Efficient microwave-assisted two-step procedure for the synthesis of 1,3-disubstituted-imidazo[1,5-a]quinazolin-5-(4H)-ones

Article abstract of DOI:10.1016/j.tet.2009.11.025

A general method has been developed for the synthesis of 1,3-disubstituted-imidazo[1,5-a]quinazolin-5-(4H)-ones. This process involves initial microwave-assisted quinazolinone formation between anthranilamide and various Boc- or acylamino acids, followed by intramolecular cyclodehydration under acidic conditions. In the case of 3-monosubstituted-imidazoquinazolinones, the procedure needs the formation of the formamide derivatives by deprotection and formylation of the Boc-intermediates.

Full text of DOI:10.1016/j.tet.2009.11.025

Tetrahedron 66 (2010) 128–133
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Efficient microwave-assisted two-step procedure for the synthesis
of 1,3-disubstituted-imidazo[1,5-a]quinazolin-5-(4H)-ones
*
´
Flavia Jankowski, Valerie Verones, Nathalie Flouquet, Pascal Carato, Pascal Berthelot, Nicolas Lebegue
Laboratoire de Chimie The´rapeutique EA1043, Faculte´ des Sciences Pharmaceutiques et Biologiques, 3 rue du Professeur Laguesse-B.P.83-59006 Lille Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A general method has been developed for the synthesis of 1,3-disubstituted-imidazo[1,5-a]quinazolin-5-
(4H)-ones. This process involves initial microwave-assisted quinazolinone formation between an-
thranilamide and various Boc- or acylamino acids, followed by intramolecular cyclodehydration under
acidic conditions. In the case of 3-monosubstituted-imidazoquinazolinones, the procedure needs the
formation of the formamide derivatives by deprotection and formylation of the Boc-intermediates.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 23 September 2009
Received in revised form 2 November 2009
Accepted 5 November 2009
Available online 10 November 2009
Approach 1
1. Introduction
O
O
N
O
N
The quinazoline skeleton, when selectively functionalized, is
a building block for the preparation of numerous alkaloids and
substances with pronounced biological activities.1 The occurrence
of the quinazolin-4-one core in various natural sources has gener-
ated interest of many groups on account of its useful biological
properties. Among them, a wide range of five-membered ring
containing nitrogen atoms based on fused [1,5- a]quinazolinones
exhibit antiarthritic,2 antihistaminic,3 phosphodiesterase IV in-
hibitor4 (1), PARP inhibitor5 (2) and GABAA receptor ligand6c (4)
activities (Fig. 1).
N
N
N
3 steps
acylation
H
N
NH2
R3
N
CH3
R1
7
5
6
O
O
3
4
R1= Ph; R2= H;
R3= H, alkyl, aryl, benzyl
N
R2
N
R1= alkyl, cycloalkyl;
N
R2= oxadiazole, carboxylate;
R3= H
R3
O
O
O
O
R
O
O
N
R
N
R
N
N
N
R
N
R1
O
O
N
O
R
N
N
R
N
N
P
OEt
N
H
O
N
H
O
OEt
N
N
8
9
10
R
R
R
Approach 2
1
2
3, 4
Scheme 1. Available approaches for the synthesis of Imidazo[1,5-a]quinazolin-5-(4H)-
ones.
Figure 1. Structure of the 1,2-fused quinazolin-5-ones.
While structures 1 and 2 are well documented, only a few pa-
pers described the synthesis and the reactivity of heterocycles in
which the quinazoline ring is fused with imidazole as imidazo[1,5-
a]quinazolin-5-(4H)-ones 3 and 4. Thus far, two major synthetic
strategies have been reported to access the core ring system 3 and 4
and these approaches are limited in that the nitrogen in position 4
was always substituted and the imidazole core monosubstituted
(Scheme 1). Singh and Chaudhury6a reported the synthesis of
aminomethyl derivative 6, which could be converted into its N-
carboxamide 7 for subsequent cyclization into imidazoquinazolone
3 (Approach 1), Scheme 1.
For this purpose, 6 was obtained from bromination of 5 by Ga-
briel synthesis followed by reaction with potassium phthalimide
and hydrolysis with hydrazine hydrate. In the second approach,6d
reaction of the desired quinazolin-2,4-diones 9, synthesized from
isatoic anhydride 8 and the corresponding amines, with sodium
hydride followed by diethyl chlorophosphate, provided an in-
termediate enol phosphonate 10. Without isolation, enol 10 was
combined with the desired isocyanide and additional potassium
* Corresponding author. Tel.: þ33 20 96 49 77; fax: þ33 20 96 49 13.
E-mail address: nicolas.lebegue@univ-lille2.fr (N. Lebegue).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.11.025

F. Jankowski et al. / Tetrahedron 66 (2010) 128–133
129
Table 1
tertbutoxide to provide the imidazo[1,5-a]quinazolin-5-(4H)-one 4
Investigation of the microwave-assisted synthesis of Quinazolinone 14aa
ring system. A general method for the synthesis of the 1,3-di-
substituted-imidazo[1,5-a]quinazolin-5-(4H)-ones 15 would be
required in order to investigate this chemical space through the
variation of the substituents on the imidazole core to include a di-
verse sampling of aliphatic, benzylic, and aromatic groups.
O
NH2
O
O
NH2
+
NH2
NH
NH
11
+
NHCOCH3
N
ROOC
NHCOCH3
NHCOCH3
2. Results and discussion
O
12a
13a
14a
A number of microwave-assisted methods have been recently
reported for the synthesis of 2-substituted quinazolin-4-(3H)-one
analogs by the use of anthranilic acid,7 anthranilamide,8 isatoic
anhydride,9 and 3,1-benzoxazinones10 as appropriate precursors.
Our approach in the retrosynthetic strategy (Scheme 2) was in-
vestigated with 14 as a key-intermediate, which could be formed
via transannular cyclization of intermediate diamide 13. The di-
amide 13 may be accessed in situ from readily available anthranil-
amide 11 and N-acylamino acids derivatives 12. Three microwave
assisted procedures for the preparation of quinazolinone 14a were
investigated. The first involved treatment of anthranilamide 11 and
N-acetylglycine 12a with HOBT and EDCI11 using various combi-
nations of solvent/power irradiation/temperature (Table 1). The
best result (entry 5) was obtained with 2 equiv of 12a in acetonitrile
under microwave irradiation at 120 ꢀC for 20 min. Previous pub-
lished synthetic studies12 toward making imidazo-[1,5-a]pyr-
imidin-4(lH)-ones have utilized ethyl N-acylamino esters in the
presence of sodium ethoxide in refluxing ethanol.
Entry
R (12a, equiv)
Conditionsb
Yieldc (products)
1
2
3
4
5
6
7
8
9
H (1)
H (1)
H (1)
H (2)
H (2)
Et (3)
Et (5)
H (1)
H (1)
A, DMF, 80 ꢀC, 10 min
A, DMF, 80 ꢀC, 20 min
A, THF/H2O, 120 ꢀC, 20 min
A, THF/H2O, 120 ꢀC, 20 min
A, CH3CN, 120 ꢀC, 20 min
B (2 equiv), 120 ꢀC, 20 min
B (3 equiv), 120 ꢀC, 20 min
C, 120 ꢀC, 20 min
10% (13aþ14a)
15% (13aþ14a)
18% (13aþ14a)
28% (13aþ14a)
50% (14a)
50% (14a)
60% (14a)
80% (13aþ14a)
C, 120 ꢀC, 20 min, then
2 N NaOEt/EtOH (2 equiv),
120 ꢀC, 10 min
80% (14a)
a
All reactions were carried out on a 1 mmol scale of anthranilamide in sealed
vials under pressure in a CEM DiscoverÒ apparatus.
b
A: HOBT (1 equiv), EDCI (1 equiv); B: 2 N NaOEt, EtOH; C: isobutyl chloroformate
(1 equiv), N-methylmorpholine (1 equiv), THF, ꢁ15 ꢀC to room temperature, then
anthranilamide (1 equiv).
c
Isolated yield.
Heating quinazolinone 14a in xylene in the presence of poly-
phosphoric acid16,17 (PPA) for 12 h at 120 ꢀC led to a mixture of the
desired 3-methyl- imidazo[1,5-a]quinazolin-5-(4H)-one 15a and
starting material in weak yield. Under microwave irradiation,18
the reaction occurred at atmospheric pressure for 15 min at 120 ꢀC
and afforded only the desired compound 15a in 85% yield. These
optimized conditions were then applied to the synthesis of a range
of imidazo[1,5-a]quinazolin-5-(4H)-one derivatives as shown in
Table 2. No alternative cyclization to nitrogen at position 3 of the
quinazolinone core occurred and the structures of some com-
pounds were unequivocally determined by NMR spectra, in-
cluding steady state NOE measurements. In the case of
3-monosubstituted-imidazoquinazolinones 15c,g,k,o, the pro-
cedure needs the formation of the formamide derivatives by
deprotection with trifluoroacetic acid and formylation with ethyl
formate19 of the corresponding Boc-intermediates 14b,f,j,n.
O
O
N
NH
N
NH
NHCOR2
R1
N
R1
15
14
R2
O
NH2
O
NH2
+
NH2
11
NH
ROOC
R1
NHCOR2
NHCOR2
O
12
R1
13
Scheme 2. Retrosynthetic strategy of 15.
3. Conclusion
These conditions were then applied and optimized (entry 6 and
7) to the microwave-assisted synthesis of 14a in 60% yield. An
improved procedure for the N-acylation of amine derivatives in-
volved treatment with a mixed anhydride,13 prepared in situ from
the corresponding carboxylic acid, isobutyl chloroformate, and N-
methylmorpholine.14 Isobutyl chloroformate was then added
dropwise to a cold (ꢁ15 ꢀC) mixture of N-acetyl-glycine 12a and
methylmorpholine in THF followed by addition of anthranilamide
then heating upon microwave irradiation at 120 ꢀC for 20 min
(entry 8). These conditions led to 80% yield formation of quinazo-
linone 14a and diamide 13a in the proportion of, respectively 55
and 45%.15 Under the final optimized microwave conditions, re-
action of anthranilamide (1 equiv) with isobutoxycarbonyl N-
acetylglycinate (1 equiv) in THF at 120 ꢀC for 20 min, followed by
addition of 2 N sodium ethoxide solution in ethanol (2 equiv) and
microwave irradiation at 120 ꢀC for 10 min to complete cyclization
reaction afforded the desired quinazolinone 14a in 80% yield (entry
9). Under conventional thermal heating conditions, longer reaction
times are necessary, which would lead to significant decomposition
of isobutoxycarbonylamino ester and supply weaker yield of the
desired quinazolinone.
In conclusion, we have developed a novel and highly efficient
two-step procedure promoted by microwave irradiation for the
synthesis of imidazo[1,5-a]quinazolin-5-(4H)-one derivatives (15)
from anthranilamide and various Boc- or acylamino acids, followed
by intramolecular cyclodehydration under acidic conditions. These
results demonstrate the value of microwave-assisted chemistry not
only to provide increased yields and shortened reaction times, but
also to expand the accessible chemical space by generating prod-
ucts, which are difficult to obtain in usual thermal conditions. This
method has now been adapted to the synthesis of diverse screening
libraries of related imidazoquinazolinones, which can be employed
as intermediates in the synthesis of expected bioactive compounds
and will be published in due course.
4. Experimental
4.1. General experimental information
All reagents and solvents were purchased and used without
¨
further purification. Melting points were determined on a BUCHI

130
F. Jankowski et al. / Tetrahedron 66 (2010) 128–133
Table 2
Microwave-assisted synthesisa of quinazolinones 14a–pb and cyclodehydration to 15a–pc
Entry
Amino acid 12
14 (yield,d %)
15 (yield,d %)
Entry
Amino acid 12
14 (yield,d %)
15 (yield,d %)
O
O
O
O
HOOC
NHCOR2
NH
N
NH
N
NH
HOOC
NHCOR2
NHCOR2
NH
N
N
NHCOR2
N
N
R2
R2
1
2
3
4
R2¼CH3
OtBu
H
14a (80)
14b (65)
14c (76)
14d (81)
15a (85)
9
R2¼CH3
OtBu
H
14i (79)
14j (73)
14k (73)
14l (71)
15i (87)
10
11
12
15c (81)
15d (79)
15k (79)
15l (92)
Ph
Ph
O
O
O
O
HOOC
NHCOR2
NH
N
NH
N
NH
HOOC
NHCOR2
CH3
NH
N
NHCOR2
NHCOR2
CH3
N
CH3
N
N
R2
R2
5
6
7
8
R2¼CH3
OtBu
H
14e (72)
14f (76)
14g (69)
14h (76)
15e (74)
13
14
15
16
R2¼CH3
OtBu
H
14m (82)
14n (87)
14o (77)
14p (88)
15m (78)
15g (95)
15h (93)
15o (81)
15p (80)
Ph
Ph
a
Microwave irradiation was performed in a CEM DiscoverÒ apparatus.
All reactions were carried out in sealed vials under pressure with isobutyl chloroformate (2 mmol), N-methylmorpholine (2 mmol), N-acylamino acid derivative (2 mmol),
b
anthranilamide (2 mmol) and NaOEt/EtOH (4 mmol).
c
The cyclodehydration occurred at atmospheric pressure at 120 ꢀC within 15 min.
Isolated yield after recrystallization from ethanol.
d
B-540 apparatus and are uncorrected. Mass spectra were per-
formed on a Finnigan MAT SSQ 710 Advantage spectrometer and
were recorded in the ESþ mode. 1H NMR (300 MHz) and 13C NMR
(75 MHz) spectra were recorded on a Bruker AC 300 P and 2D NMR
spectra on a Bruker DPX 300. Elemental analyses were performed
by C.N.R.S-Vernaison, and were in agreement with the calculated
values within ꢂ0,4%. Microwave experiments were carried out
under pressure (0–20 bar, tubes of 15 mL, sealed with a septum) or
at atmospheric pressure in a glass vessel prolonged by a condenser,
using a focused microwave reactor (CEM DiscoverÔ). The tem-
perature content of the reaction mixture is monitored using cali-
brated infrared sensor mounted under the sealed vial or the glass
vessel. The target temperature was reached with a ramp of 2 min
and the microwave power stay constant to hold the mixture at this
temperature. The time of the reaction does not include the ramp
period.
7.49 (t, J¼7.1 Hz 1H), 7.62 (d, J¼8.1 Hz,1H), 7.80 (t, J¼7.1 Hz,1H), 8.10
(d, J¼7.9 Hz, 1H), 8.39 (t, J¼5.7 Hz, 1H), 12.17 (s, 1H); 13C NMR
(75 MHz, [D6]DMSO, 25 ꢀC)
d
¼23.0, 42.0, 121.6, 126.3, 126.8, 127.3,
134.9, 148.9, 155.0, 161.9, 170.4; MS m/z 218.22 (MþH); Calcd for
C11H13N3O2: C 60.26%; H 5.98%; N 19.17%, found: C 60.45%; H 5.74%;
N 19.23%.
4.2.2. 2-N-Terbutoxycarbonylaminomethyl-quinazolin-4-(3H)-one
(14b). Anthranilamide was reacted with N-Boc-glycine to obtain
14b as a white solid in 65% yield: mp 208–210 ꢀC; 1H NMR
(300 MHz, [D6]DMSO, 25 ꢀC)
d
¼1.40 (s, 9H), 4.08 (m, 2H), 7.18 (t,
J¼5.50 Hz, 1H), 7.48 (t, J¼7.60 Hz, 1H), 7.60 (d, J¼7.9 Hz, 1H), 7.79 (t,
J¼7.6 Hz, 1H), 8.08 (d, J¼7.8 Hz, 1H), 11.83 (m, 1H); 13C NMR
(75 MHz, [D6]DMSO, 25 ꢀC)
d
¼28.6, 43.1, 78.8, 121.6, 126.3, 126.7,
127.3, 134.9, 149.0, 155.2, 156.2, 162.0; MS m/z 276.30 (MþH); Calcd
for C14H19N3O3: C 60.63%; H 6.91%; N 15.15%, found: C 60.87%; H
6.76%; N 15.27%.
4.2. General procedure for synthesis of 2-N-acylaminoalkyl-
quinazolin-4-(3H)-ones 14a,b,d–f,h–j,l–n,p
4.2.3. 2-N-Benzoylaminomethyl-quinazolin-4-(3H)-one
(14d). Anthranilamide was reacted with hippuric acid to obtain
14d as a white solid in 81% yield: mp 279–281 ꢀC; 1H NMR
In a sealed reaction vial, isobutyl chloroformate (2 mmol) was
added to a cold (ꢁ15 ꢀC) solution of N-acylamino acid derivative 12
(2 mmol) and N-methylmorpholine (2 mmol) in THF (10 mL) and
the mixture was stirred at ꢁ15 ꢀC for 30 min. Anthranilamide
(2 mmol) was then added and the sealed vial was irradiated in the
microwave for 20 min at 120 ꢀC (power of 100 W). After cooling the
mixture to room temperature, a solution of 2 N NaOEt in ethanol
(2 mL) was added and the resulting mixture was heated in the
microwave at 120 ꢀC for 10 min (power of 100 W). After evapora-
tion under reduced pressure, the resulting residue was hydrolyzed,
acidified with aqueous 1 N HCl solution untill precipitation and
recrystallized from EtOH.
(300 MHz, [D6]DMSO, 25 ꢀC)
d
¼4.42 (d, J¼5.6, 2H), 7.45–7.60 (m,
5H), 7.77 (t, J¼7.5 Hz, 1H), 7.92 (d, J¼7.7 Hz, 2H), 8.08 (d, J¼8.0 Hz,
1H), 9.03 (t, J¼5.6, 1H), 12.27 (m, 1H); 13C NMR (75 MHz, [D6]DMSO,
25 ꢀC)
d
¼42.7,121.6,126.3,126.7,127.3,127.8,128.8,131.9,134.3,134.8,
149.0,155.2,162.2,167.1; MS m/z 280.29 (MþH); Calcd for
C16H15N3O2: C 68.31%; H 5.37%; N 14.94%, found: C 68.62%; H 5.25%;
N 15.03%.
4.2.4. 2-[1-(N-Acetylamino)ethyl]-quinazolin-4-(3H)-one
(14e). Anthranilamide was reacted with N-acetylalanine to obtain
14e as a white solid in 72% yield: mp 254–256 ꢀC; 1H NMR
(300 MHz, [D6]DMSO, 25 ꢀC)
d
¼1.38 (d, J¼7.15, 3H), 1.87 (s, 3H),
4. 2.1. 2-N-Acetylaminomethyl-quinazolin-4-(3H)-one
(14a). Anthranilamide was reacted with N-acetylglycine to obtain
14a as a white solid in 80% yield: mp 267–270 ꢀC; 1H NMR
4.72 (m, 1H), 7.48 (t, J¼7.5, 1H), 7.61 (d, J¼8.0, 1H), 7.78 (t, J¼7.55,
1H), 8.08 (d, J¼8.0, 1H), 8.32 (d, J¼7.05, 1H), 12.16 (m, 1H); 13C NMR
(75 MHz, [D6]DMSO, 25 ꢀC)
d
¼19.7, 23.0, 48.2, 121.6, 126.3, 126.8,
(300 MHz, [D6]DMSO, 25 ꢀC)
d
¼1.92 (s, 3H), 4.22 (d, J¼5.7 Hz, 2H),
127.4, 134.9, 149.1, 159.0, 162.1, 169.8; MS m/z 232.25 (MþH); Calcd

F. Jankowski et al. / Tetrahedron 66 (2010) 128–133
131
for C12H15N3O2: C 61.79%; H 6.48%; N 18.01%, found: C 61.95%; H
6.29%; N 18.37%.
d
¼22.9, 54.1, 121.6, 126.3, 126.8, 126.9, 128.6, 129.7, 135.0, 138.1,
149.1, 158.2, 162.1, 169.9; MS m/z 308.34 (MþH); Calcd for
C18H17N3O2: C 70.34%; H 5.58%; N 13.67%, found: C 70.56%; H 5.47%;
N 13.78%.
4.2.5. 2-[1-(N-Terbutoxycarbonylamino)ethyl]-quinazolin-4-(3H)-one
(14f). Anthranilamide was reacted with N-Boc-alanine to obtain 14f
as a white solid in 76% yield: mp 218–220 ꢀC; 1H NMR (300 MHz,
4.2.11. 2-[1-(N-Terbutoxycarbonylamino)-2-phenylethyl]-quinazolin-
4-(3H)-one (14n). Anthranilamide was reacted with N-Boc-
phenylalanine to obtain 14n as a white solid in 87% yield: mp
211–213 ꢀC; H NMR (300 MHz, [D6]DMSO, 25 ꢀC)
[D6]DMSO, 25 ꢀC)
d
¼1.36 (m, 12H), 4.47 (m, 1H), 7.19 (d, J¼7.5 Hz,
1H), 7.48 (t, J¼7.3 Hz, 1H), 7.60 (d, J¼7.8 Hz, 1H), 7.78 (t, J¼7.3 Hz,
1H), 8.08 (d, J¼7.8 Hz, 1H), 12.08 (m, 1H); 13C NMR (75 MHz,
d
¼1.28 (m,
1
[D6]DMSO, 25 ꢀC)
d¼19.8, 28.6, 49.7, 78.7, 121.5, 126.2, 126.8, 127.4,
9H), 2.91 (m, 1H), 3.10 (m, 1H), 4.63 (m, 1H), 7.15–7.37 (m, 6H),
7.49 (t, J¼7.5 Hz, 1H), 7.62 (d, J¼8.0 Hz, 1H), 7.80 (t, J¼7.5 Hz, 1H),
8.08 (d, J¼7.8 Hz, 1H), 12.36 (s, 1H); 13C NMR (75 MHz,
134.9, 149.0, 155.5, 159.2, 162.2; MS m/z 290.32 (MþH); Calcd for
C15H21N3O3: C 61.84%; H 7.27%; N 14.42%, found: C 62.04%; H 7.17%;
N 14.56%.
[D6]DMSO, 25 ꢀC)
d
¼28.6, 55.9, 78.7, 121.6, 126.3, 126.8, 127.3,
128.5, 129.8, 134.9, 138.2, 155.8, 162.2; MS m/z 366.42 (MþH);
Calcd for C21H23N3O3: C 69.02%; H 6.34%; N 11.50%, found: C
69.18%; H 6.24%; N 11.65%.
4.2.6. 2-[1-(N-Benzoylamino)ethyl]-quinazolin-4-(3H)-one
(14h). Anthranilamide was reacted with N-Benzoylalanine to
obtain 14h as a white solid in 76% yield: mp 260–262 ꢀC; 1H
NMR (300 MHz, [D6]DMSO, 25 ꢀC)
d
¼1.55 (d, J¼7.05, 3H), 4.95
4.2.12. 2-[1-(N-Benzoylamino)-2-phenylethyl]-quinazolin -4-(3H)-one
(14p). Anthranilamide was reacted with N-benzoylphenylalanine to
obtain 14p as a white solid in 88% yield: mp 274–276 ꢀC; 1H NMR
(300 MHz, [D6]DMSO, 25 ꢀC)
(m, 1H), 7.45–7.62 (m, 5H), 7.78 (t, J¼7.3, 1H), 7.93 (d, J¼8.10, 2H),
8.10 (d, J¼8.0, 1H), 8.81 (d, J¼6.90, 1H), 12.31 (m, 1H); MS m/z
13
294.32 (MþH); C NMR (75 MHz, [D6]DMSO, 25 ꢀC)
d
¼19.4,
d¼3.22 (m, 2H), 5.14 (m, 1H), 7.17 (t,
49.2, 121.6, 126.3, 126.8, 127.5, 128.0, 128.7, 131.9, 134.3, 134.9,
149.0, 159.0, 162.2, 166.7; MS m/z 294.32 (MþH); Calcd for
C17H15N3O2: C 69.61%; H 5.15%; N 14.33%, found: C 69.84%; H
5.08%; N 14.46%.
J¼7.2 Hz, 1H), 7.27 (t, J¼7.1 Hz, 2H), 7.43–7.53 (m, 6H), 7.61 (d,
J¼7.8 Hz, 1H), 7.80 (m, 3H), 8.11 (d, J¼7.8 Hz, 1H), 8.94 (d, J¼7.7 Hz,
1H), 12.51 (s, 1H); 13C NMR (75 MHz, [D6]DMSO, 25 ꢀC)
d¼38.8, 55.0,
121.7, 126.3, 126.9, 127.4, 127.9, 128.6, 128.7, 129.8, 131.9, 134.2, 134.9,
138.4, 149.0, 158.0, 162.1, 166.9; MS m/z 370.41 (MþH); Calcd for
C23H19N3O2: C 74.78%; H 5.18%; N 11.37%, found: C 74.87%; H 5.10%; N
11.51%.
4.2.7. 2-[1-(N-Acetylamino)-3-methylbutyl]-quinazolin-4-(3H)-one
(14i). Anthranilamide was reacted with N-acetylleucine to obtain
14i as a white solid in 79% yield: mp 213–215 ꢀC; 1H NMR
(300 MHz, [D6]DMSO, 25 ꢀC)
d
¼0.90 (m, 6H), 1.63 (m, 3H), 1.88 (s,
3H), 4.75 (m, 1H), 7.48 (t, J¼7.1 Hz 1H), 7.61 (d, J¼7.6 Hz, 1H), 7.79 (t,
4.3. General procedure for synthesis of 2-N-
formylaminoalkyl-quinazolin-4-(3H)-ones 14c,g,k,o
J¼7.1 Hz, 1H), 8.09 (d, J¼7.6 Hz, 1H), 8.28 (d, J¼7.9 Hz, 1H), 12.26 (s,
13
1H); C NMR (75 MHz, [D6]DMSO, 25 ꢀC)
d¼21.9, 22.9, 23.4, 24.8,
42.4, 51.0, 121.5, 126.2, 126.7, 127.3, 134.8, 149.1, 159.0, 162.1, 169.9;
MS m/z 274.33 (MþH); Calcd for C15H19N3O2: C 65.91%; H 7.01%; N
15.37%, found: C 66.13%; H 6.95%; N 15.52%.
A mixture of the appropriate Boc-derivative 14b,f,j,n (1 mmol)
and trifluoroacetic acid (2,5 mL) in CH2Cl2 (20 mL) was stirred for
2 h at reflux. After evaporation of the solvent, triethylamine (2 mL)
and ethyl formate (10 mL) were added and the reaction mixture
was refluxed overnight. Trituration of the residue, obtained after
evaporation under vacuum, with water provided a white powder,
which was recrystallized from EtOH.
4.2.8. 2-[1-(N-Terbutoxycarbonylamino)-3-methylbutyl]-quinazolin-
4-(3H)-one (14j). Anthranilamide was reacted with N-Boc-leucine
to obtain 14j as a white solid in 73% yield: mp 178–180 ꢀC; 1H NMR
(300 MHz, [D6]DMSO, 25 ꢀC)
d
¼0.89 (m, 6H), 1.35 (s, 9H), 1.58 (m,
3H), 4.48 (m,1H), 7.13 (d, J¼8.2 Hz,1H), 7.47 (t, J¼7.6 Hz 1H), 7.60 (d,
4.3.1. 2-N-Formylaminomethyl-quinazolin-4-(3H)-one (14c). 14c was
J¼8.1 Hz, 1H), 7.78 (t, J¼7.6 Hz, 1H), 8.08 (d, J¼8.1 Hz, 1H), 12.15 (s,
obtained as a white solid (76%): mp 263–265 ꢀC; 1H NMR (300 MHz,
13
1H); C NMR (75 MHz, [D6]DMSO, 25 ꢀC)
d¼21.9, 23.3, 24.9, 28.6,
[D6]DMSO, 25 ꢀC)
d¼4.28 (d, J¼5.9 Hz, 2H), 7.49 (t, J¼7.3 Hz 1H), 7.61
42.4, 52.8, 87.7, 121.5, 126.2, 126.7, 127.4, 134.9, 155.7, 159.0, 162.2;
MS m/z 332.41 (MþH); Calcd for C18H25N3O3: C 65.23%; H 7.60%; N
12.68%, found: C 65.49%; H 7.51%; N 12.83%.
(d, J¼7.9 Hz, 1H), 7.79 (t, J¼7.3 Hz, 1H), 8.09 (d, J¼7.7 Hz, 1H), 8.17 (s,
1H), 8.50 (m, 1H), 12.18 (s, 1H); 13C NMR (75 MHz, [D6]DMSO, 25 ꢀC)
d
¼121.6, 126.3, 126.8, 127.2, 134.9, 148.8, 154.3, 162.0, 162.5; MS m/z
204.19 (MþH); Calcd for C10H11N3O2: C 58.53%; H 5.40%; N 20.48%,
4.2.9. 2-[1-(N-Benzoylamino)-3-methylbutyl]-quinazolin-4-(3H)-
one (14l). Anthranilamide was reacted with N-Benzoylleucine to
obtain 14l as a white solid in 71% yield: mp 240–242 ꢀC; 1H NMR
found: C 58.79%; H 5.35%; N 20.53%.
4.3.2. 2-[1-(N-Formylamino)ethyl]-quinazolin-4-(3H)-one
(300 MHz, [D6]DMSO, 25 ꢀC)
d
¼0.92 (m, 6H), 1.70 (m, 2H), 1.92 (m,
(14g). 14g was obtained as a white solid (69%): mp 239–241 ꢀC; 1H
1H), 5.0 (m, 1H), 7.42–7.60 (m, 5H), 7.75 (t, J¼7.6, 1H), 7.93 (d, J¼7.4,
NMR (300 MHz, [D6]DMSO, 25 ꢀC)
d¼1.40 (d, J¼6.8 Hz, 3H), 4.81 (m,
2H), 8.08 (d, J¼7.8, 1H), 8.85 (d, J¼7.6, 1H), 12.39 (m, 1H); 13C NMR
1H), 7.49 (t, J¼7.6 Hz, 1H), 7.62 (d, J¼8.0 Hz, 1H), 7.79 (t, J¼7.6 Hz,
(75 MHz, [D6]DMSO, 25 ꢀC)
d
¼21.9, 23.4, 25.1, 42.2, 52.3, 121.6,
1H), 8.07 (m, 2H), 8.59 (d, J¼6.7 Hz, 1H), 12.27 (m, 1H); 13C NMR
126.3, 126.5, 127.2, 128.0, 128.7, 131.9, 134.4, 134.6, 149.2, 159.7,
163.2, 166.8; MS m/z 336.39 (MþH); Calcd for C20H21N3O2: C
71.62%; H 6.31%; N 12.53%, found: C 71.90%; H 6.22%; N 12.65%.
(75 MHz)
d
¼20.0, 46.7, 121.6, 126.3, 126.9, 127.4, 134.9, 148.9, 158.2,
161.4,162.0; MS m/z 218.22 (MþH); Calcd for C11H11N3O2: C 60.82%;
H 5.10%; N 19.34%, found: C 60.93%; H 5.04%; N 19.47%.
4.2.10. 2-[1-(N-Acetylamino)-2-phenylethyl]-quinazolin-4-(3H)-one
(14m). Anthranilamide was reacted with N-acetylphenylalanine to
obtain 14m as a white solid in 82% yield: mp 256–258 ꢀC; 1H NMR
4.3.3. 2-[1-(N-Formylamino)-3-methylbutyl]-quinazolin-4-(3H)-one
(14k). 14k was obtained as a white solid (73%): mp 214–216 ꢀC; 1H
NMR (300 MHz, [D6]DMSO, 25 ꢀC)
d
¼0.89 (m, 6H), 1.35 (s, 9H), 1.64
(300 MHz, [D6]DMSO, 25 ꢀC)
d
¼1.80 (m, 3H), 2.92 (m, 1H), 3.15 (m,
(m, 3H), 4.84 (m, 1H), 7.48 (t, J¼7.5 Hz 1H), 7.61 (d, J¼8.1 Hz, 1H),
1H), 4.92 (m, 1H), 7.15–7.35 (m, 5H), 7.49 (t, J¼7.5 Hz, 1H), 7.64 (d,
7.79 (t, J¼7.6 Hz, 1H), 8.09 (m, 2H), 8.52 (d, J¼8.3 Hz, 1H), 12.36 (s,
13
J¼8.1 Hz, 1H), 7.80 (t, J¼7.5 Hz, 1H), 8.09 (d, J¼8.2 Hz, 1H), 8.48 (d,
1H); C NMR (75 MHz, [D6]DMSO, 25 ꢀC)
d
¼21.9, 23.4, 24.8, 42.6,
13
J¼7.8 Hz, 1H), 12.37 (s, 1H); C NMR (75 MHz, [D6]DMSO, 25 ꢀC)
49.5, 121.5, 126.3, 126.8, 127.3, 134.9, 149.1, 158.4, 161.6, 162.1; MS

132
F. Jankowski et al. / Tetrahedron 66 (2010) 128–133
m/z 260.30 (MþH); Calcd for C14H17N3O2: C 64.85%; H 6.61%; N
126.1, 129.0, 135.1, 135.3, 158.5; MS m/z 200.21 (MþH); Calcd for
C11H9N3O: C 66.32%; H 4.55%; N 21.09%, found: C 66.50%; H 4.45%;
16.21%, found: C 65.01%; H 6.53%; N 16.41%.
N 21.21%.
4.3.4. 2-[1-(N-Formylamino)-2-phenylethyl]-quinazolin-4-(3H)-one
(14o). 14o was obtained as a white solid (77%): mp 214–215 ꢀC; 1H
4.4.6. 3-Methyl-1-phenylimidazo[1,5-a]quinazolin-5-(4H)-one
NMR (300 MHz, [D6]DMSO, 25 ꢀC)
d
¼2.94 (m, 1H), 3.19 (m, 1H),
(15h). 15h was obtained as a yellow solid (93%): mp 227–229 ꢀC; 1H
5.04 (m, 1H), 7.28 (m, 5H), 7.50 (m, 1H), 7.64 (m, 1H), 7.81 (m, 1H),
7.99 (m, 1H), 8.10 (m, 1H), 8.69 (m, 1H), 12.47 (s, 1H); 13C NMR
NMR (300 MHz, [D6]DMSO, 25 ꢀC)
d
¼2.23 (s, 3H), 7.09 (d, J¼8.4 Hz,
1H), 7.38 (t, J¼7.8 Hz, 1H), 7.46–7.58 (m, 6H), 8.14 (d, J¼7.7 Hz, 1H),
13
(75 MHz, [D6]DMSO, 25 ꢀC)
d
¼52.5, 121.6, 126.3, 127.0, 127.4, 128.6,
11.85 (s, 1H); C NMR (75 MHz, [D6]DMSO, 25 ꢀC)
d¼11.6,114.7,
129.1, 129.8, 129.9, 135.0, 137.7, 148.9, 157.4, 161.6, 162.0; MS m/z
294.32 (MþH); Calcd for C17H15N3O2: C 69.61%; H 5.15%; N 14.33%,
found: C 69.80%; H 5.09%; N 14.44%.
116.3,118.1,125.9,126.5,127.9,128.7,129.3,129.8,133.3,134.0,136.2,137.3,
158.4; MS m/z 276.30 (MþH); Calcd for C17H13N3O: C 74.17%; H 4.76%;
N 15.26%, found: C 74.32%; H 4.66%; N 15.40%.
4.4. General procedure for synthesis of imidazo[1,5-
a]quinazolin-5-(4H)-ones 15a–p
4.4.7. 3-Isobutyl-1-methylimidazo[1,5-a]quinazolin-5-(4H)-one
(15i). 15i was obtained as a beige solid (87%): mp 266–268 ꢀC; 1H
NMR (300 MHz, [D6]DMSO, 25 ꢀC)
d
¼0.87 (d, J¼6.7 Hz, 6H),1.85 (m,
A mixture of the appropriate acylaminoquinazolinone de-
rivative 14 (1 mmol) and PPA (3 g/mmol) in xylene (5 mL) was
heated at 120 ꢀC under microwave irradiation at atmospheric
pressure for 15 min (power of 20 W). The xylene was decanted and
the remaining gum was washed twice with petroleum ether and
dissolved in water. The aqueous solution was filtrated and dropwise
addition of 30% NaOH led to precipitation of the product, which was
removed by filtration and recrystallized in EtOH.
1H), 2.42 (d, J¼7.0 Hz, 2H), 2.74 (s, 3H), 7.47 (t, J¼7.5 Hz, 1H), 7.81 (t,
J¼7.5 Hz, 1H), 7.99 (d, J¼8.4 Hz, 1H), 8.17 (d, J¼8.1 Hz, 1H), 11.64 (s,
13
1H); C NMR (75 MHz, [D6]DMSO, 25 ꢀC)
d¼18.8, 22.6, 28.9, 34.0,
116.4, 116.8, 117.8, 125.5, 125.7, 129.1, 134.9, 135.2, 136.8, 158.2; MS
m/z 256.31 (MþH); Calcd for C15H17N3O: C 70.56%; H 6.71%; N
16.46%, found: C 70.71%; H 6.54%; N 16.57%.
4.4.8. 3-Isobutylimidazo[1,5-a]quinazolin-5-(4H)-one (15k). 15k was
obtained as a beige solid (79%): mp 257–259 ꢀC; 1H NMR (300 MHz,
4.4.1. 1-Methylimidazo[1,5-a]quinazolin-5-(4H)-one (15a). 15a was
[D6]DMSO, 25 ꢀC)
d
¼0.88 (d, J¼6.6 Hz, 6H),1.88 (m,1H), 2.48 (m, 2H),
7.46 (t, J¼7.5 Hz, 1H), 7.82 (t, J¼7.5 Hz, 1H), 8.12 (m, 2H), 8.46 (s, 1H),
11.74 (s, 1H); 13C NMR (75 MHz, [D6]DMSO, 25 ꢀC)
obtained as a beige solid (85%): mp 200–202 ꢀC; 1H NMR (300 MHz,
[D6]DMSO, 25 ꢀC)
d
¼2.77 (s, 3H), 6.38 (s, 1H), 7.50 (t, J¼7.3 Hz, 1H),
d
¼22.5, 29.0, 34.3,
7.84 (t, J¼7.3 Hz, 1H), 8.04 (d, J¼8.4 Hz, 1H), 8.18 (d, J¼7.9 Hz, 1H),
115.4, 116.9, 119.3, 125.3, 126.1, 129.0, 135.1, 135.3, 158.6; MS m/z
242.28 (MþH); Calcd for C14H15N3O: C 69.69%; H 6.27%; N 17.41%,
found: C 69.82%; H 6.12%; N 17.53%.
13
11.79 (s, 1H); C NMR (75 MHz, [D6]DMSO, 25 ꢀC)
d
¼18.8, 105.3,
116.6, 117.9, 125.8, 129.1, 130.3, 134.9, 136.4, 136.5, 157.8; MS m/z
200.21 (MþH); Calcd for C11H9N3O: C 66.32%; H 4.55%; N 21.09%,
found: C 66.48%; H 4.49%; N 21.17%.
4.4.9. 3-Isobutyl-1-phenyllimidazo[1,5-a]quinazolin-5-(4H)-one
(15l). 15l was obtained as a yellow solid (92%): mp 283–285 ꢀC; 1H
4.4.2. Imidazo[1,5-a]quinazolin-5-(4H)-one (15c). 15c was obtained
NMR (300 MHz, [D6]DMSO, 25 ꢀC)
d
¼0.91 (d, J¼6.6 Hz, 6H),1.92 (m,
as a beige solid (81%): mp 240–242 ꢀC; 1H NMR (300 MHz,
1H), 2.52 (d, J¼7.1 Hz, 2H), 7.12 (d, J¼8.3 Hz, 1H), 7.38 (t, J¼7.6 Hz,
[D6]DMSO, 25 ꢀC)
d
¼6.52 (s, 1H), 7.49 (t, J¼7.6 Hz, 1H), 7.84 (t,
1H), 7.47–7.59 (m, 6H), 8.14 (d, J¼7.9 Hz, 1H), 11.81 (s, 1H); 13C NMR
J¼7.5 Hz, 1H), 8.12 (d, J¼7.9 Hz, 1H), 8.18 (d, J¼8.1 Hz, 1H), 8.53 (s,
(75 MHz, [D6]DMSO, 25 ꢀC)
125.9, 126.9, 129.3, 129.7, 129.9, 133.4, 134.1, 136.3, 137.5, 158.7; MS
m/z 318.38 (MþH); Calcd for C20H19N3O: C 75.69%; H 6.03%; N
13.24%, found: C 75.87%; H 5.98%; N 13.31%.
d
¼22.7, 28.9, 34.1, 116.4, 118.1, 119.0,
13
1H), 11.84 (s, 1H); C NMR (75 MHz, [D6]DMSO, 25 ꢀC)
d¼107.6,
115.6, 117.1, 126.4, 126.5, 129.0, 129.7, 135.1, 158.2; MS m/z 186.18
(MþH); Calcd for C10H7N3O: C 64.86%; H 3.81%; N 22.69%, found: C
65.02%; H 3.73%; N 22.75%.
4.4.10. 3-Benzyl-1-methylimidazo[1,5-a]quinazolin-5-(4H)-one
4.4.3. 1-Phenylimidazo[1,5-a]quinazolin-5-(4H)-one (15d). 15d was
(15m). 15m was obtained as a white solid (78%): mp 200–202 ꢀC;
obtained as a yellow solid (79%): mp 258–260 ꢀC; 1H NMR
1H NMR (300 MHz, [D6]DMSO, 25 ꢀC)
d
¼2.73 (s, 3H), 3.92 (s, 2H),
(300 MHz, [D6]DMSO, 25 ꢀC)
d
6.65 (s, 1H), 7.12 (d, J¼8.3 Hz, 1H),
7.14 (m, 1H), 7.24 (m, 4H), 7.48 (t, J¼7.9 Hz, 1H), 7.82 (t, J¼7.5 Hz,
7.42 (t, J¼7.8 Hz, 1H), 7.49–7.61 (m, 6H), 8.16 (d, J¼7.9 Hz, 1H), 11.96
1H), 8.00 (d, J¼8.3 Hz, 1H), 8.18 (d, J¼7.7 Hz, 1H), 11.91 (s, 1H); 13C
13
(s, 1H); C NMR (75 MHz, [D6]DMSO, 25 ꢀC)
d
107.3, 116.5, 118.3,
NMR (75 MHz, [D6]DMSO, 25 ꢀC)
d
¼18.8, 31.1, 116.2, 116.5, 117.7,
126.2, 129.3, 129.4, 129.9, 131.3, 133.3, 134.1, 136.1, 138.5, 158.0; MS
m/z 262.27 (MþH); Calcd for C16H11N3O: C 73.55%; H 4.24%; N
16.08%, found: C 73.72%; H 4.16%; N 16.19%.
125.6, 126.1, 128.5, 128.9, 129.2, 135.0, 135.8, 136.4, 141.4, 158.4; MS
m/z 290.33 (MþH); Calcd for C18H15N3O: C 74.72%; H 5.23%; N
14.52%, found: C 74.90%; H 5.15%; N 14.71%.
4.4.4. 1,3-Dimethylimidazo[1,5-a]quinazolin-5-(4H)-one (15e). 15e
4.4.11. 3-Benzylimidazo[1,5-a]quinazolin-5-(4H)-one (15o). 15o was
was obtained as a yellow solid (74%): mp 286–288 ꢀC; 1H NMR
obtained as a beige solid (81%): mp 274–276 ꢀC; 1H NMR (300 MHz,
(300 MHz, [D6]DMSO, 25 ꢀC)
d
¼2.15 (s, 3H), 2.74 (s, 3H), 7.48 (t,
[D6]DMSO, 25 ꢀC)
d
¼3.97 (s, 2H), 7.14 (m, 1H), 7.26 (m, 4H), 7.46 (t,
J¼7.4 Hz, 1H), 7.82 (t, J¼7.4, 1H), 7.99 (d, J¼8.2, 1H), 8.18 (dd, J¼7.9,
J¼7.4 Hz, 1H), 7.81 (t, J¼7.3 Hz, 1H), 8.12 (m, 2H), 8.48 (s, 1H), 11.96
13
13
1.7, 1H); C NMR (75 MHz, [D6]DMSO, 25 ꢀC)
d¼11.5, 18.7, 112.5,
(s, 1H); C NMR (75 MHz, [D6]DMSO, 25 ꢀC)
d¼31.4, 115.4, 117.0,
116.4, 117.7, 125.2, 125.5, 129.2, 134.9, 135.1, 136.6, 158.2; MS m/z
214.25 (MþH); Calcd for C12H11N3O: C 67.59%; H 5.20%; N 19.71%,
found: C 67.74%; H 5.11%; N 19.90%.
118.8, 125.3, 125.8, 126.1, 126.2, 128.6, 128.9, 129.0, 135.1, 135.2,
141.3, 158.6; MS m/z 276.30 (MþH); Calcd for C17H13N3O: C 74.17%;
H 4.76%; N 15.26%, found: C 74.41%; H 4.65%; N 15.39%.
4.4.5. 3-Methylimidazo[1,5-a]quinazolin-5-(4H)-one (15g). 15g was
4.4.12. 3-Benzyl-1-phenylimidazo[1,5-a]quinazolin-5-(4H)-one
obtained as a beige solid (95%): mp 220–222 ꢀC; 1H NMR (300 MHz,
(15p). 15p was obtained as a yellow solid (80%): mp 270–272 ꢀC; 1H
[D6]DMSO, 25 ꢀC)
d
¼2.18 (s, 3H), 7.45 (t, J¼7.8 Hz, 1H), 7.81 (t,
NMR (300 MHz, [D6]DMSO, 25 ꢀC)
(t, J¼7.3 Hz, 2H), 7.32 (d, J¼7.8 Hz, 2H), 7.40 (t, J¼7.5 Hz, 1H), 7.48–
d
¼4.02 (s, 2H), 7.14 (m, 2H), 7.26
J¼7.6 Hz, 1H), 8.11 (m, 2H), 8.44 (s, 1H), 11.70 (m, 1H); 13C NMR
(75 MHz, [D6]DMSO, 25 ꢀC)
d¼11.7, 115.1, 115.3, 116.9, 125.0, 125.2,
7.58 (m, 6H), 8.16 (d, J¼7.9 Hz, 1H), 12.07 (s, 1H); 13C NMR (75 MHz,

F. Jankowski et al. / Tetrahedron 66 (2010) 128–133
133
[D6]DMSO, 25 ꢀC)
129.0, 129.3, 129.9, 133.2, 134.1, 136.2, 137.9, 141.1, 158.6; MS m/z
352.40 (MþH); Calcd for C23H17N3O: C 78.61%; H 4.88%; N 11.96%,
found: C 78.78%; H 4.81%; N 12.05%.
d
¼31.2, 116.4, 118.2, 126.0, 126.2, 126.8, 128.6,
6. (a) Shingh, B. D.; Chaudhury, D. N. J. Indian Chem. Soc. 1969, 46, 21–25; (b)
Talukdar, P. B.; Sengupta, S. K.; Datta, A. K. Indian J. Chem. B 1980, 19, 638–640;
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4,771,051, 1988.
7. Rad-Moghadam, K.; Mohseni, M. J. Chem. Res., Synop. 2003, 487–488.
8. (a) Deepthi, K. S.; Reddy, D. S.; Reddy, P. P.; Reddy, P. S. N. Indian J. Chem. B 2000,
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Acknowledgements
´
´
We thank Laboratoire d’Application de Resonnance Magnetique
´
´
Nucleaire de l’Universite de Lille 2 for its help in the interpretation
9. Azizian, J.; Mohammadi, A. A.; Karimi, A. R.; Mohammadizadeh, M. R. J. Chem.
Res., Synop. 2004, 435–437.
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of the NMR spectra.
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