Direct halogenation reactions in 2,3-dihydro-4(1H)-quinazolinones

Article abstract of DOI:10.3987/COM-12-12473

Reaction of 2,3-dihydro-4(1H)-quinazolinones with NBS, Br ₂/Et₃N and NCS yields 6,8-Br/Cl-2,3-dihydro-4(1H)- quinazolinones with moderate to good yield. The method does not require a catalyst and offers extremely short reaction time.

Full text of DOI:10.3987/COM-12-12473

HETEROCYCLES, Vol. 85, No. 9, 2012
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HETEROCYCLES, Vol. 85, No. 9, 2012, pp. 2173 - 2195. © 2012 The Japan Institute of Heterocyclic Chemistry
Received, 23rd March, 2012, Accepted, 2nd July, 2012, Published online, 10th July, 2012
DOI: 10.3987/COM-12-12473
DIRECT HALOGENATION REACTIONS IN
2,3-DIHYDRO-4(1H)-QUINAZOLINONES
Fanny A. Cabrera-Rivera, a Claudia Ortíz-Nava, a Perla Román-Bravo, a
Marco A. Leyva, b and Jaime Escalantea,*
a
Chemical Research Center, Morelos Autonomous State University, Av.
Universidad No. 1001, Col. Chamilpa, C. P. 62209, Cuernavaca, Mor., Mexico
b
Tel: +52 (777) 3 29 70 00, Ext. 6040. CINVESTAV-I.P.N, Chemistry
Department, Av. Instituto Politécnico Nacional 2508, Col. San Pedro Zacatenco,
C.P. 07000, México D.F., Mexico
E-mail: jaime@ciq.uaem.mx
Abstract – Reaction of 2,3-dihydro-4(1H)-quinazolinones with NBS, Br2/Et3N
and NCS yields 6,8-Br/Cl-2,3-dihydro-4(1H)-quinazolinones with moderate to
good yield. The method does not require a catalyst and offers extremely short
reaction time.
INTRODUCTION
2,3-Dihydro-4(1H)-quinazolinones form an important class of bioactive compounds and these can easily
be oxidized to their quinazolin-4(3H)-one analogues.1 In general, the derivatives of the quinazolinones are
considered as an important building blocks2 for a large number of diverse alkaloids3 and present a wide
range of biological and pharmaceutical activities.4 In addition, numerous efforts of synthesis have been
made to obtain halogenated quinazolinones for their pharmacophoric effect.5 For example, the
incorporation of a fluorine or chlorine atom into an active compound results in beneficial changes in
molecular properties such as higher fat solubility giving different absorption and transport rate, altered
electronic effects, improved stability, and equivalent steric size.6 On the other hand, quinazolinones
halogenated with bromine have shown their importance as building blocks in the synthesis of compounds
with biological activity.7
In the literature, to obtain halogenated quinazolinones one first treats anthranilic acid (a) with bromine in
presence of acetic acid or sulfuryl chloride to form the mono- and di-halogenated derivatives b and c,

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HETEROCYCLES, Vol. 85, No. 9, 2012
respectively. The cyclocondensation of c with an anhydride or an acyl chloride affords benzoxazin-4-one
d, which under condensation conditions with an amine gives 4(3H)-quinazolinone halogenated e with
moderate to good yields (Scheme 1).8
O
X
OH
O
NH2
b
OH
i or ii
+
O
O
N
O
NH2
O
X
X
X
R2
R1
a
OH
NH2
O
N
R2NH2
R1CCl
pyridine
reflux
R1
N
i: Br2 / AcOH, 12 h
ii: SO2Cl2 / Et2O
X
X
X
c
e
d
X = Br or Cl
Scheme 1. Synthesis of halogenated quinazolinones from anthranilic acid
However, it is also reported that direct halogenation of 4(3H)-quinazolinones using iodine monochloride
and bromine in acetic acid leads to 6-iodo/bromo-4(3H)-quinazolinones derivatives.9
In this work we describe the synthesis of 6,8-bromo/cloro-2,3-dihydro-4(1H)-quinazolinones through the
direct halogenation.
RESULTS AND DISCUSSION
The synthesis of the derivatives of 2,3-dihydro-4(1H)-quinazolinones 4-8 and 10 was carried out
according to the method previously reported by our research group;10 the reaction of isatoic anhydride
with different amines yields the aminobenzamides 1-3. Direct cyclocondensation with the appropriate
aldehyde in dichloromethane and p-TsOH as catalyst afford the quinazolinones 4-8 (Scheme 2, Table 1);
it is important to mention that the reactions were carried out in the absence of light because of the
sensitive of quinazolinones.11
O
O
O
O
R1
R1
R3
O
R1NH2
AcOEt
N
N
R2
R3
H
N
H
O
NH2
N
H
R2
1, R1 = Bn, 90%
2, R1 = Ph, 96%
3, R1 = p-MeOC6H4, 92%
4-8
Scheme 2. Synthesis of 2,3-dihydro-4(1H)-quinazolinones 4-8

HETEROCYCLES, Vol. 85, No. 9, 2012
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Relevant information on the conformation in the 4(1H)-quinazolinone 5 is shown in Figure 1. In all
crystal structures, the N(1)-atom is shown to be only slightly or not at all pyramidalized (!-conjugation is
stronger than n " #* interaction).12
Table 1. Synthesis of 2,3-dihydro-4(1H)-quinazolinones 4-8
Compound
R1
R2
R3
Yielda (%)
4
5
6
7
8
Bn
Ph
t-Bu
t-Bu
H
H
H
H
86
97
94
83
68
p-MeOC6H4 t-Bu
Bn
Bn
Ph
Me Me
a: Yield after flash chromatography.
Figure 1. Crystal structure of 2-tert-butyl-3-phenyl-2,3-dihydro-4(1H)-quinazolinone (5)
3-Benzyl-2,3-dihydro-4(1H)-quinazolinone 10 was obtained by the cyclocondensation reaction of 1 with
ethyl orthoformate in toluene followed by the direct reduction of 9 with 2 equiv of NaBH4 in THF/MeOH
in 88% yield (Scheme 3).10
O
O
N
O
N
Ph
N
Ph
N
Ph
HC(OEt)3
NaBH4
H
toluene, 3 h
THF / MeOH, 2 h
NH2
N
H
1
9, 98%
10, 88%
Scheme 3. Synthesis of quinazolinone 10

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HETEROCYCLES, Vol. 85, No. 9, 2012
Halogenation reactions
Bromination Reactions
The 3-benzyl-2-tert-butyl-2,3-dihydro-4(1H)-quinazolinone 4 was selected as a model substrate to
perform the experimental conditions for the halogenation reactions (Table 2). Brominations reactions
were carried out using NBS or Br2/Et3N in CHCl3 at 68 mM. As shown in Table 2, with h! and NBS in
only 15 min afford a mixture of 4a (59%) and 4b (41%, entry 1). If the reaction is carried out under
thermal conditions, we obtained 73% of 4a, however, additional product was also detected (4b and 9,
entry 2). After considerable experimentation, we found that the best yield for 4a (87%) is obtained when
bromine and triethylamine at 50 oC (entry 3) were employed.
Table 2. Bromination reaction for 4
Entry Condition NBS (equiv) Br2 (equiv)
Et3N (equiv)
Time (min)
Yield (%)a
4a
59
73
87
4b
41
11
-
9
-
1
2
3
h!
2.2
2.2
-
-
-
-
-
15
30
30
50 oC
50 oC
14
-
2.7
1.1
a Yield after column chromatographic purification.
In order to explain the formation of 4b, the compound 4a was irradiated with h! and after 49 h, 4b was
isolated in 77% yield. However, when the compound 9 was treated with NBS and h!, the halogenation
reaction did not proceed (Scheme 4). These experiments confirmed that compound 4b was formed via 4a.
The elimination of t-Bu group of 4 and 4a in presence of NBS and h! is thought to occur through free
radicals mechanism.11

HETEROCYCLES, Vol. 85, No. 9, 2012
2177
Scheme 4
The halogenation of the aromatic ring at C-6 and C-8 occurs as a typical SEAr reaction and the mechanism
is shown in Scheme 5.
Scheme 5. Mechanism for the halogenation of 2,3-dihydroquinazolin-4(1H)-one 4
We treated the compounds 5–8 and 10 with 2.7 equiv of Br2, 1.1 equiv of Et3N at 50 °C in the absence of
light; the results are summarized in Scheme 6 and Table 3.
As shown in Table 3, quinazolinone 5 afforded 5a in 91% yield (entry 1). Quinazolinone 6 afforded a
mixture of 6a (64% yield) and only traces of 6c and 6d (entry 2). However, when the reaction was carried
o
out at 50 C with the quinazolinone 7 the reaction time was very short (1 min, entry 3) and we did not
observed 7a; in this case compounds 7b and 7d were obtained in 60 and 38% yield respectively (entry 3).

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HETEROCYCLES, Vol. 85, No. 9, 2012
Scheme 6. Bromination reaction for 5-8 and 10
Table 3. Bromination reactions for 5–8 and 10
Time
(min)
Entry QNZ
R1
Yield (%)a
R2
Conditions
50 ºC
Br2 /Et3N
50 ºC
Ph
15
3
5a, 91
6a, 64
7a, -
5b, -
5c, -
6cb
5d, -
6db
1
2
3
4
5
6
7
5
6
t-Bu
t-Bu
Ph
6b, -
7b, 60
7b, -
p-MeOC6H4
Br2 /Et3N
50 °C
Bn
Bn
Bn
Bn
Bn
1
7c, -
7c, 55
8cb
7d, 38
7d, -
8d, -
7
Br2 /Et3N
r. t.
1
7a, 39
8a, 86
10a, -
10a, -
7
Ph
Br2 /Et3N
r. t.
1
8b, -
8
Me
H
Br2 /Et3N
r. t.
1
10b, 11 10c, 11 10d, 57
10
10
Br2 /Et3N
0 ºC
1
10b, -
10c, 38
10d, -
H
Br2 /Et3N
a Yield after column chromatographic purification. b This product was observed in traces

HETEROCYCLES, Vol. 85, No. 9, 2012
2179
When the reaction was carried out at room temperature, however the compound 7a was obtained only
with moderate yield (39%) and 7c (55%, entry 4). The bromination reaction of 8 was also very fast and
heating was not necessary; compound 8a was obtained in 86% yield with traces of 8c (entry 5).
Quinazolinone 10 behaved very similar to 7, and unfortunately 10a was not obtained under these
conditions. Furthermore, compound 10a was readily converted in excellent yield (97%) by the
halogenations-elimination reaction of 4 to 4b, which was reduced with NaBH4 in THF/MeOH to give 10a
(Scheme 7).
Scheme 7. Halogenation-elimination and reduction reactions of 4 to obtain 10a
In order to explain the stability of 10a and 10c, these quinazolinones were treated with 1.1 equiv of Et3N
at room temperature, and after 30 min TLC showed only starting materials. However, when 2.7 equiv of
Br2 was added, the reaction instantaneously gave 10b and 10d, respectively (Scheme 8a). On the other
hand, when we added only Br2 to the compound 10a, immediate preciptiation of the salt of 10b and in
presence of water gave the quinazolinone 10b (Scheme 8b). These experiments confirmed that 10a and
10c are sensitive to Br2.
Scheme 8. Stability of 10a and 10c
On the basis of the above results and by referring to the literature13 we propose that the elimination of
hydrogen on the position 2 of the compounds 7a, 7c, 10a, and 10c would be carried out through
heterolytic process, according to the mechanism shown in Scheme 9.

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HETEROCYCLES, Vol. 85, No. 9, 2012
Scheme 9. Mechanism reaction for the elimination for 7a, 7c, 10a, and 10c in C(2)
Recrystallization of quinazolinones 5a, 6a, and 7c yielded a suitable crystals for X-ray diffraction
analysis. The observed structures and solid-state conformations are presented in Figures 2-4. Salient
feature in these crystallographic structures is the pyramidalized of N(1)-atom.
Chlorination Reactions
Chlorination reactions of 4-8 and 10 were carried out using NCS at 68 mM in chloroform (Scheme 10 and
Table 4).
In these reactions we observed the formation of mono-halogenated compounds in the position 8 in
addition to mono-halogenation in position 6, as observed in the bromination reaction above.
Figure 2. Crystal structure of 6,8-dibromo-2-tert-
butyl-3-phenyl-2,3-dihydro-4(1H)-quinazolinone
(5a)
Figure 3. Crystal structure of 6,8-dibromo-2-
tert-butyl-3-(4-methoxyphenyl)-2,3-dihydro-4-
(1H)-quinazolinone (6a)
Figure 4. Crystal structure of 3-benzyl-6-bromo-2-phenyl-2,3-dihydro-4(1H)-quinazolinone (7c)

HETEROCYCLES, Vol. 85, No. 9, 2012
2181
Scheme 10. Chlorination reactions of 4-8 and 10
Table 4. Chlorination reactions for 4–8 and 10
Time
(h)
Entry
QNZ
R1
R2
Conditions
Yield (%)
50 ºC
1
2
3
4
5
6
4
5
Bn
Ph
t-Bu
t-Bu
3.0
0.5
4e, 90
5e, 44
6e, 52
7e, 60b
8e, 48c
10e, 62
4f, 4
5f, -
4g, -
4h, 2
NCS (4.2 Eq)
50 ºC
NCS (2.2 Eq)
5g, 21a 5h, 37a
50 ºC
NCS (2.2 Eq)
6
p-MeOC6H4 t-Bu
1.0
6f, 12
7f, 29
8f, -
6g, -
7g, -
6h, -
7h, -
8h, -
10h, -
hv
7
Bn
Ph
Me
H
0.5
NCS (2.2 Eq)
hv
8
2.0
8g, -
NCS (2.2 Eq)
Bn
Bn
50 ºC
NCS (2.2 Eq)
10
0.25
10f, -
10g, -
a
The products 5g and 5h were isolated from a second reaction carried out at 15 min. b When the reaction was carried out at
50 oC, the product 7e was isolated at 43%. c When the reaction was carried out at 50 oC any product was isolated.
Recrystallization of quinazolinones 4e, 4h, 6e, and 6h afforded a suitable crystals for X-ray diffraction
analysis shown in Figures 5-8 respectively.

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HETEROCYCLES, Vol. 85, No. 9, 2012
Figure 5. Crystal structure of 3-benzyl-2-tert-
Figure 6. Crystal structure of 3-benzyl-2-tert-
butyl-8-chloro-2,3-dihydro-4(1H)-quinazolinone
(4h)
butyl-6,8-dichloro-2,3-dihydro-4(1H)-quinazolin-
one (4e)
Figure 7. Crystal structure of 2-tert-butyl-
Figure 8. Crystal structure of 2-tert-butyl-8-
chloro-3-(4-methoxyphenyl)-2,3-dihydro-4(1H)-
quinazolinone (6h)
6,8-dichloro-3-(4-methoxyphenyl)-2,3-dihydro-4-
(1H)-quinazolinone (6e)
Iodination reaction
Finally, the reaction of 4 with 2.2 equiv of NIS did not yield any halogenated product, and quinazolinone
9 was isolated in good yield (88%) in only 6 min (Scheme 11). It is important to mention that the
elimination reaction with h! conditions takes place in approximately 6 h.11
O
O
h!
N
Ph
N
Ph
CHCl3
NIS
N
N
H
6 min
9, 88%
4
Scheme 11

HETEROCYCLES, Vol. 85, No. 9, 2012
2183
In conclusion, we have reported the synthesis of halo-2,3-dihydro-4(1H)-quinazolinones derivatives
through direct halogenations, without catalyst, with faster reaction time and with moderate to good yields.
EXPERIMENTAL
All chemicals were obtained commercially (Aldrich) and were used without purification. Solvents were
dried using standard techniques. Reactions were monitored by thin layer chromatography, on aluminium
plates coated with silica gel with fluorescent indicator (60 F254). Separations by chromatography were
performed on silica gel (70-230 and 230-400 mesh). The reactions with microwaves were carried out in
Discover CEM equipment. The photochemical reactions were carried out in a Rayonet equipment
RPR-100 (UV light 254nm). Melting points were measured in open capillary tubes using a Melt-temp
Electrothermal apparatus, and are uncorrected. Elemental analyses were obtained on a Elementar Vario
EL III. High resolution MS measurements were obtained on a MStation JMS-700 JEOL apparatus. The
structures of X-ray were obtained using APEX-Brucker apparatus. NMR spectra were taken with a Varian
Gemini and Varian Oxford at 200 and 400 MHz (1H) and 100 and 50 MHz (13C) using CDCl3 as the
solvent with TMS as internal standard.
General procedure for the synthesis of aminobenzamides (GP-1).
A suspension of isatoic anhydride and 1.1 equiv of aryl- or benzylamine in EtOAc was stirred and heated
at 40 ºC or irradiated in microwave for the appropriate time. After completion of the reaction, which was
indicated by TLC (eluent hexane:EtOAc 6:4), the brown solution was filtered in a Büchner funnel packed
with a layer of celite and activated charcoal, then the colorless solution was concentrated under reduced
pressure.
2-Amino-N-benzylbenzamide (1)
A suspension of isatoic anhydride (10 g, 62 mmol) and 1.1 equiv of benzylamine in 50 mL of EtOAc was
stirred and heated according to GP-1 for 1.3 h. The reaction was purified by flash chromatography giving
12.7 g (90%) of 1 as white crystals; mp 121–123 ºC. 1H NMR (CDCl3, 400 MHz): ! (ppm): 4.55 (d, J =
5.6 Hz, 2H, CH2), 5.26 (br s, 2H, NH2), 6.50 (br, 1H, NH), 6.59 (t, Jortho = 7.4 Hz, 1H, C5-H), 6.65 (d, Jortho
= 8.4 Hz, 1H, C3-H), 7.18 (t, Jortho = 7.8 Hz, 1H, C4-H), 7.24–7.35 (m, 6H, C6-H, Ph); 13C NMR (CDCl3,
100 MHz): ! (ppm) 43.8, 115.8, 116.7, 117.4, 127.2, 127.5, 128.8, 132.4, 138.3, 148.8, 169.2. Anal. Calcd
for C14H14N2O: C, 74.29; H, 6.24; N, 12.38. Found: C, 74.28; H, 6.21; N, 12.38.
2-Amino-N-phenylbenzamide (2)
A suspension of isatoic anhydride (5 g, 30.6 mmol) and 1.1 equiv of aniline in 20 mL of EtOAc were
irradiated in the microwave in open system with 65-80 Watts at 90 ºC, for 4 h. The reaction was purified

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HETEROCYCLES, Vol. 85, No. 9, 2012
by flash chromatography yielding 6.25 g (96%) of 2 as cream solid; mp 124–126 ºC. 1H NMR (CDCl3,
200 MHz): ! (ppm) 5.30 (br s, 2H, NH2), 6.62-6.70 (m, 2H, C5-H, C3-H), 7.08-7.56 (m, 7H, C4-H, C6-H
and Ph), 7.85 (br s, 1H, NH); 13C NMR (CDCl3, 50 MHz): ! (ppm) 116.4, 116.9, 117.6, 120.7, 124.6,
127.3, 129.1, 132.8, 137.9, 148.9, 167.7. Anal. Calcd for C13H12N2O: C, 73.56; H, 5.70; N, 13.20. Found:
C, 73.40; H, 5.63; N, 13.11.
2-Amino-N-(4-methoxyphenyl)benzamide (3)
A suspension of isatoic anhydride (1.63 g, 10 mmol) and 1 equiv of 4-methoxyaniline (1.23 g) in 20 mL
of EtOAc were irradiated in the microwave in open system with 65-80 Watts at 90 ºC, for 2.5 h. The
reaction was purified by flash chromatography yielded 2.22 g (92%) of 3 as cream solid; mp 118–121 ºC.
1H NMR (CDCl3, 200 MHz): ! (ppm) 3.77 (s, 3H, -OCH3), 5.46 (br s, 1H, NH2), 6.61-6.69 (m, 2H, C3-H,
C5-H), 6.86 (d, 2H, Jortho 9.2 Hz, C3´-H), 7.21 (td, Jortho = 7.9 Hz, Jmeta = 1.6 Hz, 1H, C4-H), 7.36-7.45 (m,
3H, C6-H, C2´-H), 7.79 (br s, 1H, NH);13C NMR (CDCl3, 50 MHz): ! (ppm) 55.7, 114.3, 116.4, 116.9,
117.5, 122.8, 127.3, 130.9, 132.6, 148.9, 156.7, 167.7. Anal. Calcd for C14H14N2O2: C, 69.41; H, 5.82; N,
11.56. Found: C, 69.23; H, 5.71; N, 11.87.
General procedure for the synthesis of 2,3-dihydro-4(1H)-quinazolinones (GP-2).
A solution of aminobenzamide in CH2Cl2 was added 1.2 equiv of appropriate aldehyde and then was
added 2-5% by weight of p-TsOH; the reactions were carried out in the absence of light because the
quinazolinones are sensitive.11 Colorless solution was refluxed for the appropriate time. The reaction was
monitored by TLC (hexane:EtOAc 6:4). The straw yellow solution was concentrated and the crude of
reaction was purified by flash chromatography eluting with hexane:EtOAc 9:1 - 6:4.
3-Benzyl-2-tert-butyl-2,3-dihydro-4(1H)-quinazolinone (4)
A solution of aminobenzamide 1 (6 g, 26.5 mmol) in 100 mL of CH2Cl2 was added 3.26 mL (1.2 equiv) of
pivalaldehyde and then was added 0.12 g (2% by weight) of p-TsOH. The colorless solution was refluxed
for 5 h according to GP-2. The crude of reaction was purified by flash chromatography yielding 6.7 g
(86%) of 4 as white solid; mp 140–143 ºC. 1H NMR (CDCl3, 400 MHz): ! (ppm): 0.87 (s, 9H, t-Bu), 3.92
(d, J = 15.6 Hz, 1H, CH2), 4.24 (d, J = 3.2 Hz, 1H, C2-H), 4.40 (br d, J = 3.2 Hz, 1H, NH-1), 5.81 (d, J =
15.2 Hz, 1H, CH2), 6.49 (d, Jortho = 8 Hz, 1H, C8-H), 6.73 (t, Jortho = 7.5 Hz, 1H, C6-H), 7.20-7.34 (m, 6H,
C7-H y Ph), 7.85 (dd, Jortho = 7.8 Hz, Jmeta = 1.2 Hz, 1H, C5-H);13C NMR (CDCl3, 100 MHz): ! (ppm)
26.6, 42.0, 51.4, 75.7, 113.3, 116.6, 118.1, 127.3, 127.4, 128.5, 128.7, 133.6, 137.4, 146.6, 163.8. Anal.
Calcd for C19H22N2O: C, 77.52; H, 7.53; N, 9.52. Found: C, 77.61; H, 7.46; N, 9.30.
2-tert-Butyl-3-phenyl-2,3-dihydro-4(1H)-quinazolinone (5)

HETEROCYCLES, Vol. 85, No. 9, 2012
2185
A solution of aminobenzamide 2 (6.25 g, 29.5 mmol) in 100 mL of CH2Cl2 was added 3.84 mL (1.2
equiv) of pivalaldehyde and then was added 0.31 g (5% by weight) of p-TsOH. The colorless solution was
refluxed for 6 h according to GP-2. The crude of reaction was purified by flash chromatography affording
8 g (97%) of 5 as colorless needless; mp 149–151 ºC. 1H NMR (CDCl3, 400 MHz): ! (ppm): 0.82 (s, 9H,
t-Bu), 4.94 (br s, 1H, NH), 5.01 (d, J = 1.6 Hz, 1H, C2-H), 6.60 (d, Jortho = 8 Hz, 1H, C8-H), 6.76 (t, Jortho
= 7.4 Hz, 1H, C6-H), 7.19-7.27 (m, 2H, C7-H, CH), 7.37 (t, Jortho = 7.6 Hz, 2H, 2CH), 7.49 (d, Jortho = 8.2
13
Hz, 2H, CH), 7.89 (d, Jortho = 7 Hz, 1H, C5-H; C NMR (CDCl3, 100 MHz): ! (ppm): 26.9, 42.4, 80.0,
113.4, 116.8, 118.4, 126.2, 127.5, 128.7, 128.9, 133.8, 143.7, 146.8, 162.5. Anal. Calcd for C18H20N2O: C,
77.11; H, 7.19; N, 9.99. Found: C, 76.82; H, 7.12; N, 10.14. X-Ray crystallographic structure in Figure
1.14
2-tert-Butyl-3-(4-methoxyphenyl)-2,3-dihydro-4(1H)-quinazolinone (6)
A solution of aminobenzamide 3 (1.45 g, 5.98 mmol) in 50 mL of CH2Cl2 was added 0.78 mL (1.2 equiv)
of pivalaldehyde and then was added 0.04 g (3% by weight) of p-TsOH. The colorless solution was
refluxed for 5 h according to GP-2. The crude of reaction was purified by flash chromatography yielding
1.73 g (94%) of 6 as white solid; mp 165–168 ºC. 1H NMR (CDCl3, 200 MHz): ! (ppm) 0.82 (s, 9H, t-Bu),
3.78 (s, 3H, -OCH3), 4.92 (s, 1H, C2-H), 4.94 (br s, 1H, N-H), 6.56 (d, Jortho = 8 Hz, 1H, C8-H), 6.74 (td,
J
ortho = 7.5 Hz, Jmeta = 1 Hz, 1H, C6-H), 6.88 (d, Jortho = 9.2 Hz, 2H, C3´-H), 7.23 (td, Jortho = 7.7 Hz, Jmeta =
1.4 Hz, 1H, C7-H), 7.38 (d, Jortho = 8.8 Hz, 2H, C2´-H), 7.87 (dd, Jortho = 7.8 Hz, Jmeta = 1.5 Hz, 1H, C5-H);
13C NMR (CDCl3, 50 MHz): ! (ppm) 26.87 (CH3 of t-Bu), 42.3, 55.6, 80.1, 113.4, 113.9, 116.7, 118.2,
128.6, 128.8, 133.7, 136.6, 146.9, 157.5, 162.8. Anal. Calcd for C19H22N2O2: C, 73.52; H, 7.14; N, 9.03.
Found: C, 74.09; H, 7.27; N, 9.10.
3-Benzyl-2-phenyl-2,3-dihydro-4(1H)-quinazolinone (7)
A solution of aminobenzamide 1 (1 g, 4.42 mmol) in 50 mL of CH2Cl2 was added 0.53 mL (1.2 equiv) of
benzaldehyde and then was added 0.03 g (3% by weight) of p-TsOH. The colorless solution was refluxed
for 4 h according to GP-2. The crude of reaction was purified by flash chromatography yielding 1.55 g
(83%) of 7 as white solid; mp 145–148 ºC. 1H NMR (CDCl3, 200 MHz) ! (ppm):3.64 (d, J = 15.4 Hz, 1H,
CH2), 4.63 (br, 1H, NH), 5.57 (d, J = 15.4 Hz, 1H, CH2), 5.59 (s, 1H, C2-H), 6.48 (d, Jortho = 8.2 Hz, 1H,
C8-H), 6.82 (t, Jortho = 7.6 Hz, 1H, C6-H), 7.17-7.30 (m, 11H, C7-H, CH of Ph), 7.99 (d, Jortho = 7.6 Hz,
13
1H, C5-H); C NMR (CDCl3, 50 MHz): ! (ppm) 47.1, 71.2, 114.4, 115.7, 119.2, 126.6, 127.5, 128.1,
128.7, 128.8, 129.0, 129.3, 133.7, 136.8, 139.4, 145.2, 163.3. Anal. Calcd for C21H18N2O: C, 80.23; H,
5.77; N, 8.91. Found: C, 80.21; H, 5.78; N, 8.86.

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3-Benzyl-2,2-dimethyl-2,3-dihydro-4(1H)-quinazolinone (8)
A solution of aminobenzamide 1 (1.5 g, 6.62 mmol) in 50 mL of CH2Cl2 was added 0.58 mL (1.2 equiv)
of anhydrous acetone and then was added 0.045 g (3% by weight) of p-TsOH. The colorless solution was
refluxed for 4 h according to GP-2. The crude of reaction was purified by flash chromatography yielding
1.20 g (68%) of 8 as white solid; mp 199-200 ºC. 1H NMR (CDCl3, 200 MHz) ! (ppm):1.45 (s, 6H, CH3),
4.27 (br, 1H, NH), 4.79 (s, 2H, CH2), 6.60 (d, Jortho = 8.2 Hz, 1H, C8-H), 6.84 (t, Jortho = 7.5 Hz, 1H, C6-H),
13
7.19-7.33 (m, 6H, C7-H, Ph), 7.96 (d, Jortho = 7.6 Hz, 1H, C5-H); C NMR (CDCl3, 50 MHz): ! (ppm)
27.7, 45.2, 72.1, 114.4, 115.9, 119.1, 126.9, 127.2, 128.6, 129.0, 133.6, 139.4, 145.1, 164.0. HRMS:
Calcd for C17H18N2O: 266.1419, found: [M+H]+ C17H19N2O, 267.1418.
3-Benzyl-4(3H)-quinazolinone (9)
A solution of aminobenzamide 1 (2.8 g, 12 mmol) in 50 mL of toluene was added 1.99 mL (1 equiv) of
triethyl orthoformate and then was added 0.12 g (3% by weight) of p-TsOH. The colorless solution was
refluxed for 6 h according to GP-2. The crude of reaction was recrystallzed with methanol, yielding 2.7 g
(98%) of 9 as white solid. The compound 9 also can be obtained from the compound 4: a solution of 4
(0.34 mmol) in CHCl3 was stirred and irradiated with UV light in the Rayonet equipment RPR-100 for 6
hours. The reaction mixture was monitored by flash chromatography (Hex:AcOEt, 80:20) until
disappearance of starting material; the reaction mixture was concentrated under reduced pressure and the
crude of reaction was purified by flash chromatograpy, yielding 98% of 9.11 mp 118-119 ºC. 1H NMR
(CDCl3, 400 MHz) ! (ppm):5.14 (s, 2H, CH2), 7.22–7.29 (m, 5H, C6-H, 4CH), 7.43–7.47 (m, 1H, C8-H),
7.64–7.72 (m, 2H, C7-H, CH), 8.08 (s, 1H, C2-H), 8.26 (ddd, Jortho = 8.0 Hz, Jmeta = 1.6 Hz, Jortho = 0.8 Hz,
13
1H, C5-H); C NMR (CDCl3, 50 MHz): ! (ppm) 49.7, 122.3, 126.9, 127.4, 127.6, 128.1, 128.4, 129.1,
134.4, 135.8, 146.4, 148.1, 161.1. HRMS: Calcd for C15H12N2O: 236.0949, found: 236.0954.
3-Benzyl-2,3-dihydro-4(1H)-quinazolinone (10)
4(3H)-Quinazolinone 9 (1.73 g, 7.3 mmol) was dissolved in anhydrous THF (24 mL), the solution was
cooled at 0 ºC and then 0.55 g (2 equiv) of sodium borohydride was slowly added, finally was added 6
mL of MeOH. The reaction mixture was stirred at rt under nitrogen atmosphere for 2 h. The solvent was
concentrated and the residue was suspended in water, which was extracted with EtOAc. The organic
extracts were dried with anhydrous sodium sulfate and concentrated. After flash chromatography yielded
1.5 g (88%) of 10 as white solid; mp 66–68 ºC. 1H NMR (CDCl3, 200 MHz): ! (ppm) 4.49 (s, 2H, CH2),
4.50 (br s, 1H, NH), 4.71 (s, 2H, C2-H2), 6.65 (d, Jortho = 8.2 Hz, 1H, C8-H), 6.67 (td, Jortho = 7.5 Hz, Jmeta
= 0.6 Hz, 1H, C6-H), 7.22-7.30 (m, 6H, C7-H and Ph), 7.97 (dd, Jortho = 7.7 Hz, Jmeta = 1.1 Hz, 1H, C5-H);
13C NMR (CDCl3, 50 MHz): ! (ppm) 48.5, 59.0, 115.0, 117.4, 119.7, 127.7, 127.9, 128.8, 129.0, 133.3,

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136.7, 147.7, 163.8. HRMS: Calcd for C15H14N2O: 238.1106, found: [M+H]+ C15H15N2O, 239.1203.
General procedure for the halogenation reactions with N-halosuccinimides (GP-3).
A solution of 2,3-dihydro-4(1H)-quinazolinone (0.34 mmol) in CHCl3 (5 mL) was added 2.2–4.2 equiv of
NBS or NCS. The solution was stirred and irradiated with h! (254 nm) in Rayonet equipment RPR-100 or
heated at 50 °C. After this, colored solution was monitored by TLC (hexane:EtOAc 6:4) until
disappearance of starting material. The reaction mixture was concentrated under reduced pressure and the
crude of reaction was purified by flash chromatography eluting with hexane:EtOAc (9:1–6:4).
General procedure for the halogenation reactions with Br2/Et3N (GP-4).
A solution of 2,3-dihydro-4(1H)-quinazolinone (0.34 mmol) in CHCl3 (5 mL) was added 1.1–2.1 equiv of
Et3N and 2.0-2.27 equiv of Br2. The solution was stirred and heated at 50 ºC or at rt or at 0 °C. After this,
colored solution was monitored by TLC (hexane:EtOAc 6:4) until disappearance of starting material. The
reaction mixture was concentrated under reduced pressure and the crude of reaction was suspended in
water (5 mL), which was extracted with EtOAc (3 x 5 mL). The organic layer was dried with anhydrous
sodium sulfate and concentrated. The residue was purified by flash chromatography eluting with
Hex:EtOAc (9:1–6:4).
3-Benzyl-6,8-dibromo-2-tert-butyl-2,3-dihydro-4(1H)-quinazolinone (4a)
This compound was obtained from GP-3 and 4 with h$ and at 50 °C. Yield 87%, white solid; mp 116–118
ºC. 1H NMR (CDCl3, 200 MHz): ! (ppm) 0.94 (s, t-Bu, 9H), 4.00 (d, J = 15.4 Hz, 1H, CH2), 4.42 (d, J =
3.2 Hz, 1H, C2-H), 5.00 (br d, J = 2.6 Hz, 1H, NH), 5.81 (d, J = 15.4 Hz, 1H, CH2), 7.27-7.31 (m, 5H,
Ph), 7.59 (d, Jmeta = 2.2 Hz, 1H, C7-H), 7.96 (d, Jmeta = 2.2 Hz, 1H, C5-H); 13C NMR (CDCl3, 50 MHz): !
(ppm) 26.5, 42.0, 51.6, 75.7, 107.8, 109.5, 118.8, 127.5, 127.7, 128.9, 130.6, 136.8, 137.9, 143.1, 161.8.
Anal. Calcd for C19H20Br2N2O: C, 50.47; H, 4.46; N, 6.20. Found: C, 50.32; H, 4.31; N, 6.39.
3-Benzyl-6,8-dibromo-4(3H)-quinazolinone (4b)
This compound was obtained from GP-3 at 50 °C. Yield 41% (UV light), white solid; mp 176.5–178.5 ºC.
1H NMR (CDCl3, 400 MHz): ! (ppm) 5.19 (s, 2H, CH2), 7.34-7.35 (m, 5H, Ph), 8.13 (d, Jmeta = 2.2 Hz,
1H, C7-H), 8.22 (s, 1H, C2-H), 8.41 (d, Jmeta = 2.2 Hz, 1H, C5-H);13C NMR (CDCl3, 100 MHz): ! (ppm)
50.3, 120.9, 123.5, 124.5, 128.3, 128.8, 129.3, 135.0, 140.4, 144.9, 147.3, 159.4. Anal. Calcd for
C15H10Br2N2O: C, 45.72; H, 2.56; N, 7.11. Found: C, 45.97; H, 2.57; N, 7.35.
3-Benzyl-2-tert-butyl-6,8-dichloro-2,3-dihydro-4(1H)-quinazolinone (4e)

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This compound was obtained from GP-3 with UV light and at 50 °C. Yield 90% (at 50 °C), white solid;
mp 130–132 ºC. 1H NMR (CDCl3, 200 MHz): ! (ppm) 0.94 (s, t-Bu, 9H), 4.01 (d, J = 15.8 Hz, 1H, CH2),
4.43 (d, J = 3.4 Hz, 1H, C2-H), 4.96 (br d, J = 2.6 Hz, 1H, NH), 5.82 (d, J = 15.8 Hz, 1H, CH2), 7.26-7.33
13
(m, 6H, C7-H, Ph), 7.78 (d, Jmeta = 2.6 Hz, 1H, C5-H); C NMR (CDCl3, 50 MHz): ! (ppm) 26.5, 42.0,
51.6, 75.7, 117.9, 118.4, 122.6, 127.1, 127.5, 127.8, 128.9, 132.5, 136.8, 141.7, 161.9. Anal. Calcd for
C19H20Cl2N2O: C, 62.82; H, 5.55; N, 7.71. Found: C, 62.34; H, 5.37; N, 8.35. X-Ray crystallographic
structure in Figure 5.14
3-Benzyl-6,8-dichloro-4(3H)-quinazolinone (4f)
This compound was obtained from GP-3 at 50 °C. Yield 16% (UV light), white solid; mp 177–179 ºC. 1H
NMR (CDCl3, 200 MHz): ! (ppm) 5.19 (s, 2H, CH2), 7.35 (m, 5H, Ph), 7.81 (d, Jmeta = 2.2 Hz, 1H, C7-H),
8.20-8.21 (m, 2H, C2-H and C5-H);13C NMR (CDCl3, 50 MHz): ! (ppm) 50.3, 124.4, 125.4, 128.3, 128.8,
129.3, 133.1, 134.8, 135.0, 147.1, 159.4. Anal. Calcd for C15H10Cl2N2O: C, 59.04; H, 3.30; N, 9.18.
Found: C, 58.77; H, 3.36; N, 9.22.
3-Benzyl-2-tert-butyl-6-chloro-2,3-dihydro-4(1H)-quinazolinone (4g)
This compound was obtained from GP-3 at 50 °C (4 h). Yield 16%, white solid; mp 86–89 ºC. 1H NMR
(CDCl3, 200 MHz): ! (ppm) 0.93 (s, t-Bu, 9H), 3.99 (d, J = 15.8 Hz, 1H, CH2), 4.31 (d, J = 3.2 Hz, 1H,
C2-H), 4.53 (br s, 1H, NH), 5.85 (d, J = 15.8 Hz, 1H, CH2), 6.51 (d, Jortho = 8.4 Hz, 1H, C8-H), 7.18 (dd,
Jortho = 8.7 Hz, Jmeta = 2.6 Hz, 1H, C7-H), 7.26-7.34 (m, 5H, Ph), 7.84 (d, Jmeta = 2.2 Hz, 1H, C5-H);13C
NMR (CDCl3, 50 MHz): ! (ppm) 26.7, 42.1, 51.5, 75.7, 114.8, 117.9, 123.4, 127.5, 127.6, 128.3, 128.9,
133.5, 137.3, 145.0, 162.8. HRMS: Calcd for C19H21ClN2O, 328.1342; found: [M+H]+ C19H22ClN2O,
329.1391.
3-Benzyl-2-tert-butyl-8-chloro-2,3-dihydro-4(1H)-quinazolinone (4h)
This compound was obtained from GP-4 (4 h). Yield 30%, white solid; mp 123–126 ºC. 1H NMR (CDCl3,
200 MHz): ! (ppm) 0.98 (s, t-Bu, 9H), 4.01 (d, J = 15.8 Hz, 1H, CH2), 4.42 (d, J = 3 Hz, 1H, C2-H), 4.99
(br s, 1H, NH), 5.86 (d, J = 15.8 Hz, 1H, CH2), 6.70 (t, Jortho = 7.9 Hz, 1H, C6-H), 7.24-7.36 (m, 6H, C7-H,
Ph), 7.80 (dd, Jortho = 7.8 Hz, Jmeta = 1.4 Hz, 1H, C5-H);13C NMR (CDCl3, 50 MHz): ! (ppm) 26.6, 41.9,
51.5, 75.8, 117.3, 117.9, 118.1, 127.2, 127.5, 127.6, 128.9, 132.9, 137.4, 143.1, 163.0. HRMS: Calcd for
C19H21ClN2O: 328.1342 Found: [M+H]+ C19H22ClN2O, 329.1396. X-Ray crystallographic structure in
Figure 6.14
6,8-Dibromo-2-tert-butyl-3-phenyl-2,3-dihydro-4(1H)-quinazolinone (5a)

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This compound was obtained by the GP-3 and 4 at 50 °C. Yield 91% (GP-4 at 50 °C), white solid; mp
155–156 ºC. 1H NMR (CDCl3, 200 MHz): ! (ppm) 0.84 (s, t-Bu, 9H), 5.14 (d, J = 3.4 Hz, 1H, C2-H),
5.24 (br s, 1H, NH), 7.20-7.54 (m, 5H, Ph), 7.63 (d, Jmeta = 2.2 Hz, 1H, C7-H), 7.98 (d, Jmeta = 2.2 Hz, 1H,
13
C5-H); C NMR (CDCl3, 50 MHz): ! (ppm): 26.7, 42.3, 80.2, 107.8, 109.7, 118.9, 126.8, 127.3, 129.0,
130.9, 138.2, 143.0, 143.3, 160.4. HRMS: Calcd for C18H18Br2N2O, 435.9785; found: [M+H]+
C18H19Br2N2O, 436.9897.
6,8-Dibromo-3-phenyl-4(3H)-quinazolinone (5b)
This compound was obtained by the GP-3 with UV light. Yield 13%, white solid; mp 213–215 ºC. 1H
NMR (CDCl3, 200 MHz): ! (ppm) 7.38-7.62 (m, 5H, Ph), 8.18 (d, Jmeta = 1.8 Hz, 1H, C7-H), 8.23 (s, 1H,
13
C2-H), 8.44 (d, Jmeta = 1.6 Hz, 1H, C5-H); C NMR (CDCl3, 50 MHz): ! (ppm): 121.2, 123.6, 124.8,
126.9, 129.5, 129.7, 130.0, 136.9, 140.7, 147.1, 159.0 HRMS: Calcd for C14H8Br2N2O, 379.8983; found:
[M+H]+ C14H9Br2N2O, 380.9134.
6-Bromo-3-phenyl-4(3H)-quinazolinone (5d)
This compound was obtained from GP-3 at 50 °C. Yield 32% as white solid; mp 172–174 ºC. 1H NMR
(CDCl3, 200 MHz): ! (ppm) 7.38-7.56 (m, 5H, Ph), 7.63 (d, Jortho = 8.4 Hz, 1H, C8-H), 7.87 (dd, Jortho
=
8.0 Hz, J 2.8 Hz, 1H, C7-H), 8.21 (s, 1H, C2-H), 8.47 (d, Jmeta = 2.6 Hz, 1H, C5-H);13C NMR (CDCl3, 50
MHz): ! (ppm): 121.4, 123.8, 127.0, 127.0, 129.4, 129.5, 129.8, 137.2, 137.8, 146.5, 146.7, 159.6.
HRMS: Calcd for C14H9BrN2O, 299.9898; found: [M+H]+ C14H10BrN2O, 300.9949.
6,8-Dichloro-2-tert-butyl-3-phenyl-2,3-dihydro-4(1H)-quinazolinone (5e)
This compound was obtained from GP-3 with UV light and at 50 °C. Yield 44% (at 50 °C), white solid;
mp 204–206 ºC. 1H NMR (CDCl3, 200 MHz): ! (ppm) 0.83 (s, t-Bu, 9H), 5.14 (d, J = 3.8 Hz, 1H, C2-H),
5.24 (br d, J = 3 Hz, 1H, NH), 7.23 (tt, Jortho = 7 Hz, Jmeta 1.8 = Hz, 1H, C4´), 7.35-7.50 (m, 5H, C7-H, Ph),
13
7.81 (d, Jmeta = 2.2 Hz, 1H, C5-H); C NMR (CDCl3, 50 MHz): ! (ppm): 26.7, 42.3, 80.1, 118.0, 118.5,
122.8, 126.7, 127.3, 128.9, 132.7, 141.8, 143.0, 160.6. HRMS: Calcd for C18H18Cl2N2O, 348.0796; found:
[M+H]+ C18H19Cl2N2O, 349.0872.
2-tert-Butyl-6-chloro-3-phenyl-2,3-dihydro-4(1H)-quinazolinone (5g)
This compound was obtained from GP-3 at 50 °C. Yield 21% as white solid; mp 159–161 ºC. 1H NMR
(CDCl3, 200 MHz): ! (ppm) 0.82 (s, t-Bu, 9H), 5.01 (br s, 2H, C2-H, NH), 6.55 (d, Jortho = 8.8 Hz, 1H,
C8-H), 7.21 (dt, Jortho = 9.1 Hz, J = 2.5 Hz, 1H, C7-H), 7.34-7.57 (m, 5H, Ph), 7.84 (d, Jmeta = 2.2 Hz, 1H,
C5-H);13C NMR (CDCl3, 50 MHz): ! (ppm): 26.8, 42.5, 80.0, 114.9, 117.8, 123.3, 126.5, 127.4, 128.4,

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128.9, 133.7, 143.4, 145.3, 161.4. HRMS: Calcd for C18H19ClN2O, 314.1185; found: [M+H]+
C18H20ClN2O, 315.1272.
2-tert-Butyl-8-chloro-3-phenyl-2,3-dihydro-4(1H)-quinazolinone (5h)
This compound was obtained from GP-3 at 50 °C. Yield 37% as white solid; mp 145–148 ºC. 1H NMR
(CDCl3, 200 MHZ): ! (ppm) 0.84 (s, t-Bu, 9H), 5.15 (d, J = 3.4 Hz, 1H, C2-H), 5.24 (br s, 1H, NH), 6.72
(t, Jortho = 7.8 Hz, 1H, C6-H), 7.22 (tt, Jortho = 7.2 Hz, Jmeta = 1.4 Hz, 1H, C4´-H) 7.33-7.52 (m, 5H, C7-H,
Ph), 7.82 (dd, Jortho = 8.0 Hz, Jmeta = 1.1 Hz, 1H, C5-H);13C NMR (CDCl3, 50 MHz): ! (ppm): 26.7, 42.2,
80.1, 117.4, 117.8, 118.3, 126.6, 127.5, 127.5, 128.9, 133.1, 143.2, 143.3, 161.8. HRMS: Calcd for
C18H19ClN2O, 314.1185; found: [M+H]+ C18H20ClN2O, 315.1280.
6,8-Dibromo-2-tert-butyl-3-(4-methoxyphenyl)-2,3-dihydro-4(1H)-quinazolinone (6a)
This compound was obtained from GP-3 and 4. Yield 64% (GP-4 5 at 50 °C), white solid; mp 154–155
ºC. 1H NMR (CDCl3, 200 MHz): ! (ppm) 0.84 (s, 9H, t-Bu), 3.80 (s, 3H, -OCH3), 5.06 (d, J = 3 Hz, 1H,
C2-H), 5.22 (br d, J = 2.6 Hz, 1H, N-H), 6.91 (d, Jortho = 8.8 Hz, 2H, C3´-H), 7.37 (d, Jortho = 9.2 Hz, 2H,
13
C2´-H), 7.62 (d, Jmeta = 2.2 Hz, 1H, C7-H), 7.96 (d, Jmeta = 2.2 Hz, 1H, C5-H); C NMR (CDCl3, 50
MHz): ! (ppm) 26.7, 42.2, 55.6, 80.3, 107.7, 109.6, 114.20, 118.9, 128.4, 130.8, 135.8, 138.1, 143.3,
157.9, 160.7. HRMS: Calcd for C19H20Br2N2O2, 467.9871; found: [M+H]+ C19H21Br2N2O2, 467.0004.
X-Ray crystallographic structure in Figure 3.14
6-Bromo-3-(4-methoxyphenyl)-4(3H)-quinazolinone (6d)
This compound was obtained from GP-3 and 4 with UV light and at rt. Yield 40% (GP-3 with UV light),
o
white solid; mp 197-199 C. 1H NMR (CDCl3, 200 MHz): ! (ppm) 3.87 (s, 3H, -OCH3), 7.04 (d, Jortho
=
8.8 Hz, 2H, C3´-H), 7.32 (d, Jortho = 8.8 Hz, 2H, C2´-H), 7.63 (d, Jortho = 8.4 Hz, 1H, C8-H), 7.87 (dd, Jortho
= 8.6 Hz, Jmeta = 2.6 Hz, 1H, C7-H), 8.11 (s, 1H, C2-H), 8.47 (d, Jmeta = 2.6 Hz, 1H, C5-H); 13C NMR
(CDCl3, 50 MHz): ! (ppm) 55.8, 115.1, 121.4, 123.9, 128.2, 129.5, 129.8, 129.9, 137.8, 146.9, 159.9,
160.1. HRMS: Calcd for C15H12BrN2O2, 330.0004; found: [M+H]+ C15H13BrN2O2, 331.0085.
2-tert-Butyl-6,8-dichloro-3-(4-methoxyphenyl)-2,3-dihydro-4(1H)-quinazolinone (6e)
This compound was obtained from GP-3 with UV light and at 50 °C. Yield 52% (at 50 °C), white solid;
mp 200–203 ºC. 1H NMR (CDCl3, 200 MHz): ! (ppm) 0.84 (s, 9H, t-Bu), 3.80 (s, 3H, -OCH3), 5.06 (d, J
= 3.4 Hz, 1H, C2-H), 5.20 (br d, J = 2.4 Hz, 1H, N-H), 6.91 (d, Jortho = 8.8 Hz, 2H, C3´-H), 7.37 (d, Jortho
=
8.8 Hz, 3H, C2´-H, C7-H), 7.77 (d, Jmeta = 2.6 Hz, 1H, C5-H); 13C NMR (CDCl3, 50 MHz): ! (ppm) 26.7,
42.1, 55.6, 80.3, 114.2, 117.9, 118.5, 122.7, 127.2, 128.4, 132.6, 135.8, 141.9, 157.9, 160.8. HRMS:

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Calcd for C19H20Cl2N2O2, 378.0901; found: [M+H]+ C19H21Cl2N2O2, 379.0973. X-Ray crystallographic
structure in Figure 7.14
6,8-Dichloro-3-(4-methoxyphenyl)-4(3H)-quinazolinone (6f)
This compound was obtained from GP-3 at 50 °C. Yield 12%, white solid; mp 195–196 ºC. 1H NMR
(CDCl3, 200 MHz): ! (ppm) 3.87 (s, 3H, -OCH3), 7.04 (d, Jortho = 8.8 Hz, 2H, C3´-H), 7.32 (d, Jortho = 8.8
Hz, 2H, C2´-H), 7.71 (d, Jmeta = 2.2 Hz, 1H, C7-H), 7.71 (d, Jmeta = 2.2 Hz, 1H, C5-H);13C NMR (CDCl3,
50 MHz): ! (ppm) 55.8, 115.1, 126.7, 128.2, 129.4, 129.9, 133.6, 135.0, 146.5, 146.8, 160.2. HRMS:
Calcd for C15H10Cl2N2O2, 320.0119; found: [M+H]+ C15H11Cl2N2O2, 321.0201.
2-tert-Butyl-6-chloro-3-(4-methoxyphenyl)-2,3-dihydro-4(1H)-quinazolinone (6g)
This compound was obtained from GP-4 with UV light. Yield 16%, white solid; mp 189–191 ºC. 1H NMR
(CDCl3, 200 MHz): ! (ppm) 0.81 (s, 9H, t-Bu), 3.79 (s, 3H, -OCH3), 4.91 (br, 1H, C2-H), 5.09 (br d, 1H,
N-H), 6.51 (d, Jortho = 8.8 Hz, 1H, C8-H), 6.89 (d, Jortho = 8.8 Hz, 2H, C3´-H), 7.15 (dd, Jortho = 8.8 Hz, Jmeta
13
= 2.6 Hz, 1H, C7-H), 7.36 (d, Jortho = 8.8 Hz, 2H, C2´-H), 8.29 (d, Jmeta =3 Hz, 1H, C5-H); C NMR
(CDCl3, 50 MHz): ! (ppm) 26.8, 42.3, 55.6, 80.1, 114.0, 114.9, 117.7, 122.4, 127.6, 128.1, 130.2, 134.6,
147.9, 157.6, 161.0. HRMS: Calcd for C19H21ClN2O2, 344.1291; found: [M+H]+ C19H22ClN2O2, 345.1337.
2-tert-Butyl-8-chloro-3-(4-methoxyphenyl)-2,3-dihydro-4(1H)-quinazolinone (6h)
This compound was obtained from GP-3 with UV light. Yield 24%, white solid; mp 223–225 ºC. 1H NMR
(CDCl3, 200 MHZ): ! (ppm) 0.84 (s, t-Bu, 9H), 3.80 (s, 3H, -OCH3), 5.07 (d, J = 3 Hz, 1H, C2-H), 5.21
(br d, 1H, NH), 6.71 (t, Jortho = 7.9 Hz, 1H, C6-H), 6.90 (d, Jortho = 9.2 Hz, 2H, C3´-H), 7.32-7.43 (m, 3H,
C7-H, C-H), 7.81 (dd, Jortho = 7.7 Hz, Jmeta = 1.1 Hz, 1H, C5-H);13C NMR (CDCl3, 50 MHz): ! (ppm)
26.7, 42.1, 55.6, 80.3, 114.1, 117.3, 117.9, 118.2, 127.5, 128.5, 133.0, 136.2, 143.2, 157.8, 161.9. HRMS:
Calcd for C19H21ClN2O2, 344.1291; found: [M+H]+ C19H22ClN2O2, 345.1368. X-Ray crystallographic
structure in Figure 8.14
3-Benzyl-6,8-dibromo-2-phenyl-2,3-dihydro-4(1H)-quinazolinone (7a)
This compound was obtained from GP-3 and 4 at rt. Yield 39% (GP-4), white solid; mp 161–163 ºC. 1H
NMR (CDCl3, 200 MHz) ! (ppm):3.68 (d, J = 15.4 Hz, 1H, CH2), 5.03 (br, 1H, NH), 5.59 (d, J = 15.4
Hz, 1H, CH2), 5.69 (d, 1H, C2-H), 7.19-7.42 (m, 10H, Ph), 7.60 (d, Jmeta = 2.2 Hz, 1H, C7-H), 8.11 (d,
Jmeta = 2.2 Hz, 1H, C5-H);13C NMR (CDCl3, 50 MHz): ! (ppm) 47.4, 70.6, 108.8, 110.5, 117.7, 126.5,
127.8, 128.1, 128.8, 129.3, 129.7, 130.9, 136.1, 138.2, 138.7, 141.8, 161.2. HRMS: Calcd for
C21H16Br2N2O, 469.9629; found: [M+H]+ C21H17Br2N2O, 470.9644.

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3-Benzyl-6,8-dibromo-2-phenyl-4(3H)-quinazolinone (7b)
1
This compound was obtained from GP-3 at rt. Yield 24%, white solid; mp 144.5–146 ºC. H NMR
(CDCl3, 500 MHz) ! (ppm):5.28 (s, 2H, CH2), 6.90-6.91 (m, 2H, CH), 7.20-7.21 (m, 3H, CH), 7.40-7.42
(m, 5H, CH), 8.14 (d, J = 2.2 Hz, 1H, C7-H), 8.43 (d, J = 2.2 Hz, 1H, C5-H); 13C NMR (CDCl3, 125
MHz): ! (ppm) 49.57 (CH2), 120.30, 123.1, 123.9, 127.1, 127.8, 128.5, 128.7, 128.7, 129.4, 130.4, 134.9,
136.1, 140.6, 144.3, 157.3, 161.14. HRMS: Calcd for C21H14Br2N2O, 467.9472; found: [M+H]+
C21H14Br2N2O, 468.9551.
3-Benzyl-6-bromo-2-phenyl-2,3-dihydro-4(1H)-quinazolinone (7c)
This compound was obtained from GP-4 at rt. Yield 55%, white solid; mp 112–115 ºC. 1H NMR (CDCl3,
500 MHz) ! (ppm):3.65 (d, J = 15.3 Hz, 1H, CH2), 4.76 (br, 1H, NH), 5.53 (d, J = 15.3 Hz, 1H, CH2),
5.59 (s, 1H, C2-H), 6.40 (d, Jortho = 8.5, 1H, C8-H), 7.19-7.32 (m, 11H, C7-H, Ph), 8.11 (d, Jmeta = 2.2 Hz,
13
1H, C5-H); C NMR (CDCl3, 50 MHz): ! (ppm) 47.1, 71.1, 111.1, 116.2, 117.2, 126.6, 127.6 128.1,
128.7, 129.1, 129.5, 131.3, 136.3, 136.5, 139.1, 144.2, 162.1. HRMS: Calcd for C21H17BrN2O, 392.0524;
found: [M+H]+ C21H18BrN2O, 393.0482. X-Ray crystallographic structure in Figure 4.14
3-Benzyl-6-bromo-2-phenyl-4(3H)-quinazolinone (7d)
This compound was obtained from GP-3 and 4 at rt. Yield 37% (GP-4), white solid; mp 115–117 ºC. 1H
NMR (CDCl3, 500 MHz) ! (ppm): 5.26 (s, 2H, CH2), 6.89-6.91 (m, 2H, CH), 7.20-7.21 (m, 3H, CH),
7.32-7.34 (m, 2H, CH), 7.39-7.42 (m, 2H, CH), 7.47 (tt, Jortho = 7.6 Hz, Jmeta = 1.3 Hz, 1H, CH), 7.63 (d,
Jortho = 8.7 Hz, 1H, C8-H), 7.85 (dd, Jortho = 8.7 Hz, Jmeta = 2.3 Hz, 1H, C7-H), 8.49 (d, Jmeta = 2 Hz, 1H,
C5-H); 13C NMR (CDCl3, 125 MHz): ! (ppm) 47.1, 71.1, 111.1, 116.2, 117.2, 126.6, 127.6, 128.1, 128.7,
129.1, 129.5, 131.3, 136.3, 136.5, 139.1, 144.2, 162.1. HRMS: Calcd for C21H15BrN2O, 390.0368; found:
[M+H]+ C21H16BrN2O, 391.0444.
3-Benzyl-6,8-dichloro-2-phenyl-2,3-dihydro-4(1H)-quinazolinone (7e)
This compound was obtained from GP-3 with UV light and at 50 °C. Yield 60% (UV light), white solid;
mp 157–160 ºC. 1H NMR (CDCl3, 200 MHz) ! (ppm):3.67 (d, J = 15.4 Hz, 1H, CH2), 5.04 (br, 1H, NH),
5.57 (d, J = 15.4 Hz, 1H, CH2), 5.70 (d, 1H, C2-H), 7.17-7.36 (m, 11H, C7-H, Ph), 7.93 (d, Jmeta = 2.2 Hz,
13
1H, C5-H); C NMR (CDCl3, 50 MHz): ! (ppm) 47.4, 70.7, 117.3, 119.1, 123.5, 126.5, 127.4, 127.8,
128.1, 128.8, 129.3, 129.8, 132.8, 136.1, 138.8, 140.4, 161.3. HRMS: Calcd for C21H16Cl2N2O, 382.0640;
found: [M+H]+ C21H17Cl2N2O, 383.0733.
3-Benzyl-6,8-dichloro-2-phenyl-4(3H)-quinazolinone (7f)

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This compound was obtained from GP-3 with UV light and at 50 °C. Yield 32% (at 50 °C), white solid;
mp 145–147 ºC. 1H NMR (CDCl3, 200 MHz) ! (ppm): 5.26 (s, 2H, CH2), 6.86-6.91 (m, 2H, CH),
7.17-7.20 (m, 3H, CH), 7.39-7.47 (m, 5H, CH), 7.78 (d, J = 2.2 Hz, 1H, C7-H), 8.20 (d, J = 2.6 Hz, 1H,
C5-H);13C NMR (CDCl3, 50 MHz): ! (ppm) 49.4, 122.9, 125.4, 127.0, 127.7, 128.4, 128.6, 130.3, 132.4,
133.2, 134.8, 136.0, 142.8, 157.1, 161.1. Anal. Calcd for C21H14Cl2N2O: C, 66.16; H, 3.70; N, 7.35.
Found: C, 66.20; H, 3.66; N, 7.35.
3-Benzyl-6,8-dibromo-2,2-dimethyl-2,3-dihydro-4(1H)-quinazolinone (8a)
This compound was obtained from GP-3 and 4 at rt and 6 equiv of Br2 and Et3N. Yield 86% (method 5 at
rt) white solid; mp 177–177.8 °C. 1H NMR (CDCl3, 200 MHz): ! (ppm) 1.50 (s, 6H, CH3), 4.62 (br s, 1H,
NH), 4.78 (s, 2H, CH2), 7.21-7.30 (m, 5H, Ph), 7.65 (d, Jmeta = 2.2 Hz, 1H, C7-H), 8.07 (d, Jmeta = 2.2 Hz,
1H, C5-H); 13C NMR (CDCl3, 50 MHz): ! (ppm) 27.9, 45.6, 72.3, 109.1, 110.4, 117.8, 127.2, 128.7,
131.1, 138.1, 138.7, 141.6, 153.5, 161.9. HRMS: Calcd for C17H16Br2N2O, 423.9609; found: [M+H]+
C17H17Br2N2O, 424.9716.
3-Benzyl-6-bromo-2,2-dimethyl-2,3-dihydro-4(1H)-quinazolinone (8c)
This compound was obtained from GP-4 at rt and 4 Eq of Br2 and Et3N. Yield 55% white solid; mp
1
167–169 °C. H NMR (CDCl3, 200 MHz): ! (ppm) 1.45 (s, 6H, CH3), 4.26 (br s, 1H, NH), 4.78 (s, 2H,
CH2), 6.51 (d, Jortho = 8.4 Hz, 1H, C8-H), 7.19 - 7.30 (m, 5H, Ph), 7.36 (dd, Jmeta = 2.2 Hz, Jortho = 8.7 Hz,
1H, C7-H), 8.08 (d, Jmeta = 2.2 Hz, 1H, C5-H); 13C NMR (CDCl3, 50 MHz): ! (ppm) 27.7, 45.4, 72.2,
111.2, 116.5, 117.5, 127.1, 127.2, 128.7, 131.6, 136.2, 139.1, 143.9, 162.8. HRMS: Calcd for
C17H17BrN2O, 344.0524; found: [M+H]+ C17H18BrN2O, 345.0600.
3-Benzyl-6,8-dibromo-2,3-dihydro-4(1H)-quinazolinone (10a)
The compound 4b (0.68 mmol) was dissolved in anhydrous THF (16 mL), the solution was cooled at 0 ºC
and then 2 equiv of sodium borohydride was slowly added, finally was added 4 mL of MeOH. The
reaction mixture was stirred at rt under nitrogen atmosphere for 2 h. The solvent was concentrated, and
the residue was suspended in water, which was extracted with EtOAc. The extracts were dried with
anhydrous sodium sulfate and concentrated, and the residue was recrystallized with CH2Cl2 and hexane.
Yield 97%, white solid; mp 148–150 ºC. 1H NMR (CDCl3, 200 MHz): ! (ppm) 4.58 (d, 2H, C2-H2), 4.71
(s, 2H, CH2), 4.79 (br s, 1H, NH), 7.23-7.35 (m, 5H, Ph), 7.63 (d, Jmeta = 2.2 Hz, 1H, C7-H), 8.07 (d, Jmeta
= 2.2 Hz, 1H, C5-H); 13C NMR (CDCl3, 50 MHz): ! (ppm) 48.7, 58.5, 109.2, 111.0, 119.1, 128.1, 128.9,
131.8, 131.3, 136.0, 137.9, 144.1, 161.6. HRMS: Calcd for C15H12Br2N2O, 393.9316; found: [M+H]+
C15H13Br2N2O, 394.9379.

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1
This compound was obtained from GP-4 at 0 °C. Yield 38%, white solid; mp 119–121 ºC. H NMR
(CDCl3, 400 MHz): ! (ppm) 4.4 (br s, 1H, NH), 4.51 (s, 2H, C2-H2), 4.71 (s, 2H, CH2), 6.56 (d, Jortho= 8.6
Hz, 1H, C8-H), 7.28-7.33 (m, 5H, Ph), 7.35 (dd, Jortho = 8.6 Hz, Jmeta = 2.2 Hz, 1H, C7-H), 8.09 (d, Jmeta
=
13
2.2 Hz, 1H, C5-H); C NMR (CDCl3, 100 MHz): ! (ppm) 48.5, 58.7, 111.9, 116.8, 118.9, 127.8, 128.0,
128.9, 131.6, 135.9, 136.4, 146.4, 162.6. HRMS: Calcd for C15H13BrN2O, 316.0211; found: [M+H]+
C15H14BrN2O, 317.0256.
3-Benzyl-6-bromo-4(3H)-quinazolinone (10d)
This compound was obtained from GP-4 at rt. Yield 79%, white solid; mp 124–126 ºC. 1H NMR (CDCl3,
400 MHz): ! (ppm) 7.33–7.38 (br s, 5H, Ph), 7.55 (d, Jortho = 8.8 Hz, 1H, C8-H), 7.79 (dd, Jortho = 8.8 Hz,
Jmeta = 2.2 Hz, 1H, C7-H), 8.10 (s, 1H, C2-H), 8.42 (d, Jmeta = 2.2 Hz, 1H, C5-H); 13C NMR (CDCl3, 100
MHz): ! (ppm) 49.9, 121.1, 123.6, 128.1, 128.5, 129.2, 129.4, 129.5, 135.5, 135.5, 146.7, 146.9, 159.9.
HRMS: Calcd for C15H11BrN2O, 314.0055; found: [M+H]+ C15H12BrN2O, 315.0117.
3-Benzyl-6,8-dichloro-2,3-dihydro-4(1H)-quinazolinone (10e)
This compound was obtained from GP-3 with UV light and at 50 °C. Yield 62% (at 50 °C), white solid;
mp 122–124 ºC. 1H NMR (CDCl3, 200 MHz): ! (ppm) 4.57 (d, 2H, C2-H2), 4.69 (s, 2H, CH2), 4.88 (br s,
1H, NH), 7.26-7.43 (m, 5H, Ph), 7.86 (d, Jmeta = 2.2 Hz, 1H, C7-H), 8.18 (d, Jmeta = 2.2 Hz, 1H, C5-H); 13C
NMR (CDCl3, 50 MHz): ! (ppm) 48.6, 58.4, 118.6, 119.4, 123.8, 127.4, 127.9, 127.9, 128.8, 132.4, 135.9,
142.6, 161.7. HRMS: Calcd for C15H12Cl2N2O, 306.0327; found: [M+H]+ C15H13Cl2N2O, 307.0362.
ACKNOWLEDGEMENTS
Acknowledgements may be included as a separate section. We are grateful to CONACYT for financial
support (Project CB2010/151875) and for scholarships to C.O.-N. and F. A. C.-R.
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