Remarkable Rate Acceleration of Imidazole-Promoted Baylis-Hillman Reaction Involving Cyclic Enones in Basic Water Solution

Article abstract of DOI:10.1021/jo035345p

The Baylis-Hillman reaction of cyclic enones was greatly accelerated in basic water solution with imidazoles as catalysts, which resulted in short reaction time, high yields, and expanding substrate scopes. Bicarbonate solution was shown to be the optimal

Full text of DOI:10.1021/jo035345p

TABLE 1. Im id a zole (1a )-Ca ta lyzed Rea ction s of
Cyclop en ten on e w ith p-Nitr oben za ld eh yd e in Va r iou s
H2O Solu tion sa
Rem a r k a ble Ra te Acceler a tion of
Im id a zole-P r om oted Ba ylis-Hillm a n
Rea ction In volvin g Cyclic En on es in Ba sic
Wa ter Solu tion
entry
solution
1 M Na2CO3
satd NaHCO3
1 M Na HCO3
1 M NaH2PO4-Na2HPO4
H2O
1 M NaCl
1 M NaH2PO4-Na2HPO4
1 M NaH2PO4-Na2HPO4
1 M NaH2PO4-Na2HPO4
pH
time (h) yieldb (%)
1
2
3
4
5
6
7
8
9
11.9
8.9
8.6
7.3
7.0
7.0
6.8
6.5
5.9
10 min
40 min
1.5
53c
72c
Sanzhong Luo,† Peng George Wang,§ and
J in-Pei Cheng*,†,‡
88
20
87
1.5
48
Center for Molecular Science, Institute of Chemistry,
Chinese Academy of Sciences, Beijing 100080, China,
Department of Chemistry, State Key Laboratory of
Elemento-organic Chemistry, Nankai University,
Tianjin, 300071, China, and Department of Chemistry,
Wayne State University, Detroit, Michigan 48202
12
27
27
27
90
64 (88)d
60 (92)d
29 (91)d
a
Reaction were carried out on a 0.5 mmol scale in 2 mL of
water solution and 0.5 mL of THF, molar ratio of aldehyde/
b
cyclopentenone/catalyst ) 1.0:1.5:1.0. Isolated yield based on
jpcheng@nankai.edu.cn
d
aldehyde. c Decomposition of materials was observed. Yield based
on recovered aldehyde.
Received September 12, 2003
to promote the reaction of cyclic enones, and in some
cases, good results were obtained.6 In previous studies,
we found that imidazole can catalyze the Baylis-Hillman
reaction involving cyclic enones in aqueous THF solu-
tion.7 In our continued efforts, we found that the reaction
could be greatly accelerated by adjusting the pH value
Ab st r a ct : The Baylis-Hillman reaction of cyclic enones
was greatly accelerated in basic water solution with imida-
zoles as catalysts, which resulted in short reaction time, high
yields, and expanding substrate scopes. Bicarbonate solution
was shown to be the optimal reaction medium for the
reaction in this study. The apparent “enhanced basicity” of
imidazoles accounted for the rate increase in alkaline
solution.
(2) Ultrasound: (a) Roos, G. H. P.; Rampersadh, P. Synth. Commun.
1993, 23, 1261. (b) Almeida, W. P.; Coelho, F. Tetrahedron Lett. 1998,
39, 8609. (c) Coelho, F.; Almeida, W. P.; Veronese, D.; Mateus, C. R.;
Lopes, E. C. S.; Rossi, R. C.; Silveira, G. P. C.; Pavam, C. H.
Tetrahedron 2002, 58, 7437. Microwave: (c) Kundu, M. K.; Mukherjee,
S. B.; Balu, N.; Padmakumar, R.; Bhat, S. V. Synlett 1994, 444. (d)
Cablewski, T.; Faux, A. F.; Strauss, C. R. J . Org. Chem. 1994, 59, 3408.
High pressure: (e) Hayashi, Y.; Okada, K.; Ashimine, I.; Shoji, M.
Tetrahedron Lett. 2002, 43, 8683. (f) Schuurman, R. J . W.; vander-
Linden A.; Grimbergen, R. P. F.; Nolte, R. J . M.; Scheeren, H. W.
Tetrahedron 1996, 54, 8307. (g) Hill, J . S.; Isaacs, M. S. Tetrahedron
Lett. 1986, 27, 5007. Low temperature: (h) Rafel, S.; Leahy, J . W. J .
Org. Chem. 1997, 62, 1521. Lewis acid: (i) Kawamura, M.; Kobayashi,
S. Tetrahedron Lett. 1999, 40, 1539. (j) Aggarval, V. K.; Mereu, A.;
Farver, G. J .; McCague, R. J . Org. Chem. 1998, 63, 7183. (k) Kataoka,
T.; Iwama, T.; Tsujiyama, S. Chem. Commun. 1997, 197. (l) Shi, M.;
J iang, J .-K.; Feng, Y.-S. Org. Lett. 2000, 2, 2397. For other examples,
see: (m) Aggarwal, V. K.; Mereu, A. Chem. Commun. 1999, 2311. (n)
Lee, W.-D.; Yang, K.-S.; Chen, K. Chem. Coummn. 2001, 1612. (o)
Anthony, P. M. R.; Clifford, A. A.; Rayner, C. M. Chem. Commun. 2002,
968. (p) Rosa, J . N.; Afonso, C. A. M.; Santos, A. G. Tetrahedron Lett.
2001, 57, 4189.
(3) (a) Byun, H. S.; Reddy, K. C.; Bittman, R. Tetrahedron Lett. 1994,
35, 1371. (b) Auge, J .; Lubin, N.; Lubineau, A. Tetrahedron Lett. 1994,
35, 7947. (c) Rezgui, F.; El Gaied, M. M. Tetrahedron lett. 1998, 39,
5965.
(4) (a) Yu, C.; Liu, B.; Hu, L.J . Org. Chem. 2001, 66, 5413. (b) Yu,
C.; Hu, L. J . Org. Chem. 2002, 67, 219. (c) Cai, J .; Zhou, Z.; Zhao, G.;
Tang, C. Org. Lett. 2002, 4, 4723.
(5) (a) Aggarwal, V. K.; Dean, D. K.; Mereu, A.; Williams, R. J . Org.
Chem. 2002, 67, 510. (b) Aggarwal, V. K.; Emme, I.; Fulford, S. Y. J .
Org. Chem. 2003, 68, 692.
The Baylis-Hillman reaction, which involves the
coupling of Michael acceptors with carbon electrophiles
under the catalysis of a tertiary amine or phosphine, has
drawn increasing attention during the past decades.1 The
resulting densely functionalized products allow numerous
transformations and have versatile utilities in organic
synthesis. To improve the applicability of Baylis-Hill-
man reactions, a variety of methods including physical
as well as chemical attempts have been explored toward
enhancement of reaction rate and extension of substrates
scope.2 Among these methods, the use of aqueous solution
as reaction medium has been the recent research focus.3
Hu and co-workers demonstrated that the Baylis-
Hillman reaction of methyl acrylate and acrylamide could
be accelerated simply by conducting the reaction in
aqueous dioxane solution.4 Most recently, Aggarval showed
that the use of Yb(OTf)3 could produce further accelera-
tion in water or formamide.5 In an earlier report, Auge´
examined the salt effect in aqueous Baylis-Hillman
reaction.3b However, few reports have dealt with the
effect of pH on the reaction.
(6) For examples, see: (a) Li, G. G.; Wei, H. X.; Gao, J . J .; Caputo,
T. D. Tetrahedron Lett. 2000, 41, 1. (b) Sugahara, T.; Ogasawara, K.
Synlett 1999, 419. (c) Kataoka, T.; Iwama, T.; Tsujiyama, S.; Iwamura,
T.; Watanabe, S. Tetrahedron 1998, 54, 11813. (d) Yamada, Y. M. A.;
Ikegami, S. Tetrahedron Lett. 2000, 41, 2165. (e) Pei, W.; Wei, H.-X.;
Li, G. G. Chem. Commun. 2002, 2412. (e) Basavaiah, D.; Sreenivasulu,
B.; Rao, A. J . J . Org. Chem. 2003, 68, 5983. (f) Patra, A.; Batra, S.;
J oshi, B. S.; Roy, R.; Kundu, B.; Bhaduri, A. P. J . Org. Chem. 2002,
67, 5783. (g) Shi, M.; Xu, Y.-M.; Zhao, G.-L.; Wu, X.-F. Eur. J . Org.
Chem. 2002, 3666.
â-Substituted enones have been considered less reac-
tive in Baylis-Hillman reactions.1a The reaction of cyclic
enones is sluggish or does not occur at all under tradi-
tional conditions. Various catalysts have been developed
† Chinese Academy of Sciences.
‡ Nankai University.
§ Wayne State University.
(1) (a) Ciganek, E. Org. React. 1997, 51, 201. (b) Langer, P. Angew.
Chem., Int. Ed. 2000, 39, 3049. (c) Basavaiah, D.; Rao, A. J .;
Satyanarayana, T. Chem. Rev. 2003, 103, 811.
(7) (a) Luo, S. Z.; Zhang, B.; He, J .; J anczuk, A.; Wang, P. G.; Cheng,
J .-P. Tetrahedron Lett. 2002, 43, 7369. (b) Catri, R.; El Gaied, M. M.
Tetraheron Lett. 2002, 43, 7835.
10.1021/jo035345p CCC: $27.50 © 2004 American Chemical Society
Published on Web 12/20/2003
J . Org. Chem. 2004, 69, 555-558
555

SCHEME 1
TABLE 2. Scr een in g of Va r iou s Im id a zoles in th e Aqu eou s Ba ylis-Hillm a n Rea ction In volvin g 2-cyclop en ten on ea
X ) NO2 (A)
medium
X ) Cl (B)
entry
1
catalyst
time (h)
yieldb (%)
entry
8
catalyst
medium
time (h)
yieldb (%)
1b
1c
1d
THF-H2O
1M NaHCO3
THF-H2O
14
1.5
12
22
12
11
48
6
18
4
16
12
40
4
0
87
0
46
0
59
30
56
88
89
50
60
39
65
1a
THF-H2O
40
11
24
20
30
20
40
20
24
20
26
10
24
10
74
90
86
84
81
87
80
82
85
87
86
88
84
86
1 M NaHCO3
THF-H2O
2
3
4
5
6
7
9
10
11
12
13
14
1i
1 M NaHCO3
THF-H2O
1 M NaHCO3
THF-H2O
1j
1 M NaHCO3
THF-H2O
1 M NaHCO3
THF-H2O
benzoimidazole (1e)
1f
1k
1l
1 M NaHCO3
THF-H2O
1 M NaHCO3
THF-H2O
1 M NaHCO3
THF-H2O
1 M NaHCO3
THF-H2O
N-methyl imidazole (1g)
L-histidine (1h )
1m
1n
1 M NaHCO3
THF-H2O
1M NaHCO3
THF-H2O
1 M NaHCO3
1 M NaHCO3
a
Reactions were carried out on a 0.5 mmol scale in 2 mL of THF-H2O (v/v, 1/1) or 2 mL of 1 M NaHCO3 and 0.5 mL of THF, molar
b
ratio of aldehyde/cyclopentenone/catalyst ) 1.0:1.5:1.0. Isolated yield of pure products.
of the water solution. The screen process and the detailed
results are presented herein.
reaction in neutral aqueous THF was listed as compari-
son. As shown in Table 2, the EWG-substituted imida-
zoles (1b-d ), which are inert in aqueous THF, were
activated in aqueous sodium bicarbonate solution to
promote the Baylis-Hillman reaction effectively (Table
2, entries 1-3). For example, in the presence of 2-methyl-
4(3)-nitroimidazole (1b), the otherwise inert reaction in
aqueous THF occurred smoothly in basic water solution
to afford the desired Baylis-Hillman product with 87%
yield in 1.5 h (Table 2, entry 1). For less reactive catalysts
such as 1e, 1f, and 1g, conducting the reaction in basic
solution also produced obvious rate enhancement (Table
2, entries 4-6). It is noteworthy that the sluggish
reaction catalyzed by L-histidine in aqueous THF was
completed in 4 h in basic water solution affording the
desired product with 65% yield. Unfortunately, no enan-
tioselectivity was observed in this case (Table 2, entry
7). For the reaction catalyzed by only EDG-substituted
imidazoles (1i-1n ), the use of basic medium still pro-
duced rate enhancement but to a limited extent (Table
2, entries 9-14). In these cases, to make obvious com-
parison of the reaction rates, a less reactive aldehyde,
p-chlorobenzaldehyde was employed for model studies.
Among the catalysts tested, the bis alkyl-substituted
imdazoles 1m and 1n together with imidazole itself gave
the relatively better results in basic water solution in
terms of reaction time and yields (Table 2, entrie 8, 13,
and 14).
The reaction between cyclopent-2-enone and p-ni-
trobenzaldehyde in water was chosen as a model for
screening purposes (Table 1). The reaction was conducted
in 2 mL of water solution with 0.5 mL of THF added as
cosolvent to solubilize the substrates.
In strong basic media (1 M Na2CO3 solution, pH )
11.9), the aldehyde was consumed within 10 min with
the desired product isolated in only 53% yield (Table 1,
entry 1). In addition, minor aldol product was also
observed in the reaction. Reducing the basicity of the
solution (pH 8.9-7.3) improved the reaction considerably
(Table 1, entries 2-5). In a 1 M NaHCO3 solution (pH )
8.6) cyclopent-2-enone reacted smoothly with p-nitroben-
zaldehyde to afford the desired Baylis-Hillman adduct
1 in 88% yield after 1.5 h (Table 1, entry 3). As a
comparison, the same reaction in aqueous THF gave 48%
yield after 1.5 h (Table 1, entry 5). Performing the
reaction in weakly acidic (pH 7.3-5.9) NaH2PO4-
Na2HPO4 buffer system resulted in slow reactions (Table
1, entries 4 and 7-9). When applying the reaction in a
NaCl solution, a slightly shorter reaction time was also
observed (Table 1, entry 6). The above results clearly
demonstrate that the Baylis-Hillman reaction of cyclo-
pent-2-enone can be greatly accelerated in basic water
solution. Among the conditions tested, the reaction in 1
M NaHCO3 gives the best rate and yield. This was
selected as our optimal condition in the following experi-
ments.
The rate increase in basic water solution may be
rationalized by considering the interaction of imidazole
with the medium, i.e., proton transfer between imidazole
(pKa ) 7.1 in water) and its cation8 (Scheme 2). As
Other imidazole derivatives have also been tested in
the present condition (Scheme 1, Table 2). The same
556 J . Org. Chem., Vol. 69, No. 2, 2004

SCHEME 2. P r oton Tr a n sfer of Im id a zole in
Acid ic Med ia (1) a n d Ba sic Med ia (2)
SCHEME 3
revealed in Scheme 2, in alkaline solution the proton
exchange between water and imidazole is depressed,
therefore leaving more neutral imidazole to take roles
in Baylis-Hillman reaction as nucleophiles.9 This was
further supported by 15N NMR analysis of [15N] imidazole
at various pH. Previously, Alei and co-workers reported
that molar ration of ImH+ decreased consecutively fol-
lowing the rising order of pH from 1.9 to 9.6. At pH above
9.6, neutral Im is the only existing species as determined
by 15N NMR analysis.10 According to this observation,
imidazole in strong basic solution (pH > 9.0) will dem-
onstrate the best catalytic effect. However, in our reaction
system, high pH (>9.0) may also lead to various side
reactions due to the decomposition of cyclic enones under
strong basic media, which in turn resulted in low output
of the reaction. At this stage, it is clear that the increase
of the effective molarity of neutral imidazole, the appar-
ent “enhanced basicity”, is most likely responsible for the
further rate enhancement in alkaline solution.11,12 For
imidazole with low pKa,13 their protonated cations pre-
dominate at neutral pH. Consequently, neutralization of
cations becomes prominent in basic pH and drastic
change of activity will be observed as in the cases of 1b-f
(Table 2, entries 1-5). On the contrary, the nonproto-
nated form predominates for imidazoles with high pKa
at neutral pH, the consequent neutralization is less
prominent in basic pH and limited rate enhancement
were observed as in the cases of 1i-n (Table 2, enties
9-14).
TABLE 3. Rea ction s of Cyclop en ten on e w ith Ald eh yd es
in 1 M Na HCO3 Solu tion sa
entry
aldehyde (R)
cat. products time (h) yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
Ph
Ph
1a
1m
1a
1a
1a
1a
1m
2C
2C
2D
2E
2F
2G
2G
2H
2H
2I
14 (96)c
12
83 (74)c
88
3-NO2Ph
4-MePh
4-PhPh
4-MeOPh
4-MeOPh
2,4-(MeO)2Ph 1a
2,4-(MeO)2Ph 1n
4-Me2NPh
4-Me2NPh
i-Bu
3.5 (40)c 92 (91)c
30 (6d)c
20
36
36
60
87 (42)c
86
81
82
36
60
36
60
64
13
27
1a
1n
1a
1a
2I
2J
2K
18 (96)c
24
75 (27)c
29
n-C5H11
a
Reactions were carried out on a 0.5 mmol scale in 2 mL of 1
M NaHCO3 and 0.5 mL of THF, molar ratio of aldehyde/enone/
b
catalyst ) 1.0:1.5:1.0. Isolated yield based on aldehyde. c Num-
bers in parentheses refer to data of reactions in THF-H2O (1/1,
v/v).
SCHEME 4
Having established the optimum conditions, we next
explored the applicability of this acceleration strategy
using imidazole (1a ), 2-methyl-4-isopropylimidazole (1m ),
or 4-ethyl-2-methyl imidazole (1n ) as catalysts (Scheme
3, Table 3). As shown in Table 3, in the presence of
imidazole 1a both the reaction rate and yields were
improved considerably, comparing with the same reaction
in distilled water (Table 3, entries 1, 3, 4, and 12). In
aqueous THF (pH) 7), p-methylbenzaldehyde reacted
with cyclopent-2-enone to give product 2E in only 42%
yield after 6 days, while the reaction in aqueous NaHCO3
was improved to 87% output in 30 h. Notably, some
highly unreactive aldehydes were successfully coupled
with cyclopent-2-enone (Table 3, entries 6-11). For
example, 2,4-dimethoxybenzaldehyde is a hindered and
deactivated aldehyde but still gave moderate yields after
60 h (Table 3, entry 8). As an extremely deactivated
aldehyde, dimethylamino benzaldehyde could also be
applied in this condition with 13% yield after 36 h (Table
3, entry 10). The unreacted aldehydes could be recovered
quantitatively. Aliphatic aldehydes such as isovaleral-
dehyde (Table 3, entry 12) worked well, but n-hexanal
(Table 3, entry 13) afforded a low yield. In most cases,
the reactions catalyzed by 1m or 1n gave comparable or
even better results compared with the same reaction
catalyzed by imidazole (Table 3, entries 2, 7, 9, and 11).
In addition to cyclopentenone, cyclohexenone was also
successfully employed in this reaction system. Various
aldehydes were attempted to produce the desired prod-
ucts with moderate to good yields (Scheme 4, Table 4).
The acceleration effect was obvious in these cases. The
reaction of p-nitrobenzaldehyde in aqueous THF gave
52% yield after 72 h; in contrast, the reaction in 1 M
NaHCO3 solution provided significantly higher yield and
(8) For similar proton transfer of imidazole in biological systems,
see: (a) Silverman, D. N.; Lindskog, S. Acc. Chem. Res. 1988, 21, 30.
(b) Lesburg, C. A.; Christianson, D. W. J . Am. Chem. Soc. 1995, 117,
6838.
(9) Schneider, F. Angew. Chem., Int. Ed. Engl. 1978, 17, 583 and
references therein.
(10) (a) Alei, M. J r.; Morgan, L. O.; Wageman, W. E. Inorg. Chem.
1978, 17, 2288. (b) Alei, M. J r.; Morgan, L. O.; Wageman, W. E.;
Whaley, T. W. J . Am. Chem. Soc. 1980, 102, 2881.
(11) In the absence of imidazole, only minor aldol product (ca. 5%)
was detected in the reaction between 2-cyclopentenone andp-nitroben-
zaldehyde in 1 M NaHCO3 solution after 1.5 h. While in the presence
of imidazole the Baylis-Hillman reaction predominated with trace
aldol products detected.
(12) However, other factors such as salts effect (Table 1, entry 6)
cannot be excluded presently, which may account, in part, for the rate
acceleration, especially for the cases of imidazole with high pKa like
1m and 1n (pKa’s around 8.3 by relating to 2, 4-dimethylimidazole,
pKa8.36). For salt effects in aqueous Baylis-Hillman reaction, see:
Kumar, A.; Pawar, S. S. Tetrahedron 2003, 59, 5019.
(13) For pKa values of imidazoles see: Schofield, K.; Grimmett, M.
R.; Keene, B. R. T. Heteroaromatic nitrogen compounds: the azoles;
Cambridge University Press: Cambridge, 1976; p 281.
J . Org. Chem, Vol. 69, No. 2, 2004 557

TABLE 4. Rea ction s of Cycloh exen on e w ith Ald eh yd es
in 1 M Na HCO3 Solu tion sa
SCHEME 5
entry
R
cat.
products
time (h)
yieldb (%)
1
2
3
4
5
6
7
8
9
Ph
Ph
1a
1n
1a
1n
1a
1a
1a
1a
1a
3A
3A
3B
3B
3C
3D
3E
3F
90
72
72
72
45
38
50
50
4-ClPh
4-ClPh
4-NO2Ph
3-NO2Ph
2-NO2Ph
H
8 (72)c
12
69 (52)c
68
30
15
24
51
65
32
i-Bu
3G
a
Reactions were carried out on a 1 mmol scale in 2 mL of 1 M
NaHCO3 and 0.5 mL of THF, molar ratio of aldehyde/enone/
b
catalyst ) 1.0:2.0:1.0. Isolated yield based on aldehyde. c Num-
imidazole is depressed, thus increasing the real active
molarity of imidazole in catalysis. This apparent “en-
hanced basicity” most likely account for the further rate
acceleration in basic aqueous media. Under the optimal
conditions, the otherwise inert EWG-substituted imida-
zoles can be activated for effective catalysis. Finally, the
conditions developed in this work were successfully
applied to a variety of aldehydes and cyclic enones.
Notably these conditions facilitate the efficient coupling
of unreactive and hindered aldehydes.
bers in parentheses refer to data of reactions in THF-H2O (1/1,
v/v).
shorter time (69% yield, 8 h). The use of alkyl-substituted
imidazole 1n gave comparable results (Table 4, entries
2 and 4). 4,4-Dimethyl-2-cyclohexenone was tried in the
present conditions, the reaction with p-nitrobenzaldehyde
was sluggish, producing the desired product 4 with 51%
yield after 48 h. Under the optimal conditions, methyl
vinyl ketone (MVK) was also attempted in the aqueous
Baylis-Hillman reaction. The reaction between MVK and
p-nitrobenzaldehyde afforded the desired product 6 with
45% yield after 18 h (Scheme 5).
In conclusion, we have developed favorable conditions
for the Baylis-Hillman reaction involving cyclic enones.
These improved conditions employed imidazoles as cata-
lysts and sodium bicarbonate solution as reaction media.
The reaction ran much faster in sodium bicarbonate
solution than in distilled water, and showed obvious pH
dependence. In basic water solution, the protonation of
Ack n ow led gm en t. 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.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal procedure, spectra data, and 1H NMR spectra for all
adducts. This material is available free of charge via the
Internet at http://pubs.acs.org.
J O035345P
558 J . Org. Chem., Vol. 69, No. 2, 2004