Lewis base and L-proline co-catalyzed Baylis-Hillman reaction of arylaldehydes with methyl vinyl ketone

Article abstract of DOI:10.1016/S0040-4039(01)02057-3

In the Baylis-Hillman reaction of arylaldehydes with methyl vinyl ketone, we found that, in the presence of a catalytic amount of L-proline, weak Lewis bases such as imidazole and triethylamine as well as the stronger Lewis base DABCO, can promote the Bay

Full text of DOI:10.1016/S0040-4039(01)02057-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 127–130
Lewis base and -proline co-catalyzed Baylis–Hillman reaction
L
of arylaldehydes with methyl vinyl ketone
Min Shi,* Jian-Kang Jiang and Chao-Qun Li
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354
Fenglin Lu, Shanghai 200032, China
Received 25 July 2001; revised 18 October 2001; accepted 26 October 2001
Abstract—In the Baylis–Hillman reaction of arylaldehydes with methyl vinyl ketone, we found that, in the presence of a catalytic
amount of L-proline, weak Lewis bases such as imidazole and triethylamine as well as the stronger Lewis base DABCO, can
promote the Baylis–Hillman reaction to give the normal Baylis–Hillman adduct in good yields. Substituent effects were also
examined and a plausible reaction mechanism is proposed. © 2001 Elsevier Science Ltd. All rights reserved.
Lewis base reduced the yields of 1a under the same
reaction conditions (Table 1, entries 5 and 7). Using
pyridine or 1H-benzotriazole as a Lewis base, no reac-
tion occurred (Table 1, entries 6 and 8). Using other
amino acids such as glycine (30 mol%) or L-phenylala-
nine (30 mol%) as a promoter, only 20–30% of 1a was
obtained.
Recently, the Baylis–Hillman reaction has made great
progress,1 and now includes a catalytic asymmetric
version.2 Baylis and Hillman first reported the reaction
of acetaldehyde with ethyl acrylate and acrylonitrile in
the presence of catalytic amounts of strong Lewis bases
such as 1,4-diazabicyclo[2,2,2]octane (DABCO) in
1972.3 During our own investigation on this very simple
and useful reaction, we disclosed many new results.4
Herein, we wish to report that in the reaction of
arylaldehydes with methyl vinyl ketone (MVK) weak
Lewis bases such as imidazole and triethylamine can
For m-nitrobenzaldehyde, o-nitrobenzaldehyde, p-
bromo or p-chlorobenzaldehyde and pyridylaldehydes,
similar results were obtained under the optimized reac-
tion conditions (Scheme 3, Table 2, entries 1–4). How-
also promote this reaction in the presence of L-proline
to give high yields of 1.
ever,
for
benzaldehyde,
trans-cinnamaldehyde,
valeraldehyde or p-ethylbenzaldehyde, adducts 1 were
obtained only in moderate yields. It should be pointed
out that, in all cases, the adducts 1 were obtained with
Imidazole and triethylamine are weak Lewis bases and
cannot promote the reaction of arylaldehydes with
MVK at all by themselves (Scheme 1). However, we
found that, in the presence of a catalytic amount of
very low ees (5–10%), although
the co-catalyst.
L-proline was used as
L
-proline, this reaction takes place smoothly to give
Concerning the additives used for Baylis–Hillman reac-
tions, LiClO4 and NaBF4 have been used as Lewis acids
with Lewis bases DABCO and pyrrolizidine, respec-
tively, to accelerate the reaction rate.6 However, in
these systems, DABCO or pyrrolizidine itself are suffi-
cient to promote the reaction. In our system, coexis-
high yields of 1. For example, in the reaction of p-
nitrobenzaldehyde (1.0 equiv.) with MVK (3.0 equiv.),
1a can be obtained in 60% yield in the presence of 10
mol% of imidazole and 10 mol% of
for 24 h.5 By increasing the amount of imidazole and
-proline to 30 mol%, the yield of 1a reaches 91%
L-proline in DMF
L
under the same conditions (Scheme 1). Similar results
were obtained by carrying out the reaction in DMSO,
tetrahydrofuran (THF) or chloroform (Scheme 2, Table
1, entries 2–4). Using benzimidazole or triethylamine as
tence of Lewis base and
L-proline is required to
promote the Baylis–Hillman reaction. We examined the
imidazole and LiClO4 co-catalyzed Baylis–Hillman
reaction of p-nitrobenzaldehyde (1.0 equiv.) with MVK
(3.0 equiv.) under our conditions (Scheme 4). The reac-
tion was sluggish and the yield of 1a was only 30%. We
Keywords: Baylis–Hillman reaction; Lewis base; methyl vinyl ketone
believe that
reaction. Recently, many
L
-proline acts as a Lewis acid in this
-proline-catalyzed condensa-
(MVK);
L-proline; imidazole; triethylamine.
* Corresponding author. E-mail: mshi@pub.sioc.ac.cn
L
0040-4039/02/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02057-3

128
M. Shi et al. / Tetrahedron Letters 43 (2002) 127–130
CO2H
N
O
(30 mol%)
H
C
no reaction
+
p-O2NPh CHO
Me
DMF
N
N
H
O
C
(30 mol%)
DMF
no reaction
p-O2NPh CHO
+
Me
N
N
CO2H
OH
CH
O
C
N
H
O
(30 mol%)
(30 mol%)
H
C
C
+
Me
p-O2NPh CHO
p-O2NPh
Me
CH2
1a, 91%
DMF, r.t., 24 h
Scheme 1.
CO2H
(30 mol%)
Lewis base
(30 mol%)
OH
CH
O
C
N
H
O
C
+
Me
p-O2NPh CHO
C
p-O2NPh
Me
solvent
CH2
1a
Scheme 2.
tion reactions have been reported.7 List reported a very
Hillman reaction mechanism, we would like to postu-
late the mechanism for the above -proline and
imidazole (Lewis base and Lewis acid) co-catalyzed
L
exciting
L-proline-catalyzed direct asymmetric aldol
reaction with an elegant mechanism.7c Based on his
Baylis–Hillman reaction shown in Scheme 5. In order
aldol reaction mechanism and the traditional Baylis–
Table 2. Baylis–Hillman reactions of aldehydes (1.0
equiv.) with methyl vinyl ketone (3.0 equiv.) in the pres-
ence of imidazole (0.3 equiv.) and proline (0.3 equiv.)
Table 1. Baylis–Hillman reactions of p-nitrobenzaldehyde
(1.0 equiv.) with methyl vinyl ketone (MVK) (3.0 equiv.)
in the presence of Lewis base (0.3 equiv.) and proline (0.3
equiv.)
Entry
R
Time (h)
Yield (%)a
1
Entry
Lewis base
Solvent
Time
(h)
Yield (%)a
1a
1
2
3
4
5
6
7
8
9
m-NO2Ph
o-NO2Ph
p-BrPhb
24
24
48
60
72
80
24
24
72
80
90
86
85
67
45
30
90
80
43
46
1
2
3
4
5
6
7
8
Imidazole
Imidazole
Imidazole
Imidazole
Benzimidazole
1H-Benzimidazole
Et3N
DMF
DMSO
THF
Chloroform
DMF
DMF
24
24
24
24
24
36
36
40
91
90
87
88
45
–
p-ClPhb
Phb
p-EtPhb
2-Pyridyl
3-Pyridyl
trans-PhCHꢀCHb
b
DMF
DMF
66
–
10
CH3(CH2)2
Pyridine
a Isolated yields.
b Arylaldehyde:methyl vinyl ketone=1:5.
a Isolated yields.

M. Shi et al. / Tetrahedron Letters 43 (2002) 127–130
129
N
CO2H
OH
CH
O
C
N
H
N
H
O
C
(30 mol%)
(30 mol%)
DMF
R
C
+
Me
R CHO
Me
CH2
1
b: R= m-NO2Ph, c: R= o-NO2Ph, d: R= p-BrPh, e: R= p-ClPh,
f: R= Ph, g: R= p-EtPh, h: R= 2-pyridyl, i: R= 3-pyridyl, j:
R= PhCH=CH, k: R= CH3(CH2)3.
Scheme 3.
N
LiClO4
N
H
O
(30 mol%)
(30 mol%)
C
+
1a
p-O2NPh CHO
Me
DMF, r.t., 24 h
30%
Scheme 4.
CO2H
N
H
-
O
CO2
+
N
C
C
N
H O
+
2
Me
Me
N
H
A
-
CO2
N
C
N
+
N
Me
CO2H
+
N
H
N
H
N
H
-
CO2
+
N
OH
Ar CHO
O
C
OH
C
Ar
Me
Ar
Me
N
H2O
N
Scheme 5.
to obtain evidence for this mechanism, we measured the
1H NMR of MVK,
-proline and the mixture of MVK
and -proline (1:2) in CD3OD and CD3S(O)CD3, but
no useful information was obtained. This may mean
that the concentration of intermediate A is very low,
and it is difficult to find its NMR signal.
In conclusion, we have found that in the Baylis–Hill-
man reaction of arylaldehydes with methyl vinyl ketone
(MVK), weak Lewis bases can promote the reaction in
the presence of a catalytic amount of L-proline. It
should be emphasized here that although the Baylis–
Hillman adducts 1 obtained had very low optical activ-
L
L

130
M. Shi et al. / Tetrahedron Letters 43 (2002) 127–130
ity, we believe this finding could open a new way for
the design and synthesis of chiral ligands that will
catalyse the asymmetric version of the Baylis–Hillman
reaction. Efforts are underway to elucidate the mecha-
nistic details of this reaction and to disclose its scope
and limitations.
S. Chem. Commun. 1998, 197; (n) Ono, M.; Nishimura, K.;
Nagaoka, Y.; Tomioka, K. Tetrahedron Lett. 1999, 40,
1509; (o) Li, G.; Wei, H.-X.; Gao, J. J.; Caputo, T. D.
Tetrahedron Lett. 2000, 41, 1; (p) Kataoka, T.; Kinoshita,
H.; Iwama, T.; Tsujiyama, S.; Iwamura, T.; Watanabe, S.;
Muraoka, O.; Tanabe, G. Tetrahedron 2000, 56, 4725; (q)
Li, G.; Gao, J.; Wei, H.-X.; Enright, M. Org. Lett. 2000,
2, 617.
Acknowledgements
2. Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama,
S. J. Am. Chem. Soc. 1999, 121, 10219.
3. (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. US Patent 1973, 3,743,669; (b) Morita,
K.; Suzuki, Z.; Hirose, H. Bull. Chem. Soc. Jpn. 1968, 41,
2815.
4. (a) Shi, M.; Jiang, J.-K.; Feng, Y.-S. Org. Lett. 2000, 2,
2397; (b) Shi, M.; Feng, Y.-S. J. Org. Chem. 2001, 66, 406;
(c) Shi, M.; Jiang, J.-K.; Cui, S.-C.; Feng, Y.-S. J. Chem.
Soc., Perkin Trans. 1 2001, 390; (d) Shi, M.; Jiang, J.-K.
Tetrahedron 2000, 56, 4793; (e) Shi, M.; Li, C.-Q.; Jiang,
J.-K. Chem. Commun. 2001, 833; (f) Shi, M.; Xu, Y.-M.
Chem. Commun. 2001, 1876.
5. The spectral data of 1a: Mp 76–77°C; IR (KBr) w 1658
cm−1 (CꢀO); 1H NMR (CDCl3, 300 MHz, TMS) l 2.37
(3H, s, Me), 3.34 (1H, d, J=5.3 Hz, OH), 5.69 (1H, d,
J=5.3 Hz), 6.04 (1H, s), 6.28 (1H, s), 7.56 (2H, d, J=8.6
Hz, Ar), 8.25 (2H, d, J=8.6 Hz, Ar); MS (EI) m/z 220
(M+−1, 20.9), 204 (M+−17, 100), 174 (M+−47, 88.1).
6. (a) Kawamura, M.; Kobayashi, S. Tetrahedron Lett. 1999,
40, 1539; (b) Barrett, A. G.; Cook, A. S.; Kamimura, A.
Chem. Commun. 1998, 2533.
We thank the State Key Project of Basic Research
(Project 973) (No. G2000048007) and the National
Natural Science Foundation of China for financial sup-
port (20025206). We also thank the Inoue Photochiro-
genesis Project (ERATO, JST) for chemical reagents.
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