Synthesis of 4-arylquinazolines by arylation of quinazolin-4-ones under mild conditions

Article abstract of DOI:10.1055/s-0033-1339848

An efficient route to 4-arylquinazolines via arylation of quinazolin-4-ones under mild condition is described. The reaction is carried out by the palladium-catalyzed coupling of quinazolin-4-ones with arylboronic acids in the presence of TsCl leading to 4-arylquinazolines in good to excellent yields. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1339848

PAPER
▌3131
paper
Synthesis of 4-Arylquinazolines by Arylation of Quinazolin-4-ones under Mild
Conditions
Synthesis of 4-Arylquinazolines
Guanyinsheng Qiu,a Ping Huang,a Qin Yang,b Hui Lu,a Jingshi Xu,a Zhihong Deng,a Ming Zhang,a Yiyuan Peng*a,b
a
Key Laboratory of Green Chemistry, Jiangxi Province and College of Chemistry, Jiangxi Normal University, Nanchang, Jiangxi 330022,
P. R. of China
Fax +86(791)88120396; E-mail: yypeng@jxnu.edu.cn; E-mail: yiyuanpeng@yahoo.com
b
Key Laboratory of Small Functional Organic Molecule, Ministry of Education and College of Life Science, Jiangxi Normal University,
Nanchang, Jiangxi 330022, P. R. of China
Received: 05.06.2013; Accepted after revision: 25.08.2013
p-TsCl as the activator of C–OH bond, leading to the syn-
Abstract: An efficient route to 4-arylquinazolines via arylation of
quinazolin-4-ones under mild condition is described. The reaction
is carried out by the palladium-catalyzed coupling of quinazolin-4-
ones with arylboronic acids in the presence of TsCl leading to 4-ar-
ylquinazolines in good to excellent yields.
2
thesis of substituted biaryls with a new Csp –Csp2 bond.10
Wu and co-workers synthesized 4-substituted coumarins
via in situ activation of 4-hydroxycoumarins.11a However,
development of tandem reactions via the in situ activation
remain scarce.
Key words: 4-arylquinazoline, arylation, arylboronic acid, quinaz-
olin-4-one
(1)
(2)
O
Nu
Cl
Nu–
or
halogenation
NH
N
N
Quinazolines have been the object of extensive investiga-
tion due to their diverse range of biological properties,1
such as anticancer, antiviral, and antitubercular activities.2
Additionally, quinazolines have been employed as ligands
for benzodiazepine and GABA receptors in the CNS sys-
tems or as DNA binders.3 In particular, 4-functionalized
quinazolines have been demonstrated as effective fungi-
cides, anti-inflammatory, anticancer, antimicrobial, and
antihypertensive agents.4,5 Therefore, considerable prog-
ress in the synthesis of quinazoline derivatives have been
achieved during the past decade.6,7 Several protocols con-
cerning C4-functionalization of quinazolines have been
developed (Scheme 1): (1) Activation of the C–OH bond
in the enolic tautomer by halogenation with reagents such
as SOCl2, POCl3, and PCl5, and then nucleophilic substi-
tution with nucleophiles to afford the corresponding 4-
functionalized quinazolines C.4a–j,5a,7b,i–m (2) Activation of
the C–OH group with phosphonium salts (BOP, BrOP,
PyBrOP, PyBOP, or PyAOP), and then nucleophilic sub-
stitution with nucleophiles or coupling with boronic acids
to form 4-functionalized quinazolines C.8,9
lithium reagents
and
N
A
N
C
N
B1
BOP
Grignard reagents
O
Nu
BOP
N
Nu–
N
NH
or
N
B2
N
C
N
A
coupling with
boronic acids
Scheme 1 Two protocols for the synthesis of 4-functionalized quin-
azolines
In our previous report,12 we found a direct sulfanylation of
4-hydroxycoumarins and quinazolin-4-ones with thiols in
water. These reactions used p-toluenesulfonyl chloride
(TsCl) as the in situ C–OH bond activator.11 We envi-
sioned that under transition-metal-catalyzed conditions,
quinazolin-4-one might also be a suitable starting material
for the synthesis of 4-arylquinazolines in the presence of
p-toluenesulfonyl chloride as C–OH bond activator. To
verify the practicality of this route, the feasibility of the
palladium-catalyzed reaction of quinazolin-4-ones and ar-
ylboronic acid in the presence of TsCl was investigated.
On the other hand, the in situ activation strategy has a long
tradition, and many types of reactions have been devel-
oped so far, such as the combination of in situ activation
and nucleophilic attack or cross-coupling reaction. Partic-
ularly, an array of tosylate cross-coupling via in situ acti-
vation has been well documented.10,11a For example,
Ackermann and co-workers demonstrated that phenols
(bearing ester, ketones, or alkyl groups) could be success-
fully coupled with oxazolines and pyrazolyl arenes using
At the outset, 2-phenylquinazolin-4-one (1a) and phenyl-
boronic acid (2a) were selected as the model substrates for
optimizing the reaction conditions. We reasoned that the
presence of TsCl would enable an in situ activation of 2-
phenylquinazolin-4-one. Based on these considerations,
different palladium catalysts, bases, solvents, and temper-
atures were screened, and the results are listed in Table 1.
In an initial experiment, the reaction was conducted in the
presence of TsCl (120 mol%), Na2CO3 (300 mol%), and
PdCl2 (PPh3)2 (10 mol%) in THF. No desired product was
detected at room temperature (Table 1, entry 1). Gratify-
SYNTHESIS 2013, 45, 3131–3136
Advanced online publication: 23.09.2013
DOI: 10.1055/s-0033-1339848; Art ID: SS-2013-H0390-OP
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

3132
G. Qiu et al.
PAPER
Table 1 Optimization of Reaction Conditionsa
With these promising results in hand, the effects of differ-
ent palladium catalysts and solvents were next investigat-
ed. Finally, PdCl2(PPh3)2 and THF–H2O (20:1) were
proved to be the best choices (entry 4). Equally good re-
sults were obtained when the amount of catalyst and aryl-
boronic acid were decreased to 5 mol% in 1.2:1 ratio
(entries 16 and 17). A control experiment demonstrated
that no desired product was detected in the absence of
TsCl (entry 18).
O
Ph
[Pd], base, solvent
TsCl
NH
N
+
PhB(OH)2
N
Ph
N
Ph
1a
2a
3a
Entry Pd catalyst
Base
Solvent
Yield
(%)b
With the optimized conditions in hand [boronic acid (1.2
equiv), TsCl (100 mol%), Na2CO3 (300 mol%),
PdCl2(PPh3)2 (5 mol%), in THF–H2O (20:1), at 60 °C], we
next investigated the reaction scope with various quinaz-
olin-4-ones 1 and arylboronic acids 2, and the results are
summarized in Scheme 2.
1
2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
Pd (PPh3)4
Na2CO3
THF
THF
nd
62
76
85
nd
nd
30
40
nd
nd
45
nd
nd
nd
nd
88
87
nd
Na2CO3
Na2CO3
K2CO3
Et3N
3
THF–H2O (20:1)
4
THF–H2O (20:1)
THF–H2O (20:1)
5
To assess the impact of the structural and functional mo-
tifs on the reaction of 1a, a range of arylboronic acids 2
were tested. For most cases, boronic acid 2 reacted with 2-
phenylquinazolin-4-one (1a) leading to the corresponding
compounds 2-phenyl-4-arylquinazolins 3a–d in good to
excellent yields. Generally, it was found that substrates
with electron-donating groups on the arylboronic acid
were more reactive to some extent than those with the
electron-withdrawing groups. For example, the reaction
of 4-methyl- or 4-methoxyphenylboronic acid 2b or 2c
with compound 1a afforded the desired product 3b or 3c
in 88% or 90% yield, respectively (Scheme 2). The corre-
sponding yield for the 4-chloro-substituted substrate 2d
was 79% (Scheme 2). No desired product was detected
when electron-deficient 4-pyridineboronic acid was used
in the transformation (Scheme 2).
6
Et3N (DMAP) THF–H2O (20:1)
7
DABCO
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
THF–H2O (20:1)
THF–H2O (20:1)
THF–H2O (20:1)
THF–H2O (20:1)
MeCN
8
9
PdCl2
10
11
12
13
14
15
16c
Pd(OAc)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
toluene
1,4-dioxane
H2O
t-BuOH
THF–H2O (20:1)
THF–H2O (20:1)
THF–H2O (20:1)
The reactivity of quinazolin-4-ones 1 bearing a substitut-
ed aryl group at the 2 position was examined next. As ex-
pected, irrespective of the electronic nature of the
substituent on the aryl group, the corresponding products
were obtained in good to excellent yields. For example,
reactions of 2-toylquinazolin-4-one (1b) with boronic
acids 2a–d gave the corresponding products in 83, 85, 85,
and 79% yield, respectively (Scheme 2). And the reac-
tions of 2-(4-methoxyphenyl)quinazolin-4-one (1c) with
the respective boronic acids produced the desired prod-
ucts 3i–k in 81, 83, and 75% yield, respectively (Scheme
2). When 2-(4-chlorophenyl)quinazolin-4-one (1d) react-
ed with those boronic acids, the corresponding products
3l–n were obtained in 85, 90, and 80% yield, respectively
(Scheme 2). 2-Alkylquinazolin-4-ones reacted with
phenylboronic acid leading to the desired products 3o,p
only in moderate yields (Scheme 2). When 2-unsubstitut-
ed quinazolin-4-one (1e) was reacted with phenylboronic
acid, no desired product was obtained (Scheme 2). A TLC
control showed that, in this case, the formation of 4-tosyl-
ate intermediate was difficult.13 Finally, the effect of fluo-
rine attached to quinazolinone ring was also examined.
The fluorine-substituted quinazolinones reacted smoothly
with phenylboronic acid to afford the corresponding prod-
ucts 3q,r in excellent yields (Scheme 2, yields: 84% and
87%).
17d PdCl2(PPh3)2
18e
PdCl2(PPh3)2
a Reaction conditions: 2-phenylquinazolin-4-one (0.2 mmol), phenyl-
boronic acid (0.3 mmol), catalyst (10 mol%).
b Yield based on isolated product; nd = not detected.
c Catalyst 5 mol%.
d Ratio of 2a/1a = 1.2:1, and catalyst 5 mol%.
e TsCl was not added.
ingly, the desired product 2,4-diphenylquinazoline (3a)
was isolated in 62% yield after heating the reaction at 60
°C for 10 hours (entry 2). Further screening of the solvents
revealed that the reaction time sharply decreased to 2
hours and the yield of 3a was increased to 76% when
THF–H2O was used as the solvent (entry 3). Based on
these results, the effects of the bases were then studied.
When K2CO3 was used as the base, 85% yield of the prod-
uct was obtained (entry 4). The reaction did not proceed
when Et3N (or Et3N with added 5 mol% DMAP) was used
(entries 5, 6). Only 30% yield was obtained when
DABCO was employed (entry 7).
Synthesis 2013, 45, 3131–3136
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of 4-Arylquinazolines
3133
Ar
O
N
PdCl2(PPh3)2, K2CO3
N
NH
R1
R3
R3
+
Ar B(OH)2
THF–H2O (20:1)
TsCl, 60 °C
N
R1
1
2
3
Ph
C6H4-4-Me
C6H4-4-OMe
C6H4-4-Cl
N
N
N
N
N
Ph
N
Ph
N
Ph
N
Ph
3a: 85%
3b: 88%
3c: 90%
3d: 79%
Ph
C6H4-4-Me
N
C6H4-4-OMe
N
N
N
C6H4-4-Me
N
C6H4-4-Me
C6H4-4-OMe
C6H4-4-Cl
N
C6H4-4-Me
3e: 83%
3f: 85%
3g: 85%
C6H4-4-Cl
Ph
C6H4-4-Me
N
N
N
N
C6H4-4-Me
N
N
C6H4-4-OMe
3h: 79%
3i: 81%
3j: 83%
C6H4-4-Cl
N
Ph
N
C6H4-4-Me
N
N
C6H4-4-OMe
N
N
C6H4-4-Cl
3k: 75%
3l: 85%
3m: 90%
Ph
Ph
C6H4-4-Cl
N
N
N
N
C6H4-4-Cl
N
N
3n: 80%
Ph
3o: 63%
3p: 49%
F
F
C6H4-4-Me
N
Ph
N
Py
N
N
N
N
Ph
N
Ph
N
Ph
trace
trace
3q: 84%
3r: 87%
Scheme 2 Palladium-catalyzed synthesis of 4-arylquinazolines (yields are based on isolated products)
tion mass spectrometry (HRMS) spectra were obtained on a
micrOTOF II Instrument.
In conclusion, we have developed an efficient route for
the synthesis of 4-arylquinazolines via palladium-cata-
lyzed arylation of quinazolin-4-ones with arylboronic ac-
ids in the presence of TsCl as in situ C–OH activator under
mild conditions.
4-Arylquinazolines 3; General Procedure
A solution of quinazolin-4-one 1 (0.2 mmol) in THF (2 mL) was
treated with TsCl (1.2 equiv) and K2CO3 (3 equiv) at 60 °C. After
30 min, arylboronic acid 2 (1.2 equiv), Pd(PPh3)2Cl2 (5 mol%), and
H2O (0.1 mL) were added under air atmosphere. After the comple-
tion of the reaction as indicated by TLC (eluent: PE–EtOAc, 10:1 to
3:1), the solvent was evaporated, and the residue was purified by
chromatography on silica gel (eluent: PE–EtOAc, 10:1 to 3:1) to
provide the product 3. All the products were confirmed by 1H and
13C NMR spectra.
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
silica gel (60 Å pore size, 32–63 μm, standard grade). Analytical
TLC was performed using glass plates precoated with 0.25 mm
230–400 mesh silica gel impregnated with a fluorescent indicator
(254 nm). TLC plates were visualized by exposure to ultraviolet
light. Organic solutions were concentrated on rotary evaporators at
25–35 °C/~20 Torr. NMR spectra are recorded in parts per million
from internal TMS on the δ scale. 1H and 13C NMR spectra were re-
corded in CDCl3 on a Bruker DRX-400 spectrometer operating at
400 MHz and 100 MHz, respectively. All chemical shift values are
quoted in ppm and coupling constants quoted in Hz. High-resolu-
2,4-Diphenylquinazoline (3a)13
Yield: 48.0 mg (85%); white solid; mp 122–123 °C.
1H NMR (400 MHz, CDCl3): δ = 7.51–7.61 (m, 7 H), 7.88–7.90 (m,
3 H), 8.15 (t, J = 8.4 Hz, 2 H), 8.69 (dd, J = 1.6, 8.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 121.7, 127.0, 128.6, 128.7, 129.2,
129.9, 130.2, 130.5, 133.5, 137.7, 138.3, 152.0, 160.3, 168.3.
© Georg Thieme Verlag Stuttgart · New York
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2-Phenyl-4-(p-tolyl)quinazoline (3b)13
1H NMR (400 MHz, CDCl3): δ = 2.44 (s, 3 H), 7.32 (d, J = 8.0 Hz,
2 H), 7.53–7.58 (m, 3 H), 7.82–7.87 (m, 3 H), 8.05 (d, J = 8.4 Hz, 1
H), 8.13 (d, J = 8.4 Hz, 1 H), 8.56 (d, J = 8.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 30.9, 121.3, 126.5, 126.9, 128.6,
128.8, 129.2, 129.3, 131.5, 133.6, 135.3, 136.1, 136.2, 140.8, 152.0,
160.3, 166.9.
Yield: 52.2 mg (88%); white solid; mp 123–124 °C.
1H NMR (400 MHz, CDCl3): δ = 2.48 (s, 3 H), 7.38 (d, J = 7.6 Hz,
2 H), 7.48–7.53 (m, 4 H), 7.79 (d, J = 8.0 Hz, 2 H), 7.83–7.87 (m, 1
H), 8.13 (d, J = 8.8 Hz, 1 H), 8.69 (d, J = 7.6 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 21.5, 121.7, 126.8, 127.1, 128.5,
128.7, 129.1, 129.3, 130.2, 130.5, 133.4, 134.9, 138.3, 140.2, 152.0,
160.2, 168.3.
HRMS (ESI): m/z [M + H]+ calcd for C21H15ClN2: 353.0821; found:
353.0814.
4-(4-Methoxyphenyl)-2-phenylquinazoline (3c)14
Yield: 56.2 mg (90%); white solid; mp 141–142 °C.
2-(4-Methoxyphenyl)-4-phenylquinazoline (3i)14
Yield: 50.6 mg (81%); white solid; mp 165–166 °C.
1H NMR (400 MHz, CDCl3): δ = 3.80 (s, 3 H), 7.01 (d, J = 8.0 Hz,
2 H), 7.39–7.44 (m, 4 H), 7.75–7.80 (m, 3 H), 8.05 (t, J = 7.6 Hz, 2
H), 8.61 (d, J = 8.0 Hz, 2 H).
1H NMR (400 MHz, CDCl3): δ = 3.89 (s, 3 H), 7.03 (d, J = 8.8 Hz,
2 H), 7.49 (t, J = 8.0 Hz, 1 H), 7.57–7.59 (m, 3 H), 7.82–7.88 (m, 3
H), 8.09 (t, J = 7.6 Hz, 2 H), 8.65 (d, J = 8.8 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 54.4, 112.9, 120.6, 125.7, 125.9,
127.4, 127.6, 128.1, 129.1, 129.4, 130.8, 132.3, 137.3, 151.1, 159.1,
160.2, 166.6.
13C NMR (100 MHz, CDCl3): δ = 55.4, 113.8, 121.4, 126.5, 127.0,
128.5, 128.9, 129.8, 130.2, 130.3, 130.9, 133.4, 137.8, 152.1, 160.0,
161.7, 168.1.
4-(4-Chlorophenyl)-2-phenylquinazoline (3d)
Yield: 50.1 mg (79%); white solid; mp 139–140 °C.
2-(4-Methoxyphenyl)-4-(p-tolyl)quinazoline (3j)
Yield: 54.2 mg (83%); white solid; mp 112–113 °C.
1H NMR (400 MHz, CDCl3): δ = 7.50–7.60 (m, 6 H), 7.86–7.87 (m,
3 H), 8.08 (d, J = 8.4 Hz, 1 H), 8.12 (d, J = 8.4 Hz, 1 H), 8.64 (d, J =
8.8 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 121.5, 123.5, 126.6, 127.2, 128.6,
128.7, 128.9, 129.3, 130.6, 131.5, 133.7, 136.1, 138.0, 152.0, 160.2,
167.1.
1H NMR (400 MHz, CDCl3): δ = 2.49 (s, 3 H), 3.89 (s, 3 H), 7.03
(d, J = 8.4 Hz, 2 H), 7.40 (d, J = 7.6 Hz, 2 H), 7.49 (t, J = 7.6 Hz, 1
H), 7.79 (d, J = 8.0 Hz, 1 H), 7.84 (t, J = 7.6 Hz, 1 H), 8.10 (t, J =
8.0 Hz, 2 H), 8.65 (d, J = 7.6 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 21.5, 55.4, 113.8, 121.5, 126.4,
127.1, 128.9, 129.2, 130.1, 130.3, 130.9, 133.4, 134.9, 140.1, 152.2,
160.0, 161.7, 168.2.
HRMS (ESI): m/z [M + H]+ calcd for C20H13ClN2: 317.0846; found:
317.0863.
HRMS (ESI): m/z [M + Na]+ calcd for C22H18ClN2 + Na: 349.1317;
found: 349.1291.
4-Phenyl-2-(p-tolyl)quinazoline (3e)14
Yield: 49.2 mg (83%); white solid; mp 189–190 °C.
4-(4-Chlorophenyl)-2-(4-methoxyphenyl)quinazoline (3k)
Yield: 52.0 mg (75%); white solid; mp 163–164 °C.
1H NMR (400 MHz, CDCl3): δ = 2.43 (s, 3 H), 7.32 (d, J = 8.0 Hz,
2 H), 7.50 (dt, J = 0.8, 7.2 Hz, 1 H), 7.58–7.60 (m, 3 H), 7.84–7.89
(m, 3 H), 8.11 (dt, J = 0.4, 9.6 Hz, 2 H), 8.58 (d, J = 8.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 21.6, 121.6, 126.7, 127.0, 128.5,
128.7, 129.1, 129.3, 129.8, 130.2, 133.5, 135.5, 137.8, 140.7, 152.0,
160.4, 168.2.
1H NMR (400 MHz, CDCl3): δ = 3.89 (s, 3 H), 7.03 (d, J = 8.8 Hz,
2 H), 7.51–7.58 (m, 3 H), 7.82–7.86 (m, 3 H), 8.03 (d, J = 8.0 Hz, 1
H), 8.11 (d, J = 8.4 Hz, 1 H), 8.63 (d, J = 8.8 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 55.4, 113.8, 121.2, 126.6, 126.7,
128.8, 129.0, 130.2, 130.7, 131.5, 133.6, 136.2, 152.1, 160.0, 161.8,
166.9.
2,4-(Di-p-tolyl)quinazoline (3f)
Yield: 52.8 mg (85%); white solid; mp 139–140 °C.
HRMS (ESI): m/z [M + H]+ calcd for C21H15ClN2O: 347.0951;
found: 347.0963.
1H NMR (400 MHz, CDCl3): δ = 2.44 (s, 3 H), 2.48 (s, 3 H), 7.32
(d, J = 8.0 Hz, 2 H), 7.39 (d, J = 7.6 Hz, 2 H), 7.50 (dd, J = 7.2, 8.4
Hz, 1 H), 7.79 (d, J = 8.0 Hz, 2 H), 7.84 (dd, J = 6.8, 8.4 Hz, 1 H),
8.11 (d, J = 8.8 Hz, 2 H), 8.58 (d, J = 8.4 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 21.5, 21.6, 121.6, 126.7, 127.1,
128.6, 129.0, 129.2, 129.3, 130.2, 133.3, 134.9, 135.6, 140.1, 140.6,
152.0, 160.3, 168.2.
2-(4-Chlorophenyl)-4-phenylquinazoline (3l)14
Yield: 53.9 mg (85%); light yellow solid; mp 179–180 °C.
1H NMR (400 MHz, CDCl3): δ = 7.47–7.61 (m, 6 H), 7.86–7.87 (m,
3 H), 8.12 (d, J = 8.4 Hz, 2 H), 8.64 (d, J = 8.8 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 121.7, 127.0, 127.2, 128.6, 128.7,
129.1, 130.0, 130.1, 130.2, 133.7, 136.7, 137.5, 151.9, 159.2, 168.4.
HRMS (ESI): m/z [M + Na]+ calcd for C22H18N2 + Na: 333.1368;
found: 333.1367.
2-(4-Chlorophenyl)-4-(p-tolyl)quinazoline (3m)
Yield: 59.5 mg (90%); light yellow solid; mp 156–157 °C.
4-(4-Methoxyphenyl)-2-(p-tolyl)quinazoline (3g)
1H NMR (400 MHz, CDCl3): δ = 2.49 (s, 3 H), 7.40 (d, J = 8.0 Hz,
2 H), 7.47 (d, J = 7.6 Hz, 2 H), 7.54 (d, J = 8.0, 7.2 Hz, 1 H), 7.78
(d, J = 8.0 Hz, 2 H), 7.87 (t, J = 8.4 Hz, 1 H), 8.13 (t, J = 8.8, 9.2
Hz, 2 H), 8.64 (d, J = 8.0 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 21.5, 121.8, 127.1, 128.6, 128.7,
129.1, 129.3, 130.0, 130.2, 133.6, 134.8, 136.7, 136.8, 140.3, 151.9,
159.2, 168.4.
Yield: 56.8 mg (87%); white solid; mp 153–154 °C.
1H NMR (400 MHz, CDCl3): δ = 2.43 (s, 3 H), 3.90 (s, 3 H), 7.10
(d, J = 8.4 Hz, 2 H), 7.31 (d, J = 7.6 Hz, 2 H), 7.50 (t, J = 7.6 Hz),
7.82–7.87 (m, 3 H), 8.10 (d, J = 8.4 Hz, 1 H), 8.14 (d, J = 8.4 Hz, 1
H), 8.57 (d, J = 7.6 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 21.5, 55.5, 114.0, 121.6, 126.6,
127.0, 128.6, 129.1, 129.3, 130.3, 131.8, 133.3, 135.6, 140.6, 152.1,
160.3, 161.2, 167.6.
HRMS (ESI): m/z [M + Na]+ calcd for C21H15ClN2 + Na: 353.0821;
found: 353.0839.
HRMS (ESI): m/z [M + Na]+ calcd for C22H18N2O + Na: 349.1317;
found: 349.1297.
2-(Bis-4-Chlorophenyl)quinazoline (3n)
Yield: 40.0 mg (80%); light yellow solid; mp 201–202 °C.
4-(4-Chlorophenyl)-2-(p-tolyl)quinazoline (3h)
Yield: 51.6 mg (79%); white solid; mp 150–151 °C.
1H NMR (400 MHz, CDCl3): δ = 7.50 (d, J = 8.0 Hz, 2 H), 7.57–
7.59 (m, 3 H), 7.30 (d, J = 8.0 Hz, 2 H), 7.91 (t, J = 6.8 Hz, 1 H),
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Synthesis of 4-Arylquinazolines
3135
8.07 (d, J = 8.4 Hz, 1 H), 8.14 (d, J = 8.4 Hz, 1 H), 8.62 (d, J = 8.4
Hz, 2 H).
References
(1) For examples, see: (a) Deng, Y. J.; Zhou, X. L.; Desmoulin,
S. K.; Wu, J. M.; Cherian, C.; Hou, Z. J.; Matherly, L. H.;
Gangjee, A. J. Med. Chem. 2009, 52, 2940. (b) Kabri, Y.;
Gellis, A.; Vanelle, P. Green Chem. 2009, 11, 201. (c) Chen,
K.; Aowad, A. F.; Adelstein, S. J.; Kassis, A. I. J. Med.
Chem. 2007, 50, 663. (d) Witt, A.; Bergman, J. Curr. Org.
Chem. 2003, 7, 659. (e) Dempcy, R. O.; Skibo, E. B.
Biochemistry 1991, 30, 8480. (f) Calvert, A. H.; Jones, T. R.;
Dady, P. J.; Grzelakowskasztabert, B.; Paine, R. M.; Taylor,
G. A.; Harrap, K. R. Eur. J. Cancer 1980, 16, 713.
(2) For examples, see: (a) Baruah, B.; Dasu, K.; Vaitilingam, B.;
Mamnoor, P.; Venkata, P. P.; Rajagopal, S.; Yeleswarapu,
K. R. Bioorg. Med. Chem. 2004, 12, 1991. (b) Sharma, V.
M.; Prasanna, P.; Seshu, K. V.; Renuka, B.; Rao, C. V. L.;
Kumar, G. S.; Narasimhulu, C. P.; Babu, P. A.; Puranik, R.
C.; Subramanyam, D.; Venkateswarlu, A.; Rajagopal, S.;
Kumar, K. B.; Rao, C. S.; Mamidi, N. V.; Deevi, D. S.;
Ajaykumar, R.; Rajagopalan, R. Bioorg. Med. Chem. Lett.
2002, 12, 2303. (c) Foster, A.; Coffrey, H. A.; Morin, M. J.;
Rastinejad, F. Science 1999, 286, 2507.
13C NMR (100 MHz, CDCl3): δ = 121.5, 126.6 127.4, 128.7, 128.9,
129.0, 129.2, 129.9, 131.5, 133.9, 135.9, 136.4, 136.5, 151.9, 159.2,
167.1.
HRMS (ESI): m/z [M + H]+ calcd for C20H12Cl2N2: 351.0456;
found: 351.0474.
4-Phenyl-2-propylquinazoline (3o)15
Yield: 31.3 mg (63%); white solid; mp 108–109 °C.
1H NMR (400 MHz, CDCl3): δ = 1.07 (t, J = 7.6 Hz, 3 H), 1.97–2.04
(m, 2 H), 3.14 (t, J = 8.0 Hz, 2 H), 7.50–7.57 (m, 4 H), 7.75–7.77
(m, 2 H), 7.86 (t, J = 8.0 Hz, 1 H), 8.03–8.07 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 14.1, 22.4, 42.0, 121.2, 126.7,
127.0, 128.3, 128.6, 129.8, 129.9, 133.5, 137.5, 151.4, 167.1, 168.5.
4-Phenyl-2-isopropylquinazoline (3p)
Yield: 24.3 mg (49%); white solid; mp 85–86 °C.
1H NMR (400 MHz, CDCl3): δ = 1.38 (t, J = 5.6 Hz, 6 H), 3.33–3.37
(m, 1 H), 7.45–7.50 (m, 4 H), 7.68–7.77 (m, 3 H), 7.96 (d, J = 8.8
Hz, 2 H).
(3) (a) Henderson, E. A.; Bavetsias, V.; Theti, D. S.; Wilson, S.
C.; Clauss, R.; Jackman, A. L. Bioorg. Med. Chem. 2006, 14,
5020. (b) Malecki, N.; Carato, P.; Rigo, B.; Goossens, J.-F.;
Houssin, R.; Baillyc, C.; Hènichart, J.-P. Bioorg. Med.
Chem. 2004, 12, 641. (c) Colotta, V.; Catarzi, D.; Varano,
F.; Lenzi, O.; Filacchioni, G.; Costagli, C.; Galli, A.;
Ghelardini, C.; Galeotti, N.; Gratteri, P.; Sgrignani, J.;
Deflorian, F.; Moro, S. J. Med. Chem. 2006, 49, 6015.
(4) For examples of 4-aminoquinazolines, see: (a) Sirisoma, N.;
Pervin, A.; Zhang, H.; Jiang, S. C.; Willardsen, J. A.;
Anderson, M. B.; Mather, G.; Pleiman, C. M.; Kasibhatla,
S.; Tseng, B.; Drewe, J.; Cai, S. X. J. Med. Chem. 2009, 52,
2341. (b) Murai, M.; Sekiguchi, K.; Nishioka, T.; Miyoshi,
H. Biochemistry 2009, 48, 688. (c) Chappie, T. A.;
13C NMR (100 MHz, CDCl3): δ = 21.9, 38.0, 121.4, 126.6, 126.9,
128.5, 128.6, 129.7, 130.0, 133.3, 137.7, 151.5, 168.3, 171.1.
HRMS (ESI): m/z [M + H]+ calcd for C17H16N2: 249.1392; found:
249.1377.
5-Fluoro-2,4-diphenylquinazoline (3q)
Yield: 50.5 mg (84%); white solid; mp 149–150 °C.
1H NMR (400 MHz, CDCl3): δ = 7.19 (ddd, J = 1.2, 8.0 Hz, 1 H),
7.50–7.55 (m, 6 H), 7.74–7.77 (m, 2 H), 7.81–7.85 (m, 1 H), 7.98
(d, J = 8.4 Hz, 1 H), 8.66–8.68 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 112.2 (d, 2JCF = 22 Hz), 112.6 (d,
4
2JCF = 12 Hz), 125.4 (d, JCF = 4.0 Hz), 127.8, 128.5, 128.8, 129.3
(3JCF = 4.0 Hz), 129.6, 130.9, 133.6 (d, 3JCF = 11 Hz), 137.5, 140.2
(3JCF = 3 Hz), 153.4, 157.7 (d, 1JCF = 260 Hz), 160.3, 166.0 (5JCF
=
Humphrey, J. M.; Allen, M. P.; Estep, K. G.; Fox, C. B.;
Lebel, L. A.; Liras, S.; Marr, E. S.; Menniti, F. S.; Pandit, J.;
Schmidt, C. J.; Tu, M. H.; Williams, R. D.; Yang, F. V.
J. Med. Chem. 2007, 50, 182. (d) Yang, S.; Liu, G.; Song, B.
A.; Jin, L. H.; Hu, D. Y.; Zhang, S. M. Chin. J. Org. Chem.
2006, 26, 1429; Chem. Abstr. 2007, 147, 301104.
4.0 Hz).
HRMS (ESI): m/z [M + Na]+ calcd for C20H13FN2 + Na: 323.0960;
found: 323.0983.
5-Fluoro-2-phenyl-4-(p-tolyl)quinazoline (3r)
Yield: 54.7 mg (87%); white solid; mp 158–159 °C.
(e) Kanuma, K.; Omodera, K.; Nishiguchi, M.; Funakoshi,
T.; Chaki, S.; Semple, G.; Tran, T. A.; Kramer, B.; Hsu, D.;
Casper, M.; Thomsen, B.; Beeley, N.; Sekiguchi, Y. Bioorg.
Med. Chem. Lett. 2005, 15, 2565. (f) Liu, G.; Song, B. A.;
Sang, W. J.; Yang, S.; Jin, L. H.; Ding, X. Chin. J. Org.
Chem. 2004, 24, 1296; Chem. Abstr. 2004 , 142, 134667.
(g) Shreder, K. R.; Wong, M. S.; Nomanbhoy, T.; Leventhal,
P. S.; Fuller, S. R. Org. Lett. 2004, 6, 3715. (h) Tobe, M.;
Isobe, Y.; Tomizawa, H.; Nakasaki, T.; Takahashi, H.;
Fukazawa, T.; Hayashi, H. Bioorg. Med. Chem. 2003, 11,
383. (i) Rewcastle, G. W.; Denny, W. A.; Bridges, A. J.;
Zhou, H. R.; Cody, D. R.; Mcmichael, A.; Fry, D. W. J. Med.
Chem. 1995, 38, 3482. (j) Rachid, Z.; Brahimi, F.; Qiu, Q.
Y.; Williams, C.; Hartaley, J. M.; Hartaley, J. A.; Jean-
Claude, B. J. J. Med. Chem. 2007, 50, 2605. (k) Gomtsyan,
A.; Bayburt, E. K.; Schmidt, R. G.; Zheng, G. Z.; Perner, R.
J.; Didomenico, S.; Koenig, J. R.; Turner, S.; Jinkerson, T.;
Drizin, I.; Hannick, S. M.; Macri, B. S.; McDonald, H. A.;
Honore, P.; Wismer, C. T.; Marsh, K. C.; Wetter, J.; Stewar,
K. D.; Oie, T.; Jarvis, M. F.; Surowy, C. S.; Faltynek, C. R.;
Lee, C. H. J. Med. Chem. 2005, 48, 744.
1H NMR (400 MHz, CDCl3): δ = 2.47 (s, 3 H), 7.15–7.20 (m, 1 H),
7.34 (d, J = 7.6 Hz, 2 H), 7.50–7.51 (m, 3 H), 7.66–7.69 (m, 2 H),
7.78–7.82 (m, 1 H), 7.97 (d, J = 8.4 Hz, 1 H), 8.66–8.68 (m, 2 H).
2
13C NMR (100 MHz, CDCl3): δ = 21.5, 112.2 (d, JCF = 22 Hz),
112.6 (d, 2JCF = 12 Hz), 125.4 (d, 4JCF = 4.0 Hz), 128.5, 128.6, 128.8,
129.4 (JCF = 4.0 Hz), 130.8, 133.5 (d, 3JCF = 9.0 Hz), 137.3 (d, 3JCF
=
4.0 Hz), 137.6, 139.9, 153.4, 156.7 (d, JCF = 260 Hz), 160.3, 160.0
(5JCF = 4.0 Hz).
HRMS (ESI): m/z [M + H]+ calcd for C21H15FN2: 315.1298; found:
315.1319.
Acknowledgment
We are grateful to the National Natural Science Foundation of
China (grant nos. 20962010 and 21162012), Jiangxi Provincial De-
partment of Science and Technology (for Jiangxi’s Key Laboratory
of Green Chemistry, no. 20122BAB203007), and the Science Foun-
dation of Education Department of Jiangxi province (grant no.
GJJ10386 ) for their financial support.
(5) For examples of 4-alkyl(aryl)thioquinazolines, see: (a) Liu,
G.; Liu, C. P.; Ji, C. N.; Sun, L.; Wen, Q. W. Chin. J. Org.
Chem. 2008, 28, 525; Chem. Abstr. 2009, 150, 121577.
(b) Ma, Y.; Liu, F.; Yan, K.; Song, B. A.; Yang, B. S.; Hu,
D. Y.; Jin, L. H.; Xue, W. Chin. J. Org. Chem. 2008, 28,
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
n
nfomartit
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1268; Chem. Abstr. 2009, 150, 352066. (c) Xu, G. F.; Song,
B. A.; Bhadury, P. S.; Yang, S.; Zhang, P. Q.; Jin, L. H.;
Xue, W.; Hu, D. Y.; Lu, P. Bioorg. Med. Chem. 2007, 15,
3768.
F.-A.; Lanter, J. C.; Cai, C.; Sui, Z.; Murray, W. V. Chem.
Commun. 2010, 46, 1347. (f) Shi, C.; Aldrich, C. C. Org.
Lett. 2010, 12, 2286. (g) Kang, F.-A.; Kodah, J.; Guan, Q.;
Li, X.; Murray, W. V. J. Org. Chem. 2005, 70, 1957. For an
excellent review on phosphonium coupling, see: (h) Kang,
F.-A.; Sui, Z.; Murray, W. V. Eur. J. Org. Chem. 2009, 461.
(i) Mehta, V. P.; Modha, S. G.; Van der Eycken, E. V.
J. Org. Chem. 2010, 75, 976.
(6) (a) Brown, D. J. Quinazolines, In The Chemistry of
Heterocyclic Compounds (Supplement I); Vol. 55; Wiley:
New York, 1996. For recent reviews, see: (b) Connolly, D.
J.; Cusack, D.; O’Sullivan, T. P.; Guiry, P. J. Tetrahedron
2005, 61, 10153. (c) Witt, A.; Bergman, J. Curr. Org. Chem.
2003, 7, 659. (d) Mhaske, S. B.; Argade, N. P. Tetrahedron
2006, 62, 9787. (e) Fan, S.; Yang, J.; Zhang, X. Org. Lett.
2011, 13, 4374. (f) Lockman, J. W.; Klimova, Y.; Anderson,
M. B.; Willardsen, J. A. Synth. Commun. 2012, 42, 1715.
(7) For examples, see: (a) Seijas, J. A.; Vásquez-Tato, M. P.;
Martinez, M. M. Tetrahedron Lett. 2000, 41, 2215.
(b) Weber, C.; Bielik, A.; Szendrei, G. I.; Greiner, I.
Tetrahedron Lett. 2002, 43, 2971. (c) Shreder, K. R.; Wong,
M. S.; Nomanbhoy, T.; Leventhal, P. S.; Fuller, S. R. Org.
Lett. 2004, 6, 3715. (d) Costa, M.; Cai, N. D.; Gabriele, B.;
Massera, C.; Salerno, G.; Soliani, M. J. Org. Chem. 2004,
69, 2469. (e) Nakamura, H.; Onagi, S. Tetrahedron Lett.
2006, 47, 2539. (f) Roy, A. D.; Subramanian, A.; Roy, R.
J. Org. Chem. 2006, 71, 382. (g) Zhang, Y. D.; Xu, C. L.;
Houghten, R. A.; Yu, Y. P. J. Comb. Chem. 2007, 9, 9.
(h) Ferrini, S.; Ponticelli, F.; Taddei, M. Org. Lett. 2007, 9,
69. (i) Harden, D. B.; Mokrosz, M. J.; Strekowski, L. J. Org.
Chem. 1988, 53, 4137. (j) Rueping, M.; Ieawsuwan, W.
Synlett 2007, 247. (k) Milhau, L.; Guiry, P. J. Synlett 2011,
383.
(9) Kitano, Y.; Suzuki, T.; Kawahara, E.; Yamazaki, T. Bioorg.
Med. Chem. Lett. 2007, 17, 5863.
(10) For selected examples, see: (a) Kumar, R.; Van der Eycken,
E. V. Chem. Soc. Rev. 2013, 42, 1121; and references
therein. (b) Ackermann, L.; Pospech, J.; Potukuchi, H. K.
Org. Lett. 2012, 14, 2146. (c) Ackermann, L.; Mulzer, M.
Org. Lett. 2008, 10, 5043.
(11) For examples of TsCl as C–OH bond activator, see: (a) Luo,
Y.; Wu, J. Tetrahedron Lett. 2009, 50, 2103. (b) Wu, J.;
Wang, L. S.; Fathi, R.; Yang, Z. Tetrahedron Lett. 2002, 43,
4395. (c) Wu, J.; Zhang, L.; Xia, H. G. Tetrahedron Lett.
2006, 47, 1525. (d) Wang, Z. Y.; Wu, J. Tetrahedron 2008,
64, 1736. (e) Wu, J.; Zhang, L.; Luo, Y. Tetrahedron Lett.
2006, 47, 6747. (f) Lakshman, M. K.; Thomson, P. F.;
Nuqui, M. A.; Hilmer, J. H.; Sevova, N.; Boggess, B. Org.
Lett. 2002, 4, 1479. (g) Lakshman, M. K.; Gunda, P.;
Pradhan, P. J. Org. Chem. 2005, 70, 10329.
(12) (a) Peng, Y. Y.; Wen, Y. F.; Mao, X. C.; Qiu, G. Y. S.
Tetrahedron Lett. 2009, 50, 2405. (b) Peng, Y. Y.; Qiu, G.
Y. S.; Yang, Q.; Yuan, J. J.; Deng, Z. H. Synthesis 2012, 44,
1237.
(8) (a) Wacharasindhu, S.; Bardhan, S.; Wan, Z.-K.; Tabei, K.;
Mansour, T. S. J. Am. Chem. Soc. 2009, 131, 4174.
(b) Kang, F.-A.; Sui, Z. H.; Murray, W. V. J. Am. Chem. Soc.
2008, 130, 11300. (c) Wan, Z. K.; Wacharasindhu, S.;
Levins, C. G.; Lin, M.; Tabei, K.; Mansour, T. S. J. Org.
Chem. 2007, 72, 10194. (d) Wan, Z. K.; Wacharasindhu, S.;
Binnun, E.; Mansour, T. Org. Lett. 2006, 8, 2425. (e) Kang,
(13) Zhang, J.; Zhu, D.; Yu, C.; Wan, C.; Wang, Z. Org. Lett.
2010, 12, 2841.
(14) Han, B.; Wang, C.; Han, R.-F.; Yu, W.; Duan, X.; Fang, R.;
Yang, X. Chem. Commun. 2011, 47, 7818.
(15) Huang, C.; Fu, Y.; Fu, H.; Jiang, Y.; Zhao, Y. Chem.
Commun. 2008, 44, 6333.
Synthesis 2013, 45, 3131–3136
© Georg Thieme Verlag Stuttgart · New York