Novel synthesis of some phthalazinone derivatives

Article abstract of DOI:10.1002/cjoc.201180264

Dimethyl homophthalate condensed with isatin to give the unexpected five membered lactone 3 rather than the half ester 1 and the δ-lactone 2. Treatment of compound 3 with excess hydrazine hydrate afforded phthalazinone carbohydrazide 4 which represents a novel method for the synthesis of phthalazinone derivatives. The carbohydrazide 4 upon treatment with carbon disulphide afforded 1,3,4-oxadiazole derivative 5, which reacted with ethylchloroacetate to give the S-alkylated product 6. The structure of compound 3 compared with 2 was discussed using hyperchem professional (7) AM₁ calculations, X-ray single crystal structure and complete spectral data. Copyright

Full text of DOI:10.1002/cjoc.201180264

FULL PAPER
Novel Synthesis of Some Phthalazinone Derivatives
Mahmoud, Mahmoud R.
Derbala, Hamed A.
Abou-Elmagd, Wael S.I.*
Hekal, Mohamed H.
Chemistry Department, Faculty of Science, Ain Shams University, Abassia 11566, Cairo, Egypt
Dimethyl homophthalate condensed with isatin to give the unexpected five membered lactone 3 rather than the
half ester 1 and the δ-lactone 2. Treatment of compound 3 with excess hydrazine hydrate afforded phthalazinone
carbohydrazide 4 which represents a novel method for the synthesis of phthalazinone derivatives. The carbohy-
drazide 4 upon treatment with carbon disulphide afforded 1,3,4-oxadiazole derivative 5, which reacted with ethyl-
chloroacetate to give the S-alkylated product 6. The structure of compound 3 compared with 2 was discussed using
hyperchem professional (7) AM1 calculations, X-ray single crystal structure and complete spectral data.
Keywords phthalazinone carbohydrazide, oxadiazole, triazolo oxadiazole, AM1 calculation, condensation
Introduction
as well as, spectral data. The infrared spectrum of this
compound displayed three stretching absorption bands
－1
Heterocyclic compounds containing hydrazine have
received considerable attention because of their phar-
macological properties and clinical applications.1-3
Phthalazine derivatives were reported to possess anti-
convulsant,4-6 cardiotonic,7 antitumor,8-11 antihyperten-
sive,12-14 antithrombotic,15 antidiabetic,16,17 antimicro-
bial,18,19 anti-inflammatory,20-25 cytotoxic,26 vasorelex-
ant27 and vascular endothelial growth factor receptor II
(VEGFR-2) inhibitory activities.28 Therefore, a number
of methods have been reported for the synthesis of
phthalazine derivatives.29 Efficient method for the
preparation of heterocyclic compounds containing
phthalazine ring is therefore an interesting challenge.
for－the carbonyl group at 1775 cm (νCO lactone), 1715
－1
cm 1 (νCO ester) and 1619 cm (νCO amide) besides the
－1
1
ν
NH
at 3374 cm . H NMR of the product revealed a
pattern completely different from that expected for 2
and can only be intelligibly interpreted in terms of the
1
structure 3. Thus, H NMR spectrum of 3 (DMSO-d6)
shows from high to low field the following signals at δ
3.71 (s, 3H, COOMe), 5.48 (s, 1H, C3-H indolinyl), 6.54
—8.08 (m, 8H, ArH) and 10.59 (s, 1H, NH, exchange-
able with D2O). Furthermore, the mass spectrum of 3
shows the correct molecular ion peak at m/z＝323 (6%)
together with EI fragmentation pattern completely in
accord with the proposed structure (cf. experimental
part). The structure 3 was rigidly established from the
X-ray single crystal structure (deposition no. CCDC
777721) (Figure 1).
Moreover, in agreement with the experimental result,
Frontier coefficients of the reactive sites by applying the
hyperchem professional (7) AM1 calculations to the in-
termediates,32 showed the higher stability of 3 than 2.
This is due to the lower value of HOMO at O－ and
lower value of LUMO at the attacking carbocation cen-
ter (C*) (Table 1).
Results and discussion
In our laboratories, it has been found that when a
mixture of isatin and dimethyl homophthalate was
treated in absolute methanol in the presence of sodium
methoxide, the previously reported30,31 half ester 1 or
six-membered lactone (isocoumarin) 2 have not been
isolated, but the lactone 3 was obtained as the sole
product (Eq. 1).
The structure of 3 was illustrated from its analytical,
* E-mail: waelmagd97@yahoo.com
Received December 30, 2010; revised February 12, 2011; accepted March 21, 2011.
1446
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 1446— 1450

Novel Synthesis of Some Phthalazinone Derivatives
activities.
The structure of 4 was deduced from analytical and
spectroscopic data. Thus, IR spectrum of compound 4
exhibits t－he stretching absorption bands at 3428, 3309,
Figure 1 X-ray single crystal structure of the adduct 3.
Table 1 Frontier coefficient of the reactive sites in 2 and 3
1
－1
3122 cm , 1686 and 1614 cm attributable for the
group frequencies of NH2, NH, CO hydrazide and C＝N,
1
respectively. H NMR spectrum of 4 (DMSO-d6) show
the signals at δ 4.62 (s, 2H, NH2, exchangeable with
D2O), 7.8—8.3 (m, 4H, ArH), 9.7 (s, 1H, NH ex-
changeable with D2O) and 12.88 (s, 1H, NHphth., ex-
changeable with D2O). Furthermore, the EI-MS frag-
mentation shows the molecular ion peak at m/z＝204
(100%) which is the base peak (cf. experimental part).
The conversion of 3 to 4 could be explained on the
bases of the following pathway (Scheme 2).
Compd.
HOMO (O－ )/eV
LUMO (C*)/eV
2
3
－
－
11.031
11.544
－
－
1.412
1.873
The structure of 4 was rigidly confirmed chemically
by the reaction with carbon disulphide in refluxing
pyridine, which afforded 4-(5-mercapto-1,3,4-oxadi-
azol-2-yl)phthalazin-1(2H)-one (5) (Scheme 3).
The formation of methyl-1-(2-oxo-3-indolinyl)-3-
oxo-benzo[c]furan-1-carboxylate (3) could be visualized
as Scheme 1.
The elemental analyses and molecular weight deter-
mination indicate the incorporation of one sulfur atom
to the molecular structure of the p＋roduct whose mo-
Furthermore, upon treatment with excess hydrazine
hydrate compound 3 afforded a product with molecular
formula C9H8N4O2 [M＋ ＝204 (100%)], which was
analyzed and identified as 4-oxo-3,4-dihydrophtha-
lazine-1-carbohydrazide 4 (Eq. 2). Evaporation of the
excess solvent in the mother liquor left a solid product
which was detected as indolin-2-one by m.p. mixed m.p.
and TLC with an authentic sample.
lecular formula is C10H6N4O2S [M ＝246 (89.71%)].
－1
IR spectrum of 5 displayed νNH at 3169, 3110 cm , ν
CO
－1
－1
－1
at 1681cm , ν N at 1642 cm and ν S at 1230 cm .
C＝
C＝
1H NMR spectrum of compound 5 [DMSO-d6] was
completely matched with the assigned structure (cf. ex-
perimental part).
This method represents a novel and convenient
method for the synthesis of phthalazinone carbohy-
drazide 4, which was expected to have interesting bio-
The conversion of compound 4 to 5 could be ex-
plained according the following mechanism (Scheme 4).
Scheme 1
Chin. J. Chem. 2011, 29, 1446— 1450
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1447

Mahmoud et al.
FULL PAPER
Scheme 2
Scheme 3
Scheme 4
A strong clue for the structure 5 was forthcoming
from the reaction of the oxadiazole derivative 5 with
ethyl chloroacetate in refluxing ethanol in the presence
of fused sodium acetate, which yielded ethyl-2-[5-(4-
oxo-3,4-dihydraphthalazin-1-yl)-1,3,4-oxadiazol-2-yl-
thio]acetate (6) as the S-alkylation product (Eq. 3).
molecular ion peak and the EI fragmentation pattern is
completely in accord with the assigned structure (cf.
experimental part).
The formation of S-alkylated product 6 could be ex-
plained on the basis of nucleophilic substitution reaction
by the sulfur nucleophile on the electrophilic center of
ethyl chloroacetate via SN2 mechanism.
The hydrazide derivative was reported33 to give
pyrazolo derivative when treated with β-diketones.
When compound 4 was subjected to react with acetyl
acetone in refluxing dioxane, the normal condensation
product 7 was afforded (Eq. 4).
The structure of 6 was deduced from the correct ana-
lytical and spectroscopic data. Thus, the IR spectrum of
－1
6 displayed νNH at 3218, 3166 cm , νCO (ester) at 1734
－1
－1
cm , νCO (phthalazinone) at 1660 cm . 1H NMR spec-
trum of compound 6 [DMSO-d6] was completely
matched with the assigned structure. Furthermore the
highest recorded peak at m/z＝332 (44%) represents the
The structure 7 was deduced from the analysis of the
1448
www.cjc.wiley-vch.de
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 1446— 1450

Novel Synthesis of Some Phthalazinone Derivatives
General procedure for the reaction of 4-oxo-3,4-
dihydrophthalazine-1-carbohydrazide (4) with CS2
spectral data. Thus, the IR spectrum－shows two carbonyl
1
absorption bands at 1688, 1655 cm and one sharp ab-
－1
sorption band for NH group at 3236 cm . Furthermore,
Formation of 4-(5-mercapto-1,3,4-oxadiazol-2-yl)-
phthalazin-1(2H)-one (5): A mixture of acid hydrazide 4
(2.04 g, 10 mmol) and carbon disulphide (15 mL) in
pyridine (30 mL) was refluxed in water bath for 6 h.
The excess solvent was removed under reduced pressure,
the obtained yellow crystals were collected by filtration
and recrystallized from dioxane to give 5. Pale yellow
crystals (1.4 g, 57%), m.p.＞300 ℃; 1H NMR (DMSO-
d6) δ: 3.3 (br s, 1H, SH), 7.9—8.7 (m, 4H, ArH), 13.39
(s, 1H, NH, NH-COphth.); IR (KBr) νmax: 3169, 3110
1H NMR and mass spectra of 7 are completely consis-
tent with the assigned structure.
Experimental
Melting points were measured on an electrothermal
melting point apparatus. Elemental analyses were per-
formed using a Heraeus CHN Rapid analyzer at the Mi-
croanalytical unit, Cairo University. IR spectra were
measured on a Unicam SP-1200 spectrophotometer us-
－1
(NH), 1681 (C＝O), ＋1642 (C＝N), 1230 (C＝S) cm ;
1
MS m/z (%): 246 (M. , 90), 186 (62), 145 (16), 103 (68),
102 (100), 90 (36), 76 (37), 75 (49). Anal. calcd for
C10H6N4O2S (246): C 48.78, H 2.46, N 22.75, S 13.02;
found C 48.51, H 2.37, N 22.93, S 12.87.
ing KBr wafer technique. H NMR spectra were meas-
ured in DMSO-d6 on a Varian plus instrument (300
MHz). Mass spectra were recorded on a Shimadzu
GC-MS QP1000 EX instrument operating at 70 eV in
EI mode.
General procedure for the reaction of the oxadiazole
derivative 5 with ethyl chloroacetate
General procedure for the condensation of isatin
with dimethyl homophthalate
Formation of ethyl-2-[5-(4-oxo-3,4-dihydraphth-
alazin-1-yl)-1,3,4-oxadiazol-2-ylthio] acetate (6): A
mixture of 5 (2.46 g, 10 mmol), ethyl chloroacetate
(1.22 mL, 10 mmol) and fused sodium acetate (0.82 g,
10 mmol) in absolute ethanol (30 mL) was refluxed for
4 h. The reaction mixture allowed to cool was poured
into water and then stirred for 15 min. The deposited
solid was filtered off, dried and then recrystallized from
ethanol/dioxane to give 6. White crystals (1.33 g, 40%),
m.p. 210—212 ℃; 1H NMR (DMSO-d6) δ: 1.20 (t, J＝
7 Hz, 3H, CH3), 4.18 (q, J＝7 Hz, 2H, CH2CH3) 4.31 (s,
2H, CH2S), 7.92—8.92 (m, 4H, ArH), 13.37 (s, 1H, NH,
exchangeable with D2O);. IR (KBr) νmax: 3218, 3166
(NH), 1734 (C＝O ester), 1＋660 (C＝O phthalazinone)
Formation of methyl-1-(2-oxoindolin-3-yl)-3-oxo-
benzo[c]furan-1-carboxylate (3): To a solution of isatin
(1.47 g, 10 mmol) and dimethyl homophthalate (2.08 g,
10 mmol) in dry methanol (40 mL), sodium methoxide
(1 g Na in 30 mL methanol) was added and the whole
mixture was stirred overnight at r.t. The excess solvent
was removed under reduced pressure and solid residue
was treated with ice cold hydrochloride. The deposit
was filtered off, dried and crystallized from methanol to
give 3. Yellowish white crystals (2 g, 62%). m.p. 220—
1
222 ℃; H NMR (DMSO-d6) δ: 3.71 (s, 3H, OCH3),
5.48 (s, 1H, CH), 6.54—8.08 (m, 8H, ArH), 10.59 (s,
1H, NH exchangeable with D2O); IR (KBr) νmax: 3374
(NH), 1775 (C＝O lactone), 1715 (C＝O ester), 1619
－1
cm ; MS m/z (%): 232 (M. , 44), 213 (42), 189 (72),
＋
－1
173 (56), 145 (100). Anal. calcd for C14H12N4O4S (332):
C 50.60, H 3.64, N 16.86, S 9.65; found C 50.91, H 3.47,
N 16.63, S 9.87.
(C＝O Isatin) cm ; MS m/z (%): 323 (M. , 6), 264 (8),
191 (7), 163 (100), 132 (25), 104 (28), 77 (36), 76 (30).
Anal. calcd for C18H13NO5 (323): C 66.87, H 4.05, N
4.33; found C 66.52, H 4.12, N 4.41.
General procedure for the reaction of the hydrazide
derivative 4 with acetyl acetone
General procedure for the synthesis of 4-oxo-3,4-
dihydrophthalazine-1-carbohydrazide (4)
Formation of oxadiazole derivative (7): A mixture of
hydrazide derivative 4 (2.44 g, 10 mmol) and acetyl
acetone (1 mL, 10 mmol) in dioxane (20 mL) were re-
fluxed for 4 h. The excess solvent was removed under
reduced pressure, the obtained white crystals were col-
lected by filtration and recrystallized from ethanol to
give 7. White crystals (0.73 g, 22%), m.p. 180—183 ℃;
1H NMR (DMSO-d6) δ: 1.79 (s, 3H, COCH3), 2.11 (s,
3H, N＝CCH3), 2.9 (dd, J＝19, 18.5 Hz, 2H, CH2), 6.87
(s, 1H, NH, exchangeable with D2O), 7.6 (d, J＝9 Hz,
1Harom), 7.95—7.91 (m, 2Harom), 8.29 (d, J＝9 Hz,
1Harom.), 12.7 (s, 1H, NH, exchangeable with D2O); IR
Lactonic ester 3 (1 g, 3 mmol) was dissolved in di-
oxane (20 mL) and excess hydrazine (4 mL) was then
added. The reaction mixture was heated under reflux for
3 h. The excess solvent was removed under reduced
pressure and the solid residue was crystallized from
ethanol/dioxane to give 4. White crystals (0.5 g, 79.3 %).
m.p. 238—240 ℃; 1H NMR (DMSO-d6) δ: 4.62 (s, 2H,
NH2, exchangeable), 7.85—8.3 (m, 4H, ArH), 9.7 (s,
1H, NH, NH-CO, exchangeable), 12.88 (s, 1H, NH,
NH-COphth., exchangeable); IR (KBr) νmax: 3428, 3309,
3122 (NH, NH2), 1686 (C＝O hydrazide), 1614 (C＝N)
－1
(KBr) νmax: 3236 (NH), 1688, 1655 (C＝O) cm ; MS
＋
－1
m/z (%): 286 (M+, 14.7), 268 (13.9), 239 (91.2), 173
(52.9), 145 (82.4), 117 (33.6), 90 (100). Anal. calcd for
C14H14N4O3 (286): C 58.73, H 4.93, N 19.57; found C
55.14, H 4.60, N 20.75.
cm ; MS m/z (%): 204 (M , 100), 173 (75), 145 (67),
117 (32), 102 (31), 90 (99), 76 (26), 63 (26). Anal. calcd
for C9H8N4O2 (204): C 52.94, H 3.95, N 27.44; found C
52.71, H 4.17, N 27.63.
Chin. J. Chem. 2011, 29, 1446— 1450
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
1449

Mahmoud et al.
FULL PAPER
References
J.; Lohray, B. B.; Lohray, V. B.; Iqbal, J.; Raiagopalan, R.
Eur. J. Med. Chem. 2001, 36, 627.
17 Lenz, E. M.; Wilson, I. D.; Wright, B.; Partidge, E. A.;
Rodgers, C. T.; Haycock, P. R.; Lindon, J. C.; Nicholson, J.
K. J. Pharm. Biomed. Anal. 2002, 28, 31.
18 Cardia, M. C.; Distinto, E.; Maccioni, E.; Delogu, A. J.
Heterocycl. Chem. 2003, 40, 1011.
19 Shetgiri, N. P.; Nayak, B. N. Ind. J. Chem. 2005, 448, 1267.
20 Dogruer, D. S.; Kupeli, E.; Yesilada, E.; Sahin, M. F. Arch.
Pharm. (Weinheim) 2004, 337, 303.
21 Napoletano, M.; Norcini, G.; Pellacini, F.; Marchini, F.;
Moraazzoni, G.; Ferlenga, P.; Peradella, L. Bioorg. Med.
Chem. Lett. 2000, 10, 2235.
22 Van der Mey, M.; Hatzelmann, A.; Vanklink, G. B.; Van
der Lann, I. J.; Sterk, G. J.; THibaut, U.; Timmerman, H. J.
Med. Chem. 2001, 44, 2511.
23 Van der Mey, M.; Hildgard, B.; Dennis, G.; Hatzelmann, A.;
Timmerman, H. J. Med. Chem. 2002, 45, 2526.
24 Shubin, K. M.; Kuznetsov, V. A.; Galishev, V. A. Tetrahe-
dron Lett. 2004, 45, 1407.
25 Brad, H.; Qiang, G.; Partha, P. C.; Games, R. F.; Liping, P.;
Robert, M. R.; Anthony, B. R.; Andreas, R.; Kelvin, S.;
Maya, T.; Ryan, P. W.; Shimin, X.; Dawei, Z.; Faye, H.;
Matthew, R. L.; Rashed, S.; Vivian, L.; David, G.; Matthew,
H. P.; Bradley, H.; Lisa, S.; Scot, M.; Lu, M. W.; Andrew, S.
T. J. Med. Chem. 2008, 51, 6271.
26 Kim, J. S.; Lee, H. J.; Suh, M. E. Bioorg. Med. Chem. 2004,
12, 3683.
27 Chakraborti, A. K.; Gopalakrishnan, B.; Sobbia, E.; Malde,
A. Bioorg. Med. Chem. Lett. 2003, 13, 2473.
28 Duncton, M. A.; Piatnitski, E. L.; Katoch-Rouse, R. Bioorg.
Med. Chem. Lett. 2006, 16, 1579.
29 Hwang, J. Y.; Choi, H. S.; Gong, Y. D. Tetrahedron Lett.
2005, 46, 3107.
30 Mahmoud, M. R.; El-Shahawi, M. M.; El-Bordany, E. A.;
Abu El-Azm, F. S. M. Synth. Commun. 2010, 40, 666.
31 Mahmoud, M. R.; El-Shahawi, M. M.; El-Bordany, E. A.;
Abu El-Azm, F. S. M. Eur. J. Chem. 2010, 1(2), 134.
32 Dewar, M. J.; Zobisch, E.; Healy, E. F.; Stewart, J. P. J. Am.
Chem. Soc. 1985, 107, 3902.
33 Mahmoud, M. R.; El-Bordany, E. A.; Hassan, N. F.; Abu
El-Azm, F. S. M. Phosphorus, Sulfur, Silicon 2007, 182,
2507.
1
2
3
Al-assar, F.; Zelenin, K. N.; Lesiovskaya, E. E.; Benzhan, I.
P.; Chakchir, B. A. Pharm. Chem. J. 2002, 36, 598.
Jain, R. P.; Vederas, J. C. Bioorg. Med. Chem. Lett. 2004,
14, 3655.
Carling, R. W.; Moore, K. W.; Street, L. J.; Wild, D.; Isted,
C.; Lesson, P. D.; Thomas, S.; O'Conner, D.; Mckerman, R.
M.; Quirk, K.; Cook, S. M.; Atack, J. R.; Wafttord, K. A.;
Thompson, S. A.; Dawson, G. R.; Ferris, P.; Castor, J. L. J.
Med. Chem. 2004, 47, 1807.
4
5
6
7
8
Grasso, S.; Desarro, G.; Micale, N.; Zappala, M.; Puia, G.;
Baraldi, M.; Demicheli, C. J. Med. Chem. 2000, 43, 2851.
Kornet, M.; Shackleford, G. J. Heterocycl. Chem. 1999, 36,
1095.
Sivakumar, R.; Gnanasam, S. K.; Ramachandran, S.; Leo-
nard, J. T. Eur. J. Med. Chem. 2002, 37, 793.
Nomoto, Y.; Obase, H.; Takai, H.; Teranishi, M.; Nakamura,
J.; Kubo, K. Chem. Pharm. Bull. (TOKYO) 1990, 38, 2179.
Cockcrof, X.; Dillon, K. J.; Dixon, L.; Drzewiecki, J.;
Everseley, P.; Gomes, S.; Hoare, J.; Kirrigan, F.; Nalthews,
I.; Menear, K. A.; Martin, N. M.; Newton, R.; Paul, J.;
Smith, G. C.; Vile, J.; Whittler, A. J. Bioorg. Med. Chem.
Lett. 2006, 16, 1040.
9
Cockcrof, X.; Dillon, K. J.; Dixon, L.; Drzewiecki, J.; Kir-
rigan, F.; Loh, V. M.; Martin, N. M.; Menear, K. A.; Smith,
G. C. Bioorg. Med. Chem. Lett. 2005, 15, 2235.
10 Kim, J. S.; Lee, H.; Suh, M.; Choo, H. P.; Lee, S. K.; Park,
H. J.; Kim, C.; Park, S. W.; Lee, C. Bioorg. Med. Chem.
2004, 12, 3683.
11 Haider, N.; Kabicher, J.; Kaferbock, J.; Plenk, A. Molecules
2007, 12, 1900.
12 Demirayak, S.; Karaburun, K.; Beis, R. Eur. J. Med. Chem.
2004, 39, 1089.
13 Goodman and Gilman’s, 11th ed., Mc Graw-Hill Medical
Publishing Division, New York, 2006, p. 860.
14 Watanabe, N.; Kabasawa, Y.; Takase, Y.; Matsukura, M.;
Miyazaki, K.; Ishihara, H.; Kodama, K.; Adachi, H. J. Med.
Chem. 1998, 41, 3367.
15 Johnsen, M.; Rehese, K.; Pertz, H.; Stasch, J.; Bischoff, E.
Arch. Pharm. (Weinheim) 2003, 336, 591.
16 Madhavan, G. R.; Chakrabarti, R.; Kumar, S. K.; Misra, P.;
Mamidi, R. N.; Balarzu, V.; ksiram, K.; Babu, R. K.; Suresh,
(E1012303 Zhao, C.)
1450
www.cjc.wiley-vch.de
© 2011 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2011, 29, 1446— 1450