L-Proline-catalysed sequential four-component "on water" protocol for the synthesis of structurally complex heterocyclic ortho-quinones

Article abstract of DOI:10.1039/c1gc15794a

The l-proline-catalyzed synthesis of 7-(aryl)-8-methyl-10-phenyl-5H- benzo[h]pyrazolo-[3,4-b]quinoline-5,6(10H)-diones via the four-component sequential reaction of phenylhydrazine, 3-aminocrotononitrile, substituted benzaldehydes and 2-hydroxynaphthalene-1,4-dione is described. This "on water" protocol proceeds in high atom economy and leads to the generation of two rings, together with two C-C, one C-N and two CN bonds in a single operation. The environmental advantages of the method include short reaction time, excellent yield, easy work-up, and the absence of extraction and chromatographic purification steps. The Royal Society of Chemistry.

Full text of DOI:10.1039/c1gc15794a

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PAPER
L-Proline-catalysed sequential four-component “on water” protocol for the
synthesis of structurally complex heterocyclic ortho-quinones†
Stephen Michael Rajesh,a Balasubramanian Devi Bala,a Subbu Perumal*a and J. Carlos Mene´ndez*b
Received 5th July 2011, Accepted 17th August 2011
DOI: 10.1039/c1gc15794a
The L-proline-catalyzed synthesis of 7-(aryl)-8-methyl-10-phenyl-5H-benzo[h]pyrazolo-
[3,4-b]quinoline-5,6(10H)-diones via the four-component sequential reaction of phenylhydrazine,
3-aminocrotononitrile, substituted benzaldehydes and 2-hydroxynaphthalene-1,4-dione is
described. This “on water” protocol proceeds in high atom economy and leads to the generation
of two rings, together with two C–C, one C–N and two C N bonds in a single operation. The
environmental advantages of the method include short reaction time, excellent yield, easy
work-up, and the absence of extraction and chromatographic purification steps.
ideal synthetic reaction. Water is Nature’s reaction medium
Introduction
and constitutes a non-flammable, non-hazardous, non-toxic,
The development of efficient, practical and environmentally
uniquely redox-stable, inexpensive solvent that has the addi-
friendly methods for the construction of compounds with
tional advantage of being a non-exhaustible resource that is
biological significance is one of the main priorities for modern
almost freely available, even in the least-developed countries.6
organic synthesis. One of the most relevant current approaches
Furthermore, the use of water as a reaction medium enables
to synthetic efficiency is based on the use of methods that are
novel solvation and molecular assembly processes, conferring
able to generate several bonds in a single operation,1 especially
unique reactivities and selectivities.7 Although some misgiv-
multicomponent reactions (MCRs), which combine three or
ings have been expressed,8 it is generally accepted that these
more substrates, either simultaneously, leading to domino
properties mean that, in many cases, water is close to being
processes,2 or through the sequential addition of one or more
the ideal green solvent and preferable to alternatives like ionic
reactants without isolating intermediate species or changing the
liquids.9 For these reasons, the development of synthetically
solvent. MCRs offer remarkable advantages, such as operational
useful reactions using water as the reaction medium has gained
simplicity, facile automation and minimized waste generation,
considerable interest.10 Among these reactions, those that take
because of the reduction in the number of work-up, extraction
place “on water” are of particular importance. They involve
and purification stages. MCRs leading to heterocyclic scaffolds
the use of reactants initially suspended or emulsioned in water,
are key to the expedient creation of chemical libraries of drug-
and normally exhibit significant rate enhancements.11 In spite
like compounds of high levels of molecular complexity and
of their interest, on-water reactions have received relatively
diversity,3 enabling new lead identification and optimization in
little attention from a synthetic point of view,12 and this is
drug discovery.4
One aspect of multicomponent reactions that has received
particularly true for the field of multicomponent and domino
reactions, where only a few well-known transformations, such
relatively little attention is their development in aqueous
as the Passerini and Ugi reactions, have been examined in this
environments,5 which would lead to processes close to the
regard.
Against this background, and also in the context of our
interest in the synthesis of biologically important heterocycles
via multi-component and domino reactions,13 we report here
the green preparation of a library of pharmacologically relevant
fused polyheterocyclic systems containing a benzo[h]quinoline-
5,6-dione structural fragment by a process that combines the
use of aqueous media with the synthetic efficiency associ-
ated with MCRs, providing a convergence of reaction and
environmental economies.14 Quinoline-derived ortho-quinones
(Fig. 1), exemplified by pyrroloquinolinequinone 1 (PQQ),
are very important compounds from a biological point of
aDepartment of Organic Chemistry, School of Chemistry, Madurai
Kamaraj University, Madurai, 625021, India.
E-mail: subbu.perum@gmail.com; Fax: +91 4522459845; Tel: +91
4522459845
bDepartamento de Qu´ımica Orga´nica y Farmace´utica, Facultad de
Farmacia, Universidad Complutense, 28040, Madrid, Spain.
E-mail: josecm@farm.ucm.es; Fax: +34 91-3941822; Tel: +34
91-3941840
† Electronic supplementary information (ESI) available: Copies of
representative spectra and discussion of the structural characterization
of compound 9. CCDC reference number 819024. For crystallographic
data in CIF or other electronic format see DOI: 10.1039/c1gc15794a
3248 | Green Chem., 2011, 13, 3248–3254
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Fig. 1 Structures of some relevant quinoline-derived ortho-quinones.
Fig. 2 Structural assignments found in the literature for products from
a three-component reaction related to our work.
view and play crucial roles as cofactors, being involved in
biochemical reactions that range from oxidative deaminations
to free radical redox reactions.15 Furthermore, some of these
ortho-quinones, such as benzo[h]quinoline-5,6-dione (BHQD,
2), have shown potent chemotherapeutic activities.16 In choosing
the frameworks to be synthesized, we bore in mind the current
interest in heterocyclic hybrid compounds and were attracted by
the varied pharmaceutical applications of molecules containing
the pyrazole ring,17 including the pyrazolo[3,4-b]pyridine18 and
pyrazolo[3,4-b]quinoline19 structural motifs.
Hence, one of our goals has been to re-examine these divergent
structural assignments.
As shown in Scheme 1 and Table 1, we started our study by
examining the model reaction between 2-hydroxynaphthalene-
1,4-dione (5), 3-aminocrotononitrile (6), phenylhydrazine (7)
and 4-chlorobenzaldehyde (8c), which afforded compound 3c.
We employed water as the reaction medium from the onset,
and, after verifying that the uncatalyzed reaction afforded a
respectable 45% yield, we set out to identify the optimal catalyst
by comparing the reaction in the presence of several acidic
and basic potential promoters (Table 1). We found that the
best results were obtained for L-proline (40 mol%),22 which
afforded compound 3c in an excellent 91% yield. In the presence
of pyrrolidine (Table 1, entry 4), the initial reaction between
3-aminocrotononitrile and phenylhydrazine required a much
longer reaction time (1 h) than that in presence of L-proline.
This suggests that both the secondary amine and the COOH
groups in L-proline are probably involved in the catalytic cycle,
as discussed below. Subsequent experiments showed that catalyst
loading could be reduced to 30% with little effect on the yield,
but lower amounts were detrimental (Table 2). The need for a
relatively large amount of catalyst (40 mol%) may be explained
by taking into account that, in an aqueous environment,
equilibria that require the loss of water, such as the formation
of enamines, can be expected to require larger amounts of the
reactants involved. Furthermore, as depicted in the mechanism
(vide infra), L-proline is presumably involved in the catalysis of
Results and discussion
The considerations outlined above prompted us to in-
vestigate the four-component sequential reactions of 3-
aminocrotononitrile, phenylhydrazine, substituted benzaldehy-
des and 2-hydroxynaphthalene-1,4-dione, employing L-proline
as a green organocatalyst (Scheme 1), with a view to
developing a highly convergent protocol for the synthe-
sis of 7-aryl-8-methyl-10-phenyl-5H-benzo[h]pyrazolo[3,4-b]-
quinoline-5,6(10H)-diones 3 as attractive candidates for bio-
logical evaluation. While our planned reaction was unprece-
dented, there are two very recent, contradictory literature
reports describing the related three-component reaction of
3-methyl-1-aryl-1H-pyrazol-5-amines, aromatic aldehydes and
2-hydroxynaphthalene-1,4-dione. In one of these references,
describing only two examples, this reaction was carried out
under solvent-free microwave irradiation and found to give
compounds of structure 3.20 However, Wu et al.21 concluded
that they had obtained compounds 4, the regioisomers of 3,
from the same reactants under a variety of conditions (Fig. 2).
Table 1 Catalyst screening for the synthesis of 3c in water
Entry
Catalyst
Time/h
Yield (%)a
1
2
3
4
5
6
None
p-TSA
AcOH
Pyrrolidine
Glycine
L-Proline
10
45
80
77
70
73
91
5.0
3.0
4.0
3.5
1.2
a Yield after filtration through a pad of silica gel.
Scheme 1 Four-component synthesis of 7-(aryl)-8-methyl-10-phenyl-
5H-benzo[h]pyrazolo[3,4-b]quinoline-5,6(10H)-diones 3.
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Table 2 Effect of L-proline loading on the synthesis of 3c in water
Entry
L-Proline (mol%)
Time/h
Yield (%)a
1
2
3
4
10
20
30
40
3.5
3.0
1.5
1.2
60
71
87
91
a Yield after filtration through a pad of silica gel.
Table 3 Synthesis of compounds 3
Entry
Compound
Ar
Time/min
Yield (%)a
1
2
3
4
5
6
7
8
3a
3b
3c
3d
3e
3f
4-O2NC6H4
4-FC6H4
4-ClC6H4
4-MeC6H4
4-PriC6H4
3-FC6H4
3-BrC6H4
2,3-Cl2C6H3
2,6-Cl2C6H3
2-Thienyl
60
85
70
70
80
90
90
85
90
70
90 (83)
89 (85)
91 (85)
91 (81)
90 (83)
87
90
90
88
88
Fig. 3 NMR characterization of compound 3c.
1.97 ppm show a HMBC with the signals at 116.8 (C-8) and
146.2 ppm. The chemical shifts of the protons and the respective
C,H-COSY correlations facilitated the assignment of the 13C
chemical shifts of their connected carbons. The 1H NMR spectra
of two samples of compound 3c, obtained using our method and
the previous literature protocol,21 were superimposable.
3g
3h
3i
9
10
3j
While the very close chemical shifts for the carbonyl 13C NMR
signals suggested an ortho-quinone structure,23 only marginal
a Yields after filtration through a pad of silica gel. Yields in brackets are
after recrystallization from acetonitrile.
1
differences in the H and 13C chemical shifts are expected for
3 and its regioisomer 4 in simulated spectra. For this reason,
we considered it desirable to obtain independent chemical
evidence for the presence of ortho- or para-quinone units in
3. To this end, we reacted 3c with o-phenylenediamine for 5 min
under solvent-free microwave irradiation, affording compound
9 in almost quantitative yield, confirming the ortho-quinone
structure (Scheme 2). The structure of 9 was fully characterized
by spectroscopic data (one and two-dimensional NMR) and
elemental analysis, as shown in the ESI.† Finally, the proposed
structure for compounds 3 was also confirmed by an X-ray
crystallographic study, performed on a single crystal of 3b
(Fig. 4).†
several steps and therefore the effective concentration of free L-
proline available for catalysing any individual step may be low,
justifying the need for a relatively large amount of catalyst.
From these optimization studies, the L-proline–water pairing
emerged as the ideal catalyst–reaction medium combination,
and was employed subsequently for all further examples
(Scheme 1). In a typical reaction, an equimolar mixture of 3-
aminocrotononitrile (6) and phenylhydrazine (7) in water was
heated to reflux in the presence of L-proline (40 mol%). After
10 min, equimolar amounts of aromatic aldehyde (8) and 2-
hydroxynaphthalene-1,4-dione (5) were added and reflux was
maintained for 1–1.5 h, which resulted in the formation of
compounds 3 in good to excellent yields (Table 3). Interestingly,
their purification required a minimum amount of organic solvent
and involved filtration of the solid material separated from
the reaction mixture, followed by its recrystallization from
acetonitrile or filtration through a short pad of silica gel.
Because of the existence of conflicting literature reports, the
structures of benzo[h]pyrazolo[3,4-b]quinoline-5,10-diones 3a–j
had to be characterized with special care. As a representative
case, the structural assignment of 3c is described below. In its 1H
NMR spectrum, H-1 and H-4 occur as doublets, respectively,
at 8.77 (J = 8.1 Hz) and 8.12 (J = 7.5 Hz) ppm (Fig. 3). H-1
shows a H,H-COSY correlation with H-2, which appears as a
triplet at 7.83 ppm (J = 7.6 Hz), which, in turn, shows a H,H-
COSY correlation with the triplet due to H-3 at 7.59 ppm (J =
7.8 Hz). The H-2¢¢,6¢¢ protons, appearing as a doublet at 7.50
ppm (J = 8.4 Hz), show (i) a H,H-COSY correlation with the
doublet of H-3¢¢,5¢¢ at 7.23 ppm (J = 8.4 Hz) and (ii) a HMBC
with C-7 at 153.8 ppm. H-4¢ appears as a triplet at 7.39 ppm (J =
7.2 Hz), which shows a H,H-COSY correlation with the triplet
at 7.59 ppm (J = 7.8 Hz) of H-3¢,5¢. H-3¢,5¢ show a H,H-COSY
correlation with H-2¢,6¢, appearing as a doublet at 8.28 ppm
(J = 8.4 Hz). The methyl hydrogens appearing as a singlet at
Scheme 2 Proof of the ortho-quinone structure of 3c, based on its
reaction with o-phenylenediamine.
The fact that the reaction proceeds in water in the absence of
any catalyst (Table 1, entry 1) shows that water itself promotes
the reaction, in spite of the fact that the starting materials
are water-insoluble. This behaviour is characteristic of on-water
processes, and we decided to further investigate this aspect of our
reaction. We next examined the non-catalyzed reaction in homo-
geneous solution in acetonitrile, tetrahydrofuran and methanol,
and found that less than 10% of intermediate 11 was formed
after 8 h, while when water was used as the reaction medium, this
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Table 4 Solvent effect on the sequential four-component reaction in
the presence of L-proline (40 mol%)
Entry
Solvent
Time/h
Yield of 3c (%)a
1
2
3
4
5
6
7
THF
DMF
Toluene
Methanol
Ethanol
Acetonitrile
Water
15
12
12
10
8
7
1.2
30
35
43
52
57
62
91
a Yield after filtration through a pad of silica gel.
base catalysis of L-proline. This “on water” effect, synergistic
with that of L-proline, could turn out to be of general value and
be important whenever steric hindrance in the transition state
of any reaction step prevents catalysis by L-proline.
Fig. 4 ORTEP diagram of compound 3b.
A plausible mechanism for the formation of benzo[h]-
pyrazolo[3,4-b]quinoline-5,10-diones 3 is depicted in Scheme
3. In the initial step, L-proline catalyses the Michael addition
of phenylhydrazine to 3-aminocrotononitrile, with concomitant
annulation via the elimination of ammonia, affording 3-methyl-
1-phenyl-1H-pyrazol-5-amine 11. Presumably, the bi-functional
nature of L-proline effectively assists the catalysis of many steps
in this transformation. This is also aided by the “on water”
catalysis, resulting in rate and yield enhancements. For instance,
the catalysis of the formation of 11 by L-proline is evidenced by
the fact that the whole domino process is faster in the presence
of L-proline than the formation of 11 in water in the absence
of catalyst. The catalysis by L-proline of aldol-type reactions
is normally accepted to involve the formation of iminium
intermediates.25 Thus, the reaction of 11 with the iminium species
generated from the aromatic aldehyde and L-proline furnishes
pyrazoloheterodiene 14. Subsequently, 5 undergoes a Michael
addition to 14, the reaction again probably being catalysed by
the dual nature of L-proline, affording 16 in two steps. Ultimately,
the aromatization of 16 to 3 through tautomer 17 presumably
occurs via air oxidation, which could also be enabled by L-proline
catalysis.
initial stage was complete in 3 h. The four-component sequential
reaction was then investigated in several organic solvents in the
presence of L-proline (40 mol%), wherein the reactions afforded
lower yields despite the use of much longer reaction times (Table
4). The unique features of the water–organic interface explain
the enhanced reactivity of hydrophobic organic substrates “on
water”. It is pertinent to note that the surface of the water,
adjoining the oily globules encompassing the reactants, has
as many as 25% of the O–H bonds not being involved in
hydrogen bonding.24 The interactions of these unbound hydroxyl
groups with organic reactants and, more importantly, with the
transition states, lower the activation energies, enabling rate and
yield enhancements. The continuous renewal and reorganization
of the hydroxyl groups on the water surface renders water a
powerful “catalyst” for organic transformations of insoluble
emulsioned substances. Thus, the benefit due to the “on water”
nature of the present multicomponent reaction can be ascribed
to the role of non-hydrogen bonded water molecules as hydrogen
bond donors, as well as hydrogen bond acceptors enabling them
to function as both an acid and a base, similar to the dual acid–
Scheme 3 A plausible mechanistic pathway to explain the L-proline-catalyzed formation of compounds 3 (for clarity, only the key steps are shown).
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calc. for C27H16N4O4: C, 70.43; H, 3.50; N, 12.17%. Found: C,
70.53; H, 3.42; N, 12.25%.
Conclusions
The “on water”, L-proline-catalyzed, four-component reaction
between phenylhydrazine, 3-aminocrotononitrile, substituted
benzaldehydes and 2-hydroxynaphthalene-1,4-dione affords ex-
cellent yields of synthetically and biologically relevant hetero-
cyclic ortho-quinones derived from the 5H-benzo[h]pyrazolo-
[3,4-b]quinoline-5,6(10H)-dione system. Our study has also
settled the divergent structural assignment previously reported
for these compounds. The protocol described here leads to the
generation of two new rings, together with two C–C, one C–N
and two C N bonds, and has the additional advantages of not
requiring a final extraction step nor column chromatography
for compound purification, and having no side products besides
water and ammonia. Furthermore, this protocol is also of inter-
est in view of the limited number of on-water multicomponent
reactions known in the literature.
7-(4-Fluorophenyl)-8-methyl-10-phenyl-5H -benzo[h]-pyra-
zolo[3,4-b]quinoline-5,6-(10H)-dione (3b). Yellow solid;◦ yield:
1
85% (crystallization) or 89% (filtration), m.p. 283–284 C; H
NMR (300 MHz, CDCl3) dH: 1.99 (s, 3H), 7.20–7.31 (m, 4H),
7.41 (t, 1H, J = 7.5 Hz), 7.59–7.64 (m, 3H), 7.83–7.88 (m, 1H),
8.17 (d, 1H, J = 7.5 Hz), 8.30 (d, 2H, J = 7.8 Hz), 8.82 (d,
1H, J = 7.8 Hz); 13C NMR (75 MHz, CDCl3) dC: 14.4, 115.6,
117.1, 120.0, 121.5, 126.7, 127.3, 129.0, 129.1, 129.2, 131.4,
131.7, 136.0, 137.3, 138.7, 146.3, 150.6, 151.1, 153.9, 163.0,
180.1, 180.5. Anal. calc. for C27H16FN3O2: C, 74.82; H, 3.72;
N, 9.69%. Found: C, 74.92; H, 3.82; N, 9.60%.
7-(4-Chlorophenyl)-8-methyl-10-phenyl-5H-benzo-[h]pyra-
zolo[3,4-b]quinoline-5,6-(10H)-dione (3c). Yellow solid; yield:
◦
1
85% (crystallization) or 91% (filtration), m.p. 248–250 C; H
NMR (300 MHz, CDCl3) dH: 1.97 (s, 3H), 7.23 (d, 2H, J =
8.4 Hz), 7.39 (t, 1H, J = 7.2 Hz), 7.50 (d, 2H, J = 8.4 Hz), 7.59 (t,
3H, J = 7.8 Hz), 7.83 (t, 1H, J = 7.6 Hz), 8.12 (d, 1H, J = 7.5 Hz),
8.28 (d, 2H, J = 8.4 Hz), 8.77 (d, 1H, J = 8.1 Hz); 13C NMR (75
MHz, CDCl3) dC: 14.4, 116.8, 119.8, 121.3, 126.6, 127.2, 128.6,
128.7, 129.1, 129.2, 131.4, 131.7, 134.3, 134.6, 136.0, 137.2,
138.6, 146.2, 150.5, 150.7, 153.8, 179.9, 180.3. Anal. calc. for
C27H16ClN3O2: C, 72.08; H, 3.58; N, 9.34%. Found: C, 71.99; H,
3.65; N, 9.24%.
Experimental section
Melting points were measured in open capillary tubes and are
uncorrected. A CEM Discover microwave synthesizer (Model
no. 908010) operating at 180/264 V and 50/60 Hz with a
consumption of 700 W, a microwave power maximum level of
300 W and a microwave frequency of 2455 MHz was employed
for the irradiation undertaken in this work. The 1H NMR,
13C NMR, DEPT, H,H-COSY and C,H-COSY spectra were
recorded on a Bruker (Avance) 300 MHz NMR instrument
using TMS as the internal standard and CDCl3 as the solvent.
Standard Bruker software was used throughout. Chemical shifts
are given in parts per million (d scale) and the coupling constants
are given in Hz. Silica gel-G plates (Merck) were used for TLC
analyses with a mixture of petroleum ether (60–80 ◦C) and ethyl
acetate as the eluent. Elemental analyses were performed on a
Perkin-Elmer 2400 Series II elemental CHNS analyzer.
7-(4-Methylphenyl)-8-methyl-10-phenyl-5H-benzo-[h]pyra-
zolo[3,4-b]quinoline-5,6-(10H)-dione (3d). Yellow solid; yield:
81%◦(crystallization) or 91% (filtration), m.p. 276–277 (273–
274) C;21c 1H NMR (300 MHz, CDCl3) dH: 1.97 (s, 3H), 2.48
(s, 3H), 7.17 (d, 2H, J = 7.8 Hz), 7.32 (d, 2H, J = 8.1 Hz),
7.37–7.42 (m, 1H), 7.57–7.63 (m, 3H), 7.81–7.86 (m, 1H), 8.15
(dd, 1H, J = 7.8, 1.2 Hz), 8.28 (d, 2H, J = 7.8 Hz), 8.81 (d,
1H, J = 7.8 Hz); 13C NMR (75 MHz, CDCl3) dC: 14.4, 21.4,
117.1, 120.1, 121.4, 126.5, 127.1, 127.2, 129.0, 129.1, 129.2,
131.2, 131.8, 132.8, 135.8, 137.5, 138.3, 138.8, 146.6, 150.6,
152.6, 153.7, 180.2, 180.7. Anal. calc. for C28H19N3O2: C, 78.31;
H, 4.46; N, 9.78%. Found: C, 78.40; H, 4.53; N, 9.68%.
General procedure for the synthesis of 7-(aryl)-8-methyl-10-
phenyl-5H-benzo[h]pyrazolo[3,4-b]quinoline-5,6(10H)-dione (3)
A mixture of 3-aminocrotononitrile (6) (1 mmol) and phenyl-
hydrazine (7) (1 mmol) was refluxed for 10 min in the presence
of L-proline (0.4 mmol) in water. Then, an equimolar mixture
of aromatic aldehyde (8) and 2-hydroxynaphthalene-1,4-dione
(5) was added, and the resulting reaction mixture heated under
reflux for 1–1.5 h. After completion of the reaction (TLC), the
black solid that separated was filtered, washed with water and
purified by recrystallization from acetonitrile (compounds 3a–
3e) or by filtration through a pad of silica gel using 9 : 1 petroleum
ether–ethyl acetate to afford pure compounds 3.
7-(4-Isopropylphenyl)-8-methyl-10-phenyl-5H-benzo[h]pyra-
zolo[3,4-b]quinoline-5,6(10H)-dione (3e). Yellow solid; yield:
◦
1
83% (crystallization) or 90% (filtration), m.p. 239–241 C; H
NMR (300 MHz, CDCl3) dH: 1.34 (d, 6H, J = 6.9 Hz), 1.93
(s, 3H), 2.98–3.07 (m, 1H), 7.19 (d, 2H, J = 8.1 Hz), 7.34–7.41
(m, 3H), 7.52–7.62 (m, 3H), 7.80–7.85 (m, 1H), 8.14 (dd, 1H,
J = 7.8, 2.7 Hz), 8.30 (d, 2H, J = 7.8 Hz), 8.79 (d, 1H, J =
8.1 Hz); 13C NMR (75 MHz, CDCl3) dC: 14.3, 24.0, 34.0, 117.2,
120.0, 121.4, 126.3, 126.5, 127.0, 127.2, 129.0, 129.1, 131.2,
131.6, 133.0, 135.9, 137.4, 138.7, 146.7, 149.2, 150.5, 152.7,
153.7, 180.0, 180.7. Anal. calc. for C30H23N3O2: C, 78.75; H,
5.07; N, 9.18%. Found: C, 78.84; H, 4.98; N, 9.10%.
7-(4-Nitrophenyl)-8-methyl-10-phenyl-5H-benzo[h]-pyrazolo-
[3,4-b]quinoline-5,6-(10H)-dione (3a). Yellow solid; yield: 83%
(crystallization) or 90% (filtration), m.p. 334–336 ◦C; 1H NMR
(300 MHz, CDCl3) dH: 1.95 (s, 3H), 7.40–7.45 (m, 1H), 7.49–7.52
(m, 2H), 7.60–7.66 (m, 3H), 7.84–7.90 (m, 1H), 8.16–8.19 (m,
1H), 8.29 (d, 2H, J = 7.5 Hz), 8.41 (d, 2H, J = 9.0 Hz), 8.82 (d, 1H,
J = 8.1 Hz); 13C NMR (75 MHz, CDCl3) dC: 14.5, 116.1, 121.5,
123.8, 126.9, 127.3, 128.2, 129.3, 129.4, 131.7, 136.2, 136.9,
138.4, 143.1, 145.7, 147.9, 149.2, 150.6, 153.9, 179.6, 179.8. Anal.
7-(3-Fluorophenyl)-8-methyl-10-phenyl-5H -benzo[h]pyra-
zolo[3,4-b]quinoline-5,6-(10H)-dione (3f). Yellow solid; yield:
◦
1
87%, m.p. 277–278 C; H NMR (300 MHz, CDCl3) dH: 1.96
(s, 3H), 7.06–7.22 (m, 3H), 7.36–7.62 (m, 5H), 7.84 (t, 1H, J =
7.5 Hz), 8.14 (d, 1H, J = 7.5 Hz), 8.28 (d, 2H, J = 8.1 Hz), 8.78
(d, 1H, J = 8.1 Hz); 13C NMR (75 MHz, CDCl3) dC: 14.2, 114.6,
115.4, 116.7, 119.6, 121.4, 122.9, 126.7, 127.2, 129.2, 130.2,
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130.3, 131.4, 131.8, 136.0, 137.2, 137.9, 138.6, 146.2, 150.3,
150.6, 153.8, 162.8, 179.7, 180.2. Anal. calc. for C27H16FN3O2:
C, 74.82; H, 3.72; N, 9.69%. Found: C, 74.73; H, 3.83; N, 9.77%.
(300 MHz, CDCl3) dH: 2.09 (s, 3H), 7.24–7.29 (m, 1H), 7.34–7.41
(m, 3H), 7.57 (d, 2H, J = 8.4 Hz), 7.62–7.80 (m, 4H), 7.81–7.86
(m, 2H) 8.19 (d, 1H, J = 7.5 Hz), 8.51–8.54 (m, 2H), 9.25–9.31
(m, 2H); 13C NMR (75 MHz, CDCl3) dC: 14.9, 116.8, 117.0,
118.0, 120.3, 120.9, 125.5, 125.6, 126.3, 128.1, 129.0, 129.1,
129.6, 129.8, 130.1, 130.5, 132.4, 133.1, 133.5, 138.9, 139.6,
140.4, 140.8, 142.1, 144.6, 146.1, 149.7, 150.0. Anal. calc. for
C33H20ClN5: C, 75.93; H, 3.86; N, 13.42%. Found: C, 75.84; H,
3.95; N, 13.50%.
7-(3-Bromophenyl)-8-methyl-10-phenyl-5H -benzo[h]pyra-
zolo[3,4-b]quinoline-5,6-(10H)-dione (3g). Yellow solid; yield:
90%, m.p. 288–290 ◦C; 1H NMR (300 MHz, CDCl3) dH: 1.99 (s,
3H), 7.23–7.46 (m, 4H), 7.58–7.67 (m, 4H), 7.83–7.87 (m, 1H),
8.17 (d, 1H, J = 7.8 Hz), 8.29 (d, 2H, J = 8.4 Hz), 8.81 (d, 1H,
J = 7.8 Hz); 13C NMR (75 MHz, CDCl3) dC: 14.4, 116.7, 121.1,
121.4, 122.5, 125.8, 125.9, 126.7, 127.2, 129.2, 129.4, 129.9,
131.5, 131.7, 136.0, 137.1, 137.9, 138.5, 146.2, 150.0, 150.5,
153.8, 179.6, 180.1. Anal. calc. for C27H16BrN3O2: C, 65.60; H,
3.26; N, 8.50%. Found: C, 65.52; H, 3.37; N, 8.41%.
Acknowledgements
S. P. and J. C. M. thank MICINN, Spain and the Department
of Science and Technology, New Delhi for funding for the Indo-
Spanish collaborative major research projects that made this
work possible (grant nos. DST/INT/SPAIN/09 and ACI2009-
0956). S. P. and J. C. M. also gratefully acknowledge the DST
for funds under the IRHPA program for the purchase of a
high-resolution NMR spectrometer and MICINN for grant
CTQ2009-12320-BQU, respectively. S. M. R. and B. D. B. thank
the University Grants Commission, New Delhi for the award of
Senior and Junior Research Fellowships, respectively.
7-(2,3-Dichlorophenyl)-8-methyl-10-phenyl-5H-benzo[h]pyra-
zolo[3,4-b]quinoline-5,6(10H)-dione (3h). Yellow solid; yield:
90%, m.p. 266–268 ◦C; 1H NMR (300 MHz, CDCl3) dH: 2.00 (s,
3H), 7.14 (dd, 1H, J = 7.8, 1.5 Hz), 7.35–7.43 (m, 2H), 7.57–7.68
(m, 3H), 7.81–7.86 (m, 1H), 8.17–8.20 (m, 1H), 8.31 (d, 2H,
J = 7.5 Hz), 8.40–8.43 (m, 1H), 8.83 (d, 1H, J = 7.5 Hz); 13C
NMR (75 MHz, CDCl3) dC: 13.7, 116.2, 119.4, 121.1, 121.5,
126.5, 126.8, 127.2, 127.5, 127.7, 129.2, 129.3, 130.6, 131.5,
131.8, 133.7, 134.2, 136.0, 137.2, 137.4, 145.9, 147.7, 154.0,
179.3, 179.7. Anal. calc. for C27H15Cl2N3O2: C, 66.96; H, 3.12;
N, 8.68%. Found: C, 66.87; H, 3.21; N, 8.77%.
Notes and references
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as a key concept towards eco-compatible organic synthesis, see: Y.
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organic synthesis: Chem. Soc. Rev., 2009, 38, 2969–3276.
7-(2,6-Dichlorophenyl)-8-methyl-10-phenyl-5H-benzo[h]pyra-
zolo[3,4-b]quinoline-5,6(10H)-dione (3i). Yellow solid; yield:
◦
1
88%, m.p. 257–259 C; H NMR (300 MHz, CDCl3) dH: 2.04
(s, 3H), 7.38–7.64 (m, 7H), 7.83–7.86 (m, 1H), 8.20 (d, 1H, J =
7.5 Hz), 8.34 (d, 2H, J = 7.5 Hz), 8.84 (d, 1H, J = 7.8 Hz); 13
C
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NMR (75 MHz, CDCl3) dC: 13.2, 115.8, 119.3, 121.3, 126.7,
127.1, 127.9, 128.1, 129.2, 129.4, 130.2, 131.5, 131.7, 132.7,
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calc. for C27H15Cl2N3O2: C, 66.96; H, 3.12; N, 8.68%. Found: C,
66.88; H, 3.01; N, 8.77%.
7-(Thiophen-2-yl)-8-methyl-10-phenyl-5H-benzo[h]pyrazolo-
[3,4-b]quinoline-5,6-(10H)-dione (3j). Yellow solid; yield: 88%,
m.p. 323–325 ◦C; 1H NMR (300 MHz, CDCl3) dH: 2.17 (s, 3H),
7.11 (d, 1H, J = 3.6 Hz), 7.28–7.39 (m, 2H), 7.56–7.65 (m, 3H),
7.79–7.82 (m, 2H), 8.19–8.22 (m, 1H), 8.36–8.41 (m, 3H); 13C
NMR (75 MHz, CDCl3) dC: 13.7, 117.2, 120.0, 121.2, 123.7,
126.6, 126.8, 126.9, 127.0, 127.3, 127.6, 129.3, 133.3, 134.0,
134.6, 136.1, 138.8, 142.9, 145.8, 149.1, 150.3, 181.6, 182.2. Anal.
calc. for C25H15N3O2S: C, 71.24; H, 3.59; N, 9.97%. Found: C,
71.35; H, 3.48; N, 9.90%.
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phenyl-3H-benzo[a]pyrazolo[4¢,3¢:5,6]pyrido-[2,3-c]phenazine
(9)
A vial containing an equimolar mixture of 3c and o-
phenylenediamine was sealed and placed in a CEM microwave
synthesizer. The vial was subjected to microwave irradiation
for 5 min, programmed at 120 ◦C and 150 W. After a period
of 3–5 min, the temperature reached a plateau of 120 ◦C and
remained constant. After completion of the reaction, the vial
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©