Arylamines preparation

Figure 2.6 Pharmaceutically attractive aminodi(hetero)arylamines prepared using the Buchwald-Hartwig reaction as reported by Queiroz and coworkers [33].

Arylamines are generally prepared by the reduction of nitro compounds. When only small quantities are to be reduced and the time element is important and cost is a secondary consideration, tin and hydrochloric acid may be employed, for example ... 

Aryl and alkenyl phenyl sulfides are prepared by the reaction of aryl and alkenyl halides and inflates with tributylstannyl phenyl sulfide. 2-Chloropyrimidine (737) is used for the coupling[606,607]. The diaryl or divinyl sulfide 739 is prepared by the reaction of distannyl sulfide (738)[548], N,N-Diethylaminotributyltin (740) reacts with aryl halides to give arylamines[608]. 

Nitro groups are readily reduced to primary amines by a variety of methods Cat alytic hydrogenation over platinum palladium or nickel is often used as is reduction by iron or tin m hydrochloric acid The ease with which nitro groups are reduced is especially useful m the preparation of arylamines where the sequence ArH ArN02 ArNH2 IS the standard route to these compounds... 

Aryl diazonium ions prepared by nitrous acid diazotization of primary arylamines are substantially more stable than alkyl diazonium ions and are of enormous synthetic value Their use m the synthesis of substituted aromatic compounds is described m the following two sections... 

Reduction of aryl nitro compounds (Sec tion 22 9) The standard method for the preparation of an arylamine is by nitra tion of an aromatic ring followed by reduction of the nitro group Typical re ducing agents include iron or tin in hydro chloric acid or catalytic hydro genation... 

Monoureas can also be prepared using COS and an alkylamine, or an arylamine in the absence or presence of a catalyst, where R = H, alkyl, or aryl (39) ... 

In the ketone method, the central carbon atom is derived from phosgene (qv). A diarylketone is prepared from phosgene and a tertiary arylamine and then condenses with another mole of a tertiary arylamine (same or different) in the presence of phosphoms oxychloride or zinc chloride. The dye is produced directly without an oxidation step. Thus, ethyl violet [2390-59-2] Cl Basic Violet 4 (15), is prepared from 4,4 -bis(diethylamino)benzophenone with diethylaruline in the presence of phosphoms oxychloride. This reaction is very useful for the preparation of unsymmetrical dyes. Condensation of 4,4 -bis(dimethylamino)benzophenone [90-94-8] (Michler s ketone) with AJ-phenjl-l-naphthylamine gives the Victoria Blue B [2580-56-5] Cl Basic Blue 26, which is used for coloring paper and producing ballpoint pen pastes and inks. 

In a variation of this method, isolation of the ben2hydrol derivative is not required. The methane base undergoes oxidative condensation in the presence of acid with the same or a different arylamine direcdy to the dye. New fuchsine [3248-91 -7] Cl Basic Violet 2 (16), is prepared by condensation of two moles of o-toluidine with formaldehyde in nitrobenzene in the presence of iron salts to give the corresponding substituted diphenylmethane base. This base is also not isolated, but undergoes an oxidative condensation with another mole of o-toluidine to produce the dye. 

BenZotrichloride Method. The central carbon atom of the dye is supphed by the trichloromethyl group from iJ-chlorobenzotrichloride. Both symmetrical and unsymmetrical triphenyhnethane dyes suitable for acryhc fibers are prepared by this method. 4-Chlorobenzotrichloride is condensed with excess chlorobenzene in the presence of a Lewis acid such as aluminium chloride to produce the intermediate aluminium chloride complex of 4,4, 4"-trichlorotriphenylmethyl chloride (18). Stepwise nucleophihc substitution of the chlorine atoms of this intermediate is achieved by successive reactions with different arylamines to give both symmetrical (51) and unsymmetrical dyes (52), eg, N-(2-chlorophenyl)-4-[(4-chlorophenyl) [4-[(3-methylphenyl)imino]-2,5-cyclohexadien-l-yhdene]methyl]benzenaminemonohydrochloride [85356-86-1J (19) from. w-toluidine and o-chloroaniline. 

The anhydrosulfides are useful in the preparation of thionocarbamate, eg, by heating with an alcohoHc solution of the arylamine ... 

Cl Acid Gieen 25 [4403-90-1] (3) (Cl 61570) was also invented in 1894. This dye shows improved wetfastness, and is prepared from leucoquinizarin by reaction with 2 moles of i)-toluidine in a similat manner to the preparation of Cl Acid Violet 43 (134). Wetfastness and leveling properties may be altered by choosing the substituents of arylamines. The introduction of alkyl groups into aromatic amines improves the wetfastness and affinity in neutral or weekly acid baths. Examples ate Cl Acid Blue 80 [4474-24-27] (131) (Cl 61585) and Cl Acid Gieen 27 [6408-57-7] (132) (Cl 61580). 

Aryl isothiocyanates can be prepared by the action of thio-phosgene on the arylamine (this reaction fails with naphthyl compounds), by fission of a 5ym-diaryIthiourea with acidic reagents (this reaction involves the loss of half the amine used), and by the decomposition of an ammonium aryldithiocar-bamate (low yields are reported for naphthyl and other compounds).The procedure described here is that of Baxter, Cymerman-Craig, Moyle, and White. ... 

Another short protocol for preparation of 3 was recently presented by Knolker and Reddy, who devised a short sequence involving a double iron-mediated arylamine cyclization as the key step (Scheme 19). Thus, the reaction of m-phenylenediamine (140) with the tricarbonyliron-complexed cyclohexadienyl cation 141 yielded the complex 142, which was eventually transformed into indolo-[2,3-()]carbazole (3) via cyclization and dehydrogenation (98TL4007 00T4733). 

The synthesis can be conducted both in solution and without solvents. The reaction in solvent (e.g., methanol, ethanol, dioxane, dimethylformamide) is recommended for volatile 1,3-diynes and amines in this case the pyrroles are purer and the yield is higher. With disubstituted diacetylenes, ammonia and primary alkyl- and arylamines produce 1,2,3-trisubstituted pyrroles under the same conditions (65CB98 71MI1). Since disubstituted diacetylenes are readily obtained by oxidative coupling of acetylenes (98MI2), this reaction provides a preparative route to a wide range of pyrroles. 

The work of Greenfield and Malz (25) on the preparation of arylamines illustrates the sensitivity of yield to hindrance and an influence of catalyst. 

Arylamines are usually prepared by nitration of an aromatic starting material, followed by reduction of the nitro group (Section 16.2). The reduction step can be carried out in many different ways, depending on the circumstances. Catalytic hydrogenation over platinum works well but is often incompatible with... 

Arylamines are converted by diazotization with nitrous acid into arenediazonium salts, ArN2+ X-. The diazonio group can then be replaced by many other substituents in the Sandmeyer reaction to give a wide variety of substituted aromatic compounds. Aryl chlorides, bromides, iodides, and nitriles can be prepared from arenediazonium salts, as can arenes and phenols. In addition to their reactivity toward substitution reactions, diazonium salts undergo coupling with phenols and arylamines to give brightly colored azo dyes. 

Pioneering studies have shown that the yield of iV-phenyl-3//-azepin-2-amine (32, R = Ph) from the thermolysis of phenyl azide in aniline increases as the ratio of azide to aniline decreases, and in dilute solution with an azide to aniline ratio of 1 200 a 54% yield of the 3//-azepine can be achieved.34 The reaction is successful with other arylamines, but the procedure is of limited preparative value as large volumes of amine are required and only moderate yields of 3H-azepines are obtained. 

For quantitative work, it is necessary to estimate the concentration of 5-amino-l-(P-D-ribofuranosyl)imidazole in aqueous solution. It seems that the only available method is the Bratton-Marshall assay, which was originally developed for the estimation of arylamines in biological fluids. The principle of the method is the spectrometric estimation of a salmon-pink colored dyestuff obtained by diazotation in situ, followed by coupling with /V-( 1 -naphthyl)ethyl-enediamine.65 The only remaining problem then is to know the molar extinction of this dye because pure samples of AIRs are not available. A value of 16800 at 520 nM was obtained for the dyes prepared from a model compound, 5-amino-l-cyclohexylimidazole-4-carboxylic acid (54), which is crystalline. A comparable molar extinction can be expected for the dye prepared from imidazole 55, if the carboxyl group does not exert too much influence on the chromophore. Actually, its influence is perceptible even with the naked eye, the dyestuff prepared from 53 having a somewhat different, wine-red color, with max>520 nM. The molar extinction for 55 is 17400 at 500 nM. When the decarboxylation of 54 was conducted under mild acidic conditions (pH 4.8, 50°C, 1 hour), estimation of 5-aminoimidazole 55 by the Bratton-Marshall method led to the conclusion that the reaction was almost quantitative.66 Similar conditions for the final decarboxylation were adopted in the preparation of samples of AIRs labeled with stable isotopes.58... 

Fig. 17 Rapid preparation of imidazoles and thiazoles on solid-phase. Reagents a RNH2, (CH30CH2)2, MW 220°C, 15min, closed vessel b TFA in CH2CI2, rt, 60min. R = aliphatic, benzyl, or arylamines or arylhydrazine...

The treatment of acyl halides with ammonia or amines is a very general reaction for the preparation of amides.The reaction is highly exothermic and must be carefully controlled, usually by cooling or dilution. Ammonia gives unsubstituted amides, primary amines give A-substituted amides, and secondary amines give N,N-disubstituted amides. Arylamines can be similarly acylated. In some cases aqueous... 

Chlorofluorans react with a wide variety of primary amines such as alkylamines, cycloalkylamines, aralkylamines, and arylamines, as well as cyclic secondary amines such as piperidine, morpholine, etc., to prepare 3 -aminofluorans. 

The classic syntheses of the antibacterial sulfonamides involve reaction of the appropriate arylamine with an acid addition salt of p-amino-benzenesulfonyl chloride, or p-nitrobenzenesulfonyl chloride followed by reduction. Chemical interest largely resides in preparation of the corresponding arylamines. For the synthesis of sulfacytine (134), N-ethyl uracil (131) was converted to its thioamide (132) by reaction with phosphorous pentasulfide. The newly introduced sulfur is then displaced with ammonia in methanol to give 133. Standard reactions complete... 

Biologically important arylamines, various kinds of heterocycles, and macrocyclic compounds have been prepared by using resin-bound nitro halo compounds via SNAr reactions. Such a process is very important for combinatorial synthesis of biologically important compounds. Typical examples are presented in Eqs. 9.13—9.21,22-31... 

The specific ortho functionalization of arylamines is obviously important in quinoline synthesis (cf. the rc-allyl procedure devised for the preparation of o-allylanilines used as indole and quinoline precursors).76 Recently acetanilides have been subjected to orthopalladation and the ensuing complexes converted into useful precursors of 2-substituted quinoline derivatives (Scheme 143).215... 

Reaction of isothiocyanate with amine gives the corresponding thioureas. Many reports are appeared.102 111 The thiourea derivatives have been prepared by reactions of isothiocyanates with arylamines (Scheme 39) and reacted with some substrates to afford heterocyclic compounds, such as 2-amino-4//-ben-zothiazine, 1,3-thiazine, 1,3-thiazinone and l,3-thiazolidin-4-one.112 115... 

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