review article on vilsmeier-haack reaction

IJPCBS 2012, 3(1), 25-43 Rajput et al. ISSN: 2249-9504

25

INTERNATIONAL JOURNAL OF PHARMACEUTICAL, CHEMICAL AND BIOLOGICAL SCIENCES Available online at www.ijpcbs.com

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.S’s Dadasaheb Rawal College, Dondaicha, Dhule, Maharashtra, India.

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[2,3-d]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 N-methylacetanilide 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.

Review Article

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.


26

N

N

H C6H4

Me

Me

C6H4

Cl

Me

N

N

Me

Cl Cl

N

Me

Cl

Me

Me

Cl

Cl Cl

+C

(1)

+

(2) (3)

-

- -

+

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.

N CH

OPOCl2CH3

CH3

N CH

OPOCl2CH3

CH3

..

N CH

CH3

CH3

Cl

N CCl

H

OPOCl2CH3

CH3

..

OPOCl2

+

+

+

+

-

-

a 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.

R

O

C N R 1 R 2 P OCl3 R CNR 1R 2

O P O Cl2

R

NR 1R 2

CC l

P O 2Cl2R

O

C N R 1 R 2 ArS O 2 Cl

C lR C

O

NR 1R 2

S

O

OA r

R CC l

N R 1 R 2

Ar S O 3

( D ) P O 2Cl

+

+ +

+

+

(A )

-

(B )

(E)

-

C H A R T -I N a ture of V ilsm eie r-H aac k R ea gen t

-

.. .

..

......

...

...

.

. .

.

-C l

C l-

.

(F)

+ +

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 C

O POCl2

NR1R2

R

NR1R2

CCl

PO2Cl2

CO

R

NR1R2

Cl2X R C

O

NR1R2

Cl

R

NR1R2

CCl

X O

Cl

+

+

(A)

-

(B)

+

(C)

-----X

+

(D)X = CO, SO or PCl3

...

.

.... ..

.

.

...

.

.... ..

.

.

+

-

-Cl

-Cl +

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. N-Methyl formanilide and N,N- dimethyl formamide are commonly used. N-Methyl formamide, N-formylpiperidine27 and N-formylindeline28 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 POCl3 have also been used in the Vilsmeier reactions. They are COCl231, SOCl232, ClOCl33, CH3COCl34, ArCOCl34,35, ArSO2Cl35, PCl536, Me2NSO2Cl37 and RO2CNH SO2Cl38.


27

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, Arumugam S. (1994)59, 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 Vilsmeier-Haack Reaction

i) Formylation of aromatic hydrocarbons, phenols, phenolethers, olefins, ketones, Beta-chlorovinylal dehydes.

ii) Diformylation reactions. iii) Formylation with aromatization.

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-2-carbethoxypyrrole (6) from compound (4) with POCl3, DMF and heat followed by NaPF6/H2O via formation of Vinylogous iminium salt (5) (Scheme-1).

COOHNN

Me

Me

Me

Me

PF6

N CO2Et

H

POCl3 / DMF

NaPF6/H2O H2N CO2Et

DABCO.DMFand heat

+

-

and heat followed by

(4)

(5) (6)

(Scheme-1) They have also reported microwave accelerated Vilsmeier-Haack formylation of pyrrole (7) into formyl pyrrole (8) (Scheme-2).

N

YX

CO2Et N

YX

CO2EtOHC

POCl3,DMF

Microwave heating

(Scheme-2) (7) (8) Z= H, Me

Z Z

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

N NN

O

OR2R1

CF3

(105-106)

105, R1=R2 =H

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


28

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).

N

F F

EtO2C N

F F

CHOEtO2C

POCl3, DMF

DCE 800C

(9) (10)

(Scheme-3) 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 V-H reagents (Scheme-4).

POCl3

NH2NH2.H2O,

POCl3,

CH3CN,

N

OO

OH

O

N

OO

OH

O OH

NHN

NH

OEtOOC

NHNN

EtOOC Cl

2.0 equiv

DMF, 100 0C, 2 h 77%

1.5 equiv EtOH 90 0C, 3 h, 72%

2.0 equiv

80 0C, 5 h

(11)

(14)

(12)

(13)(Scheme-4)

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-5,6-dihydro-4H-pyrans (15), (16) and (17) respectively (scheme-5).

OAr H N

O

N

X( C H 2)3 Br

O

O H C A r

O

O

N

B r( C H 2)3 Br

O

O H C P h C lP Br3 / D M F

( C H 2)3 Br

N H P h C l

O O

OP h N H

O

N

B r

(C H2 )3 Br

O

O H C PhP Br3 / D M F

(5 .0 eq u iv )

8 0 0C , 1 0 m in

- 4

+- 4

(1 6 )

(1 7 )

(1 9 )

(2 0 ) (S ch em e-5 )

(3 .0 eq u iv )

8 0 0C

(1 5 ) (1 8 )

P B r3 /D M F (5 .0 eq u iv )

8 0 0C

4 -C lP h H N

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

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

DMF/POCl3

NHPhCl

O O

N

Cl

CH2CH2Cl

O

PhClOHC

N

Cl

CH2CH2ClO

PhCl

800C, 1 h

1200C, 2 h

- 4

(10.0 equiv)

(10.0 equiv)

- 4

- 4

(21)

(22)

(23)(Scheme-6)

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

N Cl

CN

(25)(24)

(Scheme-7)

R1R2

R2

R1

1. POCl3, DMF, rt, 12h

2. NCCH2CN, 90 0C, 2h3. Aq. K2CO3

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)

NN

N

CH3

R

R'Ph

NN

N

CH3

R

R'Ph

CHO

POCl3/DMF

R=H, C6H5

(Scheme-8)

(26) (27)


29

Tabuchi Y. et al73 used Vilsmeier-Haack condition for the synthesis of 4-chloro-3-formylbenzo[b]furo[3,2-b] pyridine (29) from 2-acetyl-3-acylaminobenzo[b] furans (28) (Scheme-9).

OCOCH3

O

NCHO

Cl

R1

R2

NHCOR3

R1

R2

POCl3 , DMF, 24 0C

(28) (29)(Scheme-9)

C) Synthesis of Pyrimidines Quiroga J. et al17 suggested the regioselective formylation of pyrazolo [1,5-a] 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-3-carbaldehyde (33) (Scheme-10).

NN

R'

R

Ar

NNN

R'

R

Ar

N HO

H

CHO

NN

R'

R

Ar

N NN

R'

R

Ar

N

C HO

...

P OCl3 / D MF

N BS/ Eth ano l

P OC l3 / D MF

(3 3)(32)(Sch eme-10)

(30 ) (31)

Quiroga J. et al74 extended their work & carried out microwave assisted synthesis of pyrazolo[3,4-d]pyrimidines from 2-amino-4,6-dichloropyrimidine-5-carbaldehyde under solvent free conditions (Scheme-11).

POCl3 / DMFN

N

OH

OHNH2

N

N

Cl

ClNH2

O N

N

Cl

NH2

O

N

NNH2

NNH

Ethanol, TEAHNR1R2

Reflux

Method A or Method B

NR1R2

NR1R2

(Scheme-11) D) Synthesis of Pyrazoles Aruna kumar D. B. et al75 converted benzofurans (34) into benzofuran phenyl hydrozone (35) by treatment with phenyl

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).

O

C H3

NNH

N NO

OH

NH

N H2

O

O

C H3

(35)

(34)

(Scheme-12)

(36)

R1

R1= H, CH3

R2= H, NO2

R1

R2

EtOH / AcOH

R1

R2

DM F / POCl3

R2

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(1-benzofuran-2-yl)-1-(substituted phenyl)-1H-pyrazole-4-carbaldehyde (38) (Scheme-13).

O N NH

R

O N N

R

OHC

DMF / POCl3

R= H, NO2, CH3, OCH3, Cl, F, Br

Reflux / 2 hr

(37) (38)

(Scheme - 13) 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-3-ferrocenyl-1-phenyl pyrazole-4-carboxaldehyde (42) (Scheme-14)79.

O

NHNH 2

P hN

N H

P h

NN

P h

C H O

( 4 2 )

( 4 1 )

( S c h e m e - 1 4 )

F e F e+

E th a n o l

r e fl u x

F e

P O C l3 ( 3 e q u i v )

D M F , r . t .

( 3 9 )

(4 0 )


30

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

NN

DMF / POCl3 NN

(43) (44)

Ph COOH

Et3N, Ac2O

NN

COOH

(45)

(Scheme-15)

CHO

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.

O Br

CHO

CHO

O2NN

X

O2N

POBr3,DMF

Cu, DMSO,

(X=Br or l)

10% Pd on C

+

Pd[O] (10 mol%)

H2

(46) (47) (48)

(49)(50)(Scheme -16)

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).

N

R

HN

R

H

CHO

N

R

SO2Ph

CHO

N

R

H

O

N

R

SO2Ph

O

POCl3 / DMF

NaOH

NaH / THF

ClSO2Ph

Thiazolium Salt,EtOH

(54)(Scheme- 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).

N

R

Me

N

R

Me

O

N

R

Me

O

POCl3 / DMF

NO

ON

Me

MeMe

Me

(57)

(Scheme- 18)

(56)(55)

Popowycz F. et al84 have prepared dimer (59) from 5-Methyoxy-1-methyl-7-azaindole (58) using Vilsmeier-Haack reaction conditions (Scheme-19).

N N

MeO

N N

OH

N N

OBr n

NN

OOHC

N N

On

CHO

NN

O

AcHN

N N

On

NHAc

(58)

(59)

(Scheme- 19)

NaBH4, SiO2, i-PrOH/CHCl3, rt, 12h

BBr3, CH2Cl2, 0 0C,1 h,

K2CO3, DMF, Br(CH2)nBr,n=4-6, rt, 4h,

K2CO3, DMF, 80 0C, 6h,

POCl3, DMF, rt, 3h,

MeNO2, NH4OAc, 120 0C, 4h

H2, Raney Ni, MeOH, 60 0C,6 h, Ac2O, CH2Cl2, rt, 12h,

Barraja P. et al85 have synthesized choro-bis-formylated derivatives (62) and (63) from substituted tetrahydroindolones (60) and (61) by using DMF/POCl3 and DCM at 00C (Scheme20).

NMe

MeO

NMe

MeCl

OHCCHO

NMe

O

Me NMe

ClOHC

Me

CHO

DMF/POCl3,DCM

00C then reflux

(60)(62)

DMF/POCl3,DCM

00C then reflux

(61)(63)

(Scheme-20)

G) Synthesis of Pyranones and Naphthaldehydes Xiang-Ying Tang and Min shi86 have

developed a convenient and efficient

method to synthesize3-(2-Chloroethyl)-5-aryl-4H-pyran-4-ones(65) and 2-Chloro-3-(2-chloroethyl)-1-napthaldehydes (66) in moderate to good yields via the Vilsmeier-Haack reaction of readily available 1-Cyclopropyl-2-aryl ethanones (64) at different temperatures (Scheme 21).


31

OR

O

O

ClR

Cl

Cl

CHO

RDMF/ POCl 3

DMF/POCl3

(12.0 equiv), 80-100 0C

(12.0 equiv), 120-135 0C(64)

(65)

(66)(Scheme-21)

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).

OH

NH

O

O

NH

CHO

R R

(68)(Scheme-22)

(67)

R1= H, CH3, PhR2 = CH3, Ph, CHO

DMF / POCl3

R1

R23 h, 90 0C

Tabuchi Y. et al73 have suggested, the ring closure reaction of 2-acetyl-(E)-3-aral-Kenylcarbonylaminobenzo[b] furans (69) using Vilsmeier reagent which generated oxazine (70) (Scheme-23).

OCOCH3

O

ON

CHCHO

R1

R2

NHCOR3

R1

R2

R3

1) POCl3, DMF, 25 0C

2) Method A (NaOH aq. sol.) or Method B (Et3N), 16-46%

(69) (70)

(Scheme-23) I) Synthesis of Chromones Wang B. D. et al88 have prepared the 6-hydroxy-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

OH

(CH3CO)2CO

H2SO498%

OCOCH3

OCOCH3

OH

OH

COCH3AlCl3 DMF, POCl3

O

O

OH CHO

(71) (72)

(Scheme- 24)

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)

using Vilsmeier-Haack reaction (Scheme-25). Formyl thiophene derivatives are versatile “Crossroads” intermediates.

C H 3

O

RC l

H

O

R

SO

R

C l C H 2 C O C H 3 / K 2 C O 3

SC l

RH

O

C l C H 2 C H O / K 2 C O 3 S

R

S C H O

( 7 4 )

( S c h e m e - 2 5 )

( 7 3 )

P O C l 3 / D M F / 6 0 0 C N a 2 S . 9 H 2 O / D M F

P O C l 3 / D M F / 6 0 0 C

N a 2 S . 9 H 2 O / D M F

Bhatti H.S. and Seshadri S.90 formylated benzo[b] thiophene-3(2H)-one-1,1-dioxide (75) by using DMF and POCl3 to give (76) (Scheme 26).

S

O

OO

DMF/POCl3

S

Cl

OO

CH=N(CH3)2

S

OH

OO

CHO+

75 76

(Scheme-26)

Cl_

H2O

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-(3-fluorophenyl)[1,8]naphthyridin-2-yl]-3-(2-oxo-2H-chromenyl)-H-4-pyrazolecarbalde- hydes (78) from (77) (Scheme 27).

N N NHN

F

OO

CH3

OO

NNN N

F

CHO

POCl3-DMF / SiO2

MW

(Scheme-27)

R2

R1C

R2

R1

(77)

(78)

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 β-Chlorocinnamaldehyde (80) (Scheme 28).


32

CH3

O

NO2

Cl

NO2

H CHO(79) (80)

POCl3,DMF,00C,1h

800C,4h

(Scheme-28)

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).

NR

O

NR

O

Cl

NR

Cl

ClN

Cl

Cl

O

N

Cl

Cl

N

NH

Cl

Cl

O

(81) (82) (83)(84)

(85)(86)

-DMF

- H+

_DMF

POCl3

DMF

POCl3

(Scheme-29) They have also reported, the reaction of exo-cyclic enhydroxylaminone (87) with the Vilsmeier reagent to form chlorosubstituted compound (88) (Scheme 30).

OHO

N

N

O

NH

N

Cl

POCl3,DMF

2. OH_

1.

(Scheme-30)(87) (88)

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).

O

OR

OH

OH O

OR

OH

CHO

OH

R1R1

POCl3,DMF

EtOAc,rt.1h

(89) (90)

(Scheme-31)

O) Formylation of Pyrenopyrrole Gandhi V. et al96 carried out, Vilsmeier-Haack 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).

NH N

HCHO

NH

CHN

HCHOOHC

CN

CO2Et

POCl3 / DMF

Piperidine EtO2C-CH2-CN

POCl3DMF

1.

NaOH2.C

(91)

(93)(94)

(92)

(Scheme-32)

P) Synthesis of Azeteochlorins Banerji S. et al97 have reported the formation of chlorophin monoaldehyde (96) from chlorophin (95) upon treatment with DMF/POCl3 in CHCl3 followed by addition of aq.NaHCO3. The reaction of (96) with methyl-Grignard, followed by an acid-catalyzed ring-closure reaction, generated the compound [meso-tetraphenyl-2-methylazeteo-chlorinato] Ni (II) (97) in good yields (Scheme 33).

N

Ph

Ph

N

Ph

N

Ph

N

NiN

Ph

Ph

N

Ph

CHO

N

Ph

N

Ni

N

Ph

Ph

N

Ph

Me

N

Ph

N

NiN

Ph

Ph

N

Ph

Me

OH

N

Ph

N

Ni

DMF-POCl3

NaHCO3

CH2Cl2

NaHCO3

(95) (96)

MeMgBr, dry THF

(97)(Scheme-33)

,CHCl3 (1)

(2) aq.

(1) TMSOTf,

(2) aq

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


33

in the presence of 10% Pd/C, PPh3, CuI and Et3N under nitrogen to afford 4-alkynyl-2H-chromene-3-carbaldehydes (100) (Scheme 34).

O On

DMF / POCl3

Z

(98)

On

Z

HC RPd/C, PPh3, CuI

Et3N, CH3CN80°, 2-3h

On

Z

C R

(99) (100)

(Scheme-34)

CHOCHO

Cl

n= 1, 2Z= H, Br

Bubenyak M. et al99 showed that, Deoxyvasicinone (101), upon Vilsmeier-Haack formylation using two equiv. of POCl3

in DMF at 600C for 3 hrs. gave the 3-dimethylaminomethylene derivative (102) in 94% yield (Scheme-35).

N

N

O

N

N

O

3

1

(101)(102)

(Scheme- 35)

Dimethylformamide,

2 equiv POCl3, rt, 1h, 60 0C 3h (94% yield)

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, immunosuppressive113, sedative113, anxiolytic113, anticonvulsive114 and others115. Paluchowska M. H. et al116 have showed that, the glutarimides 103 and 105 demonstrated anxiolytic activity while the

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.

N NN

O

OR2R1

CF3

(103-104)

103, R1=R2 =H104, R1=R2 = -(CH2)2-

Shaabani A. et al117 have synthesized fully functionalized N-alkyl-2-triphenyl phosph- ora-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)-alkylidine-5-substituted sulfonylpiperidine-2,6-dione (108).

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 3-piperidinol containing alkaloids and pharmaceutically relevant molecules.

NOR'

Ph3P

O

CO2R2CO2R2

(107)

NOR 2

O

(10 8 )

SR 1

O

=O

R 3

N NN

O

OR2R1

CF3

(105-106)

105, R1=R2 =H106, R1=R2 = -(CH2)2-


34

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

CO2Me

CO2Me+ O

CO2Me

CO2Me

ONH

O

O

(Scheme-36)

O

CO2Me

CO2Me

Pd(OAc)2 ( 1eq.), AcOH,600C

H2,Pd Powder,EtOAc (98%)i. KOH,MeOH

ii.Ac2O,heat

iii.NH3gas,Et2OiV.NaOAc,Ac2O,heat

2) Method due to Huang C. G. et al124

Cl Cl

O

1. R'NH2

2. NaSPh3. NaIO4

Ph S

O NR'

O1.NaH (2eq.)

2.

O

R2

MeO

NO

S

R'

Ph

O

(Scheme-37)

R2

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

N

H2N

H2NCl

HO2C CO2H

PPA, 80°C, 2h

N

NNH2

Cl

O

O(Scheme-38)

NO2

NH2

HO2C CO2H

PPA, 80°C, 12h

NO2

N

O

O(Scheme-39)

RR

4) Method due to Chen B. F. et al126 Ts

O NHR

+OEtO

OMe 3 eq. NaOH

NO O

Ts OMe

R

56

(Scheme-40)

5) Method due to Shaabani A. et al117

N CR' +CO2R

2

CO2R2

+EtO PPh3Br

O CH2Cl2

r.t. 24h NOR'

Ph3P

O

CO2R2

CO2R2

(Scheme-41) 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 anti-inflammatory 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 structure–activity relationships143-145. In addition to this formyl group present on pyridine and


35

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. Vilsmeier–Haack reaction carried out on methylene-active compounds leads mainly to the formation of β-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 nitrogen-containing 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

NPh

O ON

Ph

HOC CHO

Cl Cl

DMF / POCl3

(Scheme-42)

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

N OO

R

H

POCl3 or (COCl)2

HCl

CH=R

Cl

HC NaOAc

N

R

ClCl

HOCNMe2

R

Cl

HOC CHO

Cl NH

(NH4)2Ce(NO3)6

R

Cl

HOC CHO

Cl N

+ +

--DMF NMe2

Cl

Me2N =

H2O

H3O+

(Scheme-43)

a, R= C6H5b, R= 3-ClC6H4c, R= 3-NO2C6H4d, R= 3-CF3C6H4e, R= H

Cl

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

DMF/POCl3

NHPhCl

O ON

Cl

CH2CH2ClO

PhClOHC

800C, 1 h- 4

(10.0 equiv)- 4

(Scheme-44) 4. Method due to Tabuchi Y. et al.73

OCOCH3

O

NCHO

Cl

R1

R2

NHCOR3

R1

R2

POCl3, DMF, 24 0C

(Scheme-45) 5. Method due to Quiroga J. et al.154

NN N

HPhO

Ar

DMF / POCl3N

N NPh

Ar

CHO

Cl

(Scheme-46)

Rajput A. P.155 have synthesized 1,4-diazepine type compounds and reported their useful biological activities, pharmaceutical properties and therapeutic applications. Rajput A. P.156 have formylated 2- Aryliminothiazolid-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 4-chlorophenyl carboxylic acid hydrazide with different acetophenones and acetaldehydes afforded the corresponding acetophenones/acetaldehydes 4-chlorophenyl carbonyl hydrazones which on V-H reaction formylated the compound 1-(3-aryl/alkyl-4-formyl pyrazole-1-carbonyl)-4-chlorobenzenes.

Cl C NH

O

N C

CH3

NN

CHO

Cl C

O

Scheme-47

DMF / POCl3

00C

ON H

O

OO

O H

(1 0 9 )

NOP 1

O

( 1 1 0 )

O P 2


36

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

N OO

R

N ClCl

HOC CHO

R

R: a =H, b = 2-Cl, c = 3-Cl, d = 4-Cl, e = 4-CH3, f = 4-OCH3

DMF / POCl3

0-50C

111a-f 112a-f

(Scheme-48) Rajput A. P. and Rajput S. S.159 have formylated benzaldehyde substituted

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.

HOOC COOH

NO O

R

NCl Cl

CHOOHC

R

SOCl2 DMF, POCl3

NH2R

(Scheme-49)

113 114 a-d 115 a-d

Reflux

0-50C

R, a = -H, b = -4Me, c = -4Cl, d = -2Me

O H CN a 2 S

D M F , R 1

O H C

N

NC l C l

C H OO H C

R

NR 1 S S R 1

C H O

R

N

C H O

N 3N 3

R

NC l C l

R

N1 1 5 a - g

R , a = -H , b = -4C H 3

d = -4C l, g = -2 C H 3

1 1 6 a -g

1 1 7 a -g

1 1 8 a -f

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

R , a = -H , b = -4 C H 3

d = -4 C l , f = -4O C H 3

C A N

N H 3 ,0 0 C

N a N 3

P T S A , E tO H

S c h e m e-5 0

R 1 , a = -C 2 H 5 b = -C 2 H 5

d = -C 2 H 5 g = -C 2 H 5

C C


37

R' C

O

CH3NH2-NH2.H2O

NCl

R'

O

R'

O

Cl N C l

NN

C l

NN

HH

R'R'

NCl

CHOOHC

Cl

Ra = - Hb = - 4 CH3c = - 2 C ld = - 4 C le = - 3 C lf = - 4 OCH3

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

R R

119a-f(i)119a-f(ii)

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

(Scheme-51)

R

115 a-f

N ClCl

CHOOH C

R

N ClCl

CH =NN =H C

R

N H 2

N ClCl

N

SS

N

R

OO

HSCH 2COOH

R1

2moles

R 1R 1

R 1 R 12moles

Scheme-53

R , a = -H, b = - 4M e, c = - 2C l, d = - 4Cl, e = - 3C l, f = - 4O M e

R 1, (i) = - 4M e

(ii) = - 4Cl

115 a-f 122 a-f ( i ), ( ii )123 a-f ( i ), ( ii )

O H C

NC l C l

C H OO H C

R

N

C H O

N 3N 3

R

O H C

N

C H O

N H 2NH 2

R

N NN N H 2NH 2

R

NN

N a 2 S 2 O 4 C H 2( C N ) 2

1 1 5 a -d 1 2 4 a -d

R , a = -H , b = -4 C H 3 c = -4 C l, d = -2 C H 3

N a N 3

P T S A , E tO H

CC

1 2 5 a -d

2 2

( S c h em e - 5 4 )1 2 6 a -d

NCl

R'

O

R'

O

ClN Cl

ON

Cl

ON

R'R'

NH2OH.HCl

CH3COONa in CH3COOH

Ra = - Hb = - 4 CH3c = - 2 C ld = - 4 C le = - 3 C lf = - 4 OCH3

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

(Scheme-52)

R119a-f (i)119a-f(ii)

121a-f (i)121a-f (ii)

R


38

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

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review article on vilsmeier-haack reaction

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