Borrowing hydrogen approach

Whittlesey, Williams and co-workers fnrther developed the catalytic indirect Wittig reaction and fonnd that the more electron-rich NHC present in complex 18 provided a more reactive catalyst [8]. Catalyst 18 was used to convert benzyl alcohol 8 and phosphoninm ylide 19 into the product 20 under slightly milder reaction conditions and in a shorter time than in previous work (Scheme 11.4). Other C-C bond-forming reactions from alcohols using a borrowing hydrogen approach have been reported, with Peris and co-workers using Ir-NHC complexes for the C-3 alkylation of indoles with alcohols [9]. 

Leonard J, Blacker AJ, Marsden SP et al (2015) A survey of the borrowing hydrogen approach to the synthesis of some pharmaceutically relevant intermediates. Org Pro Res Deve 19(10) 1400-1410... 

The brute force approach to achieve this goal is to employ a solid-state photovoltaic cell to generate electricity that is subsequently passed into a commercial-type water electrolyzer. Although efficiencies obtained are relatively high, i.e., close to 8 %, these devices are very expensive. Hence the price of hydrogen produced this way cannot compete with conventional sources. The long-term outlook is better for systems that borrow their principles from natural photosynthesis (see Section 1.4.1 above). 

Hydrogen borrowing will likely become competitive with alkyl halide and reductive amination approaches as the method of choice for N-alkylation. Its broad functional group tolerance, continuously increasing scope, and facile scalability point toward a major impact in drug discovery in the coming years. 

The N-heterocyclisation of amines with alcohols represents an attractive approach to the synthesis of cyclic amines. Ir and Ru catalysts have been successfully used to form pyrrolidines, piperidines, and tetra-hydroisoquinolines. More difficult to access are piperizines and 1,2,3,4-tet-rahydroquinoxalines which require higher catalysts loadings, extended reaction times, and higher temperatures. To date, no examples exist of a catalyst controlled asymmetric N-heterocyclisation with amines and diols to produce enantiomerically enriched N-heterocycles. Still, the preparation of N-heterocycles via hydrogen borrowing offers attractive benefits no prior activation of the alcohol is required, and the only stoichiometric by-product is usually water. 

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