Friedel-Crafts Chemistry. Part 46. Unprecedented Construction of Tricyclic Pyrazolo[3,4-b]quinolines, -[1,8]naphthyridines, -azepines, -azocines, -pyrido[3,2-g]azocines, and pyrazolo[3,4-b]azonines via Friedel-Crafts Ring Closures

Article abstract of DOI:10.1071/CH15526

A series of keto-substituted pyrazolo[3,4-b]quinolines, pyrazolo[3,4-b][1,8]naphthyridines, benzo[e]pyrazolo[3,4-b]azepines, benzo[g]pyrazolo[3,4-b]azocines, pyrazolo[3,4-b]pyrido[3,2-g]azocines, and benzo[g]pyrazolo[3,4-b]azonines scaffolds were synthesi

Full text of DOI:10.1071/CH15526

CSIRO PUBLISHING
Aust. J. Chem.
Full Paper
http://dx.doi.org/10.1071/CH15526
Friedel–Crafts Chemistry. Part 46. Unprecedented
Construction of Tricyclic Pyrazolo[3,4-b]quinolines,
-[1,8]naphthyridines, -azepines, -azocines,
-pyrido[3,2-g]azocines, and pyrazolo[3,4-b]azonines
via Friedel–Crafts Ring Closures
A B
,
A
Hassan A. K. Abd El-Aal
and Ali A. Khalaf
A
Chemistry Department, Faculty of Science, Assiut University, Assiut, 71516, Egypt.
Corresponding author. Email: hassankotb33@yahoo.com
B
A series of keto-substituted pyrazolo[3,4-b]quinolines, pyrazolo[3,4-b][1,8]naphthyridines, benzo[e]pyrazolo[3,4-b]
azepines, benzo[g]pyrazolo[3,4-b]azocines, pyrazolo[3,4-b]pyrido[3,2-g]azocines, and benzo[g]pyrazolo[3,4-b]azonines
scaffolds were synthesized via a Friedel–Crafts cyclialkylation approach. The precursor acids were obtained by utilizing
the modified Ullman coupling reactions of 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid with different aryl
amines followed by ring closures in the presence of AlCl3/CH3NO2 or P2O5 or polyphosphoric acid catalysts. Particular
attention is given to the novel structures especially in regard to the promising pharmaceutical and therapeutic values
associated with their skeletons.
Manuscript received: 9 August 2015.
Manuscript accepted: 12 October 2015.
Published online: 6 November 2015.
Introduction
In particular, fused pyrazole derivatives are important sub-
structures ofcompounds with biological activity and, since the past
twodecades, have been found in some well-knowndrug molecules
(Fig. 2) such as Allopurinol (pyrazolo[3,4-d]pyrimidin-4-one),[17]
Sildenafil (pyrazolo[4,3-d]pyrimidine),[18] Zaleplon (pyrazolo
[1,5-a]pyrimidine),[19] and Zolazepam (pyrazolo[3,4-e][1,4]
diazepine)[20] as well as examples of polyfunctionalized drugs
such as Celecoxib and Rimonabant.[21] Moreover, several fused
pyrazoles possessing interesting biological activities have recently
been synthesized, such as thieno[2,3-c]pyrazoles,[22] pyrazolo
[4,3-c]quinolones,[23] and pyrazolo[5,1-a]isoquinolines.[24]
Despite the discovery of pyrazole[25] as an antipyretic agent dating
back to 1884, interest in its preparation, structural modification,
and pharmaceutical application continues unabated.
A full literature survey for applied methodologies in the
synthesis of fused pyrazolo-quinoline, naphthyridine, azepine,
azocine, and azonine systems revealed that more attention has
been given to accessing pyrazolo[3,4-b]quinolines than other
skeletons and a limited number of synthetic strategies currently
exist in the literature. Some of the important reported strategies
for the synthesis of pyrazolo[3,4-b]quinolines are summarized
in the following.
Numerous medium-sized heterocyclic rings, particularly aze-
pines, azocines, and azonines and their benzo derivatives
(Fig. 1), form parts of the structures of a large variety of
biologically active natural products[1] and pharmacological
agents.[2] Moreover, their polyfunctionalized scaffolds are
noted for their diverse industrial applications in dyes,[3] semi-
conductors,[4] and polymers.[5]
Owing to their interesting biological activities and unique
structural features, syntheses of such ring systems have become
an attractive research field for the development of new pharma-
cological compounds.[6] Despite the unfavourable enthalpy and
entropy factors, as well as transannular interactions[7] associated
with the classical synthetic methods for medium-sized rings that
pose significant restrictions in the ring formation, the last three
decades have witnessed an upsurge in research for the construc-
tion of such ring systems. Consequently, a comprehensive
review of azepine, azocine, and azonine derivatives surveying
their occurrence, synthetic strategies, and biological activities
has been attempted.[8]
However, among different fused nitrogen heterocycles,
pyrazole-based compounds occupy a special place in the history
of N-heterocycles not only owing to their wide range of
biological activity,[9] but also to their pharmacological
effects.[10] Pyrazole derivatives have wide applications in the
agrochemicals industry as herbicides,[11] fungicides,[12] pesti-
cides,[13] dyestuffs,[14] and insecticides.[15] Although pyrazoles
are rare in nature, the first natural pyrazole (1-pyrazolyl-alanine)
was isolated in 1959 from seeds of watermelons.[16]
In 1928, the first synthesis of pyrazoloquinoline described in
the literature was obtained by Friedla¨nder condensation from
anthranilic aldehydes and substituted pyrazolone.[26] Tomasik
et al.[27] have recently reported the utility of the Friedla¨nder
methodology[28] for the synthesis of pyrazoloquinoline deriva-
tives from the acid-catalyzed condensation between 2-amino-
benzophenones and pyrazolin-5-ones.
Journal compilation Ó CSIRO 2015
www.publish.csiro.au/journals/ajc

B
H. A. K. Abd El-Aal and A. A. Khalaf
O
OH
F3C
F3C
R
R ꢀ alkenyl,
alkynyl
N
R1
R ꢀ H, Cl
N
N
R
R ꢀ H, Me, Et
R1 ꢀ alkanoyl, alkenoyl
R
O
R1 ꢀ H, Me
R1
Anti-inflammatory and analgesic
Sedative and anticonvulsant
Antihypertensive
R1
R2
R3
N
Me
Imipramine; R1 ꢀ R2 ꢀ H, R3 ꢀ Me
Desipramine; R1 ꢀ R2 ꢀ R3 ꢀ H
N
Me
N
Clomipramine; R1 ꢀ Cl, R2 ꢀ H, R3 ꢀ Me
Trimipramine; R1 ꢀ H, R2 ꢀ R3 ꢀ Me
Central and blood pressure
depressant
Fig. 1. Medium-sized nitrogen heteropolycycle-containing drugs.
O
O
N
N
O
N
O
N
O
N
N
N
S
N
N
H
F
HN
N
N
Pr
N
H
N
OEt
Allopurinol
Sildenafil
Zolazepam
1-[4-Ethoxy-3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-
pyrazolo[4,3-d]pyrimidin-5-yl)phenylsulfonyl]-4-
methylpiperazine
1H-Pyrazolo[3,4-d]pyrimidin-4(2H)-one
4-(2-Fluorophenyl)-6,8-dihydro-1,3,8-
trimethylpyrazolo-[3,4-e][1,4]-diazepin-7(1H)-one
Cl
F
F
N
O
S
N
N
N
F
N
H2N
O
NH
O
N
O
N
N
N
N
Cl
Cl
Zaleplon
Celecoxib
Rimonabant
N-(3-(3-Cyanopyrazolo[1,5-a]pyrimidin-7-
yl)phenyl)-N-ethylacetamide
5-(4-Chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-
(piperidin-1-yl)-1H-pyrazole-3-carboxamide
4-[5-(4-Methylphenyl)-3-(trifluoromethyl)pyrazol-1-
yl]benzenesulfonamide
Fig. 2. Pyrazole heteropolycycle-containing pharmaceutical drugs.
Chaczatrian and coworkers[29] reported that several pyrazo-
loquinoline derivatives were obtained via condensation reac-
tions either by reaction of 5-aminopyrazoles and aromatic
aldehydes in the presence of ZnCl2 or by reactions of 4-
benzylidenepyrazolones and aromatic amines in ethylene gly-
col. The latter approach led to the development of single-step
synthetic procedures.
resulting pyrazoloquinoline ring system. Further, in 2010,
Zhang et al.[32] reported the utility of the combination reactions
to access pyrazolo[3,4-b]quinolinones from aromatic aldehydes
and 5-amino-3-methyl-1-phenylpyrazole in the presence of
Meldrum’s acid (dimedone) in [BMIM][BF4] (BMIM ¼ 1-
butyl-3-methylimidazolium) under thermal or microwave
condition.
Martini and coworkers[30] described an efficient synthesis of
pyrazoloquinolines by the condensation of 2-acetonyl-4H-
3,1-benzoxazin-4-one with arylhydrazines, affording the corre-
sponding N-(1-aryl-3-methylpyrazol-5-yl)anthranilic acids
followed by ring-closure with polyphosphoric acid providing
the 3,9-dimethyl-1-phenyl-1H-pyrazolo[3,4-b]quinolin-4-ones.
A unique strategy[31] based on consecutive reaction steps for
the formation of various pyrazoloquinolines has been developed
by Kumar et al. This strategy depends on the base-catalyzed
K2CO3-promoted alkylation of halosubstituted benzoic acids
with 5-aminopyrazoles in DMF in the presence of a catalytic
amount of Cu(OAc)2, giving the required anthranilic acid
derivatives. The latter anthranilic acids underwent ring closure
with POCl3, providing unique access to pyrazoloquinolines in
moderate yield. This methodology allowed the incorporation of
a variety of substituent types at the 3- and 4-positions of the
Other widely used methodologies that have been successful-
ly applied in the synthesis of pyrazoloquinoline[33] share a
common substrate of 2-chloroquinoline-3-carboxaldehyde and
intermediates in such a way that it can be said they are
interconnected. Although considerable attention has been
directed towards the synthesis of pyrazoloquinoline derivatives
owing to their broad spectrum in chemical, biological, and
industrial applications, the search for new methods for simple,
direct, economical, and efficient construction of this class of
heterocycles still constitutes a major challenge in organic
synthesis.
In recent years, we directed part of our Friedel–Crafts ring-
closure[34] research to developing facile methods for the synthe-
sis of known and new condensed heteropolycycles[35] of prom-
ising pharmacological value. In our previous works of this
series,[36,37] we developed a synthetic methodology for the

Friedel–Crafts Chemistry
C
COOH
R
CHO
Cl
COOH
Cl
COOH
Ar
iii
i
ii
N
N
N
N
Cl
N
N
N
N
N
Path b
Path a
Me
a: Ar ꢀ Ph
b: Ar ꢀ 2-Pyridyl
c: Ar ꢀ PhCH2
Ph
Ph
Ph
Ph
1
4a, b
2
3a–c
a: R ꢀ H
iv
b: R ꢀ Me
R
COOH
COOH
a: R ꢀ H, Ar ꢀ Ph
R
Ar
N
v
b: R ꢀ H, Ar ꢀ 2-Pyridyl
c: R ꢀ H, Ar ꢀ CH2Ph
d: R ꢀ Me, Ar ꢀ Ph
N
Cl
N
N
N
a: Ar ꢀ Ph
Me
Ph
Ph
b: Ar ꢀ 2-Pyridyl
c: Ar ꢀ PhCH2
e: R ꢀ Me, Ar ꢀ 2-Pyridyl
f: R ꢀ Me, Ar ꢀ CH2Ph
5a, b
6a–f
Scheme 1. Reagents and conditions: (i) KMnO4/H2O/t-butanol, 70–808C, 40 min; (ii) and (v) aromatic amines
(PhNHMe or 2-methylaminopyridine or MeNHCH2Ph), K2CO3/CuO/DMSO, 140–1508C, 8 h; (iii) Ac2O/
AcONa or Pr2O/PrONa, 120–1308C, 8–10 h; (iv) Na/Hg (2.5 %), NaOH, 3 h, room temperature.
COOH
O
synthesis of a series of 5H-dibenz[b,f]azepines (iminodi-
Ar
benzyls), 5H-dibenz[b,f]azocines, 11H-benzo[f]pyrido[2,3-b]
azepines, 6H-benzo[g]pyrido[2,3-c]azocines, dibenzoazepines,
-azocines, -azonines, and -azecines. In another paper,[38] we
introduced facile syntheses for nine substituted indeno[1,2-c]
pyrazoles, 2H-benzo[g]indazoles, and benzo[6,7]cyclohepta
[1,2-c]pyrazoles. This prompted us to apply the same proce-
dures for the universal construction of fused tricyclic pyrazolo-
quinoline, -naphthyridine, -azepine, -azocine, and -azonine
scaffolds via Friedel–Crafts ring closure of nitrogen-containing
carboxylic acids precursors.
N
N
Ph
Cat.
N
N
N
X
Hꢁ, ꢂH2O
Me
N
Me
n
Ph
3a–c
a: Ar ꢀ Ph
7a–c
a: n ꢀ 0, X ꢀ CH
b: n ꢀ 0, X ꢀ N
c: n ꢀ 1, X ꢀ CH
b: Ar ꢀ 2-Pyridyl
c: Ar ꢀ PhCH2
Scheme 2. Cycliacylations of acids 3a–c under Friedel–Crafts conditions
(Table 1).
R
Results and Discussion
R
O
COOH
Our synthetic routes to the desired heterocyclic acid precursors
3a–c and 6a–f are outlined in Scheme 1. The synthesis of
heteroaryl acids was planned from easily obtained 5-chloro-3-
methyl-1-phenyl-1H-pyrazole-4-carbaldehyde (1)[39] via two
different synthetic pathways. Path a included oxidation of the
aldehyde following a standard literature procedure with KMnO4
solution to afford 5-chloro-3-methyl-1-phenyl-1H-pyrazole-4-
carboxylic acid (2).[40] The resulting halo-acid 2 was then used
in the catalyzed Ullmann[41] N-coupling reaction with different
N-methylaromatic amines. The reaction was carried out in
DMSO solution and in the presence of K2CO3 to give the corre-
sponding N-aryl acids (3a–c) in good overall yields (77–82 %).
However, the second route (Path b) involved the elongation
reactions of acid precursors 4a, b. These acids were smoothly
obtained through the Perkin-type reaction[42] of aldehyde 1 with
acid anhydrides and the corresponding sodium salts of acids to
give substituted 3-(5-chloro-3-methyl-1-phenyl-1H-pyrazol-4-
yl)acrylic acids (4a, b). The resulting acids 4a, b were reduced
with sodium amalgam[43] (2.5 %) in NaOH solution to afford
reduced acids 5a, b. The latter acids were converted to the N-aryl
acids 6a–f by reaction with aromatic amines in pyridine
(Scheme 1). Examination of the 1H NMR data of the synthesized
Cat.
Hꢁ, ꢂH2O
Ar
N
N
N
N
N
N
X
Me
n
Ph
Ph
Me
6a–f
8a–f
a: R ꢀ H, Ar ꢀ Ph
a: n ꢀ 0, R ꢀ H, X ꢀ CH
b: n ꢀ 0, R ꢀ H, X ꢀ N
c: n ꢀ 1, R ꢀ H, X ꢀ CH
d: n ꢀ 0, R ꢀ Me, X ꢀ CH
e: n ꢀ 0, R ꢀ Me, X ꢀ N
f: n ꢀ 1, R ꢀ Me, X ꢀ CH
b: R ꢀ H, Ar ꢀ 2-Pyridyl
c: R ꢀ H, Ar ꢀ CH2Ph
d: R ꢀ Me, Ar ꢀ Ph
e: R ꢀ Me, Ar ꢀ 2-Pyridyl
f: R ꢀ Me, Ar ꢀ CH2Ph
Scheme 3. Cycliacylations of acids 6a–f under Friedel–Crafts conditions
(Table 2).
spectra, the characteristic peaks of the alkene proton were
absent.
Our synthetic protocol allows access to functionalized fused
tricyclic pyrazolo[3,4-b]quinolines, -[1,8]naphthyridines,
-azepines, -azocines, -pyrido[3,2-g]azocines, and -azonines by
means of the Friedel–Crafts cycliacylations of the key interme-
diate heterocyclic acids 3a–c and 6a–f.
Subsequently, we carried out the ring closures of acids 3a–c
and 6a–f, which were smoothly effected in the presence of
AlCl3/CH3NO2 or P2O5 or polyphosphoric acid (PPA) catalysts
under different reaction conditions to provide substituted azatri-
cyclicketones 7a–c and 8a–f (Schemes 2 and 3; Tables1 and 2) in
overall high reaction yields. The structures of all products were
confirmed from both analytical and spectral data.
1
acids precursors reveals that, for example, the H NMR spec-
trum for substituted pyrazol-4-propanoic acid 5a displays five
signals, including a CH2 protons triplet at d 2.55 ppm and a
methyl group attached to the pyrazole ring as one singlet at
d 2.70 ppm. The second CH2 protons appear as a triplet at
2.80 ppm and aromatic protons appear as multiplets at d 6.30–
7.75 ppm, while the fifth singlet proton at d 11.3 ppm was
assigned to the carboxyl group proton. However, in the IR
1
The H NMR data affirm clearly the formation of cyclic
heterocyclic products. Owing to the diastereotopic groups

D
H. A. K. Abd El-Aal and A. A. Khalaf
Table 1. Friedel–Crafts cycliacylations of pyrazole-containing carboxylic acids 3a–c
Entry
1
Substrate
Product
Conditions
Product (%)A
COOH
Ph
O
AlCl3/CH3NO2B, DCMC, 10 h, rt
P2O5D, toluene, 6 h, reflux
PPAE, 6 h, 160–1708C
7a (81)
7a (86)
7a (75)
N
N
N
N
N
N
Me
Ph
Ph
3a
Me
O
COOH
AlCl3/CH3NO2, DCM, 10 h, rt
P2O5, toluene, 9 h, reflux
PPA, 4 h, 160–1708C
7b (90)
7b (84)
7b (74)
N
2
3
N
N
N
N
N
N
N
Me
Ph
Ph
3b
Me
COOH
O
AlCl3/CH3NO2, DCM, 12 h, rt
P2O5, toluene, 8 h, reflux
PPA, 5 h, 160–1708C
7c (91)
7c (86)
7c (77)
N
CH2Ph
N
N
N
N
Ph
Me
N
Me
Ph
3c
AIsolated yields are relative to the substrate.
BWith AlCl3/CH3NO2 catalyst, reactant proportions were: carboxylic acid (0.002 mol), AlCl3 (0.0024 mol), CH3NO2 (0.024 mol), solvent (10 mL).
CDichloromethane.
DWith P2O5 catalyst, reactant proportions were: acid (0.4 g) and P2O5 (4 g) in anhydrous toluene (15 mL).
EWith polyphosphoric acid (PPA) catalyst, reactant proportions were: acid (0.5 g) and PPA (5 g).
Table 2. Friedel–Crafts cycliacylations of pyrazole containing carboxylic acids 6a–f
Entry
4
Substrate
Product
Conditions
Product (%)A
COOH
Ph
O
AlCl3/CH3NO2B, DCMC, 5 h, rt
P2O5D, toluene, 9 h, reflux
PPAE, 2 h, 160–1708C
8a (87)
8a (83)
8a (75)
N
N
N
N
N
N
Me
6a Ph
Me
Ph
COOH
O
AlCl3/CH3NO2, DCM, 6 h, rt
P2O5, toluene, 8 h, reflux
PPA, 1 h, 160–1708C
8b (84)
8b (89)
8b (76)
N
N
5
6
N
N
N
N
N
Me
N
O
6b Ph
Ph Me
COOH
CH2Ph
AlCl3/CH3NO2, DCM, 5 h, rt
P2O5, toluene, 5 h, reflux
PPA, 2 h, 160–1708C
8c (87)
8c (86)
8c (73)
N
N
N
N
Me
N
N
6c Ph
Ph Me
COOH
Ph
O
AlCl3/CH3NO2, DCM, 6 h, rt
P2O5, toluene, 5 h, reflux
PPA, 3 h, 160–1708C
8d (92)
8d (90)
8d (80)
N
7
8
N
N
N
N
N
N
Ph
Me
Ph
6d
Me
COOH
O
AlCl3/CH3NO2, DCM, 5 h, rt
P2O5, toluene, 7 h, reflux
PPA, 2 h, 160–1708C
8e (88)
8e (84)
8e (78)
N
N
N
N
Me
N
Ph
N
Me
N
Ph
6e
COOH
O
AlCl3/CH3NO2, DCM, 8 h, rt
P2O5, toluene, 8 h, reflux
PPA, 2 h, 160–1708C
8f (86)
8f (92)
8f (81)
CH2Ph
N
9
N
N
N
Me
N
N
Ph
6f
Me
Ph
AIsolated yields are relative to the substrate.
BWith AlCl3/CH3NO2 catalyst, reactant proportions were: carboxylic acid (0.002 mol), AlCl3 (0.0024 mol), CH3NO2 (0.024 mol), solvent (10 mL).
CDichloromethane.
DWith P2O5 catalyst, reactant proportions were: acid (0.4 g) and P2O5 (4 g) in anhydrous toluene (15 mL).
EWith polyphosphoric acid (PPA) catalyst, reactant proportions were: acid (0.5 g) and PPA (5 g).

Friedel–Crafts Chemistry
E
O
5
5
O
7
KMnO4 (6.6g, 42mmol) in H2O (30 mL) at 70–808C over a
period of 40 min. Afterwards, the reaction mixture was basified
with KOH (10 %, 50mL) at room temperature and the whole
mixture was filteredunder suction. The clear filtrate was acidified
with HCl (40 mL, 30%). The resulting precipitate was filtered
off, washed with water, dried, and crystallized from ethanol to
give 7.9 g (88 %) of pure acid 2 as white crystals, mp 219–2218C
(lit. mp 217–2198C[39]). nmax (KBr)/cmꢀ1 3105, 2560, 1684,
1620, 1585, 1473, 1440, 1360, 1140, 755. dH (90 MHz, [D6]
DMSO) 2.4 (3H, s, CH3), 6.80–7.70 (5H, m, Ar–H), 12.80 (s, 1H,
COOH). Anal. Calc. for C11H9ClN2O2 (236.5): C 55.81, H 3.80,
N 11.83, Cl 15.01. Found: C 64.52, H 3.72, N 9.33, Cl 11.80 %.
4
4
6
6
8
9
6a
3a
7
3a
6a
10a
3
3
10a
11
11a
8
12a
N
N
2
2
10
11 N
N
N
12 N
1
9
1
10
1ꢃ
Me
Me
6ꢃ
1ꢃ
6ꢃ
5ꢃ
2ꢃ
3ꢃ
2ꢃ
5ꢃ
8f
8d
3ꢃ
4ꢃ
4ꢃ
Fig. 3. Diastereotopic protons contained in condensed pyrazole
heteropolycycles.
1
presenting unresolved signals, the H NMR spectra of com-
pounds 8d–f characterized by the appearance of the diastereo-
topic hydrogens of the CH2 group directly bonded to the
pyrazole ring showed a large change in chemical shifts.
Thus, the 1H NMR spectrum of tricyclic azocinone 8d
(Fig. 3) shows the chemical shifts of the CH2 protons of the
azocine ring (H4a and H4b) characteristic of the A2B system and
is characterized by the presence of apparent quartet signals near
d 2.42 ppm with a coupling constant of 6.4 Hz for one proton and
a triplet near d 2.81 ppm with a coupling constant of 6.2 Hz for
the other proton. In comparison with compound 8d, the1H NMR
spectrum of tricyclic azoninone 8f shows the chemical shifts for
CH2 protons (H4a and H4b) as a characteristic apparent triplet
for Ha at an average of d 2.51 ppm with a coupling constant of
6.3 Hz and a triplet for Hb near d 2.84 ppm with a coupling
constant of 6.0 Hz.
General Procedure for N-Arylation of Chloropyrazole-4-
carboxylic Acid 2 with Different Aromatic Amines
A mixture of chloro-acid 2 (4.2 g, 18 mmol), K2CO3 (4.1 g,
30 mmol), aryl amine (PhNHMe or 2-methyl-2-pyridylamine or
MeNHCH2Ph) (20 mmol), and CuO (0.3 g) in anhydrous DMSO
(20 mL) was heated with continuous stirring for 8 h at 140–
1508C. After the mixture was cooled, NaOH solution (50 mL,
10 %) and decolorizing carbon (3 g) were added and the mixture
was heated for 20 min, then filtered by suction. The resulting
cold filtrate was acidified with HCl solution (40 mL, 20 %) and
the crude precipitate was filtered and recrystallized from ethanol
gave the pure acids 3a–c. The yields and spectral data are given
in the following.
5-(N-methyl-N-phenylamino)-3-methyl-1-phenyl-1H-
pyrazole-4-carboxylic Acid (3a)
Conclusions
White plates; 80 %; mp 182–1848C (ethanol). nmax (KBr)/
cmꢀ1 3090, 2984, 2524, 1690, 1605, 1580, 1475, 1430, 1355,
1143, 758. dH (90 MHz, CDCl3) 2.65 (3H, s, N-CH3), 2.80
(3H, s, CH3), 6.40–7.70 (10H, m, Ar–H), 11.3 (s, 1, COOH). m/z
(EI, 70 eV) (%), 308 (Mþ þ 1, 12), 307 (Mþ, 29), 294 (62), 292
(71), 291 (40), 277 (25), 262 (100), 247 (62), 230 (53), 215 (36),
199 (29), 166 (74), 154 (17), 122 (30), 105 (16), 90 (12), 78 (8).
Anal. Calc. for C18H17N3O2 (307): C 70.35, H 5.53, N 13.68.
Found: C 70.54, H 5.72, N 13.38 %.
In summary, we have developed a convergent protocol for
the synthesis of unprecedented fused pyrazolequinolines,
-naphthyridines, -azepines, -azocines, -azocines, and -azonines
by Friedel–Crafts cycliacylations with good yields of suitable
synthesized carboxylic acids substrates. Particular attention will
be given to the novel structures identified to date and the prom-
ising pharmaceutically and therapeutic values associated with
their tricyclic skeletons. The chemistry described and the results
obtained confirm the significant and wide versatility of Friedel–
Craftsring-closurereactionsinthesynthesis ofheteropolycycles.
5-(N-methyl-N-(pyridin-2-yl)amino)-3-methyl-1-phenyl-
1H-pyrazole-4-carboxylic Acid (3b)
Experimental
General
Brownish crystals; 77 %; mp 157–1598C (benzene). nmax
(KBr)/cmꢀ1 3110, 2565, 1695, 1600, 1590, 1460, 1445, 1330,
1120, 760. dH (90 MHz, [D6]DMSO) 2.50 (3H, s, N-CH3), 2.75
(3H, s, CH3), 6.45–7.85 (9H, m, Ar–H), 11.4 (s, 1, COOH). m/z
(EI, 70 eV) (%), 308 (Mþ, 40), 307 (19), 291 (62), 278 (31), 263
(54), 248 (27), 233 (19), 231 (38), 216 (28), 200 (33), 170 (15),
168 (63), 156 (42), 124 (42), 104 (11), 91 (16), 77 (10). Anal.
Calc. for C17H16N4O2 (308): C 66.23, H 5.19, N 18.18. Found:
C 66.16, H 5.42, N 17.95 %.
All reagents were purchased from Merck, Sigma–Aldrich
Chemical Co. and were used without further purification. Melt-
ing points were measured on a digital Gallenkamp capillary
melting point apparatus and are uncorrected. The IR spectra were
recorded with a Shimadzu 470 infrared spectrophotometer using
KBr wafer and thin film techniques (n, cmꢀ1). The H and
1
13C NMR spectra were recorded on Jeol LA 400 MHz Fourier-
transform (FT)-NMR (400 MHz for 1H, 100MHz for 13C) and on
Varian NMR (90 MHz) spectrometers using CDCl3 solvent with
TMS as internal standard. Chemical shifts (d) and J values are
reported in ppm and Hz respectively. Elemental analyses were
performed on a PerkinElmer 2400 Series II analyser. Reactions
were monitored by thin-layer chromatography (TLC) using
precoated silica plates visualized with UV light. Flash column
chromatography was performed on silica gel or basic alumina.
5-(N-benzyl-N-methylamino)-3-methyl-1-phenyl-1H-
pyrazole-4-carboxylic Acid (3c)
White crystals; 82 %; mp 120–1228C (ethanol). nmax (KBr)/
cmꢀ1 3060, 2973, 2550, 1695, 1605, 1580, 1465, 1440, 1335,
1254, 745. dH (90 MHz, CDCl3) 2.55 (3H, s, N-CH3), 2.70
(3H, s, CH3), 4.45 (2H, s, N-CH2), 6.30–7.85 (10H, m, Ar–H),
11.2 (s, 1, COOH). m/z (EI, 70 eV) (%), 322 (Mþ þ 1, 8), 321
(Mþ, 27), 304 (63), 306 (17), 291 (26), 276 (100), 274 (69), 246
(22), 244 (36), 214 (11), 199 (20), 168 (58), 155 (36), 121 (18),
104 (14), 90 (17), 78 (10). Anal. Calc. for C19H19N3O2 (321):
C 71.02, H 5.91, N 13.08. Found: C 70.81, H 9.12, N 13.20 %.
5-Chloro-3-methyl-1-phenyl-1H-pyrazole-4-carboxylic
Acid (2)
To a solution of aldehyde 1[38] (8.4g, 30mmol) in aqueous t-
butanol (t-butanol/H2O, 1 : 1, 50 mL) was added a solution of

F
H. A. K. Abd El-Aal and A. A. Khalaf
General Perkin-Type Procedure for the Synthesis
of Acrylic Acids
2.65–2.94 (3H, m, CH–CH2), 2.75 (3H, s, CH3), 6.35–7.70
(5H, m, Ar–H), 10.8 (s, 1, COOH). Anal. Calc. for
C14H15ClN2O2 (278.5): C 60.32, H 5.38, N 10.05, Cl 12.74.
Found: C 60.38, H 5.22, N 10.26, Cl 12.64 %.
A mixture of aldehyde 1 (3.5 g, 15 mmol), acid anhydride
(ethanoic or propanoic anhydride) (18 mmol), and sodium salt of
the corresponding acid (18 mmol) was heated in an oil bath at
120–1308C with occasionally stirring for 8–10 h. After reaction
completion, the warm mixture was poured with stirring into ice-
cold water (50 mL), basified with Na2CO3 solution (20 mL,
30 %), and extracted with diethyl ether (2 ꢁ 20 mL). The ether
extracts were discarded and the resulting solution was heated
with decolorizing carbon (2 g), filtered while hot, then poured
with stirring into concentrated HCl mixed with ice (50 mL). The
precipitated acid 13a or b was filtered, washed successively with
water, and left to dry. Purifications, yields and spectral data are
given in the following.
General Procedure for N-Arylation of Substituted
Pyrazole-4-propionic Acid
The titled acids were obtained by repeating the Ullmann
N-coupling reaction with the same procedure as described for
N-aryl acids 3a–c with different aromatic amines. The yields and
spectral data are given in the following.
3-(5-(N-methyl-N-phenylamino)-3-methyl-1-phenyl-
1H-pyrazol-4-yl)propanoic Acid (6a)
Greenish plates; 74 %; mp 222–2248C (ethanol). nmax (KBr)/
cmꢀ1 3030, 2980, 2590, 1730, 1590, 1550, 1440, 1435, 1335,
1260, 755. dH (90 MHz, CDCl3) 2.45(2H, t, J 7.5, CH2), 2.60(3H,
s, N-CH3), 2.70 (3H, s, CH3), 2.95 (2H, t, J 6, CH2), 6.40–7.75
(6H, m, Ar–H), 11.2 (s, 1, COOH). m/z (EI, 70 eV) (%), 335 (Mþ,
27), 318 (24), 290 (100), 275 (52), 360 (35), 258 (74), 245 (17),
232 (25), 213 (32), 204 (16), 180 (62), 178 (19), 168 (64), 105
(22), 90 (12), 78 (7). Anal. Calc. for C20H21N3O2 (335): C 71.64,
H 6.26, N 12.53. Found: C 71.72, H 6.28, N 12.68 %.
3-(5-Chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)acrylic
Acid (4a)
White needles; 74 %; mp 149–1518C (methanol). nmax (KBr)/
cmꢀ1 3110, 2945, 2545, 1705, 1600, 1585, 1460, 1445, 1350,
1140, 747. dH (90 MHz, CDCl3) 2.75 (3H, s, CH3), 2.75 (3H,
s, CH3), 6.20 (H, d, J 6, CH), 6.45–7.70 (6H, m, Ar–H; CH),
11.35 (s, 1, COOH). Anal. Calc. for C13H11ClN2O2 (262.5):
C 59.42, H 4.19, N 10.66, Cl 13.52. Found: C 59.45, H 4.07,
N 10.84, Cl 13.37 %.
3-(5-(N-methyl-N-(pyridin-2-yl)amino)-)-3-methyl-1-
phenyl-1H-pyrazol-4-yl)propanoic Acid (6b)
Pale yellowish crystals; 75 %; mp 157–1598C (acetone). nmax
(KBr)/cmꢀ1 3054, 2942, 2670, 1724, 1600, 1590, 1440, 1435,
1311, 1263, 760. dH (90 MHz, CDCl3) 2.45 (3H, s, N-CH3), 2.60
(2H, t, J 6, CH2), 2.75 (3H, s, CH3), 2.95 (2H, t, J 6, CH2),
6.40–7.95 (9H, m, Ar–H), 10.7 (s, 1, COOH). m/z (EI, 70 eV)
(%), 337 (Mþ þ 1, 14), 336 (Mþ, 44), 317 (20), 291 (100), 275
(32), 361 (52), 259 (41), 246 (10), 233 (20), 214 (12), 205 (12),
182 (74), 179 (25), 169 (86), 105 (13), 92 (7), 78 (6). Anal. Calc.
for C19H20N4O2 (336): C 67.85, H 5.95, N 16.66. Found:
C 67.62, H 6.11, N 16.81 %.
3-(5-Chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)-2-
methylacrylic Acid (4b)
Pale yellow crystals; 83 %; mp 172–1748C (cyclohexane).
nmax (KBr)/cmꢀ1 3084, 2965, 2625, 1700, 1580, 1455, 1440,
1365, 1245, 1080, 749. dH (90 MHz, CDCl3) 1.90 (3H, s, CH3),
2.75 (3H, s, CH3), 6.30–7.75 (6H, m, Ar–H, ¼CH), 10.9 (s, 1,
COOH). Anal. Calc. for C14H13ClN2O2 (276.5): C 60.75, H 4.70,
N 10.12, Cl 12.83. Found: C 60.44, H 4.93, N 10.23, Cl 12.64 %.
General Procedure for Reduction of Acids 4a, b
A solution of acid 4a or b (10 mmol) in NaOH solution (15 mL,
1 N) was treated with sodium amalgam (25 g, 2.5 %) in small
portions over a period of 20 min with vigorous stirring. The
reaction mixture was stirred for an additional 3 h at room tem-
perature and then the mercury was separated, washed with
water, and the washings were added to the main solution. The
whole solution was acidified with concentrated HCl (10 mL)
and the crude acid 5a or 5b was filtered, washed, and dried.
Yields and spectral data are given in the following.
3-(5-(N-benzyl-N-methylamino)-3-methyl-1-phenyl-
1H-pyrazol-4-yl)propanoic Acid (6c)
White crystals; 68 %; mp 184–1868C (ethanol). nmax (KBr)/
cmꢀ1 3020, 2972, 2560, 1720, 1605, 1590, 1455, 1445, 1365,
1230, 765. dH (90 MHz, CDCl3) 2.35 (3H, s, N-CH3), 2.50 (2H, t,
J 6, CH2), 2.70 (3H, s, CH3), 2.85 (2H, t, J 6, CH2), 6.40–7.95
(10H, m, Ar–H), 11.4 (s, 1, COOH). m/z (EI, 70 eV) (%), 351
(Mþ þ 2, 4), 350 (Mþ þ 1, 14), 349 (Mþ, 38), 332 (10), 304
(100), 289 (64), 274 (33), 260 (68), 246 (13), 227 (41), 206 (11),
199 (26), 191 (29), 181 (50), 178 (14), 168 (77), 105 (22),
91 (35), 78 (9). Anal. Calc. for C21H23N3O2 (349): C 72.20, H
6.59, N 12.03. Found: C 72.25, H 6.63, N 12.27 %.
3-(5-Chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)
propanoic Acid (5a)
Pale yellow crystals; 90 %; mp 167–1688C (benzene). nmax
(KBr)/cmꢀ1 3046, 2990, 2520, 1725, 1605, 1585, 1450, 1435,
1365, 1280, 1070, 760. dH (90 MHz, CDCl3) 2.55 (2H, t, J 6,
CH2), 2.70 (3H, s, CH3), 2.80 (2H, t, J 6, CH2), 6.30–7.75 (5H,
m, Ar–H), 11.3 (s, 1, COOH). Anal. Calc. for C13H13ClN2O2
(264.5): C 58.97, H 4.91, N 10.58, Cl 13.42. Found: C 58.79, H
4.82, N 10.35, Cl 13.20 %.
2-((5-(N-methyl-N-phenylamino)-3-methyl-1-phenyl-
1H-pyrazol-4-yl)methyl)propanoic Acid (6d)
Pale yellow needles; 84 %; mp 144–1468C (acetone). nmax
(KBr)/cmꢀ1 3045, 2970, 2630, 1735, 1595, 1570, 1455, 1440,
1336, 1020, 745. dH (90 MHz, CDCl3) 1.10 (3H, d, J 7.5, CH3),
2.50–2.95 (3H, m, CH–CH2), 2.60 (3H, s, N-CH3), 2.75 (3H, s,
CH3), 6.40–7.75 (10H, m, Ar–H), 11.0 (s, 1, COOH). m/z
(EI, 70 eV) (%), 350 (Mþ þ 1, 8), 349 (Mþ, 42), 332 (26), 304
(100), 289 (52), 288 (14), 274 (17), 358 (82), 261 (32), 246 (21),
227 (44), 206 (16), 198 (42), 191 (17), 180 (64), 179 (10), 167
(65), 104 (14), 90 (14), 78 (4). Anal. Calc. for C21H23N3O2 (349):
C 72.20, H 6.59, N 12.03. Found: C 72.35, H 6.38, N 12.12 %.
2-((5-Chloro-3-methyl-1-phenyl-1H-pyrazol-4-yl)
methyl)propanoic Acid (5b)
White crystals; 83 %; mp 155–1578C (ethanol). nmax (KBr)/
cmꢀ1 3035, 2952, 2610, 1718, 1600, 1578, 1450, 1445, 1370,
1035, 749. dH (90 MHz, CDCl3) 1.10 (3H, d, J 7.5, CH3),

Friedel–Crafts Chemistry
G
2-(5-(N-methyl-N-(pyridin-2-yl)amino)-)-3-methyl-1-
phenyl-1H-pyrazol-4-yl)methyl)propanoic Acid (6e)
Ar, C-6), 119.8 (1C, Ar, C-4a), 123.2 (2C, Ar, C-20, C-60), 129.3
(1C, Ar, C-40), 133.4 (2C, Ar, C-30, C-50), 141.0 (1C, Ar, C-5),
142.7 (1C, Ar, C-10), 148.5 (1C, C-9a), 151.8 (1C, C-3), 155.6
(1C, Ar, C-7), 167.5 (1C, Ar, C-8a), 188.2 (1C, C¼O, C-4). m/z
(EI, 70 eV) (%), 290 (Mþ þ 1, 17), 289 (Mþ, 100), 274 (53), 261
(42), 259 (27), 212 (15), 205 (32), 182 (54), 167 (72), 139 (15),
105 (8), 90 (20), 76 (9). Anal. Calc. for C17H14N4O (290):
C 70.34, H 4.82, N 19.31. Found: C 70.52, H 4.83, N 19.35 %.
Greenish crystals; 82 %; mp 110–1128C (benzene). nmax
(KBr)/cmꢀ1 3020, 2955, 2595, 1720, 1605, 1596, 1455, 1440,
1355, 1035, 755. dH (90 MHz, CDCl3) 1.10 (3H, d, J 7.5, CH3),
2.45 (3H, s, N-CH3), 2.50–2.95 (3H, m, CH–CH2), 2.70 (3H, s,
CH3), 6.45–7.75 (9H, m, Ar–H), 10.8 (s, 1, COOH). m/z
(EI, 70 eV) (%), 350 (Mþ, 48), 349 (15), 333 (14), 305 (100),
290 (25), 275 (24), 273 (12), 261 (64), 228 (56), 205 (20),
199 (17), 190 (12), 181 (72), 179 (14), 167 (81), 106 (21),
90 (10), 78 (12). Anal. Calc. for C20H22N4O2 (350): C 68.54,
H 6.28, N 16.00. Found: C 68.72, H 6.04, N 15.82 %.
3,10-Dimethyl-4,9-dihydro-1-phenyl-benzo[e]pyrazolo
[3,4-b]azepin-4(10H)-one (7c)
Amber crystals; 78 %; mp 164–1668C (benzene). nmax (KBr)/
cmꢀ1 3063, 2960, 1702, 1595, 1473, 1440, 1385, 1266, 1132,
1075, 745. dH (90 MHz, CDCl3) 2.50 (3H, s, CH3), 2.75 (3H, s,
CH3), 4.20 (2H, s, CH2), 6.45–7.40 (8H, m, Ar–H). dC
(100 MHz, CDCl3) 17.2 (1C, –CH3), 42.7 (1C, N-CH3), 60.3
(1C, –CH2–, C-9), 106.6 (1C, C-3a), 123.2 (2C, Ar, C-20, C-60),
129.3 (2C, Ar, C-4a, C-40), 130.2 (1C, Ar, C-6), 132.1 (1C, Ar,
C-8), 133.4 (2C, Ar, C-30, C-50), 134.5 (1C, Ar, C-5), 137.5
(2C, Ar, C-7, C-8a), 142.7 (1C, Ar, C-10), 150.8 (1C, C-3), 154.4
(1C, C-10a), 190.6 (1C, C¼O, C-4). m/z (EI, 70 eV) (%), 304
(Mþ þ 1, 22), 303 (Mþ, 100), 288 (19), 275 (37), 273 (12), 260
(61), 245 (20), 226 (12), 211 (7), 182 (70), 168 (84), 151 (22),
106 (10), 91 (12), 78 (7). Anal. Calc. for C19H17N3O (303):
C 75.24, H 5.61, N 13.86. Found: C 75.37, H 5.49, N 13.62 %.
2-((5-(N-benzyl-N-methylamino)-3-methyl-1-phenyl-
1H-pyrazol-4-yl)methyl)propanoic Acid (6f)
Yellow crystals; 65 %; mp 128–1308C (benzene). nmax
(KBr)/cmꢀ1 3010, 2940, 2517, 1722, 1595, 1584, 1460, 1440,
1335, 1265, 1020, 745. dH (90 MHz, CDCl3) 1.15 (3H, d, J 7.5,
CH3), 2.40 (3H, s, N-CH3), 2.50–3.10 (3H, m, CH–CH2), 2.75
(3H, s, CH3), 4.20 (2H, s, CH2), 6.35–7.70 (10H, m, Ar–H), 10.8
(s, 1, COOH). m/z (EI, 70 eV) (%), 363 (Mþ, 27), 346 (23), 318
(100), 303 (44), 288 (21), 274 (26), 260 (39), 241 (15), 227 (36),
205 (11), 198 (27), 180 (60), 179 (11), 168 (62), 105 (13),
91 (26), 78 (14). Anal. Calc. for C22H25N3O2 (363): C 72.72,
H 6.88, N 11.57. Found: C 72.78, H 6.65, N 11.81 %.
3,11-Dimethyl-4,5,6-trihydro-1-phenyl-benzo[g]
pyrazolo[3,4-b]azocin-6(11H)-one (8a)
Friedel–Crafts Cycliacylation Procedures
Early procedures[34,35] describing ring closure of heteroaryl
acids with AlCl3/CH3NO2 or P2O5 or PPA were followed. In all
reactions, the crude solid products were purified by flash column
chromatography (basic alumina, EtOAc/n-hexane 3 : 1) and
following crystallization from an appropriate solvent, gave
the pure products 7a–c and 8a–f. The conditions and yields for
the tricyclic products are shown in Tables 1 and 2, whereas the
physical constants and spectral data are given in the following.
Yellow crystals; 88%; mp 158–1608C (acetone). nmax (KBr)/
cmꢀ1 3020, 2985, 1735, 1600, 1584, 1459, 1443, 1375, 1270,
1135, 755. dH (400MHz, CDCl3)2.53(3H, s,N-CH3),2.62(2H,t,
J 7.5, CH2), 2.74 (3H, s, CH3), 2.93 (2H, t, J 7.5, CH2), 6.52–7.43
(9H, m, Ar–H). dC (100MHz, CDCl3) 16.5 (1C, –CH3), 19.3
(1C, –CH2–, C-4), 46.2 (1C, –CH2–, C-5), 48.0 (1C, N-CH3),
109.1 (1C, C-3a), 115.4 (1C, Ar, C-10), 118.4 (1C, Ar, C-6a),
121.1 (1C, Ar, C-8), 124.2 (2C, Ar, C-20, C-60), 130.3 (1C, Ar,
C-40), 133.4 (2C, Ar, C-30, C-50), 134.6 (1C, Ar, C-7), 137.0
(1C, Ar, C-9), 142.7 (1C, Ar, C-10), 147.3 (1C, Ar, C-10a),
151.3 (1C, C-3), 157.0 (1C, C-11a), 205.4 (1C, C¼O, C-6). m/z
(EI, 70eV) (%), 319 (Mþ þ 2, 5), 318 (Mþ þ 1, 18), 317
(Mþ, 100), 289 (25), 275 (42), 273 (10), 261 (68), 246 (14), 231
(19), 212 (13), 181 (84), 167 (91), 150 (16), 105 (14), 90 (10), 77
(5). Anal. Calc. for C20H19N3O (317): C 75.70, H 5.99, N 13.24.
Found: C 75.72, H 5.81, N 13.34 %.
3,9-Dimethyl-1-phenyl-1H-pyrazolo[3,4-b]quinolin-4
(9H)-one (7a)
Yellow crystals; 82 %; mp 228–2308C (benzene). nmax
(KBr)/cmꢀ1 3030, 2985, 1685, 1585, 1470, 1450, 1374, 1265,
1149, 1073, 746. dH (90 MHz, CDCl3) 2.55 (3H, s, CH3), 2.85
(3H, s, CH3), 6.55–7.40 (9H, m, Ar–H). dC (100 MHz, CDCl3)
16.0 (1C, –CH3), 46.7 (1C, N-CH3), 108.6 (1C, C-3a), 114.6
(1C, Ar, C-4a), 116.6 (1C, Ar, C-8), 120.3 (1C, Ar, C-6), 123.2
(2C, Ar, C-20, C-60), 129.3 (1C, Ar, C-40), 132.4 (2C, Ar, C-30,
C-50), 133.5 (1C, Ar, C-5), 136.5 (1C, Ar, C-7), 141.7 (1C, Ar,
C-10), 147.2 (1C, Ar, C-8a), 149.5 (1C, C-9a), 150.8 (1C, C-3),
185.2 (1C, C¼O, C-4). m/z (EI, 70 eV) (%), 290 (Mþ þ 1, 17),
289 (Mþ, 100), 274 (53), 261 (42), 259 (27), 212 (15), 205 (32),
182 (54), 167 (72), 139 (15), 105 (8), 90 (20), 76 (9). Anal. Calc.
for C18H15N3O (289): C 74.74, H 5.19, N 14.53. Found: C 74.82,
H 5.23, N 14.44 %.
3,11-Dimethyl-4,5,6-trihydro-1-phenyl-1H-pyrazolo
[3,4-b]pyrido[3,2-g]azocin-6(11H)-one (8b)
Yellow crystals; 80%; mp 210–2128C (ethanol). nmax (KBr)/
cmꢀ1 3055, 2958, 1740, 1600, 1485, 1440, 1373, 1265, 1134,
1082, 747. dH (400MHz, CDCl3) 2.42(3H, s, N-CH3), 2.71(2H, t,
J 6.2, CH2), 2.73 (3H, s, CH3), 2.84 (2H, t, J 6.2, CH2), 6.52–7.39
(8H, m, Ar–H). dC (100MHz, CDCl3) 16.1 (1C, –CH3), 18.4
(1C, –CH2–, C-4), 45.9 (1C, –CH2–, C-5), 47.0 (1C, N-CH3),
108.1 (1C, C-3a), 115.2(1C, Ar, C-8), 122.5 (1C, Ar, C-6a), 125.2
(2C, Ar, C-20, C-60), 128.3 (1C, Ar, C-40), 132.4 (2C, Ar, C-30,
C-50), 140.5 (1C, Ar, C-7), 141.7 (1C, Ar, C-10), 149.3 (1C, C-3),
151.2(1C, Ar, C-9), 152.0(1C, Ar, C-11a), 167.6(1C, Ar, C-10a),
200.4(1C,C¼O,C-6). m/z(EI,70eV)(%), 319(Mþ þ 1,12),318
(Mþ, 100), 290 (38), 275 (14), 273 (12), 260 (42), 245 (34), 213
(34), 180 (69), 168 (63), 152 (10), 105 (22), 91 (14), 77 (9). Anal.
Calc. for C19H18N4O (318): C 71.69, H 5.66, N 17.61. Found:
C 71.62, H 5.52, N 17.74 %.
3,9-Dimethyl-1-phenyl-1H-pyrazolo[3,4-b]
[1,8]naphthyridin-4(9H)-one (7b)
Pale green plates; 85 %; mp 184–1868C (cyclohexane). nmax
(KBr)/cmꢀ1 3065, 2940, 1690, 1605, 1590, 1475, 1440, 1380,
1270, 1130, 750. dH (90 MHz, CDCl3) 2.50 (3H, s, CH3), 2.75
(3H, s, CH3), 6.50–7.55 (8H, m, Ar–H). dC (100 MHz, CDCl3)
16.4 (1C, –CH3), 46.7 (1C, N-CH3), 109.6 (1C, C-3a), 116.9 (1C,

H
H. A. K. Abd El-Aal and A. A. Khalaf
3,12-Dimethyl-4,5,6,11-tetrahydro-1-phenyl-benzo[g]
pyrazolo[3,4-b]azonin-6(12H)-one (8c)
1270, 1130, 759. dH (400 MHz, CDCl3) 1.26 (3H, d, J 6.2, CH3),
2.44 (3H, s, N-CH3), 2.51 (1Ha, app. t, J 6.3, CH2), 2.73 (3H, s,
CH3), 2.84 (1Hb, t, J 6.0, CH2), 3.58 (2H, m, CH), 6.38–7.44
(9H, m, Ar–H). dC (100 MHz, CDCl3) 15.3 (1C, –CH3), 18.7
(1C, –CH2–, C-4), 20.5 (1C, (C-5–CH3), 44.6 (1C, N-CH3), 49.9
(1C, C-5), 62.6 (1C, –CH2–, C-11), 110.3 (1C, C-3a), 123.2
(2C, Ar, C-20, C-60), 129.3 (1C, Ar, C-40), 130.0 (2C, Ar, C-8,
C-10), 131.6 (1C, Ar, C-7), 133.4 (2C, Ar, C-30, C-50), 135.4
(1C, Ar, C-10a), 137.0 (2C, Ar, C-9, C-6a), 142.7 (1C, Ar, C-10),
152.3 (1C, C-3), 155.5 (1C, C-12a), 202.0 (1C, C¼O, C-6). m/z
(EI, 70 eV) (%), 346 (Mþ þ 1, 24), 345 (Mþ, 51), 344 (100), 317
(42), 302 (12), 287 (31), 272 (48), 268 (54), 253 (17), 240 (20),
224 (9), 181 (45), 169 (39), 152 (20), 105 (14), 91 (9), 77 (8).
Anal. Calc. for C22H23N3O (345), C 76.52, H 6.66, N 12.17.
Found: C 76.48, H 6.72, N, 12.30 %.
Yellow plates; 86 %; mp 140–1428C (cyclohexane). nmax
(KBr)/cmꢀ1 3065, 2940, 1742, 1605, 1590, 1475, 1440, 1383,
1270, 1135, 750. dH (400 MHz, CDCl3) 2.45 (3H, s, N-CH3),
2.71 (2H, t, J 7.5, CH2), 2.78 (3H, s, CH3), 2.98 (2H, t, J 7.5,
CH2), 4.24 (2H, s, CH2), 6.42–7.48 (9H, m, Ar–H). dC
(100 MHz, CDCl3) 12.2 (1C, –CH2–, C-4), 15.3 (1C, –CH3),
43.6 (1C, N-CH3), 45.5 (1C, –CH2–, C-5), 62.6 (1C, –CH2–,
C-11), 106.1 (1C, C-3a), 123.2 (2C, Ar, C-20, C-60), 129.3 (1C,
Ar, C-40), 130.4 (2C, Ar, C-8, C-10), 131.6 (1C, Ar, C-7), 132.4
(2C, Ar, C-30, C-50), 134.4 (1C, Ar, C-10a), 137.0 (2C, Ar, C-9,
C-6a), 142.7 (1C, Ar, C-10), 149.3 (1C, C-3), 152.4 (1C, C-12a),
202.5 (1C, C¼O, C-6). m/z (EI, 70 eV) (%), 332 (Mþ þ 1, 9),
331 (Mþ, 100), 303 (42), 288 (23), 273 (40), 260 (14), 245 (12),
225 (52), 211 (25), 181 (57), 168 (82), 150 (12), 104 (15), 90
(10), 77 (4). Anal. Calc. for C21H21N3O (331): C 76.13, H 6.34,
N 12.68. Found: C 76.20, H 6.25, N 12. 81 %.
Acknowledgements
The authors are grateful for the financial support and all the facilities while
performing and writing this work from the Chemistry Department, Faculty
of Science, Assiut University, Assiut, Egypt.
3,5,11-Trimethyl-4,5,6-trihydro-1-phenyl-benzo[g]
pyrazolo[3,4-b]azocin-6(11H)-one (8d)
Yellow crystals; 82 %; mp 184–1868C (acetone). nmax
(KBr)/cmꢀ1 3040, 2963, 1744, 1595, 1485, 1440, 1380, 1275,
1122, 1064, 755. dH (400 MHz, CDCl3) 1.24 (3H, d, J 6.3, CH3),
2.42 (1Ha, app. q, J 6.4, CH2), 2.62 (3H, s, N-CH3), 2.75 (3H, s,
CH3), 2.81 (1Hb, t, J 6.2, CH2), 3.61 (2H, m, CH), 6.44–7.50
(9H, m, Ar–H). dC (100 MHz, CDCl3) 17.4 (1C, –CH3), 21.5
(1C, (C-5–CH3), 25.2 (1C, –CH2–, C-4), 47.0 (1C, N-CH3), 52.6
(1C, C-5), 110.3 (1C, C-3a), 116.4 (1C, Ar, C-10), 117.4
(1C, Ar, C-6a), 120.1 (1C, Ar, C-8), 124.2 (2C, Ar, C-20,
C-60), 129.3 (1C, Ar, C-40), 130.4 (2C, Ar, C-30, C-50), 131.6
(1C, Ar, C-7), 137.0 (1C, Ar, C-9), 142.7 (1C, Ar, C-10), 146.3
(1C, Ar, C-10a), 149.3 (1C, C-3), 153.0 (1C, C-11a), 212.4
(1C, C¼O, C-6). m/z (EI, 70 eV) (%), 331 (Mþ, 29), 330 (100),
304 (37), 288 (15), 275 (20), 259 (52), 245 (16), 228 (33), 211
(15), 180 (27), 168 (74), 151 (10), 105 (12), 91 (18), 78 (7). Anal.
Calc. for C21H21N3O (331): C 76.13, H 6.34, N 12.60. Found:
C 76.30, H 6.29, N 12.52 %.
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