A Remarkable Titanium-Catalyzed Asymmetric Strecker Reaction using Hydrogen Cyanide
References
nitriles (IV, Scheme 4) and regenerates the TMSCN
for further addition to imines. A similar catalytic
cycle was proposed by Shibasaki et al.[9b] for the cyan-
ation of N-fluorenylimines using the mixture of
TMSCN and HCN. Our proposed mechanistic cycle
does not provide a rationale for the observed enantio-
selectivities and further investigation on the reaction
intermediates and the structure of the catalyst is
needed.
In summary, a highly enantioselective cyanation of
imines using HCN is described at room temperature.
In view of the importance of natural and unnatural a-
amino acids in the fine chemicals and pharmaceutical
industries, the current methodology offers the possi-
bility of utilizing the Strecker reaction economically
for large-scale synthesis. The mild reaction conditions
and the operational simplicity render this atom-eco-
nomic cyanation process extremely attractive. To the
best of our knowledge, this is the first report on the
enantioselective Strecker reaction at room temperature
using HCN as the cyanide source that gives a very
high level of enantioselectivity up to 98% ee.
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Experimental Section
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General Procedure for the Asymmetric Cyanation of
Imines
Caution: HCN is an extremely poisonous liquid and boils at
268C. Proper safety precautions will need to be adhered to
and appropriate safety equipment for example, cyanide detec-
tor and personal protection equipment MUST be used. Reac-
tions must be carried out in a well ventilated fume hood.
To the chiral ligand (0.02 mmol) in toluene (0.10 mL),
PHTA precatalyst[13] (0.20 mL, 0.02 mmol) was added and
stirred for 15 min. Imine (0.20 mmol) and trimethylsilyl cya-
nide (0.02 or 0.05 mmol) were added to the catalyst solution
in order. HCN[14] (0.24 mmol, 0.48 mL of 0.50M solution in
toluene) was added slowly over the period of 1 h using a sy-
ringe pump. After the addition was complete, the reaction
mixture was stirred at room temperature (238C) for 1–2 h.
The reaction mixture was filtered through celite, washed
with dichloromethane and the solvent evaporated to dry-
ness. In many cases no further purification was necessary.
HPLC analysis of the amino nitriles was performed to deter-
mine the enantiomeric excess (ee).
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This work was supported by the Agency for Science, Technol-
ogy and Research (A*STAR), Singapore and Mitsui Chemi-
cals Inc.
Adv. Synth. Catal. 2010, 352, 2153 – 2158
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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