Aqueous Baylis-Hillman reactions of cyclopent-2-enone using imidazole as catalyst

Article abstract of DOI:10.1016/S0040-4039(02)01716-1

In aqueous media, imidazole was found to catalyse Baylis-Hillman reactions of cyclopent-2-enone with various aldehydes to afford the desired adducts with high yields.

Full text of DOI:10.1016/S0040-4039(02)01716-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 7369–7371
Aqueous Baylis–Hillman reactions of cyclopent-2-enone using
imidazole as catalyst
a
a
a
b
b
a,
Sanzhong Luo, Baolian Zhang, Jiaqi He, Adam Janczuk, Peng G. Wang and Jin-Pei Cheng *
a
Department of Chemistry, Nankai University, Tianjin 300071, China
b
Department of Chemistry, Wayne State University, Detroit, MI 48202, USA
Received 22 May 2002; revised 9 August 2002; accepted 16 August 2002
Abstract—In aqueous media, imidazole was found to catalyse Baylis–Hillman reactions of cyclopent-2-enone with various
aldehydes to afford the desired adducts with high yields. © 2002 Elsevier Science Ltd. All rights reserved.
The Baylis–Hillman reaction, the coupling of activated
alkenes with carbon electrophiles under the catalysis of
tertiary amines, is emerging as a valuable carbon–car-
organic solvent, DABCO was able to catalyse the reac-
tion in aqueous media (Table 1, entry 1) to afford the
Baylis–Hillman adduct 1a and the aldol type product
1
bon bond forming reaction. The reaction has drawn
2
a which was the major product (Scheme 1). The use of
increasing attention because it is selective (chemo-,
regio-, diastereo-, enantio-), atom economical, and pro-
duces synthetically useful functionalised molecules
under relatively mild conditions. The traditional Baylis–
Hillman reaction involves nucleophilic and non-hin-
dered tertiary amines like 1,4-diazabicyclo[2.2.2]octane
Table 1. Lewis base effect in the Baylis–Hillman reactions
a
of cyclopent-2-enone in aqueous media
Entry
Lewis base
Time (h)
Yield (%)b
2a
1
a
(
DABCO) as catalysts. However, the reaction typically
suffers from sluggish reaction rates. To make the reac-
tion more efficient, organic chemists have explored
various other catalysts or catalytic systems such as
1
2
3
4
5
6
7
8
9
DABCO
DMAP
36
16
12
12
4d
4d
4d
48
16
32
69
28
25
5
56
None
27
29
None
Et N
3
2
3
4
5
DMAP,
chalcogenide/TiCl ,
piperidine,
DBU,
4
Me N/H O
4
3
2
6
7
c
pyrrolizidines, and phosphines. Recently, TiCl was
Pyridine
reported to catalyse the Baylis–Hillman reaction with-
Ph
3
P
No reaction
No reaction
8
Ph P/PhOH
out the use of a Lewis base. Herein, we disclose the
3
d
N-Methylimidazole
Imidazole
68
None
None
use of imidazole as an efficient catalyst in the Baylis–
Hillman reaction of cyclopent-2-enone in aqueous
media.
92
a
Mole ratio of aldehyde:cyclopent-2-enone=1:1.5.
Isolated yield.
Over 90% of aldehyde was recovered.
15% of aldehyde was recovered.
b
c
The Baylis–Hillman reaction of cyclopent-2-enone or
cyclohex-2-enone is sluggish under traditional condi-
d
9
2
tions. Various catalysts such as DMAP, TiCl /chalco-
4
3
10
genide, and Bu P/phenols have been explored but
3
with limited success. Recent reports demonstrated that
water could greatly accelerate the DABCO-catalysed
Baylis–Hillman reaction of methyl acrylates, acryloni-
11
triles, and even acrylamides. These results prompted
us to look at the aqueous Baylis–Hillman reaction
involving cyclopent-2-enone. Unlike the reaction in
*
Corresponding author. Fax: 86-10-68514074; e-mail: jpcheng@
nankai.edu.cn
Scheme 1.
0
040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01716-1

7
370
S. Luo et al. / Tetrahedron Letters 43 (2002) 7369–7371
Table 2. Solvent effects on the Baylis–Hillman reactions
of p-nitrobenzaldehyde (1.0 mmol) and cyclopent-2-enone
Baylis–Hillman adduct was obtained in 88% yield after
6 hours. Alcohols were also evaluated, but were found
to be less effective than water. The reaction carried out
in pure methanol afforded the adduct 1a in 65% yield
after 30 hours (Table 2, entry 9). By conducting the
1
(
1.5 mmol) in the presence of imidazole (1.0 mmol)
Entry
Solvent (v/v)
Time (h)
Yield (%)a
Traceb
73
Trace
82
27
reaction in aqueous methanol (MeOH:H O=1:1, v/v),
2
1
2
3
4
5
6
7
8
9
Dioxane
Dioxane–H O (1/1)
24
24
24
16
30
16
5d
16
30
20
16
the yield of 1a reached 82% in 20 hours (Table 2, entry
10). Even the reaction in pure water was effective,
producing Baylis–Hillman adduct 1a in 83% yield over
2
b
CH CN
3
CH CN–H O (1/1)
3
2
THF
1
6 hours (Table 2, entry 11). Among the solvent sys-
THF–H O (1/1)
92
2
tems examined in Table 2, we found that the binary
medium consisting of THF and water was overall the
solvent of choice.
DMF
DMF–H O (1/1)
No reaction
88
65
82
83
2
CH OH
3
1
1
0
1
CH OH–H O
3
2
H O
We next investigated the scope and feasibility of the
imidazole catalysed aqueous Baylis–Hillman reaction of
cyclopent-2-enone with various aldehydes (Scheme 2,
Table 3). For arylaldehydes bearing electron-withdraw-
ing groups, the reaction took place smoothly to afford
the desired Baylis–Hillman adducts in good to excellent
yields (Table 3, entries 1–5). Similar results were
obtained in the reaction of benzaldehyde, trans-cin-
2
a
Isolated yield.
Over 90% of aldehyde was recovered.
b
triethylamine and trimethylamine gave similar results
Table 1, entries 3 and 4), with somewhat diminished
yields. Among the other catalysts examined,
triphenylphosphine or its combination with phenol did
not exhibit any catalytic activity (Table 1, entries 6 and
(
12
namaldehyde and heterocyclic aldehydes such as 2-
furaldehyde (Table 3, entries 6, 8 and 9). However, for
7). DMAP appeared to be a promising catalyst in this
reaction, resulting in the Baylis–Hillman adduct in 69%
yield without any aldol product detected (Table 1, entry
Table 3. Aqueous Baylis–Hillman reactions of aldehydes
2
). Under aqueous conditions, even pyridine exhibited
(
1.0 equiv.) and cyclopent-2-enone (1.5 equiv.) in the pres-
some catalytic effect, albeit much slower. It is interest-
ing to note that imidazole and N-methylimidazole act
as remarkable catalysts in aqueous media with the
former giving the best results in terms of yield and
reaction rate (Table 1, entries 8 and 9).
ence of imidazole (1.0 equiv.)
Entry
R
Time (h)
Product
Yield (%)a
1
2
3
4
5
6
7
8
9
o-NO Ph
36
40
24
60
72
96
6d
70
1b
1c
1d
1e
1f
1g
1h
1i
69
91
84
88
75
74
42
84
62
47
2
m-NO Ph
2
With imidazole as our optimal catalyst, we then system-
atically evaluated the solvent effect of this reaction
using the reaction of p-nitrobenzaldehyde as a model
p-CF Ph
3
p-ClPh
m-BrPh
Ph
p-MePh
Furyl
b
c
(
Table 2). Protic solvents proved to be crucial for the
d
Baylis–Hillman reaction. Reactions in organic solvents
proved to be slow (in dioxane, THF, or CH CN) or no
3
c
(E)-PhCHꢀCH 72
72
(CH ) CHCH 96
1j
1k
1l
reaction was observed at all (in DMF). The presence of
water is essential for the success of the Baylis–Hillman
reaction. Compared with the reactions in a pure
organic solvent, both the yields and reaction rates in
aqueous media were improved dramatically. For exam-
ple, imidazole in DMF did not promote the reaction
of p-nitrobenzaldehyde with cyclopent-2-enone, while
e
1
1
0
1
H
c
27
3
2
2
a
b
c
Isolated yield.
20% of aldehyde recovered.
2.0 mmol of cyclopent-2-enone was used.
50% of aldehyde was recovered.
d
e
1
mmol cylopent-2-enone, 5 mmol formalin.
in aqueous DMF (DMF:H O=1:1, v/v), the desired
2
Scheme 2.

S. Luo et al. / Tetrahedron Letters 43 (2002) 7369–7371
7371
Scheme 3.
arylaldehydes bearing electron-donating groups such as
p-tolualdehyde and aliphatic aldehydes, the reactions
were slow (Table 3, entries 7, 10 and 11). One note-
worthy point is that the imidazole catalysed aqueous
Baylis–Hillman reaction is very clean, and in most
cases, the unreacted aldehydes can be recovered
quantitatively.
Acknowledgements
This work was supported by the National Natural
Science Foundation of China (Grant No. 29928004).
References
The typical procedure for the aqueous Baylis–Hillman
reaction is as follows: At room temperature, a clear
solution of the aldehyde (0.5 mmol), cyclopent-2-enone
1. For reviews, see: (a) Basavaiah, D.; Rao, P. D.; Hyma, R.
S. Tetrahedron 1996, 52, 8001; (b) Ciganek, E. Org. React.
1997, 51, 201; (c) Langer, P. Angew. Chem., Int. Ed. 2000,
39, 3049.
(
0.75 mmol) and imidazole (0.5 mmol) in 1 ml of THF
was charged with 1 ml of deionised water. The homoge-
neous reaction mixture was stirred at ambient tempera-
ture and monitored by TLC. Upon completion or after
the indicated reaction time, the reaction mixture was
extracted with ethyl acetate. The organic layer was
2. Rezgui, F.; El Gaied, M. M. Tetrahedron Lett. 1998, 39,
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3. Kataoka, T.; Iwama, T.; Kinoshita, H.; Tsujiyama, S.;
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dried over anhydrous MgSO , filtered and concentrated
4
under reduced pressure. The residue was purified by
flash column chromatography on silica gel to give the
desired products.
5. Aggarwal, V. K.; Mereu, A. Chem. Commun. 1999, 2311.
6. Barrett, G. M.; Cook, A. S.; Kamimura, A. Chem. Commun.
1998, 2533.
To the best of our knowledge, this is a new aqueous
Baylis–Hillman reaction involving cyclopent-2-enone.
As a weak Lewis base, imidazole alone has not been
used as a Baylis–Hillman catalyst as yet. During the
course of our work, Shi reported that using imidazole
alone could not promote the Baylis–Hillman reaction
of MVK in DMF, but could promote the reaction in
combination with proline. Our study shows that using
aqueous media affects the reaction of cyclopent-2-
enone dramatically, providing the desired Baylis–
7. Hayase, T.; Shibata, T.; Soai, K.; Wakasuki, Y. Chem.
Commun. 1998, 1271.
8. Li, G. G.; Wei, H. X.; Gao, J. J.; Caputo, T. D. Tetrahedron
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11. (a) Yu, C.; Liu, B.; Hu, L. J. Org. Chem. 2001, 66, 5413;
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1994, 58, 7947; (c) Yu, C.; Hu, L. J. Org. Chem. 2002, 67,
219.
12. It is noted that the Baylis–Hillman adducts involving
heterocycles are unstable at room temperature. The Baylis–
Hillman adduct of 2-furaldehyde turns into complicated
mixturesover1weekatroomtemperature. Similarphenom-
ena were also observed for pyridinecarboxaldehydes. The
Baylis–Hillman adduct of 4-pyridinecarboxaldehyde was
partly oxidised to the carboxylic acid over 1 h at room
temperature.
13. Shi, M.; Jiang, J.-K.; Li, C.-Q. Tetrahedron Lett. 2002, 43,
127.
14. For recent examples of the Baylis–Hillman reaction involv-
ing cyclopent-2-enone see: (a) Sugahara, T.; Ogasawara, K.
Synlett 1999, 419; (b) Aggarwal, V. K.; Dean, D. K.; Mereu,
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13
Hillman adduct
Cyclopent-2-enone has been considered as being less
reactive in the Baylis–Hillman reaction than MVK.
1 in moderate to high yields.
9,14
Besides cyclopent-2-enone, our reaction system was
also applied to cyclohex-2-enone, the reaction at room
temperature after 72 hours afforded the desired Baylis–
Hillman adduct in moderate yield (Scheme 3).
In summary, we have disclosed a new Baylis–Hillman
reaction system in aqueous media using stoichiometric
imidazole as catalyst. Work to elucidate the reaction
mechanism is under current attention. Efforts are also
being made on further improvement of the reaction, in
particular using a catalytic amount of imidazole, and
also an asymmetric version of the reaction.