Fused quinoline heterocycles VIII. Synthesis of polyfunctionally substituted pyrazolo[4,3-c]quinolin-4(5H)-ones

Article abstract of DOI:10.3184/030823408X392198

Reaction of 2,4-dichloroquinoline-3-carbonitrile (1) with 4-methylpiperidine gave 2-chloro-4-(4-methylpiperidin-1-yl)quinoline-3- carbonitrile (2). Acid hydrolysis of 2 afforded the corresponding 2-quinolinones 3, which were /v-alkylated in DMF to form th

Full text of DOI:10.3184/030823408X392198

JOURNAL OF CHEMICAL RESEARCH 2008
DECEMBER, 735-737
RESEARCH PAPER 735
Fused quinoline heterocycles VIII. Synthesis of polyfunctionally
substituted pyrazol o[4,3-c]quinol in-4(5H)-ones
Ramadan Ahmed Mekheimera*, Saeed M. Refaeya, Kamal Usef Sadeka,
Afaf Mohamed Abdel Hameeda, Mohamed Ashry Ibrahima and Anamik Shahb
aDepartment of Chemistry, Faculty of Science, EI-Minia University, EI-Minia 61519, Egypt
bDepartment of Chemistry, Saurashtra University, Rajkot-360 005, India
Reaction of 2,4-dichloroquinoline-3-carbonitrile
1-yl)quinoline-3-carbonitrile (2). Acid hydrolysis of 2 afforded the corresponding
N-alkylated in DMF to form the 1-methyl, -ethyl and -phenacyl quinolinones 6a-c. Fusion of 6a-c with hydrazine
(1) with 4-methylpiperidine
gave 2-chloro-4-(4-methylpiperidin-
2-quinolinones 3, which were
hydrate gave the 3-aminopyrazolo[4,3-c]quinolin-4-ones
azide afforded the novel 3-azidopyrazolo[4,3-c]quinolin-4-ones
8a-c. Diazotisation of 8a,b followed by reaction with sodium
9a,b.
Keywords: fused pyrazoles, quinolines, azides
The pyrazolo[ 4,3-c]quinoline skeleton is one of the
'privileged medicinal scaffolds' that show a wide rang of
pharmacological activities because of their benzodiazepine
receptor affinity and activity as immunomodulating drugs.l-4
3-Methylamino-5-propyl-IH-pyrazolo[ 4,3-c ]quinolin-4(5H)-
one has been reported to show significant activity as an anti-
inflammatory and liver protective agent. 5 More recently,
pyrazolo[4,3-c]quinoline-4-one has been identified as a novel
pharmacophore for selective cyclooxygenase-2 (COX-2)
inhibitors that could reduce pain and inflammation without
affecting the cytoprotective action of cyclooxygenase-l
(COX-I), the site of action for all the classical NSAIDS.6
Organic azides are well known as compounds with a high
level of biological activity and have proved valuable in
the treatment of cardiovascular diseases.7 Recently, some
heterocyclic azides have been synthesised as antithrombotic
and blood pressure lowering agents.8 Furthermore, they are
versatile synthetic intermediates, presenting a broad range of
chemical reactivity.9
l-phenyl-IH-pyrazole-4-carboxylate.1O
involves the thermal or acid-catalysed rearrangements
of pyrazoloindoles.l l Kappe et al.12 have prepared
pyrazolo[4,3-c]quinolin-4-one derivatives by the action of
hydrazines on 3-acyl-4-hydroxyquinolin-2-ones.
Another
method
Results and discussion
A few years ago we started a medicinal chemistry project aimed
atthe synthesis and thepharmacological study ofnew substituted
pyrazolo[ 4,3-c]quinolines.13-17As an extension ofthis research,
we report here a new, efficient and convenient procedure
for the synthesis of hitherto unreported pyrazolo[4,3-c]
quinolin-4-one derivatives which are often difficult to
obtain by other routes, using the conveniently available 2,
4-dicWoroquinoline-3-carbonitrile (1)18 as starting material.
Kinetic studies have shown that the chlorine atom in the
4-position of 1 is about twice as reactive towards nucleophiles
as that at the 2-position.19 Consequently, the reactive cWorine
atom in position 4 oft can readily be displaced by nucleophiles.
Thus, compound 1 was reacted with 4-methylpiperidine in
order to obtain the required key intermediate 3 for subsequent
pyrazole ring closure. (Scheme I)
A survey of the literature revealed that only few synthetic
routes have so far been reported for the synthesis of
pyrazolo[4,3-c]quinolin-4-ones. One of these is based on
the catalytic reduction of ethyl 3-methyl-5-(2-nitrophenyl)-
N
J;::.::::::J' Me
N
J;::.::::::J' Me
CI
ro
o
CN
cx)~CN
a
cx)~CN
b
~CN
•... I ~
CI
-
~ I I
•... I ~
-
CI
'"""
N
vN".lo
'"""
N
N
H
N,..........-'\
~Me
H
2
3
4
N
J;::.::::::J' Me
? "
~
N3
? "
~
NH2
HN
~+CN
cC
~
l
HN cC
~
l
I
~
I
-
~
N
0
(8a,b)
~
N
0
VN~O
I
\
I
R
R
R
7
8a-c
6a-c
9a,b
5-8: a, R = CH3' X = I
Reagents: a, 4-methylpiperidine, DMF, R.T.; b, H20/AcOH, 1'.;
b,
R
=
=
C2H5'
X
=
I
c, R-X (5a-c)/DMF/K2C03;
d, N2H4, 1'.; e, 1) HN02, 2) NaN3/H20
c, R
C6H5COCH2,
X
=
Br
Scheme
1
* Correspondent. E-mail: rmekh@yahoo.com

736 JOURNAL OF CHEMICAL RESEARCH 2008
Reaction of 1 with an excess of 4-methylpiperidine in DMF
solution at room temperature formed the expected kinetically
more favoured product, 2-chloro-4-(4-methylpiperidin-
l-yl)quinoline-3-carbonitrile (2), rather than the isomeric
the uncyclised azide forms are known to predominate.25-3o
Work is currently under way to prepare a new generation
of novel heterocyclic compounds containing the quinoline
ring, utilising 2,4-dichloroquinoline-3-carbonitrile as starting
material.
4-chloro-2-( 4-methylpiperidin-l-yl)
compound. This was
established by its acid hydrolysis in aqueous acetic acid,
resulting in the corresponding 4-(4-methylpiperidin-l-yl)-2-
Experimental
oxo-l,2-dihydroquinoline-3-carbonitrile
(3). The isomeric
Melting points were measured on
a Gallenkamp melting
quinolin-4-one structure 4 could be excluded because the IR
spectrum showed significantly an amide carbonyl function
at 1640 cm-I.20,2I4-Quinolinones generally have carbonyl
absorptions below 1600 cm-I.22-24Alkylation of 3 with
alkyl halides 5a-c in the presence of K 2C03 afforded the
N-substituted derivatives 6a-c. The structures ofthese products
6a-c were supported by their IR, NMR and mass spectra, and
elemental analysis. The IR spectra showed the absence of
NH absorption at 3298 cm-I. Their IH NMR spectra revealed
the presence of the N-alkyl protons in addition to signals
from the remainder of the molecules. Additionally, their
structures were supported by the 13CNMR and mass spectra,
which were all compatible with the assigned structures (see
Experimental).
point apparatus. IR spectra were recorded on a Shimadzu 470
spectrophotometer(KBr pellets). IH and BC NMR spectra were
recordedon a Bruker-AvanceII (400 MHz for IH and 100MHz for
BC) spectrometerwith DMSO as solvent and TMS as an intemal
standard. MS were measured on a Shimadzu GCMS-QP 2010
mass spectrometerat 70 eV.Microanalyseswere performedby the
MicroanalyticalData Unit at Cairo University.All reagents were
of commercialquality or were purifiedbefore use, and the organic
solventswere of analyticalgradeor purifiedby standardprocedures.
2-Chloro-4-( 4-methylpiperidin-I-yl)quinoline-3-carbonitrile
(2):
To 2,4-dichloroquinoline-3-carbonitrile(1) (1.50 g, 6.7 mmol) in
DMF (10 ml), 4-methylpiperidine(1.33 g, 13.4 mmol) was added.
The reaction mixture was stirred for 30 min at room temperature
and then poured into water (10 ml). The precipitatedsolid product
was isolatedby filtrationand recrystallisedfrom EtOH to give 2 as
yellowish crystals; (1.85 g, 96%); m.p. 177-178°C. IR: vrnax 3050
(arom CH); 2928, 2850 (aliph CH), 2210 (CN) em-I. IH NMR: B
H
We next investigated the reaction of 6a-c with hydrazine
hydrate in the hope of obtaining the novel pyrazolo[4,3-c]
quinolin-4-ones 8a-c. Indeed, it was found that refluxing the
quinolinones 6a-c with an excess ofhydrazine hydrate (80%)
for 12 h afforded the 5-alkyl-3-aminopyrazolo[4,3-c]quinolin-
4-ones 8a-c in good yields. Their structures were confirmed
on the basis of consistent elemental and spectral data. The IR
spectra revealed the absence of cyano absorption at 2210 cm-I,
but absorption bands at 3440-3136 cm-I assignable to NH
and NH2 functions were observed. Furthermore, the IH NMR
spectra showed the absence of the 4-methylpiperidino protons
and the presence of signals for two amino protons at C-3 and
a pyrazole NH proton in addition of signals due to aromatic
and N-alkyl protons in their expected positions. Moreover,
structures 8a-c were supported by correct mass spectra, which
were compatible with assigned structures (see Experimental).
Formation of the pyrazolo[4,3-c]quinolin-4-ones 8a-c can
be rationalised as follows: the 4-methylpiperidino group
at position 4 of compounds 6a-c undergoes a nucleophilic
substitution reaction with one molecule of hydrazine to give
the intermediate 7. Subsequent intramolecular cyclisation via
the attack of the NH2 of the hydrazino group at position 4 on
the nitrile carbon in the intermediate yields the pyrazolo[ 4,3-c]
quinolinones 8a-c.
1.02(d,J = 6.4 Hz, 3H, CH3),1.46(m, 2H, CH2), 1.71(m, lH, CH),
1.76(m, 2H, CH2), 3.50 (m, 2H, CH2), 3.88 (m, 2H, CH2), 7.65 (m,
lH,ArH), 7.86(m, 2H,ArH), 8.04(d,J= 8.5Hz, lH,ArH); Be 21.9
(CH3),30.0(CH),34.6(2CH2), 53.4(2CH2), 95.5(C-3), 116.8(CN),
122.05(C-4a), 125.7, 127.1, 129.0and 133.2(Ar-C), 148.2(C-8a),
149.8(C-2), 162.8(C-4). MS: m/z (%) 287, 285 (M+,36, 100),284
(M+-l, 98), 270 (20), 256 (37), 242 (73), 229 (28), 216 (26), 188
(12), 178(26), 153(54), 126(37),102 (12),75 (10),69 (11),55 (36),
41 (47).Anal: Calcdfor CIJII6ClN3(285.77):C, 67.25;H, 5.64;Cl,
12.41;N, 14.70.Found:C, 67.44;H, 5.78;Cl, 12.26;N, 14.82%.
4-( 4-M ethylpiperidin-I-yl)
carbonitrile (3): The amine 2 (0.5 g, 1.75 mmol) in a mixture of
AcOH(5ml)andH 0 (1ml)wasrefluxedfor3h.Afterconcentration
and coolingto room temperature,the precipitatedsolidproduct was
-2-oxo-I, 2-dihydroquinoline-3-
2
collectedby filtration,washedwellwithH 0, driedandrecrystallised
2
from CHC13to give compound3 as yellow crystals.(0.365g, 78%);
m.p. 304-305°C. IR: vrnax 3298 (NH),3050 (arom.CH),2944, 2848
(aliph CH), 2210 (CN), 1640 (amide CO) em-I. IH NMR: B 1.01
H
(d, J = 6.3 Hz, 3H, CH3), 1.42 (m, 2H, CH2), 1.70 (m, lH, CH),
1.79(m, 2H, CH2), 3.38 (m, 2H, CH2), 3.75 (m, 2H, CH2), 7.22 (t,
J= 7.6Hz, lH,ArH), 7.29(d,J= 8.2Hz, lH,ArH), 7.58(t,J= 7.6Hz,
lH, ArH), 7.72 (d, J
=
8.2 Hz, lH, ArH), 11.77 (s, lH, NH);
Be 21.9 (CH3),30.1 (aliph.CH), 34.5 (2CH2), 52.9 (2CH2), 91.1 (C-
3), 115.65(C-4a), 116.6(CN), 117.3, 122.0, 126.25and 133.0(Ar-
C), 140.0(C-8a), 160.9(C-4), 164.35(CO).MS: m/z (%) 268 (M++
1,21),267 (M+,100),266 (M+-l, 82),252 (10),238 (31),224 (42),
211 (26), 196 (34), 170 (47), 155 (9), 141 (28), 114 (25), 98 (70),
55 (37),41 (37).Anal: Calcd for CI6H17N30(267.30):C, 71.89;H,
6.41;N,15.72.Found:C, 71.78;H, 6.34;N, 15.89%.
The introduction of the azido group into the pyrazolo[4,3-c]
quinolin-4-ones 8 was next investigated. The reaction of
compounds 8a,b with sodium nitrite in 70% aqueous H2S04 at
-5°C followed by reaction of the non-isolated diazonium salt
with aqueous sodium azide gave the previously unreported
3-azidopyrazoloquinolines 9a,b. The compounds 9a,b, to the
best of our knowledge, are the first examples of the 3-azido-
I-Alkyl-I, 2-dihydro-4-( 4-methylpiperidin-I- yl)- 2-oxoquinoline-3-
carbonitriles 6a-c, general procedure
Toa solutionofthequnolinone3 (0.20g,0.75mmole)inDMF (5ml),
anhydrous K C03 (0.311 g, 2.25 mmole) was added and then the
2
reaction mixture was stirred for one hour at room temperature.
The alkyl halide 5a,b (1.5 mmole) was added and the reaction
mixturewas stirredat room temperaturefor 25 h. It was thenpoured
pyrazolo[4,3-c]quinolin-4-one
system. The IR spectra
displayed no amino group absorption (NH2) but an absorption
band for the N3 group was observed at 2130 cm-I. The IH
NMR spectra revealed no amino protons (NH2) and the
presence of a singlet at 8 ca 13.96 ppm, assignable to the
pyrazole NH. In addition, signals due to alkyl and aromatic
protons were observed in their expected positions. Structures
9a,b are also consistent with their 13CNMR and mass spectra
(see Experimental).
In summary: we have established a simple, and efficient
method for the synthesis of the first representatives of the 3-
azido-pyrazolo[ 4,3-c]quinolin-4-ones. Heterocyclic azides,
in particular those with azido-azomethine substructures,
are well known to cyclise spontaneously to give the fused
tetrazole forms, although in certain cases, such as the present,
into coldH
2
0 and acidifiedwith colddil. HClto pH 3. The resulting
0, driedand
solidproductwas collectedby filtration,washedwithH
2
recrystallisedfrom MeOH to give 6a,b. In the case of 6c, phenacyl
bromide (5c) (0.15 g, 0.75 mmole)was used as alkyl halide and the
reaction mixture was stirred at room temperaturefor 52 h. Then it
was workedup as describedfor 6a,b.
I,2-Dihydro-I-methyl-4-( 4-methylpiperidin-I-yl)-2-oxoquinoline-
3-carbonitrile (6a): Yellowishcrystals (0.185 g, 88%), m.p. 208-
209°C. IR: vrnax 3080 (arom. CH), 2928, 2848 (aliph CH), 2224
(CN), 1630 (amide CO) em-I.NMR: ~ 1.01 (d, J = 6.4 Hz, 3H,
CH3), 1.47 (m, 2H, CH2), 1.70 (m, lH, CH), 1.78 (m, 2H, CH2),
3.39 (m, 2H, CH2), 3.55 (s, 3H,N-CH3),3.71 (m, 2H, CH2), 7.32 (t,
J=7.3 Hz, lH,ArH), 7.53(d,J= 8.3Hz, lH,ArH), 7.72(t,J=7.3 Hz,
lH,ArH), 7.72 (d,J= 8.3Hz, lH,ArH); Be 21.9 (CH3),29.7(aliph.
CH), 30.1 (N-CH3),34.4 (2CH2), 52.9 (2CH2), 91.3 (C-3), 115.9
(C-4a), 116.6 (CN), 117.2, 122.2, 126.8 and 133.5 (Ar-C), 140.8

JOURNAL OF CHEMICAL RESEARCH 2008 737
(C-8a), 160.3 (C-4), 163.3 (CO). MS: m/z (%) 282 (M+ + 1,21),281
(M+, 100),266 (11), 252 (26), 238 (36),225 (25), 212 (19), 210 (28),
184 (60),155 (22),128 (14),114 (9), 98 (10), 77 (9), 55 (15),41 (19).
Anal: Ca1cd for C17HI9N30 (281.35): C, 72.57; H, 6.81; N, 14.94.
Found: C, 72.68; H, 6.93; N, 14.88%.
sodium nitrite (0.387 g, 5.61 mmo1) in water (1 m1). To the resulting
solution of the diazonium ion was added sodium azide (0.364 g,
5.61 mmo1) in water (1 m1) and maintained between 0 and -5°C.
Stirring was continued for one h at room temperature. The resulting
solid product was collected by filtration, washed with H20, dried and
recrystallised from CHC13to give the azide 9a,b.
I-Ethyl-l ,2-dihydro-4-( 4-methylpiperidin-I-yl)-2-oxoquinoline-3-
carbonitrile (6b): Yellow crystals (0.197 g, 89%), m.p. 173-175°C.
IR: vrnax 3080 (arom. CH), 2928, 2865 (a1iph CH), 2210 (CN), 1630
(amide CO) cm-I. NMR: BH 1.02 (d,J= 6.4 Hz, 3H, CH3), 1.19 (t,
J= 7 Hz, 3H, CH3), 1.43 (m, 2H, CH2), 1.68 (m, lH, CH), 1.77 (m,
2H, CH2), 3.37 (m, 2H, CH2), 3.70 (m, 2H, CH2), 4.23 (q, J= 7 Hz,
2H, CH2), 7.32 (t, J = 7.6 Hz, lH, ArH), 7.60 (d, J = 8.5 Hz, lH,
ArH), 7.72 (t,J = 7.6 Hz, lH, ArH), 7.83 (d, J = 8.5 Hz, lH, ArH);
Be 12.71 (CH3), 21.86 (CH3), 30.07 (a1iph. CH), 34.43 (2CH2),37.18
(N-CH2), 52.90 (2CH2), 91.44 (C-3), 115.65 (C-4a), 116.86 (CN),
117.20, 122.08, 127.06 and 133.60 (Ar-C), 139.71 (C-8a), 159.88
(C-4), 163.32 (CO). MS: m/z (%) = 296 (M+ + 1, 18),295 (M+, 85),
294 (100), 267 (43), 266 (46),252 (23), 238 (14), 224 (20), 198 (39),
183 (21), 170 (10), 155 (10), 141 (14), 128 (10), 114 (10), 98 (8),77
(7),55 (27),41 (25). Anal: Ca1cd for CIsH21N30 (295.38): C,73.19;
H, 7.17; N, 14.23. Found: C, 73.27; H, 6.95; N, 14.39%.
3-Azido-5-methyl-IH-pyrazolo{ 4,3-c]quinolin-4(5H)-one
(9a):
Colourless crystals (0.396 g, 88%), m.p. 223-224°C (decomp.).
IR: vrnax 3150 (NH), 3020 (arom. CH), 2900 (a1iph. CH), 2130
(N3), 1630 (amide CO) cm-I. NMR: ~ 3.57 (s, 3H, N-CH3), 7.35 (t,
J=7.5 Hz, lH,ArH), 7.53 (d,J= 8.5 Hz, lH,ArH), 7.63 (t,J=7.5 Hz,
lH,ArH), 8.06 (d,J= 8.5 Hz, lH,ArH), 13.95 (s, lH,pyrazole NH);
Be 28.7 (N-CH3), 101.8 (C-3a), 110.7 (C-9a), 116.1, 122.3, 122.6
and 130.8 (Ar-C), 138.9 (C-5a), 142.25 (C-9b), 145.7 (C-3), 156.85
(CO). MS: m/z (%) 241 (M+ + 1,6),240 (M+, 43), 214 (8), 184 (80),
155 (100), 141 (9), 129 (55), 114 (23), 102 (28), 88 (15), 77 (21), 63
(11),51 (14). Anal: Calcd for CllHsN60 (240.22): C, 55.00; H, 3.36;
N, 34.98. Found: C, 54.89; H, 3.49; N, 34.73%.
3-Azido-5-ethyl-1 H-pyrazolo{ 4,3-c]quinolin-4(5H)-one
(9b):
Colourless crystals, (0.290 g, 87%); m.p. 227°C (decomp.). IR: vrnax
3150(NH), 3020 (arom. CH), 2970 (a1iph.CH),2130(N3), 1630 (amide
CO) cm-I. NMR: ~ 1.22 (t,J= 7 Hz, 3H, CH3), 4.28 (q, J= 7 Hz,
2H, CH2), 7.35 (t,J= 7.6 Hz, lH,ArH), 7.62 (m,2H,ArH), 8.10 (d,
J= 8 Hz, lH, ArH), 13.97 (s, lH, pyrazo1e NH); Be 13.0 (CH3), 36.1
(N-CH2), 101.8 (C-3a), 111.0 (C-9a), 116.0, 122.2, 122.9, and 130.9
(Ar-C), 137.8 (C-5a), 142.35 (C-9b), 145.7 (C-3), 156.5 (CO).Ana1:
Ca1cd for C12HION60 (254.25), C, 56.69; H, 3.96; N, 33.05. Found:
C, 56.53; H, 4.08; N, 33.24%.
1,2 -Dihydro-4
- (4 -m ethy lpip eridin-I-yl)
-2 - oxo-l-
phenacylquinoline-3-carbonitrile
(6c): Yellow crystals (0.235 g,
82%), m.p. 243-244°C. IR: vrnax 3090 (arom. CH), 2945, 2848 (a1iph
CH), 2210 (CN) 1689 (CO), 1630 (amide CO) cm-I. NMR: BH 1.02
(d,J= 6.3 Hz, 3H, CH3), 1.46 (m, 2H, CH2), 1.73 (m, lH, CH), 1.82
(m, 2H, CH2), 3.42 (m, 2H, CH2), 3.80 (m, 2H, CH2), 5.86 (s, 2H,
CH2), 7.32 (t, J = 7.6 Hz, lH, ArH), 7.40 (d, J = 8.6 Hz, lH, ArH),
7.62 (t, J= 7.6 Hz, 3H, ArH), 7.75 (t, J= 7.6 Hz, lH, ArH), 7.86 (d,
J= 8.6 Hz, lH,ArH), 8.13 (d,J= 7.6 Hz, 2H,ArH).; Be21.86 (CH3),
30.06 (a1iph. CH), 34.5 (2CH2), 49.4 (N-CH2), 53.1 (2CH2), 90.4
(C-3), 116.2 (C-4a), 116.6 (CN), 117.1, 122.35, 127.1, 128.4, 129.1,
133.5, 134.3 and 134.7 (Ar-C), 140.65 (C-8a), 160.5 (C-4), 163.7
(CO), 193.2 (CO). MS: m/z (%) 386 (M+ + 1, 12),385 (M+, 47), 280
(100), 266 (13), 252 (12), 128 (14), 105 (73), 77 (36), 55 (15),41
(10). Anal: Ca1cd for C24H23N302(385.46): C, 74.78; H, 6.01; N,
10.90. Found: C, 74.93; H, 5.87; N, 11.09%.
Received 4 June 2008; accepted; 10 November 2008
Paper 08/5290 doi:l0.3184/030823408X392198
Published online: 17 December 2008
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(8a-c),
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1984, pp. 511-516.
To a solution of the nitrile 6a-c (0.71 mmo1) in EtOH (5 ml),
hydrazine hydrate (80%) (4.26 mmo1) was added. The reaction
mixture was refluxed for 12 h, until TLC showed the disappearance
of the starting compounds. After concentration and cooling to room
temperature, the resulting solid product was isolated by filtration,
washed with EtOH, dried and recrystallised from EtOH to give the
fused pyrazo1es 8a-c.
3-Amino-5-methyl-IH-pyrazolo{ 4,3-c]quinolin-4(5H)-one
(8a):
Colourless crystals, (0.10 g, 66%), m.p. 296-297°C. IR: vrnax 3552,
3424,3328,3152 (NH, NH2), 2928 (aliph CH), 1640 (amide CO) em-I.
NMR: ~ 3.56 (s, 3H, N-CH3), 5.42 (br s, 2H, NH2), 7.28-8.01 (m, 4H,
ArH), 12.91 (s, lH, pyrazo1eNH). MS: m/z (%) 215 (M+ + 1,29),214
(M+, 100),213 (36), 185 (34), 170 (10),159 (10),142 (10),130 (24),116
(10), 102 (12),89 (18), 77 (16). Anal: Calcd for CllHlON40 (214.22): C,
61.67; H, 4.71; N, 26.15. Found: C, 61.85; H, 4.89; N, 25.97%.
8
9
S. Kota and R. Klaus, Arch. Pharm., 1998,331,207.
R. Castillo, J. Andres and L.R Domingo, Eur. J. Org. Chem., 2005, 4705.
10 S. Dieter, R. Dieter, H. Siegfried, W. Horst and M. Gerhard, Synthesis,
1985,331.
11 D. Boujemaa and S. Mohamed, Tetrahedron, 1989,45,3351.
12 T. Kappe, R. Aigner, M. Joebstl, P. Hohengassner and W. Stadlbauer,
Heterocycl. Commun., 1995, 1, 341.
13 R. Mekheimer, E.Kh. Ahmed and A.F. Khattab, Bull. Chern. Soc. Jpn.,
1993,66,2936.
3-Amino-5-ethyl-IH-pyrazolo{ 4,3-c]quinolin-4(5H)-one
Colourless crystals, (0.117 g, 72%), m.p. 228-229°C. IR: vrnax 3408,
3328,3200,3152 (NH, NH2), 2992, 2928 (a1iph CH), 1630 (amide
(8b):
14 R. Mekheimer, Pharmazie, 1994,49,486.
15 R.A. Mekheimer and T. Kappe. Heterocyclic Commun., 1998,4, 131.
16 R.A. Mekheimer, Synth. Commun., 2001, 31,1971.
17 R.A. Mekheimer, E.Kh. Ahmed, H.A. El-Fahham, L.H. Kamel and
D. Dopp, J. Chem. Res. (S), 2003, 388.
18 R. Mekheimer,J. Chem. Soc., Perkin Trans 1, 1999,2183.
19 W. Steinschifter and W. Stadlbauer, J. Prakt. Chem., 1994,336,311.
20 W. Stadlbauer, Monatsh. Chem., 1986,117,1305.
21 T. Kappe, P.F. Fitz and E. Ziegler, Chem. Ber., 1973,106, 1927.
22 G.M. Coppola and G.E. Hardtmann,J. Heterocycl. Chem., 1981, 18, 917.
23 G.M. Coppola, A.D. Kahle and M. Shapiro, Org. Magn. Reson., 1981,
17,242.
CO) cm-I. NMR: ~ 1.22 (t,J= 7 Hz, 3H, CH3), 4.26 (q, J= 7 Hz,
2H, CH2), 5.42 (br s, 2H, NH2), 7.27-8.03 (m, 4H, ArH), 12.77 (s,
lH, pyrazo1e NH). MS: m/z (%) 229 (M++ 1, 14),228 (M+, 100),227
(31),213 (32),200 (79), 183 (25), 171 (8), 145 (10), 128 (10), 116
(13), 102 (7), 89 (10), 77 (8). Anal: Ca1cd for C12H12N40(228.25):
C, 63.15; H, 5.30; N, 24.55. Found: C, 63.29; H, 5.16; N, 24.68%.
3-Amino-5-phenacyl-IH-pyrazolo{ 4, 3-c]quinolin-4(5H)-one (8c):
Yellowish crystals (0.140 g, 62%). m.p. 281-282°C. IR: vrnax 3440,
3310, 3136 (NH, NH2), 2930 (a1iph CH), 1640 (amide CO) cm-I.
NMR: BH 4.34 (s, 2H, CH2), 5.51 (br s, 2H, NH2), 7.27 (m, 2H,ArH),
7.36 (t, J= 7.6 Hz, 2H, ArH), 7.48 (d, J= 7.5 Hz, 3H, ArH), 7.71
(d, J = 7.8 Hz, lH, ArH), 7.99 (d, J = 7.5 Hz, lH, ArH), 12.75 (s,
lH, pyrazo1e NH). MS: m/z (%) 320 (M+ + 2, 14),214 (100), 213
(95),200 (38),183 (43), 156 (9),130 (15), 116 (12),102 (10),89 (9),
77 (28). Anal: Calcd for CIsHI~402 (318.33): C, 67.91; H, 4.43; N,
17.60. Found: C, 68.02; H, 4.61; N, 17.47%.
24 J.L. Garcia Ruano, C. Pedregal and J.H. Rodriguez, Heterocycles, 1991,
32,2151.
25 J. Elguero, R. Faure, J.P. Galy and E.J. Vincent, Bull. Soc. Chim. Belg.,
1975,84,1189.
26 G.A. Reynolds, J.A. VanAllan and J.F. Tinker, J. Org. Chern., 1959,24,
1205.
27 M. Tisler, Synthesis, 1973, 123.
28 J. Elguero, C. Marzin, A.R. Katritzky and P. Linda, The tautomerism of
heterocycles, Advances in Heterocyclic Chemistry, Suppl., Academic
Press, New York, Vol. 1.,1976.
29 R. Faure, J.P. Galy, E.J. Vmcent, J.P. Fayet, P. Mauret, M.C. Vertut and
J. Elguero, Can. J. Chem., 1977, 55, 1728.
5-Alkyl-3-azido-IH-pyrazolo{ 4,3-c]quinolin-4(5H)-ones 9a,b: General
procedure
A solution of the amine 8a,b (1.87 mmo1) in H2S04 (4 m1, 70%) was
cooled until the temperature of solution was -5°C and treated with
30 M. Kanyalkar and E.C. Coutinho, Tetrahedron, 2000, 56, 8775.