Highly Efficient and Stereoselective Thioallylation of Alkynes: Possible Gold Redox Catalysis with No Need for a Strong Oxidant

Article abstract of DOI:10.1002/anie.201802540

Stereoselective thioallylation of alkynes under possible gold redox catalysis was accomplished with high efficiency (as low as 0.1 % catalyst loading, up to 99 % yield) and broad substrate scope (various alkynes, inter- and intramolecular fashion). The gold(I) catalyst acts as both a π-acid for alkyne activation and a redox catalyst for Au^I/III coupling, whereas the sulfonium cation generated in situ functions as a mild oxidant. This novel methodology provides an exciting system for gold redox catalysis without the need for a strong oxidant.

Full text of DOI:10.1002/anie.201802540

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
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International Edition
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Accepted Article
Title: Highly Efficient and Stereoselective Thioallylation of Alkynes:
Possible Gold Redox Catalysis with No Need of a Strong Oxidant
Authors: Xiaodong Shi, Jin Wang, Shuyao Zhang, Lukasz Wojtas,
Novruz Akhmedov, Hao Chen, and Chang Xu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201802540
Angew. Chem. 10.1002/ange.201802540
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10.1002/anie.201802540
Angewandte Chemie International Edition
DOI: 10.1002/anie.201((will be filled in by the editorial staff))
Gold Redox Catalysis
Highly Efficient and Stereoselective Thioallylation of Alkynes:
Possible Gold Redox Catalysis with No Need of a Strong Oxidant
Jin Wang,[a] Shuyao Zhang,[a] Chang Xu,[b] Lukasz Wojtas,[a] Novruz G. Akhmedov,[c] Hao Chen,[b]
Xiaodong Shi[a],*
oxidants to promote this gold redox catalysis is highly desirable.[7h]
Abstract:
A
possible gold redox-catalyzed stereoselective
The reaction was
Herein, we report a successful thioallylation of alkynes under
possible gold redox catalysis. A cationic Au(I) catalyst effectively
promoted nucleophilic addition of allyl sulfide toward the alkyne;
subsequently, the resulting vinyl gold intermediate can be oxidized
by the in-situ generated allylsulfonium cation, providing a vinyl
thioallylation of alkynes was achieved.
accomplished with high efficiency (as low as 0.1% catalyst loading,
up to 99% yield) and broad substrate scope (various alkynes, inter-
and intramolecular fashion). The gold(I) catalyst acts as both p-
acid for alkyne activation and redox catalyst for Au(I/III) coupling,
while the in-situ generated sulfonium cation functions as a mild
oxidant. This novel methodology provides an exciting system for
gold redox catalysis without the need of a strong oxidant.
thioether in
a
stereoselective fashion.
Notably, this novel
thioallylation reaction is highly efficient (as low as 0.1% catalyst
loading, up to 99% yield, gram scale conversions) with broad
substrate scope (Scheme 1B). To the best of our knowledge, this is
the first example of gold redox catalysis that undergoes Au(I) p-acid
activation followed by vinyl-gold oxidation with a mild oxidant,
The past two decades have witnessed a rapid growth of
homogenous gold catalysis.[1] Due to relativistic effects,[2] gold
complexes exhibit superior capability in activating p-bonds in
alkenes, allenes, and especially alkynes. Although the vinyl gold
complex generated from gold-catalyzed nucleophilic addition to an
alkyne is well-known,[3] it hasn’t been of interest by the synthetic
community for quite a while since rapid protodeauration is the
dominant decomposition pathway in most cases. Recently, the vinyl
gold complex has received more and more attention as a versatile
which
represents
an
innovative
strategy
for
alkyne
difunctionalization via gold redox catalysis.
Scheme 1. Gold redox catalysis
(A) Gold redox catalysis: combining π-acid activation and cross-coupling
Nu
R’
Ar-M
M=B, Si
Nu-
R
then R.E.
Au(I)
strong
Au(I)
ArN2+BF4
hv or base
R’
AuIII
R’
Nu
R
-
R’
or
- AuI
or
R
Ar
oxidant
Nu
R
intermediate
for
subsequent
transformations,
including
halogenation,[4] radical addition[5] and transmetallation.[6]
[AuIII
]
AuIII
Au(III) Ar Au(III)
R.E.
Ar
For a long time, oxidation of Au(I) to Au(III) species is
considered challenging due to the high oxidation potential (1.40
eV). The reluctance for Au(I) species to undergo oxidative addition,
which is usually the entry point for metal-catalyzed cross-coupling
reactions, significantly limits their synthetic applications.[7]
However, recent studies have demonstrated an alternative solution
of Au(I) oxidation to Au(III) by using strong oxidants such as
Selectfluor or PhI(OAc)2.[8] This new reaction mode thus unleashes
numerous new and unique opportunities for gold catalysis. For
example, the stronger Au(III) catalyst can activate alkenes towards
nucleophilic attack, and the resulting alkyl-Au(III) intermediate
further undergoes transmetallation and reductive elimination to yield
cross-coupling product.[9] Similar Au(I/III) reactivity can also be
achieved by using diazonium salt as oxidant under photochemical or
basic conditions (Scheme 1A).[10] Overall, this new gold redox
catalysis offers an effective route for alkene difunctionalization.
However, two major limitations of this methodology are A)
requirement of strong oxidants and B) competing reactivity between
Au(I) and Au(III) cations as p-acids. As a result, only very few
successful examples of alkyne difunctionalization have been
reported using this methodology.[11] Thus, searching for milder
Limitations: A) requiring strong oxidants (Selectfluor, PIDA etc);
B) AuIII as π-acid (challenging for alkyne due to the competing AuI activation)
(B) This work: Alkyne thioallylation enabled by gold redox catalysis
R
R
R
S
EWG
AuIII
0.1-2.0% IPrAuNTf2
Toluene, 60 o
S
EWG
+
S
R
S
EWG
AuI
+
R’
C
R’
R’
EWG
R’
Au(I) as π-acid
sulfonium as oxidant confirmed by MS
Ph
Ph
S
>50 examples;
S
S
single Z isomer;
up to 99% yield;
cat. loading as low as 0.1%
CO2Me
Br
H
Ph
97%
Ph
97%
95%
Our interest in utilizing a sulfonium cation as potential oxidant
for gold redox catalysis was initiated by our recent investigation on
gold-catalyzed thioalkyne activation.[12] In that work, we discovered
that thioalkynes could react with allyl sulfides to form
ketenedithioacetals, though in moderate yields and low E/Z
selectivity (Figure 1). To investigate the key allyl transfer process
from the proposed intermediate A, [13] we conducted the cross-over
experiment by reacting thioalkyne with two different allyl sulfides.
PhS
TolS
Bu
PhS
TolS
Bu
PhS
Bu
5% RuPhosAu(CH3CN)OTf
DCE, 60 o
[a]
Dr. J. Wang, S. Zhang, Dr. L. Wojtas, Prof. Dr. X. Shi
Department of Chemistry, University of South Florida
Tampa, FL 33620, United States
+
Tol
S
[Au]
C
A
Fax: (+1) 813-974-3203
E-mail: xmshi@usf.edu
Homepage: http://xmshi.myweb.usf.edu/index.htm
C. Xu, Prof. Dr. H. Chen
Department of Chemistry and Biochemistry, Ohio University
Athens, OH 45791, United States
Dr. Novruz G. Akhmedov
C. Eugene Bennett Department of Chemistry, West Virginia University
Morgantown, WV 26506, United States
75%, Z/E =1:1
Bu
PhS
PhS
TolS
PhS
Bu
SPh PhS
1 equiv
TolS
[b]
5% [Au]
DCE, 60 o
+
PhS
PhS
Bu
TolS
Bu
C
[c]
Bu
2 equiv.
PhS
1:1:1:0.5 by GC-MS
1 equiv.
Cross-over experiments
[**]
We are grateful to NSF (CHE-1665122), NSF (CHE-1709075), NIH
(1R01GM120240-01), NSFC (21228204, 21133011, 21373246 and
21522309) for financial support.
Figure 1. Intermolecular thioallylation by cross-over result
1
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10.1002/anie.201802540
Angewandte Chemie International Edition
O
SR’’
O
IPrAuNTf2 (1%)
toluene, 0.5 M, 60 oC, 10 h
’’RS
+
R
’R
R
’R
1
2
3
Interestingly, significant amount of cross-over products were
observed. The fact that this reaction proceeds through an
intermolecular allyl transfer process is very intriguing to us. Two
possible mechanisms are herein proposed. First, the allyl group
attached to the sulfonium cation can form a C-C bond directly with
the s- or π-bond of the vinyl-Au(I) species to generate the
thioallylation product. Alternatively, the allyl sulfonium cation can
serve as a mild oxidant for vinyl-Au(I) species to generate a
transient Au(III) intermediate, which delivers the same product via
reductive elimination. The latter mechanism is very exciting to us
because it represents a novel methodology to achieve gold redox
catalysis. In order to further explore the detailed mechanism and
substrate scope of this thioallylation reaction, we conducted
reactions between different alkynes and allyl phenyl sulfide 2a
under various gold-catalyzed conditions. The details are shown in
Table 1.
3a, R = H, 95%
3b, R = 4-F, 90%
R
3c, R = 4-Br, 89%
3d, R = 4-Me, 92%
3e, R = 4-OMe, 86%
3f, R = 4-t-Bu, 94%
3g, R = 4-Cl. 92%
3h, R = 2-F, 90%
S
O
S
O
H
OMe
H
OMe
3i, R = 2-OMe, 90%
3j, R = 3-Me, 95%
single crystal
3a - 3j
3k, 70%
3c
Ph
H
Ph
Me
H
S
H
O
S
O
S
O
S
O
OMe
OMe
H
OMe
OMe
3l, 88%
3m, 91%a
3n, 86%
Ph
3o, 64%
n-Pr
Ph
H
Ph
H
S
O
S
O
S
O
S
O
H
OMe
OBn
MeO2C
OMe
Me
Table 1. Screening of reaction conditions
SPh
cat. [Au]
3p, 75%
3q, 90%
3r, 74%b
3s, 57%b
R
R’
PhS
Z-3a: R = H,
R’ = CO2Me
R’
toluene, 60 oC, 10 h
+
1a: R = H, R’ = Ph;
R
1b: R = NMeTs, R’ = Ph;
1c: R = H, R’ = CO2Me
2a
Ph
H
Ph
H
Ph
S
O
S
O
S
O
Ph
entry alkyne
Conditions
5% JohnPhosAuNTf2
5% JohnPhosAuNTf2
5% JohnPhosAuNTf2
5% PPh3AuNTf2
5% RuPhosAuNTf2
5% IPrAuNTf2
5% IPrAuCl
Other [Au] catalysts
conversion yield of 3a (Z/E)
N
OH
H
NHPh
H
1a
1b
1c
1c
1c
1c
1c
1c
1c
1
2
3
4
5
6
7
8
9
<5%
100%
100%
100%
100%
100%
<10%
-
messy
3t, 90%
3u, 66%c
3v, 63%c
79% (3:2)
80% (3:2)
80% (3:1)
96% (Z only)
<5%
Reaction conditions: 1% catalyst was added to a toluene solution (0.6 mL) of alkyne 1
(0.45 mmol) and allyl sulfide 2 (0.3 mmol), and reaction was kept at 60 oC for 10 h. [a]
Starting with trans-crotyl phenyl sulfide. [b] 2% catalyst was used. [c] 0.3 mmol alkyne
and 0.45 mmol sulfide were used.
<90% yields (see SI)
40%-90% yields (see SI)
5% IPrAuNTf2 (other solvents)
Other metal catalysts (Ag, Cu, Fe, Pd,
Rh, Ir, Zn, La, etc.)
Overall, various aryl allyl sulfides are all suitable for this
reaction, giving excellent yields in all cases regardless of the
substitutions on the phenyl group (3a-3j). Methyl-branched allyl
sulfides successfully participated in this reaction, and desired
products were formed as a single isomer with excellent yields (3l
and 3m). Notably, the structure of 3m clearly demonstrated the
exclusive SN2’ addition of vinyl gold intermediate toward
allylsulfonium cation. Alkyl-substituted allyl sulfides also worked
well for this transformation, providing desired products in good to
excellent yields (3n-3p). Alkynes bearing other electron-
withdrawing groups were also tested. while benzylic ester (3q) and
carboxylic acid (3t) provided excellent yields, ketone (3s) and
amides (3u and 3v) were obtained with only moderate yields,
presumably due to catalyst deactivation by substrate coordination.
Phenyl or alkyl (Me and n-Bu) substituted internal propiolates gave
almost no reaction even under extended reaction time (48 h), like
due to the low reactivity of these internal alkynes. However, the di-
ester substituted internal alkyne (dimethyl acetylenedicarboxylate)
worked well, realizing 3r in 74% yield. In addition, no sulfide
conversion was observed when benzyl methyl sulfide was used,
which highlighted the unique reactivity of allyl sulfides for this
transformation. It’s worth noting that in all cases only the Z-isomers
were observed. The alkene geometry was ambiguously confirmed
by the X-ray structure of 3c.
10
11
12
13
1c
1c
1c
<5% conversion (see SI)
1% IPrAuNTf2 ([c]=0.5 M, 60 oC)
0.1% IPrAuNTf2 ([c]=2.0 M, 60 oC),
48 h, gram scale
100%
100%
93%
98% (Z only)
95% (Z only)
88% (Z only)
1c 1% IPrAuNTf2 ([c]=0.5 M, 40 oC, 48 h)
Reaction conditions: 5% catalyst was added to a toluene solution (1 mL) of alkyne 1
(0.15 mmol) and allyl sulfide 2a (0.1 mmol), and reaction was kept at 60 oC for 10 h.
Conversion and yield were determined by 1H NMR spectroscopy using dimethylsulfone
as internal standard.
Under gold-catalyzed conditions (5% JohnPhosAuNTf2, toluene
o
and 60 C), reaction of 2a and phenylacetylene 1a gave almost no
conversion with most of the starting materials recovered, suggesting
phenylacetylene was not reactive enough under these conditions.
The more electron-rich ynamide 1b gave messy reaction mixtures
with no clear product identified. We then turned our attention to the
carbonyl-activated alkyne propiolate 1c due to more facile
nucleophilic addition. To our delight, the thioallylation product 3a
was observed in 79% yield as a 3:2 Z/E mixture. Further screening
revealed IPrAuNTf2 as the optimal gold catalyst, giving product 3a
as a single isomer. The alkene geometry was later confirmed as Z-
configuration by NMR.[14] This result suggested a possible
mechanism of sulfide undergoing trans-addition to the gold(I)-
activated alkyne, followed by subsequent allyl transfer. Toluene
was optimal for this reaction, as other solvents provided inferior
results. Notably, other metal catalysts including Ag, Cu, Fe, Pd, Rh,
Ir, Zn and La were inactive for this reaction (see details in SI),
which highlighted the unique reactivity of gold catalyst for this
transformation. Finally, increasing the reaction concentration to 0.5
M gave complete conversion (10 h) and excellent yield (98%) even
with only 1% catalyst loading. Further increasing the concentration
to 2 M allowed a gram-scale synthesis of 3a in excellent yield, with
only 0.1% catalyst under extended reaction time (48 h). Lowering
To further identify if a Au(I/III) process is involved during the
allyl transfer, reaction between 1c and 2a was monitored by mass
spectrometry (Figure 2).
PhS
PhS
H
PhS
H
1c
+
CO2Me
Au(III)
[IPrAu]+
CO2Me
H
CO2Me
3a
Au(I)
IPr
2a
IPr
o
reaction temperature to 40 C resulted in incomplete conversion.
B
C
D
With the optimized conditions in hand, we tested the scope of this
reaction. The results are summarized in Table 2.
m/z: 819.3
detected
[M-H]+ m/z: 859.4
detected
confirmed by CID
m/z: 275.1
detected
confirmed by CID
Table 2. Reaction scope of carbonyl activated alkynes
Figure 2. Mechanistic study by mass spectrometry
2
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10.1002/anie.201802540
Angewandte Chemie International Edition
were observed with different aryl substitutions on bromo-alkynes
(5i-5l). Alkyl substituted allyl sulfides and bromo-alkynes are all
suitable substrates for this transformation as well, indicating the
broad substrate scope of this transformation (5m-5p). Notably, no
cyclopropane ring opening was observed in substrate 5o, which
ruled out the radical reaction pathway. Chloro-alkynes were also
prepared and charged with the reaction conditions. As expected,
superior reactivity (faster reaction) over bromo-alkynes was
observed with the chloro-alkynes, giving the desired tetra-
substituted vinyl chloride in excellent yields in most cases (5q-5x).
Moreover, single alkene isomer was obtained in all cases.
Comprehensive NMR analysis for 5a, 5c and 5p confirmed the
geometry of the alkene as exclusive Z-isomer similar to the
carbonyl-activated alkyne substrates, which is consistent with the
proposed mechanism (see details in SI). The efficient synthesis of
the tetra-substituted alkenes in a stereoselective fashion greatly
highlighted the unique advantage of this novel gold redox approach.
As mentioned in Table 1, simple internal alkynes failed to
participate in this transformation, presumably due to low reactivity
upon nucleophilic addition. To further extend the reaction scope to
regular alkynes, we propose to facilitate this reaction in an
intramolecular fashion. Alkynes 6 bearing an allyl sulfide pendant
were applied to the reaction conditions. To our delight, di-
hydrothiophenes 7 were obtained through a 5-endo-dig cyclization
in excellent yields, even with catalyst loading as low as 0.1%. The
scope of this reaction is summarized in Table 4. This intramolecular
thioallylation gave excellent yield for terminal alkyne (7a). Good to
excellent yields were obtained for aryl substituted substrates too
(7b-7i, 7k). Interestingly, strong EWG-substituted aryl alkynes (7c,
7d and 7i) reacted much slower, suggesting the more difficult Au(I)
oxidation. Notably, heterocyclic substitutions such as thiophene and
unprotected indole were also well-tolerated for this transformation
(7k, 7m). The ultra-low catalyst loading (TON around 1000) greatly
highlighted the efficiency and practicality of this transformation.
The ion at m/z = 819.3 was detected and identified as
intermediate B based on its CID data. Importantly, the ion at m/z =
859.4 corresponding to Au(III) intermediate C ([M-H]+ ion) was
clearly observed, and its structure was further confirmed by CID.
Intermediate D was also present in the mass spectrum (see detailed
MS study in SI). In addition, careful interpretation of the mass data
revealed another Au(III) ion at m/z = 735.1, which corresponds to
allyl-Au(III)-SPh ion (see details in SI). In conclusion, the MS data
largely supports the Au(I/III) pathway; herein,
a tentative
mechanism involving a vinyl gold formation (intermediate B) and
subsequent allyl transfer to form Au(III) intermediate C is proposed.
This mechanism was further backed up by additional MS evidences
with a different gold catalyst and sulfide (see details in SI). More
efforts will be made to further confirm this intriguing Au(I/III)
mechanism including NMR analysis and computational study.
This novel thioallylation method provides a rapid access to highly
functionalized alkenes in a stereoselective fashion. To further
expand its reaction scope, several terminal alkynes with electron-
deficient aromatic substitutions were tested, including C6F5 and 4-
pyridinal substituted alkynes. Unfortunately, these substrates gave
no reaction under the gold redox conditions. We then turned our
attention to internal alkynes with EWG substitution. Notably,
compared with NO2, CN and CF3 modified alkynes, halo-alkynes
are easy to prepare from readily available starting materials.
However, application of these compounds in synthesis are rather
limited to ynamide preparation[15] and Cardiot-Chodkiewicz type
coupling reaction[16]. The potential synthetic utility of halo-alkyne is
somehow neglected.[17] To our great delight, halo-alkynes 4 with Br-
or Cl- substitution worked well in the thioallylation with slightly
increased catalyst loading (2%). The desired tetra-substituted
alkenes 5 were prepared successfully in good to excellent yields as
exclusive Z-isomers. The substrate scope is summarized in Table 3.
Table 4. Intramolecular cyclization with regular alkynes
R
Table 3. Reaction scope of halo-alkynes
S
IPrAuNTf2 (0.1%)
SR'
S
toluene, 1 M, 60 oC, 6 h
X
IPrAuNTf2 (2%)
’RS
R
R
R
X
+
toluene, 0.5 M, 60 oC, time
6
7
4, X = Br or Cl
2
5
7b, R = H, 93%
7c, R = 4-CF3, 80%a
S
time = 24 h
7d, R = 4-CO2Me, 96%a
7e, R = 4-Br, 90%
7f, R = 4-Me, 91%
7g, R = 3-Cl, 90%
7h, R = 3-OMe, 95%
7i, R = 2-F, 73%a
5a, R = H, 97%
5b, R = 4-Br, 94%
5c, R = 4-F, 89%
5d, R = 4-Me, 73%
5e, R = 4-OMe, 73%
5f, R = 3-Me, 81%
5g, R = 2-F, 92%
5h, R = 2-OMe, 75%
S
R
Ph
S
5i, R = 4-F, 94%
5j, R = 4-Br, 91%
5k, R = 3-F, 87%
5l, R = 3-Me, 76%
S
H
Br
R
Br
7a, 88%
Ph
5a - 5h
R
7b - 7i
5i - 5l
S
S
Me
Ph
S
S
Ph
Ph
S
S
S
S
Br
Br
Br
Cl
Br
Ph
HN
5p, 80%
5m, 74%
5n, 64%
5o, 67%
7j, 99%
7l, 62%
7k, 93%
time = 12 h
Reaction conditions: 0.1% catalyst was added to a toluene solution (0.3 mL) of alkyne 6
5q, R = H, 92%
Me
S
R
(0.3 mmol), and reaction was kept at 60 oC for 6 h. [a] reacted for 24 h.
5r, R = 4-F, 90%
5s, R = 4-OMe, 92%
5t, R = 4-Br, 91%
5u, R = 3-Me, 87%
5v, R = 2-F, 90%
S
S
Cl
Ph
Cl
Cl
Ph
5q - 5v
Ph
To further showcase the synthetic utility of this transformation,
we aimed to convert the thioallylation products into value-added
synthetic intermediates. By treating with TFA/TFAA, thioflavone 8
was successfully formed from acid 3t via a Friedel-Crafts type
cyclization (Figure 3A). The sulfide 5a can be efficiently converted
5w, 83%
5x, 84%
Reaction conditions: 2% catalyst was added to a toluene solution (0.4 mL) of alkyne 4
(0.3 mmol) and allyl sulfide 2 (0.2 mmol), and reaction was kept at 60 oC for 12 or 24 h.
o
to sulfone 9 by oxidation with mCPBA at 0 C without interrupting
Compared with the carbonyl-activated alkynes, reactions with
halo-alkynes especially bromo-alkynes requires longer reaction time
presumably due to the reduced reactivity of alkynes. Different aryl
allyl sulfides gave good to excellent yields for this transformation,
with either EWG or EDG substitution on arene (5a-5h). In general,
excellent yields were obtained with EWG-substituted aryl sulfides,
while EDG-substituted sulfides gave lower yields due to incomplete
conversions (around 90% conv.). Similar good to excellent yields
the pendant allyl group (Figure 3B). The vinyl bromide motif in 5a
proved to be a useful synthetic handle for cross-coupling reactions
as well, as desired Suzuki coupling product 10 was obtained in
excellent yield (Figure 3C). These results clearly demonstrated the
versatile synthetic utilities of the thioallylation substrates.
In conclusion, we have reported herein an efficient and
stereoselective thioallylation of alkynes possibly enabled by gold
3
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10.1002/anie.201802540
Angewandte Chemie International Edition
1175-1177; d) A. Tamaki, J. K. Kochi, J. Organomet. Chem. 1974, 64,
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A. Wegner, M. Auzias, Angew. Chem. Int. Ed. 2011, 50, 8236-8247;
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Hashmi, M. Limbach, Organometallics 2010, 29, 4448-4458.
For early examples of Au(III)-mediated nucleophilic addition-homo-
coupling sequence, see: a) A. S. K. Hashmi, M. C. Blanco, D. Fisher,
J. W. Bats, Eur. J. Org. Chem. 2006, 1387-1389; b) H. A. Wegner, S.
Ahles, M. Neuburger, Chem. Eur. J. 2008, 14, 11310-11313; c) S.
Fustero, P. Bello, B. Fernandez, C. del Pozo, G. B. Hammond, J. Org.
Chem. 2009, 74, 7690-7696; for Au(I) catalyzed nucleophilic
addition-cross-coupling sequence, see: d) G. Zhang, L. Cui, Y. Wang,
L. Zhang, J. Am. Chem. Soc. 2010, 132, 1474-1475; e) A. D. Melhado,
W. E. Brenzovich Jr., A. D. Lacktner, F. D. Toste, J. Am. Chem. Soc.
2010, 132, 8885-8887; f) W. E. Brenzovich Jr., D. Benitez, A. D.
Lacktner, H. P. Shunatona, E. Tkatchouk, W. A. Goddard III, F. D.
Toste, Angew. Chem. Int. Ed. 2010, 49, 5519-5522.
redox catalysis. The Au(I/III) catalytic cycle is proposed with
sulfonium cation as a mild oxidant, which is confirmed by Mass
Spectrometry study. This reaction displayed a broad substrate scope.
Different alkynes including carbonyl-activated alkynes, halo-
alkynes are well-suited for this transformation; intramolecular
cyclizations proved feasible too. Subsequent transformations on
thioallylation products further indicated the synthetic utility of this
reaction. Detailed mechanistic study as well as expanding this mild
gold redox strategy to other sulfides and alkynes are currently under
investigation in our group.
[8]
[9]
Figure 3. Synthetic utilities
A) Thioflavanone synthesis
O
S
O
TFA/TFAA 2:1, rt, 2 h
H
OH
S
3t
8, 85%
B) Sulfone synthesis
Ph
S
Ph
mCPBA, DCM, 0 oC, 1 h
SO2
[10] For photoredox conditions with gold catalysts and photo-active dyes,
see: a) B. Sahoo, M. N. Hopkinson, F. Glorius, J. Am. Chem. Soc.
2013, 135, 5505-5508; b) X. Shu, M. Zhang, Y. He, H. Frei, F. D.
Toste, J. Am. Chem. Soc. 2014, 136, 5844-5847; c) M. N. Hopkinson,
A. Tlahuext-Aca, F. Glorius, Acc. Chem. Res. 2016, 49, 2261-2272;
for photoredox conditions with photo-active gold catalyst only and no
additional dyes, see: d) J. Xie, S. Shi, T. Zhang, N. Mehrkens, M.
Rudolph, A. S. K. Hashmi, Angew. Chem. Int. Ed. 2015, 54, 6046-
6050; e) J. Xie, T. Zhang, F. Chen, N. Mehrkens, F. Rominger, M.
Rudolph, A. S. K. Hashmi, Angew. Chem. Int. Ed. 2016, 55, 2934-
2938; f) L. Huang, M. Rudolph, F. Rominger, A. S. K. Hashmi,
Angew. Chem. Int. Ed. 2016, 55, 4808-4813; g) J. Xie, J. Li, V.
Weingand, M. Rudolph, A. S. K. Hashmi, Chem. Eur. J. 2016, 22,
12646-12650; h) L. Huang, F. Rominger, M. Rudolph, A. S. K.
Hashmi, Chem. Commun. 2016, 52, 6435-6438; i) S. Witzel, J. Xie, M.
Rudolph, A. S. K. Hashmi, Adv. Synth. Catal. 2017, 359, 1522-1528;
for basic conditions, see: j) R. Cai, M. Lu, E. Y. Aguilera, Y. Xi, N. G.
Akmedov, J. L. Petersen, H. Chen, X. Shi, Angew. Chem. Int. Ed.
2015, 54, 8772-8776; k) B. Dong, H. Peng, S. E. Motika, X. Shi,
Chem. Eur. J. 2017, 23, 11093-11099.
[11] For Meyer-Schuster-type rearrangement, see a) G. Zhang, Y. Peng, L.
Cui, L. Zhang, Angew. Chem. Int. Ed. 2009, 48, 3112-3115; b) Y. Yu,
W. Yang, D. Pflasterer, A. S. K. Hashmi, Angew. Chem. Int. Ed. 2014,
53, 1144-1147; c) J. Um, H. Yun, S. Shin Org. Lett. 2016, 18, 484-
487; d) A. Tlahuext-Aca, M. N. Hopkinson, R. A. Garza-Sanchez, F.
Glorius, Chem. Eur. J. 2016, 23, 5909-5913; for Sonogashira-type
coupling reaction, see: e) A. Tlahuext-Aca, M. N. Hopkinson, B.
Sahoo, F. Glorius, Chem. Sci. 2016, 7, 89-93; for oxyarylation and
aminoarylation, see: f) L. Huang, M. Rudolph, F. Rominger, A. S. K.
Hashmi, Angew. Chem. Int. Ed. 2016, 55, 4808-4813; g) Z. Wang, T.
Tan, C. Wang, D. Yuan, T. Zhang, P. Zhu, C. Zhu, J. Zhou, L. Ye,
Chem. Commun. 2017, 53, 6848-6851.
Br
Br
Ph
Ph
5a
9, 86%
C) Suzuki coupling
t-Bu
Ph
S
t-Bu
Ph
S
Pd(PPh3)2Cl2 5%
+
Br
Ph
Ph
K3PO4, toluene, 80 oC, 16 h
B(OH)2
5a
10, 98%
Keywords: gold redox catalysis · thioallylation · vinyl gold · sulfonium
cation
[1]
For reviews, see: a) A. S. K. Hashmi, Gold Bull. 2004, 37, 51-65; b) A.
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4
This article is protected by copyright. All rights reserved.

10.1002/anie.201802540
Angewandte Chemie International Edition
R
R
Gold Redox Catalysis
R
S
EWG
0.1-2.0% IPrAuNTf2
S
EWG
+
S
R S
EWG
AuI
+
Jin Wang,a Shuyao Zhang,a Chang Xu,b
Lukasz Wojtas,a Novruz G. Akhmedov,c
Hao Chen,b Xiaodong Shia,*
Toluene, 60 oC
R’
AuIII
R’
R’
EWG
R’
Au(I) as π-acid
sulfonium as oxidant confirmed by MS
Ph
Ph
S
>50 examples;
single Z isomer;
up to 99% yield;
S
Page 1 – Page 5
S
CO2Me
Br
H
Ph
Ph
cat. loading as low as 0.1%
Highly Efficient and Stereoselective
Thioallylation of Alkynes: Possible
Gold Redox Catalysis with No Need
of a Strong Oxidant
97%
95%
97%
Abstract: A possible gold redox-catalyzed stereoselective thioallylation of alkynes was
achieved. The reaction was accomplished with high efficiency (as low as 0.1% catalyst
loading, up to 99% yield) and broad substrate scope (various alkynes, inter- and
intramolecular fashion). The gold(I) catalyst acts as both p-acid for alkyne activation and
redox catalyst for Au(I/III) coupling, while the in-situ generated sulfonium cation functions
as a mild oxidant. This novel methodology provides an exciting system for gold redox
catalysis without the need of a strong oxidant.
5
This article is protected by copyright. All rights reserved.