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7. H. Muratake and M. Natsume. Heterocycles 29, 771 (1989).
Synthesis of indoles by electrophilic annelation of pyrroles
Yield (%) Ref.
H2S04, propanol 82
2 l-Methyl-4-(3-methylbut-2-enyl)- (CH3)2C=CHCH2CCH2CH2CH' >1' p-TsOH
indole SCH3 S02PhCH3
Г J OH Ts
H2S04, propanol 69
7-Phenyl- l-(4-meth ylphenylsulfonyl)-indole
Г )— СН2СН2 ^•о
(CH3)2CHCHV СНз N
H2S04, propanol 70
(CH3)2CHCHNCCH2CH П~\\ СНз
СН2=СН-С н сн/ СН3
8 INDOLES BY ANNELATION OF PYRROLI S
8.2 CATEGORY l\df AND CATEGORY II fh CYCLIZATIONS - DIELS-ALDER REACTIONS OF VINYLPYRROLES
As illustrated in Scheme 8.1, both 2-vinylpyrroles and 3-vinylpyrroles are potential precursors of 4,5,6,7-tetrahydroindolcs via Diels-Alder cyclizations. Vinylpyrroles are relatively reactive dienes. However, they are also rather sensitive compounds and this has tended to restrict their synthetic application. While l-methyl-2-vinylpyrrole gives a good yield of an indole with dimethyl acetylenedicarboxylate, эс-substituents on the vinyl group result in direct electrophilic attack at C5 of the pyrrole ring. This has been attributed to the steric restriction on access to the necessary cisoid conformation of the 2-vinyl substituent[l].
n—n /Г-ft Me02CC - CC02Me A^A^C02CH3
vv — %VCH2 -* w
CH3 CH2 CH3 R CH3
R = H 70%
-с о CH2
X СНз R (8.5) H СОгМе '
R = CH3, Ph, tBu
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, N-methylmaleimide and naphthoquinone. These tetrahydroindole adducts could be aromatized with DDQ, although the overall yields were modest.
CH;VAn>' + HC=CC02CH3
8.3 CATEGORY Weg CYCLIZATIONS
1. R. A. Jones, T. A. Saliente and J. S. Arques, J. Chem. Soc., Perkin Trans. 1 2541 (1984),
2. M Ohno, S. Shimizu and S. Eguchi, Heterocycles 32, 1199 (1991).
3. M. Murase, S. Yoshida, T, Hosaka and S. Tobinaga, Chem. Pharm. Bull. 39, 489 (1991).
8.3 CATEGORY Weg CYCLIZATIONS - CYCLOADDITIONS INVOLVING PYRROLE-2,3-QUINODIMETHANE INTERMEDIATES AND EQUIVALENTS
This category corresponds to the construction of the carbocyclic ring by 2 + 4 cycloaddition with pyrrole-2,3-quinodimethane intermediates. Such reactions can be particularly useful in the synthesis of 5,6-disubstituted indoles. Although there are a few cases where a pyrrolequinodimethane intermediate is generated, the most useful procedures involve more stable surrogates. Both 1,5-di-hydropyrano[3,4-b]pyrrol-5(ltf)-ones[l] and l,6-dihyropyrano[4,3-b]pyrrol-6-(l//)-ones can serve as pyrrole-2,3-quinodimethane equivalents. The ad-ducts undergo elimination of C02.
Reactions with mono-substituted alkynes usually give mixtures of both 5-and 6-substituted indoles, although certain combinations of substituents result in good regioselectivity. Table 8.2 provides some examples.
8.3 CATEGORY lleg CYCLIZATIONS
5-Ethyl 1 -isobutyl 6-(trimethylsilyl)indole-1,5-dicarboxylate
A mixture of iso-butyl ].6-dihydropyrano[4.3-b]pyr rol-6-( l Я)-опс-1 -carboxyl-ate (80 mg, 0.34 mmol) and ethyl 3-(trimethylsilyl)propynoate (173 mg,
1.02 mmol) in chlorobenzene (10 ml) was refluxed for 20 h. The solvent was removed in vacuo and the residue purified by chromatography to give the product (98 mg, 79%) and its regioisomer (13 mg, 11 %).
1. P. M. Jackson and C. J. Moody, Tetrahedron 48, 7447 (1992).
2. J. F. P. Andrews, P. M. Jackson and C. J. Moody. Tetrahedron 49, 7353 (1993).
3. P. M. Jackson and C. J. Moody, J. Chem. Soc., Perkin Trans. I 2156 (1990).
Synthetic Modification of Indoles by Substitution at Nitrogen
Synthetic methodology for introduction of substituents on indole has historically been dominated by electrophilic substitution. Sincc the 3-position is the most reactive on the indole ring, this position is the easiest one at which to accomplish electrophilic substitution. The nitrogen atom can be made the most reactive nucleophilic site by deprotonation, so procedures for N1 substitution normally involve base-catalysed nucleophilic substitution or conjugate addition reactions. Base-catalysed conditions are also used for introduction of acyl and sulfonyl substituents. Phase transfer catalysis has been found useful for both alkylation and acylation. 1-Substitution is also important for introduction of protecting groups. The most versatile methods for C2 substitution involve organometallic intermediates obtained by C2 lithiation. Several iV-protccting and/or directing groups have been developed in conjunction with methods for lithiation.