Facile synthesis of 6,6,8,6,6-ring fused pentacyclic heterocycles: annelation of quinolines to quinoxalines under PTC condition

Article abstract of DOI:10.1016/j.tetlet.2009.05.103

An efficient and simple synthesis of pentacyclic quinolonoquinoxalinooxazocines in a one-pot sequence has been performed by unique application of phase transfer catalysis. Preparative simplicity and conceptual novelty of the methodology offer an attractive general application for the synthesis of novel quinoline antibiotics.

Full text of DOI:10.1016/j.tetlet.2009.05.103

Tetrahedron Letters 50 (2009) 4619–4623
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Facile synthesis of 6,6,8,6,6-ring fused pentacyclic heterocycles: annelation
of quinolines to quinoxalines under PTC condition
Priyankar Paira, Rupankar Paira, Abhijit Hazra, Subhendu Naskar, Krishnendu B. Sahu, Pritam Saha,
*
Shyamal Mondal, Arindam Maity, Sukdeb Banerjee, Nirup B. Mondal
Department of Chemistry, Indian Institute of Chemical Biology, Council of Scientific and Industrial Research, 4 Raja S.C. Mullick Road, Jadavpur, Kolkata 700 032, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and simple synthesis of pentacyclic quinolonoquinoxalinooxazocines in a one-pot sequence
has been performed by unique application of phase transfer catalysis. Preparative simplicity and concep-
tual novelty of the methodology offer an attractive general application for the synthesis of novel quino-
line antibiotics.
Received 16 March 2009
Revised 20 May 2009
Accepted 27 May 2009
Available online 30 May 2009
Ó 2009 Published by Elsevier Ltd.
Keywords:
Phase transfer catalysis
Pentacyclic quinolone
Quinolono quinoxaline
1
. Introduction
Heterocyclic rings are present as fundamental components in
might lead to products of enhanced biological efficacy. We also
wanted to develop a new methodology that will increase the struc-
tural complexity of the molecules while decreasing the number of
synthetic steps, and afford high yields coupled with low cost and
operational simplicity under environment-friendly mild reaction
conditions. In this aspect phase transfer catalysis has long been
recognized as a versatile methodology for organic synthesis in
the skeletons of more than half of the biologically active com-
pounds produced by nature. Investigations toward understanding
1
the reactivity of such compounds are therefore gaining significance
and expedient syntheses particularly for N-heteroaromatics are
much sought after. Among the various heterocyclic skeletal forms,
quinolones and quinoxalines are two privileged motifs that are
found in the core of several antibiotics presently used in clinical
practices such as ofloxacin,2 norfloxacin,3 and A-62176 on the
1
0
industry, academia and in process chemistry. As a part of our
ongoing endeavor on phase transfer catalysis for the construction
1
1
of structurally unique N-heteroaromatics, herein we report the
use of this methodology for the synthesis of extended and also ex-
panded polycyclic novel heteroaromatics containing both quino-
lone and quinoxaline moieties in annelated form.
4
5
one hand, and echinomycin, leromycin, and actinomycin on the
other hand.
The quinolone drugs are potent inhibitors of lymphocyte apop-
tosis and often form the framework of DNA intercalating agents,
Our route to the targeted pentacyclic quinolonoquinoxalino-
oxazocines began with the reaction of 8-hydroxyquinoline (3a)
and 2,3-bis-(bromomethyl)-6,7-dimethylquinoxaline (2a), the
alkylating agent effortlessly prepared (Scheme 1) from 1,4-dibro-
mo-2,3-butanedione and phenylenediamine (1a). The reaction
partners 3a and 2a in 1:3 mole ratio were taken in minimum
amount of dichloromethane and then treated at room temperature
with catalytic amount of tetrabutylammonium bromide (phase
transfer catalyst) in the presence of 10% sodium hydroxide solution
6
7
whereas the quinoxaline drugs are known to inhibit the growth of
gram-positive bacteria and are also active against various trans-
5
plantable tumors. The intercalative binding of these drugs is due
8
to the presence of planar linearly fused tri cyclic system. More-
over, tetra, penta, and hexa cyclic compounds containing one or
two heteroatoms fused to quinoline ring in a linear fashion are
found in natural products as well as in synthetic compounds of bio-
9
12
logical interest that have antitumor and anticancer properties.
for several hours. The progress of the reaction was monitored by
Based on these information we contemplated that convergent syn-
theses of quinolone–quinoxaline hybrid moieties that would yield
a fused pentacyclic ring system having two or more heteroatoms
tlc, which showed that the reaction was complete within 12 hours.
Usual work-up followed by chromatographic separation afforded
the quinolone (5a) with high yield (90%). As we were interested
to isolate the putative intermediate quinolinium, the same reaction
was performed for a shorter duration to obtain the intermediate
quinolinium (4a) along with 5a after chromatographic separation.
*
Corresponding author. Tel.: +91 33 2473 3491; fax: +91 33 2473 5197.
E-mail address: nirup@iicb.res.in (N.B. Mondal).
0
040-4039/$ - see front matter Ó 2009 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2009.05.103

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P. Paira et al. / Tetrahedron Letters 50 (2009) 4619–4623
Br
Br
Br
N
N
R
R
H N
R
R
2
CH Cl2
O
2
+
rt, stir
Br
H N
2
O
1
a-b
2a-b
a. R = Me
b. R = H
Scheme 1.
Table 1
Construction of fused pentacyclic quinoliniums and quinolones using 8-hydroxyquinolines (3a–d) and 2,3-bis-bromomethyl quinoxaline derivatives (2a–b)
a
8
HQ (3a–d)
Alkylating agents (2a–b)
Time (h)
Productb (%)c
Quinoliniumd
Quinolone
O
N
N
N
N
O
3
a
2a
4
N
N
O
4
a (30)
5a (NI)
3a
3a
3a
2a
2a
2a
8
10
12
4a (50)
4a (25)
4a (NI)
5a (45)
5a (70)
5a (95)
O
N
O
N
N
N
3
b
2a
4
N
N
Cl
O
Cl
4
b (30)
5b (NI)
3
3
b
b
2a
2a
10
14
4b (30)
4b (NI)
5b (60)
5b (90)
O
N
N
N
N
N
N
3
c
2a
4
Br
O
Br
O
Br
Br
4
c (25)
5c (NI)
3
3
c
c
2a
2a
8
12
4c (40)
4c (NI)
5c (50)
5c (90)
O
N
N
N
I
N
N
N
3
d
2a
4
Cl
O
Cl
O
I
4
d (35)
5d (NI)
3
3
d
d
2a
2a
10
14
4d (30)
4d (10)
5d (50)
5d (70)

P. Paira et al. / Tetrahedron Letters 50 (2009) 4619–4623
4621
Table 1 (continued)
8
HQ (3a–d)
Alkylating agents (2a–b)
Time (h)
Productb (%)c
Quinolone
5d (80)
Quinoliniumd
4d (NI)
3
d
2a
16
O
N
N
N
3
a
2b
10
4e (NI)
O
5
e (90)
O
N
N
N
N
N
3
b
2b
12
4f (NI)
Cl
Br
O
5
f (95)
O
N
3
c
2b
10
4g (NI)
O
Br
5
g (88)
O
N
N
N
3
d
2b
10
4h (NI)
Cl
O
I
5
h (92)
NI = not isolated.
a
All the reactions were conducted with 8-hydroxyquinoline and bis-bromomethyl quinoxaline derivatives under PTC condition.
All the products are characterized by mass, H, C NMR.
Isolated yield.
b
c
1
13
d
After 4 h unreacted substrates were recovered.
Almost equivalent amounts of the quinoliniums and quinolones
could be isolated after 8 h of the reaction; however, with increased
time period, the yield of the isolated quinolinium decreased with
gradual increase in quinolone formation (Table 1). It is worthy of
mention that on termination of the reaction after 4 h only the quin-
olinium (30%) was isolated. After optimization of the reaction
parameters for the generation of 5a, the scope of this chemistry
was then extended to differently substituted 8-hydroxyquino-
lines, viz. 5-chloro- (3b), 5,7-dibromo-(3c) and 5-chloro-7-iodo-
served in the 1H NMR spectra of the quinoliniums.13 The
protons of the CH groups in 5a–h are nonequivalent and reso-
nate in different aliphatic regions as doublets. Though three pro-
tons of two CH groups in 4a–d gave rise to separate doublets in
aliphatic region, one of the two protons of the N–CH resonates in
the aromatic region (7.7–7.8 ppm). The downfield shift to the aro-
matic region is probably due to the near parallel orientation of
the C–H bond with the p-orbitals of the aromatic ring(s), allowing
greater overlap. There are reports that in the cases of quinolinium
2
2
2
(
3d), and 2,3-bis-(bromomethyl)-quinoxaline derivatives 2a,b.
2
or isoquinolinium benzyl bromides the protons of the –CH group
1
4
The results summarized in Table 1 reveal that the quinolones
can be prepared in high yields in all the cases. It is presumed that
the pathway for the formation of the quinolones proceeds
through the intermediate quinolinium, formed from 8-hydroxy-
quinoline by intramolecular O-N-dialkylation. The conversion of
the quinoliniums to quinolones might have been initiated by
nucleophilic attack of hydroxide ion onto the electrophilic C-2
carbon of the quinolinium salts forming the intermediates I
usually resonate as a singlet at d 6.05–6.70. Single crystal X-ray
analyses of quinolinium 4d and quinolone 5f unambiguously
established the proposed structures (Fig. 1).
2
. Conclusion
In summary, we have developed a new strategy for the con-
struction of structurally novel polycyclic N-heteroaromatics having
quinoxaline and quinolone moieties in one-pot sequence and dem-
onstrated a unique application of phase transfer catalysis. The pro-
cedure offers a broad synthetic feasibility of synthesizing newer
heteroaromatic systems having potential biological activity.
(Scheme 2), which then transformed to quinolones via oxidative
11
13
pathway as described earlier. The mass and C NMR spectral
data of all these quinoliniums and quinolones are well in agree-
ment with the proposed structures but some ambiguity was ob-

4
622
P. Paira et al. / Tetrahedron Letters 50 (2009) 4619–4623
:
R1
R1
O
R1
(
i)10% NaOH, CH Cl2
2
R2
N
R2
N
(
(
ii) 2(a-b)
O
R2
N
iii) Bu N Br ,rt
OH
N
4
N
OH
N
N
R
R
R
(a-h)
R
4
3(a-d)
R1
R1
O
[
O ]
H
2
R2
N
R2
N
O
OH
O
N
N
R
N
N
R
R
R
I
5(a-h)
a.R = Me, R1 = R = H
2
e.R = R1 = R = H
2
b.R = Me, R1 = Cl, R = H
2
f. R = R2 = H, R1 = Cl
1
2
1
2
c.R = Me, R = R = Br
g.R = H, R = R = Br
d.R = Me, R1 = Cl, R2 = I
h.R = H, R1 = Cl, R = I
2
Scheme 2.
Figure 1. ORTEP representations of compounds 4d (cationic part with solvent MeOH, left) and 5f (right), the displacement ellipsoids are drawn at a probability of 50%.

P. Paira et al. / Tetrahedron Letters 50 (2009) 4619–4623
4623
amount of tetra butyl ammonium bromide (phase transfer catalyst) (322.4 mg,
mmol) was added to the solution and the reaction mixture was stirred at
Acknowledgments
1
room temperature. During the course of reaction, TLC was performed after
every 1 h to monitor the progress of the reaction and after 4 h the reaction was
stopped for isolation intermediate quinolinium only. Then the contents of the
reaction mixture were poured to a separating funnel; the organic layer was
separated followed by extraction of the aqueous layer with dichloromethane
We thank CSIR for fellowships to P. Paira, R. Paira, A. Hazra, S.
Naskar, K. B. Sahu, P. Saha, S. Mondal and A. Maity, Mr. K. K. Sarkar
for HRMS analysis and Mr. Rajendra Mahato for helping hand and
Dr. B. Achari, Emeritous Scientist, CSIR, for valuable suggestions.
(
(
3 Â 25 mL). The entire aqueous layer was further extracted with n-butanol
50 ml) for collecting the rest amount of compounds. Then, all the organic
layers were mixed together, washed thoroughly with water until free from
alkali, dried over sodium sulfate, and evaporated to dryness in a rotary
evaporator under reduced pressure. The residue was chromatographed over
silica gel (100–200 mesh), eluted with a mixture of chloroform–methanol in
different ratios yielded the respective fused quinolinium cations (4a–d).
General reaction procedure for the synthesis of fused penta cyclic quinolones (5a–
h): Following similar protocols as for quinolinium cations (4a–d) the reaction
was continued for further time period. TLC studies revealed that the conversion
of quinolinium cations to quinolones used to take 12–16 h for completion of
the reaction. The content of the reaction mixture was then worked up as was
done for the quinolinium cations. The chromatographic separation was carried
out over silica gel (100–200 mesh), eluted with a mixture of petroleum
ether and chloroform in different ratios yielded the respective fused
quinolones (5a–h).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.05.103.
References and notes
1
.
.
Katritzky, A. R.; Rees, C. W. In Comprehensive Heterocyclic Chemistry; Bird, C. W.,
Cheeseman, G. W. H., Eds.; Pergamon Press: New York, 1984; pp 1–38.
(a) Seiyaku, D. Drugs Future 1983, 8, 395; (b) Hayakawa, I.; Hiramitsu, T.;
Tanaka, Y. Chem. Pharm. Bull. 1984, 32, 4907–4913; (c) Tanaka, Y.; Sujuki, N.;
Hayakawa, I.; Sujuki, K. Chem. Pharm. Bull. 1984, 32, 4923–4928.
2
1
3. (a) Spectral data of 4a: Quinolinium 4a was obtained from the column, eluted
3
.
Koga, H.; Itoh, A.; Murayama, S.; Suzue, S.; Irikura, T. J. Med. Chem. 1980, 23,
with 1% methanol–chloroform, and was crystallized from a chloroform–hexane
1
358–1363.
mixture to give the corresponding quinolinium cation as white needles in 30%
4
5
.
.
Chu, D. T. W.; Maleczka, R. E., Jr. J. Heterocycl. Chem. 1987, 24, 453–456.
(a) Dell, A.; William, D. H.; Morris, H. R.; Smith, G. A.; Feeney, J.; Roberts, G. C. K.
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Katagiri, K. J. Antibiot. 1967, 20, 270–276.
À1
yield. Mp: 218–220 °C; R
3
2
f
(1% MeOH–CHCl
3
) 0.42; IR (KBr, cm
036, 1528, 1369, 1125, 762; H NMR (600 MHz, CDCl
.50 (3H, s, Me), 5.57 (1H, d, J = 16.2 Hz), 6.05 (1H, d, J = 13.8 Hz), 6.23 (1H, d,
) m 3465, 3402,
1
3
): d 2.41 (3H, s, Me),
J = 15.6 Hz), 7.72 (1H, d, J = 13.8 Hz), 7.74 (1H, s), 8.01 (1H, t, J = 7.8 Hz,), 8.18
1H, dd, J = 6.0 Hz, J = 8.4 Hz), 8.22 (1H, d, J = 7.8 Hz), 8.26 (1H, s), 8.31 (1H, d,
J = 7.2 Hz), 9.20 (1H, d, J = 7.8 Hz), 9.81 (1H, d, J = 5.4 Hz); C NMR (CDCl
50 MHz): 20.0 (CH ), 20.1 (CH ), 65.7 (CH ), 79.3 (CH ), 123.0 (CH), 127.1
(
1
2
6
.
.
Barchechath, S. D.; Tawatao, R. I.; Corr, M.; Carson, D. A.; Cottam, H. B. Bioorg.
Med. Chem. Lett. 2005, 15, 1785–1788.
(a) Brana, M. F.; Cacho, M.; Gradillas, A.; Pascual-Teresa, B.; Ramos, A. Curr.
Pharm. Des. 2001, 7, 1745–1780; (b) Martinez, R.; Chacon-Garcia, L. Curr. Med.
Chem. 2005, 12, 127–151.
13
3
,
1
3
3
2
2
7
(
(
1
3
CH), 127.7 (CH) 128.1 (CH), 130.6 (CH), 131.2 (CH), 131.9 (C), 132.8 (C), 139.6
C), 140.5 (C), 141.9 (C), 143.0 (C), 145.2 (C), 148.6 (CH), 149.3 (C), 151.0 (C),
51.3 (CH). ESI-MS: m/z 328 [M] , HRMS: calcd 328.1450 [M] ; found
28.1443; (b) Spectral data of 5a: Quinolone 5a was obtained from the 25%
+
+
8
.
.
Loaiza, P. R.; Quintero, A.; Rod r´ ıguez-Sotres, R.; Solano, J. D.; Rocha, A. L. Eur. J.
Med. Chem. 2004, 39, 5–10.
(a) Zeng, Q.; Kwok, Y.; Kerwin, S. M.; Mangold, G.; Hurley, L. H. J. Med. Chem.
chloroform–petroleum ether fraction and was crystallized from chloroform–
9
petroleum ether mixture to give quinolone as yellowish needle crystal in 95%
1
998, 41, 4273–4278; (b) Kim, M.-Y.; Duan, W.; Gleason-Guzman, M.; Hurley,
À1
yield. Mp: 240–242 °C; R
3
f
(75% petroleum ether–CHCl
3
) 0.48; IR (KBr, cm
)
m
L. H. J. Med. Chem. 2003, 46, 571–583.
1
448, 2915, 1670, 1562, 1432, 1135, 1104, 841; H NMR (300 MHz, CDCl
3
): d
1
1
0. Maruoka, K. Org. Process Res. Dev. 2008, 12, 679–697.
2.44 (6H, s, Me), 5.35 (1H, d, J = 15.9 Hz), 5.89 (1H, d, J = 16.2 Hz), 6.12 (1H, d,
1. (a) Dutta, R.; Mandal, D.; Panda, N.; Modal, N. B.; Banerjee, S.; Kumar, S.;
Weber, M.; Lugar, P.; Sahu, N. P. Tetrahedron Lett. 2004, 45, 9361–9364; (b)
Paira, P.; Hazra, A.; Sahu, K. B.; Banerjee, S.; Mondal, N. B.; Sahu, N. P.; Weber,
M.; Lugar, P. Tetrahedron 2008, 64, 4026–4036.
J = 13.5 Hz), 6.63 (1H, d, J = 13.2 Hz), 6.72 (1H, d, J = 9.6 Hz), 7.15 (1H, t,
J = 7.8 Hz,), 7.27 (1H, m), 7.43 (1H, m), 7.54 (1H, d, J = 9.3 Hz), 7.66 (1H, s), 7.90
13
(
3 3 3 2
1H, m); C NMR (CDCl , 75 MHz): 20.2 (CH ), 20.4 (CH ), 48.1 (CH ), 78.7
(
2
CH ), 122.4 (CH), 123.3 (CH), 125.1 (CH) 125.6 (CH), 127.0 (CH), 127.7 (C),
1
2. General reaction procedure for the Synthesis of fused penta cyclic quinolinium
cations (4a–d): Appropriate amount of 8-hydroxyquinoline derivatives (3a–d)
1
1
28.6 (CH), 133.2 (C), 138.7 (CH), 139.9 (C), 140.6 (C), 141.4 (C), 146.9 (C),
+
48.5 (C), 150.5 (C), 150.9 (C), 162.4 (C, CO). ESI-MS: m/z 344 [M+H] , 366
(
3.3 mmol) were dissolved in 50 mL of dichloromethane in a 250 mL RB flask
+
+
[
M+Na] , HRMS: calcd 366.1218 [M+Na] ; found 366.1193.
4. Jean-Gérard, L.; Pauvert, M.; Collet, S.; Guingan, A.; Evain, M. Tetrahedron 2007,
3, 11250–11259.
followed by the addition of 50 mL of 10% aqueous NaOH solution, and were
stirred at room temperature for about 30 min. Quinoxaline dibromides (2a–b)
1
6
(
10 mmol, 1:3 ratio with respect to the substrate) was added successively to
the stirred solution and stirring continued for 10 min. Finally, a catalytic