Azlactone, possessing both nucleophilic and electro-
philic properities, enables a wide variety of synthetically
important transformations.5 For instance, the Mannich-
type reaction6 of aldimines with azlactones at the nucleo-
philic C-4 position has been well-studied to access the
R-disubstituted R,β-diamino acid derivatives (Scheme 1,
path a). Herein, taking advantage of both the nucleophi-
lic site at C-4 and electrophilic site at C-5 of azlactones,7
Table 1. Optimization of the Reaction Conditionsa
Scheme 1. Reactions of Azlactones with Aldimines
ee (%)c
t
yield
entry
cat.
(°C) (%)b cis:transc cis-6a trans-6a
1
2a
2a
2a
2b
3
0
0
90
90
98
98
92
92
92
98
80:20
80:20
80:20
80:20
20:80
25:75
20:80
15:85
89
92
À94
À94
À96
96
2d
3d
4d
5
À20
À20
0
94f
À94
À15
À5
we achieved the first asymmetric synthesis of optically
active 3,4-diaminochroman-2-ones8 from the domino
reaction of azlactones with o-hydroxy aromatic aldi-
mines (Scheme 1, path b).9 An interesting switch of
cis/trans selectivity was observed by the use of chiral
guanidine10 and bisguanidium salt11 catalysts. Both cis-
and trans-3,4-diaminochroman-2-ones were obtained in
excellent yields (up to 99%) with excellent diastereo- and
40
6e
7d,e
8d,e
3 HBArF
0
94
4
4
4
3
3
3
3 HBArF
0
À10
95
96f
3 HBArF
À20
À15
a Unless otherwise noted, all reactions were carried out with 2
(10 mol %) or 3 (5 mol %), 4a (0.15 mmol), and 5a (0.10 mmol) in
toluene (1.0 mL) at 0 °C for 4À7 h. b Isolated yield of the two diaster-
eomers. c Determined by chiral HPLC analysis. d THF/toluene (1/1, v/v)
was used as the solvent. e HBArF4 = HB[3,5-(CF3)2C6H3]4. f The abso-
lute configurations of cis-6a (3S, 4S) and trans-6a (3S, 4R) were both
determined by X-ray analysis.13
(5) For reviews, see: (a) Fisk, J. S.; Mosey, R. A.; Tepe, J. J. Chem.
Soc. Rev. 2007, 36, 1432. (b) Mosey, R. A.; Fisk, J. S.; Tepe, J. J.
Tetrahedron: Asymmetry 2008, 19, 2755. (c) Hewlett, N. M.; Hupp,
C. D.; Tepe, J. J. Synthesis 2009, 2825. (d) R. Alba, A.-N.; Rios, R.
Chem.;Asian J. 2011, 6, 720.
(6) (a) Uraguchi, D.; Ueki, Y.; Ooi, T. J. Am. Chem. Soc. 2008, 130,
14088. (b) Liu, X. D.; Deng, L. J.; Jiang, X. X.; Yan, W. J.; Liu, C. L.;
Wang, R. Org. Lett. 2010, 12, 876.
(7) (a) Jiang, J.; Qing, J.; Gong, L. Z. Chem.;Eur. J. 2009, 15, 7031.
(b) Dong, S. X.; Liu, X. H.; Chen, X. H.; Mei, F.; Zhang, Y. L.; Lin,
L. L.; Feng, X. M. J. Am. Chem. Soc. 2010, 132, 10650. (c) Terada, M.;
Nii, H. Chem.;Eur. J. 2011, 17, 1760.
(8) Kumar, P.; Mukerjee, A. K. Indian J. Chem., Sect. B 1981, 20B,
418.
enantioselectivities (up to >99:1 dr, 99% ee). This
method could provide all optically active isomers, which
is highly important and valuable in pharmaceutical and
bioorganic chemistry due to the remarkable biological
discrepancy of different enantiomers.12
Initially, catalytic amounts of a Brønsted base (for
example, DABCO) were found to promote the domino
reaction8 of o-hydroxy benzaldimine 4a with azlactone 5a
efficiently under mild reaction conditions to provide race-
mic diaminochroman-2-one 6a. Then, a series of chiral
guanidines were screened to access the optically pure
product. It was found that (S)-pipecolic acid derived
guanidine 2a could catalyze the reaction smoothly, afford-
ing the major cis-6a with a moderate dr value and
high enantioselectivity for both isomers (Table 1, entry 1).
Using the mixed solvent of THF/toluene (v/v, 1:1) and
lowering the reaction temperature further enhanced the
enantioselectivity to 94% ee for cis-6a and 96% ee for
trans-6a, but the diastereoselectivity did not increase
(Table 1, entries 2 and 3). Notably, the cis-product with
reversed enantioselectivity was dominantly obtained by
(R)-pipecolic acid derived guanidine as expected (Table 1,
(9) For selected examples of domino reactions involving o-hydroxy
aromatic aldimines, see: (a) Rueping, M.; Lin, M. Y. Chem.;Eur. J.
2010, 16, 4169. (b) Xie, P.; Huang, Y.; Chen, R. Org. Lett. 2010, 12, 3768.
(c) Xie, Y. W.; Guan, X. Y.; Shi, M. Org. Lett. 2010, 12, 5664. (d)
ꢀ
ꢀ~
Aleman, J.; Nunez, A.; Marzo, L.; Marcos, V.; Alvarado, C.; Ruano,
J. L. G. Chem.;Eur. J. 2010, 16, 9453.
(10) For reviews on chiral guanidine catalysts, see: (a) Ishikawa, T.;
Isobe, T. Chem.;Eur. J. 2002, 8, 552. (b) Leow, D.; Tan, C. H. Chem.;
Asian J. 2009, 4, 488. For selected examples, see:(c) Corey, E. J.;
Grogan, M. J. Org. Lett. 1999, 1, 157. (d) Ishikawa, T.; Araki, Y.;
Kumamoto, T.; Seki, H.; Fukuda, K.; Isobe, T. Chem. Commun. 2001,
245. (e) Liu, H.; Leow, D.; Huang, K. W.; Tan, C. H. J. Am. Chem. Soc.
2009, 131, 7212. (f) Yu, Z. P.; Liu, X. H.; Zhou, L.; Lin, L. L.; Feng,
X. M. Angew. Chem., Int. Ed. 2009, 48, 5195. (g) Ube, H.; Shimada, N.;
Terada, M. Angew. Chem., Int. Ed. 2010, 49, 1858. (h) Misaki, T.;
Kawano, K.; Sugimura, T. J. Am. Chem. Soc. 2011, 133, 5695. (i) Chen,
X. H.; Dong, S. X.; Qiao, Z.; Zhu, Y.; Xie, M. S.; Lin, L. L.; Liu, X. H.;
Feng, X. M. Chem.;Eur. J. 2011, 17, 2583.
(11) (a) Uyeda, C.; Jacobsen, E. N. J. Am. Chem. Soc. 2008, 130,
9228. (b) Fu, X.; Loh, W. T.; Zhang, Y.; Chen, T.; Ma, T.; Liu, H. J.;
Wang, J. M.; Tan, C. H. Angew. Chem., Int. Ed. 2009, 48, 7387. (c)
€
Tanaka, S.; Nagasawa, K. Synlett 2009, 667. (d) Uyeda, C.; Rotheli,
(12) For reviews, see: (a) Zanoni, G.; Castronovo, F.; Franzini, M.;
Vidari, G.; Giannini, E. Chem. Soc. Rev. 2003, 32, 115. (b) Sibi, M. P.;
Liu, M. Curr. Org. Chem. 2001, 5, 719.
A. R.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2010, 49, 9753. (e) Uyeda,
C.; Jacobsen, E. N. J. Am. Chem. Soc. 2011, 133, 5062.
Org. Lett., Vol. 13, No. 19, 2011
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