Synthesis of Pyrrolo[4,3,2-de]quinolines from 6,7-Dimethoxy-4-methylquinoline. Formal Total Syntheses of Damirones A and B, Batzelline C, Isobatzelline C, Discorhabdin C, and Makaluvamines A−D

Abstract

2-Amino-4-nitrophenol and 2-methoxy-5-nitroaniline were converted into the 5-nitroquinolines 6b and 6d, respectively, and then the latter into nitro-acetal 6f. 6,7-Dimethoxy-4-methylquinoline (6g) was nitrated at C-5 and then the methyl substituent converted into aldehyde 6j and then protected giving acetal 6l. Various means, notably a large excess of NiCl(2)/NaBH(4), were used to reduce both nitro group and pyridine ring, forming 1,2,3,4-tetrahydroquinolines such as 7b, 7c, 7d, which under acidic conditions closed to give 1,3,4,5-tetrahydropyrrolo[4,3,2-de]quinolines 9a, 9d, 9c, respectively. In some cases it was unnecessary to protect the aldehyde function, for example quinolinium salt 12c gave 9j and nitro-aldehyde 6j gave 9e (after BOC protection) directly by reaction with NiCl(2)/NaBH(4). Substitution of the indole and aniline nitrogens in the 1,3,4,5-tetrahydropyrrolo[4,3,2-de]quinolines was based on a combination of protection, selective deprotection, and the exploitation of the greater acidity of the indole N-hydrogen. 8-Chlorination of 6h and then conversions, as above, gave chloro-diamine-acetal 7e which on acid treatment produced iminoquinone 11b; formylation of the nitrogens in 7e and then acidic treatment allowed formation of the chlorine-substituted 1,3,4,5-tetrahydropyrrolo[4,3,2-de]quinoline 9m which was then converted into 9p. De-O-methylation and then oxidation of 9b and 9c gave o-quinones 10b and 10a, respectively.

4‐Aryl(benzyl)amino‐4‐heteroarylbut‐1‐enes as Building Blocks in Heterocyclic Synthesis. 4.1 Synthesis of 4, 6‐Dimethyl‐5‐nitro(amino)‐2‐pyridylquinolines and their Antiparasitic Activities

“…The same reaction of compound 2 e lead to the mixture of C-5 and C-8 nitroderivatives 3 e and 3 f. Regioisomer 3 e is the major product and was separated by column chromatography. The structures of the nitro compounds could be assigned from the spectroscopic data; they are in agreement with the results of related quinolines investigated previously [17,18]. Nitroderivatives 3 aϪd were subjected to a gentle reduction process with NaBH 4 in the presence of Pd/C in methanol to give the corresponding amino derivatives.…”

“…Although many synthetic methods for this heterocycle and its hydrogenated derivatives have been developed [3Ϫ5], the syntheses of 4-methyl-2-pyridylquinolines are scarcely reported [6,7]. Several antitumor antibiotics are based on the 2-(α-pyridyl)quinoline-quinone tricyclic molecule [8] and substituted 4-methylquinolines are useful starting products for ring construction of complex natural Nheterocycles [9,10]. Moreover, 8-(diethylaminohexylamino)-6-methoxy-4-methylquinoline is highly effective against the protozoan parasite Trypanosoma cruzi, which is the agent of Chagas' disease [11] and 2-(2-methylquinolin-4-ylamino)-N-phenylacetamide is more active than the standard anti-leishmanial drug sodium antimony gluconate [12].…”

Efficient Total Synthesis of Ammosamide B

“…Syntheses of these compounds have generally involved first construction of quinoline systems followed by elaboration of the pyrrole derivative,8,9 or they have started from indole derivatives followed by construction of the quinoline rings 3,10. To date, only one synthesis of the ammosamides has been reported, which produced ammosamide B in 17 steps from 4-chloroisatin in an overall yield of 2.7% 3.…”

Total Synthesis of Damirone C, Makaluvamine O, Makaluvone, Batzelline C and Batzelline D

“…In the first route the quinoline is formed and then the pyrrole ring is closed. For instance, a formal total synthesis of batzelline C ( 1e ) and total syntheses of the damirones A, B and C, using this route are described. The second route commences with the construction of the indole ring.…”