Synthesis of pyrazolopyrimidinones as sildenafil derivatives and sclerotigenin

Article abstract of DOI:10.1080/00397911.2018.1459720

A series of novel pyrazolo pyrimidinone derivatives (3(a–d), 4(a–d), and 6(a–d)) was synthesized from various pyrazolo amides (2a–d) which are synthesized by the reaction between ethyl 5-amino-3-methyl-1-phenyl-1H-pyrazole-4-carboxylate (1) and various lithium amides. In addition, we also described the synthesis of sclerotigenin drug molecule which has quinazoline moiety from simple 2-nitro benzoic acid with high yields.

Full text of DOI:10.1080/00397911.2018.1459720

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Synthesis of pyrazolopyrimidinones as sildenafil
derivatives and sclerotigenin
Hoon Gu Heo, Jin Yu, Raveendra Jillella & Chang Ho Oh
To cite this article: Hoon Gu Heo, Jin Yu, Raveendra Jillella & Chang Ho Oh (2018) Synthesis of
pyrazolopyrimidinones as sildenafil derivatives and sclerotigenin, Synthetic Communications, 48:13,
1678-1687, DOI: 10.1080/00397911.2018.1459720
To link to this article: https://doi.org/10.1080/00397911.2018.1459720
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SYNTHETIC COMMUNICATIONS®
2018, VOL. 48, NO. 13, 1678–1687
https://doi.org/10.1080/00397911.2018.1459720
Synthesis of pyrazolopyrimidinones as sildenafil derivatives
and sclerotigenin
Hoon Gu Heo, Jin Yu, Raveendra Jillella, and Chang Ho Oh
Department of Chemistry, Hanyang University, Sungdong-gu, Seoul, Korea
ABSTRACT
ARTICLE HISTORY
Received 6 January 2018
A series of novel pyrazolo pyrimidinone derivatives (3(a–d), 4(a–d),
and 6(a–d)) was synthesized from various pyrazolo amides (2a–d)
which are synthesized by the reaction between ethyl 5-amino-3-
methyl-1-phenyl-1H-pyrazole-4-carboxylate (1) and various lithium
amides. In addition, we also described the synthesis of sclerotigenin
drug molecule which has quinazoline moiety from simple 2-nitro
benzoic acid with high yields.
KEYWORDS
n-Heteropolycycle;
pyrazolopyrimidinone;
quinazolinone; sildenafil
GRAPHICAL ABSTRACT
Introduction
In recent years, pyrazolo pyrimidine derivatives and their related fused heterocylces have
received significant attention due to pharmaceutical utility as purine analogues.[1] Among
these, pyrazolo[3,4-d]pyrimidinone derivatives such as Sildenafil and Allopurinol (Fig. 1)
are of great importance because they have possessed antiviral,[2] antimicrobial,[3]
anti-inflammatory,[4] anticancer,[5] xanthine oxidase inhibitor,[6] herbicide,[7] adenosine
receptors (A3) antagonists,[8] phosphodiesterase (PDE) inhibitor[9] properties. By considering
these properties, synthesis of pyrazolo[3,4-d]-pyrimidinones have enormous roles in biological
applications. Recently, our research group has developed first time on total synthesis of
dictyopyrazole A–C (Fig. 1),[10] which is a natural alkaloid having quinazolinone moiety
similar with pyrazolopyrimidinone drug molecules but not have pyrazole ring (Fig. 1).
As per the literature, Khaled. et al.[11] reported the synthesis of N-substituted Pyrazolo
[3,4-d]pyrimidin-4-one derivatives through 3,6-dimethyl-1-phenyl-1H-pyrazolo[3,4-d]
CONTACT Chang Ho Oh
changho@hanyang.ac.kr
Department of Chemistry, Hanyang University, Wangsimniro 222,
Sungdong-gu, Seoul 04763, Korea.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplementary data for this article can be accessed on the publisher’s website.
© 2018 Taylor & Francis

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Figure 1. Pyrazolopyrimidinones and dictyoqunazole A.
[1,3]oxazin-4-one as an intermediate. Sagar et al.[12] and Wang et al.[13] reported the
biological study of the pyrazolopyrimidinone derivatives. However, due to the enormous
importance of pyrazolopyrimidinone derivatives, to the best of our knowledge, herein
we have described new pyrazolo[3,4-d]pyrimidinone derivatives with moderate to good
yields from ethyl 5-amino-3-methyl-1-phenyl-1H-pyrazole-4-carboxylate as a starting
substrate, which can be prepared by simple and easy method (Scheme 1).
In addition based on our previous method,[14] we also synthesized one more biologically
important drug sclerotigenin that contains quinzolinone skeleton (Scheme 5). This
alkaloid is a family of benzodiazepine-quinazolinones, and naturally isolated from the
plant sclerotia of Penicillium sclerotigeni.[15] Several researchers reported the synthesis of
sclerotigenin and its derivatives.[16] However, harsh reaction conditions, unsatisfactory
yields, unavailability of the starting materials, and utilization of expensive reagents and
catalysts are the disadvantages in many of these methods. Hence, it is time to develop
inexpensive and environment-friendly synthetic routes to commercialize this highly
biological active molecule. So, in this communication we reported simple and
efficient synthetic routes for sclerotigenin from easily available starting material 2-nitro
benzoic acid.
Results and discussion
Our synthesis is commenced with the preparation of the required substrate ethyl 5-amino-
3-methyl-1-phenyl-1H-pyrazole-4-carboxylate (1), which is a useful substrate for the
preparation of all fused pyrazolopyrimidinones. The starting pyrazole carboxylate (1)
was synthesized from ethyl cyanoacetate and trimethyl orthoacetate in methanol, produced
intermediate (x), then after reaction with phenyl hydrazine in ethanol under reflux
conditions as shown in Scheme 1.[17]
The synthesis of target compounds is outlined in Schemes 2 and 3. As shown in
Scheme 2, primarily pyrazole amides (2a–d) were prepared by the reaction between (1)

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H. HEO ET AL.
Scheme 1. Synthetic route for starting precursor (1) for synthesis of target molecules. (a) Methanol, rt,
2 h, (b) ethanol, 4 h, reflux.
Scheme 2. Synthesis for pyrazolo[3,4-d]pyrimidinones. (a) Aryl amine, n-BuLi (b) formic acid, acetic
acid, and chloroacetyl chloride.
and lithium amides. The lithium amides derived by reacting n-butyl lithium with
substituted anilines. The yields of corresponding amides, which are shown in Fig. 2,
(2a–2d) are 41–62%, respectively. For the synthesis of the corresponding pyrazolo[3,4-d]
pyrimidin-4-ones (3, 4, and 6), the obtained amides (2a–d) were subjected to various acids
such as formic acid, acetic acid, and chloroacetyl chloride.
According to Scheme 3, pyrazolopyrimidinone compounds (3a–d) were prepared using
precursors 2a–d by the reaction with formic acid under reflux and obtained moderate to
good yields about 48–88%, whereas the compounds 4a–d were synthesized by the reaction
of 2a–d with acetic acid (yields 41–62%) as shown in Scheme 3. In contrast, pyrazolopyr-
imidinone compounds 6a–d were synthesized in two steps. First step, the reaction of 2a–d
with chloroacetyl chloride in the presence of triethylamine produced (5a–d) with yields of
42–64%. Second step is as follows: The formed 5a–d undergoes cyclocondensation in the
presence of dehydrating reagent, i.e., trimethyl aluminum Al(CH3)3 in dichloroethane
(DCE) under reflux for 6 h and finally afford to 6a–d with 37–69% yields as shown in
Scheme 3.
In continuing our study, we also synthesized a Sildenafil derivative 11, which has
pyrazolopyrimidinone skeleton. 5-Amino-3-methyl-1-phenyl-1H-pyrazole-4-carboxamide
7 was synthesized from 1 by reaction with ammonia. Substrate 7 is transformed into 8
by the reaction with acetic anhydride under reflux condition. On the other hand,
Figure 2. Diverse precursors of pyrazolo[3,4-d]pyrimidinones.

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Scheme 3. Synthetic pathway for target compounds 3a–d, 4a–d, and 6a–d from 2a–d. (a) HCOOH, 130 °C
(b) ClCOCH2Cl, Et3N (c) Al(CH3)3, DCE, reflux (d) CH3COOH, 150–180 °C, or Ac2O. Note: DCE,
dichloroethane.
Scheme 4. Synthesis of sildenafil derivative. (a) aq Ammonia, 12 h, (b) 2-ethoxybenzoyl chloride, 47%
(c) HOSO2Cl, 53% (d) N-methyl piperazine, 84% (e) Ac2O, 61%.
Scheme 5. Synthesis of sclerotigenin. (a) ethyl 2-aminobenzoate, oxalyl chloride, DMF (10 mol%), pyri-
dine (2.7 eq.), DCE, rt, 4 h, 91% (b) 10% Pd/C (10 wt%), H2 (1 atm), MeOH, EtOAc, rt, 12 h, 97% (c) MeOH,
EtOAc rt, 12 h, Et3N (2.0 eq.), DCM, rt, 1 h 95% (d) p-TsOH (2.0 eq.), benzene, reflux, overnight, 60% (e)
7N NH3 solution in methanol 70 °C, 2 h, 98%. Note: DCE, dichloroethane; DCM, dichloromethane; DMF,
dimethylformamide.

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H. HEO ET AL.
compound 7 treated with 2-ethoxybenzoyl chloride obtained 9. We performed further
transformation of 9 into 10 by chlosulfonation in 53% yield. Finally, Sildenafil derivative
11 was obtained from compound 10 by substitution with N-methylpiperazine under mild
conditions with 844% yield (Scheme 4).
Based on these above enthusiastic results, we elaborated our method for the synthesis of
useful naturally occurring alkaloid, sclerotigenin (17). Our synthesis began with amide
coupling of commercially available 12 (2-nitro benzoic acid) and ethyl 2-amino benzoate
which afford 13 in quantitative yield. With gram quantities of 13 on hand further
proceeded to reduction of nitro group to amine in the presence of palladium on carbon
followed by amide coupling with chloroacetyl chloride afforded compound 15,[18] which
undergoes cyclization in the presence of p-TsOH and gives substituted benzoquinazolinone
16.[19] Finally, the targeted sclerotigenin[20] (17) was synthesized from compound 16 by
reacting with ammonia solution in MeOH (Scheme 5).
Conclusion
In conclusion, we have developed a novel and efficient method for the synthesis of
biologically active Sildenafil derivative and other pyrazolopyrimidinone derivatives. We
also elaborated our method for the synthesis of sclerotigenin alkaloid. Inexpensive starting
materials and reagents are the advantages in this method. Biological studies of our
heteropolycyclic compounds are now in progress for their anticancer study.
Experimental section
General procedure for synthesis of compounds (2a–d) and (3a–d)
In a round-bottomed flask, the solution of aniline (1.5 mmol) in dried tetrahydrofuran
(THF) (0.3 M) was stirred under argon atmosphere at −78 °C. After 10 min, n-BuLi
(2.5 mmol) was added to the stirring solution at −78 °C dropwise using cannula. Then after
10 min, to this stirring solution was added compound 1 (1.0 mmol) dropwise using 2-mL
syringe in THF under argon atmosphere. The reaction mixture was stirred for 2–4 h by
monitoring TLC of the reaction periodically. After completion of the reaction, mixture
was quenched by water, saturated ammonium chloride, extracted with dichloromethane
(DCM), and washed with brine. The crude mixture was dried over MgSO4 and filtered
and concentrated under vacuum. The crude mixture was purified by flash column
chromatography (SiO2, EA/Hex ¼ 1:2) to afford the pure product 2a as a solid.
In a round-bottomed flask, a substrate 2a (1.0 mmol) and acids stirred for 6–24 h under
reflux condition by monitoring TLC of the reaction periodically. The reaction mixture was
quenched by water, neutralized with 1 M NaOH, and then extracted with EA, washed
with brine. The crude mixture was dried over MgSO4 and filtered and concentrated under
vacuum. The crude mixture was purified by flash column chromatography (SiO2, EA/
Hex ¼ 1:2) to afford the pure product 3a.
5-amino-3-methyl-N,1-diphenyl-1H-pyrazole-4-carboxamide (3a)
White solid, yield 41%, mp 135–137 °C; IR (KBr, cm−1) 1694, 1570, 1542, 1506, 1224, 786,
1
692; H NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 8.03 (d, J ¼ 7.6 Hz, 2H), 7.57–7.50 (m,
5H), 7.40–7.34 (m, 3H), 2.69 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 157.8, 151.5, 149.2,

SYNTHETIC COMMUNICATIONS®
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147.8, 138.4, 137.0, 129.7, 129.4, 129.3, 127.40, 127.2, 122.2, 105.8, 13.8; HRMS (ESI)
[MþH]þ calcd for C18H15N4O: 303.116, found 303.113.
General procedure for synthesis of compounds (4a–d)
In a round-bottomed flask, a substrate 2a–d (1.0 mmol) and acetic acid were stirred for
6–24 h under reflux by monitoring TLC of the reaction periodically. After the completion
of the reaction, the mixture was quenched by water, neutralized with 1 M NaOH, extracted
with EA, washed with brine. The crude mixture was dried over MgSO4 and filtered and
concentrated under vacuum. The crude mixture was purified by flash column chromato-
graphy (SiO2, EA/Hex ¼ 1:2) to afford the pure product (4a–d) yield 88–48%.
Synthesis of 3,6-dimethyl-1,5-diphenyl-1H-pyrazolo[3,4-d]pyrimidin-4(5h)
-one (4a)
White solid, yield 88%, mp 155–157 °C; IR (KBr, cm−1) 2931, 1714, 1566, 1495, 1319, 754,
1
707; H NMR (400 MHz, CDCl3) δ 8.09 (d, J ¼ 8.0 Hz, 2H), 7.58–7.54 (m, 3H), 7.52–7.48
(m, 3H), 7.33 (t, J ¼ 7.4 Hz, 1H), 7.24 (s, 1H), 2.64 (s, 3H), 2.26 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 159.3, 158.3, 151.4, 147.5, 138.7, 137.6, 130.1, 129.5, 129.2, 128.3, 126.8,
122.0, 104.2, 25.0, 13.6; HRMS (ESI) [MþH]þ calcd for C19H17N4O: 317.132, found
317.135.
General procedure for synthesis of compounds (6a–d)
In a round-bottomed flask, the solution of compound 2a (1.0 mmol) and triethylamine
(2.0 mmol) in dried DCM (0.2 M) cooled to 0 °C, and to this stirring was added chloroa-
cetyl chloride (2.5 mmol) after 5 min at 0 °C. The reaction mixture was kept under argon
atmosphere and stirred for 24 h under reflux condition; the reaction mixture was cooled to
room temperature. The reaction mixture was quenched by water, extracted with DCM,
washed with saturated ammonium chloride and brine. The crude mixture was dried over
MgSO4 and filtered and concentrated under reduced pressure. The crude mixture was
purified by flash column chromatography (SiO2, EA/Hex ¼ 1:2) to afford the pure product
5a as a solid.
In a round-bottomed flask, the solution of compound 5a (1.0 mmol) in dried DCE
(0.1 M) was taken and to this trimethylaluminum (3.0 mmol) was added dropwise at
0 °C, followed by stirring for 3 h at room and after the completion of the reaction cooled
to room temp. The reaction mixture was quenched by water, neutralized with 1 M HCl,
extracted with EA, and washed with saturated ammonium chloride and brine. The crude
mixture was dried over MgSO4 and filtered and concentrated under vacuum. The crude
mixture was recrystallized from methanol to afford the pure product 6a as a yellow solid.
Synthesis of 6-(chloromethyl)-3-me thyl-1,5-diphenyl-1H-pyrazolo[3,4-d]
pyrimidin-4(5h)-one (6a)
1
Yellow solid, yield 37%, mp 186–188 °C; IR (KBr, cm−1) 1695, 1551, 1514, 759, 707; H
NMR (400 MHz, CDCl3) δ 8.10 (d, J ¼ 8.4 Hz, 2H), 7.57 (d, J ¼ 6.4 Hz, 3H), 7.51 (t, J ¼ 7.6,
2H), 7.35 (t, J ¼ 6.8 Hz, 3H), 4.25 (s, 2H), 2.65 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
158.89, 155.01, 150.59, 147.7, 148.5, 135.7, 130.0, 130.0, 129.2, 128.9, 127.1, 122.0, 104.8,
43.7, 13.6; HRMS (ESI) [MþH]þ calcd for C19H16ClN4O: 351.093, found 351.090.

1684
H. HEO ET AL.
Synthesis of 3,6-dimethyl-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (8)
In a round-bottomed flask, the solution of compound 7 (1.0 mmol), dimethylaminopyri-
dine (DMAP) (3 mol%), and triethylamine (2.2 mmol) in dried dimethylformamide
(DMF) was taken and followed by the addition of acetic anhydride at 0 °C through 1-ml
syringe. The reaction mixture was stirred for 24 h under reflux condition. The reaction
mixture was cooled to room temp and then quenched with water, extracted with DCM,
washed with saturated ammonium chloride and brine. The crude mixture was dried over
MgSO4 and filtered and concentrated under vacuum. The crude mixture was recrystallized
from EA/Hex or ether to afford the pure products 8 (61%) as a pale brown solid. mp >300 °C;
1
IR (KBr, cm−1) 2852, 1677, 1592, 1504, 732, 652; H NMR (400 MHz, DMSO-d6) δ 12.23
(s, 1H), 8.02 (d, J ¼ 7.6 Hz, 2H), 7.52 (t, J ¼ 7.5 Hz, 2H), 7.34 (t, J ¼ 7.0 Hz, 1H), 2.50 (s,
3H), 2.38 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 158.7, 158.6, 152.9, 145.7, 138.4,
129.1, 126.4, 121.3, 103.7, 21.5, 13.3; HRMS (ESI) [MþH]þ calcd for C13H13N4O:
241.101, found 241.098.
Synthesis of 6-(2-ethoxyphenyl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-
4(5H)-one (9)
In a round-bottomed flask, the solution of compound 7 (1.0 mmol), DMAP (3 mol%), and
triethylamine (2.2 mmol) in dried DMF of 5 mL was stirred at 0 °C. To this solution was
added 2-ethoxybenzoyl chloride (2.0 mmol) dropwise using 1-mL syringe at 0 °C, and then
followed by reflux for 24 h. The reaction mixture was cooled to room temp followed by
quenching with water, extracted with DCM, washed with brine. The crude mixture was
dried over MgSO4 and filtered and concentrated under vacuum. The crude mixture was
recrystallized from EA/Hex or ether to afford the pure products 9 (47%) as a white solid.
1
mp 144–146 °C IR (KBr, cm−1) 3080, 2978, 2929, 2217, 1686, 1543, 1484, 1302, 756; H
NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 8.19 (d, J ¼ 6.4 Hz, 1H), 7.51 (t, J ¼ 8.0 Hz,
1H), 7.46 (d, J ¼ 7.6 Hz, 2H), 7.40 (t, J ¼ 7.6 Hz, 2H), 7.35 (d, J ¼ 6.8 Hz, 1H), 7.09 (t, J ¼
7.6 Hz, 1H), 6.96 (d, J ¼ 8.4 Hz, 1H), 4.09-4.04 (q, J ¼ 6.8 Hz, 2H), 2.55 (s, 3H), 1.14 (t,
J ¼ 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 165.6, 165.5, 157.4, 149.8, 138.5, 135.1,
134.7, 133.0, 129.3, 128.3, 124.5, 121.5, 119.4, 112.6, 111.6, 65.2, 14.2, 14.1; HRMS (ESI)
[MþH]þ calcd for C20H19N4O2: 347.143, found 347.147.
Synthesis of 4-ethoxy-3-(3-methyl-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]
pyrimidin-6-yl)benzene-1-sulfonyl chloride (10)
In a round-bottomed flask, to the solution of a chlorosulfonic acid (0.2 M) was added com-
pound 9 (1.0 mmol) in DCM (0.3 M) dropwise using 5-ml syringe under argon atmosphere
at 0 °C. The reaction mixture was stirred for 1 h at 0 °C, 1 h at room. The reaction mixture
was poured into ice water carefully and extracted with DCM, washed with brine. The crude
mixture was dried over MgSO4 and filtered and concentrated under vacuum. The crude
mixture was recrystallized from EA/Hex to afford the pure product 10 (53%) as a white
solid. mp 146–148 °C; IR (KBr, cm−1) 3073, 2985, 2940, 2222, 1689, 1548, 1291, 1176,
1
769, 581; H NMR (400 MHz, CDCl3) δ 9.84 (s, 1H), 8.97 (d, J ¼ 2.4 Hz, 1H), 8.15 (dd,
J ¼ 9.2 Hz, 2.4 Hz, 1H), 7.55–7.45 (m, 5H), 7.15 (d, J ¼ 8.8 Hz, 1H), 4.20 (d, J ¼ 6.8 Hz,
2H), 2.47 (s, 3H), 1.10 (t, J ¼ 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 161.2, 160.0,

SYNTHETIC COMMUNICATIONS®
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152.8, 138.9, 137.8, 137.2, 133.3, 133.2, 130.0, 129.6, 125.1, 120.7, 113.7, 113.3, 88.6, 66.9,
13.8, 13.2; HRMS (ESI) [MþH]þ calcd for C20H18ClN4O4S: 445.065, found 445.068.
Synthesis of 6-(2-ethoxy-5-((4-methylpiperazin-1-yl)sulfonyl)phenyl)-3-methyl-1-
phenyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (11)
To the solution of compound 10 (1.0 mmol) in dry THF (0.1 M) was added 1-methylpiper-
azine (2.0 mmol) at 0 °C. The reaction mixture was stirred for 2 h at room temperature
And then quenched with water and extracted with DCM, washed with brine. The crude
mixture was dried over MgSO4 concentrated under vacuum. The crude mixture was
recrystallized from ether to afford the pure product 11(84%) as a white solid. mp 190–
1
192 °C; IR (KBr, cm−1) 3070, 2938, 2853, 2799, 2223, 1686, 1549, 1282, 1154, 920; H
NMR (400 MHz, CDCl3) δ 9.96 (s, 1H), 8.61 (s, 1H), 7.85 (d, J ¼ 8.8 Hz, 1H), 7.55–7.47
(m, 5H), 7.06 (d, J ¼ 8.8 Hz, 1H), 4.11 (q, J ¼ 6.8 Hz, 2H), 3.01 (s, 4H), 2.47 (s, 7H),
2.26 (s, 3H), 1.02 (t, J ¼ 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 160.6, 159.7, 152.7,
139.2, 137.1, 134.0, 133.2, 129.9, 129.5, 128.6, 125.2, 119.8, 113.2, 88.2, 66.3, 54.0, 46.1,
45.7, 13.7, 13.2; HRMS (ESI) [MþH]þ calcd for C25H29N6O4S: 509.189, found 509.191.
Synthesis of ethyl 2-(2-(2-chloroacetamido)benzamido)benzoate (15)
To the compound 14(1.0 mmol) in DCM was added trimethylamine (2.0 mmol) and
chloroacetyl chloride (2.0 mmol) at 0 °C under argon atmosphere. The reaction mixture
was refluxed for 1 h. The crude was diluted with NH4Cl, extracted with DCM, washed with
NaHCO3 and brine, dried over anhydrous MgSO4. The organic phase was concentrated
under reduced pressure, and the residue was recrystallized from methanol to afford the
pure product 15 (95%) as a pale brown solid. mp 118–121 °C; IR (KBr, cm−1) 1666,
1
1585, 1525, 1438, 1262; H NMR (400 MHz, CDCl3) δ 12.13 (brs, NH), 11.99 (brs, NH),
8.84 (dd, J ¼ 9.2, 0.8 Hz, 1H), 8.66 (dd, J ¼ 9.2, 0.8 HZ, 1H), 8.12 (dd, J ¼ 9.6, 1.6 Hz,
1H), 7.91 (dd, J ¼ 9.2, 1.2 Hz, 1H), 7.63 (td, J ¼ 7.2, 1.6 Hz, 1H), 7.58 (td, J ¼ 7.2 Hz,
1.6 Hz, 1H), 4.42 (q, J ¼ 7.2 Hz, 2H), 4.20 (s, 2H), 1.43 (t, J ¼ 7.2 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 168.7, 167.6, 165.3, 141.3, 139.3, 134.9, 133.1, 131.2, 127.4, 124.3,
123.4, 121.8, 120.9, 116.1, 61.9, 43.5, 14.3; HRMS (ESI) [MþH]þ calcd for C18H18ClN2O4:
361.087, found 361.090.
Synthesis of ethyl 2-(2-(chloromethyl)-4-oxoquinazolin-3(4H)-yl)benzoate (16)
To the compound 15 (1.0 mmol) in benzene, p-TsOH (2.0 mmol) under nitrogen presence.
The mixture was refluxed for 12 h and concentrated under reduced pressure followed by
diluted with water, extracted with ether, washed with NaHCO3, and dried over MgSO4.
The organic phase was concentrated under reduced pressure, and the residue was
recrystallized from ethyl acetate and hexane to afford the pure product 16 (60%) as a pale
1
yellow solid. mp 158–162 °C; IR (KBr, cm−1) 1686, 1602, 1359, 1272; H NMR (400 MHz,
CDCl3) δ 8.29–8.23 (m, 2H), 7.81–7.74 (m, 3H), 7.67–7.65 (m, 1H), 7.55–7.46 (m, 2H), 4.34
(d, J ¼ 12 Hz, 1H), 4.15-4.09 (m, 3H), 1.00 (t, J ¼ 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 164.6, 162.4, 151.7, 147.2, 136.1, 134.9, 133.9, 132.5, 131.3, 130.3, 128.8, 127.9, 127.8,
127.3, 121.4, 61.8, 43.8, 13.8; HRMS (ESI) [MþH]þ calcd for C18H16ClN2O3: 343.077,
found 343.074.

1686
H. HEO ET AL.
Synthesis of 6,7-dihydrobenzo[6,7][1,4]diazepino[2,1-b]quinazoline-5,
13-dione (17)
To the compound 16 in a sealed tube was added 7N ammonia solutions in methanol. The
mixture was heated at 70 °C for 2 h. Then, the mixture was evaporated under reduced
pressure and recrystallized from ethyl acetate to afford the pure product 17 (98%) as a pale
1
yellow solid. mp 268–272 °C; IR (KBr, cm−1) 1685, 1612, 1461, 1356, 1251; H NMR
(400 MHz, CDCl3) δ 8.34 (dd, J ¼ 9.2, 1.2 Hz, 1H), 7.97 (d, J ¼ 7.6 Hz, 1H), 7.82 (td,
J ¼ 8.4, 1.6 Hz, 1H), 7.69 (d, J ¼ 7.6 Hz, 1H), 7.65–7.61 (m, 2H), 7.58–7.53 (m, 2H), 6.58
(brs, NH), 4.36–4.20 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 168.1, 161.4, 153.6, 146.3,
135.1, 133.8, 131.5, 130.4, 129.8, 129.1, 128.1, 127.9, 127.6, 127.3, 121.5 47.1; HRMS
(ESI) [MþH]þ calcd for C16H12N3O2: 278.0851, found 278.0848.
Funding
Financial support was provided by a grant from the National Research Foundation of Korea
(NRF-2014R1A5A1011165) funded by the Korean Government, through the Center for New Direc-
tions in Organic Synthesis.
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