Palladium catalyzed direct ortho C-H acylation of 2-arylpyridines using toluene derivatives as acylation reagents

Article abstract of DOI:10.1039/c2ra22208f

A facile ortho-acylation of 2-arylpyridines by a Pd-catalyzed oxidative C-H activation was developed, in which no prefunctionalized toluene derivatives were used as acylation reagents in a tandem reaction to form 2-pyridyldiaryl ketones with moderate yiel

Full text of DOI:10.1039/c2ra22208f

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Palladium catalyzed direct ortho C–H acylation of
2-arylpyridines using toluene derivatives as acylation
Cite this: RSC Advances, 2013, 3, 1679
reagents3
Zhipeng Xu,a Biao Xianga and Peipei Sun*ab
Received 18th September 2012,
Accepted 3rd December 2012
DOI: 10.1039/c2ra22208f
www.rsc.org/advances
A facile ortho-acylation of 2-arylpyridines by a Pd-catalyzed
oxidative C–H activation was developed, in which no prefunctio-
nalized toluene derivatives were used as acylation reagents in a
tandem reaction to form 2-pyridyldiaryl ketones with moderate
yields.
in the synthesis of pharmaceutical and medicinal compounds,
dyes and fragrances, as well as in the agrochemical industry.16
Herein, we present a facile palladium-catalyzed regioselective
acylation reaction of 2-arylpyridines with no prefunctionalized
toluene derivatives as acylation reagents to afford 2-pyridyldiaryl
ketones.
Our investigations were firstly focused on the reaction of
2-phenylpyridine (1a) with toluene (2a) in the presence of Pd(OAc)2
and an oxidant. To our delight, the desired acylation product
phenyl(2-(pyridin-2-yl)phenyl)methanone (3aa) was observed.
Encouraged by this initial finding, we commenced a systematic
screening of the reaction conditions, and the results are
summarized in Table 1. The reaction could be catalyzed efficiently
by 2 mol% Pd(OAc)2. It was found that the nature of the oxidants
played a critical role in the reaction efficiency. A screening of
oxidants showed that TBHP gave the best result while (PhCOO)2,
In the last decade, palladium catalyzed regioselective C–H
functionalization has been extensively exploited in the synthesis
of complicated molecules and natural products.1 Many directing
groups, such as acetyl,2 acetamino,3 carboxyl,4 carbonyl,5
N-methoxyacylamino,6 oxime,7 cyano8 and pyridylsulfinyl9 have
been used in C–H bond activation, especially in ortho aromatic C–
H bond functionalization. Although many examples of ortho-
acetoxylation,10 arylation,11 acylation12 and halogenation13 on
2-arylpyridine have been reported using PhI(OAc)2, organoboronic
acids, organosilanes, aldehydes, benzyl alcohols, a-oxocarboxylic
acids, a-diketones and NXS (X = Br, Cl or I) as the different
functionalization reagents respectively, there are still very few
studies on direct coupling using a substrate without prefunctio-
nalization to achieve C–H functionalization. In 2007, Sanford
reported an oxidative ortho-arylation directed by a pyridyl group
using simple arenes as aryl sources.14 This discovery further
demonstrated that toluene derivatives might serve as the acylation
reagents since toluene could be partly oxidized into aldehydes in
some conditions,15 which provided a possibility to achieve a
tandem reaction including the oxidation of toluene and C–H
functionalization of 2-arylpyridine. It is well known that toluene
derivatives have low toxicity and are stable, commercially available,
and easy to handle and thus may potentially be used as ideal
acylation reagents to achieve aryl ketones, which are widely used
Table 1 Optimization of the reaction conditionsa
Entry
Oxidant
Solvent
Yield (%)c
1
2
3
(PhCOO)2
(tBuO)2
TBHP
Tol
Tol
Tol
trace
trace
74
4
5
6
7
8
9
10
11
12
O2
Tol
Tol
Tol
DMSO
H2O
DCE
—
DMSO
DMSO
0
0
0
73
59
23
K2S2O8
PhI(OAc)2
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
aJiangsu Key Laboratory of Biofunctional Materials, College of Chemistry and
Materials Science, Nanjing Normal University, Nanjing, 210097, P. R. China
bKey Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry,
Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, P.
R. China. E-mail: sunpeipei@njnu.edu.cn; Fax: (+86) 25 8589 1767;
Tel: (+86) 25 8589 1767
65
71b
71 (110 uC), 74 (100 uC), 31 (80 uC)
a
Reaction conditions: unless otherwise specified, 2-phenylprydine 1a
(0.5 mmol), toluene 2a (1.0 mmol), Pd(OAc)2 (0.01 mmol), solvent
Electronic supplementary information (ESI) available: Experimental details,
3
b
characterization data, and copies of 1H and 13C NMR spectra for all products. See
DOI: 10.1039/c2ra22208f
(0.5 mL), oxidant (1.5 mmol) under air at 90 uC for 24 h. Under Ar.
c
Isolated yield.
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(tBuO)2, O2, K2S2O8 and PhI(OAc)2 were found to be inferior
(entries 1–6). The presence of 3.0 equiv TBHP gave the highest
yield. Toluene could be used as the acylation regent as well as the
solvent for this benzoylation reaction (entry 3). A similar result was
obtained in DMSO (entry 7), which would be significant when
other toluene derivatives, except toluene, were employed as
acylation regents. When water was used as the solvent, the yield
was slightly lower (entry 8). This may have resulted from the
insolubility of the reactants in water. DCE gave a poor yield (entry
9). So DMSO was chosen as the general solvent for this acylation
reaction. The yield was almost unchanged when the reaction was
performed under either an Ar or an air atmosphere (entries 7 and
11). At 90 uC, the reaction proceeded smoothly and finished in 24
h with a yield of 73%. Increasing the temperature to 110 uC did
not lead to an obvious rise of the yield. But at the temperature of
80 uC, the yield decreased sharply (entry 12).
With the optimized reaction conditions established, we
examined the reactions of various substituted 2-phenylprydines
with toluene (Table 2). It seems that the reaction of 2-phenylpry-
dines bearing both electron-donating and electron-withdrawing
groups on the benzene ring proceeded smoothly to give the
desired products in moderate to good yields. For example, toluene
reacted well with 2-(p-tolyl)pyridine and 2-(p-methoxyphenyl)pyr-
idine to give the ortho-acylated products in 71% and 70% isolated
yield respectively (3ba and 3ea), while it reacted with 2-
(p-chlorophenyl)pyridine and ethyl 4-(pyridin-2-yl)benzoate with
yields of 72% and 75%, respectively (3ga and 3ia). But the reaction
gave trace product (3da) when 2-(o-tolyl)pyridine was used as the
substrate, possibly due to an increase of the steric hindrance
caused by the methyl group, which was disadvantageous to the
formation of
a
coplanarity of the two aromatic rings.12c
Furthermore, it is worthwhile to point out that the chloro and
bromo groups on the aromatic ring could remain in the products
(3ga and 3ha). The tolerance of the reaction to these active groups
in substrates meant that they could be further transformed into
other different functionalities. The reaction of the cyano-contain-
ing substrate also gave moderate yields (3ja), which also accounted
for an excellent functional group tolerance of this reaction even
under the oxidizing reaction conditions.
The directed acylation of 2-arylpyridine with various toluene
derivatives was conducted under the optimized reaction condi-
tions as well, and the results are shown in Table 3. In general, the
reactions of 2-phenylprydine with the toluene derivatives with
electron-donating groups (such as CH3 or OCH3) or electron-
withdrawing groups (such as Cl or Br) on the aromatic ring gave
moderate to good yields. Unfortunately, the reaction of toluene
derivatives with a strong electron-withdrawing substituent such as
NO2 only gave a trace product (3af). This may be attributed to the
electron deficiency on the aromatic ring making it difficult for the
methyl group to be oxidized. It is worthwhile to note that for the
toluene derivatives with more than one methyl group such as
xylene and mesitylene, the reaction only took place at one methyl
Table 3 Acylation of 2-arylprydine with toluene d erivativesa
Table 2 Acylation of 2-arylprydine with toluenea
3ad: 71%
b
3ac: 69%
3ab: 52%
3ae: 75%
3ai: 52%
3am: 61%
b
3aa: 72%
3ba: 71%
3fa: 73%
3ca: 75%
3ga: 72%
3da: trace
3ha: 61%
3ah: 51%
3al: 42%
3ag: 45%
3ak: 77%
3af: trace
3aj: 57%
3ea: 70%
3an: 59%
3ed: 73%
3ee: 74%
3ja: 69%
3jd: 67%
3ia: 75%
a
a
Reaction conditions: 2-arylprydine 1 (0.5 mmol), toluene 2a (1.0
Reaction conditions: 2-arylprydine 1 (0.5 mmol), toluene derivatives
mmol), Pd(OAc)2 (0.01 mmol), TBHP (1.5 mmol), DMSO (0.5 mL)
under air at 90 uC for 24 h. Isolated yield.
2 (1.0 mmol), Pd(OAc)2 (0.01 mmol), TBHP (1.5 mmol), DMSO (0.5
mL) under air at 90 uC for 24 h. Isolated yield.
b
b
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group and the others remained unreacted (3ab, 3ac, 3ad and 3ae).
This result may be attributed to one of the methyl groups on the
toluene derivatives being pre-oxidized to an aldehyde group, and
its electron-withdrawing property was unfavorable to the subse-
quent oxidation. The reaction of p- and m-methyl anisole gave the
moderate yields (3ag and 3ah), and p- and m-methoxybenzoic
acids were detected respectively in the reaction mixtures. These
acids were probably generated by the overoxidation of p- and
m-methyl anisoles. a- and b-methylnaphthalene could also react
with 2-phenylprydine and gave moderate yields (3am and 3an).
To gain more understanding of this reaction, we have
performed some control experiments. When 2-phenylprydine
was treated with toluene in the presence of radical scavengers
(ascorbic acid or 1,4-benzoquinone)17 almost no acylation product
was produced (Scheme 1), which suggested that a radical likely
existed in the catalytic cycle. Moreover, without 2-phenylprydine,
the toluene was oxidized to benzaldehyde with a low yield
regardless of the presence of the palladium catalyst. When
2-phenylprydine treated with benzaldehyde in the absence of
TBHP, we failed to get the desired product. The results showed
that the TBHP may have two different effects, oxidizing toluene
and promoting the formation of radicals.
Scheme 2 Plausible reaction mechanism.
Acknowledgements
The authors thank the national nature science foundation of
China (Project 21272117 and 20972068) and the priority
academic program development of Jiangsu higher education
institutions for the financial support of this work.
On the basis of previous studies and our observations, a
possible mechanism for the reaction is illustrated (Scheme 2). The
palladium catalyst reacted with 2-phenylpyridine to form a
cyclopalladated intermediate (A) by chelation-directed C–H activa-
tion, which was confirmed by many related reports.18 With the
effect of TBHP, the benzaldehyde, which was produced from the
oxidation of toluene, generated an acyl radical (B). Afterward, the
palladacycle (A) reacted with the acyl radical (B) to form either the
reactive Pd(IV)19 or the dimeric Pd(III)20 intermediate (C). Finally,
the reductive elimination of intermediate C afforded coupling
product 3 and regenerated Pd(II) for further catalytic cycles.
In conclusion, we developed the ortho-acylation of 2-arylpyr-
idines by a Pd-catalyzed oxidative coupling without prefunctiona-
lized toluene derivatives to form 2-pyridyldiaryl ketones. It is the
first example of using non prefunctionalized toluene as the
acylation reagent. The mild reaction conditions provide opportu-
nities for future research to apply this methodology in the
synthesis of natural products and other useful compounds.
Further development of other acylations using toluene is under-
way in our laboratories.
References
1 (a) D. Alberico, M. E. Scott and M. Lautens, Chem. Rev., 2007,
107, 174–238; (b) X. Chen, K. M. Engle, D.-H. Wang and J.-
Q. Yu, Angew. Chem., Int. Ed., 2009, 48, 5094–5115; (c) R. Jazzar,
J. Hitce, A. Renaudat, J. Sofack-Kreutzer and O. Baudoin,
Chem.–Eur. J., 2010, 16, 2654–2672; (d) C. S. Yeung and V.
M. Dong, Chem. Rev., 2011, 111, 1215–1292; (e) I. P. Beletskaya
and V. P. Ananikov, Chem. Rev., 2011, 111, 1596–1636; (f)
W. Shi, C. Liu and A. Lei, Chem. Soc. Rev., 2011, 40, 2761–2776;
(g) C. Liu, H. Zhang, W. Shi and A. W. Lei, Chem. Rev., 2011,
111, 1780–1824.
2 D. Shabashov and O. Daugulis, Org. Lett., 2006, 8, 4947–4949.
3 (a) S. Yang, B. Li, X. Wan and Z. Shi, J. Am. Chem. Soc., 2007,
129, 6066–6067; (b) M. D. K. Boele, G. P. F. van Strijdonck, A. H.
M. de Vries, P. C. J. Kamer, J. G. de Vries and P. W. N. M. van
Leeuwen, J. Am. Chem. Soc., 2002, 124, 1586–1587.
4 (a) R. Giri, N. Maugel, J.-J. Li, D.-H. Wang, S. P. Breazzano, L.
B. Saunders and J.-Q. Yu, J. Am. Chem. Soc., 2007, 129,
3510–3511; (b) Y.-H. Zhang, B.-F. Shi and J.-Q. Yu, Angew.
Chem., Int. Ed., 2009, 48, 6097–6100.
5 P. Gandeepan, K. Parthasarathy and C.-H. Cheng, J. Am. Chem.
Soc., 2010, 132, 8569–8571.
6 (a) G.-W. Wang, T.-T. Yuan and D.-D. Li, Angew. Chem., Int. Ed.,
2011, 50, 1380–1383; (b) G.-W. Wang and T.-T. Yuan, J. Org.
Chem., 2009, 75, 476–479.
7 (a) Z. Xu, B. Xiang and P. Sun, Eur. J. Org. Chem., 2012,
3069–3073; (b) L. V. Desai, H. A. Malik and M. S. Sanford, Org.
Lett., 2006, 8, 1141–1144.
8 (a) W. Li, Z. Xu, P. Sun, X. Jiang and M. Fang, Org. Lett., 2011,
13, 1286–1289; (b) W. Li and P. Sun, J. Org. Chem., 2012, 77,
8362–8366.
9 M. Yu, Z. Liang, Y. Wang and Y. Zhang, J. Org. Chem., 2011, 76,
4987–4994.
10 A. R. Dick, K. L. Hull and M. S. Sanford, J. Am. Chem. Soc., 2004,
126, 2300–2301.
Scheme 1 Control experiments.
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RSC Advances
11 (a) D. Kalyani, N. R. Deprez, L. V. Desai and M. S. Sanford, J.
Am. Chem. Soc., 2005, 127, 7330–7331; (b) W. Li, Z. Yin, X. Jiang
and P. Sun, J. Org. Chem., 2011, 76, 8543–8548.
16 H. Surburg and J. Panten, Common fragrance and flavor
materials, Wiley Online Library, 2006.
17 J. J. Warren and J. M. Mayer, J. Am. Chem. Soc., 2010, 132,
7784–7793.
18 (a) X. Chen, C. E. Goodhue and J.-Q. Yu, J. Am. Chem. Soc., 2006,
128, 12634–12635; (b) W.-Y. Yu, W. N. Sit, Z. Zhou and A. S.
C. Chan, Org. Lett., 2009, 11, 3174–3177.
19 (a) J. M. Racowski, A. R. Dick and M. S. Sanford, J. Am. Chem.
Soc., 2009, 131, 10974–10983; (b) N. R. Deprez and M.
S. Sanford, J. Am. Chem. Soc., 2009, 131, 11234–11241.
20 (a) D. C. Powers, M. A. L. Geibel, J. E. M. N. Klein and T. Ritter,
J. Am. Chem. Soc., 2009, 131, 17050–17051; (b) D. C. Powers and
T. Ritter, Nat. Chem., 2009, 1, 302–309.
12 (a) W. Zhou, H. Li and L. Wang, Org. Lett., 2012, 14, 4594–4597;
´
(b) O. Basle, J. Bidange, Q. Shuai and C.-J. Li, Adv. Synth. Catal.,
´
2010, 352, 1145–1149; (c) F. Xiao, Q. Shuai, F. Zhao, O. Basle,
G. Deng and C.-J. Li, Org. Lett., 2011, 13, 1614–1617; (d) M. Li
and H. Ge, Org. Lett., 2010, 12, 3464–3467.
13 D. Kalyani, A. R. Dick, W. Q. Anani and M. S. Sanford, Org. Lett.,
2006, 8, 2523–2526.
14 K. L. Hull and M. S. Sanford, J. Am. Chem. Soc., 2007, 129,
11904–11905.
15 S. Bose, A. Pariyar, A. N. Biswas, P. Das and P. Bandyopadhyay,
J. Mol. Catal. A: Chem., 2010, 332, 1–6.
1682 | RSC Adv., 2013, 3, 1679–1682
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