Decarboxylative/Sonogashira-type cross-coupling using PdCl2(Cy?Phine)2

Article abstract of DOI:10.1039/c6ra12916a

The PdCl₂(Cy?Phine)₂ precatalyst containing the meta-terarylphosphine ligand, Cy?Phine, can effectively mediate decarboxylative cross-coupling with a diverse range of (hetero-)aryl, aryl and alkyl chlorides including those with unprotected functionality. Using a facile and robust protocol, this process was extended to the first synthesis of symmetrical di(heteroaryl)alkynes via tandem Sonogashira/decarboxylative cross-coupling of heteroaryl chlorides and propiolic acid.

Full text of DOI:10.1039/c6ra12916a

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Decarboxylative/Sonogashira-type cross-coupling
using PdCl2(Cy*Phine)2†
Cite this: RSC Adv., 2016, 6, 72810
a
a
Yong Yang,‡ Yee Hwee Lim, Edward G. Robinsb and Charles W. Johannesa
*
*
The PdCl2(Cy*Phine)2 precatalyst containing the meta-terarylphosphine ligand, Cy*Phine, can effectively
mediate decarboxylative cross-coupling with a diverse range of (hetero-)aryl, aryl and alkyl chlorides
including those with unprotected functionality. Using a facile and robust protocol, this process was
extended to the first synthesis of symmetrical di(heteroaryl)alkynes via tandem Sonogashira/
decarboxylative cross-coupling of heteroaryl chlorides and propiolic acid.
Received 18th May 2016
Accepted 26th July 2016
DOI: 10.1039/c6ra12916a
www.rsc.org/advances
via the elimination of CO2, avoiding the formation of homo-
coupled and enyne by-products that are commonly observed.
Introduction
Other advantages of the decarboxylative cross-coupling method
include the use of stable and widely available alkynylcarboxylic
acids or carboxylate salts as substrates and potentially simpli-
ed large-scale purication procedures as CO2 is main the
stoichiometric side-product.
Compounds with acetylenic bridges are widely found in
numerous natural products,1 pharmaceuticals2 and materials.3
In particular, diarylacetylenes are of special interest in the elds
of electronic materials and metal–organic frameworks (MOF)
due to their rigidity, linear connectivity and extended p-conju-
gation.4 These complex internal alkyne (Csp–Csp2) compounds
are commonly prepared by the powerful and facile palladium-
catalyzed Sonogashira reaction.
The development of highly active catalysts and broadly
applicable synthetic protocols for Sonogashira coupling
including the copper-free variant, has led to wide scale adoption
and industrial application.5 Some notable contributions have
been reported by Buchwald,6 Beller,7 Hua,8 Colacot9 and
Plenio.10 Recently, our group advanced the scope of palladium-
catalyzed copper-free Sonogashira coupling11 to a variety of
diverse, challenging and industrially relevant substrates using
the Pd-Cy*Phine catalyst based on the monodentate meta-ter-
arylphosphine ligand, Cy*Phine (Fig. 1). Despite its versatility,
the Sonogashira reaction and its' copper-free variant tends to
produce by-products, especially for the electron-rich chal-
lenging substrates.
Since the rst reported palladium-catalyzed tandem
Sonogashira/decarboxylative coupling of propiolic acids with
aryl halides to prepare internal alkynes by Lee et al.,12a several
studies thereaer have utilized a variety of palladium and/or
copper catalysts to improve and expand the scope of the reac-
tion, although methodologies are still largely limited to aryl
bromides or iodides.12,13 It was only recently that the scope of
the decarboxylative cross-coupling of alkynyl carboxylic acids
was extended to the more challenging aryl chlorides by
employing the bulky, electron-rich biarylphosphine ligand,
XPhos as a promoter in the presence of an appropriate
Pd source. Using the Pd(OAc)2/XPhos14a catalyst system in
Cs2CO3/THF, the decarboxylative cross-coupling of electron-
withdrawing aryl chloride or chlorobenzene could be achieved
in high yields. With the ferrocene-type palladacycle/XPhos14b
catalyst system, the scope of the reaction was further expanded
to include variety of aryl chloride and (hetero-)aryl chloride
substrates. The use of PdCl2/XPhos14c catalyst system enabled
One attractive alternative synthetic strategy to access internal
alkynes that has emerged recently is the transition-metal cata-
lyzed decarboxylative cross-coupling of aryl halides or pseudo-
halides with alkynyl carboxylic acids.12–14 The reaction proceeds
aOrganic Chemistry, Institute of Chemical & Engineering Sciences (ICES), Agency of
Science, Technology and Research (A*STAR), 8 Biomedical Grove, Neuros, #07-01,
Singapore 138665. E-mail: lim_yee_hwee@ices.a-star.edu.sg
bSingapore Bioimaging Consortium (SBIC), Agency of Science, Technology and
Research (A*STAR), 11 Biopolis Way, Helios, #01-02, Singapore 138667
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c6ra12916a
‡ Present address: Qingdao Institute of Bioenergy & Bioprocess Technology,
Chinese Academy of Science, 189 Songling Road, Laoshan District, Qingdao
266101, yangyong@qibebt.ac.cn
Fig. 1 Structures of Cy*Phine and PdCl2(Cy*Phine)2 precatalyst.
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Table
1
Reaction conditions optimization: effects of bases and
solventsa
Entry
Base
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
K3PO4
CH3CN
CH3CN
Toluene
DMSO
DMF
Dioxane
THF
THF
44
85
70
41
74
98
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
>99(99)c
83
9
Na2CO3
K3PO4
THF
THF
THF
THF
THF
THF
35
80
0
Trace
Trace
0
10
11
12
13
14
NaOtBu
LiHMDS
NEt3
Piperidine
a
Reaction conditions: 1 mol% PdCl2(Cy*Phine)2, 0.5 mmol of 1a, 0.6
b
mmol of 1b, 1.2 mmol base, 2 mL of solvent, 80 ꢀC, 1.5 h. GC yield
Scheme 1 A comparison of the state of the art: (A) decarboxylative
cross-coupling of challenging aryl halides and arylpropolic acids, (B)
synthesis of diarylacetylenes and di(hetero)arylacetylenes by tandem
Sonogashira/decarboxylative cross coupling of propolic acid and aryl-
or heteroaryl-halides.
based on 0.5 mmol of 1a using dodecane as an internal standard.
Isolated yield.
c
entry 6) whereas the use of Cs2CO3/THF was able to give
quantitative yield of 3a (Table 1, entry 7). We then examine the
effect of various inorganic bases (e.g., K2CO3, Na2CO3, K3PO4,
NaOtBu, LiHMDS) or organic bases (e.g., NEt3 and piperidine) in
THF (Table 1, entries 8–14). Interestingly, while Cs2CO3
remained the better choice amongst the bases tested, K3PO4 in
THF gave an improved result of 80% (Table 1, entry 10), high-
lighting the synergistic effect of solvent and base.
the assembly of diarylalkynes from aryl chlorides and propiolic
acid in a one-pot manner, avoiding the need to use or prepare
terminal acetylene partners. Despite this improved synthetic
applicability of the decarboxylative cross-coupling, several
challenges still remain. Unprotected functional groups, such as
phenols and anilines, are generally not well tolerated and the
assembly of di(hetero)arylacetylenes from the corresponding
heteroaryl chlorides are still problematic. Herein, we report the
expansion of the scope of the decarboxylative cross-coupling to
more challenging (hetero-)aryl chlorides substrates and greater
functional group tolerance using the PdCl2(Cy*Phine)2 catalyst
system (Scheme 1). This process also enabled the rst assembly
of symmetrical di(hetero)aryl alkynes via the tandem
Sonogashira/decarboxylative coupling of heteroaryl chlorides
with propiolic acid.
To gain insights on the productivity of the PdCl2(Cy*Phine)2
catalyst system, the model reaction was carried out at lower
temperatures and lower catalyst loadings. Lowering the reaction
temperatures to 70 ꢀC led to complete conversion aer pro-
ꢀ
longed times (Table 2, entry 1) but a further decrease to 60 C
resulted in only 70% yield aer 12 h (Table 2, entry 2). A catalyst
loading of as low as 0.1 mol% is sufficient to achieve quanti-
tative 3a, albeit requiring a much longer reaction time (Table 2,
entry 4) for complete conversion. No coupling occurred in the
absence of the catalyst even under prolonged time (24 h),
indicating the essential role of the PdCl2(Cy*Phine)2 catalyst
system in facilitating the reaction (Table 2, entry 5).
Results and discussion
Using the electron-rich 2-chloroanisole (1a) and 3-phenyl-
With the best Cs2CO3/THF conditions, a diverse range of aryl
propiolic acid (2a) as the model substrates, moderate to good (1a–1l), heteroaryl (1m–1s), cinnamyl (1t), and benzyl chlorides
yields of 1-methoxy-2-(phenylethynyl)benzene (3a) in 44 and (1u–1v) with 3-phenylpropiolic acid (2a) could be decarbox-
85% could be obtained using 1 mol% of PdCl2(Cy*Phine)2, ylatively coupled in good to excellent yields (82–99%)
K3PO4 as the base at 80 ꢀC in CH3CN (Table 1, entry 1) or Cs2CO3 (Scheme 2). There is no electronic or steric bias of the aryl
in CH3CN (Table 1, entry 2) respectively, aer 1.5 h. With the chlorides that could be coupled with 2a to afford their corre-
better performing Cs2CO3 as the base, a range of solvents with sponding internal alkynes 3a–l. Unactivated electron-rich aryl
various polarities were evaluated (Table 1, entries 3–7). Of chlorides, e.g., (o, m, or, p)-chloroanisoles or chlorotolanes
which, two solvents stand out: the combination of Cs2CO3/ showed interesting rate trends whereby ortho > meta > para
dioxane was able to improve the yield of 3a to 98% (Table 1, depending on the o, m, p-aryl ring substituent of the aryl
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Table 2 Reaction conditions optimization: effect of catalyst loading
product could be achieved for the coupling of electron-rich 4-
chloroanisole and 2a aer 10 h. Pleasingly, the facile protocol is
also amenable to challenging substrates such as 4-chlorophenol
(1k) and 4-chloroaniline (1l), albeit at a higher catalyst loadings
(3 mol%). To demonstrate scalability, the reaction using 8
mmol of 2-chloroanisole (1a) and phenylpropiolic acid (2a)
could be completed within 6 h using 1 mol% PdCl2(Cy*Phine)2
to obtain 3a in near quantitative yield.
and temperaturea
Entry PdCl2(Cy*Phine)2 (mol%) Temp. (ꢀC) Time (h) Yieldb (%)
In addition, the decarboxylative cross-coupling of aliphatic
propiolic acids with various aryl-, heteroaryl- and benzyl chlo-
rides including those with unprotected functionality proceeded
smoothly in good to excellent yields (86–99%) using the general
protocol (Table 3). Typically, the reaction for alkylpropiolic
acids is slower compared to their aromatic counterparts due to
their reduced reactivity and, with more challenging substrates,
higher catalyst loading was found to be necessary for the reac-
tion to reach near completion within a reasonable timeframe
(Table 3, entries 3, 5, 6 and 9).
1
2
3
4
5
1
1
0.5
0.1
0
70
60
80
80
80
10
12
3
36
1.5
>99
70
>99
>99
0
a
Reaction conditions: PdCl2(Cy*Phine)2b, 0.5 mmol of 1a, 0.6 mmol of
1b, 1.2 mmol Cs2CO3, 2 mL of solvent. GC yield based on 0.5 mmol
of 1a using dodecane as an internal standard.
To improve the practicality of the decarboxylative cross-
coupling approach for the synthesis of complex internal
alkynes where the requisite coupling partners are not readily
available, the development of the one-pot tandem Sonogashira/
decarboxylative coupling of (hetero)aryl chlorides with propiolic
acid for the preparation of symmetrical di(heteroaryl)alkynes
became our next focus (Scheme 3).
Under our standard conditions (PdCl2(Cy*Phine)2, Cs2CO3,
THF, 80 ꢀC), 3-chloropyridine and propiolic acid (5) were chosen
as the coupling partners. However, at up to 5 mol% PdCl2-
(Cy*Phine)2 at 80 ꢀC, little conversion to the desired 1,2-
di(pyridin-3yl)ethyne was observed aer 24 h. However, substi-
tution of THF for the higher boiling solvent, 1,4-dioxane and
repeating the reaction at 120 ꢀC successfully afforded 1,2-
di(pyridin-3-yl)ethyne (6a) in 55% isolated yield. Similarly, the
tandem Sonogashira/decarboxylative cross-coupling of 2-chlor-
othiophene and 3,5-dichloropyridine yielded the desired 1,2-
di(thiophen-2-yl)ethyne (6b) and 1,2-di(3-chloropyridin-5-yl)
ethyne (6c) in 58% and 24% isolated yields, respectively, and
together this represents the rst examples of 1-pot, a tandem
Sonogashira/decarboxylative cross-coupling using heteroaryl
chloride substrates to yield 1,2-di(heteroaryl)alkyne products.
Conclusions
In summary, we have demonstrated the application of
PdCl2(Cy*Phine)2 in a decarboxylative cross-coupling between
alkynyl carboxylic acids and a diverse array of commercially
available alkyl, aryl and (hetero-)aryl chlorides with improved
Scheme 2 Decarboxylative coupling of 3-phenylpropiolic acid with
organic chloridesa,b aReaction conditions: 1 mol% PdCl2(Cy*Phine)2,
.
0.5 mmol of organic chloride 1, 0.6 mmol of 2, 1.2 mmol Cs2CO3, 2 mL
of THF, 80 ꢀC. bAverage isolated yields of two runs. c8 mmol scale
reaction completed within 6 h, isolated yields in parentheses. d3 mol%
of PdCl2(Cy*Phine)2 used instead.
functional group tolerance using
a facile protocol. As
a complementary synthetic strategy to copper-free Sonoga-
shira protocols using PdCl2(Cy*Phine)2, we have also pre-
sented the rst synthesis of symmetrical di(heteroaryl)alkynes
via the tandem Sonogashira/decarboxylative cross-coupling of
propiolic acid with heteroaryl chlorides. Further investiga-
chloride. It is noteworthy that whilst the protocol identied in tions into other tandem reaction capabilities of the PdCl2-
this study is very similar to Li et al.,14a where Pd(OAc)2/XPhos (Cy*Phine)2 system are currently underway in our laboratories
was used as the catalyst system, only 19% yield of the desired and will be reported in due course.
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Table 3 Decarboxylative of organic chlorides with alkynyl carboxylic acidsa
Entry
1
R
R2
Product
Time (h)
5
Yieldb (%)
98
2
14
24
4
99
99
99
89
86
3c
4
5c
6c
2c
2c
12
12
7
2c
2c
2c
12
12
24
89
90
96
8
9c
10
11
2e
2e
5
1
95
99
12
2e
1
98
a
Reaction conditions: 1 mol% PdCl2(Cy*Phine)2, 0.5 mmol of organic chloride 1, 0.6 mmol of alkynyl carboxylic acid 2, 1.2 mmol Cs2CO3, 2 mL of
THF, 80 ꢀC. b Average isolated yields of two runs. c 2 mol% of PdCl2(Cy*Phine)2.
Sciences (ICES) and the A*STAR Singapore Bioimaging
Consortium (SBIC).
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Scheme 3 Synthesis of symmetric di(heteroaryl)alkynes via tandem
Sonogashira/decarboxylative cross couplinga. aReaction conditions: 5
mol% PdCl2(Cy*Phine)2, 1.0 mmol of R–Cl, 0.4 mmol of propiolic acid,
1.2 mmol Cs2CO3, 2 mL of dioxane, 120 ꢀC, 16 h. bAverage isolated
yields of two runs.
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Acknowledgements
Financial support for this work was provided by the A*STAR
Joint Council Office (JCO), the Singapore 1st JCO Developmental
Programme (DP) (grant JCO 1230400020 to Y. H. L., E. R. and C.
W. J.), the A*STAR Institute of Chemical and Engineering
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