Tetrahydroindole, synthesis from oximes

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). 

SCHEME 1.29 Synthesis of 4,4,6,6-tetramethyl-4,5,6,7-tetrahydroindole from oxime of 3,3,5,5 tetramethylcyclohexanone and acetylene. 

Although true for many oximes of aliphatic and alicyclic ketones, the previous sequence is not absolute and can change depending on the reaction conditions and ketoxime type. Tetrabutylammonium hydroxide, for instance, which catalyzes fairly actively in the synthesis of 4,5,6,7-tetrahydroindole from cyclohexanon oxime and acetylene (79KGS197), turned out to be nearly inert with alkyl aryl ketoximes (78ZOR1733). 

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. 

SCHEME 1.8 Synthesis of 4,5,6,7-tetrahydroindole and its N-vinyl derivative from cyclohexanone oxime and acetylene in the KOH/DMSO system. 

The experiments related to the synthesis of 4,5,6,7-tetrahydroindole and N-vinyl-4,5,6,7-tetrahydroindole from cyclohexanone oxime and acetylene, performed in 5 and 25 L reactors under pressure 1.5 atm, give positive answer to the latter question. For instance, at 110°C and 0.4 mol/L KOH concentration, the productivity of 1 L of catalytic solution is 50-100 g of N-4,5,6,7-vinyltetrahydroindole per hour. It means that it is possible to produce up to 400 tons of N-4,5,6,7-vinyltetrahydroindole per year using small semi-industrial reactor of 1 m volume that is quite acceptable for modem technology [179]. 

SCHEME 1.115 Synthesis of Z-[N-( 3-phenylvinyl)]-3-phenyl-4,5,6,7-tetrahydroindole from cyclohexanone oxime and phenylacetylene. 

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 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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