A convenient approach to 2,4-disubstituted quinazoline-3-oxides using active MnO2 as the oxidant

Article abstract of DOI:10.1139/cjc-2018-0521

Using cheap, readily available, and economic active MnO₂ as an oxidant, a series of 2,4-disubstituted quinazoline-3-oxides were synthesized in good to excellent yields by oxidation of the corresponding 1,2-dihydroquinazoline-3-oxides under mild

Full text of DOI:10.1139/cjc-2018-0521

Page 1 of 27
An Convenient Approach To 2,4-Disubstituted
Quinazoline-3-oxides Using active MnO2 as Oxidant
Xinglin Ye a,b, Zhiyuan Chen,a Zhipeng Zhang,a Yang Fu,a,* Zhihong Deng,a
and Yiyuan Peng a,*
a Key Laboratory of Small Functional Organic Molecule, Ministry of Education
and Key Laboratory of Green Chemistry, Jiangxi Province, Jiangxi Normal
University, Nanchang, Jiangxi 330022, China; E-mail: yypeng@jxnu.edu.cn;
yiyuanpeng@yahoo.com
b Department of Chemistry and Environmental Engineering, Jiujiang University,
Jiujiang, Jiangxi 332005. P. R. of China

Page 2 of 27
Abstract – Using cheap, readily available and economic active MnO2 as an oxidant, a
series of 2,4-disubstituted quinazoline-3-oxides were synthesized in good to excellent
yields by oxidation of the corresponding 1,2-dihydroquinazoline-3-oxides under mild
conditions. The novel approach is simple and convenient, which provide a series of
2,4-Disubstituted quinazoline-3-oxides.
Key words: 2,4-Disubstituted quinazoline-3-oxides,
1,2-Dihydroquinazoline-3-oxide
Active MnO2,

Page 3 of 27
INTRODUCTION
It is well known that quinazoline derivatives exhibit a broad range of potential
biological activities, and are widely recognized as important moiety in medicinal
applications.1,2 Consequently, tremendous efforts have been devoted into this area and
various methods for the synthesis of quinazoline derivatives have been established.3
In the past few years, we have been interested in the construction of small libraries of
quinazolines and have developed useful methods for the synthesis of quinazoline
derivatives.4 In order to search new approaches for the assembly of complex
quinazoline molecules, quinazoline N-oxides attracted our attentions. Among them,
2,4-disubstituted quinazoline-3-oxides are ubiquitous for the synthesis of natural
products and biologically important compounds such as cardiotonics,5
bronchodialators,6 and fungicides.7 Quinazoline 3-oxides are also important building
blocks in organic synthesis,8 for example, many valuable drugs for the treatment of
seizures and anxiety disorders such as chlordiazepoxide (Librium®), 1,4-
benzodiazepine, and diazepam (Valium®) are prepared from the corresponding
quinazoline 3-oxides9 (Scheme 1).
Ph
Ph
Ph
MeNH2
-H+
Cl
O
Cl
O
Cl
O
N
N
N
Cl
Cl
Cl
N
N
N
N
NH
Ph
NH
Ph
Ph
O
N
O
PCl3
H2O
-MeNH2
Cl
Cl
Cl
N
-Cl-
N
N
N
NH
Chlorodiazepoxide
H
H
O
O
Diazepam
Scheme 1 Ring expansion reaction of 2-chloromethyl quinazoline-3-oxide into a
1,4-benzodiazepine

Page 4 of 27
However, the synthesis and application of the quinazoline-3-oxides received less
attention when compared to the other classes of N-oxides such as 5-membered
heteroaromatic N-oxides, pyridine N-oxides and diazine N-oxides.10 Therefore,
methods for the construction of 2,4-disubstituted quinazoline 3-oxides are scarce.
Recently, employed as versatile templates, quinazoline-3-oxides enable
transformations including metal-catalyzed direct C-H bond functionalization11 and
1,3-dipolar cycloaddition reaction.12 These inspired us to develop methods for the
construction of quinazoline 3-oxides.
In the literature, 2,4-disubstituted quinazoline 3-oxides are prepared from
2-aminoaryl ketones. Two basic strategies have been described: (1) 2-aminoaryl
ketones were first transformed to the corresponding N-acyl-2-aminoaryl ketone
oximes and then cyclized to produce 2,4-disubstituted quinazoline-3-oxides (Scheme
2a).13 In this strategy, the N-acyl 2-aminoaryl ketones were derived from acylation of
2-aminoaryl ketones with anhydrides, which are not easily accessible and their
preparation in pure form is a cumbersome process. Furthermore, the substituent group
at the C2-position of quinazoline 3-oxides was limited to 2-alkyl or vinyl group.13
Specially, Armarego reported synthesis of quinazoline 3-oxides through cyclization of
o-aminoaryl ketone oximes with triethyl orthoformate (Scheme 2b).14 Madabhushi
reported one-step method for the synthesis of 2,4-disubstituted quinazoline 3-oxides
by reaction of a 2-aminoaryl ketone with a hydroxamic acid using Zn(OTf)2 as the
catalyst (scheme 2c).15 (2) The 2-aminoaryl ketones first reacted with aldehydes to
transform to the corresponding 2-N-imine-aryl ketone oximes, and then cyclized to

Page 5 of 27
1,2-dihydroquinazoline 3-oxides, which were oxidized to the corresponding
2,4-disubstituted quinazoline-3-oxides by light activated air-oxidation (Scheme 2d).16
From the synthetic chemistry point of view, as 1,2-dihydroquinazoline 3-oxides
could readily be prepared, dehydrogenation of 1,2-dihydroquinazoline 3-oxides is one
of the most concise approach to form 2,4-disubstituted quinazoline-3-oxides. Many
regents
such
as
tetrachloro-1,4-benzoquinone
(TCQ),
2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) were used as a oxidant for this type of
dehydrogenated aromatization reactions.17 Coskun reported a reaction where
2-substituted-1,2,3,4-tetrahydroquinazolines were oxidized to quinazolin-1-oxides
with H2O2–tungstate as a oxidant.18 More recently, our group used active MnO2 as the
oxidant finished the transformation of 2-aryl-1,2,3,4-tetrahydroquinazolines to
2-arylsubstituted quinazolines.19 Considering the low toxicity and the cost of MnO2,
we conceived that MnO2 would be a powerful catalyst for the oxidation of
1,2-dihydroquinazoline-3-oxides to 2,4-disubstituted quinazoline-3-oxides. It should
be noted that the experiment process using MnO2 as oxidant is practically
straightforward, because the oxidant is easily removed by simply filtration. Thus, we
herein describe
a
convenient protocol to prepare 2-(hetero)aryl/alkyl
quinazoline-3-oxides from the oxidation of 1,2-dihydroquinazoline-3-oxides using
MnO2 as oxidant under mild conditions.

Page 6 of 27
R2
R2
R2
N
1) R3COCl
OH
O
O
O
N
R1
N
R1
(a)13
R1
2) HONH2 HCl
NH2
R3
N
H
R3
R2
N
R2
N
OH
O
N
R1
R1
R1
+
+
R3C(OEt)3
R1
(b)14
R3
NH2
R2
O
Zn(OTf)2
reflux
O
R2
N
R3CONHOH
(c)15
R1
N
R3
NH2
CH3
N
CH3
N
CH3
N
OH
OH
O
ArCHO
R1
R1
p-TsOH
NH2
N
N
H
Ar
CHAr
CH3
O
N
(d)16
Visible light
R1
N
Ar
Scheme 2 Traditional synthesis of 2,4-disubstitued quinazolines 3-oxides
RESULTS AND DISCUSSION
1,2-Dihydroquinazoline 3-oxides 1 were readily prepared in two steps from
2-aminoaryl ketones as described in the literature.16, 20 With the compound 1a in hand,
we first evaluated the reaction using 1a as the model substrate. Table 1 summarized
the optimization of the oxidation reaction. Initially, the reaction occurred at 30℃
using active MnO2 as oxidant in DCE, the desired product 2a was isolated in a yield
of 48% in 8 h (entry 1). When the reaction temperature increased to 50℃, the yield
was improved to 58% and the reaction time was significantly shortened to 2 h (entry
2). Then, several oxidants were evaluated for the transformation of
1,2-dihydroquinazoline 3-oxide 1a to the corresponding 2,4-disubstituted
quinazoline-3-oxides 2a (entries 3-7). Among the oxidants used, only MnO2 and
benzoquinone (BQ) were effective for this transformation in the yields of 58% and

Page 7 of 27
49% respectively (entry 2 and 3). Thus, MnO2 was employed subsequently as the
oxidant for further optimization. We then evaluated the solvent effects on the reaction
of 1a to 2a. The oxidation reaction did not proceed in 1,4-dioxane, C2H5OH, toluene
etc. solvents (entries 8-15). Moderate yields were obtained in CHCl3 and CH3CN
(entries 16-17). Among the various solvents tested, the reaction appears to be the
highest yield of 77% in CH2Cl2 (entry 18). Decreasing the loading of the oxidant or
raising reaction temperature, lower yields were obtained (entries 19-20). To eliminate
the light activated air-oxidation, a control experiment was done, and yield of 73% was
isolated when the reaction was performed in the absence of air and light (entry 21).
Table 1. Reaction parameters optimizationa
PhCHO
p-TsOH
OH
O
O
O
N
N
NH2OH HCl
EtOH,r.t.
Oxidant
N
NH2
EtOH,r.t.
20min
NH2
N
H
N
2a
1a
T
Yield
(%)b
48
T ( Yield
℃) (%)b
Entry Oxidant
Solvent
Entry Oxidant
Solvent
(℃)
30
50
50
50
50
50
50
1
MnO2
MnO2
BQ
DCE
DCE
DCE
DCE
DCE
DCE
DCE
12
13
14
15
16
17
18
19
20c
21d
MnO2
MnO2
MnO2
MnO2
MnO2
MnO2
MnO2
MnO2
MnO2
MnO2
DMSO
DMF
50
50
50
50
50
50
50
65
50
50
0
2
58
49
trace
0
trace
0
3
CCl4
4
DDQ
NBS
toluene
CHCl3
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
trace
51
21
77
41
53
73
5
6
Br2
0
7
Pb(OAc)4
MnO2
MnO2
MnO2
MnO2
0
8
1,4-dioxane 50
trace
0
9
C2H5OH
CH3OH
NMP
50
50
50
10
0
11
trace
a All reactions were performed in 0.2 mmol scale, standard conditions: 1a (0.2 mmol), oxidant
(3.0 equiv), solvent (2 mL), in air atmosphere.
b Isolated yield.
c The MnO2 was reduced to 2.0 equiv.
d The reaction was performed in the absence of air and light.

Page 8 of 27
With the optimal reaction conditions in hand (3.0 equiv of MnO2 at 50 °C for 2h), we
then investigated the substrates scope. The results were shown in Table 2. Initially, a
series of 1,2-dihydroquinazoline-3-oxides with various substituents at C-2 position
were investigated. When C-4 position was a methyl group and R2 was an aryl group,
we found that 1 were underwent the desired oxidation dehydrogenation reaction
smoothly affording the corresponding target products (2a-2c and 2e-2l) with the
yields of 58-88%. In particularly, product 2d slowed the reaction in only 33% yield
due to the steric effect. It can be seen that a range of various phenyl with either
electron-rich or electron-withdrawing groups, such as p-methyl, p-NO2, p-Br and
p-CN substituted phenyl quinazoline-3-oxides participated in the reaction with
excellent yields (2b, 2f, 2h and 2j). The substrates with furan-2-yl and thiophen-2-yl
group at C-2 position gave the yields of 56 and 71% (2m, 2n). As we expected,
2-aliphatic group such as 2-ethyl, 2-cyclopropyl and 2-benzyl substituted
1,2-dihydroquinazoline-3-oxides also worked well to give the corresponding products
in 54-77% yields (2o-2q).
To expand the substrate scope of this methodology, we turned our attention to
investigate the effects of substituted groups on C-4 of the substrate. Varied the
substituent groups on the C-4 position of 1,2-dihydroquinazoline-3-oxides were
probed, the corresponding products were also obtained in satisfying yields. For
example, when the C-4 position was substituted with an ethyl, benzyl, or phenyl
group, good yields of the corresponding quinazoline 3-oxides 2r-2v were obtained.
Finally, the results indicated that good to excellent yields were also obtained when the

Page 9 of 27
substitute group on the mother ring change from electron-rich to electron-withdrawing
group (2w-2za).
Table 2. Substrate scopea
R1
R1
R1
R2CHO
p-TsOH
O
O
OH
MnO2
N
N
N
CH2Cl2,50℃
EtOH,r.t.
20min
N
H
R2
N
R2
NH2
1
2
O
O
O
O
N
N
N
N
N
N
N
N
2b
,81%
2a
,77%
2d
,33%
2c
,62%
O
O
O
O
N
N
N
N
N
N
Cl
N
N
Br
Cl
F
2h
,82%
2g
,60%
2e
,66%
2f
,78%
O
N
O
O
O
N
N
N
N
N
N
N
NO2
N
OCH3
CN
2i
,88%
2l
,58%
2j
,85%
2k
,76%
O
N
O
O
O
N
N
N
N
O
S
N
N
N
2p
,77%
2n
,71%
2m
,56%
2o
,54%
O
O
N
O
N
N
N
O
N
N
N
N
Cl
2q
,74%
2r
,77%
2s
,76%
2t,
74%
Br
Br
O
N
Br
O
O
N
N
O
N
N
N
N
N
2v,
2w
, 84%
2x
, 80%
2u
,78%
72%
Cl
O
Br
O
O
N
N
N
N
N
N
Cl
2y
, 84%
2z
, 90%
2za
, 81%
a Isolated yield.

Page 10 of 27
Nitrone cycloaddition is an important tool for the building of a wide range of
heterocyclic systems. Whilst 1,3-dipolar cycloadditions to a range of heteroaromatic
N-oxides have received varying amounts of attention, additions to quinazoline
derivatives have had scarce mention in the literature. The first paper dating from 1972
describes the addition of acetylenedicarboxylate esters to quinazoline-3-oxides 3a,21
two further papers report the addition of the same dipolarophiles to
2-methylquinazoline-3-oxide 3a.22,23 In all cases the isolated products were the
products of ring transformation reactions on the primary cycloadducts, afforded the
phenylacrylates 4 (13-21%) and the benzodiazepines 5 (5-14%) together with smaller
amounts of other complex products (Scheme 3). Recently, Heaney studied the
reaction between the 4-methyl-2-styrylquinazoline-3-oxide 3b with dimethyl
acetylenedicarboxylate, and found that the reaction reached completion after 16h
heating in refluxing anhydrous THF, afforded 5H-1,3-benzodiazepine 6 only in a
yield of 36%.24
ROOC
ROOC H
Ph
Ph
N
Ph
CO2R
CO2R
O
N
+
NH2
+
NHAc
N
N
5
4
3a
Me
RO2C
RO2C
O
Me
CO2R
O
N
+
R = Me, Et
N
N
R1
CO2R
N
R1
3b
6
Scheme 3 Quinazoline 3-oxides 1,3-dipolar cycloaddition reaction
Here, we also investigated the 1,3-dipolar cycloaddition reaction between
2-arylquinazoline-3-oxide 2 with dimethyl acetylenedicarboxylate (Scheme 4). The

Page 11 of 27
results indicated that reactions between 2a or 2i and dimethyl acetylenedicarboxylate
proceeded well upon stirring in THF at 70 °C for 4 h without using any catalyst,
furnished the product 1,3-benzodiazepines 6a and 6i in the yields of 67% and 74%.
This transformation including [3+2] cycloaddition and intramolecular rearrangement
leads to 1,3-benzodiazepines in good yields. The structure of compound 6i was
confirmed by single-crystal X-ray analysis as presented in Scheme 4.
CO2CH3
Me
+ O
H3CO2C
Me
-
CO2CH3
CO2CH3
N
O
THF
+
N
N
°C
70
N
X
2
X
CO2CH3
O
CO2CH3
Me
H3CO2C
CO2CH3
H3CO2C
Me
O
H3CO2C
Me
O
N
N
N
N
N
N
X
X
X
6a
: X=H, yield 67%
6i
: X=NO2, yield 74%
Scheme 4 The 1,3-dipolar cycloaddition reaction of quinazoline-3-oxides with
DMAD
CONCLUSIONS
We here developed a convenient method for the preparation of 2,4-disubstituted
quinazoline-3-oxides. This approach provided a straightforward method for the

Page 12 of 27
synthesis of 2,4-disubstituted quinazoline-3-oxides using active MnO2 as a catalyst.
Owing to the mild reaction conditions, versatility of the substrate and easy handling,
the approach would find wide application in the context of building a quinazoline
library for drug discovery and pharmaceutical science.
EXPERIMENTAL
General
Unless otherwise stated, all commercial reagents were used as received. All the
solvents were dried and distilled according to standard procedures. Flash column
chromatography was performed using silica gel (60-Å pore size, 32-63μm, standard
grade). Analytical thin–layer chromatography was performed using glass plates
pre-coated with 0.25 mm 230-400 mesh silica gel impregnated with a fluorescent
indicator (254 nm). Thin layer chromatography plates were visualized by exposure to
ultraviolet light. Organic solutions were concentrated on rotary evaporators at ~20
Torr at 25-35°C. Nuclear magnetic resonance (NMR) spectra are recorded in parts per
1
13
million from internal tetramethylsilane on the δ scale. H and C NMR spectra were
recorded in CDCl3 on a Bruker DRX-400 spectrometer operating at 400 MHz and 100
MHz, respectively. All chemical shift values are quoted in ppm and coupling
constants quoted in Hz. High resolution mass spectrometry (HRMS) spectra were
obtained on a micrOTOF II Instrument.
25
General procedure for synthesis of active MnO2

Page 13 of 27
Concentrated aqueous potassium permanganate was added to a stirred aqueous
manganese sulphate solution kept at 90℃, until a slight excess was present (pink
coloration of the supernatant liquid). Stirring at 90℃ was continued for a further 15
min. The oxide was collected by filtration, washed well with hot water, then with
methanol and ether, and dried at 120-130℃ to constant weight. It could be kept for
several months in a well-stoppered bottle without loss in activity.
General procedure for synthesis of 2
To a mixture of 1,2-dihydroquinazoline 3-oxides 1 (0.20 mmol) and active MnO2 (3.0
equiv) in CH2Cl2 (2.0 mL) were added subsequently. The mixture was stirred at 50 °C
for 2 hours in a 25 mL of sealed tube. After completion of the reaction as indicated by
TLC, the reactant was isolated by simply filtration and the product was extracted with
ethyl acetate (10 mL). The organic layer was dried over MgSO4, and evaporated the
solvent followed by purification by chromatography on silica gel to provide the
corresponding product 2 (eluent: PE–EtOAc, 10:1 to 2:1).
General procedure for synthesis of 6
To a mixture of quinazoline 3-oxide 2 (0.20 mmol) and dimethyl
acetylenedicarboxylate (DMAD) (1.2 equiv) in THF (2.0 mL) were added
subsequently. The mixture was stirred at 70 °C for 4 hours. After completion of the
reaction as indicated by TLC, the reactant was isolated by simply filtration and the
product was extracted with ethyl acetate (10 mL). The organic layer was dried over
MgSO4, and evaporated the solvent followed by purification by chromatography on
silica gel to provide the corresponding product 6 (eluent: PE–EtOAc, 10:1 to 2:1).

Page 14 of 27
Characterization data
4-Methyl-2-phenylquinazoline-3-oxide (2a).15 White solid (36.4 mg, 77%); mp
1
140–141℃; IR (KBr):  3062, 2927, 1730, 1493, 1291, 1074, 764, 709 cm–1; H
NMR (400 MHz, CDCl3) δ 2.91 (s, 3H), 7.50–7.52 (m, 3H), 7.61–7.65 (m, 1H), 7.71
(t, J = 7.2 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 8.30 (d, J = 3.2
13
Hz, 2H); C NMR (100 MHz, CDCl3) δ 13.3, 123.0, 123.6, 127.9, 129.1, 129.2,
130.3, 130.7, 130.9, 132.7, 140.3, 152.2, 154.7; HRMS (ESI) m/z [M+H]+ calcd for
C15H13N2O: 237.1028, found 237.1017.
4-Methyl-2-(p-tolyl)quinazoline-3-oxide (2b). White solid (40.7 mg, 81%); mp
1
156–157℃; IR (KBr):  2959, 1727, 1493, 1200, 1127, 1020, 752 cm–1; H NMR
(400 MHz, CDCl3) δ 2.43 (s, 3H), 2.90 (s, 3H), 7.30 (d, J = 8.0 Hz, 2H), 7.60 (t, J =
7.2 Hz, 1H), 7.70 (d, J = 6.4 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.98 (d, J = 8.4 Hz,
1H), 8.24 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 13.3, 21.6, 123.1, 123.5,
128.6, 128.8, 129.2, 129.8, 130.3, 130.7, 140.3, 141.0, 152.1, 154.7; HRMS (ESI) m/z
[M+ H]+ calcd for C16H15N2O: 251.1184, found 251.1180.
4-Methyl-2-(m-tolyl)quinazoline-3-oxide (2c). White solid (31.0 mg, 62%); mp
1
167–168℃; IR (KBr):  3065, 2920, 1495, 1338, 1297, 1208, 759 cm–1; H NMR
(400 MHz, CDCl3) δ 2.45 (s, 3H), 2.91 (s, 3H), 7.32 (d, J = 7.8 Hz, 1H), 7.40 (t, J =
7.6 Hz, 1H), 7.63 (t, J = 7.6 Hz, 1H), 7.72 (t, J = 7.6 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H),
8.01–8.08 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 13.3, 21.5, 123.2, 123.6, 127.4,
127.9, 129.1, 129.2, 130.7, 130.9, 131.5, 132.6, 137.6, 140.3, 152.3, 155.0; HRMS
(ESI) m/z [M + H]+ calcd for C16H15N2O: 251.1184, found 251.1188.

Page 15 of 27
4-Methyl-2-(o-tolyl)quinazoline-3-oxide (2d). White solid (16.5 mg, 33%); mp
1
176–177℃; IR (KBr):  3065, 2962, 1494, 1297, 1207, 1134, 760 cm–1; H NMR
(400 MHz, CDCl3) δ 2.29 (s, 3H), 2.93 (s, 3H), 7.32–7.35 (m, 2H), 7.41 (t, J = 7.0 Hz,
1H), 7.48 (d, J = 7.2 Hz, 1H), 7.68–7.78 (m, 2H), 7.93 (d, J = 8.0 Hz, 1H), 8.03 (d, J
= 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 13.1, 19.5, 123.2, 123.9, 125.8, 129.0,
129.2, 129.4, 129.9, 130.2, 131.0, 133.3, 137.2, 139.9, 151.8, 156.9; HRMS (ESI) m/z
[M + H]+ calcd for C16H15N2O: 251.1184, found 251.1179.
2-(4-Fluorophenyl)-4-methylquinazoline-3-oxide (2e). White solid (33.5 mg, 66%);
1
mp 169–170℃; IR (KBr):  3072, 1497, 1304, 1212, 777 cm–1; H NMR (400 MHz,
CDCl3) δ 2.92 (s, 3H), 7.19 (t, J = 8.4 Hz, 2H), 7.66 (t, J = 7.6 Hz, 1H), 7.74 (t, J =
7.6 Hz, 1H), 7.88 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 8.40–8.43 (m, 2H); 13C
2
NMR (100 MHz, CDCl3) δ 13.3, 115.0 (d, J = 26.0 Hz), 123.2, 123.6, 128.6, 128.7,
3
1
129.2, 131.0, 132.9 (d, J = 19.0 Hz), 140.2, 152.4, 153.5, 164.2 (d, J = 250.0 Hz);
HRMS (ESI) m/z [M + H]+ calcd for C15H12FN2O: 255.0934, found 255.0929.
2-(4-Chlorophenyl)-4-methylquinazoline-3-oxide (2f). White solid (42.1 mg, 78%);
1
mp 183–184℃; IR (KBr):  3064, 1506, 1214, 1089, 1018, 753, 740 cm–1; H NMR
(400 MHz, CDCl3) δ 2.92 (s, 3H), 7.47 (d, J = 8.4 Hz, 2H), 7.66 (t, J = 7.6 Hz, 1H),
7.74 (t, J = 7.6 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 8.33 (d, J =
8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 13.3, 123.2, 123.6, 128.2, 129.2, 129.3,
129.4, 131.1, 131.9, 136.9, 140.3, 152.5, 153.4; HRMS (ESI) m/z [M + H]+ calcd for
C15H12ClN2O: 271.0638, found 271.0632.

Page 16 of 27
2-(3-Chlorophenyl)-4-methylquinazoline-3-oxide (2g). White solid (32.4 mg, 60%);
mp 170–171℃; IR (KBr):  3063, 2927, 1565, 1355, 1291, 1207, 1133, 763 cm–1; 1H
NMR (400 MHz, CDCl3) δ 2.92 (s, 3H), 7.43–7.51 (m, 2H), 7.67 (t, J = 7.6 Hz, 1H),
7.75 (t, J = 7.6 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 8.01 (d, J = 8.4 Hz, 1H), 8.24 (d, J =
7.6 Hz, 1H), 8.36 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 13.3, 123.2, 123.7, 128.6,
129.2, 129.3, 129.5, 130.4, 130.8, 131.1, 133.9, 134.3, 140.2, 152.5, 153.1; HRMS
(ESI) m/z [M + H]+ calcd for C15H12ClN2O: 271.0638, found 271.0636.
2-(4-Bromophenyl)-4-methylquinazoline-3-oxide (2h). Yellow solid (51.5 mg,
82%); mp 165–166℃; IR (KBr):  3062, 2920, 1609, 1488, 1341, 1212, 1103, 1072,
1013, 754 cm–1; 1H NMR (400 MHz, CDCl3) δ 2.92 (s, 3H), 7.63–7.68 (m, 3H), 7.74
(t, J = 7.2 Hz, 1H), 7.87 (d, J = 8.0 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 8.26 (d, J = 8.8
13
Hz, 2H); C NMR (100 MHz, CDCl3) δ 13.3, 123.2, 123.6, 125.5, 129.3, 129.33,
129.5, 131.1, 131.5, 132.1, 140.3, 152.5, 153.5; HRMS (ESI) m/z [M + H]+ calcd for
C15H12BrN2O: 315.0133, found 315.0139.
4-Methyl-2-(4-nitrophenyl)quinazoline-3-oxide (2i).16 White solid (49.5 mg, 88%);
1
mp 167–168℃; IR (KBr):  3066, 2921, 1514, 1349, 1305, 1213, 754cm–1; H NMR
(400 MHz, CDCl3) δ 2.95 (s, 3H), 7.73–7.80 (m, 2H), 7.93 (d, J = 7.2 Hz, 1H), 8.05
(d, J = 7.2 Hz, 1H), 8.35 (d, J = 7.2 Hz, 2H), 8.56 (d, J = 7.2 Hz, 2H); 13C NMR (100
MHz, CDCl3) δ 13.3, 122.9, 123.3, 124.0, 129.5, 130.0, 131.4, 131.5, 138.6, 140.2,
148.8, 152.4, 152.9; HRMS (ESI) m/z [M+H]+ calcd for C15H12N3O3: 282.0879, found
282.0883.

Page 17 of 27
2-(4-Cyanophenyl)-4-methylquinazoline-3-oxide (2j). White solid (44.4 mg, 85%);
mp 184–185℃; IR (KBr):  3068, 2922, 2224, 1422, 1291, 1212, 1138, 753 cm–1; 1H
NMR (400 MHz, CDCl3) δ 2.95 (s, 3H), 7.73–7.82 (m, 4H), 7.93 (d, J = 7.6 Hz, 1H),
8.04 (d, J = 8.0 Hz, 1H), 8.47 (d, J = 7.6 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 13.3,
114.0, 118.6, 123.3, 123.9, 129.4, 130.0, 131.0, 131.4, 131.7, 136.9, 140.3, 152.6,
152.9; HRMS (ESI) m/z [M+H]+ calcd for C16H12N3O: 262.0980, found 262.0983.
2-(4-Methoxyphenyl)-4-methylquinazoline-3-oxide (2k). White solid (40.4 mg,
76%); mp 158–159℃; IR (KBr):  3001, 2986, 1605, 1253, 1030, 753 cm–1; 1H NMR
(400 MHz, CDCl3) δ 2.91 (s, 3H), 3.89 (s, 3H), 7.00 (d, J = 9.2 Hz, 2H), 7.60 (t, J =
8.2 Hz, 1H), 7.70 (t, J = 7.6 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H), 7.98 (d, J = 8.4 Hz,
1H), 8.43 (d, J = 6.8 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 13.3, 55.4, 113.3, 123.1,
123.3, 125.0, 128.6, 129.0, 130.8, 132.4, 140.4, 152.2, 154.1, 161.7; HRMS (ESI) m/z
[M + H]+ calcd for C16H15N2O2: 267.1134, found 267.1132.
2-(4-(Dimethylamino)phenyl)-4-methylquinazoline-3-oxide (2l). Yellow solid
(32.4 mg, 58%); mp 168–169℃; IR (KBr):  3085, 2915, 1601, 1494, 1189, 752 cm–1;
1H NMR (400 MHz, CDCl3) δ 2.89 (s, 3H), 3.05 (s, 6H), 6.76 (d, J = 9.2 Hz, 2H),
7.53 (t, J = 8.0 Hz, 1H), 7.66 (t, J = 8.0 Hz, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.94 (d, J =
13
8.4 Hz, 1H), 8.50 (d, J = 9.2 Hz, 2H). C NMR (100 MHz, CDCl3) δ 13.4, 40.2,
110.8, 119.6, 122.8, 123.1, 127.9, 128.8, 130.6, 132.2, 140.6, 152.0, 152.1, 154.4;
HRMS (ESI) m/z [M+H]+ calcd for C17H18N3O: 280.1450, found 280.1457.
2-(Furan-2-yl)-4-methylquinazoline-3-oxide (2m).15 White solid (25.3 mg, 56%);
mp 204–205℃; IR (KBr):  3104, 2922, 1590, 1498, 1210, 1013, 776 cm–1; 1H NMR

Page 18 of 27
(400 MHz, CDCl3) δ 2.96 (s, 3H) , 6.69–6.70 (m, 1H), 7.63 (t, J = 8.2 Hz, 1H), 7.76 (t,
J = 7.7 Hz, 1H), 7.81 (s, 1H), 7.88 (d, J = 8.4 Hz, 1H), 8.11 (d, J = 8.4 Hz, 1H), 8.29
(d, J = 3.6 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 13.1, 112.6, 121.3, 122.4, 123.2,
128.8, 129.1, 131.4, 140.5, 145.2, 145.9, 146.3, 152.5; HRMS (ESI) m/z [M+H]+
calcd for C13H11N2O2: 227.0821, found 227.0811.
4-Methyl-2-(thiophen-2-yl)quinazoline-3-oxide (2n). Yellow solid (34.4 mg, 71%);
1
mp 191–192℃; IR (KBr):  3069, 1569, 1299, 1205, 1133, 724 cm–1; H NMR (400
MHz, CDCl3) δ 2.95 (s, 3H), 7.26–7.28 (m, 1H), 7.58 (t, J = 7.6 Hz, 1H), 7.68–7.74
(m, 2H), 7.83 (d, J = 8.4 Hz, 1H), 7.96 (d, J = 8.4 Hz, 1H), 8.58 (d, J = 4.0 Hz, 1H);
13C NMR (100 MHz, CDCl3) δ 13.2, 122.3, 123.3, 126.6, 128.3, 128.8, 131.4, 131.8,
133.4, 134.0, 141.0, 149.4, 151.6; HRMS (ESI): m/z [M+H]+ calcd for C13H11N2OS:
243.0592, found 243.0589.
4-Methyl-2-propylquinazoline-3-oxide (2o).15 White solid (21.8 mg, 54%); mp
1
152–153℃; IR (KBr):  3075, 2963, 1726, 1293, 1208, 1142 cm–1; H NMR (400
MHz, CDCl3) δ 1.11 (t, J = 7.4 Hz, 3H), 1.93–2.02 (m, 2H), 2.89 (s, 3H), 3.25 (t, J =
7.6 Hz, 2H), 7.62 (t, J = 7.4 Hz, 1H), 7.72 (t, J = 7.0 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H),
7.94 (d, J = 8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 12.9, 14.0, 19.1, 34.3, 123.1,
128.3, 128.6, 128.9, 130.7, 139.8, 150.5, 159.6; HRMS (ESI) m/z [M+H]+ calcd for
C12H15N2O: 203.1184, found 203.1176.
2-Cyclopropyl-4-methylquinazoline-3-oxide (2p). White solid (30.8 mg, 77%); mp
1
159–160℃; IR (KBr):  3075, 1594, 1498, 1299, 1211, 1137, 753 cm–1; H NMR
(400 MHz, CDCl3) δ 1.22–1.32 (m, 4H), 2.89 (s, 3H), 3.34–3.41 (m, 1H), 7.55 (t, J =

Page 19 of 27
8.0 Hz, 1H), 7.66 (t, J = 8.4 Hz, 1H), 7.79–7.83 (m, 2H); 13C NMR (100 MHz, CDCl3)
δ 10.5, 11.1, 13.2, 122.6, 123.2, 127.9, 128.2, 130.7, 140.1, 150.4, 160.4; HRMS (ESI)
m/z [M + H]+ calcd for C12H13N2O: 201.1028, found 201.1022.
2-Benzyl-4-methylquinazoline-3-oxide (2q).15 White solid (37.0 mg, 74%); mp
132–133℃; IR (KBr):  3065, 2922, 1727, 1211, 1129, 756 cm-1; 1H NMR (400 MHz,
CDCl3) δ 2.84 (s, 3H), 4.61 (s, 2H), 7.23 (t, J = 7.2 Hz, 1H), 7.31 (t, J = 7.4 Hz, 2H),
7.49 (d, J = 7.2 Hz, 2H), 7.59 (t, J = 8.0 Hz, 1H), 7.68 (t, J = 7.2 Hz, 1H), 7.79 (d, J =
13
8.4 Hz, 1H), 7.92 (d, J = 8.4 Hz, 1H); C NMR (100 MHz, CDCl3) δ 13.1, 39.1,
123.1, 123.5, 126.9, 128.5, 128.7, 128.9, 129.7, 130.8, 135.8, 139.8, 151.1, 158.1;
HRMS (ESI) m/z [M+H]+ calcd for C16H15N2O: 251.1184, found 251.1173.
4-Ethyl-2-(p-tolyl)quinazoline-3-oxide (2r). White solid (40.7 mg, 77%); mp
148–149℃; IR (KBr):  3069, 2930, 1611, 1493, 1183, 1075, 830, 751cm–1; 1H NMR
(400 MHz, CDCl3) δ 1.40 (t, J = 7.4 Hz, 3H), 2.43 (s, 3H), 3.44 (q, J = 7.5 Hz, 2H),
7.30 (d, J = 8.0 Hz, 2H), 7.60–7.64 (m, 1H), 7.67–7.72 (m, 1H), 7.84 (d, J = 7.6 Hz,
1H), 8.00 (d, J = 8.0 Hz, 1H), 8.25 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ
10.2, 20.0, 21.6, 122.8, 128.6, 129.0, 129.2, 129.9, 130.2, 130.4, 130.7, 140.5, 141.1,
154.9, 156.1; HRMS  (ESI) m/z [M+H]+calcd for C17H17N2O: 265.1341, found
265.1345.
2-(4-Chlorophenyl)-4-ethylquinazoline-3-oxide (2s). Yellow solid (43.2 mg, 76%);
1
mp 153–154℃; IR (KBr):  3054, 2927, 1589, 1255, 1091, 757 cm–1; H NMR (400
MHz, CDCl3) δ 1.40 (t, J = 7.4 Hz, 3H), 3.44 (q, J = 7.5 Hz, 2H), 7.46 (d, J = 8.4 Hz,
2H), 7.65 (t, J = 8.2 Hz, 1H), 7.73 (t, J = 8.4 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 8.00

Page 20 of 27
(d, J = 8.4 Hz, 1H), 8.35 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 10.2,
20.0, 122.8, 122.9, 128.1, 129.3, 129.4, 131.0, 131.2, 132.0, 136.9, 140.5, 153.6,
156.4; HRMS (ESI) m/z [M+H]+ calcd for C16H14ClN2O: 285.0795, found 285.0791.
4-Benzyl-2-(p-tolyl)quinazoline-3-oxide (2t). White solid (48.3 mg, 74%); mp
158–159℃; IR (KBr):  3027, 2920, 1597, 1488, 1121, 754 cm–1; 1H NMR (400 MHz,
CDCl3) δ 2.42 (s, 3H), 4.80 (s, 2H), 7.17–7.31 (m, 5H), 7.40 (d, J = 7.2 Hz, 2H), 7.61
(t, J = 8.2 Hz, 1H), 7.69 (t, J = 8.2 Hz, 1H), 7.95 (d, J = 7.6 Hz, 1H), 8.00 (d, J = 8.4
Hz, 1H), 8.23 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 21.6, 32.0, 123.2,
123.5, 126.9, 128.6, 128.8, 129.0, 129.2, 129.3, 129.8, 130.4, 130.7, 135.9, 140.6,
141.2, 153.0, 155.2; HRMS (ESI): m/z [M+H]+calcd for C22H19N2O: 327.1497, found
327.1490.
4-Phenyl-2-(p-tolyl)quinazoline 3-oxide (2u). White solid (48.7 mg, 78%); mp
182–183℃; IR (KBr):  3034, 2911, 1546, 1478, 1299, 1185, 1126, 1022, 764, 695
cm–1; 1H NMR (400 MHz, CDCl3) δ 2.42 (s, 3H), 7.29 (d, J = 8.0 Hz, 2H), 7.44–7.51
(m, 2H), 7.56–7.64 (m, 5H), 7.69 (t, J = 6.8 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H), 8.31 (d,
13
J = 8.4 Hz, 2H); C NMR (100 MHz, CDCl3) δ 21.6, 123.7, 124.9, 128.6, 128.7,
128.8, 129.0, 129.5, 129.7, 130.0, 130.6, 130.7, 130.8, 141.1, 141.3, 151.3, 155.6;
HRMS (ESI) m/z [M+H]+ calcd for C21H17N2O: 313.1341, found 313.1348.
4-(4-Bromophenyl)-2-(p-tolyl)quinazoline-3-oxide (2v). Yellow solid (56.2 mg,
72%); mp 178–179℃; IR (KBr):  2921, 2852, 1728, 1644, 1470, 1293, 1126, 770
cm–1; 1H NMR (400 MHz, CDCl3) δ 2.35 (s, 3H), 7.21 (d, J = 8.4 Hz, 2H), 7.36 (d, J
= 8.4 Hz, 1H), 7.43–7.46 (m, 3H), 7.62–7.68 (m, 3H), 7.97 (d, J = 8.4 Hz, 1H), 8.21

Page 21 of 27
(d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 21.6, 123.4, 124.5, 124.6, 128.3,
128.6, 128.9, 129.2, 129.4, 130.6, 130.9, 131.8, 132.0, 141.1, 141.4, 150.2, 155.5;
HRMS (ESI) m/z [M + H]+ calcd for C21H16BrN2O: 391.0446, found 391.0440.
6-Bromo-4-methyl-2-phenylquinazoline-3-oxide (2w). White solid (52.8 mg, 84%);
1
mp 160–161℃; IR (KBr):  3069, 2909, 1485, 1287, 837, 724 cm–1; H NMR (400
MHz, CDCl3) δ 2.85 (s, 3H), 7.50 (d, J = 7.2 Hz, 3H), 7.74 (dd, J = 8.8, 2.0 Hz, 1H),
7.84 (d, J = 8.8 Hz, 1H), 7.99 (d, J = 2.0 Hz, 1H), 8.27 (dd, J = 8.0, 2.0 Hz, 2H); 13C
NMR (100 MHz, CDCl3) δ 13.4, 123.3, 124.8, 125.3, 128.0, 130.3, 130.8, 131.0,
132.2, 134.1, 138.7, 151.2, 154.9; HRMS (ESI) m/z [M + H]+ calcd for C15H12BrN2O:
315.0133, found 315.0132.
6-Bromo-4-methyl-2-(p-tolyl)quinazoline-3-oxide (2x). White solid (52.5 mg, 80%);
1
mp 161–162℃; IR (KBr):  3078, 2918 ,1611, 1347, 1180, 735 cm–1; H NMR (400
MHz, CDCl3) δ 2.43 (s, 3H), 2.84 (s, 3H), 7.29 (d, J = 8.0 Hz, 2H), 7.73 (dd, J = 8.8,
2.0 Hz, 1H), 7.83 (d, J = 9.2 Hz, 1H), 7.97 (d, J = 2.0 Hz, 1H), 8.22 (d, J = 8.4 Hz,
13
2H); C NMR (100 MHz, CDCl3) δ 13.4, 21.7, 123.0, 124.7, 125.3, 128.7, 129.4,
130.3, 130.7, 134.0, 138.7, 141.5, 151.1, 155.0; HRMS (ESI) m/z [M + H]+calcd for
C16H14BrN2O: 329.0290, found 329.0294.
6-Bromo-2-(4-chlorophenyl)-4-methylquinazoline-3-oxide (2y). Yellow solid (58.3
1
mg, 84%); mp 170–171℃; IR (KBr):  3073, 2960, 1485, 1193, 817, 741 cm–1; H
NMR (400 MHz, CDCl3) δ 2.86 (s, 3H), 7.46 (d, J = 8.8 Hz, 2H), 7.77 (d, J = 8.8Hz,
13
1H), 7.85 (d, J = 9.2 Hz, 1H), 8.01 (s, 1H), 8.32 (d, J = 8.4 Hz, 2H); C NMR (100
MHz, CDCl3) δ 13.4, 123.6, 124.8, 125.4, 128.2, 130.6, 130.8, 131.9, 134.4, 137.2,

Page 22 of 27
138.6, 151.5, 153.7; HRMS (ESI) m/z [M+H]+ calcd for C15H11BrClN2O: 348.9743,
found 348.9741.
6-Chloro-4-methyl-2-(p-tolyl)quinazoline-3-oxide (2z) Yellow solid (51.1 mg,
90%); mp 169–170℃; IR (KBr):  2918, 2850, 1614, 1488, 1349, 1285, 1190, 1180,
1
745 cm–1; H NMR (400 MHz, CDCl3) δ 2.43 (s, 3H), 2.86 (s, 3H), 7.30 (d, J = 8.0
Hz, 2H), 7.61 (d, J = 8.8 Hz, 1H), 7.82 (s, 1H), 7.92 (d, J = 8.8 Hz, 1H), 8.22 (d, J =
8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 13.3, 21.6, 122.0, 124.3, 128.7, 129.4,
130.3, 130.7, 131.5, 134.9, 138.6, 141.4, 151.3, 154.9; HRMS (ESI) m/z [M + H]+
calcd for C16H14ClN2O: 285.0795, found 285.0794.
4,7-Dimethyl-2-(p-tolyl)quinazoline-3-oxide (2za). White solid (42.8 mg, 81%); mp
179–180℃; IR (KBr):  2920, 1553, 1317, 1272, 1133, 827, 727 cm–1; 1H NMR (400
MHz, CDCl3) δ 2.43 (s, 3H), 2.53 (s, 3H), 2.87 (s, 3H), 7.29 (d, J = 8.0 Hz, 2H), 7.41
(d, J = 8.4 Hz, 1H), 7.71 (d, J = 8.8 Hz, 1H), 7.77 (s, 1H), 8.24 (d, J = 8.0 Hz, 2H);
13C NMR (100 MHz, CDCl3) δ 8.5, 16.8, 17.0, 116.8, 118.1, 123.5, 123.8, 125.3,
125.6, 126.3, 135.9, 136.2, 136.9, 147.3, 149.8; HRMS (ESI) m/z [M+H]+ calcd for
C17H17N2O: 265.1341, found 265.1346.
Methyl
5-(2-methoxy-2-oxoacetyl)-4-methyl-2-phenyl-5H-benzo[d][1,3]diazepine-5-carbo
xylate (6a). White solid (50.7 mg, 67%); mp 181–182℃; IR (KBr):  3063, 2953,
1760, 1735, 1634, 1536, 1302, 1229, 1081, 1035,760, 701 cm–1; 1H NMR (400 MHz,
CDCl3) δ 2.58 (s, 3H), 3.34 (s, 3H), 3.88 (s, 3H), 7.42–7.45 (m, 5H), 7.52 (d, J = 8.2
Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 8.04–8.10 (m, 2H); 13C NMR (100 MHz, CDCl3) δ

Page 23 of 27
14.2, 25.0, 52.9, 53.5, 121.7, 126.5, 127.8, 127.9, 128.1, 128.3, 129.1, 129.2, 129.7,
131.0, 135.8, 144.2, 159.3, 166.1, 182.6; HRMS (ESI) m/z [M + H]+ calcd for
C21H19N2O5: 379.1294, found 379.1297.
Methyl
5-(2-methoxy-2-oxoacetyl)-4-methyl-2-(4-nitrophenyl)-5H-benzo[d][1,3]diazepine-5-
carboxylate (6i). White solid (62.6 mg, 74%); mp 189–190℃; IR (KBr):  3074, 2961,
1745, 1731, 1615, 1520, 1346, 1233, 1078, 1034, 758,735 cm–1; 1H NMR (400 MHz,
CDCl3) δ 2.49 (s, 3H), 3.38 (s, 3H), 3.83 (s, 3H), 7.41–7.49 (m, 2H), 7.55 (d, J = 7.6
Hz, 1H), 8.15–8.21 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 14.2, 25.0, 53.1, 53.7,
121.1, 123.4, 123.8, 126.7, 128.9, 129.0, 129.5, 129.9, 141.7, 143.9, 149.2, 159.3,
161.7, 165.7, 181.6; HRMS (ESI) m/z [M + H]+ calcd for C21H18N3O7: 424.1145,
found 424.1147.
ACKNOWLEDGEMENTS
This work was financially supported by grants from the National Natural Science
Foundation of China (grant nos. 21162012 and 21362014), Jiangxi Provincial
Department of Science and Technology (for Jiangxi’s Key Laboratory of Green
Chemistry, nos. 20122BAB203007 and 20132BAB213006), and the Science
Foundation of Education Department of Jiangxi Provice (grant no. GJJ10386).

Page 24 of 27
REFERENCES
(1) (a) Brown, D. J. Quinazolines. In The Chemistry of Heterocyclic Compounds
(supplement I); Wiley: New York, NY, 1996, Vol. 55; For selected reviews, see:
(b) Witt, A. Bergman, J. Curr. Org. Chem., 2003, 7, 659; (c) Michael, J. P. Nat.
Prod. Rep., 2002, 19, 742; (d) Michael, J. P. Nat. Prod. Rep., 2003, 20, 476; (e)
Mhaske, S. B.; Argade, N. P. Tetrahedron, 2006, 62, 9787.
(2) (a) Kung, P. P.; Casper, M. D.; Cook, K. L.; Wison-Lingard, L.; Risen, L. M.;
Vicers, T. A,; Ranken, R.; Blyn, L. B.; Wyatt, J. R.; Cook, P. D.; Ecker, D. J. J.
Med. Chem., 1999, 42, 4705; (b) Hori, M.; Iemura, R.; Hara, H.; Ozaki, A.;
Sukamoto, T.; Ohtaka, H. Chem. Pharm. Bull., 1990, 38, 681.
(3) Connolly, D. J.; Cusack, D.; O'Sullivan, T. P.; Guiry, P. J. Tetrahedron, 2005, 61,
10153.
(4) (a) Ye, X. L.; Yuan, J. J.; Zhou, Y. R.; Deng, Z. H.; Mao, X. C.; Peng, Y. Y.
Sythesis, 2016, 48, 3976; (b) Jiang, X.; Yang, Q.; Yuan, J. J.; Deng, Z. H.; Mao,
X. C.; Peng, Y. Y. Tetrahedron, 2016, 72, 1238; (c) Ye, X. L.; Yuan, Z. H.;
Zhou, Y. R.; Yang, Q.; Xie, Y. P.; Deng, Z. H.; Peng, Y. Y. J. Heterocycl. Chem.,
2016, 53, 1956; (d) Zhang, C. Y.; Zhou, Y. R.; Deng, Z. H.; Chen, X.; Peng, Y.
Y. Eur. J. Org. Chem., 2015, 8, 1735; (e) Chen, X.; Yang, Q.; Zhou, Y. R.; Deng,
Z. H.; Mao, X. C.; Peng, Y. Y. Sythesis, 2015, 47, 2055; (f) Peng, Y. Y.; Zeng,

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M. J.; Wang, H. M.; Yang, Q.; Deng, Z. H.; Yu, C. Y. Tetrahedron, 2015, 71,
9457; (g) Peng, Y.Y.; Huang, P.; Wang, Y.; Zhou, Y. R.; Yuan, J. J.;
Yang, Q.; Jiang, X.; Deng, Z. H.; Xu, J. S. Org. Biomol. Chem., 2014, 12,
5922; (h) Lu, H.; Yang, Q.; Zhou, Y. R.; Guo, Y. Q.; Deng, Z. H.; Ding, Q.
P.; Peng,Y.Y. Org. Biomol.Chem., 2014, 12, 758; (i) Qiu, G. Y. S. ;
Huang, P.; Yang, Q.; Lu, H.; Xu, J.; Deng, Z.; Zhang, M.; Peng, Y. Y.
Synthesis 2013, 45, 3131; (j) Zhao, X.; Zhou, Y.; Xie, Y.; Ding, Q.; Deng,
Z.; Zhang, M.; Xu, J.; Peng, Y. Y. Synthesis 2013, 45, 3245; (k) Peng, Y.
Y.; Qiu, G. Y. S.; Yang, Q.; Yuan, J.; Deng, Z. Synthesis 2012, 44, 1237.
(5) (a) Combs, D. W.; Rampulla, M. S.; Russell, R. K.; Rampulla, R. A.;
Klaubert, D. H.; Ritchie, D.; Meeks, A. S.; Kirchner, T. Drug Des. Deliv.
1990, 6, 241; (b) Combs, D. W.; Falotico, R. U.S. Patent 4,745,118,
1988.
(6) Combs, D. W.; Falotico, R.; Ritchie, D. M. U.S. Patent 4,963,554, 1990.
(7) King, W. F.; Singer, M. S. U.S. Patent 4,753,943, 1988.
(8) (a) Alzogaray, R. A.; Fontan, A.; Camps, F.; Masuh, H.; Santo Orihuela,
P. S.; Fernández, D.; Cork, A.; Zerba, E. Molecules 2005, 10, 1190; (b)
Trybulski, E. J.; Benjamin, L. E.; Earley, J. V.; Fryer, R. I.; Gilman, N.
W.; Reeder, E.; Walser, A.; Davidson, A. B.; Horst, W. D. J. Med. Chem.
1983, 26, 1589; (c) Miyashita, A.; Kawashima, T.; Iijima, C.; Higashino,
T. Heterocycles 1992, 33, 211; (d) Kaneko, C.; Yamada, S. Tetrahedron
Lett. 1967, 8, 5233; (e) Sternbach, L. H.; Reeder, E. J. Org. Chem. 1961,
26, 1111; (f) Stempel, A.; Reeder, E.; Sternbach, L. H. J. Org. Chem.
1965, 30, 4267; (g) Gromov, S. P.; Razinkin, M. A. Chem. Heterocycl.

Page 26 of 27
Compd. 1992, 28, 559.
(9) (a) Archer, G. A.; Sternbach, L. H. Chem. Rev. 1968, 68, 747. (b)
Sternbach, L. H. J. Med. Chem. 1979, 22, 1; (c)Walser, A.; Flynn, T.;
Mason, C.; Fryer, R. I. J. Heterocycl. Chem. 1986, 23, 1303; (d) Bell, S.
C.; Gochman, C.; Childress, S. J. J. Med. Chem. 1962, 5, 63; (e) Field, G.
F.; Zally, W. J.; Sternbach, L. H. J. Org. Chem. 1971, 36, 777; (f)
Farber, S.; Wuest, H. M.; Meltzer, R. I. J. Med. Chem. 1964, 7, 235.
(10) (a) Begtrup, M. Chapter 1 Diazole, Triazole, and Tetrazole N-Oxides
in Advances in Heterocyclic Chemistry vol. 106, pp1-109, 2012,
Elsevier Inc. For selected reviews, see: (b) Nair, V.; Suja, T. D.
Tetrahedron, 2007, 63, 12247; (c) Singh, M. S.; Chowdhury, S.; Koley,
S, Tetrahedron, 2016, 71, 1603. (d)Yan, G.B. Borah, A. J.; Yang, M.H.
Adv. Synth. Catal. 2014, 356, 2375; (e) Andersson, H.; Olsson, R.;
Almqvis, F. Org. Biomol. Chem., 2011, 9, 337; (f) Hashimoto, T.;
Maruoka, K. Chem. Rev. 2015, 115, 5366.
(11) (a) Yang, Q.; Lou, M. H.; Yin, Z. J.; Deng, Z. H.; Ding, Q. P.; Peng, Y. Y. Org.
Biomol. Chem., 2018, 16, 8724; (b) Fan, L.W.; Wang, T.; Tian, Y.; Xiong, F.;
Wu, S.M.; Liang, Q.J.; Zhao, J.F. Chem. Commun., 2016, 52, 5375.
(12) (a) An, Y.Y.; Zheng, D.Q.; Wu, J. Chem. Commun., 2014, 50, 9165; (b)
Tian, Y.; Li, R.; Wang, T.; Xiong, J.; Feng, H.Y.; Xiong, F. Tetrahedron
Letters 2015, 56, 2176.
(13) (a) Heaney, F., Lawless, E. J. Heterocyclic Chem., 2007, 44, 569.
(14) Armarego, W. L. F. J. Chem. Soc., 1962, 5030.
(15) Madabhushi, S., Mallu, K. K. R., Jillella, R., Kurva, S., Singh, R. Tetrahedron

Page 27 of 27
Letters 2014, 55, 1979.
(16) Chen, Y.-C.; Yang, D.-Y. Tetrahedron 2013, 69, 10438.
(17) Vandeneynde, J. J.; Godin, J.; Mayence, A.; Maquestiau, A.; Anders, E.
Synthesis 1993, 867.
(18) Coskun, N.; Cetin, M. Tetrahedron 2007, 63, 2966.
(19) Peng, Y. Y.; Zeng, Y. Y.; Qiu, G. Y. S.; Cai, L.; Pike, V. W. J. Heterocycl.
Chem. 2010, 47, 1240.
(20) Atmaram, S.; Forrester, A. R.; Gill, M.; Napier, R. J.; Thomson, R. H. Acta
Chem. Scand., Ser. B 1982, 36, 641.
(21) Stauss, U.; Haerter, H. P.; Neuenschwander, M.; Schindler, O. Helv.
Chim. Acta, 1972, 55, 771.
(22) Georgescu, E.; Druta, I.; Petrovanu, M. Rev. Roum. Chim., 1981,
26,109.
(23) Georgescu, E. I.; Georgescu, F.; Gheorghiu, M. G. E. G.; Petrovanu, M.
Rev. Roum. Chim., 1985, 30, 611.
(24) Heaney, F., Lawless, E., Mahon, M., McArdle, P., Cunningham, D. Org. Biomol.
Chem., 2006, 4, 2408.
(25) Mancera, O.; Rosenkranz, G.; Sondheimer, F. J. Chem. Soc., 1953, 2189.