Pyrazolo[3,4,5-de]phthalazine. Syntheses of a practically unknown heterocyclic system

Article abstract of DOI:10.1016/j.tet.2008.12.072

Simple procedures for the synthesis of 1,3-dihydropyrazolo[3,4,5-de]phthalazines (2), a practically novel type of heterocyclic compounds, have been developed. Compounds equally substituted at positions N¹ and N³ can be directly obtai

Full text of DOI:10.1016/j.tet.2008.12.072

Tetrahedron 65 (2009) 1574–1580
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Pyrazolo[3,4,5-de]phthalazine. Syntheses of a practically unknown
heterocyclic system
*
´
´
Dolores Vin˜a, Esther del Olmo , Jose L. Lopez-Perez, Arturo San Feliciano
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, CIETUS, University of Salamanca, 37007 Salamanca, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Simple procedures for the synthesis of 1,3-dihydropyrazolo[3,4,5-de]phthalazines (2), a practically novel
type of heterocyclic compounds, have been developed. Compounds equally substituted at positions N1
and N3 can be directly obtained from 4,7-dihalogenated benzalphthalides (1). Those with different R2 and
R3 substituents are prepared through intermediate phthalazin-1-ones (3), whose synthesis is also
considered.
Received 23 September 2008
Received in revised form 17 December 2008
Accepted 23 December 2008
Available online 27 December 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
heterocyclic compounds. They can be directly synthesized from
4,7-dihalogenophthalides (1) or through a one-pot two-step pro-
The development of new efficient methods to synthesize
structurally diverse azaheterocycles is of major interest for organic
chemists.1 Among a large variety of N-containing heterocycles,
those having a bridgehead hydrazine fragment, or a pyrazole ring
fused to any homocyclic or heterocyclic system, are common and
continue receiving much attention from organic and medicinal
chemists, mainly due to the pharmacological activities and clinical
applications displayed by many of them. Notably, pyrazole-fused
pyrimidines,2 quinolines3 and other systems,4 and those structur-
ally related to endogenous metabolites or drugs, have demon-
strated their potential as chemotherapeutic or pharmacodynamic
agents against disease. Pyrazolo[1,2-b]phthalazines are also well
known and have been synthesized and bioevaluated as analgesic
and anti-inflammatory.5 However, pyrazolophthalazines with
other ring fusion patterns are much less known. In the particular
case of pyrazolo[3,4,5-de]phthalazines, only one procedure, based
on the reaction between benzalthiocarbazone and tetra-
chloroquinone, describing the preparation of one unique com-
pound of this type, seems to have been reported.6
Last year we described a general one-step procedure for the
synthesis of indazoles, through copper oxide-catalyzed hydrazi-
nation of various types of o-halogeno-substituted aromatic carbo-
nyls.7 Such procedure seemed to be easily applicable on other types
of halocarbonyl substrates, and, consequently, it could serve to
synthesize novel heterocyclic systems, containing the hydrazine
fragment as part of an additional fused ring. Thus, we report here
on the research leading to a small library of pyrazolo[3,4,5-de]ph-
cedure from intermediate 5,8-dihalogenophthalazin-1-ones (3).
2. Results and discussion
To explore the possibilities of this methodology, a variety of
benzalphthalides with different substituents on the aromatic rings
were synthesized (Scheme 1).
X
X
X
R1
O
4
3
O
+
O
1
R1
COOH
7
X
O
O
1a-j
Scheme 1.
The classical synthesis of 3-arylmethylidenephthalides (1)
consists of prolonged (4–6 h) heating (240–260 ꢀC) of the phthalic
anhydride derivative with the appropriate acid and KOAc as cata-
lyst.8 Yields achieved by this method are usually lower than 70%
and tend to decrease, when thermally labile acids and/or
substituted phthalic anhydrides are used. Attempts to have an
easier access to the desired benzalphthalides using microwave
(MW) irradiation resulted partially useful.9 The method, while
shortening the exposure of the mixture to high temperature,
afforded reaction products cleaner than those from conventional
heating, though yields were not substantially improved (Table 1).
As it is shown, the best yield in phthalide was achieved for the 4-
chlorobenzylidene derivative 1b, which subsequently was the most
commonly used in the continued research. Yield attained for the
difluoro derivative 1j was lower than for the dichloro analogue 1b.
thalazine derivatives (2), which configure
a series of new
* Corresponding author.
E-mail address: olmo@usal.es (E. del Olmo).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.12.072

D. Vi˜na et al. / Tetrahedron 65 (2009) 1574–1580
1575
Table 1
Table 3
Arylmethylidenephthalides synthesized under MW irradiation
Differently substituted pyrazolo[3,4,5-de]phthalazine prepared sequentially from
benzalphthalide 1b
Compda
X
R1
Yieldb
Compda
R2 (N3)
R3 (N1)
Yieldb
1a
1b
1c
1d
1e
1f
1g
1h
1i
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
F
Ph
4-ClPh
4-FPh
4-CH3OPh
2-CH3OPh
3,4,5-(CH3O)3Ph
4-NO2Ph
1-Naphthyl
2-Naphthyl
4-ClPh
47
60
41
43
29
48
22
22
59
21
2m
2n
2o
H
CH3
(CH2)2OH
(CH2)2OH
(CH2)2OH
CH3
55
57
51
a
All new compounds were characterized by 1H/13C NMR spectral data, elemental
analysis and HRMS.
b
% after column chromatography.
1j
and 2o, N1,N3-disubstituted alternately with methyl and hydroxy-
ethyl groups, were prepared in good yields from the trichloro-
benzalphthalide 1b (Table 3).
a
All new compounds were characterized by 1H/13C NMR spectral data, elemental
analysis and HRMS.
b
% after crystallization.
In the case of equally N1,N3-disubstituted pyrazolophthalazines,
the best yields were attained by the direct procedure. However, due
to the easy formation and isolation of phthalazin-1-ones and mainly
to their pharmacological interest as vasorelaxant,10 polymerase
inhibitors11 and anxiolytic,12 in most cases, we used the sequential
procedure for studying conditions and results of the first reaction.
Phthalazin-1-ones had previously been prepared by us through
condensation of benzalphthalides with hydrazines under reflux.13
In such conditions, dihalogenophthalides react completely with
methylhydrazine, leading to the corresponding pyrazolo[3,4,5-
de]phthalazines. Even, when equal number of equivalents of both
reagents and soft heating were used, the pyrazolophthalazine was
always present in the reaction crude. On the other hand, under MW
irradiation (Scheme 3, Table 4), the reaction stopped at the phtha-
lazinone, even in the presence of excess of hydrazine.14
The reaction of benzalphthalides 1a–j with an excess of methyl-
hydrazine, under reflux and without any catalyst (Scheme 2),
directly led to the corresponding 1,3-dihydropyrazolo[3,4,5-de]-
phthalazines 2a–j (Table 2).
R1
R1
X
X
5
7
N
N
R2NHNH2
reflux
O
3
R2
1
O
N
N
X
R2
1a-j
2a-k
Scheme 2.
R1
R1
X
The formation of this type of pyrazolophthalazines (2) should
proceed through the intermediate 4-arylmethyl-5,8-dihaloge-
nophthalazin-1-ones (3), followed by the cyclocondensation of
X
X
4
R2NHNH2
MW
N
N
O
7
R2
a second methylhydrazine molecule with the b-halocarbonyl frag-
1
O
X
O
ment of the substrate. We assumed that this one-pot reaction
would similarly work with other hydrazine derivatives and con-
firmed this fact through the condensation of benzalphthalide 1b
with 2-hydroxyethylhydrazine that led to pyrazolophthalazine 2k,
with comparative better yield than in the case of the methyl de-
rivative 2b.
According to the proposed pathway, the use of a controlled
sequential procedure for the preparation of pyrazolophthalazines
should give access to a wider series of pyrazolophthalazines, having
different substituents R2 and R3 at positions N1 and N3. The pro-
cedure would include arrest of the reaction at the phthalazin-1-one
level and restart with a different hydrazine derivative. In this
manner, pyrazolophthalazines 2m, monosubstituted at N1, and 2n
1b R1 = 4-ClPh
1d R1 = 4-OCH3
3i
Scheme 3.
The reaction of 4,7-dihalogenobenzalphthalides with methyl-
hydrazine, under MW irradiation, readily led to the expected 2-
methylphthalazin-1-ones in moderate to good yields.
However, the reaction of 1b with hydrazine hydrate, along with
the expected phthalazinone 3p (15%), gave the isoindolinone de-
rivative 4a as the major product (54%, Scheme 4, Tables 4 and 5),
Table 4
5,8-Dihalogenated phthalazin-1-ones (3) prepared by MW irradiation
Compda
X
R1
R2
Yieldb
Table 2
Directly one-pot synthesized N1,N3-disubstituted pyrazolophthalazines
3a
3b
3c
3d
3e
3f
3g
3h
3i
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
F
Ph
4-ClPh
4-FPh
4-CH3OPh
2-CH3OPh
3,4,5-(CH3O)3Ph
4-NO2Ph
1-Naphthyl
2-Naphthyl
4-ClPh
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
(CH2)2OH
H
38
46
30
46
65
45
41
59
28
63
39
15c
77
Compda
X
R1
R2
Yieldb
2a
2b
2c
2d
2e
2f
2g
2h
2i
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
F
Ph
4-ClPh
4-FPh
4-CH3OPh
2-CH3OPh
3,4,5-(CH3O)3Ph
4-NO2Ph
1-Naphthyl
2-Naphthyl
4-ClPh
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
26
74
25
54
21
29
34
17
20
45
80
3j
3m
3p
3q
Cl
Cl
F
4-ClPh
4-ClPh
4-CH3OPh
CH3
CH3
2j
2k
CH3
Cl
4-ClPh
(CH2)2OH
a
All new compounds were characterized by 1H/13C NMR spectral data, elemental
a
All new compounds were characterized by 1H/13C NMR spectral data, elemental
analysis and HRMS.
b
analysis and HRMS.
% after column chromatography.
together with compound 4a (Table 5).
b
c
% after column chromatography.

1576
D. Vi˜na et al. / Tetrahedron 65 (2009) 1574–1580
R1
for 1H and 100 MHz for 13C) or Bruker AMX (500 MHz for 1H and
125.8 MHz for 13C) spectrometers in CDCl3 and DMSO-d6 using TMS
as internal reference. Chemical shift ( ) values are expressed in
Cl
Cl
R1
Cl
Cl
Cl
Cl
HO
R1
R2NHNH2
MW
N
N
d
+
O
N-NHR2
parts per million and coupling constants (J) are reported in hertz.
High resolution mass spectra (HRMS) and the corresponding low
resolution spectra (EIMS and FABMS) were obtained on a VG TS-
250 spectrometer by EI and fast atom bombardment (FAB) working
at 70 eV and using nitrobenzyl alcohol as the matrix with xenon as
the fast atom. Column chromatography (CC) was performed on
silica gel (Merck no. 9385). TLCs were carried out on silica gel 60
F254 (Merck, 0.25 mm thick) and were detected by UV. Solvents and
reagents were purified by standard procedures as necessary.
R2
O
O
O
1b R1 = 4-ClPh
1d R1 = 4-CH3OPh
3p R2 = H
4a-c
4d-e
----
Scheme 4.
Table 5
3-Hydroxyisoindolin-1-ones (4) derived from benzalphthalides 1b and 1d
Compda
R1
R2
Yieldb
MW
4.2. General procedure for synthesis of benzalphthalides
(1a–j)
Reflux
4a
4b
4c
4d
4e
4-ClPh
4-ClPh
4-ClPh
4-CH3OPh
4-CH3OPh
H
t-Bu
Ph
t-Bu
Ph
54
18
55
0
d
d
d
50
93
4,7-Dichlorophthalic anhydride (1.5 mmol) and phenylacetic
acid derivatives (2.7 mmol) were melted and KOAc (0.2 mmol) was
added. The mixture was heated (the temperature is always main-
tained between 210 and 230 ꢀC) under MW (350 W) until change of
colour, then extracted with ethyl acetate and washed with Na2CO3
10% and H2O until pH¼7. Residue was purified by crystallization in
CH2Cl2/MeOH to give the products as yellow to brown solids.
47
a
All new compounds are characterized by 1H/13C NMR spectral data, elemental
analysis and HRMS.
b
% after column chromatography.
while isoindolinones 4b and 4c, were, respectively, obtained as
unique reaction products, when tert-butylhydrazine or phenyl-
hydrazine were used as reagents.15
Similarly, changing the substrate to the 4-methoxybenzalph-
thalide 1d, the reaction with phenylhydrazine in the mentioned
conditions, and even at room temperature, led only to iso-
indolinone 4e.
4.2.1. 3-Benzylidene-4,7-dichloro-3H-isobenzofuran-1-one (1a)
1H NMR (CDCl3) (
d): 7.26 (s, 1H, –CH]), 7.39–7.45 (m, 4H, Aryl-
H), 7.63 (dd, 1H, Aryl-H, J¼1.5 and 8.4 Hz), 7.88 (d, 2H, Aryl-H,
J¼8.0 Hz). 13C NMR (CDCl3) (
d): 113.7, 126.5, 128.9, 129.3, 131.0,
131.3, 132.4, 132.9, 136.7, 137.8, 141.5, 151.3, 162.8. HRMS (EI):
(MþNa) calcd for C15H8Cl2O2Na: 312.9794, found: 312.9782. Mp:
205 ꢀC.
By contrast, previous unpublished results found by us demon-
strated that, in absence of the halogen substituents (X) on the
phthalide, both tert-butyl- and phenylhydrazine could lead to the
corresponding phthalazinones, after refluxing with benzalph-
thalides. Finally, the treatment of 5,8-dichlorophthalazinone 3m
with excess of hydrazine hydrate, under reflux for two days, left
mainly unchanged the starting phthalazinone, while a very small
amount of the reduced 8-dechlorinated-3m could be isolated from
the reacted product.
4.2.2. 4,7-Dichloro-3-(4-chlorobenzylidene)-3H-isobenzofuran-1-
one (1b)
1H NMR (CDCl3) (
d): 7.19 (s, 1H, –CH]), 7.38 (d, 2H, Aryl-H,
J¼8.4 Hz), 7.42 (d, 1H, Aryl-H, J¼8.0 Hz), 7.62 (d, 1H, Aryl-H,
J¼8.4 Hz), 7.79 (d, 2H, Aryl-H, J¼8.8 Hz). 13C NMR (CDCl3) (
d): 112.2,
122.3, 126.5, 129.1, 129.9, 131.6, 132.1, 132.5, 135.2, 136.8, 137.6, 141.7,
162.6. HRMS (EI): (MþNa) calcd for C15H7Cl3O2Na: 346.9404,
found: 346.9408. Mp: 188 ꢀC.
The mentioned failures in the formation of phthalazinones by
MWirradiation, obviously, impede thesubsequentprogresstowards
the pyrazole-fused derivatives and more research must be done to
overcome this problem. Nevertheless, these facts along with the
absence of furo[1,2,3-cd]indazoles in the reaction products serve us
to confirm the sequence phthalide–phthalazinone–pyrazoloph-
thalazine as the actual syntheticpathwaytowards the finalproducts.
4.2.3. 4,7-Dichloro-3-(4-fluorobenzylidene)-3H-isobenzofuran-1-
one (1c)
1H NMR (CDCl3) (
d
): 7.10 (t, 2H, Aryl-H, J¼8.4 Hz), 7.20 (s, 1H,
–CH]), 7.40 (d, 1H, Aryl-H, J¼8.4 Hz), 7.60 (d, 1H, Aryl-H, J¼8.4 Hz),
7.85 (dd, 2H, Aryl-H, J¼5.5 and 8.4 Hz). 13C NMR (CDCl3) (
d): 112.3,
116.0 (J¼88.2 Hz), 126.4, 129.1, 131.3, 132.4 (J¼29.4 Hz), 132.8, 136.7,
137.7, 141.0, 160.5, 162.6, 165.5. HRMS (EI): (MþNa) calcd for
C15H7O2FCl2Na: 330.9699, found: 330.9680. Mp: 189 ꢀC.
3. Conclusions
In summary, the present findings show that the reaction of 4,8-
dichlorobenzalphthalides with methylhydrazine has opened a way
to one almost hitherto unknown series of heterocyclic compounds,
1,3-dihydropyrazolo[3,4,5-de]phthalazines. Much work for opti-
mizing reaction conditions, enhancing yields and avoiding by-
products remains to be performed. New research, focused on the
application of this procedure on other substrates and reagents,
aiming to prepare novel poly-fused hydrazine-based heterocyclic
systems, is currently in progress.
4.2.4. 4,7-Dichloro-3-(4-methoxybenzylidene)-3H-isobenzofuran-
1-one (1d)
1H NMR (CDCl3) (
d): 3.87 (s, 3H, –OCH3), 6.96 (d, 2H, Aryl-H,
J¼8.8 Hz), 7.24 (s, 1H, –CH]), 7.38 (d, 1H, Aryl-H, J¼8.4 Hz), 7.60 (d,
1H, Aryl-H, J¼8.4 Hz), 7.85 (d, 2H, Aryl-H, J¼8.8 Hz). 13C NMR
(CDCl3) (d): 55.4, 113.6, 114.4, 121.9, 125.7, 126.1, 130.7, 132.2, 132.7,
136.5, 137.9, 139.9, 160.5, 163.0. HRMS (EI): (MþNa) calcd for
C16H10Cl2O3Na: 342.9899, found: 342.9897. Mp: 178 ꢀC.
4.2.5. 4,7-Dichloro-3-(2-methoxybenzylidene)-3H-isobenzofuran-
4. Experimental
4.1. General
1-one (1e)
1H NMR (CDCl3) (
d): 3.92 (s, 3H, –OCH3), 6.91 (dd, 1H, Aryl-H,
J¼1.1 and 8.4 Hz), 7.05 (td, 1H, Aryl-H, J¼1.1 and 7.7 Hz), 7.29–7.37
(m, 1H, Aryl-H), 7.38 (d, 1H, Aryl-H, J¼8.4 Hz), 7.60 (d, 1H, Aryl-H,
J¼8.4 Hz), 7.77 (s, 1H, –CH]), 8.24 (dd, 1H, Aryl-H, J¼1.5 and
All NMR spectra were recorded on Bruker WP 200 SY (200 MHz
for 1H and 50.3 MHz for 13C) or Bruker Avance 400 DRX (400 MHz
7.7 Hz). 13C NMR (CDCl3) (
d): 55.9, 107.5, 110.6, 121.1, 121.9, 126.5,

D. Vi˜na et al. / Tetrahedron 65 (2009) 1574–1580
1577
130.7 (2C), 130.9, 131.8, 132.1, 136.6, 138.1, 141.2, 157.6, 163.1. HRMS
4.3.1. 5-Benzyl-6-chloro-1,3-dimethyl-1,3-dihydropyrazolo[3,4,5-de]-
(EI): (MþNa) calcd for C16H10Cl2O3Na: 342.9899, found: 342.9921.
phthalazine (2a)
Mp: 190 ꢀC.
1H NMR (CDCl3) (
d): 3.62 (s, 3H, –CH3), 3.77 (s, 3H, –CH3), 4.30
(s, 2H, –CH2–), 6.63 (d, 1H, Aryl-H, J¼8.8 Hz), 7.07 (d, 1H,
4.2.6. 4,7-Dichloro-3-(3,4,5-trimethoxybenzylidene)-3H-
Aryl-H, J¼8.8 Hz), 7.19–7.29 (m, ArylH, 5H). 13C NMR (CDCl3) (
d):
isobenzofuran-1-one (1f)
35.6, 39.2 (2C), 107.0, 110.8, 123.0, 126.2, 128.3, 128.6, 133.5,
139.1, 139.7, 146.0, 155.6, 159.2. HRMS (EI): (MþH) calcd for
C17H16ClN4: 311.1058, found: 311.1072. Anal. Calcd for C17H15ClN4:
C, 65.70; H, 4.86; N, 18.03. Found: C, 65.66; H, 4.83; N, 17.96. Mp:
104 ꢀC.
1H NMR (CDCl3) (
d): 3.91 (s, 3H, –OCH3), 3.94 (s, 6H, –OCH3), 7.08
(s, 2H, Aryl-H), 7.15 (s, 1H, ]CH–), 7.38 (d, 1H, Aryl-H, J¼8.4 Hz),
7.59 (d, 1H, Aryl-H, J¼8.4 Hz). 13C NMR (CDCl3) (
d): 56.3, 61.0, 108.2,
113.5,122.0,126.3,128.4,131.1,132.4,136.6,137.7,139.4,140.9,153.3,
162.5. HRMS (EI): (MþNa) calcd for C18H14Cl2O5Na: 403.0110,
found: 403.0133. Mp: 200 ꢀC.
4.3.2. 6-Chloro-5-(4-chlorobenzyl)-1,3-dimethyl-1,3-
dihydropyrazolo[3,4,5-de]phthalazine (2b)
4.2.7. 4,7-Dichloro-3-(4-nitrobenzylidene)-3H-isobenzofuran-1-
1H NMR (CDCl3) (
d): 3.60 (s, 3H, –CH3), 3.77 (s, 3H, –CH3), 4.24 (s,
one (1g)
2H, –CH2–), 6.64 (d, 1H, Aryl-H, J¼8.8 Hz), 7.08 (d, 1H, Aryl-H,
1H NMR (CDCl3) (
d
): 7.31 (s, 1H, –CH]), 7.50 (d, 1H, Aryl-H,
J¼8.8 Hz), 7.23 (m, 4H, Aryl-H). 13C NMR (CDCl3) (
d): 35.6, 38.7, 39.3,
J¼8.4 Hz), 7.69 (d, 1H, Aryl-H, J¼8.4 Hz), 8.02 (d, 2H, J¼8.8 Hz), 8.28
107.2, 110.6, 122.9, 128.5, 130.0, 132.0, 133.4, 137.6, 139.1, 146.0,
155.6, 159.2. HRMS (EI): (MþH) calcd for C17H15Cl2N4: 345.0668,
found: 345.0667. Anal. Calcd for C17H14Cl2N4: C, 59.14; H, 4.09; N,
16.23. Found: C, 59.07; H, 4.01; N, 16.19. Mp: 150 ꢀC.
(d, 2H, J¼8.8 Hz). 13C NMR (CDCl3) (
d): 110.4, 123.6, 124.0, 126.6,
127.1, 129.8, 130.5, 131.3, 131.5, 132.5, 137.1, 139.2, 165.8. HRMS (EI):
(MþH) calcd for C15H8Cl2NO4: 335.9786, found: 336.0303. Mp:
192–197 ꢀC.
4.3.3. 6-Chloro-5-(4-fluorobenzyl)-1,3-dimethyl-1,3-
4.2.8. 4,7-Dichloro-3-(naphth-1-yl)methylidene-3H-
isobenzofuran-1-one (1h)
dihydropyrazolo[3,4,5-de]phthalazine (2c)
1H NMR (CDCl3) (
d): 3.61 (s, 3H, –CH3), 3.77 (s, 3H, –CH3),
1H NMR (CDCl3) (
d
): 7.44 (d, 1H, Aryl-H, J¼8.4 Hz), 7.50–7.64 (m,
4.25 (s, 2H, –CH2–), 6.65 (d, 1H, Aryl-H, J¼8.4 Hz), 6.96 (t, 2H, Aryl-
3H, Aryl-H), 7.67 (d, 1H, Aryl-H, J¼8.4 Hz), 7.86–7.92 (m, 2H, Aryl-
H), 8.07 (s, 1H, –CH]), 8.16 (d, 1H, Aryl-H, J¼8.4 Hz), 8.32 (d, 1H,
H, J¼8.8 Hz), 7.08 (d, 1H, Aryl-H, J¼8.4 Hz), 7.24 (dd, 2H, Aryl-H,
J¼5.5 and 8.8 Hz). 13C NMR (CDCl3) (
d): 35.6, 38.4, 39.2, 107.1,
Aryl-H, J¼8.4 Hz). 13C NMR (CDCl3) (
d): 109.6, 123.2, 124.8, 125.4,
110.6, 115.1 (J¼23.7 Hz), 130.0 (J¼33.0 Hz), 133.4, 134.7, 139.0,
139.5, 145.9, 159.1, 163.2. HRMS (EI): (MþH) calcd for C17H15FClN4:
329.0964, found: 329.0959. Anal. Calcd for C17H14ClFN4: C,
62.10; H, 4.29; N, 17.04. Found: C, 62.13; H, 4.20; N, 16.97. Mp:
115 ꢀC.
125.9, 126.1,126.8, 127.0,128.8, 129.1, 129.8, 131.4, 131.8, 132.4, 133.7,
136.7, 137.3, 142.4, 165.5. HRMS (EI): (MþNa) calcd for
C19H10Cl2O2Na: 362.9950, found: 362.9976. Mp: 218 ꢀC.
4.2.9. 4,7-Dichloro-3-(naphth-2-yl)methylidene-3H-
isobenzofuran-1-one (1i)
4.3.4. 6-Chloro-5-(4-methoxybenzyl)-1,3-dimethyl-1,3-
1H NMR (CDCl3) (
d
): 7.42 (d, 1H, Aryl-H, J¼8.4 Hz), 7.46 (d, 1H,
dihydropyrazolo[3,4,5-de]phthalazine (2d)
Aryl-H, J¼8.8 Hz), 7.50 (m, 1H, Aryl-H), 7.53 (s, 1H, –CH]), 7.63 (d,
1H, Aryl-H, J¼8.4 Hz), 7.88 (m, 3H, Aryl-H), 8.06 (d, 1H, Aryl-H,
1H NMR (CDCl3) (
d): 3.61 (s, 3H, –CH3), 3.77 (s, 6H, –(CH3)2), 4.23
(s, 2H, –CH2–), 6.63 (d, 1H, Aryl-H, J¼8.4 Hz), 6.82 (d, 2H, Aryl-H,
J¼8.8 Hz), 8.29 (br s, 1H, Aryl-H). 13C NMR (CDCl3) (
d): 113.8, 126.6,
J¼8.8 Hz), 7.07 (d, 1H, Aryl-H, J¼8.4 Hz), 7.22 (d, 2H, Aryl-H,
126.7, 127.2, 127.6, 127.7, 128.2, 128.6 (2C), 128.7, 130.3, 130.6, 131.3,
132.4, 133.1, 133.4, 136.7, 143.2, 165.8. HRMS (EI): (MþNa) calcd for
C19H10Cl2O2Na: 362.9950, found: 362.9981. Mp: 209 ꢀC.
J¼8.8 Hz). 13C NMR (CDCl3) (
d): 35.5, 38.3, 39.2, 55.2, 107.0, 110.8,
113.7, 123.0, 129.6, 131.0, 131.3, 133.5, 139.0, 140.0, 146.0, 158.1.
HRMS (EI): (MþH) calcd for C18H18ClN4O: 341.1164, found: 341.1157.
Anal. Calcd for C18H17ClN4O: C, 63.44; H, 5.03; N, 16.44. Found: C,
63.40; H, 5.06; N, 16.39. Mp: 122 ꢀC.
4.2.10. 3-(4-Chlorobenzylidene)-4,7-difluoro-(3H)-isobenzofuran-
1-one (1j)
1H NMR (CDCl3) (
d): 6.64 (s, 1H, –CH]), 7.16 (td, 1H, Aryl-H,
4.3.5. 6-Chloro-5-(2-methoxybenzyl)-1,3-dimethyl-1,3-
J¼1.1, 3.3 and 8.8 Hz), 7.40 (d, 2H, Aryl-H, J¼8.8 Hz), 7.59 (t,1H, Aryl-
dihydropyrazolo[3,4,5-de]phthalazine (2e)
H, J¼5.5 Hz), 7.78 (d, 2H, Aryl-H, J¼8.8 Hz). 13C NMR (CDCl3) (
d
):
1H NMR (CDCl3) (
d): 3.60 (s, 3H, –CH3), 3.79 (s, 3H, –CH3), 3.86 (s,
112.4 (d, J¼29.4 Hz), 117.9 (dd, J¼29.4 and 88.2 Hz), 123.5 (dd,
J¼29.4 and 88.2 Hz), 126.8 (t, J¼58.8 Hz), 129.2, 131.7, 135.2, 140.6,
151.9, 155.1, 157.3, 158.2, 161.9. HRMS (EI): (MþNa) calcd for
C15H8F2ClO2: 293.0136, found: 293.0158. Mp: 145 ꢀC.
3H, –CH3), 4.24 (s, 2H, –CH2–), 6.66 (d, 1H, Aryl-H, J¼8.8 Hz), 6.86 (t,
2H, Aryl-H, J¼7.3 Hz), 6.98 (d, 1H, Aryl-H, J¼8.8 Hz), 7.09 (d, 1H,
Aryl-H, J¼8.8 Hz), 7.20 (td, 1H, Aryl-H, J¼2.2 and 7.3 Hz). 13C NMR
(CDCl3) (d): 33.9, 35.6, 39.4, 55.5, 106.9, 110.1, 111.3, 120.4, 122.8,
123.3, 127.3, 127.9, 128.3, 133.7, 139.0, 139.7, 145.9, 157.2. HRMS (EI):
(MþH) calcd for C18H18ClN4O: 341.1164, found: 341.1163. Anal.
Calcd for C18H17ClN4O: C, 63.44; H, 5.03; N, 16.44. Found: C, 63.38;
H, 4.96; N, 16.35. Mp: 108 ꢀC.
4.3. General procedure for the synthesis of pyrazolo[3,4,5-
de]phthalazines (2a–k)
Method A. Benzalphthalides (1a–j) were dissolved in N-alkyl-
hydrazine (1:30 mmol) and refluxed overnight. The mixture was
cooled to room temperature, EtOAc was added and washed with
H2O and NaCl solution until pH¼7. Organic phase was dried over
Na2SO4, filtered and evaporated to dryness. The resulting solid was
purified by flash chromatography (hexane/EtOAc as eluent) to
provide the desired products (2a–k).
Method B. Phthalazinones (3b, 3m, 3p) were treated under
conditions mentioned in method A, affording the corresponding
pyrazolo[3,4,5-de]phthalazines (2m–o).
4.3.6. 6-Chloro-5-(3,4,5-trimethoxybenzyl)-1,3-dimethyl-1,3-
dihydropyrazolo[3,4,5-de]phthalazine (2f)
1H NMR (CDCl3) (
d): 3.62 (s, 3H, –CH3), 3.74 (s, 3H, –OCH3), 3.80
(s, 6H, (OCH3)2), 4.22 (s, 2H, –CH2–), 6.56 (s, 2H, Aryl-H), 6.65 (d, 1H,
Aryl-H, J¼8.8 Hz), 7.11 (d, 1H, Aryl-H, J¼8.8 Hz). 13C NMR (CDCl3)
(d): 35.6, 39.1, 39.3, 56.2, 60.9, 105.8, 107.1, 110.7, 122.9, 133.6, 134.7,
136.1, 136.6, 139.0, 139.6, 145.9, 153.1. HRMS (EI): (MþH) calcd
for C20H22ClN4O3: 401.1375, found: 401.1388. Anal. Calcd for
C20H21ClN4O3: C, 59.92; H, 5.28; N, 13.98. Found: C, 59.95; H, 5.23;
N, 13.88. Mp: 102 ꢀC.

1578
D. Vi˜na et al. / Tetrahedron 65 (2009) 1574–1580
4.3.7. 6-Chloro-1,3-dimethyl-5-(4-nitrobenzyl)-1,3-
4.3.13. 6-Chloro-5-(4-chlorobenzyl)-1-(2-hydroxyethyl)-3-methyl-
1,3-dihydropyrazolo[3,4,5-de]phthalazine (2n)
1H NMR (CDCl3) (
): 3.62 (s, 3H, –CH3), 4.02 (s, 2H, –CH2–), 4.17
dihydropyrazolo[3,4,5-de]phthalazine (2g)
1H NMR (CDCl3) (
d
): 3.61 (s, 3H, –CH3), 3.77 (s, 3H, –CH3), 4.18 (s,
d
2H, –CH2–), 6.63 (d, 1H, Aryl-H, J¼8.8 Hz), 6.67 (d, 2H, Aryl-H,
(m, 2H, –CH2–), 4.26 (s, 2H, –CH2–), 6.71 (d, 1H, Aryl-H, J¼8.8 Hz),
J¼8.4 Hz), 7.07 (d, 1H, Aryl-H, J¼8.8 Hz), 7.10 (d, 2H, Aryl-H,
7.12 (d, 1H, Aryl-H, J¼8.8 Hz), 7.23 (m, 4H, Aryl-H). 13C NMR (CDCl3)
J¼8.4 Hz). 13C NMR (CDCl3) (
d): 35.5, 38.2, 39.2, 106.9, 115.2, 123.0,
(d): 38.6, 39.5, 50.7, 62.1, 107.5, 111.4, 122.6, 122.8, 128.5, 130.0, 132.1,
128.6,128.8,129.0,129.2,129.4,133.4,138.9,140.1,144.5. HRMS (EI):
(MþH) calcd for C17H14ClN5O2: 356.0914, found: 356.1717. Anal.
Calcd for C17H14ClN5O2: C, 57.39; H, 3.97; N, 19.68. Found: C, 57.31;
H, 3.88; N, 19.57. Mp: 146 ꢀC.
134.0, 137.3, 139.2, 139.8, 146.0. HRMS (EI): (MþNa) calcd for
C18H17Cl2N4O: 375.0774, found 375.0785. Anal. Calcd for
C18H16Cl2N4O: C, 57.61; H, 4.30; N,14.93. Found: C, 57.54; H, 4.26; N,
14.81. Mp: 186 ꢀC.
4.3.8. 6-Chloro-1,3-dimethyl-5-(naphth-1-yl)methyl-1,3-
4.3.14. 6-Chloro-5-(4-chlorobenzyl)-3-(2-hydroxyethyl)-1-methyl-
dihydropyrazolo[3,4,5-de]phthalazine (2h)
1,3-dihydropyrazolo[3,4,5-de]phthalazine (2o)
1H NMR (CDCl3) (
d
): 3.58 (s, 3H, –CH3), 3.81 (s, 3H, –CH3), 4.71
1H NMR (CDCl3) (
d): 3.75 (s, 3H, –CH3), 3.96–4.02 (m, 4H, –(CH2–
(s, 2H, –CH2–), 6.67 (d, 1H, Aryl-H, J¼8.6 Hz), 7.07 (d, 1H, Aryl-H,
J¼8.6 Hz), 7.18 (dd, 1H, Aryl-H, J¼0.9 and 7.1 Hz), 7.34 (m, 1H),
7.50–7.55 (m, 2H, Aryl-H), 7.73 (d, 1H, Aryl-H, J¼8.2 Hz), 7.87 (d,
1H, Aryl-H, J¼8.0 Hz), 8.10 (d, 1H, Aryl-H, J¼8.5 Hz). 13C NMR
)2), 4.26 (s, 2H, –CH2–), 6.67 (d, 1H, Aryl-H, J¼8.8 Hz), 7.10 (d, 1H,
Aryl-H, J¼8.8 Hz), 7.19 (d, 2H, Aryl-H, J¼8.8 Hz), 7.26 (d, 2H, Aryl-H,
J¼8.8 Hz). 13C NMR (CDCl3) (
d): 35.6, 39.0, 54.6, 61.2, 107.6, 111.1,
122.5, 122.8, 128.6, 130.1, 132.2, 133.7, 136.9, 138.9, 140.2, 145.6.
HRMS (EI): (MþNa) calcd for C18H16Cl2N4O: 375.0774, found:
375.0797. Anal. Calcd for C18H16Cl2N4O: C, 57.61; H, 4.30; N, 14.93.
Found: C, 57.50; H, 4.27; N, 14.79. Mp: 143 ꢀC.
(CDCl3) (d): 35.6, 36.7, 39.7, 107.0, 111.2, 122.9, 123.2, 123.6, 124.6,
124.7, 125.4, 125.5, 125.9, 126.8, 128.8, 132.1, 133.7, 135.3, 139.0,
139.1, 146.0. HRMS (EI): (MþH) calcd for C21H18ClN4: 361.1215,
found: 361.1231. Anal. Calcd for C21H17ClN4: C, 69.90; H, 4.75; N,
15.53. Found: C, 69.81; H, 4.70; N, 15.47. Mp: 176 ꢀC.
4.4. General procedure for the synthesis of phthalazinones
(3a–j, 3m and 3p,q) and isoindolinones (4a–e)
4.3.9. 6-Chloro-1,3-dimethyl-5-(naphth-2-yl)methyl-1,3-
dihydropyrazolo[3,4,5-de]phthalazine (2i)
A solution of benzalphthalide (1a–k) and N-alkylhydrazine in
CH2Cl2 was absorbed on silica gel, 10:1 rate silica/benzalphthalide,
evaporated to dryness and heated under MW (350 W), the tem-
perature was maintained between 70 and 110 ꢀC for 45 s. Phtha-
lazinones were extracted from the silica washing with EtOAc. Then
solvent was evaporated to dryness and the residue purified by flash
chromatography (hexane/EtOAc).
1H NMR (CDCl3) (
d): 3.65 (s, 3H, –CH3), 3.78 (s, 3H, –CH3),
4.46 (s, 2H, –CH2–), 6.62 (d, 1H, Aryl-H, J¼8.8 Hz), 7.06 (d, 1H,
Aryl-H, J¼8.8 Hz), 7.38–7.49 (m, 3H, Aryl-H), 7.66–7.80 (m, 4H,
Aryl-H). 13C NMR (CDCl3) (
d): 35.6, 39.3 (2C), 107.1, 110.8, 123.0,
125.3, 125.8, 126.7, 127.5, 127.6, 127.9, 132.3, 133.5, 133.6, 135.0,
136.0, 136.7, 139.0, 139.5, 146.0. HRMS (EI): (MþH) calcd for
C21H18ClN4: 361.1215, found: 361.1231. Anal. Calcd for C21H17ClN4:
C, 69.90; H, 4.75; N, 15.53. Found: C, 69.83; H, 4.69; N, 15.49. Mp:
145 ꢀC.
4.4.1. 4-Benzyl-5,8-dichloro-2-methyl-2H-phthalazin-1-one (3a)
1H NMR (CDCl3) (
d): 3.81 (s, 3H, –CH3), 4.67 (s, 2H, –CH2–), 7.09
(m, 2H, Aryl-H), 7.24 (m, 3H, Aryl-H), 7.56 (d, 1H, Aryl-H, J¼8.8 Hz),
4.3.10. 5-(4-Chlorobenzyl)-6-fluoro-1,3-dimethyl-1,3-
7.61 (d, 1H, Aryl-H, J¼8.8 Hz). 13C NMR (CDCl3) (
d): 39.9, 42.4, 126.3,
dihydropyrazolo[3,4,5-de]phthalazine (2j)
126.7, 128.1, 128.5, 129.4, 129.9, 134.5, 134.7, 136.0, 138.8, 142.0,
157.0. HRMS (EI): (MþNa) calcd for C16H12Cl2N2ONa: 341.0219,
found: 341.0228. Mp: 101 ꢀC.
1H NMR (CDCl3) (
d): 3.59 (s, 3H, –CH3), 3.75 (s, 3H, –CH3), 3.96 (s,
2H, –CH2–), 6.62 (dd, 1H, Aryl-H, J¼2.6 and 8.8 Hz), 6.92 (dd, 1H,
Aryl-H, J¼8.8 and 10.6 Hz), 7.36 (m, 4H, Aryl-H). HRMS (EI): (MþNa)
calcd for C17H14FClN4: 351.0789, found: 351.0702. Anal. Calcd for
C17H14ClFN4: C, 62.10; H, 4.29; N, 17.04. Found: C, 62.02; H, 4.17; N,
16.98.
4.4.2. 5,8-Dichloro-4-(4-chlorobenzyl)-2-methyl-2H-phthalazin-1-
one (3b)
1H NMR (CDCl3) (
d): 3.79 (s, 3H, –CH3), 4.62 (s, 2H, –CH2–), 7.02
(d, 2H, Aryl-H, J¼8.6 Hz), 7.22 (d, 2H, Aryl-H, J¼8.6 Hz), 7.58 (d, 1H,
4.3.11. 6-Chloro-5-(4-chlorobenzyl)-1,3-bis(2-hydroxyethyl)-1,3-
Aryl-H, J¼8.8 Hz), 7.63 (d, 1H, Aryl-H, J¼8.8 Hz). 13C NMR (CDCl3)
dihydropyrazolo[3,4,5-de]phthalazine (2k)
(d): 39.8, 41.7, 126.6, 128.5, 129.1, 129.5, 129.6, 132.1, 134.5, 134.8,
1H NMR (CDCl3) (
d): 3.98–4.05 (m, 4H, (–CH2–)2), 4.12 (s, 2H,
136.3, 137.1, 141.5, 156.8. HRMS (EI): (MþNa) calcd for
–CH2–), 4.21 (t, 2H, –CH2–, J¼5.1 Hz), 4.33 (s, 2H, –CH2–), 6.83 (d,
C16H11Cl3N2ONa: 374.9829, found: 374.9839. Mp: 111 ꢀC.
1H, Aryl-H, J¼8.8 Hz), 7.21 (m, 5H, Aryl-H). 13C NMR (CDCl3) (
d):
38.7, 51.0, 54.0, 59.9, 61.0, 108.1, 111.3, 122.3, 122.5, 128.4, 130.0,
132.0, 133.8, 137.0, 139.3, 140.3, 145.9. HRMS (EI): (MþH) calcd for
C19H19Cl2N4O2: 405.0880, found: 405.0888. Anal. Calcd for
C18H16Cl2N4O: C, 57.61; H, 4.30; N,14.93. Found: C, 57.49; H, 4.25; N,
14.90. Mp: 172 ꢀC.
4.4.3. 5,8-Dichloro-4-(4-fluorobenzyl)-2-methyl-2H-phthalazin-1-
one (3c)
1H NMR (CDCl3) (
d): 3.80 (s, 3H, –CH3), 4.62 (s, 2H, –CH2–), 6.96
(dt, 2H, Aryl-H, J¼2.6 and 8.8 Hz), 7.02 (dt, 2H, Aryl-H, J¼5.8 and
8.8 Hz), 7.58 (d, 1H, Aryl-H, J¼8.4 Hz), 7.62 (d, 1H, Aryl-H, J¼8.4 Hz).
13C NMR (CDCl3) (
(J¼29.4 Hz), 134.3, 134.6, 134.8, 136.1, 141.9, 156.9, 159.1, 164.0.
HRMS (EI): (MþNa) calcd for C16H11FCl2N2ONa: 359.0125, found:
359.0133. Mp: 120 ꢀC.
d
): 39.9, 41.6, 115.3 (J¼80.9 Hz), 126.7, 129.2, 129.7
4.3.12. 6-Chloro-5-(4-chlorobenzyl)-1-(2-hydroxyethyl)-3H-1,3-
dihydropyrazolo[3,4,5-de]phthalazine (2m)
1H NMR (CDCl3þCD3OD) (
d): 3.88 (s, 2H, –CH2–), 4.09 (t, 2H,
–CH2–, J¼5.5 Hz), 4.19 (s, 2H, –CH2–), 6.73 (d, 1H, Aryl-H, J¼8.8 Hz),
7.06 (d, 1H, Aryl-H, J¼8.8 Hz), 7.13 (d, 2H, Aryl-H, J¼8.8 Hz), 7.21 (d,
4.4.4. 5,8-Dichloro-4-(4-methoxybenzyl)-2-methyl-2H-phthalazin-
2H, Aryl-H, J¼8.8 Hz). 13C NMR (CDCl3þCD3OD) (
d
): 42.6, 54.8, 64.8,
1-one (3d)
112.3,115.3,132.3,132.5,133.9,135.9,137.9,139.4,141.2,142.6,143.7,
149.1. HRMS (EI): (MþH) calcd for C17H15Cl2N4O: 362.0617, found:
362.0625. Anal. Calcd for C17H14Cl2N4O: C, 56.52; H, 3.91; N, 15.51.
Found: C, 56.56; H, 3.82; N, 15.48. Mp: 194 ꢀC.
1H NMR (CDCl3) (
d): 3.76 (s, 3H, –OCH3), 3.81 (s, 3H, –CH3), 4.60
(s, 2H, –CH2–), 6.79 (d, 2H, Aryl-H, J¼8.8 Hz), 7.00 (d, 2H, Aryl-H,
J¼8.8 Hz), 7.57 (d, 1H, Aryl-H, J¼8.6 Hz), 7.62 (d, 1H, Aryl-H,
J¼8.6 Hz). 13C NMR (CDCl3) (
d): 39.9, 41.4, 55.3, 113.9, 126.4, 126.7,

D. Vi˜na et al. / Tetrahedron 65 (2009) 1574–1580
1579
129.2, 129.4, 129.8, 130.7, 132.6, 134.5, 134.7, 136.0, 142.5, 158.1.
4.4.11. 4-(4-Chlorobenzyl)-5,8-dichloro-2-(2-hydroxyethyl)-2H-
HRMS (EI): (MþNa) calcd for C17H14Cl2N2O2Na: 371.0325, found:
phthalazin-1-one (3m)
371.0332. Mp: 133 ꢀC.
1H NMR (CDCl3) (
d
): 3.99 (t, 2H, –CH2–, J¼5.1 Hz), 4.33 (t, –CH2–,
J¼5.1 Hz), 4.63 (s, 2H, –CH2–), 7.03 (d, 2H, Aryl-H, J¼8.4 Hz), 7.25 (d,
2H, Aryl-H, J¼8.4 Hz), 7.64 (s, 2H, Aryl-H). 13C NMR (CDCl3) (
d): 42.1,
4.4.5. 5,8-Dichloro-4-(2-methoxybenzyl)-2-methyl-2H-phthalazin-
53.8, 61.4, 126.7, 128.8, 129.4, 129.8, 130.4, 132.4, 134.9, 135.3, 136.3,
136.7, 142.6, 157.5. HRMS (EI): (MþNa) calcd for C17H13Cl3N2O2Na:
404.9940, found 404.9917. Mp: 123 ꢀC.
1-one (3e)
1H NMR (CDCl3) (
d): 3.75 (s, 3H, –OCH3), 3.84 (s, 3H, –CH3), 4.57
(s, 2H, –CH2–), 6.68 (d, 1H, Aryl-H, J¼7.3 Hz), 6.79 (t, 1H, Aryl-H,
J¼7.3 Hz), 6.88 (d, 1H, Aryl-H, J¼7.7 Hz), 7.20 (t, 1H, Aryl-H,
J¼7.7 Hz), 7.58 (d, 1H, Aryl-H, J¼8.4 Hz), 7.61 (d, 1H, Aryl-H, J¼
4.4.12. 4-(4-Chlorobenzyl)-5,8-dichloro-2H-phthalazin-1-one (3p)
1H NMR (CDCl3) (
d): 4.61 (s, 2H, –CH2–), 7.04 (d, 2H, Aryl-H,
8.4 Hz). 13C NMR (CDCl3) (
d): 37.2, 39.9, 55.4, 110.1, 120.4, 126.6,
J¼8.4 Hz), 7.24 (d, 2H, Aryl-H, J¼8.4 Hz), 7.65 (s, 2H, Aryl-H). 13C
127.5, 127.9, 128.2, 129.8, 130.3, 134.4, 134.5, 136.0, 142.1, 156.9,
157.0. HRMS (EI): (MþNa) calcd for C17H14Cl2N2O2Na: 371.0325,
found: 371.0323. Mp: 142 ꢀC.
NMR (CDCl3) (d): 42.0, 127.0, 128.7, 129.8, 130.0, 130.9, 132.4, 134.8,
135.1, 136.9, 143.4, 149.9, 157.5. HRMS (EI): (MþNa) calcd for
C15H9Cl3N2ONa: 360.9673, found: 360.9673. Mp: 211 ꢀC.
4.4.6. 5,8-Dichloro-4-(3,4,5-trimethoxybenzyl)-2-methyl-2H-
4.4.13. 5,8-Difluoro-4-(4-methoxybenzyl)-2-methyl-2H-
phthalazin-1-one (3f)
1H NMR (CDCl3) (
d
): 3.75 (s, 6H, –(OCH3)2), 3.80 (s, 3H, –OCH3),
3.81 (s, 3H, –CH3), 4.60 (s, 2H, –CH2–), 6.29 (s, 2H, Aryl-H), 7.63 (s,
2H, Aryl-H). 13C NMR (CDCl3) (
): 39.9, 42.4, 56.2, 60.9, 105.5, 126.6,
phthalazin-1-one (3q)
1H NMR (CDCl3) (
d): 3.75 (s, 3H, –OCH3), 3.82 (s, 3H, –CH3), 4.20
(d, 1H, –CH2–, J¼12.0 Hz), 4.30 (d, 1H, –CH2–, J¼12.0 Hz), 6.80 (d,
d
2H, Aryl-H, J¼1.8 and 8.8 Hz), 7.13 (d, 2H, Aryl-H, J¼8.4 Hz), 7.31 (m,
129.5, 129.9, 134.4, 134.6, 134.8, 136.1, 136.7, 142.0, 153.3, 157.0.
HRMS (EI): (MþH) calcd for C19H19Cl2N2O4: 409.0716, found
409.0701. Mp: 161 ꢀC.
2H, Aryl-H). 13C NMR (CDCl3) (
d
): 39.5, 40.4 (J¼37 Hz), 55.3, 113.9,
119.2 (J¼37 and 96 Hz), 120.9 (J¼37 and 96 Hz), 129.4, 129.9, 134.9,
141.4 (J¼29 Hz), 151.0 (J¼29 Hz), 155.1, 156.0, 158.4, 160.4. HRMS
(EI): (MþNa) calcd for C17H14F2N2O2Na: 339.0921, found: 339.0913.
Mp: 181 ꢀC.
4.4.7. 5,8-Dichloro-2-methyl-4-(4-nitrobenzyl)-2H-phthalazin-1-
one (3g)
1H NMR (CDCl3) (
d): 3.79 (s, 3H, –CH3), 4.75 (s, 2H, –CH2–), 7.26
4.4.14. 2-Amino-4,7-dichloro-3-(4-chlorobenzyl)-3-
hydroxyisoindolin-1-one (4a)
(d, 2H, Aryl-H, J¼8.8 Hz), 7.60 (d, 1H, Aryl-H, J¼8.4 Hz), 7.66 (d, 1H,
Aryl-H, J¼8.4 Hz), 8.14 (d, 2H, Aryl-H, J¼8.8 Hz). 13C NMR (CDCl3)
1H NMR (CDCl3) (
d
): 2.85 (br s, 2H, NH2þOH), 3.59 (d,1H, –HCH–,
(d): 40.0, 42.5, 123.8, 126.7, 129.1, 129.6, 134.3, 134.9, 135.1,
J¼13.5 Hz), 3.72 (d, 1H, –HCH–, J¼13.5 Hz), 6.79 (d, 2H, Aryl-H,
136.1, 140.5, 146.5, 146.7, 156.1. HRMS (EI): (MþH) calcd for
J¼8.4 Hz), 6.98 (d, 2H, Aryl-H, J¼8.4 Hz), 7.22 (d, 1H, Aryl-H, J¼
C16H12Cl2N3O3: 364.0211, found: 364.0203. Mp: 235 ꢀC.
8.8 Hz), 7.39 (d, 1H, Aryl-H, J¼8.8 Hz). 13C NMR (CDCl3) (
d): 38.7,
90.1, 128.4, 128.6, 129.9, 130.3, 130.5, 132.5, 132.7, 133.4, 133.9, 141.9,
162.5. HRMS (EI): (MþNa) calcd for C15H11Cl3N2O2Na: 378.9784,
found: 378.9740. Mp: 197–202 ꢀC.
4.4.8. 5,8-Dichloro-2-methyl-4-(naphth-1-yl)methyl-2H-
phthalazin-1-one (3h)
1H NMR (CDCl3) (
d): 3.77 (s, 3H, –CH3), 5.05 (s, 2H, –CH2–), 6.82
(d, 1H, Aryl-H, J¼7.0 Hz), 7.29 (t, 1H, Aryl-H, J¼7.7 Hz), 7.49–7.57 (m,
2H, Aryl-H), 7.56 (d, 1H, Aryl-H, J¼8.4 Hz), 7.64 (d, 1H, Aryl-H,
J¼8.4 Hz), 7.73 (m, 1H, Aryl-H), 7.89 (m, 1H, Aryl-H), 8.06 (m, 1H,
4.4.15. 2-tert-Butylamino-4,7-dichloro-3-(4-chlorobenzyl)-3-
hydroxyisoindolin-1-one (4b)
1H NMR (CDCl3) (
d): 1.20 (t, 9H, C(CH3)3), 3.60 (d, 1H, –HCH–,
Aryl-H). 13C NMR (CDCl3) (
d): 39.8, 40.0, 123.2, 124.6, 125.5, 125.8,
J¼13.2 Hz), 3.86 (d, 1H, –HCH–, J¼13.2 Hz), 4.43 (br s, 1H, OH), 6.79
(d, 2H, Aryl-H, J¼8.4 Hz), 7.00 (d, 2H, Aryl-H, J¼8.4 Hz), 7.28 (d, 1H,
Aryl-H, J¼8.8 Hz), 7.44 (d, 1H, Aryl-H, J¼8.8 Hz), 7.58 (br s, 1H, NH).
126.3, 126.7, 127.1, 128.9, 129.8, 130.2, 131.7, 133.8, 134.5, 134.8,
135.6, 136.1, 141.7, 157.0. HRMS (EI): (MþH) calcd for C20H15Cl2N2O:
369.0556, found: 369.0537. Mp: 172 ꢀC.
13C NMR (CDCl3) (
d): 28.9, 38.7, 55.8, 91.3, 127.8, 128.4, 129.6, 130.8,
132.4, 132.6, 133.1, 134.0, 136.7, 142.1, 164.4. HRMS (EI): (MþNa)
calcd for C19H19Cl3N2O2Na: 435.0404, found: 435.0440. Mp: 159–
162 ꢀC.
4.4.9. 5,8-Dichloro-2-methyl-4-(naphth-2-yl)methyl-2H-
phthalazin-1-one (3i)
1H NMR (CDCl3) (
d): 3.84 (s, 3H, –CH3), 4.81 (s, 2H, –CH2–), 7.30
(dd, 1H, Aryl-H, J¼1.5 and 8.4 Hz), 7.37 (s, 1H, Aryl-H), 7.39–7.43 (m,
4.4.16. 4,7-Dichloro-3-(4-chlorobenzyl)-3-hydroxy-2-
2H, Aryl-H), 7.54 (d, 1H, Aryl-H, J¼8.8 Hz), 7.60 (d, 1H, Aryl-H,
phenylaminoisoindolin-1-one (4c)
J¼8.8 Hz), 7.65–7.78 (m, 3H, Aryl-H). 13C NMR (CDCl3) (
d): 40.0,
1H NMR (CDCl3) (
d): 3.36 (br s, 1H, OH), 3.57 (d, 1H, –HCH–,
42.6, 125.6, 126.1, 126.2, 126.8, 127.1, 127.6 (2C), 128.1, 129.5, 130.0,
132.2, 133.5, 134.6, 134.7, 136.1, 136.5, 142.0, 157.0. HRMS (EI):
(MþNa) calcd for C20H14Cl2N2ONa: 391.0375, found: 391.0368. Mp:
160 ꢀC.
J¼11.0 Hz), 3.78 (d, 1H, –HCH–, J¼11.0 Hz), 6.10 (br s, 1H, NH), 6.74
(d, 2H, Aryl-H, J¼6.8 Hz), 6.96 (m, 5H, Aryl-H), 7.17 (dd, 2H, Aryl-H,
J¼5.1 and 6.9 Hz), 7.28 (d, 1H, Aryl-H, J¼6.9 Hz), 7.46 (d, 1H, Aryl-H,
J¼6.9 Hz). 13C NMR (CDCl3) (
d): 39.6, 90.8, 115.1, 122.5, 127.8, 128.2,
128.8, 129.2, 130.3, 130.5, 132.0, 133.0, 133.5, 134.6, 141.7, 146.8,
162.8. HRMS (EI): (MþNa) calcd for C21H15Cl3N2O2Na: 455.0097,
found: 455.0119. Mp: 206 ꢀC.
4.4.10. 4-(4-Chlorobenzyl)-5,8-difluoro-2-methyl-2H-phthalazin-
1-one (3j)
1H NMR (CDCl3) (
d): 3.83 (s, 3H, –CH3), 4.24 (d, 1H, –CH2–,
J¼12.0 Hz), 4.34 (d, 1H, –CH2–, J¼12.0 Hz), 7.15 (d, 1H, Aryl-H,
4.4.17. 4,7-Dichloro-3-hydroxy-3-(4-methoxybenzyl)-2-
phenylaminoisoindolin-1-one (4e)
J¼8.8 Hz), 7.28 (d, 2H, Aryl-H, J¼8.8 Hz), 7.23–7.38 (m, 2H, Aryl-H).
13C NMR (CDCl3) (
d): 39.5, 40.6 (J¼40 Hz), 117.5, 119.3 (J¼40 and
1H NMR (CDCl3) (
d
): 3.56 (d, 1H, –HCH–, J¼13.9 Hz), 3.66 (s, 3H,
92 Hz),120.0 (J¼28 Hz),120.9 (J¼36 and 104 Hz),128.5,129.7,132.4,
136.3, 140.5 (J¼24 Hz), 154.5, 155.5, 156.4 (J¼20 Hz), 159.0
(J¼24 Hz). HRMS (EI): (MþNa) calcd for C16H11F2ClN2ONa:
343.0420, found: 343.0436. Mp: 127–131 ꢀC.
OCH3), 6.21 (br s, 1H, OH), 3.79 (d, 1H, –HCH–, J¼13.9 Hz), 6.59 (d,
2H, Aryl-H, J¼8.4 Hz), 6.77 (d, 2H, Aryl-H, J¼8.4 Hz), 6.98 (m, 3H,
Aryl-H), 7.19 (d, 2H, Aryl-H, J¼8.4 Hz), 7.31 (d, 1H, Aryl-H, J¼8.8 Hz),
7.50 (d, 1H, Aryl-H, J¼8.8 Hz). 13C NMR (CDCl3) (
d): 39.4, 55.1, 91.1,

1580
D. Vi˜na et al. / Tetrahedron 65 (2009) 1574–1580
O. A.; Aboul-Enein, H. Y.; Siddiqui, Y. M.; Al-Ahdal, M. N. J. Enzyme Inhib. Med.
Chem. 2004, 19, 33.
113.2, 114.0, 114.9, 122.2, 125.4, 128.0, 128.2, 129.2, 130.1, 130.2,
132.8, 134.4, 142.0, 147.0, 158.8, 162.8. HRMS (EI): (MþNa) calcd for
C22H18 Cl2N2O3Na: 451.0587, found: 451.0560. Mp: 202–204 ꢀC.
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Acknowledgements
Financial support from Spanish ISCIII, through the RICET The-
matic Network (RD06-0021-0022) and grant No. FIS-PI060782, is
gratefully acknowledged.
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