Cu-mediated selective O-arylation on C-6 substituted pyridin-2-ones

Article abstract of DOI:10.1016/j.tetlet.2012.12.126

A practical and mild strategy has been developed for the selective O-arylation on C-6 substituted pyridin- 2-ones with a series of arylboronic acids, using Cu(OTf)₂ as the catalyst, DABCO as the ligand, Et3N as the base, and K₂HPO₄ as the additive. This method affords O-arylated pyridin-2-ones with good selectivity and yields. Copyright

Full text of DOI:10.1016/j.tetlet.2012.12.126

Tetrahedron Letters 54 (2013) 1401–1404
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Tetrahedron Letters
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Cu-mediated selective O-arylation on C-6 substituted pyridin-2-ones
Taijie Chen a, Qingqing Huang b, Yu Luo a, , Youhong Hu c, , Wei Lu b
⇑
⇑
a Department of Chemistry, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China
b Institute of Drug Discovery and Development, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China
c Shanghai Institute of Materia Medica, Chinese Academy of Science, 555 Zu Chong Zhi Road, Shanghai 201203, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A practical and mild strategy has been developed for the selective O-arylation on C-6 substituted pyridin-
2-ones with a series of arylboronic acids, using Cu(OTf)2 as the catalyst, DABCO as the ligand, Et3N as the
base, and K2HPO4 as the additive. This method affords O-arylated pyridin-2-ones with good selectivity
and yields
Received 28 September 2012
Revised 20 December 2012
Accepted 28 December 2012
Available online 10 January 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Chan–Evans–Lam cross-coupling
Arylboronic acids
Selectivity
O-arylation
Pyridin-2-ones
Transition metal-mediated carbon–carbon and carbon–hetero-
atom coupling reactions are important tools in organic synthesis
and have been widely used in the synthesis of natural products
and pharmaceutical agents. Compared to palladium and other
transition metals, copper salts are less toxic, less expensive,
earth-abundant, and stable in air. Thus, copper-catalyzed cross-
coupling has attracted many chemists’ interest. The traditional Ull-
mann and Goldberg procedures played an important role in the
synthesis of biaryl ethers. However, vigorous reaction conditions,
such as high temperature, stoichiometric amounts of catalysts,
and specific halide substrates, limited the use of this methodology.
In 1998, Chan,1 Evans,2 and Lam3 developed a new copper-cata-
lyzed N/O-arylation methodology, using aryl boronic acids as the
substrates. This method has been soon proven to be a powerful
and attractive synthetic tool to construct carbon–heteroatom bond
and widely used in the synthesis of many biologically active
compounds.4,5
To date, many compounds with the 2-aryloxypyridine moiety
have been reported to show various biological activities, such as
herbicidal activity,6 antispasmodic activity,7 anti-bacterial activ-
ity,8 M5 positive allosteric modulators activity,9 anti-mycobacte-
rial activity,10 obesity-induced insulin resistance inhibitive
activity, and anticancer activity.11 Since 2-aryloxypyridine deriva-
tives widely occur in biologically active molecules and chemical
products, it is highly desired to develop a practical and efficient ap-
proach to diverse 2-aryloxypyridine derivatives.
Although several accounts of N-arylation of pyridin-2-ones with
aryl halides12,13 or arylboronic acids14 have been reported, few lit-
eratures exist on the selective O-arylation of pyridin-2-ones.15
Herein, we present a selective O-arylation method on C-6 substi-
tuted pyridin-2-ones, using Chan–Evans–Lam cross-coupling
reaction.
To screen suitable reaction conditions, we focused on the cou-
pling of 6-methyl pyridin-2-ones (1) and phenylboronic acid (2).
As shown in Table 1, among the six copper catalysts screened,
Cu(OTf)2 gave a 30% yield of O-arylated compound 3. Although
the N/O selectivity was not satisfactory (41% yield of N-arylated
compound 4 obtained), Cu(OTf)2 was still the most effective cata-
lyst. Cu(NO3)2ꢀ3H2O (entry 4) could also produce the desired prod-
uct 3, nevertheless the yield was slightly lower than that of
Cu(OTf)2. Thus, Cu(OTf)2 was determined as the appropriate cata-
lyst and was used in the subsequent screening.
Secondly, different solvents were surveyed as shown in entries
7–11. It was found that both the yield and the selectivity of O-ary-
lation were dramatically improved by using DMSO as the solvent
(entry 8).
Subsequently, different ligands were investigated (entries 12–
16). The most surprising results were obtained when DABCO was
used as the ligand, which produces only O-arylated compound 3
without N-arylated product in 28% yield.
⇑
Corresponding authors. Tel./fax: +86 21 6260 2475 (Y.L.); tel./fax: +86 21 5080
5896 (Y.H.).
Recently, some literatures clarified16,17 the significance of base
and K2HPO4 in Cu(II)-mediated couplings. Bases, such as Et3N could
capture hydrogen proton and thus promote the formation of the
E-mail addresses: yluo@chem.ecnu.edu.cn (Y. Luo), yhhu@mail.shcnc.ac.cn
(Y. Hu).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.126

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T. Chen et al. / Tetrahedron Letters 54 (2013) 1401–1404
Table 1
Survey of copper salts with TMEDAa
B(OH)2
N
O
N
H
O
N
O
3
2
4
1
Entry
Copper source
Solvent
Ligand
Additive
3/Yieldb (%)
4/Yieldb (%)
1
Cu(OTf)2
Cu(OAc)2
CuSO4
CH2CI2
CH2CI2
CH2CI2
CH2CI2
CH2CI2
CH2CI2
CH3CN
DMSO
DMF
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
TMEDA
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
—
30
/
/
20
/
/
41
/
/
10
/
/
/
9
/
/
/
/
/
/
/
/
/
/
2c
3d
4
Cu(NO3)2ꢀ3H2O
5c
CuCI2
6c
CuI
7c
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
/
8
45
10
/
/
/
/
/
28
/
44
85
9c
TMEDA
TMEDA
TMEDA
1,2-Ethanediamine
N,N0-Dimethyl-1,2-ethanediamine
Cyclohexane-1,2-diamine
DABCO
1,10-Phenanthroline
DABCO
DABCO
10c
11c
12c
13c
14c
15c
16c
17c
18c,d
CH3OH
H2O
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
Et3N/K2HPO4
Et3N/K2HPO4
a
Unless otherwise indicated, the reaction conditions were as following: compound 1 (1 equiv), compound 2 (2 equiv), copper source (20 mol %), ligand (20 mol %), additive
(2 equiv), 2 mL solvent, rt, air, 5 h.
b
Isolated yields.
Compound 3 or 4 is trace.
Under 50 °C.
c
d
Table 2
Table 2 (continued)
Expansion of the C-6 substituted pyridin-2(1H)-one
Entry
Product
Yielda (%)
50
B(OH)2
CF3
R
N
O
+
R
N
H
7
8
O
N
O
N
Entry
1
Product
Yielda (%)
65
F3C
81
O
N
O
N
General reaction conditions: 0.2 mmol of 2-hydroxypyridines, 0.4 mmol of phen-
ylboronic acid, 0.04 mmol of Cu(OTf)2 0.04 mmol of triethylenediamine, 0.4 mmol
Et3N, 0.4 mmol of K2HPO4, 2 mL DMSO, 50 °C for 5 h in air.
2
3
74
40
O
a
Isolated yields.
N
N
O
O
Cu(II) complex, while K2HPO4 could avoid the decomposition of
phenylboronic acid (2) to some extent. Thus, addition of Et3N
and K2HPO4 into the reaction was attempted (entry 17), which
gave a slightly improved yield (44%). When the temperature was
elevated to 50 °C, the yield was improved up to 65% (entry 18).
Unfortunately, the yield could not be further improved because
of the inevitability of the decomposition of phenylboronic acid.
Finally, the optimal conditions for the selective O-arylation18
were determined as following: 20 mol % of Cu(OTf)2 as the catalyst,
20 mol % of DABCO as the ligand, Et3N as the base and K2HPO4 as
the additives and at 50 °C for no more than 5 h.
H3CO
OCH3
4
5
50
61
N
O
H3CO
With the method18 in hand, a series of C-6 substituted pyridin-
2-ones was subjected to the coupling reaction with phenylboronic
acid (2), as illustrated in Table 2, O-arylated compounds were ob-
tained in moderate to good yields (40–81%). It was obvious that the
C-6 substituent could influence the yield of this reaction. The
N
O
6
58
F3C

T. Chen et al. / Tetrahedron Letters 54 (2013) 1401–1404
1403
Table 3
on the phenyl ring decreased the yield (entries 3–5), compared to
that of electron withdrawing groups (entries 6–8). As desired, no
N-arylated product was found in this way.
Expansion of the substituted phenylboronic acid
B(OH)2
As shown in Table 3, the effect of different substituents on
phenylboronic acid was also explored18. And, any substitution on
the boronic acid would impede the coupling reaction accordingly.
Among them, electron-rich phenylboronic acid with the electron-
donating group facilitated the coupling reaction, when compared
to the corresponding one with the electron-withdrawing group
on the phenyl ring. However, no products were obtained with o-
substituted phenylboronic acids, which implied that the reaction
was very sensitive to steric effects for these substituted phenylbo-
ronic acids.
R
+
N
H
O
N
O
R
Entry
Product
Yielda (%)
OCH3
1
2
46
On the basis of the Chan–Lam coupling reaction mechanism and
our experiment (Table 1, entries 1 and 18), we believed that there
were two crucial factors to the regioselectivity. And as shown in
Figure 1, the most important one is the steric hindrance of DABCO
catalyst system which could impede the formation of N-Cu(II)
unstable intermediate. The other is the steric hindrance of
C6-substitution such as the methyl. As shown in Scheme 1, unfor-
tunately, substituent effect on other sites of pyridin-2-one was
investigated18, this regioselectivity was not evident.
In conclusion, we have developed a mild and efficient method of
selective O-arylation on C-6 substituted 2-hydroxypyridines using
Chan–Evans–Lam cross-coupling reactions under very mild
conditions.
N
N
O
O
Trace
OCH3
3
4
56
23
N
O
OCH3
CF3
N
N
O
O
5
6
Trace
31
Acknowledgments
CF3
This work was supported by the grants of The National Natural
Science Foundation of China (No. 81172936 and No. 21102046)
and grants of The Fundamental Research Funds for the Central Uni-
versities. We also thank the Laboratory of Organic Functional Mol-
ecules, the Sino-French Institute of ECNU for support.
N
O
CF3
General reaction conditions: 0.2 mmol of 2-hydroxypyridines, 0.4 mmol of phen-
ylboronic acid, 20 mol % of Cu(OTf)2, 20 mol % of triethylenediamine, 2 equiv Et3N,
2 equiv of K2HPO4, 2 mL DMSO, 50 °C for 5 h in air.
a
Isolated yields.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
12.126. These data include MOL files and InChiKeys of the most
important compounds described in this article.
N
N
N
N
N
N
N
N
TfO
Cu II
TfO
Cu II
O
N
References and notes
O
N
1. Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P. Tetrahedron Lett. 1998,
39, 2933–2936.
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3. Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M. P.; Chan, D. M. T.;
Combs, A. Tetrahedron Lett. 1998, 39, 2941–2944.
4. Sanjeeva Rao, K.; Wu, T.-S. Tetrahedron 2012, 68, 7735–7754.
5. Qiao, J.; Lam, P. Synthesis 2010, 2011, 829–856.
unstable intermedate
stable intermedate
Figure 1. The plausible intermediate of Chan–Lam reaction.
6. Fujikawa, K.-i.; Kondo, K.; Yokomichi, I.; Kimura, F.; Haga, T.; Nishiyama, R.
Agric. Biol. Chem. 1970, 34, 68–79.
B(OH)2
OCH3
7. Hill, A. J.; McGraw, W. J. J. Org. Chem. 1949, 14, 783–789.
8. Glinka, T.; Rodny, O.; Bostian, K. A.; Wallace, D. M.; Higuchi, R. I.; Chow, C.;
Mak, C. C.; Hirst, G.; Eastman, B.; U.S. Patent 0152098A1, 2010.
9. Bridges, T. M.; Kennedy, J. P.; Hopkins, C. R.; Conn, P. J.; Lindsley, C. W. Bioorg.
Med. Chem. Lett. 2010, 20, 5617–5622.
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H.; Gegina, Y.; Knudson, D. L.; Johnson, F.; Peloquin, C. A.; Slayden, R. A.; Tonge,
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Kamenecka, T. M. Bioorg. Med. Chem. Lett. 2011, 21, 7072–7075.
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14. Mederski, W. W. K. R.; Lefort, M.; Germann, M.; Kux, D. Tetrahedron 1999, 55,
12757–12770.
H3CO
O
N
+
N
H
O
the main product 6
5
2
yield: 34%
Scheme 1. Substituent effect on other sites of pyridin-2-one. General reaction
conditions: 0.2 mmol of 2-hydroxypyridines, 0.4 mmol of phenylboronic acid,
0.04 mmol of Cu(OTf)2, 0.04 mmol of triethylenediamine, 0.4 mmol Et3N, 0.4 mmol
of K2HPO4, 2 mL DMSO, 50 °C for 5 h in air.
15. Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F.; Taillefer, M. Chem. Eur. J. 2004, 10,
5607–5622.
16. Singh, B. K.; Appukkuttan, P.; Claerhout, S.; Parmar, V. S.; Van der Eycken, E.
Org. Lett. 2006, 8, 1863–1866.
6-phenyl substituent was slightly better than 6-methyl one (en-
tries 1 and 2). In addition, the presence of electron donating groups

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T. Chen et al. / Tetrahedron Letters 54 (2013) 1401–1404
17. Collman, J. P.; Zhong, M.; Zeng, L.; Costanzo, S. J. Org. Chem. 2001, 66, 1528–
1531.
18. General procedure for O-arylation reaction: A mixture of C-6 substituents of
pyridin-2-one (0.2 mmol), related arylboronic acid (0.4 mmol), Cu(OTf)2
(20 mol %), DABCO (20 mol %), Et3N (0.4 mmol), K2HPO4 (0.4 mmol) followed
by DMSO (2 mL) was stirred at in a 25 mL round bottom flask with calcium
chloride tube for 5 h. The mixture was cooled to rt, water (12 mL) was added
and extracted with dichloromethane (20 mL) for three times. The organic
phases were combined, washed with brine, and dried over Na2SO4, and the
solvent was distilled under reduced pressure. The residue was purified by
column chromatography [CH2Cl2/petroleum ether (60–90 °C) 1:20] to afford
the product.