Microwave-assisted, sequential four-component synthesis of polysubstituted 5,6-dihydroquinazolinones from acyclic precursors and a mild, halogenation-initiated method for their aromatization under focused microwave irradiation

Article abstract of DOI:10.1039/c2gc36221j

A one-pot, microwave-assisted protocol has been developed for the synthesis of 5,6-dihydroquinazolinones that incorporate structural fragments from chalcones, acetylacetoacetate, ammonium formate and formamide. This process generates two rings, two carbon-carbon and three carbon-nitrogen bonds and does not require the use of chromatographic purification. The dihydroquinazolinones were efficiently aromatized without the need for metal-based oxidants by a microwave-assisted halogenation-elimination sequence in the presence of N-bromosuccinimide, again in the absence of chromatographic purification.

Full text of DOI:10.1039/c2gc36221j

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ARTICLE TYPE
Microwave-assisted,
sequential
four-component
synthesis
of
polysubstituted 5,6-dihydroquinazolinones from acyclic precursors and
a mild, halogenation-initiated method for their aromatization under
focused microwave irradiation
5
Damiano Rocchi,a J. Francisco Gonzáleza and J. Carlos Menéndeza*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
A
oneꢀpot, microwaveꢀassisted protocol has been developed for the synthesis of 5,6ꢀ
dihydroquinazolinones that incorporate structural fragments from chalcones, acetylacetoacetate,
10 ammonium formate and formamide. This process generates two rings, two carbonꢀcarbon and three
carbonꢀnitrogen bonds and does not require the use of chromatographic purification. The
dihydroquinazolinones were efficiently aromatized without the need for metalꢀbased oxidants by a
microwaveꢀassisted halogenationꢀelimination sequence in the presence of Nꢀbromosuccinimide, again in
the absence of chromatographic purification.
15
Quinazolinꢀ4(3H)ꢀones are an important class of heterocyclic
compounds that are widespread in nature11 and exhibit interesting
pharmacological properties. Quinazolinone is considered
1. Introduction
The search for efficiency in symnthetic protocols can be
considered as one of the primary goals of Green Chemistry. One
of the most promising approaches to this type of efficiency relies
20 on the use of multibondꢀforming reactions,1 and in particular of
multicomponent reactions (MCRs),2,3 which can be defined as
convergent processes having three or more starting materials that
contribute significantly to the final product. MCRs have emerged
as powerful tools in the synthesis of new chemical entities in
25 pharmaceutical and agrochemical research and offer advantages
such as operational simplicity, facile automation and, very
interestingly from the viewpoint of green chemistry, reduction in
the number of workꢀup, extraction and purification processes, and
hence minimized waste generation. MCRs are widely employed
30 for the creation of libraries of drugꢀlike compounds with high
levels of molecular complexity and diversity, thereby facilitating
a
privileged structure in the discovery of protein kinase inhibitors,
50 one of the current key areas in the development of
chemotherapeutic agents,12 and therefore it is not surprising that
its derivatives exhibit antitumor,13 antiviral,14 antitubercular,15
antifungal,16 antiꢀHIV17 and antibacterial activities.18 Many
synthetic methods have been reported for the preparation of
55 quinazolinone derivatives and their analogues,19 and most of
them are variations of the Von Niementowski reaction, based on
cyclocondensation reactions of anthranilic acids, their nitriles or
amides.
2. Results and discussion
60 Against this background, we describe here a new, efficient and
userꢀfriendly synthetic process involving the combination of
MCR methodology and microwave heating and allowing the oneꢀ
pot preparation of 5,6ꢀdihydroquinazolinꢀ4ꢀones 7 from readily
available materials such as chalcones 1, 1,3 dicarbonyl
65 compounds 2, butylamine 3, ammonium formate and formamide
via intermediate anthranilate derivatives 4, 5 and 6 (Scheme 1).
This work was stimulated by our interest in the study of Ce(IV)
ammonium nitrate (CAN) as a catalyst in synthesis,20 which led
to the development of a new CANꢀcatalyzed MCR for the
70 synthesis of highly substituted and functionalized derivatives of
2ꢀaminoꢀ1ꢀcyclohexeneꢀ1ꢀcarboxylic acid 4.21 Based on our
experience in handling these compounds, we predicted that it
should be possible to induce an in situ thermal dehydration
reaction leading to intermediates 5 by carrying out the threeꢀ
lead identification and optimization in drug discovery.4
particularly interesting recent development connected to MCRs is
the diversityꢀoriented synthesis of structurally varied small
35 molecules via the BuildꢀCoupleꢀPair strategy.5
A
We chose to combine the advantages of multicomponentꢀbased
strategies with those of microwave assisted organic synthesis
(MAOS),6 which is considered a green methodology7 because
this methodology usually leads to simple protocols and short
40 processing time, often with increased product yields and lower
costs. Furthermore, the use of microwave irradiation in sealed
vessels is accompanied by reduced energy consumption,8 which
has been attributed mainly to shortened reaction time.9 It has been
recently stated that these improvements in energy efficiency are
45 significant mainly for industrialꢀscale applications.10
his journal is © The Royal Society of Chemistry [year]
[journal], [year], [vol], 00–00 | 1

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35 washed with water. Importantly from the viewpoint of green
chemistry, compound purification did not require
chromatography; instead, the crude product from ethyl acetate
evaporation was crystallised from diethyl ether to yield the
desired compounds 6 in 47ꢀ67% overall yields for a process that
40 involves the formation of five different bonds (Scheme 1).
component reaction under microwaveꢀassisted conditions.
Because of the need for a primary amino substituent, which is set
to eventually become the second quinazoline nitrogen, we also
planned an in situ displacement of butylamine by ammonia via an
additionꢀelimination mechanism, which was facilitated by the
conjugation of the position bearing the butylamino substituent
with the carbonyl group. The use of a twoꢀstep sequence for the
generation of intermediate 6 instead of employing ammonia in
the initial threeꢀcomponent reaction was prompted by the fact that
5
As shown in Table 1, in our initial experiments we
investigated the effect on the overall yield of the nature of the
alkoxy substituent on the ester group, finding little difference
between the ethoxy, methoxy and tertꢀbutyloxy substituents
45 (entries 1ꢀ3). The multiꢀstep sequence was initially assayed from
starting materials bearing phenyl substituents and demonstrated
good tolerance for either electronꢀwithdrawing or electronꢀ
releasing groups at both rings (entries 4ꢀ11). In the case of the
compound bearing a 4ꢀnitrophenyl substituent, the corresponding
50 aromatic quinazolinone 8e was obtained instead of the expected
dihydro derivative (entry 7). This peculiar behaviour may be
explained by the generation of a hydroperoxide in the benzylic
position of the nonꢀisolated compound 7e by reaction of a
molecule of oxygen under freeꢀradical conditions,25 followed by
55 elimination of hydrogen peroxide, and is probably due to the
ability of the nitro group to behave as an intermediate in oneꢀ
electron transfer reactions.26 In subsequent experiments, we
proved that one or both phenyls can be replaced by heterocyclic
substituents (2ꢀfuryl and 2ꢀthienyl), which significantly extends
60 the scope of the method (entries 12ꢀ17). Complex mixtures were
obtained in all attempts to use ethyl 3ꢀoxopentenoate or ethyl 3ꢀ
oxohexenoate as the βꢀketoester component, which would have
afforded compounds 7 bearing, respectively, methyl or ethyl
substituents at the Cꢀ8 position.
10 the reactions between chalcones, βꢀketoesters and ammonia are
known to give pyridine derivatives.22 Finally, we planned to
finish the sequence by a microwaveꢀassisted Von Niementowskiꢀ
type cyclocondensation23 of
6 with formamide to give
dihydroquinolines 7. We sought to combine the three reactions
15 involved in our planned sequential multicomponent process to
yield a protocol with a minimum of manual operations and
purification steps and which was exempt from chromatographic
purification stages, since they are responsible for most of the
waste generated in synthetic procedures, in the form of volatile
20 organic solvents and discarded chromatographic stationary
phases.
After much preliminary experimentation, we arrived at suitable
conditions for carrying out all the stages of the desired
transformation. Thus, an ethanol solution of chalcones 1a-i,24
25 ethyl acetoacetate, butylamine and CAN as a catalyst was
irradiated with microwave for 2.5 h, at 150 °C. Ammonium
formate was then added to the reaction mixture, which was
further irradiated for 1 h. Finally, the solvent was removed and
this was followed by the addition of formamide and microwave
30 irradiation at 200 °C for 30 minutes. The reaction mixture was
cooled and extracted with ethyl acetate and the organic phase was
65
Table 1. Scope and yields in the oneꢀpot synthesis of compounds 7
Entry Starting
material
Ar1
Ar2
R
Product
Overall
yield, % a
56
Ar1
O
1
2
3
4
5
6
7
8
1a
1a
1a
1b
1c
1d
1e
1f
Ph
Ph
Ph
Ph
Ph
Ph
Et
Me
tꢀBu
Et
Et
Et
Et
Et
Et
Et
7a
7a
7a
7b
7c
7d
8eb
7f
CAN, EtOH,
MW, 200 W,
150 °C, 2.5 h
Ar1
O
62
54
55
48
OR
CH3
OR
4ꢀMeOC6H4 4ꢀMeOC6H4
- H2O
Ar2
O
O
Ph
4ꢀMeOC6H4
Ph
Ar2
NH
1
2
OH
4ꢀMeOPh
4ꢀNO2C6H4
4ꢀClC6H4
4ꢀBrC6H4
Ph
47
NH2
n-Bu
Ph
64b
62
4
n-Bu
4ꢀClC6H4
4ꢀClC6H4
4ꢀClC6H4
Ph
- H2O
3
9
10
11
1g
1h
1i
7g
7h
7i
46
67
48
4ꢀClPh
Et
Ar1
O
Ar1
O
-
NH4+HCO2
12
13
14
15
16
17
1j
1k
1l
Ph
Et
Et
Et
Et
Et
Et
7j
7k
7l
52
54
67
72
70
76
O
OR
OR
NH2
Ph
Ar2
NH
Ar2
O
-
n-BuNH3+HCO2
n-Bu
Same conditions, 1h
6
5
O
O
1m
1n
1o
Ph
7m
7n
7o
EtOH evaporation,
O
S
- EtOH
- H2O
Ph
S
H
NH2
MW, 200 W,
200 °C, 1 h
S
S
a
b
Ar1
O
N
Isolated yields after crystallization. This reaction led directly to the
aromatic compound 8e (see Scheme 2 and Table 2)
NH
Ar2
7
Scheme 1. Oneꢀpot synthesis of compounds 7 from openꢀchain precursors
2 | Journal Name, [year], [vol], 00–00This journal is © The Royal Society of Chemistry [year]

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The mechanistic pathway proposed in Scheme 1 was supported
position that is simultaneously benzylic and allylic (Cꢀ5) and
another one that can be considered as a vinylogous αꢀcarbonyl
45 position (Cꢀ6), we examined the possibility of carrying out the
desired aromatization by means of an halogenationꢀelimination
sequence. As shown in Scheme 2 and Table 2, microwave
irradiation for 30ꢀ60 min of an acetonitrile solution of compounds
7 in the presence of Nꢀbromosuccinimide worked generally well
50 and afforded the desired compounds 8 in 56ꢀ84% isolated yields,
without detection of the intermediate bromo derivative and also
without undesired halogenations of the aromatic substituents.
Interestingly, a radical initiator was not required and the
purification of compounds 8 could be carried out by a simple
55 crystallization of the crude reaction product.
by the isolation of the proposed intermediates 5a and 6a, which
were subsequently transformed into 7a under the conditions
employed for the oneꢀpot sequence. Thus, irradiation for 2.5
hours, at 200 W and 150 ºC, of an ethanol solution of chalcone
1a, ethyl acetoacetate 2 and butylamine 3 afforded compound 5a
in 75% isolated yield. These conditions also afforded 5a from a
sample of compound 4a,21 confirming that it is the first cyclic
intermediate of the process. When 5a was irradiated with
10 microwave for 1 h in ethanol containing ammonium formate,
under the same conditions used for the first step, compound 6a
was obtained in 80% yield. Finally, irradiation at 200 °C for 1 h
of a solution of 6a in formamide afforded compound 7a in 50%
yield. It is interesting to note that the overall yield of this
15 stepwise route is 30%, and hence significantly lower than the one
obtained in the oneꢀpot protocol, due to the unavoidable losses of
material that always happen during the purification steps.
5
3. Conclusions
In summary, we have developed a safe, inexpensive and fast
microwaveꢀassisted method for the synthesis of 5,6ꢀ
With compounds 7 in hand, we examined their aromatization
to the corresponding quinazolinones. While this transformation
20 could conceivably have been carried out by a conventional
method such as DDQꢀinduced dehydrogenation, this reaction has
to be performed in benzene, a highly toxic solvent, and requires
chromatography in order to separate the desired product from the
DDQ hydroquinone generated as a side product in the course of
25 the reaction. Alternative commonly employed dehydrogenation
methods involve the use of PdꢀC or selenium dioxide, which are
also harmful to the environment, owing to the generation of toxic
residues. Hence, we sought to develop more environmentally
friendly conditions for the desired transformation, ideally not
30 involving the use of strong oxidants. This is an important
consideration in green chemistry, since oxidation reactions
involving metalꢀbased reagents are not readily amenable to
industrial scaleꢀup and often serve as sources of toxic byproducts
that lead to considerable environmental damage.27 For these
35 reasons, and in view of the existence in our compounds of a
dihydroquinazolinꢀ4ꢀ(3H)ꢀones via
a
oneꢀpot sequential
60 multicomponent strategy that creates two rings, two carbonꢀ
carbon bonds (one of them double) and three carbonꢀnitrogen
bonds (one of them double). Furthermore, purification of the final
products does not require chromatographic separation. An
efficient and userꢀfriendly method for the aromatization of the
65 dihydroquinazolinones was also developed, based on
a
microwaveꢀassisted halogenationꢀelimination sequence in the
presence of Nꢀbromosuccinimide, which had the advantage of not
requiring the use of highly polluting traditional dehydrating
agents. Further work investigating the extension of the method to
70 the green synthesis of additional classes of biologically relevant
heterocycles is in progress in our laboratory.
4. Experimental
General experimental information. All reagents and solvents
were of commercial quality and were used as received. Reactions
75 were monitored by TLC analysis, on Merck silica gelꢀG
aluminium plates with fluorescent indicator. Melting points were
measured in open capillary tubes and are uncorrected. A CEM
Discover microwave synthesizer with microwave power
maximum level of 300 W and microwave frequency of 2455
80 MHz was employed for the microwaveꢀassisted reactions. The
1HꢀNMR, 13CꢀNMR and C,Hꢀcorrelation spectra were recorded
on a Bruker (Avance) 250 MHz NMR instrument maintained by
the CAI de Resonancia Magnética Nuclear, Universidad
Complutense, using CDCl3, d6ꢀDMSO or CD3OD as solvents and
85 residual nonꢀdeuterated solvents as internal standards. Topspin
(Bruker) or Mestrenova (Mestrelab) software packages were used
throughout for data processing; chemical shifts are given in parts
per million (δꢀscale) and coupling constants are given in Hertz.
Combustion microanalyses were performed by the CAI de
90 Microanálisis Elemental, Universidad Complutense, on a Leco
932 CHNS analyzer. IR spectra were recorded on a Perkin Elmer
Paragon 1000 FTꢀIR instrument using thin films placed on a KBr
disk, which were obtained by evaporation of a CHCl3 or CDCl3
solution of the compounds.
Ar1
O
Ar1
O
NBS, CH3CN,
MW, 200 W, 80 °C
NH
NH
Ar2
N
Ar2
N
8
6
Scheme 2. Microwaveꢀassisted aromatization of compounds 6
Table 2. Scope and yields in the aromatization of compounds 6
Entry
Product
8a
8b
8c
8d
8e
8f
8g
8h
Ar1
Ph
Ar2
Ph
Yield, % a,b
1
2
3
4
5
6
7
8
9
74
57
4ꢀMeOPh 4ꢀMeOPh
Ph
4ꢀMeOPh
4ꢀNO2C6H4
4ꢀClPh
4ꢀBrPh
Ph
4ꢀMeOPh
Ph
85
c
d
Ph
4ꢀClPh
4ꢀClPh
4ꢀClPh
Ph
60
56
84
78
8i
4ꢀClPh
10
8l
68
O
O
a
b
Isolated yields after crystallization. Reaction time was 30 min for the
c
40 synthesis of 8c, and 60 min for the other reactions. A complex mixture
was obtained in this case. d The aromatization step was unnecessary, since
8e was obtained directly from the oneꢀpot sequence shown in Scheme 1
This journal is © The Royal Society of Chemistry [year]Journal Name, [year], [vol], 00–00 | 3

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General procedure for the one-pot synthesis of 5,6-
dihydroquinazolin-4(3H)-ones 7
5-(4-Methoxyphenyl)-7-phenyl-5,6-dihydroquinazolin-4(3H)-
60 one 7d. Yield: 47 % as a white solid. Mp 202ꢀ203 ºC; IR νmax
(KBr): 2850, 1649, 1588 cmꢀ1; 1H NMR (250 MHz, d6ꢀDMSO) δ
12.37 (s, 1H), 8.11 (s, 1H), 7.61 – 7.51 (m, 2H), 7.45 – 7.26 (m,
5H), 7.15 – 7.06 (m, 2H), 6.80 – 6.71 (m, 3H), 4.29 (d, J = 8.6
Hz, 1H), 3.21 (ddd, J = 17.5, 8.6, 2.9 Hz, 1H), 2.99 (dd, J = 17.5,
A microwave tube containing a solution of the suitable chalcone
1a-o (1.1 eq), ethyl acetoacetate 2 (1.0 eq), butylamine 3 (1.3 eq)
and CAN (0.05 eq) in ethanol (5 mL), was closed and placed in
the cavity of a CEM Discover focused microwave oven. The
5
reaction mixture was irradiated with microwave for 2.5 h, at 200 65 1.1 Hz, 1H). 13C NMR (63 MHz, d6ꢀDMSO) δ 160.5, 157.9,
W and 150 °C. The tube was left to cool to 60 ºC and ammonium
formate (5.0 eq) was added to the reaction mixture, which was
10 irradiated for an additional period of 1 h, under the same
conditions. The solvent was removed under a stream of argon, the
155.4, 148.4, 144.1, 138.7, 134.9, 128.9, 128.8, 127.9, 125.6,
122.5, 119.4, 113.7, 54.9, 33.3, 33.1. Anal. Calcd: C 76.34%, H
5.49%, N 8.48%; found: C 76.11%, H 5.47%, N 8.38%;
residue was dissolved in formamide (2 mL) and the solution was 70 5,7-Bis-(4-chlorophenyl)-5,6-dihydroquinazolin-4(3H)-one 7f.
irradiated at 200 W and 200 °C for 30 min. The reaction mixture
was allowed to cool to room temperature and was diluted with
15 AcOEt (15 mL). The organic phase was washed with 1M aqueous
HCl (10 mL), water (10 mL) and brine (10 mL), dried over
Yield: 62 % as a white solid. Mp 307ꢀ308 ºC; IR νmax (KBr):
2922, 1647, 1586 cmꢀ1; 1H NMR (250 MHz, d6ꢀDMSO) δ 12.40
(s, 1H), 8.14 (s, 1H), 7.63 (d, J = 8.2 Hz, 2H), 7.42 (d, J = 8.2 Hz,
2H), 7.22 (d, J = 8.2 Hz, 2H), 6.82, (d, J = 8.2 Hz, 2H), 4.36 (d,
anhydrous Na2SO4, filtered and evaporated under reduced 75 J = 8.5 Hz, 1H), 3.25 (ddd, J = 17.5, 8.6, 2.9 Hz, 1H), 2.94 (dd, J
pressure to give a residue that was purified by recrystallization
from diethyl ether to furnish pure compounds 7a-d and 7fꢀo In
20 the case of the reaction starting from the nitrochalcone 1e, the
corresponding aromatic derivative 8e was obtained instead of the
expected compound 7e.
= 17.5, 1.1 Hz, 1H). 13C NMR (63 MHz, d6ꢀDMSO) δ 160.8,
155.8, 149.1, 143.0, 142.2, 137.6, 133.8, 131.5, 129.1, 129.1,
128.6, 127.8, 123.4, 119.1, 33.7, 33.1. Anal. Calcd: C 65.06%, H
3.82%, N 7.59%; found: C 64.86%, H 3.93%, N 7.62%.
80
5-(4-Bromophenyl)-7-(4-chlorophenyl)-5,6-dihydro-
5,7-Diphenyl-5,6-dihydroquinazolin-4(3H)-one 7a. Yield: 70%
quinazolin-4(3H)-one 7g. Yield: 46 % as a pale yellow solid. Mp
306ꢀ307 ºC; IR νmax (KBr): 2756, 1645, 1587 cmꢀ1; 1H NMR (250
MHz, d6ꢀDMSO) δ 12.45 (s, 1H), 8.14 (s, 1H), 7.60 (d, J = 8.5
25 as a pale yellow solid. Mp 272ꢀ273 ºC; IR νmax (KBr): 2918,
1
1646, 1590 cmꢀ1; H NMR (250 MHz, CDCl3) δ 12.24 (s, 1H),
8.07 (s, 1H), 7.58 – 7.48 (m, 2H), 7.46 – 7.30 (m, 6H), 7.28 – 85 Hz, 2H), 7.47 – 7.36 (m, 4H), 7.14 (d, J = 8.5 Hz, 2H), 6.82 (d,
7.15 (m, 2H), 6.85 (d, J = 2.7 Hz, 1H), 4.54 (d, J = 7.6 Hz, 1H),
3.34 (ddd, J = 17.6, 7.6, 2.7 Hz, 1H), 3.18 (dd, J = 17.6, 1.7 Hz,
30 1H). 13C NMR (63 MHz, CDCl3) δ 163.0, 157.4, 147.1, 146.2,
142.6, 139.1, 129.0, 128.7, 128.5, 127.1, 127.0, 125.8, 122.8,
J = 2.7 Hz, 1H), 4.33 (d, J = 8.4 Hz, 1H), 3.23 (ddd, J = 17.5, 9.0,
2.7 Hz, 1H), 2.97 (dd, J = 17.5, 1.3 Hz, 1H). 13C NMR (63 MHz,
d6ꢀDMSO) δ 160.33, 155.51, 148.71, 142.68, 142.31, 137.30,
133.51, 131.21, 129.20, 128.75, 127.47, 123.09, 119.63, 118.72,
119.4, 34.6, 33.6. Anal. Calcd: C 79.98%, H 5.37%, N 9.33%; 90 33.41, 32.70. Anal. Calcd: C 58.07%, H 3.41%, N 6.77%; found:
found: C 79.77%, H 5.24%, N 9.18%.
C 59.09%, H 3.24%, N 6.73%.
35 5,7-Bis-(4-methoxyphenyl)-5,6-dihydroquinazolin-4(3H)-one
7b. Yield: 55% as a pale yellow solid. Mp 256ꢀ257 ºC; IR νmax
5-Phenyl-7-(4-chlorophenyl)-5,6-dihydroquinazolin-4(3H)-
one 7h. Yield: 67 % as a pale yellow solid. Mp 279ꢀ280 ºC; IR
1
(KBr): 2924, 1643, 1587 cmꢀ1; 1H NMR (250 MHz, d6ꢀDMSO) δ 95 νmax (KBr): 2964, 1650, 1585 cmꢀ1; H NMR (250 MHz, d6ꢀ
12.33 (s, 1H), 8.08 (s, 1H), 7.56 (d, J = 8.8 Hz, 2H), 7.10 (d,
J = 8.8 Hz, 2H), 6.94 (d, J = 8.8 Hz, 2H), 6.75 (d, J = 8.8 Hz,
40 2H), 6.69 (d, J = 2.3 Hz, 1H), 4.27 (d, J = 7.7 Hz, 1H), 3.76 (s,
3H), 3.65 (s, 3H), 3.14 (ddd, J = 17.2, 7.7, 2.5 Hz, 1H), 2.99 (d,
DMSO) δ 12.41 (s, 1H), 8.13 (s, 1H), 7.64 – 7.53 (m, 2H), 7.46 –
7.38 (m, 2H), 7.27 – 7.15 (m, 5H), 6.82 (d, J = 2.7 Hz, 1H), 4.35
(d, J = 8.1 Hz, 1H), 3.24 (ddd, J = 17.6, 9.0, 2.8 Hz, 1H), 2.99
(dd, J = 17.6, 1.3 Hz, 1H). 13C NMR (63 MHz, d6ꢀDMSO) δ
J = 16.2 Hz, 1H). 13C NMR (63 MHz, d6ꢀDMSO) δ 160.0, 157.9, 100 160.40, 155.43, 148.52, 142.92, 142.75, 137.43, 133.42, 128.73,
148.2, 148.2, 143.8, 135.1, 131.0, 128.0, 127.1, 120.4, 120.3,
118.7, 114.2, 113.6, 55.3, 54.9, 33.1. Anal. Calcd: C 73.32%, H
45 5.59%, N 7.77%; found: C 73.10%, H 5.38%, N 7.62%.
128.33, 127.42, 126.90, 126.54, 123.11, 119.20, 33.84, 32.97.
Anal. Calcd: C 71.75%, H 4.52%, N 8.37%; found: C 71.40%, H
4.63%, N 8.18%.
7-(4-Methoxyphenyl)-5-phenyl-5,6-dihydroquinazolin-4(3H)-
one 7c. Yield: 48 % as a yellow solid. Mp 271ꢀ272 ºC; IR νmax
(KBr): 2917, 1665, 1580 cmꢀ1; 1H NMR (250 MHz, d6ꢀDMSO) δ
50 12.35 (s, 1H), 8.10 (s, 1H), 7.56 (d, J = 8.9 Hz, 2H), 7.27 – 7.08
(m, 6H), 6.94 (d, J = 8.9 Hz, 2H), 6.70 (d, J = 2.5 Hz, 1H), 4.33
105 5-(4-Chlorophenyl)-7-phenyl-5,6-dihydroquinazolin-4(3H)-
one 7i. Yield: 48 % as a white solid. Mp 264ꢀ265 ºC; IR νmax
1
(KBr): 2924,1639,1587 cmꢀ1; H NMR (250 MHz, d6ꢀDMSO) δ
12.28 (s, 1H), 8.14 (s, 1H), 7.57 (dd, J = 7.9, 1.7 Hz, 2H), 7.48 –
7.31 (m, 3H), 7.31 – 7.15 (m, 4H), 6.78 (d, J = 2.7 Hz, 1H), 4.35
(d, J = 7.2 Hz, 1H), 3.18 (ddd, J = 17.4, 8.6, 2.6 Hz, 1H), 3.03 110 (d, J = 8.1 Hz, 1H), 3.25 (ddd, J = 17.6, 9.0, 2.8 Hz, 1H), 3.01
(dd, J = 17.6, 1.6 Hz, 1H). 13C NMR (63 MHz, d6ꢀDMSO) δ
160.4, 159.9, 156.0, 148.4, 143.8, 143.2, 130.8, 128.3, 127.1,
55 126.9, 126.5, 120.5, 118.3, 114.2, 55.3, 33.9, 32.9. Anal. Calcd:
C 76.34%, H 5.49%, N 8.48%; found: C 76.17%, H 5.24%, N
8.21%.
(dd, J = 17.6, 1.4 Hz, 1H). 13C NMR (63 MHz, d6ꢀDMSO) δ
160.4, 155.7, 148.7, 144.1, 142.0, 138.5, 131.1, 129.0, 128.8,
128.8, 128.3, 125.6, 122.5, 118.5, 33.4, 32.9. Anal. Calcd: C
71.75%, H 4.52%, N 8.37%; found: C 71.44%, H 4.47%, N
115 8.21%.
4 | Journal Name, [year], [vol], 00–00This journal is © The Royal Society of Chemistry [year]

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1
5-(2-Furyl)-7-phenyl-5,6-dihydroquinazolin-4(3H)-one
7j. 60 1652, 1578 cmꢀ1; H NMR (250 MHz, d6ꢀDMSO) δ: 12.43 (s,
1H), 8.09 (s, 1H), 7.65 (d, J = 4.8 Hz, 1H), 7.54 (d, J = 3.2 Hz,
1H), 7.24 – 7.17 (m, 1H), 7.17 – 7.10 (m, 1H), 6.84 (d, J = 3.4
Hz, 2H), 6.66 (d, J = 1.7 Hz, 1H), 4.59 (d, J = 5.6 Hz, 1H), 3.28 –
3.06 (m, 2H).13C NMR (63 MHz, d6ꢀDMSO) δ: 148.7, 145.7,
Yield: 52 % as a brown solid. Mp 192ꢀ193 ºC; IR νmax (KBr):
2924, 1668, 1585 cmꢀ1; H NMR (250 MHz, d6ꢀDMSO) δ: 8.16
1
(1H, s), 7.56 (3H, dd, J = 7.0, 1.7 Hz), 7.48 – 7.32 (7H, m), 7.28
(1H, d, J = 1.1 Hz), 6.78 (1H, d, J = 2.7 Hz), 6.19 (2H, dd,
5
J = 3.2, 1.9 Hz), 5.93 (1H, d, J = 3.2 Hz), 4.63 (1H, d, J = 7.7 65 142.8, 138.6, 128.6, 128.0, 126.7, 126.5, 124.1, 123.7, 119.7,
Hz), 3.35 (1H, dd, J = 17.5, 1.5 Hz), 3.09 (2H, ddd, J = 17.4, 8.2,
2.7 Hz). 13C NMR (63 MHz, d6ꢀDMSO) δ: 162.8, 154.5, 147.6,
147.1, 141.9, 139.1, 129.3, 128.9, 126.1, 122.2, 117.2, 110.3,
33.4, 30.0. Anal. Calcd: C 61.51%, H 3.87%, N 8.97%; found: C
61.44%, H 3.97%, N 8.61%
.
10 107.0, 105.7, 29.8, 29.3. Anal. Calcd: C 74.47%, H 4.86%, N
9.65%; found: C 74.44%, H 4.57%, N 9.41%.
General procedure for the aromatization of compounds 6 to
5,7-diarylquinazolin-4(3H)-ones 8
70 A microwave tube containing an acetonitrile solution of the
suitable 5,6ꢀdihydroquinazolinꢀ4(3H)ꢀone 7 (1.0 eq), and Nꢀ
bromosuccinimide (1.0 eq) was sealed and placed in the cavity of
a CEM Discover microwave oven. The reaction mixture was
irradiated with microwave for 60 min, at 80 °C, except for the
75 case of compound 7c (30 min). The tube was cooled to 0 ºC and
its content was filtered to give a residue that was purified by
recrystallization from ethanol to give compounds 8.
7-(2-Furyl)-5-(2-phenyl)-5,6-dihydroquinazolin-4(3H)-one 7k.
Yield: 54 % as a yellow solid. Mp 268ꢀ270 ºC; IR νmax (KBr):
1
15 cmꢀ1; H NMR (250 MHz, d6ꢀDMSO) δ: 8.05 (1H, s), 7.74 (1H,
d, J = 1.7 Hz), 7.23 – 7.01 (6H, m), 6.83 (1H, d, J = 3.4 Hz), 6.64
(1H, d, J = 2.0 Hz), 6.53 (1H, dd, J = 3.4, 1.8 Hz), 4.28 (1H, dd,
J = 7.6, 2.3 Hz), 2.99 (2H, dd, J = 10.2, 2.5 Hz). 13C NMR (63
MHz, d6ꢀDMSO) δ: 160.3, 155.4, 152.3, 148.4, 144.9, 142.8,
20 133.3, 128.3, 126.9, 126.5, 118.9, 118.4, 112.4, 111.0, 33.4, 30.7.
Anal. Calcd: C 74.47%, H 4.86%, N 9.65%; found: C 74.24%, H
4.57%, N 9.31%.
5,7-Diphenylquinazolin-4(3H)-one 8a. Yield: 74% as a white
80 solid. Mp > 370 ºC; IR νmax (KBr): 3061, 1770, 1681 cmꢀ1 1
H
NMR (250 MHz, MeOD) δ 9.25 (s, 1H), 8.05 (s, 1H), 7.94 (d, J =
1.7 Hz, 1H), 7.83–7.79 (m, 1H), 7.77 (m, 2H), 7.54 (m, 4H), 7.42
(bs, 5H). 13C NMR (63 MHz, MeOD) δ 166.2, 149.7, 148.7,
146.8, 141.6, 139.2, 131.6, 130.5, 130.4, 129.9, 128.7, 128.5,
85 119.7, 118.5. Anal. Calcd: C 80.52%, H 4.73%, N 9.39%; found:
C 80.48%, H 4.54%, N 9.18%.
5,7-Bis-(2-furyl)-5,6-dihydroquinazolin-4(3H)-one 7l. Yield:
25 67 % as a yellow solid. Mp 250ꢀ252 ºC; IR νmax (KBr): 2926,
1
1760, 1660, 1588 cmꢀ1; H NMR (250 MHz, d6ꢀDMSO) δ 8.08
(1H, s), 7.78 (1H, d, J = 1.6 Hz), 7.45 (1H, s), 6.91 (1H, d,
J = 3.4 Hz), 6.66 – 6.52 (2H, m), 6.23 (1H, dd, J = 3.2, 1.9 Hz),
5.84 (1H, d, J = 3.2 Hz), 4.36 (1H, d, J = 7.7 Hz), 3.09 (1H, dd,
30 J = 17.3, 1.3 Hz), 2.88 (1H, ddd, J = 17.3, 8.0, 2.6 Hz). 13C NMR
(63 MHz, d6ꢀDMSO): 162.6, 160.0, 154.7, 152.2, 148.7, 144.8,
141.9, 133.4, 117.8, 116.4, 116.0, 112.4, 111.0, 110.2, 105.3,
28.2, 27.9. Anal. Calcd: C 68.56%, H 4.32%, N 9.99%; found: C
68.44%, H 4.47%, N 9.71%.
5,7-Bis(4-methoxyphenyl)quinazolin-4(3H)-one 8b. Yield:
57% as a white solid. Mp 267ꢀ268 ºC; IR νmax (KBr): 2546,
90 1659, 1605 cmꢀ1; 1H NMR (250 MHz, d6ꢀDMSO) δ 8.14 (s, 1H),
8.01 (s, 1H), 7.60 (s, 1H), 7.14 (d, J = 8.7 Hz, 2H), 7.09 (d, J =
8.7 Hz, 2H), 6.89 (d, J = 2.7 Hz, 2H), 6.86 (d, J = 2.7 Hz, 2H),
3.75 (s, 6H). 13C NMR (63 MHz, d6ꢀDMSO) δ 160.5, 158.6,
158.3, 147.8, 145.8, 138.5, 132.3, 132.1, 130.6, 128.6, 127.2,
95 113.7, 55.08, 55.1. Anal. Calcd: C 73.73%, H 5.06%, N 7.82%;
found: C 73.50%, H 4.98%, N 7.62%.
35
7-Phenyl-5-(2-thienyl)-5,6-dihydroquinazolin-4(3H)-one 7m.
Yield: 72 % as a white solid. Mp 217ꢀ219 ºC; IR νmax (KBr):
2912, 1693, 1642, 1580 cmꢀ. 1H NMR (250 MHz, CDCl3) δ:
13.17 (s, 1H), 8.11 (s, 1H), 7.65 – 7.58 (m, 2H), 7.50 – 7.36 (m,
40 3H), 7.06 (dd, J = 5.1, 1.3 Hz, 1H), 6.98 – 6.92 (m, 1H), 6.86 (dd,
J = 5.1, 3.5 Hz, 2H), 4.84 (dd, J = 6.6, 2.8 Hz, 1H), 3.29 (dd, J =
6.4, 2.4 Hz, 2H).13C NMR (63 MHz, CDCl3) δ: 163.1, 157.0,
147.6, 146.7, 145.2, 139.2, 129.3, 128.9, 126.5, 126.2, 124.5,
123.6, 122.9, 119.6, 33.9, 30.7. Anal. Calcd: C 70.56%, H 4.61%,
45 N 9.14%; found: C 70.44%, H 4.47%, N 9.21%.
7-(4-Methoxyphenyl)-5-phenylquinazolin-4(3H)-one 8c. Yield:
85% as a yellow solid. Mp 285ꢀ286 ºC; IR νmax (KBr): 2597,
100 1703, 1580 cmꢀ1; 1H NMR (250 MHz, d6ꢀDMSO) δ 8.75 (s, 1H),
7.91 (d, J = 1.8 Hz, 1H), 7.81 (d, J = 8.8 Hz, 2H), 7.58 (d, J = 1.8
Hz, 1H), 7.39 (bs, 5H), 7.08 (d, J = 8.8 Hz, 2H), 3.82 (s, 3H). 13
C
NMR (63 MHz, d6ꢀDMSO) δ 160.2, 158.7, 147.8, 145.0, 144.1,
140.7, 129.8, 129.0, 128.7, 128.6, 127.3, 127.2, 119.6, 117.1,
105 114.8, 55.4. Anal. Calcd: C 76.81%, H 4.91%, N 8.53%; found:
C 76.47%, H 4.74%, N 8.31%.
5-(2-Phenyl)-7-(2-thienyl)-5,6-dihydroquinazolin-4(3H)-one
7n. Yield: 70 % as a pale brown solid. Mp 272ꢀ274 ºC; IR νmax
1
(KBr): 3348, 1693, 1638, 1573 cmꢀ1; H NMR (250 MHz, d6ꢀ
50 DMSO) δ: 12.39 (s, 1H), 8.10 (s, 1H), 7.62 (d, J = 4.9 Hz, 1H),
7.46 (d, J = 3.5 Hz, 1H), 7.25 – 7.07 (m, 6H), 6.68 (d, J = 2.2 Hz,
1H), 4.34 (d, J = 6.1 Hz, 1H), 3.29 – 3.01 (m, 2H).13C NMR (63
MHz, d6ꢀDMSO) δ: 160.2, 155.4, 148.5, 143.0, 142.8, 138.2,
128.6, 128.4, 127.8, 126.9, 126.6, 126.5, 120.0, 118.9, 33.8, 33.3.
55 Anal. Calcd: C 70.56%, H 4.61%, N 9.14%; found: C 70.44%, H
4.47%, N 9.21%.
5-(4-Nitrophenyl)-7-phenylquinazolin-4(3H)-one 8e. Yield:
64% as a pale brown solid. Mp 317ꢀ318 ºC. IR νmax (KBr): 3276,
1
110 2947, 1656 cmꢀ1; H NMR (250 MHz, d6ꢀDMSO) δ: 8.24 (d, J =
9.0 Hz, 2H), 8.17 (s, 1H), 8.02 (d, J = 2.0 Hz, 1H), 7.99 (s, 1H),
7.88 (d, J = 7.5 Hz, 1H), 7.69 (d, J = 9.0 Hz, 2H), 7.59 (d, J = 2.0
Hz, 1H), 7.56 – 7.44 (m, 4H), 7.32 (s, 1H); 13C NMR (63 MHz,
d6ꢀDMSO) δ 160.1, 151.2, 149.1, 146.8, 146.6, 145.0, 141.5,
115 138.4, 130.8, 129.6, 129.4, 128.7, 128.1, 127.7, 125.7, 122.6.
5,7-Bis-(2-thienyl)-5,6-dihydroquinazolin-4(3H)-one 7o. Yield:
76 % as a pale brown solid. Mp 246ꢀ248 ºC; IR νmax (KBr): 3072,
This journal is © The Royal Society of Chemistry [year]Journal Name, [year], [vol], 00–00 | 5

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Coquerel, T. Boddaert, M. Presset, D. Mailhol and J. Rodriguez, in
B. Pignataro (Ed.) Ideas in Chemistry and Molecular Sciences, Vol. 1
Advances in Synthetic Chemistry, Chapter 9, WileyꢀVCH,
Weinheim, 2010, p. 187; (b) See also the Chemical Society Reviews
issue on “Rapid formation of molecular complexity in Organic
Synthesis”: Chem. Soc. Rev. 2009, 38, 2969ꢀ3276.
For selected recent reviews, see: (a) A. Dömling, W. Wang and K.
Wang, Chem. Rev. 2012, 112, 3083. (b) M. J. Climent, A. Corma and
S. Iborra, RSC Adv. 2012, 2, 16. (c) C. de Graaff, E. Ruijter and R. V.
A. Orru, Chem. Soc. Rev. 2012, 41, 3969. (d) C. M. Marson, Chem.
Soc. Rev. 2012, 41, 7712. (e) B. Jiang, T. Rajale, W. Wever, S.ꢀJ. Tu
and G. Li, Chem. Asian J. 2010, 5, 2318. (f) M. M. Sánchez Duque,
C. Allais, N. Isambert, T. Constantieux and J. Rodriguez, Top.
Heterocycl. Chem. 2010, 23, 227. (g) B. B. Touré and D. G. Hall,
Chem. Rev. 2009, 109, 4439. (h) Isambert, N.; Lavilla, R. Chem. Eur.
J. 2009, 14, 8444.
For a recent monograph, see: (a) R. V. A. Orru and E. Ruijter, Eds.
Synthesis of Heterocycles via Multicomponent Reactions I; Topics in
Heterocyclic Chemistry; Springer Verlag: New York, 2010; Volume
23. (b) R. V. A. Orru and E. Ruijter, Eds. Synthesis of Heterocycles
via Multicomponent Reactions II; Topics in Heterocyclic Chemistry;
Springer Verlag: New York, 2010; Volume 25.
(a) L. Weber, Curr. Med. Chem., 2002, 9, 2085. (b) C. Hulme and V.
Gore, Curr. Med. Chem., 2003, 10, 51.
T. E. Nielsen and S. L. Schreiber, Angew. Chem. Int. Ed., 2008, 47,
48.
For selected general monographs and reviews on microwaveꢀassisted
organic synthesis, see: (a) A. Loupy (Ed.) Microwaves in Organic
Synthesis. WileyꢀVCH, 2002. (b) R. S. Varma, Advances in Green
Chemistry: Chemical Synthesis Using Microwave Irradiation.
AstraZeneca Research Foundation India, 2002. (c) J. Tierney and P.
Lindstrom, Microwave Assisted Organic Synthesis. Blackwell, 2004.
(d) C. O. Kappe, Angew. Chem. Int. Ed. 2004, 43, 6250.
For a review of the impact of microwave irradiation on green
chemistry, see: C. R. Strauss and R. S. Varma, Top. Curr. Chem.
2006, 266, 199.
For a recent example involving experimental measurements of energy
consumption for standard and microwaveꢀassisted conditions, see: P.
Prasanna, K. Balamurugan, S. Perumal and J. C. Menéndez, Green
Chem. 2011, 13, 2123.
(a) M. J. Gronnow, R. J. White, J. H. Clark and D. J. Macquarrie,
Org. Process Res. Devel. 2005, 9, 516. (b) T. Razzaq and C. O.
Kappe, ChemSusChem 2008, 1, 123.
Anal. Calcd: C 69.96%, H 3.82%, N 12.24%; found: C 69.64%,
H 4.05%, N 12.43%.
5,7-Bis(4-chlorophenyl)quinazolin-4(3H)-one 8f. Yield: 60% as
5
a white solid. Mp > 370 ºC; IR νmax (KBr): 2922, 1672, 1603
1
cmꢀ1; H NMR (250 MHz, d6ꢀDMSO) δ 8.51 (s, 1H), 8.02 (d,
2
J = 1.9 Hz, 1H), 7.95 (d, J = 8.6 Hz, 2H), 7.64 (m, 4H), 7.48 (m,
4H).13C NMR (63 MHz, d6ꢀDMSO) δ 159.7, 148.6, 147.5, 143.9,
142.9, 140.2, 137.1, 134.3, 132.3, 131.2, 129.6, 129.5, 128.7,
10 127.6, 123.2, 118.8. Anal. Calcd: C 65.41%, H 3.29%, N 7.63%;
found: C 65.36%, H 3.43%, N 7.62%.
7-(4-Chlorophenyl)-5-(4-bromophenyl)quinazolin-4(3H)-one
8g. Yield: 56% as a white solid. Mp >370 ºC; IR νmax (KBr):
15 2931, 1672, 1604 cmꢀ1; 1H NMR (250 MHz, d6ꢀDMSO) δ 8.17 (s,
1H), 7.96 (d, J = 1.9 Hz, 1H), 7.89 (d, J = 8.5 Hz, 2H), 7.57 (d,
J = 1.9 Hz, 2H), 7.56 – 7.51 (m, 3H), 7.34 (d, J = 8.5 Hz, 2H).
13C NMR (63 MHz, d6ꢀDMSO) δ 159.7, 150.5, 146.4, 143.2,
142.4, 140.6, 137.0, 133.8, 131.2, 130.0, 129.2, 129.1, 127.8,
20 124.5, 120.4, 118.8. Anal. Calcd: C 58.35%, H 2.94%, N 6.80%;
found: C 58.09%, H 2.74%, N 6.73%;
3
4
5
6
7-(4-Chlorophenyl)-5-phenylquinazolin-4(3H)-one 8h. Yield:
84% as a white solid. Mp 309ꢀ310 ºC; IR νmax (KBr): 2587, 1672,
1
25 1604 cmꢀ1; H NMR (250 MHz, d6ꢀDMSO) δ 8.51 (s, 1H), 7.95
(d, J = 1.9 Hz, 1H), 7.90 (s, 1H), 7.87 (s, 1H), 7.59 (s, 1H), 7.57
– 7.54 (m, 2H), 7.38 (s, 5H). 13C NMR (63 MHz, d6ꢀDMSO) δ
159.1, 147.3, 144.0, 143.6, 140.9, 136.8, 133.9, 129.2, 129.2,
129.0, 128.6, 127.3, 127.1, 122.1, 118.4. Anal. Calcd: C 72.18%,
30 H 3.94%, N 8.42%; found: C 72.40%, H 3.63%, N 8.28%.
7
8
5-(4-Chlorophenyl)-7-phenylquinazolin-4(3H)-one 8i. Yield:
78% as a white solid. Mp > 370 ºC; IR νmax (KBr): 2974, 1728,
1
1652 cmꢀ1. H NMR (250 MHz, MeOD) δ 9.15 (s, 1H), 7.86 (t,
9
35 J = 7.4 Hz, 1H), 7.77 (s, 1H), 7.75 – 7.71 (m, 2H), 7.46 – 7.36
(m, 6H), 7.09 (d, J = 8.9 Hz, 2H). 13C NMR (63 MHz, MeOD) δ
162.6, 150.4, 148.8, 147.1, 141.8, 141.4, 131.4, 131.0, 129.9,
129.9, 128.8, 117.4, 115.9. Anal. Calcd: C 72.18%, H 3.94%, N
8.42%; found: C 72.34%, H 3.67%, N 8.21%.
10 J. D. Moseley and C. O. Kappe, Green Chem. 2011, 13, 794.
11 For reviews of the quinazoline alkaloids, see: (a) C. Avendaño and J.
C. Menéndez, Curr. Org. Chem. 2003, 7, 149. (b) A. Witt and J.
Bergman, Curr. Org. Chem. 2003, 7, 659. (c) S. B. Mhaske and N. P.
Argade, Tetrahedron 2006, 62, 9787. (d) S. Eguchi, Top. Heterocycl.
Chem. 2006, 6, 113.
12 (a) C. Avendaño and J. C. Menéndez, Medicinal Chemistry of
Anticancer Drugs, chapter 9. Elsevier, 2008. (b) S. K. Srivasta, V.
Kumar, S. K. Agarwal, R. Mukherjee and A. C. Burman, Anticancer
Agents Med. Chem. 2009, 9, 246. (c) O. CruzꢀLópez, A. Conejoꢀ
García, M. C. Núñez, M. Kimatrai, M. E. GarcíaꢀRubino, F. Morales,
V. GómezꢀPérez, J. Campos, Curr. Med. Chem. 2011, 18, 943.
13 a) N. J. Liverton,; Armstrong, D. J.; Claremon, D. A.; Remy, D. C.;
Baldwin, J. J.; Lynch, R. J.; Zhang, G.; Gould, R. J. Bioorg. Med.
Chem. Lett. 1998, 8, 483. b) Zhang, W.; Mayer, J. P.; Hall, S. E.;
Weigel, J. A. J. Comb. Chem. 2001, 3, 255.
40
5,7-Bis-(2-furyl)quinazolin-4(3H)-one 8j. Yield: 68% as a pale
1
brown solid. Mp 143ꢀ145ºC; IR νmax (KBr): cmꢀ1. H NMR (250
MHz, CDCl3) δ: 8.01 (2H, s), 7.90 (1H, d, J = 1.8 Hz), 7.58 (2H,
d, J = 1.8 Hz), 6.92 (1H, d, J = 3.4 Hz), 6.74 (1H, dd, J = 3.4,
45 0.8 Hz), 6.55 (2H, m). 13C NMR (63 MHz, CDCl3) δ: 161.23,
152.49, 151.98, 151.20, 144.01, 142.65, 135.62, 132.33, 125.38,
122.36, 118.60, 114.19, 112.39, 111.36, 110.04, 108.88. Anal.
Calcd: C 69.06%, H 3.62%, N 10.07%; found: C 69.34%, H
3.67%, N 10.21%.
14 (a) P. Selvam, B. Chennama and E. De Clercq, J. Chem. Sci. 2004, 2,
627. (b) M. Schleiss, J. Eickhoff, S. Auerochs, M. Leis, S. Abele, S.
Rechter, S. Ensminger, B. Klebl, T. Stamminger and M. Marschall,
Antiviral Res. 2008, 79, 49.
15 C. G. Bonde, A. Peepliwal and N. J. Gaikwad, Arch. Pharm. Chem.
Life Sci. 2010, 343, 228.
16 Z. Xu, Y. Zhang, H. Fu, H. Zhong, K. Hong and W. Zhu, Bioorg.
Med. Chem. Lett. 2011, 21, 4005.
17 T. P. Selvam, P. V. Kumar, A. S. Kumar and I. A. Emerson, J.
Pharm. Res. 2010, 3,1637.
50 Notes and references
a
Departamento de Química Orgánica y Farmacéutica, Facultad de
Farmacia, Universidad Complutense, 28040 Madrid, Spain. Fax: 34
913941822; Tel: 34 913941840; E-mail: josecm@farm.ucm.es
† Electronic Supplementary Information (ESI) available: Spectra of all
55 compounds. See DOI: 10.1039/b000000x/
1
(a) For a general overview of multiple bondꢀforming transformations
as a key concept towards ecoꢀcompatible Organic Synthesis, see: Y.
18 P. Ilangovan, S. Ganguly and V. Pandi, J. Pharm. Res. 2010, 3, 703.
6 | Journal Name, [year], [vol], 00–00This journal is © The Royal Society of Chemistry [year]

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19 For reviews, see: (a) M. M. Vögtle and A. L. Marzinzik, QSAR
Comb. Sci. 2004, 23, 440. (b) D. J. Connolly, D. Cusack, T.
P. O'Sullivan and P. J. Guiry, Tetrahedron 2005, 61, 10153.
20 For a review of the use of CAN as a catalyst in synthesis, see:
Sridharan, V. and Menéndez, J. C. Chem. Rev. 2010, 110, 3805ꢀ3849.
21 V. Sridharan, J. C. Menéndez, Org. Lett. 2008, 10, 4303.
22 (a) J. Safari, S. H. Banitaba and S. D. Khalili, J. Mol. Catal. A:
Chem. 2011, 335, 46. (b) G. Tenti, M. T. Ramos and J. C. Menéndez,
ACS Comb. Sci. 2012, 14, 551.
23 For selected literature predecent for microwaveꢀassisted Von
Niementowski reactions, see: (a) F. R. Alexandre, A. Berecibara and
T. Besson, Tetrahedron Lett. 2002, 43, 3911. (b) P. Cledera, J. D.
Sánchez, E. Caballero, E. G. Ramírez, T. Yates, C. Avendaño, M. T.
Ramos and J. C. Menéndez, Synthesis 2007, 3390.
24 For the synthesis of the starting chalcones, see: (a) D. C. G. A. Pinto,
A. M. S. Silva, A. Levai, J. A. S. Cavaleiro, T. Patonay and J.
Elguero, Eur. J. Org. Chem. 2000, 2593. (b) L. Delaude, J.
Grandjean and A. F. Noels, J. Chem. Educ. 2006, 83, 1225. (c) M. M.
C. Santos, A. M . S. Silva, J. A. S. Cavaleiro, A. Levai and T.
Patonay, Eur. J. Org. Chem. 2007, 2877ꢀ2887. (d) S. Attar, Z.
O’Brien, H. Alhaddad, M. L. Golden and A. CalderónꢀUrrea, Bioorg.
Med. Chem. 2011, 19, 2055.
25 For precedent of a related oxidation that was also peculiar to a
substrate containing an aromatic nitro substituent, see: P. Cledera, M.
Villacampa, C. Avendaño and J. C. Menéndez Arkivoc 2011 (iii), 72.
26 B. Halliwell and J. M. Gutteridge, Free Radicals in Biology and
Medicine, 3rd Ed. p. 601. Oxford University Press, 1999.
27 For a review of the concept of redox economy in synthesis, see: N. Z.
Burns, P. S. Baran and R. W. Hoffmann, Angew. Chem. Int. Ed.
2009, 48, 2854.
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