Thioamides, reduction amines

Direct reduction of a peptide bond with diborane 59 or a thioamide bond with several reductive procedures 60 is an alternative route for the production of a reduced peptide bond in a peptide. In some cases the reductive amination does not give satisfactory results. As described earlier, preparation of Boc-Pher )[CH2N]Pro-OH by reductive amination yields two diastereomers (Scheme ll). 57 In this case treatment of Boc-Phe-Pro-OBzl by diborane yielded the reduced pseudodipeptide Boc-Pher )[CH2N]Pro-OBzl without epimerization (Scheme 12). However, in some cases diborane is not entirely selective for the amide bond and can reduce ester functions when they are present. Another procedure is to prepare endothiopeptides directly from protected dipeptides 61-66 followed by their selective reduction. 60 ... 

Although the conversion of thioamides into amines by alkylation with triethyl-oxonium tetrafluoroborate has been previously reported (c/. Vol. 4, p. 172), a considerably more detailed study has now appeared, as part of a convenient, general, and selective method for the reduction of amides to amines (Scheme 19). 

The Kindler variation, - which promises to be more useful than the original Willgerodt procedure, consists in heating the ketone with approximately equimolecular amounts of sulfur and a dry amine instead of aqueous ammonium polysulfide. A thioamide is formed as the principal product and on hydrolysis with acid or alkali affords the carboxylic acid, usually in good yield. Generally a secondary aliphatic amine but sometimes a primary amine or even anhydrous ammonia is used the development of a method for the electrolytic reduction of the thioamides to amines extended the usefulness of the reaction as a new route to the synthesis of many important nitrogen bases. Early descriptions of this... 

Addition to thioamides.s Alkyl- or aryllithiums add to the carbon-sulfur bond of aromatic thioamides to give adducts that are hydrolyzed to unsymmetrical ketones. Reduction of the adducts with LiAlHj before hydrolysis provides a-alkylated amines. 

Thioamides were converted to aldehydes by cautious desulfurization with Raney nickel [1137, 1138] or by treatment with iron and acetic acid [172]. More intensive desulfurization with Raney nickel [1139], electroreduction [172], and reduction with lithium aluminum hydride [1138], with sodium borohydride [1140] or with sodium cyanoborohydride [1140] gave amines in good to excellent yields. 

Hydrolysis of nitriles.1 N itriles are converted to thioamides by reaction with I (2 equivalents) at 40° overnight. Under these conditions most other functional groups are stable. Kinetic studies indicate that the reaction with nitriles is a two-step process, the first of which is analogous to an enc reaction to give a. Thioamides arc particularly useful precursors to amines by the method of Borch (2, 430 431), reaction with triethyloxonium tetrafluoroborate followed by reduction withNaBHj..- ... 

As described above, the reduction of imines often proceeds via iminium ions particularly in acidic media, since protonation enhances the electrophilicity of the imine carbon. Thus, as expected, preformed iminium salts generated from carbonyls and secondary amines are also readily reduced by most hydride reagents. Several examples of synthetic applications with a variety of reagents are illustrated in Table 4. Entries 9-12 illustrate the use of iminium intermediates for the reductive removal of amide carbonyls. Thus, treatment of amides with POCI3 affords the iminium derivatives (e.g. 9 Scheme 3), which are reduced by NaBHt to the corresponding amines (Table 4, entries 9, 10). Likewise, reaction of amides witii trialkyloxonium salts to give imidic esters (entry 12) or thioamides with methyl iodide to give... 

Thioamides (86) are readily reduced to amines (93) (Scheme 50). The reduction generally occurs more easily than with amides and can be achieved with a variety of reducing agents, e.g. metal-acid, sodium amalgam, lithium aluminium hydride or Raney nickel. 

The yields of trifluoropyruvic thioamides 6 with common secondary amines are mostly fair and do not exceed 65 %. The reduction products - trifluorolactic thioamides 7 are formed in certain cases as by-products (about 5 %). Trifluoroacetone yields under the Willgerodt-Kindler conditions only 7 (30-35 %), besides other products. These lactic products 7 are therefore formed more expediently by reduction of 6 using ammonium formate at 100°C. 

Reduction of iV-arylimino- 1,2,3-dithiazoles 89, prepared from dithiazolium chloride and primary amines, using lithium aluminum hydride furnishes the iV-aryldithioxamides 90 (Eq. 31) [53]. The reaction is carried out for 15 min at room temperature, and the yields of 90 are moderate. It should be noted that the thioamide moiety, which is easily reduced with lithium aluminum hydride, remains in the products. 

A Pinner reaction between the primary amine (403) and the thioimidate (404) (from the thioamide and iodomethane) gave xylamidine (405) (Scheme 5.94.). Base catalysed reaction between 2-chloropropionitrile and 3-methoxyphenol followed by lithium aluminium hydride reduction provided the amine (403). Xylamidine is a powerful 5HT2 receptor antagonist, and has some value in pharmacological research [551],... 

Imines are reduced by triethylsilane to their amines when the proper Ir orNi catalysts areemployed. Non-metal-mediated reductions of C=N groups by EtsSiH are also possible. Among these, the trifluorosulfonic acid promoted reductive amidation of aliphatic and aromatic aldehydes with EtsSiH is an excellent way to mono (V-alkylate aliphatic and aromatic amides, thioamides, carbamates, and ureas (eq 26). It is also worth noting that trifluorosulfonic acid/EtsSiH reduces acyl- and tosylhydrazones to hydrazines and 2-aminopyrimidines to 2-amino-dihydro-or 2-aminotetrahydropyrimidines (eq 27). ... 

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