Facile preparation of 3-substituted 2-quinazolinones via electrogenerated base

Article abstract of DOI:10.1016/j.tet.2018.03.010

A new series of 3,4-disubstituted quinazolin-2-ones, with potential T-type calcium channel antagonist activity, and new 4-methylene-quinazolin-2-ones, promising catalysts as N-heterocyclic olefins, have been prepared in good yield by a simple reaction between 2-aminobenzophenone, or 2-aminoacetophenone, and cyanomethyl anion electrogenerated by acetonitrile reduction at a graphite electrode, followed by the addition of different organic isocyanates and subsequent heterocyclization.

Full text of DOI:10.1016/j.tet.2018.03.010

Accepted Manuscript
Facile preparation of 3-substituted 2-quinazolinones via electrogenerated base
Najwa Sbei, Belen Batanero, Fructuoso Barba, Beya Haouas, Mohamed Lamine
Benkhoud, Isidoro Barba
PII:
S0040-4020(18)30253-9
10.1016/j.tet.2018.03.010
TET 29350
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 11 January 2018
Revised Date: 13 February 2018
Accepted Date: 5 March 2018
Please cite this article as: Sbei N, Batanero B, Barba F, Haouas B, Benkhoud ML, Barba I, Facile
preparation of 3-substituted 2-quinazolinones via electrogenerated base, Tetrahedron (2018), doi:
10.1016/j.tet.2018.03.010.
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Tetrahedron
journal homepage: www.elsevier.com
Facile Preparation of 3-Substituted 2-Quinazolinones via Electrogenerated Base
Najwa Sbeic, Belen Batanero*a,b, Fructuoso Barbaa, Beya Haouasc, Mohamed Lamine Benkhoudc and
Isidoro Barbaa
a Department of Organic Chemistry, University of Alcalá, 28871 Alcalá de Henares (Madrid), Spain
b Instituto de Investigación Química “Andrés M. del Río” (IQAR), University of Alcalá, 28871 Alcalá de Henares (Madrid),
Spain
cLaboratoire de Chimie Analytique et d´Electrochimie. Faculté des Sciences, Université Tunis El Manar 2092 El-Manar (Tunis),
Tunisia
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A new series of 3,4-disubstituted quinazolin-2-ones, with potential T-type calcium
channel antagonist activity, and new 4-methylene-quinazolin-2-ones, promising catalysts
as N-heterocyclic olefins, have been prepared in good yield by a simple reaction between
2-aminobenzophenone,
or
2-aminoacetophenone,
and
cyanomethyl
anion
Available online
electrogenerated by acetonitrile reduction at a graphite electrode, followed by the addition
of different organic isocyanates and subsequent heterocyclization.
Keywords:
.
Quinazolin-2-ones,
N-heterocyclic olefins
magnesium sacrificial anode,
electrogenerated cyanomethyl anion,
organic isocyanates.
dimethoxyphenyl)-3-phenyl-urea and benzoic acid. Zhu et al.9
described an efficient synthesis of 4-alkyl-2(1H)-quinazolinones
by cyclization of 1-(2-alkynyl-phenyl)ureas catalyzed by TfOH.
More recently Odell et al.10 published a rapid access to
1. Introduction
Quinazolinone and their derivatives are building block for
approximately 150 naturally occurring alkaloids isolated from
plants, microorganisms and animals.1 Some compounds
incorporating quinazolinone motif possess antitumor activities2,3
and exhibit a variety of biological functions like DNA binding
agents4 non-steroidal anti-inflammatory potential or sedative
analgesic effects.
A vast number of 4-quinazolinones have been synthesized5 to
provide synthetic drugs and to design more effective medicines.
However there have been few reports about the synthesis of 2-
quinazolinones. The general protocol involves the cyclization of
o-disubstituted benzene derivatives such as 2-acyl or 2-
cyanoanilines in combination with appropiate electrophiles or
nucleophiles. Conley et al.6 utilized a direct metalation approach
starting with 3,4-dimethoxyanilin with n-butyllithium, then
treating with potassium cyanate and followed by cyclization in
polyphosphoric acid. Vicente et al.7 reported the first ortho-
palladated arylurea complexes, obtained by oxidative addition
reactions, and studied their reactivity toward different reagents to
prepare 2-quinazoline-2,4-dione derivatives. Ivanov8 synthesized
polyfunctionalized
3,4-dihydroquinazolinones
through
a
sequential N-acyliminium ion Mannich reaction cascade.
Merck11 was interested in the synthesis of a series of 4-
(arylethynyl)-6-chloro-4-cyclopropyl-3,4-dihydroquinazolin-2
(1H)-ones as novel non-nucleoside HIV-1 reverse-transcriptase
inhibitors. Modification at the 3- and 4-positions of the
quinazolinone ring by different substituents afforded potent and
selective T-type calcium channel antagonist12,13 that displayed in
vivo central nervous system efficacy in epilepsy and tremor
models.14 Furthermore these antagonists are attracting a lot of
interest for the treatment of peripheral and central nervous system
(CNS) disorders15 or as effective agents for pain therapies.16
The first 4-alkenylquinazolinone synthesis was described by
Brack17 as an acidic rearrangement reaction starting from
quinoline-1-carboxamides. This procedure was applied by
Zolotykh.18 Similarly, Molina et al.19 described the 4-methylene
derivatives formation when refluxing 2-[(aminocarbonyl)
amino]- 3,1-benzoxazines. However in the last 30 years only a
6,7-dimethoxy-3,4-diphenyl-2(1H)-quinazolinone from 1-(3,4-
———
* Corresponding author. Tel.: +34 91 8854617; e-mail address: belen.batanero@uah.es

2
Tetrahedron
+ 2 e-
few new approaches to prepare them have been achieved. In the
2
CH2CN
N
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2 CH3CN
- H2
synthesis of 4-methylene-3,4-dihydroquinazolin-2-ones it has
been found that 1-(o-alkynylaryl)ureas are privileged substrates
that provide an adequate framework to explore alternative
reaction pathways in the metal-catalysed hydroamidation of
alkynes.20,21 This effective gold(I)complex-catalysed approach to
4-methylenequinazolin-2-ones, similarly to their formation via
the palladium oxidative alkoxycarbonylation of 2-ethynylaniline
derivatives,22 suffer however the drawbacks that these transition
metal reagents entail.
NH2
NH
CH3CN
CN
CN
H3C
CH2CN
CN
H3C
H3C
Scheme 2. Cathodic formation of 3-amino-crotonitrile anion.
The quantity of the electrogenerated cyanomethyl anion (EGB)
depends on the total circulated charge through the
electrochemical cell (solution). In absence of a proton donor the
carbanion is produced in a 1 F/mol process, however at the
present work, to synthesize 2-quinazolinones, a significant excess
of the EGB was necessary. It was because a complete proton
abstraction from anilines (as acidic substrates) requires a higher
base concentration, but also due to the inherent dimerization of
cyanomethyl anion that, even minimized, takes place in some
extend.
4-Methylene quinazolin-2-one core structures represent, as
recently discovered,23 new potential inhibitors of FGFR kinases
with substantial therapeutic value in different cancers, including
breast, pancreatic or prostate cancers. On the other hand, 4-
methylene N-substituted quinazolin-2-one frameworks, due to
their structural exocyclic double bond, could be promising
compounds to be applied as organocatalyst in polymer chemistry,
similarly to N-heterocyclic olefins (NHO), with demonstrated
ability to promote or catalyse such reactions.24
Once the optimal quantity of electrogenerated base was formed,
the current supplier was switched off and then the corresponding
2-aminophenone (1) was added to the reaction medium.
Subsequent deprotonation of the amine to a nitride occurs by the
effect of the EGB, as indicated in Scheme 3.
Electrogenerated radical anions and anions are basic reagents,
called EGBs which can be used to deprotonate and to initiate
many base catalyzed reactions. The use of EGB in organic
synthesis is well documented.25 Carbanions, as strong bases, may
be used to generate nucleophiles from other acidic components of
the reaction mixture. Moreover radical anions as EGBs have a
great potential in organic synthesis, as demonstrated in the
stereoselective cyclopropanation to homoquinones from phenacyl
carbenes, that we have recently highlighted.26
O
O
R1
R1
CH2CN
(EGB)
+ CH3CN
+
NH2
NH
(1)
R1= Ph(a), Me(b)
Scheme 3. Deprotonation of 2-aminophenones (1a) and (1b) by EGB.
Intrigued now by promising further expectation of
acetonitrile anion, as strong EGB, in the preparation of many
heterocyclic molecules, we focused our attention on using the
electrochemistry as a tool to prepare quinazolin-2-one moieties.
Herein we report, as outlined in Scheme 1, a novel strategy for
the conversion of readily available substrates into 3,4-
disubstituted quinazolin-2-ones (3) and 4-methylene-3-
substituted quinazolin-2-ones (4). Electrogenerated cyanomethyl
anion (EGB) and 2-aminophenones evolve to 3 (or 4) when
reacted with aryl (or alkyl) isocyanates by heterocyclization.
Aromatic ketones are well known electro-reducible carbonyl
substrates, both under protic and aprotic solvents. For this reason
compounds 1 are avoided to be present in the electrolytic solution
at the applied galvanostatic conditions, needed to produce the
EGB.
The freshly generated nitride attacks further an organic
isocyanate molecule (2), subsequently introduced into the
reaction medium, providing a new anionic intermediate. The
latter finally cyclises through an addition reaction to the carbonyl
group of the ketone, leading, as detailed in Scheme 4, to the 2-
quinazolinone scaffolds after protonation during the work-up.
O
HO R1
N
CH2
R2
R2
(2)
R1
R2-N=C=O
- CH3CN
N
when R1= Me
- H2O
O
O
CH2CN
(EGB)
O
R1
N
+
N
NH2
O
R2
N
O
(2)
R2-N=C=O
H
H
3
R1
R1
1
4
N
R2
Scheme 1. Outline of the synthetic procedure described in this paper
N
O
NH
H
HN
O
2. Results and Discussion
work-up
H3O+
R2= Bn(a), Et(b), Pr(c), Bu(d), Cyclohexyl(e), Ph(f), 4-Cl-C6H4(g)
It is well established that the electrochemical reduction of
acetonitrile in the presence of a quaternary ammonium salt as
supporting electrolyte yields the corresponding cyanomethyl
anion, a strong basic entity, with a pKa value of c.a. 3227 capable
of removing a weak acidic proton. When this reduction is carried
out at a platinum, graphite or stainless steel cathode, under an
argon atmosphere, the anion of 3-aminocrotonitrile28,29 is also
formed after the nucleophilic attack of the cyanomethyl anion to
a new solvent molecule, as indicated in Scheme 2. However, the
use of low temperatures and a sacrificial magnesium anode, in an
undivided cell, avoids to a large extent this undesired reaction. It
occurs because the subsequently formed magnesium cations,
present in solution, stabilize the cyanomethyl anions by ion-pair
association.30
HO R1
CH2
R2
R2
when R1= Me
- H2O
N
N
N
O
N
O
H
H
3(a-g)
4(a-g)
Scheme 4. Formation of 3,4-disubstituted-2-quinazolinones 3(a-g) and 4-methylene-
3-substituted-2-quinazolinones 4(a-g).
Moreover, the electrolytic conditions were optimized in terms
of reaction times (once selected a constant current value of 120
mA, see experimental section) in order to get the best obtained
yield on 3 or 4, regarding the cyanomethyl anion dimerization
product, 2-aminocrotonitrile, finally formed by the excess of
EGB.
The afforded yields of a variety of substituted products 3 (a-g)
and 4 (a-g), when alkyl: benzyl (a), ethyl (b), propyl (c), butyl
(d) and cyclohexyl (e) or aryl: phenyl (f) and 4-chlorophenyl (g)

3
isocyanates were used, are summarized in the experimental
section of the manuscript. The complete characterization of these
quinazolin-2-ones was performed according to their
spectroscopic and spectrometric properties, becoming curious, at
time that relevant, the final spontaneous dehydration of 4-
hydroxy derivatives from starting acetophenone to the
corresponding isolated compounds 4, while 2-amino
benzophenone derivatives were isolated as 4-hydroxy-4-phenyl-
2-quinazolinones (3).
Although numerous organic reactions using bases as catalysts
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have already been studied, the number and types of these bases
are rather limited. Hence the generation of active bases “in situ”
with adequate control of the amount of the base is often highly
desirable in the development of new synthetic reactions, as the
preparation of quinazolin-2-one moieties now described.
Cathodic reduction is evidently one of the most efficient methods
to generate such bases in the reaction systems.
4. Experimental Section
The heterocyclization reaction that evolves to the
quinazolinone ring was further supported by the heteronuclear
multiple bond correlation (gradient HMBC) two-dimensional
spectrum (13C and 1H-NMR data) of 4-hydroxy-4-phenyl-3-butyl-
2-quinazolinone (3d), that is shown in Figure 1. The two un-
equivalent methylene hydrogen atoms, directly joined to the
nitrogen at 3-position of the ring (that appear at δ= 3.20 ppm and
3.40 ppm) correlate, according to a three-bond distance, with
quaternary sp3 carbon at the C4 position of the diazine ring (δ=
66.9 ppm) and with the carbonyl group (δ= 153.1 ppm). Such
reciprocity is essential to characterize the cyclization product.
Electrolyses were carried out using a DC-Power Promax
Model FA-672 as constant current supply. The temperature was
maintained constant at 0 ºC by a cryostat Grant Model LTD 6G.
Mass spectra (EI, ionizing voltage 70 eV) were determined using
a
THERMOFISHER ITQ-900 DIP/GC-MSn mass-selective
detector. IR spectra of the compounds were recorded as
dispersions in KBr or NaCl films on a Perkin-Elmer FT-IR
1
spectrometer Spectrum 2000. H NMR and 13C NMR spectra
were recorded in a Varian Mercury 300 (1H 300 MHz and 13C
75.4 MHz) spectrometer and a Bruker 500 spectrometer (1H 500
MHz and 13C 125 MHz) at 25 ºC, as CDCl3 solutions with
tetramethylsilane (TMS) as the internal standard. Two-
dimensional HMBC correlation NMR experiments were
performed in the Bruker 500 MHz spectrometer. The chemical
shifts are given in ppm. Melting points were measured on a
Reichert Thermovar microhot stage apparatus and are
uncorrected. Elemental analyses were performed on a Leco
CHNS Model 932 analyser.
4.1. Electrochemical formation of cyanomethyl anion:
A solution of dry acetonitrile (60 mL) and tetrabutyl
ammonium tetrafluoroborate (TBABF4) (2.6 g, 8 mmol) was
electrolyzed under galvanostatic conditions (I= 120, 140 or 200
mA) in an undivided cell, equipped with a magnetic stirrer, using
a graphite cylinder (40 cm2, empty) as the cathode and a
sacrificial magnesium rod (9 cm2) as the anode (Figure 2).
Figure 1. Two-dimensional HMBC correlation spectrum of 3d in
CDCl3.
When the reaction is performed in absence of argon, the water
molecules from air protonate the anionic intermediate evolving to
the corresponding urea (not cyclized product, Scheme 5), whose
1
HMBC spectrum does not present the above-mentioned 13C- H-
NMR correlations, because the diazine ring has not been formed.
O
O
Figure 2. Electrolytic cell for acetonitrile reduction.
R1
R1
H2O
The electrochemical reactions were performed at 0 °C under
an argon atmosphere, and different reaction times. The last
parameter was modified in order to optimize the results. The best
obtained yield on 3 (or 4) regarding the cyanomethyl anion
dimerization product was obtained when the charge consumption
corresponded to the formation of 10 mmol of the desired base
(EGB) (approximately 1000 coulombs). When shorter reaction
times were applied, with subsequent lower charges circulated
through the cell, the yields on quinazolin-2-ones were
definitively decreased.
N
R2
HN R2
N
H
N
H
O
O
Scheme 5. Obtained side product: 1-(2-acyl(aroyl)phenyl)-3-alkyl(aryl) urea.
In summary, a new alternative reaction pathway, involving
cyanomethyl anion as electrogenerated base, allows the good
yield formation of 3,4-disubstituted 4-hydroxy-quinazolin-2-ones
(3) and the obtaining of 4-methylene N-substituted quinazolin-2-
one core 4. The later is synthetically valuable when compared
with previously reported multistep reactions or the harsh
protocols described to get this interesting type of heterocycles.
4.2. Synthesis of 2-Quinazolinones (3) and (4):
Once the galvanostatic acetonitrile reduction was finished, the
imposed current was switched off and immediately 2-
aminophenone (1a, 1b) (1.0 mmol) was added to the reaction
medium. The resulting solution was stirred under argon at low
temperature for 1 hour. At the end of this period 1.1 mmol of an
3. Conclusion

4
Tetrahedron
alkyl (or aryl) isocyanate (2) was introduced in the reaction cell,
3-Butyl-3,4-dihydro-4-hydroxy-4-phenyl-quinazolin-2(1H)-
ACCEPTED MANUSCRIPT
and kept overnight under stirring at room temperature.
one (3d)
(210 mg, 71% yield). Solid. m.p: 138-140 °C; Rf (25%
EtOAc/Hex) 0.63; IR (KBr) ν= 3201 (NH), 3134, 3072, 2974,
2919, 1671 (C=O), 1604, 1501, 1460, 1406, 1367, 1334, 1264,
General Procedure:
The solvent in the reaction crude was then removed under
reduced pressure and the residue was stirred for 2h in diethyl
ether in order to extract the organic products from the insoluble
magnesium salts and the supporting electrolyte. The final
solution was filtered, the ether was then washed with water, dried
over anhydrous MgSO4 and finally the ether was removed by
evaporation in vacuo. The resulting residue was purified by
chromatography on a silica gel 60 (35-70 mesh) column (22 x 3
cm) using different mixtures (depending on the product) of
EtOAc/petroleum ether (or hexane) as eluent.
1
1073, 980, 940, 748, 696 cm-1. H NMR (CDCl3, 300 MHz): δ
0.85 (t, 3H, J= 7.4 Hz), 1.20-1.35 (m, 2H), 1.36-1.56 (m, 1H),
3.20-3.32 (m, 1H) 3.40-3.54 (m, 1H), 6.82-6.97 (m, 3H), 7.23 (td,
1H, J1= 7.0 Hz, J2= 2.2 Hz), 7.36-7.48 (m, 3H), 7.60 (d, 2H, J=
7.9 Hz), 10.09 (bs, 1H). 13C NMR (CDCl3, 75.4 MHz): δ 14.0,
20.6, 30.6, 46.9, 66.9, 115.0, 118.3, 118.9, 122.9, 126.8, 127.7,
129.3, 129.7, 130.4, 135.1, 139.6, 153.1. EI-MS: m/z (relative
intensity): 279 (M+-18+1, 23), 278 (M+-18, 29), 277(M+-18-1,
29), 261(23), 249(28), 235(100), 222(34), 221(56), 208(36),
207(95), 201(88), 194(11), 180(7), 165(5), 151(8), 145(10),
132(7), 117(8), 104(14), 91(27), 77(14). Anal. Calc. for C18 H20
N2 O2: C, 73.00; H, 6.80; N, 9.50. Found: C, 73.21; H, 6.82; N,
9.75.
Spectroscopic and physical properties of the new obtained
compounds (3) and (4) are given below.
3-Benzyl-3,4-dihydro-4-hydroxy-4-phenylquinazolin-2(1H)-
one (3a)
3-Cyclohexyl-3,4-dihydro-4-hydroxy-4-phenyl-quinazolin-
2(1H)-one (3e)
(247 mg, 75% yield). Solid. m.p: 160-163 °C; Rf (25%
EtOAc/Hex) 0.45; IR (KBr) ν= 3197 (NH), 3119, 3064, 2922,
2852, 1674 (C=O), 1606 1502, 1447, 1405, 1266, 1028, 718 cm-
(203 mg, 63% yield). Solid. m.p: 124-126 °C; Rf (25%
EtOAc/Hex) 0.52; IR (KBr) ν= 3203 (NH), 3127, 3073, 2920,
1670 (C=O), 1606, 1501, 1432, 1367, 1272, 1002, 896, 751, 702,
1; H NMR (CDCl3, 500 MHz): δ 4.59 (d, 1H, J= 15.7 Hz), 4.65
1
1
669 cm-1. H NMR (CDCl3, 300 MHz): δ 1.03 (d, 1H, J= 11.7
(d, 1H, J= 15.7 Hz), 6.80 (dd, 1H, J1= 8.3 Hz, J2= 1.0 Hz), 6.84
(dd, 1H, J1= 7.9 Hz, J2= 1.5 Hz), 6.92 (td, 1H, J1= 7.9 Hz, J2= 1.0
Hz), 7.12-7.16 (m, 2H), 7.18-7.21 (m, 3H), 7.24 (td, 1H, J1= 7.8
Hz, J2= 1.5 Hz), 7.32-7.40 (m, 3H), 7.51 (dd, 2H, J1= 7.8 Hz, J2=
1.5 Hz), 8.6 (bs, 1H). 13C NMR (CDCl3, 125 MHz): δ 49.5 (-
CH2-Ph), 66.8 (Cq), 114.5, 117.4, 119.3, 123.0, 127.2, 127.8,
127.9, 128.1, 129.0, 129.6, 130.4, 134.7, 136.9, 137.9, 153.0. EI-
MS: m/z (relative intensity): 312 (M+-18, 29), 311(M+-18-1, 81),
296(77), 234(64), 207(100), 206 (37), 180(11), 106(30), 91(40),
77(5). Anal. Calc. for C21 H18 N2 O2: C, 76.40; H, 5.50; N, 8.50.
Found: C, 76.09; H, 5.72; N, 8.48.
Hz), 1.15 (q, 1H, J= 12.7 Hz), 1.20-1.30 (m, 2H), 1.55 (t, 2H, J=
11.7 Hz), 1.84 (d, 1H, J= 12.2 Hz), 2.11 (d, 1H, J= 12.2 Hz), 2.35
(qd, 1H, J1= 12.3 Hz, J2= 3.0 Hz), 2.50 (qd, 1H, J1= 12.3 Hz, J2=
3.0 Hz), 3.01(t, 1H, J= 10.7 Hz), 6.82-6.9 (m, 3H), 7.21 (ddd, J1=
8.8 Hz, J2= 5.9 Hz, J3= 2.9 Hz, 1H), 7.37-7.45 (m, 3H), 7.62 (dd,
J1= 8.3 Hz, J2= 1.0 Hz, 1H), 9.26 (bs, 1H). 13C NMR (CDCl3,
75.4 MHz): δ 24.6, 25.5, 26.6, 29.8, 32.7, 49.3, 67.5, 114.2,
118.1, 118.3, 122.5, 126.6, 128.0, 129.0, 129.4, 130.1, 134.5,
140.6, 151.3. EI-MS: m/z (relative intensity): 304 (M+-18, 25),
303 (M+-18-1, 35), 275(7), 261(12), 249(11), 247(16), 233(12),
227(14), 223(100), 221(64), 207(17), 194(7), 179(7), 145(5),
117(6), 104(5), 77(6). Anal. Calc. for C20 H22 N2 O2: C, 74.50; H,
6.80; N, 8.70. Found: C, 74.17; H, 6.88; N, 8.68.
3-Ethyl-3,4-dihydro-4-hydroxy-4-phenylquinazolin-2(1H)-
one (3b)
(198 mg, 74% yield). Oil. Rf (25% EtOAc/Hex) 0.63; IR (NaCl)
ν= 3197 (NH), 3130, 3070, 2984, 2919, 1666 (C=O), 1602 1501,
3,4-Dihydro-4-hydroxy-3,4-diphenylquinazolin-2(1H)-one (3f)
(205 mg, 65% yield). Solid. m.p: 122-124 °C; Rf (25%
EtOAc/Hex) 0.38; IR (KBr) ν= 3202 (NH), 3133, 3079, 3064,
2975, 2915, 1675 (C=O), 1604, 1493, 1387, 1267, 860, 746, 704
1451, 1348, 1269, 975, 748, 698 cm-1. H NMR (CDCl3, 300
1
MHz): δ 1.17 (s, 3H), 3.37 (bs, 1H) 3.50 (bs, 1H), 6.89 (s, 3H),
7.23 (bs, 1H), 7.43 (bs, 3H), 7.60 (s, 2H), 9.33 (bs, 1H). 13C
NMR (CDCl3, 75.4 MHz): δ 13.6, 41.7, 66.4, 114.6, 118.1,
118.7, 122.8, 126.6, 127.7, 129.2, 129.5, 130.3, 134.8, 139.4,
152.4. EI-MS: m/z (relative intensity): 250 (M+-18, 44), 249(M+-
18-1, 100), 236(11), 221(36), 207(17), 194(15), 180(4), 151(5),
145(18), 117(10), 104(17), 91(13), 77(12). Anal. Calc. for C16
H16 N2 O2: C, 71.60; H, 6.00; N, 10.40. Found: C, 71.44; H, 5.73;
N, 10.17.
1
cm-1. H NMR (CDCl3, 300 MHz): δ 6.79 (d, 1H, J= 7.4 Hz),
6.90 (d, 1H, J= 6.8 Hz), 6.95 (t, 1H, J= 6.8 Hz), 7.00-7.10 (m,
2H), 7.24-7.28 (m, 4H), 7.30-7.36 (m, 3H), 7.4 (d, 2H, J= 7.8
Hz), 8.65 (bs, 1H). 13C NMR (CDCl3, 75.4 MHz): δ 67.9, 115.1,
117.9, 123.0, 127.6, 127.8, 128.4, 128.7, 128.9, 129.4, 130.1,
130.4, 135.0, 137.7, 138.5, 152.0. EI-MS: m/z (relative
intensity): 298 (M+-18, 100), 271(40), 257(22), 222(43), 207(12),
180(35), 151(4), 77(32). Anal. Calc. for C20 H16 N2 O2: C, 75.90;
H, 5.10; N, 8.90. Found: C, 76.20; H, 5.31; N, 9.07.
3,4-Dihydro-4-hydroxy-4-phenyl-3-propylquinazolin-2(1H)-
one (3c)
3-(4-Chlorophenyl)-3,4-dihydro-4-hydroxy-4-
phenylquinazolin-2(1H)-one (3g)
(197 mg, 70% yield). Solid. m.p: 141-143 °C; Rf (25%
EtOAc/Hex) 0.65; IR (KBr) ν= 3202 (NH), 3133, 3068, 2972,
2921, 1669 (C=O), 1605, 1502, 1450, 1409, 1364, 1265, 1066,
(235 mg, 67% yield). Solid. m.p: 123-125 °C; Rf (25%
EtOAc/Hex) 0.35; IR (KBr) ν= 3262 (NH), 3061, 2960, 2922,
1682 (C=O), 1609, 1492, 1388, 1093, 1018, 819, 756, 699 cm-1.
1H NMR (CDCl3, 300 MHz): δ 6.79 (d, 1H, J= 8.0 Hz), 6.87 (d,
1H, J= 7.7 Hz), 6.94 (t, 1H, J= 7.7 Hz), 7.18-7.26 (m, 3H), 7.26-
7.50 (m, 6H), 9.03 (bs, 1H). 13C NMR (CDCl3, 75.4 MHz): δ
68.0, 115.2, 119.2, 123.5, 127.7, 128.2, 128.4, 129.1, 129.4,
129.9, 130.8, 131.7, 135.0, 136.3, 138.3, 151.9. EI-MS: m/z
(relative intensity): 334 (M+-18+2, 24), 332 (M+-18, 70), 306(9),
304(26), 292(6), 290(16), 268(8), 257(15), 255(38), 220(10),
216(8), 214(23), 206(15), 192(7), 151(7), 113(7), 111(19), 77(8),
75(19). Anal. Calc. for C20 H15 Cl N2 O2: C, 68.50; H, 4.30; N,
8.00. Found: C, 68.77; H, 4.23; N, 8.11.
1
982, 752, 700 cm-1. H NMR (CDCl3, 300 MHz): δ 0.83 (t, 3H,
J= 7.4 Hz), 1.40-1.60 (m, 1H), 1.70-1.90 (m, 1H), 3.14-3.25 (m,
1H) 3.35-3.48 (m, 1H), 6.85-6.95 (m, 3H), 7.22-7.27 (m, 1H),
7.38-7.46 (m, 3H), 7.58 (d, 2H, J= 7.9 Hz), 9.71 (bs, 1H). 13C
NMR (CDCl3, 75.4 MHz): δ 11.8, 21.9, 48.8, 66.8, 114.9, 118.3,
118.9, 123.0, 126.7, 127.8, 129.4, 129.7, 130.4, 135.0, 139.6,
153.0. EI-MS: m/z (relative intensity): 264 (M+-18, 65), 263(M+-
18-1, 100), 247(7), 235(68), 222(70), 221(93), 207(49), 194(11),
187(19), 180(6), 145(9), 132(5), 117(5), 104(10), 91(24), 77(8).
IQ-MS: m/z (relative intensity): 305 (M+-18+41, 3), 293 (M+-
18+29, 21), 265 (M+-18+1, 100). Anal. Calc. for C17 H18 N2 O2:
C, 72.30; H, 6.40; N, 9.90. Found: C, 72.03; H, 6.22; N, 10.10.
3-Benzyl-3,4-dihydro-4-methylenequinazolin-2(1H)-one (4a)

5
(175 mg, 70% yield). Solid. m.p: 191-193 °C [Lit.20 193-195 ºC];
Acknowledgments
ACCEPTED MANUSCRIPT
Rf (20% EtOAc/Petroleum ether) 0.67; IR (KBr) ν= 3203, 3059,
2924, 1679, 1633, 1605, 1494, 1443, 1260, 958, 757, 715 cm-1;
EI-MS: m/z (relative intensity): 250 (M+, 89), 249(M+-1, 100),
235(22), 221(10), 206(7), 180(2), 145(14), 117(7), 104(6),
91(32), 89(10), 77(7), 65(14), 63(7).
The authors gratefully acknowledge the financial support of
the University of Alcala- proyect Nº CCG2017/EXP-009.
Electronic Supplementary Information (ESI) available:
3-Ethyl-3,4-dihydro-4-methylenequinazolin-2(1H)-one (4b)
(104 mg, 55% yield). Solid. m.p: 176-178 °C [Lit.20 178-180 ºC];
Rf (20% EtOAc/Petroleum ether) 0.74; IR (KBr) ν= 3200, 3061,
2980, 1676, 1600, 1442, 1372, 760 cm-1; EI-MS: m/z (relative
intensity): 188 (M+, 100), 173(3), 160(98), 145(40), 132(94),
116(13), 104(14), 89(26), 77(9), 63(13).
Copy of H/13C NMR spectrum, IR and MS (EI or IQ) of new
compounds 3 and 4 is provided. This material is available free of
charge via Internet.
1
References
1. Mhaske, S.B.; Argade, N.P. Tetrahedron 2006, 62, 9787.
2. Abdel Gawad, N.M.; Georgey, H.H.; Youssef, R.M.; El-Sayed,
N.A. Eur. J. Med. Chem. 2010, 45, 6058.
3. Voskoboynik, O.Yu.; Nosulenko, I.S.; Serest, G.G. Kovalenko,
S.I. Ukrainian Biopharmaceutical Journal 2016, 71.
4. Malecki, N.; Carato, P.; Rigo, G.; Goossens, J.F.; Houssin, R.;
Bailly, C.; Henichart, J.P. Bioorg. Med. Chem. 2004, 12, 641.
5. Khan, I.; Zaib, S.; Batool, S.; Abbas, N.; Ashraf, Z.; Iqbal, J.;
Saeed, A. Bioorg. Med. Chem. 2016, 24, 2361.
6. Conley, R.A.; Barton, D.L.; Stefanick, S.M.; Lam, M.M.;
Lindabery, G.C.; Kasulanis, Ch.F.; Cesco-Cancian, S.; Currey,
S.; Fabian, A.C.; Levine, S.D. J. Heterocycl. Chem. 1995, 32,
761.
7. Vicente, J.; Abad, J.-A.; Lopez-Serrano, J.; Jones, P.G.;
Najera, C.; Botella-Segura, L. Organometallics 2005, 24, 5044.
8. Ivanov, I. Molbank 2006, M492.
9. Wang, H.; Liu, L.; Wang, Y.; Peng, Ch.; Zhang, J.; Zhu, Q.
Tetrahedron Lett. 2009, 50, 6841.
10. Sawant, R.; Stevens, M.Y.; Odell, L.R. Eur. J. Org. Chem.
2015, 7743. And references cited herein.
11. Tucker, T.J.; Lyle, T.A.; Wiscount, C.M.; Britcher, S.F.;
Young, S.D.; Sanders, W.M.; Lumma, W.C.; Goldman, M.E.;
Obrien, J.A. J. Med. Chem. 1994, 37, 2437.
12. Schlegel, K.-A. S.; Yang, Z.-Q.; Reger, T.S.; Shu, Y.; Cube,
R.; Rittle, K.E.; Bondiskey, P.; Bock, M.G. et al. Bioorg. Med.
Chem. Lett. 2010, 20, 5147.
3,4-Dihydro-4-methylene-3-propylquinazolin-2(1H)-one (4c)
(123 mg, 61% yield). Solid. m.p: 179-182 °C [Lit.20 182-184 ºC];
Rf (20% EtOAc/Petroleum ether) 0.75; IR (KBr) ν= 3234, 2925,
1691, 1633, 1604, 1444, 1368, 1256, 1084, 791, 748 cm-1; EI-
MS: m/z (relative intensity): 202 (M+, 29), 187 (M+-15, 99),
174(7), 160(83), 145(31), 132(100), 116(27), 104(14), 89(21),
77(8), 63(7).
3-Butyl-3,4-dihydro-4-methylenequinazolin-2(1H)-one (4d)
(130 mg, 60% yield). Solid. m.p: 182-185 °C; Rf (20%
EtOAc/Petroleum ether) 0.72; IR (KBr) ν= 3202, 2927, 1688,
1633, 1373, 1295, 790, 742 cm-1; 1H NMR (CDCl3, 500 MHz): δ
0.98 (t, 3H, J= 7.3 Hz), 1.37-1.46 (m, 2H), 1.7 (c, 2H, J= 6.8 Hz),
3.86 (t, 2H, J= 7.3 Hz), 4.3 (d, 1H, J= 2.4 Hz), 4.83 (d, 1H, J= 2.4
Hz), 6.79 (d, 1H, J= 7.9 Hz), 7.00 (t, 1H, J= 7.3 Hz), 7.20 (d, 1H,
J= 8.3 Hz), 7.55 (d, 1H, J= 8.3 Hz), 8.80 (bs, 1H). 13C NMR
(CDCl3, 125 MHz): δ 13.8, 20.2, 27.6, 43.1, 84.1 (=CH2), 114.6,
116.9, 122.5, 123.9, 130.0, 135.1, 140.2, 151.2. EI-MS: m/z
(relative intensity): 216 (M+, 5), 201 (M+-15, 100), 187(10),
174(26), 160(41), 145(25), 132(60), 116(19), 104(9), 89(17),
77(5), 63(6). Anal. Calc. for C13 H16 N2 O: C, 72.20; H, 7.40; N,
13.00. Found: C, 71.99; H, 7.27; N, 13.28.
3-Cyclohexyl-3,4-dihydro-4-methylenequinazolin-2(1H)-one
(4e)
(128 mg, 53% yield). Oil. Rf (20% EtOAc/Petroleum ether) 0.63;
IR (NaCl) ν= 3207, 3072, 2937, 1675, 1618, 1508, 1450, 1374,
13. Widler, L.; Altmann, E.; Beerli, R.; Breitenstein, W.; Bouhelal,
R.; Buhl, T.; et al. J. Med. Chem. 2010, 53, 2250.
1
762 cm-1; H NMR (CDCl3, 500 MHz): δ 1.15-2.10 (m, 10H),
3.88 (t, 1H, J= 11.7 Hz), 4.56 (d, 1H, J= 2.4 Hz), 4.85 (d, 1H, J=
2.4 Hz), 6.70 (d, 1H, J= 7.8 Hz), 6.95-7.00 (m, 1H), 7.30-7.38
(m, 1H), 7.7 (d, 1H, J= 7.8 Hz). 13C NMR (CDCl3, 125 MHz): δ
24.9, 25.5, 26.5, 29.0, 33.6, 49.3, 89.1 (=CH2), 113.6, 117.2,
122.4, 124.0, 129.6, 134.2, 142.2, 151.7. EI-MS: m/z (relative
intensity): 242 (M+, 7), 227(3), 185(2), 171(5), 161(100), 145(3),
132(14), 116(8), 104(5), 89(5), 77(4), 63(2). Anal. Calc. for C15
H18 N2 O: C, 74.40; H, 7.40; N, 11.60. Found: C, 74.69; H, 7.21;
N, 11.73.
3,4-Dihydro-4-methylene-3-phenylquinazolin-2(1H)-one (4f)
(170 mg, 72% yield). Solid. m.p: 188-190 °C [Lit.20 191-192 ºC.
Rf (20% EtOAc/Petroleum ether) 0.60; EI-MS: m/z (relative
intensity): 236 (M+, 35), 235(M+-1, 100), 217(25), 207(4),
190(6), 165(3), 116(2), 89(8), 77(5).
14. Barrow, J.C.; Rittle, K.E.; Reger, T.S.; Yang, Z.Q.;
Bondiskey, P.; McGaughey, G.B.; Bock, M.G.; Hartman, G.D.;
Tang, C.; Ballard, J.; Kuo, Y. et al. ACS Medicinal Chemistry
Letters 2010, 1, 75.
15. Heron, S.E.; Khosravani, H.; Varela, D.; Bladen, Ch.;
Williams, T.C.; Newman, M.R; Scheffer, I.E.; Berkovic, S.F.;
Mulley, J.C.; Zamponi, G.W. Ann.Neurol. 2007, 62, 560.
16. Todorovic, S.M.; Jevtovic-Todorovic, V. CNS and Neurol.
Disord.: Drug Target 2006, 5 639.
17. Brack, A. Liebigs Ann. Chem. 1969, 730, 166.
18. Zolotykh, K.V.; Shikhaliev, Kh.S.; Leshcheva, E.V. Chem.
Heterocycl. Compd. 2002, 38, 751.
19. Molina, P.; Conesa, C.; Alias, A.; Arques, A.; Velasco, M.D.;
Llamas-Saiz, A.L.; Foces-Foces, C. Tetrahedron, 1993, 49,
7599.
20. Gimeno, A.; Medio-Simón, M.; de Arellano, C.R.; Asensio,
G.; Cuenca, A.B. Organic Letters 2010, 12, 1900.
21. Gimeno, A.; Cuenca, A.B.; Medio-Simón, M.; Asensio, G.
Adv. Synth. Catal. 2014, 356, 229.
22. Costa, M.; Della Ca, N.; Gabriele, B.; Massera, Ch.; Salerno,
G.; Soliani, M. J. Org. Chem. 2004, 69, 2469.
23. Ravindranathan, K.P.; Mandiyan, V.; Ekkati, A.R.; Bae, J.H.;
Schlessinger, J.; Jorgensen, W.L. J. Med. Chem. 2010, 53,
1662.
24. Blümel, M.; Noy, J.-M.; Enders, D.; Stenzel, M.H.; Nguyen,
T.V. Org. Lett. 2016, 18, 2208.
3-(4-Chlorophenyl)-3,4-dihydro-4-methylenequinazolin-
2(1H)-one (4g)
(189 mg, 70% yield). Solid. m.p: 214-217 °C; Rf (20%
EtOAc/Petroleum ether) 0.53; IR (KBr) ν= 3460, 3048, 2934,
1
1680. 1630. 1409, 1087 cm-1; H NMR (CDCl3, 300 MHz): δ
3.70 (d, 1H, J= 2.5 Hz), 4.77 (d, 1H, J= 2.5 Hz), 6.74 (d, 1H, J=
6.9 Hz), 7.03 (td, 1H, J1= 7.7 Hz, J2= 1.1 Hz), 7.20-7.50 (m, 5H),
7.55 (d, 1H, J= 7.9 Hz), 7.70 (bs, 1H). 13C NMR (CDCl3, 75.4
MHz): δ 88.2 (=CH2), 114.3, 114.9, 123.2, 124.3, 129.9, 130.4,
130.6, 130.8, 143.1, 152.8, 161.7. EI-MS: m/z (relative
intensity): 272 (M++2, 11), 271 (M++2-1, 38), 270 (M+, 35), 269
(M+-1, 100), 251(7), 234(72), 206(8), 190(4) 117(3), 89(12),
75(7). Anal. Calc. for C15 H11 Cl N2 O: C, 66.50; H, 4.10; N,
10.40. Found: C, 66.37; H, 4.29; N, 10.64.
25. Utley, J.H.P.; Folmer-Nielsen, M.; Wyatt P.W. in Organic
Electrochemistry. 5th Edition Chapter 43 “Electrogenerated

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Tetrahedron
ACCEPTED MANUSCRIPT
Bases and Nucleophiles”. Eds. Hammerich O. and Speiser B.
CRC Press, Taylor and Francis Group: 2016.
28. Batanero, B.; Barba, F.; Martin, A. J. Org. Chem. 2002, 67,
2369.
26. Hamrouni, K.; Barba, F.; Benkhoud, M.L.; Batanero, B. J.
Org. Chem. 2017, 82, 6778.
29. Otero, M.D.; Batanero, B.; Barba, F. Tetrahedron Lett. 2005,
46, 8681.
27. Matthews, W.S.; Bares, J.E.; Bartmess, J.E.; Bordwell, F.G.;
Cornforth, F.J.; Drucker, G.E.; Margolin, Z.; McCallum, R.J.;
McCollum, G.J.; Vanier, N.R. J. Am. Chem. Soc. 1975, 97,
7006.
30. Sbei, N.; Batanero, B.; Barba, F.; Haouas, B.; Fuentes, L.;
Benkhoud, M.L. Tetrahedron 2015, 71, 7654.

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Highlights:
●
●
Electrogenerated base in the Synthesis of Quinazolin-2-ones.
Influence of the anode material (Mg) and temperature (0ºC) in the stability of
cyanomethyl anion.
●
●
pKa de c.a.32 of electrogenerated acetonitrile anion deprotonates 2-Aminofenones.
Reaction of arylnitrides with organic isocyanates to 3-substituted 4-hydroxy-4-phenyl
quinazolin-2-ones.
●
Spontaneous dehydration of 3-substituted 4-methyl-4-hydroxy-quinazolin-2-ones to 4-
methylene derivatives.