Acetylene, reaction with oximes

Many such activated acyl derivatives have been developed, and the field has been reviewed [7-9]. The most commonly used irreversible acyl donors are various types of vinyl esters. During the acylation of the enzyme, vinyl alcohols are liberated, which rapidly tautomerize to non-nucleophilic carbonyl compounds (Scheme 4.5). The acyl-enzyme then reacts with the racemic nucleophile (e.g., an alcohol or amine). Many vinyl esters and isopropenyl acetate are commercially available, and others can be made from vinyl and isopropenyl acetate by Lewis acid- or palladium-catalyzed reactions with acids [10-12] or from transition metal-catalyzed additions to acetylenes [13-15]. If ethoxyacetylene is used in such reactions, R1 in the resulting acyl donor will be OEt (Scheme 4.5), and hence the end product from the acyl donor leaving group will be the innocuous ethyl acetate [16]. Other frequently used acylation agents that act as more or less irreversible acyl donors are the easily prepared 2,2,2-trifluoro- and 2,2,2-trichloro-ethyl esters [17-23]. Less frequently used are oxime esters and cyanomethyl ester [7]. S-ethyl thioesters such as the thiooctanoate has also been used, and here the ethanethiol formed is allowed to evaporate to displace the equilibrium [24, 25]. Some anhydrides can also serve as irreversible acyl donors. 

A much more efficient means of promoting the reaction is variation of the KOH content of the reaction mixture. This was convincingly shown for the conversion of cyclohexanone oxime to 4,5,6,7-tetrahydroindole (1) and its N-vinyl derivative in the reaction with acetylene in KOH/DMSO (Scheme 1) (81ZOR 1977). At a moderate temperature (100°C), an increase in the KOH content (up to an equimolar ratio to the oxime) enhances the yield of l-vinyl-4,5,6,7-tetrahydroindole (Table VI). Under more severe conditions (120°C) the alkali starts to accelerate side processes as a consequence of which an inverse dependence of the yield of l-vinyl-4,5,6,7-tetrahydroindole upon the content of base is observed (cf. Table VI). 

Oximes of alkyl phenyl ketones were successfully involved in the reaction with acetylene (Scheme 5). In this way, previously unavailable 3-alkyl(phenyl)-2-phenylpyrroles (5) and previously unknown 3-alkyl-(phenyl)-2-phenyl-l-vinylpyrroles (6) (Table XIII) were prepared (78ZOR-2182). 

Fig. 6. Typical kinetics of the reaction of cyclohexanone oxime with acetylene I. cyclohexanone oxime 2, 4,5,6.7-tetrahydroindole 3, l-vinyl-4,5,6,7-tetrahydroindolc 4. an intermediate. Reaction conditions DMSO, 86°C, PC2h2 720 mm Hg, concentration of KOH and cyclohexanone oxime 0.47 mol/L C = C,/C0. where C0and C,are the initial and present concentration of components, respectively.

Some features of the behavior of 2,2,6,6-tetramethyl-4-piperidone oxime (39) (X = H) and its oxidized derivatives (X = OH, X = 6) in the reaction with acetylene in KOH/DMSO (Scheme 22) are discussed (88KGS3S0) along with experimental details dealing with the synthesis of new pyrrolo[3,2-c]piperidines (40), previously reported either briefly (84MI2) or in general (86ZC41). 

The oxime 39 bearing a nitroxyl group (X = O) can be converted to the corresponding azaindole 40 without affecting the free-radical center (yield 6S%, nonoptimized conditions). It follows that (i) the presence of the nitroxyl function in ketoximes does not impede their pyrrolization by the reaction with acetylene in a superbase medium, and (ii) the acetylene-involved pyrrolization of ketoximes in the presence of superbase does not show any clearly defined radical stage, otherwise the nitroxyl center would have acted as a spin trap, thus inhibiting the reaction. 

With 1,2-dibromoethane (run 4) under comparable conditions (run 2), somewhat poorer results are achieved with the same total yield (about 30%), the crude product contains nearly 40% of the starting oxime. As in the reaction with free acetylene (see Section II.C.l), the substitution of KOH by NaOH and LiOH (run 5,6) makes the process completely selective, but leads to a sharp drop in the yield of products and in the oxime conversion. 

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). 

Recently, it was reported (09TL97) that N-vinylpyTrole-2-carbonitriles 163 were synthesized from N-vinylpyrrole-2-carbaldehyde oximes 161 by two methods using the above reaction with acetylene (KOH-DMSO, 70 °C, 10 min, yields 58-67%) (Scheme 11) and with acetic anhydride (90-100 °C, 5h, yields 83-93%) (Scheme 12). 

Balasubramanian, K. K. and Selvaraj, S., Studies in phenolic Mannich bases. Reaction with acetylenes. Tetrahedron Lett., 851, 1980. Von Straitdtmann, M., C ohen, M. P., and Shavcl. J., Reaction of phenolic Mannich bases with imines and oximes. Synthesis of fased ring systems containing 1,3-oxa7ine.s, J. Heterocyd. Chem.. 6, 429, 1969. 

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

A version of the pyrrole synthesis involving one-pot transformation of ketones into NH- and N-vinylpyrroles has been worked out. Preliminary isolation of oximes is always associated with consumption of reactants, solvents, and time. In some cases (e.g., for ketoximes having high solubility in water), this procedure presents certain preparative difficulties. To exclude the stage of ketoximes isolation, a possibility of ketone oximation in situ in DMSO and the subsequent application of the oxime solutions in the reaction with acetylene has been studied [181]. 

Among the advantages of this version of the reaction are its simplicity, feasibility (atmospheric pressure of acetylene), and possibility of application of more accessible (in comparison with oximes) ketones. The elimination of the oximation stage and the corresponding consumption of reactants, inevitable losses during oximes isolation lowering the total yields of the target pyrroles, increase the synthetic value of this method. 

Under harsher conditions, oxime of 1-acetyladamantane reacts with acetylene giving rise to 2-(l-adamantyl)-N-vinylpyrrole in a yield of 48% (Scheme 1.25), the minor product being 1-acetyladamantane (24%), which, if necessary, can be re-oximized and involved in the reaction with acetylene. 

SCHEME 1.40 Reaction of oxime of A -pregnen-3p-ol-20-one with 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]. 

The analysis of the reasons of lower reactivity of acetylpyridine oximes has shown that, according to the IR and NMR data, the starting oximes are pure -isomers [252], while ketoximes of Z-conflguration are the most reactive in the studied reaction [7]. Since acetylpyridine oximes exist at room temperature as -isomers exclusively, their decreased proneness to formation of pyrroles in the reactions with acetylene becomes apprehensible. With the temperature increase and under the effect of the... 

The simplest representative of a series of studied ketoximes, l-hydroxy-2-propanoe oxime, is unstable and completely resinifles under usual conditions of the reaction with acetylene. 

SCHEME 1.108 Low reactivity of i -isomer of l-methyl-2-acetylbenziinidazole oxime in the reaction with and acetylene. 

The synthesis of 4,5,6,7-tetrahydroindoles from cyclohexanone oxime and 1,2-dihaloethanes has been disclosed [303], The best overall yields (52%-61%) of NH- and N-vinyl-4,5,6,7-tetrahydroindoles are reached when molar ratio of cyclohexanone oxime-dichloroethane-KOH-DMSO is 1 1-2 7 10. For the successful synthesis of 4,5,6,7-tetrahydroindoles, it is important to add the alkali and dihaloethane to the solution of the ketoxime in DMSO in portions. Otherwise, the reaction of diether formation becomes appreciable. At the sacrifice of decreasing the yield to -30%, one can attain 94%-95% selectivity relative to the major product, 4,5,6,7-tetrahydro-indole. Like in the reaction with free acetylene, this is achieved mainly due to the addition of small amounts of water (10%-20%) to the reaction mixture. In this case, the water can be conveniently fed into the mixture by dissolving alkali in it, which simultaneously also facilitates the dispensing of both components. Somewhat poorer results are obtained with 1,2-dibromoethane under comparable conditions [303]. 

The reaction of oximes and acetylene [248,351] in the system KOH/DMSO or potassium oximate/DMSO affords the target pyrroles and N-vinylpyrroles together with l-Z-[(2-methylthio)vinyl]pyrroles in trace amounts (0.05%-1.0%) (Scheme 1.169). 

Oximes as Nucleophiles in the Reaction with Acetylenes Literature Analysis... 

N-Vinylpyrrole-2-carbonitriles are synthesized from N-vinylpyrrole-2-carbaldehyde oximes by two methods (1) reaction with acetylene (KOH/DMSO, 67% yield. Scheme 2.161) [388] and (2) reaction with acetic anhydride (90°C-100°C, up to 93% yields, Scheme 2.162, Table 2.15) [89]. 

Trofimov, B.A., A.I. Mikhaleva, A.N. Vasiliev et al. 1981. Stereospecific participation of Z-isomer of l-methyl-2-acetylbenzimidazole oxime in the synthesis of l-methyl-2-(2-pyrrolyl)benzimidazole by the reaction with acetylene. Khim Geterocicl 10 1422. 

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. 

Tigchelaar-Lutjeboer, H.D., H. Bootsma, and J.F. Arens. 1960. Chemistry of acetylenic ethers. XLIII. Reactions of oximes with ethoxyethylene. Rec Trav Chem 79 888-894. 

The authors analyze conditions of typical syntheses, limitations of their applicability, and possibility of vinyl chloride or dichloroethane application instead of acetylene. They examine chemical engineering aspects of the first synthesis of tetrahydroindole and indole from commercially available oxime of cyclohexanone and acetylene. In addition, the book discusses new facets of pyrroles and N-vinyl pyrroles reactivity in the reactions with the participation of both the pyrrole ring and N-vinyl groups. 

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