Basic ionic liquid as catalysis and reaction medium: A novel and green protocol for the Markovnikov addition of N-heterocycles to vinyl esters, using a task-specific ionic liquid, [bmIm]OH

Article abstract of DOI:10.1021/jo0600914

A basic ionic liquid, 1-methyl-3-butylimidazolium hydroxide ([OmIm]OH), has been introduced as a catalyst and reaction medium for the Markovnikov addition of N-heterocycles to vinyl esters under mild conditions. The evidence for the role of this basic ion

Full text of DOI:10.1021/jo0600914

applied in the alkylation,5 aldol condensation,6 epoxidation,7 and
Michael addition.8 Recently, basic ionic liquids have aroused
unprecedented interest because they showed more advantages
such as catalytic efficiency and recycling of the ionic liquid
than the combination of inorganic base and ionic liquid for some
base-catalyzed processes.9 A basic ionic liquid [bmIm]OH has
been successfully applied to catalyze the Michael addition of
active methylene compounds to conjugated ketones, carboxylic
esters, and nitriles.10 However, the catalytic mechanism of this
basic ionic liquid was ambiguous and other catalytic reactions
by this basic ionic liquid are worthy of exploration.
Basic Ionic Liquid as Catalysis and Reaction
Medium: A Novel and Green Protocol for the
Markovnikov Addition of N-Heterocycles to Vinyl
Esters, Using a Task-Specific Ionic Liquid,
[bmIm]OH
Jian-Ming Xu, Bo-Kai Liu, Wei-Bo Wu, Chao Qian,
Qi Wu, and Xian-Fu Lin*
Department of Chemistry, Zhejiang UniVersity, Hangzhou
310027, People’s Republic of China
Markovnikov-type addition is among the most useful carbon-
carbon, oxygen-carbon, or nitrogen-carbon bond-forming
reactions. It is especially important to synthesize bioactive
N-heterocycle derivatives with a nitrogen-carbon linkage, which
could be achieved by an addition reaction. This reaction was
traditionally promoted by harsh bases, strong acid, or high
temperature,11 which would lead to environmentally hazardous
residues and unwanted byproducts. A lot of effort have been
made in view of green synthesis. Recently, a new enzymatic
strategy to perform Markovnikov addition was developed with
use of penicillin G acylase as catalyst.12 In this Note, we
discovered that the basic ionic liquid [bmIm]OH13 also could
effectively promote this kind of addition reaction under mild
conditions. Herein we employed this tailor-made ionic liquid
in the Markovnikov addition of N-heterocycles to vinyl esters
to synthesize a series of N-heterocycle derivatives, which are
usually pharmacologically active and may be applied as potential
llc123@css.zju.edu.cn
ReceiVed January 16, 2006
A basic ionic liquid, 1-methyl-3-butylimidazolium hydroxide
([bmIm]OH), has been introduced as a catalyst and reaction
medium for the Markovnikov addition of N-heterocycles to
vinyl esters under mild conditions. The evidence for the role
of this basic ionic liquid [bmIm]OH in promoting the
Markovnikov addition has been given. On the basis of the
evidence, a mechanism was postulated.
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its significant role in controlling the reaction as catalyst.2 Since
the first successful use of ionic liquid, dialkylimidazolium
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a
number of ionic liquids with unique properties have been
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acidic ionic liquids, which exhibit a stable acidic anion, have
been utilized to catalyze esterification reaction3 and cleavages
of ethers.4 The neutral ionic liquids have also been successfully
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10.1021/jo0600914 CCC: $33.50 © 2006 American Chemical Society
Published on Web 04/13/2006
J. Org. Chem. 2006, 71, 3991-3993
3991

TABLE 1. Markovnikov Addition of Imidazoles to Vinyl Esters
Promoted by [bmIm]OHa
TABLE 2. Markovnikov Addition of Other N-Heterocycles with
Vinyl Acetate Promoted by [bmIm]OHa
entry
R1
R2
R3
CH3
CH3(CH2)2
(CH3)2CH
CH3(CH2)3
CH3(CH2)4
Ph
time (h)
yieldb of 3 (%)
1
2
3
H
H
H
H
H
H
H
H
H
H
H
CH3
CH3
NO2
NO2
NO2
NO2
NO2
NO2
H
H
H
H
CH3
H
2
8
8
12
12
12
4
3a (93)
3b (82)
3c (75)
3d (79)
3e (76)
3f (81)
3g (91)
3h (80)
3i (78)
3j (84)
3k (88)
3l (73)
3m (85)
4
5
6c
7
CH3
8
9
CH3(CH2)2
CH3(CH2)4
Ph
CH3
CH3
8
12
12
4
4
12
10c
11
12
13
NO2
CH3
a Reactions were carried out on 1.0 mmol scale of substrate with 4 equiv
of vinyl ester in 1 mL of ionic liquid at 50 °C. b Isolated yields. c Reaction
was performed at 100 °C.
therapeutic alternatives.14 On the basis of the experimental facts,
we proposed a mechanism for the Markovnikov addition
catalyzed by [bmIm]OH and designed some experiments to
support the postulated mechanism.
a Reactions were carried out on 1.0 mmol scale of substrate with 4 equiv
of vinyl ester in 1 mL of ionic liquid at 50 °C. b Isolated yields.
In view of the observation, we first examined the Markovni-
kov addition of 4-nitroimidazole to vinyl acetate. When the
reaction was carried out with 4 equiv of vinyl acetate at 50 °C
in [bmIm]OH for 2 h, a single product was prepared in 93%
isolated yield after flash chromatography. The structure of this
compound was confirmed by IR, 1H NMR, 13C NMR, and HR-
MS. We also monitored the formation of product by TLC and
HPLC. It is worthwhile to mention that no byproduct was
detected resulting from anti-Markovnikov addition, acylation
reaction, hydrolytic reaction, or other reactions.
A variety of structurally diverse imidazoles and vinyl esters
also underwent Markovnikov additions smoothly without any
other catalyst to afford the corresponding imidazole derivatives
in moderate to high yields. The results are summarized in Table
1. Generally, the Markovnikov addition of 4-nitroimidazole to
a series of vinyl esters proceeded favorably. When the chain of
the vinyl ester increased, the Markovnikov addition activity
decreased dramatically (entries 1-5, Table 1). More sterically
hindered vinyl ester provided relatively lower yield (entries 2
and 3, Table 1). The reactivity of vinyl benzoate is rather low
compared to that of the fatty acid vinyl esters (entry 6, Table
1) because the aromatic group of the vinyl ester would decrease
the basicity of the vinyl group. Accordingly, higher temperature
(100 °C) was required to afford good yields. Comparable
behavior was observed with imidazole as substrate (entries
7-10, Table 1). The four substituted imidazoles examined
underwent Markovnikov addition with vinyl acetate favorably
and all substituted imidazoles could be obtained in good yields
in short reaction times (entries 1, 7, 11, 12, and 13, Table 1).
The reactivity decreased by the following order: 4-nitroimida-
zole, imidazole, 4-methylimidazole, in agreement with their
acidity. Sterically hindered imidazole underwent Markovnikov
addition much more slowly (entry 12, Table 1).
Having obtained favorable results with imidazoles, we then
examined the addition of other N-heterocycles to vinyl acetate.
Other five-membered N-heterocycles such as pyrrole, pyrazole,
and triazole also exhibited high Markovnikov addition activity.
Among them, triazole reacted fastest due to its strong acidity
(entry 3, Table 2). However, pyrrole showed relatively lower
Markovnikov addition activity compared to pyrazole and triazole
(entries 1-3, Table 2). More complicated N-heterocycles, such
as pyrimidines and purines, also can be used as substrate to
obtain the corresponding Markovnikov adducts. The similar
reaction of fluorouracil with vinyl acetate provided a relatively
low yield of Markovnikov adduct (35%) after 1 day, since the
N-H of amide is much less acidic than that of amine (entry 4,
Table 2). Although the reactivity of pyrimidine derivatives was
low, excellent regioselective was achieved and only N-1 adducts
were prepared (also monitored by TLC and HPLC). The
Markovnikov addition of allopurinol and 6-benzylaminopurine
also proceeded smoothly to give Markovnikov adducts at the
N-9 position in moderate to high yields (entries 5 and 6, Table
2).
The ionic liquid remained intact (1H NMR) and was used
for subsequent runs without any difficulty. It has been observed
that the Markovnikov addition of 4-nitroimidazole to vinyl
acetate did not proceed in some molecular solvents such as THF,
DMF, and DMSO. Thus the ionic liquid [bmIm]OH played the
role of catalyst during the reaction process, as well as reaction
medium. The Markovnikov addition of N-heterocycles to vinyl
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3992 J. Org. Chem., Vol. 71, No. 10, 2006

SCHEME 1. Proposed Mechanism for the Markovnikov
Addition Promoted by [bmIm]OH
To trace the transfer process of C2-H, [2-D]-imidazolium
ionic liquid was also synthesized. However, hydroxide anion
was also deuterated because the hydrogen of the hydroxide anion
was more active. The deuterated ionic liquid was used to
catalyze the Markovnikov addition of 4-nitroimidazole and vinyl
acetate. The corresponding Markovnikov adduct 3a was isolated
1
and characterized by H NMR spectroscopy and ESI-MS. The
1H NMR and ESI-MS figures were showed in the Supporting
Information. The proton number at â-C was about 2.6 according
1
to the H NMR data, indicating that the Markovnikov adduct
was partially deuterated and the ratio of 3a and deuterated 3a
was about 6:4. ESI-MS data also demonstrated that the
Markovnikov adduct was the mixture of 3a and deuterated 3a.
According to the proposed mechanism, the hydroxide anion first
deprived the N-proton to form HDO. The nucleophilic anion
was added to the partial positive charged R-C position. The
resulting negative charge at the â-C carbon was stabilized by
C2-H. Finally, HDO would deliver the proton to the â-C
carbon. Considering the similar probability of H and D, the
proton number at â-C was about 2.5. This was almost in
accordance with the experimental result. Therefore, the proton
of C2 just stabilized the negative charge at the â-C carbon as
the proposed mechanism.
esters proceeded smoothly to obtain corresponding adducts.
However, none of the products were observed for the Mark-
ovnikov addition of N-heterocycles to vinyl ethers. This
indicated that the carboxyl group in vinyl ester was considerably
significant in the addition reaction. With all these results in hand,
we proposed a mechanism for the Markovnikov addition
reaction promoted by [bmIm]OH (Scheme 1). Owing to the
electron-withdrawing effect of the carboxyl group, the R-carbon
of the vinyl group carries partial positive charge. When the
substrate was added, hydroxyl anion deprived the N-proton and
the nucleophile simultaneously adds to the partial positively
charged R-C position. The resulting negative charge at the â-C
carbon could be stabilized by C2-H of [bmIm]OH. Finally,
the H2O formed would deliver the proton to obtain the
Markovnikov adduct.
In conclusion, the present procedure with a basic ionic liquid
[bmIm]OH provides an efficient and convenient protocol for
Markovnikov addition of N-heterocycles to vinyl esters without
the requirement of any other catalyst and organic solvent. This
strategy is quite general and it works with a broad range of
N-heterocycles as addition substrates, including five-membered
N-heterocycles, pyrimidines, and purines. Furthermore, this
method exhibits a simple and green procedure, mild conditions,
and general applicability and avoids hazardous organic solvent
and toxic catalysts. The catalytic mechanism was postulated and
supported by experimental facts. More applications (forming
C-O, C-S, and C-C bonds) of the Markovnikov addition
reaction promoted by this new tailor-made task specific ionic
liquid [bmIm]OH are in progress in our laboratories.
The evidence from 13C NMR spectroscopy also supported
the proposed mechanism. Imidazole and vinyl butyrate were
used as a representative example. Comparing the 13C NMR
spectra (CDCl3) of imidazole (neat) with a mixture of imidazole
and 1 equiv of [bmIm]OH, it could be observed that there is an
upfield shift of C2 (0.27 ppm) and C4 (0.55 ppm) of imidazole
in the mixture, indicating the deprivation of the N-proton of
imidazole by the hydroxyl anion of [bmIm]OH. We also
compared the 13C NMR spectra (CDCl3) of butyrate (neat) with
a mixture of butyrate and 1 equiv of [bmIm]OH to verify the
interaction of C2-H and vinyl ester. An upfield shift of 0.13
ppm for the carbonyl carbon was found. Repeating the above
experiment with ionic liquid [bmIm]BF4, a 0.04 ppm downfield
shift was observed. The results indicated the existence of
hydrogen bond of the imidazolium cation with the vinyl ester
as shown in Scheme 1. The 0.13 ppm upfield shift for the
carbonyl carbon probably resulted from the coordination effect
of the hydroxide anion with the carbonyl carbon of the vinyl
butyrate. In fact, the chemical shift of the C-2 proton of [bmIm]-
OH is 10.24 ppm, which could form a hydrogen bond as in
Scheme 1. Much literature has verified the existence of the
hydrogen bond on the C-2 proton by some methods such as
NMR, IR, and quantum calculation.15 Our 13C NMR data also
demonstrated the existence of the hydrogen bond. Therefore,
the proton of the C2 position of the ionic liquid [bmIm]OH
interacted with the carbonyl group and then first activated the
R-C partially.
Experimental Section
Materials and General Methods. 1H and 13C NMR spectra were
recorded at 500 and 125 MHz in CDCl3 or DMSO-d6, respectively.
Chemical shifts are reported in ppm (δ), relative to the internal
standard of tetramethylsilane (TMS). All chemicals were obtained
from commercial suppliers and used without further purification.
The ionic liquid remaining 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. This can be used for the reactions for up to five runs
without any appreciable loss of efficiency. After five runs, about
50% fresh ionic liquid was added and the mixture was found to be
good for several more reactions.
Acknowledgment. This investigation has enjoyed financial
support from the Natural Science Foundation of China (No.
20572099).
Supporting Information Available: Experimental procedures,
characterization data of all compounds, and the 13C NMR spec-
troscopy for the mechanism. This material is available free of charge
via the Internet at http://pubs.acs.org.
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JO0600914
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