DDQ/TBHP-induced oxidative cyclization process: A metal-free approach for the synthesis of 2-phenylquinazolines

Article abstract of DOI:10.1055/s-0031-1289768

Various 2-phenylquinazoline derivatives were synthesized under metal-free conditions from readily available 2-aminophenyl ketones and benzylamines via condensation and oxidative cyclization using 2,3-dichloro-5,6-dicyano-1,4- benzoquinone (DDQ) as a versatile reagent. The reaction gave the corresponding 2-phenylquinazoline derivatives in good to excellent yields (up to 92%). Georg Thieme Verlag Stuttgart ? New York.

Full text of DOI:10.1055/s-0031-1289768

PAPER
▌2065
paper
DDQ/TBHP-Induced Oxidative Cyclization Process: A Metal-Free Approach
for the Synthesis of 2-Phenylquinazolines
Synthesis of 2-Phenylquinazolines
Sridhar Rachakonda,a P. Surya Pratap,b Mandava V. Basaveswara Rao*b
a
Department of Chemistry, KL University, Vaddeswaram, Guntur 522502, A.P., India
b
Department of Chemistry, Krishna University, Machilipatnam 521 001, A.P., India
Fax +91(867)2225960; E-mail: vbrmandava@yahoo.com; E-mail: professormandava@gmail.com
Received: 01.01.2012; Accepted after revision: 16.04.2012
Quinazolines and their derivatives are attractive targets
Abstract: Various 2-phenylquinazoline derivatives were synthe-
for researchers worldwide due to their widespread appli-
sized under metal-free conditions from readily available 2-amino-
cations in biology and medicinal chemistry, exhibiting po-
phenyl ketones and benzylamines via condensation and oxidative
cyclization using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
tential therapeutic properties such as anticancer,4 nuclear
(DDQ) as a versatile reagent. The reaction gave the corresponding translocation induction,5 ALK5 inhibition,6 and cannabi-
noid-1 inverse agonism.7 These quinazolines also show
2-phenylquinazoline derivatives in good to excellent yields (up to
92%).
remarkable activity as antiviral, antitubercular, anticon-
vulsant, antibacterial, and antidiabetic agents.8 Due to the
significance attached to the quinazoline structural motif,
which also occur in many natural products, the develop-
ment of new methodologies to construct quinazoline moi-
ety is highly desirable. Among known routes to
quinazolines, the Bischler cyclization of dicarbonyl com-
pounds with diamines, and oxidative ring closure of 2-
aminobenzonitrile with 3-phenylacryloyl chloride under
basic conditions8a,9 are notable. Kotsuki et al. utilized the
condensation of cyano- or nitro-activated 2-fluorobenzal-
dehydes with amidines via a intramolecular nucleophilic
substitution reaction to give quinazolines in good yields.10
Recently, Wang and co-workers described the synthesis
of 2-phenylquinazolines using molecular iodine/tert-butyl
hydroperoxide as a catalytic system11a and also by sup-
ported copper oxide nanoparticles.11b A copper-catalyzed
Ullmann N-arylation coupling process was reported by
Truong and co-workers to synthesize the quinazoline de-
rivatives from 2-iodobenzaldehyde by the reaction of ben-
zamidine hydrochloride under ligand-free conditions.12
Key words: 2-aminobenzophenones,
benzylamines, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, 2-
phenylquinazolines, oxidative cyclization
2-aminoacetophenones,
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), a
pale yellow solid reagent synthesized by Thiele and Gün-
ther in 1906 from benzoquinone, has proved to be a versa-
tile reagent in organic synthesis.1 Despite remarkable
advances in transition-metal catalyzed cross-coupling re-
actions, the reactions, which involve the formation of C–
N bonds, still attract the attention of the research commu-
nity. In spite of remarkable advances in transition-metal-
catalyzed oxidative coupling between sp3C–H and prima-
ry NH2 groups leading to the formation of C–N bonds, ex-
amples of these coupling reactions under metal-free
conditions are rare and they need to be actively pursued to
address general problems, such as the use of costly transi-
tion-metal catalysts, difficulties in the preparation of li-
gands or catalysts, and the high toxicity of trace metal
impurities which pose serious concerns with regard to the
environment. Literature reports2 indicate that DDQ has
been employed elegantly to generate benzylic and naph-
thylic cations on suitably activated systems through hy-
dride abstraction, with intramolecular cyclization leading
to the formation of heterocyclic compounds, and also in
oxidative C–C bond formation through the activation of
benzylic and allylic carbons.3
However, some of these methods require metal catalysts
along with ligands and harsh basic conditions. Thus the
discovery of novel synthetic methods to obtain 2-aryl-
quinazolines from readily available starting materials de-
void of metal catalysts is highly desirable. Herein, we
describe the synthesis of 2-phenylquinazolines from 2-
aminobenzophenones or 2-aminoacetophenones and ben-
R1
O
R2
R3
R2
R1
NH2
DDQ, TBHP
N
R4
R4
toluene
90–95 °C
R3
NH2
N
1
2
3
Scheme 1 Synthesis of 2-arylquinazolines
SYNTHESIS 2012, 44, 2065–2069
Advanced online publication: 01.06.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0031-1289768; Art ID: SS-2012-Z0001-OP
© Georg Thieme Verlag Stuttgart · New York

2066
S. Rachakonda et al.
PAPER
zylamines promoted by DDQ under metal-free condi- In order to evaluate and expand the scope of the proposed
tions.
catalytic system, the reaction process was monitored with
various commercially available 2-aminobenzophenones
or 2-aminoacetophenones 1 and benzylamines 2 (Tables 1
and 2). This novel protocol was very efficiently used to
prepare a wide variety of 2-aryl-4-phenylquinazolines
3a–j and it was observed that the substituents on either of
the substrates played a substantial role in governing the
product yield (Table 1). Electron-donating groups on the
benzylamine decreased the yield of products 3b,f–i,
whereas the electron-withdrawing groups, such as chloro-,
bromo-, and trifluoromethyl, increased the yield of prod-
ucts 3c–e,j. Moreover ortho-substituted benzylamines did
not hamper the reaction and gave the corresponding 2-
phenylquinazolines 3f,h in slightly lower yield when
compared to the corresponding para-substituted benzyl-
amines. In the case of aliphatic primary amines the reac-
tion was unsuccessful and starting materials were
recovered.
In our initial study to develop a method for DDQ-cata-
lyzed quinazoline formation, we chose 2-aminobenzophe-
none (1.0 mmol) and benzylamine (1.0 mmol) as model
substrates and conducted the reaction in toluene at 90–95
°C; in this reaction, 2-aminobenzophenone did not com-
pletely react. In order to optimize the reaction conditions
and react the 2-aminobenzophenone completely, the mo-
lar ratio of benzylamine/2-aminobenzophenone was in-
creased; 2-aminobenzophenone was found to react
completely with 2.5 mmol of benzylamine yielding the
corresponding 2-phenylquinazoline in 86% (Scheme 1,
Table 1, entry 1).
Table 1 Synthesis of 2-Phenylquinazolines Using 2-Aminobenzo-
phenone (R1 = Ph, R2 = R3 = H) with Different Benzylamines
(Scheme 1)a
Entry
R4
Time(h)
Product
Yieldb (%)
The proposed reaction conditions were applied in the
preparation of 2,4-disubstituted quinazolines 3k–t by
treating various differently substituted 2-aminobenzophe-
nones or 2-aminoacetophenones with benzylamines (Ta-
ble 2). Generally, all the benzophenones reacted well and
gave the corresponding products with good to excellent
yields. When the C5 of 2-aminobenzophenones was sub-
stituted with an electron-withdrawing group, such as chlo-
ro, bromo, and nitro, the reaction gave excellent yields of
the products 3k,l,o, whereas reactions with benzophe-
nones having electron-donating groups (OMe) resulted in
slightly lowered yields of products 3p,q. 2-Aminoaceto-
phenone and 2-amino-4,5-(methylenedioxy)acetophe-
none also reacted well with benzylamines to give products
3m,n,r–t.
1
2
H
9
8.5
10
9.5
9
3a
3b
3c
3d
3e
3f
86
82
89
90
91
82
83
81
80
90
4-OMe
4-Cl
3
4
4-Br
5
4-F
6
2-OMe
4-Me
2-Me
4-OMe
4-CF3
11
12
9
7
3g
3h
3i
8
9
10.5
8
10
3j
All the products were characterized by 1H and 13C NMR,
and mass spectra and compared with authentic samples in
the case of known compounds.11a The proposed mecha-
nism for the formation of 2-phenylquinazoline is shown in
Scheme 2. The reaction is expected to proceed via a two-
step sequence with initial hydride abstraction by DDQ to
a Reaction conditions: 1 (1.0 mmol), 2 (2.5 mmol), DDQ (10 mol%),
TBHP(100 μL), toluene (10 mL), 90–95 °C, 8–12 h.
b Isolated yield.
O
N
H2N
NH2
NH2
N
DDQ
DDQ
N
N
N
NH2
DDQH2
DDQH2
N
N
H
NH2
I
II
Scheme 2 Plausible mechanistic path way for the formation of 2-arylquinazolines
Synthesis 2012, 44, 2065–2069
© Georg Thieme Verlag Stuttgart · New York

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Synthesis of 2-Phenylquinazolines
2067
2,4-Diphenylquinazoline (3a)11a
Yellow solid; yield: 243 mg (86%); mp 118–120 °C.
1H NMR (300 MHz, CDCl3, TMS): δ = 8.67–8.70 (m, 2 H), 8.11 (t,
J = 8.3 Hz, 2 H), 7.82–7.88 (m, 3 H), 7.48–7.58 (m, 7 H).
13C NMR (75 MHz, CDCl3, TMS): δ = 121.7, 126.9, 128.4, 128.7,
129.2, 129.8, 130.2, 130.4, 133.4, 137.7, 138.1, 152.0, 160.2, 168.2.
Table 2 Synthesis of 2-Phenylquinazolines Using Substituted 2-
Aminobenzophenones and 2-Aminoacetophenones 1 and Benzyl-
amines 2 (Scheme 1)a
Entry R1
R2
R3
R4
Time Product Yieldb
(h)
(%)
MS (ESI): m/z = 283 [M + H]+; C20H15N2.
1
2
Ph
Cl
H
H
H
10
8
3k
3l
89
92
90
87
89
84
71
86
84
88
2-(4-Methoxyphenyl)-4-phenylquinazoline (3b)11a
Brown solid; yield: 256 mg (82%); mp 159–162 °C.
Ph
NO2
OCH2O
OCH2O
Br
H
3
Me
Me
Ph
H
9
3m
3n
3o
3p
3q
3r
3s
1H NMR (300 MHz, CDCl3, TMS): δ = 8.11–8.17 (m, 2 H), 7.81–
7.90 (m, 4 H), 7.53–7.56 (m, 4 H), 7.37–7.43 (m, 1 H), 7.01–7.09
(m, 2 H), 3.89 (s, 3 H).
13C NMR (75 MHz, CDCl3, TMS): δ = 55.3, 113.8, 121.8, 125.7,
128.6, 128.9, 129.9, 130.1, 130.3, 130.5, 132.0, 133.9, 134.3, 137.1,
150.4, 160.1, 161.9, 167.3.
4
4-Cl
H
8.5
5
H
9
6
Ph
OMe
OMe
H
H
H
8
MS (ESI): m/z = 313 [M + H]+; C21H17N2O.
7
Ph
OMe
H
H
8.5
2-(4-Chlorophenyl)-4-phenylquinazoline (3c)11a
Brown solid; yield: 282 mg (89%); mp 193–196 °C.
8
Me
Me
Me
H
10
9
H
H
H
11.5
12
1H NMR (300 MHz, CDCl3, TMS): δ = 8.65–8.68 (m, 2 H), 8.06–
8.09 (m, 2 H), 7.77–7.87 (m, 3 H), 7.59–7.61 (m, 3 H), 7.50–7.52
(m, 3 H).
13C NMR (75 MHz, CDCl3, TMS): δ = 122.0, 125.7, 128.4, 128.6,
129.9, 130.1, 130.6, 130.7, 132.5, 133.2, 134.4, 137.0, 137.6, 150.4,
160.3, 167.4.
10
H
H
4-Cl
3t
a Reaction conditions: 1 (1.0 mmol), 2 (2.5 mmol), DDQ (10 mol%),
TBHP (100 μL), toluene (10 mL), 90–95 °C, 8–12 h.
b Isolated yield.
MS (ESI): m/z = 317 [M + H]+; C20H14N2Cl.
give the benzyl cation intermediate I and the DDQH– an-
ion. The benzyl cation I is trapped by the nitrogen lone
pair and subsequent proton abstraction by the DDQH– an-
2-(4-Bromophenyl)-4-phenylquinazoline (3d)11a
Off-white solid; yield: 325 mg (90%); mp 140–145 °C.
ion produces intermediate II and reduced DDQH2. This 1H NMR (300 MHz, CDCl3, TMS): δ = 8.64–8.67 (m, 2 H), 8.14 (d,
J = 8.4 Hz, 1 H), 8.04 (d, J = 8.3 Hz, 1 H), 7.86 (t, J = 8.4 Hz, 1 H),
intermediate II undergoes similar transformation, as men-
tioned above, to afford the 2-phenylquinazoline product.
7.70–7.77 (m, 4 H), 7.47–7.55 (m, 4 H).
13C NMR (75 MHz, CDCl3, TMS): δ = 121.4, 124.6, 126.5, 127.2,
128.5, 128.6, 129.3, 130.6, 131.7, 133.6, 134.4, 136.5, 137.9, 152.0,
160.2, 167.0.
In summary, we have described an efficient and novel
protocol for the synthesis of 2-arylquinazolines from 2-
aminobenzophenones or 2-aminoacetophenones and ben-
zylamines via DDQ-induced oxidative cyclization under
MS (ESI): m/z = 361 [M + H]+; C20H14N2Br.
2-(4-Fluorophenyl)-4-phenylquinazoline (3e)11a
Yellow solid; yield: 274 mg (91%); mp 155–157 °C.
metal-free conditions with peroxide as a co-oxidant.
1H NMR (300 MHz, CDCl3, TMS): δ = 8.67–8.70 (m, 2 H), 8.07–
All chemicals were purchased from Sigma Aldrich with not less
8.10 (m, 2 H), 7.76–7.85 (m, 3 H), 7.60–7.63 (m, 3 H), 7.52–7.54
than 99.9% purity. Analytical thin-layer chromatography (TLC)
was carried out by using silica gel 60 F254 pre-coated plates. Visual-
(m, 3 H).
13C NMR (75 MHz, CDCl3, TMS): δ = 121.8, 124.7, 128.6, 128.9,
129.7, 130.1, 130.5, 130.7, 132.3, 133.4, 134.4, 137.2, 137.7, 150.3,
160.2, 168.0.
ization was accomplished with UV lamp and/or I2 stain. All prod-
ucts were characterized by their NMR and mass spectra. 1H NMR
and 13C NMR spectra were recorded on 200 or 300 MHz instru-
ments, on samples dissolved in CDCl3 with Me4Si as the internal
standard; chemical shifts are reported in parts per million (ppm, δ).
MS (ESI): m/z = 301 [M + H]+; C20H14N2F.
2-(2-Methoxyphenyl)-4-phenylquinazoline (3f)
Brown solid; yield: 257 mg (82%); mp 160–165 °C.
2-Arylquinazolines 3; General Procedure
To a stirred soln of toluene (10 mL), 2-aminobenzophenone or 2-
aminoacetophenone (1.0 mmol), benzylamine (2.5 mmol), and
DDQ (10 mol%), TBHP (100 μL) was added, after which the mix-
ture was heated at 90–95 °C until completion of the reaction (TLC
monitoring). The mixture was cooled to r.t and the solvent was re-
moved by rotary evaporator. The crude residue was extracted with
EtOAc (3 × 10 mL). The combined organic layers were washed
with H2O and sat. brine, dried (anhyd Na2SO4) and evaporated un-
der reduced pressure. The resulting crude product was purified by
column chromatography (EtOAc–hexane) to give the correspond-
ing 2-phenylquinazolines in good to excellent yields. All the prod-
ucts were characterized by 1H and 13C NMRand mass spectroscopy
and compared with authentic samples known in literature.
1H NMR (300 MHz, CDCl3, TMS): δ = 8.10–8.16 (m, 2 H), 7.81–
7.90 (m, 4 H), 7.52–7.56 (m, 4 H), 7.37–7.42 (m, 1 H), 7.01–7.09
(m, 2 H), 3.89 (s, 3 H).
13C NMR (75 MHz, CDCl3, TMS): δ = 55.3, 114.0, 122.1, 124.9,
128.6, 128.8, 129.0, 130.1, 130.3, 130.7, 132.2, 133.7, 134.4, 137.1,
151.0, 160.3, 161.9, 167.5.
HRMS: m/z [M + H]+ calcd for C21H17N2O: 313.1166; found:
313.1160.
4-Phenyl-2-(4-tolyl)quinazoline (3g)11a
Yellow solid; yield: 246 mg (83%); mp 167–170 °C.
© Georg Thieme Verlag Stuttgart · New York
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S. Rachakonda et al.
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1H NMR (300 MHz, CDCl3, TMS): δ = 8.56–8.58 (m, 2 H), 8.07–
8.12 (m, 2 H), 7.80–7.86 (m, 3 H), 7.58–7.60 (m, 3 H), 7.46–7.51
(m, 1 H), 7.31 (d, J = 8.3 Hz, 2 H), 2.46 (s, 3 H).
13C NMR (75 MHz, CDCl3, TMS): δ = 22.0, 121.8, 126.5, 127.2,
128.6, 128.9, 129.2, 129.8, 130.1, 133.4, 134.9, 137.6, 139.8, 150.8,
160.2, 168.0.
13C NMR (75 MHz, CDCl3, TMS): δ = 22.0, 100.1, 101.9, 105.3,
119.5, 128.1, 128.3, 129.9, 138.3, 147.8, 149.7, 153.2, 159.1, 165.0.
HRMS: m/z [M + H]+ calcd for C16H13N2O2: 265.0977; found:
265.0965.
2-(4-Chlorophenyl)-4-methyl-6,7-(methylenedioxy)quinazoline
(3n)
Brown solid; yield: 260 mg (87%); mp 190–195 °C.
MS (ESI): m/z = 297 [M + H]+; C21H17N2.
1H NMR (300 MHz, CDCl3, TMS): δ = 8.48 (d, J = 8.4 Hz, 2 H),
7.44 (d, J = 8.4 Hz, 2 H), 7.25–7.28 (m, 2 H), 6.13 (s, 2 H), 2.85 (s,
3 H).
13C NMR (75 MHz, CDCl3, TMS): δ = 22.0, 101.9, 105.3, 119.5,
121.2, 128.0, 128.4, 130.0, 138.5, 146.8, 150.0, 153.2, 159.4, 165.0.
4-Phenyl-2-(2-tolyl)quinazoline (3h)11a
Yellow solid; yield: 240 mg (81%); mp 70–75 °C.
1H NMR (300 MHz, CDCl3, TMS): δ = 8.20–8.22 (m, 2 H), 8.00–
8.04 (m, 2 H), 7.86–7.92 (m, 2 H), 7.58–7.62 (m, 4 H), 7.31–7.36
(m, 3 H), 2.64 (s, 3 H).
HRMS: m/z [M]+ calcd for C16H12N2O2Cl: 299.0587; found:
299.0573.
13C NMR (75 MHz, CDCl3, TMS): δ = 21.6, 121.4, 126.4, 127.2,
128.5, 128.9, 129.0, 129.9, 130.9, 133.4, 137.4, 137.8, 139.0, 151.0,
161.2, 168.0.
6-Bromo-2,4-diphenylquinazoline (3o)
Off-white solid; yield: 322 mg (89%); mp 135–140 °C.
MS (ESI): m/z = 297 [M + H]+; C21H17N2.
1H NMR (300 MHz, CDCl3, TMS): δ = 8.64–8.67 (m, 2 H), 8.14 (d,
J = 8.4 Hz, 1 H), 8.04 (d, J = 8.4 Hz, 1 H), 7.87 (t, J = 8.3 Hz, 1 H),
7.70–7.77 (m, 4 H), 7.47–7.55 (m, 4 H).
13C NMR (75 MHz, CDCl3, TMS): δ = 121.4, 124.6, 126.5, 127.2,
128.5, 128.6, 129.3, 130.6, 131.7, 133.6, 136.5, 137.9, 152.0, 160.2,
167.0.
4-Phenyl-2-(3-tolyl)quinazoline (3i)11a
Yellow solid; yield: 237 mg (80%); mp 119–121 °C.
1H NMR (300 MHz, CDCl3, TMS): δ = 8.50–8.54 (m, 2 H), 8.10–
8.13 (m, 2 H), 7.82–7.86 (m, 3 H), 7.52–7.60 (m, 3 H), 7.40–7.46
(m, 2 H), 7.31–7.34 (m, 1 H), 2.47 (s, 3 H).
13C NMR (75 MHz, CDCl3, TMS): δ = 21.8, 121.6, 126.3, 127.3,
128.6, 128.8, 129.1, 129.6, 130.1, 131.2, 133.4, 137.6, 137.9, 139.0,
151.6, 160.2, 167.6.
HRMS: m/z [M + H]+ calcd for C20H14N2Br: 361.0535; found:
361.0529.
MS (ESI): m/z = 297 [M + H]+; C21H17N2.
6-Methoxy-2,4-diphenylquinazoline (3p)
Brown solid; yield: 263 mg (84%); mp 168–175 °C.
4-Phenyl-2-[4-(trifluoromethyl)phenyl]quinazoline (3j)11a
Yellow solid; yield: 316 mg (90%); mp 126–129 °C.
1H NMR (300 MHz, CDCl3, TMS): δ = 8.15–8.21 (m, 2 H), 7.82–
7.89 (m, 4 H), 7.52–7.55 (m, 4 H), 7.35–7.42 (m, 1 H), 7.05–7.10
(m, 2 H), 3.89 (s, 3 H).
13C NMR (75 MHz, CDCl3, TMS): δ = 55.1, 112.9, 122.8, 125.9,
128.4, 129.0, 129.4, 129.9, 130.1, 130.5, 132.7, 133.9, 134.3, 139.1,
151.4, 160.1, 167.3.
1H NMR (300 MHz, CDCl3, TMS): δ = 8.78 (d, J = 8.4 Hz, 2 H),
8.12–8.18 (m, 2 H), 7.85–7.91 (m, 3 H), 7.69–7.75 (m, 3 H), 7.54–
7.60 (m, 3 H).
13C NMR (75 MHz, CDCl3, TMS): δ = 121.9, 122.9, 124.7, 125.3,
126.0, 127.1, 127.8, 128.6, 128.9, 129.3, 130.1, 130.4, 131.7, 132.0,
132.3, 133.7, 137.2, 140.9, 151.8, 160.2, 168.0.
HRMS: m/z [M + H]+ calcd for C21H17N2O: 313.1266; found:
313.1260.
MS (ESI): m/z = 351 [M + H]+; C21H14F3N2.
6,7-Dimethoxy-2,4-diphenylquinazoline (3q)11a
6-Chloro-2,4-diphenylquinazoline (3k)11a
Brown solid; yield: 243 mg (71%); mp 181–185 °C.
Brown solid; yield: 282 mg (89%); mp 200–205 °C.
1H NMR (300 MHz, CDCl3, TMS): δ = 8.59–8.63 (m, 2 H), 7.85–
7.88 (m, 2 H), 7.55–7.60 (m, 3 H), 7.45–7.50 (m, 4 H), 7.32 (s, 1 H),
4.08 (s, 3 H), 3.88 (s, 3 H).
13C NMR (75 MHz, CDCl3, TMS): δ = 55.2, 55.8, 104.4, 108.0,
116.9, 127.9, 128.4, 129.0, 129.6, 129.8, 130.2, 138.5, 139.1, 150.4,
151.4, 155.2, 160.2, 167.0.
1H NMR (300 MHz, CDCl3, TMS): δ = 8.65–8.68 (m, 2 H), 8.06–
8.10 (m, 2 H), 7.77–7.86 (m, 3 H), 7.59–7.60 (m, 3 H), 7.50–7.52
(m, 3 H).
13C NMR (75 MHz, CDCl3, TMS): δ = 121.8, 125.7, 128.2, 128.6,
129.7, 130.2, 130.5, 130.7, 132.5, 133.2, 134.4, 136.8, 137.6, 150.4,
160.3, 168.0.
MS (ESI): m/z = 343 [M + H]+; C22H19N2O2.
MS (ESI): m/z = 317 [M + H]+; C20H14ClN2.
4-Methyl-2-phenylquinazoline (3r)
6-Nitro-2,4-diphenylquinazoline (3l)
Brown solid; yield: 190 mg (86%); mp 70–75 °C.
Brown solid; yield: 302 mg (92%); mp 214–217 °C.
1H NMR (300 MHz, CDCl3, TMS): δ = 8.60–8.63 (m, 2 H), 8.05 (d,
J = 8.3 Hz, 2 H), 7.83 (t, J = 8.3 Hz, 1 H), 7.49–7.57 (m, 4 H), 2.98
(s, 3 H).
13C NMR (75 MHz, CDCl3, TMS): δ = 21.9, 122.8, 123.7, 124.8,
126.7, 128.4, 128.8, 129.1, 130.2, 133.3, 138.1, 139.3, 150.2, 160.0,
168.1.
1H NMR (300 MHz, CDCl3, TMS): δ = 9.03 (s, 1 H), 8.71–8.73 (m,
2 H), 8.23 (d, J = 9.6 Hz, 1 H), 7.90–7.91 (m, 2 H), 7.65–7.66 (m, 3
H), 7.51–7.52 (m, 3 H), 7.24 (s, 1 H).
13C NMR (75 MHz, CDCl3, TMS): δ = 124.1, 126.9, 128.7, 129.1,
129.3, 130.3, 130.9, 131.1, 131.7, 132.5, 150.8, 160.8, 167.5.
HRMS: m/z [M + H]+ calcd for C20H14N3O2: 328.1086; found:
328.1070.
HRMS: m/z [M + H]+ calcd for C15H13N2: 221.1078; found:
221.1076.
4-Methyl-6,7-(methylenedioxy)-2-phenylquinazoline (3m)
2-(4-Methoxyphenyl)-4-methylquinazoline (3s)
Brown solid; yield: 238 mg (90%); mp 132–135 °C.
Brown solid; yield: 211 mg (84%); mp 65–70 °C.
1H NMR (300 MHz, CDCl3, TMS): δ = 8.52 (d, J = 7.9 Hz, 2 H),
7.46–7.49 (m, 3 H), 7.29 (s, 1 H), 7.22 (s, 1 H), 6.08 (s, 2 H), 2.84
(s, 3 H).
1H NMR (300 MHz, CDCl3, TMS): δ = 7.96 (d, J = 8.4 Hz, 2 H),
7.75 (t, J = 8.3 Hz, 1 H), 7.62 (d, J = 8.3 Hz, 2 H), 7.17 (t, J = 8.1
Hz, 2 H), 6.96 (d, J = 9.0 Hz, 1 H), 3.84 (s, 3 H), 2.92 (s, 3 H).
Synthesis 2012, 44, 2065–2069
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of 2-Phenylquinazolines
2069
13C NMR (75 MHz, CDCl3, TMS): δ = 21.7, 55.0, 113.6, 115.4,
122.5, 124.6, 126.0, 128.9, 130.1, 130.7, 131.7, 133.0, 134.0, 150.2,
159.6, 161.5, 167.4.
M.; Kasibhatla, S.; Tseng, B.; Drewe, J.; Cai, S. X. J. Med.
Chem. 2009, 52, 2341. (b) Henderson, E. A.; Bavetsias, V.;
Theti, D. S.; Wilson, S. C.; Clauss, R.; Jackman, A. L.
Bioorg. Med. Chem. 2006, 14, 5020.
HRMS: m/z [M + H]+ calcd for C16H15N2O: 251.1184; found:
(5) Gong, G.; Xie, Y.; Rinderspacher, A.; Deng, S.-X.; Feng, Y.;
Zhu, Z.; Tang, Y.; Wyler, M.; Aulner, N.; Toebben, U.;
Smith, D. H.; Branden, L.; Chung, C.; Schürer, S.; Vidović,
D.; Landry, D. W. Bioorg. Med. Chem. Lett. 2009, 19, 1191.
(6) Gellibert, G.; Fouchet, M.-H.; Nguyen, V.-L.; Wang, R.;
Krysa, G.; de Gouville, A.-C.; Huet, S.; Dodic, N. Bioorg.
Med. Chem. Lett. 2009, 19, 2277.
251.1181.
2-(4-Chlorophenyl)-4-methylquinazoline (3t)
Brown solid; yield: 225 mg (88%); mp 65–68 °C.
1H NMR (300 MHz, CDCl3, TMS): δ = 8.52 (d, J = 8.3 Hz, 2 H),
7.94–7.96 (m, 2 H), 7.74–7.79 (m, 1 H), 7.39–7.48 (m, 3 H), 2.89
(s, 3 H).
(7) Debenham, J. S.; Madsen-Duggan, C. B.; Wang, J.; Tong,
X.; Lao, J.; Fong, T. M.; Schaeffer, M.-T.; Xiao, J. C.;
Huang, C. C. R.-R.; Shen, C.-P.; Stribling, D. S.; Shearman,
L. P.; Strack, A. M.; MacIntyre, D. E.; Hale, J. J.; Walsh, T.
F. Bioorg. Med. Chem. Lett. 2009, 19, 2591.
13C NMR (75 MHz, CDCl3, TMS): δ = 21.7, 122.7, 123.9, 124.8,
126.8, 128.5, 128.9, 129.7, 133.4, 136.3, 136.5, 150.0, 158.8, 168.1.
HRMS: m/z [M + H]+ calcd for C15H12N2Cl: 255.0689; found:
255.0677.
(8) (a) Witt, A.; Bergman, J. Curr. Org. Chem. 2003, 7, 659.
(b) Michael, J. P. Nat. Prod. Rep. 2008, 25, 166. (c) Michael,
J. P. Nat. Prod. Rep. 2007, 24, 223. (d) Chien, T.-C.; Chen,
C.-S.; Yu, F.-H.; Chern, J.-W. Chem. Pharm. Bull. 2004, 52,
1422. (e) Herget, T.; Freitag, M.; Morbitzer, M.; Kupfer, R.;
Stamminger, T.; Marschall, M. Antimicrob. Agents
Chemother. 2004, 48, 4154. (f) Waisser, K.; Gregor, J.;
Dostal, H.; Kunes, J.; Kubicova, L.; Klimesova, V.;
Kaustova, J. Farmaco 2001, 56, 803. (g) Kunes, J.; Bazant,
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2000, 55, 725.
Acknowledgment
S.R. is thankful to KL University.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
nnfomartit
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2065–2069