Sila-sonogashira cross-coupling reactions of activated aryl chlorides with alkynylsilanes

Article abstract of DOI:10.1055/s-0028-1087345

The palladium/copper-cocatalyzed sila-Sonogashira cross-coupling reactions of activated aryl chlorides with alkynyl-silanes under strictly nonbasic conditions yield the unsymmetrical diarylethynes in moderate to good yields. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087345

LETTER
3041
Sila-Sonogashira Cross-Coupling Reactions of Activated Aryl Chlorides with
Alkynylsilanes
S
ila-Sonogashir
a
C
a
ross-Coup
s
ling React
u
ions of
A
ctiv
s
ated
A
ryl
h
Chlorides i Nishihara,* Eiji Inoue, Yoshiaki Okada, Kentaro Takagi
Division of Chemistry and Biochemistry, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushimanaka,
Okayama 700-8530, Japan
Fax +81(86)2517855; E-mail: ynishiha@cc.okayama-u.ac.jp
Received 5 July 2008
coupling Glaser-type product.20,21 This process has been
Abstract: The palladium/copper-cocatalyzed sila-Sonogashira
applied more recently to the coupling of electron-poor
cross-coupling reactions of activated aryl chlorides with alkynyl-
aryl and heteroaryl bromides or iodides and 1-aryl-2-(tri-
silanes under strictly nonbasic conditions yield the unsymmetrical
methylsilyl)acetylenes.22 We partially documented a cata-
diarylethynes in moderate to good yields.
lytic system for the sila-Sonogashira coupling of aryl
Key words: palladium, copper, Sonogashira reaction, alkynyl-
chlorides with alkynylsilanes, based on the combination
PdCl2(dppb)/CuCl.19b In continuation of our investigation
to extend the generality of this catalytic procedure, we
have further examined the reactions of aryl chlorides with
various alkynylsilanes. To the best of our knowledge,
there are no systematic reports for synthesis of unsymmet-
rical diarylethynes by Pd/Cu-cocatalyzed cross-coupling
of alkynylsilanes with aryl chlorides under neutral condi-
tions. Herein we describe sila-Sonogashira-type cross-
coupling reaction of activated aryl chlorides with alkynyl-
silanes, which provides a new route leading to unsymmet-
rical diarylethynes.
silane, aryl chloride, diarylethynes
Unsymmetrical diarylethynes are important intermediates
in the studies on functional materials.1 Currently, the
Sonogashira reaction,2–4 a cross-coupling of aryl halides
with terminal alkynes in the presence of a base with Cu(I)/
Pd(0) cocatalyst, has been proven to be one of the most
practical and widely used synthetic route to unsymmetri-
cal diarylethynes with the construction of C(sp2)–C(sp)
bonds. The original protocol since 19755 has been repeat-
edly modified and improved to overcome several signifi-
cant limitations: 1) the use of palladacycles led to catalytic
systems with higher turnover numbers (TON),6 2) copper-
free7 or silver-cocatalyzed8 protocols retarded the forma-
tion of undesired conjugate diynes from terminal
alkynes,9 and 3) coupling of aryl bromides and iodides at
room temperature was realized.10
As shown in Scheme 1, we first chose the cross-coupling
reaction of 1-phenyl-2-trimethylsilylethyne (1a, 0.4
mmol) with 4-acetylphenyl chloride (2a, 0.4 mmol) in the
presence of CuCl (10 mol%) as a cocatalyst and Pd(dba)2
(10 mol%; dba = dibenzylideneacetone) as the catalyst in
DMF (1 mL) at 120 °C for 48 hours to serve as the model
reaction to screen the catalyst and optimize the reaction
conditions. The results are summarized in Table 1. A
combination of Pd(dba)2 with PPh3 (P/Pd = 2.0) gave poor
results: the desired product, 1-phenyl-2-(4-acetylphe-
nyl)ethyne (3a) was formed in only 5% yield (entry 1).
Although PCy3 and Pt-Bu3 are known to be highly active
ligands for various cross-coupling reactions using aryl
chlorides,11a they did not give the satisfactory results (en-
tries 4 and 5). In contrast, the yield of 3a with bidentate
phosphine ligands gave a set of systematic results suggest-
ing that the appropriate bite angle is essential to proceed
the reaction. Among the bidentate phosphine ligands em-
ployed in entries 7–10, dppb [1,4-bis(diphenylphosphi-
no)butane] gave the best result to afford 3a in 43% yield
(entry 9). By using the C4-tethered bidentate phosphine
ligand, a Pd(dba)2/(–)-DIOP system improved the yield of
3a (entry 11). Deletion of Pd(dba)2 yielded no product,
confirming the requirement for a palladium catalyst. As
the catalyst precursor, Pd(OAc)2 in combination with (–)-
DIOP afforded the cross-coupled product in 62% yield
(entry 12), better than the previous result obtained by
PdCl2(dppb).19b However, Ni(cod)2 and Pt(cod)2 were
completely ineffective as the catalyst (entries 14 and 15).
Increasing the Pd(OAc)2/(–)-DIOP ratio had a significant
Recently, significant progress in the use of the efficient
palladium catalyst systems for Sonogashira couplings of
aryl chlorides has been made.11,12 Aryl chlorides are less
expensive, more easily available, but difficult starting ma-
terials for coupling reactions compared to aryl bromides
and iodides. For example, the use of Pd2(dba)3CHCl3/
phosphadamantane,13 [Pd(p-C3H5)Cl]2/tetraphosphane,14
PdCl2(PCy3)2,15 and Pd(OAc)2/rac-BINAP,16 allows cou-
pling of aryl chlorides. Other catalyst systems show high
catalytic activity in the use of CuI17 or ZnCl218 as cocata-
lyst.
On the other hand, we have developed an efficient palla-
dium-catalyzed sila-Sonogashira coupling of aryl triflates
with alkynylsilanes in the presence of a catalytic amount
of CuCl in DMF to afford unsymmetrical diarylethynes in
good to high yields.19 This reaction is the most straightfor-
ward and powerful method for the formation of unsym-
metrical diarylethynes via carbon–silicon bond activation
and thus totally avoids the formation of the alkyne homo-
SYNLETT 2008, No. 19, pp 3041–3045
Advanced online publication: 12.11.2008
DOI: 10.1055/s-0028-1087345; Art ID: U07108ST
© Georg Thieme Verlag Stuttgart · New York
1
2
.1
1
.2
0
0
8

3042
Y. Nishihara et al.
LETTER
cat.
CuCl (10 mol%)
+
Cl
Ac
Ph
TMS
Ph
Ac
DMF
120 °C, 48 h
1a
2a
3a
Scheme 1
effect on yield of 3a; 62% yield (1:1) and 25% (1:2), re-
spectively. Although the reaction with other copper salts
have been examined, lower yield of 3a was obtained with
CuTC23 (18%), CuOAc (15%), and Cu(OAc)2 (17%) un-
der the standard conditions. In all cases the reaction mix-
ture contained recovered starting materials, but 1,4-
diphenyl-1,3-butadiyne derived from homocoupling of 1a
Table 1 Sila-Sonogashira Cross-Coupling of 1a with 2a Using Var-
ious Catalystsa
Entry
1
Catalyst
GC yield of 3a (%)
Pd(dba)2/2 Ph3P
Pd(dba)2/2 (o-tolyl)3P
Pd(dba)2/2 P(OPh)3
Pd(dba)2/2 Cy3P
Pd(dba)2/2 t-Bu3P
Pd(dba)2/2 Me3P
Pd(dba)2/dppe
Pd(dba)2/dppp
Pd(dba)2/dppb
Pd(dba)2/dppf b
Pd(dba)2/(–)-DIOPc
Pd(OAc)2/(–)-DIOPd
PdCl2(dppb)d,19b
Ni(cod)2
5
29
0
2
1
was not formed (confirmed by GC and H NMR spec-
trum).
3
4
13
18
<1
5
An important observation was made during our experi-
ments: for a catalyst derived from Pd(dba)2 and (–)-DIOP,
the presence of a copper cocatalyst has a deleterious effect
on the desired cross-coupling reaction.24 As can be seen
from entries 1–4 in Table 2, more than 10 mol% of CuCl
causes suppression of the coupling process: the use of 10
mol% amounts of CuCl did not disturb the reaction
progress and produced 3a in 62% GC yield (entry 1),
whereas the use of 30 mol% and 50 mol% of CuCl for the
reaction of 1a with 2a afforded 3a in 13% and 8% yields,
respectively (entries 2 and 3). In the absence of copper the
desired transformation did not proceed (entry 4). Thus, we
employed 10 mol% of CuCl as the optimized condition.
5
6
7
8
14
43
32
58
62
47
4
9
10
11
12
13
14
15
The reactions of various activated aryl chlorides 2 with
alkynylsilanes 1 were conducted and the results are also
summarized in Table 2. Although the cross-coupling of
1a with activated aryl chlorides 2b and 2c at 120 °C took
place smoothly to give the corresponding 1-alkyl-2-phe-
nylacetylene in moderate yields (entries 5 and 6), the re-
actions of 1a with 4-nitrophenyl chloride 2d gave a lower
yield of the desired product (entry 7). Aryl chlorides hav-
ing heteroaromatics, such as 2-pyridyl and 2-thienyl
groups, showed contrasting results: the corresponding
cross-coupling products 3e and 3f were formed in 60%
and <1% yields, respectively (entries 8 and 9). In addition,
the reactions of activated aryl chlorides 2a, 2b, and 2e
Pt(cod)2
<1
a Reaction conditions: DMF (1 mL), 1a (0.4 mmol), 2a (0.4 mmol),
catalyst (10 mol%), CuCl (10 mol%), 120 °C, 48 h.
b dppf = 1,1¢-bis(diphenylphosphino)ferrocene.
c DIOP = [(2,2-dimethyl-1,3-dioxolane-4,5-diyl)bis(methylene)]bis-
phosphine.
d Alkynylsilane 1a (0.48 mmol) was used. In these cases yields of 3a
were determined on the basis of 2a.
with alkynylsilanes 1 bearing various functional groups desired cross-coupled product 3q in 81% yield (entry 20).
underwent the cross-coupling reactions similarly to give Unfortunately, electronically rich aryl chlorides, such as
the corresponding unsymmetrical diarylethynes 3g–p in 4-methoxyphenyl chloride and 4-methylphenyl chloride,
completely retard the reaction and give no desired prod-
uct.
up to 90% yields (entries 10–19). Alkyl-substituted alky-
nylsilane 1g smoothly reacted with 2b and afforded the
Pd(OAc)2 (cat.), (–)-DIOP
CuCl (10 mol%)
t-BuMe2SiO
Ac
t-BuMe2SiO
TMS
1h (0.48 mmol)
DMF
120 °C, 12 h
3r 50%
+
Pd(OAc)2 (cat.), (–)-DIOP
TBAF (1.2 equiv)
2a (0.4 mmol)
complex mixture
DMF
120 °C, 12 h
Scheme 2
Synlett 2008, No. 19, 3041–3045 © Thieme Stuttgart · New York

LETTER
Sila-Sonogashira Cross-Coupling Reactions of Activated Aryl Chlorides
3043
Table 2 Sila-Sonogashira Cross-Coupling Reactions of Activated Aryl Chlorides 2 with Alkynylsilanes 1a
Entry
1
Ar1 of Ar1C≡CTMS (1)
Ph (1a)
Ar2 of Ar2Cl (2)
4-AcC6H4 (2a)
Time (h)
24
24
24
24
6
CuCl (mol%) Product 3
Yield (%)b
10
30
50
0
3a
62 (57)
13
2
3
8
4
0
5
4-NCC6H4 (2b)
4-F3CC6H4 (2c)
4-O2NC6H4 (2d)
2-pyridyl (2e)
2-thienyl (2f)
10
3b
3c
3d
3e
3f
51 (47)
(34)
6
6
7
3
(10)
8
12
48
12
12
3
56 (60)
<1
9
10
11
12
13
14
15c
16c
17
18
19
20c
4-MeOC6H4 (1b)
3-F3CC6H4 (1c)
4-AcC6H4 (2a)
4-NCC6H4 (2b)
2-pyridyl (2e)
4-AcC6H4 (2a)
2-pyridyl (2e)
4-NCC6H4 (2b)
4-NCC6H4 (2b)
4-AcC6H4 (2a)
4-NCC6H4 (2b)
2-pyridyl (2e)
4-NCC6H4 (2b)
3g
3h
3i
50 (34)
90 (71)
51 (45)
(48)
12
12
24
24
48
48
3
3j
3k
3l
(65)
74 (63)
75 (54)
(37)
4-F3CC6H4 (1d)
2-pyridyl (1e)
3m
3n
3o
3p
3q
(38)
4-AcC6H4 (1f)
n-C6H13 (1g)
44 (36)
81 (70)
12
a Reaction conditions: DMF (8 mL), alkynylsilane 1 (2.4 mmol), aryl chloride 2 (2 mmol), Pd(OAc)2 (10 mol%), (–)-DIOP (10 mol%), CuCl
(10 mol%), 120 °C.
b GC yields. Isolated yields are shown in parentheses.
c Alkynylsilane (4 mmol) was used.
To give one example of the advantage of fluoride-free Although a detailed understanding of this cross-coupling
conditions, the result of the present reaction of TBDMS- remains to be uncovered, we can propose the reasonable
protected alkynylsilane 1h with 2a was compared with reaction mechanism in Scheme 3. Oxidative addition of
that of the reported typical Hiyama cross-coupling aryl chlorides 2 to Pd(0) generates an arylpalladium(II)
conditions25 (Scheme 2). In the presence of CuCl, selec- chloride 4. Meanwhile, alkynylsilanes 1 reacts with CuCl
tive cross-coupling occurred to generate 3r as a sole prod- and transmetalation of an alkynyl moiety from Si to Cu to
uct in 50% yield. Substituting TBAF for CuCl gave rise to give alkynylcopper species 5.26 This causes the subse-
the formation of multiple products including disiloxane quent transmetalation to palladium to produce 6, followed
derived from the starting material.
by reductive elimination to afford unsymmetrical diaryl-
R2–Cl
2
Ln
CuCl
Cl Pd R2
TMSCl
4
Pd(0)
Ln
Ln
Pd
R1
TMS
R1
R1
Cu
R2
1
5
6
R1
R2
3
Scheme 3 Plausible catalytic cycles of sila-Sonogashira cross-coupling reaction of aryl chlorides 2 with alkynylsilane 1 in Cu(I)/Pd(0) cocat-
alyst system
Synlett 2008, No. 19, 3041–3045 © Thieme Stuttgart · New York

3044
Y. Nishihara et al.
LETTER
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palladium is completed, CuCl is also regenerated to allow
it to be the catalyst.
In regard to the oxidative addition step, the pioneering
studies of the palladium-catalyzed cross-couplings of aryl
chlorides suggested that an electron-rich and sterically
bulky phosphine and N-heterocyclic carbene ligands may
activate a less reactive carbon–chlorine bond.11a We earli-
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portant role in generation of an alkynylcopper species 5
via cleavage of the carbon–silicon bond due to the good
match of the silicon and chloride anion of the copper
salt.26 In conjunction with the observation that PCy3 and
Pt-Bu3 gave poor results (Table 1, entries 4 and 5) and ex-
cess amount of CuCl can retard the desired cross-coupling
reaction (Table 2, entries 2 and 3), we postulate that the
mutual decelerating effect between the nucleophilic phos-
phine ligands and the added CuCl occurs in the oxidative
addition and transmetalation steps for the catalytic cycle.
If the oxidative addition of aryl chlorides is suppressed by
the interaction of the phosphine ligands with CuCl, the
catalytic reaction would become less efficient.
In conclusion, we have developed the synthesis of unsym-
metrical diarylethynes in moderate to good yields by the
direct cross-coupling of activated aryl chlorides with
alkynylsilanes catalyzed by Pd(OAc)2/(–)-DIOP and
CuCl as a neutral activator.27 Although the yields need im-
provement, the present coupling reaction is straightfor-
ward with great synthetic potential. Aryl chlorides are
readily available, and this reaction provides a facile meth-
odology via direct carbon–silicon bond activation of the
substrates. Detailed studies of the mechanism, as well as
further investigation of the scope and limitations of this
chemistry, are in progress.
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Acknowledgement
The authors gratefully thank Prof. Atsunori Mori at Kobe Universi-
ty for valuable discussion. This work was supported by a Grant-in-
Aid for Scientific Research on Priority Areas ‘Advanced Molecular
Transformations of Carbon Resources’ from the Ministry of Educa-
tion, Culture, Sports, Science and Technology, Japan.
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Sila-Sonogashira Cross-Coupling Reactions of Activated Aryl Chlorides
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(27) Typical Procedure for the Sila-Sonogashira Cross-
Coupling Reactions of Aryl Chlorides 2 with
Alkynylsilanes 1
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To a solution of Pd(OAc)2 (45 mg, 0.2 mmol, 10 mol%) and
(–)-DIOP (100 mg, 0.2 mmol, 10 mol%) in dry DMF (8 mL)
were added 1-(4-methoxypheny)-2-trimethylsilylethyne
(1b, 519 mL, 2.4 mmol), 4-cyanophenyl chloride (2b, 275
mg, 2 mmol), and CuCl (20 mg, 0.2 mmol, 10 mol%) at r.t.
The dark red suspension was heated for 12 h at 120 °C and
monitored by GC and TLC. After completion of the reaction,
the reaction mixture was quenched with 1 M HCl and
extracted with Et2O (3 × 20 mL). The combined organics
were washed with brine and dried over anhydrous MgSO4.
Filtration and concentration with a rotary evaporator gave a
viscous oil. The residue was purified by flash column
chromatography on SiO2 (hexane–Et2O, 8:2, Rf = 0.39), 3h
(331 mg, 1.42 mmol, 71%) was obtained as a white solid. 1H
NMR (300 MHz, CDCl3): d = 3.84 (s, 3 H), 6.89–6.92 (m,
2 H), 7.47–7.50 (m, 2 H), 7.56–7.64 (m, 4 H).
2004, 45, 8443.
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Hirabayashi, K.; Ando, J.; Mori, A.; Hiyama, T. J. Org.
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(20) The copper-free version of sila-Sonogashira cross-coupling
reaction has been achieved using a palladium/imidazolium
salt system, see: (a) Yang, C.; Nolan, S. P. Organometallics
2002, 21, 1020. (b) Hillier, A. C.; Grasa, G. A.; Viciu, M. S.;
Synlett 2008, No. 19, 3041–3045 © Thieme Stuttgart · New York