One-pot and regioselective synthesis of polysubstituted 3,4-dihydroquinazolines and 4,5-dihydro-3H-1,4-benzodiazepin-3-ones by sequential Ugi/Staudinger/aza-Wittig reaction

Article abstract of DOI:10.1016/j.tet.2019.01.014

An efficient one-pot and regioselective synthesis of 3,4-dihydroquinazolines and 4,5-dihydro-3H-1,4-benzodiazepin-3-ones by Ugi/Staudinger/aza-Wittig sequence has been developed. The Ugi reactions of 2-azidobenzylamines, aldehydes, acids (or α-keto acids)

Full text of DOI:10.1016/j.tet.2019.01.014

Accepted Manuscript
One-pot and regioselective synthesis of polysubstituted 3,4-dihydroquinazolines and
4,5-dihydro-3H-1,4-benzodiazepin-3-ones by sequential Ugi/Staudinger/aza-Wittig
reaction
Jun Xiong, Xiao Wei, Yu-Chen Wan, Ming-Wu Ding
PII:
S0040-4020(19)30029-8
https://doi.org/10.1016/j.tet.2019.01.014
TET 30066
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 15 November 2018
Revised Date: 3 January 2019
Accepted Date: 7 January 2019
Please cite this article as: Xiong J, Wei X, Wan Y-C, Ding M-W, One-pot and regioselective synthesis
of polysubstituted 3,4-dihydroquinazolines and 4,5-dihydro-3H-1,4-benzodiazepin-3-ones by sequential
Ugi/Staudinger/aza-Wittig reaction, Tetrahedron (2019), doi: https://doi.org/10.1016/j.tet.2019.01.014.
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ACCEPTED MANUSCRIPT
One-Pot and Regioselective Synthesis of Polysubstituted 3,4-Dihydroquinazolines and
4,5-Dihydro-3H-1,4-benzodiazepin-3-ones by Sequential Ugi/Staudinger/aza-Wittig
Reaction
Jun Xiong, Xiao Wei, Yu-Chen Wan, Ming-Wu Ding*
Key Laboratory of Pesticide & Chemical Biology of Ministry of Education, Hubei International Scientific
and Technological Cooperation Base of Pesticide and Green Synthesis, Central China Normal University,
Wuhan 430079, P. R. China
R2
N
CONHR4
R1
NH2
R1
PBu3
R3 = aryl
N
N
R3
N3
R2CHO
R3COOH
R4NC
R2
R3 = R5CO
PPh3
CONHR4
N
R1
O
R5

ACCEPTED MANUSCRIPT
One-Pot and Regioselective Synthesis of Polysubstituted
3,4-Dihydroquinazolines and 4,5-Dihydro-3H-1,4-benzodiazepin-3-ones
by Sequential Ugi/Staudinger/aza-Wittig Reaction
Jun Xiong,a,b Xiao Wei,a Yu-Chen Wana and Ming-Wu Dinga*
aKey Laboratory of Pesticide & Chemical Biology of Ministry of Education, Hubei International
Scientific and Technological Cooperation Base of Pesticide and Green Synthesis, Central China
Normal University, Wuhan 430079, P. R. China
bCollege of Pharmacy, Hubei University of Science and Technology, Xianning, Hubei 437100, P. R.
China
E-mail: mwding@mail.ccnu.edu.cn
ABSTRACT: An efficient one-pot and regioselective synthesis of 3,4-dihydroquinazolines and
4,5-dihydro-3H-1,4-benzodiazepin-3-ones by Ugi/Staudinger/aza-Wittig sequence has been developed.
The Ugi reactions of 2-azidobenzylamines, aldehydes, acids (or α-keto acids) and isocyanides produced
the azide intermediates, which were then treated with tributylphosphine or triphenylphosphine to give
polysubstituted 3,4-dihydroquinazolines or 4,5-dihydro-3H-1,4-benzodiazepin-3-ones in moderate to
good yields by tandem Standinger/aza-Wittig reactions.
Key words: 3,4-Dihydroquinazoline; 4,5-Dihydro-3H-1,4-benzodiazepin-3-one; Ugi reaction;
Standinger reaction; aza-Wittig reaction
1. Introduction
The 3,4-dihydroquinazoline core is a privileged heterocyclic scaffold because of a variety of
medicinal properties,1 such as anticancer,2 antiallergic,3 anti-inflammatory,4 antidepressant5 activities.
Many elegant approaches to the synthesis of 3,4-dihydroquinazolines have been developed. For
examples, some 3,4-dihydroquinazoline derivatives were prepared efficiently by cross-dehydrogenative
1

ACCEPTED MANUSCRIPT
coupling (CDC) reaction of simple aldehydes with 1,3-diamine derivatives.6 A novel intramolecular
aza-conjugate addition of a guanidinyl nucleophile to an α,β-unsaturated ester was also applied to
generate 3,4-dihydroquinazolines.7 1,4-Benzodiazepine-3-one scaffolds are another privileged
structures in medicinal chemistry because of their capability to bind specific domains of proteins.8 A
number of 1,4-benzodiazepine-3-one derivatives has been used as fibrinogen receptor antagonists,9
angiotensin analogues,10 and protein kinase C activators.11 Some synthetic methods to
1,4-benzodiazepine-3-ones have been reported, such as intramolecular nucleophilic aromatic
substitution,12 cycloaddition of the N-alkenoyl aryl azides,13 metal-catalyzed N-arylation,14 and
addition of Grignard reagents to o-aminobenzonitriles.15 Consequently, the development of practical
and
efficient
synthetic
methods
for
polysubstituted
3,4-dihydroquinazolines
and
1,4-benzodiazepine-3-ones is in growing demand.
The isocyanide based multicomponent reactions (I-MCRs) have aroused great attention due to its
wide utility in synthetic organic chemistry during last decades.16 Ugi reaction has been regarded as one
of the most important I-MCRs, which allows four-component reaction of aldehyde, amine, acid and
isocyanide to create α-acylamino amide adduct.17 Recently, the combination of Ugi reaction with other
post-transformation reactions have been used extensively to form heterocyclic compounds in drug
discovery and organic synthesis.18-26 For examples, the spirocyclic pyrrol-2-onedienone system were
synthesized diastereoselectively via sequential Ugi-4CR and gold-catalyzed ipso-cyclization.18 The
sequential Ugi/propargylation/Pictet-Spengler cyclization was applied successfully to the preparation of
benzoindolizidine alkaloids with high diversity.19 The highly functionalized benzo-fused
1,4-diazepin-3-ones and 1,5-diazocin-4-ones were prepared conveniently by sequential Ugi and
intramolecular SNAr reactions.20 The aza-Wittig reactions have also recently applied widely in the
synthesis of many heterocyclic compounds owning to that they can provide powerful method for the
construction of C=N double bond.27 In our previous study, the Ugi/aza-Wittig sequence was utilized
efficiently to generate various multisubstituted heterocycles such as 3,4-dihydroquinazolines,
benzimidazoles, quinoxalin-2(1H)-ones, 3H-1,4-benzodiazepines and 1H-imidazol-5(4H)-ones.28
However, 2-azidobenzylamines have not been used as starting materials in such Ugi/aza-Wittig
sequence before. If the 2-azidobenzylamines were used as one component of the Ugi reactions, new
diverse structure of heterocycles, which may be privileged scaffolds in many biologically active
substances in synthetic and medicinal chemistry, would be obtained with high reogioselectivity under
2

ACCEPTED MANUSCRIPT
mild reaction condition. Continuing our interests in synthesis of various heterocycles via
multicomponent reaction and aza-Wittig reaction,29 herein we wish to report a one pot and
regioselective synthesis of 3,4-dihydroquinazolines and 4,5-dihydro-3H-1,4-benzodiazepin-3-ones by
Ugi/aza-Wittig sequence starting from 2-azidobenzylamines.
2. Results and Discussion
Initially, we selected 2-azidobenzylamine 1a, benzaldehyde 2a, 4-bromobenzoic acid 3a and
t-butylisocyanide 4a as the starting materials (Scheme 1). As a mixture of 1a, 2a, 3a and 4a in
methanol was stirred at room temperature, the Ugi reaction was carried out smoothly to produce the
azide product 5a. Then the tandem Staudinger/aza-Wittig reactions of azide 5a with different
phosphines were investigated. When triphenylphosphine was used to react with azide 5a, the
Staudinger reaction occurred smoothly to generate iminophosphorane 6a at room temperature with the
nitrogen evolution. But heating of the reaction mixture at 110 °C did not produce the cyclized product
7a, implying the low reactivity of the amide carbonyl group toward triphenyliminophosphorane moiety.
Using methyldiphenylphosphine or dimethylphenylphospine either resulted in no product 7a formation
under the same reaction condition, different from the results we reported previously in similar cases.28f
Finally, as the much more reactive tributylphosphine was utilized under dry argon protection, the
3,4-dihydroquinazoline 7a was successfully obtained in 75% yield via tandem Staudinger and
intramolecular aza-Wittig reactions. It’s noteworthy that the reaction can be carried out in one-pot
fashion with changing of the solvent from methanol to toluene.
NH2
N3
Ph
1a
CONH
PR3
MeOH
r.t.
PhCHO (2a)
N
O
Toluene
Br
Br
COOH
N3
(3a)
5a
NC (4a)
Ph
N
Ph
CONH
N
CONH
110 °C
-R3PO
Br
N
O
N
Br
PR3
7a
6a
PR3 = PPh3
PPh2Me
0%
0%
PPhMe2
PBu3
0%
75%
3

ACCEPTED MANUSCRIPT
Scheme 1. Optimization of the reaction condition for preparation of 3,4-dihydroquinazolines 7a
With the optimized condition, various 2-azidobenzylamines 1, aldehydes 2, acids 3 and isocyanides 4
were employed for the reaction (Scheme 2). Most of the reactions proceeded smoothly to give the
corresponding 3,4-dihydroquinazolines 7 (Table 2) in 70-85% yields. As show in Table 2, the formation
of products 14 is related to R3 group. Good yields (compounds 7a-7k, 70-85%) are obtained when R3
are aromatic groups, however, no product is produced in case that R3 is an alkyl group (compound 7l)
probably due to the lower reactivity of the alkyl amide group.
NH2
R1
R2
N3
CONHR4
1
PBu3
MeOH
r.t.
N
O
R2CHO (2)
R3COOH (3)
R4NC (4)
R3
Toluene
Ar
R1
N3
5
R2
N
CONHR4
R3
R2
R3
110 °C
R1
N
CONHR4
R1
-Bu3PO
O
N
N
PBu3
7
6
Scheme 2. One-pot synthesis of 3,4-dihydroquinazolines 7
Table 1. Preparation of 3,4-dihydroquinazolines 7
Yielda
R1
R2
R3
R4
(%)
75
84
82
80
81
70
79
73
82
85
74
0
7a
7b
7c
H
H
H
Ph
4-BrC6H4
t-Bu
Ph
4-NO2C6H4 t-Bu
4-BrC6H4
4-CF3C6H4
t-Bu
7d 6-CH3 2-NO2C6H4 4-CF3C6H4
n-Bu
b
7e 6-CH3 2-ClC6H4
4-NO2C6H4 c-C6H11
4-CH3C6H4 t-Bu
7f 7-Cl
7g 7-Cl
4-ClC6H4
2-CH3C6H4 4-NO2C6H4 t-Bu
7h
7i
H
H
Ph
4-ClC6H4
t-Bu
t-Bu
4-ClC6H4
4-NCC6H4
7j 6-CH3 2-BrC6H4
4-NO2C6H4 t-Bu
7k 7-Cl
7l
Et
Ph
t-Bu
t-Bu
H
Ph
n-Pr
aisolated yields based on the 2-azidobenzylamines 1. bcyclohexyl.
If the α-keto acid 8 was used as the acid component of the Ugi reaction, the product would contain
4

ACCEPTED MANUSCRIPT
two carbonyl groups which might took part in the subsequent Staudinger/aza-Wittig reaction. The Ugi
reactions of α-keto acids 8, 2-azidobenzylamines 4, aldehydes 5 and isocyanides 6 also occurred
effectively at room temperature to produce the azides 9. Further tandem Staudinger/aza-Wittig reaction
of azides 9 with triphenylphosphine took place smoothly at toluene refluxing temperature to produce
4,5-dihydro-3H-1,4-benzodiazepin-3-ones 11 regioselectively, with no 2-acyl-3,4-dihydroquinazolines
12 formation (Scheme 3). This might be due to the better reactivity of the ketone carbonyl group
compared to the amide carbonyl group of the intermediate 10 toward the triphenyliminophosphorane
moiety. As indicated in Table 2, all of the reactions proceeded smoothly in one-pot fashion to give the
corresponding 4,5-dihydro-3H-1,4-benzodiazepin-3-ones 11 regioselectively in 70-90% yields with
different R1, R2, R3 and R4 substituents. In case that R5 was a phenyl group, the yield was generally
higher (79-90%) than that of a methyl group (70-78%).
NH2
R1
R2
N3
CONHR4
1
PPh3
MeOH
r.t.
N
O
R5
R2CHO (2)
R5COCOOH (8)
R4NC (4)
Toluene
R1
O
N3
9
R2
N
R2
N
CONHR4
R5
CONHR4
O
110 °C
-Ph3PO
R1
R1
O
O
N
N
R5
PPh3
10
11
R2
N
CONHR4
R5
R1
N
O
12
Scheme 3. One-pot and regioselective synthesis of 4,5-dihydro-3H-1,4-benzodiazepin-3-ones 11
Table 2. Preparation of 4,5-dihydro-3H-1,4-benzodiazepin-3-ones 11
Yielda
R1
R2
R4
R5
(%)
90
78
83
80
84
11a
11b
11c
11d
11e
H
H
H
H
H
Ph
t-Bu
t-Bu
n-Bu
Ph
4-ClC6H4
4-BrC6H4
4-ClC6H4
CH3
Ph
b
c-C6H11 Ph
t-Bu Ph
S
5

ACCEPTED MANUSCRIPT
11f 5-CH3 4-NO2C6H4
11g 5-CH3 Ph
t-Bu
t-Bu
Ph
82
72
79
81
70
82
83
CH3
Ph
11h 4-Cl
11i 4-Cl
11j 4-Cl
4-CH3OC6H4 t-Bu
4-NO2C6H4
2-ClC6H4
n-Pr
n-Bu
Ph
b
c-C6H11 CH3
t-Bu Ph
c-C6H11 Ph
11k
11l
H
H
b
2-BrC6H4
aisolated yields based on the 2-azidobenzylamines 1. bcyclohexyl.
The structure of 3,4-dihydroquinazolines 7 and 4,5-dihydro-3H-1,4-benzodiazepin-3-ones 11 and
1
were confirmed by their spectrum data. For example, the H NMR spectrum of 11a showed multiplets
at δ = 8.07-7.22 due to the aromatic hydrogen. The signals during 6.73-5.96 ppm might be due to NH,
CH and aromatic hydrogen. The signal of CH2 was found at δ = 4.46-4.08 as multiplets. The tert-butyl
protons absorbed at δ = 1.31 and 1.04 as two singlets (6.5:2.5). The 13C NMR spectrum data of 11a
showed the signals of two CON and C-2 of the 1,4-benzodiazepin-3-one at δ = 168.3, 166.5 (minor),
162.5 (minor), 162.2, 160.9, 160.8 (minor). The HRMS spectrum of 11a showed M++Na at m/z
448.2003 (calculated 448.1995). The structure of 4,5-dihydro-3H-1,4-benzodiazepin-3-ones 11 was
distinguishable from that of 2-acylquinazolines 12 mainly by their 13C NMR spectrum data. The signals
of C=O carbon of ketone in compounds 11 disappeared compared with the 2-acylquinazolines 12,
which generally absorbed at about 190 ppm.28d Furthermore
a
single crystal of
4,5-dihydro-3H-1,4-benzodiazepin-3-one 11d was obtained from the CH2Cl2/petroleum ether solution
of 11d, and X-ray structure analysis verified the proposed structure (Figure 1).31
Figure 1. ORTEP drawing of 11d with 50% probability thermal ellipsoids.
It was reported that 3,4-dihydroquinazolines could be prepared by sequential
Boc-protect/Ugi/de-Boc-protect/cyclize reaction, however, the cyclize reaction should be carried out
6

ACCEPTED MANUSCRIPT
under strong acidic condition.32 Our new synthetic approach to 3,4-dihydroquinazolines by sequential
Ugi/Staudinger/aza-Wittig reaction had the advantage of mild neutral cyclization condition.33
Furthermore, Our synthetic approach provided 4,5-dihydro-3H-1,4-benzodiazepin-3-ones 11 with high
regioselectivity, which was not reported by the literature.
3.Conclusion
In conclusion, we have developed a one-pot and regioselective synthesis of 3,4-dihydroquinazolines
and 4,5-dihydro-3H-1,4-benzodiazepin-3-ones by a new sequential Ugi/Staudinger/aza-Wittig reaction,
starting from 2-azidobenzylamines. Due to the easy availability of the synthetic approach, this method
has
potential
in
the
preparation
of
various
3,4-dihydroquinazolines
and
4,5-dihydro-3H-1,4-benzodiazepin-3-ones, which are important constituents in many biologically
active substances in synthetic and medicinal chemistry.
4. Experimental
4.1 General
1
Melting points were determined using an X-4 model apparatus and were uncorrected. H NMR were
recorded in CDCl3 on a Varian Mercury 600 spectrometer and resonances were relative to TMS. 13C
NMR spectra were recorded in CDCl3 on a Varian Mercury 600 (150 MHz) with complete proton
decoupling spectrophotometers (CDCl3: 77.0 ppm). HRMS was measured on an Agilent 6224 TOF
LC/MS spectrometer. The X-ray diffraction data were collected on a Bruker SMART AXS CCD diffract
meter, MoKα, 2θ = 1.86-27.50º. 2-Azidobenzylamines 1 were prepared by reaction of 85% aqueous
hydrazine with N-(2-azidophenyl)phthalimide, which were obtained through N-alkylation of
2-azidobenzyl bromide with potassium phthalimide according to literature report.30
4.2 One-pot preparation of 3,4-dihydroquinazolines 7
4.2.1
2-(2-(4-bromophenyl)quinazolin-3(4H)-yl)-N-(tert-butyl)-2-phenylacetamide (7a)
7

ACCEPTED MANUSCRIPT
A solution of 2-azidobenzylamine 1a (0.30 g, 2 mmol) and benzaldehyde 2a (0.21 g, 2 mmol) in
MeOH (10 mL) was stirred at room temperature for 10 min. Then 4-bromobenzoic acid 3a (0.40 g, 2
mmol) and t-butylisocyanide 4a (0.11 g, 2 mmol) were added sequentially. The reaction mixture was
stirred at ambient temperature for 48 h. After the solvent was evaporated under reduced pressure,
toluene (5 mL) was added. Then a solution of PBu3 (0.40 g, 2 mmol) in toluene (5 mL) was added
dropwise at room temperature under N2 protection. After the mixture was stirred for about 1 h, the
solution was heated to reflux for 24 h. The solvent was then evaporated under reduced pressure and the
residue was purified by column chromatography with petroleum ether/EtOAc (4:1) as the eluent to give
3,4-dihydroquinazoline 7a. Light yellow solid (yield 0.715 g, 75 %), mp 179-180 °C; 1H NMR (CDCl3,
600 MHz) δ (ppm) 7.56-6.68 (m, 13H), 5.37 (s, 1H), 5.11 (s, 1H), 4.79 (d, J = 13.2 Hz, 1H), 4.29 (d, J
= 13.2 Hz, 1H), 1.30 (s, 9H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 168.3, 157.7, 142.2, 135.0, 134.7,
131.7, 130.0, 128.7, 128.4, 127.9, 125.1, 124.6, 124.1, 123.8, 121.9, 67.1, 51.6, 45.5, 28.3. HRMS (ESI)
m/z calcd for [C26H26BrN3O+H]+: 476.1332, found: 476.1331.
4.2.2
N-(tert-butyl)-2-(2-(4-nitrophenyl)quinazolin-3(4H)-yl)-2-phenylacetamide (7b)
1
Yellow solid (yield 0.743 g, 84%), mp 233-235 °C; H NMR (CDCl3, 600 MHz) δ (ppm) 8.28 (d, J =
8.4 Hz, 2H), 7.87 (d, J = 8.4 Hz, 2H), 7.37-7.18 (m, 7H), 7.02 (t, J = 7.2 Hz, 1H), 6.74 (d, J = 7.2 Hz,
1H), 5.25 (br, 1H), 5.04 (s, 1H), 4.88 (d, J = 14.4 Hz, 1H), 4.34 (d, J = 14.4 Hz, 1H), 1.34 (s, 9H); 13C
NMR (CDCl3, 150 MHz) δ (ppm) 168.2, 156.7, 148.4, 142.7, 141.9, 134.5, 129.7, 129.1, 128.9, 128.7,
128.2, 125.9, 124.9, 124.3, 123.9, 121.9, 67.5, 52.1, 45.7, 28.6. HRMS (ESI) m/z calcd for
[C26H26N4O3+H]+: 443.2078, found: 443.2076.
4.2.3
2-(4-bromophenyl)-N-(tert-butyl)-2-(2-(4-(trifluoromethyl)phenyl)quinazolin-3(4H)-yl)aceta
mide (7c)
1
Light yellow solid (yield 0.892 g, 82%), mp 199-200 °C; H NMR (CDCl3, 600 MHz) δ (ppm)
7.79-6.75 (m, 12H), 5.25 (s, 1H), 5.00 (s, 1H), 4.82 (d, J = 14.4 Hz, 1H), 4.32 (d, J = 14.4 Hz, 1H),
1.31 (s, 9H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 167.8, 157.3, 142.0, 139.7, 133.8, 132.1, 131.9,
130.3, 128.9, 128.3, 125.9, 124.9, 124.6, 124.3, 122.9, 122.8, 121.8, 66.8, 52.1, 45.8, 28.5. HRMS (ESI)
m/z calcd for [C27H25BrF3N3O+H]+: 544.1206, found: 544.1209.
4.2.4
N-butyl-2-(6-methyl-2-(4-(trifluoromethyl)phenyl)quinazolin-3(4H)-yl)-2-(2-nitrophen-yl)ace
tamide (7d)
White solid (yield 0.839 g, 80 %); mp 94-96 °C. 1H NMR (CDCl3, 600 MHz) δ (ppm) 8.02 (d, J = 7.8
8

ACCEPTED MANUSCRIPT
Hz, 1H), 7.77-7.06 (m, 10H), 6.61 (s, 1H), 5.82 (s, 1H), 5.48 (s, 1H), 4.64 (d, J = 14.4 Hz, 1H), 4.46 (d,
J = 14.4 Hz, 1H), 3.18-3.08 (m, 2H), 2.28 (s, 3H), 1.26-1.20 (m, 4H), 0.87 (t, J = 7.2 Hz, 3H); 13C
NMR (CDCl3, 150 MHz) δ (ppm) 167.6, 156.8, 149.0, 139.4, 138.8, 136.2, 133.4, 132.2, 131.9, 130.6,
129.6, 129.5, 129.1, 129.0, 128.8, 125.7, 125.5, 125.4, 124.3, 121.5, 64.6, 46.2, 39.7, 31.1, 21.0, 19.9,
13.6. HRMS (ESI) m/z calcd for [C28H27F3N4O3+H]+: 525.2108, found: 525.2108.
4.2.5
2-(2-chlorophenyl)-N-cyclohexyl-2-(6-methyl-2-(4-nitrophenyl)quinazolin-3(4H)-yl)acetamid
e (7e)
Yellow solid (yield 0.838 g, 81 %), mp 192-194 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 8.21 (d, J =
7.2 Hz, 2H), 7.83 (d, J = 7.2 Hz, 2H), 7.40-7.30 (m, 4H), 7.05-6.96 (m, 2H), 6.48 (s, 1H), 5.43 (d, J =
7.8 Hz, 1H), 5.24 (s, 1H), 4.86 (d, J = 14.4 Hz, 1H), 4.20 (d, J = 14.4 Hz, 1H), 3.91-3.88 (m, 1H), 2.21
13
(s, 3H), 1.95-1.05 (m, 10H); C NMR (CDCl3, 150 MHz) δ (ppm) 168.2, 156.3, 148.2, 142.9, 139.6,
135.5, 135.1, 132.1, 130.5, 130.4, 130.3, 129.7, 128.7, 126.9, 125.2, 124.1, 123.6, 121.6, 64.9, 48.7,
45.6, 32.9, 32.7, 25.2, 24.7, 20.9. HRMS (ESI) m/z calcd for [C29H29ClN4O3+H]+: 517.2001, found:
517.2008.
4.2.6
N-(tert-butyl)-2-(7-chloro-2-(p-tolyl)quinazolin-3(4H)-yl)-2-(4-chlorophenyl)acetamide (7f)
1
White solid (yield 0.673 g, 70 %), mp 188-189 °C; H NMR (CDCl3, 600 MHz) δ (ppm) 7.52 (d, J =
7.2 Hz, 2H), 7.30-7.17 (m, 7H), 6.94 (d, J = 7.2 Hz, 1H), 6.62 (d, J = 7.8 Hz, 1H), 5.25 (s, 1H), 5.13 (s,
1H), 4.76 (d, J = 14.4 Hz, 1H), 4.28 (d, J = 14.4 Hz, 1H), 2.40 (s, 3H), 1.34 (s, 9H); 13C NMR (CDCl3,
150 MHz) δ (ppm) 168.2, 159.8, 143.9, 140.6, 134.4, 133.6, 133.3, 132.8, 129.8, 129.5, 129.0, 128.4,
125.6, 124.9, 123.8, 120.4, 68.4, 52.0, 45.3, 28.5, 21.4. HRMS (ESI) m/z calcd for [C27H27Cl2N3O+H]+:
480.1604, found:480.1605.
4.2.7
N-(tert-butyl)-2-(7-chloro-2-(4-nitrophenyl)quinazolin-3(4H)-yl)-2-(o-tolyl)acetamide (7g)
1
White solid (yield 0.776 g, 79 %), mp 231-233 °C; H NMR (CDCl3, 600 MHz) δ (ppm) 8.24 (d, J =
8.4 Hz, 2H), 7.85 (d, J = 9.0 Hz, 2H), 7.32-6.91 (m, 6H), 6.54 (d, J = 8.4 Hz, 1H), 5.13 (s, 1H), 4.98 (s,
1H), 4.86 (d, J = 14.4 Hz, 1H), 4.16 (d, J = 14.4 Hz, 1H), 2.05 (s, 3H), 1.40 (s, 8.5H), 1.26 (s, 0.5H);
13C NMR (CDCl3, 150 MHz) δ (ppm) 169.6, 158.0, 148.5, 143.3, 142.6, 137.7, 133.3, 133.2, 131.4,
129.7, 129.3, 126.3, 125.7, 125.4, 123.9, 123.7, 120.2, 65.3, 52.1, 45.2, 28.5, 19.3. HRMS (ESI) m/z
calcd for [C27H27ClN4O3+H]+: 491.1844, found: 491.1852.
4.2.8
N-(tert-butyl)-2-(2-(4-chlorophenyl)quinazolin-3(4H)-yl)-2-phenylacetamide (7h)
Yellow solid (yield 0.631 g, 73 %), mp 177-179 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.62 (d, J =
9

ACCEPTED MANUSCRIPT
8.4 Hz, 2H), 7.44-6.97 (m, 10H), 6.71 (d, J = 7.2 Hz, 1H), 5.27 (s, 1H), 5.13 (s, 1H), 4.83 (d, J = 14.4
13
Hz, 1H), 4.32 (d, J = 14.4 Hz, 1H), 1.33 (s, 9H); C NMR (CDCl3, 150 MHz) δ (ppm) 168.5, 158.0,
142.2, 136.0, 134.8, 134.6, 130.0, 129.1, 128.9, 128.8, 128.7, 128.1, 125.4, 124.8, 123.9, 122.0, 67.3,
51.9, 45.7, 28.5. HRMS (ESI) m/z calcd for [C26H26ClN3O+H]+: 432.1837, found: 432.1837.
4.2.9
N-(tert-butyl)-2-(4-chlorophenyl)-2-(2-(4-cyanophenyl)quinazolin-3(4H)-yl)acetamide (7i)
1
White solid (yield 0.749 g, 82 %), mp 164-165 °C; H NMR (CDCl3, 600 MHz) δ (ppm) 7.79 (d, J =
7.2 Hz, 2H), 7.72 (d, J = 7.2 Hz, 2H), 7.33-7.03 (m, 7H), 6.74 (d, J = 6.6 Hz, 1H), 5.35 (s, 1H), 4.98 (s,
1H), 4.85 (d, J = 14.4 Hz, 1H), 4.32 (d, J = 14.4 Hz, 1H), 1.33 (s, 9H); 13C NMR (CDCl3, 150 MHz) δ
(ppm) 167.9, 156.8, 141.9, 140.7, 134.7, 133.2, 132.5, 129.9, 129.3, 129.1, 128.3, 126.0, 124.9, 124.3,
121.8, 118.0, 113.4, 66.6, 52.0, 45.7, 28.5. HRMS (ESI) m/z calcd for [C27H25ClN4O+H]+: 457.1790,
found: 457.1791.
4.2.10 2-(2-bromophenyl)-N-(tert-butyl)-2-(6-methyl-2-(4-nitrophenyl)quinazolin-3(4H)-yl)acetamid
e (7j)
1
Yellow solid (yield 0.910 g, 85%), mp 194-196 °C; H NMR (CDCl3, 600 MHz) δ (ppm) 8.24 (d, J =
8.4 Hz, 2H), 7.88 (d, J = 7.2 Hz, 2H), 7.54-6.97 (m, 6H), 6.46 (s, 1H), 5.12 (s, 1H), 5.08 (s, 1H), 4.87
(d, J = 14.4 Hz, 1H), 4.17 (d, J = 14.4 Hz, 1H), 2.22 (s, 3H), 1.38 (m, 9H); 13C NMR (CDCl3, 150 MHz)
δ (ppm) 168.8, 156.5, 148.4, 143.1, 139.7, 135.5, 134.0, 133.9, 130.8, 130.6, 129.9, 128.7, 127.6, 125.6,
125.2, 124.1, 123.5, 121.7, 67.5, 52.2, 45.7, 28.5, 21.0. HRMS (ESI) m/z calcd for [C27H27BrN4O3+H]+:
535.1339, found: 535.1337.
4.2.11 N-(tert-butyl)-2-(7-chloro-2-phenylquinazolin-3(4H)-yl)butanamide (7k)
1
Yellow oil (yield 0.565 g, 74%); H NMR (CDCl3, 600 MHz) δ (ppm) 8.22-8.69 (m, 8H), 6.07 (s,
0.2H), 5.36 (s, 0.8H), 4.63-4.56 (m, 2H), 3.81 (t, J = 7.2 Hz, 1H), 2.37-0.68 (m, 14H); 13C NMR
(CDCl3, 150 MHz) δ (ppm) 169.2, 167.9 (minor), 160.4, 158.5 (minor), 147.9 (minor), 144.0, 140.7
(minor), 135.8, 135.0 (minor), 133.6, 130.2, 129.9, 128.4 (minor), 128.3, 128.1 (minor), 127.6 (minor),
126.9 (minor), 125.8, 125.1, 123.9, 119.9, 119.4 (minor), 65.4 (minor), 64.9, 51.6 (minor), 51.5, 43.8,
29.6 (minor), 28.5, 22.1, 21.3 (minor), 10.8. HRMS (ESI) m/z calcd for [C22H26ClN3O+H]+: 384.1837,
found: 384.1846.
4.3 One-pot and regioselective preparation of 4,5-dihydro-3H-1,4-benzodiazepin-3-ones 11
10

ACCEPTED MANUSCRIPT
4.3.1 N-tert-butyl-2-(3-oxo-2-phenyl-3H-benzo-1,4-diazepin-4(5H)-yl)-2-phenylacetamide (11a)
A solution of 2-azidobenzylamine 1a (0.30 g, 2 mmol) and benzaldehyde 2a (0.21 g, 2 mmol) in
MeOH (10 mL) was stirred at room temperature for 10 min. Then 2-oxo-2-phenylacetic acid 8a (0.40 g,
2 mmol) and t-butylisocyanide 4a (0.11 g, 2 mmol) were added sequentially. The reaction mixture was
stirred at ambient temperature for 24 h. After the solvent was evaporated under reduced pressure,
toluene (5 mL) was added. Then a solution of PPh3 (0.52 g, 2 mmol) in toluene (5 mL) was added
dropwise at room temperature. After the mixture was stirred for about 1 h, the solution was heated to
reflux for 12 h. The solvent was then evaporated under reduced pressure and the residue was purified
by column chromatography with petroleum ether/EtOAc (6:1) as the eluent to give
4,5-dihydro-3H-1,4-benzodiazepin-3-one 11a. Light yellow solid (yield 0.766 g, 90%), mp 164-165 °C;
1H NMR (CDCl3, 600 MHz) δ (ppm) 8.07-7.98 (m, 2H), 7.47-7.22 (m, 11H), 6.73-5.96 (m, 3H),
4.46-4.08 (m, 2H), 1.31 (s, 6.5H), 1.04 (s, 2.5H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 168.3, 166.5
(minor), 162.5 (minor), 162.2, 160.9, 160.8 (minor), 146.7 (minor), 146.2, 136.3, 135.8 (minor), 135.5,
134.6 (minor), 131.2 (minor), 130.9, 129.6, 129.2 (minor), 129.1 (minor), 128.8, 128.7, 128.6, 128.5,
128.4, 128.3, 128.2 (minor), 127.5 (minor), 126.7, 126.4 (minor), 126.2 (minor), 126.0, 125.9, 60.3
(minor), 59.6, 51.8, 51.4 (minor), 46.1, 45.7 (minor), 28.5, 28.1 (minor). HRMS (ESI) m/z calcd for
[C27H27N3O2+Na]+: 448.1995, found: 448.2003.
4.3.2 N-tert-butyl-2-(4-chlorophenyl)-2-(2-methyl-3-oxo-3H-benzo-1,4-diazepin-4(5H)-yl)acetamide
(11b)
1
Light yellow solid (yield 0.620 g, 78 %), mp 221-223 °C; H NMR (CDCl3, 600 MHz) δ (ppm)
7.39-6.01 (m, 9H), 5.74 (s, 1H), 4.26-3.94 (m, 2H), 2.55 (s, 3H), 1.39 (s, 6.5H), 1.06 (s, 2.5H); 13C
NMR (CDCl3, 150 MHz) δ (ppm) 168.0, 163.0, 162.9, 145.7, 134.4, 134.0, 130.5, 129.9, 128.8, 128.7,
126.4, 125.9, 125.7, 58.5, 51.8, 45.6, 28.5, 25.1. HRMS (ESI) m/z calcd for [C22H24ClN3O2+Na]+:
420.1449, found: 420.1450.
4.3.3 2-(4-bromophenyl)-N-butyl-2-(3-oxo-2-phenyl-3H-benzo-1,4-diazepin-4(5H)-yl)acetamide
(11c)
Light yellow solid (yield 0.837 g, 83%), mp 145-147 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.98 (d,
J = 7.8 Hz, 2H), 7.54-6.09 (m, 13H), 4.48 (d, J = 16.2 Hz, 0.6H), 4.32 (d, J = 15.6 Hz, 1H), 4.11 (d, J =
15.0 Hz, 0.4H), 3.28-2.86 (m, 2H), 1.79-0.73 (m, 7H); 13C NMR (CDCl3, 150 MHz) δ (ppm) 168.4,
166.9 (minor), 162.3, 160.5 (minor), 146.6 (minor), 146.1, 136.2, 135.7 (minor), 134.3, 133.6 (minor),
11

ACCEPTED MANUSCRIPT
132.0, 131.7, 131.4 (minor), 131.1, 130.0 (minor), 129.8, 129.3 (minor), 128.7 (minor), 128.6, 128.5,
128.3 (minor), 128.2, 127.3 (minor), 126.6, 126.5, 126.3 (minor), 126.2, 126.1, 122.8, 122.4 (minor),
58.8, 58.5 (minor), 46.1, 45.8 (minor), 39.3, 39.1 (minor), 31.2, 30.8 (minor), 20.0, 19.7 (minor), 13.7,
13.6 (minor). HRMS (ESI) m/z calcd for [C27H26BrN3O2+H]+: 504.1281, found: 504.1293.
4.3.4 2-(4-chlorophenyl)-N-cyclohexyl-2-(3-oxo-2-phenyl-3H-benzo-1,4-diazepin-4(5H)-yl)acetamid
e (11d)
White solid (yield 0.777 g, 80%), mp 221-223 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 7.98-7.94 (m,
2H), 7.43-7.08 (m, 10H), 6.80-6.07 (m, 3H), 4.52-3.45 (m, 3H), 1.96-0.51 (m, 10H); 13C NMR (CDCl3,
150 MHz) δ (ppm) 167.6, 166.1 (minor), 162.5 (minor), 162.3, 160.7, 160.4 (minor), 146.6 (minor),
146.1, 136.2, 135.8 (minor), 134.5, 134.2, 131.3 (minor), 131.0, 130.6, 129.5, 129.2 (minor), 129.0,
128.8 (minor), 128.7 (minor), 128.6, 128.5, 128.4 (minor), 128.3, 127.4 (minor), 126.7, 126.4 (minor),
126.2 (minor), 126.1, 126.0, 58.8 (minor), 58.2, 48.5, 48.2 (minor), 46.2, 45.7 (minor), 32.3, 31.7
(minor), 25.2, 25.1 (minor), 24.7 (minor), 24.6. HRMS (ESI) m/z calcd for [C29H28ClN3O2+Na]+:
508.1762, found: 508.1770.
4.3.5 N-tert-butyl-2-(3-oxo-2-phenyl-3H-benzo-1,4-diazepin-4(5H)-yl)-2-(thiophen-2-yl)acetamide
(11e)
White solid (yield 0.725 g, 84%), mp 173-174 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 8.03-7.95 (m,
2H), 7.41-6.31 (m, 12H), 4.83 (d, J = 15.6 Hz, 0.6H), 4.48 (d, J = 15.0 Hz, 0.4H), 4.32 (d, J = 14.4 Hz,
13
0.6H), 3.94 (d, J = 15.0 Hz, 0.4H), 1.16 (s, 5H), 0.94 (m, 4H); C NMR (CDCl3, 150 MHz) δ (ppm)
167.5, 165.6 (minor), 161.7, 160.3 (minor), 160.2, 146.3 (minor), 145.7, 138.0, 136.0 (minor), 135.8,
135.4 (minor), 131.0 (minor), 130.7, 128.8, 128.6 (minor), 128.5, 128.4, 128.2, 128.1 (minor), 128.0,
127.9, 127.2 (minor), 126.9 (minor), 126.8, 126.5 (minor), 126.4, 126.2 (minor), 126.1, 125.8 (minor),
125.7, 55.2 (minor), 53.8, 51.2, 50.9 (minor), 45.5, 44.7 (minor), 27.9, 27.7 (minor). HRMS (ESI) m/z
calcd for [C25H25N3O2S+Na]+: 454.1560, found: 454.1563.
4.3.6 N-tert-butyl-2-(7-methyl-3-oxo-2-phenyl-3H-benzo-1,4-diazepin-4(5H)-yl)-2-(4-nitrophenyl)ac
etamide (11f)
White solid (yield 0.795 g, 82%), mp 179-181 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 8.26-7.90 (m,
4H), 7.64-7.05 (m, 8H), 6.64-5.78 (m, 2H), 4.50 (d, J = 15.6 Hz, 0.6H), 4.31 (d, J = 16.2 Hz, 1H), 4.18
(d, J = 15.0 Hz, 0.4H), 2.32 (s, 1.2H), 1.95 (s, 1.8H), 1.29 (s, 5.7H), 1.05 (s, 3.3H); 13C NMR (CDCl3,
150 MHz) δ (ppm) 167.2, 165.7 (minor), 162.9 (minor), 162.6, 159.6, 147.6, 147.5 (minor), 144.3
12

ACCEPTED MANUSCRIPT
(minor), 143.8, 143.0, 142.2 (minor), 136.8, 136.1, 135.9, 135.8 (minor), 131.3 (minor), 131.1, 130.2,
130.1 (minor), 129.5, 129.0 (minor), 128.6 (minor), 128.5, 128.4 (minor), 128.3, 127.8 (minor), 126.9,
126.6 (minor), 126.4 (minor), 126.3, 123.8 (minor), 123.4, 59.1 (minor), 58.2, 52.0, 51.7 (minor), 48.5,
46.0 (minor), 28.4, 28.1 (minor), 20.9 (minor), 20.5. HRMS (ESI) m/z calcd for [C28H28N4O4+H]+:
485.2183, found: 485.2184.
4.3.7 N-tert-butyl-2-(2,7-dimethyl-3-oxo-3H-benzo-1,4-diazepin-4(5H)-yl)-2-phenylacetamide (11g)
1
Light yellow solid (yield 0.544 g, 72 %), mp 183-185 °C; H NMR (CDCl3, 600 MHz) δ (ppm)
7.33-5.56 (m, 10H), 4.25-4.09 (m, 2H), 2.45 (s, 3H), 1.98 (s, 3H), 1.38 (s, 7.6H), 1.07 (s, 1.4H); 13C
NMR (CDCl3, 150 MHz) δ (ppm) 168.3, 162.9, 162.4, 143.4, 135.5, 135.2, 129.4, 128.9, 128.7, 128.4,
128.1, 127.0, 125.3, 59.3, 51.7, 45.6, 28.5, 25.0, 20.5. HRMS (ESI) m/z calcd for [C23H27N3O2+Na]+:
400.1995, found: 400.2002.
4.3.8 N-tert-butyl-2-(8-chloro-3-oxo-2-phenyl-3H-benzo-1,4-diazepin-4(5H)-yl)-2-(4-methoxyphenyl
)acetamide (11h)
White solid (yield 0.768 g, 79%), mp 219-220 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 8.04-7.97 (m,
2H), 7.49-5.93 (m, 12H), 4.42-4.27 (m, 2H), 3.83 (s, 3H), 1.32 (s, 6.9H), 1.08 (s, 2.1H); 13C NMR
(CDCl3, 150 MHz) δ (ppm) 168.4, 166.7 (minor), 166.2 (minor), 161.9, 159.9, 147.8 (minor), 147.2,
135.9, 133.9, 131.6, 131.3, 130.8, 129.7 (minor), 128.9, 128.8 (minor), 128.6, 128.3, 127.7, 127.5
(minor), 127.3, 126.1 (minor), 125.8, 125.6, 114.3 (minor), 114.1, 59.5 (minor), 59.1, 55.4, 55.3
(minor), 51.8, 51.4 (minor), 45.3, 28.5, 28.1 (minor). HRMS (ESI) m/z calcd for [C28H28ClN3O3+Na]+:
512.1711, found: 512.1720.
4.3.9 N-butyl-2-(8-chloro-3-oxo-2-phenyl-3H-benzo-1,4-diazepin-4(5H)-yl)-2-(4-nitrophenyl)acetam
ide (11i)
1
Yellow solid (yield 0.818 g, 81%), mp 145-147 °C; H NMR (CDCl3, 600 MHz) δ (ppm) 8.26 (d, J =
13
8.4 Hz, 1H), 8.06-6.01 (m, 13H), 4.57-4.15 (m, 2H), 3.26-2.88 (m, 2H), 1.32-0.76 (m, 7H); C NMR
(CDCl3, 150 MHz) δ (ppm) 167.5, 166.3 (minor), 162.4, 162.3 (minor), 161.3, 161.2 (minor), 147.7,
147.6 (minor), 147.5, 147.1 (minor), 142.0, 141.8 (minor), 135.5, 135.1 (minor), 135.0, 134.7 (minor),
132.0, 131.7 (minor), 130.1, 129.9 (minor), 128.7, 128.6 (minor), 128.5, 127.5 (minor), 126.3, 126.2
(minor), 126.0, 125.9 (minor), 125.4, 125.3, 123.9, 123.6 (minor), 58.2, 45.7 (minor), 45.3, 39.4, 39.3
(minor), 31.1 (minor), 30.9, 19.9 (minor), 19.7, 13.6, 13.5 (minor). HRMS (ESI) m/z calcd for
[C27H25ClN4O4+Na]+: 527.1457, found: 527.1464.
13

ACCEPTED MANUSCRIPT
4.3.10 2-(8-chloro-2-methyl-3-oxo-3H-benzo-1,4-diazepin-4(5H)-yl)-2-(2-chlorophenyl)-N-cyclohexyl
acetamide (11j)
1
Light yellow solid (yield 0.642 g, 70 %), mp 168-170 °C; H NMR (CDCl3, 600 MHz) δ (ppm)
7.33-5.93 (m, 9H), 4.40-3.47 (m, 3H), 2.53 and 2.47 (ss, 3H), 1.94-0.70 (s, 10H); 13C NMR (CDCl3,
150 MHz) δ (ppm) 167.1, 164.2, 162.9, 146.6, 137.0, 134.6, 134.1, 129.9, 129.2, 128.8, 127.6, 127.3,
127.1, 125.9, 125.6, 58.5, 48.6, 45.2, 32.7, 25.3, 25.2, 24.6. HRMS (ESI) m/z calcd for
[C24H25Cl2N3O2+Na]+: 480.1216, found: 480.1219.
4.3.11 N-tert-butyl-2-(3-oxo-2-phenyl-3H-benzo-1,4-diazepin-4(5H)-yl)pentanamide (11k)
White solid (yield 0.642 g, 82%), mp 173-174 °C; 1H NMR (CDCl3, 600 MHz) δ (ppm) 8.04 (d, J = 6.6
Hz, 2H), 7.48-7.16 (m, 7H), 6.05 (br, 0.25H), 5.90 (s, 0.75H), 4.92-4.11 (m, 3H), 2.10-0.78 (m, 16H);
13C NMR (CDCl3, 150 MHz) δ (ppm) 169.4 (minor), 167.8, 162.8, 162.0 (minor), 161.2, 160.9 (minor),
146.6, 146.5 (minor), 136.4 (minor), 135.6, 131.2, 131.0 (minor), 129.1, 128.8, 128.6, 128.5, 128.3
(minor), 127.3, 127.0 (minor), 126.6 (minor), 126.4, 126.0, 58.1 (minor), 55.9, 51.3 (minor), 50.8, 45.2
(minor), 43.9, 31.2 (minor), 29.1, 28.5 (minor), 28.1, 19.2 (minor), 18.9, 13.7, 13.6 (minor). HRMS
(ESI) m/z calcd for [C24H29N3O2+Na]+: 414.2152, found: 414.2152.
4.3.12 2-(2-bromophenyl)-N-cyclohexyl-2-(3-oxo-2-phenyl-3H-benzo-1,4-diazepin-4(5H)-yl)acetamid
e (11l)
1
Light yellow solid (yield 0.881 g, 83%), mp 179-181 °C; H NMR (CDCl3, 600 MHz) δ (ppm)
8.11-7.22 (m, 12H), 6.76-5.74 (m, 3H), 4.34-4.07 (m, 2H), 3.81-3.53 (m, 1H), 2.01-0.63 (m, 10H); 13C
NMR (CDCl3, 150 MHz) δ (ppm) 168.0, 166.1 (minor), 162.1 (minor), 161.5, 160.9 (minor), 160.4,
146.6 (minor), 146.5, 136.5, 135.6 (minor), 134.2 (minor), 133.9, 133.6 (minor), 133.4, 131.2 (minor),
131.1, 130.7, 130.6 (minor), 130.3, 129.5 (minor), 128.9, 128.8, 128.7, 128.3 (minor), 128.1, 128.0
(minor), 127.8, 127.6 (minor), 127.3, 127.2 (minor), 126.5, 126.4 (minor), 126.0, 125.9 (minor), 125.8,
125.3 (minor), 62.1 (minor), 60.0, 48.5, 48.1 (minor), 46.1, 45.3 (minor), 32.3, 32.0 (minor), 25.3, 25.2
(minor), 24.6 (minor), 24.4. HRMS (ESI) m/z calcd for [C29H28BrN3O2+H]+: 530.1438, found:
530.1436.
Acknowledgments
We gratefully acknowledge financial support of this work by the National Natural Science Foundation
of China (No. 21572075) and the 111 Project B17019.
14

ACCEPTED MANUSCRIPT
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