Acetamide as cocatalyst for the nitrogen-directed coupling of arenes with aryl chlorides through ruthenium-catalyzed c-h activation

Article abstract of DOI:10.1002/ejoc.201201127

A simple and highly efficient method for the cross-coupling of aromatics by C-H activation is described. Acetamide was found to be an effective cocatalyst for this generally applicable ruthenium(II)-catalyzed direct arylation reaction. A wide range of dea

Full text of DOI:10.1002/ejoc.201201127

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201201127
Acetamide as Cocatalyst for the Nitrogen-Directed Coupling of Arenes with
Aryl Chlorides through Ruthenium-Catalyzed C–H Activation
Jie Zhang,[a] Qin Yang,[a] Zhu Zhu,[a] Mao Lin Yuan,[a] Hai Yan Fu,[a] Xue Li Zheng,[a]
Hua Chen,[a] and Rui Xiang Li*[a]
Keywords: Ruthenium / C–H activation / Arenes / Cross-coupling / Biaryls
A simple and highly efficient method for the cross-coupling
of aromatics by C–H activation is described. Acetamide was
found to be an effective cocatalyst for this generally appli-
cable ruthenium(II)-catalyzed direct arylation reaction. A
wide range of deactivated aryl chlorides could be efficiently
coupled under the mild temperature of 101 °C. The new pro-
cess is highly atom-economical and sustainable.
ners have been explored. Breakthroughs in the catalytic di-
rect arylation reaction by using aryl chlorides as arylating
reagents are known. For example, Bedford,[6] Buchwald,[7]
Fagnou,[8] and others[9] have reported excellent procedures
for palladium-catalyzed systems. The efficiency of ruthe-
nium-catalyzed systems has also been demonstrated by use
of the ruthenium–carbene complex,[10] the ruthenium–acet-
ate complex,[11] and the RuCl3–PPh3 system[12] developed
by the groups of Ackermann, Dixneuf, and Yu, respectively.
Inspired by this pioneering work, we developed a novel, al-
ternative, and more convenient system consisting of the
active catalyst [RuCl2(η6-benzene)MOTPP] (5 mol-%)
[MOTPP = tris(4-methoxyphenyl)phosphane] and acet-
amide (20 mol-%) as cocatalyst to carry out the direct aryl-
ation of 2-phenylpyridine with aryl chlorides. This catalytic
system appears to be highly compatible with various func-
tional groups.
Introduction
Transition-metal-catalyzed carbon–carbon bond forma-
tion is an important method used to build molecular frame-
works in synthetic organic chemistry, and cross-coupling re-
actions such as the Kumada,[1] Stille,[2] Negishi,[3] Suzuki–
Miyaura,[4] and Hiyama[5] reaction have been developed
strategically. However, prefunctionlization of at least one of
the coupling partners, often involving preparation of orga-
nometallic intermediates, is required to ensure a smooth re-
action. As is well known, organometallic compounds are
usually unstable and tedious to synthesize. Furthermore,
the formation of stoichiometric amounts of transition-
metal salts as byproducts in the arylation step is detrimental
to the environment. Catalytic direct arylation that obviates
the preliminary synthesis of the organometallic derivatives
has attracted much attention over the last decade and exten-
sive studies have been carried out in this field. Most re-
cently, chemists have attempted to activate C–H bonds with
the aid of the directing effect of coordinative functional
groups in the framework of one of the coupling partners.
Several transition-metal complexes including those pre-
Results and Discussion
At the outset of our work, the direct arylation of 2-phen-
pared from ruthenium, rhodium, iridium, and palladium ylpyridine (1) with chloro-4-methoxybenzene (2.2 equiv.)
metals have been shown to be highly active catalysts for was selected as the model reaction to determine the opti-
such reactions. Among them, ruthenium complexes are mum conditions. A low yield of 36% was obtained when
highly interesting in terms of cost and efficiency. Aryl chlor- the reaction was catalyzed by 5 mol-% [RuCl2(η6-benzene)-
ides are the most attractive arylating reagents because of MOTPP] with K2CO3 as the base in DMF at 140 °C for
their low cost, good availability, and low toxicity. Unfortu- 20 h (Table 1, entry 1). Therefore, several additives were em-
nately, the employment of less active aryl chlorides has met ployed to improve the activity. The addition of 5 mol-%
with limited success, although a variety of coupling part- MOTPP only led to a slight increase in the conversion
(Table 1, entry 2). It is well known that carboxylate com-
pounds such as acetate bases,[13] pivalate bases,[14] and piv-
[a] Key Laboratory of Green Chemistry and Technology, Ministry
of Education, Sichuan University,
alic acid[15] are often used to promote catalytic direct aryla-
Chengdu, Sichuan 610064, People’s Republic of China
tions through a widely accepted concerted metalation–de-
protonation (CMD) mechanism. In contrast, carboxamides
are seldom employed. In 2012, Doucet and co-workers[16]
realized the regioselective arylation of furan and thiophene
Fax: +86-28-8541-2904
E-mail: liruixiang@scu.edu.cn
Homepage: http://chem.scu.edu.cn/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201127.
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Nitrogen-Directed Coupling of Arenes with Aryl Chlorides
derivatives at an unfavorable position through the intermo- moderate yield was obtained (Table 2, entry 13). Consider-
lecular directing effect of a carboxamide. This result dem- ing the moderate basicity of K2CO3 and its better func-
onstrated that carboxamides can be used as potential candi- tional group compatibility, we chose K2CO3 as base in the
dates for cocatalysts in catalytic direct arylation reactions. following experiments. The yields were found to decrease
Enlightened by this work, we introduced formamide into significantly with a decrease in the temperature (Table 2,
the catalytic system. Disappointingly, no reaction took entries 9,10).
place at all (Table 1, entry 3). However, a satisfying result
was achieved when acetamide was used as the cocatalyst.
The addition of 20 mol-% acetamide resulted in 52% iso-
Table 2. Probing the reaction conditions for the arylation of 2-
phenylpyridine with chloro-4-methoxybenzene.[a]
lated yield of the desired product when DMF was used as
the solvent (Table 1, entry 4). It seems that this ruthenium/
acetamide catalyst composite is solvent dependent. For ex-
ample, only a trace amount of the product was detected in
DMSO (Table 1, entry 5), but 85% yield of the product was
obtained in N-methyl-2-pyrrolidone (NMP). To our delight,
the products could still be obtained in very high yields of
88 and 90% in toluene and dioxane, respectively, under
much milder conditions (Table 1, entries 7,8).
Entry
Time [h]
Base
Yield [%][b]
3a/4a[b]
1
2
3
4
5
6
7
8
20
15
15
15
15
15
15
15
15
15
15
15
15
K2CO3
K2CO3
NaHCO3
K3PO4
CH3COONa
KOH
NaOH
CH3ONa
K2CO3
K2CO3
K2CO3
90
93
86
94
39
98
96
89
54
16
85
71
72
69:21
72:21
78:8
70:24
35:4
67:31
73:23
69:20
48:6
9[c]
10[d]
11[e]
12[f]
13[g]
16:–
Table 1. Screening of the reaction conditions for the arylation of 2-
phenylpyridine with chloro-4-methoxybenzene.[a]
60:25
56:15
46:26
K2CO3
K2CO3
[a] Reaction conditions: 2-phenylpyridine (1 mmol), chloro-4-
methoxybenzene (2.2 mmol), catalyst (5 mol-%), cocatalyst
(20 mol-%), base (3 equiv.), dioxane (2 mL), 101 °C. [b] Isolated
yield. [c] Reaction was performed at 90 °C. [d] Reaction was per-
formed at 70 °C. [e] Base (2 equiv.). [f] Base (1 equiv.). [g] Reaction
was performed without acetamide.
Entry
Solvent
Additive (mol-%) Yield [%][b]
3a/4a
1
2
3
4
5
6
DMF
DMF
DMF
DMF
DMSO
NMP
–
36
42
–
52
trace
85
88
90
34
33:3
38:4
–
47:5
–
53:32
66:22
69:21
23:11
With the optimum reaction conditions in hand, we fur-
ther probed the scope of this novel methodology. Thus, 2-
phenylpyridine was successfully arylated with aryl chlorides
containing various functional groups (Table 3). In general,
good yields (77–99%) were obtained except for a few spe-
cific examples (Table 3, entries 3,6,8,11,15,17–19). The elec-
tronic nature of the substituents did not have an appreciable
effect on the yield, and both electron-donating and elec-
tron-withdrawing groups afforded comparable yields
(Table 3, entries 1,4,5,7,9,10,12,13,14,16,20,21). As ex-
pected, sterically hindered aryl chlorides inhibited the reac-
tion greatly (Table 3, entries 3,6,8,15,17). To our surprise, a
moderate yield was obtained for 1-chloro-2-(trifluoro-
methyl)benzene (Table 3, entry 11). Some heteroaryl chlor-
MOTPP (5)
HCONH2 (20)
CH3CONH2 (20)
CH3CONH2 (20)
CH3CONH2 (20)
CH3CONH2 (20)
7[c]
8[d]
9
toluene
1,4-dioxane CH3CONH2 (20)
1,4-dioxane pivaloate (20)
[a] Reaction conditions: 2-phenylpyridine (1 mmol), chloro-4-
methoxybenzene (2.2 mmol), catalyst (5 mol-%), and K2CO3 (3
equiv.), under an Ar atmosphere at 120 °C for 20 h. [b] Isolated
yield. [c] Reaction was performed at 110 °C. [d] Reaction was per-
formed at 101 °C.
Obviously, dioxane is the best solvent for our catalytic ides were also successfully used as arylating reagents in this
system, and the yields of the products remained at the same system. Good to excellent yields were achieved for chloro-
level even when the reaction time was shortened to 15 h thiophenes and 2-chloroquinoline (Table 3, entries 20–22).
(Table 2, entry 2). In comparison to widely used pivaloate Unfortunately, 3-chloropyridine gave a poor yield (35%;
(Table 1, entry 9), acetamide as cocatalyst showed much Table 3, entry 18), and only a trace amount of product was
higher activity. Subsequently, the influence of the base was detected for 4-chloropyridine (Table 3, entry 19). It is also
evaluated in dioxane at 101 °C. Apart from CH3COONa, noteworthy that the use of electron-deficient aryl chlorides
all the screened bases, including K2CO3, NaHCO3, K3PO4, as arylating reagents for 2-phenylpyridine resulted in a
KOH, NaOH, and CH3ONa, gave excellent yields (Table 2, greater amount of diarylation products. On the basis of this
entries 2–8). A decrease in the amount of K2CO3 resulted C–H bond-activation chemistry and the work of Dixneuf
in an obvious decrease in the yield of the product (Table 2, and Ackermann, a plausible catalytic cycle was suggested
entries 11 and 12). Similarly, in the absence of acetamide a (Scheme 1).
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R. X. Li et al.
SHORT COMMUNICATION
Table 3. Ruthenium-catalyzed ortho-arylation of 2-phenylpyridine
Table 3. (Continued)
with (hetero)aryl chlorides.[a]
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Nitrogen-Directed Coupling of Arenes with Aryl Chlorides
Table 3. (Continued)
direct arylation of 2-phenylpyridine with a broad range of
aryl chlorides through C–H bond activation to prepare the
corresponding biaryl compounds. The choice of acetamide
is essential for the success of the reaction. To the best of
our knowledge, this procedure has not been employed for
the direct arylation of 2-aromatic pyridines.
Experimental Section
Typical Procedure for the Arylation of Phenylpyridine (1) with Aryl
Chlorides under a Nitrogen Atmosphere: A mixture of [RuCl2(η6-
benzene)MOTPP] (5.0 mol-%), chloro-4-methoxybenzene (2a,
2.2 mmol), acetamide (20 mmol-%), and K2CO3 in dioxane (2 mL)
was stirred at 101 °C for 15 h. the mixture was cooled to room
temperature, and Et2O (30 mL) and H2O (20 mL) were added. The
organic phase was separated, and the aqueous layer was extracted
with Et2O (20 mL). The combined organic phase was washed with
H2O (20 mL) and brine (20 mL), dried with Na2SO4, and then con-
centrated under reduced pressure. The resulting residue was puri-
fied by flash silica gel column chromatography [petroleum ether
(60–90 °C)/EtOAc = 8:1] to afford target product 4a (77 mg, 21%)
as a white solid. The product was characterized by 1H and
13CNMR spectroscopy and further confirmed by comparison with
the reported authentic NMR spectroscopic data.
Supporting Information (see footnote on the first page of this arti-
cle): Full characterization and copies of the 1H NMR and 13C
NMR spectra for all compounds.
[a] Reaction conditions: 1 (1.0 equiv.), 2 (2.2 equiv.), [RuCl2(η6-
benzene)MOTPP] (5.0 mol-%), CH3CONH3 (20 mol-%), K2CO3
(3.0 equiv.), dioxane (2 mL), 101 °C, 20 h. [b] Yield of isolated
Acknowledgments
1
product. [c] Ratios determined by H NMR spectroscopy.
This work was supported by the National Natural Science Founda-
tion of China (No. 21202104) and the National Science Talents
Fund for Research Training and Research Ability Improvement
(j1103015).
[1] a) S.-I. Murahashi, J. Organomet. Chem. 2002, 653, 27–33; b)
H. Shinokubo, K. Oshima, Eur. J. Org. Chem. 2004, 2081–
2091; c) J.-P. Corbet, G. Mignani, Chem. Rev. 2006, 106, 2651–
2710.
[2] a) T. N. Mitchell in Metal-Catalyzed Cross-Coupling Reactions,
2nd ed. (Eds.: A. de Meijere, F. Diederich), Wiley-VCH,
Weinheim, 2004, vol. 1, pp. 125–161; b) K. C. Nicolaou, P. G.
Bulger, D. Sarlah, Angew. Chem. 2005, 117, 4516–4563; Angew.
Chem. Int. Ed. 2005, 44, 4442–4489; c) M. Kosugi, Organomet.
News 2006, 3, 75–78.
[3] a) D. Chen, S. Kotti, G. Li, Chemtracts 2005, 18, 193–199; b)
M. G. Organ, S. Avola, I. Dubovyk, N. Hadei, E. A. B.
Kantchev, C. J. O’Brien, C. Valente, Chem. Eur. J. 2006, 12,
4749–4755.
[4] a) U. Christmann, R. Vilar, Angew. Chem. 2005, 117, 370–378;
Angew. Chem. Int. Ed. 2005, 44, 366–374; b) N. T. S. Phan, M.
Van Der Sluys, C. W. Jones, Adv. Synth. Catal. 2006, 348, 609–
679.
[5] a) J.-Y. Lee, G. C. Fu, J. Am. Chem. Soc. 2003, 125, 5616–5617;
b) P. Pierrat, G. Philippe, Y. Fort, Org. Lett. 2005, 7, 697–700;
c) M. L. Clarke, Adv. Synth. Catal. 2005, 347, 303–307.
[6] R. B. Bedford, C. S. J. Cazin, Chem. Commun. 2002, 2310–
2311.
Scheme 1.
Conclusions
[7] E. Hennessy, S. L. Buchwald, J. Am. Chem. Soc. 2003, 125,
In summary, although only a few examples of such cou-
pling reactions performed with a low catalyst loading
(5 mol-%) have been reported to date, we have developed a
novel, simple, highly efficient Ru-catalyzed system for the
12084–12085.
[8] a) M. Leblanc, K. Fagnou, Org. Lett. 2005, 7, 2849–2852; b)
L.-C. Campeau, M. Parisien, M. Leblanc, K. Fagnou, J. Am.
Chem. Soc. 2004, 126, 9186–9187.
Eur. J. Org. Chem. 2012, 6702–6706
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6705

R. X. Li et al.
SHORT COMMUNICATION
[9] M. Miura, T. Satoh, Top. Organomet. Chem. 2005, 14, 55–83.
[10] a) L. Ackermann, Org. Lett. 2005, 7, 3123–3125; b) L. Ackerm-
ann, A. Althammer, R. Born, Angew. Chem. 2006, 118, 2681–
2685; Angew. Chem. Int. Ed. 2006, 45, 2619–2622; c) L. Acker-
mann, R. Born, P. Alvarez-Bercedo, Angew. Chem. 2007, 119,
6482–6485; Angew. Chem. Int. Ed. 2007, 46, 6364–6367; d) L.
Ackermann, M. Mulzer, Org. Lett. 2008, 10, 5043–5045; e) L.
Ackermann, A. Althammer, R. Born, Tetrahedron 2008, 64,
6115–6124; f) L. Ackermann, A. Althammer, S. Fenner, Angew.
Chem. 2009, 121, 207–2010; Angew. Chem. Int. Ed. 2009, 48,
201–204; g) L. Ackermann, P. Novak, R. Vicente, N. Hofmann,
Angew. Chem. 2009, 121, 6161–6164; Angew. Chem. Int. Ed.
2009, 48, 6045–6048; h) L. Ackermann, R. Vicente, H. K. Potu-
kuchi, V. Pirovano, Org. Lett. 2010, 12, 5032–5035.
Chem. 2010, 122, 6779–6782; Angew. Chem. Int. Ed. 2010, 49,
6629–6632.
[12] N. Luo, Z. Yu, Chem. Eur. J. 2010, 16, 787–791.
[13] a) F. Pozgan, P. H. Dixneuf, Adv. Synth. Catal. 2009, 351,
1737–1743; b) P. Arockiam, V. Poirier, C. Fischmeister, C. Bru-
neau, P. H. Dixneuf, Green Chem. 2009, 11, 1871–1875; c) L.
Ackermann, R. Vicente, A. Althammer, Org. Lett. 2008, 10,
2299–2302.
[14] a) Q. Huang, A. Fazio, G. Dai, M. A. Campo, R. C. Larock,
J. Am. Chem. Soc. 2004, 126, 7460; b) J. Zhao, D. Yue, M. A.
Campo, R. C. Larock, J. Am. Chem. Soc. 2007, 129, 5288; c)
X. Wang, B. S. Lane, D. Sames, J. Am. Chem. Soc. 2005.127,
4996.
[15] M. Lafrance, K. Fagnou, J. Am. Chem. Soc. 2006, 128, 16496.
[11] a) I. Ozdemir, S. Demir, B. Cetinkaya, C. Gourlaouen, F. Ma- [16] K. Si Larbi, H. Y. Fu, N. Laidaoui, K. Beydoun, A. Miloudi,
seras, C. Bruneau, P. H. Dixneuf, J. Am. Chem. Soc. 2008, 130,
1156–1157; b) P. Arockiam, V. Poirier, C. Fischmeister, C. Bru-
neau, P. H. Dixneuf, Green Chem. 2009, 11, 1871–1875; c) P.
Arockiam, C. Fischmeister, C. Bruneau, P. H. Dixneuf, Angew.
D. El Abed, S. Djabbar, H. Doucet, ChemCatChem 2012, 4,
815–823.
Received: August 18, 2012
Published Online: October 30, 2012
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