Palladium-Catalyzed Arylthiolation of Alkynes Enabled by Surmounting Competitive Dimerization of Alkynes

Article abstract of DOI:10.1021/acs.orglett.9b03056

By overcoming the unwanted catalytic dimerization of terminal alkynes, palladium-catalyzed carbothiolation of alkynes with heteroaryl sulfides has been accomplished to provide the corresponding β-heteroaryl alkenyl sulfides with high regio- and stereosele

Full text of DOI:10.1021/acs.orglett.9b03056

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Palladium-Catalyzed Arylthiolation of Alkynes Enabled by
Surmounting Competitive Dimerization of Alkynes
Daisuke Uno, Keisuke Nogi, and Hideki Yorimitsu*
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan
S
* Supporting Information
ABSTRACT: By overcoming the unwanted catalytic dimeri-
zation of terminal alkynes, palladium-catalyzed carbothiolation
of alkynes with heteroaryl sulfides has been accomplished to
provide the corresponding β-heteroaryl alkenyl sulfides with
high regio- and stereoselectivity. The key for the preferential
arylthiolation is the use of arylsulfanyl segments, instead of
alkylsulfanyl, for smooth C(heteroaryl)−SR1 bond cleavage
and/or of alkylacetylenes that are reluctant to undergo the dimerization. The reaction proceeds under mild and neutral
conditions, with various functionalities being thus tolerated.
ransition-metal-catalyzed addition of organosulfur com-
pounds to alkynes with cleavage of the C−S bonds of the
Scheme 1. Reported and Attempted Arylthiolations of
Alkynes with Aryl Sulfides
T
starting molecules is one of the most ideal methods for the
synthesis of complex alkenyl sulfides in an atom economical
manner.1 Such transformations, carbothiolation of alkynes, have
been achieved mainly with relatively activated organosulfur
compounds including thioesters,2 thioanhydrides,3 thiocarbon-
ates,4 thiocarbamates,5 iminosulfides,6 thiocyanates,7 α-thio-
ketones,8 allyl sulfides,9 alkenyl sulfides,10 and alkynyl sulfides.11
Among these addition reactions, arylthiolation with aryl
sulfides can offer simultaneous incorporation of aromatic rings
and sulfanyl groups onto alkynes to afford β-arylated alkenyl
sulfides. However, owing to the lower reactivity of aryl sulfides,
there has been only two examples of the arylthiolation of alkynes
with aryl sulfides.12−14 In 2012, Weller and Willis reported
rhodium-catalyzed arylthiolation of terminal alkynes with aryl
sulfides having carbonyl directing groups at the ortho positions
(Scheme 1a).12 Nishihara recently reported directing-group-free
arylthiolation of alkynes with a Pd−NHC (N-heterocyclic
carbene) catalyst.13 However, only azolyl sulfides are applicable
to Nishihara’s arylthiolation, and, for instance, the reaction of 2-
benzothienyl methyl sulfide (1a) with phenylacetylene (2a)
gave addition product 3aa in only 12% yield (Scheme 1b).
We have been interested in catalytic C−S-cleaving trans-
formations of organosulfur compounds.11b,15−17 For example,
we reported the palladium-catalyzed gem-arylthiolation of
isocyanides with heteroaryl sulfides in which isocyanides insert
into the C(heteroaryl)−S bonds of the sulfides.18 As a part of
our interest in development of catalytic transformations of aryl
sulfides, we extended the applicability of Nishihara’s seminal
arylthiolation. Herein, we report palladium-catalyzed arylth-
iolation of alkynes with a wider variety of heteroaryl sulfides by
careful analysis and suppression of unwanted side reactions.
We first attempted the reaction of 1a with 2a. According to
Nishihara’s report,13 we chose Pd−NHC catalysts to execute
smooth C−S bond cleavage. In the presence of 5 mol % of Pd-
PEPPSI-SIPr ([1,3-bis(2,6-diisopropylphenyl)imidazolidene]-
(3-chloropyridine)palladium(II) dichloride) and 10 mol % of
KOtBu for generation of Pd(0) species, 1a reacted with 2 equiv
of 2a. As a result, a 41% yield of 3aa was obtained with a
Received: August 27, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03056
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
considerable amount of enyne 4a via palladium-catalyzed
dimerization of alkyne19 (Scheme 1c).
observed (entry 5). Alkylacetylenes were found to be suitable for
the reaction; 1-hexyne (2g) and cyclopropylacetylene (2h)
provided the corresponding arylthiolation products in high
yields with high regioselectivities (entries 6 and 7). Owing to the
mild and almost neutral reaction conditions, a series of
functionalities such as acetoxy, cyano, malonate ester, and
chloro moieties remained intact to yield the corresponding
products 3bi−bl (entries 8−11). Probably due to the bulkiness
of the tert-butyl group, the reaction of 3,3-dimethyl-1-butyne
(2m) required an increased reaction temperature as high as 60
°C (entry 12). In contrast, hydroxy-containing 2n smoothly
underwent the reaction even at 25 °C despite the steric
congestion (entry 13). The hydroxy group might act as a
directing group to facilitate the coordination of 2n to the
palladium center. The use of trimethylsilylacetylene (2o) led to
reversal of the regioselectivity: arylthiolation product 3bo′ was
obtained as a major product in contrast to the reactions of aryl-
and alkylacetylenes (entry 14).21
We inferred that the C−S cleavage of 1a would be much
slower than the dimerization resulting in undesirable con-
sumption of 2a. To facilitate the C−S cleavage for suppression of
the undesirable dimerization, we focused on the use of an
arylsulfanyl group instead of the methylsulfanyl group. Owing to
the lower basicity of the departing arenethiolate anions, the
C(benzothienyl)−S bond of aryl 2-benzothienyl sulfides would
be cleaved more easily than that of 1a. Indeed, 2-benzothienyl 4-
methylphenyl sulfide (1b) smoothly underwent the reaction
with 2a, and the formation of 4a was fairly suppressed. Of note,
the arylthiolation proceeded even at 25 °C, and desired product
3ba was obtained in 97% yield with a trace amount of
regioisomer 3ba′ (Scheme 1d).20 The structure of major isomer
3ba was unambiguously determined by X-ray crystallographic
analysis.21,22 Although other benzothienyl sulfides having less
basic leaving groups such as −SCF3 and −SCH2CF3 were tested,
no arylthiolation products were obtained and the starting
sulfides and alkyne 2a were recovered. Whereas the C-
(benzothienyl)−S bonds would easily undergo oxidative
addition to Pd(0), the next thiopalladation step (see Scheme
3, step c) would not proceed owing to the electron deficiency of
the leaving groups.23
Next, we investigated the reaction scope with respect to aryl
sulfides 1 (Scheme 2). Instead of 1b, 2-benzothienyl 4-
Scheme 2. Reaction Scope with Respect to Heteroaryl
Sulfides
Based on the encouraging result with 1b, we then explored the
reaction scope with respect to alkynes 2 (Table 1). Electron-rich
Table 1. Reaction Scope with Respect to Alkynes
entry
R
2
3
yield, 3:3′
1
2
3
4-MeOC6H4
4-CF3C6H4
3-thienyl
3-pyridyl
2-pyridyl
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
3bb
3bc
3bd
3be
3bf
3bg
3bh
3bi
3bj
3bk
3bl
3bm
3bn
3bo
81%, 11:1
a
b
(61%, 9:1) 41%
b
63%
c
4
61%, 10:1
a
5
6
(<10%)
d
Bu
97%, 14:1
78%, >50:1
93%, 8:1
92%, 5:1
72%, 12:1
97%, 7:1
87%, 5:1
(100%, 14:1) 88%
84%, 1:3
7
8
9
10
11
12
13
14
cyclopropyl
(CH2)3OAc
(CH2)3CN
CH2CH(CO2Et)2
(CH2)4Cl
tBu
cd
,
d
c
a
b
CMe2(OH)
SiMe3
a
b
1
Determined by H NMR of a crude mixture. Isolated as a single
c
d
isomer. At 60 °C. For 24 h.
a
b
c
d
At 40 °C. At 25 °C. For 24 h. For 36 h. Obtained as a single
isomer.
4-methoxyphenylacetylene (2b) uneventfully participated in the
reaction to provide 3bb in good yield with high regioselectivity
(entry 1). On the other hand, the yield of the product decreased
in the reaction of electron-deficient 4-(trifluoromethyl)-
phenylacetylene (2c) because of the competing dimerization
of 2c to 4c (entry 2). Heteroarylacetylenes such as 3-
ethynylthiophene and -pyridine also underwent the reaction to
afford 3bd and 3be in 63 and 61% yields, respectively (entries 3
and 4). On the other hand, the reaction of 1b with 2-
ethynylpyridine (2f) afforded the product in very low yield, and
a significant amount of the dimerization product of 2f was
methoxyphenyl sulfide (1c) also reacted with 2a to afford
product 3ca in 86% yield. On the other hand, the reaction of 2-
benzothienyl 4-(trifluoromethyl)phenyl sulfide (1d) provided a
mixture of 3da and 3da′ in only 52% yield. In addition to 3da
and 3da′, diene 5 was also generated via a second insertion of
alkyne 2a into the C(alkenyl)−S bond of 3da. The electron
deficiency of the 4-(trifluoromethyl)phenylsulfanyl group would
render the C(alkenyl)−S bond of 3da more reactive. Under the
present catalysis, 3da indeed reacted with 2a to provide 5. The
B
DOI: 10.1021/acs.orglett.9b03056
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Organic Letters
Letter
methyl group at the 3 position of benzothienyl sulfide 1e did not
hamper the reaction, whereas the regioselectivity decreased to
2:1. 2-Thienyl sulfide 1f also took part in the reaction to afford
product 3fg in 92% yield.
Although Pd(0) species potentially promote the dimerization
of alkynes,19 preferential C−S bond cleavage (Scheme 3, step b)
could be executed by the use of arylsulfanyl group for
acceleration of the C−S cleavage and/or by employment of
alkylacetylenes that are less prone to undergo the dimerization.
The present arylthiolation was applicable to a gram-scale
reaction, and a 79% yield of 3ba was isolated as a single isomer
after the recrystallization process (Scheme 4a). With 5 mol % of
During the investigation of the reaction scope, we found that
alkylacetylenes are reluctant to undergo the dimerization even at
increased reaction temperatures.19c,e,24 This feature allowed us
to react less reactive 2-benzothienyl methyl sulfide (1a) at a
higher reaction temperature; the reaction of 1a with 1-hexyne
(2g) at 60 °C successfully provided desired arylthiolation
product 3ag in 80% yield with exclusive regioselectivity.
In place of benzothienyl sulfides, 2-benzofuryl sulfide 1g was
applicable to the reaction to furnish 3gg in 71% yield. The
position of the C(heteroaryl)−S bond has a great influence; no
reaction took place with 3-benzothienyl methyl sulfide (1h),
resulting in quantitative recovery of 1h.25 Azolyl sulfides 1i and
1j also reacted with 2a to afford the corresponding products in
high yields under milder reaction conditions compared with
those in Nishihara’s report.13 Nevertheless, other heteroaryl
sulfides such as methyl 2-pyrimidyl and methyl 2-quinolyl
sulfides were not applicable to the reaction with 1-hexyne (2g),
and the starting sulfides were recovered after the reaction. 4-
Methylphenyl 2-quinolyl sulfide, methyl 2-naphthyl sulfide, and
1,2-bis(phenylsulfanyl)benzene also did not undergo the
reaction with 2g even at 130 °C, resulting in the recovery of
the starting sulfides.
Scheme 4. Gram-Scale Synthesis and Further Arylation of the
C(Alkenyl)−S Bond of 3ba
The present reaction would proceed via a similar mechanism
Pd2dba3 (dba = dibenzylideneacetone) and an excess amount of
an arylmagnesium reagent,28 3ba was further converted into the
corresponding 1,1,2-triarylethene 6 with retention of the
stereochemistry (Scheme 4b).29
proposed by Nishihara (Scheme 3).13 With the aid of terminal
Scheme 3. Plausible Mechanism
In conclusion, we have developed regio- and stereoselective
palladium-catalyzed arylthiolation of alkynes with heteroaryl
sulfides to yield a variety of β-heteroaryl alkenyl sulfides under
mild and neutral conditions. Competitive dimerization of
alkynes was sufficiently suppressed by the use of arylsulfanyl
segments for smooth C(heteroaryl)−SR cleavage and/or of
alkylacetylenes that are unwilling to participate in the
dimerization. Careful optimization of reaction conditions is
necessary for inventing new and/or efficient reactions of
catalyst-poisonous organosulfur compounds. Further work is
ongoing along this line in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b03056.
Experimental procedures, X-ray crystallographic analysis,
and spectral data (PDF)
Accession Codes
CCDC 1945583−1945584 contain the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
ing data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road, Cam-
bridge CB2 1EZ, UK; fax: +44 1223 336033.
alkyne 2 and KOtBu, Pd(0) species would be generated from
Pd-PEPPSI-SIPr (step a). Oxidative addition of 1 to the Pd(0)
species would afford arylpalladium thiolate A via the cleavage of
the C(heteroaryl)−S bond (step b). Subsequent syn-thiopalla-
dation of alkyne 2 with A would generate alkenylarylpalladium-
(II) B (step c).26 Owing to its bulkiness, SIPr-ligated palladium
would avoid a steric repulsion with the substituent on alkyne
(R2) to form B preferentially.27 Finally, reductive elimination
from B would afford product 3 with regeneration of the initial
Pd(0) species (step d).
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: yori@kuchem.kyoto-u.ac.jp.
ORCID
Keisuke Nogi: 0000-0001-8478-1227
C
DOI: 10.1021/acs.orglett.9b03056
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Sulfide. Chem. - Asian J. 2011, 6, 3190−3194. (c) Shibata, T.; Mitake,
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Cleavage for Rh-Catalyzed Regioselective Alkynylthiolation of Alkynes.
Chem. Commun. 2017, 53, 9016−9019.
Hideki Yorimitsu: 0000-0002-0153-1888
Notes
The authors declare no competing financial interest.
́
́
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ACKNOWLEDGMENTS
■
This work was supported by JSPS KAKENHI Grant Numbers
JP16H04109, JP18H04254, JP18H04409, JP19H00895, and
JP18K14212.
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the silicon atom would stabilize intermediate B′, which would reverse
the regioselectivity of the thiopalladation process (Scheme 3, step c).
(28) Itami, K.; Mineno, M.; Muraoka, N.; Yoshida, J. Sequential
Assembly Strategy for Tetrasubstituted Olefin Synthesis Using Vinyl 2-
Pyrimidyl Sulfide as a Platform. J. Am. Chem. Soc. 2004, 126, 11778−
11779.
(29) Both of the two C−S bonds of 3ba were cleaved under the
conditions; 4-N,N-dimethylamino-4′-methylbiphenyl was formed in
72% NMR yield accompanied with 6. An excess amount of
arylmagnesium is thus necessary to obtain 6 in good yield.
̈
́
́
(19) A pioneering work on palladium-catalyzed dimerization of
terminal alkynes: (a) Ruhter, G.; Chan, C.; Trost, B. M. Metal-
Mediated Approach to Enynes. J. Am. Chem. Soc. 1987, 109, 3486−
3487. For dimerization reactions of alkynes catalyzed by palladium−
̈
NHC complexes, see: (b) Herrmann, W. A.; Bohm, V. P. W.;
̈
Gstottmayr, C. W. K.; Grosche, M.; Reisinger, C.-P.; Weskamp, T.
Synthesis, Structure and Catalytic Application of Palladium(II)
Complexes Bearing N-Heterocyclic Carbenes and Phosphines. J.
Organomet. Chem. 2001, 617−618, 616−628. (c) Yang, C.; Nolan, S.
P. Regio- and Stereoselective Dimerization of Terminal Alkynes to
Enynes Catalyzed by a Palladium/Imidazolium System. J. Org. Chem.
2002, 67, 591−593. (d) Jahier, C.; Zatolochnaya, O. V.; Zvyagintsev, N.
V.; Ananikov, V. P.; Gevorgyan, V. General and Selective Head-to-Head
Dimerization of Terminal Alkynes Proceeding via Hydropalladation
Pathway. Org. Lett. 2012, 14, 2846−2849. (e) Zatolochnaya, O. V.;
Gordeev, E. G.; Jahier, C.; Ananikov, V. P.; Gevorgyan, V. Carboxylate
Switch Between Hydro- and Carbopalladation Pathways in Regiodi-
vergent Dimerization of Alkynes. Chem. - Eur. J. 2014, 20, 9578−9588.
(f) Morozov, O. S.; Asachenko, A. F.; Antonov, D. V.; Kochurov, V. S.;
Paraschuk, D. Y.; Nechaev, M. S. Regio- and Stereoselective
Dimerization of Arylacetylenes and Optical and Electrochemical
Studies of (E)-1,3-Enynes. Adv. Synth. Catal. 2014, 356, 2671−2678.
(g) Ostrowska, S.; Szymaszek, N.; Pietraszuk, C. Selective Dimerization
of Terminal Acetylenes in the Presence of PEPPSI Precatalysts and
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(20) See Table S1 in the Supporting Information for details of the
optimization study.
(21) See the Supporting Information for identification of the
arylthiolation products 3.
(22) For XRD analyses, see Figures S1 and S2 in the Supporting
Information (CCDC 1945583 and 1945584).
(23) Electron-withdrawing groups on the sulfur atoms of platinum
thiolates decrease the rate of insertion of alkynes into the Pt−S bonds.
Kuniyasu, H.; Takekawa, K.; Yamashita, F.; Miyafuji, K.; Asano, S.;
Takai, Y.; Ohtaka, A.; Tanaka, A.; Sugoh, K.; Kurosawa, H.; Kambe, N.
Insertion of Alkynes into an ArS−Pt Bond: Regio- and Stereoselective
Thermal Reactions, Facilitation by “o-Halogen Effect” and Photo-
irradiation, Different Alkyne Preferences Depending on the Ancillary
Ligand, and Application to a Catalytic Reaction. Organometallics 2008,
27, 4788−4802.
(24) The reluctance of alkylacetylenes toward the palladium-catalyzed
dimerization has been also reported. See: Rubina, M.; Gevorgyan, V.
Can Agostic Interaction Affect Regiochemistry of Carbopalladation?
Reverse Regioselectivity in the Palladium-Catalyzed Dimerization of
Aryl Acetylenes. J. Am. Chem. Soc. 2001, 123, 11107−11108.
(25) We cannot exclude the possibility that the endocyclic sulfur atom
of 1b might serve as a directing group to facilitate the C2−SAr bond
cleavage.
(26) Dimethyl acetylenedicarboxylate is known to insert into the S−Pt
bond of arylplatinum thiolates to afford alkenylarylplatinums. See the
literature in ref 23.
(27) In Table 1, the reaction of 1b with trimethylsilylacetylene (2o)
afforded 3bo′ as the major product. We speculate that the α-effect of
E
DOI: 10.1021/acs.orglett.9b03056
Org. Lett. XXXX, XXX, XXX−XXX