Pd2+ and Cu2+ catalyzed oxidative cross-coupling of mercaptoacetylenes and arylboronic acids

Article abstract of DOI:10.1039/c1cc10505a

An oxidative thiolate scavenging concept in a metal catalyzed reaction is presented and demonstrated on the aerobic Pd and Cu catalyzed cross-coupling of mercaptoacetylenes with arylboronic acids. Synthetic value of the chemistry as the complementary tool to the Sonogashira protocol has been demonstrated on a series of functionalized mercaptoacetylene substrates.

Full text of DOI:10.1039/c1cc10505a

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COMMUNICATION
Pd2+ and Cu2+ catalyzed oxidative cross-coupling
of mercaptoacetylenes and arylboronic acidswz
Adam Henke and Jiri Srogl*
Received 25th January 2011, Accepted 14th February 2011
DOI: 10.1039/c1cc10505a
An oxidative thiolate scavenging concept in a metal catalyzed
reaction is presented and demonstrated on the aerobic Pd and Cu
catalyzed cross-coupling of mercaptoacetylenes with arylboronic
acids. Synthetic value of the chemistry as the complementary
tool to the Sonogashira protocol has been demonstrated on a
series of functionalized mercaptoacetylene substrates.
thioesters with aryl boronic acids,3 we wanted to extend the
whole concept of the aerobic transition metal catalyzed cross-
coupling reaction and address the unresolved issues pertaining
to the mechanism of this peculiar process. Thus, utilizing the
same structural scaffold, we have examined metal catalyzed
oxidative cross-coupling reaction of mercaptoacetylenes and
boronic acids. Obviating the selection of mercaptoacetylenes
as the cross-coupling substrates is the synthetic protocol
published recently leading to their formation under neutral
conditions from readily accessible terminal alkynes.4
One of the foremost examples of modern synthetic methods is
the chemistry that helps connect two, often highly functionalized
entities, while forming a new bond between two atoms of respective
subunits in the process. In this scenario, the cross-coupling
reaction partners possess respective, formally electrophilic
(organic halides, sulfonates etc.) and nucleophilic properties.
The presence of a transition metal, which facilitates chemistry
through the consequent oxidative addition/reductive elimina-
tion steps, is typically required.1 The ever growing demand for
sophisticated target molecules has, however, profoundly impacted
the reaction conditions, encouraging the current trend of a
gradual replacement of the traditionally used highly reactive
organomagnesium or organozinc nucleophiles by much milder
reagents such as organoboron or organotin moieties. Although
in the vast majority of all cross-coupling reactions halides and,
to a smaller extent, esters of inorganic acids are used,1 the
reaction of organosulfur compounds that falls within the same
reactivity bracket was published recently.2 The resulting
thiolate by-products, considered to be detrimental to catalytic
metals, have been in this case effectively ‘‘scavenged’’ by
stoichiometric cuprous carboxylate additives, eventually forming
highly stable Cu thiolates. Unlike in the former case however,
there is an additional path, which can be explored for the
adverse thiolate effects neutralization in the organosulfur
cross-coupling scenario. Built around the uncomplicated thiolate
oxidative transformation, this route leads, in the end, to a
more chemically accommodating environment. While the
basic framework of this concept has been outlined recently
by introducing surprising Cu catalyzed aerobic reaction of
In the cursory screening of their reactivity, the mercapto-
acetylene 1 was treated with tolylboronic acid in the presence
of metal catalysts under various conditions (Table 1). Surprisingly
when, analogically to the published account,3 Cu(I) or Cu(II)
salts were used as the catalyst, no desired product was
detected. Fortunately, when the situation was remedied by
the addition of a Pd catalyst in a separate experiment, the
desired product 2 was formed in the high yield, accompanied
Table 1 Catalyst evaluation in the aerobic cross-coupling reaction
Entry
Pd cat.
Cu cat.
Ligandb
2aa
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd 4
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
Pd(dba)2
CuMeSal
CuMeSal
CuMeSal
CuMeSal
CuMeSal
CuMeSal
CuMeSal
CuMeSal
CuMeSal
CuMeSal
CuMeSal
CuMeSal
CuCN
4 eq. (2-furyl)3P
4 eq. (2-tolyl)3P
4 eq. Cy3P
4 eq. Ph3P
4 eq. (C6F5)3P
2 eq. DIPHOS
2 eq. DPEphos
—
—
1 eq. Ph3P
1 eq. (PhO)3P
—
—
—
—
—
13
Trace
9
38
71
28
30
65
82
77
79
90
18
12
Trace
78
9
10
11
12
13
14
15
16
Institute of Organic Chemistry and Biochemistry,
Academy of Sciences of the Czech Republic, Flemingovo nam. 2,
166 10, Prague, Czech Republic. E-mail: jsrogl@uochb.cas.cz
CuI
CuCO3
Cu(OAc)2
w Dedicated to Prof. Pavel Kocovsky
´ on the occasion of his 60th
birthday.
a
z Electronic supplementary information (ESI) available: All the relevant
synthetic details as well as 1H and 13C spectra for all compounds. See
DOI: 10.1039/c1cc10505a
HPLC conversion (%), Pd cat. (5 mol%), Cu cat. (10 mol%), T = 3 h.
The ligand equivalents are relative to the catalyst amounts.
b
c
4282 Chem. Commun., 2011, 47, 4282–4284
This journal is The Royal Society of Chemistry 2011

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by the expected obligatory oxidative by-product 3 in a
1 : 1 ratio.5
In order to glean additional information about the process
and support the oxidative thiolate scavenging notion, the
same reaction was carried out under an inert atmosphere.
No product(s) were formed in this case, which further
corroborates the whole concept. An equally critical role in
the cross-coupling scenario was played by the thiosalicylamide
scaffold; the reaction of a simple p-tolylmercaptophenyl-
acetylene did not lead to the expected products leaving the
substrate unaffected. Underscoring the vital role of copper in
the reaction scheme, experiments with catalytic or stoichio-
metric amount of a Pd catalyst failed to furnish any products
in the absence of Cu ions. An unavoidable issue critical to the
mechanism of the present reaction is the question of the
metal catalyst’s oxidative state. While the reaction can be
catalyzed by a variety of the Pd complexes [various triaryl-
phosphine, trialkylphosphine complexes, Pd(OAc)2] and Cu
salts [(CuCN, CuI, Cu 3-methylsalycilate, Cu(OAc)2]6 regardless
of their respective oxidation state, the presence of air suggests
that the metals function as transformation catalysts in their
oxidized states—Pd2+ and Cu2+ respectively. In the light
of the fact that low valent palladium complexes generally
facilitate cross-coupling reactions of various substrates
through the oxidative addition step (Pd0 to Pd2+), the higher
oxidation state in the present case is rather unusual, con-
tradicting the common mechanistic scenario.7 To distinguish
between the two oxidation states of the Pd catalyst, the cyclic
complex 4 (Fig. 1), known to remain, under the relatively mild
reaction condition in the 2+ oxidation state was selected as
the metal source.8
Scheme 1 Tentative mechanism of the Pd and Cu catalyzed coupling.
Table 2 Oxidative coupling of mercaptoacetylenes with arylboronic
acids
Entry
1 (R)
Boronic acid (Ar)
2a
3a
a
b
c
d
e
f
g
h
i
Ph
Ph
4-Tolyl
83
84
64
93
82
79
85
81
82
78
86
80
75
87
78
64
95
80
70
69
4-(CHO)C6H4
2-(CH3O)C6H4
3-HOC6H4
COOEt
4-(CH3CO)C6H4
2-BrC6H4
2-Cl-5-NO2–PhCOOCH2–
4-(CH3CO)C6H4
N-Methyl phthalyl
N-Methyl phthalyl
COOEt
Indole-5-yl
Thianthrene-1-yl
3-(NH2CO)C6H4
3-BrC6H4
3-NO2C6H4
4-ClC6H4
The ensuing cross-coupling experiment provided, again, the
same set of products in excellent yields pointing thus at the
likely catalytically active Pd2+ oxidation state.
j
a
Based on the experiments above, we have proposed the
mechanism starting with the formation of arylcopper from
arylboron by transmetallation with Cu.9 The resultant inter-
Yield of isolated products (%) General procedure: mercaptoacetylene
1 (0.5–1.0 mmol), corresponding boronic acid (2.2–3.0 eq.), CuMeSal
(3 mol%) and Pd(dba)2 (1 mol%) were placed into a reaction flask
(10 ml). DMF (2–4 mL) was added and the resulting reaction mixture
was stirred for 8–20 h at 45–50 1C in the presence of air. Reaction
progress was followed by HPLC.
mediate subsequently adds, assisted by pre-coordinated Pd2+
,
in trans fashion across the alkyne triple bond.8,10 The sub-
sequent b-mercapto elimination of the Pd intermediate results
in the desired disubstituted acetylene 3 accompanied by the
corresponding metal thiolate.11 The eventual oxidative aryla-
tion of the thiolate finally leads to the requisite arylthioether,
liberating the metal(s) back to the catalytic cycle in the process
(Scheme 1).
peaking in the invention of such a stalwart tool in the synthetic
toolbox as a Pd catalyzed Sonogashira protocol,12a which
utilizes organic halides and terminal alkynes as the substrates.
In the light of the ‘‘mirror-like’’ reactivity arrangement, our
chemistry can thus be viewed as the complementary synthetic
tool for the construction of the alkyne moieties. In order to
demonstrate the scope of our chemistry and show its synthetic
advantages, a variety of functionalized substrates was exam-
ined under the reaction conditions. The results are summarized
in Table 2.
Although understanding of oxidative cross-coupling concept
has been the ultimate goal of the present study we want to illustrate
our insights into the process by the synthesis of chemically
valuable targets. Substituted alkynes belong, undeniably, in
this group. Their importance for modern chemistry is best
illustrated by numerous methods developed recently,12,13
In an effort to exemplify the complementarity of our chemistry
with the Sonogashira protocol, compound 2, prepared by the
present procedure (entry 2e), was subjected to Sonogashira
coupling conditions. The resultant substituted bis acetylene
moiety 5, formed in good yield, undoubtedly substantiates the
synthetic advantages (Scheme 2).
Overall, the aerobic Pd and Cu catalyzed cross-coupling of
mercaptoacetylenes with arylboronic acids has been presented
Fig. 1 Cyclic Pd2+ catalyst.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 4282–4284 4283

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5 Following the oxidative cross-coupling concept the thioether 3 is
formed as an expected product of refractory thiolate oxidative
scavenging.
6 While the cross-coupling can be successfully catalyzed by a variety
of Pd complexes and Cu salts, the best yields were obtained with
Pd2dba3 and copper 3-methylsalicilate as the metal sources. For
the same reason DMF was selected as the solvent of our choice,
although DMA and NMP were almost equally efficient.
7 Although the palladium complexes in the higher oxidation state are
regularly employed as the catalysts, they are reduced through
transmetallation/reductive elimination step to form catalytically
active Pd(0) species.
8 (a) W. A Herrmann, Ch. Brossmer, K. Oefele, C.-P. Reisinger,
T. Priermeier, M. Beller and H. Fischer, Angew. Chem., Int. Ed.
Engl., 1995, 34, 1844; (b) M. Beller, H. Fischer, W. A. Herrmann,
K. Oefele and Ch. Brossmer, Angew. Chem., Int. Ed. Engl., 1995,
34, 1848; (c) F. D’Orlye and A. Jutand, Tetrahedron, 2005, 61,
9670; (d) J. Louje and J. Hartwig, Angew. Chem., Int. Ed. Engl.,
1996, 35, 2359.
9 Y. Yamamoto, N. Kirai and Y. Harada, Chem. Commun., 2008,
2010.
10 Ch. Jia, W. Lu, J. Oyamada, T. Kitamura, K. Matsuda, M. Irie
and Y. Fujiwara, J. Am. Chem. Soc., 2000, 122, 7252.
11 For corresponding Pt see: H. Kunyasu, F. Yamashita, J. Terao and
N. Kambe, Angew. Chem., Int. Ed., 2007, 46, 5929.
12 (a) K. Sonogashira, Y. Tohda and N. Hagihara, Tetrahedron Lett.,
1975, 16, 4467; (b) E. Negishi and L. Anastasia, Chem. Rev., 2003,
103, 1979; (c) R. Chinchilla and C. Najera, Chem. Rev., 2007, 107,
874; (d) Y. Zhao, H. Wang, X. Hou, Y. Hy, A. Lei, H. Zhang and
L. Zhu, J. Am. Chem. Soc., 2006, 128, 15048.
13 For the recent oxidative cross-couplings of terminal acetylenes and
boronic acids see: (a) M. Chen, X. Zheng, W. Li, J. He and A. Lei,
J. Am. Chem. Soc., 2010, 132, 4101; (b) D.-H. Wang, M. Wasa,
R. Giri and J.-Q. Yu, J. Am. Chem. Soc., 2008, 130, 7190;
(c) M.-B. Zhou, W.-T. Wei, Z.-X. Xie, Y. Lei and J.-H. Li,
J. Org. Chem., 2010, 75, 5635; (d) G. Zou, J. Zhu and J. Tang,
Tetrahedron Lett., 2003, 44, 8709.
14 (a) F. Gonzales-Bobes and G. C. Fu, J. Am. Chem. Soc., 2006, 128,
5360; (b) F. O. Arp and G. C. Fu, J. Am. Chem. Soc., 2005, 127,
10482; (c) J.-H. Li, Y. Liang and Y.-X. Xie, J. Org. Chem., 2005,
70, 4393; (d) S. Li, Y. Lin, J. Cao and S. Zhang, J. Org. Chem.,
2007, 72, 4067; (e) I. D. Kostas, F. J. Andreadaki, D. Kovala-
Demertzi, C. Prentjas and M. A. Demertzis, Tetrahedron Lett.,
2005, 46, 1967; (f) C. R. LeBlond, K. M. Butler, M. W. Ferrington
and M. A. Browe, Synth. Commun., 2009, 39, 636.
Scheme 2 Synthetic comparison of the present chemistry with a
Sonogashira protocol.
which illustrates an oxidative thiolate scavenging concept in a
metal catalyzed reaction. Distinctly different from the published
protocols which are, due to the robust catalysts, air tolerant,14
the present chemistry goes one step further, requiring air for
the successful reaction outcome.13 The synthetic value of the
chemistry as the complementary tool to the Sonogashira
protocol has been demonstrated on a series of functionalized
mercaptoacetylene substrates. The coupling mechanism, likely
involving the addition/elimination step, has been proposed and
corroborated by published accounts and control experiments.
The authors wish to thank to the Czech Academy of Sciences
(Z40550506, M200550908) and GACR (203/08/1318) for the
financial support.
Notes and references
1 J.-P. Corbet and G. Mignani, Chem. Rev., 2006, 106, 2651.
2 (a) L. S. Liebeskind and J. Srogl, J. Am. Chem. Soc., 2000, 122,
11260; (b) C. Savarin, J. Srogl and L. S. Liebeskind, Org. Lett.,
2001, 3, 91; (c) J. Srogl and L. S. Liebeskind, Org. Lett., 2002, 4,
979.
3 (a) J. M. Villalobos, J. Srogl and L. S. Liebeskind, J. Am. Chem.
Soc., 2007, 129, 15734; (b) For minireview see: H. Prokopcova and
C. O. Kappe, Angew. Chem., Int. Ed., 2009, 47, 2.
4 A. Henke and J. Srogl, J. Org. Chem., 2008, 73, 7783.
c
4284 Chem. Commun., 2011, 47, 4282–4284
This journal is The Royal Society of Chemistry 2011