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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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13. M. Kawase, A. K. Smhababu and R. T. Borchardt, Chem. Pharm. Bull. 38, 2939 (1990).
Category IIab Cyclizations
The main IIa£> synthetic pathway is illustrated in Scheme 6.1 and corresponds to C-acylation of an o-aminobenzyl carbanion equivalent. Acylation is normally followed by in situ cyclization and aromatization. This route is therefore closely related to the cyclizations of o-aminobenzyl ketones described in Section 2.3 but the procedures described here do not involve isolation of the intermediates.
One type of o-aminobenzyl anion synthon is a mixed Cu/Zn reagent which can be prepared from o-toluidines by b/s-trimethylsilylation on nitrogen, benzylic bromination and reaction with Zn and CuCN[l]. Reaction of these reagents with acyl halides gives 2-substituted indoles.
Another o-aminobenzyl anion equivalent is generated by treatment of JV-trimethylsilyl-o-toluidinc with 2.2 eq. of и-butyllithium. Acylation of this intermediate with esters gives indoles[2]. This route, for example, was used to prepare 6.2D, a precursor of the alkaloid cinchonamine.
A more highly substituted analogue was successfully used in the preparation of the penitrem class of terpenoid indoles[3].
Another version of the o-aminobenzyl anion synthon is obtained by dilithi-ation of N-t-Boc-protected o-alkylanilines. These intermediates are C-acylated by DMF or JV-methoxy-N-methyl carboxamides, leading to either 3- or 2,3-disubstituted indoles. In this procedure dehydration is not spontaneous but occurs on brief exposure of the cyclization product to acid[4]. Use of C02 as the electrophile generates oxindoles.
In a related procedure ./V-methyl-o-toluidine can be JV-lithiated, carboxylated and C-lithiated by sequential addition of n-butyllithium, C02, and «-butyl-lithium[5]. The resulting dilithiated intermediate reacts with esters to give
1.2-disubstituted indoles.
In a more elaborate and specific synthesis, the terpenoid indole skeleton found in haplaindole G, which is isolated from a blue-green alga, was constructed by addition of a nucleophilic formyl equivalent to enone 6.5A. Cyclization and aromatization to the indole 6.6B followed Hg2--catalysed unmasking of the aldehyde group[6].
6.5A 6.5В СОгСНгСН^СНг
2-(5-Vinyi-1 -azabicycio[2.2.2]octan-2-yl)indoie[2]
1) n-BuLi
A solution of N-TMS-o-toluidine (200 mg, 1.12 mmol) in dry hexanes (8 ml) was cooled to 0 C and treated dropwise with a 2.5 M solution of и-BuLi in
hexanes (1.0 ml, 2.5 mmol). The pale yellow solution was heated at reflux for 6.5 h. The rebuking solution (orange) was cooled to room temperature and added via a cannula to a cold ( —78°C) solution of ethyl 5-vinyl-l-azabi-cyclo[2.2.2]octane-2-carboxylate (180 mg, 0.86 mmol) in THF (5 ml). The mixture was then allowed to warm to room temperature and diluted with ether (25 ml) and quenched with sat. aq. NaCl (10 ml). The product was isolated by extraction and purified by chromatography using 3:2 hexanes-acetone for elution. The yield was 63%.
A solution of JV-(ii?rt-butoxycarbonyl)-6-methoxy-2-methylaniline (11.9 g, 50 mmol) was coolcd to — 40°C and s-BuLi (96 ml of 1.3 M in cyclohexane. 125 mmol) was added. The mixture was stirred at —45°C to — 55cCfor 30 min and then allowed to warm slowly to — 15°C over 60min. The yellow solution was recooled to —45°C and DMF (5.8 ml, 75 mmol) was added. After 5 min the reaction mixture was diluted with water (250 ml) and the product was extracted with EtOAc (2 x 150 ml). The extract was washed with water (200 ml) and then concentrated in vacuo. The residue was dissolved in THF (100 ml) and 12 N HC1 (2 ml) was added. The solution was stirred for 5 min at room temperature and then diluted with ether (250 ml). The solution was washed with water (250 ml), sat. aq. NaHC03 (250 ml), and brine (250 ml), dried (Na2S04) and evaporated. The product was purified by chromatography using 2% EtOAc in hexane for elution. The yield (9.3 g) was 75%.
1. H, G. Chen, C, Hoechstetter and P. Knochel, Tetrahedron Lett. 30, 4795 (1989).
2. A. B. Smith, HI, M. Visnick. J. N. Haseltine and P. A. Sprengeler, Tetrahedron 42, 2957 (1986).
3. A. B. Smith, III, i. N. Haseltine and M. Visnick, Tetrahedron 45, 2431 (1989).
4. R. D. Clark, J. M. Muchowski, L. E. Fisher, L. A. Flippin, D. B. Repke and M. Souchct,
Synthesis 871 (1991).
5. A. R. Katritzky, W.-Q. Fan, K. Akutagawa and J. Wang, Heterocycles 30, 407 (1990).
6. T. Fukuyama and X, Chen, J. Am. Chem. Soc, 116, 3125 (1994),
Category Mac Cyclizations
The llac category is the most prevalent means for synthesis of 2-, 3- and
2,3-disubstituted indoles. This reaction pattern creates the indole ring from an aromatic compound and a second molecule which provides C2 and C3 and the attached substituents. This dissection allows for the synthesis to be quite general since the potential C2 and C3 substituents generally do not directly participate in the reaction. Some llac syntheses require only a mono-sub-stituted aromatic ring while others require a specific o-substitution pattern. The former type, of course, has the advantage of requiring a less complex starting material. Scheme 7.1 depicts some of the important indole syntheses which fall in category llac. Path a is the Fischer cyclization, which is the most widely applied of all indole syntheses. Paths b and с are closely related methods, which, like the Fischer cyclization, depend on a sigmatropic rearrangement to effect ortho-substitution. In each of these reactions, an iminium or carbonyl bond is in place after the sigmatropic rearrangement to permit completion of the cyclization. Path d corresponds to the Sugasawa indole synthesis which proceeds by conversion of anilines to indoles by BCl3-directed ortho-chloro-acetylation, followed by a reductive cyclization. Path f dissects the indole ring to an aniline and a-haloketone. When the ketones are a-bromoacetophenones, this corresponds to the Bischler synthesis of 2-arylindoles.
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