by the Fujioka group and used as catalyst in the asymmetric
conjugate addition of ꢀ-ketoesters to nitroolefins.13
Hiemstra and co-workers developed a synthesis of bicyclic
amidine, relying on the intramolecular reaction between a
tethered amino group and a thiolactam function.17 While this
methodology was effective, the use of Lawesson’s reagent
and lengthy synthetic sequence required for the preparation
of the key intermediate limited its applications. Shibasaki
and co-workers recently disclosed an elegant approach which
utilized an intramolecular cyclization of azido lactams. By
employing the substrates with a properly installed azido
group, facile cyclization occurred to yield a range of bicyclic
amidines.18 It was also reported that benzimidazoles can be
prepared by the condensation between benzene-1,2-diamines
and pivalaldehyde;19 however, strong acidic conditions have
to be employed and reactions typically proceeded in poor
yields.
Our group has been actively investigating amino catalysis
in the past few years, particularly those processes involving
primary amino acid/primary amine based catalysts. We have
applied a number of natural amino acids or their simple
structural derivatives in a range of asymmetric organic
reactions.14 Very recently, we started an exploration of
developing novel and efficient organic catalysts derived from
amino acids. As a proof of concept study, a tryptophan-based
bifunctional thiourea catalyst was designed and shown to
be remarkably effective in promoting enantioselective Man-
nich reactions of R-fluoro-ꢀ-ketoesters.15 Given the impor-
tance of chiral amidines in asymmetric synthesis and
catalysis, we were intrigued by the possibility of deriving
chiral cyclic amidines from natural amino acids. As shown
in Scheme 1, starting from proline, bicyclic amidines may
Our proposed synthetic strategy is illustrated in Scheme
2. We envisaged that cyclic amidines can be synthesized from
Scheme 2
.
Synthesis of Cyclic Amidines from Amino Acids/
Chiral Diamines
Scheme 1. Preparation of Bicyclic Amidines or Chiral
Imidazolines from Natural Amino Acids
be synthesized, and utilization of primary amino acids could
lead to the preparation of a range of chiral imidazolines.
Herein, we wish to report a novel approach for the synthesis
of chiral bicyclic amidines and imidazolines from readily
available 1,2-diamines.
In general, there are three methods commonly used for
the preparation of bicyclic amidines, which all employ an
intramolecular reaction between a nitrogen nucleophile and
properly activated lactam.Yamamoto and Maruoka reported
an efficient synthesis of bicyclic amidines via an intramo-
lecular nucleophilic attack of a free amino group on a lactam
in the presence of TiCl4. Alternatively, the corresponding
iminoether could be used; however, its preparation involved
strong acidic conditions.16 Apparently, harsh reaction condi-
tions posed severe disadvantages to this synthetic approach.
1,2-diamines and a properly designed condensation partner.
R-Amino acids are abundant in nature, and they can offer
easy access to various chiral 1,2-diamines with great
structural diversity. N-Phenyl imidoyl chloride intermediate
(a), which can be readily obtained from the corresponding
N-phenyl carboxylic amide, seems to be a good choice for
the condensation reaction.20 Monoprotected diamine is
expected to react with chloride a to yield amidine intermedi-
ate b, the subsequent intramolecular cyclization via a
nucleophilic attack of the neighboring amino group is
anticipated to afford cyclic amidine, expelling one molecule
of aniline at the same time.
(13) Murai, K.; Fukushima, S.; Hayashi, S.; Takahara, Y.; Fujioka, H.
Org. Lett. 2010, 12, 964.
(14) For reviews on primary amino acids and primary amines in
asymmetric catalysis, see: (a) Xu, L.-W.; Luo, J.; Lu, Y. Chem. Commun.
2009, 1807. (b) Xu, L.-W.; Lu, Y. Org. Biomol. Chem. 2008, 6, 2047. (c)
Peng, F.; Shao, Z. J. Mol. Catal. A 2008, 285, 1. (d) Chen, Y.-C. Synlett
2008, 1919. (e) Bartoli, G.; Melchiorre, P. Synlett 2008, 1759. For our work
on primary amino acid/amine mediated organocatalysis, see: (f) Jiang, Z.;
Liang, Z.; Wu, X.; Lu, Y. Chem. Commun. 2006, 2801. (g) Cheng, L.;
Han, X.; Huang, H.; Wong, M. W.; Lu, Y. Chem. Commun. 2007, 4143.
(h) Cheng, L.; Wu, X.; Lu, Y. Org. Biomol. Chem. 2007, 5, 1018. (i) Wu,
X.; Jiang, Z.; Shen, H.-M.; Lu, Y. AdV. Synth. Catal. 2007, 349, 812. (j)
Zhu, Q.; Lu, Y. Chem. Commun. 2008, 6315. (k) Zhu, Q.; Lu, Y. Chem.
Commun. 2010, 46, 2235. (l) Jiang, Z.; Yang, H.; Han, X.; Luo, J.; Wong,
M. W.; Lu, Y. Org. Biomol. Chem. 2010, 8, 1368. (m) Jiang, Z.; Lu, Y.
Tetrahedron Lett. 2010, 51, 1884. (n) Liu, C.; Lu, Y. Org. Lett. 2010, 12,
2278.
(17) (a) Kotsuki, H.; Sugino, A.; Sakai, H.; Yasuoka, H. Heterocycles
2000, 53, 2561. (b) Ostendorf, M.; Dijkink, J.; Rutjes, F. P.; Hiemstra, H.
Eur. J. Org. Chem. 2000, 115. (c) Dijkink, J.; Eriksen, K.; Goubitz, K.;
Van Zanden, M. N. A.; Hiemstra, H. Tetrahedron: Asymmetry 1996, 7,
515.
(18) Kumagai, N.; Matsunaga, S.; Shibasaki, M. Angew. Chem., Int.
Ed. 2004, 43, 478.
(19) Huang, H.-S.; Chen, T.-C.; Chen, R.-H.; Huang, K.-F.; Huang, F.-
C.; Jhan, J.-R.; Chen, C.-L.; Lee, C.-C.; Lo, Y.; Lin, J.-J. Bioorg. Med.
Chem. 2009, 17, 7418.
(15) Han, X.; Kwiatkowski, J.; Xue, F.; Huang, K.-W.; Lu, Y. Angew.
Chem., Int. Ed. 2009, 48, 7604.
(20) N-Alkyl imidoyl chloride intermediates were too unstable to be
employed in the synthesis.
(16) Yamamoto, H.; Maruoka, K. J. Am. Chem. Soc. 1981, 103, 4186.
Org. Lett., Vol. 12, No. 18, 2010
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