Palladium-catalyzed ortho-acylation of 2-aryl pyridine derivatives using arylmethyl amines as new acyl sources

Article abstract of DOI:10.1039/c3cc42106f

A facile and efficient protocol for palladium-catalyzed ortho-acylation of 2-aryl pyridines was developed. Note that this acylation utilized arylmethyl amines as new, cheap and readily available acylation reagents and exhibited high regioselectivity for 2-aryl pyridines bearing a meta-substituent in the aryl ring moiety.

Full text of DOI:10.1039/c3cc42106f

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Palladium-catalyzed ortho-acylation of 2-aryl pyridine
derivatives using arylmethyl amines as new acyl
sources†
Cite this: DOI: 10.1039/c3cc42106f
Received 22nd March 2013,
Accepted 18th April 2013
Qian Zhang, Fan Yang* and Yangjie Wu*
DOI: 10.1039/c3cc42106f
www.rsc.org/chemcomm
A facile and efficient protocol for palladium-catalyzed ortho-acylation
of 2-aryl pyridines was developed. Note that this acylation utilized
arylmethyl amines as new, cheap and readily available acylation
reagents and exhibited high regioselectivity for 2-aryl pyridines
bearing a meta-substituent in the aryl ring moiety.
Transition metal-catalyzed C–H bond functionalization has
become one of the most reliable and facile tools to construct
C–C and C–heteroatom bonds in recent years.1 Among the various
efficient C–H activation techniques, the directing group assisted
C–H bond activation is one of the most facile and powerful
strategies.2 And this type of ortho aromatic C–H bond functional-
ization has been achieved in several valuable and direct trans-
formations such as olefination, arylation, acylation, alkoxylation,
halogenation, and amination with the assistance of pyridines,
imines, esters, ketones, oxazolines, amides and nitriles as the
directing groups.3 Inspired by these pioneering reports, we
attempted ortho-amination of 2-phenylpyridine using benzyl amine
as a new amination reagent. However, the amination product
was not observed at all, and to our surprise, a large amount of
ortho-acylation product was obtained instead (Scheme 1).
Scheme 1 Transition metal-catalyzed direct ortho-acylation.
like to report facile and efficient synthesis of the aromatic
ketones via palladium-catalyzed regioselective ortho-acylation
using arylmethyl amines as new acylation reagents.
The initial optimization process of acylation of 2-phenyl-
pyridine (1a) with benzylamine (2a) was investigated, and the
Table 1 Optimization of the reaction conditionsa
The first successful acylation of ortho-C–H bonds was
reported by Cheng and coworkers, in 2009, who discovered
that ortho-C–H bonds of 2-arylpyridines could be directly acylated
under palladium catalysis using aldehydes as acylation
reagents.4e Then, such ortho-acylation type reactions were also
realized using aldehydes, a-oxocarboxylic acids, alcohols or
toluene derivatives as acylation reagents.4 Compared to these
reagents, benzylamine derivatives as new acylation reagents are
cheap, stable and easy to handle, and would be an important
complement to these reported methods. And herein, we would
Entry Palladium source (mol%) 1a/2a (mmol/mmol) Yieldb (%)
1
2
PdCl2 (5)
PdCl2 (10)
1 : 2
1 : 2
47
56
3
4
5
6
PdCl2 (10)
PdCl2 (10)
PdCl2 (10)
PdCl2 (10)
PdCl2 (10)
PdCl2 (10)
Pd(OAc)2 (10)
Pd2(dba)3 (5)
Pd(PPh3)2Cl2 (10)
1 : 1.8
1 : 1.6
1 : 1.4
1 : 1.2
1 : 1.4
1 : 1.4
1 : 1.4
1 : 1.4
1 : 1.4
66
67
69 (57)
56 (46)
81 (68)
35
47
55
40
7c
8d
9c
10c
11c
The College of Chemistry and Molecular Engineering, Henan Key Laboratory of
Chemical Biology and Organic Chemistry, Key Laboratory of Applied Chemistry of
Henan Universities, Zhengzhou University, Zhengzhou 450052, People’s Republic of
China. E-mail: yangf@zzu.edu.cn, wyj@zzu.edu.cn; Fax: +86-371-6797-9408;
Tel: +86-371-6797-9408
a
Reaction conditions: 2-phenyl pyridine (1a) (0.2 mmol), benzylamine,
palladium catalyst, TBHP (0.7 mmol) in 1 mL chlorobenzene at refluxing
temperature for 8 h. b GC yield (isolated yield) based on the amount of 1a.
c Under a nitrogen atmosphere. d At 110 1C and under a nitrogen atmosphere.
† Electronic supplementary information (ESI) available. CCDC 883839. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c3cc42106f
c
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results are displayed in Table 1. After the several effects of atmosphere, the GC yield could be up to 81% (Table 1, entry 7).
ligands, oxidants and the solvents were checked (see ESI†), we However, a lower temperature of 110 1C could result in a GC
found that the acylated product could be obtained in 47% GC yield of 35% (Table 1, entry 8). Finally, relatively lower yields
yield in the presence of 5 mol% of PdCl2 using TBHP as the were observed when other commercially available palladium
oxidant in chlorobenzene (Table 1, entry 1). When the catalyst sources such as Pd(OAc)2, Pd2(dba)3, and Pd(PPh3)2Cl2 were
loading was increased to 10 mol%, the desired product could be used as the catalysts (Table 1, entries 9–11).
obtained in a higher GC yield of 56% (Table 1, entry 2). It should
Under the optimized reaction conditions, the results of
be noted that the ratio of 2-phenyl pyridine (1a) to benzylamine acylation of 2-arylpyridines (1) with benzylamine (2a) are sum-
(2a) played an important role for the successful reaction. For marized in Table 2. The acylation could tolerate various func-
example, when this ratio was changed from 1 : 2 to 1 : 1.8, 1 : 1.6, tional groups such as OMe, Br, EtOOC, F and thienyl groups,
1 : 1.4 and 1 : 1.2, the GC yields of the desired products could be affording the desired products in moderate to good yields. The
obtained from 56% to 66%, 67%, 69% and 56%, respectively electronic effect was evident in this type of acylation, and the
(Table 1, entries 2–6). And from these obtained results, it could substrates bearing an electron-donating or electron-neutral
be found that the ratio of 1 : 1.4 is the best choice (Table 1, entry 5). group in the benzene ring would give the desired products in
Notably, when the reaction was performed under a nitrogen higher yields than those bearing an electron-withdrawing group
in the benzene ring (Table 2, 3b–3q). And especially, the acyla-
tion of 3-methyl-2-phenylpyridine with benzylamine (2a) gave a
yield of up to 81% (Table 2, 3l). Remarkably, the acylation also
Table 2 The palladium-catalyzed ortho-acylation of 2-arylpyridinesa,b
showed high regioselectivity for the substrates containing a
meta-substituent in the benzene ring, and the reaction could
occur at the less sterically hindered ortho-C–H bond of the
directing group (Table 2, 3e–3g, 3j, 3k, 3o, 3p). In addition, this
acylation could be also applicable to heterocycle-substituted
pyridines such as 2-thienylpyridine, 5-methyl-2-thienylpyridine
and benzo[h]quinoline, and moderate yields of 52%, 51% and
65% were obtained, respectively (Table 2, 3r–3t). The molecular
structure of the acylated product (3e) was unambiguously deter-
mined by the single crystal X-ray diffraction study (Fig. 1).5
The scope of palladium-catalyzed acylation of 3-methyl-2-
phenylpyridine with various substituted arylmethyl amines was
also investigated (Table 3). And the acylation showed good compati-
bility of substituents on the benzene ring of benzylamines such as
OMe, Cl, Br or even strong electron-withdrawing CF3 groups,
affording the corresponding products in moderate to good yields.
Based on the previous reports4 and our own results, a
tentative mechanism for the palladium-catalyzed ortho-C–H
acylation of 2-phenylpyridine (1a) is depicted in Scheme 2.
The reaction would be initiated by ortho-cyclometalation of
2-phenylpyridine (1a) with PdCl2 to form the palladacycle A.
Meanwhile, benzylamine (2a) would undergo oxidation, hydro-
lysis and the second radical oxidation in a solution of TBHP in
water to generate the acyl radical. Then, the intermediate A
would react with the acyl radical, affording the oxidative
a
Reaction conditions: 2-arylpyridine (0.2 mmol), benzylamine (2a)
(0.28 mmol), PdCl2 (10 mol%) and TBHP (0.7 mmol) in chlorobenzene
(1 mL) under a nitrogen atmosphere at refluxing temperature for 8 h.
Isolated yield.
b
Fig. 1 Molecular structure of 3e.
c
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Table 3 The palladium-catalyzed acylation of 2-phenyl-3-methylpyridine with
arylmethyl aminesa,b
Notes and references
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a
Reaction conditions: 2-phenyl-3-methylpyridine (0.2 mmol), aryl-
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chlorobenzene (1 mL) under a nitrogen atmosphere at refluxing temp-
erature for 8 h. Isolated yield.
b
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Scheme 2 Proposed mechanism for acylation of 2-phenylpyridine.
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addition product as intermediate B. Finally, the reductive
elimination of Pd(III) or Pd(IV) intermediate B4e would result
in the desired product (3a) and the regeneration of active
palladium species to fulfill the catalytic cycle.
In summary, we have developed convenient and efficient
synthesis of aromatic ketones via palladium-catalyzed ortho-C–H
acylation of 2-arylpyridines using arylmethyl amines as cheap
and readily available acylation reagents. This protocol showed
high regioselectivity for the substrates containing a meta-
substituent in the benzene ring. Further application of this
synthetic methodology is currently underway in our laboratory.
We are grateful to the Natural Science Foundation of China
(Nos. 21172200, 21102134) for financial support.
5 CCDC 883839 (3e).† Crystal data for compound 3e: C20H17NO, M =
287.35, triclinic, a = 7.9268(9) Å, a = 115.014(13)1, b = 10.2717(13) Å,
b = 108.424(12)1, c = 11.4612(16) Å, g = 93.149(10)1, V = 782.78(18) Å3,
%
T = 291.15 K, space group = P1, Z = 2, number of reflections = 6950,
independent reflections = 3178, [Rint = 0.0205], final R indices
[I > 2s(I)] R1 = 0.0450, wR2 = 0.1098, R indices (all data) R1 = 0.0625,
wR2 = 0.1209.
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun.