One-pot synthesis of quinazolin-4(3H)-ones and 2,3-dihydroquinazolin-4(1H)-ones utilizing N-(2-aminobenzoyl)benzotriazoles

Article abstract of DOI:10.3906/kim-1906-50

A convenient and efficient method has emerged for the one-pot synthesis of substituted quinazolin-4(3H)ones and nonaromatic alkaloids. 2-Substituted quinazolin-4(3H)-ones, 2,3-disubstituted quinazolin-4(3H)-ones, and 2,3-dihydroquinazolin-4(1H)-ones were obtained at yields of 46% to 95% by a one-pot reaction of N-(2-aminobenzoyl) benzotriazoles with amines and orthoesters or aldehydes under catalyst-free conditions.

Full text of DOI:10.3906/kim-1906-50

Turk J Chem
Turkish Journal of Chemistry
(2019) 49: 1580 – 1596
© TÜBİTAK
http://journals.tubitak.gov.tr/chem/
doi:10.3906/kim-1906-50
Research Article
One-pot synthesis of quinazolin-4(3H )-ones and
2,3-dihydroquinazolin-4(1H )-ones utilizing N -(2-aminobenzoyl)benzotriazoles
İlbilge Merve ŞENOL,, İlhami ÇELİK∗,, İlker AVAN,
Department of Chemistry, Faculty of Science, Eskişehir Technical University,
Yunusemre Campus, Tepebaşı, Eskişehir, Turkey
Received: 01.07.2019
•
Accepted/Published Online: 11.10.2019
•
Final Version: 09.12.2019
Abstract: A convenient and efficient method has emerged for the one-pot synthesis of substituted quinazolin-4(3H)-
ones and nonaromatic alkaloids. 2-Substituted quinazolin-4(3H)-ones, 2,3-disubstituted quinazolin-4(3H)-ones, and
2,3-dihydroquinazolin-4(1H)-ones were obtained at yields of 46% to 95% by a one-pot reaction of N -(2-aminobenzoyl)
benzotriazoles with amines and orthoesters or aldehydes under catalyst-free conditions.
Key words: Benzotriazole, N -(2-aminobenzoyl)benzotriazole, quinazolin-4(3H)-one, 2,3-dihydroquinazolin-4(1H)-
one, 2-substituted quinazolin-4(3H)-one
1. Introduction
4(3H)-Quinazolinones represent an important set of heterocycles, since they exist in natural products and
exhibit a broad range of pharmacological activities, including antibacterial, antimalarial, anticancer, antitumor,
antiinflammation, antihypertensive, antidepressant, and anticonvulsant activities [1–6]. Some plants containing
quinazolinone have long been used for traditional remedies. For example, a Chinese plant root called chang shan
(Dichroa febrifuga Lour.) has been used for the treatment of malaria for more than 2000 years because it contains
antimalarial active quinazolinone alkaloids, febrifugine and iso-febrifugine (lately, however, it was discontinued
due to its toxic effects) [7]. Rutaecarpine, originally extracted from Evodia rutaecarpa, is a COX-2 inhibitor and
has diverse pharmacological properties, including antithrombotic, anticancer, antiinflammatory and antiobesity
activities [8–11]. Vasicinone is another quinazolinone alkaloid that was originally isolated from the leaves of
Adhatoda vasica and has bronchodilatory activity [12]. Luotonin A is a pyrroloquinazolinoquinoline alkaloid
extracted from Peganum nigellastrum that has shown cytotoxicity against the murine leukemia P-388 cell line
[13]. Aside from natural analogs, synthetic quinazolinone derivatives are also highly active pharmaceutical cores
[14,15]. Among them, raltitrexed (Tomudex, ZD 1694) [16] is an antimetabolite drug that inhibits thymidylate
synthase and is used in the treatment of colorectal cancer species. Gefinitib (Iressa, ZD1839) [17,18], erlotinib
(Tarceva, OSI-774) [19,20], lapatinib (Tyverb, Tykerb) [21,22], and vandetanib (ZD6474, Zactima, Caprelsa)
[23,24] are 4-aminoquinazoline drugs derived from 4-quinazolinones that have all shown antineoplastic activity
and are still used in cancer chemotherapy.
As a highly active pharmaceutical core, the quinazolinone moiety has drawn much attention in synthetic
chemistry and many reaction pathways have been proposed over the years. Recent advancements in the field
∗Correspondence: ilcelik@eskisehir.edu.tr
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ŞENOL et al./Turk J Chem
of synthetic methodologies for the quinazolinone scaffold were discussed in detail by Rohokale and Kshirsagar,
He et al., and Kshirsagar [1,2,5]. Classical routes in the preparation of quinazolin-4(3H)-one have been mostly
based on the Niementowski reaction, which utilizes the ring closure of anthranilic acid or its derivatives with an
amine and a carbonyl group, whereas nonclassical methods utilize metal-catalyzed coupling reactions by C-C
or N-C bond formations [25–28] and the metal-catalyzed reduction of nitroarenes and subsequent cyclizations
[29,30]. The classical routes are often boosted by 1-pot multicomponent procedures, by featuring higher yields
in a shorter reaction time and fewer side products when compared to divergent pathways. The components of
the quinazolinone ring (anthranilic acid-derivative, carbonyl compound or its equivalent, and amine) are reacted
together in one pot under neat or solvent conditions. Those multicomponent reactions can be accelerated by
microwave heating [31–33], ionic liquids [34], or such catalysts as acids (acetic acid [35], trifluoroacetic acid [36],
or p-toluenesulfonic acid [37]) and Lewis acids (KAl(SO4)2 •12H2 O, Yb(OTf)3 [38], α-MnO2 [39], [Cp*IrCl2 ]2
[40], ZnI2 [41], CuI2 [42], InCl3 [43], La(NO3)3 •6H2 O, AlCl3 /ZnCl2 -SiO2 [44], NaHSO4 -SiO2 , amberlyst-15
[45], FeCl3 •6H2 O [46], Al(NO3)3 •9H2 O, [47] I2 /KI [48], Ga(OTf)3 [49], Sc(OTf)3 [50], Fe3 O4 nanoparticle
[51], molecular iodine [52], activated carbon (Darco KB), etc.). Recently, Yoshimura et al. examined the
catalytic activity of various heavy metal salts and Ru-complexes in the synthesis of 4(3H)-quinazolinone through
the condensation of 2-aminobenzamide with formamide [38]. The yields of those reactions in mesitylene at 165
°C for 6 h under an Ar atmosphere ranged from 5% to 99%. The best yields (>99%) were obtained when AlCl3 ,
FeCl3 , NiBr2 •xH2 O, and Yb(OTf)3 were used as catalysts. Some of the outlined procedures still have some
drawbacks, such as harsh reaction conditions, longer reaction times, and low yields, and many of them suffer
from the used catalyst because of their high cost, limited availability, and toxicity. Therefore, exploring simple,
green, efficient reaction systems is still highly desirable.
N -(2-Aminobenzoyl)benzotriazoles are versatile reagents that are stable in crystalline form and easy to
prepare and handle. These compounds have excelled as ideal synthetic auxiliaries in the synthesis of anthranilic
acid amides [53], esters-thioesters [54], and heterocycles [55–57]. Their synthetic utility was recently shown in
the preparation of 2-substituted quinolone-3-carboxylates and 4-hydroxyquinoline-2,3-dicarboxylates [56]. As
a continuation of our efforts, we herein present a new protocol for the one-pot synthesis of 2,3-disubstituted
quinazolin-4(3H)-one and its alkaloids under catalyst-free and environmentally friendly conditions starting from
N -(2-aminobenzoyl)benzotriazoles.
2. Results and discussion
2.1. Preparation of 2-substituted quinazolin-4(3H )-one (3a–3j)
N -(2-aminobenzoyl)benzotriazoles 1 were prepared following our previously reported procedure. In the prepara-
tion of 2-substituted quinazolin-4(3H)-ones 3a–3j, a model reaction between N -(2-aminobenzoyl)benzotriazole
1b or 1g, triethyl orthoacetate 2b, and ammonium acetate was initially carried out to optimize the reaction
conditions (Scheme 1 and Table 1). The reactions were performed in both polar protic and aprotic solvents,
such as ethanol (EtOH), dimethylformamide (THF), and dioxane, and also under neat conditions at the boiling
temperature of the mixtures. Upon the better yields of the desired products, 3c and 3h were obtained after
6–10 h of reactions in dioxane, and all 2-substituted quinazolin-4(3H)-ones (3a–3j) were prepared in dioxane
under reflux conditions (Table 2).
Via a 2D NOESY experiment, the structure of 3e was investigated because it might have been in the
form of 4-quinazolinone or 4-hydroxyquinazoline (Figure 1a). In the 2D NOESY spectra for compound 3e, the
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Scheme 1. Synthesis of 2-substituted quinazolin-4(3H)-one (3a–3j).
Table 1. Model reaction for the preparation of 2-substituted quinazolin-4(3H)-one 3c and 3h.
1
2
Entry
R
R
Product Solvent
Yield, %
a
b
c
d
e
f
6-Me Me 3c
6-Me Me 3c
6-Me Me 3c
6-Me Me 3c
EtOH
THF
Dioxane 82
Neat
EtOH
THF
Dioxane 68
Neat 54
52
28
45
62
40
7-Cl
7-Cl
7-Cl
7-Cl
Me 3h
Me 3h
Me 3h
Me 3h
g
h
Table 2. Synthesis of 2-substituted quinazolin-4(3H)-ones (3a–3j).
1
2
Entry
R
H
H
R
H
Product Yield, %
a
b
c
d
e
f
g
h
i
3a
85
95
82
78
80
92
81
68
95
68
Me 3b
6-Me Me 3c
6-Cl Me 3d
6-Br Ph 3e
6-I
7-F
7-Cl
Ph 3f
Me 3g
Me 3h
7-Me Me 3i
8-Me Ph 3j
j
cross peak between the H2’ and H6’ protons at 8.14 ppm and the H3 proton at 12.71 ppm indicated that these
protons interacted spatially (Figure 1b). The spatial interactions among the other protons were observed as
expected in the 2D NOESY spectra. In addition to the 2D NOESY experiment, the observation of sharp peaks
between 1707 and 1645 cm−1 in the IR spectra showed that the carbonyl group was formed in the structure
of 4-quinazolinone. The results obtained from the 2D NOESY experiment and IR spectra showed that the
obtained compounds were in the form of 4-quinazolinone.
2.2. Preparation of 2,3-disubstituted quinazolin-4(3H )-ones (4a–4d)
2,3-Disubstituted quinazolin-4(3H)-ones (4a-4d) were prepared by the reaction of N -(2-aminobenzoyl) benzo-
triazoles 1 with primary amines and orthoesters 2 under neat reaction conditions for 8 h (Scheme 2 and Table
3). While the reactions were performed in anhydrous dioxane, the cyclization reactions were completed after 16
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ŞENOL et al./Turk J Chem
h and provided lower yields than neat conditions. The structures of 2,3-disubstituted quinazolin-4(3H)-ones
(4a–4d) were characterized by NMR spectroscopy. The hydrogen atoms on C2 of 4a–4c were observed between
8.10 and 8.30 ppm, while the atoms on C4 appeared between 160 and 161 ppm (Supplemental information).
Moreover, HRMS and IR spectral data were also in accordance with the proposed structures.
Figure 1. The 2D NOESY spectrum (a) and 3D structure (b) of 3e.
Scheme 2. Synthesis of 2,3-disubstituted quinazolin-4(3H)-ones (4a–4d).
Table 3. 2,3-Disubstituted quinazolin-4(3H)-ones (4a–4d).
1
2
3
Entry
R
H
H
H
H
R
H
H
H
R
Product Yield, %
a
b
c
i-Bu
c-Hexyl
4-MeO-phenyl 4c
4d
4a
4b
79
53
51
81
d
Me i-Bu
2.3. Preparation of 2-substituted-2,3-dihydroquinazolin-4(1H )-ones (6a–6g)
2,3-Dihydroquinazolinones are the saturated derivatives of quinazolinones and can be readily oxidized to their
quinazolin-4(3H)-one analogs. 2,3-Dihydroquinazolinones were previously prepared by the reaction of isatoic
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anhydride and aldehydes or ketones in the presence of such catalysts as ZnO [58], Fe3 O4 , TiO2 [59], nanopar-
n
ticles, Fe3 O4 @SiO2 -imid-PMA nanocatalyst [60], [Al(H2 PO4)3 ] [61], and montmorillonite K-10 [62] starting
from 2-aminobenzamide using zirconium tetrakis(dodecyl sulfate) [Zr(DS)4] [63]. Herein, a new catalyst and
solvent-free methodology is proposed for the selective synthesis of 2,3-dihydroquinazolin-4(1H)-ones starting
from N -(2-aminobenzoyl)benzotriazoles.
N -(2-aminobenzoyl)benzotriazoles were reacted with aromatic or aliphatic aldehydes 5 in the presence of
ammonium acetate under neat conditions to provide 2-substituted-2,3-dihydroquinazolin-4(1H)-ones (6a–6g)
at yields of 54%–95% (Scheme 3 and Table 4). As seen in Table 4, when 1h and 1i were used as starting material,
2-substituted quinazolin-4(3H)-ones (3k and 3l), instead of 2,3-dihydroquinazolin-4(1H)-ones (6h and 6i),
were obtained at yields of 74% and 88%, respectively. It was thought that the oxidation of 2,3-dihydroquinazolin-
4(1H)-ones (6h and 6i) via atmospheric air could lead to obtaining 2-substituted quinazolin-4(3H)-ones (3k
and 3l).
Scheme 3. Synthesis of 2-substituted 2,3-dihydroquinazolin-4(1H)-ones (6a–6g).
Table 4. 2-Substituted 2,3-dihydroquinazolin-4(1H)-ones (6a–6g).
1
2
Entry
R
H
R
Product Yield, %
a
b
c
d
e
f
g
h
i
Ph
Et
6a
6b
6c
76
72
95
54
84
84
62
74
88
7-Cl
7-Me
6-Br
6-I
7-F
6,8-diCl
H
(2-Furanyl)
(2-Thiophenyl) 6d
Ph- F
Ph- Br
Ph
4-Py
4
6e
6f
4
6g
3k
3l
6,7-diMeO Ph
The structures of 2-substituted-2,3-dihydroquinazolin-4(1H )-ones (6a–6g) were characterized by NMR
1
spectroscopy. A characteristic singlet observed between 4 and 6 ppm in the H NMR spectra was assigned to the
hydrogen atom on N1. The hydrogen atom on N3 was observed between 8.63 ppm and 6.57 ppm (Supplemental
information). 2,3-Dihydroquinazolin-4(1H)-one 6a could also be formulated in a different tautomeric form,
depicted as 1,2-dihydroquinazolin-4-ol 6a’. To determine which tautomeric form was predominant or formed, a
2D NOESY experiment was performed for compound 6a in DMSO-d6 (Figure 2a). In the 2D NOESY spectra
for compound 6a, the cross peaks among the H2 protons at 5.73 ppm and the H2’ and H6’ protons at 7.47
ppm with the H3 proton at 8.27 ppm indicated that these protons interacted spatially (Figure 2b). The cross
peaks among the H2 proton at 5.73 ppm, H8 proton at 6.72 ppm, and H2’ and H6’ protons at 7.47 ppm with
the H1 proton at 7.09 ppm showed that there were spatial interactions among these protons. Similar cross
peaks among the H1 proton at 7.09 ppm, H2’ and H6’ protons at 7.47 ppm, and H3 proton at 8.27 ppm with
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ŞENOL et al./Turk J Chem
the H2 proton at 5.73 ppm were observed in the 2D NOESY spectra. The spatial interactions among other
protons were observed as expected in the 2D NOESY spectra. In addition to the 2D NOESY experiment, the
observation of sharp peaks between 1688 and 1645 cm−1 in the IR spectra showed that the carbonyl group was
formed in the structure of 2,3-dihydroquinazolin-4(1H)-one.
Figure 2. The 2D NOESY spectrum (a) and 3D structure (b) of 6a.
2.4. Preparation of 2,3-disubstituted 2,3-dihydroquinazolin-4(1H )-ones (7a–7b)
2,3-Disubstituted 2,3-dihydroquinazolin-4 (1H)-ones (7a–7b) were prepared from the reaction of N -(2-aminobenzoyl)
benzotriazoles with aromatic aldehydes 5 and primary amines in yields of 46%–74% (Scheme 4 and Table 5).
The reactions were performed in anhydrous dioxane within 4 h, while the cyclization reactions performed under
neat conditions provided poor yields. The pyrimidine ring closure of 7a and 7b was proven by NMR spec-
troscopy. The racemic hydrogen atom on C2 of 7a showed a singlet at 5.69 ppm and the C2 atom provided
a peak at 67.6 ppm, while the hydrogen atom on C2 of 7b provided a singlet at 5.68 ppm and the C2 atom
appeared at 72.1 ppm (Supplemental information).
O
O
R3
R2
O
C
Bt
R3 NH2
N
R1
R1
+
R2
Dioxane
Reflux
H
N
H
NH2
7
1
5
Scheme 4. Synthesis of 2,3-disubstituted 2,3-dihydroquinazolin-4(1H)-ones (7a–7b).
3. Conclusions
A new method for the synthesis of substituted quinazolin-4(3H)-ones and their alkaloids has been developed.
Benzotriazole-assisted synthesis of 2- and 2,3-disubstituted quinazolin-4(3H)-ones (3a–3l, 4a–4d) and 2- and
2,3-disubstituted 2,3-dihydroquinazolin-4(1H)-ones (6a–6g, 7a, and 7b) was achieved at high yields by one-pot
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ŞENOL et al./Turk J Chem
Table 5. 2,3-Disubstituted 2,3-dihydroquinazolin-4(1H)-ones (7a and 7b).
1
2
3
Entry
a
b
R
H
R
R
Product Yield, %
Ph(3,4-diMeO) c-Hexyl 7a
i-Bu 7b
46
74
6-Cl Ph
reactions of N−(2-aminobenzoyl)benzotriazoles with amines and orthoesters. In comparison with other studies,
the reactions were performed within a shorter time using stable and easily handled reagents under catalyst-free
conditions.
4. Experimental section
4.1. General information
Melting points were determined with a Mettler Toledo MP90 apparatus (Mettler Toledo International Inc.,
1
13
Columbus, OH, USA) and were uncorrected. The H (400 MHz) and
C (100 MHz) NMR spectra were
recorded on an Agilent DD2 400 MHz spectrometer (Agilent Technologies, Santa Clara, CA, USA) in DMSO-d6
with tetramethylsilane as an internal standard. HRMS analyses were measured on a Shimadzu LCMS-IT-TOF
system (Shimadzu Corporation, Kyoto, Japan). A PerkinElmer 100 FTIR spectrometer (PerkinElmer Inc.,
Waltham, MA, USA) was used for the IR analyses. DMF was dried and distilled over CaH2 . THF was dried
and distilled over metallic Na in the presence of benzophenone. Aliphatic-aromatic aldehydes 5 and primary
amines were purchased from commercial sources and used without further purification.
4.2. General method for synthesis of 2-substituted quinazolin-4(3H )-one (3a–3j)
N -(2-aminobenzoyl)benzotriazoles (0.25 mmol) 1 previously synthesized by our group were reacted with or-
thoester (0.50 mmol) 2 and ammonium acetate (1.0 mmol) in dioxane for 6–10 h. After completion of the
reaction, the solvent was evaporated under reduced pressure. The reaction mixture was purified by column
chromatography over silica gel with a EtOAc/n-hexane mixture (from 1:2 or 1:1) to obtain white crystals
(62%–95%).
Quinazolin-4(3H )-one (3a)
White solid (31 mg, 85%, lit. [64] 91%); mp: 217–218 °C (lit. [64] 217 °C). FTIR υmax (KBr): 3424, 1707,
1
1667, 1612 cm−1
.
H NMR (400 MHz, DMSO-d6): 12.24 (s, 1H) δ 8.12 (dd, J = 7.9 Hz, 1.3 Hz, 1H), 8.09
13
(s, 1H), 7.84–7.79 (m, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.54–7.50 (m, 1H). C NMR (100 MHz, DMSO-d6):
δ 161.2, 149.2, 145.9, 134.8, 127.6, 127.2, 126.3, 123.1. HRMS (ESI): m/z [M+H] calcd. for C8 H7 N2 O:
+
147.0514; found: m/z 147.0482.
2-Methylquinazolin-4(3H )-one (3b)
White solid (38 mg, 95%, lit. [65] 81%); mp: 238–240 °C (lit. [65] 235–239 °C). FTIR υmax (KBr): 3415,
1
1671, 1610, 1468 cm−1
.
H NMR (400 MHz, DMSO-d6): δ 12.17 (br s, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.73
13
(t, J = 7.4 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.41 (t, J = 7.4 Hz, 1H), 2.31 (s, 3H). C NMR (100 MHz,
DMSO-d6): δ 162.1, 154.7, 149.4, 134.7, 127.0, 126.3, 126.1, 121.0, 21.9. HRMS (ESI): m/z [M+H] calcd.
+
for C9 H9 N2 O: 161.0709; found: m/z 161.0701.
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ŞENOL et al./Turk J Chem
2,6-Dimethylquinazolin-4(3H )-one (3c)
White solid (36 mg, 82%, lit. [65] 82%); mp: 245–246 °C (lit. [65] 246–248 °C). FTIR υmax (KBr): 3440, 1679,
1
1629, 1489 cm−1
.
H NMR (400 MHz, DMSO-d6): δ 12.07 (br s, 1H), 7.83–7.82 (m, 1H), 7.55 (dd, A part of
AB system, J = 8.0 Hz, 2.8 Hz, 1H), 7.43 (d, B part of system, J = 8.4 Hz, 1H), 2.38 (s, 3H), 2.30 (s, 3H).
13
C NMR (100 MHz, DMSO-d6): δ 162.1, 153.7, 147.4, 136.0, 135.8, 126.9, 125.5, 120.8, 21.8, 21.2. HRMS
+
(ESI): m/z [M+H] calcd. for C10 H11 N2 O: 175.0886; found: m/z 175.0870.
6-Chloro-2-methylquinazolin-4(3H )-one (3d)
White solid (38 mg, 78%, lit. [65] 84%), mp: 310 °C decomp. (lit. [65] 292–294 °C). FTIR υmax (KBr): 3453,
1
1678, 1620, 1454, 830 cm−1
.
H NMR (400 MHz, DMSO-d6): δ 12.40 (br s, 1H), 7.98 (d, J = 2.4 Hz, 1H),
7.79 (dd, A part of AB system, J = 8.8, 2.4 Hz, 1H), 7.59 (d, B part of AB system, J = 8.4 Hz, 1H), 2.35
13
(s, 3H). C NMR (100 MHz, DMSO-d6): δ 161.0, 156.0, 147.1, 135.0, 130.8, 128.6, 125.2, 122.2, 21.6. HRMS
+
(ESI): m/z [M+H] calcd. for C9 H8 N2 O35 Cl: 195.0320; found: m/z 195.0322.
6-Bromo-2-phenylquinazolin-4(3H )-one (3e)
White solid (60 mg, 80%, lit. [66] 84%); mp: 303–305 °C (lit. [66] 284–286 °C). FTIR υmax (KBr): 3418, 1675,
1
1589, 1477, 689 cm−1
.
H NMR (400 MHz, DMSO-d6): δ 12.71 (s, 1H), 8.19 (s, 1H), 8.14 (d, J = 7.2 Hz,
13
2H), 7.95 (d, J = 8.8 Hz, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.58–7.50 (m, 3H). C NMR (100 MHz, DMSO-d6):
δ 161.7, 153.4, 148.2, 137.9, 132.9, 132.1, 130.3, 129.1, 128.3, 128.3, 123.0, 119.4. HRMS (ESI): m/z [M+H]
+
calcd. for C14 H10 N2 O79 Br: 300.9971; found: m/z 300.9970.
6-Iodo-2-phenylquinazolin-4(3H )-one (3f)
White solid (80 mg, 92%, lit. [67] 76%), mp: 303–305 °C (lit. [67] >300 °C). FTIR υmax (KBr): 3440, 1673,
1
1597, 1478, 699 cm−1
.
H NMR (400 MHz, DMSO-d6): δ 12.67 (s, 1H), 8.38 (d, J = 2.0 Hz, 1H), 8.15–8.12
13
(m, 2H), 8.09 (dd, J = 8.4, J = 2.0 Hz, 1H), 7.57–7.49 (m, 4H). C NMR (100 MHz, DMSO-d6): δ 161.4,
153.4, 148.5, 143.4, 134.6, 132.9, 132.1, 130.1, 129.1, 128.3, 123.3, 92.0. HRMS (ESI): m/z [M+H] calcd. for
+
C14 H10 N2 OI: 348.9832; found: m/z 348.9832.
7-Fluoro-2-methylquinazolin-4(3H )-one (3g)
White solid (36 mg, 81%, lit. [68] 91%); mp: 296–298 °C (lit. [68] 255 °C decomp.). FTIR υmax (KBr): 3437,
1
1678, 1620, 1454, 795 cm−1
.
H NMR (400 MHz, DMSO-d6): δ 12.28 (s, 1H), 8.09 (dd, J = 8.8, 6.4 Hz,
13
1H), 7.33–7.25 (m, 2H), 2.31 (s, 3H). C NMR (100 MHz, DMSO-d6): 166.1, 161.4, 156.4, 151.6, 129.2, 118.1,
114.9, 112.1, 21.9. HRMS (ESI): m/z [M+H] calcd. for C9 H8 N2 OF: 179.0615; found: m/z179.0622.
+
7-Chloro-2-methylquinazolin-4(3H )-one (3h)
White solid (30 mg, 68%, lit. [65] 83%); mp: 266–267 °C (lit. [65] 291–293 °C). FTIR υmax (KBr): 3431, 1682,
1
1627, 1440, 778 cm−1
.
H NMR (400 MHz, DMSO-d6): δ 12.30 (s, 1H), 8.02 (d, J = 8.8 Hz, 1H), 7.58 (d, J =
13
2.0 Hz, 1H), 7.44 (dd, J = 8.4 Hz, J = 2.0 Hz, 1H), 2.31 (s, 3H). C NMR (100 MHz, DMSO-d6): δ 161.7,
156.6, 150.5, 139.2, 128.2, 126.5, 126.1, 120.0, 22.0. HRMS (ESI): m/z [M+H] calcd. for C10 H11 N2 O35 Cl:
+
195.0320; found m/z 195.0316.
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2,7-Dimethylquinazolin-4(3H )-one (3i)
White solid (41 mg, 95%, lit [69] 49%); mp: 255–256 °C. (lit. [69] 263–264 °C). FTIR υmax (KBr): 3431, 1682,
1
1616, 1456 cm−1
.
H NMR (400 NMR, DMSO-d6): δ 12.06 (s, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.33 (s, 1H),
13
7.22 (d, J = 8.0 Hz, 1H), 2.38 (s, 3H), 2.28 (s, 3H). C NMR (100 MHz, DMSO-d6): 162.0, 154.7, 149.5,
141.1, 127.7, 126.7, 126.0, 118.7, 21.9, 21.8. HRMS (ESI): m/z [M+H] calcd. for C10 H11 N2 O: 175.0866;
+
found: m/z 175.0862.
8-Methyl-2-phenylquinazolin-4(3H )-one (3j)
White solid (40 mg, 68%, lit. [65] 83%); mp: 260–261 °C. (lit. [65] 237–239 °C). FTIR υmax (KBr): 3427,
1
1676, 1605, 1508 cm−1
.
H NMR (400 MHz, DMSO-d6): δ 12.53 (s, 1H), 8.20 (d, J = 6.8 Hz, 2H), 7.97 (d,
13
J = 8.0 Hz, 1H), 7.68 (d, J = 7.2 Hz, 1H), 7.57–7.52 (m, 3H), 7.38 (t, J = 7.6 Hz, 1H), 2.60 (s, 3H).
C
NMR (100 MHz, DMSO-d6): δ 163.0, 151.5, 147.6, 136.1, 135.4, 133.4, 131.8, 129.1, 128.2, 126.5, 123.9, 121.3,
+
17.6. HRMS (ESI): m/z [M+H] calcd. for C15 H13 N2 O: 237.1022; found: m/z 237.1029.
4.3. General method for synthesis of 2,3-disubstituted quinazolin-4(3H )-ones (4a–4d)
N -(2-Aminobenzoyl)benzotriazole (0.25 mmol) 1 was reacted with orthoester (1 mL) 2 and primary amines (1.0
mmol) at the boiling point of this mixture for 7–10 h in the absence of a solvent. The reaction was monitored
with thin-layer chromatography (TLC) using an eluent system of EtOAc-n-hexane (1:1 or 1:3). After completion
of the reaction, the mixture was diluted with ethyl acetate, washed with saturated sodium carbonate and brine
solution, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue
was purified over silica gel using EtOAc/n-hexane as an eluent system (from 1:4 to 1:1) to obtain the desired
product (51%–81%).
3-(2-Methylpropyl)quinazolin-4(3H )-one (4a)
1
Light yellow solid (40 mg, 79%); mp: 62–64 °C. FTIR υmax (KBr): 2965, 2873, 1679, 1611, 1461 cm−1
.
H
NMR (400 MHz, DMSO-d6): δ 8.35 (s, 1H), 8.14 (d,J = 7.6 Hz, 1H), 7.81 (t, J = 7.6 Hz, 1H), 7.66 (d, J =
8 Hz, 1H), 7.53 (t,J = 7.6 Hz, 1H), 3.80 (d, J = 7.2, 2H), 2.09 (t,J = 6.8 Hz, 1H), 0.87 (d, J = 6.4 Hz, 6H).
13
C NMR (100 MHz, DMSO-d6): δ 161.1, 148.1, 146.9, 134.1, 127.4, 127.2, 126.8, 54.1, 28.1, 19.9. HRMS
+
(ESI): m/z [M+H] calcd. for C12 H15 N2 O: 203.1179; found: m/z 203.1171.
3-Cyclohexylquinazolin-4(3H )-one (4b)
White solid (30 mg, 53%, lit. [70] 10%); mp: 112–113 °C (lit. [70] 116–118 °C). FTIR υmax (KBr): 2927, 2857,
1
1667, 1598, 1478 cm−1
.
H NMR (400 MHz, CDCl3 -d1): δ 8.31 (d, J = 7.6 Hz, 1H), 8.18 (s, 1H), 7.78–7.73
(m, 2H), 7.53–7.5 (m, 1H), 4.86–4.78 (m, 1H), 2.02–1.93 (m, 4H), 1.79 (d, J = 13.2 Hz, 2H), 1.69–1.46 (m, 2H),
13
1.32–1.21 (m, 2H). C NMR (100 MHz, CDCl3 -d1): δ 160.3, 144.2, 134.4, 127.5, 127.1, 126.5, 121.6, 53.7,
+
32.6, 26.2, 25.8, 25.2. HRMS (ESI): m/z [M+H] calcd. for C14 H17 N2 O: 229.1335; found: m/z 229.1326.
3-(4-Methoxyphenyl)quinazolin-4(3H )-one (4c)
White solid (32 mg, 51%); mp: 195–196 °C (lit. [71] 194–195 °C). FTIR υmax (KBr): 2995, 1682, 1516, 1471
1
cm−1
.
H NMR (400 MHz, CDCl3 -d1): δ 8.36 (d, J = 7.6 Hz, 1H), 8.13 (s, 1H), 7.82–7.76 (m, 2H), 7.55
13
(t, J = 7.2 Hz, 1H), 7.33 (d, J = 7.6 Hz, 2H), 7.05 (d, J = 7.8 Hz, 2H), 3.78 (s, 3H). C NMR (100 MHz,
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CDCl3 -d1): δ 160.6, 159.7, 148.2, 148.0, 135.0, 130.7, 129.1, 127.8, 127.7, 126.8, 122.4, 114.8, 55.9. HRMS
+
(ESI): m/z [M+H] calcd. for C15 H13 N2 O2 : 253.0972; found: m/z 253.0981.
2-Methyl-3(2-methylpropyl)quinazolin-4(3H )-one (4d)
1
Orange solid (44 mg, 81%); mp: 71–73 °C. FTIR υmax (KBr): 2963, 2870, 1669, 1594, 1473 cm−1
.
H NMR
(400 MHz, DMSO-d6): δ 8.07 (dd, J = 7.8 Hz, 2 Hz, 1H), 7.79–7.74 (m, 1H), 7.56 (d, J = 7.6 Hz, 1H),
7.48–7.44 (m, 1H), 3.91 (d, J = 7.2 Hz, 2H), 2.58 (s, 3H), 2.10 (t, J = 6.8 Hz, 1H), 0.88 (d, J = 6.8 Hz, 6H).
13
C NMR (100 MHz, DMSO-d6): δ 162.3, 154.6, 147.0, 134.2, 126.9, 126.4, 126.3, 120.4, 51.1, 28.1, 23.5, 20.1.
+
HRMS (ESI): m/z [M+H] calcd. for C13 H17 N2 O: 217.1335; found: m/z 217.1334.
4.4. General method for synthesis of 2-substituted 2,3-dihydroquinazolin-4(1H )-ones (6a–6g)
N -(2-Aminobenzoyl)benzotriazoles (0.2 mmol) 1 were reacted with aldehydes (0.3 mmol) 5 and ammonium
acetate (0.3 mmol) under solvent-free conditions. After completion of the reaction, the mixture was washed
with water. The desired product was recrystallized from ethyl alcohol. (54%–95%).
2-Phenyl-2,3-dihydro quinazolin-4(1H )-one (6a)
White solid (34 mg, 76%, lit. [72] 95%); mp: 235–236 °C (lit. [72] 225–227 °C). FTIR υmax (KBr): 3309, 1655,
1
1512 cm−1 . H NMR (400 MHz, DMSO-d6): δ 8.27 (s, 1H), 7.58 (d, J = 8 Hz, 1H), 7.47 (d, J = 7.2 Hz, 2H),
7.38–7.32 (m, 3H), 7.21 (t, J = 7.6 Hz, 1H), 7.09 (s, 1H), 6.72 (d, J = 8 Hz, 1H), 6.64 (t, J = 7.4 Hz, 1H),
13
5.73 (s, 1H). C NMR (100 MHz, DMSO-d6): δ 164.0, 148.3, 142.0, 133.7, 128.9, 128.8, 127.8, 127.3, 117.5,
+
115.4, 114.8, 67.0. HRMS (ESI): m/z [M+H] calcd. for C14 H13 N2 O: 225.1022; found: m/z 225.1020.
7-Chloro-2-ethyl-2,3-dihydroquinazolin-4(1H )-one (6b)
White solid (32 mg, 72%, lit. [73] 30%); mp: 133–134 °C (lit. [73] 130–132 °C). FTIR υmax (KBr): 3363, 3218,
1
2968, 1645, 1476, 779 cm−1
.
H NMR (400 MHz, DMSO-d6): δ 7.77 (d, J = 8 Hz, 1H), 6.68 (d, J = 8 Hz,
1H), 6.65 (s, 1H), 6.57 (br s, 1H), 4.83 (t, J = 5.6 Hz, 1H), 4.34 (br s, 1H), 1.82–1.72 (m, 2H), 1.02 (t, J =
13
3 Hz, 3H). C NMR (100 MHz, DMSO-d6): δ 164.6, 148.1, 139.7, 130.0, 119.5, 114.3, 114.1, 66.4, 28.6, 8.2.
+
HRMS (ESI): m/z [M+H] calcd. for C10 H12 N2 O35 Cl: 211.0633; found: m/z 211.0636.
2-(2-Furanyl)-7-methyl-2,3-dihydroquinazolin-4(1H )-one (6c)
1
Pale yellow solid (43 mg, 95%); mp: 187–188 °C. FTIR υmax (KBr): 3300, 3185, 1647, 1489, 1014 cm−1
.
H
NMR (400 MHz, DMSO-d6): δ 7.77 (d, J = 7.6 Hz, 1H), 7.38 (s, 1H), 6.68 (d, J = 8 Hz, 1H), 6.48 (s,
13
1H), 6.40 (d, J = 3.2 Hz, 1H), 6.35 (s, 1H), 6.32 (s, 1H), 5.87 (s, 1H), 2.27 (s, 3H). C NMR (100 MHz,
DMSO-d6): δ 164.6, 152.2, 146.1, 145.0, 143.1, 128.5, 121.2, 115.2, 113.3, 110.5, 108.2, 62.0, 21.8. HRMS
+
(ESI): m/z [M+H] calcd. for C13 H13 N2 O2 : 229.0972, found: m/z 229.0964.
6-Bromo-(2-thiophenyl)-2,3-dihydro quinazolin-4(1H )-one (6d)
1
White solid (33 mg, 54%), mp: 229–230 °C. FTIR υmax (KBr): 3305, 1654, 1482, 819 cm−1
.
H NMR (400
MHz, DMSO-d6): δ 8.63 (s, 1H), 7.63 (d, J = 2 Hz, 1H), 7.50 (s, 1H), 7.44 (d, J = 5.2 Hz, 1H), 7.38 (dd,
J = 8.4 Hz, J = 2.8 Hz, 1H), 7.09 (d, J = 3.6 Hz, 1H), 6.96–6.94 (m, 1H), 6.71 (d, J = 8.4 Hz, 1H), 6.02
13
(s, 1H). C NMR (100 MHz, DMSO-d6): δ 162.3, 146.7, 146.4, 136.3, 129.7, 127.0, 126.6, 126.3, 117.5, 117.1,
+
108.8, 62.7. HRMS (ESI): m/z [M+H] calcd. for C12 H10 N2 OS79 Br: 308.9692; found: m/z 308.9692.
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ŞENOL et al./Turk J Chem
2-(4-Fluorophenyl)-6-iodo-2,3-dihydroquinazolin-4(1H )-one (6e)
White solid (62 mg, 84%); mp: 222 °C decomp. (lit. [74] 294–295 °C). FTIR υmax (KBr): 3299, 1651, 1503,
1
816 cm−1
.
H NMR (400 MHz, DMSO-d6): δ 8.41 (s, 1H), 7.80 (d, J = 1.6 Hz, 1H), 7.49–7.46 (m, 3H), 7.31
13
(s, 1H), 7.20 (t, J = 8.8 Hz, 2H), 6.56 (d, J = 8.4 Hz, 1H), 5.76 (s, 1H). C NMR (100 MHz, DMSO-d6):
δ 162.6, 162.5, 147.6, 141.7, 137.9, 135.8, 129.4, 117.5, 115.7, 115.6, 78.6, 66.1. HRMS (ESI): m/z [M+H]
+
calcd. for C14 H11 N2 OFI: 368.9895; found: m/z 368.9897.
2-(4-Bromophenyl)-7-fluoro-2,3-dihydroquinazolin-4(1H )-one (6f)
1
White solid (54 mg, 84%); mp: 232–233 °C. FTIR υmax (KBr): 3300, 1688, 1487 cm−1
.
H NMR (400 MHz,
DMSO-d6): δ 8.36 (s, 1H), 7.63–7.56 (m, 3H), 7.41–7.38 (m, 3H), 6.47–6.42 (m, 2H), 5.76 (t, J = 4 Hz, 1H).
13
C NMR (100 MHz, DMSO-d6): δ 167.2, 163.9, 149.9, 141.3, 131.7, 130.7, 129.4, 122.1, 112.0, 105.1, 100.5,
+
66.2. HRMS (ESI): m/z [M+H] calcd. for C14 H11 N2 OFBr: 321.0033; found: m/z 321.0046.
6,8-Dichloro-2-phenyl-2,3-dihydroquinazolin-4(1H )-one (6g)
1
White solid (36 mg, 62%); mp: 172–173 °C. FTIR υmax (KBr): 3324, 3186, 1663, 1497, 768 cm−1
.
H NMR
13
(400 MHz, DMSO-d6): δ 8.84 (s, 1H), 7.56 (s, 1H), 7.50 (s, 1H), 7.37–7.27 (m, 6H), 5.75 (s, 1H). C NMR
(100 MHz, DMSO-d6): δ 162.5, 143.3, 133.6, 129.6, 129.4, 127.1, 126.9, 121.5, 119.8, 118.4, 65.7. HRMS (ESI):
+
35
m/z [M+H] calcd. for C14 H11 N2 O Cl2 : 293.0243; found: m/z 293.0249.
2-(4-Pyridinyl)quinazolin-4(3H )-on (3k)
White solid (30 mg, 74%, lit. [66] 82%); mp: 278–279 °C (lit. [66] 281–283 °C). FTIR υmax (KBr): 3032, 1681,
1
1552, 1469 cm−1
.
H NMR (400 MHz, DMSO-d6): δ 12.75 (s, 1H), 8.76 (d, J = 6.4 Hz, 2H), 8.15 (dd, J =
7.6, 1.6 Hz, 1H), 8.08 (dd, J = 4.4, 1.6 Hz, 2H), 7.87–7.83 (m, 1H), 7.76 (dd, J = 8.6, 2.0 Hz, 1H), 7.857–7.53
13
(m, 1H). C NMR (100 MHz, DMSO-d6): δ 162.5, 151.0, 150.7, 148.7, 140.4, 135.2, 128.2, 127.9, 126.4, 122.0,
+
121.9. HRMS (ESI): m/z [M+H] calcd. for C13 H10 N3 O; 224.0818; found: m/z 224.0810.
2-Phenyl-6,7-dimethoxyquinazolin-4(3H )-on (3l)
White solid (125 mg, 88%, lit. [66] 88%); mp: 288–289 °C (lit. [66] 307–309 °C. FTIR υmax (KBr): 3068, 1667,
1
1495, 1459, 1101 cm−1
.
H NMR (400 MHz, DMSO-d6): δ 12.40 (s, 1H), 8.13 (dd, J = 7 Hz, 2.6 Hz, 2H),
13
7.534–7.474 (m, 3H), 7.45 (s, 1H), 7.18 (s, 1H), 3.90 (s, 3H), 3.86 (s, 3H). C NMR (100 MHz, DMSO-d6): δ
162.0, 155.2, 151.2, 149.0, 145.2, 133.2, 131.5, 129.0, 127.9, 114.4, 108.7, 105.3, 56.4, 56.1. HRMS (ESI): m/z
[M+H] calcd. for C16 H15 N2 O3 ; 283.1077; found: m/z 283.1073.
+
4.5. General method for synthesis of 2,3-disubstituted 2,3-dihydroquinazolin-4(1H )-ones (7a and
7b)
N -(2-Aminobenzoyl)benzotriazoles (0.25 mmol) 1 were reacted with aldehydes (0.5 mmol) 5 and primary
amines (1 mmol) under solvent-free conditions. The reactions were monitored using TLC chromatography
[EtOAc:n-hexane (1:1)]. After completion of the reaction, the crude product was dissolved in EtOAc (10 mL)
and washed with saturated sodium carbonate, 3 N HCl, and brine solutions, respectively. The solution was
dried over sodium carbonate and the solvent was evaporated. The residue was purified over silica gel using
EtOAc/n-hexane as an eluent system (from 1:3 to 1:1) to obtain the desired product (46%–74%).
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3-Cyclohexyl-2-(3,4-dimethoxyphenyl)-2,3-dihydroquinazolin-4(1H )-one (7a)
1
Orange oil (42 mg, 46%); FTIR υmax (KBr): 3286, 2932, 1627, 1515, 1140 cm−1 . H NMR (400 MHz, CDCl3 -
d1 : δ 7.94 (dd, J = 7.9 Hz, 1.5 Hz, 1H), 7.22–7.13 (m, 1H), 6.86–6.77 (m, 2H), 6.77 (d, J = 2.1 Hz, 1H),
6.72 (d, J = 8.2 Hz, 1H), 6.44 (d, J = 8.0 Hz, 1H), 5.69 (s, 1H), 3.97–3.84 (m, 1H), 3.81 (s, 3H), 3.72 (s,
3H), 1.69 (dd, J = 12.6 Hz, 3.5 Hz, 1H), 1.65–1.53 (m, 6H), 1.41 (t, J = 12.9 Hz, 1H), 1.32–1.22 (m, 1H),
13
1.12–0.96 (m, 2H). C NMR (100 MHz, CDCl3 -d1): δ 162.5, 149.1, 149.0, 144.1, 134.8, 133.1, 128.2, 119.5,
+
118.0, 117.8, 114.8, 110.8, 108.6, 108.5, 67.6, 55.8, 53.7, 31.0, 25.9, 25.5. HRMS (ESI): m/z [M+H] calcd.
for C22 H27 N2 O3 : 367.2016; found: m/z 367.2011.
6-Chloro-3-isobutyl-2-phenyl-2,3-dihydroquinazolin-4(1H )-one (7b)
1
Orange solid (58 mg, 74%); mp: 160–162 °C. FTIR υmax (KBr): 3302, 2965, 1629, 1465, 822 cm−1
.
H NMR
(400 MHz, CDCl3 -d1): δ 10.02 (s, 1H), 8.04–7.76 (m, 1H), 7.43–7.22 (m, 5H), 7.15 (dd, J = 8.6 Hz, 2.2 Hz,
1H), 6.46 (d, J = 8.5 Hz, 1H), 5.68 (s, 1H), 3.99 (dd, J = 16 Hz, 8 Hz, 1H), 2.44 (dd, J = 14 Hz, 6 Hz, 1H),
13
2.11–1.89 (m, 1H), 0.93 (t, J = 9.2 Hz, 6H). C NMR (100 MHz, CDCl3 -d1): δ 162.2, 143.1, 139.5, 133.2,
+
129.2, 129.1, 128.1, 126.1, 124.4, 117.6, 115.9, 72.1, 52.2, 27.1, 20.2. HRMS (ESI): m/z [M+H] calcd. for
35
C18 H20 N2 O Cl: 315.1259; found: m/z 315.1248.
Acknowledgment
This work was supported by the Anadolu University Scientific Research Projects Commission (Project No:
1306F110 and 1605F395).
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Supplemental information
1H and 13C NMR spectra of 3a
1

1H and 13C NMR spectra of 3b
2

1H and 13C NMR spectra of 3c
3

1H and 13C NMR spectra of 3d
4

1H and 13C NMR spectra of 3e
5

1H and 13C NMR spectra of 3f
6

1H and 13C NMR spectra of 3g
7

1H and 13C NMR spectra of 3h
8

9

1H and 13C NMR spectra of 3i
10

1H and 13C NMR spectra of 3j
11

1H and 13C NMR spectra of 3k
12

1H and 13C NMR spectra of 3l
13