ORGANIC CHEMISTRY

FRONTIERS
View Article Online
RESEARCH ARTICLE View Journal
Published on 06 February 2017. Downloaded by University of California - San Diego on 25/03/2017 14:45:02.

Synthesis of 3-acylquinolines through

Cite this: DOI: 10.1039/c6qo00817h
Cu-catalyzed double C(sp3)H bond
functionalization of saturated ketones
Ze Wang, Guang Chen, Xinying Zhang* and Xuesen Fan*

A novel synthesis of 3-acylquinolines from Cu-catalyzed one-pot reactions of 2-aminoaryl aldehydes/

Received 15th December 2016,
Accepted 4th February 2017
DOI: 10.1039/c6qo00817h
rsc.li/frontiers-organic
ketones with inactivated ketones is presented. Mechanistically, the formation of the title compounds
involves a cascade procedure including C(sp3)H bond amination, enaminone formation, and enamine-
carbonyl condensation. To our knowledge, this should be the rst example in which 3-acylquinolines are
prepared through Cu-catalyzed double C(sp3)H bond functionalization of saturated ketones.

Introduction
Quinoline and its derivatives are privileged scaolds frequently
found in natural products and synthetic compounds posses-
sing valuable biological and chemical properties.1,2 Because of
their importance, various synthetic protocols such as
Friedlnder synthesis, Combes synthesis, Skraup synthesis
and GouldJacobs synthesis have been well established.3,4
Meanwhile, heterocycles bearing an acyl group are highly
useful in pharmacological studies.5 In particular, 3-acyl quino-
Scheme 1 Dierent synthetic routes to 3-acylquinolines.
line derivatives are novel 4-hydroxyphenyl pyruvate dioxygen-
ase inhibitors6 and antihypetensive agents.7 So far, some
ecient methods for the synthesis of 3-acylquinolines have
been developed, such as phosphine-catalyzed condensation of
and readily available simple ketones as substrates is a promis-
activated acetylenes with o-tosylamidobenzaldehydes/ketones
ing yet challenging topic.
followed by detosylation and aromatization (Scheme 1, 1),8a
Meanwhile, dehydrogenation of saturated carbonyl com-
Friedlnder type reaction of o-aminoaryl aldehydes/ketones
pounds (SCCs) to give ,-unsaturated carbonyl compounds
with diketones (Scheme 1, 2),8b Pd-catalyzed carbonylative
(UCCs) has attracted much attention since SCCs are abundant
Suzuki coupling reactions of 3-iodoquinolines with aryl
and economical while UCCs are not only ubiquitous in bio-
boronic acids (Scheme 1, 3),8c condensation of o-aminoaryl
active compounds but also valuable as intermediates for the
aldehydes/ketones with enaminones,8d Fe-catalyzed reactions
preparation of numerous fine chemicals and medicines.9,10
of ynone with o-amino aryl compounds,8e etc.6,8fj While these
Interestingly, the dehydrogenation was also found in many
methods are generally reliable, most of them involve the use of
cases to be well compatible and combinable with other kinds
pre-functionalized starting materials, which are often expen-
of organic transformations such as conjugate addition, cross
sive or commercially unavailable. Therefore, the development
coupling, etc., thus resulting in some ecient one-pot
of new synthetic routes to 3-acylquinolines by using the cheap
approaches towards complex functional molecules.1115 In this
regard, Su et al. developed a Pd-catalyzed CH olefination of
arenes by using SCCs as an olefin source.11 They also reported
School of Chemistry and Chemical Engineering, Collaborative Innovation Centre of a Pd-catalyzed coupling of aryl carboxylic acid with propio-
Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green phenones via decarboxylation and dehydrogenation.12 Cheng et al.
Chemical Media and Reactions, Ministry of Education, Henan Normal University,
developed a Pd-catalyzed dehydrogenative -arylation of simple
Xinxiang, Henan 453007, China. E-mail: xuesen.fan@htu.cn, xinyingzhang@htu.cn
Electronic supplementary information (ESI) available: Experimental pro-
SCCs by aryl halides.13 Recently, Su reported a Cu-catalyzed
cedures, mechanism studies, characterisation data and NMR spectra. See DOI: dehydrogenation of saturated ketones to give ,-unsaturated
10.1039/c6qo00817h ketones, which were captured by a wide range of nucleophiles

This journal is the Partner Organisations 2017 Org. Chem. Front.

 View Article Online

Research Article Organic Chemistry Frontiers

to give -functionalized ketones.14 Inspired by these elegant
pioneering studies, we proposed an alternative synthetic
approach to 3-acylquinolines via the C(sp3)H bond amination,
enaminone formation, and enamine-carbonyl condensation of
saturated ketones with 2-aminoaryl carbonyl compounds
(Scheme 1, 4). Herein, we wish to report our detailed studies
and the corresponding results in this regard.
Published on 06 February 2017. Downloaded by University of California - San Diego on 25/03/2017 14:45:02.
ing the reaction temperature from 120 C did not improve the
yield (entries 15 and 16 vs. 2). Finally, prolonging the reaction
period to 18 h gave 3a with a similar eciency to that with
14 h (entry 17 vs. 2).
After the optimal conditions having been established, a
range of 2-aminobenzaldehydes (1) and saturated ketones (2)
were screened to probe the scope of this new synthetic

method. First, with 2a as a model substrate, diversely substi-

Results and discussion
Our study was initiated by choosing 2-aminobenzaldehyde (1a)
and propiophenone (2a) as the model substrates, and treating
them with Cu(OAc)2, TEMPO (2,2,6,6-tetramethylpiperidine-N-
oxyl) and bpy (2,2-bipyridine) in PhCl at 120 C for 14 h. From
this reaction, the desired phenyl(quinolin-3-yl)methanone (3a)
was obtained in a yield of 72% (Table 1, entry 1). To improve
the eciency, the eect of various solvents including toluene,
dioxane, DMSO, DMF, CH3CN, and DCE was tested (entries
27). Among them, toluene turned out to be the most ecient
in mediating this reaction giving 3a in 78% yield (entry 2).
Then, Cu(OTf )2 and CuCl2 were tried as catalysts, and they
were found to be less ecient compared with Cu(OAc)2
(entries 8 and 9 vs. 2). Following studies showed that in the
absence of either Cu(II) salt or TEMPO, the formation of 3a
could not be realized (entries 10 and 11). In the absence of bpy
as a ligand, 3a was obtained in a lower yield (entry 12). When
it was carried out under an oxygen atmosphere in the absence
of TEMPO, no formation of 3a was observed (entry 13). Further
study showed that the reaction gave 3a only in a yield of 42%
with 1 equiv. of TEMPO (entry 14). Next, increasing or decreas-
tuted 2-aminobenzaldehydes (1) were tried. To our delight, all
of them underwent this reaction smoothly to aord 3a3e in
good yields (Table 2). Various functional groups, such as
methoxy, methylenedioxy and chloro, attached on the phenyl
unit were well tolerated. Second, by using 1a as a model sub-
strate, the suitability of dierent ketone substrates (2) was
tested. It was observed that a number of propiophenones were
well suitable to give 3f3i in good to excellent yields. Notably,
the electronic nature of the phenyl unit did not have an
obvious eect on the outcome of this reaction. Interestingly,
heteroaromatic ketones such as 3-propionyl pyridine and
2-propionyl thiophene took part in this cascade process to give
3j and 3k with equally good eciency. In further screening,
aliphatic ketones such as butan-2-one and 1-cyclohexylpropan-
1-one were found to be also compatible although the yields of
the corresponding products (3l and 3m) were much lower.
Furthermore, two -substituted ketones, 1-phenylbutan-1-one
and 1,3-diphenylpropan-1-one, were also tried, and they were
found to be good partners for this reaction to give 3n and 3o.
Dihydroindenone, a cyclic ketone, reacted with 1a to give tetra-
cyclic 11H-indeno[1,2-b]quinolin-11-one (3p).16 Moreover, the
reactions of 2-aminonicotinaldehyde turned out to be also suc-
cessful to aord 3q and 3r in high yields.

Table 1 Optimization studiesa

Table 2 Substrate scope for the preparation of 3a,b

Oxidant Yieldb
Entry Catalyst (equiv.) Solvent T/h t/C (%)

1 Cu(OAc)2 TEMPO (2) PhCl 14 120 72

2 Cu(OAc)2 TEMPO (2) Toluene 14 120 78
3 Cu(OAc)2 TEMPO (2) Dioxane 14 120 68
4 Cu(OAc)2 TEMPO (2) DMSO 14 120 34
5 Cu(OAc)2 TEMPO (2) DMF 14 120 55
6 Cu(OAc)2 TEMPO (2) CH3CN 14 120 56
7 Cu(OAc)2 TEMPO (2) DCE 14 120 69
8 Cu(OTf)2 TEMPO (2) Toluene 14 120 62
9 CuCl2 TEMPO (2) Toluene 14 120 53
10 TEMPO (2) Toluene 14 120
11 Cu(OAc)2 Toluene 14 120
12 Cu(OAc)2 TEMPO (2) Toluene 14 120 52c
13 Cu(OAc)2 O2 Toluene 14 120
14 Cu(OAc)2 TEMPO (1) Toluene 14 120 42
15 Cu(OAc)2 TEMPO (2) Toluene 14 140 78
16 Cu(OAc)2 TEMPO (2) Toluene 14 100 66
17 Cu(OAc)2 TEMPO (2) Toluene 18 120 79
a a
Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), catalyst Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), Cu(OAc)2
(0.05 mmol), bpy (0.1 mmol), solvent (3 mL), N2. b Isolated yield. (0.05 mmol), TEMPO (1 mmol), bpy (0.1 mmol), toluene (3 mL),
c
No bpy. 120 C, N2, 14 h. b Isolated yields. c 0.25 mmol of bpy were used.

Org. Chem. Front. This journal is the Partner Organisations 2017

 View Article Online

Organic Chemistry Frontiers Research Article

Having established a novel and ecient synthesis of 3-acyl
quinolines (3) from 1 and 2, we were then interested in
extending the substrate scope from 2-aminoaryl aldehydes (1)
to 2-aminoaryl ketones (4) with the aim to prepare 3,4-di-
substituted quinolines (5). Thus, a mixture of (2-amino-
phenyl)( phenyl)methanone (4a) and 2a was subjected to the
standard reaction conditions used for the preparation of 3
Published on 06 February 2017. Downloaded by University of California - San Diego on 25/03/2017 14:45:02.
The proposed reaction mechanism as shown in Scheme 2 is
partly supported by the following control experiments. Firstly,
a mixture of 4a and 2a was subjected to the standard reaction
conditions for 16 h, from which 1-phenylprop-2-en-1-one
(intermediate C) and 3-((2-benzoylphenyl)amino)-1-phenyl-
propan-1-one (intermediate D) were isolated along with 5a in
yields of 9%, 60% and 15%, respectively (Scheme 3, 5). Next, a

(Table 1, entry 2). From this reaction, the desired phenyl mixture of C and 4a was subjected to the standard reaction
(4-phenylquinolin-3-yl)methanone (5a) was obtained in a yield conditions with 1 equiv. of TEMPO for 24 h to aord 5a in
of 56%. Through screening the reaction conditions, we were 92% yield (Scheme 3, 6). Third, a mixture of C and 4a was sub-
delighted to find that prolonging the reaction period from jected to the standard reaction conditions but in the absence
14 h to 36 h with other conditions unchanged led to the for- of TEMPO. This reaction did not give 5a, but aorded D in a
mation of 5a in a yield of 92%. Next, the substrate scope for yield of 94% (Scheme 3, 7). Fourth, D was subjected to the
the synthesis of 5 was explored (Table 3). First, several propio- standard conditions with 1 equiv. of TEMPO to give 5a in 92%
phenones were tried by using 4a as a model substrate, and all yield (Scheme 3, 8). When the reaction of D was carried out in
of them took part in this reaction smoothly to aord 5a5c in the absence of TEMPO while other conditions were kept
excellent yields. 2-Propionyl thiophene was an ecient unchanged, the formation of 5a was not observed, and 95% of
partner to give 5d in 90% yield. Moreover, an aliphatic D was recovered (Scheme 3, 9). These results showed that both
ketone, butan-2-one, was found to be compatible to give 5e C and D are the key intermediates toward 5a from the reaction
even though the yield was lower. (2-Amino-5-chlorophenyl) of 4a and 2a, and the formation of 5a from C or D needs
( phenyl)methanone reacted with 2a to give 5f in 90% yield,
and the chloro group was not aected. When the reaction was
extended to 1-(2-aminophenyl)ethan-1-one, 5g5k were
obtained in moderate yields.17 Interestingly, with 1-amino-
anthracene-9,10-dione, the reaction gave the tetracyclic
1-benzoyl-7H-naphtho[1,2,3-de]-quinolin-7-one (5l) in a yield of
46%.
Based on our experimental results and previous reports,14 a
plausible pathway to account for the formation of 5a from the
reaction of 4a with 2a was proposed in Scheme 2. Initially, 2a
is dehydrogenated by Cu(II)/TEMPO to give enone C via inter-
mediates A and B. Next, C undergoes a conjugate addition
with 4a to give -aminoketone D. Through another Cu(II)/
TEMPO-catalyzed dehydrogenation, D is transformed into
enaminone G18 via intermediates E and F. Finally, G under-
goes an intramolecular enamine-ketone condensation to
aord 5a with H as a possible intermediate. Scheme 2 Proposed mechanism for the formation of 5a.

Table 3 Substrate scope for the preparation of 5a,b

a
Reaction conditions: 4 (0.5 mmol), 2 (0.6 mmol), Cu(OAc)2
(0.05 mmol), TEMPO (1 mmol), bpy (0.1 mmol), toluene (3 mL),
120 C, N2, 36 h. b Isolated yields. c 0.25 mmol of bpy were used. Scheme 3 Control experiments (I).

This journal is the Partner Organisations 2017 Org. Chem. Front.


Research Article
Published on 06 February 2017. Downloaded by University of California - San Diego on 25/03/2017 14:45:02.
Scheme 4 Control experiments (II).
Scheme 5 Gram-scale synthesis of 5a.
TEMPO as the oxidant. This is in consistence with our observ-
ation that 2 equiv. of TEMPO are needed for the ecient for-
mation of 5a from 4a and 2a.
Meanwhile, as the proposed intermediate G could not be
isolated from the reaction of 4a with 2a (Scheme 3, 5), most
likely due to its high reactivity under the reaction conditions,
it was prepared by treating 4a with 1-phenylprop-2-yn-1-one (6)
under the promotion of FeCl36H2O (Scheme 4, 10).8e Then, G
was subjected to the standard reaction conditions but in the
absence of TEMPO for 10 min. From this reaction, 5a was
obtained in 93% yield (Scheme 4, 11). This result suggested
that G should be one of the key intermediates toward 5a, and
the formation of 5a from G does not need the presence of
TEMPO.
Finally, to check the scalability of this 3-acylquinoline for-
mation process, the preparation of 5a on a gram-scale was
studied. Thus, a mixture of 4a (0.985 g, 5 mmol) and 2a
(0.804 g, 6 mmol) was treated with Cu(OAc)2, TEMPO and bpy
in toluene. From this reaction, 5a was obtained in a yield of
85% (Scheme 5).
Conclusions
In summary, we have developed an ecient and easy-to-run
synthetic approach toward diversely substituted 3-acyl quino-
lines from Cu-catalyzed one-pot cascade reactions of
2-aminoaryl aldehydes/ketones with saturated ketones. To our
knowledge, this should be the first example in which 3-acyl-
quinolines are prepared through Cu-catalyzed double C(sp3)H
bond functionalization of inactivated ketones. With notable
features such as simple substrates, easy operating procedure,
broad substrate scope, high eciency and atom-economy, and
good tolerance of functional groups, this novel method is
expected to find wide applications in related areas. Further
work on the detailed mechanistic study and more applications
of this 3-acylquinoline formation strategy is currently
underway.
Org. Chem. Front.
View Article Online
Organic Chemistry Frontiers
Acknowledgements
We are grateful to the National Natural Science Foundation of
China (NSFC) (grant no. 21572047), the Program for Innovative
Research Team in Science and Technology in Universities of
Henan Province (15IRTSTHN003), and the Program for Science
and Technology Innovation Talents in Universities of Henan
Province (15HASTIT005) for financial support.
Notes and references
1 (a) A.-P. Gorka, A. de Dios and P.-D. Roepe, J. Med. Chem.,
2013, 56, 5231; (b) F. Zhong, G. Geng, B. Chen, T. Pan,
Q. Li, H. Zhang and C. Bai, Org. Biomol. Chem., 2015, 13,
1792; (c) R. Deshide, S. Devari and B. A. Shah, Org. Chem.
Front., 2015, 2, 515; (d) M. Zhong, S. Sun, J. Cheng and
Y. Shao, J. Org. Chem., 2016, 81, 10825; (e) R. Zhu,
G. Cheng, C. Jia, L. Xue and X. Cui, J. Org. Chem., 2016, 81,
7539; (f ) S. Yu, Y. Li, X. Zhou, H. Wang, L. Kong and X. Li,
Org. Lett., 2016, 18, 2812; (g) J. Yuan, L. Yang, P. Mao and
L. Qu, Org. Chem. Front., 2016, DOI: 10.1039/C6QO00533K.
2 (a) S.-M. Prajapati, K.-D. Patel, R.-H. Vekariya, S.-N. Panchal
and H.-D. Patel, RSC Adv., 2014, 4, 24463;
(b) D.-E. Stephens and O.-V. Larionov, Tetrahedron, 2015,
71, 8683.
3 (a) S. Madapa, Z. Tusi and S. Batra, Curr. Org. Chem., 2008,
12, 1116; (b) J. Marco-Contelles, E. Prez-Mayoral,
A. Samadi, M.-C. Carreiras and E. Soriano, Chem. Rev.,
2009, 109, 2652; (c) J. Barluenga, F. Rodrguez and
F.-J. Fanans, Chem. Asian J., 2009, 4, 1036;
(d) V. Sridharan, P.-A. Suryavanshi and J.-C. Menndez,
Chem. Rev., 2011, 111, 7157; (e) J.-B. Bharate,
R.-A. Vishwakarma and S.-B. Bharate, RSC Adv., 2015, 5,
42020.
4 (a) Y. Wang, C. Chen, J. Peng and M. Li, Angew. Chem., Int.
Ed., 2013, 52, 5323; (b) B. Duda, S.-N. Tverdomed,
B.-S. Bassil and G.-V. Rschenthaler, Tetrahedron, 2014, 70,
8084; (c) G. Liu, M. Yi, L. Liu, J. Wang and J. Wang, Chem.
Commun., 2015, 51, 2911; (d) Y.-N. Huang, Y.-L. Li, J. Li and
J. Deng, J. Org. Chem., 2016, 81, 4645; (e) Q. Gao, S. Liu,
X. Wu, J. Zhang and A. Wu, J. Org. Chem., 2015, 80, 5984.
5 W. Ali, A. Behera, S. Guin and B.-K. Patel, J. Org. Chem.,
2015, 80, 5625 and references cited therein.
6 D.-W. Wang, H.-Y. Lin, R.-J. Cao, T. Chen, F.-X. Wu,
G.-F. Hao, Q. Chen, W.-C. Yang and G.-F. Yang, J. Agric.
Food Chem., 2015, 63, 5587.
7 H. Kumar, V. Devaraji, R. Joshi, M. Jadhao, P. Ahirkar,
R. Prasath, P. Bhavana and S. K. Ghosh, RSC Adv., 2015, 5,
65496.
8 (a) S. Khong and O. Kwon, J. Org. Chem., 2012, 77, 8257;
(b) W.-Y. Gao, K. Leng, L. Cash, M. Chrzanowski,
C.-A. Stackhouse, Y. Sun and S. Ma, Chem. Commun., 2015,
51, 4827; (c) M. V. Khedkar, P. J. Tambade, Z. S. Qureshi
and B.-M. Bhanage, Eur. J. Org. Chem., 2010, 6981;
(d) L. Luo, Z. Zhou, J. Zhu, X. Lu and H. Wang, Tetrahedron
This journal is the Partner Organisations 2017

Organic Chemistry Frontiers
Lett., 2016, 57, 4987; (e) H. Li, X. Xu, J. Yang, X. Xie,
H. Huang and Y. Li, Tetrahedron Lett., 2011, 52, 530;
(f ) M. Kuriyama, N. Hamaguchi, K. Sakata and
O. Onomura, Eur. J. Org. Chem., 2013, 3378; (g) S. Jalal,
K. Bera, S. Sarkar, K. Paul and U. Jana, Org. Biomol. Chem.,
2014, 12, 1759; (h) N. Anand, T. Chanda, S. Koley,
S. Chowdhury and M.-S. Singh, RSC Adv., 2015, 5, 7654;
Published on 06 February 2017. Downloaded by University of California - San Diego on 25/03/2017 14:45:02.
(i) E. Cini, E. Petricci, G.-I. Truglio, M. Vecchio and
M. Taddei, RSC Adv., 2016, 6, 31386; ( j) J. Zheng, Z. Li,
L. Huang, W. Wu, J. Li and H. Jiang, Org. Lett., 2016, 18,
3514.
9 (a) J. Muzart, Eur. J. Org. Chem., 2010, 3779; (b) S.-S. Stahl
and T. Diao, Compr. Org. Synth. II, 2014, 7, 178;
(c) A. Turlik, Y. Chen and T.-R. Newhouse, Synlett, 2016,
331.
10 (a) W. Gao, Z. He, Y. Qian, J. Zhao and Y. Huang, Chem.
Sci., 2012, 3, 883; (b) T. Diao, D. Pun and S.-S. Stahl, J. Am.
Chem. Soc., 2013, 135, 8205; (c) D. Pun, T. Diao and
S.-S. Stahl, J. Am. Chem. Soc., 2013, 135, 8213;
(d) A.-V. Iosub and S.-S. Stahl, ACS Catal., 2016, 6, 8201.
This journal is the Partner Organisations 2017
View Article Online
Research Article
11 Y. Shang, X. Jie, J. Zhou, P. Hu, S. Huang and W. Su, Angew.
Chem., Int. Ed., 2013, 52, 1299.
12 J. Zhou, G. Wu, M. Zhang, X. Jie and W. Su, Chem. Eur. J.,
2012, 18, 8032.
13 P. Gandeepan, P. Rajamalli and C.-H. Cheng, ACS Catal.,
2014, 4, 4485.
14 X. Jie, Y. Shang, X. Zhang and W. Su, J. Am. Chem. Soc.,
2016, 138, 5623.
15 (a) S. Ueno, R. Shimizu and R. Kuwano, Angew. Chem., Int.
Ed., 2009, 48, 4534; (b) J.-L. Zhan, M.-W. Wu, F. Chen and
B. Han, J. Org. Chem., 2016, 81, 11994.
16 (a) C.-H. Tseng, R.-W. Lin, Y.-L. Chen, G.-J. Wang, M.-L. Ho
and C.-C. Tzeng, J. Med. Chem., 2011, 54, 3103; (b) Q. Yang,
T. Xu and Z. Yu, Org. Lett., 2014, 16, 6310.
17 The fact that 5g5k were obtained only in moderate yields
is mainly due to the formation of TEMPO-related side pro-
ducts. Please see the ESI for the details.
18 (a) J.-P. Wan, Y. Jing, C. Hu and S. Sheng, J. Org. Chem.,
2016, 81, 6826; (b) J.-P. Wan, S. Cao and Y. Liu, Org. Lett.,
2016, 18, 6034.
Org. Chem. Front.