"Ligand-free" CuI-catalyzed highly efficient intramolecular S-vinylation of thiols with vinyl chlorides and bromides

Article abstract of DOI:10.1021/jo802235e

(Chemical Equation Presented) With CuI as the catalyst and K ₃PO₄·3H₂O as the base, highly efficient intramolecular S-vinylation of thiols with vinyl chlorides or bromides was successfully implemented without the help of a

Full text of DOI:10.1021/jo802235e

synthesis of substituted cyclopentenones via Ramberg-Ba¨cklund
reactions.2 They are also effective substitutes for unreactive cis-
dienes in Diels-Alder reactions.3 Vedejs et al. utilized the 1,4-
addition of an amine to dihydrothiopyran-4-ones to construct
the eight-membered ring intermediate for the synthesis of
pyrrolizidine alkaloid octonecine.4 More recently, Oh reported
the synthesis of the biotin core from a simple cyclic vinyl
sulfide.5 Despite the significance of heterocyclic thioenol ethers
in organic chemistry, methods for their synthesis are few and
are dominated by the intramolecular nucleophilic substitution6
or thio-Michael addition7 reactions. Other methods include the
iodocyclization of alkynyl sulfides,8 the nickel-catalyzed electro-
reduction of unsaturated thioacetates and thiosulfonates,9 as well
as indirect methods that do not involve the formation of C-S
bonds.10 These strategies suffer from either low efficiency or
limited scope of application. It is therefore highly desirable to
develop efficient and general methods for the preparation of
heterocyclic thioenol ethers. We report here that the copper-
catalyzed intramolecular S-vinylation of thiols with vinyl
chlorides or bromides provides a convenient and efficient entry
to 2-alkylidene-substituted thietanes, tetrahydrothiophenes, and
tetrahydro-2H-thiopyrans.
“Ligand-Free” CuI-Catalyzed Highly Efficient
Intramolecular S-Vinylation of Thiols with Vinyl
Chlorides and Bromides
Qiwu Zhao,‡ Ling Li,§ Yewen Fang,† Deqian Sun,‡ and
Chaozhong Li*,†,‡,§
Shanghai Institute of Organic Chemistry, Chinese Academy
of Sciences, 354 Fenglin Road, Shanghai 200032,
People’s Republic of China, Department of Chemistry,
UniVersity of Science and Technology of China, Hefei,
Anhui 230026, People’s Republic of China, and Department
of Chemistry, Tongji UniVersity, 1239 Siping Road,
Shanghai 200092, People’s Republic of China
clig@mail.sioc.ac.cn
ReceiVed October 07, 2008
Metal-catalyzed C-S bond formations have played an
important role in organosulfur chemistry.11 With the renaissance
of Ullmann coupling in the past few years,12 the copper-
catalyzed cross-coupling reactions of thiols and aryl halides have
been demonstrated to be a powerful tool in the formation of
aryl C-S bonds.13 By the appropriate choice of copper source,
ligand, and base, these coupling reactions have been developed
to include a wide range of substrates under mild conditions.13
The high stability and low cost of the copper catalysts, along
with the easy availability of the ligands, make these transforma-
tions a superior choice in organic synthesis.14 This method was
then successfully extended to the intermolecular S-vinylation
of thiols with vinyl iodides or bromides.15 However, the
With CuI as the catalyst and K3PO4 ·3H2O as the base, highly
efficient intramolecular S-vinylation of thiols with vinyl
chlorides or bromides was successfully implemented without
the help of an additional ligand. Moreover, the competition
experiments revealed that the 4-exo cyclization is funda-
mentally preferred over other modes (5-exo, 6-exo, and
6-endo) of cyclization.
(3) (a) Ward, D. E.; Gai, Y Can. J. Chem. 1997, 75, 681. (b) Ward, D. E.;
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3613.
Heterocyclic thioenol ethers are a group of sulfur heterocycles
with important biological interest.1 For example, the vinyl sulfide
cyclized analogues of the octapeptide angiotension II show the
agonist activity with Ki values less than 2 nM.1c Another typical
example is Griseoviridin, which contains a nine-membered
cyclic vinyl sulfide moiety and serves as a broad-spectrum
antibiotic.1d In the meantime, heterocyclic thioenol ethers are
also useful intermediates in organic synthesis.1-5 Conjugated
cyclic thioenol ethers have been used as precursors for the
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† Chinese Academy of Sciences.
‡ University of Science and Technology of China.
§ Tongji University.
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Budriesi, R.; Carosati, E.; Chiarini, A.; Cosimelli, B.; Cruciani, G.; Ioan, P.;
Spinelli, D.; Spisani, R. J. Med. Chem. 2005, 48, 2445. (c) Johannesson, P.;
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10.1021/jo802235e CCC: $40.75
Published on Web 11/26/2008
2009 American Chemical Society
J. Org. Chem. 2009, 74, 459–462 459

TABLE 1. Optimization of the Synthesis of 2a from 1a
TABLE 2. Synthesis of 2-Alkylidenethietanes 2
entrya
ligandb
base
Cs2CO3
solvent
yield (%)c
1
A
THF
0
2
3
4
5
6
7
8
9
10
11
12
13
14d
A
A
B
C
D
E
F
F
F
F
none
none
none
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
K3PO4 ·3H2O
DABCO
K3PO4 ·3H2O
none
CH3CN
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
trace
77
66
73
78
69
78
71
86
80
86
0
K3PO4 ·3H2O
0
a Reaction conditions: 1a (0.3 mmol), CuI (0.03 mmol), ligand (0.06
mmol), base (0.6 mmol), solvent (3 mL), reflux, 6 h. b A: 1,10-
phenanthroline. B: N,N′-dimethylethylenediamine. C: 3,4,7,8-tetra-
methyl-1,10-phenanthroline. D: Me2NCH2CO2H·HCl. E: L-proline. F:
triphenylphosphine. c Isolated yield based on 1a. d No CuI was used.
corresponding intramolecular S-vinylation remains virtually
unexplored. Owing to our interest in Cu(I)-catalyzed intra-
molecular vinylation reactions,16 we set out to pursue this
possibility.
a Reaction conditions: 1 (0.3 mmol), CuI (0.03 mmol), K3PO4 ·3H2O
(0.6 mmol), solvent (3 mL), reflux. Dioxane was used as the solvent for
the reactions of chlorides while acetonitrile was used as the solvent for
the reactions of bromides. b Isolated yield based on 1.
Thus, 2-chloroundec-1-ene-4-thiol (1a), which was readily
prepared from the corresponding homoallylic alcohol via
conventional methods, was used as the model substrate for the
optimization of reaction conditions. The results are summarized
in Table 1. Substrate 1a was first subjected to the following
typical conditions for Ullmann coupling: 10 mol % of CuI, 20
mol % of 1,10-phenanthroline (A), 2 equiv of Cs2CO3, THF,
reflux. No reaction occurred. Increasing the temperature to 80
°C (CH3CN, reflux) did not help. However, when the reaction
was carried out in refluxing dioxane for 6 h, the expected
coupling product 2a was achieved in 77% yield along with 22%
of 1a recovered. We then screened the ligands.17 Surprisingly,
all the ligands screened (A-F) gave similar results (entries 3-8,
Table 1). We next examined the effects of different bases. Again,
almost no difference could be observed (entries 8-11, Table
1). These results let us suspect that the ligands might not
participate in the coupling reaction at all because dramatically
different effects of ligands are usually observed in Ullmann
coupling. Indeed, we were pleased to find that, in the absence
of a ligand, the C-S coupling proceeded smoothly (entry 12,
Table 1). On the other hand, without CuI or a base, no
cyclization product could be obtained (entries 13 and 14, Table
1). The above data also suggested that the substrate thiol itself
functions as the ligand. Since thiols bind to Cu(I) more strongly
than many other ligands,18 the presence of an additional ligand
(A-F) did not make a difference.
(13) (a) Sperotto, E.; van Klink, G. P. M.; de Vries, J. G.; van Koten, G. J.
Org. Chem. 2008, 73, 5625. (b) Rout, L.; Saha, P.; Jammi, S.; Punniyamurthy,
T. Eur. J. Org. Chem. 2008, 640. (c) Rout, L.; Sen, T. K.; Punniyamurthy, T.
Angew. Chem., Int. Ed. 2007, 46, 5583. (d) Zhang, H.; Cao, W.; Ma, D. Synth.
Commun. 2007, 37, 25. (e) Zhu, D.; Xu, L.; Wu, F.; Wan, B. Tetrahedron Lett.
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L. L.; Evindar, G.; Batey, R. A. Chem. Commun. 2004, 446. (h) Deng, W.; Zou,
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Synlett 2003, 1789. (j) Naus, P.; Leseticky, L.; Smrcek, S.; Tislerova, I.; Sticha,
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Tetrahedron Lett. 1998, 39, 543.
(14) For the latest selected examples of aryl C-S coupling catalyzed by other
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Ed. 2008, 47, 2880. (b) Zhang, Y.; Ngeow, K. C.; Ying, J. Y. Org. Lett. 2007,
9, 3495. (c) Itoh, T.; Mase, T. Org. Lett. 2007, 9, 3687. (d) Fernandez-Rodriguez,
M. A.; Shen, Q.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 2180. (e) Fernandez-
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C. J. Org. Chem. 2008, 73, 8665.
The above optimized conditions (10 mol % of CuI, 2 equiv
of K3PO4 ·3H2O, dioxane, reflux) were then applied to the
reactions of a variety of homoallylic thiols 1b-1k, and the
results are summarized in Table 2. In all the cases tested, the
expected 4-exo cyclization product thietanes 2 were achieved
(17) 1,10-Pheneanthroline: (a) Wolter, M.; Klapars, A.; Buchwald, S. L Org.
Lett. 2001, 3, 3803. N,N′-Dimethylethylenediamine: (b) Klapars, A.; Huang, X.;
Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 7421. 3,4,7,8-Tetramethyl-1,10-
phenanthroline: (c) Normann, G.; Buchwald, S. L. J. Am. Chem. Soc. 2003,
125, 4978 N,N′-Dimethylglycine hydrochloride: (d) Ma, D.; Cai, Q. Org. Lett.
2003, 5, 3799. L-Proline: (e) Ma, D.; Cai, Q.; Zhang, H. Org. Lett. 2003, 5,
2453.
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460 J. Org. Chem. Vol. 74, No. 1, 2009

TABLE 3. Intramolecular S-Vinylation of Thiols 3
TABLE 4. Preference of 4-exo Ring Closure
a Reaction conditions: 5 (0.3 mmol), CuI (0.03 mmol), K3PO4 ·3H2O
(0.6 mmol), CH3CN (3 mL), reflux, 0.5 h. b Isolated yield based on 5.
Among various modes of cyclization investigated, the 5-exo
cyclization seemed to have a rate comparable to that of the
corresponding 4-exo cyclization, while a relatively longer
reaction time was required for 6-exo or 6-endo cyclization. We
recently reported that 4-exo ring closure is fundamentally
preferred in the Cu(I)-catalyzed O- and N-vinylation.15d,f It is
therefore interesting to see if this is also the case in the
S-vinylation of thiols. Thus, dibromides 5a-5d, each having
two possible modes of cyclization, were prepared and subjected
to the optimized conditions. We were delighted to find that, in
all the cases, only the corresponding 4-exo cyclization products
6a-6d were achieved, respectively (Table 4). These competition
experiments clearly illustrated that the 4-exo cyclization is
intrinsically favored over the 5-exo (5a and 5b), 6-exo (5c) and
6-endo (5d) cyclization. The results in Table 4, along with our
previous observations,15d,f strongly indicated that the preference
of the uncommon 4-exo ring closure is a common phenomenon
in Cu(I)-catalyzed vinylation reactions. Although the reason for
such a preference remains unclear, it could be possible that the
transition state for 4-exo cyclization as a Cu-containing five-
membered ring is sterically more accessible. Theoretical analyses
on this assumption are currently underway in our laboratory
and will be reported in due course.
In conclusion, the Cu(I)-catalyzed intramolecular S-vinylation
of thiols with vinyl halides has been investigated for the first
time. Our efforts have revealed that these coupling processes
are highly efficient under mild and “ligand-free” conditions,
allowing the use of vinyl chlorides as the substrates. More
importantly, the 4-exo ring closure is fundamentally preferred
over other modes of cyclization, illustrating the unique property
of Cu(I) catalysis. Furthermore, the assumption that the substrate
thiols also act as the ligands should encourage the exploration
of sulfur-based ligands for more effective Ullmann coupling,
which is currently pursued in our laboratory.
a Reaction conditions: 3 (0.3 mmol), CuI (0.03 mmol), K3PO4 ·3H2O
(0.6 mmol), CH3CN (3 mL), reflux. b Isolated yield based on 3.
in good to excellent yields. Vinyl bromides were more reactive
than the corresponding chlorides, and their reactions proceeded
at a lower temperature (CH3CN, reflux) and were complete
within a shorter period of time. The configuration of the CdC
bond was nicely retained as evidenced by the reactions of 1j
and 1k (entries 10 and 11, Table 2). Primary thiols had a
performance similar to that of secondary thiols. Tertiary thiols
were not screened because of their difficult preparations. It
should be noted that the intermolecular C-S coupling reported
in the literature13,14 required the use of alkenyl iodides or
bromides, and the reactions were typically performed at 80-110
°C. Thus, the successful S-vinylation with alkenyl chlorides
shown above clearly demonstrated the ease of the S-vinylation
via a 4-exo mode of cyclization.
The above strategy was then extended to the C-S bond
formation via other modes of cyclization (Table 3). Thiols 3a
and 3b underwent 5-exo cyclization in refluxing CH3CN to
afford the desired products 4a and 4b in high yields. The
reactions of substrates 3c-3e also proceeded smoothly, and the
expected 2-methylenetetrahydrothiophenes, which could be
observed by their crude NMR spectra, isomerized during flash
chromatography on basic alumina to give products 4c-4e,
respectively. The gem-dimethyl substitution helped to stabilize
the exocyclic double bond in 4f, and no isomerization could be
observed. Other than 5-exo cyclization, the 5-endo (3g), 6-exo
(3h), and 6-endo (3i) ring closure were also successful under
the optimized conditions.
Experimental Section
Typical Procedure for the Copper-Catalyzed S-Vinylation
of Thiols with Vinyl Halides. The mixture of 2-chloroundec-1-
ene-4-thiol (1a, 66 mg, 0.3 mmol), CuI (5.7 mg, 0.03 mmol), and
K3PO4 ·3H2O (160 mg, 0.6 mmol) in dioxane (3 mL) was refluxed
for 6 h under nitrogen atmosphere. The resulting mixture was cooled
to room temperature and filtered. The filtrate was concentrated in
The above results clearly demonstrated the efficiency of
copper catalysis in the intramolecular S-vinylation of thiols.
J. Org. Chem. Vol. 74, No. 1, 2009 461

vacuo, and the crude product was purified by flash chromatography
on basic alumina with hexane/Et3N (100:1, v/v) as the eluent to
give the pure product 2a as a colorless oil: yield 48 mg (86%); IR
(film) ν (cm-1) 2956, 2926, 2855, 1632, 1466, 1131, 829, 722, 651;
1H NMR (300 MHz, CDCl3) δ 0.88 (3H, t, J ) 6.5 Hz), 1.27 (10H,
m), 1.76-1.83 (2H, m), 3.10-3.15 (1H, m), 3.56-3.67 (2H, m),
4.70 (1H, d, J ) 1.8 Hz), 4.81 (1H, d, J ) 1.5 Hz); 13C NMR
(75.4 MHz, CDCl3) δ 14.1, 22.6, 27.2, 29.1, 29.2, 31.8, 38.8, 43.8,
103.3, 141.3; EIMS m/z (rel intensity) 184 (M+, 28), 141 (3), 127
(7), 113 (33), 99 (100), 85 (15), 81 (32). Anal. Calcd for C11H20S:
C, 71.67; H, 10.94. Found: C, 71.48; H, 11.09.
20832006) and by the Shanghai Municipal Committee of
Science and Technology (Grant No. 07XD14038). We thank
Miss Shana Zhu of Shanghai Institute of Organic Chemistry
for doubling-checking the experimental data.
Supporting Information Available: Experimental proce-
dures for S-vinylation and the characterizations of 1-6. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. This project was supported by the Na-
tional NSF of China (Grant Nos. 20672136, 20702060, and
JO802235E
462 J. Org. Chem. Vol. 74, No. 1, 2009