Grignard reagents & Reducing reagents 1/28/2019

BJM

Mg°/THF or Et2O E+
R X R Mg X R E
O
O O R2 ≠ H
δ+ R
E+ = H OR' R δ+ R' R δ+ OR2
+Mg Open Here
R– X

For example: O
O
H 3C CH3 H 3C O H H H3C OH
Br Mg°, THF MgBr
A.
CH3 workup CH3

I 1) Mg°, Et2O D
B.
2) D2O

HO
1) Mg°, Et2O Note 1: NH4Cl is a weak acid used
C. I to quench the alkoxide
O
Ph
2)
MeO Ph Note 2: When using esters assume
excess Grignard reagent is used
3) NH4Cl

The mechanism for Grignard reagent addition to esters:

O
H H
O O O
– MeO– O OH
Me MgBr MeO Et MeO Et Me Et
Me Me Et Me Et
Me Me
the tetrahedral
intermediateMe MgBr Note: In the tetrahedral intermediate,
you can kick out OR, Cl, or other
Note: Grignard reagents add to aldehydes faster than common leaving group. You cannot have
to ketones Grignard reagents add to ketones much an alkyl (R) group or hydrogen as the
faster then to esters leaving group

Using Grignard reagents to synthesize alcohols:

Nearly all carbon-carbon bonds at an alcohol functional group could
be prepared using Grignard technologies.

OH
O BrMg Br
Me +
Me H

or BrMg
OH O OH
H
Me MeMgBr + H H
+
O
And because you can
make aldehydes from
H H
alcohols...
Grignard reagents & Reducing reagents 1/28/2019

Retrosynthetic analysis tips:

OH comes O O
RMgBr + OR RMgBr +
R R from R Cl
R MeO OMe

R=R=R

OH
O O O
R R1 R1MgBr + OR RMgBr + OR RMgBr +
R R R MeO R1 Cl R1

R=R Note: OMe represents

any ester
OH
O O O
H OH
R R1 R1MgBr + Then RMgBr +
R2 R R2 R R2 R R2 H R2

For Example:

O
OH MeO H +
O O O
O MeO H O
H
Me Me ClMg
O
H
Three last notes on Grignard reagents:
1) Grignard reagents are nucleophiles that add to the specific types of electrophiles shown in this
handout (ie. that are not generally used for SN2 reactions on alkyl halides).

2) Alkyl Na, Li, and K reagents (i.e. H3CC CNa ) react very similarly to Grignard reagents.

3) An R– addition to a carbonyl is a reduction just like a hydride H– delivered from BH4—

H2 Reducing Reagents
Na, Li, or K : Used to reduce alkynes to trans-alkenes
BH3 : Adds to alkenes and alkynes (reducing them)
With the CBS Catalyst, reduces ketones to alcohols, enantioselectively
Selectively reduces carboxylic acids to alcohols (Does react with esters)
NaBH4 : Reduces aldehydes, acid chlorides, and ketones to the corresponding alcohol (reduces esters very slowly)
LiBH4 : Reduces esters, ketones, acid chlorides, and aldehydes to the corresponding alcohol
LiAlH([OC(CH3)3]3 : Used to reduce acid chlorides and esters (at –78 °C) to aldehydes (stops at the aldehyde!)
Reduces ketones, acid chlorides,and aldehydes to the corresponding alcohol
i-Bu2AlH (DIBAL): Used to reduce esters and acid chlorides (at –78 °C) to aldehydes (stops at the aldehyde!)
Reduces ketones, acid chlorides,and aldehydes to the corresponding alcohol
LiAlH4 : (LAH) Very powerful reducing agent also reduces carboxylic acids
Reduces ketones, acid chlorides,and aldehydes to the corresponding alcohol
Reduces amides to the corresponding amine
Grignard reagents & Reducing reagents 1/28/2019

Nucleophilic Additions

O O
HO Ph HO H
1. PhMgBr 1. NaBH4

2. H3O+ 2. H3O+

O
HO Ph O
HO H
1. PhLi 1. LiAlH4
2. H3O+
2. H3O+
O
1. PhMgBr HO Ph
R Cl R Ph
2. H3O+
O 1. PhMgBr OH
O Ph
1. PhMgBr HO Ph 2. H2O
R OCH3 RLi and R2CuLi will also open epoxides
2. H3O+ R Ph

O O
MgBr O C O
O MgBr H3 O+
OH

Hydroxyl Protecting Groups

Me
O Si Cl
O Me Me
Me (TBDMS-Cl) t-Bu 1. CH3MgBr HO CH3 t-Bu
OH Si Si
O Me O Me
H 2. H2O
N
OR
(Imidazole)
N
O
PROTECTION Bu4NF
OTBDMS (TBAF)
DEPROTECTION

HO CH3
OH