Synthesis of biaryl pentacyclic quinolonoquinoxalino-oxazocines in aqueous medium using Amberlite IRA 402(OH)

Article abstract of DOI:10.1016/j.tetlet.2009.07.072

Amberlite IRA 402(OH) effectively mediates biarylation via Suzuki-Miyaura cross-coupling reaction on complex systems such as dihalo quinolonoquinoxalino-oxazocines.

Full text of DOI:10.1016/j.tetlet.2009.07.072

Tetrahedron Letters 50 (2009) 5505–5509
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Tetrahedron Letters
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Synthesis of biaryl pentacyclic quinolonoquinoxalino-oxazocines
in aqueous medium using Amberlite IRA 402(OH)
Priyankar Paira, Rupankar Paira, Abhijit Hazra, Krishnendu B. Sahu, Subhendu Naskar, 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:
Amberlite IRA 402(OH) effectively mediates biarylation via Suzuki–Miyaura cross-coupling reaction on
complex systems such as dihalo quinolonoquinoxalino-oxazocines.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 30 June 2009
Revised 14 July 2009
Accepted 16 July 2009
Available online 21 July 2009
Keywords:
Amberlite IRA 402(OH)
Pentacyclic quinolonoquinoxalino-
oxazocine
Biaryl quinolone
1. Introduction
complex systems. We were therefore compelled to find an alterna-
tive for basic alumina for the synthesis of biaryl derivatives of
Green chemistry has become a major field of interest for the
community of chemists trying to overcome the challenges of the
environmental legislation, which is coming into effect all over
the world1 and has encouraged the development of cleaner chem-
ical processes and new technologies.2 Most chemical reactions that
contribute adversely toward the environment are multi-step reac-
tions which (a) involve protection and deprotection steps, (b) use
hazardous solvents and stoichiometric reagents, and (c) lack
atom-economy and effective energy source.3 To overcome these
problems concerted efforts have been made for the development
of efficient methodologies. A number of reports have appeared in
the literature where water has been used as solvent, microwave
irradiation as alternative energy resource, and metal-catalyzed
coupling reactions as convenient one-step methods for assembling
complex structures.4 Among them, palladium-catalyzed Suzuki–
Miyaura coupling reaction of aryl halides with aryl boronic acids
is a powerful tool for the synthesis of biaryl derivatives,5 which
are found in a range of pharmaceuticals, herbicides, and natural
products.6 In a recent communication we have disclosed the syn-
thesis of biaryl derivatives of fused tricyclic oxa-aza-quinolones
applying the basics of Suzuki–Miyaura reaction using basic
alumina as solid support.7 However, this methodology has some
limitations: debromination occurred when it was applied to more
fused pentacyclic quinolonoquinoxalino-oxazocines, which are
structurally similar to anti-carcinogenic pentacyclic heteroaromat-
ics8 and were recently synthesized by our group.9 In this Letter, we
wish to disclose the progression of overcoming the problem of
biarylation on complex systems such as pentacyclic quinolono-
quinoxalino-oxazocines.
At the outset, we chose 5,7-dibromoquinolonoquinoxalino-oxa-
zocine (1a) and p-methoxy phenyl boronic acid (2b) as model reac-
tion partners to evaluate the various catalytic conditions. It was
revealed from the systematic studies that the reactions catalyzed
by Pd(OAc)2/PPh3 in CH3CN using bases such as KF, K3PO4, and even
Cs2CO3 were ineffective, and only low yield was obtained with
Na2CO3. Similarreactionsperformedin solventssuchas dioxane, tol-
uene, DCE, and DMSO under otherwise identical conditions were
also found to be totally ineffective, though in DMF low to moderate
yield was obtained. Next we attempted the reaction in DMF with
PdCl2/PPh3 or PdCl2(PPh3)2 as catalyst and Na2CO3 as base; this
yielded the desired biaryl product though with only 20–30% yield.
Interestingly, reaction using Na2CO3 and Pd(PPh3)4 produced mod-
erate yield (40–50%) of the product. We then explored our optimiza-
tion protocol with Pd(PPh3)4 in aqueous medium in presence of
different inorganic bases; moderate yield (60%) was obtained in
presence of Na2CO3 in 16 h (Table 1, entry 8). Taking into account
theefficacyof thecatalyticsystem Pd(PPh3)4/H2O, the study was fur-
ther explored using an ion-exchange resin, as base. Since, in recent
years, ion-exchange resins have been increasingly utilized in differ-
* Corresponding author. Tel.: +91 33 2473 3491; fax: +91 33 2473 5197.
E-mail address: nirup@iicb.res.in (N.B. Mondal).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.07.072

5506
P. Paira et al. / Tetrahedron Letters 50 (2009) 5505–5509
Table 1
Optimization of Suzuki–Miyaura cross-coupling reaction using dibromo-quinolonoquinoxalino-oxazocine (1a) and p-methoxy benzene boronic acid (2b) in aqueous mediuma
MeO
O
O
Pd(PPh3)4 (0.1 mol%)
Amberlite IRA-402(OH)
Br
N
N
N
N
N
N
O
O
MeO
B(OH)2
Br
°
3b
2b (2.2 eqv.), 90 C, 10hr
1a
OMe
Time (h)
Entry
Base/resin
Pd(PPh3)4 (mol %)
T (°C)
Yieldb (%)
1
2
3
4
5
6
7
8
Cs2CO3
Cs2CO3
Cs2CO3
KF
KF
KF
Na2CO3
Na2CO3
Na2CO3
K3PO4
K3PO4
K3PO4
Amberlite IRA-402(OH)
Amberlite IRA-402(OH)d
Amberlite IRA-402(OH)
Amberlite IRA-402(OH)
Amberlite IRA-402(OH)
0.5
1.0
2.0
0.1
0.5
2.0
0.1
0.5
1.0
0.5
1.0
2.0
0.5
0.5
1.0
0.1
0.05
12
16
16
12
16
16
12
16
24
12
16
16
12
10
10
10
10
90
120
120
120
120
120
110
120
130
120
120
130
80
NR
NR
NR
NR
NR
NR
50
60
60
9
10
11
12
13
14
15
16
17
NRc
NR
NR
90
90
90
90
90
95
95
95
70
a
All the studies were performed by using 1a and 2b under classical heating condition and in an inert atmosphere.
Isolated yield.
No reaction.
b
c
d
Resin (400 mg) was found to be sufficient for quantitative yield of biaryl product; lesser amount resulted in low yield.
ent areas of organic synthesis including C–C coupling reactions such
as Heck and Sonogashira reaction.10 It is an inexpensive, commer-
cially available, environmentally compatible solid basic catalyst
used as reagent support and in chemical processing.11
The plausible pathway of the reaction is outlined in Scheme 1. It
is presumed that the reaction is initiated with the Amberlite resin
(III) transforming the oxidative addition product II to produce the
intermediate V, while aryl boronic acid (2) gets converted to inter-
mediate VI. The migration of Ar1 from VI to V produces intermedi-
ate VIII with liberation of quaternary ammonium borate VII.
To our satisfaction, the reaction catalyzed by Pd(PPh3)4 in H2O
at 90 °C in presence of Amberlite IRA 402(OH) proved to be the best
with respect to both the yield of the product and the reaction time
(Table 1, entries 14–16). It is notable that 0.1 mol % catalyst loading
was enough to produce almost quantitative yield; no significant ef-
fect on the yield of the product was observed on enhancement of
catalyst loading from 0.1 to 1 mol %. With an optimal set of cata-
lytic conditions thus selected, we then extended the Suzuki–Miya-
ura cross-coupling reaction of 1a/b with a number of aryl/
heteroaryl boronic acid derivatives (2a–j). This demonstrated that
the method constitutes an effective biarylation protocol with
85–96% yield (Table 2). Comparison of the coupling reactivity of
various aryl boronic acids, summarized in Table 2, indicates that
electron-donating substituents (–OMe, –Me) para to the boronic
acid could assist the reactivity and thus afford higher yield of biaryl
quinolones (Table 2, entries 2, 3, and 10) within 10–12 h. Similarly,
coupling of furan-2-boronic acid with 1a afforded the target prod-
uct in 92% yield in 12 h (Table 2, entry 6). Nitrogen and sulfur con-
taining heteroaryl boronic acids (thiophen-3-boronic acid and
pyridine-3-boronic acid) also showed high reactivity and assured
good to high yield (Table 2, entries 7 and 11). Naphthalene-1-boro-
nic acid gave the desired product in 85% yield (Table 2, entry 9),
while naphthalene-2-boronic acid furnished 95% yield under the
standard reaction conditions (Table 2, entry 8); the lower yield in
the former case may be due to steric hindrance offered by the fused
ring. All the products were characterized by their MS, 1H, and 13C
NMR spectroscopy.12 Single crystal X-ray crystallographic analysis
of biaryl derivative 3a was carried out for unambiguous determi-
nation of its structure (Fig. 1).
Figure 1. ORTEP representation of compound 3a, the displacement ellipsoid is
drawn at a probability of 50%.

P. Paira et al. / Tetrahedron Letters 50 (2009) 5505–5509
5507
Table 2
Construction of biaryl quinolono quinoxaline motifs from dibromoquinolono quinoxaline (1a–b) and boronic acid (2a–i) substrates
O
O
Pd(PPh3)4 (0.1 mol%)
Amberlite IRA-402(OH)
Br
N
N
N
Ar
N
N
N
R
R
R
R
ArB(OH)2 (2.2 eqv.)
O
O
°
90 C, 10hr
Br
Ar
3(a-i); R = H
3(j-k); R = Me
1a; R = H
1b; R = Me
Entry
Aryl bromide (1a–b)
Boronic acid (2a–j)
Producta (3a–k)
Time (h)
Yieldb (%)
O
N
N
N
B(OH)2
1
1a
12
90
O
2a
3a
MeO
Me
B(OH)2
B(OH)2
2
1a
3b
10
95
2b
3
4
5
1a
1a
1a
3c
3d
3e
10
12
12
92
90
85
2c
F
B(OH)2
2d
Cl
B(OH)2
2e
O
N
N
N
O
B(OH)2
6
1a
12
92
O
O
2f
O
3f
N
O
N
N
N
B(OH)2
7
1a
10
90
O
N
2g
N
3g
O
B(OH)2
N
N
N
8
1a
O
12
95
2h
3h
(continued on next page)

5508
P. Paira et al. / Tetrahedron Letters 50 (2009) 5505–5509
Table 2 (continued)
Entry
Aryl bromide (1a–b)
Boronic acid (2a–j)
Producta (3a–k)
Time (h)
Yieldb (%)
O
N
N
N
9
1a
12
85
O
B(OH)2
2i
3i
MeO
O
N
N
N
Me
Me
O
10
1b
2b
10
95
OMe
3j
O
N
N
N
Me
Me
S
B(OH)2
11
1b
12
92
O
S
2j
S
3k
a
All the new products were characterized by mass, 1H and 13C NMR spectral analysis.
Isolated yield.
b
Ar-Br
1
Ar-Ar1
3
Pd(0)
I
Ar-Pd(II)-Ar1
Ar-Pd(II)-Br
VIII
II
NR3 OH
III
NR3 B(OH)4
VII
Ar-Pd(II)-OH
NR3 Br
IV
V
OH
B
Ar1
OH
Ar1-B(OH)2
OH
NR3 OH
NR3
2
VI
III
Scheme 1. Mechanistic pathway for Amberlite IRA-402(OH) mediated Suzuki–Miyaura cross-coupling reaction.
Quaternary ammonium salt IV then effects the conversion of VIII
[Pd(II)] to I [Pd(0)],13 stabilizing the palladium catalyst leading to
the acceleration of Suzuki reaction. In the absence of the resin
the reaction did not yield the desired product even after 24 h. Gen-
eralization of this methodology was then ensured by performing
reactions on simpler aryl bromides with different aryl boronic
acids and this also resulted in comparable yields.4d To the best of
our knowledge this is the first report of Amberlite IRA 402(OH)
mediated Suzuki–Miyaura cross-coupling reaction.
The reusability of the resin was then investigated because it
is very important for industrial and pharmaceutical applications.
After work-up of the reaction, the resin was recovered by simple
filtration, washing with ethanol followed by sodium hydroxide
solution, and drying at 80 °C under reduced pressure. Even after

P. Paira et al. / Tetrahedron Letters 50 (2009) 5505–5509
5509
4. (a) Dallinger, D.; Kappe, C. O. Chem. Rev. 2007, 107, 2563–2591; (b) Herrero, M.
A.; Kremsner, J. M.; Kappe, C. O. J. Org. Chem. 2008, 73, 36–47; (c) Leadbeater, N.
E.; Marco, M. Org. Lett. 2002, 4, 2973–2976; (d) Leadbeater, N. E.; Marco, M.
Angew. Chem., Int. Ed. 2003, 42, 1407–1409; (e) Leadbeater, N. E.; Marco, M. J.
Org. Chem. 2003, 68, 5660–5667; (f) Dyker, G. Angew. Chem., Int. Ed. 1999, 38,
1698–1712; (g) Denmark, S. E.; Baird, J. D. Chem. Eur. J. 2006, 12, 4954–4963;
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2006, 1419–1421; (i) Kofink, C. C.; Blank, B.; Pagano, S.; Götz, N.; Knochel, P.
Chem. Commun. 2007, 1954–1956.
5. (a) Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett. 1979, 20, 3437–3440;
(b) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483; (c) Suzuki, A. J.
Organomet. Chem. 1999, 576, 147–168; (d) Suzuki, A. J. Organomet. Chem. 2002,
653, 83–90; (e) Kotha, S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002, 58, 9633–
9695; (f) Miyaura, N. In Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.;
Meijere, A. de, Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004; Vol. 1, pp 41–
124.
6. (a) Bringmann, G.; Gunther, C.; Ochse, M.; Schupp, O.; Tasler, S. In Progress in
the Chemistry of Organic Natural Products; Herz, W.; Falk, H.; Kirby, G. W.;
Moore, R. E.; Tamm, C., Eds.; Springer: Wien, Austria, 2001; Vol. 82, pp 1–249.;
(b) Bringmann, G.; Feineis, D. Acta Chim. Ther. 2000, 26, 151–171; c Bringmann,
G. In Guidelines and Issue for the Discovery and Drug Development against Tropical
Diseases; Vial, H.; Fairlamb, A.; Ridley, R. Eds.; World Health Organisation:
Geneva, 2003; pp 145–152.
100
80
60
40
20
0
1
2
3
4
5
7. Saha, P.; Naskar, S.; Paira, P.; Hazra, A.; Sahu, K. B.; Paira, R.; Banerjee, S.;
Mondal, N. B. Green Chem. 2009. doi:10.1039/B902916H.
No of cycle
8. (a) Zeng, Q.; Kwok, Y.; Kerwin, S. M.; Mangold, G.; Hurley, L. H. J. Med. Chem.
1998, 41, 4273–4278; (b) Kim, M.-Y.; Duan, W.; Gleason-Guzman, M.; Hurley,
L. H. J. Med. Chem. 2003, 46, 571–583.
Figure 2. Reusability of the Amberlite IRA 402(OH) resin tested using 1a and 2b.
9. Paira, P.; Paira, R.; Hazra, A.; Naskar, S.; Sahu, K. B.; Saha, P.; Mondal, S.; Maity,
A.; Banerjee, S.; Mondal, N. B. Tetrahedron Lett. 2009, 50, 4619–4623.
10. (a) Das, B.; Majhi, A.; Banerjee, J.; Chowdhury, N. J. Mol. Catal. A 2006, 260, 32–
34; (b) Joseph, K. J.; Jain, L. S.; Sain, B. J. Mol. Catal. A 2006, 247, 99–102; (c)
Yadav, J. S.; Reddy, B. V. S.; Gupta, M. K.; Prattap, I.; Pandey, S. K. Catal. Commun.
2007, 8, 2208–2211; (d) Garg, N. K.; Woodroofe, C. C.; Lacenere, C. J.; Quake, S.
R.; Stoltz, B. M. Chem. Commun. 2005, 36, 4551–4553; (e) Solabannavar, S. B.;
Desai, U. V.; Mane, R. B. Green Chem. 2002, 4, 347–348.
consecutive five-time use of the resin, there is only a slight
decrease in the conversion (95–85%) of the biaryl products
(Fig. 2).
2. Conclusion
11. http://www.sigmaaldrich.com/chemistry/aldrich-chemistry/tech-bulletins/al-
142/amberlite-amberlyst.html.
In summary, we have described a simple, convenient, and effi-
cient protocol for the preparation of biaryl quinolonoquinoxalino-
oxazocines from 5,7-dibromoquinolono quinoxalino-oxazocines
using Amberlite IRA 402(OH) ion-exchange resin. The attractiveness
of this protocol lies in the mild reaction conditions, greater selectiv-
ity, simplicity in operation, cleaner reaction profiles, and low cost
coupled with reusability of the resin. These make it an attractive
green process for the synthesis of biaryl heteroaromatics of biologi-
cal importance.
12. General reaction procedure for the synthesis of biaryl quinolones (3a–k):
Appropriate amount of dihaloquinolonoquinoxalino-oxazocine (1a/b)
(0.5 mmol) was taken in 20 mL of water in a 100 mL RB flask under inert
atmosphere, 400 mg of Amberlite IRA 402(OH) was added, and the mixture
was stirred at 45–50 °C till dissolution of the substrate. Then 0.0005 mmol
Pd(PPh3)4 and aryl or hetero aryl boronic acids 2a–j (1.1 mmol, 1:2.2 molar
ratio with respect to the substrate) were added to the stirred solution and the
stirring was continued for 30 min. The flask was placed in an oil bath and the
stirring was continued for 10–12 h at 90–95 °C. After completion of the
reaction, the resin was recovered by simple filtration, thoroughly washed with
ethanol followed by sodium hydroxide solution, and dried at 80 °C under
reduced pressure for subsequent runs. The filtrate was transferred to
a
separating funnel and extracted with ethyl acetate. The organic layer was
washed thoroughly with water until free from alkali, dried over anhydrous
Acknowledgments
sodium sulfate, and evaporated to dryness in
a rotary evaporator under
We like to thank the Council of Scientific and Industrial Re-
search (CSIR), New Delhi, for financial support in the form of fel-
lowships to P. Paira, R. Paira, A. Hazra, K. B. Sahu, S. Naskar, P.
Saha, S. Mondal and A. Maity, Mr. K. K. Sarkar for HRMS analysis
and Mr. Rajendra Mahato for technical help. We are also thankful
to Dr. B. Achari, Emeritus Scientist, CSIR, for critical suggestions
and encouragement.
reduced pressure. The residue was chromatographed over silica gel (60–120,
mesh), eluting with a mixture of ethyl acetate–pet. ether in different ratios to
yield the biaryl quinolones (3a–k).
Compound 3a: Obtained from 20% ethyl acetate–pet. ether fraction and
crystallized from chloroform–hexane mixture to give white crystalline solid in
90% yield. Mp 220 °C; Rf (60% pet. ether–chloroform) 0.55; IR (KBr, cmÀ1
) m
3444, 1660, 1419, 767. 1H NMR (600 MHz, CDCl3): d 4.96 (1H, d, J = 15.6 Hz),
5.49 (1H, d, J = 16.2 Hz), 6.17 (1H, d, J = 13.8 Hz), 6.53 (1H, d, J = 13.8 Hz), 6.66
(1H, d, J = 9.6 Hz), 7.22 (1H, s), 7.35 (2H, m), 7.45(4H, m), 7.51 (2H, t, J = 7.8 Hz),
7.67 (3H, m), 7.73 (2H, m), 7.91(1H, m), 8.20 (1H, m); 13C NMR (CDCl3,
150 MHz): d. 50.4 (CH2), 77.2 (CH2), 120.4 (C), 121.9 (CH), 126.7 (CH), 127.9
(CH), 128.1 (CH), 128.3 (CH), 128.5 (2 Â CH), 128.6 (2 Â CH), 128.9 (C), 129.4
(2 Â CH), 129.8 (CH), 129.9 (2 Â CH), 130.0 (CH), 130.5 (CH), 134.7 (C), 137.0
(C), 137.2 (CH), 138.1 (C), 138.7 (C), 141.1 (C), 141.8 (C), 143.9 (C), 150.1 (C),
151.7 (C), 163.1 (C, CO). ESI-MS: m/z 468 [M+H]+, 490 [M+Na]+ HRMS: calcd
490.1531 [M+Na]+; found 490.1537.
Supplementary data
Supplementary data (Experimental procedures, characteriza-
tion for all compounds and crystallographic data.) associated with
this article can be found, in the online version, at doi:10.1016/
j.tetlet.2009.07.072.
Compound 3h: Obtained from 30% ethyl acetate–pet. ether fraction and
crystallized from chloroform–hexane mixture to give a white crystalline solid
in 95% yield. Mp 202–204 °C; Rf (60% pet. ether–chloroform) 0.52; IR (KBr,
cmÀ1 3055, 3009, 1661, 1587, 754. 1H NMR (600 MHz, CDCl3): d 4.97 (1H, d,
) m
References and notes
J = 16.2 Hz), 5.49 (1H, d, J = 16.2 Hz), 6.23 (1H, d, J = 13.8 Hz), 6.59 (1H, d,
J = 13.8 Hz), 6.68 (1H, d, J = 9.6 Hz), 7.43 (1H, s), 7.49 (1H, d, J = 8.4 Hz), 7.55
(4H, m), 7.72 (3H, m) 7.86 (3H, m), 7.92 (5H, m), 7.99 (1H, d, J = 8.4 Hz), 8.1 (1H,
s), 8.20 (1H, m); 13C NMR (CDCl3, 150 MHz): d 50.2 (CH2), 77.2 (CH2), 120.7 (C),
122.0 (CH), 126.4 (CH), 126.5 (CH), 126.6 (CH), 126.7 (CH), 127.1 (CH), 127.2
(CH), 127.7 (CH), 127.8 (2 Â CH), 128.0 (CH), 128.1 (CH), 128.2 (CH), 128.3
(2 Â CH), 128.6 (CH), 128.9 (CH), 129.8 (CH), 129.9 (CH), 130.5 (CH), 132.7 (C),
132.9 (C), 133.1 (C), 133.4 (C), 134.6 (C), 134.8 (C), 136.1 (C), 137.1 (C), 137.2
(CH), 138.2 (C), 141.1 (C), 141.8 (C), 144.0 (C), 150.1 (C), 151.7 (C), 163.1 (C,
CO). ESI-MS: m/z 568 [M+H]+, 590 [M+Na]+ HRMS: calcd 590.1844 [M+Na]+;
found 590.1844.
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