Microwave-assisted efficient synthesis of aryl thioethers through C-H functionalization of arenes

Article abstract of DOI:10.1055/s-0033-1339666

Microwave-assisted iridium-catalyzed meta C-H borylation followed by copper-promoted C-S bond coupling reactions in one pot is reported. This approach enables the syntheses of aryl thioethers in short reaction times (within 2.5 hours). The system shows go

Full text of DOI:10.1055/s-0033-1339666

2320▌
LETTER
lMetteircrowave-Assisted Efficient Synthesis of Aryl Thioethers through C–H
Functionalization of Arenes
Synthesis of Aryl Thioethers
Yi-Chen Liu, Chin-Fa Lee*
Department of Chemistry, National Chung Hsing University, Taichung 402, Taiwan
Fax +886(4)22862547; E-mail: cfalee@dragon.nchu.edu.tw
Received: 21.07.2013; Accepted: 03.08.2013
nique.24–27 Herein, we report the microwave-assisted (1)
Abstract: Microwave-assisted iridium-catalyzed meta C–H bory-
iridium-catalyzed C–H borylation27 and (2) copper-cata-
lyzed C–S bond-forming process.
lation followed by copper-promoted C–S bond coupling reactions
in one pot is reported. This approach enables the syntheses of aryl
thioethers in short reaction times (within 2.5 hours). The system
As illustrated in Table 1, m-chlorotoluene (1a) was treated
shows good functional-group compatibility, as chloro, trifluoro-
with pin2B2 under microwave-promoted iridium-cata-
methyl, fluoro, and pyridine groups are tolerated by the reaction
lyzed borylation,27 after removal of the volatile compo-
conditions. Both aryl and alkyl thiols are coupled smoothly. The
nents, the resulting arylboronate was then conducted with
products were formed with excellent regioselectivity in meta posi-
thiophenol in the presence of 1.5 equivalents of Cu(OAc)2
and 3 equivalents of pyridine in methyl tert-butyl ether
(MTBE), the reaction was subjected to microwave irradi-
ation for 1.5 hours at 135 °C (without further optimiza-
tion) to give the product 2a with a 60% yield in one pot
(Table 1, entry 1).28 Other arenes were sequentially react-
ed with pin2B2 under iridium-catalyzed borylation, fol-
lowed by copper-promoted C–S coupling reaction with
aryl thiols. Aryl thiols bearing electron-donating or elec-
tron-withdrawing groups such as methoxy, trifluorometh-
yl, chloro, and fluoro in the benzene rings are suitable as
the coupling partners. Notable, this system shows good
functional-group tolerance, chloro, trifluoromethyl, and
fluoro groups are all tolerated under the reaction condi-
tions. The products were obtained with high meta regiose-
lectivity in all cases, this two-step process takes a short
reaction time of 2.5 hours.
tion.
Key words: microwave, aryl thioether, iridium, copper, C–H func-
tionalization, arene
From an atom-economy point of view, transition-metal-
catalyzed C–H functionalization1 is an attractive strategy
for constructing carbon–carbon2 and carbon–heteroatom
bonds.3,4 Compared with C–C, C–O, and C–N bond for-
mations, the C–S bond-coupling reaction through C–H ac-
tivation is relatively less studied because of the strong
binding affinity between the sulfur moiety and transition
metals which might inhibit the activity of the metals.5–9 2-
Phenylpyridine has been described to form C–S bonds
with high ortho regioselectivity through copper5 or
palladium6 catalysis. Notably, pyridine has played an im-
portant role as a directing group in these two protocols.5,6
The copper-7 and palladium-catalyzed8 C–S bond forma-
tion via C–H activation without directing group has been
reported. However, some limitations remain with these
systems.7,8 First, these systems need electron-rich arenes
as the starting materials. Second, the systems produce or-
tho and para products, moreover, the mixtures of ortho-
and para-arylthiolated products were formed at the same
time in most cases. Interestingly, Frost et al. reported the
first ruthenium-catalyzed meta sulfonation of 2-phenyl-
pyridines, however, pyridine is necessary as a directing
group.9 Aryl thioethers are important motifs in pharma-
ceuticals.10 Many methods have been reported for prepar-
ing aryl thioethers.11–20 We have recently reported the
one-pot meta C–H thioetherification of arenes without a
directing group21 through iridium-catalyzed C–H
borylation22 followed by copper-catalyzed C–S bond for-
mation.23 In general, it requires 48 hours for this two-step
process. Microwave irradiation has been widely applied to
organic synthesis due to the high efficiency of this tech-
It is known that the alkyl thiols are less reactive for the
coupling with arylboronates,21 therefore we turned our at-
tention to alkyl thiols for this one-pot reaction. To our de-
light, the products were formed in good to excellent
yields. The results are summarized in Table 2, alkyl thiols
such as dodecanethiol (Table 2, entries 1, 4, 8, 11, and 15),
2-methy-1-butanethiol (Table 2, entries 2, 5, 9, and 12),
cyclohexanethiol (Table 2, entries 3, 6, 10, and 13), ben-
zyl mercaptan (Table 2, entries 7 and 14) are coupled with
a variety of starting arenes, giving aryl alkyl thioethers in
moderate to good yields. Notably, this operation takes
only 2.5 hours for two steps in one pot. Furthermore, func-
tional groups including chloro, trifluoromethyl, and pyri-
dine are stable during the catalysis.
In conclusion, we have developed a convenient protocol
to access diaryl and aryl alkyl thioethers under micro-
wave-promoted sequential iridium-catalyzed borylation
and copper-promoted C–S bond-forming reaction from
simple arenes in one pot. This two-step process takes only
2.5 hours to give the corresponding thioethers in good to
excellent yields with excellent meta regioselectivity. This
system shows good functional-group tolerance; chloro,
trifluoromethyl, fluoro, and pyridine are all tolerated by
the reaction conditions employed.
SYNLETT 2013, 24, 2320–2326
Advanced online publication: 13.09.2013
DOI: 10.1055/s-0033-1339666; Art ID: ST-2013-W0681-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

LETTER
Synthesis of Aryl Thioethers
2321
Table 1 Microwave-Promoted Tandem Iridium-Catalyzed Borylation and Copper-Promoted Coupling with Aryl Thiolsa
Cu(OAc)2
(1.5 equiv)
pyridine
(3 equiv)
RSH
R2
S
R2
[Ir(cod)OMe]2 (1.5 mol%)
dtbpy (3 mol%), pin2B2
MTBE, MW 80 °C, 1 h, N2
R
then remove
volatile components
DMF, MW 135 °C
1.5 h, Ar
R1
2
R1
1
Entry
1
1
Product
Yield (%)
Cl
Cl
Cl
Cl
Cl
Cl
S
S
S
S
S
1a
2a
60
2
3
4
5
1a
1a
1a
1a
2b
2c
2d
2e
47
78
60
50
OMe
CF3
Cl
F
Cl
Cl
S
S
6
1a
2f
50
Cl
7
8
1b
2g
2h
2i
61
46
62
68
53
Cl
Cl
Cl
Cl
Cl
S
S
1b
1b
OMe
CF3
Cl
9
MeO
MeO
S
S
MeO
10
11
1c
1c
2j
Cl
Cl
2k
OMe
Cl
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2320–2326

2322
Y.-C. Liu, C.-F. Lee
LETTER
Table 1 Microwave-Promoted Tandem Iridium-Catalyzed Borylation and Copper-Promoted Coupling with Aryl Thiolsa (continued)
Cu(OAc)2
(1.5 equiv)
pyridine
(3 equiv)
RSH
R2
S
R2
[Ir(cod)OMe]2 (1.5 mol%)
dtbpy (3 mol%), pin2B2
MTBE, MW 80 °C, 1 h, N2
R
then remove
volatile components
DMF, MW 135 °C
1.5 h, Ar
R1
2
R1
1
Entry
12
1
Product
Yield (%)
46
MeO
MeO
S
S
CF3
1c
2l
Cl
Cl
13
14
1c
1c
2m
2n
50
65
Cl
MeO
F3C
S
Cl
S
F3C
15
16
1d
1d
2o
2p
70
70
CF3
CF3
F3C
S
CF3
CF3
F3C
S
17
1d
2q
63
CF3
a Reaction conditions unless otherwise stated: arene (1.0 mmol), [Ir(cod)OMe]2 (0.015 mol, 1.5 mol%), dtbpy (0.03 mmol, 3.0 mol%) in MTBE
(2.0 mL) for the first step; Cu(OAc)2 (0.75 mmol, 1.5 equiv), pyridine (1.5 mmol, 3 equiv), aryl thiol (0.5 mmol) in DMF (2 mL) under argon
atmosphere for the second step.
Table 2 Microwave-Assisted Sequential Iridium-Catalyzed Borylation and Copper-Promoted Coupling with Alkyl Thiolsa
Entry
1
Product
Yield (%)
90
Cl
Cl
S
S
C12H25
1
1a
3a
2
1a
3b
68
Synlett 2013, 24, 2320–2326
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Aryl Thioethers
2323
Table 2 Microwave-Assisted Sequential Iridium-Catalyzed Borylation and Copper-Promoted Coupling with Alkyl Thiolsa (continued)
Entry
3
1
Product
Yield (%)
Cl
Cl
S
S
1a
3c
91
75
C12H25
4
1b
3d
Cl
Cl
Cl
S
S
5
6
1b
1b
3e
3f
83
85
Cl
Cl
Cl
S
7
1b
3g
55
Cl
MeO
S
C12H25
8
9
1c
1c
3h
3i
78
65
Cl
Cl
MeO
MeO
F3C
S
S
10
11
1c
3j
71
60
Cl
S
C12H25
1d
3k
CF3
F3C
S
S
12
13
1d
1d
3l
57
55
CF3
F3C
3m
CF3
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2320–2326

2324
Y.-C. Liu, C.-F. Lee
LETTER
Table 2 Microwave-Assisted Sequential Iridium-Catalyzed Borylation and Copper-Promoted Coupling with Alkyl Thiolsa (continued)
Entry
14
1
Product
Yield (%)
F3C
S
1d
3n
66
CF3
t-Bu
S
t-Bu
C12H25
15
1e
3o
45
N
N
t-Bu
t-Bu
a Reaction conditions unless otherwise stated: arene (1.0 mmol), [Ir(cod)OMe]2 (0.015 mol, 1.5 mol%), dtbpy (0.03 mmol, 3.0 mol%) in MTBE
(2.0 mL) for the first step; Cu(OAc)2 (0.75 mmol, 1.25 equiv), pyridine (1.5 mmol, 2.5 equiv), alkyl thiol (0.5 mmol) in DMF (2 mL) under
argon atmosphere for the second step.
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Acknowledgment
The National Science Council, Taiwan (NSC 101-2113-M-005-
008-MY3), the National Chung Hsing University, and the Center of
Nanoscience and Nanotechnology (NCHU) are gratefully acknowl-
edged for financial support. We also thank Prof. Fung-E Hong
(NCHU) for sharing his GC–MS instruments. C.F.L. is a Golden-
Jade Fellow of Kenda Foundation, Taiwan.
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Synlett 2013, 24, 2320–2326
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LETTER
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Synthesis of Aryl Thioethers
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(28) General Procedure for the Synthesis of Compounds 2a–q
A flask equipped with a magnetic stirrer bar was charged
with [Ir(cod)OMe)]2 (99.0 mg, 0.015 mmol), 4,4′-di-tert-
butyl-2,2′-dipyridyl (82.0 mg, 0.03 mmol) and pin2B2 (254
mg, 1.0 mmol) in a nitrogen-filled glove box. This flask was
then covered with a rubber septum and removed from the
glove box. Under a nitrogen atmosphere, arene (1.0 mmol)
and MTBE (2.0 mL) were added via syringe, and the
reaction vessel was placed under microwave irradiation at
80 °C. After stirring at this temperature for 1 h, the
heterogeneous mixture was cooled to r.t., after removal of
the volatile components under vacuum. The flask was
returned to the glove box, Cu(OAc)2 (136 mg, 0.75 mmol)
was added, the flask was then covered with a rubber septum
and removed from the glove box. Under an argon
atmosphere, aryl thiol (0.5 mmol), pyridine (0.123 mL, 1.5
mmol), and DMF (2.0 mL) were added via syringe, and the
reaction vessel was placed under microwave irradiation at
135 °C. After stirring at this temperature for 1.5 h, the
heterogeneous mixture was cooled to r.t. and diluted with
EtOAc (20 mL). The resulting solution was directly filtered
through a pad of silica gel then washed with EtOAc (20 mL)
and concentrated to give the crude material which was then
purified by column chromatography (SiO2, hexane) to yield
2.
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295, 305. (f) Litvinas, N. D.; Fier, P. S.; Hartwig, J. F.
Angew. Chem. Int. Ed. 2012, 51, 536; Angew. Chem. 2012,
124, 551 . (g) Liu, T.; Shao, X.; Wu, Y.; Shen, Q. Angew.
Chem. Int. Ed. 2012, 51, 540; Angew. Chem. 2012, 124, 555.
(h) Crawford, A. G.; Liu, Z.; Mkhalid, I. A. I.; Thibault,
M.-H.; Schwarz, N.; Alcaraz, G.; Steffen, A.; Collings, J. C.;
Batsanov, A. S.; Howard, J. A. K.; Marder, T. B. Chem. Eur.
J. 2012, 18, 5022. (i) Liskey, C. W.; Liao, X.; Hartwig, J. F.
J. Am. Chem. Soc. 2010, 132, 11389. (j) Boebel, T. A.;
Hartwig, J. F. Tetrahedron 2008, 64, 6824.
Data for some representative examples are shown here.
3-Chloro-5-methylphenyl Phenyl Sulfide (2a)21a
Following the general procedure, using [Ir(cod)OMe]2 (99.0
mg, 0.015 mmol), 4,4′-di-tert-butyl-2,2′-dipyridyl (82.0 mg,
0.03 mmol), pin2B2 (254 mg, 1.0 mmol), and 3-
chlorotoluene (0.123 mL, 1.0 mmol) in MTBE (2.0 mL) for
the first step. After removal of the volatile components under
vacuum, Cu(OAc)2 (136 mg, 0.75 mmol), thiophenol (0.053
mL, 0.5 mmol), and DMF (2.0 mL) were used, then purified
by column chromatography (SiO2, hexane) to provide 2a as
a colorless oil (70.0 mg, 60% yield). 1H NMR (400 MHz,
CDCl3): δ = 2.23 (s, 3 H), 6.97–7.04 (m, 3 H), 7,25–7.38 (m,
5 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.0, 126.6,
127.5, 127.7, 128.7, 129.3, 132.0, 134.1, 134.4, 138.0, 140.4
ppm.
(23) (a) Herradura, P. S.; Pendola, K. A.; Guy, R. K. Org. Lett.
2000, 2, 2019. (b) Savarin, C.; Srogl, J.; Liebeskind, L. S.
Org. Lett. 2002, 4, 4309. (c) Taniguchi, N. J. Org. Chem.
2007, 72, 1241.
(24) (a) Kappe, C. O.; Dallinger, D.; Murphree, S. S. In Practical
Microwave Synthesis for Organic Chemists: Strategies,
Instruments, and Protocols; Wiley-VCH: Weinheim, 2009.
(b) Microwave Methods in Organic Synthesis, In Topics in
3-Chloro-5-methylphenyl 4-Methoxyphenyl Sulfide
(2b)21a
Following the general procedure, using [Ir(cod)OMe)]2
(99.0 mg, 0.015 mmol), 4,4′-di-tert-butyl-2,2′-dipyridyl
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2320–2326

2326
Y.-C. Liu, C.-F. Lee
LETTER
(82.0 mg, 0.03 mmol), pin2B2 (254 mg, 1.0 mmol), and 3-
chlorotoluene (0.123 mL, 1.0 mmol) in MTBE (2.0 mL) for
the first step. After removal of the volatile components under
vacuum, Cu(OAc)2 (136 mg, 0.75 mmol), 4-methoxy-
thiophenol (0.063 mL, 0.5 mmol), and DMF (2.0 mL) were
used, then purified by column chromatography (SiO2,
hexane) to provide 2b as a colorless oil (62.0 mg, 47%
yield). 1H NMR (400 MHz, CDCl3): δ = 2.20 (s, 3 H), 3.78
3-Chloro-5-methylphenyl 4-Chlorophenyl Sulfide (2d)21a
Following the general procedure, using [Ir(cod)OMe)]2
(99.0 mg, 0.015 mmol), 4,4′-di-tert-butyl-2,2′-dipyridyl
(82.0 mg, 0.03 mmol), pin2B2 (254 mg, 1.0 mmol), and 3-
chlorotoluene (0.123 mL, 1.0 mmol) in MTBE (2.0 mL) for
the first step. After removal of the volatile components under
vacuum, Cu(OAc)2 (136 mg, 0.75 mmol), 4-chlorothio-
phenol (74 mg, 0.5 mmol), and DMF (2.0 mL) were used,
then purified by column chromatography (SiO2, hexane) to
provide 2d as a colorless oil (0.081 g, 65% yield). 1H NMR
(400 MHz, CDCl3): δ = 2.27 (s, 3 H), 6.98 (s, 1 H), 7.03 (s,
1 H), 7.05 (s, 1 H), 7.29 (s, 4 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 21.1, 127.0, 128.0, 129.1, 129.5, 133.0, 133.1,
133.8, 134.6, 137.3, 140.7 ppm.
(s, 3 H), 6.82–6.90 (m, 5 H), 7.39–7.41 (m, 2 H) ppm. 13
C
NMR (100 MHz, CDCl3): δ = 21.1, 55.2, 115.0, 122.7,
124.0, 126.1, 126.3, 134.3, 136.0, 140.1, 140.7, 160.1 ppm.
3-Chloro-5-methylphenyl 3-Trifluoromethyl Phenyl
Sulfide (2c)
Following the general procedure, using [Ir(cod)OMe]2 (99.0
mg, 0.015 mmol), 4,4′-di-tert-butyl-2,2′-dipyridyl (82.0 mg,
0.03 mmol), pin2B2 (254 mg, 1.0 mmol), and 3-
chlorotoluene (0.123 mL, 1.0 mmol) in MTBE (2.0 mL) for
the first step. After removal of the volatile components under
vacuum, Cu(OAc)2 (136 mg, 0.75 mmol), 3-trifluoro-
methylthiophenol (0.070 mL, 0.5 mmol), and DMF (2.0 mL)
were used, then purified by column chromatography (SiO2,
hexane) to provide 2c as a colorless oil (118.0 mg, 78%
yield). 1H NMR (400 MHz, CDCl3): δ = 2.29 (s, 3 H), 7.08
(d, J = 7.6 Hz, 2 H), 7.14 (s, 1 H), 7.40–7.49 (m, 3 H), 7.58
(s, 1 H) ppm. 13C NMR (150 MHz, CDCl3): δ = 123.6 (q,
J = 271.1 Hz), 123.9 (q, J = 3.7 Hz), 127.1 (q, J = 3.9 Hz)
128.3, 128.8, 129.7, 130.3, 131.6 (q, J = 32.4 Hz), 133.7,
134.8, 135.6, 136.9, 141.0 ppm. 19F NMR (376 MHz,
CDCl3): δ = –64.4 (s) ppm. HRMS (EI): m/z calcd for
C14H10F3ClS: 302.0144; found: 302.0148.
3-Chloro-5-methylphenyl 4-Fluorophenyl Sulfide (2e)21b
Following the general procedure, using [Ir(cod)OMe)]2
(99.0 mg, 0.015 mmol), 4,4′-di-tert-butyl-2,2′-dipyridyl
(82.0 mg, 0.03 mmol), pin2B2 (254 mg, 1.0 mmol), and 3-
chlorotoluene (0.123 mL, 1.0 mmol) in MTBE (2.0 mL) for
the first step. After removal of the volatile components under
vacuum, Cu(OAc)2 (0.1362 g, 0.75 mmol), 4-fluoro-
thiophenol (0.055 mL, 0.5 mmol), and DMF (2.0 mL) were
used, then purified by column chromatography (SiO2,
hexane) to provide 2e as a colorless oil (63.0 mg, 50% yield).
1H NMR (400 MHz, CDCl3): δ = 2.26 (s, 3 H), 6.91 (s, 1 H),
6.95 (s, 1 H), 6.98 (s, 1 H), 7.03–7.08 (m, 2 H), 7.40–7.43
(m, 2 H) ppm. 13C NMR (150 MHz, CDCl3): δ = 21.1, 116.6,
116.7, 125.7, 127.3, 127.8, 128.7, 128.7, 134.6, 135.0,
135.0, 138.8, 140.5, 161.9, 163.6 ppm. 19F NMR (376 MHz,
CDCl3): δ = –114.3 (s) ppm.
Synlett 2013, 24, 2320–2326
© Georg Thieme Verlag Stuttgart · New York

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