Mol Divers (2009) 13:57–61
DOI 10.1007/s11030-008-9098-4
SHORT COMMUNICATION
Ionic liquid promoted preparation of 4H -thiopyran
and pyrimidine nucleoside-thiopyran hybrids through one-pot
multi-component reaction of thioamide
Xinying Zhang · Xiaoyan Li · Xuesen Fan ·
Xia Wang · Dongfang Li · Guirong Qu ·
Jianji Wang
Received: 12 August 2008 / Accepted: 4 November 2008 / Published online: 9 December 2008
© Springer Science+Business Media B.V. 2008
Abstract One-pot multi-component reactions of aldehydes,
cyanothioacetamide and malononitrile promoted by ionic liq-
uid proved to be an efficient way for the synthesis of thiopyran
derivatives. Without any added catalyst, both aromatic and
aliphatic aldehydes participated in this reaction smoothly.
As an application of this method, a pyrimidine nucleoside-
thiopyran chimera with potential biological activities was
obtained in high yield from 5-formyl-2’-deoxyuridine. In
addition, the ionic liquid used can be easily recovered and
effectively reused for at least 5 times.
Keywords 4H-thiopyran · Pyrimidine nucleoside
derivatives · Multi-component reaction · Ionic liquid ·
Thioamide
Abbreviations
ILs Ionic liquids
[bmim]BF4 1-Butyl-3-methylimidazolium
tetrafluoroborate
r. t. Room temperature
THF Tetrahydrofuran
VOC Volatile organic compound
m. p. Melting point
Electronic supplementary material The online version of this
article (doi:10.1007/s11030-008-9098-4) contains supplementary
material, which is available to authorized users.
X. Zhang (B) · X. Li · X. Fan (B) · X. Wang · D. Li · G. Qu ·
J. Wang
Henan Key Laboratory for Environmental Pollution Control,
School of Chemistry and Environmental Sciences, Henan Normal
University, Xinxiang, Henan 453007, People’s Republic of China
e-mail: xyzh518@sohu.com
X. Fan
e-mail: xuesen.fan@yahoo.com
Introduction
Recently there is an increasing recognition of the thioamide
group as a useful moiety in organic synthesis, and compre-
hensive studies of the use of thioamides in organic synthesis,
especially in the synthesis of heterocyclic compounds, have
been published [1–4].
Thiopyrans are used as key units in medicinal chemistry
and as versatile building blocks in organic synthesis [5,6].
For example, it has been reported that thiopyrans were widely
used in the construction of analogues of natural products with
various biological activities, such as tetrahydrodicranenone
B [7,8], serricornin [9], thromoboxanes [10,11], and cyclo-
pentanoids [12]. As a result, a great deal of efforts has been
drawn to develop new and efficient synthetic routes to thio-
pyrans [13–26]. However, these reported procedures are not
fully satisfactory with regard to operational simplicity, cost
of reagents, isolated yields, or reaction conditions. To match
the increasingly synthetic and medicinal demands for thio-
pyran derivatives, it is still of significant interest to explore
novel and efficient synthetic approaches for such thio-het-
erocycles.
In the past decades, one of the hot topics in the field
of green chemistry is the introduction and application of
ionic liquids (ILs) in organic synthesis. With the unique
properties of ILs, such as good solvating capability, wide
liquid range, negligible vapor pressure, and ease of recy-
cling, IL technology offers a new and environmentally benign
approach toward organic synthesis. Recently, how to use ILs
to promote the selectivity of various organic reactions and to
dramatically influence the outcome of chemical reactions,
especially the multi-component ones, have also attracted
much attention [27].
In this regard, our own interest has focused on the develop-
ment of novel methods for the preparation of various
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R
also noted that temperatures above 80 ◦ C did not result in
NH2 [bmim]BF4 NC CN
R-CHO + NC CN + NC significant improvements.
S 80 °C H2N S NH 2 With the above results in hand, we initiated the alde-
1 2 3 4
hyde substrate scope (Scheme 1). The results (showed in
Scheme 1 Preparation of thiopyrans 4 in [bmim]BF4 Table 2) indicated that aromatic aldehydes bearing either
electron donating or electron withdrawing functional groups
were able to participate in this reaction smoothly and pro-
biologically important heterocyclic compounds via multi- duced thiopyrans 4 in good yields (Table 2, entries 1 ∼ 8).
component reactions by using ionic liquids as novel reaction In addition, with aliphatic aldehydes as substrates, the desired
media and promoters [28–31]. Here we report the results thiopyran derivatives could also be obtained but in moderate
of our investigation that enabled an alternative preparation yields (Table 2, entries 9 ∼ 10).
of thiopyrans (4) from aldehyde (1), malononitrile (2) and As mentioned earlier, there are several methods reported
cyanothioacetamide (3) in an ionic liquid, 1-butyl-3-methyl- [13–26] for the synthesis of thiopyrans 4. However, with
imidazolium tetrafluoroborate ([bmim]BF4 ), as a recyclable these methods, thiopyrans were usually obtained via the reac-
solvent and promoter without the need of a catalyst tion of previously made arylidenemalononitrile with 2-cy-
(Scheme 1). anothioacetamide under the catalysis of N-methylmorpho-
line or other basic promoters. Tedious preparative proce-
dures are usually required and the strong basic conditions
employed could be incompatible with other functionalities
Results and discussion present in the substrates. Recently, we developed a novel and
efficient MWI-promoted one-pot preparation of thiopyrans
Initially, 4-nitrobenzaldehyde (1a) was used as model directly from aldehydes, malononitrile and cyanothioaceta-
substrate and its reaction with malononitrile (2) and cya- mide without using a catalyst [23]. However, good results
nothioacetamide (3) in [bmim]BF4 at different temperatures were only obtained with aromatic aldehyde substrates. With
was studied. aliphatic aldehydes as substrates, the reactions afforded mix-
Firstly, a mixture of 1a, 2 and 3 in [bmim]BF4 was stirred tures of unidentified products. Considering all the limitations
at room temperature and the reaction was monitored by TLC. imposed by the above methods, the procedure described in
It turned out that the reaction did occur at r. t. but underwent this report may serve as a versatile alternative for the prepa-
slowly. After 6 h, the reaction was still incomplete. At this ration of thiopyran derivatives.
stage, the reaction was interrupted and the solid product was Recently, we also pursued a chemistry-driven strategy for
collected by filtration. Spectra data of 1 H NMR and 13 C NMR the discovery of lead nucleoside molecules with
together with MS results indicated that the product is 4a with antiviral activity [32–35]. Our approach to new antiviral can-
a yield of 55 %. didates was guided by the following considerations: firstly,
To improve this reaction in terms of reaction time and since the privileged structure of nucleosides has led to a vari-
yield, it was run again at higher temperatures (Table 1). It ety of efficacious antiviral agents, the nucleosides scaffold is
turned out that higher temperatures not only gave better yields an excellent point of departure in the search for new antiviral
but also resulted in much less reaction times. As shown in drugs; secondly, other privileged molecular scaffolds, like
Table 1, when the reaction was run at 80 ◦ C, it was complete thiopyran derivatives, have spawned a significant number of
in 20 min and the yield was as high as 95%. It should be drugs and can also be used to discover molecular “master-
keys”; thirdly, 5-formyl-2’-deoxyuridine is a powerful syn-
thon for the generation of novel nucleoside structures that can
Table 1 Studies on the effect of reaction temperature on the yield of be employed in multi-component reactions to generate chem-
4a∗ ical diversity. As part of our ongoing efforts, we are interested
Entry Temperature (◦ C) Reaction time (h) Isolated yield (%) in applying the new methodology described in this article to
prepare a novel pyrimidine nucleoside–thiopyran hybrids to
1 r.t. 6 55
get new chemical entities with synergic effects on their bio-
2 40 3 62
logical activities.
3 60 1 82
Thus, a mixture of 5-formyl-2’-deoxyuridine (1k or1l,
4 80 0.3 95 Scheme 2), 2 and 3 was stirred in [bmim]BF4 at 80◦ C. As
5 100 0.3 94 expected, the reaction of 1k or 1l with 2 and 3 underwent
6 120 0.3 86 smoothly and gave the desired nucleoside-thiopyran chimera
∗ Reaction conditions: 1 mmol of 1a, 1 mmol of 2, 1 mmol of 3 and 4k or 4l in yields of 90% and 91%, respectively (Table 2,
1 mL of [bmim]BF4

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Table 2 Preparation of
thiopyrans 4 in [bmim]BF4 at Entry Aldehyde R Reaction time (h) Product Yield (%)
80◦ C
1 1a p-NO2 C6 H5 0.3 4a 95
2 1b m-NO2 C6 H4 0.5 4b 92
3 1c p-ClC6 H4 1 4c 93
4 1d p-BrC6 H4 1 4d 93
5 1e o-FC6 H4 1 4e 91
6 1f C6 H5 3 4f 92
7 1g p-CH3 C6 H4 2 4g 94
8 1h 4-OH-3-CH3 OC6 H3 4 4h 85
9 1i CH3 CH2 CH2 2 4i 70
10 1j CH3 (CH2 )4 CH2 4 4j 40
11 1k O 4 4k 90
HN
O N
AcO
O

OAc

12 1l O 3 4l 91
HN
O N
HO
O

OH

Scheme 2 Preparation of O O
CHO
pyrimidine nucleoside-thiopyran HN HN N OR1
O
hybrids O N [bmim]BF4 O
NH2
R1O + NC CN + NC CN OR1
O NC
S
OR1 H2N S NH2
1 2 3 4
1k, 4k: R1 = OAc; 1l, 4l: R1 = OH.

Table 3 Preparation of 4a in
Entry Solvent Temperature (◦ C) Product Reaction time (h) Yield (%)
different solvents*
1 [bmim]BF4 80 4a 0.3 95
2 Methanol Reflux 4a 4 81
3 Ethanol Reflux 4a 5 78
* Reaction conditions: 1 mmol 4 THF Reflux 4a 6 70
of 1a, 2 and 3 respectively, 1 mL
5 Benzene Reflux 4a 12 42
of IL or 4 mL of VOCs

entries 11 ∼ 12). The structures of 4k and 4l were fully elu-
cidated by their NMR Spectra, MS and elemental analysis.
As mentioned earlier, one of the goals in the use of ionic
liquids is to identify and exploit advantages these can offer
over conventional organic solvents besides a greener nature.
It has been documented that, compared with classical organic
solvents, reactions carried out in ionic liquids often offer
enhanced reactivity, better yields and simpler operational
process. This is demonstrated by comparing [bmim]BF4 with
several conventional volatile organic solvents including
methanol, ethanol, benzene and THF.
It is shown in Table 3 that from all the solvents used,
[bmim]BF4 gave the best result in terms of both reaction
time and product yield. Moreover, using [bmim]BF4 as reac-
tion medium made the separation process much easier since
in [bmim]BF4 product 4a is produced as a solid and can
be isolated with high purity by simple filtration. On the other
hand, with methanol, ethanol or THF as the reaction medium,

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Table 4 Studies on the recovery and reuse of [bmim]BF4
Round Time (h) Temperature (◦ C) Yield (%) IL recovery
(w/w %)
1 0.3 80 95 99
2 0.3 80 96 98
3 0.3 80 94 98
4 0.3 80 92 95
5 0.3 80 90 93
the reactions need much longer reaction times and the yields
are much lower (Table 3, entries 2–4); and in benzene the
reaction was incomplete even after 12 h (Table 3, entry 5).
Finally, the recovery and reuse of solvent and/or catalyst
are highly preferable in terms of green synthetic process. We
continued our research in this regard by studying the reuse
of [bmim]BF4 using 4-nitrobenzaldehyde (1a), 2 and 3 as
model substrates (Scheme 1). Upon completion of the con-
densation process, the precipitated products were collected
by filtration and rinsed with water and cold ethanol. The fil-
trate was concentrated under reduced pressure, washed with
ether and then dried at 100 ◦ C for several hours to recover
the ionic liquid. The recovered [bmim]BF4 was then ana-
lyzed by 1 H NMR finding no differences before and after use.
Further studies also showed that the recovered [bmim]BF4
could be successively recycled and used in subsequent reac-
tions without obvious loss in its efficiency (Table 4). It should
also be noted that even in the 5th round, reuse of [bmim]BF4
recovered from the fourth round still produced the expected
product with good yield (Table 4, entry 5).
In conclusion, ionic liquid promoted one-pot multi-com-
ponent reactions of aldehydes, cyanothioacetamide and
malononitrile and proved to be an efficient medium for the
synthesis of thiopyran derivatives without any added catalyst.
Compared with conventional organic solvents, the use of IL
endowed the methodology advantages such as high yield,
mild conditions, simple procedure and good selectivity. This
novel procedure was successfully applied in the preparation
of a nucleoside-thiopyran chimera with potential antiviral
activities. In addition, the ionic liquid used can be easily
recovered and effectively reused for at least 5 more times
without any significant loss of efficiency. The test of 4k and
4l as potential antivirals against herpes and other kinds of
viruses and the search for the application of the novel process
presented herein in organic synthesis are currently underway
and the results will be reported in due course.
Acknowledgements This work was financially supported by the
National Natural Science Foundation of China (No. 20772025) and Pro-
gram for Science & Technology Innovation Talents in Universities of
Henan Province (No. 2008HASTIT006) and Department of Education
of Henan Province (No. 2008A150013).
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Mol Divers (2009) 13:57–61
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