Scheme 3
Table 2 aza-Baylis–Hillman reactions of N-sulfonated imines (1.0 eq) with
phenyl acrylate in the presence of chiral Lewis base L1 (10 mol%) in
dichloromethane at 40 °C.
spectroscopic data of L1with MVK and imine (molar ratio =
1:5:5) elucidated a new signal at +25.297 ppm, which was
believed to relate with B, along with peak of L1 (see ESI†).
Further investigation on this new signal is ongoing.
Absolute
configuration
In conclusion, we found that in the aza-Baylis–Hillman
reaction of various N-sulfonated imines with MVK using L1 as
a chiral phosphine Lewis base, 76–94% ee can be achieved at
230 °C in THF. In addition, good to excellent yields can be
realized in the coexistence of molecular sieve 4A. In CH2Cl2
upon heating at 40 °C, the aza-Baylis–Hillman adducts 2 were
formed in high yields (60–97%) with moderate ee (52–77%). At
the present stage, this is the highest ee achieved for the Baylis–
Hillman reaction using MVK as a Michael acceptor by a chiral
phosphine Lewis base. Efforts are underway to elucidate the
mechanistic details of this reaction and to disclose its scope and
limitations. Work along this line is currently in progress.
We thank the State Key Project of Basic Research (Project
973) (No. G2000048007), Shanghai Municipal Committee of
Science and Technology, and the National Natural Science
Foundation of China for financial support (20025206 and
20272069).
Entry Ar
Time/h
Yield/%a
ee/%b
2a–i
1
2
3
4
5
6
7
8
9
C6H5
12
12
12
12
12
12
12
84
60
80
94
85
89
95
97
89
61
53
69
67
77
63
58
75
52
ND
(+)
(2)
(+)
p-EtC6H4
p-FC6H4
p-ClC6H4
p-BrC6H4
m-FC6H4
m-ClC6H4
(+)
(2)
ND
(2)
(2)
p-NO2C6H4 12
m-NO2C6H4 12
a Isolated yield; b Determined by chiral HPLC.
presence of L1 (Scheme 2). We found that in CH2Cl2 upon
heating at 40 °C for 12 h, in most cases, the corresponding aza-
Baylis–Hillman adducts 2 were formed in high yields (60–97%)
with moderate ee (52–77%) (Table 2, entries 1–9). This is the
best reaction condition for this version of aza-Baylis–Hillman
reaction (see ESI†).
Notes and references
1 (a) E. Ciganek, Org. React., 1997, 51, 201; (b) D. Basavaiah, P. D. Rao
and R. S. Hyma, Tetrahedron, 1996, 52, 8001.
In Scheme 3, we briefly gave a mechanistic speculation on
the chiral Lewis base L1.2a We believe that L1 acted as a
bifunctional chiral ligand in this reaction.7 The phosphine atom
acted as a Lewis base and the phenolic OH acted as a Lewis acid
through hydrogen bonding. Michael addition of L1 to MVK
affords enolate A, which undergoes aldol reaction with N-
sulfonated imines to give several diastereomeric intermediates
according to the generally accepted reaction mechanism for
Baylis–Hillman reaction. The key factor is the intramolecular
hydrogen bonding between the phenolic OH and nitrogen anion
stabilized by sulfonyl group to give relatively stable diaster-
eomeric intermediates B and C. However, as shown in Newman
projection D and E (top view), the steric repulsions between the
C(O)Me group with the aromatic group and aromatic group
with two phenyl groups on the phosphorus atom suggest that
intermediate B is more stable than C in this stabilized transition
state. Therefore, intermediate B undergoes facile elimination to
produce the aza-Baylis–Hillman adduct with S configuration.
In order to get more mechanistic insight into this reaction, we
carried out the 31P NMR measurement of L1 in the absence or
presence MVK and imine. We found the 31P NMR (CDCl3,
85% H3PO4) spectroscopic data of L1 showed a signal at
213.158 ppm, but the 31P NMR (CDCl3, 85% H3PO4)
2 (a) Y. Iwabuchi, M. Nakatani, N. Yokoyama and S. Hatakeyama, J. Am.
Chem. Soc., 1999, 121, 10219; (b) A. G. M. Barrett, A. S. Cook and A.
Kamimura, Chem. Commun., 1998, 2533; (c) P. Langer, Angew. Chem.
Int. Ed., 2000, 39, 3049; (d) V. K. Aggarwal, A. M. Castro, A. Mereu and
H. Adams, Tetrahedron Lett., 2002, 43, 1577.
3 (a) A. B. Baylis and M. E. D. Hillman, Ger. Offen., 1972, 2, 2,155,113;
A. B. Baylis and M. E. D. Hillman, Chem. Abs., 1972, 77, 34174q; M. E.
D. Hillman and A. B. Baylis, U. S. Patent, 1973, 3, 743, 669; (b) K.
Morita, Z. Suzuki and H. Hirose, Bull. Chem. Soc. Jpn., 1968, 41,
2815.
4 (a) M. Shi and Y.-M. Xu, Chem. Commun., 2001, 1876; (b) M. Shi and
Y.-M. Xu, Eur. J. Org. Chem., 2002, 696; (c) M. Shi, Y.-M. Xu, G.-L.
Zhao and X.-F. Wu, Eur. J. Org. Chem., 2002, 3666; (d) M. Shi and Y.-
M. Xu, Angew. Chem. Int. Ed., 2002, 41, 4503.
5 B. E. Love, P. S. Raje and T. C. Williams, Synlett., 1994, 493.
6 The crystal structure of 1e with R configuration has been deposited at the
Cambridge Crystallographic Data Center and allocated the deposition
number CCDC 167239 (see ref 4d).
7 Bifunctional chiral ligands. Please see: (a) Y. M. A. Yamada, N.
Yoshikawa, H. Sasai and M. Shibasaki, Angew. Chem. Int. Ed. Engl.,
1997, 36, 1871; (b) N. Yoshikawa, Y. M. A. Yamada, J. Das, H. Sasai and
M. Shibasaki, J. Am. Chem. Soc., 1999, 121, 4168; (c) M. Takamura, Y.
Hamanashi, H. Usuda, M. Kanai and M. Shibasaki, Angew. Chem. Int.
Ed., 2000, 39, 1650.
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