Palladium-catalyzed regio- and stereoselective chlorothiolation of terminal alkynes with sulfenyl chlorides

Article abstract of DOI:10.1002/asia.201301295

Chlorothiolation of terminal alkynes with sulfenyl chlorides yields anti-adducts without transition-metal catalysts. In sharp contrast, transition-metal-catalyzed chlorothiolation has not been developed to date, possibly because organosulfur compounds can poison catalyst. Herein, the regio- and stereoselective palladium-catalyzed chlorothiolation of terminal alkynes with sulfenyl chlorides is described. syn-Chlorothiolation offers a complementary synthetic route to chloroalkenyl sulfides. 2-Chloroalkenyl sulfides can easily be transformed into various sulfur-containing products, most of which are often found in natural products and pharmaceuticals. Copyright

Full text of DOI:10.1002/asia.201301295

COMMUNICATION
DOI: 10.1002/asia.201301295
Palladium-Catalyzed Regio- and Stereoselective Chlorothiolation of
Terminal Alkynes with Sulfenyl Chlorides
Masayuki Iwasaki,[a] Tomoya Fujii,[a] Arisa Yamamoto,[a] Kiyohiko Nakajima,[b] and
Yasushi Nishihara*[a]
Abstract: Chlorothiolation of terminal alkynes with sulfenyl
chlorides yields anti-adducts without transition-metal cata-
lysts. In sharp contrast, transition-metal-catalyzed chloro-
thiolation has not been developed to date, possibly because
organosulfur compounds can poison catalyst. Herein, the
regio- and stereoselective palladium-catalyzed chlorothiola-
tion of terminal alkynes with sulfenyl chlorides is described.
syn-Chlorothiolation offers a complementary synthetic route
to chloroalkenyl sulfides. 2-Chloroalkenyl sulfides can easily
be transformed into various sulfur-containing products, most
of which are often found in natural products and pharma-
ceuticals.
Scheme 1. Chlorothiolation of alkynes.
Addition of organosulfur compounds to alkynes is
a straightforward synthetic approach to highly functional-
ized alkenyl sulfides that are a valuable and important class
of compounds in organic synthesis.[1] Among them, success-
ful additions of various carbon–sulfur bonds to alkynes (car-
bothiolation) have been developed with palladium, plati-
num, and rhodium catalysts in the past two decades.[2] Chlor-
othiolation of alkynes has also been studied for many
years[3] because the chlorothiolation adducts, 2-chloroalkenyl
sulfides, are versatile alternatives to the carbothiolation ad-
ducts, which can be converted into various complex alkenyl
sulfides by further transformations. However, it is still diffi-
cult to control regio- and stereoselectivities of chlorothiola-
tion. In principle, chlorothiolation of sulfenyl chlorides 2
across terminal alkynes 1 could give four regio- and stereo-
isomers, that is, (E)/(Z)-3 and (E)/(Z)-4 (Scheme 1). Al-
though anti-addition can proceed without any transition-
metal catalysts and gives (E)-2-chloroalkenyl sulfides (E)-4
as sole products (path a)[3] and the formed adduct (E)-4 pre-
pared was reported to isomerize to (Z)-3 in the presence of
a catalytic amount of 2 (path e),[3d] only 3,3-dimethyl-1-
butyne could be used in this reaction, and long isomeriza-
tion time (1–3 days) is required. Therefore, a complementary,
and more practical synthetic approach to other chlorothiola-
tion adducts (E)/(Z)-3 and (Z)-4 (paths b–d) under mild
conditions has been highly desirable. Meanwhile, as another
example of the addition of chlorine–sulfur bonds to alkynes,
transition-metal-catalyzed chlorosulfonylation of alkynes
has been known to provide the corresponding adducts with
high regio- and stereoselectivities. More recently, Nakamura
and co-workers have investigated the iron-catalyzed chloro-
sulfonylation that delivers anti-addition via a radical path-
way (path b).[4,5] In addition, the copper-catalyzed chlorosul-
fonylation has been communicated to afford syn-adducts
(path c).[6] These examples prompted us to investigate the
transition-metal-catalyzed chlorothiolation of alkynes, be-
cause it is difficult to prepare the resulting (Z)-3 by reduc-
tion of the corresponding alkenyl sulfones synthesized by
the copper-catalyzed chlorosulfonylation.[7] Herein, we
report the highly regio- and stereoselective addition of sulfe-
nyl chlorides 2 to terminal alkynes 1 under palladium cataly-
sis to yield (Z)-2-chloroalkenyl sulfides (Z)-3 with a high ef-
ficiency, according to path c.
[a] Dr. M. Iwasaki, T. Fujii, A. Yamamoto, Prof. Dr. Y. Nishihara
Division of Earth, Life, and Molecular Sciences
Graduate School of Natural Science and Technology
3-1-1 Tsushimanaka, Kita-ku, Okayama 700-8530 (Japan)
Fax : (+81)86-251-7855
We found that phenylacetylene (1a) reacted with benze-
nesulfenyl chloride (2a) in the presence of 10 mol% of Pd-
AHCTUNGRTEG(NUNN tfa)2 (tfa=trifluoroacetate) in toluene at 258C to give (Z)-
2-chloro-2-phenylethenyl phenyl sulfide ((Z)-3a) in 84%
yield, as determined by NMR spectroscopy, with high regio-
and stereoselectivities (Table 1, entry 1). The reaction was
completed within 2 h, while a prolonged reaction time of
E-mail: ynishiha@okayama-u.ac.jp
[b] Prof. Dr. K. Nakajima
Department of Chemistry
Aichi University of Education
Igaya, Kariya 448-8542 (Japan)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201301295.
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Y. Nishihara et al.
Table 1. Chlorothiolation of phenylacetylene (1a) with benzenesulfenyl
chloride (2a).[a]
To confirm the configuration of the adduct (Z)-3a unam-
biguously, the liquid (Z)-3a was oxidized with mCPBA (m-
chloroperoxybenzoic acid) to the corresponding crystalline
sulfoxide 5 (Scheme 2). X-ray crystallographic analysis re-
vealed that sulfoxide
5 was in the (Z)-configuration
(Figure 1).[10]
Entry
Catalyst
Solvent
Yield [%][b]
(Z)-3a
(E)-4a
1
Pd
Pd
none
none
Pd
Pd
PdCl2
CuCl
CuCl2
Pd
Pd
Pd
Pd
Pd
U
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
1,4-dioxane
benzene
EtOAc
CH2Cl2
hexane
84 (79)
73
0
3
4
2[c]
3
13
67
<1
<1
5
7
11
0
2
2
27
5
4[d]
5
6
7
8
0
58
36
10
0
Scheme 2. Oxidation of (Z)-3a.
9
0
10
11
12
13
14
67
63
63
39
5
[a] Conditions: 1a (0.2 mmol), 2a (0.24 mmol), catalyst (10 mol%), tolu-
ene (2.4 mL). [b] Yields were determined by the 1H NMR spectroscopic
analysis of a crude mixture using dibenzyl ether as an internal standard.
An isolated yield based on 1a after silica gel column chromatography is
shown in parenthesis. [c] Performed for 12 h. [d] Performed at 1108C for
12 h.
Figure 1. ORTEP drawing of 5 with thermal ellipsoids at the 50% proba-
bility level. Hydrogen atoms, except for that on C1, are omitted for clari-
ty.
With the optimized reaction conditions in hand, we then
introduced a range of terminal alkynes 1 into the reactions
with sulfenyl chlorides 2. Chlorothiolation of various aro-
matic alkynes gave the corresponding syn-adducts (Z)-3a–
3 f in moderate to good yields with high regio- and stereose-
lectivities (Table 2, entries 1–6). The reactions of electron-
rich alkynes gave higher yields than those of electron-defi-
cient alkynes, suggesting that a stronger coordination of 1 to
palladium facilitates the migratory insertion step (see
12 h did not improve the yield of (Z)-3a (Table 1, entry 2).
By contrast, in the absence of the palladium catalyst, the
anti-adduct (E)-4a was obtained as a sole product in 13%
yield under identical conditions (Table 1, entry 3). We
assume that without the palladium catalyst compound (E)-
4a was formed through the formation of thiirenium inter-
mediate and the subsequent nucleophilic attack of the coun-
ter chloride ion at the less hindered carbon, as proposed in
the literature.[3] It is found that palladium-catalyzed syn-
chlorothiolation was much faster than anti-addition, and
indeed 61% of the palladium-catalyzed product (Z)-3a was
formed after 5 min.[8] Although anti-chlorothiolation of an
alkyne in polar ethyl acetate was known to proceed quanti-
tatively at room temperature,[3d] it took 12 h to obtain (E)-
4a in 67% yield in toluene even at reflux (Table 1, entry 4).
Table 2. Palladium-catalyzed chlorothiolation of terminal alkynes 1 with
sulfenyl chlorides 2.[a]
Yield [%][b]
PdACHTUNGTRENNUNG(OAc)2, PdACHTUNGTRENNUNG(dba)2 (dba=dibenzylideneacetone), and
Entry
R
R’
Product
PdCl2 were found to perform poorly (entries 5–7). It is note-
worthy that the palladium catalysts suppress the formation
of (E)-4a, probably due to a strong coordination of palladi-
um to 1 (Table 1, entry 3 vs. entries 1, 5–7). Although
copper salts CuCl and CuCl2 are known to catalyze the
chlorosulfonylation of alkynes,[4] they proved ineffective cat-
alysts for chlorothiolation (Table 1, entries 8 and 9).[9] The
addition of phosphine ligands (PPh3, PCy3, or dppf; dppf=
1,1’-bis(diphenylphosphino)ferrocene) decreased the yields
of (Z)-3a. Toluene proved to be the best solvent, whereas
1,4-dioxane, benzene, ethyl acetate, dichloromethane, and
hexane were inferior (Table 1, entries 10–14). At higher con-
centrations, decomposition of 2a occurred and substantial
amounts of diphenyl disulfide were detected.
1
2
3
4
5
6
7
8
Ph
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
4-MeC6H4 (2b)
4-MeOC6H4 (2c)
4-BrC6H4 (2d)
4-F3CC6H4 (2e)
2-MeC6H4 (2 f)
(Z)-3a
(Z)-3b
(Z)-3c
(Z)-3d
(Z)-3e
(Z)-3 f
(Z)-3g
(Z)-3h
(Z)-3i
(Z)-3j
(Z)-3k
(Z)-3l
(Z)-3m
79
79
62
53
41
36
55
39
80
64
37
42
66
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-F3CC6H4
4-NCC6H4
tBu
Me3Si
9
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
10
11
12
13
[a] Conditions: 1 (0.5 mmol), 2 (0.6 mmol), PdACTHNUTRGENUG(N tfa)2 (10 mol%), toluene
(6 mL). Small amounts of (E)-4 (1–9%) were present as minor products.
[b] Isolated yields based on 1 after silica gel column chromatography.
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Y. Nishihara et al.
below). The reaction of aliphatic terminal alkynes such as 1-
octyne and propargylbenzene gave a mixture of the isomers
(Z)-3 and (E)-4 with poor selectivity, whereas the sterically
hindered terminal alkynes such as 3,3-dimethyl-1-butyne
and trimethylsilylacetylene underwent the selective reaction
to yield the corresponding adducts (Z)-3g and (Z)-3h, re-
spectively (Table 2, entries 7 and 8). This selectivity can be
rationalized by considering that the electron-rich aliphatic
alkynes would accelerate non-catalyzed anti-addition, but
that the steric bulkiness of the substituents would avoid the
nucleophilic attack of the chloride counterion after the for-
mation of the thiirenium species in the uncatalyzed pathway.
On the other hand, internal alkynes such as 4-octyne and di-
phenylacetylene did not give the desired products (Z)-3
under optimized reaction conditions and instead gave anti-
products (E)-4 in 78% and 3%, respectively. These results
imply that two substituents of internal alkyne would sup-
press a coordination of palladium to the alkynes and conse-
quently lead to an acceleration of the non-catalyzed anti-ad-
dition.
Next, a variety of sulfenyl chlorides 2 were examined for
the chlorothiolation of 1a. Electron-rich aromatic sulfenyl
chlorides 2b and 2c reacted smoothly (Table 2, entries 9 and
10). The reaction of the brominated substrate 2d occurred
to provide the corresponding adduct (Z)-3k, and left the
bromo substituent intact (Table 2, entry 11). Electron-defi-
cient 2e also participated in the reaction, albeit in low yield
(Table 2, entry 12). A substituent at the ortho-position did
not retard the reaction to afford (Z)-3m in 66% yield
(entry 13).
tered radical forms divalent palladium species, in which co-
ordination of sulfur to palladium controls the regioselectivi-
ty to form the (Z)-alkenylpalladium species. Finally, reduc-
tive elimination affords the adducts and regenerates Pd0. We
then investigated the reaction of 1a with 2a in the presence
of a radical scavenger (Scheme 3). Consequently, we deter-
Scheme 3. Reactions in the presence of radical scavengers.
mined that even in the presence of TEMPO (2,2,6,6-tetra-
methylpiperidine 1-oxyl) or garvinoxyl the chlorothiolation
proceeded smoothly to form (Z)-3a in 60% and 68% yields,
respectively. We also did not observe any adduct of radical
scavengers in both reactions. These results strongly rule out
a radical process.
The utility of the chlorothiolation adducts (Z)-3 is illus-
trated in Scheme 4. The adduct (Z)-3a was treated with
mCPBA to afford the corresponding sulfone 6, which was
then treated with a thiol to give the vic-difunctionalized
alkene 7[21] bearing two different arylthio groups. Dithioal-
kene 7 is a potent ligand for transition-metal-catalyzed allyl-
ic substitution reactions,[22] which cannot be prepared from
anti-adduct (E)-4.
Although the reaction mechanism of the present chloro-
thiolation is not clear at this stage, one of the possible reac-
tion mechanisms is a Pd0/PdII pathway initiated by oxidative
addition of the sulfenyl chlorides 2 to Pd0, which has prece-
dent in the transition-metal-catalyzed addition of thiocya-
nates[11] and disulfides[12] to alkynes. Therein, oxidative addi-
tion of 2 to Pd0 would afford a chloropalladium(II) arene-
thiolate complex.[13] The subsequent chloropalladation of
terminal alkynes 1 in a syn-fashion affords 2-chloro-1-alke-
nylpalladium species.[14] Sequential reductive elimination de-
livers 3 and regenerates the initial Pd0 catalyst. We believe
that high regioselectivity can be attributed to a steric control
as the relatively bulky palladium moiety adds to the termi-
nal carbon of the alkynes. Reported examples of the inser-
tion of alkynes into a chlorine–palladium bond[15,16] are sug-
gestive of this mechanism, although the other pathways
through thiopalladation cannot be ruled out.[17,18] While it
was reported anti-adduct (E)-4 can isomerize into syn-
adduct (Z)-3 with a slight excess of sulfenyl chloride,[3d] no
isomerization was observed under our reaction conditions.[19]
Homolytic cleavage of the chlorine–sulfur bond in 2 could
occur,[4a–c,5,20] and so the reaction has the possibility to pro-
ceed via a radical pathway. Single-electron transfer (SET)
from Pd0 to sulfenyl chloride generates PdICl and a sulfenyl
radical. The subsequent radical addition at the less hindered
position of terminal alkyne gives the corresponding alkenyl
radical species. Recombination of PdICl with carbon-cen-
Scheme 4. Transformation of (Z)-3a.
Since the in situ synthesis of 2 from the corresponding
thiols and N-chlorosuccinimide (NCS) has been widely uti-
lized,[23] a more practical sequence with chlorination of thiol
and subsequent chlorothiolation of 1a was envisaged. Thus,
the in situ prepared 2a, derived from chlorination of benze-
nethiol with NCS, was treated with 1a and PdACTHNURGTNEUNG(tfa)2 to give
(Z)-3a in 83% overall yield (Scheme 5a). Encouraged by
the success of this one-pot synthesis of (Z)-3a, we thus in-
vestigated chlorothiolation with aliphatic sulfenyl chlorides.
Since methanesulfenyl chloride (2g) was found to be unsta-
ble and to decompose easily on the bench top, we per-
formed the one-pot reaction of phenylacetylene (1a), start-
ing from dimethyl disulfide. To our delight, chlorothiolation
proceeded to give the corresponding product (Z)-3n in 36%
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Y. Nishihara et al.
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3n.
1
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yield (Scheme 5b). These results suggest that various sulfe-
nyl chlorides, even those that are difficult to isolate, could
be utilized directly in the present reaction, which in turn
would expand the generality of the chlorothiolation reac-
tion.
In summary, we have developed the first regio- and ste-
reoselective addition of sulfenyl chlorides to terminal al-
kynes catalyzed by a palladium complex under mild condi-
tions. This synthetic approach can provide stereodefined al-
kenyl sulfides in a facile and straightforward manner. Stud-
ies on the detailed reaction mechanism and the application
of this reaction to the synthesis of sulfur-containing complex
molecules are currently in progress.
[8] See the Supporting Information for details of time courses with or
without the palladium catalyst.
[9] See the Supporting Information for detailed optimization studies.
[10] CCDC 931649 contains the supplementary crystallographic data for
5. These data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/
cif.
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Experimental Section
A typical procedure for palladium-catalyzed addition of sulfenyl chlor-
ides to terminal alkynes: Under an argon atmosphere, palladium trifluor-
oacetate (6.6 mg, 0.02 mmol) was placed in a 20 mL Schlenk tube. Tolu-
ene (0.80 mL) was then added at room temperature. The resulting sus-
pension was stirred for 5 min, and benzenesulfenyl chloride (2a, 34.7 mg,
0.24 mmol) was added. Phenylacetylene (1a, 20.4 mg, 0.20 mmol) in tolu-
ene (1.6 mL) was added dropwise to the reaction mixture. The mixture
was stirred at room temperature for 2 h. Saturated sodium thiosulfate so-
lution (5 mL) was added to quench the reaction. The mixture was ex-
tracted with ethyl acetate (3ꢁ5 mL). The combined organic layers were
dried over anhydrous magnesium sulfate and concentrated under reduced
pressure. The resulting residue was purified by silica gel column chroma-
tography (hexane) to give (Z)-2-chloro-2-phenylethenyl phenyl sulfide
((Z)-3a) (38.9 mg, 0.158 mmol, 79%).
[13] Oxidative addition of the chlorine–sulfur bond in sulfenyl chlorides
is known: N. Arnau, M. Moreno-MaÇas, R. Pleixats, Tetrahedron
1993, 49, 11019–11028.
[14] Although we performed a stoichiometric reaction of [PdClACHTUNGTRENNUNG(SPh)]n
with phenylacetylene (2a), the expected adduct (E)-3a was not ob-
tained, from which the present mechanism was still inconclusive.
See the Supporting Information for the experimental results.
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Acknowledgements
We thank Ms. Megumi Kosaka and Mr. Motonari Kobayashi at the De-
partment of Instrumental Analysis, Advanced Science Research Center,
Okayama University for the measurement of elemental analyses and SC-
NMR Laboratory of Okayama University for the NMR spectra measure-
ment. This work was partly supported by Okayama Foundation for Natu-
ral Sciences and Technology.
Keywords: addition
·
alkynes
·
chlorothiolation
·
[16] Lewis acid-catalyzed additions of acid chlorides and benzyl halides
to alkynes were reported, see: a) A. Miller, M. Moore, Tetrahedron
homogeneous catalysis · palladium
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unlikely. See the Supporting Information for the experimental re-
sults.
[19] See the Supporting Information for details of isomerization.
[20] a) A. G. Larsen, A. H. Holm, M. Roberson, K. Daasbjerg, J. Am.
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[17] The stoichiometric reactions of trans-[PtClACTHNUTRGENNUG(SAr)ACHTUNGTREN(NGUN PPh3)2] with al-
kynes were reported to provide the alkenylplatinum complexes via
À
an insertion of alkynes into Pt S bonds: a) H. Kuniyasu, F. Yama-
shita, J. Terao, N. Kambe, Angew. Chem. 2007, 119, 6033–6037;
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[22] R. Tokunoh, M. Sodeoka, K.-I. Aoe, M. Shibasaki, Tetrahedron Lett.
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[18] It is of note that catalytic and stoichiometric reactions of 1a with 2a
in the presence of PdBr2 did not give the corresponding bromothio-
lation adduct but rather chlorothiolation adduct (Z)-3a as a sole
product. These results imply that the PdII/PdIV mechanism is thus
Received: September 23, 2013
Published online: && &&, 0000
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Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
These are not the final page numbers! ÞÞ

COMMUNICATION
Synthetic Methods
Masayuki Iwasaki, Tomoya Fujii,
Arisa Yamamoto, Kiyohiko Nakajima,
Yasushi Nishihara*
&&&& — &&&&
Pick and choose: The first chlorothio-
lation of alkynes in a syn-fashion is
achieved by cleavage of the chlorine–
sulfur bond in sulfenyl chlorides. Treat-
ment of terminal alkynes with sulfenyl
chlorides in the presence of palladium
catalyst at ambient temperature leads
to (Z)-2-chloroalkenyl sulfides with
high regio- and stereoselectivities.
tfa=trifluoroacetate.
Palladium-Catalyzed Regio- and Ste-
reoselective Chlorothiolation of
Terminal Alkynes with Sulfenyl Chlor-
ides
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Chem. Asian J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!