Copper-catalyzed thiolation of the Di- or trimethoxybenzene arene C-H bond with disulfides

Article abstract of DOI:10.1021/jo1014849

A CuI-catalyzed direct access to sulfides from disulfides via C-H bond cleavage of di- or trimethoxybenzene is described. The procedure utilizes O ₂ as a clean and cheap oxidant. Direct selenation of the C-H bond also took place under this procedure. Furthermore, the system enables the use of two RS in (RS)₂. Thus, it represents an atom-economical procedure for the synthesis of sulfides and selenides.

Full text of DOI:10.1021/jo1014849

pubs.acs.org/joc
SCHEME 1. Formation of a C-S Bond Catalyzed by
Transition Metal
Copper-Catalyzed Thiolation of the Di- or
Trimethoxybenzene Arene C-H Bond with Disulfides
Shouhui Zhang,† Pengcheng Qian,† Manli Zhang,†
Maolin Hu,† and Jiang Cheng*,†,‡
†College of Chemistry & Materials Engineering,
Wenzhou University, Wenzhou 325027, People’s Republic of
China, and ‡State Key Laboratory of Coordination
Chemistry, Nanjing University, Nanjing 210093,
People’s Republic of China
jiangcheng@wzu.edu.cn
Received July 28, 2010
bond (Scheme 1, eq 1).2 However, thiols are prone to undergo
oxidative S-S coupling reactions, resulting in the undesired
formation of disulfides. Moreover, organic sulfur compounds
may bind to metal, causing the deactivation of metal catalyst.3
Employing PhSSPh may solve these drawbacks (Scheme 1,
eq 2).4 Nevertheless, in general, 1 equiv of reductant such as
Zn or Mg was added in the reaction of ArX and RSSR, and
prefunctionalization is still required for such transformation.
The direct functionalization of a C-H bond is a straight-
forward transformation in organic synthesis.5 Among these,
much effort has been paid on C-C6 and C-hetero bonds.7
However, few examples of the formation of a C-S bond
through C-H bond cleavage has been reported before.
In2006, Yuand co-workers reporteda Cu(OAc)2-catalyzed
thiolation of the 2-phenylpyridine with PhSH and MeSSMe
under oxygen atmosphere (Scheme 1, eq 3).8 Subsequently,
A CuI-catalyzed direct access to sulfides from disulfides
via C-H bond cleavage of di- or trimethoxybenzene
is described. The procedure utilizes O2 as a clean and
cheap oxidant. Direct selenation of the C-H bond also
took place under this procedure. Furthermore, the system
enables the use of two RS in (RS)2. Thus, it represents an
atom-economical procedure for the synthesis of sulfides
and selenides.
(5) For representative reviews, please see: (a) Dyker, G. Handbook of
C-H Transformations. Applications in Organic Synthesis; Wiley-VCH:
Weinheim, Germany, 2005. (b) Murai, S. Activation of Unreactive Bonds
and Organic Synthesis; Springer: Berlin, Germany, 1999; pp 48-78.
(c) Lewis, J. C.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2008, 41,
1013. (d) Goj, L. A.; Gunnoe, T. B. Curr. Org. Chem. 2005, 9, 671. (e) Park,
Y. J.; Park, J. W.; Jun, C. H. Acc. Chem. Res. 2008, 41, 222. (f) Mori, C. A.;
Sugie, A. Bull. Chem. Soc. Jpn. 2008, 81, 548. (g) Diaz-Requejo, M. M.;
Aryl sulfides are a common functionality found in numer-
ous pharmaceutically active compounds and medicinally
important natural products.1 The transition metal-catalyzed
cross coupling of ArX (X = Cl, Br, I, OTf, and B(OH)2) and
ArSH is a powerful method for the construction of a C-S
ꢀ
Perez, P. J. Chem. Rev. 2008, 108, 3379. (h) Lyons, T. W.; Sanford, M. S.
Chem. Rev. 2010, 110, 1147. (i) Colby, D. A.; Bergman, R. G.; Ellman, J. A.
Chem. Rev. 2010, 110, 624. (j) Mkhalid, I. A.; Barnard, J. H.; Marder, T. B.;
Murphy, J. M.; Hartwig, J. F. Chem. Rev. 2010, 110, 890.
(6) (a) Zhang, Y.-H.; Shi, B.-F.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131,
5072. (b) Norinder, J.; Matsumoto, A.; Yoshikai, N.; Nakamura, E. J. Am.
Chem. Soc. 2008, 130, 5858. (c) Wen, J.; Zhang, J.; Chen, S.-Y.; Li, J.; Yu,
X.-Q. Angew. Chem., Int. Ed. 2008, 47, 8897. (d) Ban, I.; Sudo, T.; Taniguchi,
T.; Itami, K. Org. Lett. 2008, 10, 3607. (e) Deng, G. J.; Zhao, L.; Li, C.-J.
Angew. Chem., Int. Ed. 2008, 47, 6278. (f) Seregin, I. V.; Ryabova, V.;
Gevorgyan, V. J. Am. Chem. Soc. 2007, 129, 7742. (g) He, C.; Guo, S.;
Huang, L.; Lei, A.-W. J. Am. Chem. Soc. 2010, 132, 8273. (h) Gandeepan, P.;
Parthasarathy, K.; Cheng, C. H. J. Am. Chem. Soc. 2010, 132, 8569. (i) Shuai,
(1) (a) Liu, L.; Stelmach, J. E.; Natarajan, S. R.; Chen, M.-H.; Singh,
S. B.; Schwartz, C. D.; Fitzgerald, C. E.; O’Keefe, S. J.; Zaller, D. M.;
Schmatz, D. M.; Doherty, J. B. Bioorg. Med. Chem. Lett. 2003, 13, 3979.
(b) Kaldor, S. W.; Kalish, V. J.; Davies, J. F., II; Shetty, B. V.; Fritz, J. E.;
Appelt, K.; Burgess, J. A.; Campanale, K. M.; Chirgadze, N. Y.; Clawson,
D. K.; Dressman, B. A.; Hatch, S. D.; Khalil, D. A.; Kosa, M. B.;
Lubbehusen, P. P.; Muesing, M. A.; Patick, A. K.; Reich, S. H.; Su, K. S.;
Tatlock, J. H. J. Med. Chem. 1997, 40, 3979.
ꢀ
Q.; Yang, L.; Guo, X.-Y.; Basle, O.; Li, C.-J. J. Am. Chem. Soc. 2010, 132,
12212.
(2) For reviews, please see: (a) Kondo, T.; Mitsudo, T. Chem. Rev. 2000,
100, 3205. (b) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42,
5400. (c) Hartwig, J. F. Acc. Chem. Res. 2008, 41, 1534. (d) Kunz, K.; Scholz,
U.; Ganzer, D. Synlett 2003, 2428.
(3) (a) Correa, A.; Carril, M.; Bolm, C. Angew. Chem., Int. Ed. 2008, 47,
2880. (b) Reddy, V. P.; Kumar, A. V.; Swapna, K.; Rao, K. R. Org. Lett.
2009, 11, 1697.
(7) (a) Wan, X.; Ma, Z.; Li, B.; Zhang, K.; Cao, S.; Zhang, S.; Shi, Z.
J. Am. Chem. Soc. 2006, 128, 7416. (b) Giri, R.; Chen, X.; Yu, J.-Q. Angew.
Chem., Int. Ed. 2005, 44, 2112. (c) Hull, K. L.; Anani, W. Q.; Sanford, M. S.
J. Am. Chem. Soc. 2006, 128, 7134. (d) Dick, A. R.; Hull, K. L.; Sanford,
M. S. J. Am. Chem. Soc. 2004, 126, 2300. (e) Fang, P.; Li, M.-Z.; Ge, H.
J. Am. Chem. Soc. 2010, 132, 11898. (f) Thu, H. Y.; Yu, W. Y.; Che, C.-M.
J. Am. Chem. Soc. 2006, 128, 9048. (g) Li, Z.; Capretto, D. A.; Rahaman,
R. O.; He, C. J. Am. Chem. Soc. 2007, 129, 12058. (h) Shi, Z.-S.; Cui, Y.-X.;
Jiao, N. Org. Lett. 2010, 12, 2908. (i) Mei, T.-S.; Wang, D.-H.; Yu, J.-Q. Org.
Lett. 2010, 12, 3140. (j) Wang, X.; Lu, Y.; Dai, H.; Yu, J.-Q. J. Am. Chem.
Soc. 2010, 132, 12203.
(4) (a) Taniguchi, N. J. Org. Chem. 2004, 69, 6904. (b) Taniguchi, N.;
Onami, T. Synlett 2003, 829. (c) Taniguchi, N.; Onami, T. J. Org. Chem.
ꢀ
ꢀ
2004, 69, 915. (d) Gomez-Benıtez, V.; Baldovino-Pantaleon, O.; Herrera-A
´
ꢀ
lvarez, C.; Toscano, R. A.; Morales-Morales, D. Tetrahedron Lett. 2006, 47,
5059. (e) Kumar, S.; Engman, L. J. Org. Chem. 2006, 71, 5400. (f) Baldovino-
Pantaleon, O.; Hernandez-Ortega, S.; Morales-Morales, D. Adv. Synth.
Catal. 2006, 348, 236. (g) Fukuzawa, S.-I.; Tanihara, D.; Kikuchi, S. Synlett
2006, 2145.
(8) Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc.
2006, 128, 6790.
6732 J. Org. Chem. 2010, 75, 6732–6735
Published on Web 09/07/2010
DOI: 10.1021/jo1014849
r
2010 American Chemical Society

Zhang et al.
JOCNote
TABLE 1. Screening for the Optimal Conditionsa
served as the terminal oxidant for the reaction. Among the
solvents tested, DMF was the best (Table 1, entries 12-15).
No product was detected in the absence of copper (Table 1,
entry 16). Notably, the reaction conducted on a 10 mmol
scale formed the thiolation product in an acceptable 70%
yield. The employment of cheap copper as catalyst and O2 as
clean oxidant significantly improved the practicality of this
C-H functionalization reaction.
entry
Cu source
oxidant (equiv)
oxidant
yield (%)
1
2
CuI
CuI
oxone (1.0)
K2S2O8 (1.0)
PhI(OAc)2 (1.0)
BQ (1.0)
air
air
air
air
air
air
O2
O2
O2
O2
O2
O2
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
xylene
DMSO
NMP
THF
30
46
43
48
77
<5
10
45
<5
70
Having identified the optimal reaction conditions, the
scope of RSSR was investigated, as shown in Table 2. As
expected, a series of functional groups on the phenyl ring
of disulfides, such as methoxy, bromo, fluoro, chloro, nitro,
and methoxycarbonyl, were well-tolerated under this proce-
dure, providing the thiolation products in moderate to good
yields (Table 2, 3b, 3c, 3d, 3e, 3f, 3i, 3j, 3q). Generally, the
electron-withdrawing groups on the phenyl ring of ArSSAr
were beneficial to the reaction (Table 2, 3i and 3j). The
hindrance on the phenyl ring of disulfides had quite a limited
effect on the yield of the reaction. For example, the ortho-
substituted substrate 2g delivered a 60% yield of 3g, while 3f
was isolated in 62% yield. Importantly, the halo groups on
the phenyl ring of disulfides survived in the procedure
(Table 2, 3d, 3e, 3f, and 3g). It is notable that halo products
could be easily further manipulated. Particularly, when
PhSeSePh was subjected to the procedure, the monoselena-
tion product 3o was isolated in 70% yield, along with 30% of
the diselenation product 3p. Fortunately, the benzyl and allyl
groups were compatible with the conditions (Table 2, 3k and
3m), albeit the thiolation products were isolated in low yields.
It is also noteworthy that 1,2-di(benzo[d]thiazol-2-yl)disul-
fane 3n could provide the thiolation product in good yield
with prolonged reaction time. Furthermore, the alkyl ester
2l was a good reaction partner, providing the correspond-
ing product in 71% yield (Table 2, 3l). Disappointingly,
MeSSMe did not work under the current condition.
Next, the thiolations of other electron-rich arene C-H
bonds by PhSSPh were presented in Chart 1. 3s and 3r were
formed in moderate yields, respectively. No regioisomeric
products were observed by GC-MS and 1H NMR spectros-
copy. Disappointingly, other methoxybenzene substrates
failed to work under the standard reaction conditions.
More experiments were carried out to gain preliminary
insight into the mechanism of catalytic procedure. The pro-
duct 3a could be gained in 40% yield catalyzed by 1 mol % of
PhSCu in DMF under O2 at 120 °C for 72 h (Scheme 2, eq 1),
while the stoichiometric reaction of 1,3,5-trimethoxybenzene
and PhSCu catalyzed by Cu(I) in DMF under O2 at 120 °C
for 36 h produced 3a in 65% yield (Scheme 2, eq 2). This
result indicated that PhSCu may serve as an intermediate in
the catalytic cycle. The lack of reactivity with PhSCu under
N2 suggested that the oxygen was necessary for the thiola-
tion reaction (Scheme 2, eqs 1 and 2). Furthermore, when
4-iodoanisole was submitted to our catalytic system, no cor-
responding thioether product was found (Scheme 2, eq 3),
which ruled out the possibility of an in situ iodination
followed by a conventional sulfide formation pathway. Fur-
thermore, the radical inhibitors including 2,6-di-tert-butyl-4-
methylphenol (BHT, 2 mol %) and 2,2,6,6-tetramethyl-
piperidinooxy (TEMPO, 2 mol %) were subjected to the
standard procedure, however, the product 3a were isolated in
70% and 75% yields, respectively. Thus, a radical-mediated
mechanism was also excluded.
3
4
CuI
CuI
5
CuI
6
7
8
9
10
11
12
13
14
15
16
CuF2
CuCl2
CuBr2
CuCl
CuBr
CuI
CuI
CuI
CuI
CuI
81 (27b)
15
63
60
10
<5
DMF
a1a (34 mg, 0.2 mmol), PhSSPh 2a (33 mg, 0.15 mmol), Cu (20 mmol
%), oxidant, dry solvent (2 mL), under air, 120 °C, 24 h. bUnder N2.
examples of intramolecular C-S bond forming 2-substituted
benzothiazoles through C-H functionalization were demon-
strated by Doi and Batey, respectively.9 Recently, Dong and
co-workers described the Pd-catalyzed direct sulfonylation
of a 2-phenylpyridine C-H bond with ArSO2Cl.10 In 2009,
Fukuzawa and co-workers demonstrated a copper-catalyzed
direct thiolation of a benzoxazole C-H bond with diaryl
disulfides and aryl thiols.11 Recently, Li and co-workers dis-
closed iron-catalyzed sulfenylation of an indole C-H bond
with diaryl disulfides, whereas a catalytic amount of iodine
was supplied to promote the reaction.12 Very recently, Qing
reported a Cu(II)-mediated reaction of an aryl C-H bond
with DMSO to ortho-substituted methylthiolation.13 How-
ever, a heteroatom, which mostly acted as a chelation group,
is essential for the aforementioned transformations. Herein,
we report a nonchelation-assisted Cu-catalyzed thiolation of
the di- or trimethoxybenzene arene C-H bond with ArSSAr
(Scheme 1, eq 4).
We initially tested the thiolation of 1,3,5-trimethoxyben-
zene with PhSSPh. To our delight, phenylthiolation could
take place in the presence of CuI (20 mol %) in DMF with
Oxone as oxidant. The choice of oxidant was essential to the
reaction (Table 1, entries 1-4). Intriguingly, the yield drama-
tically increased to 77% with air as the sole oxidant in DMF
(Table 1, entry 5). Further studies revealed the use of other
coppers as catalysts resulted in lower yields (Table 1, entries
6-10). Gratifyingly, the system enables the use of two RS in
(RS)2. Under an O2 atmosphere, the yield increased to 81%,
while under N2, only 27% of the desired product was isolated
(Table 1, entry 11). These results indicated the oxygen may be
(9) (a) Inamoto, K.; Arai, Y.; Hiroya, K.; Doi, T. Chem. Commun. 2008,
5529. (b) Inamoto, K.; Hasegawa, C.; Hiroya, K.; Doi, T. Org. Lett. 2008, 10,
5147. (c) Joyce, L. L.; Batey, R. A. Org. Lett. 2009, 11, 2792.
(10) Zhao, X.; Dimitrijevic, E.; Dong, V. M. J. Am. Chem. Soc. 2009, 131,
3466.
(11) Fukuzawa, S.-I.; Shimizu, E.; Atsuumi, Y.; Haga, M.; Ogata, K.
Tetrahedron Lett. 2009, 50, 2374.
(12) Fang, X.-L.; Tang, R.-Y.; Zhong, P.; Li, J.-H. Synthesis 2009, 4183.
(13) Chu, L.; Yue, X.; Qing, F.-L. Org. Lett. 2010, 12, 1644.
J. Org. Chem. Vol. 75, No. 19, 2010 6733

Zhang et al.
JOCNote
TABLE 2. CuI-Catalyzed Thiolation of the 1,3,5-Trimethoxybenzene
CHART 1. CuI-Catalyzed Thiolation of the 1,2,4-Tri- and
1,3-Dimethoxybenzene C-H Bonda
C-H Bonda
aReagents and conditions: 1a (0.2 mmol), PhSSPh 2a (33 mg, 0.2 mmol),
CuI (8 mg, 20 mmol %), dry DMF (2 mL), under O2, 120 °C, 24 h. b48 h.
SCHEME 2. Preliminary Mechanism Study
SCHEME 3. Plausible Mechanism
In conclusion, we have demonstrated an efficient Cu-
catalyzed thiolation of electron-rich arene C-H bonds with
diphenyl disulfide and diselenide. The employment of cheap
copper as catalyst and O2 as clean oxidant significantly
improved the practicality of this C-H functionalization
reaction. As such, the reaction provides a convenient and
atom-economical method for the synthesis of sulfides and
selenides
a1a (34 mg, 0.2 mmol), RSSR 2a (0.15 mmol), CuI (8 mg, 20 mol %),
dry DMF (2 mL), under O2, 120 °C, 24 h. bRSSR 2a (0.2 mmol). cRSSR
2a (0.2 mmol), 48 h.
Upon the basis of the experimental results, the plau-
sible pathway for the thiolation reaction was outlined in
Scheme 3.11 Step i involves the cuprate of the trimethoxy-
benzene C-H bond to afford intermediate A. In step ii, the
ArCu(I) species A reacts with diphenyl disulfide to afford the
product 3a and PhSCu(I) B. Then, in step iii, intermediate B
takes place with 1,3,5-trimethoxybenzene under O2 to form
ArCu(II)SPh intermediate C. Finally, the reductive elimina-
tion of the Cu(II) complex C affords the product 3a and
Cu(0), which is oxidized to Cu(I) by O2.
Experimental Section
General Procedure for Thiolation of the Corresponding
Subtrates. Under oxygen atmosphere, a reaction tube was
charged with 1,3,5-trimethoxybenzene (34 mg, 0.2 mmol),
RSSR (0.15 mmol), CuI (8 mg, 20 mol %), and dry DMF
(2 mL). The mixture was stirred at 120 °C for 24 h. After the
completion of the reaction, as monitored by TLC, the solvent
6734 J. Org. Chem. Vol. 75, No. 19, 2010

Zhang et al.
JOCNote
was concentrated in vacuo and the residue was purified by flash
column chromatography on silica gel (300-400 mesh) with
petroleum ether-EtOAc as eluent to give the desired product.
Phenyl(2,4,6-trimethoxyphenyl)sulfane (3a):14 1H NMR (CDCl3,
300 MHz) δ 7.18-7.13 (m, 2H), 7.05-7.00 (m, 3H), 6.22 (s, 2H),
3.87 (s, 3H), 3.80 (s, 6H); 13C NMR (CDCl3, 125 MHz) δ 162.9,
162.5, 138.7, 128.5, 125.6, 124.3, 100.0, 91.2, 56.3, 55.5.
Acknowledgment. We thank the National Natural Science
Foundation of China (No. 20972115), the Key Project of
Chinese Ministry of Education (No. 209054), and the State
Key Laboratory of Coordination Chemistry of Nanjing
University for financial support.
Supporting Information Available: Experimental proce-
dures along with copies of spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
(14) Matsugi, M.; Murata, K.; Gotanda, K.; Nambu, H.; Auilkumar, G.;
Matsumoto, K.; Kita, Y. J. Org. Chem. 2001, 66, 2434.
J. Org. Chem. Vol. 75, No. 19, 2010 6735