Direct 2-acetoxylation of quinoline N-oxides via copper catalyzed C-H bond activation

Article abstract of DOI:10.1039/c3cc43947j

An efficient and direct 2-acetoxylation of quinoline N-oxides via copper(i) catalyzed C-H bond activation has been developed. This transformation was achieved using TBHP as an oxidant in the cross-dehydrogenative coupling (CDC) reaction of quinoline N-oxides with aldehydes, and provided a practical pathway to 2-acyloxyl quinolines.

Full text of DOI:10.1039/c3cc43947j

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
Direct 2-acetoxylation of quinoline N-oxides via copper
catalyzed C–H bond activation†
Xuan Chen,a Chongwei Zhu,a Xiuling Cui*ab and Yangjie Wu*a
Cite this: Chem. Commun., 2013,
49, 6900
Received 26th May 2013,
Accepted 11th June 2013
DOI: 10.1039/c3cc43947j
www.rsc.org/chemcomm
An efficient and direct 2-acetoxylation of quinoline N-oxides via
copper(I) catalyzed C–H bond activation has been developed. This
transformation was achieved using TBHP as an oxidant in the
cross-dehydrogenative coupling (CDC) reaction of quinoline
N-oxides with aldehydes, and provided a practical pathway to
2-acyloxyl quinolines.
Esters are ubiquitous and important functional groups, prevalent
in a wide range of organic compounds: natural products, polymers,
and fine chemicals.1 Conventionally, esters were synthesized by the
esterification of alcohols with carboxylic acids, acyl halides and
anhydrides in the presence of a strong acid or base, which results
in a multistep transformation accompanied by pollution and
waste.2 In the past decade, transition-metal catalyzed oxidative
esterification of aldehydes with alcohols, boronic acids and aryl
halides has provided a convenient alternative approach to prepare
esters (Scheme 1, path A).3 However, stoichiometric amounts of
metal salt as an oxidant, complicate ligand and excess Lewis acid or
base as additives are required, which make these transformations
environmentally unfriendly. Recently, the cross-dehydrogenative
coupling (CDC) reaction has emerged as a powerful protocol for
C–C, C–heteroatom bond formation.4 Such a strategy is attractive
because it avoids pre-functionalization and provides a more direct
approach to build a carbogenic core of complicated molecules.
Several examples of constructing esters using this strategy have
emerged.5 For example, Wang6 and Patel7 groups have reported
pioneering work on the benzylic C–H acyloxylation of alkylarenes
catalyzed by copper and Bu4NI. However, this procedure is only
limited to benzylic C–H bond activation.
Scheme 1 Different approaches for synthesizing esters.
On the other hand, 2-acyloxyl quinoline is an important
skeleton in drugs used in the treatment of neurological and
psychiatric disorders including schizophrenia, mania, anxiety
and bipolar disorder (Scheme 2).8 Building such skeletons still
relies on prefunctionalized quinoline derivatives and acyl chloride
or lactams, and gives up to only 37% yield.8,9 The direct and
efficient catalytic transformation via dual C–H bond activation to
2-acyloxyl quinoline has not been exploited. Herein, we utilized
quinoline N-oxides and aldehydes as the substrates, tert-butyl
hydroperoxide (TBHP) as an oxidant and Cu(I) as a catalyst to
a Department of Chemistry, Henan Key Laboratory of Chemical Biology and
Organic Chemistry, Key Laboratory of Applied Chemistry of Henan Universities,
Zhengzhou University, Zhengzhou, 450052, P. R. China. E-mail: cuixl@zzu.edu.cn,
wyj@zzu.edu.cn; Tel: +86 371-67767753
b School of Biomedical Sciences, Engineering Research Center of Molecular Medicine
of Chinese Education Ministry, Xiamen Key Laboratory of Ocean and Gene Drugs,
Institute of Molecular Medicine of Huaqiao University, Huaqiao University,
Xiamen, 361021, P. R. China
† Electronic supplementary information (ESI) available: Detailed experimental
procedures and spectroscopic data. See DOI: 10.1039/c3cc43947j
Scheme 2 Examples illustrating the importance of 2-carboxyl quinoline.
c
6900 Chem. Commun., 2013, 49, 6900--6902
This journal is The Royal Society of Chemistry 2013

View Article Online
Communication
ChemComm
Table 1 Screening reaction parameters for the reaction of quinoline N-oxide 1a
with benzaldehyde 2aa
Table 2 2-Acetoxylation of quinoline N-oxides with aldehydesa
Entry
Catalyst
Oxidant
Solvent
T/1C
t/h
Yieldb
1
2
3
4
5
6
7
8
CuBr
—
CuBr
CuI
TBHPc
H2O2
H2O2
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCE
DCE
DCE
Dioxane
DMSO
MeOH
DCE
40
40
40
40
40
40
40
70
70
70
70
70
70
70
70
70
70
48
60
60
48
48
48
48
24
24
24
24
24
24
24
12
8
57
n.r.
n.r.
30
47
39
67
69
11
52
n.r.
n.r.
n.r.
77
72
84
TBHPc
TBHPc
TBHPc
TBHPd
TBHPd
TBHPd
TBHPd
TBHPd
TBHPd
TBHPd
TBHPd
TBHPd
TBHPd
TBHPd
CuBr2
Cu(OAc)2
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuOTf
CuOTf
CuOTf
CuOTf
9e
10 f
11
12
13
14
15
16
17
DCE
DCE
DCE
4
71
a
Conditions: 1a (0.2 mmol), 2a (0.6 mmol), oxidant (0.6 mmol), solvent
(2 mL), catalyst (5 mol%). b Isolated yields. TBHP (70 aq.%). d TBHP
c
(5–6 M in decane). 3 mol% CuBr. f 10 mol% CuBr. n.r. = no reaction.
e
synthesize a series of 2-acyloxyl quinoline N-oxides under mild,
operationally simple and environmentally friendly conditions
(Scheme 1, path B).
The condensation of quinoline N-oxide 1a with benzaldehyde 2a
was initially chosen as a model reaction to screen the reaction
parameters. The results are listed in Table 1. To our delight, the
desired product 3a was observed with an isolated yield of 57% in
CH2Cl2 (DCM), using 5 mol% CuBr as a catalyst and 70% TBHP in
water as an oxidant (entry 1, Table 1). Product 3a was not detected
with or without a catalyst using H2O2 as an oxidant instead of TBHP
(entries 2–3, Table 1). CuBr provided a higher yield compared to
other Cu salts tested, such as CuI, CuBr2 and Cu(OAc)2 (entry 1 vs.
4–6, Table 1). TBHP in decane (5–6 M) could improve this transfor-
mation and give the desired product 3a in 67% yield (entry 7,
Table 1). The yield could be increased slightly to 69% when the
temperature was increased up to 70 1C (entry 8, Table 1). Changing
the amount of the catalyst loading to 3 mol% or 10 mol%
disfavoured this reaction and gave 11% and 52% yields, respectively
(entries 9 and 10, Table 1). The solvent also played a crucial role. The
desired product was not observed using other solvents, such as
1,4-dioxane, DMSO and MeOH (entries 11–13, Table 1). As is well
known, the acidity of the C(2)–H bond in the heteroaromatic ring
can be enhanced by using a Lewis acid (LA) catalyst.10 To improve
this transformation, the catalyst was switched from CuBr to more
Lewis acidic CuOTf and afforded 77% yield (entry 14, Table 1). 84%
a
Conditions: 1 (0.2 mmol), 2 (0.6 mmol), CuOTf (5 mol%), TBHP
(0.6 mmol, 5–6 M in decane), (CH2)2Cl2 (2 mL), 70 1C, 8 h.
yield could be achieved by shortening the reaction time to 8 h (entry C2 of quinoline N-oxides in all cases (Table 2). When quinoline
16, Table 1). However, the yield decreased to 71% when the reaction N-oxide (1a) was subjected to the optimized reaction conditions
time was 4 h (entry 17, Table 1). The optimized reaction conditions various electron-rich arylaldehydes could be converted into 2-acyl-
were identified as 3 equiv. of benzaldehyde in the presence of oxyl quinoline N-oxides in moderate to good yields (3a–3f, Table 2).
3 equiv. TBHP in (CH2)2Cl2 and 5 mol% CuOTf as a catalyst at 70 1C Benzaldehyde and 2-methoxybenzaldehyde provided the desired
for 8 h (entry 16, Table 1).
products in 84% and 78% yields, respectively (3a and 3b,
With the optimized reaction conditions in hand, the scope and Table 2). Different quinoline N-oxides were tested for this transfor-
generality of substrates were investigated. Acetoxylation occurred at mation with electron-rich arylaldehydes. 4-Methylquinoline N-oxide
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 6900--6902 6901

View Article Online
ChemComm
Communication
could react with benzaldehyde to form intermediate C. Then C was
attacked by the quinoline N-oxide radical which was formed by
TBHP to form species D. Finally, D released the desired product and
CuOTf as well (Scheme 4).
CuOTf þ t-BuOOH ! CuOTfðOBu-tÞ þ HOꢀ
(1)
A
t-BuOOH þ A ! CuOTfðOOBu-tÞ þ t-BuOH
(2)
B
Scheme 3 Control experiments.
In summary, we have developed a direct acetoxylation of quino-
line N-oxides catalyzed by a cheap copper(I) salt. This novel protocol
provided a simple pathway to synthesize pharmaceutically active
quinoline-containing esters. The method features direct dual C–H
bond activation as a key step and uses a minimally toxic and
relatively cheap copper salt as a catalyst. The scope, applications
and mechanism of this reaction are under investigation.
This work was supported by NSF of China (21102133,
21172200) and the NSF of Henan (082300423201).
Notes and references
1 J. Otera and J. Nishikido, Esterification: methods, reactions, and
applications, Wiley-VCH, 2010.
Scheme 4 Proposed mechanism for the oxidative esterification.
2 R. C. Larock, Comprehensive organic transformations: a guide to
functional group preparations, Wiley-VCH, New York, 1999.
3 (a) K. Ekoue-Kovi and C. Wolf, Chem.–Eur. J., 2008, 14, 6302;
(b) W.-J. Yoo and C.-J. Li, Tetrahedron Lett., 2007, 48, 1033;
(c) X.-F. Wu and C. Darcel, Eur. J. Org. Chem., 2009, 1144; (d) B. Xu,
X. Liu, J. Haubrich and C. M. Friend, Nat. Chem., 2009, 2, 61; (e) C. Qin,
H. Wu, J. Chen, M. Liu, J. Cheng, W. Su and J. Ding, Org. Lett., 2008,
10, 1537; ( f ) J. o. N. Rosa, R. S. Reddy, N. R. Candeias, P. M. S. D. Cal
and P. M. P. Gois, Org. Lett., 2010, 12, 2686; (g) R. Gopinath and
B. K. Patel, Org. Lett., 2000, 2, 577; (h) R. Gopinath, B. Barkakaty,
B. Talukdar and B. K. Patel, J. Org. Chem., 2003, 68, 2944; (i) B. Maji,
S. Vedachalan, X. Ge, S. Cai and X.-W. Liu, J. Org. Chem., 2011, 76, 3016;
( j) B. R. Travis, M. Sivakumar, G. O. Hollist and B. Borhan, Org. Lett.,
2003, 5, 1031; (k) B. E. Maki and K. A. Scheidt, Org. Lett., 2008, 10, 4331.
4 (a) J.-Q. Yu and Z. Shi, C–H Activation, Springer, 2010; (b) C.-J. Li, Acc.
Chem. Res., 2008, 42, 335; (c) G. Deng, L. Zhao and C.-J. Li, Angew. Chem.,
Int. Ed., 2008, 47, 6278; (d) Z. Li and C.-J. Li, Eur. J. Org. Chem., 2005, 3173;
(e) X. Guo and C.-J. Li, Org. Lett., 2011, 13, 4977; ( f ) C. A. Correia, L. Yang
and C.-J. Li, Org. Lett., 2011, 13, 4581; (g) L. Chen, E. Shi, Z. Liu, S. Chen,
W. Wei, H. Li, K. Xu and X. Wan, Chem.–Eur. J., 2011, 17, 4085;
(h) H. Jiang, A. Lin, C. Zhu and Y. Cheng, Chem. Commun., 2013,
49, 819; (i) H. Liu, L. Cao, J. Sun, J. S. Fossey and W.-P. Deng, Chem.
Commun., 2012, 48, 2674; ( j) S. Gowrisankar, H. Neumann and M. Beller,
Angew. Chem., Int. Ed., 2011, 50, 5139; (k) C. Liu, J. Wang, L. Meng,
Y. Deng, Y. Li and A. Lei, Angew. Chem., Int. Ed., 2011, 50, 5144;
(l) Y.-M. Huang, F. J. Song, Z. Wang, P. H. Xi, N.-J. Wu, Z.-G. Wang,
J.-B. Lan and J.-S. You, Chem. Commun., 2012, 48, 2864; (m) T. K. Hyster
and T. Rovis, Chem. Commun., 2011, 47, 11846.
gave the corresponding desired products in 36–75% yield (3g–l,
Table 2). 6-Methylquinoline N-oxide reacted smoothly with 2-meth-
oxybenzaldehyde and 3,4-dimethoxybenzaldehyde, affording the
desired products in 94% and 82% yields, respectively (3n and 3r,
Table 2). 6-Methoxyquinoline N-oxide and 7-hydroxyquinoline
N-oxide provided the desired products in 55% and 75% yields,
respectively (3s and 3t, Table 2). Notably, cyclohexylaldehyde could
also be used as a substrate in this catalytic system and gave
2-(cyclohexylcarboxy)quinoline N-oxides in 56%, 59% and 52%
yields, respectively (3e, 3k and 3q, Table 2), which made the present
transformation attractive for future applications. However, this
reaction was limited to the electron-withdrawing aldehydes and
heterocyclic aldehydes. No desired product was detected for the
2-pyridinecarboxylaldehyde. And furfural only gave the desired
product in 10% yield.
To clarify the reaction mechanism and the oxygen source, control
experiments were performed (Scheme 3). When the reaction of
quinoline N-oxide 1a with benzaldehyde 2a was carried out under
an oxygen atmosphere in the absence of TBHP, no desired product
was detected (Scheme 3, eqn (1)). Whereas, the above reaction
proceeded smoothly under a nitrogen atmosphere using 3 equiv.
TBHP as an oxidant and provided the desired product 3a in 82%
yield, which is close to the result obtained under the optimal
reaction conditions (84% yield, 3a, Table 2) (Scheme 3, eqn (2)).
These results indicate that TBHP served as a terminal oxygen source.
The reaction mechanism was proposed according to the litera-
ture11 and results obtained are shown in Scheme 4 and eqn (1) and
5 (a) W.-J. Yoo and C.-J. Li, J. Org. Chem., 2006, 71, 6266; (b) C. Liu,
S. Tang, L. Zheng, D. Liu, H. Zhang and A. Lei, Angew. Chem., Int.
Ed., 2012, 51, 5662; (c) J. Feng, S. Liang, S.-Y. Chen, J. Zhang, S.-S. Fu
and X.-Q. Yu, Adv. Synth. Catal., 2012, 354, 1287.
6 J. Huang, L.-T. Li, H.-Y. Li, E. Husan, P. Wang and B. Wang, Chem.
Commun., 2012, 48, 10204.
7 S. K. Rout, S. Guin, K. K. Ghara, A. Banerjee and B. K. Patel, Org.
Lett., 2012, 14, 3982.
8 L. C. Blumberg, J. F. Remenar, O. Almarrson and T. A. Zeidan,
US. pat. US2011/041830, 2011.
9 Y. Tagawa, J. I. Tanaka, K. Hama, Y. Goto and M. Hamana, Tetra-
hedron Lett., 1996, 37, 69.
(2). Copper(I) was oxidized to copper(II) by TBHP, generating a 10 G. Deng and C.-J. Li, Org. Lett., 2009, 11, 1171.
11 (a) Z. Li and C.-J. Li, J. Am. Chem. Soc., 2004, 126, 11810; (b) E. Boess,
Cu(II) species A and a hydroxyl radical (eqn (1)). Then Cu(II) species
A reacted with the second molecule of TBHP to give a tert-butyl-
peroxy complex B and t-BuOH (eqn (2)). B and the hydroxyl radical
C. Schmitz and M. Klussmann, J. Am. Chem. Soc., 2012, 134, 5317;
(c) F. Minisci, F. Fontana, S. Araneo, F. Recupero, S. Banfi and
S. Quici, J. Am. Chem. Soc., 1995, 117, 226.
c
6902 Chem. Commun., 2013, 49, 6900--6902
This journal is The Royal Society of Chemistry 2013