Novel series of 8H-quinazolino[4,3-b]quinazolin-8-ones via two Niementowski condensations

Article abstract of DOI:10.1016/S0040-4020(03)00053-X

Efficient microwave-assisted multi-step synthesis of 8H-quinazolino[4,3-b]quinazolin-8-one was investigated. The synthesis involved two Niementowski condensations from anthranilic acids. Homogeneous or heterogeneous conditions were studied with the aim to develop convenient syntheses of the desired compounds.

Full text of DOI:10.1016/S0040-4020(03)00053-X

Tetrahedron 59 (2003) 1413–1419
Novel series of 8H-quinazolino[4,3-b]quinazolin-8-ones via two
Niementowski condensations
Franc¸ois-Rene Alexandre, Amaya Berecibar,a Roger Wriggleswortha and Thierry Bessonb
a,b
,
*
´
aPFIZER Global Research & Development, Fresnes Laboratories, 3-9 rue de la Loge, BP100, F-94265 Fresnes cedex, France
´ ´
Laboratoire de Genie Proteique et Cellulaire, EA3169, Groupe de Chimie Organique, UFR Sciences Fondamentales et Sciences pour
b
´ ˆ ´
l’Ingenieur, Batiment Marie Curie, Universite de la Rochelle, F-17042 La Rochelle cedex 1, France
Received 15 November 2002; revised 12 December 2002; accepted 9 January 2003
Abstract—Efficient microwave-assisted multi-step synthesis of 8H-quinazolino[4,3-b]quinazolin-8-one was investigated. The synthesis
involved two Niementowski condensations from anthranilic acids. Homogeneous or heterogeneous conditions were studied with the aim to
develop convenient syntheses of the desired compounds. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
recent work on the preparation of fused polyhetero-
cycles.6
The quinazoline ring skeleton is widely found in alkaloids
and many biologically active compounds.1 Among this class
of molecules, 4-aminoquinazolines 1 are useful as fungi-
cides, anti-inflammatory, anticancer, antimicrobial and anti-
hypertensive agents.2,3 Other natural fused heterocycles
such as Rutaecarpine 2, which has intrinsic hypertensive,
diuretic and uterotonic properties,4 and Luotonine A 3,
which has antitumor activity,5 possess a quinazolinone
moiety fused with indolopyrido and pyrrolloquinoline
ring systems, respectively (Fig. 1). In search of
new polyheterocyclic compounds with potential pharma-
ceutical value and in association with our work on the
application of microwaves in organic chemistry, we
planned to prepare novel tetracyclic 8H-quinazolino[4,3-
b]quinazolin-8-ones 4, from anthranilic acids, by fusing
the quinazolinone and the quinazoline rings. The
synthesis of various congeners was performed via two
Niementowski condensations, inspired by our
Microwave-assisted reactions are now well established and
have gained popularity as indicated by the large number of
papers currently published on this topic since 1986.7 The
beneficial effects of microwave irradiation are finding an
increased role in process chemistry,8 especially in cases
when usual methods require forcing conditions or prolonged
reaction times. Microwaves have also shown an advantage
where processes involve sensitive reagents or when
products may decompose under prolonged reaction con-
ditions. The possibilities offered by this technology are
particularly attractive for multi-step synthesis9 and drug
discovery process10 where high yielding protocols and
avoidance or facility of purification are highly desirable. In
this paper the multi-step synthesis of the 8H-quinazo-
lino[4,3-b]quinazolin-8-one ring was realised under micro-
wave irradiation with the aim to develop original and
environmentally friendly procedures.
Figure 1.
Keywords: nitrogen heterocycles; fused ring systems; microwave-assisted multi-steps synthesis; cyclisation.
*
Corresponding author. Tel.: þ33-5-46-45-82-76; fax: þ33-5-46-45-82-65; e-mail: tbesson@univ-lr.fr
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00053-X

1414
F.-R. Alexandre et al. / Tetrahedron 59 (2003) 1413–1419
Scheme 1. Retrosynthetic pathways.
2. Results and discussion
of the fusion between anthranilic acids 5 and various amides
or thioamides (in dry media or with solvents), was recently
re-investigated under microwave irradiation.15 Conden-
sation of formamide with various anthranilic acids afforded
substituted quinazolinones 6 in high yields and in short
reaction times (15–40 min) (Table 1).
2.1. Synthesis of (3H)-quinazolin-4-ones
The 6-unsubstituted 8H-quinazolino[4,3-b]quinazolin-8-
one skeleton was rarely published, only compound 4a
(Table 4) has been previously described.11,12 The first
descriptions of such a ring involved condensation between
methyl anthranilate and 2-chloroquinazoline followed by
thermolysis.11 The second method described dehydrogena-
tion of 9,10,11,12-tetrahydroquinazolino[4,3-b]quinazolin-
8-one.12
Formation of 4 was firstly investigated by a shorter route
which consists of condensation of the quinazolin-4-ones 6
and anthranilic acids. This strategy was rapidly judged non-
feasible in comparison with methods which favour the first
nucleophilic attack of the amino group of anthranilic acid by
introduction of a good leaving group on carbon 4 of the
quinazoline ring. Two strategies were identified: the first
one (method A) suggest a selective S-alkylation of a
mercapto group, whilst, the second pathway (method B)
consist of introduction of a chlorine at the appropriate
position.
The retrosynthetic pathway (Scheme 1) suggests that
generation of various quinazolinoquinazolines may start
with a Niementowski reaction between formamide and
anthranilic acids. Two routes were then identified from the
intermediate quinazolin-4-one 6. The first one was inspired
by recent works on base-modified nucleosides13 or indolo-
quinazolines6 and involved a modified Niementowski
condensation. The second path is more common and
suggests to prepare 4-chloroquinazolines 10 before conden-
sation with anthranilic acid derivatives.
2.2. Method A
Thionation of quinazolinones 6 was performed under
microwave irradiation using Lawesson’s reagent in the
presence of pyridine16 (Scheme 3, Table 2). Microwave
assisted transformations of 6a–c into 7a–c were completed
in 15–40 min instead of 18 h using classical heating (oil
bath). Curiously, treatment of 6d with Lawesson’s reagent
afforded the unexpected phenylthioformamide 8 in 56%
yield as the sole product (Scheme 4). The attempted
quinazolinethione 7d was synthesised from 6d using P2S5
in pyridine under microwave irradiation in a 70% yield.
Inspired by a recent microwave heterogeneous thionation
methods,17,18 an alternative approach to the thionation
reaction was studied using Lawesson’s reagent under
solvent-free conditions on solid support (graphite). In the
best case, only 40% of the attempted product 7a was
obtained and the method generated a lot of technical
problems (hazardous electric arcs and important elevation
of temperature).
The first step of the two routes studied involves preparation
of 4-(3H)-quinazolinones 6 via a traditional Niementowski
condensation14 (Scheme 2). This old reaction, which consist
Scheme 2. Synthesis of the (3H)-quinazolines-4-ones 615 under microwave
conditions (mW).
Table 1.
Compound
R1
R2
Time (min)
Yield of 6 (%)
Previous experience of the Niementowski reaction6 showed
us that direct condensation of thioamides with anthranilic
acids may be very difficult, or unsuccessful, and require
the transformation of the mercapto group of thioquinazo-
lines 7 into a better leaving group. S-Methylation of
5a
5b
5c
5d
H
Me
Br
H
H
H
MeO
20
15
20
40
90
75
75
70
MeO

F.-R. Alexandre et al. / Tetrahedron 59 (2003) 1413–1419
1415
Scheme 3. Thionation of quinazolinones 6 and S-alkylation of quinazolinethiones 7.
Table 2.
with the reactivity of such anthranilic acids in similar
reactions).
Compound
R1
R2
Time
(min)
Yield of 7
(%)
Time
(min)
Yield of 9
(%)
2.3. Method B
6a
6b
6c
6d
H
Me
Br
H
H
H
20
15
20
20
93a
87
84
75b
20
15
20
20
85
78
74
70
Reviewing literature, we decided to investigate an alterna-
tive to the preceding method and we performed microwave
assisted final cyclisation reactions in which chlorine is the
leaving group (instead of thiomethyl group).21 Short
exposure (10 min) of a mixture of the intermediate
quinazolinones 6 with phosphoryl chloride to microwaves
led to 4-chloroquinazolines 10 in very good yields (Scheme
5, Table 3). Under similar experimental conditions, with the
same quantity of starting materials, several hours are needed
by conventional heating to give the same yields.
MeO MeO
a
Same experiment using traditional heating (pyridine at reflux) gave 7a in
18 h and 92% yield.
Using P2S5 in pyridine.
b
Heating the 4-chloroquinazolines 10 and anthranilic acids
(2 equiv.) in acetic acid allowed the synthesis of the
expected quinazolino[4,3-b]quinazoline ring in very good
yields (Scheme 6, Table 4). The reaction is completed
within 20 min under microwave irradiation and needed 1 h
with classical heating. Under the same conditions (same
quantity of starting materials), a preliminary study of this
reaction showed that transposition of such experiments in
sealed tube (pressure monitored by the microwave appar-
atus) gave shorter times (10 min) and comparable yields. A
short exploration of this reaction at atmospheric pressure
under solvent-free conditions, with graphite as solid
support, gave unsatisfactory results (decomposition of
starting material).
Scheme 4.
Scheme 5. Synthesis of 4-chloroquinazolines 10 under microwave
conditions.
Table 3.
Although method A can be considered as a convenient
solventless procedure, method B afforded a more straight-
forward access to 8H-quinazolino[4,3-b]quinazolin-8-ones
4 and gave better yields than method A. Method B, which
was realised in solvents, is offering the possibility to explore
the interest of associating solid-phase synthesis and
microwave heating, as it has been recently demonstrated
in our group.22 Such a strategy is currently in course and
will be described latter.
Compound
R1
R2
Yield of 10 (%)
6a
6b
6c
6d
H
Me
Br
H
H
H
MeO
85
90
90
70
MeO
quinazolinethiones 7 was easily carried out with iodo-
methane in the presence of sodium hydroxide in a mixture
of water and methanol at room temperature according to
known procedures (Table 2).19
3. Conclusion
Graphite is one of the solids most efficiently heated by
microwaves and is also known for its adsorbing properties
of organic molecules.20 Thus, as we described before in the
synthesis of indoloquinazolines,6 the best method for the
preparation of 8H-quinazolino[4,3-b]quinazolin-8-ones 4
consists of microwave irradiation (1508C, 60 W) of a
mixture of the 4-(thiomethyl)quinazoline 9 and an excess of
anthranilic acid (6 equiv.), adsorbed on graphite (Scheme
6). This procedure led to the cyclised compounds 4 in good
yields and in a shorter time than for the purely thermal
procedures (Table 4) (the yields observed are in accordance
In conclusion, we have described an efficient microwave-
assisted multi-step synthesis of 8H-quinazolino[4,3-b]-
quinazolin-8-ones 4 via two Niementowski condensations
from anthranilic acids. This work demonstrates the real
benefit of using focussed microwave irradiation in multi-
step procedures, with commercially available reactors under
either homogeneous or heterogeneous conditions. In con-
trast to conventional heating, it gave the desired compounds
in higher overall yield with shorter reaction times and
products that are more amenable for purification. The

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F.-R. Alexandre et al. / Tetrahedron 59 (2003) 1413–1419
Scheme 6. Reagents and conditions: (a) S-methyl derivative 9, 5 (6 equiv.), graphite, mW (P 60 W) 1508C, 30 min; (b) chloroquinazolinone 10, 5 (2 equiv.),
CH3CO2H, atmopheric pressure, mW (P 100 W) 1058C, 20 min or sealed tube, mW (P 100 W) 1308C, 10 min.
Table 4. Synthesis of 8H-quinazolino[4,3-b]quinazolin-8-ones 4
Discovere focused microwave reactor (300 W, monomode
system) which has in situ magnetic stirrer, irradiation
monitored by PC computer, infrared measurement and
continuous feedback temperature control. Manipulations
were performed at atmospheric pressure or under pressure in
pressure-rated reaction tubes with continuous pressure
measurement.
Compound
R1
R2
R3
R4
Yield (%)
Method A
Method B
4a
4b
4c
4d
4e
4f
H
Me
Br
MeO
H
H
H
H
H
MeO
H
H
H
MeO
H
H
H
H
Me
Br
MeO
MeO
H
H
H
H
H
H
MeO
MeO
79
58
21
34
53
50
29
/
82
70
54
62
85
76
41
65
Quinazolin-4(3H)-one 6a–d were obtained according to the
procedure previously described.15
4g
4h
H
MeO
4.2. Synthesis of 4(3H)-quinazolinethione derivatives 7
and N-(3,4-dimethoxyphenyl)thioformamide 8: general
procedure
experimental microwave conditions described in this paper
are now well established and could be safely and
beneficially scaled up to multigram level with similar
yields, a strategy which is particular developed in our group.
A solution of quinazolin-4(3H)-one 6 (1.7 mmol) and
Lawesson’s reagent (0.8 equiv., 1.37 mmol) (or P2S5 for
6d, 2 equiv.) in pyridine(8.5 mL) was irradiated at 1158C
(power input: 60 W) until completion (TLC monitoring,
20 min). After cooling, the solvent was removed under
reduced pressure. The residue was then poured into boiling
water and was filtered off. The collected yellow solid was
dissolved into 1 M NaOH solution and the solution was
filtered again. The filtrate was neutralised with a saturated
NH4Cl solution until complete crystallisation occurred.
After filtration compound 7a as yellow solid was dried until
constant weight.
4. Experimental
4.1. General
Commercial reagents were used as received without
additional purification. Melting points were measured
using a Kofler melting point apparatus and are uncorrected.
IR spectra were recorded on a Perkin–Elmer Paragon
1
1000PC FT-IR instrument. H NMR (400 MHz) and 13C
4.2.1. 4(3H)-Quinazolinethione (7a). 93% Yield; yellow
solid; mp (H2O) .2608C (lit.23 312–3148C); IR (KBr) n
NMR (100 MHz) were recorded with a JEOL JNM LA400
spectrometer. Chemical shifts (d values) are expressed in
parts per million downfield from tetramethylsilane as an
internal standard and coupling constants (J) are expressed in
Hertz. Mass spectra were recorded on Spectrometer simple
quad platform LC micromass, electrospray. Thin-layered
chromatography (TLC), was performed on 0.2 mm pre-
coated plates of silica gel 60F-264 (Merk). Visualisation
was made with ultraviolet light. Column chromatography
was performed by using Merck silica gel (70–230 mesh).
Elemental analyses for new compounds were performed at
Centre Commun d’Analyses (University of La Rochelle).
High-resolution mass measurments were performed on a
3200–2500, 1597, 1247, 869, 763 cm21
;
1H NMR
(d6-DMSO) d 7.61 (t, J¼7.6 Hz, 1H), 7.72 (d, J¼8.0 Hz,
1H), 7.89 (td, J¼8.0, 1.6 Hz, 1H), 8.17 (s, 1H), 8.56 (dd,
J¼8.0, 1.6 Hz, 1H), 13.87 (brs, 1H); 13C NMR (d6-DMSO)
d 123.3, 123.5, 124.1, 124.4, 130.6, 139.0, 139.5, 180.8; MS
(ESI, Elþ) m/z¼163 (MHþ); HRMS: calcd for C8H6N2S,
162.0252; found, 162.0250.
4.2.2. 6-Methyl-4(3H)-quinazolinethione (7b). 87%
Yield; yellow solid; mp (H2O) .2608C (lit.24 .3008C);
IR (KBr) n 3200–2500, 1625, 1570, 1257, 865, 821, 691,
1
502 cm21; H NMR (d6-DMSO) d 2.52 (t, J¼1.2 Hz, 3H),
7.65 (d, J¼8.2 Hz, 1H), 7.75 (dd, J¼8.2, 1.2 Hz, 1H), 8.14
(s, 1H), 8.38 (s, 1H), 13.86 (brs, 1H); 13C NMR (d6-DMSO)
d 21.0, 127.9, 128.4, 128.6, 136.8, 138.1, 142.4, 143.1,
´
Varian MAT 311 in the Centre Regional de Mesures
Physiques de l’Ouest (CRMPO, Universite de Rennes).
´
Focused microwave irradiations were carried out with CEM

F.-R. Alexandre et al. / Tetrahedron 59 (2003) 1413–1419
1417
185.2; MS (ESI, Elþ) m/z¼177 (MHþ); HRMS: calcd for
MS (ESI, Elþ) m/z¼191 (MHþ); HRMS: calcd for
C9H8N2S, 176.0408; found, 176.0403.
C10H10N2S, 190.0565; found, 190.0561.
4.2.3. 6-Bromo-4(3H)-quinazolinethione (7c). 84% Yield;
yellow solid; mp (H2O) .2608C; IR (KBr) n 3200–2500,
4.3.3. 6-Bromo-4-(methylsulfanyl)quinazoline (9c). 74%
Yield; white solid, mp (CH2Cl2) 1638C; IR (KBr) n 3071,
2926, 1557, 1481, 829, 618, 494 cm21; 1H NMR (CDCl3): d
2.72 (s, 3H), 7.83 (d, J¼8.8 Hz, 1H), 7.91 (dd, J¼8.8,
2.0 Hz, 1H), 8.23 (d, J¼2.0 Hz, 1H), 9.00 (s, 1H); 13C NMR
(CDCl3) d 12.7, 120.9, 124.9, 126.2, 130.5, 137.1, 146.4,
153.8, 171.0; MS (ESI, Elþ) m/z¼255/257 (MHþ); HRMS:
calcd for C9H7BrN2S, 253.9513; found, 253.9487.
1
1621, 1286, 821, 698, 623 cm21; H NMR (d6-DMSO) d
7.68 (d, J¼8.8 Hz, 1H), 8.33 (dd, J¼8.8, 2.4 Hz, 1H), 8.21
(s, 1H), 8.64 (d, J¼2.4 Hz, 1H), 14.08 (brs, 1H); 13C NMR
(d6-DMSO) d 121.1, 130.3, 130.6, 130.9, 138.0, 143.3,
146.1, 184.4; MS (ESI, El2) m/z¼239–241 (M2Hþ);
HRMS: calcd for C8H5BrN2S, 239.9357; found, 239.9357.
4.2.4. 6,7-Dimethoxy-4(3H)-quinazolinethione (7d). 75%
Yield; yellow solid; mp (H2O) .2608C; IR (KBr) n 3200–
4.3.4. 6,7-Dimethoxy-4-(methylsulfanyl)quinazoline
(9d). 70% Yield; white solid, mp (CHCl3) 1608C; 1H
NMR (CDCl3): d 2.72 (s, 3H), 4.03 (s, 3H), 4.04 (s, 3H),
7.20 (s, 1H), 7.25 (s, 1H), 8.87 (s, 1H); 13C NMR (CDCl3) d
12.5, 56.2, 56.3, 101.4, 107.1, 119.1, 145.3, 149.9, 152.5,
155.4, 167.8; MS (ESI, Elþ) m/z¼237 (MHþ); HRMS:
calcd for C11H12N2O2S, 236. 0619; found, 236.0619.
1
2500, 1609, 1492, 1359, 1206, 880, 556 cm21; H NMR
(d6-DMSO) d 3.89 (s, 3H), 3.94 (s, 3H), 7.16 (s, 1H), 7.91 (s,
1H), 8.10 (s, 1H), 13.67 (brs, 1H); 13C NMR (d6-DMSO) d
55.7, 56.2, 107.6, 107.8, 123.2, 141.0, 142.5, 149.9, 155.9,
182.0; MS (ESI, Elþ) m/z¼223 (MHþ); HRMS: calcd for
C10H10N2O2S, 222.0463; found, 222.04605.
4.4. Synthesis of 4-chloroquinazoline derivatives 10:
general procedure
4.2.5. N-(3,4-Dimethoxyphenyl)thioformamide (8). Com-
pound purified by chromatography on silica gel; (CH2Cl2/
EtOAc 8:2); 59% yield; yellow solid; mp (CHCl3) 152–
1548C; IR (KBr) n 3200–2800, 1624, 1580, 1278, 1027,
976, 806, 622 cm21; 1H NMR (CDCl3) d 3.88 (s, 3H), 3.89
(s, 3H),6.74 (m, 2H), 6.85 (d, J¼8.4 Hz, 1H), 9.67 and 9.70
(2£s, 1H, NHCvS and NvCSH), 10.24 (brs, 1H); 13C
NMR (CDCl3) d 56.1, 56.2, 102.3, 110.1, 111.8, 123.4,
147.8, 149.9, 186.9; MS (ESI, Elþ) m/z¼197 (MHþ);
HRMS: calcd for C9H11NO2S, 197.0477; found, 197.0474.
The quinazolinone 6 (4.42 mmol) and POCl3 (6 mL) were
irradiated at 1008C (maximum power input 70 W) until
completion (TLC monitoring, 10 min). POCl3 was evapor-
ated in vacuo and the residue was dissolved in EtOAc. The
organic phase was washed with saturated NaHCO3 solution,
dried (Na2SO4) and concentrated in vacuo to furnish the
compound 10 as a white/grey solid which was used without
further purification in the next.
4.3. Synthesis of 4-(methylsulfanyl)quinazoline
derivatives 9: general procedure
4-Chloroquinazoline (10a, 85% yield)25, 4-chloro-6-
methylquinazoline (10b, 90% yield)26, 6-bromo-4-chloro-
quinazoline (10c, 90% yield)27, 4-chloro-6,7-dimethoxy-
quinazoline (10d, 70% yield)27 gave spectroscopic data in
accordance with those previously described.
To a solution of 7 (3.8 mmol) and 1 M NaOH (5.3 mL) in a
1:1 mixture of MeOH and water (20 mL), was added CH3I
(260 mL, 4.2 mmol) at room temperature. The reaction
mixture was stirred until completion (TLC monitoring,
20 min). MeOH was then evaporated under reduced
pressure and the remaining aqueous layer was extracted
with EtOAc. The organic phase was dried (MgSO4) and
concentrated in vacuo. The residue was purified by
chromatography on silica gel (petroleum ether/EtOAc 9:1)
to furnish 9 as a white solid.
4.5. Synthesis of 8H-quinazolino[4,3-b]quinazolin-8-one
4: general procedures
Method A. A mixture of compound 9 (0.57 mmol) and
anthranilic acid (3.4 mmol) was adsorbed (with AcOEt) on
graphite (1 g) and was placed in a microwave oven in a
quartz vial. The irradiation was programmed at a fixed
temperature 1508C (maximum power input 60 W) and the
powder was stirred for 30 min. After cooling, the graphite
powder was filtered off and washed with dichloromethane.
The solution was washed with saturated NaHCO3 solution,
dried (MgSO4) and concentrated under reduced pressure.
Recrystallisation from ethanol or DMF afforded compound 4.
4.3.1. 4-(Methylsulfanyl)quinazoline (9a). 85% Yield;
white solid; mp (EP/EtOAc) 628C (lit.23 658C); IR (KBr)
n 3000, 2927, 1614, 1570, 999, 755, 679, 653 cm21; H
NMR (CDCl3) d 2.72 (s, 3H), 7.59 (dt, J¼8.4, 1.6 Hz, 1H),
7.85 (td, J¼8.0, 1.0 Hz, 1H), 7.96 (d, J¼8.4 Hz, 1H), 8.10
(d, J¼8.0 Hz, 1H), 9.01 (s, 1H). 13C NMR (CDCl3) d 12.6,
123.8, 124.0, 127.3, 128.8, 133.6, 147.7, 153.6, 171.9; MS
(ESI, Elþ) m/z¼177 (MHþ); HRMS: calcd for C9H8N2S,
176.0408; found, 176.0403.
1
Method B. A mixture of compound 10 (0.61 mmol) and
anthranilic acid (467 mg, 3.4 mmol) in CH3CO2H (2 mL)
was introduced in a pressure-rated reaction tube. The tube
was irradiated at 1308C (maximum power input 100 W) for
10 min. After reaction, solvent was evaporated under
reduced pressure. Recrystallisation from ethanol or purifi-
cation by chromatography on silica gel (CH2Cl2/EtOAc
95:5) afforded compound 4.
4.3.2. 6-Methyl-4-(methylsulfanyl)quinazoline (9b). 78%
Yield; cream/white solid; mp (CH2Cl2) 728C (lit.24 96–
988C); IR (KBr) n 3022, 2930, 1536, 799, 685, 500 cm21
1H NMR (CDCl3) d 2.54 (s, 3H), 2.70 (s, 3H), 7.66 (dd, 1H,
J¼8.4, 2.0 Hz, 1H), 7.82 (d, J¼2.0 Hz, 1H), 7.84 (d,
J¼8.4 Hz, 1H), 8.95 (s, 1H); 13C NMR (CDCl3) d 12.4,
21.7, 122.6, 123.8, 128.3, 135.6, 137.5, 146.0, 152.8, 170.7;
;
4.5.1. 8H-Quinazolino[4,3-b]quinazolin-8-one (4a). 79%
Yield from 9a (method A) and 82% yield from 10a (method

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F.-R. Alexandre et al. / Tetrahedron 59 (2003) 1413–1419
B); white solid; mp (EtOH) 1988C (lit.11,12 1978C); 1H NMR
(CDCl3) d 7.55 (m, 1H), 7.66 (m, 1H), 7.86 (m, 4H), 8.45 (d,
J¼8.0 Hz, 1H), 8.84 (d, 1H, J¼8.0 Hz, 1H), 9.46 (s, 1H);
13C NMR (CDCl3) d 118.7, 121.4, 125.8, 126.5, 127.5,
127.7, 128.1, 128.9, 128.9, 133.6, 135.8, 137.7, 143.0,
144.3, 147.5, 159.1; HRMS: calcd for C15H9N3O, 247.0745;
found, 247.0743. Anal. calcd for C15H9N3O: C 72.87, H
3.67, N 16.99. Found: C 72.93, H 3.66, N 16.89.
120.01, 121.2, 125.9, 128.3, 129.2, 129.5, 129.9, 134.0,
137.5, 139.0, 143.1, 144.8, 146.5, 158.2; HRMS: calcd for
C15H8BrN3O, 324.9851; found, 324.9849. Anal. calcd for
C15H8BrN3O: C 55.24, H 2.47, N 12.88. Found: C 55.33, H
2.53, N 13.06.
4.5.7. 10,11-Dimethoxy-8H-quinazolino[4,3-b]quinazo-
lin-8-one (4g). 29% Yield from 9a (method A) and 41%
yield from 10a (method B); yellow solid; mp (DMF)
1
4.5.2. 2-Methyl-8H-quinazolino[4,3-b]quinazolin-8-one
(4b). 58% Yield from 9b (method A) and 70% yield from
.2608C. H NMR (CDCl3): d 4.07 (s, 3H), 4.11 (s, 3H),
7.25 (s, 1H), 7.65 (dt, J¼6.8, 1.6 Hz, 1H), 7.71 (s, 1H), 7.80
(dt, J¼6.8, 1.6 Hz, 1H), 7.86 (dd, J¼8.0, 1.2 Hz, 1H), 8.78
(dd, J¼8.0, 1.2 Hz, 1H), 9.51 (s, 1H). 13C NMR (CDCl3): d
56.4, 56.5, 105.9, 107.9, 111.9, 121.4, 125.4, 128.1, 128.8,
133.3, 137.9, 142.9, 143.6, 144.4, 149.1, 156.5, 158.2;
HRMS: calcd for C17H13N3O3, 307.0957; found, 309.0963.
Anal. calcd for C17H13N3O3: C 66.44, H 4.26, N 13.67.
Found: C 66.21, H 4.38, N 13.89.
1
10b (method B); white solid; mp (DMF) 1798C; H NMR
(CDCl3) d 2.45 (s, 3H), 7.55 (dt, J¼7.6, 1.2 Hz, 1H), 7.67
(m, 2H), 7.79 (d, J¼8.0 Hz, 1H), 7.93 (dt, J¼7.6, 1.2 Hz,
1H), 8.27 (dd, J¼8.0, 1.2 Hz, 1H), 8.47 (s, 1H), 9.20 (s, 1H);
13C NMR (CDCl3) d 21.1, 118.7, 120.9, 124.9, 126.4, 127.0,
127.3, 127.6, 135.0, 135.9, 137.3, 138.9, 141.0, 144.4,
147.2, 158.8; HRMS: calcd for C16H11N3O, 261.0902;
found, 261.0900. Anal. calcd for C16H11N3O: C 73.55, H
4.24, N 16.08. Found: C 73.24, H 4.22, N 15.96.
4.5.8. 2,3,10,11-Tetramethoxy-8H-quinazolino[4,3-
b]quinazolin-8-one (4h). 65% Yield from 10d (method
B); light yellow solid; mp (DMF) .2608C; 1H NMR
(CDCl3) d 4.04 (s, 3H), 4.06 (s, 3H), 4.09 (s, 3H), 4.14 (s,
3H), 7.24 (s, 1H), 7.28 (s, 1H), 7.69 (s, 1H), 8.13 (s, 1H),
9.47 (s, 1H); 13C NMR (CDCl3) d 56.39, 56.42, 56.43,
56.49, 104.9, 105.9, 107.5, 108.9, 114.9, 136.8, 139.0,
143.5, 144.9, 150.3, 154.0, 156.5, 158.4; HRMS: calcd for
C19H17N3O5, 367.1168; found, 367.1173. Anal. calcd for
C19H17N3O5: C 62.12, H 4.66, N 11.44. Found: C 61.63, H
4.89, N 11.54.
4.5.3. 2-Bromo-8H-quinazolino[4,3-b]quinazolin-8-one
(4c). 21% Yield from 9c (method A) and 54% yield from
1
10c (method B); white solid; mp (DMF) 2348C; H NMR
(CDCl3) d 7.63 (m, 1H), 7.78 (d, J¼8.8 Hz, 1H), 8.00 (m,
1H), 8.06 (dd, J¼8.8, 2.4 Hz, 1H), 8.33 (d, J¼8.4 Hz, 1H),
8.79 (d, J¼2.0 Hz, 1H), 9.30 (s, 1H); 13C NMR (CDCl3) d
118.9, 121.6, 123.2, 126.9, 127.1, 127.4, 127.5, 130.0,
136.1, 136.6, 138.9, 142.0, 143.3, 146.8, 158.6; HRMS:
calcd for C15H8BrN3O, 324.9851; found, 324.9865. Anal.
calcd for C15H8BrN3O: C 55.24, H 2.47, N 12.88. Found: C
55.19, H 2.53, N 12.72.
Acknowledgements
4.5.4. 2,3-Dimethoxy-8H-quinazolino[4,3-b]quinazolin-
8-one (4d). 34% Yield from 9d (method A) and 62%
yield from 10d (method B); white solid; mp (DMF)
We thank CEM Corporation for multiform support and
´
technical assistance. T. B. thanks the ‘Comite de Charente
Maritime de la Ligue Nationale Contre le Cancer’ for
financial support.
1
.2608C; H NMR (CDCl3) d 4.04 (s, 3H), 4.13 (s, 3H),
7.24 (s, 1H), 7.49 (m, 1H), 7.85 (m, 2H), 8.14 (s, 1H), 8.40
(d, J¼8.4 Hz, 1H); 9.39 (s, 1H); 13C NMR (CDCl3) d 56.4,
56.5, 105.4, 109.0, 114.7, 118.0, 125.9, 127.3, 127.6, 135.8,
136.6, 139.3, 144.3, 148.0, 150.4, 154.4, 159.3; HRMS:
calcd for C17H13N3O3, 307.0957; found, 309.0963. Anal.
calcd for C17H13N3O3: C 66.44, H 4.26, N 13.67. Found: C
65.80, H 4.15, N 13.53.
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1
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