One-pot synthesis of unsymmetrical diarylacetylenes via Sonogashira/deacetonation/Sonogashira cross-coupling of two different aryl chlorides with 2-methyl-3-butyn-2-ol

Article abstract of DOI:10.1039/c4ra02720e

With the assistance of PdCl₂/X-Phos as the catalyst system, a green and efficient protocol for one-pot Sonogashira/Deacetonation/Sonogashira coupling reaction of two different aryl chlorides with 2-methyl-3-butyn-2-ol was developed, affording various unsymmetrical diarylacetylenes in mostly moderate to excellent yields. Note that the cheap and economically available aryl chlorides and 2-methyl-3-butyn-2-ol as the starting materials could be added to the catalyst system directly and simultaneously. Moreover, this tandem reaction could tolerate substrates bearing one or even two ortho-sterically hindered groups and was also applicable to the synthesis of symmetrical diarylacetylenes. In addition, the competitive reaction was performed and a possible mechanism was also proposed. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4ra02720e

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One-pot synthesis of unsymmetrical
diarylacetylenes via Sonogashira/deacetonation/
Sonogashira cross-coupling of two different aryl
chlorides with 2-methyl-3-butyn-2-ol†
Cite this: RSC Adv., 2014, 4, 32643
a
a
a
a
Kai Xu,ab Suyan Sun, Guodong Zhang, Fan Yang and Yangjie Wu
*
*
With the assistance of PdCl2/X-Phos as the catalyst system, a green and efficient protocol for one-pot
Sonogashira/Deacetonation/Sonogashira coupling reaction of two different aryl chlorides with 2-methyl-
3-butyn-2-ol was developed, affording various unsymmetrical diarylacetylenes in mostly moderate to
excellent yields. Note that the cheap and economically available aryl chlorides and 2-methyl-3-butyn-2-
ol as the starting materials could be added to the catalyst system directly and simultaneously. Moreover,
this tandem reaction could tolerate substrates bearing one or even two ortho-sterically hindered groups
and was also applicable to the synthesis of symmetrical diarylacetylenes. In addition, the competitive
reaction was performed and a possible mechanism was also proposed.
Received 27th March 2014
Accepted 16th July 2014
DOI: 10.1039/c4ra02720e
www.rsc.org/advances
substituted diarylacetylenes from aryl iodides or bromides
using 2-methyl-3-butyn-2-ol as the acetylene source
(Scheme 2a).5a Notably, Hua and co-workers reported a one-pot
Introduction
Sonogashira coupling has become one of the most powerful and
reliable tools for the preparation of diarylacetylenes, which have
wide application as valuable building blocks in organic
synthetic, pharmaceutical and materials sciences.1 However,
this coupling also suffers from an inevitable drawback and
limitation: using terminal alkynes as the acetylene sources.
Terminal alkynes bearing functional groups are usually expen-
sive and not commercially available, which has hampered their
large scale industrial applications. Therefore, much work has
been devoted to seeking for the easily available replacement to
terminal alkynes, such as monoprotected acetylene derivatives
bearing the hydroxyl, carboxyl, or other metal (Sn, Si, Zn, B)
moieties (Scheme 1).2–5 Comparatively, 2-methyl-3-butyn-2-ol
has a clear advantage over other acetylene sources due to its
low cost.5 Promisingly, in the near future, the coupling reaction
using 2-methyl-3-butyn-2-ol as the acetylene source may emerge
as a widely applicable alternative to Sonogashira reaction,
namely as Sonogashira/Deacetonation/Sonogashira (SDS) cross-
coupling (Scheme 2).
SDS catalytic system for the preparation of symmetrical diary-
lacetylenes from the direct reaction of aryl chlorides with 2-
methyl-3-butyn-2-ol, but the unsymmetrical diarylacetylenes
were obtained in 20–32% yields from two different aryl chlo-
rides with 2-methyl-3-butyn-2-ol (Scheme 2b).5b Very recently, we
also reported the rst deacetonative coupling of aryl propargyl
alcohols with aryl chlorides, but this catalyst system employed a
complicated palladacycle as the catalyst. In addition, the aryl
propargyl alcohols are not commercially available and need the
preparation in advance (Scheme 2c).5c Therefore, the successful
direct synthesis of unsymmetrical diarylacetylenes just
employing aryl chlorides and 2-methyl-3-butyn-2-ol as the
coupling partners is still a challenge, and the reports remain
rare.
Inspired by the above pioneering works, we envisioned that
the one-pot synthesis of unsymmetrical diarylacetylenes could
The pioneering work of the tandem SDS cross-coupling
´
belonged to Kotschy and Novak, who realized the synthesis of
aHenan Key Laboratory of Chemical Biology and Organic Chemistry, Key Laboratory of
Applied Chemistry of Henan Universities, The College of Chemistry and Molecular
Engineering, Zhengzhou University, Zhengzhou 450052, People's Republic of China.
E-mail: yangf@zzu.edu.cn; wyj@zzu.edu.cn
bThe College of Chemistry & Chemical Engineering, Shangqiu Normal University,
Shangqiu 476000, People's Republic of China
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ra02720e
Scheme 1 The reported acetylene sources.
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generation of 2ab in 4% GC yield. Other possible products such
as 2bx, 2aa, and 2bb were not detected at all. The results indi-
cate that the reactivity of electron-poor 4-nitrochlorobenzene
(1a) is far higher than that of 4-chlorotoluene (1b), and we
predicted that increasing the loading of the base and prolong-
ing the reaction time would result in the continuous coupling of
2ax with 4-chlorotoluene (1b) to afford the unsymmetrical dia-
rylacetylene 2ab as the main product.
According to the above viewpoints, we then performed the
SDS coupling reaction by adding a larger loading of the base
and prolonging the reaction time in favour of the deacetonation
step. And a mixture of 4-nitrochlorobenzene (1a), 2-methyl-3-
butyn-2-ol, 4-chlorotoluene (1b) and 4 equivalents K2CO3 was
added in acetonitrile simultaneously under a nitrogen atmo-
sphere for 16 h. To our surprise, the unsymmetrical diary-
lacetylene 2ab as the only product could be assembled in an
excellent yield of 98% without any other byproducts, which was
in accordance with the hypotheses derived from the competitive
reaction (Scheme 4).
According to the above viewpoints, the scope of the aryl
chlorides was then investigated under the optimized reaction
conditions (Scheme 5). Generally, the catalyst system afforded
the desired unsymmetrical diarylacetylenes with unexpected
high yields mostly ranging from 69% to 99%, and few byprod-
ucts such as symmetrical diarylacetylenes or diyne compounds
derived from the dimerization of alkynes were detected, which
is different from the results from Hua's report (Scheme 5).5b In
detail, one aryl chloride is a higher reactive electron-poor
substrate and the other is an inactive electron-rich or
electron-neutral aryl chloride, which would conform to our
designed reaction model, and the unsymmetrical diary-
lacetylenes were afforded in good to excellent yields (Scheme 5,
2ac–2ap). In the case of the two electron-poor aryl chlorides
selected, large difference of their reactivity in our system would
be necessary (Scheme 5, 2aq–2kr). However, the reaction of the
two electron-rich aryl chlorides only generated the desired
product in a yield of 38%, which may be attributed to their
similar reactivity in this SDS reaction (Scheme 5, 2gd). Notably,
the reaction scope could be extended to the aryl chloride
bearing two ortho-sterically hindered groups such as 2-choro-m-
Scheme
2 Synthesis of symmetrical or unsymmetrical diary-
lacetylenes by a tandem or one-pot SDS strategy.
be accomplished via a simple and facile protocol by adding two
different aryl chlorides and 2-methyl-3-butyn-2-ol to the reac-
tion system directly and simultaneously (Scheme 2d). Once the
new catalyst system was established, it would cut the cost
signicantly due to the more commercially available and inex-
pensive raw materials. The main challenges in this one-pot SDS
coupling include activation of two C–Cl bonds, the deacetona-
tion of 2-methyl-3-butyn-2-ol and the suppression of diverse
kinds of side reactions.
Results and discussion
Alkylphosphane ligands bearing a biphenyl skeleton, well-
known as Buchwald's ligands, could be affective for the activa-
tion of C–Cl bond, and signicant progress has been achieved
by the groups of Buchwald, Fu, and others.6 With the aid of a
Buchwald's ligand: 2-dicyclohexylphosphino-20,40,60-triisopro-
pylbiphenyl (X-Phos), we initially performed a competitive
reaction by performing the equivalent loading of 4-nitro-
chlorobenzene (1a), 4-chlorotoluene (1b), 2-methyl-3-butyn-2-ol,
and the base in CH3CN for 5 h (Scheme 3). Surprisingly, the
product 2ax was observed in GC 72% yield, accompanied by the
Scheme 3 The competitive reaction of two aryl chlorides with 2- Scheme
4 The one-pot SDS coupling reaction of 4-nitro-
methyl-3-butyn-2-ol: (a) Reagents and conditions: 4-Nitro- chlorobenzene, 4-chlorotoluene, and 2-methyl-3-butyn-2-ol: (a)
chlorobenzene (1a) (0.5 mmol), 2-methyl-3-butyn-2-ol (0.5 mmol), 4- Reagents and conditions: 4-nitrochlorobenzene (1a) (0.5 mmol), 2-
chlorotoluene (1b) (0.5 mmol), PdCl2 (4 mol%), X-Phos (4 mol%), and methyl-3-butyn 2-ol (0.5 mmol), 4-chlorotoluene (1b) (0.5 mmol),
K2CO3 (0.5 mmol) in CH3CN (2 mL) at 110 ꢀC under a nitrogen PdCl2 (4 mol%), X-Phos (4 mol%), and K2CO3 (2 mmol) in CH3CN (2 mL)
atmosphere for 5 h. (b) GC yield based on the amount of 4-nitro- at 110 ꢀC under a nitrogen atmosphere for 16 h. (b) Isolated yield based
chlorobenzene (1a).
on the amount of 4-nitrochlorobenzene (1a).
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Scheme 6 The Sonogashira cross-coupling of aryl chloride with
phenylacetylene: (a) Reagents and conditions: ArCl (0.5 mmol),
terminal alkyne (0.6 mmol), PdCl2 (2 mol%), X-Phos (4 mol%), and
K2CO3 (0.75 mmol) in CH3CN (2 mL) at 110 ꢀC under a nitrogen
atmosphere for 16 h. (b) Isolated yield based on the amount of ArCl.
Scheme 7 Synthesis of symmetrical diarylacetylenes via one-pot SDS
coupling: (a) 2-methyl-3-butyn-2-ol (0.5 mmol), ArCl (1.2 mmol),
PdCl2 (4 mol%), X-phos (4 mol%), K2CO3 (2 mmol), in CH3CN (2 mL) at
110 ꢀC under a nitrogen atmosphere for 16 h. (b) Isolated yield based
on the amount of 2-methyl-3-butyn-2-ol.
Scheme 5 The substrate scope of the one-pot SDS reaction: (a)
Reagents and conditions: Ar1Cl (0.5 mmol), 2-methyl-3-butyn-2-ol
(0.6 mmol), Ar2Cl (0.6 mmol), PdCl2 (4 mol%), X-Phos (4 mol%), and
K2CO3 (2 mmol) in CH3CN (2 mL) at 110 ꢀC under a nitrogen atmo-
sphere for 16 h. (b) Isolated yield based on the amount of Ar1Cl.
substrates ratio. Two representative substrates: 2-chloro-p-
xylene (1f) and 4-chlorobenzotriuoride (1q) could be tolerated
well to give the corresponding products in the yields of 67% and
85%, respectively.
On the basis of the reported works and our own results, a
proposed mechanism for this type one-pot SDS coupling was
outlined in Scheme 8. The rst step was the oxidative addition
of the more reactive aryl chloride (1) to Pd(0) species to give the
Pd(II) intermediate I. Then, in the presence of the base the
reaction took place between intermediate I and 2-methyl-3-
butyn-2-ol to form the Pd(II) intermediate II. The reductive
xylene (1g) and 2-chloromesitylene (1h) (Scheme 5, 2ag, 2ah, 2jg,
2jh, 2kg, 2kh, and 2lg). Moreover, the reaction could tolerate
various functional groups (e.g., CH3O, methoxycarbonyl, NO2,
CN, CHO, and vinyl) and heterocyclic chlorides (1r and 1s)
(Scheme 5, 2ac–2kr). Especially, during the reaction process of
the aryl chloride bearing a vinyl group, the classical Heck
coupling products were not detected at all (Scheme 5, 2ao
and 2ap).
As expected, the catalytic system could be applicable to the
Sonogashira cross-coupling of phenylacetylene with aryl chlo-
rides. In detail, whether the aryl chloride was electron-poor or
electron-rich, the desired products could be obtained in good to
excellent yields (Scheme 6). The reaction could also tolerate
heterocyclic chlorides (2rm and 2sm). Also, the cross-coupling
of the ortho-sterically hindered aryl chloride could give the
product in a good yield (2gm and 2gd). In particular, this
protocol provides the 2gd with a signicantly higher yield of
78% attributed to the reduction of competitive reaction
compared to the method applied in Scheme 5.
In addition, synthesis of symmetrical diarylacetylenes could
also be achieved via this type of one-pot SDS coupling strategy,
which was presented as Scheme 7. The reaction employed one
aryl chloride and 2-methyl-3-butyn-2-ol under the above opti-
mized reaction conditions apart from the adjustment of the
Scheme 8 A proposed mechanism of palladium-catalyzed one-pot
SDS coupling reaction.
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elimination of the intermediate II generated the Sonogashira
product of aryl propargyl alcohol A and the active Pd(0) species.
On the other hand, the oxidative addition of the less reactive
aryl chloride (10) to Pd(0) species afforded the Pd(II) interme-
diate III. The reaction of arylpropargyl alcohol A with the
intermediate III in the presence of the base occurred to form the
Pd(II) intermediate IV and release a molecular acetone. Finally,
the reductive elimination of the intermediate IV took place to
afford the unsymmetrical diarylacetylene (2) and regenerate the
active Pd(0) species.
References
1 (a) K. Sonogashira, Y. Tohda and N. Hagihara, Tetrahedron
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Conclusions
2 For the representative review on the acetylene source, see:
E. Negishi and L. Anastasia, Chem. Rev., 2003, 103, 1979–
2017.
In conclusion, we developed
a general and efficient
palladium-catalyzed one-pot SDS coupling reaction of two
different aryl chlorides with 2-methyl-3-butyn-2-ol, affording
various unsymmetrical diarylacetylenes in mostly moderate to
excellent yields. Notably, the economical and readily available
aryl chlorides and 2-methyl-3-butyn-2-ol as the raw materials
could be added to the catalyst system simultaneously, thus
providing the possibility of this simple and green catalyst
system in industrial application. Interestingly, when the aryl
chloride possessed a vinyl group, the SDS reaction could
selectively occur and classical Heck coupling products were
not detected at all. Moreover, this SDS reaction could
tolerate the substrates bearing one or even two ortho-sterically
hindered groups. In addition, the reaction system was
also applicable to the synthesis of symmetrical diary-
lacetylenes and the classical Sonogashira cross-coupling
using phenylacetylene as the substrate. Further synthetic
applications of these methodologies are currently underway
in our laboratory.
3 For examples using the ethynyltrimethylsilane as the
acetylene source, see: (a) M. R. Buchmeiser and K. Wurst, J.
Am. Chem. Soc., 1999, 121, 11101–11107; (b) M. J. Wu,
L. M. Wei, C. F. Lin, S. P. Leou and L. L. Wei, Tetrahedron,
2001, 57, 7839–7844; (c) G. W. Kabalka, L. Wang and
R. M. Pagni, Tetrahedron, 2001, 57, 8017–8028; (d)
M. J. Mio, L. C. Kopel, J. B. Braun, T. L. Gadzikwa,
K. L. Hull, R. G. Brisbois, C. J. Markworth and P. A. Grieco,
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M. Weck, Adv. Synth. Catal., 2006, 348, 2101–2113; (g)
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Q. Zhang, X. Q. Sun and C. Y. Wang, J. Am. Chem. Soc.,
2013, 135, 4628–4631.
4 For examples using the propiolic acid as the acetylene source,
see: (a) J. Moon, M. Jeong, H. Nam, J. Ju, J. H. Moon,
H. M. Jung and S. Lee, Org. Lett., 2008, 10, 945–948; (b)
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Experimental
Representative procedure for the one-pot synthesis of
unsymmetrical diarylalkynes via the SDS cross-coupling
4-Nitrochlorobenzene (78.7 mg, 0.5 mmol), 2-methyl-3-butyn-
2-ol (59 mL, 0.6 mmol), 4-chlorotoluene (71 mL, 0.6 mmol),
PdCl2 (3.6 mg, 4 mol%), X-Phos (9.5 mg, 4 mol%) and K2CO3
(276 mg, 2 mmol) were dissolved in CH3CN (2 mL) in a 10 mL
vial under a nitrogen atmosphere. Aer the reaction was
5 For examples using 2-methyl-3-butyn-2-ol as the acetylene
´
source, see: (a) Z. Novak, P. Nemes and A. Kotschy, Org.
ꢀ
heated at 110 C for 16 h, the mixture was ltered through a
Lett., 2004, 6, 4917–4920; (b) C. Y. Yi, R. M. Hua, H. X. Zeng
and Q. F. Huang, Adv. Synth. Catal., 2007, 349, 1738–1742;
(c) H. Hu, F. Yang and Y.-J. Wu, J. Org. Chem., 2013, 78,
10506–10511.
6 For examples using Buchwald's ligands in Sonogashira
reaction, see: (a) T. Hundertmark, A. F. Littke,
S. L. Buchwald and G. C. Fu, Org. Lett., 2000, 2, 1729–1731;
(b) B. H. Lipshutz, D. W. Chung and B. Rich, Org. Lett.,
2008, 10, 3793–3796; (c) W. W. Zhang, X. G. Zhang and
pad of Celite and washed with ethyl acetate. The mixture was
added into H2O (25 mL) and extracted with ethyl acetate
(10 mL) three times. The combined organic layer was dried
over anhydrous Na2SO4 and ltered. Aer removal of the
solvent in vacuum, the residue was puried by ash chro-
matography on silica gel (ethyl acetate/hexane ¼ 1 : 5) to give
the pure product 2ab (116.3 mg, 98%).
´
J. H. Li, J. Org. Chem., 2010, 75, 5259–5264; (d) B. D. Carne-
Acknowledgements
´
Carnavalet, A. Archambeau, C. Meyer, J. Cossy, B. Folleas,
We are grateful to the Natural Science Foundation of China (nos
J.-L. Brayer and J.-P. Demoute, Org. Lett., 2011, 13, 956–959.
21172200, 21102134) for nancial support.
32646 | RSC Adv., 2014, 4, 32643–32646
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