Pd(II)-catalyzed monoarylation of 2-phenylpyridine N-oxide with iodobenzene in water

Article abstract of DOI:10.1080/00397911.2017.1285937

A Pd(II)-catalyzed activation and arylation of C(sp²)–H bond directed by pyridine N-oxide in water is achieved with high regioselectivity to form monoarylated products in yields up to 91%. The wide substrate scope highlights the flexibility of the catalyst. The reaction mechanism was proposed and the application of this method was taken as an example by the synthesis of COX-2 inhibitor analog.

Full text of DOI:10.1080/00397911.2017.1285937

Pd(II)-Catalyzed Monoarylation of 2-Phenylpyridine N-Oxide with Iodobenzene in
Water
Wei Zhang1, Zhengkai Li1, Yihan Zhang1, Li Yang1,2, Xiangge Zhou1
1College of Chemistry, Sichuan University, Chengdu, P. R. China 2College of Chemistry
& Chemical Engineering, Yibin University, Yibin, P. R. China
Corresponding author Xiangge Zhou E-mail: zhouxiangge@scu.edu.cn
Abstract
A Pd(II)-catalyzed activation and arylation of C(sp2)-H bond directed by pyridine N-
oxide in water is achieved with high regioselectivity to form monoarylated products in
yields up to 91%. The wide substrate scope highlights the flexibility of the catalyst. The
reaction mechanism was proposed and the application of this method was taken example
by the synthesis of COX-2 inhibitor analog.
Graphical Abstract
KEYWORDS: palladium; catalysis; pyridine N-oxide; aqueous; arylation
INTRODUCTION
The transition metal-catalyzed functionalization of C-H bonds has emerged as a powerful
tool for the formation of C-C and C-heteroatom bonds in recent years.[1] Nickel,[2]
palladium,[3] iron,[4] rhodium,[5] copper[6] and other metals have been appealing catalysts
1

for these transformations. Among them, palladium is now perhaps the most widely used
for this type of reactions. Indeed, the past decade has witnessed the development of many
Pd-catalyzed C-H arylation reactions employing various C(sp2)-H electrophiles.[7] For
example, the arylation of anilides[8] and benzoic acids[9] with aryl halides by Pd(II)
catalysis has been studied by Daugulis and co-workers. The intramolecular arylation
involving C(sp2)-H activation to synthesize new polycyclic skeletons was then reported
by Raboin and co-workers.[10] In 2015, Yu and co-workers reported Pd(II)-catalyzed
meta-C(sp2)-H arylation of amides with various aryl iodides as arylation reagents.[11]
Recently, the groups of Shi,[12] Babu,[13] Hu[14] et al. also achieved the arylation in the
presence of Pd(II) catalyst via C(sp2)-H activation process.
On the other hand, 2-(2-arylphenyl)pyridine-containing heterocyclic molecules and their
derivatives exist widely in natural products, functional materials and pharmaceuticals.
For example, compound A was utilized as a cyclooxygenase-2 (COX-2) inhibitor;[15]
compound B (GSK345931A), which demonstrated good metabolic stability in the rat and
lower molecular weight, showed measurable CNS penetration in the mouse and rat and
potent analgesic efficacy in acute and sub-chronic models of inflammatory pain;[16]
compound C exhibited efficient activity to induce inhibition of 11β-HSD1;[17] while the
supramolecular zinc ensemble of compound D exhibits ‘ON-ON’ response to Thr in the
nanomolar range (Figure 1).[18]
The widespread applications of this kind of compounds have resulted in the development
of synthetic methodology to construct them. For example, Studer et al. reported the
2

transition metal-catalyzed C(sp2)-H arylation of 2-phenylpyridine with arylboronic acid,
aryl halide, aryl acylperoxides etc., which were performed in organic solvents.[19] Then,
Dixneuf, Gimeno and co-workers reported this reaction by using water as the reaction
medium in the presence of ruthenium catalyst.[20,21] Considering the relatively high
solubility of pyridine N-oxide in water as well as the certain coordination ability of
oxygen atom of N-oxide,[22] we envisioned its potential application as ligand in aqueous
catalysis. Actually, several groups have performed transition metal-catalyzed ortho C-H
bond alkylation, alkenylation, and arylation of pyridine N-oxides in organic solvents.[23]
Notably, Wu and co-workers revealed the copper-catalyzed direct C-H arylation of
pyridine N-oxides with arylboronic esters for the synthesis of 2,6-diphenylpyridine and
its derivatives (Scheme 1)[24], in which the copper catalyst coordinated and activated the
ortho-position of pyridine ring[25]
.
RESULTS AND DISCUSSION
Inspired by the above studies, it is reasonable to assume that the activation of C(sp2)-H
bonds might be achieved through palladium catalysis with the assistance of 2-
phenylpyridine N-oxide. In continuation of our recent work on aqueous catalysis and C-H
activation,[26] we commenced our studies by investigating the possibility of activation and
arylation of 2-phenylpyridine N-oxide in water.
As shown in Table 1, 2-phenylpyridine N-oxide 1a (0.25 mmol) was reacted with
iodobenzene (1.5 equiv.) in the presence of Pd(OAc)2 (10 mol%) in 1 mL H2O at 100 oC
for 12 h, affording the desired high regioselective ortho-monoarylated product 3a in 23%
3

yield (Table 1, entry 1). Among different silver salt additives, AgOTf gave the best yield
of 68% (Table 1, entries 2-11). Further experiments showed that other palladium sources
such as Pd(TFA)2 or Pd(PPh3)Cl2 gave lower yields (Table 1, entries 12-14). After
addition of phase transfer reagent tetrabutylammonium bromide, the yield increased to 84%
(Table 1, entry 15). Subsequently, other reaction parameters including the ratio of two
substrates, reaction time, reaction temperature, and the amount of catalyst were also
investigated (Table 1, entry 23-27). Finally, a combination of Pd(OAc)2 (10 mol%),
TBAB (20 mol%), 1.1 equiv. AgOTf, 1.5 equiv. iodobenzene, and 1 mL H2O was
established to be the best reaction conditions for this reaction. However, when
chlorobenzene and bromobenzene were used as arylation reagents, the reaction didn’t
proceed well with only trace of product, which might be caused by the fact that the easier
C-I cleavage than C-Cl and C-Br bonds.[27] More importantly, when the substrate 2-
phenylpyridine N-oxides was replaced by 2-phenylpyridine, the reaction did not occur
smoothly with only trace of product under the same reaction conditions, which indicated
the necessity of N-oxide group in reaction.
With the optimized reaction conditions in hand, the scope of various iodobenzenes was
then studied, and the results were listed in Table 2. A wide range of iodobenzenes with
different functional groups, such as methyl (2i, 2k and 2u), methoxy (2j and 2l), fluoro
(2b, 2c and 2s), chloro (2d, 2m and 2t), bromo (2e and 2n), nitro (2h and 2q),
trifluoromethyl (2f and 2o), cyano (2g and 2p), and ester (2r) groups, underwent efficient
monoarylation to afford the corresponding substituted pyridine, 2-(1,1’-biphenyl)-2-yl-N-
oxides in good to excellent yields ranging from 62% to 91%. Substrates bearing either
4

electron-donating (2i-2l, 2u) or electron-withdrawing groups (2b-2h, 2m-2t) could also
be coupled with 1a in high isolated yields. Meanwhile, ortho-substituted substrates (2w)
gave lower yield except fluoro group (2b), which might be ascribed to the less steric
hindrance of the fluoro atom. Moreover, non-ortho- disubstituted aryl iodides could also
be coupled under the standard conditions to afford the desired products in moderate to
good yields (3s-3u). The reaction also proceeded well with heterocyclic coupling partner,
such as 2-iodothiophene (2v). The structure of the arylated products (3t) was
unambiguously established by X-ray crystallographic analysis (Figure 2).
Next, substituted 2-phenylpyridine N-oxides were applied for this reaction with
iodobenzene as substrate. As summarized in Table 3, in general, substrates bearing
electron-donating substituents resulted in better yields than those bearing electron-
withdrawing groups (4d-4e).[28] The position (ortho, meta, para) of the substituents, on
the other hand, appeared to have few effects on the results.
To gain insight into the reaction pathway, the deuteration experiments were performed.
At first, a hydrogen/deuterium exchange experiment showed that the hydrogen atom of
ortho C-H bond was almost replaced by deuterium (eq. 1). Next, a primary kinetic
isotopic effect (KIE) of 1.0 was observed in the parallel reaction between 1a and [D2]-1a
with aryl iodide (2a) (eq. 2), which revealed that the C-H bond cleavage might not be
involved in the rate-determining step.[29]
5

On the basis of our experiments and reported literatures,[30] which suggested the Pd(II)-
catalyzed arylation reactions with ArI in the presence of Ag(I) salt would involve a
Pd(II/IV) mechanism. A plausible reaction pathway for the present process was proposed
as shown in Figure 3. Firstly, Pd(II) catalyst coordinates with 2-phenylpyridine N-oxides
1a and attacks C(sp2)-H bond to produce complex E. Then E is transformed to be Pd(IV)
F after oxidative addition with iodobenzene. At last, the product is formed by reductive
elimination from the high valent Pd(IV) species, while the Pd(IV) species is reduced to
be Pd(II) to fulfil the catalytic cycle.
Additionally, 2-(2-phenylphenyl)pyridine N-oxide could be easily deoxygenated by
reaction with zinc powder in THF at room temperature,[31] making the present route an
attractive approach to form 2-(2-phenylphenyl)pyridine (Scheme 2).
Attracted by the medicinal value of compound A, we then tried to synthesize its analogue
2-(4,5-difluoro-4'-methoxy-biphenyl-2-yl)-5-methyl-pyridine 6. As shown in Scheme 3, 6
could be synthesized by the sequential arylation of 2-chloro-5-methylpyridine, oxidation
by H2O2, catalysis under standard condition, and at last reduction in a 48% total yield,
which could shorten two-steps compared with the reported synthetic method.[15] The
structure of 6 was also confirmed by X-ray crystallographic analysis (Figure 4), and as
expected, the only arylated position is the less steric ortho position of pyridine ring.
EXPERIMENTAL
Typical Procedure For The Synthesis Of Compound 3a
6

A Schlenk tube with a magnetic stir bar was charged with catalyst (10 mol%), silver salt
(1.1 equiv.), additive (20 mol%), 2-phenylpyridine N-oxide 1a (0.25 mmol, 0.0388 g),
iodobenzene 2a (1.5 equiv.) and H2O (1 mL). The resulting solution was stirred at the
indicated temperature. The resulting organic layer was extracted with trichloromethane,
treated with Na2SO4 and concentrated in vacuo. The residue was purified by silica gel
column chromatography (EtOAc/CH3OH = 100/1, v/v) to provide 3a. 1H NMR (400
MHz, CDCl3) δ 6.93 (d, J = 7.8 Hz, 1H), 7.02 (t, J = 7.7 Hz, 1H), 7.11 (t, J = 6.0 Hz, 1H),
7.16-7.30 (m, 5H), 7.40-7.58 (m, 4H), 8.24 (d, J = 6.4 Hz, 1H). 13C NMR (100 MHz,
CDCl3) δ 123.53, 123.94, 126.11, 126.24, 127.08, 127.38, 127.52, 128.48, 128.97,
129.00, 130.71, 138.79, 139.44, 140.66, 149.03. HRMS (ESI): calcd for C17H13NO
[M+H]+ 248.0997, found 248.1067.
CONCLUSION
In summary, we have disclosed an efficient and practical protocol for the C-H
monoarylation of 2-phenylpyridine N-oxide by using water as an environmentally benign
solvent. This reaction enables highly selective installation of aryl scaffolds into the ortho
site of benzene ring with the assistance of 2-phenylpyridine N-oxides auxiliary. Good
structural versatility in both aryl iodides and 2-phenylpyridine N-oxides and high
functional group tolerance provide an efficient protocol for the synthesis of COX-2
inhibitor derivatives. Further investigations of this system for use in other reactions is
currently ongoing in our laboratory.
ACKNOWLEDGEMENTS
7

We are grateful to the Natural Science Foundation of China (grant nos. 21472128,
21401163, J1310008). We also acknowledge Comprehensive training platform of
specialized laboratory, College of chemistry, Sichuan University for HRMS analysis.
REFERENCES
[1] For recent reviews on functionalization of C(sp2)-H bonds, see: (a) Li, B.; Dixneuf, P.
H. Chem. Soc. Rev. 2013, 42, 5744-5767; (b) Zhang, F. Z.; Spring, D. R. Chem. Soc. Rev.
2014, 43, 6906-6919; (c) Chen, X.; Engle, K. M.; Wang, D. H.; Yu, J. Q. Angew. Chem.
Int. Ed. 2009, 48, 5094-5115.
[2] (a) Xiao, L. J.; Fu, X. N.; Zhou, M. J.; Xie, J. H.; Wang, L. X.; Xu, X. F.; Zhou, Q. L.
J. Am. Chem. Soc. 2016, 138, 2957-2960; (b) Yang, K.; Zhang, C.; Wang, P.; Zhang, Y.;
Ge, H. B. Chem. Eur. J. 2014, 20, 7241-7244.
[3] (a) Hu, T. J.; Zhang, G.; Chen, Y. H.; Feng, C. G.; Lin, G. Q. J. Am. Chem. Soc. 2016,
138, 2897-2900; (b) Guo, L.; Zhang, F. Y.; Hu, W. M.; Li, L.; Jia, Y. X. Chem. Commun.
2014, 50, 3299-3302; (c) Obora, Y.; Ishii, Y. Catalysts 2013, 3, 794-810; (d) Guo, H. M.;
Jiang, L. L.; Niu, H. Y.; Rao, W. H.; Liang, L.; Mao, R. Z.; Li, D. Y.; Qu, G. R. Org. Lett.
2011, 13, 2008-2011.
[4] (a) Zhang, Y.; Ni, M. J.; Feng, B. N. Org. Biomol. Chem. 2016, 14, 1550-1554; (b)
Shang, R.; Ilies, L.; Asako, S.; Nakamura, E. J. Am. Chem. Soc. 2014, 136, 14349-14352.
[5] (a) Collins, K. D.; Lied, F.; Glorius, F. Chem. Commun. 2014, 50, 4459-4461; (b)
Wang, J.; Wang, M. Y.; Chen, K. H.; Zha, S.; Song, C.; Zhu, J. Org. Lett. 2016, 18,
1178-1181; (c) Ng, F. N.; Zhou, Z. Y.; Yu, W. Y. Chem. Eur. J. 2014, 20, 4474-4480; (d)
8

Ng, K. H.; Zhou, Z. Y.; Yu, W. Y. Org. Lett. 2012, 14, 272-275; (e) Ng, K. H.; Zhou, Z.
Y.; Yu, W. Y. Chem. Commun. 2013, 49, 7031-7033.
[6] (a) Miura, W.; Hirano, K.; Miura, M. Org. Lett. 2015, 17, 4034-4037; (b) Xu, J.; Zhu,
X. L.; Zhou, G. B.; Ying, B. B.; Ye, P. P.; Su, L. Y.; Shen, C.; Zhang, P. F. Org. Biomol.
Chem. 2016, 14, 3016-3021.
[7] Recent reviews of Pd-catalyzed C-H functionalization: (a) Campbell, A. N.; Stahl, S.
S. Acc. Chem. Res. 2012, 45, 851-863; (b) Topczewski, J. J.; Sanford, M. S. Chem. Sci.
2015, 6, 70-76.
[8] (a) Daugulis, O.; Zaitsev, V. G. Angew. Chem. Int. Ed. 2005, 44, 4046-4048; (b)
Shabashov, D.; Daugulis, O. J. Org. Chem. 2007, 72, 7720-7725; (c) Daugulis, O.; Do, H.
Q.; Shabashov, A. D. Acc. Chem. Res. 2009, 42, 1074-1086.
[9] Chiong, H. A.; Pham, Q. N.; Daugulis, O. J. Am. Chem. Soc. 2007, 129, 9879-9884.
[10] Koubachi, J.; Berteina-Raboin, S.; Mouaddib, A.; Guillaumet, G. Tetrahedron 2010,
66, 1937-1946.
[11] Shen, P. X.; Wang, X. C.; Wang, P.; Zhu, R. Y.; Yu, J. Q. J. Am. Chem. Soc. 2015,
137, 11574-11577.
[12] Liu, X. W.; Shi, J. L.; Yan, J. X.; Wei, J. B.; Peng, K.; Dai, L.; Li, C. G.; Wang, B.
Q.; Shi, Z. J. Org. Lett. 2013, 15, 5774-5777.
[13] (a) Bisht, N.; Babu, S. A. Tetrahedron 2016, 72, 5886-5897; (b) Parella, R.; Babu, S.
A. J. Org. Chem. 2015, 80, 12379-12396; (c) Reddy, C.; Bisht, N.; Parella, R.; Babu, S.
A. J. Org. Chem. 2016, 81, 12143-12168.
[14] Xiao, C. Q.; Wang, Z. Y.; Lei, M.; Hu, L. H. Tetrahedron 2017, 73, 204-211.
9

[15] Li, J. J.; Norton, M. B.; Reinhard, E. J.; Anderson, G. D.; Gregory, S. A.; Isakson, P.
C.; Koboldt, C. M.; Masferrer, J. L.; Perkins, W. E.; Seibert, K.; Zhang, Y.; Zweifel, B.
S.; Reitz, D. B. J. Med. Chem. 1996, 39, 1846-1856.
[16] Hall, A.; Brown, S. H.; Budd, C.; Clayton, N. M.; Giblin, G. M. P.; Goldsmith, P.;
Hayhow, T. G.; Hurst, D. N.; Naylor, A.; Rawlings, D. A.; Scoccitti, T.; Wilson, A. W.;
Winchester, W. J. Bioorg. Med. Chem. Lett. 2009, 19, 497-501.
[17] Wang, H. X.; Ruan, Z. M.; Li, J. J.; Simpkins, L. M.; Smirk, R. A.; Wu, S. C.;
Hutchins, R. D.; Nirschl, D. S.; Kirk, K. V.; Cooper, C. B.; Sutton, J. C.; Ma, Z. P.; Golla,
R.; Seethala, R.; Salyan, M. E. K.; Nayeem, A.; Krystek, S. R.; Sheriff, Jr, S.; Camac, D.
M.; Morin, P. E.; Carpenter, B.; Robl, J. A.; Zahler, R.; Gordon, D. A.; Hamann, L. G.
Bioorg. Med. Chem. Lett. 2008, 18, 3168-3172.
[18] Kaur, S.; Bhalla, V.; Kumar, M. Chem. Commun. 2014, 50, 9725-9728.
[19] (a) Kirchberg, S.; Vogler, T.; Studer, A. Synlett. 2008, 18, 2841-2845; (b) Feng, J.;
Lu, G. P.; Lv, M. F.; Cai, C. Synlett. 2013, 24, 2153-2159; (c) Reddy, G. M.; Rao, N. S.
S.; Satyanarayana, P.; Maheswaran, H. RSC Adv. 2015, 5, 105347-105352; (d) Yu, W. Y.;
Sit, W. N.; Zhou, Z. Y.; Chan, A. S. C. Org. Lett. 2009, 11, 3174-3177.
[20] (a) Arockiam, P. B.; Fischmeister, C.; Bruneau, C.; Dixneuf, P. H. Angew. Chem. Int.
Ed. 2010, 49, 6629-6632; (b) Arockiam, P. B.; Fischmeister, C.; Bruneau, C.; Dixneuf, P.
H. Green Chem, 2013, 15, 67-71.
[21] Adrio, L. A.; Gimeno, J.; Vicent, C. Chem. Commun. 2013, 49, 8320-8322.
[22] (a) Do, H. Q.; Khan, R. M. K.; Daugulis, O. J. Am. Chem. Soc. 2008, 130, 15185-
15192; (b) Ding, S. T.; Yan, Y. P.; Jiao, N. Chem. Commun. 2013, 49, 4250; (c) Jha, A.
K.; Jain, N. Chem. Commun. 2016, 52, 1831-1834.
10

[23] (a) Andersson, H.; Gustafsson, M.; Boström, D.; Olsson, R.; Almqvist, F. Angew.
Chem. Int. Ed. 2009, 48, 3288-3291; (b) Xiao, B.; Liu, Z. J.; Liu, L.; Fu, Y. J. Am. Chem.
Soc. 2013, 135, 616-619; (c) Ryu, J.; Cho, S. H.; Chang, S. Angew. Chem. Int. Ed. 2012,
51, 3677-3681; (d) Campeau, L. C.; Rousseaux, S.; Fagnou, K. J. Am. Chem. Soc. 2005,
127, 18020-18021.
[24] Shen, Y.; Chen, J. X.; Liu, M. C.; Ding, J. C.; Gao, W. X.; Huang, X. B.; Wu, H. Y.
Chem. Commun. 2014, 50, 4292-4295.
[25] (a) Odani, R.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2015, 80, 2384-2391;
(b) Larionov, O. V.; Stephens, D.; Mfuh, A.; Chavez, G. Org. Lett. 2014, 16, 864-867.
[26] Wu, Z. Q.; Chen, S.; Hu, C. X.; Li, Z. K.; Xiang, H. F.; Zhou, X. G. ChemCatChem
2013, 5, 2839-2842.
[27] ArBr and ArCl showed obviously lower conversions as negligible arylation products
were obtainbed under the standard conditions (Table S1, entries 28 and 29).
[28] Jordan-Hore, J. A.; Johansson, C. C. C.; Gulias, M.; Beck, E. M.; Gaunt, M. J. J. Am.
Chem. Soc. 2008, 130, 16184-16186.
[29] (a) Yan, Q. Q.; Xiao, T. X.; Liu, Z. X.; Zhang, Y. H. Adv. Synth. Catal. 2016, 358,
2707-2711; (b) Simmons, E. M.; Hartwig, J. F. Angew. Chem. Int. Ed. 2012, 51, 3066-
3072.
[30] (a) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147-1169; (b) Deprez, N.
R.; Sanford, M. S. J. Am. Chem. Soc. 2009, 131, 11234-11241; (c) Kalyani, D.; Deprez,
N. R.; Desai, L. V.; Sanford, M. S. J. Am. Chem. Soc. 2005, 127, 7330-7331; (d)
Hickman, A. J.; Sanford, M. S. ACS Catal. 2011, 1, 170-174; (e) Deprez, N. R.; Sanford,
M. S. Inorg. Chem. 2007, 46, 1924-1935.
11

[31] Campeau, L. C.; Fagnou, K. Org. Synth. 2011, 88, 22-32.
12

Table 1. Optimization of reaction conditionsa
entry catalyst
silver salt
additive Yieldb of 3a(%) Conv.c of 1a (%)
1
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
23
37
51
18
trace
36
48
20
23
59
68
64
39
28
30
43
61
27
10
45
56
27
29
67
79
77
48
36
90
84
79
78
2
AgOAc
3
AgTFA
4
Ag2O
5
Ag2CO3
6
AgSbF6
7
AgBF4
8
CH3(CH2)2COOAg
CH3(CH2)3COOAg
AgNO3
9
10
11
12
13
14
15
16
17
18
AgOTf
AgOTf
Pd(PPh3)2Cl2 AgOTf
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
TBAB 84
TPPTS 73
TBAI
SDS
72
70
13

19
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
SDBS
TsOH
PPh3
75
74
30
NR
83
85
41
0
20
21
22
Phen
23d
24e
25f
26g
27h
TBAB 75
TBAB 70
TBAB 84
TBAB 61
TBAB 74
91
85
92
90
82
aThe reactions were conducted with 0.25 mmol 1a, 0.375 mmol 2a, 10 mol% of catalyst,
1.1 equiv. silver salt, 20 mol% additive, 1 mL H2O at 100 oC for 12 h unless otherwise
noted.
bIsolated yields.
cConsideration determined by GC/MS based on 2-phenylpyridine N-oxides (internal
standard: tetradecane).
d110 oC.
e90 oC.
f4 equiv. 2a.
g24 h.
h5 mol% Pd(OAc)2 TBAB: tetrabutylammonium bromide; TPPTS: triphenylphosphine-
3,3',3''-trisulfonicacidtrisodium salt; TBAI: tetrabutylammonium iodide; SDS: sodium
dodecyl sulfonate; SDBS: sodium dodecyl benzene sulfonate; TsOH: 4-
methylbenzenesulfonic acid; Phen: 1,10-phenanthroline.
14

Table 2. Scope of aryl iodidesa,b,c
a The reactions were conducted with 0.25 mmol 1, 0.375 mmol 2a, 10 mol% Pd(OAc)2,
1.1 equiv. AgOTf, 20 mol% TBAB, 1 mL H2O and stirred for 12 h unless otherwise
noted.
b Isolated yields.
15

c Conversion in parenthesis.
16

Table 3. Scope of 2-phenylpyridine N-oxidea,b,c
a The reactions were conducted with 0.25 mmol of 1, 0.375 mmol of 2a, 10 mol% of
Pd(OAc)2, 1.1 equiv. of AgOTf, 20 mol% of TBAB, and 1 mL of H2O for 12 h unless
otherwise noted.
b Isolated yields.
c Conversion in parenthesis.
17

Scheme 1. The catalyzed-arylation of 2-phenylpyridine N-oxides
18

Scheme 2. Deoxygenation of 2-(2-phenylphenyl)pyridine-N-oxide by zinc powder.
19

Scheme 3. Synthesis of compound 6. a. Pd(PPh3)4, K2CO3, toluene/CH3CH2OH (7.5:1),
80 oC, 48 h, 81% yield; b. H2O2; c. Pd(OAc)2, AgOTf, TBAB, H2O, 100 oC, 12 h, 78%
yield; d. zinc powder, THF, NH4Cl, 10 h, 92% yield.
20

Figure 1. Examples of bioactive 2-(2-phenylphenyl)pyridine
21

Figure 2. The crystal structure of compound 3t
22

Figure 3. Proposed plausible catalytic pathway
23

Figure 4. The crystal structure of compound 6
24