Improved intermolecular hydride transfer using task-specific ionic liquid: A reasonable and environmentally benign approach for the synthesis of bioactive 2H-thiopyran derivatives

Article abstract of DOI:10.1080/17415993.2015.1077388

The present study describes, for the first time, the application of 1-n-butyl-3-methylimidazolium borohydride ([bmim]BH4) as task-specific ionic liquid for highly regioselective reduction of triarylthiopyrylium salts. This method furnished a straightforwa

Full text of DOI:10.1080/17415993.2015.1077388

Journal of Sulfur Chemistry
ISSN: 1741-5993 (Print) 1741-6000 (Online) Journal homepage: http://www.tandfonline.com/loi/gsrp20
Improved intermolecular hydride transfer
using task-specific ionic liquid: a reasonable
and environmentally benign approach for the
synthesis of bioactive 2H-thiopyran derivatives
Arash Mouradzadegun, Zeynab Najafi & Somayeh Elahi
To cite this article: Arash Mouradzadegun, Zeynab Najafi & Somayeh Elahi (2015):
Improved intermolecular hydride transfer using task-specific ionic liquid: a reasonable and
environmentally benign approach for the synthesis of bioactive 2H-thiopyran derivatives,
Journal of Sulfur Chemistry, DOI: 10.1080/17415993.2015.1077388
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Date: 31 October 2015, At: 06:32

Journal of Sulfur Chemistry, 2015
http://dx.doi.org/10.1080/17415993.2015.1077388
Improved intermolecular hydride transfer using task-specific
ionic liquid: a reasonable and environmentally benign approach
for the synthesis of bioactive 2H-thiopyran derivatives
Arash Mouradzadegun∗, Zeynab Najafi and Somayeh Elahi
Department of Chemistry, Faculty of Science, Shahid Chamran University, Ahvaz, Iran
(Received 11 June 2015; accepted 25 July 2015)
The present study describes, for the first time, the application of 1-n-butyl-3-methylimidazolium borohy-
dride ([bmim]BH4) as task-specific ionic liquid for highly regioselective reduction of triarylthiopyrylium
salts. This method furnished a straightforward route for the synthesis of valuable 2H-thiopyrans deriva-
tives, which are widely present as motifs in an assortment of biologically active molecules, in satisfactory
yields, and excellent conversions without any conventional catalyst and organic solvent.
X
X
N
N
BH4
H
S
S
ClO4
Y
Y
Y
Y
Major Product
X = H, Cl, NO2, CH3, OCH3
Y= H, OCH3
Keywords: thiopyrylium salts; 2H- and 4H-thiopyrans; hydride ion; task-specific ionic liquid; green
chemistry
1. Introduction
The ubiquitous use of heterocyclic compounds is undeniably due to their wide spectrum of
unique features and applications. In this context, six membered rings containing sulfur atom
are an intriguing class of heterocycles that exhibit a wide range of biological activities and
appear as key structural units in many important pharmaceuticals, natural products, and other
materials. Among this family of compounds, 2H-thiopyran derivatives have attracted a spe-
cial attention because they represent the core units of many naturally occurring compounds that
possess fungicidal and medicinal activities.[1–3]
*Corresponding author. Email: arash_m@scu.ac.ir
© 2015 Taylor & Francis

2
A. Mouradzadegun et al.
Although a variety of strategies have been reported for the synthesis of thiopyran derivatives,
many of these protocols are multi-step synthesis and suffer from several shortcomings such as the
use of toxic, expensive, and unrecyclable catalysts, poor product yields, low selectivity, difficult
work-up procedures, and the use of organic solvents, all of which render the approach unsatis-
factory from the standpoint of green chemistry.[4–6] Hence, further improvements are required
for the synthesis of these molecules.
Among the recent developments in environmentally benign synthetic methodologies, the
use of task-specific ionic liquids (TSILs) has become an active area of research. The merit
of the TSILs is due to their particular properties, such as undetectable vapor pressure, broad
liquid range as well as air and moisture stability.[7–12] TSILs also have the ability to dis-
solve a wide range of organic, inorganic, and polymeric materials. These features render them
efficient catalysts, solvents, and/or reagents, for conducting chemical transformations under
various conditions according to the principles of green chemistry. Consequently, as part of
our continuing effort to develop efficient and environmental-friendly transformations and to
apply them to the synthesis of biologically important molecules,[13–23] we developed a highly
practical, straightforward, and green approach to the synthesis of 2H-thiopyran derivatives via
highly regioselective reduction of thiopyrylium salts in the presence of a TSIL as a reagent
and solvent.
2. Results and discussion
A key principle of green chemistry is to design new synthetic procedures that eliminate the
generation of waste and that avoid the use of toxic and hazardous reagents, solvents, and cata-
lysts, thereby reducing costs and producing an environmentally benign process.[24–26] With this
principle in mind and considering the importance of 2H-thiopyran derivatives, herein, we decided
to investigate the formation of 2H-thiopyran via regioselective reduction of thiopyrylium salts in
the presence of [bmim]BH4 as a green and efficient reagent and medium.
To achieve this objective, initially, [bmim]Br was prepared according to a literature procedure,
starting from 1-bromo butane and 1-methylimidazole.[27] Subsequently, BH4 anion was incor-
porated into the ionic liquid along with the imidazolium group via a well-known ion exchange
reaction,[27] thereby providing a green and efficient reagent for achieving synthetic goals.
To identify and optimize the reaction conditions, triphenylthiopyrylium perchlorate (1a) was
chosen as the model compound and preliminary tests were carried out to survey the requisite
reaction conditions and establish the modifications required for this methodology (Scheme 1).
N
Ph
N
Ph
Ph
H
BH4
H
+
Ph
S
Ph
Ph
S
Ph
Ph
S
Ph
ClO4
(2a)
(3a)
(1a)
Scheme 1. Regioselective reduction of triphenylthiopyrylium salt with [bmim]BH4 as TSIL.
The reaction of the model compound with varying amounts of [bmim]BH4 was investigated.
As depicted in Table 1, the target reaction is favored by increasing the nucleophile/substrate ratio
as shown from the significant decrease in the reaction time. This is consistent with a bimolecular

Journal of Sulfur Chemistry
Table 1. Trend of the model reaction with different amounts of [bmim]BH4.
3
Entry
[Nu]/[Sub]
Time (min)
Yield (%)
1
2
3
1
1.2
1.5
70
40
35
95
95
72
Table 2. Regioselective reduction of triphenylthiopyrylium salt with
different methods.
Yield (%)
Entry
Reaction condition
2H-isomer
4H-isomer
Ref.
1
2
3
NaBH4/MeOH
NaBH4 /alumina
[BMIM]BH4
69
73
95
31
27
5
[4]
[6]
Present work
addition mechanism. The decrease in the yield (72%) by employing a ratio of 1.5 (Entry 3) can
probably be explained by the generation of other products. The best results were obtained when
1.2 mmol of nucleophile and 1 mmol of substrate were used (Table 1).
We also examined the effect of reaction temperature under otherwise similar experimen-
tal conditions. According to the TLC analysis, reaction did occur at r.t. to give a high yield
of 2H-thiopyran as major product ( >95%) along with poor yield of 4H-thiopyran ( <5%).
Raising the temperature reduced the selectivity of the reaction (2H-thiopyran = 60% and
2H-thiopyran = 40%).
In order to show the merit of this methodology for regioselective reduction of thiopy-
rylium salts, Table 2 compares our results obtained from the model reaction in the presence
of [bmim]BH4 with the results reported in the literature. The data in Table 2 clearly show that,
our procedure (Entry 3) has a greater efficiency and a higher regioselectivity than other methods,
and the thermodynamically more stable 2H-thiopyran was preferentially obtained >95%.
We believe that, the viscous reaction medium decreases the rate of reaction with thiopyrylium
salts with hydride ion. Thus, a noticeable amount of thiopyrylium ions remains intact and can
function as a catalyst in the equilibrium isomerization between the corresponding 2H- and 4H-
thiopyrans, thereby improving the regioselectivity of the reaction (Scheme 2). To the best of our
knowledge, this is the first reported reaction of TSIL as a nucleophile source for green synthesis
of 2H-thiopyrans via regioselective reduction of a thiopyrylium salt.
Ph
Ph
Ph
Ph
H
H
+
Ph
S
..
Ph
Ph
S
Ph
Ph
S
Ph
Ph
S
Ph
Scheme 2. Plausible mechanism for equilibrium isomerization between the 2H- and 4H-thiopyranes.
These extraordinary results prompted us to demonstrate the efficiency and the applicability
of the present method with a broader spectrum of substrates. We performed the reaction of
triarylthiopyrylium salts containing electron-withdrawing groups (such as halide and nitro) or
electron-donating groups (such as alkyl and methoxy) with hydride ion under our optimized
reaction conditions (Table 3).

4
A. Mouradzadegun et al.
Table 3. Reaction of thiopyrylium salts with [bmim]BH4 as a TSIL.
Yield (%)
2H-isomer (2)
Entry
A
Substrate
Time (min)
50
4H-isomer (3)
5
Ph
95
82
Ph
S
Ph
C6H4(p-OMe)
B
C
D
55
80
80
18
14
13
Ph
S
Ph
Ph
86
87
(Mep-O)C6H4
S
C6H4(p-OMe)
C6H4(p-Me)
(Mep-O)C6H4
S
C6H4(p-OMe)
C6H4(p-0Me)
E
F
82
45
81
70
19
30
(Mep-O)C6H4
S
C6H4(p-OMe)
C6H4(p-NO2)
Ph
Ph
S
Ph
C6H4(p-Cl)
G
30
76
23
S
Ph
Electron-donating substituents resulted in a decreased reaction rate (Entry B, Table 3), possibly
because these groups decrease the positive charge at the α-position of the heterocyclic ring.
Increasing the number of strongly electron-donating groups led to a longer reaction time (Entries
C–E, Table 3). In contrast, the presence of an electron-withdrawing group (Entries F and G,
Table 3) accelerated the reaction.
Overall, this protocol offers the possibility of considerably improved regioselectivity in com-
parison with conventional conditions. Furthermore, [bmim]BH4 is much less hazardous to
use than organic solvents. We believe that this method is a useful alternative to the existing
methodologies for the synthesis of these important compounds.
3. Conclusion
In summary, [bmim]BH4 was introduced as an efficient hydride donor for highly regioselective
reduction of triarylthiopyrylium salts. It plays the special dual role as the medium as well as
the reagent for the synthesis of 2H-thiopyrans in this reaction. This method offers marked
improvements with regard to operational simplicity, excellent conversions, and isolated yields
of products. It is also a green procedure avoiding hazardous organic solvents and toxic catalysts.

Journal of Sulfur Chemistry
5
4. Experimental
4.1. General
Chemicals were purchased from Fluka, Merck, and Aldrich chemical companies. Monitoring of
the reactions was accomplished by TLC. 1HNMR spectra were recorded on a 400 MHz Brucker
using CDCl3 as the solvent and TMS as the internal standard.
4.2. Synthesis
4.2.1. Synthesis of triarylthiopyrylium perchlorates
All triarylthiopyrylium perchlorates were synthesized by the method previously described.[6]
4.2.2. Synthesis of [bmim][BH4]
A mixture of 1-methylimidazole (4.1 g, 0.05 mol) and 1-bromobutane (6.85 g, 0.05 mol) in the
absence of solvent was heated with stirring at 80°C for 3 h. Then, the product was washed with
dimethyl ether and dried in vacuum to afford [bmim]Br. On completion, 50 ml of CH3CN and
2.28 g of NaBH4 (0.06 mol) were added in sequence. The mixture was stirred for 24 h at room
temperature. After filtering, the filtrate was evaporated in vacuum to give [bmim][BH4] (7.39
g, 0.048 mol, yield 96%) as a viscous liquid. All spectral data were compared with literature
values.[27]
4.3. General procedure
4.3.1. Reaction of thiopyrylium salts with [bmim]BH4
Reactions were typically carried out by the addition of 0.1 mol thiopyrylium salts to the 0.12 mol
[bmim]BH4 at room temperature. After the completion of the reaction, as monitored by the TLC,
products were extracted from a quenched reaction mixture with n-hexane.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
This work was supported by the Research Council at the Shahid Chamran University.
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