RuCl3-catalyzed regioselective diarylation with aryl tosylates via C-H activation

Article abstract of DOI:10.1080/00397911.2012.688160

The direct arylation of arylpyridines with aryl tosylates was carried out smoothly in the presence of 2.5 mol% RuCl₃ using MesCOOH as crucial promoter to generate biarylated products. The method is simple, efficient, safe, and regioselective, c

Full text of DOI:10.1080/00397911.2012.688160

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RuCl -Catalyzed Regioselective
3
Diarylation with Aryl Tosylates via C-H
Activation
a
Baoli Zhao
a
Institute of Applied Chemistry and Department of Chemistry,
University of Shaoxing, Shaoxing, Zhejiang Province, China
Accepted author version posted online: 05 Mar 2013.Published
online: 28 Apr 2013.
To cite this article: Baoli Zhao (2013): RuCl -Catalyzed Regioselective Diarylation with Aryl Tosylates
3
via C-H Activation, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 43:15, 2110-2118
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1
Synthetic Communications , 43: 2110–2118, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2012.688160
RuCl -CATALYZED REGIOSELECTIVE DIARYLATION
3
WITH ARYL TOSYLATES VIA C-H ACTIVATION
Baoli Zhao
Institute of Applied Chemistry and Department of Chemistry,
University of Shaoxing, Shaoxing, Zhejiang Province, China
GRAPHICAL ABSTRACT
Abstract The direct arylation of arylpyridines with aryl tosylates was carried out smoothly
3
in the presence of 2.5 mol% RuCl using MesCOOH as crucial promoter to generate biaryl-
ated products. The method is simple, efficient, safe, and regioselective, can be performed in
the absence of expensive ligands, and does not require any precautions with regard to the
exclusion of air and moisture. The biarylated products were obtained in good yields.
Supplemental materials are available for this article. Go to the publisher’s online edition
1
of Synthetic Communications to view the free supplemental file.
Keywords Aryl tosylates; C–H activation; diarylation; ruthenium catalysis
INTRODUCTION
Transition-metal-catalyzed C-C bond-forming reactions have emerged as a
powerful tool in organic synthesis, allowing access to structural backbones with high
selectivity and efficiency. Suzuki–Miyaura, Heck, and Stille reactions are the most
[
1]
often used examples of this synthetic strategy. More recently, much attention
has been paid to green and sustainable reactions for developing environmentally
friendly processes. Catalytic processes involving C-H bond activation are highly
desirable, not only because they allow the functionalization of more readily available
[
2]
[3]
starting materials but also because they produce clean products. Nowadays, for-
mally unactivated C-H bonds are used as the functionalization site on the nucleophi-
[
lic coupling partner in transition-metal-catalyzed direct arylation. Regioselective
4]
Received March 20, 2012.
Address correspondence to Baoli Zhao, Institute of Applied Chemistry and Department of
Chemistry, University of Shaoxing, Shaoxing, Zhejiang Province 312000, China. E-mail: babygarfield@
126.com
2
110

DIARYLATION WITH ARYL TOSYLATES
2111
conversion of C-H to C-C bonds would result in shortening of synthetic schemes by
[
allowing the use of readily available starting materials.
5–16]
The research focus has shifted to the direct arylation of aromatic substrates by
C-H bond functionalizations to make aryl–aryl linkages ecologically and economi-
cally friendly alternatives, which sets the stage for novel routes to substituted biaryls.
The intermolecular coupling of arenes with aryl halides is a principal reaction system
in the rapidly growing area of transition-metal-catalyzed direct arylation. Among the
known direct arylations of arenes, the majority have been accomplished applying
[
17–20]
aryl halides=pseudohalides as electrophiles.
The possibility of using aryl tosy-
lates, which can be easily prepared from readily available corresponding phenols
or ketones as electrophiles in cross-coupling chemistry is very attractive because they
are convenient to use. However, the great stability makes aryl tosylates less reactive
in transition-metal-catalyzed processes. Methods for cross-coupling reactions
[
21–25]
between aryl tosylates and organometallic complexes have been developed.
Direct arylations through C-H bond activation using tosylates under catalyses have
[
26]
proven rare. Ackermann and co-workers
reported an example for nitrogen-
coordinating functional groups that employed direct mono-arylation and controlled
the regioselectivity. Pyridine has been proven to be an effective directing group for
6
C-H bond activation, usually using ruthenium(II) complex ([RuCl (g -C H )] and
2
6 6 2
27–37]
[
[RuCl (p-cymene)] ) as catalysts, and good selectivity was achieved.
recently, RuCl has shown catalytic activity to achieve biarylated products.
Very
38–42]
2
2
[
3
In 2010, Arackiam et al. reported a transformation by C-H bond functionalization
[
43]
catalyzed by carboxylato ruthenium(II) systems in water.
In this article, we
describe our findings regarding the direct arylation of aryl tosylates and arylpyri-
dines substrates catalyzed by RuCl3 using simple carboxylic acids such
as MesCOOH (2,4,6-trimethylbenzoic acid) as promoters. The reactions can be per-
formed in the absence of expensive ligands and do not require any precautions with
regard to the exclusion of air and moisture, and biarylated products were obtained in
good yields.
Our investigations into the development of an efficient arylation catalyst began
with the reaction of 2-phenylpyridine and phenyl 4-methylbenzenesulfonate in the
ꢀ
presence of 2.5 mol% [RuCl (PPh ) ] at 120 C for 12 h in NMP (1-methylpyrroli-
2
3 3
din-2-one), which afforded no arylation products. After the addition of 1 equiv
MesCOOH, 53% of the desired product was detected when the mixture was heated
ꢀ
at 140 C for 12 h (Table 1, entry 1). Use of [RuCl (p-cymene)] increased the yield to
2
2
6
markedly accelerated in the presence of RuCl , and the biphenylated product was
0%. However, we were delighted to find that the rate of arylation reaction was
3
isolated in 85% yield (Table 1, entry 4). PdCl , Pd(OAc) , Pd(PPh ) , and Pd (dba)
3
2
2
3 4
2
were then chosen as catalyst precursors. However, in all cases, the arylation reactions
were sluggish (Table 1, entries 4–7). [RhCl(PPh ) ] was ineffective under these con-
ditions (Table 1, entry 8).
3
3
The screening of various acids summarized in Table 2 revealed MesCOOH was
the best. The steric effect and electronic properties of the arene did not significantly
influence the arylation (Table 2, entries 1–10). Many aliphatic acids were also tested,
and the arylation reactions were sluggish (Table 2, entries 11–13). The effect of base
was also investigated (Table 3). The additions of acid and base are indispensable to
the reaction.

2112
B. ZHAO
a
Table 1. Arylation reaction in the presence of various catalysts
b
Entry
Catalyst
Yield (%)
1
2
3
4
5
6
7
8
[RuCl
[RuCl2(p-cymene)]
RuCl
PdCl
Pd(OAc)
Pd(PPh
Pd (dba)
[RhCl(PPh
2
(PPh
3
)
3
]
53
60
85
35
32
25
22
—
2
3
2
2
3
)
4
2
3
3 3
) ]
a
Reaction conditions: 2-phenylpyridine (1 mmol), 4-methylbenzenesulfonate (2.2 mmol),
ꢀ
catalyst (2.5 mol%), MesCOOH (1 mmol), K
b
2
CO
3
(2 mmol), NMP (5 mL), 140 C, 12 h.
Isolated yields.
a
Table 2. Screening of various acids
b
Entry
Acid
Yield (%)
1
2
3
4
5
6
7
8
9
Benzoic acid
2-Methylbenzoic acid
3-Methylbenzoic acid
4-Methylbenzoic acid
2-Nitrobenzoic acid
3-Nitrobenzoic acid
4-Nitrobenzoic acid
4-Aminobenzoic acid
4-Aminobenzenesulfonic acid
2,4,6-Trimethylbenzoic acid
Octanoic acid
56
72
71
70
65
71
67
71
43
85
22
—
29
—
1
1
1
1
1
0
1
2
3
4
Acetic acid
2-Phenylacetic acid
—
a
Reaction conditions: 2-phenylpyridine (1 mmol), 4-methylbenzenesulfonate (2.2 mmol),
ꢀ
RuCl
b
3
(2.5 mol%), acid (1 mmol), K
2
CO
3
(2 mmol), NMP (5 mL), 140 C, 12 h.
Isolated yields.

DIARYLATION WITH ARYL TOSYLATES
2113
a
Table 3. Base effect of the arylation in the presence of MesCOOH
b
Entry
Base (mol %)
Yield (%)
1
2
3
4
5
6
7
8
9
K
2
CO
PO
3
85
70
61
53
51
44
42
33
—
—
K
3
4
KOH
KF
KOAc
Na
NaOAc
NaBF
Et
2
CO
3
4
3
N
1
0
—
a
Reaction conditions: 2-phenylpyridine (1 mmol), 4-methylbenzenesulfonate (2.2 mmol),
ꢀ
RuCl
b
3
(2.5 mol%), MesCOOH (1 mmol), base (2 mmol), NMP (5 mL), 140 C, 12 h.
Isolated yields.
The superior efficiencies obtained with RuCl in the presence of MesCOOH
3
prompted us to select this reagent combination for further exploration. The scope
of the arylation reaction with respect to the aryl tosylate component was investigated
(Table 4). A variety of aryl tosylates that incorporate electron-donating and
electron-withdrawing groups were well tolerated (Table 4, entries 1–5). In addition,
the electronic properties of the substituents on arylpyridines proved to have little
effect on the arylation processes, and good to excellent yields were obtained
(
Table 4, entries 6–8). It should be noted that the clean biarylated products were
delivered in these reactions. However, when a methyl group was located at the
-position of phenylpyridine, the monophenylated and diphenylated products were
3
isolated in a ratio of 1:1 (Table 4, entry 9, 36% diphenylated and 37% monophenyl-
ated product), showing that the steric effect influenced the arylation. Placing the less
bulky fluoride attenuated the steric effect, and the biarylated product could be
isolated as the main product (Table 4, entry 10). 2-(Naphthalen-2-yl)pyridine also
delivered the diarylated product in good yield (Table 4, entry 11). As expected,
the arylation proceeded in comparable yield and efficiency when structurally diverse
heterocycles, including pyrazole, pyrimidine, pyridazine, and quinoline, were used as
the substrates (Table 4, entries 12–15).
The experimental evidence at present to explain the exact reaction pathway for
the direct arylation processes is rare. When equimolar quantities of aryl tosylates and
2
-arylpyridine are employed under the reaction condition, we can afford correspond-
ing monoarylated and diarylated products in the ratio of 36:64. (The total yield
is 69%.) The monoarylation may occur first and then another arylation at the

2114
B. ZHAO
a
Table 4. RuCl
3
-catalyzed arylation in the presence of MesCOOH
b
Entry
Aryl iodide
Product
Yield (%)
1
67
2
3
80
85
4
72
5
66
6
71
(
Continued )

DIARYLATION WITH ARYL TOSYLATES
2115
Table 4. Continued
b
Entry
Aryl iodide
Product
Yield (%)
7
73
8
67
c
36
9
10
77
11
71
1
1
2
3
69
68
(
Continued )

2116
B. ZHAO
Table 4. Continued
b
Entry
Aryl iodide
Product
Yield (%)
14
78
15
80
a
Reaction conditions: substrate (1 mmol), aryl tosylates (2.2 mmol), RuCl
ꢀ
3
(2.5 mol%), MesCOOH
(
1 mmol), K
b
2
CO
3
(2 mmol), NMP (5 mL), 140 C, 12 h.
Isolated yields.
Monoarylated product was isolated in 37% yield.
c
6-position C-H bond. Ackermann proposed a proton abstraction mechanism, which
provides a satisfactory explanation for the Ru-catalyzed arylation via C-H bond
[
44–47]
activation. On the basis of this C-H bond activation chemistry and our results,
a plausible mechanism for the diarylation process is shown in Scheme 1. Proton
Scheme 1. Mechanism proposed.

DIARYLATION WITH ARYL TOSYLATES
2117
abstraction by the benzoate anion coordinated to ruthenium results in intermediate
b. Afterward, dissociation of MesCO H to form intermediate c, followed by inser-
2
tion of ArOTs, leads to intermediate d, which liberates the arylated product and
ruthenium catalyst by protodemetalation. Then a similar process occurs at another
C-H bond.
The research herein used directing groups for C-H bond cleavage with a special
focus on utilizing simple carboxylic acids such as MesCOOH to promote the diaryla-
tion of 2-arylpyridines. We have developed a new selective RuCl -catalyzed C-H
3
functionalization process that can arylate arylpyridines without the use of additional
ligands with high regioselectivity with aryl tosylates as electrophiles. The scope of the
arylation is broad and tolerates a variety of functional groups. Further mechanistic
studies of the activation pathways are still in progress in our laboratory.
EXPERIMENTAL
MesCOOH (1 mmol) was added to a mixture of the 2-arylpyridine (1 mmol),
aryl tosylates (2.2 mmol), anhydrous RuCl (2.5 mol%), and NMP (3 mL). The sol-
3
ꢀ
ution was stirred at 140 C under air for 12 h, then cooled to rt and filtered through
a filter paper. Brine (25 ml) was added to the solution, which was extracted with Et O
2
(
3 Â 20 mL). After washing with H O and brine, the combined organic phases were
2
evaporated under reduced pressure, and the residue was subjected to flash column
chromatography to obtain the desired product.
Complete experimental details are available online in the Supplemental
Materials.
ACKNOWLEDGMENT
This study was supported by the Science Technology Department of Zhejiang
Province (Grant No. 2010-R-50014-15).
REFERENCES
1
2
3
4
. Martin, R.; Buchwald, S. L. Acc. Chem. Res. 2008, 41, 1461.
. Trost, B. M. Science 1991, 254, 1471.
. Dyker, G.. Angew. Chem. Int. Ed. 1999, 38, 1699.
. Wan, X.; Ma, Z.; Li, B.; Zhang, K.; Cao, S.; Zhang, S.; Shi, Z. J. Am. Chem. Soc. 2006,
128, 7416.
5
6
7
8
9
. Sun, C. L.; Liu, N.; Li, B. J.; Yu, D. G.; Wang, Y.; Shi, Z. J. Org. Lett. 2010, 12, 184.
. Chen, X.; Goodhue, C. E.; Yu, J. Q. J. Am. Chem. Soc. 2006, 128, 12634.
. Wang, D. H.; Mei, T. S.; Yu, J. Q. J. Am. Chem. Soc. 2008, 130, 17676.
. Willis, M. C. Chem. Rev. 2010, 110, 725.
. Colby, D. A.; Bergman, R. G.; Ellmann, J. A. Chem. Rev. 2010, 110, 624.
10. Jazzar, R.; Hitce, J.; Renaudat, A.; Sofack-Kreutzer, J.; Baudoin, O. Chem. Eur. J. 2010,
16, 2654.
1
1
1
1
1. Dudnik, A. S.; Gevorgyan, V. Angew. Chem, Int. Ed. 2010, 49, 2096.
2. Ackermann, L.; Vicente, R. Top. Curr. Chem. 2010, 292, 211.
3. Kulkarni, A. A.; Daugulis, O. Synthesis 2009, 4087.
4. Ackermann, L.; Vicente, R.; Kapdi, R. A. Angew. Chem. Int. Ed. 2009, 48, 9792.

2118
B. ZHAO
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
5. Li, C. J. Acc. Chem. Res. 2009, 42, 335.
6. Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174.
7. Wang, D. H.; Wasa, M.; Giri, R.; Yu, J. Q. J. Am. Chem. Soc. 2008, 130, 7190.
8. Zhao, J.; Zhang, Y.; Cheng, K. J. Org. Chem. 2008, 73, 74281.
9. Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147.
0. Michael, J. P. Nat. Prod. Rep. 2002, 19, 742.
1. Percec, V.; Golding, G. M.; Smidrkal, J.; Weichold, O. J. Org. Chem. 2004, 69, 3447.
2. Tang, Z. Y.; Hu, Q. S. J. Am. Chem. Soc. 2004, 126, 3058.
3. Zhou, J.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 12527.
4. Limmert, M. E.; Roy, A. H.; Hartwig, J. F. J. Org. Chem. 2005, 70, 9364.
5. Roy, A. H.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125, 8704.
6. Ackermann, L.; Althammer, A.; Born, R. Angew. Chem. Int. Ed. 2006, 45, 2619.
7. Prades, A.; Poyatos, M.; Perisa, E. Adv. Synth. Catal. 2010, 352, 1155.
8. Ackermann, L.; Vicente, R.; Althammer, A. Org. Lett. 2008, 10, 2299.
9. Ackermann, L.; Mulzer, M. Org. Lett. 2008, 10, 5043.
0. Ackermann, L.; Nov a´ k, P.; Vicente, R.; Hofmann, N. Angew. Chem. 2009, 121, 6161.
1. Ackermann, L.; Vicente, R. Org. Lett. 2009, 11, 4922.
2. Ackermann, L.; Nov a´ k, P.; Vicente, R.; Pirovano, V.; Potukuchi, H. K. Synthesis 2010,
2245.
3
3
3
3. Ackermann, L.; Vicente, R.; Potukuchi, H. K.; Pirovano, V. Org. Lett. 2010, 12, 5032.
4. Ackermann, L.; Lygin, A. V. Org. Lett. 2011, 13, 3332.
¨
5. Ozdemir, I.; Demir, S.; G u¨ rb u¨ z, N.; C¸ etinkaya, B.; Toupet, L.; Bruneau, C.; Dixneuf,
P. H. Eur. J. Inorg. Chem. 2009, 1942.
3
3
3
3
4
4
4
4
6. Ackermann, L.; Potukuchi, H. K.; Landsberg, D.; Vicente, R. Org. Lett. 2008, 10, 3081.
7. Ackermann, L.; Althammer, A.; Fenner, S. Angew. Chem. Int. Ed. 2009, 48, 201.
8. Cheng, K.; Yao, B.; Zhao, J.; Zhang, Y. Org. Lett. 2008, 10, 5309.
9. Ackermann, L.; Althammer, A.; Born, R. Tetrahedron 2008, 64, 6115.
0. Seki, M. ACS Catalysis 2011, 1, 607.
1. Luo, N.; Yu, Z. K. Chem. Eur. J 2010, 16, 787.
2. Ackermann, L.; Althammer, A.; Born, R. Synlett. 2007, 2833.
3. Arockiam, P. B.; Fischmeister, C.; Bruneau, C.; Dixneuf, P. H. Angew. Chem. Int. Ed.
2010, 49, 6629.
44. Cheng, K.; Zhang, Y.; Zhao, J.; Xie, C. Synlett. 2008, 1325.
45. Ackermann, L. Chem. Rev. 2011, 111, 1315.
46. Flegeau, E. F.; Bruneau, C.; Dixneuf, P. H.; Jutand, A. J. Am. Chem. Soc. 2011, 133,
10161.
¨
4
7. Demir, S.; Ozdemir, I.; S¸ ahin, O.; C¸ etinkaya, B.; B u¨ y u¨ kg u¨ ng o¨ r, O. Synlett. 2010, 496.