Heterocyclization of Ketoximes with Acetylene

The reaction of ketoximes with acetylene proceeds smoothly at 70°C-140°C, usually at 80°C-100°C. Sometimes, heating of the reactants up to this temperature would suffice to initiate a mild exothermic process, which can be regulated by the addition of acetylene. 

The synthesis is extremely feasible acetylene under atmospheric pressure is passed through the heated stirring solution of the reactants and a catalyst in DMSO. The process takes 3-5 h to complete. Also, the reaction can be carried out in autoclave where the reaction time is reduced under pressure. 

R2 = alkyl, alkenyl,aryl, hetaryl M = alkali metal SCHEME 1.1 Synthesis of pyrroles and N-vinylpyrroles from ketoximes and acetylene. 1.1.1 Superbase System Alkali Metal Hydroxide-Dimethyl 

The reaction is catalyzed by a superbase pair alkali metal hydroxide/DMSO [6,10,22,32,34,105,106], although specially prepared alkali metal oximates are also active in the process. 

Superbase systems are known to contain a strong base and a solvent or reactant capable of specifically binding the cation baring the conjugated anion [138]. Such systems can be prepared on the basis of linear or cyclic glycol ethers, microcyclic polyethers (crown ethers), highly polar non hydroxylic solvents (sulfoxides, e.g., DMSO), sulfones (sulfolane), amides (N-methylpyrrolidone, dimethylformamide, hexametapol), and phosphine oxides as well as from liquid anunonia, amines, etc. For example, basicity of sodium methylate in 95% DMSO is by seven orders higher than in pure methanol [139]. 

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The catalytic function of the KOH/DMSO system in heterocyclization of ketoximes with acetylene is manifested when mixed DMSO/dioxane solvent is used. The results obtained for the reaction of cyclohexanone... 

The tridentate nature of the oximate-anion, i.e., its ability to act as O-, N-, and C-nucleophile, complicates analysis of the mechanism of the superbase-catalyzed heterocyclization of ketoximes with acetylene. 

Catalytic function of the KOH/DMSO system in heterocyclization of ketoximes with acetylene is clearly demonstrated in the example of application of mixed solvent DMSO-dioxane. The interaction of cyclohexanone oxime with acetylene [159] occurs when DMSO is added to dioxane solution already in the amount of 5%-10%. Varying DMSO concentration, one can accomplish the process selectively, that is, to obtain either 4,5,6,7-tetrahydroindole (at small concentration of DMSO) or N-vinyl-4,5,6,7-tetrahydroindole (in pure DMSO, Scheme 1.8). 

In autoclave, heterocyclization of ketoximes with acetylene into pyrroles and N-vinylpyrroles is usually performed under pressure (initial pressure at room temperature is 8-16 atm, predominantly 10-12 atm). The maximum pressure of acetylene in the reaction can reach 20-25 atm. 

The heterocyclization of ketoximes with acetylene leading to NH- and N-vinylpyrroles is viable for all ketoximes having at least one methylene or methyl group in a-position to the oxime moiety and containing no substituents sensitive to the action of bases [4,5,7]. 

Systematic investigations into heterocyclization of ketoximes with acetylene to pyrroles and N-vinylpyrroles have shown that in certain conditions, O-vinyl oximes, 47f-2-hydroxy-2,3-dihydropyrroles, 3//-pyrroles, a-acetylenic alcohols, pyridines, and some other minor products are formed. 

Currently, the most intensively developed method for the synthesis of NH- and N-vinylpyrroles is based on heterocyclization of ketones (in the form of ketoximes) with acetylene in the superbase system alkali metal hydroxide-dimethyl sulfoxide (DMSO) (Scheme 1.1). This reaction was discovered about 30 years ago. 

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). 

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. 

Enehydroxylamines (102) are invoked as intermediates in the rearrangement of O-vinyl, acyl or aryl oximes (101) (equation 31). Varlamov and coworkers demonstrated that the heterocyclization of ketoximes (103) with acetylene in snper basic medium and in the presence of metal hydroxides proceeds by a [3,3]-sigmatropic rearrangement of the enehydroxylamine 105 of the corresponding oxime vinyl ethers 104 (equation 32). The unreactivity of 3-methyl-2-azabicyclo[3.3.1]nonan-9-one oxime (106) in the same reaction conditions was explained by its inability to isomerize to the corresponding enehydroxylamine. 

Under standard conditions (90°C-95°C, 3 h, initial acetylene pressure 10-12 atm), the pyrrolization of terpenoid ketoximes proceeds with the participation of a-methylene group of the ketoxime alkenyl radicals (Scheme 1.37). 2-(3-Alkenyl)pyrroles, which could be formed due to involvement of the methyl moiety into heterocyclization, are not detected in the reaction mixtures. This fact correlates well with the findings [7,16,18] that upon condensation of alkyl methyl ketoximes with acetylene, the methyl group participates in the pyrrole ring assembly only at above 120°C. Prototropic isomerization of the alkenyl radical also does not occur. 

In more recent work (85ZOR406), important experimental details concerning heterocyclization of other ketoximes of the thiophene series with acetylene in the MOH/DMSO (M = Li, K) system have been reported (Scheme 14). 

Preparation of Af-Vinylpyrroles. The reaction of ketoximes having at least one a-CHa group with acetylene in DMSO/KOH at 80-120 °C under atmospheric pressure gave (V-vinylpyrroles in average yields of 70-80% via an intermediate pyrrole (eq 6). The conditions are also suitable for AAvinylation of pyrroles and other NH heterocycles in good yields. ... 

Unsymmetrical dialkyl ketoximes in heterocyclization reaction with acetylene can give two isomeric pyrroles or N-vinylpyrroles in the case of acetylene excess (Scheme 1.102). 

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