C O M M U N I C A T I O N S
Table 1. Sulfinyl Urea Catalyzed Aza-Henry Reaction
Table 3. Catalytic Enantioselective Aza-Henry Reaction with
Representative N-Boc Imines
conva
(%)
drb
10 eeb
entry
catalyst
(10:11)
(%)
major
yielda
(%)
drb
10 eeb
entry
R
R
′
product
(10:11)
(%)
1
2
3
4
5
6
7
8
9
none
4a
6a
6b
6c
6d
6e
7a
7b
8a
23
75
59
17
36
73
71
85
56
82
25:75
18:82
57:43
30:70
50:50
38:62
16:84
75:25
45:55
80:20
0
10
30
0
28
5
1
2
3
4
5
6
7
8
9
C6H5
Me
Me
Me
Me
Me
Me
Me
Me
Bn
H
10a
10b
10c
10d
10e
10f
10g
10h
10i
84
64
68
92
88
80
80
76
62
64
85:15
90:10
79:21
77:23
80:10
84:16
92:8
95
95
95
92
94
93
96
96
96
95
p-MeOC6H4
p-MeC6H4
p-CF3C6H4
o-ClC6H4
2-naphthyl
n-Bu
8
89
60
-90c
i-Bu
i-Bu
i-Bu
93:7c
88:12
10
10
10j
a Conversion to product was determined by H NMR analysis of crude
product relative to hexamethylbenzene as an internal standard. b Diaste-
reomeric ratio and enantiomeric excess were determined by chiral HPLC.
c Opposite enantiomer obtained as the major product.
1
a Isolated yield after chromatography. b Diastereomeric ratio and enan-
tiomeric excess were determined by chiral HPLC. c Absolute configuration
rigorously determined by chemical correlation (see Supporting Information).
Table 2. Sulfinyl Urea Catalyzed Aza-Henry Reaction
In conclusion, N-sulfinyl ureas are a new class of organocatalysts
with the sulfinyl group serving both as an acidifying agent and as
a chiral controlling element. The effectiveness of this class of
organocatalysts was demonstrated by catalysis of the aza-Henry
reaction with high selectivity, including the first examples of
enantioselective H-bonding-catalyzed additions to aliphatic N-Boc
imines.
conva
(%)
drb
10 eeb
entry
catalyst
(10:11)
(%)
Acknowledgment. The support of NSF (CHE-0446173) and
Merck is gratefully acknowledged.
1
2
3
4
5
6
7
8
8a
8b
8c
8d
8e
8f
99
42
90
73
99
35
82
65
83:17
43:57
71:29
19:81
21:79
26:74
83:17
76:24
94
58
80
-7
0
16
80
79
Supporting Information Available: Experimental procedures and
characterization data. This material is available free of charge via the
8g
8h
References
(1) For reviews of H-bonding organocatalysis, see: (a) Taylor, M. S.;
Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520. (b) Connon, S.
J. Chem.sEur. J. 2006, 12, 5418. (c) Takemoto, Y. Org. Biomol. Chem.
2005, 3, 4299. (d) Schreiner, P. R. Chem. Soc. ReV. 2003, 32, 289.
(2) Other sulfinamide-based catalysts: (a) Owens, T. D.; Hollander, F. J.;
Oliver, A. G.; Ellman, J. A. J. Am. Chem. Soc. 2001, 123, 1539-1540.
(b) Owens, T. D.; Souers, A. J.; Ellman, J. A. J. Org. Chem. 2003, 68,
3-10. (c) Schenkel, L. B.; Ellman, J. A. Org. Lett. 2003, 5, 545-548.
(d) Pei, D.; Wang, Z. Y.; Wei, S. Y.; Zhang, Y.; Sun, J. Org. Lett. 2006,
8, 5912-5915. (e) Sola, J.; Reves, M.; Riera, A.; Verdaguer, X. Angew.
Chem., Int. Ed. 2007, 46, 5020-5023. (f) Tan, K. L.; Jacobsen, E. N.
Angew. Chem., Int. Ed. 2007, 46, 1315-1317.
1
a Conversion to product was determined by H NMR analysis of crude
product relative to hexamethylbenzene as an internal standard. b Diaste-
reomeric ratio and enantiomeric excess were determined by chiral
HPLC.
(Table 3). Excellent enantioselectivity was observed with imines
bearing both electron-rich and electron-poor aromatic substituents
(entries 1-6). More significantly, aliphatic N-Boc imines were
found to be effective substrates, yielding adducts 10g-j, which
were previously unreported, with very high selectivity. High
diastereoselectivities and enantioselectivities were achieved with
additions to unbranched and â-branched imine substrates (entries
7-10). The addition of â-phenylnitroethane to give 10i with high
selectivity demonstrates that larger nitroalkanes can be used (entry
9), and the addition of nitromethane to give 10j demonstrates that
high enantioselectivity can be achieved even when a product that
lacks R-branching is obtained (entry 10).
(3) Other organocatalytic aza-Henry reactions: (a) Yoon, T. P.; Jacobsen, E.
N. Angew. Chem., Int. Ed. 2005, 44, 466. (b) Okino, T.; Nakamura, S.;
Furukawa, T.; Takemoto, Y. Org. Lett. 2004, 6, 625. (c) Xu, X.; Furukawa,
T.; Okino, T.; Miyabe, H.; Takemoto, Y. Chem.sEur. J. 2006, 12, 466.
(d) Bernardi, L.; Fini, F.; Herrera, R. P.; Ricci, A.; Sgarzani, V.
Tetrahedron 2005, 62, 375. (e) Nugent, B. M.; Yoder, R. A.; Johnston, J.
N. J. Am. Chem. Soc. 2004, 126, 341. (f) Sohtome, Y.; Hashimoto, Y.;
Nagasawa, K. AdV. Synth. Catal. 2005, 347, 1643.
(4) Matthews, W. S.; Bares, J. E.; Bartmess, J. E.; Bordwell, F. G.; Cornforth,
F. J.; Drucker, G. E.; Margolin, Z.; McCallum, R. J.; McCollum, G. J.;
Vanier, N. R. J. Am. Chem. Soc. 1975, 97, 7006.
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