Molecules 27 04681

Review molecules
Syntheses and Applications of 1,2,3-Triazole-Fused Pyrazines

Review
and Pyridazines
Syntheses and Applications of 1,2,3-Triazole-Fused Pyrazines
andR.Pyridazines
Gavin Hoffman and Allen M. Schoffstall *
Gavin R. Hoffman and Allen M. Schoffstall *

Department of Chemistry and Biochemistry, University of Colorado Colorado Springs,
Colorado Springs, CO 80918, USA; ghoffman@uccs.edu
* Correspondence:
Department aschoffs@uccs.edu;
of Chemistry Tel.: +1-719-255-3479
and Biochemistry, University of Colorado Colorado Springs,
Colorado Springs, CO 80918, USA; ghoffman@uccs.edu
Correspondence:
* Abstract: aschoffs@uccs.edu;
Pyrazines Tel.: +1-719-255-3479
and pyridazines fused to 1,2,3-triazoles comprise a set of heterocycles obtaine
through a variety of synthetic routes. Two typical modes of constructing these heterocyclic rin
Abstract: Pyrazines and pyridazines fused to 1,2,3-triazoles comprise a set of heterocycles obtained
systems are cyclizing a heterocyclic diamine with a nitrite or reacting hydrazine hydrate with dica
through a variety of synthetic routes. Two typical modes of constructing these heterocyclic ring
bonyl 1,2,3-triazoles. Several unique methods are known, particularly for the synthesis of 1,2,3-tri
systems are cyclizing a heterocyclic diamine with a nitrite or reacting hydrazine hydrate with
zolo[1,5-a]pyrazines
dicarbonyl andSeveral
1,2,3-triazoles. their benzo-fused
unique methodsquinoxaline andparticularly
are known, quinoxalinone-containing analogs. R
for the synthesis of
cent applications detail and
1,2,3-triazolo[1,5-a]pyrazines the their
use benzo-fused
of these heterocycles
quinoxaline in
andmedicinal chemistry (c-Met
quinoxalinone-containing inhibition
analogs.
GABA
Recent A modulating
applications activity)
detail the use as fluorescent
of these probes
heterocycles in and as structural
medicinal units
chemistry of polymers.
(c-Met inhibition or
GABAA modulating activity) as fluorescent probes and as structural units of polymers.
Keywords: synthesis; 1,2,3-triazole; fused 1,2,3-triazole; 1,2,3-triazolo[4,5-b]pyrazine; 1,2,3-tri
Keywords: synthesis; 1,2,3-triazole;
zolo[4,5-c]pyridazine; fused 1,2,3-triazole; 1,2,3-triazolo[4,5-b]pyrazine;
1,2,3-triazolo[4,5-d]pyridazine; 1,2,3- 1,2,3-tri
1,2,3-triazolo[1,5-a]pyrazine;
triazolo[4,5-c]pyridazine; 1,2,3-triazolo[4,5-d]pyridazine; 1,2,3-triazolo[1,5-a]pyrazine;
zolo[1,5-b]pyridazine; triazolopyrazine; triazolopyridazine; practical applications 1,2,3-
triazolo[1,5-b]pyridazine; triazolopyrazine; triazolopyridazine; practical applications
1.1.Introduction
Introduction
Within
Within thethe 1,2,3-triazole-fused
1,2,3-triazole-fused pyrazines
pyrazines and pyridazines,
and pyridazines, a series
a series of of congeners
congeners exists exis
Citation: Hoffman, G.R.; depending
depending on on whether
whether a nitrogen
a nitrogen atomatom occupies
occupies a position
a position at the
at the ring ring
fusion fusion1).(Figure 1).
(Figure
Schoffstall, A.M. Syntheses and
Applications of 1,2,3-Triazole-Fused N NH2 N N NH2 N
Pyrazines
Citation: and Pyridazines.
Hoffman, Molecules
G.R.; Schoffstall, N N
N N N
A.M. 27, 4681. https://doi.org/
2022,Syntheses and Applications of N N N N N NH2 N
10.3390/molecules27154681
1,2,3-Triazole-Fused Pyrazines and H H
Pyridazines. Molecules
Academic Editor: 2022,
Joseph 27, x.
Sloop 1 2 3 4
https://doi.org/10.3390/xxxxx
Received: 21 June 2022
O N N N
Accepted:Editor:
Academic 19 July Joseph
2022 Sloop N N
Published: 22 July 2022 O N N N
Received: 21 June 2022
Publisher’s Note: MDPI stays neutral
Accepted: 19 July 2022
with regard to jurisdictional claims in 5 6
Published: 22 July 2022
published maps and institutional affil-
iations.
Publisher’s Note: MDPI stays neu-
tral with regard to jurisdictional N O N O
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claims in published maps and institu- N N N N N N
N N
tional affiliations.
Copyright: © 2022 by the authors.
Licensee MDPI, Basel, Switzerland.
7 8 9 10
This article is an open access article
distributed under the terms and = H, alkyl, aryl
Copyright: © 2022 by the authors.
conditions of the Creative Commons
Submitted for possible open access
Attribution (CC BY) license (https:// Figure
Figure1. 1. Structures
Structuresofof 1,2,3-triazole-fused
1,2,3-triazole-fusedpyrazines
pyrazinesandandpyridazines:
pyridazines:1H-1,2,3-triazolo[4,5-
1H-1,2,3-triazolo[4,5-b]pyr
publication under the terms and con-
creativecommons.org/licenses/by/ b]pyrazine (2); 1H-1,2,3-triazolo[4,5-c]pyridazine (4); 1H-1,2,3-triazolo[4,5-d]pyridazine
zine (2); 1H-1,2,3-triazolo[4,5-c]pyridazine (4); 1H-1,2,3-triazolo[4,5-d]pyridazine (6); 1,2,3-
(6); 1,2,3-tri
ditions of the Creative Commons At-
4.0/). triazolo[1,5-a]pyrazine
zolo[1,5-a]pyrazine (8);(8);1,2,3-triazolo[1,5-b]pyridazine
1,2,3-triazolo[1,5-b]pyridazine(10);(10);
common precursors
common 1, 3, 5, 1,
precursors 7, 9.
3, 5, 7, 9.
tribution (CC BY) license (https://cre-
ativecommons.org/licenses/by/4.0/).
Molecules 2022, 27, 4681. https://doi.org/10.3390/molecules27154681 https://www.mdpi.com/journal/molecules

Molecules 2022,
Molecules 2022, 27,
27, 4681
x FOR PEER REVIEW 22of
of 29
28
Webecame
We becameinterested
interestedin instructures
structurescontaining
containing heterocyclic
heterocyclic nuclei
nuclei 2,2, 4, 6, 8 and 10
following reportsdetailing
following reports detailingpotent
potentmesenchymal–epithelial
mesenchymal–epithelial transition
transition factor
factor (c-Met)
(c-Met) pro-
protein
tein kinase
kinase inhibition,
inhibition, such such
as theascurrent
the current clinical
clinical candidate
candidate Savolitinib
Savolitinib [1] (Figure
[1] (Figure 2, Struc-
2, Structure A)
and specifically
ture those containing
A) and specifically substructures
those containing 2 and 8 [1,2].
substructures 2 andIn 8addition
[1,2]. Intoaddition
c-Met inhibition,
to c-Met
structures containing
inhibition, these heterocyclic
structures containing nuclei have
these heterocyclic shown
nuclei GABA
have shownA allosteric
GABAA modulat-
allosteric
ing activity [3] (Figure 2, Structure B), have been incorporated into
modulating activity [3] (Figure 2, Structure B), have been incorporated into polymerspolymers for usefor
in
solarincells
use solar[4,5] (Figure
cells [4,5] 2, Structure
(Figure C), and have
2, Structure demonstrated
C), and have demonstrated
β-secretase 𝛽 -secretase
1 (BACE-1) 1
inhibition inhibition
(BACE-1) [6] (Figure[6]2,(Figure
Structure D). TheirD).
2, Structure piperazine derivatives
Their piperazine have demonstrated
derivatives have demon-
potent
stratedPDP-IV inhibition
potent PDP-IV [7].
inhibition [7].
A B O O C
S
F
N N S
N
N N N N N N
N N N
N N N N N
N N
c-Met inhibitory activity GABAA allosteric Incorporated into polymers

(Savolitinib) modulating activity (m-Prz-TAZ-based)
D NH2
F N
N
N N
N
NH
N
O
BACE-1
inhibitory activity
Figure
Figure 2.2. Examples
Examplesof useful structures
of useful containing
structures 1,2,3-triazole-fused
containing pyrazines
1,2,3-triazole-fused and pyridazines:
pyrazines and pyri-
(A) c-Met inhibitor Savolitinib [1], containing a 1,2,3-triazolo[4,5-b]pyrazine, (B) a compound with
dazines: (A) c-Met inhibitor Savolitinib [1], containing a 1,2,3-triazolo[4,5-b]pyrazine, (B) a com-
GAGAA allosteric modulating activity containing a 1,2,3-triazolo[4,5-c]pyridazine [3], (C) a 1,2,3-
pound with GAGAA allosteric modulating activity containing a 1,2,3-triazolo[4,5-c]pyridazine [3],
triazolo[4,5-d]pyridazine derivative used in polymers for solar cells [4,5], and (D), a 1,2,3-tria-
(C) a 1,2,3-triazolo[4,5-d]pyridazine
zolo[1,5-a]pyrazine derivative
derivative with BACE-1 used activity
inhibitory in polymers
[6]. for solar cells [4,5], and (D),
a 1,2,3-triazolo[1,5-a]pyrazine derivative with BACE-1 inhibitory activity [6].
Emphasis in this review is placed on the more common derivatives of 2 and 8. In
Emphasis in this review is placed on the more common derivatives of 2 and 8. In com-
comparison to the heterocyclic scaffolds outlined in Figure 2, derivatives of 4, 6 and 10 are
parison to the heterocyclic scaffolds outlined in Figure 2, derivatives of 4, 6 and 10 are less
less common in the literature. Among fused heterocycles containing the more well-known
common in the literature. Among fused heterocycles containing the more well-known fused
fused 1,2,4-triazoles, both 1,2,4-triazolo[1,5-a]pyrimidines [8] and 1,2,4-triazolo[4,3-a]py-
1,2,4-triazoles, both 1,2,4-triazolo[1,5-a]pyrimidines [8] and 1,2,4-triazolo[4,3-a]pyrazines [9]
razines [9] have been recently reviewed. Kumar and coworkers [10] surveyed 1,2,3-tria-
have been recently reviewed. Kumar and coworkers [10] surveyed 1,2,3-triazoles fused
zoles fused to various rings, both aromatic and non-aromatic. In the present review, we
to various rings, both aromatic and non-aromatic. In the present review, we address ap-
address approaches to the synthesis of 1,2,3-triazole-fused pyrazines and pyridazines and
proaches to the synthesis of 1,2,3-triazole-fused pyrazines and pyridazines and their related
their related congeners, while setting two limitations:
congeners, while setting two limitations:
Molecules 2022, 27, x FOR PEER REVIEW 3 of 29
Molecules 2022, 27, 4681 3 of 28
1. This review covers synthetic methods of preparing structures containing fused het-
erocycles 2, 4, 6, 8, 10 (Figure 1). Tricyclic and tetracyclic congeners containing these
1. heterocycles
This review are
covers synthetic methods of preparing structures containing fused hete-
included.
rocycles 2, 4, 6, 8, 10 (Figure
2. 1,2,3-Triazolopyrimidines do 1).
notTricyclic
appear inand
thistetracyclic congeners
review. They containing
have received these
attention
heterocycles
in areon
the literature included.
purine chemistry [11–13].
1,2,3-Triazolopyrimidines do
2. 1,2,3-Triazolopyrimidines, not appear
which form inthe
thiscore
review. They have
structure of received attention
8-azapurines, 8-
in the literature on purine chemistry [11–13].
azaadenines, and 8-azaguanines, have been well-studied and reviewed [13–15] owing to
their 1,2,3-Triazolopyrimidines,
similarity to the respective which form the core
nucleobases. Withstructure of 8-azapurines,
both scope 8-azaadenines,
and limitations in place,
and 8-azaguanines, have been well-studied and reviewed [13–15]
this review addresses synthetic approaches to the 1,2,3-triazolodiazine family: owing to their simi-
1,2,3-tria-
larity to the respective nucleobases. With both scope and limitations in place,
zolo[4,5-b]pyrazine, 1,2,3-triazolo[4,5-c]pyridazine, 1,2,3-triazolo[4,5-d]pyridazine, 1,2,3- this re-
view addresses syntheticand
triazolo[1,5-a]pyrazine, approaches to the 1,2,3-triazolodiazine
1,2,3-triazolo[1,5-b]pyridazine. Thefamily: 1,2,3-triazolo[4,5-
literature covered in-
b]pyrazine,
cludes 1,2,3-triazolo[4,5-c]pyridazine,
articles published since the most recent 1,2,3-triazolo[4,5-d]pyridazine, 1,2,3-triazolo[1,5-
review of each type of compound, or earlier
a]pyrazine, and 1,2,3-triazolo[1,5-b]pyridazine. The literature covered includes
if no review exists. Reports are covered until the spring of 2022 and exclude tetrahydro- articles
published
derivatives. since the most recent review of each type of compound, or earlier if no review
exists. Reports are covered until the spring of 2022 and exclude tetrahydro-derivatives.
2. Synthetic Approaches
2. Synthetic Approaches
This overview of synthetic methods is organized according to the type of heterocycle.
This overview of synthetic methods is organized according to the type of heterocycle.
In the case of 1H-1,2,3-triazolo[1,5-a]pyrazines, methods are subdivided into pyrazines
In the case of 1H-1,2,3-triazolo[1,5-a]pyrazines, methods are subdivided into pyrazines
and benzopyrazines. Reaction times are included along with solvents, catalysts, and other
and benzopyrazines. Reaction times are included along with solvents, catalysts, and
reagents in most examples. Commercial availability of precursors is emphasized where
other reagents in most examples. Commercial availability of precursors is emphasized
applicable.
where applicable.
2.1.
2.1. Syntheses
Syntheses ofof 1H-1,2,3-triazolo[4,5-b]pyrazines
1H-1,2,3-Triazolo[4,5-b]pyrazines
One
One of the first reported
of the first reported preparations
preparations of of aa 1H-1,2,3-triazolo[4,5-b]pyrazine
1H-1,2,3-triazolo[4,5-b]pyrazine came came from
from
Lovelette and coworkers [16], who utilized condensation of a 4,5-diamino-1,2,3-triazole,
Lovelette and coworkers [16], who utilized condensation of a 4,5-diamino-1,2,3-triazole,
14,
14, and
and aa 1,2-dicarbonyl
1,2-dicarbonyl compound
compound 15 15 (Scheme
(Scheme 1) 1) to
to give
give the
the desired
desired triazolopyrazines
triazolopyrazines 1616
in
in yields
yields inin the range 30–35%.
the range 30–35%. A A useful precursor, 4,5-diamino-1,2,3-1H-triazole
useful precursor, 4,5-diamino-1,2,3-1H-triazole 14, 14, was
was
prepared by byreacting
reactingcarbamate
carbamate1313with
with a strong
a strong base.
base. This
This carbamate
carbamate waswas readily
readily pre-
prepared
pared
from thefrom the carbonyl
carbonyl azide azide by refluxing
by refluxing in ethanol.
in ethanol. The carbonyl
The carbonyl azideazide
can becan be prepared
prepared from
from
benzyl benzyl
azideazide 11, ethyl
11, ethyl cyanoacetate
cyanoacetate 12, and
12, and sodiumsodium ethoxide,
ethoxide, all commercially
all commercially avail-
available
able starting materials.
starting materials.
commercially available
precursors
O
N3
11 + NC O 12
3 steps 15
O
R1
R2
H2N N H 2N N O R1 N
1M NaOH N
N N N
HN N EtOH, reflux, H 2N N H2O or EtOH R2 N N
3h
EtO O
13 14 16
Scheme
Scheme 1. 1. One
One of
of the
the first
first reported
reported syntheses
syntheses of
of 1H-1,2,3-triazolo[4,5-b]pyrazines, 16. (R
1H-1,2,3-triazolo[4,5-b]pyrazines, 16. (R1,, R2 = alkyl,
1 R2 = alkyl,
aryl, H.)
aryl, H.)
Molecules 2022, 27, x FOR PEER REVIEW
4 of 29
4 of 29
Molecules 2022, 27, 4681 4 of 28

Dicarbonyl
Dicarbonylcompounds
compounds included glyoxal(R
included glyoxal (R11==RR2 2==H),
H),benzil
benzil(R(R1= = 2R=2 Ph),
1R = Ph),andand oth-
oth-
ers.
ers.This
Thiswas
wasone oneof of the
the first
first reports of of 1,2,3-triazole-fused
1,2,3-triazole-fusedpyrazines,
pyrazines,highlighted
highlighted within
within
a astudy of fused
studyDicarbonyl 1,2,3-triazoles.
of fused 1,2,3-triazoles.
compounds included
This method
method offers
glyoxaloffers
three-point
(R1 = three-point
R2 = H), benzil
diversity,
diversity,
(R1 = Rone
onefrom the tri-tri-
from the
2 = Ph), and
azole
azole substituent,
substituent,
others. This was andonethe
and of other
the other two
the first fromof
from
reports the
the respectivedicarbonyl
respective dicarbonyl
1,2,3-triazole-fused substituents.
substituents.
pyrazines, highlighted Despite
Despite
this,
this,a apotential
a studydrawback
potential
within drawback lay
lay in the restriction
of fused 1,2,3-triazoles. restriction
This method tooffers
to aasymmetrically
symmetrically substituted
substituted
three-point diversity, 1,2-dicar-
1,2-dicar-
one from
bonyl
bonyl species
thespecies
triazoleto to avoid mixtures
avoid
substituent, mixtures
and theof isomers.
isomers.
other two fromIndeed,
Indeed, the
theauthors
authors
the respective noted
notedthe
dicarbonyl the two
two condensa-
condensa-
substituents.
tionDespite
tion products
products this, a potential
using
using an drawback lay in
an asymmetrically
asymmetrically the restriction
substituted
substituted to a symmetrically
diketone,
diketone, where
whereR1R=1 =CH substituted
CH3 and
3 andR2R=2H,= H,
as 1,2-dicarbonyl
being species
indistinguishable. to avoid mixtures of isomers. Indeed, the authors noted the two
as being indistinguishable.
condensation
Mongeand and products
coworkersusing[17]
an asymmetrically substituted diketone, where R1 = CH3 and
RMonge coworkers [17] prepared
prepared benzo-fused
benzo-fused1H-1,2,3-triazolo[4,5-b]pyrazines
1H-1,2,3-triazolo[4,5-b]pyrazines
2 = H, as being indistinguishable.
through
through Monge the acid-catalyzed
the acid-catalyzed cyclization of 2-azido-3-cyanoquinoxaline, 18,18,
obtained from
and coworkerscyclization
[17] prepared of benzo-fused
2-azido-3-cyanoquinoxaline, obtained
1H-1,2,3-triazolo[4,5-b]pyrazines from
2-chloro-3-cyanoquinoxaline
through the acid-catalyzed cyclization 17, yielding
17, yielding 1-hydroxy-1H-1,2,3-triazolo[4,5-b]quinoxaline
1-hydroxy-1H-1,2,3-triazolo[4,5-b]quinoxaline
of 2-azido-3-cyanoquinoxaline, 18, obtained from
19 (Scheme 2) in 52%
2-chloro-3-cyanoquinoxaline yield. Though
17, uncommon,
yielding acid-catalyzed cyclization
1-hydroxy-1H-1,2,3-triazolo[4,5-b]quinoxaline
19 (Scheme 2) in 52% yield. Though uncommon, acid-catalyzed cyclization ofofortho-sub-
19
ortho-sub-
stituted
(Scheme azidocyanoaryl
2) in 52% yield. species
Though may
uncommon,represent an underutilized
acid-catalyzed
stituted azidocyanoaryl species may represent an underutilized method of obtaining cyclization method
of of obtaining
ortho-substituted
structures with the
azidocyanoaryl 1,2,3-triazolo[4,5-b]pyrazine
species may represent an underutilized core. Despite
methodthis, the use of
of obtaining costly start-
structures
structures with the 1,2,3-triazolo[4,5-b]pyrazine core. Despite this, the use of costly start-
ingwith the 1,2,3-triazolo[4,5-b]pyrazine
materials hinders wider applicability. core. Despite this, the use of costly starting materials
ing materials
hinders wider hinders wider applicability.
applicability.
N N
N N NaN3
N N 6% aq. HCl
N N
N N N N
NaN3 6% aq. HCl N
N
DMSO, 80 °C
Cl DMSO, 80 °C N N3
reflux
N N N
reflux N
N Cl N N3 N OH
OH
17 18 19
17 18 19
Scheme 2. Conversion of 2-chloro-3-cyanoquinoxaline 17 to 2-azido-3-cyanoquinoxaline 18 and
Scheme 2. Conversion
benzo-fused
Scheme Conversion ofof2-chloro-3-cyanoquinoxaline
2. 1H-1,2,3-triazolo[4,5-b]pyrazine 19. 17 17 to 2-azido-3-cyanoquinoxaline
to 2-azido-3-cyanoquinoxaline 18 and 18 and
benzo-fused 1H-1,2,3-triazolo[4,5-b]pyrazine
benzo-fused 19.
1H-1,2,3-triazolo[4,5-b]pyrazine 19.
Unexpectedly, Starchenkov and coworkers [18] determined that, upon treatment of
Unexpectedly, Starchenkov and coworkers [18] determined that, upon treatment of
Unexpectedly,
diamine Starchenkov
20 with trifluoroacetic and coworkers
anhydride (TFAA) [18] determined
and HNO that, uponvia
3 and proceeding treatment
interme- of
diamine 20 with trifluoroacetic anhydride (TFAA) and HNO3 and proceeding via inter-
diamine
diate 20
21, with trifluoroacetic
triazolopyrazine N-oxideanhydride
22 was (TFAA)
formed and HNO
(Scheme 3). and
3 This proceeding
was one of
mediate 21, triazolopyrazine N-oxide 22 was formed (Scheme 3). This was one of the first via
the interme-
first re-
ports
diate oftriazolopyrazine
21,
reportstheofpreparation of
the preparation a fused
N-oxide
of 1,2,3-triazole
22
a fused was formed
1,2,3-triazole 2-N-oxide, namely
(Schemenamely
2-N-oxide, 3). This [1,2,5]oxadiazolo[3,4-
was one of the first re-
[1,2,5]oxadiazolo[3,4-
,b][1,2,3]triazolo[4,5-e]pyrazine-6-oxide
portsb][1,2,3]triazolo[4,5-e]pyrazine-6-oxide 22,
of the preparation of a fused 1,2,3-triazole formed
22, formed in in 92%
2-N-oxide,yield.
92% yield. namely [1,2,5]oxadiazolo[3,4-
,b][1,2,3]triazolo[4,5-e]pyrazine-6-oxide 22, formed in 92% yield.
TFAA + HNO3
NO2
TFAA + HNO3 H
N N NH2 N N NH
NO2 N N N
NO2
O O N NH O H
N O
N N NH2 N N N N
N NO2 N N N
O N NH2 O N NH O N N O
HNO3
N N N NO
NH2 N N N
N NH2
HNO3
20 21 NO2 22
20 Scheme
Scheme 3. Formation
3. Formation of of 21
triazolopyrazine
triazolopyrazineN-oxide
N-oxide 22
22 from 22 20,
from diaminopyrazine
diaminopyrazine 20,proceeding
proceedingviavia in-
termediate 21.
intermediate 21.
Scheme 3. Formation of triazolopyrazine N-oxide 22 from diaminopyrazine 20, proceeding via in-
termediate
Forming21. aa mesoionic
Forming mesoionicring system
ring whilewhile
system studying luminescence,
studying Slepukhin and
luminescence, cowork- and
Slepukhin
ers [19] obtained the 1H-1,2,3-triazolo[4,5-b]pyrazine core within the azapentalene
coworkers [19] obtained the 1H-1,2,3-triazolo[4,5-b]pyrazine core within the azapentalene inner
salt 27 in 50%
Forming a yield after intramolecular
mesoionic ring system cyclization
while of 8-(benzotriazole-1-yl)tetrazolo[1,5-
studying luminescence, Slepukhin and
inner salt 27 in 50% yield after intramolecular cyclization of 8-(benzotriazole-1-yl)te-
a]pyrazine
coworkers 25 in refluxing
[19] obtained25the DMF, causing loss of nitrogen via intermediate 26 and formation
trazolo[1,5-a]pyrazine in 1H-1,2,3-triazolo[4,5-b]pyrazine
refluxing DMF, causing loss of nitrogen core within the azapentalene
via intermediate 26
of 5H-pyrazino[20 ,30 :4,5][1,2,3]triazol[1,2-a]benzotriazol-6-ium, inner salt 27 (Scheme 4).
inner salt 27 in of
andPyrazine
formation 50% yield after intramolecular cyclization of 8-(benzotriazole-1-yl)te-
5H-pyrazino[2′,3′:4,5][1,2,3]triazol[1,2-a]benzotriazol-6-ium, inner salt
25 was prepared in 48% yield by nucleophilic aromatic substitution of chloride by
trazolo[1,5-a]pyrazine
27 (Scheme ion25
4). Pyrazine
the benzotriazolyl inwas
25
after refluxing DMF,
prepared
deprotonation causing
yieldloss of nitrogen
in 1H-1,2,3-benzotriazole
of 48% by nucleophilic via intermediate
aromatic
24 by carbonate. substitu- 26
and
tionformation
of chlorideof
by5H-pyrazino[2′,3′:4,5][1,2,3]triazol[1,2-a]benzotriazol-6-ium, inner24salt
the benzotriazolyl ion after deprotonation of 1H-1,2,3-benzotriazole
27by(Scheme 4). Pyrazine 25 was prepared in 48% yield by nucleophilic aromatic substitu-
carbonate.
tion of chloride by the benzotriazolyl ion after deprotonation of 1H-1,2,3-benzotriazole 24
by carbonate.
Molecules
Molecules 27,x 4681
2022,27,
2022, FOR PEER REVIEW 55 of
of 28
29
24
24 H
N
H
NN
NN N
N Cl N N N N N N
N NN N N
N Cl
Na2CO3
N N
N DMF, NN N N NN
N N NN N
N N NN N
N ACN,
Na2COreflux, N reflux,
DMF,3 h N2
3 NN N
NN NN 1 h
ACN, reflux, NN NN reflux, 3 h N N2 N
N N 1h N N NN
N
23 25 26 27
23 25
Scheme 4. Synthesis 26 27
of an azapentalene, 5H-pyrazino[2′,3′:4,5][1,2,3]triazolo[1,2-a]benzotriazol-6-
ium, inner
Scheme 4. salt 27, after
Synthesis of intramolecular cyclization
an azapentalene, of 25 and loss of nitrogen via intermediate 26.
5H-pyrazino[2′,3′:4,5][1,2,3]triazolo[1,2-a]benzotriazol-6-
Scheme 4. Synthesis of an azapentalene, 5H-pyrazino[20 ,30 :4,5][1,2,3]triazolo[1,2-a]benzotriazol-6-ium,
ium, inner salt 27, after intramolecular cyclization of 25 and loss of nitrogen via intermediate 26.
innerAzapentalenes,
salt 27, after intramolecular
containingcyclization of 25 and loss of nitrogen via intermediate
the 1H-1,2,3-triazolo[4,5-b]pyrazine 26. gained
nucleus, have
attention for their useful properties,
Azapentalenes, such as in luminescence and complexation [19].gained
Com-
Azapentalenes, containing
containing the the 1H-1,2,3-triazolo[4,5-b]pyrazine
1H-1,2,3-triazolo[4,5-b]pyrazine nucleus, nucleus,havehave gained
pounds
attention of this type have demonstrated low toxicity, high solubility, and other properties
attentionfor fortheir
theiruseful
usefulproperties,
properties,such suchas asin
inluminescence
luminescence and and complexation
complexation [19]. [19]. Com-
Com-
desirableofasthis
pounds potential
type fluorescence
have demonstratedprobes low[20]. This intramolecular
toxicity, high solubility,approach
and hasproperties
other remained
pounds of this type have demonstrated low toxicity, high solubility, and other properties
popular
desirable
desirable in
asasobtaining
potential various
potentialfluorescence substituted
fluorescence probes
probes[20]. azapentalenes,
[20]. This anotherapproach
Thisintramolecular
intramolecular example has
approach being
has that of
remained
remained
Nyffenegger
popular and
popularininobtaining coworkers
obtaining various [21]. Here,
varioussubstituted the azapentalene,
substitutedazapentalenes,
azapentalenes, 5H-pyrazolo[1′,2′:1,2][1,2,3]tria-
another
another example
example beingbeing that
that of of
Nyf-
zolo[4,5-b]pyrazin-6-ium,
Nyffenegger
fenegger andand coworkers
coworkers inner
[21]. salt,
[21].
Here,Here,
the31, wasazapentalene,
the obtained
azapentalene, in yields up0 ,2to 85% via cyclization
0 :1,2][1,2,3]triazolo[4,5-
5H-pyrazolo[1′,2′:1,2][1,2,3]tria-
5H-pyrazolo[1
with loss of nitrogen
zolo[4,5-b]pyrazin-6-ium,
b]pyrazin-6-ium, after
inner amination
inner
salt, 31, salt, of 2-azido-3-chloropyrazine,
31,
was obtainedwas obtained
in yields in
upyields
to 85%up 28,
via with
85% either
tocyclization pyrazole
via cyclization
with loss
29
withor 1,2,4-triazole
loss of nitrogen
of nitrogen affording 2-azido-3-(1H-pyrazol-1-yl)pyrazine
after amination
after amination of 2-azido-3-chloropyrazine,
of 2-azido-3-chloropyrazine, 30 (Scheme
28, with
28, with either 5).
either
pyrazole Other
29pyrazolede-
or 1,2,4-
rivatives
29triazole using
or 1,2,4-triazole nitro-substituted
affordingaffording pyrazoles were formed
2-azido-3-(1H-pyrazol-1-yl)pyrazine
2-azido-3-(1H-pyrazol-1-yl)pyrazine in yields
30 (Schemein the
30 (Scheme range
5). Other5).63–97%. This
Other de-
derivatives
method
rivatives offers
usingconvenience
nitro-substituted
using nitro-substituted in that
pyrazoles a precursor
pyrazoles
were wereto
formed in28, 2,3-dichloropyrazine,
formed
yields in
in yields in the
the range is commercially
range
63–97%. 63–97%.
This This
method
available.
offers convenience
method in that ain
offers convenience precursor to 28, 2,3-dichloropyrazine,
that a precursor is commercially
to 28, 2,3-dichloropyrazine, available.
is commercially
available.
29
29
H
N
H N
N dichlorobenzene,
N Cl N N N N
commercially available N 165 °C, 2 h
dichlorobenzene, N
2,3-dichloropyrazine N Cl N N 165 °C, 2 h N NN
commercially available pyridine, N
2,3-dichloropyrazine N N3 N N N NN
MeCN
pyridine, 3 N2
N N3 N N3 N N
MeCN N2
28 30 31
28
Scheme 5. Synthesis of the azapentalene 31, 30from pyrazine 30, derived from 2-azido-3-chloropyra-
31
Scheme 5. Synthesis of the azapentalene 31, from pyrazine 30, derived from 2-azido-3-chloropyrazine 28.
zine 28. 5. Synthesis of the azapentalene 31, from pyrazine 30, derived from 2-azido-3-chloropyra-
Scheme
zine 28.
Notably, in addition to having an azido group substituted ortho to the pyrazole of
Notably,
30 [20,21], in addition
reports have also to made
having anofazido
use group substituted
the respective amine viaorthoring to the pyrazole
closure of 30
by displace-
[20,21], reports
Notably, inhave also
addition made
to use
having of
an the
azido respective
group amine
substituted via ring
ortho
ment of an N-iodonium intermediate by an adjacent nitrogen atom of the attached pyrazole closure
to the by displace-
pyrazole of 30
ment
[20,21],of an N-iodonium
reports have alsointermediate
made use ofby
the an adjacent
respective nitrogen
amine viaatom
ring
to form azapentalenes [22,23]. Compounds of this type have been thoroughly characterized of the
closure attached
by pyra-
displace-
zole
via to
ment ofform
NMR azapentalenes
an spectroscopy
N-iodonium [22,23].
intermediate
[24]. Compounds
A Pfizer by of this
an adjacent
patent [25] type
nitrogen
filed have
in 2007 atombeenof thoroughly
detailed the use of charac-
theattached pyra-
either
terized
zole
isoamyl via
to form NMR
nitrite inspectroscopy
azapentalenes
DMF or NaNO [24].
[22,23].
2
A Pfizer
Compounds
in aqueous patent
of
aceticthis[25]
acid,typefiled
have
after in
first 2007
been detailed
thoroughly
aminating the use of
charac-
commercially
either
terized isoamyl nitrite in DMF or[24].
via 2-amino-3,5-dibromopyrazine
available NMR spectroscopy NaNO 2 in
A Pfizer32aqueous
inpatent acetic acid,
[25] filed
the presence aafter
of in 2007first aminating
detailed
sterically the use
hindered com-
of
base,
mercially
either available
isoamyl nitrite2-amino-3,5-dibromopyrazine
N,N-diisopropylethylamine in DMF(DIPEA),
or NaNO then
2 in treating 32 in the
aqueousdiaminopyrazine
acetic presence
acid, of aminating
with
after33first a nitrite
sterically hin-
to form
com-
dered base, N,N-diisopropylethylamine
3,5-disubstituted
mercially (DIPEA),
available1H-1,2,3-triazolo[4,5-b]pyrazine
2-amino-3,5-dibromopyrazine34 then treating
32(Scheme 6).
in the presencediaminopyrazine 33 with
of a sterically hin-
nitrite base,
dered to form 3,5-disubstituted 1H-1,2,3-triazolo[4,5-b]pyrazine
N,N-diisopropylethylamine 34 (Scheme 6). 33 with
(DIPEA), then treating diaminopyrazine
nitrite to form 3,5-disubstituted 1H-1,2,3-triazolo[4,5-b]pyrazine 34 (Scheme 6).
Molecules 2022,
Molecules 27, x4681
2022, 27, FOR PEER REVIEW 6 6ofof29
28
Isoamyl nitrite, DMF

H or R
Br N Br Br N N NaNO2, AcOH Br N N
n-BuOH R
+ H2N R N
DIPEA, N
N NH2 N NH2 N
reflux
32 33 34
Scheme
Scheme6. 6.Amination
Aminationof of2-amino-3,5-dibromopyrazine
2-amino-3,5-dibromopyrazine32 32totoform
formdiaminopyrazine
diaminopyrazine33,
33,followed
followedby
by
cyclization to form triazolo[4,5-b]pyrazine 34. (R = alkyl or aryl.)
cyclization to form triazolo[4,5-b]pyrazine 34. (R = alkyl or aryl.)
The
The use
useofofnitrite
nitriteforfortriazole
triazolecyclization,
cyclization, viavia
thethe
nitrosonium
nitrosonium ion,ion,
hashasalsoalso
beenbeen
re-
ported
reportedbybyYeYeand coworkers
and coworkers [26,27], CuiCui
[26,27], andand
coworkers
coworkers[2] (who
[2] (whowere cited
were in the
cited in original
the orig-
patent
inal patent [25]), and others. Thottempudi and coworkers [28] used a combination of
[25]), and others. Thottempudi and coworkers [28] used a combination of
TFAA/HNO
TFAA/HNO3 3asasananininsitu situnitronium
nitroniumsource,
source,giving
givingaatriazole
triazole2-N-oxide,
2-N-oxide, while while Jia
Jia and
and
coworkers
coworkers[1],[1],and
andothers
others[29,30]
[29,30]used
usednitrosonium
nitrosonium generated
generated from
from nitrite. Both
nitrite. syntheses
Both synthe-
offer straightforward introduction of the triazole based on the amine
ses offer straightforward introduction of the triazole based on the amine chosen during chosen during ami-
nation. TheyThey
amination. alsoalso
have the the
have advantage
advantageof short reaction
of short times
reaction timesandandlittle
littleorornonorequired
requiredpu-
pu-
rification.
rification. Likely
Likelyowing
owingto tothese
thesebenefits,
benefits,cyclization
cyclizationusing
usingnitrite
nitriteto togenerate
generatenitrosonium
nitrosonium
ion,
ion, such
such as
asinin33
33to
to34
34(Scheme
(Scheme6), 6),continues
continuesto todominate
dominatereports
reportsin inthe
theliterature.
literature.Indeed,
Indeed,
the reaction
the reaction of various diazinyl diamines with nitrite represents a central theme
diazinyl diamines with nitrite represents a central theme throughout through-
out
the the discussion
discussion of syntheses
of syntheses of 1H-1,2,3-triazole-fused
of 1H-1,2,3-triazole-fused pyrazines
pyrazines andand pyridazines.
pyridazines.
2.2. Syntheses
2.2. Synthesesofof1,2,3-Triazolo[1,5-a]pyrazines
1,2,3-Triazolo[1,5-a]pyrazines
More well-known
More well-known thanthan 1,2,3-triazolo[4,5-b]pyrazines
1,2,3-triazolo[4,5-b]pyrazines are are the
the fused
fused [1,5-a]pyrazine
[1,5-a]pyrazine
derivatives. While benzo[b]pyrazines (i.e., quinoxalines) are not commonly
derivatives. While benzo[b]pyrazines (i.e., quinoxalines) are not commonly encountered encountered
as part of 1,2,3-triazolo[4,5-b]pyrazines, they are widespread in
as part of 1,2,3-triazolo[4,5-b]pyrazines, they are widespread in the literature inthe literature in com-
com-
pounds containing
pounds containingthe the1,2,3-triazolo[1,5-a]pyrazine
1,2,3-triazolo[1,5-a]pyrazine nucleus.
nucleus. Therefore,
Therefore, thisthis section
section is
is or-
organized
ganized into
into thethe synthesesofofbenzo-fused
syntheses benzo-fusedstructures
structures(e.g.,
(e.g.,1,2,3-triazolo[1,5-a]pyrazines
1,2,3-triazolo[1,5-a]pyrazines
containing quinoxaline
containing quinoxaline or or quinoxalinone),
quinoxalinone),and and those
those that
that are
are bicyclic
bicyclic 1,2,3-triazolo[1,5-
1,2,3-triazolo[1,5-
a]pyrazines. A recent brief review of 4,5,6,7-tetrahydro[1–3]triazolo[1,5-a]pyrazines
a]pyrazines. A recent brief review of 4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]pyrazines has has
been published [31]. An earlier review detailed aspects of the chemistry of
been published [31]. An earlier review detailed aspects of the chemistry of 1,2,3-tria- 1,2,3-triazolo[1,5-
a]pyrazines [32]. A review
zolo[1,5-a]pyrazines [32]. Aon the synthesis
review of triazoloquinazolines
on the synthesis also appeared
of triazoloquinazolines alsoin 2016 [33].
appeared
in 2016 [33].
2.2.1. Syntheses of Bicyclic 1,2,3-Triazolo[1,5-a]pyrazines
2.2.1. The first method
Syntheses of synthesizing
of Bicyclic a 1,2,3-triazolo[1,5-a]pyrazine by Wentrup [34] was,
at the time, the synthesis of a novel purine isomer. Wentrup utilized the thermolysis of
The first method of synthesizing a 1,2,3-triazolo[1,5-a]pyrazine by Wentrup [34] was,
5-(2-pyrazinyl)tetrazole 36 (400 ◦ C, 10−5 Torr), affording 38, 1,2,3-triazolo[1,5-a]pyrazine in
at the time, the synthesis of a novel purine isomer. Wentrup utilized the thermolysis of 5-
20% yield proceeding via diazo intermediate 37. The precursor 2-(2H-tetrazol-5-yl)pyrazine
(2-pyrazinyl)tetrazole 36 (400 °C, 10−5 Torr), affording 38, 1,2,3-triazolo[1,5-a]pyrazine in
36 was readily prepared from 2-cyanopyrazine, 35, upon treatment with hydrazoic acid
20% yield proceeding
generated in situ fromvia diazo intermediate
ammonium 37. The
chloride and precursor
sodium 2-(2H-tetrazol-5-yl)pyra-
azide (Scheme 7). This method,
zine 36 was readily prepared from 2-cyanopyrazine, 35, upon treatment
while suffering from harsh reaction conditions and poor yields, was the with
firsthydrazoic
utilizing
acid generated in
intramolecular situ fromofammonium
cyclization chloride and
diazo intermediates in thesodium azide
formation of (Scheme 7). This
1,2,3-triazolo[1,5-
method, while suffering from harsh reaction conditions and poor yields, was the 7 of
first 29
uti-
a]pyrazines. Lead tetraacetate oxidation of the hydrazone of pyrazine-2-carbaldehyde
lizing intramolecular
similarly gave 38 in 75%cyclization
yield [35].of diazo intermediates in the formation of 1,2,3-tria-
zolo[1,5-a]pyrazines. Lead tetraacetate oxidation of the hydrazone of pyrazine-2-carbal-
NH4Cldehyde
+ NaN3similarly gave 38 in 75% yield [35].
N NH 400 °C,
N N
HN3 10-5 Torr
N N N N N N
N N
N DMF, 100 °C N N N N
N2
35 36 37 38
Scheme
Scheme 7.7. Conversion
Conversionofof2-cyanopyrazine
2-cyanopyrazine3535 to 1,2,3-triazolo[1,5-a]pyrazine
to 1,2,3-triazolo[1,5-a]pyrazine 38 via38tetrazolylpyrazine
via tetrazolylpyra-
36.
zine 36.
In addition to syntheses of neutral compounds of this type, several reports have ap-
peared for the preparation of fused pyrazinium salts. A method by Beres and coworkers
[36] afforded 1-(4-bromophenyl)-3-methyl-1,2,3-triazolo[1,5-a]pyrazinium tetrafluorobo-
N DMF, 100 °C N N N N
N2
35 36 37 38
Scheme 7. Conversion of 2-cyanopyrazine 35 to 1,2,3-triazolo[1,5-a]pyrazine 38 via tetrazolylpyra-
Molecules 2022, 27, 4681 zine 36. 7 of 28
In addition to syntheses of neutral compounds of this type, several reports have ap-
pearedIn for the preparation
addition of of
to syntheses fused pyrazinium
neutral compounds salts.ofAthis
method
type, by Beresreports
several and coworkers
have ap-
[36] afforded 1-(4-bromophenyl)-3-methyl-1,2,3-triazolo[1,5-a]pyrazinium
peared for the preparation of fused pyrazinium salts. A method by Beres and coworkers tetrafluorobo-
[36]
rates 31 in
afforded 55% yield (when R1 = p-chlorophenyl) and 81% yield (when
1-(4-bromophenyl)-3-methyl-1,2,3-triazolo[1,5-a]pyrazinium R1 = CH3) after
tetrafluoroborates 31
reaction of 4-bromophenylhydrazones
in 55% yield (when R1 = p-chlorophenyl) 39 and
(prepared from(when
81% yield the respective
R1 = CH32-pyrazinyl ke-
) after reaction
tone) with tribromophenol bromine
of 4-bromophenylhydrazones (TBB) and
39 (prepared fromNHthe4BF 4 (Scheme 8). When R1 = CH3, the
respective 2-pyrazinyl ketone) with
yield of 40 was 81%.
tribromophenol Interestingly,
bromine (TBB) and after
NHtreatment
4 BF 4
of
(Scheme 40 with
8). pyrrolidine
When R1 = CH3in methanol,
, the yield ofthe
40
ring-opened 2-aza-1,3-butadienes can be valuable starting materials for other
was 81%. Interestingly, after treatment of 40 with pyrrolidine in methanol, the ring-opened conversions.
For example, a ring-opened
2-aza-1,3-butadienes can be triazolyl-2-aza-1,3-butadiene
valuable starting materials for was converted
other to a fused
conversions. pyri-
For exam-
dine after treatment with N-phenylmaleinimide, or an imidazoline when treated
ple, a ring-opened triazolyl-2-aza-1,3-butadiene was converted to a fused pyridine after with tosyl
azide [36].
treatment with N-phenylmaleinimide, or an imidazoline when treated with tosyl azide [36].
R1 (i) TBB R1
H
N (ii) NH4BF4
N N N
N
N N N
Br
BF4
39 40 Br
Scheme 8. Intramolecular cyclization of a 4-bromophenylhydrazone 39 forming triazolopyrazinium

Scheme triazolopyrazinium
tetrafluoroborate 40.
tetrafluoroborate (R11 == alkyl
40. (R alkyl or
or aryl.)
aryl.)
Methods have been reported for the the preparation

preparation of
of 1,2,3-triazolo[1,5-a]pyrazinones.
1,2,3-triazolo[1,5-a]pyrazinones.
In work
work by
by Nein
Nein and
and coworkers
coworkers [37,38],
[37,38], the
the reaction
reaction of
of 5-hydroxy-N-diphenyl-1H-1,2,3-
5-hydroxy-N-diphenyl-1H-1,2,3-
triazole-4-carboxamide 41 with chloroacetonitrile in DMF and base gave gave the
the alkylated
alkylated
product 42, which,
product 42, which, after
after refluxing
refluxing in
in sodium
sodium ethoxide,
ethoxide, gave 6-amino-4-oxo-2,5-diphenyl-
4,5-dihydro-2H-1,2,3-triazolo[1,5-a]pyrazinium-5-olate
4,5-dihydro-2H-1,2,3-triazolo[1,5-a]pyrazinium-5-olate 43 in 80% yield (Scheme 9). They
43 in
proposed
proposed the geometry of 3-phenacyl- and 3-cyanomethyl derivatives
the geometry of 3-phenacyl- and 3-cyanomethyl derivatives ofof triazolium-5-
triazolium-5-
olates indicated interaction of the carboxamide nitrogen at position
olates indicated interaction of the carboxamide nitrogen at position 4 of the
Molecules 2022, 27, x FOR PEER REVIEW 4 of triazole
the triazole
8 with
of 29
with cyano groups, which was then confirmed experimentally after
cyano groups, which was then confirmed experimentally after obtaining the obtaining the desired
desired
mesoionic
mesoionic 4242 [37].
[37].
O O
O OH ClCH2CN
N
N Na2CO3, DMF, H N
H N 100 °C N N
N N
CN
41 42
NaOEt
EtOH, reflux,
5h
O O
N
N
N N
H 2N
43
Scheme9.9.Intramolecular
Scheme Intramolecularcyclization
cyclizationof
ofaatriazolium
triazoliumsalt
salt42,
42,forming
formingzwitterionic
zwitterionic43.
43.
Similarly involving reaction of triazolium olates such as 42, during a synthesis of

1,2,5-triazepines by Savel’eva and coworkers [39], [1,5-a]triazolopyrazines were formed
as byproducts (5–7%) from the intramolecular cyclization of 1-amino-3-(p-phenacyl)-4-{[2-
(1-methylethylidene)hydrazino]carbonyl}-[1,2,3]-triazolium-5-olates. Jug and coworkers
[40] took a novel approach for the reaction of 4-(ethoxymethylene)-2-phenyloxazol-5(4H)-
N
N
N N
H 2N
43
Molecules 2022, 27, 4681 8 of 28
Scheme 9. Intramolecular cyclization of a triazolium salt 42, forming zwitterionic 43.

1,2,5-triazepines by Savel’eva and coworkers [39], [1,5-a]triazolopyrazines were formed
1,2,5-triazepines by Savel’eva and coworkers [39], [1,5-a]triazolopyrazines were formed as
as byproducts
byproducts (5–7%)
(5–7%) fromfrom
the the intramolecular
intramolecular cyclization
cyclization of 1-amino-3-(p-phenacyl)-4-{[2-
of 1-amino-3-(p-phenacyl)-4-{[2-(1-
(1-methylethylidene)hydrazino]carbonyl}-[1,2,3]-triazolium-5-olates.
methylethylidene)hydrazino]carbonyl}-[1,2,3]-triazolium-5-olates. Jug and Jugcoworkers
and coworkers
[40]
[40] took a novel approach for the reaction of 4-(ethoxymethylene)-2-phenyloxazol-5(4H)-
took a novel approach for the reaction of 4-(ethoxymethylene)-2-phenyloxazol-5(4H)-one
one
44 44 commercially
with with commercially available
available diaminomaleonitrile
diaminomaleonitrile 45, forming
45, forming adductadduct
46 which,46 which,
after
after conversion to triazole 47 with nitrite, afforded the substituted 1,2,3-triazolo[1,5-a]py-
conversion to triazole 47 with nitrite, afforded the substituted 1,2,3-triazolo[1,5-a]pyrazine
razine
48 48 (Scheme
(Scheme 10).derivatives
10). Later, Later, derivatives
of 48 such ofas
48ethyl
such4-amino-3-cyano-1,2,3-triazolo[1,5-
as ethyl 4-amino-3-cyano-1,2,3-tria-
zolo[1,5-a]pyrazine-6-carboxylate were further reacted
a]pyrazine-6-carboxylate were further reacted by Trcek and bycoworkers
Trcek and[41]
coworkers [41] to
to form 1,2,3-
form 1,2,3-triazolo[1,5-a]-1,2,4-triazolo[5,1-c]pyrazines
triazolo[1,5-a]-1,2,4-triazolo[5,1-c]pyrazines in 55–65% yield.
in 55–65% yield.
O OEt
H2N NH2 PhOCHN NH2
O H
+ N
N EtOH R1OOC CN
NC CN
Ph CN
44 45 46
Isoamyl nitrite,
AcOH
PhOCHN CN CN
EtOH/AcOH, NC
N or TEA PhOCHN
N N
N N N N
R1OOC R1OOC
48 47 .
Scheme10.
Scheme 10.Reaction
Reactionof
of4-(ethoxymethylene)-2-phenyloxazol-5(4H)-one
4-(ethoxymethylene)-2-phenyloxazol-5(4H)-one 4444 and
and diaminomaleonitrile
diaminomaleonitrile
45forming
45 formingan
anadduct
adduct46,
46,which
whichled
ledtototriazole
triazole4747and
and pyrazine
pyrazine 48.48.
(R(R
1 =
1 = alkyl.)
alkyl.)
Raghavendra
Raghavendraand andcoworkers
coworkers[42] [42]reported
reporteda atriazolopyrazine
triazolopyrazine synthesis
synthesis employing
employing
solid-phase polystyrene p-toluenesulfonyl hydrazide, a common carbonyl
solid-phase polystyrene p-toluenesulfonyl hydrazide, a common carbonyl scavenging scavenging resin.
After reaction of the polystyrene p-toluenesulfonyl hydrazide 49 with an
resin. After reaction of the polystyrene p-toluenesulfonyl hydrazide 49 with an acetylpy-acetylpyrazine
in the50presence
50razine of 5% of
in the presence TiCl in MeOH,
5%4 TiCl 4 in MeOH,hydrazone
hydrazone was
5151 wasobtained. Reactionofof 51
obtained. Reaction
with morpholine
51 with gavegave
morpholine the desired 1,2,3-triazolo[1,5-a]pyrazines,
the desired 1,2,3-triazolo[1,5-a]pyrazines, (Scheme
52 52 (Scheme 11), in in
11), yields
ranging
yields from 33–62%.
ranging This regiospecific,
from 33–62%. tracelesstraceless
This regiospecific, protocolprotocol
represented the firstthe
represented solid-phase
first
assisted synthesis
solid-phase ofsynthesis
assisted a triazolopyrazine and wasand
of a triazolopyrazine alsowas
used
alsofor theforsynthesis
used of several
the synthesis of
non-fused 1,2,3-triazoles
several non-fused in the same
1,2,3-triazoles in thereport in yields
same report up to up
in yields 60%.to 60%.
50
O
N
R1 R2
R2
O O O O N R1
N
S NH2 S N N morpholine
N N N
H H N
5% TiCl4, R1 95 °C, 4 h N N
MeOH, 12 h, r.t. R2
49 51 52
= solid-phase polystyrene
Scheme 11. Intramolecular cyclization of hydrazone 51, derived from tosylhydrazide 49, in the for-
Scheme 11. Intramolecular cyclization of hydrazone 51, derived from tosylhydrazide 49, in the
mation of disubstituted 1,2,3-triazolo[1,5-a]pyrazines 52. (R1, R2 = alkyl.)
formation of disubstituted 1,2,3-triazolo[1,5-a]pyrazines 52. (R1 , R2 = alkyl.)
Copper-catalyzed [3 + 2] cycloaddition of propiolamide 53, followed by halide dis-
placement to form a fused product, was utilized in the synthesis of saturated derivatives
of 1,2,3-triazolo[1,5-a]pyrazine (i.e., triazolopiperazines) 54 in 80% yield [43] (Scheme 12).
Koguchi and coworkers used ynones and β-amino azides to afford 6,7-dihydro-1,2,3-tria-
zolo[1,5-a]pyrazines. These authors verified that the one-pot reaction gave cycloaddition
Scheme 11. Intramolecular cyclization of hydrazone 51, derived from tosylhy
mation of disubstituted 1,2,3-triazolo[1,5-a]pyrazines 52. (R1, R2 = alkyl.)
Molecules 2022, 27, 4681 9 of 28

Copper-catalyzed [3 + 2] cycloaddition of propiolamide 53, follo
placement to form a fused product, was utilized in the synthesis of sa
of 1,2,3-triazolo[1,5-a]pyrazine
Copper-catalyzed [3 + 2] cycloaddition(i.e., triazolopiperazines)
of propiolamide 54 indis-
53, followed by halide 80% yie
placement to form a fused product, was utilized in the synthesis of saturated derivatives
Koguchi and coworkers used ynones and β-amino azides to afford 6,7
of 1,2,3-triazolo[1,5-a]pyrazine (i.e., triazolopiperazines) 54 in 80% yield [43] (Scheme 12).
zolo[1,5-a]pyrazines.
Koguchi and coworkers usedTheseynones authors
and β-amino verified
azides tothat
affordthe one-pot reaction
6,7-dihydro-1,2,3-
triazolo[1,5-a]pyrazines. These authors verified that the
of the alkyne and azide first, followed by reaction of the one-pot reaction gave cycloaddition
amine with th
of the alkyne and azide first, followed by reaction of the amine with the ketone [44].
R2 O R1
N O R2
CuI (10 mol%), NaN3 N
N
R3 N N
I DMSO, 110 °C,
R4 4-6 h
R1 R3 R4
53 54
Scheme
Scheme 12. Cycloaddition
12. Cycloaddition of propiolamide
of propiolamide 53 and displacement53 and displacement
of iodide of iodide
to form triazolopiperazine to
54. (R , R ,
zine1 54.2 (RR , R = alkyl or aryl.)
3 1, 4R2, R3, R4 = alkyl or aryl.)
2.2.2. Syntheses of Benzo-Fused 1,2,3-Triazolo[1,5-a]pyrazines

2.2.2.OneSyntheses of Benzo-Fused
of the first reported preparations of 1,2,3-Triazolo[1,5-a]pyrazines
a 1,2,3-triazolo[1,5-a]pyrazine by Kauer and
coworkers [45] started with dimethyl l-(o-nitrophenyl)-lH-triazole-4,5-dicarboxylate 59, and
One ofwith
upon treatment thetributyl
first reported
phosphine inpreparations
refluxing toluene,of a 1,2,3-triazolo[1,5-a]pyr
afforded methyl 4-methoxy-
1,2,3-triazolo[3,4-a]quinoxaline-3-carboxylate 60 (Scheme 13). Triazole 59 was readily pre-
coworkers [45] started with dimethyl l-(o-nitrophenyl)-lH-triazole-4,
pared from o-azidonitrobenzene 57 (which in turn was prepared from o-chloronitrobenzene
and
55 upon treatment56)
or o-aminonitrobenzene with tributylacetylenedicarboxylate
and dimethyl phosphine in refluxing 58 in CHCltoluene,
3. affor
oxy-1,2,3-triazolo[3,4-a]quinoxaline-3-carboxylate 60 (Scheme 13). Tria
precursors prepared from o-azidonitrobenzene 57 (which in turn was prepared
Cl benzene
NH2 55 or o-aminonitrobenzene 56) and dimethyl acetylenedicarbo
55 or 56
NO2 NO2
O N N N N
N3 N CO2Me N CO2Me
O PBu3
+ O
CO2Me toluene,
NO2 O NO2 reflux N OMe
57 58 59 60
Scheme 13. Treatment of triazolyl-o-nitrobenzene 59 with tributyl phosphine, PBu3, resulting in
Scheme 13. Treatment of triazolyl-o-nitrobenzene 59 with tributyl phosphine, PBu3 , resulting in
1,2,3-triazolo[3,4-a]quinoxaline 60.
1,2,3-triazolo[3,4-a]quinoxaline 60.
Through a different approach, Cue and coworkers [46] accessed 1,2,3-triazolo[l,5-
Through a different approach, Cue and coworkers [46] accessed 1,2,3-triazolo[l,5-
a]quinoxaline N-oxides 62 in yields ranging from 52–70% by cyclization of quinoxaline-3-
a]quinoxaline N-oxides 62 in yields ranging from 52–70% by cyclization of quinoxaline-
carboxaldehyde-1-oxide-p-toluenesulfonylhydrazone 61 (Scheme 14). The starting sul-
3-carboxaldehyde-1-oxide-p-toluenesulfonylhydrazone 61 (Scheme 14). The starting sul-
fonylhydrazone 61 was prepared by reaction of a 3-substituted quinoxaline N-oxide with
fonylhydrazone 61 was prepared by reaction of a 3-substituted quinoxaline N-oxide with
p-toluenesulfonylhydrazide [45].
R1 R2 R1 R2
H
O N O
N N S NaOMe N
O O N
N 1h N N
61 62
1,2,3-triazolo[3,4-a]quinoxaline
a]quinoxaline N-oxides 62 in60. yields ranging from 52–70% by cyclization of quinoxalin
carboxaldehyde-1-oxide-p-toluenesulfonylhydrazone 61 (Scheme 14). The starting
Through a different approach, Cue and coworkers [46] accessed 1,2,3-triazolo[l,
fonylhydrazone 61 was prepared by reaction of a 3-substituted quinoxaline N-oxide
a]quinoxaline N-oxides 62 in yields ranging from 52–70% by cyclization of quinoxaline-
Molecules 2022, 27, 4681 carboxaldehyde-1-oxide-p-toluenesulfonylhydrazone 61 (Scheme 14). The 10 ofstarting
28 su
fonylhydrazone 61 was prepared by reaction of a 3-substituted quinoxaline N-oxide wi
R1 R2
p-toluenesulfonylhydrazide [45]. R1 R2
H
O N O
N N S NaOMe N
R1 R2
N O
H O R1
N R2N
O N 1h O N
N N S NaOMe N
O O N
N 1h N N
61 62
Scheme 14. Synthesis of substituted 1,2,3-triazolo[l,5-a]quinoxaline N-oxides, 62, via intramole
61
cyclization of sulfonylhydrazone 61. (R1, R2 = H, methyl.) 62
Scheme
Scheme Synthesis
14. 14. of substituted
Synthesis 1,2,3-triazolo[l,5-a]quinoxaline
of substituted N-oxides,N-oxides,
1,2,3-triazolo[l,5-a]quinoxaline 62, via intramolecular
62, via intramolecu
For of
cyclization
cyclizationtheofintramolecular
sulfonylhydrazone 61. cyclization
sulfonylhydrazone (R61.
1 , R(R
2 =1,H, =of
H,ortho-substituted
R2methyl.)
methyl.) amines to prepare 1,2,3-
zoles using nitrite, as is commonly reported for non-fused derivatives [2,25], Ager
For the intramolecular cyclization of ortho-substituted amines to prepare 1,2,3-triazoles
For the intramolecular
coworkers cyclization of ortho-substituted amines to prepare 1,2,3-tri
using nitrite, [47]
as is illustrated that
commonly reported thefor
amines used
non-fused in cyclization
derivatives do not
[2,25], Ager andneed
cowork-to be prim
zoles
Through using nitrite,
reaction of as
a is commonly
secondary aminereported
within for
a non-fused
ring and a derivatives
primary amine
ers [47] illustrated that the amines used in cyclization do not need to be primary. Through [2,25],
63 Ager
with an
isoa
coworkers
nitrite in
reaction [47] illustrated
of achloroacetic
secondary amine that
acid, the amines
theya obtained
within used in cyclization
1,2,3-triazoles
ring and a primary amine 63fused do not need
to both
with isoamyl to be
lactones
nitrite in primar
and
Through
chloroacetic reaction
acid, theyof a secondary
obtained amine within
1,2,3-triazoles fused a ring
to bothand a primary
lactones and
tams, 64, in yields in the range 54–76% (Scheme 15). In the case of lactams, 1,2,3-triaz amine
lactams,63 with
64, in isoam
nitrite
yields in range
in the
quinoxalinones chloroacetic
54–76% acid, they
(Scheme
were formed. 15).obtained
In the case1,2,3-triazoles fused to both lactones and la
of lactams, 1,2,3-triazoloquinoxalinones
were formed.
tams, 64, in yields in the range 54–76% (Scheme 15). In the case of lactams, 1,2,3-triazol
quinoxalinones were formed.
NH2 N N
H
N Isoamyl nitrite N CO2Me
NH CO
2 2Me N N
H
N Isoamyl
ClCCOnitrite
2H, N CO2Me
X O CO 2Me X O
0 °C, 12 h
ClCCO2H,
X O 0 °C, 12 h X O
63 64
Molecules 2022, 27, x FOR PEER REVIEW 63 64 11
X = NH, O
X = NH, O
Scheme15.15.Synthesis
Scheme Synthesis of 1,2,3-triazole-fused
of 1,2,3-triazole-fused quinoxalinones,
quinoxalinones, using a in
using a diamine diamine in which
which one amine one am
secondary.
is secondary.
Synthesizing
Scheme compounds
15. Synthesis of the same
of 1,2,3-triazole-fused type, Bertelli,
quinoxalinones, and
using coworkers
a diamine [48]one
in which first for
amine
a secondary.
triazole diestercompounds
Synthesizing on a ring ofortho
the to a nitro
same type, group,
Bertelli,65,
andwhich was[48]
coworkers intramolecularly
first formed cycl
atotriazole
formdiester
ethylon a4,5-dihydro-4-oxo-[1,2,3]triazolo[1,5-a]quinoxaline-3-carboxylate,
ring ortho to a nitro group, 65, which was intramolecularly cy-
(Scheme
clized 16).ethyl
to form This4,5-dihydro-4-oxo-[1,2,3]triazolo[1,5-a]quinoxaline-3-carboxylate,
reaction was conducted by hydrogenation with a 10% Pd/C 66 cataly
(Scheme 16). This reaction was conducted by hydrogenation with a 10% Pd/C
by reaction with FeCl3 and Fe powder. Biagi and coworkers [49] cyclized the tria catalyst
or by reaction
diester with FeCl3 and Fe powder. Biagi
into 1,2,3-triazoloquinoxalinone 66and coworkers
with [49]in
10% Pd/C cyclized
ethanol theintriazole
an excellent
diester into 1,2,3-triazoloquinoxalinone 66 with 10% Pd/C in ethanol in an excellent 98%
yield. Shen and coworkers further modified the ester group of 66 to prepare a deriva
yield. Shen and coworkers further modified the ester group of 66 to prepare a derivative
suitableforfor
suitable biological
biological testing
testing [50]. [50].
N N 5 mol% FeCl3, N N
N CO2Et Fe powder N CO2Et
CO2Et EtOH, reflux,
NO2 4h N O
H
65 66
Scheme16.16.
Scheme Synthesis
Synthesis of 1,2,3-triazole-fused
of 1,2,3-triazole-fused quinoxalinone
quinoxalinone 66, using a 66, using a1,2,3-triazole
pre-formed pre-formed651,2,3-triazo
in
in the
the presence
presence ofcatalysts.
of iron iron catalysts.
Abbott and coworkers [51] prepared 1,2,3-triazoloquinoxalines in an analogous m

ner, but opted for use of an amide instead of a nitro group, giving mesoionic 1,2,3-triaz
68, which were derived from the lithium salt of [2-(acetylamino)phenyl]amino acetic
67 (Scheme 17). A series of 1,2,3-triazoloquinoxalines, 69, was synthesized after cycliza
NO2 4h N O
H
65 66
Scheme 16. Synthesis of 1,2,3-triazole-fused quinoxalinone 66, using a pre-formed 1,2,3-triazole 65
Molecules 2022, 27, 4681 in the presence of iron catalysts. 11 of 28
Abbott and coworkers [51] prepared 1,2,3-triazoloquinoxalines in an analogous man

ner, Abbott andfor
but opted coworkers
use of an[51] prepared
amide 1,2,3-triazoloquinoxalines
instead in an
of a nitro group, giving analogous1,2,3-triazoles
mesoionic man-
ner, but opted for use of an amide instead of a nitro group, giving mesoionic 1,2,3-triazoles
68, which were derived from the lithium salt of [2-(acetylamino)phenyl]amino acetic acid
68, which were derived from the lithium salt of [2-(acetylamino)phenyl]amino acetic acid
67 (Scheme 17). A series of 1,2,3-triazoloquinoxalines, 69, was synthesized after cyclization
67 (Scheme 17). A series of 1,2,3-triazoloquinoxalines, 69, was synthesized after cyclization
with p-toluenesulfonic acid (p-TSA) in refluxing toluene in yields in the range 16–59%.
with p-toluenesulfonic acid (p-TSA) in refluxing toluene in yields in the range 16–59%.
R2
(i) R2-Ar-NH2, N N
H
N CO2Li NaNO2, aq. HCl N O
(ii) pyridine, Ac2O

NHCOR1 NHCOR1
67 68
p-TSA, toluene,
reflux
R2
N N
N O
N R1
69
Scheme 17.
Scheme 17. Synthesis
Synthesis of
of mesoionic
mesoionic 1,2,3-triazoloquinoxalines
1,2,3-triazoloquinoxalines 6969from
fromortho-substituted
ortho-substituted 1,2,3-tria-
1,2,3-
zolobenzamides 68.
triazolobenzamides (R1,1R
68.(R , R2 2==alkyl
alkylor
or aryl.)
aryl.)
Saha
Sahaandandcoworkers
coworkers [52][52]
usedused
the intramolecular cyclization
the intramolecular of ortho-substituted
cyclization anilines
of ortho-substituted ani
with tethered 1,2,3-triazoles, 72, a Pictet–Spengler reaction, to form 1,2,3-triazoloquinoxalines 73
lines with tethered 1,2,3-triazoles, 72, a Pictet–Spengler reaction, to form 1,2,3-triazolo
in yields in the range 61–70% (Scheme 18). This sequence offers two-point diversity: one
quinoxalines
diversity:
from 72, and
73other
onethe
fromin 72,
yields
and in
from thethe range
other
an aryl from61–70%
aldehydean aryl (Scheme
aldehyde
73. The
18). This
73. The
prerequisite
sequence
prerequisite
triazole
offers
72 wastriazoletwo-poin
conve-
72 was prepared
niently conveniently
fromprepared from readily
readily available available
starting starting
materials, materials,
including including o-fluo-
o-fluoronitrobenzene
ronitrobenzene 70, phenylacetylene
70, phenylacetylene 71, and sodium azide. 71, and sodium azide.
73
O
commercially available precursors

N N R2 N N
F N N
+ + NaN3 R1 R1
p-TsOH, toluene,
NO2 NH2 N
reflux, 12 h R2
70 71 72 74
Scheme 18. 3-Phenyl-4-p-tolyl-1,2,3-triazolo[1,5-a]quinoxalines 74 synthesized from ortho-substi-
Scheme 18. 3-Phenyl-4-p-tolyl-1,2,3-triazolo[1,5-a]quinoxalines 74 synthesized from ortho-substituted
tuted 2-(4-phenyl-[1,2,3]triazol-1-yl)anilines 72. (R1, R2 = alkyl or aryl.)
2-(4-phenyl-[1,2,3]triazol-1-yl)anilines 72. (R1 , R2 = alkyl or aryl.)
Chen and coworkers [53] used a novel approach for the synthesis of 4-(trifluorome-
thyl)-1,2,3-triazolo[1,5-a]quinoxaline 76 via cascade reactions of N-(o-haloaryl)al-
kynylimine 75 with sodium azide in the presence of copper iodide and L-proline (Scheme
19). Among a series of amine-containing catalysts, L-proline resulted in a 98% isolated
yield, while tetramethylethylenediamine and N,N’-dimethylethylenediamine gave lower
yields, and higher percentages of the uncyclized imine product.
2 2 reflux, 12 h
Chen and coworkers [53] used a novel approach for the synthesis of 4-(trifluorome-
70 thyl)-1,2,3-triazolo[1,5-a]quinoxaline
71 76 via72 cascade reactions of N-(o-haloaryl)al- 74
kynylimine 75 with sodium azide in the presence of copper iodide and L-proline (Scheme
Scheme 18. 3-Phenyl-4-p-tolyl-1,2,3-triazolo[1,5-a]quinoxalines 74 synthesized from ortho-sub
Molecules 19). Among
2022, 27, 4681 a series
tutedof amine-containing catalysts, 72.
2-(4-phenyl-[1,2,3]triazol-1-yl)anilines L-proline resulted
(R1, R2 = alkyl or aryl.)in a 98% 12
isolated
of 28
yield, while tetramethylethylenediamine and N,N’-dimethylethylenediamine gave lower
Chen and coworkers
yields, and higher percentages [53] used imine
of the uncyclized a novelproduct.
approach for the synthesis of 4-(trifluorom
Chen and coworkers [53] used a novel approach
thyl)-1,2,3-triazolo[1,5-a]quinoxaline 76 viafor cascade
the synthesis of 4-(trifluoromethyl)-
reactions of N-(o-haloaryl
1,2,3-triazolo[1,5-a]quinoxaline 76 via cascade reactions of N-(o-haloaryl)alkynylimine
kynylimine 75 with sodium azide in the presence of copper iodide and L-proline 75 (Sche
I with sodium azide in the presence of copper iodide and L-proline (Scheme 19). Among
19). Among a series of amine-containing catalysts, N N
a series of amine-containing catalysts, L-proline resulted
L-proline resulted in a 98% isola
in a 98% isolated yield, while
yield, while tetramethylethylenediamine and N,N’-dimethylethylenediamine
tetramethylethylenediamine and N,N0 -dimethylethylenediamine
gave low
N N gave lower yields, and
yields,percentages
higher and higher NaN
of percentages
the 3
uncyclizedofimine
the uncyclized
product. imine product.
F3C I 10 mol% CuI,

N CF3
20 mol% L-proline, N N
N DMSO, r.t. NaN3
N
75 F3C 10 mol% CuI, 76

N CF3
20 mol% L-proline,
Scheme 19. Synthesis of 3-phenyl-4-(trifluoromethyl)-1,2,3-triazolo[1,5-a]quinoxaline
DMSO, r.t. 76 from N-(o-
haloaryl)alkynylimine 75.
75 76
Using photoredox
Scheme
Scheme catalysis,
19.
19. ofHe
Synthesis
Synthesis ofand coworkers [54] used [fac-Ir(ppy)3] as76
3-phenyl-4-(trifluoromethyl)-1,2,3-triazolo[1,5-a]quinoxaline
3-phenyl-4-(trifluoromethyl)-1,2,3-triazolo[1,5-a]quinoxaline a from
photocata-76 from N
N-(o-
haloaryl)alkynylimine
lyst to afford the corresponding 75.
haloaryl)alkynylimine1,2,3-triazoloquinoxaline
75. 78 from isonitrile 77 in 60% yield
(Scheme 20). Due to poorUsing solubility
photoredox of the catalyst,
catalysis, He and ACN resulted
coworkers [54] usedin[fac-Ir(ppy)
decreased yields com-
3 ] as a 3photo-
Using photoredox catalysis, He and coworkers [54] used [fac-Ir(ppy) ] as a photoca
pared to DMF. This work
catalyst is
to afford a rare
the example
corresponding of free-radical generation
1,2,3-triazoloquinoxaline of 1,2,3-triazole-
78 from isonitrile
lyst to afford the corresponding 1,2,3-triazoloquinoxaline 78 from isonitrile 77 in 60% yi
77 in 60%
yield (Scheme 20). Due to poor solubility of the catalyst, ACN resulted in decreased
fused ring systems, as cyclohexyl
(Scheme 20). Due toradicals
poor are proposed
solubility to have formed from phenylio-
yields compared to DMF. This work is a of theexample
rare catalyst,
of ACN resulted
free-radical in decreased
generation of 1,2,3-yields co
dine(III)dicarboxylate.
pared The
triazole-fused radicals
to DMF.ringThis yield
work
systems, isonitrile
as iscyclohexyl carbonof
a rare example
radicals radicals,
are proposed followed
free-radical to generation
have formed by ofreaction
1,2,3-triaz
from
fused ring systems,
with carbon 5 of phenyliodine(III)dicarboxylate.
the triazole. Various as cyclohexyl
fused The ringsradicals
radicals yieldare
were proposed
synthesized
isonitrile carbontoinhave formed
addition
radicals, followed from
to pheny
1,2,3-
by
reaction with carbon 5 of the
dine(III)dicarboxylate. Thetriazole. Various
radicals yieldfused rings were
isonitrile synthesized
carbon radicals, in followed
addition toby react
triazoles including tetrazoles, pyrazoles, and imidazoles in yields as high as 80%.
1,2,3-triazoles
with carbonincluding
5 of the tetrazoles, pyrazoles,fused
triazole. Various and imidazoles
rings werein yields as high as
synthesized in 80%.
addition to 1,
triazoles including tetrazoles, pyrazoles, and imidazoles in yields as high as 80%.
N N N N
PhI(OCOCy)2 (1.5 eq.)
N N N N N N
PhI(OCOCy) (1.5 eq.)
N 1 mol% [fac-Ir(ppy)3], 2 N
N 26W fluorescent bulb,[fac-Ir(ppy)3], N
1 mol% Cy
C N DMF 26W fluorescent bulb, N Cy
C DMF
77 78
77 78
Scheme 20. PhotoredoxSchemeapproach
20. Photoredoxfor the synthesis
approach of a
for the synthesis 1,2,3-triazoloquinoxaline
of 78.= cyclohexyl,
a 1,2,3-triazoloquinoxaline 78. (Cy
Scheme 20. Photoredox approach for the synthesis of a 1,2,3-triazoloquinoxaline (Cy =78.cyclo-
(Cy = cy
fac
hexyl, fac = facial, ppy = facial,
= ppy = 2-phenylpyridine).
2-phenylpyridine).
hexyl, fac = facial, ppy = 2-phenylpyridine).
In the presence of Cu(OAc)2 and base in DMSO/THF, Li and coworkers [55] re-
ported an efficient one-pot synthesis of 1,2,3-triazolo[1,5-a]quinoxalines 81 from 1-azido-2-
isocyanoarenes 79 in yields in the range 40–84% (Scheme 21). They outlined the option of
using terminal acetylenes 80 or substituted acetaldehydes 82, the former being cyclized into
81 in one step (in yields ranging from 40–83%), and the latter forming uncyclized triazole 83,
which was annulated using Togni’s reagent II and tetra-n-butylammonium iodide (TBAI),
forming 84, or phenylboronic acid, forming 85. Derivatives of 84 were prepared in yields
in the range 26–78%, and one synthesis of 85 yielded 86%.
forming 84, or phenylboronic acid, forming 85. Derivatives of 84 were prepared in yields
in the range 26–78%, and one synthesis of 85 yielded 86%.
Owing to the versatility of intermediate 83, many functionalized 1,2,3-triazolo-
quinoxalines were prepared, and indeed, Li and coworkers reported several compounds
containing the 1,2,3-triazolo[1,5-a]quinoxaline core with a variety of functionalities. Addi-
Molecules 2022, 27, 4681 13 of 28
tionally, in this report, the fused products were further reacted into diversified quinoxa-
line derivatives via Rh(II)-catalyzed carbenoid insertion reactions [55].
80
N N
N3 R2 N R2
R1 R1
10 mol% Cu(OAc)2, N
N
C Na2CO3, 4:1 THF/DMSO,
65 °C, 12-20 h
79 81
82 R2 10 mol% DBU,
O
DMSO, 25 °C, 3 h
N N N N N N
10 mol% TBAI,
N R2 N R2 N R2
PhB(OH)2 Togni’s reagent II
R1 R1 R1
Mn(acac)3, DMSO, 85 °C,
N Ph N N CF3
toluene, C 10 h
85 80 °C, 1 h 83 84
O
O
I
CF3
Togni’s reagent II
Scheme 21.
Scheme 21. Copper-catalyzed
Copper-catalyzedsynthesis of 1,2,3-triazolo[1,5-a]quinoxalines
synthesis 81 from
of 1,2,3-triazolo[1,5-a]quinoxalines 811-azido-2-isocy-
from 1-azido-2-
isocyanoarenes 79. Annulation of intermediate 83 with 1) Togni’s reagent II and TBAI
anoarenes 79. Annulation of intermediate 83 with 1) Togni’s reagent II and catalytic forming
catalytic TBAI
84, or 2) phenylboronic acid and a manganese catalyst forming 85. (R1, R2 = alkyl or aryl.)
forming 84, or 2) phenylboronic acid and a manganese catalyst forming 85. (R1 , R2 = alkyl or aryl.)
Employing
Owing to theaversatility
Pd-catalyzed intramolecular
of intermediate cyclization
83, many of triazole
functionalized 86, Kotovshchikov
1,2,3-triazoloquinoxalines
and coworkers [56] synthesized 3-butyl-[1,2,3]triazolo[1,5-a]quinoxalin-4(5H)-one
were prepared, and indeed, Li and coworkers reported several compounds containing 87 in
the
1,2,3-triazolo[1,5-a]quinoxaline core with a variety of functionalities. Additionally, inthe
77% yield. As this reaction was conducted under CO (1 atm), the carbonyl carbon of this
quinoxalinone
report, the fusedwas introduced
products were by Pd-catalyzed
further insertion
reacted into of COquinoxaline
diversified (Scheme 22).derivatives via
Rh(II)-catalyzed carbenoid insertion reactions [55].
Employing a Pd-catalyzed intramolecular cyclization of triazole 86, Kotovshchikov
and coworkers [56] synthesized 3-butyl-[1,2,3]triazolo[1,5-a]quinoxalin-4(5H)-one 87 in 14 of 2
77% yield. As this reaction was conducted under CO (1 atm), the carbonyl carbon of the
quinoxalinone was introduced by Pd-catalyzed insertion of CO (Scheme 22).
N N N N
5 mol% Pd(OAc)2
N n-Bu N n-Bu
CO (1 atm)
I MeOH, TEA,
NH2 N O
50 °C, 17 h H
86 87
Scheme22.
Scheme 22.Pd-catalyzed
Pd-catalyzed synthesis
synthesis of quinoxalinone
of quinoxalinone 87ortho-substituted
87 from from ortho-substituted aniline 86.
aniline 86.
Xiao
Xiaoand
andcoworkers
coworkers [43] and
[43] Chen
and andand
Chen coworkers [57] [57]
coworkers usedused
in situ
in conversion of
situ conversion of N
N-propargyl-N-(2-iodoaryl)amides 88 to azides, which underwent 1,3-dipolar cycload-
propargyl-N-(2-iodoaryl)amides 88 to azides, which underwent 1,3-dipolar cycloaddition
dition with the adjacent alkyne to form substituted 1,2,3-triazolo[1,5-a]quinoxalines 89
with the adjacent alkyne to form substituted 1,2,3-triazolo[1,5-a]quinoxalines 89 (Scheme
(Scheme 23) in yields in the range 58–91%. Chen and coworkers suggested that cycload-
23) in yields
dition in the first.
might occur rangeThe58–91%. Chen
sequence andconducted
was coworkersin suggested that
the presence ofcycloaddition
DIPEA and migh
occur first. The sequence was
1,2-dimethylethylenediamine (DMEDA). conducted in the presence of DIPEA and 1,2-dimethyleth
ylenediamine (DMEDA).
R2
Xiao
Xiaoand
andcoworkers
coworkers[43]
[43]and
andChen
Chenand
andcoworkers
coworkers[57]
[57]used
usedininsitu
situconversion
conversionofofN-
N-
with
withthe
theadjacent
adjacentalkyne
alkynetotoform
formsubstituted
substituted1,2,3-triazolo[1,5-a]quinoxalines
1,2,3-triazolo[1,5-a]quinoxalines8989(Scheme
(Scheme
23)
23)in
inyields
yieldsin
inthe
therange
range58–91%.
58–91%.Chen
Chenand
andcoworkers
coworkerssuggested
suggestedthat
thatcycloaddition
cycloadditionmight
might
Molecules 2022, 27, 4681 occur 14 of 28
occurfirst.
first.The
Thesequence
sequencewaswasconducted
conductedin inthe
thepresence
presenceof ofDIPEA
DIPEAand and1,2-dimethyleth-
1,2-dimethyleth-
ylenediamine
ylenediamine(DMEDA).
(DMEDA).
RR22
OO NN NN
NaN
NaN33,,CuI,
CuI,DIPEA
DIPEA
DMEDA RR11 NN RR44
RR33 NN DMEDA
II RR44 DMF,
DMF,50
50°C
°C NN
RR22
RR11 88
88 89
89
Scheme
Scheme23.
Scheme 23.Intramolecular
23. Intramolecular
Intramolecular cyclization
cyclization of
cyclizationofN-propargyl-N-(2-iodoaryl)amides
N-propargyl-N-(2-iodoaryl)amides
of N-propargyl-N-(2-iodoaryl)amides 88,
88,yielding
yielding
88, 1,2,3-tria-
1,2,3-tria-
yielding 1,2,3-
zoloquinoxalines
zoloquinoxalines 89
89after
afterin
insitu
situconversion
conversion of
of88
88to
tothe
theazide.
azide.(R
(R
1, R , R , R = alkyl or aryl.)
1, R2, R3, R4 = alkyl or aryl.)
2 3 4
triazoloquinoxalines 89 after in situ conversion of 88 to the azide. (R1 , R2 , R3 , R4 = alkyl or aryl.)
Preparative
Preparative thermolysis
Preparative thermolysis of
thermolysis of tetrazoloquinoxaline
of tetrazoloquinoxaline 90
tetrazoloquinoxaline 90 proceeded
proceeded by
proceeded by loss
by loss of
loss of nitrogen
of nitrogen
nitrogen
through
throughdiazo
through diazointermediate
diazo intermediate91
intermediate 91and
91 andthen
and thento
then to1,2,3-triazolo[1,5-a]quinoxaline
to 1,2,3-triazolo[1,5-a]quinoxaline92
1,2,3-triazolo[1,5-a]quinoxaline 92in
92 in67%
in 67%yield
67% yield
yield
(Scheme
(Scheme24)
(Scheme 24)[58].
24) [58].Using
[58]. Usingaaaring-closure
Using ring-closuremethod
ring-closure methodsimilar
method similarto
similar tothat
to thatused
that usedby
used byboth
by bothRaghavendra
both Raghavendra
Raghavendra
and
andcoworkers
and coworkers[42]
coworkers [42] and
andCue
Cueandandcoworkers
and coworkers[46],
coworkers [46],Vogel
[46], Vogeland
Vogel andLippmann
and Lippmann[59]
Lippmann [59]developed
[59] developed
developed aa
route
arouteto derivatives
routetotoderivatives
derivativesofof 92
of92in
92in 47–89%
in47–89% yield
47–89% yield via
yield via conversion from tosylhydrazones
via conversion from tosylhydrazones 93 93 using
93 using
using
base
base(Bamford-Stevens
(Bamford-Stevensconditions)
conditions)or, or,in
incertain
certaincases,
cases,heat (Scheme
heat(Scheme 24).
(Scheme24).
24).
N NN NN
HN N
HN
NN NN NN NN
NN heat
heat 165
165°C
°C
NN22
89
89hh
NN NN22 NN NN RR
90
90 91
91 92
92
NaOMe,
NaOMe,
MeOH
MeOH
HH
NN N
RR==HH(ref.
(ref.58)
58) NN N SS
RR==O-alkyl,
O-alkyl,O-aryl,
O-aryl,NH
NH22(ref.
(ref.59)
59) OO OO
NN RR
93
93
Scheme
Scheme24.
Scheme 24.Cyclization
24. Cyclizationmethods
Cyclization methodsfor
methods forpreparing
for preparing1,2,3-triazolo[1,5-a]quinoxalines.
preparing 1,2,3-triazolo[1,5-a]quinoxalines.
1,2,3-triazolo[1,5-a]quinoxalines.
Overall, there exist diverse methods for the synthesis of both bicyclic 1,2,3-triazolo[1,5-
a]pyrazines and 1,2,3-triazolo[1,5-a]quinoxalines.
2.3. Syntheses of 1H-1,2,3-Triazolo[4,5-d]pyridazines

Livi and coworkers [60] reviewed syntheses of this heterocyclic system covering re-
ports prior to 1996. Another review on condensed 1,2,3-triazoles appeared in 2008, which
includes synthesis of 1H-1,2,3-triazolo[4,5-d]pyridazines [32]. Here, we summarize both
older and newer reports. A common theme in the literature regarding the synthesis of
1H-1,2,3-triazolo[4,5-d]pyridazines is the reaction of 1,2,3-triazole dicarbonyl species with
hydrazine hydrate. This yields a diacylhydrazide, which can be cyclized with either high
heat or acid. One of the first examples (Scheme 25) is from Fournier and Miller [61], who
used 2-(4,5-dibenzoyl-1H-1,2,3-triazol-1-ylmethyl)-3,4,6-trimethylhydroquinone diacetate
and hydrazine hydrate in ethanol to form 4,5-diphenyl-1H-1,2,3-triazolo[4,5-d]pyridazine.
In a comparable manner, Erichomovitch [62] used triazole diesters 94 to obtain diacylhy-
drazides 95, which were heated to form 1H-1,2,3-triazolo[4,5-d]pyridazines 96 in 80% yield
with loss of hydrazine.
heat or acid.
drazine OneThis
hydrate. of the firstaexamples
yields (Schemewhich
diacylhydrazide, 25) is can
frombeFournier
cyclized and
withMiller
either [61],
highwho
used
heat or2-(4,5-dibenzoyl-1H-1,2,3-triazol-1-ylmethyl)-3,4,6-trimethylhydroquinone
acid. One of the first examples (Scheme 25) is from Fournier and Miller [61], who diace-
tate
usedand hydrazine hydrate in ethanol to form 4,5-diphenyl-1H-1,2,3-triazolo[4,5-d]pyri-
2-(4,5-dibenzoyl-1H-1,2,3-triazol-1-ylmethyl)-3,4,6-trimethylhydroquinone diace-
tate and In
dazine. hydrazine hydrate
a comparable in ethanol
manner, to form 4,5-diphenyl-1H-1,2,3-triazolo[4,5-d]pyri-
Erichomovitch [62] used triazole diesters 94 to obtain
dazine. In a comparable
diacylhydrazides manner,
95, which wereErichomovitch
heated to form[62] used triazole diesters 94 to obtain96 in
1H-1,2,3-triazolo[4,5-d]pyridazines
Molecules 2022, 27, 4681 15 of 28
diacylhydrazides 95, which were
80% yield with loss of hydrazine. heated to form 1H-1,2,3-triazolo[4,5-d]pyridazines 96 in
80% yield with loss of hydrazine.
O O O
O O O
N NH2NH2 H2NHN N 240 °C HN N
O N N N N
O NH2NH2 H2NHN N 240 °C HN N
O N
N MeOH, 40 min H2NHN N
N 6 h HN HN NN
O N MeOH, 40 min H2NHN N 6h N
O
R
R11 O R1
R1 O R1 R1
O O O
94
94 9595 96 96
Scheme
Scheme 25.Intramolecular
Scheme 25.
25. Intramolecularcyclization
Intramolecular cyclization
cyclization of of
of diacylhydrazide
diacylhydrazide
diacylhydrazide 95, forming
95,forming
95, forming 1,2,3-triazolo[4,5-d]pyri-
1,2,3-triazolo[4,5-d]pyri-
1,2,3-triazolo[4,5-d]pyridazine
dazine
dazine 96 upon
96 uponhigh
highheat
heatwith
withloss
lossofof hydrazine.
hydrazine. (R (R1 = alkyl.)
1 = alkyl.)
96 upon high heat with loss of hydrazine. (R1 = alkyl.)
Janietz and
Janietz
Janietz andcoworkers
and coworkers[63]
coworkers [63]developed
[63] developed
developed aa scheme
scheme
a scheme thatthat proceeded
proceeded
that proceeded through
through dichlorotri-
dichlorotri-
through dichlorotria-
zole 97, which, after conversion to a dinitrone and subsequent treatment with acid, acid,
azole 97,
97, which,
which, after
after conversion
conversion toto
a a dinitrone
dinitrone andand subsequent
subsequent treatment
treatment withwith
acid, af- af-
afforded
forded
forded the
the dialdehyde
dialdehyde 98,
98, which
which cyclized
cyclized to to form
form the
the desired
desired 1H-1,2,3-triazolo[4,5-d]pyr-
1H-1,2,3-triazolo[4,5-d]pyr-
the dialdehyde 98, which cyclized to form the desired 1H-1,2,3-triazolo[4,5-d]pyridazine 99
idazine
idazine
after 99
99 after
aftertreatment
treatment treatment
with with
withhydrazine
hydrazine hydrazine
(Scheme (Scheme
(Scheme
26). 26).26).
33steps
steps
Cl
Cl N
N OO N N NHNH
2NH
2NH
2 2N N N
NN N N N N
N N
Cl
Cl N OO N N N N N
N dinitrone intermediate,
RR dinitrone intermediate, R R R R
then
then2M 2MHCl
HCl
97 98 99
97 98 99
Scheme 26. Synthesis of substituted 1,2,3-triazolo[4,5-d]pyridazines 99 from 4,5-dichloromethyltri-
Scheme 26.
Scheme 26. Synthesis
Synthesisof
ofsubstituted
substituted1,2,3-triazolo[4,5-d]pyridazines
1,2,3-triazolo[4,5-d]pyridazines 99 from
99 from 4,5-dichloromethyltri-
4,5-dichloromethyltriazoles
azoles 97, proceeding through dialdehyde 98. (R = aryl.)
azoles
97, 97, proceeding
proceeding throughthrough dialdehyde
dialdehyde 98. (R =98. (R = aryl.)
aryl.)
Reports of forming 1,2,3-triazolo[4,5-d]pyridazones or pyridazines using this method
Reports
include those ofofforming
Gilchrist1,2,3-triazolo[4,5-d]pyridazones
[64,65], Milhelcic [66], Ramesh [67], or
or pyridazines
pyridazines using
using
Theocharis [68], this
thismethod
method
Bussolari
include
include those of Gilchrist [64,65], Milhelcic [66], Ramesh [67], Theocharis
[69], Biagi [70–72], Abu-Orabi [73], Ramanaiah [74], Bankowska [75], and others [5,76–78]. [69],
those of Gilchrist [64,65], Milhelcic [66], Ramesh [67], Theocharis [68],
[68], Bussolari
Bussolari
[69], Martin
Biagi Biagi [70–72],
[70–72],and Abu-Orabi
Abu-Orabi
Castle [79][73],
used[73], Ramanaiah
Ramanaiah
ring closure by [74],
[74], Bankowska
Bankowska
nitrosonium [75],[75],
ion inand and others
others
their [5,76–78].
[5,76–78].
treatment of a
Martin
Martin and
and Castle
Castle [79]
[79] used
used ring
ring closure
closure by
by nitrosonium
nitrosonium ion
ion
4,5-diamino-6-pyridazinone 101 in forming 3,5-dihydro-4H-1,2,3-triazolo[4,5-d]pyri- in in their
their treatment
treatment of aof4,5-
a
4,5-diamino-6-pyridazinone
diamino-6-pyridazinone 101 101
in in
forming forming 3,5-dihydro-4H-1,2,3-triazolo[4,5-d]pyri-
3,5-dihydro-4H-1,2,3-triazolo[4,5-d]pyridazin-4-
dazin-4-one 102 in 91% yield (Scheme 27). Commercially available 4,5-dichloro-3(2H)-pyr-
dazin-4-one
one 102 in 100
idazinone 102
91% inconverted
91%
yield
was yieldto(Scheme
(Scheme 27). 27). steps.
101 Commercially
in three Commercially
available
Similar available
of 4,5-dichloro-3(2H)-pyr-
4,5-dichloro-3(2H)-pyridazinone
methods reacting substituted
idazinone
100 100
diaminopyridazineswas converted
was converted towith 101 nitrite to
in three 101 in
steps.
have three
been steps.
Similar Similar
methods
conducted methods
of reacting
by Yanai of reactingofsubstituted
substituted
[80] (conversion diaminopy-
103 to
diaminopyridazines
104 in Scheme
ridazines with27), with
Chen
nitrite nitrite
[81],
have beenhave
Draper been
[82], andconducted
conducted Mataka
by Yanai by
[83]. Yanai
[80] (conversion of 10316of
[80] (conversion toof103
29
104 to
in
104 in Scheme
Scheme 27),[81],
27), Chen ChenDraper
[81], Draper [82],
[82], and and Mataka
Mataka [83]. [83].
precursor
O O O
Cl 3 steps NH2 aq. H2SO4 N
HN HN HN
N
N N NaNO2, H2O N N
Cl NH2 H
100 101 102
R1 R1
NH2 NaNO2 N
N N
N
N AcOH N N
NH2
R2 R2 Ph
103 104
Scheme 27.
Scheme 27. Formation
Formation of of 3,5-dihydro-4H-1,2,3-triazolo[4,5-d]pyridaz-4-one
3,5-dihydro-4H-1,2,3-triazolo[4,5-d]pyridaz-4-one 102102
upon treatment
upon of of
treatment
4,5-diamino-6-pyridazone 101 with nitrite, and a similar reaction of diaminopyridazine 103 cycliz-
4,5-diamino-6-pyridazone 101 with nitrite, and a similar reaction of diaminopyridazine 103 cyclizing
ing to 104 with nitrite. (R1 = H, O-alkyl, SH, SCH3, OH, NH2, R2 = H, CH3, O-alkyl, OH, Cl.)
to 104 with nitrite. (R1 = H, O-alkyl, SH, SCH3 , OH, NH2 , R2 = H, CH3 , O-alkyl, OH, Cl.)
Smolyar and coworkers [84] reported a novel synthesis of a 1H-1,2,3-triazolo[4,5-

d]pyridaz-4-one, 106 by a ring-opening/ring-closing “cyclotransformation” involving
treatment of 1H-1,2,3-triazole-fused 5-nitropyridin-2(1H)-ones 105 with a large excess of
hydrazine hydrate (Scheme 28). They reported that after heating for 3–4 h, at 140 °C, the
R2 R2 Ph
103 104
Scheme 27. Formation of 3,5-dihydro-4H-1,2,3-triazolo[4,5-d]pyridaz-4-one 102 upon treatment of
Molecules 2022, 27, 4681 4,5-diamino-6-pyridazone 101 with nitrite, and a similar reaction of diaminopyridazine16103 cycliz-
of 28
ing to 104 with nitrite. (R1 = H, O-alkyl, SH, SCH3, OH, NH2, R2 = H, CH3, O-alkyl, OH, Cl.)
Smolyarand
Smolyar andcoworkers
coworkers[84][84]reported
reported a novel
a novel synthesis
synthesis of aof1H-1,2,3-triazolo[4,5-
a 1H-1,2,3-triazolo[4,5-
d]pyridaz-4-one, 106 by a ring-opening/ring-closing “cyclotransformation”
d]pyridaz-4-one, 106 by a ring-opening/ring-closing “cyclotransformation” involving involving
treatment of
treatment of 1H-1,2,3-triazole-fused
1H-1,2,3-triazole-fused5-nitropyridin-2(1H)-ones
5-nitropyridin-2(1H)-ones105 105with
witha alarge
largeexcess
excess of
hydrazine
of hydrazinehydrate
hydrate(Scheme
(Scheme28).
28).They
Theyreported
reportedthat
thatafter
after heating
heating for 3–4 h, h, at 140 ◦°C,
at 140 C, the
desired
the pyrazinone
desired pyrazinonewaswasobtained
obtainedinin86%
86%yield
yieldwith
with no
no chromatography required.5-5-Ni-
chromatography required.
Nitropyridin-2(1H)-ones fused with
tropyridin-2(1H)-ones fused with benzene
benzeneandandpyridine
pyridinewere
werealso
alsostudied in this
studied report.
in this report.
NO2 R1 CH3 R1
NH2NH2
N (20 eq.) N N
N N (via ring-opening/ring-closing)
HN N 140 °C, 3-5 h HN N
O O
105 106
Scheme
Scheme28. 28.Cyclotransformation
Cyclotransformation ofof
1,2,3-triazole-fused
1,2,3-triazole-fused lactams to 1,5-dihydro-1,7-dimethyl-1,5-
105105
lactams to 1,5-dihydro-1,7-dimethyl-1,5-
4H-1,2,3-triazolo[4,5-d]pyridazin-4-ones106
4H-1,2,3-triazolo[4,5-d]pyridazin-4-ones 106in in
thethe presence
presence of excess
of excess hydrazine
hydrazine hydrate
hydrate and high
and high
heat. (R = methyl, ethyl, butyl, cyclohexyl, and (CH )
heat. (R1 = methyl, ethyl, butyl, cyclohexyl, and (CH2 )3 NMe2 .)
1 2 3 NMe 2.)
AA number
numberof of methods
methodsexist
existfor
forthe
thepreparation
preparationof
ofmolecules
moleculescontaining
containingthe
the1,2,3-
1,2,3-tri-
triazolo[4,5-d]pyridazine core, the majority of which involve the treatment of 1,2,3-triazole
azolo[4,5-d]pyridazine core, the majority of which involve the treatment of 1,2,3-triazole
dicarbonyl
dicarbonylspecies
specieswith
withhydrazine
hydrazine hydrate
hydratefollowed by by
followed acid or heat-promoted
acid or heat-promotedcyclization,
cyclization,
or the cyclization of a diaminopyridazine with nitrite.
or the cyclization of a diaminopyridazine with nitrite.
2.4. Syntheses of 1,2,3-Triazolo[1,5-b]pyridazines
2.4. Syntheses of 1,2,3-Triazolo[1,5-b]pyridazines
Despite being reported as early as 1949 by Schofield and coworkers [85] in their
studyDespite being reported
of cinnolines, as early as 1949 by Schofield
1,2,3-triazolo[1,5-b]pyridazines remainandrarecoworkers [85] in in
in the literature, their study
part
of cinnolines,
owing 1,2,3-triazolo[1,5-b]pyridazines
to few methods remain While
available for their synthesis. rare insynthesizing
the literature, in part owing
azepinones,
to fewand
Evans methods available
coworkers for their
[86] instead synthesis. While
serendipitously synthesizing
obtained azepinones, Evans and
3,6-diphenyl-1,2,3-triazolo[1,5-
coworkers [86]
b]pyridazine 108. instead
This wasserendipitously
obtained from the obtained 3,6-diphenyl-1,2,3-triazolo[1,5-b]pyri-
intramolecular cyclization of diketo-oxime
107 (Scheme
dazine
Molecules 2022, 27, x FOR PEER REVIEW 29) after
108. This wasrefluxing
obtainedinfromHCl.the
This gave up to 22%
intramolecular of a pyrazinylhydrazone
cyclization of diketo-oxime 17 of107
29
byproduct.
(Scheme 29)Aafter
similar method
refluxing inin the This
HCl. samegave
report
upused
to 22%HOAc, but this resulted in poor
of a pyrazinylhydrazone byprod-
yields
uct. A(about 15%)
similar and upintothe
method three products.
same report used HOAc, but this resulted in poor yields
(about 15%) and up to three products.
O O
NH2NH2
N
HCl, reflux, N N
N N
OH 2h
107 108
Scheme29.
Scheme 29.Formation
Formationofofaa1,2,3-triazolo[1,5-b]pyridazine
1,2,3-triazolo[1,5-b]pyridazine 108
108 after
after the
the intramolecular
intramolecular cyclization of
cyclization
oxime 107.
of oxime 107.
AAfluoroborate
fluoroboratesaltsaltwas
wasprepared
preparedbybyRiedl
Riedland
andcoworkers
coworkers [87]
[87] inin a manner
a manner similar to
similar
to that
that of of Beresand
Beres andcoworkers
coworkers[36].
[36].The
Theacyl-substituted
acyl-substitutedpyridazine,
pyridazine, 111, after treatment
111, after treat-
ment
with with p-bromophenyl
p-bromophenyl hydrazine
hydrazine hydrochloride
hydrochloride 112 112
gavegave
the the hydrazone
hydrazone 113.113. Tribro-
Tribromophe-
mophenol bromine (TBP) in DCM afforded the desired ring-closed
nol bromine (TBP) in DCM afforded the desired ring-closed product 114 in 67% product 114 in 67%yield
yield
(Scheme(Scheme 30). The
30). The initial
initial bromide
bromide saltsalt
waswas converted
converted to to thefluoroborate
the fluoroboratesaltsalt with
with 40%
40% fluoroboric acid in ACN. Ketone 111 was prepared by the same
fluoroboric acid in ACN. Ketone 111 was prepared by the same group via reaction group via reaction of of a
a commercially available 3-cyanopyridizine 109 with p-chlorophenylmagnesium bromide
commercially available 3-cyanopyridizine 109 with p-chlorophenylmagnesium bromide
110, also synthesized from commercially available p-chlorobromobenzene and Mg. This
was followed by acidic workup to afford the desired ketone. Compounds of this type were
also prepared by Vasko and coworkers [88] using a similar method, which gave a 27%
yield. A third method for the synthesis of 1,2,3-triazolo[1,5-b]pyridazines consisted of in-
tramolecular oxidative ring closure of a hydrazone derived from 111 to afford the neutral
A fluoroborate salt was prepared by Riedl and coworkers [87] in a manner similar to
that of Beres and coworkers [36]. The acyl-substituted pyridazine, 111, after treatment
with p-bromophenyl hydrazine hydrochloride 112 gave the hydrazone 113. Tribromophe-
nol bromine (TBP) in DCM afforded the desired ring-closed product 114 in 67% yield
(Scheme 30). The initial bromide salt was converted to the fluoroborate salt with 40%
Molecules 2022, 27, 4681 fluoroboric acid in ACN. Ketone 111 was prepared by the same group via reaction17of of 28
a
commercially available 3-cyanopyridizine 109 with p-chlorophenylmagnesium bromide
wasfollowed
was followedby byacidic
acidic workup
workup to afford
to afford thethe desired
desired ketone.
ketone. Compounds
Compounds of thisoftype
thiswere
type
wereprepared
also also prepared
by Vaskoby Vasko and coworkers
and coworkers [88] ausing
[88] using a similar
similar method,method, whicha gave
which gave 27%
a 27%Ayield.
yield. thirdAmethod
third method
for the for the synthesis
synthesis of 1,2,3-triazolo[1,5-b]pyridazines
of 1,2,3-triazolo[1,5-b]pyridazines consisted
consisted of in-
of intramolecular
tramolecular oxidative
oxidative ring closure
ring closure of a hydrazone
of a hydrazone derived
derived fromfrom to afford
111afford
111 to the neu-
the neutral
tral 1,2,3-triazolo[1,5-b]pyridazine
1,2,3-triazolo[1,5-b]pyridazine 115 [89].
115 [89]. Kvaskoff
Kvaskoff and and coworkers
coworkers employed
employed MnO MnO as
2 as 2an
an oxidant using a similar procedure [35,89,90], where purification by sublimation
oxidant using a similar procedure [35,89,90], where purification by sublimation afforded afforded
thedesired
the desiredproduct
product 115 (where RR11==RR2 2= =H)
115 (where H)inin71%
71%yield.
yield.
CN R2 commercially available
109 + BrMg 110 precursors
N
R1 N
112
H
N
H2N
R2
R2 R2 (i) TBP, DCM
Br
(ii) 40% HBF4, ACN N
O N N N
N EtOH N HN R1 N
R1 N reflux, 3 h R1 N BF4
Br
111 113 114
Br
(i) NH2NH2
(ii) Pb(OAc)4
R2
olecules 2022, 27, x FOR PEER REVIEW
N
N N
R1 N
115
2.5. Syntheses of 1,2,3-Triazolo[4,5-c]pyridazines
Scheme
Scheme30.30.Cyclization of of
Cyclization hydrazone
hydrazone 113, derived
113, from
derived acylpyridazine
from 111, 111,
acylpyridazine to afford the 1,2,3-tria-
to afford the 1,2,3-
More prevalent
zolo[1,5-b]pyridazinium salt 114, in
or the literature than
1,2,3-triazolo[1,5-b]pyridazine1,2,3-triazolo[1,5-b]pyridazi
115. (R1, R2 = alkyl or aryl.)
triazolo[1,5-b]pyridazinium salt 114, or 1,2,3-triazolo[1,5-b]pyridazine 115. (R , R = alkyl or aryl.)
1 2
mon are the 1,2,3-triazolo[4,5-c]pyridazines. One of the first reports o
2.5. Syntheses of 1,2,3-Triazolo[4,5-c]pyridazines
came Morefrom Gerhardt
prevalent and coworkers
in the literature [91], whereas in previous
than 1,2,3-triazolo[1,5-b]pyridazines reports
but still un-
cyclizeare
common 5-chloro-3,4-diaminopyridazine
the 1,2,3-triazolo[4,5-c]pyridazines. One of 116
the to
firstafford 7-chloro-3H-1,2,3
reports of such a com-
pound came from Gerhardt and coworkers [91], whereas in previous reports, nitrite was
idazine
used 1175-chloro-3,4-diaminopyridazine
to cyclize (Scheme 31) in 83% yield. Nitrite
116 to afford in the presence of an ac
7-chloro-3H-1,2,3-triazolo[4,5-
used for 117
c]pyridazine the(Scheme
synthesis of yield.
31) in 83% thisNitrite
heterocyclic
in the presencering
of ansystem from
acid catalyst has the r
been used for the synthesis of this heterocyclic ring system from the respective diaminopy-
pyridazines in other reports by Murakami [92], Lunt [93], Ramanaiah
ridazines in other reports by Murakami [92], Lunt [93], Ramanaiah [74], and Owen [3].
Cl Cl
NH2 NaNO2 N
N
N aq. H2SO4 N N
N NH2 N
H
116 117
Scheme 31. Cyclization of diaminopyridazine 116 to give the triazolo[4,5-c]pyridazine 117.
Scheme 31. Cyclization of diaminopyridazine 116 to give the triazolo[4,5-c]py
In a report by Pokhodylo and coworkers [94], nitrite was used i

substituted 1,2,3-triazolo[4,5-c]pyridazine despite only having one am
N116 NH2 N 117
2 4 N
H
Scheme 31. Cyclization of diaminopyridazine 116 to give the triazolo[4,5-c]pyridazine 117
116 117
Scheme In 31.
a report by Pokhodylo
Cyclization and coworkers
of diaminopyridazine [94],
116 to give thenitrite was used in the 117.
triazolo[4,5-c]pyridazine synth
Molecules 2022, 27, 4681 18 of 28
substituted 1,2,3-triazolo[4,5-c]pyridazine despite only having one amine group
(as opposed
In a reportto other cyclizations,
by Pokhodylo and which have[94],
coworkers two nitrite
aminewasgroups
usedpresent). For exa
in the synthesis
(3,4-dimethoxyphenyl)-1-phenyl-1H-1,2,3-triazol-5-amine
substituted
In a report1,2,3-triazolo[4,5-c]pyridazine
by Pokhodylo and coworkers [94], despite
nitriteonly having
was used 118
in was
one
the reacted
amine
synthesis of with
group pre
nitrite
a(as and glacial acetic acid to
opposed1,2,3-triazolo[4,5-c]pyridazine
substituted give
to other cyclizations, which the desired
haveonly
despite twohaving 3-(4-chlorophenyl)-7,8-dimeth
amineone groups
amine present). For examp
group present
[1,2,3]triazolo[4,5-c]cinnoline 119 have
in 35%
two yield
amine (Scheme
(3,4-dimethoxyphenyl)-1-phenyl-1H-1,2,3-triazol-5-amine
(as opposed to other cyclizations, which 32).was
118
groups present). Yields maywith
Forreacted
example, havesod
b
4-(3,4-dimethoxyphenyl)-1-phenyl-1H-1,2,3-triazol-5-amine
nitrite
compared and toglacial
otheracetic
nitriteacid to give the
cyclizations duedesired 118 was reacted with sodium
to the 3-(4-chlorophenyl)-7,8-dimethoxy
formation of a C-N bond directl
nitrite and glacial acetic acid to give the desired 3-(4-chlorophenyl)-7,8-dimethoxy-3H-
[1,2,3]triazolo[4,5-c]cinnoline
carbon of an aromatic ring. 119 in 35% yield (Scheme 32). Yields may have been
[1,2,3]triazolo[4,5-c]cinnoline 119 in 35% yield (Scheme 32). Yields may have been low
compared to other nitrite cyclizations due to the formation of a C-N bond directly w
compared to other nitrite cyclizations due to the formation of a C-N bond directly with
acarbon
carbon ofof an
Oanaromatic
aromatic ring.
ring. O
O O
O O
O N NaNO2, AcOH O N
N N
NN NaNO15 min
2, AcOH
N N N
H2N N
N N
N 15 min N N
H2N N
Cl Cl
118 119
Cl Cl
Scheme 32.118 119
Cyclization of aminotriazole 118 to give triazolo[4,5-c]cinnoline 119.
Scheme
Scheme 32.32. Cyclization
Cyclization of aminotriazole
of aminotriazole 118 triazolo[4,5-c]cinnoline
118 to give to give triazolo[4,5-c]cinnoline
119. 119.
Daniel and coworkers [22] formed tricyclic ylides 121 in 65% yield by oxid
Daniel and
clization of andcoworkers
the [22] formed
respective tricyclic ylides 121
ortho-substituted in 65%
amino yield by oxidative
pyridazine cycliza- 33). U
Daniel coworkers [22] formed tricyclic ylides 121 in 65%120 (Scheme
yield by oxidativ
tion of the respective ortho-substituted amino pyridazine 120 (Scheme 33). Unfortunately,
nately, compounds
clization of the containing
respective the 1,2,3-triazolo[4,5-c]pyridazine
ortho-substituted amino pyridazine 120 nucleus33).
(Scheme remain
Unf
compounds containing the 1,2,3-triazolo[4,5-c]pyridazine nucleus remain rare in the litera-
the literature,
nately,
ture, and compounds and little
little is known is known
containing
of their the of
biological ortheir biological properties.
or pharmacological
1,2,3-triazolo[4,5-c]pyridazine
pharmacological propertie
nucleus remain ra
the literature, and little is known of their biological or pharmacological properties.
(i) NaH, DMF, r.t.
F3C N (ii)
(i) PhI(OAc)
NaH, DMF,2 (2
r.t.eq.) F3C N
N (ii) PhI(OAc)2 (2 eq.) F3C
F3C N N N
N N 24 h N NN
N N NH2 24 h N N
N
N NH2 N
120 121
120 121
Scheme
Scheme 33.33. Cyclization
Cyclization of aminotriazole
of aminotriazole 120 into 1,2,3-triazolo[4,5-c]pyridazinium
120 into 1,2,3-triazolo[4,5-c]pyridazinium ylide 1
ylide 121.
Scheme 33. Cyclization of aminotriazole 120 into 1,2,3-triazolo[4,5-c]pyridazinium ylide 121.
3. Applications
Recent applications of the aforementioned heterocyclic systems, covering both medici-
nal and non-medicinal topics, are discussed in the following section.
3.1. Applications of 1H-1,2,3-Triazolo[4,5-b]pyrazines

In the last decade, 1H-1,2,3-triazolo[4,5-b]pyrazines have garnered an interest within
the field of medicinal chemistry for serving as the scaffold of selective c-Met inhibitors.
Medicinal studies of 1H-1,2,3-triazolo[4,5-b]pyrazines have extended well into the patent
literature, with one patent even exploring antiviral efficacy against SARS-CoV-2 [95]. The
first notable report of physiological activity came from Cui and coworkers [2], who reported
the discovery of PF-04217903, a 1,2,3-triazolo[4,5-b]pyrazine that demonstrated potent
(IC50 = 0.005 µM) and selective inhibition of over 200 c-Met kinases [2]. This heterocyclic
scaffold in general gave rise to derivatives (altering substituents at the 2 and 6 ring positions)
with potent inhibition, of which PF-04217903 was the best. This compound was selected as
a preclinical candidate for the treatment of cancer [96].
tent (IC50 = 0.005 µM) and selective inhibition of over 200 c-Met kinases [2]. This heterocy-
clic scaffold in general gave rise to derivatives (altering substituents at the 2 and 6 ring
positions) with potent inhibition, of which PF-04217903 was the best. This compound was
selected
Molecules 2022, 27, 4681 as a preclinical candidate for the treatment of cancer [96]. 19 of 28
Later, using PF-04217903 as a reference, Jia, and coworkers [1] reported the discovery
of a compound now known as Savolitinib (Figure 3). This compound, also an exquisite c-
Met inhibitor with an Later, usingIC
equal PF-04217903
50 of 0.005 asµM,
a reference, Jia, and coworkers
demonstrated [1] reported
favorable the discovery
pharmacokinetic
of a compound now known as Savolitinib (Figure 3). This compound, also an exquisite
properties in mice [1]. Savolitinib possessed equal potency. Having recently passed phase
c-Met inhibitor with an equal IC50 of 0.005 µM, demonstrated favorable pharmacokinetic
II clinical trials for the treatment
properties in mice [1].of metastatic
Savolitinib non-small
possessed cell lung
equal potency. cancer,
Having papillary
recently and
passed phase
clear cell renal cell carcinoma, gastric cancer, and colorectal cancer, Savolitinib has been
II clinical trials for the treatment of metastatic non-small cell lung cancer, papillary and
granted conditional clearapproval
cell renal cell
forcarcinoma, gastricat
use in China cancer, and colorectal
the time cancer, Savolitinib
of this review has been
[97]. A review of
granted conditional approval for use in China at the time of this review [97]. A review of
c-Met inhibitors in non-small
c-Met inhibitors cell lung cancer
in non-small has
cell lung recently
cancer appeared
has recently [98].
appeared [98].
N
N N
N N
N N N
N N N
HO N N
N N N N
PF-04217903 Savolitinib
c-Met Ki = 0.004 µM c-Met cell IC50 = 0.005 µM

c-Met cell IC50 = 0.005 µM
Figure 3. Two potent and3.selective
Figure Two potentc-Met inhibitors
and selective c-Metcontaining the 1,2,3-triazolo[4,5-b]pyrazine
inhibitors containing the 1,2,3-triazolo[4,5-b]pyrazine core:
core:
PF-04217903 and Savolitinib.
PF-04217903 and Savolitinib.
Sirbu and coworkers [20] recently reported a novel class of small molecules contain-
Sirbu and coworkers [20] recently reported
ing the 1,2,3-triazolo[4,5-b]pyrazine a novel
scaffold with class of small
excellent molecules
properties for use as contain-
versatile
ing the 1,2,3-triazolo[4,5-b]pyrazine scaffold
fluorescent probes in optical with
imaging excellent
(Figure properties
4). Specifically, for use
a phenyl asderivative
ester versatile
fluorescent probes wasinused to dye
optical HeLa cells
imaging in epifluorescence
(Figure microscopy.
4). Specifically, a phenylCompared to commercially
ester derivative was
available LysoTracker Green DND-26, the tested triazolopyrazine derivative demonstrated
used to dye HeLacomparable
cells in epifluorescence microscopy. Compared to commercially availa-
properties. In addition, it showed low cytotoxicity when evaluated in Alamar
Molecules 2022,ble
27, xLysoTracker Green
FOR PEER REVIEW
Blue assayDND-26, the tested
(>95% cell viability triazolopyrazine
up to 170 µM) and showed highderivative demonstrated
solubility with a variety of
comparable properties.
desirableIn addition, itAshowed
characteristics. low
phenyl ester cytotoxicity
derivative, when evaluated
when evaluated as a dye inin Alamar
HeLa cells,
showed high photostability and low cytotoxicity [20].
Blue assay (>95% cell viability up to 170 µM) and showed high solubility with a variety of
desirable characteristics. A phenyl ester derivative, when evaluated as a dye O in HeLa cells,
showed high photostability and low cytotoxicity [20].
O
Ar
N N N N
N N
N N N N
Substructure >95% cell viability up to 170 µM,

high photostability, low cytotoxicity
Figure
Figure 4.novel
4. A A novelclassclass of molecule
of small small molecule fluorescent
fluorescent probes
probes developed bydeveloped by Sirbu[20]
Sirbu and coworkers and cowo
for use in optical and/or cellular imaging.
for use in optical and/or cellular imaging.
Intriguingly, another application lay in the monitoring of hypoxic regions w

mor cells. This was explored by Janczy-Cempa and coworkers [23], who looke
fluorescent products produced after reduction of nitrotriazolopyrazine probes by
ductases (enzymes often overexpressed in tumor regions). Both probes studied (
Substructure >95% cell viability up to 170 µM,
high photostability, low cytotoxicity
Figure 4. A novel class of small molecule fluorescent probes developed by Sirbu and coworkers [20]
Molecules 2022, 27, 4681 for use in optical and/or cellular imaging. 20 of 28
Intriguingly, another application lay in the monitoring of hypoxic regions within tu-
Intriguingly,
mor cells. This wasanother
explored application lay in the and
by Janczy-Cempa monitoring
coworkersof hypoxic regions
[23], who lookedwithin
at the
tumor cells.
fluorescent This was
products exploredafter
produced by Janczy-Cempa and coworkers [23], who
reduction of nitrotriazolopyrazine looked
probes by at the
nitrore-
fluorescent products produced after reduction of nitrotriazolopyrazine probes
ductases (enzymes often overexpressed in tumor regions). Both probes studied (Figure 5) by nitrore-
ductases
had (enzymes
very weak often overexpressed
fluorescence in normoxicinregions,
tumor regions).
but theirBoth probes studied
reduction (Figure 5)
by nitroreductases
had very weak fluorescence in normoxic regions, but their reduction by nitroreductases
led to a 15-fold increase in intensity in hypoxic regions. This was evaluated using the hu-
led to a 15-fold increase in intensity in hypoxic regions. This was evaluated using the
man melanoma cell line A2058. In contrast to the fluorescence probes developed by Sirbu
human melanoma cell line A2058. In contrast to the fluorescence probes developed by
and coworkers [20], probes in this study had substitutions on the pyrazine ring as opposed
Sirbu and coworkers [20], probes in this study had substitutions on the pyrazine ring as
toopposed
the triazole-fused pyrazole. While additional work is still to be done, this report demon-
to the triazole-fused pyrazole. While additional work is still to be done, this
strates
report demonstratesfor
the potential thethese highly
potential forconjugated
these highly compounds
conjugatedto be useful in
compounds to bebiomedical
useful
monitoring.
in biomedical monitoring. Legentil and coworkers [99] obtained compounds similaron
Legentil and coworkers [99] obtained compounds similar to the structure
the
toright in Figureon
the structure 5 in
theyields
rightas inhigh
Figureas 79%, whichas
5 in yields were
highused to develop
as 79%, which awere
luminescence
used to
layered
develop double-hydroxide filter. This
a luminescence layered material was dispersed
double-hydroxide into
filter. This a polymer
material for use as a
was dispersed
dye.
into a polymer for use as a dye.
O2N
O2N
HO2C
N N N N
N N
N N N
N N N N N N
Probes exhibiting fluorescence Demonstrated photoluminescence

following nitroreductase reduction properties
Figure
Figure 5. Compounds
5. Compounds containing
containing 1,2,3-triazolo[4,5-b]pyrazines
1,2,3-triazolo[4,5-b]pyrazines based on the nitro-pyra-
based on the nitro-pyrazinotriazapentalene
zinotriazapentalene
scaffold [20]. scaffold [20].
Overall,applications
Overall, applicationsofof compounds
compounds containing
containing1,2,3-triazolo[4,5-b]pyrazines
1,2,3-triazolo[4,5-b]pyrazinesinin thethe
currentliterature
current literatureare
arefocused
focusedon onc-Met
c-Metinhibition
inhibition(i.e.,
(i.e.,the
thetreatment
treatmentofofdistinct
distinct types
types of
of cancers),
cancers), andand optical
optical and/or
and/or cellularimaging,
cellular imaging, with
with triazapentalene-type
triazapentalene-typemolecules
molecules
demonstratinga awide
demonstrating widerange
rangeofof favorable
favorable characteristics
characteristicsasasfluorescent
fluorescentprobes.
probes.
3.2. Applications of 1H-1,2,3-Triazolo[4,5-c]pyridazines
3.2. Applications of 1H-1,2,3-triazolo[4,5-c]pyridazines
After being initially evaluated by Gerhardt and coworkers [91] as potential purine
After being
antagonists, initially evaluated by Gerhardthave
1H-1,2,3-triazolo[4,5-c]pyridazines andsince
coworkers [91] as potential
found broader purine
interest within
antagonists, 1H-1,2,3-triazolo[4,5-c]pyridazines
medicinal chemistry. In a report by Owen and have since found
coworkers [3], abroader interest within
1H-1,2,3-triazolo[4,5-
medicinal chemistry. In a report by Owen and coworkers [3], a 1H-1,2,3-triazolo[4,5-c]pyr-
c]pyridazine was found to have GABAA modulating activity during a structure–activity
idazine was found
relationship studytoofhave GABAA modulating
the respective activity during
imidazolopyridazine. a structure–activity
Compounds containing therela-
tionship study of the respectivescaffold
1,2,3-triazolo[4,5-c]pyridazine imidazolopyridazine. Compounds
have been investigated containing
in the patent the 1,2,3-
literature for
triazolo[4,5-c]pyridazine scaffolddisease
the treatment of Huntington’s have been
[100] investigated in the of
and as modulators patent literature
Janus-family for the
kinase-
related diseases [101].
Other recent patents have been filed regarding fused pyridazines with herbicidal
activity, of which 1,2,3-triazolo[4,5-c]pyridazine is included [102]. In another recent patent,
compounds of this type were implicated in controlling unwanted plant growth [103].
Reports of compounds containing the 1,2,3-triazolo[4,5-c]pyridazine scaffold are
uncommon in the current literature beyond synthetic reports and patents. Undoubt-
edly, there is still work to be done in exploring the potential applications of this unique
heterocyclic system.
Other recent patents have been filed regarding fused pyridazines with herbicidal ac-
tivity, of which 1,2,3-triazolo[4,5-c]pyridazine is included [102]. In another recent patent,
compounds of this type were implicated in controlling unwanted plant growth [103].
Reports of compounds containing the 1,2,3-triazolo[4,5-c]pyridazine scaffold are un-
common in the current literature beyond synthetic reports and patents. Undoubtedly,
Molecules 2022, 27, 4681 there is still work to be done in exploring the potential applications of this unique hetero-
21 of 28
cyclic system.
3.3.
3.3. Applications
Applications ofof 1H-1,2,3-triazolo[4,5-d]pyridazines
1H-1,2,3-Triazolo[4,5-d]pyridazines
In
In a recent development, Li,Li,
a recent development, andand coworkers
coworkers [4] outlined
[4] outlined a series
a series of triazole-based
of triazole-based struc-
structures
tures for the construction of conjugated polymers for solar cells. In additionIn
for the construction of conjugated polymers for solar cells. addition to
to demonstrat-
demonstrating desirableasproperties
ing desirable properties as units incorporated
units incorporated into polymers into polymers
(Figure (Figure
6), their 6), their
reported syn-
reported
thetic routesynthetic route uses
uses affordable, affordable, available
commercially commercially available
starting starting
materials materialsunits
and produces and
produces
compatible units
withcompatible with other
other monomers. monomers.
Structures Structures
containing containing 1,2,3-triazolo[4,5-
1,2,3-triazolo[4,5-d]pyridazine
d]pyridazine
components offercomponents offer aconjugated
a privileged, privileged,unit
conjugated
for the unit for the construction
construction of polymersofowing
poly-
mers
in partowing
to theinconvenient
part to the convenient para substitution
para substitution of the pyridazine
of the pyridazine ring and perpen-
ring and perpendicular N2
dicular N2 substitution of the
substitution of the triazole ring. triazole ring.
Sn
S
S
Br
S
S S
Sn
C4H9 N S TAZ-based polymer
N
C6H13 N
N N Pd2(dba)3, CHCl3, N
N
P(o-tol)3 N
N N
S o-xylene, MW
Br S
(m-TAZ)
n
Figure 6. Structures containing the 1,2,3-triazolo[4,5-d]pyridazine-based monomer, m-TAZ, used to

Figure 6. Structures containing the 1,2,3-triazolo[4,5-d]pyridazine-based monomer, m-TAZ, used to
construct highly conjugated TAZ-based polymers.
construct highly conjugated TAZ-based polymers.
Another notableoutcome
Another notable outcomeofofthethe study
study of 1,2,3-triazolo[4,5-d]pyridazines
of 1,2,3-triazolo[4,5-d]pyridazines was from
was that that
from
Biagi Biagi and coworkers
and coworkers [104],[104], who reported
who reported compounds
compounds of thisoftype
this with
type high
with selectivity
high selectiv-
for
ity for the A 1 receptor subtype in radioligand binding assays at bovine brain adenosine A1
the A1 receptor subtype in radioligand binding assays at bovine brain adenosine A1 and
and
A A2A receptors. The most potent compound contained a 4-amino-substituted 7-hy-
2A receptors. The most potent compound contained a 4-amino-substituted 7-hydroxy-
droxy-1,2,3-triazolo[4,5-d]pyridazine,
1,2,3-triazolo[4,5-d]pyridazine, and after and after substitution
substitution of the hydroxyl
of the hydroxyl group forgroup for a
a chlorine,
chlorine, affinity decreased and suggested a hydrogen-bond donating substituent
affinity decreased and suggested a hydrogen-bond donating substituent at position 7 was at po-
sition
critical7for
wasbinding
criticalaffinity.
for binding affinity.
3.4. Applications of 1,2,3-Triazolo[1,5-a]pyrazines
Among applications
applicationsofofcompounds
compoundscontaining thethe
containing 1,2,3-triazolo[1,5-a]pyrazine
1,2,3-triazolo[1,5-a]pyrazineunitunit
are
those
are of benzo-fused
those 1,2,3-triazoloquinoxalines
of benzo-fused and saturated
1,2,3-triazoloquinoxalines 1,2,3-triazole-fused
and saturated piperidines.
1,2,3-triazole-fused pi-
In a recent In
peridines. report by Pérez
a recent Morales
report by and coworkers
Pérez Morales[105],
anda coworkers
1,2,3-triazoloquinoxalinone
[105], a 1,2,3-
(Structure A, Figure 7) was identified via high-throughput screening as inducing expres-
sion of Rgg2/3-regulated genes in the presence of short hydrophobic pheromones at low
concentrations. This work stemmed from interest in the Rgg2/3 quorum sensing circuit of
the pathogen Streptococcus pyogenes, with the objective of manipulating and inhibiting the
bacteria. After analyzing its mode of action, it was determined this compound directly un-
competitively inhibited recombinant PepO in vitro, and induced quorum sensing signaling
by stabilizing short hydrophobic pheromones.
triazoloquinoxalinone (Structure A, Figure 7) was identified via high-throughput screen-
ing as inducing expression of Rgg2/3-regulated genes in the presence of short hydropho-
bic pheromones at low concentrations. This work stemmed from interest in the Rgg2/3
quorum sensing circuit of the pathogen Streptococcus pyogenes, with the objective of ma-
nipulating and inhibiting the bacteria. After analyzing its mode of action, it was deter-
Molecules 2022, 27, 4681 22 of 28
mined this compound directly uncompetitively inhibited recombinant PepO in vitro, and
induced quorum sensing signaling by stabilizing short hydrophobic pheromones.
A B
F
O F
N N H NH2 O
N CF3
N
N
O N
F N N
F3C N O
H
• HO C CO2H
2
P516-0475
Inducer of Rgg2/3-related genes of Potent DPP-IV inhibitor,

Streptococcus pyogenes IC50 = 50.66 nM
C NH2
F N
N
N N
N
NH
N
O
BACE-1 inhibitor,
pIC50 = 8.70 (IC50 = 0.002 µM)
Figure7.7.Compounds
Figure Compounds containing
containing congeners
congeners of 1,2,3-triazolo[1,5-a]pyrazine
of the the 1,2,3-triazolo[1,5-a]pyrazine corea with
core with a diverse
diverse set
set of biological activities: (A) an inducer of Rgg2/3-related genes of the human pathogen
of biological activities: (A) an inducer of Rgg2/3-related genes of the human pathogen Streptococcus Streptococ-
cus pyogenes
pyogenes [105],[105], (B) a potent
(B) a potent DPP-IV DPP-IV inhibitor
inhibitor evaluated
evaluated for the for the treatment
treatment ofdiabetes
of type II type II diabetes
[7], and [7],
and (C), an identified BACE-1 inhibitor
(C), an identified BACE-1 inhibitor [6]. [6].
Basedononthe
Based theantidiabetic
antidiabetic 1,2,4-triazolopiperazine-containing
1,2,4-triazolopiperazine-containing drug
drug Sitagliptin
Sitagliptin (brand
(brand
nameJanuvia),
name Januvia), Shan
Shan andand coworkers
coworkers [7] identified
[7] identified a dipeptidyl
a dipeptidyl peptidase
peptidase (DPP)(DPP) IV inhib-
IV inhibitor
containing a 1,2,3-triazolopiperazine
itor containing a 1,2,3-triazolopiperazine (Structure B, Figure
(Structure 7) for7)use
B, Figure for in
usethe
in treatment
the treatmentof of
type II diabetes.
type II diabetes.
Partially
Partiallysaturated
saturated1,2,3-triazolo[1,5-a]pyrazines
1,2,3-triazolo[1,5-a]pyrazineshave havedemonstrated
demonstratedBACE-1BACE-1inhi-inhibi-
bition,
tion, anan enzyme
enzyme implicated
implicated in in the
theformation
formationofofamyloid
amyloidbeta in in
beta Alzheimer’s
Alzheimer’s disease.
disease.
Oehlrich
Oehlrichand andcoworkers
coworkers [6] [6]
identified one one
identified suchsuch
candidate, (R)-N-(3-(4-amino-6-methyl-6,7-
candidate, (R)-N-(3-(4-amino-6-methyl-
dihydro-[1,2,3]triazolo[1,5-a]pyrazin-6-yl)-4-fluorophenyl)-5-cyanopicolinamide,
6,7-dihydro-[1,2,3]triazolo[1,5-a]pyrazin-6-yl)-4-fluorophenyl)-5-cyanopicolinamide, (Structure
C,(Structure
Figure 7).C,
This demonstrated an inhibition of the BACE-1 enzyme
Figure 7). This demonstrated an inhibition of the BACE-1 enzyme of pIC 50 = 8.70.of pIC50 =
These reports, while not exhaustive, demonstrate recent applications of compounds
8.70.
containing the 1,2,3-triazolo[1,5-a]pyrazine scaffold or congeners thereof. Particularly
These reports, while not exhaustive, demonstrate recent applications of compounds
prominent in the literature are benzo-fused and piperazine-containing analogs.
containing the 1,2,3-triazolo[1,5-a]pyrazine scaffold or congeners thereof. Particularly
prominent
3.5. in the
Applications literature are benzo-fused and piperazine-containing analogs.
of 1,2,3-Triazolo[1,5-b]pyridazines
There are no reported applications of compounds containing the 1,2,3-triazolo[1,5-
b]pyridazine ring system, and little regarding its physiological and/or pharmacological
effects are known. Aside from one recent patent [106] regarding immunoregulatory func-
tions, additional applications remain scarce at the time of this review.
Molecules 2022, 27, 4681 23 of 28
4. Conclusions
In reviewing synthetic approaches to and reported applications of members of the 1,2,3-
triazolodiazine family of fused bicyclic heterocycles, the following conclusions can be drawn
regarding the most common synthetic methods and applications in the present literature:
(a) 1,2,3-Triazolo[4,5-b]pyrazines: The most common synthetic method is cyclization of
an ortho-substituted diaminopyrazine [2], in which one of the amines does not need
to be primary [18,25]. Given the current commercial availability and affordability of 2-
amino-3,5-dibromopyrazine, this serves as a convenient starting material. Other meth-
ods include condensation of a dicarbonyl species with a 4,5-diamino-1,2,3-triazole [16],
cyclization of a 2-azido-3-cyanoquinoxaline [17], or formation of azapentalenes from
tetrazolopyrazines [19] or pyrazolopyrazines [21] with loss of nitrogen. Primary Appli-
cations: Primarily c-Met inhibition [1,2,25,96] and use as fluorescent probes in optical
and/or cellular imaging [20,23,99].
(b) 1,2,3-Triazolo[1,5-a]pyrazines: For non-fused derivatives, the most common meth-
ods are: intramolecular cyclization of pyrazinyl hydrazones [36,42], formation of
1,2,3-triazolo[1,5-a]pyrazinium-5-olates from cyano and amide groups [37,40], or
reaction of iodopropiolamides to form triazolopiperazine [43]. For benzo-fused
derivatives (i.e., those containing quinoxaline or quinoxalinone), the most common
methods are: cyclization of a ring-bound 1,2,3-triazole with an ortho-substituted
amine [52] or nitro [45] group (if a nitro group, either PBu3 to give a quinoxaline [45]
or FeCl3 [48] to give a quinoxalinone), cyclization of 1-azido-2-isocyanoarenes or
1-triazolyl-2-isocyanoarenes [54,55], or intramolecular cyclization of alkynes [53,57].
Primary Applications: Primarily GABAA modulating activity [3], and patents detailing
use as Janus-family kinase modulators [101] or for the treatment of Huntington’s
disease [100]. There also exist recent patents describing use as herbicides [102] and plant
growth attenuators [103].
(c) 1,2,3-Triazolo[4,5-d]pyridazines: The most common synthetic method is reaction of a 4,5-
dicarbonyl-1,2,3-triazole species with hydrazine to form the hydrazone, followed
by acid or heat promoted cyclization [5,64–70,73–78,104]. The second most common
method is treatment of the respective diaminopyridazine with nitrite [80–83]. Ring-
opening/ring-closing of lactams has also been reported [84]. Primary Applications: Use
as highly conjugated linkers in triazole-based polymers [4] for the evaluation of solar
cell materials is the main reported application.
(d) 1,2,3-Triazolo[1,5-b]pyridazines: The most common synthetic method is treatment of
a keto-substituted pyridazine with p-bromophenyl hydrazine hydrochloride forming
the hydrazone, then treatment with TBP in DCM [87,88]. A report of intramolecular
cyclization of a diketo-oxime has been reported [86]. Primary Applications: Benzo-fused
or saturated piperazine-containing analogs are common. Notable reports include
identification of a 1,2,3-triazole-fused quinoxalinone as inducing Rgg2/3-related
gene expression in the human pathogen Streptococcus pyrogenes, as a potent DPP IV
inhibitor [7], and as a BACE-1 inhibitor [6].
(e) 1,2,3-Triazolo[4,5-c]pyridazines: The most common method is cyclization of the re-
spective diaminopyridazine with nitrite [3,74,91–93]. The intramolecular cyclization
to form a pyridazine [94] or a tricyclic ylide have also been reported [22]. Primary
Applications: Outside of a patent [106] detailing immunoregulatory functions, no other
applications exist in the literature at the time of this review.
The potential for new synthetic contributions is considerable for the triazole-fused
pyrazines and pyridazines. Given the diversity of synthetic methods summarized in this
review, new contributions that could be most beneficial are new routes to some of the
precursors of the fused systems. In many of the reports cited, the starting materials are
either not available commercially or are very expensive. For example, some diamino
pyrazines are available as unsubstituted compounds or as halogenated derivatives, but all
are USD 500–1000 per gram. Future studies of methods employing additional intramolec-
ular cycloadditions leading to 1,2,3-triazolo[1,5-a]pyrazine derivatives would appear to
Molecules 2022, 27, 4681 24 of 28
have potential. Work on synthesis of the 1H-1,2,3-triazolo[4,5-c]pyridazines and the 1,2,3-

triazolo[1,5-b]pyridazines would be welcome for these less frequently studied areas.
Overall, diverse methods exist for the preparation of 1,2,3-triazole-fused diazines,
spanning the last seven decades with numerous reports in the last five years. Currently,
drugs containing these ring systems remain scarce with only a handful of exceptions, par-
ticularly containing either the 1,2,3-triazolo[4,5-b]pyrazine or 1,2,3-triazolo[4,5-c]pyridazine
scaffold. Applications of the aforementioned types of compounds span from medicinal
chemistry into the development of dyes, probes, and inhibitors of enzymes implicated in
various diseases. Despite this, there lies underrealized and exciting potential for employing
triazolopyrazines and triazolopyridazines as diverse substrates in the generation of novel
molecules with a wide array of applications.
Author Contributions: Conceptualization: G.R.H., A.M.S. (these authors contributed equally);

writing—original draft preparation: G.R.H.; preparation of graphics: G.R.H.; validation: A.M.S.;
writing—review and editing: G.R.H., A.M.S. (these authors contributed equally). All authors have
read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Acknowledgments: G.R.H. would like to acknowledge his grandparents, Bob and Shirley Hoffman,
for their support and encouragement throughout the research and writing process.
Conflicts of Interest: The authors declare no conflict of interest.
Sample Availability: Samples of compounds are not available from the authors.
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Review molecules

Syntheses and Applications of 1,2,3-Triazole-Fused Pyrazines

Gavin R. Hoffman and Allen M. Schoffstall *

Molecules 2022, 27, 4681. https://doi.org/10.3390/molecules27154681 https://www.mdpi.com/journal/molecules

c-Met inhibitory activity GABAA allosteric Incorporated into polymers

Molecules 2022, 27, 4681 3 of 28

Molecules 2022, 27, 4681 4 of 28

Isoamyl nitrite, DMF

Scheme 8. Intramolecular cyclization of a 4-bromophenylhydrazone 39 forming triazolopyrazinium

Methods have been reported for the the preparation

Similarly involving reaction of triazolium olates such as 42, during a synthesis of

Similarly involving reaction of triazolium olates such as 42, during a synthesis of

Molecules 2022, 27, 4681 9 of 28

2.2.2. Syntheses of Benzo-Fused 1,2,3-Triazolo[1,5-a]pyrazines

Abbott and coworkers [51] prepared 1,2,3-triazoloquinoxalines in an analogous m

Abbott and coworkers [51] prepared 1,2,3-triazoloquinoxalines in an analogous man

(ii) pyridine, Ac2O

commercially available precursors

F3C I 10 mol% CuI,

75 F3C 10 mol% CuI, 76

2.3. Syntheses of 1H-1,2,3-Triazolo[4,5-d]pyridazines

100 101 102

Smolyar and coworkers [84] reported a novel synthesis of a 1H-1,2,3-triazolo[4,5-

In a report by Pokhodylo and coworkers [94], nitrite was used i

3.1. Applications of 1H-1,2,3-Triazolo[4,5-b]pyrazines

c-Met Ki = 0.004 µM c-Met cell IC50 = 0.005 µM

Substructure >95% cell viability up to 170 µM,

Intriguingly, another application lay in the monitoring of hypoxic regions w

Probes exhibiting fluorescence Demonstrated photoluminescence

Figure 6. Structures containing the 1,2,3-triazolo[4,5-d]pyridazine-based monomer, m-TAZ, used to

Inducer of Rgg2/3-related genes of Potent DPP-IV inhibitor,

have potential. Work on synthesis of the 1H-1,2,3-triazolo[4,5-c]pyridazines and the 1,2,3-

Author Contributions: Conceptualization: G.R.H., A.M.S. (these authors contributed equally);

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