Baylis-Hillman reaction in [bdmim][PF6] ionic liquid

Article abstract of DOI:10.1016/j.tetlet.2004.04.099

A new use of ionic liquid [bdmim][PF₆] as solvent for the Baylis-Hillman reaction is presented. Unlike the commonly used [bmim][PF ₆] that evidently reacts with electrophilic aldehydes under basic conditions, ionic liquid [bdmim][PF<

Full text of DOI:10.1016/j.tetlet.2004.04.099

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 4673–4676
Baylis–Hillman reaction in [bdmim][PF ] ionic liquid
6
Jen-Chuah Hsu, Ya-Hew Yen and Yen-Ho Chu*
Department of Chemistry and Biochemistry, National Chung Cheng University, Chia-Yi, Taiwan 621, Republic of China
Received 12 April 2004; accepted 19 April 2004
Abstract—A new use ofionic liquid [bdmim][PF
used [bmim][PF ] that evidently reacts with electrophilic aldehydes under basic conditions, ionic liquid [bdmim][PF
Baylis–Hillman reaction in [bdmim][PF ] proceeds smoothly with better yield.
2004 Elsevier Ltd. All rights reserved.
6
] as solvent for the Baylis–Hillman reaction is presented. Unlike the commonly
6
6
] is inert and the
6
ꢀ
The Baylis–Hillman reaction has recently attracted
much attention as a useful C–C bond-forming reaction,
mainly because it readily undergoes the tandem
Michael–aldol sequence reaction facilitated by a base to
result in the formation of the b-hydroxy-a-methylene
carbonyl compounds starting from simple acrylic com-
OH O
O
O
DABCO
+
R
OCH
3
R
H
OCH
3
ionic liquid, 24 h, rt
Scheme 1. DABCO-catalyzed Baylis–Hillman reaction ofaldehydes.
1
pounds and aldehydes. The adduct consists ofrich
functionalities, which can be employed for further
transformations to lead to the preparation of, for
example, the potent immunosuppressant ())-mycesteri-
cin E and the plant cell wall biosynthesis inhibitor
recently been employed to facilitate the reaction
(Scheme 1).
10
Room-temperature ionic liquids are a new class of
highly polar solvents that are entirely constituted of
2
;3
epopromycin B. However, the Baylis–Hillman reac-
tion often suffers from being inconveniently slow even
for the most favorable systems. Acrylates with aldehydes
in the presence of1,4-diazabicyclo[2.2.2]octane (DAB-
CO) may require reaction times ofdays to weeks, and
11
ions. Ionic liquids have been considered as recyclable
and environmentally friendly substitutes for volatile
organic solvents, mainly owing to their attractive neg-
ligible vapor pressure, chemical and thermal stability,
nonflammability, and high ionic conductivity. Because
ofthese intriguing properties, ionic liquids have been
found to be the solvents of choice for a large array of
1
ketones are often unreactive. Various efforts have been
made to find effective catalysts and optimal experimental
conditions to circumvent the sluggish nature ofthe
reaction and to improve the overall efficiency ofthis a-
substitution ofacrylic compounds. Ofnitrogen bases,
11
organic reactions. Also, the high solubility ofionic
liquids to many organic and inorganic compounds can
in principle lead to enhanced rates and improved yields
4
5
DABCO, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),
6
12
and most recently quinuclidine are by far most effective.
7
in reactions. We report here that, in comparison with
the popular 1-n-butyl-3-methylimidazolium hexafluoro-
Physical methods such as high pressure and micro-
8
waves have also been recommended. Since polar sol-
13
phosphate ([bmim][PF
proceeds smoothly and cleanly in a new ionic liquid, 1-n-
6
]), the Baylis–Hillman reaction
6;9
vents such as methanol were known to accelerate the
Baylis–Hillman reaction by stabilizing its polar reaction
intermediate, room-temperature ionic liquids have
butyl-2,3-dimethylimidazolium
([bdmim][PF
hexafluorophosphate
with moderate to excellent yields.
14;15
6
]),
N
N
CH
3
N
N
CH
3
PF6
H
3
C
PF6
Keywords: Baylis–Hillman reaction; Ionic liquid.
*
3
H C
CH
3
Corresponding author. Tel.: +886-5-2428148; fax: +886-5-2721965;
e-mail: cheyhc@ccu.edu.tw
[
bmim][PF6]
[bdmim][PF6]
0
040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.04.099

4674
J.-C. Hsu et al. / Tetrahedron Letters 45 (2004) 4673–4676
10c
10a
Recently, Afonso and Santos,
reported that ionic liquids such as [bmim][PF
and later Ko,
] appeared
Table 1. Baylis–Hillman reaction ofaliphatic, aromatic, and a,b-
unsaturated aldehydes with methyl acrylate
a
6
to accelerate the rates ofthe Baylis–Hillman reactions
studied. In addition, the reactions reported were, in
general, low yielding. In those studies, gas chromato-
graphy was employed to quantitatively measure the
conversion ofthe reaction and determine the rate
acceleration by comparing the ratio ofintegration ofthe
desired product and the starting aldehyde. Aggarwal
et al. quickly and elegantly pointed out, however, that
the ionic liquids used were all 1-n-butyl-3-methylimi-
dazolium-based and, in the presence ofbases such as
DABCO or 3-hydroxyquinuclidine, the imidazolium
moiety in ionic liquids could be deprotonated at its C-2
position and the resulting nucleophile directly reacted
with and thereby consumed the aldehyde, leading to the
misinterpretation ofboth the reaction rates and lower
yields. Aggarwal, therefore, concluded that the com-
monly used ionic liquids are not all inert to chemical
Entry
RCHO
Isolated yield (%)
[
bmim][PF
6
]
6
[bdmim][PF ]
Aliphatic aldehyde
1
2
3
Butyraldehyde
Propionaldehyde
Valeraldehyde
44
29
34
58
59
66
Aromatic aldehyde
10b
4
5
6
7
8
9
1
1
1
1
o-Anisaldehyde
p-Anisaldehyde
Benzaldehyde
50
39
63
52
69
66
78
38
45
58
61
65
79
74
73
99
99
73
79
79
p-Bromobenzaldehyde
o-Chlorobenzaldehyde
p-Chlorobenzaldehyde
p-Fluorobenzaldehyde
2-Furaldehyde
0
1
2
3
o-Nitrobenzaldehyde
2-Thiophenecarbox-
aldehyde
reactions. The apparent reactivity of[bmim][PF
basic conditions prompted us to prepare [bdmim][PF
6
] under
]
14
15
p-Tolualdehyde
3,4,5-Trimethoxybenz-
aldehyde
57
70
80
96
6
in which its C-2 carbon is methylated and to study its
application to the Baylis–Hillman reaction and other
organic reactions, with the ultimate goal to develop
chemically inert ionic liquids. Our preliminary result of
its use as solvent for the Baylis–Hillman reaction dem-
a,b-Unsaturated aldehyde
1
1
1
6
7
8
trans-Cinnamaldehyde
Crotonaldehyde
3-Methylcrotonaldehyde
23
18
13
57
27
19
a
The reaction condition: methyl acrylate, 190 lL (2.0 mmol); aldehyde,
.0 mmol; DABCO, 2.0 mmol (224 mg); ionic liquid, 100 lL; ambient
temperature, 24 h.
onstrated that the [bdmim][PF
inert, while the [bmim][PF ] ionic liquid was evidently
reactive under our experimental conditions.
6
] ionic liquid is indeed
1
6
We investigated reactions ofmethyl acrylate and
DABCO with a variety ofaldehydes such as aliphatic,
aromatic, and a,b-unsaturated aldehydes in both
Baylis–Hillman product was contaminated with the
aldehyde-conjugated [bmim][PF ] adduct (1) (Fig. 1c).
As expected, the reaction carried out in [bdmim][PF
proceeded smoothly and was free of 1 (Fig. 1b). The
chemical nature ofthe adduct 1 can be readily verified
and unambiguously confirmed using proton NMR (Fig.
6
6
]
16
[
bdmim][PF
6
] and [bmim][PF
6
] ionic liquids (Table 1).
All reactions were performed at ambient temperature
for 24 h. Simple aliphatic and aromatic aldehydes
worked well (entries 1–15). Our results shown in Table 1
clearly indicate that, regardless ofthe nature ofalde-
hydes studied, the Baylis–Hillman reactions were all
2). The disappearance ofthe C-2 proton signal at
9.07 ppm indicated the site ofconjugation of
d
6
[bmim][PF ] with the aldehyde. For the results shown in
with higher yields in [bdmim][PF
ionic liquid. In cases ofaromatic aldehydes in
bdmim][PF ], good to excellent yields were obtained
6
] than in [bmim][PF
6
]
Table 1, ionic liquid ofonly limited amount (100 lL,
corresponding to 0.33 equiv) was used. If1 equiv ofionic
liquid (300 lL) was employed for 2-furaldehyde reaction
with methyl acrylate and DABCO, a dramatic difference
in the isolated yields from two ionic liquids was
[
6
(
61–99%, entries 4–15). Both electron-deficient and
electron-rich aromatic aldehydes work equally well in
this new ionic liquid. It is noted that p-anisaldehyde
previously described as a slow reacting aldehyde in the
observed: 27% in [bmim][PF
respectively. This result confirmed again that
[bmim][PF ] ionic liquid is chemically reactive under
6 6
] and 88% in [bdmim][PF ],
Baylis–Hillman reaction was found to give satisfactory
6
6
yield in [bdmim][PF
6
] after only 24 h (65%, entry 5). As
basic conditions. Finally, the usefulness of this new ionic
liquid in the Baylis–Hillman reaction is illustrated with
a,b-unsaturated aldehydes, compounds that often are
either poor substrates or unreactive. Low to moderate
isolated yields were obtained after 24 h (19–57%, entries
16–18). Among a,b-unsaturated aldehydes tested, cin-
expected, aliphatic aldehydes with enolizable protons
tended to produce less Baylis–Hillman adducts, pre-
sumably due to possible competing aldol reactions
under basic conditions (58–66%, entries 1–3). The fact of
higher reaction yields obtained in [bmim][PF
bdmim][PF ] under our experimental conditions is in
line with what Aggarwal previously suggested that
6
] than in
[
6
namaldehyde reaction in [bdmim][PF
6
] gave the best
result.
1
0b
[
bmim][PF
6
] ionic liquid is chemically reactive.
verify that the low-yielding reaction in [bmim][PF
To
] was
Using the reaction of p-chlorobenzaldehyde with methyl
acrylate and DABCO as the representative example, we
6
in part attributed to its apparent reactivity with the
electrophilic aldehydes, we conducted the 2-furaldehyde
reaction with methyl acrylate in the presence ofDABCO
as the representative example (Fig. 1). Results ofthe
HPLC analysis ofthe reactions clearly demonstrated
also demonstrated that the ionic liquid [bdmim][PF
6
]
was a useful solvent substitute and could be recycled for
17
the Baylis–Hillman reaction (Table 2). As shown in
Table 2, the Baylis–Hillman reaction was readily carried
out at room temperature for 24 h and the ionic liquid
6
that, for the reaction performed in [bmim][PF ], the

J.-C. Hsu et al. / Tetrahedron Letters 45 (2004) 4673–4676
Table 2. Reuse ofionic liquid [bdmim][PF
4675
a
6
]
Cycle
Isolated yield (%)
1
2
3
4
94
95
95
98
a
The experimental condition: p-chlorobenzaldehyde, 422 mg (3 mmol);
methyl acrylate, 600 lL (6 mmol); DABCO, 672 mg (6 mmol);
6
[bdmim][PF ], 300 lL; room temperature, 24 h.
6
monly employed [bmim][PF ], due to the fact that the
deprotonated 1-butyl-3-methylimidazolium could read-
ily react with electrophilic reactants, for example, alde-
hyde present in reaction mixtures. We are currently
investigating the general applicability ofthis room-
temperature ionic liquid for use in other important
reactions, including multi-step combinatorial organic
synthesis.
Acknowledgements
Figure 1. HPLC analysis ofcrude reaction mixtures fr om the Baylis–
Hillman reaction of2- uf raldehyde with methyl acrylate and DABCO
We gratefully acknowledge support of this work by the
Taichung Science-Based Industrial Park (Taiwan, ROC)
both in [bmim][PF
Baylis–Hillman adduct and aldehyde-conjugated [bmim][PF
The crude mixture ofthe reaction carried out in [bdmim][PF
crude mixture ofthe reaction carried out in [bmim][PF ]. Each sepa-
6
] and in [bdmim][PF
6
]. (a) Co-injection ofpurified
] (1). (b)
]. (c) The
6
(NSC91-2218-E-194-012) and the National Science
6
Council (Taiwan, ROC) (NSC91-2113-M-194-023). We
thank our colleague Professor Guor-Tzo Wei for his
valuable comments in the subject ofionic liquid.
6
ration was carried out using a reversed phase column (Mightysil RP-
C18 GP) under the same conditions. The analysis was monitored at
254 nm.
References and notes
could be reused at least four times. In addition, no
apparent loss ofyield ofthe reaction was observed.
1
. (a) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem.
Rev. 2003, 103, 811–891; (b) Basavaiah, D.; Rao, P. D.;
Hyma, R. S. Tetrahedron 1996, 52, 8001–8062.
6
In summary, the use ofionic liquid [bdmim][PF ] f or
base-mediated reactions such as the Baylis–Hillman
reaction is recommended as a substitute for the com-
2. Iwabuchi, Y.; Furukawa, M.; Esumi, T.; Hatakeyama, S.
Chem. Commun. 2001, 2030–2031.
1
Figure 2. H NMR spectrum ofthe 2- fu raldehyde-conjugated [bmim][PF
6
] adduct, 1, in DMSO-d
6
. In the spectrum, the adduct 1 was associated with
6
a small amount of[bmim][PF ] ionic liquid whose NMR signals were indicated as asterisks (*).

4676
J.-C. Hsu et al. / Tetrahedron Letters 45 (2004) 4673–4676
3
. Iwabuchi, Y.; Sugihara, T.; Esumi, T.; Hatakeyama, S. (39.8 mL, 0.27 mol). The reaction mixture was allowed to
Tetrahedron Lett. 2001, 42, 7867–7871.
. Rafel, S.; Leahy, J. W. J. Org. Chem. 1997, 62, 1521–1522.
. Aggarwal, V. K.; Mereu, A. Chem. Commun. 1999, 2311–
proceed the ion exchange for 12 h at ambient temperature.
The upper acidic aqueous layer was decanted and the
lower ionic liquid portion was then washed with water
until the washings were no longer acidic. The resulting
ionic liquid was further heated at 80 ꢁC in vacuo to remove
water. The desired product, 1-n-butyl-2,3-dimethylimi-
4
5
2
312.
. Aggarwal, V. K.; Emme, I.; Fulford, S. Y. J. Org. Chem.
003, 68, 692–700.
. (a) Hill, J. S.; Isaacs, N. S. J. Chem. Res. (S) 1988, 330–
6
7
2
6
dazolium hexafluorophosphate ([bdmim][PF ]), was ob-
1
331; (b) Hill, J. S.; Isaacs, N. S. Tetrahedron Lett. 1986, 27,
5007–5010.
tained in 61% overall yield (34.0 g). H NMR (DMSO-d
400 MHz) d 0.90 (t, J ¼ 7:4 Hz, CH , 3H), 1.28 (m, CH
2H), 1.68 (m, CH , 2H), 2.56 (s, CH , 3H), 3.73 (s, NCH
3H), 4.09 (t, J ¼ 7:3 Hz, CH
@CH, 1H), 7.62 (d, J ¼ 2:0 Hz, @CH, 1H); C NMR
(DMSO-d , 100 MHz) d 9.21, 13.48, 18.99, 31.27, 34.77,
6
2
3
,
,
,
3
8
9
. Kundu, M. K.; Mukherjee, S. B.; Balu, N.; Padmakumar,
R.; Bhat, S. V. Synlett 1994, 444.
. Aggarwal, V. K.; Dean, D. K.; Mereu, A.; Williams, R. J.
Org. Chem. 2002, 67, 510–514.
2
3
2
, 2H), 7.59 (d, J ¼ 2:0 Hz,
1
3
6
1
0. (a) Kim, E. J.; Ko, S. Y.; Song, C. E. Helv. Chim. Acta 2003,
6, 894–899; (b) Aggarwal, V. K.; Emme, I.; Mereu, A.
47.43, 120.98, 122.43, 144.
8
16. General procedure for the Baylis–Hillman reaction: To a
stirred mixture ofthe substrate aldehyde (1.0 mmol) and
methyl acrylate (2 mmol) were added DABCO (2 mmol)
and ionic liquid (100 lL). The homogeneous reaction
mixture was stirred at ambient temperature for 24 h and, if
needed, the progress ofthe reaction could be monitored by
TLC. The reaction mixture was first diluted with dichloro-
methane, extracted with 10% citric acid (3·), dried over
anhydrous sodium sulfate, filtered, and then concentrated
in vacuo. The resulting crude oil was further purified by
flash column chromatography on silica gel, using the
mixed solvent ofethyl acetate and hexane (1:3 or 1:4, v/v),
to give the desired product. All desired products were fully
Chem. Commun. 2002, 1612–1613; (c) Rosa, J. N.; Afonso,
C. A. M.; Santos, A. Tetrahedron 2001, 57, 4189–4193.
1. (a) Zhao, H.; Malhotra, S. V. Aldrichim. Acta 2002, 35,
1
75–83; (b) Hagiwara, R.; Ito, Y. J. Fluorine Chem. 2000,
105, 221–227; (c) Welton, T. Chem. Rev. 1999, 99, 2071–
2083; (d) Holbrey, J. D.; Seddon, K. R. Clean Products
Process. 1999, 1, 223–236.
2. Fraga-Dubreuil, J.; Bazureau, J. P. Tetrahedron Lett.
1
2000, 41, 7351–7355.
1
3. Huddleston, J. G.; Willauer, H. D.; Swatloski, R. P.;
Visser, A. E.; Rogers, R. D. Chem. Commun. 1998, 1765–
1766.
1
13
1
1
4. The ionic liquid [bdmim][PF
6
] was previously prepared
characterized by H NMR, C NMR, MS, and HRMS.
Yields refer to spectroscopically and chromatographically
homogeneous (>95%) materials.
and used solely to study its affinity with water: Camma-
rata, L.; Kazarian, S. G.; Salter, P. A.; Welton, T. Phys.
Chem. Chem. Phys. 2001, 3, 5192–5200.
17. Reuse of[bdmim][PF
6
] ionic liquid: Methyl acrylate
5. Synthesis and characterization of[bdmim][PF
6
] ionic
(600 lL, 6 mmol) was added to a stirred solution of
p-chlorobenzaldehyde (422 mg, 3 mmol) and DABCO
liquid: To a round-bottomed flask containing 1,2-di-
methylimidazole (20 g, 0.21 mol) was added 1-bromobu-
tane (31.4 g, 0.23 mol). The mixture was stirred and
refluxed at 80 ꢁC for 2 h. Using iodine for compound
visualization, TLC could be employed to monitor the
progress ofthe reaction. The resulting viscous reaction
solution was allowed to cool to room temperature and
mixed with water (104 mL), and then washed five times
with ethyl acetate (300 mL). The residual ethyl acetate
present in aqueous solution was removed by heating to
(672 mg, 6 mmol) in [bdmim][PF ] (300 lL) at ambient
6
temperature. The Baylis–Hillman reaction was allowed to
proceed for 24 h at ambient temperature. The reaction
mixture was first diluted with dichloromethane, washed
with 10% citric acid three times, and then concentrated
under reduced pressure. The product in the ionic liquid
solution was extracted using diethyl ether (5·) and the
combined ethereal mixture was reduced to dryness
in vacuo. Ifnecessary, flash chromatography was
employed to purify the Baylis–Hillman adduct. A new
portion ofreactants and DABCO was added to the
recycled ionic liquid and the cycle was repeated.
6
1
0 ꢁC under reduced pressure. To the solution containing
-n-butyl-2,3-dimethylimidazolium bromide ([bdmim]
[Br]), was added slowly the hexafluorophosphoric acid