TMSOTf-catalyzed synthesis of substituted quinazolines using hexamethyldisilazane as a nitrogen source under neat and microwave irradiation conditions

Article abstract of DOI:10.1039/d0ob01507e

In this article, we report an efficient and mild synthetic route for the construction of substituted quinazolines from functionalized 2-aminobenzophenones with various benzaldehydes usingcat. TMSOTf and hexamethyldisilazane (HMDS) under neat, metal-free and microwave irradiation conditions in which gaseous ammonia was formedin situ. This synthetic protocol provided the desired quinazolines with a broad substrate scope in good to excellent yields. Some structures were confirmed by X-ray single-crystal diffraction analysis.

Full text of DOI:10.1039/d0ob01507e

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DOI: 10.1039/D0OB01507E
TMSOTf-Catalyzed Synthesis of Substituted
Quinazolines Using Hexamethyldisilazane as
Nitrogen Source under Neat and Microwave
Irradiation
Chieh-Kai Chan, Chien-Yu Lai and Cheng-Chung Wang*
Institute of Chemistry, Academia Sinica, Taipei 115, Taiwan
ABSTRACT: In this article, we report an efficient and mild synthetic route for the construction of substituted quinazolines from
functionalized 2-aminobenzophenones with various benzaldehydes by cat. TMSOTf and hexamethyldisilazane (HMDS) under neat,
metal-free and microwave irradiation condition in which the gaseous ammonia was formed in situ. This synthetic protocol provided
the desired quinazolines with a broad substrate scope in good to excellent yields. Some structures were confirmed by X-ray single-
crystal diffraction analysis.
Br
F
Quinazoline is a privileged skeleton occurring commonly in
many natural products,1 some metal complex ligands2 and
various synthetic molecules with diverse pharmaceutical
NH2
N
NH
MeO
MeO
MeO
N
N
N
N
O
N
O
N
antibacterial,3
anticancer,4
OH
N
N
properties,
including
Prazosin
Vasicine
Vandetanib
anticonvulsant,5
antitumor,8
anti-inflammatory,6
antiplasmodial,7
O
Cl
antimicrobial,9
antioxidant,10
anti-HIV,11
F
antitubercular12 and as an α-adrenergic blocker.13 Additionally,
its derivatives have been applied as photochemotherapeutic
agents,14 DNA-gyrase, JAK2, PDE5 and EGFR (epidermal
growth factor receptor) tyrosine kinase inhibitors15 and CB2
receptor agonists.16 Some quinazoline-based drugs are shown
in Figure 1. Prazosin, an orally available sympatholytic drug
is used for the treatment of hypertension, anxiety and post-
traumatic stress disorder.17 Vasicine is a quinazoline alkaloid
isolated from Adhatoda vasica with bronchodilatory activity
displayed both in vivo and in vitro.18
O
NH
NH
N
N
O
O
N
MeO
MeO
MeO
N
N
Gefitinib
Erlotinib
Figure 1. Examples of Bioactive Quinazoline-based Drugs
Vandetanib is the first FDA approved drug applied for the
treatment of late-stage medullary thyroid cancer.19 Gefitinib
and Erlotinib demonstrated promising clinical activity acting
as EGFR tyrosine kinase inhibitors,20 and used for treating
lung and pancreatic cancers.21 Owing to many biologically
active properties and pharmaceutically applications of
quinazoline derivatives, the development of these compounds
has evoked great interest.22
Numerous synthetic strategies were well-established for the
construction of substituted quinazoline scaffold starting from
various
aminobenzyl alcohols,23 2-aminobenzoic acids,24 2-
aminobenzonitriles,25 2-aminobenzylamines,26
2-
ortho-functionalized
anilines,
including
2-

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(i) two component synthetic routes
aminobenzaldehydes and 2-aminobenzophenones.27 In
additions to ortho-functionalized anilines, o-
ref 27a: I2, TBHP (Wang, 2010)
ref 27b: SCONP-3, TBHP
(Wang, 2010)
ref 27c: 4-OH TEMPO, O2
(Han, 2011)
ref 27d: [Ru]/L (Yi, 2019)
NH2
Ph
nitroacetophenone were used as raw materials for the synthesis
of substituted quinazolines via a hydrogen-transfer strategy,28
and non-substituted aniline were used as starting materials for
the preparation of substituted quinazolines via a four-
component intermolecular condensation method.29 Among
these, most popular synthetic routes for the preparation of
functionalized quinazoline skeletons were performed from 2-
aminobenzophenones with various N sources and diverse one
carbon synthons. As illustrated in Scheme 1, a variety of
synthetic protocols from 2-aminobenzophenone have been
developed, including: (i) two components synthetic routes
with benzylamine by using I2/TBHP,27a SCONP-3/TBHP,27b 4-
OH TEMPO/O2,27c ruthenium catalytic system [Ru]/L,27d with
α-amino acid catalyzed by I2/TBHP oxidative decarboxylative
amination,27e (ii) three components synthetic routes with
ammonium acetate as N source with one carbon synthon
obtained from benzylic carbon in KI/TBHP catalytic system,27f
arylacetic acid by using Cu(OAc)2/O2/NMP,27g or aromatic
aldehyde catalyzed by ionic liquid bmim[FeCl4],27h and (iii)
NH4OAc as N source with DMA as one carbon synthon by the
involvement of NIS/TBHP system.27i These methodologies
were broadly established, considering their substrate
generality, multistep procedure, requirement of inert
atmosphere, stringent condition and involvement of expensive
catalysts, ligands or additives. Due to the importance of
quinazoline derivatives in biological and medicinal chemistry,
the development of a facile, effective and environmentally
benign protocol that is obtained from readily available starting
materials and reagents would be highly desired.30
N
O
NH2
Ph
ref 27e: I2, DMA
(Wang, 2011)
N
NH2
HOOC
(ii) three component synthetic routes
H
H
ref 27f: KI, TBHP
Ph
H
(Li, 2015)
ref 27g: Cu(OAc)2, O2, NMP
Ph
NH4OAc
HOOC
N
O
(Yan, 2016)
N
NH2
ref 27h: bmim[FeCl4
(Saha, 2013)
]
O
Ph
(iii) aqueous ammonia as N source
ref 27i: NIS, TBHP
(Wang, 2012)
O
N
NH3 (aq)
+
+
O
N
NH2
N
R
N
(iv) This work
R
TMSOTf
H
N
N
O
+
+
Ar
Si
Si
Ar
R1
O
(This work)
R1
NH2
Initially, the reaction of 2-aminobenzophenone (1a) with
benzaldehyde (2a) and use of HMDS as N source were
selected as model substrates under microwave irradiation to
optimize the reaction conditions, as shown in Table 1. Based
on the reported literature,34 gaseous ammonia was found when
the silylation of alcohol occurred in presence of nitromethane
at room temperature. In entries 1-3, the formation of 3a failed
when we used EtOH as additive and MeNO2 as solvent at rt
and only 30% yield of product was obtained under heating. To
the best of our knowledge, HMDS could be activated by
various catalysts.34 Therefore, we further changed the additive
to Lewis acids for the generation of gaseous ammonia. In
entries 4-9, some metal triflates were used such as AgOTf,
Fe(OTf)2, Sn(OTf)2, Fe(OTf)3, Fe(OTf)3 and non-metal triflate
TMSOTf catalyzed the formation of desired quinazoline 3a
under microwave irradiation resulting in high yields. Non-
metal Lewis acids such as InCl3 catalyzed the formation of 3a
in 45% yield, but AlCl3 provided some unknown products
(entries 10 and 11). Other Brønsted acids, including p-TsOH
and TfOH were also investigated, but no reaction occurred
with these (entries 12 and 13). Replacing the reaction solvents
with DCM, MeCN and 1,4-dioxane, the yields showed that
toluene was the best medium (entries 14-16). As we know,
HMDS is a liquid reagent, we further examined its reaction
properties in a solvent-free and neat condition, no obvious
yield changes was observed (entry 17). Decreasing the
reaction temperature from 150oC to 100oC showed that only
50% yield of 3a was isolated and it turned complicated at
room temperature (entries 18-19). Increasing the reaction
temperature to 200oC demonstrated that the yield of 3a was
slightly lowered (entry 20). Considering the fact that
conventional experimental operation resulted in the formation
of unnecessary waste, conducting neat reaction condition
served as a good reaction medium. Therefore, we think that
non-metal TMSOTf catalyzed HMDS in situ generation of
gaseous ammonia to synthesize quinazoline scaffold from 2-
aminobenzophenone (1a) and benzaldehyde (2a) was the
optimized reaction condition for conducting the experiments.
Hexamethyldisilazane (HMDS) is a stable, commercially
available reagents used for the silylation reactions by utilizing
various catalysts and high temperature to increase the
silylating power.31 In our previous work, the TMSOTf-
catalyzed HMDS silylation carbohydrates which provided
gaseous ammonia as the only by-product.32 Therefore,
TMSOTf/HMDS could be considered as an appropriate
system to obtain ammonium as N source. Furthermore, based
on our successful experience associated with the synthesis of
quinoline skeletons under microwave irradiation condition.33
Herein, we developed an effective and conventional synthetic
protocol for the construction of quinazoline scaffold by using
TMSOTf/HMDS catalytic system under neat and microwave
irradiation condition, as illustrated in Scheme 1, equation (iv).
Scheme 1. Synthetic Methods For Developing Quinazolines
from 2-Aminobenzophenone

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OMe
OMe
OMe
MeO
Table 1. Optimization of the Reaction Conditionsa
OMe
OMe
OMe
N
N
N
N
N
N
N
N
N
N
NH2
O
HMDS, additive, solvent
MW (T oC), 0.5 h
N
N
+
3u (89%)
OMe
3v (85%)
3w (89%)
3x (86%)
OBn
OMe
3y (84%)
OMe
OBn
O
OMe
OMe
MeO
OMe
MeO
OMe
1a
2a
3a
Entry
Additive
Solvent
Temperature (oC)
Yield (%)b
N.R.
N.R.
30
N
N
N
N
N
N
N
N
N
N
1
2
EtOH
--
MeNO2
MeNO2
MeNO2
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DCM
25
25
3z (85%)
3aa (93%)
3ab (90%)
3ac (88%)
3ad (86%)
3
--
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
100
25
4
AgOTf
Fe(OTf)2
Sn(OTf)2
Fe(OTf)3
Bi(OTf)3
TMSOTf
InCl3
87
O
O
5
85
S
6
86
N
N
N
N
N
N
N
N
N
N
7
84
8
88
3ae (88%)
3af (83%)
3ag (82%)
3ah (85%)
3ai (83%)
9
88
N
N
10
11
12
13
14
15
16
17 d
18 d
19 d
20 d
45
O
N
N
AlCl3
__c
N.R.
N.R.
88
N
N
N
N
N
N
N
N
N
N
p-TsOH
TfOH
3aj (84%)
3ak (90%)
3al (88%)
3am (92%)
3an (81%)
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
a Reaction conditions: 1a (1.0 mmol), 2 (1.05 mmol), HMDS (1.0 mL),
TMSOTf (0.1 mmol), MW, 0.5 h. b Isolated yields.
MeCN
20
1,4-Dioxane
60
On the basis of the optimal reaction conditions in hand, 3a
was prepared at 90% yield. Next, the substrate scope of
aromatic benzaldehyde
--
--
--
--
90
50
__c
2
was investigated with 2-
aminobenzophenone (1a) under optimized reaction conditions.
As shown in Table 2, the aromatic benzaldehydes 2b-2q with
electron-withdrawing groups, such as -F, -Cl, -Br, -NO2 and -
CF3 were well reacted with 1a to afford corresponding
products 3b-3q in moderate to good yields. The reaction of 1a
with various electron-donating functional groups on aromatic
benzaldehydes 2r-2ah were conducted smoothly for the
preparation of desired quinazolines 3r-3ah resulting in good to
excellent yields. Nevertheless, an array of heterocyclic
carbaldehydes, such as 2-thiophenyl 2ai, 2-furanyl 2aj, 2-
pyridyl 2ak, 3-pyridyl 2al, 4-pyridyl 2am and 2-quinolinyl
2an were also well tolerated and the corresponding
quinazolines 3ai-3an were obtained in modest yields.35 The
structures of 3c, 3l, 3w, 3aa and 3ab were confirmed by
single-crystal X-ray crystallography.36
200
75
a Reaction conditions: 1a (1.0 mmol), 2a (1.05 mmol), HMDS (0.3 mL),
b
c
additive (0.1 mmol), solvent (5 mL), MW, 0.5 h. Isolated yields.
Complicated products were formed. d HMDS (0.5 mL).
Table 2. Substrate Scope of Aromatic Aldehydes 2a,b
Ar
NH2
O
Ar
TMSOTf, HMDS
+
N
N
3
MW (150 oC), 0.5 h
O
1a
2
F
F
F
Cl
N
N
N
N
N
N
N
N
N
N
We subsequently investigated the structural diversity of
substituted 2-aminobenzophenones 1b-1o by assessing the
substitution effect on both the two aromatic rings. As shown in
Table 3, the functional groups on Ar1 and Ar2 with a wide
range of substitution were examined. The electron-
withdrawing groups, (-F, -Cl, -Br and -NO2), or electron-
donating groups (methyl, methoxy) at Ar1 or Ar2 rings were
appropriately managed in this synthetic protocol. The reaction
of 1 with 2a were conducted smoothly and the corresponding
products 4a-4n were isolated in moderate to good yields. The
structures of 4h was also confirmed by single-crystal X-ray
crystallography.36
3a (90%)
3b (87%)
3c (88%)
3d (89%)
3e (91%)
Br
Cl
Cl
Br
Br
N
N
N
N
N
N
N
N
N
N
3f (86%)
3g (92%)
3h (92%)
F
3i (94%)
3j (89%)
NO2
F
F
F
F
F
NO2
N
N
N
N
N
N
N
N
N
N
3k (85%)
3l (86%)
CF3
3m (84%)
3n (83%)
3o (86%)
Me
Me
Table 3. Substrate Scope of 2-aminobenzophenones 1a,b
Me
CF3
N
N
N
N
N
N
N
N
N
N
NH2
Ar1
O
TMSOTf, HMDS
+
N
N
4
Ar2
MW (150 oC), 0.5 h
O
3p (87%)
3q (92%)
3r (81%)
3s (90%)
3t (87%)
Ar1
Ar2
1
2a

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intermolecular cyclization in 1.5 h, it was seen that the desired
quinazolines 5a and 5b were isolated in 90% and 91% yields
respectively. The results showed that the substituents on the
substrates 1 and 2 did not influence the results in gram-scale
synthesis.
N
N
N
N
N
N
N
N
NO2
Br
Cl
4a (90%)
4b (88%)
4c (93%)
4d (88%)
Scheme 3. Gram-Scale Synthesis of Quinazolines 5
R
N
N
R
NH2
Cl
O
N
N
N
N
N
N
TMSOTf, HMDS
+
N
N
MeO
MW (150 oC), 1.5 h
OMe
Cl
Br
F
O
4e (86%)
4f (84%)
4g (94%)
4h (82%)
1b
2d, R = F
2t, R = Me
Cl
(1.16g, 5.0 mmol)
5a, R = F (90%, 1.50g)
5b, R = Me (91%, 1.50g)
N
N
Cl
N
N
N
N
N
N
MeO
Interestingly, the quinazolines prepared from our synthetic
protocol can smoothly undergo further synthetic modification,
as illustrated in Scheme 4. The desired biaryl product 6 could
be prepared via Suzuki-Miyaura coupling reaction of 4b with
phenylboronic acid. Nevertheless, Pd(PPh3)4/CuI-catalyzed
Sonogashira coupling reaction of 4b with phenylacetylene
gave the alkynylated quinazoline 7 in a moderate yield.
OMe
Cl
OMe
4i (84%)
4j (85%)
4k (89%)
4l (82%)
N
N
N
N
OMe
OMe
MeO
OMe
MeO
OMe
OMe
OMe
OMe
4m (87%)
4n (83%)
Scheme 4. Synthetic Applications of Quinazolines
a Reaction conditions: 1 (1.0 mmol), 2a (1.05 mmol), HMDS (1.0 mL),
TMSOTf (0.1 mmol), MW, 0.5 h. b Isolated yields.
Suzuki-Miyuara coupling
B(OH)2
Sonogashira coupling
On the basis of the experimental results as shown in Tables
1-2, a plausible mechanism was speculated as demonstrated in
Scheme 2. Initially, the system of TMSOTf and HMDS could
form complex I with the releases of triflate anion. The reaction
of benzaldehyde 2a took place with I to generate oxonium A.
Next, the intermolecular addition of 2-aminobenzophenone 1a
with intermediate A occurred to form intermediate B. The
deprotonation of C was performed by the involvement of
HMDS to afford intermediate D. At the same time, the
complex II reacted with TMSOH to give the silylated product
TMSOTMS ether and complex III, which could be further
transformed to gaseous ammonia by triflate anion, and
TMSOTf could be regenerated. Finally, the imination and
oxidation of in situ ammonia with intermediate D to form E
under microwave irradiation to obtain desired quinazoline 3a.
Notably, the in situ mass spectrometry analysis of TMSOH,
TMSOTMS and intermediate E were detected.37
N
N
N
N
N
N
Br
6 (90%)
4b
7 (88%)
Notably, the preparation of 3a from 1a and 2a by using a
normal hot plate as a heating source was also examined in
some control experiments, as shown in Scheme 5. It was
noticed that increasing the amount of TMSOTf led to the
isolation of our desired product 3a in poor yield with
recovered starting materials (eq. a). Additionally, to extend the
reaction time from 1 h to 8 h, the reaction could afford 3a with
a significant growth (eq. b). When the reaction was performed
in the presence of cosolvent, toluene and HMDS, the product
yield increased by 10% (eq. c). On the basis of the findings
observed in these control experiments and reported literatures,
we can conclude that microwave irradiation is a better heating
source than a normal hot plate for the preparation of
substituted quinazoline scaffolds.38
Scheme 2. Plausible Mechanism
2a
ref 32
H
O
Ph
H
TMS
TMS
N
TMS
N
TMS
TMS
TMS
A
TMSOTf
(HMDS)
HMDS
I
1a
OTf
H
Scheme 5. Control Experiments
TMS
N
NH3
TMSO
H
Ph
III
H
H
Ph
N
H O
H
TMS
TMS
+
TMS
H
N
O
H
N
O
II
H
Ph
TMSOTMS
Ph
TMSOH
B
C
Ph
O
N
Ph
-H2O
Ph
D
Ph
N
NH
N
N
Intermediates were detected by HMRS
TMSOH: C3H11OSi+ , found [M+H]+ = 91.0573
TMSOTMS: C6H18OSi2Na+ , found [M+H]+ = 185.0788
Ph
Ph
MW
E: C20H17N2+, found [M+H]+ = 285.1379
E
3a
In summary, we developed a methodology for TMSOTf-
catalyzed HMDS in situ generation of gaseous ammonia for
the synthesis of substituted quinazolines from functionalized
2-aminobenzophenones and aromatic aldehydes via a neat,
metal-free under microwave irradiation reaction conditions.
This protocol could afford substituted quinazolines in high
yields by the involvement of quantitative ammonia through
Furthermore, the gram-scale synthesis of quinazolines 5 is
shown in Scheme 3.When the reaction scale of 1b increased to
5.0 mmol (1.16 g) with the addition of 2d (650 mg) and 2t
(630 mg) for conducting the TMSOTf-catalyzed

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controlling the exact amounts of HMDS and catalytic amount
151.74, 137.32, 133.71, 132.15, 131.41 (d, J = 8.375 Hz),
130.17 (2x), 129.99, 129.19, 128.59 (2x), 127.59, 127.37 (d, J
= 10.125 Hz), 126.98, 124.11 (d, J = 3.625 Hz), 121.36,
116.81 (d, J = 22.125 Hz).
of TMSOTf. The plausible mechanism was proposed. Some
structures were confirmed by X-ray single-crystal diffraction
analysis. Considering the functions of the quinazoline
scaffold, further investigation of biological and medicinal
activities will be conducted and published in due course.
2-(3-Fluorophenyl)-4-phenylquinazoline (3c).39 Yield =
o
88% (264 mg); Colorless solid; mp = 180-181 C (literature:
o
EXPERIMENTAL SECTION
160 C); HRMS (ESI, M++H) calcd for C20H14FN2 301.1136,
1
found 301.1135; H NMR (500 MHz, CDCl3): δ 8.50 (d, J =
General Information. All reagents and solvents were
commercially available and used without further purification.
Reactions were routinely performed using the Discover SP
system (CEM) in the sealed reaction vessels in standard mode
with the temperature monitored using a vertically focused IR
sensor. All reactions were monitored by TLC on silica gel 60
F254 (Merck) with detection by UV light. Column
chromatography was performed using silica gel (200–300
mesh). Products in organic solvents were dried with anhydrous
magnesium sulfate before concentration in vacuo. Melting
8.0 Hz, 1H), 8.42 (d, J = 10.5 Hz, 1H), 8.15 (t, J = 8.5 Hz,
2H), 7.92-7.88 (m, 3H), 7.62-7.60 (m, 3H), 7.57 (t, J = 7.0 Hz,
1H), 7.51-7.47 (m, 1H), 7.22-7.18 (m, 1H); 13C NMR (125
MHz, CDCl3): δ 168.39, 163.22 (d, J = 243.125 Hz), 158.99
(d, J = 2.875 Hz), 151.86, 140.64 (d, J = 7.75 Hz), 137.45,
133.66 130.16 (2x), 130.01, 129.92 (d, J = 7.875 Hz), 129.18,
128.54 (2x), 127.31, 127.02, 124.23 (d, J = 2.375 Hz), 121.81,
117.30 (d, J = 21.125 Hz), 115.42 (d, J = 23.125 Hz). Single-
crystal X-ray diagram: crystal of 3c was grown by slow
diffusion of EtOAc into a solution of 3c in CH2Cl2 to yield
colorless prisms. The compound crystallizes in the monoclinic
crystal system, space group P 21/n, a = 10.3439(4) Å, b =
6.8286(2) Å, c = 20.1913(7) Å, V = 1412.80(8) Å3, Z = 4, dcalcd
= 1.407 Mg/m3, F(000) = 620, 2θ range 3.152-27.101, R
indices (all data) R1 = 0.0481, wR2 = 0.1140. CCDC number
is 1996087.
1
points were determined with a MP-2D melting apparatus. H
and 13C NMR spectra were recorded on a Bruker AVIII 500
spectrometer operating at 500 and at 125 MHz, respectively.
Data are reported as follows: chemical shift, multiplicity (s =
singlet, d = doublet, t = triplet, m = multiplet, br = broad),
coupling constants (Hz) and integration. HRMS were obtained
on a Waters LCT Premier XE (Waters Corp., Manchester,
UK) instrument equipped with an electrospray source. The X-
ray intensity data were measured at low temperature 100 K
using Mo Kα radiation diffractometer equipped with a kappa
geometry goniometer and corrected for absorption effects
using the numerical method (SADABS).
2-(4-Fluorophenyl)-4-phenylquinazoline (3d).39 Yield =
89% (267 mg); White solid; mp = 149-150 oC (literature: 149-
o
150 C); HRMS (ESI, M++H) calcd for C20H14FN2 301.1136,
found 301.1128; 1H NMR (500 MHz, CDCl3): δ 8.73-8.70 (m,
2H), 8.13 (t, J = 8.0 Hz, 2H), 7.90-7.87 (m, 3H), 7.62-7.58 (m,
3H), 7.54 (t, J = 8.0 Hz, 1H), 7.20 (t, J = 9.0 Hz, 2H); 13C
NMR (125 MHz, CDCl3): δ 168.35, 164.61 (d, J = 248.5 Hz),
159.26, 151.92, 137.56, 134.36 (d, J = 2.625 Hz), 133.60,
130.72 (d, J = 8.625 Hz, 2x), 130.12 (2x), 129.95, 129.03,
128.52 (2x), 127.00 (d, J = 2.8875 Hz, 2x), 121.54, 115.39 (d,
J = 21.525 Hz, 2x).
General procedure for the synthesis of skeletons 3, 4 and
5: A mixture of 2-aminobenzophenones 1 (1.0 mmol),
aromatic aldehydes
2
(1.05 mmol), trimethylsilyl
trifluoromethanesulfonate (0.1 mmol) in hexamethyldisilazane
o
(0.5 mL), in a dried 15 mL microwave vial at 25 C. The
mixture was subjected to a microwave irradiation instrument
o
and stirred at 150 C for 0.5 h (for gram-scale: 1.5 h). The
2-(2-Chlorophenyl)-4-phenylquinazoline (3e).40 Yield
=
o
consumption of the starting materials were confirmed by TLC.
The reaction was cooled to 25 oC, the mixture of crude product
was transferred to a 100 mL round bottom flask, and the
solvent was concentrated. The residue was diluted with water
(10 mL) and the mixture was extracted with CH2Cl2 (3 x 15
mL). The combined organic layers were washed with brine,
dried, filtered and evaporated to afford crude product under
reduced pressure. Purification on silica gel (hexanes/EtOAc =
10/1~4/1) afforded compounds 3a-3an, 4a-4n and 5a-5b.
2,4-Diphenylquinazoline (3a).30b Yield = 90% (254 mg);
White solid; mp = 118-119 oC (literature: 119-121 oC); HRMS
(ESI, M++H) calcd for C21H15N2 283.1230, found 283.1222;
1H NMR (500 MHz, CDCl3): δ 8.72 (d, J = 8.0 Hz, 2H), 8.17
(d, J = 8.5 Hz, 1H), 8.13 (d, J = 8.5 Hz, 1H), 7.93-7.85 (m,
3H), 7.64-7.58 (m, 3H), 7.57-7.49 (m, 4H); 13C NMR (125
MHz, CDCl3): δ 168.26, 160.19, 151.95, 138.18, 137.64,
133.48, 130.46, 130.15 (2x), 129.87, 129.13, 128.63 (2x),
128.49 (4x), 126.95 (2x), 121.64.
91% (288 mg); White solid; mp = 81-82 C (literature: 93-94
oC); HRMS (ESI, M++H) calcd for C20H14ClN2 317.0840,
1
found 317.0831; H NMR (500 MHz, CDCl3): δ 8.20 (d, J =
10.0 Hz, 2H), 7.96-7.87 (m, 4H), 7.66-7.62 (m, 1H), 7.60-7.56
(m, 3H), 7.55-7.52 (m, 1H), 7.43-7.37 (m, 2H); 13C NMR
(125 MHz, CDCl3): δ 168.26, 161.29, 151.53, 138.45, 137.19,
133.80, 133.05, 131.78, 130.52, 130.18 (3x), 130.01, 129.10,
128.60 (2x), 127.77, 127.03, 126.84, 121.34.
2-(3-Chlorophenyl)-4-phenylquinazoline (3f).30b Yield =
86% (272 mg); White solid; mp = 126-127 oC (literature: 115-
117 oC); HRMS (ESI, M++H) calcd for C20H14ClN2 317.0840,
found 317.0831; 1H NMR (500 MHz, CDCl3): δ 8.71 (s, 1H),
8.61-8.59 (m, 1H), 8.14 (t, J = 8.5 Hz, 2H), 7.91-7.87 (m, 3H),
7.62-7.60 (m, 3H), 7.56 (t, J = 8.0 Hz, 1H), 7.48-7.44 (m, 2H);
13C NMR (125 MHz, CDCl3): δ 168.43, 158.83, 151.83,
140.04, 137.41, 134.62, 133.68, 130.40, 130.15 (2x), 130.02,
129.71, 129.15, 128.65, 128.54 (2x), 127.33, 127.02, 126.72,
121.80.
2-(2-Fluorophenyl)-4-phenylquinazoline (3b).22b Yield =
2-(4-Chlorophenyl)-4-phenylquinazoline (3g).30b Yield =
92% (291 mg); White solid; mp = 190-191 oC (literature: 187-
188 oC); HRMS (ESI, M++H) calcd for C20H14ClN2 317.0840,
87% (261 mg); Colorless solid; mp = 88-89 oC (literature: 90-
o
92 C); HRMS (ESI, M++H) calcd for C20H14FN2 301.1136,
found 301.1133; 1H NMR (500 MHz, CDCl3): δ 8.24-8.16 (m,
3H), 7.92 (t, J = 8.5 Hz, 1H), 7.89-7.86 (m, 2H), 7.62-7.57 (m,
4H), 7.48-7.44 (m, 1H), 7.30 (td, J = 1.0, 7.5 Hz, 1H), 7.23
(ddd, J = 1.0, 8.0, 11.0 Hz, 1H); 13C NMR (125 MHz, CDCl3):
δ 168.44, 161.32 (d, J = 253.0 Hz), 159.13 (d, J = 4.25 Hz),
found 317.0836; H NMR (500 MHz, CDCl3): δ 8.65 (d, J =
1
8.5 Hz, 2H), 8.15-8.12 (m, 2H), 7.91-7.87 (m, 3H), 7.63-7.58
(m, 3H), 7.58-7.55 (m, 1H), 7.49 (d, J = 8.5 Hz, 2H); 13C
NMR (125 MHz, CDCl3): δ 168.42, 159.21, 151.91, 137.52,

Organic & Biomolecular Chemistry
Page 6 of 12
View Article Online
DOI: 10.1039/D0OB01507E
136.69, 133.68, 130.14 (2x), 130.00 (2x), 129.11, 128.70 (2x),
128.56 (2x), 127.19, 127.06, 121.71.
2-(3,4-Difluorophenyl)-4-phenylquinazoline (3m). Yield =
o
84% (267 mg); White solid; mp = 180-181 C; HRMS (ESI,
1
M++H) calcd for C20H13F2N2 319.1041, found 319.1043; H
2-(2-Bromophenyl)-4-phenylquinazoline (3h). Yield = 92%
o
NMR (500 MHz, CDCl3): δ 8.56-8.52 (m, 1H), 8.49-8.46 (m,
1H), 8.13 (d, J = 9.0 Hz, 2H), 7.92-7.85 (m, 3H), 7.62-7.55
(m, 4H), 7.28 (q, J = 9.6 Hz, 1H); 13C NMR (125 MHz,
CDCl3): δ 168.47, 158.16, 152.15 (d, J = 12.875, 152.15 Hz),
151.83, 150.52 (dd, J = 12.75, 245.75 Hz), 137.37, 135.40 (q,
J = 3.375 Hz), 133.77, 130.12 (2x), 130.08, 129.08, 128.57
(2x), 127.33, 127.06, 124.95 (q, J = 3.25 Hz), 121.68, 117.47
(d, J = 18.75 Hz), 117.15 (d, J = 17.375 Hz).
(331 mg); White solid; mp = 76-77 C; HRMS (ESI, M++H)
1
calcd for C20H14BrN2 361.0335, found 361.0326; H NMR
(500 MHz, CDCl3): δ 8.22-8.19 (m, 2H), 7.95 (td, J = 1.0, 7.0
Hz, 1H), 7.91-7.88 (m, 3H), 7.74 (dd, J = 1.0, 8.5 Hz, 1H),
7.65 (td, J = 1.0, 7.0 Hz, 1H), 7.61-7.55 (m, 3H), 7.46 (td, J =
1.0, 7.5 Hz, 1H), 7.31 (td, J = 1.5, 7.0 Hz, 1H); 13C NMR (125
MHz, CDCl3): δ 168.20, 162.13, 151.51, 140.32, 137.19,
133.84, 133.69, 131.73, 130.30, 130.20 (2x), 130.03, 129.11,
128.61 (2x), 127.80, 127.45, 127.07, 122.13, 121.36.
30b
2-(2-Nitrophenyl)-4-phenylquinazoline (3n).30b Yield
=
o
83% (271 mg); Colorless solid mp = 159-160 C (literature:
2-(3-Bromophenyl)-4-phenylquinazoline (3i).
Yield
=
159-161 oC); HRMS (ESI, M++H) calcd for C20H14N3O2
o
94% (338 mg); White solid; mp = 135-136 C (literature: 98-
1
328.1081, found 328.1081; H NMR (500 MHz, CDCl3): δ
o
+
99 C); HRMS (ESI, M +H) calcd for C20H14BrN2 361.0335,
8.22 (d, J = 7.5 Hz, 1H), 8.17 (d, J = 8.5 Hz, 1H), 8.14 (d, J =
8.5 Hz, 1H), 7.94-7.86 (m, 2H), 7.83-7.79 (m, 2H), 7.72-7.67
(m, 1H), 7.64-7.54 (m, 5H); 13C NMR (125 MHz, CDCl3): δ
168.31, 158.74, 151.58, 150.08, 136.80, 133.90, 133.73,
132.09, 131.69, 130.14 (2x), 130.12, 129.96, 129.03, 128.54
(2x), 127.98, 127.04, 123.9, 121.45.
1
found 361.0326; H NMR (500 MHz, CDCl3): δ 8.87 (s, 1H),
8.64 (d, J = 7.5 Hz, 1H), 8.14 (t, J = 9.0 Hz, 2H), 7.91-7.87
(m, 3H), 7.63-7.60 (m, 4H), 7.56 (t, J = 8.0 Hz, 1H), 7.39 (t, J
= 8.0 Hz, 1H); 13C NMR (125 MHz, CDCl3): δ 168.44,
158.69, 151.82, 140.26, 137.40, 133.69, 133.32, 131.55,
130.15 (2x), 130.02, 130.00, 129.16, 128.55 (2x), 127.35,
127.18, 127.02, 122.81, 121.80.
2-(4-Nitrophenyl)-4-phenylquinazoline (3o).30b Yield = 86%
o
(281 mg); White solid; mp = 217-218 C (literature: 200-201
2-(4-Bromophenyl)-4-phenylquinazoline (3j).30b Yield =
89% (320 mg); White solid; mp = 193-194 oC (literature: 185-
186 oC); HRMS (ESI, M++H) calcd for C20H14BrN2 361.0335,
oC); HRMS (ESI, M++H) calcd for C20H14N3O2 328.1081,
1
found 328.1072; H NMR (500 MHz, CDCl3): δ 8.88 (d, J =
1
8.5 Hz, 2H), 8.35 (d, J = 8.5 Hz, 2H), 8.18 (t, J = 8.0 Hz, 2H),
7.95 (t, J = 8.0 Hz, 1H), 7.91-7.87 (m, 2H), 7.66-7.61 (m, 4H);
13C NMR (125 MHz, CDCl3): δ 168.71, 157.94, 151.81,
149.13, 144.04, 137.21, 134.01, 130.24, 130.15 (2x), 129.43
(2x), 129.36, 128.66 (2x), 128.05, 127.14, 123.65 (2x),
121.96.
found 361.0328; H NMR (500 MHz, CDCl3): δ 8.58 (d, J =
8.5 Hz, 2H), 8.15-8.12 (m, 2H), 7.92-7.87 (m, 3H), 7.65 (d, J
= 8.5 Hz, 2H), 7.62-7.59 (m, 3H), 7.58-7.55 (m, 1H); 13C
NMR (125 MHz, CDCl3): δ 168.42, 159.28, 151.90, 137.50,
137.14, 133.69, 131.66 (2x), 130.24 (2x), 130.14 (2x), 130.01,
129.12, 128.56 (2x), 127.22, 127.06, 125.27, 121.74.
4-Phenyl-2-(2-(trifluoromethyl)phenyl)quinazoline
(3p).
2-(2,4-Difluorophenyl)-4-phenylquinazoline (3k). Yield =
85% (270 mg); Colorless solid; mp = 109-110 C; HRMS
o
Yield = 87% (305 mg); White solid; mp = 113-114 oC; HRMS
(ESI, M++H) calcd for C21H14F3N2 351.1104, found 351.1094;
1H NMR (500 MHz, CDCl3): δ 8.21 (d, J = 8.5 Hz, 1H), 8.19
(d, J = 8.5 Hz, 1H), 7.97-7.92 (m, 2H), 7.90-7.86 (m, 2H),
7.85 (d, J = 8.0 Hz, 1H), 7.70-7.62 (m, 2H), 7.61-7.54 (m,
4H); 13C NMR (125 MHz, CDCl3): δ 168.18, 161.75, 151.40,
139.02, 137.04, 133.91, 131.63, 130.15 (2x), 130.06, 129.10,
128.98, 128.82 (q, J = 30.4125 Hz), 128.76, 128.59 (2x),
127.83, 127.08, 126.82 (q, J = 5.0 Hz), 124.21 (q, J =
272.1875 Hz), 121.33.
(ESI, M++H) calcd for C20H13F2N2 319.1041, found 319.1037;
1H NMR (500 MHz, CDCl3): δ 8.28 (ddd, J = 6.5, 8.5, 15.5
Hz, 1H), 8.18-8.15 (m, 2H), 7.92 (t, J = 7.0 Hz, 1H), 7.87-7.86
(m, 2H), 7.62-7.58 (m, 4H), 7.05-6.96 (m, 2H); 13C NMR
(125 MHz, CDCl3): δ 168.50, 162.88 (t, J = 11.125 Hz),
162.85 (dd, J = 11.875, 518.0 Hz), 158.28 (d, J = 4.875 Hz),
151.73, 137.23, 133.81, 133.46 (dd, J = 3.0, 9.75 Hz), 130.14
(2x), 130.06, 129.12, 128.61 (2x), 127.64, 127.00, 123.72 (dd,
J = 3.625, 9.75 Hz), 121.33, 111.46 (dd, J = 3.625, 9.75 Hz),
105.02 (t, J = 25.5 Hz).
4-Phenyl-2-(4-(trifluoromethyl)phenyl)quinazoline (3q).30b
Yield = 92% (322 mg); White solid; mp = 120-121 oC
(literature: 123-124 oC); HRMS (ESI, M++H) calcd for
2-(2,6-Difluorophenyl)-4-phenylquinazoline (3l). Yield =
o
86% (273 mg); Colorless solid; mp = 117-118 C; HRMS
1
C21H14F3N2 351.1104, found 351.1096; H NMR (500 MHz,
(ESI, M++H) calcd for C20H13F2N2 319.1041, found 319.1042;
1H NMR (500 MHz, CDCl3): δ 8.20 (d, J = 9.5 Hz, 2H), 7.98-
7.94 (m, 1H), 7.87-7.82 (m, 2H), 7.69-7.65 (m, 1H), 7.61-7.55
(m, 3H), 7.43-7.37 (m, 1H), 7.08-7.01 (m, 2H); 13C NMR
(125 MHz, CDCl3): δ 168.85, 160.95 (d, J = 250.0 Hz), 161.90
(d, J = 250.0 Hz), 155.34, 151.51, 136.94, 133.96, 130.58 (t, J
= 10.275 Hz), 130.13 (2x), 130.07, 129.11, 128.66 (2x),
128.17, 127.12, 121.70, 111.87 (d, J = 25.25 Hz, 2x), 111.87
(d, J = 14.625 Hz). Single-crystal X-ray diagram: crystal of
3l was grown by slow diffusion of EtOAc into a solution of 3l
in CH Cl to yield colorless prisms. The compound
CDCl3): δ 8.82 (d, J = 8.0 Hz, 2H), 8.17 (t, J = 8.4 Hz, 2H),
7.95-7.87 (m, 3H), 7.74 (d, J = 8.0 Hz, 2H), 7.65-7.58 (m,
4H); 13C NMR (125 MHz, CDCl3): δ 168.57, 158.81, 151.88,
141.51, 137.41, 133.80, 132.00 (q, J = 32.0 Hz), 130.16 (2x),
131.00, 129.28, 128.90 (2x), 128.61 (2x), 127.60, 127.09,
125.40 (q, J = 3.625 Hz, 2x), 123.16, 121.93.
4-Phenyl-2-(o-tolyl)quinazoline (3r).39 Yield = 81% (240
mg); White solid; mp = 74-75 oC (literature: 73-75 oC);
HRMS (ESI, M++H) calcd for C21H17N2 297.1386, found
297.1378; 1H NMR (500 MHz, CDCl3): δ 8.17 (d, J = 8.5 Hz,
2H), 8.01-7.97 (m, 1H), 7.92 (t, J = 8.0 Hz, 1H), 7.88-7.84 (m,
2H), 7.62-7.56 (m, 4H), 7.38-7.31 (m, 3H), 2.68 (s, 3H); 13C
NMR (125 MHz, CDCl3): δ 168.01, 163.38, 151.67, 138.81,
137.50, 137.39, 133.55, 131.23, 130.71, 130.12 (2x), 129.87,
129.19, 129.10, 128.53 (2x), 127.25, 126.95, 125.94, 121.01,
21.23.
2
2
crystallizes in the triclinic crystal system, space group P -1, a
= 7.8602(2) Å, b = 8.9830(2) Å, c = 11.3189(3) Å, V =
736.11(3) Å3, Z = 2, d
= 1.436 Mg/m3, F(000) = 328, 2θ
calcd
range 1.919-27.100o, R indices (all data) R1 = 0.0391, wR2 =
0.0874. CCDC number is 1994079.

Page 7 of 12
Organic & Biomolecular Chemistry
4-Phenyl-2-(m-tolyl)quinazoline (3s).25b Yield = 90% (266
View Article Online
DOI: 10.1039/D0OB01507E
for C22H19N2O2 343.1441, found 343.1434; 1H NMR (500
MHz, CDCl3): δ 8.15 (d, J = 8.5 Hz, 1H), 8.10 (d, J = 8.5 Hz,
1H), 7.94 (d, J = 8.5 Hz, 1H), 7.88-7.83 (m, 3H), 7.57-7.51
(m, 3H), 6.65-6.61 (m, 3H), 3.91 (s, 3H), 3.86 (s, 3H); 13C
NMR (125 MHz, CDCl3): δ 167.90, 161.98, 161.27, 159.28,
151.64, 137.56, 133.28, 133.08, 130.05 (2x), 129.64, 128.92,
128.40 (2x), 126.82, 126.78, 122.08, 120.92, 104.90, 99.47,
55.99, 55.38.
o
o
mg); White solid; mp = 116-117 C (literature: 113-114 C);
HRMS (ESI, M++H) calcd for C21H17N2 297.1386, found
1
297.1378; H NMR (500 MHz, CDCl3): δ 8.52-8.48 (m, 2H),
8.16 (d, J = 8.0 Hz, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.97-7.87
(m, 3H), 7.63-7.58 (m, 3H), 7.55 (t, J = 7.5 Hz, 1H), 7.42 (t, J
= 7.5 Hz, 1H), 7.32 (d, J = 7.5 Hz, 1H), 2.49 (s, 3H); 13C
NMR (125 MHz, CDCl3): δ 168.30, 160.42, 151.98, 138.13,
137.70, 133.50, 131.32, 130.19 (2x), 129.89, 129.15, 129.14,
129.13, 128.52 (2x), 128.45, 127.01, 126.92, 125.90, 121.68,
21.55.
2-(2,5-Dimethoxyphenyl)-4-phenylquinazoline (3y). Yield
= 84% (287 mg); White solid; mp = 102-103 oC; HRMS (ESI,
M++H) calcd for C22H19N2O2 343.1441, found 343.1435; H
1
4-Phenyl-2-(p-tolyl)quinazoline (3t).30b Yield = 87% (258
NMR (500 MHz, CDCl3): δ 8.19 (d, J = 8.5 Hz, 1H), 8.14 (d,
J = 8.5 Hz, 1H), 7.92-7.87 (m, 1H), 7.86-7.82 (m, 2H), 7.60-
7.53 (m, 4H), 7.45 (d, J = 3.0 Hz, 1H), 7.02-6.96 (m, 2H), 3.87
(s, 3H), 3.83 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 168.14,
161.32, 153.66, 152.15, 151.54, 137.40, 133.45, 130.09 (2x),
129.98, 129.74, 129.04, 128.44 (2x), 127.25, 126.86, 121.23,
116.68, 116.20, 114.10, 56.98, 55.80.
o
o
mg); White solid; mp = 169-170 C (literature: 164-165 C);
HRMS (ESI, M++H) calcd for C21H17N2 297.1386, found
297.1384; 1H NMR (500 MHz, CDCl3): δ 8.61 (d, J = 8.5 Hz,
2H), 8.15 (d, J = 8.0 Hz, 1H), 8.11 (d, J = 8.0 Hz, 1H), 7.91-
7.85 (m, 3H), 7.63-7.58 (m, 3H), 7.54-7.51 (m, 1H), 7.35 (d, J
= 8.0 Hz, 2H), 2.46 (s, 3H); 13C NMR (125 MHz, CDCl3): δ
168.16, 160.29, 151.98, 140.66, 137.72, 135.47, 133.40,
130.15 (2x), 129.82, 129.25 (2x), 129.04, 128.60 (2x), 128.47
(2x), 126.95, 126.70, 121.56, 21.50.
2-(3,4-Dimethoxyphenyl)-4-phenylquinazoline (3z). Yield =
85% (291 mg); White solid; mp = 109-110 C; HRMS (ESI,
o
M++H) calcd for C22H19N2O2 343.1441, found 343.1433; H
1
2-(2-Methoxyphenyl)-4-phenylquinazoline (3u).27j Yield =
NMR (500 MHz, CDCl3): δ 8.34 (dd, J = 2.0, 8.5 Hz, 1H),
8.27 (d, J = 2.0 Hz, 1H), 8.14-8.07 (m, 2H), 7.90-7.84 (m,
3H), 7.62-7.57 (m, 3H), 7.52-7.48 (m, 1H), 7.00 (d, J = 8.5
Hz, 1H), 4.06 (s, 3H), 3.97 (s, 3H); 13C NMR (125 MHz,
CDCl3): δ 168.10, 159.89, 151.97, 151.28, 148.95, 137.72,
133.43, 131.09, 130.12 (2x), 129.80, 128.88, 128.46 (2x),
126.98, 126.55, 122.17, 121.40, 111.16, 110.72, 56.00, 55.92.
89% (278 mg); White solid; mp = 160-161 oC (literature: 160-
165 C); HRMS (ESI, M++H) calcd for C21H17N2O 313.1335,
o
1
found 313.1331; H NMR (500 MHz, CDCl3): δ 8.19 (d, J =
8.5 Hz, 1H), 8.13 (d, J = 8.5 Hz, 1H), 7.91-7.82 (m, 4H), 7.59-
7.52 (m, 4H), 7.45-7.41 (m, 1H), 7.10 (td, J = 1.0, 7.5 Hz,
1H), 7.06 (d, J = 8.0 Hz, 1H); 13C NMR (125 MHz, CDCl3): δ
168.08, 161.63, 157.73, 151.53, 137.43, 133.41, 131.65,
130.59, 130.06 (2x), 129.70, 129.23, 129.01, 128.44 (2x),
127.16, 126.84, 121.17, 120.68, 112.06.
2-(3,5-Dimethoxyphenyl)-4-phenylquinazoline (3aa). Yield
= 93% (318 mg); Colorless solid; mp = 150-151 C; HRMS
o
(ESI, M++H) calcd for C22H19N2O2 343.1441, found 343.1433;
1H NMR (500 MHz, CDCl3): δ 8.16 (d, J = 8.5 Hz, 1H), 8.13
(d, J = 8.0 Hz, 1H), 7.92-7.86 (m, 5H), 7.63-7.58 (m, 3H),
7.57-7.53 (m, 1H), 6.63 (t, J = 2.0 Hz, 1H), 3.93 (s, 6H); 13C
NMR (125 MHz, CDCl3): δ 168.16, 161.00 (2x), 159.83,
151.91, 140.37, 137.63, 133.49, 130.25 (2x), 129.91, 129.21,
128.49 (2x), 127.07, 126.98, 121.77, 106.48 (2x), 103.36,
55.58 (2x). Single-crystal X-ray diagram: crystal of 3aa was
grown by slow diffusion of EtOAc into a solution of 3aa in
CH2Cl2 to yield colorless prisms. The compound crystallizes
in the triclinic crystal system, space group P -1, a = 5.9542(2)
Å, b = 10.6468(4) Å, c = 13.6281(5) Å, V = 834.81(5) Å3, Z =
2, dcalcd = 1.362 Mg/m3, F(000) = 360, 2θ range 1.976-27.103,
R indices (all data) R1 = 0.0552, wR2 = 0.1237. CCDC
number is 1996086.
2-(3-Methoxyphenyl)-4-phenylquinazoline (3v). Yield =
o
85% (265 mg); White solid; mp = 129-130 C; HRMS (ESI,
M++H) calcd for C21H17N2O 313.1335, found 313.1327; H
1
NMR (500 MHz, CDCl3): δ 8.34 (d, J = 7.5 Hz, 1H), 8.30 (s,
1H), 8.17 (d, J = 8.0 Hz, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.93-
7.85 (m, 3H), 7.63-7.57 (m, 3H), 7.54 (t, J = 8.0 Hz, 1H), 7.46
(t, J = 8.0 Hz, 1H), 7.08 (dd, J = 2.0, 8.0 Hz, 1H), 3.96 (s, 3H);
13C NMR (125 MHz, CDCl3): δ 168.16, 159.94, 159.90,
151.90, 139.67, 137.60, 133.44, 130.16 (2x), 129.85, 129.46,
129.13, 128.45 (2x), 126.97, 126.92, 121.67, 121.26, 116.76,
113.35, 55.39.
2-(4-methoxyphenyl)-4-phenylquinazoline (3w).30b Yield =
o
89% (278 mg); Colorless solid; mp = 158-159 C (literature:
158-160 oC); HRMS (ESI, M++H) calcd for C21H17N2O
1
313.1335, found 313.1329; H NMR (500 MHz, CDCl3): δ
4-Phenyl-2-(3,4,5-trimethoxyphenyl)quinazoline
(3ab).
o
8.66 (d, J = 9.0 Hz, 2H), 8.10 (t, J = 8.5 Hz, 2H), 7.89-7.85
(m, 3H), 7.60-7.57 (m, 3H), 7.51 (t, J = 7.5 Hz, 1H), 7.04 (d, J
= 9.0 Hz, 2H), 3.90 (s, 3H); 13C NMR (125 MHz, CDCl3): δ
168.14, 161.73, 160.02, 152.04, 137.76, 133.42, 130.91,
130.28 (2x), 130.13 (2x), 129.81, 128.91, 128.47 (2x), 126.98,
126.49, 121.38, 113.83 (2x), 55.35. Single-crystal X-ray
diagram: crystal of 3w was grown by slow diffusion of
EtOAc into a solution of 3w in CH2Cl2 to yield colorless
prisms. The compound crystallizes in the orthorhombic crystal
system, space group P b c a, a = 14.6384(3) Å, b =
6.90900(10) Å, c = 30.7229(7) Å, V = 3107.21(11) Å3, Z = 8,
dcalcd = 1.335 Mg/m3, F(000) = 1312, 2θ range 2.877-65.073, R
indices (all data) R1 = 0.0433, wR2 = 0.0997. CCDC number
is 1988309.
Yield = 90% (335 mg); Colorless solid; mp = 200-201 C;
HRMS (ESI, M++H) calcd for C23H21N2O3 373.1547, found
373.1537; 1H NMR (500 MHz, CDCl3): δ 8.15 (d, J = 8.5 Hz,
1H), 8.11 (d, J = 8.5 Hz, 1H), 8.01 (s, 2H), 7.90-7.86 (m, 3H),
7.63-7.59 (m, 3H), 7.56-7.52 (m, 1H), 4.03 (s, 6H), 3.95 (s,
3H); 13C NMR (125 MHz, CDCl3): δ 168.18, 159.70, 153.29
(2x), 151.91, 140.40, 137.65, 133.67, 133.52, 130.14 (2x),
129.86, 129.02, 128.49 (2x), 127.01, 126.88, 121.53, 105.83
(2x), 60.92, 56.26 (2x). Single-crystal X-ray diagram: crystal
of 3ab was grown by slow diffusion of EtOAc into a solution
of 3ab in CH2Cl2 to yield colorless prisms. The compound
crystallizes in the orthorhombic crystal system, space group P
b c a, a = 14.2321(7) Å, b = 13.7476(6) Å, c = 19.4973(9) Å,
V = 3814.8(3) Å3, Z = 8, dcalcd = 1.297 Mg/m3, F(000) = 1568,
2θ range 2.309-27.103, R indices (all data) R1 = 0.0608, wR2
= 0.1031. CCDC number is 1996497.
2-(2,4-Dimethoxyphenyl)-4-phenylquinazoline (3x). Yield
= 86% (294 mg); Colorless gum; HRMS (ESI, M++H) calcd

Organic & Biomolecular Chemistry
Page 8 of 12
View Article Online
DOI: 10.1039/D0OB01507E
2-(4-(Benzyloxy)-3-methoxyphenyl)-4-phenylquinazoline
8.82 (dd, J = 1.5, 8.5 Hz, 1H), 8.21 (d, J = 8.5 Hz, 1H), 8.15
(d, J = 8.5 Hz, 1H), 8.08-8.03 (m, 1H), 7.99 (d, J = 8.5 Hz,
1H), 7.96-7.88 (m, 4H), 7.66-7.60 (m, 3H), 7.58-7.50 (m, 3H);
13C NMR (125 MHz, CDCl3): δ 168.39, 160.21, 152.04,
137.70, 135.57, 134.68, 133.60, 133.41, 130.22 (2x), 129.96,
129.28, 129.17, 128.98, 128.58 (2x), 128.14, 127.71, 127.08,
127.04, 126.96, 126.10, 125.58, 121.76.
o
(3ac). Yield = 88% (368 mg); White solid; mp = 137-138 C;
HRMS (ESI, M++H) calcd for C28H23N2O2 419.1754, found
1
419.1745; H NMR (500 MHz, CDCl3): δ 8.30-8.26 (m, 2H),
8.12 (d, J = 8.5 Hz, 1H), 8.09 (d, J = 8.5 Hz, 1H), 7.88-7.84
(m, 3H), 7.62-7.58 (m, 3H), 7.53-7.47 (m, 3H), 7.40-7.36 (m,
2H), 7.33-7.29 (m, 1H), 7.03 (d, J = 8.5 Hz, 1H), 5.26 (s, 2H),
4.07 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 168.10, 159.88,
151.97, 150.39, 149.56, 137.71, 136.87, 133.42, 131.50,
130.11 (2x), 129.80, 128.90, 128.52 (2x), 128.45 (2x), 127.83,
127.26 (2x), 126.98, 126.57, 122.04, 121.39, 113.32, 111.72,
70.80, 56.14.
4-Phenyl-2-(thiophen-2-yl)quinazoline (3ai).30b Yield
=
o
83% (239 mg); Colorless solid; mp = 147-148 C (literature:
146-147 oC); HRMS (ESI, M++H) calcd for C28H13N2S
1
289.0794, found 289.0794; H NMR (500 MHz, CDCl3): δ
8.21 (d, J = 3.0 Hz, 1H), 8.08 (d, J = 8.5 Hz, 2H), 7.90-7.83
(m, 3H), 7.62-7.56 (m, 3H), 7.53-7.48 (m, 2H), 7.19 (t, J = 5.0
Hz, 1H); 13C NMR (125 MHz, CDCl3): δ 168.38, 157.21,
151.83, 144.16, 137.25, 133.69, 130.16 (2x), 129.99, 129.78,
129.29, 128.69, 128.50 (2x), 128.20, 127.12, 126.69, 121.50.
2-(3-(Benzyloxy)-4-methoxyphenyl)-4-phenylquinazoline
o
(3ad). Yield = 86% (359 mg); White solid; mp = 165-166 C;
HRMS (ESI, M++H) calcd for C28H23N2O2 419.1754, found
1
419.1747; H NMR (500 MHz, CDCl3): δ 8.39-8.33 (m, 2H),
8.10 (t, J = 8.5 Hz, 2H), 7.90-7.83 (m, 3H), 7.64-7.59 (m, 3H),
7.56 (d, J = 7.5 Hz, 2H), 7.50 (t, J = 8.0 Hz, 1H), 7.40 (t, J =
7.5 Hz, 2H), 7.32 (t, J = 7.5 Hz, 1H), 7.03 (d, J = 8.5 Hz, 1H),
5.32 (s, 2H), 3.97 (s, 3H); 13C NMR (125 MHz, CDCl3): δ
168.06, 159.87, 152.07, 151.98, 148.22, 137.80, 137.27,
133.46, 131.07, 130.24 (2x), 129.89, 128.98, 128.54 (2x),
128.51 (2x), 127.89, 127.76 (2x), 127.02, 126.59, 122.55,
121.43, 113.94, 111.32, 71.12, 56.07.
2-(Furan-2-yl)-4-phenylquinazoline (3aj).22b Yield = 84%
o
(228 mg); Colorless solid; mp = 174-175 C (literature: 167-
o
168 C); HRMS (ESI, M++H) calcd for C18H13N2O 273.1022,
1
found 273.1020; H NMR (500 MHz, CDCl3): δ 8.15 (d, J =
8.5 Hz, 1H), 8.04 (d, J = 8.5 Hz, 1H), 7.88-7.79 (m, 3H), 7.69
(s, 1H), 7.58-7.53 (m, 3H), 7.52-7.47 (m, 2H), 6.60-6.57 (m,
1H); 13C NMR (125 MHz, CDCl3): δ 168.73, 153.46, 152.72,
151.48, 145.16, 137.12, 133.80, 129.98 (2x), 129.93, 128.82,
128.46 (2x), 127.07, 126.90, 121.50, 114.13, 112.11.
2-(Benzo[d][1,3]dioxol-5-yl)-4-phenylquinazoline (3ae).40
Yield = 88% (287 mg); White solid; mp = 155-156 oC
(literature: 169-170 oC); HRMS (ESI, M++H) calcd for
4-Phenyl-2-(pyridin-2-yl)quinazoline (3ak).35 Yield = 90%
o
(255 mg); Colorless solid; mp = 179-180 C (literature: 178-
1
C21H15N2O2 327.1128, found 327.1119; H NMR (500 MHz,
o
179 C); HRMS (ESI, M++H) calcd for C19H14N3 284.1182,
CDCl3): δ 8.32 (d, J = 8.5 Hz, 1H), 8.21 (s, 1H), 8.10 (d, J =
8.5 Hz, 1H), 8.09 (d, J = 8.5 Hz, 1H), 7.90-7.82 (m, 3H), 7.62-
7.57 (m, 3H), 7.50 (t, J = 8.0 Hz, 1H), 6.95 (d, J = 8.0 Hz,
1H), 6.04 (s, 2H); 13C NMR (125 MHz, CDCl3): δ 168.05,
159.63, 151.93, 149.74, 148.03, 137.64, 133.44, 132.65,
130.11 (2x), 129.83, 128.91, 128.45 (2x), 126.94, 126.60,
123.55, 121.41, 108.77, 108.18, 101.34.
1
found 284.1180; H NMR (500 MHz, CDCl3): δ 8.91 (d, J =
5.0 Hz, 1H), 8.75 (d, J = 8.0 Hz, 1H), 8.36 (d, J = 8.5 Hz, 1H),
8.14 (d, J = 8.0 Hz, 1H), 7.94-7.84 (m, 4H), 7.62-7.55 (m,
4H), 7.42-7.37 (m, 1H); 13C NMR (125 MHz, CDCl3): δ
168.79, 159.08, 155.35, 151.97, 150.23, 137.36, 136.85,
133.72, 130.13 (2x), 129.94, 129.86, 128.50 (2x), 127.79,
126.92, 124.58, 124.32, 122.17.
2-([1,1'-Biphenyl]-4-yl)-4-phenylquinazoline (3af). Yield =
83% (297 mg); Colorless solid; mp = 155-156 C; HRMS
4-Phenyl-2-(pyridin-3-yl)quinazoline (3al).30b Yield = 88%
o
o
(249 mg); White solid; mp = 158-159 C (literature: 143-144
(ESI, M++H) calcd for C26H19N2 359.1543, found 359.1533;
1H NMR (500 MHz, CDCl3): δ 8.81 (d, J = 8.0 Hz, 2H), 8.19
(d, J = 8.0 Hz, 1H), 8.14 (d, J = 8.0 Hz, 1H), 7.95-7.87 (m,
3H), 7.80 (d, J = 8.0 Hz, 2H), 7.72 (d, J = 8.0 Hz, 2H), 7.66-
7.60 (m, 3H), 7.55 (t, J = 7.5 Hz, 1H), 7.50 (t, J = 7.5 Hz, 2H),
7.40 (t, J = 7.0 Hz, 1H); 13C NMR (125 MHz, CDCl3): δ
168.24, 159.93, 151.98, 143.06, 140.66, 137.64, 137.15,
133.49, 130.15 (2x), 129.87, 129.10 (3x), 128.77 (2x), 128.49
(2x), 127.56, 127.18 (2x), 127.14 (2x), 126.98, 126.92,
121.64.
oC); HRMS (ESI, M++H) calcd for C19H14N3 284.1182, found
1
284.1180; H NMR (500 MHz, CDCl3): δ 9.88 (s, 1H), 8.93
(d, J = 8.0 Hz, 1H), 8.73 (d, J = 5.0 Hz, 1H), 8.15 (t, J = 7.5
Hz, 2H), 7.94-7.86 (m, 3H), 7.64-7.55 (m, 4H), 7.44 (dd, J =
5.0, 7.5 Hz, 1H); 13C NMR (125 MHz, CDCl3): δ 168.54,
158.37, 151.83, 151.11, 150.34, 137.30, 135.82, 133.79,
133.66, 130.15 (2x), 130.10, 129.15, 128.57 (2x), 127.49,
127.07, 123.28, 121.87.
4-Phenyl-2-(pyridin-4-yl)quinazoline (3am). Yield = 92%
(260 mg); White solid; mp = 162-163 oC; HRMS (ESI,
M++H) calcd for C19H14N3 284.1182, found 284.1175; 1H
NMR (500 MHz, CDCl3): δ 8.79 (d, J = 6.0 Hz, 2H), 8.52 (d,
J = 6.0 Hz, 2H), 8.17 (t, J = 9.0 Hz, 2H), 7.92 (t, J = 7.5 Hz,
1H), 7.89-7.85 (m, 2H), 7.63-7.58 (m, 4H); 13C NMR (125
MHz, CDCl3): δ 168.65, 158.06, 151.74, 150.37 (2x), 145.43,
137.19, 133.85, 130.13 (3x), 129.34, 128.58 (2x), 127.97,
127.05, 122.36 (2x), 122.19.
2-(Naphthalen-1-yl)-4-phenylquinazoline (3ag).22b Yield =
82% (272 mg); White solid; mp = 124-125 oC (literature: 171-
o
173 C); HRMS (ESI, M++H) calcd for C24H17N2 333.1386,
1
found 333.1379; H NMR (500 MHz, CDCl3): δ 8.84 (d, J =
8.5 Hz, 1H), 8.29 (d, J = 7.5 Hz, 1H), 8.26 (d, J = 8.5 Hz, 1H),
8.22 (d, J = 8.5 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 7.98-7.90
(m, 4H), 7.67-7.52 (m, 7H); 13C NMR (125 MHz, CDCl3): δ
168.41, 162.72, 151.68, 137.39, 136.49, 134.17, 133.71,
131.31, 130.20, 130.10 (2x), 129.90, 129.64, 129.11, 128.55
(2x), 128.40, 127.42, 127.00, 126.68, 126.05, 125.75, 125.27,
121.21.
4-Phenyl-2-(quinolin-2-yl)quinazoline (3an).35 Yield = 81%
o
(270 mg); White solid; mp = 171-172 C (literature: 157-158
oC); HRMS (ESI, M++H) calcd for C23H16N3 334.1339, found
334.1333; 1H NMR (500 MHz, CDCl3): δ 8.88 (d, J = 8.5 Hz,
1H), 8.46 (d, J = 9.0 Hz, 1H), 8.43 (d, J = 8.5 Hz, 1H), 8.36
(d, J = 8.5 Hz, 1H), 8.20 (d, J = 8.5 Hz, 1H), 7.99-7.93 (m,
3H), 7.89 (d, J = 8.0 Hz, 1H), 7.80-7.75 (m, 1H), 7.67-7.58
(m, 5H); 13C NMR (125 MHz, CDCl3): δ 168.96, 159.32,
2-(Naphthalen-2-yl)-4-phenylquinazoline (3ah).25b Yield =
85% (282 mg); White solid; mp = 172-173 oC (literature: 172-
o
173 C); HRMS (ESI, M++H) calcd for C24H17N2 333.1386,
found 333.1384; 1H NMR (500 MHz, CDCl3): δ 9.25 (s, 1H),

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Organic & Biomolecular Chemistry
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155.50, 152.15, 148.40, 137.43, 136.96, 133.75, 131.04,
130.34 (2x), 130.19, 130.10, 129.52, 128.59 (2x), 128.56,
128.07, 127.40, 127.37, 127.00, 122.28, 121.58.
4-(4-Bromophenyl)-2-phenylquinazoline (4g).25b
DOI: 10.1039/D0OYB0i1e5ld07E=
94% (338 mg); White solid; mp = 159-160 oC (literature: 152-
153 oC); HRMS (ESI, M++H) calcd for C20H14BrN2 361.0335,
1
found 361.0333; H NMR (500 MHz, CDCl3): δ 8.68 (d, J =
6-Chloro-2,4-diphenylquinazoline (4a).25b Yield = 90%
o
7.5 Hz, 2H), 8.16 (d, J = 8.5 Hz, 1H), 8.06 (d, J = 8.5 Hz, 1H),
7.89 (t, J = 7.5 Hz, 1H), 7.77 (d, J = 8.5 Hz, 2H), 7.74 (d, J =
8.5 Hz, 2H), 7.58-7.49 (m, 4H); 13C NMR (125 MHz, CDCl3):
δ 167.06, 160.20, 152.04, 137.99, 136.53, 133.67, 131.77 (2x),
131.71 (2x), 130.59, 129.30, 128.61 (2x), 128.53 (2x), 127.18,
126.49, 124.59, 121.40.
(284 mg); White solid; mp = 194-195 C (literature: 193-195
oC); HRMS (ESI, M++H) calcd for C20H14ClN2 317.0840,
found 317.0840; 1H NMR (500 MHz, CDCl3): δ 8.68 (dd, J =
1.5, 8.0 Hz, 2H), 8.11-8.09 (m, 2H), 7.88-7.86 (m, 2H), 7.81
(dd, J = 1.5, 9.0 Hz, 1H), 7.64-7.62 (m, 3H), 7.56-7.51 (m,
3H); 13C NMR (125 MHz, CDCl3): δ 167.51, 160.45, 150.49,
137.77, 137.11, 134.45, 132.57, 130.86, 130.73, 130.18,
130.03 (2x), 128.71 (2x), 128.66 (2x), 128.55 (2x), 125.75,
122.17.
4-(4-Fluorophenyl)-2-phenylquinazoline (4h).25b Yield =
o
82% (246 mg); Colorless solid; mp = 140-141 C (literature:
132-134 oC); HRMS (ESI, M++H) calcd for C20H14FN2
1
301.1136, found 301.1132; H NMR (500 MHz, CDCl3): δ
6-Bromo-2,4-diphenylquinazoline (4b).25b Yield = 88%
o
8.69 (d, J = 8.5 Hz, 2H), 8.16 (d, J = 8.5 Hz, 1H), 8.09 (d, J =
8.5 Hz, 1H), 7.94-7.87 (m, 3H), 7.59-7.48 (m, 4H), 7.30 (t, J =
8.5 Hz, 2H); 13C NMR (125 MHz, CDCl3): δ 167.33, 163.95
(d, J = 248.75 Hz), 160.19, 152.06, 138.08, 133.77 (d, J =
3.125 Hz), 133.62, 132.18 (d, J = 8.375 Hz, 2x), 130.56,
129.28, 128.62 (2x), 128.54 (2x), 127.13, 126.68, 121.55,
115.67 (d, J = 21.625 Hz, 2x). Single-crystal X-ray diagram:
crystal of 4h was grown by slow diffusion of EtOAc into a
solution of 4h in CH2Cl2 to yield colorless prisms. The
compound crystallizes in the triclinic crystal system, space
group P -1, a = 6.0455(5) Å, b = 11.0023(10) Å, c =
11.7294(10) Å, V = 714.87(11) Å3, Z = 2, dcalcd = 1.395
Mg/m3, F(000) = 312, 2θ range 2.009-27.096, R indices (all
data) R1 = 0.0783, wR2 = 0.1408. CCDC number is 2002377.
(317 mg); White solid; mp = 205-206 C (literature: 204-205
oC); HRMS (ESI, M++H) calcd for C20H14BrN2 361.0335,
found 361.0328; 1H NMR (500 MHz, CDCl3): δ 8.69-8.67 (m,
2H), 8.26 (d, J = 2.0 Hz, 1H), 8.02 (d, J = 8.5 Hz, 1H), 7.94
(dd, J = 2.0, 8.5 Hz, 1H), 7.90-7.84 (m, 2H), 7.65-7.59 (m,
3H), 7.56-7.50 (m, 3H); 13C NMR (125 MHz, CDCl3): δ
167.40, 160.48, 150.69, 137.77, 137.08, 137.00, 130.94,
130.76, 130.20, 130.04 (2x), 129.07, 128.73 (2x), 128.68 (2x),
128.56 (2x), 122.66, 120.61.
6-Nitro-2,4-diphenylquinazoline (4c).41 Yield = 93% (304
o
o
mg); White solid; mp = 246-247 C (literature: 245-247 C);
HRMS (ESI, M++H) calcd for C20H14N3O2 328.1081, found
328.1085; 1H NMR (500 MHz, CDCl3): δ 9.06 (d, J = 2.5 Hz,
1H), 8.77-8.71 (m, 2H), 8.64 (dd, J = 2.5, 9.0 Hz, 1H), 8.26 (d,
J = 9.0 Hz, 1H), 7.94-7.89 (m, 2H), 7.70-7.65 (m, 3H), 7.59-
7.54 (m, 3H); 13C NMR (125 MHz, CDCl3): δ 170.45, 162.87,
154.50, 145.42, 137.10, 136.38, 131.71, 131.02, 130.95,
130.23 (2x), 129.21 (2x), 129.06 (2x), 128.73 (2x), 126.95,
124.25, 120.46.
2-Phenyl-4-(p-tolyl)quinazoline (4i).25b Yield = 84% (249
o
mg); Colorless solid; mp = 101-102 C (literature: 126-127
oC); HRMS (ESI, M++H) calcd for C21H17N2 297.1386, found
1
297.1385; H NMR (500 MHz, CDCl3): δ 8.73-8.68 (m, 2H),
8.19-8.12 (m, 2H), 8.91-8.86 (m, 1H), 7.81 (d, J = 8.0 Hz,
2H), 7.58-7.47 (m, 4H), 7.41 (d, J = 8.0 Hz, 2H), 2.51 (s, 3H);
13C NMR (125 MHz, CDCl3): δ 168.28, 160.21, 151.98,
140.14, 138.27, 134.88, 133.40, 130.41, 130.17 (2x), 129.23
(2x), 129.12, 128.64 (2x), 128.48 (2x), 127.07, 126.85,
121.71, 21.45.
6-Methyl-2,4-diphenylquinazoline (4d).25b Yield = 88%
o
(260 mg); Colorless solid; mp = 173-174 C (literature: 173-
o
176 C); HRMS (ESI, M++H) calcd for C21H17N2 297.1386,
found 297.1385; 1H NMR (500 MHz, CDCl3): δ 8.70-8.65 (m,
2H), 8.06 (d, J = 8.5 Hz, 1H), 7.91-7.85 (m, 3H), 7.72 (dd, J =
2.0, 8.5 Hz, 1H), 7.64-7.57 (m, 3H), 7.55-7.46 (m, 3H), 2.52
(s, 3H); 13C NMR (125 MHz, CDCl3): δ 167.52, 159.60,
150.56, 138.33, 137.89, 137.12, 135.74, 130.26, 130.10 (2x),
129.73, 128.86, 128.49 (6x), 125.59, 121.63, 21.86.
4-(4-Methoxyphenyl)-2-phenylquinazoline (4j).25b Yield =
o
85% (265 mg); Colorless solid; mp = 105-106 C (literature:
120-121 oC); HRMS (ESI, M++H) calcd for C21H17N2O
1
313.1335, found 313.1338; H NMR (500 MHz, CDCl3): δ
8.72 (d, J = 7.5 Hz, 2H), 8.17 (d, J = 9.0 Hz, 1H), 8.14 (d, J =
8.5 Hz, 1H), 7.90 (d, J = 9.0 Hz, 2H), 7.88-7.84 (m, 1H), 7.57-
7.49 (m, 4H), 7.12 (d, J = 8.5 Hz, 2H), 3.92 (s, 3H); 13C NMR
(125 MHz, CDCl3): δ 167.62, 161.18, 160.08, 152.02, 138.28,
133.29, 131.81 (2x), 130.37, 130.12, 129.08, 128.59 (2x),
128.44 (2x), 126.98, 126.77, 121.57, 113.96 (2x), 55.40.
6,7-Dimethoxy-2,4-diphenylquinazoline (4e).25b Yield =
86% (294 mg); White solid; mp = 176-177 oC (literature: 176-
178 oC); HRMS (ESI, M++H) calcd for C22H19N2O2 343.1441,
1
found 343.1431; H NMR (500 MHz, CDCl3): δ 8.63 (d, J =
8.0 Hz, 2H), 7.89 (d, J = 7.5 Hz, 2H), 7.63-7.55 (m, 3H), 7.54-
7.45 (m, 4H), 7.36 (s, 1H), 4.11 (s, 3H), 3.92 (s, 3H); 13C
NMR (125 MHz, CDCl3): δ 165.16, 159.37, 155.66, 149.98,
149.92, 138.51, 138.23, 130.01, 129.77 (2x), 129.62, 128.59
(2x), 128.44 (2x), 128.24 (2x), 117.12, 107.40, 104.14, 56.41,
56.07.
6-Chloro-4-(2-chlorophenyl)-2-phenylquinazoline (4k).30a
Yield = 89% (312 mg); White solid; mp = 178-179 oC
(literature: 172-173 oC); HRMS (ESI, M++H) calcd for
1
C20H13Cl2N2 351.0450, found 351.0442; H NMR (500 MHz,
CDCl3): δ 8.67-8.61 (m, 2H), 8.11 (d, J = 9.0 Hz, 1H), 7.82
(dd, J = 2.0, 9.0 Hz, 1H), 7.65-7.57 (m, 2H), 7.56-7.47 (m,
6H); 13C NMR (125 MHz, CDCl3): δ 166.38, 160.70, 149.90,
137.66, 135.94, 134.87, 132.89, 132.79, 131.07, 130.84,
130.82, 130.79, 130.17, 128.76 (2x), 128.62 (2x), 127.05,
125.57, 122.82.
4-(4-Chlorophenyl)-2-phenylquinazoline (4f).25b Yield =
84% (265 mg); White solid; mp = 154-155 oC (literature: 143-
145 oC); HRMS (ESI, M++H) calcd for C20H14ClN2 317.0840,
found 317.0831; 1H NMR (500 MHz, CDCl3): δ 8.72-8.64 (m,
2H), 8.16 (d, J = 8.5 Hz, 1H), 8.07 (d, J = 8.5 Hz, 1H), 7.89 (t,
J = 8.0 Hz, 1H), 7.84 (d, J = 8.5 Hz, 2H), 7.58 (d, J = 8.5 Hz,
2H), 7.56-7.49 (m, 4H); 13C NMR (125 MHz, CDCl3): δ
167.00, 160.19, 152.03, 138.00, 136.25, 136.06, 133.66,
131.48 (2x), 130.58, 129.29, 128.81 (2x), 128.60 (2x), 128.53
(2x) , 127.17, 126.51, 121.44.
6,7-Dimethoxy-2-phenyl-4-(p-tolyl)quinazoline (4l). Yield
= 82% (292 mg); White solid; mp = 168-169 oC; HRMS (ESI,
1
M++H) calcd for C23H21N2O2 357.1598, found 357.1591; H
NMR (500 MHz, CDCl3): δ 8.64 (d, J = 8.0 Hz, 2H), 7.79 (d,

Organic & Biomolecular Chemistry
Page 10 of 12
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DOI: 10.1039/D0OB01507E
J = 7.5 Hz, 2H), 7.55-7.41 (m, 4H), 7.40-7.36 (m, 3H), 4.08 (s,
3H), 3.90 (s, 3H), 2.48 (s, 3H); 13C NMR (125 MHz, CDCl3):
δ 165.06, 159.21, 155.45, 149.77, 139.67, 138.50, 135.32,
129.88, 129.68 (2x), 129.22 (2x), 128.34 (2x), 128.16 (2x),
117.02, 107.02, 107.29, 104.17, 56.29, 55.96, 21.37.
8.16 (d, J = 2.0, 8.5 Hz, 1H), 7.98-7.92 (m, 2H), 7.67-7.60 (m,
5H), 7.58-7.51 (m, 3H), 7.48 (t, J = 7.5 Hz, 2H), 7.40 (t, J =
7.5 Hz, 1H); 13C NMR (125 MHz, CDCl3): δ 168.36, 160.13,
151.37, 139.98, 139.82, 138.16, 137.69, 133.19, 130.49,
130.18 (2x), 129.95, 129.60, 129.02 (2x), 128.64 (2x), 128.62
(2x), 128.52 (2x), 127.92, 127.36 (2x), 124.52, 121.85.
4-(3,4-Dimethoxyphenyl)-6,7-dimethoxy-2-
phenylquinazoline (4m). Yield = 87% (350 mg); White solid;
6-(4-methoxyphenyl)-2,4-diphenylquinazoline
(7).
o
mp = 183-184 C; HRMS (ESI, M++H) calcd for C24H23N2O4
PdCl2(PPh3)2 (49 mg, 0.07 mmol) and CuI (26.5 mg, 0.14
mmol) dissolved in triethylamine (5 mL) and toluene (10 mL)
at rt for 30 minutes. Then 6-bromo-2,4-diphenylquinazoline
4b (1.0 mmol) dissolved in triethylamine (3 mL) and
phenylacetylene (1.2 mmol) were added to the solution
directly. The reaction mixture was stirred at reflux for 6 h and
cooled to rt, and the solvent was concentrated. The residue
was diluted with water (10 mL), and the mixture was extracted
with EtOAc (3 × 20 mL). The combined organic layers were
washed with brine, dried, filtered, and evaporated to afford
crude product. Purification on silica gel (hexanes/EtOAc =
15/1−10/1) afforded compounds 7. Yield = 88% (336 mg);
White solid; mp = 191-192 oC; HRMS (ESI, M++H) calcd for
1
403.1652, found 403.1643; H NMR (500 MHz, CDCl3): δ
8.62 (d, J = 8.5 Hz, 2H), 7.53-7.40 (m, 7H), 7.06 (d, J = 8.0
Hz, 1H), 4.09 (s, 3H), 3.99 (s, 3H), 3.98 (s, 3H), 3.92 (s, 3H);
13C NMR (125 MHz, CDCl3): δ 164.66, 159.21, 155.51,
150.39, 149.91, 149.83, 149.11, 138.48, 130.81, 129.97,
128.40 (2x), 128.17 (2x), 122.78, 116.98, 112.92, 110.87,
107.97, 104.25, 56.36, 56.07, 56.03, 56.01.
6,7-Dimethoxy-2-phenyl-4-(3,4,5-
trimethoxyphenyl)quinazoline (4n). Yield = 83% (359 mg);
White solid; mp = 196-197 oC; HRMS (ESI, M++H) calcd for
1
C25H25N2O5 433.1758, found 433.1752; H NMR (500 MHz,
CDCl3): δ 8.62 (d, J = 7.0 Hz, 2H), 7.54-7.47 (m, 3H), 7.46 (s,
1H), 7.42 (s, 1H), 7.11 (s, 2H), 4.11 (s, 3H), 3.97 (s, 3H), 3.95
(s, 6H), 3.94 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 164.87,
159.27, 155.70, 153.39 (2x), 149.98, 149.95, 139.35, 138.37,
133.54, 130.09, 128.45 (2x), 128.23 (2x), 116.97, 107.42,
107.10 (2x), 104.13, 60.98, 56.44, 56.35 (2x), 56.13.
1
C28H19N2 383.1543, found 383.1533; H NMR (500 MHz,
CDCl3): δ 8.71 (d, J = 8.0 Hz, 2H), 8.29 (s, 1H), 8.12 (d, J =
8.5 Hz, 1H), 7.98 (dd, J = 2.0, 8.5 Hz, 1H), 7.94-7.89 (m, 2H),
7.67-7.59 (m, 3H), 7.58-7.50 (m, 5H), 7.41-7.34 (m, 3H); 13C
NMR (125 MHz, CDCl3): δ 167.96, 160.63, 151.48, 137.94,
137.39, 136.20, 131.69 (2x), 130.72, 130.19 (2x), 130.09 (2x),
129.32, 128.72 (3x), 128.68 (2x), 128.55 (2x), 128.43 (2x),
122.67, 122.09, 121.53, 91.30, 88.83.
6-Chloro-2-(4-fluorophenyl)-4-phenylquinazoline (5a).25b
Yield = 90% (1500 mg); White solid; mp = 189-190 oC;
HRMS (ESI, M++H) calcd for C20H13ClFN2 335.0746, found
1
335.0736; H NMR (500 MHz, CDCl3): δ 8.68 (dd, J = 2.5,
9.0 Hz, 2H), 8.08 (d, J = 2.5 Hz, 1H), 8.06 (d, J = 9.0 Hz, 1H),
7.86-7.84 (m, 2H), 7.81 (dd, J = 2.5, 9.0 Hz, 1H), 7.63-7.62
(m, 3H), 7.19 (t, J = 9.0 Hz, 2H); 13C NMR (125 MHz,
CDCl3): δ 167.58, 164.76 (d, J = 249.25 Hz), 159.50, 150.44,
136.99, 134.57, 133.94 (d, J = 2.625 Hz), 132.61, 130.74 (2x),
130.54 (d, J = 68.5 Hz, 2x), 129.99 (2x), 128.75 (2x), 125.79,
122.05, 115.50 (d, J = 21.375 Hz, 2x).
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1039/xxxxxxxxxx.
Detailed experimental procedures and spectroscopic data for all
compounds and X-ray analysis data for 3c, 3l, 3w, 3aa, 3ab and
4h (PDF)
6-Chloro-4-phenyl-2-(p-tolyl)quinazoline (5b).25b Yield =
91% (1500 mg); White solid; mp = 203-204 oC; HRMS (ESI,
1
M++H) calcd for C21H16ClN2 331.0997, found 331.0993; H
Accession Codes
NMR (500 MHz, CDCl3): δ 8.57 (d, J = 8.5 Hz, 2H), 8.08 (d,
J = 2.5 Hz, 1H), 8.07 (d, J = 8.5 Hz, 1H), 7.87-7.85 (m, 2H),
7.81-7.79 (m, 1H), 7.64-7.60 (m, 3H), 7.33 (d, J = 8.0 Hz,
2H), 2.45 (s, 3H); 13C NMR (125 MHz, CDCl3): δ 167.42,
160.54, 150.51, 141.03, 137.16, 135.05, 134.38, 132.29,
130.76, 130.14, 130.02 (2x), 129.33 (2x), 128.70 (2x), 128.62
(2x), 125.74, 122.07, 21.53.
CCDC 1988309, 1994079, 1996086, 1996087, 1996497 and
2002377 contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif,
or
by
emailing
data_request@ccdc.cam.ac.uk, or by containing The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
2,4,6-triphenylquinazoline (6).29 Pd(OAc)2 (5.6 mg, 2.5 mol
%) and PPh3 (13 mg, 5.0 mol %) were added to a solution of
6-bromo-2,4-diphenylquinazoline 4b (1.0 mmol) in
DME/EtOH (9/1, 10 mL) at reflux. Then Na2CO3 (159 mg, 1.5
mmol) and phenlboronic acid (1.1 mmol) were added to the
solution directly. The reaction mixture was stirred at reflux for
18 h and cooled to rt, and the solvent was concentrated. The
residue was diluted with water (10 mL), and the mixture was
extracted with EtOAc (3 × 20 mL). The combined organic
layers were washed with brine, dried, filtered, and evaporated
to afford crude product. Purification on silica gel
(hexanes/EtOAc = 10/1−6/1) afforded compounds 6. Yield =
90% (322 mg); White solid; mp = 137-138 oC (literature: 143-
AUTHOR INFORMATION
Corresponding Author
*E-mail: wangcc7280@gate.sinica.edu.tw (Cheng-Chung Wang).
ORCID
Chieh-Kai Chan: 0000-0002-5178-165X.
Chien-Yu Lai: 0000-0003-1509-9747.
Cheng-Chung Wang: 0000-0002-2562-0658.
Notes
o
145 C); HRMS (ESI, M++H) calcd for C26H19N2 359.1543,
The authors declare no competing financial interest.
1
found 359.1541; H NMR (500 MHz, CDCl3): δ 8.73 (d, J =
ACKNOWLEDGMENT
8.0 Hz, 2H), 8.31 (d, J = 2.0 Hz, 1H), 8.24 (d, J = 8.5 Hz, 1H),

Page 11 of 12
Organic & Biomolecular Chemistry
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DOI: 10.1039/D0OB01507E
(17) (a) B. Akduman and E. D. Crawford, Urology 2001, 58, 49-
54; (b) M. A. Raskind, E. R. Peskind, B. Chow, C. Harris, A.
Davis-Karim, H. A. Holmes, K. L. Hart, M. McFall, T. A.
Mellman, C. Reist, J. Romesser, R. Rosenheck, M.-C. Shih,
M. B. Stein, R. Swift, T. Gleason, Y. Lu and G. D. Huang, N.
Engl. J. Med. 2018, 378, 507-517.
The authors thank the Academia Sinica (AS-SUMMIT-109) and
Ministry of Science and Technology (MOST 108-3114-Y-001-
002, 108-2113-M-001-019-) for financial support.
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Table of Content Entry
TMSOTf
�
Ar
TMS
TMS
NH2
Ar1
O
�
NH
Ar
+
N
N
Ar2
Microwave Irradiation
O
Ar1
Ar2
☑
☑
☑
☑
54 examples
good FG tolerance
high yields
ammonia Neat
An efficient synthetic route for the synthesis of substituted quinazolines under neat, metal-free and microwave irradiation condition has
been developed by using TMSOTf as an acid catalyst and HMDS as a nitrogen source.