4.5.6.7- Tetrahydroindole, synthesis

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]. 

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],... 

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. 

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. 

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). 

For a preparative synthesis of 4,5,6,7-tetrahydroindole (1), the following conditions have been recommended (86ZOR489) 110°C, 3 hr, the oxime 116/KOH/vinyl chloride molar ratio 1 6 5, yield 46% based on the oxime consumed with oxime conversion of 75%. 

Tetrahydroindole (1) was isolated by extraction of the reaction mixture with organic solvents (Et20, benzene) and purified by distillation or recrystallization. This process for preparing 4,5,6,7-tetrahydroindole is simple enough, industrially feasible, safe, and based on the cheap and accessible raw materials. Cyclohexanone oxime is an inexpensive large-scale commercial product (caprolactam synthesis intermediate), vinyl chloride being one of the cheapest commercial vinyl compounds. 

A synthesis of 4,5,6,7-tetrahydroindole (1) and its N-vinyl derivatives (2) using 1,2-dihaloethanes (Scheme 61) has been described in detail (82KGS1202). In spite of lower yields of pyrroles, this version of the reaction may prove to be the most suitable for laboratories that have no acetylene or experience working with this gas. 

Data on the N-phosphorylated derivatives of pyrrole have been reported [29], and the synthesis of 1-methyl-2-diphenylphosphinyl-3-formylindole dimethylhydrazone 31 and tetrahydroindole derivative 32 has also been mentioned [30] ... 

C. Diels-Alder Reactions and the Synthesis of Indoles Synthesis of Tetrahydroindole Complexes... 

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). 

The Larock synthesis was used by Chen and co-workers to synthesize the 5-(triazolyl-methyl)tryptamme MK-0462, a potent 5-HTjn receptor agonist, as well as a metabohte [366], Larock employed his methodology to prepare tetrahydroindoles [367], and Maassarani used this method for the synthesis of /V-(2-pyridyl)indoles [368]. The latter study features the isolation of cyclopalladated Y-phenyl-2-pyridylammes. Rosso and coworkers have employed this method for the industrial-scale synthesis of an antimigraine drug candidate 331. In this paper removal of spent palladium was best effected by trimer-captotriazine (332) although many techniques were explored [369]. 

Demetalation of 4 with trimethylamine N-oxide yields car-bazole 5. Methylation gives carbazomycin A (1) [12]. In addition to carbazoles, Kndiker and his students applied this iron-mediated chemistry to the preparation of dihydroindoles [13, 14], (anhydrolycotine), tetrahydroindoles [15], dihydrocarbazoles [16], perhydroacenaphihenes [17], and azaspiroannelated ring systans [18-21], Several shorter accounts of Kndlker s carbazole syntheses [22-25] and the overall utility of tricarbonyl(Tl -diene)iron complexes in organic synthesis are available [26-32],... 

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