Ferna´ndez-Rodr´ıguez and Hartwig
Migita and co-workers first reported the coupling of iodo and
bromoarenes with thiols catalyzed by Pd(PPh3)4.19,20 More
recently, these reactions have been conducted with catalyst
systems containing bidentate phosphines or dialkylphosphine
oxide ligands.21-28 However, even recent catalysts react with
short lifetimes and are, therefore, limited in their ability to form
biologically active thioethers or precursors of biologically active
compounds in a practical fashion. Nickel-, copper-, and more
recently cobalt- and iron-catalyzed coupling of thiols with aryl
halides has also been reported.29-32 However, these processes
require high temperatures or high catalyst loadings and have
typically been conducted with aryl iodides.33-36
The limitations of this coupling reaction could result from a
sensitivity of late metal catalysts to substrates containing reactive
sulfur functionality. Although palladium thiolates are easily
formed and undergo relatively fast reductive eliminations with
aryl groups,37-39 the lifetime and concentrations of the catalysts
used for the coupling of aryl halides with thiols is likely to be
limited by the formation of species that lie off of the catalytic
cycle.38 Thus, a more reactive catalyst for the coupling of
thiolates might contain a bisphosphine that binds the metal
strongly enough to prevent formation of anionic or bridging
thiolate complexes, while simultaneously promoting oxidative
addition and reductive elimination.
FIGURE 1. Josiphos CyPF-tBu ligand.
halides with high turnover numbers. We have recently shown
that palladium complexes generated from this hindered bispho-
sphine ligand overcome some of the current limitations on
catalyst activity and scope for the amination of aryl halides and,
therefore, could be considered a fourth-generation catalyst for
forming carbon-heteroatom bonds.40 In particular, this system
efficiently catalyzed the coupling of aryl and heteroaryl halides
and pseudohalides with nitrogen nucleophiles including primary
amines,41-44 ammonia, and lithium amide.45,46
We previously communicated47 that the combination of a
palladium precursor and CyPF-tBu catalyzes the coupling of a
wide range of thiols with aryl halides and pseudohalides with
turnover numbers typically 2 or 3 orders of magnitude higher
than those of previous catalysts. The reactions of chloroarenes
were then studied in more depth,48 and these reactions occurred
with broad scope and high tolerance for functionality. However,
reactions of aromatic thiols with aryl chlorides that are hindered
and chloroarenes that contain carboxaldehyde functionality or
enolizable hydrogens proceeded to partial conversion, formed
significant amounts of side products, or both. Herein, we report
a detailed study of the couplings of aryl bromides and iodides
with this catalyst system. The reactions of aryl bromides and
iodides occur with lower catalyst loadings and under milder
conditions than the reactions of aryl chlorides and overcome
the limitations previously reported for the reactions of chloro-
arenes. Moreover, reactions of aryl iodides with thiols, unlike
reactions of aryl iodides with amines, occur with high turnover
numbers and broad scope under mild conditions.
On the basis of this hypothesis, we considered that the
particularly restricted backbone conformation, severe steric
hindrance, and strong electron donation of the commercially
available Josiphos ligand CyPF-tBu (1-dicyclohexylphosphino-
2-di-tert-butylphosphinoethylferrocene (1) in Figure 1) could
create practical catalysts for the coupling of thiols with aryl
(18) Liu, G.; Huth, J. R.; Olejniczak, E. T.; Mendoza, R.; DeVries, P.; Leitza,
S.; Reilly, E. B.; Okasinski, G. F.; Fesik, S. W.; von Geldern, T. W. J. Med.
Chem. 2001, 44, 1202–1210.
(19) Migita, T.; Shimizu, T.; Asami, Y.; Shiobara, J.; Kato, Y.; Kosugi, M.
Bull. Chem. Soc. Jpn. 1980, 53, 1385–1389.
(20) Kosugi, M.; Shimizu, T.; Migita, T. Chem. Lett. 1978, 13–14.
(21) Cai, L.; Cuevas, J.; Peng, Y.-Y.; Pike, V. W. Tetrahedron Lett. 2006,
47, 4449–4452.
2. Results and Discussion
(22) Mispelaere-Canivet, C.; Spindler, J.-F.; Perrio, S.; Beslin, P. Tetrahedron
2005, 64, 5253–5259.
(23) Itoh, T.; Mase, T. Org. Lett. 2004, 6, 4587–4590.
(24) Murata, M.; Buchwald, S. L. Tetrahedron 2004, 60, 7397–7403.
(25) Li, G. Y.; Zheng, G.; Noonan, A. F. J. Org. Chem. 2001, 66, 8677–
8681.
(26) Li, G. Y. Angew. Chem., Int. Ed. 2001, 40, 1513–1516.
(27) Schopfer, U.; Schlapbach, A. Tetrahedron 2001, 57, 3069–3073.
(28) Zheng, N.; McWilliams, J. C.; Fleitz, F. J.; Armstrong, J. D., III; Volante,
R. P. J. Org. Chem. 1998, 63, 9606–9607.
(29) Nickel-catalyzed: Cristau, H. J.; Chabaud, B.; Chene, A.; Christol, H.
Synthesis 1981, 89, 2–894.
(30) For a review on cooper-catalyzed coupling, see: Ley, S. V.; Thomas,
A. W. Angew. Chem., Int. Ed. 2003, 42, 5400–5449.
(31) Wong, Y.-C.; Jayanth, T. T.; Cheng, C.-H. Org. Lett. 2006, 8, 5613–
5616.
(32) Correa, A.; Carril, M.; Bolm, C. Angew. Chem., Int. Ed. 2008, 47, 2880–
2883.
(33) Nickel-catalyzed coupling (3-4 mol %) of bromoarenes with aromatic
thiols has been recently described: Zhang, Y.; Ngeow, K. C.; Ying, J. Y. Org.
Lett. 2007, 9, 3495–3498.
2.1. Establishment of Reaction Conditions. We studied the
coupling of 4-tolyl bromide and iodide to assess the catalyst
activity and determine the optimum reaction conditions. We
previously showed that the combination of Pd(OAc)2 and CyPF-
tBu as catalyst, NaOtBu as base, and DME as solvent at 110
°C led to the coupling of aliphatic thiols with chloroarenes,47,48
but these reaction conditions produced undesired symmetrical
sulfides in a 5-10% combined yield from reactions of aromatic
thiols with chloroarenes. Therefore, couplings of aryl chlorides
with aromatic thiols were conducted with toluene solvent,
KOtBu as base and Pd(dba)2 as precursor to obtain the desired
diaryl sulfide in high yield without formation of appreciable
amounts of side products. In the current studies we showed that
the conditions for reactions of aryl chlorides with aliphatic thiols
(34) For a recent report of the coupling of bromobenzene with benzenethiol
catalyzed by CuI (5 mol %)/N,N-dimethylglycine (20 mol %) see: Deng, W.;
Zou, Y.; Wang, Y.-F.; Liu, L.; Guo, Q.-X. Synlett 2004, 1254–1258.
(35) Three examples of coupling of aryl bromides were reported with use of
CuI (10 mol %) under microwave heating: Wu, Y.-J.; He, H. Synlett 2003, 178,
9–1790.
(36) A recent report describes the coupling of bromoarenes with arylthiols
in water catalyzed by CuCl (8.5 mol%) in the presence of trans-1,2-diaminocy-
clohexane (3.9 equiv): Carril, M.; SanMartin, R.; Dom´ınguez, E.; Tellitu, I. Chem.
Eur. J. 2007, 13, 5100–5105.
(40) Hartwig, J. F. Acc. Chem. Res. 2008, 41, 1534–1544.
(41) Shen, Q.; Shekhar, S.; Stambuli, J. P.; Hartwig, J. F. Angew. Chem.,
Int. Ed. 2005, 44, 1371–1375.
(42) Shen, Q.; Ogata, T.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 6586–
6596.
(43) Shen, Q.; Hartwig, J. F. Org. Lett. 2008, 10, 4109–4112.
(44) Ogata, T.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 13848–13849.
(45) For a highlight on direct coupling of ammonia and lithium amide see:
Willis, M. C. Angew. Chem., Int. Ed. 2007, 46, 3402–3404.
(46) Shen, Q.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 10028–10029.
(47) Ferna´ndez-Rodr´ıguez, M. A.; Shen, Q.; Hartwig, J. F. J. Am. Chem.
Soc. 2006, 128, 2180–2181.
(37) Mann, G.; Baran˜ano, D.; Hartwig, J. F.; Rheingold, A. L.; Guzei, I. A.
J. Am. Chem. Soc. 1998, 120, 9205–9219.
(38) Louie, J.; Hartwig, J. F. J. Am. Chem. Soc. 1995, 117, 11598–11599.
(39) Baran˜ano, D.; Hartwig, J. F. J. Am. Chem. Soc. 1995, 117, 2937–2938.
(48) Ferna´ndez-Rodr´ıguez, M. A.; Shen, Q.; Hartwig, J. F. Chem. Eur. J.
2006, 12, 7782–7796.
1664 J. Org. Chem. Vol. 74, No. 4, 2009