Novel 6-substituted benzothiazol-2-yl indolo[1,2-c]quinazolines and benzimidazo[1,2-c]quinazolines

Article abstract of DOI:10.1016/S0040-4020(02)01593-4

The synthetic route to and a preliminary biological evaluation of novel indolo[1,2-c]quinazolines (8) and benzimidazo[1,2-c]quinazolines (9) are described. The products were obtained by condensation of the appropriate diamines (e.g. 2-(2-aminophenyl)indol

Full text of DOI:10.1016/S0040-4020(02)01593-4

Tetrahedron 59 (2003) 773–779
Novel 6-substituted benzothiazol-2-yl indolo[1,2-c]quinazolines
and benzimidazo[1,2-c]quinazolines
a
Stephane Frere, Valerie Thiery, Christian Bailly and Thierry Besson
a
b
a
,
,
*
*
´
`
´
´
a
´
LGPC UPRES EA3169, Groupe de Chimie Organique, UFR Sciences Fondamentales et Sciences pour l’Ingenieur,
´
ˆ
Universite de la Rochelle, Batiment Marie-Curie, F-17042 La Rochelle Cedex 1, France
bINSERM U-524, Institut de Recherches sur le Cancer, 1 Place de Verdun, Lille 59045, France
Received 17 October 2002; revised 26 November 2002; accepted 10 December 2002
Abstract—The synthetic route to and a preliminary biological evaluation of novel indolo[1,2-c]quinazolines (8) and benzimidazo[1,2-
c]quinazolines (9) are described. The products were obtained by condensation of the appropriate diamines (e.g. 2-(2-aminophenyl)indole or
2-(2-aminophenyl)benzimidazole) with 2-cyanobenzothiazoles. This work further demonstrates the general applicability of microwaves for a
facile and rapid access to original heterocycles with potential pharmaceutical value. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
skeletons which often represent potent cytotoxic agents13
(Fig. 1).
The thiazole ring is present in various marine or terrestrial
natural compounds and a number of structure-activity
studies have been made to determine the essential structural
requirements associated with its biological activity.1 In
connection with recent works on thiazoloacridines,2 thia-
zoloquinolines3 and substituted benzothiazoles,4 we
previously described the synthesis of new thiazole deriva-
tives5–9 derived from natural alkaloids extracted from
marine organisms (e.g. dercitine and kuanoniamines1,2) or
plants (e.g. ellipticine).10 In these studies, our strategy
consisted to combine the thiazole ring with various
heterocyclic structures and some molecules showed inter-
esting cytotoxicity profiles.5–9
In this paper we describe the synthetic route and a
preliminary biological evaluation to these novel substituted
polyheterocyclic compounds which are structurally related
to terrestrial or marine alkaloids (e.g. hinckdentine A14 for
the indolo[1,2-c]quinazoline ring, see Figure 1). In the
course of our work on the application of microwaves in the
preparation of bioactive molecules, we have transposed
many of the reactions described in this paper to a focused
microwave oven specifically designed for organic syn-
thesis,15 with the aim of achieving striking reduction in
reaction times, better yields and cleaner reactions compared
to the purely thermal processes.
Fusion of the thiazole ring onto the heterocyclic skeletons
suggested the use of imino-1,2,3-dithiazoles11,12 which have
proved to be highly versatile intermediates in heterocyclic
synthesis, undergoing a variety of reactions initiated by
nucleophilic attack at different sites on the dithiazole ring
(the driving force being the regeneration of the latent cyano
group in the dithiazole ring).
2. Results and discussion
2.1. Synthesis of benzothiazoles 3 and benzoxazole 4
Using a standard method applied for the preparation of
various N-arylimino-1,2,3-dithiazoles, the starting anilines
were condensed with 4,5-dichloro-1,2,3-dithiazolium
chloride 1 (Appel salt)11 in dichloromethane at room
temperature to give the desired imines 2 in good yields.
In order to increase the biological activity of the molecules,
extensive modifications of the carbonitrile function in
position 2 of the thiazole ring were performed in our
group.6 It was decided to associate the benzothiazole ring
with various polyheterocyclic structures such as indolo[1,2-
c]quinazoline (I) and benzimidazo[1,2-c]quinazoline (II)
In the course of a study on the chemistry of Appel salt 1 and
its derivatives, we previously showed that 5-(N-arylimino)-
4-chloro-5H-1,2,3-dithiazoles 2, which are stable crystalline
solids, cyclised by vigorous heating to give sulphur,
hydrogen chloride and 2-cyanobenzothiazoles.12 The
thermolysis procedure consisted of heating the starting
material in the presence of N-methylpyrrolidin-2-one
Keywords:
benzimidazo[1,2-c]quinazoline; benzothiazoles.
microwave
irradiation;
indolo[1,2-c]quinazoline;
*
Corresponding authors. Tel.: þ33-5-46-45-82-76; fax: þ33-5-46-45-82-
47; e-mail: vthiery@univ-lr.fr, tbesson@univ-lr.fr.
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01593-4

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S. Frere et al. / Tetrahedron 59 (2003) 773–779
774
Figure 1.
In the previously described thermolysis procedure12
(which consisted of heating the neat imines 2 under
argon at 200–2508C with a metal bath for 1 or 2 min),
the amount of starting material was limited to 0.2 g and
the products were usually accompanied by complicated
mixtures of carbonaceous compounds and impurities
which are difficult to eliminate. The alternative micro-
wave method allows a significant scale-up of the quantity
of starting material (1 or 5 g instead of 0.2 g in the
conventional method) in safe, useful and convenient
conditions.
Table 1. Microwave synthesis of benzothiazoles 3 and benzoxazole 4
Starting imine 2 Reaction time
(R)
Product
(R)
Yields of product
(%)
(min)
a (H)
b (4-F)
c (4-CH3)
d (4-OCH3)
e (2,5-diCH3)
f (2,5-diOCH3)
g (2-Br, 4-NO2)
h (2-OH)
1
1
2
1
1
3
0.5
0.5
3a (H)
3b (6-F)
49
29
55
48
58
64
75a
69
3c (6-CH3)
3d (6-OCH3)
3e (4,7-diCH3)
3f (4,7-diOCH3)
3g (6-NO2)
4 (–)
a
Yield of the cyclisation of the intermediate o-bromoimine in the presence
of CuI with pyridine as solvent (Scheme 1).
Following the same strategy, a benzoxazole analogue
(4) was also obtained from 2-aminophenol by an intra-
molecular attack of the o-hydroxy group in the C5 of the
intermediate imine. Cyclisation of the 4-nitroaniline
derivative was more difficult and, as we previously
described,12 the presence of a strong electron withdrawing
group on the aromatic moiety of the imine 2 reduced
dramatically the yield of 3, to favour the cyanoimidoyl
chloride 5 as the major reaction product. A mild procedure,
which consists to heat an ortho bromoimine in the presence
of cuprous iodide in pyridine at reflux, afforded 3 in good
yield (Table 1, Scheme 1).
(NMP), a polar solvent well adapted for microwave heating.
Among the various combinations tested (fixed temperature
or/and irradiation power), the best results were obtained by
heating the mixture with an irradiation programmed at 90 W
and a fixed temperature (1508C) (Table 1). Here again, the
comparative study of this methodology performed under
classical heating (using oil or metal bath) or microwave
irradiation showed that reaction time was considerably
reduced, from hours to a few minutes, with the latter
technique.
Scheme 1. Reagents and conditions (for time and yield see Table 1): (a) Appel salt 1, CH2Cl2, room temperature, 2 h, 2g (12 h, 70%), 7 (70%);
(b) N-methylpyrrolidin-2-one, mw (1508C, 90 W) 1–3 min, 3g (mw 1508C, 150 W, 0.5 min, 47%); (c) Br2, acetic acid, room temperature, 9 h, 88%; (d) CuI,
pyridine reflux, mw (1108C, 90 W), 15 min, 75%.

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775
Table 2. Synthesis of indolo[1,2-c]quinazoline and benzimidazo[1,2-
c]quinazoline derivatives from 3 and 4
,35%). Whichever method was applied, none of the
alternative ring closed product, indolo[3,2-c]quinoline
(III), was detected.
Starting material Product Time Yield Product Time Yield
(min)a
(R)
(min)a
(%)
(%)
Following the conditions described above, the parent
benzimidazo[1,2-c]quinazolines 9a–f and 9h were obtained
in good yield by condensation of 2-cyanobenzothiazoles
3a–f, or the benzoxazole 4, with 2-(2-aminophenyl)benzi-
midazole (Table 2). As observed above for the formation of
the benzothiazoles, reactions with the nitro compound were
more difficult than for the other molecules. Then, conden-
sation of the 2-cyano-6-nitrobenzothiazole 6g with the
heterocyclic diamines yielded to complex mixtures devoid
of the desired product. Activation of the carbonitrile group
was expected by using adapted methods using sulphur
derivatives (e.g. S, CS2 and P2S5).17 The synthesis of
compounds 8g and 9g was then attempted by nucleophilic
addition of the appropriate diamine to the aromatic nitrile 8g
in 1,2-dichlorobenzene in the presence of a catalytic amount
of P2S5 (Scheme 2). The yields were relatively low but
sufficient material was obtained for a complete chemical
characterisation of the new products and their preliminary
biological evaluation.18
3a (H)
3b (6-F)
3c (6-CH3)
3d (6-OCH3)
3e (4,7-diCH3)
3f (4,7-diOCH3) 8f
3g (6-NO2)
4 (–)
8a
8b
8c
8d
8e
135
240
150
30
64
53
60
68
61
54
12b
69
9a
9b
9c
9d
9e
9f
90
150
60
10
65
80
70
56
71
73
65
58
18b
77
90
115
24 h
70
8g
8h
9g
9h
10 h
45
a
Time of the microwave irradiation.
P2S5, 1,2-dichlorobenzene reflux, mw heating (1308C, 90 W).
b
2.2. Synthesis of indolo[1,2-c]quinazoline and
benzimidazo[1,2-c]quinazoline derivatives
In contrast to its well studied indolo[3,2-c]quinoline
counterpart (III) (Fig. 1), the indolo[1,2-c]quinazoline ring
system (I) is little known and its synthesis has been achieved
in only a limited number of ways. Preparation of these two
skeletons may involve the use of 2-(2-aminophenyl)indole
as a starting material.2
3. Conclusion
It is known that the cyano group in position 2 of the
benzothiazole ring is very reactive and that its transform-
ation into acid, amide, amidine and imidate may be easily
realised. According to this strategy, the condensation of
2-cyanobenzothiazoles with the commercially available
2-(2-aminophenyl)indole in various solvents (e.g. ethanol,
dimethylformamide or NMP) was studied. Unfortunately,
the usual conditions did not allow an access to the expected
rings. Transposition of this process (same conditions of
solvents, quantities and temperatures) in a microwave
reactor was also unsuccessful. An alternative procedure,
which consists to heat the benzothiazoles and the 2-(2-
aminophenyl) indole neat at 2208C (metal bath), required
lengthy and tedious conditions. The yields were very low
and various impurities were detected in the final mixture. In
connection with our recent work on heterocyclic reactions
with carbon graphite as support,16 we discovered that
microwave irradiation (150 W) of the two starting com-
pounds at 2208C in the presence of graphite (10% by
weight) afforded the indolo[1,2-c]quinazoline derivatives
(8a–f and 8h) in good yields (Table 2). Under similar
experimental conditions (with same quantity of starting
material, graphite and same reaction time), a conventional
heating allowed a small amount of the products (yields
In conclusion, a successful strategy is presented for the
synthesis of novel indolo[1,2-c]quinazolines (8a–h) and
benzimidazo[1,2-c]quinazolines (9a–h) obtained by con-
densation of the appropriate diamines (e.g. 2-(2-amino-
phenyl)indole or 2-(2-aminophenyl)benzimidazole) with
2-cyanobenzothiazoles. The compounds presented in this
paper can be considered as synthetic analogues of the
natural alkaloid hinckdentine A and present a close
structural analogy with other cytotoxic agents containing a
synthetic benzimidazo[1,2-c]quinazoline core. In connec-
tion with recent published results on the utility of
microwaves in multistep organic synthesis, this work
confirms that reaction mixtures exposed to microwaves
allow an easy and rapid access to original heterocycles with
potential pharmaceutical value.
4. Experimental
4.1. General
Commercial reagents were used as received without
Scheme 2. Reagents and conditions for compounds 8a–f,h, 9a–f,h, (for time and yield see Table 2): graphite (10% by weight), mw (1508C, 150 W); for
compounds 8g and 9g: P2S5 cat., 1,2-dichlorobenzene reflux, mw (1308C, 90 W).

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S. Frere et al. / Tetrahedron 59 (2003) 773–779
776
additional purification. Melting points were determinate on
¨
spectra were obtained on a Perkin–Elmer Paragon 1000 PC
FT-IR. 1H and 13C NMR were recorded on a JEOL JNM LA
400 (400 MHz) spectrometer (Centre Commun d’Analyses,
3H), 2.56 (s, 3H). 13C NMR (CDCl3) d 151.6, 136.1, 134.7,
132.9, 129.15, 128.64, 128.4, 21.1, 17.9. HRMS (EI) calcd
for C9H8N2S (M2Hþ) 188.0408. Found: 188.0414.
a Kofler melting point apparatus and are uncorrected. IR
4.3.2. 6-Nitrobenzothiazolyl-2-carbonitrile (3g). 2-
Bromo-4-nitro-N-(4-chloro-5H-1,2,3-dithiazol-5-ylidenyl)-
aniline 7 (1 g, 3.1 mmol), was irradiated in presence of
1.1 equiv. of copper iodure (0.58 g, 3.4 mmol) in pyridine
(10 mL) as the solvent. The irradiation was programmed to
obtain reflux with a maximal power output of 90 W. After
cooling, the mixture was concentrated in vacuo, and washed
with water and EtOAc. The organic layer was dried over
MgSO4 and removed in vacuo. Purification by column
chromatography with light petroleum–dichloromethane
(7:3) as the eluent afforded compound 3g as a pale yellow
solid (0.47 g, 75%), mp 1638C. IR(KBr): 3097, 2236, 1613,
´
Universite de La Rochelle). The mass spectra (HRMS) were
recorded on a Varian MAT 311 in the Centre Regional de
´
´
Mesures Physiques de l’Ouest (CRMPO, Universite de
Rennes). Analytical thin layer chromatography (tlc) was
performed on Merck 60F-254 silica gel plates. Column
chromatography was performed by using Merck silica gel
(70–230 mesh). Focused microwave irradiations were
carried out with a Synthewavee S402 microwave reactor
(monomode system, 2450 MHz, 300 W) which has variable
speed rotation, visual control, irradiation monitored by PC
computer, infrared measurement and continuous feedback
temperature control (by PC).
1
1567, 1334 cm21. H NMR (CDCl3) d 8.96 (d, J¼2.4 Hz,
1H), 8.53 (dd, J¼8.8, 2,4 Hz, 1H), 8,39 (d, J¼8.8 Hz, 1H).
13C NMR (CDCl3) d 112.0, 118.5, 123.1, 126.0, 135.5,
141.7, 147.2, 155.3. HRMS (EI) calcd for C8H3N3O2S (Mþ)
204.9946. Found: 204.9947.
4.2. Synthesis of N-(4-chloro-5H-1,2,3-dithiazol-5-
ylidene) derivatives 2: general procedures
Appel salt 1 (1.1 equiv.) was added to a solution of aniline
derivative (1 g) in dichloromethane (20 mL). The mixture
was stirred at room temperature for 2 h (10 h for 2g) and
then washed twice with water (20 mL). The organic layer
was dried over MgSO4 and concentrated in vacuo.
Purification by column chromatography with light
petroleum-dichloromethane (7:3) as the eluent afforded
the title compounds 2a–d, 2f and g as yellow solids.
4.3.3. 2-Bromo-4-nitroaniline (6). To a solution of
4-nitroaniline (1 g, 2.24 mmol) in acetic acid (30 mL) was
added dropwise 1.1 equiv. of bromine (0.409 mL,
2.46 mmol). The reaction mixture was stirred at room
temperature for 2 h, quenched with H2O and Na2S2O3
(30 mL), then extracted with EtOAc (30 mL). The organic
layer was washed with a saturated solution of NaHCO3;
dried over MgSO4 and concentrated in vacuo. Purification
by column chromatography with light petroleum–dichloro-
methane (4:6) as the eluent afforded the title compound as a
yellow solid (1.38 g, 88%), mp 1068C. IR(KBr): 3488,
3376, 3234, 3206, 3100, 1616, 1482, 1326 cm21. 1H NMR
(CDCl3) d 8.36 (d, J¼2.4 Hz, 1H), 8.02 (dd, J¼9.6, 2.4 Hz,
1H), 6.76 (d, J¼9.6 Hz, 1H), 4.91 (bs, 2H). 13C NMR
(CDCl3) d 150.0, 138.8, 129.2, 124.9, 113.5, 106.9. HRMS
(EI) calcd for C6H3BrN2O2 (Mþ) 215.9534. Found:
215.9531.
Spectral data for N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)
derivatives 2a–d, 2f and g were consistent with the assigned
structures.12c,19
4.2.1. 2,5-Dimethyl-N-(4-chloro-5H-dithiazol-5-ylidene)-
aniline (2e). Yellow needles (89%), mp 1108C. IR (KBr):
1
2928, 1610, 1152, 872 cm21. H NMR (CDCl3) d 7.17 (d,
J¼8.0 Hz, 1H), 6.95 (d, J¼8.0 Hz, 1H), 6.87 (s, 1H), 2.33
(s, 3H), 2.20 (s, 3H). 13C NMR (CDCl3) d 158.2, 150.3,
147.7, 137.0, 131.1, 127.1, 126.6, 116.3, 21.1, 17.1. HRMS
(EI) calcd for C9H9N2S2Cl (M2Hþ) 255.9896. Found:
255.9909.
4.3.4. 2-Bromo-4-nitro-N-(4-chloro-5H-1,2,3-dithiazol-
5-ylidenyl)aniline (7). A solution of 2-bromo-4-aniline 6
(1 g, 4,63 mmol) in tetrahydrofuran (20 mL) was added to
1.1 equiv. of Appel salt 1 (1.07 g, 5.14 mmol). After 9 h at
room temperature, the mixture is concentrated in vacuo and
purification by column chromatography with light
petroleum–dichloromethane (7:3) as the eluent afforded a
pale orange solid (1.15 g, 71 %), mp 1248C. IR(KBr): 3481,
3373, 3098, 1590, 1509, 1349, 860 cm21. 1H NMR (CDCl3)
d 8.58 (d, J¼2.4 Hz, 1H), 8.27 (dd, J¼8.8, 2.4 Hz, 1H), 7.24
(d, J¼8.8 Hz, 1H). 13C NMR (CDCl3) d 162.5, 155.5, 147.3,
145.2, 129.5, 124.6, 118.6, 115.3. HRMS (EI) calcd for
C8H3N3O2BrS2Cl (Mþ) 350.8539. Found: 350.8540.
4.3. Synthesis of 2-cyanobenzothiazoles 3 and 2-cyano-
benzoxazoles 4: general procedures
N-arylimino-1,2,3-dithiazole 2 (1 g) was irradiated with
N-methylpyrrolidin-2-one (10 mL) as the solvent. The
irradiation was programmed to maintain a constant
temperature (1508C) with a maximal power output of
90 W. After cooling, dichloromethane was added, the
organic layer washed with water, dried over MgSO4, and
the crude product was purified by column chromatography
(silica gel) with light petroleum–dichloromethane as the
eluent.
4.4. Synthesis of indolo[1,2-c]quinazolines (8a–f,h) and
benzimidazo[1,2-c]quinazolines (9a–f,h): general
procedures
Spectral data for benzothiazoles derivatives 3a–d, 3f and g
were consistent with the assigned structures.12c,19
Benzothiazoles or benzoxazoles (0,15 g) and commercial
diamine (2-(2-aminophenyl) benzimidazole or 2-(2-amino-
phenyl)indole, 1 equiv. were irradiated in the presence of
graphite (10 wt% to the reactants). The irradiation was
programmed to obtain a constant temperature (2208C) with
4.3.1. 4,7-Dimethylbenzothiazole-2-carbonitrile (3e).
Orange needles (58%), mp 908C. IR (KBr): 3018–2928,
1
2236, 1904, 1476, 1146, 836 cm21. H NMR (CDCl3) d
7.35 (d, J¼8.0 Hz, 1H), 7.30 (d, J¼8.0 Hz, 1H), 2.75 (s,

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S. Frere et al. / Tetrahedron 59 (2003) 773–779
777
a maximal power output of 150 W. After cooling, the
mixture was dissolved in dichloromethane and purified by
column chromatography (silica gel) with light petroleum–
ethyl acetate (8:2) as the eluent.
130.4, 129.3, 129.1, 128.4, 128.2, 127.5, 126.9, 123.8,
122.8, 121.7, 121.2, 120.5, 155.6, 96.6, 21.3, 18.1. HRMS
(EI) calcd for C24H17N3S (Mþ) 379.1143. Found: 379.1146.
4.4.6. 6-(4,7-Dimethoxybenzothiazol-2-yl)-indolo[1,2-
c]quinazoline (8f). Orange needles (54%), mp 2218C
(DMF). IR (KBr): 3128, 3068, 3018, 2950, 2848, 1782,
4.4.1. 6-Benzothiazol-2-yl-indolo[1,2-c]quinazoline (8a).
Orange needles (64%), mp 1708C (toluene). IR (KBr): 3105,
1
3064, 3045, 1381, 758 cm21
.
1H NMR (CDCl3) d
1530, 776 cm21. H NMR (CDCl3) d 8.05–8.12 (m, 1H),
8.22–8.25 (m, 1H), 8.10–8.16 (m, 2H), 7.81–7.88 (m,
2H), 7.56–7.68 (m, 4H), 7.35–7.39 (m, 2H), 7.18 (dd,
J¼8.5, 1.0 Hz, 1H), 7.11 (ddd, J¼8.8, 6.9, 1.2 Hz, 1H). 13C
NMR (CDCl3) d 161.4, 152.8, 142.2, 138.4, 136.0, 135.0,
131.3, 130.4, 129.1, 128.6, 128.3, 126.9, 126.9, 124.7,
123.9, 122.8, 122.0, 121.9, 121.3, 120.7, 115.1, 96.7. HRMS
(EI) calcd for C22H13N3S (M2Hþ) 351.0830. Found:
351.0822.
7.72–7.85 (m, 2H), 7.49–7.56 (m, 2H), 7.25–7.34 (m, 2H),
7.04–7.10 (m, 2H), 6.86–6.96 (m, 2H), 4.00 (s, 3H), 3.99
(s, 3H). 13C NMR (CDCl3) d 160.3, 149.0, 148.2, 144.1,
142.1, 138.3, 134.7, 131.3, 130.2, 129.0, 128.3, 128.2,
126.8, 123.7, 122.7, 121.9, 121.1, 120.4, 115.0, 107.8,
106.8, 96.5, 56.5, 56.2. HRMS (EI) calcd for C24H17N3O2S
(Mþ) 411.1041. Found: 411.1042.
4.4.7. 6-(Benzoxazol-2-yl)-indolo[1,2-c]quinazoline (8h).
Orange solid (70%), mp 1628C (toluene). IR (KBr): 3098,
4.4.2. 6-(6-Fluorobenzothiazol-2-yl)-indolo[1,2-c]quina-
zoline (8b). Orange needles (53%), mp 1868C (DMF). IR
1
3058, 2966, 2942, 1606, 1534, 1390, 744 cm21. H NMR
1
(KBr): 3122, 3072, 1610, 1544, 1446, 738 cm21. H NMR
(CDCl3) d 8.10–8.14 (m, 1H), 7.98–8.02 (m, 1H), 7.89–
7.93 (m, 1H), 7.81 (d, J¼8.0 Hz, 1H), 7.23 (t, J¼8.0 Hz,
1H), 7.47–7.59 (m, 4H), 7.37 (t, J¼7.6 Hz, 1H), 7.33 (s,
1H), 7.12 (t, J¼8.8 Hz, 1H), 6.88 (d, J¼8.8 Hz, 1H). 13C
NMR (CDCl3) d 150.3, 140.6, 138.1, 134.4, 130.4, 130.1,
129.2, 128.9, 128.6, 127.5, 127.1, 125.7, 124.1, 122.8,
122.3, 121.6, 121.4, 120.8, 113.3, 111.4, 111.4, 96.6. HRMS
(EI) calcd for C22H13N3O (Mþ) 335.1059. Found:
335.1043.
(CDCl3) d 8.13–8.20 (m, 2H), 7.81–7.88 (m, 2H,), 7.77
(dd, J¼7.6, 2.4 Hz, 1H), 7.55 (m, 2H), 7.36–7.39 (m, 3H),
7.28 (d, J¼8.8 Hz, 1H), 7.13 (td, J¼6.8, 0.8 Hz, 1H). 13C
NMR (CDCl3) d 162.8, 161.3, 161.3, 160.3, 149.4, 141.9,
138.3, 137.3, 137.2, 135.0, 131.2, 130.4, 129.2, 128.6,
128.2, 125.8, 125.7, 124.0, 122.8, 122.0, 121.2, 120.7,
166.1, 115.8, 115.2, 108.2, 107.9, 96.8. HRMS (EI) calcd
for C22H12FN3S (Mþ) 369.0736. Found: 369.0734.
4.4.3. 6-(6-Methylbenzothiazol-2-yl)-indolo[1,2-c]quina-
zoline (8c). Orange needles (60%), mp 2018C (toluene). IR
4.4.8. 6-Benzothiazol-2-yl-benzo[4,5]imidazo[1,2-
c]quinazoline (9a). Yellow needles (70%), mp 1888C
.
(toluene). IR (KBr): 3109, 3072, 1320, 754 cm21 1H
1
(KBr): 3064, 2924, 1599, 1539, 1463, 1381, 735 cm21. H
NMR (CDCl3) d 8.08–8.13 (m, 2H), 7.83–7.87 (m, 2H),
7.79 (d, J¼8.0 Hz, 1H), 7.52 (m, 2H), 7.44 (dd, J¼8.0,
1.2 Hz, 1H), 7.35 (td, J¼8.4, 1.2 Hz, 1H), 7.33 (s, 1H), 7.16
(d, J¼8.0 Hz, 1H), 7.09 (td, J¼8.4, 1.2 Hz, 1H), 2.58 (s,
3H). 13C NMR (CDCl3) d 160.1, 150.9, 142.3, 138.4, 137.3,
136.2, 135.0, 131.3, 130.4, 129.1, 128.6, 128.5, 128.2,
124.1, 123.9, 122.8, 121.9, 121.6, 121.0, 120.6, 115.1, 96.6,
21.8. HRMS (EI) calcd for C23H15N3S (Mþ) 365.0987.
Found: 365.0979.
NMR (CDCl3) d 8.79 (d, J¼7.8 Hz, 1H), 8.28 (d, J¼8.0 Hz,
1H), 8.16 (d, J¼8.8 Hz, 1H), 8.11 (d, J¼7.6 Hz, 1H), 8.05
(t, J¼7.6 Hz, 1H), 7.83 (t, J¼7.2 Hz, 1H) 7.78 (t, J¼6.8 Hz,
1H), 7.55–7.68 (m, 3H), 7.33 (t, J¼8.0 Hz, 1H). 13C NMR
(CDCl3) d 161.4, 153.0, 148.0, 144.4, 141.9, 141.4, 136.3,
132.0, 129.4, 129.4, 128.5, 127.3, 127.0, 126.2, 124.7,
124.5, 122.9, 122.0, 119.9, 119.1, 116.4. HRMS (EI) calcd
for C21H12N4S (Mþ) 352.0783. Found: 352.0808.
4.4.9. 6-(6-Fluorobenzothiazol-2-yl)-benzo[4,5]imi-
dazo[1,2-c]quinazoline (9b). Yellow needles (56%), mp
2238C (toluene). IR (KBr): 3122, 3050, 3014, 1518, 1194,
4.4.4. 6-(6-Methoxybenzothiazol-2-yl)-indolo[1,2-
c]quinazoline (8d). Orange needles (68%), mp 1748C
(toluene). IR (KBr): 3099, 3064, 3013, 2944, 1610, 1510,
1269 cm21. 1H NMR (CDCl3) d 8.09–8.14 (m, 2H), 7.80–
7.86 (m, 2H), 7.54–7.59 (m, 2H), 7.52 (d, J¼2.5 Hz, 1H),
7.35–7.39 (m, 2H), 7.25–7.28 (m, 1H) 7.24 (dd, J¼9.0,
2.5 Hz, 1H), 7.12 (td, J¼8.6, 1.3 Hz, 1H), 3.97 (s, 3H). 13C
NMR (CDCl3) d 159.1, 158.6, 147.4, 142.3, 138.4, 137.7,
135.1, 131.4, 130.4, 129.1, 128.4, 128.2, 125.2, 123.9,
122.8, 121.9, 121.2, 120.6, 116.8, 115.3, 103.8, 96.6, 55.9.
HRMS (EI) calcd for C23H15N3OS (Mþ) 381.0936. Found:
381.0935.
851, 746 cm21
.
1H NMR (CDCl3) d 8.78 (dd, J¼8.4,
1.6 Hz, 1H), 8.30 (d, 1H), 8.23 (dd, J¼8.8, 5.2 Hz, 1H), 8.04
(d, J¼8.4 Hz, 2H), 7.84 (td, J¼7.2, 1.6 Hz, 1H), 7.74–7.79
(m, 2H), 7.58 (t, J¼6.8 Hz, 1H), 7.34–7.43 (m, 2H). 13C
NMR (CDCl3) d 163.0, 161.5, 161.5, 160.6, 149.7, 148.0,
144.4, 141.6, 141.3, 137.7, 137.5, 131.9, 129.5, 129.4,
128.4, 126.2, 125.9, 125.8, 124.5, 122.9, 120.0, 119.0,
116.5, 116.2, 116.0, 108.2, 107.9. HRMS (EI) calcd for
C21H11N4FS (Mþ) 370.0688. Found: 370.0665.
4.4.10. 6-(6-Methylbenzothiazol-2-yl)-benzo[4,5]imi-
dazo[1,2-c]quinazoline (9c). Yellow needles (71%), mp
2128C (toluene). IR (KBr): 3100, 3077, 3030, 1623, 1586,
4.4.5. 6-(4,7-Dimethylbenzothiazol-2-yl)-indolo[1,2-
c]quinazoline (8e). Orange needles (61%), mp 2048C
(DMF). IR (KBr): 3380, 3048, 2924, 2850, 1598, 1466,
1524, 762 cm21
.
1H NMR (CDCl3) d 8.76 (dd, J¼7.6,
1
1374, 720 cm21. H NMR (CDCl3) d 8.12–8.15 (m, 1H),
1.2 Hz, 1H), 8.13–8.17 (m, 2H), 8.13–8.06 (m, 2H), 7.88
(s, J¼1.2 Hz, 1H), 7.82 (td, J¼7.2, 1.6 Hz, 1H), 7.75 (td,
J¼7.6, 0.8 Hz,1H), 7.56 (td, J¼6.8, 0.8 Hz, 1H), 7.47 (dd,
J¼8.4, 1.2 Hz, 1H), 7.32 (td, J¼8.4, 0.8 Hz, 1H), 2.60 (s,
3H). 13C NMR (CDCl3) d 160.1, 151.2, 148.0, 144.5, 142.0,
7.85–7.88 (m, 1H), 7.81 (d, J¼8.0 Hz, 1H), 7.53–7.58 (m,
2H), 7.32–7.38 (m, 4H), 7.27 (d, J¼8.0 Hz, 1H), 7.08–7.13
(m, 1H), 2.74 (s, 3H), 2.66 (s, 3H). 13C NMR (CDCl3) d
159.8, 152.0, 142.6, 138.4, 136.6, 135.1, 132.0, 131.5,

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S. Frere et al. / Tetrahedron 59 (2003) 773–779
778
141.4, 137.8, 136.5, 131.9, 129.4, 129.3, 128.8, 128.4,
126.1, 124.4, 124.1, 122.8, 121.5, 119.9, 119.0, 116.4, 21.8.
HRMS (EI) calcd for C22H14N4S (Mþ) 366.0939. Found:
366.0943.
commercial diamine (2-(2-aminophenyl)benzimidazole or
2-(2-aminophenyl)indole, 1 equiv.) were irradiated in the
presence of a catalytic amount (10%) of phosphorous
pentasulfur with 1,2-dichlorobenzene (10 mL) as the
solvent. The irradiation was programmed to reach 110–
1208C with a maximal power output of 90 W. After cooling,
the mixture was dissolved in dichloromethane and purified
by column chromatography (silica gel) with dichloro-
methane as the eluent.
4.4.11. 6-(6-Methoxybenzothiazol-2-yl)-benzo[4,5]imi-
dazo[1,2-c]quinazoline (9d). Yellow needles (73%), mp
2008C (toluene). IR (KBr): 3128, 3071, 2966, 2916, 2832,
1602, 1525, 1277, 751 cm21. 1H NMR (CDCl3) d 8.75 (dd,
J¼10.1, 1.3 Hz, 1H), 8.30 (d, J¼8.6 Hz, 1H), 8.11 (d,
J¼9.0 Hz, 1H), 8.00 (t, J¼8.1 Hz, 1H), 7.77 (ddd, J¼7.6,
7.5, 1.6 Hz, 1H), 7.71 (ddd, J¼7.4, 7.1, 1.2 Hz, 1H), 7.54
(ddd, J¼8.1, 7.8, 1.0 Hz, 1H), 7.46 (d, J¼2.5 Hz, 1H), 7.32
(ddd, J¼8.5, 7.2, 1.2 Hz, 1H), 7.21 (dd, J¼9.0, 2.5 Hz, 1H),
3.95 (s, 3H). 13C NMR (CDCl3) d 159.3, 158.6, 148.0,
147.5, 144.2, 141.9, 141.3, 138.1, 131.8, 129.4, 129.1,
128.2, 126.1, 125.2, 124.4, 122.7, 119.8, 118.8, 117.0,
116.7, 103.6, 55.9. HRMS (EI) calcd for C22H14N4OS (Mþ)
382.0888. Found: 382.0866.
4.5.1. 6-(6-Nitrobenzothiazol-2-yl)-indolo[1,2-c]quinazo-
line (8g). Red solid (12%), mp 1868C (toluene). IR (KBr):
1
3131, 3002, 3068, 1526, 1337, 1078, 750 cm21. H NMR
(CDCl3) d 8.98 (d, J¼3.5 Hz, 1H), 8.45 (dd, J¼14.0, 3.5 Hz,
1H), 8.28 (d, J¼16.0 Hz, 1H), 7.78–7.86 (m, 1H), 7.53–
7.59 (m, 2H), 7.34–7.42 (m, 3H), 7.14 (td, J¼12.0, 2.0 Hz,
1H). 13C NMR (CDCl3) d 167.5, 156.2, 146.1, 141.3, 138.0,
136.4, 135.0, 131.1, 130.4, 129.2, 129.1, 128.3, 124.9,
124.1, 122.8, 122.1, 122.0, 121.3, 120.8, 118.5, 115.2, 97.0.
HRMS (EI) calcd for C22H12N4O2S (Mþ) 396.0681. Found:
396.0684.
4.4.12. 6-(4,7-Dimethylbenzothiazol-2-yl)-benzo[4,5]imi-
dazo[1,2-c]quinazoline (9e). Yellow needles (65%), mp
2288C (DMF). IR (KBr): 3125, 3075, 2966, 2916, 1583,
4.5.2. 6-(6-Nitrobenzoxazol-2-yl)-benzo[4,5]imidazo[1,2-
c]quinazoline (9g). Orange solid (18%), mp 2558C
(toluene). IR (KBr): 3084, 3062, 1572, 1522, 1345,
1
1517, 1450, 1326, 736 cm21. H NMR (CDCl3) d 8.80 (d,
J¼7.6 Hz, 1H), 8.42 (d, J¼8.4 Hz, 1H), 8;06 (t, J¼7.2 Hz,
2H), 7.84 (t, J¼7.2 Hz, 1H), 7.76 (t, J¼7.6 Hz, 1H), 7.58 (t,
J¼8.4 Hz, 1H), 7.37 (t, J¼7.6 Hz, 2H), 7.31 (t, J¼7.2 Hz,
1H), 2.82 (s, 3H), 2.68 (s, 3H). 13C NMR (CDCl3) d 160.0,
152.7, 148.5, 144.84, 142.7, 141.8, 137.3, 132.4, 132.2,
130.0, 129.7, 129.65, 128.0, 127.7, 126.5, 124.8, 122.9,
120.2, 119.4, 117.4, 21.6, 18.5. HRMS (EI) calcd for
C23H16N4S (Mþ) 380.1096. Found: 380.1093.
1
754 cm21. H NMR (CDCl3) d 9.04 (d, J¼2.4 Hz, 1H),
8.81 (d, J¼8.0 Hz, 1H), 8.52 (dd, J¼9.2, 2.0 Hz, 1H), 8.42
(t, J¼7.2 Hz, 2H), 8.05–8.10 (m, 2H), 7.87 (t, J¼8.0 Hz,
1H), 7.81 (t, J¼8.0 Hz, 1H), 7.62 (t, J¼7.2 Hz, 1H), 7.41 (t,
J¼7.6 Hz, 1H). 13C NMR (CDCl3) d 167.7, 156.4, 147.9,
146.4, 144.3, 141.0, 136.7, 132.1, 130.1, 129.3, 128.5,
126.4, 125.7, 125.1, 124.5, 123.0, 122.2, 120.1, 119.2,
118.4, 116.6. HRMS (EI) calcd for C21H11N5O2S (Mþ)
397.0634. Found: 397.0665.
4.4.13. 6-(4,7-Dimethoxybenzothiazol-2-yl)-benzo[4,5]-
imidazo[1,2-c]quinazoline (9f). Orange needles (58%),
mp 2238C (DMF). IR (KBr): 3132, 3075, 3007, 2932, 1772,
1
1632, 1524, 1276, 770 cm21. H NMR (CDCl3) d 9.40 (s,
Acknowledgements
1H), 8.49 (d, J¼8.8 Hz, 1H), 8.27 (d, J¼8.0 Hz, 1H), 8.15
(d, J¼8.4 Hz, 1H), 8.02 (m, 1H), 7.94 (m, 1H), 7.70 (m,
1H), 7.50 (m, 1H), 6.97 (s, 2H), 4.04 (s, 6H). 13C NMR
(CDCl3) d 150.1, 150.0, 147.3, 142.3, 138.4, 135.1, 131.4,
130.4, 129.1, 128.6, 128.4, 128.2, 123.8, 122.8, 121.9,
121.1, 120.6, 119.8, 115.2, 105.4, 102.1, 96.5, 56.4, 56.2.
HRMS (EI) calcd for C23H16N4O2S (Mþ) 412.0994. Found:
412.1009.
´
We thank the Comite de Charente-Maritime de la Ligue
Nationale contre le Cancer for financial support. S. F. is
´
´
thankful to the Communaute d’Agglomeration de La
Rochelle for a research fellowship. We also thank CEM
Corp. for multiform support. C. B. thanks C. Bal, B.
Baldeyrou and N. Wattez for expert technical assistance
with the biological assays.
4.4.14. 6-(Benzoxazol-2-yl)-benzo[4,5]imidazo[1,2-
c]quinazoline (9h). Yellow solid (77%), mp 1948C
(toluene). IR (KBr): 3122, 3078, 1588, 1554, 1150,
1
739 cm21. H NMR (CDCl3) d 8.80 (dd, J¼8.0, 1.6 Hz,
References
1H), 8.14 (d, J¼8.0 Hz, 1H), 8.04 (t, J¼8.0 Hz, 2H), 7.86
(td, J¼8.4, 2.0 Hz, 1H), 7.80 (t, J¼8.4 Hz, 2H), 7.55–7.64
(m, 3H), 7.34 (td, J¼7.2, 1.6 Hz, 1H). 13C NMR (CDCl3) d
154.8, 150.6, 147.5, 144.3, 141.2, 140.6, 136.6, 132.1,
129.9, 128.9, 128.7, 127.7, 126.3, 125.8, 124.4, 123.3,
121.7, 120.2, 119.4, 114.8, 111.8. HRMS (EI) calcd for
C21H12N4O (Mþ) 336.1011. Found: 336.1009.
1. (a) Molinski, T. F. Chem. Rev. 1993, 93, 1825–1838.
(b) Gunawardana, G. P.; Kohmoto, S.; Gunasekara, S. P.;
McConnel, O. J.; Koehn, F. E. J. Am. Chem. Soc. 1988, 110,
4856–4858. (c) Gunawardana, G. P.; Kohmoto, S.; Burres,
N. S. Tetrahedron Lett. 1989, 30, 4359–4362.
´
2. (a) Robin, M.; Faure, R.; Perichaud, A.; Galy, J. P.
Heterocycles 2000, 53, 387–395. (b) Hanoun, J. P.; Faure,
R.; Galy, J. P.; Elguero, J. J. Heterocycl. Chem. 1996, 33,
747–750. (c) Barbe, J.; Boyer, G.; Carignano, I.; Elguero, J.;
Galy, J. P.; Morel, S.; Oughedani, R. Tetrahedron Lett. 1991,
32, 6709–6710.
4.5. Synthesis of 6-(6-nitrobenzoxazol-2-yl)-benzo-
[4,5]imidazo[1,2-c]quinazoline (8g) and 6-(6-nitro-
benzothiazol-2-yl)-indolo[1,2-c]quinazoline (9g)
6-Nitrobenzothiazol-2-carbonitrile (0.15 g, 0.73 mmol) and
3. Alvarez-Ibarra, C.; Fernandez-Granda, R.; Quiroga, M. L.;

`
S. Frere et al. / Tetrahedron 59 (2003) 773–779
779
Carbonell, A.; Cardenas, F.; Giralt, E. J. Med. Chem. 1997, 40,
668–676.
atmospheric pressure with a Synthewave S402 Prolabo
microwave reactor (300 W, monomode system) which has
quartz reactors, visual control, irradiation monitored by PC
computer, infrared measurement and continuous feedback
temperature control (by PC). Equipment of the oven can be
completed by an external stirring system, a condenser and
dropping funnel allowing conditions close to those involved in
classical methods; it is also possible to work under dry
atmosphere or in vacuo if necessary. Commarmot, R.;
Didenot, R.; Gardais, J. F. French Patent 84/03496, 1986;
Chem. Abstr. 1986, 105, 17442. A CEM Discovere focused
microwave reactor (300 W, monomode system) which has in
situ magnetic variable speed, may also be used.
4. (a) Wells, G.; Bradshaw, T. D.; Diana, P.; Seaton, A.; Shi,
D.-F.; Westwell, A. D.; Stevens, M. F. G. Bioorg. Med. Chem.
Lett. 2000, 10, 513–515. (b) Bradshaw, T. D.; Wrigley, S.;
Shi, D.-F.; Schultz, R. J.; Paull, K. D.; Stevens, M. F. G. Br.
J. Cancer 1998, 77, 745–752.
5. Besson, T.; Guillard, J. Tetrahedron 1999, 55, 5139–5144.
´ ´
´
6. Beneteau, V.; Besson, T.; Guillard, J.; Leonce, S.; Pfeiffer, B.
Eur. J. Med. Chem. 1999, 34, 1053–1060.
7. Besson, T.; Guillard, J.; Rees, C. W. Tetrahedron Lett. 2000,
41, 1027–1030.
´
´
´
8. Lamazzi, C.; Chabane, H.; Thiery, V.; Pierre, A.; Leonce, S.;
Pfeiffer, B.; Renard, P.; Guillaumet, G.; Besson, T. J. Enz. Inh.
Med. Chem. 2002. in press.
`
´
16. (a) Frere, S.; Thiery, V.; Besson, T. Tetrahedron Lett. 2001,
42, 2791–2794. (b) Soukri, M.; Guillaumet, G.; Besson, T.;
Aziane, D.; Aadil, M.; Essassi, El M.; Akssira, M.
Tetrahedron Lett. 2000, 41, 5857–5860.
´
9. Chabane, H.; Lamazzi, C.; Thiery, V.; Guillaumet, G.; Besson,
T. Tetrahedron Lett. 2002, 43, 2483–2486.
10. (a) Sengupta, S. K.; Cheng, X. C. C. In Cancer
Chemotherapeutic Agents; Foye, W. O., Ed.; ACS
Professional Reference Books: Washington, DC, 1995;
pp 246–251. (b) Moody, C. J. Synlett 1994, 681–688.
(c) Kansal, V. K.; Potier, P. Tetrahedron 1986, 42,
2389–2408. (d) Sainsbury, M. Synthesis 1977, 437–448.
11. Appel, R.; Janssen, H.; Siray, M.; Knoch, F. Chem. Ber. 1985,
118, 1632–1643.
17. Anastassiadou, M.; Danoun, S.; Crane, L.; Baziard-Mouysset,
G.; Payard, M.; Caignard, D.-H.; Rettori, M.-C.; Renard, P.
Bioorg. Med. Chem. 2001, 9, 585–592, and references cited
therein.
18. Biological evaluation. No precise target has been yet identified
for this type of compounds in the benzothiazol-6-yl indolo- or
benzimidazoquinazoline series. By analogy with related
molecules bearing a indolo[3,2-c]quinoline or benzimi-
dazo[1,2-c]quinazoline planar ring system,13 it was postulated
that the newly designed compounds might bind to DNA and
interfere with the DNA cleaving activities of topoisomerases.
Unfortunately, no inhibition of human topoisomerases I or II
was observed but a few compounds appear to bind to DNA.
This is the case, for example, with compound 9h which
slightly stabilises duplex DNA against heat denaturation and
presents a significant hypochromic effect upon interaction with
DNA. Nucleic acids might be considered as possible receptors
for these molecules, at least some of them. Detailed studies are
in progress to delineate further the strength and mode of
binding to DNA by these molecules. A preliminary study has
been carried out to investigate the cytotoxic potential of the
molecules. They were all found to be only modestly cytotoxic
toward CEM human leukaemia cells with IC50 values .5 mM.
Other cell lines are currently tested and the results of the
biological and pharmacological studies will be reported in due
course.
´ ´
12. (a) Beneteau, V.; Besson, T.; Rees, C. W. Synth. Commun.
´ ´
1997, 27, 2275. (b) Beneteau, V.; Besson, T.; Guillard, J.;
´
Leonce, S.; Pfeiffer, B. Eur. J. Med. Chem. 1999, 34, 1053.
´
(c) Besson, T.; Rees, C. W.; Roe, D. G.; Thiery, V. J. Chem.
Soc., Perkin Trans. 1 2000, 555–561.
13. (a) Helissey, P.; Cros, S.; Giorgi-Renault, S. Anti-Cancer Drug
Des. 1994, 9, 51–57. (b) Brana, M. F.; Castellano, J. M.;
Keilhauer, G.; Machuca, A.; Martin, Y.; Redondo, C.; Schlick,
E.; Walker, N. Anti-Cancer Drug Des. 1994, 9, 527–538.
(c) Riou, J. F.; Helissey, P.; Grondard, L.; Giorgi-Renault, S.
Mol. Pharmacol. 1991, 40, 699–706. (d) Ibrahim, E.;
Montgomerie, A. M.; Sneddon, A. H.; Proctor, G. R.; Green,
B. Eur. J. Med. Chem. 1988, 23, 183–188.
14. (a) Billimmoria, A. D.; Cava, M. P. J. Org. Chem. 1994, 59,
6777–6782. (b) Hinckdentine A (1) as been isolated from the
bryozoan Hincksinoflustra denticulata, collected off the
eastern coast of Tasmania: Blackman, A.; Hambley, T. W.;
Picker, R.; Taylor, W. C.; Thirasana, N. Tetrahedron Lett.
1987, 28, 5561–5564.
19. English, R. F.; Rakitin, O. A.; Rees, C. W.; Vlasova, O. G.
J. Chem. Soc., Perkin Trans. 1 1997, 201–205.
15. Focused microwave irradiations were carried out at