Rhodium-Catalyzed Synthesis of Unsymmetric Di(heteroaryl) Sulfides Using Heteroaryl Ethers and S-Heteroaryl Thioesters via Heteroarylthio Exchange

Article abstract of DOI:10.1021/acs.joc.6b02585

Unsymmetric di(heteroaryl) sulfides were synthesized by a rhodium-catalyzed heteroarylthio exchange reaction of heteroaryl aryl ethers and S-(heteroaryl) thioesters. The reaction has broad applicability, giving diverse unsymmetric di(heteroaryl) sulfides containing five- and six-membered heteroarenes. No base is required in this reaction, which has been developed by the judicious design of organic substrates.

Full text of DOI:10.1021/acs.joc.6b02585

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Note
Rhodium-Catalyzed Synthesis of Unsymmetric Di(heteroaryl) Sulfides Using
Heteroaryl Ethers and S-Heteroaryl Thioesters via Heteroarylthio Exchange
Mieko Arisawa, Takeru Tazawa, Saori Tanii, Kiyofumi Horiuchi, and Masahiko Yamaguchi
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02585 • Publication Date (Web): 12 Dec 2016
Downloaded from http://pubs.acs.org on December 12, 2016
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The Journal of Organic Chemistry
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Rhodium-Catalyzed Synthesis of Unsymmetric Di(heteroaryl) Sul-
fides Using Heteroaryl Ethers and S-Heteroaryl Thioesters via Het-
eroarylthio Exchange
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Mieko Arisawa*, Takeru Tazawa, Saori Tanii, Kiyofumi Horiuchi, and Masahiko Yamaguchi*
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Sendai, 980-
8578, Japan
KEYWORDS: Unsymmetric di(heteroaryl) sulfides, Rhodium-catalysis, Heteroarylthio exchange reaction, Heteroaryl ethers,
Heteroaryl thioesters
ABSTRACT: Unsymmetric di(heteroaryl) sulfides were synthesized by a rhodium-catalyzed heteroarylthio ex-
change reaction of heteroaryl aryl ethers and S-(heteroaryl) thioesters. The reaction has broad applicability, giv-
ing diverse unsymmetric di(heteroaryl) sulfides containing five- and six-membered heteroarenes. No base is re-
quired in this reaction, which has been developed by the judicious design of organic substrates.
Unsymmetric diaryl sulfides are widely used in the prepara-
tion of materials and pharmaceuticals, and their heteroaryl
derivatives, unsymmetric di(heteroaryl) sulfides, are an inter-
esting group of multiple heteroatom compounds, that exhibit
notable chemical and biological functions.1 They are generally
synthesized by the substitution reaction of heteroaryl halides
and heteroaryl thiols in the presence of stoichiometric
amounts of bases2 by classical aromatic nucleophilic substitu-
tion reactions1,3 or copper- and palladium-catalyzed substitu-
tion reactions.4 Silver-catalyzed oxidative C–H heteroarylthio-
lation of benzothiazole with 2-pyridylthiol using a stoichio-
metric amount of Cu(OAc)2 has recently been reported.5
form diphenyl sulfide and phenyl benzoate is exothermic (-
39.5 kJ/mol).8 It is more exothermic than the reaction of di-
phenyl ether and S-phenyl methansulfonic acid giving diphen-
yl sulfide and methansulfonic acid phenyl ester (-4.8 kJ/mol),
the reaction of diphenyl ether and thioanisole to give diphenyl
sulfide and anisole (+13.4 kJ/mol), and the reaction of diphe-
nyl ether and N-(phenylthio)succinimide to give diphenyl
sulfide and N-(phenoxy)succinimide (+115.3 kJ/mol).
This analysis suggests that the synthesis of di(heteroaryl)
sulfides can be conducted without using bases by the judicious
design of organic substrates.9 Described in this paper is the
rhodium-catalyzed synthesis of unsymmetric di(heteroaryl)
sulfides by the heteroarylthio exchange reaction of heteroaryl
aryl ethers10 and S-(heteroaryl) thioesters (Scheme 1). The C–
O bonds of the heteroaryl aryl ethers are converted to the C–S
bonds to yield unsymmetric di(heteroaryl) sulfides with con-
comitant C–O and C–S bond exchange. This method is appli-
cable to the synthesis of various unsymmetric di(heteroary)
sulfides containing five- and six-membered heteroarenes.
Base, which would provide large chemical energy, is not em-
ployed here to make the reaction exothermic, and the synthe-
sis is conducted using neutral and stable organic substrates,
heteroaryl aryl ethers and thioesters, in an energy-saving man-
ner.6 In the present reaction, esters are formed as the organic
co-product, which can easily be recovered and used for other
purposes. It is considered preferable compared with the for-
mation of inorganic metal halides derived from metal bases.
The use of bases is required for kinetic and thermodynamic
reasons. In the absence of base, hydrogen halides are formed
from aryl halides and thiols, and the addition of base neutral-
izes hydrogen halides to give metal halides and water, which
makes the reaction largely exothermic owing to the large neu-
tralization energy.6 According to the Bell–Evans–Polanyi
principle,7 the exothermic nature of the reaction, when strong-
er bases are used, can reduce the required activation energy,
which largely accelerates the reaction. Thus, the use of a base
implies the release of large chemical energy, which can be
inferred by considering, for example, that NaOH is regenerat-
ed from NaCl using large electrochemical energy. Develop-
ment of a versatile method for the synthesis of unsymmetric
bis(heteroaryl) sulfides without using stoichiometric amounts
of bases is desired to conduct the synthesis energy-saving
manner. It is also worth noting that such a method avoids the
use of thiols, which makes manipulation of the reaction more
facile.
Scheme 1. Rhodium-catalyzed synthesis of unsymmetric
di(heteroaryl) sulfides
It was considered interesting to use the less chemical energy
derived from neutral organic compounds in place of bases,
and the reactions of diphenyl ether with different phenylthio-
lating reagents were examined by calculations. Thermody-
namic analysis by preliminary DFT calculations shows that
the reaction of diphenyl ether and S-phenyl thiobenzoate to
RhH(PPh3)4 (5 mol%)
dppBz (10 mol%)
O
HetAr
+
OAr
HetAr
PhCl, refl., 5 h
Ph
S
O
Ar = 4-ClC6H4
HetAr
+
HetAr
OAr
S
Ph
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The study began with the examination of rhodium-catalyzed
Scheme 4. Rhodium-catalyzed synthesis of heteroaryl aryl
sulfides
1
2
3
4
5
6
arylthio exchange reactions of diaryl ethers: Diaryl sulfides
were formed from diaryl ethers and thioesters. When 4-(4-
chlorophenoxy)benzonitrile 1a was reacted with S-(4-tolyl)
benzothioate 2 (1 equiv.) in the presence of RhH(PPh3)4 (5
RhH(PPh3)4 (5 mol%)
dppBz (10 mol%)
O
+
Cl
HetAr
O
S
PhCl, refl., 5 h
Ph
mol%) and dppBz (10 mol%, dppBz
bis(diphenylphosphino)benzene) in refluxing chlorobenzene
for h, 4-(4-tolylthio)benzonitrile 3a (71%) and (4-
=
1,2-
11
2
Cl
O
+
HetAr
O
Ph
S
12
5
7
8
9
4
chlorophenyl) benzoate 4 (71%) were obtained with recovery
of 1a (25%) and 2 (28%) (Scheme 2). 4-Chlorophenyl 4-tolyl
sulfide was not formed. No reaction occurred in the absence of
RhH(PPh3)4 or dppBz. The reaction of 1a and S-(4-tolyl) do-
decanethioate 5 also gave 3a (72%). Neutral and stable thioe-
ster 2 can be used as a thiolating reagent of diaryl ethers. The
reaction of 4-(phenoxy)benzonitrile (33%) and 4-(4-
tolyloxy)benzonitrile (17%) with 2 also proceeded, where
yields of the sulfides were reduced, likely because of the
stronger C–O bonds.
HetAr =
5-CN-2-pyridyl (a)
4-quinazolyl (b)
5-Cl-2-benzothiazolyl (c) 99%
4-phenyl-2-oxazolyl (d) 70%
5-CN-2-thienyl (e)
5-Acetyl-2-furyl (f)
95%
96%
96%
94%
98%
66%
92%
97%
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97%
97%
The reverse reaction to form a heteroaryl aryl ether from a
heteroaryl aryl sulfide did not proceed. When 12b was reacted
with an aryl ester 4 using the same rhodium complex, 11b and
2 were not formed (Scheme 5). The heteroaryl aryl sulfide
formation reaction is energetically favorable, perhaps because
of the formation of a thermodynamically more stable ester
from the thioester.
Scheme 2. Rhodium-catalyzed arylthio exchange reactions
of diaryl ethers
RhH(PPh3)4 (5 mol%)
dppBz (10 mol%)
O
Scheme 5. Reverse reaction
NC
O
X +
PhCl, refl., 5 h
S
R
S
X
2
1a
O
RhH(PPh3)4 (5 mol%)
dppBz (10 mol%)
S
O
NC
+
O
R
+
N
N
PhCl, refl., 5 h
OAr
Ph
3a
12b
4
R =
Ph (2)
n-C11H23 (5)
Ph (2)
X =
71%
72%
33%
71% (4)
68% (6)
27% (4)
20% (4)
Cl
Cl
H
O
OAr
Ar = 4-ClC6H4
+
S
Ph
N
N
17%
Me
Ph (2)
2 n.d.
11b n.d.
Without Rh cat. n.r.
without dppBz n.r.
The use of S-(heteroaryl) benzothioates as thiolating rea-
gents provided unsymmetric bis(heteroaryl) sulfides from
heteroaryl (4-chlorophenyl) ethers. The reaction of six-
membered heteroaryl aryl ethers and S-(heteroaryl) benzothio-
ates (1 equiv.) proceeded in high yields (Table 1). The het-
eroaryl 4-chlorophenyl ethers containing 2-triazyl, 4-
quinazolinyl, 2-pyrimidyl, and 2-pyridyl groups reacted with
S-(2-pyridyl) benzothioate, and the corresponding heteroaryl
2-pyridyl sulfides 15a–15e were obtained in high yields. The
reaction of benzooxazolyl, benzothiazolyl, and 2-acetylfulyl
4-chlorophenyl ethers with S-(2-pyridyl) benzothioate also
gave the corresponding sulfides containing five-membered
heteroarenes 15f and 15g. The reaction of S-(3-pyridyl) and S-
(4-pyridyl) benzoates gave the 4-pyridyl and 3-pyridyl deriva-
tives 15h-15o. The position of the nitrogen atom in the S-
pyridyl thioester was not crucial, which indicated a broad
scope for this method. S-(2-Furyl) and S-(2-thienyl) benzothi-
oates reacted with heteroaryl 4-chlorophenyl ethers to give the
heteroaryl sulfides 15p-15u in high yields. The sulfide struc-
ture was confirmed by X-ray crystal structure analysis of 15m
and 15r (See Supporting Information).11 This method is a
novel catalytic procedure for the synthesis of diverse unsym-
metric di(heteroaryl) sulfides from readily available heteroaryl
aryl ethers. The oxidation reaction of unsymmetric
di(heteroaryl) sulfide 15e using m-CPBA gave sulfoxide de-
rivative 16 (See Experimental section).12 This is a simple and
facile synthetic method of unsymmetric diheteroaryl sulfoxide.
Several diaryl sulfides were obtained in quantitative yields
from diaryl ethers 1 with electron-withdrawing groups and
benzothioates 2, 7, and
8
with S-(4-tolyl), S-(4-
methoxyphenyl), and S-(4-chlorophenyl) groups, respectively
(Scheme 3). 1b reacted with 2 even using a lower catalyst
loading (1 mol%), giving 3b (89%) and 4 (88%).
Scheme 3. Rhodium-catalyzed synthesis of unsymmetric
diaryl sulfides
RhH(PPh3)4 (5 mol%)
dppBz (10 mol%)
X
O
+
Cl
4
O
S
Ph
PhCl, refl., 5 h
R
3
2
1
Cl
X
O
+
O
Ph
S
R
4
R =
3-CF3-4-CN (b)
3-CF3-4-CN (b)
3-CF3-4-CN (b)
3-CF3-4-CN (b)
2-CF3-4-CN (c)
4-PhCO (d)
99% (3b)
89% (3b)a)
91% (9)
99% (10)
99% (3c)
98% (3d)
99%
88%a)
91%
99%
95%
98%
X = Me (2)
Me (2)
MeO (7)
Cl (8)
Me (2)
Me (2)
a) RhH(PPh3)4 (1 mol%) and dppBz (2 mol%) were used.
Using this method, heteroaryl p-tolyl sulfides containing
five- and six-membered heteroarenes 12a–12f were obtained
in quantitative yields by the reaction of heteroaryl 4-
chlorophenyl ethers 11a–11f and thioester 2 (Scheme 4). The
weak heteroaryl C–O bonds of the heteroaryl aryl ethers 11
were selectively cleaved and converted to the C–S bonds.
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The Journal of Organic Chemistry
ester, and the unsymmetrical di(heteroaryl) sulfides are liber-
Table 1. Rhodium-catalyzed synthesis of unsymmetric
1
2
bis(heteroaryl) sulfides. The C–S bonds formed by the reac-
tion are shown in red.
ated by the reductive elimination with the regeneration of the
rhodium catalyst. In the present reaction, the heteroaryl C-O
bond is regioselectively cleaved, and the other C-O bond does
not react. It is considered that the heteroaryl groups and aryl
groups with electron withdrawing substituent weaken the C-O
bond.13
3
4
Y'
Y'
X
O
O
X
Y
Rh cat.
+
+
OAr
X'
X'
Y
S
OAr
S
Ph
Ph
5
6
14 (1 eq.)
X, Y, X', Y' = C, N, O, S
13 Ar = 4-ClC6H4
15
4
7
8
9
S
S
Ph
R
F3C
N
N
Scheme 7. Proposed reaction mechanism
R
N
N
N
N
N
S
N
RhH(PPh3)4
Ph
10
11
12
13
14
15
16
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N
N
dppBz
PPh3
15d 54%
15a 95%
15b R = H, 95%
Y'
O
15c R = OMe, 96%
Y'
X
H
Ph2P
(s)
(s)
X'
S
S
N
S
N
Ph
S
X'
Y
S
Rh
O
N
N
O
N
Ph2P
NC
Ac
(s) = solvent
Cl
15e 73%
15f 90%
15g 73%
Y'
Y
Y'
S
S
S
X
N
X
X'
Ph2P
Ph2P
X'
Ph2P
Ph2P
S
S
Rh
N
N
X
N
Rh
Ph
NC
N
N
NC
A
X
B
R
O
15i R = Cl, X = O, 87%
15j R = H, X = S, 95%
15k R = Me, X = S, 89%
15l R = H,
15h 94%
15m 80%
O
X
X = NMe, 84%
OAr
Ph
OAr
S
N
S
F3C
Y
S
N
N
N
N
O
N
O
NC
Cl
In summary, unsymmetric di(heteroaryl) sulfides were syn-
thesized from heteroaryl aryl ethers and S-(heteroaryl) thioe-
sters by a rhodium-catalyzed heteroarylthio exchange reaction.
Diverse unsymmetric di(heteroaryl) sulfides containing five-
and six-membered heteroarenes were obtained in high yield.
The reaction, which does not require stoichiometric amount of
a base, does not rely on the neutralization, which releases
large chemical energy. Compared to the method employing
metal bases, the less chemical energy is used in the present
method employing organic substrates. In addition, the organic
substrate method has an advantage of the reaction to be fine-
tuned, and then energy-saving reaction can be developed by
the judicious design of organic substrates.
15p 61%
15n 51%
S
N
15o 60%
S
S
O
N
Ph
O
X
O
X
O
Ac
Ph
Cl
15q X = O, 80%
15r X = S, 93%
15s 45%
15t X = O, 99%
15u X = S, 80%
Di(heteroaryl) sulfide was not formed by the reaction of het-
eroaryl thiol and heteroaryl aryl ether under these reaction
conditions. The reaction of 2-(4-chlorophenyloxy)-5-
cyanopyridine 13e and 4-pyridylthiol 17 did not provide 5-
cyanopyridyl 4-pyridyl sulfide 15m in the presence of
RhH(PPh3)4 (5 mol%) and dppBz (10 mol%) (Scheme 6). The
involvement of a benzoylrhodium intermediate in the rhodi-
um-catalyzed heteroarylthio exchange reaction is suggested
(vide infra).
EXPERIMENTAL SECTION
General Information. H- and 13C-NMR spectra were rec-
1
orded on 400 MHz instrument and tetramethylsilane were
used as standard. The following abbreviations (or combina-
tions thereof) were used to explain multiplicities: s = singlet, d
= doublet, t = triplet, q = quadruplet, m = multiplet. IR spectra
were measured on a FT/IR spectrometer. Melting points were
determined with a micro melting point apparatus without cor-
rection. High-resolution mass spectra (HRMS) were measured
on quadrupole or EI-TOF. S-(2-Pyridyl) and S-(4-pyridyl)
benzothioates14, S-(3-pyridyl) benzothioate15, S-(2-furyl) ben-
zothioate16, and S-(2-thienyl) benzothioate17 were synthesized
by the literature methods.
Scheme 6. Heteroarylthio exchange reaction using 4-
pyridylthiol
RhH(PPh3)4 (5 mol%)
dppBz (10 mol%)
N
N
NC
OAr +
N
SH
NC
S
N
PhCl, refl., 5 h
17
13e
Ar = 4-ClC6H4
15m n.d.
A possible mechanism of the reaction is as follows (Scheme
7). The phosphine ligand in RhH(PPh3)4 is exchanged with
dppBz, and the oxidative addition of S-(heteroaryl) thioester
provides the benzoylrhodium intermediate A. The intermedi-
ate A then undergoes the exchange reaction with heteroaryl
aryl ether forming HetAr’-Rh(III)-SHetAr complex B and
General Procedure for synthesis of the 4-(4-
tolylthio)benzonitrile 3a. In a two-necked flask were placed
RhH(PPh3)4
(14.4
mg,
5
mol%),
1,2-
bis(diphenylphosphino)benzene dppBz (11.2 mg, 10 mol%),
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4-(4-chlorophenoxy)benzonitrile (0.25 mmol, 57.3 mg),
(M+, 100%). HRMS Calcd for C15H10F3NS: 293.0486. Found:
293.0491.
1
2
3
4
5
6
7
8
and S-(p-tolyl) benzothioate (0.25 mmol, 57.0 mg) in chloro-
benzene (0.5 mL) under an argon atomosphere, and the mix-
ture was heated at reflux for 5 h. The solvent was removed
under reduced pressure, and the residue was purified by flash
column chromatography on silica gel (eluent: hexane/ethyl
acetate = 10/1) giving 4-(4-tolylthio)benzonitrile 3a (40.0 mg,
71%) and 4-chlorophenyl benzoate 4 (41.4 mg, 71%). Other
complexs such as RhCl(PPh3)3, [RhCl(cod)2]2, Rh(acac)3, and
Pd(OAc)2 in the presence of dppBz were ineffective. The use
of several bidentate ligands revealed a high efficiency of
dppBz for this reaction: 1,2-bis(diphenylphosphino)ethane
(60%), cis-1,2-bis(diphenylphosphino)ethylene (10%), 1,3-
4-(4-Tolylthio)-3-(trifluoromethyl)benzonitrile (3c). Color-
less solid (72.5 mg, 99%). M.p. 96.5-97.5 °C (Hexane:Ethyl
1
acetate = 4:1). H NMR (400 MHz, CDCl3) δ 2.43 (3H, s),
6.94 (1H, d, J = 8.4 Hz), 7.29 (2H, d, J = 7.6 Hz), 7.35 (2H, d,
J = 8.4 Hz), 7.47 (1H, dd, J = 8.4, 1.6 Hz), 7.87 (1H, d, J = 1.6
Hz). 13C{1H} NMR (100 MHz, CDCl3) δ 21.3, 108.2, 117.6,
122.7 (q, J = 273.3 Hz), 125.3, 127.4 (q, J = 32.1 Hz), 128.6,
130.1 (q, J = 5.9 Hz), 131.1, 134.5, 135.7, 140.9, 146.8. 19F-
NMR (376 MHz, CDCl3) δ -62.6. IR (KBr) ν 3099, 3067,
2232, 1133 cm-1. MS (EI) m/z 293 (M+, 100%), 91 (M+-202,
26%). HRMS Calcd for C15H10F3NS: 293.0486. Found:
293.0491.
4-(4-Tolylthio)benzophenone (3d).23 Colorless solid (74.6
mg, 98%). M.p. 74.0-75.0 °C (Hexane). 1H NMR (400 MHz,
CDCl3) δ 2.39 (3H, s), 7.18 (2H, d, J = 8.4 Hz), 7.24 (2H, d, J
= 7.6 Hz), 7.43 (2H, d, J = 8.0 Hz), 7.46 (2H, d, J = 7.2 Hz),
7.56 (1H, t, J = 7.2 Hz), 7.67 (2H, d, J = 8.4 Hz), 7.75 (2H, d,
J = 7.2 Hz). 13C{1H} NMR (100 MHz, CDCl3) δ 21.3, 126.5,
128.0, 128.2, 129.8, 130.5, 130.7, 132.2, 134.4, 134.5, 137.7,
139.3, 145.2, 195.8. IR (KBr) ν 3028, 2232, 1310 cm-1. MS
(EI) m/z 304 (M+, 100%), 227 (M+-77, 57%). HRMS Calcd
for C20H16OS: 304.0922. Found: 304.0905.
9
10
11
12
13
14
15
16
17
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48
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60
bis(diphenylphosphino)propane
bis(diphenylphosphino)butane (not detected). Monodentate
ligands tris(4-methoxyphenyl)phosphine and tris(4-
chlorophenyl)phosphine, and tridentate ligand bis(2-
(not
detected),
1,4-
a
diphenylphosphinoethyl)phenylsphine were ineffective. These
results show that the bidentate phosphine ligands with phos-
phino groups separated by two carbon atoms are essential. The
reaction did not proceed in refluxing o-dichlorobenzene and
THF.
Characterization Data. 4-(4-Tolylthio)benzonitrile (3a).
Colorless solid (40.0 mg, 71%). M.p. 100.0-101.0 ℃ (Hex-
1
ane). Lit.18 100 °C (Hexane). H NMR (400 MHz, CDCl3) δ
4-[(4-Methoxyphenyl)thio]-2-(trifluoromethyl)benzonitrile
(9). Colorless oil (70.1 mg, 91%). 1H NMR (400 MHz, CDCl3)
δ 3.87 (3H, s), 7.01 (2H, d, J = 8.8 Hz), 7.16 (1H, dd, J = 8.4,
1.6 Hz), 7.39 (1H, d, J = 1.6 Hz), 7.48 (2H, d, J = 8.8 Hz),
7.59 (1H, d, J = 8.4 Hz). 13C{1H} NMR (100 MHz, CDCl3) δ
55.4, 105.1 (d, J = 2.2 Hz), 115.6 (d, J = 6.7 Hz), 115.8, 118.8,
122.1 (q, J = 273.3 Hz), 123.1 (q, J = 4.4 Hz), 128.1, 132.9 (q,
J = 32.8 Hz), 134.6, 137.2, 148.9, 161.3 (d, J = 3.0 Hz). 19F-
NMR (376 MHz, CDCl3) δ -62.3. IR (KBr) ν 2944, 2229,
1253, 1174, 1030 cm-1. MS (EI) m/z 309 (M+, 100%), 294
(M+-15, 34%). HRMS Calcd for C15H10F3NOS: 309.0435.
Found: 309.0427.
2.41 (3H, s), 7.12 (2H, d, J = 8.4 Hz), 7.25 (2H, d, J = 8.8 Hz),
7.42 (2H, d, J = 8.4 Hz), 7.45 (2H, d, J = 8.4 Hz). 13C{1H}
NMR (100 MHz, CDCl3) δ 21.3, 108.2, 118.9, 126.7, 126.8,
130.7, 132.3, 134.9, 140.0, 146.6. IR (KBr) ν 3081, 2224,
1591, 1484, 1402, 1081 cm-1. MS (EI) m/z 225.0 (M+, 100%).
HRMS Calcd for C14H11NS: 225.0612. Found: 225.0600.
4-Chlorophenyl benzoate (4).19 Colorless solid (41.4 mg,
71%). M.p. 87.0-87.5 ℃ (Hexane). Lit.20 82.0-83.0 °C (Hex-
ane/benzene). H NMR (400 MHz, CDCl3) δ 7.20 (2H, d, J =
1
8.8 Hz), 7.39 (2H, d, J = 8.8 Hz), 7.51 (2H, t, J = 7.6 Hz),
7.64 (1H, t, J = 7.6 Hz), 8.19 (2H, d, J = 8.0 Hz). 13C{1H}
NMR (100 MHz, CDCl3) δ 123.0, 128.6, 129.1, 129.5, 130.1,
130.2, 131.2, 133.7, 149.4, 164.8. IR(KBr) 1732, 1585, 1488,
1402 cm-1. MS (EI) m/z 232 (M+, 10%), 105 (M+-COC6H5,
100%). HRMS Cald for C13H9O2Cl: 232.0291. Found:
232.0285.
4-(4-Chlorophenyl)-2-(trifluoromethyl)benzonitrile
(10).
Colorless solid (77.6 mg, 99%). M.p. 75.0-76.0 °C (Hexane).
1H NMR (400 MHz, CDCl3) δ 7.25 (1H, ddd, J = 8.4, 2.0, 0.8
Hz), 7.47 (5H, m), 7.64 (1H, d, J = 8.8 Hz). 13C{1H} NMR
(100 MHz, CDCl3) δ 106.2 (d, J = 2.2 Hz), 115.4, 122.0 (q, J
= 273.3 Hz), 124.2 (q, J = 5.2 Hz), 127.7, 129.2, 130.5, 133.2
(q, J = 32.8 Hz), 134.9, 136.1, 136.7, 146.7. 19F-NMR (376
MHz, CDCl3) δ -62.3. IR (KBr) ν 3082, 2225, 1593, 1475,
1308 cm-1. MS (EI) m/z 313 (M+, 100%). HRMS Calcd for
C14H7ClF3NS: 312.9940. Found: 312.9917.
4-Chlorophenyl dodecanoate (6). Colorless solid (52.9 mg,
68%). M.p. 34.5-35.0 ℃ (Hexane). Lit.21 40.0-42.0 °C (Ace-
tone). H NMR (400 MHz, CDCl3) δ 0.88 (3H, t, J = 7.2 Hz),
1
1.23-1.43 (16H, m), 1.74 (2H, q, J = 7.6 Hz), 2.54 (2H, t, J =
7.6 Hz), 7.03 (2H, d, J = 8.0 Hz), 7.32 (2H, d, J = 8.0 Hz).
13C{1H} NMR (100 MHz, CDCl3) δ 14.1, 22.7, 24.9, 29.1,
29.2, 29.3, 29.4, 29.6, 31.9, 34.3, 122.9, 129.4, 131.0, 149.2,
172.0. IR (KBr) 2917, 2848, 1749, 1490, 1147 cm-1. MS (EI)
m/z 310.0 (M+, 15%), 183 (M+-127, 100%). HRMS Cald for
C18H27O2Cl: 310.1700. Found: 310.1693. One carbon peak of
aliphatic region was overlapped in 13C-NMR.
4-(4-Tolylthio)-2-(trifluoromethyl)benzonitrile (3b).22 Color-
less solid (72.4 mg, 99%). M.p. 65.5-66.5 °C (Hexane). 1H
NMR (400 MHz, CDCl3) δ 2.43 (3H, s), 7.19 (1H, dd, J = 8.4,
2.0 Hz), 7.29 (2H, d, J = 8.0 Hz), 7.43 (3H, d, J = 8.0 Hz),
7.59 (1H, d, J = 8.0 Hz). 13C{1H} NMR (100 MHz, CDCl3) δ
21.3, 105.4 (d, J = 2.3 Hz), 115.6, 122.9 (q, J = 272.6 Hz),
123.6 (q, J = 4.4 Hz), 125.2, 128.6, 131.1, 133.0 (q, J = 32.8
Hz), 134.6, 135.2, 140.8, 148.3. 19F-NMR (376 MHz, CDCl3)
δ -62.3. IR (KBr) ν 3028, 2232, 1310 cm-1. MS (EI) m/z 293
6-(4-Tolylthio)-3-pyridinecarbonitrile (12a). Colorless solid
1
(53.6 mg, 95%). M.p. 75.0-75.5 °C (Hexane). H NMR (400
MHz, CDCl3) δ 2.43 (3H, s), 6.87 (1H, d, J = 8.8 Hz), 7.29
(2H, d, J = 8.0 Hz), 7.48 (2H, d, J = 8.0 Hz), 7.61 (1H, dd, J =
8.4, 2.0 Hz), 8.63 (1H, d, J = 1.6 Hz). 13C{1H} NMR (100
MHz, CDCl3) δ 21.4, 104.8, 116.9, 119.9, 124.8, 130.9, 135.6,
138.8, 140.7, 152.1, 168.6. IR (KBr) ν 3053, 2228, 1581,
1449, 826 cm-1. MS (EI) m/z 226 (M+, 47%), 225 (M+-1,
100%). HRMS Calcd for C13H10N2S: 226.0565. Found:
226.0546.
4-(4-Tolylthio)quinazoline (12b). Yellow solid (60.3 mg,
96%). M.p. 102.2-102.5 °C (Hexane). Lit.24 104.0-105.0 °C.
1H NMR (400 MHz, CDCl3) δ 2.43 (3H, s), 7.30 (2H, d, J =
8.0 Hz), 7.51 (2H, d, J = 8.0 Hz), 7.62 (1H, t, J = 8.0 Hz),
7.87 (1H, t, J = 8.4 Hz), 7.96 (1H, d, J = 8.4 Hz), 8.21 (1H, d,
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The Journal of Organic Chemistry
J = 8.0 Hz), 8.87 (1H, s). 13C{1H} NMR (100 MHz, CDCl3) δ
1559, 1542, 1482, 989 cm-1. MS (EI) m/z 239 (M+, 79%), 238
(M+-1, 100%). HRMS Calcd for C13H9N3S: 239.0517. Found:
239.0515. One carbon peak of 15b of aliphatic region was
overlapped in 13C-NMR.
1
2
3
4
5
6
7
8
21.5, 123.3, 123.4, 123.8, 127.5, 128.8, 130.3, 133.8, 135.7,
140.1, 148.3, 154.0, 171.8. IR (KBr) ν 2915, 1909, 1502,
1540, 1485 cm-1. MS (EI) m/z 252 (M+, 50%), 251 (M+-1,
100%). HRMS Calcd for C15H12N2S: 252.0721. Found:
252.0718.
4-(2-Pyridinylthio)-6,7-dimethoxyquinazoline (15c). Color-
less solid (72.0 mg, 96%). M.p. 134.0-135.0 °C (Hex-
ane/AcOEt = 4/1). 1H NMR (400 MHz, CDCl3) δ 4.05 (3H, s),
4.06 (3H, s), 7.29 (1H, s), 7.33 (1H, ddd, J = 7.2, 4.8, 1.6 Hz),
7.36 (1H, s), 7.77 (1H, dt, J = 7.2, 2.0 Hz), 7.81 (1H, ddd, J =
7.6, 1.2, 0.8 Hz), 8.66 (1H, ddd, J = 5.2, 2.0, 1.2 Hz), 8.81 (1H,
s). 13C{1H} NMR (100 MHz, CDCl3) δ 56.3, 56.4, 101.7,
107.1, 119.4, 123.2, 130.0, 137.2, 146.8, 150.3, 150.5, 152.7,
156.0, 165.7. IR (KBr) ν 2925, 2854, 1232, 1017 cm-1. MS
(EI) m/z 299 (M+, 100%), 284 (M+-15, 89%). HRMS Calcd
for C15H13N3O2S: 299.0728. Found: 299.0728. One carbon
peak of aliphatic region was overlapped in 13C-NMR.
2-(4-Tolylthio)-5-chlorobenzothiazole (12c). Colorless solid
1
(71.8 mg, 99%). M.p. 93.0-94.0 °C (Hexane). H NMR (400
MHz, CDCl3) δ 2.44 (3H, s), 7.30 (2H, d, J = 7.6 Hz), 7.35
(1H, dd, J = 8.8, 2.0 Hz), 7.59 (1H, d, J = 2.0 Hz), 7.62 (2H, d,
J = 8.0 Hz), 7.75 (1H, d, J = 8.8 Hz). 13C{1H} NMR (100
MHz, CDCl3) δ 21.4, 120.4, 122.5, 125.8, 126.8, 130.0, 130.8,
135.6, 136.6, 141.4, 152.6, 171.6. IR (KBr) ν 2917, 1430,
1099, 1004, 810 cm-1. MS (EI) m/z 291 (M+, 78%), 290 (M+-1,
100%). HRMS Calcd for C14H10ClNS2: 290.9894. Found:
290.9910.
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59
60
2-(4-Tolylthio)-4-phenyloxazole (12d). Colorless solid (46.9
mg, 70%). M.p. 66.5-67.0 °C (Hexane). 1H NMR (400 MHz,
CDCl3) δ 2.37 (3H, s), 7.20 (2H, d, J = 8.0 Hz), 7.29 (1H, t, J
= 7.2 Hz), 7.37 (2H, t, J = 7.2 Hz), 7.51 (2H, d, J = 8.0 Hz),
7.69 (2H, d, J = 7.2 Hz), 7.87 (1H, s). 13C{1H} NMR (100
MHz, CDCl3) δ 21.2, 125.2, 125.5, 128.2, 128.7, 130.2, 130.5,
133.4, 135.5, 139.4, 142.4, 158.9. IR (KBr) ν 3108, 1491,
1445 cm-1. MS (EI) m/z 267 (M+, 100%), 135 (M+-132, 39%).
HRMS Calcd for C16H13NOS: 267.0718. Found: 267.0732.
2-(2-Pyridinylthio)-4-(trifluoromethyl)pyrimidine
(15d).25
1
Yellow oil (34.8 mg, 54%). H NMR (400 MHz, CDCl3) δ
7.32 (1H, d, J = 4.8 Hz), 7.34 (1H, dd, J = 4.8, 1.6 Hz), 7.77
(1H, dt, J = 8.0, 2.0 Hz), 7.81 (1H, td, J = 8.0, 1.2 Hz), 8.66
(1H, ddd, J = 4.8, 0.8 Hz), 8.74 (1H, d, J = 4.8 Hz). 13C{1H}
NMR (100 MHz, CDCl3) δ 112.8 (q, J = 3.0 Hz), 120.0 (q, J =
274.1 Hz), 123.6, 130.0, 137.3, 150.5, 152.2, 156.0 (q, J =
36.5 Hz), 159.8, 173.1. 19F-NMR (376 MHz, CDCl3) δ -70.3.
IR (neat) ν 3051, 2992, 1572, 1560, 1335, 1224, 1120, 834
cm-1. MS (EI) m/z 257 (M+, 100%). HRMS Calcd for
C10H6F3N3S: 257.0235. Found: 257.0234.
5-(4-Tolylthio)-2-thiophenecarbonitrile (12e). Colorless oil
(56.1 mg, 97%). 1H NMR (400 MHz, CDCl3) δ 2.34 (3H, s),
7.00 (1H, d, J = 4.0 Hz), 7.16 (2H, d, J = 8.0 Hz), 7.32 (2H, d,
J = 8.0 Hz), 7.44 (1H, d, J = 4.0 Hz). 13C{1H} NMR (100
MHz, CDCl3) δ 21.1, 110.9, 113.6, 130.1, 130.4, 131.7, 137.7,
139.1, 146.1. IR (KBr) ν 3094, 2920, 2212, 1492, 1415, 807
cm-1. MS (EI) m/z 231 (M+, 100%). HRMS Calcd for
C12H9NS2: 231.0176. Found: 231.0185.
6-(2-Pyridinylthio)-3-pyridinecarbonitrile (15e). Pale yel-
low solid (38.9 mg, 73%). M.p. 95.5-97.0 °C (Hexane). H
1
NMR (400 MHz, CDCl3) δ 7.32 (1H, ddd, J = 7.6, 4.8, 0.8
Hz), 7.44 (1H, dd, J = 8.4, 0.8 Hz), 7.63 (1H, dd, J = 8.0, 0.8
Hz), 7.74 (1H, dd, J = 7.2, 2.0 Hz), 7.76 (1H, dd, J = 8.8, 2.4
Hz), 8.64 (1H, dt, J = 4.4, 0.8 Hz), 8.67 (1H, d, J = 2.0 Hz).
13C{1H} NMR (100 MHz, CDCl3) δ 106.3, 116.6, 122.7,
123.4, 128.5, 137.6, 139.0, 150.8, 152.2, 153.1, 164.4. IR
(KBr) ν 3045, 2228, 1582, 1572, 1454, 1107, 833 cm-1. MS
(EI) m/z 213 (M+, 45%), 212 (M+-1, 100%). HRMS Calcd for
C11H7N3S: 213.0361. Found: 213.0342.
1-[5-(4-Tolylthio)-2-furanyl]ethanone (12f). Yellow solid
1
(56.4 mg, 97%). M.p. 86.0-86.5 °C (Hexane). H NMR (400
MHz, CDCl3) δ 2.34 (3H, s), 2.44 (3H, s), 6.52 (1H, d, J = 3.6
Hz), 7.13 (1H, d, J = 3.2 Hz), 7.14 (2H, d, J = 8.0 Hz), 7.29
(2H, d, J = 8.4 Hz). 13C{1H} NMR (100 MHz, CDCl3) δ 21.1,
26.0, 117.2, 118.2, 128.9, 130.2, 131.1, 138.3, 151.7, 154.7,
186.3. IR (KBr) ν 3084, 2920, 1650, 1447, 1306, 1036 cm-1.
MS (EI) m/z 232 (M+, 100%), 190 (M+-42, 50%). HRMS
Calcd for C13H12O2S: 232.0558. Found: 232.0550.
6-Chloro-2-(2-pyridinylthio)benzoxazole (15f). Colorless
solid (59.1 mg, 90%). M.p. 77.0-78.0 °C (Ethyl acetate). H
1
NMR (400 MHz, CDCl3) δ 7.27 (1H, m), 7.30 (1H, dd, J =
8.8, 2.0 Hz), 7.49 (1H, d, J = 2.0 Hz), 7.58 (1H, d, J = 8.4 Hz),
7.73 (2H, m), 8.56 (1H, dt, J = 4.8, 1.2 Hz). 13C{1H} NMR
(100 MHz, CDCl3) δ 110.9, 119.9, 123.0, 125.2, 126.3, 130.7,
137.6, 140.5, 150.4, 151.9, 152.4, 161.2. IR (KBr) ν 3070,
3045, 1504, 1424, 1210, 1101, 760 cm-1. MS (EI) m/z 262 (M+,
100%), 227 (M+-35, 15%). HRMS Calcd for C12H7ClN2OS:
261.9968. Found: 261.9966.
2,4-Diphenyl-6-(2-pyridinylthio)-1,3,5-triazine (15a). Color-
less solid (81.4 mg, 95%). M.p. 162.0-163.0 °C (Ethyl acetate).
1H NMR (400 MHz, CDCl3) δ 7.40 (1H, ddd, J = 7.6, 5.2, 1.2
Hz), 7.47 (4H, t, J = 7.6 Hz), 7.56 (2H, tt, J = 7.2, 1.2 Hz),
7.84 (1H, dt, J = 7.6, 2.0 Hz), 7.92 (1H, td, J = 6.8, 0.8 Hz),
8.46 (4H, td, J = 8.4, 1.6 Hz), 8.73 (1H, ddd, J = 4.8, 0.8 Hz).
13C{1H} NMR (100 MHz, CDCl3) δ 123.6, 128.6, 129.0,
130.9, 132.7, 135.3, 136.9, 150.4, 152.2, 170.5, 182.1. IR
(KBr) ν 3049, 2880, 1505, 1362, 1252 cm-1. MS (EI) m/z 342
(M+, 95%), 136 (M+-206, 100%). HRMS Calcd for C20H14N4S:
342.0939. Found: 342.0934.
1-[5-(2-pyridinylthio)-2-furanyl]ethanone (15g). Red solid
(40.1 mg, 73%). M.p. 103.5-104.5 °C (Hexane). 1H NMR
(400 MHz, CDCl3) δ 2.51 (3H, s), 6.91 (1H, d, J = 3.6 Hz),
6.98 (1H, d, J = 8.4 Hz), 7.09 (1H, t, J = 4.8 Hz), 7.26 (1H, d,
J = 3.2 Hz), 7.55 (1H, dt, J = 8.0, 0.8 Hz), 8.43 (1H, d, J = 4.0
Hz). 13C{1H} NMR (100 MHz, CDCl3) δ 26.1, 118.0, 121.0,
121.6, 121.8, 137.2, 146.5, 149.9, 155.8, 158.0, 186.2w26. IR
(KBr) ν 3128, 3085, 1673, 1453, 1287, 942 cm-1. MS (EI) m/z
219 (M+, 100%), 176 (M+-43, 52%). HRMS Calcd for
C11H9NO2S: 219.0354. Found: 219.0374.
4-(2-Pyridinylthio)quinazoline (15b). Pale orange solid
(56.7 mg, 95%). M.p. 116.5-117.5 °C (Hexane/AcOEt = 3/1).
1H NMR (400 MHz, CDCl3) δ 7.37 (1H, t, J = 4.8 Hz), 7.65
(1H, t, J = 8.0 Hz), 7.77-7.85 (2H, m), 7.90 (1H, dt, J = 8.0,
0.8 Hz), 7.99 (1H, d, J = 8.8 Hz), 8.22 (1H, dd, J = 8.4 Hz),
8.71 (1H, dd, J = 5.2, 1.2 Hz), 8.91 (1H, s). 13C{1H} NMR
(100 MHz, CDCl3) δ 123.6, 124.0, 127.8, 128.9, 131.0, 134.1,
137.2, 148.7, 150.7, 151.6, 153.7, 170.3. IR (KBr) ν 3045,
6-(3-Pyridinylthio)-3-pyridinecarbonitrile (15h). Colorless
oil (50.1 mg, 94%). 1H NMR (400 MHz, CDCl3) δ 7.09 (1H,
dd, J = 8.8, 1.2 Hz), 7.44 (1H, ddd, J = 7.6, 4.8, 0.8 Hz), 7.73
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Page 6 of 9
(1H, dd, J = 8.4, 2.0 Hz), 7.93 (1H, dt, J = 8.0, 2.0 Hz), 8.61
13C{1H} NMR (100 MHz, CDCl3) δ 106.7, 116.4, 122.0,
1
2
3
4
5
6
7
8
(1H, dd, J = 2.0, 0.8 Hz), 8.72 (1H, dd, J = 4.8, 1.6 Hz), 8.78
(1H, dd, J = 2.0, 0.8 Hz). 13C{1H} NMR (100 MHz, CDCl3) δ
105.8, 116.5, 120.5, 124.4, 125.9, 139.0, 143.0, 150.7, 152.2,
155.2, 165.2. IR (neat) ν 3046, 2231, 1582, 1455, 1103 cm-1.
MS (EI) m/z 213 (M+, 28%), 212 (M+-1, 100%). HRMS Calcd
for C11H6N3S (M+-H): 212.0277. Found: 212.0274. The mass
spectrometry of the compound 15i (C11H7N3S, Calcd:
213.0361) was not analyzed to overlap with the mass peak
including a isotope of the carbon (C1013CH7N3S, Calcd:
213.0311). Therefore, the high-resolution mass spectrometry
was analyzed in M+-H.
127.6, 139.3, 140.3, 150.6, 152.5, 163.3. IR (KBr) ν 3077,
2228, 1099, 806 cm-1. MS (EI) m/z 213 (M+, 44%), 212 (M+-1,
100%). HRMS Calcd for C14H7ClF3NS: 312.9940. Found:
312.9917. The structure of 15m was also determined by x-ray
analysis. X Ray Crystallography: CCDC-1484411 contains the
supplementary crystallographic data for this paper. The data
can be obtained free of charge from the Cambridge Crystal-
lographic
www.ccdc.cam.ac.uk/data_request/cif.
2-(4-Pyridinylthio)-4-(trifluoromethyl)pyrimidine
Data
Centre
via
9
(15n).
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19
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Brown solid (33.0 mg, 51%). M.p. 149.0-150.0 °C (Ethyl
1
6-Chloro-2-(3-pyridinylthio)benzoxazole (15i). Colorless
solid (57.3 mg, 87%). M.p. 121.0-122.0 °C (Ethyl acetate). 1H
NMR (400 MHz, CDCl3) δ 7.27 (1H, d, J = 8. 0 Hz), 7.46 (3H,
m), 8.06 (1H, d, J = 8.0 Hz), 8.72 (1H, d, J = 4.4 Hz), 8.89
(1H, d, J = 1.2 Hz). 13C{1H} NMR (100 MHz, CDCl3) δ 110.7,
119.5, 124.3, 124.4, 125.2, 130.2, 140.4, 142.0, 150.8, 151.9,
154.2, 162.7. IR (KBr) ν 3102, 3048, 3008, 1506, 1017 cm-1.
MS (EI) m/z 262 (M+, 100%), 227 (M+-35, 15%). HRMS
Calcd for C12H7ClN2OS: 261.9968. Found: 261.9966.
acetate:Hexane = 4:1). H NMR (400 MHz, CDCl3) δ 7.43
(2H, d, J = 6.0 Hz), 7.64 (1H, d, J = 5.2 Hz), 8.64 (2H, d, J =
6.0 Hz), 9.06 (1H, dd, J = 4.8, 0.4 Hz). 13C{1H} NMR (100
MHz, CDCl3) δ 114.7, 119.7 (q, J = 274.0 Hz), 127.4, 130.8,
155.7, 157.6 (q, J = 37.3 Hz), 161.9, 199.9. 19F-NMR (376
MHz, CDCl3) δ -70.0. IR (KBr) ν 3049, 2880, 1505, 1362,
1252 cm-1. MS (EI) m/z 257 (M+, 100%). HRMS Calcd for
C10H6F3N3S: 257.0235. Found: 257.0225.
6-Chloro-2-(4-pyridinylthio)benzoxazole (15o). Colorless
solid (39.3 mg, 60%). M.p. 145.0-146.0 °C (Hexane:Ethyl
acetate = 4:1). 1H NMR (400 MHz, CDCl3) δ 7.33 (1H, dd, J
= 8.4, 2.0 Hz), 7.50 (1H, d, J = 2.0 Hz), 7.57 (2H, dd, J = 4.8,
1.6 Hz), 7.58 (1H, d, J = 8.4 Hz), 8.64 (2H, dd, J = 4.8, 1.6
Hz). 13C{1H} NMR (100 MHz, CDCl3) δ 111.0, 119.9, 125.47,
125.52, 131.0, 139.2, 140.2, 150.4, 151.8, 160.3. IR (KBr) ν
3028, 2980, 1508, 1209, 809 cm-1. MS (EI) m/z 262 (M+,
100%), 227 (M+-35, 21%). HRMS Calcd for C12H7ClN2OS:
261.9968. Found: 261.9945.
2-(3-Pyridinylthio)benzothiazole (15j). Colorless solid (57.9
1
mg, 95%). M.p. 98.0-99.0 °C (Ethyl acetate). H NMR (400
MHz, CDCl3) δ 7.30 (1H, m), 7.42 (2H, m), 7.69 (1H, ddd, J
= 8.0, 1.2, 0.4 Hz), 7.89 (1H, ddd, J = 7.6, 1.2, 0.4 Hz), 8.05
(1H, ddd, J = 8.0, 2.4, 1.6 Hz), 8.72 (1H, dd, J = 4.8, 2.0 Hz),
8.92 (1H, dd, J = 2.4, 0.8 Hz). 13C{1H} NMR (100 MHz,
CDCl3) δ 120.8, 122.1, 124.4, 124.7, 126.3, 127.5, 135.5,
142.3, 150.9, 153.5, 154.6, 166.6. IR (KBr) ν 3033, 1566,
1461, 1426, 1407, 1006 cm-1. MS (EI) m/z 244 (M+, 66%),
243 (M+-1, 100%). HRMS Calcd for C12H7N2S2 (M+-H):
243.0045. Found: 243.0050. The mass spectrometry of the
compound 15g (C12H8N2S2, Calcd: 244.0129) was not ana-
lyzed to overlap with the mass peak including a isotope of the
carbon (C1113CH8N2S2, Calcd: 244.0079). Therefore, the high-
resolution mass spectrometry was analyzed in M+-H.
6-(2-Furylthio)-3-pyridinecarbonitrile (15p). Brown solid
1
(30.8 mg, 61%). M.p. 73.0-74.0 °C (Ethyl acetate). H NMR
(400 MHz, CDCl3) δ 6.54 (1H, dd, J = 2.0, 0.8 Hz), 7.07 (1H,
dd, J = 8.4, 0.8 Hz), 7.62 (1H, t, J = 2.0 Hz), 7.70 (1H, dd, J =
8.4, 2.0 Hz), 7.73 (1H, dd, J = 1.6, 0.8 Hz), 8.65 (1H, dd, J =
2.0, 0.8 Hz). 13C{1H} NMR (100 MHz, CDCl3) δ 105.3, 109.9,
114.6, 116.7, 119.6, 139.0, 145.0, 147.7, 152.1, 167.1. IR
(KBr) ν 3033, 2225, 1584, 1435 cm-1. MS (EI) m/z 202 (M+,
100%). HRMS Calcd for C10H6N2OS: 202.0201. Found:
202.0191.
6-Methyl-2-(3-pyridinylthio)benzothiazole (15k). Colorless
1
solid (53.9 mg, 89%). M.p. 96.0-97.0 °C (Ethyl acetate). H
NMR (400 MHz, CDCl3) δ 2.44 (3H, s), 7.09 (1H, d, J = 7.6
Hz), 7.22 (1H, s), 7.39 (1H, ddd, J = 8.0, 5.2, 0.8 Hz), 7.46
(1H, d, J = 8.0 Hz), 8.04 (1H, ddd, J = 8.0, 2.4, 2.0 Hz), 8.68
(1H, dd, J = 4.8, 1.6 Hz), 8.88 (1H, dd, J = 2.4, 0.8 Hz).
13C{1H} NMR (100 MHz, CDCl3) δ 21.6, 110.3, 118.5, 124.3,
125.2, 125.7, 135.1, 139.5, 141.7, 150.5, 152.1, 153.9, 160.7.
IR (KBr) ν 1510, 1217, 1091 cm-1. MS (EI) m/z 242 (M+,
100%), 241 (M+-1, 52%). HRMS Calcd for C13H10N2OS:
242.0514. Found: 242.0515.
6-Chloro-2-(furylthio)benzoxazole (15q). Colorless solid
1
(50.3 mg, 80%). M.p. 87.0-87.5 °C (Ethyl acetate). H NMR
(400 MHz, CDCl3) δ 6.67 (1H, dd, J = 1.6, 0.8 Hz), 7.26 (1H,
dd, J = 8.4, 2.0 Hz), 7.45 (1H, d, J = 2.0 Hz), 7.50 (1H, d, J =
8.4 Hz), 7.59 (1H, t, J = 1.6 Hz), 7.79 (1H, dd, J = 1.6, 0.8
Hz). 13C{1H} NMR (100 MHz, CDCl3) δ 107.6, 110.7, 114.6,
119.4, 125.1, 129.9, 140.7, 144.5, 147.1, 152.0, 163.7. IR
(KBr) ν 3130, 1508, 1461, 1257 cm-1. MS (EI) m/z 251 (M+,
100%). HRMS Calcd for C11H6ClNO2S: 250.9808. Found:
250.9789.
N-Methyl-2-(3-pyridinylthio)benzimidazole (15l). Colorless
1
solid (50.5 mg, 84%). M.p. 95.5-96.5 °C (Ethyl acetate). H
NMR (400 MHz, CDCl3) δ 3.79 (3H, s), 7.28 (4H, m), 7.77
(1H, ddd, J = 8.0, 2.4, 1.6 Hz), 8.51 (1H, dd, J = 4.4, 1.6 Hz),
8.66 (1H, dd, J = 2.4, 0.4 Hz). 13C{1H} NMR (100 MHz,
CDCl3) δ 30.7, 109.4, 119.8, 122.6, 123.4, 124.1, 129.3, 136.4,
138.4, 143.1, 146.6, 148.8, 150.9. IR (KBr) ν 3050, 1567,
1327, 1017 cm-1. MS (EI) m/z 241 (M+, 78%), 240 (M+-1,
100%). HRMS Calcd for C13H11N3S: 241.0674. Found:
241.0672.
6-Chloro-2-(2-thienylthio)benzoxazole (15r). Yellow solid
1
(62.3 mg, 93%). M.p. 75.0-76.0 °C (Ethyl acetate). H NMR
(400 MHz, CDCl3) δ 7.15 (1H, dd, J = 5.6, 4.0 Hz), 7.25 (1H,
dd, J = 8.4, 1.6 Hz), 7.42 (1H, d, J = 2.0 Hz), 7.48 (1H, dd, J =
3.6, 1.2 Hz), 7.50 (1H, d, J = 8.8 Hz), 7.63 (1H, dd, J = 5.6,
1.6 Hz). 13C{1H} NMR (100 MHz, CDCl3) δ 110.8, 119.6,
122.4, 125.1, 128.1, 130.0, 133.3, 138.0, 140.6, 151.9, 163.7.
IR (KBr) ν 3065, 1493, 1458, 1216, 911 cm-1. MS (EI) m/z
267 (M+, 100%), 115 (M+-152, 37%). HRMS Calcd for
C11H6ClNOS2: 266.9579. Found: 266.9610. The structure of
15r was also determined by x-ray analysis. X-Ray Crystallog-
raphy: CCDC-1506251 contains the supplementary crystal-
6-(4-Pyridinylthio)-3-pyridinecarbonitrile (15m). Orange
solid (42.8 mg, 80%). M.p. 114.5-115.5 °C (Ethyl acetate). 1H
NMR (400 MHz, CDCl3) δ 7.26 (1H, dd, J = 8.4, 1.2 Hz),
7.48 (2H, dd, J = 4.4, 1.2 Hz), 7.79 (1H, dd, J = 8.4, 2.4 Hz),
8.67 (2H, dd, J = 4.4, 1.6 Hz), 8.69 (1H, dd, J = 2.0, 0.8 Hz).
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AUTHOR INFORMATION
lographic data for this paper. The data can be obtained free of
1
charge from the Cambridge Crystallographic Data Centre via
Corresponding Author
2
www.ccdc.cam.ac.uk/data_request/cif.
* E-mail: yama@m.tohoku.ac.jp, arisawa@m.tohoku.ac.jp
3
4
5
6
7
8
9
4,5-Diphenyl-2-(2-furylthio)oxazole (15s). Colorless solid
(36.0 mg, 45%). M.p. 93.0-94.0 °C (Ethyl acetate). H NMR
1
ACKNOWLEDGMENT
(400 MHz, CDCl3) δ 6.68 (1H, dd, J = 1.6, 0.8 Hz), 7.34 (6H,
m), 7.51 (3H, m), 7.62 (2H, dd, J = 8.4, 4.0 Hz), 7.76 (1H, m).
13C{1H} NMR (100 MHz, CDCl3) δ 109.3, 114.6, 126.3,
127.9, 128.3, 128.4, 128.5, 128.6, 131.8, 136.8, 144.0, 146.2,
147.7, 156.6. IR (KBr) ν 3128, 1505, 1206, 1014 cm-1. MS
(EI) m/z 319 (M+, 100%). HRMS Calcd for C19H13NO2S:
319.0667. Found: 319.0666. One carbon peak of aromatic
region was overlapped in 13CNMR.
This research is partially supported by the Platform Project for
Supporting in Drug Discovery and Life Science Research (Plat-
form for Drug Discovery, Informatics,and Structural Life Sci-
ence) from the Ministry of Education, Culture, Sports, Science
and Technology (MEXT) and Japan Agency for Medical Re-
search and development (AMED). M. A. expresses her apprecia-
tion to the financial supports from JSPS KAKENHI Grant Num-
ber JP15H00911.
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1-[5-(2-Furylthio)-2-furanyl]ethanone (15t). Brown oil
(51.6 mg, 99%). 1H NMR (400 MHz, CDCl3) δ 2.44 (3H, s),
6.41 (1H, d, J = 3.6 Hz), 6.50 (1H, dd, J = 1.6, 0.8 Hz), 7.12
(1H, d, J = 3.6 Hz), 7.47 (1H, t, J = 1.6 Hz), 7.64 (1H, dd, J =
1.6, 1.2 Hz). 13C{1H} NMR (100 MHz, CDCl3) δ 25.8, 111.9,
113.8, 114.5, 118.5, 144.1, 145.4, 151.9, 154.1, 185.9. IR
(neat) ν 3139, 1677, 1456, 1012 cm-1. MS (EI) m/z 208 (M+,
100%), 166 (M+-42, 29%). HRMS Calcd for C10H8O3S:
208.0194. Found: 208.0202.
REFERENCES
[1] For examples, a) Li, W.-W.; Wang, X.-Y.; Zheng, R.-L.; Yan, H.-
X.; Cao, Z.-X.; Zhong, L.; Wang, Z.-R.; Ji, P.; Yang, L.-L.; Wang,
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Q.-Z.; Wei, Y.-Q.; Yang, S.-Y. J. Med. Chem. 2012, 55, 3852. b) De,
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Pellecchia, M. J. Med. Chem., 2009, 52, 1943. c) Zhang, L.; Fan, J.;
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Fitchett, C. M.; Steel, P. J. Inorg. Chim. Acta, 2000, 310, 127.
[2] Exceptionally, the reaction of heteroaryl chlorides and thiourea
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nakumar, V.; Khan, F.-R. N.; Maiyalagan, T. Ind. Eng. Chem. Res.
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[3] Using thiol, a) Pathak, A. K.; Pathak, V.; Seitz, L. E.; Suling, W.
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[4] Copper-catalyzed reaction, a) Lee, O. S.; Lee, H.; Kim, H.; Shin,
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Cao, X.; Wu, D.; Wan, J.-P. RSC Adv., 2014, 4, 37733. c) Aleshunin,
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1-[5-(2-Thienylthio)-2-furyl]ethanone (15u). Yellow solid
1
(44.9 mg, 80%). M.p. 73.5-74.5 °C (Ethyl acetate). H NMR
(400 MHz, CDCl3) δ 2.44 (3H, s), 6.46 (1H, d, J = 3.6 Hz),
7.03 (1H, dd, J = 5.2, 3.6 Hz), 7.11 (1H, d, J = 4.0 Hz), 7.33
(1H, dd, J = 3.2, 1.2 Hz), 7.45 (1H, dd, J = 5.6, 1.6 Hz).
13C{1H} NMR (100 MHz, CDCl3) δ 25.9, 115.3, 118.2, 127.8,
128.3, 131.3, 135.3, 152.0, 154.3, 186.2. IR (KBr) ν 3079,
1651, 1448, 1027 cm-1. MS (EI) m/z 224 (M+, 100%), 182
(M+-42, 34%). HRMS Calcd for C10H8O2S2: 223.9966. Found:
223.9968.
Procedure for Oxidation reaction of 6-(2-pyridinylthio)-
3-pyridinecarbonitrile
15e.
(2-Pyridinylthio)-3-
pyridinecarbonitrile 15e (0.25 mmol, 53.3 mg) dissolved
in CH2Cl2 (1.25 mL) at 0°C under an argon atomosphere. A
solution of m-CPBA (0.25 mmol, 43.4 mg) in CH2Cl2 (1.0
mL) was added dropwise to the cooled solution. The mixture
was stirred at 0°C for 6 h and then extracted sequentially with
2M NaOH, 1M HCl, and 10% NaHCO3. The organic layer
was dried over MgSO4, and filtered. Solvent was removed
under reduced pressure, and the residue was purified by flash
column chromatography on silica gel (eluent: ethyl acetate)
giving 6-(2-pyridinylsulfinyl)-3-pyridinecarbonitrile 16 (25.8
mg, 45%). M.p. 140.0-141.0 °C (Ethyl acetate). 1H NMR (400
MHz, CDCl3) δ 7.39 (1H, ddd, J = 8.0, 4.8, 1.2 Hz), 7.90 (1H,
dt, J = 7.6, 1.6 Hz), 8.01 (1H, d, J = 8.0 Hz), 8.14 (1H, dd, J =
8.0, 1.6 Hz), 8.23 (1H, dd, J = 8.0, 0.8 Hz), 8.65 (1H, m), 8.87
(1H, dd, J = 2.0, 0.8 Hz). 13C{1H} NMR (100 MHz, CDCl3) δ
111.2, 115.6, 119.5, 119.9, 125.6, 138.3, 141.2, 150.5, 152.3,
162.8, 168.7. IR (KBr) ν 3434, 2233, 1576, 1450, 1054 cm-1.
MS (EI) m/z 229 (M+, 100%). HRMS Calcd for C11H7N3OS:
229.0310. Found: 229.0309.
[5] Dai, C.; Xu, Z.; Huang, F.; Yu, Z.; Gao, Y.-F. J. Org. Chem. 2012,
77, 4414.
[6] Arisawa, M. Tetrahedron Lett. 2014, 55, 3391.
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31G**//B3LYP_6-311G** were used.
[9] It was reported that diphenyl ether can be synthesis by dehydra-
tion of phenol, and accordingly diaryl/heteroaryl sulfides can in prin-
ciple be obtained from phenols without using base, employing the
present method. a) Zsolczai, D.; Németh, J.; Hell, Z. Tetrahedron
Lett., 2015, 56, 6389. b) Buske, G. R.; Garces, J. M.; Dianis, W. P.
U.S. (1994), US 5288922. c) Karuppannasamy, S.; Narayanan, K.;
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ASSOCIATED CONTENT
[10] Li, G.; Arisawa, M.; Yamaguchi, M. Chem. Commun., 2014, 50,
4328.
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI:
1H, 13C, and 19F spectra of compounds 3a-3d, 4, 6, 9, 10, 12a-
12f, 15a-15u, and 16, X-ray crystallographic data of 15m and 15r,
and Computational Studies including cartesian coordinates.
[11] Crystallographic data including structure factors have been de-
posited with the Cambridge Crystallographic Data Centre as supple-
mentary publication number CCDC 1484411 and 1506251 for com-
pounds 15k and 15p. A copy of the data can be obtained free of
charge from CCDC, 12 Union Road, Cambridge CB2 1EZ, UK or e-
mail: deposit@ccdc.cam.ac.uk.
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[19] Qi, X.; Li, C.-L.; Jiang, L.-B.; Zhang, W.-Q.; Wu, X.-F. Catal.
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5
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O
Y'
Y'
O
X
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Rh cat.
+
+
OAr
X'
X'
OAr
Ph
Y
Ph
S
S
Ar = 4-ClC6H4
X
Y
X'
Y'
Five- and Six-membered heteroarenes,
Arenes
=
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