A novel rearrangement to 1,2,4-triazolo[1,5-α]quinoxalines

Article abstract of DOI:10.1021/jo011028b

Reactions of benzyl bromide or benzyl cinnamate with N-(benzotriazol-1-ylmethyl)arylimidoyl chlorides (2a,b) in the presence of t-BuOK occur with opening of the benzotriazole ring affording 1,2,4-triazolo[1,5-α]quinoxalines (3a,b). A possible reaction mechanism is discussed.

Full text of DOI:10.1021/jo011028b

3118
J . Org. Chem. 2002, 67, 3118-3119
Sch em e 1
A Novel Rea r r a n gem en t to
1,2,4-Tr ia zolo[1,5-a ]qu in oxa lin es
Alan R. Katritzky,* Tian-Bao Huang, and
Olga V. Denisko
Center for Heterocyclic Compounds,
Department of Chemistry, University of Florida,
Gainesville, Florida 32611-7200
Peter J . Steel†
Department of Chemistry, University of Canterbury,
Christchurch, New Zealand
for the preparation of nitrogen-containing fused hetero-
cyclic systems such as pyrazolo[5,1-b]benzimidazoles8 and
tetrazolo[1,5-e][1,2,5]triazepines.9 We now demonstrate
its applicability to 1,2,4-triazolo[1,5-a]quinoxalines.
Following earlier work,10 we reacted benzyl cinnamate
with N-(benzotriazol-1-ylmethyl)furylimidoyl chloride (2a),
prepared in situ from the corresponding R-benzotriazolyl
amide 1a , in the presence of potassium tert-butoxide and
obtained, along with the expected pyrrole 410 (49%),
2-furyl-4-phenyl-1,2,4-triazolo[1,5-a]quinoxaline (3a ) as
a minor product (2%) (Scheme 1). Structure 3a , assigned
katritzky@chem.ufl.edu
Received October 25, 2001
Abstr a ct: Reactions of benzyl bromide or benzyl cinnamate
with N-(benzotriazol-1-ylmethyl)arylimidoyl chlorides (2a ,b)
in the presence of t-BuOK occur with opening of the
benzotriazole ring affording 1,2,4-triazolo[1,5-a]quinoxalines
(3a ,b). A possible reaction mechanism is discussed.
1
on the basis of H and 13C NMR data,2,4 was confirmed
1,2,4-Triazolo[1,5-a]-pyrazines and -quinoxalines pos-
sess a broad spectrum of physiological and biological
activities, which have attracted much recent attention
from medicinal chemists. Thus, Cecchi et al. showed
1,2,4-triazolo[1,5-a]quinoxalines to be potent benzodiaz-
epine receptor ligands,1 adenosine receptor ligands,2 and
highly selective glycine/NMDA and AMPA receptor an-
tagonists.3
The rather limited synthetic approaches to such poly-
cycles include (i) simultaneous formation of both triazole
and pyrazine heterorings on treatment of 2-aza-1,3-diene-
1,1-dicarbonitriles with hydrazides,4 (ii) pyrazine ring
formation by intramolecular reductive cyclization of 1-(2-
nitroaryl)-2-alkoxycarbonyl-1,2,4-triazoles, themselves pre-
pared in four steps from the corresponding o-nitro-
anilines,1,3,5 (iii) triazole ring formation by acid-induced
intramolecular cyclization of quinoxaline amidine or
formamidoxime,6 and (iv) substituent modification of the
already existing bis(heterocyclic) core system, prelimi-
narily obtained by aforementioned methods.2,6,7
by X-ray crystallography.
Apparently, only one nonaromatic carbon of the origi-
nal benzyl cinnamate molecule is retained in the struc-
ture 3a . From this, we hypothesized that an early step
in the formation of 3a was benzylation of an R-amino
carbanion, formed by deprotonation of the intermediate
N-(benzotriazol-1-ylmethyl)furylimidoyl chloride (2a); this
affords the R-benzylated product of type 5 and potassium
cinnamate. Indeed, treatment of N-(benzotriazol-1-yl-
methyl)aryl(heteroaryl)imidoyl chlorides 2a ,b (prepared
in situ) with the more efficient benzyl group donor, benzyl
bromide, and t-BuOK in THF under reflux smoothly gave
1,2,4-triazolo[1,5-a]quinoxalines 3a ,b in 25-31% yields.
These reactions also proceed at 0 °C, but in lower yields.
Compounds 3a ,b give blue fluorescent spots on TLC
plates under UV irradiation and are easily monitored
during purification by column chromatography. The
structure of compound 3b is assigned by analogy and by
comparison of its NMR data with those of 3a .
The mechanism of the transformation 5 f 3 suggested
in Scheme 2 is speculative. Ring closure of 5 induced by
participation of the benzotriazole N-2 electron lone pair
could give 6, which ring opens to the eight-membered
1,2,4,6-tetrazocane 7. The latter rearranges to the enam-
ine form 8. Further ring closure-ring opening, possibly
via 9, would result in the 4,5-dihydro-1,2,4-triazolo[1,5-
a]quinoxaline 10, which is oxidatively aromatized into
1,2,4-triazolo[1,5-a]quinoxaline 3.
In conclusion, we have shown that benzylation of
N-(benzotriazol-1-ylmethyl)-substituted imidoyl chlorides
under basic conditions induces an unusual rearrange-
ment, accompanied by benzotriazole ring opening, with
Intramolecular benzotriazole ring opening-ring clo-
sure without elimination of nitrogen is a powerful tool
† E-mail (P.J .S.): p.steel@chem.canterbury.ac.nz.
(1) Catarzi, D.; Cecchi, L.; Colotta, V.; Melani, F.; Filacchioni, G.;
Martini, C.; Giusti, L.; Lucacchini, A. J . Med. Chem. 1994, 37, 2846.
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Tacchi, P.; Lucacchini, A. Eur. J . Med. Chem. 1995, 30, 133.
(3) (a) Catarzi, D.; Colotta, V.; Varano, F.; Cecchi, L.; Filacchioni,
G.; Galli, A.; Costagli, C. J . Med. Chem. 1999, 42, 2478. (b) Catarzi,
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(6) (a) Cheeseman, G. W. H.; Cookson, R. F. Condensed Pyrazines.
In The Chemistry of Heterocyclic Compounds; Weissberger, A., Taylor,
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(b) Vogel, M.; Lippmann, E. J . Prakt. Chem. 1989, 331, 75; Chem.
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(8) Katritzky, A. R.; Wang, Z.; Lang, H.; Steel, P. J . Khim.
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10.1021/jo011028b CCC: $22.00 © 2002 American Chemical Society
Published on Web 04/06/2002

Notes
J . Org. Chem., Vol. 67, No. 9, 2002 3119
Gen er a l P r oced u r e for th e P r ep a r a tion of 1,2,4-Tr ia -
zolo[1,5-a ]qu in oxa lin es 3 fr om N-(Ben zotr ia zolylm eth yl)
Am id es 1a ,b a n d Ben zyl Br om id e. N-(Benzotriazol-1-yl-
methyl)furylcarboxamide 1a (1.21 g, 5 mmol) was dissolved in
toluene (100 mL) and treated with phosphorus pentachloride
(1.25 g, 6 mmol). The reaction mixture was heated at 90-100
°C for 3 h and then filtered, and the solvent was removed under
reduced pressure. The crude imidoyl chloride 2a obtained was
used in the subsequent reaction without additional purification.
A mixture of crude imidoyl chloride 2a (0.83 g, 3 mmol) and
benzyl bromide (0.62 g, 3.6 mmol) in dry tetrahydrofuran (30
mL) was treated with potassium tert-butoxide (1.12 g, 10 mmol).
The reaction mixture was stirred for 0.5 h at room temperature,
heated under reflux for an additional 4 h, allowed to cool, and
filtered. The residue obtained after solvent evaporation was
purified by column chromatography (eluting with 50/1 hexane/
EtOAc) to give 2-furyl-4-phenyl-1,2,4-triazolo[1,5-a]quinoxaline
3a (0.23 g, 25%) as pale yellow needles.
Sch em e 2
2-Fu r yl-4-ph en yl-1,2,4-tr iazolo[1,5-a ]qu in oxalin e 3a: pale
1
yellow needles (25%), mp 189-190 °C; H NMR (CDCl3) δ 6.61
(dd, J ) 3.5, 1.7 Hz, 1H), 7.32 (d, J ) 3.5 Hz, 1H), 7.55-7.74
(m, 6H), 8.21 (dd, J ) 8.1, 1.5 Hz, 1H), 8.50 (dd, J ) 8.1, 1.7 Hz,
1H), 8.83-8.87 (m, 2H); 13C NMR δ 111.8, 112.1, 115.4, 127.4,
127.6, 128.6(2), 129.6(2), 129.7, 130.2, 131.1, 135.1, 136.4, 144.0,
144.4, 146.0, 148.5, 156.7. Anal. Calcd for C19H12N4O: C, 73.07;
H, 3.87; N, 17.94. Found: C, 72.79; H, 3.74; N, 18.00.
2,4-Dip h en yl-1,2,4-tr ia zolo[1,5-a ]qu in oxa lin e 3b: colorless
needles (31%), mp 131-132 °C; 1H NMR (CDCl3) δ 7.50-7.65
(m, 6H), 7.70 (t, J ) 7.7 Hz, 1H), 7.77 (t, J ) 7.7 Hz, 1H), 8.25
(d, J ) 8.0 Hz, 1H), 8.46 (dd, J ) 8.0, 1.4 Hz, 2H), 8.54 (d, J )
8.0 Hz, 1H), 8.95 (dd, J ) 8.0, 1.6 Hz, 2H); 13C NMR δ 115.4,
127.4, 127.5(2), 127.8, 128.6(2), 128.8(2), 129.6, 129.7(2), 130.2,
130.3, 130.4, 131.1, 135.4, 136.4, 144.3, 148.6, 164.0. Anal. Calcd.
for C21H14N4: C, 78.24; H, 4.38; N, 17.38. Found: C, 77.87; H,
4.73; N, 17.14.
the formation of 1,2,4-triazolo[1,5-a]quinoxalines. A pos-
sible mechanism of the rearrangement is discussed.
Exp er im en ta l Section
Gen er a l Com m en ts. Melting points were measured on a hot-
stage apparatus and are uncorrected. 1H and 13C NMR data were
recorded on a 300 MHz NMR spectrometer (300 and 75 MHz,
respectively) in CDCl3 as a solvent and with TMS (for 1H) or
the solvent (for 13C) as an internal standard. Column chroma-
tography was carried out on silica gel (activated, neutral, 50-
200 µm). Tetrahydrofuran was purified by distillation from Na/
benzophenone under nitrogen. N-(Benzotriazol-1-ylmethyl) amides
1a ,b were prepared as described previously.11
Su p p or tin g In for m a tion Ava ila ble: Perspective view of
the X-ray crystal structure of 3a . This material is available
free of charge via the Internet at http://pubs.acs.org.
J O011028B
(11) Katritzky, A. R.; Drewniak, M. J . Chem. Soc., Perkin Trans. 1
1988, 2339.