This is ppt presentation of Dr. P.T. Perumal on the topic of preparation and reactions various Vilsmeir reagent and their applications in Heterocyclic chemistry. This is very useful presentation and will be useful as a good reference for work on Heterocyclic chemistry.

1. SYNTHESIS OF NOVEL HETEROCYCLIC COMPOUNDS USING VILSMEIER REAGENT P.T. PERUMAL ORGANIC CHEMISTRY DIVISION CENTRAL LEATHER RESEARCH INSTITUTE ADYAR, CHENNAI-600 020.

2. Aromatic Formylation Reimer-Tiemann reaction Formylations using Friedel-Crafts catalyst Gatterman reaction

3. VILSMEIER-HAACK FORMYLATION ‘ The Vilsmeier aldehyde synthesis’ or ‘The Vilsmeier-Haack formylation’ is a typical aldehyde synthesis employing a formylating agent derived from a formamide and POCl 3 . It is a special type of Friedel-crafts reaction, which involves electrophilic substitution of an activated aromatic ring with a halomethyleniminium salt.

4. The scope of the Vilsmeier reagent is not confined to aromatic formylation reaction alone. A wide variety of alkene derivatives and activated methyl and methylene groups exhibit reactivity towards the Vilsmeier reagent. In addition to the carbon nucleophiles, some oxygen and nitrogen nucleophiles are also reactive towards Vilsmeier reagent. Numerous transformations of the iminium salts into products other than aldehydes have been achieved and these transformations enhance the scope and versatility of the Vilsmeier-Haack reaction

5. Formation, structure and nature of halomethyleniminium salts

9. Porphobilinogen pyoluteorin prodigiosin porphyrin

10. Di-O-methylstrepcillin Biotin Vincamine dendrolasin

11. Methoxy pyrazine Aspergillic acid Nicotinamide adenine dinucleotide Folinic acid Nicotinamide Pyridoxine Nicotine

12. Quinine Riboflavin Thiamine Uridine riboside

13. Synthesis of Pyridine, Pyran and Oxazine derivative. α-Hydroxyketenedithioacetals upon treatment with two equivalents of Vilsmeier reagent yield a iminium intermediate which on treatment with ammonium acetate result 2-methylsulfanyl substituted 4-aryl pyridines.

14. 2-Chloro-5-aryl-3-pyridine carboxylaldehydes was obtained from 4-aryl-3-butene-2-one. R.R.Amaresh,P.T.Perumal, Synth. Commu. 30, 2269 (2000) Dibenzyl ketone undergoes diformylation followed by 6π-electrocyclic ring closure to yield 3,5-diphenyl-4-pyrone. 20-30%, 30-40%.

15. 1,3,5-Triaryl-1,5-diketones on treatment with Vilsmeier reagent have furnished pentasubstituted 4( H )-pyrans in good yield. M. Venugopal , P.T. Perumal, Tetrahedron Letters 32, 3235-3238 (1991) 45-55%.

16. Mechanism for cyclisation M. Venugopal , P.T. Perumal, Tetrahedron Letters 32, 3235-3238 (1991)

17. Synthesis of 2-imino-2 H -pyran carboxaldehydes from β- keto amides. N -Phenylacetoacetamide on treatment with 8 equivalents of Vilsmeier reagent in DMF solvent has undergone cyclisation to yield 2-phenylimino-4-chloro-2 H -pyran-5-carboxaldehyde in 12% yield along with 2-phenylimino-4-chloro-2 H -pyran-3-carboxaldehyde in 32% yield. R.R.Amaresh, P. T. Perumal, Tetrahedron 55 (1999) 8083-8094

18. 50% 23% Synthesis of 2-(phenylmethyl)imino-4-chloro-2H-pyran-5-carboxaldehyde and 4-chloro-2-imino-2H-pyran-3,5-dicarboxaldehyde

20. Synthesis of Furan and benzo-4-pyrone derivatives M.Venugopal,B.Balasundaram ,P.T.Perumal, Synth.Commu. 23,2593 (1993)

21. Synthesis of 2, 4, 6- Triaryl- 2H- 1, 3- oxazines by Vilsmeier reagent from 3-(α-hydroxybenzyl-N-hydroxylamine)-1, 3- diarylpropen-1-ols. B.Balasundarm ,P.T.Perumal ,Indian J.Chem 32B, 1061, 1993.

22. Synthesis of pyroles and furans 1,4- Ketoacids were converted to furan carboxaldehydes Acetylacetone was converted to furan aldehyde M.Venugopal,B.Balasundaram ,P.T.Perumal, Synth.Commun. 23,2593 (1993) VR , 90 o C 70-85% 68%

23. N-Acetylglycine was converted to dichlorodiformylpyrrole V.J.Majo, P.T.Perumal, J.Org.Chem. 61, 6523,1996 82% 30% B.Balasundaram,M.Venugopal, P.T.Perumal, Tetrahedron letters 34, 4249, 1993. Synthesis of chlorodiformylpyrrole

24. Synthesis of Oxazolines & Isoxazolines Oxazolidin-5-ones from N-acetyl amino acids The azido group possesses the essential qualities required to make it an excellent precursor in organic synthesis. Intramolecular cyclizations of aryl and heteroaryl azides are well known general, high yielding processes for the construction of five-, six- and seven - membered heterocyclic rings.

25. SYNTHESIS OF OXAZOLE CARBOXALDEHYDES V.J.Majo, P.T.Perumal, Tetrahedron Letters. 38,6889,1997. V.J.Majo, P.T.Perumal, J.Org.Chem. 63, 7136,1998. 45-61% 62-80% 45-61%

26. A possible mechanism of the formation of oxazole carboxaldehydes is outlined below.

27. Synthesis of 5-benzyl-2-chlorooxazoles from 1-bromo-1-aryl acetone 33-38%

29. L.Vijalakshmi, V.Parathasarathi, P.T.Perumal, V.J.Majo, Acta Cryst C54,1683,1998 78%

30. Synthesis of isoxazolines from chalcones M.Venugopal ,P.T.Perumal, Proc.Indian Acad.Sci, 105,19,1993 40-50%

31. Synthesis of Imidazoles from 2-azidoacetanilide 45-62% V.J.Majo, P.T.Perumal, J.Org.Chem. 63, 7136,1998.

32. Mechanism for Cyclization

33. Pyrazole derivatives which have been the basis of numerous dyes, are also useful as analgesic, antipyretic, anti-inflammatory and anaesthetic drugs. They are also used as chemical bleaching agents, luminescent, fluorescent substances and as antioxidants in motor fuels. Sulphonamides based pyrazoles has prolonged bacteriostatic action in vivo . Pyrazole-4-carboxamide and acetamide have been used as antialcoholic agents. Synthetic Studies on Pyrazole

34. Pyrazoles are synthesised from hydrazone derivatives. Pyrazole synthesis exploits the reaction of 1,3-diketones with hydrazine derivativest to give 3,5-Dimethylpyrazole in 80% yield Ethyl diazoacetate reacts with the acetylacetone to yield ethyl 4-methyl-3-acetylpyrazole-5-carboxylate via the pyrazoline

35. The Michael addition / elimination protocol has been extended to the hydrazides and semicarbazides providing a general route to 1-aryl-3-hydroxy-1H-pyrazoles from 4-ethoxymethylene-2-phenyloxazol-5(4H)-one via the intermediates. The reaction of ketone arylhydrazone with phosphorous trichloride and methyl acetoacetate r gives 2-alkenylpyrazole-3(2 H )-one.

36. The one-pot synthesis of the enaminoketone by treatment of  -phthaloylaminoacetophenone with dimethylformamide-dimethylacetal, followed by cyclization to form 4-aminopyrazole.

38. Synthesis of pyrazoles under Vilsmeier conditions Kira et al have reported the formation of pyrazole-4-carboxaldehyde by treating acetophenone phenylhydrazone with DMF/POCl 3 complex.

39. Acetophenone azine has also been converted into the pyrazole-4-carboxaldehyde derivative on treatment with the Vilsmeier reagent. Synthesis of [1]benzopyrano[4,3-c]pyrazoles has been achieved by the Vilsmeier cyclization of o -hydroxyacetophenone phenylhydrazones followed by the treatment of the resulting pyrazole-4-carboxaldehydes with mineral acid.

40. We have reported the synthesis of 4-alkyl-1,3-diarylpyrazoles with DMF and POCl 3 using conventional thermal methods. N N R 5 R 1 R 2 R 3 R 4 DMF/POCl 3 MWI, 30-50 sec or , 4-5 h N N R 1 R 2 R 3 R 4 R 5 H MWI 49-70%,  41-76% S. Selvi, P.T. Perumal, J. Heterocyclic Chem. 39, 1129, 2002.

41. 53-76% S. Selvi, P.T. Perumal, Indian J. Chem. 41B, 1887, 2002. Synthesis of [1]benzopyrano[4,3-c]pyrazoles has been achieved by the Vilsmeier cyclization of o -hydroxyacetophenone phenylhydrazones followed by the treatment of the resulting pyrazole-4-carboxaldehydes with mineral acid.

43. Reaction with commercially available Vilsmeier reagent. When semicarbazones of β-keto esters were chosen as substrates, we obtained 1 H -pyrazole-4-carboxylates after the removal of –CONH 2 group upon neutralisation. 85-92% 86%

44. During our studies it was observed that when the active methylene proton was substituted with more electronegative chlorine atom, the reaction resulted in the formation of 1 H -pyrazole-4-carboxylate substituted with N,N -dimethyl amino group at 5-position. 75-88%

45. Synthesis of 4-formyl-1 H- pyrazole-3-carboxylate Synthesis of 2,4-dinitrophenyl-4-formyl-1( H ) - pyrazole-3-carboxylate was achieved by us from hydrazones of α-keto esters upon treatment with Vilsmeier reagent. 79-88% R. Sridhar, G.Sivaprasad, P.T.Perumal, J. Heterocyclic Chem., 41, 405, 2004.

46. Synthesis of 4-formyl-1 H- pyrazole-3-carboxylate Synthesis of 2,4-dinitrophenyl-4-formyl-1( H ) - pyrazole-3-carboxylate was achieved by us from hydrazones of α-keto esters upon treatment with Vilsmeier reagent. 79-88%

47. Synthesis of 3-arylethenylpyrazole-4- carboxaldehydes The synthesis of pyrazole derivatives by the Vilsmeier cyclization of acetophenone phenylhydrazones prompted us to study the effect of Vilsmeier reagents on the 4-aryl-3-buten-2-one phenylhydrazones. 4-aryl-3-buten-2-one phenylhydrazones are known to undergo tautomerism under acidic conditions to give the corresponding pyrazolines and we expected such a rearrangement to occur under the Vilsmeier conditions followed by formylation of the resulting pyrazoline system to give 1,2-diphenyl-3- N,N -dimethylaminomethylene-4-methyl-1 H -pyrazolines or the pyrazole aldehyde

48. Reaction of 4-aryl-3-buten-2-one 2,4-dinitrophenyl hydrazones with vilsmeier reagent gave the corresponding 1-(2,4-dinitrophenyl)-3-(2-arylethenyl)-1 H -pyrazole-4-carboxaldehydes in excellent yields 1 2 1 2 3 3 DMF/POCl 3 C H 3 N NH R R R N N C H C H O R R R 72-85%

49. Mechanism

50. Synthesis of pyrazolylcarbazoles We have synthesized pyrazolylcarbazoles from carbazoles. The key steps include conversion of acetylcarbazoles to chlorovinylaldehydes, condensation followed by cyclization with hydrazine hydrate. 71-80% i ) BiCl 3, Ac 2 O, ii)DMF, POCl 3, iii) N 2 H 4 .H 2 O R. Nagarajan, P.T.Perumal, Synthesis, 1269, 2004 .

51. Synthesis of substituted indoles, Benzoxazolines and benzthiazolines O O V R COOH COOH CHO Cl 80 o C V.J. Majo, P.T. Perumal; J.Org. Chem. 61, 6523, 1996. 51% 61-75% 21%

52. Mechanism

53. Phosgene reacts with o -phenylenediamines to gives 2(3 H )-benzimidazolones in excellent yield in organic solvents such as benzene, toluene or chloroform . Wright, J. B. Chem. Rev. 1951, 48, 446. Usually the synthesis of 2(3 H )-benzothiazolones is achieved by the reaction of o -amino thiophenol with urea.

54. Most of the synthetic routes to 2(3 H )-benzimidazolone involve o -phenylenediamine as the starting material, which is a suspected carcinogen and is costlier. And there is no generalized strategy available for the synthesis of these title compounds in one-pot. Hence we aimed at a simplified generalized procedure for the preparation of 2(3 H )-benzimidazolones, 2(3 H )-benzoxazolone and 2(3 H )-benzothiazolone.

55. Synthesis of acyl azides Phosgene employed along with DMF in the earlier method for the synthesis of acyl azide, is highly toxic. We have chosen DMF and POCl 3 , which are milder, for the preparation of acyl azide. Addition of POCl 3 facilitates the reaction to be one-pot since it forms the Vilsmeier adduct with DMF at first, which then complexes with the carboxylic acid and reacts with sodium azide to form the acyl azide in excellent yield. R. Sridhar, P.T.Perumal, Synth. Comm.,33, 607, 2003. 90-95% 80-90%

56. Acyl azides are derived in situ from ortho amino benzoic acids upon treatment with DMF/POCl 3 and azide ion. These acyl azides after curtius rearrangement upon stirring for 8-10 hours yield 2(3 H )-benzimidazolones. 75-88% R. Sridhar, P.T.Perumal, Synth. Comm.,34, 735, 2004

57. Synthesis of 2(3 H )-benzothiazolone and 2-chlorobenzothiazole Salicylic acid and thiosalicylic acid yield 2(3 H )-benzoxazolone and 2(3 H )-benzothiazolone respectively in good yields upon treatment with ammonium azide and three equivalents of DMF-POCl 3 complex. Stirring the reaction mixture at room temperature for about 6-10 hours effected both rearrangement and cyclization. Excess POCl 3 replaces –OH group with –Cl yielding 94% of 2-chlorobenzothiazole. R. Sridhar, P.T.Perumal, Synth. Comm.,34, 735, 2004 94% 70%

58. Synthesis of Quinoline derivatives D M F / P O C l 3 N C H O C l N O N O H H

59. Synthesis of Chloro methyl quinoline R.R Amaresh, P.T.Perumal, Synthetic communications, 1997, 27, 337.

61. R.R.Amaresh, P.T.Perumal, Indian journal of chemistry, 36 B 541, 1997

62. The Vilsmeier cyclization of 2'-aminochalcones provides a mild one pot synthesis of 2-aryl-4-chloro- N -formyl-1,2-dihydroquinolines. The scope of the reaction has been extended for the synthesis of quinolines themselves, by replacing 2'-aminochalcones with 2'-azidochalcones as the starting material. 68-85%

63. R.Nagarajan, P.T.Perumal, Synthesis, 1269, 2004. Synthesis of quinolone antibiotics ciprofloxacin, and norfloxacin Synthesis of carbazolyl-dihydroquinolines

64. R.R.Amaresh, P.T.Perumal, Tetrahedron letters, 1998,39, 3837, Tetrahedron, 1998,54, 14327.

65. SYNTHESIS OF 2-ARYL 4-CHLORO QUINOLINES A possible mechanism for the formation of 2-aryl-4-chloro quinolines is presented below. 62-72%

66. Synthesis of tetrahydro-1-2H-benzazepine-oxo-2-carboxaldehydes and dihydro-5-oxo-1,4-benzoxoazepine-4-(5H)-carboxaldehydes. V.J. Majo, A.M. Prince, M.Venugopal & P.T.Perumal, Synth. Comm.25, 3863, 1995. 32-46% 30-60%

67. 2-Dimethylaminoformylidene-3-chloro-1,4-benzoxazine S.Selvi, P.T.Perumal. Synth. Comm. 31, 2199, 2001. 50-82%

68. 2-Dimethylaminoformylidene-3-chloro-1,4-benzthiazine Dimerization reactions Preparation of 2-[3,4-dihydro-4-oxo-3-quinazolinyl]-N,N-dimethylbezamide 60-72% 80-86% V. J. Majo, P.T.Perumal, Tetrahedron Letters, 37, 5015, 1996.

69. Mechanism

70. 3-Substituted-1-oxo-2,4-benzoxazine from N-acetyl anthranilic acid Synthesis of imidazoquinozolindiones from 2-(2-azido)acetamido benzoic acid 42-60%

72. Attempted synthesis of indazoles

73. Synthesis of benzindazoles by cyclisation of tetralone hydrazones DMF/POCl 3 MWI 71-87%  54-67 %

74. G.Sivaprasad, R.Sridhar, P.T.Perumal.(Communicated ) Synthesis of 4,5-dihydro-2H-benzo[e]indazole from aryl hydrazones Synthesis of 4,5-dihydro-2H-benzo[g]indazole from semi carbazones 5% MWI 76-77%  53-59 %

75. Synthesis of 4,5 dihydropyrazolo[4,3c]quinolinesfrom tetrahydroquinoline hydrazones K.Hemanth kumar, S. Selvi, P.T.Perumal. J Chem Research 218, 2004. Yield  (90 o C) = 35-60%, MWI=55-85%

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