Quinazolin-4(3H)-ones and 5,6-dihydropyrimidin-4(3H)-ones from β-aminoamides and orthoesters

Article abstract of DOI:10.3390/molecules23112925

Quinazolin-4(3H)-ones have been prepared in one step from 2-aminobenzamides and orthoesters in the presence of acetic acid. Simple 2-aminobenzamides were easily converted to the heterocycles by refluxing in absolute ethanol with 1.5 equivalents of the orthoester and 2 equivalents of acetic acid for 12–24 h. Ring-substituted and hindered 2-aminobenzamides as well as cases incorporating an additional basic nitrogen required pressure tube conditions with 3 equivalents each of the orthoester and acetic acid in ethanol at 110^?C for 12–72 h. The reaction was tolerant towards functionality on the benzamide and a range of structures was accessible. Workup involved removal of the solvent under vacuum and either recrystallization from ethanol or trituration with ether-pentane. Several 5,6-dihydropyrimidin-4(3H)-ones were also prepared from 3-amino-2,2-dimethylpropionamide. All products were characterized by melting point, FT-IR, ¹H-NMR, ¹³C-NMR, and HRMS.

Full text of DOI:10.3390/molecules23112925

molecules
Article
Quinazolin-4(3H)-ones and
5,6-Dihydropyrimidin-4(3H)-ones from
β-Aminoamides and Orthoesters
Joshua T. Gavin, Joel K. Annor-Gyamfi and Richard A. Bunce *
Department of Chemistry, Oklahoma State University, Stillwater, OK 74078-3071, USA;
jtgavin@csbsju.edu (J.T.G.); jannorg@okstate.edu (J.K.A.-G.)
* Correspondence: rab@okstate.edu; Tel.: +1-405-744-5952; Fax: +1-405-744-6007
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀꢁꢂꢃꢄꢅꢆ
Received: 28 October 2018; Accepted: 8 November 2018; Published: 9 November 2018
Abstract: Quinazolin-4(3H)-ones have been prepared in one step from 2-aminobenzamides and
orthoesters in the presence of acetic acid. Simple 2-aminobenzamides were easily converted to
the heterocycles by refluxing in absolute ethanol with 1.5 equivalents of the orthoester and 2
equivalents of acetic acid for 12–24 h. Ring-substituted and hindered 2-aminobenzamides as
well as cases incorporating an additional basic nitrogen required pressure tube conditions with
3 equivalents each of the orthoester and acetic acid in ethanol at 110 ◦C for 12–72 h. The reaction
was tolerant towards functionality on the benzamide and a range of structures was accessible.
Workup involved removal of the solvent under vacuum and either recrystallization from ethanol
or trituration with ether-pentane. Several 5,6-dihydropyrimidin-4(3H)-ones were also prepared
from 3-amino-2,2-dimethylpropionamide. All products were characterized by melting point, FT-IR,
1H-NMR, 13C-NMR, and HRMS.
Keywords: quinazolin-4(3H)-ones; 5,6-dihydropyrimidin-4(3H)-ones; heterocycle synthesis;
2-aminobenzamides; orthoesters
1. Introduction
Quinazolin-4(3H)-ones are valuable scaffolds in pharmaceutical chemistry due to their diverse
biological activities. Drugs possessing the quinazolinone unit are used as anti-anxiety, antibacterial
anticonvulsant, antifungal, anti-inflammatory, and antitumor agents [
1]. Some examples of 2-alkyl-
and 2-arylquinazolin-4(3H)-ones currently on the market include the sedative-hypnotics methaqualone
(quaalude,
compound
1
4
) [
2
] and afloqualone (
2) [3,4] as well as the antifungal albaconazole (3) [5]. Additionally,
[6] is currently under evaluation as an antibacterial agent against both Gram-positive and
Gram-negative organisms.
In this study, we report the synthesis of 2-alkyl- and 2-arylquinazolin-4(3H)-ones from inexpensive
2-aminobenzamide and orthoester substrates without the need for metal catalysts or Lewis acids.
The process is similar to earlier acid-catalyzed processes reported by our group for the preparation
of 2-substituted 2,3-dihydroquinazolin-4(1H)-ones [
7
] and benzimidazoles [8] as well as for a
synthesis of benzimidazo[1,2-c]quinazolines described by others [9]. Using the conditions disclosed
herein, a small library of substituted quinazolin-4(3H)-ones has been generated with high yields
(Figure 1). We also report the synthesis of a modest selection of 5,6-dihydropyrimidin-4(3H)-ones from
3-amino-2,2-dimethyl-propionamide under identical conditions.
To date, orthoesters have received minimal use for the preparation of these systems. Syntheses
that did employ these building blocks focused almost exclusively on the use of triethyl orthoformate to
prepare derivatives without C2 substitution [
5,
10]. Although the current method is somewhat limited
Molecules 2018, 23, 2925; doi:10.3390/molecules23112925
www.mdpi.com/journal/molecules

Molecules 2018, 23, 2925
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by the sparse number of available orthoesters, the simplicity of our approach and its ability to provide
a wide range of targets makes it a valuable addition to the field.
Figure 1. Bioactive quinazolin-4(3H)-ones.
The current reaction is a variant of the classical Niementowski quinazoline synthesis, which
involved the cyclocondensation of an N-alkylamide with anthranilic acid [11]. The original conditions
for this transformation, however, proved somewhat limiting as they required extended heating at
>200 ◦C and resulted in significant decarboxylation of the acid. Further work showed that methyl
◦
anthranilate was more stable at 200 C and afforded higher yields with less degradation of the
substrate [12]. The decarboxylation problem was also minimized through the application of microwave
conditions, which considerably reduced the reaction time [13–15], and the use of thioamides, which
permitted lower reaction temperatures [16]. Later efforts found that isatoic anhydride with amines
and orthoesters under neat conditions gave clean cyclization to the quinazolinones at temperatures of
120 ◦C [17]. In a related procedure, heating isatoic anhydride with benzylamines at 120 ◦C in ionic
liquids led to oxidation of the benzylic amine to the imine, followed by cyclization [18]. More recently,
phosphoric acid was employed to promote the synthesis of 2,3-disubstituted quinazolin-4(3H)-ones
from 2-amino-N- substituted benzamides and β-ketoesters [19]. Likewise, n-propanephosphonic
anhydride was used as a condensing agent to assemble 2-fluoroalkyl-substituted derivatives from
fluoroalkanoic acids and anthranilic acid [20]. Along a different line, two separate reports detailed
the synthesis of quinazolinones by oxidative cyclization of aldehydes with 2-aminobenzamide
under aerobic conditions [6] and in the presence of tert-butyl hydroperoxide (TBHP)-potassium
iodide [21]. A similar oxidative condensation of primary alcohols with 2-aminobenzamide to
generate quinazolinones was promoted by TBHP alone [22] and together with iodine and dimethyl
sulfoxide [23,24]. Numerous metals such as manganese [25], iron [26], nickel [27], zinc [28],
ruthenium [29], iridium [30], and platinum [31] in conjunction with TBHP were also reported to
promote this reaction. The option of using primary alcohols for this transformation dramatically
increased the scope of the synthesis due to the vast array of available substrates. Finally, other methods
involved the reaction of lithium 2-(diethylaminocarbonyl)anilide with aryl- and alkylnitriles [32] as
well as various copper [33–40] and palladium [2,41–44] catalyzed heterocyclizations.
2. Results and Discussion
The results of our study are summarized in Table 1. The products listed illustrate the breadth of
systems accessible using our procedure. Several acid catalysts were evaluated, but the most convenient
and inexpensive was acetic acid. For 2-aminobenzamide (5), the reaction required heating 1 equivalent

Molecules 2018, 23, 2925
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of the amide with 1.5–2 equivalents of the orthoester and 2 equivalents of acetic acid in absolute
◦
ethanol at reflux (78 C) for 12–24 h (Method 1). Less reactive ring-substituted derivatives (
7,
9, and 11),
more hindered 2-amino-N-substituted benzamides (15 and 17) and substrates incorporating a second
basic nitrogen (13 and 19) required pressure tube conditions with 3 equivalents of the orthoester and 3
equivalents of acetic acid in ethanol at 110 ◦C for 12–72 h (Method 2). Comparisons of Methods 1 and
2 are shown in the Table for several substrates and clearly demonstrate the advantage of using higher
temperatures. Beyond these few examples, however, additional comparisons were not possible as
pure material was often difficult to isolate from reactions run at 78 ◦C. Two examples that did permit
comparison were the chloro-substituted 2-aminobenzamides
9 and 11 with triethyl orthobenzoate.
Using Method 1, this reaction gave low conversions, and except for a small amount of product that
initially crystallized from the cooling reaction mixture, the quinazolinones were contaminated with
unreacted starting material and inseparable by-products. Increasing the stoichiometry of the orthoester
under these conditions failed to improve the conversion to a satisfactory level. Alternatively, increasing
the amount of acid to 6 equivalents, improved the yields of 10d and 12d to 56% and 77%, respectively,
but repeated crystallizations were required for purification. Reacting these substrates according to
Method 2, with 2–3 equivalents of the orthoester and 3 equivalents of acetic acid, however, gave
nearly quantitative conversions to the products. Under this protocol, trituration of the crude products
with 5% ether in pentane was sufficient to obtain spectroscopically pure material. Clearly, Method
2 proved superior for the broadest range of substrates. All reported yields were isolated, but not
1
all were fully optimized. Procedures and copies of the H and 13C-NMR spectra are given in the
Supplemental Material.
Table 1. Synthesis of quinazolin-4(3H)-ones.
O
O
5
3
EtO OEt
6
7
4
AcOH
EtOH
NHR
'
NR
'
X
X
+
EtO
R
2
Y
NH2
Y
8
N
1
R
Substrate
Product
R
Method a
Yield (%)
a: Me
b: Et
c: Pr
d: P
1
1
1
1
1
92
89
93
81
87
O
O
NH2
NH2
NH
N
R
e: H
5
6a-e
a: Me
b: Et
c: Pr
2
2
2
2
90
91
O
O
N
ND b
84
NH2
NH
d: Ph
Me
NH2
Me
R
7
8a-d
a: Me
b: Et
c: Pr
2
2
2
92
92
88
O
O
Cl
Cl
NH
NH2
NH2
d: Ph
1(2)
33(97)
N
R
10a-d
9

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Table 1. Cont.
Substrate
Product
R
Method a
Yield (%)
a: Me
b: Et
c: Pr
2
2
2
94
93
89
O
O
NH
NH2
NH2
d: Ph
1(2)
7(98)
Cl
Cl
N
R
12a-d
11
a: Me
b: Et
c: Pr
1(2)
1(2)
1(2)
1(2)
71(86)
70(92)
55(87)
68(80)
O
O
NH
NH2
NH2
d: Ph
N
N
R
N
14a-d
13
a: Me
b: Et
c: Pr
2
2
2
2
87
83
O
O
Me
Ph
Me
R
ND b
89
N
N
H
d: Ph
NH2
N
15
16a-d
a: Me
b: Et
c: Pr
2
2
2
2
95
92
O
O
Ph
R
N
H
ND b
95
N
d: Ph
NH2
N
17c
18a-d
a: Me
b: Et
c: Pr
1(2)
2
2
21(82)
80
O
O
NH2
NH2
R
ND b
95
N
N
H
d: Ph
2
NH2
N
19
20a-d
a
For 1 equiv of the 2-aminobenzamide: Method 1: 1.5 equiv of orthoester, 2 equiv of AcOH, 3 mL of EtOH, 78 ◦C,
12–24 h; Method 2: 2–3 equiv of orthoester, 3 equiv of AcOH, 3 mL of EtOH, 110 ◦C, pressure tube, 12–72 h; b ND =
not done; c Prepared from 2-nitrobenzoic acid as described in the experimental section.
The yields using Method 2 were generally high for all of the substrates evaluated. While reactions
were followed by thin layer chromatography, attempts at preparative purifications using silica gel
often led to decomposition of the products, even when the eluting solvent contained 1% triethylamine.
Sublimation also afforded limited success. Thus, product purification was restricted to crystallization
from ethanol or trituration with 5% ether in hexanes. Fortunately, all of the derivatives prepared were
highly crystalline solids, which facilitated purification using these techniques.

Molecules 2018, 23, 2925
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Finally, we were able to extend the cyclization process to the preparation of a small family of
5,6-dihydropyrimidin-4(3H)-ones from 3-amino-2,2-dimethylpropionamide (21) (see Scheme 1). These
compounds were prepared by Method 3 using 1.5 equivalents of the orthoester and 2 equivalents
of acetic acid in ethanol at reflux for 24 h. Cyclizations to produce 22a–d were assisted by the
Thorpe–Ingold (gem-dialkyl) effect [45 46], but the yields were modest due to difficulties in crystallizing
,
the final products. Since the pyrimidinones were water-soluble and hygroscopic, it was necessary to
utilize dry solvents for the crystallization. Best results were achieved by adding dry chloroform to the
crude product and allowing the mixture to sit under nitrogen for four to seven days. The use of higher
temperatures (Method 2) for these substrates had little effect on the yields.
Scheme 1. Synthesis 5,6-dihydropyrimidin-4(3H)-ones.
There are a number of very positive features in this synthesis. The reaction was free of metals
and corrosive Lewis acids, requiring only a 2–3-fold excess of acetic acid to promote the reaction.
This simplified the purification of the final products and eliminated the possibility of residual
contaminants. Both sets of conditions were tolerant of alkyl, halide and basic functional groups
present on the 2-aminobenzamide reacting partner and a small library of substituted derivatives
was prepared. Employing Method 2, it was possible to obtain high yields of quinazolinones
from ring-substituted 2-aminobenzamides
7, 9, and 11. This procedure also promoted excellent
conversions of relatively hindered 2-amino-N-methyl- and 2-amino-N-phenylbenzamides 15 and 17
,
respectively, to 2,3-disubstituted quinazolinones 16 and 18. These hindered ring closures were likely
facilitated by the rigid aromatic scaffold, which held the ortho-disposed reactive centers in close
proximity. Finally, 13 and 19, which both possessed basic nitrogen groups, gave superb yields as
well. In ring closures of hydrazide 19, it was noted that the less reactive amide nitrogen cyclized
in preference to the more nucleophilic terminal nitrogen of the hydrazide to give exclusively the
six-membered cyclic product, with none of the seven-membered ring observed. The preparation of
the 5,6-dihydropyrimidin-4(3H)-ones was more limited due to challenges during the purification
process. Additional experiments attempted to cyclize 3-aminopropionamide, which was commercially
available as the hydrochloride salt. This substrate, however, lacked the gem-dimethyl moiety and did
not undergo significant ring closure.
A plausible mechanism for quinazolinone formation is depicted for the reaction of
2-aminobenzamide with triethyl orthoacetate (see Figure 2). The process involves initial protonation of
the orthoester and loss of ethanol to afford the stabilized carbocation
aniline amino group, proton exchange, and loss of a second molecule of ethanol would then yield the
iminium ion . Finally, closure of the amide nitrogen on the iminium carbon, proton exchange, and
A. Subsequent attack on A by the
B
loss of ethanol would generate the quinazolinone product. A similar mechanism is likely operating for
the closure of the 5,6-dihydropyrimidin-4(3H)-ones.

Molecules 2018, 23, 2925
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Figure 2. Mechanism for quinazolin-4(3H)-one formation.
3. Experimental Section
3.1. General Methods
Most commercial chemicals and solvents were used as received,
2-amino-4-methylbenzamide, which required recrystallization from
except
ethanol.
for
2-Amino-N-phenylbenzamide was prepared from 2-nitrobenzoic acid, according to the following
sequence: (i) SOCl2 (2.0 equiv), benzene, reflux, 2 h; (ii) PhNH2 (1.1 equiv), CH2Cl2, Et3N (2.0 equiv),
◦
◦
0 C to r.t., 4 h; (iii) Fe (3.2 equiv)/NH4Cl (1.0 equiv), aq EtOH, 85 C, 2 h [47]; 82% overall, white solid,
m.p. 123–125 ◦C (lit [48] m.p. 128–129.5 ◦C). The spectral data matched those reported [48].
Unless otherwise indicated, all reactions were carried out under dry N2 in oven-dried glassware.
Reactions were monitored by thin layer chromatography on silica gel GF plates (Analtech no. 21521,
Newark, DE, USA). Band elution was monitored using a hand-held UV lamp (Fisher Scientific,
Pittsburgh, PA, USA). Melting points were obtained using a MEL-TEMP apparatus (Cambridge, MA,
USA) and are uncorrected. FT-IR spectra were run using a Varian Scimitar FTS 800 spectrophotometer
(Randolph, MA, USA) as thin films or nujol mulls on NaCl disks. H- and 13C-NMR spectra were
1
measured using a Bruker Avance 400 system (Billerica, MA, USA) in the indicated solvents at 400 MHz
and 101 MHz, respectively, with (CH3)4Si as the internal standard; coupling constants (J) are given
in Hz. High-resolution mass spectra (HRMS-ESI) were obtained using a Thermo LTQ-Orbitrap XL
mass spectrometer (Thermo Scientific, Waltham, MA, USA).
3.2. General Procedures to Prepare Quinazolin-4(3H)-ones
3.2.1. Method 1
The orthoester (1.5 equiv) was added to a mixture of the 2-aminobenzamide (1.0 equiv) in absolute
ethanol (3 mL). Glacial acetic acid (2 equiv) was added and the reaction was heated at reflux for 12–24 h.
The reaction mixture was cooled and concentrated under vacuum. If the crude product was pure by
1H-NMR, it was triturated with 5% ether in pentane. If it was not pure, it was recrystallized from
◦
ethanol. In some cases, it was necessary to remove excess orthoester under high vacuum at 50 C prior
to purification. The following compounds were prepared:
2-Methylquinazolin-4(3H)-one (6a). This compound was prepared from 2-aminobenzamide (125 mg,
0.92 mmol), triethyl orthoacetate (224 mg, 253 µL, 1.38 mmol) and acetic acid (110 mg, 105 µL,

Molecules 2018, 23, 2925
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1.84 mmol) in refluxing absolut◦e ethanol (3 mL). Yield: 135 mg (92%) as an off-white solid, m.p.
◦
236–238 C (lit [40] m.p. 242–244 C); IR (CHCl3): 3176, 1674 cm−1; 1H-NMR (400 MHz, CDCl3):
δ 11.2
(br s, 1H), 8.28 (dd, J = 8.0, 1.0 Hz, 1H), 7.78 (td, J = 8.1, 1.5 Hz, 1H), 7.68 (d, J = 8.1 Hz, 1H), 7.48 (td,
J = 8.0, 1.0 Hz, 1H), 2.58 (s, 3H); 13C-NMR (101 MHz, CDCl3):
δ 163.9, 153.1, 149.6, 135.1, 127.2, 126.7,
126.4, 120.5, 22.4; HRMS (ESI): m/z for C9H8N2O [M + 1]+: calcd.: 161.0715; found: 161.0714.
2-Ethylquinazolin-4(3H)-one (6b). This compound was prepared from 2-aminobenzamide (125 mg,
0.92 mmol), triethyl orthopropionate (244 mg, 278
1.84 mmol) in refluxing absolute ethanol (3 mL). Yield: 155 mg (89%) as an off-white solid, m.p.
235–237 ◦C (lit [15] m.p. 238–240 ◦C); IR (CHCl3): 3169, 1681 cm−1; 1H-NMR (400 MHz, CDCl3):
µL, 1.38 mmol) and acetic acid (110 mg, 105 µL,
δ
11.2 (br s, 1H), 8.29 (dd, J = 8.0, 1.2 Hz, 1H), 7.78 (ddd, J = 8.3, 7.0, 1.6 Hz, 1H), 7.71 (d, J = 8.1 Hz, 1H),
7.47 (ddd, J = 8.1, 7.1, 1.2 Hz, 1H), 2.82 (q, J = 7.3 Hz, 2H), 1.45 (t, J = 7.4 Hz, 3H); 13C-NMR (101 MHz,
CDCl3):
δ 164.0, 157.5, 149.5, 134.9, 127.4, 126.6, 126.4, 120.8, 29.3, 11.6; HRMS (ESI): m/z for C10H10N2O
[M + 1]+: calcd.: 175.0871; found: 175.0873.
2-Propylquinazolin-4(3H)-one (6c). This compound was prepared from 2-aminobenzamide (125 mg,
0.92 mmol), triethyl orthobutyrate (262 mg, 298 µL, 1.38 mmol) and acetic acid (110 mg, 105 µL,
1.84 mmol) in refluxing absolut◦e ethanol (3 mL). Yield: 160 mg (93%) as an off-white solid, m.p.
◦
212–214 C (lit [15] m.p. 210–212 C); IR (CHCl3): 3165, 1675 cm−1; 1H-NMR (400 MHz, CDCl3):
δ 11.2
(br s, 1H), 8.29 (d, J = 7.8 Hz, 1H), 7.77 (t, J = 7.8 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.47 (t, J = 7.8 Hz, 1H),
2.76 (t, J = 7.4 Hz, 2H), 1.92 (sextet, J = 7.4 Hz, 2H), 1.08 (t, J = 7.3 Hz, 3H) ; 13C-NMR (101 MHz, CDCl3):
δ
169.3, 156.6, 149.5, 134.9, 127.4, 126.6, 126.4, 120.7, 38.0, 21.1, 13.9; HRMS (ESI): m/z for C11H12N2O
[M + 1]+: calcd.: 189.1028; found: 189.1025.
2-Phenylquinazolin-4(3H)-one (6d). This compound was prepared from 2-aminobenzamide (125 mg,
0.92 mmol), triethyl orthobenzoate (309 mg, 312
1.84 mmol) in refluxing absolute ethanol (3 mL). Yield: 134 mg (81%) as an off-white solid, m.p.
234–236 ◦C (lit [40] m.p. 233–235 ◦C); IR (CHCl3): 3196, 1668 cm−1; 1H-NMR (400 MHz, CDCl3):
11.1 (br s, 1H), 8.33 (d, J = 8.0 Hz, 1H), 8.21 (m, 2H), 7.86–7.78 (complex, 2H), 7.61-7.57 (complex, 3H),
µL, 1.38 mmol) and acetic acid (110 mg, 105 µL,
δ
7.52 (ddd, J = 7.9, 6.8, 1.2 Hz, 1H); 13C-NMR (101 MHz, CDCl3):
δ 169.9, 151.5, 149.4, 134.9, 132.8,
131.7, 129.2, 128.1, 127.1, 126.9, 126.5, 121.0; HRMS (ESI): m/z for C14H10N2O [M + 1]+: calcd.: 223.0871;
found: 223.0870.
Quinazolin-4(3H)-one (6e). This compound was prepared from 2-aminobenzamide (125 mg,
0.92 mmol), triethyl orthoformate (204 mg, 229
1.84 mmol) in refluxing absolute ethanol (3 mL). Yield: 117 mg (87%) as an off-white solid, m.p.
212–214 ◦C (lit [16] m.p. 215.5–216.5 ◦C); IR (CHCl3): 3202, 1664 cm−1; 1H-NMR (400 MHz, CDCl3):
8.31 (dd, J = 8.0, 1.0 Hz, 1H), 8.08 (s, 1H), 7.28 (td, J = 8.1, 1.4 Hz, 1H), 7.77 (dd, J = 8.1, 1.0 Hz, 1H), 7.55
µL, 1.38 mmol) and acetic acid (110 mg, 105 µL,
δ
(td, J = 7.4, 1.4 Hz, 1H), NH not observed; 13C-NMR (101 MHz, CDCl3):
δ 162.8, 149.0, 143.5, 135.1,
128.0, 127.6, 126.6, 122.7; HRMS (ESI): m/z for C8H6N2O [M + 1]+: calcd.: 147.0558; found: 147.0557.
3.2.2. Method 2
The 2-aminobenzamide (1 equiv), the orthoester (2–3 equiv) and absolute ethanol (2–3 mL) were
placed in a 15-mL Chemglass screw-cap pressure tube (No. CG-1880-01, Chemglass, Vineland, NJ,
USA). Glacial acetic acid (3 equiv) was added, N2 was introduced to the vessel and the cap was
◦
tightened. The vessel was heated at 110 C for 12–72 h, then cooled and concentrated to give the
quinazolinone, which was purified by crystallization from absolute ethanol or trituration from 5%
ether in pentane. The following compounds were prepared:
2,7-Dimethylquinazolin-4(3H)-one
(
8a).
This
compound
was
prepared
from
2-amino-4-methylbenzamide (100 mg, 0.67 mmol), triethyl orthoacetate (217 mg,◦245
µ
L, 1.34 mmol)
and acetic acid (121 mg, 115
µ
L, 2.01 mmol) in absolute ethanol (2 mL) at 110 C for 24 h to gi−v1e
◦
◦
105 mg (90%) as a white solid, m.p. 260–262 C (lit [49] m.p. 263–264 C); IR (CHCl3): 3169, 1677 cm
;

Molecules 2018, 23, 2925
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1H-NMR (400 MHz, CDCl3):
δ
11.6 (br s, 1H), 8.16 (d, J = 8.1 Hz, 1H), 7.47 (br s, 1H), 7.29 (dd, J =
8.1, 1.0 Hz, 1H), 2.57 (s, 3H), 2.51 (s, 3H); 13C-NMR (101 MHz, CDCl3):
δ 163.9, 153.2, 149.5, 146.0,
128.0, 126.8, 126.1, 117.9, 22.1, 22.0; HRMS (ESI): m/z for C10H10N2O [M + 1]+: calcd.: 175.0871; found:
175.0867.
2-Ethyl-7-methylquinazolin-4(3H)-one
2-amino-4-methylbenzamide (100 mg, 0.67 mmol), triethyl orthopropionate (236 mg, 269
1.34 mmol) and acetic acid (121 mg, 115
L, 2.01 mmol) in absolute ethanol (2 mL) at 110 ◦C for 24
h. Yield: 114 mg (91%) as a white solid, m.p. 244–245 C; IR (CHCl3): 3178, 1674 cm−1; H-NMR
(400 MHz, CDCl3): 11.2 (br s, 1H), 8.17 (d, J = 8.1 Hz, 1H), 7.50 (br s, 1H), 7.30 (dd, J = 8.1, 0.9 Hz,
(8b).
This compound was prepared from
µL,
µ
◦
1
δ
1H), 2.80 (q, J = 7.6 Hz, 2H), 2.51 (s, 3H), 1.43 (t, J = 7.6 Hz, 3H); 13C-NMR (101 MHz, CDCl3):
δ 163.8,
157.4, 149.5, 145.8, 128.0, 127.0, 126.1, 118.2, 29.2, 22.0, 11.5; HRMS (ESI): m/z for C11H12N2O [M + 1]+:
calcd.: 189.1028; found: 189.1031.
7-Methyl-2-phenylquinazolin-4(3H)-one
2-amino-4-methylbenzamide (100 mg, 0.67 mmol), triethyl orthobenzoate (300 mg, 303
1.34 mmol) and acetic acid (121 mg, 115
L, 2.01 mmol) in absolute ethanol (2 mL) at 110 ◦C for 48 h.
Yield: 133 mg (84%) as a light yellow solid, m.p. 239–241 ◦C (lit [40] m.p. 240–241 ◦C); IR (CHCl3):
3156, 1672 cm−1; 1H-NMR (400 MHz, CDCl3):
10.9 (br s, 1H), 8.21 (d, J = 8.1 Hz, 1H), 8.18 (m, 2H),
7.64 (br s, 1H), 7.61–7.56 (complex, 3H), 7.33 (dd, J = 8.2, 0.9 Hz, 1H), 2.54 (s, 3H); 13C-NMR (101 MHz,
CDCl3): 163.3, 151.6, 149.6, 146.0, 132.9, 131.6, 1291, 128.5, 127.8, 127.2, 126.2, 118.5, 22.0; HRMS (ESI):
m/z for C15H12N2O [M + 1]+: calcd.: 237.1028; found: 237.1023.
(
8d).
This compound was prepared from
µL,
µ
δ
δ
6-Chloro-2-methylquinazolin-4(3H)-one 10a). This compound was prepared from
(
2-amino-5-chlorobenzamide (100 mg, 0.59 mmol) triethyl orthoacetate (191 mg, 216
µ
L, 1.18 mmol)
◦
and acetic acid (106 mg, 101
µ
L, 1.77 mmol) in ◦absolute ethanol (3 mL) at 110 C for 24 h. Yield:
◦
106 mg (92%) as a light tan powder, m.p. 288–290 C (lit [49] m.p. 289–291 C); IR (CHCl3): 3166, 1693,
1
1631 cm−1; H-NMR (400 MHz, CDCl3):
δ 12.4 (br s, 1H), 8.00 (d, J = 2.5 Hz, 1H), 7.79 (dd, J = 8.7,
2.5 Hz, 1H), 7.59 (d, J = 8.7 Hz, 1H), 2.35 (s, 3H); 13C-NMR (101 MHz, DMSO-d6):
δ 160.7, 154.9, 147.7,
134.4, 130.1, 128.9, 124.7, 121.9, 21.5; HRMS (ESI): m/z for C9H735ClN2O [M + 1]+: calcd.: 195.0325;
found: 195.0323.
6-Chloro-2-ethylquinazolin-4(3H)-one
2-amino-5-chlorobenzamide (100 mg, 0.59 mmol), triethyl orthopropionate (208 mg, 237
1.18 mmol) and acetic acid (106 mg, 101
L, 1.77 mmol) in absolute ethanol (3 mL) at 110 ◦C for 24 h.
Yield: 114 mg (92%) as a light tan powder, m.p. 262–264 C; IR (nujol): 3169, 1681, 1627 cm−1; 1H-NMR
(400 MHz, DMSO-d6): 12.3 (br s, 1H), 8.01 (d, J = 2.5 Hz, 1H), 7.79 (dd, J = 8.7, 2.5 Hz, 1H), 7.62 (d, J =
(
10b).
This compound was prepared from
µL,
µ
◦
δ
8.7 Hz, 1H), 2.62 (q, J = 7.5 Hz, 2H), 1.24 (t, J = 7.5 Hz, 3H); 13C-NMR (101 MHz, DMSO-d6):
δ 160.8,
159.0, 147.7, 134.3, 130.1, 129.1, 124.7, 122.1, 27.8, 11.2; HRMS (ESI): m/z for C10H935ClN2O [M + 1]+:
calcd.: 209.0482; found: 209.0484.
6-Chloro-2-propylquinazolin-4(3H)-one
(
10c).
This compound was prepared from
L,
2-amino-5-chlorobenzamide (100 mg, 0.59 mmol), triethyl orthobutyrate (224 mg, 255
µ
1.18 mmol) and acetic acid (106 mg, 101 µ
L, 1.77 mmol) in absolute ethanol (3 mL) at 110 ◦C for 24 h.
Yield: 116 mg (88%) as a light tan powder, m.p. 252–254 ◦C (lit [33] m.p. 257–259 ◦C); IR (nujol): 3165,
1
1681, 1618 cm−1; H-NMR (400 MHz, CDCl3):
δ 12.4 (br s, 1H), 8.01 (d, J = 2.4 Hz, 1H), 7.80 (dd,
J = 8.7, 2.4 Hz, 1H), 7.62 (d, J = 8.7 Hz, 1H), 2.57 (t, J = 7.4 Hz, 2H), 1.74 (sextet, J = 7.4 Hz, 2H), 0.93 (t,
J = 7.4 Hz, 3H); 13C-NMR (101 MHz, DMSO-d6):
160.8, 158.0, 147.7, 134.4, 130.1, 129.1, 124.7, 122.1,
36.3, 20.1, 13.5; HRMS (ESI): m/z for C11H1135ClN2O [M + 1]+: calcd.: 223.0638; found: 223.0637.
δ
6-Chloro-2-phenylquinazolin-4(3H)-one 10d). This compound was prepared from
2-amino-5-chlorobenzamide (100 mg, 0.59 mmol), triethyl orthobenzoate (264 mg, 267 L,
1.18 mmol) and acetic acid (106 mg, 101
L, 1.77 mmol) in absolute ethanol (3 mL) at 110 ◦C for 24 h.
Yield: 147 mg (97%) as white crystals, m.p. 292–293 ◦C (lit [37] m.p. 295–296 ◦C); IR (nujol): 3151,
(
µ
µ

Molecules 2018, 23, 2925
9 of 16
1
1679 cm−1; H-NMR (400 MHz, DMSO-d6):
δ
12.7 (br s, 1H), 8.18 (dm, J = 6.8 Hz, 2H), 8.10 (d, J =
2.5 Hz, 1H), 7.87 (dd, J = 8.7, 2.5 Hz, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.64–7.53 (complex, 3H); 13C-NMR
(101 MHz, DMSO-d6):
δ 161.8, 153.3, 148.0, 135.2, 132.9, 132.1, 131.2, 130.2, 129.1, 128.3, 125.3, 122.7;
HRMS (ESI): m/z for C14H935ClN2O [M + 1]+: calcd.: 257.0482; found: 257.0477.
7-Chloro-2-methylquinazolin-4(3H)-one 12a). This compound was prepared from
(
2-amino-4-chlorobenzamide (100 mg, 0.59 mmol) triethyl orthoacetate (191 mg, 216
µ
L, 1.18 mmol)
◦
and acetic acid (106 mg, 101
µ
L, 1.77 mmol) in absolute ethanol (3 mL) at 110 C for 24 h. Yield:
108 mg (94%) as a light tan powder, m.p. 293–295 ◦C (lit [38] m.p. 295–297 ◦C); IR (nujol): 3163, 1674,
1636, 1609 cm−1; 1H-NMR (400 MHz, DMSO-d6):
J = 1.6 Hz, 1H), 7.48 (d, J = 8.5, 1.7 Hz, 1H), 2.35 (s, 3H); 13C-NMR (101 MHz, DMSO-d6):
δ
12.3 (br s, 1H), 8.06 (d, J = 8.5 Hz, 1H), 7.62 (dd,
δ 161.1,
156.0, 150.1, 138.8, 127.8, 126.1, 125.7, 119.5, 21.5; HRMS (ESI): m/z for C9H735ClN2O [M + 1]+: calcd.:
195.0325; found: 195.0322.
7-Chloro-2-ethylquinazolin-4(3H)-one
2-amino-4-chlorobenzamide (100 mg, 0.59 mmol), triethyl orthopropionate (208 mg, 237
1.18 mmol) and acetic acid (106 mg, 101
L, 1.77 mmol) in absolute ethanol (3 mL) at 110 ◦C for 24 h.
Yield: 115 mg (93%) as a light tan powder, m.p. 235–237 ◦C (lit [29] m.p. 205–207 ◦C); IR (nujol): 3172,
1681, 1620, 1607 cm−1; 1H-NMR (400 MHz, DMSO-d6):
12.3 (br s, 1H), 8.07 (d, J = 8.5 Hz, 1H), 7.65
(dd, J = 2.0 Hz, 1H), 7.49 (dd, J = 8.5, 2.0 Hz, 1H), 2.62 (q, J = 7.5 Hz, 2H), 1.23 (t, J = 7.5 Hz, 3H);
13C-NMR (101 MHz, DMSO-d6):
161.2, 160.1, 150.1, 138.9, 127.8, 126.2, 126.0, 119.7, 27.9, 11.2; HRMS
(ESI): m/z for C10H935ClN2O [M + 1]+: calcd.: 209.0482; found: 209.0481.
(
12b).
This
compound
was
prepared
µL,
µ
δ
δ
7-Chloro-2-propylquinazolin-4(3H)-one 12c). This compound was prepared from
(
2-amino-4-chlorobenzamide (100 mg, 0.59 mmol), triethyl orthobutyrate (224 mg, ◦255 µL, 1.18 mmol)
and acetic acid (106 mg, 101
µ
L, 1.77 mmol) in ◦absolute ethanol (3 mL) at 110 C for 24 h. Yield:
117 mg (89%) as a light tan powder, m.p. 214–216 C; IR (nujol): 3169, 1681, 1613, 1603 cm−1; 1H-NMR
(400 MHz, DMSO-d6):
8.5, 1.9 Hz, 1H), 2.57 (t, J = 7.4 Hz, 2H), 1.73 (sextet, J = 7.4 Hz, 2H), 0.93 (t, J = 7.4 Hz, 3H); 13C-NMR
(101 MHz, DMSO-d6): 161.2, 159.1, 150.1, 138.9, 127.8, 126.2, 125.9, 119.6, 36.4, 20.2, 13.5; HRMS (ESI):
m/z for C11H1135ClN2O [M + 1]+: calcd.: 223.0638; found: 223.0635.
δ 12.3 (br s, 1H), 8.06 (d, J = 8.5 Hz, 1H), 7.65 (dd, J = 1.8 Hz, 1H), 7.49 (dd, J =
δ
7-Chloro-2-phenylquinazolin-4(3H)-one 12d). This compound was prepared from
2-amino-4-chlorobenzamide (100 mg, 0.59 mmol), triethyl orthobenzoate (264 mg, 267 L,
1.18 mmol) and acetic acid (106 mg, 101
L, 1.77 mmol) in absolute ethanol (3 mL) at 110 ◦C for 24 h.
Yield: 148 mg (98%) as light yellow crystals, m.p. 276–278 C (lit [43] m.p. > 300 C); IR (nujol):
3151, 1679 cm−1; 1H-NMR (400 MHz, DMSO-d6):
12.7 (br s, 1H), 8.18 (dm, J = 6.9 Hz, 2H), 8.15 (d,
J = 8.5 Hz, 1H), 7.81 (d, J = 2.0 Hz, 1H), 7.64–7.53 (complex, 4H); 13C-NMR (101 MHz, DMSO-d6):
(
µ
µ
◦
◦
δ
δ
162.1, 154.3, 150.4, 139.6, 132.8, 132.2, 129.1, 128.42, 128.38, 127.3, 127.1, 120.3; HRMS (ESI): m/z for
C14H935ClN2O [M + 1]+: calcd.: 257.0482; found: 257.0480.
2-Methylpyrido[2,3-d]pyrimidin-4(3H)-one
(14a).
This compound was prepared from
2-aminonicotinamide (126 mg, 0.92 mmol), triethyl orthoacetate (224 mg, 253
µL, 1.38 mmol)
◦
and acetic acid (165 mg, 158
µ
L, 2.76 mmol) in ab◦solute ethanol (3 mL) at 110 C for 12 h. Yield:
◦
127 mg (86%) as an off-white solid, m.p. 261–263 C (lit [14] m.p. 262–264 C); IR (CHCl3): 3207,
1698 cm−1; 1H-NMR (400 MHz, DMSO-d6):
δ 12.5 (br s, 1H), 8.90 (dd, J = 4.6, 1.9 Hz, 1H), 8.45 (dd, J =
7.8, 1.9 Hz, 1H), 7.48 (td, J = 7.8, 4.6 Hz, 1H), 2.40 (s, 3H); 13C-NMR (101 MHz, DMSO-d6):
δ 162.3,
158.9, 157.9, 155.7, 135.3, 121.7, 115.6, 21.8; HRMS (ESI): m/z for C8H7N3O [M + 1]+: calcd.: 162.0667;
found: 162.0671.
2-Ethylpyrido[2,3-d]pyrimidin-4(3H)-one
(14b).
This compound was prepared from
2-aminonicotinamide (126 mg, 0.92 mmol) and triethyl orthopropionate (244 mg, ◦278
µL, 1.38 mmol)
and acetic acid (165 mg, 158 µL, 2.76 mmol) in absolute ethanol (3 mL) at 110 C for 12 h. Yield:
◦
148 mg (92%) as an off-white solid, m.p. 197–198 C; IR (CHCl3): 3198, 1674 cm−1; 1H-NMR (400 MHz,

Molecules 2018, 23, 2925
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CDCl3):
δ 11.6 (br s, 1H), 9.02 (dd, J = 4.6, 2.1 Hz, 1H), 8.62 (dd, J = 7.9, 2.1 Hz, 1H), 7.44 (dd, J = 7.9,
4.6 Hz, 1H), 2.91 (q, J = 7.6 Hz, 2H), 1.48 (t, J = 7.6 Hz, 3H); 13C-NMR (101 MHz, CDCl3):
δ 164.3, 161.2,
159.4, 156.5, 135.9, 122.0, 115.8, 29.2, 11.0; HRMS (ESI): m/z for C9H9N3O [M + 1]+: calcd.: 176.0824;
found: 176.0819.
2-Propylpyrido[2,3-d]pyrimidin-4(3H)-one
2-aminonicotinamide (126 mg, 0.92 mmol), triethyl orthobutyrate (262 mg, 298
acetic acid (165 mg, 158
L, 2.76 mmol) in absolute ethanol (3 mL) at 110 ◦C for 12 h. Yield: 164 mg
(87%) as a tan solid, m.p. 168–170 C; IR (CHCl3): 3205, 1674 cm−1; 1H-NMR (400 MHz, CDCl3):
(br s, 1H), 9.00 (dd, J = 4.6, 2.1 Hz, 1H), 8.60 (dd, J = 7.9, 2.1 Hz, 1H), 7.43 (dd, J = 7.9, 4.6 Hz, 1H), 2.81
(
14c).
This compound was prepared from
µL, 1.38 mmol) and
µ
◦
δ
11.4
(t, J = 7.5 Hz, 2H), 1.97 (sextet, J = 7.5 Hz, 2H), 1.07 (t, J = 7.5 Hz, 3H); 13C-NMR (101 MHz, CDCl3):
δ
164.5, 160.5, 159.4, 156.5, 135.9, 122.0, 115.7, 37.7, 20.5, 13.7; HRMS (ESI): m/z for C10H11N3O [M + 1]+:
calcd.: 190.0980; found: 190.0977.
2-Phenylpyrido[2,3-d]pyrimidin-4(3H)-one
2-aminonicotinamide (126 mg, 0.92 mmol) and triethyl orthobenzoate (309 mg, 312
acetic acid (165 mg, 158
L, 2.76 mmol) in absolute ethanol (3 mL) at 110 ◦C for 12 h. Yield: 164 mg
(80%) as an off-white solid, m.p. 181–182 ◦C (lit [35] m.p. 178–180 ◦C); IR (CHCl3): 3210, 1672 cm−1
1H-NMR (400 MHz, DMSO-d6):
12.8 (br s, 1H), 8.99 (dd, J = 4.5, 2.0 Hz, 1H), 8.54 (dd, J = 7.8, 2.0 Hz,
1H), 8.25 (d, J = 8.1 Hz, 2H), 7.67–7.56 (complex, 3H), 7.55 (dd, J = 7.8, 4.5 Hz, 1H); 13C-NMR (101 MHz,
DMSO-d6): 163.4, 159.2, 156.6, 155.9, 136.0, 132.9, 132.4, 129.1, 128.5, 122.7, 116.6; HRMS (ESI): m/z for
C13H9N3O [M + 1]+: calcd.: 224.0824; found: 224.0820.
(14d).
This compound was prepared from
µL, 1.38 mmol) and
µ
;
δ
δ
2,3-Dimethylquinazolin-4(3H)-one 16a). This compound was prepared from
(
2-amino-N-methylbenzamide (100 mg, 0.67 mmol), triethyl orthoacetate (22◦4 mg, 253
µL, 1.38 mmol)
and acetic acid (121 mg, 115 µL, 2.01 mmol) in absolute ethanol (2 mL) at 110 C for 12 h. Yield: 102 mg
◦
◦
(87%) as a light tan solid, m.p. 108–109 C (lit [19] m.p. 112–114 C); IR (CHCl3): 1661 cm−1; 1H-NMR
(400 MHz, CDCl3): 8.27 (dd, J = 8.0, 1.2 Hz, 1H), 7.72 (ddd, J = 8.3, 7.2, 1.5 Hz, 1H), 7.61 (d, J = 8.0 Hz,
δ
1H), 7.44 (td, J = 8.0, 1.0 Hz, 1H), 3.63 (s, 3H), 2.63 (s, 3H); 13C-NMR (101 MHz, CDCl3):
δ 162.5, 154.6,
147.4, 134.3, 126.9, 126.8, 126.5, 120.4, 31.2, 23.8; HRMS (ESI): m/z for C10H10N2O [M + 1]+: calcd.:
175.0871; found: 175.0874.
2-Ethyl-3-methylquinazolin-4(3H)-one
2-amino-N-methylbenzamide (100 mg, 0.67 mmol), orthopropionate (236 mg, 269
acetic acid (121 mg, 115
L, 2.01 mmol) in absolute ethanol (2 mL) at 110 ◦C for 24 h. Yield: 105 mg
(83%) as a light tan solid, m.p. 118–120 C (lit [50] m.p. 120–121 C); IR (CHCl3): 1684 cm−1; 1H-NMR
(400 MHz, CDCl3): 8.26 (dd, J = 8.1, 1.2 Hz, 1H), 7.72 (ddd, (J = 8.2, 7.0, 1.5 Hz, 1H), 7.65 (d, J =
8.0 Hz, 1H), 7.43 (ddd, J = 8.2, 7.0, 1.3 Hz, 1H), 3.64 (s, 3H), 2.87 (q, J = 7.4 Hz, 2H), 1.41 (t, J = 7.4 Hz,
3H); 13C-NMR (101 MHz, CDCl3):
162.6, 157.8, 147.3, 134.0, 126.9, 126.7, 126.3, 120.2, 30.3, 28.9, 11.1;
HRMS (ESI): m/z for C11H12N2O [M + 1]+; calcd.: 189.1028; found: 189.1025.
(16b).
This compound was prepared from
µL, 1.34 mmol) and
µ
◦
◦
δ
δ
2-Phenyl-3-methylquinazolin-4(3H)-one 16d). This compound was prepared from
(
2-amino-N-methylbenzamide (100 mg, 0.67 mmol), triethyl orthobenzoate (300 mg, 303 L,
µ
1.34 mmol) and acetic acid (121 mg, 115 µ
L, 2.01 mmol) in absolute ethanol (2 mL) at 110 ◦C for 48
h. Yield: 140 mg (89%) as a light tan solid, m.p. 133–135 ◦C (lit [19] m.p. 134–138 ◦C); IR (CHCl3):
1
1674 cm−1; H-NMR (400 MHz, CDCl3):
δ 8.34 (d, J = 7.8 Hz, 1H), 7.79 (complex, 2H), 7.60–7.49
(complex, 6H), 3.50 (s, 3H); 13C-NMR (101 MHz, CDCl3):
128.0, 127.5, 127.0, 126.7, 120.6, 34.3; HRMS (ESI): m/z for C15H12N2O [M + 1]+: calcd.: 237.1028; found:
δ 162.7, 156.1, 147.3, 135.4, 134.3, 130.1, 128.9,
237.1024.
2-Methyl-3-phenylquinazolin-4(3H)-one
2-amino-N-phenylbenzamide (100 mg, 0.47 mmol), triethyl orthoacetate (228 mg, 258
and acetic acid (85 mg, 81
L, 1.41 mmol) in absolute ethanol (2 mL) at 110 ◦C for 24 h. Yield: 105 mg
(95%) as a white solid, m.p. 142–143 ◦C (lit [21] m.p. 142–144 ◦C); IR (CHCl3): 1684 cm−1; 1H-NMR
(18a).
This compound was prepared from
µL, 1.41 mmol)
µ

Molecules 2018, 23, 2925
11 of 16
(400 MHz, CDCl3):
δ
8.27 (dd, J = 7.9, 0.7 Hz, 1H), 7.77 (td, J = 8.1, 1.3 Hz, 1H), 7.68 (d, J = 8.1 Hz,
1H), 7.60–7.44 (complex, 4H), 7.27 (d, J = 7.1 Hz, 2H), 2.25 (s, 3H); 13C-NMR (101 MHz, CDCl3):
δ
162.3, 154.2, 147.5, 137.8, 134.6, 130.0, 129.3, 128.0, 127.1, 126.8, 126.6, 120.8, 24.4; HRMS (ESI): m/z for
C15H12N2O [M + 1]+: calcd.: 237.1028; found: 237.1023.
2-Ethyl-3-phenylquinazolin-4(3H)-one
2-amino-N-phenylbenzamide (100 mg, 0.47 mmol), triethyl orthopropionate (248 mg, 283
1.41 mmol) and acetic acid (85 mg, 81
L, 1.41 mmol) in absolute ethanol (2 mL) at 110 ◦C for 24 h.
Yield: 108 mg (92%) as an off-white solid, m.p. 120–122 C (lit [21] m.p. 124–125 C); IR (CHCl3):
1684 cm−1; 1H-NMR (400 MHz, CDCl3):
8.28 (dd, J = 8.0, 1.4 Hz, 1H), 7.77 (ddd, J = 8.2, 6.8, 1.5 Hz,
1H), 7.73 (dd, J = 8.1, 1.5 Hz, 1H), 7.59–7.47 (complex, 4H), 7.27 (m, 2H), 2.45 (q, J = 7.4 Hz, 2H), 1.22
(18b).
This compound was prepared from
µL,
µ
◦
◦
δ
(t, J = 7.4 Hz, 3H); 13C-NMR (101 MHz, CDCl3):
δ 162.5, 157.8, 147.6, 137.4, 134.5, 129.9, 129.2, 128.3,
127.1, 127.0, 126.6, 120.8, 29.3, 11.7; HRMS (ESI): m/z for C16H14N2O [M + 1]+: calcd.: 251.1184; found:
251.1179.
2,3-Diphenylquinazolin-4(3H)-one
(
18d).
This compound was prepared from
2-amino-N-phenylbenzamide (100 mg, 0.47 mmol), triethyl orthobenzoate (316 mg, 319
µL,
1.41 mmol) and acetic acid (85 mg, 81
µ
L, 1.41 mmol) ◦in absolute ethanol (2 mL) at 110 ◦C for 24 h.
◦
Yield: 132 mg (95%) as an off-white solid, m.p. 154–156 C (lit [21] m.p. 154–155 C); IR (CHCl3): 1692,
1664 cm−1; 1H-NMR (400 MHz, CDCl3):
δ
8.37 (d, J = 8.0 Hz, 1H), 7.85–7.78 (complex, 2H), 7.54 (ddd,
162.3, 155.2, 147.5,
J = 8.1, 5.6, 2.8 Hz, 1H), 7.36–7.13 (complex, 10H); 13C-NMR (101 MHz, CDCl3):
δ
137.7, 135.5, 134.7, 129.3, 129.1, 129.0 (2C), 128.4, 128.0, 127.8, 127.3, 127.2, 121.0; HRMS (ESI): m/z for
C20H14N2O [M + 1]: calcd.: 299.1184; found: 299.1180.
3-Amino-2-methylquinazolin-4(3H)-one
(20a).
This compound was prepared from
2-aminobenzhydrazide (100 mg, 0.67 mmol), triethyl orthoacetate (217 mg, 245 µL, 1.34 mmol) and
acetic acid (121 mg, 115
µ
L, 2.01 ◦mmol) in absolute ethano◦l (2 mL) at 110 ◦C for 24 h. Yield: 97 mg
(82%) a tan solid, m.p. 147–149 C (lit [51] m.p. 146–148 C); IR (CHCl3): 3455, 3413, 1635 cm−1
;
1H-NMR (400 MHz, CDCl3):
δ 7.72 (dd, J = 8.0, 1.2 Hz, 1H), 7.26 (td, J = 8.1, 1.2 Hz, 1H), 6.79 (d, J =
8.1 Hz, 1H), 6.75 (td, J = 8.1, 0.9 Hz, 1H), 5.81 (br s, 2H), 2.61 (s, 3H); 13C-NMR (101 MHz, CDCl3):
δ
165.0, 161.9, 147.0, 132.4, 127.9, 116.9, 116.3, 106.0, 11.1; HRMS (ESI): m/z for C9H9N3O [M + 1]+: calcd.:
176.0824; found: 177.0898.
3-Amino-2-ethylquinazolin-4(3H)-one
2-aminobenzhydrazide (100 mg, 0.67 mmol), triethyl orthopropionate (235 mg, 269
acetic acid (121 mg, 115
L, 2.01 mmol) in absolute ethanol (2 mL) at 110 ◦C for 24 h. Yield: 100 mg
(80%) as a tan solid, m.p. 116–117 ◦C (lit [52] m.p. 121.5–122.5 ◦C); IR (CHCl3): 3421, 3320, 1627 cm−1
1H-NMR (400 MHz, CDCl3):
7.73 (dd, J = 7.9, 1.5 Hz, 1H), 7.25 (td, J = 8.1, 1.6 Hz, 1H), 6.79 (d,
J = 8.2 Hz, 1H), 6.74 (t, J = 8.1 Hz, 1H), 5.82 (br s, 2H), 2.95 (q, J = 7.6 Hz, 2H), 1.44 (t, J = 7.6 Hz, 3H);
13C-NMR (101 MHz, CDCl3):
166.0, 164.7, 146.8, 132.2, 127.7, 116.7, 116.1, 106.0, 19.0, 10.9; HRMS
(ESI): m/z for C10H11N3O [M + 1]+: calcd.: 190.0980; found: 190.0978.
(20b).
This compound was prepared from
µL, 1.34 mmol) and
µ
;
δ
δ
3-Amino-2-phenylquinazolin-4(3H)-one 20d). This compound was prepared from
2-aminobenzhydrazide (100 mg, 0.67 mmol), triethyl orthobenzoate (300 mg, 303 L, 1.34 mmol) and
acetic acid (121 mg, 115
L, 2.01 mmol) in absolute ethanol (2 mL) at 110 ◦C for 24 h. Yield: 151 mg
(95%) as a tan solid, m.p. 160–161 ◦C (lit [53] m.p. 181–182 ◦C); IR (CHCl3): 3435, 3316, 1612 cm−1
1H-NMR (400 MHz, CDCl3):
8.15 (m, 2H), 7.87 (dd, J = 8.0, 1.5 Hz, 1H), 7.55 (m, 3H), 7.31 (ddd, J =
8.4, 7.2, 1.5 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 6.80 (td, J = 7.9, 1.1 Hz, 1H), 5.90 (br s, 2H); 13C-NMR
(101 MHz, CDCl3): 164.6, 162.8, 147.1, 132.5, 131.7, 129.1, 127.8, 126.9, 123.9, 116.8, 116.2, 105.8; HRMS
(ESI): m/z for C14H11N3O [M + 1]+: calcd.: 238.0980; found: 238.0974.
(
µ
µ
;
δ
δ

Molecules 2018, 23, 2925
12 of 16
3.2.3. Method 3: General Procedure to Prepare 5,6-dihydropyrimidin-4(3H)-ones
The orthoester (1.5 equiv) was added to a mixture of the 3-amino-2,2-dimethylpropionamide
(1.0 equiv) in anhydrous ethanol (3 mL). Glacial acetic acid (2 equiv) was added and the reaction
was heated at reflux for 24 h. The reaction mixture was cooled and concentrated under vacuum.
The product was hygroscopic and was best crystallized by adding purified chloroform and allowing it
to sit under nitrogen for 4–7 days. Filtration and drying yielded the pure product.
2,5,5-Trimethyl-5,6-dihydropyrimidin-4(3H)-one (22a).
This compound was prepared from
3-amino-2,2-dimethylpropionamide (100 mg, 0.86 mmol), triethyl orthoacetate (209 mg, 2◦36
µL,
1.29 mmol) and acetic acid (103 mg, 99
µ
L, 1.72 mmol) ◦in absolute ethanol (3 mL) at 110 C for
1
24 h. Yield: 60 mg (50%) as a white solid, m.p. 196–198 C; IR (nujol): 3223, 1669 cm−1; H-NMR
(400 MHz, D2O):
184.4, 165.3, 43.0, 23.3 (2C), 18.4; HRMS (ESI): m/z for C7H12N2O [M + 1]+: calcd.: 141.1028; found:
141.1028.
δ
3.35 (s, 2H), 2.23 (s, 3H), 1.16 (s, 6H), NH exchanged; 13C-NMR (101 MHz, D2O):
δ
2-Ethyl-5,5-dimethyl-5,6-dihydropyrimidin-4(3H)-one (22b). This compound was prepared from
3-amino-2,2-dimethylpropionamide (100 mg, 0.86 mmol), triethyl orthopropionate (227 mg, 259
µ
L,
◦
1.29 mmol) and acetic acid (103 mg, 99
µ
L, 1.72 mmol) ◦in absolute ethanol (3 mL) at 110 C for
1
24 h. Yield: 59 mg (44%) as a white solid, m.p. 185–187 C; IR (nujol): 3184, 1642 cm−1; H-NMR
(400 MHz, D2O):
δ 3.36 (s, 2H), 2.50 (q, J = 7.7 Hz, 2H), 1.24 (t, J = 7.7 Hz, 3H), 1.15 (s, 6H), NH
exchanged; 13C-NMR (101 MHz, D2O):
δ 184.5, 169.7, 51.0, 43.8, 26.5, 23.3 (2C), 10.7; HRMS (ESI): m/z
for C8H14N2O [M + 1]+: calcd.: 155.1184; found: 155.1187.
5,5-Dimethyl-2-propyl-5,6-dihydropyrimidin-4(3H)-one (22c). This compound was prepared from
3-amino-2,2-dimethylpropionamide (100 mg, 0.86 mmol), triethyl orthobutyrate (245 mg, 279
1.29 mmol) and acetic acid (103 mg, 99
L, 1.72 mmol) in absolute ethanol (3 mL) at 110 ◦C for 24 h.
Yield: 52 mg (36%) as a white solid, m.p. 118–120 ◦C; IR (nujol): 3199, 1652 cm−1; 1H-NMR (400 MHz,
D2O): 3.37 (s, 2H), 2.46 (t, J = 7.4 Hz, 2H), 1.69 (sextet, J = 7.4 Hz, 2H), 1.16 (s, 6H), 0.96 (t, J = 7.4 Hz,
µL,
µ
δ
3H), NH exchanged; 13C-NMR (101 MHz, D2O):
δ 184.4, 168.5, 51.0, 43.8, 34.5, 23.3 (2C), 20.2, 12.3;
HRMS (ESI): m/z for C9H16N2O [M + 1]+: calcd.: 169.1341; found: 169.1339.
5,5-Dimethyl-2-phenyl-5,6-dihydropyrimidin-4(3H)-one (22d). This compound was prepared from
3-amino-2,2-dimethylpropionamide (100 mg, 0.86 mmol), triethyl orthobenzoate (289 mg, 292
1.29 mmol) and acetic acid (103 mg, 99
L, 1.72 mmol) in absolute ethanol (3 mL) at 110 ◦C for 24 h.
Yield: 126 mg (72%) as a white solid, m.p. 153–155 ◦C; IR (nujol): 3231, 1700, 1651 cm−1; 1H-NMR
(400 MHz, CDCl3): 8.46 (br s, 1H), 7.78 (d, J = 7.6 Hz, 2H), 7.53–7.43 (complex, 2H), 3.62 (s, 2H), 1.21
µL,
µ
δ
(s, 6H), NH exchanged; 13C-NMR (101 MHz, CDCl3):
δ 177.2, 151.5, 133.3, 131.4, 129.0, 126.4, 57.7, 36.5,
23.4 (2C); HRMS (ESI): m/z for C12H14N2O [M + 1]+: calcd.: 203.1184; found: 203.1180.
4. Conclusions
We have developed an efficient strategy for the synthesis of 2-alkyl- and
2-arylquinazolin-4(3H)-ones. The procedure is straightforward, and gives the desired heterocycles
in yields
≥
80% without contamination by residual metals or Lewis acids. Although almost all of
the compounds have been reported previously, the current work provides a unified approach that
allows the convenient preparation of a broad range of targets derived from 2-aminobenzamides;
ring-substituted 2-aminobenzamides, 2-aminonicotinamides, 2-amino-N-methyl (and N-phenyl)
benzamides; as well as 2-aminobenzhydrazides. The conditions are mild and purification of the final
products is easily accomplished. Additionally, we have extended the method to the synthesis of
5,6-dihydropyrimidin-4(3H)-ones, although these compounds proved difficult to purify due to their
hygroscopic nature. The only limitation to our approach is that relatively few substituted orthoesters
are available commercially. Nevertheless, the simplicity and high yields provided by the current

Molecules 2018, 23, 2925
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procedure, as well as its ability to provide the target heterocycles free of contaminants, makes this
method an important contribution to the field.
Supplementary Materials: The following are available online. Electronic Supplementary Information (ESI)
available: Copies of 1H and 13C-NMR spectra of the final products.
Author Contributions: J.T.G. and J.K.A. did the experimental work. R.A.B. optimized several of the procedures
and wrote the paper. All of the authors read and approved the final version of the manuscript before submission.
Funding: This research was funded by the NSF REU Program (NSF CHE–1559874) and the NSF MRI Program
(NSF BIR-9512269).
Acknowledgments: J.T.G. wishes to thank the 2018 NSF-supported REU Program at Oklahoma State University
(CHE-1559874) for a summer appointment. The authors also wish to acknowledge the NSF (BIR-9512269), the
Oklahoma State Regents for Higher Education, the W. M. Keck Foundation, and Conoco, Inc. for funds to establish
our Oklahoma State-Wide NMR Laboratory. The OSU College of Arts and Sciences is also acknowledged for
funds to purchase a new 400 MHz NMR for this facility.
Conflicts of Interest: The authors declare no conflicts of interest.
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Sample Availability: Samples of the compounds are not available from the authors.
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2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).