Palladium-Catalyzed Regio- and Stereoselective Carbothiolation of Terminal Alkynes with Azolyl Sulfides

Article abstract of DOI:10.1021/acs.orglett.6b00503

Palladium-catalyzed carbothiolation of terminal alkynes with azolyl sulfides affords various 2-(azolyl)alkenyl sulfides with perfect regio- and stereoselectivities. The present addition reaction proceeded through a direct cleavage of carbon-sulfur bonds i

Full text of DOI:10.1021/acs.orglett.6b00503

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Regio- and Stereoselective Carbothiolation of
Terminal Alkynes with Azolyl Sulfides
Masayuki Iwasaki,† Nikola Topolovcan,† Hao Hu,† Yugo Nishimura,† Glwadys Gagnot,†
̌
Rungsaeng Na nakorn,† Ramida Yuvacharaskul,† Kiyohiko Nakajima,‡ and Yasushi Nishihara*,†
†Division of Earth, Life, and Molecular Sciences, Graduate School of Natural Science and Technology, Okayama University, 3-1-1
Tsushimanaka, Kita-ku, Okayama 700-8530, Japan
‡Department of Chemistry, Aichi University of Education, Igaya, Kariya 448-8542, Japan
S
* Supporting Information
ABSTRACT: Palladium-catalyzed carbothiolation of terminal
alkynes with azolyl sulfides affords various 2-(azolyl)alkenyl
sulfides with perfect regio- and stereoselectivities. The present
addition reaction proceeded through a direct cleavage of
carbon−sulfur bonds in azolyl sulfides. The resulting adducts
that are useful intermediates in organic synthesis are further
transformed to multisubstituted olefins containing azolyl
moieties.
arbothiolation of alkynes has been regarded as the ideal
ligated with an N-heterocyclic carbene (NHC) catalyzed regio-
Capproach to the highly substituted alkenyl sulfides in and stereoselective addition of azolyl sulfides to terminal
organic synthesis, which can generate carbon−carbon and
carbon−sulfur bonds simultaneously.1 Regio- and stereo-
selective addition of various carbon−sulfur bonds to alkynes
has been achieved by using transition metal catalysts:
thioesterification,2 cyanothiolation,3 allylthiolation,4 alkenylth-
iolation,5 acylthiolation,6 iminothiolation,7 alkynylthiolation,8
and alkylthiolation.9,10 Although only decarbonylative addition
reaction of thioesters is known,11 the atom-economical
arylthiolation across alkynes has yet to be disclosed to date
because carbon−sulfur bonds in aryl sulfides tend to cause a
reversible oxidative addition.12 While it was previously found
that aryl sulfides underwent cross-coupling with organometallic
reagents13 probably because of the high reactivity of the once
formed oxidative adducts for subsequent transmetalation,
arylthiolation of alkynes is unprecedented.
alkynes.
The reaction of 2-(methylthio)benzothiazole (1a) with
phenylacetylene (2a) was carried out in 1,4-dioxane at 100
°C for 24 h. The results employing various palladium catalysts
are summarized in Table 1. In the presence of Pd(PPh3)4, the
Table 1. Palladium-Catalyzed Addition of 2-
(Methylthio)benzothiazole (1a) to Phenylacetylene (2a)
a
b
entry
Pd cat.
additive
yield (%)
Recently, Weller and Willis have reported rhodium-catalyzed
addition of aryl sulfides bearing unique activating groups to
terminal alkynes as a specific case.14 On the other hand, the
addition reaction of heteroaryl sulfides with alkynes, which can
construct the ubiquitous skeletons in pharmaceuticals and
agrochemicals,15 is significantly limited despite its utility.
Although only platinum-catalyzed furylthiolation,11b,16 thie-
nylthiolation,17 and pyridylthiolation18 of terminal alkynes with
thioesters or with heteroaryl halides and arenethiolate salts are
known, those reactions produce toxic carbon monoxide or
undesired byproducts. We recently disclosed the regio- and
stereocontrolled chlorothiolation of alkynes with transition
metal catalysts through the chlorine−sulfur bond cleavage of
sulfenyl chlorides.19 During the course of our research on
selective addition of organosulfur compounds to alkynes, we
investigated carbothiolation with a direct activation of
heteroaryl sulfides. Herein, we report that a palladium complex
1
2
3
4
5
6
7
Pd(PPh3)4
none
28
Pd(OAc)2/PPh3 (1/4)
none
10
Pd(dba)2/PCy3 (1/2)
none
7
75
Pd-PEPPSI-IPr/nBuLi (1/4)
Pd-PEPPSI-IPr/nBuLi (1/4)
Pd-PEPPSI-IPr/LiOH·H2O (1/4)
Pd-PEPPSI-IPr/nBuLi (1/4)
Pd-PEPPSI-IPr/nBuLi (1/4)
none
H2O
89
none
84
MeOH
MeOH
95 (93)
80
c
8
a
Conditions: 1a (1.0 mmol), 2a (2.0 mmol), Pd catalyst (0.10 mmol),
nBuLi (0.40 mmol), additive (0.25 mL), in 1,4-dioxane (8.0 mL) at
b
100 °C for 24 h, unless otherwise stated. NMR yields. An isolated
yield is shown in parenthesis. Microwave irradiation at 160 °C for 40
min.
c
Received: February 23, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00503
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
desired carbothiolation proceeded to yield the adduct 3aa as a
single product in 28% yield, while no reaction occurred without
the catalyst (entry 1). The conventional palladium/phosphine
catalytic systems were found to be less active (entries 2 and 3).
Further screening of palladium catalysts revealed that Pd-
PEPPSI-IPr ([1,3-bis(2,6-diisopropylphenyl)imidazol-2-
ylidene](3-chloropyridine)palladium(II) dichloride)20 was the
most effective (entry 4). Unexpectedly, the addition of a small
amount of water improved the product yield (entry 5). The
effect of water is unclear at this stage, but we presume that the
two alkyne moieties to afford the 1:1 adducts 3aj and 3ak,
albeit in low yields (entries 9 and 10). The reactions of diynes
gave only a trace amount of 1:2 adducts because the high-
yielding reaction required an excess amount of alkynes on 1a.
As a small variant of the terminal alkynes, 5-hexyn-1-ol (2l)
was employed in the reaction of 1a (Scheme 1). The expected
Scheme 1. Carbothiolation of 5-Hexyn-1-ol (2l) with 1a
n
in situ formed LiOH from BuLi and water might act as an
efficient reductant of a palladium(II) precursor. This
assumption was strongly supported by the reaction with
LiOH·H2O, affording 3aa in comparable yield (entry 6).
Among the additives examined, MeOH gave the best result
(entry 7).21 It is of note that the present reaction was complete
within 40 min under microwave irradiation at 160 °C (entry 8).
With the optimized conditions in hand, various aromatic and
aliphatic terminal alkynes 2 were examined for the reaction with
1a, as shown in Table 2. The reaction of electron-rich
Table 2. Palladium-Catalyzed Addition of 2-
(Methylthio)benzothiazole (1a) to Terminal Alkynes 2
a
carbothiolation adduct 3al was not obtained, while carboether-
ification product 3al′ was obtained in 74% yield. After the
formation of carbothiolation adduct 3al, palladium-catalyzed
etherification of alkenyl sulfide 3al might give 3al′ through
oxidative addition of 3al, ligand exchange between thiolate and
alkoxide, and reductive carbon−oxygen bond formation.22 To
the best of our knowledge, there are no reports on
etherification of alkenyl sulfides with alcohols despite their
seeming simplicity. The configuration of 3al′ was determined
by NOESY analysis.21
Next, we explored the scope of heteroaryl sulfides 1 in the
reaction with phenylacetylene (2a) (Table 3). The addition of
2-benzothiazolyl phenyl sulfide (1b) gave 3ba as a sole product
through chemoselective cleavage of the C(2-benzothiazolyl)−S
bond rather than the C(phenyl)−S bond (entry 1). The
stereochemistry of 3ba was unambiguously determined by X-
ray crystallographic analysis, which provides clear evidence of
the regio- and stereoselective carbothiolation process.23 In
addition to naphthothiazolyl sulfide 1c, thiazolyl sulfides 1d and
1e were also amenable to the reaction (entries 2−4).
Carbothiolation adduct 3fa was obtained from benzoxazolyl
sulfide 1f, while the reaction of benzothienyl sulfide 1g gave the
product 3ga in 12% yield. In the case giving the products 3 in
low yields, the starting azoryl sulfides 1 were recovered. The
increase of catalyst loading did not improve the product yields.
It is of note that methyl 2-pyridyl sulfide and methyl phenyl
sulfide did not undergo the reaction. Further optimization of
carbothiolation with versatile heteroaryl sulfides is necessary for
the efficient reaction.
A plausible reaction mechanism of the present carbothiola-
tion is shown in Scheme 2. Oxidative addition of 1 to the
palladium(0) species occurs to generate the (2-benzothiazolyl)-
palladium(II) thiolate A. A cleavage of the C(heteroaryl)−S
bond would occur in preference to those of C(methyl)−S and
C(phenyl)−S bonds, which would result from a favorable
coordination of heteroatoms in 1 to a palladium center prior to
oxidative addition.12,13 The subsequent regio- and stereo-
selective insertion of terminal alkynes 2 into the palladium−
sulfur bond affords alkenyl(2-benzothiazolyl)palladium(II)
intermediate B. The regioselectivity can be rationalized as
follows. During migratory insertion of A with terminal alkynes
b
entry
R
2
3
yield (%)
1
2
p-MeOC6H4
p-MeC6H4
p-CF3C6H4
1-naphthyl
Hex
2b
2c
2d
2e
2f
3ab
3ac
3ad
3ae
3af
81
91
44
34
67
70
60
75
52
30
c
3
c
4
c
5
c
6
7
8
9
nBu
tBu
2g
2h
2i
3ag
3ah
3ai
c
CH(OEt)2
p-(HCC)C6H4
HCC(CH2)3
2j
3aj
10
2k
3ak
a
Reaction conditions: 1a (1.0 mmol), 2 (2.0 mmol), Pd-PEPPSI-IPr
(0.10 mmol), nBuLi (0.40 mmol), in 1,4-dioxane (8.0 mL) and MeOH
b
c
(0.125 mL) at 100 °C for 24 h. Isolated yields. Microwave
irradiation at 160 °C for 40 min.
arylacetylenes 2b and 2c proceeded smoothly to provide the
corresponding adducts 3ab and 3ac in 81% and 91% yields,
respectively (entries 1 and 2). In contrast, the reaction was
slightly affected by a coordination ability of alkynes to a
palladium center: carbothiolation of electron-poor or bulkier
arylacetylenes 2d and 2e gave the products 3ad and 3ae in
moderate yields (entries 3 and 4). In addition, internal alkynes
such as diphenylacetylene and dimethyl acetylenedicarboxylate
did not undergo the desired reaction, recovering the starting
substrates quantitatively. Moreover, alkylacetylenes 2f and 2g
were applicable to the reaction, providing 3af and 3ag in 67%
and 70% yields, respectively (entries 5 and 6). The steric
congestion of 2h did not influence the efficiency of the reaction
(entry 7). 3,3-Diethoxyl-1-propyne (2i) also reacted with 1a to
give 3ai with the acetal moiety remaining intact (entry 8).
Furthermore, when an excess amount of diynes 2j and 2k on 1a
was employed, carbothiolation selectively occurred at one of
B
DOI: 10.1021/acs.orglett.6b00503
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 3. Palladium-Catalyzed Addition of Azolyl Sulfides 1
to Phenylacetylene (2a)
Scheme 3. Transformations of 3aa
a
confirmed by X-ray crystallographic analysis.23 Pummerer-
type reaction of alkenyl sulfoxide 6 with allyltrimethylsilane in
the presence of Tf2O and K2CO3 furnished the allylated
product 7 in 89% yield with a high stereoselectivity.8b,26,27 It is
noteworthy that allylation proceeded with an inversion of
configuration and the formation of the E-isomer predominated,
which was determined by NOESY analysis.21
In summary, the palladium/NHC complex Pd-PEPPSI-IPr
catalyzed the addition of azolyl sulfides to terminal alkynes to
afford (Z)-2-(azolyl)alkenyl sulfides with perfect regio- and
stereoselectivities. The reaction proceeds with a direct cleavage
of heteroaryl−sulfur bonds, which is widely applicable to
substrates with various functionalities. The present method can
be utilized for the construction of the highly functionalized
olefin skeletons, which are often found in natural products and
biologically active compounds.
a
Conditions: 1 (1.0 mmol), 2a (2.0 mmol), Pd-PEPPSI-IPr (0.10
mmol), nBuLi (0.40 mmol), in 1,4-dioxane (8.0 mL) and MeOH
(0.125 mL) at 100 °C for 24 h. Isolated yields. Microwave
irradiation at 160 °C for 40 min.
b
c
Scheme 2. Plausible Reaction Mechanism
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00503.
Details of all experiments procedures and spectroscopic
data of new compounds (PDF)
Crystallographic data (CIF)
Crystallographic data (CIF)
2, bulkier carbene-ligated palladium avoids a steric repulsion
with the substituents of the alkyne 2. The proposed mechanism
is consistent with a previous observation of an alkyne insertion
into the metal−sulfur bond,24 but an alternative pathway
through carbopalladation of alkyne cannot be ruled out. Finally,
reductive elimination proceeds to furnish 3, regenerating the
initial palladium complex.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: ynishiha@okayama-u.ac.jp.
Notes
The authors declare no competing financial interest.
The synthetic utility of the carbothiolation adduct 3 as
synthetic intermediates was successfully demonstrated as shown
in Scheme 3. Alkenyl methyl sulfide 3aa can act as an alkenyl
pseudohalide in cross-coupling: palladium-catalyzed Negishi
coupling of 3aa with phenylzinc chloride occurred to give 4 in
77% yield.13 Nickel-catalyzed reduction of 3aa with zinc
provided 2-(phenethyl)benzothiazole (5) in 92% yield.25
Oxidation of 3aa with m-chloroperbenzoic acid (mCPBA)
proceeded with a retention of stereochemistry to afford the
corresponding sulfoxide 6. The configuration of 6 was
ACKNOWLEDGMENTS
■
This work was partly supported by ACT-C, JST, as well as a
Grant-in-Aid for Scientific Research (KAKENHI) (No.
26810060) from JSPS, and the Program for Promoting the
Enhancement of Research Universities from MEXT and a
Special Project of Okayama University. The authors gratefully
thank Ms. Megumi Kosaka and Mr. Motonari Kobayashi
(Department of Instrumental Analysis, Advanced Science
Research Center, Okayama University) for measurement of
C
DOI: 10.1021/acs.orglett.6b00503
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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DOI: 10.1021/acs.orglett.6b00503
Org. Lett. XXXX, XXX, XXX−XXX