Microwave-assisted preparation of quinolone and quinoline derivatives

Article abstract of DOI:10.1055/s-0029-1219565

Quinolinone derivatives can be obtained in microwave-assisted syntheses by reaction of aniline derivatives with acetylene dicarboxylic esters, a malonic acid diester or -keto ester derivatives. The reaction proceeds under mild conditions in short reaction

Full text of DOI:10.1055/s-0029-1219565

LETTER
1081
Microwave-Assisted Preparation of Quinolone and Quinoline Derivatives
Microwave-Assiste
d
S
a
ynthesis rkus Albrecht,*a Olga Osetska,a Toni Rantanen,a Roland Fröhlich,b Carsten Bolma
c
Institut für Organische Chemie, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
Fax +49(241)8092385; E-mail: markus.albrecht@oc.rwth-aachen.de
Organisch-Chemisches Institut, Universität Münster, Corrensstr. 40, 48149 Münster, Germany
d
Received 18 January 2010
Here, we present a facile procedure for the preparation of
quinolinones that are functionalized in the 2- or 3-posi-
tion. The compounds can easily be modified to obtain the
respective 4-chloro quinolines.
Abstract: Quinolinone derivatives can be obtained in microwave-
assisted syntheses by reaction of aniline derivatives with acetylene
dicarboxylic esters, a malonic acid diester or b-keto ester deriva-
tives. The reaction proceeds under mild conditions in short reaction
times. Two of the quinolinones were transformed into the corre-
sponding 4-chloroquinolines either by conventional heating or in a
microwave-assisted reaction. Further modifications resulted in the
formation of the boron adduct or in an agglomerate. The latter was
characterized by X-ray crystal structure analysis.
CO2Me
2a
O
CO2Me
A or B
MeO2C
MeOH, r.t.
95–98%
Key words: quinoline, quinolinone, one-pot synthesis, microwave
N
CO2Me
H
N
CO2Me
OMe
H
3
OMe
4
Many natural products are based on the quinoline hetero-
cyclic system. As the most prominent, the cinchona alka-
loids have to be mentioned.1 This kind of nitrogen-
heterocycle is important in medicinal chemistry for the
treatment of various diseases.2,3 In the form of the 8-hy-
droxyquinolinate, quinolines are effective metal chelators
that can be used for analytical purposes.4
A: PPA, 120 °C, 1 h, 12%
B: MW, 250 °C, Ph2O, 10 min, 81%
NH2
OMe
1
EtO2C
CO2Et
C or D
O
CO2Et
88–90%
N
H
CO2Et
5
6
N
H
OMe
In course of our studies on metallosupramolecular sys-
tems (helicates)5 as well as anion receptors,6 we became
interested in the quinoline skeleton. Despite the simple
structure, facile approaches, especially to highly substitut-
ed derivatives, are still lacking. Traditional synthetic
routes (Skraup, Doebner-von Miller, Friedländer) involve
the use of arylamines or aminoaryl ketones or aldehydes
and a reactive component. Usually the synthesis proceeds
under extremely harsh conditions. In particular, the pyri-
dine rings are difficult to functionalize. Substitution at this
unit is usually approached by condensation of anilines
with b-keto esters, b-diketones or b-keto aldehydes fol-
lowed by thermal cyclization.7
7
OMe
OMe
EtO2C
benzene, reflux, 15 h
C: Dowtherm or Ph2O, 235 °C, 0%
D: MW, 250 °C, Ph2O, 10 min, 78%
Scheme 1 Synthesis of quinolinones bearing substituents in the 2-
position (4) or the 3-position (7). The cyclization was investigated
using classical (A, C) or microwave (B, D) conditions.
In order to prepare ester-substituted quinolones, we used
condensation reactions of 2-methoxyaniline (1) with ei-
ther acetylene dicarboxylic acid esters 2 or with diethyl
methoxymethylene malonate (5; Scheme 1).
Aniline 1 and dimethyl acetylene dicarboxylate (2a) re-
acted in an aza-Michael-type reaction, forming the addi-
tion product 3 in 95–98% yield. Cyclization to form the
heterocycle 4 proceeded at 120 °C in the presence of poly-
phosphoric acid (PPA) in low yield (12%). However,
when the same reaction was conducted under microwave
irradiation (Ph2O, 250 °C, 1 h) in the absence of PPA, the
yield increased to 81%. Isolation of 4 was achieved by
simply adding n-hexane to the reaction mixture to precip-
itate the product.11 Thus, under microwave irradiation the
yields were improved and the reaction times were short-
ened.
Recently, microwave-assisted synthesis was identified as
a method that can allow coupling reactions to proceed un-
der mild conditions, very often with high selectivity.8
However, this technique has been only rarely used for the
preparation of quinoline derivatives. In most cases, acidic
conditions, solid supports, or metal catalysts are still re-
quired.9 One approach was described in which quinoline
derivatives were obtained in a one-pot, microwave-assist-
ed coupling–isomerization reaction. However, functional-
ization at the heterocycle of the quinoline system was
restricted to only a few positions.10
Similar results were obtained for the preparation of 7. The
first condensation step between 1 and 5 proceeded well
(88–90% yield), but even at elevated temperatures
(235 °C) under conventional heating, the cyclization to 7
did not take place either in Dowtherm or in diphenyl ether.
SYNLETT 2010, No. 7, pp 1081–1084
Advanced online publication: 02.03.2010
DOI: 10.1055/s-0029-1219565; Art ID: G00510ST
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
1
0

1082
M. Albrecht et al.
LETTER
CO2Et
O
MeO2C
CO2Me
2
2b
NH2
EtO2C
N
H
CO2Me
MeO
CO2Et
CO2Et
MeOH, reflux,
15 h
OMe
4
9
MW, Ph2O
5 min, 120 °C
then
95%
N
closed vessel: 54%
open vessel: 38%
8
H
NH2
OMe
15 min, 250 °C
MW, Ph2O
44%
OMe
O
1
CO2Et
O
MeO
CO2Et
N
5
H
7
OMe
OMe
EtO2C
N
H
CO2Et
closed vessel: 41%
open vessel: 19%
10
CO2Et
Scheme 3 One-pot synthesis of quinolinones 4 and 7 under micro-
wave conditions at 1 mmol (closed vessel) or 10 mmol (open vessel)
scales of starting materials
2b
EtO2C
NH2
CO2Et
CO2Et
MeOH, r.t.,
15 h
diation for 5 minutes at 120 °C and then for 15 minutes at
250 °C. Quinolinone 4 was obtained in the closed vessel
reaction in 54%, whereas in the open vessel reaction the
yield dropped to 38%. In case of 7, yields of 41% (closed
vessel) and 19% (open vessel) were obtained. Thus, for
small-scale reactions, the simple one-pot procedure ap-
pears appropriate, but for larger scales, the multi-step pro-
cedure is beneficial.
12
82%
O2N
N
H
O2N
11
MW, Ph2O,
10 min
NO2
O
O
+
N
H
CO2Et
O2N
N
H
CO2Et
30%
To extent the scope of the reaction, b-keto esters 15 and
17 were then introduced into the microwave-assisted one-
pot, two-step procedure (Scheme 4). Surprisingly, only
the reaction between 1 and 15 produced the expected
quinolinone 16 (48% yield); condensation of 1 with 17 re-
sulted in the formation of urea 18.15 From a mechanistic
point of view, we assume that aniline 1 formed an amide
with the ester unit of 17. In a second step, an additional
aniline 1 attacked the amide carbonyl carbon and acetone
was split off in a retro-Claisen condensation type reaction.
13
14
32%
Scheme 2 Preparation of 6-methoxy- (10) and 7- or 5-nitroquino-
linone derivatives (13 or 14, respectively) in the microwave-assisted
cyclization reaction
On the other hand, under microwave irradiation (250 °C)
product 7 was obtained in 78% yield after 10 minutes.
In order to study the versatility of this approach, various
anilines were reacted with diester 2b (Scheme 2). The
aza-Michael reaction with the electron-rich 8, as well as
the electron-deficient aniline 11, proceeded in almost
quantitative yield to produce 9 and 12, respectively. After
microwave-assisted cyclization of 9, 6-methoxy-substi-
tuted quinolone 10 was obtained in 44% yield.14
In a follow-up reaction, quinolinone 4 was transformed
into the quinoline 19 by reacting 4 with POCl3
(Scheme 5).16 In this manner, 4-chloro quinoline 19 was
obtained in 68% yield. In order to include the last reaction
Cyclization of 12 under similar conditions (MW, Ph2O, 10
min) led to two regioisomers. The 7-nitro-, as well as the
5-nitro compounds were each obtained in approximately
30% yield and could be easily separated by crystalliza-
tion. The overall yield in the latter transformation was
good (62% combined yield of 13/14).
OEt
O
O
O
15
N
H
OMe
16
48%
Next, we wished to simplify the method further and to de-
velop a one-pot aza-Michael – cyclization protocol. To
this end, one-pot reaction sequences starting with 1 were
tested in order to obtain either 4 or 7 on both 1 and 10
mmol scales (Scheme 3). The small-scale reactions could
be performed using a closed vessel, whereas an open ves-
sel had to be used on the larger scale in order to allow vol-
atile side products (e.g. methanol) to exhaust. In the
experimental procedure, 1 and 2 (or 1 and 5) were dis-
solved in diphenyl ether and submitted to microwave irra-
MW, 250 °C,
Ph2O
NH2
OMe
1
O
OEt
N
N
H
H
17
OMe
OMe
O
O
18
52%
Scheme 4 One-pot reaction of b-keto esters 15 and 17 to give 16
and 18, respectively
Synlett 2010, No. 7, 1081–1084 © Thieme Stuttgart · New York

LETTER
Microwave-Assisted Synthesis
1083
step into the microwave-assisted reaction sequence, we ir-
radiated the precursor 3 for 5 minutes at 120 °C. After
this, POCl3 was added and the mixture was irradiated for
a further 5 minutes at 150 °C. Following this procedure,
quinoline 19 was obtained in 24% yield. In contrast, the
corresponding three-step procedure starting from 1 did
not lead to the formation of significant amounts of 19 in
the one-pot sequence. In a similar manner, chloroquino-
line 20 was prepared in 65% yield by microwave-assisted
reaction from 7 using POCl3 as solvent.
In order to further transform 19 by cleaving the methyl
ether, BBr3 was added. However, the desired hydroxy-
quinoline could not be isolated. Instead, boron adduct 21
was obtained in small quantities.
Figure 1 Solid-phase structure of the 1:1 adduct 22·23·2H2O
showing the formation of an agglomerate by p–p stacking [C (black),
H (white), O (red), N (green), Cl (brown), Br (orange)]
pounds, whereas the esters were hydrolyzed to the carbox-
ylic acids.
Attempts to cleave the methyl ether of 19 by reaction with
aqueous HBr resulted in a precipitate, NMR (DMSO-d6)
analysis of which indicated the presence of quinolines 22
and 23 in a ratio of 1:1. It was not possible to separate the
two compounds.
In conclusion, we have developed a two-step, one-pot pro-
tocol for the synthesis of substituted quinolones, which
can be transformed to the corresponding quinolines. Mi-
crowave irradiation proved to be a suitable tool to obtain
the products by simple procedures with short reaction
times, in good yields.
X-ray crystal structure analysis of a single crystal revealed
that 22 and 23 formed a strong aggregate with p–p stack-
ing (distance of approximately 3.5 Å) between the proto-
nated 4-hydroxyquinoline 22 and the chloroquinoline 23
(Figure 1).17 The methyl ether remained in both com-
Acknowledgment
This work was supported by the Fonds der Chemischen Industrie
and the Deutsche Forschungsgemeinschaft (SPP 1166 and SPP
1179).
O
CO2Me
N
CO2Me
N
CO2Me
References and Notes
H
H
OMe
OMe
4
3
(1) (a) Michael, J. P. Nat. Prod. Rep. 2001, 18, 543.
(b) Balasubramanian, M.; Kelay, J. G. In Comprehensive
Heterocyclic Chemistry II, Vol. 5; Katritzky, A. R.; Rees,
C. W.; Scriven, E. F. V., Eds.; Pergamon: Oxford, 1996, 245.
(2) Polanski, J.; Zouhiri, F.; Jeanson, L.; Desmaele, D.;
d’Angelo, J.; Mouscadet, J.-F.; Gieleciak, R.; Gasteiger, J.;
Le Bret, M. J. Med. Chem. 2002, 45, 4647.
(3) (a) Kacprzak, K.; Gawronski, J. Synthesis 2001, 961.
(b) Yoon, T. P.; Jacobsen, E. N. Science 2003, 299, 1691.
(4) Hollingshead, R. G. W. Oxine and its Derivatives;
Buttersworths: London, 1954.
5 min, 120 °C
+ POCl3, then
5 min, 150 °C
24%
POCl3,
reflux, 1 h
68%
Cl
N
Cl
N
CO2Et
CO2Me
19
20
OMe
OMe
(5) Albrecht, M.; Fiege, M.; Osetska, O. Coord. Chem. Rev.
2008, 252, 812.
HBraq
94%
BBr3, CH2Cl2
trace
(6) Albrecht, M.; Triyanti; Schiffers, S.; Osetska, O.; Raabe, G.;
Wieland, T.; Russo, L.; Rissanen, K. Eur. J. Org. Chem.
2007, 2850.
Cl
N
OH
(7) (a) Abass, M. Heterocycles 2005, 65, 901. (b) Kouznetsov,
V. K.; Vargas Méndez, L. Y.; Meléndez Gómez, C. M. Curr.
Org. Chem. 2005, 9, 141. (c) Larsen, L. D.; Kai, D.
Quinolines, In Science of Synthesis; Georg Thieme Verlag:
Stuttgart, 2005. (d) Skraup, K. Ber. Dtsch. Chem. Ges. 1880,
13, 2086. (e) Mansake, R. H. F.; Kulka, M. Org. React.
1953, 7, 59. (f) Friedländer, P. Ber. Dtsch. Chem. Ges. 1882,
15, 2572. (g) Gould, R. G.; Jacobs, W. A. J. Am. Chem. Soc.
1939, 61, 2890.
Br–
CO2Me
N
CO2H
Cl
OMe H+
O
BBr2
21
N
CO2H
OMe
(8) (a) Kappe, C. O.; Stadler, A. Microwaves in Organic and
Medicinal Chemistry; Wiley-VCH: Weinheim, 2005.
(b) Hamelin, J.; Bazureau, J.-P.; Texier-Boulet, F. In
Microwaves in Organic Synthesis; Loupy, A., Ed.; Wiley-
VCH: Weinheim, 2002, 253.
22.23
Scheme 5 Formation of the 4-chloroquinoline derivatives 19 and 20
and attempts to cleave the methyl ether of 19, which led to boron com-
pound 21 and to the 1:1 adduct 22·23
Synlett 2010, No. 7, 1081–1084 © Thieme Stuttgart · New York

1084
M. Albrecht et al.
LETTER
(9) (a) Kidwai, M.; Misra, P.; Kumar, R.; Saxena, R. K.; Gupta,
R.; Bradoo, S. Monatsh. Chem. 1998, 129, 961. (b)Sabitha,
G.; Babu, R. S.; Reddy, B. V. S.; Yadav, J. S. Synth.
Commun. 1999, 29, 4403. (c) Perzyna, A.; Houssin, R.;
Barbry, D.; Hénichart, J.-P. Synlett 2002, 2077. (d) Ranu,
B. C.; Hajra, A.; Jana, U. Tetrahedron 2003, 59, 813.
(e) Ranu, B. C.; Hajra, A.; Jana, U. Tetrahedron Lett. 2000,
41, 531. (f) Gãinã, L.; Cristea, C.; Moldovan, C.; Porumb,
D.; Surducan, E.; Deleanu, C.; Mahamoud, A.; Barbe, J.;
Silberg, I. A. Int. J. Mol. Sci. 2007, 8, 70. (g) Jia, C.-S.;
Zhang, Z.; Tu, S.-J.; Wang, G.-W. Org. Biomol. Chem.
2006, 4, 104. (h) Theoclitou, M.; Robinson, L. A.
A brown oil or solid precipitated. Solvent was removed and
the residue was washed with n-hexane and recrystallized
from acetone–n-hexane to yield a colourless crystalline solid
in 54% yield. Characterization of key products: The
analytical data of 4,12 13 and 2013 were in agreement with
7
literature data. Derivative 19: Mp 146 °C. 1H NMR (400
MHz, CDCl3): d = 8.32 (s, 1 H), 7.84 (dd, J = 8.5, 1.1 Hz,
1 H), 7.68 (dd, J = 8.5, 8.0 Hz, 1 H), 7.15 (dd, J = 8.0, 1.1
Hz, 1 H), 4.10 (s, 3 H), 4.05 (s, 3 H). 13C NMR (75 MHz,
CDCl3): d = 165.0 (C), 156.1 (C), 146.1 (C), 143.7 (C), 140.1
(C), 130.1 (CH), 128.6 (C), 121.8 (CH), 115.4 (CH), 108.9
(CH), 56.3 (CH3), 53.2 (CH3). MS (EI, 70 eV): m/z
(%) = 251.0(36) [M]+, 235.9 (100) [M – Me]+. IR (KBr):
3094, 1721, 1611, 1557, 1498, 1470, 1448, 1334, 1259,
1204, 1139, 1108, 1009, 969, 896, 819, 784, 747 cm–1. Anal.
Calcd for C12H10ClNO3·1/3H2O (257.7): C, 55.94; H, 4.17;
N, 5.44. Found: C, 55.70; H, 4.10; N, 5.56.
Tetrahedron Lett. 2002, 43, 3907. (i) Yadav, J. S.; Reddy,
V. S.; Rao, R. S.; Naveenkumar, V.; Nagaiah, K. Synthesis
2003, 1610. (j) Chaudhuri, M. K.; Hussain, S. J. Chem. Sci.
2006, 118, 199. (k) Duvelleroy, D.; Perrio, C.; Parisel, C.;
Lasne, M.-C. Org. Biomol. Chem. 2005, 3, 3794.
(l) Alexandre, F.-R.; Berecibar, A.; Wrigglesworth, R.;
Besson, T. Tetrahedron 2003, 59, 1413.
(12) Zewge, D.; Chen, C.; Deer, C.; Dormer, P. G.; Hughes, D. L.
J. Org. Chem. 2007, 72, 4276.
(10) (a) Schramm, O. G.; Oeser, T.; Kaiser, M.; Brun, R.; Müller,
T. J. J. Synlett 2008, 359. (b) For the synthesis of
(13) Lauer, W. M.; Arnold, R. T.; Tiffany, B.; Tinker, J. J. Am.
Chem. Soc. 1946, 68, 1268.
(14) For 10, see: Wright, R.; Gordon, M. Synthesis 1984, 1058.
(15) (a) For 16, see: Stephen, J. M. L.; Tonkin, I. M.; Walker, J.
J. Chem. Soc. 1947, 1034. (b) For 18, see: Etter, M. C.;
Urbanczyk-Lipkowska, Z.; Zia-Ebrahimi, M.; Panunto,
T. W. J. Am. Chem. Soc. 1990, 112, 8415.
functionalized quinolines, see: Bernini, R.; Cacchi, S.;
Fabrizi, G.; Filisti, E.; Sferrazza, A. Synlett 2009, 1245.
(11) Microwave experiments were performed using a CEM
Discover BenchMate Plus microwave oven with IR
temperature detection. Preparation of 4: O-Anisidine (0.123
g, 1.0 mmol), dimethyl acetylenedicarboxylate (0.156 g, 1.1
mmol) and Ph2O (6 mL) were placed in a 10 mL vessel,
which was sealed with a septum. The flask was placed in the
MW cavity and was locked with the pressure device. MW
irradiation at 120 °C without air-cooling was used during the
first 5 min of reaction time, and then irradiation power was
increased to 250 °C for the next 15 min. After cooling to r.t.,
the reaction mixture was diluted with n-hexane (150 mL).
(16) Agui, H.; Mitani, T.; Nakashita, M.; Nakagome, T.
J. Heterocycl. Chem. 1971, 8, 357.
(17) CCDC 761359 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
at www.ccdc.cam.ac.uk/conts/retrieving.html [or from the
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 (1223)336033, E-mail:
deposit@ccdc.cam.ac.uk].
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