N-Vinyl-4,5,6,7-tetrahydroindoles

Noteworthy, N-vinyl-4,5,6,7-tetrahydroindole 3 also entered readily into the cross-coupling with acetylene 146 to give selectively propynoate 147 (R = Vinyl) in 71% yield (Equation (41)). 

The radical copolymeiization of N-vinyl-4,5,6,7-tetrahydroindole with vinyl chloride was accompanied by dehydrochlorination of polyvinyl chloride blocks (Equation (56)) (08MI315). 

An important advantage of the Trofimov pyrrole synthesis is its technological feasibility, that is, the opportunity of applying it for the commercial production of difficultly accessible, though pharmaceutically and technically useful pyrroles. This was convincingly demonstrated and proved by N-vinyl-4,5,6,7-tetrahydroindole piloting (84M17). 

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). 

A much more efficient and facile tool influencing the process is the change of KOH concentration in the reaction medium. It is especially clearly shown on the example of cyclohexanone oxime transformation to 4,5,6,7-tetrahydroindole and N-vinyl-4,5,6,7-tetrahydroindole via the interaction with acetylene in the system KOH/DMSO [159]. Under quite mild conditions (100°C), the increase of KOH concentration (up to equimolar ratio with the starting oxime) leads to augmentation of N-vinyl-4,5,6,7-tetrahydroindole yield. In harsher conditions (120°C), alkali starts to accelerate the side processes. As a consequence, a reverse dependency of N-vinyl-4,5,6,7-tetrahydroindole yield upon base concentration is also possible [159]. 

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]. 

N-vinyl-4,5,6,7-tetrahydroindole appears to be the first representative of N-vinylpyrroles synthesized from ketoximes and acetylene (Scheme 1.26) [190-195], Later on, the conditions allowing to stop the reaction and the stages of... 

The fundamental peculiarities and experimental details of this synthesis are discussed in the work [161]. The formation of N-vinyl-4,5,6,7-tetrahydroindole from... 

The synthesis of NH- and N-vinyl-4,5,6,7-tetrahydroindoles is implanented successfully at cyclohexanone oxime-acetylene molar ratio of l (2-5) at 90 C-140 C. At temperature below 90°C, the reaction proceeds slowly, and the rate of side processes increases above 140°C. The bases (alkali metal hydroxides and alcoholates) taken in 10%-50% amounts relative to cyclohexanone oxime serve as the reaction catalysts. The reaction is efficiently catalyzed by potassium, rubidium, and tetrabutylammonium hydroxides. It should be noted that the last two bases have a selective effect on the construction of the tetrahydroindole ring (synthesis of... 

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]. 

Tetrahydroindole and N-vinyl-4,5,6,7-tetrahydroindole, which are now readily prepared from cyclohexanone oxime and acetylene, may become a source of difficult-to-obtain octahydroindole and N-ethyloctahydroindole. 

The catalytic hydrogenation of N-vinyl-4,5,6,7-tetrahydroindole over Raney Ni (ethanol, SO C -W C, hydrogen pressure 40-60 atm) proceeds selectively to deliver N-ethyl-4,5,6,7-tetrahydroindole in 90% yield (Scheme 2.17) [432]. When the reaction temperature increases up to MO C, only N-ethyloctahydroindole is formed (96% yield) [433],... 

The discovery of highly reactive superbase catalytic system KOH/DMSO has provided new wide and fundamental opportunities for direct vinylation of NH heterocycles with acetylene. Using this method, large pilot batches of N-vinyl-4,5,6,7-tetrahydroindole have been produced in Angarsk plant of chemicals [179,490]. Direct vinylation of carbazole with acetylene under atmospheric pressure (100°C, 5-7 h) in the system KOH/DMSO furnishes especially pure N-vinylcarbazole in a high yield [491-493]. Its structural isomer, N-vinylbenz[g]indole, is synthesized in 78% yield by vinylation of benz[g]indole (85% conversion) under atmospheric pressure in the same system (Scheme 2.38, Table 2.3) [442]. 

N-Vinyl-4,5,6,7-tetrahydroindole reacts with both ethyl bromopropynoate and ethyl iodopropynoate to furnish a cross-coupling product, ethyl 3-(l-vinyl-4,5,6,7-tetrahydroindol-2-yl)-2-propynoate (R=CH=CH2, up to 71% yield. Table 2.6) [38,517],... 

Formylation of N-vinylpyrroles proceeds under conditions of the Vilsmeier-Haack classical reaction (dimethylformamide (DMF)/POCl3, 1,2-dichloroethane, reflux) to afford mixtures of N-vinyl- and NH-pyrrole-2-carbaldehydes in low yields. For example, from N-vinyl-4,5,6,7-tetrahydroindole, a mixture of the expected N-vinyl-4,5,6,7-tetrahydroindole-2-carbaldehyde and 4,5,6,7-tetrahydroindole-2-carbalde-hyde is formed ( 1 1) (Scheme 2.131) [87]. 

SCHEME 2.131 Reaction of N-vinyl-4,5,6,7-tetrahydroindole with DMF/POCI3 complex. 

Phenylazo-N-vinyl-4,5,6,7-tetrahydroindole under similar conditions is oxidized at position 7 of the cyclohexanone ring to deliver 7-hydroxy-2-phenylazo-N-vinyl-4,5,6,7-tetrahydroindole (58% yield. Scheme 2.176, Table 2.17) [635]. 

As one should expect, N-vinylpyrroles with alkyl substituents in the ring are the least resistant to acidic hydrolysis [648]. They are readily hydrolyzed by dilute acids at room temperature. For example, N-vinyl-4,5,6,7-tetrahydroindole is hydrolyzed by 35% in dilute aqueous solution of HCl (0.6%-l%) at room temperature after 1 h. At 65°C, the same pyrrole is converted completely into an orange-red substance for 2.5 h, whereas at 90°C-96 C, this is achieved for 1.5 h. 

Some regularities of electrophilic addition of alcohols to N-vinylpyrroles have been elucidated on the example of the reaction between 2-phenyl-N-vinylpyrrole and N-vinyl-4,5,6,7-tetrahydroindole resulting in earlier unknown N-(a-alkoxyethyl)pyr-roles (Scheme 2.194, Table 2.19) [657],... 

Noncatalytic addition of phenols to N-vinyl-4,5,6,7-tetrahydroindole affords N-(l-aroxyethyl)-4,5,6,7-tetrahydroindoles (Scheme 2.196, Table 2.19) [659]. The yields of adducts decrease as a result of N-vinyl-4,5,6,7-tetrahydroindole oligomerization, with an increase in the acidity of phenol and in the presence of CF3COOH. 

SCHEME 2.196 Noncatalytic electrophilic addition of phenols to N-vinyl-4,5,6, 7-tetrahydroindole. 

N-Vinylpyrroles selectively add thiophenols under the conditions of free radical initiation to form p-adducts, N-(2-arylthioethyl)pyrroles (Scheme 2.200, Table 2.19) [668]. In analogous conditions, the reaction without an initiator leads to a mixture of p- (20%) and a-adduct (80%). Thiylation of a mixture of N-vinyl-4,5,6,7-tetrahydroindole (28.5%), 4,5,6,7-tetrahydroindole (61%), and cyclohexanone oxime both with and without the initiator selectively affords the a-adducts only. Probably, 4,5,6,7-tetrahydroindole and cyclohexanone oxime inhibit the radical addition thus hindering the p-adducts formation. Hence, owing to their increased acidity, thiophenols show a marked tendency to electrophilic addition to produce a-adducts [668]. 

Methyl-2-trifluoroacetyl-N-vinyl-pyrroles and 2-trifluoroacetyl-N-vinyl-4,5,6,7-tetrahydroindole are phosphorylated with phosphorus pentachloride selectively at the vinyl group to furnish hexachlorophosphates 54 in high yields, which are further converted under the action of SO2 into phosphonic acid dichloroanhydrides 55 (Scheme 2,217, Table 2.19) [681]. 

The efficacy of the process depends on the structure of the initial N-vinylpyrrole. For example, only traces of the corresponding NH derivative are obtained from N-vinyl-4,5,6,7-tetrahydroindole CH NMR data), though the substrate is consumed completely. Obviously, in this case, successful devinylation requires even milder conditions (lower temperature, shorter time, and smaller oxidant concentration). 

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