One-pot, three-component route to 2H-indazolo[2,1-b]phthalazine-triones

Article abstract of DOI:10.1016/j.tet.2008.01.006

2H-Indazolo[2,1-b]phthalazine-1,6,11(13H)-trione derivatives were synthesized in a simple and efficient method from the three-component condensation reaction of phthalhydrazide, dimedone, and aromatic aldehydes under solvent-free conditions in excellent y

Full text of DOI:10.1016/j.tet.2008.01.006

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Tetrahedron 64 (2008) 2375e2378
www.elsevier.com/locate/tet
One-pot, three-component route to 2H-indazolo[2,1-b]phthalazine-triones
*
Maryam Sayyafi, Mozhdeh Seyyedhamzeh, Hamid Reza Khavasi, Ayoob Bazgir
Department of Chemistry, Shahid Beheshti University, PO Box 19396-4716, Tehran, Iran
Received 23 September 2007; received in revised form 8 December 2007; accepted 3 January 2008
Available online 5 January 2008
Abstract
2H-Indazolo[2,1-b]phthalazine-1,6,11(13H)-trione derivatives were synthesized in a simple and efficient method from the three-component
condensation reaction of phthalhydrazide, dimedone, and aromatic aldehydes under solvent-free conditions in excellent yields and short reaction
times.
Ó 2008 Published by Elsevier Ltd.
Keywords: Dimedone; Phthalhydrazide; Indazolophtalazine; One-pot reaction
1. Introduction
reported to possess anticonvulsant,7 cardiotonic,8 and vasorelax-
ant9 activities. Therefore, a number of methods have been
reported for the synthesis of phthalazine derivatives.7,10e16 De-
spite the available methods, the development of new synthetic
methods for the efficient preparation of heterocycles containing
phthalazine ring fragment is therefore an interesting challenge.
Multicomponent reactions of dimedone (5,5-dimethylcy-
clohexane-1,3-dione), an aldehyde, and N-nucleophilic hetero-
cycles have recently attracted the interest of the synthetic
community because the formation of different condensation
products can be expected depending on the specific conditions
and structure of the building blocks17e21 Phthalhydrazide (2,3-
dihydro-1,4-phthalazinedione) containing two NH-nucleo-
philic groups is a very interesting heterobicyclic compound.
In the present work, we took advantage of NH groups in
a three-component condensation reaction of dimedone 1,
phthalhydrazide 2, and aromatic aldehydes 3aeh in the prepara-
tion of 3,4-dihydro-3,3-dimethyl-13-aryl-2H-indazolo[2,1-b]-
phthalazine-1,6,11(13H)-trione derivatives 4aeh (Scheme 1).
The rapid assembly of molecular diversity utilizing multi-
component reaction (MCRs) has received a great deal of
attention, most notably for the construction of heterocyclic
‘drug-like’ libraries.1e3 These methodologies have great util-
ity, particularly, when they lead to the formation of privileged
medicinal heterocyclic compounds.
In the past few decades, the synthesis of new heterocyclic
compounds has been a subject of great interest due to their
wide applicability. Heterocyclic compounds occur very widely
in nature and are essential to life. Among a large variety of het-
erocyclic compounds, heterocycles containing phthalazine moi-
ety are of interest because they show some pharmacological and
biological activities (Fig. 1).4e6 Phthalazine derivatives were
CONMe2
O
O
O
O
Me
H
N
AcHN
N
N
N
H
N
H
N
O
O
HN
NHAr
O
O
O
O
5
HAV 3C inhibitor
antihypoxic and antipyretic agent 4
Figure 1.
NH
NH
p-TSA
Solvent-free/80 °C
O
N
N
+
O
ArCHO
+
O
Ar
O
O
4a-h
1
2
3a-h
* Corresponding author. Fax: þ98 21 2403041.
E-mail address: a_bazgir@sbu.ac.ir (A. Bazgir).
Scheme 1.
0040-4020/$ - see front matter Ó 2008 Published by Elsevier Ltd.
doi:10.1016/j.tet.2008.01.006

2376
M. Sayyafi et al. / Tetrahedron 64 (2008) 2375e2378
2. Results and discussion
80 ꢀC under solvent-free conditions for several minutes to pro-
duce 2H-indazolo[2,1-b]phthalazine-1,6,11(13H)-triones 4aeh
(Table 1). The results were excellent in terms of yields and
product purity in the presence of p-TSA, while without it
for long period of time (4e5 h) the yields of products were
low (<30%).
Dimedone 1, phthalhydrazide 2, and aromatic aldehydes
3aeh in the presence of a catalytic amount of p-toluenesul-
fonic acid (p-TSA) undergo a fast 1:1:1 addition reaction at
The nature of these compounds as 1:1:1 adducts was appar-
ent from their mass spectra, which displayed, in each case, the
molecular ion peak at appropriate m/z values. Compounds 4aeh
are stable solids whose structures are fully supported by IR,
1H, and 13C NMR spectroscopies, mass spectrometry, and
elemental analysis. The structure of 4c was confirmed by a sin-
gle-crystal X-ray analysis22 (Fig. 2).
Under the same conditions, this reaction almost could not
be observed when the aliphatic aldehyde was used as a starting
material.
Table 1
Synthesis of indazolo[2,1-b]phthalazine-triones 4
Entry
Aldehyde
Product
Time
(min)
Yield
(%)
O
CHO
O
N
N
1
10
86
Ph
O
4a
A possible mechanism for the formation of 4aeh is pro-
posed in Scheme 2. It is reasonable to assume that 4aeh
results from initial formation of a heterodiene 5 by standard
Knoevenagel condensation of the dimedone 1 and aldehyde
O
O
N
N
CHO
2
3
4
10
10
10
93
90
80
Cl
Br
O
4b
Cl
C21
O
O
C20
C19
N
N
CHO
CHO
CHO
C22
C18
O
4c
Br
C17
O3
O1
C23
N1
O
C12
C16
C11
C10
O
N
Br1
C13
C14
C1
C2
N
F
O
C9
4d
C3
C4
N2
C8
F
C15
O
C7
O
N
N
O2
C5
5
6
10
15
91
88
C6
O2N
O
4e
O2N
Figure 2. X-ray crystal structure of 4c.
O
CHO
O
N
O
O
N
Cl
NH
NH
O
Cl
4f
+
ArCHO
CHO
O
O
O
O
O
O
1
N
7
8
15
20
86
83
5
Ar
N
O2N
NO2
O
4g
O
O
O
-H2O
H
N
O
N
N
O
CHO
Ar
O
N
O
N
N
Ar
O
H3C
O
O
4a-h
4h
Me
Scheme 2.

M. Sayyafi et al. / Tetrahedron 64 (2008) 2375e2378
2377
3. Then, the subsequent Michael-type addition of the phthal-
hydrazide 2 to the heterodyne 5 followed by cyclization
affords the corresponding products 4 (Scheme 2).
156.0, 192.1; MS, m/z (%): 451 (Mþ, 7), 295 (100), 104
(28), 76 (34). Anal. Calcd for C23H19BrN2O3: C, 61.21; H,
4.24; N, 6.21%. Found: C, 61.14; H, 4.17; N, 6.30%.
In summary, we have described an efficient and one-pot
synthesis of 2H-indazolo[2,1-b]phthalazine-triones via a cyclo-
condensation reaction of dimedone, phthalhydrazide, and aro-
matic aldehydes under solvent-free conditions. To the best of
our knowledge, this new procedure provides the first example
of the efficient synthetic method for 2H-indazolo[2,1-b]phthal-
azine-1,6,11(13H)-trione by a three-component reaction.
3.4. 3,4-Dihydro-3,3-dimethyl-13-(4-fluorophenyl)-2H-
indazolo[2,1-b]phthalazine-1,6,11(13H)-trione (4d)
Yellow powder (80%); mp 217e219 ꢀC; IR (KBr) (nmax
,
cmꢁ1): 2958, 1664, 1655, 1626; dH (300 MHz, CDCl3) 1.21
(6H, s, 2 Me), 2.34 (2H, s, CH2CO), 3.23 and 3.41 (2H, AB
system, J 19.0 Hz, CHaHbCO), 6.43 (1H, s, CHN), 6.99e
8.35 (8H, m, Ph); dC (75 MHz, CDCl3) 28.5, 28.7, 34.7,
38.0, 50.9, 64.3, 115.5, 115.9, 118.2, 127.7, 128.0, 128.9,
129.1, 132.2, 133.7, 134.6, 151.1, 154.4, 156.0, 192.2; MS,
m/z (%): 390 (Mþ, 9), 295 (100), 104 (52). Anal. Calcd for
C23H19FN2O3: C, 70.76; H, 4.91; N, 7.18%. Found: C,
70.69; H, 4.96; N, 7.10%.
3. Experimental
3.1. Typical procedure for the preparation of 3,4-dihydro-
3,3-dimethyl-13-phenyl-2H-indazolo[2,1-b]phthalazine-
1,6,11(13H)-trione (4a)
A mixture of dimedone (0.14 g, 1 mmol), phthalhydrazide
(0.16 g, 1 mmol), benzaldehyde (0.13 g, 1.2 mmol), and
p-TSA (0.3 mmol) was heated at 80 ꢀC for 10 min (TLC). After
cooling, the reaction mixture was washed with water (15 mL)
and the residue recrystallized from ethyl acetate/n-hexane
(1:3) to afford the pure product 4a (0.32 g, 86%) as a yellow
powder. Mp 204e206 ꢀC; IR (KBr) (nmax, cmꢁ1): 2958, 1661,
1575; dH (300 MHz, CDCl3) 1.23 (6H, s, 2Me), 2.35 (2H, s,
CH2CO), 3.26 and 3.44 (2H, AB system, J 18.6 Hz, CHaHbCO),
6.47 (1H, s, CHN), 7.33e8.37 (9H, m, Ph); dC (75 MHz, CDCl3)
28.5, 28.7, 34.7, 38.1, 50.9, 64.9, 118.6, 127.1, 127.7, 127.9,
128.7, 128.9, 129.1, 133.6, 134.5, 136.4, 150.9, 154.3, 156.1,
192.2; MS, m/z (%): 372 (Mþ, 15), 295 (100), 104 (84), 76
(67). Anal. Calcd for C23H20N2O3: C, 74.18; H, 5.41; N,
7.52%. Found: C, 74.25; H, 5.36; N, 7.45%.
3.5. 3,4-Dihydro-3,3-dimethyl-13-(4-nitrophenyl)-2H-
indazolo[2,1-b]phthalazine-1,6,11(13H)-trione (4e)
Yellow powder (91%); mp 223e225 ꢀC; IR (KBr) (nmax
,
cmꢁ1): 2924, 1695, 1659, 1615; dH (300 MHz, CDCl3) 1.21
(3H, s, Me), 1.23 (3H, s, Me), 2.33 and 2.38 (2H, AB system,
J 16.5 Hz, CHaHbCO), 3.26 and 3.43 (2H, AB system, J
19.2 Hz, CHaHbCO), 6.52 (1H, s, CHN), 7.61e8.41 (8H, m,
Ph); dC (75 MHz, CDCl3) 28.4, 28.7, 34.7, 38.0, 50.8, 64.2,
117.3, 124.1, 127.8, 128.1, 128.3, 128.6, 128.9, 133.9,
134.9, 143.4, 147.9, 151.7, 154.6, 155.9, 192.1; MS, m/z
(%): 417 (Mþ, 5), 295 (100), 104 (48), 76 (75). Anal. Calcd
for C23H19N3O5: C, 66.18; H, 4.59; N, 10.07%. Found: C,
66.24; H, 4.65; N, 9.98%.
3.2. 3,4-Dihydro-3,3-dimethyl-13-(4-chlorophenyl)-2H-
3.6. 3,4-Dihydro-3,3-dimethyl-13-(2-chlorophenyl)-2H-
indazolo[2,1-b]phthalazine-1,6,11(13H)-trione (4b)
indazolo[2,1-b]phthalazine-1,6,11(13H)-trione (4f)
White powder (93%); mp 262e264 ꢀC; IR (KBr) (nmax, cmꢁ1):
2957, 1656, 1623; dH (300 MHz, CDCl3) 1.22 (3H, s, Me),
1.23 (3H, s, Me), 2.35 (2H, s, CH2CO), 3.25 and 3.43 (2H,
AB system, J 19.1 Hz, CHaHbCO), 6.43 (1H, s, CHN),
7.31e8.39 (8H, m, Ph); dC (75 MHz, CDCl3) 28.5, 28.7,
34.7, 38.0, 50.9, 64.3, 118.1, 127.7, 128.1, 128.5, 128.8,
128.9, 129.0, 133.7, 134.5, 134.6, 134.9, 151.1, 154.3,
156.0, 192.2; MS, m/z (%): 406 (Mþ, 5), 295 (100), 104
(43), 76 (46). Anal. Calcd for C23H19ClN2O3: C, 67.90; H,
4.71; N, 6.89%. Found: C, 67.81; H, 4.66; N, 6.81%.
Yellow powder (88%); mp 264e266 ꢀC; IR (KBr) (nmax
,
cmꢁ1): 2956, 1663, 1625; dH (300 MHz, CDCl3) 1.22 (3H,
s, Me), 1.23 (3H, s, Me), 2.33 (2H, s, CH2CO), 3.24 and
3.42 (2H, AB system, J 19.1 Hz, CHaHbCO), 6.69 (1H, s,
CHN), 7.25e8.40 (8H, m, Ph); dC (75 MHz, CDCl3) 28.4,
28.8, 34.6, 38.0, 50.9, 64.0, 116.7, 127.2, 127.6, 128.0,
128.7, 129.0, 129.9, 130.5, 132.6, 133.0, 133.6, 134.5,
151.9, 154.2, 156.2, 192.1; MS, m/z (%): 406 (Mþ, 8), 295
(100), 104 (43), 76 (46). Anal. Calcd for C23H19ClN2O3: C,
67.90; H, 4.71; N, 6.89%. Found: C, 67.83; H, 4.79; N, 6.80%.
3.3. 3,4-Dihydro-3,3-dimethyl-13-(4-bromophenyl)-2H-
3.7. 3,4-Dihydro-3,3-dimethyl-13-(3-nitrophenyl)-2H-
indazolo[2,1-b]phthalazine-1,6,11(13H)-trione (4c)
indazolo[2,1-b]phthalazine-1,6,11(13H)-trione (4g)
White powder (90%); mp 265e267 ꢀC; IR (KBr) (nmax, cmꢁ1):
2957, 1656, 1623; dH (300 MHz, CDCl3) 1.21 (3H, s, Me),
1.22 (3H, s, Me), 2.35 (2H, s, CH2CO), 3.24 and 3.41 (2H,
AB system, J 19.2 Hz, CHaHbCO), 6.41 (1H, s, CHN),
7.29e8.38 (8H, m, Ph); dC (75 MHz, CDCl3) 28.5, 28.7,
34.7, 38.0, 50.9, 64.4, 118.0, 122.8, 127.8, 128.1, 128.8,
128.9, 129.0, 131.9, 133.7, 134.7, 135.5, 151.1, 154.4,
Yellow powder (86%); mp 270e272 ꢀC; IR (KBr) (nmax
,
cmꢁ1): 2926, 1660, 1625; dH (300 MHz, DMSO-d6) 1.12
(6H, s, 2Me), 2.27 (2H, s, CH2CO), 3.23 (2H, br s, CH2CO),
6.46 (1H, s, CHN), 7.60e8.37 (8H, m, Ph); dH (300 MHz,
DMSO-d6) 28.3, 28.9, 34.6, 38.2, 51.5, 64.2, 116.9, 127.3,
127.3, 128.4, 128.7, 129.2, 129.8, 131.5, 132.7, 133.1,
133.6, 134.5, 135.5, 151.8, 154.4, 156.4, 192.2; MS, m/z

2378
M. Sayyafi et al. / Tetrahedron 64 (2008) 2375e2378
(%): 417 (Mþ, 10), 295 (100), 104 (48), 76 (75). Anal. Calcd
for C23H19N3O5: C, 66.18; H, 4.59; N, 10.07%. Found: C,
66.11; H, 4.52; N, 10.15%.
7. Grasso, S.; DeSarro, G.; Micale, N.; Zappala, M.; Puia, G.; Baraldi, M.;
Demicheli, C. J. Med. Chem. 2000, 43, 2851.
8. Nomoto, Y.; Obase, H.; Takai, H.; Teranishi, M.; Nakamura, J.; Kubo, K.
Chem. Pharm. Bull. (Tokyo) 1990, 38, 2179.
9. Watanabe, N.; Kabasawa, Y.; Takase, Y.; Matsukura, M.; Miyazaki, K.;
Ishihara, H.; Kodama, K.; Adachi, H. J. Med. Chem. 1998, 41, 3367.
10. Sheradsky, T.; Moshenberg, R. J. Org. Chem. 1986, 51, 3123.
11. Heine, H. W.; Baclawski, L. M.; Bonser, S. M.; Wachob, G. D. J. Org.
Chem. 1976, 41, 3229.
3.8. 3,4-Dihydro-3,3-dimethyl-13-(4-methylphenyl)-2H-
indazolo[2,1-b]phthalazine-1,6,11(13H)-trione (4h)
Yellow powder (83%); mp 227e229 ꢀC; IR (KBr) (nmax
,
12. Ramtohup, Y. K.; James, M. N. G.; Vederas, J. C. J. Org. Chem. 2002, 67,
3169.
cmꢁ1): 2956, 1663, 1621; dH (300 MHz, CDCl3) 1.23 (6H,
s, 2Me), 2.30 (3H, s, CH3), 2.35 (2H, s, CH2CO), 3.24 and
3.43 (2H, AB system, J 18.5 Hz, CHaHbCO), 6.43 (1H, s,
CHN), 7.12e8.38 (8H, m, Ph); dC (75 MHz, CDCl3) 21.3,
28.5, 28.8, 34.7, 38.1, 50.9, 64.9, 118.7, 127.1, 127.7, 127.9,
128.9, 129.2, 129.5, 133.4, 133.5, 134.5, 138.5, 150.8,
154.2, 156.1, 192.2; MS, m/z (%): 386 (Mþ, 10), 295 (100),
104 (45), 76 (46). Anal. Calcd for C23H22N2O3: C, 74.59; H,
5.74; N, 7.25%. Found: C, 74.53; H, 5.69; N, 7.36%.
13. Liu, L. P.; Lu, J. M.; Shi, M. Org. Lett. 2007, 9, 1303.
14. Csampai, A.; Kormendy, K.; Ruff, F. Tetrahedron 1991, 47, 4457.
15. Amarasekara, A. S.; Chandrasekara, S. Org. Lett. 2002, 4, 773.
16. Hwang, J. Y.; Choi, H. S.; Gong, Y. D. Tetrahedron Lett. 2005, 46, 3107.
17. Quiroga, J.; Mejia, D.; Insuasty, B.; Abonia, R.; Nogueras, M.; Sanchez,
A.; Cobo, J.; Low, J. N. Tetrahedron 2001, 57, 6947.
18. Quiroga, J.; Hormaza, A.; Insuasty, B.; Ortiz, A. J.; Sanchez, A.; Nogueras,
M. J. Heterocycl. Chem. 1998, 35, 231.
19. Tu, S.; Fang, F.; Li, T.; Zhu, S.; Zhang, X. J. Heterocycl. Chem. 2005, 42,
707.
20. Quiroga, J.; Insuasty, B.; Hormaza, A.; Saitz, C.; Jullian, C. J. Heterocycl.
Chem. 1998, 35, 575.
Acknowledgements
21. Shaabani, A.; Rahmati, A.; Naderi, S. Bioorg. Med. Chem. Lett. 2005, 15,
5553.
We gratefully acknowledge financial support from the
Research Council of Shahid Beheshti University.
22. X-ray data for 4c: (C23H19BrN2O3), M¼451.30 g/mol, monoclinic sys-
˚
tem, space group P21/n, a¼6.2540(9), b¼13.3953(12), c¼24.335(3) A,
3
b¼93.320(11)ꢀ, V¼2035.3(4) A , Z¼4, Dc¼1.473 g cmꢁ3
,
m(Mo
˚
Ka)¼2.047 mmꢁ1, crystal dimension of 0.5ꢂ0.1ꢂ0.1 mm. The structure
was solved by using SHELXS. The structural refinement and data reduc-
tion were carried out with SHELXL of the X-Step32 suite of programs.
The non-hydrogen atoms were refined anisotropically by full matrix
least-squares on F2 values to final R1¼0.0756, wR2¼0.1396 and
S¼1.145 with 263 parameters using 5473 independent reflection
(q range¼1.68e29.26ꢀ). Hydrogen atoms were located from expected
geometry and were not refined. Crystallographic data for 4c have been
deposited with the Cambridge Crystallographic Data Centre. Copies of
the data can be obtained, free of charge, on application to The Director,
CCDC 660455, Union Road, Cambridge CB2 1EZ, UK. Fax: þ44 1223
336033 or e-mail: deposit@ccdc.cam.ac.uk.
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