Copper-catalyzed domino oxidation-acyloxylation reaction of 2-arylpyridines with aldehydes or methylarenes

Article abstract of DOI:10.1055/s-0030-1261224

A domino oxidation-acyloxylation reaction of 2-arylpyridines with aldehydes or methylarenes under the catalysis of Cu(OAc)has been developed. The strategy via C-H bond functionalization has the advantages of good functional-group tolerance, high ortho reg

Full text of DOI:10.1055/s-0030-1261224

LETTER
2407
Copper-Catalyzed Domino Oxidation–Acyloxylation Reaction of
2-Arylpyridines with Aldehydes or Methylarenes
Domino
O
xidation
o
–Acyloxylat
n
ion Reaction
g
s
of 2-Arylpy
-
r
idines
J
ith
A
lde
u
hyde
s
n Bian,a Chang-Bing Xiang,a Zhi-Ming Chen,a Zhi-Zhen Huang*a–c
a
School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, P. R. of China
Fax +86(25)83686231.; E-mail: huangzz@nju.edu.cn
b
c
Department of Chemistry, Zhejiang University, Hangzhou 310028, P. R. of China
State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071, P. R. of China
Received 4 June 2011
ifyingly, the desired ortho-acyloxylated product 3a was
obtained in 23% yield when Cu(OTf)2 and tert-butyl hy-
droperoxide (TBHP) was used as a catalyst and an oxidant
in chlorobenzene, respectively (Table 1, entry 1).
Abstract: A domino oxidation–acyloxylation reaction of 2-aryl-
pyridines with aldehydes or methylarenes under the catalysis of
Cu(OAc)2 has been developed. The strategy via C–H bond func-
tionalization has the advantages of good functional-group tolerance,
high ortho regioselectivity and no need of any ligand or additive.
Subsequently, various copper and other transition-metal
catalysts were examined in the reaction (Table 1, entries
2–9). Among them, Cu(OAc)2 proved to be best to give
the desired acyloxylated product 3a in 54% yield
(Table 1, entry 7). When oxygen was used as an oxidant
Key words: C–H activation, copper catalysis, domino reaction,
acyloxylation, oxidation
Carbon–oxygen bond formation via C–H bond function-
alization has been paid much attention in recent years, due
to a lot of bioactive or medicinal compounds containing
oxygen atoms.1–4 Among them, great interest has been fo-
cused on the ortho C–O bond formation of 2-arylpyridines
via C–H activations.2–4 In 2004 and 2005, Sanford’s re-
search group disclosed palladium-catalyzed ortho-acetox-
ylations of 2-arylpyridines using PhI(OAc)2 as an
oxidant.2a,b In 2009, Cheng et al. reported Rh-catalyzed
ortho-benzoxylation of 2-arylpyridines with carboxylic
acid in the presence of a preligand and an additive.3a Sub-
sequently, they also demonstrated copper-catalyzed
ortho-acyloxylations of 2-arylpyridines with carboxylic
anhydrides or acyl chlorides.3b,c On the other hand, domi-
no reactions can decrease environmental impacts as well
as productive costs, and have great potential to be widely
used in the synthesis of natural products and pharmaceu-
ticals, chemical industry, etc.5 Recently, Li’s research
group reported the domino acylation reaction of 2-aryl-
pyridines with alcohols which were oxidized to aldehydes
in situ.6 However, to the best of our knowledge, there is no
report on a domino acyloxylation reaction of 2-aryl-
pyridines for the formation of a C–O bond. Considering
that aldehydes or methylarenes are readily oxidized to
correponding carboxylic acids under the catalysis of cop-
per catalysts,7 we envisioned to carry out the studies on
copper-catalyzed domino oxidation–acyloxylation reac-
tions of 2-arylpyridines with aldehydes or methylarenes
via C–H bond functionalization.
Table 1 Optimization of the Reaction Conditions of 2-Phenylpyri-
dine (1a) with 4-Methylbenzaldehyde 2aa
O
N
CH3
N
[M]
H
+
O
oxidant,
solvent
H3C
O
1a
Entry
1
2a
3a
Metal cat.
Cu(OTf)2
CuBr
Oxidant
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
Yield (%)b
23
13
18
51
43
31
54
0
2
3
CuCl
4
CuI
5
Cu(acac)2
CuCl2
6
7
Cu(OAc)2
8
Zn(OAc)2×4H2O
Pd(OAc)2
9
<5
37
51c
56d
46e
10
11
12
13
Cu(OAc)2
O2 (1 atm)
TBHP
Cu(OAc)2
Cu(OAc)2
TBHP
Initially, the reaction of 2-phenylpyridine (1a) with 4-
methylbenzaldehyde (2a) was chosen as a model reaction
for the optimization of domino-reaction conditions. Grat-
Cu(OAc)2
TBHP
a Conditions: 1a (0.25 mmol), 2a (0.5 mmol), metal cat. (0.025 mmol,
10mol%), tert-butyl hydroperoxide (TBHP) (2.0 equiv, 5.5 M in de-
cane), in PhCl, 135 °C, 24 h.
b Isolated yield.
SYNLETT 2011, No. 16, pp 2407–2409
x
x
.x
x
.2
0
1
1
c Under N2.
Advanced online publication: 08.09.2011
DOI: 10.1055/s-0030-1261224; Art ID: W13211ST
© Georg Thieme Verlag Stuttgart · New York
d 20 mol% Cu(OAc)2 were used.
e 1.0 equiv TBHP was used.

2408
Y.-J. Bian et al.
LETTER
instead of TBHP, the yield of 3a was reduced to 37% phenylpyridines 1 and aldehydes 2 could undergo the
(Table 1, entry 10). In addition, the amount of Cu(OAc)2 domino reaction smoothly in mild conditions to give the
and TBHP had slight effects on the reaction (Table 1, en- desired ortho-acyloxylated products 3a–n (Table 2). Our
tries 12 and 13). Solvent was also crucial for this reaction. experiment also demonstrated that the reaction could tol-
When using solvents such as DMSO, MeCN, DMF, or erate various functional groups, such as methoxyl, bromo,
NMP other than chlorobenzene, no desired product 3a chloro, fluoro, and nitro groups. Electron-donating groups
was observed (see Supporting Information). A small on the benzene rings of aromatic aldehydes seem more
amount of diacyloxylated product was also obtained, and beneficial for this transformation than electron-withdraw-
no acylated product was observed in the reaction. Nota- ing groups (Table 2, compare entries 1 and 3 with entries
bly, in the absence of a copper catalyst, no desired product 4–7). The position of the substituents on the benzene rings
3a was obtained.
of aromatic aldehydes 2 have effects on the reaction
yields. When the substituents were located at the ortho or
meta position, the yields decreased significantly (Table 2,
compare entries 1, 3, and 6 with entries 8–10, respective-
ly). To our delight, aliphatic aldehydes could also result in
desired ortho-acyloxylation products 3k,l (Table 2, en-
tries 11 and 12). In all cases except for aliphatic alde-
hydes, a small amount of diacyloxylated products were
isolated.
Table 2 The Domino Oxidation–Acyloxylation Reaction of 2-
Arylpyridines with Aldehydes8
O
Cu(OAc)2 (10 mol%)
TBHP (2.0 equiv)
N
N
O
R2
+
R2
H
PhCl, 135 °C
O
R1
R1
1
2
3
Table 3 The Domino Oxidation–Acyloxylation Reaction of 2-
Arylpyridines with Methylarenesa
3a: R1 = H, R2 = 4-CH3C6H4
3b: R1 = H, R2 = C6H5
3h: R1 = H, R2 = 2-CH3C6H4
3i: R1 = H, R2 = 3-CH3OC6H4
3j: R1 = H, R2 = 3-BrC6H4
3c: R1 = H, R2 = 4-CH3OC6H4
3d: R1 = H, R2 = 4-FC6H4
3e: R1 = H, R2 = 4-ClC6H4
3f: R1 = H, R2 = 4-BrC6H4
3g: R1 = H, R2 = 4-NO2C6H4
3k: R1 = H, R2 = n-CH3(CH2)3
3l: R1 = H, R2 = n-CH3(CH2)2
R3
N
Cu(OAc)2 (10 mol%)
TBHP (4.0 equiv)
CH3
N
3m: R1 = 4-CH3, R2 = 4-CH3C6H4
3n: R1 = 2-CH3O, R2 = 4-CH3C6H4
+
neat, 135 °C
O
R3
R1
Entry
1
R1
R2
2a 4-MeC6H4
Yield (%)a
O
R1
1
4
3
1a H
1a H
1a H
1a H
1a H
1a H
1a H
1a H
1a H
1a H
1a H
1a H
1b 4-Me
1c 2-MeO
54
45
51
40
38
38
32
36
41
33
28b
30b
37
42
3a: R1 = H, R3 = 4-CH3
3o: R1 = H, R3 = 4-CN
3c: R1 = H, R3 = 4-CH3O 3p: R1 = H, R3 = 3-CH3
2
2b Ph
3d: R1 = H, R3 = 4-F
3e: R1 = H, R3 = 4-Cl
3l: R1 = 4-CH3, R3 = 4-CH3
3m: R1 = 2-CH3O, R3 = 4-CH3
3
2c 4-MeOC6H4
2d 4-FC6H4
2e 4-ClC6H4
2f 4-BrC6H4
2g 4-O2NC6H4
2h 2-MeC6H4
2i 3-MeOC6H4
2j 3-BrC6H4
2k n-Bu
'
4
Entry
R1
R3
Yield (%)b
5
1
2
3
4
5
6
7
8
1a H
4a 4-Me
4c 4-MeO
4d 4-F
42
38
20
33
24
40
28
33
6
1a H
7
1a H
8
1a H
4e 4-Cl
9
1a H
4o 4-CN
4p 3-Me
4a 4-Me
4a 4-Me
10
11
12
13
14
1a H
1b 4-Me
1c 2-MeO
2l n-Pr
2a 4-MeC6H4
2a 4-MeC6H4
a Conditions: 1 (0.25 mmol), 2 (7.4 mmol), Cu(OAc)2 (0.025 mmol),
TBHP (4 equiv, 5.5 M in decane), 135 °C, 30 h.
b Isolated yield.
a Isolated yield.
b 40 h.
The pathway of the domino reaction may be as following.
First, aldehyde 2 was oxidized to the corresponding car-
boxylic acid under the catalysis of copper.7a Then, the car-
boxylic acid undergoes the oxidative coupling reaction
with 2-arylpyridine 1 by C–H bond activation to give the
desired ortho-acyloxylated product 3 through the mecha-
nism reported in the literature.3b Considering that benzylic
After screening of reaction conditions, it can be concluded
that the optimized reaction should be performed under the
catalysis of 10 mol% Cu(OAc)2 using TBHP as an oxidant
and chlorobenzene as a solvent at 135 °C. Under the opti-
mal conditions, it was found that various substituted 2-
Synlett 2011, No. 16, 2407–2409 © Thieme Stuttgart · New York

LETTER
Domino Oxidation–Acyloxylation Reactions of 2-Arylpyridines with Aldehydes
2409
alcohols or methylarenes can be oxidized to the corre-
sponding benzaldehydes, and then be further oxidized to
benzoic acids, benzyl alcohol and 4-chlorotoluene 4e
were chosen as substrates instead of benzaldehyde to
probe this transformation. The experiment showed that no
reaction was occurred in chlorobenzene as the case of
benzaldehyde. When the reactions were performed under
solvent-free conditions, it was found that 4-chlorotoluene
could lead to the desired ortho-acyloxylated product 3e,
and no desired acyloxylated product was obtained using
benzyl alcohol.
References and Notes
(1) Papers on C–O bond formations via C–H bond
functionalizations: (a) Jiang, H.-F.; Chen, H.-J.; Wang,
A.-Z.; Liu, X.-H. Chem. Commun. 2010, 46, 7259. (b) Zhu,
M.-K.; Zhao, J.-F.; Loh, T.-P. J. Am. Chem. Soc. 2010, 132,
6284. (c) Van Humbeck, J. F.; Simonovich, S. P.; Knowles,
R. R.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132,
10012. (d) Terent’ev, A. O.; Borisov, D. A.; Yaremenko, I.
A.; Chernyshev, V. V.; Nikishin, G. I. J. Org. Chem. 2010,
75, 5065. (e) Mills, D. P.; Soutar, L.; Lewis, W.; Blake,
A. J.; Liddle, S. T. J. Am. Chem. Soc. 2010, 132, 14379.
(f) Wang, G.-W.; Yuan, T.-T. J. Org. Chem. 2010, 75, 476.
(g) Ueda, S.; Nagasawa, H. J. Org. Chem. 2009, 74, 4272.
(h) Wang, G.-W.; Yuan, T.-T.; Wu, X.-L. J. Org. Chem.
2008, 73, 4717. (i) Lee, J. M.; Park, E. J.; Cho, S. H.; Chang,
S. J. Am. Chem. Soc. 2008, 130, 7824.
After the optimization with 2-phenylpyridine (1a) and 4-
chlorotoluene (4e) as model substrates (see Supporting In-
formation), it was concluded that the optimized reaction
should be performed by the catalysis of 10 mol%
Cu(OAc)2 using TBHP as an oxidant under neat condi-
tions at 135 °C. It was noteworthy that if either Cu(OAc)2
or TBHP was present, no desired product was obtained.
Under the optimal conditions, our experiment demonstrat-
ed that various substituted 2-phenylpyridines 1 and meth-
ylarenes 49 could undergo the domino reaction smoothly
in mild conditions to give the desired ortho-acyloxylated
product 3 (Table 3). The result also indicated that the
domino reaction could tolerate various functional groups
as well, such as methoxyl, chloro, fluoro, and cyano
groups. Similar to that using aromatic aldehydes, elec-
tron-donating groups on benzene rings of methylarenes 4
led to better yields than electron-withdrawing groups
(Table 3, compare entries 1, 2, 6 with entries 3–5). In
some cases, a trace amount of diacyloxylated products
were observed.
(2) (a) Dick, A. R.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc.
2004, 126, 2300. (b) Kalyani, D.; Sanford, M. S. Org. Lett.
2005, 4, 4149. (c) Racowski, J. M.; Dick, A. R.; Sanford,
M. S. J. Am. Chem. Soc. 2009, 131, 10974.
(3) (a) Ye, Z.-S.; Wang, W.-H.; Luo, F.; Zhang, S.-H.; Cheng, J.
Org. Lett. 2009, 11, 3974. (b) Wang, W.-H.; Luo, F.; Zhang,
S.-H.; Cheng, J. J. Org. Chem. 2010, 75, 2415. (c) Wang,
W.-H.; Pan, C.-D.; Chen, F.; Cheng, J. Chem. Commun.
2011, 47, 3978.
(4) Chen, X.; Hao, X.-S.; Goodhua, C. E.; Yu, J.-Q. J. Am.
Chem. Soc. 2006, 128, 6790.
(5) A book and reviews on domino or cascade reactions:
(a) Tietze, L. F.; Brasche, G.; Gericke, K. Domino Reactions
in Organic Synthesis; Wiley-VCH: Weinheim, 2006.
(b) Tietze, L. F. Chem. Rev. 1996, 96, 115. (c) Wasilke, J.
C.; Obrey, S. J.; Baker, R. T.; Bazan, G. C. Chem. Rev. 2005,
105, 1001. (d) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P.
G. Angew. Chem. Int. Ed. 2006, 45, 7134. (e) Enders, D.;
Grondal, C.; Hüttl, M. R. M. Angew. Chem. Int. Ed. 2007,
46, 1570. (f) Grondal, C.; Jeanty, M.; Enders, D. Nature
Chem. 2010, 2, 167. (g) Westermann, B.; Ayaz, M.; Berkel,
S. S. Angew. Chem. Int. Ed. 2010, 49, 846.
(6) Xiao, F.-H.; Shuai, Q.; Zhao, F.; Baslé, O.; Deng, G.-J.; Li,
C.-J. Org. Lett. 2011, 13, 1614.
(7) (a) Mannam, S.; Sekar, G. Tetrahedron Lett. 2008, 49,
1083. (b) Shaikh, T. M. A.; Sudalai, A. Eur. J. Org. Chem.
2008, 4877. (c) Rogovin, M.; Neumann, R. J. Mol. Catal. A:
Chem. 1999, 138, 315.
(8) General Procedure for the Oxidation–Acyloxylation
Reaction of 2-Arylpyridine 1 with Aldehydes 2
To a mixture of 2-arylpyridine (0.25 mmol), aldehyde (0.5
mmol), Cu(OAc)2 (10 mol%, 4.5 mg), and chlorobenzene (2
mL) was added tert-butyl hydroperoxide (2 equiv, 5.5 M in
decane) dropwise at r.t. The reaction mixture was stirred at
135 °C for 24 h. After the reaction, EtOAc (10 mL) was
added, and the mixture was washed with aq NaOH (1 M, 5
mL), H2O (10 mL), and brine (10 mL), respectively. The
filtrate was dried over Na2SO4 and then concentrated in
vacuo. The residue was purified by column chromatography
(silica gel, PE–EtOAc as eluent) to afford the desired
products 3a–n.
In conclusion, we have developed a domino oxidation–
acyloxylation reaction of 2-arylpyridines with aldehydes
or methylarenes under the catalysis of Cu(OAc)2. The
strategy for the formation of C–O bond via C–H bond
functionalization has the advantages of good functional-
group tolerance, high ortho regioselectivity, using inex-
pensive Cu(OAc)2, and no need of any ligand or additive.
Further investigations on the domino oxidation–acyloxy-
lation reaction using other substrates than 2-arylpyridines
for C–H bond activations are currently under way.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
Financial supports from National Natural Science Foundation of
China (No. 20872059 and 21072091) and MOST of China (973 pro-
gram 2011CB808600) are gratefully acknowledged.
(9) Unexpectedly, when toluene was employed under the
optimal conditions, only a trace amount of benzoxylated
product was obtained.
Synlett 2011, No. 16, 2407–2409 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.