Efficient synthesis of thiazoloquinazolinone derivatives

Article abstract of DOI:10.1016/S0040-4039(03)01026-8

An original route to the rare 8H-thiazolo[5,4-f]quinazolin-9-one 1 and the novel 7H-thiazolo[4,5-h]quinazolin-6-one 2 is described. Access to the regioisomers was realized by fusion of a thiazole and a quinazoline ring via Appel's salt chemistry. Thermal

Full text of DOI:10.1016/S0040-4039(03)01026-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4455–4458
Efficient synthesis of thiazoloquinazolinone derivatives
Franc¸ois-Rene´ Alexandre,a,b Amaya Berecibar,b Roger Wrigglesworthb and Thierry Bessona,*
aLaboratoire de Ge´nie Prote´ique et Cellulaire, EA3169, Groupe de Chimie Organique, UFR Sciences Fondamentales et Sciences
pour l’Inge´nieur, Baˆtiment Marie Curie, Universite´ de la Rochelle, F-17042 La Rochelle cedex 1, France
bPFIZER Global Research & Development, Fresnes Laboratories, 3–9 rue de la Loge, BP100, F-94265 Fresnes cedex, France
Received 10 April 2003; accepted 19 April 2003
Abstract—An original route to the rare 8H-thiazolo[5,4-f ]quinazolin-9-one 1 and the novel 7H-thiazolo[4,5-h]quinazolin-6-one 2
is described. Access to the regioisomers was realized by fusion of a thiazole and a quinazoline ring via Appel’s salt chemistry.
Thermal reactions were carried out using a focused microwave reactor, reducing the overall time of the multi-step synthesis.
© 2003 Elsevier Science Ltd. All rights reserved.
Present in many natural and synthetic products, the
thiazole ring has generated interest of many groups
on account of its interesting biological properties.1,2
Thus, we recently published the synthesis of
thiazoloheterocycles3 mainly related to marine or terres-
trial alkaloids (e.g. dercitine, kuanoniamine1,2 and
ellipticine4). Inspired by previous work describing the
synthesis and the biological activity of a linear 7H-thia-
zolo[5,4-g]quinazolin-8-one,5 we studied the prepara-
tion of the angular 8H-thiazolo[5,4-f ]quinazolin-9-one
ring 16 via another route using Appel’s salt7 (4,5-
dichloro-1,2,3-dithiazolium chloride) chemistry. Unfor-
tunately, this pathway was not adapted for easy
introduction of various substituents on the skeleton
which was essential for its pharmaceutical evaluation.
Thus, we decided to re-investigate the synthetic
approach to the planar compound 1 and, in the same
time, we performed the synthesis of its novel regio-iso-
mer 2 (Fig. 1), with the aim to allow the presence of
further substituents. In connection with our work on
the application of microwaves in the preparation of
bio-active molecules,8 we have performed many of the
reactions described in this paper using a focused
microwave oven specifically designed for organic syn-
thesis,9 achieving short reaction times and clean
reactions.
For the preparation of such compounds, two routes
were possible. The first one was to create the thiazole
ring before the quinazoline moiety, whilst the first step
of the second pathway consisted of formation of the
quinazoline ring. As may be predicted, the synthesis
starting with the formation of the thiazole ring induced
a low subsequent reactivity.
The first step of the chosen route involved preparation
of 3H-nitroquinazolin-4-ones
3 via a traditional
Niementowski condensation (Scheme 1).10 This old
reaction which consists of the fusion between
anthranilic acid and formamide was recently re-investi-
gated under microwave irradiation.11 The quinazolin-4-
ones rings were rapidly obtained and the reduction of
the nitro group was realized using catalytic transfer
hydrogenation in good yields. It was followed by con-
densation of the aromatic amines 4a–b with 4,5-
dichloro-1,2,3-dithiazolium chloride in order to obtain
the intermediate imino-1,2,3-dithiazoles 5a–b. The mod-
est observed yields may be due to the presence of the
deactivating 3H-quinazoline-4-one moiety. Cyclization
(thermolysis in N-methylpyrrolidin-2-one (NMP)3a) of
the imines 5a–b into the corresponding thiazoles was
unfructuous and gave the corresponding cyanoimidoyl
chloride 6 or the starting amine 4b for 5b.
Figure 1. The 8H-thiazolo[5,4-f ]quinazolin-9-one 1 and 7H-
thiazolo[4,5-h]quinazolin-6-one 2.
Keywords: thiazoloquinazolinones; quinazolines; 4,5-dichloro-1,2,3-
dithiazolium chloride; microwave-assisted chemistry.
* Corresponding author. Tel.: +33 (0)5 46 45 82 76; e-mail: tbesson@
univ-lr.fr
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01026-8

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F.-R. Alexandre et al. / Tetrahedron Letters 44 (2003) 4455–4458
Scheme 1. Reagents and conditions: (a) formamide (5 equiv.), mW 150°C (P 60W), 40 min; (b) ammonium formate/Pd/C, MeOH,
mW 65°C (P 60W), 10 min; (c) Appel’s salt, pyridine, CH2Cl2, rt, 3 h; (d) NMP, mW 150°C (P 90W), 10 min.
To circumvent the low yields of Appel’s salt condensa-
tion, a second route starting by N-alkylation (benzyl
group) of the nitrogen atom in position 3 of the
quinazolin-4-one was investigated (Scheme 2). The
protected compounds 7a–b were obtained in good
yields and introduced in the sequence of reactions
described above. Then, reduction of the nitro group
and condensation of the amine with Appel’s salt gave
the imino-intermediates 9a–b in good yields. Again,
thermolysis of the imines 9a–b gave the corresponding
cyanoimidoyle chlorides 10a–b as major reaction prod-
ucts together with the desired benzothiazoles 11a–b
albeit in low yields.
products possess a cyano group in position 2 (which is
latent in the dithiazole ring7), offering many possibili-
ties of introduction of various functions or rings.
Access to the parent rings 1 and 2 were performed by
heating the precursors 11a–b in sulfuric acid, involving
deprotection of the nitrogen group and decyanation
(hydrolysis+decarboxylation) of the thiazole moiety
(Scheme 3).12
The pharmaceutical interest of the 8H-thiazolo[5,4-f ]-
quinazolin-9-one skeleton 1 may be limited because
of the lack of substituents, such as basic amino
groups.13 The interest of the multi-step (seven steps
from the nitroanilines) synthesis described in this
paper is to allow further modulations of the ring in
various positions. In particular, N-alkylations of the
nitrogene in position 8, and transformation of the
cyano group present in the thiazole moiety may be
studied in order to generate novel series of bio-active
molecules.14
An alternative access to the thiazole ring was then
studied. Bromation of the two isomers 7a–b and con-
densation with Appel’s salt gave the iminobromo-
quinazolin-4-ones 12a–b in quite good yields. Rapid
heating in pyridine at reflux in the presence of cuprous
iodide gave the expected rings 11a–b.6,8c The resulting
Scheme 2. Reagents and conditions: (a) BnBr, NaH, DMF, mW 70°C (P 60W), 15 min; (b) ammonium formate/Pd/C, EtOH, mW
65°C (P 60W), 10 min; (c) Appel’s salt, pyridine, CH2Cl2, rt, 3 h; (d) N-methylpyrolidin-2-one, mW 150°C (P 90W), 10 min.

F.-R. Alexandre et al. / Tetrahedron Letters 44 (2003) 4455–4458
4457
Scheme 3. Reagents and conditions: (a) Br2, acetic acid, rt, 2 h; (b) Appel’s salt, pyridine, CH2Cl2, rt, 3 h; (c) CuI, pyridine, mW
115°C (P 90W), 15 min; (d) conc. H2SO4, mW 130°C (P 80W), 15 min.
Among all the reactions performed, five were trans-
posed with success to a focused microwave reactor. The
short reaction times of these reactions (10–40 min) and
the purity of the observed products compared to the
purely thermal procedures allowed a quick realization
of these multi-step synthesis.
Guillaumet, G.; Besson, T. Tetrahedron Lett. 2002, 43,
2483–2486; (d) Besson, T.; Guillard, J. Tetrahedron 1999,
55, 5139–5144.
4. (a) Sengupta, S. K.; Cheng, X. C. C. Cancer Chemothera-
peutic Agents; ACS Professional Reference Books: Wash-
ington DC, 1995, W.O. Foye editor, pp. 246–251; (b)
Moody, C. J. Synlett 1994, 681–688; (c) Kansal, V. K.;
Potier, P. Tetrahedron 1986, 42, 2389–2408; (d) Sains-
bury, M. Synthesis 1977, 437–448.
5. Rewcastle, G. W.; Palmer, B. D.; Bridges, A. J.; Showal-
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Kraker, A. J.; Fry, D. W.; Denny, W. A. J. Med. Chem.
1996, 39, 918–928.
In conclusion we have described a rapid and convenient
multi-step access to the rare 8H-thiazolo[5,4-f ]-
quinazolin-9-one 1, and, at the same time, we per-
formed the synthesis of its novel regioisomer (7H-
[1,3]thiazolo[4,5-h]quinazolin-6-one 2) via Appel’s salt
chemistry. In this paper, we show the interest to com-
bine drug discovery strategy with microwave heating
allowing a rapid access to novel molecules with poten-
tial pharmacological value.
6. Besson, T.; Guillard, J.; Rees, C. W. Tetrahedron Lett.
2000, 41, 1027–1030.
7. (a) Appel, R.; Janssen, H.; Siray, M.; Knoch, F. Chem.
Ber. 1985, 118, 1632–1643; (b) English, R. F.; Rakitin, O.
A.; Rees, C. W.; Vlasova, O. G. J. Chem. Soc., Perkin
Trans. 1 1997, 201–205; (c) Besson, T.; Rees, C. W. J.
Chem. Soc., Perkin Trans. 1 1995, 1659–1662.
Acknowledgements
8. (a) Fre`re, S.; Thie´ry, V.; Besson, T. Tetrahedron Lett.
2001, 42, 2791–2794; (b) Domon, L.; Le Coeur, C.;
Grelard, A.; Thie´ry, V.; Besson, T. Tetrahedron Lett.
2001, 42, 6671–6674; (c) Besson, T.; Dozias, M. J.; Guil-
lard, J.; Rees, C. W. J. Chem. Soc., Perkin Trans. 1 1998,
3925–3926; (d) Besson, T.; Dozias, M. J.; Guillard, J.;
Jacquault, P.; Legoy, M. D.; Rees, C. W. Tetrahedron
1998, 54, 6475–6484.
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.
References
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(0–20 bar) if necessary.
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12. Selected data for compound 11a–b, 2. 8-Benzyl-9-oxo-
8,9-dihydrothiazolo[5,4-f ]quinazoline-2-carbonitrile 11a:
pale yellow solid; mp (CH2Cl2) 190°C; IR (KBr) w 3064,
1
2230, 1665, 1588, 856, 729, 695 cm−1; H NMR (CDCl3)

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F.-R. Alexandre et al. / Tetrahedron Letters 44 (2003) 4455–4458
1
l 5.34 (s, 2H), 7.39 (m, 5H), 8.00 (d, J=8.8 Hz, 1H), 8.36
>260°C; H NMR (d6-DMSO) l 8.13 (d, J=8.8 Hz, 1H),
8.19 (d, J=8.8 Hz, 1H), 8.30 (s, 1H), 9.64 (s, 1H); 13C NMR
(d6-DMSO) l 118.9, 121.3, 123.8, 130.9, 145.1, 147.7,
156.7, 160.0, 160.8; MS (ESI, El+) m/z=204 (MH+);
HRMS: calcd for C9H5N3OS, 203.0153; found, 203.0145.
13. Preliminary evaluation for in vitro antiproliferative activity
of the 8H-thiazolo[5,4-f ]quinazolin-9-ones 1 was per-
formed using the murine L1210 leukemia cell line as
described in ref. cited below. The results have shown that
the final product is considerably less active than its
substituted precursors (described in Ref. 6). Le´once, S.;
Pe´rez, V.; Casabianca-Pine`de, M. R.; Anstett, M.; Bisagni,
E.; Atassi, G. Invest. New Drugs 1996, 14, 169–180.
14. Be´ne´teau, V.; Besson, T.; Guillard, J.; Le´once, S.; Pfeiffer,
B. Eur. J. Med. Chem. 1999, 34, 1053–1060.
(s, 1H), 8.54 (d, J=8.8 Hz, 1H); 13C NMR (CDCl3) l 50.2,
113.1, 116.3, 128.1, 128.2, 128.8, 129.3, 130.5, 132.4, 134.7,
140.2, 147.3, 148.8, 151.5, 159.4; MS (ESI, El+) m/z=319
(MH+); HRMS: calcd for C17H10N4OS, 318.0575; found,
318.0566.
7-Benzyl-6-oxo-6,7-dihydrothiazolo[4,5-h]-
quinazoline-2-carbonitrile 11b: white solid; mp (CH2Cl2)
193°C; IR (KBr) w 3078, 2235, 1688, 1600, 1455, 1369, 1350,
708 cm−1; 1H NMR (CDCl3) l 5.27 (s, 2H), 7.39 (m, 5H),
8.23 (d, J=8.8 Hz, 1H), 8.28 (s, 1H), 8.50 (d, J=8.8 Hz,
1H); 13C NMR (CDCl3) l 50.2, 112.6, 120.4, 123.4, 126.4,
128.2, 128.7, 129.2, 133.5, 135.0, 140.4, 144.2, 148.4, 156.0,
160.2; MS (ESI, El+) m/z=319 (MH+); HRMS: calcd for
C17H10N4OS, 318.0575; found, 318.0566. Thiazolo[4,5-
h]quinazolin-6(7H)-one 2: white solid, mp (EtOAc)