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

INTERNATIONAL JOURNAL OF PHARMACEUTICAL, CHEMICAL AND BIOLOGICAL SCIENCES

Available online at www.ijpcbs.com 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.S’s 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 intrinsic pharmacological properties and The application of the Vilsmeier-Haack (VH) chemical reactivity14. Formylation reactions reagent (POCl3/DMF) for the formylation of have been described for pyrido[2,3- a variety of both aromatic and d]pyrimidines as a key step for the heteroaromatic substrates is well introduction of functionalities via the documented1. The Vilsmeier-Haack reagent intermediate carboxaldehydes15. is an efficient, economical and mild reagent The Vilsmeier-Haack reaction can also be for the formylation of reactive aromatic and applied to introduce an acetyl group on heteroaromatic substrates2. It is now used activated aromatic or hetero aromatic as a powerful synthetic tool for the compounds, many other conversions can be construction of many heterocyclic achieved with this technology. In general, compounds3. N,N- (DMF) and The classical Vilsmeier-Haack reaction4, phosphorus oxychloride (POCl3) are used to however, involves electrophilic substitution generate a halomethyleniminium salt used of an activated aromatic ring with a in the synthesis of a large number of halomethyleniminium salt to yield the heterocyclic compounds16-19. corresponding iminium species, which In 1896, Friedel noted the formation of a facilitates easy entry into various nitrogen red dye on treatment of N- and oxygen based heterocycles5,3a,d. methylacetanilide with Vilsmeier reagent serves not only as a to which he assigned the problematic formylating agent6, but also as an activating structure (1)20. This was corrected by reagent for carboxylic acids to give esters7, Fischer, Miller and Vilsmeier in 192521 who amides8 and acid chlorides9 and for alcohols assigned the cynine-dye structure (2) and to give alkyl chlorides10, esters11, alkyl aryl argued cogently that this product derived sulfides12 and imides13. Besides this, the from the self condensation of the reagent has also been extensively used for quinolinium salt (3). It was the realization effecting various chemical transformations by Vilsmeier & Haack22 that one molecule of with other classes of compounds. N-methylacetanilide had acetylated a There is a growing interest in formylation second molecule prior to cyclisation that led as an interesting strategy to form to the discovery of the Vilsmeier-Haack intermediate carboxaldehydes, due to their formylation using N-dimethylformanilide.

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C6H4 N Me Me C Recent studies on the NMR spectra of the Me + N Cl H C6H4 DMF/POCl3 complex pointed to the imidoyl - Cl chloride salt structure (B)26-28 (Chart-1). (1) Challis and Challis29 suggested that O- acyl Cl Cl Cl + Me structure (A) might be more stable for N POCl3 than for other halides such as SOCl2, N + N Me Me Me COCl2 and PCl5. - - Cl Cl (2) (3) + O POCl2 Cl The formyl group thus, introduced in to a . . .. - . - R C PO Cl R C . Cl 2 2 substrate is, of course, a highly reactive .. ... + NR R NR1R2 species and the versatility of this reaction, 1 2 (A) (B) to a large extent, is due to the variety of + O O -----X . . . . - R + . synthetically useful transformations that C Cl2X R C . Cl .. .. . Cl NR R may subsequently be performed. The V.H. 1 2 NR1R2

Cl (C) reaction has been extensively studied and R C - Cl X O 23 + + reviewed . NR R 1 2 X = CO, SO or PCl3 The structure of the electrophilic adduct (D) has aroused much interest. The behavior of the adduct appears to be consistent with an The Vilsmeier complexes are generally ionic character rather than a covalent prepared at low temperatures (250C). If character24. The structures a & b were the reaction with nucleophile is carried out 0 considered most likely for the DMF/POCl3 at low temperature (30 C) the adduct. rearrangement of (A) and (B) does not seem to be favoured. Furthermore, the Vilsmeier - complex undergoes a much wide range of OPOCl2 OPOCl H C Cl H3C .. 2 3 .. nucleophilic substitution reactions. N C + N C + H H H3C H3C Reagents The Vilsmeier complexes employed in the formylation reactions are usually derived OPOCl H C 2 H C Cl 3 + 3 + from N,N-disubstituted amide and POCl3. N- N C N C H C H H C H Methyl formanilide and N,N- dimethyl 3 3 -

OPOCl2 are commonly used. N-Methyl a b formamide, N-formylpiperidine27 and N- formylindeline28 have also been used. The Structure of the Vilsmeier-Haack use of unsubstituted formamide has also Complex been investigated30, but the complex was Phosphorous oxychloride reacts with found to be less reactive than the DMF / tertiary amides to give adduct which POCl3 or MFA / POCl3 complexes. exhibits salt like properties. These adducts Other amides such as N, N-dimethyl have been referred to as the Vilsmeier acetamide, N-methyl acetamide, N, N-dimethyl ,,-pentamethyl ,‘׀ complexes25. benzamide, N, N acetamide, etc. have been employed in the + O O P O Cl2 .. . . . presence of POCl3 but these amides are P OCl . - R C N R 1 R 2 + 3 R C . . . . . C l ( D ) + P O 2 Cl NR R 1 2 prone to undergo self condensation. Acid

(A) chlorides other than POCl3 have also been

C l - O used in the Vilsmeier reactions. They are R C P O 2 Cl2 R C N R R + ArS O Cl 31 32 33 34 + 1 2 2 COCl2 , SOCl2 , ClOCl , CH3COCl , NR 1 R 2 (B) 34,35 35 36 37 + ArCOCl , ArSO2Cl , PCl5 , Me2NSO2Cl O - C l 38 - C l and RO2CNH SO2Cl . O S A r - . . . C l R C . . Ar S O 3 R . O + C . . . . . N R 1 R 2 NR R 1 2 (E) (F)

CHART-I Nature of Vilsmeier-Haack Reagent

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Solvents iv) Regiospecific formylation. In the case of amides like DMF, dimethyl v) Oxygen and nitrogen nucleophiles are acetamide, N-methyl pyrrolidone, etc. which also reactive towards Vilsmeier are liquids, an excess of the amide can be reagent. used as solvent. Other solvents like vi) Formylation with dimerization. , methylchloride, , vii) Transformation of iminium salt into toluene, o-dichlorobenzene, dioxane and product other than . tetrahydrofuran have also been used. viii) Miscellaneous V-H reactions. In view of the vastness of the literature, we Temperatures have endeavored in this review to Normally the reactions are carried out at demonstrate the powerful potential of room temperature or between 600 and Vilsmeier-Haack reaction in the synthesis of 800C. Reactions at temperature as high as different compounds. Only few 1200C have also been described39. The representative reactions are illustrated Vilsmeier reaction has been the subject of under the following titles. many review articles of varying scope and length. Some of the reviews are enlisted A) Synthesis of here in chronological order. Vilsmeier Gupton J. T. et al.65 have studied and (1951)40, Bayer (1954)41, Bredereck et al. reported the synthesis of 4-Aryl-2- (1959)42, Eilingsfeld, Seefeder and carbethoxypyrrole (6) from compound (4) Weidinger (1960)43, Minkin and Darofeenko with POCl3, DMF and heat followed by 44 45 (1960) , Oda and Yamamoto (1960) , De NaPF6/H2O via formation of Vinylogous Maheas (1962)46, Hofner et al. (1963)47, iminium salt (5) (Scheme-1). Gore (1964)48, Hazebroucq (1966)49, Jutz (1968)50, Ulrich (1968)51, Kuehne (1969)52, 24 53 Seshadri (1973) , Jutz (1976) , Meth-cohn O CF3 54 55 and Tarnowski (1982) , Smichen (1983) , N N N Marson (1992)56 , Meth-cohn and Stanforth R1 R2 O (1991)57 and Meth-cohn (1993)58, (105-106) 59 Arumugam S. (1994) , Duduzile M. M. 105, R1=R2 =H 60 61 (2007) , Carsten Borek (2008) , Jones G. 1 2 106, R =R = -(CH2)2- 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

POCl3 / DMF chloromethyliminium salt with and heat followed by NaPF /HO 6 2 Me Me HN CO Et nucleophiles. Liebscher and Hartmann 2 2 COOH + N N 64 Me Me DABCO.DMF (1979) have published an article relating and heat N CO2Et (4) - PF H to vinylogous chloroiminium salts. These 6 excellent reviews deal with the Vilsmeier (5) (6) reaction, its mechanism and the structure of (Scheme-1) the various eletrophilic reagents. In this They have also reported microwave study we have restricted our coverage to accelerated Vilsmeier-Haack formylation of important concepts rather than reiterate all (7) into formyl pyrrole (8) the literature material. (Scheme-2).

Synthetic Applications of the Vilsmeier- X Y X Y POCl3,DMF Haack Reaction N CO2Et Microwave heating OHC N CO Et i) Formylation of aromatic 2 Z Z hydrocarbons, , phenolethers, (7) (8) Z= H, Me olefins, ketones, Beta-chlorovinylal (Scheme-2) dehydes. ii) Diformylation reactions. Pfefferkorn J. A. et al.66 have described iii) Formylation with aromatization. formylation of pyrrole (9) under Vilsmeier-

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Haack conditions into pyrrole under different temperature conditions carboxaldehyde (10) as a part of (scheme 6). development of an efficient and scalable Functionalized -2(1H)-ones and second generation synthesis of novel, their benzo/hetero-fused analogues pyrrole-based HMG-COA reductase represent an important class of organic inhibitors (Scheme-3). heterocycles for their presence in numerous natural products and synthetic organic N N EtO2C EtO C 2 CHO compounds along with diverse bio-physico POCl , DMF 3 70-71 DCE 800C and pharmacological activities .

F F F F (10) OHC PhCl - 4 (9) DMF/POCl3 N (10.0 equiv) (Scheme-3) 800C, 1 h Cl O 67 O O Cho T. P. et al. have discovered the series (22) CH2CH2Cl of novel pyrrolopyridazine derivatives by NHPhCl - 4 carrying out synthesis of pyrrolopyridazine DMF/POCl3 PhCl- 4 (10.0 equiv) N (14) from pyrrole diesters (11) by using V- (21) 1200C, 2 h H reagents (Scheme-4). Cl O CH CH Cl 2 2 (23) (Scheme-6) O O O O O H O POCl 2.0 equiv 3 O 72 N Asokan C. V. et al. have reported the DMF, 100 0C, 2 h 77% N O O H H (12) conversion of enolizable ketones such as (11) 1.5 equiv 0 acetophenones and benzal acetones (24) NH NH .H O, EtOH 90 C, 3 h, 72% 2 2 2 into 2-chloronicotinonitriles (25) upon O EtOOC Cl EtOOC treatment with malononitrile under

N 2.0 equiv POCl3, NH HN HN Vilsmeier-Haack reaction conditions. N CH CN, 80 0C, 5 h N 3 (Scheme-7).

(14) (13) (Scheme-4) 2 1. POCl , DMF, rt, 12h R CN O 3 2 B) Synthesis of Functionalized R 2. NCCHCN, 90 0C, 2h R1 2 1 68 R N Cl Xiang D. et al. developed a facile and 3. Aq. K2CO3 efficient one- pot synthesis of highly (24) (25) substituted pyridin-2(1H)-ones(18), (19) (Scheme-7) and (20) via Vilsmeier-Haack reactions of radily available 2-arylamino-3-acetyl-5,6- Quiroga J. et al17 formylated dihydro-4H-pyrans (15), (16) and (17) pyrazolopyridine (26) into pyrazolo[3,4-b] respectively (scheme-5). pyridine-5-carbaldehyde (27) by using DMF

O and POCl (Scheme-8). O H C Ph 3 (3.0 equiv) P Br 3 / D M F N 8 0 0 C They have concluded that, the formylation P h N H O B r O

(C H2 )3 Br (1 5 ) (1 8 ) on the pyridine ring only takes place when

O there is a dihydroderivative on the O H C A r P B r /DM F(5.0 equiv) N 3 appropriate pyrazolo-fused system. They Ar H N O 8 0 0 C X O

( C H 2 ) 3 Br (1 6 ) have also observed that the use of the (1 9 ) Vilsmeier-Haack condition developed a fast O P Br / D M F 3 O H C P h C l- 4 (5.0 equiv) N O O and efficient method for the formation of 0 + 8 0 C , 1 0 m in B r O N H P h C l - 4 4 -C lP h H N O ( C H ) Br ( C H 2 ) 3 Br pyrazolo[3,4-b] pyridine-5-carbaldehyde 2 3 (1 7 ) (2 0 ) (27) (Scheme-5)

R R 69 H C H C Pan W. et al. also reported the synthesis of 3 3 CHO

POCl3/DMF functionalized pyridine-2(1H)-ones (22) N N N N N N and (23) from 1-acetyl, 1-carbamoyl Ph Ph R' R' cyclopropanes (21) by using POCl3 and DMF (27) (26) R=H, C6H5

(Scheme-8)

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Tabuchi Y. et al73 used Vilsmeier-Haack hydrazine in ethanol and acetic acid. The condition for the synthesis of 4-chloro-3- intermediate phenyl hydrazone (35) when formylbenzo[b]furo[3,2-b] pyridine (29) subjected to Vilsmeier-Haack reaction from 2-acetyl-3-acylaminobenzo[b] furans condition, cyclized to afford substituted (28) (Scheme-9). pyrazoles (36) which are well documented to posses antihypertensive, antibacterial, NHCOR3 N 1 0 R1 anti-inflammatory and antitumor R POCl3 , DMF, 24 C CHO 76 COCH activities (Scheme-12). 3 Cl O O

R1 R1 2 2 H R R N R 2 O N H2 C H3 (28) (29) EtOH / AcOH O C H3 O N (Scheme-9) HN (34)

H O R1 C) Synthesis of Pyrimidines DM F / POCl 3 R2 17 Quiroga J. et al suggested the (35) regioselective formylation of pyrazolo [1,5- O N N R1= H, CH3 a] pyrimidine system using Vilsmeier-Haack R2= H, NO2 conditions. They have synthesized pyrazolo R (36) 2 [1,5-a] pyrimidine-3,6-dicarbaldehyde (31) (Scheme-12) from 6,7-dihydroderivatives (30).They have also converted 6,7-dihydroderivative (30) Goudarshivannanavar B. C. et al77 have into aromatic pyrazolo pyrimidine (32) reported that, 2-acetyl which was formylated with DMF & POCl3 benzofurohydrozones (37) on reaction with and afforded pyrazolopyrimidine-3- Vilsmeier-Haack reagent at appropriate carbaldehyde (33) (Scheme-10). molar ratio, underwent smooth cyclization followed by formylation afforded 3(1- H Ar Ar benzofuran-2-yl)-1-(substituted phenyl)- O ... N N H 1H-pyrazole-4-carbaldehyde (38) (Scheme- N N POCl / D MF N N 3 13). R R CHO (30 ) R' (31) R' N BS/ Eth ano l OHC Ar Ar C HO H DMF / POCl N O N N 3 N N N N O N N N Reflux / 2 hr POC l3 / D MF R R (38) (32) (3 3) R' (37) R R' (Scheme-10) R R= H, NO , CH , OCH , Cl, F, Br 2 3 3 Quiroga J. et al74 extended their work & (Scheme - 13) carried out microwave assisted synthesis of Damljanovic I. et al78 reported that the pyrazolo[3,4-d]pyrimidines from 2-amino- condensation of acetylferrocene (39) with 4,6-dichloropyrimidine-5-carbaldehyde phenyl hydrazine (40) followed by under solvent free conditions (Scheme-11). intramolecular cyclization of the intermediate hydrazone (41) under OH Cl Cl Vilsmeier-Haack conditions formed 1H-3- N POCl / DMF Ethanol, TEA N O 3 N O HNR1R2 ferrocenyl-1-phenyl pyrazole-4- H N N OH 2 H N N Cl Reflux H 2N N NR1R2 2 carboxaldehyde (42) (Scheme-14)79. Method A or Method B

HN N P h

N H N O N P h E th a n o l + N r e fl u x H2N N NR1R2 H 2 N H (Scheme-11) F e F e (4 0 ) ( 3 9 ) ( 4 1 ) P h N D) Synthesis of Pyrazoles N P O C l 3 ( 3 e q u i v ) Aruna kumar D. B. et al75 converted D M F , r .t . C H O benzofurans (34) into benzofuran phenyl F e hydrozone (35) by treatment with phenyl ( 4 2 ) (Scheme-14)

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Vera-Divaio M. A. F. et al80 illustrated R O Me N Vilsmeier-Haack formylation of compound Me N Me N Me O (43) into 1-Phenyl-1H-pyrazole-4- Me (56) POCl / DMF carboxaldehyde (44) in 65% yield. The (55) 3 aldehyde functional group has been utilized O O to synthesize corresponding acid (45) R R (Scheme-15). N N (57) Me Me CHO (Scheme- 18) 84 Ph COOH COOH Popowycz F. et al have prepared dimer N DMF / POCl3 N N N N N (59) from 5-Methyoxy-1-methyl-7- Et N, Ac O 3 2 azaindole (58) using Vilsmeier-Haack reaction conditions (Scheme-19). (43) (44) (45) MeO BBr , CHCl , HO KCO DMF, Br(CH) Br Br 3 2 2 2 3, 2 n , n O (Scheme-15) 0 0C,1 h, n=4-6, rt, 4h, N N N N N N E) Synthesis of Quinolines (58) 81 OHC CHO Some S. et al developed a new protocol for O O KCO DMF, 80 0C, 6h, n 2 3, the preparation of quinolines (50) involving POCl DMF, rt, 3h, 3, N N N N the subjection of certain enolizable ketones (46) to a Vilsmeier-Haack haloformylation 0 MeNO2, NH4OAc, 120 C, 4h AcHN NHAc 82 NaBH, SiO, i-PrOH/CHCl , rt, 12h reaction (Scheme-16) . 4 2 3 O n O 0 H2, Raney Ni, MeOH, 60 C,6 h, Ac O, CHCl , rt, 12h, 2 2 2 N N N N POBr , 3 CHO X (59) DMF + (Scheme- 19) O Br O N 2 (46) (47) (X=Br or l) (48) Barraja P. et al85 have synthesized choro- Cu, DMSO, Pd[O] (10 mol%) bis-formylated derivatives (62) and (63) CHO from substituted tetrahydroindolones (60)

H2 and (61) by using DMF/POCl3 and DCM at 10% Pd on C 0 N 0 C (Scheme20). O N 2 (50) (49) (Scheme -16) Cl Me O Me OHC CHO DMF/POCl3,DCM N F) Synthesis of 00C then reflux N Me 83 Me Diana P. et al have reported a rapid access (62) to 1,4-Bis-indolyl-diketones (54) using (60) Cl CHO Vilsmeier-Haack reaction (Scheme-17). O OHC DMF/POCl3,DCM Me Me N 00C then reflux R R CHO R CHO N Me POCl3 / DMF Me NaH / THF (63) N NaOH N N (61) ClSO2Ph H H SO Ph 2 (Scheme-20) Thiazolium Salt, EtOH O O R R G) Synthesis of Pyranones and Naphthaldehydes N N Xiang-Ying Tang and Min shi86 have H (54) SO Ph (Scheme- 17) 2 developed a convenient and efficient method to synthesize3-(2-Chloroethyl)-5- They have also converted N-methyl aryl-4H-pyran-4-ones(65) and 2-Chloro-3- derivatives (55) into 1, 4-diketones (57) by (2-chloroethyl)-1-napthaldehydes (66) in Vilsmeier-Haack reaction using moderate to good yields via the Vilsmeier- phosphorous oxychloride and tetramethyl Haack reaction of readily available 1- succinamide (56) (Scheme-18). Cyclopropyl-2-aryl ethanones (64) at different temperatures (Scheme 21).

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O using Vilsmeier-Haack reaction (Scheme- DMF/POCl 3 Cl R (12.0 equiv), 80-100 0C O 25). Formyl thiophene derivatives are (65) versatile “Crossroads” intermediates. R CHO O Cl DMF/ POCl 3 (64) R O (12.0 equiv), 120-135 0C O Cl 0 H P O C l 3 / DM F / 60 C N a 2 S . 9 H 2 O / D M F C H 3

(Scheme-21) (66) C l C l C H 2 C O C H 3 / K 2 C O 3 R ( 7 3 ) R

H) Synthesis of Oxazines O R R 0 87 O P O C l 3 / DM F / 60 C H Damodiran M. et al have reported the S S synthesis of highly functionalized oxazines C l

N a S . 9 H O / D M F R (68) by Vilsmeier-cyclization of amidoalkyl 2 2

C l C H 2 C H O / K 2 C O 3 S C H O naphthols (67) (Scheme-22). S ( 7 4 ) (Scheme-25)

R R 90 O DMF / POCl3 Bhatti H.S. and Seshadri S. formylated R1 N 3 h, 90 0C NH benzo[b] thiophene-3(2H)-one-1,1-dioxide H R2 OH O (75) by using DMF and POCl3 to give (76)

1 CHO R = H, CH3, Ph (Scheme 26). R2 = CH , Ph, CHO 3 (67) (68) (Scheme-22) O Cl OH DMF/POCl + H2O 3 CHO CH=N(CH3)2 Tabuchi Y. et al73 have suggested, the ring S S S O O _ O O O Cl O closure reaction of 2-acetyl-(E)-3-aral- 75 76 Kenylcarbonylaminobenzo[b] furans (69) (Scheme-26) using Vilsmeier reagent which generated oxazine (70) (Scheme-23). K) Synthesis of Naphthyridinepyrazoles Mogilaiah K. et al91 used V-H reaction R3 condition to develope a simple and efficient NHCOR3 N 1 1) POCl , DMF, 25 0C R1 R 3 O method for the synthesis of 1-[3-(3-

COCH3 O 2) Method A (NaOH aq. sol.) O CHCHO fluorophenyl)[1,8]naphthyridin-2-yl]-3-(2- or 2 R Method B (Et3N), 16-46% R2 oxo-2H-chromenyl)-H-4-pyrazolecarbalde- (69) (70) hydes (78) from (77) (Scheme 27). (Scheme-23)

F I) Synthesis of Chromones CH 3 1 Wang B. D. et al88 have prepared the 6- N N NHN C R (77) O O hydroxy-3-carbaldehyde chromone via R2 Vilsmeier-Haack reaction. The compounds POCl3-DMF / SiO2 6-hydroxy-4-chromone-3-carbaldehydes MW (72) were easily prepared by the reaction of 2,5,-dihydroxy acetophenone (71) with F N N N N

DMF in POCl3 solution (Scheme-24). R1 (78) CHO O O OH OCOCH3 OH R2 O COCH3 (Scheme-27) (CH3CO)2CO AlCl3 DMF, POCl3 98%HSO 2 4 HO CHO OCOCH O OH 3 OH L) Synthesis of Quindolines (71) (72) Dutta B. et al92 have reported the V-H (Scheme- 24) formylation of 2-nitroacetophenone (79)

with POCl in DMF, to produce the β- J) Synthesis of Bithiophenes and 3 Chlorocinnamaldehyde (80) (Scheme 28). Benzothiophene dioxides Herbivo C. et al89 synthesized a series of formyl substituted 5-aryl-2,2-bithiophenes (74) starting from acetophenones (73)

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NO NO2 2 0 O) Formylation of Pyrenopyrrole POCl3,DMF,0 C,1h Cl 96 CH3 Gandhi V. et al carried out, Vilsmeier- 800C,4h O H CHO Haack formylation of pyrenopyrrole (91) to (79) (80) afford monoaldehyde (92) which after (Scheme-28) protection of pyrrole and further treatment with POCl3-DMF afforded the dialdehyde M) Formylation of Pyrrolones (94) (Scheme 32). Becker C. et al93 have used Vilsmeier-Haack reaction conditions for the synthesis of POCl / DMF enaminoimine (85) and enaminoaldehyde 3 (86) starting from Pyrrolin-3-on-1-oxide N N CHO H H derivatives (81) (Scheme 29). (92) (91) Piperidine EtO C-CH -CN 2 2 R R R O N N N DMF DMF _ N 1.POCl3 Cl Cl DMF POCl3 POCl3 Cl O O Cl Cl 2.NaOH CN (81) (82) C C (83) OHC N CHO N H H (84) H CO2Et (94) (93) -DMF + - H (Scheme-32)

N O P) Synthesis of Azeteochlorins H 97 N N Banerji S. et al have reported the

Cl Cl formation of chlorophin monoaldehyde Cl Cl (96) from chlorophin (95) upon treatment (86) (85) with DMF/POCl3 in CHCl3 followed by (Scheme-29) addition of aq.NaHCO3. The reaction of (96) They have also reported, the reaction of with methyl-Grignard, followed by an acid- exo-cyclic enhydroxylaminone (87) with the catalyzed ring-closure reaction, generated Vilsmeier reagent to form chlorosubstituted the compound [meso-tetraphenyl-2- compound (88) (Scheme 30). methylazeteo-chlorinato] Ni (II) (97) in good yields (Scheme 33).

Ph POCl , Ph 1. 3 DMF CHO O O _ N N N N DMF-POCl ,CHCl OH 2. OH Cl (1) 3 3 H Ph Ni Ph Ph Ni Ph N N N N N (2) aq. NaHCO3 N N N Ph Ph (95) (96) (87) (88) (Scheme-30) MeMgBr, dry THF Ph Ph Me Me N) Formylation of Phloroglucinols OH N N N N Naturally occurring phloroglucinol Ph Ni Ph (1) TMSOTf, CH2Cl2 Ph Ni Ph N N compounds have shown diverse range of N N (2) aq NaHCO3 biological activities94. Bharate S. B. et al95 Ph Ph formylated monoacyl phloroglucinol (89) to (97) (Scheme-33) acylphloroglucinols (90) using V-H reaction (Scheme 31). Q) Miscellaneous V-H reactions Bera R. et al98 used Vilsmeier-Haack CHO HO O HO O reaction condition for alkynylation of β- R POCl3,DMF R R Chloroacroleins. β-Chloroacroleins(99) R1 1 EtOAc,rt.1h were readily prepared from the O OH O OH corresponding Ketones (98) by a Vilsmeier- (89) (90) Haack-Arnold reaction, which were then treated with terminal alkynes in acetonitrile (Scheme-31)

32 IJPCBS 2012, 3(1), 25-43 Rajput et al. ISSN: 2249-9504 in the presence of 10% Pd/C, PPh3, CuI and glutarimides 103, 104and 106 Et3N under nitrogen to afford 4-alkynyl-2H- demonstrated antidepressant like activity in chromene-3-carbaldehydes (100) (Scheme the four-plate and the swim tests in mice, 34). respectively. These glutarimides also inhibited the locomotor activity of mice. The CHO CHO antidepressant-like effect of 106 was n n HC R n O O O Cl O C R DMF / POCl3 Pd/C, PPh3, CuI reported significantly stronger than that

Et3N, CH3CN induced by imipramine used as a reference 80°, 2-3h Z Z Z antidepressant.

(98) n= 1, 2 (100) (99) Z= H, Br O CF3 N N N (Scheme-34) R1R2 O Bubenyak M. et al99 showed that, (103-104) Deoxyvasicinone (101), upon Vilsmeier- 103, R1=R2 =H 1 2 104, R =R = -(CH2)2- Haack formylation using two equiv. of POCl3 0 in DMF at 60 C for 3 hrs. gave the 3- O CF3 dimethylaminomethylene derivative (102) N N N in 94% yield (Scheme-35). R1 R2 O (105-106) 1 2 3 N 105, R =R =H Dimethylformamide, N 106, R1=R2 = -(CH ) - N 2 2 2 equiv POCl , rt, 1h, 60 0C N 1 3 O 3h (94% yield) O (101) 117 (102) Shaabani A. et al have synthesized fully functionalized N-alkyl-2-triphenyl phosph- (Scheme- 35) ora-hylidene glutarimides (107) and

concluded that these glutarimide Glutarimides derivatives constitute an essential part of Piperidine-2,6-diones(glutarimides, cyclic many natural products with antibacterial, imides) have various biological antitumor or fungicidal activity. activities100 and the 2,6-piperidinedione Chen C. Y. et al107 have reported one-pot moiety constitutes an important facile synthesis of N-alkyl 3-(E)-alkylidine- substructure in several new anticancer 5-substituted sulfonylpiperidine-2,6-dione agents which have recently been introduced (108). into experimental chemotherapy101,102. R 3 2 O Furthermore, these have been used as CO2R 2 S=

R O precursors in the synthesis of a variety of Ph3P CO2R 1 O N O 103 O N O heterocyclic compounds . Therefore, the R 2 R' synthesis of piperidine-2,6-dione (107) (108) derivatives have attracted considerable attention of synthetic chemists and several Kiyota H. et al118 suggested the synthesis of methods have been reported in the actiketal (RK-441S) (109) as a new acetal literature104-112, most of which have used type glutarimide antibiotic119 which is multi-step reactions using harsh reaction expected to be a new anti-cancer agent and conditions. Many compounds possessing a an immunosuppressant because of its low cyclic imide moiety exhibit pharmacological cytotoxicity119,120. activity such as antitumor113, In recent years Fu R. et al121 have developed immunosuppressive113, sedative113, protected (R) and (S)-glutarimides (110) as anxiolytic113, anticonvulsive114 and a versatile building blocks122,123 for the others115. asymmetric synthesis of substituted 3- Paluchowska M. H. et al116 have showed piperidinol containing alkaloids and that, the glutarimides 103 and 105 pharmaceutically relevant molecules. demonstrated anxiolytic activity while the

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

2 CO2R 2 2 CO2R PhP COR O CH2Cl2 3 2 R' N C + +EtO In view of these useful pharmacological PPh3Br r.t. 24h 2 O N O properties, biological activities and CO2R R' synthetic applications of glutarimides, various methods have been developed for (Scheme-41) their synthesis. Some of the important methods are described in the following Dihydropyridines schemes. 1,4-dihydropyridines and their derivatives 1) Method due to Kiyota H. et al118 are an important class of bioactive molecules in the pharmaceutical field127.

0 The dihydropyridine heterocyclic ring is a O CO Me Pd(OAc)2 ( 1eq.), AcOH,60 C COMe + 2 O 2 common feature of a variety of bioactive CO Me 2 CO2Me compounds including anticonvulsant,

H2,Pd antidiabetic, antianxiety, antidepressive, Powder,EtOA antitumor, analgesic, sedative, vasodilator, O i. KOH,MeOH c (98%) bronchodilator, hypnotic and anti- O ii.Ac2O,heat NH 128 O CO Me inflammatory agents . iii.NH gas,Et O 2 O 3 2 iV.NaOAc,Ac2O,heat CO2Me Diydropyridines are reported as calcium channel blockers129 and are clinically useful (Scheme-36) agents for the treatment of cardiovascular diseases such as anginapectoris130 and 124 2) Method due to Huang C. G. et al hypertension131.These are also used as O O 2 antioxidants and are important for Cl 1. R'NH2 S 1.NaH (2eq.) R S Cl Ph Ph developing drugs. However, these are 2. NaSPh 2. 2 O O N R O N relatively difficult to synthesize. 3. NaIO R' 4 R' MeO O During the years 1980-1990 considerable (Scheme-37) importance was acquired by derivatives of 1,4-dihydropyridines, as the first 3) Methods due to Mederski Werner representatives of highly effective W. K. R. et al125 vasodilators and antihypertensive agents, H N HO C the calcium channel blockers (Nicardipine, 2 2 CO H O N 2 Nifedipine, Felodipine, etc)132-134. Many N N Cl H2N PPA, 80°C, 2h derivatives of 1,4-dihydropyridines with NH2 Cl O more valuable pharmacological (Scheme-38) properties135-137, which make further searches in the 1,4-dihydropyridine series NO2 extremely urgent. Till date an enormous HO2C NO R CO2H O 2 number of symmetrical and unsymmetrical R PPA, 80°C, 12h N derivatives of 1,4-dihydropyridine with NH2 O various functional substituents have been synthesized, and a great number of methods (Scheme-39) 4) Method due to Chen B. F. et al126 of obtaining them (including microwave) have been developed by further Ts OMe 3 eq. NaOH Ts 5 OMe conversions and aromatization138-142. + 6 Scientists from the Latvian Institute of O NH EtO O O N O R R Organic Synthesis have carried out the systematic synthesis of numerous (Scheme-40) derivatives of 1,4-dihydropyridines with the aim of searching for new cardiotonic 5) Method due to Shaabani A. et al117 and ionotropic preparations, and clarification of structure–activity relationships143-145. In addition to this formyl group present on pyridine and

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

69 O O P 2 3. Method due to Pan W. et al. O O H N H O N O O O - 4 1 DMF/POCl OHC PhCl O O P 3 N (10.0 equiv) (1 0 9 ) ( 1 1 0 ) NHPhCl - 4 800C, 1 h Cl O

CH2CH2Cl dihydropyridine molecules make them (Scheme-44) promising precursors for further synthetic transformations. 4. Method due to Tabuchi Y. et al.73 The use of formylation reaction as synthetic strategy to form versatile carboxaldehyde NHCOR3 N 1 0 R1 R POCl3, DMF, 24 C CHO intermediates is still of interest, due to both COCH 3 Cl their intrinsic pharmacological properties O O

146 2 and chemical reactivity . Formylation R2 R reactions have been described for (Scheme-45) 5. Method due to Quiroga J. et al.154 pyrazoles147, pyridines148 and pyrimidines149 as a key step to the Ar Ar introduction of functionalities via the DMF / POCl3 CHO N N intermediate carboxaldehydes, and further N N N O N Cl Ph cyclization to fused heterocycles. Ph H Vilsmeier–Haack reaction carried out on (Scheme-46) methylene-active compounds leads mainly to the formation of β-halo-carboxaldehyde Rajput A. P.155 have synthesized 1,4- derivatives, which are useful precursors in diazepine type compounds and reported the construction of different heterocyclic their useful compounds by means of numerous biological activities, pharmaceutical transformations150-151. We have properties and therapeutic applications. concentrated much of our recent work on Rajput A. P.156 have formylated 2- the preparation of bioactive nitrogen- Aryliminothiazolid-4-ones using V-H containing heterocycles. reagent. The formylated synthones were By considering the importance of formyl used to synthesize various fused pyridines different researchers have heterocyclic ring systems containing developed the various methods for the thiazole moiety and some heterocyclic synthesis of chloroformylation of pyridines Schiff bases to get some compounds of and dihydropyridines as described in the interesting biological activities following schemes. Rajput A. P. and Rajput S. S.157 have 1. Method due to Kvitko I. Y. et al.15 reported that, the condensation of 4- chlorophenyl carboxylic acid hydrazide HOC CHO with different acetophenones and DMF / POCl3 O N O acetaldehydes afforded the corresponding Cl N Cl Ph acetophenones/acetaldehydes 4- Ph chlorophenyl carbonyl hydrazones which (Scheme-42) on V-H reaction formylated the compound

1-(3-aryl/alkyl-4-formyl pyrazole-1- 2. Method due to Maddox M. L. et al.153 R carbonyl)-4-chlorobenzenes. R + + O CH3 DMF Me N = HC 2 CH= NMe2 NaOAc DMF / POCl3 POCl or (COCl) - - Cl C NH N C 3 2 Cl Cl O N O H2O 00C Cl H Cl H O R R HOC + HOC CHO Cl C N N NMe2 H O 3 (NH4)2Ce(NO3)6

Cl N Cl Cl N Cl H CHO R a, R= C6H5 HOC CHO Scheme-47 b, R= 3-ClC6H4 c, R= 3-NO C H 2 6 4 Cl N Cl d, R= 3-CF3C6H4 e, R= H (Scheme-43)

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

They158 have also prepared various phenyl carbonyl hydrazones by using V-H dichloro, diformyl derivatives of pyrrole on reaction. formylation using V-H reagent from various Rajput A. P. and Bhadane S. J.160 have succinimide derivatives. carried out formylation of N-substituted phenyl succinimides. From these HOC CHO compounds various heterocyclic

O O Cl compounds have been synthesized. N DMF / POCl3 N Cl 161-166 0-50C Rajput A. P. and Girase P. D. have reported the synthesis, characterization and R R 111a-f 112a-f microbial screening of various nitrogen, R: a =H, b = 2-Cl, c = 3-Cl, d = 4-Cl, e = 4-CH , f = 4-OCH 3 3 oxygen and sulphur heterocyclic (Scheme-48) compounds from 2,6-dichloro 3,5-diformyl Rajput A. P. and Rajput S. S.159 have (N-substituted Phenyl)-4-hydropyridines. formylated benzaldehyde substituted OHC CHO

SOCl O N O Cl N Cl 2 DMF, POCl HOOC COOH 3 NH 2 0-50C R Reflux R R

113 114 a-d 115 a-d

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

(Scheme-49)

O H C N a 2 S C H O

D M F , R 1 R, a = -H, R 1 , a = -C 2 H 5 R 1 S N S R 1 b = -4CH 3 b = -C 2 H 5

d = -4Cl, d = -C 2 H 5 g = -2CH 3 g = -C 2 H 5

R 11 6 a-g

O H C C H O

O H C C H O R, a = -H, N a N N 3 N N 3 3 b = -4CH 3 C l N C l d = -4Cl, P T S A , E tO H g = -2CH 3

R 11 7 a-g R

1 15 a- g N C C N

R, a = -H , b = -4CH CAN C l N C l 3 d = -4Cl,

0 f = -4O CH 3 NH 3 ,0 C

R 11 8 a -f S c h e m e-5 0

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

R' R' O O N N OHC CHO R' R' N N H H Cl N Cl O Cl N Cl C l N C l NH -NH .H O R' 2 2 2 C CH3

R R R 115 a-f 119a-f(i) R 120a-f(i) 119a-f(ii) a = - H 120a-f(ii) b = - 4 CH3 R', (i) = -Ph c = - 2 C l (ii) = -4OH-Ph d = - 4 C l e = - 3 C l

f = - 4 OCH3 (Scheme-51)

R' R'

O O N N O O R' R' NH OH.HCl 2 Cl N Cl Cl N Cl CH3COONa in CH3COOH

R R 119a-f (i) 121a-f (i) 119a-f(ii) 121a-f (ii)

R R', (i) = -Ph a = - H (ii) = -4OH-Ph b = - 4 CH3 c = - 2 C l d = - 4 C l e = - 3 C l

f = - 4 OCH3 (Scheme-52)

R 1 R 1

OH C CHO S S N =H C CH =N O O N N Cl N Cl 2moles Cl N Cl HSCH 2COOH Cl N Cl

N H 2 2moles 1 R 1 R R 1 R R R 115 a-f 122 a-f ( i ), ( ii ) 123 a-f ( i ), ( ii )

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

R 1, (i) = - 4M e (ii) = - 4Cl Scheme-53

O H C O H C C H O C H O O H C C H O

2 N a 2 S 2 O 4 2 C H 2 ( C N ) 2 C l N C l N N N N a N 3 3 3 H 2 N N N H 2 P T S A , E tO H

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

N C C N

R, a = -H , H 2 N N N N N H 2 b = -4CH 3 c = -4Cl,

d = -2CH 3 R

1 2 6 a -d (Scheme-54)

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CONCLUSIONS 7483; (b) Procopiou, P. A.; This review has attempted to summarize Brodie, A. C.; Deal, M. J.; Hayman, the synthetic methods and reactions of D. F. J. Chem. Soc. Perkin Trans. glutarimides and dihydropyridines. Many 1 1996, 2249. biologically active heterocyclic compounds 8. Zaoral, M.; Arnold, Z. have been synthesized from that Tetrahedron Lett. 1960, 1, 9 heterocycle. These reactions greatly 9. Eilingsfeld, H.; Seefelder, M.; extended synthetic possibilities in organic Weidinger, H. Angew. Chem. chemistry. 1960, 72, 836. 10. Hepburn, D. R.; Hudson, H. R. J. REFERENCES Chem. Soc., Perkin Trans. 1 1. Jones, G.; Stanforth, S. P. Org. 1976, 754 React. 2001, 49, 1. 11. (a) Barrett, A. G. M.; Braddock, 2. (a) Meth-Cohn, O.; Narine, A. B. D. C.; James, R. A.; Koike, N.; Tetrahedron Lett. 1978, 23, Procopiou, P. A. J. Org. Chem. 2045. (b) Khan, A. K.; Shoeb, A. 1998, 63, 6273;(b) Barrett, A. G. Indian J. Chem. Sect. B, 1985, 24, M.; Koike, N.; Procopiou, P. A. 62 Chem. Commun. 1995, 1403. 3. (a) Sreenivasulu, M.; Rao, K. G. S. 12. Kawano, Y.; Kaneko, N.; Indian J. Chem. Sect. B, 1989, 28, Mukaiyama, T. Chem. Lett. 2005, 584.(b) Mahata, P. K.; 34, 1612. Venkatesh, C.; Syam Kumar, U. 13. Barrett, A. G. M.; Braddock, D. K.; Ila, H.; Junjappa, H. J. Org. C.; James, R. A.; Procopiou, A. Chem. 2003, 68, 3966.(c) Chupp, Chem. Commun. 1997, 433. J. P.; Metz, S. J. Heterocycl. Chem. 14. (a) Vovk, M. V.; Mel’nichenko, N. 1979, 16, 65; (d) Katrtizky, A.R.; V.; Sukach, V. A.; Chubaruk, N. G. Arend, M. J. Org. Chem. 1998, 63, Chem. Heterocycl. Compd. 2004, 9989 40, 1485; (b) Lipson, V. V.; 4. Vilsmeier, A. and Haack, A. Che. Desenko, S. M.; Shirobokova, M. Ber. 1927, 60, 199 G.; Borodina, V. V.; Musatov, 5. (a) Lilienkampf, A.; Johansson, V. I. Chem. Heterocycl. Comp. M. P.; Wähälä, K. Org. Lett. 2003, 2005, 41, 492. 5, 3387; (b) Perumal, P. T. 15. Girreser, U.; Heber, D.; Schu¨tt, Indian J. Heterocycl. Chem. M. Tetrahedron 2004, 60, 11511 2001, 11, 1;(c) Wang, K.-W.; 16. (a) Ali, M. M.; Tasneem; Rajanna, Xiang, D.-X.; Dong, D.-W. Org. K. C.; Saiprakash, P. K. Synlett Lett. 2008, 10, 1691; (d) Jones, 2001, 251;(b) Rajanna, K. C.; Ali, G.; Stanforth, S. P. Org. React. M. M.; Sana, S.; Tasneem; 2000, 56, 355; (e) Chen, L.; Zhao, Saiprakash, P. K. Synth.Commun. Y.-L.; Liu, Q.; Cheng, C.; Piao, C.- 2002, 32, 1351; (c) J. Disp. R. J. Org. Chem. 2007, 72, 9259; Sci.Tech. 2004, 25, 17. (f) Zhang, R.; Zhang, D.; Guo, Y.; 17. Quiroga, J.; Trilleras, J.; Insuasty, Zhou, G.; Jiang, Z.; Dong, D. J. Org. B.; Abonı´a, R.; Nogueras, M.; Chem. 2008, 73, 9504;(g) Wuts, Marchal, A.; Cobo, J. Tetrahedron P. G. M.; Northuis, J. M.; Kwan, T. Lett. 2008, 49, 2689. A. J.Org. Chem. 2000, 65, 9223. 18. Marson, C. M.; Giles, P. R. 6. (a) Campaigne, E.; Archer, W. L. Synthesis Using Vilsmeier J. Am. Chem. Soc. 1953, 75, 989; Reagents. CRC Press: Boca (b) Treihs, W.; Neupert, H. J.; Raton, FL, 1994. Hiebsch J. Chem. Ber. 1959, 92, 19. Rajanna, K. C.; Ali, M. M.; 141 Solomon, F.; Saiprakash, P. K. 7. (a) Procopiou, P. A.; Brodie, A. Int. J. Chem. Kinetics. 1996, 28, C.; Deal, M. J.; Hayman, D. F. 865. Tetrahedron Lett.1993, 34,

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