A gold(I)-catalyzed route to α-sulfenylated carbonyl compounds from propargylic alcohols and aryl thiols

Article abstract of DOI:10.1039/c2cc32042h

A one-step atom efficient gold(i)-catalyzed route to α-sulfenylated ketones and aldehydes from propargylic alcohols and aryl thiols is described.

Full text of DOI:10.1039/c2cc32042h

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COMMUNICATION
A gold(I)-catalyzed route to a-sulfenylated carbonyl compounds from
propargylic alcohols and aryl thiolswz
Srijit Biswas and Joseph S. M. Samec*
Received 20th March 2012, Accepted 26th April 2012
DOI: 10.1039/c2cc32042h
A one-step atom efficient gold(I)-catalyzed route to a-sulfenylated
ketones and aldehydes from propargylic alcohols and aryl thiols
is described.
a-Sulfenylated carbonyl compounds and their derivatives are
important in agrochemicals and pharmaceuticals.1 The traditional
Scheme 1 a-Sulfenylation of propargylic alcohol 1a.
synthesis of a-sulfenylated carbonyl compounds involves substitu-
employed. An interesting question to ask is whether gold(I)
benzenethiolate or gold(I) chloride operates as the true catalyst
in the a-sulfenylation reaction. Therefore, the two gold complexes
were evaluated in generating 3a from 1a and 2a (Table 1). In the
presence of gold(I) chloride (2 mol%), 62% conversion to 3a was
observed (Table 1, entry 1). In the presence of gold(I) benzenethio-
late (2 mol%), 25% conversion to 3a was observed after 15 h
performing the reaction at 65 1C (Table 1, entry 2). This is
consistent with gold(I) chloride being responsible for the observed
reactivity. The reaction proceeds to yield the desired product in
polar solvents such as 1,2-dichloroethane (1,2-DCE), chloroform
or nitromethane (Table 1, entries 1, 3 and 4). An excess of
thiophenol 2a (1.5 equivalent) was required for completion of
the reaction (Table 1, entries 1, 5 and 6). To inhibit the competing
disulfide formation, the reaction was performed in an inert
atmosphere (Table 1, entries 1 and 7). Under the optimized
reaction conditions, the reaction was run in 1,2-DCE at 65 1C
for 24 hours to generate 3a in 92% yield (Table 1, entry 8).
tion of the corresponding a-halogenated precursor by sulphide
anions (eqn (1)).2 These intermediates are toxic, difficult to
handle, and generate a stoichiometric amount of chemical
waste. Alternatively, the a-sulfenylated carbonyl compounds
can be synthesized by the reaction of a carbonyl compound with
sulfenylating agents (eqn (2)).3 However, these sulfenylating
agents have to be prepared in a separate step and also generate
a stoichiometric amount of waste.
ð1Þ
ð2Þ
We found that gold(I) chloride catalyzed4 a chemo- and regio-
selective reaction with thiophenol (2a) and 4-phenyl-3-butyn-2-ol
(1a) to generate a-sulfenylated carbonyl compound 3a. Other metal
catalysts, such as rhenium(I), bismuth(III) or iron(III), allowed direct
substitution of the hydroxyl group to generate the corresponding
propargylic thioether.5 The lack of an efficient, atom-economical6
and sustainable route to synthesize a-sulfenylated carbonyl
compounds motivated us to explore this novel transformation
and study the reaction mechanism (Scheme 1).7
Table 1 Optimisation of the reaction conditionsa
Entry
Catalyst
Equiv. of 2a
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
AuCl
AuSPh
AuCl
AuCl
AuCl
AuCl
AuCl
AuCl
1.5
1.5
1.5
1.5
1.0
2.0
1.5
1.5
1,2-DCE
1,2-DCE
CHCl3
MeNO3
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
62
25
31
54
48
62
39c
92d
Thiophenol 2a is known to reduce tetrachloro aureate(III) to
generate gold(I) benzenethiolate.8 Gold(I) chloride and 2a may
generate gold(I) benzenethiolate under the reaction conditions
Dept. of Chemistry, BMC, Uppsala University, Box 576,
SE 751 23 Uppsala, Sweden. E-mail: Joseph.Samec@kemi.uu.se;
Fax: +18-471 3818; Tel: +18-471 3817
w Dedicated to Professor Robert H. Grubbs on the occasion of his
70th birthday.
z Electronic supplementary information (ESI) available: Detailed
experimental procedures, characterization data, and copy of 1H and
13C NMR spectra. See DOI: 10.1039/c2cc32042h
a
Reaction conditions: 1a (1 mmol), 2a (X mmol) and Au (2 mol%)
were run at 65 1C in 2.5 mL 1,2-DCE solvent for 15 h under an argon
atmosphere. Yields refer to isolated yields. c The reaction was performed
b
d
open to air. Reaction run for 24 h.
c
6586 Chem. Commun., 2012, 48, 6586–6588
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The optimized reaction conditions were employed on a variety
of propargylic alcohols 1a–f and aromatic thiols 2a–f (Table 1).
Secondary aromatic propargylic alcohols 1a–c reacted smoothly
with 2a to produce the corresponding a-thio ketones 3a–c in good
to excellent yields (Table 1, entries 1–3). Also, secondary aliphatic
propargylic alcohol 1d generated the corresponding a-sulfenylated
ketone 3d albeit in a lower yield (Table 1, entry 4). Primary
propargylic alcohols were also transformed to generate the corre-
sponding a-thio aldehydes 3e and 3f in high yields (Table 1,
entries 5 and 6). Alcohols with a terminal triple bond were
unreactive under the employed reaction conditions. Reactions
using thiophenols having halogen substituents at the para-position
(2b–d) were studied. In the case of para-bromo (2b) and chloro (2c)
thiophenol the reaction with 1f proceeded to generate the products
3g and 3h in comparable yields to 2a (Table 1, entries 7 and 8).
However, the use of para-fluoro thiophenol leads to a decrease in
the yield of the desired product 3i even when the reaction was run
at 90 1C for 48 h (Table 1, entry 9). Thiophenols having electron
donating isopropyl and methoxy groups at the para-position lead
to a decrease in reactivity. The isopropyl substituted thiophenol 2e
reacted with 1f to generate 3j in 76% yield and the methoxy
substituted thiophenol 2f generated 3k in 43% yield (Table 2,
entries 10 and 11). Aliphatic propargylic alcohol 1g having a
cyclopentyl ring also reacted with thiophenol to produce 3l
(Table 2, entry 12). Attempts to employ aliphatic thiol under the
same reaction conditions were unsuccessful.
Scheme 2 The a-sulfenylation proceeds in the presence of DTBP.
a-sulfenylated carbonyl product. The a-hydrogen of the alcohol
and the protons of the alcohol and thiol are transferred to the
triple bond of 1 during the course of the reaction. We wanted to
determine where the individual hydrogens are transferred.
Therefore, a series of reactions were carried out with deuterium
labelled 1f-OD (D in the protic position), 1f-CD (D in the
hydridic position) and 2a-SD (D in the protic position).
The reaction between 1f-OD and 2a-SD (80% deuterium
purity) was run for 24 hours in CHCl3 at reflux using 5 mol%
gold(I) chloride and the product was isolated in 80% yield
1
2
(Scheme 3). H NMR and H NMR spectroscopic studies of
the purified product revealed that the total deuterium content
was 75%, of which deuterium incorporation at the benzylic
position (3f-D1) was 90% (Scheme 3).9 This labelling experiment
shows that the protons from both the OH of 1f and the SH of 2a
are transferred to the benzylic position of 3f.
Table 2 a-Sulfenylation of propargylic alcohols by aryl thiolsa
Scheme 3 Deuterium incorporation using labelled 1f-OD and 2a-SD.
Alcohol 1f-CD (90% deuterium purity) labelled by one
deuterium in the hydridic position was used as the substrate
in the a-sulfenylation reaction. The reaction was run for
24 hours and the product was isolated in 91% yield
Entry
1
R1
R2
2
Ar
3
Yieldb
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1f
1f
1f
1f
1f
1g
Ph
Ph
Ph
Et
1-Naph
Ph
Ph
Ph
Me
Pr
iPr
Me
H
H
H
H
H
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
2f
Ph
Ph
Ph
Ph
Ph
Ph
p-Br-Ph
p-Cl-Ph
p-F-Ph
p-iPr-Ph
p-OMe-Ph
Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
92
89
88
50c
90
93
88
92
48d
76
43
48d
1
2
(Scheme 4). H NMR and H NMR spectroscopic studies of
the purified product show that the total deuterium content of
the product was 90%, of which deuterium incorporation at the
aldehyde position (3f-D2) was 79% and the remaining 11%
deuterium was incorporated at the a-position of the product
(3f-D3). The labelling study shows that the hydride or deuteride
of 1f-CD is transferred to the a-position of the product.
9
Ph
Ph
10
11
12
H
H
Me
3j
3k
3l
Ph
Cyclopentyl
2a
a
Reaction conditions: 1 (1 mmol), 2 (1.5 mmol) and AuCl (2 mol%)
b
1,2-DCE (2.5 mL) for 24 h at 65 1C. Yields refer to isolated yields.
c
d
3 Equiv. of 1d was used. The reaction was run at 90 1C for 48 h.
Scheme 4 Deuterium incorporation using labelled 1f-CD.
To rule out AuCl is operating as a HCl generator, the reaction
between 1a and 2a was performed in the presence of 30 mol%
2,6-di-t-butyl pyridine (DTBP) (Scheme 2). The reaction was
found to proceed with equal efficiency (90% yield) compared to
running the reaction in the absence of DTBP (92% yield). As a
control, the a-sulfenylation reaction was attempted using HCl in
ether (20 mol%) as catalyst, where below 15% conversion of 1a
was observed after 24 hours and no 3a was observed. This
supports that the gold(I) and not HCl generated from the metal
salt is acting as the catalyst in the a-sulfenylation reaction.
The a-sulfenylation is an atom efficient reaction where all
the atoms of the reacting alcohol and thiol end up in the
To investigate the intramolecularity of the hydride migration,
a cross-over experiment was carried out using 1f-CD, 1e and 2a
1
2
(Scheme 5). H and H NMR spectral studies of the purified
products showed no deuterium incorporation in 3e, whereas
deuterium incorporation in 3f was obtained in similar ratios as
mentioned in Scheme 4.
The ratio of 3f-D2 to 3f-D3 (7.2 : 1) in Scheme 4 is the ratio of
the rate constants from the primary and secondary kinetic
isotope effects of the 1,2-hydride or deuteride migration from
the a-position of the 1f to the a-position of the product 3f-D2 or
3f-D3. Because the observed rates are a combination of a primary
c
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thiols has been reported. In this protocol, primary, secondary,
aromatic, and aliphatic alcohols are transformed to generate the
a-sulfenylated carbonyl compounds in good to excellent yields.
When a secondary alcohol is used, an a-sulfenylated ketone is
generated and when a primary alcohol is used, an a-sulfenylated
aldehyde is obtained. Mechanistic studies showed that gold(I)
chloride is the active catalyst. The reaction proceeds through an
initial regioselective thiol attack at the triple bond b to the
alcohol. Protodeauration generates an alkene as a mixture of
Scheme 5 Investigation of intramolecularity of the hydrogen migra-
tion by cross-over experiment.
diastereomers.
A rate-limiting gold(I)-catalyzed 1,2-hydride
and a secondary isotope effect, the kinetic isotope effect was
determined indirectly (see ESIz for experimental details and
determination of the KIE). Given this, the observed primary
migration generates the a-sulfenylated carbonyl compounds.
We thank Wenner-Gren foundation, Stiftelsen Olle Engqvist
Byggmastare, and Vetenskapsradet for financial support. We thank
Professors J.-E. Backvall and O. Matsson for valuable discussions.
deuterium kinetic isotopic effect was determined to be kH/kD
=
8.4 ꢀ 0.2 and the observed secondary deuterium kinetic isotopic
effect was determined to be kH/kD = 1.17 ꢀ 0.1.10
During the course of the reaction a diastereomeric mixture
of 5 (Z : E = 7 : 1) was observed in the reaction mixture
(Scheme 6).11 We were able to isolate and fully characterise
intermediate 5 in 30% yield.12
Notes and references
1 (a) R. J. Cremlyn, An Introduction to Organo-Sulfur Chemistry,
Wiley & Sons, New York, 1996; (b) T. Kondo and T.-A. Mitsudo,
Chem. Rev., 2000, 100, 3205; (c) Organosulfur Chemistry in Asymmetric
Synthesis, ed. T. Toru and C. Bolm, Wiley & Sons, New York, 2008.
2 (a) B. M. Trost, Chem. Rev., 1978, 78, 363; (b) B. M. Trost,
Acc. Chem. Res., 1978, 11, 453.
3 (a) M. E. Kuehne, J. Org. Chem., 1963, 28, 2124; (b) S. Murai,
Y. Kuroki, K. Hasegawa and S. Tsutsumi, Chem. Commun., 1972,
946; (c) E. Okragla, S. Demkowicz, J. Rachon and D. Witt,
Synthesis, 2009, 1720.
4 (a) N. Bongers and N. Krause, Angew. Chem., Int. Ed., 2008,
47, 2178; (b) D. J. Gorin, B. D. Sherry and F. D. Toste, Chem.
Rev., 2008, 108, 3351; (c) E. Jimenez-Nunez and A. M. Echavarren,
Chem. Rev., 2008, 108, 3326; (d) Z. Li, C. Brouwer and C. He, Chem.
Rev., 2008, 108, 3239; (e) A. Arcadi, Chem. Rev., 2008, 108, 3266;
(f) J. Muzart, Tetrahedron, 2008, 64, 5815; (g) D. J. Gorin and
F. D. Toste, Nature, 2007, 446, 395; (h) A. Furstner and
P. W. Davies, Angew. Chem., Int. Ed., 2007, 46, 3410; (i) A. S.
K. Hashmi, Chem. Rev., 2007, 107, 3180; (j) A. S. K. Hashmi and
G. J. Hutchings, Angew. Chem., Int. Ed., 2006, 45, 7896; (k) A. S.
K. Hashmi and M. Rudolph, Chem. Soc. Rev., 2008, 37, 1766;
(l) T. C. Boorman and I. Larrosa, Chem. Soc. Rev., 2011, 40, 1910.
5 (a) N. Ljungdahl and N. Kann, Angew. Chem., Int. Ed., 2009,
48, 642 (Angew. Chem., 2009, 121, 652); (b) S. Biswas and J. S. M.
Samec, unpublished work; (c) F. Howard, S. Sawadjoon and
J. S. M. Samec, Tetrahedron Lett., 2010, 51, 4208.
Scheme 6 Intermediate 5 formed in the AuCl catalysed reaction of 1a
and 2a.
Compound 5 was tested as an intermediate in the transfor-
mation to 3f (Scheme 7). Gold(I) chloride transformed 5 to
generate 3f in full conversion within 16 hours using standard
reaction conditions. Attempts to perform this reaction step
using acetic acid or 2a as Brønsted acids were not successful.
6 (a) R. A. Sheldon, Pure Appl. Chem., 2000, 72, 1233;
(b) B. M. Trost, Science, 1991, 254, 1471.
7 a-Thio carbonyls have been prepared from propargylic sulfoxides
via oxygen transfer and 1,2-thio migration, see: N. D. Shapiro and
F. D. Toste, J. Am. Chem. Soc., 2007, 129, 4160.
8 M. T. Raisanen, N. Runeberg, M. Klinga, M. Nieger, M. Bolte,
P. Pyykko, M. Leskela and T. Repo, Inorg. Chem., 2007, 46, 9954.
9 L. Gong, Y. Lin, T. B. Wen and H. Xin, Organometallics, 2009,
28, 1101.
10 See ESIz for rate determination and kinetic isotope effects. For
review of kinetic isotope effect; (a) M. Gomez-Gallego and
M. A. Sierra, Chem. Rev., 2011, 111, 4857. For the kinetic isotope
effect of 1,2-hydride shifts;; (b) A. E. Hours and J. K. Snyder,
Organometallics, 2008, 27, 410.
Scheme 7 Testing 5, as an intermediate to generate 3f.
We propose a mechanism where gold(I) coordinates to the triple
bond of 1a and thiophenol attacks regioselectively the triple bond
in the b-position of the alcohol 1a. Protodeauration generates 5 as
an intermediate in the reaction. A rate-limiting gold(I)-mediated
1,2-hydride migration13 generates 3f from 5 (Scheme 8).
11 Similar diastereomeric ratios have been reported for gold(I)-cata-
lyzed addition of methanol to diphenylacetylene, see: J. H. Teles,
S. Brode and M. Chabanas, Angew. Chem., Int. Ed., 1998, 37, 1415.
12 For
gold-catalyzed
hydrothiolation
reactions,
see:
(a) M. Menggenbateer, M. Narsireddy, G. Ferrara, N. Nishina,
T. Jin and Y. Yamamoto, Tetrahedron Lett., 2010, 51, 4627;
(b) A. Corma, C. Gonzalez-Arellano, M. Iglesias and
F. Sanchez, Appl. Catal., A, 2010, 375, 49.
13 For gold promoted pinacol shift, see: (a) J. P. Markham,
S. T. Staben and F. D. Toste, J. Am. Chem. Soc., 2005,
127, 9708; (b) F. Kleinbeck and F. D. Toste, J. Am. Chem. Soc.,
2009, 131, 9178; (c) X. Huang and L. Zhang, J. Am. Chem. Soc.,
2007, 129, 6398; (d) K.-D. Kim, H.-S. Yeom, S. Shin and S. Shin,
Tetrahedron, 2012, DOI: 10.1016/j.tet.2012.03.018, in press.
Scheme 8 Proposed mechanism for the gold chloride catalysed a-
sulfenylation of propargylic alcohols.
In conclusion, a novel gold-catalyzed route to a-sulfenylated
carbonyl compounds from propargylic alcohols and aromatic
c
6588 Chem. Commun., 2012, 48, 6586–6588
This journal is The Royal Society of Chemistry 2012