Copper-Catalyzed N- and O-arylation of amides: Alternative approaches to 3,4-dihydroquinolin-2-ones, quinolin-2-ones, and 12h-chromeno[2,3-b]quinolin-12- ones

Article abstract of DOI:10.1002/ejoc.201301373

The efficient syntheses of 3-cyanoquinolin-2-ones, 3-(2-bromobenzyl)-3- cyano-3,4-dihydroquinolin-2-ones, 3-(2-bromobenzyl)quinolin-2-ones, and 12H-chromeno[2,3-b]quinolin-12-ones through copper-catalyzed N- and O-arylation of amides by using readily avai

Full text of DOI:10.1002/ejoc.201301373

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201301373
Copper-Catalyzed N- and O-Arylation of Amides: Alternative Approaches to
3,4-Dihydroquinolin-2-ones, Quinolin-2-ones, and 12H-Chromeno[2,3-b]-
quinolin-12-ones
Xinying Zhang,*[a] Xiaojie Guo,[a] Liangliang Fang,[a] Yunping Song,[a] and Xuesen Fan*[a]
Keywords: Nitrogen heterocycles / Oxygen heterocycles / Copper / Domino reactions
The efficient syntheses of 3-cyanoquinolin-2-ones, 3-(2-
bromobenzyl)-3-cyano-3,4-dihydroquinolin-2-ones, 3-(2-
bromobenzyl)quinolin-2-ones, and 12H-chromeno[2,3-b]-
quinolin-12-ones through copper-catalyzed N- and O-aryl-
ation of amides by using readily available 2-bromobenzyl
bromides and cyanoacetamides as starting materials were
developed.
due to the fact that copper compounds are generally in-
expensive, easy to handle, and efficient. Through these
Introduction
Quinolin-2-ones and 3,4-dihydroquinolin-2-ones have at- reactions, various N-fused heterocyclic compounds could
tracted much attention, because these scaffolds exist in nu- be prepared with good efficiency.[13] As a continuation of
merous natural products and synthetic compounds showing our study in this field[14] and considering that quinolin-2-
potent biological and pharmaceutical properties.[1–6] In ad- ones bearing an electron-withdrawing group at the 3-
dition, functionalized quinolin-2-ones and 3,4-dihydroquin- position are attractive synthetic targets owing to their
olin-2-ones are valuable synthetic intermediates for the con- pharmacological properties,[15] we proposed a domino re-
struction of sophisticated heterocyclic systems.[7] As a re- action toward 3-cyano-3,4-dihydroquinolin-2-one (A,
sult, extensive efforts have been made in developing efficient Scheme 1) on the basis of the envisioned C-benzylation of
methods for their synthesis.[8] In general, the quinolin-2-one cyanoacetamide (2a) with 2-bromobenzyl bromide (1a)
framework could be constructed through either acid-cata- followed by intramolecular N-arylation of the in situ
lyzed cyclization of acyl acetoanilides, commonly known as formed 3-(2-bromophenyl)-2-cyanopropanamide (3a,
the Knorr synthesis,[9] or through the Friedländer reac- Scheme 1). To the best of our knowledge, there are only
tion[10] of 2-aminophenyl ketones. Along with their growing two pioneering works on the copper-catalyzed synthesis of
importance, some more efficient and practical synthetic quinolin-2-ones, in which 3,3-diarylacrylamides were used
strategies toward quinolin-2-ones have also been success- as substrates and 4-arylquinolin-2-ones were obtained as
fully developed.[11]
the final products.[16] So far, the copper-catalyzed synthe-
Copper-catalyzed coupling reactions have emerged as a sis of 3-substituted quinolin-2-ones has yet to be devel-
promising field in synthetic chemistry.[12] This is mainly oped.
Scheme 1. Proposed synthesis of 3-cyano-3,4-dihydroquinolin-2-one (A).
Results and Discussion
[a] School of Chemistry and Chemical Engineering, Key
Laboratory of Green Chemical Media and Reactions, Ministry
of Education, Henan Normal University,
The proposed transformation (Scheme 1) was first exam-
Xinxiang, Henan 453007, P. R. China
ined by treating a mixture of 1a and 2a with CuI and
K2CO3 in DMF. After stirring the mixture at 110 °C for
3 h, to our surprise, envisioned 3-cyano-3,4-dihydroquin-
olin-2-one (A) was not obtained. Instead, 3-(2-bromo-
E-mail: xinyingzhang@htu.cn
xuesen.fan@htu.cn
http://www.htu.cn/s/57/t/1350/a/28234/info.jspy
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301373.
Eur. J. Org. Chem. 2013, 8087–8093
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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X. Zhang, X. Guo, L. Fang, Y. Song, X. Fan
SHORT COMMUNICATION
Table 1. Study of the reaction of 1a and 2a under copper catalysis.[a] bromobenzyl bromides bearing various functional groups
were prepared and tested. We were delighted to find that
substrates with either electron-donating or electron-with-
drawing substituents on the aryl ring underwent this tan-
dem reaction smoothly (Table 2). Moreover, it allowed di-
verse functional groups, such as chloro, fluoro, cyano, and
methoxy, to be tolerated under the reaction conditions. No-
tably, with ortho-, meta-, and para-substituted substrates,
the reaction proceeded in an almost equally smooth man-
ner, and therefore, the substituents show little steric effect
on the outcome of this tandem reaction. With a naphthyl
Entry 1a/2a Catalyst
Base
Solvent
T
t
Yield [%][b]
[°C] [h] 4a 5a
or heteroaryl unit, corresponding products 5k and 5l were
successfully obtained.
1
2
3
4
5
6
7
8
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:2
1:3
2:1
3:1
3:1
CuI
CuBr
CuCl
K2CO3 DMF
K2CO3 DMF
K2CO3 DMF
110
110
110
110
110
3
3
3
3
3
4
4
4
3
3
3
2
2
2
trace 55
trace 50
trace 52
trace 45
trace 42
trace 21
trace 44
trace 39
trace 75
trace 70
trace 66
Having established an efficient protocol for the prepara-
tion of 3-(2-bromobenzyl)-3-cyano-3,4-dihydroquinolin-2-
ones 5, we then moved our focus back to the synthesis of
3-cyanoquinolin-2-one (4a). As mentioned above, treatment
of a mixture of 1a and 2a with a copper catalyst and a base
promoter gave 5a as the major product, whereas 4a was
formed only in trace amount (Table 1). Detailed studies on
how to suppress the formation of 5a and increase the yield
of 4a were then performed. After some trials and errors,
we found that if 2a (3 equiv.) was first treated with K2CO3
(1 equiv.) in DMF at 90 °C for 5 min followed by the ad-
dition of 1a (1 equiv.) and stirring of the resulting mixture
at 90 °C for 2 h, 3-(2-bromophenyl)-2-cyanopropaneamide
(3a), the precursor of 4a, was formed as the main product.
Addition of CuI to the resulting mixture containing 3a,
however, resulted in a complicated mixture, and 4a was iso-
Cu(OAc)2 K2CO3 DMF
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
Cs2CO3 DMF
K2CO3 DMSO 110
K2CO3 toluene 110
K2CO3 iPrOH
K2CO3 glycol
K2CO3 glycol
K2CO3 glycol
K2CO3 glycol
K2CO3 glycol
K2CO3 glycol
110
110
110
110
110
110
90
9
10
11
12
13
14
–
–
–
85
98
90
[a] Reagents and conditions: 1a (0.5 mmol, in entries 1–11), 2a
(0.5 mmol, in entries 12–14), catalyst (0.1 mmol), base (1.5 mmol),
solvent (3 mL). [b] Yield of isolated product.
benzyl)-3-cyano-3,4-dihydroquinolin-2-one (5a) was fur- lated in 5% yield. Under these circumstances, we decided
nished in 55% yield. In addition, 3-cyanoquinolin-2-one to try the synthesis of 4a in two discrete steps. Thus, 3a was
(4a), the dehydrogenation product of A, was also formed first synthesized on the basis of the optimized conditions
but only in trace amount (Table 1, entry 1). Next, different described above. Then, it was treated with CuI and K2CO3
Cu sources including CuI, CuBr, CuCl, and Cu(OAc)2; in different solvents. We were pleased to find that 4a was
bases such as K2CO3 and Cs2CO3; various solvents (DMF, obtained in 35% yield if the reaction was run in ethylene
DMSO, toluene, 2-propanol, ethylene glycol); and different glycol at 110 °C (Table 3, entry 3). Remarkably, a study on
molar ratios of substrates (1a/2a = 1:1, 1:2, 1:3, 2:1, 3:1) the effects of various additives on this reaction revealed that
were screened. Under these conditions, however, the forma- the addition of l-proline improved the yield of 4a to 70%
tion of A was not observed and the yield of 4a was not (Table 3, entry 8). Experiments with different copper cata-
clearly improved (Table 1). In contrast, 5a was found to be lysts showed that CuCl2, CuCl, CuBr, and Cu(OAc)2 were
the main product in all cases and its yield could be im- inferior to CuI in promoting this reaction (Table 3, en-
proved to as high as 98% if 3 equiv. of 1a and 1 equiv. of tries 9–12). In addition, the use of Cs2CO3 as the base pro-
2a were treated with 0.2 equiv. of CuI and 3 equiv. of moter did not improve the reaction (Table 3, entry 13). It
K2CO3 in ethylene glycol at 110 °C for 2 h (Table 1, en- was also observed that reaction temperatures lower than
try 13). At this stage, it occurred to us that even though the 110 °C resulted in decreased yields of 4a (Table 3, entries 14
originally envisioned 3-cyanoquinolin-2-one was not ob- and 15).
tained, the unexpected formation of 5a with excellent effi-
To study the scope of this copper-catalyzed tandem reac-
ciency could be equally interesting and rewarding owing to tion leading to 3-cyanoquinolin-2-ones, 3-(2-bromophenyl)-
the following two reasons. First, the above reaction provides 2-cyanopropanamides 3 were prepared and treated with
an easy and highly efficient approach toward 3,3-disubsti- CuI in the presence of l-proline in ethylene glycol. Sub-
tuted 3,4-dihydroquinolin-2-one. Second, as amide, cyano, strates with either electron-rich or electron-deficient phenyl,
and bromo groups are exceptionally versatile in organic naphthyl, and pyridinyl moieties reacted smoothly to afford
transformations, compounds bearing these functional the corresponding products in moderate to good yields (i.e.,
groups, such as 5a, are expected to be used as valuable and 4a–k, Table 4). The halogenated aromatic moiety of the
versatile synthetic intermediates.
substrates survived the reaction conditions very well. More-
With our preliminary studies complete, we next exam- over, N-benzyl- and N-propyl-substituted substrates under-
ined the generality of the synthetic protocol toward 3,4- went the N-arylation efficiently to give N-substituted 3-
dihydroquinolin-2-ones 5. For this purpose, a series of 2- cyanoquinolin-2-ones 4l–o in moderate yields (Table 4).
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Copper-Catalyzed N- and O-Arylation of Amides
Table 2. Preparation of 3,3-disubstituted 3,4-dihydroquinolin-2-ones 5.[a,b]
[a] Reagents and conditions: 1 (3 mmol), 2a (1 mmol), CuI (0.2 mmol), K2CO3 (3 mmol), ethylene glycol (5 mL), 110 °C, 2 h. [b] Yields
of isolated products are given. [c] The structure of 5a was confirmed by X-ray diffraction analysis.[17]
Table 3. Optimization of the conditions for the synthesis of 4a.[a]
As mentioned above, the bromo, cyano, and amide
groups embedded in 5a offer the opportunity for further
structural elaboration. In this regard, we envisioned an in-
tramolecular O-arylation of 5a with the aim to obtain quin-
oline-annulated chromene derivative I (Scheme 2) by taking
advantage of the reactivities of the 2-bromo and amide
functionalities. To check this feasibility, 5a was subjected to
several copper catalysts and different organic and inorganic
bases. Expected chromene I was not obtained under the re-
action conditions screened. However, during this investiga-
tion, we made a serendipitous discovery that under basic
conditions, 5a underwent elimination of hydrogen cyanide
to give 3-(2-bromobenzyl)quinolin-2(1H)-one (6a). After
some trials, we were gratified to find that 6a could be pre-
pared in 87% yield by treating 5a with sodium methoxide
in DMSO, and this results in an efficient approach toward
3-substituted quinolin-2-ones (Scheme 2). Considering that
the benzyl group is easily oxidized to a benzoyl moiety, 6a
is a potential precursor of quinolin-2-ones bearing an elec-
tron-withdrawing group at the 3-position. More rewardin-
gly, further explorations revealed that treatment of 6a with
CuI and K2CO3 in DMF in air initiated intramolecular O-
arylation to give quinoline-annulated chromene B, but it
also brought about an added bonus by accomplishing
Entry Catalyst
Base
Ligand[b]
Solvent
T
[°C]
Yield
[%][c]
1
2
3
4
5
6
7
8
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
–
–
–
DMF
iPrOH
glycol
110
110
110
110
110
110
110
110
110
110
110
110
110
60
15
22
35
22
30
52
26
70
25
47
52
45
48
35
50
DMEDA glycol
TMEDA
DMAP
glycol
glycol
1,10-phen glycol
l-proline
l-proline
l-proline
l-proline
l-proline
glycol
glycol
glycol
glycol
glycol
glycol
glycol
glycol
9
CuCl2
CuCl
CuBr
10
11
12
13
14
15
Cu(OAc)2 K2CO3
CuI
CuI
CuI
Cs2CO3 l-proline
K2CO3
K2CO3
l-proline
l-proline
90
[a] Reagents and conditions: 3a (0.5 mmol), catalyst (0.1 mmol),
base (1.0 mmol), additive (0.10 mmol), solvent (3 mL), 10 h.
[b] DMEDA
N,N,NЈ,NЈ-tetramethylethylenediamine, DMAP
=
N,NЈ-dimethylethylenediamine, TMEDA
=
=
4-dimethyl-
aminopyridine, 1,10-phen = 1,10-phenanthroline. [c] Yield of iso-
lated product.
Eur. J. Org. Chem. 2013, 8087–8093
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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X. Zhang, X. Guo, L. Fang, Y. Song, X. Fan
SHORT COMMUNICATION
Table 4. Synthesis of 3-cyanoquinolin-2-one derivatives 4.[a,b]
It is well established that heteroannulated chromone de-
rivatives such as 7a are endowed with valuable pharmaco-
logical properties such as cytotoxic, antiviral, antifungal,
and antioxidant activities.[18] Notwithstanding their impor-
tance, efficient synthetic methods toward 12H-chromeno-
[2,3-b]quinolin-12-ones are very limited. In regard, Ishar
and Queguiner have reported two synthetic strategies inde-
pendently by using 3-formylchromone and 2-chloroquinol-
ine as the starting materials following the synthetic path-
ways shown in Scheme 3.[19] Although these elegant strate-
gies are reliable and efficient, their use of functionalized
Table 5. Preparation of 3-(2-bromobenzyl)-quinolin-2-ones 6.[a,b]
[a] Reagents and conditions: 3 (0.5 mmol), CuI (0.1 mmol), K2CO3
(1.0 mmol), l-proline (0.10 mmol), glycol (3 mL), 110 °C, 10 h.
[b] Yields of isolated products are given.
[a] Reagents and conditions: 5 (1 mmol), CH3ONa (3 mmol),
DMSO (5 mL), 110 °C, 2 h. [b] Yields of isolated products are
given.
benzyl oxidation to afford 12H-chromeno[2,3-b]quinolin-
12-one (7a) in good efficiency (Scheme 2).
Scheme 2. Formation of 6a and 7a from 5a.
Scheme 3. Literature procedures for the synthesis of 7a.
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Copper-Catalyzed N- and O-Arylation of Amides
Scheme 4. Plausible pathways for the formations of 4a, 5a, 6a, and 7a.
chromone and chlorinated quinoline as starting materials
On the basis of the above facts, plausible pathways for
and corrosive acid and air- and moisture-sensitive base as the formation of 4a, 5a, 6a, and 7a are proposed in
reagents may limit their application scope and substrate Scheme 4. First, base-promoted C-benzylation of cyano-
generality. Therefore, the formation of 7a from readily ob- acetamide (2a) with 2-bromobenzyl bromide (1a) affords 3-
tainable 5a under relatively mild conditions validates the (2-bromophenyl)-2-cyanopropanamide (3a). Subsequent in-
potentiality of this method as an alternative protocol for tramolecular N-arylation of 3a under copper catalysis gives
the synthesis of 12H-chromeno[2,3-b]quinolin-12-ones.
unstable intermediate A, from which 4a is formed through
In the next stage, the transformation of 5 into 3-benzyl- in situ dehydrogenation. In contrast, 3a could undergo an-
quinolin-2-ones 6 was studied. The results listed in Table 5 other C-benzylation with 1a to give intermediate C. Cop-
show that under the optimized reaction conditions, 5 under- per-catalyzed intramolecular N-arylation of C gives 5a. Un-
went the base-catalyzed elimination smoothly to afford 6 in der suitable basic conditions, elimination of HCN occurs
moderate to good yields.
with 5a to give 6a. Under the catalysis of CuI, 6a undergoes
As for the synthesis of 12H-chromeno[2,3-b]quinolin-12- intramolecular O-arylation to give intermediate B. Subse-
ones 7, the results listed in Table 6 show that the transfor- quent oxidation of B by air as a plausible oxidant affords
mation of 3-(2-bromobenzyl)-substituted quinolin-2-ones 6 7a as the final product.
into 7 was generally efficient, and this thus results in a novel
and practical approach toward N- and O-containing poly-
cyclic frameworks.
Conclusions
In summary, we have uncovered some novel and interest-
ing copper-catalyzed intramolecular N-arylation and O-
arylation reactions of amides. Through these reactions, a
variety of 3,3-disubstituted 3,4-dihydroquinolin-2-ones, 3-
substituted quinolin-2-ones, and 12H-chromeno [2,3-b]-
quinolin-12-ones were obtained in moderate to excellent
yields by using readily available 2-bromobenzyl bromides
and cyanoacetamides as starting materials. Compared with
literature procedures toward 3,4-dihydroquinolin-2-ones,
quinolin-2-ones, and 12H-chromeno [2,3-b]-quinolin-12-
ones, the strategies developed herein showed advantages
such as readily available starting materials, high efficiency,
and practical reaction conditions. Efforts to further eluci-
date the reaction mechanism and to find more applications
of copper-catalyzed N-arylation and O-arylation reactions
of amides are currently underway in our laboratory.
Table 6. Preparation of 12H-chromeno[2,3-b]quinolin-12-ones
7.[a,b]
Experimental Section
General Methods: All commercial reagents and solvents were used
without further purification. Melting points were recorded with a
micromelting point apparatus. 1H NMR and 13C NMR spectra
were recorded at 400 and 100 MHz, respectively. Splitting patterns
[a] Reagents and conditions: 6 (0.5 mmol), CuI (0.1 mmol), K2CO3
(1.0 mmol), DMF (3 mL), 110 °C, 10 h. [b] Yields of isolated prod-
ucts are given.
Eur. J. Org. Chem. 2013, 8087–8093
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X. Zhang, X. Guo, L. Fang, Y. Song, X. Fan
SHORT COMMUNICATION
are designated as s (singlet), d (doublet), t (triplet), q (quartet), m
(multiplet), and br. (broad). High-resolution mass spectra (HRMS)
were obtained by using a MicrOTOF mass spectrometer. All reac-
tions were monitored by thin-layer chromatography (TLC) by using
silica gel plates (silica gel 60 F254 0.25 mm), and components were
visualized by observation under UV light.
Changjiang Scholars and Innovative Research Team in University
(PCSIRT) (IRT 1061) for financial support.
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General Procedure for the Preparation of 3-Cyanoquinolin-2-ones 4:
To a flask containing a solution of 3-(2-bromophenyl)-2-cyano-
propanamide 3 (0.5 mmol) in ethylene glycol (3 mL) was added CuI
(190 mg, 0.1 mmol), l-proline (11.5 mg, 0.1 mmol), and K2CO3
(138 mg, 1.0 mmol). Then, the mixture was stirred at 110 °C for
10 h. After cooling the reaction mixture to room temperature,
water (10 mL) was added. The mixture was extracted with ethyl
acetate. The combined organic layer was washed with brine and
then dried with anhydrous Na2SO4. The solvent was evaporated
under vacuum, and the crude product was purified by chromatog-
raphy on silica gel to afford 3-cyanoquinolin-2-ones 4.
General Procedure for the Preparation of 3-(2-Bromobenzyl)-3-
cyano-3,4-dihydroquinolin-2-ones 5: To a flask containing a solution
of 2-bromobenzyl bromide (3 mmol) and cyanoacetamide (84 mg,
1 mmol) in ethylene glycol (5 mL) was added CuI (380 mg,
0.2 mmol) and K2CO3 (415 mg, 3 mmol). Then, the mixture was
stirred at 110 °C for 2 h. After cooling the reaction mixture to room
temperature, water (10 mL) was added. The mixture was extracted
with ethyl acetate. The combined organic layer was washed with
brine and then dried with anhydrous Na2SO4. The solvent was
evaporated under vacuum, and the crude product was purified by
chromatography on silica gel to afford 3-(2-bromobenzyl)-3-cyano-
3,4-dihydro quinolin-2-ones 5.
General Procedure for the Preparation of 3-(2-Bromobenzyl)quin-
olin-2-ones 6: To
a flask containing a solution of 3-(2-
bromobenzyl)-3-cyano-3,4-dihydroquinolin-2-one 5 (1 mmol) in
DMSO (5 mL) was added sodium methoxide (162 mg, 3 mmol).
Then, the mixture was stirred at 110 °C for 2 h. After cooling the
reaction mixture to room temperature, water (10 mL) was added.
The mixture was extracted with ethyl acetate. The combined or-
ganic layer was washed with H2O and brine and then dried with
anhydrous Na2SO4. The solvent was evaporated under vacuum,
and the crude product was purified by chromatography on silica
gel to afford 3-(2-bromobenzyl)quinolin-2-ones 6.
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General Procedure for the Preparation of 12H-Chromeno[2,3-b]quin-
olin-12-ones 7: To a flask containing a solution of 3-(2-bromo-
benzyl)quinolin-2-one 6 (0.5 mmol) in DMF (3 mL) was added CuI
(190 mg, 0.1 mmol) and K2CO3 (138 mg, 1.0 mmol). Then, the
mixture was stirred at 110 °C for 10 h. After cooling the reaction
mixture to room temperature, water (10 mL) was added. The mix-
ture was extracted with ethyl acetate. The combined organic layer
was washed with brine, dried, and then evaporated under vacuum.
The crude product was purified by chromatography on silica gel to
afford 12H-chromeno[2,3-b]quinolin-12-ones 7.
Supporting Information (see footnote on the first page of this arti-
1
cle): Experimental details; characterization data; copies of the H
NMR and 13C NMR spectra of 4a–o, 5a–l, 6a–f, and 7a–f; and the
X-ray crystal structure of 5a.
Acknowledgments
The authors are grateful to the National Natural Science Founda-
tion of China (NSFC) (grant numbers 21272058, 21172057), the
Research Fund for the Doctoral Program of Higher Education
(RFDP) (grant number 20114104110005), and the Program for
8092
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Received: September 10, 2013
Published Online: November 19, 2013
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