Robust synthesis of linear and angular furoquinolines using Rap–stoermer reaction

Article abstract of DOI:10.1007/s10593-016-1885-8

We have synthesized novel linear and angular furoquinolines via the Rap–Stoermer reaction by conventional as well as microwave method that furnished an enhanced yield. Initially, we synthesized linear furo[2,3-b]quinolines from 3-acetyl-6-chloro-4-phenyl-

Full text of DOI:10.1007/s10593-016-1885-8

DOI 10.1007/s10593-016-1885-8
Chemistry of Heterocyclic Compounds 2016, 52(5), 322–325
Robust synthesis of linear and angular furoquinolines
using Rap–Stoermer reaction
1
,2
2
Devadoss Karthik Kumar , Rayappan Rajkumar ,
2
Subramaniam Parameswaran Rajendran *
1
PSG College of Arts and Science,
Avinashi road, Civil Aerodrome post, Coimbatore-641014, Tamilnadu, India
e-mail: dskarthik06@gmail.com
Bharathiar University, Coimbatore-641046, Tamilnadu, India;
e-mail: rajendransp@yahoo.com
2
Published in Khimiya Geterotsiklicheskikh Soedinenii,
Submitted April 14, 2016
Accepted May 15, 2016
2
016, 52(5), 322–325
We have synthesized novel linear and angular furoquinolines via the Rap–Stoermer reaction by conventional as well as microwave
method that furnished an enhanced yield. Initially, we synthesized linear furo[2,3-b]quinolines from 3-acetyl-6-chloro-4-phenyl-
1
H-quinolin-2-one and three different α-halocarbonyl compounds: chloroacetophenone, ethyl chloroacetate, and chloroacetamide.
The scope of the methodology was further extended to the synthesis of angular furo[3,2-c]quinolines by utilizing 3-acetyl-4-hydroxy-
-methyl-1H-quinolin-2-one and α-halocarbonyl compounds.
1
Keywords: 3-acetyl-6-chloro-4-phenyl-1H-quinolin-2-one, 3-acetyl-4-hydroxy-1-methyl-1H-quinolin-2-one, angular furo[3,2-c]quino-
lines, linear furo[2,3-b]quinolines, Rap–Stoermer reaction.
Several naturally occurring compounds and their synthe-
tic analogs containing the quinoline scaffold are known to
(triphenylphosphoranylidene)acetate,11 synthesis of 2-alkyl-
furo[3,2-c]quinolin-4(5H)-ones by reacting 1-alkyl-
4-hydroxyquinolin-2(1H)-ones with a number of alkynyl
halides,12 and the synthesis of furo[2,3-c]-condensed
1,2,3,4-tetrahydro-1,10-phenanthrolines from 8-amino-
quinolines.13 These methods required multiple steps and
gave low yields. Previously we also reported the synthesis
1
possess promising pharmacological properties. Primarily,
various substituted linear furo[2,3-b]quinolines and angular
furo[3,2-c]quinolines have attracted considerable attention
as a result of their significant role in medicinal chemistry
2,3
and their presence in a variety of alkaloids. This class of
14
compounds mainly isolated from Rutaceae plant family
of 2-benzoylfuro[2,3-b]quinolines and 2-acetylfuro[2,3-b]-
4
4
5
15
exhibit antiallergic, anti-inflammatory, cytotoxic, pla-
quinolines. In a continuation of our attempts to access this
5
6
telet aggregation inhibiting, antimicrobial, voltage-gated
class of compounds, we herein report an efficient metho-
dology for the synthesis of linear 4-phenylfuro[2,3-b]-
quinolines and angular N-methylfuro[3,2-c]quinolines with
amide, ester, and ketone groups as substituents at position 2
7
8
8
potassium channel blocking, spasmolytic, antimalarial,
8
and mutagenic activity. In addition, furoquinolines have a
long and successful history in the treatment of Alzheimer's
9
16
disease. Such diverse types of biological activity have
via the Rap–Stoermer reaction.
encouraged us to synthesize new linear and angular furo-
quinolines with different substituents at position 2.
The Rap–Stoermer reaction has been already applied in
the synthesis of linear 2-substituted furo[2,3-b]quinolines
by utilizing 3-formyl-2-hydroxyquinolines and α-halo-
carbonyl compounds.17 There are no reports available in the
literature regarding the reaction of 2- and 4-hydroxy-3-acetyl-
quinolines with α-halocarbonyl compounds to obtain linear
and angular furoquinolines in the Rap–Stoermer reaction.
We performed the Rap–Stoermer reaction with 3-acetyl-
Some reports are available in the literature regarding the
construction of angular furo[3,2-c]quinolines, such as the
synthesis of 5-methylfuro[3,2-c]quinolin-4(5H)-one via
Perkin rearrangement of 3-bromo-6-methyl-5,6-dihydro-2H-
10
pyrano[3,2-c]quinoline-2,5-dione, synthesis of 2-alkyl/aryl-
-oxo-4,5-dihydrofuro[3,2-c]quinoline-3-carboxylic acids by
treating 3-acyl-4-hydroxy-1H-quinolin-2-ones with ethyl
4
18
6-chloro-4-phenyl-1H-quinolin-2-one (1) and three different
0
009-3122/16/52(5)-0322©2016 Springer Science+Business Media New York
3
22

Chemistry of Heterocyclic Compounds 2016, 52(5), 322–325
Scheme 1
has the potential to undergo methylation either at the
oxygen or nitrogen atoms due to amido-imido tautomerism.
However, in the presence of K
2
CO in DMF the methy-
3
lation occurred solely at the nitrogen atom, rather than the
oxygen atoms (Scheme 2).
N-Methylation was confirmed by spectral studies, in
particular the 13C NMR spectrum of compound 4 clearly
showed the NCH group carbon signal at 31.5 ppm. In the
3
case if methylation had occurred at an oxygen atom, the
OCH group carbon signal would be around 60 ppm.
Table 1. Conditions* and yields for the synthesis
of linear furo[2,3-b]quinolines 2a–c
3
Next, we synthesized angular N-methylfuro[3,2-c]-
quinolin-4-ones 5a–c via the Rap–Stoermer reaction by
treating 3-acetyl-4-hydroxy-1-methyl-1H-quinolin-2-one (4)
with α-chlorocarbonyl compounds (chloroacetamide, ethyl
chloroacetate, and chloroacetophenone) in the presence of
Method I
Method II
Com-
pound
R1
Time, h
15
Yield, % Time, min Yield, %
2
a
OEt
Ph
72
70
64
5
4
7
93
91
88
2
b
19
K
2
CO in DMF (Scheme 2). In the case of compound 4,
3
2
c
NH
2
24
due to the presence of N-methyl group, the formation of
linear furo[2,3-b]quinolines is impossible, thus we isolated
only angular N-methylfuro[3,2-c]quinolinones 5a–c. These
reactions were initially carried out by a conventional
procedure (method I), which provided only moderate yields
(56–63%). We were able to increase the yield up to 84–
94% by using microwave methodology (method II). The
variations of yields obtained according to these two
methods are presented in Table 2.
*
Method I – conventional heating at 160°C; method II – microwave irra-
diation.
α-halocarbonyl compounds, namely, ethyl chloroacetate,
chloroacetophenone, and chloroacetamide to synthesize
linear 2,3,4,6-tetrasubstituted furo[2,3-b]quinolines 2a–c
(
Scheme 1). Initially we carried out these reactions by a
conventional method (method I, Table 1) using DMF as
solvent and K
2
CO
3
as base, reaching yields of 64–72%. The
The synthesized angular furo[3,2-c]quinolinones 5 were
characterized by spectral studies. For instance, the
yields of the reactions were further enhanced up to 88–93%
by using microwave methodology (method II).
–1
appearance of the IR absorption peaks at 1712 cm for
–1
The structures of all the synthesized compounds were
confirmed by spectral techniques. For instance, the dis-
ester carbonyl, at 1666 cm for phenone carbonyl, and at
1625 cm–1 for amide carbonyl confirmed the formation of
–1
appearance of IR absorption frequency at 1645 cm , cor-
compounds 5a, 5b, and 5c, respectively. Furthermore, in
1
responding to the NHCO group of compound 1 and the
H NMR spectrum a triplet signal at 1.35 ppm for CH
3
–
1
appearance of peaks at 1721 cm , corresponding to the
–
1
COOC
COC
2
H
H
5
5
carbonyl, at 1661 cm corresponding to
Scheme 2
–
1
6
carbonyl, and at 1649 cm corresponding to the
NHCO carbonyl confirmed the formation of compounds
1
2
a, 2b, and 2c, respectively. In H NMR spectrum, the
and a quartet at
confirmed the formation of compound
appearance of a triplet at 1.35 ppm for CH
3
4
.26 ppm for OCH
2
2
a. There was a multiplet for thirteen aromatic protons over
the range of 7.53–8.12 ppm, apparently due to the
1
formation of compound 2b. H NMR spectrum of
compound 2c showed a broad singlet at 5.15 ppm for the
NH group. The mass spectrum of compound 2a contained
2
+
a peak at the m/z value of 366.27 [M+H] , confirming the
formation of compound 2a. The appearance of the m/z
+
value of 398.33 [M+H] confirmed the formation of
compound 2b, while compound 2c gave a peak at the
+
expected m/z value of 338.07 [M+H] .
Table 2. Conditions* and yields for the synthesis
of angular furo[3,2-c]quinolin-4-ones 5a–c
Further, we extended this methodology to the synthesis
of angular furoquinolines by utilizing 3-acetyl-4-hydroxy-
Method I
Method II
1
-methyl-1H-quinolin-2-one (4). The precursor 4 has been
Com-
pound
R1
prepared previously by a ring opening reaction of pyrano-
quinolone and direct acylation of 4-hydroxyquinolin-2-one.
These two methodologies resulted in very low yields and
Time, h
Yield, % Time, min Yield, %
5
a
OEt
Ph
21
18
24
63
58
56
7
6
9
94
86
84
1
9
5
b
gave mixtures of products. In this context, we are
reporting an elegant and convenient methodology for the
synthesis of compound 4 by regioselective methylation of
5c
NH2
*
Method I – conventional heating at 160°C; method II – microwave irra-
3
-acetyl-4-hydroxy-1H-quinolin-2-one (3). Compound 3
diation.
3
23

Chemistry of Heterocyclic Compounds 2016, 52(5), 322–325
group and a quartet at 4.36 ppm for OCH
2
group confirmed
complete (control by TLC) the mixture was poured onto
crushed ice. The resulting precipitate was filtered off,
dried, and then separated by silica gel column
chromatography using 4:1 petroleum ether–ethyl acetate as
eluent.
6-Chloro-3-methyl-4-phenylfuro[2,3-b]quinoline-
2-carboxylic acid ethyl ester (2a). Yield 72% (method I),
93% (method II), colorless solid, mp 250–251°C.
the formation of compound 5a. There were multiplet
signals in the aromatic region (7.40–8.06 ppm) correspond-
ing to nine aromatic protons of compound 5b. For
compound 5c, the NH group signals were observed in the
2
aromatic region as well. The elemental analysis data for
compounds 5a–c were in agreement with the molecular
formulas.
–
1
1
Thus, we have synthesized novel linear and angular
furoquinolines via the Rap–Stoermer reaction by conven-
tional as well as microwave methods. The microwave
method furnished an enhanced yield compared to the
conventional method. We have chosen 3-acetyl-6-chloro-
IR spectrum, ν, cm : 1721 (C=OOC
2
H
5
). H NMR spect-
rum, δ, ppm (J, Hz): 1.35 (3H, t, J = 7.0, OCH
(3H, s, 3-CH ); 4.26 (2H, q, J = 7.0, OCH CH
(8H, m, H Ar), C NMR spectrum, δ, ppm: 11.6 (3-CH
2
CH ); 2.31
3
3
2
3
); 7.36–7.69
);
13
3
15.2 (OCH CH ); 60.5 (OCH CH ); 112.3; 114.2 (2C);
2
3
2
3
4
-phenyl-1H-quinolin-2-one
and
3-acetyl-4-hydroxy-
118.1; 123.8; 124.6; 129.3; 132.6; 135.3; 138.2; 139.6;
1
-methyl-1H-quinolin-2-one for synthesizing linear and
141.5; 146.5; 148.2; 153.4; 176.0 (CO). Mass spectrum, m/z:
+
angular furoquinolines, respectively. We have utilized three
different α-halocarbonyl compounds, namely, chloroaceto-
phenone, ethyl chloroacetate, and chloroacetamide for
obtaining the title compounds.
366.27 [M+H] . Found, %: C 68.71; H 4.66; N 4.06.
C H ClNO . Calculated, %: C 68.95; H 4.41; N 3.83.
21
16
3
6-Chloro-3-methyl-4-phenyl(furo[2,3-b]quinolin-2-yl)-
phenylmethanone (2b). Yield 70% (method I), 91%
(
method II), colorless solid, mp 234–235°C. IR spectrum,
Experimental
–1
1
ν, cm : 1661 (COC
(3H, s, 3-CH
spectrum, δ, ppm: 11.5 (3-CH
6
H
5
). H NMR spectrum, δ, ppm: 2.29
13
IR spectra in KBr pellets were recorded on a Shimadzu
3
); 7.53–8.12 (13H, m, H Ar). C NMR
1
13
FT-IR 8201 PC spectrometer. H and C NMR spectra
3
); 110.5; 112.3; 114.1;
were acquired for DMSO-d
6
solutions on a Bruker AVIII
115.8; 116.1; 120.6; 121.4; 122.5; 123.6; 125.8; 126.1;
128.5; 130.5; 131.6; 132.2; 134.8; 139.6; 140.7; 153.2;
spectrometer (500 and 125 MHz, respectively), using TMS
as an internal standard. Mass spectra were recorded on a
Thermo Finnigan LCQ Advantage Max HRMS (ESI) ion
trap mass spectrometer. Elemental analysis was performed
on a Vario EL III CHNS Analyzer and a Perkin Elmer
+
165.5 (C=O). Mass spectrum, m/z: 398.33 [M+H] . Found, %:
C 75.71; H 4.27; N 3.36. C25
C 75.47; H 4.05; N 3.52.
H
16ClNO . Calculated, %:
2
6-Chloro-3-methyl-4-phenylfuro[2,3-b]quinoline-
2-carboxylic acid amide (2c). Yield 64% (method I), 88%
(method II), colorless solid, mp 265–266°C. IR spectrum,
2
400 Series II CHNS analyzer. Melting points were
determined by open capillary method using a Raga melting
point apparatus and are uncorrected. The purity of the
compounds was checked by TLC on silica gel plates using
petroleum ether – ethyl acetate, 4:1, as the eluent. For
–
1
1
ν, cm : 1649 (CONH
(3H, s, 3-CH
2
). H NMR spectrum, δ, ppm: 2.23
3
); 5.15 (2H, s, NH ); 7.20–7.65 (8H, m,
2
H Ar). 13C NMR spectrum, δ, ppm: 22.3 (3-CH
); 108.6;
3
microwave irradiation,
domestic (LG) microwave oven was used at 360 W power
setting.
a
conventional (unmodified)
113.4; 114.8; 119.6; 120.6; 122.6; 123.4; 124.6; 125.2;
126.4; 132.1; 133.5; 135.5; 137.6; 138.2; 168.4 (CO). Mass
+
spectrum, m/z: 338.07 [M+H] . Found, %: C 67.94; H 3.65;
Synthesis of 3-acetyl-4-hydroxy-1-methyl-1H-quinolin-
N 8.55. C19
N 8.32.
H
13ClN
2
O . Calculated, %: C 67.76; H 3.89;
2
2
-one (4). Anhydrous K
2
CO (691 mg, 5 mmol) and methyl
3
iodide (0.3 ml, 5 mmol) were added to a mixture of
3,5-Dimethyl-4-oxo-4,5-dihydrofuro[3,2-c]quinoline-
2-carboxylic acid ethyl ester (5a). Yield 63% (method I),
94% (method II), colorless solid, mp 188–189°C (mp 182–
3
5
2
-acetyl-4-hydroxy-1H-quinolin-2-one (3) (1015.0 mg,
mmol) in DMF (40 ml) and the mixture was stirred for
4 h at room temperature. After completion of the reaction
11
189°C ).
2-Benzoyl-3,5-dimethyl-5H-furo[3,2-c]quinolin-4-one
(
control by TLC) the mixture was poured onto crushed ice.
The precipitate was filtered off, dried, and separated by
silica gel column chromatography using petroleum ether –
ethyl acetate, 9:1, as eluent. Yield 984.5 mg (97%),
(5b). Yield 58% (method I), 86% (method II), colorless
–1
solid, mp 189–190°C. IR spectrum, ν, cm : 1666 (C–CO),
1
1660 (N–CO). H NMR spectrum, δ, ppm: 2.71 (3H, s,
1
9
colorless solid, mp 137–138°C (mp 138°C ).
3-CH
3
); 3.69 (3H, s, NCH ); 7.40–8.06 (9H, m, H Ar).
3
13
Synthesis of linear 6-chloro-4-phenylfuro[2,3-b]-
quinolines 2a–c and angular N-methylfuro[3,2-c]quino-
linones 5a–c (General methods I and II). Anhydrous
C NMR spectrum, δ, ppm: 11.2 (3-CH
3
); 29.4 (NCH );
3
111.7; 115.1; 116.4; 118.2; 119.3; 120.4; 121.2; 122.2;
122.8; 123.2; 124.5; 130.1; 131.8; 139.5; 140.7; 155.5;
158.9 (C=O); 159.1 (NCO). Found, m/z: 340.0948 [M+Na] .
+
K
2
CO
3
(345.5 mg, 2.5 mmol) was added to a solution of
3
2
2
-acetyl-6-chloro-4-phenyl-1H-quinolin-2-one (1) (742 mg,
.5 mmol) or 3-acetyl-4-hydroxy-1-methyl-1H-quinolin-
-one (4) (542.6 mg, 2.5 mmol) then the appropriate
C
20
H
15NO . Calculated, m/z: 340.0950.
3
3,5-Dimethyl-4-oxo-4,5-dihydrofuro[3,2-c]quinoline-
2-carboxylic acid amide (5c). Yield 56% (method I), 84%
α-chlorocarbonyl compound (2.5 mol) in DMF (40 ml) was
(Method II), colorless solid, mp 210–211°C. IR spectrum,
–1
added dropwise. The resulting mixture was heated at 160°C
ν, cm : 3417 (NH
2
), 1656 (N–CO), 1647 (CONH
2
).
);
); 7.52
1
(
methods I) or irradiated with microwaves (methods II) for
H NMR spectrum, δ, ppm (J, Hz): 2.72 (3H, s, 3-CH
3.55 (3H, s, NCH ); 7.31–7.82 (4H, m, H-7,8, NH
3
the time indicated in Table 1 and 2. After the reaction was
3
2
3
24

Chemistry of Heterocyclic Compounds 2016, 52(5), 322–325
1
(
1H, d, J = 8.5, H-6); 8.09 (1H, d, J = 7.5, H-9). 3C NMR
6. Venkataraman, S.; Barange, D. K.; Pal, M. Tetrahedron Lett.
2
006, 47, 7317.
spectrum, δ, ppm: 20.2 (3-CH
3
); 29.8 (NCH
3
); 109.5;
7
.
Butenschon, I; Moller, K.; Hansel, W. J. Med. Chem. 2001,
1
14.6; 118.4; 122.4; 123.4; 124.5; 131.6; 132.4; 137.2;
4
4, 1249.
1
38.9; 160.8 (NCO); 166.7 (CO). Mass spectrum, m/z: 257.09
+
8. Nandini, D.; Asthana, M.; Mishra, K.; Singh, R. P.;
[
M+H] . Found, %: C 65.40; H 4.96; N 10.75. C14
H
12
N
2
O .
3
Singh, R. M. Tetrahedron Lett. 2014, 55, 6257.
Calculated, %: C 65.62; H 4.72; N 10.93.
9.
Cardoso-Lopes, E. M.; Maier, J. A.; Silva, M. R.;
Regasini, L. O.; Simote, S. Y.; Lopes, N. P.; Pirani, J. R.;
Bolzani, V. S.; Marx Young, M. C. Molecules 2010, 15, 9205.
We thank the NMR Research Center of Indian Institute
of Science, Bangalore and Sophisticated Analytical
Instrument Facility, Indian Institute of Technology at
Madras for providing spectral and analytical services.
10. Ohta, T.; Mori, Y. Pharm. Bull. 1957, 5, 80.
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1
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