the classical lastic materials such as major p PMMA, is dominated by the higher harmonics of the carbon-hydrogen stretching vibrations. The value of polymers
It
lent yields from
is
3-3Reactions
at a nitrogen
center
from
chloroformates derivatives has to 2,2-dichlorovinyl to their lower optical absorption as compared standard plastics in the visible and near-infrared regions of the Some new 1,2-dichlorovinyl carto l\177m). spectrum i % yield bonatespreparedby standard proceduresn
I i
do with
(0.6 1.5
I\177ighlights
of
for that
purpose are gathered
in
table
3-19 169). (Ref.
90-95
ome reactions
with
o|phosgene
amines, imines, oxazolines
ted
tertiary amines at low temperaunstable crystalline I or phosgeneamine adducts. In the case of tertiary alkylamines, these comp.lexes decomposewith elimination of alkyl chlorides to give carbamoyl chlorides and then isocyanates s depica tures
Phosgenereacts with
to
afford
:I 1:2
in
scheme117.
104
105)))
Phosg\177_ne
in ex\177ces\177s
R3 N
COCI 2
- 60to + 20\"C
R-N-C-CI
I
,R+
Cl-
1
T>20\302\260C
F\177NH
0\302\260C
+ OOOI 2
2) Reflux
Toluene
R2NH'HCI
R',N-
C-Cl
Ioi
00 RCI
N-O-N
R'
R
,R
COCI2
Reflux
\177 \177 \177
/N--% O
of carbamoyl
chlorides from secondary amines.
Amine in
excess
COCI 2
R3N
- 60to+20'C
CI-+
+ Cl
R3N-\177-NR3
Scheme
117: Reaction
of phosgene with tertiary
alkyl amines.
structure (11)for the phosproposed1:2 was deducedby analogy to the comgene-pyridine salt (I) as shown in scheme pyridinium monly observed as a conclusionof a study of low temperaHowever, ture 130 NMR and solid-state130 CP/MAS spectra,King
The originally
adduct
118.
and
1:1
mutagenic Low molecular weight and carcinogenicsuspectedagents. dimeproducts exhibit high toxicity levels.For example, chloride is a powerful lachrymator and a thylcarbamoyl confirmed carcinogen and mutagen. Extreme care should be taken to avoid inhalation or skin contact. In orderto developvarious new applications of carbamoyl Caution chlorides,
!several carbamoyl
chlorides are
Jr.
coworkers (Ref. 170)assigned a to structure (111) the pyridinium (2-DHPP)

ol
dihydropyridine-
salt. 1:2 ol-
in the synthesis of compounds such as ether oxidesof tertiary containing functional groups amines. Thus, we studied and scaled an improved process up for the production of N-chlorocarbonyl morpholine basedon [Scheme a modification of literature data (Ref. valuable N-chlorocarbonyl morpholine has found some amino acids to N-morpholinocarapplications to convert
we were interested
172)
120].
o,+
bonyl \177/=\177
amino
COCI 2
/=\177_//o
o (,)
phenylalanine
inhibiting
acids,for example N-morpholinocarbonyl-(L)for [Scheme120] the preparation of renin-
peptides.
Toluene
I
% 92.4 yield
m\177.
84-7\177'C
6ec.
z/\177
Scheme 118 Structure of the Note that the
\177
adduct.
. +
cr
/---N
I
COCl 2
Reflux
_---
(I)
O,k___./NHIHC
1:2 phosgene-pyridine
c\177N\177 > 95 % distilled yield / 73 mm bp. :

153\302\260C
which can be stored at least adduct (111) one year at room temperature and which reverts easily to its components in solution was proposedas a convenient (safe ?) storage system for phosgene under the term in phosgene- - can (Ref. 170). The reaction of phosgenewith secondaryamines or their hydrochlorides is a well known useful route to carba(Ref. 171. ) moyl chlorides as shown in scheme
/ H2O
(I)
+ H-Phe-OH
NaOHTH
\177'-
\177
morpholine
/---%N \177O
N
a-
))
80 % yield mp. :
134\302\260C
-\177
coOH
107

L-phenylalanine.
of N-chlorocarbonyl
and condensation with
119
]06)))

Such modified peptideswere proposedfor the treatment of hypertension, in a patent from Squibb originally and then in numerous patents from other companies. (Ref. In another example, N-chlorocarbonylmorpholine is used

in our laboratories was also devoted to the preparation of process carbamoyl chlorides as N-chlorofunctions,such containing tertiary alkylamine This carbacarbonyl, N'-methyl piperazine hydrochloride. chloride is for example used in the synthesis of the moyl sedative and hypnotic pharmaceutical Zopiclone as shown
Some work
173)
improve
s (besideseveral other phosgenederivatives)

synthesis from Fujisawa
of FK-906,an
in
antihypertensive
in
in a multi-step renin inhibitor
121 174). (Ref.

CI
phase II
Japan, as depictedin scheme
in
scheme122 (Ref.1T5).
O/---\177N\177
\177
H3C,
N\177 H
\177--N,
Et3N
\177-
,OH3
Me
\177
N
\\\177
Aproticsolvent
+
./
NH
COCl2
0\302\260C,
2-3h
\177-
MeN
\177 N-C-CI. HCI \177

Oii
t.BOC
H3Q
CF3COOH
\177.__
97% yield
H3C,
N
\177N._\177
\177 O
O -\":/\177
II
o
H2
N,CH3
't.aoc
\177
O/\177'kN
\177
__\177N
-'\177. N,C
\"\177)
H3
\177
N\177J\177
O O
el H2N\177
\177
N--
\177N\177
:/\177__
\177\177
\177N
\177/
O'/'hf\177
H3C
\177
uction
Red_
O
N
\177,[\177 \177.\177Z\177N
2) BASE
\177
q
\177
\177L\177/
#
\177.
//
Cl
\177 MeN N-C-CI. HCI X ./

II
OH
Pd/C
N% \177 O\177 \177 H3C

\177
\177
,N\177 \177R
,P
\177OH
O\177
C-N
\177
H3C
o\177
\177)
(coco\177
.30
H3C
\177
CH3
Scheme 122 5ynthesis of carbamoyl \177hloride its use in the prepe\177tion of Zopidone.
//
\177
N-Me
derived #ore N-methyl piperezine end
Scheme 121
renin inhibitor
\177
morpholine
CH3
While studying the reactivity of carbamoyl chlorides, we found that they react easily with aldehydes in the presence of a Lewis acid as the catalyst to afford 1-chloroalkyl carbamates in goodyield as shown in scheme The (Ref.
\177
in the preperetion
chemical properties of 1-chloroalkyl carbamates which can
be obtained
by other
123 176). in routes are discussed section 3-3-2.

109)))
N-Chlorocerbonyl FK-905.
of the
hypertensive
108

CI
RI\\

AWithout Two
RNH
R2
N-C-Cl
+ R-CHO
ZnCl2
\17760\302\260C
acid scavenger
R\177
O
R 1\\ R2
II
-5h
R2
N-C-O-CH-R
O
90% yield
II
stepsprocess
2 +
N-- =
\177
N--
COCI 2
\177 T<
20\302\260C
RNH-C-CI +
RNH
2.HCI
O
2 RNCO+4HCI
100\302\260C
II
Scheme 123 Reaction of carbamoyl
chlorides with aldehydes.
RNH--C-CI + RNH 2.HCI
0
chloride made by phosN-MethyI-N-methoxycarbamoyl of methoxy methyl amine hydrochloride is a very genation useful intermediate for the synthesis of N-methoxy ureas A 2 One step process
II
\177 T>
OOOI 2
\177,
Chlorobenzene
RNH
to be unsatisfor the production on a large scale, because of factory rather low yields and also of technical difficulties. To overcome these problems, we developeda new procedure based on the reaction of phosgenewith methoxy methyl amine sulfate as depictedin scheme Sulfuric acidformed is easily removed by decantation (Ref. 177).
the method
herbicides. owever, we found H
2.HCI
COCI 2
RNCO
+3
HCI
T = 100-140\"C
124.
- With acid scavenqer

B1 Anhydrous
Example
medium
Toluene
N,N-Dimethyl
:
aniline
MeO\\
Me
NHJ
/
'\177
.\"
\342\200\242
H2SO4 +
2 OOOI 2
Toluene
\177-
95\302\260C,
5h
2MeO\\ N-C-CI +
HCI
Me/ O
[I
t2
H2SO4
80% dist. yield / 36 mBar bp.

60-7\302\260C
\177__NH
COCI 2
( 1 eq. )
+
5\302\260C
-NCO
87%
Scheme 124 Preparation of methyl methoxy ric acid salt of methoxy methyl amine.
bp
60\302\260C
/ 8 mm
carbamoyl
chloride from the sulfu-
B2 Biphasic
Example
NH
process
o. Dichlorobenzene
COCl 2
methods available for the Among the more than preparation of isocyanates, phosgenation of primary amines or their hydrochlorides still remains the most popular. The method is employed on a large scalefor the industrial production of mono and polyisocyantes. Four phosgenation proceduresare used.The procedures without any acid scavengerare the methods commonly employed for the production of almost all commercial
30
:
2 +
\177,
\177
NaOH +
/ H20
5\302\260C
---NCO
73 %
bp.
yield
84-5\302\260C
isocyanates.
111)))
110
blocks a and Phos\177ene derivatives s buildin\177
as a Phosgenend derivatives
This dimer
buildi\177n\177
blocks
/
devoted to the synIn the course of several studies an we developed improved theses of unusual isocyanates, of the already known ethylprocessfor the preparation hexanoate by phogenation of L-Lysine
2,6-diisocyanato in scheme125 (Ref. 178). ethyl ester as depicted

COCI 2
NH2\"HCI
HCI.H2N\177 COOEt
Scheme
.----
OCN\177
50% dist. yield / 0.01mm bp.
101\302\260C
NCO
of reacts as two molecules free 5- alkyliamines or with alcowith soxazolyl-3-isocyanate secondary carbamatesuseful hols to give the corresponding ureas or intermediates. For as agrochemicals or fine chemicals is isoxazole a key intermeexample, 3-amino-5-tert-butyl urea (comdiate for 3-(5-tert-butylisoxazolyl)-1,1-dimethyl as a herbicide for which is useful mon name [Scheme127]. cane and other crops(Ref. 180) sugar
Isouro______O_n)
CHCI3/NaOH
COOEt H
Me
N-Me
125 Phosgenation
.'
of L-Lysine ethyl ester to the
corresponding
isocyanate.
useful in the preparation This diisocyanate is especially of biocompatible polyurethanes or polyureas. that the In another example, surprisingly, we found substituted isoxazolamine hydrochloride phosgenation of a but free isocyanate a peculiar the expected doesn't afford to the mechanism depicted on scheme
Scheme 127
.\"
Isouron.
by
dehydrochloridation affords N-substituted
dimer according
126 179). (Ref.

NH
carbamoyl chlorides in good carbamoyl chloride was yields. For example, N-methyl-N-vinyl of ethyin 67%distilled yield through phosgenation
vinyl
imines followed with CH-acid The reaction of phosgene of triethylamine in the presence
prepared
2.HCI
+
TOLUENE
35\"60\302\260C
NH-C-CI
II
IsOxazOlamlne
). (Ref. lidene methyl amine as depicted in scheme available on the p-carbon, If there is no hydrogen atom of tert-butyl in the case of the Schiff's base for chloamine and formaldehyde, N-(1-chloralkyl) carbamoyl
ride
128 181
example
\177
COCl2
\"-
O R
\177o\177N
- HCl
are obtained
in
excellent ields [Scheme128]. y
CH3N:C .CH3\177
H
COCl 2
\302\260'k\177-
Cl
IMe--N
0.10o0
3h
CI)---Me\177
Toluene
N\177CH2
COCl2
20\302\260C
\"\"
\177_
1.5h
| |
Et3N
1\177
Reflux
Toluene
\177X
,N--\177
Cl
Me
63\302\260C
67% yield / 23mm bp.

CH2Cl
\177._N,
\177-Cl
90% yield
117\302\260C/25
17\302\260C
bp.
mp.
mm
' Scheme 126 A peculiar isocyanate dimer

zolamines.
from phosgenation
of substituted
isoxa-
Scheme 128 Reaction

.\"
ofphosgene with
Schif
t\177s
bases.
113)))
112

It is noteworhy
a as Phosgenend derivatives buildin\177 blocks \177 H20

175\302\260C
that
starting materials for the synthesis of W pesticides. e have carried out some trials based on literature data (Ref. in order to synthesize N-phenyI-N-
rides are valuable
N-(1-chloroalkyl) carbamoylchloEt
\177
\177--
182)
H-CH3
CH2OH 96.5%
100\302\260C
98%
chloromethyl
carbamoyl
chloride to
by
1,3,5-triphenylhexahydro-s-triazine However, all the efforts
12c).
as
of phosgenation shown in scheme

improve the
OOOI 2 NaOH / H20

\177-
appreciably
described yield (24 %) failed, around 50%.

Ph-N\177N.Ph +
L\177N/I
I\177h
the
best yield obtained being
10to
\177 /CH2CH2-NCO
18\302\260C
\1770\177
I.E.I\177I.
88 %
bp.
211\302\260C
Scheme 131 .'Industrial process for the
preparation
of I.E.M.
30OCI 2
\1773\177
X.\177__\177
\1770H2Cl
< 50%
.'
tC
I
Scheme 129 Attempt to prepare good yield.
an interesting monomer which combines to in on molecule. functionalities Unfortunately, I.E.M.exhibits a very high level of toxicity. It is recommended that the averageeight-hour working environment not well-known
chlonde in
I.E.M.is
N-pheny-N-chloromethyl
carbamoyl
exceed0.025 ppm.
Phosgenereacts also readily with substituted oxazoto afford depending lines, for example 2-phenyloxazoline, on the conditions either N-(2-chloroethyI-N-chlorocarbonyl
me
amides or isocyanato ethyl estersas depictedon sche(Ref.
130
(a)
183, 184).
\177
-3-2 Rea(liens
ioroformales
ith
l-chloroelhyl
//
Toluene
COC[ 2
1
oo\302\260c
O.\177,N -CH2CH2-Cl
0\177
O
47 %
bp.
132-4\302\260C
amines:
synlhesis
/ 0.7mm
cI
COCI2 (b)\177 NaOH / H20

\177_
0\302\260C
\177c \177
and useful o pplicalions f
l-(hloroallql
carbamales
\177O-CH2CH2-NCO
97 %
bp.
mm 109-16/0.1
oxazoline.
Scheme
130 The two pathways

.\"
for the phosgenation
ofphenyl
The process illustrated in the conversion of piperidiis ne to N(1-chloroethyloxycarbonyl) piperidine. Piperidine eq.)in ether was addedto a cooledsolution of 1-chloroethyl chloroformate in ether.The piperidine hydrochloride was filtered off and the expectedcarbamate was isolated from the filtrate in 77% yield (Ref. 127). Someexamples f representative carbamates o obtained by this method are gathered in table
chloroformates react easily with primary amines under the same standard conditions secondary used with classical hloroformates (Ref. 21 c ).
1-Chloroalkyl and
(2.3
3-20.
Process(b) in scheme130 applied to the was depictedin scheme131 185). (Ref.

preparation
industrial
of
isocyanatoethyl
methacrylate
a (I.E.M.)s
114
115)))

R
R1

Ref.
R2
Yield
bp.
(\302\260C/mm)
(%)
H H H OH Ple
68
76 77
83/3
rap.
186
187 127 127
3-CLC0H4
55-7
\177N
-et
(I)
---.DCE
ACE-Cl //\177x
/\\
Me
Et
i-Pr
(CH2)5 CH2CH2-O-CH2CH2
Me
N
Cyclohexyl
84 92
73
70-2/0.4 95-7/0.9
O
II
L--et
of N-ethyl
,C-O-CH'CH31 .., c,- /

+
(11)
CI
I
127 111-13/0.6
N-C-OCHCH3 \177 Warm

(111)
\177
Me-OH
\177,
99\302\260/\177
/NH.HCI (IV)
+ CH3CH(OMe)2 +
Pie GI
--N,,\177
80/0.5
CI
I
188
1
Scheme 132
CO 2
N-Deethylation
piperidine
via N-(1-chloroethyl-car
+ R-CH-O-C-CI
HN,R 2
1-chloroalkyl
--\177
_
Base
HCI
O
II
/R
2 R-CH-O-C-N\\R
by reaction
Table
3-20 Preparation
We
of
chloroformates
with primary
carbamates and secondary amines.
of
1-chloroalkyl
decarboxylaof the chloroformate. Phenyl chloroformate itself prefor N-dealkylation (Ref. 190)afforviously recommended
tion
Thus, only trace yields of alkylcarbamates and the tertiary amine primarily catalyzes the
are obtained
ded PhOC(=O)-piperidineonly 34% yield. in

The
high-yield
discoveredthat 1-chloroethyl chloroformate is undoubtedly the best reagent for the selective N-dealkylaof tertiary amines (Ref. Thus, in the initial test system (N-deethylation of Nthe use of oechloroethyl chloroformate ethylpiperidine), (acronym ACE-C surpassedthe yield obtained with vinyl 0 chloroformate : (I) -> (IV), 99% vs 90% as shown in scheme (Ref. Besidests interest for the synthesis of 1-chloroethyl i carbamatesfrom tertiary amines and the N-dealkylation of tertiary amines, this result is also quite unexpected. With most chloroformates other than vinyl chloroformate (VOC-Cl), for example EtOCOCl, l3CH2OCOCl , PhC the cationic intermediate analogous to (11) CH2OCOCl, fragments to alkyl chloride, carbon dioxide and (I).
tion
189).
dealkylation with ACE-Cl is therefore very surprising. Presumably, the -CHCl-CH unit is too hin3 deredto undergo competitive SN 2 attack by Cl- and the chloroethyl cation generated by an alternative SN 1 (El) must be too unstable. Because the cleavage substituent is
1-
electron withdrawing,
tiary
ACE-Cl is
132
189).
Olofsonand
of
amines than simple alkyl Hartz have thoroughly
more reactive toward terchloroformates.

studied the
orderas those of VOC-Cl : benzyl; allyl; t.butyl >> s.alkyl > I n. alkyl >> piperidine ring scission.n its reactivity, ACE-Cl
parallels VOC-Cl with the advantage that the conditions required for ACE removal are much milder thus expanding the functionalities allowed in the amine to be dealkylated.
with
191)
the new N-dealkylation process with ACE-Cl (Ref. 68that the selectivities follow the same and shown
scope
Even N-dealkylation of aromatic amines occurscleanly ACE-Cl as it is illustrated in a strigent test by the
conversion
N-phenyl
of N,N-diethyl
aniline
to
1-chloroethyl
N-methyl-
carbamatein 87 % yield (R.ef. 68).Caub\177re and Bachelet sed this methodology while operating without a u solvent for the demethylations as well as for the deethylations
of dialkylamino
benzofurans
in
good yields (Ref.
192).
116
117)))
a Phosgenend derivatives s building a blocks

Olofsonand
of
ACE-CI Plartz have

F
to the N-dealkylation of significant tertiary amines, especially in the field of analgesics and narcotic antagonists alkaloids, for example in a brilliant synthesis of in % overall yield (Ref. Nalbuphine from Oxycodone The scope limitations of ACEoCI as a new reagent and ). for the selective,high-yield of tertiary N-dealkylation amines will be examined in section4-.5of vol.
developednumerous
applications
Tertiary amine
Carbamate
yield
(%)
191
69
H
OX___/N-
Me
O,x__/N-
O C-O CH2CI
96 99 96
2.
Me-N
N-Me
193). For example, N-methylpiperidine 1..5q.of chloromethyl chloroformate e thane (DCE)for 30 min.. After vacuum
(Ref.
volatiles, the distilled
Chloromethyl chloroformate reacts also selectively with tertiary alkyl amines to afford O-chloromethyl carbamatesin yields ranging from N,N-dialkyl to %
O CICH20C-N O
Me, CH2CI ,N- C-O
II
O N-C-O CH2CI
83 99
Me,
N-Et
Me'
Et
Me,
\177
was
in
refluxed with
0
II
(a)
(a): (b)
1,2-dichlorome0 C'OMe
N\177
Me
N- C-O CH2CI
Me
(b)
8:1
ted ter
in
97 %
of the O-chloromethyl carbamate was isolaevaporation
Totest
antitussive
yield. the scope the of Dextromethorphan

in
the morphinan
87
% yield
as depictedin scheme133.
Me
reaction, the over-the-counwas N-demethylated to
\177C'OMe
N
83
o.C.o CH2C
I
Et,
Et3N
\177
Scheme 133
mate.
CICH2.0_C.CI
\177'
o N-C-O CH-CH 3
II I
96
Et
'\177 \177
ReflDuCx\177
'1
r\"le
[\177N-Me
,5h
by chloromethyl chlorofor-
Me OX__/NO,x__/N-
0 CI C-O CH-CH 3
by reaction
84
of R-CHCI-
N-Demethylation
of Dextromethorphan
Table
3-21
.\"
Preparation
of
1-chloroalkyl
carbamates
with OC(=O)CI
tertiary amines.
Some examplesof
through N-dealkylation
table 3-21 (Ref. 127,
193).
1-chloroalkyl carbamatesobtained of tertiary amines are gathered in
carbamatespresenttwo
attacked
shown in
by
The value of 1-chloroethylcarbamatesstarting mateas rials for the synthesis of vinyl carbamates has been already pointed out in section3-2-2-4of this volume. As already discussedin section 3-2-2-3,1-chloroalkyl
scheme134.
which may electrophilic centers differents pathways nucleophiles following
be as
Similar to he caseof reaction with 1-chloroalkyl nates studied in section3-2-2-3,carboxylatesanions

with
carboreact
119)))
1-chloroalkyl
carbamatesto give
alkylation
derivatives
118

through

THF
used in
numerous
a B attack mechanism. This reaction was widely patents on prodrugs.

R Nu 1
25\302\260C
C-N
+ R-CHO + \\R2
A1
A\177
cr
\\
A1
O
\177
II
O
-O\177
O\177
F
\177
Me
+
\177o
\\\177
0.1eq.:80O/o,18h : 97 % 3 h
1
No catalyst Nal
: 60%, 8h 1 '
eq. Nal
CH
0
Nu
C--N
2 A1,
\177
R-CH-O Nu
C-N, O
II
CI
B \177\"\177
Scheme 136 Reaction of N

,\"
(1-chloroethyloxycarbonyl)
piperidine
with sodium
4-
phenoxyphenoxide.
A2\177 \177,
R1 + HN
R2
R-CH-O
C-Nu
Scheme 134 Possible types of nucleophilic attacks to
cI
1-chloroalkyl
Someresults obtained in our laboratoriesfor pesticides screening purposesare gathered in table
3-22.
Time
carbamates.
R
-NR
1R2
Ar-O
Yield
For example this
conceptwas applied to
of novel
(acyloxyalkoxy) carbonyl amines functions in drugs as primary as well as secondary illustrated with the caseof a prodrug from the antibacterial Norfloxacin
in
the synthesis bioreversible moietiesfor
(h)
(%)
scheme135 (Ref. 194). o
He He He He CH2=CH
Cl
-NHe2
Ph-O-Ph-O p.CF3-Ph-O-Ph-O
Ph-O-Ph-O pmCF3-Ph-O-Ph-O
-NHe2
Plorpholino Morpholino -NEt2
o
O
\"\177\"
Ph-OPh-O
THF + Ar-ONa
\177
4 4 4 3 1
90
76
90 83 82
,R1
N
\"\177'\"1
Et
CH3COO
\"
1. 4..] N
mp.
215-7\302\260C
Et
I
0
II
ArO
I
R-CH-O-C-N
R1
0
II
F\177'\177\"COOH O
From reachon
with 1-chloroethyl of Nodloxac\177n chloroformate
\177 O Me
R
g\177\"-\177\"\177/\177'
Nal,
COOH
25 Table 3-22 Reaction of

,\"
eq.
R-CH-O-C-N
\302\260C
1-chloroalkyl
carbamates with sodium phenoxides.
Scheme
135: Preparation
of a prodrug
derived from Norfloxacin.
Sincethe -NR 1R2 group makes center A and B both much lessharder than doesthe ORgroup, we expectsome differences etween the reactivities of 1-chloroalkyl carbab mates and 1-chloroalkyl carbonates.For example the reaction the hard-soft borderline nucleophiles phenoxide protype anions with 1-chloroalkyI-N,N-dilakyl carbamates ceedsselectively through B mechanism to give exclusively instead of acylation as shown in scheme alkylation
scheme137.
CI
opposition to the preceding case,the reaction of phenoxides anions with 1-chloroalkyI-N-monoalkyl carbamates leadsto acylation instead of alkylation as shown in
In
O
II
Ph-O.-Ph-ONa
\177.,
of
CH3-CH-O C-NHCH3
O 65%
\177
O-C-NHCH
136.
Scheme 137 Reaction of sodium

carbamate.
THF, Nal 25\"C, 12h

phenoxy
phenoxide with 1-chloroethyI-N-methyl

121)))
120
a a Phosgenend derivatives s buildinblocks

However,
a as Phosgenendderivatives buildinblocks
More than twenty
carbarnate is
as depictedin scheme138, it
is not certain whether the the acylating agent in such

it
isocyanate or the reaction.In fact, is possible that this reaction

the transient through the group
could proceedthrough a mechanism involving formation of methyl isocyanaterather than normal addition (A1) directly to the carbonyl wed by lossof acetaldehyde. cI
some interest in the design of new prodrugs. The same kind of reactionsoccurswith thiols phenols as shown in scheme140.
has been preparedby
1-alkoxyethyI-N,N-dialkyl this methodology which
carbamates
should have and thio-
follo-
(
./
car5cheme
CI
2
\177
THF +
50\302\260C
S
70 %
O\177N\177.
, 2h
Ar-O
C-NHCH 3
CI
O
\177
THF
Et
Scheme 138 Possible mechanism of the reaction of bamate with phenols.
o
1-chloroethyI-N-methyl
II
+ PhSNa
,
Et
25\"C, 2 h
O\177
o
N
79 %
Et
The study of the reaction of 1-chloroethyI-N-methyl carbamate with phenols was undertaken in the hope that it in might replacethe noxious methyl isocyanate (M.l.C) the preparation of insecticidal N-methyl carbamates. Surprisingly, we found that the reaction of an alcohol can proceed with 1-chloroethyI-N,N-dialkylcarbamates through B mechanism to give alkylation rather than acylation (Ref. This result appearsto be a violation of the HSAB theory. In a typical example, N-(1-chloroethyloxycarbonyl) piperidine was added to a stirred mixture of sodium hydrocarbonate and methanol at The reaction was instantaneous. Solidswere removed by filtration, excess lcoholwas then distilled off and the resulting proa duct was isolated by flash chromatography in 96% yield
Et
140 Reaction
\342\200\242
of thiols with
1-chloroethyI-N,N-dialkyl
carbamates.
According
to
the HSAB theory,
195).
amines react as hard nucleophiles through A 1 attack mechanism with 1-chloroalkyl carbamates affords ureas. to However, the reaction is slower and lesseasy than the reaction of amines with 1-chloroalkyl carbonates and strong nucleophilic amines are generally required to reach
secondaryand
primary
goodyields.
Thus, the reaction has some value for the synthesis known ureas derived from methoxymethyl amine such the herbicide Linuron scheme (Ref.
25\302\260C.
of
as
[see
\177OMe
141] 196).
[Scheme139].
HN..
CI
I
Excess Me-OH O
.\"
O-Me
I
Me
\177
CI---\177.l-\177-O-CH2CI
O
Scheme 141
phenyl) piperidine. Preparation carbamate.
.\"
CI \177-N\177H
\177/\177
93%
Linuron
\177
N'MeOMe
NaHCO 3
25
96%
of the herbicide
from chloromethyI-N(4-chloro-
\302\260C
Scheme 139 Synthesis of N-(1-methoxyethyloxycarbonyl)
122
123)))
a as Phosgenend derivalives buildin\177 blocks I

The
reaction

chloroformate just 1,2,2,2-tetrachloroethyl THF or dioxane without any acid scavenby refluxing ger.Thereaction mixture is easily freed from hydrochloric
in
of secondaryamines
with
imidazole demonstrates the powerful thyloxycarbonyl) nucleofugacity (leaving group efficiency) of the chloroethoxide anion as shown in scheme (Ref.
1-(1-chloroe-
red amine
and
142
Et\"
197).
Ol
acid
by
heating
and evaporation
of
the solvent
generally
gives (I) as pure crystals. Table 3-23 gives some examples of carbamatesobtained by this method. Cl
-\177
CI N\177
[
\177I....\177N-C-O-CH-CH II
2 HN\\
/Et
Et \177\\
C-O-CH-CH 3 O
II
0
+ R'NH 2
CI
THF
Et
\"
CI3C\177O\177CI
Reflux,
.-\177 2
Dioxane
h
CI
\177'\177
O O
\177\" N\"
R1
72-99%
N204 / NaOAc
\177
OI30
(I)
mp.
50\302\260C
78 %
-J
\302\260C
/ bp. : 106 0.2mm

Scheme
II
Et
O
\177. N\"
142 Reaction
In the
mp.: 41
of
1 (1-chloroethyloxycarbonyl)
( Lit.
38-43\302\260C)
CCI4'
C, 0r CI3
\177
R1 NO
R2NH2
\177,\177
O
R2..N.I\177.N.R1H
0\302\260C
(11)
imidazole
with diethylamine.
K2CO3/ H20 THF,

20\302\260C
72-95 %
from (I)
1'40
(111)
courseof our studies dedicatedto the reactivity of 1-chloroalkyl carbamatestoward primary and secondathat the easyto prepare1,2,2,2ry amines, we discovered carbamatesare valuable versatile intermetetrachloroethyl diatesfor the synthesis of N-nitrosoureas (Ref. 198). ureas are an active classof N-(2-Chloroethyl)-N-nitroso antitumor agents, which are usually obtained by nitrosation of the previously prepared urea. Because difficulof ties in achieving regioselectiveitrosation, several authors n
have su\177ested alternatives processes. the Unfortunately, starting materials proposedare either unstable such as carbamoyl azides (Ref. lC)9)or extremely toxic such as the 2-
Scheme 143 Novel
preparation
of N-nitrosoureas.
Entry
R1
Yield
(%)
or mp. bp (\302\260C/mbar)
(\302\260C)
1 2 3
Cl-CH2CH2-
96
72
9c\177
81-2
F-CH2CH2C 2C (L)-HO2-CH H(COOH)-
11.5-20/7
131-3
Table 3-23 1,2,2,2-tetrachloroethylcarbamates (I) prepared.
isocyanate (Ref. Although we have noticed that 1,2,2,2-tetrachloroethyl carbamates (I) do react with amines to give ureas in modest yield, we thought that when the carbamates are (I) nitrosated to (11),the reactivity of the carbonyl should be greatly enhanced and good yiels of N-nitrosoureas (111)
chloroethyl
200).
be obtained.As depictedin scheme143, results the are quite good,the only drawback being that some minor impurities may arisefrom the reaction of the amino compounds with the releasechloral (Ref. 201). The carbamates(I) are easily preparedfrom the requiwould
The 1,2,2,2-tetrachloroethyl carbamates(I) are then with nitrogen tetroxide by a known procedure. The intermediates nitrosocarbamates are obtained as (11) oils and used as are in the next step to afford the expected N-nitrosoureas (111).For example, the antitumor drug Lomustine was preparedin 87 % yield from the carbamate 5ome results obtained by this [(I),entry 1of table method are gathered in table 3-24.
nitrosated
3-23].
124
125)))
a blocks as Phosgenend derivalives building

Entry R1 R2 Yield from
(\177o)

mp.
(\302\260C)
(I)
1 2
3
4 5
.\"
Cl-CH2CH2F-CH2CH2CI-CH2CH2Cl-CH2CH2ClCH2CH2(111)
c-C6H11c-C6H11C6H5HOCH2CH2Et-OOC-CH2-'
prepared
87 72 75
87-8 44-5 78-80

oil oil
9.5 88
of our studies on the synthesis and of 1-chloroalkyl carbamates,and because our group was involved in the chemistry of 1,1-dimethyl hydrazine (UDMH), we have examined the reactionsof 1-chloroalkyl chloroformates with unsymmetrical dialkyl hydrazines.During this work, we discovered unexpectedly a new efficient generatorof the heretoforedifficult to prepare
In
continuation
reactivity
N,N-dimethylamino
Table 3-24 N-Nitrosoureas
(seescheme 143), miscellaneous chemistry of
Some
other
interesting
chloroalkyl carbamateshas been also explored.Thus, as already mentioned, acrolein add its congenersH2C=CRClioare easily converted to the chloroformates H2C= which CRCH(Cl)OC(=O)Cl rearrange in the presence of ZnCl 2 to the allylic isomer ClCH2-CR=CHOC(=O)Cl. We preparedsome carbamatesderived from these chloroformates for testing as agrochemicals. One example using 2-chloroacrolein as starting material is
given in easily
scheme144(Ref. 202).ndustrially, I
in up to
by
2-chloroacrolein is
In a preferredexample, when UDMH in anhydrous THF was added to a solution of 1-chloroethyl chloroformate in THF at the intermediate carbazate(a) was formed. After filtration to remove the UDMH hydrochloride, we accomplished cyclisation to (b)just by refluxing the a THF solution for 1 h..The resulting hygroscopic salt (b)
10-20\302\260C,
carbalkoxy aminimides were prepared from UDMH and 1-chloroalkyl chloroformates in three steps [Scheme Upon heating, these aminimides give high This yields of Me2N-N=C=O. unusual isocyanate dimerizes or can be trapped in the presenceof a nucleophile.
bered ring
isocyanate Thus, (Ref.203).
five
men-
145].
made
97%yield
by adding chlorine
to aqueous
acrolein followed
steam
distillation
of the
resulting mixture.
CI
0
+
COCI 2
\177
BTBAC
overall yield. In solid form, precipited immediately in is stable undefinitely at room temperature. The cyclic (b) aminimide (c) was then easily preparedfrom (b) by treatment with a resin supported base in high yield. The three stepsof the synthesis are depictedin scheme
71%
145.
/N
..OCCI
CI
ZnCI
eq. 2 , 0.01
5h
Me
Me, Me
U
91%distilled / bp 71-82 20 mm
(31
100\302\260C,
NH
2 +
DM H
0 Me 0 ACE-Cl
\177/\177
CI
----\177.CI
10-20\302\260C
THF
Me,
N
NH
Me,
NH2.HCI
Me/
\177/
(a)
Me
0
.\177
\177-0
Me
CI
o
Cl
Me,
N
0
NH
THE
O'\177NH Reflux,
\177--\177OCCl
/ bp, 94-7 22 mm Z:E
H 63 % distilled
Me Me
N
mp.
103\302\260C
Me
\1770
Me\177/
\177 Me\177e,\177,
CIMe
Amberlite IRA-4OO(OH
0
0/.\177. N-
0
Me
N
m\177.
5\177 \177C
\177
lh
Me/\177N'
15:1
.\"
(b)
Me +
Me Me Me +
\177
0
for testing.
Scheme 144 Example of 3\177hloroalkenyl carbamate synthesis
Scheme 145 New cyclic aminimide
71%from (a) dec. mp :

145-50\302\260C
(c)
91%from (b) mp.
170-2\302\260C
from UDMH and ACE-CI,
126
127)))
a b a Phosgenend derivatives s building locks

the
little attention in Carbalkoxy aminimides have received literature and to our knowledge, cyclic carbalkoxy ami-

Entry
:Nu-
beforebeen synthesized. a Dialkylamino isocyanates re known transient intermediates and, in the absence of other reagents,have been shown to dimerize. When the cyclic aminimide (c)was heated at under vacuum (0.3 ram) for 3 h, (d) was obtained in 89% yield. At higher temperature (d) was formed but rearranged to (e)as depictedin scheme146. The chemistry of aminimides has been reviewed elsewhere (Ref. 204, 205)and the chemistry of dimethyl amino isocyanate, repared in the form of dimer (d) through a p
nimides have never
130\302\260C
Nu-COINH-NMe 2 Yield (%)
1 2
Et-O-
87
Ph-CH2-N(He)-
89 95
O S-Me = Me2N-C-C N-OII I
4 5
.,\177\"--.\177
s Me -N
N/\177--
74 76
carbal-
\177]\177...
EtO2C-CH2-NH-
phosphoramide synthesis,
studied
(206).
Table Preparation koxy aminimide (c) with
3-25
a nucleophile
of UDMH derivatives through reaction of cyclic

:Nu-H.
o
Me\177
N=C=O
+ CH3CHO
Me Me +
(\321\236)
130\302\260C/003mm
Me'
or refluxing
in acetonitrile
....
+ Me ,
Me\177
Me
N N
o\177-.\177o 190o\"c,o\177.\177o ' 5 min 89%or 100% (e)

(d)
MeZ
N
\"
Me
N-
carbonates as
acylatin\177
/ Chloroalkyl
333
Me
Scheme 146 Thermal decomposition of the cyclic

N,N-dimethyl
Me 92% ; bp,
\177N
Me
agents for the synthesisof

(c) to give
The reaction of secondaryand primary amines with carbonatesto afford carbamatesin high yield has been already tackled in term of mechanism in section 3-2-2-3(Ref. 64, 107).
chloroalkyl
1-
66,105, 106,
100\302\260C
/ 0,06mm
amin/de
carbamates
and
carbalkoxy
amino isocyanate.
liocarbamates
At the beginning, while studying the synthetic potential of 1-chloroethyl ethyl carbonate,we found that it readily reactswith amines at the carbonyl function to give the corresponding ethyl carbamatesin good to excellent yields. We thought therefore that 1,2,2,2-tetrachloroethyl tertbutyl
Our method representsa simple, rapid and high yield This isocyanate. interespreparation of N,N-dimethylamino intermediate has been the subject of several publicating
tions and the synthesis of a wide variety a carbazates, nd other moleculesontaining c heterocycles,
valuable
carbonate (I) (codenumber CN 916)should be a o reagent for the Boc-protectionf amino acids 66, 07). [Scheme147] (Ref. 2 (I) was easily preparedin goodyield from 1,2,2,2-tetrachloroformate
In
is useful for
of a
hydrazine group. We have preparedseveral carbazatesand semicarbazides by heating the cyclic carbalkoxyaminimide (c) and just the nucleophile (:Null) for 1 h in refluxing 1,2-dichloroe-
thane. Some examples are given 128
in
table
3-25.
and tert-butanol by a simple a typical example, pyridine (1 eq.)was slowprocedure. solution of t.butyl alcohol and ly added to a cooled chloroformate (1 eq. of each). 1,2,2,2-tetrachloroethyl After stirring for 4 h at washing with water and evaof the solvent and recrystallization from hexane, poration (I) was obtained in 87% yield (mp. chloroethyl
(0\302\260C) 20\302\260C, 70\302\260C). 129)))
a b as Phosgenend derivalives building locks

We
amino
with
a as Phosgenend derivalives building locks b

t
discovered (I) satisfactorily reactswith various that acidsin standard conditions.The reaction mixture is
and byproducts crystallisation
by extraction
freed from excess reagent

ether and
conventional extraction
the Boc-amino and
acidsare readily obtained by

pr-ocedu,e\177
according to scheme147. O
II
CI
I
R
I
O-C-OCH-CCI H2N CH-COOH20oc 3 +

0)
78
Dioxane
/ H20 / Et3N
.-\177
o
- 91%Yield --t
O-C-NH-CH-COOH + CI3C-CHO of amino acids by 1,2,2,2-tetrachloroethyl

Entry
The crystalline 1,2,2,2-tetrachloroethyl fluorenyl methyl carbonateobtained in 98% yield (mp. from 1,2,2,2-tetraethyl chloroformate and fluorene methanol proved to be suitable for the preparation of Fmocamlnu acids good to excellent yields (Ref, The reaction was also performed with various types of amines using different kinds of 1-chloroalkyl carbonates (Ref. 64) and was proved to be quite general exceptwith weakly nucleophilic amines. Someexamplesof carbamates obtained by the reaction of 1-chloroethyl carbonateswith primary and secondaryamines are given in table 3-27.
98-100\302\260C)
iI\177 \302\2514).
Scheme 147 tert-Butoxycarbonylation - tert-butyl carbonate
R1
Yield
mp
(\302\260C)
(1).
(%)
1
bp.
(\302\260C/ram)
useful in the case of Reagent (I) proved to be especially amino acids as examplified by the hydroxy unprotected and table synthesis of Boc-L-Serine Boc-L-Tyrosine [.See The 1-chloroethyl congenerof (I), the 1-chloroethyltert-butyl
Ph-CH Ph-CH
3-26].
3 4 5
carbonate(11)which is a
mm), was
found
medium
boiling liquid
to give unsatisfactory (bp. becauseit is much lessreactive than (I), and also results, becauseof the formation of acetaldehyde its conseand quent reaction with the starting amino compound. Some examples of preparation of N-Boc-amino acids with (I) are shown in table
88\302\260C/20
Ph-CH
/
Et
-(CH2)5H H
Ph-CH2-
88
84
74
bp
bp bp
95/18
22-
HO-CH2CH2He
\177O\177
79
175/0.1 170/0.5 rap. 62-3 mp. 148
-(CH2)2-O-(CH2)2-
84 0
bp. 140/1 mp. 49.5
CI
O /
HN, R
3-26.
(\302\260C)
1 CH3-CH-O-C-O-R +
--\177,.
R\177-O-C--N,
R3
Table 3-27 Carbamates prepared

.\"
from
1-chloroethyl
carbonates.
Amino acid
Yield
of
P1elting point
[cz]20D
Imidazole
butyl
N-Boc-AA (%)
Gly
L-AIa L-Phe
86 90
79
L-Pro
L-Tyr
L-Asp L-Ser
Table butyl
91 82 60 78
.\"
85-8 80-I 85-87 132-3 206 (DCHA salt)
alsoreactswith 1,2,2,2-tetrachloroethyl-tertcarbonate(I) or with 1-chloroethyl-tert-butyl carboscheme148.

derivative
in _50
117-9
139-40
acids using
-24,c 2.1AcOH EtOH +28,c 1.5 AcOH -60,c 2.0 MeOH +32,c 1.8 c 1.0eOH H -5,
+8, c
nate (II) to give its tert-butyloxycarbonyl and % yield respectively as shown in
86
O-C-O-CH-R
t
CIi
HN/\177N
2.8 HeOH
(I)
3-26 Preparation
carbonate (I).
(11) R
of N-Boc-amino
1,2,2,2-tetrochloroethyl-tert-
Scheme 148
::
= CCl 3
CH3
0'
With:
(11)
O\177
N,,\177N
K2CO3/H20
5\"10\302\260C
rap.
47\302\260C
(I) 50%
86%
Preparation
of 8oc-imidazole.
131)))
130
a Phosgenend derivatives s buildinblocks a

The application of the above method to the syntheses of insecticidescarbamates Carbofuran (entry 4, table 3-2T) and Aldicarbe was briefly studied.Thus, Carbofuran was readily obtained in 79% yield from 1-chloroethyl benzofuranyl carbonate which was itself obtained in 89% yield from the corresponding hydroxy benzofuran. The method was also successfully applied to the reaction of 1-chloroethyl-S-ethyl thiocarbonate to give thiocarbamates,for example the herbicide Molinate as depictedin

/\177
H2
\177
Cl\177/
CI
,,-\"\177
NO 2
\177 C' \177 '/\177NHOH

\1777 CI
CH3NCO
\342\200\242
\177,-
Pt/C
poisoned
O
C,
CI
O
COCI2
},-
CI\177/\177/
N\177'\177NMe
\177N-C-NHMe OH
\"
.\"
or MeOCOCI
CI
\177
M\177th\177zol\177
scheme149.
CI
Scheme 150 Classical synthesis of the herbicide Methazole.
O
Et-SH
-\177
CI
80% bp :
O
78\302\260C
CH3-CH-O C-CI +
/
HN\\
\177
CH3-CH-O C-S-Et
/ 20mm
\177
r/\177
\\ tl
C-S-Et
/'\177
70%
bp.
141\"C/13 mm
Scheme 149 New
preparation
of the herbicide
Molinate.
laboratories,the reaction of phosgene with carbamateby an improvement of the procedure described in the literature (Ref. 208) afforded methyl carbamate (I) in high N-chlorocarbonyI-N-methyl of yield. The one-potcondensation the intermediate (I) led to Methazole in excellentield as depictedin scheme y For safety reasons,we thoroughly studied the thermal of the intermediate (I). e found that it decomW stability posesto methyl isocyanateon heating, very slowly when in presence of a pure, more rapidly and quantitatively to the mechanism depicted scheme in nucleophile, according
In
our
methyl
N-methyl
151.
152.
o
II
o
COCl 2
Selected solvent
\177\"
\177--
CI
4 Reaction of phosgene and its deriva rives with

\177 \177
As part alternatives
methyl
(arbamates, ureasand amides
lopment derivatives
In
of our program concerning the study of safe to the handle of the extremely hazardous isocyanate (MIC), we were interested in the deveof new routes to 3,5-dioxo-l,2,3-oxadiazolidine
which
MeNH-C OMe +
Me
Pyridine
60\302\260C,
2h 93 %
(I)
bp.
)/OMe
/ 13mm
85\302\260C
are
valuable
as pharmaceuticals
and
(I)
agrochemicals.
example, we developeda new synthetic strategy that doesnot use MIC for the preparation of the herbicide Methazole.Methazole was classically made the reaction of MIC with through 3,4-dichlorophenyl followed by treatment with methyl chlorohydroxylamine
typical
CI\177NH-OH 2)Heating\" IC'\177?-C'I\177 / OH Me

\"C-OMe\177
Ci
(\")
\177
\177
CI
.J
formate and cyclisation
as shown
in
scheme1.50.
of Methozole \177ithout
methyl isocyonote.
132
133)))
a as b Phossene nd derivatives buildin8 locks
Me
O\177CICI
/\177
--\177,-Me-N=C=O+ MeCI + CO 2
of methyI-N{hlorocarbonyI-N-methyl
carbemate
Heat
,\177
SiMe3
O...\177/N-
2 -\177
\"
SCI
\177
O\177
\177N-s_cI
\177F\"
Me3SiCI
O O
II
O \177-O --\177\"\177 Me /-CH2CI2 ,

\177le\177
(IV)
(v)
-',
O-C-N
II
Pyridine
Scheme
152 Thermal
instability
(I).
O
MeO-CC-NHMe
II
o Me
\"S
N,
Horeover,I) exhibits a high level of toxidty. In orderto ( these problems, we investigated other routes and a novel and safer route to Hethazole, tars from the interesting intermediate ting (111)as shown in scheme
over\321\236ome dis\321\236overed
Me sQ2 \177 MeO-CC--N-S-CI
0
Me
O-C-NH
O
II
(VI)
153.
CH3
COCI
I
MeN
(\177)
C-OMe
MeOH
0
Me - N
Scheme 154 Syntheses
O
of new sulfenyl
II
N O-C-N--S C-C-OMe Me Me O O
tt
Carbofurans.
0
C-OMe
.C-OMe 'C-OMe
(111)
MeNH
....
NaH
---
-- T
_
O
(111)
II
MeOCOCI
//
The reaction of phosgenewith

known.
in high
mm
Low
15 CI\177NHOH h , CI
Scheme 153
-Cat. H+
\177 60\302\260C
bp, 86
mp. stable solid

\302\260C/8
Phosgenereacts with
substituted tetrasubstituted
ureas is well ureas as a
LD5o(Rat)
:2850mg / kg
92 %
Methazole
Novel
and safe preparation
of Methazole.
be modified by other acylating chloroformates. In the courseof our attempts dedicated to the search of new pesticides,we were interested in the design of proinsecticides, especially procarbamateswhich are less toxic to mammalians than the parent carbamates. N-Acylor N-sulfenyI-N-methyl carbamatesderived from N-methyl Carbofuran or Aldicarbe are quite effective insecticides and are often equal to superior to their parent compound against insects.
collaboration with SIPCAM (Italia) we studied the o synthesis and activity as insecticides f two new types of Carbofuran derivatives (V) et (VI) depictedin scheme
In
Also, carbamatescan agents than phosgeneand
chlorides agent to afford chloroformamidinium This topic will be discussed volume in yields. In the caseof ureas,phosgeneis attacked N,N'-dialkyl both oxygen and nitrogen atoms to give a mixture of by chloroformamidinium chlorides (A) (O-acylation of the and allophanoyl chlorides (B) (N-acylation) as ureas) shown in scheme (Ref. ). chlorinating
2.
155
211
\177-
CA)
+
I
CI4-
O
RNH-C-NHR
+
O-Acylation
RNH--=C--=NHR
CO 2
COCI 2
.\177 N-Acylation (B)
Q'XC-CI
\177
R-N'
+ HCI
Scheme 155 Phosgenation pathways of N,N'-dialkyl
\177,C-NHR
ureas.
(Ref. 134
209, 210).
154
The distribution of O-acylation and N-acylation can be controlled by the reaction conditions, but structural features of the N,N'-dialkyl ureas seemto be the dominant
slightly
factors.
135)))

Acylation reaction which affords chloroformamidinium chloride is of great interest for the commercial synthesis of carbodiimides, especially dicyclohexylcarbodiimide (seevolu-

o
II
MeNH--C-NHMe
let?orlOn
\177
200-250\302\260C
2MeN=C=O
me
2).
In
+
5\177henle
2 Ph-OH
w\177th
the
case of
separation of
the insolubility stituted
low molecular weight subtituents, the and (B) is very easy becauseof products (A)
158
Pmparc/tson
of MIC through
Of
dlpl'lenyl
ca/bonate
156 presentstwo
ureas.
of the
salt (A) in organic solvents. Scheme of examples phosgenation of N,N'-disub-
COCI=
II
O\\xc_
\177
CI
MeNH-C-NHMe
DCE
1
Me--N
+ CI+ MeNH--=C--=NHMe
CI
h, 20\"C 71%
-NHMe
O
mp.
36\302\260C
insoluble in ether
\177
HN
DCE
+
y O
NH
COCI 2
\177
\177
l h
80\"C
Y (C) O
HN
N
\177[\177
CI
86%
mp.
155-7\302\260C
Scheme 156
.\"
Examples
of phosgenation
of N,N'-disubstituted
ureas.
that in this process,one mole of pheis releasedfor one mole of HIC produced. We studied at a laboratory scale a similar route of synthesis starting from phenyl chloroformate instead of carbonate(Ref. The new process resents diphenyl p the advantage that only half a mole of phenol is formed per mole of MIC. Thus, phenyl chloroformate was reactedwith dimethyl urea in toluene at reflux to give methyl N-phenoxycarbonylN-methyl urea (D)in 95 % yield. No addedbasewas required. The intermediate (D) decomposedon heating at in presenceof a selected basic catalyst to afford
It is noteworthy
nol
213).
180\302\260C
HIC in quantitative
N-Chlorocarbonyl-2-imidazolidone (C) is for instance used in the preparation of pharmaceuticals such as the antibiotic Azlocillin
yield
[Scheme159].
[Scheme157].
ococl
+
o
II
Toluene
\177
\177
N
Phenylglycine
\177I...CI
MeNH-C-NHMe
Reflux
Me-
NO\177_
0__\177
NH
(C)
HNy O O
O O
COOH
0 \177 Ph
Me:B
Catalyst
\177_
),-0
Me
(D)
95%
mp.
98\"C
2 Me-N=C=O + PhOH
Coupling
H2N
agent
\177,,
S COOH
H\177/NA
N\177
N\177IC 0
Scheme 159 Novel
.\"
180\302\260C
preparation
of MIC
from phenyl
chloroformate.
COOH
of the antibiotic Azlocillin,
It is well known
Scheme 157
Preparation
that oxalyl
chloride
reacts with
non-
order to produce methyl isocyanate in good safety's an conditions, Bayer A.-G.has developed industrial process based the reaction of diphenyl carbonate with N,N'-climethyl on
In
urea at high temperature
according
to scheme
158 212). (Ref.
amides to afford acyl isocyanatesn high yields i (Ref. 214).In contrast, phosgeneacts as a dehydrating This interagent to give nitriles as shown in scheme esting reaction, its mechanism and applications will be
substituted
160.
discussed volume in
2.
136
137)))
a as Phosgenend derivalives buildinblocks 0 cl-c-c-cl

II II

F
Et3N
o
II
o
R_C_NH
\177
R--C-N=C=O +
CO +
HCI
\177-'\177C.NH 2 + Me3SiCI
\177---\177
\177
Reflux
\177
O
F
II
F
\177-'\177C
\"\177-\177
- 'SiMe3
N
IOI
SiMe3
mm
65 % dist.
bp. 68\302\260C/0.15
CI--C-CI \177
O
Scheme \1770
.\"
R--C\177_\177N
CO 2
2 HCI
omides.
Neat
\177,
II
-N=C=O
F
+ Me3SiCI ( 100% recovery)
\177eoctions
of oxalyl chloride and phosgene with
primor\177
COCI 2 78\302\260C
O
100\302\260C
trichloro acetyl Acyl isocyanates, specially e (TAI),
isocyanate
Scheme 161 Novel

lyl)-2,6-difluoro
2,6-difluoro benzoyl isocyanate (DFBI)andmethacryloyl isocyanate (HAl) are very valuable intermediates and for pharmaceuticals, agrochemicals, plastics,adhesives The structures, physical data and types of applicoatings. cations of these three major acyl isocyanates re given in a
table
Name
benzamide.
54% dist. ; bp. mm / 0.25 of DFBI by phosgenation of N,N-bis(trimethylsipreparation

DFBI
3-28.
Structure
Data
Applications Pharmaceuticals antibiotics Cefuroxime
chlorideswith sodium cyanates.We found that special catalysts and solvants must be used for receiving satisfactory yields as depictedin scheme162 (Ref. 216, 217).
: prep. of
F F
It is noteworthy that, in the course of our studies on the preparation of acylisocyanates, put some we improvements to the known procedureby condensation of aroyl
CI3C_C_NCO TAI
bp : 80\302\260C/27 mm
O
CH3
I
II
> LDso 20OOmg
such as sodium
-CI
F
+ NaOCN
\177,
HAl
bp. 122 H2C=C-C-NCO (Atm. press.)

\302\260C
resins Vinyl functionalized for adhesives, coatings, fibers, electronic, medical materials
SRCI4
180\302\260C,
0.05 eq.
2h
F
-N=C=O
O
F
II
etc.
Scheme 162
70% dist. bp.

83-8\302\260C
/ 10mm
Preparation
of DfBI
from
2,6-difluoro benzoyl
chloride.
Synthesis of difluoro
bp. 80\302\260C/0.3
mm
-benzoylureas (numerous
as insecticides
patents)
\177-\177-NCO
Table
3-28 Valuable
sented in volume 2 in the chapter dedicatedto mistry of acid chlorides.
The scopeand
limitations
of
this
w process ill be pre-
the
che-
industrial acyl isocyanates.
The demonstrated utility of these high-reactive isocyanates prompted us to search for a phosgenation process more economicalthan the oxalyl chloride route. Our in attempts succeeded the development at a laboratory scaleof a method basedon the reaction of phosgenewith N,N-disilyl amides as depictedin scheme (Ref. 21_5).
insecticides effective against larvae, especially from lepiThe doptera (Ref. 218). synthesis is depictedin scheme
collaboration with Ishihara During our continuous Kaisha Ltd, we prepared 2-chloronicotinoyl Sangyo isocyanate and patented the synthesis of interesting new
161
163.
138
139)))
a a blocks Phosgenend derivatives s building

CI \177/='\177--C-NCO
a as Phosgenend derivatives building
blocks]
CI
+ H2N
CF3
('\177'00
In
Ci
N'\321\236'\177
c
\177, 68\302\260/\302\260
3-3-5
R,a\321\236tion
of
with
i p. Toluene sulfonyl isocyanate (PTSI)s an
hlos\177ene
Yield
fmamides : preparation
el sulfonyl
for -
which highly-reactive isocyanate such as applications
interesting has found several valuable
iso\177yanates
agent for mastic and filler resins, especially trade ; building chemical intermediate for the synthesis of hypoglycemic pharmaceuticals, for example Tolbutamide or Gliclazide :
dehydrating
of a new
N-pyridylcarbonyI-N\177p\177enyl
urea
as insecticide
0
key starting
the
generally
a\177ts
reactionswith N-substituded amides, phosgene as a \177hlorinating agent yo give Vilsmeier

\177ase
material
for the
preparation
of resinsfor nail
salts (see volume 2).As in the of primary amides, the use of N-silyl amides is often required to observeN-a\177ylation in reasonable yields. The preparation of 4-ethyl-2,3-dioxo-l-piperazine\177arbonyl provides with a good illustration of a commerdal pro\177ess through a silylation (Ref. We studied
\320\210hloride
lacquers,to replaceconventional arylsulfonamido formalformol (Ref. 220). dehyde resins which releasecarcinogenic The synthesis of p. toluene sulfonyl isocyanate by phosgenation of p.toluenesulfonamide in presenceof an alkyl i isocyanate as the catalyst, generally n-butyl isocyanate,s well described several patents and publications in [Scheme
in s\177heme thoroughly the pro\177ess depi\320\210ted brought some improvements. This \177arbamoyl \320\210hloride is used for the preparation of antibiotics as Piperadllin
su\320\210h
219). 164, and
165].
Chlorobenzene
Me---\177SO2NH
Scheme
2 +
COcI 2
BUNCO
\177,
Me--\177SO2NCO
rap. bp.
or Cefoperazone.
Et--N
PT$1
2\302\260C
270\302\260C
Dioxane
\177
NH
+ Me3SiCI
Et3N
165 Preparation
In
Et--N
SiMe 3
of p.toluene sulfonyl isocyanate (PTSI).
o
COCI 2
and
to
orderto economically improve the industrial process avoid side reaction such as the formation of tosyl
the mechanism that contrary
+ Me3SiCI
we thoroughly studied phosgenation. We demonstrated

chloride,
of to
the the
to be recycled
Piperacillin
Et_N\177N\177O\177
in the literature, the sulfonyl urea (11)is true intermediate in the reaction [Scheme only Our trials showedthat the phosgenation proceeds in a first stagethrough the readily and quantitative formation of the insoluble symmetrical sulfonyl urea (I) which reacts
impressions given
not
the
100].
Scheme 164 Phosgenation

bio tic Piperacillin.
COOH
of dioxo piperazine
and structure of the derived
anti-
with butyl isocyanateto afford sulfonyl urea (11)and PTSI. The intermediate (11) reacts then, more slowly, with phosgeneto give PTSI and regeneratesbutyl isocyanate. The assumedmechanism is depictedin scheme106 (Ref.
221).
140
141)))

The formation of tosyl chloride was shown to of PTSIitself, thus affording through phosgenation which polymerizes. carbonyl isocyanate 1)
2 Me---\177SO2NH
+

34
proceed chloro-
formation reactions
Rin\177
COCI 2
\177
H-\177I
This chapter usesan organization based the nature on of the two hetero atoms involved in the closing of the ring by the carbonyl group : O<->O O<->N N<->N ; N<->S. ; ;
Me---\177SO2N
2) (I) + Bu-NCO
\177
Me o HSO2-\177 O)
-N
34 /
Cyclisation
between two oxygen atoms

(II)
Although ethylene carbonate can be easily made by phosgenation of ethylene glycol, the only industrial process is the carbonatation of ethylene oxide [Scheme
167].
PTSI PTSI +
+
HO-CH2CH2-OH +
COcI 2
- 2HCl
3)
(11)
OOOi 2
\177
+
Bu-NCO
2 HCI
\177--70
002
\177
Catalyst
/\177
oyo O
Sidereaction :
Scheme 167
Pressure of ethylene carbonate.
Preparation
Me---\177--SO2NCO
COCI 2
\177 Me---\177--SO2-CI
+
value in
in
CI-C-NCO
o
II
section3-2-2-I the
which
However, the phosgenation processhas much more lesssimple products.We previously have treated
affords reaction of excess phosgenewith a monochloroformate containing a
glycerol
five
Scheme 166 Mechanism

.\"
fo the catalysed
synthesis of PT51.
membered cyclic carbonatefunction. The phosgenation of catechols of high interest, becaui se the resulting o-phenylene carbonateis the key starting material for the preparation of the insecticide Propoxur as
shown in
OH + OH
scheme168.
Toluene
/ H20
\177-
COCI2
0-
NaOH
5\302\260C
\177==
85%
mp.
120\302\260C \177
O
Me
\177
MeNH 2
\177,\177,,\177O-C-NH
\177,\177O-C-NHMe \177
\"OH
\1771\"\1770---// insecticide Propoxur.
Scheme 168
Preparation
of the
142
143)))

of 2,3-butanediol presentsa high potenpharmaceutical field. The cyclic carbonate chlorinated to give a thus obtained can be photochemically in carbonate (I) as depicted scheme vinylene (Ref. 222).
Phosgenation
tial value in the

DCE
+ OX\177O H
COCl 2
N,N,-Dimethyl aniline
169
HO
W
hv
DCE
+
COCI 2
20\302\260C
W
O,,,\177O
6%
bp.
120\302\260C
/ 12mm
\"\177/
\177
OH
O...,/O
.\"
II O
72% mp.
79-80\302\260C
\177 63%
\177 \177
Scheme 171 Phosgenation
ofacetoin.
0\1770
Scheme 169
- HCI
160\302\260C
(\177)
%0 o
from
bp.
130\302\260C/
6 mm
diol.
Preparation
of vinylene
carbonate derived
2,3-butane
The substituted the
vinylene
carbonate(I) can be used for
King Jr reporteda facile synthesis of chlorinated dioxolanonesby a simple, one-pot,direct addition of phosgene to 1,2-diones 225). the reaction of 2,3-butane Thus, (Ref. dione with phosgenein the presenceof pyridine affords in trans-4,5-dichloro-4,5-dimethyl-l,3-dioxolane-2-one
preparation through chlorination and dehydrochlorination of the intermediate (11) which is the key reagent for the production of Lenampicillin [.Scheme
170].
82% yield as shown
in
scheme172.
CH2CI2
CICH2x\177CH3
(\177l)
COcI 2
CI
iPyridine in catalytic am.
\177
OyO
O
%0 o
HCI
Me
\177
0\177.--
NH
/\177'
k\177 S,k\177
\\
carbonate
Lenampicillin (Antibiotic)
\177
Meb'.\177 /CI
O..\177O
82 %
mp.
88\302\260C
Scheme 172 Phosgenation Scheme 170 Substituted
of2,3-butane
dione. formation of unusual ther-
vinylene
for the modification
of antibiotics.
mal
In
an
bromomethyl
me 169 be obtained by phosgenation can depictedin scheme171 (Ref.224).
a synthesis of Cefcanel, new cephalosporin from Kyoto Yakuhin and Astra (Ref. It is noteworthy that the vinylene carbonate in sche(I)
(11) is
also used in the
obscurepaper, Pews reportedthe ethylene carbonate through an
223).
of acetoinas
shown in
rearrangement of 2,3-dibromopropyl ethyl carbonate We studied the scopeand limitations of this (Ref. reaction and defined the best conditions of the process s a
226).
scheme173.
144
145)))
blocks a a Phosgenend derivatives s building

a)
Br or
\177
a as Phosgenend derivatives buildinglocks b

2 CI2 , hv -2
HCl
(111)
200\302\260C,
without
Br
catalyst
\177
\177
CI
\177_\177,.c
cI
/__\177CI
O
B:
b)
150\302\260C
presence a selectedatalyst c
of
in the
v\177
/ Et
\177.
O-----\177
%0 o
O
O.\177O
%0+ O
(\177v)
%o O
0
Decomposition
Q\321\207
of (IV)
Br
---\177
- EtBr
Scheme 173.'Unusual
O,.\177O
a) 88%
b) 95%
Cl
O route access
to substituted ethylene carbonate.

\177
derivatives of ethylene carbonateitself very interesting and valuable compounds. When ethylene carbonate is monochlorinated, Chlorinated
are
the
Scheme 175
CICH2-C-CI + CO 2
of pure dichloro ethylene carbonate
key
(111).
Preparation
was claimed as the (111)
for the
carbonate thus obtained is the starting chloroethylene material for the synthesis of vinylene carbonatewhich is
to yield high-molecular polymerization or and copolymers in Diels-Alder cycloadweight polymers ditions [Scheme174] (Ref. used
in
a explosives s shown
Cl
in
scheme176 (Ref. 228).

02N\"
\177
synthesis
of
novel
radical
,\177/Cl
(111)
227).
oyO O
, H2C
.NHNO 2 NHNO2
N/\177 N
-NO2
\177
CI \177 CI2 , hv
%O O
\177 ----\177HCI
Ether
Et3N
\177
\177 5h
Scheme 176
Vinylene
oyO O
ethylene carbonate.
Novel explosive
from dichlora
Scheme 174
%O O
Reflux,
%O O
carbonate mp. bp. 162

22\302\260C
\302\260C
Preparation
of vinylene carbonate.
When ethylene carbonateis partly chlorinated, the two dichlorinated products (111)and (IV) formed cannot be : mixture of (111) (IV) separatedby distillation and an
85:15
only
is available commercially.
We
\177
of ethylene carbonate carbonate (V) in high yield treated with a trace of a nucleo(Ref. 229). to oxalyl chloride and phosphile, it cleaves quantitatively gene[Scheme177] (Ref. 230). This decomposition today's standard is f processor the manufacture of oxalyl chloride.
affords tetrachloroethylene When (V) is
Photochemical perchlorination
to that discovered (IV) cleanly decomposes chloraThis chloride anion cetyl chloride in presenceof naked method which destroys preferentially (IV) allows to recover fractional distillation (111)in 92 % yield by subsequent 1 [.Scheme 75].
\177.
146
147)))

CI CI
mm Neat
\177.
o
/\177k
4 CI2
hv
CI_
m
-4
\177
i i --u'Y\302\260
CI CI
_Ci
mp.bp. : d25:1.71
17\302\260C
78-80\302\260C/35
2 R-COOH +CI.\177]\177oCI
O\177
100-150\302\260C
0
Scheme 179
4-CO 002+ 2 4-
2 RCOCI
HCI
No catalyst
CI CI
Cl-\177_\177CI
O'-,]i/\302\260
Catalyst
\"
95-100%
ofacid chlorides
using tetrachloreethylene
Preparation
carbonate.
cr\"
\177-
+ COCl 2
CI
O
carbonate and its decomposition
Scheme 177 Preparation of tetrachloroethylene to oxalyl chloride and phosgene. While studying the
Oxalyl chloride
of catalyzed decomposition tetraonium salts, we observed chloroethylene carbonate(V) by chloride. Since(V) the formation of a little trichloroacetyl centers : the carbonyl present three reactive electrophilic linked with two chlorine group and the two carbon both atoms, it can be attacked following two different pathways
The main issue under discussion is how this reaction can work without any catalyst. In contrast to oxalyl chloride, phosgenerequires a catalyst to convert carboxylic acid to acid chloride.Thus, the above reaction would give acid chloride in no more than 50% yield. we studied the describeddechlorination Furthermore, of tetrachloroethylene carbonate(V) to dichlorovinylene
with zinc (Ref. (Vl) is an interesting intermediate which as a cyclophile permits simultaneous introduction of masked o,-hydroxy keto and o,-diketo functions respectively into the cycloadducts (Ref. One
carbonate(Vl)
229).
as diagrammed
in
scheme178.
Cl
example is given
in
scheme180.
232).
O O
I
O.3.O
\177)
CI
CI
Cl'd/\177 OyO
O
CI
Ether Zn(Cu)(DMF)
\177-
85%dist.
Cl,\177=.\177CI
\"\177-\C,-")
C,\177
,\\ \",
If
attack to the
Reflux,
10h
(Vl)
O O
YO
H20
mp. bp.
19.5\302\260C
147\302\260C
C012
CI
=
Scheme 178 Possible types of nucleophific
nate by
CO2
\177H2
Acetone
CI.
O
attacks to tetrachloroethylene carbo-
CH2
+ (Vl) hv
=
Room temp.
O \177 \177 [\177OOH

\177O\177%O
80%
OH
Scheme 180 Synthesis and example

.\"
of use of dichlorovinylene
carbonate.
We thought that if a catalyst for directing cleanly the reaction either to the formation of oxalyl chloride or to trichloroacetyl chloride could be devised,the ready availability of (V) would seemto make this compound a very attactive intermediate. This work is currently under investigation. carbonate Also, we discoveredthat tetrachloroethylene can be used as a highly effective chlorinating agent for acid 179 in ). chlorides preparation as depicted scheme (Ref.
Phosgenation of hydroxamic acidsaffords nitrile carbonates which has been suugested as isocyanates recursors p
(Ref.
231
One demonstrative exampleapplied to the synthesis of is isopropenyl isocyanate given in scheme181 (Ref. 234). Note that the use of a catalyst such as ferric salts permits to lower the required decomposition temperature.
]49)))
233).
148
Phosgene
blocks as and derivatives building
a as Phosgenend derivatives building locks b

reactseasily with amines containing a hydroxyl Phosgene in 2 or-3 position to afford oxazolidones (cyclic five membered carbamates) oxazinones or (cyclic six membered carbamates)respectively. The preparation of 3-H-benzoxazol-2-one o-amifrom nophenol and urea is well known but the reaction is accompanied by the formation of tars and other side reactions. In contrast, phosgenereacts cleanly with o-aminophenol. We have deviseda simple process without any acid scain venger which affords pure benzoxazolone excellentield y as depictedin scheme183 (Ref. 236).
function Chlorobenzene
H
\177-
+ ==k
NH2OH.\1772SO\177
coOMe
CH2C\1772
\177\177
H2
NaOH
NHOH
Cydisation between
oxygen and nitrogen atoms
\177
H20 /
COC\1772
=\177
'\177N\177
85 % yield
bp. rap.
38-40\302\260C
34\302\260C
dist.
/
0.1mm
O,..,/O
O
NaOH
pH
: 4-6
\177
\177
:
of isopropenyl phosgenation
N=C=O
O
scheme
181 Preparation
isocyanate.
\177'\177NH2 \177
COCI2
100\302\260C
-OH
,4h
[\177 O \177=
96% yield
rap.
139\302\260C
of
o\177-hydroxy
carboxy\177ic-carbonic
vated form of
afford
anhydrides reaction acid function in

by
acidsaffords cyclic actiused as which can be

with
mixed
- 2 HCI
Scheme 183
amines to
in
me
182
OOH
amides as i\177ustrated (Ref.
the
example given
sche-
Improved
phosgenation process to benzoxazolone. valuable
235).
COC\1772
Benzoxazolones a i
compound for several
\177
NaHCO3
applications, for example as a key starting material for the manufacture of Phosalone,an insecticide used mainly on cotton [Scheme
184].
_\177oCH
Mandelic acid
0
Me k
--\177
CI
0
S
II
H2N,\177S,\177
COOH
I
CI
s
,CH2CI
II
(eto)2P-SNa
\177
,CH2_S.P_(OEt)2
\177\177=
O
of Phosalone.
O
CI
Cefamandole
(Antibiotic)
Scheme 184 Synthesis
GOOH
scheme
182 Preparation
.\"
of Cefamandole.
Someother interesting substituted benzoxazolones are also used as pharmaceuticals, for example the muscle relaxant Chlorzoxazone[Scheme185] (Ref. 237).)))

outlines the utility of the NCA's. This brief presentation But this is only part of the picture. Added to this are urethane N-carbo\320\247y anhydrides calledUNCA's we developed UNCA's which I of under license Bioresearchnc. (Ref. both protectedand activated form of amino acidsare are

improved phosgenation
and purity
w processhich leadsto higher yield as demonstrated in scheme200 (Ref. 251 ).
249).
1)H20/ HCI 2) COCI . T< 2
50\302\260C
highly
effective coupling agents for

in
tides
as illustrated
scheme198.
the synthesis
of pep-
j
]\177.COOH
95%pure O
R +
Z-O- -N
H2N,,,,,v,.,,\177
\177
0
NH2
\177O
Z-O-C-NHCH-C-NH-,\177,',v\177w
\177N
Chlorobenzene,
20\302\260C,
.,,\177
CO2
N-protected peptide agents in peptides synthesis. the and
Scheme 198 Principle of use of UNCA's
then
COCI 2
mp.
105\302\260C
(Vl)
252\302\260C
as coupling
are crystalline solids which are stable in They absenceof water and nucleophiles. react readily
UNCA's
with cleanly
96.5 yield % 99.9% pure

Scheme 200..Comparison
anhydride.
between described (a) and SNPE
(b) routes to isatoic
amino functions without

which
dioxide is the only by-product tion and isolation.
racemization. Carbon allows facile purificais given in
199.
Fmoc-CI +
One example of synthesis of UNCA's
scheme
O
Isatoic anhydride (Vl) is an extremely versatile combecauseof the ease of its reactionswith nucleophiles or electrophiles s outlined in a rewiew a (Ref. For example it is claimed as a starting material in the synthesis of the analgesic Glafenine as shown in scheme (Ref.
pound
252).
201
O
253).
50-70%
Fmoc--N\177oo
mp.
c\177
106-7\302\260C
: + 28.7
\302\260
Scheme 199
Example
of preparation
of UNCA's.
(Vl)
CI
o\321\236-amino
O
'-L,,,.\177% N
\177-
t Let us now considero what extent the previous reaction acid can be applied to p-amino with of phosgene carbamates. acidsto yield six membered cyclic O-acyl known as isatoic 2H-3,1-Benzoxazine-2,4(1H)-dione six memberedcyclic anhydride (VI) is the most popular of isatoic anhydride by O-acyicarbamate.The synthesis acid with phosgene is well ring closure of anthranilic However, we have developedan described(Ref.
CI
Deprotection Scheme 201
OH H
CI'\177
of Glafenine.
159)))
Preparation
250).
158
b as a Phosgenendderivatives building locks

according
+ COCi 2
\177
OI4
:
mp.
relaxant).
to the
in process epicted scheme188 240). d (Ref. Neat
O 191
\302\260C
O O
\177
Scheme 185
Preparation
of Chlorzoxazone(muscle
Y O
HN
,CH2CH2-OH
Catalyst
\177
O
(IV)
/--k
\177C\"2CH2-O\"
115\"45\302\260C
3-4mbar
oxazolidone.
now such as the novel analgesic(111) Oxazolopyridines, a medicinal classof hetebeing in clinical trials, constitute of 2-amino-3-hydroxy rocyclic compounds.Phosgenation and as scavenger solof pyridine in the presence pyridine y (I) in excellent ield as vent leads to the oxazolopyridine shown in scheme (Ref.
- HOCH2CH20 H
Scheme 188
.\"
Y O
--\177'--- OH
100%
Preparation
of N-(2-hydroxyethyl)
186
238).
\177--
The substituted oxazolidone is especially useful as (IV) building block for acrylic monomers syntheses for pharor
maceuticals.
Pyridine
\177OH NH2 \177>
COCl 2
(I)
\177== H
1\177)
Thus, the esterification of (IV) by acrylic acid affords a new acrylic monomer, SNPE code number CL in good yield as shown in scheme
189.
959,
95.5%
mp.
210\302\260C
/---k 0 N
Toluene
+
o
\177\177
N/---\177N
Y O
\177---OH Ov)
H2C=CH-COOH
H2SO4
75\302\260C/300
\177
mm
Novel analgesic
\177
O....../N--\177
\\\\0
\"--u
CL959
bp.
155\302\260C/2
and
u\177e
of an
oxazolopyridine.
_./\177
\",,
mm
is 3-amino-2-pyridone less easy to prepare. via Guillaumet and coworkers eportedthe synthesis of (11) r The reaca one-stepprocesssin\177 diphos\177ene (Ref. 239). u mixture in presenceof tion was carried out in CH2CI2/THF
available
triethyl
\177e re\177ioisomeric
system (11)derived from the readily
0
II
Low viscosity
Scheme 189 Preparation oxazolidone.

.\"
of new
UV-curable
monomer from N-(2-hydroxy-ethyl)
Acticryl
CL
amine
at-78\302\260C,
and
the
fied by flash chromatography
[Scheme187].
H
(\177)
product
isolated and
puri-
c.3cococ,
\177.\177H2
H
;--
THF / CH2CI , 2
78\302\260C,
6h
L\177
(1H)-one.
=0
rap.
78%
252\302\260C
- classical for - adhesives,pressure wood,paper, plastics, adhesives ; - fibers ; - electronics,photo-resists.

coatings
in fast drying coatings (Ref. useful in various industrial sectorsfor :
as reactive diluent
959 widespreadapplications,mainly has

241).It
is
metals ; sensitive
optical
Scheme 187
N-(2-Hydroxyethyl) valuable intermediate
oxazolidone (IV)
should
be also a
of pharma-
Preparation
ofoxazolo[5,4-b] pyridin-2
zines which are widely
the serie, we have developed synthesis of oxazolidoneIV) at an industrial scale, ( N-(2-hydroxyethyl)

In
aliphatic
ceuticals such as the neuroleptic Fluanisone. Squibb reported an interesting example at the 207 th ACS National l'leeting depictedin scheme190 (Ref. 242).
153)))
for the synthesis of used in the preparation
N-arylpipera-
152

\177
N
O\"'\177\"

NH3
\177.-
Ts-CI
\177
\177
ArNH
2 I\177H\177NHCH2COOE t
\177 OH
0v)
OH
Base
OY N\177- O'Ts
O
/\177k
HN
I\177
'CH2NHCH2-\177I-NH
HBr
N --\177__
O'-,\177\"
30%/ AcOH
\177
N-Ar
COCI2
=, \"\177
O
2
Caroxazone
N H_Ar
Heat of N-arylpiperazines.
Scheme 190 Novel
40-91%
the
NaHCO3 H20/ CH2CI2 Scheme 192 Preparation
\177,\177 NV\177NH
preparation
of the antidepressant Caroxazone.
c Oxazolidonesan be also preparedfrom of
reaction
primary amines with 2-haloalkyl chloroformates. This method has found widespread applications in various sectors of the chemical industry. The industrial preparation
The intermediary synthesis of oxazinonesderivatives is the key for the N-hydroxypropylation of substituted anilines used as componentsin hair dyes 245,
of process the systemic

illustration
[Scheme191] 243). (Ref.

CICH2CH2\"O-C-CI
Me
fungicide
Oxadixyl
is
a good first
One example is given

NH
in
scheme193.
(Ref.
246).
O CI-(CH2)3-O-C-CI
NaOH
Me
--NH-NH2
0
Me H
HO
K2CO3 Me
Me
O
Me
HO
O
II
Me
Me-O-CH2-C-CI
HY
CI
NaOH
O
=.
Me
HO
CI
NH-(CH2)3-OH
Scheme
hair dyes.
,N
193.'Hydroxypropylation
of substituted anilines
for the preparation
of
\177,O
\302\260xadixyL
\177/\177----kO
and
M\177
5theme
191 Industrial scale preparation
reactswith cz and \177amino acidsto yield Phosgene six memberedO-acylcarbamates respectively. Thus, phosgenehas proven to be very effective in
of N-carboxy
anhydrides
five
of the
fungicide Oxadixyl.
preparation
The reaction of phosgenewith amines containing an -OH function in 3-position readily affords oxazinones as
already mentioned.
acids.Thesecompounds 2,5-dioxo-1,3-oxazolidines (V), also calledLeuch'sanhydrides have widespreadapplications especially not only in peptides but synthesis [Scheme
the from cz-amino (NCA)
depictedin scheme192
(Ref. 244). 154
The
preparation
of
the antidepressant Caroxazone illustrates the value of the method
194].
155)))

COOH
R--\177 NH2
NH-\177-CI
a Phosgenend derivatives s building locks a b

cooMe\\--/
NH3\321\207
coc, (large excess)

\177,
i
L
OOH
R
CoCI , excess 2 3.5h,

\177 30\302\260C
O
Me --\177N<
H
/\177-r\177
95 % O
unisolated
O
C-CI
L-Alanine
o
2
R
__\177N\177,
HCI
1)
\177-\177N\177COOKH
\177,
=
H
Ala-Pro\177
R---\177
(V)
- CO 2
NH2'HCI
2) H
\321\207
H2N
.\"
Me\177N\177cooH 90% O
Ala-NCA.
--. --.
NCA

Enalapril
of Ala-Pro through (structure

in
COCI 2
C-CI
II
C-CI
N=C=O
and
%
scheme196)is an
O C, OH
angiotensin-
converting
R----\177
NH-C-Cl
- HCI
R----\177
tension.
enzyme (ACE) inhibitor for the control of hyper-
O
Scheme 194 5eneral picture reactions.
.\"
COOEt Me
anhydrides preparation
further
of N-carboxy
--N /,)--CH2CH2--C --C--C--N\177
Although
generally and sold in large quantities. The scopeand limitations of their chemistry, as well as their.applications are not discus-
to
sensitive to traces of moisture and more nucleophilic attacks, NCA are now produced
Scheme 196 Enalapril.

In
sedin
tion
details here in this section and are reserved secfor 4-4 in vol. 2 dedicated the protection and activation to
of functional groups.
However,
tions
(Ref. 248).
MeNHCH2_COOH
another example, Sarcocine-NCA prepared by of sarcosine,followed by cyclisation in the presenceof triethyl amine is used for the preparation of lipopeptide-basedranched polymers forming thermotrob pic and lyotropic liquid crystals as shown in scheme 197
phosgenation THF
\177-
are given
some representative examplesof applicain the presentsection.

coupling
O
Me_N,/\177
Sar-NCA
The NCA
method is conceptually
simple and
1)COCI 2
2) Et3N Boc-F
elegant.This method is now used in efficient large scale f production of peptides, or example for the preparation of dipeptides Enalapril and Lisinopril (Ref. semi-synthetic
O
\177
yO
H2N(CH2) 2-NH2 1
247).The synthesis of
block to synthesize
Ala-Pro which
195.
Enalapril
key building is diagrammed in scheme
is the
O
II
Boc--HN-(CH2)12-NH 2
H2C-----CH-C-C
I
\342\200\242
THF, Et3N
H2C\177---CH-C--HN-(CH2)12.NH.Bo
O
H2C\177CH-C-HN-(CH2)\1772-NH-(Sar)6-Sar_H
II
1)Sar-NCA
2) Deprotection
.\"
Scheme 197 Preparation mers for lipopeptides.
O
of Sarcosine.NCA
and use in the preparation
II
ofoligo157)))
156

Phosgenereacts with
hydrazides to afford
a as Phosgenend derivalives building locks b

Compound (VII) can
1,3,4-oxa-
diazolinones.One well known example is the synthesis of the selectiveherbicide Oxadiazonfrom Rh6ne-Poulenc [Scheme (Ref. 254).
be further
transformed
Iones,useful
building
blocks for pharmaceuticals
202]
cl
CI NH-NH
-cl
--I--\1771
o
\177'
c\177
CI
NH-NH-\177:
iPr-O
iPr-O
Etoperidone or Nefazodone (seecyclisation nitrogen atoms, next section).In the case of Etoperidone, this transfomation avoids the use of toxic ethyl isocyanate to get the required intermediate as shown in scheme 3,5-Dioxo-l,2,4-Oxadiazolidines been found as a have moiety of the natural excitatory amino acid Quisqualic acid and their synthesis by numerous methods has been extensively studied by Zinner
to triazosuch as betweentwo
203.
COCI 2
Oxadiazon
iPr-O
=
Scheme 202
O
Oxadiazon.
scheme204 (Ref. 2.57).

O\177_
and co-workers (Ref. Reaction methyI-N-chlorocarbonyI-N-methyl carbamate, (VIII), (preparation given in section 3-3-4, this volume) with affords 3,5-dioxo-4-methyl-l,2,4-oxadiahydroxylamine zolidine (Acronym i as shown in P1ODD)n good
of
256).
yield
Preparation
of the herbicide
O cI
+ HCINH2OH
Me--N\">,-1
) NaOH / H20
\177\"
We have studied the preparation

diazolinone
(VII)
,/\177
of 5-ethyl-1,3,4-oxaof
propionyl hydrazide
NH
(\177
as depictedin scheme203 (Ref. 255).

Et
by phosgenation
O_Me//
(VIII)
2)) HCl
Me-Ny 90% O
mp.
101 \"c
(CHCl3)
Toluene Et-C-NHNH2
+
Scheme 204.'Improved
preparation
of MODD.
COCI2
60\302\260C,
\177'
O
Toluene
(VII)
II
5h
100%
+ EtNH 2
50-70\302\260C,
\177
II O
O
II
NH
(VII)
While exploring new alternatives to the handle of lower w alkyl isocyanates, e thought that the nitrosated MODD could be a good candidate for a new synthesis of methyl ding isocyanate through a t\177vo-components safe processaccorto the mechanism depicted scheme in
4h
Et-C-NH-NH-C-NHEt
97 %
Et-C-NH-NH 2 + Et-NCO
II
205(Ref. 258).
O
\177
O
I
\177,,
O
Scheme 203.'Preparation and use of 5-ethyl 1,3,4-oxadiazolinone.
II
N-Me
HN_/
O
\177 +
a
CO 2
ON/\177
of methyl
\177ocyanate by
+ N20
two-components
Scheme 205.' Expected generation safe process.
160
161)))

Sometrials applied to a model reaction by trapping the carbamatewere very methyl isocyanate as butyl N-methyl in scheme206. promising as demonstrated O
n-Bu-OH
z\177NH

MODDreadily reacts with hydroxy compounds to afford 2-alkoxycarbonyI-MODD. These intermediates do not need to be isolatedand are reacted with an excess f o amine to give the corresponding carbamate in
n-Bu-OH t-Bu-ONO
50\302\260C,
\177,
Bu-O-C-NHMe
+ t-BuOH
Me-Ny\177
2h
O
85 % as methyl
isocyanate precursor.
II
good yield as depictedin scheme208 (Ref. 260).For example, the insecticide Aldicarbe was obtained in 85% yield without use of the noxious methyl isocyanate. O
COMODD
R2-NH2
Scheme 205 Use ofMODD/t-butyl nitrite

while
+ R'-OH
\177.
Furthermore, studying the potential applications HODD as a building block for the synthesis of 2-acylof that we 3,5-dioxo-l,2,4-oxadiazolidines,discovered it is a This led us to the design of the very good leaving group. unknown symmetrical 2,2'-carbonyl-bis(3,5dioxo-4-methyl-l,2,4-dioxazolidine), (acronym COHODD), previously
- 1 MODD
R,O.Io\177_N,o\177..\177-\177e
-1
\177-
MODD
R\177O-C-NHR2
85-90%
without MeNCO
\177
It
O
of AIdicarbe
II
: Synthesis
I
as a
ry
new coupling mates from hydroxy
reagent for the preparation of carbacompounds and primary or seconda-
Me2-C-CH=N_O_C.NHMe
Scheme 208..COMODD
85% overall
mp.
amines (Ref.
was COHHOD readily obtained in goodyield by simple in of HODD refluxing toluene in presenceof phosgenation
hexamethylguanidinium
259).
SMe as an useful
O
tool
for
II
99-100oc
yield
carbamates synthesis.
chloride hydrochloride
(HHGCI.HCl)
as the
catalyst
[Scheme207].
Toluene HMGCI.HCI,0.5mol %
O
O,k\177
N\177J\177
O
N..\177
\177-NH
COCI2
Reflux,
\177-
Me-Ny
O
Scheme 207
\177)
3h
\177)
\"MODD\"
82 % O
mp.
204\302\260C
MeNy
(\177NMe
\"COMODD\"
Preparation
of EOMODD.
is COHODD Comparedwith 1,1'-carbonyldiimidazole, a crystalline, stable and non-hygroscoDic compound. HODD releasedafter use of COHODDas coupling reagent is Horewater soluble and thereforecan be easily recycled. over, in contrast to imidazole, HODDis acidic (pKa meaThis characteristic can be very useful sured at in the caseof substrates sensitive to basicconditions.
20\302\260C
:3.6).
mainly senof 2-alkoxycarbonyI-P1ODD toward hydrolysis. However, Z-amino acids were obtained in medium yields and were found to be free of dipeptides impurities. We discoveredalso that COMODD reacts with carboxylic acids to give the unstable mixed anhydrides (IX) which are rapidly to decarboxylated the 2-acyI-P1ODD (X). As above mentioned, (X) are not isolated but are reacted in situ with an amine to afford the corresponding amides as shown in scheme209 (Ref. 260). This reaction has been successfully applied to the coupling of amino acids. Yields are generally good and the dipeptides are easily freed of by-products by washes.The HODDreleasedor its sodium salt are simple readily soluble in water and thus are easily separated from the fully protecteddipeptide. sitivity
is possibleto prepare BOC- Z-amino or acids from isolated 2-BOC- r 2-Z- HODDbut the method was o found of little synthetic interest becauseof the
the
162
163)))

The reaction was
efficient
with
both
COMODD
R1-COOH
\177
alcohols. o secondary Providing that an excess f the alcohol is added,tertiary alcohols are esterified in medium but still
satisfactory yields. The reaction is catalyzed with DHAP, but no basewas necessary the alcohol already contained if a pyridine function. We assumethat the reaction proceeds through the mixed anhydride (IX) as depicted in scheme
\177-.
primary
and
-1
MODD
O
.\177
210. 1
- CO 2
\"\177_
N,o\177.\177\302\260\177)e
R2-NH2
-1 as an
R\177-C-NHR
2
COMODD +
R\177-COOH
\177_
MODD
II
(X)
R\177_C.O_C_N
\"\177N-Me
Scheme 209
COMODD
useful
tool for amides synthesis.
-1
MODD
o o
Ii II
'o---& /
procedure,one equivalent of COHODD a solution of the protected amino acid and is added to N-methylmorpholine (2 eq.)in acetonitrile or dichloromeIn
(\177x)
typical
thane and stirred at room temperature for I h. The amino acid esteror its hydrochloride is then addedand the reaction mixture is stirred for an additionnal hour. After conventional
--'\177\"R'L
-CO\177
NMe2, Me
\177RLC-OR2
\177
MOOD
O
acids.
II
the organic phase, the dipeptide is crystallized several from a suitable solvent. As shown in table dipeptides werepreparedand no deviations werefound in
washesof
Scheme210 COMODD
asa reagent
for the direct estefification
ofcarboxylic
3-29,
their optical rotations. Dipeptide

BOC-Phe-GIy-OEt
Z-VaI-GIy-OEt
Yield
(%)
mp.
\302\260
(\302\260C)
[c\177]D
80 06
74
80-8 80-81 90-98
105-16627 (c I EtOH)
-4 (c I
EtOH)
Z-Leu-Phe-OHe
Z-Ala-Phe-OP1e Z-Phe-Ala-OP1e Bz-Leu-Gly-OEt BOC-Tyr(OBzl)-GIy-OEt
88 83 78 79
10 127-129-22(c 1.25 EtOH) 137-139 - 4 (c 3.1 EtOH)

+ 117-119 2 (c 0.5EtOH)
COMODD
- 20 (c 2 HeOH) - (c I EtOH)
Table 3-29 Preparation

In
ofdipeptides using
the
asa coupfing
agent.
ester in 89% yield (rap. No sign of racemization the syntheses amino esters examined. of AcyI-I\"IODD (X) provided by activation of N-protected0\177-amino acids and O-protected-0\177-hydroxy acids with COHODD been proved to be suitable for the synthesis have of ]3-keto ester as depictedin scheme211 (Ref. 262).
95-96\302\260C).
In a typical procedure, COHODD(I eq.) and the appropriate alcohol eq.)are addedwithin 5 rain. to a solution of the acid (I eq.),triethylamine eq.) and DI\"IAP in dichloromethane and the reaction mixeq.) ture is stirred at room temperature for 2 h. Conventional acidicand basicwashesafford the corresponding ester in good yield. For example esterification of Z-AIa-OH with pnitrobenzylic alcoholusing this method gave the expected
(1.1
(0.1
(1,1
was detectedin
second publication, we reported the use of

one-potesterification of carboxylic acids, acids,under mild conditions (Ref. 261).
165)))
for COHODD
especiallyamino 164
a as b Phosgenendderivalives building locks

O
\177O\177

diamine type compounds is a for the preparation of 2-imidazolidones (cyclic five membered ureas). The utility of this method is illustrated by the synthesis of a valuable intermediate (I) for D-biotine manufacture. We have developed an improved interracial process hich affords w (I) in good yield and high purity as shown in scheme Phosgenation
well
COMODD
R \177-COOH
\177
R2
.io\302\260
>
75\177C
CHR3
{\177yclisalion be\177veen
of ethylene
80-98% O
II
Et3N, 0cC
yNMe
(X)
established method
lwo
75-95%
nitrogen
a\177oms
R3
I
R\177-C-CHCOOR
.\"
213.
Scheme 211 Use of COMODD in the synthesis
of
\177-keto
esters.
of
This activation was successfully used in the preparation unusual \177amino-[3-hydroxy esterssuch as the protected
\177_
H
N
\177
N
\177
\177
1) KOH / H20 / Hydrophobic

COCl2 2) H20: HCI
solvent
\177,
derivative shown in
of (354R55)-Isostatine scheme (Ref. 1)

M
COMODD98%
212 202).
from
D-allo-isoleucine as
HOOC
Me...y/Et
Z-N/\"\177COOH H
e...y/Et
H
2)
Li
O
\177CH2
EtO
82%
Me...y/Et
O
Anti
.
.\"
H.\177\\H \"e
\177COOH
O
mp.
172.5\302\260C
o.
H H
(0
D-Biotine
(Vitamin H)
NaBH4
\177\"
-OH
Z-N/'\"r''\177COOEt ( de < 96 %)
H
\177H
(GH2)4GOOH

COMODD.
of the

.\"
key intermediate
of (354R55) Isostatine with
for the synthesis of Biotine.
of the key intermediate for the by the preparation production of the soil-applied nematocide Isazofos(Ref. of 1-cyano-l-isopropyl Thus, phosgenation hydrazine in THF gives a transient N-chlorocarbonyl compound (11) which is cyclized to (111). This salt, insoluble in THF is recovetrated
r Phosgeneeactswith cyanohydrazines to yield 3-hydroxyThe 5-chloro-l,2,4-triazoles. utility of the processis demons-
263).
red
by filtration by
and the
goodyield
simple acidification
desiredproduct (IV) is isolated in as depicted scheme214. in
166
167)))

CI-CN THF
.\177/
\177\"

Note also that reaction of
methyl carbamate(preparation through in section 3-3-zLthis is
/H
COCl 2
,,\177N_NH2
,N-NH2 CN
preparation of numerous urazoles..Some examplesare presentedin table 3-30 265). (Ref.

\177, N-N
k/\177\"
methyI-N-chlorocarbonyI-Nphogenation given very suitable for the volume)
Cl\"
--NH .\177N
\177,\177*\177
N
Anhydrous NH3
O
\177
N-N
Cl\177,\177
k/\177-
\"
R O-NH+
(Ill)
Yield
(%)
mp.
(\302\260C)
CI.\177Z\177
Cl
[II)
\177
H Pie
56
HCl
/ H20
\177
81.4
89.5
+
(IV)
Ph
Scheme 214 Describedprocess for the m an ufacture of Isazofos.
OH 92% yield ofa intermediate

used for the
RNH--NH2
238-9 122-3 222-3

R.N_NH
preparation
O'\177cI
Me-N\177__
1) I-bO / NaOH
\177
OMe
2)
HCl
/H20
\321\236=:Z,
\"\177O
chloride.The new synthesis of (IV) is diagrammed scheme21.5 264). (Ref.

Acet\302\260ne
While exploring the synthesis and chemistry of urazoles, an alternative processtarting from carbazate s which avoids the handling of the extremely noxious cyanogen
AcOEt extract. carbamate
Me
for the
we studied
tion
Table 3130 Use of rnethyI-N-chlorocarbonyI-N-rnethyl ofurazoles.
prepara-
in
MeO-C-NH-NH 2
\177
NINH\177=:=
\1771
-OMe
Pt/H2 ---\177
O
MeOH
II
O
/ H2SO 4
\177
-N-NHICIOMe
H
WN-NHIC-OMe
O\177
NH
85%
rnp.
II
KOCN
,20\302\260C
O
.\177
N-N
Cl\177'\177
k/\177\"
II
161
\302\260C
The biological activities of condensedpyrimidine systems as diuretics, antitumor agents or as antagonists of constituents of nucleic acid and of folic-folinic acid family of vitamins prompted differents authors to study the synthesis of cyclic six membered acylureas such as pyrido[2,3-d] yrimidinones (Ref. p Reaction of phosgenewith 1-amino nicotinic acid affordedthe 3-azaisatoic anhydride (V). Treatment of (V)
266).
H20 / KOH
\177
oiDichlorobenzene
\177/\177
N-N
O\177=/\"N/\177--\"
POCI3
propargylamine yielded the 1-aminonicotinamide (VI). Phosgenation of (VI) in pyridine under reflux gave the expected product (VII) as depicted in scheme
in DMF with
100%
216.
Catalyst
160\302\260C
OH
78%
(IV)
26%
mp.
105.5\302\260C
Scheme 215 Synthesis and use of l-isopropyl
mp.
186\302\260C
urazole.
168
169)))

O
COCi 2
\177,

In
HC--CCH2NH2
lone
[\177COOH NH
O \177N.\177
(V)
DMF , 50 C
57\302\260'\302\260
O
NHC H2
O --C--CH2
Pyridine,
137-8\302\260C
done as depictedin scheme219 255,268). (Ref. Nefazodone.HCI launched in 1994 the US and was in in Canada by BristoI-Meyers Squibb as Serzone for the treatment of depression (Ref. 269).
\177
another study, we devised new route to the triazoa intermediate (X) useful for the synthesis of Nefazo-
(v0
mp.
63%
reflux,
6h
mp.
240-2\302\260C
O
H
(VII)
OH
\177
a
Et
O\177
Scheme 216 Example of preparation double phosgenation process.

\177
\177 175
Neat
\302\260C
II
of cyclic six membered acytureas through
0h
glycol
\177-
OCH2CH2NH-C-Et (A)
H20
/ 4h
bp.
99-102\302\260C/7
5-Ethyl-l,3,4-oxadiazolinone prepared by phos(VIII), genation of propionyl hydrazide as already describedin section3-4-2,is a key building block for the synthesis for the synthesis of 1,2,4-triazol-3-ones type antidepressants
(Ref
\177
ethylene
(A)
+ NaOH
145\302\260C,
OCH2CH2NH 2
(B)
dist. yield
mm
Steps1 + 2 : 86%overall
Et
\"\177N,
we obtained the triazolone (IX) in 7_3 % overall without the need of the yield according to scheme 217 toxic ethyl isocyanate.IX) is suitable for the manuhighly ( facture of Etoperidone [Stucture given in scheme (Ref.
Thus,
255).
Toluene
NH
80-85\302\260C
St_e#33
(B)
O
(VIII)
4h
O
II
O
II
267).
Toluene Et-CNH-NH2
+
218]
4h
Et.C.NH_NH_C_NHC
Et
COCI2
60\302\260c,
\"\177-\177 \177'
N.
2 Toluene
50-70\302\260C,
Et-NH
II
5h
(vm)
H20 / NaOH Et-C-NH-NH-C-NH-Et
y o
NH
) KO H / H20
\177
2 h reflux
(C)
2) HCI
Et\177NAN
loo\302\260c,
H73% mp. 125-7.5\302\260C of Etoperidone.
/ H20
.
useful
H2CH20_@
O
__N.
_\177H
O\177OCHCH2
Recryst.
138\302\260C
\177.\177N
(X)
Et from MEK
Steps3 + 4 : 80%yield
mp.
O
97%
Scheme
II
0
II
h
(IX}
Et!
\177--\177
from propiohydrazide
217 Preparation ofthe key intermediate
CI
for the manufacture
0
Et-- NAN
Et
,
:
\"\177-1\177
(CH2)\177--
Et
N/--XN-\177 CI
(anti\177lepressant).
Scheme 219 New synthesis
Nefazodone (Anti-depressant)
intermediate
(X) for Nefazodone.
of an
Scheme 218 Etopefidone
170
171)))

carbamatesare valuable products, especially N-Hethyl as pesticides, or example the insecticide Carbofuran, as f well as numerous pharmaceuticals. Industrially, the reaction far

Without catalyst
/[J\177
isocyanate with hydroxy compounds is by one of the most widely utilized proceduresfor the production of numerous N-methyl carbamates. The Bhopal incident (India, 1984) dramatically outhas lined the high toxicity level of methyl isocyanate and moreover its very exothermic self-polymerization which requires extreme care during its production and storage (Ref. 270). In this volume, we have already examined some alternatives to the synthesis in situ and/orto the use of methyl
methyl
of
N- Me
(Xll)
2 Me-NCO
BusP
Me-N,\177/O
Scheme
221 Use of (XII) as methyl
0.5h ,
90\302\260C
isocyanate generator.
isocyanate.We
dione (XlI) which can releasemethyl isomethyl isocyanate precursor in safe conditions. This dimer was preparedfrom cyanate urea (XI) obtained by N-chlorocarbonyI-N-methyl N'-methyl of N,N'-dimethyl urea as previously described phosgenation in scheme section 1.56, 3-3-4. yclization of (X]) in a suitable C solvent and in presence a base such as DABCO afforded of
the
1,3-dimethyl diazetidine (methyl isocyanate dimer) should be a suitable

thought
that
3 4-4 lion C.vclisa belween a nilro\177en atom and a sulfur atom
L-2-Oxothiazolidine-4-carboxylate (OTC)
/COOH
S\177NH
dimer expected
Solvent
in (X]I) as depicted
scheme220.
(XlI)
Me-N
O'k\177
CI
DABCO
\177
\177,
Me-N N-Me Cas: 36909-44-1

\177/
o\177--N.
Me
1 h, 83%
30\302\260C
(Xl)
mp.
Preparation
98\302\260C
Recryst. hexane
Scheme
220:
wing
of methyl isocyanate and IR analytical
dimer.
a non-toxic precursorof cysteine proposedas a prodrug capableof penetrating into living cells.Therefore,ts i orally or parenterally administering to humans provides a method of restoring the glutathione level of numerous tissueswhere 5-oxoprolinase present, especially the liver is in I (Ref. 271).n HIV-seropositive patients, it was proved to increasethe levelsof gluthatione, the lack of which is suspectedto be a factor of their immunodeficiency (Ref. 272). OTCis available by several methods, among them the reactions phosgene(Ref. 273) more of or recently triphosgene(Ref. 274), with L-Cysteine or L-Cysteine methyl ester appearthe more convenient. We developed a laboratory scalea biphasic phosat
is genation
The NHR
data of (XlI) are the
follo-
led pH as depictedin scheme
f processrom
L-Cysteine hydrochloride
222 275). (Ref.
at control-
1H NHR (CDCI3) 2.87 8 ppm

IR
cm 1780 1.
This dimer
was
t decomposedo
221.
172
100% methyl
thermically (170\302\260C) or catalytically isocyante as shown in scheme
173)))

Toluene KOH/H20
/__\177,COOH

This is the end of volume 1 mainly dedicated the use to of phosgeneand its direct derivatives as blocks building providing the carbonyl group in organic molecules. Obviously, several major topicsrelated to this type of applications are inadequately discussed even purely and or simply forgotten. Pleaseforgive me for these inadequacies which are not at all intentional. Also, the reader wiil understand that some sensitive
HS
/_\177COOH
NH2.HC
I
1)COCI 2, T:
10\302\260C
2) 3) Solvent
HCI
S.\177NH
extraction
0
0
OTC
70%
Cas: 19771-63-2
mp.
[c\177]\177 168\302\260C
:-61
\302\260
Scheme 222.' Preparation
of OTCby
phosgenation.
It
is noteworthy
that
OTC have other types of pharcan
maceutical applications than the delivery of cystein into the human body. For example, nitrated derivatives of OTC were recently patented as valuable coronary vasodilators
which
subjectshave been deliberately omitted for confidentiality reasons. It is obvious that substantial work remains to be done and it is the author's secret hope that this first volume will serveas a catalyst to open the way to new researchon the chemistry of phosgene.
replace nitroglycerin without having its disadvanAn tages (Ref. 276). example of synthesis of these new interesting pharmaceuticals is given in scheme223.
Et3N
/_.\177/COOH
NH
(EtO)2P(O)CN
+
HNO3.H2N-CH2CH2ONO2
in
THF
\177
OTC
O
N
S\177,[\177,
mp.
130-1\302\260C
( AcOEt )
Scheme 223
.\"
Preparation
ofa nitrated derivative of OTCasa vasodilator.
174
175)))
Relerences
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1 2
1833,
1992,
J.T.(SNPE)
Gauthier,
EP
40153 1980
Pr. Pr.
II.
12,
l\177lartz,
6
7
21376; U5 4 806 286 9

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11alfroot, T. ; Wolf, R (SNPE) EP
850723
A.F. ; Comprehensive Organic Chemistry

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Ltd)
Imprimd
en France par ['lmprimerie
GPA
9 Nanterre
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]997- Pour
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Nationale
des Poudres et
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Phosgene chemistry: A concise history

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Phosgene chemistry: A concise history

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qui peut tout aussi bien chlorure d'oxidede carbone, offre une composition si simple et si remarquable que, s'il

r\177alisait toutes les r\177actions que I'on a droit d'en esp\177rer,

on parviendrait reproduire, les plus curieuses de la chimie

desSciences on december 6 1 and

son aide, les combinaisons organique... (Read to the french

Die Chlorkohlens\177ure als das ChlorLir

setzung, man die Recht davon erwarten gen

Jean Baptiste Dumas

(b.1800 1821), 1821

after world war two,

phosgenechemistry has experienced and wide interest. Vast numbers)))

researchlaboratories. although phosgene chemistry

fessorRoy Olofson(The Pennsylvania

patience,wisdom and kidness scientist and a teacher.

and for being

tion, protection Consequently,

and activation etc. have chosento divide this

some considerations introduction, propertiesand chemical reactivity, and four

Jean-Pierre SENET G. France Seine-ebMarne,

chapters devoted to phosgeneand

Contents first volume

Section Section Section

Section1-4 Classification of phosgenereactions

Section2-1 Physical properties Section2-2 Chemical reactivity of phosgene

Phosgeneand derivatives as building blocks Section3-1 Reaction at a carbon center

Section3-2 Reactionsat an oxygen or sulfur center 3-2-1Highlights of some particular chloroformates

of phosgene at oxygen center of unconventional substrates

3-2-2-1eaction R 3-2-2-2eaction R 3-2-2-3eaction R

of phosgene Breakdown of consumption

phosgene with glycerol phosgene with epoxides phosgene with aldehydes

ketones.novel c\177-chlorinated and related reagents

53 ...................................... carbonates 81 ............................................

Section3-3 : Reactions at a nitrogen center 3-3-1 Highlights of some reactions of phosgene

......... 105 105 .................. 115 .................... ..................

of phosgene with sulfonamides, preparation of sulfonyl isocyanates formation

Section3-4 : Ring 3-4-1Cyclisation

................. ................. .................. 143 ........... .............................................. 151 ......... ................................................................1)

The story of phosgenediscovery (Ref.

Dr. 1810, John

(Nitriles and Isonitriles) Alkylation

of phenols and amines

Section4-4 Protection and

de- oxygenation opening

between Dr. John

of the so called chlorine controDavy and Dr. Murray, fervent

the ammoniacal salt formed with

noticed that the new

mentioning any reaction. French chemist Jean-Baptiste umas while D

had an inkling of the with this prediction

les plus curieusesde la chimie organique Translation Phosgeneexhibits such a simple

remarkable composition that, should

realizeall the reactions one is entitled to hopefor, one could reproduce,

thanks to it, the strangest combinations

since then have expectation of

To designateit, he suggesteda simple name,

Phosgene (or phosphene), , and to produce

ancient Greek roots

Dumas who may be thereforeconsideredas the pioneerin the chemistry of phosgene.

toxic gas which was

chemical weapon during World War I.

Some relationships between phosgene

are summarized in table The table son betweensome toxic gases.