Reductive diamination

The most noteworthy reaction of azo-compounds is their behaviour on reduction. Prolonged reduction first saturates the azo group, giving the hydrazo derivative (C NH-NH C), and then breaks the NH NH linkage, with the formation of two primary amine molecules. If method (1) has been employed to prepare the azo-compound, these two primary amines will therefore be respectively (a) the original amine from which the diazonium salt was prepared, and (6) the amino derivative of the amine or phenol with which the diazonium salt was coupled. For example, amino-azobenzene on complete reduction gives one equivalent of aniline, and one of p-phenylene diamine, NHaCeH NH benzene-azo-2-naphthoI similarly gives one equivalent of aniline and one of... 

Only the mono-amines are described here. The diamines are more frequently encountered as reduction products of dinitrobenzenes and nitro-anilines, and the chief reactions of the phenylenediamines are therefore given in Section 23, pp. 384-388. 

Compounds containing two primary amino groups attached to a benzene ring can be prepared by the reduction of dinitro compounds and of nitroanilines, usually with tin or stannous chloride and hydrochloric acid or with iron and very dilute hydrochloric acid. / ara-diamines may also be obtained by the reduction of aromatic amino-azo compounds (e.g., p-aminodimethylanihne from methyl orange, see Section IV,78). p-Phenylenediamine may also be prepared from p-nitroacetanilide reduction with iron and acid yields p-amino-acetaniUde,.which may be hydrolysed to the diamine. 

The desired pyridylamine was obtained in 69 % overall yield by monomethylation of 2-(aminomethyl)pyridine following a literature procedure (Scheme 4.14). First amine 4.48 was converted into formamide 4.49, through reaction with the in situ prepared mixed anhydride of acetic acid and formic acid. Reduction of 4.49 with borane dimethyl sulfide complex produced diamine 4.50. This compound could be used successfully in the Mannich reaction with 4.39, affording crude 4.51 in 92 % yield (Scheme 4.15). Analogous to 4.44, 4.51 also coordinates to copper(II) in water, as indicated by a shift of the UV-absorption maximum from 296 nm to 308 nm. 

Reduction. Hydrogenation of dimethyl adipate over Raney-promoted copper chromite at 200°C and 10 MPa produces 1,6-hexanediol [629-11-8], an important chemical intermediate (32). Promoted cobalt catalysts (33) and nickel catalysts (34) are examples of other patented processes for this reaction. An eadier process, which is no longer in use, for the manufacture of the 1,6-hexanediamine from adipic acid involved hydrogenation of the acid (as its ester) to the diol, followed by ammonolysis to the diamine (35). 

Some of these compounds show antibacterial activity. Reduction gives 2-[(2-aminoethyl)amino]ethanols which react with organic acids to form amides that, on further heating, cyclize to imidazolines (6). For example, the diamine obtained by reducing (1) reacts with an organic acid (R"COOH) to give... 

MCHD from ring reduction of I DA (60,78) has been cited as an epoxy curative (79) and is available from Air Products and Chemicals as a developmental cycloaHphatic diamine. Ring reduction of stericaHy hindered arylenediamines such as diethyltoluenediamine [68479-98-1J -ptovides slower-reacting alkylated 1,3-cyclohexanediamines for polyurethane, polyurea, and epoxy use (80). 

The synthesis which forms the basis of production at Hoffmaim-La Roche (Fig. 5) proceeds via the pyrimidinenitrile [698-29-3] (26) made from malononittile, trimethylorthoformate, ammonia, and acetonitrile (42,43). High pressure catalytic reduction of the nitrile furnishes diamine (16). The overall sequence is short, highly efficient, and generates almost no waste. However, malononittile is a relatively expensive and ha2ardous three-carbon source. 

A study of the degradation of two azo disperse dyes. Disperse Orange 5 [6232-56-0] (1) Cl 11100) and Disperse Red 5 [3769-57-1] Cl 11215) showed reduction of the azo linkage into aromatic amines and further dealkylation to -phenylene-diamine [106-50-3] (2) (255). 

The final reduction product of pyrazine, piperazine (89), is a stable compound which behaves as a typical diamine. It has found extensive use in medicinal chemistry as a linking agent and as a medicine in its own right for the treatment of helminths both in human and veterinary medicine. 

Bell and Hall have incorporated an organometallic unit into a crown by using the ferrocenyl unit as part of the ring or as a third strand. The unit is incorporated either as the 1,1 -diformylferrocene or the corresponding acid. In the former case, the bis-imine is prepared and reduced to give the saturated crown (see structure 24). In the latter case, the acid is converted into its corresponding chloride and thence into the diamide by reaction with a diamine. Diborane reduction affords the saturated amino-crown. Structure 24 could be prepared by either of these methods but the dialdehyde approach was reported to be poor compared to the amide approach which afforded the product in ca. 60% yield . 

Macrocycles have been prepared by formation of macrocyclic imines as well as by using variations of the Williamson ether synthesis ". Typically, a diamine or dialdehyde is treated with its counterpart to yield the Schiff s base. The saturated macrocycle may then be obtained by simple reduction, using sodium borohydride, for example. The cyclization may be metal-ion templated. In the special case of the all-nitrogen macrd-cycle, 15, the condensation of diamine with glyoxal shown in Eq. (4.14), was unsuccess-ful ... 

Some instances of incomplete debromination of 5,6-dibromo compounds may be due to the presence of 5j5,6a-isomer of wrong stereochemistry for anti-coplanar elimination. The higher temperature afforded by replacing acetone with refluxing cyclohexanone has proved advantageous in some cases. There is evidence that both the zinc and lithium aluminum hydride reductions of vicinal dihalides also proceed faster with diaxial isomers (ref. 266, cf. ref. 215, p. 136, ref. 265). The chromous reduction of vicinal dihalides appears to involve free radical intermediates produced by one electron transfer, and is not stereospecific but favors tra 5-elimination in the case of vic-di-bromides. Chromous ion complexed with ethylene diamine is more reactive than the uncomplexed ion in reduction of -substituted halides and epoxides to olefins. ... 

Further substitution of benzoic acid leads to a drug with antiemetic activity. Alkylation of the sodium salt of p-hydroxy-benzaldehyde (8) with 2-dimethylaminoethyl chloride affords the so-called basic ether (9). Reductive amination of the aldehyde in the presence of ammonia gives diamine, 10. Acylation of that product with 3,4,5-trimethoxybenzoyl chloride affords trimetho-benzamide (11). ... 

Treatment of the heterocycle, 38 (obtained from ethylene-diamine and carbon disulfide), with nitrous acid affords the N-nitroso compound, 39. Reduction with zinc leads to the corre-... 

Alkylation of the tetrahydropyridine, 52 (obtained by reaction of a suitable protected derivative of 4-piperidone followed by dehydration and deprotection), with chloroacetonitrile affords 53, Reduction of the cyano group gives the diamine (54). Reaction of this intermediate with the S-methyl ether of thiourea affords guancycline (55). 

A variation on this theme consists in first displacement of the chlorine in 73 with ethylaminoethanol. Reductive amination of the ketone by means of ammonia in the presence of hydrogen gives the hydroxylated diamine (77). Use of this intermediate to effect displacement of the halogen at the 4 position of 70 affords hydroxychloroquine (78). ... 

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