An easy and fast ultrasonic selective S-alkylation of hetaryl thiols at room temperature

Article abstract of DOI:10.1016/j.ultsonch.2010.03.002

A series of 2-alkylthio derivatives of hetaryl thiols were synthesized by selective S-alkylation with alkyl halides (bromides and iodides) with ultrasonic irradiation at room temperature. The reaction was found to be generally applicable to hetaryl thiol derivatives with different substituents in the aromatic nucleus and various alkyl halides. The reaction gives high to excellent yields of products with high purity.

Full text of DOI:10.1016/j.ultsonch.2010.03.002

Ultrasonics Sonochemistry 17 (2010) 783–788
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Ultrasonics Sonochemistry
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An easy and fast ultrasonic selective S-alkylation of hetaryl thiols
at room temperature
a
b
Todor Deligeorgiev a, Stefka Kaloyanova a, , Nedyalko Lesev , Juan J. Vaquero
*
a University of Sofia, Faculty of Chemistry, 1164 Sofia, Bulgaria
b Universidad de Alcalá, Facultad de Farmacia, 28871 Alcalá de Henares, Madrid, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 4 January 2010
Received in revised form 15 February 2010
Accepted 4 March 2010
Available online 12 March 2010
A series of 2-alkylthio derivatives of hetaryl thiols were synthesized by selective S-alkylation with alkyl
halides (bromides and iodides) with ultrasonic irradiation at room temperature. The reaction was found
to be generally applicable to hetaryl thiol derivatives with different substituents in the aromatic nucleus
and various alkyl halides. The reaction gives high to excellent yields of products with high purity.
Ó 2010 Elsevier B.V. All rights reserved.
Keywords:
Selective S-alkylation
Mercaptoazoles
Ultrasound irradiation
1. Introduction
2-Mercaptobenzothiazole (MBT), 2-mercaptobenzoxazole (MBO),
2-mercaptobenzimidazole (MBI) and S-alkylated heterocyclic
The use of ultrasound in chemistry (sonochemistry) offers the
synthetic chemist a method of chemical activation that has broad
applications and involves the use of relatively inexpensive equip-
ment. The driving force for sonochemistry is cavitation and so a
general requirement is that at least one of the phases of the reac-
tion mixture should be a liquid. The simple ultrasonic cleaning
bath is by far the most widely available and cheapest source of
ultrasonic irradiation in the chemical laboratory. Normal usage of
this equipment involves the immersion of standard glass reaction
vessels into the bath, which provides a fairly even distribution of
energy into the reaction medium [1].
Ultrasound irradiation has been increasingly used in organic
synthesis in the last three decades. In comparison with more tradi-
tional methods, this approach is more convenient and is easily con-
trolled. A large number of organic reactions have been carried out
and give higher yields, have shorter reaction times and milder con-
ditions under ultrasound irradiation [2–5]. Recently, we published
an easy and novel method for oxidation of isatins to isatoic anhy-
drides under ultrasonic irradiation with a urea hydrogen peroxide
complex [6].
derivatives represent an important group of compounds that have
been used to protect copper and copper alloys against corrosion
[7–9]. MBT is a vulcanization catalyst in the rubber industry [10]
and it plays a role in analytical chemistry as a reagent for cadmium,
as well as for the determination of copper, lead, bismuth, silver,
mercury, thallium, gold, platinum, and iridium [11]. MBT deriva-
tives were also found to be useful in the leather industry [12–14].
2-Thiosubstituted derivatives of MBT, MBO and MBI have many
applications based on their wide spectrum of biological activity;
for example, they were reported to possess antifungal, antibacte-
rial and antitumor activities [15,16]. These structural moieties
are found in numerous molecules of pharmaceutical interest
[17,18]. Furthermore, MBT and MBO derivatives are very useful
intermediates in the synthesis of cyanine dyes [19].
To the best of our knowledge there has yet to be a report on the
S-alkylation of hetaryl thiols at room temperature promoted by
ultrasound. We report here a highly reproducible and effectively
accelerated S-alkylation reaction under ultrasonic irradiation with
different alkyl halides under very mild conditions.
In our research program there is also some interest in improv-
ing the methodologies for the preparation of hetaryl sulfur deriva-
tives using alternative methods.
2. Results and discussion
The S-alkylation reaction of hetaryl thiols is known and has
been applied to different heterocycles. The most common alkyl-
ation procedure includes direct reaction with alkyl halides in
the presence of base (e.g. KOH, Et3N, NaOMe, K2CO3, pyridine)
* Corresponding author. Tel.: +359 2 8161 270; fax: +359 2 8625 438.
E-mail address: ohtsk@chem.uni-sofia.bg (S. Kaloyanova).
1350-4177/$ - see front matter Ó 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.ultsonch.2010.03.002

784
T. Deligeorgiev et al. / Ultrasonics Sonochemistry 17 (2010) 783–788
A
B
Y
N
A
B
Y
SH
SR
4-30
Z
N
Z
1a - 1n
SH
+
RX
SR
)))
2a - 2i
N
N
31
N
N
N
1o
CH3
N
CH3
N
acetone
(water or
32
SR
glycerol/water)
H3C
N
H3C
1p
N
SH
A, B = H, F, Cl, NH2, NO2, CH3
R = CH3, C2H5, C3H7, C4H9, CH2C6H5, CH2CH=CH2, C2H4CN, CH2CH2CH2N(CH3)2
X = Br, I Y = O, S, N Z = CH or N
Scheme 1. S-alkylation of hetarylthiols with alkyl halides.
Table 1
Structures of the starting compounds, alkyl halides and reaction products.
Starting compound
Alkyl halide
Product
Starting compound
Alkyl halide
Product
CH3I 2a
1g
2f
Cl
S
S
O
N
SH 1a
SCH3
4
19
SCH2CH CH2
N
N
S
1a
1a
1a
1a
1a
1a
CH3CH2I 2b
1g
1g
2g
Cl
O
SCH2CH3
5
20
21
SCH2CH2CN
N
S
N
CH3CH2CH2I 2c
CH3CH2CH2CH2I 2d
Cl
CH3
O
SCH2CH2CH3
6
.HI
2i
S(CH2)3N(CH3)2
ICH2CH2CH2N
N
S
N
CH3
2a
O2N
Cl
O2N
O
N
O
N
SCH2CH2CH2CH3
7
1h
22
SCH3
SH
N
S
2a
2a
2a
O
O
2e
Br H2C
SCH2
8
SH
SCH3
23
1i
N
S
N
N
Cl
BrCH2CH@CH2 2f
BrCH2CH2CN 2g
O
N
O
SCH2CH=CH2
9
SH
SCH3
24
1j
N
S
N
N
H3C
N
H3C
S
N
S
N
SCH2CH2CN 10
SH 1k
SCH3 25
SCH3 26
N
N
N
1a
BrCH2CH2Br 2h
2a
2a
Cl
Cl
S
S
S
N
S
11
SCH2CH2S
SH 1l
N
N
N
N
N
N
N
Cl
S
2a
Cl
S
1b
SH
SCH3
27
SH
12
SCH3
1m
N
H
N
H
N
N
F
2a
2a
2a
1m
1m
H3C
2f
F
N
S
S
1c
SCH2CH=CH2
SCH2CH2CN
SH
13
SCH3
28
N
N
H
N
N
H2N
2g
2a
H2N
S
N
S
N
1d
1e
SH
SH
14
SCH3
29
N
H
S
S
H3C
N
N
SCH3
15
SCH3
SH
30
1n
N
Cl
N
Cl
N
H
N
H
2a
2g
2a
2a
2a
O
N
O
SH
SCH3
N
SH 1f
SCH3 16
N
1o
31
N
N
CH3
N
CH3
1f
O
N
SCH2CH2CN 17
N
N
N
32
1p
H3C
SCH3
H3C
N
SH
Cl
Cl
O
O
1g
SH
18
SCH3
N
N

T. Deligeorgiev et al. / Ultrasonics Sonochemistry 17 (2010) 783–788
785
Table 2
Reaction of starting compounds with alkyl halides under different conditions.
Starting
compound
Alkyl halide
Solvent
t (°C)
Base
Time
Product structure
By-producta
–
1a
2g
Acetone
r.t.
(i-Pr)2NEt
1 h Stirring/without
sonication
S
SCH2CH2CN
N
b
10 9% yieldb
2 h Stirring/without
sonication
S
SCH2CH2CN
N
10 51% yield
3 h Stirring/without
sonication
S
SCH2CH2CN
N
10 66% yield
S
30 min Sonication
SCH2CH2CN
N
10 74% yield
S
1a
1f
2g
2g
Water
Acetone
70
56
NaOH
NEt3
30 min Sonication
35 min Sonication
S
SCH2CH2CN
S
N
N
CH2CH2CN
10 66–71% yield
33 4–7%
Water
Acetone
70
56
NaOH
NEt3
15 min Sonication
20 min Sonication
O
O
SCH2CH2CN
S
N
N
CH2CH2CN
17 60–69% yield
34 3–5%
1m
2f
Acetone
Water
56
NEt3
20 min Sonication
30 min Sonication
–
–
N
SCH2CH=CH2
N
H
28 95% yield
2g
100
NaOH
N
SCH2CH2CN
N
H
29 97% yield
a
Formation of N-alkylated products 33 and 34 was monitored by TLC and compared with samples obtained by standard procedures [33,37].
The product was isolated using the better solubility of the starting thiol in NaOH/H2O solution.
b
Y
Y
N
BrCH2CH2CN
derivatives (Table 1) was carried out with the corresponding alkyl
halides (Table 1) in acetone, water or mixtures of glycerol and
water. The reactions were carried out at room temperature in the
presence of N-diisopropylethylamine and required only short reac-
tion times to give high yields of the desired products (Table 3). The
reaction was found to be generally applicable to various alkyl bro-
mides and iodides.
S
S
N
H
CH2CH2CN
Y = O, S
Scheme 2. Synthesis of N-alkylated products.
Initially we studied the reaction progress by conventional con-
ditions – without using of ultrasound (Table 2, compound 10). The
desire product was isolated with lower yield, for longer reaction
time, in comparison with the same reaction carried out by
sonication.
[20–26]. This reaction can be carried out in aqueous media or an
appropriate solvent, at room temperature [19,27] or higher tem-
perature [19,28], for between 1 and 24 h [19,20,24,29] and gives
low [30] or excellent yields [10,19–21]. In some cases the N-
alkylated compounds are obtained as by-products [31–36].
In recent years the trend in organic synthesis research has been
increasingly to prevent pollution and to design environmentally
benign reaction conditions. For example, ionic liquids are used as
reusable reaction media in the selective S-alkylation of 2-merca-
ptobenzothia(oxa)zoles with alkylhalides [20]. Microwave-assisted
fly-ash-supported alkylation of 2-mercaptobenzothiazoles is also
known [10].
We became interested in a more detailed study of this reaction
and the opportunity to carry it out under milder conditions and
with reduced environmental impact. With this aim in mind we
investigated the use of ultrasound to assist the reaction.
A series of alkylthio derivatives of benzothia(oxa)azoles, benz-
imidazoles, 1,3-thiazolo(oxazolo)pyridines, pyrimidines and quin-
azolines were synthesized by an ultrasound-enhanced procedure
(Scheme 1). The selective S-alkylation of different hetaryl thiol
A literature survey revealed contradictory results concerning
the S-selectivity of the alkylation reaction in cases where the start-
ing compound contains an SH group and an N atom in the structure
[31,32,34–36]. Formation of the N-alkylated product under high
temperature conditions and reaction with alkenyl halides [32,33]
has been reported. For this reason, we examined various reaction
conditions and carried out some supplementary experiments.
S-alkylated and N-alkylated benzazoles were synthesized by stan-
dard procedures [33,37] and these compounds were used to mon-
itor the progress of ultrasound-promoted reaction by TLC (Scheme
2, Table 2). It was found that use of strong bases, like NaOH and
NEt3, and reaction temperatures over 55–60 °C led to concurrent
formation of small amounts of N-alkylated products – the level
of which increased on increasing the temperature and heating
time. The formation of the N-substituted product was not observed
in the case of 2-thiobenzimidazole even on using strong bases and
higher reaction temperatures [38].

786
T. Deligeorgiev et al. / Ultrasonics Sonochemistry 17 (2010) 783–788
Table 3
Optimization of the reaction conditions.
Product
Solvent (s)
Amount of solvent (ml)/(ratio)
Sonication time (min)
Isolated yield (%)
4
Acetone
Acetone
Water
Glycerol
Glycerol/water
Glycerol/water
10
5
10
10
10 (1:1)
10 (3:1)
5
83
95
81
78
84
80
<1
10
20
10
15
8
Acetone
Acetone
Water
10
5
10
5
1
30
75
82
95
10
12
Acetone
10
30
74
Acetone
Acetone
Water
10
5
10
15
5
20
65
86
94
13
18
20
25
31
Acetone
Acetone
10
5
15
5
59
77
Acetone
Water
5
10
2
10
99
90
Acetone
Acetone
10
5
25
25
60
87
Acetone
Acetone
10
5
20
20
58
71
Acetone
Acetone
10
5
25
25
45
73
Taking into account these results, and in order to avoid the for-
mation of N-alkylated products, N-diisopropylethylamine was
used as a base, which is know as a sterically hindered Hünig’s base
and affords only a proton separation.
The nature of the reaction medium was also investigated in
more detail. Three solvent systems were investigated – acetone,
water and mixtures of glycerol and water in different proportions.
The amount of solvent has an influence on the yields of products
(Table 3). In general, the rate of reaction increases as the solubility
of the starting compounds in the reaction medium improves. In or-
der to identify a synthetic procedure with reduced environmental
impact mixtures of water/glycerol were used as reaction media. It
was found that under these conditions the reaction mixture is a
suspension and, in some cases, this led to a decrease in the reaction
Table 4
S-alkylated products 4–32, sonication times, isolated yields, reported yields and melting points.
Product
Sonication time (min)
Isolated yield (%)
Yield (%) [conventional methods]
M.p. (b.p.)c/lit. M.p. (b.p.)d (°C)
4
5
6
7
8
9
1
95
90
79
84
82
92
74
81
86
77
79
79
97
77
99
99
87
91
96
79
91
67
71
93
96
99
89
73
88
83 [10]; 90 [20]; 85 [30]
46–47/46 [35]
23–24/26 [39]
Oil/134 (760 mm Hg) [30]
Oil/163–165 (760 mm Hg) [34]
37–38/39–40 [40]
Oil/126–128 (0.05 mm Hg) [41]
oil/oil [31]
138–139/139–140 [10]
92–94/95 [42]
70–71/70 [43]
102–104/105–107 [44]
75–76/76–78 [46]
Oil/8 [47]
45–46/43–44 [31]
88–90
46–48
128–130
Oil
189–192/193 [48]
86–88/89 [49]
61–62/63 [50]
115–118
20
20
15
1
81 [10]
63 [30]
65 [34]
83 [10]
71.4 [41]
39 [31]
85[10]
65 [42]
34 [43]
65 [45]
67 [42]
64 [30]
8.2 [31]
–
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
30
25
5
5
15
5
5
25
2
5
–
–
–
25
25
25
15
5
20
15
1
3
1
5
25
20
68.1 [47]
77 [48]
72 [51] – 91 [52]
–
81 [53]
94 [55]
18 [51]; 65–68 [57]
–
146–148
199–201/201–203 [54]
136–138/138.5–140 [56]
108–110
152–154
66–67/68 [58]
Oil/24 [60]
–
85 [59]
88 [60]
c
Experimental data.
[Literature data].
d

T. Deligeorgiev et al. / Ultrasonics Sonochemistry 17 (2010) 783–788
787
Table 5
1H NMR spectra of the unknown compounds and liquid products (oils).
Compound
1H NMR (250 MHz, CDCl3) d (ppm)
5
6
7
1.27 t (3H, –CH2CH3); 3.37 q (2H, –SCH2); 7.39–7.42 m (2H, ArH); 7.67 d (1H, ArH); 7.73 d (1H, ArH)
1.23 t (3H, –CH2CH2CH3); 1.96 m (2H, –CH2CH2CH3); 3.62 t (2H, –SCH2); 7.45–7.49 m (2H, ArH); 7.62 d (1H, ArH); 7.76 d (1H, ArH)
1.12 t (3H, –CH2CH2CH2CH3); 1.42 m (2H, –CH2CH2CH2CH3); 1.73 m (2H, –CH2CH2CH2CH3); 3.52 t (2H, –SCH2); 7.43–7.58 m (2H, ArH); 7.61 d (1H, ArH);
7.69 d (1H, ArH)
9
3.92 dt (2H, –SCH2); 5.19–5.23 m (1H, –CH@CH2); 5.34–5.42 m (1H, –CH@CH2); 5.96–6.09 m (1H, –CH@CH2); 7.22–7.26 m (1H, ArH); 7.43 dd (1H, ArH);
7.47 dd (1H, ArH)
10
18
19
3.07 t (2H, CH2CH2CN); 3.52 t (2H, CH2CH2CN); 7.26–7.37 m (2H, ArH); 7.52 d (1H, ArH); 7.63 d (1H, ArH)
2.73 s (3H, –SCH2); 7.22–7.26 m (1H, ArH); 7.42 dd (1H, ArH); 7.47 dd (1H, ArH)
3.87 dt (2H, –SCH2); 5.13–5.19 m (1H, –CH@CH2); 5.29–5.37 m (1H, –CH@CH2); 5.90–6.01 m (1H, –CH@CH2); 7.17–7.21 m (1H, ArH); 7.39 dd (1H, ArH);
7.42 dd (1H, ArH)
20
21
25
26
29
30
3.04 t (2H, –CH2CH2CN); 3.52 t (2H, CH2CH2CN); 7.24–7.30 m (2H, ArH); 7.46 d (1H, ArH)
2.02–2.10 m (2H, –CH2CH2CH2); 2.46 s (6H, N(CH3)2); 2.75 t (2H, NCH2); 3.31 t (2H, –SCH2) 7.15–7.19 m (2H, ArH); 7.38 d (1H, ArH)
2.84 s (1H, –SCH3); 8.03 d (1H, ArH); 8.51 d (1H, ArH)
2.82 s (1H, –SCH3); 7.98 d (1H, ArH); 8.49 d (1H, ArH)
2.89 t (2H, –CH2CH2CN); 3.43 t (2H, –SCH2); 7.23–7.27 m (2H, ArH); 7.43–7.49 m (2H, ArH); 9.47 brs (NH)
2.41 s (3H, –CH3); 2.73 s (3H, –SCH3); 6.99 dd (1H, ArH); 7.24–7.27 m (1H, ArH); 7.39 d (1H, ArH); 9.15 brs (1H, NH)
rate due to the low solubility of the starting compounds in water
and glycerol. The best yields and shorter sonication times to obtain
the desired products were achieved in acetone. It is worth noting
that, in the experiments carried out, the use of different kinds of
solvents did not give rise to significant changes in the yields and
that decreasing the amount of acetone led to increases in the reac-
tion rate (Table 3).
In conclusion, we have demonstrated that highly selective S-
alkylation of different hetaryl thiols can be performed with alkyl
halides under mild conditions in conjunction with ultrasonic irra-
diation at room temperature (Table 4). The method can be ap-
tion mixture was sonicated at a frequency of 40 kHz at room tem-
perature for a time ranging between less than 1 min up to 30 min
(Table 1). The product was precipitated by dilution with water
(50 ml) and isolated by filtration. In cases when the product pre-
cipitated as oil (5, 6, 7, 8, 9, 10, 16, 21, 32) the isolation was carried
out by extraction with CH2Cl2 (2 Â 10 ml). The combined organic
extracts were dried over Na2SO4 and the solvent was evaporated
under reduced pressure to give the desired product.
Acknowledgements
plied to the synthesis of
a variety of 2-alkylthio hetaryl
The work has been partly supported by the Bulgarian Scientific
Research Fund under Grant DO 02-82/2008, Project ‘‘Union” and by
the Spanish Ministerio de Ciencia e Innovación (project CTQ2008/
04313/BQU).
derivatives with different substituents in the aromatic nucleus
(see Table 5) and gives products with high purity and in short
reaction times – from less than 1 min up to 30 min. Minimal
amounts of solvents were used and the reaction procedure en-
sures the easy isolation of the products.
A selective S-alkylation procedure that is applicable to wide
range of hetaryl thiol derivatives has been developed. This ap-
proach ensures energy efficiency, mild work-up conditions, easy
isolation, good to high yields and high purity of the products in
short reaction times.
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3.1. General procedure for S-alkylation of hetarylthiols by a
sonochemical method
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