DOI: 10.1002/chem.201302007
Oxazoline-Based Organocatalyst for Enantioselective Strecker Reactions: A
Protocol for the Synthesis of Levamisole
Arghya Sadhukhan,[a] Debashis Sahu,[b, c] Bishwajit Ganguly,*[b, c] Noor-ul H. Khan,*[a, c]
Rukhsana I. Kureshy,[a, c] Sayed H. R. Abdi,[a, c] E. Suresh,[b, c] and Hari C. Bajaj[a, c]
Abstract: A chiral oxazoline-based or-
ganocatalyst has been found to effi-
ciently catalyze asymmetric Strecker
reactions of various aromatic and ali-
phatic N-benzhydrylimines with trime-
thylsilyl cyanide (TMSCN) as a cyanide
source at À208C to give a-aminoni-
triles in high yield (96%) with excel-
lent chiral induction (up to 98% ee).
DFT calculations have been performed
to rationalize the enantioselective for-
mation of the product with the organo-
catalyst in these reactions. The organo-
catalyst has been characterized by
single-crystal X-ray diffraction analysis,
as well as by other analytical methods.
This protocol has been extended to the
synthesis of the pharmaceutically
important drug molecule levamisole in
Keywords: aminonitriles · enantio-
selectivity · organocatalysis · oxazo-
line · Strecker reaction
high
yield
and
with
high
enantioselectivity.
Introduction
transfer catalysts.[18,19] Close inspection of previous reports
reveals that the activity of an organocatalyst mainly depends
on weakly acidic sites capable of forming hydrogen bonds
with the substrate, and at the same time weakly basic sites
are also required in order to activate the cyanide source.[19]
With this understanding, we designed an organocatalyst in
which an oxazoline ring is appended to a sulfonamide group
(Figure 1). Such a design should not only fulfill the require-
Chiral a-aminonitriles constitute a valuable class of com-
pounds[1–4] and can be synthesized by an elegant asymmetric
Strecker reaction.[5] Although in the last ten years both
metal-containing[6] and metal-free[7] asymmetric Strecker re-
actions have been accomplished, metal-free protocols are
desirable in the pharmaceutical industry in order to avoid
metal contamination in the final drug formulations. Lipton
et al.[8] in 1996 were the first to apply organocatalysis (a
chiral cyclic dipeptide) to the asymmetric Strecker reaction,
which was followed by various other organocatalysts, such
as bicyclic guanidine,[9] ureas and thioureas,[10] carbohy-
drates,[11] N-oxides,[12] bisformamides,[13] ammonium salts,[14]
Brønsted acids,[15] amino acids,[16] alkaloids,[17] and phase-
[a] A. Sadhukhan, Dr. N.-u. H. Khan, Dr. R. I. Kureshy,
Dr. S. H. R. Abdi, Dr. H. C. Bajaj
Figure 1. Structural features of the organocatalyst.
Discipline of Inorganic Materials and Catalysis
Central Salt & Marine Chemicals Research Institute
(CSIR-CSMCRI)
ment of acidic and basic sites, but also facilitate the con-
struction of analogues with varying steric features, which is
critical for practical application. Although oxazoline deriva-
tives have been used as ligands with metals for various
asymmetric transformations, they have been rarely used as
organocatalysts.[20] The design of the present catalyst also
allows flexibility in terms of creating chiral centers with
matched or mismatched stereogenicity, which may have a
bearing on the product enantioselectivity. As anticipated, all
of the catalysts with the present design were found to be
fairly active (product yield up to 93%) at a moderate reac-
tion temperature (À208C). However, the catalyst (S,S)-1j
gave a-aminonitriles with excellent enantioselectivity (up to
98% ee in some cases) with trimethylsilyl cyanide (TMSCN)
as the cyanide source. We also extended the present
G.B. Marg, Bhavnagar, 364002 (India)
[b] D. Sahu, Dr. B. Ganguly, Dr. E. Suresh
Computation and Simulation Unit
(Analytical Discipline and Centralized Instrument Facility)
Central Salt & Marine Chemicals Research Institute
(CSIR-CSMCRI)
G.B. Marg, Bhavnagar, 364002 (India)
[c] D. Sahu, Dr. B. Ganguly, Dr. N.-u. H. Khan, Dr. R. I. Kureshy,
Dr. S. H. R. Abdi, Dr. E. Suresh, Dr. H. C. Bajaj
Academy of Scientific and Innovative Research
Central Salt & Marine Chemicals Research Institute
(CSIR-CSMCRI)
Bhavnagar, 364002 (India)
Supporting information for this article is available on the WWW
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Chem. Eur. J. 2013, 19, 14224 – 14232