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

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

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

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

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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
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Scheme 4 Control experiments (II).

Province (15HASTIT005) for financial support.

Notes and references

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