furyl aldimines; isoxazole aldimines; cyano aldimines;
and keto aldimines.
Cya n id e-Ca ta lyzed Cycliza tion s via
Ald im in e Cou p lin g
B. J esse E. Reich, Aaron K. J ustice,
Brittany T. Beckstead, J oseph H. Reibenspies, and
Stephen A. Miller*
Department of Chemistry, Texas A&M University,
College Station, Texas 77843-3255
samiller@mail.chem.tamu.edu
Received August 26, 2003
Abstr a ct: Aldimine coupling (AIC) is the nitrogen analogue
of the benzoin condensation and has been applied to dialdi-
mines, providing the first examples of cyclizations effected
by cyanide-catalyzed AIC. Sodium cyanide promoted the
facile, intramolecular cyclization of several dialdimines in
N,N-dimethylformamide, methanol, or methylene chloride/
water (phase-transfer conditions) yielding a variety of six-
membered heterocycles. Under aerobic conditions, an oxi-
dative cyclization occurs to provide the diimine heterocycle.
Oligomerization was observed with rigid dialdimines for
which cyclization was precluded.
While further investigating the scope and generality
of the aldimine dimerization reaction, we discovered the
first examples of applying this aldimine coupling (AIC)
reaction8 to the cyclization of difunctional substrates. Our
initial experiments involved the cyanide-catalyzed cy-
clization of the well-known salen ligand and its phenylene
derivative (Scheme 1). To our knowledge, these represent
The cyanide-catalyzed benzoin condensation (eq 1) was
first reported in 1824 by Stange1 and has since been the
subject of a large number of investigations.2 For example,
a detailed mechanismsattributable to Lapworth3shas
been substantiated, and several competent catalysts have
been identified.4 The corresponding aldimine variation
(eq 2) of this reaction was recognized in 1928 by Strain.5
Subsequent reports related to this aldimine reaction have
been scattered and provide comparatively little informa-
tion on substrate variability, mechanism, and reaction
scope.6 The examples reported in the literature7 are
exclusively limited to simple dimerizations (eq 3) and fall
into five general substrate classifications: aryl aldimines;
SCHEME 1. P yr a zin e a n d Qu in oxa lin e
Heter ocycles P r ep a r ed by a Novel Rin g Closin g
Ald im in e Cou p lin g Rea ction (Th er m a l Ellip soid s
Ar e Sh ow n w ith 50% P r oba bility)
* To whom correspondence should be addressed.
(1) Stange Buch. Rep. Pharm. 1824, 16 (No. 93).
(2) (a) Ide, W. S.; Buck, J . S. Org. React. 1948, 4, 269-304. (b)
Lachman, A. J . Am. Chem. Soc. 1924, 46, 708-723.
(3) (a) Lapworth, A. J . Chem. Soc. 1903, 83, 995-1005. (b) Lapworth,
A. J . Chem. Soc. 1904, 85, 1206-1213. (c) Kuebrich, J . P.; Schowen,
R. L.; Wang, M.; Lupes, M. J . Am. Chem. Soc. 1971, 93, 1214-1220.
(4) Most alternatives to cyanide are thiazole derivatives. For
example, 3,4,5-trimethylthiazolium iodide: (a) Breslow, R.; Kim, R.
Tetrahedron Lett. 1994, 35, 699-702. Thiamine: (b) Breslow, R. J .
Am. Chem. Soc. 1958, 80, 3719-3726.
(5) Strain, H. H. J . Am. Chem. Soc. 1928, 50, 2218-2223.
(6) (a) Strain, H. H. J . Am. Chem. Soc. 1929, 51, 269-273. The
dehydrogenative pinacol-type coupling of aromatic aldimines can be
effected with stoichiometric ytterbium metal and an oxidant: (b) J in,
W.-S.; Makioka, Y.; Taniguchi, Y.; Kitamura, T.; Fujiwara, Y. Chem.
Commun. 1998, 10, 1101-1102. (c) J in, W.-S.; Makioka, Y.; Kitamura,
T.; Fujiwara, Y. J . Org. Chem. 2001, 66, 514-520.
(7) (a) Aryl aldimine example: Becker, H.-D. J . Org. Chem. 1970,
35, 2099-2102. (b) Furyl aldimine example: Cariou, M.; Carlier, R.;
Simonet, J . Bull. Soc. Chim. Fr. 1986, 5, 781-792. (c) Isoxazole
example: Walia, J . S.; Guillot, L.; Singh, J .; Chattha, M. S.; Satya-
narayana, M. J . Org. Chem. 1972, 37, 135-137. (d) Cyano aldimine
example: Ferris, J . P.; Donner, D. B.; Lotz, W. J . Am. Chem. Soc. 1972,
94, 6968-6974. (e) Keto aldimine example: McKay, W. R.; Proctor,
G. R. J . Chem. Soc., Perkin Trans. 1 1981, 9, 2443-2450.
the first known examples of ring-closing aldimine cou-
pling.9 Complete characterization of the heterocycles 5,6-
(8) The benzoin condensation is technically a dimerization since the
molecular weight of benzoin is twice that of benzaldehyde. Hence, the
term “coupling” is introduced to avoid the misleading descriptor
“condensation”, and is meant to apply generally to intermolecular and
intramolecular reactions.
(9) For recent examples of intramolecular benzoin condensa-
tions (dialdehyde substrates) see: Modler-Spreitzer, A.; Fritsch, R.;
Mannschreck, A. Collect. Czech. Chem. Commun. 2000, 65, 555-560.
Yang, Z.; Wong, H. N. C.; Hon, P. M.; Chang, H. M.; Lee, C. M. J . Org.
Chem. 1992, 57, 4033-4034. Intramolecular cyclization of aldehyde-
ketone substrates has recently been reported: Hachisu, Y.; Bode, J .
W.; Suzuki, K. J . Am. Chem. Soc. 2003, 125, 8432-8433.
10.1021/jo035245j CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/27/2004
J . Org. Chem. 2004, 69, 1357-1359
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