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Indoles - Sundberg R.J.

Sundberg R.J. Indoles - Academic press, 1996. - 95 p.
ISBN 0-12-676945-1
Download (direct link): indoles1996.djvu
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3-substituent[4-6], Table 2.4 gives examples of reductive cyclizations of o-nitrostyrenes to indoles.
Ethyl indole-2-carboxylate[7]
Ethyl o-nitrocinnamate (1 mmol) was dissolved in triethyl phosphite (5 mmol) and heated at 170°C for 3 h. The triethyl phosphite and triethyl phosphate were removed in vacuo. The residue was eluted through a column of silica gel using CHC13 and the product recrystallized from CHCl3-hexane. The yield was 94%.
o-Nitrostilbene (2mmol), PdCl2(PPh3)2 (0.10mmol), SnCl2 (l.Ommol) and dioxane (10 ml) were placed in a glass liner in a 50 ml stainless steel autoclave equipped for stirring. The apparatus was sealed, purged three times with CO (10 kg/cm2) and pressurized to 20 kg/cm2 with CO and heated quickly (within lOmin) to 100°C and maintained at that temperature for 16 h. The apparatus was then rapidly cooled and the gases discharged. The solvent was removed in vacuo and the product purified by medium pressure column chromatography on silica gel.
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Category lb Cyclizations
Category lb cyclizations effect closure of the C2 C3 bond. Scheme 3.1 depicts retrosynthetic transformations corresponding to syntheses in category lb. Included are three variations of the intramolecular aldol condensation and reductive coupling of o,iV-diacylanilines.
a? t
R /^CH2P+Ph3
о ,CR
The classical conditions for the Madelung indole synthesis are illustrated by the Organic Syntheses preparation of 2-methylindole which involves heating o-methylacetanilide with sodium amide at 250°C[1].
These conditions are so harsh that they are applicable only to indoles with the most inert substituents. Cyclization can be achieved at much lower temperatures by using alkyllithium reagents as the base. For example, treatment of o-methylpivalanilide with 3 eq. of и-butyllithium at 25“C gives 2-tm-butylindole in 87% yield[2], These conditions can be used to make
Table 3.1
Indoles by base-mediated cyclization of o-alkylanilides
Entry Substituents Cyclization conditions Yield (%) Ref.
1 2-Methyl NaNH2, 250°C 80 ГП
2 2-Nonyl NaNH2, 250°С 81 Г51
3 2-(2-lndolyl) K*t-BuO“, 25°C 80 Г61
4 2-( 1 -Methylpiperid-4-ylmethyl) K't-BuO”, 340°C 92 m
5 5-C.hloro-2-phenyl n-BuLi, — 20/25' С >90 Г21
6 2-Cyclohexyl-5-methoxy и-BuLi, 25“C 40 [8]
2-arylindoles from benzanilides and have also been applied to the synthesis of azaindoles[3]. The reaction is presumed to proceed through a dilithiated intermediate which eliminates Li,()[4]. Table 3.1 gives some examples.
CH3 ^ CH2Li
2 n-BuLi
A variation of the Madelung cyclization involves installing a functional group at the o-methyl group which can facilitate cyclization. For example, a triphenylphosphonio substituent converts the reaction into an intramolecular Wittig condensation. The required phosphonium salts can be prepared by starting with o-nitrobenzyl chloride or bromide[9]. The method has been applied to preparation of 2-alkyl and 2-arylindoles as well as to several 2-alkenylindoles. Tabic 3.2 provides examples.
CH,P Ph3 -
as — o>
v NCR i
Table 3.2
2-Substituted indoles from o-carboxamidobenzylphosphonium salts
Entry Substituents Yield (%) Ref.
1 2-Benzyl 64 [10]
2 2-(2-Methylprop-l -enyl) 93 [11]
3 2-( 1 -Methylethenyt) 65 [12]
4 2-(Ethoxycarbonylmethyl) 72 [13]
5 2-(4-Phenylbutyl) 78 [14]
Another variation of the Madelung synthesis involves use of an O-alkyl or O-silyl imidate as the C2 electrophile. The mechanistic advantage of this modification stems from avoiding competing N-deprotonation, which presumably reduces the electrophilicity of the amide group under the classical conditions. Examples of this approach to date appear to have been limited to reactants with a EW substituent at the o-alkyl group[15,16].
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