A rapid and convenient synthesis of novel 1-imino-2,3-dihydro-1H- pyrazino[2,1,-b]quinazolin-5-ones

Article abstract of DOI:10.1016/j.tetlet.2004.02.095

Exploring original approaches for the synthesis of therapeutic agents having a quinazoline part, we discovered that novel 3,4-dihydro-2H-pyrazino[2,1, -b]quinazolines (3) may be rapidly and easily obtained via the chemistry of 4,5-dichloro-1,2,3-dithiazol

Full text of DOI:10.1016/j.tetlet.2004.02.095

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3097–3099
A rapid and convenient synthesis of novel 1-imino-2,3-dihydro-1H-
pyrazino[2,1,-b]quinazolin-5-ones
*
ꢀ
Maria de Fatima Pereira, Francois Rene Alexandre, Valerie Thiery and Thierry Besson
ꢀ
ꢀ
ß
Laboratoire de Biotechnologie et Chimie Bioorganique, CNRS FRE-2766, UFR Sciences Fondamentales et Sciences pour lÕIngꢀenieur,
B^atiment Marie Curie, Universitꢀe de la Rochelle, F-17042 La Rochelle cedex 1, France
Received 14 January 2004; revised 17 February 2004; accepted 18 February 2004
Abstract—Exploring original approaches for the synthesis of therapeutic agents having a quinazoline part, we discovered that novel
3,4-dihydro-2H-pyrazino[2,1,-b]quinazolines (3) may be rapidly and easily obtained via the chemistry of 4,5-dichloro-1,2,3-di-
thiazolium chloride (1). Our synthetic approach of this reaction is described with the aim of obtaining a well-controlled access to this
very rarely described pyrazino[2,1,-b]quinazoline skeleton.
Ó 2004 Elsevier Ltd. All rights reserved.
The quinazoline skeleton, when selectively functional-
ized, is a building block for the preparation of numerous
alkaloids and substances with pronounced biological
activities.1 The main activity of our group consists in the
synthesis of heterocyclic structures with potential phar-
maceutical value. Our molecular targets are inspired by
natural marine (e.g., hinkdentine, dercitine and kua-
noniamines) or terrestrial (e.g., rutaecarpine and luoto-
nine) alkaloids for which interesting biological activity
was detected. We recently described the synthesis of
novel heterocycles in which the quinazoline ring is fused
with indole (I), benzimidazole (II) or quinazoline rings
(III) (Scheme 1)2 and concentrated our work on the
synthesis of 2,3-condensed (3H)-quinazolin-4-one
derivatives (IV in Scheme 1), which can be employed as
intermediates in the synthesis of expected bioactive
compounds. Although a wide range of 2,3-condensed
(3H)-quinazolin-4-ones occurs in different families of
plants and micro-organisms, only a few papers describe
the synthesis and the reactivity of such ring systems.3
Studying the chemistry of 4,5-dichloro-1,2,3-dithiazo-
lium chloride4 (1) and its derivatives,5 we discovered
that novel 3,4-dihydro-2H-pyrazino[2,1,-b]quinazolines
may be rapidly and easily obtained from methyl
N-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-anthranilates,
accompanied by the known 2,3-dihydro-1H-imi-
dazo[2,1,-b]quinazolin-5-ones. In this paper, we describe
our synthetic approach using this reaction with the aim
of obtaining a well-controlled access to the very rarely
described pyrazino[2,1,-b]quinazoline skeleton. Increas-
ing the range of methyl anthranilate derivatives that
condense with the salt 1, we successfully varied the
substituents on the aromatic moiety of the new poly-
cyclic products.
O
X
N
O
N
N
N
O
NH
It is now well known that reaction of 4,5-dichloro-1,2,3-
dithiazolium chloride 1 with primary aromatic amines in
dichloromethane at room temperature allows access to
stable N-arylimino-4-chloro-5H-1,2,3-dithiazoles (e.g.,
2).4 These compounds have proved to be highly versatile
intermediates in heterocyclic synthesis, undergoing a
variety of reactions initiated by inter- or intra-molecular
nucleophilic attack at S-1, S-2 or C-5 of the dithiazole
ring.5
N
N
N
N
O
IV
X = CH (I) or N (II)
III
Scheme 1.
Keywords: Quinazolin-4-ones; 4,5-dichloro-1,2,3-dithiazolium chlor-
ide; Pyrazino[2,1,-b]quinazolines; Imidazo[2,1,-b]quinazolin-5-ones;
Anthranilate derivatives.
Following the usual methods, treatment of methyl
anthranilates
* Corresponding author. Tel.: +33-05-4645-8276; fax: +33-05-4645-
8247; e-mail: tbesson@univ-lr.fr
with
4,5-dichloro-1,2,3-dithiazolium
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.02.095

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M. F. Pereira et al. / Tetrahedron Letters 45 (2004) 3097–3099
chloride 1 in dichloromethane at room temperature gave
the corresponding methyl N-(4-chloro-5H-1,2,3-di-
thiazol-5-ylidene)-anthranilates 2a–d in quantitative yield.
Stirring of a solution of these imines and ethylenedi-
amine at room temperature in tetrahydrofuran, gave a
mixture of two compounds, which could be easily sep-
arated by column chromatography and isolated in rea-
sonable yields. The products then obtained were
identified as the novel 1-imino-2,3-dihydro-1H-pyraz-
ino[2,1,-b]quinazolin-5-ones (3) (only one example of a
similar heterocyclic skeleton was given in literature from
isatoic anhydride via a 2-chloroformyl-4H-3,1-benzox-
azin-4-one6) accompanied by a small amount of the
known 2,3-dihydro-1H-imidazo[2,1,-b]quinazolin-5-one
(4) derivatives7 (see Table 1).
pyrazine ring on the quinazoline skeleton would occur
by final nucleophilic attack of the primary amino group
on the carbonitrile carbon to generate the cyclic ami-
dines 3, whilst the nucleophilic substitution of the cyano
group leads to the five-membered derivatives 4.
Studying various experimental conditions we varied the
amount of the diamine (1 or 3 equiv). The results show
that a large quantity of ethylenediamine is favourable to
the imidazoquinazolines 4a–c, reducing considerably the
amount of isolated six-membered pyrazino[2,1,-b]-
quinazolines (3a–c) (Table 1). Surprisingly, methyl 4,5-
dimethoxyanthranilate gave the expected product 3d
only in the presence of 3 equiv of the diamine (see Table
1), in contrast to other anthranilates. Whichever method
was used (1 or 3 equiv of diamine, heating or not) no
trace of the five-membered product 4d was detected.
A possible mechanism for the reaction is shown in
Scheme 2. Opening of the dithiazole ring by the aliphatic
amine is presumably initiated by attack at C-5 and
generation of the cyano group, which is latent in the
iminodithiazole ring (e.g., 5). The following intramo-
lecular cyclization by nucleophilic attack of the sec-
ondary amino group to the ester carbonyl carbon would
give the intermediate N-substituted quinazolines (e.g.,
6).10 In a second step, the formation of the imidazo-
Exploring possible alternative routes to this rarely
described ring, we tried to condense ethylene diamine
with a 2-cyano-4H-3,1-benzoxazin-4-one 7, itself obtain
by condensation of anthranilic acid R1 ¼ H in Scheme 1
with salt 1, in the presence of a base.11 In this case, and
whatever condition were experimented, no trace of the
expected pyrazino[2,1,-b]quinazoline 3a was detected.
In connection with our work on the utility of micro-
waves in organic synthesis, we also decided to investi-
gate the microwave-assisted heating of the reaction
mixture. Conventional heating was experimented under
the same conditions of reactants. Whichever method
was used, the cyclized products were obtained in lower
yield than at room temperature. Here again the main
products were the five-membered derivatives (4) and,
curiously, in the case of compound 2a, starting methyl-
anthranilate was recovered in modest yield (less than
10%), showing a possible hydrolysis of the intermediate
imino-1,2,3-dithiazoles 2a.
Table 1. Synthesis of 3 and 4 from anthranilic esters.a8;9
Starting ester
(R)
Diamine
equiv
Yield of 2 Yield of 3 Yield of 4
(%)
(%)
(%)
a (H)
a (H)
1
3
1
3
1
3
1
3
98
––
98
––
71
––
99
––
54
56
74
4
8b
18
17b;c
b (5-Br)
b (5-Br)
28
22
c (4-Cl)
c (4-Cl)
61
8
57
––
d (4,5-diOMe)
d (4,5-diOMe)
––
62
––
a Conditions and reagents: ethylene diamine (1 or 3 equiv), tetra-
hydrofurane (THF), rt.
Hydrochloric acid hydrolysis (refluxing HCl for 2 h or
more) of the novel 1-imino-2,3-dihydro-1H-pyraz-
ino[2,1,-b]quinazolin-5-ones 3a and 3b was also experi-
mented. Unfortunately, no trace of the corresponding
amides was detected and the starting material was
completely recovered.
b The same reaction (same quantities of reactants and solvent) was
performed at 0or À20 °C. The yields obtained are similar to those
observed at room temperature.
c Under these conditions (1 equiv of diamine), heating at reflux (oil
bath or microwaves) caused a decrease in the amount of 3b (40%) in
favour of 4b (41%).
Scheme 2. Suggested mechanism and alternative route for the generation of 3 and 4.

M. F. Pereira et al. / Tetrahedron Letters 45 (2004) 3097–3099
3099
9. All compounds were fully characterized by spectroscopic
and elemental analysis. Spectral data for compounds 2 and
4 are consistent with structures published (in Ref. 5 and
references cited for 2 and Ref. 7 for 4a,c and 8).
In conclusion, we describe here the rapid synthesis of
novel 1-imino-2,3-dihydro-1H-pyrazino[2,1,-b]quinazo-
lin-5-ones (3) via the intermediate methyl N-(4-chloro-
5H-1,2,3-dithiazol-5-ylidene)-anthranilates (2). This
work is a further example of the applicability of 4,5-
dichloro-1,2,3-dithiazolium chloride (AppelÕs salt) in the
preparation to novel polyheterocyclic systems. The high
solubility of such compounds and their chemical sta-
bility open the door to promising pharmaceutical
applications. Investigations are currently under way and
will be published later.
Selected data for new compounds 3a–d and 4b (R ¼ Br).
1-Imino-1,2,3,4-tetrahydro-2,4a,9-triaza-anthracen-10-one
(3a), white solid; mp 208 °C; IR (KBr) m 3474, 3098, 2332,
2060, 1734, 1669, 1602, 1293, 1174, 783 cmÀ1 1H NMR
;
(d6-DMSOþD2O) d 8.18 (dd, J ¼ 8:0Hz and J ¼ 2:0Hz,
1H), 7.88 (td, J ¼ 8:0Hz and J ¼ 2:0Hz, 1H), 7.77 (d,
J ¼ 8:0Hz, 1H), 7.62 (td, J ¼ 8:0Hz and J ¼ 2:0Hz, 1H),
4.03 (t, J ¼ 6:0Hz, 2H), 3.61 (t, J ¼ 6:0Hz, 2H); 13C
NMR (d6-DMSOþD2O) d 159.57, 152.00, 145.65, 139.98,
134.79, 129.71, 128.34, 127.82, 126.25, 121.42, 41.12; MS
(EI) m=z ¼ 214 (Mþ); HRMS: calcd for C11H10N14O,
214.0855; found, 214.0852.
Acknowledgements
6-Bromo-1-imino-1,2,3,4-tetrahydro-2,4a,9-triaza-anthra-
cen-10-one (3b), white solid; mp>260 °C decomp.; IR
ꢀ
We thank the Comite de Charente-Maritime de la Ligue
Nationale contre le Cancer for financial support.
1
(KBr) m 3438, 3076, 2950, 1684, 1594, 1470, 828 cmÀ1; H
NMR (d6-DMSOþD2O) d 8.26 (d, J ¼ 1:6 Hz, 1H), 8.03
(dd, J ¼ 8:8 Hz and J ¼ 1:6 Hz, 1H), 7.74 (d, J ¼ 8:8 Hz,
1H), 4.03 (t, J ¼ 6:4 Hz, 2H), 3.62–3.56 (m, 2H); 13C
NMR (d6-DMSOþD2O) d 158.61, 151.08, 144.92, 140.66,
137.34, 129.98, 128.94, 122.94, 120.19, 42.54, 38.48; MS
(EI) m=z ¼ 292 (Mþ); HRMS: calcd for C11H9N14OBr,
291.9956; found, 291.9969.
References and notes
1. (a) Johne, S. In Progress in the Chemistry of Organic
Natural Products; Herz, W., Grisebach, H., Kirby, G. W.,
Tamm, Ch., Eds.; Spinger, Wien, 1984; p 159–229 (b)
Johne, S. In The Alkaloids, Chemistry and Pharmacology;
Brossi, A., Ed.; Academic: New York, 1986; Vol. 29,
pp 99–140.
7-Chloro-1-imino-1,2,3,4-tetrahydro-2,4a,9-triaza-anthra-
cen-10-one (3c), white solid; mp 188 °C (dec); IR (KBr) m
3472, 3093, 1678, 1586, 1366, 782 cmÀ1 1H NMR (d6-
;
DMSOþD2O) d 8.14 (d, J ¼ 8:8 Hz, 1H), 7.60(dd,
J ¼ 8:8 Hz and J ¼ 2:0Hz, 1H), 7.80 (d, J ¼ 2:0Hz,
1H), 3.97 (t, J ¼ 6:4 Hz, 2H), 3.55 (t, J ¼ 6:4 Hz, 2H);
13C NMR (d6-DMSOþD2O) d 159.80, 151.78, 147.67,
141.86, 139.71, 128.85, 128.65, 127.33, 120.78, 42.82,
38.94; MS (EI) m=z ¼ 248 (Mþ); HRMS: calcd for
C11H9N14OCl, 248.0465; found, 248.0449.
6,7-Dimethoxy-1-imino-1,2,3,4-tetrahydro-2,4a,9-triaza-
anthracen-10-one (3d), white solid; mp>260 °C; IR (KBr)
m 3440, 3008, 2960, 2832, 1740, 1643, 1354, 1002, 782,
603 cmÀ1; 1H NMR (d6-DMSOþD2O) d 7.48 (s, 1H), 7.23
(s, 1H), 4.10(t, J ¼ 6:0Hz, 2H), 3.90(s, 3H), 3.87 (s, 3H),
3.65–3.60(m, 2H); 13C NMR (d6-DMSOþD2O) d 158.62,
154.78, 152.30, 150.00, 141.62, 138.66, 115.05, 108.35,
105.46, 56.03, 55.93, 41.05, 38.29; MS (EI) m=z ¼ 274
(Mþ); HRMS: calcd for C13H14N14O3, 274.1066; found,
274.1074.
2. (a) Alexandre, F.-R.; Berecibar, A.; Wrigglesworth, R.;
Besson, T. Tetrahedron 2003, 59, 1413–1419; (b) Domon,
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L.; Le Coeur, C.; Grelard, A.; Thiery, V.; Besson, T.
Tetrahedron Lett. 2001, 42, 6671–6674; (c) Soukri, M.;
Guillaumet, G.; Besson, T.; Aziane, D.; Aadil, M.; Essassi,
El M.; Akssira, M. Tetrahedron Lett. 2000, 41, 5857–5860;
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(d) Frere, S.; Thiery, V.; Bailly, C.; Besson, T. Tetrahedron
2003, 59, 773–779.
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3. (a) Armarego, W. L. F. Adv. Heterocycl. Chem. 1979, 24,
1–62; (b) Comprehensive Heterocyclic Chemistry II; Kat-
rizky, A. R., Rees, C. W., Eds.; Pergamon: Oxford, 1996.
4. Appel, R.; Janssen, H.; Siray, M.; Knoch, F. Chem. Ber.
1985, 118, 1632–1643.
5. For reviews on the chemistry of AppelÕs salt derivatives
see: (a) Kim, K. Sulfur Reports 1998, 21, 147–207; (b)
Rees, C. W. J. Heterocycl. Chem. 1992, 29, 639–651.
6. Motohiro, T.; Motome, H. Heterocycles 1984, 21, 706,
This paper (only one page) is an abstract of a congress,
there is no description of the physical data of the
compound cited.
7. (a) Dean, W. D.; Papadopoulos, E. P. J. Heterocycl.
Chem. 1982, 1117–1124; (b) Jen, T.; Dienel, B.; Bowman,
H.; Helt, A.; Loev, B. J. Med. Chem. 1972, 15, 727–731.
8. Typical procedure for the synthesis of 1-imino-2,3-
dihydro-1H-pyrazino[2,1,-b]quinazoline-5-ones 4 (1-imi-
no-1,2,3,4-tetrahydro-2,4a,9-triaza-anthracen-10-ones): A
solution of ethylene diamine (0.083 g, 1.38 mmol) in
tetrahydrofuran (10mL) was added slowly to a solution of
N-(4-chloro-5H-1,2,3-dithiazol-5-yliden)-methyl-5-bromo-
benzoate (0.504 g, 1.38 mmol) in tetrahydrofuran (10 mL).
The mixture was stirred under argon at room temperature,
for 2 h. After evaporation of the solvent under reduced
pressure, the residue was purified by column chromato-
graphy on silica gel (dichloromethane/methanol, 95:5) to
furnish 3 and 4 as colourless solids.
7-Bromo-2,3-dihydro-1H-imidazo[2,1-b]quinazolin-5one
(4b), white solide; mp>260 °C ; IR (KBr) m 3046, 2884,
1706, 1654, 1469, 1278, 822, 674 cmÀ1 1H NMR (d6-
;
DMSOþD2O) d 7.97 (d, J ¼ 2:4 Hz, 1H), 7.66 (dd,
J ¼ 8:8 Hz and J ¼ 2:4 Hz, 1H), 7.18 (d, J ¼ 8:8 Hz,
1H), 4.12 (t, J ¼ 8:8 Hz, 2H), 3.64 (t, J ¼ 8:8 Hz, 2H);
13C NMR (d6-DMSOþD2O) d 158.98, 154.90, 150.31,
136.41, 127.64, 126.57, 118.82, 113.01, 12.21; MS (EI)
m=z ¼ 265 (Mþ); HRMS: calcd for C10H8N3OBr,
264.9851; found, 264.9853.
10. Opening of the dithiazole ring by aliphatic amines has also
been described by Kim and co-workers to be synthetically
useful for the synthesis of 3-alkyl-2-cyanoquinazolin-4-
ones Lee, H. S.; Chang, Y.-G.; Kim, K. J. Heterocycl.
Chem. 1998, 35, 659–668, In our group the same quinaz-
oline ring was also isolated after nucleophilic attack of
alkylated and aromatic polyamines: Pereira, M. de F.
unpublished results.
11. Besson, T.; Kumaraswamy, E.; Rees, C. W. J. Chem. Soc.,
Perkin. Trans. 1 1995, 2097–2102.