Efficient copper-catalyzed coupling of aryl iodides and thiobenzoic acid

Article abstract of DOI:10.1016/j.tetlet.2006.07.008

A highly efficient copper-catalyzed coupling reaction of aryl iodides and thiobenzoic acid, using 10 mol % of copper iodide, 20 mol % of 1,10-phenanthroline, and ⁱPr₂NEt in toluene, was developed. This methodology is applicable to a variety of aryl iodides.

Full text of DOI:10.1016/j.tetlet.2006.07.008

Tetrahedron Letters 47 (2006) 6595–6597
Efficient copper-catalyzed coupling of aryl iodides
and thiobenzoic acid
Naotaka Sawada,a,* Takahiro Itoha and Nobuyoshi Yasudab
aProcess Research, Banyu Pharmaceutical Co. Ltd., 9-1, Kamimutsuna 3-Chome, Okazaki, Aichi 444-0858, Japan
bMerck Research Laboratories, Department of Process Research, PO Box 2000, Rahway, NJ 07065, USA
Received 6 June 2006; revised 5 July 2006; accepted 6 July 2006
Available online 27 July 2006
Abstract—A highly efficient copper-catalyzed coupling reaction of aryl iodides and thiobenzoic acid, using 10 mol % of copper
iodide, 20 mol % of 1,10-phenanthroline, and iPr2NEt in toluene, was developed. This methodology is applicable to a variety of aryl
iodides.
Ó 2006 Elsevier Ltd. All rights reserved.
MS
KS
R2
Aryl thiols are essential building blocks in the synthesis
of sulfur-containing natural products and biologically
active compounds. Traditional methods for constructing
aryl–sulfur bonds include thermal rearrangement of
N,N-dialkylthiocarbamates1 or substitution via an addi-
tion–elimination mechanism.2 However, these reactions
often require harsh conditions (ꢀ280 °C, or long reac-
tion times). Since 1980, coupling reactions catalyzed
by transition metals (Pd, Ni, Cu) have been developed
as an efficient method for aryl–sulfur bond forma-
tion,3–5 using alkyl thiols as a sulfur source. The desired
aryl thiols are obtained after cleavage of the alkyl–sulfur
bond, which typically requires harsh conditions.6
-
N2+BF4
M = K or Na
O
(1)
(2)
(3)
R1
DMSO
R2
I+X-
S
R2
X = Cl, I
DMSO, 70 - 80 ºC
O
R1
R1
O
2
CuS
R2
I
O
R1
HMPT, 100 -110 ºC
Scheme 1. Reported methods for synthesis of S-aryl thiocarboxylates.
For this reason, the development of efficient methods for
the synthesis of S-aryl thiocarboxylates has been the
subject of much interest, since acyl groups may be
removed under milder conditions than alkyl groups.7
Various methods have already been reported (Scheme
1): the reaction of arenediazonium tetrafluoroborates
with alkali metal thiocarboxylates (Eq. 1),8 the reaction
of diaryliodonium salts with potassium thiocarboxylates
(Eq. 2),9 and the reaction of aryl halides with the copper
salt of thiobenzoic acid (Eq. 3).10 However, all of these
methods require hazardous reagents, uncommon start-
ing materials or undesirable solvents such as HMPT,
and thus are not suitable for the preparation of more
functionalized S-aryl thiocarboxylates. We envisioned
that transition-metal-catalyzed coupling reactions
would proceed under milder conditions, under which
many functional groups are tolerated. To the best of
our knowledge, there have yet been no reports of transi-
tion-metal-catalyzed coupling reactions of aryl halides
and thiobenzoic acid. Herein, we report an efficient cop-
per-catalyzed synthetic method for S-aryl thiocarboxyl-
ates from aryl iodides and thiobenzoic acid.
Iodobenzene was selected as a model substrate for
optimization of the copper-catalyzed coupling reaction
(Table 1). As expected, the reaction did not proceed at
all under simple addition–elimination conditions (entry
1). Buchwald reported high-yield copper-catalyzed
carbon–oxygen bond formation from aryl iodides, using
10 mol % of copper iodide, 20 mol % of 1,10-phenan-
throline, and Cs2CO3;11 this system, however, was less
effective in our case, giving only trace amounts of S-aryl
thiobenzoate (entry 2).
*
Corresponding author. Tel.: +81 564 51 5668; fax: +81 564 51
7086; e-mail: naotaka_sawada@merck.com
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.07.008

6596
N. Sawada et al. / Tetrahedron Letters 47 (2006) 6595–6597
Table 1. Evaluation of various reaction conditions
HS Ph
Table 2. Copper-catalyzed coupling of thiobenzoate with various
substratesa
Entry
Substrate
Product
Yieldb (%)
97
I
S
Ph
O
I
S
Ph
Ph
conditions
O
1
O
1a
Conditionsa
2a
Entry
Yieldb
(%)
O
O
1b
2b
2c
tBuONa, DMI, 120 °C
CuI, 1,10-phen, Cs2CO3, toluene, 110 °C
Nd
Trace
Nd
63
99
51
6
O2N
I
O2N
S
1
2
3
4
5
6
7
8
9
2
3
99
94
O
t
CuI, 1,10-phen, BuONa, toluene, 110 °C
CuI, 1,10-phen, K3PO4, toluene, 110 °C
1c
i
CuI, 1,10-phen, Pr2NEt, toluene, 110 °C
I
S
Ph
i
CuI, 1,10-phen, Pr2NEt, DMI, 120 °C
i
CuI, Pr2NEt, toluene, 110 °C
O
Br
Br
i
CuI, DMEDA, Pr2NEt, toluene, 110 °C
4
4
2d
1d
i
CuI, HO(CH2)2OH, Pr2NEt, toluene, 110 °C
O
a All reactions were conducted using 2.45 mmol of iodobenzene,
10 mol % of CuI, 20 mol % of 1,10-phenanthroline, 1.2 equiv of
thiobenzoic acid, 2.0 equiv of base, and 5 mL of solvent for 24 h.
b Product yields are the average of two runs, determined by HPLC.
I
S
Ph
S
4
5
6
7
8
9
97
99
1e
2e
I
Ph
Several bases were screened for the coupling reaction
using 10 mol % of copper iodide and 20 mol % of 1,10-
O
t
MeO
MeO
phenanthroline as a ligand. When BuONa was used
2f
1f
as a base,12 the coupling reaction did not proceed and
gave none of the desired product (entry 3). Inorganic
bases such as K3PO4, which are widely used in copper-
catalyzed protocols for the formation of aryl–nitrogen,
aryl–oxygen and aryl–sulfur bonds,5 gave the desired
S-aryl thiobenzoate only in moderate yield (63%, entry
4). iPr2NEt was eventually found to be the most effective
base for this reaction. The use of less polar solvents such
as toluene (99%, entry 5) was found to result in better
yields than that of polar solvents such as DMI (51%, en-
try 6). The effects of various ligands were then investi-
gated. The reaction did not proceed well in the
absence of ligands (6%, entry 7). The reaction using
N,N0-dimethylethylenediamine, which has been found
to be an effective ligand for copper-catalyzed amidation
of aryl halides,13 failed in our case (4%, entry 8). Like-
wise, the use of diol-type ligands such as ethylene glycol
gave the product in 4% yield (entry 9); thus, 1,10-phe-
nanthroline was confirmed to be the most effective
ligand for this reaction.
I
S
Ph
100
99
O
1g
2g
I
S
Ph
O
O
O
1h
2h
I
S
Ph
Ph
99
N
N
1i
2i
Br
S
Trace
1j
2a
a All reactions were conducted using 2.45 mmol of aryl iodide,
10 mol % of CuI, 20 mol % of 1,10-phenanthroline, 1.2 equiv of
To investigate the scope of the copper-catalyzed cou-
pling reaction, a variety of aryl iodides (1b–i) were used
(Table 2). Electron-deficient aryl iodides (1b–d) were
effectively converted into the desired S-aryl thiobenzo-
ates in excellent yields (entries 1–3). High chemoselectiv-
ity was observed for p-bromoiodobenzene (1d) (entry 3).
Even electron-rich aryliodides (1f–h) and an electron-
neutral aryliodide (1e) were completely converted to
the corresponding S-aryl thiobenzoates in almost quan-
titative yields (entries 4–7). It is notable that coupling
proceeded even with a sterically hindered substrate such
as o-iodotoluene (1h) (entry 6). A heteroaryl iodide (3-
iodopyridine, 1i) also underwent coupling with an excel-
lent yield of 99% (entry 8). However, bromobenzene (1j)
gave only trace amounts of S-aryl thiobenzoate under
the conditions described (entry 9).
i
thiobenzoic acid, 2.0 equiv of Pr2NEt, and 5 mL of toluene for 24 h
at 110 °C. Reaction time was not optimized for each substrate.
b Product yields were the average of two runs, determined by HPLC.
Deprotection of the resulting S-aryl thiobenzoates pro-
ceeded smoothly under mild conditions, and the corre-
sponding aryl thiols were obtained in quantitative
yield (Scheme 2).
In conclusion, we have developed a highly efficient
copper-catalyzed coupling reaction of aryl iodide and
thiobenzoic acid in toluene using 10 mol % of copper io-
dide and 20 mol % of 1,10-phenanthroline. This method
is applicable to both electron-deficient and electron-rich
aryl iodides, and even to sterically hindered substrates,

N. Sawada et al. / Tetrahedron Letters 47 (2006) 6595–6597
6597
Zhang, G.; Noonan, A. F. J. Org. Chem. 2001, 66,
8677.
4. Ni-catalyzed reaction: (a) Cristau, H. J.; Chabaud, B.;
Cheˆne, A.; Christol, H. Synthesis 1981, 892; (b) Millois,
C.; Diaz, P. Org. Lett. 2000, 2, 1075; (c) Percec, V.; Bae, J.
Y.; Hill, D. H. J. Org. Chem. 1995, 60, 6895.
1) K2CO3 (1.5 eq.)
MeOH, rt
S
Ph
SH
2) H+
O
quant.
Scheme 2. Deprotection of S-phenyl thiobenzoate.
5. Cu-catalyzed reaction: (a) Bates, C. G.; Gujadhur, R. K.;
Venkataraman, D. Org. Lett. 2002, 4, 2803; (b) Bates, C.
G.; Saejueng, P.; Doherty, M. Q.; Venkataraman, D. Org.
Lett. 2004, 6, 5005; (c) Kwong, F. Y.; Buchwald, S. L.
Org. Lett. 2002, 4, 3517; (d) Herradura, P. S.; Pendola, K.
A.; Guy, R. K. Org. Lett. 2000, 2, 2019; For recent
reviews: (e) Beletskaya, I. P.; Cheprakov, A. V. Coord.
Chem. Rev. 2004, 248, 2337; (f) Ley, S. V.; Thomas, A. W.
Angew. Chem., Int. Ed. 2003, 42, 5400; (g) Kunz, K.;
Scholz, U.; Ganzer, D. Synlett 2003, 2428.
giving S-aryl thiobenzoates in excellent yields as pro-
tected thiols.
General procedure
To a solution of aryl iodide (2.45 mmol), thiobenzoic
acid (2.94 mmol), 1,10-phenanthroline (0.49 mmol),
i
and Pr2NEt (4.90 mmol) in toluene (5 mL) was added
6. (a) Shaw, J. E. J. Org. Chem. 1991, 56, 3728; (b) Testaferri,
L.; Tiecco, M.; Tingoli, M.; Chianelli, D.; Montanucci, M.
Synthesis 1983, 751; (c) Testaferri, L.; Tiecco, M.; Tingoli,
M.; Bartoli, D.; Massoli, A. Tetrahedron 1985, 41, 1373;
(d) Pinchart, A.; Dallaire, C.; Van Bierbeek, A.; Gingras,
M. Tetrahedron Lett. 1999, 40, 5479; (e) Cabiddu, S.;
Melis, S.; Piras, P. P.; Sotgiu, F. Synthesis 1982, 583.
7. Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 3rd ed.; John Wiley & Sons, Inc.: New
York, 1999; Chapter 6.
CuI (0.25 mmol). The resulting mixture was degassed
and then stirred under N2 at 110 °C for 24 h. The reac-
tion mixture was then cooled to rt and diluted to 50 mL
with CH3CN. The resulting mixture was analyzed by
HPLC.14
Acknowledgements
8. (a) Petrillo, G.; Novi, M.; Garbarin, G.; Filliberti, M.
Tetrahedron Lett. 1988, 29, 4185; (b) Petrillo, G.; Novi,
M.; Garbarin, G.; Filliberti, M. Tetrahedron 1988, 45,
7411.
We thank Dr. Atsushi Akao for useful discussions and
Dr. Toshiaki Mase for helpful directions.
9. You, Jin-Zen; Chen, Zhen-Chu Synthesis 1992, 521.
10. Osuka, A.; Ohmasa, N.; Uno, Y.; Suzuki, H. Synthesis
1983, 68.
11. Wolter, M.; Nordmann, G.; Job, G. E.; Buchwald, S. L.
Org. Lett. 2002, 4, 973.
12. Copper-catalyzed coupling of aryl iodides and alkyl/aryl
thiols was conducted under similar reaction conditions
(see Ref. 5a).
13. Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem.
Soc. 2002, 124, 7421.
References and notes
1. (a) Newman, M. S.; Karnes, H. A. J. Org. Chem. 1966, 31,
3980; (b) Miyazaki, K. Tetrahedron Lett. 1968, 23, 2379.
2. Delogu, G.; Fabbri, D.; Dettori, M. Tetrahedron: Asym-
metry 1998, 9, 2819.
3. Pd-catalyzed reaction: (a) Migita, T.; Shimizu, T.; Asami,
Y.; Shiobara, J.; Kato, Y.; Kosugi, M. Bull. Chem. Soc.
Jpn. 1980, 53, 1385; (b) Kondo, T.; Shimizu, T. Chem.
´
´
Rev. 2000, 100, 3205; (c) Fernandez-Rodrıguez, M. A.;
Shen, Q.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128,
2180; (d) Itoh, T.; Mase, T. Org. Lett. 2004, 6, 4587; (e)
Mispelaere-Caniven, C.; Spindler, J. F.; Perrio, S.; Beslin,
P. Tetrahedron 2005, 61, 5253; (f) Zheng, N.; McWilliams,
J. C.; Fleitz, F. J.; Armstrong, J. D.; Volante, R. P. J. Org.
Chem. 1998, 63, 9606; (g) Gao, G. Y.; Colvin, A. J.; Chen,
Y.; Zhang, P. J. Org. Chem. 2004, 69, 8886; (h) Li, G. Y.;
14. Compound 2a–2g and 2i are known compounds. Physical
1
data for 2h: H NMR (500 MHz, CHCl3, ppm) d 8.05 (d,
J = 8.0 Hz, 2H), 7.60 (t, J = 7.4 Hz, 1H), 7.51–7.46 (m,
3H), 7.38–7.34 (m, 2H), 7.28–7.24 (m, 1H), 2.40 (s, 3H);
13C NMR (125 MHz, CHCl3, ppm) d 189.6, 142.6, 136.8,
136.4, 133.5, 130.8, 130.2, 128.7, 127.5, 126.8, 126.6, 20.8.
HRMS (EI positive) m/z calcd for C14H12OS [M+]:
229.0609, found: 229.0609.