Laccase-Based Oxidative Catalytic Systems for the Aerobic Aromatization of Tetrahydroquinazolines and Related N-Heterocyclic Compounds under Mild Conditions

Article abstract of DOI:10.1002/ejoc.201800466

In this work, for the first time, laccase (metalloenzyme)/3,5-di-tert-butylcatechol (DTBC) as a new class of bioinspired quinone-based cooperative catalytic oxidation system and laccase/2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) catalyst system were used for the aerobic oxidative synthesis of 2-substituted quinazolines through cascade reaction of structurally divers aldehydes with 2-aminobenzylamine. The products were obtained in good to high yields in phosphate buffer (0.1 m, 12.5 mL, pH = 4.5) and acetonitrile (4 vol.-%) mixture as solvent at 45 °C. Other N-heterocycles are also successfully oxidized to their aromatic counterparts.

Full text of DOI:10.1002/ejoc.201800466

A Journal of
Accepted Article
Title: Laccase-based oxidative catalytic systems for the aerobic
aromatization of tetrahydroquinazolines and related N-
heterocyclic compounds under mild conditions
Authors: Shaghayegh Saadati, Nadya Ghorashi, Amin Rostami, and
Farzad Kobarfard
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800466
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800466
Supported by

10.1002/ejoc.201800466
European Journal of Organic Chemistry
COMMUNICATION
Laccase-based oxidative catalytic systems for the aerobic
aromatization of tetrahydroquinazolines and related N-
heterocyclic compounds under mild conditions
Shaghayegh Saadatia] Nadya Ghorashi,[b] Amin Rostami,*[b] and Farzad Kobarfard [a]
Abstract: In this work, for the first time, laccase (metalloenzyme)/3,5-
di-tert-butylcatechol (DTBC) as a new class of bioinspired quinone-
based cooperative catalytic oxidation system and laccase/2,2,6,6-
tetramethylpiperidine-1-oxyl (TEMPO) catalyst system were used for
the aerobic oxidative synthesis of 2-substituted quinazolines through
cascade reaction of structurally divers aldehydes with 2-
aminobenzylamine. The products were obtained in good to high yields
in phosphate buffer (0.1 M, 12.5 mL, pH=4.5) and acetonitrile (4 vol%)
mixture as solvent at 45 oC. Other N-heterocycles are also
successfully oxidized to their aromatic counterparts.
One strategy for the synthesis of these valuable compounds is
through the oxidative cyclization of 2-aminobenzylamines with
aldehydes mediated by stoichiometric amounts of strong oxidant
such as DDQ, [9] MnO2, [10] NaClO[11] and etc.[12] However, these
reagents are often toxic and show poor atomic efficiency. Thus,
the development of more efficient and environmentally benign
reactions is necessary to realize sustainable and green methods
for quinazolines synthesis.
Molecular oxygen or air as the cheapest and greenest oxidizing
agent represents an ideal alternative to traditionally used
oxidants. Thus, oxidation of organic compounds using molecular
oxygen in the presence of transition-metal catalysts or
organocatalysts have been developed. [13] Only a few examples
of aerobic oxidative cyclization of 2-aminobenzylamines with
aldehydes to synthesize 2-aryl quinazolines have been
developed. Typical examples include i) the use of Cu/N-
ligand/TEMPO catalytic system,[14] ii) the assembly of rhodium
nanoparticles (RhNPs) on carbon nanotubes (CNTs) along with
redox-active quinone-type co-catalyst,[15] iii) 1,10-phenanthroline-
5,6-dione associated to different metals (Zn, Fe, or Ru),[16] vi) Pt/
Ir nanoclusters in combination with catechol co-catalysts.[17]
Although these catalyst systems could efficiently perform
oxidation reactions, these methods still require high reaction
temperatures which are not suitable for thermally unstable
substrates[14] and transition metals catalysts which may possibly
leave toxic traces of heavy metals in the products. It is vital to
eliminate the metallic catalyst (especially in pharmaceutical
industry) because metal contamination is highly regulated.
Therefore, the development of green and non-metallic catalysts
for the aerobic oxidative synthesis of these important compounds
is still desirable and is in demand. [18] A potential approach to
overcome this problem is to change the transition metals catalysts
to safe catalysts such as biocatalysts for the aerobic oxidation.
Laccases (p-benzenediol: oxygen oxidoreductase; [E.C.
1.10.3.2)] are extracellular enzymes that contain four copper
centres per protein molecule and catalyze the oxidation of
electron rich aromatic substrates, usually phenols or aromatic
amines. The unique properties of laccases such as mild reaction
conditions and substrate selectivity make them attractive for use
in chemical synthesis.[19] Its good thermal stability coupled with its
lack of substrate inhibition and high rates of oxidation (10-100 fold
higher than those of lignin peroxidase or manganese peroxidase)
make laccase an ideal candidate for the development of
enzymatic oxidation processes.[20] In view of the low redox
potential, native laccases can oxidize only electron rich aromatic
substrates,[21] with the concomitant reduction of O2. However, the
Introduction
Nitrogen-containing heterocycles have been extensively studied
as the core structural skeletons in a variety of drugs. Of these
heterocycles, quinazolines have been particularly studied for their
biological activity and have been reported to display hypotensive,
[1]
[2]
[3]
[4]
anti-cancer,
anti-inflammatory,
anticonvulsant,
kinase
[5]
[6]
inhibitory
and antidiabetic properties.
Also quinazolin has
been stupendously utilized as a drug-like template in medicinal
chemistry. Prazosin and lapatinib have been used as α-
adrenergic blockers for the treatment of high blood pressure,
anxiety and panic disorder [7] and as tyrosine kinase inhibitor for
the treatment of breast cancer and solid tumor, respectively (Fig.
1). [8]
Figure 1. Drugs containing quinazoline moieties
[a]
[b]
Shaghayegh Saadati and Farzad Kobarfard
Department of Medicinal Chemistry
Shahid Beheshti University of Medical Sciences,
Tehran, Iran, Fax: (+98) 2188200092; phone: (+98) 9123434595
E-mail: kobarfard@sbmu.ac.ir
oxidation of non-phenolic substrates can also take place on
[22]
mediation by appropriate substances.
In fact, the oxidized
Nadya Ghorashi and Amin Rostami
Department of Chemistry
mediator can rely on an oxidation mechanism that is not available
to the enzyme. A conceivable role of the mediator could be that
of a sort of -electron shuttle- between the enzyme and the
substrate. [23] Therefore, the range of laccase substrates can be
extended by the simultaneous use of the enzyme and redox
mediators. Artificial mediators commonly used in laccase
University of Kurdistan
Zip Code 66177-15175, Sanandaj, Iran, Fax: (+98) 8733624004;
phone: (+98) 9183730910
E-mail: a.rostami@uok.ac.ir
Supporting information for this article is given via a link at the end of
the document
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10.1002/ejoc.201800466
European Journal of Organic Chemistry
COMMUNICATION
catalysis studies include HBT (1-hydroxybenzotriazole), HPI (N-
hydroxyacetanilide), TEMPO (2,2,6,6-tetra-methyl-piperidin-1-
system in the toxic transition-metal-free and halogen free aerobic
oxidation of organic compounds. Herein, we present for the first
time the simple and efficient methods for the synthesis of 2-
substituted quinazolins from aminobenzylamine and aldehydes
via aerobic oxidative cyclization in the presence of laccase-
catechol or laccase-TEMPO as catalytic oxidation system, using
O2 or air as oxidant and a phosphate buffer solution as solvent at
45 oC (Scheme 1).
yloxy)
and
ABTS(2,20-azino-bis(3-ethylbenzthiazoline-6-
sulfonate). [24]
Results and Discussion
To the best of our knowledge, there has been no report on the
use of laccase/catechol as a cooperative catalytic oxidation
Laccase/Co-catalyst (Cat.), O2 or air
NH2
N
NH
CH3CN, r.t.
+
ArCHO
NaPBS, CH3CN (4%), 45oC
NH2
N
Ar
N
Ar
H
Scheme 1. Aerobic oxidative synthesis of 2-arylquinazoline catalyzed by laccase/ co-catalyst system
In order to optimize the reaction conditions initially, the
dehydrogenation of 2-phenyl tetrahydroquinazoline was
conducted in the presence of laccase (200 U) and O2 as oxidant
in MeCN/NaPBS (sodium phosphate buffer solution) mixture
(1:25) as solvent at 45oC. Under these conditions, low yield of 2-
phenyl quinazoline was obtained (Table 1, entry 1). When 20
mol% of pyrocatechol was added as a mediator, the yield
increased to 50% (Table 1, entry 2). By changing mediator to 4-
tert-butylcatechol the yield slightly improved (Table 1, entry 3),
using a bulkier catechol, 3,5-di-tert-butylcatechol (DTBC) in this
reaction resulted in a drastic enhancement in the yield of the
desired product (Table1, entry 4). Employing hydroquinone
afforded 2-phenyl quinazoline in only 30% yield (Table 1, entry 5).
was also checked in both high and low temperatures. When the
reaction temperature was increased up to 60 oC, the yield
dropped due to enzyme deactivation[25] (Table 1, entry 7). At room
temperature, the desired product was obtained in low yield (Table
1, entry 8). When the amount of DTBC was reduced to 15 mol%,
the GC yield dropped to 70 % (Table 1, entry 9). Using air as an
oxidant instead of molecular oxygen in the reaction, gave 90%
yield of the 2-phenyl quinazoline (Table 1, entry 10). When
laccase/DTBC catalyst system was replaced with stoichiometric
amount
3,5-di-tert-butyl-o-benzoquinone,
the
2-phenyl
quinazoline was obtained in 80 % yield (Table 1, entry 11).
Encouraged by the initial success, the generality and applicability
of this method was further examined for the synthesis of 2-
substituted quinazolines from the oxidative cyclization reactions
of 2-aminobenzylamine and structurally diverse aldehydes. Under
optimized reaction conditions (Table 1, entries 4 and 10), the
expected products were obtained in moderate to high yields
(Table 2). Various substituents, including both electron-donating
(methyl and methoxy) and electron-withdrawing (fluoro, chloro,
bromo and nitro) groups at the different positions of the
benzaldehyde ring would be compatible with the present oxidative
system and gave the desired products in good to high yields
(Table 2, entries 2-13). Terephthaldehyde as a bifunctional
aromatic aldehyde was satisfactorily subjected to oxidative
cyclization as well (Table 2, entry 14).
Although, the exact mechanism is not clear and should be further
studied in detail, however, based on our observation during the
course of the reaction (Table 1, entries 5, 11) and previously
reported mechanisms about application of laccase in oxidation of
catechol in tandem reactions[29] and oxidative dehydrogenation
of N-heterocyclic rings using catechol as a co-catalyst[15-17], a
plausible reaction pathway for the dehydrogenation of 2-
substituted tetrahydroquinazolines in the presence of
laccase/catechol catalyst system has been proposed in scheme
2. Mechanism involves oxidation of catechol to o-benzoquinone
using laccase followed by the reduction of one molecule of oxygen
to two molecules of water. Then, quinone catalyzes the aerobic
dehydrogenation of secondary amines via an addition-elimination
reaction.
Table 1. Optimization of reaction conditions for aerobic dehydrogenation of
2-phenyl tetrahydroquinazoline[a]
Entry
Co-catalyst
Temp oC)
Laccase
(U)
GC Yield (%)
1
2
3
-
Pyrocatechol
4-tert-
45
45
45
200
200
200
20
50
70
butylcatechol
DTBC
Hydroquinone
DTBC
DTBC
DTBC
DTBC
DTBC
3,5-di-tert-butyl-
o-benzoquinone
4
5
6
7
8
9
10
11
45
45
45
60
r.t
45
45
45
200
200
100
200
200
200
200
100 [b]
30
70
30
50
70[c]
90 [b], [d]
80[e]
[a]Reaction conditions unless stated otherwise:yl tetrhydroquinazoline (1 mmol),
Laccase (200 U), mediator (20 mol%), O2 (balloon), phosphate buffer (0.1 M,
pH 4.5, 12.5 mL)/ CH3CN (4 %, 0.5 mL), and 24 h. [b]The bolds represent the
effective reaction conditions. [c]15 mol% of DTBC was used. [d]The reaction was
performed under air conditions. [e] 1 mmol of 3,5-di-tert-butyl-o- benzoquinone
was used.
The effect of laccase concentration on the reaction rate was next
investigated. When the amount of laccase was reduced to 100 U,
the GC yield dropped to 70% (Table 1, entry 6). The optimal
enzyme concentration was found to be 200 U (Table 1, entry 4),
and therefore it was selected as a standard concentration in all
further reactions. The effect of temperature on the reaction yield
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COMMUNICATION
Table 2. Substrate scope for the synthesis of 2-substituted quinazoline derivatives[a]
NH2
1- CH3CN, rt, 3-5 h
N
ArCHO
+
2- Laccase/DTBC, O2 or air,
NaPBS/CH3CN, 45oC
Product
NH2
N
Ar
Entry
1
RCHO
Time (h)
24
Yield (air)[b] (%)
95 (82)
Mp oC [Lit.]
97-98 [15]
2
3
4
20
20
24
96 (88)
94 (84)
55 (44)
78-80 [15]
91-93 [17]
218-119 [15]
O2N
CHO
N
5
24
50 (40)
194-195 [28]
NO2
N
6
7
24
22
60 (55)
93 (83)
71-73 [11]
89-90[ 26]
8
9
24
24
80 (75)
70 (60)
120-122 [11]
140-142 [27]
10
11
12
24
24
24
60 (50)
96 (87)
90 (80)
78-80
148-150[15]
153-155[15]
13
22
24
90 (83)
95 (82)
195-197
270
14[c]
[a] General procedure: aldehyde (1 mmol), 2-aminobenzyl amine (1 mmol), Laccase (200U), DTBC (20 mol%), O2 (balloon), NaPBS (12.5 mL), CH3CN (0.5 mL), 45
oC. [b] solated yield under air conditions is shown in parentheses. [c] Conditions: Aldehyde (1 mmol), 2-aminobenzyl amine (2 mmol), laccase (400 U), DTBC (40
mol%), O2 (balloon), NaPBS (25 mL), CH3CN (1 mL), 45 oC.
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1/2 O2
H2O
Laccase (Red)
Laccase (OX)
tBu
HO
tBu
O
tBu
HO
Ar
tBu
O
tBu
H2N
H2N
But
HO
H
R
N
N
O
H
Cyclocondensation
+
N
H
HN
Ar
tBu
N
ArCHO
HO
N
O
tBu
Scheme 2. Plausible mechanism for the synthesis of 2-substituted quinazolines in the presence of laccase/catechol catalyst system
Table 3. The optimization of the reaction conditions for the dehydrogenation of
Laccase/TEMPO has been reported as an efficient catalyst
system in the oxidation of some organic compounds.[24] These
investigations prompted us to explore the prospects of this
catalytic system for the synthesis of 2-substuted quinazolines
from oxidative cyclization of aldehydes and 2-aminobenzylamine.
Inspired by the successful result above, we first conducted
dehydrogenation of 2-phenyl tetrhydroquinazoline in the presence
of laccase (200 U) and TEMPO (20 mol%) under O2 in NaPBS
(pH=4.5, 0.1 M) and 4 vol% of MeCN at 45 oC. Under these
conditions, the desired product was obtained in 100% GC yield
(Table 3, entry 1). When the amount of laccase or TEMPO was
reduced, the GC yield dropped (Table 3, entries 2 and 3).
Employing MeOH/NaPBS as a solvent in the reaction gave 80%
yield of the desired product (Table 3, entry 4). By decreasing the
reaction temperature to 25 oC, the lower yield was observed
(Table 3, entry 5). For comparison purposes, the combination of
TEMPO with NiFe2O4 or CuFe2O4 magnetic nanoparticles has
been also studied in MeCN at 80oC on the model reaction.
Subsequently, a series of various 2-substituted quinazoline
derivatives were synthesized successfully with optimal conditions
in hand (Table 3, entries 1 and 8).
2-phenyl tetrahydroquinazoline[a]
NH
Catalyst/TEMPO
N
solvent, O2, ToC, 24 h
N
Ph
N
Ph
H
Entry
1[b]
2
Catalyst (U or mmol)
Laccase (200)
Laccase (100)
Laccase (200)
Laccase (200)
Laccase (200)
NiFe2O4 (0.4)
Temp (oC)
GC Yield (%)
45
45
45
45
r.t
45
45
45
100
50
80
80
50
60
50
90
3[c]
4
5
6
7
CuFe2O4 (0.4)
Laccase (200)
8[b], [d)
[a]Reaction conditions unless stated otherwise: 2-phenyl tetrquinazoline (1
mmol), TEMPO (20 mol%), O2 (balloon) and solvent (13 mL). [b]The bolds
represent the effective reaction conditions. [c]The reaction was performed in the
presence of 15 mol % of TEMPO. [d]Under air conditions.
The result obtained from the oxidative cyclization of different
aldehydes with 2-aminobenzylamine have been summarized in
Table 4.
Table 4. Laccase /TEMPO -catalyzed aerobic oxidation of 2-substituted tetrahydroquinazolines [a]
Entry
RCHO
Product
Time (h)
24
Yield (air)b (%)
95 (82)
1
2
20
93 (80)
3
4
22
24
96 (85)
40 (35)
CHO
N
5
24
40 (35)
NO2
N
NO2
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European Journal of Organic Chemistry
COMMUNICATION
Table 4. (Continued)
Entry
RCHO
Product
Time (h)
26
Yield (air)[b] (%)
70 (60)
6
7
24
80 (73)
8
24
24
24
85 (78)
75 (62)
72 (60)
9
10
11
12
13
22
24
23
94 (83)
90 (80)
90 (80)
14[c]
24
90 (83)
[a] General procedure: aldehyde (1 mmol), 2-aminobenzyl amine (1 mmol), Laccase (200U), TEMPO (20 mol %), O2 (balloon), NaPBS (12.5 mL), CH3CN (0.5 mL),
45 oC. [b] Isolated yield under air conditions is shown in parentheses. [c]Conditions: Aldehyde (1 mmol), 2-aminobenzyl amine (2 mmol), Laccase (400 U), TEMPO
(40 mol%), O2 (balloon), NaPBS (25 mL), MeCN (0.5 mL), 45 oC.
Mechanism for this reaction is proposed on the basis of previously
reported mechanism for the oxidation of organic compounds
catalyzed by laccase/TEMPO system.[24] As shown in scheme 3,
one electron oxidation of TEMPO by the oxidized (cupric) form of
the laccase followed by the reaction of oxidized mediator with the
substrate. One electron oxidation of TEMPO affords the
oxoammonium cation, which oxidizes the C-N bond of substrate
via a heterolytic pathway, giving the product.
1/2 O2
H2O
Laccase (Red)
Laccase (OX)
N
O
H2N
H2N
N
O
H2O
H
Ar
N
Cyclocondensation
+
HN
1/2 O2
ArCHO
OH
N
N
O
N
Ar
H
N
Ar
N
H
N
Scheme 3. Plausible mechanism for the synthesis of 2-substituted quinazolines catalyzed by Laccase/TEMPO system
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10.1002/ejoc.201800466
European Journal of Organic Chemistry
COMMUNICATION
Having successfully achieved the aerobic oxidative synthesis of
yields (Table 5, entry 1). Tetrahydroquinoline, indoline and
Hantzsch-type dihydropyridine exhibited more activity as
2-substituted
quinazolines
from
2-substituted
tetrahydroquinazolines, we expanded Laccase/DTBC and
Laccase/TEMPO catalytic systems for the synthesis of other
heteroaromatics such as quinoxaline, quinoline, indole and
Hantzsch-type pyridine from aerobic dehydrogenation of their
partial saturated counterparts. The aerobic dehydrogenation of
1,2,3,4-tetrahydroquinoxaline using both two catalyst systems
under optimized reaction conditions led to quinoxaline in high
compared
to
the
tetrahydroquinoxaline
and
tetrahydroquinazolines (Table 5, entries 2-4) and afforded high
yields of products at room temperature. Strange, the oxidation of
Hantzsch-type dihydropyridine in the presence of laccase/DTBC
catalyst system afforded the desired product in only 20% yield
even after prolonged reaction time and using higher temperature
(Table 5, entry 4).
Table 5. Laccase /DTBC or Laccase /TEMPO -catalyzed aerobic oxidation of other classes of N-Heterocycles [a]
Entry
substrate
Product[b]
Temp (oC)
DTBC
Time (h)
TEMPO
Yield (%)
Yield (%)
95
Time (h)
24
1
45
24
93
2
3
25
25
24
24
90[c]
95
24
24
80[c]
90
4
25
24
20[d]
15
97
[a] Conditions: Substrate (1 mmol), Laccase (200U), TEMPO or DTBC (20 mol %), O2 (balloon), NaPBS (12.5 mL), CH3CN (0.5 mL). [b]
All compounds are known and were characterized by 1H NMR (see supporting information). [c] A trace amount of dihydroquinloline was
also formed. [d] Temp: 45 oC
Conclusions
Experimental Section
General Remarks
2,2',6,6'-tetramethyl-1-piperidinyloxy free radical
azinobis(3-ethylbenzthiazolin-6-sulfonate
In summary, we have developed laccase/DTBC and
laccase/TEMPO as efficient catalyst systems for the aerobic
oxidative synthesis of 2-substitited quinazolines and other
important N-heterocycles compounds such as quinoxaline,
quinoline, indole and Hantzsch-type pyridine under mild reaction
conditions. These procedures offer several novelties and
advantages are as following:
1) This is the first report of laccase/DTBC for use as an
efficient cooperative catalytic oxidation system for aerobic
oxidation of organic compounds.
(TEMPO), 2,2'-
(ABTS), 3,5-di-tert-
butylcatechol (DTBC) were obtained from Sigma-Aldrich Co. Llc. (St. Louis,
America). Laccase (E.C 1.10.3.2) from Trametes Versicolor was also
purchased from Sigma and used without further purification. Sodium
phosphate buffer (0.1 M) at pH 4.5 was used for preparing solutions for the
activity assay. All other chemicals were of analytical grade and used
without further purification.
1H NMR spectra were recorded on 400 or 250 MHz Bruker NMR
spectrometers. MS spectra were recorded on an Agilent Technologies
7890A GC system with an Agilent 5975 inert mass selective detector or a
triple-axis detector (EI). Melting points were measured on a Barnstead
Electrothermal IA 9100 and are uncorrected.
2) This is the first time that laccase/TEMPO has been used for
the
aerobic
oxidative
dehydrogenation
tetrahydroquinazolines.
Activity assays of free laccase from T. Versicolor
3) The synthesis of structurally diverse 2-substituted
quinazolines using ideal oxidant with good to high yields in
green solvent.
4) The present methods are superior to other currently
available methods due to being free from any halide and
toxic and expensive transition metals co-catalysts.
Therefore thes methods can be applied in pharmaceutical
and other sensitive synthetic procedures.
The activity of commercial enzyme laccase from T. Versicolor was
determined via UV-Vis spectroscopy by monitoring the oxidation of 2,2’-
azino-bis-(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS, ε = 36000 M-1.cm-
1). The reaction mixture contained 5 mM of ABTS (100 µL) in acetate buffer
(100 mM, pH=5.0) and laccase enzyme. The absorbance change was
observed at 420 nm for 5 min at room temperature.[30] One unit was
defined as the amount of enzyme that oxidizes 1 µmol of ABTS per minute.
The activity of laccase enzyme batch applied in this investigation was
evaluated at 0.87 U/mg.
5) The methods conform to several of the guiding principles of
green chemistry.
General procedure for the synthesis of 2-substituted quinazolines
from aldehydes and 2-aminobenzylamine
A solution of 2-aminobenzylamine (1 mmol) and aldehyde (1 mmol) in
CH3CN (5 mL) was stirred at room temperature for 3-5 h. After
complete conversion of 2-aminobenzylamine to 2-substituted
tetrahydroquinazoline (TLC), the solvent was concentrated to ca. 0.5
mL. Then, phosphate buffer (0.1 M, 12.5 mL, pH=4.5), DTBC or
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10.1002/ejoc.201800466
European Journal of Organic Chemistry
COMMUNICATION
TEMPO (20 mol%) and Laccase (174 mg, 200U) were added and the
mixture was stirred at under O2 (balloon) or air at 45 C for the time
[14]
B. Han, X. L. Yang, C. Wang, Y. W. Bai, T. C. Pan, X. Chen, W. Yu, J.
Org. Chem. 2012, 77, 1136-1142.
o
specified in Tables 2 and 4. After completion of the reaction (monitored
by TLC), the product was extracted with EtOAc (3 × 10 mL). The
combined organic phases were dried over anhydrous Na2SO4, filtered
and evaporated under reduced pressure. The crude product was
purified by silica gel column chromatography using hexane/ethyl
acetate (75:25) as a mobile phase. All products were characterized by
1H NMR, MS (see supporting information) and melting point (Table 2).
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General procedure for the synthesis N-heterocyclic aromatic
compounds (quinoxaline, quinoline, indole and Hantzsch
pyridine)
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Acknowledgements
We gratefully acknowledge financial support of this research by
Shahid Beheshti University of Medical Sciences, University of
Kurdistan and the Iranian National Science Foundation (INSF,
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Keywords: laccase; cooperative catalytic oxidation system;
aerobic oxidative dehydrogenation; 2-substituted quinazolines;
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This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800466
European Journal of Organic Chemistry
COMMUNICATION
Aerobic oxidative synthesis of
Cooperative catalyst system*
quinazolines and other N-heterocyclic
Shaghayegh Saadati, Nadya Ghorashi,
Amin Rostami* and Farzad Kobarfard*
aromatic compounds
accomplished
has been
using
O2/laccase/catechol (or TEMPO) as
bioinspired catalytic oxidation system.
Page 1 – Page 8
Laccase-based oxidative catalytic
systems for the aerobic
aromatization of
tetrahydroquinazolines and related
N-heterocyclic compounds under
mild conditions
This article is protected by copyright. All rights reserved.