1.3.4.5- Tetrahydrobenz indole

If the internal nucleophile is an alkenic group, then 5,6-dihydropyridine (Scheme 18) " or 1-pyrroline (Scheme 19) rings are produced. In a recent development of the latter process, the diol (44) follows the same sequence to yield the carbenium ion (45 R = Bn). However, this now cyclizes onto the aromatic group originating from the nitrile component and produces the tetrahydrobenz indole (46) in good yield, with the conventional pyrroline structure (47) now being only a minor product. Compound (46), present as a tautomeric mixture, was rapidly autoxidized to (48 Scheme 20). A further unusual variant of this process is the production of small quantities of the 3-azabicyclo[3.3.0]octanes (49) and (50) from Ritter reaction of l-vinylbicyclo(2.1.1]hexane (equation 32). ... 

The Madelung indole synthesis has been employed in the preparation of some complex indole systems. Uhle et al. reported the conversion of N-formyl-5,6,7,8-tetrahydronaphthylamine 28 into 1,3,4,5-tetrahydrobenz[c,ti]indole 29 with t-BuOK in 11% yield in regard to synthesis of ergot alkaloids. ... 

Other ring types prepared from thioureas include those of Petersen and. Heitzer, who prepared the naphthoxathiolones 233 (X = 0, Y = OH) from 2-(2-methylpropanal-2-yl)-1,4-naphthoquinone and 233 (X = NH, Y = H) starting with a tetrahydrobenz[gr]indol-5-one, each through reaction with thiourea in hydrochloric acid. Kaushal and Narang jirepared a series of dihydrothiazolo[4,5-c]cinnolines... 

Carboxy-3-indole)propionic acid refluxed 20 hrs. with a little KCN in acetic anhydride —5-keto-l,3,4,5-tetrahydrobenz[cd] indole. Y 80%. Other methods were not successful. (F. C. Uhle, Am. Soc. 71, 761 (1949).)... 

Lilly chemists prepared 998b as part of a series of 4-amino-6-heteroaryl-l,3,4,5-tetrahydrobenz[c,d]indoles evaluated as anti-emetic agents via coupling of 2-(tributylstannyl)oxazole 996 with (+)- 2aR, 45)-l-benzoyl-6-iodo-4-(di-n-pro-pylamino)-l,2,2a,3,4,5-hexahydrobenz[c,d]indole 997. They isolated 998b after deprotection as shown in Scheme 1.266. 

The tricyclic system has also been constructed from an indole via electrophilic substitution reactions at positions 3 and/or 4. Synthesis of tricyclic ergoline synthons from 5-methoxy-lH-indole-4-carboxaldehyde has been described [45]. Sodium cyanoborohydride mediated reductive amination provided easy access to l,3,4,5-tetrahydrobenz[cd]indole-4-amines, compounds which show specificity for serotonin and dopamine receptors. 

Various 4-substituted indoles were prepared and a synthetic method for 4-nitro-l,3,4,5-tetrahydrobenz[cd]-indole derivatives was carried out [46] and also for 4,5-disubstituted lH-l,3,4,5-tetrahydrobenz[cd]indole derivatives [47] using intramolecular Michael addition. Furthermore, a method [48] was published describing the successful syntheses of 4-nitro-l,3,4,5-tetrahydro-benz[cd] indole and its 1-hydroxy derivative. 

It has recently been shown that Vicarious Nucleophilic Substitution (VNS) can be a useful tool for the synthesis of biologically active compounds containing the l,3,4,5-tetrabenz[cd]indole nucleus, such as 6-methoxy-l,3,4,5-tetrahydrobenz [ cd] indole-4-amine [49]. 

A solution of 143 mg p-(4-carboxy-3-indole)-propionic acid (0.6 mmol) and 15 mg potassium acetate (0.15 mmol) in 5 mL acetic anhydride was maintained at reflux temperature for 16 h. The acetic anhydride was distilled under reduced pressure. The residue was extracted with refluxing benzene. The solution was clarified by filtration and concentrated under diminished pressure. The remainder (125 mg) was recrystallized from a mixture of dichloromethane and ether to give 104 mg l-acetyl-5-keto-l,3,4,5-tetrahydrobenz(ed) indole, m.p. 120-140°C. Further recrystallization from a mixture of dichloromethane and ether gave 90 mg pure product, in a yield of 71%, m.p. 147-152°C. 

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