C-S Bond Alkynylation of Diaryl Sulfoxides with Terminal Alkynes by Means of a Palladium-NHC Catalyst

Article abstract of DOI:10.1055/s-0036-1591676

Sonogashira-Hagihara-type alkynylation of diaryl sulfoxides with unactivated terminal alkynes has been developed. With a combination of a palladium-NHC catalyst and LiO t Bu as a base, a series of diaryl sulfoxides were converted into the alkynylated products via C-S bond cleavage.

Full text of DOI:10.1055/s-0036-1591676

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© Georg Thieme Verlag Stuttgart · New York
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Y. Yoshida et al.
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C–S Bond Alkynylation of Diaryl Sulfoxides with Terminal Alkynes
by Means of a Palladium–NHC Catalyst
Yuto Yoshida
O
S
cat. Pd-NHC
LiOtBu
R
Keisuke Nogi
R
+
Ar
Ar
Hideki Yorimitsu*
0
0
0
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0-
0
0
2
0-
1
5
3
1-
8
8
8
Ar
14 examples
up to 100%
Department of Chemistry, Graduate School of Science, Kyoto
University, Sakyo-ku, Kyoto 606-8502, Japan
yori@kuchem.kyoto-u.ac.jp
Published as part of the Cluster C–O Activation
Received: 02.10.2017
Accepted: 27.10.2017
Published online: 08.11.2017
DOI: 10.1055/s-0036-1591676; Art ID: st-2017-r0729-c
sulfides. Inspired by our recent borylation10 and arylation11
of aryl sulfoxides, we have addressed alkynylation of aryl
sulfoxides with unactivated terminal alkynes.
Abstract Sonogashira–Hagihara-type alkynylation of diaryl sulfoxides
with unactivated terminal alkynes has been developed. With a combi-
nation of a palladium–NHC catalyst and LiOtBu as a base, a series of dia-
ryl sulfoxides were converted into the alkynylated products via C–S
bond cleavage.
Table 1 Optimization of reaction conditions
O
S
catalyst (2.5 mol%)
base (1.5 equiv)
C10H21
1a
Key words C–S bond alkynylation, palladium catalyst, aryl sulfoxide,
alkyne
+
THF, 70 °C, 6 h
C10H21
3aa
2a (1.2 equiv)
Arylalkynes are important structural motifs in organic
chemistry owing to the unique properties of C–C triple
bonds. Collective efforts have been directed toward devel-
opment of efficient and versatile protocols for the synthesis
of arylalkynes.1 Sonogashira–Hagihara-type alkynylation1,2
is considered as a prevailing synthetic route to arylalkynes
from aryl electrophiles and terminal alkynes. In analogy
with other cross-coupling reactions, the scope of usable
aryl electrophiles has been expanding beyond reactive aryl
iodides and bromides. Indeed, alkynylation of aryl to-
sylates,3 mesylates,4 and fluorides,5 and decarbonylative
alkynylation of aryl esters6 have been recently reported.
On the other hand, Sonogashira–Hagihara-type alky-
nylation of C–S bonds has been only sporadically investigat-
ed due to the robustness of the C–S bonds. Therefore, usable
substrates are limited to activated organosulfur compounds
such as azaaryl sulfides7 and mercaptoazaarenes.8 Very re-
cently, we reported alkynylation of common aryl sulfides
such as methyl phenyl sulfide with the aid of an electron-
rich palladium–NHC (N-heterocyclic carbene) catalyst.9
However, highly reactive alkynylmagnesium reagents were
indispensable as the alkynylating reagents.
Entry Catalyst
Base
NMR yield of 3aa (%)
1
SPhos Pd G2
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
LiOtBu
0
2
XPhos Pd G2
0
3
Pd(PPh3)4
0
4
PdCl2(dppf)
0
5
Pd-PEPPSI-IPr
SingaCycle-A1
SingaCycle-A3
Pd–PEPPSI–SIPr
Pd–PEPPSI–SIPr
Pd–PEPPSI–SIPr
Pd–PEPPSI–SIPr
Pd–PEPPSI–SIPr
Pd–PEPPSI–SIPr
Pd–PEPPSI–SIPr
51
39
61
90
99
1
6
7
8
9
10
11
12
13
14a
KOtBu
Li2CO3
0
Li3PO4
0
LiN(SiMe3)2
NEt3
0
0
a5 mol% CuI was added.
To accomplish Sonogashira–Hagihara-type alkynylation
with more general organosulfur compounds, we focused on
aryl sulfoxides as electrophilic substrates. Owing to the
electron deficiency of the sulfoxide unit, their C–S(=O)
bonds should be more readily cleavable than those of aryl
Our study began with alkynylation of diphenyl sulfoxide
(1a) with 1-dodecyne (2a) as a model reaction. In the pres-
ence of NaOtBu as a base, an array of palladium catalysts
were screened (Table 1). SPhos Pd G212 (Figure 1), which
showed good catalytic activity for our previous borylation
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

B
Y. Yoshida et al.
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of diaryl sulfoxides,10 did not afford the desired coupling
product 3aa at all (Table 1, entry 1). Other phosphine-ligat-
ed palladium complexes were also ineffective (Table 1, en-
tries 2–4). To our delight, IPr (1,3-bis(2,6-diisopropylphe-
nyl)imidazol-2-ylidene)-ligated Pd–PEPPSI–IPr13 gave 3aa
in 51% yield (Table 1, entry 5). After further screening of
palladium–NHC complexes, we found Pd–PEPPSI–SIPr
(SIPr = 1,3-bis(2,6-diisopropylphenyl)imidazolidin-2-
ylidene) to be optimal, and 3aa was obtained in 90% yield
(Table 1, entry 8). The alkynylation heavily depends on the
base, and the product was obtained quantitatively with Li-
OtBu (Table 1, entry 9). In sharp contrast, the yield of 3aa
was dramatically decreased with KOtBu (Table 1, entry 10).
In that case, isomerization of 1-dodecyne (2a) to 2-do-
decyne occurred,14 which would be one reason for the very
low yield of 3aa. Other lithium bases were totally ineffec-
tive (Table 1, entries 11–13). Triethylamine, a typical base
for Sonogashira–Hagihara-type alkynylation, also did not
afford 3aa even in the presence of a copper co-catalyst (Ta-
ble 1, entry 14).
Having identified optimal reaction conditions (Table 1,
entry 9), we then investigated the scope of aryl sulfoxides
and terminal alkynes (Scheme 1).15 Trifluoromethyl-substi-
tuted electron-deficient aryl sulfoxide 1b smoothly reacted
with 1-octyne (2b) to afford 3bb in 88% yield. In contrast,
electron-rich aryl sulfoxide 1c furnished 3cb only in 14%
NMR yield. We infer that the electron-donating MeO group
would suppress the oxidative addition of the C–S(=O) bond.
Steric congestion also hampered the coupling reaction; di-
o-tolyl sulfoxide (1d) was reluctant to undergo the cou-
iPr
NH2 MeO
OMe
NH2 iPr
iPr
Pd
Cl
P
Pd
Cl
P
Cy
Cy
Cy
Cy
SPhos Pd G2
XPhos Pd G2
NHC
IPr
IPr
Pd Cl
Pd Cl
O
Cl Pd Cl
N
N
Me
Me
N
H
Me
Cl
SingaCycle-A1
SingaCycle-A3
Pd-PEPPSI-NHC
Figure 1 Palladium precatalysts used in Table 1; IPr = 1,3-bis(2,6-diiso-
propylphenyl)imidazol-2-ylidene, SIPr = 1,3-bis(2,6-diisopropylphe-
nyl)imidazolidin-2-ylidene, Cy = cyclohexyl
pling. As a heteroaryl sulfoxide, di-2-benzofuryl sulfoxide
(1f) coupled with methyl propargyl ether (1c) albeit the
yield of the product 3fc was low. Notably, our alkynylation
selectively proceeded at C–S(=O) bonds, and potentially re-
active C–SMe and C–Cl bonds were compatible to afford
3gc, 3hc, and 3id in 67%, 64%, and 70% yields, respectively.
Cyano and tert-butoxycarbonyl units on 3ae and 3if re-
mained intact. Instead of alkylacetylene, trimethylsilylacet-
ylene (2g) furnished alkyne 3ig in moderate yield. Probably
due to the weaker basicity of the corresponding acetylide
anion, tert-butyl propiolate (2h) did not afford the product
3ah at all.
O
R
Pd-PEPPSI-SIPr (2.5 mol%)
S
R
LiOtBu (1.5 equiv)
+
Ar
Ar
Ar
THF (0.2 M), 70 °C, 6 h
1a–i
2a–l (1.2 equiv)
3aa–il
C10H21
C6H13
C6H13
C6H13
OMe
O
R
Me
3db: (29%)a
3aa: 93%
3eb: 88%
3fc: 35%
R = CF3 (3bb): 88%
OMe (3cb): (14%)a
COOtBu
SiMe3
OMe
Cl
CN
R
OMe
OMe
OMe
R = SMe (3gc): 67%
Cl (3hc): 64%
3id: 70%
3ae: 91%
3if: 89%
3ig: 48%
NMe2
S
COOtBu
OMe
3ah: (0%)a
3ai: (77%)a 100%b
3ij: 92%b
3ak: 84%b
3il: 68%b
OMe
Scheme 1 Scope of substrates. a NMR yield. b 2 equiv of 2, THF (0.05 M), 80 °C, 12 h.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

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Y. Yoshida et al.
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Alkynylation of 1a with phenylacetylene (2i) furnished
diphenylacetylene (3ai) in 77% NMR yield under the stan-
dard conditions. Eventually, 3ai was obtained quantitatively
when the reaction was conducted with two equivalents of
2i at 80 °C for 12 h under more diluted conditions. By
means of the modified reaction conditions, diarylalkynes
3ij and 3ak were obtained in good yields. Enyne 2l also par-
ticipated to provide desired coupling product 3il in 68%
yield.
A plausible reaction mechanism is shown in Scheme 2.
Diaryl sulfoxide 1 would undergo oxidative addition to low-
valent palladium to generate oxidative adduct A.10 The are-
nesulfenate anion on A would be replaced with the
acetylide anion derived from alkyne 2 with the aid of LiOt-
Bu, which results in the formation of palladium species B.
Finally, reductive elimination from B would afford the alky-
nylated product 3.
nylated product 3aa along with the 90% recovery of 1j
(Scheme 4, a). tert-Butyl p-tolyl sulfoxide (1k) did not react
at all; 1k was recovered quantitatively (Scheme 4, b). The
C(sp2)–S(=O) bonds of alkyl aryl sulfoxides would be more
electron-rich than those of diaryl sulfoxides, and the former
would be less reactive toward electron-rich Pd(0) species.
Moreover, alkanesulfenate anions generated during the re-
action would be unstable and catalyst poisonous species to
impede the catalyst turnover.11,16 To overcome these prob-
lems, further investigations should be necessary.
(a)
O
S
1j: 90% recovered
C10H21
Me
standard
conditions
1j
+
2a (1.2 equiv)
3aa: 10%
(b)
O
SIPr
S
1k: 95% recovered
Ar
R
Ar
Ar
tBu
S
Pd
3
standard
C10H21
O
1
1k
Me
conditions
+
2a (1.2 equiv)
3ka: 0%
Me
SIPr
Pd
SIPr
Pd
Scheme 4 Alkynylation of alkyl aryl sulfoxides
Ar
Ar
Ar
R
S
B
R
O
In conclusion, we have developed Sonogashira–Hagiha-
ra-type alkynylation of diaryl sulfoxides by means of Pd–
PEPPSI–SIPr catalyst and LiOtBu as a base. A series of diaryl
sulfoxides and terminal alkynes could be converted into the
products.
A
Ar
Ar
Li
S
S
O
H
LiOtBu
O
Li
2
HOtBu
Scheme 2 Plausible reaction mechanism
Funding Information
To confirm the formation of the arenesulfenate anion as
a leaving group, we tried to trap it with an electrophile
(Scheme 3). After the alkynylation of 1a with 2a, the reac-
tion mixture was treated with an excess amount of io-
domethane. As a consequence, the expected methylated by-
product, methyl phenyl sulfoxide (1j), was obtained in 98%
yield along with a 99% yield of the alkyne 3aa. This indi-
cates that arenesulfenate anions would be generated and
stay intact in the reaction flask.
This work was supported by JSPS KAKENHI Grant Numbers
JP16H01019, JP16H04109, JP16H06887, as well as JST ACT-C Grant
Number JPMJCR12ZE, Japan. H.Y. thanks Japan Association for Chemi-
cal Innovation, Tokuyama Science Foundation, and The Naito Founda-
tion for financial support.
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Supporting Information
Supporting information for this article is available online at
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https://doi.org/10.1055/s-0036-1591676.
S
u
p
p
o
nrtogI
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rmoaitn
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p
p
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References and Notes
1a
(2.7 equiv)
conditions
O
+
rt, 2 h
(1) (a) Brandsma, L. Synthesis of Acetylenes, Allenes and Cumulenes:
Methods and Techniques; Elsevier: Oxford, 2004, 293. (b) Nájera,
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Anastasia, L. Chem. Rev. 2003, 103, 1979.
S
C10H21
Me
2a (1.2 equiv)
1j: 98%
Scheme 3 Electrophilic trap of arenesulfenate anion
(2) Reviews
of
Sonogashira–Hagihara-type
alkynylation:
(a) Sonogashira, K. J. Organomet. Chem. 2002, 653, 46.
(b) Tykwinski, R. Angew. Chem. Int. Ed. 2003, 42, 1566.
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(d) Doucet, H.; Hierso, J.-C. Angew. Chem. Int. Ed. 2007, 46, 834.
Finally, we examined the alkynylation with alkyl aryl
sulfoxides instead of diaryl sulfoxides. However, methyl
phenyl sulfoxide (1j) furnished only a 10% yield of the alky-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

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Y. Yoshida et al.
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(e) Chinchilla, R.; Nájera, C. Chem. Soc. Rev. 2011, 40, 5084.
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(15) Alkynylation of 1a with 2a – Representative Procedure
An oven-dried Schlenk tube was charged with diphenyl sulfox-
ide (1a, 61 mg, 0.30 mmol), 1-dodecyne (2a, 60 mg, 0.36 mmol),
Pd–PEPPSI–SIPr (5.1 mg, 0.0075 mmol), LiOtBu (36 mg, 0.45
mmol), and THF (1.5 mL). The resulting mixture was stirred at
70 °C for 6 h. The reaction was quenched with sat. aq NH4Cl
(0.10 mL), and the resulting mixture was passed through pads
of anhydrous Na2SO4, activated alumina, and silica gel with Et2O
as an eluent. The ethereal solution was concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography with an eluent (hexane/toluene = 25:1) to
provide 3aa as a colorless oil (68 mg, 0.28 mmol, 93% yield). All
the resonances in 1H NMR and 13C NMR spectra were consistent
with reported values. See: Yasukawa, T.; Miyamura, H.;
Kobayashi, S. Org. Biomol. Chem. 2011, 9, 6208.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D