Atom-efficient gold(I)-chloride-catalyzed synthesis of α-sulfenylated carbonyl compounds from propargylic alcohols and aryl thiols: Substrate scope and experimental and theoretical mechanistic investigation

Article abstract of DOI:10.1002/chem.201302485

Gold(I)-chloride-catalyzed synthesis of α-sulfenylated carbonyl compounds from propargylic alcohols and aryl thiols showed a wide substrate scope with respect to both propargylic alcohols and aryl thiols. Primary and secondary aromatic propargylic alcohol

Full text of DOI:10.1002/chem.201302485

FULL PAPER
DOI: 10.1002/chem.201302485
Atom-Efficient Gold(I)-Chloride-Catalyzed Synthesis of a-Sulfenylated
Carbonyl Compounds from Propargylic Alcohols and Aryl Thiols: Substrate
Scope and Experimental and Theoretical Mechanistic Investigation
Srijit Biswas,[a] Christian Dahlstrand,[a] Rahul A. Watile,[a] Marcin Kalek,[b]
Fahmi Himo,*[b] and Joseph S. M. Samec*[a]
Abstract:
Gold(I)-chloride-catalyzed
two separate steps. A sulfenylated al-
lylic alcohol, generated by initial regio-
selective attack of the aryl thiol on the
triple bond of the propargylic alcohol,
was isolated, evaluated, and found to
be an intermediate in the reaction.
Density functional theory (DFT) calcu-
lations showed that the observed regio-
selectivity of the aryl thiol attack to-
wards the 2-position of propargylic al-
cohol was determined by a low-energy,
five-membered cyclic protodeauration
transition state instead of the strained,
four-membered cyclic transition state
found for attack at the 3-position. Ex-
perimental data and DFT calculations
supported that the second step of the
reaction is initiated by protonation of
the double bond of the sulfenylated al-
lylic alcohol with a proton donor coor-
dinated to gold(I) chloride. This in turn
allows for a 1,2-hydride shift, generat-
ing the final product of the reaction.
synthesis of a-sulfenylated carbonyl
compounds from propargylic alcohols
and aryl thiols showed a wide substrate
scope with respect to both propargylic
alcohols and aryl thiols. Primary and
secondary aromatic propargylic alco-
hols generated a-sulfenylated alde-
hydes and ketones in 60–97% yield.
Secondary aliphatic propargylic alco-
hols generated a-sulfenylated ketones
in yields of 47–71%. Different gold
sources and ligand effects were studied,
and it was shown that gold(I) chloride
gave the highest product yields. Experi-
mental and theoretical studies demon-
strated that the reaction proceeds in
Deuterium
labeling
experiments
showed that the protons from the prop-
argylic alcohol and aryl thiol were
transferred to the 3-position, and that
the hydride from the alcohol was trans-
ferred to the 2-position of the product.
Keywords: gold
·
homogeneous
catalysis · reaction mechanisms ·
sulfenylation · synthetic methods
Introduction
be found in anti-infective, anti-tumor, anti-inflammatory,
and nervous-system agents.[2,3]
À
Formation of C S bonds is a fundamental transformation in
The carbonyl group of a-sulfenylated carbonyl com-
pounds can easily be transformed into other functional
groups such as alcohol, imine, amine, and cyanohydrin. Al-
ternatively, the sulfur atom can be oxidized, producing the
corresponding b-carbonyl sulfoxides, which are important
starting materials for biotransformation to produce chiral b-
organic synthesis. Sulfur-containing compounds have biolog-
ical activity and thus have applications in the pharmaceuti-
cal and agrochemical industries.[1] Compounds with a thio
group in the position alpha to a carbonyl group are referred
to as a-thio- or a-sulfenylated carbonyl compounds and can
[a] Dr. S. Biswas, Dr. C. Dahlstrand, R. A. Watile,
Prof. Dr. J. S. M. Samec
Department of Chemistry, BMC, Uppsala University
Box 576, 75123, Uppsala (Sweden)
Fax : (+46)018-471-3818
E-mail: joseph.samec@kemi.uu.se
[b] Dr. M. Kalek, Prof. Dr. F. Himo
Department of Organic Chemistry, Stockholm University
10691, Stockholm, Sweden
E-mail: himo@organ.su.se
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201302485.
ꢀ 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co.
KGaA. This is an open access article under the terms of the Creative
Commons Attribution Non-Commercial NoDerivs License, which
permits use and distribution in any medium, provided the original
work is properly cited, the use is non-commercial and no modifica-
tions or adaptations are made.
Chem. Eur. J. 2013, 19, 17939 – 17950 ꢀ 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
17939

hydroxy sulfoxides.[4] These types of sulfone derivatives have
potential anti-infective activity.[5] Various b-amino thioether
compounds, which could easily be synthesized by functional
group interconversion of a-sulfenylated carbonyl com-
pounds, are reported to be apoptosis promoters;[6] their
enantiomerically pure isomers are also widely employed as
chiral ligands in asymmetric catalysis.[7] Moreover, in synthe-
sis, a-sulfenylated carbonyl compounds[8] are used for the
mono- and dialkylation of carbonyl compounds,[8d] prepara-
tion of 1,2-dicarbonyl compounds by disulfenylation,[8f] 1,2-
carbonyl transposition,[8g] and for the synthesis of a,b-unsat-
Scheme 2. Traditional synthesis of a-sulfenylated carbonyl compounds.
ACHTUNGTRENNUNG
urated carbonyl compounds (Scheme 1).[8h] These classes of
pounds and in the subsequent substitution reaction to gener-
ate the a-sulfenylated carbonyl products. Moreover, the re-
active a-halo carbonyl intermediates are known warfare
agents, for example, tear gas.[15] Alternatively, a-sulfenylated
carbonyl compounds are synthesized by the reaction of a car-
bonyl compound or a preformed enolate with sulfenylating
agents such as disulfides, N-(phenylsulfanyl)succinimides,
and sulfenyl chlorides (Scheme 2, route B).[16] This alterna-
tive route also suffers from severe limitations of multiple re-
action steps, toxicity, difficulty in handling intermediates,
and low atom efficiency.
In recent years, stoichiometric versions of electrophilic
asymmetric a-sulfenylation,[17] as well as catalytic asymmet-
ric transformations employing organocatalysts[18] and enan-
tiopure titanium(IV) or nickel(II) complexes,[19] have been
reported. These synthetic methods generally suffer from
Scheme 1. a-Sulfenylated carbonyl compounds as important synthetic in-
termediates. a) Preparation of 1,2-dicarbonyl compounds by disulfenyla-
tion (ref. [8f]); b) traditional sulfur oxidation; c) mono- and dialkylation
(ref. [8d]); d) biotransformation to chiral b-hydroxy sulfoxides (ref. [4]);
e) synthesis of a,b-unsaturated carbonyl compounds (ref. [8f]); f) tradi-
tional imine formation through carbonyl–imine condensation; g) reduc-
tive removal of sulfur substituent (ref. [8i]).
stoiACTHUNRTGNEUNGchiometric use of toxic and expensive catalysts, waste
generation, long reaction times, and/or low product yields
with limited substrate scope. Therefore, an efficient, atom-
economical,[20] and sustainable method to synthesize a-sulfe-
nylated carbonyl compounds from readily available, simple
starting materials is desirable.
compounds are employed as starting materials to synthesize
butenolides[9] as well as in silyl carbonyl chemistry for regio-
and stereoselective synthesis of the corresponding enol silyl
ethers[10] and oxetanes.[11] The sulfur substituent alpha to the
carbonyl group can be reductively removed, making these
compounds convenient precursors for acylations and alkyla-
tions.[8f] Substituted a-sulfenylated carbonyl compounds also
serve as starting materials for the synthesis of 2-halobenyl-3-
arylbenzo[b]thiophene ethers, which act against breast
cancer MCF7 cells, indicating antiproliferative activity
against estrogen-dependent neoplasms.[12] Moreover, these
types of compounds are used as starting materials for the
preparation of therapeutically useful tumor-necrosis-factor-
a-converting enzyme (TACE)-inhibitors, such as imidazoli-
dinedione,[13] and photochromic compounds, such as thieno-
2H-chromene derivatives.[14]
During a study on catalytic substitution of propargylic al-
cohol with thiophenol[21] all screened catalysts except gold
gave the expected thioether product by direct substitution
of the hydroxyl group. Surprisingly, a different reactivity
was observed in the presence of Au catalyst. Instead of the
expected thioether, the corresponding a-sulfenylated car-
bonyl product was observed (Scheme 3). The initial findings
on this transformation were published in a recent communi-
cation.[22] As an extension of this work, we herein report on
the detailed scope and limitations of the regioselective sulfe-
nylation of propargylic alcohols with gold catalysts. An ex-
perimental and theoretical mechanistic study on this trans-
formation was also performed.
Traditionally, a-sulfenylated carbonyl compounds are pre-
pared by SN2 displacement of the corresponding a-halogen-
ated carbonyl compounds by sulfide anions (Scheme 2,
route A).[8] These reactive intermediates must be prepared
in separate reaction steps. This is often associated with the
generation of stoichiometric amounts of chemical waste
both in the preparation of the a-halogenated carbonyl com-
Scheme 3. Unique reactivity of gold catalyst.
17940
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Synthesis of a-Sulfenylated Carbonyl Compounds
FULL PAPER
Results and Discussion
(Table 1, entry 15).[22] A further increase in the amount of
2a to two equivalents did not increase the conversion to 3a
(Table 1, entry 16). Substituting 1,2-dichloroethane (DCE)
by nitromethane (MeNO2) increased the efficiency of the re-
action to generate 97% of 3a (Table 1, entry 17). Moreover,
nitromethane is a nonhalogenated solvent having a higher
boiling point than 1,2-dichloroethane. In contrast to the pre-
vious report, we chose nitromethane as solvent in the pres-
ent study instead of 1,2-dichloroethane to obtain a better
yield of the product, especially when aliphatic propargylic
alcohols were employed as substrates at higher reaction
temperature.[26] Chloroform and acetonitrile gave poor re-
sults (Table 1, entries 18–19), and no reaction was observed
in toluene (Table 1, entry 20).
The optimized reaction conditions were applied to differ-
ent substrates having an aromatic group in the R1 position
(Table 2). The reaction was general with respect to the aro-
matic propargylic alcohols. Both primary and secondary
propargylic alcohols were employed to produce the desired
a-sulfenylated ketones and aldehydes in high yields. Secon-
dary alcohols with different aliphatic groups at the R2 posi-
tion reacted smoothly to produce the corresponding a-sulfe-
nylated products (Table 2, entries 1–4). The reactions also
showed high generality for the aryl group at the R1 position
of the alcohol. Excellent yields of the products were ob-
served for alcohols with a 1-naphthyl group at the R1 posi-
tion (Table 2, entries 7 and 10). The effect of substituents of
the phenyl ring at the R1 position of the alcohol was investi-
gated. Electron-withdrawing substituents such as 4-phenyl
and 3,4-dichloro resulted in 89 and 95% of 3 f and 3h, re-
spectively (Table 2, entry 6 and 8), whereas a 4-methyl sub-
stituent led to 3e in 87% yield (Table 2, entry 5). 1,3-Diphe-
nylprop-2-yn-1-ol with a phenyl ring in both R1 and R2 posi-
tions did not react with thiophenol to yield the desired prod-
uct under the present reaction conditions. Aryl thiols with
different substituents in the para position of the aryl group
were studied (Table 2, entries 12–25). 4-Chlorobenzenethiol
(2b) and 4-bromobenzenethiol (2c) reacted smoothly with
different primary and secondary propargylic alcohols to
form the products in high yields (Table 2, entries 12–17).
Carrying out the reaction at reflux for 48 h was required for
reactions involving aryl thiols with electron-withdrawing
substituents at the para position of the phenyl ring. Thus, 4-
fluorobenzenethiol (2d) gave 80–86% yield of product
(Table 2, entries 18–20,) whereas N-(4-mercaptophenyl)ace-
For optimization of the reaction conditions, 4-phenylbut-3-
yn-2-ol (1a) and thiophenol (2a) were chosen as model sub-
strates. Different gold sources and additives were screened
in the transformation of 1a and 2a into the a-sulfenylated
carbonyl product 3a in different solvents at 658C (Table 1).
Table 1. Optimization of reaction conditions.[a]
Entry Catalyst ([mol%])
Equiv Solvent Yield[b]
of 2a
[%]
DCE[c] 11
1
2
3
4
5
6
7
8
AuBr3 (5)
AuI (5)
AuSPh (5)
1
1
1
DCE[c] 32
DCE[c] 29
DCE[c] 21
DCE[c] 0[e]
DCE[c] 29
MeNO2 47
MeNO2 0[e]
MeNO2 0[e]
MeNO2 0[e]
DCE[c] 65
DCE[c] 69
DCE[c] 69
DCE[c] 79
DCE[c] 93
DCE[c] 92
MeNO2 97
(PPh3)AuCl (5)
1
(PPh3)AuCl (5)+AgSbF6 (10)
1
1
1
1
AuCl (5)+NHC (5)[d]
AuCl (5)+NHC (5)[d]
AuCl (5)+NHC (5)[d] +Ag
A
9
AuCl (5)+NHC (5)[d] +AgSbF6 (10)
1
10
11
12
13
14
15
16
17
18
19
20
Ag
(OTf) (5)
1
NaAuCl4·2H2O (5)
AuCl (10)
AuCl (2)
1
1
1
AuCl (2)
AuCl (2)
AuCl (2)
AuCl (2)
AuCl (2)
AuCl (2)
AuCl (2)
1.2
1.5
2
1.5
1.5
1.5
1.5
CHCl3
MeCN 42
PhCH3
40
0
[a] Reaction conditions: 1a (1 mmol), 2a (1 mmol), and the catalyst were
heated at 658C in 2.5 mL of solvent for 24 h. [b] NMR yield with toluene
as internal standard. [c] DCE: 1,2-dichloroethane. [d] NHC: 1,3-bis(2,6-
diisopropylphenyl)imidazol-2-ylidene. [e] Formation of a new product re-
sulting from Meyer–Schuster rearrangement followed by Michael addi-
tion of thiophenol was observed.
When a 1:1 mixture of 1a and 2a reacted in the presence
of 5 mol% of goldACHTUNGTRENNUNG(III) bromide, only 11% product forma-
tion was observed after 24 h (Table 1, entry 1), whereas,
gold(I) iodide and gold(I) thiophenolate[23] gave 32 and
29% product, respectively (Table 1, entries 2 and 3) in 1,2-
dichloroethane. Attempts to increase the efficiency of the
catalysis by adding different ligands to the reaction mixture
were unsuccessful (Table 1, entries 4–9). No a-sulfenylated
product 3a was formed on addition of AgSbF6 to the
(PPh3)AuCl catalyst (Table 1, entry 5). Instead, a different
product resulted from Meyer–Schuster rearrangement of 1a
followed by Michael addition of 2a.[24] Also, an N-heterocy-
clic carbene ligand and silver additives were tested, but gave
poor results (Table 1, entries 6–9). Using only silver(I) tri-
fluoromethanesulfonate as catalyst also led to Meyer–Schus-
ter rearrangement followed by Michael addition (Table 1,
entry 10). Increased conversion to 3a was observed when
the reaction was performed with 2 mol% of gold(I) chloride
catalyst and 1.5 equivalents of 2a with respect to 1a
tamide (2e) generated 3u in
a 67% yield (Table 2,
entry 21). Aryl thiols with electron-donating groups such as
4-methoxyl (2 f) and 4-isopropyl (2g) gave the products 3v–
3y in lower yields (Table 2, entries 22–25), whereby signifi-
cant formation of disulfides as side products was ob-
served.[25] Attempts to use aliphatic thiols were unsuccessful
under the present reaction conditions, and no product for-
mation was observed.
Propargylic alcohols with different aliphatic groups at the
R1 positions were also studied (Table 3, entries 1–6). Ali-
phatic alcohols generally showed lower reactivity than aro-
matic alcohols, and an increased catalyst loading to 5 mol%
Chem. Eur. J. 2013, 19, 17939 – 17950 ꢀ 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.chemeurj.org
17941

F. Himo, J. S. M. Samec et al.
Table 2. a-Sulfenylated carbonyl compounds from aromatic propargyl al-
Table 2. (Continued)
cohols.[a]
Entry Alcohol 1
Thiol 2
Product 3
Yield[b]
[%]
4-iPr-C6H4-SH
2g
24
25
1i
78
73
Entry Alcohol 1
Thiol 2
Product 3
Yield[b]
[%]
1a
2g
Ph-SH
2a
1
94
[a] Reaction conditions: 1 (1 mmol), 2 (1.5 mmol), and AuCl (2 mol%)
were heated at 658C in 2.5 mL of nitromethane for 24 h. [b] Yield of iso-
lated product. [c] Reactions at 1008C for 48 h.
2
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
93
3
92
Table 3. a-Sulfenylated carbonyl compounds from aliphatic propargyl al-
cohols.[a]
4
88
5
87
Yield[b]
[%]
6
89
Entry
Alcohol 1
Product 4
7
97
1
2
3
4
5
6
71
8
95[c]
95
70
9
10
11
97
63[c]
71
89
4-Cl-C6H4-SH
2b
12
13
14
15
16
17
18
19
20
21
22
23
1i
92
1a
1b
1i
2b
2b
90
67
90
47
4-Br-C6H4-SH
2c
88
[a] Reaction conditions: 1 (1 mmol), 2 (3 mmol), and AuCl (5 mol%)
were heated at 1008C in 2.5 mL of nitromethane for 72 h. [b] Yield of
isolated product. [c] Three equivalents of 1n were used with respect to
2a.
1a
1b
1i
2c
2c
85
81
4-F-C6H4-SH
2d
86[c]
80[c]
81[c]
67[c]
62
was required. The reactions were also performed for 72 h
with an excess (3 equiv) of thiophenol with respect to the al-
cohol at 1008C oil bath temperature.[26] Propargylic alcohols
with cyclopentyl (1l) and cyclohexyl (1m) groups at the R1
position generated the products in 71 and 70% yields, re-
spectively (Table 3, entries 1 and 2). Due to the low boiling
point of alcohol 1n with an ethyl group at the R1 position,
three equivalents were used to yield the product 4c in 63%
(Table 3, entry 3), whereas 71% yield of product was ob-
served for alcohol 1o with a 2-phenylethyl substituent
(Table 3, entry 4). Importantly, alcohols with functional
groups such as an olefinic double bond (1p) or ester (1q) at
the R1 position gave the products 4e and 4 f in 67 and 47%
yield, respectively (Table 3, entries 5 and 6).
1a
1b
1a
1i
2d
2d
4-AcNH-C6H4-SH
2e
4-MeO-C6H4-SH
2 f
1a
2 f
60
17942
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Synthesis of a-Sulfenylated Carbonyl Compounds
FULL PAPER
Table 5. Formation
of
product
3i
from
intermediate
5.[a]
Mechanistic studies
Experimental studies: During the course of the reaction be-
tween primary propargyl alcohol 1i and thiophenol 2a, we
observed the appearance of new 1H NMR signals in the
crude reaction mixture which did not correspond to the
starting materials or the product. In a control experiment,
a new compound was isolated. After structural elucidation,
we concluded that the new compound was an E/Z mixture
(2/7)[27] of sulfenylated allylic alcohol 5 (Scheme 4),[28] which
Entry
Catalyst
Equiv of 2a
Additive
Yield[b] [%]
1
2
3
4
5
6
7
8
–
–
0
1.5
0
0
0
0
1.5
0
–
–
–
0
0
99
0
0
0
93
10
AuCl
AuCl
AuCl
AcOH
AuCl
AuSPh
proton sponge[c]
molecular sieves[d]
–
proton sponge[c]
–
[a] Reaction conditions: 5 (1 mmol) and AuCl (2 mol%) were heated at
658C in 2.5 mL of nitromethane for 8 h. [b] NMR yield. [c] 30 mol% of
1,8-bis(dimethylamino)naphthalene was used. [d] Activated (4 ꢁ).
Scheme 4. Intermediate 5 formed in the AuCl-catalyzed reaction of 1i
and 2a.
2 mol% of AuCl (Table 5, entry 3). However, no conversion
of 5 to 3i was observed when 30 mol% of proton sponge or
molecular sieves was used together with AuCl (Table 5, en-
tries 4 and 5, respectively). The above results suggest that
the reaction may be catalyzed by a protic acid. To verify
this, compound 5 was treated with acetic acid, but no con-
version to 3i was observed (Table 5, entry 6). Interestingly,
the reaction took place in the presence of the proton sponge
(30 mol%) if a combination of 2 mol% of AuCl with
1.5 equiv of thiophenol 2a was used (Table 5, entry 7).
Moreover, application of AuI thiophenolate[23] led only to
a low conversion (Table 5, entry 8). These experiments sup-
port that the presence of both AuCl and a proton source
(e.g., HCl or thiophenol) is necessary for the reaction to
proceed efficiently.
was found to be the true intermediate of this reaction (see
below). Such intermediates were observed during the course
of all reactions of propargylic alcohols and aryl thiols.
The hydrothiolation reaction to generate 5 from 1i and
2a without a catalyst has recently been reported.[29] The
effect of a gold catalyst on the formation of allylic alcohol 5
was therefore investigated. Three separate reactions be-
tween 1i and 2a to generate 5 were carried out with and
without the AuCl (2 mol%) catalyst at room temperature in
nitromethane. The gold-catalyzed reaction produced 60% of
5, whereas only a trace amount of 5 (<10%) was observed
in the uncatalyzed reaction after 2 h (Table 4). We also
The above experiments also confirmed that the overall re-
action is indeed a two-step process and identified sulfenylat-
ed allylic alcohol 5 as the true intermediate. The first step is
a regioselective AuCl-catalyzed addition of thiophenol 2a to
the triple bond of alcohol 1i, and the second step is a rear-
rangement of the resulting intermediate 5 into the final
product 3i (Scheme 5). Efficient transformation of 5 into 3i
requires both AuCl and a proton source.
Table 4. Effect of AuCl on the formation of
5
from 1i and 2a.[a]
Entry
Mol% of AuCl
Additive ([mol%])
Conversion to 5
1
2
3
2
0
2
–
–
60%
<10%
58%
proton sponge (30)
[a] Reaction conditions: 1i (1 mmol), 2a (1.5 mmol), AuCl, and additive
were stirred at room temperature in nitromethane (2.5 mL) for 2 h.
tested whether addition of a proton sponge affects the for-
mation of compound 5 in the presence of AuCl, but there
was no difference to the reaction in the absence of the
proton sponge (Table 4, entry 3 vs. entry 1).
Scheme 5. The overall reaction between 1i and 2a to form product 3i via
intermediate allylic alcohol 5.
Since the experimental data showed that sulfenylated al-
lylic alcohol 5 is an intermediate in the overall reaction, we
studied the conversion of 5 to the final product 3i separate-
ly. Compound 5 was stable in nitromethane at 658C, and no
conversion was observed (Table 5, entry 1). Also, addition of
thiophenol 2a did not result in any conversion to 3i, and
compound 5 remained intact under these reaction conditions
(Table 5, entry 2). On the other hand, quantitative formation
of aldehyde 3i was observed in 8 h in the presence of
Formation of the a-sulfenylated carbonyl compound is
atom-efficient, since all atoms of the reacting alcohol and
thiol end up in the a-sulfenylated carbonyl product. The a-
hydrogen atom at the 1-position of the alcohol and the pro-
tons of the alcohol and thiol are transferred to the triple
bond of the alcohol during the course of the reaction. To de-
termine the positions to which the individual hydrogen
atoms are transferred, reactions were carried out with deu-
Chem. Eur. J. 2013, 19, 17939 – 17950 ꢀ 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.chemeurj.org
17943

F. Himo, J. S. M. Samec et al.
terium-labeled 1i-OD (D in the protic position), 1i-CD (D
in the hydridic position), and 2a-SD (D in the protic posi-
tion).
First, the OH proton of alcohol 1i and SH proton of thio-
phenol 2a were exchanged for deuterium atoms. The reac-
tion between 1i-OD and 2a-SD (80% deuterium purity)
was carried out for 24 h in CDCl3 at reflux with 5 mol% of
gold(I) chloride, and the product was isolated in a 80%
Scheme 8. Crossover experiment to investigate the intramolecularity of
the hydride shift.
1
2
yield (Scheme 6). H and H NMR spectroscopic studies on
Scheme 6. Deuterium incorporation with labeled 1i-OD and 2a-SD.
Scheme 9. Investigation of chirality transfer for the conversion of (S)-1a
into 3a.
the purified product revealed that the total deuterium con-
tent was 75%, of which deuterium incorporation at the ben-
zylic 3-position (3i-D1) was 90% (Scheme 6).[30] No deuteri-
um incorporation was observed at the 2-position of the
product. This labeling experiment shows that the protons
from both the OH group of 1i and the SH group of 2a are
transferred to the benzylic 3-position of 3i.
Alcohol 1i-CD (90% deuterium purity) labeled with
a deuterium atom in the hydridic 1-position was prepared
and used as substrate in the a-sulfenylation reaction. The re-
action was run for 24 h and the product was isolated in
a 73% yield (Scheme 7). 1H NMR and 2H NMR spectro-
thioACTHUNRTGNEUNGphenol 2a under the optimized reaction conditions, and
rac-3a was generated.
Theoretical studies: To gain further insight into the reaction
mechanism, a theoretical study was performed with the
DFT functional M06[31] (see Experimental Section). First,
formation of the experimentally observed sulfenylated allyl-
ic alcohol intermediate 5 by gold-catalyzed regioselective
addition of thiophenol 2a to the triple bond of propargylic
alcohol 1i was studied. Second, gold-catalyzed rearrange-
ment of compound 5 to the final product 3i was investigat-
ed. While the gold-catalyzed additions of various nucleo-
philes to triple and double bonds have been the subject of
both experimental and theoretical mechanistic studies,[32] the
corresponding reaction with aryl thiol nucleophiles has been
less studied. The present calculations on the gold-catalyzed
hydrothiolation reaction complement our experimental re-
sults and increase the mechanistic understanding of this
class of reactions.
Scheme 7. Deuterium incorporation with labeled 1i-CD.
The experimental results presented above point to AuCl
being the true catalyst of the reaction (Tables 1 and 4).
Therefore, we considered several different complexes of
AuCl with thiophenol 2a and propargylic alcohol 1i as the
starting point for the catalytic cycle of the hydrothiolation
reaction. The lowest-energy complex is formed between
AuCl and thiophenol 2a (INT0, Figure 1) with a binding
energy of 22.1 kcalmolÀ1. Therefore, INT0 serves as the zero
point in the free-energy plots below. The catalytically rele-
vant AuCl complex with propargylic alcohol 1i (INT1,
Figure 1) is, however, only 1.4 kcalmolÀ1 less stable (see
Figure 1 for the calculated free-energy profile).[33]
The first step in the mechanism is nucleophilic attack of
thiophenol on the triple bond of the propargylic alcohol
bound to AuCl.[34] Thiophenol can attack at the 2- or 3-posi-
tion with formation of isomeric products. Furthermore, both
the syn addition of thiophenol and AuCl (which can be
termed inner-sphere) and anti addition (outer-sphere) path-
ways are possible. These options were evaluated by calcula-
scopic studies on the purified product showed that the total
deuterium content of the product was 90%, of which deute-
rium retention at the aldehyde 1-position (3i-D2) was 79%
and the remaining 11% deuterium was incorporated at the
2-position of the product (3i-D3). This labeling study shows
that the hydride or deuteride of 1i-CD is transferred to the
2-position of the product.
To investigate the intramolecularity of the hydride migra-
tion, a crossover experiment was carried out with 1i-CD, 1j,
1
2
and 2a (Scheme 8). H and H NMR spectral studies on the
purified products showed no deuterium incorporation in 3j,
whereas deuterium incorporation in 3i was obtained in simi-
lar ratios to Scheme 7. This points to a mechanism involving
an intramolecular 1,2-hydride transfer.
To study the scope of chirality transfer of the present re-
action, optically pure (S)-1a was used as substrate in the
gold(I)-catalyzed a-sulfenylation reaction (Scheme 9). No
chirality transfer was observed when (S)-1a reacted with
17944
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Synthesis of a-Sulfenylated Carbonyl Compounds
FULL PAPER
Figure 1. Free-energy profile for the regioselective gold-catalyzed addition of thiophenol 2a to the triple bond of propargylic alcohol 1i.
tions. The barriers for the two outer-sphere attacks via TS1a
and TS1b (see Figure 2 for optimized structures) were both
calculated to be 23.8 kcalmolÀ1 relative to INT0. In both
TS1a and TS1b, and also in the resulting intermediates
INT2a and INT2b, a hydrogen bond is present between the
thiol proton and the oxygen atom of the hydroxyl group.
The calculations show that the transition states for the alter-
native inner-sphere additions (TS1c and TS1d) have signifi-
cantly higher energies than those of the outer-sphere addi-
tions (6-11 kcalmolÀ1, see Figure 1 for energy diagram and
Figure 2 for optimized structures). This result is in line with
previous findings on gold-catalyzed additions to double and
triple bonds, which were shown to take place preferentially
by an outer-sphere mechanism.[35] Therefore, the subsequent
steps of the inner-sphere addition pathways were not further
evaluated in the present study. The outer-sphere course of
thiophenol addition implies that the reaction will afford
only the Z isomer of allylic alcohol 5. However, since a mix-
Figure 2. Optimized transition-state structures for the key steps of the gold-catalyzed hydrothiolation of propargylic alcohol 1i. The phenyl hydrogen
atoms have been omitted for clarity.
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17945

F. Himo, J. S. M. Samec et al.
ture of E and Z isomers of 5 was observed experimentally,
some other process must be responsible for the formation of
the E isomer. This is indeed the case (see below).
The next step in the gold-catalyzed addition of thiophenol
to propargylic alcohol is a protodeauration. This reaction
cannot take place directly from INT2a or INT2b, because
that would require transferring the proton from the sulfur
atom to a distant carbon atom. Instead, this step is facilitat-
ed by the adjacent hydroxyl group, which can transfer the
proton intramolecularly in a stepwise fashion.[36] Hence, an
initial proton transfer from sulfur to oxygen takes place
(TS2a and TS2b, Figure 2), followed by protodeauration
(TS3a and TS3b). Transition states TS3a and TS3b are the
highest points in the free-
in hydride transfer and the fact that this process requires the
presence of both AuCl and a proton source (Table 5) sug-
gests that this gold-catalyzed isomerization of 5 to 3i follows
a different mechanistic route compared with previous reac-
tions catalyzed by other metals.
We have evaluated theoretically a number of possible
mechanisms for the isomerization of 5 to 3i which comply
with the results of the experimental investigations discussed
above. The calculations show that the only pathway that has
plausible barriers is initiated by protonation of allylic alco-
hol 5 by an external proton source activated with AuCl
(Figure 3). All of the other alternative mechanisms tested,
such as those involving hydride shift promoted by coordina-
energy profiles of the respective
pathways, and their relative en-
ergies therefore determine the
overall regioselectivity of the
addition. Protodeauration via
TS3a is calculated to be favored
by 6.0 kcalmolÀ1 compared to
TS3b (25.9 versus 31.9 kcal
molÀ1 relative to INT0, respec-
tively). This difference in
energy corresponds well to the
experimental finding that only
a-sulfenylated carbonyl com-
pounds were observed. The dif-
ference in barriers can be ex-
plained by the fact that the
TS3b contains a strained, four-
membered cyclic structure,
while TS3a has a more relaxed,
Figure 3. Free-energy profile for the gold-catalyzed isomerization of allylic alcohol 5 to aldehyde 3i.
five-membered cyclic structure.
Thus, according to the calcula-
tions, the hydroxyl group of the reactant plays an important
role in controlling the regioselectivity of the reaction.
tion of AuCl to the double bond of 5 or intramolecular pro-
tonation of the double bond by the AuCl-activated hydroxyl
group, were found to proceed via high-energy routes with
barriers exceeding 30 kcalmolÀ1 (see Supporting Informa-
tion for details).
The protodeauration was found to be very exergonic and
thus irreversible, and it results in the formation of complex
INT4(Z), with AuCl coordinated to the double bond of in-
termediate 5Z. To close the catalytic cycle for thiophenol
addition, compound 5Z is released by 1i to regenerate
INT1. Overall, the formation of intermediate 5Z is calculat-
ed to be exergonic by 11.1 kcalmolÀ1.
In the second part of the reaction, intermediate 5 rear-
ranges to the final product, aldehyde 3i. The isomerization
of allylic alcohols to the corresponding ketones is known to
be catalyzed by complexes of transition metals such as Ru,
Rh, and Fe.[37] However, to the best of our knowledge, no
examples of gold-catalyzed isomerization of allylic alcohols
have been reported. Interestingly, the above-mentioned re-
actions usually follow a redox pathway involving intermedi-
ate formation of metal hydride and a,b-unsaturated ketone,
and result in an intra- or intermolecular 1,3-hydride transfer
to the 3-position of the product. In contrast, the gold-cata-
lyzed process described here results in a selective intramo-
lecular 1,2-hydride shift (Schemes 7 and 8). The dissimilarity
The catalytic cycle for the rearrangement of 5Z into 3i
starts with complex INT4(Z). Under the normal reaction
conditions thiophenol 2a is present in the reaction mixture
in excess and may act as a proton donor. Thus, in the first
step of the reaction, 2a, acidified by coordination of AuCl
to the sulfur atom, protonates the double bond of allylic al-
cohol 5Z at the 3-position (TS4(Z), see Figure 4 for the op-
timized structure). The calculated barrier is 16.4 kcalmolÀ1
relative to INT4(Z), and the resulting dissociated ion-pair
intermediate INT5 lies 7.0 kcalmolÀ1 higher than INT4(Z)
(see Figure 3 for the free-energy diagram). Since the transi-
tion state for the following step of the catalytic cycle (TS5)
is higher in energy than TS4(Z), the protonation is reversi-
ble.
Importantly, the intermediate INT5 can undergo rotation
À
around the C C single bond and a subsequent reprotonation
via TS4(E), which results in the formation of the isomeric
17946
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Synthesis of a-Sulfenylated Carbonyl Compounds
FULL PAPER
Figure 4. Optimized transition-state structures for the key steps of the gold-catalyzed isomerization of allylic alcohol 5 to aldehyde 3i.
INT4(E). Hence, although the preceding hydrothiolation re-
action delivers the Z-configured allylic alcohol 5Z exclusive-
ly, as discussed above, it may interconvert with 5E under the
reaction conditions to afford the experimentally observed
mixture of isomers. The calculated energy difference be-
tween free 5E and 5Z is 0.5 kcalmolÀ1 in favor of 5E. This
corresponds to a 5E:5Z ratio of about 2:1, which differs
slightly from the experimentally observed 2:7 mixture,
which corresponds to 0.8 kcalmolÀ1 in favor of 5Z. This dis-
crepancy may be ascribed to the errors of the theoretical
methodology.
The subsequent step of the reaction is the key 1,2-hydride
shift (TS5), driven by the electron-deficient character at the
2-position in INT5. This takes place via TS5 with an overall
barrier of 24.3 kcalmolÀ1 relative to INT4(Z). Interestingly,
although both INT5 preceding TS5 and the resulting INT6
were found to be more stable as dissociated ion pairs, the
transition state has slightly lower energy as an associated
ion pair. This is due to the interaction between the gold
center and the hydride (Figure 4), that is, gold assists the hy-
dride shift.
After the hydride shift, the proton is returned to the thio-
phenol (TS6, see Figure 4 for the optimized structure) and
a complex of AuCl with the product is formed (INT7). The
calculated barrier for this is very low, only 3.3 kcalmolÀ1 rel-
ative to INT6. To close the catalytic cycle, product 3i is re-
leased and INT4 regenerated. The latter ligand exchange is
slightly endergonic (by 0.1 and 1.4 kcalmolÀ1 for INT4(Z)
and INT4(E), respectively). This means that INT4(Z) and
INT7 are the most stable gold complexes present in the re-
action mixture.
porting Information). However, from the calculations it is
difficult to say which of the two alternative pathways is op-
erational under the normal reaction conditions, due to the
much higher concentration of 2a compared to HCl in the re-
action mixture.
Proposed reaction mechanism: On the basis of the experi-
mental and computational studies the following reaction
mechanism is proposed[38] for the gold-catalyzed reaction be-
tween propargylic alcohols and thiophenols producing a-sul-
fenylated carbonyl compounds. The mechanism consists of
two catalytic cycles (Scheme 10), corresponding to the two
sequential processes taking place in the course of the reac-
tion: 1) hydrothiolation of propargylic alcohol 1i and 2) iso-
merization of sulfenylated allylic alcohol 5 to the final alde-
hyde 3i.
For the hydrothiolation cycle (Scheme 10, left part), it was
established that the initial addition of the thiophenol to the
triple bond of the propargylic alcohol proceeds by an outer-
sphere mechanism and can occur at both the 2- and 3-posi-
tions (TS1a and TS1b), affording both INT2a and INT2b.
However, this step and the subsequent proton transfer
(TS2a and TS2b) were found to be reversible, and thus the
final regioselectivity is determined by the protodeauration.
According to the calculations, protodeauration is favored
for the a-adduct (TS3a), in agreement with the experimental
results.
Once formed, the intermediate sulfenylated allylic alcohol
5 can undergo isomerization to the final product, following
the second catalytic cycle (Scheme 9, right part). The first
step of the cycle involves protonation of the double bond of
5 by a proton donor (e.g., thiophenol 2a), acidified by coor-
dination to AuCl. The protonation step was found to be re-
versible, and this may account for the Z–E isomerization of
allylic alcohol 5, which is produced in the hydrothiolation
step as the Z isomer exclusively, whereas a mixture of 5Z
and 5E was observed experimentally. From INT5 a 1,2-hy-
dride shift takes place (TS5), which is driven by the elec-
tron-deficient character at the 2-position. In the final step of
the cycle, the proton donor is regenerated.
As discussed above, it was experimentally shown that
AuCl can promote the isomerACHUTGNERTNiUNG zAHCTNUETGRNNUNGaACTHNUGTRENtNNGU ion of allylic alcohol 5 to
aldehyde 3i even in the absence of the thiophenol (Table 5,
entry 3). The reaction was, however, inhibited by the addi-
tion of 30 mol% of proton sponge (Table 5, entry 4) or mo-
lecular sieves (Table 5, entry 5). From these results, we con-
cluded that the role of the proton donor may also be played
by HCl, which could be present in AuCl or might be gener-
ated under the reaction conditions. Therefore, we also calcu-
lated the free-energy profile for the reaction involving HCl
as the proton source instead of thiophenol. The results indi-
cated that such process is indeed feasible and in fact more
energetically favorable than that with thiophenol (see Sup-
The gold-catalyzed pathway described here is a new
mechanism for the isomerization of allylic alcohols and is
distinct from those followed in the presence of other transi-
tion metal catalysts.[37]
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17947

F. Himo, J. S. M. Samec et al.
Scheme 10. Proposed reaction mechanism.
Experimental Section
Conclusion
4-Phenyl-3-(phenylthio)butan-2-one (3a): AuCl (5 mg, 2 mol%) was
transferred to a 5 mL microwave vial with a small magnet in a glove box
under nitrogen atmosphere. The cap of the vial was closed tightly and
the vial was removed from the glove-box. Dry nitromethane (2.5 mL), al-
cohol 1a (145 mL, 1 mmol), and benzenethiol (2a, 154 mL, 1.5 mmol)
were added to the vial by syringe and the mixture was stirred with a mag-
netic stirrer at 658C for 24 h. After completion of the reaction (shown by
TLC or crude NMR spectroscopy), the solvent was evaporated under re-
duced pressure and the residue was purified by silica-gel (100–200 mesh)
column chromatography with 3 vol% ethyl acetate/pentane as eluent to
yield the desired product 3a as a pale yellow oil (240 mg, 0.94 mmol,
94%). 1H NMR (300 MHz, CDCl3): d=2.20 (s, 3H, H-1), 3.00 (dd, J=
6.9 Hz, 14.4 Hz, 1H, H-4), 3.19 (dd, J=8.4 Hz, 14.1 Hz, 1H, H-4), 3.90
(dd, J=6.9 Hz, 8.4 Hz, 1H, H-3), 7.18–7.37 ppm (m, 10H, H-arom).
13C NMR (75 MHz, CDCl3): d=28.1, 36.9, 59.0, 127.1, 128.5, 128.8, 129.4,
133.0, 133.3, 138.3, 204.5 ppm.
An atom-efficient, gold-catalyzed route to a-sulfenylated
carbonyl compounds from propargylic alcohols and aromatic
thiols was studied. By utilizing this protocol, primary aro-
matic, secondary aromatic, and secondary aliphatic propar-
gylic alcohols were transformed into a-sulfenylated carbonyl
compounds in good to excellent yields. When a secondary
alcohol was used, an a-sulfenylated ketone was generated,
and when a primary alcohol was used, an a-sulfenylated al-
dehyde was obtained. The protocol was found to be general
with respect to a variety of substituents on the aromatic ring
of the alcohols and thiols. Aliphatic propargylic alcohols
were also successfully employed to produce the desired a-
sulfenylated ketones. Experimental and theoretical investi-
gations were performed to elucidate the mechanism and the
source of regioselectivity of the reaction. The initial thiol
attack at the 2-position of the propargylic alcohol was sug-
gested to be due to a favored protodeauration step via an
energetically favored five-membered cyclic transition state,
instead of the unfavorable four-membered cyclic transition
state found for attack at the 3-position of the triple bond.
Furthermore, experimental data and calculations showed
that protonation of the double bond of the sulfenylated al-
lylic alcohol intermediate in the next step was promoted by
a proton-transfer mediator coordinated to gold chloride.
The protonation was required for the 1,2-hydride shift that
generated the final product.
Computational details: The calculations were performed with the M06
functional[31] as implemented in the Gaussian 09 package.[39] Geometries
were optimized by using the def2-SVP double-z basis set with polariza-
tion functions on all atoms.[40] Relativistic effects were accounted for by
using the relativistic SDD effective core potential for gold.[41] The station-
ary points were characterized by frequency calculations to confirm their
character as minima (no imaginary frequencies) or transition states (one
imaginary frequency corresponding to the reaction coordinate). The sol-
vation energies were calculated as single-point energy corrections at the
same level of theory as the geometry optimization by using the conduc-
tor-like polarizable continuum model (CPCM) formalism[42] with the pa-
rameters for nitromethane (e=36.562). Thermal corrections to Gibbs
free energies were calculated for 338.15 K, which is the temperature at
which the reactions were performed experimentally. The final Gibbs free
energies reported in this article were obtained from single-point calcula-
tions with the larger 6-311+GACTHUNRTGNEUNG(2d,2p) basis set for H, C, O, S, and Cl, and
17948
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Synthesis of a-Sulfenylated Carbonyl Compounds
FULL PAPER
SDD for Au, corrected for zero-point and thermal effects, as well as sol-
vation.[43]
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B3LYP functional and recalculated the energies with all corrections, in-
cluding dispersion. Some differences were observed, but the results were
in general consistent with the M06 results presented here (see Supporting
Information for details).
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Received: June 27, 2013
Revised: September 13, 2013
Published online: November 22, 2013
17950
www.chemeurj.org ꢀ 2013 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Chem. Eur. J. 2013, 19, 17939 – 17950