Synthesis of polysubstituted quinolines via copper(ii)-catalyzed annulation of 2-aminoaryl ketones with alkynoates

Article abstract of DOI:10.1039/c3ra45576a

Copper triflate catalyzed annulation of 2-aminoaryl ketones with internal alkynes has been developed for the synthesis of polysubstituted quinolines in high yields under solvent-free conditions. Phenyl propiolic acid afforded the 3-unsubstituted quinoline

Full text of DOI:10.1039/c3ra45576a

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Synthesis of polysubstituted quinolines via copper(II)-
catalyzed annulation of 2-aminoaryl ketones with
alkynoates†
Cite this: RSC Adv., 2013, 3, 24034
Received 4th October 2013
Accepted 10th October 2013
Avik Kumar Bagdi, Sougata Santra, Matiur Rahman, Adinath Majee
and Alakananda Hajra
*
DOI: 10.1039/c3ra45576a
www.rsc.org/advances
Copper triflate catalyzed annulation of 2-aminoaryl ketones with involving condensation between 2-aminoaryl ketone/aldehyde
internal alkynes has been developed for the synthesis of poly- and carbonyl compound bearing a reactive a-methylene group.
substituted quinolines in high yields under solvent-free conditions. However, strong acid or base and high reaction temperature are
Phenyl propiolic acid afforded the 3-unsubstituted quinolines via required for this transformation. Synthesis of diversied quin-
decarboxylation. The protocol is compatible with various internal olines is more challenging to meet up the need of medicinal and
alkynes and is expected to find wide applications due to its opera- material chemists. So the development of new approaches to
tional simplicity.
synthesize quinolines from common building blocks other than
carbonyl compounds is attractive. In this context, only a few
methods have been developed to construct the quinoline
moieties using alkynes as the precursor.11 However, these
methods are focused on the use of terminal alkynes, which is a
notable limitation in terms of substrates applicability. Internal
alkynes have rarely been used as the starting materials to
construct these scaffolds directly. Recently a one-step InCl3
catalyzed procedure has been reported; however this is not very
satisfactory with regards to yield and substrates scope.11d Liu
and co-workers also developed a method to synthesize 2-aryl-
quinolines in presence of a combination of Au and Ag.12
However, the use of highly expensive metal catalyst makes this
method less feasible in common laboratory as well as industry.
In addition, variation of alkynes is necessary to afford the
diverse substituents in these scaffolds. So there is a require-
ment for simple, versatile and effective method to construct
Quinolines represent a major class of nitrogen-containing
heterocyclic compounds which are found to be the key structural
unit in many natural products (Fig. 1).1 Quinoline derivatives
show a wide range of biological activities such as anti-malarial,2a
anti-microbial,2b anti-bacterial,2c anti-inammatory,2d anti-dia-
betic,2e anti-alzheimer,2f tyrosine kinase inhibitor,2g anti-platelet
activity,2h and anti-hypertensive.2i Quinolines, in particular,
constitute the core structure of many currently marketed drugs
such as Singulair, Tafenoquine, and Hydroxychloroquine etc.3 In
addition, quinoline based polymers have applications in the
eld of electronics, optoelectronics and nonlinear optics.
Furthermore, quinoline derivatives have been used as organo-
catalysts and are well known as useful tools for asymmetric
synthesis.4 Among various quinoline derivatives, 2-arylquinoline
scaffolds are associated with a wide range of biological proper-
ties, such as P-selectin antagonism, antimalarial, and antitumor
activities.5
Due to their wide range of bioactivities, synthesis of 2-aryl-
quinoline derivatives has gained special attention. Established
strategies for assembling quinoline rings are the classic annu-
lation reactions like Friedlander,6 Combes,7 Povarov,8 Doebner-
von Miller9 and Skraup10 syntheses etc. Among these reported
methods, Friedlander reaction is one of the simple methods
Department of Chemistry, Visva-Bharati (A Central University), Santiniketan 731235,
India. E-mail: alakananda.hajra@visva-bharati.ac.in; Fax: +91 3463 261526; Tel: +91
3463 261526
† Electronic supplementary information (ESI) available: Experimental procedure,
characterization data and NMR spectra for all compounds. See DOI:
10.1039/c3ra45576a
Fig. 1 Some biologically active compounds containing quinoline moiety.
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quinoline derivative was obtained in 66% yield aer 3 hours
and no further improvement was noticed by increasing reaction
time. Encouraged by this initial result, we proceeded to opti-
mize the reaction conditions which are summarized in Table 1.
Other common solvents such as toluene, CH3CN, dichloro-
ethane, ethanol, DMSO did not improve the yields (Table 1,
Entries 2–6). These poor results prompted us to investigate the
reaction under solvent-free conditions. Gratifyingly, the desired
product was obtained in 90% yield under neat conditions at
Scheme 1 Synthesis of polysubstituted quinolines.
ꢀ
110 C (Table 1, Entry 7). Yield of the reaction was reduced at
lower temperature (80 ꢀC, Table 1, Entry 8). Finally, the opti-
ꢀ
polysubstituted quinolines with selective control of substitution
patterns from easily available basic chemical materials.
During the last few years, signicant interest has been focused
on the development of new protocols for environmentally benign
processes those are both economically and technologically
feasible. Especially nonhazardous and less expensive metals as
well as solvent-free reactions have gained much interest in organic
synthesis. In this context, we are actively engaged for the devel-
opment of newer methodologies under solvent-free conditions.13
Due to their unique catalytic properties, copper triate have been
widely used for a variety of organic transformations.14 Based on
our continuing efforts to achieve copper-catalyzed C–C and C-
heteroatom bond formations,15 we envisaged another application
of copper triate for the synthesis of 2-arylquinoline derivatives by
the annulation of 2-aminoaryl ketones with internal alkynes
under solvent-free conditions (Scheme 1).
mized reaction conditions were set at 110 C. The variation of
the amount of the copper salt from 5 mol% to 15 mol% gave
81%, 90% and 92% yields respectively (Table 1, Entries 9, 7, 10).
Thus it was cleared that decreasing the catalyst loading gave
lower yield whereas increasing the amount did not improve the
yield so much. Among the readily available copper salts; copper
triate was proven to be the most efficient catalyst for this
reaction in terms of yields (Table 1, Entries 11–14). Other metal
triates such as Zn(OTf)2, In(OTf)3, La(OTf)3 were also surveyed
and found to be less effective for this transformation. However
no desired product was detected without the catalyst (Table 1,
Entry 15). Triic acid is not also effective, producing only 20%
desired product (Table 1, Entry 16).
Aer optimizing the reaction conditions, we turned our
attention to the substrate scope of the reaction which is
summarized in Table 2. Ethyl phenylpropiolate was reacted with
various 2-aminoaryl ketones and in all cases the desired prod-
ucts were obtained in high to excellent yields (3aa, 3ba, 3ca,
3da). It is noteworthy to mention that the reaction of 2-amino-5-
nitrobenzophenone with ethyl phenylpropiolate also gave the
corresponding annulated product with high yield (3ca). The
reaction proceeded smoothly in case of 2-aminoacetophenone
also (3ea). Ethyl methyl propiolate reacted efficiently with
2-aminoaryl ketones to afford the products (3ab, 3eb). Other
internal alkynes such as dimethyl acetylenedicarboxylate and
diethyl acetylenedicarboxylate reacted well with 2-aminoaryl
ketones under the present reaction conditions to afford various
quinoline derivatives in high yields (3bc, 3ac, 3ec, 3bd, 3ad,
3ed). Although a method reported by Taylor and Hiendel11i
described the preparation of a few phenyl substituted quinoline
derivatives such as 3ac and 3bc by the reaction of dimethyl
acetylenedicarboxylate with 2-aminobenzophenones in benzene
under reux in absence of any catalyst, it required much more
longer reaction times (24 h) compare to our present solvent-free
method. Additionally, it was unsuccessful to other alkynes and
2-aminoaryl ketones. Our present protocol is also effective for
the synthesis of 2-unsubstituted derivatives. Methyl propiolate
regioselectively produced the corresponding 2-unsubstituted
quinolines when it was reacted with various 2-aminoaryl
ketones (3be, 3de, 3ee).
We commenced our study taking 2-amino-5-chlor-
obenzophenone (1a) and ethyl phenylpropiolate (2a) as the
model substrates using copper triate (10 mol%) as catalyst in
DMF solvent at 110 ꢀC (Table 1, Entry 1). To our delight, desired
Table 1 Optimization of the reaction conditionsa
Entry
Catalyst (mol%)
Solvent
Temp (ꢀC)
Yieldb (%)
1
2
3
4
5
6
7
8
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (10)
Cu(OTf)2 (5)
Cu(OTf)2 (15)
Cu(OAc)2 (10)
CuCl2 (10)
DMF
Toluene
CH3CN
DCE
EtOH
DMSO
Neat
Neat
Neat
Neat
Neat
110
66
64
52
60
48
30
90
70
81
92
40
41
43
<10
—
Reux
Reux
Reux
Reux
110
110
80
110
110
110
110
110
110
110
110
9
10
11
12
13
14
15
16
Neat
Neat
Neat
Neat
To extend our methodology, phenyl propiolic acid was used
as an internal alkyne. Interestingly the reaction proceeded very
well and 3-unsubstituted quinolines were obtained in high
yields. Decarboxylation was occurred during the course of the
reaction (Scheme 2). So it could be used as an alternative source
of phenylacetylene. However, direct use of phenylacetylene
CuBr2 (10)
CuI (10)
—
TfOH (10)
Neat
20
a
Carried out with 1 mmol of 1a and 1 mmol of 2a in solvent (2 mL) for
3 h. b Isolated yields.
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Table 2 Substrate scopea
Scheme 4 Self condensation of 2-aminoaryl ketone.
Scheme 5 Probable mechanism.
examined. Reaction between ynone (6) and 2-aminoaryl ketone
(1e) successfully produced the corresponding quinoline (7eg) in
high yield (Scheme 3).
Other kind of internal alkynes such as diphenylacetylene,
4-octyne and alkynylphosphonate were also tested, but they did
Reaction conditions: 1 mmol of 1 and 1 mmol of 2 in the presence of not afford the desired products. In these cases self condensa-
a
Cu(OTf)2 (10 mol%) at 110 ꢀC; Isolated yields.
tion of 2-aminobenzophenone was occurred under the present
reaction conditions (Scheme 4).
Based on the literature the probable mechanism for this
produced a mixture of product including dimerization of phe-
nylacetylene. 2-Amino-5-chlorobenzophenone and 2-amino-
acetophenone both gave the corresponding decarboxylative
products under the present reaction conditions (5af, 5ef).
In addition to phenyl propiolic acid and different alkynoates,
conjugated ynone such as diphenylpropynone (6) was also
cyclization reaction is outlined in Scheme 5. Presumably, the
process proceeds through Michael addition of 2-aminoaryl
ketones to alkynes followed by intramolecular condensation
and dehydration. However, we are unable to isolate the Michael
adduct under the present reaction conditions. Probably, aer
forming the Michael adduct, it transformed to the nal product
quickly. In case of phenyl propiolic acid, decarboxylation might
occur aer cyclization.
Conclusions
In conclusion, we have developed a sustainable method for the
synthesis of densely functionalized quinolines via copper tri-
ate catalyzed annulation of 2-aminoaryl ketones with various
internal alkynes. To the best of our knowledge this is the rst
report for the use of phenyl propiolic acid as an alternative of
terminal alkyne for the synthesis of quinolines. Various types of
substituted quinolines could be synthesized by choosing proper
alkynes employing this methodology. Furthermore, H2O as the
only byproduct makes this transformation atom efficient. In
nutshell, simple reaction procedure, environmentally friendly
reaction conditions avoiding toxic organic solvent, cheap cata-
lyst and aerobic reaction conditions make this procedure
Scheme 2 Synthesis of quinolines via decarboxylation of phenyl propiolic acid.
Scheme 3 Synthesis of quinoline from ynone.
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convenient and useful for the synthesis of diversied quino-
lines. Further study to broaden the scope of this methodology
towards pharmaceuticals and biologically active compounds are
under investigation.
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Acknowledgements
A. H. and A. M. acknowledge the nancial support from the
DST, Govt. of India (Grant no. SR/S5/GC-05/2010). We are
thankful to DST-FIST and UGC-SAP. A. K. B. and S. S. thank
CSIR, New Delhi, India and UGC, New Delhi, India for their
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