Catalyst-free and base-free water-promoted SNAr reaction of heteroaryl halides with thiols

Article abstract of DOI:10.1055/s-0029-1216644

A simple and efficient route for the synthesis of biaryl sulfides have been developed in aqueous medium under base- and catalyst-free conditions. A wide variety of heteroaryl halides and thiols underwent S_NAr reaction to provide diaryl sulfides in good to excellent yields. The remarkable key features of the reaction include the use of water as an inexpensive and environmentally benign reaction medium, absence of any additional reagent or catalyst, and easy isolation of the products. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1216644

1732
PAPER
Catalyst-Free and Base-Free Water-Promoted SNAr Reaction of Heteroaryl
Halides with Thiols
S
A
r
Reaction of
.
H
eteroaryl
Halides with
T
r
hiols in
e
W
ater edhar,* P. Surendra Reddy, M. Amarnath Reddy
N
Inorganic and Physical Chemistry Division, Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax +91(40)27160921; E-mail: sreedharb@iict.res.in
Received 12 January 2009; revised 22 January 2009
most no waste and is industrially favorable due to its cost
Abstract: A simple and efficient route for the synthesis of biaryl
sulfides have been developed in aqueous medium under base- and
catalyst-free conditions. A wide variety of heteroaryl halides and
thiols underwent SNAr reaction to provide diaryl sulfides in good to
excellent yields. The remarkable key features of the reaction in-
clude the use of water as an inexpensive and environmentally be-
nign reaction medium, absence of any additional reagent or catalyst,
and easy isolation of the products.
effectiveness.8
Initial attempts were focused on exploring the influence of
different solvent systems on SNAr reaction of 2-bromopy-
ridine and thiophenol as the model substrates at 100 °C
under base and catalyst-free conditions. The reaction was
monitored by GC and the results are shown in Table 1.
Key words: heteroaryl halides, thiophenol, SNAr reaction, water,
2-thiopyridines
Table 1 Reaction of 2-Bromopyridine with Thiophenola
HS
+
Functionalization of nitrogen heterocycles constitutes a
powerful tool for the synthesis of natural products and
bioactive substances.1 According to a recent MDL Drug
Data Report pyridines are the most common heterocycles
in pharmaceutically active compounds.2 2-Thiopyridines
are useful starting materials for the preparation of unique
building blocks in the synthesis of new drug candidates.3
The most commonly employed methodologies for the
synthesis of thioethers use harsh coupling conditions,
harmful metal catalyst, bases and highly polar solvents.4
Moreover, these synthetic methods frequently involve
elaborate workup procedures and operate for a relatively
narrow range of substrates. Direct nucleophilic aromatic
substitution (SNAr) provides an alternative approach to
these syntheses, but also suffers from the use of strong
bases and polar organic solvents.5 Though, water is the
most abundant and environmentally friendly solvent in
nature, its use in organic chemistry is limited because of
the insolubility of a large number of reactants or the reac-
tion intermediates formed during the reaction.
N
Br
N
S
Entry
Solvent
1,4-dioxane
NMP
Time (h)
Yield (%)b
1
2
3
12
12
14
33
DMSO
12
24
23
34
4
DMF
12
24
43
52
5
6
7
DMF–H2O (3:1)
24
8
67
H2O
–
87, 81c
12
24
a Reaction conditions: 2-bromopyridine (1 mmol), thiophenol (1.2
mmol), solvent (5 mL)
b GC yields.
c With 10 mmol of 2-bromopyridine.
However, in certain situations,6 the special physical and
chemical properties of water, such as high dielectric con-
stant, heat capacity, hydrophobic interactions between re-
actants, hydrogen bond formation with reactants, and acid
or base characters may be utilized to promote organic re-
actions.
Among the different polar aprotic solvents screened, 1,4-
dioxane, NMP, and DMSO gave the product, 2-phenylsul-
fanylpyridine, in 10–30% yield and the reaction in DMF
gave the product in 50% yield after 24 hours (Table 1, en-
tries 1–4). The reaction using a mixture of DMF–H2O
(3:1) afforded the product in 67% yield after 24 hours
(Table 1, entry 6). The presence of even trace amount of
the highly polar protic solvent, water, resulted in compar-
atively higher yield suggesting the unique role of water in
promoting the reaction. It was observed that none but wa-
ter (5 mL) alone as the reaction media facilitates this reac-
tion with formation of the product in quantitative yield in
shorter reaction time. Therefore, the amount of water used
as the solvent for the reaction is also found to be important
for the high yield of the product.
In continuation of our interest in organic reactions in wa-
ter,7 herein we report the SNAr reaction of heteroaryl ha-
lides with thiols in water without the use of any metal
catalyst and base, leading to an easy and highly efficient
synthesis of 2-thiopyridine compounds. This elegant syn-
thetic protocol is environmentally benign, producing al-
SYNTHESIS 2009, No. 10, pp 1732–1738
x
x.
x
x
.
2
0
0
9
Advanced online publication: 14.04.2009
DOI: 10.1055/s-0029-1216644; Art ID: Z00509SS
© Georg Thieme Verlag Stuttgart · New York

PAPER
SNAr Reaction of Heteroaryl Halides with Thiols in Water
1733
Table 2 SNAr Reaction of 2-Halopyridines with Different Thiolsa
To test the feasibility and practicable applicability, a reac-
tion on large scale (10 mmol) was conducted in water (50
mL) at 100 °C; 85% conversion was observed after eight
hours by GC and the product, 2-phenylsulfanylpyridine,
was isolated in 81% yield after purification by column
chromatography (Table 1, entry 6). As the yields of the
products obtained in ordinary tap water and distilled water
were comparable, all the reactions were carried out in tap
water so that the consumption of energy and efforts need-
ed to prepare distilled water can be avoided. However,
only trace amount of product was formed when the reac-
tion was performed under neat conditions (Table 1, entry
7). The major drawback of water as a solvent is the low
solubility of organic substrates in water, which is avoided
since the above reactions are performed at 100 °C. The di-
electric constant of ambient water is 80 and this number
quickly reduces to 55 at 100 °C, which implies that water
is more like a polar organic solvent at high temperature.
Therefore, some substrates that were originally insoluble
in water, dissolve at elevated temperatures and undergo
reaction.9
Entry Halopyridine
1
Thiol
Time (h) Yield (%)b
HS
92 (X = Br)
6
86 (X = Cl)
N
X
HS
HS
2
3
8
8
87
91
N
Cl
N
Cl
HS
HS
4
5
6
7
8
8
8
8
8
8
90
85
82
80
75
N
N
N
N
N
Cl
Cl
Cl
Cl
Cl
MeO
HS
Cl
Br
Under the optimized reaction conditions, the scope of the
reaction was explored with structurally and electronically
diverse heteroaryl halides with a wide range of thiols. Dif-
ferent 2-halopyridines were subjected to SNAr reaction
with a variety of 2-, 3- and 4-substituted thiophenols and
the results are presented in Table 2. In general, 2-bro-
mopyridine was more reactive than 2-chloropyridine and
gave the corresponding product in higher yield (entry 1).
The presence of methyl substitution at the 4 position of the
pyridine ring in 2-halopyridines hampered the reaction
and led to the formation of the products in lower yields
and also required longer reaction times (entries 9–11). 3-
Chloro- and 3-cyano-substituted 2-chloropyridines were
highly reactive and the desired products were obtained in
good yields (entries 12–16). To our surprise, we observed
that the reaction of thiophenol with 2-chloro-5-nitropyri-
dine gave the product in excellent yield within two hours
(entry 17). Furthermore, the SNAr reaction proceeded se-
lectively at position 2 in 2,3-dichloropyridine (entries 12–
14). It was found that the rate of the reaction of various
thiols with 2-halopyridines was found to be influenced by
the nucleophilicity of the thiols. Among the thiols used,
thiophenol and 4-chloro- or 4-bromo-substituted thiophe-
nols were less reactive than methoxy- and 4-methyl-sub-
stituted thiophenols. However, no reaction was observed
with the arylalkanethiols (e.g., benzylmethanethiol) and
alkanethiols (e.g., ethanethiol). It was also observed that
in all these reactions, there was no formation of any side
products.
HS
HS
HS
58 (X = Br)
51 (X = Cl)
9
24
N
N
X
HS
HS
10
11
24
24
61
65
Br
Cl
N
N
N
N
N
N
Br
Cl
HS
HS
HS
HS
HS
12
13
14
15
16
6
6
6
2
2
90
90
90
95
90
Cl
Cl
Cl
Cl
Br
Cl
CN
The reaction methodology was further extended to other
heterocycles such as 2-chloroquinoline and isoquinolines
(Table 3). Different substituted thiophenols were equally
effective as substrates for the reaction to generate SNAr
products in good to excellent yields (entries 1–5).
Cl
CN
Cl
Synthesis 2009, No. 10, 1732–1738 © Thieme Stuttgart · New York

1734
B. Sreedhar et al.
PAPER
Table 2 SNAr Reaction of 2-Halopyridines with Different Thiolsa
Br
S
HS
K2CO3 (1 equiv)
+
Time (h) Yield (%)b
93
H2O, 100 °C, 48 h
Entry Halopyridine
Thiol
N
N
HS
O2N
56%
17
2
Scheme 1
N
Cl
a Reaction conditions: 2-halopyridine (1 mmol), thiol (1.2 mmol),
H2O (5 mL), and reflux for an appropriate time.
b Isolated yields.
Table 4 SNAr Reaction of Heteroaryl Halides with Different Thiolsa
Time (h) Yield (%)b
Entry Heteroaryl halide Thiol
N
Cl
HS
1
2
2
2
90
96
Table 3 SNAr Reaction of 2-Chloroquinolines with Different Thiolsa
N
HS
Entry Quinoline
Thiol
Time (h) Yield (%)b
N
HS
N
Cl
Cl
1
2
2
2
2
91
83
90
96
HS
HS
N
Cl
3
4
4
1
81
90
N
N
HS
2
3
4
N
Ph
Ph
Cl
Cl
HS
HS
N
N
Cl
N
HS
5
4
92
N
N
H
HS
5
4
78
N
a Reaction conditions: heteroaryl halide (1 mmol), thiol (1.2 mmol),
Cl
H2O (5 mL).
b Isolated yields.
a Reaction conditions: 2-chloroquinoline (1 mmol), thiol (1.2 mmol),
H2O (5 mL).
b Isolated yields.
The possible role of water in promoting the reaction is
proposed by the mechanism depicted in Scheme 2. The
faster rate of reaction in water compared to other solvents
and neat conditions indicates that water plays a specific
role in promoting the SNAr reaction. Water possibly ex-
hibits ampiphilic dual activation catalysis by cooperative
hydrogen bond formation with the nitrogen atom of ha-
lopyridine and the SH hydrogen of thiophenol (I) fol-
lowed by addition of the nucleophile to the substrate to
form a 1:1 s-adduct (II) which, on elimination of the leav-
ing group, gives SNAr product. Hydrogen bond formation
between oxygen atom of the water and the sulfhydroxyl
hydrogen of the thiol increase the nucleophilicity of the
sulfur atom of the thiol6d and coordination of the ring ni-
trogen atom with the hydrogen10 stabilizes the intermedi-
ate s adduct to a greater extent.
Furthermore, as shown in Table 4, the SNAr reaction using
different thiophenols was also successful with other het-
erocycles including pyrimidines, purines, and quinazo-
lines. Excellent results were obtained in each case. The
reactions were complete within three hours affording 85–
95% yield of the corresponding products. Both 2-chloro-
quinoxaline and 2-chloropyrimidines underwent the de-
sired reaction to furnish the SNAr products in good yields
(Table 4, entries 1 and 2). Amexol reacted even more fast-
er to give desired products in excellent yields (Table 4,
entries 3 and 4). It was found that this method could be
readily applicable to 6-chloropurines (Table 4, entry 5).
Even though 3-halopyridines proved to be unsuitable sub-
strates and failed to give the desired products when the re-
action was carried out under the above optimized reaction
conditions, but in the presence of one equivalent of K2CO3
the desired product was obtained in 56% yield
(Scheme 1).
In summary, a simple and efficient base and catalyst-free
synthesis of diaryl sulfides in good to excellent yields
have been described in aqueous medium. Water promotes
the reaction by dual activation catalysis. In light of its op-
erational simplicity, easy purification procedures, high
yields, ability to proceed without any catalyst or addition-
al reagents, general applicability to a wide range of sub-
Synthesis 2009, No. 10, 1732–1738 © Thieme Stuttgart · New York

PAPER
SNAr Reaction of Heteroaryl Halides with Thiols in Water
1735
13C NMR (75 MHz, CDCl3): d = 21.3, 119.5, 120.9, 127.2, 130.4,
135.2, 136.6, 139.4, 149.4, 162.1.
X
N
ESI MS: m/z = 202 (M + H), 224 (M + Na).
+
HSPh
S
H
N
N
X
S
O
H
Ph
2-m-Tolylsulfanylpyridine (Table 2, Entry 3)
H
I
Colorless liquid.
IR (neat): 2923, 1571, 1448, 1415, 1122, 758 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.37 (s, 3 H), 6.85 (d, J = 8.0 Hz,
1 H), 6.91 (ddd, J = 0.9, 4.8, 7.4 Hz, 1 H), 7.18 (d, J = 7.6 Hz, 1 H),
7.27 (d, J = 9.0 Hz, 1 H), 7.36 (s, 1 H), 7.38–7.41 (m, 2 H), 8.24 (br
d, J = 4.8 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 21.2, 119.6, 121.2, 129.4, 129.9,
130.6, 131.9, 135.5, 136.6, 139.5, 149.5, 167.8.
– X
X
S
N
Ph
H
H
O
II
Scheme 2
ESI MS: m/z = 202 (M + H).
2-o-Tolylsulfanylpyridine (Table 2, Entry 4)
Colorless liquid.
IR (neat): 2983, 1573, 1448, 1417, 1120, 755 cm–1.
strates, and environment friendly conditions, this protocol
is indeed superior to the existing methods.
1H NMR (300 MHz, CDCl3): d = 2.40 (s, 3 H), 6.69 (d, J = 8.0 Hz,
1 H), 6.93 (ddd, J = 1.0, 4.8, 7.4 Hz, 1 H), 7.19–7.25 (m, 1 H), 7.31–
7.33 (m, 2 H), 7.36–7.42 (m, 1 H), 7.58 (d, J = 7.4 Hz, 1 H), 8.37
(br d, J = 5.1 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 20.8, 119.5, 120.3, 127.0, 129.8,
130.9, 136.5, 136.6, 142.7, 149.5, 161.2.
All chemicals were purchased from Sigma-Aldrich and S.D. Fine
Chemicals, Pvt. Ltd. India and used as received. ACME silica gel
(100–200 mesh) was used for column chromatography and TLC
was performed on Merck precoated silica gel 60 F254 plates. All the
other chemicals and solvents were obtained from commercial
sources and purified using standard methods. Melting points were
measured in open capillary tubes and are uncorrected. The IR spec-
tra of all compounds were recorded on a PerkinElmer, Spectrum
GX FTIR spectrometer using KBr pellet method. The IR values are
ESI MS: m/z = 202 (M + H).
2-(2-Methoxyphenylsulfanyl)pyridine (Table 2, Entry 5)
Colorless liquid.
IR (KBr): 2836, 1574, 1477, 1274, 1122, 755 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.81 (s, 3 H), 6.80 (d, J = 8.0 Hz,
1 H), 6.88–7.03 (m, 3 H), 7.33–7.45 (m, 2 H), 7.52–7.59 (m, 1 H),
8.36 (br d, J = 5.1 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 55.8, 111.5, 119.5, 120.7, 121.3,
131.2, 136.4, 136.4, 136.9, 149.3, 159.6, 160.7.
1
reported in reciprocal centimeters (cm–1). The H and 13C NMR
spectra were recorded on a Varian Gemini 200 MHz, Bruker
Avance 300 MHz spectrometer. Chemical shifts (d) are reported in
ppm, using TMS (d = 0) as an internal standard in CDCl3 or DMSO-
d6. ESI mass spectra were recorded on a Finnigan LCQ Advantage-
max spectrometer. EI mass spectra were recorded on a GC-MS
QP2010 Plus (Shimadzu).
SNAr Reaction of Heteroaryl Halides; General Procedure
A suspension of heteroaryl halide (1 mmol) and thiol (1.1 mmol) in
pure H2O (5 mL) was added to a 50 mL round-bottomed flask and
stirred at 100 °C for the indicated time (Tables 2– 4). After comple-
tion of the reaction (as indicated by TLC), the product was extracted
with EtOAc (3 × 10 mL), and the combined organic extracts were
dried (Na2SO4). The solvent was removed under reduced pressure
to give the crude product, which was purified by column chroma-
tography on silica gel using hexanes–EtOAc mixture as eluent.
ESI MS: m/z = 216 (M – 1).
2-(4-Chlorophenylsulfanyl)pyridine (Table 2, Entry 6)
Light yellow liquid.
IR (KBr): 3044, 1551, 1443, 1083, 816, 743 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.93 (d, J = 8.0 Hz, 1 H), 6.98
(ddd, J = 0.9, 4.8, 7.4 Hz, 1 H), 7.37 (d, J = 8.3 Hz, 2 H), 7.42–7.48
(m, 1 H), 7.49 (d, J = 8.3 Hz, 2 H), 8.37 (br d, J = 4.8 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 120.2, 121.6, 129.8, 135.3, 136.0,
2-Phenylsulfanylpyridine (Table 2, Entry 1)
Colorless liquid.
IR (neat): 3050, 1573, 1446, 1417, 1121, 752 cm–1.
136.7, 149.7, 160.4.
ESI MS: m/z = 222 (M + H).
1H NMR (300 MHz, CDCl3): d = 6.86 (d, J = 7.5 Hz, 1 H), 6.96
(ddd, J = 1.1, 4.8, 7.4 Hz, 1 H), 7.37–7.42 (m, 4 H), 7.55–7.60 (m,
2 H), 8.39 (br d, J = 4.5 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 119.8, 121.3, 129.0, 129.6, 131.1,
134.9, 136.6, 149.5, 161.5.
2-(4-Bromophenylsulfanyl)pyridine (Table 2, Entry 7)
White solid; mp 78–81 °C.
IR (KBr): 3045, 1571, 1416, 1123, 1009, 758 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.94 (d, J = 8.0 Hz, 1 H), 6.99
(ddd, J = 0.8, 4.8, 7.4 Hz, 1 H), 7.38–7.47 (m, 3 H), 7.53 (d, J = 8.8
Hz, 2 H), 8.38 (br d, J = 4.8 Hz, 1 H).
ESI MS: m/z = 189 (M + 2).
13C NMR (75 MHz, CDCl3): d = 120.2, 121.6, 123.3, 130.2, 132.7,
136.1, 136.7, 149.6, 160.1.
2-p-Tolylsulfanylpyridine (Table 2, Entry 2)
Colorless liquid.
IR (neat): 3042, 2920, 1571, 1448, 1417, 1123, 758 cm–1.
ESI MS: m/z = 266 (M + H).
1H NMR (300 MHz, CDCl3): d = 2.41 (s, 3 H), 6.80 (d, J = 7.4 Hz,
1 H), 6.92 (ddd, J = 0.9, 4.8, 7.4 Hz, 1 H), 7.20 (d, J = 7.8 Hz, 2 H),
7.34–7.39 (m, 1 H), 7.47 (d, J = 7.8 Hz, 2 H), 8.36 (br d, 1 H, J = 4.8
Hz).
2-(Naphthalen-2-ylsulfanyl)pyridine (Table 2, Entry 8)
Light yellow oil.
IR (KBr): 2922, 1570, 1447, 1414, 1121, 752 cm–1.
Synthesis 2009, No. 10, 1732–1738 © Thieme Stuttgart · New York

1736
B. Sreedhar et al.
PAPER
2-(4-Bromophenylsulfanyl)-3-chloropyridine (Table 2, Entry
1H NMR (300 MHz, CDCl3): d = 6.89 (d, J = 7.8 Hz, 1 H), 6.96
(ddd, J = 0.9, 4.8, 7.5 Hz, 1 H), 7.36–7.44 (m, 1 H), 7.45–7.54 (m,
2 H), 7.8 (d, J = 8.4 Hz, 1 H), 7.77–7.88 (m, 3 H), 8.11 (s, 1 H), 8.40
(d, J = 4.8 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 119.9, 121.4, 126.6, 127.0, 127.8,
129.2, 133.8, 134.6, 134.5, 136.7, 149.5, 161.4.
14)
White solid; mp 100–102 °C.
IR (KBr): 3037, 1902, 1560, 1387, 1143, 1004, 789 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.96 (dd, J = 4.5, 7.5 Hz, 1 H),
7.40 (d, J = 8.2 Hz, 2 H), 7.51–7.58 (m, 3 H), 8.16 (dd, J = 1.5, 4.5
Hz, 1 H).
EI MS: m/z = 237 (M+, 100%).
13C NMR (75 MHz, CDCl3): d = 120.8, 123.6, 128.6, 132.3, 136.3,
4-Methyl-2-phenylsulfanylpyridine (Table 2, Entry 9)
Colorless liquid.
IR (neat): 2921, 1558, 1546, 1458, 1120, 749 cm–1.
136.8, 147.4, 156.8.
EI MS: m/z = 300 (M+).
1H NMR (300 MHz, CDCl3): d = 2.24 (s, 3 H), 6.72 (s, 1 H), 6.80
(d, J = 5.0 Hz, 1 H), 7.39–7.43 (m, 3 H), 7.56–7.60 (m, 2 H), 8.26
(d, J = 5.0 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 20.9, 121.6, 122.2, 129.5, 129.8,
135.1, 135.9, 148.2, 149.5, 159.9.
2-Phenylsulfanylnicotinonitrile (Table 2, Entry 15)
Pale yellow solid; mp 78–81 °C.
IR (KBr): 2923, 2221, 1571, 1389, 1135, 1072, 735 cm–1.
1H NMR (200 MHz, CDCl3): d = 7.07 (dd, J = 5.1, 7.3 Hz, 1 H),
7.40–7.45 (m, 3 H), 7.53–7.59 (m, 2 H), 7.80 (d, J = 7.3 Hz, 1 H),
8.42 (d, J = 5.1 Hz, 1 H).
EI MS: m/z = 200 (M –1).
13C NMR (75 MHz, CDCl3): d = 115.4, 119.5, 122.1, 129.3, 129.5,
4-Methyl-2-p-tolylsulfanylpyridine (Table 2, Entry 10)
Colorless liquid.
IR (neat): 2920, 1587, 1545, 1547, 1373, 1118, 809 cm–1.
135.3, 140.8, 142.5, 152.6, 162.8.
EI MS: m/z = 211 (M – 1).
1H NMR (300 MHz, CDCl3): d = 2.21 (s, 3 H), 2.41 (s, 3 H), 6.64
(s, 1 H), 6.75 (d, J = 6.1 Hz, 1 H), 7.20 (d, J = 8.3 Hz, 2 H, 2-phe-
nylsulfanylpyridine), 7.45 (d, J = 8.3 Hz, 2 H), 8.22 (d, J = 6.1 Hz,
1 H).
13C NMR (75 MHz, CDCl3): d = 20.9, 21.3, 120.9, 121.5, 127.3,
130.4, 135.1, 139.2, 147.9, 149.2, 161.6.
2-(Naphthalen-2-ylsulfanyl)nicotinonitrile (Table 2, Entry 16)
White solid; mp 118–120 °C.
IR (KBr): 3051, 2223, 1568, 1389, 811, 734 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.18 (dd, J = 4.8, 8.0 Hz, 1 H),
7.52–7.57 (m, 3 H), 7.83–7.90 (m, 3 H), 7.98 (d, J = 8.0 Hz, 1 H),
8.10 (s, 1 H), 8.43 (d, J = 4.8 Hz, 1 H).
ESI MS: m/z = 216 (M + H).
13C NMR (75 MHz, CDCl3): d = 115.4, 119.5, 122.2, 128.2, 129.4,
129.6, 135.3, 140.8, 142.5, 152.6, 152.8, 162.9.
2-(4-Chlorophenylsulfanyl)-4-methylpyridine (Table 2, Entry
11)
ESI MS: m/z = 263 (M + H).
White solid; mp 48–50 °C.
IR (KBr): 2923, 1588, 1468, 1086, 816 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.25 (s, 3 H), 6.77 (s, 1 H), 6.81
(d, J = 5.3 Hz, 1 H), 7.36 (d, J = 9.0 Hz, 2 H), 7.49 (d, J = 9.0 Hz,
2 H), 8.23 (d, J = 5.3 Hz, 1 H).
5-Nitro-2-phenylsulfanylpyridine (Table 2, Entry 17)
Yellow solid; mp 106–109 °C.
IR (KBr): 2921, 1584, 1505, 1331, 1134, 755 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.93 (d, J = 9.0 Hz, 1 H), 7.47–
7.51 (m, 3 H), 7.58–7.62 (m, 2 H), 8.18 (dd, J = 2.3, 9.0 Hz, 1 H),
9.18 (d, J = 2.3 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 119.9, 128.4, 130.1, 130.4, 131.2,
135.5, 141.1, 145.1, 170.3.
13C NMR (75 MHz, CDCl3): d = 20.9, 121.5, 122.3, 129.6, 135.0,
135.8, 148.2, 149.4, 159.9.
ESI MS: m/z = 236 (M + H), 238 (M + 2).
ESI MS: m/z = 233 (M + H).
3-Chloro-2-phenylsulfanylpyridine (Table 2, Entry 12)
Light yellow oil.
IR (KBr): 3053, 1560, 1477, 1387, 1151, 1026, 749 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.96 (dd, J = 4.5, 7.5 Hz, 1 H),
7.41–7.44 (m, 3 H), 7.55–7.60 (m, 3 H), 8.20 (d, J = 4.5 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 120.6, 123.2, 129.0, 129.1, 135.4,
136.2, 138.8, 147.3, 157.4.
2-Phenylsulfanylquinoline (Table 3, Entry 1)
Colorless liquid.
IR (KBr): 3052, 1583, 1494, 1418, 1137, 1091, 818, 746 cm–1.
1H NMR (300 MHz, CDCl3): d = 6.98 (d, J = 8.7 Hz, 1 H), 7.34–
7.47 (m, 4 H), 7.57–7.69 (m, 4 H), 7.85 (d, J = 8.8 Hz, 1 H), 7.89
(d, J = 8.5 Hz, 1 H).
EI MS: m/z = 220 (M – 1).
13C NMR (75 MHz, CDCl3): d = 119.5, 125.7, 127.5, 128.3, 129.1,
129.6, 129.9, 130.8, 135.1, 136.4, 148.0, 161.5.
3-Chloro-2-p-tolylsulfanylpyridine (Table 2, Entry 13)
White solid; mp 54–56 °C.
ESI MS: m/z = 238 (M + H).
IR (KBr): 3035, 2919, 1563, 1388, 1149, 1022, 894 cm–1.
2-(4-Chlorophenylsulfanyl)quinoline (Table 3, Entry 2)
White solid; mp 77–80 °C.
IR (KBr): 3052, 1576, 1470, 1296, 1139, 1085, 814, 746 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.03 (d, J = 9.0 Hz, 1 H), 7.39–
7.44 (m, 3 H), 7.58 (d, J = 8.3 Hz, 2 H), 7.64 (d, J = 8.3 Hz, 1 H),
7.67 (d, J = 7.6 Hz, 1 H), 7.85–7.90 (m, 2 H).
1H NMR (300 MHz, CDCl3): d = 2.40 (s, 3 H), 6.91 (dd, J = 4.4, 8.0
Hz, 1 H), 7.20 (d, J = 8.0 Hz, 2 H), 7.40 (d, J = 8.0 Hz, 2 H), 7.52
(d, J = 8.0 Hz, 1 H), 8.15 (d, J = 4.4 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 21.4, 120.4, 126.8, 128.5, 130.0,
135.5, 136.1, 139.3, 147.5, 157.9.
ESI MS: m/z = 236 (M + H), 238 (M + 2).
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SNAr Reaction of Heteroaryl Halides with Thiols in Water
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13C NMR (75 MHz, CDCl3): d = 119.6, 125.9, 127.5, 128.4, 129.7,
1H NMR (200 MHz, CDCl3): d = 7.28–7.35 (m, 3 H), 7.49–7.56 (m,
4 H), 7.67–7.72 (m, 2 H), 7.85 (d, J = 8.1 Hz, 1 H), 7.99 (d, J = 8.8
Hz, 1 H), 8.15–8.21 (m, 3 H).
13C NMR (75 MHz, CDCl3): d = 121.8, 123.6, 126.8, 128.3, 128.4,
129.1, 129.5, 130.4, 133.7, 136.2, 137.6, 149.4, 158.9, 171.2.
130.0, 135.4, 136.2, 136.5, 148.0, 160.4.
ESI MS: m/z = 272 (M + H).
2-o-Tolylsulfanylquinoline (Table 3, Entry 3)
Colorless liquid.
IR (KBr): 3048, 2924, 1578, 1465, 1417, 1137, 1090, 813 cm–1.
ESI MS: m/z = 315.6 (M + H).
2-Phenyl-4-p-tolylsulfanylquinazoline (Table 4, Entry 4)
White solid; mp 87–89 °C.
IR (KBr): 3056, 2924, 1535, 1478, 1338, 1304, 1248, 753, 700 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.43 (s, 3 H), 7.29–7.30 (m, 4 H),
7.44–7.49 (m, 2 H), 7.60 (d, J = 7.3 Hz, 1 H), 7.66 (d, J = 7.3 Hz, 1
H), 7.81–7.89 (m, 1 H), 8.03 (d, J = 8.7 Hz, 1 H), 8.13–8.19 (m, 2
H), 8.22 (d, J = 8.1 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 20.8, 122.0, 123.8, 126.6, 126.9,
128.3, 128.9, 130.2, 130.5, 130.6, 133.7, 137.1, 143.8, 149.2, 158.7,
170.6.
1H NMR (300 MHz, CDCl3): d = 2.42 (s, 3 H) 6.83 (d, J = 8.6 Hz,
1 H), 7.21–7.28 (m, 1 H), 7.34 (m, 2 H), 7.40 (d, J = 7.9 Hz, 1 H),
7.59 (d, J = 8.3 Hz, 1 H), 7.64 (d, J = 7.4 Hz, 2 H), 7.80 (d, J = 8.6
Hz, 1 H), 7.88 (d, J = 8.1 Hz, 1 H).
13C NMR (75 MHz, CDCl3): d = 20.95, 118.6, 125.5, 125.7, 127.0,
127.5, 128.2, 129.9, 131.0, 136.4, 136.7, 142.9, 148.1, 161.4.
ESI MS: m/z = 252 (M + H).
2-p-Tolylsulfanylquinoline (Table 3, Entry 4)
White solid; mp 49–51 °C.
IR (KBr): 3053, 2920, 1585, 1491, 1418, 1141, 1089, 815 cm–1.
ESI MS: m/z = 330 (M + 2 H).
1H NMR (300 MHz, CDCl3): d = 2.43 (s, 3 H) 6.94 (d, J = 8.2 Hz,
1 H), 7.23 (d, J = 8.9 Hz, 2 H), 7.39 (t, J = 7.4 Hz, 1 H), 7.53 (d,
J = 8.2 Hz, 2 H), 7.61–7.67 (m, 2 H), 7.83 (d, J = 8.3 Hz, 1 H), 7.90
(d, J = 8.2 Hz, 1 H).
6-Phenylsulfanyl-9H-purine (Table 4, Entry 5)
White solid; mp 95–98 °C.
IR (KBr): 3053, 1611, 1551, 1489, 1141, 1055, 807 cm–1.
13C NMR (75 MHz, CDCl3): d = 21.3, 119.1, 125.6, 125.7, 127.1,
1H NMR (300 MHz, CDCl3 + DMSO-d6): d = 2.40 (s, 3 H), 7.21–
7.26 (m, 1 H), 7.34–7.37 (m, 2 H), 7.59 (d, J = 7.6 Hz, 1 H), 8.08 (s,
1 H), 8.45 (s, 1 H), 13.5 (s, 1 H).
13C NMR (100 MHz, CDCl3 + DMSO-d6): d = 19.79, 125.5, 125.6,
128.9, 129.6, 135.6, 141.1, 142.1, 150.7.
127.5, 128.2, 129.9, 130.4, 135.3, 136.3, 139.5, 148.0, 162.2.
ESI MS: m/z = 252 (M + H).
1-Phenylsulfanylisoquinoline (Table 3, Entry 5)
Brown liquid.
IR (KBr): 3052, 1551, 1259, 1038, 983, 744 cm–1.
EI MS: m/z = 242 (M+).
1H NMR (200 MHz, CDCl3): d = 7.31–7.46 (m, 4 H), 7.51– 7.80 (m,
5 H), 8.18 (d, J = 5.14 Hz, 1 H), 8.35 (d, J = 8.0 Hz, 1 H).
Acknowledgment
P.S.R. thanks the Council of Scientific and Industrial Research
(CSIR), India, for a Senior Research Fellowship.
13C NMR (75 MHz, CDCl3): d = 118.4, 125.0, 127.1, 127.3, 128.5,
129.9, 130.4, 130.7, 134.6, 135.9, 142.3, 159.2.
ESI MS: m/z = 236 (M – 1).
References
2-Phenylsulfanylquinoxaline (Table 4, Entry 1)
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White solid; mp 79–82 °C.
IR (KBr): 2924, 1535, 1473, 1073, 956, 756 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.44–7.48 (m, 3 H), 7.60–7.69 (m,
4 H), 7.82–7.88 (m, 1 H), 7.94–7.99 (m, 1 H), 8.45 (s, 1 H).
13C NMR (75 MHz, CDCl3): d = 128.2, 128.7, 128.8, 129.1, 129.6,
129.7, 130.4, 134.9, 143.3, 157.1.
EI MS: m/z = 238 (M+).
2-Phenylsulfanylpyrimidine (Table 4, Entry 2)
Colorless liquid.
IR (KBr): 3443, 1554, 1379, 1184, 750 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.47 (s, 3 H), 6.87 (t, J = 4.5 Hz,
1 H), 7.14–7.20 (m, 1 H), 7.26–7.30 (m, 2 H), 7.54 (d, J = 7.5 Hz, 1
H), 8.38 (d, J = 4.5 Hz, 2 H).
13C NMR (75 MHz, CDCl3): d = 20.82, 116.6, 126.5, 128.6, 130.0,
130.6, 136.4, 142.8, 157.5, 172.5.
ESI MS: m/z = 203 (M + H).
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2-Phenyl-4-phenylsulfanylquinazoline (Table 4, Entry 3)
White solid; mp 113–115 °C.
IR (KBr): 3052, 2923, 1536, 1480, 1339, 1307, 1248, 693 cm–1.
Synthesis 2009, No. 10, 1732–1738 © Thieme Stuttgart · New York

1738
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Synthesis 2009, No. 10, 1732–1738 © Thieme Stuttgart · New York