This might be especially usefull for the prep. of 4-subst indoles that there has been much talk about lately:
ProcedureA. 6-Benzyloxy-2-nitrotoluene. A stirred mixture of 124.7 g (0.81 mol) of 2-methyl-3-nitrophenol (Note 1), 113.2 g (0.90 mol) of benzyl chloride, 112.2 g (0.81 mol) of anhydrous potassium carbonate, and 800 mL of dimethylformamide (DMF) is heated at 90¡ãC for 3 hr. Most of the DMF is removed on a rotary evaporator (20 mm) and the oily residue is poured into 400 mL of 1 N sodium hydroxide and extracted with ether (3 ¡Á 800 mL). The combined extracts are dried (Na2SO4), filtered, and evaporated to give 203.5 g of yellowish solid. Recrystallization from 1 L of methanol cooled to 0¡ãC affords 177.6 (90%) of 6-benzyloxy-2-nitrotoluene as pale-yellow crystals, mp 61¨C63¡ãC3 (Note 2).
B. (E)-6-Benzyloxy-2-nitro-¦Â-pyrrolidinostyrene. To a solution of 175.4 g (0.72 mol) of 6-benzyloxy-2-nitrotoluene in 400 mL of DMF are added 102.5 g (0.84 mol) of N,N-dimethylformamide dimethyl acetal (Note 3) and 59.8 g (0.84 mol) of pyrrolidine. The solution is heated at reflux (110¡ãC) for 3 hr (Note 4) under nitrogen and allowed to cool to room temperature. The volatile components are removed on a rotary evaporator, and the red residue (Note 5) is dissolved in 200 mL of methylene chloride and 1.60 L of methanol. The solution is concentrated to a volume of about 1.40 L on the steam bath and then is cooled to 5¡ãC. Filtration and washing of the filtercake with 200 mL of cold methanol affords 209.8 g of red crystals, mp 87¨C89¡ãC (Note 6). The mother liquors are evaporated, and the residue is recrystallized from 50 mL of methanol (5¡ãC) to give an additional 12.30 g of red solid, mp 81¨C83¡ãC (Note 7). Thus the total yield is 222.1 g (95%) of a 15 : 1 mixture of (E)-6-benzyloxy-2-nitro-¦Â-pyrrolidinostyrene (Note
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and (E)-6-benzyloxy-¦Â-dimethylamino-2-nitrostyrene.
C. 4-Benzyloxyindole. To a stirred solution of 162.2 g (0.50 mol) of (E)-6-benzyloxy-2-nitro-¦Â-pyrrolidinostyrene (Note 9) in 1 L of THF and 1 L of methanol at 30¡ãC under nitrogen is added 10 mL of Raney nickel (Note 10) followed by 44 mL (0.75 mol) of 85% hydrazine hydrate. Vigorous gas evolution is observed. The red color turns to dark brown within 10 min, and the reaction temperature rises to 46¡ãC. An additional 44 mL of 85% hydrazine hydrate is added after 30 min and again 1 hr later. The temperature is maintained between 45 and 50¡ãC with a water bath during the reaction and for 2 hr after the last addition. The mixture is cooled to room temperature and the catalyst is removed by filtration through a bed of Celite (Note 11) and is washed several times with methylene chloride. The filtrate is evaporated and the residue dried by evaporating with 500 mL of toluene. The reddish residue (118.5 g), dissolved in ca. 1 L of toluene-cyclohexane (1 : 1), is applied to a column of 500 g of silica gel (70¨C230-mesh, Merck) prepared in the same solvent. Elution with 6.0 L of toluene¨Ccyclohexane (1 : 1) followed by 3 L of toluene¨Ccyclohexane (1 : 2) affords 108.3 g of white solid, which is crystallized from 150 mL of toluene and 480 mL of cyclohexane (Note 12). A total of 107.3 g (96% yield) of 4-benzyloxyindole (Note 13) is obtained in three crops as white prisms, mp 60¨C62¡ãC (Note 14).
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