Ruthenium-catalyzed oxidative homo-coupling of 2-arylpyridines

Article abstract of DOI:10.1002/adsc.200900375

A ruthenium-catalyzed oxidative homocoupling reaction of 2-arylpyridines via C-H activation was developed. The reaction could tolerate various functional groups on both the aryl and the pyridyl rings to afford a series of dimerized products with iron(III)

Full text of DOI:10.1002/adsc.200900375

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DOI: 10.1002/adsc.200900375
Ruthenium-Catalyzed Oxidative Homo-Coupling of
2-Arylpyridines
Xiangyu Guo,a Guojun Deng,a,b,* and Chao-Jun Lia,*
a
Department of Chemistry, McGill University, Montreal, QC, H3A 2K6, Canada
Fax : (+1)-514-398-3797; e-mail: cj.li@mcgill.ca
School of Chemistry, Xiangtan University, Xiangtan, Hunan 411105, Peopleꢀs Republic of China
b
Fax : (+86)-732-8292477; e-mail: gjdeng@xtu.edu.cn
Received: May 29, 2009; Published online: September 8, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900375.
Abstract: A ruthenium-catalyzed oxidative homo-
coupling reaction of 2-arylpyridines via C H activa-
tion was developed. The reaction could tolerate var-
ious functional groups on both the aryl and the pyr-
idyl rings to afford a series of dimerized products
Hull recently reported that 2-arylpyridines underwent
a highly regioselective Pd-catalyzed oxidative C C
coupling at room temperature with oxone as a termi-
nal oxidant.[7] On the other hand, Yu and Chen dis-
covered that such a reaction could be carried out with
À
À
with iron
G
an in situ iodination followed by a CuACTHNGURETNNU(G OAc)2-mediat-
oxidant. A tentative mechanism was proposed for
this oxidative C H/C H homo-coupling.
ed Ullmann coupling to give the homodimerized
product.[8]
À
À
During our recent studies on the ruthenium-cata-
lyzed cross-dehydrogenative coupling (CDC) of 2-phe-
nylpyridine with cycloalkanes mediated by perox-
ides,[9] we observed a trace amount of the oxidative
homo-coupling product of 2-phenylpyridine. Subse-
quently, various conditions regarding the ruthenium
catalyst and the oxidant were examined to optimize
À
Keywords: C H activation; oxidative coupling; 2-
phenylpyridines; ruthenium
The biaryl moiety is a common structural motif in the formation of this homo-coupling product
natural products, agrochemicals, chiral ligands and (Table 1). It was found that using FeCl3, instead of
pharmaceuticals.[1] Many methodologies have been peroxide, as the stoichiometric oxidant, increased the
developed to achieve the synthesis of both symmetri- product yield to 27% (Table 1, entry 1). No reaction
cal and unsymmetrical biaryls.[2] In the past two de- was observed in the absence of the ruthenium catalyst
À
cades, transition metal-catalyzed C H bond activation (Table 1, entry 2). Other ruthenium catalysts were
followed by C C bond formation has emerged as a also examined (Table 1, entries 3–7). Whereas
À
powerful synthetic methodology,[3] which is more effi- Ru3(CO)12 was inactive, the use of Ru
U
cient and simpler than the traditional metal-catalyzed RuCl2ACTHUNGRTEN(NUGN PPh3)3, and [RuACHTNUGTRENNUNG
AHCTUNGTRENNUNG
when this strategy is applied to both substrates, using gave an 84% yield of the desired product (Table 1,
À
C H bonds as the only starting functionality can fur- entry 7). Other oxidants were also examined (Table 1,
ther simplify the syntheses. Such reactions will only entries 8–12), and all led to lower product yields. The
require one to remove 2 H atoms from the reactants reaction temperature and solvents were also investi-
by using a hydrogen acceptor.[1a,5] Therefore, the syn- gated (Table 1, entries 13–18) with the optimal condi-
À
À
thesis of biaryls using oxidative C H/C H coupling is tions being 2.5 mol% [Ru
attracting increasing attention.[5]
0.8 equiv. of FeCl3 in chlorobenzene at 1108C under
For the oxidative homo-coupling of aryls via the air for 16 h, giving the product in 87% NMR yield
ACHTUNGTREN(UNGN p-cymene)Cl2]2 with
À
À
direct reaction of C H/C H bonds, classical examples (Table 1, entry 20). Reasonable yields can also be ob-
are the oxidative dimerization of various phenols and tained when conducting the reaction in other
their analogues to generate various biphenol and common solvents, such as toluene, benzene and ani-
poly
arenes in the absence of a phenol group, Sanford and lower yield (Table 1, entries 7, 13 and 14). Decreasing
ACHTUNGTRENNUNG
phenol products.[6] For the homo-dimerization of sole. A lower reaction temperature resulted in a
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Table 1. Reactions of 2-phenyl pyridine 1a under various
With the optimized reaction conditions in hand, dif-
ferent substituted 2-arylpyridines were investigated
using this reaction (Table 2). No significant change
was observed with 4-phenylphenylpyridine (compare
entries 1 and 2). Electronic effects of the phenyl ring
of the substrates did not have a great impact on the
reaction (Table 2, entries 1–7). Substrates with halide
substituents also proceeded in this reaction (Table 2,
entries 5 and 6). The location of substituents on both
rings also played an important role in this reaction. A
good yield was obtained with 2-(4-methylphenyl)pyri-
dine (Table 2, entry 7). With two potential reaction
sites on the phenyl ring of 2-(3-methylphenyl)pyri-
dine, the reaction took place regioselectively at the
conditions.[a]
Entry Catalyst
Oxidant
Yield [%][b]
1
2
3
4
5
6
7
8
RuCl3
–
Ru3(CO)12
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
27
0
0
60
77
59
84
Ru
T
RuCl CHTUNGTRENNUNG
[Ru
[Ru
[Ru
[Ru
[Ru
[Ru
[Ru
[Ru
[Ru
[Ru
[Ru
[Ru
[Ru
[Ru
[Ru
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG(p-cymene)Cl2]2 FeCl3
ACHTUNGTRENNUNG(p-cymene)Cl2]2 benzoquinone 43
T
N
R
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
Table 2. Substrate scope of ruthenium-catalyzed homo-cou-
pling of substituted 2-arylpyridines.[a]
9
A
18
66
10
11
12
13
14
15
16
17
18
19
20
A
trace
30[c]
87[d]
74[e]
68[f]
80[g]
81[h]
74[i]
72[j]
87[k]
[a]
Conditions: 1a (0.5 mmol), catalyst (0.0125 mmol), chlor-
obenzene (1 mL), oxidant (1.0 equiv.=0.5 mmol), 1108C,
16 h in air unless otherwise noted.
1H NMR yield [%].
O2 1 atm.
1308C.
1008C.
In anisole.
In benzene.
In toluene.
[b]
[c]
[d]
[e]
[f]
[g]
[h]
[i]
In dichloroethane.
FeCl3 0.5 equiv.
FeCl3 0.8 equiv.
[j]
[k]
the amount of the FeCl3 to 50% decreased the yield
(Table 1, entry 19); more oxidant amount did not help
the reaction either (compare entries 7 and 20). We
reasoned that with more FeCl3 being added, it coordi-
nated with the nitrogen atom in 2-phenylpyridine,
which prevented ruthenium from coordinating to the
À
same site, and thus reduced the efficiency of the C H
activation. Interestingly, when only 0.8 equiv. of FeCl3
is used, an 87% yield is obtained rather than the ex-
pected 80% (the highest theoretical yield). This unex-
pected “higher” yield is most likely due to the fact
that the reaction was conducted under air and O2 (in
the air) acted as an extra oxidant (Table 1, entries 12
and 20).
[a]
Conditions:
1
(0.5 mmol),
[RuACTHNGUTERU(NNG p-cymene)Cl2]2
(0.0125 mmol), FeCl3 (0.4 mmol), chlorobenzene (1 mL),
1108C, 16 h in air unless otherwise noted.
Isolated yield [%], average yield of two parallel reac-
tions.
48 h.
[b]
[c]
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Ruthenium-Catalyzed Oxidative Homo-Coupling of 2-Arylpyridines
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less hindered C H bond (Table 2, entry 8). However, C is formed.[7] Subsequently, a second 2-phenylpyri-
when changing the location of the methyl group on dine 1a reacts with intermediate C and undergoes the
the phenyl ring from para- or meta-substituted to same process forming intermediate E. Finally, reduc-
ortho-substituted, the yield decreased dramatically. tive elimination affords the oxidative coupling prod-
This might be due to the increased steric compulsion uct, and ruthenium catalyst A was regenerated via ox-
between the methyl group and the hydrogen atom on idation by FeCl3.
À
the C-3 position on the pyridine ring during the nitro-
In summary, we have developed a homo-coupling
À
gen-directed C H activation process in 2-(2-methyl- of 2-arylpyridines using a ruthenium complex as the
phenyl)pyridine (Table 2, entries 9 and 10). The reac- catalyst and FeCl3 as the oxidant to generate biaryls
tion also proceeded well when changing the substitu- efficiently and regioselectively. The reaction proceed-
ents on the pyridine ring. When the methyl group is ed well for a range of different substrates. A tentative
at the 3- and 4- sites, reasonable yields were also ob- mechanism for this reaction was also proposed.
tained (Table 2, entries 11 and 12). However, a sub-
strate with a methyl group at the ortho-position on
the pyridine ring could not undergo this reaction Experimental Section
which could also be explained by the steric effect in
which the methyl group next to the nitrogen atom Representative Experimental Procedure (2a)
blocked ruthenium from coordination (Table 2,
An oven-dried reaction vessel was charged with [{RuACHTUNGTRENNUNG(p-cym-
entry 13).
ene)Cl2}2] (7.6 mg, 0.0125 mmol), 2-phenylpyridine (1a,
77.5 mg, 0.5 mmol), FeCl3 ( 65 mg, 0.4 mmol), and chloro-
benzene (1.0 mL). The reaction vessel was then sealed and
the resulting solution was stirred at 1108C for 16 h. After
cooling to room temperature, triethylamine (1.0 mL) and di-
chloromethane (1.0 mL) were added to the mixture and the
resulting solution was stirred at room temperature for
30 min. Then the resulting mixture was filtered through a
short silica gel plug in a filter by using dichloromethane as
the eluent. The volatiles were removed under vacuum and
the residue was purified by column chromatography (SiO2,
hexane/diethyl ether=1:1) to give 2a as a yellow solid;
yield: 65 mg (84%).
A tentative mechanism to rationalize the dimerized
product formation is illustrated in Scheme 1. The
active ruthenium species A reacts with 2-phenylpyri-
À
dine 1a (and other arenes) by a chelation-directed C
H activation to generate intermediate B.[10] After
loosing HCl via a reductive-elimination, intermediate
Acknowledgements
We are grateful to the Canada Research Chair (Tier I) Foun-
dation (to CJL.), CFI, and NSERC for support of our re-
search.
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Scheme 1. Proposed mechanism for the ruthenium-catalyzed
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