A general, efficient, and inexpensive catalyst system for the coupling of aryl iodides and thiols

Article abstract of DOI:10.1021/ol0266673

(matrix presented) An efficient copper-catalyzed carbon-sulfur bond formation reaction was developed. This method is particularly noteworthy given its experimental simplicity, high generality, and exceptional level of functional group toleration and the low cost of the catalyst system.

Full text of DOI:10.1021/ol0266673

ORGANIC
LETTERS
2002
Vol. 4, No. 20
3517-3520
A General, Efficient, and Inexpensive
Catalyst System for the Coupling of Aryl
Iodides and Thiols
Fuk Yee Kwong and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology,
Cambridge, Massachusetts 02139
sbuchwal@mit.edu
Received August 4, 2002
ABSTRACT
An efficient copper-catalyzed carbon−sulfur bond formation reaction was developed. This method is particularly noteworthy given its experimental
simplicity, high generality, and exceptional level of functional group toleration and the low cost of the catalyst system.
During the past few years, the efficiency of metal-catalyzed
methods for the preparation of aryl ethers and, in particular,
aniline derivatives using palladium catalysts has increased
greatly.1 More recently, our laboratory and others have begun
to reinvestigate the use of copper catalysis for the preparation
of these classes of important compounds.2,3
industry,4 have lagged behind. Transition metal-catalyzed and
-mediated methods for the construction of aryl-sulfur bonds5
have usually required either forcing reaction conditions6 or
substrates with ortho carbonyl groups that are both electron-
withdrawing and capable of chelating copper.7 As in the case
of C-N bond formation, the first report of a mild palladium-
catalyzed carbon-sulfur bond formation came from Migita’s
laboratory.8 More recently, substantial contributions by the
Merck group,9 Li,10 and Schopfer11 have appeared.12
The use of copper catalysts for C-S bond-formation is
attractive from an industrial perspective.13 Traditional copper
systems have lacked the efficiency and wide applicability
to polyfunctionalized substrates that is desirable.6,7,14 Of the
catalytic processes that have appeared, the most attractive
is that of Palomo and co-workers.15 However, their protocol
In contrast, methods for the analogous formation of aryl
sulfides, which are of great significance to the pharmaceutical
(1) For reviews, see: (a) Muci, A. R.; Buchwald, S. L. Practical
Palladium Catalysts for C-N and C-O Bond Formation. In Topics in
Current Chemistry; Miyaura, N., Ed.; Springer-Verlag: Berlin, 2002; Vol.
219, p 133. (b) Yang, B. H.; Buchwald, S. L. J. Organomet. Chem. 1999,
576 (1-2), 125. (c) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S.
L. Acc. Chem. Res. 1998, 31, 805. (d) Hartwig, J. F. Angew. Chem., Int.
Ed. 1998, 37, 2046. (e) Prim, D.; Campagne, J.-M.; Joseph, D.; Andrioletti,
B. Tetrahedron 2002, 58, 2014.
(2) (a) Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
124, 7421. (b) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J.
Am. Chem. Soc. 2001, 123, 7727. (c) Kwong, F. Y.; Klapars, A.; Buchwald,
S. L. Org. Lett. 2002, 4, 581. (d) Wolter, M.; Nordmann, G.; Job, G.;
Buchwald, S. L. Org. Lett. 2002, 4, 973. (e) Wolter, M.; Klapars, A.;
Buchwald, S. L. Org. Lett. 2001, 3, 3803. (f) Kiyomori, A.; Marcoux,
J.-F.; Buchwald, S. L. Tetrahedron Lett. 1999, 40, 2657. (g) Marcoux,
J.-F.; Doye, S.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 10539. (h)
Antilla, J. C.; Buchwald, S. L. Org. Lett. 2001, 3, 2077.
(3) (a) Gujadhur, R.; Venkataraman, D.; Kintigh, J. T. Tetrahedron Lett.
2001, 42, 4791. (b) Gujadhur, R. K.; Bates, C. G.; Venkataraman, D. Org.
Lett. 2001, 3, 4135. (c) Kang, S.-K.; Kim, D.-H.; Park, J.-N. Synlett 2002,
427. (d) Fagan, P. J.; Hauptman, E.; Shapiro, R.; Casalnuovo, A. J. Am.
Chem. Soc. 2000, 122, 5043. (e) Goodbrand, H. B.; Hu, N.-X. J. Org. Chem.
1999, 64, 670. (f) Buck, E.; Song, Z. J.; Tschaen, D.; Dormer, P. G.; Volante,
R. P.; Reider, P. J. Org. Lett. 2002, 4, 1623.
(4) (a) Liu, G.; Link, J. T.; Pei, Z.; Reilly, E. B.; Leitza, S.; Nguyen, B.;
Marsh, K. C.; Okasinski, G. F.; von Geldern, T. W.; Ormes, M.; Fowler,
K.; Gallatin, M. J. Med. Chem. 2000, 43, 4025. (b) Beard, R. L.; Colon, D.
F.; Song, T. K.; Davies, P. J. A.; Kochhar, D. M.; Chandraratna, R. A. S.
J. Med. Chem. 1996, 39, 3556. (c) Nagai, Y.; Irie, A.; Nakamura, H.; Hino,
K.; Uno, H.; Nishimura, H. J. Med. Chem. 1982, 25, 1065. (d) Wang, Y.;
Chackalamannil, S.; Chang, W.; Greenlee, W.; Ruperto, V.; Duffy, R. A.;
McQuade, R.; Lachowicz, J. E. Bioorg. Med. Chem. Lett. 2001, 11, 891.
(e) Bonnet, B.; Soullez, D.; Girault, S.; Maes, L.; Landry, V.; Davioud-
Charvet, E.; Sergheraert, C. Bioorg. Med. Chem. 2000, 8, 95. (f) Sawyer,
J. S.; Schmittling, E. A.; Palkowitz, J. A.; Smith, W. J., III. J. Org. Chem.
1998, 63, 6338.
(5) Kondo, T.; Mitsudo, T. Chem. ReV. 2000, 100, 3205.
10.1021/ol0266673 CCC: $22.00 © 2002 American Chemical Society
Published on Web 09/11/2002

utilizes 20% CuBr and the extremely expensive phosphazene
bases.16 Our recent results on Cu-catalyzed C-N coupling
chemistry suggested to us that similar catalysts for C-S
couplings might be tolerant of a wide variety of functional
groups.2c Herein, we report a general, efficient, and opera-
tionally simple Cu-catalyzed C-S bond-forming reaction.
During the completion of this work, Venkataraman reported
an interesting Cu-catalyzed method for the combination aryl
iodides with thiols in the presence of NaOt-Bu.17
Table 1. Cu-Catalyzed Carbon-Sulfur Bond Formationa
5-Iodo-m-xylene and thiophenol was used as the proto-
typical substrate combination for preliminary optimization
of the reaction conditions. Copper(I) complexes generally
gave superior results compared to copper(II) sources in terms
of conversion and yield of the desired product. A variety of
these were efficient, but we chose to focus on the use of
CuI due to its stability to air.18 Both K3PO4 and K2CO3 were
found to be effective bases for this coupling reaction; the
use of other bases such as DBU or Et3N gave somewhat
lower yields.19 As we recently reported for Cu-catalyzed
amination,2c the use of ethylene glycol (2 equiv) in 2-pro-
panol provides an active and general catalyst system.
Presumably, it serves as a cosolvent and ligand in the
reaction. Its major function may be to get and keep the Cu(I)
species in solution. In accordance with this notion, fairly
good results were obtained using DME, DMF, or dioxane
as a solvent in the absence of any additional ligand. In fact,
in several cases, we found that DME was the solvent of
choice. Presumably, it can function in much the same way
that ethylene glycol does. Control experiments revealed that
only a trace amount of aryl-aryl sulfide coupled product was
observed from GC-MS in the absence of copper catalyst.
Thus, the optimized reaction conditions utilized 5 mol %
CuI, K2CO3 (2 equiv), and ethylene glycol (2 equiv) in
reagent-grade 2-propanol (without drying or degassing) at
80 °C under argon.20 In the first part of this study, these
reaction conditions were applied to the coupling of various
functionalized aryl iodides and thiophenol counterparts,
neither of which contained ortho substitutents (Table 1). As
can be seen, the process is extremely tolerant of a variety of
(6) (a) Using stoichiometric Cu2O reagent in a 1:4 pyridine/quinoline
solvent at 160 °C: Pinchart, A.; Dallaire, C.; Gingras, M. Tetrahedron Lett.
1998, 39, 543. (b) Using 5 mol % Cu in refluxing NMP: Sindela´r, K.;
Hrubantova´, M.; Sva´tek, E.; Matousova´, O.; Metysova´, J.; Valcha´r, M.;
Protiva, M. Collect. Czech. Chem. Commun. 1989, 54, 2240. (c) Use of a
stoichiometric amount of CuI to prepare S-arylated cysteine derivatives at
100 °C in ∼30% yield: Hickman, R. J. S.; Christie, B. J.; Guy, R. W.;
White, T. J. Aust. J. Chem. 1985, 38, 899.
a Reaction conditions: ArI (1.0 mmol), ArSH (1.0 mmol), 5 mol % CuI,
2.0 equiv of K2CO3, 2.0 equiv of HO(CH2)2OH, in iPrOH at 80 °C under
argon. b Isolated yield (average of two runs). c DME used as a solvent.
(7) (a) Kalinin, A. V.; Bower, J. F.; Riebel, P.; Snieckus, V. J. Org.
Chem. 1999, 64, 2986. (b) Baxter, A. J. G.; Teague, S. J. Tetrahedron 1993,
49, 9089. (c) Ra´bai, J.; Kapovits, I.; Tana´cs, B.; Tama´s, J. Synthesis 1990,
847. (d) Kulkarni, N. N.; Kulkarni, V. S.; Lele, S. R.; Hosangadi, B. D.
Tetrahedron 1988, 44, 5145. (e) Dhareshwar, G. P.; Chhaya, P. N.;
Hosangadi, B. D. Indian J. Chem. Sect. B. 1980, 831. (f) Rajsner, M.; Sva´tek,
E.; Metysova´, J.; Protiva, M. Collect. Czech. Chem. Commun. 1975, 40,
1604. (g) Rajsner, M.; Metysova´, J.; Sva´tek, E.; Miks´ık, F.; Protiva, M.
Collect. Czech. Chem. Commun. 1975, 40, 719. (h) Machek, V. G.; Haas,
H. J. Prakt. Chem. 1942, 41. (i) Steinkopf, von W.; Schmitt, H. F.; Fiedler,
H. Liebigs Ann. Chem. 1937, 527, 237. (j) Roberts, K. C.; Smiles, S. J.
Chem. Soc. 1929, 863.
(8) (a) Migita, T.; Shimizu, T.; Asami, Y.; Shiobara, J.-i.; Kato, Y.;
Kosugi, M. Bull. Chem. Soc. Jpn. 1980, 53, 1385. (b) Kosugi, M.; Ogata,
T.; Terada, M.; Sano, H.; Migita, T. Bull. Chem. Soc. Jpn. 1985, 58, 3657.
(9) (a) Zheng, N.; McWilliams, J. C.; Fleitz, F. J.; Armstrong, J. D., III;
Volante, R. P. J. Org. Chem. 1998, 63, 9606. (b) McWilliams, J. C.; Fleitz,
F. J.; Zheng, N.; Armstrong, J. D., III. Org. Synth. 2002, 79, 43.
common functional groups. Thus, aryl iodides containing a
nitrile, nitro group, ketone, free anilino NH2 and phenolic
OH moieties, a carboxylic acid, an aldehyde, and a free
alkylamino group were all efficiently converted to product.
The presence of an ethyl ester could be accommodated by
using DME as the reaction solvent (in the absence of ethylene
glycol), under our normal conditions transesterification to
(10) (a) Li, G. Y. Angew. Chem., Int. Ed. 2001, 40, 1513. (b) Li, G. Y.;
Zheng, G.; Noonan, A. F. J. Org. Chem. 2001, 66, 8677. (c) Li, G. Y. J.
Org. Chem. 2002, 67, 3643.
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Org. Lett., Vol. 4, No. 20, 2002

the isopropyl ester occurs. These results speak to the
importance of using mild bases for transformations of this
type. Also of interest is the result in entry 8 in which
chemoselective C-S bond formation occurs in the presence
of a phenolic OH group.15
A second portion of this work involved the application of
our protocol to the combination of ortho-substituted aryl and
of heteroaryl iodide substrates (Table 2). The presence of
and a free NH2 group. As can be seen from the results in
entry 4, a thiophenol with an ortho carboxymethyl group
can be coupled in good yield. This demonstrates that the
protocol can be applied even with electron-deficient thiols.
The process is also extremely tolerant of steric hindrance,
although the reaction is, in some cases, slightly more
demanding. For example, the coupling of 2-isopropylthio-
phenol with 2-iodotoluene takes place in 88% yield. In
comparison, the reaction of p-methoxythiophenol with 2-iso-
propyliodobenzene is carried out with 20% CuI at 100 °C
in tert-amyl alcohol to give a 94% yield of the desired
Table 2. Cu-Catalyzed Carbon-Sulfur Bond Formation of
Ortho-Substituted and Heterocylic Substratesa
Table 3. Cu-Catalyzed Carbon-Sulfur Bond Formation of
Alkyl Thiolsa
a Reaction conditions: ArI (1.0 mmol), alkyl-SH (1.0 mmol), 5 mol %
CuI, 2.0 equiv of K2CO3, 2.0 equiv of HO(CH2)2OH, in 2-propanol at 80
°C under argon. b Isolated yield in average of two runs. c Isolated yield.
Reaction only proceeded to 78% conversion.
product. The combination of substrates that both possess an
ortho isopropyl group can be accomplished in 91% yield
(entry 8) under the latter conditions. As seen in entries 9
and 10, 3-iodopyridine and 5-iodoindole are also excellent
substrates for this method.
Alkanethiols were also found to be effective nucleophiles
in these reaction conditions (Table 3). Butanethiol and
(11) Schopfer, U.; Schlapbach, A. Tetrahedron 2001, 57, 3069.
(12) (a) Harr, M. S.; Presley, A. L.; Thorarensen, A. Synlett 1999, 1579.
(b) Ishiyama, T.; Mori, M.; Suzuki, A.; Miyaura, N. J. Organomet. Chem.
1996, 525, 225. (c) Ciattini, P. G.; Morera, E.; Ortar, G. Tetrahedron Lett.
1995, 36, 4133.
(13) Ullmann couplings: (a) Ullmann, F. Ber. Dtsch. Chem. Ges. 1903,
36, 2382. For a review, see: (b) Lindley, J. Tetrahedron 1984, 40, 1433.
(c) Hassan, J.; Se´vignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem.
ReV. 2002, 102, 1359.
(14) For an alternative process using a stoichiometric amount of Cu-
(OAc)2 and arylboronic acids as S-arylating agents, see: Herradura, P. S.;
Pendola, K. A.; Guy, R. K. Org. Lett. 2000, 2, 2019.
(15) Palomo, C.; Oiarbide, M.; Lo´pez, R.; Go´mez-Bengoa, E. Tetrahe-
dron Lett. 2000, 41, 1283.
(16) Schwesinger’s phosphazene P2-Et base ($ 260 for 5 mL from
Aldrich) was used.
a Reaction conditions: ArI (1.0 mmol), ArSH (1.0 mmol), 5 mol % CuI,
2.0 equiv of K2CO3, 2.0 equiv of HO(CH2)2OH, in 2-propanol at 80 °C
under argon. b Isolated yield in average of two runs. c DME solvent.
d Reaction conditions: ArI (1.0 mmol), ArSH (1.2 mmol), 20 mol % CuI,
2.0 equiv of K2CO3, 2.0 equiv of HO(CH2)2OH in tert-amyl alcohol at 100
°C under argon for 24 h.
functional groups in the ortho position of the aryl iodide
substrates are tolerated, including a hydroxymethyl group
Org. Lett., Vol. 4, No. 20, 2002
3519

benzylmercaptan were S-arylated in excellent yield (Table
3, entries 2 and 3). The selective S-arylation was observed
when 6-mercaptohexanol was used as the substrate (Table
3, entry 4).
In summary, we have developed a general and efficient
Cu-catalyzed carbon-sulfur bond formation for both aro-
matic and alkanethiols under mild conditions. This method
is particularly noteworthy given its experimental simplicity,
high generality, and exceptional level of functional group
toleration and the low cost of the catalyst system. Further
studies of this and related Cu-catalyzed cross-coupling
reactions are in progress.
Acknowledgment. We thank the NIH (GM 58160).
Pfizer, Merck, and Bristol-Myers Squibb are acknowledged
for support in the form of unrestricted funds. F.Y.K. is
grateful to The Croucher Foundation for a postdoctoral
fellowship.
Supporting Information Available: Detailed experi-
mental procedures and characterization data of each com-
pound. This material is available free of charge via the
Internet at http://pubs.acs.org.
(17) The coupling of ArI with thiols, 10 mol % CuI, 10 mol % of the
relatively expensive neocuproine ligand, and 1.5 equiv NaOt-Bu in toluene
at 110 °C was reported. The authors indicated that K3PO4 may be used as
the base, where needed, for functionalized substrates. No examples, however,
were provided: Bates, C. G.; Gujadhur, R. K.; Venkataraman, D. Org. Lett.
2002, 4, 2803-2806.
(18) For examples, CuX (X ) I, Br, Cl, OAc), CuX2 (X ) Cl (as
hydrate), Br, F, OAc, acac) and Cu2O all worked well. We are currently
examining the latter as an industrially interesting precatalyst.
(19) % Conversion (% GC yield); DBU, 72 (70); Et3N 68 (64).
OL0266673
(20) Control experiments revealed that (a) anhydrous 2-propanol (packed
under argon from Aldrich in a Sure-Seal bottle) gave the same conversion
and yield of the reaction and (b) the oxidative coupling product, diaryl
disulfide (ArS-SAr), was the major product if the reaction was performed
in air.
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Org. Lett., Vol. 4, No. 20, 2002