Carbon dioxide mediated stereoselective copper-catalyzed reductive coupling of alkynes and thiols

Article abstract of DOI:10.1021/ol3003699

A simple protocol for the stereoselective copper-catalyzed hydrothiolation of alkynes under a CO₂ atmosphere has been developed. The stereoselectivity is determined by the presence/absence of a CO₂ atmosphere. The reaction system is robust and utilizes inexpensive, readily available substrates. A cyclic alkene/carboxylate copper complex intermediate is proposed as the key step in determining the stereoselectivity, and an equivalent amount of water is found to play an active role as a proton donor.

Full text of DOI:10.1021/ol3003699

ORGANIC
LETTERS
2012
Vol. 14, No. 7
1780–1783
Carbon Dioxide Mediated Stereoselective
Copper-Catalyzed Reductive Coupling of
Alkynes and Thiols
Siti Nurhanna Riduan, Jackie Y. Ying,* and Yugen Zhang*
Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, The Nanos,
Singapore 138669, Singapore
jyying@ibn.a-star.edu.sg; ygzhang@ibn.a-star.edu.sg
Received February 15, 2012
ABSTRACT
A simple protocol for the stereoselective copper-catalyzed hydrothiolation of alkynes under a CO2 atmosphere has been developed. The
stereoselectivity is determined by the presence/absence of a CO2 atmosphere. The reaction system is robust and utilizes inexpensive, readily
available substrates. A cyclic alkene/carboxylate copper complex intermediate is proposed as the key step in determining the stereoselectivity,
and an equivalent amount of water is found to play an active role as a proton donor.
Vinyl sulfides are ubiquitous in many natural products
and pharmaceuticals and are important synthetic inter-
mediates due to their ease of transformation.1 The most
convenient way to synthesize such analogs includes hydro-
thiolation of alkynes, commonly through transforma-
tions with transition metal catalysts, bases, or free radicals.
Both Markovnikov2ꢀ6 and anti-Markovnikov7ꢀ11 selec-
tivity can be realized in transition metal catalyzed pro-
cesses (Scheme 1). High selectivity for Markonikov
products was achieved with nickel,2 rhodium,3 organo-
actinide and organolanthanide,4 and zirconium complexes as
catalysts.5 Selective formation of E and Z isomers of anti-
Markovnikov products has also been accomplished,
whereby the selective synthesis of E-vinyl sulfides was first
successfully demonstrated by Ogawa et al. using a Wilkin-
son catalyst, Rh(PPh3)3Cl,7 and more recently by Corma
et al. usingbothgold(I) and (III) complexes.8 The synthesis
of Z-vinyl sulfides over transition metal catalysts has been
limited to neutral and cationic complexes of rhodium and
iridium but suffered from a limited substrate scope and low
stereoselectivity.9 Base-mediated hydrothiolations were
first reported in 1956 by Truce et al.,10 and more recently,
a cesium carbonate catalyzed process to form Z-vinyl sul-
fides was reported.11 However, such a process required the
(1) Cremlyn, R. J. An Introduction to Organosulfur Chemistry; John
Wiley & Sons: Chichester, 1996.
(2) (a) Malyshev, D. A.; Scott, N. M.; Marion, N.; Stevens, E. D;
Ananikov, V. P.; Beletskaya, I. P; Nolan, S. P. Organometallics 2006, 25,
4462–4470. (b) Ananikov, V. P.; Malyshev, D. A.; Beletskaya, I. P.;
Aleksandrov, G. G.; Eremenko, I. L. Adv. Synth. Catal. 2005, 347, 1993–
2001.
(3) (a) Cao, C.; Fraser, L. R.; Love, J. A. J. Am. Chem. Soc. 2005, 127,
17614–17615. (b) Fraser, L. R.; Bird, J.; Wu, Q.; Cao, C.; Patrick, B. O.;
Love, J. A. Organometallics 2007, 26, 5601–5611. (c) Yang, J.; Sabarre,
A.; Fraser, L. R.; Patrick, B. O.; Love, J. A. J. Org. Chem. 2009, 74, 182–
187.
(4) (a) Weiss, C. J.; Wobser, S. D.; Marks, T. J. J. Am. Chem. Soc.
2009, 131, 2062–2063. (b) Weiss, C. J.; Wobser, S. D.; Marks, T. J.
Organometallics 2010, 29, 6308–6320. (c) Weiss, C. J.; Marks, T. J.
Dalton Trans. 2010, 39, 6576–6588.
(5) Weiss, C. J.; Marks, T. J. J. Am. Chem. Soc. 2010, 132, 10533–
10546.
(6) Markovnikov hydrothiolation of alkenes: (a) Cabrero-Antonino,
ꢀ
ꢀ
(8) Corma, A.; Gonzalez-Aellano, C.; Igesias, M.; Sanchez, F. Appl.
Catal., A 2010, 375, 49–54.
(9) (a) Burling, S.; Field, L. D.; Messerle, B. A.; Vuong, K. Q.;
Turner, P. Dalton Trans. 2003, 4181–4191. (b) Field, L. D.; Messerle,
B. A.; Vuong, K. Q.; Turner, P. Dalton Trans. 2009, 3599–3614.
(10) (a) Truce, W. E.; Simms, J. A.; Boudakian, M. M. J. Am. Chem.
Soc. 1956, 78, 695–696. (b) Truce, W. E.; Simms, J. A. J. Am. Chem. Soc.
1956, 78, 2756–2759.
ꢀ
J. R.; Leyva-Perez, A; Corma, A. Adv. Synth. Catal., DOI: 10.1002/
adsc.201100731. (b) Leyva-Perez, A.; Vidal-Moya, J. A.; Cabrero-
Antonino, J. R.; Al-Deyab, S. S.; Al-Resayes, S. I.; Corma, A.
J. Organomet. Chem. 2011, 696, 362–367.
(7) (a) Ogawa, A.; Ikeda, T.; Kimura, K.; Hirao, T. J. Am. Chem.
Soc. 1999, 121, 5108–5114. (b) Shoai, S.; Bichler, P.; Kang, B.; Buckley,
H.; Love, J. A. Organometallics 2007, 26, 5778–5781. (c) Yang, Y.;
Rioux, R. M. Chem. Commun. 2011, 47, 6557–6559.
ꢀ
(11) Kondoh, A.; Takami, K.; Yorimitsu, H.; Oshima, K. J. Org.
Chem. 2005, 70, 6468–6473.
r
10.1021/ol3003699
Published on Web 03/20/2012
2012 American Chemical Society

use of a radical inhibitor, and the substrate scope was
limited to alkyl thiols. Alkyne hydrothiolation via a radical
mechanism was first reported in 1970, whereby a free radical
process yielded anti-Markovnikov products with typically
low E/Z selectivity.12,13 Thus, a general and simple method
for the synthesis of Z-vinyl sulfides from alkynes remains a
challenge to be addressed.
stereoselectivity of this reaction was controlled by CO2,
and the mechanism of this stereoselectivity controlling
process was also investigated.
The study was initiated with phenylacetylene and thio-
phenol as model substrates for the reaction. The proof of
concept was conducted with phenylacetylene (0.5 mmol),
thiol (0.75 mmol), K2CO3 (0.6 mmol), and 5 mol % CuI
catalyst in 3 mL of N,N0-dimethylformamide (DMF) with
a CO2 balloon. After a 16-hreaction, vinyl sulfide products
were obtained at a yield of 85% and an E/Z ratio of 13:87.
Control experiments for this reaction under the same
conditions, except for the use of argon or air, gave similar
products withreverse stereoselectivity (E/Z ratio = 80:20).
These results clearly demonstrated that the stereoselectivity
of this Cu(I)-catalyzed alkyne hydrothiolation reaction
could be controlled with the presence or absence of the
CO2 atmosphere. Further study showed that a trace
amount of water also played an important role in this
reaction. With 2 equiv of H2O additive, the reaction rate
was remarkably increased (Supporting Information (SI)
Table S1). With that, reaction conditions were further
screened. Dimethyl sulfoxide (DMSO) proved to be the
optimum solvent for the reaction, while a DMSO/H2O
volume ratio of 1:1 was found to be detrimental to the
selectivity. The use of ligands, such as tetramethylethyle-
nediamine (TMEDA) and IPr (1,3-bis(2,6-diisopropylphe-
nyl imidazolylidene) did not improve the yields, while
the use of organic bases such as TMEDA and DBU (1,8-
diazabicyclo[5.4.0]undec-7-ene) did not lead to any E/Z
selectivity. The use of K2CO3, with DMSO as solvent,
proved to be the best for the reaction, with the presence
of 5 mol % of CuI catalyst, 1 atm of CO2 atmosphere, and
1.4 equiv (25 μL) of H2O (SI Table S1).
It was found that a reaction temperature of 90 °C was
optimal to the yield and selectivity of this hydrothiolation
reaction. The selectivity was kept high with the use of a
slight excess of thiol. In addition, allowing the reaction
mixture of phenylacetylene and potassium carbonate in
DMSO to be stirred in an atmosphere of CO2 prior to the
addition of thiol proved to be beneficial for enhanced
stereoselectivity (SI Table S1).
With the optimal reaction conditions, we proceeded to
expand the reaction scope for a wide range of thiol sub-
strates (see Figure 1). In general, it was observed that the
hydrothiolation of phenylacetylene in the presence of CO2
mediator generated the anti-Markovnikov products with
high Z selectivity, in good-to-excellent yields. Aryl, ben-
zylic, and aliphatic thiols reacted cleanly to furnish the cor-
responding Z-vinyl sulfides with high selectivity.
Scheme 1. Transition Metal Catalyzed Hydrothiolation of Al-
kynes
In the past decade, immense efforts in research have been
dedicated to utilizing CO2 in organic synthesis.14,15 Recently,
we reported a room-temperature conversion of terminal
alkynes to propiolic acids with 1 atm of CO2 in the presence
of a Cu(I) catalyst.16,17 With this result, we envisioned the
use of CO2 as a mediator18 to achieve the stereoselective
coupling of alkynes and thiols to form Z-vinyl sulfides via a
propiolic acid intermediate.19 Herein we reported a simple
procedure for the synthesis of Z-vinyl sulfides by hydro-
thiolation of terminal alkynes under a CO2 atmosphere. The
(12) Griesbaum, K. Angew. Chem., Int. Ed. 1970, 9, 273–287.
(13) Wang, Z.-L.; Tang, R.-Y.; Luo, P.-S.; Deng, C.-L.; Zhong, P.;
Li, J.-H. Tetrahedron 2008, 64, 10670–10675.
(14) (a) Carbon Dioxide as Chemical Feedstock; Aresta, M., Ed.; Wiley-
VCH: Weinheim, 2010. (b) Aresta, M.; Dibenedetto, A. Key Issues in
Carbon Dioxide Utilization as a Building Block for Molecular Organic
Compounds in the Chemical Industry; CO2 Conversion and Utilization;
ACS Symposium Series 809; American Chemical Society: Washington, DC,
2002; pp 54ꢀ70. (c) Riduan, S. N.; Zhang, Y. Dalton Trans. 2010, 39,
3347–3357. (d) Zhang, Y.; Chan, J. Y. G. Energy Environ. Sci. 2010, 3,
408–417. (e) Sakakura, T.; Kohon, K. Chem. Commun. 2009, 1312–1330.
(f) Sakakura, T.; Choi, J.-C.; Yasuda, H. Chem. Rev. 2007, 107, 2365–
2387. (g) Marks, T. J.; et al. Chem. Rev. 2001, 101, 953–996. (h) Coates,
G. W.; Moore, D. R. Angew. Chem., Int. Ed. 2004, 43, 6618–6639. (i)
Darensbourg, D. J. Chem. Rev. 2007, 107, 2388–2410. (j) Behr, A.;
Henze, G. Green Chem. 2011, 13, 25–39. (k) Huang, K.; Sun, C.-L.; Shi,
Z.-J. Chem. Soc. Rev. 2011, 40, 2435–2452. (l) Zhang, Y.; Riduan, S. N.
Angew. Chem., Int. Ed. 2011, 50, 6210–6212.
(15) (a) Zhang, L.; Cheng, J.; Ohishi, T.; Hou, Z. Angew. Chem., Int.
Ed. 2010, 49, 8670–8674. (b) Ohishi, T.; Nishiura, M.; Hou, Z. Angew.
Chem., Int. Ed. 2008, 47, 5792–5795. (c) Boogaerts, I. I. F.; Fortman,
G. C.; Furst, M. R. L.; Cazin, C. S. J.; Nolan, S. P. Angew. Chem., Int.
Ed. 2010, 49, 8674–8677. (d) Mizuno, H.; Takaya, J.; Iwasawa, N. J. Am.
Chem. Soc. 2011, 133, 1251–1253. (e) Correa, A.; Martin, R. J. Am.
Chem. Soc. 2009, 131, 15974–15975. (f) Yeung, C. S.; Dong, V. M. J. Am.
Chem. Soc. 2008, 130, 14936–14937. (g) Johnson, M. T.; Johansson, R.;
Kondrashov, M. V.; Steyl, G.; Ahlquist, M. S. G.; Roodt, A.; Wendt,
O. F. Organometallics 2010, 29, 3521–3529. (h) Yu, D.; Zhang, Y. Green
Chem. 2011, 13, 1275–1279. (i) Riduan, S. N.; Zhang, Y.; Ying, J. Y.
Angew. Chem., Int. Ed. 2009, 48, 3322–3325. (j) Gu, L.; Zhang, Y. J. Am.
Chem. Soc. 2010, 132, 914–915.
It should be noted that the synthesis of aryl Z-vinyl sul-
fides with base-mediated hydrothiolation reactions have been
met with limited success.11 The current reaction was tolerant
toward electron-rich and -deficient aryl thiols and a number
of other functional groups, including amines, furan rings, and
alcohols. It was also observed that aliphatic thiols were slower
to react, and reaction was promoted with an extended
reaction time and/or the change of base from potassium
carbonate to cesium carbonate (Figure 1, 3nꢀ3q). No reac-
tion was observed with 4-mercaptobenzoic acid.
(16) Yu, D.; Zhang, Y. Proc. Natl. Acad. Sci. U.S.A. 2010, 107,
20184–20189.
(17) Carboxylation of terminal alkynes with CO2 under pressure and
heating conditions: (a) Goossen, L. J.; Rodriguez, N.; Manjolinho, F.;
Lange, P. P. Adv. Synth. Catal. 2010, 352, 2913–2917. (b) Zhang, X.;
Zhang, W. Z.; Ren, X.; Zhang, L. L.; Lu, X. B. Org. Lett. 2011, 13, 2402–
2405.
(18) Nicolau, K. C.; Sarlah, D.; Shaw, D. M. Angew. Chem., Int. Ed.
2007, 46, 4708–4711.
(19) Ranjit, S.; Duan, Z.; Zhang, P.; Liu, X. Org. Lett. 2010, 12,
4134–4136.
Org. Lett., Vol. 14, No. 7, 2012
1781

To further improve the utility of our reaction, various
alkynes were screened in this reaction. No conversion was
observed with the use of terminal aliphatic alkynes, even
t
with strong bases such as BuOK. In contrast, the use
of terminal aryl alkynes yielded vinyl sulfides in good-
to-excellent yields. Itwas alsoobservedthat the presence of
electron-withdrawing groups on the phenyl ring dimin-
ished the selectivity of the reaction toward forming the
Z-vinyl sulfide. Remarkably, modifying the reaction setup
by adding a σ-donor ligand (TMEDA) and leaving the
ethynylbenzene to stir in a CO2 atmosphere for 6 h before
the thiol addition improved the selectivity toward Z-vinyl
sulfides, as exemplified in Figure 2, 3ak and 3al.
Figure 2. Coupling of terminal alkynes with thiophenols. Reac-
tion conditions: alkyne (0.5 mmol), thiol (0.75 mmol), 5 mol %
of CuI with respect to alkynes, K2CO3 (0.6 mmol), 25 μL of H2O
and DMSO (3 mL), 16 h, unless otherwise noted. aIsolated
yields, average of 2 separate experiments. bE/Z ratio determined
1
c
by H NMR analysis. 12 mol % of TMEDA was added; the
ethynylbenzene was allowed to stir in the reaction mixture at
room temperature for 6 h before the thiol was added.
Scheme 2. Conditions for the Decarboxylation of
(Phenylthio)phenylpropenoic Acid
Figure 1. Coupling of phenylacetylene with various thiols. Reac-
tion conditions: phenylacetylene (0.5 mmol), thiol (0.75 mmol),
5 mol % of CuI with respect to alkynes, K2CO3 (0.6 mmol),
25 μL of H2O and 3 mL of DMSO, 16 h, unless otherwise noted.
b
aIsolated yields were average of 2 separate experiments. E/Z
1
c
ratio determined by H NMR analysis. Cs2CO3 was used in-
stead of K2CO3. dReaction time = 40 h.
Scheme 3. Reaction with D2O Additive
The reaction was examined in further detail to establish
the crucial factor in determining its stereoselectivity. First,
webelieve thatthe reaction went through the propiolicacid
intermediate, followed by the hydrothiolation decarboxyla-
tion process. As previously mentioned, the additional time
allowed for the stirring of alkynes and base in a DMSO
solution in a CO2 atmosphere was beneficial for stereo-
selectivity. This process allowed for propiolic acid formation
in the system.16 Ranjit et al. reported the direct hydrothiola-
tion reaction using propiolic acids as starting materials.19 Our
observations from replication of experiments with Ranjit’s
protocol,19 which were performed under air, led us to believe
that a small amount of water was beneficial to the reaction.
Experiments performed in a closed system or under an argon
atmosphere did not yield the same published results.
thiols did not occur in the absence of a Cu catalyst. Experi-
ments with different combinations of variables were exam-
ined (SI Table S2). From these studies, one could conclude
that the CO2 atmosphere was the determining factor in the
stereoselectivity of the desired product, and the terminal
alkyne was converted to a propiolic acid in CO2 before a
stereoselective decarboxylative hydrothiolation occurred.
However, the reaction mechanism of this decarboxylative
hydrothiolation process has not yet been studied.19
The addition of thiophenols across propiolic esters has
been examined and was found to provide the resulting
Z-selective (phenylthio)phenylpropenoic acid cleanly,
after acid workup.22 The decarboxylation of such acids was
investigated further, whereby the as-prepared Z-3-phenyl-
2-(4-methoxyphenylthio)propenoic acid was subjected to
However, when the reaction was conducted in an open
system or with trace amounts of water, the decarboxyla-
tion hydrothiolation reaction worked well to give high Z
selectivity. The reductive coupling of propiolic acids and
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Org. Lett., Vol. 14, No. 7, 2012

several conditions (Scheme 2). The acid decarboxylated
only in the presence of a Cu catalyst, 1.2 equiv of K2CO3,
and excess thiols in DMSO solvent, similar to the typical
reaction conditions in Figures 1 and 2. Attempts to isolate
such a propenoic acid intermediate in the reaction of 3a
using equimolar amounts of Cu or the addition of iodo-
methane were not successful.
electron-withdrawing groups could be attributed to the
lower activity for carboxylation with CO2 under Cu(I)-
catalyzed conditions.16 For 3ak, the competitive hydro-
thiolation of the alkynes occurred, instead of hydrothiola-
tion of the propiolic acid intermediate, due to the slower
rate of carboxylation of such alkynes. The presence of a
σ-donor ligand was beneficial for the carboxylation of
such inactive alkynes,16 and as expected, better selectivities
were observed for 3al when TMEDA was used as a ligand
for the reaction.
The role of water in the reaction was also examined. It is
known that water can improve the yield of hydrothiolation
of alkynes in the presence of an amine as a solvent and
mediator, through H-atom donation to vinyl radical inter-
mediates.20 The addition of radical inhibitors (TEMPO) to
the reaction mixture of the current system did not prove to
be detrimental to both the yield and selectivity, indicating
that the reaction did not proceed via a radical mechanism.
Reactions with diphenyl disulfide did not yield any re-
sults.13,21 To understand the role of water in the reaction
mechanism, experiments were performed using deuterated
water (D2O) instead of H2O. It was found that the proton at
the β-position of the vinyl sulfide was mostly replaced by
deuterium (D/H = 3/1, see Scheme 3 and SI). Meanwhile,
the proton at the R-position was 51% replaced by deuterium.
This observation supported the proposed mechanism
(Scheme 4) and also corresponded to the result of controlled
H/D exchange experiments, in which the different deuterium
substitution ratios at both the R- and β-positions were a
result of the RSH/D2O deuteriumꢀhydrogen exchange
during the course of the reaction. The acidic proton in
4-methyl thiophenol was found to be partially replaced by
deuterium (52%), when 2 equiv of D2O was mixed with the
thiol and base in DMF-D7. Quenching of a typical reaction
mixture with an aliquot of deuterated hydrochloric acid
(DCl) inD2O did not result in the replacement of the protons
with deuterium at both the R- and β-positions.
The proposed mechanism included the initial carboxyla-
tion of terminal alkyne (1) with CO2 to form propiolic acid
(2). It is known that the electron density of the CꢀC triple
bond of a propiolic acid is weaker16 as compared to that of
an acetylene, due to the electron-withdrawing nature of the
carboxyl group. Thus, as the Cu center of the catalytic species
approached the triple bond, the nucleophilic attack of the
thiyl anion was induced.23 The reductive CꢀS coupling to
form a cyclic alkene/carboxylate copper complex intermedi-
ate 3 was the key step determining the stereoselectivity. The
subsequent proton attack on the cyclic intermediate (3) to
the β-carbon generated the intermediate 4. The newly co-
ordinated thiol on intermediate 4 induced decarboxyla-
tion under the prescribed conditions (Scheme 4), releasing
CO2 gas and furnishing the Z-vinyl sulfide (5).21 The dimin-
ished stereoselectivity observed for ethynylbenzenes with
Scheme 4. Proposed Mechanism for the Hydrothiolation of
Alkyne with CO2
In conclusion, a simple procedure for the stereoselective
hydrothiolation of alkynes under a CO2 atmosphere has
been developed. To the best of our knowledge, this is the
first instance of stereoselectivity determination with CO2
as a mediator. A cyclic alkene/carboxylate copper complex
intermediate was proposed as the key step in determining
the stereoselectivity, and an equivalent amount of water
was found to play an active role as a proton donor. The
reaction system was robust and utilized inexpensive and
readily available substrates. It provided a promising meth-
od for stereoselective Z-vinyl sulfides synthesis and new
insight into carbon dioxide utilization.
Acknowledgment. This work was supported by the
Institute of Bioengineering and Nanotechnology (IBN)
(Biomedical Research Council, Agency for Science,
Technology and Research, Singapore). The authors would
like to thank Dr. Michael Reithofer (IBN) for helpful dis-
cussions on the reaction mechanism.
(20) Taniguchi, T.; Fujii, T.; Idota, A.; Ishibashi, H. Org. Lett. 2009,
11, 3298–3301.
(21) Bieber, L. W.; da Silva, M. F.; Menezes, P. H. Tetrahedron Lett.
2004, 45, 2735–2737.
(22) (a) Zhou, F.; Rosen, J.; Zebrowshi-Young, J. M.; Freihammer,
P. M.; Detty, M. R.; Lachiotte, R. J. J. Org. Chem. 1998, 63, 5403–5412.
(b) Freihammer, P. M.; Detty, M. R. J. Org. Chem. 2000, 65, 7203–7207.
(23) Overberger, C. G.; Mallon, H. J.; Fine, R. J. Am. Chem. Soc.
1950, 72, 4958–4961.
Supporting Information Available. A description of
materials and methods for experiments, along with spectro-
scopic data are included in the Supporting Information.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
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