Tetrahydroindoles

Donor substituents on the vinyl group further enhance reactivity towards electrophilic dienophiles. Equations 8.6 and 8.7 illustrate the use of such functionalized vinylpyrroles in indole synthesis[2,3]. In both of these examples, the use of acetyleneic dienophiles leads to fully aromatic products. Evidently this must occur as the result of oxidation by atmospheric oxygen. With vinylpyrrole 8.6A, adducts were also isolated from dienophiles such as methyl acrylate, dimethyl maleate, dimethyl fumarate, acrolein, acrylonitrile, maleic anhydride, W-methylmaleimide and naphthoquinone. These tetrahydroindole adducts could be aromatized with DDQ, although the overall yields were modest[3]. 

Heterocyclic enamines often undergo two-step 1,3 cycloaddition with methyl vinyl ketone. This involves electrophilic attacks by an olefinic carbon and by a carbonyl carbon (24,25). For example, 1,2-dimethyl-Zl -pyrroline (14), when treated with methyl vinyl ketone, produces 1,6-dimethyl-2,3,4,5-tetrahydroindole (15) (24). The requirement which must be met so that this type of cyclization reaction can take place is that the a position of the heterocyclic enamine be carbon substituted. This provides... 

Reacdoti of cyclohexanone imines v/ith nitroalkenes provides a new synthedc method of tetrahydroindole derivadves fEq. 10.9. ... 

The intramolecular cycloaddition of munchnone intermediates (derived from the cyclodehydration of A-acyl amino acids) with 1,3-dipolarophiles was employed to construct the mitomycin skeleton. Thus, heating alkynyl acids 23 with acetic anhydride forms the intermediates 24 which undergo cyclization with loss of carbon dioxide to afford the 4-oxo-tetrahydroindoles 25 <96TL2887>... 

Reaction of cyclohexanone imines with nitroalkenes provides a new synthetic method of tetrahydroindole derivatives (Eq. 10.9).11... 

Intramolecular nucleophilic additions by nitrogen functional groups onto pendant alkynes and allenes represent an important class of type la approaches to functionalized pyrroles. A platinum-catalyzed (PtCl4) cyclization of homopropargyl azides provided an entry to 2,5-disubstituted pyrroles and 4,5,6,7-tetrahydroindoles (fused pyrroles) <06OL5349>. 

N-Alkyl carprofen analogs (e.g. 60, A[542 IC50 = 2.9gM) were found to be nearly devoid of COX-1 and COX-2 activity [133,134], Multiple patent applications have disclosed a variety of alkanoic acids that are based on tetrahydroindole (61) [135], piperidine (62) [136], and indole (63) [137] scaffolds, which selectively lower A (542. 

Pyrrole rings frequently serve as precursors to indole rings [37] and PdCl2 induces the oxidative cyclization of pyrrole 37 to a mixture of 38 and 39 [38]. Since the oxidation of tetrahydroindoles to indoles, such as 38 to 39, is usually straightforward, this transformation can be viewed as a novel and efficient indole ring synthesis. 

The Larock synthesis was used by Chen and co-workers to synthesize the 5-(triazolylmethyl)tryptamine MK-0462, a potent 5-HTid receptor agonist, as well as a metabolite [391, 392]. Larock employed his methodology to prepare tetrahydroindoles [393],... 

The reported reaction times of 20 h could be excessive and good yields could probably be obtained after ca, 5 h. 4,5,6,7-tetrahydroindole. 

Molindone Molindone, 3-ethyl-6,7-dihydro-2-methyl-5-(morpholinomethyl)indol-4(5F0-one (6.4.3), is synthesized by the nitrozation of diethylketone using nitric acid or methyl-nitrite into nitrozodiethylketone (6.4.1). Reduction of this product with zinc in acetic acid into 2-aminodiethylketone in the presence of cyclohexandion-1,3 gives 3-ethyl-2-methyl-4,5,6,7-tetrahydroindol-4-one (6.4.2). Aminomethylation of this product using morpholine and formaldehyde gives molindone (6.4.3) [51-52]. 

Reaction of cyclohexanone oxime (59) with phenylacetylene in the presence of KOH/ DMSO afforded Z-[l-(2-phenylvinyl)]-3-phenyl-4,5,6,7-tetrahydroindole (60) (equation 25) °. Transformation of 0-vinylacetophenone oxime (61) in the system f-BuOK/THF has been studied. The reaction at 60-65 °C afforded 2,4-diphenylpyrrole (62) and oligomeric products instead of the desired 2-phenylpyrrole (equation 26) . ... 

Pinho e Melo et al. (89) employed an intramolecular miinchnone cycloaddition to constmct several l/7-pyrrolo[l,2-c]thiazole derivatives from N-acylthiazolidines and acetic anhydride. Martinelli and co-workers (90,91) employed an intramolecular miinchnone cycloaddition to craft a series of 4-keto, 5,6,7-tetrahydroindoles (168-171) in two steps. The requisite acetylenic precursors were prepared from glutaric anhydride (or 3-methylglutaric anhydride). The overall sequence is illustrated for the synthesis of 168. An electrophilic acetylenic unit appears to be necessary for successful intramolecular 1,3-dipolar cycloaddition. 

The natural product, anhydrolycorinone was prepared in the palladium mediated intramolecular Heck reaction of a tetrahydroindole derivative. The coupling, which is run in air and requires the use of a stoichiometric amount of palladium, is accompanied by the dehydrogenation of the cyclohexadiene moiety and the oxidation at the benzylic position to a lactam (4.11.).12... 

Michael addition reaction at the 5-position <8lUP30500). The dihydroindoles are readily dehydrogenated with DDQ to give the indoles, but the 4,5,6,7-tetrahydroindoles have resisted all attempts to convert them into the fully aromatic systems (81JOC4515, cf. 81ACS(B)77>. 

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). 

Dependence of the Yield of 4,5,6,7-Tetrahydroindole 1 and Its N-Vinyl Derivative (2) on the Composition of DMSO/Dioxane Mixture"... 

It can be seen that the reaction takes place when DMSO is added to the dioxane solution in as small amounts as 5-10%. Varying the DMSO concentration makes it possible to carry out the reaction selectively, which means that either 4,5,6,7-tetrahydroindole (1) (with a small DMSO content) or l-vinyl-4,5,6,7-tetrahydroindole (2) (in pure DMSO) can be obtained. 

Effect of Alkali Metal Hydroxide (MOH) Cation on Yield of Tetrahydroindole (1) and (2)"... 

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). 

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). 

Dependence of Tetrahydroindoles Yield (1,2) from Cyclohexanone Oxime and Acetylene on KOH Concentration0... 

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. 

Operation of the plant on a large scale has shown that when the reaction is carried out in DMSO using KOH in an amount of 1 mol per 1 mol of cyclohexanone oxime, it is possible to obtain l-vinyl-4,5,6,7-tetrahydroindole in a yield higher than 80% and purity of up to 99% under an acetylene pressure from 0.3 to 1.5 atm without heat supply, at the expense of the exothermic character of the process. 

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). 

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