Palladium(II)-Catalyzed Three-Component Tandem Cyclization Reaction for the One-Pot Assembly of 4-Arylquinazolines

Article abstract of DOI:10.1055/s-0040-1707329

A one-pot method for joining three separate components leading to an assortment of 4-arylquinazolines (27 examples) in good to excellent yields is described. The method consists of a palladium(II)-catalyzed?-cascade reaction involving C(sp)-C(sp ²

Full text of DOI:10.1055/s-0040-1707329

SYNTHESIS
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Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart
2020, 52, A–I
paper
A
en
Z. Wang et al.
Paper
Synthesis
Palladium(II)-Catalyzed Three-Component Tandem Cyclization
Reaction for the One-Pot Assembly of 4-Arylquinazolines
Zijuan Wang
Wenteng Chen
Chang He
NH2
R1
R2
CN
Pd(OAc)2, bpy
R3 OH
B
N
N
2 steps
78%
N
Et
N
Guolin Zhang*
Yongping Yu*
R2
AcOH, DMF, 100 °C
OH
R3
R1
EtO
OEt
N
O
OEt
TSPO ligand
(IC50 = 1.13 nM)
Zhejiang Province Key Laboratory of Anti-Cancer Drug
Research, College of Pharmaceutical Sciences, Zhejiang
University, 866 Yuhangtang Road, Zijin Campus,
Hangzhou 310058, P. R. of China
• 27 examples, up to 95% yield
• one-pot cascade reaction
• gram-scale synthesis
• good functional group tolerance
guolinzhang@zju.edu.cn
yyu@zju.edu.cn
Corresponding Authors
Received: 24.08.2020
Accepted after revision: 16.09.2020
Published online: 19.10.2020
Because of the broad biological properties of 4-
arylquinazolines, a large number of synthetic strategies for
their preparation have been developed. Especially, the strat-
egies using nitriles to attain 4-arylquinazolines have drawn
attention. In 2018, Chen and co-workers reported the ac-
cess to 2-(4-arylquinazolin-2-yl)anilines by a palladium-
catalyzed tandem reaction of 2-(quinazolinone-3(4H)-
yl)benzonitriles with arylboronic acids (Scheme 1a).17 This
preparation of 2-(4-arylquinazolin-2-yl)anilines involves
sequential nucleophilic addition and intramolecular cy-
clization, followed by ring opening. Then, they described a
palladium-catalyzed three-component tandem reaction of
2-aminobenzonitriles, aldehydes, and arylboronic acids to
obtain quinazolines (Scheme 1b).18 However, only benzal-
dehydes were researched for this reaction. In 2019, Liu and
co-workers reported the synthesis of 4-arylquinazolines
DOI: 10.1055/s-0040-1707329; Art ID: ss-2020-g0450-op
Abstract A one-pot method for joining three separate components
leading to an assortment of 4-arylquinazolines (27 examples) in good to
excellent yields is described. The method consists of a palladium(II)-
catalyzed cascade reaction involving C(sp)–C(sp2) coupling followed by
intramolecular C–N bond formation. The reaction was readily scaled up
to gram quantity and successfully applied to the synthesis of a
translocator protein (TSPO) ligand.
Key words 4-arylquinazolines, palladium(II) catalysis, one-pot assem-
bly, tandem cyclization reaction, ligands
The transition-metal-catalyzed transformation of ni-
triles is emerging as an important strategy for direct C–N
bond formation.1 Quinazoline derivatives, as an essential
family of N-fused heterocyclic compounds, have drawn
much attention due to their potential medicinal properties
and broad biological activities such as anti-inflammatory,2,3
antihypertensive,4 anticonvulsant, anticancer,5–8 and anti-
microbial activities.9–12 Among quinazoline derivatives, 4-
arylquinazolines are frequently found in bioactive com-
pounds and pharmaceuticals, such as NTRC-808 and trans-
locator protein (TSPO) ligand (Figure 1).13–16
from
(E)-N′-(2-cyanophenyl)-N,N-dimethylformimid-
amides and arylboronic acids via a palladium-catalyzed
tandem cyclization reaction (Scheme 1c).19
Although these methods successfully achieved the syn-
thesis of 4-arylquinazolines, it remains necessary to ex-
plore a new synthetic method for these compounds which
is more convenient and practical. Herein, to achieve the
high-value transformation of nitriles, we report a one-pot
method for the construction of 4-arylquinazolines from
commercially available 2-aminobenzonitriles, triethyl or-
thocarboxylates, and boronic acids via a palladium(II)-
catalyzed cascade reaction (Scheme 1).
Initially, the commercially available 2-amino-4-chloro-
benzonitrile (1a), triethyl orthoformate (2a), and phenylbo-
ronic acid (3a) were chosen as starting materials, and ex-
tensive investigations were carried out to establish the op-
timal reaction conditions. As shown in Table 1, the desired
product 4a was obtained in 11% yield when 1a, 2a, and 3a
were treated with Pd(OAc)2 (20 mol%) in DMF (2.0 mL) at
40 °C for 12 hours (entry 1). A study of the effect of
MeO
OMe
Cl
N
O
N
Et
N
H
N
N
OH
N
O
O
NTRC-808
TSPO ligand
Figure 1 Selected examples of bioactive molecules containing
4-arylquinazolines
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B
Z. Wang et al.
Paper
Synthesis
Table 1 Optimization of the Reaction Conditionsa
Previous work:
(a)
Ar
N
N
N
Cl
NH2
CN
[Pd], ligand
CN
O
EtO
OEt
OEt
N
OH
+
+
B
Pd(OAc)2, bpy
Ar
OH
additive, solvent
B
OH
+
Cl
N
TsOH·H2O, toluene, 80 °C
OH
1a
2a
3a
4a
H2N
Ar1
N
N
(b)
N
N
N
N
Pd(acac)2
5,5'-dimethyl-2,2'-dipyridyl
CN
Ar1
OH
NH2
L2
N
+ Ar2CHO
B
L1
L3
+
N
Ar2
TfOH, KF, DMF, 80 °C
OH
NH2
R
R
Entry [Pd]
Ligand Solvent
Temp Additive
(°C)
Yield
(%)b
(c)
R1
Ar
CN
R2
Ar
OH
N
Pd(acac)2, bpy
1
2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
L1
L1
L1
L1
L1
L1
L1
L1
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
40 AcOH
60 AcOH
11
R1
B
+
N
R2
TfOH, H2O, 60 °C
OH
N
N
48
3
80 AcOH
64
This work: Palladium(II)-catalyzed C(sp)–C(sp2) coupling and C–N condensation cascade
reactions
4
100 AcOH
120 AcOH
100 HCOOH
100 CF3COOH
100 FeCl3
100 AcOH
100 AcOH
100 AcOH
100 AcOH
100 AcOH
100 AcOH
100 AcOH
100 AcOH
100 AcOH
100 AcOH
100 AcOH
100 AcOH
100 AcOH
100 AcOH
100 AcOH
100 AcOH
72
R2
5
65
R2
Pd(OAc)2, bpy
R3 OH
B
+
NH2
CN
N
N
EtO
OEt
R1
6
28
+
AcOH, DMF, 100 °C
R3
OH
OEt
R1
7
36
8
21
Scheme 1 Construction of the 4-arylquinazoline skeleton
9
Pd(PPh3)2Cl2 L1
33
10
11
12
13
14
15
16
17
18
19c
20d
21e
22f
23g
24h
Pd(PPh3)4
–
L1
L1
L2
L3
–
trace
trace
31
temperature showed that 100 °C was the best temperature
for this reaction (entries 1–5). Replacement of acetic acid
with other additives, including formic acid, trifluoroacetic
acid, and FeCl3, resulted in relatively lower yields (entries 6–
8). Next, different palladium catalysts were used to explore
their catalytic capability; the results revealed that Pd(OAc)2
was the best catalyst for this cascade reaction (entries 4, 9–
11). Ligand screening showed that 2,2′-bipyridine (bpy, L1)
gave the highest yield of 4a (entries 4, 12–14). Clearly, DMF
stood out as the best choice of solvent for further reactions,
with its highest product yield (entries 4, 15–18). A de-
creased amount of Pd(OAc)2 reduced the reaction yield,
while an increase in the catalyst loading did not lead to a
significant increase in the yield (entries 19 and 20). Similar-
ly, decreasing the amount of triethyl orthoformate (2a) to 3
equivalents or phenylboronic acid (3a) to 1.5 equivalents
influenced the reaction, with lower yields (entries 21 and
22). Increasing the amount of 2a to 5 equivalents or 3a to
2.5 equivalents did not produce a noticeable change in the
yield of 4a (entries 23 and 24). Therefore, the best reaction
conditions were obtained when 2-amino-4-chlorobenzoni-
trile (1 mmol), triethyl orthoformate (4 mmol), and phenyl-
boronic acid (2 mmol) were stirred in DMF (2.0 mL) at 100
°C for 12 hours in the presence of Pd(OAc)2 (20 mol%), bpy
(20 mol%), and AcOH (1 equiv) (Table 1, entry 4).
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
56
trace
13
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
toluene
MeCN
EtOH
DMSO
DMF
trace
28
21
47
DMF
73
DMF
67
DMF
61
DMF
73
DMF
73
a Reaction conditions: 1a (1 mmol), 2a (4 mmol), 3a (2 mmol), [Pd] (20
mol%), ligand (20 mol%), additive (1.0 equiv), solvent (2 mL), 12 h.
b Isolated yield.
c Pd(OAc)2 catalyst (10 mol%) was used.
d Pd(OAc)2 catalyst (30 mol%) was used.
e 2a (3 equiv) was used.
f 3a (1.5 equiv) was used.
g 2a (5 equiv) was used.
h 3a (2.5 equiv) was used.
Having optimized the reaction conditions, we evaluated
the scope of 2-aminobenzonitriles. As shown in Scheme 2,
the corresponding products 4a–4m were obtained in good
to excellent yields (61–91%) regardless of the electronic na-
ture and position of the substituent attached to the phenyl
ring of the 2-aminobenzonitriles. When the substituent
was at different positions of the phenyl ring, the results
showed that steric effects affected the yield of this transfor-
mation to some extent (Scheme 2, 4a–4c, 4d–4f). Then,
when 2-aminobenzonitriles bearing an electron-withdraw-
ing group were used, the reaction gave the desired 4-
arylquinazolines in higher yields (4g vs 4i, 4j vs 4k). Nota-
bly, products 4l and 4m with a bromo substituent were
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

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Z. Wang et al.
Paper
Synthesis
R2
R2
H/Me
NH2
EtO
Pd(OAc)2, bpy
AcOH, DMF, 100 °C
N
N
OEt
R1
+
+
B
OEt
CN
R1
HO
OH
H/Me
1
2
3
4
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Cl
Cl
Cl
Cl
Cl
Cl
Cl
4a, 72%
4b, 61%
4c, 80%
4d, 86%
4e, 77%
4f, 66%
4g, 86%
N
N
N
N
N
N
N
N
N
N
N
N
Br
Cl
Br
4h, 77%
4i, 71%
4j, 91%
4k, 82%
4l, 84%
4m, 76%
Scheme 2 Reaction scope of 2-aminobenzonitriles. Reagents and conditions: 1 (1 mmol), 2 (4 mmol), 3 (2 mmol), Pd(OAc)2 (20 mol%), bpy (20 mol%),
AcOH (1.0 equiv), DMF (2 mL), 100 °C, 12 h; isolated yields.
smoothly produced in excellent yields (4l, 84%; 4m, 76%),
thus allowing for further transformations to form more
complex molecules via cross-coupling reactions.
evaluated, and the results demonstrated that the steric ef-
fect of the substituent had an obvious impact on the reac-
tion. For example, treatment of 2-aminobenzonitrile and
triethyl orthoacetate with p- and m-chlorophenylboronic
acid provided 5j in 74% yield and 5k in 66% yield, respec-
tively, while o-chlorophenylboronic acid did not afford the
desired product 5l. Cyclohexylboronic acid did not give the
desired product 5m, probably because it is not easy to un-
dergo the transmetalation reaction with Pd(OAc)2 as cata-
lyst.
We next turned our attention to the effect of boronic ac-
ids on the reaction under the standard conditions. Boronic
acids containing an electron-donating substituent were
more compatible for this transformation, giving higher
yields (Scheme 3; 5a–5d, 5e–5g vs 5j). However, 4-(trifluo-
romethyl)phenylboronic acid had no activity under the re-
action conditions, possibly due to the strong electron-with-
drawing effects of the trifluoromethyl group (5d). 4-Bi-
phenylboronic acid gave product 5h in 46% yield, probably
due to the steric effects of the phenyl ring. Then, the reac-
tivities of p-, m-, and o-chlorophenylboronic acid were
As for triethyl orthocarboxylates, the scope of the reac-
tion was also examined under the standard reaction condi-
tions. The results showed that triethyl orthoacetate gave
higher yields than triethyl orthoformate (Scheme 3; 5b vs
R2
R2
R3 OH
B
Pd(OAc)2, bpy
NH2
CN
N
N
EtO
OEt
+
+
R3
OH
AcOH, DMF, 100 °C
OEt
1d
2
3
5
N
N
N
N
N
N
N
N
N
N
N
N
N
N
CF3
O
Cl
O
5a, 81%
5b, 64%
5c, 56%
5d, trace
5e, 95%
5f, 88%
5g, 90%
N
N
N
N
N
N
N
N
N
N
Cl
N
N
N
N
Cl
Cl
5h, 46%
5i, 79%
5j, 74%
5k, 66%
5l, trace
5m, trace
5n, 46%
Scheme 3 Reaction scope of boronic acids. Reagents and conditions: 1d (1 mmol), 2 (4 mmol), 3 (2 mmol), Pd(OAc)2 (20 mol%), bpy (20 mol%), AcOH
(1.0 equiv), DMF (2 mL), 100 °C, 12 h; isolated yields.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

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Synthesis
N
N
NH2
EtO
Pd(OAc)2, bpy
OEt
OEt
OH
+
+
B
AcOH, DMF, 100 °C
CN
OH
1d
2b
3a
5i
1.06 g
1.50 g, 76%
COOH
N
N
H
N
N
N
SeO2
N
N
Et
N
pyridine, reflux
DIEA, HOBt, HBTU
THF/DMF (7:2), rt
O
5i
6
7, 78%
TSPO ligand (IC50 = 1.13 nM)
Scheme 4 Gram-scale synthesis of 5i and its further derivatization
5i, 5c vs 5j), possibly because intermediate 8 is more stable
(see Scheme 6). Additionally, triethyl orthobenzoate afford-
ed product 5n in 46% yield, which demonstrated that the
steric effect of the substituent (R2) had an impact on the re-
action (5f vs 5n).
To further demonstrate the practicality of this method,
we next scaled up the reaction. The reaction with 2-amino-
benzonitrile was performed on a gram scale (1.06 g, 9
mmol), and product 5i was obtained in 76% yield (Scheme
4). Then, product 5i was applied to the synthesis of bioac-
tive compound 7, which is a highly potent and selective
TSPO ligand,11 in a two-step method with high efficiency.
Similarly, our 4-arylquinazoline products could also be used
to synthesize other TSPO ligands.
Then, (2-amino-4-chlorophenyl)(phenyl)methanone (9a)
was gained in 42% yield from the reaction of 1a with 3a in
the absence of 2a. However, conducting the reaction of 1a
and 3a for 12 hours, then adding 2a to the reaction mixture,
did not afford product 4a, indicating that 8a is the possible
intermediate for this transformation.
On the basis of the preliminary results and previous re-
ports,17,20–22 a plausible mechanism for this transformation
is illustrated in Scheme 6. The reaction of 1 with 2 will pro-
duce intermediate 8, which participates in the catalytic cy-
cle. Initially, the transmetalation reaction of the Pd(II) cata-
lyst with arylboronic acid provides intermediate B, which is
followed by coordination of the N atom of the cyano group
to give intermediate C. Carbopalladation of the cyano group
generates the corresponding ketimine–Pd(II) complex D.
Then, intermediate D exchanges with AcOH to produce ket-
imine derivative E and to regenerate the Pd(II) catalyst.
Finally, cyclization of ketimine derivative E affords the cor-
responding 4-arylquinazoline F.
To gain insight into the reaction mechanism, four con-
trol experiments were performed (Scheme 5). First, the re-
action of 1a with 2a produced intermediate 8a in 87% yield.
The desired product 4a could be synthesized successfully in
considerable yield (74%) from the reaction of 8a with 3a.
(a)
Cl
NH2
CN
Cl
N
OEt
Pd(OAc)2, bpy
EtO
OEt
OEt
+
AcOH, DMF, 100 °C, 12 h
CN
1a
2a
8a, 87%
N
N
OH
B
(b)
(c)
(d)
Pd(OAc)2, bpy
Cl
Cl
N
OEt
OH
+
AcOH, DMF, 100 °C, 12 h
Cl
CN
8a
1a
3a
4a, 74%
Ph
OH
NH2
CN
B
Pd(OAc)2, bpy
OH
O
+
+
AcOH, DMF, 100 °C, 12 h
Cl
NH2
9a, 42%
3a
3a
OEt
OH
B
N
N
Cl
NH2
CN
Pd(OAc)2, bpy
EtO
OEt
OH
AcOH, DMF, 100 °C, 12 h
Cl
1a
4a, no reaction
Scheme 5 Control experiments
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

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Synthesis
Pd(OAc)2
L
EtO
R2
HN
Ar
HO
OH
Pd(OAc)2L
N
B
R1
Ar
A
E
AcOH
AcO
Pd
N
L
R2
EtO Ar
R2
ArPd(OAc)L
N
N
N
R2
B
R1
R2
OEt
EtO
OEt
Ar
Ar
L
R1
OAc
NH2
N
Pd
N
OEt
2
D
CN
CN
F
R1
EtO
R2
R1
N
8
1
R1
C
Scheme 6 Plausible mechanism for the transformation
In conclusion, a straightforward one-pot assembly of 4-
arylquinazolines has been successfully developed. It in-
volves a palladium(II)-catalyzed cascade reaction from
commercially available 2-aminobenzonitriles, triethyl or-
thocarboxylates, and boronic acids in good to excellent
yields (up to 95% yield). This reaction features good func-
tional group tolerance and can be scaled up to gram quanti-
ty. Moreover, this synthetic protocol is able to act as an effi-
cient strategy to synthesize biologically active 4-
arylquinazoline derivatives.
HRMS (ESI): m/z calcd for C14H10ClN2 [M + H]+: 241.0527; found:
241.0521.
8-Chloro-4-phenylquinazoline (4b)
Yield: 146.8 mg (61%); pale yellow solid; mp 96–97 °C (Lit.23 95–97
°C).
IR (KBr): 3389, 3346, 3034, 2875, 1745, 1568, 1034, 855, 776 cm–1
.
1H NMR (500 MHz, CDCl3):  = 9.49 (s, 1 H), 8.07 (dd, J = 8.5, 1.5 Hz, 1
H), 8.02 (dd, J = 7.5, 1.5 Hz, 1 H), 7.80–7.72 (m, 2 H), 7.62–7.56 (m, 3
H), 7.53 (dd, J = 8.5, 7.5 Hz, 1 H).
HRMS (ESI): m/z calcd for C14H10ClN2 [M + H]+: 241.0527; found:
241.0534.
All solvents were purified according to standard methods prior to use.
Melting points were recorded on a Büchi B-540 melting point appara-
6-Chloro-4-phenylquinazoline (4c)
tus. NMR spectra were recorded at 500 MHz (1H NMR) and 125 MHz
Yield: 192.6 mg (80%); pale yellow solid; mp 135–137 °C.
IR (KBr): 3366, 3335, 3065, 2965, 1776, 1534, 1034, 834, 723 cm–1
1H NMR (500 MHz, CDCl3):  = 9.38 (s, 1 H), 8.11 (d, J = 2.5 Hz, 1 H),
8.07 (d, J = 9.0 Hz, 1 H), 7.85 (dd, J = 9.0, 2.5 Hz, 1 H), 7.78–7.74 (m, 2
H), 7.63–7.58 (m, 3 H).
13C NMR (125 MHz, CDCl3):  = 167.75, 154.14, 149.80, 140.26,
137.90, 135.95, 134.61, 130.00, 129.46, 128.66, 125.85, 123.30.
HRMS (ESI): m/z calcd for C14H10ClN2 [M + H]+: 241.0527; found:
1
(
13C NMR). For H NMR, TMS served as internal standard ( = 0) and
.
data are reported as follows: chemical shift, multiplicity (standard
abbreviations), coupling constant(s) in hertz, and integration. For 13
C
NMR, TMS ( = 0) was used as internal standard and spectra were ob-
tained with complete proton decoupling. HRMS data were obtained
using an Agilent Technologies 6224 TOF LC/MS system. The starting
materials were commercially available.
241.0533.
4-Arylquinazolines 4 and 5; General Procedure
A mixture of 2-aminobenzonitrile 1 (1.0 mmol, 1.0 equiv), triethyl or-
thocarboxylate 2 (4.0 mmol, 4.0 equiv), boronic acid 3 (2.0 mmol, 2.0
equiv), AcOH (1.0 mmol, 1.0 equiv), bpy (0.2 mmol, 0.2 equiv), and
Pd(OAc)2 (0.2 mmol, 0.2 equiv) was stirred in DMF (2.0 mL) at 100 °C
for 12 h. After reaction completion, the mixture was filtered through
diatomite. Water (10 mL) was added to the filtrate. The aqueous phase
was extracted with EtOAc (3 × 10 mL). The organic layer was washed
with brine, dried over Na2SO4, concentrated in vacuo, and purified by
flash column chromatography (PE/EtOAc, 20:1) to yield 4 or 5.
6-Chloro-2-methyl-4-phenylquinazoline (4d)
Yield: 218.5 mg (86%); white solid; mp 105–106 °C (Lit.25 105–107
°C).
IR (KBr): 3323, 3286, 3024, 2928, 1726, 1524, 1068, 857, 702 cm–1
.
1H NMR (500 MHz, CDCl3):  = 8.01 (s, 1 H), 7.95 (d, J = 9.0 Hz, 1 H),
7.79 (d, J = 9.0 Hz, 1 H), 7.76–7.69 (m, 2 H), 7.61–7.55 (m, 3 H), 2.93 (s,
3 H).
HRMS (ESI): m/z calcd for C15H12ClN2 [M + H]+: 255.0684; found:
255.0687.
7-Chloro-4-phenylquinazoline (4a)
Yield: 173.3 mg (72%); pale yellow solid; mp 134–135 °C (Lit.23 134–
136 °C).
7-Chloro-2-methyl-4-phenylquinazoline (4e)
Yield: 196.1 mg (77%); pale yellow solid; mp 104–105 °C.
IR (KBr): 3299, 3278, 3023, 2943, 1756, 1523, 1074, 867, 723 cm–1
IR (KBr): 3390, 3301, 3044, 2946, 1711, 1543, 1069, 820, 723 cm–1
1H NMR (500 MHz, CDCl3):  = 9.36 (s, 1 H), 8.11 (d, J = 2.0 Hz, 1 H),
8.08 (d, J = 9.0 Hz, 1 H), 7.78–7.72 (m, 2 H), 7.60–7.52 (m, 4 H).
.
.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

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Synthesis
1H NMR (500 MHz, CDCl3):  = 8.02–7.96 (m, 2 H), 7.76–7.68 (m, 2 H),
7.60–7.52 (m, 3 H), 7.46 (dd, J = 8.5, 2.0 Hz, 1 H), 2.93 (s, 3 H).
13C NMR (125 MHz, CDCl3):  = 168.61, 165.15, 152.20, 139.99,
136.98, 130.26, 129.91, 128.87, 128.61, 127.93, 127.37, 119.56, 26.77.
HRMS (ESI): m/z calcd for C15H12ClN2 [M + H]+: 255.0684; found:
1H NMR (500 MHz, CDCl3):  = 8.04 (d, J = 2.0 Hz, 1 H), 7.94 (d, J = 9.0
Hz, 1 H), 7.78 (dd, J = 9.0, 2.0 Hz, 1 H), 7.64 (d, J = 8.0 Hz, 2 H), 7.39 (d,
J = 7.5 Hz, 2 H), 2.92 (s, 3 H), 2.48 (s, 3 H).
13C NMR (125 MHz, CDCl3):  = 167.89, 164.28, 150.03, 140.58,
134.54, 133.97, 132.31, 129.99, 129.87, 129.62, 125.96, 121.70, 26.69,
21.58.
255.0687.
HRMS (ESI): m/z calcd for C16H14ClN2 [M + H]+: 269.0840; found:
269.0845.
8-Chloro-2-methyl-4-phenylquinazoline (4f)
Yield: 168.1 mg (66%); pale yellow solid; mp 83–84 °C.
IR (KBr): 3323, 3304, 3024, 2945, 1767, 1578, 1035, 831, 703 cm–1
1H NMR (500 MHz, CDCl3):  = 7.95 (t, J = 8.5 Hz, 2 H), 7.75–7.69 (m, 2
H), 7.59–7.52 (m, 3 H), 7.42 (t, J = 8.0 Hz, 1 H), 3.01 (s, 3 H).
13C NMR (125 MHz, CDCl3):  = 169.15, 164.88, 148.19, 137.05,
133.51, 132.65, 130.19, 129.99, 128.77, 126.42, 126.20, 122.40, 27.06.
HRMS (ESI): m/z calcd for C15H12ClN2 [M + H]+: 255.0684; found:
255.0693.
2,6-Dimethyl-4-(p-tolyl)quinazoline (4k)
.
Yield: 203.6 mg (82%); pale yellow solid; mp 104–105 °C.
IR (KBr): 3336, 3327, 3046, 2928, 1780, 1503, 1035, 867, 789 cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.89 (d, J = 8.5 Hz, 1 H), 7.81 (s, 1 H),
7.68 (dd, J = 9.0, 2.0 Hz, 1 H), 7.64 (d, J = 8.5 Hz, 2 H), 7.37 (d, J = 8.0 Hz,
2 H), 2.91 (s, 3 H), 2.47 (s, 3 H), 2.47 (s, 3 H).
13C NMR (125 MHz, CDCl3):  = 167.96, 163.10, 150.09, 139.98,
136.71, 135.85, 134.74, 129.89, 129.40, 127.89, 125.79, 121.10, 26.63,
21.88, 21.56.
6-Chloro-4-(p-tolyl)quinazoline (4g)
Yield: 219.1 mg (86%); white solid; mp 162–163 °C (Lit.24 163–164
°C).
HRMS (ESI): m/z calcd for C17H17N2 [M + H]+: 249.1386; found:
249.1393.
IR (KBr): 3334, 3299, 3034, 2956, 1745, 1535, 1046, 846, 756 cm–1
.
6-Bromo-2-methyl-4-(p-tolyl)quinazoline (4l)
1H NMR (500 MHz, CDCl3):  = 9.35 (s, 1 H), 8.13 (d, J = 2.5 Hz, 1 H),
8.05 (d, J = 9.0 Hz, 1 H), 7.84 (dd, J = 9.0, 2.5 Hz, 1 H), 7.68 (d, J = 8.0 Hz,
2 H), 7.41 (d, J = 7.5 Hz, 2 H), 2.49 (s, 3 H).
HRMS (ESI): m/z calcd for C15H12ClN2 [M + H]+: 255.0684; found:
255.0685.
Yield: 263.1 mg (84%); pale yellow solid; mp 116–117 °C.
IR (KBr): 3379, 3334, 3056, 2937, 1739, 1555, 1096, 857, 710 cm–1
1H NMR (500 MHz, CDCl3):  = 8.21 (d, J = 2.0 Hz, 1 H), 7.94–7.85 (m, 2
H), 7.64 (d, J = 8.0 Hz, 2 H), 7.39 (d, J = 7.5 Hz, 2 H), 2.92 (s, 3 H), 2.48
(s, 3 H).
.
13C NMR (125 MHz, CDCl3):  = 167.86, 164.41, 150.27, 140.66,
137.16, 133.98, 130.11, 129.92, 129.69, 129.33, 122.27, 120.35, 26.77,
21.62.
HRMS (ESI): m/z calcd for C16H14BrN2 [M + H]+: 313.0335; found:
313.0338.
4-(p-Tolyl)quinazoline (4h)
Yield: 169.6 mg (77%); pale yellow solid; mp 42–43 °C (Lit.19 41–42
°C).
IR (KBr): 3322, 3298, 3034, 2945, 1756, 1578, 1039, 833, 721 cm–1
.
1H NMR (500 MHz, CDCl3):  = 9.36 (s, 1 H), 8.16 (dd, J = 8.5, 1.5 Hz, 1
H), 8.10 (d, J = 8.5 Hz, 1 H), 7.91 (ddd, J = 8.5, 7.0, 1.5 Hz, 1 H), 7.70 (d,
J = 8.0 Hz, 2 H), 7.60 (ddd, J = 8.5, 7.0, 1.5 Hz, 1 H), 7.38 (d, J = 8.0 Hz, 2
H), 2.48 (s, 3 H).
HRMS (ESI): m/z calcd for C15H13N2 [M + H]+: 221.1073; found:
221.1068.
6-Bromo-4-phenylquinazoline (4m)
Yield: 215.8 mg (76%); pale yellow solid; mp 88–89 °C (Lit.19 89–90
°C).
IR (KBr): 3334, 3307, 3045, 2966, 1736, 1564, 1078, 835, 778 cm–1
.
1H NMR (500 MHz, CDCl3):  = 9.39 (s, 1 H), 8.27 (dd, J = 2.0, 1.0 Hz, 1
H), 8.02–7.95 (m, 2 H), 7.80–7.73 (m, 2 H), 7.64–7.57 (m, 3 H).
HRMS (ESI): m/z calcd for C14H10BrN2 [M + H]+: 285.0022; found:
6-Methyl-4-(p-tolyl)quinazoline (4i)
Yield: 166.4 mg (71%); yellow solid; mp 96–97 °C.
285.0029.
IR (KBr): 3345, 3235, 3055, 2967, 1745, 1587, 1023, 845, 767 cm–1
.
1H NMR (500 MHz, CDCl3):  = 9.30 (s, 1 H), 8.00 (d, J = 8.5 Hz, 1 H),
7.90 (s, 1 H), 7.73 (dd, J = 9.0, 2.0 Hz, 1 H), 7.68 (d, J = 8.0 Hz, 2 H), 7.39
(d, J = 7.5 Hz, 2 H), 2.51 (s, 3 H), 2.48 (s, 3 H).
13C NMR (125 MHz, CDCl3):  = 167.75, 154.14, 149.80, 140.26,
137.90, 135.95, 134.61, 130.00, 129.46, 128.66, 125.85, 123.30, 22.04,
21.60.
4-(4-Methoxyphenyl)quinazoline (5a)
Yield: 191.4 mg (81%); white solid; mp 82–83 °C (Lit.19 83–84 °C).
IR (KBr): 3369, 3305, 3064, 2936, 1757, 1584, 858, 722 cm–1
1H NMR (500 MHz, CDCl3):  = 9.33 (s, 1 H), 8.17 (d, J = 8.5 Hz, 1 H),
8.09 (d, J = 8.5 Hz, 1 H), 7.89 (ddd, J = 8.5, 7.0, 1.5 Hz, 1 H), 7.78 (d, J =
9.0 Hz, 2 H), 7.60 (ddd, J = 8.5, 7.0, 1.5 Hz, 1 H), 7.09 (d, J = 8.5 Hz, 2 H),
3.91 (s, 3 H).
.
HRMS (ESI): m/z calcd for C16H15N2 [M + H]+: 235.1230; found:
235.1232.
HRMS (ESI): m/z calcd for C15H13N2O [M + H]+: 237.1022; found:
237.1024.
6-Chloro-2-methyl-4-(p-tolyl)quinazoline (4j)
Yield: 244.6 mg (91%); pale yellow solid; mp 125–126 °C.
IR (KBr): 3306, 3300, 3045, 2945, 1745, 1565, 1034, 832, 726 cm–1
4-Phenylquinazoline (5b)
Yield: 132.0 mg (64%); pale yellow solid; mp 96–97 °C (Lit.26 95–97
.
°C).
IR (KBr): 3301, 3035, 2968, 1677, 1589, 1057, 857, 798 cm–1
.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

G
Z. Wang et al.
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Synthesis
1H NMR (500 MHz, CDCl3):  = 9.38 (s, 1 H), 8.12 (t, J = 8.5 Hz, 2 H),
7.91 (t, J = 6.5 Hz, 1 H), 7.81–7.74 (m, 2 H), 7.63–7.55 (m, 4 H).
HRMS (ESI): m/z calcd for C14H11N2 [M + H]+: 207.0917; found:
2-Methyl-4-phenylquinazoline (5i)
Yield: 170.4 mg (79%); yellow solid; mp 48–49 °C (Lit.19 47–48 °C).
IR (KBr): 3378, 3356, 3078, 2945, 1789, 1530, 1035, 864, 773 cm–1
1H NMR (500 MHz, CDCl3):  = 8.04 (d, J = 8.5 Hz, 1 H), 8.02–7.99 (m, 1
H), 7.86 (t, J = 8.5 Hz, 1 H), 7.77–7.71 (m, 2 H), 7.58–7.54 (m, 3 H), 7.51
(t, J = 7.0 Hz, 1 H), 2.95 (s, 3 H).
.
207.0923.
4-(4-Chlorophenyl)quinazoline (5c)
Yield: 134.8 mg (56%); pale yellow solid; mp 117–119 °C (Lit.26 116–
118 °C).
HRMS (ESI): m/z calcd for C15H13N2 [M + H]+: 221.1073; found:
221.1077.
IR (KBr): 3409, 3345, 3005, 2960, 1706, 1500, 1057, 857, 713 cm–1
.
1H NMR (500 MHz, CDCl3):  = 9.37 (s, 1 H), 8.12 (d, J = 8.5 Hz, 1 H),
8.08 (d, J = 8.5 Hz, 1 H), 7.93 (ddd, J = 8.5, 7.0, 1.5 Hz, 1 H), 7.74 (d, J =
8.0 Hz, 2 H), 7.63 (ddd, J = 8.5, 7.0, 1.5 Hz, 1 H), 7.56 (d, J = 8.5 Hz, 2 H).
HRMS (ESI): m/z calcd for C14H10ClN2 [M + H]+: 241.0527; found:
241.0537.
4-(4-Chlorophenyl)-2-methylquinazoline (5j)
Yield: 188.5 mg (74%); white solid; mp 127–128 °C (Lit.19 128–129
°C).
IR (KBr): 3387, 3324, 3078, 2685, 1774, 1504, 1025, 876, 711 cm–1
1H NMR (500 MHz, CDCl3):  = 8.01 (t, J = 9.5 Hz, 2 H), 7.88 (ddd, J =
.
8.5, 7.0, 1.5 Hz, 1 H), 7.74–7.68 (m, 2 H), 7.58–7.52 (m, 3 H), 2.94 (s, 3
H).
HRMS (ESI): m/z calcd for C15H12ClN2 [M + H]+: 255.0684; found:
4-(4-Methoxyphenyl)-2-methylquinazoline (5e)
Yield: 237.8 mg (95%); yellow solid; mp 47–48 °C (Lit.19 48–49 °C).
IR (KBr): 3466, 3336, 3046, 2888, 1768, 1536, 1089, 858, 725 cm–1
.
255.0691.
1H NMR (500 MHz, CDCl3):  = 8.09 (d, J = 8.5 Hz, 1 H), 7.99 (d, J = 8.5
Hz, 1 H), 7.84 (ddd, J = 8.5, 7.0, 1.5 Hz, 1 H), 7.74 (d, J = 8.5 Hz, 2 H),
7.51 (ddd, J = 8.0, 7.0, 1.0 Hz, 1 H), 7.08 (d, J = 9.0 Hz, 2 H), 3.90 (s, 3 H),
2.93 (s, 3 H).
HRMS (ESI): m/z calcd for C16H15N2O [M + H]+: 251.1179; found:
251.1184.
4-(3-Chlorophenyl)-2-methylquinazoline (5k)
Yield: 168.1 mg (66%); pale yellow solid; mp 84–85 °C.
IR (KBr): 3396, 3324, 3066, 2846, 1766, 1589, 1038, 868, 710 cm–1
.
1H NMR (500 MHz, CDCl3):  = 8.03 (d, J = 8.5 Hz, 1 H), 8.00 (d, J = 8.0
Hz, 1 H), 7.88 (ddd, J = 8.5, 7.0, 1.5 Hz, 1 H), 7.75 (t, J = 1.5 Hz, 1 H),
7.62 (dt, J = 7.5, 1.5 Hz, 1 H), 7.58–7.52 (m, 2 H), 7.52–7.47 (m, 1 H),
2.95 (s, 3 H).
13C NMR (125 MHz, CDCl3):  = 167.15, 163.96, 151.60, 139.09,
134.90, 134.03, 130.08, 130.01, 129.95, 128.43, 128.15, 127.19,
126.67, 120.93, 26.71.
2-Methyl-4-(p-tolyl)quinazoline (5f)
Yield: 206.2 mg (88%); white solid; mp 94–95 °C (Lit.19 93–94 °C).
IR (KBr): 3406, 3357, 3078, 2964, 1736, 1568, 1047, 857, 709 cm–1
.
1H NMR (500 MHz, CDCl3):  = 8.08 (d, J = 8.5 Hz, 1 H), 8.00 (d, J = 8.5
Hz, 1 H), 7.89–7.81 (m, 1 H), 7.66 (d, J = 6.5 Hz, 2 H), 7.55–7.49 (m, 1
H), 7.37 (d, J = 7.5 Hz, 2 H), 2.94 (s, 3 H), 2.47 (s, 3 H).
HRMS (ESI): m/z calcd for C15H12ClN2 [M + H]+: 255.0684; found:
255.0680.
HRMS (ESI): m/z calcd for C16H15N2 [M + H]+: 235.1230; found:
235.1239.
2-Phenyl-4-(p-tolyl)quinazoline (5n)
Yield: 136.3 mg (46%); yellow solid; mp 125–126 °C (Lit.18 126–127
2-Methyl-4-(4-ethylphenyl)quinazoline (5g)
°C).
IR (KBr): 3357, 3300, 3057, 2967, 1734, 1512, 866, 744 cm–1
.
Yield: 223.5 mg (90%); colorless oil.
IR (KBr): 3356, 3308, 3111, 2946, 1756, 1567, 1068, 865, 727 cm–1
.
1H NMR (500 MHz, CDCl3):  = 8.73–8.66 (m, 2 H), 8.18–8.13 (m, 2 H),
7.88 (ddd, J = 8.5, 7.0, 1.5 Hz, 1 H), 7.81 (d, J = 8.0 Hz, 2 H), 7.58–7.48
(m, 4 H), 7.41 (d, J = 7.5 Hz, 2 H), 2.50 (s, 3 H).
HRMS (ESI): m/z calcd for C21H17N2 [M + H]+: 297.1386; found:
297.1381.
1H NMR (500 MHz, CDCl3):  = 8.01 (d, J = 8.5 Hz, 1 H), 7.86 (ddd, J =
8.5, 7.0, 1.5 Hz, 1 H), 7.61 (d, J = 8.0 Hz, 1 H), 7.46 (ddd, J = 8.0, 7.0, 1.5
Hz, 2 H), 7.41 (d, J = 6.5 Hz, 1 H), 7.33 (td, J = 7.5, 1.5 Hz, 1 H), 7.27 (dd,
J = 7.5, 1.5 Hz, 1 H), 2.95 (s, 3 H), 1.73 (s, 2 H), 1.02 (t, J = 7.5 Hz, 3 H).
HRMS (ESI): m/z calcd for C17H17N2 [M + H]+: 249.1386; found:
249.1378.
Synthesis of TSPO Ligand 7
4-Phenylquinazoline-2-carboxylic Acid (6)
4-(1,1′-Biphenyl-4-yl)-2-methylquinazoline (5h)
Yield: 139.3 mg (46%); white solid; mp 156–157 °C (Lit.19 155–156
°C).
A mixture of 5i (5 mmol), selenium dioxide (5 mmol), and pyridine (5
mL) was refluxed for 2 h. Reaction progress was monitored by TLC. Af-
ter reaction completion, the mixture was concentrated under reduced
pressure, then water (10 mL) was added, which was followed by acid-
ification with 1 N HCl. The mixture was filtered to afford product 6.
IR (KBr): 3357, 3346, 3035, 2467, 1746, 1556, 1024, 867, 778 cm–1
.
1H NMR (500 MHz, CDCl3):  = 8.14 (d, J = 8.5 Hz, 1 H), 8.03 (d, J = 8.5
Hz, 1 H), 7.93–7.82 (m, 3 H), 7.83–7.76 (m, 2 H), 7.70–7.65 (m, 2 H),
7.56 (ddd, J = 8.0, 7.0, 1.0 Hz, 1 H), 7.52–7.46 (m, 2 H), 7.45–7.37 (m, 1
H), 2.97 (s, 3 H).
Yield: 1.1 g (91%); pale pink solid; mp 97–98 °C (Lit.16b 98 °C).
IR (KBr): 3511, 3356, 3035, 2888, 2135, 1464, 1068, 811, 703 cm–1
.
1H NMR (500 MHz, DMSO-d6):  = 8.25–8.06 (m, 3 H), 7.89–7.77 (m, 3
H), 7.65 (s, 3 H), 3.36 (s, 1 H).
HRMS (ESI): m/z calcd for C21H17N2 [M + H]+: 297.1386; found:
297.1381.
HRMS (ESI): m/z calcd for C15H11N2O2 [M + H]+: 251.0815; found:
251.0811.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

H
Z. Wang et al.
Paper
Synthesis
N-Benzyl-N-ethyl-4-phenylquinazoline-2-carboxamide (7)
(d) 2-Aminobenzonitrile 1a (1.0 mmol), phenylboronic acid (3a; 2.0
mmol), AcOH (1.0 mmol), bpy (0.2 mmol), and Pd(OAc)2 (0.2 mmol)
were stirred in DMF (2.0 mL) at 100 °C for 12 h. Then, triethyl ortho-
formate (2a; 4.0 mmol) was added to the solution for further reaction.
A solution of acid 6 (268 mg, 1.07 mmol), HOBt (328 mg, 2.14 mmol),
HBTU (812 mg, 2.14 mmol), and DIEA (0.76 mL, 4.28 mmol) in anhy-
drous THF/DMF (7:2, 9 mL) was added to a solution of N-benzylethan-
amine (144 mg, 1.07 mmol) in anhydrous THF (3 mL) under an N2 at-
mosphere. The reaction mixture was stirred at room temperature
overnight and then concentrated in vacuo. The residue was dissolved
in EtOAc (100 mL), and the mixture was washed with sat. aq NaHCO3
solution (3 × 30 mL) and brine. The organic solution was dried
(Na2SO4), filtered, and concentrated in vacuo. Purification by flash
column chromatography (PE/EtOAc, 10:1) afforded compound 7.
Funding Information
This project was supported by the National Key Research and Devel-
opment Program of China (No. 2017YFE0102200), the National Natu-
ral Science Foundation of China (No. 81673291), and the Diabetes
National Research Group, USA (to Y.Y.). The authors also acknowledge
the Natural Science Foundation of Zhejiang Province (No.
LY18H300001) and the Multiple Sclerosis National Research Institute,
Yield: 307 mg (78%, based on 6); white solid; mp 69–70 °C (Lit.16b 68–
71 °C).
IR (KBr): 3478, 3356, 3025, 2977, 1630, 1036, 827, 711 cm–1
.
USA (to W.C.).Nati
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1H NMR (500 MHz, DMSO-d6):  = 8.19–8.05 (m, 3 H), 7.85–7.77 (m, 2
H), 7.73–7.68 (m, 1 H), 7.67–7.57 (m, 3 H), 7.44–7.37 (m, 3 H), 7.33–
7.23 (m, 2 H), 4.76, 4.44 (2 s, 2 H), 3.42, 3.14 (2 q, J = 7.0 Hz, 2 H), 1.12,
1.07 (2 t, J = 7.0 Hz, 3 H).
HRMS (ESI): m/z calcd for C24H22N3O [M + H]+: 368.1757; found:
368.1764.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1707329. Su
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ortingInformatio
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Control Experiments (Scheme 5)
References
(a) 2-Aminobenzonitrile 1a (1.0 mmol), triethyl orthoformate (2a; 4.0
mmol), AcOH (1.0 mmol), bpy (0.2 mmol), and Pd(OAc)2 (0.2 mmol)
were stirred in DMF (2.0 mL) at 100 °C for 12 h. After reaction comple-
tion, the mixture was filtered through diatomite. Water (10 mL) was
added to the filtrate. The aqueous phase was extracted with EtOAc (3
× 10 mL). The organic layer was washed with brine, dried over Na2SO4,
concentrated in vacuo, and purified by flash column chromatography
(PE/EtOAc, 10:1) to afford ethyl N-(5-chloro-2-cyanophenyl)form-
imidate (8a).
(1) Kukushkin, V. Y.; Pombeiro, A. J. L. Chem. Rev. 2002, 102, 1771.
(2) Tinker, A. C.; Beaton, H. G.; Smith, N. B.; Cook, T. R.; Cooper, S. L.;
Rae, L. F.; Hallam, K.; Hamley, P.; Inally, T. M.; Nicholls, D. J.;
Pimm, A. D.; Wallace, A. V. J. Med. Chem. 2003, 46, 913.
(3) Baba, A.; Kawamura, N.; Makino, H.; Ohta, Y.; Taketomi, S.;
Sohda, T. J. Med. Chem. 1996, 39, 5176.
(4) Honkanen, E.; Pippuri, A.; Kairisalo, P.; Nore, P.; Karppanen, H.;
Paakkari, I. J. Med. Chem. 1983, 26, 1433.
(5) Siddique, M. U. M.; McCann, G. J. P.; Sonawane, V. R.; Horley, N.;
Gatchie, L.; Joshi, P.; Bharate, S. B.; Jayaprakash, V.; Sinha, B. N.;
Chaudhuri, B. Eur. J. Med. Chem. 2017, 130, 320.
Yield: 181.5 mg (87%); pale pink solid; mp 72–73 °C (Lit.27 71–73 °C).
IR (KBr): 3401, 3344, 3325, 3022, 2925, 1777, 1554, 1064, 878 cm–1
.
1H NMR (500 MHz, CDCl3):  = 7.75 (s, 1 H), 7.53 (d, J = 8.5 Hz, 1 H),
7.16 (dd, J = 8.5, 2.0 Hz, 1 H), 7.00 (d, J = 2.0 Hz, 1 H), 4.41 (q, J = 7.0 Hz,
2 H), 1.41 (t, J = 7.0 Hz, 3 H).
HRMS (ESI): m/z calcd for C10H10ClN2O [M + H]+: 209.0476; found:
209.0471.
(6) Krapf, M. K.; Gallus, J.; Wiese, M. Eur. J. Med. Chem. 2017, 139,
587.
(7) Zhang, Y.; Tortorella, M. D.; Liao, J.; Qin, X.; Chen, T.; Luo, J.;
Guan, J.; Talley, J. J.; Tu, Z. ACS Med. Chem. Lett. 2015, 6, 1086.
(8) (a) Cai, X.; Zhai, H. X.; Wang, J.; Forrester, J.; Qu, H.; Yin, L.; Lai,
C. J.; Bao, R.; Qian, C. J. Med. Chem. 2010, 53, 2000. (b) Mahboobi,
S.; Sellmer, A.; Winkler, M.; Eichhorn, E.; Pongratz, H.; Ciossek,
T.; Baer, T.; Maier, T.; Beckers, T. J. Med. Chem. 2010, 53, 8546.
(9) Smutny, T.; Nova, A.; Drechslerová, M.; Carazo, A.; Hyrsova, L.;
Hrušková, Z. R.; Kuneš, J.; Pour, M.; Špulák, M.; Pavek, P. J. Med.
Chem. 2016, 59, 4601.
(10) Wang, X.; Li, J.; Huang, Y.; Zhu, J.; Hu, R.; Wu, W.; Jiang, H. J. Org.
Chem. 2018, 83, 10453.
(11) Satish, G.; Polu, A.; Kota, L.; Ilangovan, A. Org. Biomol. Chem.
2019, 17, 4774.
(b) Ethyl N-(5-chloro-2-cyanophenyl)formimidate (8a; 1.0 mmol),
phenylboronic acid (3a; 2.0 mmol), AcOH (1.0 mmol), bpy (0.2
mmol), and Pd(OAc)2 (0.2 mmol) were stirred in DMF (2.0 mL) at 100
°C for 12 h. After reaction completion, the mixture was filtered
through diatomite. Water (10 mL) was added to the filtrate. The aque-
ous phase was extracted with EtOAc (3 × 10 mL). The organic layer
was washed with brine, dried over Na2SO4, concentrated in vacuo, and
purified by flash column chromatography (PE/EtOAc, 20:1) to afford
4a; yield: 154 mg (74%).
(12) Imtiaz, K.; Aliya, I.; Waqas, A.; Aamer, S. Eur. J. Med. Chem. 2015,
90, 124.
(13) Okumura, K.; Yamada, Y.; Oine, T.; Tani, J.; Ochiai, T.; Inoue, I.
J. Med. Chem. 1972, 15, 518.
(14) Chen, J.; Chang, D.; Xiao, F.; Deng, G. J. Green Chem. 2018, 20,
5459.
(15) Yao, S.; Zhou, K.; Wang, J.; Cao, H.; Yu, L.; Wu, J.; Qiu, P.; Xu, Q.
Green Chem. 2017, 19, 2945.
(c) 2-Aminobenzonitrile 1a (1.0 mmol), phenylboronic acid (3a; 2.0
mmol), AcOH (1.0 mmol), bpy (0.2 mmol), and Pd(OAc)2 (0.2 mmol)
were stirred in DMF (2.0 mL) at 100 °C for 12 h. After reaction comple-
tion, the mixture was filtered through diatomite. Water (10 mL) was
added to the filtrate. The aqueous phase was extracted with EtOAc (3
× 10 mL). The organic layer was washed with brine, dried over Na2SO4,
concentrated in vacuo, and purified by flash column chromatography
(PE/EtOAc, 10:1) to afford 9a; yield: 97 mg (42%).
(16) (a) Thomas, J. B.; Giddings, A. M.; Olepu, S.; Wiethe, R. W.;
Harris, D. L.; Narayanan, S.; Warner, K. R.; Sarret, P.; Longpre, J.-
M.; Runyon, S. P.; Gilmour, B. P. Bioorg. Med. Chem. Lett. 2015,
25, 292. (b) Castellano, S.; Taliani, S.; Viviano, M.; Milite, C.; Da
HRMS (ESI): m/z calcd for C13H11ClNO [M + H]+: 232.0524; found:
232.0519.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I

I
Z. Wang et al.
Paper
Synthesis
Pozzo, E.; Costa, B.; Barresi, E.; Bruno, A.; Cosconati, S.;
Marinelli, L.; Greco, G.; Novellino, E.; Sbardella, G.; Da Settimo,
F.; Martini, C. J. Med. Chem. 2014, 57, 2413.
(22) Wang, Z.; Chen, W.; Luo, H.; He, C.; Zhang, G.; Yu, Y. Synthesis
2020, 52, 1659.
(23) Zhang, L.; Li, J.; Hu, Z.; Dong, Z.; Zhang, X.; Xu, X. Adv. Synth.
Catal. 2018, 360, 1938.
(24) Ezaki, K.; Kobayashi, K. Helv. Chim. Acta 2014, 97, 822.
(25) Saikia, U. P.; Borah, G.; Pahari, P. Eur. J. Org. Chem. 2018, 1211.
(26) Yan, Y.; Xu, Y.; Niu, B.; Xie, H.; Liu, Y. J. Org. Chem. 2015, 80,
5581.
(17) Zhang, Y.; Shao, Y.; Gong, J.; Hu, K.; Cheng, T.; Chen, J. Adv. Synth.
Catal. 2018, 360, 3260.
(18) Hu, K.; Zhen, Q.; Gong, J.; Cheng, T.; Qi, L.; Shao, Y.; Chen, J. Org.
Lett. 2018, 20, 3083.
(19) Yuan, S.; Yu, B.; Liu, H. Chem. Eur. J. 2019, 25, 13109.
(20) Yu, H.; Xiao, L.; Yang, X.; Shao, L. Chem. Commun. 2017, 53, 9745.
(21) Wang, Z.-J.; Chen, W.-T.; He, C.; Luo, H.-F.; Zhang, G.-L.; Yu, Y.-P.
Tetrahedron 2020, 76, 130953.
(27) Marinho, E.; Araújo, R.; Proença, F. Tetrahedron 2010, 66, 8681.
© 2020. Thieme. All rights reserved. Synthesis 2020, 52, A–I