A mild, nonbasic synthesis of thioethers. The copper-catalyzed coupling of boronic acids with N-thio(alkyl, aryl, heteroaryl)imides

Article abstract of DOI:10.1021/ol026948a

(equation presented) A new synthesis of thioethers is described. The reaction of boronic acids with aryl, heteroaryl, and alkyl N-thioimides in the presence of catalytic quantities of a Cu(I) carboxylate affords good to excellent yields of thioethers. This reaction takes place in the absence of a base under mild conditions (THF, 45-50°C, 2.5-12 h) and represents an interesting complement to known methods for thioether synthesis.

Full text of DOI:10.1021/ol026948a

ORGANIC
LETTERS
2002
Vol. 4, No. 24
4309-4312
A Mild, Nonbasic Synthesis of
Thioethers. The Copper-Catalyzed
Coupling of Boronic Acids with
N-Thio(alkyl, aryl, heteroaryl)imides
Cecile Savarin,1 Jiri Srogl,* and Lanny S. Liebeskind*
Emory UniVersity, Department of Chemistry, 1515 Pierce DriVe,
Atlanta, Georgia 30322
chemll1@emory.edu
Received September 23, 2002
ABSTRACT
A new synthesis of thioethers is described. The reaction of boronic acids with aryl, heteroaryl, and alkyl N-thioimides in the presence of
catalytic quantities of a Cu(I) carboxylate affords good to excellent yields of thioethers. This reaction takes place in the absence of a base
under mild conditions (THF, 45−50 °C, 2.5−12 h) and represents an interesting complement to known methods for thioether synthesis.
Aryl, alkenyl, and alkyl thioethers are important intermediates
in organic synthesis. In addition to their routine synthesis
by the SN2 substitution of alkylating agents with thiolate
anions, a variety of other methods have been used for their
preparation.2 Even so, there still are synthetic difficulties that
need to be addressed. High temperatures, several equivalents
of base, or strong reducing agents are often required.3
A recent article by Guy and co-workers described the
preparation of aryl alkyl sulfides by the reaction of arylbo-
ronic acids (2.0-2.2 equiv) and alkanethiols in the presence
of stoichiometric copper Cu(OAc)2 (1.5 equiv) and pyridine
(3.0 equiv) in refluxing DMF (Scheme 1).4 The authors
(1) Current address: Merck Process Research, PO Box 2000, RY800-
C264, Rahway, NJ 07065.
(2) (a) Still, I. W. J.; Toste, F. D. J. Org. Chem. 1996, 61, 7677-7680
and references cited therein. (b) Lee, S. B.; Hong, J.-I. Tetrahedron Lett.
1995, 36, 8439-8442. (c) Ogawa, A.; Ikeda, T.; Kimura, K.; Hirao, T. J.
Am. Chem. Chem. 1999, 121, 5108-5114. (d) Ogawa, A.; Kawakami, J.-
I.; Mihara, M.; Ikeda, T.; Sonoda, N.; Hirao, T. J. Am. Chem. Chem. 1997,
119, 12380-12381. (e) Ogawa, A.; Takeda, M.; Kawakami, J.-I.; Ryu, I.;
Kambe, N.; Sonoda, N. J. Am. Chem. Soc. 1995, 117, 7564-7565. (f)
Kuniyasu, H.; Ogawa, A.; Sato, K.-I.; Ryu, I.; Kambe, N.; Sonoda, N. J.
Am. Chem. Soc. 1992, 114, 5902-5903. (g) Kuniyasu, H.; Ogawa, A.;
Miyazaki, S.-I.; Ryu, I.; Kambe, N.; Sonoda, N. J. Am. Chem. Soc. 1991,
113, 9796-9803. (h) Ishiyama, T.; Nishijima, K.-I.; Miyaura, N.; Suzuki,
A. J. Am. Chem. Soc. 1993, 115, 7219-7225. (i) Tetrahedron Lett. 1987,
28 (50), 6321-6324. (j) Trost, B.; Lavoie, A. C. J. Am. Chem. Soc. 1983,
105, 5075-5090. (k) Tobias, M. A.; Strong, J. G.; Napier, R. P. J. Org.
Chem. 1970, 35, 1709-1711. (l) Melandri, D.; Montevecchi, P. C.;
Navacchia, M. L. Tetrahedron 1999, 55, 41, 12227-12236. (m) Takeda,
T.; Watanabe, M.; Nozaki, N.; Fujiwara, T. Chem. Lett. 1998, 115-116.
(m) Horikawa, Y.; Watanabe, M.; Fujiwara, T.; Takeda, T. J. Am. Chem.
Soc. 1997, 119, 1127-1128. (n) Okamura, H.; Miura, M.; Takei, H.
Tetrahedron Lett. 1979, 1, 43-46. (o) Bergstrom, D.; Beal, P.; Husain, A.;
Lind, R.; Jenson, J. J. Am. Chem. Soc. 1989, 111, 374-375. (p) Bates, C.
G.; Gujadhur, R. K.; Venkataraman, D. Org. Lett. 2002, 4 (16), 2803-
2806.
Scheme 1. Copper-Mediated Coupling of Boronic Acids and
Thiols
implied a mechanism that parallels that proposed for related
arylations of phenols and amines by arylboronic acids in the
10.1021/ol026948a CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/08/2002

presence of CuII catalysts under oxidative conditions,5
namely, transmetalation of the boronic acid to CuII followed
by a ligand substitution to introduce the phenol or amine to
the coordination sphere of the Cu. Two additional steps of
undefined sequence, reductive elimination and metal oxida-
tion, complete the process. While this mechanism likely
operates for the CuII-mediated arylation of phenols and
amines by arylboronic acids, it is unlikely in the case of the
corresponding thiols. Why? Thiols are easily oxidized to
disulfides by CuII;6 therefore, it is most probable, particularly
given the harsh reaction conditions, that the transformation
described by Guy and co-workers is actually a CuI-mediated
coupling of an arylboronic acid with a dialkyl disulfide (both
the CuI and the dialkyl disulfide can be generated in situ
under Guy’s reaction conditions). If so, it might be feasible
to generate thioethers under much milder conditions by
coupling boronic acids with disulfides or disulfide equivalents
using a CuI catalyst.
-heteroaryl, -alkenyl) have been described in the literature8
and used as sources of electrophilic sulfur.9 N-Thioimides
are easily and efficiently prepared from their corresponding
thiols and N-chlorosuccinimide,10 or by reaction of the
corresponding disulfide with 2 equiv of an N-bromoimide.11
The N-thioimides 2-6 used in this study (Figure 1) were
Figure 1. N-Thioimides used in this study.
prepared by the first method, while N-thiophthalimide 1 was
prepared by the reaction of dimethyl disulfide with N-
bromophthalimide.12 Some thioimides, such as S-methyl- and
S-phenyl-N-thiophthalimide, are now commercially available.
As depicted in Table 1, treatment of a boronic acid (1.5-
2.0 equiv) with an N-thioimide (1.0 equiv) in the presence
of 20-30% CuMeSal in THF at 45-50 °C afforded
thioethers in moderate to good yields (51-79%) within 2-12
h. The only exception was the unsuccessful coupling of Z-â-
styrylboronic acid with N-thioimide 3 (entry 6), which
contrasts with the successful coupling achieved using the
isomeric E-â-styrylboronic acid (entry 5). In the former case,
the Z-â-styrylboronic acid is essentially unchanged after 24
h under the reaction conditions. The lack of reactivity cannot
be attributed to steric effects alone, since o-tolylboronic acid
couples rapidly and in good yield with N-thioimide 3 (entry
7). Electron-withdrawing groups as well as electron-donating
In support of this mechanistic speculation, diphenyl sulfide
was formed in 74% yield when diphenyl disulfide and
phenylboronic acid were treated with 1.3 equiv CuI-3-
methylsalicylate (CuMeSal)7 in DMA for 18 h at 100 °C
(Scheme 2). While this experiment demonstrated the potential
Scheme 2. Copper-Mediated Coupling of Boronic Acids and
Disulfides
for S-arylation under nonbasic conditions, it also revealed
the empirical requirement for stoichiometric CuI in the
reaction. Alhough the putative mechanism is catalytic in CuI,
the observed requirement for stoichiometric CuI can be
understood if half of the disulfide is converted into a
catalytically inactive CuI-thiolate. If true, then appropriate
modification of the disulfide moiety could render this process
catalytic in CuI and deliver a valuable addition to the
repertoire of methods for the construction of thioethers
(Scheme 3).
(5) (a) Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P.
Tetrahedron Lett. 1998, 39, 2933-2936. (b) Lam, P. Y. S.; Clark, C. G.;
Saubern, S.; Adams, J.; Winters, M. P.; Chan, D. M. T.; Combs, A.
Tetrahedron Lett. 1998, 39, 2941-2944. (c) Evans, D. A.; Katz, J. L.; West,
T. R. Tetrahedron Lett. 1998, 39, 2937-2940. (d) Jung, M. E.; Lazarova,
T. I. J. Org. Chem. 1999, 64, 2976-2977. (e) Collman, J. P.; Zhong, M.
Org. Lett. 2000, 2 (9), 1233-1236. (f) Lam, P. Y. S.; Vicent, G.; Clark, C.
G.; Deudon, S.; Jadhav, P. K. Tetrahedron Lett. 2001, 42, 3415-3418. (g)
Antilla, J. C.; Buchwald, S. L. Org. Lett. 2001, 3, 2077-2079. (h) Cundy,
D. J.; Forsyth, S. A. Tetrahedron Lett. 1998, 39, 7979-7982.
(6) Smith, R. C.; Reed, W. D.; Hill, W. E. Phosphor. Sulfur, Silicon
1994, 90, 147-154.
(7) See Supporting Information for: Savarin, C.; Srogl, J.; Liebeskind,
L. S. Org. Lett. 2001, 3 (1), 91-93.
Scheme 3. Copper-Catalyzed Coupling of Boronic Acids and
(8) Representative references: (a) Klose, J.; Reese, C. B.; Song, Q.
Tetrahedron 1997, 53 (42), 14411-14416. (b) Abe, Y.; Nakabayashi, T.;
Tsurugi, J. Bull. Chem. Soc. Jpn. 1973, 46, 1898-1899. (c) Furukawa, M.;
Fujino, Y.; Kojima, Y.; Ono, M.; Hayashi, S. Chem. Pharm. Bull. 1972,
26, 2024-2028. (d) Busi, E.; Capozzi, G.; Menichetti, S.; Nativi, C.
Synthesis 1992, 643-645.
Disulfide Equivalents
(9) For example, see: (a) Graybill, T. L.; Casillas, E. G.; Pal, K.;
Townsend, C. A. J. Am. Chem, Soc. 1999, 121 (34), 7729-7746. (b) Barrett,
A. G. M.; Hamprecht, D.; White, A. J. P.; Williams, D. J. J. Am. Chem,
Soc. 1996, 118, 7863-7864. (c) Refvik, M. D.; Schwan, A. L. J. Org. Chem.
1996, 61, 4232-4239. (d) Busi, E.; Capozzi, G.; Menic Synthesis 1992,
643-645. (e) Toste, F. D.; De Stefano, V.; Still, I. W. J. Synth. Commun.
1995, 25, 1277-1286. (f) Zyk, N. B.; Beloglazkina, Russ. J. Org. Chem.
1995, 31, 1300.
We now report the CuMeSal-mediated coupling of N-
thioimide derivatives with boronic acids as a new route to
thioethers. Many organoboron reagents are now readily
available, and more than 350 N-thioimides (S-alkyl, -aryl,
(10) (a) Furukawa, M.; Fujino, Y.; Kojima, Y.; Ono, M.; Hayashi, S.
Chem. Pharm. Bull. 1972, 26, 2024-2028. (b) Abe, Y.; Nakabayashi, T.;
Tsurugi, J. Bull. Chem. Soc. Jpn. 1973, 46, 1898-1899.
(11) Bu¨chel, K. H.; Conte, A. Chem. Ber. 1967, 100, 1248-1251.
(12) Klose, J.; Reese, C. B.; Song, Q. Tetrahedron 1997, 53, 14411-
14416.
(3) Kwong and Buchwald very recently described a mild, copper-
catalyzed coupling of aryl iodides with thiols: Kwong, F. Y.; Buchwald,
S. L. Org. Lett. 2002, 4, 3517-3520.
(4) Herradura, P. S.; Pendola, K. A.; Guy, R. K. Org. Lett. 2000, 2 (14),
2019-2022.
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Org. Lett., Vol. 4, No. 24, 2002

was completed efficiently within 4 h. This new coupling gave
best yields with 1.5-2.0 equiv of the boronic acid, although
in some cases this amount could be diminished without
affecting the yield. Among the various solvents tested
(dimethylacetamide, THF, EtOH, dioxane, N-methylpyrroli-
done, toluene, dichloroethane), dioxane and THF were the
best. The reaction was rapid in most cases (3-4 h) at 45-
50 °C. The use of bases (TBAF, K2CO3, NaOH, pyridine,
Et3N) inhibited the reaction. The corresponding disulfides
could be used in place of the N-thioimide, although stoi-
chiometric copper(I) carboxylate was required.
Table 1. CuI-Catalyzed Synthesis of Thioethers
From a mechanistic perspective, the coupling may start
with a reversible oxidative addition13 of the N-thioimide to
Cu(I), followed by a transmetalation from boron to copper
(Scheme 4). Carbonssulfur reductive elimination would
Scheme 4. Possible Mechanism of the Copper-Catalyzed
Coupling of Boronic Acids and N-Thioimides
afford the thioether and regenerate a catalytically viable CuI
carboxylate. Consistent with this premise, different copper-
(I) carboxylates were effective (CuMeSal,7 CuOAc, CuTC14),
but no reaction was observed with CuCN, Cu2O, or CuCl.
These observations suggest that the transmetalation step in
Scheme 4 delivers the imide moiety to the boron and that
the catalytic cycle is carried by the copper(I) carboxylate.
For clarity, we depict the coupling proceeding through a
CuI-CuIII mechanism. We note, however, that the reaction
of disulfides with CuI has been studied in detail and is
dramatically sensitive to the structure of the disulfide.
Whether the disulfide is cleaved and, if so, the oxidation
state of the copper cannot be easily predicted.15
In conclusion, we have described a new, base-free, and
mild method for the synthesis of thioethers, which provides
a useful alternative to known copper-mediated routes to
thioethers that proceed under basic conditions.2p,4 The
CuMeSal-catalyzed cross-coupling of organoboronic acids
and N-thioimide derivatives afforded the desired thioethers
in moderate to good yields.
groups on both the N-thioimide and boronic acid partners
were compatible with the reaction conditions. Nitroaryl
sulfides, which cannot be obtained with protocols involving
the use of strong reducing reagents, were easily synthesized
using this new reaction (entries 4, 9, and 11). Finally,
heteroaromatic N-thioimides 5 and 6 also underwent the
coupling (entries 10-13).
As a suitable control experiment, no reaction was observed
after treating the N-thiosuccinimide derivative 2 with the
phenylboronic acid at 50 °C for 24 h in THF; however, upon
addition of catalytic CuMeSal the reaction commenced and
(13) Cohen, T.; Wood, J.; Dietz, A. G., Jr. Tetrahedron Lett. 1974, 3555-
3558.
(14) CuI-thiophene-2-carboxylate is commercially available from Frontier
Scientific Inc. of Logan, Utah.
(15) See, for example: Itoh, S.; Nagagawa, M.; Fukuzumi, S. J. Am.
Chem. Soc. 2001, 123, 4087-4088.
Org. Lett., Vol. 4, No. 24, 2002
4311

Acknowledgment. The National Cancer Institute, DHHS
supported this investigation through grant No. CA40157. We
are most grateful to Dr. Gary Allred of Frontier Scientific,
Inc. of Logan, Utah for facilitating this study with a generous
supply of boronic acids.
Supporting Information Available: A complete descrip-
tion of experimental details and product characterization. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL026948A
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Org. Lett., Vol. 4, No. 24, 2002