Table 1. Catalyst and Condition Optimizationa
Figure 1. Phosphine-catalyzed (formal) [3 þ 2] and [2 þ 4]
entry
cat.
Ad
solvent
yield (%)b
ee (%)c
reactions.
1
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
0
ꢀ
2
PPh3
B1
B2
B3
B4
B5
C
51
49
55
62
61
10
22
43
39
61
50
70
14
6
ꢀ
equivalents as three carbon synthons for Lu’s [3 þ 2]
reactions.8ꢀ10 The related [4 þ 2] reactions using phosphine
or nucleophilic NHC catalysts, on the other hand, are much
less developed. In 2003, Kown and co-workers initiated the
use of R-substituted allenoates as four carbon synthons in
[4 þ 2] reactions to make tetrahydropyridines (Figure 1a).11
Further variants, including enantioselective reactions of the
Kown-type [4 þ 2] cycloadditions based on R-substituted
allenoates, were realized by the groups of Fu,12a Kown,12b,c,e,g
Zhao,12f and Lu.12h In 2008, Waldmann, Kumar and
co-workers released the first report of phosphine-catalyzed
activation of electron-deficient alkynes (nonallenoate-
based substrates) for [2 þ 4] reactions with oxo-dienes
(Figure 1a);13 no asymmetric versions of such [2 þ 4]
3
97
99
93
98
64
75
97
97
99
98
93
77
93
88
99
4
5
6
7
8
9
B2
B2
B2
B2
B2
B2
B2
B2
B2e
10
11
12
13
14
15
16
17
dioxane
toluene
Et2O
MeCN
EtOH
hexane
DMF
50
80
toluene
a Unless otherwise noted, all the reactions were carried out at rt using
1a (0.10 mmol), 10 mol % of catalyst, and 0.5 mL of solvent. b Isolated
yield. c Enantiomeric excess of 2a, determined via chiral HPLC. d 20 mol
% of Et3N was added. e 5.0 mol % of catalyst was used.
(9) Zhang reported the first chiral version of Lu’s [3 þ 2] cycloaddi-
tion; see: (a) Zhu, G.; Chen, Z.; Jiang, Q.; Xiao, D.; Cao, P.; Zhang, X.
J. Am. Chem. Soc. 1997, 119, 3836. Miller pioneered the use of amino
acid derived chiral phosphines as organocatalyst; see: (b) Cowen, B. J.;
Miller, S. J. J. Am. Chem. Soc. 2007, 129, 10988. Jacobsen introduced
the first chiral bifunctional phosphine-thiourea catalyst in this type of
[3 þ 2] reaction, see: (c) Fang, Y. Q.; Jacobsen, E. N. J. Am. Chem. Soc.
2008, 130, 5660.
(10) For other elegant examples on asymmetric phosphine catalyzed
[3þ 2] reactions, see: (a) Wilson, J. E.; Fu, G. C. Angew. Chem., Int. Ed. 2006
45, 1426. (b) Voituriez, A.; Panossian, A.; Fleury-Bregeot, N.; Retailleau
P.; Marinetti, A. J. Am. Chem. Soc. 2008, 130, 14030. (c) Xiao, H.; Chai, Z.;
Zheng, C.-W.; Yang, Y.-Q.; Liu, W.; Zhang, J.-K.; Zhao, G. Angew.
Chem., Int. Ed. 2010, 49, 4467. (d) Fujiwara, Y.; Fu, G. C. J. Am. Chem.
Soc. 2011, 133, 12293. (e) Han, X.; Wang, S.-X.; Zhong, F.; Lu, Y. Synthesis
2011, 1859. (f) Zhong, F.; Han, X.; Wang, Y.; Lu, Y. Angew. Chem., Int. Ed.
2011, 50, 7837. (g) Tan, B.; Candeias, N. R.; Barbas, C. F., III. J. Am. Chem.
Soc. 2011, 133, 4672. (h) Han, X.; Wang, Y.; Zhong, F.; Lu, Y. J. Am.
Chem. Soc. 2011, 133, 1726. (i) Zhao, Q.-Y.; Han, X.; Wei, Y.; Shi, M.; Lu,
Y. Chem. Commun. 2012, 48, 970. (j) Han, X.; Zhong, F.; Wang, Y.; Lu, Y.
Angew. Chem., Int. Ed. 2012, 51, 767.
(11) Zhu, X.-F.; Lan, J.; Kwon, O. J. Am. Chem. Soc. 2003, 125, 4716.
(12) (a) Wurz, R. P.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 12234.
(b) Tran, Y. S.; Kwon, O. J. Am. Chem. Soc. 2007, 129, 12632. (c) Guo, H.;
Xu,Q.;Kwon,O.J. Am. Chem. Soc. 2009,131, 6318. (d) Wang, T.; Ye, S. Org.
Lett. 2010, 12, 4168. (e) Tran, Y. S.; Martin, T. J.; Kwon, O. Chem.;Asian
J. 2011, 6, 2101. (f) Xiao, H.; Chai, Z.; Wang, H.-F.; Wang, X.-W.; Cao,
D.-D.; Liu, W.; Lu, Y.-P.; Yang, Y.-Q.; Zhao, G. Chem.;Eur. J. 2011,
11, 10562. (g) Na, R.; Jing, C.; Xu, Q.; Jiang, H.; Wu, X.; Shi, J.; Zhong,
J.; Wang, M.; Benitez, D.; Tkatchouk, E.; Goddard, W. A., III; Guo, H.;
Kwon, O. J. Am. Chem. Soc. 2011, 133, 13337. (h) Zhong, F.; Han, X.;
Wang, Y.; Lu, Y. Chem. Sci. 2012, 3, 1231.
(13) (a) Waldmann, H.; Khedhar, V.; Duckert, H.; Schurmann, M.;
Oppel, I. M.; Kumar, K. Angew. Chem., Int. Ed. 2008, 47, 6869. (b)
Duckert, H.; Khedkar, V.; Waldmann, H.; Kumar, K. Chem.;Eur.
J. 2011, 17, 5130. For a related enantioselective [2 þ 3] reaction based on
electron-deficient alkynes, see: (c) Sampath, M.; Loh, T.-P. Chem. Sci.
2010, 1, 739.
reactions have been reported. Here we report the first
chiral phosphine-catalyzed activation of electron-deficient
alkenes14 for intramolecular formal [2 þ 4] reactions
with R,β-unsaturated imines (Figure 1b). The bicyclic N,
O-containing compounds were obtained as essentially a
single diastereomer with 99% ee. Asymmetric transforma-
tions of the catalytic products led to potentially useful
molecules suchasfunctionalizedpyridines and piperidines.
We started by first identifying suitable catalysts for the
activation of acrylates as two carbon building blocks for
(formal) [2 þ 4] intramolecular reactions with unsaturated
imines (Table 1). Our efforts with N-heterocyclic carbenes
(such as A)15 and cinchona alkaloid-based nucleophilic
(14) During the preparation of this manuscript, Sasai et al. reported
an excellent chiral phosphine-catalyzed enantioselective intramolecular
RauhutꢀCurrier reaction of electron-deficient alkenes; see: Takizawa,
S.; Nguyen, T. M.-N.; Grossmann, A.; Enders, D.; Sasai, H. Angew.
Chem., Int. Ed. 2012, 51, 5423.
(15) For N-heterocyclic carbene-catalyzed BaylisꢀHillman-type re-
actions, see: (a) He, L.; Jian, T.-Y.; Ye, S. J. Org. Chem. 2007, 72, 7466.
(b) He, L.; Zhang, Y.-R.; Huang, X.-L.; Ye, S. Synthesis 2008, 2825. For
examples of our efforts on NHC catalyzed-reactions, see: (c) Fang, X.;
Jiang, K.; Xing, C.; Hao, L.; Chi, Y. R. Angew. Chem., Int. Ed. 2011, 50,
1910. (d) Fang, X.; Chen, X.; Chi, Y. R. Org. Lett. 2011, 13, 4708.
(e) Fang, X.; Chen, X.; Lv, H.; Chi, Y. R. Angew. Chem., Int. Ed. 2011,
50, 11782. (f) Hao, L.; Du, Y.; Lv, H.; Chen, X.; Jiang, H.; Shao, Y.; Chi,
Y. R. Org. Lett. 2012, 14, 2154.
B
Org. Lett., Vol. XX, No. XX, XXXX