Nickel-mediated inter- and intramolecular C-S coupling of thiols and thioacetates with aryl iodides at room temperature

Article abstract of DOI:10.1021/ol303366u

A Ni(0)-catalyzed intermolecular cross-coupling of various functionalized thiols and aryl iodides has been developed and successfully extended to less explored intramolecular versions, where thioacetates could also be utilized as the strategic surrogate. Air-stable precatalysts, very mild conditions, and an easy protocol allow rapid access to medicinally useful aryl thioethers, as demonstrated in the facile synthesis of (±)-chuangxinmycin as a key step.

Full text of DOI:10.1021/ol303366u

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Nickel-Mediated Inter- and Intramolecular
CꢀS Coupling of Thiols and Thioacetates
with Aryl Iodides at Room Temperature
Xiao-Bo Xu, Jian Liu, Jian-Jian Zhang, Ya-Wen Wang, and Yu Peng*
State Key Laboratory of Applied Organic Chemistry and College of Chemistry and
Chemical Engineering, Lanzhou University, Lanzhou 730000, China
pengyu@lzu.edu.cn
Received December 10, 2012
ABSTRACT
A Ni(0)-catalyzed intermolecular cross-coupling of various functionalized thiols and aryl iodides has been developed and successfully extended
to less explored intramolecular versions, where thioacetates could also be utilized as the strategic surrogate. Air-stable precatalysts, very mild
conditions, and an easy protocol allow rapid access to medicinally useful aryl thioethers, as demonstrated in the facile synthesis of (()-
chuangxinmycin as a key step.
Aryl thioether moieties are prevalent in a wide range of
bioactive natural products and pharmaceuticals. As de-
monstrated in Figure 1: gemmacin1 shows broad-spectrum
Gram-positive antibacterial activity in vitro, including
growth inhibition of vancomycin-intermediate S. aureus
and vancomycin-resistant enterococci; diltiazem2a as a
typical calcium antagonist has been used as a remedy for
angina and hypertension; and F 158453 shows cardiac
sodium current inhibition and antiischemic effects. Thus,
there have already been some advances in arylꢀsulfur
bond construction,4 among which transition-metal-
catalyzed cross-coupling of aryl halides and thiols played
an important role.5 However, this progress is limited com-
pared to that of well-established CꢀN and CꢀO coupling
reactions,6 since organic sulfur compounds easily poison
the catalyst due to their superfluous coordination with the
metal in the catalyst, and therefore most of the known
methods often rely on harsh conditions such as strong
bases (t-BuOK, t-BuONa, etc.), high reaction tempera-
tures (80ꢀ135 °C),5aꢀd,fꢀh and use of expensive or air-
sensitive ligands and excessive reagents. Consequently, an
alternative protocol is still in high demand; in particular,
intramolecular CꢀS cross-coupling remains much less
explored.7 Recently, we disclosed a CꢀC reductive cross-
coupling reaction under mild conditions by using a readily
(1) Thomas, G. L.; Spandl, R. J.; Glansdorp, F. G.; Welch, M.;
Bender, A.; Cockfield, J.; Lindsay, J. A.; Bryant, C.; Brown, D. F. J.;
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Ed. 2008, 47, 2808.
(2) (a) Nagao, T.; Sato, M.; Nakajima, H.; Kiyomoto, A. Chem.
Pharm. Bull. 1973, 21, 92. For thiazesim as an antidepressant drug, see:
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(3) Grand, B. L.; Pignier, C.; Letienne, R.; Cuisiat, F.; Rolland, F.;
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(b) Kondo, T.; Mitsudo, T. Chem. Rev. 2000, 100, 3205.
(5) For recent examples, see: (Cu) (a) Kwong, F. Y.; Buchwald, S. L.
(6) (a) Corbet, J.-P.; Mignani, G. Chem. Rev. 2006, 106, 2651. (b) Ley,
S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400 and
references cited therein.
(7) For an isolated example in which CuI/N,N-dimethylglycine cat-
alyzed Ullmann-type coupling was utilized, see: Gan, J.; Ma, D. Org.
Lett. 2009, 11, 2788.
Org. Lett. 2002, 4, 3517. (b) Bates, C. G.; Gujadhur, R. K.; Venkataraman,
D. Org. Lett. 2002, 4, 2803. (Pd) (c) Fernadez-Rodrıguez, M. A.; Shen, Q.;
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Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 2180. (d) Itoh, T.; Mase, T. Org.
Lett. 2004, 6, 4587. (e) Sayah, M.; Organ, M. G. Chem.;Eur. J. 2011, 17,
11719. (Fe) (f) Correa, A.; Carril, M.; Bolm, C. Angew. Chem., Int. Ed. 2008,
47, 2880. (Co) (g) Wong, Y.-C.; Jayanth, T. T.; Cheng, C.-H. Org. Lett. 2006,
8, 5613. (Ni) (h) Zhang, Y.; Ngeow, K. C.; Ying, J. Y. Org. Lett. 2007, 9,
3495.
(8) Yan, C.-S.; Peng, Y.; Xu, X.-B.; Wang, Y.-W. Chem.;Eur. J
2012, 18, 6039.
r
10.1021/ol303366u
XXXX American Chemical Society

Scheme 2. Intermolecular CꢀS Cross-Couplinga
Figure 1. Bioactive aryl thioether molecules.
Scheme 1. CꢀC versus CꢀS Cross-Coupling
a Reaction conducted on 1 mmol scale, and the isolated product yield
b
is shown. 2,20-Bipyridine (36 mol %) as the ligand was employed
instead of ethyl crotonate (EC). c Reaction conducted on 6 mmol (1.07 g)
of thiol, Zn (0.5 equiv), NiCl2 (10 mol %), and 2,20-bipyridine (12 mol %),
and the isolated yield of 1e is 94%. d 2.4 equiv of 4-iodoanisole relative to
1,6-hexanedithiol, Zn (2 equiv), NiCl2 (50 mol %), and 2,20-bipyridine
(60 mol %) were employed. The isolated yield of 1i is 52% when EC (2 equiv)
accessible and extremely cheap Ni(0) complex (Scheme 1,
top);8 herein, this versatile catalyst has been extended to
inter- and intramolecular CꢀS coupling where broad
tolerance to functional groups and practical application
were demonstrated preliminarily.
e
was employed. Zn (2 equiv), NiCl2 (50 mol %), and 2,20-bipyridine
(60 mol %) were employed for a corresponding thioester.
Our studies commenced with examining intermolecular
CꢀS coupling between p-iodoanisole and benzenethiol
(see Table S1 in Supporting Information (SI)) using Ni(0)•
2EC•Py as the catalyst, which is readily generated in situ
from a mixture of Zn/NiCl2/pyridine/ethyl crotonate (EC)
at 55 °C according to a previously established procedure.8
After screening the different solvents, MeOH was found to
be the best choice. With a stoichiometric amount of this
complex, the intended cross-coupling indeed occurred at
rt, and the desiredthioether1a wasformedin 88% yield; its
yield slightly decreased to 72% when 30 mol % Ni(0) complex
was employed. The addition sequence of two coupling
partners also proved to be important: first, the introduction
of p-iodoanisole into the above Ni(0) catalyst followed by
the addition of PhSH (1.2 equiv) could guarantee the
efficient formation of a carbonꢀsulfur bond. The analogous
Ni(0) catalyst generated by 2,20-bipyridine9 as a ligand
afforded a comparable result.
With the above optimized conditions in hand, cross-
couplings of various functionalized aryl thiols with
p-iodoanisole were then investigated (Scheme 2a). To our
delight, benzenethiols with Me and Cl groups, even penta-
fluorobenzenethiol, reacted smoothly, affording the corre-
sponding unsymmetrical diaryl thioethers (1bꢀ1d) in
moderate yields. Moreover, 5-mercapto-1-phenyl-1H-
tetrazole was also suitable, and the corresponding aryl-
heteroaryl thioether 1e could be isolated in 70% yield.
Importantly, this reaction can be also carried out in gram
scale with a significant increase of efficiency even with
10 mol % Ni(0) catalyst (see SI). Aliphatic (1°, 2°, 3°) thiols,
a class of relatively difficult substrates,5f were examined
next, and all of the lauryl, cyclohexyl, and tert-butyl
mercaptans10,5e gave the desired alkyl aryl thioethers
(1fꢀ1h) with good to moderate yields, respectively. Inter-
estingly, double S-arylation11 of 1,6-hexanedithiol pro-
ceeded smoothly, and symmetrical bisthioether 1i was
obtained in 62% yield. The present CꢀS cross-coupling
showed excellent tolerance to a wide range of functional
groups such as acetal (1j), NPhth (1k), OTBS (1l), and
OTHP (1m). Especially, thioether 1n with a free hydroxyl
group was also formed in 81% yield without accident,
obviously demonstrating the mild nature of this cross-
coupling reaction since its acidic proton apparently cannot
be compatible with the previous conditions with a strong
base. Utilization of the neopentyl thiol in CꢀS cross-
coupling is unprecedented due to its notorious steric
hindrance; however, 9-mercaptan camphor ethylene ketal
derived from (þ)-camphor indeed can participate in the
above-described coupling, leading to the chiral thioether
1o that would be served as a potential ligand in asymmetric
catalysis,12 in 50% isolated yield. Besides p-iodoanisole,
(10) Li, G. Y. Angew. Chem., Int. Ed. 2001, 40, 1513.
(11) For two examples where CuO nanoparticle catalyzed Ullmann
coupling was utilized, see: (a) Xu, H.-J.; Liang, Y.-F.; Zhou, X.-F.;
Feng, Y.-S. Org. Biomol. Chem. 2012, 10, 2562. (b) Rout, L.; Sen, T. K.;
Punniyamurthy, T. Angew. Chem., Int. Ed. 2007, 46, 5583.
(9) For recent applications of this kind of ligands in Ni-catalyzed
synthesis of trifluoromethyl thioethers and CꢀC coupling respectively,
see: (a) Zhang, C.-P.; Vicic, D. A. J. Am. Chem. Soc. 2012, 134, 183. (b)
Wang, S.; Qian, Q.; Gong, H. Org. Lett. 2012, 14, 3352.
ꢀ
ꢀ
(12) Gomez Arrayas, R.; Carretero, J. C. Chem. Commun. 2011, 47,
2207 and references cited therein.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 3. Intramolecular CꢀS Cross-Couplinga
Scheme 4. Intramolecular CꢀS Coupling with Thioacetatesa
a Reaction conducted on 1 mmol scale, and the isolated product yield
is shown. b 2,20-Bipyridine (60 mol %) as a ligand was employed instead
of ethyl crotonate (EC).
a Reaction conducted on 1 mmol scale, and the isolated product yield
is shown. b The isolated yield of 3i is 35% when K2CO3 (1.5 equiv) as an
extra base was employed. The isolated yield of 3b is 92% at rt when
c
NiCl2 (10 mol %) and 2,20-bipyridine (20 mol %) were employed.
other electron-rich and -deficient phenyl iodides bearing
(OMe, OH) and (F, CF3, COMe, CO2Et) groups, respec-
tively, also worked well with either aryl or alkyl thiols
(Scheme 2b), affording the corresponding cross-coupling
products (1pꢀ1r and 1uꢀ1w) in 59%ꢀ87% yields. Both
hindered o-iodoanisole and o-iodophenol also furnished
the desired thioethers 1s and 1t in good yields. Notably, the
present method provided a complementary approach for
the synthesis of 2-(phenylthio)phenols, which had already
been obtained through Cu(I)-catalyzed tandem transfor-
mation of CꢀS coupling/CꢀH oxidation by Pan.13
addition15a or alkylation15b,c of thiols, to the core of two
drugs, diltiazem and thiazesim. This catalytic system was
also applicable in the efficient construction of 1,5-benzox-
athiepines such as 3g. Finally, two addional 1,4-benzox-
athiine products 3h and 3i bearing either an electron-
donating OMe group or electron-withdrawing CO2Me
group were also demonstrated.
The direct use of thiols has some drawbacks such as a
foul smell and sensitivity of oxidation to disulfides. Thioa-
cetate, asa superior surrogateover other sulfur sourcesdue
to ease of its installation and cleavage, has been applied in
the CꢀS coupling but only to a limited extent in the
intermolecular reactions with base.16 We surmised that
the intramolecular counterpart would be plausible. Grat-
ifyingly, cyclization of thioacetate 40 derived from 4-bro-
moindole (vide infra; see SI for preparation) proceeded
smoothly under standard Ni(0)-mediated conditions ex-
cept in the replacement of EC by 2,20-bipyridine as a
ligand, and the desired tricyclic thioether 5 with some
strain could be isolated in 66% yield (Scheme 4, eq 1).
Other examples were demonstrated in the cyclizations of
thioacetates 2a0 and 2i0 (eqs 2 and 3), affording the
corresponding thioethers in comparable or even better
yields considering this essential two-step (deprotection
and coupling) transformation. The unmasked thiol could
be detected during the course of reaction; however, intro-
duction of an extra base (e.g., K2CO3) in order to facilitate
release of thiol led to the decreased yield of thioether (e.g.,
3i) instead, suggesting the mild nature imparted from this
unique system. Notably, the above method worked
even better on a gram-scale reaction with only 5 mol %
Ni(0) catalyst as demonstrated in the case of 2b0 (eq 4),
indicating that this protocol would be practically
valuable.
Extension of the above intermolecular CꢀS cross-cou-
plings to a less explored intramolecular version was then
explored. The needed cyclization precursors 2 could be
prepared conveniently according to procedures described
in the SI. As shown in Scheme 3, two 1,4-benzothiazines (3a
and 3b) can be obtained in high yields through intramole-
cular CꢀS coupling. More challenging 1,5-benzothiazepine,
a valuable structural unit in the pharmaceutical industry as
aforementioned, also can be obtained in moderate yield, as
exemplified in the case of 3c, whose structure was confirmed
by the X-ray diffraction of its single crystal.14 Two addi-
tional 1,5-benzothiazepines 3d and 3e bearing CF3 and
CO2Me groups on the benzene ring respectively were pre-
pared in useful yields as well, indicating that the present
CꢀS coupling is more efficient for the construction of a
seven-membered ring than that by our previous CꢀC
coupling.8 Notably, the access to 1,5-benzothiazepine-
4(5H)-one 3f is feasible albeit in moderate yield, and this
intramolecular CꢀS cross-coupling strategy provides a new
approach which complements those based on Michael
(13) (a) Xu, R.; Wan, J.-P.; Mao, H.; Pan, Y. J. Am. Chem. Soc. 2010,
132, 15531. (b) (Additions and Corrections) J. Am. Chem. Soc. 2011, 133,
387.
(14) See the CIF file in the Supporting Information for more details.
(15) (a) Ogawa, T.; Kumagai, N.; Shibasaki, M. Angew. Chem., Int.
Ed. 2012, 51, 8551. (b) Choudary, B. M.; Chowdari, N. S.; Madhi, S.;
Kantam, M. L. J. Org. Chem. 2003, 68, 1736. (c) Watson, K. G.; Fung,
Y. M.; Gredley, M.; Bird, G. J.; Jackson, W. R.; Gountzos, H.; Mattews,
B. R. J. Chem. Soc., Chem. Commun. 1990, 1018.
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Park, N.; Park, K.; Jang, M.; Lee, S. J. Org. Chem. 2011, 76, 4371.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 5. Sequential Twofold CꢀS Cross-Coupling
Scheme 7. Proposed Mechanism
effective platform to further evaluate our newly developed
methodology. As shown in Scheme 6, model thiol 4 was
subjected to an optimized Ni(0) system, and the desired 5
with a tricyclic thioether skeleton was produced in 76%
isolated yield. It is noteworthy that this intramolecular
reaction can proceed even at 0 °C, the lowest temperature
for this kind of CꢀS coupling reaction, to the best of our
knowledge. The successful synthesis of the core structure
of chuangxinmycin prompted us to investigate the applica-
tion in the secondary thiol 8, which was prepared from
4-bromoindole in a few steps. Similar conditions afforded
chuangxinmycin methyl 9a14 in a higher yield, and surpris-
ingly the free amine group did not interfere the expected
cyclization. Thus, formal synthesis of (()-chuangxinmycin
has already been accomplished.
Scheme 6. Formal Synthesis of (()-Chuangxinmycin
Based on previous mechanistic hypotheses about Ni-5h
or Pd-catalyzed19 CꢀS coupling, a similar mechanism for
the present reaction is proposed in Scheme 7. First, oxida-
tive addition of aryl iodide to Ni0 gives an ArNiIII species
that is subjected to coordination by thiol. The resulting
intermediate IArNiIIS(H)R would proceed to the Ar-
NiIISR species through elimination of HIassistedbyexcess
pyridine. Subsequent reductive elimination of ArNiIISR
furnishes the desired cross-coupling product ArꢀSR while
regenerating the Ni0 catalyst.
In summary, we have developed a practical method for
CꢀS bond construction catalyzed by a Ni(0) complex
generated in situ under mild, convenient conditions. The
less explored but more valuable intramolecular CꢀS cross-
coupling of thiolsorthioesterswas alsoachieved, affording
diverse medicinally useful aryl thioethers.
The unprecedented but interesting sequential twofold CꢀS
cross-coupling reaction was investigated next (Scheme 5).
This challenging transformation is orthogonal, distinctively
different from the usual parallel double CꢀS bond construc-
tion as exemplified by 1i and previous reports.11 The expected
bis-coupling product 7 cannot be detected when free thiol 6a
was employed, and only monocoupling thioether 7a was
obtained except for 1a and some oligomeric substances.
However, with thioacetate 6b as the substrate, the desired
bisthioether 7 was indeed formed in fairly good yield
(ca. 70% per step) along with 20% of 7a.
Chuangxinmycin 9b with an arylthioether functionality
was isolated from Actinoplanes tsinanensis n. sp. in China;
it exhibits in vitro activity against a number of Gram-
positive and -negative bacteria and is particularly effective
for the treatment of Escherichia coli infection.17 Its synth-
esis had been achieved by a variety of approaches.18 We
envisioned that this natural product would be served as a
Acknowledgment. We thank Mr. Jian Xiao and Miss
Hui-Qing Song (Lanzhou University) for their assistance.
This work was supported by NSFC (Nos. 20802029 and
21172096) and the Scientific Research Foundation for the
Returned Overseas Chinese Scholars, the Fundamental Re-
search Funds for the Central Universities (lzujbky-2012-57),
the IRT1138 Program, and the “111” Project of MoE.
(17) Liang, H.-T.; Hsu, H.-D.; Chang, C.-P.; Ku, H.-E.; Wang, W.-S.
Sci. Sin. 1977, 20, 106. Chem. Abstr. 1977, 87, 98565g.
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H.-S.; Yu, C.-L.; Chao, C.-L. Acta Chim. Sin. 1976, 34, 133. Chem. Abstr.
1978, 88, 62309h. (b) Kozikowski, A. P.; Greco, M. N. J. Am. Chem. Soc.
1980, 102, 1165. (c) Kozikowski, A. P.; Greco, M. N.; Springer, J. P. J. Am.
Chem. Soc. 1982, 104, 7622. (d) Ishibashi, H.; Tabata, T.; Hanaoka, K.;
Iriyama, H.; Akamatsu, S.; Ikeda, M. Tetrahedron Lett. 1993, 34, 489. (e)
Kato, K.; Ono, M.; Akita, H. Tetrahedron Lett. 1997, 38, 1805. (f) Dickens,
M. J.; Mowlem, T. J.; Widdowson, D. A.; Slawin, A. M. Z.; Williams, D. J.
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Supporting Information Available. Experimental de-
tails; characterization data for new compounds; copies of
1H, 13C NMR; and crystallographic information files
(CIFs) for 3c and 9a. This material is available free of
charge via the Internet at http://pubs.acs.org.
(19) (a) Alvaro, E.; Hartwig, J. F. J. Am. Chem. Soc. 2009, 131, 7858.
~
(b) Baranano, D.; Hartwig, J. F. J. Am. Chem. Soc. 1995, 117, 2937. (c)
The authors declare no competing financial interest.
Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852.
D
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