Gold-catalyzed C-S bond formation from thiols

Article abstract of DOI:10.1016/j.tetlet.2009.11.025

ortho-Alkynylbenzoic acid alkyl esters act as alkylating agents of thiol derivatives with PPh₃AuCl in combination with AgOTf in 1,2-dichloroethane at 80 °C. The corresponding sulfide compounds are obtained in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2009.11.025

Tetrahedron Letters 51 (2010) 378–381
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Gold-catalyzed C–S bond formation from thiols
b
Mickaël Jean a, Jacques Renault a, Pierre van de Weghe a, , Naoki Asao
*
a EA Substances Lichéniques et Photoprotection, Faculté des Sciences Biologiques et Pharmaceutiques, Université de Rennes 1, 2 Avenue du Prof. Léon Bernard, F-35043 Rennes, France
b Department of Chemistry and Research and Analytical Center for Giant Molecules, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
ortho-Alkynylbenzoic acid alkyl esters act as alkylating agents of thiol derivatives with PPh3AuCl in com-
bination with AgOTf in 1,2-dichloroethane at 80 °C. The corresponding sulfide compounds are obtained in
good to excellent yields.
Received 1 October 2009
Revised 2 November 2009
Accepted 9 November 2009
Available online 12 November 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Gold catalysis
Substitution
Sulfide
During the last decade, the use of homogenous gold catalysts for
organic transformations has enjoyed tremendous popularity
among chemists working in the field of catalysis and organic syn-
thesis.1 To date, gold complexes have been employed for efficient
C–C, C–N, C–S, and C–O bond-forming reactions. Since aryl or alkyl
thioethers were known to be important for many biologically ac-
tive and pharmaceutical compounds,2 the formation of C–S bonds
received much attention.3 Many catalytic systems using transition
metals have been studied for the preparation of aryl thioethers
such as palladium,4 nickel,5 copper,6 indium,7 and iron8 in combi-
nation with ligands and bases. Other methods without the use of
transition metals were also described to obtain alkyl sulfides.9
Although gold salts and thiols were shown to have a good affinity,
to our knowledge only one work was reported describing the addi-
tion of thiols to allenes corresponding to a gold-catalyzed cycloiso-
phenol 2a could be carried out in the presence of 5 mol % PPh3AuCl
and 5 mol % AgOTf in 1,2-dichloroethane at 80 °C to afford the iso-
coumarin 3a and the thioether 4a in 95% and 85% yields, respec-
tively (Table 1, entry 1). In the absence of either PPh3AuCl or
AgOTf, no reaction occurred. Having found a satisfactory system,
we turned our attention to the scope of this reaction. The results
are reported in Table 1. The benzylation of various thiophenol
derivatives worked well, the thioethers 4 being isolated in good
yields along with a nearly quantitative yield of isocoumarin 3a.
On the other hand the benzylation of the phenethyl thiol afforded
the thioether 4e in low yield and no reaction took place with the n-
decanethiol probably due to its low reactivity.10b
To overcome this drawback, we decided to study the influence
of the electronic density of the alkynyl group of 1 (Table 2). Having
a plausible mechanism in mind (Scheme 2),11 we thought that
increasing the affinity of the gold cationic species for the triple
bond could promote the formation of the zwitterionic intermediate
A allowing a better electrophilic transfer of the group R1 to the
thiol. Various o-alkynylbenzoic acid benzyl ester have been pre-
pared and treated with 1.1 equiv of phenethyl thiol 2e in the pres-
ence of 10 mol % PPh3AuCl and 10 mol % AgOTf in dichloroethane
at 80 °C. Best yields of thioether 4e were obtained when the o-alky-
nylbenzoic acid alkyl ester possessed an electron-rich alkynyl part
merization of
a
-thioallenes to 2,5-dihydrothiophenes.10 In this
Letter, we report our efforts to prepare various aryl or alkyl sulfide
derivatives from thiols by the use of a combination of triphenyl-
phosphine gold chloride and silver triflate as catalytic system.
Recently, one of us described an efficient gold-catalyzed ether-
ification of alcohol using o-alkynylbenzoic acid alkyl ester as an
electrophile, and the reaction proceeding through a gold-induced
construction of leaving group and subsequent nucleophilic at-
tack.11 Relying on these previous results, we felt that this concept
could be used to prepare sulfide derivatives from thiols as nucleo-
philes (Scheme 1).
O
O
The preliminary studies have revealed that the reaction of o-
OR1
O
[Au]
[Ag]
pent-1-ynylbenzoic acid benzyl ester12 1a with 1.1 equiv of thio-
+
HSR3
+
R1SR3
R2
1
2
3
4
R2
* Corresponding author. Tel.: +33 (0)2 23 23 38 03; fax: +33 (0)2 23 23 44 25.
E-mail address: pierre.van-de-weghe@univ-rennes1.fr (P. van de Weghe).
Scheme 1. Gold-catalyzed sulfides synthesis.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.11.025

M. Jean et al. / Tetrahedron Letters 51 (2010) 378–381
379
Table 1
O
O
O
+ R1SR3
First results of sulfide formation
OR1
[Au]
O
O
4
5 mol% PPh3AuCl
1
R2
OBn
O
5 mol% AgOTf
3
R2
+ HSR3
+ BnSR3
ClCH2CH2Cl
15 h, 80 °C
Pr
OR1
O
1a
2
3a
4
Pr
R3SH
Entry
2
R3
Yield (3a) (%)
4
Yield (4) (%)
OR1
O
2
1
2
3
4
5
6
7
2a
2b
2c
2d
2e
2e
2f
C6H5
95
4a
4b
4c
4d
4e
4e
4f
85
79
93
96
R2
4-CH3–C6H4
4-Cl–C6H4
4-CH3O–C6H4
C6H4CH2CH2
C6H4CH2CH2
C10H21
90
94
100
28
R2
[Au]
A
[Au]
28
44
45a
n.d.b,c
n.d.c
Scheme 2. Plausible mechanism.
a
b
c
10 mol % PPh3AuCl, 10 mol % AgOTf.
Conversion <20%.
n.d. = not determined.
O
10 mol% PPh3AuCl
10 mol% AgOTf
+ C10H21SH
(entries 5 and 6). However the reaction seems sensitive to the ste-
ric hindrance, the presence of a methoxy group in the ortho posi-
tion decreasing slightly the yield (entry 6). This shows the
importance of the substituent R2 on the efficiency of the reaction.
Using the o-[2-(4-methoxyphenyl)ethynyl]benzoic acid benzyl
ester 1e as alkylating agent in the presence of 1.1 equiv n-decane-
thiol 2f in our catalytic system, the thioether 4f was isolated in 37%
yield. Interestingly, when 3.0 equiv of 2f was employed the chem-
ical yield was improved significantly and 4f was obtained in 86%
yield along with 89% yield of isocoumarin 3e (Scheme 3).
OBn
3e + C10H21SBn
ClCH2CH2Cl
15 h, 80 °C
1e
2 = 4-CH3O-C6H4
2f
4f
R2
1.1 equiv
3.0 equiv
37% yield
86% yield
R
Scheme 3. Benzylation of n-decanethiol 2f.
We next investigated the scope of this gold-catalyzed alkylation
of thiols. The results are reported in Table 3. As expected the ben-
zylation of various thiophenol derivatives led to the thioethers in
high yields (91–99%, entries 1–5). On the other hand the n-butyl
transfer to thiophenol derivatives afforded the thioethers in satis-
factory but in lower yields (54–80%, entries 6–13). In general, the
reaction was unaffected by electronic factor of the aryl group.
We also examined the formation of dialkyl sulfides. Using
10 mol % PPh3AuCl and 10 mol % AgOTf the reaction also furnished
the sulfides 4s and 4t but the yields were low (17–42%, entries 14–
16). Unsatisfactory results were observed when we tried to trans-
fer an iso-propyl group to the thiophenol 2a. Although the iso-
coumarin 3e was quantitatively isolated, the resulting thioether
4u was obtained in very low yield (24%, entry 17). In the case of
a cyclohexyl moiety, only the isocoumarin 3e was formed and no
thioether was observed. The reaction proceeding probably via a
SN1 mechanism,11 the carbocationic species decomposed in these
Table 3
Evaluation of the scope of thioether formation
O
5 mol% PPh3AuCl
OR1
5 mol% AgOTf
+ HSR3
3e + R1SR3
ClCH2CH2Cl
15 h, 80 °C
1
2
4
OCH3
1e = R1 = Bn
1g = R1 = nBu 1i = R1 = CH(iBu)2
1h = R1 = iPr 1j = R1 = CH(CH2Ph)2
Entry
1
2
R3
4
Yield (4) (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
1e
1e
1e
1e
1e
1g
1g
1g
1g
1g
1g
1g
1g
1g
1g
1g
1h
1i
2d
2g
2h
2i
4-CH3O–C6H4
3-CF3–C6H4
3-Br–C6H4
4-Br–C6H4
2-Naphthyl
C6H5
4-CH3–C6H4
4-Cl–C6H4
4-CH3O–C6H4
3-CF3–C6H4
3-Br–C6H4
4-Br–C6H4
2-Naphthyl
C6H4CH2CH2
C6H4CH2CH2
C10H21
4d
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
93
94
99
99
91
65
68
80
54
72
75
70
2j
2a
2b
2c
2d
2g
2h
2i
Table 2
Electronic effect of the alkynyl group
O
10 mol% PPh3AuCl
OBn
10 mol% AgOTf
2j
65
+ HSCH2CH2Ph
3 + BnSCH2CH2Ph
2ea
2ea
2fa
2a
2a
2a
4s
4s
4t
25b,c
42b,d,e
17b,f
24g
55
ClCH2CH2Cl
15 h, 80 °C
R2
1
2e
4e
C6H5
C6H5
C6H5
4u
4vh
4wh
Entry
1
R2
Yield (4e) (%)
28a,b
18a,b
37b
46b
75c
1j
82
1
2
3
4
5
6
1b
1c
1d
1a
1e
1f
4-NO2–C6H4
4-CF3–C6H4
C6H5
a
b
c
3.0 equiv of 2.
10 mol % PPh3AuCl, 10 mol % AgOTf.
60% conversion.
PhCl used as a solvent.
70% conversion.
50% conversion.
Pr
4-CH3O–C6H4
2,4-(CH3O)2–C6H3
d
e
f
61c
a
b
c
Isolation of a mixture of isocoumarin and isobenzofuranone in 20% yield.
Incomplete reaction.
>95% yield of isocoumarin 3.
g
h
>95% yield of 3e.
See structure Fig. 1.

380
M. Jean et al. / Tetrahedron Letters 51 (2010) 378–381
Table 4
Competitive reaction
10 mol% PPh3AuCl
10 mol% AgOTf
1e + Ph(CH2)2SH + Ph(CH2)2OH
3e + Ph(CH2)2SBn + Ph(CH2)2OBn
ClCH2CH2Cl
15 h, 80 °C
2e
2f
4e
4x
Entry
1e (equiv)
2e (equiv)
2f (equiv)
Yield (4e) (%)
Yield (4x) (%)
1
2
3
1.0
1.0
1.0
1.0
0
1.0
0
1.0
1.0
75
—
51
—
70
26
reaction conditions faster than its reaction with 2a. The SN1 mech-
anism was also consolidated when the thiophenol 2a was treated
with the esters 1i and 1j. In each case the carbocationic secondary
alkyl group, generated from the species A, rearranges in a more sta-
ble tertiary carbocation before its reaction with 2a to afford 4v and
4w in good yields (55 and 82%, respectively, entries 18–19) (Fig. 1).
A competitive reaction was also conducted to determine the
chemoselectivity between the alkylation of an alcohol and a thiol.
The o-[2-(4-methoxyphenyl)ethynyl]benzoic acid benzyl ester 1e
was placed with 1.0 equiv phenethyl alcohol 2f and 1.0 equiv
phenethyl thiol 2e in the presence of the gold/silver catalytic sys-
tem (Table 4). While the reaction of benzylation of the alcohol 2f
gave similar yield as the reaction with the thiol 2e, surprisingly
we obtained the thioether 4e as a major product in the competitive
reaction, 4e being isolated with 51% yield and the ether 4x with
26% yield (entry 3).13 In a similar manner, a competitive reaction
was realized between phenol and thiophenol. Only the benzylation
of the thiophenol was observed. However after a control experi-
ment we noticed the absence of reactivity of phenol in these reac-
tion conditions.
On the one hand the use of the disulfide allows the obtaining of
the thioether and on the other hand it leads to a functionalized iso-
coumarin. This last point could be later used to prepare new func-
tionalized isocoumarin derivatives.15
In conclusion, we have described a gold-catalyzed C–S bond for-
mation from various thiols. The reaction proceeded with PPh3AuCl
in combination with AgOTf as a catalytic system in 1,2-dichloro-
ethane at 80 °C via an activation of leaving group. This procedure
was shown to furnish arylalkyl sulfides in good to high yields but
afforded dialkyl sulfides in low yields. Further investigations of
the scope as well as synthetic applications are currently in progress
and will be reported in due course.
Acknowledgments
This work was supported by the Université de Rennes 1, the
Région Bretagne and Rennes Metropole. One of us, Professor Naoki
Asao, thanks the Université de Rennes 1 for financial support dur-
ing his stay as visiting professor at the Université de Rennes 1.2
We were also curious to see if our methodology could be
extended to disulfides as synthetic equivalents of thiols.14 The
o-[2-(4-methoxyphenyl)ethynyl] benzoic acid benzyl ester 1e and
diphenyl disulfide 2k were treated with 5 mol % PPh3AuCl and
5 mol % AgOTf in 1,2-dichloroethane at 80 °C for 15 h, the expected
thioether 4a was isolated in a satisfactory yield (Scheme 4). Besides
4a, a mixture of the usual isocoumarin 3e and a functionalized iso-
coumarin 3i was obtained in 2:3 ratio, 3i being isolated in 48% yield.
A heterolytic cleavage of the disulfide 2k occurred probably, one
moiety acting as a nucleophile to afford 4a and the second moiety
playing the role of an electrophile to cleave the gold-carbon bond
in the intermediate A (Scheme 2). This result appears interesting.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.11.025.
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5 mol% AgOTf
O
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Scheme 4. Thioether formation from diphenyl disulfide 2k.

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