The azoles: Effective catalysts for Baylis-Hillman reaction in basic water solution

Article abstract of DOI:10.1016/j.tetlet.2004.04.136

The azoles, which were inactive in neutral aqueous media, could be activated in alkaline solution and effectively catalyze the Baylis-Hillman reaction involving cyclic enones.

Full text of DOI:10.1016/j.tetlet.2004.04.136

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 5171–5174
The azoles: effective catalysts for Baylis–Hillman reaction
in basic water solution
Sanzhong Luo,a Xueling Mi,b Peng George Wangc and Jin-Pei Chenga,b,
*
aCenter for Molecular Science, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100080, China
bDepartment of Chemistry, State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071, China
cDepartment of Chemistry, Wayne State University, Detroit, MI 48202-3489, USA
Received 14 October 2003; revised 5 April 2004; accepted 9 April 2004
Abstract—The azoles, which were inactive in neutral aqueous media, could be activated in alkaline solution and effectively catalyze
the Baylis–Hillman reaction involving cyclic enones.
Ó 2004 Elsevier Ltd. All rights reserved.
The Baylis–Hillman reaction, the combination of acti-
vated alkene with carbon electrophile under the catalysis
of nucleophile, has progressed dramatically during the
Baylis–Hillman reactions of cyclic enones without the
presence of a Lewis base.8 Although these methods of-
fered good access to the increasingly important a-
substituted cyclic a,b-enones,9 there still remains an
active research area concerning the related unsolved
aspects such as the applicability of the catalysts, the
generality of the reaction and most importantly, the
asymmetric version of the reaction.
1
pastdecade and now includes several asymmetric ver-
sions.2 However, as a versatile carbon–carbon bond-
forming reaction, Baylis–Hillman reaction is generally
sluggish and has limited substrate scope, which restricts
its further applications in organic synthesis. Due to their
low reactivity, cyclic enones are less explored among
various activated alkenes. It was previously noted that
the reaction was slow or did not work at all in the
presence of traditional catalysts such as DABCO.3
Rezgui and El Gaied reported that DMAP could cata-
lyze the reaction of 2-cyclohexenone with formaldehyde
in aqueous media.4 Later, DMAP was also applied to
the reaction of arenecarbaldehydes and N-arylidene-4-
methylbenzenesulfonamide.5 Tertiary phosphorus may
also catalyze the reaction of cyclic enones. Yamada and
Ikegami showed that the addition of a weak Bronsted
acid such as phenol could accelerate the Bu3P-catalyzed
reaction of cyclic enones.6 In addition, the use of Lewis
acid and Lewis base pair such as TiCl4/Me2S and TiCl4/
DBU could also promote the Baylis–Hillman reaction
involving cyclic enones, albeit with narrow substrate
scope.5b;7 More recently, Li reported that Lewis acids
(such as TiCl4 and Et2AlI) alone could catalyze the
Previously, we found that imidazole could effectively
catalyze the Baylis–Hillman reaction of cyclic enones in
neutral aqueous media (Scheme 1).10 During our further
investigations, we found that not all azoles are active in
neutral solution, but they can be activated to be an
effective catalysts in alkaline solution. Herein we present
the primary results.
The reaction of 2-cyclopentenone (1) with p-nitrobenz-
aldehyde (2a) was chosen as a model for screening
purpose. The reaction was conducted in 2 mL of water
solution with 0.5 mL of THF added as co-solvent to
solubilize the substrates. Various pyrazoles and triazoles
were examined and the results were summarized in
H
N
O
n
O
n
OH
(100 mol%)
N
+
RCHO
R
THF-H2O
r. t.
Keywords: Baylis–Hillman; Azoles; Cyclic enones.
* Corresponding author. Tel.: +86-22-23499174; fax: +86-10-685140-
74; e-mail: jpcheng@nankai.edu.cn
Scheme 1.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.136

5172
S. Luo et al. / Tetrahedron Letters 45 (2004) 5171–5174
Table 1. Screening of the azoles (100 mol %) in the reaction of p-nitrobenzaldehyde (0.5 mmol) and 2-cyclopentenone (0.75 mmol)
Entry
1
Cat. (100 mol %)
pKb (as base)b
Medium
Time (h)
Yield (%)a
THF–H2O
24
9
NRc
68
N
2.53
N
H
1 M NaHCO3
THF–H2O
1 M NaHCO3
24
20
19
80
2
3
4.37
1.17
N
N
H
N
N
THF–H2O
1 M NaHCO3
24
50 min
NR
85
N
H
N
N
THF–H2O
1 M NaHCO3
24
50 min
NR
84
4
5
––
N
H
N
N
THF–H2O
1 M NaHCO3
24
50 min
NR
82
2.19
N
H
N
N
THF–H2O
1 M NaHCO3
24
24
NR
78
6
7
3.2
7.0
N
Bu
N
THF–H2O
16
90
N
H
a Isolated yields.
b Cited from Ref. 11.
c NR ¼ no reaction.
Table 1. As itshows, in neurtal aqueous THF boht
pyrazoles and triazoles demonstrate low activity or do
not catalyze the reaction at all; whereas in weakly basic
NaHCO3 solution (pH ¼ 8.6) they are activated and
catalyze the reaction effectively (Table 1, entries 1–6). It
appears that the catalytic activity of the azoles is related
closely to their pKa (as base) in neutral aqueous media.
3,5-Dimethyl pyrazole, which has higher pKa than pyr-
azole, could catalyze the reaction while the latter was
inactive in neutral medium. Triazoles generally have low
pKa (<3) and did not catalyze the Baylis–Hillman reac-
tion (Table 1, entries 3–6). In contrast, we found pre-
viously that imidazole, with a pKa value of 7.1, could
effectively catalyze the Baylis–Hillman reaction in neu-
tral aqueous THF (Table 1, entry 7),10 however.
state that is the azolium, at neutral or acidic solution
according to equilibrium (1). The azolium is deactivated
and cannot participate in the Baylis–Hillman reaction as
nucleophile. While in an alkaline solution, as shown in
equilibrium (2), the proton exchange between water and
the azoles is depressed, leaving more unprotonated az-
oles to take roles in Baylis–Hillman reaction as nucle-
ophiles. This kind of proton transfer in water has been
well studied for azoles, especially for imidazole,12 which
may account for the activation of the azoles in alkaline
solution for Baylis–Hillman catalysis.
The reaction was then tried at various pH values and the
optimal condition was found to be with the reaction in
1 M NaHCO3 solution (pH ¼ 8.6). Athigher pH, hte
reaction led to poor results due to various by-pathways.
As shown in Table 1, triazoles are superior catalysts
compared to pyrazoles. In the presence of triazoles, the
reactions conducted in 1 M NaHCO3 solution pro-
ceeded smoothly to afford the desired Baylis–Hillman
products with good yields in 50 min (Table 1, entries 3–
5). N-Substituted triazoles such as 1-butyl-1,2,4-triazole
could also promote the reaction, albeit much slower
(Table 1, entry 6).
The dramatic pH effect on the catalytic activity may be
attributed to the protonation of the azoles in aqueous
media (Scheme 2). Azoles generally have low pKa (<5),
so consequently, they mainly exist in the protonated
pKa
H+
NH+
N
(1)---- Acidic pH
+
To examine the applicability of the present reaction,
1,2,3-triazole (3) and 1,2,4-trizaole (4) were selected as
catalysts and tested in the reaction of various cyclic
enones and aldehydes in 1 M NaHCO3 solution (Scheme
OH-
(2)---- Basic pH
NH+
+
+
H2O
N
Scheme 2.

S. Luo et al. / Tetrahedron Letters 45 (2004) 5171–5174
5173
smoothly, and in most cases, the former showed a
superior catalytic activity than the latter.
O
O
OH
R'
Triazole (100 mol%)
+
R'CHO
n
R
n
1M NaHCO
r. t.
3
In summary, we have found that the azoles could be
activated in alkaline solution and effectively catalyze the
Baylis–Hillman reaction involving cyclic enones. The
present reaction condition is suitable for a range of
cyclic enones and aldehydes. And notably, it facilitated
the coupling of unreactive aldehyde with cyclic enones.
Further improvement and asymmetric version using
chiral azoles are currently underway in our laboratory.
R
R
R
a: R'= 4-NO Ph b: R'= Ph
1: n= 1, R= H
5: n= 2, R= H
2
c: R'= 4-ClPh
d: R'= 4-MePh
7: n= 1, R= Me
9: n= 2, R= Me
e: R'= 2, 4-(MeO) Ph
2
f: R'= i-Bu
Scheme 3.
3, Table 2).13 As revealed in Table 2, the current reaction
showed good scopes for both cyclic enones and alde-
hydes. For aldehydes, both aromatic and aliphatic
aldehydes showed similar effectiveness when treating
with 2-cyclopentenone (Table 1, entries 1–7). It is
noteworthy that even the strong electron-rich 2,4-di-
methoxybenzaldehyde can give 47% yield after 60 h. In
addition, the reactions of 2-cyclohexenone and 4,4-di-
methyl cyclic enones also gave very good yields (up to
89%, Table 2, entries 8–12). On the other hand, the
substituted cyclic enones 7 and 9 demonstrated lower
reactivity than the unsubstituted counterparts 1 and
5, probably due to steric hindrance. Both 1,2,3-triazole
and 1,2,4-triazole promoted Baylis–Hillman reaction
Acknowledgements
We thank the Natural Science Foundation of China
(NSFC), the Ministry of Science and Technology
(MoST) and the Institute of Chemistry (CAS) for
financial support.
References and notes
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Table 2. Baylis–Hillman reaction of cyclic enones and aldehydes catalyzed by triazoles in 1 M NaHCO3 solution
Entry
Cylic enones
Aldehyde (R0)
Cat.
Products
Time (h)
Yield (%)a
98
O
N
N
35b
1
1
Ph (2b)
12
N
H
2
3
1
1
4-ClPh (2c)
4-ClPh (2c)
35c
11
18
90
90
N
N
4
5c
5d
N
H
4
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6
7
1
1
1
1
4-MePh (2d)
4-MePh (2d)
2,4-(MeO)2Ph (2e)
i-Bu (2f)
35d
4
36
40
60
18
86
67
47
69
35e
35f
O
8
5
4-NO2Ph (2a)
4-NO2Ph (2a)
4-NO2Ph (2a)
36a
4
3
3
74
51
89
9
5
6a
O
10
7
38a
12
11
12
7
4-NO2Ph (2a)
4-NO2Ph (2a)
4
8a
12
46
61
50
O
9
310a
a Isolated yields.

5174
S. Luo et al. / Tetrahedron Letters 45 (2004) 5171–5174
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residue was purified by flash column chromatograph on
silica gel to give the desired product. Spectra data for
representative compounds: 5e: 1H NMR (CDCl3,
300 MHz): d 2.44–2.47 (2H, m), 2.58–2.59 (2H, m), 3.75–
3.77 (1H, m), 3.80 (6H, s), 5.75–5.76 (1H, m), 6.46–6.50
(2H, m), 7.24–7.31 (2H, m). 13C NMR (CDCl3, 75 MHz):
d 26.6, 35.3, 55.4, 65.1, 98.6, 104.2, 122.0, 128.1, 147.0,
157.5, 159.3, 160.5, 209.8. HRMS calcd for C14H15O3
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1H NMR (CDCl3, 300 MHz): d 1.09 (3H, s), 1.22 (3H, s),
2.25 (2H, s), 3.45 (1H, br s), 5.53 (1H, s), 6.96 (1H, s), 7.47
(2H, d, J ¼ 8:7 Hz), 8.11 (2H, d, J ¼ 8:7 Hz). 13C NMR
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(3H, s), 1.20 (3H, s), 1.87 (2H, t, J ¼ 6:9 Hz), 2.50 (2H, t,
J ¼ 6:9 Hz), 3.60 (1H, br s), 5.56 (1H, s), 6.56 (1H, s),
7.54 (2H, d, J ¼ 8:7 Hz), 8.21 (2H, d, J ¼ 8:7 Hz). 13C
NMR (CDCl3, 75 MHz): d 27.6, 27.8, 33.1, 34.8, 35.5,
72.2, 123.6, 127.2, 136.9, 147.3, 149.5, 157.1, 200.0. MS
(FAB): 258 (100) [Mþ+1)H2O], 276 [Mþ+1], 298
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