Synthetic entries to 6‐fluoro‐7‐substituted indole derivatives

Abstract

Three practical synthetic entries of functionalized 6‐fluoro‐7‐substituted indole derivatives were developed in connection with the preparation of 7‐fluoro‐8‐substituted‐1,3,4,9‐tetrahydropyrano[3,4‐b]indole‐1‐acetic acid derivatives 11. The first route, which permits group modification about position 8 of the pyranoindole skeleton, employs 2‐bromo‐3‐fluoroaniline (18) as a key intermediate, the preparation of which was achieved by either a novel ortho metalation of 15 or via the intermediacy of 22. The second route utilizes 32 to append a terminally functionalized three carbon side chain onto the indole template and in addition leads to 43 from 40. The third route to the 7‐fluoro‐8‐substituted‐pyranoindole skeleton complements route two in that the synthetic pathway exploits 32 in a nucleophilic fashion to construct a terminally functionalized two carbon appendage onto the indole nucleus.

Synthesis of indole derivatives as prevalent moieties present in selected alkaloids

“…The total synthesis of makaluvamine D (37) starts from 2,3-dimethoxybenzoic acid (27) and within ve steps affords (3,4-dimethoxyphenyl)hydrazine (28). The latter was reacted with dihydrofuran 118 and provided a 1 : l mixture of the tetrahydrofuran (THF) 29 and the hydrazone 30 (as an E/Z mixture). The mixture was exposed to Fischer indolization reaction conditions in the presence of ZnCl 2 and gave the desired tryptophol 31, accompanied by the 4,5-dimethoxyindole derivative 32.…”

“…The unit structure of asteropusazole (118) and racemosin B (117) was synthesized using Fischer indolization of cyclohexanone 113 and N-methylphenylhydrazine (112) (prepared from the commercially available aniline derivative 111) 176 that afforded carbazole 114. Using the DDQ oxidation reaction, 111 gave the keto derivative 115.…”

Fischer indole synthesis applied to the total synthesis of natural products

“…As a result, the starting material for this method was 2,3-dimethoxybenzoic acid 71 that has been transformed to crystalline (3,4-dimethoxyphenyl)hydrazine 72 upon several steps. Then, this hydrazine has been reacted with dihydrofuran 73 according to a procedure established by McKittrick 78 and gave a 1 : 1 mixture of the tetrahydrofuran 74 and the hydrazone 75 (an E/Z mixture). The mixture has been exposed to FIS by using ZnCl 2 to afford the desired tryptophol 76.…”

The Oxa-Pictet-Spengler Cyclization: Synthesis of Isochromans and Related Pyran-Type Heterocycles

“…Soll's group prepared these in moderate-to-excellent yields by the oxa-Pictet-Spengler condensation of appropriately substituted tryptophols with methyl-3-methoxypentenoate under BF 3 •Et 2 O catalysis. 145 During research work related to the synthesis of etodolac, Chou prepared chloro derivative 274 by oxa-Pictet-Spengler reaction of 7-ethyltryptophol 215b with ketal ester 275, while reaction with enol ether 276 gave diester 277a, which was converted into nitrile 277b by simple functional group transformations (Scheme 43). 146 Interestingly, upon submission to reaction with sodium cyanide in DMF, the g-chloroester 274 produced a rearrangementchain-extension reaction, 147 leading to cyanoester 278.…”