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-dimethylformamide (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 phosphoryl chloride 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. 25 IJPCBS 2012, 3(1), 25-43 Rajput et al. ISSN: 2249-9504 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 formamide 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 26 IJPCBS 2012, 3(1), 25-43 Rajput et al. ISSN: 2249-9504 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. chloroform, methylchloride, benzene, vii) Transformation of iminium salt into toluene, o-dichlorobenzene, dioxane and product other than aldehyde. 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 Pyrroles 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 pyrrole (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, phenols, 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.