An aqueous and recyclable copper(i)-catalyzed route to α-sulfenylated carbonyl compounds from propargylic alcohols and aryl thiols

Article abstract of DOI:10.1039/c3gc41251b

A highly efficient one-step copper(i)-catalyzed method for the synthesis of α-sulfenylated carbonyl compounds from propargylic alcohols and aryl thiols in aqueous media is described. A variety of α-sulfenylated carbonyl compounds can be synthesized in good to excellent yields. The catalyst has been successfully recycled up to 4 times without any loss of activity in an aqueous medium.

Full text of DOI:10.1039/c3gc41251b

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An aqueous and recyclable copper(I)-catalyzed route to
α-sulfenylated carbonyl compounds from propargylic
alcohols and aryl thiols†
Cite this: DOI: 10.1039/c3gc41251b
Received 27th June 2013,
Accepted 23rd August 2013
DOI: 10.1039/c3gc41251b
Rahul A. Watile, Srijit Biswas and Joseph S. M. Samec*
www.rsc.org/greenchem
A highly efficient one-step copper(I)-catalyzed method for the
synthesis of α-sulfenylated carbonyl compounds from propargylic
alcohols and aryl thiols in aqueous media is described. A variety
of α-sulfenylated carbonyl compounds can be synthesized in
good to excellent yields. The catalyst has been successfully
recycled up to 4 times without any loss of activity in an aqueous
medium.
Scheme 1 Traditional synthesis of α-sulfenylated carbonyl compounds.
The formation of C–S bonds represents a key step to the
synthesis of a wide variety of biologically active molecules,
functional materials and synthetic reagents.1–4 In particular,
α-sulfenylated carbonyl compounds are chemical building
blocks which can also be found in several pharmaceutically
active molecules.2 While the metal catalyzed C–O and C–N
bond forming reactions have been widely explored,5 the for-
mation of C–S bonds has been less investigated,6 perhaps due
to poisoning of transition metal catalysts by thiols.
Scheme 2 CuI mediated synthesis of α-sulfenylated carbonyl compounds.
Traditionally, α-sulfenylated carbonyl compounds are syn-
thesized via the reaction of an α-halogenated precursor with
sulphide anions (Scheme 1).3 The reaction of a carbonyl com-
pound with sulfenylating agents is an alternative traditional
method for the synthesis of α-sulfenylated carbonyl com-
pounds.4 We have recently reported a new strategy for the syn-
thesis of α-sulfenylated carbonyl compounds using a gold
catalyst in 1,2-dichloroethane as a solvent.7,8 We herein report
a copper catalyzed9,10 synthesis of α-sulfenylated carbonyl
compounds from readily available propargylic alcohols and
aryl thiols using water as the reaction medium (Scheme 2).11
The catalyst has been recycled successfully up to 4 times
without any significant loss of its catalytic activity.
catalyst, catalyst loading, and the reaction temperature were
studied (Table 1).
To make the synthetic protocol greener, we examined water
as a reaction solvent and, gratifyingly, it provided an excellent
yield of the desired product. Water was found to be superior
compared to traditional organic solvents such as acetonitrile,
toluene, 1,2-dichloroethane and nitromethane (see ESI† for
details). Different copper(I) halides such as CuCl, CuBr and
CuI were screened, among which CuI was found to be the best
catalyst providing an excellent yield of the desired product 3a
in aqueous media (Table 1, entries 1–3). Furthermore, the
activity of CuI was compared with that of the copper(I) trifluoro-
methanesulfonate/benzene complex which gave a lower yield
of 3a (Table 1, entries 3 and 4). The catalyst loading was
studied in the range of 1 to 5 mol% where 2 mol% of catalyst
loading was found to be sufficient for this transformation
(Table 1, entries 3 and 8–10).
4-Phenyl-3-butyn-2-ol (1a) and thiophenol (2a) were chosen
as model substrates for the optimization of the reaction con-
ditions. Various reaction parameters such as the nature of the
To investigate the temperature effect, the reaction was
carried out at temperatures ranging from 70 °C to reflux
(Table 1, entries 3, 11 and 12). Under the optimised reaction
conditions, the reaction between 1a (1 mmol) and 2a
(1.5 mmol) was run at reflux in the presence of 2 mol% CuI in
Department of Chemistry, BMC, Uppsala University, Box 576, SE-751 23 Uppsala,
Sweden. E-mail: joseph.samec@kemi.uu.se; Fax: (+) 018-471 3818
†Electronic supplementary information (ESI) available: Experimental details,
copies of NMR spectra. See DOI: 10.1039/c3gc41251b
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Table 1 Optimization of reaction conditionsa
Table 2 α-Sulfenylation of propargylic alcohols by aryl thiolsa
Equiv. Catalyst loading Yieldb
Entry
1
R1
R2
2
Ar
3
Yieldb (%)
Entry Catalyst
of 2a
(mol%)
(%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1a
1a
1a
1a
1a
Ph
Ph
Ph
Ph
Me 2a Ph
Et 2a Ph
iPr 2a Ph
2a Ph
Me 2a Ph
Me 2a Ph
3a
3b
3c
3d
3e
3f
3g
3h
3i
94
92
86
96
83
90
91
95
85
90
73
64
1
2
3
4
5
6
7
8
CuCl
CuBr
CuI
1.5
1.5
1.5
2.0
2.0
2.0
2.0
2.0
2.0
2.0
0.0
1.0
5.0
2.0
2.0
Traces
89
97
Traces
—
79
60
—
71
97
H
Cu(I)OTf-Benzene Complex 1.5
Cu(OAc)2
CuI
CuI
CuI
CuI
CuI
CuI
CuI
p-Me–Ph
p-Ph–Ph
m,p-Di-Cl–Ph Me 2a Ph
1-Naph
p-COMe–Ph
p-CF3–Ph
p-COMe–Ph
p-OMe–Ph
Ph
Ph
Ph
Ph
Ph
1.5
1.2
1.0
1.5
1.5
1.5
1.5
1.5
Me 2a Ph
Me 2a Ph
9
9
10
11
12
13
14
15
16
17
18c
19d
20d
21d,e
H
H
H
2a Ph
2a Ph
2a Ph
3j
3k
3l
10
11c
12d
Trace
84
Me 2b p-Br–Ph
Me 2c p-Cl–Ph
Me 2d p-F–Ph
Me 2e p-iPr–Ph
3m 74
3n
3o
3p
77
90
73
64
67
73
75
81
a Reaction conditions: 1a (1 mmol), 2a (1.5 mmol) and Cu-catalyst
(2 mol%), at reflux in 2.0 mL of water for 48 h. b Conversion based on
1H NMR analysis. c The reaction was run at 70 °C. d The reaction was
run at 90 °C.
Me 2f
p-OMe–Ph 3q
1m Et
Me 2a Ph
Me 2a Ph
Me 2a Ph
3r
3s
3t
1n
1o
1p
Cyclopentyl
Cyclohexyl
Ph–CH2–CH2 Me 2a Ph
3u
2 mL of water as solvent for 48 h to produce the desired
product 3a in 97% yield (Table1, entry 3).
a Reaction conditions: 1 (1 mmol), 2 (1.5 mmol) and CuI (2 mol%),
water (2.0 mL) for 48 h at reflux. b Yields refer to isolated yields. c 3
Equiv. of 1j was used with respect to 2a and the yield was calculated
with respect to 2a. d 3 Equiv. of 2a was used with respect to 1 and
the yields were calculated with respect to 1. e The reaction was run
for 72 h.
To test the substrate scope, we examined the transform-
ation between a variety of propargylic alcohols 1a–p and
aromatic thiols 2a–f under the optimized reaction conditions
(Table 2). Both secondary (1a–c) and primary (1d) aromatic
propargylic alcohols reacted with 2a to furnish the corres-
ponding α-sulfenylated aldehyde and ketone products 3a–d in
excellent yields (Table 2, entries 1–4). The electronic character
of the propargylic alcohols did not influence the outcome
of the reaction when water was used as the solvent (Table 2,
entries 5–12). Importantly, alcohols having a strong electron
withdrawing p-COMe (1i, 1k) or electron donating p-OMe (1l)
group at the phenyl ring also tolerated the reaction conditions
to furnish the corresponding products in moderate to good
yields (Table 2, entries 9, 11, and 12). Alcohols with terminal
triple bonds were unreactive under the given reaction
conditions.
We investigated the effect of substituents at the para-
position of the phenyl ring of aryl thiols under the optimized
reaction conditions (Table 2, entries 13–17). It was found that
the reaction of para-bromo (2b) and para-chloro (2c) thiophe-
nols with 1a proceeded to generate the products 3m and 3n in
moderate yields (Table 2, entries 13 and 14). With para-fluoro
thiophenol (2d), 90% yield of the product 3o was achieved
under the given reaction conditions (Table 2, entry 15). The
corresponding gold(I)-catalyzed reaction in 1,2-dichloroethane
generated 48% of 3o in our previous report, showing advan-
tages of the current Cu-catalyzed aqueous system.7 Electron
donating substituents such as -isopropyl (2e) and -methoxy
(2f) in the para position of the phenyl ring of aryl thiols gener-
ated the desired products in 73% and 64% yield respectively
under the optimized reaction conditions (Table 2, entries 16
and 17). This protocol was also successfully applied to pro-
pargylic alcohols having different aliphatic groups at R1-posi-
tion (1m–1p) which provided good to excellent conversions to
the desired products 3r–3u (Table 2, entries 18–21). Aliphatic
thiols were unreactive under the optimized reaction
conditions.
To investigate the scalability of the reaction, the transfor-
mation of 1a and 2a was scaled up to 5 g of alcohol. Gratifyingly,
the reaction proceeded to generate 3a in 90% yield after
48 hours. We would like to investigate whether the catalyst
loading could be decreased in the future.
In order to investigate the greener and economical aspects
of the developed catalytic system, a recyclability study was
carried out for the α-sulfenylation reaction (Fig. 1). The catalyst
was efficiently recycled through four consecutive cycles
without any loss in catalytic activity. After each cycle, the
aqueous reaction mixture was extracted using reusable ethyl
acetate to remove all traces of the product or reactants. The
resulting aqueous solution containing the CuI catalyst was
directly used for the next catalytic cycle.
The reaction proceeded via the formation of a diastereo-
meric mixture of intermediate 4 (Scheme 3) (Z : E = 7 : 2).12 We
were able to isolate and fully characterise intermediate 4
during the course of the reaction. Interestingly, CuI did not
catalyse the transformation of intermediate 4 to 3d alone.
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The reaction is scalable and the catalyst in aqueous phase can
be easily recycled.
Experimental
Representative experimental procedure for the synthesis of
4-phenyl-3-(phenylthio)butan-2-one (3a)
CuI (4 mg, 2 mol%) was weighed and transferred to a 5 mL
vial containing a magnet under a nitrogen atmosphere. The
cap of the vial was closed tightly and 2 mL of degassed water
followed by alcohol 1a (145 μL, 1 mmol) and benzenethiol 2a
(154 μL, 1.5 mmol) were added to the vial by a syringe. The
reaction mixture was stirred using a magnetic stirrer at reflux
for 48 h. After allowing the mixture to cool to room tempera-
ture, the reaction mixture was extracted with ethyl acetate
(3 × 15 mL). The combined organic phase was washed with
water and brine, dried with anhydrous Na2SO4 and concen-
trated under reduced pressure. The residue was purified by
silica-gel (100–200 mesh) column chromatography using a 3%
(v/v) ethyl acetate–pentane solution to afford the desired
product 3a (240 mg, 0.94 mmol, 94%). 1H NMR (300 MHz,
CDCl3): δ = 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 =
Fig. 1 Catalyst recyclability.
Scheme 3 Intermediate 4 formed in the CuI catalysed reaction of 1d and 2a.
6.9 Hz, 8.4 Hz, 1H, H-3), 7.18–7.37 (m, 10H, H-arom) ppm. 13
C
NMR (75 MHz, CDCl3): δ = 28.1, 36.9, 59.0, 127.1, 128.5, 128.8,
129.4, 133.0, 133.3, 138.3, 204.5 ppm.
Catalyst recyclability
The reaction was carried out as mentioned above using 1a
(145 μL, 1 mmol), 2a (154 μL, 1.5 mmol) and CuI (4 mg, 2 mol%).
The reaction mixture was cooled to room temperature after
48 h and was extracted by ethyl acetate (3 × 5 mL). The recov-
ered aqueous layer containing the catalyst (catalyst particles
are suspended in aqueous layer) was washed with ethyl acetate
(3 × 5 mL) to remove all traces of the product or reactants
present. The aqueous layer containing the catalyst was then
directly used as the solvent for the next run of the catalyst
recyclability experiment. The same procedure was followed for
consecutive recycling. The combined organic phase obtained
in each run was concentrated under reduced pressure.
1H NMR of the crude reaction mixture was checked using
toluene as an internal standard and the conversions were
determined by comparing the chemical shift of aromatic
methyl protons of the toluene internal standard at 2.31 ppm
with that of H-3 proton of the product 3a at 3.90 ppm.
Scheme 4 Proposed mechanism.
Instead, a combination of CuI and a catalytic amount of 2a
was required for the isomerization of 4 to 3d. A possible expla-
nation is that a coordination between CuI and 2a acidifies the
thiol proton that protonates the double bond of intermediate
4, thus promoting the 1,2-hydride shift.
A plausible mechanism has been proposed in Scheme 4
similar to that previously reported for the gold mediated
synthesis of α-sulfenylated carbonyl compounds.7 Copper(I)
coordinates to the triple bond of 1d to form a complex A. Thio-
phenol 2a regioselectively attacks the β-position of the triple
bond to form intermediate 4. A CuI coordinated 2a protonates
4
in intermediate B. This protonation promotes the
1,2-hydride transfer and generates 3d (Scheme 4).
The recyclability of the catalyst used was checked up to 4
times and >95% formation of 3a was observed for all the
runs.13
Conclusions
An efficient and environmentally benign route to α-sulfeny-
lated carbonyl compounds catalysed by copper iodide catalyst
in aqueous media has been developed. In this protocol, aryl
thiols and either aromatic alcohols with different electron
Acknowledgements
donating and withdrawing substituents at the phenyl ring or We acknowledge Stiftelsen Olle Engqvist Byggmästare and
aliphatic alcohols are transformed to generate the α-sulfeny- Vetenskapsrådet for financial support. RAW thanks the
lated carbonyl compounds in good to excellent yields. Swedish Institute (SI) for providing a scholarship.
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6 (a) I.-P. Beletskaya and V.-P. Ananikov, Chem. Rev., 2011,
111, 1596; (b) H. Huang, J. Li, C. Lescop and Z. Duan, Org.
Lett., 2011, 13, 5252.
7 S. Biswas and J. S. M. Samec, Chem. Commun., 2012, 48, 6586.
8 α-Thio carbonyls have been prepared from propargylic sulf-
oxides via oxygen transfer and 1,2-thio migration, see:
N. D. Shapiro and F. D. Toste, J. Am. Chem. Soc., 2007, 129,
4160.
9 For copper-catalyzed C–S bond formations through cross-
coupling reactions, see: (a) M. S. Kabir, M. Lorenz,
M. L. V. Linn, O. A. Namjoshi, S. Ara and J. M. Cook, J. Org.
Chem., 2010, 75, 3626 and references cited therein;
(b) G. Yuan, J. Zheng, X. Gao, X. Li, L. Huang, H. Chen and
H. Jiang, Chem. Commun., 2012, 48, 7513; (c) D. Zhu, L. Xu,
F. Wu and B. Wan, Tetrahedron Lett., 2006, 47, 5781.
References
1 (a) R. J. Cremlyn, An Introduction to Organo-Sulfur Chem-
istry, Wiley & Sons, New York, 1996; (b) For a review on
metal catalyzed C–S bond formation, see: 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; (d) P. Bichler and J. Love, in
Topics of Organometallic Chemistry, ed. A. Vigalok, Springer,
Heidelberg, 2010, vol. 31, pp. 39; (e) I. P. Beletskaya and
V. P. Ananikov, Chem. Rev., 2011, 111, 1596; (f)
C. A. Dvorak, W. D. Schmitz, D. J. Poon, D. C. Pryde,
J. P. Lawson, R. A. Amos and A. I. Meyers, Angew. Chem.,
Int. Ed., 2000, 39, 1664, (Angew. Chem., 2000, 112, 1730).
2 (a) D. Giles, M. S. Prakash and K. V. Ramseshu, E-Journal of
Chemistry, 2007, 4, 428; (b) J. Krapcho and C. F. Turk, 10 For a very recent report on the copper-catalyzed arylative
J. Med. Chem., 1973, 16, 776; (c) T. Siatra-Papastaikoudi,
A. Tsotinis, I. Chinou and C. Roussakis, Farmaco, 1994, 49,
221.
Mayer–Schuster rearrangement of propargyl alcohols, see:
B. S. L. Collins, M. G. Suero and M. J. Gaunt, Angew. Chem.,
Int. Ed., 2013, 52, 5799.
3 (a) B. M. Trost, Chem. Rev., 1978, 78, 363; (b) B. M. Trost, 11 (a) G.-L. Li, K. K.-Y. Kung and M.-K. Wong, Chem.
Acc. Chem. Res., 1978, 11, 453; (c) R. B. Woodward,
I. J. Pachter and M. L. Scheinbaum, J. Org. Chem., 1971, 36,
1137; (d) B. M. Trost, T. N. Salzmann and K. Hiroi, J. Am.
Chem. Soc., 1976, 98, 4887.
4 For selected examples, see: (a) M. E. Kuehne, J. Org. Chem.,
1963, 28, 2124; (b) S. Murai, Y. Kuroki, K. Hasegawa and
S. Tsutsumi, J. Chem. Soc., Chem. Commun., 1972, 946;
(c) T. Kumamoto, S. Kobayashi and T. Mukaiyama, Bull.
Chem. Soc. Jpn., 1972, 45, 866; (d) D. Seebach and
M. Teschner, Chem. Ber., 1976, 109, 1601; (e) C. H. Huang,
Commun., 2012, 48, 4112; (b) U. M. Lindström, Chem. Rev.,
2002, 102, 2751; (c) S. Kobayahi and K. Manabe, Acc. Chem.
Res., 2002, 35, 209; (d) N. Akiya and P. E. Savage, Chem.
Rev., 2002, 102, 2725; (e) J. M. DeSimone, Science, 2002,
297, 799; (f) M. Poliakoff, J. M. Fitzpatrick, T. R. Farren and
P. T. Anastas, Science, 2002, 297, 807; (g) C. J. Li, Chem.
Rev., 2005, 105, 3095; (h) D. G. Blackmond, A. Armstrong,
V. Coombe and A. Wells, Angew. Chem., Int. Ed., 2007, 46,
3798, (Angew. Chem., 2007, 119, 3872); (i) S. Minakata and
M. Komatsu, Chem. Rev., 2008, 108, 825.
K.-S. Liao, S. K. De and Y.-M. Tsai, Tetrahedron Lett., 12 (a) For copper-catalyzed regio- and stereoselective addition
2000, 41, 3911; (f) J. S. Yadav, B. V. S. Reddy, R. Jain
and G. Baishya, Tetrahedron Lett., 2008, 49, 3015;
(g) E. Okragla, S. Demkowicz, J. Rachon and D. Witt,
Synthesis, 2009, 1720.
5 (a) A. Klapars, J.-C. Antilla, X. Huang and S.-L. Buchwald,
J. Am. Chem. Soc., 2001, 123, 7727; (b) N.-J. Turner, Chem.
Rev., 2011, 111, 4073; (c) F. Monnier and M. Taillefer,
Angew. Chem., Int. Ed., 2009, 48, 6954.
of thiols to C–C triple bonds, see: I. G. Trostyanskaya and
I. P. Beletskaya, Synlett, 2012, 535; (b) For palladium-
catalyzed regioselective thiophenol addition to conjugated
enynes, see: J.-E. Bäckvall and A. Ericsson, J. Org. Chem.,
1994, 59, 5850; (c) For copper and palladium catalyzed
intramolecular C–S bond formation reactions, see: L. L. Joyce,
G. Evindar and R. A. Batey, Chem. Commun., 2004, 446.
13 >90% product formation was observed after the 5th recycle.
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