DMAP as a new efficient catalyst for the one-pot synthesis of condensed phthalazines

Article abstract of DOI:10.1515/znb-2016-0262

A new, convenient, and efficient method for the synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-diones is developed starting from phthalhydrazide, aromatic aldehydes, and malononitrile using 4-N,N-dimethylaminopyridin as catalyst. This modified route provides much higher yields and a simple work-up procedure of products. Also this methodology is of interest due to the use of ethanol as a solvent without use of any toxic metals as catalyst, thus minimizing the cost, the operational hazards, and environmental pollution.

Full text of DOI:10.1515/znb-2016-0262

Z. Naturforsch. 2017; 72(5)b: 361–368
Esma Lamera, Sofiane Bouacida, Hocine Merazig, Aissa Chibani, Marc Le Borgne,
Zouhair Bouaziz and Abdelmalek Bouraiou*
DMAP as a new efficient catalyst for the one-pot
synthesis of condensed phthalazines
DOI 10.1515/znb-2016-0262
Received December 10, 2016; accepted February 15, 2017
nitrogen atoms in a fused ring system are of particular
interest.
The different structures of condensed phthala-
zine compounds showed different biological activities.
They have been reported to possess antimicrobial [3,
4], anti-inflammatory [5, 6], anticancer [7], inotropic
[8], anticonvulsant [9], antihypertensive [10], cytotoxic,
and antioxidant activities [11, 12]. Over time, numerous
studies have been reported for the synthesis of condensed
phthalazine derivatives [13–18]. Thus, the development of
simple methods for the preparation of heterocycles con-
taining phthalazine moiety is an interesting challenge in
organic synthesis.
On the other hand, multicomponent reactions con-
stitute an efficient synthetic strategy for drug design and
drug discovery because of their simplicity, efficiency,
and high selectivity [19]. The products are obtained in a
one-pot and one step synthesis and diver skeletons can be
obtained by changing the reaction components [20, 21].
Recently, several well-designed multicomponent
strategies for the synthesis of condensed phthalazines
such as 1H-indazolo[1,2-b]phthalazine-1,6,11-triones and
1H-pyrazolo[1,2-b]phthalazine-5,10-diones have been
reported by one-pot reactions of various aldehydes,
activated methylene, and phthalhydrazide using differ-
ent types of catalysts such as Fe3O4/SiO2ꢀnanoparticles,
sodium hydrogenocarbonate, piperidine, and basic ionic
liquids [22–26].
Abstract: A new, convenient, and efficient method for the
synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-diones is
developed starting from phthalhydrazide, aromatic alde-
hydes, and malononitrile using 4-N,N-dimethylamino-
pyridin as catalyst. This modified route provides much
higher yields and a simple work-up procedure of prod-
ucts. Also this methodology is of interest due to the use
of ethanol as a solvent without use of any toxic metals as
catalyst, thus minimizing the cost, the operational haz-
ards, and environmental pollution.
Keywords: catalyst; DMAP; heterocycles; multicomponent
reaction; phthalazine; X-ray structure determination.
1 Introduction
Numerous research programs have been devoted to the
establishment of new synthetic methods and new het-
erocyclic combination because several biological active
compounds contain a heterocyclic moiety as a funda-
mental subunit [1]. Bridgehead nitrogen-containing hete-
rocycles are important targets in synthetic and medicinal
chemistry due to their useful biological activities [2].
Condensed phthalazines which have two bridgehead
Herein we report a new efficient synthesis of structur-
ally diverse 1H-pyrazolo[1,2-b]phthalazine-5,10-diones via
a three-component reaction of various aromatic aldehydes
1, malononitrile as active methylene 2 and phthalhy-
drazide 3, in the presence of 4-N,N-dimethylaminopyridin
(DMAP) as catalyst (Scheme 1).
*Corresponding author: Abdelmalek Bouraiou, Unité de Recherche
de Chimie de l’Environnement et Moléculaire Structurale, Université
des frères Mentouri, Constantine 25000, Algérie,
e-mail: bouraiou.abdelmalek@yahoo.fr
Esma Lamera, Hocine Merazig and Aissa Chibani: Unité de
Recherche de Chimie de l’Environnement et Moléculaire Structurale,
Université des frères Mentouri, Constantine 25000, Algérie
Sofiane Bouacida: Unité de Recherche de Chimie de
l’Environnement et Moléculaire Structurale, Université des frères
Mentouri, Constantine 25000, Algérie; and Département Sciences
de la Matière, Université Oum El Bouaghi, 04000 Oum El Bouaghi,
Algérie
Marc Le Borgne and Zouhair Bouaziz: Université Lyon 1, Faculté
de Pharmacie, ISPB, EA 4446 Bioactive Molecules and Medicinal
Chemistry (B2MC), SFR Santé Lyon-Est CNRS UMS3453-INSERM US7,
F-69373 Lyon Cedex 8, France
2 Results and discussion
After some experimentation with respect to the molar
ratio of the reactants, reaction temperature, reaction
time, and possible solvents, we found optimized condi-
tions for benzaldehyde as a representative example. The
results indicate that 20% mol of DMAP with respect to
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ꢀE. Lamera et al.: DMAP for the one-pot synthesis of condensed phthalazines
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O
O
O
Ar
N
N
DMAP
NH
NH
+
+
Ar CHO
NC
CN
CN
NH2
EtOH, reflux
O
3
1
2
4
Scheme 1:ꢁDMAP catalyze the synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-diones.
to the analytical data reported in the literature [3, 24,
27–34]. For example, the
phthalhydrazide suffices for complete conversion of the
starting materials and the yield was not obviously affected
with different amounts of DMAP.
1H NMR spectrum of 4a shows
one singlet at 7.89 ppm due to the –NH2 substituent at
Ethanol was chosen as a solvent due to some advan- the pyrazole ring. The signals of the aromatic protons of
tages, including its low cost and low toxicity. Moreover, the phthalazine nucleus are found at 8.29 and 7.93 ppm
we found that the best results were observed when the as multiplets. The signals of the aromatic protons of the
molar ratio of phthalhydrazide to malononitrile to benza- phenyl group appear between 7.47 and 7.30 ppm as multi-
ldehyde was 1:1.1:1.1.
plets. The signal attributable to the proton of the pyrazole
After completion of the reaction, ethanol was removed ring is found at 6.16 ppm as singlet.
13
and water was added to the reaction mixture in order to
The C NMR spectrum data in 4a showed the signals
solidify the residual and dissolve the catalyst before the of the two C=O carbon at 157.1 and 154.1 ppm. The carbon
precipitated product is isolated by filtration. The crude of the pyrazolo ring absorbs at 63.6 ppm. The signal
product 4a was isolated in good yield and no further puri- attributable to the carbon atom of the nitrile is found at
fication processes were required (Table 1, Entry 1).
62.5 ppm. The signals of the other aromatic carbon atom
In order to determine the effects of substituents on the appear between 151.1 and 116.0 ppm. The MS spectrum of
phenyl moiety, several substituted benzaldehydes were 4a shows a molecular ion peak at m/zꢀ=ꢀ317.1.
used instead of benzaldehyde under the conditions men-
Furthermore, single crystals of 4c suitable for X-ray
tioned above (Table 1). In most cases, the envisaged com- diffraction were obtained from a hot acetone-dimethyl-
pounds were obtained in similar yields indicating that the formamide solution of 4c. The structure determination
change in the substituent on the phenyl moiety did not verified the proposed structure (Fig. 1, Tables 2 and 3) con-
affect the result of the reaction (Entries 2–9). However, sisting of a phthalazine ring fused to a pyrazolo moiety
the use of aromatic aldehydes possessing either strong and one phenyl group linked to the pyrazole ring.
electron-donating substituents at para-position, such as
The fragment pyrazolo[1,2-b]phthalazine is essen-
dimethylamino, hydroxy, or methoxy group, inhibited the tially planar and forms a dihedral angle of 86.25(5)° with
reaction, and the Knoevenagel condensation compound the phenyl ring. The packing of the molecules in the crystal
(A) (Scheme 2) was the sole isolated product. The reason can be described as double layers running parallel to the
̅
(2ꢀ2ꢀ0) plane along the crystallographic c axis (Fig. 2).
for this behavior is not clear to us.
Next, we examined a variety of heterocyclic alde- These layers are interconnected by N–H⋅⋅⋅O and N–H⋅⋅⋅N
hydes to establish the scope of the catalyst. As represented hydrogen bond interactions (Fig. 3, Table 4). The crystal
in Table 1 (Entries 10–12), all reactions worked well and structure is also supported by one strong intermolecular
the results were excellent in terms of yields and product Cg⋅⋅⋅Cg (π–π stacking) interaction with an inter-ring dis-
purity using DMAP.
tance of 3.8109(12) Å and C–H⋅⋅⋅π interactions (Table 5).
According to the literature [24, 25], aromatic aldehyde These interactions link the molecules within the layers
and malononitrile undergo base-catalyzed Knoevenagel and also link layers together thus reinforcing the cohesion
condensation to obtain the intermediate (A) in the pres- of the crystal structure.
ence of DMAP [26], which reacts with phthalhydrazide via
Michael addition followed by cyclization and tautomeri-
zation to afford the corresponding 1H-pyrazolo[1,2-b]
phthalazine-5,10-dione derivatives (Scheme 2).
3 Conclusions
In conclusion, as demonstrated herein, the approaches
developed in this work allow an efficient access to some
All compounds 4a–l obtained according to this pro-
tocol were characterized and identified by their melting
points, mass spectra, and NMR spectra in comparison
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E. Lamera et al.: DMAP for the one-pot synthesis of condensed phthalazinesꢀ
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Table 1:ꢁSynthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-diones 4a–l catalyzed by DMAP.
Entry
Product
Yield (%)
Time (h)
Entry
Product
Yield (%)
Time (h)
Cl
O
O
N
N
Cl
CN
CN
96
1
97
1
1
7
N
N
NH2
O
NH2
O
O
4a
4g
Et
O
O
OMe
N
97
1
94
2
2
8
N
N
CN
NH2
N
CN
NH2
O
O
4b
4h
O
N
N
CN
NH2
N
N
88
97
92
2
1.5
2
95
92
85
2
3
4
5
9
CN
NH2
O
O
4i
4c
OMe
N
O
O
O
O
N
N
N
CN
NH2
N
1
10
11
CN
NH2
4d
4j
OH
N
O
O
O
O
N
N
N
N
CN
NH2
0.5
CN
NH2
4e
4k
OMe
Cl
N
Cl
O
O
N
94
2
92
1
6
12
N
N
CN
NH2
N
CN
NH2
O
O
4l
4f
condensed phthalazines using new appropriate cata- phthalazine-5,10-diones. In all cases, quantitative yields
lyst, DMAP as Brønsted base catalyst. These approaches and pure products were obtained without the need for
allow a diverse range of substituted 1H-pyrazolo[1,2-b] recrystallization or chromatographic separation.
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ꢀE. Lamera et al.: DMAP for the one-pot synthesis of condensed phthalazines
CN
O
Ar
H
O
O
2
H
H
CN
CN
− H
CN
NC
N
N
+
Ar CHO
N
N
Ar
C
N
DMAP
+ H
1
O
(A)
(− H , − H2O)
3
O
O
Ar
O
Ar
N
N
NC
NC
N
N
H2N
HN
O
4
Scheme 2:ꢁProposed mechanism for the synthesis of 1H-pyrazolo[1,2-b]phthalazine-5,10-diones catalyzed by DMAP.
Table 2:ꢁCrystal structure data for 4c.
Formula
C19 H14 N4 O2
330.34
Mr
Cryst. size, mm3
Crystal system
Space group
a, Å
b, Å
c, Å
α, deg
β, deg
γ, deg
V, Å3
0.11ꢂ×ꢂ0.13ꢂ×ꢂ0.16
Triclinic
̅
P1 (#2)
5.5916(2)
10.9002(4)
14.8247(5)
111.067(2)
91.269(2)
98.131(2)
832.08(5)
2
Z
D
calcd, g cm−3
1.318
μ(MoKα), cm−1
0.089
F(000), e
344
hkl range
6, 12, 17
0.717
((sinθ)/λ)max, Å−1
Refl. measured/unique/Rint
Param. refined
Fig. 1:ꢁOrtep plot of the molecular structure of 4c in the crystal and
atom numbering scheme adopted (displacement ellipsoids at the
50% probability level; H atoms with arbitrary radii; blue: nitrogen,
red: oxygen).
13ꢂ210/2821/0.0313
227
R(F)/wR(F2)a,b (Iꢂꢂ>ꢂꢂ2σ(I))
R(F)/wR(F2)a,b (all data)
GoF (F2)c
0.0474/0.1395
0.0654/0.1595
1.045
Δρfin(max/min), e Å−3
0.242/–0.284
4 Experimental section
2
2
aR(F)ꢂ=ꢂΣꢂ|ꢂ|ꢂFoꢂ|ꢂ–ꢂ|ꢂFcꢂ|ꢂ|ꢂ/Σꢂ|ꢂFoꢂ|; bwR(F2)ꢂ=[Σw(Fo –Fc2)2/Σw(Fo )2]1/2
;
wꢂ=[σ2(Fo )ꢂ+(AP)2ꢂ+ꢂBP]−1, where Pꢂ=(Max(Fo , 0)ꢂ+ꢂ2Fc2)/3;
2
2
The starting materials were generally used as received
(Acros, Fontenay-sous-Bois, France) without any further
purification. Melting points were determined in open cap-
2
cGoFꢂ=ꢂSꢂ=[Σw(Fo –Fc2)2/(nobs–nparam)]1/2
.
with a gradient mobile phase of H2O–CH3CN (90:10, v/v)
with 0.1% of formic acid to H2O–CH3CN (10:90, v/v) with
0.1% of formic acid at a flow rate of 0.5 mL/min, with UV
monitoring at the wavelength of 254 nm with a run time of
10 min. The mass spectra were performed by direct ioniza-
tion on a ThermoFinnigan MAT 95 XL apparatus.
1
13
illary tubes and were uncorrected. H NMR and C NMR
spectra were recorded on Bruker Avance 300 spectrom-
eters. Phthalhydrazide was synthesized following a lit-
erature procedure starting from phthalic anhydride [3].
Fourier transform-infrared (FT-IR) measurements were
carried out by the KBr method using a Shimadzu FT/
IR-8201 PC spectrophotometer. The purity of the final com-
pound (greater than 95%) was determined by uHPLC/MS
on an Agilent 1290 system (Lyon 1 University, Lyon,
4.1 General procedure
France) using an Agilent 1290 Infinity ZORBAX Eclipse A mixture of aromatic aldehyde 1 (1.1 mmol), malononitrile
Plus C18 column (2.1 mmꢀ×ꢀ50 mm, 1.8 μm particle size) 2 (1.1 mmol), phthalhydrazide 3 (1.0 mmol), and DMAP
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Table 3:ꢁSelected bond lengths (Å) and angles (deg) for 4c with
(20 mol%) was placed in 10 mL of ethanol. The reaction
mixture was then refluxed for appropriate time (the reac-
tion was monitored by thin-layer chromatography; see
Table 1). After completion, ethanol was evaporated under
vacuum and 10 mL of water was added. The resulting solid
was filtered, and washed with water and then hexane. The
structures of the products were fully established on the
estimated standard deviations in parentheses.
Distances
ꢀN1–C1
1.371(2)
ꢀN1–C11
ꢀN2–C8
ꢀN2–C9
1.406(2)
1.354(2)
1.477(2)
1.327(2)
1.151(2)
1.224(2)
1.225(2)
ꢀN3–C11
ꢀN4–C12
ꢀO1–C1
1
13
basis of their H NMR, C NMR, and IR spectra as well as
MS spectral analysis.
ꢀO2–C8
Angles
ꢀC1–N1–C11
ꢀC8–N2–C9
ꢀN2–C9–C13
ꢀC10–C9–C13
128.71(14)
124.47(14)
112.57(14)
114.33(14)
4.2 Spectral data
4.2.1 3-Amino-5,10-dioxo-1-phenyl-5,10-dihydro-1H-
pyrazolo[1,2-b]phthalazine-2-carbonitrile (4a)
Yield 92%; yellow solid; m.p. 278–281°C (lit. 275–276°C [28,
30]). – IR (KBr): ʋꢀ=ꢀ3359, 2194, 1654, 1380, 1276, 1149, 698,
1
582. – H NMR ([D6]DMSO, 300 MHz): δꢀ=ꢀ8.29–8.26 (m,
1H, Harom), 8.13–8.11 (m, 1H, Harom), 7.99–7.93 (m, 2H,
Harom), 7.89 (sL, 2H, NH2), 7.47–7.30 (m, 5H, Harom), 6.16
13
(s, 1H, H-1) ppm. – C NMR ([D6]DMSO, 75 MHz): δꢀ=ꢀ157.1
(C), 154.2 (C), 151.1 (C), 138.7 (C), 135.3 (CH), 134.1 (CH),
129.2 (C), 129.1 (C), 128.9 (CH), 128.7 (CH), 127.7 (CH), 127.2
(CH), 127.2 (CH), 116.0 (C), 63.6 (CH), 62.5 (C) ppm. – MS
Fig. 2:ꢁA diagram of the layered crystal structure of 4c as viewed
down the crystallographic c axis.
+
(ES-API): m/zꢀ=ꢀ317.1 [Mꢀ+ꢀH] .
4.2.2 3-Amino-1-(2-methoxyphenyl)-5,10-dioxo-5,
10-dihydro-1H-pyrazolo[1,2-b]phthalazine-
2-carbonitrile (4b)
Yield 97%; yellow solid; m.p. 260–263°C (lit. 259–260°C
1
[27]). – IR (KBr): ʋꢀ=ꢀ3382, 2198, 1666, 1380, 698, 497. – H
NMR ([D6]DMSO, 300 MHz): δꢀ=ꢀ8.31−8.28 (m, 1H, Harom),
8.12–8.09 (m, 1H, Harom), 8.03–7.97 (m, 4H, 2Harom and
NH2), 7.33–7.28 (m, 2H, Harom), 7.05 (d, 1H, Jꢀ=ꢀ8.0 Hz,
Harom), 6.93 (t, 1H, Jꢀ=ꢀ7.0 Hz, Harom), 6.36 (s, 1H, H-1), 3.75
(s, 3H, OMe) ppm. – 13C NMR ([D6]DMSO, 75 MHz): δꢀ=ꢀ157.1
(C), 156.9 (C), 153.7 (C), 151.4 (C), 135.1 (CH), 134.2 (CH), 129.8
(CH), 129.1 (C), 129.0 (C), 127.8 (CH), 127.7 (CH), 127.1 (CH),
126.3 (C), 121.1 (CH), 116.5 (C), 112.1 (CH), 61.1 (C), 59.4 (CH),
Fig. 3:ꢁN–H⋅⋅⋅O and N–H⋅⋅⋅N hydrogen bond interactions resulting in
the formation of an infinite two-dimensional network of compound
4c in the crystal (in red N–H⋅⋅⋅N and in green N–H⋅⋅⋅O).
+
56.3 (OCH3) ppm. – MS (ES-API): m/zꢀ=ꢀ347.1 [Mꢀ+ꢀH] .
Table 4:ꢁHydrogen bond distances (Å) and angles (deg) for 4c.
4.2.3 3-Amino-5,10-dioxo-1-p-tolyl-5,10-dihydro-1H-
pyrazolo[1,2-b]phthalazine-2-carbonitrile (4c)
D–H⋅⋅⋅A
ꢁ
d(D–H)ꢁ d(H⋅⋅⋅A)ꢁ
d(D–A)ꢁ D–H⋅⋅⋅Aꢁ Symmetry
N3–H3a⋅⋅⋅N4 ꢃ
N3–H3b⋅⋅⋅O1 ꢃ
N3–H3b⋅⋅⋅O1 ꢃ
0.86ꢃ 2.2000ꢃ 3.060(2)ꢃ
0.86ꢃ 2.1100ꢃ 2.725(2)ꢃ
0.86ꢃ 2.2400ꢃ 3.018(2)ꢃ
177ꢃ 2–x, 2–y, 1–z
128ꢃ x, y, z
151ꢃ 2–x, 1–y, 1–z
Yield 88%; yellow solid; m.p. 261–262°C (lit. 253–255°C
[29]). – IR (KBr): ʋꢀ=ꢀ3359, 2194, 1658, 1380, 1276, 1149, 694,
574. – 1H NMR ([D6]DMSO, 300 MHz): δꢀ=ꢀ8.26–8.25 (m, 1H,
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Table 5:ꢁIntramolecular C–H⋅⋅⋅π interaction in the crystal structure of 4c (Å, deg).a
C–H⋅⋅⋅Cg
d(C–H)
0.93
d(H⋅⋅⋅Cg)
2.69
d(C–Cg)
C–H⋅⋅⋅Cg
Symmetry
C(18)–H(18)⋅⋅⋅Cg1 (N1 N2 C9 C10 C11)
aCg1ꢂ=ꢂcenter of gravity of N1-N2-C9-C10-C11.
2.978(2)
99
x, y, z
Harom), 8.11–8.09 (m, 3H, 1Harom and NH2), 8.00–7.96 4.2.6 3-Amino-1-(4-chlorophenyl)-5,10-dioxo-5,
(m, 2H, Harom), 7.35 (d, 2H, Jꢀ=ꢀ7.9 Hz, Harom), 7.18 (d, 2H,
Jꢀ=ꢀ7.9 Hz, Harom), 6.10 (s, 1H, H-1), 2.31 (s, 3H, CH3) ppm.
10-dihydro-1H-pyrazolo[1,2-b]phthalazine-
2-carbonitrile (4f)
–
13C NMR ([D6]DMSO, 75 MHz): δꢀ=ꢀ157.0 (C), 154.0 (C),
151.0 (C), 138.1 (C), 135.9 (C), 135.1 (CH), 134.1 (CH), 129.5 Yield 94%; yellow solid; m.p. 274–276°C (lit. 272–274°C
(CH), 129.2 (C), 129.1 (C), 127.7 (CH), 127.3 (CH), 127.1 (CH), [28]). – IR (KBr): ʋꢀ=ꢀ3371, 2198, 1662, 1566, 1377, 1265,
1
116.5 (C), 63.3 (CH), 61.9 (C), 21.2 (CH3) ppm. – MS (ES-API): 1141, 833, 694, 551. – H NMR ([D6]DMSO, 300 MHz):
+
m/zꢀ=ꢀ331.1 [Mꢀ+ꢀH] .
δꢀ=ꢀ8.30−8.26 (m, 1H, Harom), 8.14–8.09 (m, 3H, 1Harom
and NH2), 8.00–7.96 (m, 2H, Harom), 7.54 (d, 1H, Jꢀ=ꢀ8.4 Hz,
Harom), 7.44 (d, 1H, Jꢀ=ꢀ8.4 Hz, Harom), 6.17 (s, 1H, H-1)
ppm. – 13C NMR ([D6]DMSO, 75 MHz): δꢀ=ꢀ157.1 (C), 154.1
(C), 151.2 (C), 137.9 (C), 136.7 (C), 135.1 (CH), 134.2 (CH),
133.3 (C), 129.3 (CH), 129.1 (C), 129.0 (CH), 127.7 (CH), 127.1
4.2.4 3-Amino-1-(3-methoxyphenyl)-5,10-dioxo-5,
10-dihydro-1H-pyrazolo[1,2-b]phthalazine-
2-carbonitrile (4d)
(CH), 116.4 (C), 62.7 (CH), 61.4 (C) ppm. – MS (ES-API):
+
Yield 95%; yellow solid; m.p. 265–269°C (lit. 264–266°C m/zꢀ=ꢀ351.1 [Mꢀ+ꢀH] .
[30]). – IR (KBr): ʋꢀ=ꢀ3355, 2191, 1651, 1384, 1153, 690.
– H NMR ([D6]DMSO, 300 MHz): δꢀ=ꢀ8.29−8.26 (m, 1H,
Harom), 8.12–8.10 (m, 3H, 1Harom and NH2), 7.99–7.95 (m, 4.2.7 3-Amino-1-(2,4-dichlorophenyl)-5,10-dioxo-5,
1
2H, Harom), 7.30 (t, 1H, Jꢀ=ꢀ8.3 Hz, Harom), 7.04–7.01 (m,
2H, Harom), 6.93–6.89 (m, 1H, Harom), 6.11 (s, 1H, H-1),
3.76 (s, 3H, OMe) ppm. – 13C NMR ([D6]DMSO, 75 MHz):
10-dihydro-1H-pyrazolo[1,2-b]phthalazine-
2-carbonitrile (4g)
δꢀ=ꢀ159.8 (C), 157.1 (C), 154.1 (C), 151.1 (C), 140.5 (C), 135.1 Yield 97%; yellow solid; m.p. 245–247°C (lit. 242–244°C
1
(CH), 134.1(CH), 130.1 (C), 129.3 (C), 129.2 (C), 127.7 (CH), [30]). – IR (KBr): ʋꢀ=ꢀ3259, 2202, 1380, 1149, 698, 505. – H
127.1 (C), 119.2 (CH), 116.5 (C), 113.8 (CH), 113.1 (CH), 63.3 NMR ([D6]DMSO, 300 MHz): δꢀ=ꢀ8.31–8.28 (m, 1H, Harom),
(CH), 61.8 (C), 55.6 (OCH3) ppm. – MS (ES-API): m/zꢀ=ꢀ3 47.1 8.19 (sL, 2H, NH2), 8.12–8.09 (m, 1H, Harom), 8.01–7.98
+
[Mꢀ+ꢀH] .
(m, 2H, Harom), 7.71–7.67 (m, 2H, Harom), 7.43 (dd, 1H,
13
Jꢀ=ꢀ8.4 Hz, Jꢀ=ꢀ1.9 Hz, Harom), 6.46 (s, 1H, H-1) ppm. – C
NMR ([D6]DMSO, 75 MHz): δꢀ=ꢀ157.1 (C), 154.1 (C), 151.7
(C), 135.2 (CH), 135.0 (C), 134.4 (CH), 134.0 (C), 132.7 (CH),
129.6 (C), 129.3 (C), 128.7 (C), 128.5 (CH), 127.8 (CH), 127.1
(CH), 116.0 (C), 60.5 (CH), 59.7 (C) ppm. – MS (ES-API):
4.2.5 3-Amino-1-(3-hydroxyphenyl)-5,10-dioxo-5,
10-dihydro-1H-pyrazolo[1,2-b]phthalazine-
2-carbonitrile (4e)
+
m/zꢀ=ꢀ385.0 [Mꢀ+ꢀH] .
Yield 92%; yellow solid; m.p. 270–271°C (lit. 270–272°C [31,
34]). – IR (KBr): ʋꢀ=ꢀ3355, 2191, 1651, 1384, 1153, 690, 563.
– 1H NMR ([D6]DMSO, 300 MHz): δꢀ=ꢀ9.48 (s, 1H, OH), 8.29– 4.2.8 3-Amino-1-(4-ethylphenyl)-5,10-dioxo-5,
8.24 (m, 1H, Harom), 8.14–8.09 (m, 3H, 1Harom and NH2),
10-dihydro-1H-pyrazolo[1,2-b]phthalazine-
8.01–7.97 (m, 2H, Harom), 7.17 (t, 1H, Jꢀ=ꢀ8.2 Hz, Harom),
2-carbonitrile (4h)
6.87 (d, 1H, Jꢀ=ꢀ7.7 Hz, Harom), 6.73 (dd, 1H, Jꢀ=ꢀ8.0 Hz,
13
Jꢀ=ꢀ1.7 Hz, Harom), 6.06 (s, 1H, H-1) ppm. – C NMR ([D6] Yield 94%; yellow solid; m.p. 275–276°C. – IR (KBr):
1
DMSO, 75 MHz): δꢀ=ꢀ157.9 (C), 157.0 (C), 154.0 (C), 151.0 ʋꢀ=ꢀ3359, 2194, 1658, 1380, 694, 578; – H NMR ([D6]DMSO,
(C), 140.3 (C), 135.2 (CH), 134.2 (CH), 130.0 (CH), 129.1 (C), 300 MHz): δꢀ=ꢀ8.28–8.25 (m, 1H, Harom), 8.11–8.09 (m, 3H,
129.1 (CH), 127.7 (CH), 127.2 (CH), 117.7 (CH), 116.5 (C), 115.7 1Harom and NH2), 7.98–7.96 (m, 2H, Harom), 7.37 (d, 2H,
(CH), 113.8 (CH), 63.2 (CH), 61.7 (C) ppm. – MS (ES-API): Jꢀ=ꢀ7.7 Hz, Harom), 7.22 (d, 2H, Jꢀ=ꢀ7.7 Hz, Harom), 6.12 (s, 1H,
+
m/zꢀ=ꢀ333.1 [Mꢀ+ꢀH] .
H-1), 2.60 (q, 2H, Jꢀ=ꢀ7.4 Hz, CH2CH3), 1.18 (t, 3H, Jꢀ=ꢀ7.5 Hz,
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E. Lamera et al.: DMAP for the one-pot synthesis of condensed phthalazinesꢀ
ꢀ367
13
13
CH2CH3) ppm. – C NMR ([D6]DMSO, 75 MHz): – C NMR (C), 144.6 (C), 135.5 (CH), 134.6 (CH), 130.5 (CH), 129.9 (CH),
([D6]DMSO, 75 MHz): δꢀ=ꢀ157.0 (C), 154.0 (C), 151.0 (C), 129.2 (C), 128.5 (C), 127.9 (CH), 127.7 (CH), 127.2 (CH), 125.3
144.3 (C), 136.1 (C), 135.1 (CH), 134.1 (CH), 129.2 (C), 129.1 (C), 123.5 (CH), 116.1 (C), 83.5 (CH), 60.8 (C), 49.0 (CH) ppm.
(C), 128.3 (CH), 127.7 (CH), 127.3 (CH), 127.1 (CH), 116.6 (C), – ESI-HRMS: m/zꢀ=ꢀ368.1134 (calcd. 368.1142 for C21H14N5O2,
+
63.3 (CH), 61.9 (C), 28.3 (CH2), 15.9 (CH3) ppm. – ESI-HRMS: [Mꢀ+ꢀH] ).
+
m/zꢀ=ꢀ345.1349 (calcd. 345.1346 for C20H17N4O2, [Mꢀ+ꢀH] ).
4.2.12 3-Amino-1-(2-chloro-6-methoxyquinolin-3-yl)-
4.2.9 3-Amino-5,10-dioxo-1-o-tolyl-5,10-dihydro-1H-
pyrazolo[1,2-b]phthalazine-2-carbonitrile (4i)
5,10-dioxo-5,10-dihydro-1H-pyrazolo[1,2-b]
phthalazine-2-carbonitrile (4l)
Yield 95%; yellow solid; m.p. 249–250°C (lit. 248–251°C Yield 92%; yellow solid; m.p. 285–286°C (lit. 220–222°C
[32]). – IR (KBr): ʋꢀ=ꢀ3371, 2194, 1670, 1573, 1423, 1272, 1149, [24]). – IR (KBr): ʋꢀ=ꢀ3371, 2206, 1666, 1569, 1496, 1377, 1276,
1
1095, 759, 694. – H NMR ([D6]DMSO, 300 MHz): δꢀ=ꢀ8.31– 1234, 1168, 1045, 833, 694. – 1H NMR ([D6]DMSO, 300 MHz):
8.26 (m, 1H, Harom), 8.11–8.07 (m, 3H, 1Harom and NH2), δꢀ=ꢀ8.68 (s, 1H, Harom), 8.36–8.35 (m, 1H, Harom), 8.26 (sL,
8.01–7.97 (m, 2H, Harom), 7.35 (d, 1H, Jꢀ=ꢀ7.4 Hz, Harom), 2H, NH2), 8.12–7.97 (m, 3H, Harom), 7.91 (d, 1H, Jꢀ=ꢀ9.2 Hz,
7.22–7.20 (m, 3H, 1Harom), 6.34 (s, 1H, H-1), 2.47 (s, 3H, Me) Harom), 7.48 (dd, 1H, Jꢀ=ꢀ9.1 Hz, Jꢀ=ꢀ2.4 Hz, Harom), 7.34 (s,
ppm. – 13C NMR ([D6]DMSO, 75 MHz): δꢀ=ꢀ157.1 (C), 153.9 (C), 1H, Harom), 6.57 (s, 1H, H-1), 3.86 (s, 3H, OMe) ppm. – 13C
151.2 (C), 136.9 (C), 135.6 (C), 135.2 (CH), 134.2 (CH), 134.0 NMR ([D6]DMSO, 75 MHz): δꢀ=ꢀ158.4 (C), 157.2 (C), 154.1 (C),
(CH), 131.6 (CH), 130.9 (CH), 129.2 (C), 129.0 (C), 128.4 (CH), 153.3 (C), 151.8 (C), 143.3 (C), 135.3 (CH), 134.4 (CH), 129.5
127.8 (CH), 127.1 (CH), 116.5 (C), 61.5 (C), 60.4 (CH), 19.1 (CH3) (CH), 129.3 (C), 129.0 (C), 128.8 (C), 127.8 (CH), 127.2 (CH),
+
ppm. – MS (ES-API): m/zꢀ=ꢀ331.1 [Mꢀ+ꢀH] .
124.4 (CH), 116.1 (C), 106.0 (CH), 83.5 (C), 61.5 (CH), 56.0
+
(CH3) ppm. – MS (ES-API): m/zꢀ=ꢀ432.1 [Mꢀ+ꢀH] .
4.2.10 3-Amino-5,10-dioxo-1-(pyridin-3-yl)-5,10-dihydro-
4.3 X-ray structure determination
1H-pyrazolo[1,2-b]phthalazine-2-carbonitrile (4j)
Yellow crystals of compound 4c were obtained from
acetone-dimethylformamide solution. Diffraction data
were collected with a Bruker Apex II CCD area detector
diffractometer with graphite-monochromatized MoK
radiation (λꢀ=ꢀ0.71073 Å) at 298 K. Tables 2 and 3 summaα-
rize important crystal structure data and selected bond
lengths and angles of 4c, respectively.
CCDC 1476723 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
Yield 91%; yellow solid; m.p. 267–270°C (lit. 268–270°C
1
[33]). – IR (KBr): ʋꢀ=ꢀ3259, 2191, 1569, 1280, 698, 567; – H
NMR ([D6]DMSO, 300 MHz): δꢀ=ꢀ8.75 (d, 1H, Jꢀ=ꢀ1.8 Hz,
Harom), 8.55 (dd, 1H, Jꢀ=ꢀ4.7 Hz, Jꢀ=ꢀ1.5 Hz, Harom),
8.30–8.24 (m, 1H, Harom), 8.19 (sL, 2H, NH2), 8.13–8.07
(m, 1H, Harom), 7.01–7.92 (m, 3H, Harom), 7.44–7.40 (m,
13
1H, Harom), 6.24 (s, 1H, H-1) ppm. – C NMR ([D6]DMSO,
75 MHz): δꢀ=ꢀ157.2 (C), 154.2 (C), 151.4 (C), 150.0 (CH), 149.1
(CH) 135.1 (CH), 135.1 (CH), 134.4 (C), 134.2 (CH), 129.4 (C),
128.9 (C), 127.7 (CH), 127.1 (CH), 124.2 (CH), 116.4 (C), 61.3
+
(CH), 60.8 (C) ppm. – MS (ES-API): m/zꢀ=ꢀ318.1 [Mꢀ+ꢀH] .
4.2.11 3-Amino-5,10-dioxo-1-(quinolin-4-yl)-5,
10-dihydro-1H-pyrazolo[1,2-b]phthalazine-
2-carbonitrile (4k)
5 Supplementary information
Pictures of the NMR and mass spectra of compounds 4a–
4l are given as Supporting Information available online
Yield 84%; yellow solid; m.p. 256°C; IR (KBr): ʋꢀ=ꢀ3382, (DOI: 10.1515/znb-2016-0262).
2206, 1662, 1562, 1423, 1369, 1276, 1149, 752, 694; – 1H NMR
([D6]DMSO, 300 MHz): δꢀ=ꢀ8.87 (d, 1H, Jꢀ=ꢀ4.5 Hz, Harom), Acknowledgments: We are grateful to the Ministère de
8.42–8.33 (m, 2H, Harom), 8.23 (sL, 2H, NH2), 8.15–7.99 l’Enseignement Supérieur et de la Recherche Scientifique
(m, 4H, Harom), 7.85 (t, 1H, Jꢀ=ꢀ7.5 Hz, Harom), 7.75–7.7. (m, – Algérie (MESRS) for financial support. Z. Bouaziz and M.
13
2H, Harom), 7.05 (s, 1H, H-1) ppm; – C NMR ([D6]DMSO, Le Borgne would like to gratefully thank Elodie Monniot
75 MHz): δꢀ=ꢀ157.3 (C), 154.4 (C), 151.6 (C), 150.9 (CH), 148.0 for her assistance in the realization of LCMS experiments.
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ꢀE. Lamera et al.: DMAP for the one-pot synthesis of condensed phthalazines
368ꢀ
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(DOI: 10.1515/znb-2016-0262) offers supplementary material,
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