Pyrroles synthesis from oximes

In attempts (76IZV690 80KGS1299 81MI4) to extend the pyrrole synthesis from ketoximes and acetylenes to aldoximes, the oximes of both aliphatic and aromatic aldehydes have been found to readily convert to the corresponding nitriles upon moderate heating (60-140°C) in KOH/DMSO. 

Pyrroles, synthesis from keto oximes and aeetylene 80KGS1299. 

Therefore, three intermediates of the pyrrole synthesis from ketoximes and acetylene, namely, O-vinyl oximes, hydroxypyrroUnes, and 3F/-pyrroles, have been isolated and characterized. In certain cases, they are quite stable. Besides, very recently [45], it has been shown that iminoaldehyde is detected (NMR) in catalytic ([(cod)lrCl], AgOTf, NaBH4, THF) version of the O-vinyl oxime rearrangement to pyrroles. This is another evidence in favor of the aforementioned mechanism of pyrroles formation. 

Nevertheless, concluding this section, one can state that all now available experimental data correlate better with the O-vinyl oxime mechanism. At the same time, it should be remembered that all, even the most plausible, mechanistic schemes cannot be considered adequate if they do not explain why the pyrrole synthesis from ketox-imes and acetylene successfully proceeds only in the presence of specific superbase systems KOH/DMSO. 

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. ... 

Bis[(]V-vinylpyrrol-2-yl)]diphenyloxide (85), 4,4 -bis(pyrrol-2-yl) diphenylsulfide (86), 4-(pyrrol-2-yl)-4 -[(N-vinylpyrrol-2-yl)]diphe-nylsulfide (87) and 4,4 -bis[(N-vinylpyrrol-2-yl)]diphenylsulfide (88) were synthesized in a one-pot procedure from oximes of the corresponding diacetylphenylenoxide 89 and -sulfide 90 through reaction with acetylene (MOH-DMSO, M = Li, K), thus illustrating the applicability and general character of the synthesis of diverse dipyrrole-phenylene assemblies and their N-vinyl derivatives (Equation (23)) (05T7756). 

Another synthesis of pyrroles 4 from a-diazo oxime ethers 3 was developed and enabled by the strong inherent tendency of 1,3-dienyl nitrenes to undergo 4rt-electrocyclization reactions. It is important to note that the reaction pathway can be modulated to afford pyridines (14CS2347). 

The Knorr pyrrole synthesis was also employed for the synthesis of 3-trifluoropyrroles [91]. Treatment of ethyl trifluoroacetoacetate 267 with sodium nitrite in acetic acid led to the oxime 268. Refluxing with zinc dust and addition of 1,3-dicarbonyl compounds 269 afforded the 3-trifluoromethylpyrroles 270 in moderate yields. Using more acidic trifluoroacetic acid allowed to lower the reaction temperature to 70 °C [92]. Using a similar approach, the tricarboxylic acid ester 273 was prepared starting from the acetone dicarboxylic acid ester 271 and the fluorinated keto ester 272 [93]. 

SCHEME 1.31 Synthesis of pyrroles from oximes of macrocycUc ketones and acetylene. 

The synthesis of 2-(2-selenophenyl)pyrrole (10% yield) and 2-(2-selenophenyl)-N-vinylpyrrole (2% yield) from 2-acetylselenohene oxime and acetylene at 95°C-97°C has been reported for the first time in [249]. Seventeen years later, this reaction was employed to prepare 3-alkyl-2-(2-selenophenyl)pyrroles and their N-vinyl derivative from oximes of acylselenophenes (Scheme 1.63) [250]. The process is carried out in the system MOH/DMSO (M=Na, K) under acetylene pressure at 100°C (30-60 min). 

The assessment of application scopes of novel pyrrole synthesis has revealed [274] that it can be extended to such essentially new group of oximes as aromatic dioximes. For example, dipyrroles separated by the phenylene fragment, dipyrrolylben-zenes, can be prepared in a one-stage fashion from 1,4-diacetylbenzene dioxime. 

The most probable way of the pyrrole ring assembly from ketoximes and acetylene in the system KOH/DMSO is a heteroatomic version of Claisen rearrangement of the intermediate O-vinyl oxime, preliminarily isomerized to 0,N-divinylhydroxylamine [4,7,16,18]. As shown in the previous section, O-vinyl oximes are isolable intermediates of the pyrrole synthesis capable of transformation to pyrroles under the action of KOH/DMSO and also in DMSO itself. However, other tentative intermediate stages of the rearrangement remained disputable for a long. 

The informative tables included in this book contain structural formulas, yields, and classical physical and chemical characteristics (melting and boiling points) of all pyrroles and N-vinylpyrroles synthesized from ketoximes and acetylene. The same data are also given for selected O-vinyl oximes, key intermediates of new pyrrole synthesis, as well as for the functionalized compounds of the pyrrole series obtained in the course of pyrrole chanistry development. The tables provide references to original works, thns providing the reader a guide to a variety of the reactions and synthesized compounds discussed. 

As discussed in Chapter 6, nitro compounds are converted into amines, oximes, or carbonyl compounds. They serve as usefid starting materials for the preparation of various heterocyclic compounds. Especially, five-membered nitrogen heterocycles, such as pyrroles, indoles, ind pyrrolidines, are frequently prepared from nitro compounds. Syntheses of heterocyclic compounds using nitro compounds are described partially in Chapters 4, 6 and 9. This chapter focuses on synthesis of hetero-aromadcs fmainly pyrroles ind indolesi ind saturated nitrogen heterocycles such as pyrrolidines ind their derivadves. 

Experiments on the synthesis of 4,5,6,7-tetrahydroindole and 1 -vinyl-4, 5,6,7-tetrahydroindole from cyclohexanone oxime and acetylene on bench reactors of 5 and 25 L performed under a 1.5 atm pressure give positive answers to these questions. Thus, at 100°C and KOH concentration of 0.4 mol/L, the output of 1 L of catalyst solution can amount to 50-100 g of pyrroles per hour. This means that in a small 1 m3 reactor, it is possible to produce up to 400 tons of 4,5,6,7-tetrahydroindoles (1 and/or 2) per year, which is quite acceptable to meet an initial demand for these products. It can initiate, for instance, a cheap indole manufacture by catalytic dehydrogenation of tetrahydroindoles 1 and 2. 

When the reaction is carried out under pressure, the yields of pyrroles 1 and 2 are 74-81 and 93%, respectively (Table XIX). Under atmospheric or slightly excess pressure (1.2-1.5 atm), they are 50 and 90%, respectively (78MIP1, 79KGS197). The synthesis of 4,5,6,7-tetrahydroindole (1) from cyclohexanone oxime and acetylene at atmospheric pressure (the yield is 45% when based on the initial oxime and 56% on the oxime reacted) has already been included in the manual (88MI1). Principle features and experimental details of this synthesis have been discussed (79KGS197). 

Pyrroles 36 with n = 4, 8 have been isolated and characterized (Table XIX). These include4,5,6,7,8,9-hexahydro-l//-cycloocta >]pyrrole (yield 60%, optimal synthesis time about 3 hr), which shows a reduced stability as compared with other pyrroles of this series (n = 2,3,8). Nevertheless, the reason for the unsuccessful attempt to synthesize this compound from cyclooctanone oxime and acetylene [87JCS(P 1)2829] is not very clear. 

A synthesis of a set of 2-pyridylpyrroles has been described, involving annulation of 1,3-dicarbonyl compounds with 2-(aminomethyl)pyridine under acidic conditions, as illustrated by the construction of compound 437 (Equation 121) <20020L435>. Likewise, pyrroles have also been obtained from reactions between 1,3-diaryl-l,3-dicarbonyl compounds and imines or oximes promoted by the TiCU/Zn-system <2004SL2239>. Yet another approach involves rhodium-catalyzed reactions of isonitriles with 1,3-dicarbonyl synthons, which enables for instance preparation of fluorinated pyrroles <20010L421>. 

The synthesis of pyrroles 13 and 14 from tropinone oxime in 49% and 41% yields, respectively, was performed (Equation (3)) (99CHE613). 

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