Structurally diversified synthesis of 2,3-dihydroquinazolin-4-(1H)-ones from 2-aminobenzamides and 1,2-dicarbonyl compounds in ionic liquids catalyzed by iodine

Article abstract of DOI:10.1007/s11164-016-2807-1

Abstract: A green procedure for the rapid diversification of quinazolin-4-(1H)-one scaffolds is described in this paper. Various types of 1,2-dicarbonyl compounds are treated with 2-aminobenzamides in ionic liquids catalyzed by iodine and unexpectedly afford structurally diversified single-quinazoline derivatives. The recyclability of the ionic liquids makes this protocol to be an environmentally benign procedure. Graphical Abstract: A total of 39 quinazolin-4-(1H)-one scaffolds were synthesized via a green procedure of 1,2-dicarbonyl compounds and 2-aminobenzamides in ionic liquids catalyzed by iodine.[Figure not available: see fulltext.]

Full text of DOI:10.1007/s11164-016-2807-1

Res Chem Intermed
DOI 10.1007/s11164-016-2807-1
Structurally diversified synthesis of
2,3-dihydroquinazolin-4-(1H)-ones from
2-aminobenzamides and 1,2-dicarbonyl
compounds in ionic liquids catalyzed by iodine
Jie Wang1 Mei-Mei Zhang1 Xiang-Shan Wang1
•
•
Received: 10 July 2016 / Accepted: 8 November 2016
Ó Springer Science+Business Media Dordrecht 2016
Abstract A green procedure for the rapid diversification of quinazolin-4-(1H)-one
scaffolds is described in this paper. Various types of 1,2-dicarbonyl compounds are
treated with 2-aminobenzamides in ionic liquids catalyzed by iodine and unexpectedly
afford structurally diversified single-quinazoline derivatives. The recyclability of the
ionic liquids makes this protocol to be an environmentally benign procedure.
Graphical Abstract A total of 39 quinazolin-4-(1H)-one scaffolds were synthesized
via a green procedure of 1,2-dicarbonyl compounds and 2-aminobenzamides in ionic
liquids catalyzed by iodine.
O
R
N
R'
H
NH2
O
O
O
O
O
O
O
O
O
O
O
=
=
R
=
R
4-MeC6H4
4-MeOC6
H4
=
4-FC6H4CH2
R
2-BrC6H4
R
=
R
4-MeC6H4CH2
=
R' 5-Br
=
R' 4-Cl
Electronic supplementary material The online version of this article (doi:10.1007/s11164-016-2807-1)
contains supplementary material, which is available to authorized users.
&
Xiang-Shan Wang
xswang1974@yahoo.com
1
School of Chemistry and Chemical Engineering, Jiangsu Key Laboratory of Green Synthetic
Chemistry for Functional Materials, Jiangsu Normal University, Xuzhou 221116, Jiangsu,
People’s Republic of China
123

J. Wang et al.
Keywords Quinazoline Á 2-Aminobenzamide Á 1,2-Dicarbonyl compound Á Iodine Á
Ionic liquids
Introduction
Quinazoline derivatives have remarkable activities including anti-cancer [1], anti-
viral [2–5], anti-tuberculosis [6], and others [7–10]; therefore, they are of great
interest to both organic and medicinal chemists. Figure 1 shows the representative
pharmaceuticals (A, B, and C) [11] containing quinazoline moiety with noteworthy
anti-cancer activities. Of these, Gefitinib is an efficient drug used for the treatment
of certain breast, lung, and other cancers, while Erlotinib is a marketed medicine
used to treat non-small cell lung cancer and pancreatic cancer.
In addition, quinazolinones are also found in many natural products [12, 13]. As
shown in Fig. 2, D was isolated from Bacillus cereus [14] and E came from
Peganum nigellastrum [15]. F and G were separated from Dichroa febrifuga [16]
and Bouchardatia neurococca [17]. It is clear that they are all useful heterocycles
based on quinazolinone moiety.
The earliest method for synthesizing quinazolines was a condensation of
2-aminobenzamides with aldehydes catalyzed by hydrochloric acid, and yields were
obtained within 37–83% [18]. In order to avoid the use of the corrosive hydrochloric
acid, many new catalysts have been reported in recent years [19–32]. However,
some disadvantages such as expensive reactants, using organic solvents, or low
yields still exist. Thus, a simple, green, mild, and versatile preparation of 2,3-
dihydroquinazolin-4-(1H)-one derivatives in one-pot reaction is also highly
desirable.
Fig. 1 The representative pharmaceuticals containing quinazoline
123

Structurally diversified synthesis of…
Fig. 2 The natural products containing quinazolinone
In our previous paper [33, 34], ketones were used as single-carbonyl compounds
to react with 2-aminobenzamide 1, with high yields of 2,3-dihydroquinazolin-4-
(1H)- ones being obtained in ionic liquids catalyzed by iodine. However, 1,3-
dicarbonyl compounds, such as dimedone [35], were used to react with 1 instead of
ketone and unexpectedly gave a series of biquinazolin-4-(1H)-one derivatives via
ring-opening reaction of dimedone. At the same time, cyclohexane-1,4-dione [36]
was used to replace dimedone, and the normal biquinazolin-4-(1H)-ones were
obtained in the presence of two equivalents of 2-aminobenzamides. Thererfore, in
our initial assumption, if biacetyl, which is similar to cyclohexane-1,4-dione, was
used to react with 1, it would also consume two equivalents of 1 to give
diquinazolin-4-(1H)-one derivatives. However, it reacted with 2-aminobenzamide
smoothly and gave 2-acetyl-2-methyl-2,3-dihydroquinazolin-4(1H)-one unexpect-
edly (Scheme 1), although two equivalents of 1 were added to the reaction. Other
1,2-dicarbonyl compounds, including acenaphthylene-1,2-dione and phenanthrene-
Scheme 1 The model reaction
123

J. Wang et al.
9,10-dione, all gave the products with a raw material ratio of 1:1. Furthermore, bi-
carbonyl or tri-carbonyl compounds with different activity, such as 1H-indene-
1,2,3-trione and 1-phenylpropane-1,2-dione, chemselectively gave 10H-spiro[in-
dene-2,20-quinazoline]-1,3,40(30H)-trione and 2-benzoyl-2-methyl-2,3-dihydro-
quinazolin-4(1H)-one derivatives in high yields, respectively. In this paper, we
would like to report the iodine-catalyzed reaction of 2-aminobenzamides and 1,2-
dicarbonyl compounds in ionic liquids.
Results and discussion
In our initial study, two equivalents of 2-amino-N-(2-bromophenyl)benzamide (1a)
and an equivalent of biacetyl was treated in ionic liquids of [BMIm]Br at room
temperature, the designed reaction carried out smoothly, and the new product was
found as yellow precipitate in ionic liquids. However, we surprised to find that still
much amount of 1a was observed by TLC. At first, we thought that the reason why
the reaction did not continue was insolubilization of intermediate products or low
reaction temperature. Subsequently, the reaction temperature was raised to 80 °C or
higher, no other new product was observed except for the original product. It was
isolated and confirmed by X-ray diffraction analysis as 2-acetyl-3-(2-bromophenyl)-
2-methyl-2,3-dihydroquinazolin-4(1H)-one 3a, and its crystal structure is shown in
Fig. 3.
In our continued study, the equivalent ratio of the raw materials in the model
reaction was controlled down to 1:1 to screen optimal reaction conditions. It was
found that 3a was obtained only in 58% yield at room temperature, and at 50 °C the
reaction gave the highest yield of 92%. Acidic catalysts were indispensable in this
transformation, such as iodine, TsOH, HOAc, but iodine gave the best results in
ionic liquids of [BMIm]Br. Then, 1, 5, and 10 mol% iodine was used to promote the
Fig. 3 The crystal structure of 3a
123

Structurally diversified synthesis of…
reaction, gaving 3a in 78, 92, and 91% yields, respectively. Therefore, it was
concluded that iodine (5 mol%) was enough to promote the reaction at 50 °C. In
addition, different imidazolium cations ([BMIm]?, [EMIm]? , and [PMIm]?) and
anions (Br- and BF4-) were tested for this reaction to further improve the yield of
3a, [BMIm]Br was proved to be the best one for this transformation.
After completion of the model reaction as monitored by TLC, products were
isolated by simple filtration after the addition of 5 mL water to the cooled reaction
mixture. Water in the filtrate was removed by distillation under reduced pressure,
and the [BMIm]Br in the residue could be reused after being evaporated at 80 °C for
4 h in vacuum. Successive reuse of the recycled ionic liquid of [BMIm]Br in the
model reaction gave high yields of 3a (Table 1, 88%) even after the fourth cycle.
Subsequently, various types of 2-aminobenzamides 1, were tested to react with
2a under the optimized reaction conditions. They all reacted well to give 3 as
expected in high yields (Table 2, entries 1–5). Then, acenaphthylene-1,2-dione 2b
and phenanthrene-9,10-dione 2c (Fig. 4) were used as 1,2-dicarbonyl compounds to
react with 1 (Scheme 2), with 10H,2H-spiro[acenaphthylene-1,20-quinazoline] -
2,40(30H)-dione and 10H,10H-spiro[phenanthrene-9,20-quinazoline]-40,10(30H)-dione
Table 1 The reuse of [BMIm]Br for the synthesis of 3a
Cycles
1
2
3
4
Yields (%)
90
91
90
88
Table 2 The synthetic results of 3
Entry
R
R0
2
Products
Time/h
Yields/%
1
2-BrC6H4
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
2a
3a
3b
3c
3d
3e
3f
6
6
3a
3b
3c
3d
3e
3f
92
89
90
85
89
92
91
89
91
87
86
86
90
91
84
89
89
2
4-MeC6H4
PhCH2
3
7
4
2-ClC6H4CH2
4-ClC6H4
8
5
6
6
H
2b
9
7
PhCH2CH2
4-MeOC6H4CH2
PhCH2
3g
3h
3i
10
8
3g
3h
3i
8
9
6
10
11
12
13
14
15
16
17
Piperonylethyl
4-MeC6H4CH2
4-FC6H4CH2
4-BrC6H4
3j
7
3j
3k
3l
8
3k
3l
8
3m
3n
3o
3p
3q
8
3m
3n
3o
3p
3q
3-ClC6H4
10
8
4-MeOC6H4
4-MeC6H4
2-Naphthyl
8
8
123

J. Wang et al.
Yields/%
Table 2 continued
Entry
R
R0
2
Products
Time/h
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
H
H
2c
3r
10
8
3r
82
86
89
90
85
85
83
89
88
86
87
92
85
86
89
91
90
86
90
87
90
92
4-MeOC6H4CH2
4-BrC6H4
4-MeOC6H4
PhCH2
H
3s
3s
H
3t
8
3t
H
3u
7
3u
5-Cl
5-Br
5-Me
H
3v
8
3v
4-FC6H4CH2
H
3w
3x
7
3w
3x
6
4-MeOC6H4(CH2)2
H
3y
8
3y
H
2d
2e
3z
10
6
3z
4-FC6H4CH2
4-MeC6H4
Ph
H
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
3aj
3ak
3al
3am
3aa
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
3aj
3ak
3al
3am
H
7
H
7
H
H
6
Piperonylethyl
4-BrC6H4
4-MeC6H4
4-FC6H4CH2
4-FC6H4
H
9
H
10
10
10
8
H
5-Br
H
2-BrC6H4
4-FC6H4
H
6
5-Me
H
8
3,4-(MeO)2C6H3
4-MeC6H4CH2
8
4-Cl
8
Reaction conditions 1 (1.0 mmol), 2 (1.0 mmol), iodine (13 mg, 0.05 mmol), [BMIm]Br (2.0 mL), 50 °C
Fig. 4 The diversity of 2
Scheme 2 The synthetic route of 3
123

Structurally diversified synthesis of…
derivatives being obtained in high yields (Table 2, entries 6–25, 82–92%),
respectively. Of thesse, the structures of 3o and 3w were confirmed by X-ray
diffraction analysis, and their crystal structures were shown in Figs. 5 and 6. It was
Fig. 5 The crystal structure of 3o
Fig. 6 The crystal structure of 3w
123

J. Wang et al.
observed clearly that they all gave the single 2,3-dihydroquinazolin- 4-(1H)-one,
respectively.
It should be noted that asymmetric center dicarbonyl compounds, such as
1-phenylpropane-1,2-dione 2d, were treated with 1 and gave 2-benzoyl-2-methyl-
2,3-dihydroquinazolin-4(1H)-ones (Table 2, entries 26–29) rather than 2-acetyl-2-
phenyl-2,3-dihydroquinazolin-4(1H)-ones (Scheme 3), and 3ab was also con-
firmed by X-ray diffraction analysis (Fig. 7). The best reason to explain this result
Scheme 3 The 2d involving reaction
Fig. 7 The crystal structure of 3ab
123

Structurally diversified synthesis of…
is that the carbonyl near methyl group is more active than that of benzene group in
theory.
When 1,2,3-indantrione hydrate 3e was used as a tricarbonyl compound with
different activity to this reaction, it was still more active carbonyl in 2-position to
react with 1 to give 10H-spiro[indene-2,20-quinazoline]-1,3,40(30H)-triones chems-
electively (Table 2, entries 30–39; Scheme 4). The structure of 3am was confirmed
by X-ray diffraction analysis as shown in Fig. 8. The crystal data of 3a, 3o, 3w, 3ab,
and 3am are summarised in Table 3.
In the possible reaction mechanism, we think that the iodine works as a mild
Lewis acid to activate the carbonyl and carbon–nitrogen double bonds. The
probable reaction mechanism is shown in Scheme 5 as follows (using 2a as a
model).
Scheme 4 The 2e involving reaction
Fig. 8 The crystal structure of 3am
123

J. Wang et al.
123

Structurally diversified synthesis of…
Scheme 5 The probable reaction mechanism
Conclusion
In summary, total of 39 2,3-dihydroquinazoline derivatives were obtained by a
reaction of 2-aminobenzamides and 1,2-dicarbonyl compounds in high yields in
ionic liquids catalyzed by iodine. This procedure had the advantages of mild
reaction conditions, high yields, one-pot operational simplicity, and it was
environmentally benign.
Experimental
Melting points were determined in open capillaries and are uncorrected. IR spectra
1
were recorded on a Tensor 27 spectrometer in KBr pellet. H NMR and 13C NMR
spectra were obtained from a solution in DMSO-d6 with Me4Si as internal standard
using a Bruker-400 spectrometer. HRMS analyses were carried out using a Bruker
micro-TOF-Q-MS analyzer. TLC was determined in our lab using a mixture of ethyl
acetate and petroleum ether (volume ratio 3:1) as the developing solvent. The isatin
anhydride, amine, 1,2-dicarbonyl compounds, N-methylimidazole, 1-bromobutane
were purchased from Beijing InnoChem Science & Technology Co., Ltd.
2-Aminobenzamides [37] were prepared from isatin anhydride and amine by a
known method. The [BMIm]Br [38] is obtained via a reaction of N-methylimidazole
and 1-bromobutane under solvent-free conditions.
General procedure for the syntheses of 3
A dry 50-mL flask was charged with 2-aminobenzamide 1 (1.0 mmol) and 1,2-
dicarbonyl compound 2 (1.0 mmol), iodine (13 mg, 0.05 mmol), and [BMIm]Br
(2.0 mL). The reaction mixture was stirred at 50 °C under anhydrous atmosphere
for 6–10 h. After the completion of the reaction as indicated by TLC [a small
amount of reaction mixture was dissolved in EtOH, and the developing solvent is a
mixture of ethyl acetate and petroleum ether (volume ratio 3:1)], 5 mL water was
added to the mixture. The yellow precipitate was filtered off and purified by
recrystallization from 95% EtOH to give final product 3.
2-Acetyl-3-(2-bromophenyl)-2-methyl-2,3-dihydroquinazolin-4(1H)-one (3a) M.p.
223–225 °C; Rf = 0.63; 1H NMR (DMSO-d6, 400 MHz): dH 7.96 (s, 1H, NH), 7.75
(dd, J = 7.6 Hz, J0 = 0.8 Hz, 1H, ArH), 7.61 (d, J = 7.6 Hz, 1H, ArH), 7.49–7.40
123

J. Wang et al.
(m, 2H, ArH), 7.37–7.30 (m, 2H, ArH), 7.84 (d, J = 8.0 Hz, 1H, ArH), 6.79–6.76
(m, 1H, ArH), 2.18 (s, 3H, CH3), 1.33 (s, 3H, CH3). 13C NMR (DMSO-d6,
100 MHz): dC 20.9, 24.1, 79.2, 114.6, 115.9, 118.7, 125.4, 128.5, 129.1, 130.2,
132.2, 133.4, 134.2, 138.5, 145.6, 162.8, 206.5. IR (KBr): m 3219, 3105, 3019, 2898,
2850, 1678, 1638, 1598, 1590, 1463, 1336, 1190, 1035, 1010, 816, 769, 721, 695,
602, 566 cm-1. HRMS (ESI, m/z): Calcd for C17H14BrN2O2 [M-H]- 357.0239,
found 357.0233.
2-Acetyl-2-methyl-3-(p-tolyl)-2,3-dihydroquinazolin-4(1H)-one (3b) M.p. 210–212 °C;
Rf = 0.68; 1H NMR (DMSO-d6, 400 MHz): dH 7.82 (s, 1H, NH), 7.61 (dd,
J = 8.0 Hz, J0 = 1.6 Hz, 1H, ArH), 7.35–7.31 (m, 1H, ArH), 7.21 (d, J = 8.0 Hz,
2H, ArH), 7.11 (d, J = 8.0 Hz, 2H, ArH), 6.82 (d, J = 7.6 Hz, 1H, ArH), 6.78–6.74
(m, 1H, ArH), 2.33 (s, 3H, CH3), 2.17 (s, 3H, CH3), 1.33 (s, 3H, CH3). IR (KBr): m
3293, 3001, 2876, 2851, 1678, 1666, 1591, 1373, 1330, 1272, 1113, 1097, 1037,
954, 823, 785, 761, 720, 699, 625, 594, 524 cm-1. HRMS (ESI, m/z): Calcd for
C18H17N2O2 [M-H]- 293.1290, found 293.1279.
2-Acetyl-3-benzyl-2-methyl-2,3-dihydroquinazolin-4(1H)-one (3c) M.p. 231–233 °C;
Rf = 0.69; 1H NMR (DMSO-d6, 400 MHz): dH 7.64 (dd, J = 7.6 Hz, J0 = 1.2 Hz,
1H, ArH), 7.60 (s, 1H, NH), 7.32–7.30 (m, 2H, ArH), 7.28–7.24 (m, 3H, ArH),
7.22–7.18 (m, 1H, ArH), 6.78–6.73 (m, 2H, ArH), 5.29 (d, J = 16.4 Hz, 1H, CH),
4.06 (d, J = 16.4 Hz, 1H, CH), 2.13 (s, 3H, CH3), 1.57 (s, 3H, CH3). IR (KBr): m
3280, 3100, 3003, 2987, 2894, 1677, 1610, 1586, 1540, 1518, 1487, 1314, 1297,
1151, 1099, 1003, 987, 955, 778, 690, 611 cm-1. HRMS (ESI, m/z): Calcd for
C18H17N2O2 [M-H]- 293.1290, found 293.1287.
2-Acetyl-3-(2-chlorobenzyl)-2-methyl-2,3-dihydroquinazolin-4(1H)-one (3d) M.p. 188–
190 °C; Rf = 0.65; 1H NMR (DMSO-d6, 400 MHz): dH 7.75 (s, 1H, NH), 7.62 (dd,
J = 8.0 Hz, J0 = 1.6 Hz, 1H, ArH), 7.45 (dd, J = 7.6 Hz, J0 = 1.2 Hz, 1H, ArH),
7.36–7.30 (m, 2H, ArH), 7.28 (dd, J = 7.6 Hz, J0 = 2.4 Hz, 1H, ArH), 7.26–7.23
(m, 1H, ArH), 6.82 (d, J = 8.0 Hz, 1H, ArH), 6.78–6.74 (m, 1H, ArH), 5.24 (d,
J = 17.6 Hz, 1H, CH), 4.12 (d, J = 17.6 Hz, 1H, CH), 2.17 (s, 3H, CH3), 1.59 (s,
3H, CH3). IR (KBr): m 3250, 3006, 2946, 2856, 1641, 1628, 1608, 1515, 1486, 1392,
1345, 1313, 1269, 1051, 1040, 994, 753, 692 cm-1. HRMS (ESI, m/z): Calcd for
C18H16ClN2O2 [M-H]- 327.0900, found 327.0907.
2-Acetyl-3-(4-chlorophenyl)-2-methyl-2,3-dihydroquinazolin-4(1H)-one (3e) M.p. 215–
217 °C; Rf = 0.60; 1H NMR (DMSO-d6, 400 MHz): dH 7.92 (s, 1H, NH), 7.62 (dd,
J = 8.0 Hz, J0 = 1.2 Hz, 1H, ArH), 7.48 (d, J = 8.4 Hz, 2H, ArH), 7.37–7.33 (m,
1H, ArH), 7.29–7.25 (m, 2H, ArH), 6.83 (d, J = 7.6 Hz, 1H, ArH), 6.80–6.76 (m,
1H, ArH), 2.17 (s, 3H, CH3), 1.36 (s, 3H, CH3). IR (KBr): m 3300, 3105, 2928, 2851,
1655, 1634, 1613, 1585, 1540, 1489, 1330, 1170, 1093, 1016, 829, 761, 780, 717,
698, 623, 592 cm-1. HRMS (ESI, m/z): Calcd for C17H14ClN2O2 [M-H]-
313.0744, found 313.0755.
10H,2H-Spiro[acenaphthylene-1,20-quinazoline]-2,40(30H)-dione (3f) M.p. 153–155 °C;
Rf = 0.52; 1H NMR (DMSO-d6, 400 MHz): dH 8.50 (s, 1H, NH), 8.38 (d,
123

Structurally diversified synthesis of…
J = 8.0 Hz, 1H, ArH), 8.15 (dd, J = 7.6 Hz, J0 = 1.2 Hz, 1H, ArH), 8.02 (d,
J = 6.4 Hz, 1H, ArH), 7.93–7.83 (m, 3H, ArH), 7.68 (dd, J = 7.6 Hz, J0 = 1.6 Hz,
1H, ArH), 7.47 (s, 1H, NH), 7.28–7.23 (m, 1H, ArH), 6.75–6.71 (m, 1H, ArH), 6.57
(d, J = 8.0 Hz, 1H, ArH). IR (KBr): m 3213, 3129, 3035, 2930, 1663, 1642, 1591,
1527, 1486, 1361, 1325, 1257, 1134, 978, 911, 837, 786, 682 cm-1. HRMS (ESI, m/
z): Calcd for C19H13N2O2 [M ? H]? 301.0977, found 301.0975.
30-Phenethyl-10H,2H-spiro[acenaphthylene-1,20-quinazoline]-2,40(30H)-dione (3g) M.p.
1
193–195 °C; Rf = 0.70; H NMR (DMSO-d6, 400 MHz): dH 8.54–8.49 (m, 4H,
ArH), 8.53 (s, 1H, NH), 7.94–7.90 (m, 2H, ArH), 7.69–7.63 (m, 2H, ArH),
7.58–7.54 (m, 1H, ArH), 7.48 (dd, J = 7.6 Hz, J0 = 1.2 Hz, 1H, ArH), 7.25–7.21
(m, 2H, ArH), 7.17–7.11 (m, 3H, ArH), 3.25–3.20 (m, 2H, CH2), 2.64–2.61 (m, 2H,
CH2). IR (KBr): m 3316, 3058, 3002, 2869, 1678, 1638, 1587, 1468, 1437, 1375,
1356, 1281, 1193, 1095, 903, 781, 699 cm-1. HRMS (ESI, m/z): Calcd for
C27H19N2O2 [M-H]- 403.1452, found 403.1466.
30-(4-Methoxybenzyl)-10H,2H-spiro[acenaphthylene-1,20-quinazoline]-2,40(30H)-dione
(3h) M.p. 243–244 °C; Rf = 0.71; 1H NMR (DMSO-d6, 400 MHz): dH 8.90–8.87
(m, 1H, NH), 8.54–8.50 (m, 4H, ArH), 7.94–7.90 (m, 2H, ArH), 7.75 (dd,
J = 7.6 Hz, J0 = 1.6 Hz, 1H, ArH), 7.69–7.65 (m, 1H, ArH), 7.61–7.57 (m, 1H,
ArH), 7.50 (dd, J = 7.6 Hz, J0 = 1.2 Hz, 1H, ArH), 7.02–7.00 (m, 2H, ArH),
6.68–6.65 (m, 2H, ArH), 4.16 (d, J = 6.4 Hz, 2H, CH2), 3.68 (s, 3H, OCH3). IR
(KBr): m 3408, 3065, 3003, 2858, 1678, 1637, 1602, 1580, 1511, 1460, 1304, 1231,
1215, 1173, 1129, 1612, 985, 775 cm-1. HRMS (ESI, m/z): Calcd for C27H19N2O3
[M-H]- 419.1401, found 419.1397.
30-Benzyl-10H,2H-spiro[acenaphthylene-1,20-quinazoline]-2,40(30H)-dione (3i) M.p.
1
251–253 °C; Rf = 0.71; H NMR (DMSO-d6, 400 MHz): dH 9.00–8.97 (m, 1H,
NH), 8.52 (s, 2H, ArH), 8.51 (s, 2H, ArH), 7.94–7.90 (m, 2H, ArH), 7.79 (dd,
J = 7.6 Hz, J0 = 1.2 Hz, 1H, ArH), 7.70–7.66 (m, 1H, ArH), 7.62–7.58 (m, 1H,
ArH), 7.52 (dd, J = 7.6 Hz, J0 = 1.2 Hz, 1H, ArH), 7.17–7.10 (m, 5H, ArH), 4.25
(d, J = 6.0 Hz, 2H, CH2). IR (KBr): m 3360, 3029, 3011, 2879, 1666, 1651, 1589,
1537, 1487, 1436, 1376, 1358, 1299, 1280, 1243, 1200, 1118, 988, 967, 901, 781,
754, 703 cm-1. HRMS (ESI, m/z): Calcd for C26H17N2O2 [M-H]- 389.1296,
found 389.1302.
30-(2-(Benzo[d] [1, 3] dioxol-5-yl)ethyl)-10H,2H-spiro[acenaphthylene-1,20-quina-
1
zoline]-2,40(30H)-dione (3j) M.p. 211–213 °C; Rf = 0.65; H NMR (DMSO-d6,
400 MHz): dH 8.54–8.49 (m, 4H, ArH), 8.48–8.46 (m, 1H, NH), 7.94–7.90 (m, 2H,
ArH), 7.69–7.63 (m, 2H, ArH), 7.59–7.54 (m, 1H, ArH), 7.48 (dd, J = 7.6 Hz,
J0 = 1.2 Hz, 1H, ArH), 6.77–6.75 (m, 1H, ArH), 6.71 (d, J = 1.6 Hz, 1H, ArH),
6.56 (dd, J = 8.0 Hz, J0 = 1.6 Hz, 1H, ArH), 5.94 (s, 2H, OCH2O), 3.21–3.16 (m,
2H, CH2), 2.53 (s, 2H, CH2). IR (KBr): m 3349, 3096, 3031, 2973, 2863, 1674, 1653,
1588, 1542, 1489, 1433, 1377, 1366, 1355, 1283, 1246, 1193, 903, 786, 757 cm-1
HRMS (ESI, m/z): Calcd for C28H19N2O4 [M-H]- 447.1350, found 447.1355.
.
123

J. Wang et al.
30-(4-Methylbenzyl)-10H,2H-spiro[acenaphthylene-1,20-quinazoline]-2,40(30H)-
1
dione (3k) M.p. 226–227 °C; Rf = 0.70; H NMR (DMSO-d6, 400 MHz): dH
8.91–8.88 (m, 1H, NH), 8.53–8.49 (m, 4H, ArH), 7.94–7.90 (m, 2H, ArH), 7.77 (dd,
J = 7.6 Hz, J0 = 1.6 Hz, 1H, ArH), 7.69–7.65 (m, 1H, ArH), 7.61–7.57 (m, 1H,
ArH), 7.50 (dd, J = 7.6 Hz, J0 = 1.2 Hz, 1H, ArH), 6.99–6.91 (m, 4H, ArH), 4.19
(d, J = 6.0 Hz, 2H, CH2), 2.20 (s, 3H, CH3). IR (KBr): m 3342, 3066, 3001, 2864,
1674, 1656, 1589, 1543, 1515, 1436, 1377, 1359, 1300, 1243, 1200, 1147, 992, 902,
820, 771, 751, 671, 645 cm-1. HRMS (ESI, m/z): Calcd for C27H19N2O2 [M-H]-
403.1452, found 403.1459.
30-(4-Fluorobenzyl)-10H,2H-spiro[acenaphthylene-1,20-quinazoline]-2,40(30H)-dione
1
(3l) M.p. 209–210 °C; Rf = 0.68; H NMR (DMSO-d6, 400 MHz): dH 8.99–8.96
(m, 1H, NH), 8.53–8.50 (m, 4H, ArH), 7.94–7.90 (m, 2H, ArH), 7.77 (dd,
J = 7.6 Hz, J0 = 1.6 Hz, 1H, ArH), 7.69–7.66 (m, 1H, ArH), 7.62–7.58 (m, 1H,
ArH), 7.51 (dd, J = 7.6 Hz, J0 = 1.2 Hz, 1H, ArH), 7.16–7.13 (m, 2H, ArH),
6.97–6.93 (m, 2H, ArH), 4.22 (d, J = 6.0 Hz, 2H, CH2). IR (KBr): m 3305, 3068,
2885, 1678, 1639, 1588, 1510, 1374, 1356, 1240, 1191, 902, 846, 829, 781, 758,
669 cm-1. HRMS (ESI, m/z): Calcd for C26H16FN2O2 [M-H]- 407.1196, found
407.1200.
30-(4-Bromophenyl)-10H,2H-spiro[acenaphthylene-1,20-quinazoline]-2,40(30H)-dione
(3m) M.p. 210–211 °C; Rf = 0.69; 1H NMR (DMSO-d6, 400 MHz): dH 10.37 (s,
1H, NH), 8.53–8.49 (m, 4H, ArH), 7.92–7.86 (m, 3H, ArH), 7.74–7.03 (m, 1H,
ArH), 7.65–7.54 (m, 1H, ArH), 7.55 (dd, J = 7.6 Hz, J0 = 1.2 Hz, 1H, ArH), 7.40
(s, 1H, ArH), 7.31 (d, J = 8.4 Hz, 1H, ArH), 7.11–7.07 (m, 1H, ArH), 6.81 (d,
J = 7.6 Hz, 1H, ArH). IR (KBr): m 3376, 3056, 1670, 1656, 1589, 1551, 1434,
1375, 1358, 1248, 1196, 1069, 903, 848, 782, 750, 691, 679, 649 cm-1. HRMS
(ESI, m/z): Calcd for C25H14BrN2O2 [M-H]- 453.0239, found 453.0242.
30-(3-Chlorophenyl)-10H,2H-spiro[acenaphthylene-1,20-quinazoline]-2,40(30H)-dione
1
(3n) M.p. 209–210 °C; Rf = 0.65; H NMR (DMSO-d6, 400 MHz): dH 10.65 (s,
1H, NH), 8.54–8.49 (m, 4H, ArH), 7.92–7.88 (m, 3H, ArH), 7.77-7.73 (m, 1H,
ArH), 7.70–7.65 (m, 2H, ArH), 7.57 (dd, J = 8.0 Hz, J0 = 1.2 Hz, 1H, ArH), 7.49
(dd, J = 8.4 Hz, J0 = 1.2 Hz, 1H, ArH), 7.28–7.23 (m, 1H, ArH), 7.08–7.05 (m,
1H, ArH). IR (KBr): m 3346, 3055, 3009, 1672, 1656, 1588, 1535, 1476, 1424, 1375,
1359, 1248, 1204, 1070, 903, 872, 781, 754, 689, 649 cm-1. HRMS (ESI, m/z):
Calcd for C25H14ClN2O2 [M-H]- 409.0744, found 409.0755.
30-(4-Methoxyphenyl)-10H,2H-spiro[acenaphthylene-1,20-quinazoline]-2,40(30H)-dione
(3o) M.p. 223–225 °C; Rf = 0.70; 1H NMR (DMSO-d6, 400 MHz): dH 8.28–8.26
(m, 1H, ArH), 8.02–7.96 (m, 4H, ArH), 7.85–7.81 (m, 1H, ArH), 7.77 (s, 1H, NH),
7.76–7.71 (m, 2H, ArH), 7.34–7.29 (m, 1H, ArH), 6.83–6.79 (m, 2H, ArH), 6.65 (d,
J = 8.0 Hz, 1H, ArH), 6.58 (d, J = 9.2 Hz, 2H, ArH), 3.54 (s, 3H, OCH3). 13C
NMR (DMSO-d6, 100 MHz): dC 55.5, 79.8, 114.1, 114.4, 115.2, 118.4, 123.2,
123.8, 126.9, 128.0, 128.8, 129.36, 129.41, 130.2, 131.1, 133.0, 134.2, 136.3, 141.2,
146.3, 158.5, 162.8, 200.9. IR (KBr): m 3479, 3082, 3004, 2935, 2880, 1663, 1642,
1510, 1485, 1435, 1384, 1337, 1249, 1188, 1154, 1096, 1028, 997, 886, 830, 784,
123

Structurally diversified synthesis of…
758 cm-1. HRMS (ESI, m/z): Calcd for C26H17N2O3 [M-H]- 405.1239, found
405.1233.
30-p-Tolyl-10H,2H-spiro[acenaphthylene-1,20-quinazoline]-2,40(30H)-dione (3p) M.p.
1
221–222 °C; Rf = 0.71; H NMR (DMSO-d6, 400 MHz): dH 8.26 (d, J = 8.0 Hz,
1H, ArH), 8.01–7.95 (m, 3H, ArH), 7.84–7.81 (m, 1H, ArH), 7.78 (s, 1H, NH),
7.76–7.70 (m, 2H, ArH), 7.34–7.30 (m, 1H, ArH), 6.85–6.79 (m, 5H, ArH), 6.65 (d,
J = 8.0 Hz, 1H, ArH), 2.05 (s, 3H, CH3). IR (KBr): m 3238, 3096, 2927, 1657,
1624, 1512, 1485, 1435, 1335, 1258, 1191, 1117, 1095, 1023, 997, 886, 782, 770,
757, 694, 661, 520 cm-1. HRMS (ESI, m/z): Calcd for C26H17N2O2 [M-H]-
389.1296, found 389.1309.
30-(Naphthalen-2-yl)-10H,2H-spiro[acenaphthylene-1,20-quinazoline]-2,40(30H)-dione
1
(3q) M.p. 255–257 °C; Rf = 0.67; H NMR (DMSO-d6, 400 MHz): dH 10.67 (s,
1H, NH), 8.53–8.49 (m, 4H, ArH), 8.19 (d, J = 5.6 Hz, 1H, ArH), 7.95–7.92 (m,
1H, ArH), 7.91–7.87 (m, 2H, ArH), 7.80–7.73 (m, 3H, ArH), 7.70–7.66 (m, 2H,
ArH), 7.63 (dd, J = 8.8 Hz, J0 = 2.0 Hz, 1H, ArH), 7.58 (dd, J = 7.6 Hz,
J0 = 1.2 Hz, 1H, ArH), 7.41–7.33 (m, 2H, ArH). IR (KBr): m 3207, 3079, 3001,
1673, 1654, 1577, 1375, 1349, 1325, 1262, 1242, 1236, 1165, 1155, 1143, 1140,
989, 969, 829, 812, 805, 732, 655 cm-1. HRMS (ESI, m/z): Calcd for C29H17N2O2
[M-H]- 425.1290, found 425.1289.
10H,10H-spiro[phenanthrene-9,20-quinazoline]-40,10(30H)-dione (3r) M.p. 209–211 °C;
Rf = 0.51; 1H NMR (DMSO-d6, 400 MHz): dH 8.29 (s, 1H, NH), 8.25 (d,
J = 8.0 Hz, 1H, ArH), 8.21 (dd, J = 8.0 Hz, J0 = 1.2 Hz, 1H, ArH), 7.98–7.96 (m,
1H, ArH), 7.86 (dd, J = 7.6 Hz, J0 = 1.2 Hz, 1H, ArH), 7.82–7.78 (m, 1H, ArH),
7.66 (dd, J = 7.6 Hz, J0 = 1.2 Hz, 1H, ArH), 7.61–7.57 (m, 1H, ArH), 7.55 (dd,
J = 7.6 Hz, J0 = 1.2 Hz, 1H, ArH), 7.52–7.48 (m, 2H, ArH ? NH), 7.21–7.17 (m,
1H, ArH), 6.72–6.68 (m, 1H, ArH), 6.54 (d, J = 8.0 Hz, 1H, ArH). IR (KBr): m
3250, 3124, 3050, 1678, 1664, 1608, 1509, 1480, 1452, 1360, 1266, 1232, 1155,
1026, 982 cm-1. HRMS (ESI, m/z): Calcd for C21H13N2O2 [M-H]- 325.0983,
found 325.0980.
30-(4-Methoxybenzyl)-10H,10H-spiro[phenanthrene-9,20-quinazoline]-40,10(30H)-dione
(3s) M.p. 219–221 °C; Rf = 0.65; 1H NMR (DMSO-d6, 400 MHz): dH 8.30–8.27
(m, 2H, ArH), 7.81–7.78 (m, 2H, ArH), 7.77 (d, J = 1.2 Hz, 1H, ArH), 7.73 (dd,
J = 8.0 Hz, J0 = 1.2 Hz, 1H, ArH), 7.60 (s, 1H, NH), 7.57–7.53 (m, 1H, ArH),
7.47–7.44 (m, 1H, ArH), 7.33–7.29 (m, 1H, ArH), 7.24–7.20 (m, 1H, ArH),
6.77–6.75 (m, 1H, ArH), 6.73 (s, 1H, ArH), 6.71 (s, 1H, ArH), 6.58–6.54 (m, 2H,
ArH), 6.51 (d, J = 8.0 Hz, 1H, ArH), 4.30–4.13 (m, 2H, CH2), 3.61 (s, 3H, OCH3).
IR (KBr): m 3254, 3095, 3065, 2952, 2854, 1676, 1653, 1595, 1528, 1512, 1487,
1450, 1372, 1354, 1302, 1268, 1254, 1175, 1030, 925, 759, 731, 533 cm-1. HRMS
(ESI, m/z): Calcd for C29H21N2O3 [M-H]- 445.1558, found 445.1539.
30-(4-Bromophenyl)-10H,10H-spiro[phenanthrene-9,20-quinazoline]-40,10(30H)-dione
(3t) M.p. 240–241 °C; Rf = 0.63;1H NMR (DMSO-d6, 400 MHz): dH 8.20 (d,
J = 8.0 Hz, 1H, ArH), 8.09–8.05 (m, 2H, ArH), 7.97 (dd, J = 7.6 Hz, J0 = 1.6 Hz,
123

J. Wang et al.
1H, ArH), 7.83 (s, 1H, NH), 7.80 (dd, J = 8.0 Hz, J0 = 1.2 Hz, 1H, ArH), 7.73 (dd,
J = 8.0 Hz, J0 = 1.6 Hz, 1H, ArH), 7.58–7.74 (m, 1H, ArH), 7.40–7.33 (m, 2H,
ArH), 7.30–7.26 (m, 1H, ArH), 6.95–6.91 (m, 1H, ArH), 6.82 (d, J = 7.6 Hz, 1H,
ArH), 6.79–6.54 (m, 1H, ArH), 6.67 (s, 1H, ArH), 6.63 (d, J = 8.0 Hz, 1H, ArH),
6.47 (d, J = 8.0 Hz, 1H, ArH). IR (KBr): m 3242, 3061, 1678, 1635, 1614, 1598,
1508, 1486, 1405, 1348, 1267, 908, 688, 583, 532 cm-1. HRMS (ESI, m/z): Calcd
for C27H16BrN2O2 [M-H]- 479.0395, found 479.0375.
30-(4-Methoxyphenyl)-10H,10H-spiro[phenanthrene-9,20-quinazoline]-40,10(30H)-dione
1
(3u) M.p. 186–188 °C; Rf = 0.62; H NMR (DMSO-d6, 400 MHz): dH 8.20 (d,
J = 8.0 Hz, 1H, ArH), 8.10 (dd, J = 8.4 Hz, J0 = 1.6 Hz, 1H, ArH), 8.06 (dd,
J = 8.0 Hz, J0 = 1.6 Hz, 1H, ArH), 8.00 (dd, J = 7.6 Hz, J0 = 1.6 Hz, 1H, ArH),
7.83–7.79 (m, 1H, ArH), 7.80 (s, 1H, NH), 7.73 (dd, J = 7.6 Hz, J0 = 1.2 Hz, 1H,
ArH), 7.57–7.53 (m, 1H, ArH), 7.43–7.35 (m, 2H, ArH), 7.29–7.25 (m, 1H, ArH),
6.79–6.75 (m, 1H, ArH), 6.73–6.69 (m, 2H, ArH), 6.65–6.60 (m, 3H, ArH), 3.59 (s,
3H, OCH3). IR (KBr): m 3302, 3058, 2998, 2927, 1663, 1635, 1609, 1510, 1485,
1450, 1351, 1297, 1265, 1249, 1170, 1030, 894, 835, 811, 731, 583 cm-1. HRMS
(ESI, m/z): Calcd for C28H19N2O3 [M-H]- 431.1396, found 431.1389.
30-Benzyl-60-chloro-10H,10H-spiro[phenanthrene-9,20-quinazoline]-40,10(30H)-dione
1
(3v) M.p. 183–185 °C; Rf = 0.62; H NMR (DMSO-d6, 400 MHz): dH 8.28 (d,
J = 8.0 Hz, 2H, ArH), 7.84 (s, 1H, NH), 7.84–7.78 (m, 2H, ArH), 7.72–7.70 (m,
2H, ArH), 7.56–7.52 (m, 1H, ArH), 7.50–7.46 (m, 1H, ArH), 7.29–7.23 (m, 2H,
ArH), 7.07–7.03 (m, 3H, ArH), 6.86–6.84 (m, 2H, ArH), 6.57 (d, J = 8.8 Hz, 1H,
ArH), 4.44 (d, J = 15.6 Hz, 1H, CH2), 4.05 (d, J = 15.6 Hz, 1H, CH2). IR (KBr): m
3288, 3067, 2977, 2876, 1665, 1648, 1610, 1541, 1533, 1493, 1451, 1337, 1275,
1127, 927, 762, 730, 696, 533 cm-1. HRMS (ESI, m/z): Calcd for C28H18ClN2O2
[M-H]- 449.1062, found 449.1056.
60-Bromo-30-(4-fluorobenzyl)-10H,10H-spiro[phenanthrene-9,20-quinazoline]-40,10(30H)-
1
dione (3w) M.p. 251–253 °C; Rf = 0.59; H NMR (DMSO-d6, 400 MHz): dH
8.29–8.26 (m, 2H, ArH), 7.83–7.81 (m, 2H, ArH), 7.80 (s, 1H, ArH), 7.78 (s, 1H,
NH), 7.73 (dd, J = 8.0 Hz, J0 = 1.2 Hz, 1H, ArH), 7.57–7.53 (m, 1H, ArH),
7.48–7.44 (m, 1H, ArH), 7.38 (dd, J = 8.4 Hz, J0 = 2.4 Hz, 1H, ArH), 7.32–7.30
(m, 1H, ArH), 6.81 (d, J = 8.0 Hz, 2H, ArH), 6.69 (d, J = 8.0 Hz, 2H, ArH), 6.50
(d, J = 8.4 Hz, 1H, ArH), 4.31–4.27 (m, 1H, CH), 4.15–4.11 (m, 1H, CH). 13C
NMR (DMSO-d6, 100 MHz): dC 48.1, 75.5, 109.1, 116.7 (d, JF-C = 30.8 Hz), 124.3
(d, JF-C = 16.9 Hz), 127.5, 128.3, 128.58, 128.62, 129.4, 129.7 (d, JF-C = 5.6 Hz),
130.8, 131.2, 131.5, 133.9, 135.8, 136.1, 136.21, 132.27, 136.5, 143.6, 163.9 (d, JF-
= 220.1 Hz), 192.3. IR (KBr): m 3255, 3005, 2996, 2897, 1678, 1632, 1513, 1488,
C
1467, 1347, 1239, 1248, 1176, 1031, 890, 822, 758, 687, 519 cm-1. HRMS (ESI, m/
z): Calcd for C28H17BrFN2O2 [M-H]- 511.0463, found 511.0453.
60-Methyl-10H,10H-spiro[phenanthrene-9,20-quinazoline]-40,10(30H)-dione (3x) M.p.
1
161–163 °C; Rf = 0.51; H NMR (DMSO-d6, 400 MHz): dH 8.24–8.22 (m, 2H,
ArH ? NH), 8.19 (d, J = 8.0 Hz, 1H, ArH), 7.95 (dd, J = 7.2 Hz, J0 = 1.2 Hz,
1H, ArH), 7.84 (dd, J = 7.6 Hz, J0 = 0.8 Hz, 1H, ArH), 7.81–7.76 (m, 1H, ArH),
123

Structurally diversified synthesis of…
7.60–7.56 (m, 1H, ArH), 7.54 (dd, J = 7.6 Hz, J0 = 1.2 Hz, 1H, ArH), 7.51–7.48
(m, 2H, ArH), 7.32 (s, 1H, NH), 7.01 (dd, J = 8.4 Hz, J0 = 2.0 Hz, 1H, ArH), 6.54
(d, J = 8.4 Hz, 1H, ArH), 2.20 (s, 3H, CH3). IR (KBr): m 3265, 3109, 3062, 2998,
2857, 1675, 1645, 1598, 1559, 1482, 1438, 1351, 1295, 1257, 1089, 983, 814, 795,
730, 667, 530 cm-1. HRMS (ESI, m/z): Calcd for C22H15N2O2 [M-H]- 339.1134,
found 339.1143.
30-(4-Methoxyphenethyl)-10H,10H-spiro[phenanthrene-9,20-quinazoline]-40,10(30H)-
dione (3y) M.p. 205–207 °C; Rf = 0.63; 1H NMR (CDCl3, 400 MHz): dH
8.13–8.08 (m, 3H, ArH ? NH), 8.05 (d, J = 7.2 Hz, 2H, ArH), 7.75–7.13 (m,
1H, ArH), 7.64–7.60 (m, 2H, ArH), 7.57 (d, J = 7.6 Hz, 1H, ArH), 7.48–7.44 (m,
2H, ArH), 6.93–6.89 (m, 1H, ArH), 6.81 (d, J = 8.8 Hz, 2H, ArH), 6.67 (d,
J = 8.4 Hz, 2H, ArH), 6.45 (d, J = 8.0 Hz, 1H, ArH), 4.80 (s, 4H, 2CH2), 3.71 (s,
3H, CH3). IR (KBr): m 3312, 3009, 2981, 2844, 1669, 1652, 1420, 1349, 1256, 1089,
910, 890, 766, 725, 674, 563 cm-1. HRMS (ESI, m/z): Calcd for C30H23N2O3
[M-H]- 459.1709, found 459.1725.
2-Benzoyl-2-methyl-2,3-dihydroquinazolin-4(1H)-one (3z) M.p. 190–192 °C;
1
Rf = 0.42; H NMR (DMSO-d6, 400 MHz): dH 8.64 (s, 1H, NH), 7.93–7.91 (m,
2H, ArH), 7.60–7.56 (m, 2H, ArH ? NH), 7.54 (d, J = 8.8 Hz, 1H, ArH),
7.50–7.46 (m, 2H, ArH), 7.27–7.23 (m, 1H, ArH), 6.76 (d, J = 8.4 Hz, 1H, ArH),
6.69–6.66 (m, 1H, ArH), 1.68 (s, 3H, CH3). IR (KBr): m 3390, 3175, 3004, 2927,
1667, 1654, 1595, 1583, 1482, 1380, 1280, 1227, 1149, 1027, 957, 793, 780, 758,
714, 663, 580 cm-1. HRMS (ESI, m/z): Calcd for C16H13N2O2 [M-H]- 265.0977,
found 265.0988.
2-Benzoyl-3-(4-fluorobenzyl)-2-methyl-2,3-dihydroquinazolin-4(1H)-one (3aa) M.p.
1
215–217 °C; Rf = 0.58; H NMR (DMSO-d6, 400 MHz): dH 7.88–7.86 (m, 2H,
ArH), 7.83 (s, 1H, NH), 7.70 (dd, J = 8.0 Hz, J0 = 1.6 Hz, 1H, ArH), 7.59–7.55
(m, 1H, ArH), 7.48–7.43 (m, 2H, ArH), 7.32–7.26 (m, 3H, ArH), 7.14–7.08 (m, 2H,
ArH), 6.77–6.74 (m, 2H, ArH), 5.21 (d, J = 16.4 Hz, 1H, CH), 4.19 (d,
J = 16.4 Hz, 1H, CH), 1.74 (s, 3H, CH3). IR (KBr): m 3293, 3004, 2876, 1681,
1639, 1597, 1445, 1339, 1295, 1127, 1030, 978, 954, 808, 792, 758, 708, 697, 661,
637 cm-1. HRMS (ESI, m/z): Calcd for C23H18FN2O2 [M-H]- 373.1352, found
373.1355.
2-Benzoyl-2-methyl-3-(p-tolyl)-2,3-dihydroquinazolin-4(1H)-one (3ab) M.p. 209–
211 °C; Rf = 0.62; 1H NMR (DMSO-d6, 400 MHz): dH 8.05 (s, 1H, NH),
7.92–7.90 (m, 2H, ArH), 7.68 (dd, J = 7.6 Hz, J0 = 1.2 Hz, 1H, ArH), 7.60–7.56
(m, 1H, ArH), 7.49–7.45 (m, 2H, ArH), 7.32–7.28 (m, 1H, ArH), 7.21 (d,
J = 8.0 Hz, 2H, ArH), 7.13 (d, J = 8.0 Hz, 2H, ArH), 6.81–6.75 (m, 2H, ArH),
2.32 (s, 3H, CH3), 1.51 (s, 3H, CH3). 13C NMR (DMSO-d6, 100 MHz): dC 21.1,
24.2, 78.9, 114.9, 116.4, 118.8, 128.4, 128.9, 129.0, 129.8, 130.3, 132.8, 140.0,
135.7, 136.3, 137.4, 144.7, 164.0, 199.3. IR (KBr): m 3278, 3057, 2865, 2851, 1676,
1655, 1612, 1510, 1484, 1368, 1374, 1181, 1134, 953, 754, 669, 521 cm-1. HRMS
(ESI, m/z): Calcd for C23H19N2O2 [M-H]- 355.1447, found 355.1456.
123

J. Wang et al.
2-Benzoyl-2-methyl-3-phenyl-2,3-dihydroquinazolin-4(1H)-one (3ac) M.p. 205–
1
207 °C; Rf = 0.60; H NMR (DMSO-d6, 400 MHz): dH 8.11 (s, 1H, NH), 7.92 (d,
J = 7.2 Hz, 2H, ArH), 7.68 (d, J = 7.6 Hz, 1H, ArH), 7.61–7.57 (m, 1H, ArH),
7.50–7.46 (m, 2H, ArH), 7.44–7.41 (m, 2H, ArH), 7.37–7.31 (m, 2H, ArH),
7.29–7.26 (m, 3H, ArH), 6.81 (d, J = 8.0 Hz, 1H, ArH), 1.51 (s, 3H, CH3). IR
(KBr): m 3292, 3060, 2930, 2877, 1675, 1633, 1628, 1541, 1484, 1383, 1367, 1230,
1178, 1091, 955, 769, 698, 660 cm-1. HRMS (ESI, m/z): Calcd for C22H17N2O2
[M-H]- 341.1290, found 341.1280.
10H-Spiro[indene-2,20-quinazoline]-1,3,40(30H)-trione (3ad) M.p. 195-197 °C;
1
Rf = 0.41; H NMR (DMSO-d6, 400 MHz): dH 13.43 (s, 1H, NH), 12.76 (s, 1H,
NH), 8.18 (d, J = 7.6 Hz, 1H, ArH), 7.97 (d, J = 6.8 Hz, 1H, ArH), 7.83–7.78 (m,
2H, ArH), 7.75–7.71 (m, 1H, ArH), 7.66 (d, J = 7.2 Hz, 1H, ArH), 7.64–7.60 (m,
1H, ArH), 7.55 (d, J = 8.0 Hz, 1H, ArH). IR (KBr): m 3215, 3150, 3103, 3047,
1690, 1651, 1633, 1438, 1345, 1285, 1152, 907, 770, 755 cm-1. HRMS (ESI, m/z):
Calcd for C16H9O3N2 [M-H]- 277.0613, found 277.0613.
30-(2-(Benzo[d] [1, 3] dioxol-5-yl)ethyl)-10H-spiro[indene-2,20-quinazoline]-
1,3,40(30H)-trione (3ae) M.p. 220–221 °C; Rf = 0.52; 1H NMR (DMSO-d6,
400 MHz): dH 8.18–8.12 (m, 4H, ArH), 7.74 (s, 1H, NH), 7.72 (dd, J = 7.6 Hz,
J0 = 1.2 Hz, 1H, ArH), 7.31–7.27 (m, 1H, ArH), 6.83–6.79 (m, 1H, ArH), 6.67 (d,
J = 8.0 Hz, 1H, ArH), 6.58 (d, J = 8.0 Hz, 1H, ArH), 6.50 (d, J = 1.2 Hz, 1H,
ArH), 6.41 (dd, J = 8.0 Hz, J0 = 1.6 Hz, 1H, ArH), 5.90 (s, 2H, OCH2O),
3.26–3.22 (m, 2H, CH2), 2.68–2.62 (m, 2H, CH2). IR (KBr): m 3243, 3009, 2966,
2891, 1677, 1651, 1634, 1503, 1488, 1445, 1329, 1250, 1159, 1099, 924, 808, 757,
748, 694, 660 cm-1. HRMS (ESI, m/z): Calcd for C25H17N2O5 [M-H]- 425.1137,
found 425.1149.
30-(4-Bromophenyl)-10H-spiro[indene-2,20-quinazoline]-1,3,40(30H)-trione
(3af)
1
M.p. 217–218 °C; Rf = 0.50; H NMR (DMSO-d6, 400 MHz): dH 8.09–8.06 (m,
2H, ArH), 8.04–8.01 (m, 2H, ArH), 7.97 (s, 1H, NH), 7.73 (dd, J = 7.6 Hz,
J0 = 1.2 Hz, 1H, ArH), 7.49–7.46 (m, 2H, ArH), 7.40–7.35 (m, 1H, ArH),
6.92–6.88 (m, 2H, ArH), 6.87–6.83 (m, 1H, ArH), 6.68 (d, J = 8.0 Hz, 1H, ArH).
IR (KBr): m 3258, 3089, 3044, 1654, 1649, 1633, 1598, 1515, 1445, 1357, 1331,
1262, 1197, 1157, 1066, 887, 754, 690, 636, 529 cm-1. HRMS (ESI, m/z): Calcd for
C22H12N2O3Br [M-H]- 431.0031, found 431.0054.
30-p-Tolyl-10H-spiro[indene-2,20-quinazoline]-1,3,40(30H)-trione (3ag) M.p. 212–
1
214 °C; Rf = 0.54; H NMR (DMSO-d6, 400 MHz): dH 8.05–8.02 (m, 2H, ArH),
8.01–7.97 (m, 2H, ArH), 7.88 (s, 1H, NH), 7.72 (dd, J = 7.6 Hz, J0 = 1.2 Hz, 1H,
ArH), 7.36 (d, J = 7.6 Hz, 1H, ArH), 7.04 (d, J = 8.0 Hz, 2H, ArH), 6.85–6.81 (m,
3H, ArH), 6.66 (d, J = 8.0 Hz, 1H, ArH), 2.17 (s, 3H, CH3). IR (KBr): m 3308,
3028, 2922, 2890, 1670, 1647, 1628, 1594, 1510, 1488, 1432, 1348, 1287, 1254,
1228, 1155, 1020, 886, 808, 753, 739, 651, 520 cm-1. HRMS (ESI, m/z): Calcd for
C23H15N2O3 [M-H]- 367.1083, found 367.1106.
123

Structurally diversified synthesis of…
60-Bromo-30-(4-fluorobenzyl)-10H-spiro[indene-2,20-quinazoline]-1,3,40(30H)-trione
(3ah) M.p. 251–253 °C; Rf = 0.50; 1H NMR (DMSO-d6, 400 MHz): dH
8.03–8.01 (m, 2H, ArH), 7.95 (s, 1H, NH), 7.90–7.86 (m, 2H, ArH), 7.83 (d,
J = 2.4 Hz, 1H, ArH), 7.46 (dd, J = 8.4 Hz, J0 = 2.4 Hz, 1H, ArH), 6.76 (s, 4H,
ArH), 6.58 (d, J = 8.8 Hz, 1H, ArH), 4.54 (s, 2H, CH2). IR (KBr): m 3247, 3007,
2944, 2880, 1678, 1635, 1627, 1499, 1411, 1376, 1319, 1294, 1277, 1263, 1241,
1158, 1126, 911, 896, 825, 776, 752, 726, 667, 529 cm-1. HRMS (ESI, m/z): Calcd
for C23H13BrFN2O3 [M-H]- 463.0099, found 463.0109.
30-(4-Fluorophenyl)-10H-spiro[indene-2,20-quinazoline]-1,3,40(30H)-trione (3ai) M.p.
1
211–212 °C; Rf = 0.50; H NMR (DMSO-d6, 400 MHz): dH 8.07–8.04 (m, 2H,
ArH), 8.02–7.99 (m, 2H, ArH), 7.93 (s, 1H, NH), 7.73 (dd, J = 7.6 Hz,
J0 = 1.2 Hz, 1H, ArH), 7.39–7.35 (m, 1H, ArH), 7.13–7.07 (m, 2H, ArH),
7.01–6.96 (m, 2H, ArH), 6.85–6.82 (m, 1H, ArH), 6.67 (d, J = 8.0 Hz, 1H, ArH).
IR (KBr): m 3236, 3015, 1678, 1651, 1643, 1598, 1427, 1354, 1234, 1220, 1155,
1094, 786, 749, 739, 670, 526 cm-1. HRMS (ESI, m/z): Calcd for C22H12N2O3F
[M-H]- 371.0832, found 371.0830.
30-(2-Bromophenyl)-10H-spiro[indene-2,20-quinazoline]-1,3,40(30H)-trione (3aj) M.p.
1
220–222 °C; Rf = 0.56; H NMR (DMSO-d6, 400 MHz): dH 8.11–8.10 (m, 1H,
ArH), 8.09 (d, J = 0.8 Hz, 1H, ArH), 8.06–8.02 (m, 1H, ArH), 7.94 (s, 1H, NH),
7.91 (d, J = 7.6 Hz, 1H, ArH), 7.75 (dd, J = 7.6 Hz, J0 = 1.6 Hz, 1H, ArH), 7.66
(dd, J = 8.0 Hz, J0 = 2.0 Hz, 1H, ArH), 7.40–7.36 (m, 1H, ArH), 7.19–7.11 (m,
2H, ArH), 6.88–6.84 (m, 1H, ArH), 6.74 (dd, J = 7.6 Hz, J0 = 1.6 Hz, 1H, ArH),
6.71 (d, J = 8.0 Hz, 1H, ArH). IR (KBr): m 3223, 3080, 3011, 1668, 1651, 1633,
1487, 1388, 1355, 1338, 1228, 1194, 1106, 1032, 888, 795, 756, 689, 662,
619 cm-1. HRMS (ESI, m/z): Calcd for C22H12N2O3Br [M-H]- 431.0031, found
431.0054.
30-(4-Fluorophenyl)-60-methyl-10H-spiro[indene-2,20-quinazoline]-1,3,40(30H)-trione
(3ak) M.p. 208–210 °C; Rf = 0.50; 1H NMR (DMSO-d6, 400 MHz): dH
8.06–8.03 (m, 2H, ArH), 8.01–7.98 (m, 2H, ArH), 7.75 (s, 1H, NH), 7.55 (d,
J = 1.6 Hz, 1H, ArH), 7.20 (dd, J = 8.0 Hz, J0 = 1.6 Hz, 1H, ArH), 7.13–7.07 (m,
2H, ArH), 7.00–6.95 (m, 2H, ArH), 6.60 (d, J = 8.0 Hz, 1H, ArH), 2.26 (s, 3H,
CH3). IR (KBr): m 3228, 3089, 2973, 2876, 1678, 1636, 1629, 1598, 1481, 1353,
1264, 1230, 1217, 1157, 848, 819, 760, 654, 589, 527 cm-1. HRMS (ESI, m/z):
Calcd for C23H14FN2O3 [M-H]- 385.0994, found 385.0984.
30-(3,4-Dimethoxyphenyl)-10H-spiro[indene-2,20-quinazoline]-1,3,40(30H)-trione (3al)
1
M.p. 227–228 °C; Rf = 0.52; H NMR (DMSO-d6, 400 MHz): dH 8.06–8.03 (m,
2H, ArH), 8.02–7.98 (m, 2H, ArH), 7.85 (s, 1H, NH), 7.73 (dd, J = 8.0 Hz,
J0 = 1.6 Hz, 1H, ArH), 7.38–7.34 (m, 1H, ArH), 6.85–6.81 (m, 1H, ArH), 6.77 (d,
J = 8.4 Hz, 1H, ArH), 6.67 (d, J = 8.0 Hz, 1H, ArH), 6.48 (d, J = 2.4 Hz, 1H,
ArH), 6.43 (dd, J = 8.4 Hz, J0 = 2.4 Hz, 1H, ArH), 3.64 (s, 3H, OCH3), 3.55 (s,
3H, OCH3). IR (KBr): m 3316, 3044, 2954, 2937, 1666, 1643, 1631, 1512, 1487,
1354, 1331, 1249, 1217, 1137, 1026, 883, 799, 778, 763, 654, 640 cm-1. HRMS
(ESI, m/z): Calcd for C24H17N2O5 [M-H]- 413.1143, found 413.1151.
123

J. Wang et al.
70-Chloro-30-(4-methylbenzyl)-10H-spiro[indene-2,20-quinazoline]-1,3,40(30H)-tri-
1
one (3am) M.p. 225–226 °C; Rf = 0.51; H NMR (DMSO-d6, 400 MHz): dH
8.04–8.01 (m, 2H, ArH), 7.98 (s, 1H, NH), 7.89–7.87 (m, 2H, ArH), 7.77 (d,
J = 8.4 Hz, 1H, ArH), 6.86 (dd, J = 8.4 Hz, J0 = 2.0 Hz, 1H, ArH), 6.76 (s, 4H,
ArH), 6.60 (d, J = 1.6 Hz, 1H, ArH), 4.53 (s, 2H, CH2), 2.09 (s, 3H, CH3). 13C
NMR (DMSO-d6, 100 MHz): dC 20.9, 45.6, 73.6, 113.7, 114.0, 119.1, 124.5, 128.8,
129.2, 130.1, 132.6, 137.1, 138.1, 138.7, 139.3, 146.8, 162.9, 194.4. IR (KBr): m
3298, 3062, 2942, 2921, 1676, 1657, 1645, 1560, 1514, 1482, 1440, 1376, 1349,
1316, 1260, 1234, 934, 885, 797, 748, 683, 545, 516 cm-1. HRMS (ESI, m/z):
Calcd for C24H16ClN2O3 [M-H]- 415.0855, found 415.0841.
Supporting information available
NMR spectra of 3 are available free of charge via the internet. The crystal data of
3a, 3o, 3w, 3ab, and 3am have been deposited at the Cambridge Crystallographic
Data Centre and have been assigned to the eposition numbers as CCDC
1474919–1474923. Copies of available material can be obtained, free of charge,
on application to the director, CCDC, 12UnionRoad, Cambridge CB21EZ, UK,
(fax: ?44-(0)-1223-336033 or e-mail: deposit@ccdc.cam.ac.uk).
Acknowledgements We are grateful to the National Natural Science foundation of China (20802061),
the Major Natural Science Foundation of Jiangsu Province (14KJA150004), and a project funded by the
Priority Academic Program Development of Jiangsu Higher Education Institutions for financial support.
References
1. E.A. Henderson, V. Bavetsias, D.S. Theti, S.C. Wilson, R. Clauss, A.L. Jackman, Bioorg. Med.
Chem. 14, 5020 (2006)
2. T.C. Chien, C.S. Chen, F.H. Yu, J.W. Chern, Chem. Pharm. Bull. 52, 1422 (2004)
3. Y.S. Lee, H.K. Park, J.Y. Lee, B.S. Yang, S.H. Suh, Preparation of 4-phenylamino-[1,4]dioxano[2,3-
g]quinazolines as tyrosine kinase inhibitors. Jpn. Kokai Tokkyo Koho 2003, JP 2003026682 A
20030129
4. G.F. Xu, B.A. Song, P.S. Bhadury, S. Yang, P.Q. Zhang, L.H. Jin, W. Xue, D.Y. Hu, P. Lu, Bioorg.
Med. Chem. 15, 37682 (2007)
5. P.R. Marsham, L.R. Hughes, A.L. Jackman, A.J. Hayter, J. Oldfield, J.M. Wardleworth, J.A.M.
Bishop, B.M. O’Connor, A.H. Calvert, J. Med. Chem. 34, 1594 (1991)
6. K. Waisser, J.V. Gregor, H. Dostal, J. Kunes, L. Kubicova, V. Klimesova, J. Kaustova, Farmaco 56,
803 (2001)
7. I. Khan, A. Ibrar, N. Abbas, A. Saeed, Eur. J. Med. Chem. 76, 193 (2014)
8. I. Khan, A. Ibrar, W. Ahmed, A. Saeed, Eur. J. Med. Chem. 90, 124 (2015)
9. I. Khan, S. Zaib, S. Batool, N. Abbas, Z. Ashraf, J. Iqbal, A. Saeed, Bioorg. Med. Chem. 24, 2361
(2016)
10. T.M. Maiden, J.P. Harrity, Org. Biomol. Chem. 14, 8014 (2016)
11. B. Moy, P. Kirkpatrick, S. Kar, P. Goss, Nat. Rev. Drug Discov. 6, 431 (2007)
12. J.B. Koepfli, J.F. Mead, J.A. Brockman, J. Am. Chem. Soc. 69, 1837 (1947)
13. J.B. Koepfli, J.F. Mead, J.A. Brockman, J. Am. Chem. Soc. 69, 1848 (1947)
14. S. Yoshida, T. Aoyagi, S. Harada, N. Matsuda, T. Ikeda, H. Naganawa, M. Hamada, T. Takeuchi, J.
Antibiot. 441, 111 (1991)
15. Z.Z. Ma, Y. Hano, T. Nomura, Y.J. Chen, Heterocycles 46, 541 (1997)
16. Y.H. Deng, R. Xu, Y. Yang, J. Chin. Pharm. Sci. 9, 116 (2000)
123

Structurally diversified synthesis of…
17. C. Wattanapiromsakul, P.I. Forster, P.G. Waterman, Phytochemistry 64, 609 (2003)
18. R.J. Alaimo, H.E. Russell, J. Med. Chem. 15, 335 (1972)
19. F. Liu, X. Chen, A. Allali-Hassani, A.M. Quinn, T.J. Wigle, G.A. Wasney, A. Dong, G. Senisterra, I.
Chau, A. Siarheyeva, J. Med. Chem. 53, 5844 (2010)
20. J.W. Lockman, B.R. Murphy, D.F. Zigar, W.R. Judd, P.M. Slattum, Z.H. Gao, K. Ostanin, J. Green,
R. McKinnon, R.T. Terry-Lorenzo, J. Med. Chem. 53, 8734 (2010)
21. I. Beria, D. Ballinari, J.A. Bertrand, D. Borghi, T. Bossi Roberto, M.G. Brasca, P. Cappella, M.
Caruso, W. Ceccarelli, A. Ciavolella, J. Med. Chem. 53, 3532 (2010)
22. L.-Y. Zeng, C. Cai, J. Heterocycl. Chem. 47, 1035 (2010)
23. J. Chen, W. Su, H. Wu, M. Liu, C. Jin, Green Chem. 9, 972 (2007)
24. D. Rambabu, S.K. Kumar, B.Y. Sreenivas, S. Sandra, A. Kandale, P. Misra, M.V.B. Rao, M. Pal,
Tetrahedron Lett. 54, 495 (2013)
25. G.-C. Arash, T. Tahereh, Lett. Org. Chem. 8, 470 (2011)
26. P.V. Murthy, D. Rambabu, G.R. Krishna, C.M. Reddy, K.R.S. Prasad, M.V.B. Rao, M. Pal, Tetra-
hedron Lett. 53, 863 (2012)
27. N.B. Darvatkar, S.V. Bhilare, A.R. Deorukhkar, D.G. Raut, M.M. Salunkhe, Green Chem. Lett. Rev.
3, 301 (2010)
28. P.P. Naidu, A. Raghunadh, K.R. Rao, R. Mekala, J.M. Babu, B.R. Rao, V. Siddaiah, M. Pal, Synth.
Commun. 44, 1475 (2014)
29. A. Shaabani, A. Maleki, H. Mofakham, Synth. Commun. 38, 3751 (2008)
30. K.R. Rao, R. Mekala, A. Raghunadh, S.B. Meruva, S.P. Kumar, D. Kalita, E. Laxminarayana, B.
Prasad, M. Pal, RSC Adv. 5, 61575 (2015)
31. K.R. Rao, A. Raghunadh, R. Mekala, S.B. Meruva, T.V. Pratap, T. Krishna, D. Kalita, E. Laxmi-
narayana, B. Prasad, M. Pal, Tetrahedron Lett. 55, 6004 (2014)
32. A. Davoodnia, S. Allameh, A.R. Fakhari, N. Tavakoli-Hoseini, Chin. Chem. Lett. 21, 550 (2010)
33. X.S. Wang, K. Yang, J. Zhou, S.J. Tu, J. Comb. Chem. 12, 417 (2010)
34. X.S. Wang, J. Sheng, L. Lu, K. Yang, Y.L. Li, Acs Comb. Sci. 13, 196 (2011)
35. L. Lu, M.M. Zhang, H. Jiang, X.S. Wang, Tetrahedron Lett. 54, 757 (2013)
36. M.M. Zhang, L. Lu, X.S. Wang, J. Heterocycl. Chem. 51, 1363 (2014)
37. L.H. Wang, P. Wang, Guangxi Qinggongye 10, 33 (2009)
38. M. Bakavoli, O. Sabzevari, M. Rahimizadeh, Chin. Chem. Lett. 18, 533 (2007)
123