Chiral phosphine Lewis bases catalyzed asymmetric aza-Baylis-Hillman reaction of N-sulfonated imines with activated olefins

Article abstract of DOI:10.1021/ja0447255

In the aza-Baylis-Hillman reaction of N-sulfonated imines (N-arylmethylidene-4-methylbenzenesulfonamides and others) with methyl vinyl ketone, ethyl vinyl ketone, and acrolein, we found that, in the presence of a catalytic amount of chiral phosphine Lewis

Full text of DOI:10.1021/ja0447255

Published on Web 02/26/2005
Chiral Phosphine Lewis Bases Catalyzed Asymmetric
aza-Baylis-Hillman Reaction of N-Sulfonated Imines with
Activated Olefins
Min Shi,* Lian-Hui Chen, and Chao-Qun Li
Contribution from the State Key Laboratory of Organometallic Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
Received September 1, 2004; E-mail: mshi@pub.sioc.ac.cn
Abstract: In the aza-Baylis-Hillman reaction of N-sulfonated imines (N-arylmethylidene-4-methylben-
zenesulfonamides and others) with methyl vinyl ketone, ethyl vinyl ketone, and acrolein, we found that, in
the presence of a catalytic amount of chiral phosphine Lewis base such as (R)-2′-diphenylphosphanyl-
[1,1′]binaphthalenyl-2-ol LB1 (10 mol %) and molecular sieve 4A, the corresponding aza-Baylis-Hillman
adducts could be obtained in good yields with good to high ee (70-95% ee) at low temperature (∼-30 to
-20 °C) or at room temperature in THF, respectively. In CH2Cl2 upon heating at 40 °C, the aza-Baylis-
Hillman reaction of N-sulfonated imines with phenyl acrylate or naphthyl acrylate gave the adducts in good
to high yields (60-97%) with moderate ee (52-77%). The mechanistic insight has been investigated by
1
31P and H NMR spectroscopic measurements. The key enolate intermediate, which has been stabilized
1
by intramolecular hydrogen bonding, has been observed by 31P and H NMR spectroscopy. An effective
bifunctional Lewis base and Brønsted acid phosphine Lewis base system has been disclosed in this catalytic,
asymmetric aza-Baylis-Hillman reaction.
Introduction
the normal aza-Baylis-Hillman adducts in good yields for many
N-sulfonated imines 1 under mild conditions because the
Great progress has been made in the execution of the Baylis-
Hillman reaction,1 for which several catalytic, asymmetric
versions have been published2,3 since Baylis and Hillman first
reported the reaction of acetaldehyde with ethyl acrylate and
acrylonitrile in the presence of catalytic amounts of strong Lewis
base (LB) such as 1,4-diazabicyclo[2,2,2]octane (DABCO) in
1972.4 However, the catalytic, asymmetric Baylis-Hillman
reaction is still not fruitful, because it is limited to the specialized
R,â-unsaturated ketones or acrylates such as ethyl vinyl ketone
(EVK) (71% ee),2a 2-cyclohexen-1-one (96% ee),2b or 1,1,1,3,3,3-
hexafluoroisopropyl acrylate (99% ee)2c and naphthyl acrylate
(91% ee).2d For the simplest methyl vinyl ketone (MVK), 81%
ee has been attained in the presence of a special nucleophile-
loaded peptide and L-proline.2e No high enantioselectivity
(>90% ee) has thus far been reported in Baylis-Hillman
reactions involving simple Michael acceptors such as MVK or
methyl acrylate by a chiral Lewis base promoter.
N-sulfonated imino group has high reactivity toward nucleo-
philic attack, even when the phenyl ring bears electron-donating
groups.4,6b We then sought a suitable chiral Lewis base for a
catalytic, asymmetric version of this reaction. Previously, we
reported an unprecedented catalytic, asymmetric aza-Baylis-
(2) (a) Barrett, A. G. M.; Cook, A. S.; Kamimura, A. Chem. Commun. 1998,
2533-2534. (b) McDougal, N. T.; Schaus, S. E. J. Am. Chem. Soc. 2003,
125, 12094-12095. (c) Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.;
Hatakeyama, S. J. Am. Chem. Soc. 1999, 121, 10219-10220. (d) Yang,
K.-S.; Lee, W.-D.; Pan, J.-F.; Chen, K.-M. J. Org. Chem. 2003, 68, 915-
919. (e) Imbriglio, J. E.; Vasbinder, M. M.; Miller, S. J. Org. Lett. 2003,
5, 3741-3743 and Miller, S. J. Acc. Chem. Res. 2004, 37, 601-610. For
others, see: (f) Langer, P. Angew. Chem., Int. Ed. 2000, 39, 3049-3051.
(g) Kawahara, S.; Nakano, A.; Esumi, T.; Iwabuchi, Y.; Hatakeyama, S.
Org. Lett. 2003, 5, 3103-3105. (h) Krishna, P. R.; Kannan, V.; Reddy, P.
V. N. AdV. Synth. Catal. 2004, 346, 603-606. (i) Sohtome, Y.; Tanatani,
A.; Hashimoto, Y.; Nagasawa, K. Tetrahedron Lett. 2004, 45, 5589-5592.
(j) Yang, K. S.; Chen, K. M. Org. Lett. 2000, 2, 729-731. For alternative
approaches for asymmetric Baylis-Hillman reactions, see: (k) Brzezinski,
L. J.; Rafel, S.; Leahy, J. W. J. Am. Chem. Soc. 1997, 119, 4317-4318.
(l) Hayase, T.; Shibata, T.; Soai, K.; Wakatsuki, Y. Chem. Commun. 1998,
1271-1272. (m) Yamada, Y. M. A.; Ikegami, S. Tetrahedron Lett. 2000,
41, 2165-2169. (n) Krishna, P. R.; Kannan, V.; Reddy, P. V. N. AdV.
Synth. Catal. 2004, 346, 603-606. (o) Balan, D.; Adolfsson, H. Tetrahedron
Lett. 2003, 44, 2521-2524. (p) Hayase, T.; Shibata, T.; Soai, K.; Wakatsuki,
Y. Chem. Commun. 1998, 1271-1272. (q) Shi, M.; Xu, Y. M. Tetrahe-
dron: Asymmetry 2002, 13, 1196-1200. (r) Mocquet, C. M.; Warriner, S.
L. Synlett 2004, 356-357. (s) Hayashi, Y.; Tamura, T.; Shoji, M. AdV.
Synth. Catal. 2004, 346, 1106-1110. (t) Pan, J.-F.; Chen, K.-M. Tetra-
hedron Lett. 2004, 45, 2541-2543. (u) Langer, P. Organic Synthesis
Highlights V; Schmalz, H.-G., Wirth, T., Eds.; Wiley-VCH: Weinheim,
Germany, 2003; pp 165-177. (v) Krishna, P. R.; Kannan, V.; Sharma, G.
V. M.; Rao, M. H. V. Synlett 2003, 888-890. (w) Wei, H.-X.; Chen, D.;
Xu, X.; Li, G.-G.; Pare, P. W. Tetrahedron: Asymmetry 2003, 14, 971-
974 and references therein. (x) Aggarwal, V. K.; Castro, A. M. M.; Mereu,
A.; Adams, H. Tetrahedron Lett. 2002, 43, 1577-1581. (y) Iwabuchi, Y.;
Sugihara, T.; Esumi, T.; Hatakeyama, S. Tetrahedron Lett. 2001, 42, 7867-
7871. (z) Basavaiah, D.; Kumaragurubaran, N.; Sharada, D. S.; Reddy, R.
M. Tetrahedron 2001, 57, 8167-8172.
During our ongoing investigation on the Baylis-Hillman
reaction,5 we disclosed that the aza-Baylis-Hillman reactions
of N-sulfonated imines 1 such as N-arylmethylidene-4-meth-
ylbenzenesulfonamides (ArCHdNTs)6 with MVK were pro-
moted in the presence of catalytic amounts of Lewis bases such
as DABCO or triphenylphosphine (PPh3) to exclusively give
(1) For reviews, see: (a) Basavaiah, D.; Rao, P. D.; Hyma, R. S. Tetrahedron
1996, 52, 8001-8062. (b) Drewes, S. E.; Roos, G. H. P. Tetrahedron 1988,
44, 4653-4670. (c) Ciganek, E. Org. React. 1997, 51, 201-350. (d)
Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. ReV. 2003, 103, 811-
892. (e) Iwabuchi, Y.; Hatakeyama, S. J. Synth. Org. Chem. Jpn. 2002,
60, 2-14. (f) Cai, J.-X.; Zhou, Z.-H.; Tang, C.-C. Huaxue Yanjiu 2001,
12, 54-64.
9
3790
J. AM. CHEM. SOC. 2005, 127, 3790-3800
10.1021/ja0447255 CCC: $30.25 © 2005 American Chemical Society

aza-Baylis−Hillman Reaction of N-Sulfonated Imines
A R T I C L E S
Table 1. aza-Baylis-Hillman Reactions of
N-(4-chlorobenzylidene)-4-methylbenzenesulfonamide 1e (1.0
equiv) with Methyl Vinyl Ketone (3.0 equiv) in the Presence of
Chiral Lewis Base LB1 (10 mol %)
absolute
entry
solvent
temp/
°
C
time/h
yield/%a/2e
ee/%
configuration
1
2
3
4
5
6
7
8
9
THF
THF
THF
THF
CH2Cl2
toluene
MeCN
Et2O
DMF
MeOH
20
10
0
-30
10
10
10
10
10
12
12
48
48
12
24
24
12
12
24
86
76
84
72
38
17
38
76
63
20b
84
88
90
94
82
67
70
80
74
-
S
S
S
S
S
S
S
S
S
-
Figure 1. Structures of chiral Lewis bases.
10
10
Hillman reaction of N-sulfonated imines 1 with MVK utilizing
a chiral nitrogen Lewis base [4-(3-ethyl-4-oxa-1-azatricyclo-
[4,4,0,03,8]dec-5-yl)-quinolin-6-ol: â-ICD2a,7] (Figure 1) to
achieve >90% ee in good yield.6d This is the first case in which
high ee (>90%) can be realized using the simple Michael
acceptor MVK. The structure of this nitrogen Lewis base such
as the phenolic hydroxy group plays a significant role in this
reaction for achieving high ee.2c,6d Currently, the exploration
of a novel and highly efficient chiral Lewis base for catalytic,
asymmetric Baylis-Hillman reaction is a very attractive and
competitive field. Therefore, we attempted to seek out a chiral
a Isolated yields. b Michael addition product derived from methanol to
2e was obtained at the same time (Supporting Information).
phosphine Lewis base for this reaction since a phosphine Lewis
base such as PPh3 is also an effective promoter for this
reaction.6b After screening several chiral phosphine Lewis base
catalysts, we found that (R)-2′-diphenylphosphanyl-[1,1′]bi-
naphthalenyl-2-ol LB1, having a phenolic hydroxy group, is
also an effective chiral phosphine Lewis base for the catalytic,
asymmetric aza-Baylis-Hillman reaction in which high enan-
tioselectivities (94% ee) can also be realized (Figure 1). The
preliminary result has already been communicated.8 Herein, the
full details on the scope and limitations and the mechanistic
insight of this catalytic, asymmetric aza-Baylis-Hillman reac-
tion are described. On the basis of these results, exploration of
a chiral phosphine Lewis base for R,â-unsaturated cyclic ketone
is also reported.
(3) Other references related to asymmetric Baylis-Hillman reaction: (a) Li,
G.-G.; Hook, J. D.; Wei, H.-X. Org. Bioorg. Chem. 2001, 49-61. (b) Fox,
D. J.; Medlock, J. A.; Vosser, R.; Warren, S. J. Chem. Soc., Perkin Trans
1
2001, 2240-2249. (c) Iwabuchi, Y.; Furukawa, M.; Esumi, T.;
Hatakeyama, S. Chem. Commun. 2001, 2030-2031. (d) Bauer, T.; Tarasiuk,
J. Tetrahedron: Asymmetry 2001, 12, 1741-1745. (e) Radha, K. P.;
Kannan, V.; Ilangovan, A.; Sharma, G. V. M. Tetrahedron: Asymmetry
2001, 12, 829-837. (f) Li, G.-G.; Wei, H.-X.; Phelps, B. S.; Purkiss, D.
W.; Kim, S. H. Org. Lett. 2001, 3, 823-826. (g) Alcaide, B.; Almendros,
P.; Aragoncillo, C. J. Org. Chem. 2001, 66, 1612-1620. (h) Jauch, J. J.
Org. Chem. 2001, 66, 609-611. (i) Suzuki, D.; Urabe, H.; Sato, F. Angew.
Chem., Int. Ed. 2000, 39, 3290-3292. (j) Alcaide, B.; Almendros, P.;
Aragoncillo, C. Tetrahedron Lett. 1999, 40, 7537-7540. (k) Evans, M.
D.; Kaye, P. T. Synth. Commun. 1999, 29, 2137-2146. (l) Kataoka, T.;
Iwama, T.; Tsujiyama, S.-i.; Kanematsu, K.; Iwamura, T.; Watanabe, S.-i.
Chem. Lett. 1999, 257-258. (m) Bocknack, B. M.; Wang, L.-C.; Krische,
M. J. Proc. Natl. Acad. Sci. U.S.A. 2004, 101, 5421-5424 and references
therein. (n) Jang, H.-Y.; Huddleston, R. R.; Krische, M. J. J. Am. Chem.
Soc. 2004, 126, 4664-4668. (o) Jellerichs, B. G.; Kong, J.-R.; Krische,
M. J. J. Am. Chem. Soc. 2003, 125, 7758-7759. (p) Cauble, D. F.; Gipson,
J. D.; Krische, M. J. J. Am. Chem. Soc. 2003, 125, 1110-1111.
Results and Discussion
1. The aza-Baylis-Hillman Reaction of N-Sulfonated
Imines 1 with MVK Catalyzed by a Chiral Phosphine Lewis
Base LB1. Concerning the chiral phosphine Lewis bases, we
selected LB1 as a chiral Lewis base for this reaction because it
has a phenolic OH group similar to the chiral nitrogen Lewis
base â-ICD (Figure 1).2a We first used MVK as the Michael
acceptor for the aza-Baylis-Hillman reaction with N-(4-
chlorobenzylidene)-4-methylbenzenesulfonamide 1e to develop
the optimal reaction conditions. The results are summarized in
Table 1. We were delighted to find that in this aza-Baylis-
Hillman reaction, high enantiomeric excess (∼80-90% ee) of
the corresponding aza-Baylis-Hillman adduct 2e with S con-
figuration8 can be achieved in good yields in tetrahydrofuran
(THF), ether (Et2O), or dichloromethane (CH2Cl2) at ∼0-20
°C (room temperature) (Table 1, entries 1, 2, 3, 5, and 8). The
coexistence of Lewis acid [Ti(OPri)4] (10 mol %) did not
improve the chemical yield and the ee of 2e (see Supporting
Information). At lower temperature (-30 °C), the ee of 2e can
reach 94% in 72% yield (Table 1, entry 4). When the reactions
were carried out in toluene, acetonitrile (MeCN), or N,N-
dimethylformamide (DMF), the corresponding aza-Baylis-
Hillman adduct 2e was obtained in lower ee and lower yields
(4) (a) Baylis, A. B.; Hillman, M. E. D. Ger. Offen. 1972, 2,155,113; Chem.
Abstr. 1972, 77, 34174q; Hillman, M. E. D.; Baylis, A. B. U.S. Patent
1973, 3,743,669. (b) Morita, K.-I.; Suzuki, Z.; Hirose, H. Bull. Chem. Soc.
Jpn. 1968, 41, 2815-2819.
(5) (a) Shi, M.; Jiang, J.-K.; Feng, Y.-S. Org. Lett. 2000, 2, 2397-2400. (b)
Shi, M.; Feng, Y.-S. J. Org. Chem. 2001, 66, 406-411. (c) Shi, M.; Li,
C.-Q.; Jiang, J.-K. Chem. Commun. 2001, 833-834.
(6) (a) Shi, M.; Xu, Y.-M. Chem. Commun. 2001, 1876-1877. (b) Shi, M.;
Xu, Y.-M. Eur. J. Org. Chem. 2002, 696-701. (c) Shi, M.; Xu, Y.-M.;
Zhao, G.-L.; Wu, X.-F. Eur. J. Org. Chem. 2002, 3666-3679. (d) Shi,
M.; Xu, Y.-M. Angew. Chem., Int. Ed. 2002, 41, 4507-4510. (e) Xu, Y.-
M.; Shi, M. J. Org. Chem. 2004, 69, 417-425. (f) Shi, M.; Xu, Y. M. J.
Org. Chem. 2003, 68, 4784-4790. (g) Zhao, G.-L.; Huang, J.-W.; Shi, M.
Org. Lett. 2003, 5, 4737-4739. For reports related to the aza-Baylis-
Hillman reaction of methyl acrylate with N-sulfonated imines, please see:
(h) Perlmutter, P.; Teo, C. C. Tetrahedron Lett. 1984, 25, 5951-5952. (i)
Takagi, M.; Yamamoto, K. Tetrahedron 1991, 47, 8869-8882. For reports
related to the aza-Baylis-Hillman reaction of MVK with N-sulfonated
imine generated in situ, please see: (j) Bertenshow, S.; Kahn, M.
Tetrahedron Lett. 1989, 30, 2731-2732. (k) Balan, D.; Adolfsson, H. J.
Org. Chem. 2002, 67, 2329-2334 and references therein.
(7) The catalyst â-ICD was first prepared by Prof. Hoffman: von Riesen, C.;
Jones, P. G.; Hoffmann, H. M. R. Chem.-Eur. J. 1996, 2, 673-679.
(8) Shi, M.; Chen, L. H. Chem. Commun. 2003, 1310-1311.
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J. AM. CHEM. SOC. VOL. 127, NO. 11, 2005 3791

A R T I C L E S
Shi et al.
Table 2. aza-Baylis-Hillman Reactions of N-(Arylmethylidene)arylsulfonamide 1 (1.0 equiv) with Methyl Vinyl Ketone (3.0 equiv) in the
Presence of Chiral Lewis Base LB1 (10 mol %) and MS 4A
entry
Ar
R
No.
time/h
yield/%a/2
ee/%b
absolute configuration
1
2
3
4
5
6
7
8
9
10
11d
12d
13d
14d
15d
16d
17d
C6H5
p-MeC6H4
p-EtC6H4
p-FC6H4
p-ClC6H4
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ms
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
1o
1p
1q
24 (36)c
24 (36)
36 (36)
18
24 (24)
18
36 (24)
18 (24)
12 (24)
12 (24)
24
24
24
24
24
24
72
2a, 49 (83)c
2b, 53 (82)
2c, 62 (84)
2d, 84
2e, 72 (90)
2f, 85
2g, 26 (96)
2h, 62 (88)
2i, 60 (86)
2j, 54 (91)
2k, 85
83 (83)c
80 (81)
76 (79)
81
94 (87)
83
91 (85)
88 (88)
94 (92)
90 (88)
61
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
p-BrC6H4
m-FC6H4
m-ClC6H4
p-NO2C6H4
m-NO2C6H4
o-ClC6H4
o-NO2C6H4
trans-C6H5-CHdCH
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
2l, 88
2m, 94
2n, 94
84
95
82
p-ClC6H4SO2
Ns
SES
2o, 94
89
2p, -e
-
e
2q, 53
89
a Isolated yields. b Determined by chiral HPLC. c Values in parentheses are the results in the presence of MS 4A (100 mg). d The reaction was carried out
at -20 °C in the presence of MS 4A (100 mg). e The corresponding aza-Baylis-Hillmn adduct was not formed because this N-sulfonated imine decomposed
quickly under reaction conditions.
Scheme 1
(Table 1, entries 6, 7, and 9). In methanol, 2e was obtained in
20% yield along with a Michael addition product derived from
methanol to 2e (Table 1, entry 10; see Supporting Information).9
Thus, these optimized reaction conditions for this reaction are
to carry out this reaction in THF at -30 °C in the presence of
LB1 (10 mol %).
imine 1m, the achieved ee of the corresponding adduct 2m
reached 95% in 94% yield (Table 2, entry 13).
In the reaction of other N-(arylmethylidene)-4-methylbenzene-
sulfonamides 1 with MVK using LB1 as a chiral Lewis base
under the optimized conditions, good to high enantioselectivities
(∼76-91% ee) were achieved with S configuration (Table 2).8
In general, for N-sulfonated imines 1 having electron-donating
groups on the phenyl ring, the reaction rate was slightly slower
and the corresponding aza-Baylis-Hillman adducts 2 were
obtained in lower yields (∼41-62%) with ∼76-83% ee under
the same conditions (Table 2, entries 1-3). This is because the
prolonged reaction time at low temperature caused the decom-
position of N-sulfonated imines 1 because of the ambient
moisture. To improve the yields of 2, we added molecular sieve
4A (100 mg for 0.5 mmol of substrate) into the reaction system
to get rid of the ambient moisture. As a result, the isolated yields
of 2 were greatly improved with the addition of molecular sieve
4A (Table 2, entries 1-3, 5, 7-10) and the ee of 2 was not
significantly affected. Only in some cases, the ee of 2 dropped
∼2-6%. Values in parentheses are the results obtained in the
presence of molecular sieve 4A in Table 2. For ortho-substituted
N-sulfonated imines 1k and 1l, the corresponding adducts 2k
and 2l were obtained in 85 and 88% yields with 61 and 84%
ee, respectively, at -20 °C in the presence of molecular sieve
4A (Table 2, entries 11 and 12). For cinnamoyl N-sulfonated
Moreover, for other N-sulfonated imines such as N-mesylated
imine 1n (ArCHdN-Ms), N-p-chlorobenzenesulfonated imine
1o (ArCHdN-SO2C6H4Cl-p), and N-SES protected imine 1q
(â-trimethylsilylethanesulfonamide: Me3SiCH2CH2SO2Nd
CHAr), this catalytic, asymmetric aza-Baylis-Hillman reaction
also proceeded smoothly at -20 °C in the presence of chiral
phosphine promoter LB1 and molecular sieve 4A in THF to
give the corresponding adducts 3n, 3o, and 3q in good to high
yields with 89, 82, and 89% ee, respectively (Table 2, entries
14, 15, and 17). However, for N-4-nitrobenzenesulfonated imine
1p (ArCHdN-Ns), which should be the most active electro-
phile in this aza-Baylis-Hillman reaction, we found that it
decomposed rapidly under the reaction conditions, and the
corresponding aza-Baylis-Hillman adduct 3p was not formed
(Table 2, entry 16).
2. Michael Acceptor Generality in This Reaction. Using
EVK as a Michael acceptor, we also examined this aza-Baylis-
Hillman reaction with N-sulfonated imines 1 using LB1 as a
chiral phosphine Lewis base under various reaction conditions.
The results are shown in Supporting Information. The best
reaction conditions to carry out this reaction are in THF at -20
°C in the presence of MS 4A to give 3a in 77% yield with
86% ee as S configuration (Scheme 1). In general, the aza-
Baylis-Hillman reaction rate of N-sulfonated imines 1 with
(9) The reaction mechanism for the Michael addition of methanol to R,â-
unsaturated ketones has been disclosed recently: Stewart, I. C.; Bergman,
R. G.; Toste, F. D. J. Am. Chem. Soc. 2003, 125, 8696-8697.
9
3792 J. AM. CHEM. SOC. VOL. 127, NO. 11, 2005

aza-Baylis−Hillman Reaction of N-Sulfonated Imines
A R T I C L E S
Table 3. aza-Baylis-Hillman Reactions of N-Sulfonated Imines 1 (1.0 equiv) with EVK (2.0 equiv) in the Presence of Chiral Lewis Base
LB1 (10 mol %) and MS 4A
entry
Ar
No.
reaction conditions
time/h
yield/%a/3
ee/%b
absolute configuration
1
2
3
4
5
6
7
8
9
C6H5
p-FC6H4
p-FC6H4
p-BrC6H4
p-BrC6H4
m-FC6H4
m-ClC6H4
p-NO2C6H4
p-FC6H4
1a
1d
1d
1f
-20 °C, MS 4A
-20 °C
96
24
84
48
84
48
48
96
7 d
7 d
3b, 52
3c, 50
3c, 56
3d, 66
3d, 78
3e, 61
3f, 61
3g, 85
3c, 17
3d, 40
80
78
86
86
85
89
92
88
88
88
S
S
S
S
S
S
S
S
S
S
-20 °C, MS 4A
-20 °C
1f
-20 °C, MS 4A
-20 °C, MS 4A
-20 °C, MS 4A
-20 °C, MS 4A
-30 °C, MS 4A
-30 °C, MS 4A
1g
1h
1i
1d
1f
10
p-BrC6H4
a Isolated yield. b Determined by chiral HPLC.
Scheme 2
Table 4. aza-Baylis-Hillman Reactions of N-Sulfonated Imine 1e
(1.0 equiv) with Phenyl Acrylate (1.5 equiv) in the Presence of
Chiral Lewis Base LB1 (10 mol %) in Various Solvents
yield/
%a/5a
absolute
entry
temp (
°
C)
solvent
time/h
ee/%b
configuration
1
2
3
4
5
6
7
8
9
10
10
10
10
10
THF
DMF
72
20
20
12
12
15
24
24
20
12
12
40c
27
70
54
70
NR
NR
25
59
94
36
70
40
58
50
71
-
S
S
S
S
S
CH3CN
Toluene
CH2Cl2
CH3OH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
iPrOPri
EVK is slower than that of N-sulfonated imines 1 with MVK
under identical conditions. In addition, this reaction is sluggish
at -30 °C in the presence of chiral phosphine Lewis base LB1
(Supporting Information).
10
-40
-20
0
40
40
-
60
67
67
63
S
S
S
S
Under these optimized reaction conditions (-20 °C in THF
with MS 4A), we next examined the aza-Baylis-Hillman
reaction of other N-sulfonated imines 1 with EVK. The results
are summarized in Table 3. The corresponding aza-Baylis-
Hillman adducts 3 were obtained in ∼78-92% ee in moderate
to good yields (Table 3, entries 1-8). The yields of 3 were
indeed improved in the presence of MS 4A for other N-
sulfonated imines 1 as well (Table 3, entries 2-5). Moreover,
we further confirmed that at -30 °C in the presence of MS
4A, the aza-Baylis-Hillman reactions of N-sulfonated imines
1d and 1f having electron-withdrawing groups on the benzene
ring with EVK are also sluggish and the adducts 3 were
produced in low yields even after 7 days (Table 3, entries 9
and 10).
It should be noted that the ee of 2 and 3 can reach >99%
after one recrystallization from CH2Cl2/hexane (1/6).
To extend the scope and limitations of this novel catalytic,
asymmetric aza-Baylis-Hillman reaction catalyzed by chiral
phosphine Lewis base, we examined the reaction of N-sulfonated
imines 1 with methyl acrylate and phenyl acrylate using LB1
as a promoter. As a result, we found that the aza-Baylis-Hill-
man reaction of N-(4-chlorobenzylidene)-4-methylbenzene-
sulfonamide 1e with methyl acrylate is sluggish in the presence
of tertiary phosphine Lewis base in many solvents. Using PPh3
as a Lewis base in CH2Cl2, we obtained the corresponding aza-
Baylis-Hillman adduct 4a in 37% after 36 h at room temper-
ature (Scheme 2). By means of chiral phosphine Lewis base
LB1 under the same conditions, 4a was produced in 67% yield
with 18% ee (Scheme 2). On the other
10
11
a Isolated yield. b Determined by chiral HPLC. c In THF after 12 h, 5a
was obtained in 17 with 70% ee.
hand, the aza-Baylis-Hillman reaction of N-(4-chloroben-
zylidene)-4-methylbenzenesulfonamide 1e with phenyl acrylate
proceeded fairly smoothly in various solvents under mild
conditions in the presence of PPh3. Using LB1 as a chiral Lewis
base promoter in aza-Baylis-Hillman reaction of N-(4-chlo-
robenzylidene)-4-methylbenzenesulfonamide 1e with phenyl
acrylate, we obtained the corresponding adduct 5a in moderate
ee in various solvents (Table 4, entries 1-5). In THF, the
achieved ee can reach 70%, but the yield is 40% after 72 h and
17% after 12 h (Table 4, entry 1). When the reaction was carried
i
out in DMF, MeCN, toluene, and PrOiPr, the achieved ee is
∼40-63% (Table 4, entries 2-4, and 11). In dichloromethane
at room temperature, the achieved ee is 71% in 70% yield (Table
4, entry 5). Thus, it seems to us that dichloromethane is the
best solvent for this type of catalytic, asymmetric aza-Baylis-
Hillman reaction. The reaction temperature significantly affected
the reaction rate and the achieved ee in dichloromethane as well.
At -40 °C, no reaction occurred, and at -20 °C, the yield is
25% with 60% ee. We eventually found that, upon heating in
CH2Cl2 at 40 °C for 12 h, the aza-Baylis-Hillman adduct 5a
was obtained in 94% yield with 67% ee (Table 4, entry 10).
This is the best reaction condition for this type of aza-Baylis-
Hillman reaction. The addition of Lewis acid Ti(OPri)4 did not
9
J. AM. CHEM. SOC. VOL. 127, NO. 11, 2005 3793

A R T I C L E S
Shi et al.
Table 5. aza-Baylis-Hillman Reactions of N-Sulfonated Imines 1
(1.0 equiv) with Phenyl Acrylate (1.5 equiv) in the Presence of
Chiral Lewis Base LB1 (10 mol %) in Dichloromethane at 40 °C
Table 6. aza-Baylis-Hillman Reactions of N-Sulfonated Imines 1
(1.0 equiv) with Acrolein (2.0 equiv)) in the Presence of Chiral
Lewis Base LB1 (10 mol %) in THF at Room Temperature
absolute
temp.
time
h
yield
%a/6
ee
absolute
entry
Ar
No.
time/h
yield/%a/5
ee/%b
configuration
b
entry
Ar
No.
°
C
%
configuration
1
2
3
4
5
6
7
8
C6H5
p-EtC6H4
p-FC6H4
p-BrC6H4
m-FC6H4
m-ClC6H4
p-NO2C6H4
m-NO2C6H4
1a
1c
1d
1f
1g
1h
1i
12
12
12
12
12
12
12
12
5b, 84
5c, 60
5d, 80
5e, 85
5f, 89
5g, 95
5h, 97
5i, 89
61
53
69
77
63
58
75
52
S
S
S
S
S
S
S
S
1
2
3
4
5
6
7
8
9
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
C6H5
p-MeC6H4
p-MeOC6H4 1r
p-FC6H4
p-BrC6H4
m-ClC6H4
1e
1e
1e
1e
1e
1a
1b
40
rt
0
-20
-30
rt
rt
rt
rt
rt
2
4
12
12
12
4
12
12
4
6a, 94
6a, 91
6a, 76
6a, 63
6a, 78
81
83c
78
68
49
S
S
S
S
S
S
S
S
S
S
S
6b, 88 86c
6c, 97
76c
1j
6d, 99 78c
1g
1f
1h
6c, 86
6f, 96
6g, 74
84c
79c
82c
a Isolated yield. b Determined by chiral HPLC.
Scheme 3
10
11
4
4
rt
a Isolated yield. b Determined by chiral HPLC. c After one recrystalli-
zation from CH2Cl2/hexane (1/5), the achieved ee can reach 99.9%.
reaction of other N-sulfonated imine substrates 1 with acrolein
at room temperature (20 °C). As a result, we found that the
corresponding aza-Baylis-Hillman adducts 6 were formed in
high yields with good ee for most of N-sulfonated imines 1
with S configuration (Table 6, entries 6-11). After one
recrystallization from CH2Cl2/hexane (1/6), the ee of 6 can reach
99.9% (Table 6, entries 7-9).
significantly improve the result under the same conditions (see
Supporting Information).
We also tried to utilize the aliphatic N-sulfonated imines 1
(Me2CHdNTs and BuCHdNTs) for this reaction under the
same conditions as those described above.10 However, the
reaction was unsuccessful, and the corresponding aza-Baylis-
Hillman adduct was not formed.
Under these optimized reaction conditions, we next carried
out the aza-Baylis-Hillman reactions of various N-sulfonated
imines 1 with phenyl acrylate. The results are shown in Table
5. In most cases, the corresponding aza-Baylis-Hillman adducts
5 were formed in good to high yields (60-97%) with moderate
to good ee (52-77%) (Table 5, entries 1-8).
Using R- or â-naphthyl acrylate as Michael acceptor under
these reaction conditions, we obtained similar results for the
corresponding adducts 5j and 5k (Scheme 3). This result
suggests that the ee is not affected by the steric bulkiness in
the ester moiety of acrylate in this reaction.
In addition to R,â-unsaturated ketones and esters, we also
examined the aza-Baylis-Hillman reaction of N-sulfonated
imines 1 with acrolein in the presence of chiral phosphine Lewis
base LB1. In this type of aza-Baylis-Hillman reaction, THF is
the best solvent on the basis of examination of the solvent effects
in the way similar to that described above. The results are
summarized in Table 6. Using N-(4-chlorobenzylidene)-4-
methylbenzenesulfonamide 1e as the substrate at room temper-
ature (20 °C) and 40 °C in THF, we obtained the corresponding
aza-Baylis-Hillman adduct 6a in high yields (91 and 94%) with
good ee (83 and 81% ee) for ∼2-4 h, respectively (Table 6,
entries 1 and 2). At lower reaction temperatures (∼-30 to 0
°C), this reaction became sluggish and the achieved ee decreased
dramatically (Table 6, entries 3-5). We believe that in this case,
the equilibrium of the Baylis-Hillman reaction leans toward
the reaction product at higher temperature, whereas at lower
temperature, the equilibrium leans toward the reversed way. This
reversibility always impairs the enantioselectivity of Baylis-
Hillman reaction. Thus, we carried out this aza-Baylis-Hillman
3. The Additives on This Catalytic, Asymmetric aza-
Baylis-Hillman Reaction. It is well-known that some additives
such as LiClO4 and Yb(OTf)3 can improve the reaction rate
and enantioselectivity in Baylis-Hillman reaction.2d,i,j,11 There-
fore, in addition to Ti(OiPr)4 we examined other additives in
the presence of chiral phosphine Lewis base LB1 in THF in
this catalytic, asymmetric reaction. The results are shown in
Supporting Information. Additive B(OiPr)3 did not affect the
ee and reaction rate. In the presence of Lewis acid Yb(OTf)3
(4 mol %), this reaction became sluggish (42% yield and 74%
ee for 72 h). No reaction occurred in the presence of Yb(OTf)3
(10 mol %). These results suggest that the coexistence of Lewis
acid impairs this reaction because of the coordination to the
Lewis base active site. Using LiClO4 as an additive, we observed
a similar result (42% yield and 54% ee for 72 h; see Supporting
Information). At any rate, these additives did not improve the
enantioselectivities in this reaction.
4. The Structure of Chiral Phosphine Lewis Base on This
Reaction. It should be emphasized here that the phenolic
hydroxy group (Ar-OH) on the naphthyl ring is crucial for this
reaction because this reaction becomes sluggish and gives the
product 2e in 13% yield with only 20% ee (R configuration)
(10) For the synthesis of aliphatic imines, see: Chemla, F.; Hebbe, V.; Normant,
J. F. Synthesis 2000, 1, 75-77.
(11) (a) Kawamura, M.; Kobayashi, S. Tetrahedron Lett. 1999, 40, 1539-1542.
(b) Shi, M.; Jiang, J.-K.; Li, C.-Q. Tetrahedron Lett. 2002, 43, 127-130.
(c) Shi, M.; Jiang, J.-K. Tetrahedron: Asymmetry 2002, 13, 1941-1947.
9
3794 J. AM. CHEM. SOC. VOL. 127, NO. 11, 2005

aza-Baylis−Hillman Reaction of N-Sulfonated Imines
A R T I C L E S
Figure 2.
using O-methylated ligand (MOP) LB2 as a chiral Lewis base12a
and in 17% yield with 22% ee (R configuration) using (2′-ethyl-
[1,1′]binaphthalenyl-2-yl)diphenylphosphane LB3 as a chiral
Lewis base12a under the same conditions (Figure 2). The BINAP
LB4 shows no catalytic activity for this reaction. The (R)-2′-
diphenylphosphanyl-[1,1′]binaphthalenyl-2-thiol LB5 having a
thiophenolic group on the naphthyl ring12b,c and the [2,3-bis-
(2-diphenylphosphanylphenyl)-4-hydroxymethylcyclobutyl]meth-
anol LB612d having two aliphatic hydroxy groups show low
catalytic activities under the same conditions. These results
suggest that the acidity of the hydroxy group plays a very
important role for chiral Lewis base LB1 to be effective in the
aza-Baylis-Hillman reaction. Other chiral ferrocene phosphine
ligands LB7 and LB812e,f also have low catalytic activities for
this reaction under the same conditions. Thus, the structure of
phosphine Lewis base plays a significant role in this reaction
(Figure 2). Only (R)-2′-diphenylphosphanyl-[1,1′]binaphthal-
enyl-2-ol LB1 having a phenolic hydroxy group can effectively
catalyze this catalytic, asymmetric aza-Baylis-Hillman reaction
to give the products in good yields and higher ee.
We described here an unprecedented catalytic, asymmetric
aza-Baylis-Hillman reaction of N-sulfonated imines 1 with
various activated olefins by a chiral phosphine Lewis base LB1.
A catalytic, asymmetric aza-Baylis-Hillman reaction version
using a variety of Michael acceptors was disclosed. Moreover,
since chiral Lewis base LB1 is a known compound that can be
easily prepared according to the literature (Experimental Section
in Supporting Information), we can carry out the above reaction
in gram scale; for example, 1e (2 g) with LB1 (310 mg) under
the same conditions as those shown in entry 5 of Table 2. It
was confirmed that a similar result could be obtained (70% yield
and 93% ee).
Moreover, to further explore the effective chiral phoshine
Lewis bases for this reaction, we attempted to modify the
structure of chiral phosphine Lewis base LB1 to achieve higher
ee and isolated yields under milder conditions.
5. The Modification of the Structure of Chiral Lewis Base
LB1. We first decided to synthesize the 6-substituted and 6,6′-
disubstituted chiral phosphine Lewis bases LB9 and LB10
because, on the basis of the previous reports related with (R)-
binol in asymmetric catalysis, it is well-known that the introduc-
tion of substituents in the 6,6′-position of binol can improve
the enantioselectivity to some extent.13 As shown in Scheme
SI-1, chiral phosphine Lewis base LB9 was readily prepared
by the bromination of the precursor of LB1 to furnish LB9-1
in 80% yield, which was reduced with HSiCl3 and Et3N in
toluene at 120 °C to give LB9 in 70% yield.14 Chiral phosphine
Lewis base LB10 was prepared according to the Scheme SI-2
shown in Supporting Information. Dibromination of (R)-binol
at -78 °C gave LB10-1 in 92% yield in dichloromethane. Two
phenolic hydroxy groups were protected by MOMCl in THF at
0 °C to afford LB10-1 in quantitative yield. Kumada cross-
coupling reaction with PhMgBr and deprotection of MOM group
with aqueous HCl solution produced LB10-3 in 90% yield.15
The compound LB10-4 was obtained by the reaction of LB10-3
with Tf2O in the presence of pyridine. The coupling reaction
of LB10-4 with diphenyl phosphite and hydrolysis with aqueous
sodium hydroxide solution in MeOH/dioxane mixing solvent
produced the compound LB10-6 in good yield. The reduction
of phosphate LB10-6 by HSiCl3 and Et3N in toluene at 120 °C
(13) (a) Catalytic Asymmetric Synthesis; Ojima, I., Ed.; VCH: New York, 1993.
(b) ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer-Verlag: Berlin, 2001. Also see: (c) Han,
J.-W.; Hayashi, T. Tetrahedron: Asymmetry 2002, 13, 325. (d) Tian, Y.;
Yang, Q.-C.; Mak, T. C. W.; Chan, K.-S. Tetrahedron 2002, 58, 3951. (e)
Han, J.-W.; Hayashi, T. Chem. Lett. 2001, 976. (f) Hodgson, D. M.; Stupple,
P. A.; Johnstone, C. Chem. Commun. 1999, 2185. (g) Hodgson, D. M.;
Stupple, P. A.; Pierard, F. Y. T. M.; Labande, A. H.; Johnstone, C. Chem.-
Eur. J. 2001, 7, 4465.
(14) Nozaki, K.; Shibahara, F.; Itoi, Y.; Shirakawa, E.; Ohta, T.; Takaya, H.;
Hiyama, T. Bull. Chem. Soc. Jpn. 1999, 72, 1911-1918.
(15) (a) Chen, R.-F.; Qian, C.-T.; de Vries, J. G. Tetrahedron Lett. 2001, 42,
6919-6921. (b) Qian, C.-T.; Huang, T.-S.; Zhu, C.-J.; Sun, J. J. Chem.
Soc., Perkin Trans. 1 1998, 2097-2103.
(12) (a) Uozumi, Y.; Tanahashi, A.; Lee. S.-Y.; Hayashi, T. J. Org. Chem. 1993,
58, 1945-1948. (b) Kang, J.; Yu, S. H.; Kim, J. I.; Cho, H. G. Bull. Korean
Chem. Soc. 1995, 16, 439-443. (c) Gladiali, S.; Medici, S.; Pirri, G.;
Pulacchini, S.; Fabbri, D. Can. J. Chem. 2001, 79, 670-678. (d) Zhao, D.
B.; Ding, K.-L. Org. Lett. 2003, 5, 1349-1351. (e) You, S.-L.; Hou, X.-
L.; Dai, L.-X.; Cao, B.-X.; Sun, J. Chem. Commun. 2000, 1933-1934. (f)
Deng, W.-P.; Hou, X.-L.; Dai, L.-X.; Dong, X.-W. Chem. Commun. 2000,
1483-1484.
9
J. AM. CHEM. SOC. VOL. 127, NO. 11, 2005 3795

A R T I C L E S
Scheme 4
Shi et al.
Figure 3. 31P NMR spectrum of LB1 in CDCl3.
a phenyl substituent on the 3-position adjacent to the phenolic
hydroxy group in the aza-Baylis-Hillman reaction of N-
sulfonated imines 1 with MVK, is slightly less effective than
LB1 because at -20 °C, 2e was obtained in 60% yield with
87% ee after 3 days in THF (Scheme 4). However, at 0 °C or
25 °C, 2e was obtained in 91% yield with 86 and 85% ee,
respectively, after 12 h (Scheme 4). At relatively higher
temperature, this reaction proceeded smoothly to give the adduct
in good enantioselectivity. Therefore, no MS 4A is required in
this catalytic system. Overall, we found that chiral Lewis base
LB12 having a phenyl substituent adjacent to the phenolic
hydroxy group produced the adducts in relatively higher ee
under slightly milder conditions (0 and 25 °C) in the aza-
Baylis-Hillman reaction using MVK as a Michael acceptor.
We also confirmed that this Lewis base promoter is difficult to
be oxidized to the corresponding phosphine oxide during the
reaction under identical conditions as those of LB1, LB9, and
LB10. It is still active and can be reused again for this reaction
after recovery by silica gel column chromatography (Table SI-
4, entry 4 in Supporting Information).
afforded LB10 in good yield (see Scheme SI-2 in Supporting
Information).
By means of similar reaction procedures, we prepared another
chiral phosphine Lewis base LB11, which has two methyl
groups adjacent to the phosphine atom (see Scheme SI-3 in
Supporting Information). On the other hand, chiral phosphine
Lewis base LB12, having a phenyl group on the 3-position
adjacent to the phenolic hydroxy group, was prepared according
to Scheme SI-4 shown in Supporting Information. MOM-
t
protected (R)-binol was treated by BuLi in THF at -78 °C,
and then the resulted solution was treated with BrCF2CF2Br to
give compound LB12-1 in 75% yield.16a The Suzuki-type cross-
coupling reaction of LB12-1 with PhB(OH)2 in the presence of
Pd(0) catalyst produced compound LB12-2 in 99% yield. The
MOM-protecting group in LB12-2 was removed to give the
corresponding modified binol LB12-3, which was treated with
Tf2O to produce LB12-4.16b Upon transformations similar to
those described above, chiral phosphine Lewis base LB12 was
obtained in good yield (see Scheme SI-4 in Supporting
Information).
These chiral phosphine Lewis bases LB9-LB12 were em-
ployed in the same catalytic, asymmetric aza-Baylis-Hillman
reaction of N-sulfonated imines 1 with MVK or phenyl acrylate.
The results are summarized in Tables SI-1-SI-5 in Supporting
Information, respectively. The summarized results have been
indicated in Scheme 4. The outcomes for comparison of chiral
phosphine Lewis bases LB1, LB9, and LB10 in the aza-Baylis-
Hillman reaction of N-(4-chlorobenzylidene)-4-methylben-
zenesulfonamide 1e with MVK disclosed that LB9 and LB10
are similarly as effective as LB1 in the aza-Baylis-Hillman
reaction using MVK as a Michael acceptor. In addition, they
have similar enantioselective induction abilities in this reaction.
Moreover, we found that LB11 has no catalytic ability for this
reaction. These results suggest that Br and phenyl substituents
on the 6,6′-position of binaphthalene framework do not signifi-
cantly affect the reaction rate and enantioselectivity in this
catalytic, asymmetric reaction, but the steric bulkiness around
the phosphine atom plays a key role to initiate the reaction. It
should be pointed out that by using LB1, LB9, and LB10 as
chiral Lewis base promoters in this reaction, we found that they
are gradually oxidized into the corresponding phosphine oxides
during the reaction. Chiral phosphine Lewis base LB12, having
6. Mechanistic Survey. The absolute configuration of adduct
2 was determined to be (S)-enriched by comparison of the sign
of specific rotation with its antipode.17 For adducts 5 and 6,
their absolute configurations were unambiguously confirmed to
be (S)-enriched by the method reported by Li and Hatakeyama,
namely, transforming the products to the corresponding phen-
ylglycine derivatives and comparing their signs of specific
rotation to those of authentic samples prepared from (R)-
phenylglycine as shown in Scheme SI-5 in Supporting
Information.2g,18,19 To get more mechanistic insight into this
1
reaction, we carried out the 31P NMR and H NMR spectro-
scopic measurements of phosphine Lewis base in the absence
or presence of MVK or N-sulfonated imines 1. We found that
the 31P NMR (CDCl3, 85% H3PO4) spectroscopic data of LB1
showed a signal at -13.16 ppm (Figure 3), but the 31P NMR
(CDCl3, 85% H3PO4) spectroscopic data of LB1 with MVK
(molar ratio ) 1:5) elucidated a new signal at +25.30 ppm,
which was believed to correspond to the phosphonium enolate,
(17) The absolute configuration of 2e with R configuration was determined by
X-ray analysis in our previous article, which has been deposited at the
Cambridge Crystallographic Data Centre and allocated the deposition
numbers CCDC 167239. The absolute configuration of the major enantiomer
of 2 reported in this article was assigned according to the sign of their
specific rotations by comparison of the [R]D.
(18) (a) Li, G.-G.; Wei, H.-X.; Whittlesey, B. R.; Batrice, N. N. J. Org. Chem.
1999, 64, 1061-1064. (b) Reddy, K. L.; Sharpless, K. B. J. Am. Chem.
Soc. 1998, 120, 1207-1217.
(19) Kobayashi, K.; Okamoto, T.; Oida, T.; Tanimoto, S. Chem. Lett. 1986,
2031-3034.
(16) (a) Cox, P. J.; Wang, W.; Snieckus, V. Tetrahedron Lett. 1992, 33, 2253-
2256. (b) Ishihara, K.; Kurihara, H.; Matsumoto, M.; Yamamoto, H. J.
Am. Chem. Soc. 1998, 120, 6920-6930.
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3796 J. AM. CHEM. SOC. VOL. 127, NO. 11, 2005

aza-Baylis−Hillman Reaction of N-Sulfonated Imines
A R T I C L E S
Figure 6. 31P NMR spectrum of LB1 with phenyl acrylate in CDCl3.
Figure 4. 31P NMR spectrum of LB1 with MVK in CDCl3.
Figure 7. 31P NMR spectrum of phosphonium iodide salt A in CDCl3.
Figure 5. 31P NMR spectrum of LB1 with MVK and imine in CDCl3.
Scheme 5
along with the signal of LB1 (Figure 4).20 The 31P NMR
spectroscopic data of LB1 with MVK and N-sulfonated imines
did not change again (Figure 5). However, for the 31P NMR
spectroscopic data of phosphine Lewis base LB2 (MOP) under
the same conditions, no such alteration could be observed in
the presence of MVK or N-sulfonated imines (see Figures SI-
1-SI-3 in Supporting Information). The 1H NMR spectroscopic
data of LB1 and LB1 with MVK clearly indicated that the
phenolic hydroxy group at 4.62 ppm in LB1 shifted to another
place with the addition of MVK (see Figures SI-4 and SI-5 in
Supporting Information), suggesting the existence of a hydrogen-
bonding interaction (O-H‚‚‚O-). In the 31P NMR spectrum of
LB1, the new signal that appeared at plus field with the addition
of MVK along with the signal at minus field (free phosphine
ligand) also indicated that the positively charged phosphine atom
(P+) species was formed and it was in equilibrium with free
LB1. The interaction of the phenolic hydroxy group with the
oxygen atom of MVK (hydrogen bonding) does indeed exist
which stabilizes the in situ formed phosphonium enolate and
leans the equilibrium to the formation enolate intermediate.20
Scheme 6
This is why a similar phenomenon was not observed in the 31
P
NMR spectrum of LB2 with the addition of MVK. In the case
of LB1 with phenyl acrylate, a similar phenomenon was
observed (Figure 6).
NMR measurements were carried out for the phosphonium
bromide salt B derived from the reaction of LB1 with 3-bro-
mopropionic acid phenyl ester22 as shown in Scheme 6. A signal
at +25.44 ppm was recognized in the 31P NMR spectrum under
the same conditions (Figure 8), a result similar to that of
phosphonium iodide salt A. These chemical shifts of phospho-
The 31P NMR spectrum of an authentic phosphonium iodide
salt A derived from LB1 with 4-iodobutan-2-one21 was mea-
sured under the same conditions (Scheme 5). A signal at +26.07
ppm was recognized (Figure 7). Meanwhile, similar 1H and 31
P
(20) The 31P NMR signal of phosphine oxide of L1 is at +31.38 ppm. The 31
P
NMR signal of the positively charged phosphine (P+) is in the range of
∼+10 to +30 ppm (please see: Kayser, M. M.; Hatt, K. L.; Hopper, D. L.
Can. J. Chem. 1991, 69, 1929-1939).
(22) (a) Eussen, von D. K. Justus Liebigs Ann. Chem. 1905, 342, 128-137. (b)
Bruice, T. C.; Hegarty, A. F.; Felton, S. M.; Donzel, A.; Kundu, N. G. J.
Am. Chem. Soc. 1970, 92, 1370-1378.
(21) Marx, J. M. Tetrahedron 1983, 39, 1529-1532.
9
J. AM. CHEM. SOC. VOL. 127, NO. 11, 2005 3797

A R T I C L E S
Scheme 7
Shi et al.
nium salts A and B are similar to those observed in Figures 4
and 6, suggesting that the signals at plus field in Figures 4 and
6 should be structurally similar to those of phosphonium
spectrum of LB1 (Figure 10). These results further strongly
1
enolates. In Figure 9, we indicated the H NMR spectrum of
phosphonium iodide salt B in which the signal of phenolic
hydroxy group dramatically shifted to the low field at 9.78 ppm
along with some small amount of ethyl acetate as compared
with that of phenolic hydroxy group at 4.60 ppm in the 1H NMR
Figure 10. 1H NMR spectrum of LB1 in CDCl3.
suggest that the reaction of LB1 with R,â-unsaturated ketone
or ester indeed produces a phosphonium enolate immediately
and there is an intramolecular hydrogen bonding between the
phenolic hydroxy group and oxygen atom of carbonyl group to
stabilize the in situ formed phosphonium enolate and leans the
equilibrium to the formation of enolate intermediate.
We believe that this kind of interaction is the driving force
for the aza-Baylis-Hillman reaction catalyzed by LB1 to be
more effective than LB2 (MOP). This unusual phenomenon also
corresponds to the high chiral induction in this aza-Baylis-
Hillman reaction catalyzed by LB1.
In Scheme 7, we give a detailed mechanistic explanation and
rationalize the outcome of absolute stereochemistry of adducts
on the catalysis of chiral phosphine Lewis base LB1.8 We
believe that LB1 acts as a bifunctional chiral ligand in this
reaction.23 The phosphine atom acts as a Lewis base, and the
phenolic OH group acts as a Lewis acid through hydrogen
bonding (BA: Brønsted acid as a Lewis acid). LB is used to
initiate the Baylis-Hillman reaction, and BA is utilized to
stabilize the in situ formed key enolate intermediate and the
reaction intermediate through hydrogen bonding. Thus, this is
Figure 8. 31P NMR spectrum of phosphonium iodide salt B in CDCl3.
(23) Bifunctional chiral ligands: Please see: (a) Yamada, Y. M. A.; Yoshikawa,
N.; Sasai, H.; Shibasaki, M. Angew. Chem., Int. Ed. Engl. 1997, 36, 1871-
1873. (b) Yoshikawa, N.; Yamada, Y. M. A.; Das, J.; Sasai, H.; Shibasaki,
M. J. Am. Chem. Soc. 1999, 121, 4168-4178. (c) Takamura, M.;
Hamanashi, Y.; Usuda, H.; Kanai, M.; Shibasaki, M. Angew. Chem., Int.
Ed. 2000, 39, 1650-1652. (d) Shibasaki, M.; Yoshikawa, N. Chem. ReV.
2002, 102, 2187-2209. (e) Trost, B. M.; Fettes, A.; Shireman, B. T. J.
Am. Chem. Soc. 2004, 126, 2660-2661.
Figure 9. 1H NMR spectrum of phosphonium iodide salt B with MVK in
CDCl3.
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3798 J. AM. CHEM. SOC. VOL. 127, NO. 11, 2005

aza-Baylis−Hillman Reaction of N-Sulfonated Imines
A R T I C L E S
Figure 12. Structures of chiral Lewis bases.
Scheme 8
2-cyclopenten-1-one in the presence of a more nucleophilic
chiral phosphine Lewis base under mild reaction conditions.
The selection of chiral phosphine compounds is a key point for
success in this reaction. On the basis of the above results, we
decided to synthesize (R)-2′-dimethylphosphanyl-[1,1′]bi-
naphthalenyl-2-ol LB13 and utilized it as a chiral phosphine
Lewis base in this reaction because it has a structure similar to
that of chiral Lewis base LB1 (a phenolic hydroxy group and
a phoshine atom as a nucleophilic source) and Lewis base
PPhMe2 (a NaphthylPMe2 group) (Figure 12). The synthesis of
chiral phosphine Lewis base LB13 has been indicated in
Supporting Information (Scheme SI-6).12a,24
The reaction conditions for the catalytic, asymmetric version
of N-sulfonated imines 1 with 2-cyclopenten-1-one were
systematically examined using N-(4-chlorobenzylidene)-4-me-
thylbenzenesulfonamide 1e as substrate. The results are briefly
summarized in Scheme 8. When the reaction temperature was
kept at low temperature such as -78 °C for 1 h and then raised
to room temperature naturally, the ee of 7a could reach 64% in
93% yield (Scheme 8). Further exploration of chiral phosphine
Lewis base for this reaction is required. The detailed results
will be reported in due course.
Moreover, it should be pointed out that when 4-(3-ethyl-4-
oxa-1-azatricyclo[4,4,0,03,8]dec-5-yl)-quinolin-6-ol â-ICD6d was
used as a chiral nitrogen Lewis base for the above catalytic,
asymmetric aza-Baylis-Hillman reaction, no reaction occurred.
On the basis of these results, it is very clear that the catalytic,
asymmetric aza-Baylis-Hillman reaction of imines with â-sub-
stituted Michael acceptor is more difficult and is highly
dependent on the structure of chiral Lewis base.
In conclusion, we found that in the aza-Baylis-Hillman
reaction of N-sulfonated imines 1 with MVK using LB1 as a
chiral phosphine Lewis base, 76-95% ee can be achieved at
-30 or -20 °C in THF. In addition, good to excellent yields
can be realized in the coexistence of molecular sieve 4A. For
Michael acceptors such as EVK and acrolein, similar results
are obtained to give the corresponding adducts 3 and 6 in high
ee. In CH2Cl2 upon heating at 40 °C, the aza-Baylis-Hillman
adducts 5 derived from N-sulfonated imines 1 with phenyl
acrylate were formed in high yields (60-97%) with moderate
ee (52-77%). The substituent effects of this chiral phosphine
Lewis base promoter system have been examined as well. In
Figure 11.
a Lewis base and Brønsted acid (LBBA) bifunctional chiral
ligand system (Figure 11). Michael addition of LB1 to MVK
affords the key enolate intermediate C, which undergoes aldol
reaction with N-sulfonated imines 1 to give several diastereo-
meric intermediates according to the generally accepted reaction
mechanism for the Baylis-Hillman reaction. The key factor is
the intramolecular hydrogen bonding between the phenolic OH
and the oxygen atom of carbonyl group for intermediate C. In
addition, the intramolecular hydrogen bonding between the
phenolic O-H and the nitrogen anion stabilized by sulfonyl
group can produce relatively stable diastereomeric intermediates
D and E. However, as shown in Newman projection F and G
(top view), the steric repulsions between the C(O)Me group with
the aromatic group and the aromatic group with two phenyl
groups in the phosphorus atom suggest that intermediate D is
more stable than E in this relatively stabilized transition state.
Moreover, the use of N-sulfonated imines, instead of aldehydes,
can drive the reaction forward and perhaps cut down on
reversibility shown in Scheme 7, which usually erodes the
enantioselectivity in Baylis-Hillman reaction. Therefore, in-
termediate D undergoes facile elimination to produce the aza-
Baylis-Hillman adduct with (S)-enriched configuration.
7. The aza-Baylis-Hillman Reaction of N-Sulfonated
Imines 1 with â-Substituted Michael Acceptor. The aza-
Baylis-Hillman reaction of N-sulfonated imines 1 with â-sub-
stituted Michael acceptor is a more difficult task for organic
chemists since the aza-Baylis-Hillman reaction using these
substrates with DABCO or PPh3 as a Lewis base leads to no
reaction under normal conditions. Previously, we reported that
when using a more nucleophilic phosphine Lewis base such as
PBu3 or PPhMe2 to promote the aza-Baylis-Hillman reaction
of N-sulfonated imines 1 with 2-cyclopenten-1-one, the corre-
sponding aza-Baylis-Hillman adducts can be obtained in high
yields within 5 h.6a On the basis of this result, we attempted
the catalytic, asymmetric aza-Baylis-Hillman reaction of N-
sulfonated imines 1 with 2-cyclopenten-1-one in the presence
of chiral phosphine Lewis base. A more nucleophilic chiral
phosphine Lewis base is required for this reaction because LB1
showed no catalytic activity for this reaction. Therefore, we wish
to report in this section an unprecedented catalytic, asymmetric
aza-Baylis-Hillman reaction of N-sulfonated imines 1 with
(24) Chen, J.-X.; Daeuble, J. F.; Stryker, J. M. Tetrahedron 2000, 56, 2789-
2798.
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J. AM. CHEM. SOC. VOL. 127, NO. 11, 2005 3799

A R T I C L E S
Shi et al.
general, the substituents on the 6- or 6,6-positions of bi-
naphthalene framework did not significantly affect the efficiency
of this enantioselective catalytic system. The introduction of
phenyl substituent on the position adjacent to the phenolic
hydroxy group led this kind of phosphine Lewis base to be more
stable and more efficient under milder conditions. A divergent
structure of chiral phosphine Lewis bases can be designed and
synthesized on the basis of the structure of LB1. We also found
a simple and more nucleophilic chiral phosphine Lewis base
(R)-2′-dimethylphosphanyl-[1,1′]binaphthalenyl-2-ol LB13 to
achieve the catalytic enantioselective aza-Baylis-Hillman reac-
tion using cyclopent-2-en-1-one as a Michael acceptor. This is
the first example of a catalytic, asymmetric aza-Baylis-Hillman
reaction using R,â-unsaturated cyclic ketones as Michael
acceptors, although the achieved ee is not very high. We believe
that the chiral Lewis base of LB1 acted as a bifunctional chiral
ligand in this reaction (LBBA). The phosphine atom acted as a
Lewis base, and the phenolic OH acted as a Lewis acid (BA)
through hydrogen bonding. The key factor is the intramolecular
hydrogen bonding between the phenolic OH and the oxygen
atom of carbonyl group to stabilize the in situ formed key
enolate intermediate on the basis of NMR spectroscopic
investigation. In addition, the intramolecular hydrogen bonding
between the phenolic OH and the nitrogen anion stabilized by
the sulfonyl group can give a relatively stable or rigid transition
state for achieving high enantioselectivity in the aza-Baylis-
Hillman reaction. Efforts are underway to elucidate the mecha-
nistic details of this reaction and the key factors of chiral Lewis
bases in the Baylis-Hillman reaction and to disclose the scope
and limitations of this reaction. Work along this line is currently
in progress.
Acknowledgment. We thank the State Key Project of Basic
Research (Project 973) (No. G2000048007), Shanghai Municipal
Committee of Science and Technology, Chinese Academy of
Sciences (KGCX2-210-01), and the National Natural Science
Foundation of China for financial support (20025206, 203900502,
and 20272069).
Supporting Information Available: 13C and 1H NMR spec-
troscopic and analytic data for chiral phosphine Lewis bases
LB1-LB13, the aza-Baylis-Hillman reaction products, ex-
perimental details, and chiral HPLC traces of the compounds
shown in Tables 1-6 and Schemes 1-4 and 8. This material
is available free of charge via the Internet at http://pubs.acs.org.
JA0447255
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3800 J. AM. CHEM. SOC. VOL. 127, NO. 11, 2005