Synthesis of Difluoromethyl-Substituted Quinazolines through Selective Difluoromethylation

Article abstract of DOI:10.1055/a-1375-3538

A highly selective difluoromethylation of quinazolines has been achieved by using commercially available ethyl bromodifluoroacetate as difluorocarbene precursor, providing the corresponding difluoromethyl substituted quinazoline derivatives with up to 83% yield.

Full text of DOI:10.1055/a-1375-3538

SYNTHESIS
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2021, 53, A–G
paper
A
en
J. Peng et al.
Paper
Synthesis
Synthesis of Difluoromethyl-Substituted Quinazolines through
Selective Difluoromethylation
Jing Peng
Selective difluoromethylation
Ludan Hu
O
OCF2H
N
Mu-Wang Chen
Zhihong Deng
Yiyuan Peng*
K2CO3, MeCN
80 °C, 20 h
NH
Ar
Ar
+
BrCF2CO2Et
N
R
N
R
0
0
0
0
-
0
0
0
3
-3
4
7
1
-
8
5
6
6
21 examples
up to 83% yield
Key Laboratory of Small Functional Organic Molecule, Ministry
of Education and Key Laboratory of Green Chemistry, Jiangxi
Province, Jiangxi Normal University, Nanchang, Jiangxi 330022,
P. R. of China
yypeng@jxnu.edu.cn
yiyuanpeng@yahoo.com
Corresponding Author
Received: 26.12.2020
Accepted after revision: 27.01.2021
Published online: 27.01.2021
routes have several drawbacks including the use of ozone-
depleting gaseous reagents, commercially unavailable re-
agents, and harsh reaction conditions, which has prohibited
their wider application.9b,15 Therefore, the development of a
mild and efficient method for the rapid synthesis of difluo-
romethyl ether derivatives would be very desirable in or-
ganic synthesis and drug research.
DOI: 10.1055/a-1375-3538; Art ID: ss-2020-g0662-op
Abstract A highly selective difluoromethylation of quinazolines has
been achieved by using commercially available ethyl bromodifluoroace-
tate as difluorocarbene precursor, providing the corresponding difluo-
romethyl substituted quinazoline derivatives with up to 83% yield.
Quinazoline derivatives are unique structural skeletons
in many natural products and bioactive compounds.16 Con-
sidering the importance of introducing fluorine-containing
groups into the molecules,1 we attempted to synthesize di-
fluoromethyl substituted quinazolines by using ethyl bro-
modifluoroacetate as fluorine reagent, which has been re-
ported in a limited number of cases for the synthesis of flu-
orine-containing or multifluoro-substituted quinazoline
compounds. Ethyl bromodifluoroacetate is a commercially
available liquid that can be purchased in bulk quantities,17
and it has been successfully implemented for the synthesis
of difluoromethyl ether compounds through generation of
difluorocarbene in situ under mild conditions.18 However,
the quinazolinone has two electrophilic sites on oxygen and
nitrogen (Scheme 1), and the synthesis of difluoromethyl
substituted quinazolines with high chemical selectivity is a
great challenge.19 Herein, we disclose an efficient and con-
venient method to prepare difluoromethyl substituted
quinazoline derivatives through selective difluoromethyla-
tion.
Key words difluoromethylation, quinazoline, ethyl bromodifluoroace-
tate, difluoromethyl substituted quinazoline, difluorocarbene
Recently, the development of an efficient method for in-
troduction of fluorine or fluorine-containing groups into
organic molecules has attracted increasing attention be-
cause of the often remarkable change of the special acidity,
dipole moment, and lipophilicity of the derivatives com-
pared to their nonfluorinated counterparts.1 Among the
fluorinated molecules, the difluoromethyl ether group is
isosteric and isopolar to the hydroxyl group and acts as a
more lipophilic hydrogen donor than hydroxyl, improving
membrane-permeability, which is increasingly important
in various fields.2 For example, roflumilast is a selective
phosphodiesterase 4 inhibitor for the treatment of severe
chronic obstructive pulmonary disease,3a pantoprazole is a
frequently prescribed proton pump inhibitor (PPI) that is
commonly utilized in the management of gastrointestinal
symptoms.3b These drugs all contain difluoromethoxy
groups (Figure 1). Thus, their synthesis has attracted a great
deal of interest.
OCF2H
OCF2H
O
N
Cl
H
N
N
S
General methodologies for the construction of difluoro-
methyl ether compounds are based on the difluoromethyl-
ation of nucleophilic substrates with generation of difluoro-
carbene4 in situ from HCF2Cl,5 HCF3,6 PhSO2CF2Cl,7 ArCOCF2Cl,8
ClCF2CO2Na,9 FSO2CF2CO2H,10 BrCF2P(O)(OEt)2,11 TMSCF2Br,12
HCF2OTf,13 and PhS(O)(NTs)CF2H.14 However, the existing
O
N
H
N
O
Cl
MeO
OMe
Pantoprazole
Roflumilast
Figure 1 Examples of drugs containing a difluoromethoxyl moiety
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–G
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
J. Peng et al.
Paper
Synthesis
Table 1 Optimization of Reaction Conditions for Difluoromethylationa
Selective difluoromethylation
OH
N
O
OCF2H
O
N
OCF2H
N
O
N
R
CF2H
R
:CF2
N
:CF2
base, solvent
T °C, 20 h
NH
N
N
N
+
BrCF2CO2Et
N
N
R
1a
2
3a
NH
R
Entry
Base
K2CO3
Solvent
T (°C)
Yield (%)b
Scheme 1 Selective difluoromethylation of quinazolines
1
2
MeCN
MeCN
MeCN
1,4-dioxane
DMF
50
80
20
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
32
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
t-BuOK
NaOH
74
Our initial investigation was conducted with 2-(p-
tolyl)quinazolin-4(3H)-one (1a; 1.0 equiv) and ethyl bro-
modifluoroacetate (2a; 1.25 equiv) at 50 °C, using K2CO3
(1.0 equiv) as the base and MeCN as the solvent. Pleasingly,
4-(difluoromethoxy)-2-(p-tolyl)quinazoline (3a) was isolat-
ed in 32% yield and the difluoromethylation of nitrogen nu-
cleophile product was not observed (Table 1, entry 1). To
our delight, 74% yield of 3a was obtained when temperature
was raised to 80 °C (entry 2); only 20% yield of 3a was ob-
tained at 20 °C (entry 3). Subsequently, a series of solvents
were screened (entries 4–10) but no better result was ob-
tained. Different bases were also examined. The use of ei-
ther t-BuOK or Cs2CO3 afforded moderated yield (entries 11
and 12). Low yield was obtained when NaOH, Na2CO3, NaH-
CO3, or AcONa were used as base (entries 13–16). Interest-
ingly, no product was obtained when organic bases such as
DBU, Et3N or DABCO, were used instead of inorganic base
(entries 17–19). Gratifyingly, the yield of the desired prod-
uct increased to 83% with 2.0 equiv of K2CO3 and 3.0 equiv
of 2a (entry 20). Finally, the optimal reaction conditions
were established: K2CO3 (2.0 equiv) as the base and MeCN
as the solvent, the reaction at 80 °C.
3
20
4
12
5
21
6
DMSO
THF
13
7
11
8
MeOH
DCE
9
9
16
10
11
12
13
14
15
16
17
18
19
20c
toluene
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
20
58
60
19
Na2CO3
NaHCO3
AcONa
DBU
28
27
11
trace
trace
trace
83
Et3N
DABCO
K2CO3
a Reaction conditions: 1a (0.2 mmol), 2 (0.25 mmol, 1.25 equiv), base (1.0
equiv), solvent (2.0 mL).
Under the optimized reaction conditions, the substrate
scope was explored; the results are summarized in the
Scheme 2. Firstly, the effects of electronic properties of sub-
stituent R on 2-position of quinazoline were examined, and
it was found that they all have some effect on reactivity
(3a–i and 3l–m). Substrates with electron-rich groups such
as alkyl and alkoxy both gave good yields (3a–g, 3l), but
those with electron-withdrawing groups such as Cl and Br
only gave moderate yield (3j, 3k and 3m), and starting ma-
terial 1 was recovered; ortho-substituted quinazolin (3g)
also provided good yield.
Next, the heterocyclic aromatic groups of R were exam-
ined under the reaction conditions, and the products 3n–p
were obtained with moderate to good yields. In addition,
several electron-donating groups such as OMe (3q–s) as
well as electron-withdrawing groups such as Cl, Br (3t–u)
on quinazoline mother ring were compatible under the re-
action conditions with moderate yields. We found that 3q
was transform into starting material 1q under air atmo-
sphere; thus, low yield was obtained in this case.
b Isolated yields.
c K2CO3 (2.0 equiv), 2 (0.60 mmol, 3.0 equiv).
Based on the above results, we speculated that the pres-
ent O-difluoromethylation reaction proceeds first through
base-promoted ethyl bromodifluoroacetate hydrolysis to
give the product potassium bromodifluoroacetate. Subse-
quently, the potassium bromodifluoroacetate instanta-
neously eliminates potassium bromide, releases carbon di-
oxide, and generates difluorocarbene, which is subsequent-
ly trapped by a quinazolin-4-ol or quinazolin-4-one and
further protonated by water to produce the final difluoro-
methyl ether product (Scheme 3).
In summary, we have developed a concise approach for
the synthesis of difluoromethyl substituted quinazolines
using commercially available difluorocarbene precursor
ethyl bromodifluoroacetate. The direct selective O-difluo-
romethylation of quinazolines proceeds smoothly to give
the corresponding products in moderate to good yields, and
did not give the N-difluoromethylation product. Further in-
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–G

C
J. Peng et al.
Paper
Synthesis
O
OCF2H
N
O
decarboxylative
carbene formation
O
K2CO3
Br
K2CO3, MeCN
Br
NH
Ar
OK
:CF2
O
Ar
+
BrCF2CO2Et
ester hydrolysis
F
F
F
F
80 °C, 20 h
N
R
N
R
1
3
2
OH
N
O
N
trapping
by O–H
NH
Ph
OCF2H
OCF2H
OCF2H
N
Ph
N
N
N
N
N
N
OCF2H
N
3a, 83%
3b, 82%
3c, 80%
N
Ph
OCF2H
OCF2H
OCF2H
Scheme 3 Plausible mechanism
N
N
N
N
N
N
OMe
OMe
Unless otherwise stated, all commercial reagents were used as re-
ceived. All solvents were dried and distilled according to standard
procedures. Flash column chromatography was performed using sili-
ca gel (60Å pore size, 32–63 m, standard grade). Analytical thin-lay-
er chromatography was performed using glass plates pre-coated with
0.25 mm 230–400 mesh silica gel impregnated with a fluorescent in-
dicator (254 nm). Thin-layer chromatography plates were visualized
by exposure to ultraviolet light. Organic solutions were concentrated
on rotary evaporators at ca. 20 Torr at 25–35 °C. Nuclear magnetic
resonance (NMR) spectra are recorded in parts per million from inter-
nal tetramethylsilane on the  scale. 1H and 13C NMR spectra were re-
corded in CDCl3 with a Bruker DRX-400 spectrometer operating at
400 MHz and 100 MHz, respectively. All chemical shift values are
quoted in ppm and coupling constants are quoted in Hz. High-resolu-
tion mass spectrometry (HRMS) spectra were obtained with a micrO-
TOF II Instrument.
3d, 79%
3e, 78%
3f, 72%
OCF2H
OCF2H
OCF2H
N
N
N
N
OEt
N
N
F
3g, 80%
3h, 60%
3i, 79%
OCF2H
OCF2H
OCF2H
N
N
N
N
N
N
Cl
Br
3j, 24%a
3k, 49%b
3l, 66%
OCF2H
OCF2H
OCF2H
Synthesis of Starting Materials 1; General Procedure20
N
N
N
N
N
N
O
S
o-Aminobenzamide (10 mmol), benzaldehyde (1.2 equiv), NaHSO3
(1.2 equiv) and DMAc (50 mL) were added in a 100 mL round-bottom
flask. The mixture was heated at 150 °C and the progress of the reac-
tion was monitored by TLC. After the reaction was complete, the mix-
ture was poured into ice water, and the crude product solid that pre-
cipitated out was recrystallize from EtOH to give pure product.
F
3m, 52%
3n, 75%
3o, 63%
OCF2H
OCF2H
OCF2H
MeO
MeO
N
N
N
N
N
N
N
Synthesis of 3 through Selective Difluoromethylation; General
Procedure
CF3
3p, 73%
3q, 35%c
3r, 79%
A solution of quinazolin-4(3H)-one 1 (0.2 mmol), ethyl bromodifluo-
roacetate 2 (0.6 mmol, 0.122 g) and K2CO3 (0.4 mmol, 0.055 g) in
MeCN (2 mL) was stirred at 80 °C for 20 h. After completion of the re-
action, the solution was concentrated under reduced pressure and the
product was purified by column chromatography on silica gel (200–
300 mesh) with petroleum ether and EtOAc (30:1 to 10:1) as eluent to
give the pure product 3.
OCF2H
OCF2H
OCF2H
MeO
Cl
Cl
Br
N
N
N
N
N
N
3s, 49%d
3t, 34%e
3u, 57%
Scheme 2 Substrate scope for difluoromethylation. Reagents and
conditions: 1a (0.2 mmol), 2 (0.6 mmol, 3.0 equiv), K2CO3 (2.0 equiv),
MeCN (2.0 mL), isolated yields. a 61% of 1j was recovered. b 42% of 1k
was recovered. c 60% of 1q was recovered. d 43% 1s was recovered.
e 58% of 1t was recovered.
2-(2,4-Dimethylphenyl)quinazolin-4(3H)-one (1l)19e
White solid; mp 208.1–209.4 °C.
1H NMR (400 MHz, DMSO-d6):  = 12.41 (s, 1 H), 8.20 (d, J = 7.6 Hz, 1
H), 7.86 (t, J = 7.2 Hz, 1 H), 7.72 (d, J = 8.0 Hz, 1 H), 7.56 (t, J = 7.4 Hz, 1
H), 7.44 (d, J = 7.6 Hz, 1 H), 7.19–7.16 (m, 2 H), 2.41 (s, 3 H), 2.38 (s, 3
H).
13C NMR (100 MHz, DMSO):  = 162.3, 154.9, 149.3, 139.9, 136.5,
134.9, 131.9, 131.7, 129.7, 127.8, 127.0, 126.7, 126.2, 121.4, 21.3, 20.1.
vestigations on difluoromethylation reactions using ethyl
bromodifluoroacetate as difluorocarbene precursor are on-
going in our laboratory.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–G

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J. Peng et al.
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Synthesis
HRMS: m/z [M + H]+ calcd. for C16H15N2O: 251.1179; found: 251.1187.
19F NMR (376 MHz, CDCl3):  = –90.19.
HRMS: m/z [M + H]+ calcd. for C16H13F2N2O: 287.0990; found:
287.0991.
2-(4-Fluoro-2-methylphenyl)quinazolin-4(3H)-one (1m)
White solid; mp 255.5–257.0 °C.
1H NMR (400 MHz, DMSO-d6):  = 12.49 (s, 1 H), 8.21 (d, J = 7.6 Hz, 1
H), 7.87 (t, J = 7.4 Hz, 1 H), 7.73 (d, J = 7.6 Hz, 1 H), 7.63 - 7.56 (m, 2 H),
7.26 (d, J = 9.6 Hz, 1 H), 7.20 (t, J = 8.2 Hz, 1 H), 2.44 (s, 3 H).
4-(Difluoromethoxy)-2-(4-ethylphenyl)quinazoline (3b)
Yield: 82%; white solid; mp 67.1–68.2 °C.
1H NMR (400 MHz, CDCl3):  = 8.42 (d, J = 8.2 Hz, 2 H), 8.15 (d, J = 7.8
Hz, 1 H), 8.02 (d, J = 8.5 Hz, 1 H), 7.91–7.85 (m, 1 H), 7.89 (t, JC–F = 71.6
Hz, 1 H), 7.57 (t, J = 7.6 Hz, 1 H), 7.34 (d, J = 8.2 Hz, 2 H), 2.74 (q, J = 7.6
Hz, 2 H), 1.30 (t, J = 7.6 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 162.7, 159.2, 152.8, 147.7, 134.6 (t, JC–F
= 12.0 Hz), 128.8, 128.7, 128.4 (d, JC–F = 42.0 Hz), 128.2, 127.2, 123.1,
113.7 (t, JC–F = 257 Hz), 113.6, 28.8, 15.4.
1
13C NMR (100 MHz, DMSO):  = 163.1 (d, JC–F = 245.0 Hz), 162.3,
154.0, 149.1, 140.1 (d, JC–F = 8.0 Hz), 134.9, 132.0 (d, 2JC–F = 9 Hz), 131.2
2
(d, JC–F = 3 Hz), 127.8, 127.2, 126.2, 121.5, 117.5 (d, JC–F = 21.0 Hz),
113.0 (d, 2JC–F = 21.0 Hz), 20.06.
19F NMR (376 MHz, DMSO):  = –111.63.
HRMS: m/z [M
+
H]+ calcd. for C15H12FN2O: 255.0928; found:
255.0933.
19F NMR (376 MHz, CDCl3):  = –90.17.
HRMS: m/z [M + H]+ calcd. for C17H15F2N2O: 301.1147; found:
301.1148.
2-(1-Methyl-1H-pyrrol-2-yl)quinazolin-4(3H)-one (1p)21
Black solid; mp 217.6–219.2 °C.
1H NMR (400 MHz, DMSO-d6):  = 12.08 (s, 1 H), 8.13 (d, J = 7.6 Hz, 1
H), 7.80 (t, J = 7.2 Hz, 1 H), 7.65 (d, J = 8.4 Hz, 1 H), 7.46 (t, J = 7.4 Hz, 1
H), 7.26 (d, J = 2.4 Hz, 1 H), 7.13 (s, 1 H), 6.19–6.18 (m, 1 H), 4.10 (s, 3
H).
13C NMR (100 MHz, DMSO):  = 162.4, 149.3, 147.2, 134.9, 130.6,
127.5, 126.2, 126.1, 124.4, 120.9, 115.3, 108.1, 38.0.
4-(Difluoromethoxy)-2-(4-isopropylphenyl)quinazoline (3c)
Yield: 80%; white solid; mp 54.0–56.0 °C.
1H NMR (400 MHz, CDCl3):  = 8.44 (d, J = 8.3 Hz, 2 H), 8.16 (d, J = 8.2
Hz, 1 H), 8.04 (d, J = 8.4 Hz, 1 H), 7.91–7.86 (m, 1 H), 7.90 (t, JC–F = 71.6
Hz, 1 H), 7.58 (t, J = 7.6 Hz, 1 H), 7.38 (d, J = 7.6, 8.3 Hz, 2 H), 3.01
(hept, J = 6.9 Hz, 1 H), 1.33 (s, 3 H), 1.31 (s, 3 H).
HRMS: m/z [M + H]+ calcd. for C13H12N3O: 226.0975; found: 226.0972.
13C NMR (100 MHz, CDCl3):  = 162.8, 159.3, 152.9, 152.3, 134.6,
128.7, 128.6, 128.2, 127.2, 126.7, 123.1, 113.6 (t, JC–F = 256 Hz), 113.5,
34.2, 23.9.
6-Methoxy-2-(4-(trifluoromethyl)phenyl)quinazolin-4(3H)-one
(1r)22
19F NMR (376 MHz, CDCl3):  = –90.19.
HRMS: m/z [M + H]+ calcd. for C18H17F2N2O: 315.1303; found:
White solid; mp 270.2–271.2 °C.
1H NMR (400 MHz, DMSO-d6):  = 12.66 (s, 1 H), 8.35 (d, J = 8.0 Hz, 2
H), 7.90 (d, J = 8.4 Hz, 2 H), 7.73 (d, J = 9.2 Hz, 1 H), 7.56 (d, J = 2.8 Hz,
1 H), 7.46 (dd, J = 8.8, 2.4 Hz, 1 H), 3.90 (s, 3 H).
315.1303.
2-(4-(tert-Butyl)phenyl)-4-(difluoromethoxy)quinazoline (3d)
13C NMR (100 MHz, DMSO):  = 162.4, 159.5, 158.6, 149.4, 143.3,
137.1, 129.9, 128.9, 125.9 (q, JC–F = 245 Hz), 125.8, 124.6, 123.8, 123.1,
122.6, 106.4, 56.2.
Yield: 79%; white solid; mp 69.3–71.4 °C.
1H NMR (400 MHz, CDCl3):  = 8.44 (d, J = 8.5 Hz, 2 H), 8.16 (d, J = 8.2
Hz, 1 H), 8.04 (d, J = 8.5 Hz, 1 H), 7.92–7.86 (m, 1 H), 7.89 (t, J = 71.6
Hz, 1 H), 7.59 (d, J = 7.4 Hz, 1 H), 7.55 (d, J = 8.4 Hz, 2 H), 1.40 (s, 9 H).
19F NMR (376 MHz, DMSO):  = –61.32.
HRMS: m/z [M + H]+ calcd. for C16H12F3N2O2: 321.0845; found:
321.0847.
13C NMR (100 MHz, CDCl3):  = 162.8, 159.3, 154.5, 152.9, 134.6,
134.2, 128.3, 128.2, 127.2, 125.6, 123.1, 113.7 (t, JC–F = 257 Hz), 113.6,
34.9, 31.2.
6-Chloro-2-(o-tolyl)quinazolin-4(3H)-one (1t)23
19F NMR (376 MHz, CDCl3):  = –90.16.
HRMS: m/z [M + H]+ calcd. for C19H19F2N2O: 329.1460; found:
White solid; mp 288.6–289.7 °C.
1H NMR (400 MHz, DMSO-d6):  = 12.65 (s, 1 H), 8.13 (s, 1 H), 7.89 (d,
J = 6.8 Hz, 1 H), 7.75 (d, J = 8.4 Hz, 1 H), 7.55 (d, J = 7.2 Hz, 1 H), 7.47 (t,
J = 6.8 Hz, 1 H), 7.40–7.35 (m, 2 H), 2.42 (s, 3 H).
329.1461.
4-(Difluoromethoxy)-2-(4-methoxyphenyl)quinazoline (3e)
13C NMR (100 MHz, DMSO):  = 161.3, 155.4, 147.9, 136.6, 135.0,
Yield: 78%; white solid; mp 104.1–106.2 °C.
134.4, 131.3, 131.0, 130.5, 130.1, 129.6, 126.2, 125.3, 122.7, 20.0.
HRMS: m/z [M + H]+ calcd. for C15H12ClN2O: 271.0633; found:
271.0633.
1H NMR (400 MHz, CDCl3):  = 8.46 (d, J = 8.9 Hz, 2 H), 8.14 (d, J = 8.2
Hz, 1 H), 7.99 (d, J = 8.4 Hz, 1 H), 7.91–7.84 (m, 1 H), 7.87 (t, JC–F = 71.6
Hz, 1 H), 7.55 (t, J = 7.5 Hz, 1 H), 7.01 (d, J = 8.9 Hz, 2 H), 3.89 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 162.7, 162.2, 159.0, 152.9, 134.6,
130.2, 129.6, 128.0, 126.9, 123.1, 113.9, 113.6 (t, JC–F = 257 Hz), 113.3,
55.4.
4-(Difluoromethoxy)-2-(p-tolyl)quinazoline (3a)
Yield: 83%; white solid; mp 85.8–88.9 °C.
19F NMR (376 MHz, CDCl3):  = –90.13.
HRMS: m/z [M + H]+ calcd. for C16H13F2N2O2: 303.0940; found:
1H NMR (400 MHz, CDCl3):  = 8.43 (d, J = 8.2 Hz, 2 H), 8.20–8.16 (m, 1
H), 8.08 (d, J = 7.0 Hz, 1 H), 7.95–7.88 (m, 1 H), 7.90 (t, JC–F = 71.6 Hz, 1
H), 7.60 (t, J = 7.6 Hz, 1 H), 7.32 (d, J = 8.0 Hz, 2 H), 2.45 (s, 3 H).
303.0939.
13C NMR (100 MHz, CDCl3):  = 162.7, 159.3, 152.9, 141.4, 134.6,
134.3, 129.3, 128.4, 128.2, 127.2, 123.1, 113.7 (t, JC–F = 257 Hz), 113.6,
21.5.
4-(Difluoromethoxy)-2-(3-methoxyphenyl)quinazoline (3f)
Yield: 72%; white solid; mp 70.9–73.7 °C.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–G

E
J. Peng et al.
Paper
Synthesis
1H NMR (400 MHz, CDCl3):  = 8.16 (d, J = 8.2 Hz, 1 H), 8.11 (d, J = 7.8
Hz, 1 H), 8.06 (d, J = 3.6 Hz, 2 H), 7.90 (t, J = 8.0 Hz, 1 H), 7.88 (t, J =
71.6 Hz, 1 H), 7.60 (t, J = 7.6 Hz, 1 H), 7.42 (t, J = 8.0 Hz, 1 H), 7.06 (dd,
J = 8.2, 2.4 Hz, 1 H), 3.93 (s, 3 H).
19F NMR (376 MHz, CDCl3):  = –90.15.
HRMS: m/z [M + H]+ calcd. for C15H10ClF2N2O: 307.0444; found:
307.0442.
13C NMR (100 MHz, CDCl3):  = 162.8 (t, JC–F = 4 Hz), 159.9, 158.9,
152.8, 138.4, 134.7, 129.5, 128.3, 127.5, 123.1, 121.0, 117.1, 113.7,
113.6 (t, JC–F = 257 Hz), 113.4, 55.4.
19F NMR (376 MHz, CDCl3):  = –90.14.
HRMS: m/z [M + H]+ calcd. for C16H13F2N2O2: 303.0940; found:
2-(4-Bromophenyl)-4-(difluoromethoxy)quinazoline (3k)
Yield: 49%; white solid; mp 131.2–133.6 °C.
1H NMR (400 MHz, CDCl3):  = 8.39 (d, J = 8.6 Hz, 2 H), 8.19 (d, J = 8.2
Hz, 1 H), 8.04 (d, J = 7.6 Hz, 1 H), 7.93 (t, J = 7.8 Hz, 1 H), 7.87 (t, J =
71.6 Hz, 1 H), 7.63 (t, J = 7.8 Hz, 3 H).
303.0940.
13C NMR (100 MHz, CDCl3):  = 162.9, 158.3, 152.7, 135.9, 134.9,
131.8, 130.0, 128.3, 127.7, 125.9, 123.2, 113.7 (t, JC–F = 258 Hz, ), 113.6.
19F NMR (376 MHz, CDCl3):  = –90.14.
HRMS: m/z [M + H]+ calcd. for C15H10BrF2N2O: 350.9939; found:
350.9938.
4-(Difluoromethoxy)-2-(2-ethoxyphenyl)quinazoline (3g)
Yield: 41%; white solid; mp 73.4–75.7 °C.
1H NMR (400 MHz, CDCl3):  = 8.21 (d, J = 8.2 Hz, 1 H), 8.07 (d, J = 8.8
Hz, 1 H), 7.92 (t, J = 7.7 Hz, 1 H), 7.88 (t, J = 71.6 Hz, 1 H), 7.86 (d, J =
7.8 Hz, 1 H), 7.64 (t, J = 7.6 Hz, 1 H), 7.43 (t, J = 7.8 Hz, 1 H), 7.11–7.02
(m, 2 H), 4.13 (q, J = 7.0 Hz, 2 H), 1.39 (t, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3):  = 162.3 (t, JC–F = 4 Hz), 160.5, 157.6,
152.7, 134.5, 131.8, 131.3, 128.3, 128.0, 127.6, 123.0, 120.6, 113.7 (t,
JC–F = 257 Hz), 113.4, 113.3, 64.4, 14.8.
4-(Difluoromethoxy)-2-(2,4-dimethylphenyl)quinazoline (3l)
Yield: 66%; white solid; mp 59.7–62.3 °C.
1H NMR (400 MHz, CDCl3):  = 8.21 (d, J = 8.2 Hz, 1 H), 8.05 (d, J = 8.5
Hz, 1 H), 7.95–7.88 (m, 2 H), 7.81 (t, JC–F= 71.6 Hz, 1 H), 7.64 (t, J = 7.6
Hz, 1 H), 7.16 (d, J = 6.6 Hz, 2 H), 2.64 (s, 3 H), 2.40 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 162.2 (t, JC–F = 3 Hz), 161.9, 152.6,
139.9, 137.7, 134.6, 134.5, 132.4, 130.8, 128.2, 127.5, 126.7, 123.0,
113.7 (t, JC–F = 257 Hz), 113.0, 21.5, 21.2.
19F NMR (376 MHz, CDCl3):  = –90.35.
HRMS: m/z [M + H]+ calcd. for C17H15F2N2O2: 317.1096; found:
317.1095.
19F NMR (376 MHz, CDCl3):  = –90.30.
HRMS: m/z [M + H]+ calcd. for C17H15F2N2O: 301.1147; found:
4-(Difluoromethoxy)-2-phenylquinazoline (3h)
Yield: 60%; white solid; mp 72.4–73.7 °C.
301.1148.
1H NMR (400 MHz, CDCl3):  = 8.53 (dd, J = 6.2, 2.8 Hz, 1 H), 8.20 (d, J =
8.2 Hz, 1 H), 8.06 (d, J = 8.4 Hz, 1 H), 7.92 (t, J = 8.2 Hz, 1 H), 7.91 (t, J =
71.6 Hz, 1 H), 7.62 (t, J = 7.6 Hz, 1 H), 7.55–7.49 (m, 3 H).
13C NMR (100 MHz, CDCl3):  = 162.9, 159.2, 152.9, 137.0, 134.7,
131.1, 128.6, 128.5, 128.3, 127.5, 123.2, 113.7, 113.6 (t, JC–F = 257 Hz).
19F NMR (376 MHz, CDCl3):  = –90.19.
HRMS: m/z [M + H]+ calcd. for C15H11F2N2O: 273.0834; found:
4-(Difluoromethoxy)-2-(4-fluoro-2-methylphenyl)quinazoline
(3m)
Yield: 52%; white solid; mp 109.1–112.2 °C.
1H NMR (400 MHz, CDCl3):  = 8.22 (d, J = 8.2 Hz, 1 H), 8.05 (d, J = 8.4
Hz, 1 H), 7.99 (dd, J = 9.6, 6.1 Hz, 1 H), 7.97–7.92 (m, 1 H), 7.79 (t, JC–F
71.6 Hz, 1 H), 7.66 (t, J = 7.6 Hz, 1 H), 7.06–6.99 (m, 2 H), 2.66 (s, 3 H).
=
273.0835.
13C NMR (100 MHz, CDCl3):  = 164.7 (t, JC–F = 248 Hz), 162.4 (t, JC–F = 4
Hz), 160.9, 152.5, 140.8 (d, JC–F = 9 Hz), 134.8, 133.4 (d, JC–F = 3 Hz),
132.9 (d, JC–F = 9 Hz), 128.2, 127.8, 123.1, 118.1 (d, JC–F = 21 Hz), 113.6
(t, JC–F = 257 Hz), 113.0, 112.8, 21.8.
4-(Difluoromethoxy)-2-(4-fluorophenyl)quinazoline (3i)
Yield: 79%; white solid; mp 113.4–114.8 °C.
1H NMR (400 MHz, CDCl3):  = 8.53–8.48 (m, 2 H), 8.16 (d, J = 8.2 Hz, 1
H), 8.01 (d, J = 8.4 Hz, 1 H), 7.90 (t, J = 7.5 Hz, 1 H), 7.86 (t, J = 71.6 Hz,
1 H), 7.61 (dt, J = 15.2, 7.4 Hz, 1 H), 7.17 (t, J = 8.6 Hz, 2 H).
19F NMR (376 MHz, CDCl3):  = –90.29, –111.93.
HRMS: m/z [M + H]+ calcd. for C16H12F3N2O: 305.0896; found:
305.0896.
13C NMR (100 MHz, CDCl3):  = 164.9 (d, JC–F = 250 Hz), 162.9 (t, JC–F = 4
Hz), 158.2, 152.75, 134.8, 133.1 (d, JC–F = 3 Hz), 130.8 (d, JC–F = 8 Hz),
128.2, 127.5, 123.1, 115.6 (d, JC–F = 22 Hz), 113.6 (t, JC–F = 257 Hz),
113.5.
19F NMR (376 MHz, CDCl3):  = –90.13, –109.61.
HRMS: m/z [M + H]+ calcd. for C15H10F3N2O: 291.0740; found:
4-(Difluoromethoxy)-2-(furan-2-yl)quinazoline (3n)
Yield: 75%; white solid; mp 106.2–108.5 °C.
1H NMR (400 MHz, CDCl3):  = 8.15 (d, J = 8.2 Hz, 1 H), 8.07 (d, J = 8.5
Hz, 1 H), 7.90 (t, J = 7.7 Hz, 1 H), 7.82 (t, J = 71.2 Hz, 1 H), 7.68 (s, 1 H),
7.59 (t, J = 7.6 Hz, 1 H), 7.36 (d, J = 3.4 Hz, 1 H), 6.59 (d, J = 1.5 Hz, 1 H).
291.0740.
13C NMR (100 MHz, CDCl3):  = 162.8, 152.5, 151.9, 151.6, 145.7,
135.0, 128.1, 127.5, 123.2, 114.8, 113.7, 113.5 (t, JC–F = 257 Hz), 112.2.
19F NMR (376 MHz, CDCl3):  = –90.29.
HRMS: m/z [M + H]+ calcd. for C13H9F2N2O2: 263.0627; found:
263.0627.
2-(4-Chlorophenyl)-4-(difluoromethoxy)quinazoline (3j)
Yield: 24%; white solid; mp 127.3–129.7 °C.
1H NMR (400 MHz, CDCl3):  = 8.46 (d, J = 8.5 Hz, 2 H), 8.19 (d, J = 8.2
Hz, 1 H), 8.04 (d, J = 8.7 Hz, 1 H), 7.92 (t, J = 7.4 Hz, 1 H), 7.87 (t, JC–F
71.6 Hz, 1 H), 7.62 (t, J = 7.6 Hz, 1 H), 7.48 (d, J = 8.6 Hz, 2 H).
13C NMR (100 MHz, CDCl3):  = 162.9, 158.1, 152.8, 137.3, 135.5,
134.9, 129.8, 128.8, 128.3, 127.7, 123.2, 113.7 (t, JC–F = 257 Hz, ), 113.6.
=
4-(Difluoromethoxy)-2-(thiophen-2-yl)quinazoline (3o)
Yield: 63%; white solid; mp 108.3–110.4 °C.
© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–G

F
J. Peng et al.
Paper
Synthesis
1H NMR (400 MHz, CDCl3):  = 8.14 (d, J = 8.2 Hz, 1 H), 8.06 (d, J = 3.6
Hz, 1 H), 7.98 (d, J = 8.5 Hz, 1 H), 7.88 (dd, J = 8.0, 7.4 Hz, 1 H), 7.84 (t,
J = 71.6 Hz, 1 H), 7.57 (t, J = 7.6 Hz, 1 H), 7.52 (d, J = 5.0 Hz, 1 H), 7.17
(t, J = 4.3 Hz, 1 H).
13C NMR (100 MHz, CDCl3):  = 162.6, 155.8, 152.7, 142.8, 134.9,
130.4, 129.7, 128.2, 127.9, 127.2, 123.2, 113.5 (t, JC–F = 257 Hz), 113.5.
13C NMR (100 MHz, CDCl3):  = 161.4, 159.1, 157.5, 148.5, 137.0,
133.1, 131.8, 130.7, 130.4, 129.9, 127.6, 126.8, 114.2, 113.8 (t, JC–F
=
257 Hz), 100.3, 56.0.
19F NMR (376 MHz, CDCl3):  = –90.16.
HRMS: m/z [M + H]+ calcd. for C16H12ClF2N2O2: 337.0550; found:
337.0550.
19F NMR (376 MHz, CDCl3):  = –90.26.
HRMS: m/z [M + H]+ calcd. for C13H9F2N2OS: 279.0398; found:
6-Chloro-4-(difluoromethoxy)-2-(o-tolyl)quinazoline (3t)
279.0396.
Yield: 34%; white solid; mp 69.6–70.4 °C.
1H NMR (400 MHz, CDCl3):  = 8.11 (d, J = 2.0 Hz, 1 H), 7.93 (d, J = 8.9
Hz, 1 H), 7.90–7.86 (m, 1 H), 7.79 (dd, J = 9.0, 2.1 Hz, 1 H), 7.70 (t, J =
71.2 Hz, 1 H), 7.31–7.24 (m, 3 H), 2.56 (s, 3 H).
4-(Difluoromethoxy)-2-(1-methyl-1H-pyrrol-2-yl)quinazoline
(3p)
Yield: 73%; white solid; mp 78.5–80.7 °C.
13C NMR (100 MHz, CDCl3):  = 162.1, 161.5 (t, JC–F = 4 Hz), 151.0,
137.9, 136.9, 135.7, 133.5, 131.6, 130.8, 130.0, 129.9, 126.0, 122.1,
113.7, 113.5 (t, 1JC–F = 257 Hz), 21.5.
19F NMR (376 MHz, CDCl3):  = –90.34.
HRMS: m/z [M + H]+ calcd. for C16H12ClF2N2O: 321.0601; found:
1H NMR (400 MHz, CDCl3):  = 8.09 (d, J = 8.2 Hz, 1 H), 7.87 (d, J = 8.4
Hz, 1 H), 7.82 (t, J = 7.6 Hz, 1 H), 7.77 (t, J = 71.6 Hz, 1 H), 7.49 (t, J = 7.6
Hz, 1 H), 7.25–7.19 (m, 1 H), 6.83 (s, 1 H), 6.25–6.20 (m, 1 H), 4.19 (s, 3
H).
13C NMR (100 MHz, CDCl3):  = 162.1 (t, JC–F = 3 Hz), 154.6, 152.6,
134.5, 130.4, 129.3, 127.6, 126.3, 123.1, 116.4, 113.6 (t, JC–F = 256 Hz),
112.7, 108.2, 38.2.
321.0603.
6-Bromo-4-(difluoromethoxy)-2-(p-tolyl)quinazoline (3u)
19F NMR (376 MHz, CDCl3):  = –90.21.
HRMS: m/z [M + H]+ calcd. for C14H12F2N3O: 276.0943; found:
Yield: 57%; white solid; mp 158.3–160.9 °C.
1H NMR (400 MHz, CDCl3):  = 8.42 (d, J = 8.2 Hz, 2 H), 8.27 (d, J = 2.0
Hz, 1 H), 7.95 (dd, J = 9.0, 2.2 Hz, 1 H), 7.89 (d, J = 9.0 Hz, 1 H), 7.86 (t,
J = 71.2 Hz, 1 H), 7.31 (d, J = 8.2 Hz, 2 H), 2.44 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 161.7, 159.6, 151.6, 141.8, 138.2,
133.9, 129.9, 129.4, 128.5, 125.5, 120.8, 114.6, 113.5 (t, 1JC–F = 258 Hz),
21.6.
276.0942.
4-(Difluoromethoxy)-6-methoxy-2-phenylquinazoline (3q)
Yield: 35%; white solid; mp 126.3–128.6 °C.
1H NMR (400 MHz, CDCl3):  = 8.51–8.46 (m, 2 H), 7.97 (d, J = 9.2 Hz, 1
H), 7.92 (t, J = 71.6 Hz, 1 H), 7.57–7.48 (m, 4 H), 7.38 (d, J = 2.6 Hz, 1
H), 3.98 (s, 3 H).
13C NMR (100 MHz, CDCl3):  = 161.8 (t, JC–F = 4 Hz), 158.6, 157.2,
148.8, 137.1, 130.6, 129.9, 128.6, 128.1, 127.4, 114.3, 113.7 (t, JC–F
19F NMR (376 MHz, CDCl3):  = –90.21.
HRMS: m/z [M + H]+ calcd. for C16H12BrF2N2O: 365.0096; found:
365.0095.
=
257 Hz), 100.5, 55.9.
19F NMR (376 MHz, CDCl3):  = –90.00.
HRMS: m/z [M + H]+ calcd. for C16H13F2N2O2: 303.0940; found:
Funding Information
Financial support from National Natural Science Foundation of China
(nos: 21502188, 21362014, 21762020), Jiangxi Provincial Depart-
ment of Science and Technology (no. 20171BAB203006), and Key Lab-
oratory of Functional Small Organic Molecules, Ministry of Education,
Jiangxi Normal University (no. KLFS-KF-201702) is gratefully ac-
303.0941.
4-(Difluoromethoxy)-6-methoxy-2-(4-(trifluoromethyl)-phe-
nyl)quinazoline (3r)
Yield: 35%; white solid; mp 100.6–103.2 °C.
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1H NMR (400 MHz, CDCl3):  = 8.57 (d, J = 8.2 Hz, 2 H), 7.96 (d, J = 9.2
Hz, 1 H), 7.87 (t, J = 71.6 Hz, 1 H), 7.73 (d, J = 8.2 Hz, 2 H), 7.56 (dd, J =
9.2, 2.8 Hz, 1 H), 7.37 (d, J = 2.6 Hz, 1 H), 3.98 (s, 3 H),
Supporting Information
13C NMR (100 MHz, CDCl3):  = 161.9, 159.0, 155.6, 148.6, 140.3, 132.1
(q, JC–F = 32 Hz), 123.0, 128.3, 127.7, 125.4 (q, JC–F = 3 Hz), 122.8, 114.6,
113.7 (t, JC–F = 257 Hz), 100.5, 55.9.
Supporting information for this article is available online at
https://doi.org/10.1055/a-1375-3538. Su
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19F NMR (376 MHz, CDCl3):  = –62.72, –89.96.
HRMS: m/z [M + H]+ calcd. for C17H12F5N2O2: 371.0813; found:
References
371.0812.
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H), 7.58 (dd, J = 9.2, 2.4 Hz, 1 H), 7.54–7.49 (m, 1 H), 7.44–7.37 (m, 3
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© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–G

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J. Peng et al.
Paper
Synthesis
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© 2021. Thieme. All rights reserved. Synthesis 2021, 53, A–G