Efficient Baylis-Hillman reaction via a 1,4-diazabicyclo[2.2.2]octane-based ionic catalyst

Article abstract of DOI:10.1007/s00706-007-0693-3

A novel ionic catalyst, 1-butyl-4-aza-1-azoniabicyclo[2.2.2]octane chloride based on 1,4-diazabicyclo[2.2.2]octane was synthesized and applied in the Baylis-Hillman reaction, which occurred readily at room temperature to afford the corresponding adducts i

Full text of DOI:10.1007/s00706-007-0693-3

Monatshefte f u¨ r Chemie 138, 1163–1166 (2007)
DOI 10.1007/s00706-007-0693-3
Printed in The Netherlands
Efficient Baylis-Hillman Reaction via a 1,4-Diazabicyclo[2.2.2]octane-based
Ionic Catalyst
ꢀ
Yueqin Cai, Ye Liu , and Guohua Gao
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, East China Normal University,
Shanghai, P.R. China
Received April 3, 2007; accepted April 15, 2007; published online July 13, 2007
#
Springer-Verlag 2007
Summary. A novel ionic catalyst, 1-butyl-4-aza-1-azoniabi-
cyclo[2.2.2]octane chloride based on 1,4-diazabicyclo[2.2.2]
octane was synthesized and applied in the Baylis-Hillman
reaction, which occurred readily at room temperature to afford
the corresponding adducts in good yield. The ionic catalyst
could be recycled for seven runs without diminution in its
catalytic activity.
theless, these methods did have some limitations.
The heterogeneous catalysis of polymer-DMAP lim-
ited the reaction rate greatly, probably due to resin
retardation and mass transfer effect [7]. On the other
hand, despite of the successful catalysis of the im-
idazolium ionic liquid-supported quinuclidine, it suf-
fered from the drawbacks including the tedious
preparation, and that the 2-C position of the imida-
zolium cation could be deprotonated under surpris-
ingly mild conditions [9]. As a result, the undesired
side-reaction of aldehydes with imidazolium ionic
liquid-supported catalyst occurred. Therefore, we
focused our attention on a simple and efficient syn-
thesis of a highly active catalyst with features of re-
cyclability and homogeneity. For this purpose, we
now wish to report on a novel and appealing strategy
for the synthesis of 1-butyl-4-aza-1-azoniabicyclo
[2.2.2]octane chloride (1) as catalyst with an ionic
nature. Using this catalyst the Baylis-Hillman reac-
tion of aldehydes with ethyl acrylate was investi-
gated in terms of reaction conditions, recyclability,
and generality to substrates.
Keywords. Catalysts; Baylis-Hillman reaction; Aldehydes;
Acrylates; Homogeneous catalysis.
Introduction
Carbon–carbon bond formation is one of the most
fundamental reactions in organic syntheses [1]. The
Baylis-Hillman reaction, which involves the cou-
pling of activated alkenes with carbon electrophiles
in the presence of Lewis base catalysts (most com-
monly tertiary amines, particularly 1,4-diazabicyclo
[2.2.2]octane (DABCO)), is among the useful C–C
bond-forming tools to afford the structural blocks
in biological and medicinal chemistry, such as 3-
hydroxy-2-methylenepropionate [2–6]. In recent
years organic chemists have shown considerable in-
terests in the development of recyclable catalysts
from the environmental and economical points of
view. For example, the polymer-attached DMAP
Disscussion
(4-dimethylaminopyridine) [7] and the imidazolium
ionic liquid-supported quinuclidine [8] have been re-
ported as recyclable Baylis-Hillman catalysts. Never-
The ionic catalyst 1 could easily be prepared via
quaternization using the readily available reagents
DABCO ꢁ 6H O and 1-chlorobutane (Scheme 1). The
2
1
catalyst 1 was characterized by MS (ESI), H NMR,
and FT-IR.
ꢀ Corresponding author. E-mail: yliu@chem.ecnu.edu.cn.

1
164
Y. Cai et al.
Scheme 1
Table 1. Reactions of 3-nitrobenzaldehyde with ethyl acry-
a
late at room temperature catalyzed by ionic catalyst 1
The catalytic performance of catalyst 1 was exam-
ined in the Baylis-Hillman reaction for the coupling
of 3-nitrobenzaldehyde with ethyl acrylate at room
temperature, in which methanol was chosen as the
solvent according to the reported facts that the car-
bonyl of aldehyde was activated by forming a hydro-
gen bond with protic solvent of methanol [10–12].
The results in Table 1 also indicated that the amount
of methanol influenced the coupling of 5 mmol
3-nitrobenzaldehyde and 10 mmol ethyl acrylate dra-
matically, probably, since the intermolecular hydro-
gen bonding between the methanol molecules could
deteriorate the interaction between methanol and
3-nitrobenzaldehyde if too much methanol was pre-
sented [10]. Only when less methanol (2 equiv.) was
applied, the adduct product was obtained with a
yield of 91% (Table 1, entry 2). Nevertheless, much
excess of ethyl acrylate could be harmful because of
the formation of diadduct coming from the coupling
Entry Methanol= Ethyl Catalyst= Time= Conv.= Sel.=
mmol
b
%
b
%
acrylate= mmol
mmol
h
1
2
3
4
5
15
10
10
10
10
10
10
6
6
6
10
10
10
2.5
1.25
24
2
2
3
5
40
100
100
100
100
94
91
97
95
96
a
3-Nitrobenzaldehyde (5 mmol)
Determined by GC
b
a
Table 2. Baylis-Hillman reactions of aldehydes with ethyl acrylate catalyzed by ionic catalyst 1
b
c
c
Entry
Aldehydes
Time=h
Product
Conv.=%
Sel.=%
1
2
3
4
5
6
7
8
9
3-Nitrobenzaldehyde
Benzaldehyde
5
14
6
10
8
2a [14]
2b [3c]
2c [12a]
2d
100
97
99
99
100
100
98
98
90
97
92
99
95
99
98
92
93
99
96
2-Chlorobenzaldehyde
4-Dimethylaminobenzaldehyde
4-Hydroxybenzaldehyde
Pyridine-2-carboxaldehyde
Valeraldehyde
Propionaldehyde
Cinnamaldehyde
Phenyl acetaldehyde
2e
3
2f [15]
2g [14]
2h [3c]
2i [15]
2j
16
16
20
18
1
0
100
a
b
c
Aldehyde (5 mmol), ethyl acrylate (6 mmol), methanol (10 mmol), catalyst 1 (1.25 mmol)
Identified by MS and IR (KBr)
Determined by GC

1
,4-Diazabicyclo[2.2.2]octane-based Ionic Catalyst
1165
reaction of the desired adduct with excess ethyl acry-
late. Further inspection revealed that the optimal
conversion and selectivity to the desired product
were achieved when 1.2 equiv. of ethyl acrylate were
applied (Table 1, entry 3–5). Additionally, by ex-
tending the reaction time from 2 to 5 h, the amount
of catalyst 1 could be decreased eight-fold from 10 to
alkanes, the separation of products=DABCO is very
tedious, though the catalytic activity was competi-
tive to that of ionic catalyst 1.
In conclusion, we have developed a simple and
efficient method for the Baylis-Hillman reaction using
the homogeneous ionic catalyst 1, which was featured
with an ammonium salt tag. This catalyst allowed
efficient coupling of aldehydes with ethyl acrylate
at room temperature affording high conversion and
selectivity without activity loss even after seven recy-
cling uses. Furthermore, the workup of product=cata-
lyst separation was facilitated greatly compared to the
conventional DABCO catalytic system.
1
.25mmol without loss of activity (Table 1, entry 5).
The recycling of catalyst 1 under conditions in
entry 5 indicates that the activity and stability was
maintained very well (conv.: 100%, sel.: 90–96%)
even after seven recycles.
To explore the generality of the Baylis-Hillman
reaction catalyzed by catalyst 1, we examined the
reactions by selecting a variety of aryl or aliphatic
aldehydes to react with ethyl acrylate. All coupling
products were easily separated by simple extraction
with diethyl ether, leaving behind the solid catalyst 1
simultaneously. As summarized in Table 2, both the
electron-rich (deactivated) and electron-poor (acti-
vated) aldehydes could be efficiently converted to
the desired products with high conversion (90–
Experimental
Ionic Catalyst 1 Based on DABCO
A mixture of 2.20 g DABCO ꢁ 6H O (10 mmol) and 0.74g
2
3
n-chlorobutane (8mmol) in 10cm acetonitrile was refluxed
with stirring for 24 h. Excess DABCO was washed off with
ethyl acetate, leaving behind the desired product as a white
solid (1.62g, yield 81%). IR (KBr): ꢀꢀ ¼ 2967, 2870, 1631,
ꢂ1
1
1
464, 1379, 1324, 1099, 1056 cm ; H NMR (500MHz,
100%) and selectivity (92–99%). All products were
confirmed by MS and IR (KBr) spectra.
DMSO-d ): ꢁ ¼ 0.90 (t, J ¼ 7 Hz, 3H, CH ), 1.35 (m, 2H, CH –
6
3
2
CH ), 1.70 (m, 2H, CH –CH ), 3.15 (t, J ¼ 7 Hz, 6H, N–CH ),
3
2
2
2
The separation step in organic synthesis and ca-
talysis is of practical importance in both of academia
and industry. Using a ‘‘phase tag’’ for a substrate,
reagent, or catalyst could simplify reaction workup,
product isolation, and catalyst recovery [13]. In our
study, catalyst 1, tagged with an ammonium salt,
could be separated easily from the reaction mixture
by precipitation with diethyl ether and could be used
in next run without further purification. Compared to
the base catalyst DABCO for the Baylis-Hillman re-
action, the most advantageous merits of the devel-
oped ionic catalyst 1 system was the facilitation of
product=catalyst separation and the simple workup
for catalyst recycling uses. Through quaternization of
one base-site of DABCO by chlorobutane, the ionic
feature was endued to solid catalyst 1 with the prop-
erties of strong polarity, negligible vapor pressure,
and high thermal stability. In such case, catalyst 1
and the substrates (aldehydes and ethyl acrylate) with
relatively high polarity were miscible as a homoge-
neous system, overcoming the mass transfer limita-
tion. Upon completion of the reaction, diethyl ether
with poor polarity was applied to extract the non-ionic
organic compounds leaving behind solid 1 directly
for a next pass. As for the conventional DABCO cat-
alyst, which is very soluble in ethers, alcohols, and
3.20 (t, J ¼ 8 Hz, 2H, N–CH
2
–CH
N–CH ) ppm; MS (ESI): m=z (%) ¼ 169 ([M–Cl] , 100).
2
), 3.35 (t, J ¼ 7 Hz, 6H,
þ
2
General Procedures for the Baylis-Hillman Reaction
of Aldehydes with Ethyl Acrylate
A mixture of 5 mmol aldehyde, 6 mmol ethyl acrylate, and
1
.25mmol catalyst 1 in 10 mmol methanol was stirred at room
temperature (monitored by TLC). Upon completion, the ob-
tained residues after stripping of methanol were extracted
with diethyl ether. The combined organic extracts were dried
(MgSO ), and concentrated in vacuo to give the product as
yellow oily liquid.
4
The left residues were dried in vacuo to give the recovered
catalyst, which could be used without further treatment for the
next run.
All the products (except 2d, 2e, and 2j) are known com-
pounds, which were characterized by IR and MS spectra and
compared with their literature data reports [3c, 12a, 14, 15].
Ethyl 2-[hydroxy(4-dimetylaminophenyl)methyl]acrylate
(2d, C H NO )
14 19 3
Yellow oily liquid (conversion: 99%, selectivity: 95%); IR
(KBr): ꢀꢀ ¼ 3471, 3087, 2986, 1709, 1526, 1351, 1145, 1044,
ꢂ1
þ
1091cm ; MS: m=z (%) ¼ 250 (M , 2), 234 (90), 204 (80),
1
88 (70), 177 (25), 150 (100), 134 (40), 105 (30), 77 (40), 55
1
(
30), 29 (20); H NMR (500 MHz, DMSO-d ): ꢁ ¼ 1.10 (t,
6
J ¼ 8 Hz, CH –CH ), 3.60 (s, 6H, N–CH ), 4.10 (q, J ¼ 7 Hz,
2 3 3
2
H, CH –CH ), 5.60 (d, J ¼ 4 Hz, 1H, CH–OH), 6.10 (s, 2H,
2
3
C¼CH ), 6.30 (d, J ¼ 6 Hz, 1H, CH–OH), 7.60–7.70 (m, 2H,
2
Ph), 8.10–8.20 (m, 2H, Ph) ppm.

1
166
Y. Cai et al.: 1,4-Diazabicyclo[2.2.2]octane-based Ionic Catalyst
G, Wei HX, Gao JJ, Caputo TD (2000) Tetrahedron Lett
Ethyl 2-[hydroxy(4-hydroxyphenyl)methyl]acrylate
2e, C H O )
Yellow oily liquid (conversion: 100%, selectivity: 99%); IR
4
1: 1; d) Yu C, Liu B, Hu L (2001) J Org Chem 66: 5413;
(
1
2 14 4
e) Kim JN, Kim HS, Gong JH, Chung YM (2001)
Tetrahedron Lett 42: 8341; f) Lee WD, Yang KS, Chen
K (2001) Chem Commun 1612; g) Aggarwal VK, Castro
AMM, Mereu A, Adams H (2002) Tetrahedron Lett 43:
(
1
KBr): ꢀꢀ ¼ 3208, 3169, 3040, 2963, 1719, 1596, 1448, 1282,
ꢂ1
þ
219, 1157cm ; MS: m=z (%) ¼ 221 (M , 1), 204 (10), 177
(
20), 160 (40), 132 (60), 105 (100), 77 (50), 55 (10), 28 (20);
H NMR (500MHz, DMSO-d ): ꢁ ¼ 1.15 (t, J ¼ 7 Hz, 3H,
1
1
577; h) Shi M, Jiang JK, Li CQ (2002) Tetrahedron Lett
3: 127; i) Frank SA, Mergott DJ, Roush WR (2002)
6
4
J Am Chem Soc 124: 2404
CH –CH ), 3.65 (s, 1H, CH–OH), 4.05 (q, J ¼ 6 Hz, 2H,
2
3
CH –CH ), 5.55 (s, 1H, Ph–OH), 6.15 (s, 2H, C¼CH ),
2
3
2
[
5] a) Basavaiah D, Gowriswari VVL (1986) Tetrahedron
Lett 27: 2031; b) Basavaiah D, Krishnamacharyulu M,
Suguna Hyma R, Sarma PKS, Kumaragurubaran N
6
.35 (d, J ¼ 5 Hz, 1H, CH–OH), 7.65–7.75 (m, 2H, Ph),
.05–8.15 (m, 2H, Ph) ppm.
8
(
1999) J Org Chem 64: 1197; c) Basavaiah D,
Ethyl 2-[hydroxy(benzyl)methyl]acrylate (2j, C H O )
1
3 16 3
Kumaragurubaran N, Sharada DS (2001) Tetrahedron
Lett 42: 85; d) Basavaiah D, Kumaragurubaran N (2001)
Tetrahedron Lett 42: 477; e) Basavaiah D, Satyanarayana
T (2001) Org Lett 3: 3619
Yellow oily liquid (conversion: 100%, selectivity: 96%); IR
(
1
(
(
KBr): ꢀꢀ ¼ 3448, 3060, 3025, 2974, 2928, 1732, 1596, 1491,
ꢂ1
þ
398, 1177, 1029 cm ; MS: m=z (%) ¼ 222 (M , 10), 204
2), 178 (2), 165 (2), 149 (1), 131 (2), 103 (5), 77 (2), 28
1
[6] E.g. see: a) Hoveyda AH, Evans DA, Fu GC (1993)
Chem Rev 93: 1307; b) Atkinson RS, Fawcett J, Russell
DR, Williams P (1994) Chem Commun 2031; c) Roush
WR, Brown BB (1993) J Org Chem 58: 2151; d) Yu LC,
Helquist P (1981) J Org Chem 46: 4536; e) Smith AB,
Branca SJ, Guaciaro MA, Wovkulich PM, Korn A
(1990) Organic Syntheses, vol. VII. Wiley & Sons,
New York, p 271
100); H NMR (500 MHz, DMSO-d ): ꢁ ¼ 1.20 (t, J ¼ 6 Hz,
6
3
H, CH –CH ), 2.60 (d, J ¼ 7 Hz, 2H, Ph–CH ), 3.50 (s, 1H,
2 3
2
3
2
CH–OH), 3.90 (q, J ¼ 6 Hz, 2H, CH –CH ), 4.10 (m, 1H,
CH–OH), 7.05 (s, 2H, C¼CH ), 7.40–7.50 (m, 5H, Ph) ppm.
2
Acknowledgements
We acknowledge the National Natural Science Foundation
of China (Nos. 20673039, 20533010) and the Science and
Technology Commission of Shanghai Municipality (No.
[
7] a) Huang JW, Shi M (2003) Adv Synth Catal 345: 953;
b) Corma A, Garca H, Leyva A (2003) Chem Commun
2
8] Mi XL, Luo SZ, Cheng JP (2005) J Org Chem 70: 2338
9] Aggarwal K, Emme I, Mereu A (2002) Chem Commun
61
806
0
6JC14023) for financial support.
[
[
1
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