6,8-dibromo-4-chloroquinoline-3-carbaldehyde as a synthon in the development of novel 1,6,8-triaryl-1H-pyrazolo[4,3-c]quinolines

Article abstract of DOI:10.1016/j.tet.2012.10.103

2-Amino-3,5-dibromoacetophenone undergoes Vilsmeier reaction with a phosphoryl chloride-dimethylformamide mixture to afford 6,8-dibromo-4- chloroquinoline-3-carbaldehyde. The latter was reacted with arylhydrazine hydrochlorides in ethanol in the presence

Full text of DOI:10.1016/j.tet.2012.10.103

Tetrahedron 69 (2013) 699e704
Contents lists available at SciVerse ScienceDirect
Tetrahedron
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6,8-Dibromo-4-chloroquinoline-3-carbaldehyde as a synthon in the
development of novel 1,6,8-triaryl-1H-pyrazolo[4,3-c]quinolines
*
Marole M. Maluleka, Malose J. Mphahlele
Department of Chemistry, College of Science, Engineering and Technology, University of South Africa, PO Box 392, Pretoria 0003, South Africa
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 August 2012
Received in revised form 8 October 2012
Accepted 29 October 2012
Available online 15 November 2012
2-Amino-3,5-dibromoacetophenone undergoes Vilsmeier reaction with
a
phosphoryl chlor-
ideedimethylformamide mixture to afford 6,8-dibromo-4-chloroquinoline-3-carbaldehyde. The latter
was reacted with arylhydrazine hydrochlorides in ethanol in the presence of triethylamine to afford the
corresponding arylhydrazone derivatives. These hydrazones were, in turn, cyclized with ethanolic KOH
(5% in ethanol) to afford the corresponding 1-aryl-6,8-dibromo-1H-pyrazolo[4,3-c]quinolines. Suzu-
kieMiyaura cross-coupling of these 1-aryl-6,8-dibromo-1H-pyrazolo[4,3-c]quinolines with arylboronic
acids afforded novel 1,6,8-triaryl-1H-pyrolo[4,3-c]quinolines.
Keywords:
6,8-Dibromo-4-chloroquinoline-3-
carbaldehyde
Ó 2012 Elsevier Ltd. All rights reserved.
N0-[(6,8-Dibromo-4-chloroquinolin-3-yl)
methylene]-2-arylhydrazides
1-Aryl-6,8-dibromo-1H-pyrazolo[4,3-c]
quinolines
SuzukieMiyaura cross-coupling
1,6,8-Triaryl-1H-pyrazolo[4,3-c]quinolines
1. Introduction
alkenyl, or alkynyl) on the fused benzo ring remain surprisingly
unexplored. The arylquinoline moiety, for example, is an important
With their rich biological activity and excellent pharmacological
properties, pyrazolo[4,3-c]quinoline-based compounds have been
the target of a great deal of research.1 Pyrazolo[4,3-c]quinolines are
associated with high affinity benzodiazepine receptor ligands,2,3
selective cyclooxygenase-2 (COX-2) inhibitors,4 anticancer,5 and
anti-inflammatory agents.6 The two main approaches for the syn-
thesis of these systems involve either the annulations of the pyr-
azole onto a quinoline scaffold or annulations of the quinoline ring
onto a pyrazole scaffold.1 Halogenated quinoline precursors such as
2-chloroquinoline-3-carbaldehyde and 2,4-dichloroquinoline-3-
carbaldehyde have received considerable attention as key in-
termediates for various functional group transformation and for
further annulations into pyrazolo derivatives.1,7e10 A few examples
involving modification of 4-chloroquinoline-3-carbaldehyde have
also been reported in the literature, however, these do not involve
annulation.11e13 Although a wide variety of polysubstituted 1H-
pyrazolo[4,3-c]quinolinones and quinoline derivatives have been
reported earlier,1 a thorough literature search revealed that de-
rivatives containing carbon-bearing substituents (alkyl, aryl,
scaffold broadly present in many molecules with a wide array of
biological activity14 and constitute an important structural element
in materials chemistry.15
During our research on the development of novel annulated
quinoline derivatives with potential biological activity,16 we became
interested in the synthesis of pyrazolo[4,3-c]quinoline derivatives
bearing aryl or alkenyl substituents on the fused benzo ring. We
envisioned 6,8-dibromo-4-chloroquinoline-3-carbaldehyde as
a potential candidate for the synthesis of the 6,8-dibromo-
4-chloroquinoline arylhydrazones to serve as precursors for the
requisite 1-aryl-6,8-dibromo-1H-pyrazolo[4,3-c]quinolines. The
1-aryl-6,8-dibromo-1H-pyrazolo[4,3-c]quinolines appeared suit-
able substrates for the synthesis of the requisite polyaryl-1H-pyr-
azolo[4,3-c]quinolines via palladium-catalyzed SuzukieMiyaura
cross-coupling with arylboronic acids as models for Csp2eCsp2
bond formation.
2. Results and discussion
The first task in this investigation was to synthesize the requisite
precursor, 6,8-dibromo-4-chloroquinoline-3-carbaldehyde, from the
known 1-(2-amino-3,5-dibromophenyl)ethanone. The latter has been
* Corresponding author. Tel.: þ27 12 429 8805; fax: þ27 12 429 8549; e-mail
address: mphahmj@unisa.ac.za (M.J. Mphahlele).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.10.103

700
M.M. Maluleka, M.J. Mphahlele / Tetrahedron 69 (2013) 699e704
prepared before as a sole product (83%) from 2-aminoacetophenone
using NaBreoxone in CH3CNeH2O mixture.17 Bheemanapalli et al.
recently reported the synthesis of a compound described as 1-(2-
NHAr
H
Cl
N
N
Cl
O
Br
Br
(i)
H
amino-3,5-dibromophenyl)ethanone (80%) along with
a minor
N
product, 1-(2-amino-3,5-dibromophenyl)-2-bromoethanone, which
was erroneously reported as 1-(2-amino-5-dibromophenyl)etha-
none.18 Since we required significant amounts of 2-amino-3,5-
dibromoacetophenone as starting material for the synthesis of the
Br
Br
2
3a-c
requisite
6,8-dibromo-4-chloroquinoline-3-carbaldehyde,
we
3
Ar
Time
% Yield
employed N-bromosuccinimide (NBS) in a chloroformecarbon tetra-
chloridemixture (3/2,v/v)atroom temperaturefor78 htoafford 1-(2-
amino-3,5-dibromophenyl)ethanone 1 as a single product (90%)
without the need for column chromatographic separation. Its 1H and
13C NMR spectral data were found to compare favorably with the an-
alytical data reported by Lee and co-workers,17 but to differ from
spectral dataof the major product described by Bheemanapalli et al. as
the 1-(2-amino-3,5-dibromophenyl)ethanone.16 The analogous com-
mercially available 2-amino-3,5-dibromobenzaldehyde was pre-
viously subjected to Friedlander reaction with substituted
3a 4-FC6H4-
6 h
80
83
88
3b 4-ClC6H4-
3c 4-MeOC6H4-
12 h
6 h
Scheme 2. Conversion of 2 into 6,8-dibromo-4-chloroquinoline-3-arylhydrazone de-
rivatives 3. Reagents and conditions: (i) Cl$NH3NHAr, NEt3, EtOH, heat, 6e12 h.
carboxaldehyde were previously found to exhibit significant cyto-
toxic activity when tested in vitro.25
cyclohexanones19 and C- -glycosidic ketones,20 to afford novel mul-
b
We took advantage of the known ease of displacement of the 4-
chloro atom on the quinoline framework by heteroatom-containing
(N, O, S) nucleophiles, and subjected the 6,8-dibromo-4-
chloroquinoline arylhydrazones 3 to intramolecular cyclization
with ethanolic potassium hydroxide (5% in ethanol) under reflux
for 3 h. From the cooled mixture, we isolated by simple filtration
the corresponding 1-aryl-6,8-dibromo-1H-pyrazolo[4,3-c]quino-
lines 4 in high yield and purity (Scheme 3). These heteroannulated
derivatives were characterized using a combination of NMR, IR, and
mass spectroscopic techniques and their accurate calculated m/z
values [MHþꢀ35/37] represent closest fit consistent with the
assigned structures.
tifunctional quinoline derivatives. In our case, we required 6,8-
dibromoquinoline bearing a chloro/bromo atom and carbaldehyde
at the 4- and 3-position, respectively, and this compound cannot be
easily accessible via the known classical methods such as Friedlander
or Doebnerevon Miller reactions. The VilsmeiereHaackeArnold re-
action that was initially used for the formylation of carbonyl com-
pounds21 has now evolved into a powerful synthetic tool for the
construction of quinolines22 including the 2/4-chloroquinoline-3-
carbaldehydes.1,7e13,23 Consequently, we subjected compound 1 to
the Vilsmeier reaction conditions with POCl3eDMF mixture under
reflux and isolated the corresponding novel 6,8-dibromo-4-
chloroquinoline-3-carbaldehyde 2 in reasonable yield (Scheme 1).
Ar
NHAr
Cl
N
N
N
N
Br
Br
(i)
H
H
N
Br
Br
3a-c
4a-c
Scheme 1. Preparation of 6,8-dibromo-4-chloroquinoline-3-carbaldehyde 2. Reagents
4
Ar
% Yield
82
and conditions: (i) POCl3, DMF, 60 ꢁC, 4 h.
4a 4-FC6H4-
4b 4-ClC6H4-
89
Compound 2 contains several reactive centers for possible modi-
fication with nucleophilic reagents (Cl or eCHO), metal-catalyzed
cross-coupling reactions (Br and/or Cl), etc. The carbaldehyde moi-
ety of both 2/4-chloroquinoline-3-carbaldehydes has been found to be
more reactive than the CeCl bond toward nucleophilic attack by am-
monia derivatives.1,9,24 The analogous 2-chloro-3-formylquinolines
with hydrazine hydrate/phenylhydrazine hydrochloride in ethanol
under reflux (5/7 h), for example, previouslyafforded pyrrazolo[3,4-d]
quinolines in 44e82%yieldinasingle-potoperation.24 In analogy with
this literature precedent, we subjected 6,8-dibromo-4-chloro-
4c 4-MeOC6H4- 88
Scheme 3. Base-mediated cyclization of 3 to 1-aryl-6,8-dibromo-1H-pyrazolo[4,3-c]
quinolines 4. Reagents and conditions: (i) 5% KOH in EtOH, 80 ꢁC, 3 h.
Bromoquinolines have been of interestforchemists as precursors
for heterocyclic compounds with multifunctionality, giving a wide
variety of compounds through, e.g., couplings26 and metal exchange
reactions.27 The presence of the two bromine atoms in compounds 4
makes them suitable candidates for further transformation through
transition metal-catalyzed cross-coupling reactions to enable ade-
quate diversity on the fused benzo ring. Prompted by the scarcity of
1H-pyrazolo[4,3-c]quinolines bearing aryl or alkenyl substituents
on the fused benzo ring, we decided to explore the reactivity of 4 in
SuzukieMiyaura cross-coupling reactions with arylboronic acids.
While it is possible to control the regioselectivityof SuzukieMiyaura
cross-couplings for dihaloquinolines bearing different halogen
atoms (I vs Br/Cl or Br vs Cl), it is relatively difficult to achieve high
levels of regioselectivity in the case involving derivatives bearing
quinoline-3-carbaldehyde
2
to an arylhydrazine hydro-
chlorideetriethylamine mixture in ethanol under reflux. After 6/12 h
we isolated the corresponding 6,8-dibromo-4-chloroquinoline aryl-
hydrazones 3aec in highyield and purity without the need for column
chromatography (Scheme 2). The prepared products were easily dis-
tinguished from the corresponding precursors by the increased reso-
nances in the aromatic region of their 1H NMR and 13C NMR spectra.
The molecular ion region of the mass spectra of these polyhalogenated
derivatives reveal the presence of the Mþ and Mþ2 peaks in the ratio
3/1 typical for the 35Cl and 37Cl isotopes, thus confirming their
b-
chlorohydrazone nature. The analogous N-[(2-chloroquinolin-3-yl)
methylene]benzohydrazides derived from 2-chloroquinoline-3-

M.M. Maluleka, M.J. Mphahlele / Tetrahedron 69 (2013) 699e704
701
similar halogen atoms.26 It has also been observed that the dibro-
moquinolines undergo Suzuki cross-coupling with less or no se-
lectivity compared to many of the other dibromoheteroaromatics.26
afford products 5ael. In all cases, the products were isolated in
reasonable yield by filtration and purified by recrystallization
without the need for column chromatography.
The
SuzukieMiyaura
cross-coupling
reaction
of
5,7-
dibromoquinoline26 and 8-benzyloxy-5,7-dibromoquinoline28
with arylboronic acids, for example, have been found to occur
without selectivity to afford the corresponding double coupled de-
rivatives. The most common outcome in SuzukieMiyaura cross-
coupling reactions involving dihaloaromatic precursors bearing
similar halogen atoms is exhaustive multiple coupling and an excess
of the arylboronic acid orestercoupling partner is often employed to
drive the reaction to completion.28 Based on the literature pre-
cedence,26,28,29 we subjected 4a to SuzukieMiyaura cross-coupling
with phenylboronic acid (2.5 equiv) using dichlorobis(-
triphenylphosphine)palladium(II) as Pd(0) catalyst source in di-
methyl formamideewater (3/1, v/v) in the presence of K2CO3 as
a base. After18 h weisolatedbycolumnchromatographyonsilica gel
the 1,6,8-triaryl-1H-pyrazolo[4,3-c]quinoline 5a in 40% along with
starting material (Scheme 4). Prolonged reaction time and reduced
yield prompted us to use dichlorobis(triphenylphosphine)
palladium(II)etricyclohexylphosphine catalyst complex in dimethyl
formamideewater (3/1, v/v) in the presence of K2CO3 as a base, and
the reaction was found to be complete after 3 h to afford 5a in 77%
yield (Scheme 4). Reduced reaction time and complete conversion of
the substrate to the products are attributed to addition of tricyclo-
hexylphosphine. Alkylphosphine ligands, are known to coordinate
with palladium and increase its electron density more so than
arylphosphines and, in turn, accelerate the oxidative addition and
reductive elimination steps in the catalytic cycle.30 The cross-
coupling reaction using the PdCl2(PPh3)2ePCy3 catalyst complex
was extended to other derivatives using phenylboronic and
4-fluorophenylboronic acids as well as arylvinylboronic acids to
3. Conclusions
In summary, the results of this investigation present the readily
available 6,8-dibromo-4-chloroquinoline-3-carbaldehyde as a valu-
able precursor for the synthesis of diversely functionalized poly-
substituted and annulated quinoline derivatives through
substitution and metal-catalyzed cross-coupling reactions. Poly-
arylquinoline-based compounds constitute an important compo-
nent in optoelectronic materials31 and thus exhaustive metal-
catalyzed SuzukieMiyaura or Sonogashira cross-coupling of 6,8-
dibromo-4-chloroquinoline-3-carbaldehyde could lead to poly(-
aryl/alkynyl)quinolines with potential photophysical properties.
Since the analogous 1-phenyl-1H-indazole undergoes metal-
catalyzed CeH arylation with haloarenes,32 it is our view that the
1-aryl-1H-pyrazole moiety of systems 5 represents a suitable scaf-
fold for possible metal-catalyzed CeH arylation. Studies are cur-
rently underway in our laboratory to investigate the reactivity,
anticancer, and photophysical properties of the compounds pre-
pared in this investigation.
4. Experimental
4.1. General
Melting points were recorded on a Thermocouple digital
melting point apparatus and are uncorrected. IR spectra were
recorded as powders using a Bruker VERTEX 70 FT-IR Spectrom-
eter with a diamond ATR (attenuated total reflectance) accessory
by using the thin-film method. For column chromatography,
Merck kieselgel 60 (0.063e0.200 mm) was used as stationary
phase. NMR spectra were obtained as CDCl3 or DMSO-d6 solutions
using Varian Mercury 300 MHz NMR spectrometer and the
chemical shifts are quoted relative to the solvent peaks. Low- and
high-resolution mass spectra were recorded at an ionization po-
tential of 70 eV using Micromass Autospec-TOF (double focusing
high resolution) instrument.
Ar
Ar
N
N
N
N
N
N
Ar'
Br
(i)
H
H
Ar'
Br
4a-c
5a-l
5
Ar
Ar
% Yield
4.1.1. Bromination of 2-aminoacetophenone with NBS. Synthesis of 1
5a 4-FC6H4-
5b 4-ClC6H4-
-C6H5
-C6H5
77
69
69
4.1.1.1. 1-(2-Amino-3,5-dibromophenyl)ethanone (1). A stirred
solution of 2-aminoacetophenone (7.50 g, 55.5 mmol) in CHCl3eCCl4
(3/2, v/v, 300 mL) was treated with N-bromosuccinimide (24.69 g,
138.7 mmol). The mixture was stirred at room temperature for 78 h
and then quenched with a saturated solution of NaHCO3 (100 mL).
The aqueous phase was extracted with chloroform (2ꢂ50 mL) and
the combined organic extracts were washed with water (50 mL). The
organic phase was dried over anhydrous MgSO4, filtered, and then
evaporated under reduced pressure to afford 1 as a solid (14.70 g,
90%), mp 124e125 ꢁC (ethanol) (lit. 119e121 ꢁC,14 120e122 ꢁC,15
123e124 ꢁC33); nmax (ATR) 870.3, 1230.3, 1355.0, 1520.6, 1570.0,
5c 4-MeOC6H4- -C6H5
5d 4-FC6H4-
5e 4-ClC6H4-
4-FC6H4-
4-FC6H4-
71
68
5f 4-MeOC6H4- 4-FC6H4-
60
72
70
81
5g 4-FC6H4-
5h 4-ClC6H4-
4-FC6H4CH=CH-
4-FC6H4CH=CH-
1599.2, 1646.1, 3411.7 cmꢀ1
; dH (300 MHz, CDCl3) 2.57 (s, 3H), 6.90
(br s, 2H), 7.68 (d, J 2.1 Hz, 1H), 7.79 (d, J 2.1 Hz, 1H); dC (75 MHz,
CDCl3) 27.9, 105.8, 111.7, 119.6, 133.7, 139.2, 146.3, 199.1.
5i 4-MeOC6H4- 4-FC6H4CH=CH-
5j 4-FC6H4-
5k 4-ClC6H4-
4-MeOC6H4CH=CH- 65
4-MeOC6H4CH=CH- 82
4.1.2. Vilsmeier reaction of 1 with POCl3/DMF mixture. Synthesis of 2
4.1.2.1. 6,8-Dibromo-4-chloroquinoline-3-carbaldehyde
(2). A
two-necked flask equipped with a stirrer, condenser, and rubber
septum was charged with dry DMF (30 mL) at 0 ꢁC under a nitrogen
atmosphere. Phosphoryl chloride (10 mL, 102.4 mmol) was added
dropwise to the flask at 0 ꢁC. The mixture was allowed to warm up
to room temperature and stirred at this temperature for 15 min. A
5l 4-MeOC6H4- 4-MeOC6H4CH=CH- 70
Scheme 4. Suzuki cross-coupling of 4 to afford the 1,6,8-triaryl-1H-pyrazolo[4,3-c]
quinolines. Reagents and conditions: (i) Ar0B(OH)2 (2.5 equiv), PdCl2(PPh3)2, PCy3,
K2CO3, DMFewater (3/1, v/v), heat, 3 h.

702
M.M. Maluleka, M.J. Mphahlele / Tetrahedron 69 (2013) 699e704
solution of 1 (3.90 g, 13.3 mmol) in DMF (20 mL) was added
dropwise by means of a syringe and the mixture was heated at
60 ꢁC for 4 h under nitrogen. The cooled mixture was added to
crush ice and then neutralized with saturated NaHCO3 solution. The
product was extracted into chloroform and the combined organic
phases were washed with water and then dried over anhydrous
MgSO4. The mixture was filtered off and the solvent was evaporated
under reduced pressure to afford 2 as an off-white solid (3.40 g,
73%), mp 212e214 ꢁC; nmax (ATR) 742.4, 897.2, 1330.9, 1451.8,
470 (100%, C
17H13N3O37Cl79Br2þ); HRMS (ES): MHþ, found
467.9114. C17H13N3O35Cl79Br2þ requires 467.9115.
4.1.4. Cyclization of the 2-arylhydrazone derivatives 3 to afford 4.
Typical procedure
4.1.4.1. 6,8-Dibromo-1-(2-fluorophenyl)-1H-pyrazolo[4,3-c]quin-
oline (4a). A stirred mixture of 3a (0.50 g, 1.09 mmol) and 5%
ethanolic KOH (5% in ethanol, 20 mL) was heated at 80 ꢁC for 3 h
and allowed to cool to room temperature. The solid product was
filtered, washed with ice-cold ethanol, and then dried on a sintered
funnel to afford 4a as an off-white solid (0.40 g, 82%), mp
299e301 ꢁC; nmax (ATR) 637.9, 787.8, 840.9, 878.9, 1087.2, 1216.7,
1686.5 cmꢀ1
; dH (300 MHz, CDCl3) 8.32 (dd, J 0.9 and 2.1 Hz, 1H),
8.52 (dd, J 0.9 and 2.1 Hz, 1H), 9.34 (s, 1H), 10.68 (s, 1H); dC (75 MHz,
CDCl3) 122.7, 125.1, 126.7, 127.1, 127.8, 139.5, 146.5, 146.9, 149.4,
188.2; m/z 350 (100%, C10H5NO37Cl79Br2þ); HRMS (ES): MHþ, found
1510.3, 1576.8 cmꢀ1
; dH (300 MHz, CDCl3) 7.35 (t, J 8.7 Hz, 2H), 7.57
þ
347.6421. C10H5NO35Cl79Br2 requires 347.6425.
(t, J 8.7 Hz, 2H), 7.66 (s, 1H), 8.14 (s, 1H), 8.41 (d, J 2.1 Hz, 1H), 9.35 (s,
2
1H); dC (75 MHz, CDCl3) 117.1 (d, JCF 23.0 Hz), 118.1, 119.3, 119.7,
4.1.3. Reaction of 2 with arylhydrazine hydrochlorides to afford hy-
drazones 3. Typical procedure. A stirred mixture of 2 (1 equiv),
arylhydrazine hydrochloride (1.5 equiv), and triethylamine
(1.5 equiv) in ethanol (ca. 10 mL/mmol of 2) was heated at 60 ꢁC for
6e12 h. The mixture was allowed to cool to room temperature and
filtered on a sintered funnel. The product was washed with cold
ethanol and dried to afford pure 6,8-dibromo-4-chloroquinoline-3-
arylhydrazone 3. The following products were prepared in this
fashion.
123.7, 127.1, 128.9 (d, 3JCF 8.8 Hz), 135.5, 135.7, 135.8 (d, 4JCF 3.0 Hz),
1
138.2, 141.8, 146.7, 163.3 (d, JCF 250.4 Hz); m/z 422 (100%,
C16H9N379Br81BrFþ); HRMS (ES): MHþ, found 419.9150.
C16H9N379Br2Fþ requires 419.9147.
4.1.4.2. 6,8-Dibromo-1-(2-chlorophenyl)-1H-pyrazolo[4,3-c]quin-
oline (4b). A mixture of 3b (0.50 g, 1.05 mmol) and 5% ethanolic
KOH (20 mL) afforded 4b as an off-white solid (0.41 g, 89%), mp
282e284 ꢁC; nmax (ATR) 640.2, 807.7, 880.0, 1039.7, 1088.6, 1390.9,
1460.6, 1505.0, 1597.5 cmꢀ1
; dH (300 MHz, CDCl3) 7.54 (t, J 8.7 Hz,
4.1.3.1. N0-[(6,8-Dibromo-4-chloroquinolin-3-yl)methylene]-2-(4-
fluorophenyl)hydrazide (3a). A mixture of 2 (1.00 g, 2.80 mmol), 4-
fluorophenylhydrazine hydrochloride (0.425 g, 4.20 mmol), and
triethylamine (0.68 g, 4.18 mmol) in ethanol (40 mL) was heated
for 6 h to afford 2b as a orange solid (1.05 g, 80%), mp 232e235 ꢁC
(ethanol); nmax (ATR) 735.5, 759.5, 823.0, 897.2, 1159.7, 1192.12,
2H), 7.64 (d, J 8.7 Hz, 2H), 7.74 (d, J 1.5 Hz, 1H), 8.15 (d, J 1.5 Hz, 1H),
8.41 (s, 1H), 9.35 (s, 1H); dC (75 MHz, CDCl3) 118.0, 119.5, 119.7, 123.7,
127.1, 128.1, 130.2, 135.6, 136.0, 136.2, 138.0, 138.4, 141.9, 146.7; m/z
438 (100%, C16H9N335Cl79Br2þ); HRMS (ES): MHþ, found 435.8847.
C16H9N335Cl79Br2þ requires 435.8852.
1325.4, 1461.7, 1501.4, 1557.0 cmꢀ1
; dH (300 MHz, DMSO-d6) 7.06
4.1.4.3. 6,8-Dibromo-1-(2-methoxyphenyl)-1H-pyrazolo[4,3-c]
quinoline (4c). A mixture of 3c (0.50 g, 1.06 mmol) and 5% ethanolic
KOH (20 mL) afforded 4c as a pink solid (0.405 g, 88%), mp
208e209 ꢁC; nmax (ATR) 637.7, 809.6, 837.0, 860.7, 1023.7, 1044.7,
(t, J 8.7 Hz, 2H), 7.13 (t, J 8.7 Hz, 2H), 8.17 (s, 1H), 8.19 (d, J 2.1 Hz,
1H), 8.21 (d, J 2.1 Hz, 1H), 9.47 (s, 1H), 11.09 (s, 1H); dC (75 MHz,
3
2
DMSO-d6) 113.7 (d, JCF 6.8 Hz), 115.6 (d, JCF 22.5 Hz), 121.3,
4
121.9, 125.8, 125.9, 128.0, 128.2, 129.2, 135.3, 140.6, 142.7 (d, JCF
1181.3,1246.7,1516.0,1608.6 cmꢀ1
; dH (300 MHz, CDCl3) 3.95 (s, 3H),
1
3.0 Hz), 149.1, 157.2 (d, JCF 236.5 Hz); m/z 458 (100%,
7.13 (d, J 8.7 Hz, 2H), 7.47 (d, J 8.7 Hz, 2H), 7.70(d, J 2.1 Hz,1H), 8.12 (d, J
2.1 Hz, 1H), 8.38 (s, 1H), 9.33 (s, 1H); dC (75 MHz, CDCl3) 55.8, 115.0,
118.3, 119.1, 119.5, 123.9, 126.8, 128.2, 132.6, 135.2, 135.3, 138.2, 141.7,
146.7,160.8; m/z 434 (100%, C17H12N3O79Br81Brþ); HRMS (ES): MHþ,
found 431.9345. C17H12N3O79Br2þ requires 431.9347.
C16H10N3F37Cl79Br2þþ); HRMS (ES): MHþ, found 455.8910.
C16H10N3F35Cl79Br2 requires 455.8914.
4.1.3.2. N0-[(6,8-Dibromo-4-chloroquinolin-3-yl)methylene]-2-
(4-chlorophenyl)hydrazide (3b). A mixture of 2 (1.00 g, 2.80 mmol),
4-chlorophenylhydrazine hydrochloride (0.75 g, 4.20 mmol), and
triethylamine (0.425 g, 4.20 mmol) in ethanol (40 mL) was heated
for 12 h to afford 2c as an yellow solid (1.10 g, 83%), mp 254e256 ꢁC
(ethanol); nmax (ATR) 622.1, 638.2, 742.0, 818.5, 1090.7, 1160.7,
4.1.5. Suzuki cross-coupling of 4 with arylboronic acids. Typical
procedure. 1-Aryl-6,8-dibromo-1H-pyrazolo[4,3-c]quinoline
4
(1 equiv), arylboronic acid (2.5 equiv), PdCl2(PPh3)2 (5% of 4), PCy3
(10% of 4), K2CO3 (2 equiv), and 3/1 DMFewater (ca. 5 mL/mmol of 4)
were added to a two-necked flask equipped with a stirrer bar, rubber
septum, and a condenser. The mixture was flushed for 20 min with
argon gas and a balloon filled with argon gas was connected to the
top of the condenser. The mixture was heated with stirring at
80e90 ꢁC under argon atmosphere for 3 h and then allowed to cool
to room temperature. The cooled mixture was poured into ice-cold
water and the precipitate was filtered on a sintered funnel. The
solid product was taken-up into chloroform and the solution was
dried with MgSO4, filtered, and then evaporated under reduced
pressure. The product was recrystallized to afford the 1,6,8-triaryl-
1H-pyrazolo[4,3-c]quinoline 5. The following products were pre-
pared in this fashion.
1254.4, 1325.2, 1458.5, 1484.7, 1516.2, 1566.6, 1587.1 cmꢀ1
; dH
(300 MHz, DMSO-d6) 7.11 (d, J 7.8 Hz, 2H), 7.25 (d, J 7.8 Hz, 2H),
8.15 (s, 1H), 8.18 (d, J 2.1 Hz, 1H), 8.23 (d, J 2.1 Hz, 1H), 9.42 (s, 1H),
11.18 (s, 1H); dC (75 MHz, DMSO-d6) 114.5, 121.6, 124.1, 126.0, 126.5,
127.9, 128.2, 129.3, 130.3, 135.4, 135.7, 142.9, 143.3, 149.3; m/z 474
(100%, C16H10N335Cl37Cl79Br2þ); HRMS (ES): MHþ, found 471.8621.
C16H10N335Cl729Br2þ requires 471.8619.
4.1.3.3. N0-[(6,8-Dibromo-4-chloroquinolin-3-yl)methylene]-2-
(4-methoxyphenyl)hydrazide (3c). A mixture of
2
(1.00 g,
2.80 mmol), 4-methoxyphenylhydrazine hydrochloride (0.73 g,
4.20 mmol), and triethylamine (0.425 g, 4.20 mmol) in ethanol
(40 mL) was heated for 6 h to afford 2d as an orange solid (1.19 g,
88%), mp 232e234 ꢁC (ethanol); nmax (ATR) 613.3, 643.5, 826.0,
4.1.5.1. 1-(4-Fluorophenyl)-6,8-diphenyl-1H-pyrazolo[4,3-c]quin-
oline (5a). A mixture of 4a (0.50 g. 1.19 mmol), phenylboronic acid
(0.36 g, 2.97 mmol), PdCl2(PPh3)2 (0.04 g, 0.059 mmol), PCy3
(0.033 g, 0.119 mmol), and K2CO3 (0.328 g, 2.38 mmol) in
DMFewater (20 mL) afforded 5a as an off-white solid (0.381 g,
77%), mp 260e262 ꢁC (ethanol); nmax (ATR) 697.7, 759.7, 820.4,
1019.9, 1190.5, 1226.8, 1461.9, 1502.1, 1584.4 cmꢀ1
; dH (300 MHz,
DMSO-d6) 3.72 (s, 3H), 6.87 (d, J 8.7 Hz, 2H), 7.12 (d, J 8.7 Hz, 2H),
8.15 (s, 1H), 8.26 (d, J 2.1 Hz, 1H), 8.27 (d, J 2.1 Hz, 1H), 9.50 (s, 1H),
11.03 (s, 1H); dC (75 MHz, DMSO-d6) 55.8, 114.3, 115.2, 121.8, 126.0,
126.6, 128.3, 128.4, 128.6, 134.4, 135.5, 138.4, 142.7, 149.5, 154.2; m/z

M.M. Maluleka, M.J. Mphahlele / Tetrahedron 69 (2013) 699e704
703
3
884.6, 1213.6, 1378.9, 1512.8, 1582.6 cmꢀ1
;
dH (300 MHz, CDCl3)
118.7, 118.8, 128.5 (2ꢂC), 128.6 (d, JCF 8.3 Hz), 129.1, 129.9, 132.2
3 4 4
7.32e7.47 (m, 8H), 7.52 (t, J 7.8 Hz, 2H), 7.65e7.73 (m, 4H), 7.81 (d, J
2.1 Hz, 1H), 7.97 (d, J 2.1 Hz, 1H), 8.37 (s, 1H), 9.26 (s, 1H); dC
(d, JCF 8.0 Hz), 135.8 (d, JCF 3.4 Hz), 135.9, 136.0 (d, JCF 3.4 Hz),
137.3, 139.3, 139.7, 141.6, 142.7, 145.3, 162.5 (d, 1JCF 245.3 Hz), 162.8
(d, 1JCF 246.7 Hz); m/z 470 (37%, C28H17N3F237Clþ), 468.1085 (100%,
C28H17N3F235Clþ); HRMS (ES): MHþ, found C28H17N335ClFþ2 requires
468.1085.
2
(75 MHz, CDCl3) 116.7 (d, JCF 23.0 Hz), 116.8, 118.4, 118.8, 127.0,
3
127.6, 127.9, 128.0, 129.0, 129.2 (d, JCF 8.8 Hz), 129.5, 130.6, 135.6,
3
136.9 (d, JCF 3.0 Hz), 138.3, 139.8 (2ꢂC), 140.2, 142.5, 142.9, 145.2,
1
163.1 (d, JCF 249.3 Hz); m/z 416 (100%, MHþ); HRMS (ES): MHþ,
found 416.1560. C28H19N3Fþ requires 416.1563.
4.1.5.6. 6,8-Bis(4-fluorophenyl)-1-(4-methoxyphenyl)-1H-pyr-
azolo[4,3-c]quinoline (5f). A mixture of 4c (0.50 g, 1.14 mmol), 4-
fluorophenylboronic acid (0.40 g, 2.86 mmol), PdCl2(PPh3)2
(0.041 g, 0.057 mmol), PCy3 (0.032 g, 0.114 mmol), and K2CO3
(0.314 g, 2.308 mmol) in DMFewater (20 mL) afforded 5f as a pink
solid (0.317 g, 60%), mp 256e258 ꢁC (ethanol); nmax (ATR) 802.4,
4.1.5.2. 1-(4-Chlorophenyl)-6,8-diphenyl-1H-pyrazolo[4,3-c]quin-
oline (5b). A mixture of 4b (0.50 g. 1.15 mmol), phenylboronic acid
(0.35 g, 2.87 mmol), PdCl2(PPh3)2 (0.04 g, 0.058 mmol), PCy3
(0.032 g, 0.115 mmol), and K2CO3 (0.317 g, 2.30 mmol) in DMFewater
(20 mL) afforded 5b as an off-white solid (0.320 g, 65%), mp
280e282 ꢁC (ethanol); nmax (ATR) 797.7, 822.3, 833.4, 866.9, 1090.1,
1220.3, 1378.9, 1515.2, 1584.8, 1601.6 cmꢀ1
; dH (300 MHz, CDCl3)
3.96 (s, 3H), 7.08 (t, J 8.4 Hz, 2H), 7.16 (d, J 8.7 Hz, 2H), 7.20 (t, J
8.4 Hz, 2H), 7.41 (t, J 8.4 Hz, 2H), 7.58 (d, J 8.7 Hz, 2H), 7.68 (t, J
8.4 Hz, 2H), 7.78 (d, J 2.1 Hz, 1H), 7.87 (d, J 2.1 Hz, 1H), 8.37 (s, 1H),
1223.7, 1379.1, 1507.3, 1582.9 cmꢀ1
; dH (300 MHz, CDCl3) 7.35e7.55
(m, 8H), 7.65 (s, 4H), 7.71 (d, J 8.1 Hz, 2H), 7.83 (d, J 2.1 Hz,1H), 7.98 (d,
J 2.1 Hz,1H), 8.38 (s,1H), 9.26 (s,1H); dC (75 MHz, CDCl3) 116.7,118.6,
118.9 (2ꢂC),127.0,127.6,127.9,128.0,128.5,129.1,129.4,129.9,130.6,
135.7, 135.8, 138.3, 139.3, 139.8, 140.2, 142.5, 142.9, 145.2; m/z 434
(38%, C28H19N335Clþ), 432 (100%, MHþ); HRMS (ES): MHþ, found
432.1266. C28H19N335Clþ requires 432.1266.
2
9.26 (s, 1H); dC (75 MHz, CDCl3) 55.8, 114.8, 114.9 (d, JCF 21.3 Hz),
2
3
115.9 (d, JCF 21.3 Hz), 117.1, 118.3, 119.0, 128.5 (2ꢂC), 128.7 (d, JCF
8.2 Hz), 132.2 (d, 3JCF 8.1 Hz), 133.5, 135.2, 135.9 (d, 3JCF 3.6 Hz), 136.1
(d, JCF 3.5 Hz), 137.0, 139.7, 141.3, 142.6, 145.4, 160.6, 162.4 (d, 1JCF
3
255.1 Hz), 162.7 (d, JCF 246.2 Hz); m/z 464 (100%, MHþ); HRMS
1
(ES): MHþ, found 464.1576. C29H20N3OF2þ requires 464.1574.
4.1.5.3. 1-(4-Methoxyphenyl)-6,8-diphenyl-1H-pyrazolo[4,3-c]
quinoline (5c). A mixture of 4c (0.50 g, 1.154 mmol), phenylboronic
acid (0.35 g, 2.88 mmol), PdCl2(PPh3)2 (0.041 g, 0.057 mmol), PCy3
(0.032 g, 0.115 mmol), and K2CO3 (0.319 g, 2.308 mmol) in
DMFewater (20 mL) afforded 5c as a red solid (0.340 g, 69%), mp
238e240 ꢁC (ethanol); nmax (ATR) 696.6, 758.6, 847.7, 883.5, 1019.0,
4.1.5.7. 1-(4-Fluorophenyl)-6,8-bis[2-(4-fluorophenyl)ethenyl]-
1H-pyrazolo[4,3-c]quinoline (5g). A mixture of 4a (0.50 g,
1.19 mmol), trans-2-(4-fluorophenyl)vinylboronic acid (0.49 g,
2.97 mmol), PdCl2(PPh3)2 (0.04 g, 0.059 mmol), PCy3 (0.033 g,
0.119 mmol), and K2CO3 (0.328 g, 2.380 mmol) in DMFewater
(20 mL) afforded 5g as a light brown solid (0.43 g, 72%), mp
234e236 ꢁC (ethanol); nmax (ATR) 789.0, 813.1, 844.5, 956.6, 1156.1,
1027.4,1177.4,1528.4,1583.5 cmꢀ1
; dH (300 MHz, CDCl3) 3.95 (s, 3H),
7.16 (d, J 9.0 Hz, 2H), 7.31e7.55 (m, 8H), 7.59 (d, J 9.0 Hz, 2H), 7.72 (dd, J
1.5 and 7.8 Hz, 2H), 7.85 (d, J 1.8 Hz,1H), 7.96 (d, J 1.8 Hz, 1H), 8.36 (s,
1H), 9.25 (s, 1H); dC (75 MHz, CDCl3) 55.8, 114.9, 117.0, 118.2, 119.1,
127.1,127.5,127.7,128.0,128.6,128.9,129.2,130.6,133.6,135.2,137.9,
139.8, 139.9, 140.4, 142.3, 142.8, 145.3, 160.6; m/z 428 (100%, MHþ);
HRMS (ES): MHþ, found 428.1758. C29H22N3Oþ requires 428.1763.
1230.9, 1523.6, 1600.0 cmꢀ1
; dH (300 MHz, CDCl3) 6.92 (d, J 2.7 Hz,
2H), 7.07 (t, J 8.7 Hz, 2H), 7.09 (t, J 8.7 Hz, 2H), 7.30 (d, J 16.5 Hz, 1H),
7.38 (t, J 8.7 Hz, 2H), 7.45 (t, J 8.7 Hz, 2H), 7.52 (d, J 1.8 Hz,1H), 7.65 (t,
J 8.7 Hz, 2H), 7.66 (t, J 8.7 Hz, 2H), 8.13 (d, J 1.8 Hz, 1H), 8.37 (s, 1H),
8.46 (t, J 16.5 Hz, 1H), 9.24 (s, 1H); dC (75 MHz, CDCl3) 115.6 (d, 2JCF
2
2
21.6 Hz), 115.7 (d, JCF 21.6 Hz), 116.4, 116.6 (d, JCF 22.8 Hz), 118.3,
118.6, 122.8, 125.2, 127.3, 128.1 (d, 3JCF 8.0 Hz), 128.5 (d, 3JCF 8.0 Hz),
128.9, 129.2 (d, 3JCF 8.9 Hz), 129.6, 132.8 (d, 4JCF 3.5 Hz), 133.7 (d, 4JCF
3.2 Hz), 134.5, 135.6, 136.8 (d, 4JCF 3.4 Hz), 137.0, 139.4, 142.8, 144.2,
4.1.5.4. 1,6,8-Tris(4-fluorophenyl)-1H-pyrazolo[4,3-c]quinoline
(5d). A mixture of 4a (0.50 g, 1.19 mmol), 4-fluorophenylboronic
acid (0.42 g, 2.975 mmol), PdCl2(PPh3)2 (0.04 g, 0.059 mmol),
PCy3 (0.033 g, 0.119 mmol), and K2CO3 (0.328 g, 2.38 mmol) in
DMFewater (20 mL) afforded 5d as a light brown solid (0.380 g,
71%), mp 252e254 ꢁC (ethanol); nmax (ATR) 833.2, 858.0, 936.2,
1
1
1
162.5 (d, JCF 246.2 Hz), 162.6 (d, JCF 246.8 Hz), 163.0 (d, JCF
248.8 Hz); m/z 504 (100%, MHþ); HRMS (ES): MHþ, found 504.1688.
C32H21N3F3þ requires 504.1688.
1157.9, 1221.3, 1503.9, 1601.9 cmꢀ1
; dH (300 MHz, CDCl3) 7.11 (t, J
8.1 Hz, 2H), 7.20 (t, J 7.8 Hz, 2H), 7.36 (t, J 8.4 Hz, 2H), 7.37 (m, 4H),
7.39 (d, J 8.4 Hz, 2H), 7.73 (d, J 2.1 Hz, 1H), 7.87 (d, J 2.1 Hz, 1H), 8.38
(d, 1.2 Hz, 1H), 9.26 (d, J 1.2 Hz, 1H); dC (75 MHz, CDCl3) 115.0 (d, 2JCF
21.4 Hz), 116.0 (d, 2JCF 21.4 Hz), 116.8 (d, 2JCF 23.04 Hz), 118.5, 118.8,
128.6 (d, 3JCF 8.0 Hz), 129.0, 129.1, 129.2 (d, 3JCF 8.8 Hz), 132.2 (d, 3JCF
4.1.5.8. 1-(4-Chlorophenyl)-6,8-bis[2-(4-fluorophenyl)ethenyl]-
1H-pyrazolo[4,3-c]quinoline (5h). A mixture of 4a (0.50 g,
1.15 mmol), trans-2-(4-fluorophenyl)vinylboronic acid (0.476 g,
2.87 mmol), PdCl2(PPh3)2 (0.04 g, 0.058 mmol), PCy3 (0.032 g,
0.115 mmol), and K2CO3 (0.320 g, 2.300 mmol) in DMFewater
(20 mL) afforded 5h as a gray solid (0.421 g, 70%), mp 257e259 ꢁC
(ethanol); nmax (ATR) 788.8, 811.4, 836.0, 955.6, 1091.5, 1156.9,
4
4
8.0 Hz), 135.6, 135.9 (d, JCF 3.2 Hz), 136.0 (d, JCF 3.2 Hz), 136.9 (d,
4JCF 3.2 Hz), 137.3, 139.7, 141.5, 142.7, 145.3, 162.5 (d, 1JCF 245.2 Hz),
1
1
162.7 (d, JCF 246.7 Hz), 163.1 (d, JCF 249.6 Hz); m/z 452 (100%,
1229.2, 1522.9, 1599.8 cmꢀ1
; dH (300 MHz, CDCl3) 6.94 (s, 2H), 7.08
þ
MHþ); HRMS (ES): MHþ, found 452.1372. C28H17N3F3 requires
(t, J 8.7 Hz, 2H), 7.09 (t, J 8.7 Hz, 2H), 7.30 (d, J 16.5 Hz, 1H), 7.47
(t, 8.7 H, 2H), 7.59 (d, J 1.5 Hz, 1H), 7.608e7.69 (m, 6H), 8.13 (d, J
1.5 Hz, 1H), 8.38 (s, 1H), 8.46 (d, J 16.5 Hz, 1H), 9.23 (s, 1H); dC
(75 MHz, CDCl3) 115.6 (d, 2JCF 21.3 Hz), 115.8 (d, 2JCF 21.3 Hz), 116.5,
118.3, 118.8, 123.1, 125.3, 127.3, 128.2 (d, 3JCF 8.0 Hz), 128.5, 128.6 (d,
3JCF 8.0 Hz), 129.1, 129.7, 132.8 (d, 4JCF 3.4 Hz), 133.8 (d, 4JCF 3.4 Hz),
452.1375.
4.1.5.5. 1-(4-Chlorophenyl)-6,8-bis(4-fluorophenyl)-1H-pyrazolo
[4,3-c]quinoline (5e). A mixture of 4b (0.50 g, 1.15 mmol), 4-
fluorophenylboronic acid (0.402 g, 2.875 mmol), PdCl2(PPh3)2
(0.04 g, 0.0575 mmol), PCy3 (0.032 g, 0.115 mmol), and K2CO3
(0.318 g, 2.30 mmol) in DMFewater (20 mL) afforded 5e as an off-
white solid (0.366 g, 68%), mp 260e262 ꢁC (ethanol); nmax (ATR)
1
134.7, 135.6, 135.9, 137.2, 139.3, 139.4, 142.9, 144.2, 162.5 (d, JCF
1
246.7 Hz), 162.6 (d, JCF 246.7 Hz); m/z 522 (41%,C32H21N335ClF2þ),
520 (100%, C32H21N335ClF2þ); HRMS (ES): MHþ, found 520.1392.
C32H21N335ClF2þ requires 520.1396.
799.5, 857.1, 935.9, 1090.1, 1223.7, 1507.3, 1600.4 cmꢀ1
; dH
(300 MHz, CDCl3) 7.12 (t, J 8.4 Hz, 2H), 7.20 (t, J 8.4 Hz, 2H), 7.40 (t, J
8.4 Hz, 2H), 7.64 (s, 4H), 7.68 (t, J 8.4 Hz, 2H), 7.75 (d, J 1.8 Hz, 1H),
7.88 (d, J 1.8 Hz, 1H), 8.40 (d, J 1.2 Hz, 1H), 9.26 (d, J 1.2 Hz, 1H); dC
(75 MHz, CDCl3) 115.0 (d, 2JCF 21.4 Hz), 116.0 (d, 2JCF 21.4 Hz), 116.8,
4.1.5.9. 6,8-Bis[2-(4-fluorophenyl)ethenyl]-1-(4-methoxyphenyl)-
1H-pyrazolo[4,3-c]quinoline (5i). A mixture of 4a (0.50 g,
1.14 mmol), trans-2-(4-fluorophenyl)vinylboronic acid (0.472 g,

704
M.M. Maluleka, M.J. Mphahlele / Tetrahedron 69 (2013) 699e704
2.85 mmol), PCl2(PPh3)2 (0.041 g, 0.057 mmol), PCy3 (0.032 g,
0.144 mmol), and K2CO3 (0.315 g, 2.28 mmol) in DMFewater
(20 mL) afforded 5i as a pink solid (0.48 g, 81%), mp 224e226 ꢁC
(ethanol); nmax (ATR) 790.2, 842.3, 955.7, 1227.9, 1505.5, 1585.9,
8.7 Hz, 2H), 7.64 (d, J 8.7 Hz, 2H), 8.10 (d, J 1.5 Hz, 1H), 8.34 (s, 1H),
8.42 (d, J 16.5 Hz, 1H), 9.21 (s, 1H); dC (75 MHz, CDCl3) 55.3, 55.4,
55.7, 114.0, 114.2, 114.8, 116.7, 117.7, 118.4, 122.7, 123.5, 125.7, 127.8,
128.3, 128.6, 129.5, 129.6, 130.2, 130.6, 133.6, 134.9, 135.1, 137.2,
139.6, 142.6, 143.9, 159.5, 160.5; m/z 540 (100%, MHþ); HRMS (ES):
MHþ, found 540.2294. C35H30N3O3þ requires 540.2287.
1599.0 cmꢀ1
; dH (300 MHz, CDCl3) 3.97 (s, 3H), 6.91 (s, 2H), 7.07 (d, J
8.7 Hz, 2H), 7.08 (d, J 8.7 Hz, 2H), 7.17 (d, J 8.7 Hz, 2H), 7.26 (d, J
16.5 Hz, 1H), 7.44 (d, J 7.8 Hz, 2H), 7.56 (d, J 8.7 Hz, 2H), 7.58 (s, 1H),
7.66 (d, J 8.7 Hz, 2H), 8.10 (d, J 1.5 Hz, 1H), 8.35 (s, 1H), 8.46 (d, J
16.5 Hz,1H), 9.23 (s,1H); dC (75 MHz, CDCl3) 55.7,114.8,115.6 (d, 2JCF
21.4 Hz), 115.7 (d, 2JCF 21.4 Hz), 116.7, 118.4, 118.5, 122.9, 125.4, 127.5,
128.1 (d, 3JCF 8.0 Hz), 128.4 (d, 3JCF 8.0 Hz), 128.5, 128.8, 129.5, 132.9
(d, 4JCF 3.4 Hz), 133.6, 133.8 (d, 4JCF 3.4 Hz), 134.4, 135.2, 136.9, 139.5,
142.8, 144.4, 160.5, 162.4 (d, 1JCF 245.9 Hz), 162.5 (d, 1JCF 246.7 Hz);
m/z 516 (100%, MHþ); HRMS (ES): MHþ, found 516.1887.
C33H24N3OF2þ requires 516.1887.
Acknowledgements
The authors are grateful to the University of South Africa for
financial assistance. MMM thanks the College of Science, Engi-
neering and Technology’s ‘Cultivating Woman Leaders in Sciences
Program’ for BSc Hon. Research Assistantship.
References and notes
4.1.5.10. 1-(4-Fluorophenyl)-6,8-bis[2-(4-methoxyphenyl)
ethenyl]-1H-pyrazolo[4,3-c]quinoline (5j). A mixture of 4a (0.50 g,
1.19 mmol), trans-2-(4-methoxyphenyl)vinylboronic (0.529 g,
2.97 mmol), PdCl2(PPh3)2 (0.04 g, 0.057 mmol), PCy3 (0.033 g,
0.119 mmol), and K2CO3 (0.330 g, 2.380 mmol) in DMFewater
(20 mL) afforded 5j as an orange solid (0.404 g, 65%), mp
216e218 ꢁC (ethanol); nmax (ATR) 841.6, 1031.6, 1173.5, 1247.5,
1. See review by Merkheimer, R. A.; Ahmed, E. A.; Sadek, K. U. Tetrahedron 2012,
68, 1637e1667.
2. (a) Savini, L.; Chiasserini, L.; Pellerano, C.; Biggio, C.; Sanna, E. Bioorg. Med.
Chem. 2001, 9, 431e444; (b) Baraldi, P. G.; Tabrizi, M. A.; Preti, D.; Bovero, A.;
Fruttarolo, F.; Romagnoli, R.; Zaid, N. A.; Moorman, A. R.; Varani, K.; Borea, P. A.
J. Med. Chem. 2005, 48, 5001e5008.
3. Carotti, A.; Altoma, C.; Savini, L.; Chiasserini, L.; Pellerano, C.; Mascia, M. P.;
Maciocco, E.; Busonero, F.; Mameli, M.; Biggio, G.; Sanna, E. Bioorg. Med. Chem.
2003, 11, 5259e5272.
1508.3, 1601.6 cmꢀ1
; dH (300 MHz, CDCl3) 3.84 (s, 3H), 3.85 (s, 3H),
6.90 (s, 2H), 6.92 (d, J 8.7 Hz, 2H), 6.94 (d, J 8.7 Hz, 2H), 7.29 (d, J
16.5 Hz, 1H), 7.37 (t, J 8.7 Hz, 2H), 7.42 (d, J 8.7 Hz, 2H), 7.48 (d, J
1.8 Hz, 1H), 7.64 (d, J 8.7 Hz, 2H), 7.65 (t, J 8.7 Hz, 2H), 8.12 (d, J
1.8 Hz, 1H), 8.35 (s, 1H), 8.41 (d, J 16.5 Hz, 1H), 9.20 (s, 1H); dC
(75 MHz, CDCl3) 55.3, 55.4, 114.0, 114.2, 116.7 (d, 2JCF 22.7 Hz), 117.7,
4. Baruah, B.; Dasu, K.; Vaitilingam, B.; Vanguri, A.; Casturi, S. R.; Yeleswarapu, K.
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731e742.
3
118.6, 122.7, 123.4, 125.6, 127.4, 127.9, 128.3, 129.2 (d, JCF 8.9 Hz),
3
129.5, 129.7, 130.4, 130.5, 135.1, 135.6, 136.9 (d, JCF 3.2 Hz), 137.4,
1
139.6, 142.7, 143.9, 159.4, 159.6, 163.0 (d, JCF 249.0 Hz); m/z 528
(100%, MHþ); HRMS (ES): MHþ, found 528.2093. C34H26N3O2Fþ
requires 528.2087.
4.1.5.11. 1-(4-Chlorophenyl)-6,8-bis[2-(4-methoxyphenyl)
ethenyl]-1H-pyrazolo[4,3-c]quinoline (5k). A mixture of 4b (0.50 g,
1.15 mmol), trans-2-(4-methoxyphenyl)vinylboronic acid (0.512 g,
2.87 mmol), PdCl2(PPh3)2 (0.04 g, 0.057 mmol), PCy3 (0.032 g,
0.144 mmol), and K2CO3 (0.320 g, 2.380 mmol) in DMFewater
(20 mL) afforded 5k as a light brown solid (0.445 g, 82%), mp
229e231 ꢁC (ethanol); nmax (ATR) 841.1, 954.9, 1173.4, 1508.7,
14. Huang, C. Q.; Wilcoxen, K.; McCarthy, J. R.; Haddach, M.; Webb, T. R.; Gu, J.; Xie,
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17. Lee, K. J.; Cho, H. K.; Sung, C. E. Bull. Korean Chem. Soc. 2002, 23, 773e775.
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N. M. Med. Chem. Res. 2012, 21, 1741e1750.
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24. Rajendram, S. P.; Manonmani, M.; Vijayalakshmi, S. Org. Prep. Proc. 1994, 26,
383e385.
1601.9 cmꢀ1
; dH (300 MHz, CDCl3) 3.84 (s, 3H), 3.85 (s, 3H), 6.89 (s,
2H), 6.92 (d, J 8.7 Hz, 2H), 6.93 (d, J 8.7 Hz, 2H), 7.29 (d, J 16.5 Hz,
1H), 7.44 (d, J 7.8 Hz, 2H), 7.54 (s, 1H), 7.61e7.67 (m, 6H), 8.10 (s, 1H),
8.34 (d, J 0.9 Hz, 1H), 8.39 (d, J 16.5 Hz, 1H), 9.19 (s, 1H); dC (75 MHz,
CDCl3) 55.2, 55.3, 114.1, 114.2, 116.3, 117.4, 118.7, 122.8, 123.3, 125.4,
127.9, 128.3, 128.5, 129.4, 129.7, 129.8, 130.3, 130.5, 135.1, 135.4,
135.7, 137.3, 139.2, 139.3, 142.6, 143.7, 159.4, 159.6; m/z 544
(100%, C34H27N3O235Clþ); HRMS (ES): MHþ, found 544.1790.
C34H27N3O235Clþ requires 544.1792.
25. Reddy, L. V.; Nallapati, S. B.; Beevi, S. S.; Mangamoori, L. N.; Mukkanti, K.; Pal, S.
J. Braz. Chem. Soc. 2011, 22, 1742e1749.
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10068e10074.
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ꢀ
ꢀ
29. Guillen, E.; Hierrezuelo, J.; Martinez-Mallorquin, R.; Lopez-Romero, J. M.; Rico,
4.1.5.12. 1,6,8-Tris[2-(4-methoxyphenyl)ethenyl]-1H-pyrazolo
[4,3-c]quinoline (5l). A mixture of 4c (0.50 g,1.14 mmol), trans-2-(4-
methoxyphenyl)vinylboronic acid (0.507 g, 2.80 mmol),
PdCl2(PPh3)2 (0.041 g, 0.057 mmol), PCy3 (0.032 g, 0.144 mmol),
and K2CO3 (0.316 g, 2.28 mmol) in DMFewater (20 mL) afforded 5l
as a red solid (0.427 g, 70%), mp 227e229 ꢁC (ethanol); nmax (ATR)
R. Tetrahedron 2011, 67, 2555e2561.
30. (a) Amatore, C.; Jutand, A. J. Organomet. Chem. 1999, 576, 254e278; (b) She, W.
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38e45.
31. (a) Kimnyonok, A.; Wang, X. Y.; Weck, M. J. Macromol. Sci. Part C. Polym. Rev.
2006, 46, 47e77; (b) Wu, F. I.; Su, S. J.; Shu, C. F.; Luo, L.; Diau, W. G.; Cheng, C.-
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H.; Yang, C.; Zhang, X.; Qin, J.; Ma, D. J. Mater. Chem. 2006, 16, 3332e3339.
32. Hattori, K.; Yamaguchi, K.; Yamaguchi, J.; Itami, K. Tetrahedron 2012, 68,
7605e7612.
813.3, 833.8, 844.4, 1026.8, 1172.8, 1242.6, 1507.7, 1600.4 cmꢀ1
; dH
(300 MHz, CDCl3) 3.85 (s, 3H), 3.86 (s, 3H), 3.98 (s, 3H), 6.89 (s, 2H),
6.93 (d, J 8.7 Hz, 2H), 6.94 (d, J 8.7 Hz, 2H), 7.18 (d, J 8.7 Hz, 2H), 7.30
(d, J 16.5 Hz, 1H), 7.42 (d, J 8.7 Hz, 2H), 7.54 (d, J 1.5 Hz, 1H), 7.57 (d, J
33. Leonard, N. J.; Boyd, S. N., Jr. J. Org. Chem. 1946, 11, 405e418.