Direct carbo-acylation reactions of 2-arylpyridines with α-diketones via Pd-catalyzed C-H activation and selective C(sp2)-C(sp2) cleavage

Article abstract of DOI:10.1021/ol3020557

An efficient carbo-acylation reaction of 2-arylpyridines with α-diketones via Pd-catalyzed C-H bond activation and C-C bond cleavage in the presence of TBHP was developed that generated aryl ketones in good yields. The highly selective formation of aryl ketones was observed when 2-arylpyridines reacted with aromatic/aliphatic α-diketones.

Full text of DOI:10.1021/ol3020557

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Direct Carbo-Acylation Reactions of
2‑Arylpyridines with r‑Diketones via
Pd-Catalyzed CꢀH Activation and
Selective C(sp2)ꢀC(sp2) Cleavage
Wei Zhou,† Hongji Li,† and Lei Wang*,†,‡
Department of Chemistry, Huaibei Normal University, Huaibei, Anhui 235000,
P. R. China, and State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Shanghai 200032, P. R. China
leiwang@chnu.edu.cn
Received July 25, 2012
ABSTRACT
An efficient carbo-acylation reaction of 2-arylpyridines with R-diketones via Pd-catalyzed CꢀH bond activation and CꢀC bond cleavage in the
presence of TBHP was developed that generated aryl ketones in good yields. The highly selective formation of aryl ketones was observed when
2-arylpyridines reacted with aromatic/aliphatic R-diketones.
In past years, the transition-metal-catalyzed carbonꢀ
carbon bond cleavage has attracted considerable attention
for its broad applications in organic synthesis.1 To the best
of our knowledge, three modes of the CꢀC bond cleavage
process have been developed, i.e., formation of a stable
complex by chelation,1b,2 relief of ring strain,3 and the
selective cleavage of substrates with functional groups as
leaving groups such as carboxylic acids,4 nitriles,5 carbonyls6
and so on.7 In general, Rh, Ru, Fe, Pd,1ꢀ7 and Cu6b,8 are
often used to activate the inert CꢀC bonds and behave
in high activity. Different from the selective CꢀC cleav-
age of tertiary1c,d and secondary alcohols,7d β-diketones,6b
epoxides,7f and others,4,5 the CꢀC cleavage of R-diketones
has not so far been reported.
† Huaibei Normal University.
(5) For selected examples, see: (a) Hirata, Y.; Yada, A.; Morita, E.;
Nakao, Y.; Hiyama, T.; Ohashi, M.; Ogoshi, S. J. Am. Chem. Soc. 2010,
132, 10070. (b) Tobisu, M.; Kinuta, H.; Kita, Y.; Remond, E.; Chatani,
N. J. Am. Chem. Soc. 2012, 134, 115.
‡ Shanghai Institute of Organic Chemistry.
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Acc. Chem. Res. 2008, 41, 222. (b) Jun, C.-H. Chem. Soc. Rev. 2004, 33,
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J. F. J. Am. Chem. Soc. 2006, 128, 3124. (d) Iwasaki, M.; Hayashi, S.;
Hirano, K.; Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc. 2007, 129,
4463. (e) Niwa, T.; Yorimitsu, H.; Oshima, K. Angew. Chem., Int. Ed.
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r
10.1021/ol3020557
XXXX American Chemical Society

Recently, CꢀH activation has become a hot topic9
because of its economic advantages and it provides a direct
route for CꢀC bond formations.10 A wide range of transi-
tion-metal catalysts, such as PdII, CuII, RhIII, and CoII
complexes have been applied in the direct CꢀC cross-
coupling via C(sp2)ꢀH functionalization.11 These CꢀH
bond activation reactions often require a suitable catalyst,
functionalized partner, and oxidant.12 Importantly, the
functionalized partner containing a directing group played
an important role in the reactions because the CꢀH bond
adjacent to a heteroatom can be selectively activated.11
Several directing groups, including pyridines, oximes,
amides, amines, alcohols, carboxylic acids, esters, ketones,
aldehdyes, and triazenes, were effective to realize the ortho-
selective CꢀH functionalizations.13 It is noteworthy that
aryl ketones could be directly synthesized through transi-
tion-metal-catalyzed CꢀH activation (Scheme 1), and
carbonyl sources, such as aldehydes, alcohols, and
R-ketone acids, were needed.14 However, R-diketone as a
coupling partner15 and a potential carbonyl source via
CꢀC cleavage to form arylketones was rarely reported. In
continuing our efforts on the organic reactions through
CꢀH activation,16 herein, we wish to report a novel
approach to aryl ketones from arylpyridines and R-dike-
tones via Pd-catalyzed CꢀH bond activation of 2-arylpyr-
idine and selective C(sp2)ꢀC(sp2) bond cleavage of
R-diketones in the presence of tert-butyl hydroperoxide.
Scheme 1. Transition-Metal-Catalyzed Carbo-acylations
In our initial attempts to realize the carbo-acylation
reaction of 2-phenylpyridine (1a) with R-diphenyl ketone
(2a), the catalyst screening was first investigated. As shown
in Table 1, all Pd/TBHP systems could catalyze the model
reaction in THF. To our delight, Pd(OAc)2 exhibited the
highest activity among the Pd sources in Table 1, and the
desired product 3a was isolated in 82% yield (Table 1,
entry 1). Other Pd catalysts, such as Pd(CH3CN)2Cl2,
Pd(PPh3)4, Pd(PPh3)2Cl2, and PdCl2 were inferior and
generated 3a in 34ꢀ62% yields (Table 1, entries 2ꢀ5).
Next, a variety of oxidants were examined on the model
reactiontofurther optimizethe reaction conditions. TBHP
was found to be the best one among the oxidants tested in
Table 1. Other organic oxidizers, such as di-tert-butyl per-
oxide (DTBP), R,R-dimethylbenzyl hydroperoxide (DBHP),
dicumyl peroxide (DCP), tert-butyl peroxybenzoate (TBPB),
and peroxyacetic acid (PAA), gave the inferior yields of 3a
in 21ꢀ50% (Table 1, entries 6ꢀ10). However, the inorganic
oxidants K2S2O8 and Cu(OAc)2 showed very poor perfor-
mance (Table 1, entries 11 and 12). In addition, the effect of
solvent on the reaction was also investigated, and the results
indicated that THF was the best medium among the screened
solvents in Table S1 (see the Supporting Information).
Under the optimized reaction conditions, the scope of
the carbo-acylation reactions between the substituted ar-
ylpyridines with various R-diketones was investigated. As
can be seen from Scheme 2, the reaction of arylpyridines
with R-diketones gave the corresponding products in good
yields. A variety of arylpyridines bearing substituents on
the benzene rings were examined. The results indicated
that the functional groups, including electron-donating
and -withdrawing ones, were tolerated.
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2-Phenylpyridines with the electron-rich groups on the
phenyl rings, such as MeO, Me groups, reacted smoothly
with R-diphenyl ketone and gave the corresponding carbo-
acylation products 3bꢀf in 67ꢀ83% yields. Meanwhile,
2-phenylpyridines with the electron-poor groups on the
phenyl rings, such as Cl and F groups, also reacted with
R-diphenyl ketone and generated 3h and 3i in 74% and 68%
yields respectively. The reaction of 2-((1,10-biphenyl)-4-yl)-
pyridine with 2a provided the corresponding product 3g in
70% yield. On the other hand, R-diaryl ketones bearing
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Optimization of the Reaction Conditionsa
Scheme 2. Scope of the Direct Carbo-acylation of Arylpyridines
with R-Diketonesa
entry
Pd source
Pd(OAc)2
oxidant
yieldb (%)
1
2
TBHP
TBHP
TBHP
TBHP
TBHP
DTBP
DBHP
DCP
82
62
56
40
34
21
50
29
22
48
trace
0
Pd(CH3CN)2Cl2
Pd(PPh3)4
Pd(PPh3)2Cl2
PdCl2
3
4
5
6
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
7
8
9
TBPB
PAA
10
11
12
K2S2O8
Cu(OAc)2
a Reaction conditions: 2-phenylpyridine (1a, 0.50 mmol), R-diphenyl
ketone (2a, 0.75 mmol), Pd source (3 mol %), oxidant (1.5 mmol), THF
(2.0 mL), sealed tube, 100 °C, air, 12 h. b Isolated yields.
with different substituted groups on the benzene rings,
such as Me, MeO, F, and Cl, could react with 2-phenyl-
pyridine, affording the products 3kꢀn in good yields.
We were delighted to find that the reactions of 2-phenyl-
pyridine with challenging R-di(aliphatic)ketones also
proceeded well. For example, R-dimethyl ketone and
R-diethyl ketone showed almost the comparable reactivity
with R-diaryl ketones in the carbo-acylation reactions and
offered the satisfactory yields of the corresponding pro-
ducts 3oꢀt. It is important to note that it provides an
efficient route to introduce an aliphatic carbonyl group,
such as acetyl or propionyl to 2-arylpyridines, com-
paring with the reported CꢀH functionalizations.14 To
extend the scope of arylpyridines, the cross-coupling reac-
tion of benzo[h]quinoline with R-diarylketones and
R-di(aliphatic)ketones was examined and the excellent
yields of the products 3uꢀy were obtained. The factor
for the improved yields may result from the planar struc-
ture of benzo[h]quinoline.14b,17
Interestingly, the highly selective formation of the deri-
vatives of ketones was investigated when 2-arylpyridines
reacted with asymmetric R-diketones. The results in Table 2
indicate that asymmetric aromatic R-diketones with an
electron-donating group (MeO) and electron-withdrawing
one (F) on the benzene rings showed the selective forma-
tion of arylketones withthe ratio of 27:56 to25:47 (Table 2,
entry 1 vs 2). However, asymmetric aromatic/aliphatic
a Reaction conditions: 2-arylpyridine (1, 0.50 mmol), R-diketone (2a,
0.75 mmol), Pd(OAc)2 (3 mol %), TBHP (1.5 mmol), THF (2.0 mL),
sealed tube, 100 °C, air, 12 h. b Isolated yields.
R-diketones, such as 1- phenylpropane-1,2-dione and 1-phe-
nylbutane-1,2-dione, reacted with 2-phenylpyridine, 2-(p-
methoxyphenyl)pyridine, and 2-(p-fluorophenyl)pyridine
smoothly and generated the products in good yields with
high selectivity (Table 2, entries 3ꢀ6). Aliphatic/aromatic
ketoneswereobtainedinmajority, comparingtoaromatic/
aromatic ones in the selective formation of arylketones,
(17) Dick, A. R.; Remy, M. S.; Kampf, J. W.; Sanford, M. S.
Organometallics 2007, 26, 1365.
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99, 1991. (c) Bentrude, W. G.; Darnall, K. R. J. Am. Chem. Soc. 1968, 90,
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2004, 126, 2300. (b) Arnold, P. L.; Sanford, M. S.; Pearson, S. M. J. Am.
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Org. Lett., Vol. XX, No. XX, XXXX
C

reaction probably proceeds involving (i) the formation of a
cyclopalladated dimer intermediate (I)19 by chelate-direc-
ted CꢀH activation of the benzene ring of 2-arylpyridine
with Pd(OAc)2, (ii) the reaction of I with benzoyl radical,
which was generated in situ by the reaction of R-diphenyl
ketone with TBHP,18 providing reactive PdIV intermediate
(II),14b,16a,20 and finally, (iii) carbonꢀcarbon bond formation
via reductive elimination of II affording the acylation pro-
duct of 2-arylpyridine and regenerating the PdII species for
next run. It should be noted that tert-butyl benzoate and
benzoic acid were isolated during the reaction of 1a with 2a.
In addition, the carbo-acylation did not occur in the presence
of a radical scavenger, such as TEMPO (2,2,6,6-tetramethyl-
piperidyl-1-oxyl) or ascorbic acid up to 2 equiv.14d,21
Table 2. Selective Cleavage of Asymmetric R-Diketones in the
Carbo-acylation Reactionsa
Scheme 3. Proposed Reaction Mechanism
In summary, we have developed a direct carbo-acylation
reaction of arylpyridines with R-diketones via palladium-
catalyzed CꢀH bond activation and selective cleavage of
the CꢀC bond in the presence of TBHP. 2-Arylpyridines
could react with diverse symmetric and asymmetric
R-diketones in the presence of Pd(OAc)2 and TBHP in
THF and generated arylketones in good yields. It is
important to note that the highly selective formation of
arylketones was observed when 2-arylpyridines reacted
with asymmetric aromatic/aliphatic R-diketones. A de-
tailed mechanistic study is currently underway.
a Reaction conditions: 2-arylpyridine (1, 0.50 mmol), R-diketone (2,
0.75 mmol), Pd(OAc)2 (3 mol %), TBHP (1.5 mmol), THF (2.0 mL),
sealed tube, 100 °C, air, 12 h. b Isolated yields.
providing the ratio of 59/10 to 64/9. The reason of this
selectivity between alkyl ketone vs aryl ketone for unsym-
metric diketone is probably that the reactivity of arylcar-
bonyl reacted with free radical is superior to that of
alkylcarbonyl with same radical.18
A proposed mechanism of the palladium-catalyzed car-
bo-acylation reaction of 2-arylpyridine with R-diketone
via direct CꢀH bond activation and C(sp2)ꢀC(sp2) cleav-
age in the presence of TBHP is shown in Scheme 3. The
Acknowledgment. This work was financially supported
by the National Science Foundation of China (Nos.
21172092, 20972057).
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Soc. 2009, 131, 10974. (c) Rosewall, C. F.; Sibbald, P. A.; Liskin, D. V.;
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Supporting Information Available. Analytical data and
spectra (1H and 13C NMR) for all products; typical
procedure. This material is available free of charge via
the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX