resulting from the acyclic imine intermediates make
stereoselective reduction difficult; (3) the amine used as
a nitrogen source inhibits the reactivity of the transition
metal.1,7b
asymmetric reductive amination of simple ketones using
phenylhydrazide as the nitrogen source. To our knowledge,
this is the first time phenylhydrazide was used for the
reductive amination of ketones. With the help of several
additives, excellent reactivity (up to 1000 TONs) and
enantioselectivities (up to 99% ee) were achieved in this
iridiumꢀf-Binaphane (Figure 2) catalyzed reaction.
The chiral hydrazide products were made in high en-
antioselectivities by Burk and Feaster in 1992 from the
asymmetric hydrogenation of N-benzoylhydrazone.9a
However, direct reductive amination was not realized in
this system.9b Phenylhydrazide is a desired nitrogen source
due to its carbonyl group acting as a chelation group,
formation of an E-imine structure in Burk’s system to
ensure high enantioselectivities, and ease in cleaving the
NꢀN orNꢀC(O) bond toformchiralhydrazineand chiral
amine.9b Chiral hydrazines, arylhydrazide, and its deriva-
tives, pyrazolidines, are of great importance in biolog-
ical and medicinal chemistry, as well as important
synthetic intermediates (Figure 1).10ꢀ13In our experi-
ment, we explored phenylhydrazide as a nitrogen
source for reductive amination using acetophenone as a
standard ketone, and results are summarized in
Table 1. We selected an iridiumꢀf-Binaphane complex
as the catalyst because it does not promote ketone reduc-
tion, and it exhibited excellent performance in the asym-
metric hydrogenation of imines and reductive
amination.14
Figure 2. Structures of chiral phosphine ligands.
In 1999, Blaser et al. explored the first asymmetric
reductive amination in the synthesis of (S)-metolachlor.7c
Then Kadyrov reported highly enantioselective hydrogen -
transfer reductive amination using ammonium formate.
But this system created a large amount of side products.7d
Ammonium salts were proven to be good nitrogen sources
for the synthesis of β-amino ester and β-amino amide.7eꢀg
Chiral 1-methyl-1,2,3,4-tetrahydro-6,7-dimethoxyisoqui-
noline was synthesized by Wills and co-worker via intra-
molecular reductive amination.7h Our group contributed
efficient reductive amination of simple aryl ketones using
aniline in the presence of titanium(IV) isopropoxide and
iodine with excellent enantioselectivities in high yields.7i
Since then, several papers were published using anilines as
nitrogensources.7jꢀl Although in somesystems7i,k,l anilines
offered excellent enantioselectivities, the removal of ani-
lines as protecting groups is not easy.8 So it is still a
challenge to find out suitable nitrogen sources that can
be used and removed for asymmetric reductive amination
of simple ketones. Herein, we report highly efficient direct
Additives are key to the success of this reaction.Without
any additive, there was no reaction (Table 1, entry 1). With
the addition of 10 mol % p-toluenesulfonic acid, the major
product was N-benzoylhydrazone intermediate 4 and
some alcohol product 5. After using iodine along with p-
toluenesulfonic acid, some product 3a started to appear.
˚
And when molecular sieves (4 A), p-toluenesulfonic acid,
and iodine were added at the same time, the desired
product 3a was obtained as the major product with 88%
ee, and the alcohol side product 5 disappeared (Table 1,
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