Palladium-Catalyzed Copper-Promoted Hiyama-Type Carbon-Carbon Cross-Coupling Reactions of Dihetaryl Disulfides as Electrophiles

Article abstract of DOI:10.1055/s-0036-1589116

Dihetaryl disulfides were used as electrophiles in a palladium-catalyzed carbon-carbon cross-coupling reaction with arylsilanes to realize a Hiyama-type reaction. This unique transformation shows high reactivity, excellent functional-group tolerance, and mild reaction conditions, making it an attractive alternative to conventional cross-coupling approaches for carbon-carbon bond construction.

Full text of DOI:10.1055/s-0036-1589116

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© Georg Thieme Verlag Stuttgart · New York
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M.-X. Liu et al.
Letter
Synlett
Palladium-Catalyzed Copper-Promoted Hiyama-Type Carbon–
Carbon Cross-Coupling Reactions of Dihetaryl Disulfides as
Electrophiles
Ming-Xia Liua
O
Ar
Hai-Peng Gongb
Zheng-Jun Quan*a
Xi-Cun Wang*a
O
Ar
R1O
N
Pd / Cu
TBAF
R1O
N
Si(OCH3)3
R2
N
+
R3
R2
N
S
2
R3
a Key Laboratory of Polymer Materials, College of Chemistry
and Chemical Engineering, Northwest Normal University,
Gansu 730070, P. R. of China
R1 = Me, Et, i-Pr ; R2 = Me, i-Pr ; R3 = H, Me
19 examples, 61–78%
quanzhengjun@hotmail.com
wangxicun@nwnu.edu.cn
b College of Natural Science, Gansu Agricultural University,
No. 1 Yingmen Village, Anning District, Lanzhou, Gansu
730070, P. R. of China
Received: 14.07.2017
Accepted after revision: 11.09.2017
Published online: 26.10.2017
er ease of handling. For instance, we have demonstrated
that dihetaryl disulfides are potential C–C, C–S, and C–N
coupling partners.13–15 In our previous reports, we de-
scribed the possible mechanism of the disulfide reaction
process, and we showed that cleavage of the C–S bond re-
quires an equivalent amount of the copper salt. To the best
of our knowledge, there are no previous reports on the use
of a disulfide as an electrophilic reactant with an organosil-
icon compound in a C–C coupling reaction.
DOI: 10.1055/s-0036-1589116; Art ID: st-2017-w0558-l
Abstract Dihetaryl disulfides were used as electrophiles in a palladium-
catalyzed carbon–carbon cross-coupling reaction with arylsilanes to
realize a Hiyama-type reaction. This unique transformation shows
high reactivity, excellent functional-group tolerance, and mild reaction
conditions, making it an attractive alternative to conventional cross-
coupling approaches for carbon−carbon bond construction.
In continuation of our interest in cross-coupling reac-
tions of dipyrimidin-2-yl disulfides, and because com-
pounds containing a pyrimidine ring display a wide range
of pharmacological and biological properties,16 such as cal-
cium-channel modulation, antifungal, and antibacterial ac-
tivities,17 we examined use of dihetaryl disulfides as reac-
tion partners in Hiyama cross-couplings, thereby providing
an important extension of the scope of this reaction in het-
erocyclic chemistry.
Initially, we studied the effect of various catalysts on the
C–C coupling reaction of the dipyrimidin-2-yl disulfide 1a
with trimethoxy(phenyl)silane (2a), with TBAF as an activa-
tor and 1,4-dioxane as the solvent under a nitrogen atmo-
sphere for 24 hours at 110 °C (Table 1, entries 1–6). Unfor-
tunately, we did not detected the formation of the desired
product of 3a when Cu(OAc)2or NiCl2 was used as a catalyst
(entries 1 and 2). When we used Ni(PPh3)2Cl2 or Pd(PPh3)2as
the catalyst, we found that the byproduct 4 was obtained
selectively, and no product 3a was formed (entries 3 and 4).
It was gratifying to note, however, that when PdCl2 or
Pd(OAc)2was selected as the catalyst, a small amount of the
C–C coupling product 3a was obtained (entries 3 and 4).
However, when Pd(OAc)2was used as a catalyst and cop-
per(I) iodide was added as an activator, the desired product
3a was obtained in 18% yield (entry 7). This result prompt-
ed us to investigate the copper activator in detail. Copper (I)
thiophene-2-carboxylate (CuTC) was found to be the most
Key words dihetaryl disulfides, arylsilanes, Hiyama reactions, cross-
coupling, platinum catalyst, arylation
Metal-mediated Hiyama cross-coupling reactions are
among the most powerful methods for producing C–C
bonds in organic chemistry.1 Compared with some other
organometallic reagents, such as organomagnesium
(Kumada–Corriu),2 organoboron (Suzuki–Miyaura),3 or-
ganotin (Stille),4 or organozinc compounds (Negishi),5 as
nucleophilic partners for cross-coupling processes, organo-
silicon compounds are attractive owing to their ease of han-
dling, low toxicity, high chemical stability, and broad avail-
ability. They would therefore appear to be interesting part-
ners for the development of cross-coupling reactions in the
synthesis of natural products or biologically active com-
pounds.6 Consequently, it would be useful to develop new
electrophilic reagents for Hiyama cross-coupling reactions
to extend their substrate scope and to increase the general-
ity of their synthetic applications.
Aryl halides, and arenesulfonates7–11 are usually em-
ployed as electrophiles in this reaction, owing to their high
reactivities in transition-metal-catalyzed processes. These
electrophiles can be easily generated from cheap and readi-
ly available thiophenols or thio ketones.12 However, the use
of dihetaryl disulfides as substrates in cross-coupling reac-
tions has the advantage of greater atom economy and great-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

B
M.-X. Liu et al.
Letter
Synlett
efficient activator in this system (entry 9). Inspired by this
result, we went on to examine the effects of various ligands
(entries 10–12), and PCy3 was shown to be the optimal li-
gand. Only a 15% yield of product 3a was obtained in the
absence of a Pd catalyst (entry 13). We then screened vari-
ous bases. KF and CSF provided the desired product in lower
yields (entries 14 and 15). No product was observed when
NaOH was used as the base (entry 16). A series of solvents
Table 1 Optimization of the Hiyama Reaction of Disulfide 1a with Trimethoxy(phenyl)silane (2a)a
O
O
O
catalyst, ligand
solvent, 24 h
EtO
N
EtO
N
EtO
N
Si(OCH3)3
+
+
Me
N
S
Me
N
Me
N
OCH3
2
1a
2a
3a
4
Entry
Catalyst
Additive
Ligand
Activator
Solvent
Temp (°C)
Yieldb (%)
3a
4
1
2
Cu(OAc)2
NiCl2
–
Phenc
dpppd
–
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
KF
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
THF
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
60
0
0
0
0
–
3
Ni(PPh3)2Cl2
Pd(PPh3)2
PdCl2
–
0
70
20
25
42
8
4
–
–
0
5
–
dppp
dppp
dppp
dppp
dppp
PPh3
PCy3
X-Phose
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
<5
<10
18
27
32
45
50
22
15
Trace
<5
0
6
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
–
–
7
CuI
8
CuCl
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
15
<5
<5
0
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27f
N.D
0
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
<5
<5
<5
<5
<5
23
17
45
<5
<5
<5
<5
<5
<5
CsF
NaOH
TBAF
TBAF
TBAF
TBAF
-
72
58
47
45
<5
72
64
36
18
<10
35
toluene
140
140
140
60
DMF
xylene
THF
CuTC (4.0)
CuTC (2.0)
CuTC (1.0)
CuTC (0.5)
CuTC(0.15)
CuTC
TBAF
TBAF
TBAF
TBAF
TBAF
TBAF
THF
60
THF
60
THF
60
THF
60
THF
60
THF
60
a Reaction conditions: 1a (0.2 mmol, 0.1094 g), PhSi(OMe)3 (2a; 3.0 equiv, 0.6 mmol, 0.1188 g), catalyst (3 mol%), additive (3.0 equiv), ligand (6 mol%), activa-
tor (3.0 equiv, 0.6 mmol), solvent (2 mL) under N2, 24 h.
b Isolated yield after column chromatography (based on one pyrimidine group from one molecule).
c 1,10-phenanthroline.
d Ph2P(CH2)3PPh2.
e 2-(Dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl.
f Under air.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

C
M.-X. Liu et al.
Letter
Synlett
were also studied (entries 17–20). A 72% yield of 3a was ob-
tained when THF was used as the solvent (entry 17). Other
solvents might add to the copper salt to produce copper salt
complexes, resulting in low yields. When TBAF was omitted
from the reaction system, the yield of the target product fell
to less than 5%, demonstrating the importance of TBAF (en-
try 21). When the loading of CuTC was increased to 4.0
equivalents (entry 22), the yield was the same as that ob-
tained with 3.0 equivalents (entry 17), and when the load-
ing of CuTC was decreased to 2.0, 1.0, 0.5, or 0.15 equiva-
lents, considerably lower yields of 3a were obtained (en-
tries 23–26). It is interesting that the reaction gave a 35%
yield of 3a when conducted in air (entry 27). On the basis of
the above studies, the reaction is best conducted with
Pd(OAc)2 as the catalyst, CuTC as the additive, TBAF as the
activator, and THF as the solvent at 60 °C for 24 hours.
With the optimized conditions in hand, we then ex-
plored the scope of this reaction (Scheme 1). A broad range
of substituted disulfides were found to undergo this trans-
formation.18 In general, disulfides with electron-donating
or electron-withdrawing groups in the para-positions of
the benzene rings reacted with 2a to afforded the desired
products 3a–e in good yields. The yield of the target prod-
uct 3f–h was slightly reduced because steric hindrance by
the substituents in the ortho-position of the phenyl rings of
the corresponding disulfides. Disulfides with substituents
in the meta-positions of the phenyl rings gave better yields
(3i–m). This reaction also proceeded well with the
Pd(OAc)2 (3 mol%)
CuTC ( 3.0 equiv )
TBAF (3.0 equiv)
PCy3 (6 mol%)
O
Ar
O
Ar
N
R1O
N
R1O
N
Si(OCH3)3
2
+
R2
N
THF, 60 °C, 24 h
R3
R2
S
2
R3
1
3a–u
Me
F
Cl
Br
O
O
O
O
O
EtO
N
EtO
N
EtO
N
N
EtO
Me
N
EtO
N
Me
N
Me
N
Me
N
Me
N
3e 65%
3a 72%
3b 78%
3c 70%
3d 68%
Me
NO2
O
Me
O
F
O
Cl
O
O
EtO
N
N
EtO
Me
N
N
EtO
N
N
EtO
N
N
EtO
N
N
Me
Me
Me
Me
3f 67%
3g 61%
Cl
3h 62%
3i 73%
3j 70%
F
Br
O
O
O
O
O
EtO
Me
N
N
EtO
Me
N
EtO
Me
N
i-PrO
N
N
EtO
N
N
N
Me
iPr
N
3k 69%
3l 64%
3m 65%
3n 70%
3o 68%
Me
F
O
O
O
O
O
EtO
N
MeO
Me
N
N
MeO
Me
N
N
MeO
Me
N
N
EtO
Me
N
Me
N
N
R
3p 75%
3q 78%
3r 71%
3s 0%
R = CH2Cl, 3t = 0%
R = Me, 3u = 70%
Scheme 1 Cross-coupling of disulfides with aryl(trimethoxy)silanes
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

D
M.-X. Liu et al.
Letter
Synlett
isopropyl ester of the pyrimidine (3n–o), and when the
methyl ester was used instead of the ethyl ester, compounds
3p, 3q, and 3r were obtained in high yields (75, 78, and 71%,
respectively). The fact that variations in the substituents on
the hetaromatic reactant were tolerated indicates that there
were no substantial electronic effects. Further investiga-
tions of the substrate scope were carried out by using
aryl(trimethyl)silanes with various para-substituents un-
der the standard reaction conditions, and a 70% yield of 3u
(R3 = Me) was obtained, indicating that the electronic na-
ture of the substituent on the arylsilane had little impact on
the yield. Unfortunately, the reactions of diaryl disulfides
and di-2-pyridyl disulfide with 2a did not generate the cor-
responding products; in comparison with dihetaryl disul-
fides, the electrophilic activity of the aryl groups of these
disulfides is lower, possibly due to the coordination of a ba-
sic atom (such as a N atom) to the copper salt that promotes
C–S activation. When we explored the reactions of [(4-
(chloromethyl)phenyl](trimethoxy)silane and trimethoxy-
(vinyl)silane with dipyrimidin-2-yl disulfide, we failed to
obtain the desired products.
Finally, to confirm that the activity of dihetaryl disul-
fides was higher than that of aryl disulfides, we investigated
the coupling of unsymmetrical disulfides with arylsilane 2a
(Scheme 2). We obtained the target products 3a, 3b, and 3c
containing the pyrimidine groups, together with the diaryl
disulfide 6, but we did not detect the product 7. These re-
sults confirmed that pyrimidinyl-containing disulfides have
a higher activity than 4-tolyl-group-containing disulfides
in this reaction.
Pd(OAc)2 (3 mol%)
CuTC ( 3.0 equiv)
TBAF (3.0 equiv)
PCy3 (6 mol%)
O
O
EtO
N
EtO
N
+
2a
Me
THF, 60 °C, 24 h
Me
N
S
Me
N
Ph
3a
42%
Scheme 3
tions, and we found that target product 3a was obtained in
a lower yield of 42% (Scheme ).
On the basis of our experimental results, the following
mechanistic discussion seems to be reasonable, although
there is no definite evidence. A formal oxidative addition of
copper to the S–S bond affords Cu(II) dithiolato intermedi-
ate A (Scheme 4). Subsequent reductive cleavage of the S–S
bond leads to the formation of the corresponding copper(II)
species B and E. (When the reaction was complete, BnCl
was added to the reaction mixture and thio ether 8 was ob-
tained,19 indicating the formation of intermediate E.) Simul-
taneously, activation of the inert C–Si bond takes place in
the presence of TBAF to form F. This reacts with divalent
palladium intermediate B to form the metalated complex C.
Transmetalation from boron to palladium next occurs, fol-
lowed by reductive elimination to give the C–C cross-
coupling product 3a.
In summary, we have developed a new protocol for the
construction of C–C bonds by the Pd(OAc)2-catalyzed cross-
coupling of dihetaryl disulfides with arylsilanes. This pro-
vides an effective method for selectively activating S–S
bonds of disulfides and constructing C–C bonds to give a se-
ries of molecules with potentially biologically active struc-
tures in good yields.
To compare the reactivity of disulfides with that of het-
aryl methyl sulfides, we examined the reaction of a het-
eroaryl methyl sulfide with 2a under the optimized condi-
Me
R
R
S
Pd(OAc)2 (3 mol%)
CuTC ( 3.0 equiv )
TBAF (3.0 equiv)
PCy3 (6 mol%)
2
O
6, 23%
O
EtO
N
+
Me
+
EtO
N
2a
S
THF, 60 °C, 24 h
Me
N
S
Me
N
Ph
Ph
3
Me
7, 0%
5
Me
F
O
O
O
EtO
N
EtO
Me
N
EtO
Me
N
Me
N
Ph
N
Ph
N
Ph
3a 65%
3b 71%
3c 59%
Scheme 2 Cross-coupling of unsymmetrical disulfides with arylsilanes
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

E
M.-X. Liu et al.
Letter
Synlett
T
O
F
O
H3CO
H3CO
CuII
Ph
Si
EtO
O
N
N
S
PdII
OCH3
L
L
F
H2CO
H3CO
F
Me
Ph
(H3CO)3Si
Si
OCH3
C
TC–
+
CuS2
TC
CuII
Ph
Ph
Me
S-
O
L
PdII
N
N
F
EtO
N
N
S
PdII
EtO
L
O
L
L
Me
D
O
Ph
O
Ph
N
B
EtO
Me
N
Pd(OAc)2 + PCy3
Pd0Ln (L = PCy3)
EtO
N
BnCl
Bn
Ph
N
S
Me
O
EtO
N
E
8
N
Me
3a
Me
Ph
O
Ph
N
O
O
CuII
N
N
CuTC
EtO
Me
N
OEt
EtO
S
S
N
N
S
2
Ph
Me
A
1
Scheme 4 Proposed reaction mechanism
Funding Information
B.; Zhang, W.; Yalaoui, I.; Hong, X.; Yang, Y.-F.; Houk, K. N.;
Newman, S. G. J. Am. Chem. Soc. 2017, 139, 1311. (e) Sharma, P.;
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Cherney, A. H.; Davis, E. K.; Burke, M. D. J. Am. Chem. Soc. 2010,
132, 6941.
We are grateful for financial support from the National Natural Sci-
ence Foundation of China (Nos. 21362032, 21362031, and 21562036)
and from the Scientific and Technological Innovation Engineering
program of Northwest Normal University (NWNU-LKQN-15-1).
N
oaitn
a
l
N
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F
o
u
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n
i
a
2(
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3
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3
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a
utarl
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o
u
n
d
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C
h
n
i
a
2(
1
3
6
2
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3
1
N)oaitn
a
l
N
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utra
l
S
ecin
c
e
F
o
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n
d
oaitn of
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a
2(
1
5
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1589116.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F

F
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(18) Ethyl 4-Methyl-2,6-diphenylpyrimidine-5-carboxylate (3a);
Typical Procedure
A Schlenk tube was charged with disulfide 1a (0.2 mmol,
0.1094 g), Pd(OAc)2 (3 mol%), CuTC (3.0 equiv), and PCy3 (6
mol%), and the tube was sealed. PhSi(OMe)3 (2a; 3.0 equiv, 0.6
mmol, 0.1188 g), TBAF (3.0 equiv, 0.6 mmol), and THF (2 mL)
were then injected by syringe into the sealed tube under N2,
and the mixture was stirred at 60 °C for 24 h until the reaction
as complete (TLC; silica gel). The mixture was cooled to r.t., the
reaction was quenched with sat. aq NH4Cl (2 mL), and the
mixture was extracted with EtOAc (3 × 10 mL). The organic
layers were combined, dried (MgSO4), and concentrated in
vacuo, and the resulting residue was purified column chroma-
tography [silica gel, EtOAc–PE (1:50)] to give a white solid;
yield: 45 mg (72%); mp 66–67 °C.
1H NMR (400 MHz, CDCl3): δ = 8.51–8.49 (m, 2 H), 7.71–7.69
(m, 2 H), 7.44–7.41 (m, 6 H), 4.15 (q, J = 7.2 Hz, 2 H), 2.64 (s, 3
H), 1.03 (t, J = 7.2 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ =
168.44, 165.40, 163.68, 163.65, 138.23, 137.10, 131.11, 130.04,
128.69, 128.54, 128.52, 128.49, 123.40, 61.82, 22.87, 13.70.
HRMS (ESI+): m/z [M + H]+ Calcd for C20H19N2O2: 319.1441;
found: 319.1447.
(12) (a) Liu, Y.; Wang, H.; Wang, C.; Wan, J.-P.; Wen, C. RSC Adv. 2013,
3, 21369. (b) Du, Y.; Yang, H.-C.; Xu, X.-L.; Wu, J.; Xu, Z.-K. Chem-
CatChem 2015, 7, 3822. (c) Wang, H.; Huang, G.; Sun, Y.; Liu, Y. J.
Chem. Res. 2014, 38, 96. (d) Wang, G.; Guo, Y.; Lü, Y.; Wang, X.;
Quan, Z. Chin. J. Org. Chem. 2016, 36, 1375.
(13) For examples of C–C coupling, see: (a) Quan, Z.-. J.; Lv, Y.; Wang,
X.-C.; Jing, F.-Q.; Jia, X.-D.; Huo, C.-D. Adv. Synth. Catal. 2014,
356, 325. (b) Du, B.-X.; Da, Y.-X.; Zhang, Z. Adv. Synth. Catal.
2015, 357, 1270. (c) Wei, K.-J.; Quan, Z.-J.; Zhang, Z.; Da, Y.-X.;
Wang, X.-C. RSC Adv. 2016, 6, 78059.
(14) For examples of C–N coupling, see: (a) Wei, K.-J.; Quan, Z.-J.;
Zhang, Z.; Da, Y.-X.; Wang, X.-C. Synlett 2016, 27, 1743. (b) Wei,
K.-J.; Quan, Z.-J.; Zhang, Z.; Da, Y.-X.; Wang, X.-C. Org. Biomol.
Chem. 2016, 14, 2395.
(19) Ethyl
2-(Benzylthio)-4-methyl-6-phenylpyrimidine-5-car-
boxylate (8)
Oil; yield: 12 mg (16%). 1H NMR (600 MHz, CDCl3): δ = 7.63–
7.56 (m, 2 H), 7.45–7.43 (m, 3 H), 7.37–7.35 (m, 2 H), 7.20–7.17
(m, 3 H), 4.46 (s, 2 H), 4.16 (q, J = 7.2 Hz, 2 H), 2.57 (s, 3 H), 1.03
(t, J = 7.2 Hz, 3 H). 13C NMR (150 MHz, CDCl3): δ = 170.65,
168.01, 165.60, 163.75, 141.16, 130.05, 129.08, 128.65, 128.40
(2 C), 128.31, 128.28, 127.13, 125.83, 61.70, 35.34, 22.59, 13.58.
HRMS (ESI+): m/z [M + H]+ Calcd for C21H21N2O2S: 365.1318;
found: 365.1315.
(15) For examples of C–S coupling, see: Guo, Y.; Quan, Z.-J.; Da, Y.-X.;
Zhang, Z.; Wang, X.-C. RSC Adv. 2015, 5, 45479.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–F