IJPCBS 2012, 3(1), 25-43

Rajput et al.

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INTERNATIONAL JOURNAL OF PHARMACEUTICAL, CHEMICAL AND BIOLOGICAL SCIENCES

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Review Article

REVIEW ARTICLE ON VILSMEIER-HAACK REACTION

AP. Rajput1* and PD. Girase2
1P.G.

Research Center, Department of Chemistry, Z.B. Patil College, Dhule, Maharashtra, India. 2S.V.Ss Dadasaheb Rawal College, Dondaicha, Dhule, Maharashtra, India.

ABSTRACT This review article represents a survey covering the literatures on Vilsmeier-Haack reaction, glutarimides and dihydropyridines. This short review also provides an update on recent reports and demonstrates the usefulness and the efficiency of this approach. The data on the methods of synthesis, chemical reactions, and biological activity of these heterocycles published over the last years are reviewed here for the first time. Keywords: Vilsmeier-Haack reaction, Glutarimides, dihydropyridines.

INTRODUCTION The application of the Vilsmeier-Haack (VH) reagent (POCl3/DMF) for the formylation of a variety of both aromatic and heteroaromatic substrates is well documented1. The Vilsmeier-Haack reagent is an efficient, economical and mild reagent for the formylation of reactive aromatic and heteroaromatic substrates2. It is now used as a powerful synthetic tool for the construction of many heterocyclic compounds3. The classical Vilsmeier-Haack reaction4, however, involves electrophilic substitution of an activated aromatic ring with a halomethyleniminium salt to yield the corresponding iminium species, which facilitates easy entry into various nitrogen and oxygen based heterocycles5,3a,d. Vilsmeier reagent serves not only as a formylating agent6, but also as an activating reagent for carboxylic acids to give esters7, amides8 and acid chlorides9 and for alcohols to give alkyl chlorides10, esters11, alkyl aryl sulfides12 and imides13. Besides this, the reagent has also been extensively used for effecting various chemical transformations with other classes of compounds. There is a growing interest in formylation as an interesting strategy to form intermediate carboxaldehydes, due to their

intrinsic pharmacological properties and chemical reactivity14. Formylation reactions have been described for pyrido[2,3d]pyrimidines as a key step for the introduction of functionalities via the intermediate carboxaldehydes15. The Vilsmeier-Haack reaction can also be applied to introduce an acetyl group on activated aromatic or hetero aromatic compounds, many other conversions can be achieved with this technology. In general, N,N-dimethylformamide (DMF) and phosphorus oxychloride (POCl3) are used to generate a halomethyleniminium salt used in the synthesis of a large number of heterocyclic compounds16-19. In 1896, Friedel noted the formation of a red dye on treatment of Nmethylacetanilide with phosphoryl chloride to which he assigned the problematic structure (1)20. This was corrected by Fischer, Miller and Vilsmeier in 192521 who assigned the cynine-dye structure (2) and argued cogently that this product derived from the self condensation of the quinolinium salt (3). It was the realization by Vilsmeier & Haack22 that one molecule of N-methylacetanilide had acetylated a second molecule prior to cyclisation that led to the discovery of the Vilsmeier-Haack formylation using N-dimethylformanilide.

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IJPCBS 2012, 3(1), 25-43

C6H4 N Me Me C +N H C6H4 Cl (1) Cl Cl + Me N N Me Cl +N Me Cl (3) Me Cl Cl Me

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Recent studies on the NMR spectra of the DMF/POCl3 complex pointed to the imidoyl chloride salt structure (B)26-28 (Chart-1). Challis and Challis29 suggested that O- acyl structure (A) might be more stable for POCl3 than for other halides such as SOCl2, COCl2 and PCl5.
+ R POCl2 O .. . . . C . ... .. . NR1R2 (A) O R C NR1R2 Cl R C + NR1R2 (D) Cl + X O X = CO, SO or PCl3 + Cl2X R Cl Cl R C + NR1R2 (B) + O ----- X .... . C . ... Cl Cl .. . NR1R2 (C)
-

(2)

The formyl group thus, introduced in to a substrate is, of course, a highly reactive species and the versatility of this reaction, to a large extent, is due to the variety of synthetically useful transformations that may subsequently be performed. The V.H. reaction has been extensively studied and reviewed23. The structure of the electrophilic adduct has aroused much interest. The behavior of the adduct appears to be consistent with an ionic character rather than a covalent character24. The structures a & b were considered most likely for the DMF/POCl3 adduct.
H 3C H 3C .. N OPOCl2 C + H H 3C H 3C OPOCl2 Cl .. C + N H

PO2Cl2

The Vilsmeier complexes are generally prepared at low temperatures (250C). If the reaction with nucleophile is carried out at low temperature (300C) the rearrangement of (A) and (B) does not seem to be favoured. Furthermore, the Vilsmeier complex undergoes a much wide range of nucleophilic substitution reactions. Reagents The Vilsmeier complexes employed in the formylation reactions are usually derived from N,N-disubstituted amide and POCl3. NMethyl formanilide and N,N- dimethyl formamide are commonly used. N-Methyl formamide, N-formylpiperidine27 and Nformylindeline28 have also been used. The use of unsubstituted formamide has also been investigated30, but the complex was found to be less reactive than the DMF / POCl3 or MFA / POCl3 complexes. Other amides such as N, N-dimethyl acetamide, N-methyl acetamide, N, N-dimethyl benzamide, N, N , ,,-pentamethyl acetamide, etc. have been employed in the presence of POCl3 but these amides are prone to undergo self condensation. Acid chlorides other than POCl 3 have also been used in the Vilsmeier reactions. They are COCl231, SOCl232, ClOCl33, CH3COCl 34, ArCOCl34,35, ArSO2Cl35, PCl536, Me2NSO2Cl37 and RO2CNH SO2Cl38.

H3C H 3C

+ N

OPOCl2 C H

H 3C H 3C

+ N

Cl C H

OPOCl2 b

Structure of the Vilsmeier-Haack Complex Phosphorous oxychloride reacts with tertiary amides to give adduct which exhibits salt like properties. These adducts have been referred to as the Vilsmeier complexes25.
O R C N R 1 R 2 + P O C l3 R + O P O Cl 2 .. . . . C .. . . . . N R 1R 2 (A ) ( D ) + P O 2C l

Cl

Cl R C + N R 1R 2 (B )

P O 2C l2 R

O C N R1R2 + A rS O 2 Cl

+ O R S O .... . .. O .. .. N R 1R 2 (E ) C H A R T -I N a tu re o f V ilsm eie r-H a a c k R ea g en t Ar Cl Cl R C + N R1R2 Cl ArS O3

(F )

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Solvents In the case of amides like DMF, dimethyl acetamide, N-methyl pyrrolidone, etc. which are liquids, an excess of the amide can be used as solvent. Other solvents like chloroform, methylchloride, benzene, toluene, o-dichlorobenzene, dioxane and tetrahydrofuran have also been used. Temperatures Normally the reactions are carried out at room temperature or between 600 and 800C. Reactions at temperature as high as 1200C have also been described39. The Vilsmeier reaction has been the subject of many review articles of varying scope and length. Some of the reviews are enlisted here in chronological order. Vilsmeier (1951)40, Bayer (1954)41, Bredereck et al. (1959)42, Eilingsfeld, Seefeder and Weidinger (1960)43, Minkin and Darofeenko (1960)44, Oda and Yamamoto (1960)45, De Maheas (1962)46, Hofner et al. (1963)47, Gore (1964)48, Hazebroucq (1966)49, Jutz (1968)50, Ulrich (1968)51, Kuehne (1969)52, Seshadri (1973)24, Jutz (1976)53, Meth-cohn and Tarnowski (1982)54, Smichen (1983)55, Marson (1992)56 , Meth-cohn and Stanforth (1991)57 and Meth-cohn (1993)58, 59 Arumugam S. (1994) , Duduzile M. M. (2007)60, Carsten Borek (2008)61, Jones G. and Stanforth S. P. (1997)62, Kantlehner (1976)63 has reviewed adducts from acid amides and acylation reagents and also the preparation and reaction of chloromethyliminium salt with nucleophiles. Liebscher and Hartmann (1979)64 have published an article relating to vinylogous chloroiminium salts. These excellent reviews deal with the Vilsmeier reaction, its mechanism and the structure of the various eletrophilic reagents. In this study we have restricted our coverage to important concepts rather than reiterate all the literature material. Synthetic Applications of the VilsmeierHaack Reaction i) Formylation of aromatic hydrocarbons, phenols, phenolethers, olefins, ketones, Beta-chlorovinylal dehydes. ii) Diformylation reactions. iii) Formylation with aromatization.

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iv) Regiospecific formylation. v) Oxygen and nitrogen nucleophiles are also reactive towards Vilsmeier reagent. vi) Formylation with dimerization. vii) Transformation of iminium salt into product other than aldehyde. viii) Miscellaneous V-H reactions. In view of the vastness of the literature, we have endeavored in this review to demonstrate the powerful potential of Vilsmeier-Haack reaction in the synthesis of different compounds. Only few representative reactions are illustrated under the following titles. A) Synthesis of Pyrroles Gupton J. T. et al.65 have studied and reported the synthesis of 4-Aryl-2carbethoxypyrrole (6) from compound (4) with POCl3, DMF and heat followed by NaPF6/H2O via formation of Vinylogous iminium salt (5) (Scheme-1).

O N O
1 2 R R

CF3 N N

(105-106)

105, R1=R2 =H 106, R1=R2 = -(CH2)2-

POCl3 / DMF and heat followed by NaPF6/H2O COOH (4)

Me + N Me PF6 (5)

Me N

H2N

CO2Et N H (6) CO2Et

Me DABCO.DMF and heat

(Schem e-1)

They have also reported microwave accelerated Vilsmeier-Haack formylation of pyrrole (7) into formyl pyrrole (8) (Scheme-2).
X Y POCl3,DMF N Z (7) (Scheme-2) CO2Et Microwave heating OHC N Z (8) Z= H, Me CO2Et X Y

Pfefferkorn J. A. et al.66 have described formylation of pyrrole (9) under Vilsmeier-

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Haack conditions into pyrrole carboxaldehyde (10) as a part of development of an efficient and scalable second generation synthesis of novel, pyrrole-based HMG-COA reductase inhibitors (Scheme-3).
EtO 2 C N POCl3, DMF DCE 800 C F (9) (Scheme-3) F F (10) F EtO 2C N CHO

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under different temperature conditions (scheme 6). Functionalized pyridine-2(1H)-ones and their benzo/hetero-fused analogues represent an important class of organic heterocycles for their presence in numerous natural products and synthetic organic compounds along with diverse bio-physico and pharmacological activities70-71.
DMF/POCl3 (10.0 equiv) O O NHPhCl - 4 DMF/POCl3 (10.0 equiv) 1200C, 2 h Cl 800C, 1 h OHC Cl N PhCl - 4 O CH2CH2Cl (22)

Cho T. P. et al.67 have discovered the series of novel pyrrolopyridazine derivatives by carrying out synthesis of pyrrolopyridazine (14) from pyrrole diesters (11) by using VH reagents (Scheme-4).
O O O N O (11) H 2.0 equiv POCl3 DMF, 100 0C, 2 h 77% O O N O 1.5 equiv NH2NH2.H2O, Cl N N 2.0 equiv POCl3, CH3CN, 80 0C, 5 h H (12) O O H

(21)

PhCl - 4 O

CH2CH2Cl (Scheme-6)

(23)

EtOH 90 0C, 3 h, 72%

EtOOC HN

EtOOC HN

O NH N

Asokan C. V. et al.72 have reported the conversion of enolizable ketones such as acetophenones and benzal acetones (24) into 2-chloronicotinonitriles (25) upon treatment with malononitrile under Vilsmeier-Haack reaction conditions. (Scheme-7).
O 1. POCl3, DM F, rt, 12h R2
0 2. N CCH 2CN, 90 C, 2h 3. A q. K2CO3

(14) (Scheme-4)

(13)

R2

CN N (25) Cl

B) Synthesis of Functionalized Pyridines Xiang D. et al.68 developed a facile and efficient one- pot synthesis of highly substituted pyridin-2(1H)-ones(18), (19) and (20) via Vilsmeier-Haack reactions of radily available 2-arylamino-3-acetyl-5,6dihydro-4H-pyrans (15), (16) and (17) respectively (scheme-5).
O

R1 (24)

R1

(Scheme-7)

P Br 3 / D M F (3 .0 e q u iv )
PhN H

O HC Br

Ph O

8 0 0C

( C H 2 ) 3 Br

(1 5 )

(1 8 )

O OHC P B r 3 /D M F (5 .0 e q u iv ) Ar H N (1 6 ) (1 9 ) O P Br 3 / D M F (5 .0 e q u iv ) 4 -C lP h H N (1 7 ) (S c h e m e -5 ) O 8 0 0 C , 1 0 m in Br O 8 0 0C X N Ar O ( C H 2 ) 3 Br

OHC

P h C l- 4

O N H PhC l - 4 ( C H 2 ) 3 Br

+
O ( C H 2 ) 3 Br (2 0 )

Quiroga J. et al17 formylated pyrazolopyridine (26) into pyrazolo[3,4-b] pyridine-5-carbaldehyde (27) by using DMF and POCl3 (Scheme-8). They have concluded that, the formylation on the pyridine ring only takes place when there is a dihydroderivative on the appropriate pyrazolo-fused system. They have also observed that the use of the Vilsmeier-Haack condition developed a fast and efficient method for the formation of pyrazolo[3,4-b] pyridine-5-carbaldehyde (27)
R H3 C N POCl 3/DMF N Ph N R' (26) R=H, C6 H 5 (Schem e-8) (27) H3 C N N Ph N R' R CHO

Pan W. et al.69 also reported the synthesis of functionalized pyridine-2(1H)-ones (22) and (23) from 1-acetyl, 1-carbamoyl cyclopropanes (21) by using POCl3 and DMF

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Tabuchi Y. et al73 used Vilsmeier-Haack condition for the synthesis of 4-chloro-3formylbenzo[b]furo[3,2-b] pyridine (29) from 2-acetyl-3-acylaminobenzo[b] furans (28) (Scheme-9).
NHCOR3 R1 COCH3 O R2 (28) (Scheme-9) R2 (29)
1 POCl3 , DMF, 24 0C R

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N CHO O Cl

hydrazine in ethanol and acetic acid. The intermediate phenyl hydrazone (35) when subjected to Vilsmeier-Haack reaction condition, cyclized to afford substituted pyrazoles (36) which are well documented to posses antihypertensive, antibacterial, anti-inflammatory and antitumor activities76 (Scheme-12).
R1 O O (34) C H3
R2
H N

R1
N H2

C H3 O HN N

EtOH / AcOH

C) Synthesis of Pyrimidines Quiroga J. et al17 suggested the regioselective formylation of pyrazolo [1,5a] pyrimidine system using Vilsmeier-Haack conditions. They have synthesized pyrazolo [1,5-a] pyrimidine-3,6-dicarbaldehyde (31) from 6,7-dihydroderivatives (30).They have also converted 6,7-dihydroderivative (30) into aromatic pyrazolo pyrimidine (32) which was formylated with DMF & POCl3 and afforded pyrazolopyrimidine-3carbaldehyde (33) (Scheme-10).
H Ar N N R (30 ) N BS/ Eth ano l Ar N N R (32) R' (Sch em e-10) N P OC l 3 / D MF R (3 3) R' R' N P O C l 3 / D MF R (31) Ar N N N CHO C HO R' Ar O . N N N H

R1

O DM F / POCl 3 (35) R2

N R 1 = H, CH 3 R 2 = H, NO 2

(36)

R2 (Scheme-12)

..

Goudarshivannanavar B. C. et al77 have reported that, 2-acetyl benzofurohydrozones (37) on reaction with Vilsmeier-Haack reagent at appropriate molar ratio, underwent smooth cyclization followed by formylation afforded 3(1benzofuran-2-yl)-1-(substituted phenyl)1H-pyrazole-4-carbaldehyde (38) (Scheme13).
OHC H N N DMF / POCl3 O Reflux / 2 hr (37) R R= H, NO2, CH3, OCH3, Cl, F, Br (Scheme - 13) (38) R N

Quiroga J. et al74 extended their work & carried out microwave assisted synthesis of pyrazolo[3,4-d]pyrimidines from 2-amino4,6-dichloropyrimidine-5-carbaldehyde under solvent free conditions (Scheme-11).
OH N H 2N N POCl3 / DMF OH H 2N N N Cl Cl O Ethanol, TEA HNR 1 R 2 Reflux H 2N N N Cl O NR 1 R 2

Method A or Method B HN N H2N (Scheme-11) N NR 1 R 2 N

Damljanovic I. et al78 reported that the condensation of acetylferrocene (39) with phenyl hydrazine (40) followed by intramolecular cyclization of the intermediate hydrazone (41) under Vilsmeier-Haack conditions formed 1H-3ferrocenyl-1-phenyl pyrazole-4carboxaldehyde (42) (Scheme-14)79.
Ph O Ph E th a n o l H r e fl u x Fe (4 1) Ph N P O C l3 ( 3 e q u i v ) D M F , r .t. Fe (42 ) (S ch e m e-14 ) N C HO N N H

+
Fe (39 )

H2N

(4 0 )

D) Synthesis of Pyrazoles Aruna kumar D. B. et al75 converted benzofurans (34) into benzofuran phenyl hydrozone (35) by treatment with phenyl

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Vera-Divaio M. A. F. et al80 illustrated Vilsmeier-Haack formylation of compound (43) into 1-Phenyl-1H-pyrazole-4carboxaldehyde (44) in 65% yield. The aldehyde functional group has been utilized to synthesize corresponding acid (45) (Scheme-15).
CHO N N Ph N Et3N, Ac2O COOH COOH N N

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O Me N (55) Me Me POCl3 / DMF O R N Me O R N Me N O (56) N Me Me

(57) (Scheme- 18)

DMF / POCl3

Popowycz F. et al 84 have prepared dimer (59) from 5-Methyoxy-1-methyl-7azaindole (58) using Vilsmeier-Haack reaction conditions (Scheme-19).
MeO BBr3, CH2Cl2, HO 0 0C,1 h, N N N N K2CO3, DM F, Br(CH 2)nBr, Br n=4-6, rt, 4h, O n N N

(43)

(44) (Scheme-15)

(45)

E) Synthesis of Quinolines Some S. et al81 developed a new protocol for the preparation of quinolines (50) involving the subjection of certain enolizable ketones (46) to a Vilsmeier-Haack haloformylation reaction (Scheme-16)82.
POBr3, DMF O (46) (47) Cu, DMSO, CHO X

(58) OHC K2CO3, DM F, 80 0C, 6h, POCl3, DM F, rt, 3h, N N O O n N N CHO

M eNO2, NH4OAc, 120 0C, 4h NaBH4, SiO 2, i-PrOH/CHCl3, rt, 12h H2, RaneyNi, M eOH, 600C,6h, Ac2O, CH2Cl2, rt, 12h,

AcHN O N N (59) (Schem e- 19) O n N N

NHAc

+
Br O2N (X=Br or l) (48) Pd[O] (10 mol%) CHO H2

10% Pd on C N (50) (Scheme -16) O2N (49)

Barraja P. et al85 have synthesized chorobis-formylated derivatives (62) and (63) from substituted tetrahydroindolones (60) and (61) by using DMF/POCl3 and DCM at 00C (Scheme20).
Cl O Me DMF/POCl3,DCM N N Me (60) Cl O DMF/POCl3,DCM Me N 00C then reflux Me (63) OHC Me CHO 00C then reflux Me (62) OHC CHO Me

F) Synthesis of Indoles Diana P. et al83 have reported a rapid access to 1,4-Bis-indolyl-diketones (54) using Vilsmeier-Haack reaction (Scheme-17).
R N H R POCl3 / DMF NaOH N H CHO R N SO2Ph Thiazolium Salt, EtOH O R N N (54) SO2Ph CHO NaH / THF ClSO2Ph

N Me (61)

(Scheme-20)

O R

(Schem e- 17)

They have also converted N-methyl derivatives (55) into 1, 4-diketones (57) by Vilsmeier-Haack reaction using phosphorous oxychloride and tetramethyl succinamide (56) (Scheme-18).

G) Synthesis of Pyranones and Naphthaldehydes Xiang-Ying Tang and Min shi86 have developed a convenient and efficient method to synthesize3-(2-Chloroethyl)-5aryl-4H-pyran-4-ones(65) and 2-Chloro-3(2-chloroethyl)-1-napthaldehydes (66) in moderate to good yields via the VilsmeierHaack reaction of readily available 1Cyclopropyl-2-aryl ethanones (64) at different temperatures (Scheme 21).

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O DM F/POCl 3 (12.0 equiv), 80-100
0C

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using Vilsmeier-Haack reaction (Scheme25). Formyl thiophene derivatives are versatile Crossroads intermediates.
O O CH P O C l3 / D M F / 6 0
3 0C

O DM F/ POCl 3 (64) (12.0 equiv), 120-135 0C (Scheme-21) R

CHO Cl Cl (66)
R (73 ) R

H Cl

N a 2S .9H 2O / D M F ClC H 2 C O C H3 / K2 C O
3

H) Synthesis of Oxazines Damodiran M. et al87 have reported the synthesis of highly functionalized oxazines (68) by Vilsmeier-cyclization of amidoalkyl naphthols (67) (Scheme-22).
R O R1 N H OH R1 = H, CH3, Ph (67) (Scheme-22) 3 h, 90 0C O CHO R2 = CH3, Ph, CHO (68) DMF / POCl 3 NH R2 R

O R O S P O C l3 / D M F / 6 0
0C

R H S Cl

N a 2S .9H 2O / D M F ClC H 2 C H O / K2 C O
3

R S S (7 4 ) (S c h em e -2 5 ) CHO

Bhatti H.S. and Seshadri S.90 formylated benzo[b] thiophene-3(2H)-one-1,1-dioxide (75) by using DMF and POCl 3 to give (76) (Scheme 26).
O DMF/POCl3 Cl + CH=N(CH3)2 S O O _ Cl H2O S O 76 (Scheme-26) O OH CHO

Tabuchi Y. et al73 have suggested, the ring closure reaction of 2-acetyl-(E)-3-aralKenylcarbonylaminobenzo[b] furans (69) using Vilsmeier reagent which generated oxazine (70) (Scheme-23).
R3 NHCOR3 R1 COCH3 O R2 (69) 2) Method A (NaOH aq. sol.) or Method B (Et3N), 16-46% O R2 (70) (Scheme-23) 1) POCl3, DMF, 25 0C R1 N O CHCHO

S O 75

K) Synthesis of Naphthyridinepyrazoles Mogilaiah K. et al91 used V-H reaction condition to develope a simple and efficient method for the synthesis of 1-[3-(3fluorophenyl)[1,8]naphthyridin-2-yl]-3-(2oxo-2H-chromenyl)-H-4-pyrazolecarbaldehydes (78) from (77) (Scheme 27).

I) Synthesis of Chromones Wang B. D. et al88 have prepared the 6hydroxy-3-carbaldehyde chromone via Vilsmeier-Haack reaction. The compounds 6-hydroxy-4-chromone-3-carbaldehydes (72) were easily prepared by the reaction of 2,5,-dihydroxy acetophenone (71) with DMF in POCl3 solution (Scheme-24).
OH (CH3CO)2CO 98%H2SO4 OH OCO CH3 OH (71) (Schem e- 24) OCO CH3 AlCl3 OH COCH3 D MF, PO Cl3 HO O (72) CHO O

F CH3 N N NHN (77) C O O R2 POCl3 -DMF / SiO2 MW R1

F N N N N R1 (78) CHO O O R2 (Scheme-27)

J) Synthesis of Bithiophenes and Benzothiophene dioxides Herbivo C. et al89 synthesized a series of formyl substituted 5-aryl-2,2-bithiophenes (74) starting from acetophenones (73)

L) Synthesis of Quindolines Dutta B. et al92 have reported the V-H formylation of 2-nitroacetophenone (79) with POCl3 in DMF, to produce the Chlorocinnamaldehyde (80) (Scheme 28).

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NO 2 CH 3 O (79) (Scheme-28) POCl3,DMF,00C,1h 800C,4h H CHO (80) NO 2 Cl

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M) Formylation of Pyrrolones Becker C. et al93 have used Vilsmeier-Haack reaction conditions for the synthesis of enaminoimine (85) and enaminoaldehyde (86) starting from Pyrrolin-3-on-1-oxide derivatives (81) (Scheme 29).
R N D MF POCl3 O (81) Cl O (82) R N DMF POCl3 Cl Cl (83) R N _ Cl Cl O N

O) Formylation of Pyrenopyrrole Gandhi V. et al96 carried out, VilsmeierHaack formylation of pyrenopyrrole (91) to afford monoaldehyde (92) which after protection of pyrrole and further treatment with POCl3-DMF afforded the dialdehyde (94) (Scheme 32).
POCl3 / DMF

N H (91) Piperidine

N H

CHO (92) EtO2C-CH2-CN

1. POCl3 DMF 2. NaOH OHC N H (94) CHO N H (93) C H C CO2Et CN

(84) -D MF - H+

(Scheme-32)

O H N Cl Cl (86)

N Cl Cl (85)

(Scheme-29)

They have also reported, the reaction of exo-cyclic enhydroxylaminone (87) with the Vilsmeier reagent to form chlorosubstituted compound (88) (Scheme 30).
POCl3, DMF _ 2. OH

P) Synthesis of Azeteochlorins Banerji S. et al 97 have reported the formation of chlorophin monoaldehyde (96) from chlorophin (95) upon treatment with DMF/POCl3 in CHCl 3 followed by addition of aq.NaHCO3. The reaction of (96) with methyl-Grignard, followed by an acidcatalyzed ring-closure reaction, generated the compound [meso-tetraphenyl-2methylazeteo-chlorinato] Ni (II) (97) in good yields (Scheme 33).
Ph Ph CHO

1. O OH N N (87)

O Cl H N N
Ph

N Ni N

N Ph N (1) DMF-POCl3 ,CHCl3 (2) aq. NaHCO 3 Ph

N Ni N

N Ph N

Ph (95)

Ph (96) MeMgBr, dry THF

(88) (Scheme-30)
Ph

Ph Me Me OH

N) Formylation of Phloroglucinols Naturally occurring phloroglucinol compounds have shown diverse range of biological activities94. Bharate S. B. et al95 formylated monoacyl phloroglucinol (89) to acylphloroglucinols (90) using V-H reaction (Scheme 31).
CHO HO R1 EtOAc,rt.1h O (89) (Scheme-31) OH O OH (90) O R POCl3,DMF R1 HO O R

N Ph N Ni

N Ph (1) TMSOTf, CH 2Cl2 N (2) aq NaHCO 3 Ph

N Ni N

N Ph N

Ph (97) (Scheme-33)

Ph

Q) Miscellaneous V-H reactions Bera R. et al98 used Vilsmeier-Haack reaction condition for alkynylation of Chloroacroleins. -Chloroacroleins(99) were readily prepared from the corresponding Ketones (98) by a VilsmeierHaack-Arnold reaction, which were then treated with terminal alkynes in acetonitrile

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in the presence of 10% Pd/C, PPh3, CuI and Et3N under nitrogen to afford 4-alkynyl-2Hchromene-3-carbaldehydes (100) (Scheme 34).
CHO O n O DMF / POCl3 O n Cl HC R Pd/C, PPh3, CuI Et3N, CH3CN 80, 2-3h Z (98)
n= 1, 2 Z= H, Br

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CHO O n C R

Z (99)

Z (100)

glutarimides 103, 104and 106 demonstrated antidepressant like activity in the four-plate and the swim tests in mice, respectively. These glutarimides also inhibited the locomotor activity of mice. The antidepressant-like effect of 106 was reported significantly stronger than that induced by imipramine used as a reference antidepressant.
O N R1R2 N N CF3

(Scheme-34)

Bubenyak M. et al99 showed that, Deoxyvasicinone (101), upon VilsmeierHaack formylation using two equiv. of POCl3 in DMF at 600C for 3 hrs. gave the 3dimethylaminomethylene derivative (102) in 94% yield (Scheme-35).
3 N 1 O (101) N

(103-104) 103, R =R2 =H 104, R1=R2 = -(CH2)2O N O R1 R2 N N CF3

1

(105-106)

105, R1=R2 =H
Dimethylformamide, 2 equiv POCl3, rt, 1h, 60 0C 3h (94% yield) N O (102) (Scheme- 35) N

106, R1=R2 = -(CH2)2-

Glutarimides Piperidine-2,6-diones(glutarimides, cyclic imides) have various biological activities100 and the 2,6-piperidinedione moiety constitutes an important substructure in several new anticancer agents which have recently been introduced into experimental chemotherapy101,102. Furthermore, these have been used as precursors in the synthesis of a variety of heterocyclic compounds103. Therefore, the synthesis of piperidine-2,6-dione derivatives have attracted considerable attention of synthetic chemists and several methods have been reported in the literature104-112, most of which have used multi-step reactions using harsh reaction conditions. Many compounds possessing a cyclic imide moiety exhibit pharmacological activity such as antitumor113, 113 immunosuppressive , sedative113, 113 114 anxiolytic , anticonvulsive and others115. Paluchowska M. H. et al 116 have showed that, the glutarimides 103 and 105 demonstrated anxiolytic activity while the

Shaabani A. et al117 have synthesized fully functionalized N-alkyl-2-triphenyl phosphora-hylidene glutarimides (107) and concluded that these glutarimide derivatives constitute an essential part of many natural products with antibacterial, antitumor or fungicidal activity. Chen C. Y. et al107 have reported one-pot facile synthesis of N-alkyl 3-(E)-alkylidine5-substituted sulfonylpiperidine-2,6-dione (108). 3
Ph3P O CO2R2 CO2R2 N R' O

R1

O S O

=O

N 2 R (10 8 )

(107)

Kiyota H. et al118 suggested the synthesis of actiketal (RK-441S) (109) as a new acetal type glutarimide antibiotic119 which is expected to be a new anti-cancer agent and an immunosuppressant because of its low cytotoxicity119,120. In recent years Fu R. et al121 have developed protected (R) and (S)-glutarimides (110) as a versatile building blocks122,123 for the asymmetric synthesis of substituted 3piperidinol containing alkaloids and pharmaceutically relevant molecules.

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IJPCBS 2012, 3(1), 25-43

Rajput et al.
2 C O 2R

ISSN: 2249-9504
O E tO + C O 2R
2

C H l2 2C PPh3B r r.t. 24h

Ph3P

2 C O 2R 2 C O 2R

In view of these useful pharmacological properties, biological activities and synthetic applications of glutarimides, various methods have been developed for their synthesis. Some of the important methods are described in the following schemes. 1) Method due to Kiyota H. et al118
O
0 CO2M e Pd(OAc)2 ( 1eq.), AcOH,60 C

R ' NC +

O N O R '

(Schem e-41)

CO2Me CO2Me H2,Pd Powder,EtOA c (98%) O CO2M e CO2M e

CO2M e

O O NH O

i. KOH,MeOH ii.Ac2O,heat iii.NH3gas,Et2O iV.NaOAc,Ac2O,heat (Scheme-36)

2)
Cl O Cl

Method due to Huang C. G. et al124

O 1. R'NH2 2. NaSPh 3. NaIO4 Ph S O N R' 1.NaH (2eq.) 2. R
2

O R2 O N R' S Ph

MeO O

(Scheme-37)

3) Methods due to Mederski Werner W. K. R. et al125

H2N H2N Cl (Scheme-38)
NO2 R NH2 (Scheme-39) HO2C CO2H O N O NO2 R

HO2C N

CO2H

O N O

N Cl NH2

PPA, 80C, 2h

PPA, 80C, 12h

4)
Ts

Method due to Chen B. F. et al126

OMe + NH R EtO O 3 eq. NaOH Ts O 5 OMe 6 N O R

(Scheme-40)

5)

Method due to Shaabani A. et al117

Dihydropyridines 1,4-dihydropyridines and their derivatives are an important class of bioactive molecules in the pharmaceutical field127. The dihydropyridine heterocyclic ring is a common feature of a variety of bioactive compounds including anticonvulsant, antidiabetic, antianxiety, antidepressive, antitumor, analgesic, sedative, vasodilator, bronchodilator, hypnotic and antiinflammatory agents128. Diydropyridines are reported as calcium channel blockers129 and are clinically useful agents for the treatment of cardiovascular diseases such as anginapectoris130 and hypertension131.These are also used as antioxidants and are important for developing drugs. However, these are relatively difficult to synthesize. During the years 1980-1990 considerable importance was acquired by derivatives of 1,4-dihydropyridines, as the first representatives of highly effective vasodilators and antihypertensive agents, the calcium channel blockers (Nicardipine, Nifedipine, Felodipine, etc)132-134. Many derivatives of 1,4-dihydropyridines with more valuable pharmacological properties135-137, which make further searches in the 1,4-dihydropyridine series extremely urgent. Till date an enormous number of symmetrical and unsymmetrical derivatives of 1,4-dihydropyridine with various functional substituents have been synthesized, and a great number of methods of obtaining them (including microwave) have been developed by further conversions and aromatization138-142. Scientists from the Latvian Institute of Organic Synthesis have carried out the systematic synthesis of numerous derivatives of 1,4-dihydropyridines with the aim of searching for new cardiotonic and ionotropic preparations, and clarification of structureactivity relationships143-145. In addition to this formyl group present on pyridine and

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IJPCBS 2012, 3(1), 25-43

Rajput et al.

ISSN: 2249-9504

O O OH NH
O N 1 P (1 1 0)

OP O

3. Method due to Pan W. et al.69

O O NHPhCl - 4 DMF/POCl3 (10.0 equiv) 800C, 1 h OHC Cl N PhCl - 4 O CH2CH2Cl

O (1 0 9 )

dihydropyridine molecules make them promising precursors for further synthetic transformations. The use of formylation reaction as synthetic strategy to form versatile carboxaldehyde intermediates is still of interest, due to both their intrinsic pharmacological properties and chemical reactivity146. Formylation reactions have been described for pyrazoles147, pyridines148 and pyrimidines149 as a key step to the introduction of functionalities via the intermediate carboxaldehydes, and further cyclization to fused heterocycles. VilsmeierHaack reaction carried out on methylene-active compounds leads mainly to the formation of -halo-carboxaldehyde derivatives, which are useful precursors in the construction of different heterocyclic compounds by means of numerous transformations150-151. We have concentrated much of our recent work on the preparation of bioactive nitrogencontaining heterocycles. By considering the importance of formyl pyridines different researchers have developed the various methods for the synthesis of chloroformylation of pyridines and dihydropyridines as described in the following schemes. 1. Method due to Kvitko I. Y. et al.15
HOC O N Ph (Scheme-42) O DMF / POCl3 Cl N Ph Cl CHO

(Scheme-44)

4. Method due to Tabuchi Y. et al.73

NHCOR3 R1 COCH3 O R2 R2 (Scheme-45) POCl3, DMF, 24 0C R1 N CHO O Cl

5. Method due to Quiroga J. et al.154

Ar DMF / POCl3 N N Ph N H O (Scheme-46) N N Ph N Cl Ar CHO

2. Method due to Maddox M. L. et al.153

R
+

Rajput A. P.155 have synthesized 1,4diazepine type compounds and reported their useful biological activities, pharmaceutical properties and therapeutic applications. Rajput A. P.156 have formylated 2Aryliminothiazolid-4-ones using V-H reagent. The formylated synthones were used to synthesize various fused heterocyclic ring systems containing thiazole moiety and some heterocyclic Schiff bases to get some compounds of interesting biological activities Rajput A. P. and Rajput S. S.157 have reported that, the condensation of 4chlorophenyl carboxylic acid hydrazide with different acetophenones and acetaldehydes afforded the corresponding acetophenones/acetaldehydes 4chlorophenyl carbonyl hydrazones which on V-H reaction formylated the compound 1-(3-aryl/alkyl-4-formyl pyrazole-1carbonyl)-4-chlorobenzenes.
O Cl C NH N CH3 C DMF / POCl3 00 C O

DMF O N H R HOC Cl N R HOC Cl N CHO Cl NMe2 H O + 3 Cl O POCl3 or (COCl)2

Me2 N = HC Cl Cl H R HOC Cl N H CHO Cl

CH= NMe2 NaOAc Cl H 2O Cl

(NH 4)2Ce(NO 3) 6

Cl

CHO
a, R= C6H5 b, R= 3-ClC6 H4 c, R= 3-NO2 C6H4 d, R= 3-CF3C 6H4 e, R= H

Scheme-47

(Scheme-43)

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IJPCBS 2012, 3(1), 25-43

They158 have also prepared various dichloro, diformyl derivatives of pyrrole on formylation using V-H reagent from various succinimide derivatives.
HOC O N O Cl N CHO Cl

Rajput et al.

ISSN: 2249-9504

DMF / POCl3 0-50C

111a-f

R 112a-f

R: a =H, b = 2-Cl, c = 3-Cl, d = 4-Cl, e = 4-CH 3, f = 4-OCH3 (Scheme-48)

Rajput A. P. and Rajput S. S.159 have formylated benzaldehyde substituted

SOCl 2 HOOC COOH R Reflux NH2 R O N

phenyl carbonyl hydrazones by using V-H reaction. Rajput A. P. and Bhadane S. J. 160 have carried out formylation of N-substituted phenyl succinimides. From these compounds various heterocyclic compounds have been synthesized. Rajput A. P. and Girase P. D.161-166 have reported the synthesis, characterization and microbial screening of various nitrogen, oxygen and sulphur heterocyclic compounds from 2,6-dichloro 3,5-diformyl (N-substituted Phenyl)-4-hydropyridines.
OHC CHO

O DMF, POCl3 0-50C

Cl

Cl

R 114 a-d 115 a-d

113

R, a = -H, b = -4Me, c = -4Cl, d = -2Me (Scheme-49)

Na2 S D M F, R1

OHC

CHO N S R1
R, a b d g = = = = -H , -4C H 3 - 4 C l, -2 C H 3 R1 , a b d g = = = = -C 2H 5 -C 2H 5 -C 2H 5 -C 2H 5

R 1S

R 11 6 a-g

OHC OHC CHO NaN3 Cl N Cl P T S A , E tO H R R 1 15 a- g N C 11 7 a-g N3 N

CHO N3
R, a b d g = = = = -H , -4 C H 3 -4 C l, -2C H 3

N
R, a = -H , b = -4 C H 3 d = -4 C l , f = -4O C H 3

C AN N H 3 ,0 0 C

Cl

Cl

R 11 8 a -f Sc he m e-5 0

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IJPCBS 2012, 3(1), 25-43

O OHC Cl N CHO R' O R' R 115 a-f R a=-H b = - 4 CH3 c=-2Cl d=-4Cl e=-3Cl f = - 4 OCH 3 C CH 3 Cl

Rajput et al.
R' O R' N Cl NH2-NH2 .H2 O N N H Cl N Cl N H

ISSN: 2249-9504
R' N

Cl

R 119a-f(i) 119a-f(ii) R', (i) = -Ph (ii) = -4OH-Ph

R 120a-f(i) 120a-f(ii)

(Scheme-51)

R' O R' Cl N Cl CH3 COONa in CH3COOH R R 119a-f (i) 119a-f(ii) R a=-H b = - 4 CH3 c=-2Cl d=-4Cl e=-3Cl f = - 4 OCH3 R', (i) = -Ph (ii) = -4OH-Ph 121a-f (i) 121a-f (ii) O R' NH2OH.HCl N O Cl N Cl O

R' N

(Scheme-52)

R1

R1

OH C

CHO

S N =H C CH =N O N

S O N

Cl

Cl 2m oles

Cl

Cl

H S C H 2C O O H

Cl

Cl

N H2 R 1 1 5 a-f R1 R 1 2 2 a-f ( i ), ( ii )

2 m oles

R1 R 1 2 3 a-f ( i ), ( ii )

R1

R , a = -H , b = - 4 M e, c = - 2C l, d = - 4 C l, e = - 3C l, f = - 4 O M e R 1 , (i) = - 4 M e (ii) = - 4 C l Sch em e -5 3

OHC Cl N

CHO Cl NaN 3

O HC N3 N

CHO 2 N a2 S2 O4 N3

OHC H2 N N

CHO 2 C H 2( C N ) 2 N H2

P T S A , E tO H R 115 a-d R 1 24 a-d R 125 a-d C N N N N H2 N

N R, a b c d = = = = -H , -4C H - 4 C l, -2C H

C H2 N

R 1 26a-d

(S c h em e -54 )

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CONCLUSIONS This review has attempted to summarize the synthetic methods and reactions of glutarimides and dihydropyridines. Many biologically active heterocyclic compounds have been synthesized from that heterocycle. These reactions greatly extended synthetic possibilities in organic chemistry. REFERENCES 1. Jones, G.; Stanforth, S. P. Org. React. 2001, 49, 1. 2. (a) Meth-Cohn, O.; Narine, A. B. Tetrahedron Lett. 1978, 23, 2045. (b) Khan, A. K.; Shoeb, A. Indian J. Chem. Sect. B, 1985, 24, 62 3. (a) Sreenivasulu, M.; Rao, K. G. S. Indian J. Chem. Sect. B, 1989, 28, 584.(b) Mahata, P. K.; Venkatesh, C.; Syam Kumar, U. K.; Ila, H.; Junjappa, H. J. Org. Chem. 2003, 68, 3966.(c) Chupp, J. P.; Metz, S. J. Heterocycl. Chem. 1979, 16, 65; (d) Katrtizky, A.R.; Arend, M. J. Org. Chem. 1998, 63, 9989 4. Vilsmeier, A. and Haack, A. Che. Ber. 1927, 60, 199 5. (a) Lilienkampf, A.; Johansson, M. P.; Whl, K. Org. Lett. 2003, 5, 3387; (b) Perumal, P. T. Indian J. Heterocycl. Chem. 2001, 11, 1;(c) Wang, K.-W.; Xiang, D.-X.; Dong, D.-W. Org. Lett. 2008, 10, 1691; (d) Jones, G.; Stanforth, S. P. Org. React. 2000, 56, 355; (e) Chen, L.; Zhao, Y.-L.; Liu, Q.; Cheng, C.; Piao, C.R. J. Org. Chem. 2007, 72, 9259; (f) Zhang, R.; Zhang, D.; Guo, Y.; Zhou, G.; Jiang, Z.; Dong, D. J. Org. Chem. 2008, 73, 9504;(g) Wuts, P. G. M.; Northuis, J. M.; Kwan, T. A. J.Org. Chem. 2000, 65, 9223. 6. (a) Campaigne, E.; Archer, W. L. J. Am. Chem. Soc. 1953, 75, 989; (b) Treihs, W.; Neupert, H. J.; Hiebsch J. Chem. Ber. 1959, 92, 141 7. (a) Procopiou, P. A.; Brodie, A. C.; Deal, M. J.; Hayman, D. F. Tetrahedron Lett.1993, 34,

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