Expedient Synthesis of Quinazoline Analogues through Direct Nucleophilic Arylation/Alkylation of 2-Chloroquinazoline

Article abstract of DOI:10.1055/s-0035-1561587

A practical approach was developed for the synthesis of 4-arylquinazoline compounds through a one-pot nucleophilic arylation/alkylation of 2-chloroquinazoline with aryl lithium compounds generated in situ, followed by ring oxidation. The obtained 2-chloro-4-arylquinazoline adducts were further used as versatile intermediates that undergo a variety of synthetic transformations to provide functionalized quinazoline compounds. The arylation intermediate dihydroquinazoline was also elaborated to the tricyclic dihydroimidazo[2,1-b]quinazolinone.

Full text of DOI:10.1055/s-0035-1561587

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–H
paper
A
Y. Yang
Paper
Synthesis
Expedient Synthesis of Quinazoline Analogues through Direct
Nucleophilic Arylation/Alkylation of 2-Chloroquinazoline
Ar
Yang Yang*
N
Ar
N
Genomics Institute of the Novartis Research Foundation,
N
Cs2CO3
Pd/C H2
10675 John Jay Hopkins Drive, San Diego, California 92121,
USA
yyang@gnf.org
Ar2B(OH)2
[Pd]
N
Ar2
I2/Et3N
or
DDQ
Ar
N
Ar
N
Ar
Ar-Br
+
BuLi
Nu:
N
N
N
conditions
Et2O
–78 °C
THF, r.t.
N
Cl
Cl
N
Nu
Ar
N
Cl
HCl
dioxane
H2O
N
H2O
N
H
Ar
O
Br
Ar
Ar
COOMe
Cl
NH3
COOMe
K2CO3
N
NH
N
O
MeOH
N
H
N
N
Cl
N
Received: 05.01.2016
Accepted after revision: 23.02.2016
Published online: 13.04.2016
demonstrates multiple bioactivities, including antitumor,
bronchodilating, and antianaphylactic properties.7 Clearly,
efforts towards the synthesis and modification of bioactive
natural quinazoline alkaloids may provide viable routes to
discover novel quinazoline compounds of pharmaceutical
interest.8
DOI: 10.1055/s-0035-1561587; Art ID: ss-2016-m0010-op
Abstract A practical approach was developed for the synthesis of 4-
arylquinazoline compounds through
a one-pot nucleophilic aryla-
tion/alkylation of 2-chloroquinazoline with aryl lithium compounds
generated in situ, followed by ring oxidation. The obtained 2-chloro-4-
arylquinazoline adducts were further used as versatile intermediates
that undergo a variety of synthetic transformations to provide function-
alized quinazoline compounds. The arylation intermediate dihydro-
quinazoline was also elaborated to the tricyclic dihydroimidazo[2,1-
b]quinazolinone.
In our research, we recently required an efficient ap-
proach for the synthesis of 4-aryl quinazoline compounds.
Most reported methods are based on the cyclization of an
aniline-like compound bearing a functionalized ortho
group,9 with the 4-aryl group installed prior to the quinazo-
line ring formation. To facilitate SAR exploration of the 4-
aryl group, we were interested in probing an alternative
synthetic approach that would install the 4-aryl/heteroaryl
group on an existing quinazoline scaffold. We envisioned
that direct nucleophilic arylation of inexpensive, commer-
cially available 2-chloro-quinazoline 1 by an aryl lithium
reagent could be an efficient approach. A similar strategy
has been extensively exploited on the pyridine ring to syn-
thesize substituted pyridines and piperidine-based com-
pounds.10 Moreover, direct nucleophilic arylation/alkyla-
tion was also applied to the 2-chloro-pyrimidine ring sys-
tem by using organolithium or Grignard reagents as
nucleophiles;11 such methodology has also been investigat-
ed as part of the process development of the antifungal
agent Voriconazole, which incorporates a substituted py-
rimidine structure.12 However, to our knowledge, nucleop-
hilic arylation/oxidation on the 2-chloro-quinazoline 1 by
an organometallic reagent was not known.13
Keywords arylation, heterocycles, quinazoline, nucleophilic addition,
alkylation
Quinazoline is one of the most common heterocycles
present in pharmaceutical compounds.1 This could be, in
part, due to its structural similarities with some naturally
occurring biological molecules such as adenine and gua-
nine. Quinazoline compounds have been found to possess a
variety of pharmacological properties including antimicro-
bial, anticancer, anti-inflammatory, anticonvulsive, antihy-
pertensive, antiobesity, antipsychotic and antidiabetic ac-
tivities.2 The range of biologically active quinazolines in-
cludes several marketed drugs that are currently being used
to treat patients across a diverse range of diseases (Figure
1).3 Quinazoline structures have also been frequently found
in naturally occurring products (Figure 1). So far, about 150
naturally occurring quinazoline alkaloids have been identi-
fied, with many showing interesting bioactivities.4 For ex-
ample, quinazolinone alkaloid Febrifugine, isolated from
the Chinese herb Dichroa febrifugasuch, was found to have
antimalarial properties.5 The natural alkaloid Vasicinone,
isolated6 from the leaves of the bush Adhatoda vasica,
To test our idea, 1-bromo-3-fluorobenzene 2 was treat-
ed with n-butyllithium solution (2.5 M in hexane) at –78 °C
to generate the corresponding aryllithium in situ. Upon the
addition of 2-chloro-quinazoline, the corresponding 4-aryl-
2-chloro-dihydroquinazoline 4 formed smoothly, and was
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

B
Y. Yang
Paper
Synthesis
NH2
N
F
MeO
MeO
Cl
O
Me
NH
N
N
H
N
O
N
N
O
O
N
O
N
N
N
H
Me
N
O
MeO
N
Me
Me
Gefitinib
(/EGFR inhibitor
anti-cancer)
Proquazone
(NSAID)
Prazosine
(anti-hypertension)
Quazinone
(PDE3 inhibitior)
NH2
O
N
O
N
N
H
N
Me
N
N
N
O
N
O
N
HO
N
N
OH
N
Me
Febrifugine
(–)-Vasicinone
Me
O
Linagliptin
(DPP-4 inhibitor)
Figure 1 Examples of marketed drugs and natural occurring alkaloids containing the quinazoline ring system
isolated in good yield after quenching with aqueous ammo-
nium chloride solution. We next screened conditions that
could be used to oxidize the obtained dihydroquinazoline
into the desired quinazoline ring (Table 1). Among the con-
ditions screened, treatment with 2,3-dichloro-5,6-dicya-
no-1,4-benzoquinone (DDQ) in tetrahydrofuran (THF) gave
the best yield of the expected product 5 (entry 3). It was
also found that the reaction can be conveniently carried out
in one-pot without isolation of the dihydroquinazoline in-
termediate. In such a procedure, oxidant dissolved in THF as
solution was added into the reaction after the arylation by
aryllithium. Interestingly, when the one-pot procedure was
applied, the use of I2/Et3N also afforded the desired 4-
arylquinazoline product in moderate yield (entry 4).
Table 1 Oxidation of Dihydroquinazoline to Quinazoline
F
F
F
O
N
BuLi
+
Br
Et2O
–78 °C
85%
THF
N
Cl
N
NH
2
1
N
Cl
N
Cl
BuLi
Et2O
–78 °C
4
5a
F
F
O
THF
N
N
N
Cl
N
Cl
3
5a
"one-pot"
Entry
Reaction conditions
Procedure
Yield (%)
1
2
3
4
5
H2O2/BuOOH/MeCN
I2/Et3N/THF
DDQ/THF
stepwise
stepwise
stepwise
one-pot
one-pot
no reaction
<10
86
I2/Et3N/THF
DDQ/THF
55
78
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

C
Y. Yang
Paper
Synthesis
Through application of the optimized one-pot proce-
dure, several other 4-aryl quinazoline compounds (5a, 5b,
and 5e; Table 2) were prepared by employing the appropri-
ate aryl bromide as starting material. Besides arylation, het-
eroarylation could also proceed under similar conditions,
resulting in different 2-chloro-4- heteroarylquinazolines
including pyridinyl, thiophenyl, and thiazolyl compounds
5c, 5d, 5f, and 5g. Addition to 2-chloroquinazoline 1 by ali-
phatic organometallics was also investigated. By adding n-
butyllithium (2h) or isopropyl Grignard reagent (2i) to 2-
chloroquinazolines at low temperature in toluene, similar
addition/oxidation processes could be carried out to give
the corresponding 2-chloro-4-alkylated quinazoline deriva-
tives 5h and 5i in good to moderate yields. In general, the
reaction showed good tolerance to a range of structural fea-
tures, giving products in moderate to good yields (Table 2).
Table 2 Synthesis of 4-Aryl-2-choloroquinazoline through Nucleophilic Arylation
Ar
Ar
BuLi
Et2O
N
DDQ
THF
N
N
Ar-Br
+
N
Cl
N
Cl
N
Cl
N
2a–g
1
"one pot"
5a–g
R
R
N
toluene
N
DDQ
THF, r.t.
N
RM
+
–78 to –10 °C
N
Cl
N
Cl
Cl
2h–i
1
"one pot"
5h–i
Entry
Ar-Br/RM
Product 5
Yield (%)
1
Ph-Br 2b
57
79
N
N
Cl
5b
5c
5d
N
N
Br
N
2
3
2c
N
Cl
N
Br
N
85
77
N
2d
N
Cl
F
Br
F
4
N
2a
N
Cl
5a
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

D
Y. Yang
Paper
Synthesis
Table 2 (continued)
Entry
Ar-Br/RM
Product 5
Yield (%)
F
F
Br
5
63
N
2e
N
Cl
5e
S
N
Br
6
7
S
61
54
2f
N
Cl
5f
N
S
N
N
S
Br
2g
N
Cl
Cl
5g
5h
Bu
N
N
8
9
n-BuLi 2h
66
31
N
N
i-PrMgBr 2i
Cl
5i
The 2-chloro-4-aryl/heteroaryl-quinazolines 5 obtained
by using our method can serve as versatile intermediates to
access more complex quinazoline compounds. To demon-
strate this, compound 5a was subjected to a series of trans-
formations (Scheme 1). In the presence of cesium carbon-
ate, the 2-cholro group can be cleaved cleanly under hydro-
genation conditions to give compound 6. Treatment of 5a in
dioxane with aqueous 4 N HCl gave the 4-aryl quinazoli-
none hydrolysis product 7 in good yield. Moreover, under
Suzuki coupling conditions, by using tetrakis triphenyl-
phosphine palladium [Pd(PPh3)4] as catalyst and sodium bi-
carbonate as base, a pyridyl group was introduced in high
yield to give 2-pyridinyl-4-arylquinazoline product 8. Dif-
ferent nucleophilic substitution reactions can also be per-
formed. For example, amination with aniline can be carried
out under acidic conditions14 to give the corresponding
compound 9, whereas phenoxide displacement to yield the
final compound 10 proceeded in good yield under basic
conditions (Scheme 1).
type heterocycles are interesting scaffolds in medicinal
chemistry research that have led to the discovery of the
marketed drug Quazinone, which is a selective PDE3 inhibi-
tor to treat heart disease.15 We found that by treating 4 with
methyl 2-bromoacetate in the presence of cesium carbon-
ate in N,N-dimethylformamide (DMF), N-alkylation pro-
ceeds smoothly to give 11 (Scheme 2). Cyclization of 11 can
be realized through treatment with ammonia in methanol
in a sealed tube to provide 5-aryl dihydroimidazo[2,1-
b]quinazolinone compound 12 in good yield (Scheme 2).
In summary, a practical approach for the synthesis of
structurally diverse 4-aryl/heteroaryl/alkylated quinazoline
compounds has been developed. The strategy relies on a
nucleophilic arylation/alkylation on a 2-chloroquinazoline
followed by a one-pot oxidation mediated by DDQ. The ob-
tained 2-chloro-4-aryl-quinazoline compound 5 can be fur-
ther utilized as a versatile intermediate to synthesize a vari-
ety of novel 4-aryl quinazoline compounds through various
synthetic transformations. The adduct intermediate from
nucleophilic arylation of 2-chloroquinolizidine 4 was also
applied as a key intermediate to synthesize novel dihydro-
imidazo[2,1-b]quinazolinone compound 12.
Finally, we found that 2-chloro-3,4-dihydroquinazoline
4 could also be a useful intermediate for the synthesis of di-
hydroimidazoquinzolinone type compounds. Such tricyclic
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

E
Y. Yang
Paper
Synthesis
F
B(OH)2
N
N
F
N
N
8
Pd/C, H2
EtOAc
Cs2CO3
Pd(PPh3)4
91%
N
F
F
N
70%
6
(p-Cl)-PhNH2
N
F
HCl
dioxane
H2O
TsOH
64%
N
N
N
H
Cl
N
Cl
55%
NaH
9
5a
PhOH
N
F
THF, 60 °C
61%
N
O
H
7
N
N
O
10
Scheme 1
F
F
F
BuLi
NH3
Br
Cs2CO3/DMF
COOMe
Br
N
+
Et2O
H2O
N
N
Cl
N
NH
F
COOMe
O
N
1
2
N
N
Cl
H
N
Cl
4
11
12
(68% in two steps)
Scheme 2
All commercial reagents and solvents were used without purification.
¹H and ¹³C NMR spectra were recorded with a Bruker 400-MHz spec-
trometer using TMS as the internal standard (0 ppm). TLC analyses
were carried out with aluminum sheets precoated with silica gel 60
F254, and UV radiation was used for detection. Flash column chroma-
tography was performed on silica gel (SiliaFlash F60, 230–400 mesh).
LC/MS analysis was performed with an Agilent 1100 series system
equipped with an Agilent 1100 series binary pump, Agilent 1100 se-
ries autosampler, Agilent 1100 series DAD UV detector, Agilent 1100
series single quadrupole mass spectrometer with ESI source, and a
SEDEX 75 ELSD. The mass spectrometer was set to scan from 100 to
1000 AMU. Mass spectrometric data were acquired in the positive
ionization mode. The mobile-phase solvents used were (A) 0.05% aq
TFA; and (B) 0.035% TFA in MeCN. The total mobile phase flow rate
was 1.0 mL/min. The gradient was 10–90% in 3 min with an isocratic
hold of 100% mobile-phase B for 0.49 min at the end of the gradient. A
Nucleophilic Addition to 2-Chloroquinazoline; General Procedure
To a solution of aryl bromide (0.5 mmol, 0.2 M) in Et2O at –78 °C was
added n-butyl lithium (1.6 M in hexane, 0.6 mmol, 0.375 mL). After
stirring at this temperature for 30 min, a solution of 2-choloroquinzo-
line (0.5 mmol) in Et2O (2 mL) was added dropwise at –78 °C. The re-
sulting reaction mixture was stirred at –78 °C for 1 h, then allowed to
warm to r.t. LC-MS analysis showed that starting materials had disap-
peared. A solution of DDQ (3 equiv) in THF (3 mL) was added drop-
wise and the resulting solution was stirred at r.t. for 2 h. H2O (20 mL)
was added and the mixture was extracted with EtOAc (3 × 20 mL).
The organic layer was washed with aqueous ammonium chloride
solution, followed by brine, and then dried over sodium sulfate and
concentrated in vacuo. The crude mixture was purified by silica gel
flash chromatography to give 5a–g.
2-Chloro-4-(3-fluorophenyl)quinazoline (5a)
Waters Atlantis T3 (5 μm, 2.1 × 50 mm) column was used. 1H and 13
C
White needle-like crystals; yield: 99 mg (77%).
NMR spectra were recorded using a 400 MHz/100 MHz Bruker spec-
trometer. Chemical shifts are reported in ppm, multiplicities are indi-
cated by s (singlet), d (doublet), t (triplet), q (quartet), and m (multi-
plet). The reactions were carried out in oven-dried glassware under
air atmosphere. 2-Chloroquinazoline was purchased from Bellen
Chemistry Co. Ltd.
1H NMR (400 MHz, CDCl3): δ = 8.07–8.02 (m, 1 H), 7.99 (dd, J = 8.7,
1.1 Hz, 1 H), 7.89 (ddd, J = 8.5, 6.9, 1.3 Hz, 1 H), 7.58 (ddd, J = 8.4, 7.0,
1.3 Hz, 1 H), 7.53–7.47 (m, 2 H), 7.44 (dt, J = 9.7, 1.8 Hz, 1 H), 7.27–
7.20 (m, 1 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

F
Y. Yang
Paper
Synthesis
13C NMR (101 MHz, CDCl3): δ = 170.13, 163.95, 161.49, 156.91,
153.05, 137.84, 137.76, 135.18, 130.53, 130.45, 128.34, 128.22,
127.06, 125.92, 121.38, 117.84, 117.63, 117.28, 117.06.
LC-MS: 100% (purity): m/z = 247 [M + H].
HRMS: m/z [M + H] calcd. for C12H8ClN2S: 247.0096; found: 247.0097.
LC-MS: 100% (purity): m/z = 259 [M + H].
2-(2-Chloroquinazolin-4-yl)thiazole (5g)
HRMS: m/z [M + H] calcd. for C14H9ClFN2: 259.0433; found: 259.0439.
Yellow powder; yield: 66 mg (54%).
1H NMR (400 MHz, CDCl3): δ = 9.62–9.54 (m, 1 H), 8.05 (d, J = 3.2 Hz,
1 H), 7.92–7.80 (m, 2 H), 7.66–7.56 (m, 2 H).
2-Chloro-4-phenylquinazoline (5b)
White needle-like crystals; yield: 68 mg (57%).
1H NMR (400 MHz, CDCl3): δ = 7.42–7.32 (m, 5 H), 7.26–7.12 (m, 2 H),
7.08–6.99 (m, 1 H), 6.79 (d, J = 7.7 Hz, 1 H).
13C NMR (101 MHz, CDCl3): δ = 171.2, 156.5, 152.5, 135.3, 134.5,
130.3, 129.7, 128.3, 127.55, 13.02, 121.1.
13C NMR (101 MHz, CDCl3): δ = 166.7, 158.7, 156.2, 154.0, 145.5,
135.3, 129.1, 128.3, 127.7, 124.7, 119.5.
LC-MS: 100% (purity): m/z = 248.
HRMS: m/z [M + H] calcd. for C11H7ClN3S: 248.0049; found: 248.0050.
LC-MS: 100% (purity): m/z = 241 [M + H].
4-Butyl-2-chloroquinazoline (5h)
HRMS: m/z [M + H] calcd. for C14H10ClN2: 241.0532; found: 241.0527.
To a solution of 2-choloroquinzoline (84 mg, 0.5 mmol) in toluene
was added n-butyllithium (1.6 M in hexane, 0.6 mmol, 0.375 mL) at
–78 °C. After stirring at this temperature for 30 min, the reaction was
allowed to warm to –10 °C. LC-MS analysis showed that starting ma-
terials had disappeared. A solution of DDQ (1 mmol, 2 equiv) in THF
(3 mL) was then added dropwise and the resulting solution was
stirred at r.t. for 2 h. The reaction was quenched by the addition of aq
sodium thiosulfate (15 mL). The resulting solution was extracted with
EtOAc (3 × 20 mL) and the organic layer was washed with aq ammoni-
um chloride solution, followed by brine, and then dried over sodium
sulfate and concentrated in vacuo. The crude mixture was purified by
silica gel flash chromatography to give 5h.
2-Chloro-4-(pyridin-3-yl)quinazoline (5c)
Gray powder; yield: 95 mg (79%).
1H NMR (400 MHz, CDCl3): δ = 8.98 (s, 1 H), 8.79 (d, J = 3.2 Hz, 1 H),
8.15 (dt, J = 7.9, 1.9 Hz, 1 H), 8.08–7.99 (m, 2 H), 7.93 (ddd, J = 8.4, 6.9,
1.4 Hz, 1 H), 7.74–7.59 (m, 1 H), 7.53 (dd, J = 7.7, 4.9 Hz, 1 H).
13C NMR (101 MHz, CDCl3): δ = 168.3, 157.0, 153.1, 150.9, 149.9,
138.1, 138.1, 135.4, 132.2, 128.7, 128.4, 126.5, 126.5, 123.9, 121.5,
121.4.
LC-MS: 100% (purity): m/z = 242 [M + H].
Gray powder; yield: 72 mg (66%).
HRMS: m/z [M + H] calcd. for C13H9ClN3: 242.0480; found: 242.0485.
1H NMR (400 MHz, CDCl3): δ = 8.04 (d, J = 8.4 Hz, 1 H), 7.98–7.74 (m,
2 H), 7.56 (ddd, J = 8.3, 6.8, 1.3 Hz, 1 H), 3.29–3.05 (m, 2 H), 1.93–1.62
(m, 2 H), 1.53–1.36 (m, 2 H), 0.90 (t, J = 7.4 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 175.8, 156.9, 151.7, 134.7, 128.3,
127.7, 125.1, 122.3, 34.5, 31.3, 22.9, 13.9.
2-Chloro-4-(pyridin-2-yl)quinazoline (5d)
Gray powder; yield: 102 mg (85%).
1H NMR (400 MHz, CDCl3): δ = 8.96 (dd, J = 8.7, 1.4 Hz, 1 H), 8.90–8.76
(m, 1 H), 8.27 (dt, J = 8.0, 1.2 Hz, 1 H), 8.04 (dd, J = 8.5, 1.3 Hz, 1 H),
7.96 (qd, J = 8.1, 1.6 Hz, 2 H), 7.68 (ddd, J = 8.4, 6.8, 1.3 Hz, 1 H), 7.52
(ddd, J = 7.5, 4.9, 1.2 Hz, 1 H).
LC-MS: 100% (purity): m/z = 221.
HRMS: m/z [M + H] calcd. for C12H14ClN2: 221.0845; found: 221.0842.
13C NMR (101 MHz, CDCl3): δ = 167.1, 156.5, 155.1, 153.7, 148.9,
137.4, 134.9, 128.5, 128.3, 127.8, 125.7, 125.1, 121.4.
2-Chloro-4-isopropylquinazoline (5i)
LC-MS: 100% (purity): m/z = 242 [M + H].
Similar procedure as above was applied to prepare compound 5i.
HRMS: m/z [M + H] calcd. for C13H9ClN3: 242.0480; found: 242.0483.
Gray powder; yield: 63 mg (61%).
1H NMR (400 MHz, CDCl3): δ = 8.10 (d, J = 8.4 Hz, 1 H), 7.91 (d, J =
7.9 Hz, 1 H), 7.82 (ddd, J = 8.4, 6.9, 1.4 Hz, 1 H), 7.57 (ddd, J = 8.3, 6.9,
1.3 Hz, 1 H), 3.84 (sept, J = 6.8 Hz, 1 H), 1.38 (d, J = 6.8 Hz, 6 H).
2-Chloro-4-(2-fluorophenyl)quinazoline (5e)
White needle-like crystals; yield: 81 mg (63%).
1H NMR (400 MHz, CDCl3): δ = 7.99 (dd, J = 8.5, 1.1 Hz, 1 H), 7.88 (ddd,
J = 8.5, 6.9, 1.5 Hz, 1 H), 7.77 (ddd, J = 8.5, 3.8, 1.2 Hz, 1 H), 7.58–7.53
(m, 2 H), 7.53–7.46 (m, 1 H), 7.30 (td, J = 7.6, 1.3 Hz, 1 H), 7.23–7.16
(m, 1 H).
13C NMR (101 MHz, CDCl3): δ = 179.9, 157.4, 152.0, 134.5, 128.5,
127.7, 124.5, 121.6, 31.4, 21.6.
LC-MS: 100% (purity): m/z = 207.
HRMS: m/z [M + H] calcd. for C11H12ClN2: 207.0689; found: 207.0691.
13C NMR (101 MHz, CDCl3): δ = 167.7, 160.9, 158.4, 156.8, 152.4,
135.2, 131.6, 128.2, 127.9, 127.2, 124.8, 122.3, 116.3, 116.1.
4-(3-Fluorophenyl)quinazoline (6)
LC-MS: 100% (purity): m/z = 259 [M + H].
To a suspension of 2-chloro-4-(3-fluorophenyl) quinazoline (5a; 26
mg, 0.1 mmol, 1 equiv) and Cs2CO3 (16 mg, 0.05 mmol, 0.5 equiv) in
EtOAc (2 mL) was added palladium on carbon (10%, 10 mg) cautiously
under a nitrogen stream. The flask was then flushed and filled with
hydrogen gas. The mixture was stirred at r.t. for 4 h under hydrogen
atmosphere and the progress of the reaction was monitored by LC-MS
until starting material disappeared. After filtration to remove the cat-
alyst, the solvent was removed under vacuum and the crude product
was purified by ISCO silica gel chromatography (CH2Cl2/MeOH) to af-
ford the product.
HRMS: m/z [M + H] calcd. for C14H9ClFN2: 259.0433; found: 259.0439.
2-Chloro-4-(thiophen-2-yl)quinazoline (5f)
Yellow powder; yield: 75 mg (61%).
1H NMR (400 MHz, CDCl3): δ = 8.45–8.38 (m, 1 H), 7.95–7.89 (m, 1 H),
7.88–7.84 (m, 1 H), 7.84–7.79 (m, 1 H), 7.64 (dd, J = 5.0, 1.1 Hz, 1 H),
7.62–7.55 (m, 1 H), 7.26–7.15 (m, 1 H).
13C NMR (101 MHz, CDCl3): δ = 163.5, 156.7, 153.3, 139.4, 134.8,
132.5, 132.0, 128.4, 128.3, 126.5, 126.4, 120.5.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

G
Y. Yang
Paper
Synthesis
Gray powder; yield: 11 mg (51%).
mL). After drying over sodium sulfate, the solution was concentrated
in vacuo. The crude mixture was purified by silica gel flash chroma-
tography (EtOAc/hexane) to give the product.
1H NMR (400 MHz, CDCl3): δ = 9.33 (s, 1 H), 8.16–8.01 (m, 2 H), 7.90
(ddd, J = 8.5, 6.9, 1.4 Hz, 1 H), 7.60 (ddd, J = 8.3, 6.9, 1.2 Hz, 1 H), 7.53–
7.48 (m, 2 H), 7.48–7.42 (m, 1 H), 7.26–7.20 (m, 1 H).
Yellow powder; yield: 45 mg (64%).
13C NMR (101 MHz, CDCl3): δ = 167.0, 163.9, 161.5, 154.5, 154.4,
150.9, 139.1, 139.0, 134.0, 130.4, 130.3, 128.9, 128.1, 126.6, 125.7,
122.9, 117.2, 117.1, 117.0, 116.9.
1H NMR (400 MHz, CDCl3): δ = 7.85–7.60 (m, 5 H), 7.51–7.41 (m, 2 H),
7.38 (dd, J = 9.6, 2.9 Hz, 1 H), 7.29–7.12 (m, 4 H).
13C NMR (101 MHz, CDCl3): δ = 169.8, 163.9, 161.5, 154.9, 138.7,
138.6, 137.5, 135.0, 130.5, 130.4, 129.1, 128.9, 127.9, 127.4, 125.5,
125.5, 124.6, 124.5, 120.6, 118.6, 117.6, 117.4, 116.9, 116.7, 116.2.
LC-MS: 100% (purity): m/z = 225 [M + H].
HRMS: m/z [M + H] calcd. for C11H10FN2: 225.0828; found: 225.0828.
LC-MS: 100% (purity): m/z = 350 [M + H].
4-(3-Fluorophenyl)quinazolin-2(1H)-one (7)
HRMS: m/z [M
+ H] calcd. for C20H14ClFN3: 350.0861; found:
350.0869.
To a suspension of 2-chloro-4-(3-fluorophenyl) quinazoline (52 mg,
0.2 mmol, 1 equiv) in dioxane (2 mL) was added 4N HCl (1 mL), and
the mixture was stirred at 90 °C overnight. The mixture was concen-
trated in vacuo and the crude residue was purified by silica gel flash
chromatography (CH2Cl2/MeOH) to give the product.
4-(3-Fluorophenyl)-2-phenoxyquinazoline (10)
To a vial containing phenol (27 mg, 0.3 mmol, 3 equiv) in THF (2 mL)
was added NaH (60% in oil, 12 mg, 3 equiv). The mixture was stirred
for 30 min and then 2-chloro-4-(3-fluorophenyl)quinazoline (25 mg,
0.1 mmol, 1 equiv) was added. The mixture was heated at 60 °C and
stirred for 2 h. The reaction was allowed to cool to r.t. and then
quenched by addition of sat. aq sodium bicarbonate (10 mL). The mix-
ture was extracted with CH2Cl2 (3 × 10 mL) and the organic layer was
washed with sat. aq sodium carbonate (10 mL) followed by brine (10
mL). After drying over sodium sulfate, the solution was concentrated
in vacuo. The crude mixture was purified by flash chromatography
(EtOAc/hexane) to give the product.
Gray powder; yield: 33 mg (67%).
1H NMR (400 MHz, DMSO-d6): δ = 12.06 (s, 1 H), 7.77 (ddd, J = 8.4, 7.1,
1.4 Hz, 1 H), 7.71–7.58 (m, 2 H), 7.58–7.42 (m, 3 H), 7.40 (dd, J = 8.4,
1.2 Hz, 1 H), 7.24 (ddd, J = 8.3, 7.1, 1.1 Hz, 1 H).
13C NMR (101 MHz, DMSO-d6): δ = 173.6, 163.0, 160.6, 154.6, 143.38,
138.6, 138.5, 135.4, 130.6, 130.5, 128.2, 125.3, 122.5, 117.2, 117.0,
116.0, 115.8, 115.5, 113.9.
LC-MS: 100% (purity): m/z = 241 [M + H].
HRMS: m/z [M + H] calcd. for C14H10FN2O: 241.0777; found: 241.0776.
Colorless oil; yield: 19 mg (61%).
1H NMR (400 MHz, CDCl3): δ = 8.09 (d, J = 8.3 Hz, 1 H), 7.92–7.79 (m,
2 H), 7.61 (ddd, J = 9.0, 6.8, 2.1 Hz, 1 H), 7.58–7.52 (m, 1 H), 7.53–7.42
(m, 3 H), 7.41–7.34 (m, 2 H), 7.30 (dq, J = 9.4, 2.5 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 170.9, 163.9, 161.5, 161.5, 153.1,
153.0, 138.7, 138.6, 134.5, 130.2, 129.5, 127.7, 127.0, 125.9, 125.2,
121.7, 120.3, 117.5, 117.3, 117.0.
4-(3-Fluorophenyl)-2-(pyridin-3-yl)quinazoline (8)
To a solution of 2-chloro-4-(3-fluorophenyl) quinazoline (52 mg, 0.2
mmol, 1 equiv) and pyridin-3-ylboronic acid (33 mg, 0.3 mmol, 1.5
equiv) in dioxane (2 mL) was added aq Na2CO3 (1 M, 0.5 mL) and tre-
trakis(triphenyl)phosphine-palladium (12 mg, 0.01 mmol). The re-
sulting solution was flushed with nitrogen gas and heated at reflux at
LC-MS: 100% (purity): m/z = 317 [M + H].
90 °C for 1 h under
a nitrogen atmosphere. The reaction was
HRMS: m/z [M + H] calcd. for C20H14FN2O: 317.1090; found: 317.1088.
quenched by the addition of H2O (10 mL) and extracted with EtOAc
(3 × 10 mL). The organic layer was then washed with brine, dried over
sodium sulfate and concentrated in vacuo. The crude mixture was pu-
rified by ISCO (CH2Cl2/MeOH) to give the product.
2-Chloro-4-(3-fluorophenyl)-3,4-dihydroquinazoline (4)
To a solution of aryl bromide (0.2 M, 0.5 mmol) in Et2O at –78 °C was
added n-butyl lithium (1.6 M in hexane, 0.6 mmol, 0.375 mL). After
stirring at this temperature for 30 min, a solution of 2-chloro quinzo-
line (0.5 mmol) in Et2O (2 mL) was added dropwise at –78 °C. The re-
sulting reaction mixture was stirred at –78 °C for 1 h and then al-
lowed to warm to r.t. LC-MS analysis showed that starting materials
had disappeared. H2O (20 mL) was added and the mixture was ex-
tracted with EtOAc (3 × 20 mL). The organic layer was washed with aq
ammonium chloride, followed by brine, and was then dried over sodi-
um sulfate and concentrated in vacuo. The crude mixture was puri-
fied by silica gel flash chromatography. Compound 4 was not stable
and required to be applied into next step in 24 h.
Needle-like crystals; yield: 55 mg (91%).
1H NMR (400 MHz, CDCl3): δ = 9.83 (s, 1 H), 8.86 (d, J = 7.8 Hz, 1 H),
8.71 (s, 1 H), 8.08 (dd, J = 19.4, 8.4 Hz, 2 H), 7.86 (t, J = 7.7 Hz, 1 H),
7.69–7.46 (m, 4 H), 7.41 (ddd, J = 10.6, 6.5, 3.0 Hz, 1 H), 7.23 (td, J =
8.3, 2.5 Hz, 1 H).
13C NMR (101 MHz, CDCl3): δ = 167.1, 164.0, 161.5, 158.3, 151.9,
139.3, 135.9, 134.1, 130.3, 130.2, 129.3, 127.8, 126.6, 125.9, 121.6,
117.2, 117.2, 117.0.
LC-MS: 100% (purity): m/z = 302 [M + H].
HRMS: m/z [M + H] calcd. for C19H13FN3: 302.1094; found: 302.1095.
Gray powder; yield: 110 mg (85%).
1H NMR (400 MHz, CDCl3): δ = 7.25 (td, J = 7.9, 5.8 Hz, 1 H), 7.12 (td,
J = 7.7, 1.5 Hz, 1 H), 7.04 (ddt, J = 7.5, 2.4, 1.3 Hz, 1 H), 7.01–6.84 (m,
4 H), 6.75–6.68 (m, 1 H), 5.76 (s, 1 H).
13C NMR (101 MHz, CCDl3): δ = 164.3, 161.9, 146.0, 145.9, 144.4,
139.3, 130.6, 130.5, 128.8, 126.9, 125.7, 123.1, 123.0, 122.3, 115.4,
115.2, 114.6, 114.4, 60.5.
N-(4-Chlorophenyl)-4-(3-fluorophenyl)quinazolin-2-amine (9)
To
a vial containing a mixture of 2-chloro-4-(3-fluorophe-
nyl)quinazoline (52 mg, 0.2 mmol, 1 equiv), 4-chloroaniline (40 mg,
1.5 equiv), and dioxane (2 mL) was added a solution of TsOH·H2O (0.8
equiv) in dioxane (1 mL). The mixture was heated at 100 °C and
stirred for 2 h. The reaction was allowed to cool to r.t. and quenched
by the addition of sat. aq sodium bicarbonate (10 mL). The mixture
was extracted with CH2Cl2 (3 × 10 mL) and the organic layer was then
washed with sat. aq sodium carbonate (10 mL) followed by brine (10
LC-MS: 100% (purity): m/z = 261 [M + H].
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H

H
Y. Yang
Paper
Synthesis
5-(3-Fluorophenyl)-3,5-dihydroimidazo[2,1-b]quinazolin-2(1H)-
one (12)
M. Synthesis 1980, 505. (d) Johne, S. Prog. Drug Res. 1982, 26,
259. (e) Johne, S. Prog. Chem. Org. Nat. Prod. 1984, 46, 159.
(f) Michael, J. P. Nat. Prod. Rep. 2000, 17, 603.
To a suspension of 2-chloro-4-(3-fluorophenyl)-3,4-dihydroquinazo-
line (4; 52 mg, 0.2 mmol) and Cs2CO3 (64 mg, 0.2 mmol) in DMF (3
mL) was added methyl 2-bromoacetate. The reaction was stirred at r.t.
overnight. H2O (20 mL) was added and the mixture reaction was ex-
tracted with EtOAc (3 × 20 mL). The organic layer was washed with aq
ammonium chloride, followed by brine, and then dried over sodium
sulfate and concentrated in vacuo to give crude 11.
(5) (a) Wiesner, J.; Ortmann, R.; Jomaa, H.; Schlitzer, M. Angew.
Chem. Int. Ed. 2003, 42, 5274. (b) Mital, A. Curr. Med. Chem.
2007, 14, 759. (c) Kumar, V.; Mahajan, A.; Chibale, K. Bioorg.
Med. Chem. 2009, 17, 2236.
(6) (a) Amin, A. H.; Mehta, D. R. Nature 1959, 183, 1317. (b) Mehta,
D. R.; Naravane, J. S.; Desai, R. M. J. Org. Chem. 1963, 28, 445.
(c) Jain, M. P.; Koul, S. K.; Dhar, K. L.; Atal, C. K. Phytochemistry
1980, 19, 1880; and references cited therein.
(7) (a) Duan, J.; Zhou, R.; Zhao, S.; Wang, M.; Che, C. Zhongguo
Yaoke Daxue Xuebao 1998, 29, 21. (b) Fan, Z.; Yao, X.; Gu, L.;
Wang, J.; Wang, J.; He, A.; Zhang, B.; Wang, X.; Wang, H. Shen-
yang Yaoxueyuan Xuebao 1993, 10, 136. (c) Rahman, A. U.;
Sultana, N.; Akhter, F.; Nighat, F.; Choudhary, M. I. Nat. Prod.
Lett. 1997, 10, 249. (d) Bhide, M. B.; Mahajani, S. S. Bull. Haffkine
Inst. 1975, 3, 128.
(8) For some examples, see: (a) Zhu, S.; Meng, L.; Zhang, Q.; Wei, L.
Bioorg. Med. Chem. Lett. 2006, 16, 1854. (b) Bilbro, J.; Mart, M.;
Kyprianou, N. Anticancer Res. 2013, 33, 4695. (c) Zhu, S.;
Chandrashekar, G.; Meng, L.; Robinson, K.; Chatterji, D. Bioorg.
Med. Chem. 2012, 20, 927.
The crude product 11 obtained above was dissolved in i-PrOH (3 mL),
and ammonia in MeOH (7 M, 3 mL, 1 mol, 10 equiv) was added. The
reaction was heated in a sealed tube at 120 °C for 10 h. After concen-
tration to remove the solvent, the crude product was purified by silica
gel flash chromatography (EtOAc/hexane) to give the product.
Gray powder; yield: 38 mg (68% in two steps).
1H NMR (400 MHz, CDCl3): δ = 8.17 (s, 1 H), 7.31 (ddd, J = 9.0, 7.7,
5.7 Hz, 1 H), 7.17–7.07 (m, 2 H), 7.04–6.92 (m, 2 H), 6.91–6.80 (m,
2 H), 6.79–6.70 (m, 1 H), 5.64 (s, 1 H), 4.92 (d, J = 17.5 Hz, 1 H), 3.58
(d, J = 17.5 Hz, 1 H).
13C NMR (101 MHz, CDCl3): δ = 164.5, 162.0, 152.4, 142.4, 134.2,
131.1, 131.0, 129.0, 127.1, 123.1, 123.0, 119.8, 116.3, 116.1, 114.9,
114.5, 114.4, 114.2, 63.0, 32.8.
(9) Khan, I.; Ibrar, A.; Ahmed, W.; Saeed, A. Eur. J. Med. Chem. 2015,
90, 124; and references therein.
LC-MS: 100% (purity): m/z = 282 [M + H].
HRMS: m/z [M + H] calcd. for C16H13FN3O: 282.1042; found: 282.1041.
(10) (a) Andersson, H.; Almquist, F.; Olsson, R. Org. Lett. 2007, 9,
1335. (b) Bull, J. A.; Mousseau, J. J.; Pelletier, G.; Charette, A. B.
Chem. Rev. 2012, 112, 2642; and references therein.
(11) (a) Bursavich, M. G.; Lombardi, S.; Gilbert, A. M. Org. Lett. 2005,
7, 4113. (b) Epifani, E.; Florio, S.; Ingrosso, G. Tetrahedron Lett.
1987, 28, 6385. (c) Harden, D. B.; Mokrosz, M. J.; Strekowski, L.
J. Org. Chem. 1988, 53, 4137.
(12) Butters, M.; Ebbs, J.; Green, S. P.; MacRae, J.; Morland, M. C.;
Murtiashaw, C. W.; Petman, A. J. Org. Process Res. Dev. 2001, 5,
28.
Acknowledgment
The author sincerely appreciates helpful opinions and proof reading
from Dr. John Tellew, Dr. Yahu, A. Liu, and also management supports
from Dr. Valentina Molteni and Dr. Shifeng Pan. The author is grateful
to Ms. Agnela Betz, Mr. Kevin Johnson, and Dr. Perry Gordon for pro-
viding all high resolution MS data of all reported compounds.
(13) A few reports on nucleophilic addition to quinazoline substrate
can be found in the literature, see: Anderson, C.; Moreno, J.;
Hadida, S. Synlett 2014, 25, 677.
(14) Bursavich, M. G.; Lombardi, S.; Gibert, A. M. Org. Lett. 2005, 7,
4113.
(15) For examples, see: (a) Chern, J.-W.; Tao, P.-L.; Wang, K.-C.;
Gutcait, A.; Liu, S.-W.; Yen, M.-H.; Chien, S.-L.; Rong, J.-K. J. Med.
Chem. 1998, 41, 3128. (b) Váradia, A.; Horvátha, P.; Kurtánb, T.;
Mándib, A.; Tótha, G.; Gergelya, A.; Kökösia, J. Tetrahedron 2012,
68, 10365. For marketed drug Quazinone: (c) Eigenmann, R.;
Gerold, M.; Holck, M. J. Cardiovasc. Pharmacol. 1984, 6, 511.
(d) Belz, G. G.; Stern, H. C.; Butzer, R. J. Cardiovasc. Pharmacol.
1985, 7, 86. (e) Holck, M.; Thorens, S.; Muggli, R.; Eigenmann, R.
J. Cardiovasc. Pharmacol. 1984, 6, 520.
References
(1) Vijaychand, A.; Manjula, S. N.; Bharath, E. N.; Divya, B. Int. J.
Pharma Bio Sci. 2011, 2, 780.
(2) (a) Wang, D.; Gao, F. Chem. Cent. J. 2013, 7, 97. (b) Marzaro, G.;
Guiotto, A.; Chilin, A. Expert Opin. Ther. Pat. 2012, 22, 223.
(c) Ravez, S.; Castillo-Aguilera, O.; Depreux, P.; Goossens, L.
Expert Opin. Ther. Pat. 2015, 25, 789.
(3) (a) Selvam, T. P.; Kumar, P.; Vijayaraj, P. Res. Pharm. 2011, 1, 1.
(b) Abida Parvez, N.; Rana, A.; Imran, M. Int. J. Pharm. Bio. Arch.
2011, 2, 1651. (c) For an early review, see: Johne, S. Pharmazie
1981, 36, 583.
(4) (a) Khan, I.; Ibrar, A.; Abbas, N.; Saeed, A. Eur. J. Med. Chem.
2014, 76, 193; and references therein. For early reviews, see:
(b) Johne, S.; Groger, D. Pharmazie 1970, 25, 22. (c) Coppola, G.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–H