Sridar, V

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Indian Journal of ChemistryVol. 36B, January 1997, pp. 86-87Rate acceleration of Fischer-indolecyclization by microwave irradiationV SridarOrganic Chemistry Division, Central Leather ResearchInstitute, Adyar, Madras 600 020, IndiaReceived 8 December 1995; accepted 24 June 1996Rate acceleration in Fischer-indole synthesis hasbeen observed in a microwave oven and the reactiongoes to completion within 28 see in good yield in one-pot.Microwave induced rate enhancement of variousreactions is becoming popular with organic che-mists 1. This technique has found applications inDiels-Alder reaction", nucleophilic substitutionreactions", Claisen rearrangement", Fries rear-rangements, Ferrier rearrangement", reactions indry media with solid support", etc. Recently, ithas been observed that microwave irradiation alsochanges the course of reaction from that of ther-mal process".We report herein the application of microwaveirradiation to Fischer-indole synthesis which isone of the important processes in organic synthe-sis. It produces indoles with different substituentsat 2- and 3-positions. The reaction can be carriedout by performing the hydrazone and then treat-ing the hydrazone with protic acids or Lewis ac-ids. A one-pot synthesis of indoles in acetic acidmedium from phenylhydrazine hydrochloride withvarious acyclic ketones has been reported in liter-ature? and the reaction requires 3 hr at 90°C. Wewere interested in performing the reaction in amicrowave oven for achieving rate acceleration.However, two reports have appeared on the mic-rowave induced Fischer-indole synthesis. One ofthem involves heating of the preformed hydra-zone in a Parr microwave bomb for 2 min at fullpower (with a brief cooling period after 1 min ofheating)'? and the other utilises montmorilloniteas the absorption medium for phenylhydrazineand ketone and the mixture was irradiated for 5min at 160Wl. Herein we descrfibe Fischer-in-dole synthesis in a microwave oven in a muchshorter time (28 see at High power) in one-pot inan Erlenmeyer flask.Solvents possessing high dielectric constantshave to be used for reactions in microwave ovenNoteRtCtJQOJ(~ R :::::,... N nH H1 R =CH, R' = CH, 6 n = 12 R = C2H5 R'= CH, 7 n = 23 R = iPr R'=CH, 8 n = 34 R=¢ R'= H 9 n = 45 R = CH, R'=¢since they get superheated rapidly". Acetic acidhas a dielectric constant of only 6.15 but still itwas effective as we found out during our investi-gation.We subjected a heterogeneous mixture of phen-ylhydrazine hydrochloride in acetic acid with2-butanone in a 100 mL Erlenmeyer flask to mic-rowave conditions at high power (100%, 700W)and 2450 MHz frequency. Within 28 sec aceticacid boils and the irradiation was stopped. Theyield of 2,3-dimethylindole was 50% as shown inTable I. Cyclic ketones produce the correspond-ing indoles in high yields. These reactions werecarried out by thermal process (heating over wa-ter bath for 3 hrs) as well for comparison pur-poses (Table I). In the case of 2-butanone, thereaction at 50% power produces only 35% yieldin 50 see whereas other ketones provide compar-able yields. This we reasoned that at 50% powerthe microwaves are switched on only in alternat-ing 10 sec and this would facilitate the rapid eva-poration of 2-butaone. Better yield is notachieved even at 100% power in the case of2-butanone mainly because of evaporation due toits higher dielectric constant (18.5) and lowerboiling point. However, yield could be improvedby taking excess of 2-butanone. We also observedthat indoles 3 and 4 tend to undergo aerial oxida-tion.In conclusion we have shown that there is arate acceleration of 385 fold under microwaveconditions over thermal process in Fischer-indolesynthesis.Experimental SectionTypical procedure. An Erlenmeyer flask (capac-ity 100 mL) containing a heterogenous mixture ofphenylhydrazine hydrochloride (1.45 g, 0.01Table I - Yields of indoles 1-9 under microwave and thermalconditionsSI KetoneNo.Product" Yield (%)bMicrowave Thermalcondition conditiona 2-Butanone 1 50 63db 3-Pentanone 2 63 68dc Isobutyl methyl ketone 3 63< 64dd Acetophenone 4 65 55e Benzyl methyl ketone S 68< 60f Cyclopentanone 6 53 40g Cyclohexanone 7 90 75h Cycloheptanone 8 68 65Cyclooctanone 9 67< 65"m.ps., IH NMR, GCMSD data were consistent with the pro-ducts."Yields based on phenylhydrazine hydrochloride.<Chromatographically isolated.dReported9•mole) and 2-butanone (0.87 g, 0.012 mole) in 20JiL glacial acetic acid was kept in a commercialmicrowave oven and subjected to microwave irra-diation at 100% power for 28 sees. Subsequently,it was cooled to room temperature and pouredslowly into 90 mL of ice-cold water. The solidwas filtered under suction, dissolved in 30 mLNOTES 87ether, washed successively with 2 N NaOH(2 x 15 ml.), water (2 x 15 mL) and brine (1 x 15mL). The ethereal layer was dried over NaZS04and evaporated to dryness resulting in 0.86 g(60%) of 2,3-dimethylindole 1. This was againdissolved in 10 mL ether and 10. mL pet. etherand kept aside. Recrystallization produces 0.73 g(50%) of 1.References1 Abramovitch R A, Org Prep Proced Int, 23, 1991,683.2 (a) Giguere R J, Bray T L, Duncan S M & Megetich G,Tetrahedron Lett, 27, 1986,4945.(b) Berian J, Giboreau P Le, Feuvre S & Marchand C,Tetrahedron Lett, 32, 1991,2363.(c) Bose A K, Manhas M S, Ghosh M, Shah M, Raju V S,Bari S S, Newaz S N, Banik B K, Chaudhany A G & Bar-akar K J, J Org Chern, 58,1991,6968.3 Chen S T, Chiou S H & Wang K T, J Chern Soc ChernCommun; 1990,807.4 Srikrishna A & Nagaraju S, J Chern Soc Perkin Trans-I,1992,311.5 Sridar V & Sundara Rao V S, Indian J Chern, 33B,1994,326.6 Sowmya S & Balasubramanian K K, Synth Commun, 24,1994,2097.7 (a) Gutierrez E, Lousy A, Bram G & Ruiz-Hitzoky E, Te-trahedron Len; 30, 1989,945.(b) Alloum A B, Labiad B & Villemin D, J Chern SocChern Commun; 1989,386.8 Srikrishna A & Praveen Kumar P, Tetrahedron Lett, 36,1995,6313.9 Dave V, Org Prep Proced Int, 8, 1976,41.10 Abramovitch R A & Bulman A, Synlett, 1992,795.11 Villemin D, Labiad B & Ouhilal Y, Chern Ind (London),1989,607.

Rate acceleration of Fischer-indole cyclization by microwave irradiation

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Rate acceleration of Fischer-indole cyclization by microwave irradiation

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