Dramatic Rate Acceleration of the Baylis-Hillman Reaction in Homogeneous Medium in the Presence of Water

Article abstract of DOI:10.1021/ol027197f

(Matrix Presented) In homogeneous H₂O/solvent medium, the reaction rate of aromatic aldehydes and acrylonitrile or acrylate was greatly accelerated, which led to shorter reaction time, lower reaction temperature, and higher yield. In this react

Full text of DOI:10.1021/ol027197f

ORGANIC
LETTERS
2002
Vol. 4, No. 26
4723-4725
Dramatic Rate Acceleration of the
Baylis−Hillman Reaction in
Homogeneous Medium in the Presence
of Water
Juexiao Cai, Zhenghong Zhou, Guofeng Zhao, and Chuchi Tang*
State Key Laboratory of Elemento-Organic Chemistry, Institute of Elemento-Organic
Chemistry, Nankai UniVersity, Tianjin 300071, People’s Republic of China
c.c.tang@eyou.com
Received October 29, 2002
ABSTRACT
In homogeneous H O/solvent medium, the reaction rate of aromatic aldehydes and acrylonitrile or acrylate was greatly accelerated, which led
2
to shorter reaction time, lower reaction temperature, and higher yield. In this reaction, Me3N, DMAP, DABCO, and urotropine were good
catalysts. Except for low-carbon alcohols, tetrahydrofuran, 1,4-dioxane, and acetonitrile could be chosen as the solvent. Under this condition,
the diastereoselective reaction of nitrobenzaldehyde and L-menthyl acrylate was realized with 88−99% de.
The Baylis-Hillman reaction was first reported in 1972.1
This carbon-carbon bond-forming reaction can afford multi-
functional adducts, which have been widely utilized in
organic synthesis. Therefore, the Baylis-Hillman reaction
has been drawing much attention from synthetic organic
chemists in the past decade.2 The major problem associated
with this reaction is its slow reaction rate. In view of this
situation, numerous methods, including chemical as well as
physical attempts, have been made to accelerate the reaction
with some good results.3 Since 1994, several research groups
reported that the Baylis-Hillman reaction could be acceler-
ated in the presence of water. Bittman4a and Gaied4b have
investigated the reaction of activated alkene and formalde-
hyde in the presence of water using DABCO (1,4-
diazabicyclo[2,2,2]octane) and DMAP (4-(dimethylamino)-
pyridine) as the catalyst, respectively. Lubineau4c has studied
the rate acceleration effect of water on the DABCO-catalyzed
coupling of benzaldehyde and acrylonitrile from the kinetic
aspect. Most recently, Basaviah4d and Hu4e have investigated
the trimethylamine- and DABCO-catalyzed Baylis-Hillman
reaction in the presence of water. However, none of the
aforementioned reports have dealt with the homogeneous
medium in the presence of water.
Recently, we found that an obvious rate acceleration was
observed by the addition of low-carbon alcohols or other
polar solvents, such as THF, 1,4-dioxane, acetonitrile, etc.,
to transform the heterogeneous mixture of aqueous tri-
methylamine and the substrate into a clear homogeneous
(3) (a) Masunari, A.; Ishida, E.; Trazzi, G.; Almeida, W. P.; Coelho, F.
Synth. Commun. 2001, 31, 2127. (b) Almeida, W. P.; Coelho, F. Tetrahedron
Lett. 1998, 39, 8609. (c) Brzezinski, L. J.; Rafel, S.; Leahy, J. W.
Tetrahedron 1997, 53, 16423. (d) Brzezinski, L. J.; Rafel, S.; Leahy, J. W.
J. Am. Chem. Soc. 1997, 119, 4317. (e) Hill, J. S.; Isaacs, M. S. Tetrahedron
Lett. 1986, 27, 5007. (f) Bode, M. L.; Kaye, P. T. J. Chem. Soc., Perkin
Trans. 1 1993, 1809. (g) Kundu, M. K.; Mukherjee, S. B.; Balu, N.;
Padmakumar, R.; Bhat, S. V. Synlett 1994, 444. (h) Roos, G. H. P.;
Rampersadh, P. Synth. Commun. 1993, 23, 1261. (i) Hill, J. S.; Isaacs, N.
S. J. Chem. Res. (S) 1988, 330. (j) Isaacs, N. S. Tetrahedron 1991, 47,
8463. (k) Rozendaal, E. L. M.; Voss, B. M. W.; Scheeren, H. W.
Tetrahedron 1993, 49, 6931.
(1) Baylis, A. B.; Hillman, M. E. D. German Patent 2155113, 1972;
Chem. Abstr. 1972, 77, 34174.
(2) (a) Drewes, S. E.; Roos, G. H. P. Tetrahedron 1988, 44, 4653. (b)
Basavaiah, D.; Rao P. O.; Hyma, R. S. Tetrahedron 1996, 52, 8001. (c)
Langer, P. Angew. Chem., Int. Ed. 2000, 39, 3049.
(4) (a) Byun, H. S.; Reddy, K. C.; Bittman, R. Tetrahedron Lett. 1994,
35, 1371. (b) Rezgui, F.; Gaied, M. M. E. Tetrahedron Lett. 1998, 5965;
(c) Auge, J.; Lubin, N.; Lubineau, A. Tetrahedron Lett. 1994, 35, 7947.
(d) Basavaiah, D.; Krishnamacharyulu, M.; Rao, A. J. Synth. Commun. 2000,
30, 2061. (e) Yu, C. Z.; Liu, B.; Hu, L. Q. J. Org. Chem. 2001, 66, 5413.
10.1021/ol027197f CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/06/2002

Table 1. The Reaction of Aldehydes and Activated Alkene in HomogeneousH2O/solvent medium at ambient temperaturea
entry
r
ewg
CN
CO2Me
CO2Et
cat.
Me3N
solvent
MeOH
MeOH
EtOH
react. time (h)
productb
yield (%)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
4-O2NC6H4
4-O2NC6H4
4-O2NC6H4
4-O2NC6H4
4-O2NC6H4
4-O2NC6H4
4-O2NC6H4
4-O2NC6H4
4-O2NC6H4
4-O2NC6H4
4-NO2C6H4
4-NO2C6H4
3-NO2C6H4
2-furan
0.5
2
3.5
4
2.5
2.5
3
4 (0 °C)
2.5
96
36
144
48
2.5
4
24
6
20
2.5
8
14d,5
24d,5
34d
44d
24d
24d
24d
24d
24d
24d
24d
5
85
86
92
92
99
97
88
96
94
Me3N
Me3N
Me3N
Me3N
Me3N
Me3N
DMAP
DABCO
Urotropine
Ph3P
Me3N
Me3N
Me3N
Me3N
Me3N
Me3N
Me3N
Me3N
Me3N
Me3N
Me3N
Me3N
Me3N
CO2Bu-n
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Men
CO2Men
CO2Me
CO2Et
CO2Bun
CN
CO2Me
CN
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
n-BuOH
THF
1,4-dioxane
MeCN
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
MeOH
EtOH
n-BuOH
MeOH
MeOH
MeOH
87 (52% conversion)
58
88 (83% de)d
45 (99% de)d
6
74d,6
84d
94d
107
118
12
91
96
94
92
88
79
77
87
85
87
92
2-furan
2-furan
C6H5
C6H5
4-ClC6H4
4-ClC6H4
4-FC6H4
2,4-Cl2C6H4
4-CF3C6H4
4-MeC6H4
MeOH
MeOH
MeOH
MeOH
134d
14
15
16
60
6
3
MeOH
168
17
a When 33% (w/v) aqueous trimethylamine was used as catalyst, all reactions of solid aldehydes were carried out on 2 mmol scale of the aldehyde, 6
mmol of activated alkene, and 2.5 mmol aqueous trimethylamine in 2 mL of solvent, all reactions of liquid aldehydes were carried out on 5 mmol scale of
the aldehyde, 15 mmol of activated alkene, and 5 mmol of aqueous trimethylamine in 2 mL solvent. When other catalysts were used all reactions were
carried out on a 1 mmol scale of the aldehyde, 3 mmol of activated alkene, and 0.5 mL of H2O in 2 mL of solvent. b Structures of all the products, the known
or unknown molecules, were confirmed by 1H NMR and elemental analysis. c Isolated yield based on aldehydes. d De value was determined by HPLC with
silica column (250 × 4.6, dp 5 µm), petroleum ether/2-propanol (95:5) as the eluent.
liquid. Hence, compared with the literature reported results,
the addition product was obtained in less time and at low
temperature with good to excellent yield (Table 1).
results of 86-92% (entries 2-4) and 91-96% (entries 14-
16). Under the same conditions, the diastereoselective
Baylis-Hillman reaction of 4- or 3-nitrobenzaldehyde and
L-(-)-menthyl acrylate was realized with 83% and 99% de,
respectively (entries 12 and 13).
As shown in Table 1, in the aqueous trimethylamine
homogeneous medium, the reaction of active aldehydes (such
as 4-nitrobenzaldehyde) and acrylonitrile or acrylate has a
fast reaction rate and high yield. Additionally, the reaction
of nonactive aldehydes (such as benzaldehyde, fluoro-,
chloro-, or methyl-substituted benzaldehydes, etc.) also has
good results. On the other hand, in heterogeneous medium,
the reaction of these nonactive aldehydes cannot provide
good results because the reaction is extremely sluggish under
this condition.4d Even the highly active 4-nitrobenzaldehyde
and furaldehyde reacted with acrylate in heterogeneous
medium can afford the product with only 56-59% and 30-
35% yield, respectively, which was much lower than our
When DMAP, DABCO, and urotropine were used as
catalysts, the reaction of 4-nitrobenzaldehyde and methyl
acrylate can be carried out with good results (entries 8-10)
in the homogeneous H2O/1,4-dioxane medium. Nevertheless,
when triphenylphosphine was used as catalyst, the same
reaction runs quite slowly with unsatisfactory results (entry
11).
Except for low-carbon alcohols, THF, 1,4-dioxane, and
acetonitrile can also be used in the aqueous trimethylamine-
catalyzed coupling of 4-nitrobenzaldehyde and methyl acry-
late with satisfactory results.
In conclusion, the Baylis-Hillman reaction in H2O/solvent
homogeneous medium runs faster than that in heterogeneous
medium in the presence of water. Furthermore, a better result
(higher yield) was obtained. Under this condition, the
diastereoselective Baylis-Hillman reaction was also realized
(5) Kataoka, T.; Iwama, T.; Tsujiyama, S.; Iwamura, T.; Watanabe, S.
Tetrahedron 1998, 54, 11813.
(6) Drewes, S. E.; Emslie, N. D.; Khan, A. A.; Roos, G. H. P. Synth.
Commun. 1989, 19, 959.
(7) Basavaiah, D.; Gowriswari, V. V. L. Synth. Commun. 1987, 17, 587.
(8) Fort, Y.; Berthe, M. C.; Caubere, P. Tetrahedron 1992, 48, 6371.
4724
Org. Lett., Vol. 4, No. 26, 2002

with high de value. These results are helpful to the wider
application of the Baylis-Hillman reaction in organic
synthesis.
Supporting Information Available: General experimen-
tal procedure and spectroscopic characterizaton (1H NMR
and elemental analysis) of all prepared adducts. This material
is available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We thank the National Natural Sci-
ence Foundation of China (No. 20272025) for generous
financial support of our program.
OL027197F
Org. Lett., Vol. 4, No. 26, 2002
4725