pHarmacist (Hive Bee)
12-29-02 08:04
No 393845
      Indoles from 2-methylnitrobenzenes  Bookmark   

This might be especially usefull for the prep. of 4-subst indoles that there has been much talk about lately:



Procedure

A. 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∼C 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 ℅ 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∼C affords 177.6 (90%) of 6-benzyloxy-2-nitrotoluene as pale-yellow crystals, mp 61每63∼C3 (Note 2).
B. (E)-6-Benzyloxy-2-nitro-汕-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∼C) 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∼C. Filtration and washing of the filtercake with 200 mL of cold methanol affords 209.8 g of red crystals, mp 87每89∼C (Note 6). The mother liquors are evaporated, and the residue is recrystallized from 50 mL of methanol (5∼C) to give an additional 12.30 g of red solid, mp 81每83∼C (Note 7). Thus the total yield is 222.1 g (95%) of a 15 : 1 mixture of (E)-6-benzyloxy-2-nitro-汕-pyrrolidinostyrene (Note 8) and (E)-6-benzyloxy-汕-dimethylamino-2-nitrostyrene.
C. 4-Benzyloxyindole. To a stirred solution of 162.2 g (0.50 mol) of (E)-6-benzyloxy-2-nitro-汕-pyrrolidinostyrene (Note 9) in 1 L of THF and 1 L of methanol at 30∼C 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∼C. 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∼C 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每230-mesh, Merck) prepared in the same solvent. Elution with 6.0 L of toluene每cyclohexane (1 : 1) followed by 3 L of toluene每cyclohexane (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每62∼C (Note 14).

http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?rxntypeid=30&prep=CV7P0034



"Turn on, Tune in and Drop Out"
 
 
 
 
    flipper
(Hive Bee)
12-29-02 13:15
No 393937
      indole  Bookmark   

SWIM had a question. If you use methylaniline (without the nitro group). Can Indole be synthesized in a good yield instead of Nitroindole.

Organic Syntheses, CV 8, 493



1. Procedure
A. Ethyl N-(2-methyl-3-nitrophenyl)formimidate. A 1-L, one-necked, round-bottomed flask, fitted with a Claisen condenser protected from moisture with a drying tube, is charged with 200 g (1.35 mol) of freshly distilled triethyl orthoformate, 1 g of p-toluenesulfonic acid and 152 g (1 mol) of 2-methyl-3-nitroaniline (Note 1) and (Note 2). The solution is heated to 120蚓 and all of the ethanol formed is continuously distilled off during ca. 1 hr. Fractional vacuum distillation of the residue gives at 156158蚓/6 mm, the imidate ester, 184 g (88%), as a light-yellow, solidifying oil, mp 5758蚓.
B. 4-Nitroindole. To a solution of 22 g (0.15 mol) of diethyl oxalate in 50 mL of dry dimethylformamide in a 200-mL beaker is added, under cooling, 11 g (0.13 mol) of potassium ethoxide with vigorous stirring (Note 3) and (Note 4). The solution is immediately (within a few seconds) poured into a 250-mL flask containing a solution of 20.8 g (0.10 mol) of ethyl N-(2-methyl-3-nitrophenyl)formimidate in 75 mL of dry dimethyl sulfoxide (Note 5). The resulting deep-red solution is stirred for 1 hr at ca. 40蚓 (Note 6) and (Note 7). The solution is then transferred into a 1-L beaker and water is added under stirring at a rate that gives smooth precipitation of 4-nitroindole. The product is filtered off and dried, giving 16.3 g (ca. 100%) of a brownish-yellow solid, mp 195201蚓 [sublimation (subl.)], which is sublimed at 170蚓/0.5 mm giving 11.5 g (71%) of yellow crystals, mp 204205蚓 (subl.) (Note 8).

 
 
 
 
    flipper
(Hive Bee)
12-30-02 03:50
No 394141
      indole  Bookmark   

Can this be done without the phenyl group so you make just Indole?



1. Procedure
In a tall 1-l. beaker is placed an intimate mixture of 53 g. (0.25 mole) of freshly prepared acetophenone phenylhydrazone (Note 1) and 250 g. of powdered anhydrous zinc chloride (Note 2). The beaker is immersed in an oil bath at 170, and the mixture is stirred vigorously by hand. The mass becomes liquid after 34 minutes, and evolution of white fumes begins. The beaker is removed from the bath, and the mixture is stirred for 5 minutes. In order to prevent solidification to a hard mass, 200 g. of clean sand is thoroughly stirred into the reaction mixture. The zinc chloride is dissolved by digesting the mixture overnight on the steam cone with 800 ml. of water and 25 ml. of concentrated hydrochloric acid (sp. gr. about 1.2). The sand and crude 2-phenylindole are removed by filtration, and the solids are boiled with 600 ml. of 95% ethanol. The hot mixture is decolorized with Norit and filtered through a hot 10-cm. Bchner funnel, and the sand and Norit are washed with 75 ml. of hot ethanol. After the combined filtrates are cooled to room temperature, the 2-phenylindole is collected on a 10-cm. Bchner funnel and washed three times with small amounts (1520 ml.) of cold ethanol. The first crop is quite pure; after drying in a vacuum desiccator over calcium chloride it weighs 3033 g. and melts at 188189 (cor.) (Note 3) and (Note 4).
A little Norit is added to the combined filtrate and washings, which are then concentrated to a volume of 200 ml. and filtered. The filtrate, on cooling, deposits a second crop of 56 g. (Note 5) of impure product, which melts at 186188. The total yield of 2-phenylindole is 3539 g. (7280%).

Organic Syntheses, CV 3, 725 (http://www.orgsyn.org/orgsyn/prep.asp?prep=cv3p0725)