Application of laccase/DDQ as a new bioinspired catalyst system for the aerobic oxidation of tetrahydroquinazolines and Hantzsch 1,4-dihydropyridines

Article abstract of DOI:10.1016/j.crci.2019.03.003

Laccase/DDQ as a new bioinspired quinone-based cooperative catalytic system was used for the biomimetic aerobic oxidative synthesis of 2-substituted quinazolines and Hantzsch pyridines from the oxidative cyclocondensation of 2-aminobenzylamine and aldehyd

Full text of DOI:10.1016/j.crci.2019.03.003

C. R. Chimie xxx (xxxx) xxx
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Full paper/Memoire
Application of laccase/DDQ as a new bioinspired catalyst
system for the aerobic oxidation of tetrahydroquinazolines
and Hantzsch 1,4-dihydropyridines
,
, *
Mastaneh Shariati a, Gholamhassan Imanzadeh a **, Amin Rostami b
,
Nadya Ghoreishy b, Somayyeh Kheirjou a
a Department of Chemistry, Faculty of Basic Science, University of Mohaghegh Ardabili, Ardabil, 56199-11367, Iran
b Department of Chemistry, Faculty of Science, University of Kurdistan, Sanandaj, 66177-15175, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Laccase/DDQ as a new bioinspired quinone-based cooperative catalytic system was used
for the biomimetic aerobic oxidative synthesis of 2-substituted quinazolines and Hantzsch
pyridines from the oxidative cyclocondensation of 2-aminobenzylamine and aldehydes
and the oxidative aromatization of 1,4-dihydropyridines, respectively. The products were
obtained in good to high yields in a phosphate buffer (0.1 M, 12.5 mL, pH 4.5) and
acetonitrile (4 vol%) mixture as a solvent. These methods are more eco-friendly, efficient,
simple, and practical than other currently available ones because of mild reaction condi-
tions and because they are free from any halide and toxic and expensive transition metals.
Therefore, these methods can be applied in pharmaceutical and other sensitive synthetic
procedures.
Received 7 August 2018
Accepted 13 March 2019
Available online xxxx
Keywords:
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone
Laccase
Aerobic oxidation
Quinazolines
Pyridines
© 2019 Académie des sciences. Published by Elsevier Masson SAS. All rights reserved.
1. Introduction
there has been a spurt at activity to synthesize quinazolines
because of their biological importance [10,5a]. A growing
Nitrogen-containing heterocycles are the most abun-
dant and integral scaffolds that exist ubiquitously in a va-
riety of synthetic drugs, pharmaceuticals, bioactive natural
products, and agrochemicals [1,2]. Among these heterocy-
cles, quinazolines and their derivatives are important
compounds in organic synthesis and the industrial pro-
duction of pharmaceutical compounds that show various
biological activities [3e9] such as anticancer [3e5], anti-
viral [6], antibacterial [7], and antitubercular [9] ones. The
first synthesis of a quinazoline derivative, 2-cyano-3,4-
dihydro-4-oxoquinazoline, by reacting cyanogen with an-
thranilic acid was reported by Griess in 1869. Since then,
importance of quinazolines provides a strong rationale to
the development of various synthetic methodologies.
Substituted quinazolines have been synthesized by various
methods involving several substrates such as 2-
aminobenzylamines (I), 2-aminobenzaldehydes and 2-
aminobenzoketones (II), or 2-bromobenzylamines (III)
(Scheme 1) [11].
Pyridines also are among the most important hetero-
cycles that are often found in natural products, flavors and
fragrances, pharmaceuticals, additives, agrochemicals,
dyes, and polymers. They are used as ligands in coordina-
tion chemistry and as reagents and building blocks in
organic synthesis [12]. One of the most popular methods
for preparation of pyridines is oxidation of corresponding
1,4-dihydropyridines, which in turn can be synthesized via
the classical Hantzsch 1,4-dihydropyridine synthesis
(Scheme 2) [13].
* Corresponding author.
** Corresponding author.
E-mail addresses: imanzad2000@yahoo.com (G. Imanzadeh),
arostami372@gmail.com (A. Rostami).
https://doi.org/10.1016/j.crci.2019.03.003
1631-0748/© 2019 Académie des sciences. Published by Elsevier Masson SAS. All rights reserved.
Please cite this article as: M. Shariati et al., Application of laccase/DDQ as a new bioinspired catalyst system for the aerobic
oxidation of tetrahydroquinazolines and Hantzsch 1,4-dihydropyridines, Comptes Rendus Chimie, https://doi.org/10.1016/
j.crci.2019.03.003

2
M. Shariati et al. / C. R. Chimie xxx (xxxx) xxx
Scheme 1. Approaches for the synthesis of quinazolines.
Scheme 2. Synthesis and oxidation of Hantzsch 1,4-dihydropyridines.
In view of the importance of quinazolines and pyridines,
Fe(ClO4)3/acetic acid [27a], Fe(ClO4)3/N-hydroxyph-
thalimide [27b], Fe(ClO4)3/triarylaminium radical cation
salt [27c], and FeCl3/NaNO2/TEMPO [27d]. Although these
catalyst systems could efficiently perform oxidation re-
actions, these procedures still suffer from some problems
such as high reaction temperatures, low catalytic efficiency,
tedious catalyst preparation, and the use of toxic organic
solvents and toxic transition metals as catalyst, which are
essentially challenging to separate from the reaction
mixture. Even when it is possible to separate the catalyst,
trace amounts of the catalyst are possible to stay in the final
product. It is vital to eliminate the catalyst (especially in
pharmaceutical industry) because metal contamination is
highly regulated. Therefore, it seems that there is still a
great interest in developing efficient, eco-friendly, and
nonmetallic catalysts for the aerobic oxidative synthesis of
quinazolines and Hantzsch pyridines.
One particular stoichiometric organo-oxidant that is
capable of performing a wide range of organic trans-
formations is DDQ [28,29]. However, the stoichiometric
use of DDQ results in equimolar quantities of the 2,3-
dichloro-5,6-dicyano-hydroquinone (DDQH2) byproduct
that leads to difficult purification on a large scale. Also,
DDQ is relatively expensive ($680/mol) and toxic (LD50 of
82 mg/kg). Consequently, to avoid these disadvantages,
the use of a catalytic amount of DDQ in the presence of
economically and environmentally benign oxidants that
regenerate DDQ from its reduced hydroquinone form has
received increasing attention as a possible alternative to
the widely used traditional DDQ in organic synthesis.
Some of the stoichiometric co-oxidants that have been
used for the regeneration of DDQ include FeCl3 (3 equiv)
[30], Mn(OAc)3 (3 equiv) [31], and MnO2 (up to 6 equiv)
[32]. Although these methods have partly addressed some
problems of the stoichiometric DDQ, however these
a large number of stoichiometric or large excess amounts of
oxidants and homogenous and heterogeneous catalysts
have been reported in the literature for synthesis of 2-
substituted quinazolines and Hantzsch pyridines from
oxidative cyclocondensation of 2-aminobenzylamines and
aldehydes and oxidative aromatization of 1,4-
dihydropyridines, respectively. Typical examples such as
MnO2 [14], NaClO [15], and 2,3-dichloro-5,6-dicyano-l,4-
benzoquinone (DDQ) [16], Ir-catalyzed hydrogen transfer
reaction [17], Pt/CeO2 [18], FeCl3 [19], pyridinium chlor-
ochromate [20a], (NH4)2Ce(NO3)6 [20b], MnO2 [20c], NO
[20d], HNO3 [20e], Zr(NO3)4 [20f], and 1,2,4-triazolinedione
[20g]. However, most of these methods suffer from one or
more following drawbacks: hard reaction conditions, poor
atom efficiency, utilization of environmentally unfavorable
and expensive oxidants and catalysts, tedious procedure for
the preparation of homogenous and heterogeneous cata-
lysts, and the formation of large amounts of toxic waste.
Therefore, the development of more efficient and green
methods is important for synthesis of quinazolines and
pyridines. The use of “green oxidants” such as molecular
oxygen or air is attractive, because they are readily avail-
able, inexpensive, and environmentally benign [21]. Thus,
aerobic oxidative synthesis of these valuable compounds in
the presence of transition metal catalysts or organo-
catalysts has been developed [22]. Typical examples
include the use of 5 mol% of CuCl/DABCO/TEMPO (DABCO,
1,4-diazabicyclo[2.2.2]octane and TEMPO, 2,2,6,6-tetra-
methyl-piperidin-1-yloxy) catalytic system [23], Pt/Ir
bimetallic nanoclusters in combination with catechol co-
catalysts [24], the assembly of rhodium (Rh) nanoparticles
on carbon nanotubes (CNTs) along with redox-active
quinone-type cocatalyst [25], 1,10-phenanthroline-5,6-
dione associated with different metals (Zn, Fe, or Ru) [26],
Please cite this article as: M. Shariati et al., Application of laccase/DDQ as a new bioinspired catalyst system for the aerobic
oxidation of tetrahydroquinazolines and Hantzsch 1,4-dihydropyridines, Comptes Rendus Chimie, https://doi.org/10.1016/
j.crci.2019.03.003

M. Shariati et al. / C. R. Chimie xxx (xxxx) xxx
3
reagents show poor atom efficiency. Green chemistry
encourages the design of green processes using O2 or air
as the highly atom-economical, environmentally benign,
and abundant oxidant and minimizing the generation of
hazardous materials. So, it would be ideal if molecular
oxygen or air can serve as a terminal oxidant in DDQ-
mediated reactions. Nonetheless, molecular oxygen
cannot directly oxidize DDQH2 to DDQ under mild con-
ditions [33]. Indeed, a redox compound should be used as
the bridge among molecular oxygen and the cycling
DDQH2/DDQ. In this context, several research groups have
used NO/NO2-based redox cycle systems in combination
with DDQ to catalyze the aerobic oxidation of organic
compounds, including oxidation of alcohols [34], oxida-
tive cleavage of benzylic ethers [35], dehydrogenation of
saturated CeC bonds [36], oxidative CeC coupling re-
actions, and amination of arenes [37]. Very recently,
Fe(NO3)3 has been used as a cocatalyst with catalytic DDQ
in aerobic oxidation of alcohols [38]. Although these
methods presented interesting breakthrough in the field
of aerobic oxidation reactions in the presence of catalytic
amount of DDQ, the development of an efficient and eco-
friendly cocatalyst in combination with DDQ to catalyze
the aerobic oxidation of organic compounds under mild
conditions is still highly desired.
Laccases (p-benzenediol: oxygen oxidoreductase
[E.C. 1.10.3.2]) are extracellular enzymes that contain
four copper centers per protein molecule and catalyze
the oxidation of electron-rich aromatic substrates,
usually phenols or aromatic amines [39]. The unique
properties of laccases such as mild reaction conditions
and substrate selectivity make them attractive for use
in chemical synthesis [40]. Furthermore, the redox
potential of laccases can be extended via natural me-
diators such as 3-hydroxyanthranilic acid and 4-
hydroxybenzoic acid as well as by artificial mediators
including TEMPO, 1-hydroxybenzotriazole, and 2,20-
In continuation to our systematic study about applica-
tion of laccase and laccase mediator system in organic
synthesis [45], herein we present for the first time the
nonmetallic, simple, and efficient methods for the synthe-
sis of 2-substituted quinazolines and Hantzsch pyridines
via aerobic oxidative in the presence of the laccase/DDQ
catalyst system, using O2 or air as an oxidant and a phos-
phate buffer solution as a solvent.
2. Experimental section
2.1. Materials and instruments
Laccase (E.C. 1.10.3.2) from Trametes versicolor was pur-
chased from SigmaeAldrich (St. Louis, MO, USA). Sodium
acetate buffer (100 mM) at pH 5 was used for preparing
solutions for the activity assay. All chemicals and solvents
were of analytical grade and used without further purifica-
tion.1H NMR spectra were recorded using a 250 MHz Bruker
NMR spectrometer. Melting points were measured on a
Barnstead Electrothermal IA 9100 and are uncorrected.
2.2. Enzyme activity assays
The activity of commercial enzyme laccase from T. versi-
color was determined spectrophotometrically by monitoring
the oxidation of 2,20-azino-bis-(3-ethylbenzothiazoline-6-
sulfonic acid) (ABTS, ε ¼ 36,000 Mꢀ1 cmꢀ1). The reaction
mixture included 5 mM of ABTS (100 mL) in 100 mM of acetate
buffer (pH 5.0) and laccase enzyme. The change in absorption
was observed via UVevis spectroscopy at 420 nm for 5 min at
room temperature [46]. One unit was defined as the amount
of enzyme that oxidizes 1 mmol of ABTS per minute. The ac-
tivity of laccase enzyme batch applied in this investigation
was evaluated at 0.89 U/mg.
2.3. General procedure for the aerobic oxidative synthesis of
2-substituted quinazolines by laccase/DDQ catalyst system
azino-bis-(3-ethylbenzothiazoline-6-sulfonic
acid
(ABTS) [41]. This allows the oxidation of substrates
with higher redox potentials. Meanwhile, laccases and
laccase/mediator systems have been applied for the
oxidation of a number of functional groups [42e44]. To
the best of our knowledge, there has been no report on
the use of laccase/DDQ as a bioinspired cooperative
catalyst system in the transition metalefree and
halogen-free aerobic oxidation of organic compounds
(Scheme 3).
A solution of 2-aminobenzylamine (1 mmol) and alde-
hydes (1 mmol) in 5 mL of CH3CN was stirred at room
temperature until the cyclocondensation was completed
(about 3e5 h). After complete conversion of 2-
aminobenzylamine to tetrahydroquinazoline (TLC), the
solvent was concentrated to 0.5 mL and DDQ (45.4 mg,
0.2 mmol), and sodium phosphate buffer solution (NaPBS)
(0.1 M, pH 4.5, 12.5 mL) and laccase from T. versicolor
Scheme 3. Proposed DDQ-mediated aerobic oxidation reactions.
Please cite this article as: M. Shariati et al., Application of laccase/DDQ as a new bioinspired catalyst system for the aerobic
oxidation of tetrahydroquinazolines and Hantzsch 1,4-dihydropyridines, Comptes Rendus Chimie, https://doi.org/10.1016/
j.crci.2019.03.003

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M. Shariati et al. / C. R. Chimie xxx (xxxx) xxx
(100 U, 89 mg) were added. Then, the mixture was stirred
at 45 ꢁC under molecular oxygen (balloon) or air for the
time given in Table 1. After completion of the reaction
(monitored by TLC), the mixture was extracted by EtOAc
(3 ꢂ 10 mL) and dried over anhydrous Na2SO4. The crude
product obtained after the removal of a solvent under
vacuum was purified by chromatography on silica gel (n-
hexane/ethyl acetate, 3/1). All of the products were iden-
tified and characterized by comparing their spectral data
(1H NMR) and physical properties (melting point) with
those of authentic samples (see Supplementary data).
air at room temperature for the time given in Table 2. After
completion of the reaction (monitored by TLC), the mixture
was extracted by ethyl acetate (3 ꢂ 10 mL) and dried over
anhydrous Na2SO4. The crude product obtained after the
removal of a solvent under vacuum was purified by chro-
matography on silica gel (n-hexane/ethyl acetate, 3/1). All
of the products were identified and characterized by
comparison of their spectral data (1H NMR) and physical
properties (melting point) with those of authentic samples
(see Supplementary data).
2.4. General procedure for the aerobic oxidative synthesis of
pyridines by laccase/DDQ catalyst system
Table 2
Laccase/DDQ-catalyzed aerobic oxidative synthesis of pyridine deriva-
tives.a
O
R
O
A 25 mL round-bottomed flask equipped with a mag-
netic stirrer bar was charged with 1,4-dihydropyridine
(1 mmol), DDQ (45.4 mg, 0.2 mmol), and acetonitrile
(0.5 mL). NaPBS (0.1 M, pH 4.5, 12.5 mL) and laccase from T.
versicolor (100 U, 89 mg) were added and the reaction
mixture was stirred under molecular oxygen (balloon) or
O
R
N
O
Cat. Laccase/DDQ, Oxidan: O2 or air
NaPBS 0.1M, pH 4.5, CH3CN (4%) , rt
O
O
O
O
N
H
R = Aryl or Alkyl
Entry
Substrates
Product
Time
(h)
Yield
(air)b (%)
1
2
7
98 (87)
Table 1
Laccase/DDQ-catalyzed aerobic oxidative synthesis of quinazoline deriv-
atives.a
10
96 (84)
3
4
8
6
94 (80)
97 (85)
Entry
RCHO
Product
Time
(h)
Isolated
yield (air)b (%)
1
2
22
20
95 (87)
96 (84)
5
6
7
93 (79)
95 (81)
3
4
24
26
94 (86)
93 (85)
12
7
8
14
12
90 (78)
98 (89)
5
20
93 (82)
6c
7
24
24
91 (80)
83 (77)
9
12
16
97 (86)
98 (88)
8
22
24
24
24
93 (84)
91 (80)
72 (64)
87 (79)
9
10
10
11
11
12
11
14
96 (83)
90 (76)
a
General procedure: Aldehyde (1 mmol), 2-aminobenzylamine
(1 mmol), laccase (100 U), DDQ (20 mol%), O2 (balloon), NaPBS
(12.5 mL), CH3CN (0.5 mL), 45 ꢁC.
b
Isolated yield under air conditions is shown in parentheses.
Conditions: Aldehyde (1 mmol), 2-aminobenzylamine (2 mmol), lac-
c
a
General procedure: 1,4-Dihydropyridine (1 mmol), laccase (100 U),
DDQ (20 mol%), O2 (balloon), NaPBS (12.5 mL), rt.
case (200 U), DDQ (40 mol%), O2 (balloon), NaPBS (25 mL), CH3CN (1 mL),
45 ꢁC.
b
Isolated yield under air conditions is shown in parentheses.
Please cite this article as: M. Shariati et al., Application of laccase/DDQ as a new bioinspired catalyst system for the aerobic
oxidation of tetrahydroquinazolines and Hantzsch 1,4-dihydropyridines, Comptes Rendus Chimie, https://doi.org/10.1016/
j.crci.2019.03.003

M. Shariati et al. / C. R. Chimie xxx (xxxx) xxx
5
2.5. Selected spectra data
2.5.9. Diethyl 2,6-dimethyl-4-(4-methoxyphenyl)-3,5-
pyridinedicarboxylate
2.5.1. 2-Phenyl quinazoline
Colorless solid; mp 49e51 ꢁC: 94% yield (335 mg,
Pale yellow solid; mp 97e98 ꢁC: 95% yield (196 mg,
0.95 mmol) [23] (Table 1, entry 1).
0.94 mmol) [48] (Table 2, entry 3).
1H NMR (250 MHz, CDCl3):
6.8 (d, J ¼ 8.2 Hz, 2H), 4.03 (q, J ¼ 7 Hz, 4H), 3.80 (s, 3H),
2.56 (s, 6H), 0.96 (t, J ¼ 7 Hz, 6H).
d
¼ 7.17 (d, J ¼ 8.2 Hz, 2H),
1H NMR (250 MHz, DMSO-d6):
d
¼ 9.70 (s, 1H),
8.54e8.57 (m, 2H), 8.16 (d, J ¼ 8.0 Hz, 1H), 7.99e8.04 (m,
2H), 7.70e7.76 (m, 1H), 7.55e7.56 (m, 1H).
2.5.10. Diethyl 2,6-dimethyl-4-(3,4,5-trimethoxyphenyl)-3,5-
pyridinedicarboxylate [49]
2.5.2. 2-(4-Methoxylphenyl) quinazoline
White solid; mp 78e80 ꢁC: 96% yield (226 mg,
0.96 mmol) [23] (Table 1, entry 2).
White solid; mp 105e107 ꢁC: 97% yield (404 mg,
0.97 mmol) (Table 2, entry 4).
1H NMR (250 MHz, DMSO-d6):
d
¼ 9.61 (s, 1H), 8.49 (d,
1H NMR (250 MHz, CDCl3):
d
¼ 6.49 (s, 2H), 4.06 (q,
J ¼ 8.0 Hz, 2H), 8.10 (d, J ¼ 7.5 Hz, 1H), 7.98 (br s, 2H),
7.66e7.67 (m, 1H), 7.08 (d, J ¼ 8.0 Hz, 2H), 3.82 (s, 3H).
J ¼ 7.0 Hz, 4H), 3.84 (s, 3H), 3.80 (s, 6H), 2.58 (s, 6H), 0.98 (t,
J ¼ 7.0 Hz, 6H).
2.5.3. 2-(3-Methoxyphenyl) quinazoline
2.5.11. Diethyl 2,6-dimethyl-4-n-butyl-3,5-
pyridinedicarboxylate
Light yellow solid; mp 91e93 ꢁC: 94% yield (222 mg,
0.94 mmol) [26] (Table 1, entry 3).
Oil; 93% yield (285 mg, 0.93 mmol) [48] (Table 2, entry
5).
1H NMR (250 MHz, DMSO-d6):
d
¼ 9.69 (s, 1H),
8.05e8.17 (m, 5H), 7.73e7.76 (m, 1H), 7.47 (t, J ¼ 8.0 Hz, 1H),
1H NMR (250 MHz, CDCl3):
2.53e2.56 (m, 2H), 2.49 (s, 6H), 1.51e1.60 (m, 4H), 1.37 (t,
J ¼ 7.0 Hz, 6H), 0.91 (t, J ¼ 7.0 Hz, 3H).
d
¼ 4.39 (q, J ¼ 7.0 Hz, 4H),
7.11e7.13 (m, 1H), 3.86 (s, 3H).
2.5.4. 2-(3-Fluorophenyl) quinazoline
Gray solid; mp 89e90 ꢁC: 83% yield (186 mg, 0.83 mmol)
[47] (Table 1, entry 7).
2.5.12. Diethyl 2,6-dimethyl-4-(3-chlorophenyl)-3,5-
pyridinedicarboxylate
1H NMR (250 MHz, DMSO-d6):
J ¼ 8.0 Hz, 1H), 8.15e8.25 (m, 2H), 8.03e8.05 (m, 2H),
7.72e7.78 (m, 1H), 7.60 (dd, J ¼ 21.7, 6.2 Hz, 1H), 7.36e7.42
(m, 1H).
d
¼ 9.70 (s, 1H), 8.39 (d,
Pale yellow solid; mp 42e44 ꢁC: 98% yield (354 mg,
0.98 mmol) [50] (Table 2, entry 8).
1H NMR (250 MHz, CDCl3):
7.12e7.15 (m, 1H), 4.05 (q, 7.0 Hz, 4H), 2.60 (s, 6H), 0.97 (t,
J ¼ 7.0 Hz, 6H).
d
¼ 7.25e7.34 (m, 3H),
2.5.5. 2-(3-Chlorophenyl) quinazoline
Pale yellow solid; mp 148e150 ꢁC: 93% yield (223 mg,
0.93 mmol) [23] (Table 1, entry 8).
2.5.13. Diethyl 2,6-dimethyl-4-(2-fluorophenyl)-3,5-
pyridinedicarboxylate [51]
1H NMR (250 MHz, DMSO-d6):
d
¼ 9.70 (s, 1H), 8.51 (br
Oil; 97% yield (334 mg, 0.97 mmol) (Table 2, entry 9).
s, 2H), 8.17 (d, J ¼ 8.0 Hz, 1H), 8.0e8.06 (m, 2H), 7.72e7.78
1H NMR (250 MHz, CDCl3):
6.97e7.10 (m, 3H), 4.03 (q, J ¼ 7.0 Hz, 4H), 2.59 (s, 6H), 0.95
(t, J ¼ 7.0 Hz, 6H).
d
¼ 7.25e7.34 (m, 1H),
(m, 1H), 7.60 (br s, 2H).
2.5.6. 2-(3-Bromophenyl)quinazoline
Yellow solid; mp 153e155 ꢁC: 91% yield (259 mg,
0.91 mmol) [23] (Table 1, entry 9).
2.5.14. Diethyl 2,6-dimethyl-4-(4-nitrophenyl)-3,5-
pyridinedicarboxylate
1H NMR (250 MHz, DMSO-d6):
1H), 8.53 (d, J ¼ 7.5 Hz, 1H), 8.17 (d, J ¼ 8.0 Hz, 1H),
8.01e8.06 (m, 2H), 7.73e7.76 (m, 2H), 7.53 (t, J ¼ 8.0 Hz,
1H).
d
¼ 9.71(s, 1H), 8.67 (s,
Pale yellow solid; mp 115e117 ꢁC: 98% yield (364 mg,
0.98 mmol) [48] (Table 2, entry 10).
1H NMR (250 MHz, CDCl3):
7.44 (d, J ¼ 8.0 Hz, 2H), 4.02 (q, J ¼ 7.0 Hz, 4H), 2.62 (s, 6H),
0.97 (t, J ¼ 7.0 Hz, 6H).
d
¼ 8.24 (d, J ¼ 8.0 Hz, 2H),
2.5.7. Diethyl 2,6-dimethyl-4-phenyl-3,5-pyridinedicarboxylate
Pale yellow solid; mp 60e61 ꢁC: 98% yield (320 mg,
0.98 mmol) [48] (Table 2, entry 1).
2.5.15. Diethyl-2,6-dimethyl-4-cinamyl-3,5-
pyridinedicarboxylate
1H NMR (250 MHz, CDCl3):
(q, J ¼ 6.7 Hz, 4H), 2.59 (s, 6H), 0.88 (t, J ¼ 6.7 Hz, 6H).
d
¼ 7.25e7.35 (m, 5H), 3.98
Pale yellow solid; mp 164e165 ꢁC: 90% yield (318 mg,
0.90 mmol) [48] (Table 2, entry 12).
1H NMR (250 MHz, CDCl3):
(d, J ¼ 16.5 Hz, 1H), 6.79 (d, J ¼ 16.5 Hz, 1H), 4.32 (q,
J ¼ 7.0 Hz, 4H), 2.56 (s, 6H), 1.27 (t, J ¼ 7.0 Hz, 6H).
d
¼ 7.26e7.41 (m, 5H), 7.10
2.5.8. Diethyl 2,6-dimethyl-4-(p-tolyl)-3,5-
pyridinedicarboxylate
Pale yellow solid; mp 72e74 ꢁC: 96% yield (327 mg,
0.96 mmol) [48] (Table 2, entry 2).
3. Results and discussion
1H NMR (250 MHz, CDCl3):
d
¼ 7.14e7.26 (m, 4H), 4.02
(q, J ¼ 7.0 Hz, 4H), 2.58 (s, 6H), 2.36 (s, 3H), 0.95 (t,
To optimize the reaction conditions, the dehydrogena-
tion of 2-phenyl tetrahydroquinazoline as the model
J ¼ 7.0 Hz, 6H).
Please cite this article as: M. Shariati et al., Application of laccase/DDQ as a new bioinspired catalyst system for the aerobic
oxidation of tetrahydroquinazolines and Hantzsch 1,4-dihydropyridines, Comptes Rendus Chimie, https://doi.org/10.1016/
j.crci.2019.03.003

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M. Shariati et al. / C. R. Chimie xxx (xxxx) xxx
reaction was investigated. Initially, the reaction was carried
out in the presence of laccase (100 U) and O2 as the oxidant
in a CH3CN/NaPBS mixture (1:25) as the solvent at 45 ꢁC.
Very low conversions of starting materials were observed,
by performing the reactions in the absence of DDQ (Table 3,
entry 1). When DDQ (5 mol %) was added as a mediator in
the reaction, the product was obtained in moderate yield
(Table 3, entry 2). These results demonstrated that DDQ is
necessary for an efficient reaction. By increasing the
amount of DDQ to 10 mol% the yield slightly improved
(Table 3, entry 3). The excellent result was obtained when
20 mol% of DDQ was used (Table 3, entry 4). Subsequently,
the effect of laccase concentration on the reaction was
explored. When the amount of laccase was reduced to 50 U,
the yield dropped to 70% (Table 3, entry 5). A blank reaction
was carried out to evaluate the catalytic efficiency of lac-
case where only 30% of desired product was obtained
(Table 3, entry 6). The optimal enzyme concentration was
found to be 100 U (entry 4). So, it was selected as a standard
concentration in all further reactions. Among various sol-
vents screened, such as CH3CN/NaPBS (pH 4.5, 0.1 M),
CH3OH/NaPBS (pH 4.5, 0.1 M), NaPBS buffer, and H2O,
CH3CN/NaPBS (pH 4.5, 0.1 M) gave the best result (Table 3,
entries 4 and 7e9). In organic solvents, such as CH3CN, THF,
DMF, and DMSO the reactions did not occur, probably
because of laccase denaturation (Table 3, entries 10e13).
The effect of temperature, both high and low, on the reac-
tion yield was also tested. It was found that by increasing
the reaction temperature up to 60 ꢁC, the yield was
dropped because of enzyme deactivation [52] (Table 3,
entry 14). At room temperature, the desired product was
obtained in moderate yield (Table 3, entry 15). Using air as
an oxidant instead of molecular oxygen in the reaction gave
90% conversion of 2-phenyl tetrahydroquinazoline (Table 3,
entry 16).
With having the optimized catalytic system laccase/
DDQ in hand, the general applicability of this method was
further examined for the synthesis of 2-substituted qui-
nazolines from the oxidative cyclocondensation of 2-
aminobenzylamine and structurally various aldehydes.
Under the optimized reaction conditions (Table 3, entries 4
and 16), the expected products were obtained in excellent
yields and the results are shown in Table 1. Different sub-
stituents, including both electron-poor (fluoro, chloro, and
bromo) and electron-rich (methyl, methoxy) groups, at
various positions of the benzaldehyde ring would be
compatible by the present oxidative system and gave the
desired products in high yields (Table 1, entries 2e11).
Notably, terephthaldehyde as
a bifunctional aromatic
aldehyde was satisfactorily subjected to oxidative cyclo-
condensation as well (Table 1, entry 6).
Having successfully achieved the aerobic oxidative
synthesis of 2-substituted quinazolines, we expanded
the application of laccase/DDQ catalytic system for
aerobic oxidation of Hantzsch 1,4-dihydropyridines to
pyridines. 1,4-Dihydropyridines were synthesized ac-
cording to the reported procedure [53]. The effect of
amount of laccase and DDQ, solvent, and temperature
Table 4
Table 3
Optimization of reaction conditions for aerobic oxidation of diethyl 2,6-
Optimization of reaction conditions for aerobic oxidation of 2-phenyl
dimethyl-4-phenyl-1,4-dihydropyridine-3,5-dicarboxylate.a
tetrahydroquinazoline.a
O
Ph
N
O
O
Ph
O
Cat. Laccase/ DDQ,
Oxidan: O2
Cat. Laccase/ DDQ,
Oxidan: O2
O
O
O
O
N
NH
Ph
Solvent, Temp (oC)
Solvent, Temp (oC)
N
Ph
N
H
N
H
Entry Laccase (U) Solvent
Temperature DDQ
GC yield
Entry Laccase Solvent
(U)
Temperature DDQ
GC yield
(ꢁC)
(mol %) (%)
(oC)
(mol %) (%)
1
100
CH3CN/NaPBS 45
1
100
CH3CN/NaPBS rt
e
e
e
e
2
3
4
5
6
100
100
100
50
CH3CN/NaPBS 45
CH3CN/NaPBS 45
CH3CN/NaPBS 45
CH3CN/NaPBS 45
CH3CN/NaPBS 45
5
60
70
100
70
2
3
4
5
6
100
100
100
50
CH3CN/NaPBS rt
CH3CN/NaPBS rt
CH3CN/NaPBS rt
CH3CN/NaPBS rt
CH3CN/NaPBS rt
5
70
80
100
70
40
10
20
20
20
10
20
20
20
30
e
e
7
8
9
10
100
100
100
100
CH3OH/NaPBS 45
NaPBS buffer 45
20
20
20
20
90
50
40
7
8
9
10
100
100
100
100
CH3OH/NaPBS rt
20
20
20
20
90
60
40
NaPBS buffer
H2O
CH3CN
rt
rt
rt
H2O
CH3CN
45
45
e
e
e
e
e
e
e
e
11
12
13
100
100
100
THF
45
45
45
20
20
20
11
12
13
100
100
100
THF
rt
rt
rt
20
20
20
DMF
DMSO
DMF
DMSO
14
100
100
100
CH3CN/NaPBS 60
CH3CN/NaPBS rt
CH3CN/NaPBS 45
20
20
20
40
50
90
14
100
100
100
CH3CN/NaPBS 60
CH3CN/NaPBS 45
CH3CN/NaPBS rt
20
20
20
40
100
90
15
15b
16c
16b
GC, gas chromatography. The bold represents the most effective reaction
conditions.
The bold represents the most effective reaction conditions.
a
Reaction conditions: 1,4-Dihydropyridine (1 mmol), laccase (100 U),
O2 (balloon), and solvent (13 mL).
a
Reaction conditions: 2-Phenyl tetraquinazoline (1 mmol), laccase (100
b
U), O2 (balloon), and solvent (13 mL).
Reaction time was 3 h.
The reaction was carried out under air conditions.
b
c
The reaction was carried out under air conditions.
Please cite this article as: M. Shariati et al., Application of laccase/DDQ as a new bioinspired catalyst system for the aerobic
oxidation of tetrahydroquinazolines and Hantzsch 1,4-dihydropyridines, Comptes Rendus Chimie, https://doi.org/10.1016/
j.crci.2019.03.003

M. Shariati et al. / C. R. Chimie xxx (xxxx) xxx
7
on the oxidation reaction of diethyl 2,6-dimethyl-4-
phenyl-1,4-dihydropyridine-3,5-dicarboxylate to diethyl
up of reaction gave limited success and shows the lower
substrate conversion (60%) [54].
2,6-dimethyl-4-phenyl-3,5-pyridinedicarboxylate as
a
Although the exact mechanisms of the reactions are not
clear at this stage, however according to previous reports
on the application of DDQ in organic reactions and aerobic
oxidation of hydroquinone to quinone by laccase
[45,55e57], the proposed mechanisms for the aerobic
oxidation of 2-substituted tetrahydroquinazolines and 1,4-
dihydropyridines are presented in Schemes 4 and 5,
respectively.
One explanation is that a single electron transfer from
the 2-substituted tetrahydroquinazolines or 1,4-
dihydropyridines to DDQ generates a radical cation (in-
termediates A and B in Scheme 4) and a DDQ radical anion.
model reaction was investigated (Table 4). Laccase (100
U) and 20 mol% of DDQ under O2 or air in NaPBS
(0.1 M, pH 4.5)/CH3CN (4%) mixture at room tempera-
ture was found to be ideal for complete conversion of
1,4-dihydropyridines to the corresponding pyridines
(Table 4, entry 4).
To generalize the scope of the reaction, a series of
structurally diverse Hantzsch 1,4-dihydropyridines were
subjected to aerobic oxidation under the optimized reaction
conditions, and the results are presented in Table 2.
To investigate the feasibility of applying this chemo-
enzymatic synthetic method on a preparative scale, the
aerobic oxidation of diethyl 2,6-dimethyl-4-phenyl-1,4-
dihydropyridine-3,5-dicarboxylate was carried out on a
5 mmol scale of starting materials. We have found the scale
The radical oxygen of the DDQ radical anion abstracts an a-
H-atom and then the anionic oxygen of DDQ radical anion
abstracts proton from nitrogen to form target products (2-
substituted quinazolines and pyridines) and DDQH2. The
reduced DDQH2 (hydroquinone type compound) is subse-
quently regenerated by laccase leading to DDQ and reduced
form of laccase. Finally, laccase can be reoxidized by mo-
lecular oxygen, thus completing the catalytic cycle (Scheme
4a and b).
Scheme 4. Radical path mechanism for the aerobic oxidation of 2-
substituted tetrahydroquinazolines (a) and 1,4-dihydropyridine (b) in the
presence of laccase/DDQ catalyst system.
Scheme 5. Electron transfer path or anomeric-based oxidation mechanism
for the aerobic oxidation of 2-substituted tetrahydroquinazolines (a) and
1,4-dihydropyridine (b) in the presence of the laccase/DDQ catalyst system.
Please cite this article as: M. Shariati et al., Application of laccase/DDQ as a new bioinspired catalyst system for the aerobic
oxidation of tetrahydroquinazolines and Hantzsch 1,4-dihydropyridines, Comptes Rendus Chimie, https://doi.org/10.1016/
j.crci.2019.03.003

8
M. Shariati et al. / C. R. Chimie xxx (xxxx) xxx
Table 5
Comparison of the laccase/DDQ catalyst system with other reagent or catalysts for oxidation of 2-phenyl tetrahydroquinazoline to 2-phenyl quinazoline.
Entry
Reagent
or catalyst
Reaction
conditions
Time (h)
Isolated
yield (%)
Reference
1
2
3
4
5
6
7
8
MnO2 (4 mmol)
CHCl3, reflux
12
5
70
98
66
85
70
88
95
95
[14]
[15]
[17]
[18]
[19]
[57]
[23]
[24]
NaOCl (3 mmol)
MeOH, rt
[CpIrCl2]2 (2.5 mol%), styrene (4 equiv)
Pt/CeO2 (1 mol %)
N2, xylene, reflux
Mesitylene, N2, reflux
DMSO, N2, 60 ꢁC
CH3CN, rt
24
30
6
FeCl3 (2 mol%), TBHP (1.5 mol%)
IBX (2 equiv)
6
CuCl (5 mol%)/DABCO (10 mol%)/TEMPO (5 mol%)
CH3CN, O2, 80 ꢁC
CHCl3: H2O (9:1, 0.5 M), O2, 35 ꢁC
6
PI/CB-Pt/Ir (0.5 mol%), TTSBI (3.5 mol%), K2CO3
(0.5 equiv)
16
9
RhCNT (1 mol%), TBC (10 mol%)
CHCl3/H2O (3:1), rt
21
24
8
94
84
87
95
[25]
[26]
10
11
12
phd (5 mol%), ZnI2 (2.5 mol%), PPTS (15 mol%)
MgI2 (5 mol%)
CH3CN, O2, rt
EtOAC, visible light, O2, rt
NaPBS/CH3CN, O2 or air, 45 ꢁC
[59]
Laccase (100 U)/DDQ (20 mol%)
22
This work
Table 6
Comparison of laccase/DDQ catalyst system, with other reagent or catalysts for oxidation of diethyl 2,6-dimethyl-4-phenyl-1,4-dihydropyridine-3,5-
dicarboxylate to diethyl 2,6-dimethyl-4-phenyl-3,5-pyridinedicarboxylate.
Entry
1
Reagent or catalyst
MnO2
Reaction conditions
CH2Cl2, MW 100 ꢁC
Time
Isolated yield (%)
99
Reference
1 min
[20c]
[20d]
[20f]
[59]
2
NO (20 equiv)
Benzene, under Ar atmosphere
AcOH, rt
3 h
96
96
90
93
99
78
97
80
98
3
Zr(NO3)4 (1 equiv)
15 min
1 h
4
DDQ (0.5 mmol)
THF, rt
5
Fe(ClO4)3 (2 mol%)
HOAC, rt
1.5 h
4 h
[27a]
[27b]
[27c]
[27d]
6
NHPI (20 mol%)
CH3CN, O2, reflux
CH3CN, air, 60 ꢁC
7
TBPAþ_
18 h
30 min
9 h
8
FeCl3 (0.05 mmol)/NaNO2 (0.05 mmol)/TEMPO (0.05 mmol)
Laccase (168 U)/ABTS (10 mol%)
Laccase (100 U)/DDQ (20 mol%)
CH3CN, CH3COOH, O2, rt
Acetate buffer/MeOH, air, 50 ꢁC
NaPBS/CH3CN, O2 or air, rt
9
[44]
10
7 h
This work
Another explanation for these processes is that
oxidation of the substrate occurs by hydride transfer
from the C2 and C4 position on 2-substituted tetrahy-
droquinazolines and C4 position on 1,4-dihydropyridines
to the carbonyl oxygen atom of DDQ (transition states C
and E), thereby forming ion-pairs (intermediates D and F)
[56]. It should be mentioned that these transformations
may proceedvia anomeric-based oxidation [20g]. Depro-
tonation of the substrate by DDQHꢀ can afford the cor-
responding dehydrogenated product. The reduced
DDQH2 is oxidized by laccase leading to DDQ and
reduced form of laccase. Finally, laccase can be reoxidized
by molecular oxygen, thus completing the catalytic cycle
(Scheme 5).
phenyl-1,4-dihydropyridine-3,5-dicarboxylate with the
bestof thewell-knowndata fromthe literature(Tables 5 and
6). As shown in Tables 5 and 6, the previously reported
procedures suffer from one or more disadvantages such as
the use of stoichiometric oxidant [14,15,20c,20d,20f,58,59],
toxic and expensive transition metal catalysts or reagent
[14,17,19,20c,20f,23e26,27a,27d], special efforts for the
preparation of catalyst [17,24,25], toxic and volatile solvents
[14e19,20c,20d,23e25,27be27d,56,60], elevated reaction
temperatures [14,17,19,23,20c,27b,27c,44], and low yield
[14,17,19,27c,44].
4. Conclusion
To illustrate the efficiency of laccase/DDQ catalyst sys-
tem, we compared our results for dehydrogenation of 2-
phenyl tetrahydroquinazoline and diethyl 2,6-dimethyl-4-
We have developed laccase/DDQ as a simple, efficient,
and environmentally friendlycatalyst system for the aerobic
oxidative synthesis of structurally diverse 2-substituted
Please cite this article as: M. Shariati et al., Application of laccase/DDQ as a new bioinspired catalyst system for the aerobic
oxidation of tetrahydroquinazolines and Hantzsch 1,4-dihydropyridines, Comptes Rendus Chimie, https://doi.org/10.1016/
j.crci.2019.03.003

M. Shariati et al. / C. R. Chimie xxx (xxxx) xxx
9
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oxidation of tetrahydroquinazolines and Hantzsch 1,4-dihydropyridines, Comptes Rendus Chimie, https://doi.org/10.1016/
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Please cite this article as: M. Shariati et al., Application of laccase/DDQ as a new bioinspired catalyst system for the aerobic
oxidation of tetrahydroquinazolines and Hantzsch 1,4-dihydropyridines, Comptes Rendus Chimie, https://doi.org/10.1016/
j.crci.2019.03.003