O-Bromoaniline

Esters of indole-3-carboxylic acid can be made in two steps starting with an o-bromoaniline and an acrylate cstcr[2]. 

In a 600-ml. beaker fitted with a thermometer and mechanical stirrer are placed 150 ml. of concentrated hydrochloric acid and 55 g. (0.32 mole) of o-bromoaniline. After brief stirring, 100 g. of ice is added and the beaker is surrounded by an ice-salt bath. The solution is then diazotized by the dropwise addition with stirring of a solution of 24.3 g. (0.35 mole) of sodium nitrite in 100 ml. of water, the temperature being kept at 0-5°. 

A. o-Bromobenzenediazonium hexafluorophosphate. A solution of 95 ml. of 12N hydrocMoric acid in 650 ml. of water is added with stirring to 60 g. of o-bromoaniline (0.35 mole Note 1) in a 2-1. three-necked flask equipped with stirrer and thermometer. Solution is effected by heating the mixture on a steam bath (Note 2). A solution of 29 g. (0.42 mole) of sodium nitrite in 75 ml. of water is added with stirring while the mixture is maintained at — 5° to —10° by means of a bath of ice and salt or of dry ice and acetone. At the end of the addition there is an excess of nitrous acid, which can be detected with starch iodide paper. Seventy-four milliliters (134 g., 0.60 mole) of 65% hexafluorophosphoric acid (Note 3) is added in one portion, with vigorous stirring, to the cold solution of the diazonium salt. Cooling and slow stirring are continued for an additional 30 minutes, and the precipitated diazonium hexafluorophosphate is then collected on a Bilchner funnel. The diazonium salt is washed on the funnel with 300 ml. of cold water and with a solution of 80 ml. of methanol in 320 ml. 

The oil, which is heavier than water, is separated, and the aqueous layer is extracted with three 50-ml. portions of methylene chloride. The oil and extracts are combined, dried over anhydrous sodium sulfate, and distilled from a Claisen flask with an indented neck. Colorless l-bromo-2-fluorobenzene is collected at 58-59°/17 mm. or 156—157°/760 mm. weight 45-47 g. (73— 75% based on o-bromoaniline) d 1.5320-1.5325. 

Chlorobromobenzene has been prepared by the diazotiza-tion of o-bromoaniline followed by replacement of the diazonium group by chlorine 1 by the elimination of the amino group from 3-chloro-4-bromoaniline 2 by the chlorination of bromobenzene in the presence of thallous chloride,3 aluminum chloride,4 or ferric chloride 4 by the bromination of chlorobenzene without a catalyst6 or in the presence of aluminum,4 iron,4 or ferric bromide 6 by the diazotization of o-chloroaniline followed by replacement of the diazonium group with bromine 4,6 and from o-chlorophenylmercurie chloride by the action of bromine.7... 

A combination of organometallic procedures has been used in the design of a simple, efficient synthesis of 2-alkylindoles from o-bromoanilines.76 The arylamines are converted in reactions with 73-allylnickel dimers77 into 2-allylarylamines (36, Scheme 48) which can be cyclized in a separate step... 

Sakamoto described similar reactions of o-bromoaniline derivatives with (Z)-tributyl-2-ethoxyvinyltin and subsequent cyclization of the coupled product with TsOH to yield, for example, N-acetylindole (29% yield overall) [185], This research group also used this methodology to synthesize a series of azaindoles, an example of which is illustrated below [204]. Halonitropyridines were particularly attractive as coupling partners with tributyl-2-ethoxyvinyltin and precursors to azaindoles. Although the (Z)-isomer of 202 is obtained initially, it isomerizes to the ( )-isomer which is the thermodynamic product. This strategy represents a powerful method for the synthesis of all four azaindoles (l//-pyrrolopyridines). In fact, this method, starting with 2,6-dibromoaniline, is one of the best ways to synthesize 7-bromoindole (96% overall yield) [36]. 

A related Heck reaction of substituted o-bromoacetanilides with styrenes followed by selenium-induced cyclization of the resulting o-styiylacetanilides gives 2-arylindoles [378], Substituted o-bromonitrobenzenes react with ethyl vinyl ether under the influence of Pd(OAc)2 to give the corresponding o-ethoxyethenylnitrobenzenes. Zinc reduction then yields indoles [379]. The one-step Pd-catalyzed conversion of o-bromoanilines to indoles 302 with enamines (or with A/-vinyl-2-pyrrolidone) has been reported [380]. 

Similarly, benzene and hydrazoic acid in the presence of a mixture of fluorosulphonic and trifluoromethanesulphonic acid give aniline quantitatively. From toluene 100% of a mixture of o-, m- and p-toluidines is obtained and bromobenzene yields 42% o-bromoaniline and 47% p-bromoaniline, Butyl azide gives iV-butylarylamines under these conditions89. Photolysis of 1-aminoquinolinium perchlorate (76) in aromatic hydrocarbons (benzene, toluene, ethylbenzene or mesitylene) in the presence of 18-crown-6 affords arylamines, e.g. aniline and p-toluidine, by way of the nitrenium ion90 cf Reference 91. 

Bromochloroaniline, see o-Bromoaniline Bromochloromethane, see Dibromochloromethane Bromochloronaphthalene, see Naphthalene l-Bromo-3-chloropropan-2-one, see l,2-Dibromo-3-chloropropane... 

Diaminotoluene, see 2,6-Dinitrotoluene Diazoxon, see Diazinon Dibenzodioxin, see TCDD p,//-DDT Dibenzo[6,e][l,4]dioxin, see TCDD Dibenzophenone, see p,p -DDT Dibromoaniline, see o-Bromoaniline... 

A related scheme can be applied to indole synthesis, with the aromatization being the result of elimination of Pd(0) and a proton (equation 27) (76JA2674). This scheme has been put into practice for AT-alkyl-o-allylanilines, a few aryl-substituted analogs and methyl-substituted allyl groups. The requisite o-allylanilines were obtained from o-bromoanilines and allylnickel. Provided the requisite starting materials can be constructed, the mild conditions of this cyclization would seem to recommend it for sensitive molecules. 

Organometallic chemistry may provide another approach to cyclization of JV-allylanilines. The procedures developed to date require additional functionalization, specifically a halogen on the aromatic ring. Treatment of JV-allyl-Af-methyl-o-bromoaniline first with methylmag-... 

A limited number of reports of indoles arising from o-bromoaniline and enolates have appeared (equation 107) (80JOC1546,8lT(S9)393). The final cyclization step is of the condensation type already recognized in several other procedures. The inertness of unactivated halobenzenes, such as o-bromoaniline, requires an alternative to direct aromatic nucleophilic substitution and those cases where success has been reported depend upon photoinitiated substitution by an electron transfer process. The scope of this method remains to be explored but it appears that alkyl, alkoxy and carboxy groups can be tolerated on the aromatic ring. When the enolates are derived from an unsymmetrical ketone in which one group is methyl, there appears to be a preference for exclusive involvement of the less substituted enolate, leading to 2-alkylindoles. 

A recent procedure which utilizes the pivaloyl derivative of o-bromoaniline as one of the fragments is also a type llac approach. The compound is converted to its dilithio derivative at -78 °C. Reaction with a-halo ketones then affords indole hydrates by N-alkylation and reaction of the o-lithiated position with the carbonyl group dehydration subsequently yields indoles (equation 108) (81TL1475). The (V-trifluoroacetyl and N-t-butoxycarbonyl derivatives of o-bromoaniline exhibit similar reactivity. 

No practical type B syntheses of quinoxalines are commonly in use, largely because of the fact that type A syntheses are more facile however, some phenazine syntheses of this type are known, particularly those described in the older chemical literature. Hillemann (38CB42) has effected dimerization of o -bromoaniline by heating its solution in nitrobenzene with K2C03 and copper powder. The reaction is believed to proceed through the intermediacy of 5,10-dihydrophenazine, but the latter has not been isolated (Scheme 68). 

The synthesis of a number of substituted thioureides by treatment of isothiocyanates 2 and 30-32 with aniline, 2-aminopyridine, 1-adamantyl-amine, benzylamine, 2-aminobenzimidazole, 2-aminobenzothiazole, o-bromoaniline, 2-aminopyridine, 5-amino-1 -phenylpyrazole-4-carboxylic acid, and various classes of sulfamines, in benzene or xylene solution, has been reported.54... 

Intramolecular vinyl substitutions are commonly used to form cyclic products. In a typical reaction, p-in-doleacetic acid has been prepared in up to 43% yield from an o-bromoaniline derivative, as shown in equation (23).74... 

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