2-Chloro-4,6-dimethylaniline

Ring closure of 2-chloro-l-phenethylpyridinium ion (247) (prepared in situ) to l,2-dihydro-3,4-benzoquinolizium ion involves intramolecular nucleophilic displacement of the chloro group by the phenyl 77-electrons. A related intermolecular reaction involving a more activated pyridine ring and more nucleophilic 7r-electrons is the formation of 4-( -dimethylaminophenyl)pyridine (and benzaldehyde) from dimethylaniline and 1-benzoylpyridinium chloride (cf. Section III,B,4,c). 

The common hydroxylic chlorinating agents were not particularly successful in transforming the 3-hydroxy derivative of 136 into its 3-chloro derivative. Yields with phosphoryl chloride and dimethylaniline only reached 15% (66JOC265). 

Phosphoryl chloride and dimethylaniline converted the pyridoazepinone (227) into its 9-chloro derivative. The corresponding 7-oxo derivative reacted similarly, but thiones were unaffected [86JCR(S)204]. 

It is prepd by the action of methylamine on 4-chloro-l-nitrobenzene (Ref 5) by the action of methyl iodide (Ref 6), or methyl sulfate on 4-nit roaniline (Ref 7) or by the hydrolysis of 4-nitro-N-methylformanilide with hot coned aq HC1 (Ref 8). In a study of the effect of nitric acid concn on the prods of the nitration of N,N-dimethylaniline to form Tetryl, it was isolated in low yield by the action of nitric acid, d 1.046g/cc, plus Na nitrite on N,N-dimethylaniline (Ref 10). A eutectic mixt with N-ethyl-4-nitroaniline has been patented as a stabilizer for NC (Ref 12). Studies at NPF indicate that 4-nitro-N-methyl-aniline is superior to Centralite, 2-nitrodiphenyl-amine, or Acardite in stabilizing. NC Refs 1) Beil 12, 586, (295) 1125 ... 

Dimethylaniline (h/ f 5-10), 4-chloroaniline (h/if 10-15), 3-chloroaniline hRf 20-25), 4-chloro-2-nitroaniline (bRf 30-35), 2-chloroaniline (hRf 35-40) and diphenyl-amine (hRf 70-75) appeared as yellow chromatogram zones on a pale yellow background. The detection limits were between 4 ng (4-chloroaniline) and 20 ng (diphenyl-amine) substance per chromatogram zone. 

Fig. 1 Reflectance scan of a chromatogram track with 200 ng 2,3-dimethylaniline (1), 100 ng each of 4-chloro-2-methylamline (2), 3,4-dichloroaniline (3), 3,S-dichloroaniline (4) and 200 ng each of 2,3-dichloroaniline (S) and 2,S-dichloroaniline (6) per chromatogram zone.

After a few minutes 2,4-diamino-6-methylphenol (hRf 5-10), 3-chloro-4-methoxy-aniline (hJ f 25-30), aniline (hRf 35-40), 4-bromoaniline (hRf 40-45), 3-chloroaniline (hJ f 50-55), 2,6-dimethylaniline (hi f 60-65), 2-methyl-6-ethylaniline (hi f 65-70) and 2-chloroaniline (hRj 70-75) yielded orange-colored chromatogram zones on a yellow background. The detection limits were between 5 ng (2,4-diamino-6-methylphenol) and 30 ng (2,6-dimethylaniline) substance per chromatogram zone. 

Fig. 1 Reflectance scans of a chromatogram track with 100 ng each of 1 = 2,4-diamino-6-methylphenol, 2 = 3-chloro-4-methoxyaniline, 3 = aniline, 4 = 4-bromoaniline, 5 = 3-chloro-aniline, 6 = 2,6-dimethylaniline, 7 = 2-methyl-6-ethylaniline and 8 = 2-chloroaniline.

In a similar way, numerous P-chloroalkylphosphonic acids undergo fast and quantitative hydrolysis at pH > 5 94). A typical example is the fragmentation of 2-chloro-decyl-l-phosphonic acid in the presence of cyclohexylamine with formation of 1-decene (in contrast, other bases such as pyridine, triethylamine, and dimethylaniline effect only HC1 elimination to form 1-decene-l-phosphonic acid). Added alcohols, such as ethanol, allyl alcohol, cyclohexanol, tert-butanol, and phenol are phosphorylat-ed. 

Fig. 3.61. HPLC-UV chromatogram at 230 nm for the analysis of the aromatic amines listed. (1) 1,4-Diaminobenzene (2) 2-chloro-l,4-diaminobenzene (3) 2,4-diaminotoluene (4) benzidine (5) 4,4 -oxidianiline (6) aniline and 4-nitroaniline (7) o-toluidine (8) 4,4 -methylenedianiline (9) 3,3 -dimethoxibenzidine (10) 3,3 -dimethylbenzidine (11) 4-chloroaniline and 2-amino-4-nitrotoluene (12) 4,4 -thiodianiline (13) p-cresidine (14) 2,4-dimethylaniline (15) 2-naphty-lamine (16) 4-chloro-o-toluidine (17) 4,4 -methylene-di-o-toluidine (18) 2,4,5-trimethylaniline (19) 4-aminobiphenyl (20) 3,3 -dichlorobenzidine (21) 4,4 -methylenbis (2-chloroaniline) and (22) o-aminoazotoluene. Reprinted with permission from M. C. Garrigos et al. [130].

Carbon tetrachloride. Chloroform, 2-Chlorophenol, Cyclohexanol, Cyclopentene, 1,1-Dichloroethylene, irans-l, 2-Dichloroethylene, IV.yV-Dimethylaniline, lV,lV-Dimethylformamide, 2,4-Dimethylphenol, 2,4-Dinitrotoluene, 1,4-Dioxane, 1,2-Diphenylhydrazine, Ethyl formate. Formaldehyde, Glycine, Methanol, Methylene chloride. Methyl formate, 2-Methvlphenol. Monuron, 4-Nitrophenol, Oxalic acid, Parathion, Pentachlorophenol, Phenol, l idine. Styrene, Trichloroethylene, Vinyl chloride Formylacetic acid, see cis-l,3-Dichloropropylene, irans-1,3-Dichloropropylene IV-Formylcarbamate of 1-naphthol, see Carbaryl Formyl chloride, see Chloroethane, Chloroform, sym-Dichloromethyl ether, ds-1,3-Dichloropropylene, irans-ES-Dichloropropylene, Methyl chloride. Methylene chloride. Trichloroethylene, Vinyl chloride lV-Formyl-4-chloro-o-toluidine, see Chlornhenamidine. 

A more promising approach to a synthesis of vinblastine-type compounds can be derived from the significant observation that reaction of one enantiomer of the carboline ester (-l- )-38 with p-nitrobenzyl chloro-formate and 3-methoxy-A/, A-dimethylaniline, at 25°C, gave a model (-t-)-congener of 39 in 72% yield and 55% enantiomeric excess, thus indicating a conformational retention in the nine-membered cationic intermediate formed on acylation of the carboline ester 38 (37b). 

Lidocaine Lidocaine, 2-(diethylamino)-A-(2,6-dimethylphenyl)acetamide (2.2.2), is synthesized from 2,6-dimethylaniline upon reaction with chloroacetic acid chloride, which gives a-chloro-2,6-dimethylacetanilide (2.1.1), and its subsequent reaction with diethy-lamine [11]. 

Flucytosine Flucytosine, 5-fluorocytosine (35.4.4), is synthesized from fluorouracil (30.1.3.3). Fluorouracil is reacted with phosphorous oxychloride in dimethylaniline to make 2,4-dichloro-5-fluoropyrimidine (35.4.2), which is reacted with ammonia to make a product substituted with chlorine at the fourth position of the pyrimidine ring—4-amino-2-chloro-5-fluoropyrimidine (35.4.3). Hydrolysis of the chlorovinyl fragment of this compound in a solution of hydrochloric acid gives the desired flucytosine [52-55]. 

DinitTO-l,3-(diamino-N,N,N, N -tetra-methyl)-benzene, yel nds (from chlf + ale), mp 191° sol in chlf si sol in hot ale was prepd by heating l,3-dinitro-4,6-dichlorobenzene with dimethylaniline in ale or from 2,4-dinitro-5-chloro-N,N- iimethylani-line 8c NH(CH3)2 (Ref 2)... 

The unusual formation of N,N-dimethylaminophenyl substituted pyrimido[4,5-c]-pyridazines (74) by the reaction of the oxo compound (73) with phosphorus oxychloride and iV,AT-dimethylaniline has been reported (71CPB1849). The chlorination of other oxo substituted pyrimido[4,5-c]pyridazines with phosphorus oxychloride has been reported to be unsuccessful. Chloro derivatives of this heterocyclic ring undergo nucleophilic displacement with amines and hydrazine to give the corresponding amino and hydrazino substituted products. The catalytic dechlorination of these chloro substituted heterocycles has also been reported (68JHC523). 

The usual procedure for the preparation of benzo[6]thiophene- 2,3-quinones, which involves acidic hydrolysis of an anil obtained from a thioindoxyl and an aromatic nitroso compound (usually p-nitroso-iV,iV-dimethylaniline), has been used to prepare 5-methyl-,625 5-chloro-,117 and 5- and 6-nitrobenzo[h]thiophene-2,3-quinone.626... 

---