Improved Methodology for the Preparation of Chiral Amines

This is a straight forward, environmentally friendly with easy procedures, but incompatible
with the coexisting functional groups such as nitro, cyano and C-C multiple bonds. [19] The
second strategy is based on the transfer hydrogenation conditions utilizing formic acid or one
of its derivative (Leuckart-Wallach type). [20] The third strategy uses hydride reductants e.g.
NaBH 3 CN, [21] LiBH 3 CN, [22] [23] [24] [25]
NaBH 3 CN-ZnCl 2, NaBH 3 CNMg(ClO 4 ) 2, NaBH 4 -NiCl 2,
[26]
NaBH 4 -ZnCl 2, borohydride exchange resin, [27] [28]
[29]
ZnBH 4, ZnBH 4 -ZnCl 2, pyridineborane,
[30] picoline-borane, [31] etc. Recently organocatalysts were used in reductive amination
utilizing Hantzsch esters or silanes as hydride sources with organocatalysts as chiral
phosphoric acid and its derivatives. [32]
Reviewing the literature of the last 50 years it is obvious that among the different reductive
amination strategies discussed above, hydride reduction with NaBH 3 CN which was
introduced by Borch [33] has been used extensively. This may be due to the ease of use of these
hydride sources. Borohydride salts are furthermore cheap, available in kg quantities and do
not require special precautions in handling. Despite these advantages borohydride salts suffer
from other drawbacks.
This reductant is used in excess quantity, toxic and produces toxic byproducts such as HCN
and NaCN upon workup which limits its applications according to the new environmental
standards. Abdel-Magid aimed to avoid this toxicity by using NaBH(OAc) 3 , (introduced by
Gribble) as a mild reductant. [34,35] The mild nature of this reductant is due to the steric and
electronic effects of the acetoxy groups which stabilize the B-H bond. His system was
applicable for different types of aldehydes and unhindered aliphatic ketones. In spite of the
significant applications of the above reductants they are not free from limitations regarding
functional group tolerance and side reactions. [36] Also the formation of tertiary or secondary
amine from primary amine (the desired product) due to over alkylation represents another
limitation. [37]
Bhattacharyya and coworkers developed a highly efficient mild system for reductive
amination utilizing Ti(O i Pr) 4 , and NaBH 4 as the hydride donor and an amine source e.g.
ammonia, ammonium chloride or methylamine. He was able to obtain high yields for
different aldehydes, cyclic ketones and ketone with acid labile groups (scheme 3.7). [38]
58