Tetrahydroindoles, formation

Early qualitative observations (see Section 1.1.2) that pyrrolization rate considerably increases on going from LiOH to NaOH and further to the KOH and the LiOH/CsF systems are confirmed. In the presence of LiOH and NaOH/CsF systems, the vinylation is suppressed and selectivity of 4,5,6,7-tetrahydroindole formation rises. 

The formation of the 3H-3-morpholinopyrrole 82 from the cyanoazabu-tadiene 81 also involves a Thorpe-Ziegler type cyclization (Scheme 21) (for a further example in the tetrahydroindole series and the mechanism see Scheme 26) (87HCA187). 

Heating either the dimedonylmethane 377 or 9-aroyl-octahydro-xanthene 58 with ammonia at 130-150 °C led to the formation of pyrrolo-acridine 378. But, at lower temperature, 90-120 °C, the tetrahydroindoles 379 were initially formed which can be converted to 378 (88CHE417) (Scheme 77). 

Reaction of tetrahydroindoles 57 (R1 = dimedone-2-yl, R2 = Ar), obtained from 58 upon reaction with primary amines, with hydrazine at 80-130 °C in autoclave led to the formation of l-aryl-4,4,9,9-tetramethyl-2,3,4,5,8,9,10,ll-octahydro-7H-benzo[/J[l,2Jdiazepino[5,4,3-c,dJ-indol-ll-one (587) (97HC073) (Scheme 124). 

Another pioneer in the Diels-Alder reactions of vinylpyrroles was Noland, who also developed the reactions of vinylindoles to yield carbazoles. Some examples of the former are shown in Scheme 2 (equations 1 and 2) [4-7], Jones and his colleagues were equally active in this cycloaddition chemistry of vinylpyrroles (equations 3 and 4) [8-12], These workers measured the rates of the reaction between 1-methyl-2-vinylpyrrole and seven dienophiles, with maleic anhydride being 4800 to 50,000 times more reactive than the other dienophiles (DMAD, maleonitrile, fumaronitrile, dimethyl maleate, methyl acrylate, and acrylonitrile) [8], In a clever tactic to thwart the formation of dihydroindoles, Jones used an excess of methyl propio-late to convert the initial adduct to a second Diels-Alder cycloadduct that subsequently loses ethene by a retro-Diels-Alder reaction to afford the dimethyl 1-methyl (phenyl)-4,7-dicarboxylates (equation 4). The reactions are concerted and were consistent with FMO calculations (HOMO[vinylpyrrole]-LUMO[alkene]). The yields are 54% to 81%, but attempts to dehydrogenate the tetrahydroindole products to indoles were unsuccessful. 2-Vinylpyrrole itself undergoes Michael additions and polymerization with these dienophiles. Domingo, Jones, and coworkers subsequently... 

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 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]. 

SCHEME 2.39 Formation of 4,5,6,7-tetrahydroindolyl radical in the vinylation of 4,5,6,7-tetrahydroindole with acetylenes. 

The reaction of 4,5,6,7-tetrahydroindole with alkylthiochloroacetylenes stops at the stage of acetylene formation (41%-42% yield. Table 2.5). It proceeds with much more difficulties than the reaction with unsubstituted pyrrole in 5 h, the conversion of 4,5,6,7-tetrahydroindole is 56%-58%. Such distinction in behavior of these pyrroles is probably due to the steric factors. 2-Phenylpyrrole interacts with l-propylthio-2-chloroacetylene (1 1 ratio, the same conditions) forming a mixture of... 

SCHEME 2.64 Tentative mechanism of the pyrrole-dihydrofuranone formation from DDQ-ethyl 3-(4,5,6,7-tetrahydroindol-2-yl)propynoate adduct with under the action of alcohol. 

The formation of 4,5,6,7-tetrahydroindole in -5% yield from its vinyl derivative is observed [648] only when hydrolysis is accomplished in the excess additied NH2OH HCI. A special experiment has confirmed that 4,5,6,7-tetrahydroindole is unstable under conditions of acid-catalyzed hydrolysis at 65°C (1% aqueous HCl solution, 2.5 h), it undergoes 66% conversion to a brown-red resin. In the presence of acetaldehyde under the same conditions, the degree of conversion of 4,5,6,7-tetrahydroindole to a polymer is 90%. 

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]. 

The reaction of equimolar amounts of N-vinyl-4,5,6,7-tetrahydroindole with PCI3 can be stopped at the stage of the formation of phosphine 43. The latter undergoes... 

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