N-Ethyl-/>-chloroaniline

The submitters distilled the product through the 30-cm. packed column which was wrapped with a heating tape for this purpose. If this is done, there are collected about 20 g. of recovered triethyl orthoformate at 65-67°/40 mm. and about 2 g. of ethyl N-/>-chlorophenylformimidate at 82-83°/40 mm., followed by the product, which has n2 1.5559. The checkers obtained the same results when this distillation was carried out through a fractionating column however, the yield and properties of N-ethyl- -chloroaniline obtained from this material were the same as those of amine obtained from material distilled through a Claisen head. 

N-Ethyl-/>-chloroaniline has been prepared by alkylation of / -chloroaniline with ethyl bromide 4 5 and by reduction of aceto-/-chloroanilide with lithium aluminum hydride.6 The present procedure, which is based on the results of an investigation by Roberts and Vogt,3 is a convenient general method for preparation of pure N-alkyl aromatic amines. 

B. N-Ethyl-p-chloroaniline. In a 500-ml. round-bottomed flask are placed 70 g. (0.38 mole) of N-ethyl-/>-chloroformanilide and 170 ml. of 10% hydrochloric acid. The mixture is heated under reflux for 1 hour, cooled, then neutralized, and finally made basic with 15% potassium hydroxide solution. The lower layer of N-ethyl- -chloroaniline is separated, and the aqueous layer is saturated with potassium carbonate and extracted with two 200-ml. portions of ether. The ether extracts are combined with the bulk of the product, washed with two 100-ml. portions of water, and then dried over calciiun chloride. After the ether has been removed by distillation, the residue is distilled at reduced pressure from a 125-ml. Claisen flask. N-Ethyl- -chloroaniline is collected at 108-110°/5 mm. or 149-150°/40 mm., 1.5650-1.5661, weight 52-55 g. (87-92%) (Note 5). 

Anthracene Anthranilic acid Anthraquinone Antimony pentachloride Benzaldehyde Benzidine dihydrochloride 2,2 -Benzidinedisulfonic acid Benzoguanamine Benzotrifluoride Benzoyl chloride N-Benzylamine N-Benzyl-N-ethyl-m-toluidine Bisphenol A Bromine 4-Bromochloro benzene Butyl acetoacetate n-Butylamine t-Butylamine Ceteareth-15 o-Chloroaniline p-Chloroaniline m-Chlorobenzoic acid o-Chlorobenzoic acid p-Chlorobenzoic acid m-Chlorobenzotrifluoride o-Chlorobenzotrifluoride p-Chlorobenzotrifluoride Chloroform 4-Chloro-2-nitroaniline 2-Chloronitrobenzene... 

Creosol, 33, 17 Crotonaldehyde, 33, IS 34, 29 diethyl acetal, 32, 5 Cupric acetate monohydrate, 36, 77 Cuprous oxide-silver oxide, 36, 36, 37 Cyanamide, 34, 67 36, 8 Cyanoacetamide, 32, 34 Cyanoacetic acid, 31, 25 Cyanoacetylurea, 37, 16 >-Cyanobenzaldehyde, 30, 100 >-Cyanobenzaldiacetate, 36, 59 3-Cyano-5,6-dimethyl-2(l)-pyridone, 32,34 N-2-Cyanoethylaniline, 36, 6 N-2-Cyanoethyl- -anisidine, 36, 7 Cyanoethylation, of aniline, 36, 6 of ethyl phenylcyanoacetate, 30, 80 N-2-Cyanoethyl-m-chloroaniline, 36, 7 Cyanogen, 32, 31 Cyanogen iodide, 32, 29 Cyanogen iodide, complex with sodium iodide, 32, 31... 

Snyder and Jones obtained ethyl N-(3-chlorophenyl)aminomethyl-enemalonamate (244) in 77% yield when 2 mol of 3-chloroaniline was reacted with 1 mol of diethyl malonate and 1 mol of ethyl orthoformate at 160-165°C. The ethanol formed during the reaction was distilled off (46JA1253). 

Egri et al. investigated the one-pot synthesis of N-(3-chlorophenyl)-aminomethylenemalonate (250), starting from equimolar amounts of 3-chloroaniline, diethyl malonate, and ethyl formimidate hydrochloride or ethyl orthoformate (73ACH217). The reaction involving ethyl formimidate hydrochloride was conducted in the presence of triethylamine at 120-130°C for 2 hr and then at 140°C for 80 hr. The ethanol formed in the reaction was continuously distilled off. N-(3-Chlorophenyl)aminomethyl-enemalonate (250) was obtained in 98-99% yields. 

AM3-Chlorophenyl)aminomethylenemalonate (250) was obtained in pure form in 94% yield when /V,A, -bis(3-chlorophenyl)formamidine (248) (1 mol), diethyl malonate (I mol), and ethyl orthoformate (1.2 mol) were reacted for 20 hr at 126°C, the ethanol evolved being continuously distilled off. More diethyl malonate (1 mol) was then added to the half-converted reaction mixture, and the reaction mixture was stirred at 126°C for 48 hr (65MIP1 66JOC4003). Under these conditions, the formation of N- 3-chlorophenyl)aminomethylenemalonamate (252, R = 3-C1) could be excluded because the 3-chloroaniline formed in the reaction of amidine and malonate was simultaneously converted to amidine by ethyl orthoformate. 

The establishment of the stereocenter in efavirenz provides a challenging goal for the synthetic chemist (Pierce et al., 1998 Thompson et al., 1995). The synthesis starts by treating 4-chloroaniline with pivaloyl chloride under biphasic conditions to provide the desired amide 10 (Scheme 6.2). Ortho metallation as directed by the amide is accomplished with two equivalents of n-butyllithium (or w-hexyllithium) in tetramethylethylene diamine (TMEDA) and MTBE. The resulting dianion is quenched with ethyl trifluoroacetate to provide pivaloylamide ketone 11 (Euhrer and Gschwend, 1979). The amide is hydrolyzed in situ to provide the trifluoroketone hydrate hydrochloride 12, which crystallizes from the reaction mixture (>98% pure). 

N-2-Cyanoethylaniline, 36, 6 N-2-Cyanoethyl-/>-anisidine, 36, 7 Cyanoethylation, of aniline, 36, 6 of o-chloroaniline, 38,14 of ethyl phenylcyanoacetate, 30, 80 N-2-Cyanoethyl-ftt-chloroaniline,... 

N,N -Bis(0-cMorophenyl)fonnamidine 810 Ethyl orthoformate (104 g, 0.7 mole) and o-chloroaniline (179 g, 1.4 moles) are placed in a 500-ml flask under an externally heated, filled column (about 40 cm long). The flask is heated for 1.5 h in a bath at 145° while the column is kept at 90-100°. The bath temperature is then raised to 180° for 0.5 h, which should complete the distillation of the ethanol released. The contents of the flask must then be poured rapidly into a porcelain dish as they quickly solidify on cooling. This gives a crude product of m.p. 137-141° in almost quantitative yield. Recrystallization from dry benzene gives colorless prisms (150 g, 81 %), m.p. 139-141°. 

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