Copper-catalyzed oxidative coupling between quinazoline 3-oxides and unactivated aldehydes: An efficient approach to functionalized quinazolines

Article abstract of DOI:10.1039/c6cc00946h

A copper-catalyzed oxidative coupling between quinazoline 3-oxides and unactivated aldehydes was described. The reaction worked well for both aliphatic and aromatic aldehydes and produced not only the direct oxidative coupling ketones but also cyclic hydroxamic esters derived from quinazolines.

Full text of DOI:10.1039/c6cc00946h

ChemComm
View Article Online
View Journal
COMMUNICATION
Copper-catalyzed oxidative coupling between
quinazoline 3-oxides and unactivated
aldehydes: an efficient approach to
functionalized quinazolines†
Cite this:DOI: 10.1039/c6cc00946h
Received 2nd February 2016,
Accepted 29th February 2016
Liwen Fan,a Tao Wang,*ab Ying Tian,a Fei Xiong,a Simei Wu,a Qingjin Lianga and
DOI: 10.1039/c6cc00946h
Junfeng Zhao*ab
www.rsc.org/chemcomm
A copper-catalyzed oxidative coupling between quinazoline 3-oxides
Quinazoline represents one of the privileged scaffolds of
and unactivated aldehydes was described. The reaction worked well pharmaceutical agents and natural products with interesting
for both aliphatic and aromatic aldehydes and produced not only the biological activities.6 As a consequence, considerable efforts
direct oxidative coupling ketones but also cyclic hydroxamic esters have been made for the synthesis and direct functionalization
derived from quinazolines.
of quinazoline derivatives.7 However, it is still far from being
developed due to the low efficiency and poor regioselectivity of
Oxidative coupling of two C–H bonds for the construction of the current available methods. In the past decade, the N-oxide
C–C bond has emerged as an attractive and ideal tool for organic functional group has been recognized as a powerful and
chemists because prior functionalization is avoided thus making removable directing group for ortho C–H bond activation of
this strategy environmentally friendly, atom- and step-economic, N-containing heterocycles.8 We believed that the oxidative
and sustainable.1 Among these transformations, the oxidative coupling between Csp2–H of quinazoline 3-oxides and Csp2–H
acylation of arenes involving cross-dehydrogenative coupling of aldehydes would be an efficient method for site selective
between Csp2–H of arenes and Csp2–H of aldehydes has attracted acylation of quinazoline 3-oxides and furnish quinazoline
a great deal of attention because it offered a straightforward ketone derivatives. It is noted that some copper reagents have
approach to aryl ketones, which have found widespread applica- been proved to be effective catalysts for oxidative acylation of
tions in pharmaceuticals, agrochemicals and materials science. In Csp2–H with aldehydes. Li and co-workers demonstrated that
the past decade, extensive efforts have been made on transition the synthesis of isatin derivatives could be accomplished by
metal such as Pd,2 Rh3 and Fe4 catalyzed oxidative acylation of employing a copper-catalyzed intramolecular C–H oxidative
arenes. However, most of these studies are limited to electron-rich acylation of formyl-N-arylformamides (Fig. 1, eqn (1)).9 Later,
arenes while few methods are available for oxidative acylation the Fu group developed a copper-catalyzed intermolecular
of heteroarenes and electron-deficient arenes with aldehydes version by employing secondary anilines and reactive ethyl
because both coupling partners are electron-deficient. Very glyoxalate (Fig. 1, eqn (2)).10 Very recently, Lei and co-workers
recently, transition metal-free oxidative acylation of arenes reported an elegant direct oxidative coupling between aldehydes
has been reported and showed promising solution for oxidative
acylation of heteroarenes including isoquinolines, quinolines
and quinoxalines.5 These efforts addressed the challenge
of oxidative acylation of heteroarenes with aldehydes to some
extent, however, more robust strategies are still in great
demand regarding the versatility and potential applications of
aryl ketones.
a College of Chemistry & Chemical Engineering, Jiangxi Normal University,
99, Ziyang Road, Nanchang, Jiangxi, 330022, P. R. China.
E-mail: wangtao@jxnu.edu.cn, zhaojf@jxnu.edu.cn
b National Research Center for Carbohydrate Synthesis, Key Laboratory of Chemical
Biology, Jiangxi Province, China
† Electronic supplementary information (ESI) available. CCDC 1450112 and
1450113. For ESI and crystallographic data in CIF or other electronic format
Fig. 1 Copper-catalyzed oxidative coupling of Csp2–H with aldehydes.
see DOI: 10.1039/c6cc00946h
This journal is ©The Royal Society of Chemistry 2016
Chem. Commun.

View Article Online
Communication
ChemComm
and alkenes (Fig. 1, eqn (3)).11 Significantly different from Li and
Fu’s work, in which the activated aldehyde glyoxalates were
employed, unactivated aldehydes were used as valid coupling
partners in Lei’s work. Inspired by these accomplishments and
considering the low toxicity and cost of copper catalysts, we
conceived that copper would be a useful catalyst for the oxidative
coupling of N-containing heterocycles with unactivated aldehydes.
Herein, we report a copper-catalyzed oxidative coupling of quin-
azoline 3-oxides with unactivated aldehydes to furnish quinazoline
ketones, which could be further transformed into quinazolinone
esters in a one-pot manner (Fig. 1, eqn (4)). To the best of our
knowledge, the copper catalyzed oxidative acylation of heteroarenes
with unactivated aldehydes remains unexplored.
To test the validity of our hypothesis, various copper salts were
evaluated with quinazoline 3-oxide as the model substrate. As
shown in Table 1, however, no matter what kinds of reaction
conditions are employed, only a trace amount of 3a was isolated.
On the other hand, quinazolinone benzoate 4a (3a and 4a were
confirmed by X-ray crystallography, see the ESI†) was isolated in a
significant amount. This unexpected result provided a straight-
forward approach to synthesize cyclic hydroxamic esters derived
from quinazoline,12 which are a series of important heterocyclic
compounds in drug discovery. For example, 4a analogues had
been identified as novel inhibitors of Mycobacterium tuberculosis
acetohydroxyacid synthase (MTB-AHAS).13 Their synthesis generally
required several steps and efficient synthetic strategies are highly
Scheme 1 Copper(II)-catalyzed reaction of quinazoline-3-oxide with
various aldehydes. Reaction conditions: 1a (0.2 mmol), 2 (0.6 mmol), TBHP
(5.5 M in decane, 0.6 mmol), CH2Cl2 (2 mL), Cu(OAc)2 (10 mol%), N2.
Isolated yields based on 1a.
demanded.14 In this regard, we believed that the reaction disclosed reaction. In terms of benzylaldehyde derivatives, both electron-
here would be an efficient approach to these compounds. As shown donating and -withdrawing groups on the phenyl ring are
in Table 1, copper catalysts influenced the reaction remarkably and compatible albeit the strong electron-withdrawing group such
cyclic hydroxamic esters 4a could be obtained directly from quin- as –NO2 (Scheme 1, entry 4k) caused a drop in yield. The
azoline 3-oxides up to 84% yield in the presence of 10 mol% of reaction is less susceptible to steric hindrance (Scheme 1,
Cu(OAc)2, (Table 1, entry 9).
entries 4f and 4i) and even sterically demanding ortho substi-
Next, the substrate scope of this reaction was evaluated. It is tuents are tolerated (Scheme 1, entry 4n). a,b-Unsaturated
observed that a variety of aldehydes are valid substrates for this aldehydes are also valid substrates for this transformation
(Scheme 1, entry 4z). Heteroaryl aldehydes and aliphatic aldehydes
can also be used as acyl donors to give cyclic hydroxamic esters in
good to excellent yields (Scheme 1, entries 4p–4y).
Table 1 Optimization of reaction conditionsa
The versatility regarding the quinazoline 3-oxide moiety had
also been examined. The substituent at the 2-position of quinazo-
line 3-oxide has a minor effect on the reaction efficiency (Scheme 2,
entries 4aa–4ea). For example, both aliphatic and aromatic sub-
stituents are tolerated at this position. It is observed that the
yields decreased with the increase of the chain length from
the methyl to the propyl group (Scheme 2, entries 4ba–4da). In
contrast, substituents on the phenyl ring moiety of quinazoline
3-oxide influenced the reaction remarkably. Both the electron-
withdrawing and -donating groups have a significant negative
effect on the reaction efficiency (Scheme 2, entries 4fa–4ka).
During the extensive study of the synthesis of cyclic hydroxamic
esters 4 derived from quinazoline, careful monitoring of the
reaction disclosed that the direct cross coupling product 3 was
indeed formed but disappeared slowly along the reaction
course. In some cases, compound 3 could be isolated in a
small amount if the reactions were quenched prematurely. One
oxygen atom component difference between compounds 3 and
4 stimulated us to envision a cascade reaction involving the
Entry
Catalyst
Ratio of 3 : 4
Yield of 4b (%)
1
2
3
4
5
6
7
8
CuBr
CuCl
CuI
Cu2O
CuBr2
CuCl2
CuF2
Cu(OTf)2
Cu(OAc)2
Cu(BF)2
Cu(OH)2
CuCO3
—
o1 : 99
7 : 8
65
32
41
80
49
11
84
39
o1 : 99
o1 : 99
o1 : 99
o1 : 99
o1 : 99
1 : 2
9
o1 : 99
88 (84)
44
10
11
12
13
1 : 7
o1 : 99
3 : 1
68
5
—
—
a
Reaction conditions: 1a (0.2 mmol), 2a (0.6 mmol), TBHP (5.5 M in
b
decane, 0.6 mmol), 4 h, catalyst (10 mol%), CH2Cl2 (2 mL), N2. GC
yield, isolated yield is indicated in parentheses.
Chem. Commun.
This journal is ©The Royal Society of Chemistry 2016

View Article Online
ChemComm
Communication
Scheme 3 Copper(II)-catalyzed direct oxidative coupling reaction of
quinazoline-3-oxides with various aldehydes. Reaction conditions:
1
(0.2 mmol), 2 (0.6 mmol), CH2Cl2 (2 mL), TBHP (70% aqueous solution,
0.6 mmol), TMSN3 (0.6 mmol), CuCO3 (5 mol%), N2. Isolated yields based on 1.
formation of compound 4, is beneficial for stopping the reaction
at ketone 3. To our delight, TMSN3, which played an important
role in the metal-free cross-dehydrogenative coupling of hetero-
cycles with aldehydes,5c could suppress the subsequent reaction
efficiently. Finally, we found that 3 could be obtained as the major
product in good yield in the presence of TMSN3 with CuCO3 as the
catalyst. As shown in Scheme 3, all of the tested aryl aldehydes
Scheme 2 Copper(II)-catalyzed reaction of quinazoline-N-oxides with
p-tolualdehyde. a Reaction conditions: 1 (0.2 mmol), 2a (0.6 mmol), TBHP
(5.5 M in decane, 0.6 mmol), CH2Cl2 (2 mL), Cu(OAc)2 (10 mol%),
N2. Isolated yields based on 1. b 2a (1.0 mmol), TBHP (5.5 M in decane,
1.0 mmol).
Baeyer–Villiger oxidation of 3 and a subsequent intramolecular
acyl transfer to realize the transformation from 3 to 4. This including heteroaryl aldehydes proceeded smoothly to afford the
target diaryl ketone in moderate to good yields. Aliphatic alde-
hydes also worked well albeit slightly lower yields were obtained.
A substituent on the phenyl ring moiety of quinazoline 3-oxide
could be tolerated.
Based on our experimental results, a tentative reaction mecha-
nism was proposed (Scheme 4). The treatment of aldehyde with
TBHP gave rise to acyl radical I, which could be trapped by
proposal was confirmed by a control experiment and we
observed that 4a was formed smoothly with 51% isolated yield
when 3a was treated with 3 equiv. of m-chloroperbenzoic acid
(m-CPBA) and 1 equiv. of CF3CO2H, under the classic Baeyer–
Villiger oxidation reaction conditions (Fig. 2, eqn (1)). Similarly,
4a could be isolated in 60% yield in the presence of 3 equiv. of
aldehyde under the standard reaction conditions after 12 hours
(Fig. 2, eqn (2)). This result clearly illustrated that 3a would be quinazoline 3-oxide 1 to release a new radical II. Further oxidation
of radical II furnished aryl ketone 3. Followed by a Baeyer–Villiger
oxidation, in which aryl ketone 3 was transformed into an ester
intermediate III, which offered cyclic hydroxamic ester 4 upon a
subsequent intramolecular acyl transfer (path I). Path II is also
operative because it is well established that nitroxides are effective
radical trapping reagents.15 The tert-butylperoxy radical, formed
in situ from TBHP, was trapped by quinazoline 3-oxide to form a
an intermediate for the formation of 4a. Encouraged by these
experimental results, we hypothesized that aryl ketone 3 would
be obtained as the major product if the subsequent Baeyer–
Villiger oxidation could be suppressed. To this end, we examined
the factors which governed the reaction efficiency (for details of
reaction condition optimization, see the ESI†). Decreasing the
loading of the oxidant and aldehyde only led to a sluggish reaction
while it did not change the ratio between 3 and 4. Screening of
copper catalysts disclosed that CuCO3, a poor catalyst for the
Fig. 2 Control experiments.
Scheme 4 Proposed reaction mechanism.
This journal is ©The Royal Society of Chemistry 2016
Chem. Commun.

View Article Online
Communication
ChemComm
4 S. Wertz, D. Leifert and A. Studer, Org. Lett., 2013, 15, 928.
new O-centered radical IV, which coupled with the acyl radical
to afford the ester V. Both IV and V were detected by ESI-MS
(for details, see the ESI†). Further fragmentation16 of the ester V
produced the cyclic hydroxamic ester 4. TMSN3 might inhibit both
the Baeyer–Villiger oxidation of path I and path II directly, thus
making 3 as the major product.
5 (a) Z. Shi and F. Glorius, Chem. Sci., 2013, 4, 829; (b) Z. Zheng,
L. Dian, Y. Yuan, D. Zhang-Negrerie, Y. Du and K. Zhao, J. Org.
Chem., 2014, 79, 7451; (c) K. Matcha and A. P. Antonchick, Angew.
Chem., Int. Ed., 2013, 52, 2082; (d) Y. Siddaraju, M. Lamani and
K. R. Prabhu, J. Org. Chem., 2014, 79, 3856; (e) J. Chen, M. Wan,
J. Hua, Y. Sun, Z. Lv, W. Li and L. Liu, Org. Biomol. Chem., 2015,
13, 11561.
We have developed the first copper-catalyzed oxidative coupling
of heteroarenes with unactivated aldehydes as acyl donors. This
method not only offered a straightforward approach to synthesize
quinazoline based diaryl ketones but also provided an unexpected
synthetic strategy for the cyclic hydroxamic esters derived from
quinazolines. Owing to the mild reaction conditions, easy hand-
ling and versatility of the substrate, this method should find broad
application in the context of building a quinazoline library for drug
discovery and materials science.
This work was supported by the National Natural Science
Foundation of China (21462023, 21262018) and the Natural
Science Foundation of Jiangxi Province (20143ACB20007,
20133ACB20008).
6 (a) G. Marzaro, A. Guiotto and A. Chilin, Expert Opin. Ther. Pat.,
2012, 22, 223; (b) I. E. Anglin, D. T. Glassman and N. Kyprianou,
Prostate Cancer Prostatic Dis., 2002, 5, 88.
7 (a) D. Wang and F. Gao, Chem. Cent. J., 2013, 7, 95; (b) Y.-F. Wang,
F.-L. Zhang and S. Chiba, Org. Lett., 2013, 15, 2842; (c) Y. An,
D. Zheng and J. Wu, Chem. Commun., 2014, 50, 9165; (d) X. Chen,
C. Zhu, X. Cui and Y. Wu, Chem. Commun., 2013, 49, 6900;
(e) Y. Tian, R. Li, T. Wang, J. Xiong, H. Feng and F. Xiong, Tetra-
hedron Lett., 2015, 56, 2176.
8 For reviews, see: (a) G. Yan, A. J. Borah and M. Yang, Adv. Synth.
Catal., 2014, 356, 2375; (b) S. Tang, K. Liu, C. Liu and A. Lei, Chem.
Soc. Rev., 2015, 44, 1070; (c) R.-J. Song, Y. Liu, Y.-X. Xie and J.-H. Li,
Synthesis, 2015, 1195; for selected pioneering studies using N-oxide
as the directing group for C–H functionalization, see: (d) L.-C.
Campeau, S. Rousseaux and K. Fagnou, J. Am. Chem. Soc., 2005,
127, 18020; (e) J. A. Pool, B. L. Scott and J. L. Kiplinger, J. Am. Chem.
Soc., 2005, 127, 1338; ( f ) J. P. Leclerc and K. Fagnou, Angew. Chem.,
Int. Ed., 2006, 45, 7781; (g) S. H. Cho, S. J. Hwang and S. Chang,
J. Am. Chem. Soc., 2008, 130, 9254; (h) L. C. Campeau, D. R. Stuart,
J. P. Leclerc, M. Bertrand-Laperle, E. Villemure, H. Y. Sun,
S. Lasserre, N. Guimond, M. Lecavallier and K. Fagnou, J. Am. Chem.
Soc., 2009, 131, 3291; (i) J. Wu, X. Cui, L. Chen, G. Jiang and Y. Wu,
J. Am. Chem. Soc., 2009, 131, 13888; ( j) L.-C. Campeau, M. Bertrand-
Laperle, J.-P. Leclerc, E. Villemure, S. Gorelsky and K. Fagnou, J. Am.
Chem. Soc., 2008, 130, 3276; (k) B. Yao, R.-J. Song, Y. Liu, Y.-X. Xie,
J.-H. Li, M.-K. Wang, R.-Y. Tang, X.-G. Zhang and C.-L. Deng,
Adv. Synth. Catal., 2012, 354, 1890; (l) B. Yao, C.-L. Deng, Y. Liu,
R.-Y. Tang, X.-G. Zhang and J.-H. Li, Chem. Commun., 2015, 51, 4097;
(m) K. S. Kanyiva, Y. Nakao and T. Hiyama, Angew. Chem., Int. Ed.,
2007, 46, 8872.
References
1 (a) C. S. Yeung and V. M. Dong, Chem. Rev., 2011, 111, 1215;
(b) S. H. Cho, J. Y. Kim, J. Kwak and S. Chang, Chem. Soc. Rev.,
2011, 40, 5068; (c) S. A. Girard, T. Knauber and C.-J. Li, Angew.
Chem., Int. Ed., 2014, 53, 74; (d) Y. Wu, J. Wang, F. Mao and
F. Y. Kwong, Chem. – Asian J., 2014, 9, 26; (e) C. Liu, H. Zhang,
W. Shi and A. Lei, Chem. Rev., 2011, 111, 1780; ( f ) C. Liu, D. Liu and
A. Lei, Acc. Chem. Res., 2014, 47, 3459; (g) C. J. Li, Acc. Chem. Res.,
2009, 42, 335.
2 (a) X. Jia, S. Zhang, W. Wang, F. Luo and J. Cheng, Org. Lett., 2009,
11, 3120; (b) C.-W. Chan, Z. Zhou, A. S. C. Chan and W.-Y. Yu, Org.
9 B.-X. Tang, R.-J. Song, C.-Y. Wu, Y. Liu, M.-B. Zhou, W.-T. Wei,
G.-B. Deng, D.-L. Yin and J.-H. Li, J. Am. Chem. Soc., 2010, 132, 8900.
10 T. Liu, H. Yang, Y. Jiang and H. Fu, Adv. Synth. Catal., 2013,
355, 1169.
11 J. Wang, C. Liu, J. Yuan and A. Lei, Angew. Chem., Int. Ed., 2013, 52, 2256.
12 C. B. Schapira and S. Lamdan, J. Heterocycl. Chem., 1972, 9, 569.
13 (a) W. Lu, I. A. Baig, H.-J. Sun, C.-J. Cui, R. Guo, I.-P. Jung, D. Wang,
M. Dong, M.-Y. Yoon and J.-G. Wang, Eur. J. Med. Chem., 2015,
94, 298; (b) D. Wang, X. Zhu, C. Cui, M. Dong, H. Jiang, Z. Li, Z. Liu,
W. Zhu and J.-G. Wang, J. Chem. Inf. Model., 2013, 53, 343.
14 (a) L. Bauer and C. N. V. Nambury, J. Org. Chem., 1961, 26, 1106;
(b) M. Z. A. Badr, H. A. H. El-Sherief and A. M. Mahmoud, Bull.
Chem. Soc. Jpn., 1980, 53, 2389.
´
Lett., 2010, 12, 3926; (c) O. Basle, J. Bidange, Q. Shuai and C.-J. Li,
Adv. Synth. Catal., 2010, 352, 1145; (d) Y. Wu, B. Li, F. Mao, X. Li and
F. Y. Kwong, Org. Lett., 2011, 13, 3258; (e) Y.-F. Liang, X. Li, X. Wang,
Y. Yan, P. Feng and N. Jiao, ACS Catal., 2015, 5, 1956; ( f ) J.-H. Chu,
S.-T. Chen, M.-F. Chiang and M.-J. Wu, Organometallics, 2015,
34, 953; (g) S. Sharma, J. Park, E. Park, A. Kim, M. Kim, J. H.
Kwak, Y. H. Jung and I. S. Kim, Adv. Synth. Catal., 2013, 355, 332;
(h) C.-W. Chan, Z. Zhou and W.-Y. Yu, Adv. Synth. Catal., 2011,
353, 2999; (i) C. Li, L. Wang, P. Li and W. Zhou, Chem. – Eur. J., 2011,
17, 10208; ( j) S. Wang, Z. Yang, J. Liu, K. Xie, A. Wang, X. Chen and
Z. Tan, Chem. Commun., 2012, 48, 9924.
3 (a) J. Park, E. Park, A. Kim, Y. Lee, K.-W. Chi, J. H. Kwak, Y. H. Jung
and I. S. Kim, Org. Lett., 2011, 13, 4390; (b) S. Sharma, E. Park, J. Park
and I. S. Kim, Org. Lett., 2012, 14, 906; (c) B. Zhou, Y. Yang and Y. Li, 15 (a) E. G. Janzen and B. J. Blackburn, J. Am. Chem. Soc., 1969,
Chem. Commun., 2012, 48, 5163; (d) P. Wang, H. Rao, R. Hua and
C.-J. Li, Org. Lett., 2012, 14, 902.
91, 4481; (b) E. G. Janzen, Acc. Chem. Res., 1971, 4, 31.
16 N. Kornblum and H. E. DeLaMare, J. Am. Chem. Soc., 1951, 73, 880.
Chem. Commun.
This journal is ©The Royal Society of Chemistry 2016