A novel and highly efficient protocol for Markovnikov's addition using ionic liquid as catalytic green solvent

Article abstract of DOI:10.1016/j.tetlet.2006.01.001

A novel and highly efficient protocol for Markovnikov's addition using ionic liquid as a catalytic green solvent is described. The strategy is especially useful in the synthesis of N-heterocycle derivatives with biological activity. This reaction widens l

Full text of DOI:10.1016/j.tetlet.2006.01.001

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1555–1558
A novel and highly efficient protocol for Markovnikov’s
addition using ionic liquid as catalytic green solvent
Jian-Ming Xu, Wei-Bo Wu, Chao Qian, Bo-Kai Liu and Xian-Fu Lin*
Department of Chemistry, Zhejiang University, Hangzhou 310027, People’s Republic of China
Received 17 September 2005; revised 26 December 2005; accepted 4 January 2006
Available online 23 January 2006
Abstract—A novel and highly efficient protocol for Markovnikov’s addition using ionic liquid as a catalytic green solvent is
described. The strategy is especially useful in the synthesis of N-heterocycle derivatives with biological activity. This reaction widens
largely the applicability of ionic liquid in organic synthesis.
ꢀ
2006 Elsevier Ltd. All rights reserved.
9
Markovnikov’s addition is an effective method to form
C–C, C–N, and C–S bonds and has wide applications
in organic chemistry and pharmaceutical synthesis. This
reaction was generally promoted by harsh bases, strong
imidazolium tetrafluoroborate ([bmim]BF ) have been
4
demonstrated as an efficient catalyst for Michael addi-
tion in a solventless system. Considering these elegant
discoveries of addition activity of ionic liquid, we envis-
age that other types of addition could also be catalyzed
by ionic liquid. Herein we report for the first time the
use of ionic liquid as a novel and recyclable reaction
media, as well as an efficient catalyst for Markovnikov’s
addition of N-heterocyclic compounds to vinyl esters to
afford corresponding N-heterocycle derivatives in high
yields under mild and neutral conditions (Scheme 1).
The Markovnikov’s adducts obtained provided thera-
1
acid or high temperature, which would lead to environ-
mentally hazardous residues and undesirable by-prod-
ucts. Recently, a new enzymatic strategy to perform
Mrakovnikov’s addition was developed using penicillin
2
G acylase as the catalyst. Although the reaction was
conducted under mild and neutral conditions, the polar
solvent DMSO was used as reaction medium, which
resulted in complex isolation and recovery procedures.
Thus, the development of simple, more convenient and
environmentally friendly approaches for Markovnikov’s
addition poses a great challenge to organic chemists.
1
0
peutical and pharmaceutical alternatives.
An initial experiment on the reaction of 4-nitroimid-
azole and vinyl acetate was carried out in different
conditions, which was shown in Table 1. The results
indicated that ionic liquid containing a BF4 anion
exhibited excellent catalytic activity (entries 1 and 3).
In contrast, no reaction was observed in the ionic liquid
containing a PF anion (entries 2 and 4). This was prob-
ably attributed to the poor solubility of 4-nitroimidazole
in hydrophobic ionic liquid [bmim]PF . It is interesting
During the past few years, ionic liquids3,4 have been dem-
onstrated as efficient and practical alternatives to organic
solvents for many important organic transformations.
Recently ionic liquids are attracting more attention due
to their significant role in controlling the reaction as a
catalyst. A variety of ionic liquids have been successfully
applied in many types of reactions such as Friedel–Crafts
11
À
À
6
6
5
6
acylations and alkylations. However, the relevant
reports about addition reaction are relatively scarce.
A molten cinchonidine-derived bifluoride salt was
developed to catalyze enantioselective aldol addition
to note that ionic liquids with longer cationic carbon
chain exhibited higher Markovnikov’s addition activity
(entries 1 and 3). At room temperature, Markovnikov’s
7
reactions. Recently, molten tetrabutylammonium bro-
mide8 and ionic liquid 1-butyl-3-methylimidazolium
O
[
bmim]BF
4
O
Nu
hexafluorophosphate ([bmim]PF ) and 1-butyl-3-methyl-
6
Nu-H +
R1
O
R
50 C
˚
R1
O
1
*
Corresponding author. Tel.: +86 571 87951588; fax: +86 571
7952618; e-mail: llc123@ccc.zju.edu.cn
8
Scheme 1.
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.01.001

1556
J.-M. Xu et al. / Tetrahedron Letters 47 (2006) 1555–1558
Table 1. Markovnikov’s addition of 4-nitroimidazole to vinyl acetate
promoted by ionic liquid under various reaction conditions
addition reaction could also proceed smoothly and good
yield was obtained but required longer reaction time (en-
try 7). Systematically reducing the number of equiva-
lents of vinyl acetate led to somewhat longer reaction
times but still provided good isolated yield of Markovni-
kov’s adduct (entries 1, 5, and 6).
a
b
Entry Ionic liquid Vinyl acetate (equiv) Time (h) Yield (%)
1
2
3
4
5
6
7
8
9
[bmim]BF
[bmim]PF
[emim]BF
[emim]PF
4
6
6
6
6
4
2
6
—
6
12
48
48
48
24
48
96
96
96
98
n.d.
96
n.d.
95
96
97
n.d.
0.3
c
6
4
c
6
[bmim]BF
[bmim]BF
[bmim]BF
4
4
4
Some blank experiments were also carried out to dem-
onstrate the catalysis of [bmim]BF . When the reaction
4
d
e
was performed in a solventless system, no product was
detected after 4 days due to the poor solubility of 4-
nitroimidazole in vinyl acetate (entry 8). When DMSO
was used as solvent, only 0.3% of Markovnikov’s adduct
was formed even after 4 days (entry 9). The results
c
Solventless
DMSO
a
All reactions were run on a 1.0 mmol scale of 4-nitroimidazole in
mL of ionic liquid at 50 ꢁC.
Isolated yields.
n.d. = no product detected.
Reaction was carried out at 25 ꢁC.
1
b
c
showed that ionic liquid [bmim]BF played the role of
4
catalyst as well as a reaction medium during the reaction
process.
d
e
1.0 mmol 4-nitroimidazole in 1.0 mL of vinyl acetate at 50 ꢁC.
a
Table 2. Markovnikov’s addition of N-heterocycles to vinyl esters promoted by [bmim]BF
4
O
O
[bmim]BF4
Nu
Nu-H +
R
1
O
50 C
˚
R
1
O
1
2
3a-3o
b
Entry
1
Nu–H
O N
R
1
Time (h)
12
Yield 3 (%)
2
N
CH
3
3a (98)
N
H
O N
2
N
2
3
CH
3
(CH
2
)
2
48
48
3b (90)
3c (86)
N
H
O N
2
N
N
N
3 2
(CH ) CH
N
H
O N
2
4
5
CH
3
(CH
2
2
)
)
3
6
72
72
3d (91)
3e (89)
N
H
O N
2
CH
3
(CH
N
H
O N
2
N
N
N
6
7
CH
CH
Ph
2
@CHOOC(CH
2
2
)
2
4
36
60
48
3f (93)
3g (94)
3h (92)
N
H
O N
2
2
@CHOOC(CH
)
N
H
O N
2
c
8
N
H
N
9
CH
3
2
24
48
3i (97)
3j (93)
N
H
10
N
CH
@CHOOC(CH
2
)
2
N
H

J.-M. Xu et al. / Tetrahedron Letters 47 (2006) 1555–1558
1557
Table 2 (continued)
b
Entry
Nu–H
R
1
Time (h)
72
Yield 3 (%)
N
11
CH
3
3k (97)
N
H
N
12
13
14
15
CH
CH
CH
CH
3
3
3
3
48
72
72
48
3l (96)
3m (80)
3n (86)
3o (94)
N
H
N
H
N
N
H
N
N
N
H
a
b
c
All reactions were run on a 1.0 mmol scale of N-heterocycles with 6.0 equiv of vinyl ester in 1 mL of ionic liquid at 50 ꢁC.
Yields refer to those of pure isolated products characterized by H and C NMR spectroscopic data.
Reaction was carried out at 100 ꢁC.
1
13
With optimal conditions in hand, we then examined the
generality of these conditions to other substrates. The
results are summarized in Table 2. All the reactions pro-
philicity. The reaction activity dramatically decreased
for sterically hindered imidazole (entry 11). Apart from
imidazole derivatives, other N-heterocycles such as pyr-
role, pyrazole, and triazole also exhibited high Mark-
ovnikov’s addition activity, and triazole reacted fairly
faster due to its strong nucleophilicity (entry 15). How-
ever, pyrrole showed relatively lower Markovnikov’s
addition activity compared to pyrazole and triazole
(entries 13–15).
ceeded smoothly in [bmim]BF without the need of any
4
other catalyst. Interestingly, no by-product generated
from anti-Markovnikov’s addition, acylation or other
reaction was detected by TLC and HPLC. All novel
Markovnikov’s adducts obtained were characterized
1
13
by H NMR, C NMR, and HRMS and the results
indicated that all adducts were N-1-alkylated.
With the success of the above reactions, we continued
our study by exploring the recyclability of the ionic
The Markovnikov’s addition of 4-nitroimidazole with
vinyl acetate proceeded smoothly at 50 ꢁC and almost
quantitative yield was obtained after 12 h (entry 1). In
addition to vinyl acetate, the reaction also took place
with other fatty acid vinyl esters and aromatic acid vinyl
esters (entries 2–8). The activity of vinyl esters was
dependent on the structure of acid moiety. As the chain
length of fatty acid vinyl ester increased, the reactivity
decreased (entries 1, 2, 4, and 5). When the chain length
was comparable, divinyl dicarboxylate proceeded faster
than mono-acid vinyl ester (entries 2, 5, 6, and 7). The
sterically hindered fatty acid vinyl ester exhibited
slightly lower Markovnikov’s addition activity (entries
liquid. The remaining ionic liquid [bmim]BF was recov-
4
ered and recycled in subsequent reactions five times
without loss of activity (Fig. 1).
In summary, an efficient and environmentally friendly
method for aza-Markovnikov’s addition was developed
using recyclable ionic liquid [bmim]BF as the reaction
4
9
7
97
97
1
00
80
95
96
2
and 3). The reactivity of vinyl benzoate was rather
low in comparison with the fatty acid vinyl esters (entry
) because the aromatic group of vinyl ester decreased
8
6
4
2
0
0
0
0
the nucleophilicity of the double bond. Accordingly,
higher temperature (100 ꢁC) was required in order to
afford good yield.
The structure of the N-heterocycles also affected the
results of the Markovnikov’s addition reaction. The
four substituted imidazoles examined underwent Mark-
ovnikov’s addition with vinyl acetate favorably and all
substituted imidazole could be obtained in good yield
1
2
3
4
5
Recycling times
(
entries 1, 9, 11, and 12). The reactivity decreased by
the following order, 4-nitroimidazole, imidazole, and
-methyl-imidazole, in agreement with their nucleo-
Figure 1. Recycling of [bmim]BF
imidazole with vinyl acetate. Conditions: 1.0 mmol scale of imidazole
and 6.0 equiv of vinyl acetate in 1 mL of [bmim]BF at 50 ꢁC for 24 h.
4
in Markovnikov’s addition of
4
4

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J.-M. Xu et al. / Tetrahedron Letters 47 (2006) 1555–1558
media. It is noteworthy that our procedure does not
require any catalyst. This method is quite general and
it works with a series of N-heterocycles and vinyl esters.
More applications (forming C–O, C–S, and C–C bonds)
of Markovnikov’s addition reaction promoted by ionic
6. (a) Jorapur, Y. R.; Lee, C. H.; Chi, D. Y. Org. Lett. 2005,
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2
3
11. Representative experimental procedure for the Markovni-
kov’s addition of 4-nitroimidazole with vinyl acetate (3a).
4-Nitroimidazole (113 mg, 1 mmol) and vinyl acetate
(512 mg, 6 mmol) were added to a 10 mL conical flask
. For reviews, see: (a) Sheldon, R. Chem. Commun. 2001,
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containing 1 mL [bmim]BF and the mixture was shaken
at 200 rpm and 50 ꢁC for 12 h. The reaction mixture was
4
extracted from the ionic liquid phase with ethyl ether
(10.0 mL · 5). The organic layer was dried over anhydrous
sodium sulfate and evaporated under reduced pressure.
The residue was purified by flash column chromatography
(silica gel) to obtain 1-(1-(4-nitroimidazole))-ethyl acetate
(196 mg) as a white solid. The ionic liquid left in the
conical flask was further washed with ether, dried under
vacuum at 90 ꢁC for 2 h to eliminate any water trapped
from moisture and reused for subsequent reactions. 1-(1-
4
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1
(4-Nitroimidazole))-ethyl acetate: white solid, mp 82–
1
6
83 ꢁC; H NMR (DMSO-d , 500 MHz, d, ppm): 8.68 (s,
6
Y. Tetrahedron Lett. 2002, 43, 8741–8743.
1H), 8.11 (s, 1H), 6.77 (q, 1H, J = 6.20 Hz), 2.05 (s, 3H),
1.78 (d, 3H, J = 6.20 Hz).
1
3
5
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C NMR (DMSO-d6,
125 MHz, d, ppm): 169.8, 147.8, 137.2, 120.1, 77.3, 21.1,
20.1. HRMS (ESI) m/z calcd for [M+Na] C H N O Na
7
9
3
4
8616–8620.
222.0485, found 222.0476.