Efficient synthesis of quinazolines by the iron-catalyzed acceptorless dehydrogenative coupling of (2-aminophenyl)methanols and benzamides

Article abstract of DOI:10.1016/j.tet.2020.131825

The acceptorless dehydrogenation coupling (ADC) of (2-aminophenyl)methanols with benzamides was achieved with catalytic FeCl₂·4H₂O in an efficient synthesis of quinazolines. This simple catalytic system is atom-economical, environmentally benign and suited to a variety of substrates.

Full text of DOI:10.1016/j.tet.2020.131825

Journal Pre-proof
Efficient synthesis of quinazolines by the iron-catalyzed acceptorless dehydrogenative
coupling of (2-aminophenyl)methanols and benzamides
Shi-Qi Zhang, Yao Cui, Bin Guo, David J. Young, Ze Xu, Hong-Xi Li
PII:
S0040-4020(20)31073-5
https://doi.org/10.1016/j.tet.2020.131825
TET 131825
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 3 September 2020
Revised Date: 24 November 2020
Accepted Date: 27 November 2020
Please cite this article as: Zhang S-Q, Cui Y, Guo B, Young DJ, Xu Z, Li H-X, Efficient synthesis of
quinazolines by the iron-catalyzed acceptorless dehydrogenative coupling of (2-aminophenyl)methanols
and benzamides, Tetrahedron, https://doi.org/10.1016/j.tet.2020.131825.
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Graphical Abstract
Efficient synthesis of quinazolines by the iron-catalyzed
acceptorless dehydrogenative coupling of (2-aminophenyl)-
methanols and benzamides
Leave this area blank for abstract info.
Shi-Qi Zhanga, Yao Cuia, Bin Guoa, David J. Youngb*, Ze Xua, Hong-Xi Lia*
a College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, PR
China.
b College of Engineering, Information Technology and Environment, Charles Darwin University, Northern
Territory 0909, Australia.

Tetrahedron
journal homepage: www.elsevier.com
Efficient synthesis of quinazolines by the iron-catalyzed acceptorless dehydrogenative
coupling of (2-aminophenyl)methanols and benzamides
Shi-Qi Zhanga, Yao Cuia, Bin Guoa, David J. Youngb , Ze Xua, Hong-Xi Lia
a College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou 215123, PR China
b College of Engineering, Information Technology and Environment, Charles Darwin University, Northern Territory 0909, Australia.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The acceptorless dehydrogenation coupling (ADC) of (2-aminophenyl)methanols with
benzamides was achieved with catalytic FeCl2·4H2O in an efficient synthesis of quinazolines.
This simple catalytic system is atom-economical, environmentally benign and suited to a variety
of substrates.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Iron catalyst
Acceptorless dehydrogenative coupling
Quinazoline
Phosphine-free
Mild conditions
1. Introduction
bipyridine]-6,6'-diol; bpy = 2,2-dipyridy) [55] as the catalyst. The
groups of Zhang, Paul and Srimain have reported the synthesis of
The quinazoline moiety is at the core of numerous natural
products, pharmacologically active molecules and organic
functional materials [1-6], and much attention has focused on its
synthesis and derivatization [7-13]. Typical methods for
constructing 2-substituted quinazolines include (i) oxidative
condensation of 2-aminobenzylamines with aldehydes [14-17], or
alcohols [18-21], carboxylic acids [22], amines [23-25], α,α,α-
trihalotoluenes [26], nitriles [27]; (ii) oxidative cyclization of 2-
aminobenzophenones with benzylic amines [28-31], or nitriles
[32], arylacetic acids [33]; (iii) oxidative cross-coupling of 2-
aminoarylmethanols with nitriles [34, 35] or oxime ether [36];
(iv) Ullmann-type coupling and oxidation [37-39]; and (v) three-
component oxidative coupling [40-47] (Scheme 1 (a)). These
synthetic protocols often suffer from the use of stoichiometric or
excessive amounts of inorganic oxidants, the production of large
proportions of hazardous or toxic waste (low atom efficiency)
and poor functional-group tolerance [48-51]. In recent years,
some effective methodologies to overcome these drawbacks have
been reported [52]. From the viewpoint of atom efficiency and
safety, metal-catalyzed acceptorless dehydrogenative coupling
(ADC) with the liberation of H2O and H2 as by-products is an
attractive alternative for the synthesis of nitrogen-containing
heteroaromatics [53]. The groups of Balaraman and Li have
independently developed syntheses of quinazolines by ADC
reaction of 2-aminobenzyl alcohols, or aldehydes with
benzamides in the presence of Mn(CO)5Br/NNN(NNN = N1-(3-
(dimethylamino)propyl)-N3,N3-dimethylpropane-1,3-diamine)
quinazolines via the ADC reaction of 2-aminobenzyl alcohol
with nitriles catalyzed by Ru3(CO)12/Xantphos [56],
[Ni(MeTAA)] (MeTAA = tetramethyltetraaza[14]annulene) [57]
or [(NNS)Mn(CO)3]Br (NNS
= 2-(ethylthio)-N-(pyridin-2-
ylmethyl)ethan-1-amine) [58] using t-BuOK as the base. Yi and
co-authors demonstrated the ADC reaction of 2-aminophenyl
ketones with amines to quinazolines catalyzed by
[(C6H6)(PCy3)(CO)RuH]BF4/tbphOH (tbphOH
=
4-(1,1-
dimethylethyl)-1,2-benzenediol) at 140 °C [59] (Scheme 1 (b)).
The reported ADC methodologies required the use of expensive
organometallic precursors, toxic phosphine organic ligands, t-
BuOK as the base, and/or relatively high temperatures [60-63].
Therefore, it is highly desirable to develop phosphine-free and
inexpensive metal catalyzed reaction systems for synthesis of
quinazolines under mild reaction conditions. Iron catalysts for
ADC are attractive due to their abundance, low price and low
toxicity [64]. Following on from our studies of the transition
metal-catalysed ADC reaction [65-68], we herein report a cheap
and environmentally friendly route to construct quinazolines via
iron-catalysed coupling of (2-aminophenyl)methanols with
benzamides with CsOH as the base in refluxing toluene.
2. Results and discussion
(2-Aminophenyl)methanol (1a) and benzamide (2a) were
chosen as the model substrates to optimize reaction conditions
(Table 1). Reaction of 1a with 2a (1.5 equiv.) in the presence of
10 mol% FeCl2·4H2O, 20 mol% 1,10-phenanthroline (phen) and
[54] or [Cp*Ir(6,6’-(OH)2bpy)(H2O)]2+ (6,6’-(OH)2bpy = [2,2'-
———
Corresponding author. e-mail: david.young@cdu.edu.au
Corresponding author. e-mail: lihx@suda.edu.cn
1

phenylquinazoline (3aa) in high yield (91% by HPLC analysis,
entry 1). Replacing FeCl2·4H2O with FeCl3, FeSO4·7H2O,
Fe(BF4)2·6H2O, Fe(CH3COO)2 or FeC2O4 generated 3aa in 23-
73% HPLC yields (entries 2-6). To our surprise, the reaction of
1a with 2a proceeded even without the addition of phen ligand,
albeit providing the product in only 31% HPLC yield (entry 7).
In the absence of FeCl2·4H2O and phen, 3aa was isolated in 30%
yield (entry 8). Increasing the amount of FeCl2·4H2O from 10
mol% to 15 mol% did not further promote the reaction. The yield
of the product was decreased from 91% to 78% when the
FeCl2·4H2O loading was decreased from 10 mol% to 5 mol%
(entries 9-10). Other similar N-heterocyclic organic ligands, such
as 2,2’-bipyridine (bipy), N,N’-dimethylethane-1,2-diamine
(dmeda), 4,7-diphenyl-1,10-phenanthroline (dphphen), 2,9-
dimethyl-1,10-phenanthroline (dmphen), 3,4,7,8-tetramethyl-
1,10-phenanthroline (tmphen) provided the product 3aa in lower
yields (entries 11-15). A higher yield was not observed when the
molar ratio of phen : FeCl2∙4H2O was changed from 2 : 1 to 3 : 1
(entry 16). While only 55% yield of 3aa was obtained when the
FeCl2∙4H2O/phen ratio was 1 : 1 (entry 17). The screening of
different bases revealed that t-BuOK also gave a good yield of
3aa (entry 18). KOH, NaOH, K3PO4·3H2O, and Cs2CO3 provided
more moderate yields (entries 19-22). No coupling product was
formed when weak base Na2CO3 or K2CO3 was employed
(entries 23 and 24). The coupling reaction didn’t proceed without
base (entry 25). A decreased loading of CsOH·H2O to 70 mol%
did not affect the conversion, but reducing its loading to 0.5
equiv. decreased the yield of 3aa to 54% (entries 26-27). The
choice of solvent also played an important role. Toluene and
xylene were the most suitable solvents at 130 °C (entries 1, 26
and 28). The same coupling cyclization gave a 75% yield in t-
amyl-alcohol and 48% yield in 1,4-dioxane (entries 29-30).
However, this model ADC reaction did not proceed at all in
DMSO or DMF (entries 31-32). The product yield was decreased
from 91% to 86% when the molar ratio 1a/2a was changed from
1 : 1.5 to 1 : 1.2 (entry 33).
Scheme 1. Synthesis of 2-substituted quinazolines.
CsOH·H2O (1 equiv.) in refluxing toluene (at 130 °C) for 24 h
resulted in the formation of the desired product 2-
Table 1 Optimizing conditions for the dehydrogenative condensation/coupling reaction of (2-aminophenyl)methanols and benzamides.
O
N
OH
NH2
[Fe], Ligand
Base, Solv.
+
2H2O + H2
N
NH2
2a
3aa
1a
Entrya
Cat.
Ligand
Base
Solvent
Yield of 3aa (%)b
1
2
FeCl2·4H2O
FeCl3
phen
phen
CsOH·H2O
CsOH·H2O
toluene
toluene
91%
69%
3
4
5
FeSO4·7H2O
Fe(BF4)2·6H2O
Fe(CH3COO)2
phen
phen
phen
CsOH·H2O
CsOH·H2O
CsOH·H2O
toluene
toluene
toluene
40%
23%
62%
6
7
8
9b
FeC2O4
FeCl2·4H2O
-
phen
-
-
phen
phen
bipy
dmeda
dphphen
dmphen
tmphen
phen
phen
phen
phen
CsOH·H2O
CsOH·H2O
CsOH·H2O
CsOH·H2O
CsOH·H2O
CsOH·H2O
CsOH·H2O
CsOH·H2O
CsOH·H2O
CsOH·H2O
CsOH·H2O
CsOH·H2O
t-BuOK
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
73%
31%
30%
91%
78%
17%
38%
58%
85%
81%
89%
55%
88%
66%
FeCl2·4H2O
FeCl2·4H2O
FeCl2·4H2O
FeCl2·4H2O
FeCl2·4H2O
FeCl2·4H2O
FeCl2·4H2O
FeCl2·4H2O
FeCl2·4H2O
FeCl2·4H2O
FeCl2·4H2O
10c
11
12
13
14
15
16d
17e
18
19
KOH
2

20
21
22
23
24
25
26f
27g
28
29
30
31
32
33h
FeCl2·4H2O
FeCl2·4H2O
FeCl2·4H2O
FeCl2·4H2O
FeCl2·4H2O
FeCl2·4H2O
FeCl2·4H2O
FeCl2·4H2O
FeCl2·4H2O
FeCl2·4H2O
FeCl2·4H2O
FeCl2·4H2O
FeCl2·4H2O
FeCl2·4H2O
phen
phen
phen
phen
phen
phen
phen
phen
phen
phen
phen
phen
phen
phen
NaOH
K3PO4·3H2O
Cs2CO3
Na2CO3
K2CO3
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
xylene
t-amyl-alcohol
1,4-dioxane
DMSO
DMF
toluene
60%
72%
76%
Trace
Trace
Trace
91%
54%
91%
75%
48%
Trace
Trace
86%
-
CsOH·H2O
CsOH·H2O
CsOH·H2O
CsOH·H2O
CsOH·H2O
CsOH·H2O
CsOH·H2O
CsOH·H2O
a Reaction conditions: 1a (1.0 mmol), 2a (1.5 mmol), Fe catalyst (10 mol% of Fe), ligand (20 mol%), base (1.0 mmol), solvent (2 mL) reflux under N2 in open
system for 24 h, HPLC yields by using diphenyl as the internal standard.
b Using 15 mol% FeCl2·4H2O and 30 mol% phen.
c Using 5 mol% FeCl2·4H2O and 10 mol% phen.
d Using 30 mol% phen.
e Using 10 mol% phen.
f Using 0.7 equiv. CsOH·H2O.
g Using 0.5 equiv.CsOH·H2O.
h Using 2a (1.2 mmol).
(Fig. S2), confirming the generation of H2 (eqn 1, Scheme 2).
Optimization of the reaction conditions revealed that the best
The reaction of only (2-aminophenyl)methanol with FeCl2·4H2O,
yield was obtained with 1 (1 mmol), 2 (1.5 equiv.) and
phen and CsOH∙H2O in refluxing toluene for 24 h afforded the
CsOH∙H2O (0.7 equiv.) in refluxing toluene for 24 h (Table 1,
dehydrogenated product 2-aminobenzaldehyde (1a’) in 36%
entry 26). The scope of possible substrates was next explored
isolated yield, together with H2 (identified by GC analysis) (Fig.
(Table 2). Arylamides 2a-2f and 2j bearing para electron
S1). This reaction did not proceed without the addition of
donating substituents on phenyl rings were readily coupled with
FeCl2·4H2O or phen in refluxing toluene (eqn 2, Scheme 2). The
1a to give the corresponding quinazolines 3aa-3af and 3aj in 78-
condensation of 2-aminobenzaldehyde 1a’ with 2a resulted in the
91% yield. The use of electron-withdrawing arylamides 2g-2i
(para) and 2j-2n (meta) afforded the desired products 3ag-2ai,
3aj-3an in the lower yield range of 60–72%. Steric hindrance of
the reactive functionality similarly had a detrimental influence on
formation of 3aa. This reaction occurred in the absence of
FeCl2·4H2O and phen, but did not proceed without CsOH (eqn 3,
Scheme 2).
yield (Table 2, entries 15-16). 2-Methylbenzamide was reacted
with 1a to generate 3aq in 71% yield. 2-Naphthamide was
converted to the corresponding quinazoline 3ar in a high yield of
92%. Heteroatom-containing substrates like nicotinamide also
delivered the corresponding quinazolines 3as and 3at in
moderate yields.
Based on the studies above and on relevant literature [54-
62], we propose
proceeding through
a
mechanism for ADC transformation
one-pot dehydrogenation of (2-
a
aminophenyl)methanol to the corresponding aldehyde followed
by base-promoted condensation with benzamide to form
quinazoline (Scheme 3).
Next, the substrate scope of the partner 2-amino-benzyl was
studied (Table 2, entries 21–26) and revealed that deactivating
groups or steric hindrance similarly had a deleterious influence
on yield. The dehydrogenative condensation/coupling reaction of
2-amino-5-methylbenzyl alcohol (1b) with 2a, [1,1'-biphenyl]-4-
carboxamide (2f), or 2-naphthamide (2r) gave the desired
products 3ba, 3bf and 3br in a good 76-81% yield. Chloro-
substituted 1c reacted less efficiently with 2a, 2b or 2r, affording
the respective products 3ca, 3cb and 3cr in 54-69% yield.
Sterically hindered 1-(2-aminophenyl)ethan-1-ol (1d) coupled
with 2a to afford the cyclized product 3da in 43% isolated yield.
This dehydrogenative condensation/coupling reaction of 1a (1.11
g, 9 mmol) and 2a (1.63 g, 13.5 mmol) also worked on the gram-
scale to give 3aa in 41% yield (0.76 g) under the optimized
conditions.
O
N
Standard Condition
OH
NH2
+
+ 2H2O + H2
N
NH2
1a
(1)
3aa
2a
Pd/C (10 mol%)10 mg
t-amyl alcohol, 120 o
C
O
OH
NH2
Conditions
+
H2
(2)
NH2
1a'
Yield
1a
Conditions:
1) Standard Conditions
36%
detected by GC
2) Standard Conditions without FeCl2 4H2O
3) Standard Conditions without phen
Trace
Trace
O
O
N
Conditions
H
NH2
+
(3)
+
2H2O
N
NH2
1a'
Molecular hydrogen as by-product was identified by gas
3aa
2a
chromatography
(GC)
during
the
dehydrogenative
Conditions:
1) Standard Conditions
Yield
95%
95%
Trace
condensation/coupling reaction of 1a and 2a to give 3aa (see
supporting information, Fig. S1). Likewise, when this model
reaction was connected with a second reaction vessel containing
2-vinylnaphthalene and Pd/C, 2-ethylnaphthalene was formed
2) with CsOH H2O without FeCl2 4H2O/phen
3) with FeCl2 4H2O/phen without CsOH H2O
Scheme 2. Verification experiments
3

derivatives via iron-catalysed acceptorless dehydrogenative
condensation/coupling reaction of (2-aminophenyl)methanol with
benzamides under mild reaction conditions.
A series of
substituted benzamides efficiently reacted with various (2-
aminophenyl)methanols, furnishing the desired products and only
H2 and H2O as by-products. This protocol had high functional
group tolerance, did not require the use of toxic phosphine
ligands, stoichiometric oxidants or t-BuOK as strong base. The
construction of other heterocycles catalyzed by iron catalysts is
undergoing in our lab.
Scheme 3. Proposed mechanism
3. Conclusions
In summary, we have developed
a
sustainable and
operationally simple method for synthesis of quinazoline
Table 2 Synthesis of quinazolines.
Entrya
1
1
2
Product
Yield (%)b
87%
1a
1a
1a
2a
2b
2c
3aa
3ab
3ac
2
3
4
5
88%
78%
85%
91%
1a
1a
1a
1a
1a
1a
2d
2e
2f
3ad
3ae
3af
3ag
3ah
3ai
6
7
8
9
89%
68%
72%
60%
2g
2h
2i
10
11
1a
1a
2j
3aj
84%
63%
N
OMe
2k
3ak
N
4

12
13
14
1a
1a
1a
2l
3al
65%
70%
63%
2m
2n
3am
3an
15
16
1a
1a
2o
2p
3ao
3ap
56%
51%
17
18
1a
1a
2q
2r
3aq
3ar
71%
92%
N
19
20
21
1a
1a
1b
2s
2t
2a
3as
3at
3ba
43%
53%
76%
N
N
22
23
24
25
1b
1b
1c
1c
2f
3bf
3br
3ca
3cb
81%
81%
54%
58%
2r
2a
2b
26
27
1c
2r
3cr
69%
1d
2a
3da
43%
a Reaction conditions: 1 (1.0 mmol), 2 (1.5 mmol), FeCl2·4H2O (10 mol%), phen (20 mol%) and CsOH·H2O (0.7 mmol), refluxing in 2 mL toluene under N2, 24
h.
b Isolated yield.
5

127.2, 125.7, 123.4, 34.9, 31.3. HRMS (CI-TOF) m/z calcd for
C18H18N2 [M + H]+ 263.1543, found 263.1531.
4. Experimental
4.1. General
4.2.5. N,N-dimethyl-4-(quinazolin-2-yl)aniline (3ae) [56]
All reagents were used as obtained from commercial sources
without further purification. All solvents were obtained from
commercial sources and were purified according to standard
procedures. Column chromatography was performed on silica gel.
1H (400 MHz), 13C (101 MHz or 150 MHz) and 19F (376 MHz)
NMR spectra were recorded at ambient temperature on a Varian
UNITY plus-400 spectrometer and Bruker Avance III HD
spectrometer. HPLC was conducted on a LC-20A with MeCN
and H2O as the mobile phase. High resolution mass spectra
(HRMS) were obtained with a MICRO TOF-Q III. IR spectra
(KBr disk) were recorded on a Nicolet MagNa-IR550 FT-IR
spectrometer (4000-400 cm−1).
1
Yellow solid (227 mg, 91%). H NMR (400 MHz, CDCl3,
ppm) δ 9.38 (s, 1H), 8.53 (d, J = 8.6 Hz, 2H), 8.05 (d, J = 7.3 Hz,
1H), 7.85 (t, J = 7.6 Hz, 2H), 7.52 (t, J = 7.3 Hz, 1H), 6.83 (d, J =
8.6 Hz, 2H), 3.08 (s, 6H). 13C NMR (151 MHz, CDCl3, ppm) δ
161.4, 160.2, 152.2, 150.9, 133.8, 129.9, 128.1, 127.1, 126.1,
125.6, 123.0, 111.7, 40.2. HRMS (CI-TOF) m/z calcd for
C16H15N3 [M + H]+ 250.1339, found 250.1321.
4.2.6. 2-([1,1'-biphenyl]-4-yl)quinazoline (3af) [40]
1
White solid (252 mg, 89%). H NMR (400 MHz, CDCl3,
ppm) δ 9.51 (s, 1H), 8.72 (d, J = 8.2 Hz, 2H), 8.16 (d, J = 8.3 Hz,
1H), 7.94 (t, J = 8.8 Hz, 2H), 7.79 (d, J = 8.2 Hz, 2H), 7.71 (d, J
= 7.5 Hz, 2H), 7.64 (t, J = 7.5 Hz, 1H), 7.48 (t, J = 7.5 Hz, 2H),
7.39 (t, J = 7.2 Hz, 1H). 13C NMR (151 MHz, CDCl3, ppm) δ
160.6, 150.5, 143.5, 140.5, 136.5, 134.4, 129.1, 128.8, 128.4,
127.7, 127.4, 127.4, 127.2, 127.2, 123.5. HRMS (CI-TOF) m/z
calcd for C20H14N2 [M + H]+ 283.1230, found 283.1228.
4.2. General procedure for synthesis of quinazolines
A 25 mL Schenk tube containing 1 (1.0 mmol), 2 (1.5 mmol),
FeCl2·4H2O (10 mol%), phen (20 mol%) and CsOH·H2O (0.7
mmol) was evacuated and flushed with nitrogen three times.
Dried toluene (2 mL) was added under an N2 atmosphere. The
tube was then placed in an oil bath at 130 °C. The reaction was
continued for 24 h under a slow and steady N2 flow. After
cooling to room temperature, the reaction mixture was
partitioned between water and ethyl acetate. The organic layer
was separated, and the aqueous layer was extracted with ethyl
acetate (3 × 5 mL). The combined organic layer was washed with
brine, dried over anhydrous Na2SO4 and concentrated under
reduced pressure. The crude product was purified by column
chromatography on silica gel using petroleum ether and ethyl
acetate as eluent.
4.2.7. 2-(4-chlorophenyl)quinazoline (3ag) [57]
1
White solid (164 mg, 68%). H NMR (400 MHz, CDCl3,
ppm) δ 9.47 (s, 1H), 8.59 (d, J = 8.4 Hz, 2H), 8.11 (d, J = 8.4 Hz,
1H), 7.94 (t, J = 8.1 Hz, 2H), 7.64 (t, J = 7.5 Hz, 1H), 7.51 (d, J =
8.4 Hz, 2H). 13C NMR (151 MHz, CDCl3, ppm) δ 160.5, 159.9,
150.5, 137.0, 136.2, 134.4, 129.9, 128.8, 128.5, 127.6, 127.2,
123.6. HRMS (CI-TOF) m/z calcd for C14H9ClN2 [M + H]+
241.0527, found 241.0544
4.2.8. 2-(4-bromophenyl)quinazoline (3ah) [57]
1
4.2.1. 2-phenylquinazoline (3aa) [37]
White solid (205 mg, 72%). H NMR (400 MHz, CDCl3,
White solid (180 mg, 87%). 1H NMR (400 MHz, CDCl3, ppm)
δ 9.47 (s, 1H), 8.62 (d, J = 6.8 Hz, 2H), 8.10 (d, J = 8.3 Hz, 1H),
7.92 (t, J = 9.4 Hz, 2H), 7.61 (t, J = 7.4 Hz, 1H), 7.54 (d, J = 7.4
Hz, 3H). 13C NMR (151 MHz, CDCl3, ppm) δ 161.0, 160.5,
150.7, 138.0, 134.1, 130.6, 128.6, 128.6, 127.2, 127.1, 123.6.
HRMS (CI-TOF) m/z calcd for C15H12N2 [M + H]+ 207.0917,
found 207.0928.
ppm) δ 9.44 (s, 1H), 8.50 (d, J = 8.4 Hz, 2H), 8.07 (d, J = 8.6 Hz,
1H), 7.91 (t, J = 7.4 Hz, 2H), 7.66 (s, 1H), 7.65–7.57 (m, 2H).
13C NMR (151 MHz, CDCl3, ppm) δ 160.59, 160.0, 150.6, 136.8,
134.3, 131.8, 130.1, 128.6, 128.5, 127.5, 127.1, 125.4, 123.6.
HRMS (CI-TOF) m/z calcd for C14H9BrN2 [M + H]+ 285.0022,
found 284.9985.
4.2.9. 2-(4-(trifluoromethyl)phenyl)quinazoline (3ai) [57]
1
4.2.2. 2-(p-tolyl)quinazoline (3ab) [37]
White solid (165 mg, 60%). H NMR (400 MHz, CDCl3,
1
ppm) δ 9.53 (s, 1H), 8.77 (d, J = 7.9 Hz, 2H), 8.24–8.11 (m, 1H),
7.98 (t, J = 8.1 Hz, 2H), 7.80 (d, J = 8.0 Hz, 2H), 7.69 (t, J = 7.3
Hz, 1H). 13C NMR (101 MHz, CDCl3, ppm) δ 160.6, 159.5,
150.6, 141.2, 134.5, 132.2 (d, J = 32 Hz), 128.9, 128.7, 128.0,
127.2, 125.6 (q, J = 3.8 Hz), 123.8. 19F NMR (376 MHz, CDCl3,
ppm) δ -62.67. HRMS (CI-TOF) m/z calcd for C15H9F3N2 [M +
H]+ 275.0791, found 275.0788..
White solid (195 mg, 88%). H NMR (400 MHz, CDCl3,
ppm) δ 9.45 (s, 1H), 8.52 (d, J = 7.9 Hz, 2H), 8.08 (d, J = 8.3 Hz,
1H), 7.89 (t, J = 8.4 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.34 (d, J =
7.9 Hz, 2H), 2.45 (s, 3H). 13C NMR (151 MHz, CDCl3, ppm) δ
161.1, 160.4, 150.7, 140.9, 135.2, 134.1, 129.4, 128.5, 128.5,
127.1, 127.0, 123.5, 21.5. HRMS (CI-TOF) m/z calcd for
C15H12N2 [M + H]+ 221.1073, found 221.1079.
4.2.10. 2-(m-tolyl)quinazoline (3aj) [57]
4.2.3. 2-(4-(methylthio)phenyl)quinazoline (3ac) [56]
1
1
White solid (186 mg, 84%). H NMR (400 MHz, CDCl3,
Yellow solid (197 mg, 78%). H NMR (400 MHz, CDCl3,
ppm) δ 9.47 (s, 1H), 8.42 (d, J = 10.4 Hz, 2H), 8.11 (d, J = 8.3
Hz, 1H), 7.91 (t, J = 8.1 Hz, 2H), 7.61 (t, J = 7.3 Hz, 1H), 7.43 (t,
J = 7.5 Hz, 1H), 7.33 (d, J = 7.2 Hz, 1H), 2.49 (s, 3H). 13C NMR
(151 MHz, CDCl3, ppm) δ 161.1, 160.5, 150.7, 138.3, 137.8,
134.2, 131.5, 129.1, 128.6, 127.2, 127.1, 125.8, 123.6, 21.5.
HRMS (CI-TOF) m/z calcd for C15H12N2 [M + H]+ 221.1073,
found 221.1078.
ppm): δ 9.44 (s, 1H), 8.54 (d, J = 8.0 Hz, 2H), 8.06 (d, J = 8.0
Hz, 1H), 7.91 (t, J = 8.0 Hz, 2H), 7.69 (t, J = 8.0 Hz, 1H), 7.38
(d, J = 8.0 Hz, 2H), 2.56 (s, 3H). 13C NMR (101 MHz, CDCl3,
ppm): δ 160.7, 160.4, 150.8, 142.0, 134.6, 134.1, 128.9, 128.5,
127.1, 127.0, 125.8, 123.5, 15.3. HRMS (CI-TOF) m/z calcd for
C15H13N2S [M + H]+ 253.0794; found: 253.0799.
4.2.4. 2-(4-(tert-butyl)phenyl)quinazoline (3ad) [57]
4.2.11. 2-(3-methoxyphenyl)quinazoline (3ak) [57]
1
White solid (224 mg, 85%). H NMR (400 MHz, CDCl3,
1
White solid (150 mg, 63%). H NMR (400 MHz, CDCl3,
ppm) δ 9.48 (s, 1H), 8.55 (d, J = 7.8 Hz, 2H), 8.15 (d, J = 8.0 Hz,
1H), 7.92 (t, J = 8.8 Hz, 2H), 7.62 (t, J = 7.5 Hz, 1H), 7.57 (d, J =
7.8 Hz, 2H), 1.39 (s, 10H). 13C NMR (151 MHz, CDCl3, ppm) δ
160.9, 160.5, 154.2, 150.6, 134.9, 134.3, 128.5, 128.4, 127.2,
ppm) δ 9.48 (s, 1H), 8.31–8.17 (m, 2H), 8.13 (d, J = 8.4 Hz, 1H),
7.93 (t, J = 9.5 Hz, 2H), 7.63 (t, J = 7.5 Hz, 1H), 7.45 (t, J = 7.9
Hz, 1H), 7.08 (d, J = 8.0 Hz, 1H), 3.96 (s, 3H). 13C NMR (151
6

1
MHz, CDCl3, ppm) δ 160.7, 160.4, 160.0, 150.6, 139.2, 134.2,
129.6, 128.6, 127.4, 127.1, 123.6, 121.2, 117.4, 113.0, 55.5.
HRMS (CI-TOF) m/z calcd for C15H12N2O [M + H]+ 237.1022,
found 237.1021.
White solid (236 mg, 92%). H NMR (400 MHz, CDCl3,
ppm) δ 9.54 (s, 1H), 9.18 (s, 1H), 8.74 (d, J = 8.5 Hz, 1H), 8.18
(d, J = 8.2 Hz, 1H), 8.06 (d, J = 6.6 Hz, 1H), 8.03–7.88 (m, 4H),
7.65 (t, J = 7.3 Hz, 1H), 7.60–7.45 (m, 2H). 13C NMR (151 MHz,
CDCl3, ppm) δ 160.8, 160.6, 150.6, 135.0, 134.7, 134.4, 133.4,
129.3, 129.1, 128.5, 128.3, 127.7, 127.4, 127.2, 127.2, 126.3,
125.4, 123.6. HRMS (CI-TOF) m/z calcd for C18H12N2 [M + H]+
257.1073, found 257.1063.
4.2.12. 2-(3-chlorophenyl)quinazoline (3al) [57]
1
White solid (157 mg, 65%). H NMR (400 MHz, CDCl3,
ppm) δ 9.50 (s, 1H), 8.65 (s, 1H), 8.54 (s, 1H), 8.15 (d, J = 8.2
Hz, 1H), 7.96 (t, J = 7.7 Hz, 2H), 7.67 (t, J = 7.3 Hz, 1H), 7.49
(s, 2H). 13C NMR (151 MHz, CDCl3, ppm) δ 160.6, 159.4, 150.5,
139.4, 134.8, 134.6, 130.7, 129.9, 128.7, 128.5, 127.8, 127.2,
126.7, 123.7. HRMS (CI-TOF) m/z calcd for C14H9ClN2 [M +
H]+ 241.0527, found 241.0526.
4.2.19. 2-(pyridin-3-yl)quinazoline (3as) [37]
1
White solid (89 mg, 43%). H NMR (400 MHz, CDCl3,
ppm) δ 9.84 (s, 1H), 9.50 (s, 1H), 8.95 (d, J = 7.7 Hz, 1H), 8.75
(d, J = 3.5 Hz, 1H), 8.12 (d, J = 8.3 Hz, 1H), 7.97 (t, J = 8.5 Hz,
2H), 7.68 (t, J = 7.4 Hz, 1H), 7.61–7.43 (m, 1H). 13C NMR (151
MHz, cdcl3) δ 160.7, 158.8, 150.6, 150.2, 149.4, 136.5, 134.5,
134.0, 128.7, 127.9, 127.2, 123.9, 123.7. HRMS (CI-TOF) m/z
calcd for C13H9N3 [M + H]+ 208.0869, found 208.0865
4.2.13. 2-(3-bromophenyl)quinazoline (3am) [57]
1
White solid (200 mg, 70%). H NMR (400 MHz, CDCl3,
ppm) δ 9.50 (s, 1H), 8.81 (s, 1H), 8.60 (d, J = 7.7 Hz, 1H), 8.17
(d, J = 8.5 Hz, 1H), 7.97 (t, J = 7.7 Hz, 2H), 7.67 (dd, J = 14.0,
7.2 Hz, 2H), 7.42 (t, J = 7.8 Hz, 1H). 13C NMR (151 MHz,
CDCl3, ppm) δ 160.5, 159.3, 150.5, 139.7, 134.6, 133.6, 131.6,
130.2, 128.5, 127.8, 127.2, 127.2, 123.7, 122.9. HRMS (CI-TOF)
m/z calcd for C14H9BrN2 [M + H]+ 285.0022, found 284.9984
4.2.20. 2-(thiophen-2-yl)quinazoline (3at) [37]
1
White solid (113 mg, 53%). H NMR (400 MHz, CDCl3,
ppm) δ 9.37 (s, 1H), 8.21 (d, J = 1.6 Hz, 1H), 8.06 (d, J = 8.6 Hz,
1H), 7.96–7.83 (m, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.54 (d, J = 4.7
Hz, 1H), 7.21 (t, J = 4.1 Hz, 1H). 13C NMR (151 MHz, CDCl3,
ppm) δ 160.7, 157.7, 150.3, 143.5, 134.5, 130.2, 129.5, 128.5,
128.0, 127.3, 127.1, 123.3. HRMS (CI-TOF) m/z calcd for
C12H8N2S [M + H]+ 213.0481, found 213.0455
4.2.14. 2-(3-(trifluoromethyl)phenyl)quinazoline (3an) [40]
1
White solid (173 mg, 63%). H NMR (400 MHz, CDCl3,
ppm) δ 9.50 (s, 1H), 8.94 (s, 1H), 8.84 (d, J = 7.8 Hz, 1H), 8.13
(d, J = 8.4 Hz, 1H), 7.95 (t, J = 8.1 Hz, 2H), 7.76 (d, J = 7.6 Hz,
1H), 7.66 (t, J = 7.4 Hz, 2H). 13C NMR (101 MHz, CDCl3, ppm)
δ 160.7, 159.4, 150.6, 138.6, 134.6, 131.7, 131.3, 131.0, 129.1,
128.7, 127.9, 127.2 (dd, J =8.7, 5.0 Hz), 125.6 (q, J = 4.0 Hz),
123.8, 122.9. 19F NMR (376 MHz, CDCl3, ppm) δ -62.54.
HRMS (CI-TOF) m/z calcd for C15H9F3N2 [M + H]+ 275.0791,
found 275.0809.
4.2.21. 6-methyl-2-phenylquinazoline (3ba) [56]
1
Yellow solid (168 mg, 76%). H NMR (400 MHz, CDCl3,
ppm) δ 9.43 (s, 1H), 8.62 (d, J = 7.0 Hz, 2H), 8.07 (d, J = 8.5 Hz,
1H), 7.78 (d, J = 8.6 Hz, 1H), 7.72 (s, 1H), 7.62–7.48 (m, 3H),
2.59 (s, 3H). 13C NMR (151 MHz, CDCl3, ppm) δ 159.8, 149.0,
137.9, 137.3, 137.0, 130.7, 128.7, 128.6, 128.0, 125.9, 123.5,
21.7. HRMS (CI-TOF) m/z calcd for C15H12N2 [M + H]+
221.1073, found 221.1064
4.2.15. 2-(3,5-dimethoxyphenyl)quinazoline (3ao)
White solid (150 mg, 56%). Mp: 77.0–78.0 °C. 1H NMR (400
MHz, CDCl3, ppm) δ 9.48 (s, 1H), 8.15 (d, J = 8.1 Hz, 1H), 7.94
(t, J = 7.7 Hz, 2H), 7.85 (s, 2H), 7.64 (t, J = 7.2 Hz, 1H), 6.65 (s,
1H), 3.94 (s, 6H). 13C NMR (151 MHz, CDCl3, ppm) δ 161.1,
160.4, 150.4, 139.6, 134.4, 128.5, 127.5, 127.1, 123.6, 106.3,
104.1, 55.6. HRMS (CI-TOF) m/z calcd for C16H14N2O2 [M + H]+
267.1128, found 267.1099. IR (KBr disk, cm-1): 3001 (w), 2833
(w), 2026 (m), 1575 (s), 1553 (m), 1489 (w), 1400 (m), 1348 (s),
1306 (m), 1045 (m), 728 (m), 717 (m).
4.2.22. 2-([1,1'-biphenyl]-4-yl)-6-methylquinazoline (3bf)
1
White solid (241 mg, 81%). Mp: 159.9–160.9 °C. H NMR
(400 MHz, CDCl3, ppm) δ 9.40 (s, 1H), 8.68 (d, J = 8.0 Hz, 2H),
8.03 (d, J = 8.5 Hz, 1H), 7.76 (t, J = 8.1 Hz, 3H), 7.70 (d, J = 6.2
Hz, 3H), 7.48 (t, J = 7.4 Hz, 2H), 7.38 (t, J = 7.1 Hz, 1H), 2.58
(s, 3H). 13C NMR (151 MHz, CDCl3, ppm) δ 160.0, 159.8, 149.3,
143.1, 140.6, 137.5, 136.9, 136.5, 128.9, 128.8, 128.2, 127.6,
127.3, 127.2, 125.8, 123.6, 21.6. HRMS (CI-TOF) m/z calcd for
C21H16N2 [M + H]+ 297.1386, found 297.1383. IR (KBr disk, cm-
1): 2831 (w), 2779 (w), 2026 (m), 1631 (s), 1597 (s), 1424 (m),
1367 (s), 1352 (s), 1060 (w), 829 (m), 756 (m), 734 (m).
4.2.16. 2-(3,5-bis(trifluoromethyl)phenyl)quinazoline (3ap) [30]
1
Yellow solid (175 mg, 51%). H NMR (400 MHz, CDCl3,
ppm) δ 9.49 (s, 1H), 9.13 (s, 2H), 8.14 (d, J = 8.6 Hz, 1H), 8.03–
7.93 (m, 3H), 7.70 (t, J = 7.4 Hz, 1H). 13C NMR (151 MHz,
CDCl3, ppm) δ 160.8, 157.9, 150.5, 134.0, 134.7, 132.0 (q, J =
33.5 Hz), 128.7, 128.6(d J = 2.8 Hz), 128.3, 127.2, 124.3, 124.0,
123.8(m), 122.5. 19F NMR (376 MHz, CDCl3, ppm) δ -62.76, -
62.92. HRMS (CI-TOF) m/z calcd for C16H8F6N2 [M + H]+
343.0664, found 343.0653.
4.2.23. 6-methyl-2-(naphthalen-2-yl)quinazoline (3br)
Yellow solid (220 mg, 81%). Mp: 179.3–180.3 °C. 1H NMR
(400 MHz, CDCl3, ppm) δ 9.43 (s, 1H), 9.14 (s, 1H), 8.72 (d, J =
8.5 Hz, 1H), 8.02 (dd, J = 25.5, 8.5 Hz, 3H), 7.90 (d, J = 5.4 Hz,
1H), 7.76 (d, J = 8.5 Hz, 1H), 7.71 (s, 1H), 7.59–7.45 (m, 2H),
7.26 (s, 1H), 2.58 (s, 3H). 13C NMR (151 MHz, CDCl3, ppm) δ
160.2, 159.8, 149.3, 137.6, 136.6, 135.2, 134.6, 133.4, 129.2,
128.8, 128.2, 128.2, 127.7, 127.0, 126.2, 125.9, 125.3, 123.6,
21.7. HRMS (CI-TOF) m/z calcd for C19H14N2 [M + H]+
271.1230, found 271.1235. IR (KBr disk, cm-1): 2831 (w), 2779
(w), 2026 (w), 1631 (s), 1596 (s), 1555 (m), 1365 (s), 1354 (s),
1186 (m), 951 (w), 830 (m), 747 (m).
4.2.17. 2-(o-tolyl)quinazoline (3aq) [34]
1
White solid (157 mg, 71%). H NMR (400 MHz, CDCl3,
ppm) δ 9.52 (s, 1H), 8.12 (d, J = 8.4 Hz, 1H), 8.02–7.86 (m, 3H),
7.67 (t, J = 7.5 Hz, 1H), 7.36 (d, J = 6.6 Hz, 3H), 2.61 (s, 3H).
13C NMR (151 MHz, CDCl3, ppm) δ 163.9, 160.0, 150.3, 138.3,
137.4, 134.2, 131.3, 130.6, 129.4, 128.5, 127.6, 127.1, 126.0,
122.9, 21.0. HRMS (CI-TOF) m/z calcd for C15H12N2 [M + H]+
221.1073, found 221.1062.
4.2.24. 7-chloro-2-phenylquinazoline (3ca) [40]
1
Yellow solid (130 mg, 54%). H NMR (400 MHz, CDCl3,
ppm) δ 9.43 (s, 1H), 8.60 (d, J = 5.2 Hz, 2H), 8.09 (s, 1H), 7.86
4.2.18. 2-(naphthalen-2-yl)quinazoline (3ar) [34]
(d, J = 8.6 Hz, 1H), 7.64–7.42 (m, 4H). 13C NMR (101 MHz,
7

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128.5, 128.4, 127.8, 122.0. HRMS (CI-TOF) m/z calcd for
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4.2.25. 7-chloro-2-(p-tolyl)quinazoline (3cb) [57]
1
Yellow solid (147 mg, 58%). H NMR (400 MHz, CDCl3,
ppm) δ 9.43 (d, J = 17.5 Hz, 1H), 8.50 (t, J = 7.3 Hz, 2H), 8.08
(d, J = 8.2 Hz, 1H), 7.95–7.81 (m, 1H), 7.64–7.51 (m, 1H), 7.34
(d, J = 7.7 Hz, 2H), 2.45 (s, 3H). 13C NMR (101 MHz, CDCl3,
ppm) δ 162.0, 161.2, 160.5, 160.1, 151.4, 150.8, 141.4, 140.9,
140.3, 135.3, 134.9, 134.1, 129.5, 129.4, 128.7, 128.5, 128.4,
128.2, 127.7, 127.1, 127.1, 123.5, 121.9, 21.6. HRMS (CI-TOF)
m/z calcd for C15H11ClN2 [M + H]+ 254.0611, found 254.0618.
4.2.26. 7-chloro-2-(naphthalen-2-yl)quinazoline (3cr)
1
Yellow solid (200 mg, 69%). Mp: 192.3–193.3 °C. H NMR
(400 MHz, CDCl3, ppm) δ 9.48 (s, 1H), 9.15 (s, 1H), 8.70 (d, J =
8.6 Hz, 1H), 8.14 (s, 1H), 8.02 (dd, J = 19.3, 7.8 Hz, 2H), 7.89 (t,
J = 7.7 Hz, 2H), 7.57 (d, J = 8.6 Hz, 3H). 13C NMR (101 MHz,
CDCl3, ppm) δ 161.9, 160.2, 151.4, 140.5, 134.9, 133.4, 129.4,
129.3, 128.5, 128.5, 128.4, 127.8, 127.8, 127.3, 126.4, 125.3,
122.0. HRMS (CI-TOF) m/z calcd for C18H11ClN2 [M + H]+
290.0611, found 290.0601. IR (KBr disk, cm-1): 2831 (w), 2779
(w), 2026 (m), 1631 (s), 1598 (s), 1383 (m), 1364 (m), 1065 (m),
739 (w), 787 (m), 772 (m).
4.2.27. 4-methyl-2-phenylquinazoline (3da) [57]
White solid (91 mg, 41%). 1H NMR (400 MHz, CDCl3, ppm)
δ 8.07 (d, J = 8.3 Hz, 1H), 7.98 (d, J = 8.2 Hz, 1H), 7.68 (d, J =
10.4 Hz, 3H), 7.53 (t, J = 7.4 Hz, 1H), 7.20 (t, J = 7.4 Hz, 1H),
6.81 (t, J = 9.0 Hz, 2H), 2.75 (s, 3H). 13C NMR (151 MHz,
CDCl3, ppm) δ 158.8, 147.2, 146.5, 144.9, 130.2, 129.8, 129.3,
129.2, 126.5, 125.9, 123.5, 121.7, 121.1, 117.5, 117.3, 19.0.
HRMS (CI-TOF) m/z calcd for C15H12N2 [M + H]+ 221.1073,
found 221.1075.
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We thank the National Natural Science Foundation of China
(21971182 and 21771131), and the "Priority Academic Program
Development" of Jiangsu Higher Education Institutions.
Supplementary data
The identification of molecular hydrogen by gas chromatography and
1H and 13C NMR spectra for the isolated products for this article
can be found in online version at doi:
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Received: ((will be filled in by the editorial staff))
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9

Highlights
► The Fe-catalyzed acceptorless dehydrogenative coupling of (2-aminophenyl)methanols and
benzamides produces quinazolines.
► This simple catalytic system is atom-economical, environmentally benign.
► This coupling reaction is suited to various substrates under mild conditions.

Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: