Benzothiazoline: Versatile hydrogen donor for organocatalytic transfer hydrogenation

Chen Zhu, Kodai Saito, Masahiro Yamanaka, Takahiko Akiyama

Research output: Contribution to journalArticlepeer-review

141 Citations (Scopus)


ConspectusThe asymmetric reduction of ketimines is an important method for the preparation of amines in optically pure form. Inspired by the biological system using NAD(P)H, Hantzsch ester has been extensively employed as a hydrogen donor in combination with chiral phosphoric acid for the transfer hydrogenation of ketimines to furnish amines with high to excellent enantioselectivities.We focused on 2-substituted benzothiazoline as a hydrogen donor in the phosphoric acid catalyzed transfer hydrogenation reaction of ketimines for the following reasons: (1) benzothiazoline is readily prepared just by mixing 2-aminobenzenethiol and aldehyde, (2) both reactivity (hydrogen donating ability) and enantioselectivity would be controlled by tuning the 2-substituent of benzothiazoline, and (3) benzothiazoline can be stored in a refrigerator under inert atmosphere without conceivable decomposition. Both the 2-position of benzothiazoline and the 3,3′-position of phosphoric acid are tunable in order to achieve excellent enantioselectivity.Benzothiazoline proved to be useful hydrogen donor in combination with chiral phosphoric acid for the transfer hydrogenation reaction of ketimine derivatives to afford the corresponding amines with high to excellent enantioselectivities by tuning the 2-substituent of benzothiazoline. Ketimines derived from acetophenone, propiophenone, α-keto ester, trifluoromethyl ketone, and difluoromethyl ketone derivatives proved to be suitable substrates. Benzothiazoline could be generated in situ starting from 2-aminobenzenethiol and aromatic aldehyde in the presence of ketimine and chiral phosphoric acid and successfully worked in the sequential transfer hydrogenation reaction. The reductive amination of dialkyl ketones also proceeded with high enantioselectivities. Use of 2-deuterated benzothiazoline led to the formation of α-deuterated amines with excellent enantioselectivities. The kinetic isotope effect (kH/kC = 3.8) was observed in the competitive reaction between H- and D-benzothiazoline, which explicitly implies that the cleavage of the C-H (C-D) bond is the rate-determining step in the transfer hydrogenation reaction.Benzothiazoline yielded products with higher enantioselectivity in the transfer hydrogenation reaction of ketimines, particularly ketimines derived from propiophenone derivatives, than Hantzsch ester. DFT study elucidated the mechanism, as well as the difference in selectivity, between benzothiazoline and Hantzsch ester. The chiral phosphoric acid activates ketimines and benzothiazoline by means of the Brønsted acidic site (proton) and the Brønsted basic site (phosphoryl oxygen), respectively, to accelerate the hydride transfer reaction.

Original languageEnglish
Pages (from-to)388-398
Number of pages11
JournalAccounts of Chemical Research
Issue number2
Publication statusPublished - 2015 Feb 17
Externally publishedYes

ASJC Scopus subject areas

  • General Chemistry


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