Ketoximes, pyrroles from, with acetylenes

The reaction of acetoxime with acetylene under the conditions optimal for the synthesis of pyrroles from other ketoximes affords lower yields of 2-methyl- and 2-methyl- 1-vinylpyrrole, only 42% (40% KOH, 1 10 acetoxime/DMSO ratio, 4% water of DMSO volume, 97-100°C, 14-18 hr). Under analogous conditions, other ketoximes are converted to pyrroles in a yield of about 70%. Under the best conditions for the synthesis of N-vinyl pyrroles, 2-methyl-1-vinylpyrrole is obtained in yields of 7-21%. In order to find the reason for such a low conversion of acetoxime to the N-vinylpyrrole, the authors varied the reaction conditions thus the synthesis was performed in an autoclave under an acetylene pressure of 10-20 atm, in a bench reactor (acetylene pressure of about 1.5-2.0 atm), and under atmospheric pressure with the KOH and DMSO concentration temperature and reaction time being varied in a wide range (Table IX). 

Benzofuranyl)pyrroles, 2-(2-thienyl)pyrroles , 2,2 -dipyrroles, 3-(2-pyr-rolyl)indoles , 2-(2-benzimidazolyl)pyrroles and2-(2-, 3- and4-pyridyl)pyrroles were prepared using this method. Reaction of alkynes (for example, propyne) or allene with ketoximes in a superbase system (MOH/DMSO) leads to 2,5-di- or 2,3,5-trisubstituted pyrroles Pyrroles and dipyrroles were synthesized also from corresponding dioximes and acetylene in a KOH/DMSO system It has also been shown that 1,2-dichloroeth-ane can serve as a source of acetylene in pyrrole synthesis. Oxime 52 in the system acetylene/RbOH/DMSO at 70 °C afforded a mixture of three pyrroles 53-55 in low yields (equation 23). The formation of product 53 occurred through recyclization of pyrrolopy-ridine intermediate. ... 

This order of base activity corresponds almost exactly to that observed in the formation of pyrroles from ketoximes and acetylene, evidently for the same causes. The failure of trimethylbenzylammonium hydroxide to catalyze the reaction of vinylation is believed (59MI1 66MI1) to be caused by its lack of coordination. Along with inhibition of the reaction with water, pyridine, o-phenanthroline, and diketones, this indicates the reaction occurs by complex ionic mechanisms in which the participation of the complex ion as an intermediate is possible. 

So in comparison with DMSO, other nonhydroxylic polar solvents such as HMPA and sulfolane form systems rather less active in catalyzing the synthesis of pyrroles from ketoximes and acetylene. At least, alternative routes based on their application have not been well developed and remain of less preparative importance. In solvents such as ethers, alcohols, and hydrocarbons, the reaction fails to occur (80KGS1299 84MI1). 

Under the conditions favorable for the synthesis of pyrroles from alkyl aryl ketoximes (100°C, 3 hr, 30% KOH of ketoximes mass, DMSO, acetylene under 12-16 atm pressure), the reaction with methyl naphthyl ketoximes is accompanied by considerable resinification to give low yields of pyrroles 14-17. The best results were achieved at 90°C. From methyl 1-naphthyl ketoxime at this temperature (2 hr, KOH), 2-(l-naphthyl)pyrrole (14) and 2-(l-naphthyl)-1-vinylpyrrole (15) are formed in 15 and 48% yield, respectively. 

It would be attractive from both mechanistic and preparative standpoints to obtain pyrroles by condensation of acetylene with ketoxime derivatives or analogs, e.g., their ethers or hydrazones, i.e., to realize the... 

The corresponding 2-hydroxy-2,3-dihydropyrrole (94a), the product of rearrangement of the O-vinyloxime 93a (see Section IV.B), is converted to the 3//-pyrrole 97 under the conditions of the reaction with acetylene (85KGS1573), and this provides more evidence for the O-vinyloxime route to pyrroles from ketoximes and acetylene. 

Recently, (88ZOR1789) in the synthesis of pyrroles from ketoximes and acetylene (KOH/DMSO, 95°C, 5 hr, atmospheric pressure), the formation of dipyrrylethanes (98a-c) along with the normal products, NH-pyrroles and /V-vinylpyrroles, was observed in a number of cases. 

This condensation helps one understand why the yield of pyrroles from ketoximes and acetylene is reduced in some cases and consequently allows a more directed search for ways to overcome this obstacle. Optimization of this side reaction would make possible a one-pot preparation of valuable dipyrroles with cyclopropyl or vinyl substituents, such as 98a,c for example. 

Preparation of pyrroles from ketoximes and acetylenes 90AHC(51)177. Pyrrole derivatives with phosphorus-containing substituents 93MI1. Pyrroles, general monograph 90CH(48,1)1 92CH(48,2)1. 

The synthesis of NH- and Af-vinylpyrroles from ketones (ketoximes) and acetylenes has stimulated physicochemical and theoretical studies of ketoximes as well as pyrroles and N-vinylpyrroles. The easy access to diversely substituted representatives of pyrrole series made it possible to systematically examine the structural effect on their reactivity and spectral properties. This section is a concise account on the research related to NH- and N-vinylpyrroles originated from the reaction of ketones with acetylenes along with investigation of stereoelectronic properties of intermediate ketoximes. 

Such order of bases activity corresponds almost precisely to that observed in the synthesis of pyrroles from ketoximes and acetylene and, obviously, is caused by the same reasons. It is assumed [109,152] that the inability of trimethylbenzylam-monium hydroxide to catalyze vinylation reaction is due to the lack of coordination ability of this base. This fact as well as inhibition of the reaction with water, pyridine, phenanthroline, and diketones evidences [109,152] that the reaction proceeds via two mechanisms, that is, complex and ionic ones (in the latter case, participation of a complex ion as intermediate is not excluded). 

Synthesis of N-vinylpyrroles from symmetric and asymmetric ketoximes is generally carried out in autoclave (10-20 atm, 120°C-140°C, 1-3 h) with a large excess acetylene, KOH-ketoxime ratio being 0.1-0.3 [185]. Preferable ketoxime-DMSO ratio is 1 8-16. NH-pyrroles are successfully obtained when acetylene is passed through the reaction mixture (atmospheric pressure, 93°C-100°C, 6-10 h, 40%-100% KOH from the ketoxime weight) in the presence of DMSO containing 4%-10% of water that suppresses vinylation reaction [186]. 

For the first time, the reaction of ketoximes with acetylene has been applied for the preparation of pyrroles bonded with the thiophene ring in the work [244], which describes synthesis of 2-(2-thienyl)pyirole (in 60% yield) from 2-acetylthio-phene (via its oxime) in the system KOH/DMSO (100°C-140°C). In the presence of acetylene excess under the same conditions, 2-(2-thienyl)-N-vinylpyrroles (50% yield) is formed. 

SCHEME 1.148 Synthesis of 3//-pyrroles from acetylene and ketoximes with just one C-H bond adjacent to the oxime function. 

Data from a systematic study of the vinylation of a number of pyrroles obtained by the reaction of acetylene with ketoximes are presented in the paper [484], N-Vinylpyrroles are prepared in up to 97% yield (Schone 2.36, Table 1.3). 

MUdialeva, A.I., A.N. VasiUev, and B.A. Trofimov. 1981. Pyrroles from ketoximes and acetylene. 17. A study of the reaction of cyclohexanone oxime with acetylene in superbase media. Zh Org Khim 17 (9) 1977-1980. 

Trofimov, B.A., S.E. Korostova, L.N. Balabanova, and A.I. Mikhaleva. 1978. Pyrroles from ketoximes and acetylene. 6. A study of the reaction of aceto- and propiophenox-imes with acetylene. Zh Org Khim 14 (8) 1733-1736. 

Mikhaleva, A.I., B.A. Trofimov, A.N. Vasiliev, and G.A. Komarova. Method for the preparation of 2- or 2,3-substituted pyrroles. 1982. USSR Author s Certificate 979,337. Mikhaleva, A.I., B.A. Trofimov, A.N. Vasiliev et al. 1982. Pyrroles from ketoximes and acetylene. XXII. Dihaloethanes instead of acetylene in the reaction with cyclohexanone oxime. Khim Geterocicl 9 1202-1204. 

In general, however, methyl 1-naphthyl ketoxime starts to condense with acetylene under pressure at about 60°C. At 80°C (3 hr, KOH) 2-(l-naphthyl)- 1-vinylpyrrole (15) becomes the predominant reaction product, however its yield decreases due to resinification on further elevating the temperature and increasing the reaction time. 2-(l-Naphthyl)pyrrole (14), free from the corresponding N-vinylpyrrole (15), was isolated in 22% yield when use was made of a catalytic pair LiOH/DMSO (90°C, 3 hr). The temperature effect (3 hr, 30% KOH, initial acetylenic pressure of 12 atm) on the yield of naphthylpyrroles was examined in condensation of methyl 2-naphthyl ketoxime with acetylene as an example (82KGS1351) ... 

Pyrroles with unsaturated substituents are known as deficient starting materials for the synthesis of diverse functional derivatives of pyrrole. The method of building up the pyrrole ring from ketoximes and acetylene with a simultaneous introduction of a vinyl group to the nitrogen atom proved to be useful in this case as well. 

Despite the isolation of O-vinyloximes from the products of reaction of ketoximes with acetylene, and the demonstration of their conversion to pyrroles by superbase KOH/DMSO (see Section IV.A), the suggested (81MI4) intermediate stages of this rearrangement long remained unproved. The intermediate 4//-2-hydroxy-2,3-dihydropyrroles (94) (Scheme 45) were first isolated by Trofimov et al. (83KGS276). 

In the preparation of pyrroles and N-vinylpyrroles from ketoximes, along with vinyl halides, dihaloalkanes as acetylene equivalents can also be used. Pyrroles and /V-vinylpyrroles are formed in a yield of about 30% in the reaction of ketoximes with dihaloalkanes in the presence of excess alkali metal hydroxide in DMSO (Scheme 60) (79IZV2840). 

Systematic research on this novel synthesis of pyrroles and especially of N-vinylpyrroles from ketoximes and acetylene is in progress. This is expected to lead to not only further extension of the preparative possibilities of the reaction, but also to discovery of new versions and analogs. The increased access to N-vinylpyrroles stimulates more and more synthetic and theoretical investigations in this field as well as work dealing with polymerization and practical application of these compounds (84MI1). For the 20 years since its discovery, the reaction of ketoximes with acetylene has become popular as a reliable preparative tool for wide application in the chemistry of pyrroles. 

Interestingly, in aqueous medium, acetylene and ketoximes interact in an absolutely different fashion, delivering pyridines instead of pyrroles [4,174] (see Section 1.5.4). The reaction occurs also with acetylene obtained directly in the autoclave from calcium carbide [174]. 

Further investigations have elaborated upon the conditions that ensure the synthesis of pyrroles and their N-vinyl derivatives under atmospheric pressure in the simplest reactor equipped with mixer and bubbler for acetylene supply (reaction temperature is 93°C-97°C). To reach this goal, the increase of alkali concentration in the reaction mixture (up to 50% from weight of the initial ketoxime) and approximately two-time-longer reaction time are required. The yield of N-vinylpyrroles remains rather high (-80%). 

The reaction smoothly proceeds also at 100°C in the presence of 30% (from ketoxime weight) KOH in DMSO in autoclave under initial acetylene pressure of 8-16 atm. The maximum pressure reached at the reaction temperature is 20-25 atm. Then, intensive consumption of acetylene begins, and pressure quickly decreases. As it was already noted, initially, N-unsubstituted pyrroles are formed, which further are vinylated in the presence of acetylene excess. If it is necessary to obtain the corresponding NH-pyrrole, the synthesis is carried out with calculated amount of acetylene or with its lack. LiOH appears to be a selective catalyst of the pyrrole ring construction, the application of which does not require strict dosing of acetylene. 

In the conditions developed for alkyl aryl ketoximes (100°C, 3 h, 30% KOH from ketoxime weight, acetylene pressure 12-16 atm), the reaction with acetylnaphthalene oximes is accompanied by considerable resiniflcation, and the yields of pyrrole are low. The best results are attained at 90°C a mixture of 2-(l-naphthyl)pyrrole and 2-(l-naphthyl)-N-vinylpyrrole in 15% and 48% yields, respectively, is formed from 1-acetylnaphthalene oxime (2 h, KOH) [225]. 

At 120°C, all methyl alkyl ketoximes react with acetylene exclusively at the methylene group of the alkyl radical irrespective of a structure of its other part Q.so- or normal, the exception makes methyl-iso-propyl ketoxime that reacts exclusively at the methyl group, forming the only one isomer). With temperature increase, the regioselectivity of reaction is broken at 140°C, pyrroles are already formed involving the methyl group in amount of 20%-50% from the mass of the mixture, though the total yield drops. 

Along with vinyl halides as synthetic equivalents of acetylene, dihaloethanes can also be employed in the synthesis of pyrroles and N-vinylpyrroles from ketoximes (Scheme 1.129) [299], The reaction of ketoximes with dihaloethanes in the presence of excess of alkali metal hydroxide in DMSO gives pyrroles and N-vinylpyrroles in -30% yields. In further experiments, higher yields have been achieved [7],... 

The formation of the pyridine ring, observed in this cases, implies the interception of iminoaldehyde (intermediate G) by phenylacetylene and represents an additional experimental support of the ketoxime-acetylene mechanism of pyrrole synthesis that is presently accepted. On the other hand, this new direction of the reaction of ketoximes with acetylene, despite moderate yields of pyridylpyrroles, can have preparative value as straightforward one-pot synthesis of the unnatural nicotine-like alkaloid from simple available starting reactants (1,2-dioximes and acetylene). 

Thus, the stereoselective methylthiovinylation of pyrroles, formed from ketoximes and acetylene in the KOH/DMSO system, represents a rare example of interaction of the vinyl carbanion with sulfoxide function. Despite the negligible yield of methylthiovinylpyrroles, the fact of their formation sheds additional light on peculiarities of the reaction of ketoximes with acetylene in the systems MOH/DMSO. 

The investigations of the reaction of ketoximes with acetylene have shown that the superbase system KOH/DMSO essentially facilitates vinylation of pyrroles with acetylene. This finding constitutes the basis of a new efficient method for vinylation of componnds having the N-H-bond. The process fnndamentally differs from the known protocols since it is brought about under atmospheric pressnre at moderate temperatnres (80°C-100°C). The method is recommended for vinylation of any NH heterocycles (resistant to the action of alkalis) in simple reactors. Apart from the obvions promise for industry, the method is also indispensable for laboratories that do not have special operating building and equipment (autoclaves working with acetylene nnder pressure). 

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