Rapid and efficient Pd-catalyzed sonogashira coupling of aryl chlorides

Article abstract of DOI:10.1021/jo800994f

(Chemical Equation Presented) An efficient and effective microwave-assisted cross-coupling of terminal alkynes with various aryl chlorides including sterically hindered, electron-rich, electron-neutral, and electron-deficient aryl chloride is developed. It proceeds faster and generally gives good to excellent yields and also can be extended successfully to the Suzuki coupling and Buchwald-Hartwig amination, as well as the Heck coupling with inert aryl chlorides. The short reaction times and simple reaction conditions coupling with a broad substrate scope render this method particularly attractive for the efficient preparation of biologically and medicinally interesting molecules.

Full text of DOI:10.1021/jo800994f

TABLE 1. Optimization of Catalysis Conditionsa
Rapid and Efficient Pd-Catalyzed Sonogashira
Coupling of Aryl Chlorides
He Huang, Hong Liu,* Hualiang Jiang, and Kaixian Chen
Drug DiscoVery and Design Centre, State Key Laboratory of
Drug Research, Shanghai Institute of Materia Medica,
Shanghai Institutes for Biological Sciences, and Graduate
School, Chinese Academy of Sciences, 555 Zuchongzhi Road,
Shanghai 201203, China
entry
solvent
palladium
phosphane
base
yield [%]
1
2
3
4
5
6
7
8
9
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2
0
<5
53
<5
<5
78
70
68
84
PPh3
PtBu3
PtBu3
PtBu3
PtBu3
PtBu3
PtBu3
PtBu3
Pd(OAc)2
hliu@mail.shcnc.ac.cn
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
Cs2CO3
NaOMe
NaOEt
ReceiVed May 11, 2008
Cs2CO3
a Reaction conditions: 2% Pd source, 4% phosphane (except entry 1),
10% DBU, 1.0 equiv base, 150 °C, 10 min.
as coupling partners in virtue of increased availability and
decreased expense of aryl chlorides relative to aryl bromides
and iodides. To date, only limited success has been obtained in
the Sonogashira cross-coupling of alkynes with aryl chlorides.
The state of the art in the area includes utilizing the P(Cy)2Ar
as ligand, reported by Buchwald and co-workers.4a Eberhard
and Plenio et al. have achieved significant success with zinc or
palladium catalysts.4b–e Recently, Hua and Li et al. have reported
efficient catalyst systems using PdCl2(PCy3)2 as catalyst or
TBAF as promoter.4f,g Although these methods are highly
effective, there is still much room for improvement. For
example, the requirement of long reaction times is a shortcoming
in the method of Eberhard, and low substrate generality is also
a problem in the methods of Hua and Li. Therefore, the purpose
of our research work is to develop an effective, copper-free,
easily available catalyst condition for Sonogashira coupling of
a wide variety of aryl chlorides. Developing catalytic systems
that perform more efficiently with aryl chlorides in short times
is an ongoing effort. Herein we described cross-couplings of
terminal alkynes with various aryl chlorides including sterically
hindered, electron-rich, electron-neutral, and electron-deficient
aryl chloride in excellent yield with commercially available
reagents under microwave (MW) irradiation.
An efficient and effective microwave-assisted cross-coupling
of terminal alkynes with various aryl chlorides including
sterically hindered, electron-rich, electron-neutral, and electron-
deficient aryl chloride is developed. It proceeds faster and
generally gives good to excellent yields and also can be
extended successfully to the Suzuki coupling and Buchwald-
Hartwig amination, as well as the Heck coupling with inert
aryl chlorides. The short reaction times and simple reaction
conditions coupling with a broad substrate scope render this
method particularly attractive for the efficient preparation
of biologically and medicinally interesting molecules.
Transition-metal-mediated cross-coupling reactions represent
extremely powerful and versatile methods in organic synthesis.1
Reactions leading to C(sp)-C(sp2) bond formation are often
key steps in a wide range of organic processes.2 Among these,
the Sonogashira reaction, involving the coupling of aryl or vinyl
halides with terminal alkynes, has emerged as a favorite.3 One
current challenge associated with Sonogashira coupling reaction
is its inefficiency when “unreactive” aryl chlorides are employed
Consistent with other cross-coupling processes, the Sono-
gashira reaction proceeds more rapidly with more electron-poor
halides.4 In this study, we chose the cross-coupling of pheny-
lacetylene (1) and p-chloroanisole (2), a relatively challenging
test substrate because of its electron-richness, as the model
reaction to screen the catalysts and optimize the reaction
(1) For recent reviews on this topic, see: (a) Alberico, D.; Scott, M. E.;
Lautens, M. Chem. ReV. 2007, 107, 174. (b) Beccalli, E. M.; Broggini, G.;
Martinelli, M.; Sottocornola, S. Chem. ReV. 2007, 107, 5318.
(2) For selected references, see: (a) Cwik, A.; Hell, Z.; Figueras, F.
Tetrahedron Lett. 2006, 47, 3023. (b) Ruiz, J.; Cutillas, N.; Lo´pez, F.; Lo´pez,
G.; Bautista, D. Organometallics 2006, 25, 5768. (c) Hundertmark, T.; Littke,
A. F.; Buchwald, S. L.; Fu, G. C. Org. Lett. 2000, 2, 1729. (d) Li, J.-H.; Li,
J-L.; Wang, D.-P.; Pi, S.-F.; Xie, Y.-X.; Zhang, M.-B.; Hu, X.-C. J. Org. Chem.
2007, 72, 2053. (e) Choudary, B. M.; Madhi, S.; Kantam, M. L.; Sreedhar, B.;
Iwasawa, Y. J. Am. Chem. Soc. 2004, 126, 2292. (f) Gonza´lez-Arellano, C.;
Abad, A.; Corma, A.; Garc´ıa, H.; Iglesias, M.; Sa´nchez, F. Angew. Chem., Int.
Ed. 2007, 46, 1536. (g) Li, J.-H.; Zhang, X.-D.; Xie, Y.-X. Eur. J. Org. Chem.
2005, 4256. (h) Me´ry, D,; Heuze´, K.; Astruc, D. Chem. Commun. 2003, 15,
1934.
(4) For representative papers on the Sonogashira cross-coupling reactions
of aryl chlorides with alkynes, see: (a) Gelman, D.; Buchwald, S. L. Angew.
Chem., Int. Ed. 2003, 42, 5993. (b) Eberhard, M. R.; Wang, Z. H.; Jensen, C. M.
Chem. Commun. 2002, 8, 818. (c) Ko¨llhofer, A.; Pullmann, T.; Plenio, H. Angew.
Chem., Int. Ed. 2003, 42, 1056. (d) Remmele, H.; Ko¨llhofer, A.; Plenio, H.
Organomet. 2003, 22, 4098. (e) Fleckenstein, C. A.; Plenio, H. Organomet. 2007,
26, 2758. (f) Yi, C. Y.; Hua, R. M. J. Org. Chem. 2006, 71, 2535. (g) Liang,
Y.; Xie, Y. -X.; Li, J. -H. J. Org. Chem. 2006, 71, 379. (h) Protti, S.; Fagnoni,
M.; Albini, A. Angew. Chem., Int. Ed. 2005, 44, 5675. (i) Heuze´, K.; Me´ry, D.;
Gauss, D.; Blais, J. -C.; Astruc, D. Chem. Eur. J. 2004, 10, 3936. (j) Choudary,
B. M.; Madhi, S.; Chowdari, N. S.; Kantam, M. L.; Sreedhar, B. J. Am. Chem.
Soc. 2002, 124, 14127. (k) Yi, W.-B.; Cai, C.; Wang, X. Eur. J. Org. Chem.
2007, 3445.
(3) (a) For recent reviews on Sonogashira reaction, see: Doucet, H.; Hierso,
J. -C. Angew. Chem., Int. Ed. 2007, 46, 834. (b) Chinchilla, R.; Carmen Na´jera,
C. Chem. ReV. 2007, 107, 874.
10.1021/jo800994f CCC: $40.75
Published on Web 07/04/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 6037–6040 6037

TABLE 2. Sonogashira Coupling of Aryl Chlorides ArCl with Alkynes RCt CHa
a Reaction conditions: 2% PdCl2(PPh3)2, 4% PtBu3, 10% DBU, 1.0 equiv of Cs2CO3, DMF, 150 °C, 10 min.
SCHEME 1. Sonogashira Coupling of Aryl Chlorides with
Trimethylsilyl Acetylene
conditions. As illustrated in Table 1, we observed little or no
coupling in the absence of phosphane (entry 1) or in the presence
of triarylphosphanes and basefree condition (entry 2), indicating
that phosphane and base were very crucial to the cross-coupling
reaction. The steric bulk and the electron-richness of PtBu3 are
critical for this unprecedented reactivity (entry 3). It was found
that the nature of palladium source had a pronounced impact
on the process. PdCl2(PPh3)2 turned out to be better than PdCl2
and Pd(OAc)2 (entries 3-5, Table 1). The most effective base
among those that we have surveyed is Cs2CO3 (entry 6). Strong
bases (e.g., NaOMe and NaOEt) also accelerated the cross-
coupling process but not as effectively as Cs2CO3 (entries 7
and 8 vs entry 6). Remarkably, switching the solvent to DMF
led to a superior yield (entry 9). The Sonogashira cross-coupling
reaction usually proceeds with Pd/CuI catalysts; however, the
CuI is unnecessary in our catalyst system. Further more, the
absence of CuI in the reaction medium allowed avoidance of
the oxidative Glaser homocoupling of the acetylenic reagent.4a
Under our optimized reaction conditions (2% PdCl2(PPh3)2,
4% PtBu3, 10% DBU, 1.0 equiv Cs2CO3), we accomplished
Sonogashira cross-couplings of a wide array of electronically
and structurally diverse aryl chlorides in minutes (Table 2). With
respect to the aryl chlorides, both electron-neutral and electron-
poor aryl chlorides react with alkynes to provide the products
6038 J. Org. Chem. Vol. 73, No. 15, 2008

TABLE 3. Microwave-Assisted C-C and C-N Bond-Forming
Reactions with Aryl Chlorides
activity to catalyze the cross-coupling reaction of aryl
chlorides with 1-aryl-2-(trimethylsilyl) acetylene via activa-
tion of the C-Si bond.4f
We also proceeded to examine its utility in several different
Pd-catalyzed C-C and C-N bond-forming reactions using the
MW-assisted method. Remarkably, this protocol can indeed be
extended successfully to the Suzuki coupling and Buchwald-
Hartwig amination, as well as the Heck coupling with unreactive
aryl chlorides. The best conditions for these reactions were
similar to those for Sonogashira coupling. In addition, it was
observed that whereas PdCl2(PPh3)2 was the preferred palladium
source for the Sonogashira coupling, Pd(OAc)2 gave the higher
conversion for the other types of reactions. As can be seen from
the results compiled in Table 3, it is important to note that very
high yields can be obtained for these reactions by using
representative sterically hindered aryl chloride and electron-
rich aryl chloride as starting materials.
In summary, we have described a solution to a longstanding
challenge in Sonogashira coupling reaction: the development
of a rapid and efficient method for the cross-coupling of
unactivated aryl chlorides. Our catalytic system, which
employs commercially available components, is also effective
for Suzuki coupling, Buchwald-Hartwig amination, and Heck
coupling reactions with unactivated aryl chlorides. A broad
spectrum of substrates coupled effectively under MW ir-
radiation to provide the desired products in minutes. The short
reaction times and simple reaction conditions coupled with
a broad substrate scope render this method particularly
attractive for the efficient preparation of biologically and
medicinally interesting molecules. Given that numerous
alkynes, anilines, olefins, and inexpensive aryl chlorides are
readily available, the method demonstrated could be readily
adopted to prepare large libraries rapidly, and the versatility
of this methodology is suitable for library synthesis in drug
discovery efforts.
in excellent yields. These conditions were tolerant of aryl
chlorides bearing nitrile and ketone substituents (Table 2, entries
5-7, 11, and 20). More remarkable was that even extremely
electron-rich aryl chlorides, including 4-chloroanisole and
4-chlorothioanisole, coupled efficiently with alkynes in the
presence of this catalyst system (entries 2 and 9). In further
experiments to establish the scope of this method, we investi-
gated the cross-coupling of alkynes with heterocyclic chloride.
Reactions under these conditions afford high yields of desired
products in short reaction times (Table 2, entries 13, 14, 21,
and 22). Although sterically hindered substrates are often
problematic,3a,b the method is also tolerant of ortho-substitution
in aryl chlorides (Table 2, entries 4 and 7), and even the highly
sterically hindered 2-chloro-1,3-dimethylbenzene coupled with
phenylacetylene without any difficulty (Table 2, entry 12).
Another noteworthy result is the efficient coupling between
phenylacetylene and 1-chloro-2-methylpropene (Table 2, entry
15). To the best of our knowledge, the vinyl chlorides were
rarely reported as coupling partners in Sonogashira processes.5
The successful reaction reveals that the present catalyst system
is also effective in the cross-coupling reactions of alkynes with
vinyl halides. In comparison to phenylacetylene, use of 1-octyne
generally gives superior yields of corresponding products (Table
2, entries 16-22).
Experimental Section
General Procedure for the Synthesis of 1,2-diphenylethyne
(Table 2, entry1). A mixture of chlorobenzene (56 µL), pheny-
lacetylene (50 µL), and Cs2CO3 (148 mg) was dissolved in DMF
(1.5 mL). Two mole percent PdCl2(PPh3)2, 4 mol % PtBu3, and 10
mol % DBU subsequently were added under nitrogen. The vial
was sealed, and this mixture was then irradiated for 10 min at 150
°C. After the reaction was cooled to ambient temperature, the crude
reaction mixture was diluted with ethyl acetate and then filtered
through celite. The filtrate was washed three times with brine, and
the combined aqueous phase was extracted with ethyl acetate. The
combined organic layers were dried with Na2SO4, concentrated,
and purified by flash column chromatography (petroleum ether/
ethyl acetate) to give the expected product (see Supporting
Information for details).
Interestingly, application of trimethylsilyl acetylene under
the same conditions led predominantly to the corresponding
diaryl acetylenes (Scheme 1). These results indicated that
the present catalyst system also displayed the high catalytic
(5) (a) Moonen, N. N. P.; Pomerantz, W. C.; Gist, R.; Boudon, C.;
Gisselbrecht, J. -P.; Kawai, T.; Kishioka, A.; Gross, M.; Irie, M.; Diederich, F.
Chem. Eur. J. 2005, 11, 3325. (b) Lemay, A. B.; Vulic, K. S.; Ogilvie, W. W.
J. Org. Chem. 2006, 71, 3615.
J. Org. Chem. Vol. 73, No. 15, 2008 6039

Acknowledgment. We gratefully acknowledge financial
support from the State Key Program of Basic Research of
China (Grant 2002CB512802), the National Natural Sci-
ence Foundation of China (Grants 30672539, 20721003,
20472094), and the 863 Hi-Tech Program of China (Grants
2006AA020602).
Supporting Information Available: Detailed experimental
procedures and compound characterization data for all products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO800994F
6040 J. Org. Chem. Vol. 73, No. 15, 2008