Trofimov reaction

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). 

The dioxime of cyclohexane-1,4-dione reacts with acetylene in an autoclave in the presence of KOH/dimethyl sulfoxide (DMSO) (Trofimov reaction) to give l,5-divinyl-4,8-dihydropyrrolo[2,32f]indole by sequential [1,3]- and [3,3]-rearrangements in poor yield (Equation 91) <2004TL3789>. 

Trofimov reaction.1 The reaction of ketoximes with acetylene in the super base KOH/DMSO forms N-vinylpyrroles. An extension is the reaction of the unsaturated ketoxime 1 under the same conditions to form either 2 or 3 as the major product.2... 

TRANSAMINATION 4-Pyridinecarboxaldchyde. TRANSESTERIFICATIONS Titanium(IV) ethoxide. Titanium(lV) isopropoxide. TRIFLUOROMETHYLATION Zinc. TROFIMOV REACTION Potassium hydroxidc-Dimethyl sulfoxide. 

Since the publication of the latest review (02MI(1)334) summarizing the results of the Trofimov reaction, many new reports have appeared. These are the subject of the present review, which covers publications of the last decade only. 

Rearrangement of the vinyl ether of acetylparacyclophane oxime 26, the key intermediate in the Trofimov reaction, gave 2-([2,2]paracyclophan-5-yl)pyrrole (27) in 74% yield (Scheme 4) (04TL5489). The intermediate O-vinyl oxime 26 was synthesized (78%) by vinylation of a Cs-derivative of the oxime of 5-acetyl[2,2]paracyclophane (28) with acetylene (Scheme 4) under pressure in a DMSO-n-pentane two-phase system (04TL5489). 

A number of hitherto inaccessible or unknown NH- and N-vinylpyrroles, becoming available through the Trofimov reaction, has opened new horizons for further developing pyrrole chemistry. Here, the reactions of pyrroles and Af-vinylpyrroles synthesized from ketones and acetylenes are briefly discussed. 

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

A one-pot Trofimov reaction (type Ilac cyclization) has been developed <05ARK(vii)ll>. Treatment of ketoximes with acetylene in the presence of superbase (KOH/DMSO) gave 2-substituted and 2,3-disubstituted p)Troles. 

Scheme 14.S The Trofimov reaction and recent advances in substrate scope.

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. 

A review of the Trofimov reaction describes the work done up to 1994. The review covers aliphatic and aromatic ketoximines, heterocyclic ketoximines. Typical reaction yields ranged from 40-70%, some examples reported yields > 90%, and several reported single-digit yields. This report will cover the literature published post-1994. ... 

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 modified procedure for the classical Trofimov reaction (conversion of a ketone to a pyrrole via the corresponding ketoximine) showed that preformation of the ketoximine at mild temperatures and with a mild base (70 °C, NaHCOs) followed by subjection to the standard conditions (KOH/DMSO, acetylene, 100-120 °C) provided the desired vinyl pyrroles in improved yields. ... 

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... 

Interesting applications of the Trofimov reaction in optoelectronic materials have been reported. The preparation of pyrrolo[2,2]-paracyclophanes is one example. Starting from the acetyl-substituted compound 61, conversion to the ketoximine followed by reaction with acetylene and KOH/DMSO, in one pot, gave the two pyrroloparacyclophanes in low yield. However, formation of the O-vinyl ketoximine [Cs(OH)2, acetylene, 70 °C, 78% yield], followed by conversion to the pyrrole in two separate steps gave 64 in 53% yield. 

A review of synthetic methods for arylpyrroles focuses particularly on the Trofimov reaction of oximes of alkyl aryl ketones with acetylene (192 references). ... 

Tetramethyl-4,5,6,7-tetrahydroindole is synthesized in 70% yield by the Trofimov reaction from the corresponding ketone (via oxime) and acetylene (Scheme 1.29) [198]. 

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. 

A possibility of successful application of the Trofimov reaction for the construction of the pyrrole ring bonded to the steroid skeleton has been exemplified by oximes of ketosteroids. 

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. 

Recently, 2-mesityl-3-methylpyrrole, synthesized from mesityl ethyl ketone and acetylene via the Trofimov reaction, has been used for the preparation of sterically encumbered fluorophores of BODIPY family (Scheme 2.183) [222]. The fluoro-phore assembled in a one-pot manner through the following procedure the pyrrole is condensed with mesityl aldehyde (TFAA, CHjClj, 20°C-25 C, 24 h), dipyrro-methane is oxidized to dipyrromethene (DDQ, CHjClj, 20°C-25 C, 0.5 h), and the latter is treated with BF3-Et20 in the presence of diisopropylethylamine (CH2CI2, 20°C-25°C, 0.5 h). 

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., N.V. Zorina, A.B. Zaitsev et al. 2004. A selective synthesis of 2-([2,2] paracyclophan-5-yl)pynole liom 5-acetyl[2,2]paracyclophane via the Trofimov reaction. Tetrahedron Lett 45 5489-5491. 

VasU tsov, A.M., E.Yu. Schmidt, A.I. Mikhaleva et al. 2005. Synthesis and electroehem-ical characterization of dipyrroles separated by diphenyleneoxide and diphenylenesul-fide spacers via the Trofimov reaction. Tetrahedron 61 7756-7762. 

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. 

VasiTtsov, A.M., A.I. Mikhaleva, R.N. Nesterenko, and M.V. Sigalov. 1991. Alkenylpyrroles from 5-hexen-2-one oxime Prototropie isomerization under eonditions of the Trofimov reaction. Khim Geterocicl 4 477-480. 

Vasil tsov, A.M., A.B. Zaitsev, E.Yu. Schmidt et al. 2001. Unexpected foimation of l-vinyl-2-[2 -(6 -methylpyridyl)]pyrrole from dimethylglyoxime and acetylene in the Trofimov reaction. Mendeleev Commun 2 74—75. 

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