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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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5. К. T. Potts and J. E. Saxton, Org. Synth., Coll. Vol. V 769 (1973).
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The mechanistic principles underlying iV-acylation and sulfonylation are the same as for Y-alkylations. The reaction conditions are designed so that the indole anion is the reactive nucleophile. The usual acylating agents are acid anhydrides, acyl chlorides or chloroformate esters and sulfonyl chlorides are used for sulfonylation. The ferf-butoxvcarbonvl group is introduced using di-fm-butyl dicarbonate[l] or fert-butyl phenyl carbonate[2]. The iV-acyl derivatives of indoles are less stable to hydrolysis than normal amides because of the diminished capacity of the indole nitrogen to act as an electron donor toward the carbonyl group.
o ' 'R 0 'R о R
Nevertheless, they are stable to standard work-up and purification methods. The benzenesulfonyl group can be introduced using base and an aprotic solvent[3] or under phase transfer conditions [4]. Table 9.2 gives some representative examples of acylation and sulfonylations.
1-(\eri -Butoxycarbonyl)indole[ 1 ]
Indole (10mmol) was added to dry CH3CN (20ml) and the mixture stirred while DMAP (122mg, l.OOmmol) and di-fert-butyl dicarbonate (2.62 g, 12 mmol) were added. Evolution of gas was noted and stirring was continued
Table 9.2
Acylation and sulfonylation of indoles
Entry Substituents Conditions Yield (%) Ref.
1 1-Acetvl (CH3C0)20, DMF, K2COj na Г31
2 1-Benzoyl PhCOCl, DME, NaOH 83 Г41
3 1-fm-Butoxycarbonyl (CH3)3C0C02C6H5, THF, NaH 78 ГЯ
4 1-Phenylsulfonyl C6H5S02C1, benzene, 50% NaOH, (C4H9)4N + HS04 (10mol%) 96 [6]
for 1 h or until the reaction was judged to be complete by TLC. The solvent was removed in vacuo and the residue purified by being eluted through silica gel with CH2Cl2-hexancs.
1 ~(Benzyloxycarbonyl)indole[2]
To a stirred ice-cooled suspension of indole (12.0 g, 0.102 mmol), Bu4N + Br~ (1.16 g, 3.6 mmol) and powdered NaOH (5.24 g, 0.13 mol) in CH2C12 (100 ml) there was added over a period of 50 min a solution of benzyl chloroformate (15 ml, 0.11 mol) in CH2C12 (50 ml). After stirring for an additional 10 min, the reaction mixture was diluted with water (200 ml) and extracted with CH2C12 (2 x 100 ml). The extracts were dried (Na2S04) and evaporated. The residue crystallized on cooling and was recrystallized from ether to give pure product in 84% yield.
1 (Phenylsulfonyl)indole[6, adapted]
Indole (25.0 g, 0.213 mol) was dissolved in CH2C12 (200 ml). Powdered NaOH (17.1 g, 0.426mol) and n-Bu4N+HS04 (0.103g, 03mmol) were added. The solution was stirred for 1 h. The solution was then cooled in an ice bath and PhS02Cl (30 ml, 0.234 mol) was added dropwise over 30 min. The solution was then stirred overnight. The solution was mixed with water (300 ml) and CH2C12 (300 ml) and the layers separated. The CH2C12 was washed with 10% aq. NaCl and dried (Na2S04). The solution was filtered and concentrated in vacuo to give crude product which was triturated with MeOH to yield 44.9 g (82% yield) of product.
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Introduction of Substituents at C2
The most versatile procedures for C2 substitution are based on lithiation, which is selective for C2 because of the influence of the heteroatom. 1-Alkyl-indoles such as 1-methylindole are readily lithiated and undergo typical reactions with electrophiles. For syntheses requiring iV-unsubstituted indoles, removable protecting groups are used. The most widely used are phenylsulf-onyl[l-3], tert-butoxycarbonyl[4] and carboxy[5]. For cases where protective groups must be removed under highly selective conditions, the l-(2-trimethyl-silylethoxymethyl) (SEM) group may be useful[6]. These groups can by introduced as described in the preceding chapter. The original procedure for lithiation of 1-phenylsulfonylindole used t-butyllithium because n-butyllithium caused competing reaction at the sulfonyl group[l]. Subsequently it was shown that LDA could readily effect lithiation[2,3]. More recently other workers have reported good results using n-butyllithium directly[7,8]. Lithiation of tert-butoxycarbonylindole is done using f-butyllithium in THF at — 78°C[4], The lithiocarboxy protecting group is introduced by allowing .V-lithioindole to react with solid C02 in THF. The salt is then lithiated at C2 with an equivalent of f-butyllithium[5].
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