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Rueping et al. [123], List et al. [124], and MacMillan et al. [125] independently reported a transfer hydrogenation of ketimines using CPA as the Brønsted acid and Hantzsch ester as the hydrogen donor, and enzymes and cofactors in the biological system were replaced by small organocatalysts and nicotinamide adenine dinucleotide (NADH) analogues (Scheme 2.64). The combination of CPA and Hantzsch ester was extended to the transfer hydrogenation of numerous kinds of substrates, such as α‐imino esters;[126] heterocycles, including pyridines [127], 2‐, 3‐, 4‐substituted quinolines [128], benzoxazines, benzothiazines, benzoxazinones [129], quinoxalines, quinoxalinone [130], indolines [131], and [1,4]benzodiazepines;[132] and others (Figure 2.12) [133].

Scheme 2.64. Transfer hydrogenation of ketimines by Hantzsch ester.

Theoretical studies by Goodman [134] and Himo [135] led to the elucidation of the mechanism, wherein hydrogen bond between N‐H and phosphoryl oxygen is important (Figure 2.13).

One of the drawbacks of the transfer hydrogenation by the combined use of Hantzsch ester and CPA is that a stoichiometric amount of Hantzsch ester is required. In order to resolve the issue, Zhou employed 9,10‐dihydrophenanthridine (DHPD) as the hydrogen donor in place of Hantzsch ester and reported transfer hydrogenation of benzoxazinone, quinoxalines, and quinolines by the combined use of CPA 12d, Ru catalyst, and phenanthridine (29), wherein hydrogen gas was employed as the terminal reductant for the regeneration of DHPD (Scheme 2.65) [136].

Xiao reported a direct asymmetric reductive amination reaction between aromatic amines and aryl methyl ketones by the combined use of CPA 6e and Ir catalyst 30 (Scheme 2.66) [137]. Chiral Ir catalyst bearing phosphate counteranion was generated.

Figure 2.12. Results of the transfer hydrogenation of ketimines.

Source: Based on [133].

Figure 2.13. Transition state of the transfer hydrogenation with Hantzsch ester.

Scheme 2.65. Transfer hydrogenation of benzoxazine using DHPD.

Source: Based on [136].

The transfer hydrogenation reaction by the combined use of CPA and Hantzsch ester required use of N‐aryl ketimines as substrates due to the catalyst deactivation through salt formation with the highly basic amine product. List reported a transfer hydrogenation of N‐alkyl‐substituted ketimine using more acidic chiral DSI 9d, which was derived from BINOL in the presence of Boc₂O to furnish Boc‐protected N‐alkyl amine. A range of ketimines bearing methyl, ethyl, propyl, butyl, benzyl, allyl, and other alkyl moieties participated in the transfer hydrogenation successfully to furnish corresponding amines with 81–97% ee (Scheme 2.67a) [138]. Subjecting N‐H ketimines with the combination of DSI 9e and Hantzsch ester resulted in the reductive condensation reaction of the N‐H ketimines to afford C₂‐symmetric secondary amines (Scheme 2.67b) [139]. List subsequently employed N‐H ketimine HCl salt as the substrate and achieved an enantioselective reduction efficiently to furnish crystalline primary amines using DSI 9f (Scheme 2.67c). A kinetic study suggested the bifunctional nature of DSI [140].

Scheme 2.66. Metal‐Brønsted acid cooperative catalysis.

Source: Based on [137].

Scheme 2.67. Transfer hydrogenation of N‐alkyl ketimines (a) (

Source: Based on [138]

), reductive condensation of N‐H ketimines (b) (

Source: Based on [139]

), and transfer hydrogenation of HCl salt of N‐H ketimines (c) [140].

In addition to Hantzsch ester, benzothiazoline was also found to function as a hydrogen donor in combination with CPA because benzothiazoline releases dihydrogen to generate benzothiazole (Figure 2.14) [141]. A range of ketimines derived from acetophenones [142], propiophenones [143], α‐imino esters [144], trifluoromethylated ketimines [145], difluoromethylated ketimines [146], alkynylated ketimines [147], and 1,4‐benzodiazepine [148] successfully participated in the transfer hydrogenation (Figure 2.15). The reductive amination also proceeded efficiently [149]. Interestingly, use of 2‐aryl‐2‐deuterated benzothiazoline resulted in the formation of α‐deuterated amines with high enantioselectivity [150]. Benzothiazoline sometimes afforded higher enantioselectivity in the transfer hydrogenation of ketimines in combination with CPA in comparison with Hantzsch ester as a hydrogen donor. Theoretical study by Yamanaka elucidated the transition state, wherein hydrogen bond between N‐H and phosphoryl oxygen is critical [151]. Higher selectivity of benzothiazoline may be ascribed to the position of the transferred hydrogen. Hydrogen at the α‐position of nitrogen of benzothiazoline was transferred, whereas γ‐hydrogen was transferred in the case of Hantzsch ester (Figure 2.16).

Figure 2.14. Transfer hydrogenation of ketimines by benzothiazoline.

Source: Based on [141].

Figure 2.15. Results of the transfer hydrogenation of ketimines by benzothiazoline.

Furthermore, 2‐arylindoline also functioned as a hydrogen donor for the transfer hydrogenation of ketimines (Scheme 2.68a) [152]. (R)‐2‐Arylindole reacted much faster than its (S)‐isomer in combination with (R)‐BINOL‐derived phosphoric acid. Taking advantage of the difference in the reactivity, Akiyama developed oxidative kinetic resolution of 2‐substituted indoline. On treatment of 2‐substituted indoline with 0.6 equivalent of ketimine in the presence of CPA 6e, (R)‐indoline underwent transfer hydrogenation with N‐3,4,5‐(MeO)₃C₆H₂‐substituted ketimine much faster than (S)‐indoline, and (S)‐indoline was recovered in approximately 50% chemical yields with excellent enantioselectivity (Scheme 2.68b) [153]. In particular, 2‐arylindolines were obtained with >99% ee.

Figure 2.16. Transition state of the transfer hydrogenation with Hantzsch ester.

Subsequently, Akiyama reported a self‐redox strategy for the oxidative kinetic resolution of indolines to furnish 2‐aryl indolines with 87–99% ee using salicyl aldehyde derivative as the preresolving reagent in place of ketimine catalyzed by CPA 6t, bearing bulky 9‐anthryl‐2,6‐diisopropylphenyl group at 3,3′‐positions. Iminium ion intermediate 31, which was formed by the condensation of indoline with salicyl aldehyde derivative, was hydrogenated from the 2‐aryl indoline (Scheme 2.68c) [154].

Scheme 2.68. Transfer hydrogenation using indoline as a hydrogen donor (a) (

Source: Based on [152]

), oxidative kinetic resolution of indolines using ketimine (b) (

Source: Based on [153]

), and oxidative kinetic resolution of indolines based on self‐redox reaction (c) (

Source: Based on [154]).