Investigations on Gold-Catalyzed Thioalkyne Activation Toward Facile Synthesis of Ketene Dithioacetals

Article abstract of DOI:10.1002/chem.201702710

Nucleophilic addition to thioalkynes was investigated under various catalytic conditions with gold(I) complexes being identified as the optimal catalysts. Structural evaluation of the product revealed an unexpected cis-addition, arising from a gold-associated thioketene intermediate. Based on this interesting mechanistic insight, a gold(I)-catalyzed thioether addition to thioalkynes was developed as a novel approach to prepare ketene dithioacetals with good yields and high efficiency.

Full text of DOI:10.1002/chem.201702710

A Journal of
Accepted Article
Title: Investigations on Gold Catalyzed Thioalkyne Activation toward
Facile Synthesis of Ketene Dithioacetals
Authors: Xiaodong Shi, Xiaohan Ye, Jin Wang, Shengtao Ding,
Seyedmorteza Hosseyni, Lukasz Wojtas, and Novruz
Akhmedov
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To be cited as: Chem. Eur. J. 10.1002/chem.201702710
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10.1002/chem.201702710
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COMMUNICATION
Investigations on Gold Catalyzed Thioalkyne Activation toward
Facile Synthesis of Ketene Dithioacetals
Xiaohan Ye,†[a] Jin Wang,† [a] Shengtao Ding,† [a] Seyedmorteza Hosseyni, [a] Lukasz Wojtas, [a] Novruz G.
Akhmedov, [b] and Xiaodong Shi [a]*
Abstract: Nucleophilic addition to thioalkynes was investigated
under various catalytic conditions with gold(I) complexes being
identified as the optimal catalysts. Structural evaluation of the
product revealed an unexpected cis-addition, arising from a gold-
associated thioketene intermediate. Based on this interesting
investigations on gold-catalyzed thioalkyne activation. An
interesting cis-addition was identified, which suggested the
formation of a thioketene intermediate in the overall process.
Inspired by this mechanistic discovery, a general synthetic
strategy was developed for the synthesis of ketene dithioacetals
under mild conditions (Scheme 1C).
mechanistic insight,
a gold(I)-catalyzed thioether addition to
thioalkynes was developed as a novel approach to prepare ketene
dithioacetals with good yields and high efficiency.
A) Heteroatom-modified alkyne
R'
R'
+
•
X
R
[M]
Nucleophile
(reactions)
X
R
[M]
Sulfur-containing molecules are among the most important
compounds in chemical, material and bio-medicinal research.
Organosulfur compounds such as thiols and sulfides, in which
sulfur atoms possess a low oxidation state, are synthetically
versatile reactants as nucleophiles,[1] radical promoters,[2] and
reductants.[3] Despite the vast application of sulfides and thiols in
synthesis, utilizing these compounds in transition metal-
catalyzed transformations remains a challenging task, which is
largely due to the strong coordination of sulfur to the metal
center.[4]
X = S: limited examples
X = NR'' and O
well-developed;
various metal cat.
[M] = Ir, azide-alkyne cycloaddition, ref 8a;
Ru, hydrosilylation, ref 8b;
Au, no reports yet.
B) Challenges in thioalkyne activation
uncertain reactivity
[Au]+
R1
+
R2
R1
[L-Au]+
R1S
R2
S
R2
or
•
S
[Au]
Au
A
B
competing coordination;
thio-nucleophile
L
different activation modes; regioselectivity issues
C) This work: Au catalyzed thioalkyne activation utilizing different nucleophiles
O
Nu = C
Nu = S
PhS
Nu = O
SPh
n-Bu
n-Bu
SPh
O
O
[Au] cat.
H
The intrinsic reactivity of C-C triple bonds allows alkynes to
•
Nu
PhS
75%
n-Bu
5
]
occupy
a
privileged position in organic synthesis.[
n-Bu
PhS
64%, cis addition
Scheme 1. Gold catalyzed thioalkyne activation
n-Bu
cascade reaction,
60% for two steps
Functionalized alkynes bearing a heteroatom, such as N, O, P,
and S, connected directly to the triple bond are especially
intriguing, since these electron-rich heteroatoms will not only
make the triple bond more reactive by donating electron density
to the alkyne p-bond, but also provide valuable functional
handles in the resulting products.[6] Interestingly, compared with
the well-developed transformation of N/O-substituted alkynes,
reactions of thioalkynes are significantly less developed despite
the simple preparation of the thioalkyne substrates. This dearth
in reaction development is proposed to arise from undesired
sulfur coordination to the metal center, and the diminished
capability of sulfur’s 3p electrons to effectively conjugate with the
carbon 2p orbital of the alkyne p-system. Thus, studies of
thioalkyne towards A) elucidation of its reactivity and B)
development of effective transformations from this highly
functional building block are of great interest for general
chemical and biomedicinal research. Herein, we report our
The carbophilic nature of the Au cation makes it an
excellent catalyst for the activation of alkenes, allenes and, most
commonly, alkynes.[7] During the past decade, studies on gold-
catalyzed transformations involving ynamides (N-alkynes) have
grown tremendously due to their increased reactivity in
comparison with regular alkynes (Scheme 1A).[8] According to
the literature, only a few successful examples have been
reported that involve gold cation and substrates bearing sulfur-
containing moieties.[
Particularly, the activation of
9
][ 10 ]
thioalkynes using gold cations has not been reported. Some key
challenges of gold-catalyzed thioalkyne activation include the: A)
sulfur coordination to gold due to its nucleophilicity, preventing
the desired electrophilic activation of the alkyne; B) unknown
reactivity of the C-C triple bond due to the conjugation of sulfur’s
3p electrons to the alkyne p system, resulting in different
activation modes (Scheme 1B). Thus, investigations into the
gold-catalyzed activation of thioalkynes are not only practical for
the preparation of sulfur-containing compounds, but also
relevant towards providing mechanistic insight into the reactivity
of thioalkynes.
[a]
X. Ye,[+] J. Wang,[+] S. Ding,[+] S. Hosseyni, L. Wojtas and Dr. Prof.
X. Shi
Department of Chemistry
University of South Florida
Tampa, FL 33620, United States
E-mail: xmshi@usf.edu
We initiated our study by treating thioalkyne 1a with the
electron-rich carbon nucleophile 1,3-benzodioxzole 2a under
various metal-catalyzed conditions. 11 As shown in Table 1,
screening of reaction conditions (see detailed in SI) revealed the
important role of group XI metal cations (Cu, Ag and Au) in
promoting alkyne activation. Treating 1a and 2a with HOTf or
other metal catalysts, such as Pd, Ru, Rh, Ir and Pt, gave almost
no conversion of thioalkyne 1a, suggesting that the productive
[b]
Dr. N. G. Akhmedov
Department of Chemistry
West Virginia University
Morgantown, WV26505, United States
[+] These authors contribute equally to this work.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/chem.201702710
Chemistry - A European Journal
COMMUNICATION
activation of the thioalkyne towards carbo-nucleophilic addition
did not occur under these conditions. Conversely, the group XI
transition metal catalysts were able to effectively activate the
thioalkyne at elevated temperatures, as evidenced by the high
conversion of 1a when Cu, Ag or Au catalysts were employed.
Typically, nucleophilic addition towards gold activated
alkynes gives trans products. This arises due to formation of the
gold-alkyne π-complex and
a
subsequent outer-sphere
nucleophile trans addition. However, for the gold-catalyzed
thioalkyne activation, a mixture of cis and trans isomers were
observed, with cis-3a obtained as the major isomer (confirmed
by X-ray). In comparison with the silver-catalyzed reaction,
which afforded a cis/trans ratio of 3:1, the gold-catalyzed
conditions exhibited better cis/trans selectivity (up to 7:1). This
Table 1. Gold catalyzed C-nucleophile addition to thioalkyne
O
O
O
result suggested the formation of the sulfonium cation
A
O
PhS
PhS
H
O
O
cat.
12
2a
(Scheme 1B).
Reactions of other C-nucleophiles with
H
n-Bu
+
DCE
n-Bu
thioalkynes are shown in Table 2.
4a
PhS
n-Bu
PhS
n-Bu
PhS
H
1a
cis-3a
trans-3a
With electron-rich arenes, the desired addition products 3
were formed in moderate yields, and cis-isomers were the major
products in all cases. Less electron-rich substrates such as
anisol resulted in no addition products under the optimal
conditions. Furan and indole gave messy reactions. Alkyl
substituted thioalkynes (R = Me or n-Bu) also provided very low
conversion. Although the reaction scope is limited, this work is
the first successful example of carbon nucleophile addition to
yield of 3a
(cis:trans)
yield of 3a
convn.
of 1a (cis:trans)
convn.
of 1a[a]
conditions
conditions
HOTf (10%), 80 oC, 16 h
AgOTf (5%), 80 oC, 6 h
Cu(OTf)2 (5%), 80 oC, 16 h
XPhosAuNTf2 (5%)
<5% <5%
93% 47% (3:1)
rt or 40 oC, 16 h
80 oC, 10 h
80 oC, 16 h
<5%
70%
n.d.
100%
<10%
<5%
<5%
75% 45% (7:1) other [M], Ir, Ru, Rh, Pt etc.
[a] Conversion and yield were determined by 1H NMR using dimethylsulfone
as internal standard.
Interestingly, although 1a was converted completely (100%,
total consumption) when using Cu(OTf)2 as catalyst, the desired
C-nucleophilic addition product 3a was not observed. Using 5%
AgOTf as catalyst afforded the desired product 3a along with
significant 1a decomposition (93% convn. and 47% yield).
Finally, utilizing 5% of the gold catalyst XPhosAuNTf2 furnished
the desired 3a in 64% yield. Extending the reaction time from 10
h to 16 h resulted in diminished yields (45%) due to significant
decomposition of the product 3a under the reaction conditions.
In comparison with copper and silver, gold catalysts yielded the
optimal results due to better alkyne activation while minimizing
substrate/product decomposition. Solvent screening revealed
DCE (ClCH2CH2Cl) as the optimal solvent for this transformation.
thioalkynes under metal catalytic conditions.
provides a good platform to further explore the general reactivity
associated with the unique thioalkyne building block.
Moreover, it
To better understand the reaction mechanism, the
decomposition byproducts from the reactions were analyzed.
Interestingly, ketene dithioacetal 4a was identified as the major
sulfur-containing byproduct. To explore the origin of compound
4a, reactions of thiophenol addition to thioalkyne 1a were
performed as shown in Scheme 2A.
A) PhSH addition study
PhS
PhS
H
[PhS(AuL)2]+OTf-
6a: L = JohnPhos
5% XPhosAuOTf
n-Bu
PhS
n-Bu
DCE, 80 oC, 10 h
4a, 38%
1a
+
PhS
SPh
No [Au]
Table 2. Substrates scope for C-nucleophile addition to
thioalkyne[a][b]
PhSH
DCE, 60 oC, 4 h
H
n-Bu
X-ray 6a
4a', 63%, single Z-isomer
ref 11
PhS
n-Bu
PhS
Cy
Tol
S
n-Bu
PhS
t-Bu
O
Ar
5% XPhosAuNTf2
X
O
+
n-Bu
PhSH
3a not observed
DCE, 80 oC, 10 h
Ar:
PhS
n-Bu
5a
O
O
O
O
O
O
O
O
X-ray of 3d
3a, 62%
3b, 67%
3c, 35%
3d, 65%
E:Z=9:1
B) Proposed ketene dithioacetal synthesis: thioether addition to thioalkyne
E:Z= 7:1
E:Z=8:1
E:Z=8:1
p-Cl-C6H4
S
n-Bu
Tol S
t-Bu
p-Cl-C6H4
S
t-Bu
PhS
t-Bu
thioether as Nu?
Ar
R
S
[Au]
R
[Au]
+
S
ArS
R
Me
MeO
R' migration
Ar
S
•
Ph
n-Bu
PhS
n-Bu
O
O
O
O
Me
O
O
PhS
n-Bu
sulfonium A
ketene dithioacetal
3e, 45%
E:Z=6:1
3g, 34%
E:Z= 4:1
3f, 60%
E:Z=5:1
3h, 35%
E:Z=6:1
Scheme 2. Mechanistic study and proposed thioether addition
PhS
t-Bu
Reaction of thioalkyne 1a and PhSH with Au-catalyst gave
ketene dithioacetal 4a in 38% yield. This result is interesting
since the reaction between only thiophenol and thioalkyne 1a
gave 1,2-disulfide 4a’ (based on our experiment and previous
literature reports).[ 13 ] Monitoring the reaction with 31P NMR
revealed the formation of a new complex while treating PhSH
unsuccessful nucleophiles
unsuccessful thioalkynes
R
MeO
OMe
S
t-Bu
OMe
O
N
R = Me or n-Bu
MeO
3i, 70%
E:Z=18:1
[a] Reaction conditions: 5 mol% catalyst was added to a DCE solution (1.2
mL) of thioalkyne (0.2 mmol) and C-nucleophile (3 equiv.), and reaction was
kept at 80 oC for 10 h. [b] Isolated yield.
with various LAuOTf permutations.
The structure of this
complex was confirmed by X-ray as a sulfur-bridged bis-gold
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10.1002/chem.201702710
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COMMUNICATION
complex 6, [(PhS)(AuL)2]+OTf-. Using complex 6 as catalyst to
promote the reaction between 1a and 2a gave almost no
[a] Reaction conditions: 5 mol% catalyst was added to a DCE solution (0.6
mL) of thioalkyne (0.1 mmol) and thioether (1.2 equiv.), and reaction was kept
at 60 oC for 6 h. [b] Conversion and yield were determined by 1H NMR
spectroscopy using dimethylsulfone as internal standard.
conversion, implying that complex
6 was likely the gold
decomposition product instead of the effective catalyst in this
reaction. Additionally, the reaction between thiophenol (PhSH)
and internal alkyne 5a gave almost no conversion of both
starting materials under gold catalyzed conditions, which ruled
out PhSH addition to alkyne as potential reaction path for the
formation of 3a. Based on these results, it is reasonable to
rationalize that this reaction proceeded through sulfonium
intermediate A. The major decomposition path of thioalkyne
was through the dissociation of PhS-, which poisoned the gold
cation and gave rise to byproduct 4a likely by adding to the
sulfonium A.
As shown in Table 4, aryl sulfide derived aliphatic
thioalkyne in general provided good yield (7a-7e, 7l-7q), while
the alkyl sulfide derived aliphatic thioalkyne gave lower yield (7f-
7h). We believe the 1:1 E/Z regioselectivity is due to the thermal
equilibration of the product under gold catalytic conditions. As a
result, using the bulkier alkyl derived aromatic thioalkynes
increased the regioselectivity to 1.5:1, favoring the
thermodynamically more stable trans-alkene (7i-7k). More
sterically hindered allyl sulfides could also participate in this
reaction, as demonstrated in product 7r and 7s. Notably, the
formation of 7s was observed when treating the thioalkyne with
crotyl phenyl sulfide, suggesting that this reaction underwent an
SN2’ type rearrangement.
The employment of gold for the activation of thioalkynes is
important, as gold catalyst clearly altered the reactivity of the
thioalkyne to facilitate the formation of the ketene dithioacetal 4a
instead of the regioisomeric 1,2-disulfide alkene 4a’. To reduce
the impact of thiophenol-mediated gold decomposition, we
Table 4. Substrate scope for S-nucleophile addition to thioalkyne[a][b]
R''S
5% RuPhosAu(CH3CN)OTf
+
RS
R'
R''S
postulated that thiol ether (RSR’) could be used as a suitable
DCE, 60 oC, 6 h
RS
R'
7
14
nucleophile towards sulfonium A.
With an appropriate
migrating group as R’, ketene dithioacetal 7 may be prepared in
a single step. Notably, compound 7 represents a class of sulfur-
containing compounds that have been reported to react as enol
equivalents in aldol reactions,[15 ] and as Michael receptor in
radical cyclizations.[16 ] Furthermore, similar to dithianes, the
resulting dithioacetal exhibits potential synthetic utility as an
PhS
PhS
PhS
PhS
PhS
PhS
n-Bu
n-Bu
t-Bu
PhS
Cy
S-Php-Cl
n-Bu
7a, 75%
7c, 55%
7b, 76%
PhS
Me
7d, 80%
E/Z= 1:1
PhS
STol
PhS
i-PrS
PhS
n-BuS
7h, 50%
S
n-Bu
n-Bu
17
]
umpulong synthon.[
Currently, there are few synthetic
7e, 50%
E/Z= 1:1
7f, 45%
E/Z= 1:1
7g, 36%
E/Z= 1:1
E/Z= 1:1
strategies for the synthesis of these compounds, especially the
un-symmetrical substrates (two different RS groups).[18] The
proposed synthesis shown in Scheme 2B, if successful, will
provide a new strategy to access these compounds with high
efficiency. To test this reaction design, several thioethers
bearing alkyl, allyl, propargyl and benzyl at the R’ position were
prepared. These compounds were treated with thioalkyne 1a
under gold catalytic conditions. Gratifyingly, the reaction of
allylic thioether 8a and 1a gave the desired ketene dithioacetal
PhS
PhS
i-PrS
PhS
MeS
S
n-BuS
7i, 74%
E/Z= 2:1
Ph
Ph
Ph
PhS
n-Bu
7j, 77%
7k, 65%
E/Z= 1.5:1
7l, 70%
E/Z= 1:1
E/Z= 1.5:1
TolS
TolS
TolS
PhS
p-ClPhS
p-ClPhS
n-Bu
n-Bu
p-ClPhS
n-Bu
p-ClPhS
7p, 82%
t-Bu
7n, 79%
7o, 66%
7m, 72%
E/Z= 1:1
TolS
TolS
7q, 72%
PhS
PhS
PhS
PhS
7a in good yield. Other thioethers (8b, 8c and 8d) gave very low
19
conversion with no desired product detected.
After a
t-Bu
n-Bu
n-Bu
comprehensive screening of reaction conditions (see details in
SI), RuPhosAu(CH3CN)OTf (5%) was revealed as the optimal
catalyst to afford 7a in 75% isolated yield. Results from
alternative conditions are summarized in Table 3.
7r, 54%[c]
7s, 60%[d]
X-ray of 7p
[a] Reaction conditions: 5 mol% catalyst was added to a DCE solution (1.2
mL) of thioalkyne (0.2 mmol) and allyl sulfide (1.2 equiv.), and reaction was
kept at 60 oC for 6 h. [b] Isolated yield. [c] Crotyl phenyl sulfide was applied. [d]
2-Methylpropenyl phenyl sulfide was applied.
Table 3. Conditions of Au catalyzed thioether addition to thioalkyne[a]
We recently achieved the intermolecular addition of
propargyl alcohol to terminal alkyne utilizing triazole-gold
catalyst (TA-Au).[20] This result inspired us to investigate the
performance of thioalkyne in an analogous system. As shown in
Scheme 3A, the desire allene product 10a was obtained in 60%
yield with tiaozle-gold catalyst. We then compared the reactivity
of thioalkyne 1b and phenylacetylene by treating them with
equal amount of propargyl alcohol 9a. Only product 10a was
detected, with no indication of products derived from
phenylacetylene. This result suggested that by conjugating with
sulfur, the triple bond in thioalkyne became more reactive than
phenylacetylene towards nucleophilic attack.
R'=
PhS
n-Bu
8b
8c
8d
PhS
PhS
5% RuPhosAu(CH3CN)OTf
DCE, 60 o
1a
+
C
n-Bu
PhS
R'
7a
Ph
7a yield
75%
8a
Alternation from above conditions
none
1a convn[b]
>95%
>95%
>95%
>95%
<5%
5% Cu(OTf)2 instead of [Au]
5% AgOTf instead of [Au]
[Au] = IPrAuNTf2
39%
49%
60%
8b, 8c, 8d
<5%
Other catalysts: Pd, Ir, Ru, Rh, Pt, HOTf
<20%
<5%
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10.1002/chem.201702710
Chemistry - A European Journal
COMMUNICATION
A) O-nucleophile addition to thioalkyne
[Au]+
SMe
Ph
Ph
Chem. Int. Ed. 2012, 51, 6209; e) T. J. Montavon, Y. E. Turkmen, N. A.
Shamsi, C. Miller, C. S. Sumaria, V. H. Rawal, S. A. Kozmin, Angew.
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O
•
Ph
HO
9a
JohnPhosAu(TA)OTf
DCE, 60 oC, 16 h
O
+
MeS
Ph
Ph
MeS
Ph
1b
10a, 60%
B) Competition study between terminal alkyne and thioalkyne
Ph
H
Ph
O
•
SMe
Ph
OH
1.0 eq
O
•
same condition
Ph
Ph
+
Ph
or
9a, 1.0 eq.
MeS
[7]
a) A. S. K. Hashmi, G. J. Hutchings, Angew. Chem. Int. Ed. 2006, 45,
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O
Ph
1b, 1.0 eq
Ph
ref 20
not detected
10a, 36%
Ph
Scheme 3. Propargyl alcohol addition to thioalkyne
In summary, for the first time we successfully disclosed the
possibility of gold-catalyzed intermolecular functionalization of
thioalkynes. With the proper choice of gold catalysts, different
nucleophiles could be used to afford trisubstituted alkenyl
sulfides, ketene dithioacetal and allenyl thioesters efficiently.
These newly synthesized products are a range of highly
functionalized sulfur-containing compounds whose previous
syntheses are not straightforward. Sulfur is both advantageous
[8]
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Z. F. Mao, X. L. Huang, Org. Lett. 2015, 17, 30.
and
deleterious
in
homogeneous
gold-catalyzed
functionalization of thioalkynes. Although the sulfur-containing
substrate can poison the gold catalyst by forming stable
deactivated complexes, it enhances the reactivity of the triple
bond and promotes formation of sulfonium intermediate A. Thus,
this reported transformations represent novel methodologies to
functionalize thioalkynes, and serve as the foundation for the
development of other gold-catalyzed reactions involving sulfur.
[9]
a) L. Song, S. Ding, Y. Wang, X. Zhang, Y. Wu, J. Sun, J. Org. Chem.
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We are grateful to the NSF (CHE-1619590), NIH
(1R01GM120240-01) and NSFC (21629201) for financial
support.
Keywords: gold· thioalkyne· thio-ketene · ketene dithioacetal
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Entry for the Table of Contents
COMMUNICATION
Xiaohan Ye,† Jin Wang,† Shengtao
Ding,† Seyedmorteza Hosseyni , Lukasz
Wojtas, Novruz G. Akhmedov, and
Xiaodong Shi*
Page No. – Page No.
Investigations on Gold Catalyzed
Thioalkyne Activation toward Facile
Synthesis of Ketene Dithioacetals
Nucleophilic addition to thioalkynes was investigated under various catalytic
conditions with gold(I) complexes being identified as the optimal catalysts.
Structural evaluation of the product revealed an unexpected cis-addition, arising
from
a gold-associated thioketene intermediate. Based on this interesting
mechanistic insight, a gold(I)-catalyzed thioether addition to thioalkynes was
developed as a novel approach to prepare ketene dithioacetals with good yields
and high efficiency.
This article is protected by copyright. All rights reserved.