Microwave assisted palladium-catalyzed synthesis of phthalazinones and pyridopyridazinones

Article abstract of DOI:10.1016/j.tetlet.2013.05.006

Microwave assisted palladium-catalyzed efficient synthesis of phthalazinones and pyridopyridazinones from O-bromoarylaldehydes, Mo(CO) ₆, and arylhydrazines is described. This methodology avoids the use of toxic CO gas and can be carried out even on a small scale.

Full text of DOI:10.1016/j.tetlet.2013.05.006

Tetrahedron Letters 54 (2013) 3694–3696
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Microwave assisted palladium-catalyzed synthesis of phthalazinones
and pyridopyridazinones
⇑
K. Penta Rao, Ashok K. Basak, Prasant K. Deb, Somesh Sharma, L. Krishnakanth Reddy
Jubilant Chemsys Limited, B-34, Sector-58, Noida 201301, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Microwave assisted palladium-catalyzed efficient synthesis of phthalazinones and pyridopyridazinones
from O-bromoarylaldehydes, Mo(CO)6, and arylhydrazines is described. This methodology avoids the
use of toxic CO gas and can be carried out even on a small scale.
Received 9 April 2013
Revised 30 April 2013
Accepted 3 May 2013
Available online 13 May 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Carbonylation
Phthalazinones
Pyridopyridazinones
Microwave synthesis
The significance and widespread use of the phthalazinone1 and
pyridopyridazinones2 framework in many drugs of natural and
synthetic origin, have led to interest in their synthesis. There is a
continuing interest in the development of new synthetic method-
ologies for the preparation of phthalazinones3 and pyridopyridaz-
inones.4 These methods are encouraging; however, there is still a
need for an original methodology that avoids the use of highly
toxic CO gas and allows for an efficient assembly of the phthalazi-
none and pyridopyridazinone cores from readily available materi-
als in high yields.
microwave irradiation (BiotageÒ Initiator) at 140 °C for 1 h and
obtained similar results (Scheme 1).7
The smooth conversion of 2-bromobenzaldehyde 2 to 2-phen-
ylphthalazin-1(2H)-one 3 under thermal and microwave condi-
tions encouraged us to investigate this reaction under similar
N
N
O
NH2
+
N
H
Br
O
3
1
2
Inspired by the emergence of molybdenum hexacarbonyl5 as an
alternate source of toxic CO gas under palladium catalyzed
carbonylation, we designed a straightforward method to prepare
phthalazinones and pyridopyridazinones by condensation of
O-bromoarylaldehydes with arylhydrazines and subsequent
carbonylation reaction. We herein describe a general and efficient
palladium-catalyzed synthesis of phthalazinones and pyridopyrid-
azinones from commercially available O-bromoarylaldehydes,
Mo(CO)6, and arylhydrazines.
The carbonylation of 2-bromobenzaldehyde with phenylhydr-
azine, Mo(CO)6, and Cs2CO3 in dioxane at 140 °C under thermal
heating was investigated as a model reaction in the presence of
Pd(OAc)2 and di-1-adamantyl-n-butylphosphine (BuPAd2) which
has been proved to be a useful catalyst system for various carbon-
ylation reactions. Under this reaction condition, we observed the
formation of product 33k in good yield (58%). With the successful
result of this reaction, we studied the scope of this reaction under
Scheme 1. Reagents and conditions: Mo(CO)6, Pd(OAc)2, di-1-adamantyl-n-butyl-
phosphine Cs2CO3, dioxane, 140 °C, 16 h, 58% yield or microwave, 140 °C, 1 h, 60%
yield.
Table 1
Optimization of reaction conditions in microwave
Entry
Ligand
Base
Solvent
Yielda (%)
1
2
3
4
5
6
7
8
9
10
BuPAd2
BuPAd2
BuPAd2
BuPAd2
BuPAd2
dppf
X-phos
Xantphos
BINAP
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
Na2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
THF
DMF
DME
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
38
32
34
—
—
26
38
41
45
22
PPh3
a
Isolated yields obtained using 1.0 mmol of 2-bromobenzaldehyde, 0.9–
1.0 mmol of phenylhydrazine, 3.0 mmol of base, 2.50 mmol of Mo(CO)6, 0.1 mmol
of Pd(OAc)2 and 0.2 mmol of ligand at 140 °C for 1 h under microwave irradiation.
⇑
Corresponding author.
E-mail address: lkkreddy@gmail.com (L.K. Reddy).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.05.006

K. P. Rao et al. / Tetrahedron Letters 54 (2013) 3694–3696
3695
Table 2
Microwave assisted synthesis of substituted phthalazinones (3a–3h)
Entry
Substrate 1
Substrate 2
Product 3
Isolated yielda (%)
H
N
N
O
N
H2N
Br
1
72b
1
Cl
O
2a
Cl
3a
H
N
F
F
H2N
N
N
O
2
2
65
Br
O
3b
1a
F
F
H
N
H2N
N
N
O
3
4
69
Cl
Br
2a
O
3c
1a
Cl
H
N
O
O
N
N
O
H2N
64b
Br
2
O
1b
3d
H
N
N
N
O
H2N
Br
5
6
7
62b
66
O
3e
1c
2
H
N
N
O
N
H2N
Br
Cl
O
3f
1c
2a
Cl
H
N
O
O
O
N
N
O
H2N
63b
O
Br
2
O
1d
3g
O
O
H
N
O
O
N
N
O
H2N
Br
8
75
Cl
1d
O
Cl
2a
3h
a
Isolated yields obtained using 1.0 mmol of aldehyde, 0.9–1.0 mmol of hydrazine, 3.0 mmol of Cs2CO3, 2.50 mmol of Mo(CO)6, 0.1 mmol of
Pd(OAc)2 and 0.2 mmol of BuPAd2 in dioxane at 140 °C for 1 h under microwave irradiation.
b
Ref. 3k.
Table 3
Microwave assisted synthesis of substituted pyridopyridazinones (5a–5e)
Entry
Substrate 4
Substrate 2
Product 5
Isolated yielda (%)
H
N
N
N
O
H2N
N
N
N
Br
1
40
O
4
2b
5a
H
N
N
N
N
O
O
H2N
2
3
67
Br
Br
Cl
O
Cl
2a
4a
5b
H
N
N
N
N
N
H2N
65
O
2
4a
5c
(continued on next page)

3696
K. P. Rao et al. / Tetrahedron Letters 54 (2013) 3694–3696
Table 3 (continued)
Entry
Substrate 4
Substrate 2
Product 5
Isolated yielda (%)
N
H
N
N
O
N
N
Cl
H2N
Cl
4
63
Br
O
2c
4a
5d
H
N
N
N
N
N
O
H2
N
5
62
Br
F
O
2d
F
4a
5e
a
Isolated yields obtained using 1.0 mmol of aldehyde, 0.9–1.0 mmol of hydrazine, 3.0 mmol of Cs2CO3, 2.50 mmol of Mo(CO)6, 0.1 mmol of
Pd(OAc)2 and 0.2 mmol of BuPAd2 in dioxane at 140 °C for 1 h under microwave irradiation.
Supplementary data
N
O
N
+
NH2
Supplementary data (synthesized compounds) associated with
this article can be found, in the online version, at http://dx.doi.org/
10.1016/j.tetlet.2013.05.006.
N
N
H
N
4
Br
O
5
2
References and notes
Scheme 2. Reagents and conditions: Mo(CO)6, Pd(OAc)2, di-1-adamantyl-n-butyl-
phosphine, Cs2CO3, dioxane, microwave, 140 °C, 1 h, 71% yield.
1. (a) Nakajima, M.; Ohyama, K.; Nakamura, S.; Shimada, N.; Yamazaki, H.; Yokoi,
T. Drug Metab. Dispos. 1999, 27, 792–797; (b) Prime, M. E.; Courtney, S. M.;
Brookfield, F. A.; Marston, R. W.; Walker, V.; Warne, J.; Boyd, A. E.; Kairies, N. A.;
Von der Saal, W.; Limberg, A.; Georges, G.; Engh, R. A.; Goller, B.; Rueger, P.;
Rueth, M. J. Med. Chem. 2011, 54, 312–319. and references cited therein.
2. Epsztajn, J.; Brzezifiski, J. Z.; Czech, K. Monatsh. Chem. 1993, 124, 549–558. and
references cited therein.
3. (a) Csámpai, A.; Körmendy, K.; Sohár, P.; Ruff, F. Tetrahedron 1989, 45, 5539–
5548; (b) Sutherland, J. B.; Freeman, J. P.; Williams, A. J. Appl. Microbiol.
Biotechnol. 1998, 49, 445–449; (c) Haider, N.; Käferböck, J. K.; Mátyus, P.
Heterocycles 1999, 51, 2703–2710; (d) Morgan, D. O.; Ollis, W. D.; Stanforth, S. P.
Tetrahedron 2000, 56, 5523–5534; (e) Franck, P.; Hostyn, S.; Dajka-Halász, B.;
Polonka-Bálint, A.; Monsieurs, K.; Mátyus, P.; Maes, B. U. W. Tetrahedron 2008,
64, 6030–6037; (f) El Nezhawy, A. O. H.; Gaballah, S. T.; Radwan, M. A. A.
Tetrahedron Lett. 2009, 50, 6646–6650; (g) Outerbridge, V. M.; Landge, S. M.;
Tamaki, H.; Török, B. Synthesis 2009, 1801–1806; (h) Zare, L.; Mahmoodi, N. O.;
Yahyazadeh, A.; Mamaghani, M.; Tabatabaeian, K. Chin. Chem. Lett. 2010, 21,
538–541; (i) Li, W.; Li, H.; Li, Z. Tetrahedron Lett. 2010, 51, 5448–5450; (j) Poli,
D.; Catarzi, D.; Colotta, V.; Varano, F.; Filacchioni, G.; Daniele, S.; Trincavelli, L.;
Martini, C.; Paoletta, S.; Moro, S. J. Med. Chem. 2011, 54, 2102–2113; (k) Wu, X-.
F.; Neumann, H.; Neumann, S.; Beller, M. Chem. Eur. J. 2012, 18, 8596–8599. and
references cited therein.
conditions on substrate 1 and 2 as shown in Table 1 and observed
better yield with the original condition (Cs2CO3 as base, BuPAd2 as
ligand in dioxane at 140 °C for 1 h under microwave irradiation).
With the successful results of these investigations we studied
the scope of this reaction on various substrates (Table 2). As shown
in Table 2, diverse phthalazinones were isolated in moderate to
good yields (62–75%).
To expand the scope of this methodology, we investigated the
synthesis of pyridopyridazinones. Under this reaction condition,
2-bromopyridine-3-aldehyde (4) and phenylhydrazine (2) led to
the smooth formation of product 56 in 71% yield (Scheme 2).
The extent of this reaction was further examined with
O-bromopyridine aldehydes and various arylhydrazines for the
synthesis of substituted pyridopyridazinones. As shown in Table
3, various pyridopyridazinones were isolated in moderate to good
yields (40–67%).
4. Brzezmski, J. Z.; Bzowski, H. B.; Epsztajn, J. Tetrahedron 1996, 52, 3261–3272.
and references cited therein.
5. Odell, L. R.; Russo, F.; Larhed, M. Synlett 2012, 685–698. and references cited
therein.
6. Sako, M. Science of Synthesis In Houben Weyl Methods of Molecular
Transformations Category 2; Yamamoto, Y., Ed.; Georg Thieme: Stuttgart–New
York, 2004; Vol. 16, pp 1109–1153.
In conclusion, phthalazinones and pyridopyridazinones have
been successfully synthesized from O-bromoarylaldehydes and
arylhydrazines using Mo(CO)6 as an alternative to the toxic CO
gas. This methodology is simple, efficient, and environmentally
friendly which can be carried out even on a small scale under ther-
mal and/or microwave irradiation.
7. General experimental procedure: To
(1.00 mmol) and phenylhydrazine (2) (1.00 mmol) in anhydrous 1,4-dioxane
(2 mL) was added cesium carbonate (3.00 mmol) in 2–5 mL capacity
a solution of 2-bromobenzaldehyde (1)
a
microwave vial. The mixture was stirred and degassed with argon gas for
5 min. To this mixture were added Pd(OAc)2 (0.10 mmol) and di-1-adamantyl-
n-butylphosphine (0.20 mmol) under argon atmosphere, and purged with argon
gas for 2 min and then molybdenum hexacarbonyl (2.50 mmol) was added and
the vial was sealed and irradiated in microwave at 140 °C for 1 h. The vial was
cooled to room temperature over a period of 10 min and filtered through Celite
pad, washed with ethyl acetate (10 mL). The combined filtrate was concentrated
in vacuo and the obtained residue was purified by flash column chromatography
over 4 g SNAP cartridge by eluting with gradient of 20–40% ethyl acetate in
hexane to afford 2-phenylphthalazin-1(2H)-one (3) (60%).
Acknowledgments
We are thankful to Jubilant Chemsys management for providing
financial support and analytical facilities for the execution of this
research work.