Synthesis of 9-alkyl-6-amino[1,2,4]triazolo[3,4-c]-5-azaquinoxalines. Mild and effective SNAr amination of highly electron-poor heterocycles

Article abstract of DOI:10.1016/j.tetlet.2010.02.109

The synthesis and characterization of five different 9-alkyl-6-amino[1,2,3]triazolo[3,4-c]-5-azaquinoxalines is described. Due to the notable electrophilic character of the C-6 position of the [1,2,4]triazolo[3,4-c]-5-azaquinoxaline tricyclic system, S_NAr amination was achieved simply by reacting the corresponding 6-chloro derivative with ammonia-saturated acetonitrile (a non-nucleophilic polar solvent) in a sealed reaction vessel, using microwave-mediated or conventional heating.

Full text of DOI:10.1016/j.tetlet.2010.02.109

Tetrahedron Letters 51 (2010) 2262–2264
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of 9-alkyl-6-amino[1,2,4]triazolo[3,4-c]-5-azaquinoxalines. Mild
and effective SNAr amination of highly electron-poor heterocycles
b
b
b
Asier Unciti-Broceta a, , María José Pineda-de-las-Infantas , Miguel Ángel Gallo , Antonio Espinosa
*
a School of Chemistry, University of Edinburgh, West Mains Road, Edinburgh EH9 3JJ, UK
b Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, Universidad de Granada, Campus Cartuja s/n, 18071 Granada, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis and characterization of five different 9-alkyl-6-amino[1,2,3]triazolo[3,4-c]-5-azaquinoxa-
lines is described. Due to the notable electrophilic character of the C-6 position of the [1,2,4]triazol-
o[3,4-c]-5-azaquinoxaline tricyclic system, SNAr amination was achieved simply by reacting the
corresponding 6-chloro derivative with ammonia-saturated acetonitrile (a non-nucleophilic polar sol-
vent) in a sealed reaction vessel, using microwave-mediated or conventional heating.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 10 January 2010
Revised 8 February 2010
Accepted 19 February 2010
Available online 23 February 2010
Many nitrogen-containing heterocycles are regarded as privi-
leged structures due to their ability to bind to multiple cell receptors
with high affinity.1,2 Among them, 6:6:5 fused nitrogen-containing
tricycles have been investigated for their binding affinity to adeno-
sine receptors,3,4 with many examples showing excellent activities
as adenosine antagonists of different receptor subtypes and a selec-
tivity highly modulated by the nature of the substituents attached to
the polycyclic ring system.5,6 Based on their structural similarity
with adenosine (seeFig. 1) and related structures with high selectiv-
ity for the adenosine A2a receptor,6 we decided to investigate the
synthesis of [1,2,4]triazolo[3,4-c]-5-azaquinoxaline tricycles7 with
an amino group at the C-6 position.
strong nucleophiles (e.g., alkoxides, hydrazine, alkylamines, etc.) in
deactivated aromatic rings.11–14 While this direct displacement is
generally disallowed for weaker nucleophiles such as ammonia
(thus, requiring the employment of ammonia surrogates and metal
catalysis15–20), if the aromatic ring is highly deactivated by the pres-
ence of several electron-withdrawing groups or pyridine-like nitro-
gen atoms, metal-free direct SNAr amination can be achieved using
either methanolic or liquid ammonia.21–23 Herein, we report a study
of the synthesis of five distinct 9-alkyl-6-amino[1,2,4]triazolo[3,4-
c]-5-azaquinoxalines (Fig. 1) which were obtained by direct SNAr
amination of the 6-chloro derivative using an effective and conve-
nient procedure that avoids the use of liquid ammonia.
Electron-poor heterocycles undergo nucleophilic aromatic sub-
stitution (SNAr) in the presence of a variety of nucleophiles at the
electrophilic carbon to which a good leaving group is attached.8–10
This reaction is widely used for displacing halogen atoms with
The construction of the 6:6:5 fused tricyclic system was carried
out from commercially available 2,3-diaminopyridine 1 using the
three-step pathway outlined in Scheme 1.7 2,3-Dichloro-5-azaqui-
noxaline 2 was synthesized by condensation of compound 1 with
2
NH2
N
1 N
NH2
N
3
Flip
R
9
N
N
4
8 N
7N
N10
N
N
N
N
N 5
HO
6
R
N
O
NH2
OH OH
adenosine
9-alkyl-6-amino[1,2,3]triazolo[3,4-c]-5-azaquinoxaline
Figure 1. Adenosine and 9-alkyl-6-amino[1,2,4]triazolo [3,4-c]-5-azaquinoxaline.
* Corresponding author. Tel.: +44 0131 650 4821; fax: +44 0131 650 6453.
E-mail address: asier.ub@ed.ac.uk (A. Unciti-Broceta).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.109

A. Unciti-Broceta et al. / Tetrahedron Letters 51 (2010) 2262–2264
2263
O
a) Oxalic Acid
4N HCl
H2N
N
N
H
R
3a R= Me
3b R= Et
3c R= Pr
3d
3e
R
b) SOCl2
NH2
NH2
N
N
Cl
Cl
(1 equiv)
DMF (cat)
N
N
N
THF or MeCN
H2SO4 (cat), reflux
R= cPr
R= Bn
N
N
N
Cl
12-24 h, 51-74%
1
2
3a-e
Scheme 1. Synthesis of 9-alkyl-6-chloro[1,2,4]triazolo[3,4-c]-5-azaquinoxalines 3a–e from commercially available 2,3-diaminopyridine 1.7
oxalic acid in 4 N HCl followed by chlorination of the dihydroxy
N
N
R
R
intermediate using excess of thionyl chloride and DMF in catalytic
amount. To introduce the triazolo-fused ring we used the one-pot
synthetic procedure developed by our group,7 involving the use of
aliphatic hydrazides to first perform regioselective SNAr reaction of
the 3-chloro atom of compound 2 followed by heat-induced cyclo-
condensation. Thereby, tricycles were synthesized by refluxing
compound 2, aliphatic hydrazides and H2SO4 (catalytic amount)
in THF or acetonitrile for 12–24 h (Scheme 1), giving 6-chloro
derivatives 3a–e in moderate to good yields (51–74%). The unique
formation of the [1,2,4]triazolo[3,4-c]-5-azaquinoxaline system is
due to the pyridine-type nitrogen atom in position 5 of compound
2, which dictates the regiochemistry of the reaction by inducing
different electrophilicity between the 2- and the 3-carbon
positions.
It has been recently reported that the use of microwave-medi-
ated heating significantly improves the rate of the cyclization step
in the synthesis of a similar tricyclic system.24 In order to investi-
gate this trend in the synthesis of compounds 3a–e, reactions were
carried out under microwave heating at different temperatures.
However, even though the reaction times were reduced, lower
yields were obtained due to the increased formation of tetracyclic
side products.7
NH3 / MeCN
N
N
N
N
N
N
Δ or μw
N
N
NH2
4a-e
Cl
3a-e
Product
4a
R
Me
Et
Temp, ºC Time, h
Yield, %
99 (98)
98 (99)
95 (96)
98 (98)
97 (98)
80 (100)
80 (110)
80 (110)
80 (110)
80 (110)
4 (0.5)
6 (0.5)
8 (0.5)
8 (0.5)
6 (0.5)
4b
4c
Pr
4d
cPr
4e
Bn
a Conditions and yields using microwave heating in brackets.
Scheme 2. Treatment of 6-chloro derivatives 3a–e with ammonia-saturated
Due to the anticipated high electrophilicity of the [1,2,4]triazol-
o[3,4-c]-5-azaquinoxaline ring system, direct amination by nucle-
ophilic displacement of the 6-chloro atom was first attempted
using saturated methanolic ammonia at room temperature. The
reactions were monitored by TLC and, surprisingly, no traces of
starting material were observed after 10 min. However, the 6-
methoxy derivatives were the only products isolated from the
reactions (see Supplementary data). An alternative procedure for
the amination of electron-poor heterocycles involves (i) halogen
displacement with hydrazine, and (ii) subsequent cleavage of the
N–N bond using Raney Ni.19,22 However, the use of this method re-
sulted in very low yields, leading almost exclusively to the dehy-
drazination byproduct.25 This result is in accordance with
previous studies12,26 in relation to the instability of hydrazino
groups when attached to electron-deficient nitrogen-containing
heterocycles.
The use of anhydrous ammonia in its liquid form has also been
employed for performing SNAr amination of electron-poor hetero-
cycles; a protocol that requires the application of high pressure in a
steel bomb.23 In order to explore a milder procedure, dry acetoni-
trile was saturated with ammonia gas and then used for the direct
SNAr amination of compounds 3a–e in a sealed glass vessel. Reac-
tions were carried out using conventional oil-bath heating at 80 °C
for 4–8 h, affording the expected 6-amino derivatives 4a–e in
quantitative yield (Scheme 2). As the reagent (ammonia) and sol-
vent (acetonitrile) were easily evaporated under vacuum, reaction
work-up consisted simply of re-dissolving in ethyl acetate, wash-
ing with water (to remove ammonium chloride) and evaporation
to dryness, with no further purification required.
acetonitrile.a
reaction times but providing slightly lower yields. In order to im-
prove the reaction rates while still using acetonitrile as solvent,
microwave-mediated heating was explored under a pressure-mon-
itored system using a biotage initiator. Thereby, compounds 3a–e
were treated with ammonia-saturated acetonitrile under micro-
wave heating (using conventional microwave caps and vials), lead-
ing to pure 6-amino compounds 4a–e after 30 min irradiation at
100–110 °C (Scheme 2).
In conclusion, the synthesis and characterization (see Supple-
mentary data) of five 9-alkyl-6-amino[1,2,4]triazolo[3,4-c]-5-
azaquinoxalines has been described. The [1,2,4]triazolo[3,4-c]-5-
azaquinoxaline ring system was demonstrated to be exceptionally
electron-poor, hindering access to the 6-amino derivatives by tra-
ditional methods. Substitution of the chloro atom at C-6 by an ami-
no group was carried out by heating the chloro derivative with
ammonia-saturated acetonitrile (non-nucleophilic solvent) in a
sealed reaction vessel, thus avoiding the employment of liquid
ammonia and allowing the use of microwave-mediated heating.
Acknowledgement
A.U.-B. thanks Fundación Ramón Areces for funding.
Supplementary data
Supplementary data (experimental procedures and characteriza-
tion data of all the compounds) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2010.02.109.
Different non-nucleophilic, high-boiling point, polar solvents
such as dioxane and DMF were also investigated, requiring shorter

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13. Hamilton, G. L.; Backes, B. J. Tetrahedron Lett. 2006, 47, 2229–2231.
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