Cobalt-Catalyzed C?H Thiolation through Dehydrogenative Cross-Coupling

Article abstract of DOI:10.1002/anie.201605193

A cobalt-catalyzed dehydrogenative cross-coupling of thiols and indoles is reported. Using a cooperative reaction system, a new mode of action for the cobalt-catalyzed C?heteroatom bond formation was found. The directed C?H activation catalysis overrides

Full text of DOI:10.1002/anie.201605193

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International Edition: DOI: 10.1002/anie.201605193
German Edition: DOI: 10.1002/ange.201605193
Dehydrogenative Cross-Coupling
À
Cobalt-Catalyzed C H Thiolation through Dehydrogenative Cross-
Coupling
Tobias Gensch+, Felix J. R. Klauck+, and Frank Glorius*
Dedicated to Professor Gerhard Erker on the occasion of his 70th birthday
Abstract: A cobalt-catalyzed dehydrogenative cross-coupling
of thiols and indoles is reported. Using a cooperative reaction
À
system, a new mode of action for the cobalt-catalyzed C
À
heteroatom bond formation was found. The directed C H
activation catalysis overrides an undirected thiolation of indole
in the 3-position that occurs in the absence of cobalt.
À
Mechanistic studies indicate a sequence of C H activation,
thiolate transfer, and reductive elimination.
À
T
he direct functionalization of C H bonds is one of the most
À
Scheme 1. Cobalt-catalyzed formation of a C heteroatom bond by
À
expedient ways of introducing and expanding molecular
complexity[1] and research is currently focused on developing
applicable transformations using abundant metals such as
cobalt as catalysts.[2] Several distinct catalyst systems featuring
cobalt in various oxidation states and employing unique
precursors and ligands have been found.[3] On the one hand,
modular systems typically consisting of a CoII precursor,
ligands, and catalyst modifiers such as Grignard reagents or
C H activation.
process involves two main challenges. Firstly, sulfur com-
pounds can cause catalyst deactivation. We reasoned that the
“hard” nature of the Cp*CoIII moiety might alleviate this
problem. Secondly, the transformation requires a finely tuned
oxidant system to achieve catalyst turnover and prevent
overoxidation.
À
oxidants are powerful catalysts for the directed C H activa-
À
tion followed by C C coupling with organometallic reagents,
The thioether moiety is common in bioactive compounds
electrophiles, or unsaturated moieties.[4] On the other hand,
and intermediates in the synthesis of organic materials.[14] The
well-defined Cp*CoIII complexes (Cp* = C5Me5) proved to be
direct thiolation of C H bonds presents an attractive strategy
À
À
C H activation catalysts that can compete with the perfor-
for the introduction of this valuable motif. Nevertheless,
despite recent advances in this direction[15] there is still need
for complementary methods in order to attain a broader
utility of this transformation. Herein we report the unique
reactivity of the Cp*CoIII catalyst to promote the first cobalt-
mance of their noble metal congeners in the synthesis of
functionalized products and in some cases offer distinct
reactivity.[5] Introduced by the group of Matsunaga and
Kanai[6] and taken up by Ackermann,[7] Chang,[8] Ellman,[9]
Glorius,[10] and others,[11] Cp*CoIII complexes have been used
in directed C C and, less commonly, C N and C Hal
coupling reactions.[12] The general mechanistic patterns of
metallacycle functionalization in these examples tend to be
limited to addition/insertion with unsaturated reaction part-
ners and formal nucleophilic substitution reactions where the
À
catalyzed C H thiolation. C2-Thiolated indoles are obtained
À
À
À
selectively in good to excellent yields with a high degree of
functional-group tolerance employing a cooperative system
with CuII as well as Lewis acid additives.
Initially, we explored the thiolation of N-pyrimidyl indole
(1) in 1,2-dichloroethane (DCE) at 808C in the presence of
various oxidants (Scheme 2). Cu(OAc)2 selectively mediates
the thiolation in the 3-position of the indole in the absence of
Cp*CoIII (3a’).[16] However, a switch in regioselectivity was
observed in the presence of Cp*CoIII: with thiophenol, the
desired 2-phenylthioindole 3a is formed nearly exclusively in
29% yield. Optimization of the reaction conditions led to
À
organocobalt intermediate generated by C H activation is
the nucleophile (Scheme 1).
À
We envisioned a dehydrogenative C H thiolation based
on C H activation catalyzed by the Cp*CoIII catalyst.[13] This
À
[*] T. Gensch,[+] F. J. R. Klauck,[+] Prof. Dr. F. Glorius
Organisch-Chemisches Institut
Westfꢀlische Wilhelms-Universitꢀt Mꢁnster
Corrensstrasse 40, 48149 Mꢁnster (Germany)
E-mail: glorius@uni-muenster.de
Homepage: http://www.uni-muenster.de/chemie.oc/glorius
[+] These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201605193.
À
Scheme 2. Initial studies on the regioselective C H thiolation of 1.
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83% yield of 3a; the reaction was conducted with a co-
oxidant system of Cu(OAc)2 and benzoquinone[6c] as well as
In(OTf)3 as an additive in 1,4-dioxane at 608C after 5 h (for
more information on the optimization, see the Supporting
Information (SI)). The desired regioselectivity was confirmed
by crystal structure analysis of 3a.[17] A gram-scale reaction
with 5 mol% of [Cp*CoI2]2 gave 72% yield of 3a.
The reaction tolerates a wide range of substituents on
both the thiol and the indole reaction partners (Scheme 3).
Scheme 4. Scope of indoles. Reactions performed on 0.5 mmol scale
with 2.0 equiv of 2a in 1.25 mL solvent, yields of isolated product are
given. [a] 0.2 mmol scale. [b] 20 h reaction time.
89% yield. The presence of a benzylether resulted in a lower
yield (5d, 42%). Products containing pinacol boronate (5e,
75%), halides (5 f–h, 70–98%), or a silyl alkyne (5i, 40%) can
be used for further derivatization. The product of a sterically
hindered 3-methyl indole (5k) was obtained in 45% yield
even after a prolonged reaction time. The N-pyridyl moiety
can be employed as a directing group in the thiolation (5l,
76%), yet other directing groups were found to be inefficient.
A robustness screen[18] was carried out to expediently
characterize further functional-group and heterocycle toler-
ance of the protocol (for details see the Supporting Informa-
tion). The pyrimidyl directing group can be removed under
basic conditions from the products to generate thiolated free
N–H indoles, as exemplified with product 3a in 90% yield.
Intrigued by the novelty of the reactivity underlying this
transformation, we wanted to gain insight into its mechanism
and the role of each reaction component. Firstly, control
experiments confirmed the unique role of Cp*CoIII as the
catalyst in this transformation. Only traces of 3a were
detected when [Cp*RhCl2]2, other cobalt salts, or Sc(OTf)3
(a Lewis acid substitute) were used. Both Cu(OAc)2 and
In(OTf)3 are essential for product formation as well, while the
absence of benzoquinone lowers the yield of 3a to 41%.
Under the optimized reaction conditions, a mixture of the 3-
and 2-thiolated indoles 3a’ and 3a (8% and 12%, respec-
tively) is obtained when Cp*Co is omitted.[19]
Scheme 3. Scope of thiols. Reactions performed on 0.5 mmol scale
with 2.0 equiv of 2 in 1.25 mL solvent, yields of isolated product are
given. [a] 5 mmol scale, 5 mol% [Cp*CoI2]2 as catalyst, 11 h. [b] With
3-methyl-1-pyrimidylindole and (PhSe)2 (1 equiv), 22 h.
We found no systematic influence of substituents in the
ortho-, meta-, or para-positions or slight modifications of the
electronic properties at the thiol. Thus, halide- (3b–d, 3 f, 3g,
3j), methyl- (3e, 3h, 3k), and methoxy-substituted (3i, 3l) 2-
arylthioindoles as well as a naphthylthioindole (3m) were
obtained in 72–95% yield. Notably, both of the electronically
most varied thiols afforded the corresponding dimethoxy-
(3n) and bis(trifluoromethyl)- (3o) substituted products in
slightly decreased yields of 66% and 47%, respectively.
Gratifyingly, the thiolation could be extended to benzyl
mercaptan, providing benzylthio indole 3p in 21% yield.
Using our protocol, we furthermore achieved the directed
selenation in 55% yield (3q) using diphenyl diselenide as
reaction partner. No desired product was obtained from
heteroaryl or saturated alkyl thiols.
While the reaction can be performed using AgSbF6,
In(OTf)3 provided better yields than those obtained with the
silver salt commonly used for abstracting halides from the
cobalt precatalyst. To probe the role as a halide abstractor, we
employed a precatalyst featuring very weakly coordinating
B(C6F5)4 anions that does not require halide abstractors.[9]
Under the standard conditions, 59% yield of 3a was formed
using this precatalyst, along with an increased amount of 3a’.
Without In(OTf)3, only 10% yield of 3a was formed. Thus, we
A wide range of indoles with protecting groups and
functionalities commonly used in synthesis can be thiolated
under the optimized reaction conditions (Scheme 4). For
example, ester (5b), methyl ether (5c), and silyl ether (5j) are
well tolerated, providing protected 2-phenylthioindoles in 66–
2
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assume this additive has a secondary role besides halide
interchange of the sulfur species in the reaction, we per-
abstraction from the precatalyst. As most other Lewis and
carboxylic acid additives did not improve the yield, we assume
InIII has a beneficial effect on the coordination chemistry of
thiolates, which are known to form polynuclear complexes
with copper and other metals.
formed a pretreatment test, adding the indole substrate only
after stirring the rest of the reaction mixture at 608C for
30 min. After another 15 min, 22% yield of 3a had formed in
the reaction with the disulfide. Conversely, the yield with
CuSPh was decreased to 33% and no significant difference in
yield was observed with PhSH (Table 1). Evidently, PhSH is
transformed into an active thiolating agent much faster than
the disulfide. PhSCu is converted into a less reactive species
under the reaction conditions, likely to the disulfide. Anionic
CuI complexes like [Cu(SPh)2]À have been suggested as the
Thiophenol can be oxidized to thiolate radicals by CuII.
From radical trapping studies and the selectivity of thiolation
of N-methyl indole at the 3-position, we conclude that the
occurrence of radical species in the reaction cannot be ruled
out but a mechanism involving radicals for the formation of
the desired product seems unlikely (for details see the
Supporting Information).
In a competition experiment, the electron-rich 5-OMe
indole 4c is favored over the electron-poorer 5-CO2Me indole
4b (23% vs. 10% yield after 10 min). This can either reflect
active species in copper-catalyzed C S cross-coupling.[20] Our
À
results are indicative of similar species as intermediates for
the transmetalation of thiolates to cobalt.
On the basis of the evidence and literature precedent, we
tentatively propose the mechanism shown in Scheme 5. The
À
properties of an electrophilic C H activation mechanism,
À
a higher stability of a C H metalated intermediate of more
electron-rich indoles, or
a beneficial influence of the
increased nucleophilicity on a functionalization step. Like-
wise, the electron-rich 4-methoxythiophenol (2l) was favored
over 3,5-bis(trifluoromethyl)thiophenol (2o) (17% vs. 13%
yield after 10 min), yet the small effect precludes an
interpretation.
Mass spectrometric analysis of the reaction mixture after
5 min revealed the presence of the cobaltacycle generated by
À
C H activation of 1 as well as the complex of this cobaltacycle
with a phenyl thiolate. Other detected species include
[Cp*Co(OAc)]+, cobalt thiolates, and coordination com-
plexes of copper(I) and copper(II) with 1 and/or 3a.
Copper plays an essential role in the formation of an
active thiolation agent. Also, the original sulfur source
influences the reaction outcome (Table 1). While the thio-
lation reaction occurs with both thiophenol and diphenyl
disulfide, lower regioselectivity is observed with the disulfide.
The thiolation also proceeds readily with CuSPh, providing
75% yield of 3a with, and 27% without Cu(OAc)2. The
nature of the ultimate thiol source in the reaction was probed
by a reactivity analysis of these sulfur compounds. After only
15 min, the reaction is almost complete with both PhSH and
CuSPh, yet only traces of 3a are present with (PhS)2. Clearly,
more time is required for the formation of an active thiolating
agent from the disulfide. For additional insight on the
Scheme 5. Proposed mechanism.
active catalyst A is formed from the precursor by iodide
abstraction with In(OTf)3 and acetate transfer. Directed C H
À
activation generates cobaltacycle B. Several copper and sulfur
compounds can be present in varying oxidation states and
degrees of association. Presumably, anionic CuI species
transfer thiolate to B, forming cobalt thiolate C. Reductive
elimination releases the product and a cobalt(I) species that is
reoxidized by copper or benzoquinone to the active catalyst
A. Alternative mechanisms include nucleophilic attack of B
to an electrophilic CuII or CuIII thiol species or transmetala-
tion of the indole from B onto a copper species with
subsequent reductive elimination of the product at copper.
We have developed a cobalt-catalyzed dehydrogenative
cross-coupling of thiols and indoles. A cooperative reaction
system is employed to achieve a regioselective and robust
transformation. This reaction represents a new mode of action
for the cobalt-catalyzed formation of C–heteroatom bonds.
Table 1: Reactivity study with different sulfur reagents in the reaction
with 1.[a]
Entry [S]
3a; 3a’ 3a; 3a’
5 h 15 min
3a; 3a’, delayed addition
of 1[b]
1
2
3
PhSH
(2 equiv)
(PhS)2
(1 equiv)
PhSCu
95%; – 79%; –
82: –
63%;
5%
trace;
trace
22%; trace
33%; trace
À
The directed C H activation catalysis overrides an undirected
75%; – 69%; –
thiolation of indole in the 3-position that occurs in the
absence of cobalt. Evidence is provided to support a mecha-
(2 equiv)
[a] 10 mol% Cp*Co(CO)I2, 1.5 equiv Cu(OAc)2, 1.25 equiv benzoqui-
none, 25 mol% In(OTf)3, 1,4-dioxane, 608C. Yields determined by GC-
FID with mesitylene as internal standard. [b] 30 min at 608C before
addition of 1, then 15 min at 608C.
À
nism including C H activation, thiolate transfer, and subse-
quent reductive elimination.
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Acknowledgements
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This work was supported by the European Research Council
under the European Communityꢀs Seventh Framework Pro-
gram (FP7 2007–2013)/ERC Grant Agreement 25936, by the
DFG (Leibniz Award), and by the Fonds der Chemischen
Industrie (F.J.R.K.). We thank Dr. Constantin G. Daniliuc for
X-ray crystallographic analysis, Suhelen Vꢁsquez-Cꢂspedes,
Eric A. Standley, and Ghazal Tavakoli (all WWU Mꢃnster)
for helpful discussions.
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À
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Keywords: C H activation · C heteroatom coupling · cobalt ·
cross-coupling · thiolation
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[16] Reports on copper-catalyzed 3-thiolation of indoles: a) W. Ge, Y.
Wei, Synthesis 2012, 44, 934; b) F. Shibahara, T. Kanai, E.
Yamaguchi, A. Kamei, T. Yamauchi, T. Murai, Chem. Asian J.
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[19] A Cu(OAc)2-mediated 2-thiolation of N-pyrimidyl indoles at
very high reaction temperature (1608C) has been described
previously: L. Zhu, X. Cao, R. Qiu, T. Iwasaki, V. P. Reddy, X.
Xu, S.-F. Yin, N. Kambe, RSC Adv. 2015, 5, 39358.
[20] Y. S. Panova, A. S. Kashin, M. G. Vorobev, E. S. Degtyareva,
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[17] CCDC 1480898 (3a) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre.
Received: May 27, 2016
Published online: && &&, &&&&
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Dehydrogenative Cross-Coupling
T. Gensch, F. J. R. Klauck,
F. Glorius*
&&&& — &&&&
À
Cobalt-Catalyzed C H Thiolation through
Dehydrogenative Cross-Coupling
À
Co-laboration! A new method for the
dehydrogenative cross-coupling of thiols
and indoles features a novel mode of
action for the cobalt-catalyzed formation
of a C heteroatom bond. Mechanistic
À
studies indicate a sequence of C H
activation, thiolate transfer, and reductive
elimination.
6
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!