Gold-Catalyzed Anti-Markovnikov Selective Hydrothiolation of Unactivated Alkenes

Article abstract of DOI:10.1021/acs.orglett.6b00746

Despite the widespread use of transition-metal catalysts in organic synthesis, transition-metal-catalyzed reactions of organosulfur compounds, which are known as catalyst poisons, have been difficult. In particular, the transition-metal-catalyzed addition of organosulfur compounds to unactivated alkenes remains a challenge. A novel gold-catalyzed hydrothiolation of unactivated alkenes is presented, which proceeds effectively to give the anti-Markovnikov-selective adducts in good yields and in a regioselective manner.

Full text of DOI:10.1021/acs.orglett.6b00746

Letter
pubs.acs.org/OrgLett
Gold-Catalyzed Anti-Markovnikov Selective Hydrothiolation of
Unactivated Alkenes
Taichi Tamai, Keiko Fujiwara, Shinya Higashimae, Akihiro Nomoto, and Akiya Ogawa*
Department of Applied Chemistry, Graduate School of Engineering, Osaka Prefecture University, 1-1 Gakuen-cho, Nakaku, Sakai,
Osaka 599-8531, Japan
S
* Supporting Information
ABSTRACT: Despite the widespread use of transition-metal
catalysts in organic synthesis, transition-metal-catalyzed
reactions of organosulfur compounds, which are known as
catalyst poisons, have been difficult. In particular, the
transition-metal-catalyzed addition of organosulfur compounds
to unactivated alkenes remains a challenge. A novel gold-catalyzed hydrothiolation of unactivated alkenes is presented, which
proceeds effectively to give the anti-Markovnikov-selective adducts in good yields and in a regioselective manner.
Table 1. Screening of Catalysts for Hydrothiolation of 1-
Decene
ransition-metal-catalyzed addition of heteroatom com-
pounds is a very attractive strategy for the selective
a
T
synthesis of heteroatom-functionalized molecules.1 Organo-
sulfur compounds, for example, have widespread utility as
synthetic intermediates, bioactive compounds, and functional
materials.2 Although organosulfur compounds are known to
poison transition-metal catalysts,3 several examples of transition-
metal-catalyzed additions of organosulfur compounds to alkynes
and allenes have been reported in the last two decades.4,5
However, there are very limited examples of the transition-metal-
catalyzed addition of organosulfur compounds to alkenes,6 as the
poor coordination ability of alkenes renders this reaction difficult.
We recently reported the Pd-catalyzed hydrothiolation of alkenes
bonded directly to heteroatoms, such as vinyl ethers and vinyl
lactams;7 however, the transition-metal-catalyzed hydrothiola-
tion of unactivated alkenes remains an unresolved challenge.8,9
Recently, gold catalysts have gained importance because of
their unique affinity toward unsaturated compounds, including
unactivated alkenes.10,11 Hence, we focused on the use of gold
catalysts to overcome the limitations of the hydrothiolation of
alkenes. Herein, we report a novel gold-catalyzed addition of
thiols 2 to unactivated alkenes 1, which proceeds with excellent
regioselectivity to afford the corresponding anti-Markovnikov
adducts 3 in good yields (eq 1).
b
entry
catalyst
yield (%)
1
2
3
4
5
6
7
8
PPh3AuNTf2 (2 mol %)
PPh3AuNTf2 (1 mol %)
PPh3AuNTf2 (5 mol %)
none
65
73
23
trace
66
(Me2S)AuCl (1 mol %)
PPh3AuCl (1 mol %)
AuCl3 (1 mol %)
trace
16
PPh3AuNTf2 (2 mol %) + CuCl2 (2 mol %)
ND
a
Reaction conditions: 1-decene (1a, 0.5 mmol), benzenethiol (2a, 0.5
b
1
mmol), THF (0.3 mL). Determined by H NMR analysis.
ineffective when the catalyst amount was increased to 5 mol %,
giving 3aa in only 23% yield; on the other hand, in the absence of
the catalyst, only a trace amount of the desired product was
formed (entries 3 and 4).
(Me2S)AuCl as the gold catalyst also promoted the desired
hydrothiolation and afforded the product in good yield (entry 5).
PPh3AuCl and AuCl3 were ineffective for the reaction, and the
product yield was unsatisfactory (entries 6 and 7). Furthermore,
when Pd, Ru catalysts and Lewis acid were used, the
hydrothiolation did not proceed at all (see the Supporting
Information). Moreover, when 2 mol % of CuCl2 was used as an
oxidant with PPh3AuNTf2 (to clarify whether higher valent Au
species exhibits catalytic activity toward the hydrothiolation of
alkene), the hydrothiolation product was not obtained (entry 8).
Next, we optimized the reaction conditions for the gold-
catalyzed hydrothiolation using PPh3AuNTf2 as the catalyst
We first attempted to search for a catalyst that would aid the
selective hydrothiolation of unactivated alkenes (Table 1). The
reaction of 1-decene 1a and benzenethiol 2a in the presence of 2
mol % of PPh3AuNTf2, a highly reactive gold catalyst,12 at 45 °C
for 17 h led to the formation of the anti-Markovnikov-type
adduct 3aa in 65% yield; no Markovnikov-type adduct was
observed (entry 1). With a slight reduction in the amount of
PPh3AuNTf2 to 1 mol %, the anti-Markovnikov hydrothiolation
proceeded efficiently (entry 2). However, the reaction was
Received: March 15, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00746
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(Table 2). First, we focused on the solvents and reaction
temperatures for the hydrothiolation. The use of toluene and
Table 3. Gold-Catalyzed Hydrothiolation of Several
Unactivated Alkenes
a
Table 2. Optimization of Reaction Conditions for
a
Hydrothiolation of 1-Decene
b
entry
1
solvent
temp (°C)
time (h)
yield (%)
THF (0.3 mL)
THF (0.3 mL)
THF (0.3 mL)
toluene (0.3 mL)
toluene (0.3 mL)
CH3CN (0.3 mL)
THF (0.15 mL)
THF (0.15 mL)
THF (0.15 mL)
THF (0.15 mL)
45
45
70
45
90
45
45
45
45
45
17
17
17
17
17
17
17
17
20
20
65
73
11
3
c
2
3
4
5
6
10
2
c
7
13
80
87
99
8
9
d
10
a
Reaction conditions: 1-decene (1a, 0.5 mmol), benzenethiol (2a, 0.5
b
1
mmol), PPh3AuNTf2 (2 mol %). Determined by H NMR analysis.
c
d
PPh3AuNTf2 (1 mol %) was used. Excess amounts of benzenethiol
(2a, 0.33 mmol) were added after 4 h.
CH3CN as solvents for the hydrothiolation led to a substantial
decrease in the yields of the desired adducts (entries 4 and 6). In
comparison, the reaction yields were reasonable when using
tetrahydrofuran (THF). Further, high temperatures were
unsuitable for the gold-catalyzed hydrothiolation (entries 3 and
5), probably because of the decomposition of PPh3AuNTf2.
Next, we examined the amounts of THF for the gold-catalyzed
hydrothiolation (see the Supporting Information) and found
that a combination of 2 mol % of PPh3AuNTf2 and 0.15 mL of
THF gave 3aa in good yield, 80% (entry 8). In addition, the yield
of the hydrothiolation product was improved by prolonging the
reaction to 20 h (entry 9). Furthermore, when excess PhSH was
added to the reaction mixture additionally after 4 h, the desired
product 3aa was obtained in almost quantitative yield (entry 10).
We next examined the scope and limitations of the gold-
catalyzed hydrothiolation of unactivated alkenes; the results are
summarized in Table 3. The reaction of allylbenzene 1b and 4-
phenyl-1-butene 1c afforded the corresponding anti-Markovni-
kov hydrothiolation products in excellent yields (entries 2 and 3).
The reaction of phenyl allyl ether gave the desired hydro-
thiolation product in moderate yield (entry 4). Alkenes bearing a
variety of functional groups such as nitrile, hydroxyl, and chloro
were tolerated in the gold-catalyzed hydrothiolation, and the
corresponding adducts 3ea, 3fa, and 3ga were obtained in
moderate yields, respectively (entries 5−7). In the case of 1,6-
heptadiene 1h, the bishydrothiolation product 3ha was obtained
in 47% yield, along with 20% of the monohydrothiolation
product 3ha′ (entry 8). The reaction of a 1,1-disubstituted
alkene, 2-methyl-1-hexene 1i, proceeded efficiently to afford the
hydrothiolation product 3ia in 50% yield (entry 9). In the cases
of norbornene 1j and 2,2-dimethyl-3-methylene-bicyclo[2.2.1]-
heptane 1k, the hydrothiolation products were obtained in
moderate yield; exo- and endo-isomers, respectively, were
obtained stereoselectively (entries 10 and 11). Furthermore,
when the sterically demanding alkenes, such as 3,3-disubstituted
alkene and tri- and tetrasubstituted alkenes, were used for the
gold-catalyzed hydrothiolation, the desired reaction did not
proceed at all.13
a
Reaction conditions: alkene (1, 0.5 mmol), benzenethiol (2a, 0.83
mmol), PPh3AuNTf2 (2 mol %), THF (0.15 mL), 45 °C, 20 h. Anti-
Markovnikov adducts were obtained regioselectively without for-
mation of Markovnikov adduct in all entries.
Subsequently, the gold-catalyzed hydrothiolation of unactive
alkene 1a was extended to several thiols; the results are
summarized in Table 4. Benzenethiols bearing an electron-
donating or electron-withdrawing group such as methyl, fluoro,
or chloro were suitable for this catalytic hydrothiolation, and the
anti-Markovnikov adducts were obtained in high yields (entries
2−4). The use of pentafluorobenzenethiol resulted in a moderate
yield of the anti-Markovnikov adduct (entry 5). Aliphatic thiols
such as phenylmethanethiol 2f, cyclohexanethiol 2g, and
dodecanethiol 2h afforded the desired anti-Markovnikov-type
hydrothiolation products in a regioselective fashion (entries 6−
8).
To clarify whether the present gold-catalyzed hydrothiolation
reaction involves a radical pathway, we examined the hydro-
thiolation of a vinylcyclopropane derivative (Scheme 1). The rate
constant for the ring opening of the cyclopropylcarbinyl radical is
very large (k = 1.3 × 108 s−1).14 Therefore, if the gold-catalyzed
hydrothiolation proceeds via a radical pathway, ring opening of
cyclopropane may be observed. The hydrothiolation of 1-
cyclopropyl-1-phenylethene 1l afforded anti-Markovnikov ad-
duct 3la without cyclopropyl ring opening. This result indicated
that the present gold-catalyzed hydrothiolation did not proceed
via a radical reaction (also see the Supporting Information).
To obtain insights into the reaction mechanism, the catalytic
hydrothiolation of 1-decene 1a with benzenethiol 2a was
monitored by 31P NMR analysis. The 31P NMR spectrum during
the hydrothiolation immediately showed peaks at 35.3 ppm,
B
DOI: 10.1021/acs.orglett.6b00746
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Organic Letters
Letter
Table 4. Gold-Catalyzed Hydrothiolation Using Several
Thiols
Scheme 2. Effects of Gold Catalyst on Hydrothiolation
a
a
Reaction conditions: 1-decene (1a, 0.5 mmol), thiol (2, 0.5 mmol),
PPh3AuNTf2 (2 mol %), THF (0.15 mL), 45 °C, 20 h. Anti-
Markovnikov adducts were obtained regioselectively without for-
mation of Markovnikov adduct in all entries.
Figure 1. ORTEP drawing of gold−sulfide complex A (50% thermal
ellipsoids). For clarity, all hydrogen atoms and counteranion have been
omitted, and only the ipso-carbons of the phenyl ring of
triphenylphosphine are shown.
Scheme 1. Examination of Radical Pathway of Gold-Catalyzed
Hydrothiolation
Scheme 3. Plausible Reaction Pathway for Gold-Catalyzed
Hydrothiolation of Unactivated Alkenes
attributed to the formation of gold−thiolate complex A. To
determine the structure of A, a stoichiometric reaction of
PPh3AuNTf2 with PhSH was performed (Scheme 2). After the
reaction, the 31P NMR spectrum showed a signal at 35.3 ppm.
Complex A was recrystallized, and X-ray analysis unambiguously
established that it was a tetranuclear gold complex,
[(PPh3)4Au4(SPh)2](NTf2)2 (Figure 1). The NMR data of
[(PPh3)4Au4(SPh)2](NTf2)2 were identical to those for a very
similar tetranuclear gold complex reported in the literature.15
Next, we conducted the hydrothiolation using the synthesized
[(PPh3)4Au4(SPh)2](NTf2)2. Interestingly, the desired hydro-
thiolation proceeded efficiently, indicating that tetranuclear gold
complex A is a key intermediate in the hydrothiolation of
unactivated alkenes (or one of the resting state of catalyst).
Based on these mechanistic studies and previous studies,11,16
we propose a plausible reaction pathway for the hydrothiolation
of unactivated alkene 1 with thiol 2 (Scheme 3). The
PPh3AuNTf2 catalyst reacts with the thiol to form PPh3AuSR2,
which in turn reacts with PPh3AuNTf2 to form tetranuclear gold
complex A. Then, 1 is activated by the coordination of complex
A. Subsequent addition of the Au−S species into the double
bond of the unactivated alkene affords gold−alkene complex D
through a transition structure C. Finally, protonation of
C
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Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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In summary, we have developed a novel gold-catalyzed anti-
Markovnikov-selective hydrothiolation of unactivated alkenes.
Conventional transition-metal-catalyzed reactions of organo-
sulfur compounds to unactivated alkenes are difficult. However,
our results reveal that the highly cationic gold catalyst enables
selective hydrothiolation of unactivated alkenes to afford the
desired anti-Markovnikov adducts. We believe that this gold-
catalyzed hydrothiolation will open up the possibility of
synthesizing diverse functionalized alkenes with potential
applications in chemistry.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b00746.
■
S
Coulombel, L.; Dunach, E. Chem. Commun. 2006, 332. (c) Wu, J.;
̃
Savolainen, M. A. US Patent US8816094, 2014.
X-ray data for complex A (CIF)
Detailed experimental procedures and compound charac-
terization data (PDF)
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thiols to unactivated alkenes, see: (a) Posner, T. Ber. Dtsch. Chem. Ges.
1905, 38, 646. (b) Griesbaum, K. Angew. Chem., Int. Ed. Engl. 1970, 9,
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AUTHOR INFORMATION
Corresponding Author
■
́
(10) (a) Corma, A.; Leyva-Perez, A.; Sabater, M. J. Chem. Rev. 2011,
111, 1657. (b) Li, Z.; Brouwer, C.; He, C. Chem. Rev. 2008, 108, 3239.
(c) Arcadi, A. Chem. Rev. 2008, 108, 3266. (d) Hashmi, A. S. K.;
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Rev. 2007, 107, 3180. (f) Modern Gold Catalyzed Synthesis; Hashmi, A. S.
K., Toste, F. D., Eds.; Wiley-VCH: Weinheim, 2012. (g) Chiarucci, M.;
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*E-mail: ogawa@chem.osakafu-u.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by a Grant-in-Aid for Scientific
Research for JSPS Fellows (1381002900). T.T. thanks the Japan
Society for the Promotion of Science for the Research Fellowship
for Young Scientists. We also thank the Nara Institute of Science
and Technology (NAIST) for assistance with the X-ray crystal
structural analysis.
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compounds to alkynes and activated alkenes, see: (a) Morita, N.;
Krause, N. Angew. Chem., Int. Ed. 2006, 45, 1897. (b) Brouwer, C.;
Rahaman, R.; He, C. Synlett 2007, 1785. (c) Biswas, S.; Samec, J. S. M.
Chem. Commun. 2012, 48, 6586. (d) Corma, A.; Gonzal
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Iglesias, M.; Sanchez, F. Appl. Catal., A 2010, 375, 49. (e) Jean, M.;
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(h) Zalesskiy, S. S.; Khrustalev, V. N.; Kostukovich, A. Yu.; Ananikov, V.
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(12) Mezailles, N.; Ricard, L.; Gagosz, F. Org. Lett. 2005, 7, 4133.
́
PPh3AuNTf2 was prepared by the reaction of PPh3AuCl with AgNTf2 in
CH2Cl2.
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