The cascade synthesis of quinazolinones and quinazolines using an α-MnO2 catalyst and tert-butyl hydroperoxide (TBHP) as an oxidant

Article abstract of DOI:10.1039/c5cc02785c

Heterogeneously catalyzed synthesis of quinazolinones or quinazolines is reported in this study. An α-MnO₂ catalyst is found to be highly active and selective in the oxidative cyclization of anthranilamides or aminobenzylamines with alcohols using TBHP as an oxidant. This protocol exhibits a broad substrate scope, and is operationally simple without an additive.

Full text of DOI:10.1039/c5cc02785c

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DOI: 10.1039/C5CC02785C
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A cascade synthesis of quinazolinones and
quinazolines using -MnO2 catalyst and tert-
butyl hydroperoxide (TBHP) as oxidant
Cite this: DOI: 10.1039/x0xx00000x
Zhe Zhang,a,b Min Wang,b Chaofeng Zhang, a,b Zhixin Zhang, a Jianmin Lu, a and
Feng Wang*a
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
Table 1. Synthesis of quinazolinones.a
Heterogeneously catalyzed synthesis of quinazolinones or
quinazolines is reported in this study. An α-MnO2 catalyst is
found to be highly active and selective in the oxidative
cyclization of anthranilamides or aminobenzylamines with
alcohols using TBHP as oxidant. This protocol exhibits broad
substrate scope, and is operationally simple without additive.
Entry
1
Catalyst
α-MnO2
Solvent
PhCl
Yield [%] b
71
67
40
54
63
46
20
23
45
21
6
48
51
57
49
46
81
59
51
11
0
2
β-MnO2
PhCl
3
δ-MnO2
PhCl
There is considerable interest in cascade organic synthesis using
heterogeneous catalysts,1 such as metal oxides, metals and zeolites, the
merits of which include easy catalyst separation, recycling and high
synthetic efficiency even under flow conditions.2 Quinazolinone and its
derivatives are important compounds,3 and have been widely used in
hypnotic, sedative, and anti-inflammatory reagents.4 Among the various
synthetic efforts,5 the direct oxidative cyclization forming N-heterocyclic
rings has attracted more attention on account of abundantly available
reactants, such as anthranilamides and alcohols. However, it requires a
catalyst to be highly active and selective toward the dehydrogenation of
C–H bond and N–H bond in one-pot, which usually leads to poor
selectivity. Many studies have reported on the catalytic synthesis of
quinazolinones from aldehydes and amides using the catalysts of FeCl3,6
4
γ-MnO2
PhCl
5
OMS-2
PhCl
6
Mn3O4
PhCl
7
Fe2O3
PhCl
8
CuO
PhCl
9
Cu2O
PhCl
10
11
12
13
14
15
16
17
18
19
20 c
21 d
22
23
24
25
26
Co3O4
CeO2
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
PhCl
Zn/α -MnO2
Co/α-MnO2
Ni/α-MnO2
Mg/α-MnO2
Cu/α-MnO2
α-MnO2-150
α-MnO2-250
α-MnO2-350
α-MnO2-150
α-MnO2-150
-
I2,4b Pd(OAc)2,7 Ru(PPh3)3(CO)(H)2 and [Cp*IrCl2]2.9 However, little
8
attention has been paid to the heterogeneously catalyzed approaches,
primarily due to lack of efficient catalysts.
PhCl
Acetonitrile
Dichloromethane
Dimethyl sulphoxide 13
Tetrahydrofuran 10
0
17
77
α-MnO2-150
α-MnO2-150
α-MnO2-150
α-MnO2-150
With the advance of nanoscience, many new nanocrystalline oxides
have been synthesized and used as catalysts.10 Depending on the reaction
conditions and crystalline morphologies, some oxides may show very
different catalytic behaviors. Manganese oxide is one of such classes, and
is commonly used as stoichiometric oxidant, but in some cases as
excellent catalysts.11 We have recently reported the α-MnO2 catalyst and
TBHP oxidant is efficient in the oxidative self-coupling of amines to
imines forming C=N bond at room temperature.2b In our continuous
exploration of catalytic system of α-MnO2 catalyst and TBHP oxidant,
we find that this system can be used in the dehydrogenation of C–H bond
a Reaction conditions, 1.5 mmol 1a, 0.5 mmol 1b, 2 mmol TBHP, 0.05
o
b
mmol catalyst, 80 C, 12 h, 2 mL solvent. GC yields by internal
standard (n-dodecane) based on amine. c In 0.3 MPa O2 and 120 oC. d
Without TBHP.
and N–H bond in one-pot, and realize the direct oxidative cyclization of
anthranilamides with alcohols. A wide range of quinazolinones and
quinazolines are synthesized with 71-99% yields. This study
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Table 2. α-MnO2-catalyzed synthesis of quinazolinone and quinazoline.a
demonstrates that α-MnO2 and TBHP consist of an efficient oxidative
dehydrogenation catalytic system for C–H bond and N–H bond
transformation.
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DOI: 10.1039/C5CC02785C
The initial studies were carried out using the reaction of benzyl
alcohol and anthranilamide in the presence of 10 mol% catalyst and 1.3
eqv. TBHP at 80 oC. Among the screened manganese oxides, α-MnO2
offered 71% yield (Table1, entry 1), which surpassed other manganese
oxides (Table1, entries 2-6). Other metal oxides, which are frequently
used as oxidation catalysts, gave much lower yields (Table 1, entries 7-
11). We tried to increase the catalytic activity by heteroatom-doping of
α-MnO2 (M/α-MnO2, M denotes heteroatom) or thermal annealing of α-
MnO2 in Ar (
-MnO2-T, T denotes temperature).12 Both operations on
α-MnO2 were intended to create more active sites and thus increase
activities.13 However, in a contrary, doping α-MnO2 with Zn, Co, Ni,
Mg, and Cu elements resulted in even lower yields (Table 1, entries 12-
16). The annealing temperature has strong effect on the catalytic
performance. The yields over α-MnO2-250 and α-MnO2-350 were lower
than that over the pristine α-MnO2 (Table 1, entries 18-19). -MnO2-
150 exhibited the best catalytic performance with 81% yield (Table 1,
entry 17). After reaction, the catalyst can be separated by centrifugation
and reused for several times with no apparent loss of catalytic
performance (Figure S1). The SEM and TEM images of α-MnO2
revealed the catalyst has nanoflower morphology (Figure S2). The
inductively coupled plasma-mass analysis revealed that no Mn species
were leached in the reaction mixture, indicating the catalyst is robust
and the reaction is heterogeneous in nature. Thermal annealing under
inert conditions removes some surface oxygen and creates more
vacancy sites, which may function as substrate activation sites.
However, due to the variable valence and structure of manganese
oxides, the annealing at much higher temperature (>150 oC) may induce
phase reconstruction and result in lower activity.
Replacement of TBHP with molecular oxygen gave only 11% yield
(Table 1, entry 20). H2O2 is an instable oxidant, and quickly decomposes
over α-MnO2 during the reaction at room temperature. As a result, no
conversion is observed with the use of H2O2 as oxidant. In contrast, only
1.3 eqv. of TBHP relative to alcohol is required with the utilization
efficiency at least 77%. The control tests show that both TBHP and α-
MnO2 is indispensable in this reaction (Table 1, entries 21-22).
Next we evaluated the effect of solvent. Chlorobenzene is the best
solvents among acetonitrile, dichloromethane, dimethyl sulphoxide and
tetrahydrofuran (Table 1, entries 23-26).
a Reaction conditions: 0.5 mmol amines, α-MnO2-150 (10 mol%), 2 mmol
TBHP, 1.5 mmol alcohols, 2 mL chlorobenzene, 80 oC, 16 h. GC yields
by internal standard (n-dodecane) based on amine. Data in the parenthesis
indicate isolated yields. b Two mL of alcohol were used.
Encouraged by these initial results, we then chosen α-MnO2-150 as
the catalyst and PhCl as the solvent to investigate the substrate scope.
A wide range of quinazolinones were synthesized with good yields
(Table 2). Electron-donating and -withdrawing substituents (–CH3, –
OCH3, –F, –Cl, –Br) on the phenyl group of aromatic alcohols have
minor effect, affording 82-99% quinazolinones yields (Table 2, entries
1-10). The olefinic C=C bond survives under the reaction conditions in
the case of cinnamyl alcohol (Table 2, entry 11). 1-Naphthalenemethanol
is relatively inert to be oxidized due to steric hindrance (Table 2, entry
12). Heteroatoms may poison the noble metal site because of strong
coordination. However, in the present study, heterocyclic alcohols could
be efficiently transformed into the desired products with high yields
(Table 2, entries 13-16). Furthermore, inert aliphatic alcohols were
converted with reasonably good yields (Table 2, entries 17-24).
The success of the above experiments drove us to further apply the
method to the quinazolines synthesis using aminobenzylamines and
alcohols. Various alcohols, including aromatic alcohols, heterocyclic
alcohols and aliphatic alcohols, are all transformed into the
corresponding quinazolines with 59-91% yields (Table 2, entries 25-40).
BHT (2 mmol)
Yield 3%
TEMPO (2 mmol)
Yield 4%
Scheme 1. Control experiments in the presence of radical inhibitors.
2 | J. Name., 2012, 00, 1‐3
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The reaction mechanism was further studied. Benzaldehyde was a State Key Laboratory of Catalysis, Dalian National Laboratory for Clean
generated during the reaction as detected by GC. In the presence of the Energy, Dalian Institute of Chemical Physics, Chinese Academy of
α-MnO2 catalyst and TBHP,
a
reaction of benzaldehyde and Sciences, Dalian 116023, China. E-mail: wangfeng@dicp.Vaicew.cnAr.ticle Online
DOI: 10.1039/C5CC02785C
anthranilamide generated 2a. While, without the catalyst and TBHP, 2,3- b University of Chinese Academy of Sciences, Beijing 100049, China.
dihydroquinazolinone was obtained.14 These results indicate that Electronic Supplementary Information (ESI) available: the experimental
aldehyde and 2,3-dihydroquinazolinone should be the reaction section and characterization data. See DOI: 10.1039/c000000x/
intermediates. The addition of (2,2,6,6-tetramethylpiperidin-1-yl)oxy
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greatly inhibited the reaction (Scheme 1), indicating the radical process
nature.15 Based on the above-mentioned results, we propose a reaction
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route (Figure 1). First, benzyl alcohol is oxidized to benzaldehyde (step
1). Then, benzaldehyde reacts with anthranilamide to form 2,3-
dihydroquinazolinone (step 2), which is then oxy-dehydrogenated over
catalyst to 2a (step 3). Oxy-dehydrogenation of alcohol is the rate-
determining step since the step has the lowest reaction rate (3.0 × 10-5 M
s-1). Oxy-dehydrogenation of 2,3-dihydroquinazolinone was not affected
by the presence of BHT, indicating this step does not involve radical
mechanism. Catalytic reactions may take place on surface defect sites of
α-MnO2, the property of which is altered during doping with other metals
and thermal annealing. The TBHP radical generated on defect site,
probably forming TBHP-MnO2 adduct, oxidizes alcohol to aldehyde, and
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Figure 1.
Rates of each step at 80 oC with and without 1 eqv BHT in 30 min.
Reaction conditions: 0.5 mmol substrate, 1 mmol TBHP, 0.5 mmol BHT, 0.05
mmol catalyst, 2 mL chlorobenzene.
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In summary, a robust and reusable α-MnO2 catalyst is shown to be
highly active for the cascade synthesis of quinazolinones or quinazolines
from anthranilamides or aminobenzylamines with alcohols. The α-MnO2
could be reused without loss of its high catalytic performance. In general,
the simple, cost-effective and efficient protocol is expected to contribute
to its utilization for the synthesis of various products.
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This work was supported by the National Natural Science
Foundation of China (Projects No. 21303189, 21273231, and 21233008).
Notes and references
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J. Name., 2012, 00, 1‐3 | 3