Cu(i)-catalyzed aerobic cross-dehydrogenative coupling of terminal alkynes with thiols for the construction of alkynyl sulfides

Article abstract of DOI:10.1039/c3gc41330f

Highly active and selective aerobic cross-dehydrogenative coupling of terminal alkynes with thiols to construct alkynyl sulfides catalyzed by Cu(i) using molecular oxygen as the oxidant has been demonstrated under mild reaction conditions. The process is applicable to a wide range of alkynes and various thiols and is compatible with a variety of functional groups on both alkyne and thiol coupling partners.

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Cu(I)-Catalyzed Aerobic Cross-Dehydrogenative Coupling of Terminal
Alkynes with Thiols for Construction of Alkynyl Sulfides
Yong Yang,*a, b Weibing Dong, ‡ c Yisong Guo, ‡ d Robert M. Rioux*b
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
Highly active and selective aerobic crossꢀdehydrogenative coupling of terminal alkynes with thiols to
construct alkynyl sulfides catalyzed by Cu(I) using molecular oxygen as the oxidant has been developed
under mild reaction conditions. The process is applicable to a wide range of alkynes and various thiols
and is compatible with a variety of functional groups on both alkyne and thiols coupling partners.
10 Introduction
Table 1. Optimization results for Cu(I)ꢀcatalyzed aerobic crossꢀ
dehydrogenative coupling of 4ꢀmethylphenylacetylene and thiophenol.a
Alkynyl sulfides are extremely versatile and essential building
blocks in organic synthesis and intermediates for sulfurꢀrich
functional polymers.1ꢀ6 The vast majority have commonly used
metalꢀacetylides and sulfuryl halides or disulfides for synthesis of
15 alkynyl sulfides up to date.7ꢀ9 However, these methods require a
prefunctionalization process of terminal alkynes or sulfur
nucleophiles coupling partner, resulting in inevitable formation of
large amounts of sideꢀproducts during the preactivation steps. In
addition, these methods lack generality, suffer from the forcing
20 reaction conditions, low chemoselectivity, and/or limited
substrate scopes making these methods less attractive and
practical. It is therefore of considerable importance to develop a
direct, efficient, and practical catalytic procedure for synthesis of
alkynyl sulfides without preactivation of terminal alkynes and
25 thiols.
Entry
Base
Conv.
(%)b
100
100
98
Yield (%)c
4a (Z/E)d
3a
96
85
90
0
5a
0
6a
0
1
K2CO3
Na2CO3
Cs2CO3
N(Et)3
Pyridine
TBD
2 (100/0)
11 (89/11)
5 (92/8)
3 (100/0)
5 (100/0)
<2
2
0
0
3
0
0
4
94
87
78
0
0
5
89
0
0
6
100
100
100
65
25
45
87
0
70
0
Metalꢀcatalyzed direct functionalization of CꢀH bonds has
gained enormous attention as a powerful and straightforward
7
DBU
<2
50
9
8
TMG
<2
0
method to construct new CꢀX bonds (X = heteroatom) over the
9e
10f
11g
12h
13i
14j
ꢀ
40 (77/23)
32 (80/20)
14 (80/20)
63 (59/41)
3 (100/0)
5 (90/10)
21
0
0
11
past decades,10,
providing a toolbox of tunable reaction
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
82
49
0
0
30 conditions for a large range of substrates. In particular, oxidative
crossꢀdehydrogenative coupling reactions catalyzed by metals
provides an elegant protocol for creation such compounds
through direct activation of CꢀH and/or XꢀH bonds, which is now
emerging as an important reaction in organic synthesis.12 Despite
35 considerable progress, the activation of C(sp)ꢀH bond of terminal
alkynes for the incorporation with heteroatom into organic
molecules still remains a significant challenge because of the
undesired diyne formation through Glaser coupling.13 Another
major concern is the predominant use of stoichiometric oxidants
40 for the coupling such as metal salts (CuII or AgI), organohalide,
PhI(OAc)2, or benzoquinone which are not either environmental
or economical viable. Replacement of these oxidants by
molecular oxygen is highly desirable from the standpoint of green
chemistry. A few known examples of the direct oxidative crossꢀ
45 dehydrogenative coupling of terminal alkynes with nitrogen
nucleophiles and Hꢀphosphonates using air or O2 as the sole
90
72
22
0
0
88
0
0
98
91
90
0
100
0
0
Reaction conditions: 5 mol% CuICl with respect to 1a, 10 mol% base
with respect to 1a, 0.5 mmol 1a, 0.55 mmol 2a, 2 mL DMSO, 70ºC, 1
atm O2, 1 h. Conversion was determined by H NMR of the reaction
a
b
1
c
mixture, based on 1a. NMR yield based on 1a using CH2Br2 as an
internal standard. d Stereoselecivity was determined by 1H NMR. In the
e
absence of base. 5 mol% of K2CO3. g In the absence of CuICl, 2 h.
f
h
Under argon atmosphere, 2 h. i In open air, 1.5 h. j At room temperature,
3 h.
oxidant to form CꢀN and CꢀP acetylenes have been developed
recently by Stahl,14, Bolm15, Evano,16 Han17a and Wang,17b
respectively. In terms of the incorporation of S atom into
50 acetylenes to form alkynyl sulfides using direct oxidative crossꢀ
dehydrogenative coupling method, there is still no precedent
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Table 2. Scopes for the aerobic crossꢀdehydrogenative coupling reaction.a
using O2 or air as a terminal oxidant.
Recent considerable advances in the broad
array of copperꢀcatalyzed oxidative CꢀH
functionalization highlight the potential to
5
construct
sulfurꢀincorporated
functional
acetylenes.18 Herein, we report the successful
application of CuICl as an efficient catalyst for
the direct oxidative crossꢀdehydrogenative
coupling of a wide scope of terminal alkynes
10 with variant thiols to afford the corresponding
alkynyl sulfides in moderate to high yield and
excellent selectivity in the presence of base using
molecular oxygen as the sole oxidant under mild
conditions.
15
Results and discussion
We initiated our studies by examining the
oxidative crossꢀdehydrogenative coupling of 4ꢀ
methyl phenylacetylene (1a) with thiophenol (2a)
20 as a model reaction in the presence of CuCl as a
catalyst and K2CO3 as
a
base in
dimethylsulfoxide (DMSO) at 70ºC under 1 atm
of oxygen. The reaction took place efficiently to
produce the desired 4ꢀmethylphenyl alkynyl
25 benzonic sulfide (3a) in 96% yield with excellent
selectivity (Table 1, entry 1). Only a trace
amount of (E + Z) vinyl sulfide (4a) (Z/E =
100/0) due to the occurrence of antiꢀ
Markovnikov addition was detected without the
30 observation of the undesirable dinye resulting
from homocoupling dimerization. Based on this
finding, we then tried to optimize the reaction
a Reaction conditions: 5 mol% CuICl, 10 mol% K2CO3, 0.5 mmol alkyne, 0.55 mmol thiol,
2 mL DMSO, 70ºC, 1 atm O2. Yields of the isolated product are given based on the
terminal alkyne. 4 h. 0.5 mmol 1,3ꢀdiethynylbenzene, 1.1 mmol thiophenol, 2 h. 1.0
b
c
d
mmol phenylacetylene, 0.55 mmol benzeneꢀ1,3ꢀdithiol, 2 h.
conditions starting with
a screen of bases.
Na2CO3, or Cs2CO3 as an inorganic base worked
Next, the copper sources were investigated and we found that
CuIBr, CuII, or even CuCl2 and Cu(NO3)2 also worked efficiently
60 and selectively to afford 3a in high yield under otherwise
identical reaction conditions (Table S2 in the Supporting
Information). In the absence of any copper sources, no 3a was
produced at all (entry 11). O2 as an oxidant is necessary for the
highly selective crossꢀdehydrogenative coupling reaction to
65 produce the alkynyl sulfide. In the presence of an argon
atmosphere, the reaction readily switched to the antiꢀ
Markovnikov addition to yield 4a as major product along with the
formation of 5a, no 3a was formed under these conditions (entry
12). The reaction proceeded efficiently to afford 3a in high yield
70 even in open air (entry 13) or at room temperature with relatively
longer reaction time (entry 14). Impressively, the selectivity for
either 3a or 4a could be tuned by a slight modification of reaction
conditions e.g. reaction atmosphere.
35 well albeit with slightly lower yield to 3a, respectively, under
otherwise identical reaction conditions (entries 2 and 3). No
formation of 3a was observed when triethylamine or pyridine was
employed as the base, which showed good yield to
diphenyldisulfide (5a) due to dimerization of thiophenol along
40 with a small amount of antiꢀMarkovnikov adducts (entries 4 and
5). Other organic bases, such as 1,8ꢀDiazabicyclo[5.4.0]undecꢀ7ꢀ
ene (DBU), 1,5,7ꢀtrizazbicyclo[4.4.0]decꢀ5ꢀene (TBD), and
1,1,3,3ꢀtetramethylguanidine (TMG), however, exhibited poor to
good yield to 3a (entries 6ꢀ8). Notably, when TBD was used as a
45 base, the reaction showed considerably high selectivity to the
unwanted alkyne homocoupling byꢀproduct (6a) (entry 6), which
stands apart from the results with other bases. However, in the
absence of any base, 40% and 21% yield to 4a (Z/E = 77/23) and
5a were produced without the formation of 3a (entry 9).
50 Decreasing the amount of K2CO3 (5 mol%, equal molar to Cu)
led to lower activity and selectivity (entry 10). Apparently, base
plays a critical role for the reaction and K2CO3 proved to be the
best choice among all bases investigated. The solvent also had a
considerable influence on the reaction (Table S1, see the
55 Supporting Information for details). Among the solvents
investigated, DMSO gave the best results for activity and
selectivity.
With the optimized conditions in hand, we subsequently
75 investigated the scope of the direct oxidative crossꢀ
dehydrogenative coupling of various alkynes with thiophenol
(Table 2). A set of alkynes including aromatic and aliphatic could
efficiently couple with thiophenol to selectively deliver the
desired alkynyl sulfides in moderate to high yields. Electronꢀ
80 donating and electronꢀwithdrawing substituents at the m-, o-, and
p- positions on the phenyl ring of aromatic alkynes all gave high
2
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(2t and 2u). Aliphatic thiol (2v) readily coupled with the aliphatic
alkyne (1l) to afford 3v in moderate yield (34%) with prolonged
40 reaction time.
Finally, the coupling reactions of the terminal diynes with thiol
or dithiol with terminal alkyne also operated efficiently to give
the corresponding sulfides. For example, 1,6ꢀheptadiyne (1w) or
1,3ꢀdiethynlbenzene (1x) could couple with 2 equivalents of
45 thiophenol to form the corresponding 3w and 3x in 88 and 93%
yields, respectively. Similarly, the reaction between benzeneꢀ1,3ꢀ
dithiol (2y) and 2 equivalents of phenylacetylene proceeded
efficiently to afford 3y in 87% yield. These results highlight the
power of this procedure for preparation of sulfurꢀrich πꢀ
50 conjugated polymers, which have unique properties for materials
applications.1, 19
In an attempt to determine the reaction mechanism, some
control experiments were carried out. When the coupling reaction
of phenylacetylene and thiophenol was performed in the presence
55 of an equimolar amount galvinoxyl with respect to CuICl, as a
radical scavenger, methylphenyl alkynyl benzonic sulfide (3d)
was obtained in 92% yield with roughly equal activity with its
absence under otherwise identical reaction conditions. This result
indicates that the involvement of a free radical pathway for this
60 transformation might be ruled out. The kinetic study of tracing
the concentration changes as a function of reaction time for the
coupling partners, e.g. phenylacetylene, thiophenol, and the
produced product 3d demonstrates (Figure 1): 1) thiophenol is
consumed more quickly via the reaction with CuICl compared to
65 phenylacetylene in the same reaction vessel. Especially in the
first 10 minutes of the reaction, almost no consumption of
phenylacetylene was found, meanwhile the formation of the
desired product 3d was marginally observed during this period;
2) phenylacetylene starts to be consumed and its concentration
70 gradually decreases after 10 min accompanied with a linear
increase of the formation of 3d. It was wellꢀdocumented that
Figure 1. Plot of concentration change as a function of reaction
time for oxidative crossꢀcoupling of phenylacetylene (○) with
thiophenol (●) and the produced product methylphenyl alkynl
benzonic sulfide 3d (△). Reaction conditions: 5 mol% CuICl, 10
mol% K2CO3, 0.5 mmol (0.25 M in solution) phenylacetylene, 0.55
(0.275 M in solution) mmol thiophenol, 2 mL DMSO, 70°C, 1 atm
O2.
yields to their corresponding alkynyl sulfides. Reactions of m-, o,
and p-ethynyltoluenes (1a, 1b, and 1c) or o-, p-ethynylanisole (1e
and 1f) proceeded well, and almost equal yields were achieved,
suggesting the steric effect of substituents on aromatic rings is
negligible. Importantly, in the case of haloꢀsubstituted aromatic
alkynes (1g and 1h), excellent chemoselectivities were observed
and afforded the desired 3g and 3h in high yields without the
occurrence of dehalogenation. The electronꢀdonating substituted
aromatic alkynes showed superior reaction efficiency to that of
10 the electronꢀwithdrawing ones. The sulfurꢀcontaining alkyne, 3ꢀ
ethynylthiophene (1j), coupled with thiophenol efficiently to
afford the corresponding 3j in 84% yield, while the presence of a
pyridyl moiety in the alkyne, 2ꢀethynylpyridine (1i),
significantly decreased the reaction selectivity and only
15 14% isolated yield of 3i was obtained. In this case, the
selectivity to antiꢀMarkovnikov addition became the
predominant reaction, affording the Zꢀvinyl sulfide in
63% yield. Notably, the conjugated terminal enyne, 1ꢀ
ethynylhexene (1k), readily reacted with thiophenol to
20 convert 3k in 91% yield; the conjugated CꢀC double
bond did not cause any influence on the selectivity and
remained intact during the reaction. In addition, aliphatic
alkynes could act as good coupling partners. The
reaction proceeded efficiently to afford their
25 corresponding alkynyl sulfides in good to high yields,
even for the aliphatic alkynes bearing functional groups
such as hydroxyl and chloro (1n and 1o).
5
Along this line, both aromatic and aliphatic thiols
coupled with phenylacetylene in moderate to high yields.
30 In the cases for the coupling reaction of aromatic thiols
bearing electronꢀdonating and electronꢀwithdrawing
substituents (2pꢀs), the electronꢀwithdrawing substituted
thiophenols (2r and 2s) displayed superior reaction
efficiency to the electronꢀdonating ones (2p and 2q)
35 under otherwise identical reaction conditions. Longer
reaction times are required to achieve a satisfactory yield
for the coupling of aliphatic thiols with phenylacetylene
Figure 2. Xꢀband EPR spectra acquired from monitoring the reaction at variable
reaction time (a) 0 min; (b) 10 min; (c) 12 min;(d) 15 min; (e) 20 min; (f) 30 min;
(g) 40 min; (h) 50 min; and (i) 60 min. (left) Experimental and simulated EPR
spectra of the active CuII species for the reaction at 30 min (right). Reaction
conditions: 5 mol% CuICl, 10 mol% K2CO3, 0.5 mmol phenylacetylene, 0.55
mmol thiophenol, 2 mL DMSO, 70°C, 1 atm O2.
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phenylacetylene could react with CuICl to form copper 45 to disulfide in the presence of O2 atmosphere,25 which could also
phenylacetylide in the presence of K2CO3 in DMSO or DMF.20
Considering this result and in combination with our observation,
we believe that an initial deprotonation of a SꢀH bond of
thiophenol in the presence of K2CO3 followed by further reaction
react with alkyne to form the desired alkynyl sulfide.8a Secondly,
a CuII intermediate (B) possibly formed albeit with no direct
evidence by subsequent transmetalation of alkyne into copper
thiolate via activation of terminal alkynes with assistance of O2.
5
with CuCl to form copper phenylthiolate is more reactive and 50 Finally, the desired alkynyl sulfide was reductively eliminated
favorable rather than the formation of copper phenylacetylide as
and regenerated the CuI thiolate (A) in the excess of thiol.
Molecular oxygen plays an essential role on facilitating the
formation of the CuII intermediate (B) via activation of CꢀH bond.
When the reaction was performed under argon atmosphere, the
previously proposed in most Cuꢀcatalyzed oxidative processes.14ꢀ
16, 21
10
EPR spectroscopic studies were further performed to gain
insight into copper species that might be relevant to the reaction, 55 entire process operated in completely different way to give antiꢀ
as shown in Figure 2. No EPR signal was observed for the
reaction mixture in the first 10 minutes of the reaction, indicating
that only EPR silent CuI species is present (Figure 2a and b). The
Markovnikov addition product with a mixture of stereoselective
isomers. However, an intermediacy of radicals associated to Cu
or dinuclear Cu species18a involves in the reaction could not be
totally ruled out at this point. Further studies for understanding of
15 observation is consistent with the result of kinetic studies that
only CuI phenolthiolate was formed in the first 10 minutes of the 60 reaction mechanism are necessary and are currently underway in
reaction. After 10 minutes, a weak EPR signal was observed at g
= 2 region and its intensity considerably increased with elapsed
reaction times without any change in the signal pattern (Figure
20 2cꢀf); while a gradual decrease of such EPR signal (Figure 2gꢀi)
was observed after 40 min. At the completion of the reaction,
most of EPR signal disappeared. This EPR signal is originated
from S = ½ species, it can be simulated as a single species with
nearly axial g values ((gx = 2.03, gy = 2.04, gz = 2.16), and the
25 presence of an I = 3/2 nucleus having axial nuclear hyperfine
constants (Ax = 110 MHz, Ay = 110 MHz, Az = 550 MHz). The
larger Az value together with ꢀgz ~ 4ꢀgx,y are typical parameters
from type 2 CuII centers.22, 23 The relative low gz value suggests
the presence of sulfur coordination to the cooper center.22ꢀ24 The
30 decrease of this CuII signal after 40 minutes of the reaction
indicates the regeneration of the CuI species after the completion
of the catalytic cycle. EPR spectroscopic data strongly reflected
and supported the control experiment results described above and
also further reveal that no radical signal is present in the reaction.
35 More interestingly, a similar observation in EPR study was found
when CuCl2 was chosen as a catalyst instead of CuICl for the
reaction (Figure S2, see the Supporting Information for details).
We failed to isolate the intermediate CuII species from the
reaction at this point.
our lab.
Conclusions
In summary, we demonstrated that inexpensive copper catalyze
the oxidative crossꢀdehydrogenativecoupling of terminal alkynes
65 with thiols to selectively construct alkynyl sulfides with the aid of
K2CO3 under an atmosphere of O2. This simple straightforward
and atomꢀeconomical procedure is applicable to a wide range of
alkynes and various thiols and is compatible with a variety of
functional groups on both alkyne and thiols reaction partners. The
70 process represents a new methodology for selective synthesis of
alkynyl sulfides and highlights the feasibility for preparations of
sulfurꢀrich πꢀconjugated polymers.
Acknoledgements
This work was supported by the Pennsylvania State University
75 and The Penn State Institutes of Energy and the Environment
through startꢀup funds and a 3M NonꢀTenured Faculty Grant
awarded to R. M. R.
Notes and references
a Organic Chemistry, Institute of Chemical & Engineering Sciences
80 (ICES), 11 Biopolis way, Helios #03-08, 138667 Singapore.
E-mail: yangyo@ices.a-star.edu.sg
40
On the basis of the observed results, a plausible mechanism for
the present process is proposed as shown in Scheme 1. Firstly, an
initial deprotonation of a SꢀH bond of thiol in the presence of a
base to form CuI thiolate (A). At this stage, a possible
dimerization pathway of copper thiolate is operative to give rise
b Department of Chemical Engineering, The Pennsylvania State
University, University Park, PA 16802, USA. E-mail:
rioux@engr.psu.edu
85 c Liaoning Provincial Key Laboratory of Biotechnology and Drug
Discovery, Liaoning Normal University, Dalian 116081, China
d Department of Chemistry, The Pennsylvania State University, University
Park, PA 16802, USA
†Electronic Supplementary Information (ESI) available: Detailed
90 experimental procedures, and spectral data for all compounds, including
scanned images of 1H and 13C NMR spectra. See
DOI: 10.1039/b000000x/
‡ Equal contributions
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Scheme 1. Mechanistic proposal for Cu(I)ꢀcatalyzed aerobic crossꢀ
dehydrogenative coupling of terminal alkyne with thiol.
3
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Green Chemistry
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DOI: 10.1039/C3GC41330F
Table of Contents
Highly active and selective aerobic cross-dehydrogenative coupling of terminal alkynes with thiols to construct
alkynyl sulfides catalyzed by Cu(I) using molecular oxygen as the oxidant has been developed under mild reaction
conditions.