Synthesis of 2-amino 3-substituted quinazolin-4(3h)-one derivatives via iodine-mediated guanidinylation of pbf-activated thiourea

Article abstract of DOI:10.1002/jhet.1067

2-Amino 3-substituted-quinazolin-4(3H)-one derivatives were synthesized from Pbf-isothiocyanate and methyl anthranilate. The construction of the guanidine-containing quinazolinone heterocyclic skeleton was achieved using Pbf-activated thiourea treated wit

Full text of DOI:10.1002/jhet.1067

Month 2013
Synthesis of 2‐Amino 3‐Substituted Quinazolin‐4(3H)‐one
Derivatives via Iodine‐Mediated Guanidinylation of Pbf‐Activated
Thiourea
a
a
a
a
b
*
Jizhen Li, Yuhua Mi, Jianghua He, Xuyang Luo, and Erkang Fan
aCollege of Chemistry, Jilin University, Changchun 130023, China
bBiomolecular Structure Center, Department of Biochemistry, University of Washington, Seattle, Washington 98195
*
E-mail: ljz@jlu.edu.cn
Received May 20, 2011
DOI 10.1002/jhet.1067
Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com).
2‐Amino 3‐substituted‐quinazolin‐4(3H)‐one derivatives were synthesized from Pbf‐isothiocyanate and
methyl anthranilate. The construction of the guanidine‐containing quinazolinone heterocyclic skeleton was
achieved using Pbf‐activated thiourea treated with primary amines via iodine‐mediated guanidinylation.
The desired compounds were obtained after Pbf cleavage by trifluoroacetic acid.
J. Heterocyclic Chem., 00, 00 (2013).
INTRODUCTION
construction of guanidine functionality [9]. We have
developed thiourea guanylating reagents N‐(Ar or alkyl)
substituted‐N′‐Pbf thiourea (Pbf: 2,2,4,6,7‐pentamethy-
ldihydrobenzofuran‐5‐sulfonyl) [10], and provided efficient
access to guanidine‐containing heterocycles of five‐membered
[11] and six‐membered rings from α or β‐amino acids, respec-
tively [12]. Moreover, due to the strong electron‐withdrawing
ability of the Pbf group, we also found in our previous work
that iodine is a good desulfurization reagent promoting guani-
dine formation through a carbodiimide intermediate [13].
In our efforts directed toward developing new methodol-
ogy for the synthesis of guanidine‐containing heterocycles,
we report herein a direct synthetic route to 2‐amino 3‐
substituted‐quinazolin‐4(3H)‐one derivatives 1 via iodine‐
mediated guanidine transformation of Pbf‐activated
thiourea 4 with primary amines, shown in Scheme 1.
4(3H)‐Quinazolinone derivatives exhibit a range of
biological properties such as anti‐inflammatory and antihy-
pertensive activities [1,2]. As a result, there are a number
of synthetic methods reported for this class of compounds,
especially concerning 2‐amino derivatives. The majority of
these methods generally fall into the category of either uti-
lizing guanidine transformation of S‐methylthiourea with
isatoic anhydride [3], or utilizing aza‐wittig‐mediated
annulation reaction from o‐azido benzoic acid or imino‐
phosphoranes [4]. Furthermore, novel synthesis method
involving Friedel‐Craft’s type substitution from aniline
was reported recently [5]. However, despite the simple
skeleton of 2‐amino 3‐substituted‐quinazolin‐4(3H)‐ones
with a free amino group at position 2, to date, only a
limited number of synthesis strategies have been disclosed
[6a,6b,7,8]. Among them, the representative pathways
involved one‐carbon compounds as synthetic intermediate
[7] and the guanidine conversion of S‐methyl isothiourea,
respectively [8]. The major limitations of the methods
mentioned above to 2‐amino 3‐substituted‐quinazolin‐4
(3H)‐ones are the harsh reaction conditions and the
difficulties in introducing substitutions at the 3‐position.
Therefore, novel synthesis method to the title compounds
is still desirable.
RESULTS AND DISCUSSION
As illustrated in Scheme 1, our synthesis journey com-
menced from Pbf‐isothiocyanate 3 and methyl anthranilate
2 to afford Pbf‐activated thiourea 4. The reaction of
PbfNCS with
1
equiv methyl anthranilate in
dichloromethane at room temperature produced Pbf‐acti-
vated thiourea 4 in 90% yield, which can be easily purified
through recrystallization in petroleum ether. Highly
reactive Pbf‐isothiocyanate may be obtained from Pbf‐Cl
The reaction of thioureas with amines in the presence of
a desulfurization reagent is one common method in the
© 2013 HeteroCorporation

J. Li, Y. Mi, J. He, X. Luo, and E. Fan
Vol 000
Scheme 1. Synthesis of 2‐amino 3‐substituted‐quinazolin‐4(3H)‐one derivatives via Pbf‐activated thiourea. Reagents and conditions: (a) CH2Cl2, 4 h, rt;
(b) I2, DIPEA, THF, 20 min, rt, then 30–40 h, 30–40°C; (c) TFA/H2O = 95:5, 12 h, 40–60°C.
and Bu4NNCS directly [14], or by treatment of Pbf‐NH2
with KOH and CS2 followed by triphosgene in toluene,
similar to the preparation of Pmc‐isothiocyanate (Pmc:
2,2,5,7,8‐pentamethyl chroman‐6‐sulfonyl) reported by
Madalengoitia and Flemer [15].
With the reaction conditions described above, we
screened a range of different primary amines to explore
the scope and limitations of the synthetic methodology.
The result was shown in Table 1. To our delight,
unhindered aliphatic amines and aromatic amine afforded
the desired Pbf‐protected guanidine heterocycles 5 (entries
1–4, 6, and 7) in moderate to good isolated yields, showing
that the guanidine transformation procedure can easily
tolerate a range of substituted functional groups such as
hydroxy or ester groups on the amines (entries 3 and 4).
But Pbf cleavage of compound 5d with ester group cannot
afford the isolated product 1d due to the formation of
multicomponent mixtures. Unexpectedly, severely
hindered amines such as t‐butylamine under these reaction
conditions or even upon heating at reflux for 2 days, did
not produce detectable amount of cyclized compound 5e,
indicating that steric bulk in the primary amines used is
of consequence to the reaction outcome. We then investi-
gated the effect of substituents on the phenyl ring of the
amines on the reactivity of the reaction. Aromatic amines
with electron‐donating substituents promote the
guanidinylation reaction (entries 8–11), at the same time
electron‐withdrawing substituents such as a nitro or a
chloro group failed to afford compounds 5l and 5m (entries
12 and 13). This result was consistent with our previous
reported study on iodine‐mediated guanidinylation reaction
with benzosulfonyl‐activated thiourea [13]. All the desired
compounds except 1d were obtained in high isolated yield
after the Pbf cleavage by TFA and identified by standard
spectroscopic techniques. The spectral data of compounds
1a and 1g is identical to that reported earlier [7,8].
Subsequently, at room temperature, 1 equiv iodine was
added slowly to the solution of thiourea 4 and DIPEA (N,
N′‐diisopropylethylamine) in THF. About 20 min later,
when thiourea was completely consumed in the reaction,
primary amine was added to allow the guanidine forma-
tion. After removing solvent, the corresponding Pbf‐
protected heterocycle 5 was purified by column chroma-
tography using ethyl acetate and petroleum ether as eluent.
Finally, deprotection was accomplished by treatment with
trifluoroacetic acid (TFA) and water (95:5) at 40–60°C
for about 12 h to afford the desired product 1. Final purifi-
cation was performed by washing the residue with petro-
leum ether, neutralization with triethyl amine, and
recrystallization from toluene. Thus, the synthesis route
provided 2‐amino 3‐substituted‐quinazolin‐4(3H)‐ones 1
in three short steps from starting materials methyl anthrani-
late and Pbf‐isothiocyanate.
During the reaction process, the heterocyclic framework
was constructed via the guanidine intermediate 6, which
smoothly underwent intramolecular cyclization reaction.
According to this mechanism, from thiourea 4 to heterocy-
cles 5, prolonged reaction time and elevated reaction tem-
perature helped product formation in high yield.
Additionally, using 1 equiv iodine was critical to the reac-
tion, because excess of iodine decreased the product yield.
It is also noteworthy that the cyclization procedures are dif-
ferent between the guanidine heterocyclic skeletons of 1
and six‐membered 2‐(N‐alkylamino)‐pyrimidin‐4‐one de-
rivatives [12]. In the latter case, the guanidine heterocycle
was constructed after Pbf cleavage.
Compared to the literature reports [6a,6b,7,8], the
substituted groups were readily introduced from available
diverse primary amines in our synthetic protocol. More-
over, all the reaction procedures were carried out under
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Synthesis of 2‐Amino 3‐Substituted Quinazolin‐4(3H)‐one Derivatives via
Iodine‐Mediated Guanidinylation of Pbf‐Activated Thiourea
Month 2013
Table 1
Conversion of Pbf‐thiourea to 2‐amino 3‐substituted‐4(3H)‐one derivatives.
Entries
R
Product
Yield (%)
Product
Yield (%)
1
2
3
4
5
6
7
8
n‐C4H9
n‐C3H7
HOCH2CH2
EtO2CCH2CH2
t‐C4H9
5a
5b
5c
5d
5e
5f
5g
5h
5i
61
75
57
42
0
72
64
73
74
69
66
0
1a
1b
1c
1d
1e
1f
1g
1h
1i
85
84
83
/
/
C6H5CH2
C6H5
88
86
87
75
80
83
/
p‐CH3O‐C6H4
p‐C2H5O‐C6H4
o‐CH3O‐C6H4
o‐CH3‐C6H4
p‐NO2‐C6H4
m‐Cl‐C6H4
9
10
11
12
13
5j
5k
5l
1j
1k
1l
5m
0
1m
/
General synthesis procedure of Pbf protective guanidine
heterocycles 5a–5m. At room temperature, thiourea 4 (0.33
mmoL) and DIPEA (0.97 mmoL) were dissolved in anhydrous
THF 5 mL, then iodine (0.33 mmoL) was added slowly to the
stirring mixture. After 20 min, RNH2 (0.33 mmoL) was added
to the solution, and the reaction was kept for about 30–40 h at
30–40°C. The solvent was evaporated under vacuum and the
residue was purified on silica gel chromatography (eluent:
EtOAc/petroleum ether = 1:5) to give compounds 5a–5d and
5f–5k.
mild reaction conditions, and the chemical reagents such as
methyl anthranilate and iodine were inexpensive and easy
to handle.
In summary, we have developed a simple method for the
synthesis of 2‐amino 3‐substituted‐quinazolin‐4(3H)‐ones
derivatives that introduced substitutions at the 3‐position
from commonly available primary amines at the step of
guanidine formation. Our research result reaffirms the ad-
vantage of Pbf‐activated thiourea as guanidinylating re-
agent in the synthesis of diverse guanidine‐containing
heterocycles.
3‐Butyl‐2‐[(2′,2′,4′,6′,7′‐pentamethyl‐2′,3′‐dihydrobenzofuran‐
5′‐sulfonyl)imino]‐4‐oxo‐1,2,3,4‐tetrahydroquinazoline (5a).
1
White solid, mp 155–157°C. H‐NMR (300 MHz, CDCl3), δ:
0.85–0.90 (t, J = 7.2Hz, 3H), 1.26–1.39 (m, 2H), 1.47 (s,
6H), 1.55–1.64 (m, 2H), 2.12 (s, 3H), 2.57 (s, 3H), 2.67 (s,
3H), 2.97 (s, 2H), 4.04–4.09 (t, J = 7.2 Hz, 2H), 7.13–7.15
(d, J = 7.5 Hz, 1H), 7.26–7.32 (m, 1H), 7.62–7.68 (m, 1H),
8.13–8.15 (d, J = 7.5 Hz, 1H), 11.00 (s, 1H). 13C‐NMR (75
MHz, CDCl3), δ: 11.2, 12.4, 13.6, 19.2, 20.1, 20.6, 28.5,
42.2, 43.1, 86.7, 115.1, 115.6, 117.8, 124.47, 124.9, 128.2,
131.4, 132.6, 135.3, 136.9, 138.9, 147.7, 159.3, 160.5. MS:
470.0 (M+H)+, 491.8 (M+Na)+. Anal. Calcd. for
EXPERIMENTAL
All reagents were purchased from commercial sources and
used without treatment, unless otherwise indicated. Melting
points were determined on a X‐5 melting point apparatus and
are uncorrected. H‐NMR and 13C‐NMR spectra were recorded
1
on a Varian mercury 300 and 75 MHz FT‐NMR spectrometer,
chemical shifts (δ) were given with (CH3)4Si as an internal refer-
ence (δ = 0). Element analyses were taken on a perkin‐Elmer
CHN2400 elemental analysis instrument. Mass spectra (MS) data
were obtained on a Bruker HCT system. PbfNCS 3 was
synthesized according to refs. 14 and 15.
C
25H31N3O4S: C, 63.94; H, 6.65; N, 8.95. Found: C, 63.89;
H, 6.62; N, 9.01.
3‐Propyl‐2‐[(2′,2′,4′,6′,7′‐pentamethyl‐2′,3′‐dihydrobenzofuran‐
5′‐sulfonyl)imino]‐4‐oxo‐1,2,3,4‐tetrahydroquinazoline (5b). White
1
N‐(2′‐Methyl benzoate)‐N′‐(2,2,4,6,7‐pentamethyl‐2,3‐
dihydrobenzofuran‐5‐sulfonyl)‐thiourea (4). At room temperature,
Pbf‐isothiocyanate (1.51 g, 0.01 moL) in dichloromethane (2 mL)
was added dropwise to the stirring solution of methyl anthranilate
(3.11 g, 0.01 moL) in 20 mL of anhydrous dichloromethane, the
reaction mixture was kept for 4 h. Solvent was removed under
reduced pressure and recrystallization from petroleum ether,
produced compound 4 4.15 g, yield 90%.
solid, mp 172–174°C. H‐NMR (300 MHz, CDCl3), δ: 0.89–0.94
(t, J = 7.5 Hz, 3H), 1.47 (s, 6H), 1.59–1.69 (m, 2H), 2.12 (s, 3H),
2.57 (s, 3H), 2.64 (s, 3H), 2.98 (s, 2H), 4.01–4.06 (t, J = 7.5 Hz,
2H), 7.13–7.15 (d, J = 7.5 Hz, 1H), 7.29–7.32 (m, 1H), 7.62–7.68
(m, 1H), 8.13–8.16 (d, J = 7.5 Hz, 1H), 11.00 (s, 1H). 13C‐NMR
(75 MHz, CDCl3), δ: 11.2, 12.4, 17.3, 18.6, 20.6, 28.5, 43.0, 43.8,
86.7, 115.1, 115.6, 117.8, 124.5, 124.6, 126.2, 131.4, 132.5, 136.3,
136.9, 138.8, 147.7, 159.3, 160.5. MS: 456.7 (M+H)+, 478.0
(M+Na)+. Anal. Calcd. for C24H29N3O4S: C, 63.27; H, 6.42;
N, 9.22. Found: C, 63.31; H, 6.49; N, 9.27.
3-(2′-Hydroxyethyl)-2-[(2′,2′,4′,6′,7′-pentamethyl-2′,3′-
dihydrobenzofuran-5′-sulfonyl)imino]-4-oxo‐1,2,3,4‐tetrahydro-
quinazoline (5c). White solid, mp 168–170°C. 1H‐NMR (300
MHz, CDCl3), δ: 1.47 (s, 6H), 2.11 (s, 3H),2.17 (s, 1H), 2.55 (s,
3H), 2.61 (s, 3H), 2.98 (s, 2H), 3.85–3.86 (t, J = 4.8 Hz, 2H),
4.35–4.38 (t, J = 4.8 Hz, 2H), 7.16–7.19 (d, J = 8.1 Hz, 1H),
7.30–7.35 (m, 1H), 7.66–7.71 (m, 1H), 8.14–8.17 (d, J = 8.1 Hz,
1
White solid, mp 115–117°C. H‐NMR (300 MHz, CDCl3), δ:
1.45 (s, 6H), 2.12 (s, 3H), 2.50 (s, 3H), 2.65 (s, 3H), 2.92 (s, 2H),
3.96 (s, 3H), 7.19–7.24 (m, 1H), 7.43–7.48 (m, 1H), 7.97–8.05 (m,
2H), 8.18 (s, 1H), 11.39 (s, 1H). 13C‐NMR (75 MHz, CDCl3), δ:
12.5, 17.6, 19.2, 28.4, 42.8, 52.7, 87.3, 116.7, 118.6, 125.0, 125.2,
125.6, 130.7, 132.5, 134.0, 134.8, 139.3, 140.2, 160.8, 166.9,
177.8. MS: 463.0 (M+H)+, 484.8 (M+Na)+. Anal. Calcd. for
C22H26N2O5S2: C, 57.12; H, 5.67; N, 6.06. Found: C, 57.19; H,
5.63; N, 6.09.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

J. Li, Y. Mi, J. He, X. Luo, and E. Fan
Vol 000
1H), 11.03 (s, 1H). 13C‐NMR (75 MHz, CDCl3), δ: 12.4, 17.9,
19.2, 28.5, 43.0, 44.5, 61.0, 86.8, 114.9, 115.8, 117.9, 124.8,
126.0, 128.3, 130.9, 132.8, 135.7, 137.0, 138.9, 148.3, 158.6,
161.4. MS: 457.9 (M+H)+, 479.7 (M+Na)+. Anal. Calcd. for
C23H27N3O5S: C, 60.38; H, 5.95; N, 9.18. Found: C, 60.43; H,
5.92; N, 9.22.
3‐[3′‐(Carbonyl ethyl ester)‐propyl]‐2‐[(2′,2′,4′,6′,7′‐pentamethyl‐
2′,3′‐dihydrobenzofuran‐5′‐sulfonyl)imino]‐4‐oxo‐1,2,3,4‐
tetrahydroquinazoline (5d). White solid, mp 125–128°C.
1H‐NMR (300 MHz, CDCl3), δ: 1.20–1.27 (t, J = 7.2 Hz,
3H), 1.49 (s, 6H), 2.13 (s, 3H), 2.57 (s, 3H), 2.63 (s,
3H), 2.63–2.69 (t, J = 7.8 Hz, 2H), 2.99 (s, 2H), 4.07–4.14 (q,
J = 7.2 Hz, 2H), 4.36–4.41 (t, J = 7.8 Hz, 2H), 7.15–7.18 (d,
J = 7.5 Hz, 1H), 7.29–7.34 (m, 1H), 7.65–7.71 (m, 1H),
8.14–8.17 (d, J = 7.5 Hz, 1H), 11.02 (s, 1H). 13C‐NMR
(75 MHz, CDCl3), δ: 12.3, 14.0, 17.8, 19.1, 28.5, 31.3,
31.9, 43.1, 61.3, 86.7, 115.0, 115.7, 117.9, 122.4, 124.6,
128.3, 130.2, 133.9, 135.5, 137.0, 138.9, 147.5, 159.5,
160.3, 171.1. MS: 513.9 (M+H)+, 535.8 (M+Na)+. Anal.
Calcd. for C26H31N3O6S: C, 60.80; H, 6.08; N, 8.18.
Found: C, 60.84; H, 6.06; N, 8.93.
J = 8.1 Hz, 1H), 7.29–7.34 (t, J = 8.1 Hz, 1H), 7.67–7.72 (t, J = 8.1
Hz, 1H), 8.15–8.17 (d, J = 8.1 Hz, 1H), 11.02 (s, 1H). 13C‐NMR
(75 MHz, CDCl3), δ: 12.3, 14.8, 17.6, 18.9, 28.5, 43.2, 63.8, 86.6,
115.2, 115.6, 115.8, 117.6, 124.6, 127.6, 128.7, 129.5, 131.4, 132.6,
135.6, 135.7, 137.4, 139.2, 148.6, 159.1, 159.3, 161.0. MS: 534.0
(M+H)+, 555.8 (M+Na)+. Anal. Calcd. for C29H31N3O5S: C, 65.27;
H, 5.86; N, 7.87. Found: C, 65.28; H, 5.90; N, 7.82.
3‐(2′‐Methoxy‐phenyl)‐2‐[(2′,2′,4′,6′,7′‐pentamethyl‐2′,3′‐
dihydrobenzofuran‐5′‐sulfonyl)imino]‐4‐oxo‐1,2,3,4‐tetrahy-
droquinazoline (5j). White solid, mp 210–213°C. 1H‐NMR
(300 MHz, CDCl3), δ: 1.45 (s, 3H), 1.46 (s, 3H), 2.04 (s, 3H),
2.23 (s, 3H), 2.36 (s, 3H), 2.92 (s, 2H), 3.52 (s, 3H), 6.91–6.94 (d,
J = 8.1 Hz, 1H), 7.00–7.05 (m, 1H), 7.12–7.15 (m, 1H), 7.19–7.22
d, J = 8.1 Hz, 1H), 7.29–7.34 (m, 1H), 7.37–7.43 (m, 1H),
7.68–7.73 (m, 1H), 8.16–8.18 (m, 1H), 11.01 (s, 1H). 13C‐
NMR (75 MHz, CDCl3), δ: 12.4, 17.3, 18.9, 28.4, 43.0, 55.2,
86.5, 111.6, 115.8, 117.4, 120.7, 122.2, 124.0, 126.6, 129.0,
129.6, 130.2, 130.5, 131.6, 132.4, 135.5, 137.4, 139.0, 148.0,
154.4, 159.0, 160.4. MS: 520.2 (M+H)+, 541.9 (M+Na)+. Anal.
Calcd. for C28H29N3O5S: C, 64.72; H, 5.63; N, 8.09. Found: C,
64.71; H, 5.66; N, 8.05.
3‐Benzyl‐2‐[(2′,2′,4′,6′,7′‐pentamethyl‐2′,3′‐dihydrobenzofuran‐
5′‐sulfonyl)imino]‐4‐oxo‐1,2,3,4‐tetrahydroquinazoline (5f). White
solid, mp 201–203°C.1H‐NMR (300 MHz, CDCl3), δ: 1.50 (s, 6H),
2.07 (s, 3H), 2.41 (s, 3H), 2.46 (s, 3H), 2.96 (s, 2H), 5.26 (s, 2H),
7.05–7.17 (m, 3H), 7.28–7.33 (m, 4H), 7.63–7.69 (m, 1H),
8.15–8.18 (m, 1H), 10.93 (s, 1H). 13C‐NMR (75 MHz,
CDCl3), δ: 12.4, 17.7, 19.1, 38.5, 43.1, 45.0, 86.7, 115.1, 115.7,
117.7, 124.6, 124.8, 127.5, 128.1, 128.5, 129.9, 131.1, 132.8, 135.5,
136.1, 137.0, 139.0, 147.7, 159.4, 160.6. MS: 504.9 (M+H)+, 526.0
(M+Na)+. Anal. Calcd. for C28H29N3O4S: C, 66.78; H, 5.80; N,
8.34. Found: C, 66.81; H, 5.78; N, 8.36.
3‐Phenyl‐2‐[(2′,2′,4′,6′,7′‐pentamethyl‐2′,3′‐dihydrobenzofuran‐
5′‐sulfonyl)imino]‐4‐oxo‐1,2,3,4‐tetrahydroquinazoline (5g). White
solid, mp 120–122°C.1H‐NMR (300 MHz, CDCl3), δ: 1.45 (s, 6H),
2.02 (s, 3H), 2.10 (s, 3H), 2.33 (s, 3H), 2.91 (s, 2H), 7.15–7.18 (m,
2H), 7.20–7.23 (d, J = 8.1 Hz, 1H), 7.30–7.35 (m, 1H), 7.42–7.48
(m, 3H), 7.68–7.74 (m, 1H), 8.15–8.18 (m, 1H), 11.06 (s,1H). 13C‐
NMR (75 MHz, CDCl3), δ: 12.3, 17.4, 18.9, 28.5, 43.0, 86.5,
115.5, 115.8, 117.5, 124.1, 124.5, 124.6, 126.2, 128.5, 128.7, 129.2,
132.4, 135.1, 135.7, 137.3, 139.1, 148.2, 159.2, 160.8. MS: 490.0
(M+H)+, 511.8 (M+Na)+. Anal. Calcd. for C27H27N3O4S: C, 66.24;
H, 5.56; N, 8.58. Found: C, 66.27; H, 5.52; N, 8.63.
3‐(2′‐Methyl‐phenyl)‐2‐[(2′,2′,4′,6′,7′‐pentamethyl‐2′,3′‐
dihydrobenzofuran‐5′‐sulfonyl)imino]‐4‐oxo‐1,2,3,4‐tetrahydro-
quinazoline (5k). White solid, mp 203–205°C.1H‐NMR (300
MHz, CDCl3), δ: 1.45 (s, 6H), 1.99 (s, 3H), 2.02 (s, 3H), 2.19 (s,
3H), 2.31 (s, 3H), 2.90 (s, 2H), 7.02–7.05 (d, J = 8.1 Hz, 1H),
7.20–7.23 (d, J = 8.1 Hz, 1H), 7.29–7.35 (m, 4H), 7.68–7.74 (m,
1H), 8.15–8.18 (m, 1H), 11.06 (s, 1H). 13C‐NMR (75 MHz,
CDCl3), δ: 12.3, 17.2, 17.3, 18.8, 28.4, 43.0, 85.5, 115.4, 115.8,
117.5, 124.6, 126.9, 128.3, 129.0, 129.0, 130.8, 131.0, 132.4,
134.4, 135.6, 135.7, 137.4, 139.1, 147.8, 152.0, 159.1, 160.3.
MS: 504.0 (M+H)+, 525.9 (M+Na)+. Anal. Calcd. for
C28H29N3O4S: C, 66.78; H, 5.80; N, 8.34. Found: C, 66.74; H,
5.86; N, 8.39.
General synthesis procedure of target compound 1. Compound
5 (0.06 mmoL) was dissolved in solution of TFA/H2O (95:5) (3 mL),
stirred for about 12 h at 40–60°C, the reaction was monitored by TLC
until starting material 5 disappeared completely. The solvent was
evaporated under reduced pressure, then washed the residue with
petroleum ether and neutralized with the solution of Et3N in water
separately. The precipitate was collected by filtration and air‐dried.
The desired compounds 1a–1c and 1f–1k were obtained after
recrystallization from toluene.
3‐(4′‐Methoxy‐phenyl)‐2‐[(2′,2′,4′,6′,7′‐pentamethyl‐2′,3′‐
dihydrobenzofuran‐5′‐sulfonyl)imino]‐4‐oxo‐1,2,3,4‐tetrahydro-
quinazoline (5h). White solid, mp 228–230°C. 1H‐NMR (300
MHz, CDCl3), δ: 1.45 (s, 6H), 2.03 (s, 3H), 2.27 (s, 3H), 2.36 (s,
3H), 2.91 (s, 2H), 3.85 (s, 3H), 6.94–6.97 (d, J = 9.0 Hz, 2H),
7.05–7.08 (d, J = 9.0 Hz, 2H), 7.18–7.20 (d, J = 8.1 Hz, 1H),
7.28–7.34 (t, J = 7.5 Hz, 1H), 7.67–7.72 (t, J = 7.5 Hz, 1H),
8.14–8.17 (d, J = 8.1 Hz, 1H), 11.03 (s, 1H). 13C‐NMR (75
MHz, CDCl3), δ: 12.3, 17.6, 19.0, 28.6, 43.1, 55.5, 87.0, 114.5,
115.0, 115.8, 117.1, 124.6, 126.7, 127.7, 128.7, 129.4, 130.5,
132.5, 133.5, 135.6, 137.3, 139.1, 148.5, 155.5, 159.6. MS:
519.9 (M+H)+, 541.8 (M+Na)+. Anal. Calcd. for C28H29N3O5S:
C, 64.72; H, 5.63; N, 8.09. Found: C, 64.73; H, 5.60; N, 8.11.
x3‐(4′‐Ethoxy‐phenyl)‐2‐[(2′,2′,4′,6′,7′‐pentamethyl‐2′,3′‐
dihydrobenzofuran‐5′‐sulfonyl)imino]‐4‐oxo‐1,2,3,4‐tetrahydro-
quinazoline (5i). White solid, mp 180–182°C. 1H‐NMR (300
MHz, CDCl3), δ: 1.42–1.47 (m, 9H), 2.04 (s, 3H), 2.27 (s, 3H),
2.37 (s, 3H), 2.92 (s, 2H), 4.04–4.12 (q, J = 7.2 Hz, 2H), 6.93–6.95
(d, J = 8.7 Hz, 2H), 7.04–7.06 (d, J = 8.7 Hz, 2H), 7.19–7.21 (d,
2‐Amino‐3‐butyl‐4‐oxo‐3,4‐dihydro‐quinazoline (1a). White
solid, mp 185–187°C. H‐NMR (300 MHz, DMSO), δ: 0.89–0.94
1
(t, J = 7.2 Hz, 3H), 1.28–1.40 (m, 2H), 1.52–1.62 (m, 2H), 3.97–
4.01 (t, J = 7.2 Hz, 2H), 7.01 (s, 2H), 7.06–7.11 (d, J = 7.5 Hz,
1H), 7.16–7.19 (t, J = 8.4 Hz, 1H), 7.53–7.58 (d, J = 7.2 Hz, 1H),
7.88–7.91 (t, J = 7.5 Hz, 1H). 13C‐NMR (75 MHz, DMSO), δ:
18.7, 24.4, 34.3, 45.8, 121.1, 126.3, 128.6, 131.5, 139.0, 154.6,
156.9, 166.7. MS: 218.0 (M+H)+, 239.9 (M+Na)+. Anal. Calcd. for
C12H15N3O: C, 66.34; H, 6.96; N, 19.34. Found: C, 66.37; H, 7.02;
N, 19.36.
2‐Amino‐3‐propyl‐4‐oxo‐3,4‐dihydro‐quinazoline (1b). White
solid, mp 215–218°C. 1H‐NMR (300 MHz, DMSO), δ:
0.89–0.94 (t, J = 7.5 Hz, 3H), 1.56–1.67 (m, 2H), 3.92–3.97
(t, J = 7.5 Hz, 2H), 7.03–7.12 (m, 3H), 7.16–7.19 (m, 1H),
7.54–7.59 (m, 1H), 7.88–7.91 (m, 1H). 13C‐NMR (75 MHz,
DMSO), δ: 10.8, 19.8, 43.3, 114.5, 116.8, 125.0, 127.4,
136.0, 137.9, 151.0, 159.3. MS: 203.8 (M+H)+, 225.7 (M
+Na)+. Anal. Calcd. for C11H13N3O: C, 65.01; H, 6.45; N,
20.68. Found: C, 65.03; H, 6.43; N, 20.65.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Synthesis of 2‐Amino 3‐Substituted Quinazolin‐4(3H)‐one Derivatives via
Iodine‐Mediated Guanidinylation of Pbf‐Activated Thiourea
Month 2013
2‐Amino‐3‐(2′‐hydroxyethyl)‐4‐oxo‐3,4‐dihydro‐quinazoline
(1c). White solid, mp 190–192°C. 1H‐NMR (300 MHz, DMSO),
δ: 3.65–3.69 (t, J = 5.7 Hz, 2H), 4.10–4.14 (t, J = 5.7 Hz, 2H),
5.13 (s, 1H), 7.18–7.29 (m, 2H), 7.48 (s, 2H), 7.62–7.68 (m,
1H), 7.93–7.96 (m, 1H). 13C‐NMR (75 MHz, DMSO), δ: 44.2,
58.4, 115.9, 121.8, 122.4, 126.7, 134.6, 152.4, 161.3. MS:
205.9 (M+H)+, 227.8 (M+Na)+. Anal. Calcd. for C10H11N3O2:
C, 58.53; H, 5.40; N, 20.48. Found: C, 58.45; H, 5.42; N, 20.52.
2‐Amino‐3‐benzyl‐4‐oxo‐3,4‐dihydro‐quinazoline (1f). White
267.9 (M+H)+, 298.0 (M+Na)+. Anal. Calcd. for C15H13N3O2: C, 67.40;
H, 4.90; N, 15.72. Found: C, 67.37; H, 4.98; N, 15.68.
2‐Amino‐3‐(2′‐methyl‐phenyl)‐4‐oxo‐3,4‐dihydro‐quinazoline
(1k). White solid, mp 169–172°C. 1H‐NMR (300 MHz, DMSO), δ:
2.11 (s, 3H), 734–7.39 (t, J = 7.8 Hz, 1H), 7.39–7.43 (m, 6H), 7.79–
7.85 (m, 2H), 7.99–7.02 (m, 1H). 13C‐NMR (75 MHz, DMSO), δ:
16.7, 115.4, 119.0, 124.1, 127.3, 127.9, 128.9, 130.3, 131.6, 132.3,
135.8, 136.2, 141.8, 151.3, 159.6. MS: 251.7 (M+H)+, 273.7 (M
+Na)+. Anal. Calcd. for C15H13N3O: C, 71.70; H, 5.21; N, 16.72.
Found: C, 71.73; H, 5.18; N, 16.65.
1
solid, mp 197–199°C. H‐NMR (300 MHz, DMSO), δ: 5.30 (s,
2H), 7.09–7.17 (m, 3H), 7.24–7.36 (m, 6H), 7.59–7.64 (t, J =
7.5 Hz, 1H), 7.93–7.96 (d, J = 7.5 Hz, 1H). 13C‐NMR (75
MHz, DMSO), δ: 48.9, 121.0, 126.7, 128.6, 131.7, 131.7,
132.2, 133.4, 139.4, 141.2, 154.3, 156.9, 166.6. MS: 251.7 (M
+H)+, 273.7 (M+Na)+. Anal. Calcd. for C15H13N3O: C, 71.70;
H, 5.21; N, 16.72. Found: C, 71.75; H, 5.23; N, 16.75.
Acknowledgments. This work was supported by the Scientific
Forefront and Interdisciplinary Innovation Project, JiLin
University (Grant No. 2009–421031531412) and was partially
supported by the Jilin Provincial Research Foundation for
Basic Research, P.R. China (Grant No. 3D109K856604).
2‐Amino‐3‐phenyl‐4‐oxo‐3,4‐dihydro‐quinazoline (1g). White
1
solid, mp 220–222°C. H‐NMR (300 MHz, DMSO), δ: 6.25 (s,
2H), 7.11–7.15 (t, J = 7.2 Hz, 1H), 7.24–7.27 (d, J = 7.8 Hz, 1H),
7.36–7.38 (d, J = 7.2 Hz, 2H), 7.53–7.65 (m, 4H), 7.89–7.91 (d, J
= 7.8 Hz, 1H). 13C‐NMR (75 MHz, DMSO), δ: 121.8, 126.5,
128.9, 131.5, 133.8, 134.2, 135.0, 139.4, 140.5, 155.1, 156.6,
166.8. MS: 237.9 (M+H)+, 259.7 (M+Na)+. Anal. Calcd. for
C14H11N3O: C, 70.87; H, 4.67; N, 17.71. Found: C, 70.95; H, 4.69;
N, 17.73.
REFERENCES AND NOTES
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2‐Amino‐3‐(4′‐methoxy‐phenyl)‐4‐oxo‐3,4‐dihydro‐quinazoline
(1h). White solid, mp 233–235°C. 1H‐NMR (300 MHz, DMSO), δ:
3.83 (s, 3H), 6.29 (s, 2H), 7.08–7.13 (m, 3H), 7.22–7.28 (m, 3H),
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(1i). White solid, mp 243–245°C. 1H‐NMR (300 MHz, DMSO), δ:
1.35–1.39 (t, J = 6.9 Hz, 3H), 4.06–4.13 (q, J = 6.9 Hz, 2H), 6.26 (s,
2H), 7.06–7.13 (m, 3H), 7.21–7.25 (m, 3H), 7.57–7.62 (t, J = 8.7
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Found: C, 68.38; H, 5.45; N, 14.96.
2‐Amino‐3‐(2′‐methoxy‐phenyl)‐4‐oxo‐3,4‐dihydro‐quinazoline
(1j). White solid, mp 228–230°C. 1H‐NMR (300 MHz, DMSO), δ:
3.74 (s, 3H), 6.29 (s, 2H), 7.08–7.13 (t, J = 7.5Hz, 2H), 7.22–7.25
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet