Reductive alkylation amine precursors

Cyclohexanones may serve as precursors to aromatic amines in a reductive alkylation, the source of hydrogen being aromatization of the cyclohexanone (66). In a variation, an aromatic nitro compound acts as both an amine precursor and a hydrogen acceptor (64). 

The reduction of nitrobenzene to aniline is a major industrial process at the heart of the production of polyurethanes, and it is also often used as a marker reaction to compare activities of catalysts [1,2], It can be performed over a variety of catalysts and in a variety of solvents. As well as its main use in polymethanes, aniline is used in a wide range of industries such as dyes, agrochemicals, by further reaction and functionalisation. Reductive alkylation is one such way of functionalising aromatic amines [3, 4], The reaction usually takes place between an amine and a ketone, aldehyde or alcohol. However it is possible to reductively alkylate direct from the nitro precursor to the amine and in this way remove a processing step. In this study we examined the reductive alkylation of nitrobenzene and aniline by 1-hexanol. 

These results indicate that the one-pot reductive alkylation using nitro-precursors rather than the amine may be more complex than previously thought. 

Dovell and Greenfield have shown that base metal sulfides as well as noble metal sulfides are excellent catalysts for the preparation of secondary amines by the reductive alkylation of primary amines (or their nitro precursors) with ketones.36,37 There was little or no hydrogenation of aromatic rings for arylamines, an important side re-... 

Rhenium sulfide was the most active and hydrogenated excess ketone to the corresponding alcohols. The platinum metal sulfides were found to be more active than the base metal sulfides and highly selective for the formation of (V-alkylarylamines. They usually produce a pure product with little or no side reactions, require no excess above the stoichiometric amount of ketone, and are active at relatively low pressures of hydrogen. An example with (V-phenyl-p-phcnylencdiaminc is shown in eq. 6.15.37 Platinum metal sulfides may also be used for the reductive alkylation of aliphatic amines and their nitroalkane precursors with aliphatic ketones. 

In reductive amination, the alkylation is performed under hydrogen in the presence of a catalyst and an aldehyde or ketone as the alkylating agent. The method was developed for anilines and extended to amide N-alkylation [36]. A notable example is the use of nitro derivatives as aniline precursors in a one-pot reduction of the nitro group and subsequent reductive alkylation of the resulting aniline (Fig. 3.12). 

Another of the arylalanines, L-tryptophan, was used at the same laboratories [81] for the synthesis of novel benzazepines (56) as dual inhibitors of ACE and thromboxane synthase (Scheme 5.25). Ozonolysis of 7V-acetyl l-tryptophan to effect scission of the indole ring followed by 7V-protection gave the 4-keto acid (57) as a cyclization precursor. Downstream transformations included diastereoselective reduction of the ketone functionality and reductive alkylation of the amine substituent with ethyl 2-oxo-4-phenyl-butanoate. 

Amine precursors, such as nitro, nitrile, and azido compounds, which can be converted to amines under the hydrogenation reaction conditions, can also be used in the reductive alkylation reaction (Scheme 26). 

There are two major differences between the reduction of imines and aldehydes by 2-tol imines are reduced more rapidly than aldehydes and give amine complexes as stable products (Scheme 10) [57]. Substituents on the imine affect the rate of reduction and the stability of the amine complex product. PhCH=NPh reacts with 2-lol in THF at —40°C at a rate about 150 times faster than benzaldehyde. The more basic imine PhCH=NCH2Ph reacts with 2-lol in THF at —57°C at a rate about 15 times faster than PhCH=NPh. The stability of the amine complexes depends on the basicity and steric requirements of the complexed amine. Dialkylamine complex 10 is stable to 80°C, while the less basic aryl(alkyl)amine complex 9 is stable to only 50 C. The complex of the very bulky t-Bu(PhCH2)NH complex 11 decomposed above O C. In general, amine complexes with greater number of substituents are less stable. Beller has isolated the NH3 complex 12 from catalytic systems it is unusually stable and acts as a viable catalyst precursor [58]. 

N-Alkylated derivatives could be obtained by catalytic reductive amination from a mixture of D-fagomine, or its linear precursor, and the corresponding aldehyde. 

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