E-Book, Englisch, 520 Seiten, ePub
Joule / Murai Science of Synthesis: Knowledge Updates 2018 Vol. 2
1. Auflage 2018
ISBN: 978-3-13-242319-0
Verlag: Thieme
Format: EPUB
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E-Book, Englisch, 520 Seiten, ePub
ISBN: 978-3-13-242319-0
Verlag: Thieme
Format: EPUB
Kopierschutz: Adobe DRM (»Systemvoraussetzungen)
The Science of Synthesis Editorial Board, together with the volume editors and authors, is constantly reviewing the whole field of synthetic organic chemistry as presented in and evaluating significant developments in synthetic methodology. Several annual volumes updating content across all categories ensure that you always have access to state-of-the-art synthetic methodology.
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10.23 Product Class 23: Pyrido[X,Y-]indoles (Carbolines)
J. A. Joule
General Introduction
The four isomeric pyrido[X,Y-]indoles are most frequently referred to as “carbolines”, thus 9-pyrido[2,3-]indole (1) is a-carboline, 9-pyrido[3,4-]indole (2) is ß-carboline, 5-pyrido[4,3-]indole (3) is ?-carboline, and 5-pyrido[3,2-]indole (4) is d-carboline (? Scheme 1).
Scheme 1 Structures, Names, and Numbering of the Pyrido[X,Y-]indoles (Carbolines)
The name “carboline” was coined by W. H. Perkin Jr. and Robert Robinson[1] during their work on the structural elucidation of the harmala alkaloids, e.g. harmine (12; see below), and was chosen to indicate the structural similarity between the tricyclic nucleus of the alkaloid and carbazole on one hand and isoquinoline on the other; it was then extrapolated for other isomers with designations to indicate the location of the pyridine ring nitrogen. All the carbolines are stable, colorless, almost odorless solids with melting points in the range of 200–220°C.
There are only a few reviews of carboline synthesis and chemistry: a-carboline synthesis,[2] a-, ?-, and d-carboline properties,[3] a-, ?-, and d-carboline synthesis,[4] ß-carbolines as synthetic intermediates,[5] ?-carbolines,[6] ß-carboline synthesis,[7] carbolines (mainly ß-carbolines and mainly reduced derivatives),[8] and carbolines.[9]
In each of the carbolines, the typical characters of a pyridine ring nitrogen and an indole/pyrrole ring -hydrogen can be discerned and are illustrated in ? Scheme 2 using the ß-isomer. Thus, reaction with an alkyl halide leads easily to a quaternary (carbolinium) salt (e.g., 5),[10,11] whereas by using a strong base to deprotonate the -hydrogen, and then reaction with an alkyl halide, indole nitrogen alkylation is achieved, giving for example 6.[12,13]
The basicities of the pyridine ring nitrogens measured by the pa values of their conjugate acids in water are shown in ? Table 1.[14,15] The acidities of the -hydrogens, measured by their pa values, are shown in ? Table 2.[6,14] One may compare these values with the pa for the pyridine-type nitrogen in isoquinoline (5.4) and the pa for the indole -hydrogen (16.2).
Table 1 pa Values of Pyridine Ring Nitrogens in Carbolines[14–16]
| Compound | pa (H2O) | Ref |
|---|
| 1 | 4.2 | [14] |
| 2 | 6.9 (7.2)a | [14,15] |
| 3 | 7.5 | [14] |
| 4 | 5.3 | [14] |
| isoquinoline | 5.4 | [16] |
| a The two references cited give slightly different values for the pa. |
Table 2 pa Values of -Hydrogens in Carbolines[14,17]
| Compound | pa (H2O) | Ref |
|---|
| 1 | 14.7 | [14] |
| 2 | 14.5 | [14,17] |
| 3 | 14.0 | [14] |
| 4 | 15.1 | [14] |
| indole | 16.2 | [16] |
The -hydrogens of carbolinium salts are more acidic (? Table 3).[18,19] These figures measure the formation of “anhydronium bases”, e.g. in the ?-series 2-methyl-2-pyrido[4,3-]indole 8 from 2-methyl-5-pyrido[4,3-]indol-2-ium salt 7 (? Scheme 3). The yellow-orange anhydronium bases can be isolated;[19–22] neutral and dipolar resonance forms contribute to their structures, thus 8A and 8B for 8.
Table 3 pa Values of the N-Hydrogens of Pyridine--methyl Carbolinium Salts[18,19]
| Compound | pa (H2O) | Ref |
|---|
| 7.75 (7.6)a | [18,19] |
| 11.1 (10.9)a | [18,19] |
| 10.5 | [18] |
| 10.8 | [18] |
| a The two references cited give slightly different values for the pa. |
Anhydronium bases such as 9 react with alkyl halides at the five-membered ring nitrogen to give carbolinium salts (e.g., 10) from which the N-alkylated carboline (e.g., 6) can be obtained by demethylation on strong heating (? Scheme 4).[22–24]
Scheme 4 Formation of an Anhydronium Base from a ß-Carbolinium Iodide, Its Reaction with Iodomethane, and Demethylation of a ß-Carbolinium Methiodide[22–24]
All carbolinium salts can be easily selectively reduced in the pyridinium ring to give tetrahydro derivatives using sodium borohydride. For example, 2-methyl-9-pyrido[3,4-]indol-2-ium iodide (5) is reduced to 2-methyl-2,3,4,9-tetrahydro-1-pyrido[3,4-]indole (11) in 99% yield (? Scheme 5).[25]
? Scheme 5 Conversion of 2-Methyl-9-pyrido[3,4-]indol-2-ium Iodide into 2-Methyl-2,3,4,9-tetrahydro-1-pyrido[3,4-]indole[25]
The role of electrophilic substitution in the chemistry of carbolines is relatively minor. All of them are attacked only in the benzene ring mainly to the pyrrolic nitrogen but occasionally to it.
The 13C and 1H NMR spectra of the four carboline isomers are summarized in ? Scheme 6.[26,27]
Scheme 6 13C (90.6 MHz) and 1H (360.1 MHz) NMR Shifts and Coupling Constants for the Four Carbolines in DMSO-6[26,27]
ß-Carboline units occur naturally in various indole alkaloids ranging in complexity from harmine (12) from and congeners[28,29] and canthinone (13) from [30] through the ß-carbolinium-containing flavopereirine (14) from [31] to the very large number of alkaloids that contain a 1,2,3,4-tetrahydro-ß-carboline unit,[32–39] yohimbine (15)[34–37] from may be considered typical (? Scheme 7). The synthesis of carbolines with a further fused aromatic ring such as 14 and the synthesis of 1,2,3,4-tetrahydrocarbolines are not covered in this chapter (except in so far as reduced carbolines can lead to fully aromatic systems by dehydrogenation). Lavendamycin (16) from has significant activity against topoisomerase I, but has high toxicity.[40] Manzamine C (17) is the simplest of a family of oncolytic marine alkaloids isolated from Okinawan marine sponges;[41] the others also all have a ß-carboline unit but with a more complex C1 substituent.
By comparison, there are only a few natural substances containing any of the other carboline isomers. a-Carboline-containing grossularine-2 (18) was isolated from and is cytotoxic.[42] produces mescengricin (19), another a-carboline, which prevents L-glutamate toxicity.[43]
Isocanthinone (20)[44] and isoperlolyrine (21; from )[45] were named by analogy with ß-carboline analogues canthinone (13) and perlolyrine...
