Basic alumina-supported highly effective Suzuki-Miyaura cross-coupling reaction under microwave irradiation: Application to fused tricyclic oxa-aza-quinolones

Article abstract of DOI:10.1039/b902916h

Basic alumina used in lieu of traditional mineral bases efficiently promotes a solvent free, Pd(PPh₃)₄ catalyzed Suzuki-Miyaura cross-coupling reaction under microwave irradiation.

Full text of DOI:10.1039/b902916h

View Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/greenchem | Green Chemistry
Basic alumina-supported highly effective Suzuki–Miyaura cross-coupling
reaction under microwave irradiation: application to fused tricyclic
oxa-aza-quinolones†
Pritam Saha, Subhendu Naskar, Priyankar Paira, Abhijit Hazra, Krishnendu B. Sahu, Rupankar Paira,
Sukdeb Banerjee and Nirup B. Mondal*
Received 11th February 2009, Accepted 21st April 2009
First published as an Advance Article on the web 28th April 2009
DOI: 10.1039/b902916h
Basic alumina used in lieu of traditional mineral bases
efficiently promotes a solvent free, Pd(PPh3)4 catalyzed
Suzuki–Miyaura cross-coupling reaction under microwave
irradiation.
A systematic study was performed for optimization of yield
of the products on our model systems varying the catalysts,
bases, solvents, solid supports, and the time period. Herein, we
report an efficient system for the Suzuki–Miyaura reaction of
fused tricyclic dihalo quinolones using basic alumina as solid
support and Pd(PPh3)4 as catalyst in a solvent-free medium
under microwave irradiation.
Introduction
The Suzuki–Miyaura cross-coupling reaction of aryl halides
with aryl boronic acids is one of the most versatile and widely
used reactions for the selective construction of carbon–carbon
bonds, in particular for the formation of biaryl derivatives.1
As the biaryl motifs are found in a range of pharmaceuticals,
herbicides and natural products,2 the development of this
versatile reaction has received much attention in recent years.
A plethora of reports have appeared in the literature regarding
improvements that comprise modification of the catalysts1,3
(with or without palladium), variation of solvents1,3,4 (organic,
aqueous or none), use of bases1,3,5 (with or without), and reaction
tools like classical heating1,6 or microwave irradiation,7 with par-
ticular emphasis for cleaner and more environmentally benign
ways to make target molecules. As biaryl quinolones are known
to possess neuroprotective properties,8 we became interested in
constructing the biaryl derivatives from our recently synthesized
novel fused tricyclic quinolones9 using the Suzuki–Miyaura
reaction. The emphasis was on the optimization of yield of the
biaryl products under green reaction conditions. The microwave
irradiation technique was employed in the reactions, as this tool
is well known for achieving energy efficiency and enhancing the
rate of reaction as well as product yields. We were particularly
attracted by the possibility of using a solid-supported reaction,
as it is well documented that in such cases organic compounds
get adsorbed on the surface of inorganic oxides like alumina or
silica which themselves do not absorb or restrict the transmission
of microwave irradiation.10 This is also the case with reagents
immobilized on porous solid supports which have an advantage
over the conventional solution phase reactions because of the
good dispersion of active sites, associated selectivities and easier
work up.10
Results and discussion
At the outset, we chose 5,7-dibromo-1,4-oxazino quinolone
and p-methoxy phenyl boronic acid as model reaction partners
to evaluate the effects of various conditions under microwave
irradiation. The results revealed that the reactions catalyzed by
Pd(OAc)2/PPh3 in toluene-H2O using bases like KF, Cs2CO3 or
even K3PO4 were ineffective and only low yield was obtained
with Na2CO3. In alternative solvents, viz. dioxane and CH3CN,
the reaction yielded no products, though in DCE and DMF low
to moderate yields were obtained. In reactions carried out in
DMF using Na2CO3 along with PdCl2/PPh3 or PdCl2(PPh3)2
as the catalyst, the yields of the products were found to be
45–50%. Similar reaction protocols with Na2CO3 and Pd(PPh3)4
instead of PdCl2(PPh3)2 produced better results. Further studies
with Pd(PPh3)4 using different solvents and bases revealed that
moderate yield could be obtained in DMF or H2O in the
presence of Na2CO3 within 5 min of the reaction. Taking into
account the efficacy of the catalyst Pd(PPh3)4, the study was
further extended using solid supports like silica and alumina
because of the fact that organic groups can robustly anchor to
their surface.11 Moreover, these are excellently stable and readily
available. Indeed, using 1 mol% of Pd(PPh3)4, the silica gel-
supported reaction in the presence of Na2CO3 yielded 75%,
neutral alumina in the presence of KF yielded 80% (Table 1,
entry 8, 11), whilst basic alumina afforded the most effective
conversion (90%) to the biaryl product (Table 1, entry 20).
However, lower yields were obtained when the reactions were
performed by changing the combination of bases with solid
supports with different proportions of the catalyst. It is notable
that only 0.1 mol% of Pd (PPh3)4 with basic alumina could
afford 90% yield even in 3 min (Table 1, entry 21), whereas
neutral alumina was found to be totally ineffective in absence of
a base (Table 1, entry 23–25).
Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road,
Jadavpur, Kolkata, 700 032, India. E-mail: nirup@iicb.res.in;
Fax: +91-33-2473-5197; Tel: +91-33-2473-3491
† CCDC reference number 711585. For crystallographic data in CIF or
other electronic format see DOI: 10.1039/b902916h
The good performance of basic alumina could be ascribed
to the presence of ‘interfacial’ boronic esters, originating from
electrostatic interaction between the electron deficient boron
This journal is
The Royal Society of Chemistry 2009
Green Chem., 2009, 11, 931–934 | 931
©

View Online
Table 1 Optimization of catalyst [Pd(PPh3)4] loading on different solid supports in the reaction between 1a and p-methoxyphenyl boronic acid
under microwave irradiationa
Entry
Solid support–base
Pd(PPh3)4 (mol%)
Temperature/◦C
Time (min)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
Silica gel–KF
Silica gel–KF
Silica gel–KF
Silica gel–KF
0.5
0.5
0.5
1.0
2.0
0.5
0.5
1.0
2.0
0.5
1.0
2.0
0.5
1.0
2.0
0.5
0.5
0.5
0.5
1.0
0.1
0.05
0.5
1.0
2.0
90
110
120
120
120
110
120
120
120
120
120
120
120
130
130
90
110
120
130
120
120
120
120
120
120
5
5
5
3
5
5
3
3
6
5
4
5
5
5
5
3
3
40
50
50
55
55
60
65
75
80
75
80
80
55
60
60
80
85
90
90
90
90
70
NRc
NR
NR
Silica gel–KF
Silica gel–Na2CO3
Silica gel–Na2CO3
Silica gel–Na2CO3
Silica gel–Na2CO3
Neutral alumina–KF
Neutral alumina-KF
Neutral alumina–KF
Neutral alumina–Na2CO3
Neutral alumina–Na2CO3
Neutral alumina–Na2CO3
Basic alumina
Basic alumina
Basic alumina
Basic alumina
Basic alumina
Basic alumina
Basic alumina
Neutral alumina
Neutral alumina
Neutral alumina
3
3
3
3
5
15
20
20
a All the studies were performed by using 1a and p-methoxyphenyl boronic acid under microwave irradiation at 180 W. b Isolated yield. c No reaction.
atom of boronic acid and the oxygen atom of the solid
framework, as depicted in Scheme 1, which facilitates the
reaction. However, the remarkable difference of efficacy between
the two forms of alumina might be due to the structural and
compositional differences among various forms of alumina that
are associated with differing surface reactivity and catalytic
activity.
reaction condition is an effective biarylation protocol with 80–
90% yield.
Finally, generalization of this methodology was also estab-
lished satisfactorily by performing reactions on simpler aryl
bromides (viz. substituted bromobenzene) with different aryl
and heteroaryl boronic acids. The products were characterized
1
by MS, H and 13C NMR spectroscopy. Single crystal X-ray
crystallographic analysis of a biaryl derivative (2c) was carried
out for unambiguous determination of its structure (Fig. 1).†
Scheme 1 Plausible pathway for basic alumina-supported Suzuki–
Miyaura cross coupling reaction.
In order to compare the advantages of the use of microwave
irradiation, we performed the reaction for 2a using an oil bath
at 120 ◦C. It is noteworthy that only 21% of 2a could be isolated
after 23 hours of reaction. On the contrary 90% of the same was
obtained in 3 min under microwave irradiation.
We then examined the optimal set of reaction conditions
with a variety of oxazino (1a), oxazepino (1b), and oxazocino
(1c) quinolones with different aryl/heteroaryl boronic acids,
(Table 2). It can be seen from the table that the newly developed
Fig. 1 ORTEP Diagram of 7,9-di-thiophen-3-yl-2,3-dihydro-1-oxa-3a-
aza-phenalen-4-one (2c); ellipsoids are drawn at 50% probability level.
We also investigated the reusability of the solid support, as it
is very important for industrial and pharmaceutical application.
It was found that basic alumina, on calcination at 150 ◦C for
5 h (after washing with water and acetone) could be recycled
4–5 times with insignificant change in its activity (Fig. 2).
932 | Green Chem., 2009, 11, 931–934
This journal is
The Royal Society of Chemistry 2009
©

View Online
Table 2 Suzuki cross coupling reaction of 5,7-dibromoquinolone (1a–c) with different boronic acids under microwave irradiation
Aryl bromide
Boronic acid
Time/min
Producta
Pd(PPh3)4 (mol%)
Yieldb (%)
1a
1a
3
3
2a: Ar = p-OMe Ph
2b: Ar = furan-2-yl
0.1
0.1
90
86
1a
1a
3
3
2c: Ar = thiophen-3-yl
0.1
0.1
88
88
2d: Ar = pyridin-3-yl
1a
1a
3
3
2e: Ar = naphthalen-2-yl
2f: Ar = quinoline-8-yl
0.1
0.1
90
85
1b
1b
3
3
3a: Ar = p-OMe Ph
3b: Ar = furan-2-yl
0.1
0.1
90
84
1b
1b
3
3
3c: Ar = thiophen-3-yl
0.1
0.1
88
88
3d: Ar = pyridin-3-yl
1c
1c
3
3
4a: Ar = p-OMe Ph
4b: Ar = furan-2-yl
0.1
0.1
90
83
1c
1c
3
3
4c: Ar = thiophen-3-yl
0.1
0.1
88
89
4d: Ar = pyridin-3-yl
a The products were characterized by MS, 1H and 13C NMR spectroscopy. b Isolated Yield.
To the best of our knowledge this is the first report of basic
alumina-supported Suzuki-Miyaura cross-coupling reaction.
Conclusion
In conclusion, we have developed an environmentally benign
solid support system for Suzuki–Miyaura cross coupling reac-
tion of heteroaryl bromides and boronic acids under microwave
irradiation using basic alumina. The novelty of the system
lies in its energy efficiency, low cost, easy availability of the
solid support and also elimination of the use of any base or
solvent. The operational simplicity and general applicability
of the procedure as well as reusability of the basic alumina is
expected to contribute to the development of a green technology
of biaryl heteroaromatics.
Fig. 2 Reusability of the basic alumina.
This journal is The Royal Society of Chemistry 2009
Green Chem., 2009, 11, 931–934 | 933
©

View Online
168; (d) A. Suzuki, J. Organomet. Chem., 2002, 653, 83–90; (e) S.
Kotha, K. Lahiri and D. Kashinath, Tetrahedron, 2002, 58, 9633–
9695; (f) N. Miyaura, Metal-Catalyzed Cross-Coupling Reactions,
ed. A. de Meijere and F. Diederich, Wiley-VCH, Weinheim, 2nd edn,
2004, vol. 1, pp 41–124.
2 (a) G. Bringmann, C. Gunther, M. Ochse, O. Schupp and S. Tasler, in
Progress in the Chemistry of Organic Natural Products; ed. W. Herz,
H. Falk, G. W. Kirby, R. E. Moore and C. Tamm, Springer, Wien,
Austria, 2001, vol. 82, pp 1–249; (b) G. Bringmann and D. Feineis,
Act. Chim. The´rapeut., 2000, 26, 151–171; (c) G. Bringmann, in
Guidelines and Issue for the Discovery and Drug Development Against
Tropical Diseases, ed. H. Vial, A. Fairlamb and R. Ridley, World
Health Organisation, Geneva, 2003, p. 145–152.
Experimental
General procedure
The substrate, fused tricyclic-oxa-aza-quinolone (1 mol), was
dissolved in a minimum amount of chloroform, added to a
round-bottomed flask and basic alumina (500 mg) was added to
it. The organic solvent was evaporated to dryness under reduced
pressure. To the residue, boronic acid (2 mol) and Pd(PPh3)4
(0.1 mol%) were added. The solid mixture was then stirred at
room temperature under inert atmosphere for an additional 10–
15 minutes to ensure efficient mixing. The flask was then fitted
with a septum, and the mixture was subjected to irradiation in a
microwave reactor (CEM, Discover, USA) at 120 ◦C (180 W) for
3 min (as monitored by TLC). After cooling, ethyl acetate was
added and the slurry stirred at room temperature for 10 minutes.
The mixture was then vacuum filtered through a sintered glass
funnel. The filtrate was evaporated to dryness under reduced
pressure and the residue was purified by flash chromatography
to isolate the product. In the recycling experiment the residue
obtained was washed with acetone and water (3–4 times) and
subjected to calcination at 150 ◦C. The calcinated material could
be further utilised in coupling reactions.
3 (a) J. Yan and Z.-S. Zhou, Tetrahedron Lett., 2005, 46, 8173–8175;
(b) J. Yan, W. Hu and W. Zhou, Synth. Commun., 2006, 36, 2097–
2102.
4 (a) C. -J. Li and T. H. Chan, Organic Reaction in Aqueous Media,
Wiley, New York, 1997; (b) P. A. Grieco, Organic Synthesis in Water,
Academic Press, Dordrecht, The Netherlands, 1997; (c) B. Cornils
and W. A. Herrmann, Aqueous Phase Organometallic Catalysis, 2nd
edn, Wiley-VCH, Weinheim, 2004; (d) N. E. Leadbeater, Chem.
Commun., 2005, 2881–2902; (e) C.-J. Li, Chem. Rev., 2005, 105, 3095–
3166; (f) S. Shi and Y. Zhang, Green Chem., 2008, 10, 868–872.
5 (a) B. R. Lipshutz, T. B. Petersen and A. R. Abela, Org. Lett., 2008,
10, 1333–1336; (b) N. Cousaert, P. Toto, N. Willand and B. Deprez,
Tetrahedron Lett., 2005, 46, 6529–6532.
6 J. Lemo, K. Heuze and D. Astruc, Org. Lett., 2005, 7, 2253–2256.
7 (a) N. E. Leadbeater and M. Marco, Org. Lett., 2002, 4, 2973–2976;
(b) N. E. Leadbeater and M. Marco, Angew. Chem., Int. Ed., 2003,
42, 1407–1409; (c) N. E. Leadbeater and M. Marco, J. Org. Chem.,
2003, 68, 5660–5667.
8 Z. Wang, B. Wang and J. Wu, J. Comb. Chem., 2007, 9, 811–817.
9 (a) R. Dutta, D. Mandal, N. Panda, N. B. Mondal, S. Banerjee, S.
Kumar, M. Weber, P. Lugar and N. P. Sahu, Tetrahedron Lett., 2004,
45, 9361–9364; (b) P. Paira, A. Hazra, K. B. Sahu, S. Banerjee, N. B.
Mondal, N. P. Sahu, M. Weber and P. Lugar, Tetrahedron, 2008, 64,
4026–4036.
10 (a) G. Bram, A. Loupy and D. Villemin, in Solid Supports and
Catalysts in Organic Synthesis, ed. K. Smith, Ellis Horwood Prentice
Hall, Chichester, 1992, ch. 12, p. 302; (b) R. S. Varma, Green Chem.,
1999, 1, 43–55.
Acknowledgements
We would like to thank the Council of Scientific and Industrial
Research (CSIR), New Delhi, for financial support in the form of
fellowships to P. Saha, S. Naskar, P. Paira, A. Hazra, K. B. Sahu
and R. Paira. We are also thankful to Dr B. Achari, Emeritus
Scientist, CSIR, for critical suggestions and encouragement. Our
special thanks are due to Professor B. C. Ranu and Mr. S. Guha
of IACS, Kolkata, for their generous cooperation in utilizing the
MW instrument and crystallographic analysis.
11 (a) S. Gronowitz and C. Roos, Acta Chem. Scand., 1975, 29b, 990–
998; (b) S. Gronowitz, J. Malm and A. B. Hoernfeldt, Collect. Czech.
Chem. Commun., 1991, 56, 2340–2351; (c) C. A. Fleckenstein and H.
Plennio, Green Chem., 2007, 9, 1287–1291; (d) N. T. S. Phan and P.
Styring, Green Chem., 2008, 10, 1055–1060; (e) F. Schneider and B.
Ondruschka, ChemSusChem, 2008, 1, 622–625; (f) G. W. Kabalka,
R. M. Pagri, L. Wang, V. Namboodiri and C. M. Hair, Green Chem.,
2000, 2, 120–122; (g) J.-H. Li, C.-L. Deng and Y.-X. Xie, Synth.
Commun., 2007, 37, 2433–2448.
Notes and references
1 (a) N. Miyaura, K. Yamada and A. Suzuki, Tetrahedron Lett., 1979,
20, 3437–3440; (b) N. Miyaura and A. Suzuki, Chem. Rev., 1995,
95, 2457–2483; (c) A. Suzuki, J. Organomet. Chem., 1999, 576, 147–
934 | Green Chem., 2009, 11, 931–934
This journal is
The Royal Society of Chemistry 2009
©