Synthesis of diarylalkynes via tandem Sonogashira/decarboxylative reaction of aryl chlorides with propiolic acid

Article abstract of DOI:10.1039/c3ra47712f

A facile and efficient protocol for one-pot synthesis of diarylalkynes via tandem Sonogashira/decarboxylative coupling has been developed. The remarkable features of this reaction include using commercially available aryl chlorides as starting materials and taking the propiolic acid instead of expensive terminal alkynes as an acetylene source. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c3ra47712f

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Synthesis of diarylalkynes via tandem Sonogashira/
decarboxylative reaction of aryl chlorides with
propiolic acid†
Cite this: RSC Adv., 2014, 4, 13738
Received 17th December 2013
Accepted 6th March 2014
*
*
Xiang Li, Fan Yang and Yangjie Wu
DOI: 10.1039/c3ra47712f
www.rsc.org/advances
A facile and efficient protocol for one-pot synthesis of diarylalkynes via aryl chlorides is still challenging but highly desirable, and the
tandem Sonogashira/decarboxylative coupling has been developed. relative reports remain rare.7,8 Moreover, the reported reaction
The remarkable features of this reaction include using commercially procedure usually includes two isolated steps and must add
available aryl chlorides as starting materials and taking the propiolic the two aryl halides in sequential process, which may make
acid instead of expensive terminal alkynes as an acetylene source.
the operation more complicated. Therefore, we envisioned to
develop a simple, economically convenient catalytic system
using aryl chlorides and propiolic acid as the starting materials.
Especially in the preparation of unsymmetrical diarylalkynes,
two different aryl chlorides along with the propiolic acid would
be added to the reaction system in one-step (Scheme 1d).
Our initial investigation was performed on the screening the
effect of bases, additives and solvents (see ESI†), and we found
that the reaction of 4-chlorotoluene with propiolic acid in the
presence of DBU in DMSO under catalysis of PdCl2/PCy3 could
afford desired product 3a in a low yield of 11% (Table 1, entry 1).
Then, a series of commercially available ligands (e.g., PPh3,
PCy3, Ruphos, Davephos, Johnphos, CyJohnphos and Xphos)
were checked (Fig. 1), and the product could be obtained in a
moderate but acceptable yield of 61% by using Xphos as the
ligand (Table 1, entries 2–7). However, lower yields of 53% and
The palladium-catalyzed Sonogashira reaction has become one
of the most powerful and facile methods for the synthesis of
internal alkynes,1 which has been widely applied in the elds of
organic synthesis,2 pharmaceuticals,3 and materials science.4
Sonogashira reaction typically utilizes terminal alkynes as the
coupling partner. However, terminal alkynes bearing functional
groups are not commercially available and usually expensive,
which has hampered its large scale industrial applications.
In recent years, transition metal-catalyzed decarboxylative
Sonogashira reaction of arylpropiolic acids with aryl halides has
emerged an alternative route to Sonogashira reaction for the
synthesis of internal alkynes.5 Nevertheless, arylpropiolic acids
still suffered from the high-cost and multistep synthetic route.
To address these limitations, propiolic acid, which is usually
commercial available and stable as well as easy to store, could
act as the an acetylene source to fulll the synthesis of various
diarylalkynes.6 In 2008, Lee and co-workers reported the rst
example for the synthesis of diarylalkynes using the propiolic
acid and aryl iodides or bromides as the starting materials
(Scheme 1a and b).6a,b Recently, Goossen's group realized the
efficient synthesis of unsymmetrical diarylalkynes from two
different aryl bromides and propiolic acid (Scheme 1c).6c
However, the substrate scope is mainly limited to aryl iodides
and bromides. The reaction of the more commercially available
ꢀ
56% were obtained when the temperature decreased to 100 C
ꢀ
or increased to 140 C, respectively (Table 1, entries 8 and 9).
The College of Chemistry and Molecular Engineering, Henan Key Laboratory of
Chemical Biology and Organic Chemistry, Key Laboratory of Applied Chemistry
of Henan Universities, Zhengzhou University, Zhengzhou 450052, People's Republic
of China. E-mail: yangf@zzu.edu.cn; wyj@zzu.edu.cn; Fax: +86-371-6797-9408; Tel:
+86-371-6797-9408
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c3ra47712f
Scheme 1 Sonogashira/decarboxylative coupling of propiolic acid
with aryl halides.
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Table 1 Reaction of propiolic acid with 4-chlorotoluenea
Table 2 Tandem Sonogashira/decarboxylative reaction of propiolic
acid with aryl chloridesa,b
Entry
Catalyst
Ligand
Yieldb (%)
1
2
3
4
5
6
7
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
—
Pd(OAc)2
Pd2dba3
PdCl2(PPh3)2
PCy3
PPh3
11
<10
28
15
18
23
61
53
56
—
Ruphos
Davephos
Johnphos
CyJohnphos
Xphos
Xphos
Xphos
Xphos
Xphos
8c
9d
10e
11
12
13f
14
—
Xphos
Xphos
Xphos
18
33
15
a
Reaction conditions: propiolic acid 1a (0.4 mmol), 4-chlorotoluene 2a
(1.0 mmol), palladium catalyst (2 mol%), ligand (4 mol%), DBU (4
equiv.), DMSO (2 mL) at 120 ꢀC for 24 h under a nitrogen atmosphere.
b
c
d
e
f
Isolated yield. At 100 ꢀC. At 140 ꢀC. Under air. 1 mol% of
Pd2dba3 was used.
a
Reaction conditions: propiolic acid 1a (0.4 mmol), aryl chlorides 2 (1.0
mmol), PdCl2 (2 mol%), Xphos (4 mol%), DBU (4 equiv.), DMSO (2 mL)
b
at 120 ꢀC for 24 h under a nitrogen atmosphere. Isolated yield.
Fig. 1 Phosphine ligands.
this process the corresponding symmetrical diarylacetylenes
were also obtained in about 15–25% yields. It is necessary to
point out that two different aryl chlorides along with propiolic
Finally, some controlling experiments were also carried out. For acid were added to the catalytic system in one-step, which made
example, the reaction did not occur at all under air or palla- the operation simpler and more facile.
dium-free conditions, and other palladium sources such as
Pd(OAc)2, Pd2dba3, or PdCl2(PPh3)2 did not exhibit higher gram-scale experiment of Sonogashira/decarboxylative reaction
catalytic activity (Table 1, entries 10–14). of 4-chlorotoluene with propiolic acid was performed under
To further highlight the synthetic utility of this protocol, a
With the optimized conditions in hand, we next explored the standard conditions, and the desired product was obtained in a
substrate scope and the result was summarized in Table 2. yield of 42% (Scheme 2).
Generally, various functional groups such as vinyl, OMe, NMe2,
As we know, the Sonogashira reaction could not well applied
CF3 and F could be tolerated in this reaction and electron-rich, to electron-poor terminal alkynes. Therefore, we conducted a
electron-neutral, or electron-poor aryl chlorides could smoothly comparative experiment of 4-chlorotoluene (2a) with an elec-
be transferred into the corresponding products. It is noteworthy tron-decient acetylene source ethyl propiolate (4a) and pro-
that the sterically hindered aryl chlorides could also afford the piolic acid (1a). The reaction of 4a did not occur at all and 1a
desired products in moderate yields (Table 2, 3d–i). Especially, gave the product (3a) in a high yield of 61%, which indicated
2-chloro-m-xylene could be coupled with propiolic acid in a that propiolic acid as an acetylene source had its unique
moderate yield of 61% (Table 2, 3g). Surprisingly, the reaction of advantages (Scheme 3). It may be attributed to the carboxylic
1-chloronaphthalene generated the product in a high yield of up acid anion generated by the reaction of propiolic acid with DBU
to 81% (Table 2, 3p). However, the reaction could not tolerate in situ, which can remarkably enhance the electronic density
the heterocyclic chloride 2-chloropyridine (Table 2, 3s).
from the electron-poor propiolic acid to propiolic acid anion.
To further investigate the mechanism for palladium-
In addition, the synthesis of unsymmetrical diarylacetylenes
was also performed, and Table 3 shows that the unsymmetrical catalyzed tandem Sonogashira/decarboxylative coupling, the
diarylacetylenes (3r–u) could be obtained in yields of 30–36%. In reaction of phenylpropiolic acid (5a) with chlorobenzene (2o)
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Table 3 One-pot synthesis of unsymmetrical diarylacetylenes from
two different aryl chlorides and propiolic acida,b
Scheme 5 A tentative mechanism.
elimination of intermediate II afforded Sonogashira product as
arylpropiolic acid anion A and the active Pd(0) species to fulll
the catalytic cycle. On the other hand, the reaction of aryl
a
Reaction conditions: propiolic acid 1a (0.6 mmol), Ar1Cl (0.4 mmol),
Ar2Cl (0.4 mmol), PdCl2 (2 mol%), Xphos (4 mol%), DBU (4 equiv.),
DMSO (2 mL) at 120 ꢀC for 24 h under a nitrogen atmosphere. chloride (20) with Pd(0) species could form the Pd(II) interme-
b
Isolated yield.
diate III. The ligand exchange between the arylpropiolic acid
anion A and intermediate III occurred to give the Pd(II) inter-
mediate IV. Aer intermediate IV underwent the decarbox-
ylative reaction to release one molecular CO2 to form
intermediate V, the reductive elimination of intermediate V
could afford the desired product (3) and regenerate the active
Pd(0) species.
In conclusion, we have developed the rst palladium-cata-
lyzed tandem Sonogashira/decarboxylative cross coupling
reaction of propiolic acid with the more challenging aryl chlo-
rides as the coupling partners. Notably, the reaction could well
tolerate ortho-sterically hindered aryl chlorides affording the
desired products in moderate yields, and the substrate scope
could be extended to electron-rich, electron-neutral, and even
electron-poor aryl chlorides. Moreover, adding two different aryl
chlorides simultaneously in one-pot makes the method more
convenient and practical for the preparation of unsymmetrical
diarylalkynes.
Scheme 2 The gram-scale experiment.
Scheme 3 The comparative experiment.
We are grateful to the Natural Science Foundation of China
(no.: 21172200, 21102134) for nancial support.
Notes and references
1 For recent reviews on Sonogashira reactions, see: (a)
K. Sonogashira, J. Organomet. Chem., 2002, 653, 46; (b)
E.-I. Negishi and L. Anastasia, Chem. Rev., 2003, 103, 1979;
(c) K. C. Nicolaou, P. G. Bulger and D. Sarlah, Angew. Chem.,
Int. Ed., 2005, 44, 4442; (d) R. Chinchilla and C. Najera,
Chem. Rev., 2007, 107, 874; (e) R. R. Tykwinski, Angew.
Chem., Int. Ed., 2003, 42, 1566; (f) L. Yin and J. Liebscher,
Chem. Rev., 2007, 107, 133; (g) H. Doucet and J.-C. Hierso,
Angew. Chem., Int. Ed., 2007, 46, 834.
Scheme 4 The controlling experiment.
was performed and the desired product was obtained in 50%
yield (Scheme 4). This result suggested that the phenylpropiolic
onion was an intermediate in the reaction.
On the basis of the above-mentioned results and reported
works,9 a tentative mechanism for palladium-catalyzed tandem
Sonogashira/decarboxylative coupling was outlined in Scheme 2 L. Brandsma, S. F. Vasilevsky and H. D. Verkruijsse,
5. The initial step would be the oxidative addition of aryl chlo-
ride (2) to Pd(0) species to form the Pd(II) intermediate I. And
Application of Transition Metal Catalysts in Organic Synthesis,
Springer, Berlin, 1998.
then, the ligand replacement between intermediate I and the 3 (a) K. C. Nicolaou and W.-M. Dai, Angew. Chem., Int. Ed., 1991,
propiolic acid anion, which was generated from propiolic acid
1a and base, took place to form intermediate II. The reductive
30, 1387; (b) J. M. Grissom, G. U. Gunawardena, D. Klingberg
and D. Huang, Tetrahedron, 1996, 52, 6453; (c) M. DeKort,
13740 | RSC Adv., 2014, 4, 13738–13741
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RSC Advances
V. Correa, A. R. P. M. Valentijin, G. A. Van der Marel,
B. V. L. Potter, C. W. Taylor and J. H. Van Boom, J. Med.
Chem., 2000, 43, 3295; (d) P. Lang, G. Magnin, G. Mathis,
A. Burger and J.-F. Biellmann, J. Org. Chem., 2000, 65, 7825;
J. Wagler, N. Mirzadeh and M. L. Kantam, Adv. Synth.
Catal., 2013, 355, 705; (k) X. Li, F. Yang and Y.-J. Wu, J. Org.
Chem., 2013, 78, 4543; (l) X. Li, F. Yang, Y.-J. Wu and
Y.-S. Wu, Org. Lett., 2014, 16, 992.
(e) J.-I. Uenishi, K. Matsui and H. Ohmiya, J. Organomet. 6 (a) J. Moon, M. Jeong, H. Nam, J. Ju, J. H. Moon, H. M. Jung
Chem., 2002, 653, 141; (f) J. Boukouvalas, S. Cote and
B. Ndzi, Tetrahedron Lett., 2007, 48, 105; (g) D. Falcone,
J. Li, A. Kale and G. B. Jones, Bioorg. Med. Chem. Lett., 2008,
18, 934.
4 (a) T. McQuade, A. E. Pullen and T. M. Swager, Chem. Rev.,
2000, 100, 2537; (b) T. H. Kim and T. M. Swager, Angew.
Chem., Int. Ed., 2003, 42, 4803; (c) J. H. Moon, W. McDaniel,
and S. Lee, Org. Lett., 2008, 10, 945; (b) K. Park, G. Bae,
J. Moon, J. Choe, K. H. Song and S. Lee, J. Org. Chem., 2010,
75, 6244; (c) S. Tartaggia, O. D. Lucchi and L. J. Goossen,
Eur. J. Org. Chem., 2012, 1431; (d) K. Park, G. Bae, A. Park,
Y. Kim, J. Choe, K. H. Song and S. Lee, Tetrahedron Lett.,
2011, 52, 576; (e) H. J. Lee, K. Park, G. Bae, J. Choe,
K. H. Song and S. Lee, Tetrahedron Lett., 2011, 52, 5064.
P. MacLean and L. F. Hancock, Angew. Chem., Int. Ed., 2007, 7 For recent papers on decarboxylative reactions with aryl
´
46, 8223; (d) J. Liu, J. W. Y. Lam and B. Z. Tang, Chem. Rev.,
2009, 109, 5799.
chlorides, see: (a) L. J. Goossen, N. Rodrıguez, B. Melzer,
C. Linder, G. Deng and L. M. Levy, J. Am. Chem. Soc., 2007,
129, 4824; (b) L. J. Goossen and T. Knauber, J. Org. Chem.,
2008, 73, 8631; (c) L. J. Gooßen, B. Zimmermann and
T. Knauber, Angew. Chem., Int. Ed., 2008, 47, 7103; (d)
R. Shang, Y. Fu, J.-B. Li, S.-L. Zhang, Q.-X. Guo and L. Liu,
J. Am. Chem. Soc., 2009, 131, 5738; (e) R. Shang, Z. Yang,
Y. Wang, S. Zhang and L. Liu, J. Am. Chem. Soc., 2010, 132,
14391; (f) R. Shang, Z. Huang, L. Chu, Y. Fu and L. Liu, Org.
Lett., 2011, 13, 4240.
5 For the review on decarboxylative coupling of alkynyl
carboxylic acids, see: K. Park and S. Lee, RSC Adv., 2013, 3,
14165. For representative papers, see: (a) J. Moon, M. Jang
and S. Lee, J. Org. Chem., 2009, 74, 1403; (b) H. Kim and
P. H. Lee, Adv. Synth. Catal., 2009, 351, 2827; (c) D.-B. Zhao,
C. Gao, X.-Y. Su, Y.-Q. He, J.-S. You and Y. Xue, Chem.
Commun., 2010, 46, 9049; (d) W.-W. Zhang, X.-G. Zhang and
J.-H. Li, J. Org. Chem., 2010, 75, 5259; (e) D.-L. Pan,
C. Zhang, S.-T. Ding and N. Jiao, Eur. J. Org. Chem., 2011, 8 For reactions of arylchlorides with other actylene sources,
4751; (f) T.-Y. Li, X.-M. Qu, Y. Zhu, P. Sun, H.-L. Yang,
Y.-Q. Shan, H.-X. Zhang, D.-F. Liu, X. Zhang and J.-C. Mao,
Adv. Synth. Catal., 2011, 353, 2731; (g) X.-M. Qu, T.-Y. Li,
P. Sun, Y. Zhu, H.-L. Yang and J.-C. Mao, Org. Biomol.
see: (a) C. Yi, R. Hua, H. Zeng and Q. Huang, Adv. Synth.
Catal., 2007, 349, 1738; (b) C. Yi and R. Hua, J. Org. Chem.,
2006, 71, 2535; (c) H. Huang, H. Liu, H. Jiang and K. Chen,
J. Org. Chem., 2008, 73, 6037.
Chem., 2011, 9, 6938; (h) J. Park, E. Park, A. Kim, S.-A. Park, 9 (a) J. Cheng, Y. Sun, F. Wang, M. Guo, J.-H. Xu, Y. Pan and
Y. Lee, K. W. Chi, Y. H. Jung and I. S. Kim, J. Org. Chem.,
2011, 76, 2214; (i) T.-Y. Li, P. Sun, H.-L. Yang, Y. Zhu,
H. Yan, L.-H. Lu and J.-C. Mao, Tetrahedron, 2012, 68, 6413;
(j) P. V. Reddy, P. Srinivas, M. Annapurna, S. Bhargava,
Z. Zhang, J. Org. Chem., 2004, 69, 5428; (b) Y. Liang,
Y.-X. Xie and J.-H. Li, J. Org. Chem., 2006, 71, 379; (c)
K. Park, J.-M. You, S. Jeon and S. Lee, Eur. J. Org. Chem.,
2013, 1973.
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