Rapid assembly of quinazolinone scaffold via copper-catalyzed tandem reaction of 2-bromobenzamides with aldehydes and aqueous ammonia: Application to the synthesis of the alkaloid tryptanthrin

Article abstract of DOI:10.1039/c4ra10799c

An efficient and practical procedure for the preparation of 2-substituted and 2,3-disubstituted quinazolinones was achieved through copper-catalyzed tandem reaction of 2-bromobenzamides with aldehydes and aqueous ammonia under air. Control experimental results indicated that this tandem reaction is triggered by a copper-catalyzed direct amination of 2-bromobenzamides with aqueous ammonia, followed by cyclocondensation and oxidative aromatization. As an application, this novel methodology provides a concise and practical one-pot route to the synthesis of alkaloid tryptanthrin. This journal is

Full text of DOI:10.1039/c4ra10799c

RSC Advances
View Article Online
View Journal | View Issue
PAPER
Rapid assembly of quinazolinone scaffold via
copper-catalyzed tandem reaction of
2-bromobenzamides with aldehydes and aqueous
ammonia: application to the synthesis of the
alkaloid tryptanthrin†
Cite this: RSC Adv., 2014, 4, 59289
a
b
a
a
a
*
*
Shenghai Guo, Yan Li, Li Tao, Wenwen Zhang and Xuesen Fan
An efficient and practical procedure for the preparation of 2-substituted and 2,3-disubstituted
quinazolinones was achieved through copper-catalyzed tandem reaction of 2-bromobenzamides with
aldehydes and aqueous ammonia under air. Control experimental results indicated that this tandem
reaction is triggered by a copper-catalyzed direct amination of 2-bromobenzamides with aqueous
ammonia, followed by cyclocondensation and oxidative aromatization. As an application, this novel
methodology provides a concise and practical one-pot route to the synthesis of alkaloid tryptanthrin.
Received 19th September 2014
Accepted 31st October 2014
DOI: 10.1039/c4ra10799c
www.rsc.org/advances
2-aminobenzamides.8 While these approaches are efficient, they
usually suffer from difficult-to-prepare starting materials, use of
1. Introduction
stoichiometric or large excess oxidants, low yields, or harsh
reaction conditions. Therefore, the development of more prac-
tical and efficient approaches toward quinazolinone derivatives
remains an attractive task for organic chemists.
Recently, transition-metal-catalyzed reactions have emerged
as versatile tools for the construction of quinazolinones. For
Quinazolinone derivatives, as an important class of six-
membered nitrogen-containing heterocyclic skeletons, have
been extensively studied since they are present in many natu-
rally occurring alkaloids and synthetic drug candidates (Fig. 1),1
and also exhibit signicant antitumor,2 anticonvulsant,3 anti-
fungal,4 antitubercular,5 and antimicrobial6 activities.
example,
palladium-catalyzed
carbonylation/cyclization
In view of their importance, many approaches have been
developed for the preparation of quinazolinone derivatives.
Among them, typical synthetic approaches mostly involve the
acid- or base-promoted condensation of carboxylic acid deriv-
atives with 2-aminobenzoic acids or their derivatives7 and the
cascade condensation/oxidation sequence of aldehydes with
cascades turned out to be an efficient approach toward quina-
zolinone derivatives.9 Moreover, these compounds can also be
conveniently prepared through copper-catalyzed tandem reac-
tions of 2-halobenzoic acid derivatives with amidines, a-amino
acids, benzylamines, or amides.10 As a continuation of our
recent studies on the synthesis of N-heterocycles,11 we found
that copper-catalyzed tandem reaction of 2-bromobenzamides
with aldehydes and aqueous ammonia, being more readily
available and less expensive, offers a more practical and effi-
cient route toward quinazolinone derivatives. Herein, we wish
to disclose the details of our research work.
Fig. 1 Selected naturally occurring alkaloids and drug candidate with
quinazolinone skeleton.
2. Results and discussion
Initially, 2-bromobenzamide (1a), benzaldehyde (2a), and
aqueous ammonia were employed as model substrates to opti-
aCollaborative Innovation Center of Henan Province for Green Manufacturing of Fine mize the reaction parameters such as catalysts, bases, ligands,
Chemicals, Key Laboratory of Green Chemical Media and Reactions, Ministry of
solvents, and temperature. As listed in Table 1, ve copper salts
Education, School of Chemistry and Chemical Engineering, Henan Normal
were screened by using DMSO as solvent and K2CO3 as base at
University, Xinxiang, Henan 453007, P. R. China. E-mail: shguo@htu.cn; xuesen.
ꢀ
100 C under air atmosphere (entries 1–5). Among them, CuBr
fan@htu.cn
exhibited slightly higher catalytic activity (entry 5). We next
examined different bases (entries 5–8), and Cs2CO3 provided the
highest yield (entry 6). When DMF and dioxane were used to
bSchool of Science, Jiaozuo Teachers' College, Jiaozuo, Henan 450001, P. R. China
† Electronic supplementary information (ESI) available: The copies of 1H NMR
and 13C NMR spectra of 3a–w, 5a–l, 6, 7, and 9. See DOI: 10.1039/c4ra10799c
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 59289–59296 | 59289

View Article Online
RSC Advances
Paper
Table 1 Optimization for the synthesis of 2-phenylquinazolin-4(3H)-
one (3a)a
investigated under our optimized reaction conditions, and it
was observed that the tandem reactions of amides 1b–d with
different aldehydes
2 and aqueous ammonia proceeded
smoothly to afford 2-substituted quinazolinones 3o–w in yields
ranging from 30–79% (entries 15–23).
Having accomplished an efficient protocol for the synthesis
of 2-substituted quinazolinones through the tandem reaction of
Entry Catalyst
Base
Ligand
Solvent T (ꢀC) Yieldb (%)
1
2
3
4
5
6
7
8
Cu(OAc)2 K2CO3
—
—
—
—
—
—
—
—
—
—
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
100
100
100
100
100
100
100
100
100
53
52
52
50
56
60
52
14
23
0
64
58
48
72
65
66
Table 2 Synthesis of 2-substituted quinazolinones 3a–wa,b
CuCl2
CuCl
CuI
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
K3PO4
NaOAc
Cs2CO3
Cs2CO3
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
9
10
11
12
13
14c
15c
16c
Dioxane 100
DMSO
DMSO
Cs2CO3 L-proline
Cs2CO3 DMEDA
100
100
100
100
120
80
Cs2CO3 1,10-Phen DMSO
Cs2CO3 L-proline
Cs2CO3 L-proline
Cs2CO3 L-proline
DMSO
DMSO
DMSO
a
Unless otherwise noted, the reactions were carried out with 1a
(0.4 mmol), 2a (0.6 mmol), aqueous ammonia (0.5 mL), base (0.8
mmol), catalyst (0.04 mmol), ligand (0.08 mmol), and solvent (1.5 mL)
b
at 100 ꢀC in a sealed tube under air for 24 h. Isolated yield of 3a.
c
2a (0.8 mmol) was used.
replace DMSO as the reaction medium, the yields of 3a
decreased signicantly (entries 6 vs. 9–10). The effect of ligands
on this reaction was also investigated (entries 6 and 11–13), and
L-proline proved to be optimal (entry 11). Increasing the amount
of 2a from 1.5 to 2.0 equiv. (relative to 1a) gave 3a in a higher
yield (72%) (entry 11 vs. 14). In addition, the reaction temper-
atures higher or lower than 100 ꢀC resulted in decreased yields
of 3a (entries 14–16).
With the optimized conditions (Table 1, entry 14) in hand,
the scope and limitation of this copper-catalyzed tandem reac-
tion leading to 2-substituted quinazolinones were investigated
and the results are shown in Table 2. First, aryl-substituted
aldehydes bearing either electron-donating or electron-
withdrawing groups on the aromatic ring (including: Me,
MeO, CF3, Cl, F) reacted very well with 1a and aqueous
ammonia to provide the desired products 3a–i in 67–83% yields
(entries 1–9). And it was found that the steric hindrance of
aromatic aldehydes has slightly inuence on the outcome of the
reactions (entries 7–9). With 1-naphthaldehyde, quinazolinone
3j was formed in 73% yield (entry 10). Heteroaryl aldehydes also
underwent this tandem reaction smoothly, and it was observed
that electron-rich thiophene-2-carbaldehyde provided the cor-
responding product in yield higher than that of electron-poor
pyridine-4-carbaldehyde (entries 11–12). In addition, both
alkenyl- and alkyl-substituted aldehydes were well compatible
with the reaction conditions to generate the desired products
3m and 3n in moderate yields (entries 13–14). Next, 2-bromo-
a
Reaction conditions: 1 (0.4 mmol), 2 (0.8 mmol), aqueous ammonia
(0.5 mL), CuBr (0.04 mmol), Cs2CO3 (0.8 mmol), L-proline
b
(0.08 mmol), DMSO (1.5 mL), 100 ꢀC, under air, 24 h. Isolated yields
are shown.
benzamides
1 with different substitution patterns were
59290 | RSC Adv., 2014, 4, 59289–59296
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
RSC Advances
2-bromobenzamides with aldehydes and aqueous ammonia, we benzaldehyde (2a) and aqueous ammonia as reaction partners,
were then interested in whether this protocol could be and it turned out that N-alkyl substituted amides 4a–c generally
successfully applied in the preparation of 2,3-disubstituted provided the corresponding products in yields higher than N-
quinazolinones by using N-substituted 2-bromobenzamides as aryl substituted amide 4d (entries 1, 5, 8 vs. 11).
starting materials. Thus, N-methyl 2-bromobenzamide (4a) was
To explore the reaction mechanism, several control experi-
then treated with benzaldehyde (2a) and aqueous ammonia ments were carried out and the results are illustrated in Scheme
under the optimized conditions for the synthesis of 3a (Table 1, 1. First, treatment of 1a with aqueous ammonia by using CuBr
entry 14). To our delight, the expected tandem reaction pro- as catalyst and L-proline as ligand under air afforded 2-amino-
ceeded smoothly to afford 3-methyl-2-phenylquinazolin-4(3H)- benzamide (6) in 83% yield; subsequent cyclocondensation of 6
one (5a) in 68% yield (Table 3, entry 1). Due to the good effi- with benzaldehyde (2a) followed by oxidation gave rise to qui-
ciency of the above catalytic process, no further optimization of nazolinone 3a in a yield of 91% (Scheme 1, eqn (1)). Next,
the reaction conditions was tried. Next, the generality of this treating a mixture of 6 and 2a under nitrogen atmosphere could
reaction was examined. As shown in Table 3, aryl-, heteroaryl-, afford intermediate 7 (85%) along with 3a (7%) (Scheme 1, eqn
alkyl-, and alkenyl-substituted aldehydes were compatible with (2)); then, the oxidation of 7 in the presence of CuBr under air
the reaction conditions to afford the corresponding 2,3-disub- provided the nal product 3a in 90% yield (Scheme 1, eqn (3)).
stituted quinazolinones 5 in modest to good yields, and aryl-
Based on the above results, a plausible mechanism for the
substituted aldehydes generally showed higher reactivity than formation of quinazolinone 3a is depicted in Scheme 2.
alkyl- and alkenyl-substituted aldehydes (entries 4 and 10). In Initially, copper-catalyzed direct amination of 1a with aqueous
addition, with thiophene-2-carbaldehyde, the corresponding ammonia by using L-proline as ligand affords intermediate 6.
product 5c was obtained in 39% yield under standard condi- Cyclocondensation of 6 with benzaldehyde (2a) gives rise to
tions, whereas elevating reaction temperature to 140 ꢀC gave 5c intermediate 7, which is subsequently oxidized by air under the
in a higher yield (61%) (entry 3). Then, the scope of N- catalysis of CuBr to generate the nal product 3a.
substituted amides 4 was also investigated by employing
To showcase the usefulness of this novel methodology, we
designed and developed a practical three-step one-pot proce-
dure for the construction of alkaloid tryptanthrin, which is
frequently found in a number of plants and exhibits potent
cytotoxicity against human cell lines (MCF-7, NCI-H460, and
Table 3 Synthesis of 2,3-disubstituted quinazolinones 5a–la
Scheme 1 Control experiments.
Scheme 2 Plausible mechanism for the formation of 3a.
a
Reaction conditions: 4 (0.4 mmol), 2 (0.8 mmol), aqueous ammonia
(0.5 mL), CuBr (0.04 mmol), Cs2CO3 (0.8 mmol), L-proline
b
(0.08 mmol), DMSO (1.5 mL), 100 ꢀC, under air, 24 h. The reaction
c
was performed at 140 ꢀC for 30 h. Butyraldehyde (1.2 mmol) was
used. d Some unknown by-products were formed.
Scheme 3 Copper-catalyzed one-pot synthesis of alkaloid tryptan-
thrin (9).
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 59289–59296 | 59291

View Article Online
RSC Advances
Paper
SF-268).12 As shown in Scheme 3, tryptanthrin (9) could be d 121.4, 126.3, 127.1, 128.0, 128.2, 129.1, 131.9, 133.2, 135.1,
conveniently prepared in 36% total yield through copper- 149.2, 152.8, 162.7. MS (ESI) m/z 223.2 [M + H]+.
catalyzed amination of 1a with aqueous ammonia followed by
2-p-Tolylquinazolin-4(3H)-one (3b).10e Petroleum ether/ethyl
condensation/oxidation13 cascade of the in situ formed 2-ami- acetate (3 : 1) as eluent; light yellow solid; yield: 78 mg (83%);
nobenzamide with aldehyde (8) and base-promoted intra- mp 238–240 ꢀC (lit.10e 261–263 ꢀC). 1H NMR (DMSO-d6, 400
molecular cross-coupling reaction. It should be noted that the MHz) d 2.34 (s, 3H), 7.30 (d, J ¼ 8.0 Hz, 2H), 7.45–7.49 (m, 1H),
present protocol is a concise and practical alternative toward 7.69 (d, J ¼ 8.4 Hz, 1H), 7.77–7.81 (m, 1H), 8.08 (d, J ¼ 8.4 Hz,
tryptanthrin derivatives.14
2H), 8.13 (d, J ¼ 7.2 Hz, 1H), 12.42 (s, 1H); 13C NMR (DMSO-d6,
100 MHz) d 21.4, 121.4, 126.3, 126.8, 127.9, 128.1, 129.6, 130.4,
134.9, 141.9, 149.4, 152.7, 162.7. MS (ESI) m/z 237.2 [M + H]+.
2-m-Tolylquinazolin-4(3H)-one (3c).9i Petroleum ether/ethyl
acetate (3 : 1) as eluent; white solid; yield: 70 mg (74%); mp
3. Conclusions
In summary, we have developed a convenient and rapid
synthetic route to 2-substituted and 2,3-disubstituted quinazo-
linones via copper-catalyzed tandem reaction of 2-bromo-
benzamides with aldehydes and aqueous ammonia under air.
The present protocol exhibits good functional group tolerance,
readily available and inexpensive starting materials, and oper-
ational simplicity. Moreover, this novel methodology has been
successfully applied in the construction of alkaloid tryptan-
thrin. To further explore novel synthetic approaches toward
other nitrogen-containing heterocyclic compounds is underway
in our laboratory.
1
217–218 ꢀC. H NMR (DMSO-d6, 400 MHz) d 2.39 (s, 3H), 7.36–
7.43 (m, 2H), 7.47–7.51 (m, 1H), 7.72 (d, J ¼ 8.0 Hz, 1H), 7.79–
7.83 (m, 1H), 7.96 (d, J ¼ 7.2 Hz, 1H), 8.01 (s, 1H), 8.14 (d, J ¼ 7.2
Hz, 1H), 12.44 (s, 1H); 13C NMR (DMSO-d6, 100 MHz) d 21.4,
121.5, 125.4, 126.3, 127.0, 128.0, 128.8, 128.9, 132.5, 133.1,
135.0, 138.4, 149.3, 152.8, 162.7. MS (ESI) m/z 237.3 [M + H]+.
2-(4-Methoxyphenyl)quinazolin-4(3H)-one (3d).10e Petroleum
ether/ethyl acetate (3 : 1) as eluent; light yellow solid; yield: 71
mg (70%); mp 238–240 ꢀC (lit.10e 247–248 ꢀC). 1H NMR (DMSO-
d6, 400 MHz) d 3.82 (s, 3H), 7.06 (d, J ¼ 8.8 Hz, 2H), 7.45 (t, J ¼
8.0 Hz, 1H), 7.68 (d, J ¼ 8.4 Hz, 1H), 7.78 (t, J ¼ 7.6 Hz, 1H), 8.11
(d, J ¼ 7.6 Hz, 1H), 8.17 (d, J ¼ 8.4 Hz, 2H), 12.37 (s, 1H); 13C
NMR (DMSO-d6, 100 MHz) d 55.9, 114.5, 121.2, 125.3, 126.3,
126.5, 127.8, 129.9, 134.9, 149.5, 152.3, 162.4, 162.7. MS (ESI) m/
z 253.4 [M + H]+.
4. Experimental
General methods
2-(4-(Triuoromethyl)phenyl)quinazolin-4(3H)-one (3e).9b
Petroleum ether/ethyl acetate (4 : 1) as eluent; white solid;
Unless noted, all commercial reagents and solvents were used
without further purication. High-resolution mass spectra
(HRMS) were obtained by using a MicrOTOF mass spectrom-
eter. 1H and 13C NMR spectra were recorded at 400 and 100
MHz, respectively. All reactions were monitored by thin-layer
chromatography (TLC) using silica gel plates (silica gel 60
F254 0.25 mm) and components were visualized by observation
under UV light (254 and 365 nm).
1
ꢀ
yield: 84 mg (72%); mp 260–262 C. H NMR (DMSO-d6, 400
MHz) d 7.54 (t, J ¼ 7.2 Hz, 1H), 7.76 (d, J ¼ 7.6 Hz, 1H), 7.83–
7.86 (m, 1H), 7.90 (d, J ¼ 7.6 Hz, 2H), 8.15 (d, J ¼ 7.2 Hz, 1H),
8.36 (d, J ¼ 8.0 Hz, 2H), 12.76 (s, 1H); 13C NMR (DMSO-d6, 100
MHz) d 121.7, 124.4 (q, J ¼ 270.5 Hz, CF3), 125.9 (q, J ¼ 3.8 Hz,
2C), 126.4, 127.5, 128.1, 129.2, 131.6 (q, J ¼ 32.0 Hz, 1C),
135.2, 137.1, 148.9, 151.7, 162.7. HRMS (ESI) calcd for
C
15H10F3N2O [M + H]+ 291.0740, found 291.0737.
2-(4-Chlorophenyl)quinazolin-4(3H)-one (3f).15 Puried by
Typical procedure for the preparation of quinazolinone 3a
To a mixture of 2-bromobenzamide 1a (80 mg, 0.4 mmol), washing crude product with CH2Cl2 (3 mL); light yellow solid;
benzaldehyde 2a (82 mL, 0.8 mmol), CuBr (5.8 mg, 0.04 mmol), yield: 70 mg (68%); mp 281–283 ꢀC (lit.15 298–300 ꢀC). 1H NMR
Cs2CO3 (261 mg, 0.8 mmol), and L-proline (9.2 mg, 0.08 mmol) (DMSO-d6, 400 MHz) d 7.52 (t, J ¼ 7.2 Hz, 1H), 7.61 (d, J ¼ 8.4 Hz,
in DMSO (1.5 mL) was added 26% aqueous ammonia (0.5 mL) 2H), 7.73 (d, J ¼ 7.6 Hz, 1H), 7.83 (t, J ¼ 8.0 Hz, 1H), 8.14 (d, J ¼
in a tube under air atmosphere. Then the tube was sealed, and 8.0 Hz, 1H), 8.19 (d, J ¼ 8.4 Hz, 2H), 12.58 (br s, 1H); 13C NMR
ꢀ
the mixture was stirred at 100 C for 12 h. Next, the tube was (DMSO-d6, 100 MHz) d 121.5, 126.4, 127.3, 128.0, 129.2, 130.1,
opened to air and the mixture was stirred at 100 ꢀC for another 132.0, 135.2, 136.8, 149.0, 151.9, 162.6. MS (ESI) m/z 257.8
12 h. Aer being cooled to room temperature, the resulting [M + H]+.
mixture was quenched with NH4Cl solution and extracted with
2-(4-Fluorophenyl)quinazolin-4(3H)-one (3g).9b Petroleum
ethyl acetate. The combined organic layer was washed with H2O ether/ethyl acetate (3 : 1) as eluent; yellow solid; yield: 79 mg
1
ꢀ
and brine, and then dried over anhydrous Na2SO4. The solvent (82%); mp 254–256 C. H NMR (DMSO-d6, 400 MHz) d 7.36–
was evaporated under reduced pressure and the crude product 7.40 (m, 2H), 7.49–7.53 (m, 1H), 7.72 (d, J ¼ 7.2 Hz, 1H), 7.80–
was puried by chromatography on silica-gel to afford quina- 7.84 (m, 1H), 8.12–8.15 (m, 1H), 8.22–8.25 (m, 2H), 12.55 (s,
zolinone 3a in 72% isolated yield.
1H); 13C NMR (DMSO-d6, 100 MHz) d 116.1 (d, J ¼ 21.8 Hz,
2-Phenylquinazolin-4(3H)-one (3a).10e Petroleum ether/ethyl 2C), 121.3, 126.3, 127.1, 127.9, 129.7 (d, J ¼ 2.9 Hz, 1C), 130.8
acetate (3 : 1) as eluent; white solid; yield: 64 mg (72%); mp (d, J ¼ 9.5 Hz, 2C), 135.1, 149.1, 151.9, 162.7, 164.5 (d, J ¼
1
231–233 ꢀC (lit.10e 234–235 C). H NMR (DMSO-d6, 400 MHz) 248.0 Hz, 1C). MS (ESI) m/z 241.1 [M + H]+.
ꢀ
d 7.49–7.59 (m, 4H), 7.73 (d, J ¼ 8.4 Hz, 1H), 7.80–7.84 (m, 1H),
2-(3-Fluorophenyl)quinazolin-4(3H)-one (3h).16 Petroleum
8.13–8.18 (m, 3H), 12.55 (s, 1H); 13C NMR (DMSO-d6, 100 MHz) ether/ethyl acetate (3 : 1) as eluent; light yellow solid; yield:
59292 | RSC Adv., 2014, 4, 59289–59296
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
RSC Advances
1
ꢀ
72 mg (75%); mp 229–231 C. H NMR (DMSO-d6, 400 MHz) MHz) d 0.91 (t, J ¼ 7.2 Hz, 3H), 1.68–1.77 (m, 2H), 2.55 (t, J ¼ 7.6
d 7.40–7.44 (m, 1H), 7.50–7.61 (m, 2H), 7.73 (d, J ¼ 8.0 Hz, Hz, 2H), 7.43 (t, J ¼ 7.2 Hz, 1H), 7.57 (d, J ¼ 8.0 Hz, 1H),
1H), 7.83 (t, J ¼ 7.2 Hz, 1H), 7.97–8.05 (m, 2H), 8.14 (d, J ¼ 7.2 7.73–7.76 (m, 1H), 8.06 (d, J ¼ 7.2 Hz, 1H), 12.15 (s, 1H); 13C
Hz, 1H), 12.58 (s, 1H); 13C NMR (DMSO-d6, 100 MHz) d 115.0 NMR (DMSO-d6, 100 MHz) d 13.9, 20.6, 36.8, 121.2, 126.1, 126.3,
(d, J ¼ 23.6 Hz, 1C), 118.7 (d, J ¼ 21.3 Hz, 1C), 121.6, 124.4 (d, J 127.2, 134.7, 149.4, 157.7, 162.2. MS (ESI) m/z 189.2 [M + H]+.
¼ 3.0 Hz, 1C), 126.3, 127.3, 128.1, 131.2 (d, J ¼ 8.4 Hz, 1C),
6-Methyl-2-phenylquinazolin-4(3H)-one (3o).15 Petroleum
135.1, 135.5 (d, J ¼ 7.6 Hz, 1C), 148.9, 151.5, 162.57 (d, J ¼ ether/ethyl acetate (3 : 1) as eluent; light yellow solid; yield: 73
242.4 Hz, 1C), 162.58. MS (ESI) m/z 241.2 [M + H]+.
mg (77%); mp 220–222 C (lit.15 238–240 C). H NMR (DMSO-
ꢀ ꢀ
1
2-(2-Fluorophenyl)quinazolin-4(3H)-one (3i). Petroleum d6, 400 MHz) d 2.43 (s, 3H), 7.52–7.62 (m, 5H), 7.93 (s, 1H), 8.15–
ether/ethyl acetate (3 : 1) as eluent; light yellow solid; yield: 64 8.16 (m, 2H), 12.42 (s, 1H); 13C NMR (DMSO-d6, 100 MHz) d 21.3,
mg (67%); mp 153–155 ꢀC. 1H NMR (DMSO-d6, 400 MHz) d 7.34– 121.2, 125.7, 127.9, 128.1, 129.0, 131.7, 133.3, 136.3, 136.7,
7.40 (m, 2H), 7.53–7.64 (m, 2H), 7.70–7.86 (m, 3H), 8.16 (dd, J ¼ 147.2, 151.9, 162.6. MS (ESI) m/z 237.3 [M + H]+.
1.2, 8.0 Hz, 1H), 12.56 (s, 1H); 13C NMR (DMSO-d6, 100 MHz) d
2-(4-Methoxyphenyl)-6-methylquinazolin-4(3H)-one
(3p).
116.6 (d, J ¼ 21.3 Hz, 1C), 121.6, 122.8 (d, J ¼ 13.0 Hz, 1C), 125.1 Petroleum ether/ethyl acetate (2 : 1) as eluent; light yellow solid;
(d, J ¼ 3.8 Hz, 1C), 126.3, 127.5, 128.0, 131.5 (d, J ¼ 2.3 Hz, 1C), yield: 64 mg (60%); mp 258–260 ꢀC. 1H NMR (DMSO-d6, 400
133.3 (d, J ¼ 8.4 Hz, 1C), 135.1, 149.2, 150.4, 160.1 (d, J ¼ 248.4 MHz) d 2.42 (s, 3H), 3.82 (s, 3H), 7.05 (d, J ¼ 8.8 Hz, 2H), 7.56–
Hz, 1C), 162.0. HRMS (ESI) calcd for C14H10FN2O [M + H]+ 7.61 (m, 2H), 7.90 (s, 1H), 8.15 (d, J ¼ 8.8 Hz, 2H), 12.29 (s, 1H);
241.0772, found 241.0768.
13C NMR (DMSO-d6, 100 MHz) d 21.3, 55.9, 114.4, 120.9, 125.4,
2-(Naphthalen-1-yl)quinazolin-4(3H)-one (3j).10e Petroleum 125.7, 127.6, 129.8, 136.21, 136.25, 147.4, 151.5, 162.2, 162.7.
ether/ethyl acetate (2 : 1) as eluent; light yellow solid; yield: 79 HRMS (ESI) calcd for C16H15N2O2 [M + H]+ 267.1128, found
mg (73%); mp 251–253 ꢀC (lit.10e 278–281 ꢀC). 1H NMR (DMSO- 267.1125.
d6, 400 MHz) d 7.55–7.65 (m, 4H), 7.72 (d, J ¼ 7.6 Hz, 1H), 7.78
6-Methyl-2-(thiophen-2-yl)quinazolin-4(3H)-one (3q). Petro-
(d, J ¼ 6.8 Hz, 1H), 7.85 (t, J ¼ 6.8 Hz, 1H), 8.02–8.05 (m, 1H), leum ether/ethyl acetate (3 : 1) as eluent; yellow solid; yield: 77
8.11 (d, J ¼ 8.4 Hz, 1H), 8.15–8.17 (m, 1H), 8.21 (d, J ¼ 7.6 Hz, mg (79%); mp 244–247 ꢀC. 1H NMR (DMSO-d6, 400 MHz) d 2.39
1H), 12.66 (s, 1H); 13C NMR (DMSO-d6, 100 MHz) d 121.7, 125.6, (s, 3H), 7.18–7.20 (m, 1H), 7.49–7.57 (m, 2H), 7.80 (d, J ¼ 4.4 Hz,
125.7, 126.3, 126.8, 127.3, 127.6, 128.0, 128.2, 128.8, 130.7, 1H), 7.88 (s, 1H), 8.18 (d, J ¼ 2.4 Hz, 1H), 12.53 (s, 1H); 13C NMR
130.9, 132.2, 133.6, 135.0, 149.2, 154.2, 162.4. MS (ESI) m/z 273.5 (DMSO-d6, 100 MHz) d 21.3, 121.1, 125.9, 127.3, 128.9, 129.5,
[M + H]+.
2-(Pyridin-4-yl)quinazolin-4(3H)-one (3k).15 Petroleum ether/ for C13H11N2OS [M + H]+ 243.0587, found 243.0583.
ethyl acetate (3 : 1) as eluent; light yellow solid; yield: 38 mg
6-Methoxy-2-phenylquinazolin-4(3H)-one (3r).9i Petroleum
132.2, 136.3, 136.5, 138.0, 147.1, 147.5, 162.2. HRMS (ESI) calcd
1
(43%); mp 270–272 C (lit.15 281–283 C). H NMR (DMSO-d6, ether/ethyl acetate (3 : 1) as eluent; light yellow solid; yield: 75
400 MHz) d 7.53–7.57 (m, 1H), 7.76 (d, J ¼ 7.6 Hz, 1H), 7.82–7.86 mg (74%); mp 246–247. 1H NMR (DMSO-d6, 400 MHz) d 3.87 (s,
(m, 1H), 8.08–8.09 (m, 2H), 8.15 (d, J ¼ 7.6 Hz, 1H), 8.76–8.77 3H), 7.42 (dd, J ¼ 3.2, 8.8 Hz, 1H), 7.49–7.55 (m, 4H), 7.68 (d, J ¼
(m, 2H), 12.72 (br s, 1H); 13C NMR (DMSO-d6, 100 MHz) d 121.9, 8.8 Hz, 1H), 8.14 (dd, J ¼ 1.6, 8.0 Hz, 2H), 12.49 (s, 1H); 13C NMR
122.0, 126.4, 127.9, 128.2, 135.2, 140.4, 148.7, 150.7, 151.0, (DMSO-d6, 100 MHz) d 56.1, 106.3, 122.3, 124.6, 128.0, 129.0,
ꢀ
ꢀ
162.5. MS (ESI) m/z 224.2 [M + H]+.
2-(Thiophen-2-yl)quinazolin-4(3H)-one (3l).10e Petroleum [M + H]+.
129.7, 131.5, 133.3, 143.7, 150.6, 158.2, 162.5. MS (ESI) m/z 253.1
ether/ethyl acetate (3 : 1) as eluent; light yellow solid; yield: 85
2-(4-Fluorophenyl)-6-methoxyquinazolin-4(3H)-one (3s).
mg (93%); mp 256–258 ꢀC (lit.10e 275–276 ꢀC). 1H NMR (DMSO- CH2Cl2/MeOH (50 : 1) as eluent; white solid; yield: 60 mg (56%);
1
ꢀ
d6, 400 MHz) d 7.20–7.22 (m, 1H), 7.44–7.48 (m, 1H), 7.63 (d, J mp 265–266 C. H NMR (DMSO-d6, 400 MHz) d 3.88 (s, 3H),
¼ 8.0 Hz, 1H), 7.75–7.78 (m, 1H), 7.83–7.85 (m, 1H), 8.10 (d, J 7.36 (t, J ¼ 8.8 Hz, 2H), 7.42–7.44 (m, 1H), 7.53 (s, 1H), 7.68 (d, J
¼ 8.0 Hz, 1H), 8.21–8.22 (m, 1H), 12.63 (s, 1H); 13C NMR ¼ 8.8 Hz, 1H), 8.19–8.22 (m, 2H), 12.52 (s, 1H); 13C NMR (DMSO-
(DMSO-d6, 100 MHz) d 121.3, 126.5, 126.8, 127.4, 129.0, 129.9, d6, 100 MHz) d 56.1, 106.3, 116.1 (d, J ¼ 22.3 Hz, 2C), 122.2,
132.6, 135.2, 137.8, 148.3, 149.1, 162.3. MS (ESI) m/z 229.3 124.6, 129.7, 129.8 (d, J ¼ 2.4 Hz, 1C), 130.5 (d, J ¼ 9.0 Hz, 2C),
[M + H]+.
143.6, 149.7, 158.3, 162.5, 164.3 (d, J ¼ 248.1 Hz, 1C). HRMS
(E)-2-Styrylquinazolin-4(3H)-one (3m). Petroleum ether/ethyl (ESI) calcd for C15H12FN2O2 [M + H]+ 271.0877, found 271.0877.
acetate (4 : 1) as eluent; light yellow solid; 52 mg (52%); mp 226–
6-Methoxy-2-propylquinazolin-4(3H)-one (3t). Petroleum
1
ꢀ
228 C. H NMR (DMSO-d6, 400 MHz) d 7.00 (d, J ¼ 16.0, 1H), ether/ethyl acetate (2 : 1) as eluent; white solid; yield: 26 mg
7.39–7.49 (m, 4H), 7.64–7.67 (m, 3H), 7.77–7.82 (m, 1H), 7.94 (d, (30%); mp 227–229. 1H NMR (DMSO-d6, 400 MHz) d 0.89 (t, J ¼
J ¼ 16.0 Hz, 1H), 8.09–8.11 (m, 1H), 12.33 (s, 1H); 13C NMR 7.2 Hz, 3H), 1.65–1.75 (m, 2H), 2.52 (t, J ¼ 7.6 Hz, 2H), 3.82 (s,
(DMSO-d6, 100 MHz) d 121.6, 126.3, 126.7, 127.6, 128.1, 129.6, 3H), 7.34 (dd, J ¼ 3.2, 8.8 Hz, 1H), 7.44 (d, J ¼ 3.2 Hz, 1H), 7.52
130.3, 135.0, 135.5, 138.7, 149.5, 151.9, 162.2 (one 13C signal was (d, J ¼ 8.8 Hz, 1H), 12.16 (br s, 1H); 13C NMR (DMSO-d6, 100
not observed). HRMS (ESI) calcd for C16H13N2O [M + H]+ MHz) d 13.9, 20.7, 36.6, 56.0, 106.2, 121.9, 124.2, 128.8, 143.7,
249.1022, found 249.1021.
2-Propylquinazolin-4(3H)-one (3n).10d Petroleum ether/ethyl 219.1128, found 219.1124.
155.5, 157.7, 162.1. HRMS (ESI) calcd for C12H15N2O2 [M + H]+
acetate (3 : 1) as eluent; light yellow solid; yield: 34 mg (45%);
7-Chloro-2-phenylquinazolin-4(3H)-one (3u).15 Petroleum
mp 180–183 ꢀC (lit.10d 200–202 ꢀC). 1H NMR (DMSO-d6, 400 ether/ethyl acetate (3 : 1) as eluent; light yellow solid; yield: 76
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 59289–59296 | 59293

View Article Online
RSC Advances
Paper
1
mg (74%); mp 267–269 C (lit.15 286–288 C). H NMR (DMSO-
d6, 400 MHz) d 7.50–7.61 (m, 4H), 7.75 (d, J ¼ 2.0 Hz, 1H),
8.10–8.16 (m, 3H), 12.65 (s, 1H); 13C NMR (DMSO-d6, 100 MHz) d
120.3, 127.0, 127.2, 128.4, 129.1, 132.2, 132.8, 139.6, 150.3,
154.2, 162.1 (one 13C signal was not observed). MS (ESI) m/z
257.6 [M + H]+.
ꢀ
ꢀ
3-Ethyl-2-phenylquinazolin-4(3H)-one (5e). Petroleum ether/
ethyl acetate (8 : 1) as eluent; white solid; yield: 73 mg (73%);
mp 127–129 ꢀC. 1H NMR (CDCl3, 400 MHz) d 1.20 (t, J ¼ 6.8
Hz, 3H), 4.02 (q, J ¼ 6.8 Hz, 2H), 7.46–7.51 (m, 6H), 7.72–7.73
(m, 2H), 8.32 (d, J ¼ 8.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d
14.1, 41.2, 121.0, 126.7, 127.0, 127.4, 127.7, 128.8, 129.8, 134.3,
135.5, 147.1, 156.2, 162.0. HRMS (ESI) calcd for C16H15N2O [M +
H]+ 251.1179, found 251.1180.
3-Ethyl-2-p-tolylquinazolin-4(3H)-one (5f). Petroleum ether/
ethyl acetate (6 : 1) as eluent; white solid; yield: 79 mg (75%);
mp 100–103 ꢀC. 1H NMR (CDCl3, 400 MHz) d 1.20 (t, J ¼ 6.8 Hz,
3H), 2.42 (s, 3H), 4.04 (q, J ¼ 6.8 Hz, 2H), 7.30 (d, J ¼ 8.0 Hz, 2H),
7.41 (d, J ¼ 7.6 Hz, 2H), 7.45–7.49 (m, 1H), 7.70–7.73 (m, 2H),
8.31 (d, J ¼ 8.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d 14.1, 21.4,
41.2, 120.9, 126.7, 126.9. 127.4, 127.6, 129.4, 132.7, 134.3, 139.9,
147.2, 156.4, 162.1. HRMS (ESI) calcd for C17H17N2O [M + H]+
265.1335, found 265.1333.
7-Chloro-2-(pyridin-4-yl)quinazolin-4(3H)-one (3v). Petro-
leum ether/ethyl acetate (3 : 2) as eluent; light yellow solid;
yield: 43 mg (42%); mp 235–237 ꢀC. 1H NMR (DMSO-d6, 400
MHz) d 7.58 (d, J ¼ 8.8 Hz, 1H), 7.81 (s, 1H), 8.07 (d, J ¼ 4.8 Hz,
2H), 8.14 (d, J ¼ 8.4 Hz, 1H), 8.78 (d, J ¼ 4.4 Hz, 2H), 12.88 (s,
1H); 13C NMR (DMSO-d6, 100 MHz) d 120.8, 122.1, 127.3, 128.0,
128.5, 139.8, 140.1, 149.9, 150.8, 152.5, 161.9. HRMS (ESI) calcd
for C13H9ClN3O [M + H]+ 258.0429, found 258.0425.
(E)-7-Chloro-2-styrylquinazolin-4(3H)-one (3w). Petroleum
ether/ethyl acetate (2 : 1) as eluent; light yellow solid; yield: 42
mg (37%); mp 267–269 ꢀC. 1H NMR (DMSO-d6, 400 MHz) d 6.97
(d, J ¼ 16.0 Hz, 1H), 7.40–7.48 (m, 4H), 7.62–7.67 (m, 3H), 7.93
(d, J ¼ 16.4 Hz, 1H), 8.06 (d, J ¼ 8.4 Hz, 1H), 12.44 (s, 1H); 13C
NMR (DMSO-d6, 100 MHz) d 120.4, 121.2, 126.6, 126.9, 128.2,
128.4, 129.6, 130.5, 135.3, 139.56, 139.60, 150.6, 153.3, 161.6.
HRMS (ESI) calcd for C16H12ClN2O [M + H]+ 283.0633, found
283.0630.
2-(4-Chlorophenyl)-3-ethylquinazolin-4(3H)-one (5g). Petro-
leum ether/ethyl acetate (6 : 1) as eluent; white solid; yield: 72
mg (63%); mp 110–113 ꢀC. 1H NMR (CDCl3, 400 MHz) d 1.20 (t, J
¼ 6.8 Hz, 3H), 4.01 (q, J ¼ 6.8 Hz, 2H), 7.47–7.51 (m, 5H), 7.68–
7.76 (m, 2H), 8.30 (d, J ¼ 8.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz)
d 14.2, 41.2, 121.0, 126.8, 127.2, 127.4, 129.1, 129.2, 133.9, 134.4,
136.1, 147.0, 155.1, 161.9. HRMS (ESI) calcd for C16H14ClN2O [M
+ H]+ 285.0789, found 285.0790.
3-Methyl-2-phenylquinazolin-4(3H)-one (5a).17 Petroleum
ether/ethyl acetate (4 : 1) as eluent; white solid; yield: 64 mg
1
(68%); mp 122–124 C (lit.17 130–132 C). H NMR (CDCl3, 400
MHz) d 3.48 (s, 3H), 7.46–7.56 (m, 6H), 7.73 (m, 2H), 8.31 (d, J ¼
8.0 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d 34.2, 120.5, 126.7,
127.0, 127.5, 128.0, 128.9, 130.1, 134.3, 135.4, 147.3, 156.1,
162.7. HRMS (ESI) calcd for C15H13N2O [M + H]+ 237.1022,
found 237.1020.
ꢀ
ꢀ
3-Benzyl-2-phenylquinazolin-4(3H)-one (5h).18 Petroleum
ether/ethyl acetate (6 : 1) as eluent; white solid; yield: 84 mg
1
(67%); mp 126–128 C (lit.18 140–142 C). H NMR (CDCl3, 400
MHz) d 5.28 (s, 2H), 6.92–6.94 (m, 2H), 7.19–7.21 (m, 3H), 7.33–
7.36 (m, 2H), 7.38–7.42 (m, 2H), 7.45–7.49 (m, 1H), 7.51–7.55
(m, 1H), 7.77–7.78 (m, 2H), 8.38 (d, J ¼ 7.6 Hz, 1H); 13C NMR
(CDCl3, 100 MHz) d 48.8, 120.9, 127.0, 127.1, 127.2, 127.5, 127.6,
128.0, 128.56, 128.63, 130.0, 134.6, 135.2, 136.6, 147.2, 156.5,
162.5. MS (ESI) m/z 313.4 [M + H]+.
ꢀ
ꢀ
3-Methyl-2-p-tolylquinazolin-4(3H)-one (5b).17 Petroleum
ether/ethyl acetate (4 : 1) as eluent; white solid; yield: 74 mg
1
(74%); mp 131–133 C (lit.17 139–140 C). H NMR (CDCl3, 400
MHz) d 2.41 (s, 3H), 3.48 (s, 3H), 7.30 (d, J ¼ 7.6 Hz, 2H), 7.44–
7.48 (m, 3H), 7.71 (m, 2H), 8.29 (d, J ¼ 7.6 Hz, 1H); 13C NMR
(CDCl3, 100 MHz) d 21.4, 34.3, 120.5, 126.6, 126.9, 127.4, 128.0,
129.5, 132.5, 134.3, 140.3, 147.3, 156.3, 162.8. HRMS (ESI) calcd
for C16H15N2O [M + H]+ 251.1179, found 251.1197.
ꢀ
ꢀ
3-Benzyl-2-(4-methoxyphenyl)quinazolin-4(3H)-one
(5i).19
Petroleum ether/ethyl acetate (6 : 1) as eluent; white solid; yield:
92 mg (67%); mp 101–103 ꢀC. 1H NMR (CDCl3, 400 MHz) d 3.83
(s, 3H), 5.30 (s, 2H), 6.90 (d, J ¼ 8.8 Hz, 2H), 6.96–6.98 (m, 2H),
7.19–7.24 (m, 3H), 7.32 (d, J ¼ 8.8 Hz, 2H), 7.48–7.52 (m, 1H),
7.76 (d, J ¼ 4.0 Hz, 2H), 8.35 (d, J ¼ 7.6 Hz, 1H); 13C NMR (CDCl3,
100 MHz) d 49.0, 55.5, 114.0, 120.7, 126.9, 127.0, 127.1, 127.4,
127.5, 127.7, 128.6, 129.7, 134.6, 136.7, 147.3, 156.4, 160.8,
162.6. HRMS (ESI) calcd for C22H19N2O2 [M + H]+ 343.1441,
found 343.1430.
3-Methyl-2-(thiophen-2-yl)quinazolin-4(3H)-one (5c). Petro-
leum ether/ethyl acetate (3 : 1) as eluent; light yellow solid;
1
ꢀ
yield: 59 mg (61%); mp 64–66 C. H NMR (CDCl3, 400 MHz) d
3.74 (s, 3H), 7.13–7.15 (m, 1H), 7.43–7.54 (m, 3H), 7.68–7.74 (m,
2H), 8.27 (d, J ¼ 7.6 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d 34.1,
120.1, 126.8, 127.0, 127.4, 129.4, 129.8, 134.3, 137.1, 147.2,
150.1, 162.7 (one 13C signal was not observed). HRMS (ESI) calcd
for C13H11N2OS [M + H]+ 243.0587, found 243.0588.
3-Methyl-2-propylquinazolin-4(3H)-one (5d). Petroleum
ether/ethyl acetate (5 : 1) as eluent; light yellow solid; yield: 23
mg (28%); mp 66–69 ꢀC. 1H NMR (CDCl3, 400 MHz) d 1.08 (t, J ¼
7.2 Hz, 3H), 1.81–1.91 (m, 2H), 2.80 (t, J ¼ 8.0 Hz, 2H), 3.62 (s,
3H), 7.39–7.43 (m, 1H), 7.62 (d, J ¼ 8.4 Hz, 1H), 7.69 (dt, J ¼ 1.6,
8.4 Hz, 1H), 8.24 (dd, J ¼ 1.6, 8.4 Hz, 1H); 13C NMR (CDCl3, 100
MHz) d 13.8, 20.3, 30.5, 37.5, 120.1, 126.3, 126.7, 126.8, 134.0,
147.2, 157.1, 162.6. HRMS (ESI) calcd for C12H15N2O [M + H]+
203.1179, found 203.1182.
(E)-3-Benzyl-2-styrylquinazolin-4(3H)-one (5j). Petroleum
ether/ethyl acetate (8 : 1) as eluent; light yellow solid; yield: 49
1
ꢀ
mg (36%); mp 132–134 C. H NMR (CDCl3, 400 MHz) d 5.52
(s, 2H), 7.03 (d, J ¼ 15.2 Hz, 1H), 7.29–7.39 (m, 8H), 7.45–7.49
(m, 3H), 7.76 (m, 2H), 7.94 (d, J ¼ 15.2 Hz, 1H), 8.35 (d, J ¼ 8.0
Hz, 1H); 13C NMR (CDCl3, 100 MHz) d 46.9, 119.4, 120.5, 126.6,
127.2, 127.3, 127.8, 128.9, 129.1, 129.8, 134.5, 135.3, 136.3,
141.1, 147.6, 152.5, 162.5 (two 13C signals were not observed).
HRMS (ESI) calcd for C23H19N2O [M + H]+ 339.1492, found
339.1483.
2,3-Diphenylquinazolin-4(3H)-one (5k).9f Petroleum ether/
ethyl acetate (8 : 1) as eluent; light yellow solid; yield: 46 mg
59294 | RSC Adv., 2014, 4, 59289–59296
This journal is © The Royal Society of Chemistry 2014

View Article Online
Paper
RSC Advances
1
(39%); mp 150–152 C (lit.9f 158–159 C). H NMR (CDCl3, 400 tube under air atmosphere. Then the tube was sealed, and the
MHz) d 7.15 (d, J ¼ 8.0 Hz, 2H), 7.19–7.34 (m, 8H), 7.54 (t, J ¼ 7.2 mixture was stirred at 100 ꢀC for 10 h. Aer the excess ammonia
Hz, 1H), 7.79–7.85 (m, 2H), 8.36 (d, J ¼ 7.6 Hz, 1H); 13C NMR was removed from the reaction mixture under reduced pres-
(CDCl3, 100 MHz) d 121.0, 127.2, 127.4, 127.7, 128.0, 128.5, sure, a solution of 2-(2-bromophenyl)-2-oxoacetaldehyde 8
129.0, 129.1, 129.4, 134.8, 135.4, 137.6, 147.4, 155.3, 162.3 (one (0.8 mmol) in DMSO (1.6 mL) was added into the same tube.
ꢀ
ꢀ
13C signal was not observed). MS (ESI) m/z 299.2 [M + H]+.
When the resulting mixture was stirred at 100 ꢀC for 1 h under
3-Phenyl-2-p-tolylquinazolin-4(3H)-one (5l).9f Petroleum nitrogen atmosphere, K3PO4$3H2O (213 mg, 0.8 mmol) was
ether/ethyl acetate (5 : 1) as eluent; white solid; yield: 28 mg added and the mixture was stirred at 100 ꢀC for another 2 h
1
(22%); mp 169–171 C (lit.9f 171–172 C). H NMR (CDCl3, 400 under nitrogen atmosphere. At last, the reaction was quenched
MHz) d 2.27 (s, 3H), 7.01 (d, J ¼ 8.0 Hz, 2H), 7.15–7.17 (m, 2H), with NH4Cl solution and extracted with CH2Cl2. The combined
7.22–7.35 (m, 5H), 7.51–7.55 (m, 1H), 7.78–7.85 (m, 2H), 8.34– organic layer was washed with H2O and brine, and then dried
8.36 (m, 1H); 13C NMR (CDCl3, 100 MHz) d 21.3, 120.9, 127.20, over anhydrous Na2SO4. The solvent was evaporated under
127.22, 127.6, 128.4, 128.7, 129.00, 129.02, 129.1, 132.4, 134.8, reduced pressure and the crude product was puried by chro-
ꢀ
ꢀ
137.8, 139.6, 147.5, 155.4, 162.4. MS (ESI) m/z 313.4 [M + H]+.
matography on silica-gel, eluting with CH2Cl2/ethyl acetate
(100 : 1), to afford tryptanthrin 9 (36 mg) as yellow solid in 36%
total yield. Mp 257–259 ꢀC (lit.14a 268.2–270.1 ꢀC). 1H NMR
(CDCl3, 400 MHz)14a d 7.40 (t, J ¼ 7.6 Hz, 1H), 7.62–7.66 (m, 1H),
7.73–7.77 (m, 1H), 7.82 (dt, J ¼ 1.2, 8.0 Hz, 1H), 7.88 (d, J ¼ 7.2
Hz, 1H), 7.99 (d, J ¼ 8.4 Hz, 1H), 8.38 (dd, J ¼ 1.2, 8.0 Hz, 1H),
8.57 (d, J ¼ 8.4 Hz, 1H); 13C NMR (CDCl3, 100 MHz) d 117.9,
121.9, 123.7, 125.4, 127.2, 127.5, 130.2, 130.7, 135.1, 138.2,
144.3, 146.3, 146.5, 158.0, 182.5. HRMS (ESI) calcd for
Preparation of 2-aminobenzamide 6
To a tube containing 2-bromobenzamide 1a (80 mg, 0.4 mmol),
CuBr (5.8 mg, 0.04 mmol), and L-proline (9.2 mg, 0.08 mmol) in
DMSO (1.5 mL) was added 26% aqueous ammonia (0.5 mL).
Then, the tube was sealed, and the mixture was stirred at 100 ꢀC
for 10 h under air atmosphere. Aer being cooled to room
temperature, the resulting mixture was quenched with NH4Cl
solution and extracted with ethyl acetate. The combined organic
layer was washed with H2O and brine, and then dried over
anhydrous Na2SO4. The solvent was evaporated under reduced
C
15H9N2O2 [M + H]+ 249.0659, found 249.0658.
pressure and the crude product was puried by chromatog- Acknowledgements
raphy on silica-gel, eluting with CH2Cl2/ethyl acetate (1 : 1), to
This work was nancially supported by the National Natural
afford 2-aminobenzamide 6 (45 mg) as white solid in 83% iso-
lated yield. Mp 98–100 ꢀC (lit.20 110 ꢀC). 1H NMR (DMSO-d6, 400
MHz)20 d 6.44 (t, J ¼ 7.2 Hz, 1H), 6.52 (s, 2H), 6.64 (d, J ¼ 8.0 Hz,
1H), 7.02 (br s, 1H), 7.07–7.11 (m, 1H), 7.49 (d, J ¼ 8.4 Hz, 1H),
7.68 (br s, 1H); 13C NMR (DMSO-d6, 100 MHz) d 114.2, 114.8,
116.9, 129.2, 132.3, 150.7, 171.8. MS (ESI) m/z 137.2 [M + H]+.
Science Foundation of China (Grants 21202040 and 21272058),
Project funded by China Postdoctoral Science Foundation
(2014M552007), and PCSIRT (IRT1061).
Notes and references
Preparation of compound 7
1 (a) S. B. Mhaske and N. P. Argade, Tetrahedron, 2006, 62,
9787; (b) J. P. Michael, Nat. Prod. Rep., 2007, 24, 223; (c)
J. L. Liang, H. C. Cha and Y. Jahng, Molecules, 2011, 16,
4861; (d) P. P. Bandekar, K. A. Roopnarine, V. J. Parekh,
T. R. Mitchell, M. J. Novak and R. R. Sinden, J. Med. Chem.,
2010, 53, 3558; (e) W.-F. Chiou, J.-F. Liao and C.-F. Chen, J.
Nat. Prod., 1996, 59, 374; (f) R. Garlapati, N. Pottabathini,
V. Gurram, K. S. Kasani, R. Gundla, C. Thulluri,
P. K. Machiraju, A. B. Chaudhary, U. Addepally, R. Dayam,
V. R. Chunduri and B. Patro, Org. Biomol. Chem., 2013, 11,
4778; (g) M. Sharma, K. Chauhan, R. Shivahare,
P. Vishwakarma, M. K. Suthar, A. Sharma, S. Gupta,
J. K. Saxena, J. Lal, P. Chandra, B. Kumar and
P. M. S. Chauhan, J. Med. Chem., 2013, 56, 4374.
A mixture of compound 6 (54.4 mg, 0.4 mmol) and benzalde-
hyde 2a (82 mL, 0.8 mmol) in DMSO (1.5 mL) was stirred at 100 ꢀC
for 5 h under nitrogen atmosphere, and then the reaction was
quenched with NH4Cl solution and extracted with ethyl acetate.
The combined organic layer was washed with H2O and brine,
and then dried over anhydrous Na2SO4. The solvent was evap-
orated under reduced pressure and the crude product was
puried by chromatography on silica-gel, eluting with CH2Cl2/
ethyl acetate (6 : 1), to afford 2-phenyl-2,3-dihydroquinazolin-
4(1H)-one 7 (76 mg) as white solid in 85% isolated yield. Mp
220–223 ꢀC (lit.17 222–225 ꢀC). 1H NMR (DMSO-d6, 400 MHz)17 d
5.68 (s, 1H), 6.59 (t, J ¼ 7.6 Hz, 1H), 6.67 (d, J ¼ 8.4 Hz, 1H), 7.05
(s, 1H), 7.15 (t, J ¼ 8.0 Hz, 1H), 7.23–7.31 (m, 3H), 7.42 (d, J ¼ 6.8
Hz, 2H), 7.54 (d, J ¼ 7.6 Hz, 1H), 8.25 (s, 1H); 13C NMR (DMSO-
d6, 100 MHz) d 67.0, 114.9, 115.4, 117.6, 127.3, 127.8, 128.8,
128.9, 133.8, 142.1, 148.3, 164.1. MS (ESI) m/z 225.2 [M + H]+.
2 (a) S.-L. Cao, Y.-P. Feng, Y.-Y. Jiang, S.-Y. Liu, G.-Y. Ding and
R.-T. Li, Bioorg. Med. Chem. Lett., 2005, 15, 1915; (b) A. M. Al-
Obaid, S. G. Abdel-Hamide, H. A. El-Kashef, A. A.-M. Abdel-
Aziz, A. S. El-Azab, H. A. Al-Khamees and H. I. El-Subbagh,
Eur. J. Med. Chem., 2009, 44, 2379.
Preparation of alkaloid tryptanthrin (9)
To a mixture of 2-bromobenzamide 1a (80 mg, 0.4 mmol), CuBr
(5.8 mg, 0.04 mmol), and L-proline (9.2 mg, 0.08 mmol) in
DMSO (1.5 mL) was added 26% aqueous ammonia (0.5 mL) in a
3 M. M. Aly, Y. A. Mohamed, K. A. M. El-Bayouki,
W. M. Basyouni and S. Y. Abbas, Eur. J. Med. Chem., 2010,
45, 3365.
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 59289–59296 | 59295

View Article Online
RSC Advances
Paper
4 M. S. Mohamed, M. M. Kamel, E. M. M. Kassem, N. Abotaleb, 10 (a) C. Huang, Y. Fu, H. Fu, Y. Jiang and Y. Zhao, Chem.
S. I. Abd El-moez and M. F. Ahmed, Eur. J. Med. Chem., 2010,
45, 3311.
5 U. Pandit and A. Dodiya, Med. Chem. Res., 2013, 22, 3364.
6 O. M. O. Habib, H. M. Hassan and A. El-Mekabaty, Med.
Chem. Res., 2013, 22, 507.
7 (a) D. J. Connolly, D. Cusack, T. P. O'Sullivan and P. J. Guiry,
Tetrahedron, 2005, 61, 10153; (b) L. He, H. Li, J. Chen and
X.-F. Wu, RSC Adv., 2014, 4, 12065; (c) X.-F. Wu, S. Oschatz,
Commun., 2008, 6333; (b) X. Liu, H. Fu, Y. Jiang and
Y. Zhao, Angew. Chem., Int. Ed., 2009, 48, 348; (c) L. Yu,
M. Wang, P. Li and L. Wang, Appl. Organomet. Chem.,
2012, 26, 576; (d) W. Xu and H. Fu, J. Org. Chem., 2011, 76,
3846; (e) W. Xu, Y. Jin, H. Liu, Y. Jiang and H. Fu, Org.
Lett., 2011, 13, 1274; (f) L. Xu, Y. Jiang and D. Ma, Org.
Lett., 2012, 14, 1150; (g) L.-X. Wang, J.-F. Xiang and
Y.-L. Tang, Eur. J. Org. Chem., 2014, 2682.
A. Block, A. Spannenberg and P. Langer, Org. Biomol. 11 (a) S. Guo, J. Wang, X. Fan, X. Zhang and D. Guo, J. Org.
Chem., 2014, 12, 1865.
Chem., 2013, 78, 3262; (b) X. Fan, B. Li, S. Guo, Y. Wang
and X. Zhang, Chem.–Asian J., 2014, 9, 739; (c) X. Zhang,
X. Guo, L. Fang, Y. Song and X. Fan, Eur. J. Org. Chem.,
2013, 8087; (d) X. Fan, Y. He, L. Cui, S. Guo, J. Wang and
X. Zhang, Eur. J. Org. Chem., 2012, 673.
8 (a) T. Hisano, M. Ichikawa, A. Nakagawa and M. Tsuji, Chem.
Pharm. Bull., 1975, 23, 1910; (b) Y. Mitobe, S. Ito, T. Mizutani,
T. Nagase, N. Sato and S. Tokita, Bioorg. Med. Chem. Lett.,
2009, 19, 4075; (c) C. Balakumar, P. Lamba, D. P. Kishore,
B. L. Narayana, K. V. Rao, K. Rajwinder, A. R. Rao, 12 C.-W. Jao, W.-C. Lin, Y.-T. Wu and P.-L. Wu, J. Nat. Prod.,
B. Shireesha and B. Narsaiah, Eur. J. Med. Chem., 2010, 45, 2008, 71, 1275 and references cited therein.
4904; (d) D. Zhan, T. Li, H. Wei, W. Weng, K. Ghandi and 13 DMSO was supposed to act as oxidant in the formation of
Q. Zeng, RSC Adv., 2013, 3, 9325; (e) W. Ge, X. Zhu and
Y. Wei, RSC Adv., 2013, 3, 10817; (f) N. Y. Kim and
C.-H. Cheon, Tetrahedron Lett., 2014, 55, 2340; (g)
M. Sharif, J. Opalach, P. Langer, M. Beller and X.-F. Wu,
RSC Adv., 2014, 4, 8.
tryptanthrin 9, see: (a) W. Yang, L. Ye, D. Huang, M. Liu,
J. Ding, J. Chen and H. Wu, Tetrahedron, 2013, 69, 9852;
(b) E. Schipper, M. Cinnamon, L. Rascher, Y. H. Chiang
and W. Oroshnik, Tetrahedron Lett., 1968, 9, 6201; (c)
T. Tsuji, Tetrahedron Lett., 1966, 7, 2413.
9 (a) L. He, H. Li, H. Neumann, M. Beller and X.-F. Wu, Angew. 14 (a) C. Wang, L. Zhang, A. Ren, P. Lu and Y. Wang, Org. Lett.,
Chem., Int. Ed., 2014, 53, 1420; (b) X.-F. Wu, L. He,
H. Neumann and M. Beller, Chem.–Eur. J., 2013, 19, 12635;
(c) X.-F. Wu, H. Neumann and M. Beller, Chem. Rev., 2013,
113, 1; (d) F. Zeng and H. Alper, Org. Lett., 2010, 12, 3642;
(e) F. Zeng and H. Alper, Org. Lett., 2010, 12, 1188; (f)
Z. Zheng and H. Alper, Org. Lett., 2008, 10, 829; (g)
2013, 15, 2982 and references cited therein; (b) Z.-J. Cai,
S.-Y. Wang and S.-J. Ji, Org. Lett., 2013, 15, 5226; (c)
S. D. Vaidya and N. P. Argade, Org. Lett., 2013, 15, 4006; (d)
K. C. Jahng, S. I. Kim, D. H. Kim, C. S. Seo, J.-K. Son,
S. H. Lee, E. S. Lee and Y. Jahng, Chem. Pharm. Bull., 2008,
56, 607.
C. Larksarp and H. Alper, J. Org. Chem., 2000, 65, 2773; (h) 15 X. Zhang, D. Ye, H. Sun, D. Guo, J. Wang, H. Huang,
J. E. R. Sadig, R. Foster, F. Wakenhut and M. C. Willis, J. X. Zhang, H. Jiang and H. Liu, Green Chem., 2009, 11, 1881.
Org. Chem., 2012, 77, 9473; (i) B. Ma, Y. Wang, J. Peng and 16 A. H. Romero, J. Salazar and S. E. Lopez, Synthesis, 2013, 45,
Q. Zhu, J. Org. Chem., 2011, 76, 6362; (j) X. Jiang, T. Tang, 2043.
J.-M. Wang, Z. Chen, Y.-M. Zhu and S.-J. Ji, J. Org. Chem., 17 H. Hikawa, Y. Ino, H. Suzuki and Y. Yokoyama, J. Org. Chem.,
2014, 79, 5082; (k) J. Chen, K. Natte, A. Spannenberg, 2012, 77, 7046.
H. Neumann, P. Langer, M. Beller and X.-F. Wu, Angew. 18 B. Li, L. Samp, J. Sagal, C. M. Hayward, C. Yang and Z. Zhang,
Chem., Int. Ed., 2014, 53, 7579; (l) H. Li, L. He, J. Org. Chem., 2013, 78, 1273.
H. Neumann, M. Beller and X.-F. Wu, Green Chem., 2014, 19 Y.-F. Wang, F.-L. Zhang and S. Chiba, Org. Lett., 2013, 15,
16, 1336; (m) L. He, M. Sharif, H. Neumann, M. Beller and 2842.
´
X.-F. Wu, Green Chem., 2014, 16, 3763; (n) X.-F. Wu, 20 H. Zhao, H. Fu and R. Qiao, J. Org. Chem., 2010, 75, 3311.
S. Oschatz, M. Sharif, M. Beller and P. Langer, Tetrahedron,
2014, 70, 23.
59296 | RSC Adv., 2014, 4, 59289–59296
This journal is © The Royal Society of Chemistry 2014