Trofimov reaction, pyrrole synthesis

General synthesis of pyrroles and 1-vinylpyrroles by the reaction of ketoximes with acetylenes and their synthetic equivalents (vinyl halides and dihaloethanes) in the presence of the strongly basic KOH/DMSO system (Trofimov reaction) has been reviewed ° in recent years. Therefore, in the present work this reaction will be described very shortly. In principle, pyrrole (51) synthesis can be carried out as a one-pot procedure by treating ketones (49) with hydroxylamine and then reacting the ketoximes (50) formed with acetylenes (equation 22). 

Two-step synthesis of pyrroles from ketones and acetylenes via the Trofimov reaction 03MI20. 

Trofimov and co-workers have developed a pyrrole synthesis which involves reactions of ketox-imes with alkynes under strongly basic conditions (Scheme 51) <90AHC178,94H(37)l 193>. The key step in the reaction is a sigmatropic rearrangement of an 0-vinyloxime which is followed by a typical... 

The Trofimov pyrrole synthesis (the Trofimov Reaction) refers to the conversion of ketones to pyrroles in the presence of NH2OH, KOH and DMSO at elevated temperatures. The reaction was shown to occur via hydroxylamine and 0-vinylhydroxylamine intermediates. 

In the 1980s, Boris A. Trofimov published several manuscripts describing the synthesis of pyrroles and vinylpyrroles from ketones, hydroxylamine and acetylene. The reaction was believed to occur via hydroxylimine formation, followed by O-vinylation, rearrangement, then ring closure. The Trofimov reaction has been studied in limited detail but has been shown to have application to the synthesis of a variety of pyrroles. 

One of the weaknesses of the Trofimov reaction is the requirement for using acetylene under high pressure. To obviate this requirement, acetylene analogs (vinyl halides and 1,2-dihaloethanes) were examined for the utility as components in the Trofimov reaction. The results are promising and indicated that further development of this variation in the Trofimov reaction could lead to a more practical and attractive method for pyrrole synthesis. 

A nice application of the Trofimov reaction to the synthesis of steroidal pyrroles is shown in the reaction above. Reaction of pregnenolone ketoximine 39 with acetylene in KOH/DMSO gave four vinyl ether products... 

Varlamov et al. [204] have reported the synthesis of pyrrole and N-vinylpyrrole from tropinone oxime and acetylene via the Trofimov reaction (Scheme 1.33), the yields being 49% and 41%, respectively. 

Synthesis of pyrroles from ketones (through ketoximes) and propyne-allene mixture, a large-scale side product of hydrocarbons pyrolysis, essentially expands the preparative possibilities of the Trofimov reaction. 5-Methyl-substituted pyrroles, having diverse substituents in the positions 2 and 3, become readily available for the first time. 

Over the last decades, a novel branch of the pyrrole chemistry, based on the reaction of ketones (ketoximes) with acetylenes in the superbase catalytic systems (the Trofimov reaction), has emerged and keeps progressing rapidly. New facile and highly efficient approaches to the diverse compounds of the pyrrole series have been developed. The investigations in this line are gathering momentum. Not only the discoverers and developers of novel pyrrole synthesis (the authors of this monograph) but many other research teams both in Russia and abroad are engaged in these studies. 

For 40 years since its discovery, the reaction of ketones (ketoximes) with acetylene has recommended itself as a reliable preparative tool for wide application in chemistry of pyrroles and their N-vinyl derivatives. Systematic development of novel syntheses of pyrroles, and especially N-vinylpyrroles via the Trofimov reaction, is still progressing. There is reason to hope that this will lead not only to the further enhancement of the preparative importance of this synthesis but also to the discovery of its new variants and analogs. The increased availability of N-vinylpyrroles stimulates synthetic, physical-chemical [507,729-755], and theoretical [756-759] investigations in the field and also works on polymerization and practical application of these compounds [697-700,709-728]. 

Mikhaleva, A.L and E.Yu. Schmidt. 2002. Two-step synthesis of pyrroles from ketones and acetylenes through the Trofimov reaction. In Selected Methods for Synthesis and Modification of Heterocycles, vol. 1, ed. V.G. Kartsev, pp. 334-352. Moscow, Russia IBS Press. 

Schmidt, E.Yu., A.I. Mikhaleva, A.M. VasU tsov et al. 2005. A straightforward synthesis of pyrroles from ketones and acetylene A one-pot version of the Trofimov reaction. Arkivoc vii 11-17. 

Mikhaleva, A.I., E.Yn. Schmidt, A.V. Ivanov et al. 2007. Selective synthesis of 1-vinyl-pyrroles directly from ketones and acetylene Modification of the Trofimov reaction. Zh Org Khim 43 (2) 236-238. 

Trofimov has extended his previously reported heterocyclization of ketoximes 39 with acetylene to propyne or its isomer allene in superbase systems (MOR/DMSO M = K, Cs, R = H, t-Bu) to afford a facile synthesis of substituted pyrroles 40 and 41 . Due to a fast propyne to allene protropic isomerization under the reaction conditions, the product is the same regardless of which species is employed. 

Extention of the reaction of ketoximes with acetylene to oximes of hydroxyalkyl ketones can lead to the synthesis of inaccessible, functionally substituted pyrroles and A-vinyl derivatives. However, the methyl a- and /3-hydroxyalkyl ketoximes used by Trofimov et al. (80ZOR410) appeared to react with acetylene in the KOH/DMSO system in an abnormal way. 

In brief communications concerning the use of dialkyl ketoximes (79IZV2840 81MI7, 81MI8) in this reaction, no comprehensive synthetic procedures are described. The experimental details for the synthesis of 2,3-dialkyl-substituted pyrroles from symmetrical and unsymmetrical dialkyl ketoximes and dichloroethane in the KOH/DMSO system (Scheme 63) were first discussed by Trofimov et al. (85KGS59). 

Volume 51 of Advances consists of three chapters, V. V. Mezheritskii and V. V. Tkachenko (Rostov-on-Don, U.S.S.R.) review the synthesis of peri-annelated heterocycles, a large and interesting class which has not previously been treated in a systematic fashion. R. M. Acheson (Oxford, U.K.) provides the first detailed survey of 1-hydroxypyrroles and their benzo derivatives, compounds which show an interesting and unusual chemistry. Finally, B. A. Trofimov (Irkutsk, U.S.S.R.) describes the minifold preparative possibility for pyrroles from ketoximes and acetylenes, a reaction discovered by Trofimov and developed by him into a most important entry into pyrrole chemistry. 

Trofimov, B.A. and A.I. Mikhaleva. 1980. Reactions of ketoximes with acetylene A novel general method for the synthesis of pyrroles. Khim Geterocicl 10 1299-1312. 

Trofimov, B.A., L.N. Sobenina, A.I. Mikhaleva et al. 2000. Reaction of pyrrole anions with carbon disulfide. Synthesis of pyrrole-3-carbodithioates. Tetrahedron 56 7325-7329. 

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