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10.1 ALKYLATION AND HYDROXYALKYLATION
Lithiated indoles can be alkylated with primary or allylic halides and they react with aldehydes and ketones by addition to give hydroxyalkyl derivatives. Table 10.1 gives some examples of such reactions. Entry 13 is an example of a reaction with ethylene oxide which introduces a 2-(2-hydroxyethyl) substituent. Entries 14 and 15 illustrate cases of addition to aromatic ketones in which dehydration occurs during the course of the reaction. It is likely that this process occurs through intramolecular transfer of the phenylsulfonyl group.
Synthetic procedures involving other types of intermediates can be based on
2-lithiation. An indirect 2-alkylation can be carried out via indol-2-ylborates which can be prepared by addition of 2-lithioindoles to trialkylboranes.
10 INTRODUCTION OF SUBSTITUENTS AT C2
Treatment of the borates with iodine leads to boron ->C2 migration of an alkyl group. This reaction has not been widely applied synthetically but it might be more applicable for introduction of branched alkyl groups than direct alkylation of an indol-2-yllithium intermediate.
Alkylation and hydroxalkylation of 2-lithioindoles
Entry Substituents Electrophile Yield (%) Ref.
1 1 -(Phenylsulfonyl)-2-raethyl CH3I 85 
2 l-Carboxy-2-methyl CH3I 68 
3 2-(4-Bromobutyl)-l-(phenylsulfonyl) Br(CH2)4Br 76 
4 2-(£,£-Farnesyl)-l-phenylsulfonyl £,£-Farnesyl bromide 70 
5 l-(Phenylsulfonyl)-2-( 1 -hydroxyethyl) CH 3CH—О 93 
6 l-(Phenylsulfonyl)-2-[hydroxy- 4-Methoxybenzalde- 65 
7 l-(Phenylsulfonyl)-2-[hydroxy- Pyridine-2-carboxalde- 32 
8 l-(Phenylsulfonyl)-2-[ 1 -hydroxy- Ethyl phenyl ketone na 
9 l-Carboxy-2-[hydroxy(4-methoxy- 4-Methoxybenzalde- 72 
10 l-(Phenylsulfonyl)-2-[l-hydroxy- Methyl pyruvate 64 
11 l-(Dimethylaminomethyl)-2- Benzaldehyde 77 
12 2-[l-[3-(t-Butoxycarbonyl)-2,2- 3-(t-Butoxycarbonyl)- 71“ 
dimethyloxazolidin-4-yl)] -1 - 2,2-dimethyloxa-
hydroxyraethyl]-1 -(phenylsulfonyl) zolidine-4-carboxal-
13 2-(2-Hydroxyethyl)-l-(phenylsulfonyl) Ethylene oxide 69 
14 2-(2-Methyl-1-phenylpropenyl) lsobutyrophenone 68 
15 2-(2-Methylphenyleihenyl) o-Methylacetophenone 33 
aProduci is a 4:1 mixture of stereoisomers.
10.1 ALKYLATION AND HYDROXYALKYLATION
Indol-2-ylcopper reagents can also be prepared from 2-lithioindoles and they have some potential for the preparation of 2-substituted indoles. 1-Methyl-indol-2-ylcopper can be prepared by reaction of 2-lithio-l-methylindole with CuBr. It reacts with aryl iodides to give 2-aryl-l-methylindoles. Mixed cyanocuprate reagents can be prepared using CuCN[ll], The cyan-ocuprate from 1-methylindole reacts with allyl bromide to give 2-allyl-l-methylindole.
A solution of 2-lithio-l-(phenylsulfonyl)indole was prepared by adding 1-(phenylsulfonyl)indole (11.7 mmol) dissolved in THF (30 ml) to a solution of LDA prepared from (i-Pr)2NH (1.12 eq) and n-BuLi (1.05 eq) in THF (30 ml) at — 75°C. The solution was stirred at — 70°C for 1 h and then warmed slowly to 5DC over 1 h. The solution was recooled to — 78JC. A solution of acetalde-hyde (1.00 g, 22.7 mmol) in THF (5 ml) was added rapidly by syringe. The reaction mixture was then allowed to come slowly to room temperature and poured into 1% HC1 (350 ml). The solution was extracted with CH,C12 (3 x 250 ml) and the combined extract was washed with water (400 ml) and brine (2 x 400 ml) and then dried over K2C03. The solvent was evaporated in vacuo and the residue purified by chromatography to give the product (3.28 g, 93%).
Methyl г-hydroxy-y. methyl-1 -(phenylsulfonyl)indole-2-acetate[13, as subsequently modified]
Dry THF (150 ml) was added to a flame-dried flask protected from the atmosphere and (/-Pr),NH (10.2 ml, 0.073 mol) was added. The flask was cooled to 0C using an ice-bath. n-Butyllithium (0.068 mol) was added as a hexane solution and the solution stirred at 0°C for 30 min. The solution was then cooled to — 78°C. A solution of 1-(phenylsulfonyl)indole (14.0g, 0.055 mol) was dissolved in THF (50 ml) and cooled to — 78°C. The indole solution was cannulated into the LDA solution over 15-20 min and the mixture stirred at -78°C for an additional 45 min. The solution was then
10 INTRODUCTION OF SUBSTITUENTS ЛТ C2
brought to 0°C and stirred for 1 h before being recooled to — 78CC. A solution of methyl pyruvate (14.7 ml, 0.163mol) was dissolved in THF (50 ml) and cannulated into the solution of 2-lithio-l-(phenylsulfonyl)indole over a period of 15-20min. The solution was stirred at — 78CC for 30min and then allowed to come gradually to room temperature over 2 h. The reaction mixture was poured into sat. NH4C1 (400 ml) and the phases separated. The aqueous phase was extracted further with ether (3 x 150 ml). The original organic phase was washed with water (3 x 150 ml) and the organic phases combined and dried (MgS04). The solvent was removed in vacuo. The residual oil was crystallized by trituration with ether to give 14.3 g (73%) of product.