Synthesis of diverse nitrogen-enriched heterocyclic scaffolds using a suite of tunable one-pot multicomponent reactions

Article abstract of DOI:10.1021/jo500723d

Five elegant and switchable three-component reactions which enable access to a new series of nitrogen-containing heterocycles are reported. A novel one-step addition of an isocyanide to a hydrazine derived Schiff base affords unique six-membered pyridotriazine scaffolds (A and E). With slight modification of reaction conditions and replacement of the nucleophilic isocyanide moiety with different electrophiles (i.e., isocyanates, isothiocyanates, cyclic anhydrides, and acyl chlorides) five-membered triazolopyridine scaffolds (B, D, F, G) are generated in a single step. Furthermore, the use of phenyl hydrazine enables access to dihydroindazole-carboxamides, devoid of a bridge-head nitrogen (C). All protocols are robust and tolerate a diverse collection of reactants, and as such, it is expected that the new scaffolds and associated chemistry will garner high interest from medicinal chemists involved in either file enhancement or specific target-related drug discovery campaigns.

Full text of DOI:10.1021/jo500723d

Article
pubs.acs.org/joc
Synthesis of Diverse Nitrogen-Enriched Heterocyclic Scaffolds Using
a Suite of Tunable One-Pot Multicomponent Reactions
Guillermo Martinez-Ariza,† Muhammad Ayaz,† Federico Medda,† and Christopher Hulme*,†,‡
†Department of Pharmacology and Toxicology, College of Pharmacy BIO5 Oro Valley, The University of Arizona, 1580 East Hanley
Boulevard, Oro Valley, Arizona 85737, United States
‡Department of Chemistry and Biochemistry, The University of Arizona, Tucson, Arizona 85721, United States
S
* Supporting Information
ABSTRACT: Five elegant and switchable three-component reactions which enable
access to a new series of nitrogen-containing heterocycles are reported. A novel one-
step addition of an isocyanide to a hydrazine derived Schiff base affords unique six-
membered pyridotriazine scaffolds (A and E). With slight modification of reaction
conditions and replacement of the nucleophilic isocyanide moiety with different
electrophiles (i.e., isocyanates, isothiocyanates, cyclic anhydrides, and acyl chlorides)
five-membered triazolopyridine scaffolds (B, D, F, G) are generated in a single step.
Furthermore, the use of phenyl hydrazine enables access to dihydroindazole-
carboxamides, devoid of a bridge-head nitrogen (C). All protocols are robust and
tolerate a diverse collection of reactants, and as such, it is expected that the new
scaffolds and associated chemistry will garner high interest from medicinal chemists
involved in either file enhancement or specific target-related drug discovery
campaigns.
Indeed, such efforts have produced numerous active ligands,
exemplified by inhibitors of the cyclin-dependent kinase family
(CDK),11 modulators of G-protein coupled receptors impli-
cated in Parkinson’s disease,12 and inhibitors of glycogen
synthase kinase 3β (GSK3β) for oncology indications.13
Thus, given our ongoing interest in utilizing MCRs for the
efficient production of medicinally relevant scaffolds,14 it was
envisioned that use of 2-hydrazinopyridines 5 would feasibly
lead to fused 6,6-bicyclic pyrido[2,1-c][1,2,4]triazines 6
(Scheme 2) with enhanced fsp3 character over GBB-derived
scaffolds that possess a relatively planar architechture.15
Although similar reactions have been performed with p-
methoxyphenyl hydrazine16 and 2-piconilic amine,17 to the
best of our knowledge the use of 2-hydrazinoazines in this
INTRODUCTION
■
Pyridotriazines are an important class of fused heterobicyclics
with biological activity observed in antifungals,1 anthelmintics,2
antibacterials,3 5-hydroxytryptamine α-receptor antagonists,4
hypotensives,5 gastric acid secretase inhibitors6 and kinase
inhibitors for cell proliferative disorders.7 However, reported
syntheses of pyrido-triazine scaffolds usually require lengthy
multistep efforts that hinder structure activity−relationship
studies.8 To circumvent this and initially access the unique
pyrido[2,1-c][1,2,4]triazine scaffold 6, inspiration was derived
́
from the Groebke−Blackburn−Bienayme three-component
reaction (GBB-3CR),10 a highly versatile example of an
isocyanide based multicomponent reaction (IMCR).9 Discov-
ered in 1998, the typical GBB-3CR assembles an isocyanide 1,
aldehyde 2, and α-amino-nitrogen containing heterocycle 3 via
a [4 + 1] cycloaddition reaction to afford bicyclic 3-amino-
imidazo-heterocycles with a bridge-head nitrogen 4 (Scheme
1).
Scheme 2. Synthesis of Pyridotriazines 6 and
Triazolopyridines 9
As such, libraries derived from this methodology have
inherent high skeletal diversity due to the plethora of α-amino-
heterocycles compatible with the transformation, producing
bicyclic rigid congeners where fine-tuning of preferable “lead”
or “drug-like” physicochemical properties is readily achieved.
Scheme 1. Groebke−Blackburn−Bienayme Reaction
́
Received: March 28, 2014
© XXXX American Chemical Society
A
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context is unprecedented, affording a unique chemotype with a
built-in H-bond donor−acceptor war-head that can be readily
applied to engage target families that utilize nucleotide-based
substrates or secondary messengers to elicit their biological
function.18 Replacement of the isonitrile 1 with electrophiles 7
(R4NCY, YO or S) was postulated as a potential new route
to enticing molecules with generic structure 8 via [5 + 2]-
cycloaddition. However, intriguingly triazolopyridines of
generic structure 9 were produced in a one-pot fashion
(Scheme 2).
of reagents, a library of congeners of generic structure 6 was
generated (Scheme 4, Figure 1). Encouragingly, products were
Scheme 4. Substrate Scope for Bicyclic Triazines 6
RESULTS AND DISCUSSION
Proof of concept studies for the synthesis of pyridotriazines 6a
were conducted with a model reaction (Scheme 3) screening a
■
obtained in good to excellent isolated yields with both aliphatic
aldehydes and ketones being well-tolerated, the latter
generating spirocyclic products 6g (90%) and 6h (54%). Of
note, the tricyclic product 6n was also accessible from the
corresponding benzothiazolo-hydrazine (39% yield). However,
aromatic aldehydes performed poorly under the model
conditions and attempts to facilitate reaction through heating
to 140 °C proved fruitless (6o, 6p). The only observed product
through reaction monitoring via LC/MS was the Schiff base.
Gratifyingly, however, both the use of an aqueous solution of
formaldehyde (6f, 60% yield) and replacement of a classical
isocyanide with TMSCN20 (6l, 42% yield; 6m, 55% yield)
proved successful.
Scheme 3. Pyridotriazine 6a Model Reaction
The reaction mechanism is likely to involve a nonconcerted
[5 + 1]-cycloaddition between isocyanides 1 and the
corresponding Schiff base I to endow bicyclic product 6
(Scheme 5). Importantly, there are only a few reports involving
such a process with isocyanides21a,b and none involve a 2-
hydrazinopyridine moiety. Of note is that unlike a typical GBB-
3CR product, the resultant chemotype 6c (as confirmed by X-
ray analysis, Figure S1, Supporting Information)19 does not
undergo imine−enamine tautomerization, presumably due to
the stability of the nonaromatic imine form (6, Scheme 5)
compared to the antiaromatic enamine form (6′, Scheme 5).
The successful development of a [5 + 1]-cycloaddition
process to synthesize bicyclic-triazines 6 prompted us to pursue
an analogous [5 + 2]-cycloaddition21c using isocyanates 7, with
the goal of producing novel seven-membered dihydropyrido-
tetrazepinones 8 (Scheme 2). However, while exploring this
transformation we serendipitously discovered a new highly
efficient one-pot strategy to produce novel arrays of
triazolopyridines 9 (Scheme 8, Figure 2), the strategy being
in fact enticingly compatible with a variety of electrophilic
reagents in one-pot fashion [Note: structure of 9c was
confirmed by X-ray diffraction, Figure S3, Supporting
Information].19 Interestingly, triazolopyridines are known to
display a variety of biological activities including antifungal,22
inhibition of 11β-hydroxysteroid dehydrogenase type 1 (11β-
HSD-1) as a potential treatment of type 2 diabetes,23 and
inhibition of phosphoinositide 3-kinase γ (PI3Kγ) for the
prospective treatment of inflammatory diseases.24a,b Consider-
ing these and possibly undiscovered potential applications,
optimal reaction conditions to access scaffold 9 were thus
investigated via a “one-pot” model reaction (Scheme 6, Table
2). [Note: no preformation of Schiff base is necessary, and
reagents may be added simultaneously]. The transformation
was found to be favored in nonpolar solvents such as DCE and
toluene (Table 2, entries 1, 3, 5−7), whereas in polar and/or
protic solvents such as TFE and THF, product yields were
diminished (Table 2, entries 2 and 4).
Table 1. Solvent and Catalyst Screening for the Preparation
of Pyridotriazine 6a
a
entry
solvent
MeOH
catalyst (20 mol %)
yield [%]
1
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
AcOH
46
51
56
5
2
DCM
3
DCM/MeOH (3:1)
DCM/MeOH (3:1)
DCM/MeOH (3:1)
DCM/MeOH (3:1)
DCM/MeOH (3:1)
DCM/MeOH (3:1)
DCM/MeOH (3:1)
DCM/MeOH (3:1)
DCM/MeOH (3:1)
DCM/MeOH (3:1)
DCM/MeOH (3:1)
4
5
TsOH
25
23
4
6
HClO4
ZnCl2
7
8
Pd(OAc)2
CuI
0
9
0
10
11
CaCl2
18
36
71
39
ZrCl4
b
12
c
Sc(OTf)3
Sc(OTf)3
13
a
Reactions were carried out on a 0.25 mmol scale at rt for 20 h.
Reported % yields are “Area under the Curve” of desired product (A
b
%) as judged by LC/MS at UV 254 nm. 1.3 equiv (5a) employed.
c
1.3 equiv (5a) employed and reaction irradiated with microwaves at
50 °C for 1 h.
variety of reaction conditions and catalysts (Table 1). Scandium
triflate in dichloromethane/methanol (3:1) accompanied by a
slight excess of the hydrazinoazine 5a (entry 12) proved
optimal, furnishing 6a in 71% yield as judged by LC/MS at UV
254 nm. Brønsted acid catalysis proved unsatisfactory under the
given reaction conditions (Table 1, entries 4−6), including
perchloric acid often cited as the catalyst of choice for the GBB-
3-component reaction.10a An additional attempt to accelerate
the reaction via microwave irradiation witnessed a significant
drop in product formation (Table 1, entry 13).
With the optimized reaction conditions in hand, the substrate
scope of the transformation was explored. Thus, using five
isocyanides, one isocyanide equivalent (TMSCN), eight
aldehydes, four ketones, and four hydrazinoazines as a pool
B
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Figure 1. Synthesis of pyrido-, pyrimido-, and benzothiazolo-triazines via a novel one-pot 3-CR. Successful conversion with TMSCN required
microwave irradiation (100 °C, 30 min).
isothiocyanate afforded triazolopyridine thioureas 9g−9i albeit
in moderate yields, requiring elevated temperatures and 5 equiv
of isothiocyanate (Figure 2). Highly noteworthy was the
successful use of tosyl-isocyanate affording 9j containing an ‘N-
acyl-sulfonamide-like’ bioisostere of a carboxylic acid.24c
Tricyclic scaffolds were also accessible as exemplified by 9f
(47%). Importantly, 9c was synthesized on a larger scale (6.5
mmol of hydrazine−azine) with an acceptable isolated yield
(61%).
Scheme 5. Proposed Mechanism for Pyridotriazine
Formation
A highly plausible mechanism for the transformation involves
initial condensation of 2-hydrazinopyridine 5 and aldehyde 2 to
produce imine I followed by intramolecular cyclization25 to
afford intermediate III which in turn undergoes an amidation
reaction with 7 (Schemes 7 and 8).
Remarkably, the protocol was also amenable to the simple
hydrazine 10, resulting in the one-pot formation of the novel
dihydroindazole-carboxamides 11a−d (Scheme 9) with good
overall isolated yields (Figure 3).
As expected, the use of desiccants slightly improved overall
yields, probably attributable to a promotion of Schiff base
formation and extension of the isocyanate half-life through
removal of water. Optimal conditions proved to include
calcium chloride in dichloroethane (DCE), while irradiating
at 80 °C for 20 min (Table 2, entry 5, 77%). The reaction
scope was subsequently studied, employing three aldehydes and
ketones, six hydrazinoazines, and six isocyanates and iso-
thiocyanates, to generate products 9a−9j (Figure 2). In similar
fashion to prior trends with the pyridotriazine scaffold 6,
aromatic aldehydes were found to be incompatible (9k, 9l)
whereas aliphatic aldehydes and ketones worked efficiently to
furnish final products in isolated yields ranging from 36% to
91% (Figure 2). Replacing the isocyanate input with an
Encouraged by these results, we further investigated the
compatibility of the one-pot reaction with other electrophiles.
On replacement of an isocyanate with bromomaleic anhydride,
the reaction proceeded smoothly and exclusively yielded the E-
alkene isomer 14a at room temperature (Scheme 10). A
possible explanation for the high observed stereoselectivity is
the hydrogen-bonding interaction between the proton of the
carboxylic acid and the carbonyl of the amide moiety that
confers stability, as observed by the X-ray structure of 14a
(Figure S5, Supporting Information).19 Similarly, the use of
C
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Figure 2. Exemplification of reaction scope. For 9a−9f: 1 equiv of isocyanate was used with microwave irradiation at 80 °C for 20 min. For 9g−9i: 5
equiv of isothiocyanate were used with microwave irradiation at 120 °C for 60 min. For 9j: 1 equiv of tosyl isocyanate was used at room temperature
with stirring for 30 min.
Scheme 6. Triazolopyridine-carboxamide 9b Model Reaction with Isocyanate 7a
Table 2. Optimization of Reaction Conditions for the
Synthesis of Triazolopyridines, 9
Scheme 8. Generic Reaction for Triazolo-carboxamide and
Carbothiamide Synthesis
a
entry
solvent
desiccant
yield [%]
1
2
3
4
5
6
7
DCE
TFE
−
−
−
−
65
13
54
38
77
68
66
toluene
THF
DCE
DCE
DCE
Scheme 9. Synthesis of Indazole-carboxamides
CaCl2
MgSO4
5 Å M.S.
a
All reactions were carried out on a 0.25 mmol scale, irradiating with
microwaves at 80 °C. Reported % yields are “Area under the Curve” of
desired product (A%) as judged by LC/MS at UV 254 nm.
Scheme 7. Proposed Mechanism of Triazolopyridines Synthesis
D
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Figure 4. Small library of triazolopyridine-carboxylic acids, 14a−14d.
Figure 3. Collection of indazole carboxamides, 11a−11d.
Scheme 11. Model Reaction of 2-Hydrazino-pyridine 5b,
Aldehyde 2b, and Acyl Chloride 15a
phthalic anhydride as an electrophilic input rendered
triazolopyridine-carboxylic acids 14c−d (Figure 4) in good
yields wherein the carboxylic acid moiety may be utilized for
further diversification of the product.
Subsequently, the one-pot procedure involving condensation
of benzoyl chloride 15a with propanaldehyde 2b and 2-
hydrazino-5-nitro-pyridine 5b was studied under different
reaction conditions (Scheme 11). Surprisingly, use of base as
an additive resulted in complex mixtures and the desired
product was not observed by LC/MS (Table 3, entries 3−5).
However, employing DCE as the solvent and microwave
irradiation at 120 °C for 30 min proved highly satisfactory for
the desired one-pot transformation (Table 3, entry 10). In this
case, the use of calcium chloride as a desiccant did not improve
yields (Table 3, entry 12).
Using these optimized reaction conditions, the scope of the
transformation was further explored. Thus, employing three
aldehydes, two hydrazino-pyridines, and six acyl chlorides (both
aromatic and aliphatic), a small collection of compounds (16a−
f) was prepared in moderate yields (Scheme 12, Figure 5).
Table 3. Reaction Optimization for the Preparation of Acyl-
triazolopyridine 16a
a
entry
solvent
temp (°C)
time (min)
additive
yield [%]
1
DCE
DCE
DCE
DCE
DCE
DCE
THF
dioxane
toluene
DCE
DCE
DCE
rt, 30
30
15
15
15
15
30
30
30
30
30
30
30
−
−
nr
25
nd
nd
nd
46
21
26
5
2
MW, 80
MW, 80
MW, 80
MW, 80
MW, 100
MW, 100
MW, 100
MW, 100
MW, 120
MW, 140
MW, 120
3
DIPEA
4
DBU
5
Na2CO3
6
−
−
−
−
−
−
CaCl2
7
8
9
10
11
12
56
49
51
CONCLUSIONS
■
a
All reactions were carried out at 0.25 mmol scale. nr = no reaction, nd
= not determined (complex mixture). Reported % yields are “Area
under the Curve” of desired product (A%) as judged by LC/MS at UV
254 nm.
In conclusion, a plethora of robust “one-pot” multicomponent
synthetic strategies have been developed delivering novel
scaffolds and representative sets with high skeletal diversity,
namely pyridotriazines 6, triazolopyridines 9, 14, and 16, and
dihydroindazoles 11. Interestingly, a diverse set of triazolopyr-
idines were generated employing various electrophiles (iso-
cyanates, tosyl-isocyanates, isothiocyanates, cyclic anhydrides,
and acyl chlorides) representative of a suite of “one-pot” three-
component reactions where all reagents may be optimally
added to the reaction mixture at the same time. The protocols
are simple and straightforward and accommodate an assort-
ment of miscellaneous reaction inputs delivering products with
high atom economy. The majority of the starting materials are
Scheme 10. Multicomponent Reaction of 2-Hydrazino-pyridine, Aldehydes, and Cyclic Anhydrides 12 and 13
E
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purified by flash chromatography (0−60% AcOEt/Hexane) to afford
title compounds, 6a−6n. For compounds 6i−k and 6m flash
chromatography was performed using a more polar system (0−20%
MeOH/DCM).
Scheme 12. Synthesis of Acyl-triazolopyridines 16
(E)-N-(3-Butyl-9-chloro-2H-pyrido[2,1-c][1,2,4]triazin-4(3H)-
ylidene)-2,6-dimethylaniline (6a). Yellow solid, 61 mg, 71% yield;
mp 136−138 °C; Rf = 0.57 (silica gel, 20% AcOEt/Hexane); 1H NMR
(400 MHz, CDCl3) δ ppm 8.17 (d, J = 7.5 Hz, 1H), 7.03 (d, J = 7.4
Hz, 2H), 6.92 (t, J = 7.5 Hz, 1H), 6.73 (d, J = 6.7 Hz, 1H), 5.79 (t, J =
7.2 Hz, 1H), 5.61 (s, 1H), 3.49 (dd, J = 10.7, 2.8 Hz, 1H), 2.10 (d, J =
10.7 Hz, 6H), 1.61−1.50 (m, 1H), 1.26 (s, 2H), 1.06−1.04 (m, 3H),
0.73 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ ppm 148.4,
144.1, 138.0, 128.3, 128.0, 127.9, 127.0, 126.4, 125.9, 123.4, 110.0,
104.6, 48.7, 26.8, 25.6, 21.8, 18.2, 18.0, 13.6; [M + H]+ = 343; HRMS
(ESI) m/z calculated for C19H24ClN4 [M + H]+ = 343.16840; found
343.16852.
(E)-N-(3-Butyl-7-(trifluoromethyl)-2H-pyrido[2,1-c][1,2,4]-
triazin-4(3H)-ylidene)cyclohexanamine (6b). Yellow oil, 33 mg,
1
37% yield; Rf = 0.14 (silica gel, 20% AcOEt/Hexane); H NMR (400
MHz, CDCl3) δ ppm 8.36 (s, 1H), 6.47 (d, J = 9.9 Hz, 1H), 6.38 (d, J
= 9.9 Hz, 1H), 5.30 (s, 1H), 4.11 (dd, J = 9.7, 3.8 Hz, 1H), 3.35 (t, J =
9.6 Hz, 1H), 1.86−1.25 (m, 16H), 0.93 (t, J = 6.5 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 147.0, 140.2, 128.5, 125.2, 123.3, 122.5, 122.3,
108.9, 56.6, 47.7, 34.3, 33.6, 29.7, 27.5, 25.5, 24.4 (d, JC−F = 13.1 Hz),
22.3, 13.9; [M + H]+ = 355; HRMS (ESI) m/z calculated for
C18H26F3N4 [M + H]+ = 355.21041; found 355.21055.
Figure 5. Small library of acyl-triazolopyridines 16a−16f.
(E)-N-(9-Chloro-3-cyclopentyl-2H-pyrido[2,1-c][1,2,4]triazin-
4(3H)-ylidene)-4-methoxyaniline (6c). Orange solid, 46 mg, 52%
yield; mp 154−155 °C, Rf = 0.12 (silica gel, 20% AcOEt/Hexane); 1H
NMR (400 MHz, CDCl3) δ 8.06 (d, J = 7.6 Hz, 1H), 6.91−6.82 (m,
2H), 6.78 (d, J = 8.8 Hz, 2H), 6.73−6.67 (m, 1H), 5.74 (m, 1H), 3.96
(d, J = 10.2 Hz, 1H), 3.81 (s, 3H), 1.93−1.79 (m, 1H), 1.68−1.65 (m,
2H), 1.48−1.37 (m, 6H), 1.12−1.07 (m, 1H); 13C NMR (100 MHz,
CDCl3) δ 155.9, 151.3, 148.5, 147.0, 140.3, 138.2, 136.9, 127.0, 125.5,
121.7, 114.4, 104.3, 55.4, 52.4, 37.5, 29.5, 25.6, 24.9, 24.1; [M + H]+ =
357; HRMS (ESI) m/z calculated for C19H22ClN4O [M + H]+ =
357.14767; found 357.14771. Crystals for X-ray analysis were obtained
by recrystallization using a mixture of Hexane/AcOEt (4:1).19
(E)-N-(9-Chloro-3-cyclopentyl-2H-pyrido[2,1-c][1,2,4]triazin-
4(3H)-ylidene)-2,6-dimethylaniline (6d). Yellow solid, 76 mg, 85%
yield; mp 147−148 °C; Rf = 0.42 (silica gel, 20% AcOEt/Hexane); 1H
NMR (400 MHz, CDCl3) δ 8.13 (d, J = 6.6 Hz, 1H), 7.02 (d, J = 7.5
Hz, 2H), 6.97−6.86 (m, 1H), 6.74 (d, J = 6.7 Hz, 1H), 5.83−5.69 (m,
2H), 3.31 (d, J = 9.7 Hz, 1H), 2.15 (d, J = 15.6 Hz, 6H), 2.04 (d, J =
7.1 Hz, 1H), 1.85−1.69 (m, 1H), 1.49−1.37 (m, 5H), 1.10 (dd, J =
12.1, 8.5 Hz, 1H), 0.65 (s, 1H); 13C NMR (100 MHz, CDCl3) δ
143.8, 138.1, 129.5, 128.2, 127.9, 127.5, 126.7, 126.4, 125.6, 123.5,
104.4, 37.4, 29.7, 28.0, 25.0, 24.2, 18.7, 18.3, 18.2; [M + H]+ = 355;
HRMS (ESI) m/z calculated for C20H24ClN4 [M + H]+ = 355.16840;
found 355.16846.
commercially available or can be prepared by well-known one-
to two-step protocols.26 The procedural simplicity, skeletal
diversity, and high exploratory power associated with the
chemistry presented herein render them suitable for high-
throughput production of small molecules. Indeed, studies on
the biological activity of these compounds against targets of
interest are currently ongoing in our laboratory and results will
be published in due course.
EXPERIMENTAL SECTION
■
General. All reagents and solvents were acquired from
commercially available suppliers and used without further purification,
unless specified. The products were purified using an automated flash
chromatography apparatus. Low resolution mass spectra were obtained
using positive ESI methods in a mass spectrometer. High resolution
mass spectra were obtained using positive ESI methods for all
compounds, except for 14b−d for which negative ionization ESI
methods were used and spectra were obtained with a Ion Cyclotron
Resonance (ICR) spectrometer. 1H and 13C NMR spectra were
obtained at 400 and 100 MHz, respectively. The data are reported as
follows: chemical shift in ppm (δ), multiplicity (s = singlet, d =
doublet, t = triplet, m = multiplet). Coupling constants are reported in
hertz (Hz) and were automatically generated using known NMR
analyzer software. Melting points were obtained with open glass
capillaries and are uncorrected. All microwave irradiation experiments
were carried out in a Biotage Initiator, operating at a frequency of 2.45
GHz with continuous irradiation power from 0 to 300 W with
utilization of the standard absorbance level of 220 W maximum power
using an external sensor of temperature. The reactions were either
carried out in 5 mL microwave vials sealed with a Teflon septum
through heating in the microwave cavity or stirring at room
temperature. The scaled synthesis of 9c was conducted in a 20 mL
microwave vial.
(E)-N-(3-Isopropyl-9-(trifluoromethyl)-2H-pyrido[2,1-c]-
[1,2,4]triazin-4(3H)-ylidene)-1-phenylmethanamine (6e). Or-
ange solid, 43 mg, 49% yield; mp 171−172 °C; Rf = 0.33 (silica gel,
1
20% AcOEt/Hexanes); H NMR (400 MHz, CDCl3) δ 8.20 (d, J =
7.6 Hz, 1H), 7.35−7.26 (m, 6H), 6.94 (d, J = 6.5 Hz, 1H), 5.74−5.70
(m, 1H), 4.63 (dd, J = 38.2, 15.6 Hz, 2H), 3.84 (dd, J = 9.8, 1.7 Hz,
1H), 1.98 (ddt, J = 13.5, 9.8, 6.8 Hz, 1H), 1.06 (d, J = 6.6 Hz, 3H),
0.89 (d, J = 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 148.9, 139.3,
132.1, 129.2, 129.1, 128.5, 127.2, 126.9, 102.4, 53.0, 52.2, 25.5, 19.3,
18.6; [M + H]+ = 349; HRMS (ESI) m/z calculated for C18H20F3N4
[M + H]+ = 349.16346; found 349.16379.
(E)-N-(9-Chloro-2H-pyrido[2,1-c][1,2,4]triazin-4(3H)-ylidene)-
2,6-dimethylaniline (6f). Brown solid, 43 mg, 60% yield; mp 109−
G e n e r a l P r o c e d u r e f o r t h e S y n t h e s i s o f
Pyrido/Pyrimido/Benzothiazolo-triazines 6a−6n. The corre-
sponding 2-hydrazinyl-azine (1.3 equiv, 0.325 mmol), isocyanide
(1.0 equiv, 0.25 mmol), aldehyde or ketone (1.0 equiv, 0.25 mmol),
and scandium triflate (0.2 equiv, 0.05 mmol) were dissolved in a
mixture of DCM/MeOH (3:1, 1 mL) and stirred at room temperature
for 20 h. After reaction completion (monitored by TLC and LC/MS),
the solvent was evaporated in vacuo, and the crude product was
1
111 °C; Rf = 0.39 (silica gel, 20% AcOEt/Hexane); H NMR (400
MHz, CDCl3) δ 8.20 (d, J = 7.6 Hz, 1H), 7.00 (t, J = 19.2 Hz, 3H),
6.96−6.88 (m, 1H), 6.76 (dd, J = 6.8, 1.2 Hz, 1H), 5.80 (dd, J = 7.6,
6.8 Hz, 1H), 3.34 (s, 2H), 2.06 (s, 6H); 13C NMR (100 MHz, CDCl3)
δ 144.7, 143.4, 136.8, 135.4, 128.4, 127.9, 125.1, 123.9, 114.7, 114.1,
110.0, 29.7, 18.0; [M + H]+ = 287; HRMS (ESI) m/z calculated for
C15H16ClN4 [M + H]+ = 287.10580; found 287.10572.
F
dx.doi.org/10.1021/jo500723d | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(E)-N-(9′-Chlorospiro[cyclohexane-1,3′-pyrido[2,1-c][1,2,4]-
triazin]-4′(2′H)-ylidene)-2,6-dimethylaniline (6g). Yellow solid,
80 mg, 90% yield; mp 185−187 °C; Rf = 0.71 (silica gel, 10% AcOEt/
m/z calculated for C10H16N5 [M + H]+ = 206.13274; found
206.13271.
(E)-N-(3-Ethyl-2H-benzo[4,5]thiazolo[2,3-c][1,2,4]triazin-
4(3H)-ylidene)-2,6-dimethylaniline (6n). Beige solid, 33 mg, 39%
yield; mp 135−136 °C; Rf = 0.30 (silica gel, 20% AcOEt/Hexane); 1H
NMR (400 MHz, CDCl3) δ 8.89−8.70 (m, 1H), 7.33 (dd, J = 7.7, 1.4
Hz, 1H), 7.28−7.19 (m, 1H), 7.19−7.12 (m, 1H), 7.06 (d, J = 7.5 Hz,
2H), 6.95 (d, J = 7.5 Hz, 1H), 3.42 (dd, J = 10.8, 3.7 Hz, 1H), 2.16 (d,
J = 6.5 Hz, 6H), 1.70 (ddd, J = 13.9, 10.8, 7.2 Hz, 1H), 1.26 (br s, 1H),
1.10 (ddd, J = 13.8, 7.4, 3.8 Hz, 1H), 0.78 (t, J = 7.4 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 150.8, 144.6, 143.6, 137.9, 128.3, 128.2,
128.1, 126.6, 126.0, 124.6, 123.9, 123.4, 121.7, 117.4, 51.7, 20.3, 18.7,
18.4, 9.8; [M + H]+ = 337; HRMS (ESI) m/z calculated for
C19H21N4S [M + H]+ = 337.14814; found 337.14847.
1
Hexane); H NMR (400 MHz, CDCl3) δ 7.00 (d, J = 7.5 Hz, 2H),
6.88 (d, J = 7.3 Hz, 1H), 6.86 (s, 1H), 6.55 (d, J = 6.7 Hz, 1H), 5.65
(s, 1H), 5.36 (t, J = 7.1 Hz, 1H), 2.09 (s, 6H), 1.81−1.44 (m, 10H);
13C NMR (100 MHz, CDCl3) δ 144.3, 128.2, 128.1, 126.0, 125.8,
125.5, 122.8, 103.6, 103.5, 52.7, 29.9, 25.5, 21.8, 18.5, 18.4; [M + H]+
= 355; HRMS (ESI) m/z calculated for C20H24ClN4 [M + H]+
=
355.16840; found 355.16846.
N-[(4″E)-9″-Chloro-dispiro[1,3-dioxolane-2,1′-cyclohexane-
4′,3″-pyrido[2,1-c][1,2,4]triazin]-4′(2H)-ylidene]-2,6-dimethyl-
aniline (6h). Yellow solid, 56 mg, 54% yield; mp 194−196 °C; Rf =
0.42 (silica gel, 10% AcOEt/Hexane); 1H NMR (400 MHz, CDCl3) δ
7.01 (d, J = 7.5 Hz, 2H), 6.89 (t, J = 7.5 Hz, 1H), 6.63 (s, 1H), 6.54 (d,
J = 6.7 Hz, 1H), 5.55 (s, 1H), 5.37−5.28 (m, 1H), 3.96 (s, 4H), 2.10
(s, 6H), 2.09−2.02 (m, 2H), 1.94 (s, 2H), 1.81−1.66 (m, 4H); 13C
NMR (100 MHz, CDCl3) δ 144.1, 143.3, 135.7, 128.1, 127.9, 126.0,
125.4, 123.2, 110.0, 108.1, 103.5, 64.4, 64.4, 51.7, 31.1, 29.7, 28.1, 18.5,
18.4; [M + H]+ = 413; HRMS (ESI) m/z calcd for C22H26ClN4O2 [M
+ H]+ = 413.17443; found 413.17428
General Procedure for the Synthesis of Triazolo Azines
Carboxamides 9a−9f. To a stirring solution of 2-hydrazinyl-azine
(1.0 equiv, 0.25 mmol) dissolved in DCE (1 mL) were added the
aldehyde or ketone (1.0 equiv, 0.25 mmol) and the isocyanate (1.0
equiv, 0.25 mmol), followed by the addition of calcium chloride (0.1
equiv). The reaction was heated via microwave irradiation for 20 min
at 80 °C. Upon reaction completion (monitored by LC/MS and
TLC), the solvent was evaporated in vacuo and the crude product was
separated with an automated flash chromatography system (using a
gradient of 0−30% AcOEt/Hexane) to obtain title compounds, 9a−9f.
Procedure for the Synthesis of Triazolo-azine Carboxamide
9c (Scaled Version). To a stirring solution of 2-hydrazinyl-5-
nitropyridine (1.0 equiv, 6.5 mmol, 1.0 g) dissolved in DCE (15 mL)
were added cyclopentantecarboxaldehyde (1.0 equiv, 6.5 mmol, 0.693
mL) and 4-fluorophenyl isocyanate (1.0 equiv, 6.5 mmol, 0.738 mL).
The reaction was heated via microwave irradiation for 20 min at 80 °C.
Upon reaction completion (monitored by LC/MS and TLC), the
solvent was evaporated in vacuo and the crude product was separated
with an automated flash chromatography system (using a gradient of
0−30% AcOEt/Hexane) to obtain compound 9c (61% yield, 1.47 g).
8-Chloro-3-cyclopentyl-N-(4-fluorophenyl)-[1,2,4]triazolo-
[4,3-a]pyridine-2(3H)-carboxamide (9a). Orange solid, 82 mg,
91% yield; mp 157−159 °C; Rf = 0.24 (silica gel, 25% AcOEt/
Hexane); 1H NMR (400 MHz, CDCl3) δ 7.94 (s, 1H), 7.55−7.35 (m,
2H), 7.05−6.96 (m, 4H), 6.39 (d, J = 4.4 Hz, 1H), 5.81 (t, J = 6.9 Hz,
1H), 2.48−2.35 (m, 1H), 1.78−1.47 (m, 8H); 13C NMR (100 MHz,
CDCl3) δ 159.9, 157.5, 154.3, 148.5, 134.4, 133.9, 129.3, 120.9, 117.1,
115.5, 115.3, 104.2, 79.6, 47.0, 27.4, 26.4, 25.4, 24.8; [M + H]+ = 361;
(E)-N-(3-(2-(Methylthio)ethyl)-2H-pyrimido[2,1-c][1,2,4]-
triazin-4(3H)-ylidene)naphthalen-2-amine (6i). Orange oil, 31
1
mg, 35% yield; Rf = 0.43 (silica gel, 10% MeOH/DCM); H NMR
(400 MHz, CDCl3) δ 8.80 (dd, J = 4.4, 2.2 Hz, 1H), 8.45−8.29 (m,
3H), 7.83−7.69 (m, 4H), 7.44 (dd, J = 6.2, 3.2 Hz, 2H), 7.04 (dd, J =
6.5, 4.4 Hz, 1H), 4.71 (dd, J = 10.1, 5.3 Hz, 1H), 2.66−2.50 (m, 2H),
2.07 (dd, J = 13.5, 7.2 Hz, 1H), 2.00 (s, 3H), 1.56 (ddd, J = 14.1, 8.4,
4.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 163.5, 161.7, 158.6,
152.7, 148.2, 133.6, 133.3, 132.0, 129.1, 128.5, 127.8, 126.9, 126.6,
121.3, 113.8, 113.1, 50.9, 29.3, 15.5; [M + H]+ = 350; HRMS (ESI)
m/z calculated for C19H20N5S [M + H]+ = 350.14339; found
350.14371.
(E)-N-(3,3-Dimethyl-2H-pyrimido[2,1-c][1,2,4]triazin-4(3H)-
ylidene)-1-phenylmethanamine (6j). Yellow oil, 40 mg, 59% yield;
Rf = 0.21 (silica gel, 10% MeOH/DCM); 1H NMR (400 MHz,
CDCl3) δ 8.81 (dd, J = 4.4, 2.1 Hz, 1H), 8.38 (dd, J = 6.6, 2.2 Hz, 1H),
7.49−6.98 (m, 7H), 4.84 (s, 2H), 1.39 (s, 6H); 13C NMR (100 MHz,
CDCl3) δ 168.1, 162.8, 152.6, 146.3, 135.7, 128.8, 128.5, 128.0, 113.1,
51.9, 46.1, 21.6; [M + H]+ = 268; HRMS (ESI) m/z calculated for
C15H18N5 [M + H]+ = 268.15567; found 268.15590.
(E)-2,6-Dimethyl-N-(3-methyl-3-pentyl-2H-pyrimido[2,1-c]-
HRMS (ESI) m/z calculated for C18H19ClFN4O [M + H]+
=
[1,2,4]triazin-4(3H)-ylidene)aniline (6k). Orange solid, 73 mg, 87%
361.12259; found 361.12258.
1
yield; mp 118−120 °C; Rf = 0.32 (silica gel, 10% MeOH/DCM); H
3-Butyl-6-nitro-N-phenyl-[1,2,4]triazolo[4,3-a]pyridine-
NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.23 (d, J = 6.4 Hz, 1H),
7.84 (s, 1H), 7.11 (d, J = 7.5 Hz, 1H), 7.05 (d, J = 7.1 Hz, 2H), 6.98−
6.92 (m, 1H), 2.23 (d, J = 30.3 Hz, 6H), 1.68 (s, 3H), 1.47−1.36 (m,
2H), 1.25 (dd, J = 11.0, 4.7 Hz, 6H), 0.85 (t, J = 6.9 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 166.0, 162.6, 157.7, 155.1, 152.6, 152.6,
146.5, 138.9, 128.4, 121.7, 118.5, 55.1, 35.0, 31.6, 22.4, 22.3, 19.0, 13.8;
[M + H]+ = 338; HRMS (ESI) m/z calculated for C20H28N5 [M + H]+
= 338.23392; found 338.23388.
2(3H)-carboxamide (9b). Brown solid, 63 mg, 74% yield; mp 149−
1
151 °C; Rf = 0.51 (silica gel, 25% AcOEt/Hexane); H NMR (400
MHz, CDCl3) δ 8.23 (d, J = 2.0 Hz, 1H), 7.76 (d, J = 23.5 Hz, 1H),
7.58−7.52 (m, 1H), 7.47 (dd, J = 11.5, 3.8 Hz, 2H), 7.32 (d, J = 7.5
Hz, 2H), 7.06 (td, J = 7.5, 1.0 Hz, 1H), 6.34 (dd, J = 7.8, 4.3 Hz, 1H),
2.27 (m, 1H), 2.01−1.88 (m, 1H), 1.54−1.19 (m, 5H), 0.92 (t, J = 7.2
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 151.5, 145.5, 137.9, 134.0,
134.0, 131.0, 129.0, 128.9, 123.4, 119.1, 111.3, 34.7, 23.9, 22.2, 13.9;
[M + H]+ = 342; HRMS (ESI) m/z calculated for C17H20N5O3 [M +
H]+ = 342.15607; found 342.15616.
3-Cyclopentyl-N-(4-fluorophenyl)-6-nitro-[1,2,4]triazolo[4,3-
a]pyridine-2(3H)-carboxamide (9c). Orange solid, 81 mg, 87%
yield; mp 154−155 °C; Rf = 0.48 (silica gel, 25% AcOEt/Hexane); 1H
NMR (400 MHz, CDCl3) δ 8.32 (d, J = 2.1 Hz, 1H), 7.76 (s, 1H),
7.59 (dd, J = 10.3, 2.1 Hz, 1H), 7.47−7.37 (m, 2H), 7.06−6.96 (m,
2H), 6.39 (dd, J = 7.3, 5.5 Hz, 2H), 2.52−2.39 (m, 1H), 1.72−1.59
(m, 8H); 13C NMR (100 MHz, CDCl3) δ 160.1, 157.7, 153.2, 146.7,
134.3, 129.1, 120.9, 115.7, 115.5, 111.1, 110.0, 78.3, 47.3, 27.2, 26.1,
25.2, 24.7; [M + H]+ = 372; HRMS (ESI) m/z calculated for
C18H19FN5O3 [M + H]+ = 372.14664; found 372.14662. Crystals for
X-ray analysis were obtained from a mixture of hexane/DCM (4:1) via
slow solvent evaporation.19
3-Butyl-9-chloro-2H-pyrido[2,1-c][1,2,4]triazin-4(3H)-imine
(6l). Yellow oil, 25 mg, 42% yield; Rf = 0.63 (silica gel, 40% AcOEt/
1
Hexane); H NMR (400 MHz, CDCl3) δ 8.08 (dd, J = 4.9, 1.1 Hz,
1H), 7.56−7.42 (m, 1H), 6.72 (dd, J = 7.6, 4.9 Hz, 1H), 6.55 (s, 1H),
5.04 (s, 1H), 4.03 (t, J = 7.0 Hz, 1H), 1.92−1.79 (m, 2H), 1.64−1.50
(m, 2H), 1.42 (dd, J = 14.6, 7.4 Hz, 2H), 0.96 (t, J = 7.3 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 153.5, 145.5, 136.9, 119.9, 115.8, 115.6,
53.1, 30.7, 27.6, 22.3, 13.8; [M + H]+ = 239; HRMS (ESI) m/z
calculated for C11H16ClN4 [M + H]+ = 239.10580; found 239.10581.
3-Butyl-2H-pyrimido[2,1-c][1,2,4]triazin-4(3H)-imine (6m).
Yellow oil, 28 mg, 55% yield; Rf = 0.30 (silica gel, 10% MeOH/
DCM); 1H NMR (400 MHz, CDCl3) δ 8.43 (d, J = 4.8 Hz, 1H), 8.38
(d, J = 4.8 Hz, 1H), 7.26−7.22 (m, 1H), 7.06 (d, J = 3.9 Hz, 1H),
6.74−6.68 (m, 1H), 4.73 (t, J = 4.4 Hz, 1H), 2.47−2.36 (m, 1H),
1.87−1.80 (m, 1H), 1.62−1.49 (m, 2H), 1.45−1.37 (m, 2H), 0.95 (t, J
= 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 158.4, 146.9, 119.8,
113.1, 52.9, 30.8, 29.4, 27.7, 22.4, 13.9; [M + H]+ = 206; HRMS (ESI)
N-(3-Methoxyphenyl)-6-nitro-2H-spiro[[1,2,4]triazolo[4,3-a]-
pyridine-3,1′-cyclohexane]-2-carboxamide (9d). Brown solid, 65
mg, 68% yield; mp 183−185 °C ; Rf = 0.37 (silica gel, 25% AcOEt/
G
dx.doi.org/10.1021/jo500723d | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
1
Hexane); H NMR (400 MHz, CDCl3) δ 8.68 (d, J = 1.9 Hz, 1H),
pyridine (1.0 equiv, 0.25 mmol) in DCE (1 mL) were added the
aldehyde (1.0 equiv, 0.25 mmol) and tosyl isocyanate (1.0 equiv, 0.25
mmol), followed by the addition of calcium chloride (0.1 equiv). The
reaction was stirred at room temperature for 30 min. Upon reaction
completion (monitored by LC/MS and TLC), the solvent was
evaporated in vacuo and the crude product was purified by flash
chromatography with an automated flash chromatography system
(using a gradient of 0−60% AcOEt/Hexane) to obtain the title
compound 9j.
3-Ethyl-N-tosyl-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]-
pyridine-2(3H)-carboxamide (9j). Orange solid, 50 mg, 48% yield;
mp 136−138 °C; Rf = 0.47 (silica gel, 60% AcOEt/Hexane); 1H NMR
(400 MHz, CDCl3) δ 8.51 (br. s, 1H), 7.97 (d, J = 8.4 Hz, 2H), 7.32
(d, J = 8.2 Hz, 2H), 7.27−7.24 (m, 1H), 7.04−6.98 (m, 1H), 6.10 (t, J
= 3.4 Hz, 1H), 5.88 (t, J = 6.8 Hz, 1H), 2.42 (s, 3H), 2.17 (m, 1H),
1.83 (m, 1H), 0.85 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 147.9, 145.1, 144.7, 136.5, 135.9, 133.9, 129.6, 128.4, 122.9, 120.2,
113.4, 103.5, 76.6, 26.9, 21.8, 6.1; [M + H]+ = 415; HRMS (ESI) m/z
calculated for C17H18F3N4O3S [M + H]+ = 415.10462; found
415.10526.
General Procedure for the Synthesis of Indazole-carbox-
amides 11a−d. To a stirring solution of 4-methoxyphenylhydrazine
(1.0 equiv, 0.25 mmol) and aldehyde (1.0 equiv, 0.25 mmol) dissolved
in DCE (1 mL) was added the isocyanate (1.0 equiv, 0.25 mmol),
followed by the addition of calcium chloride (0.1 equiv), and the
reaction was heated under microwave irradiation for 20 min at 80 °C.
Upon reaction completion (monitored by LC/MS and TLC), the
solvent was evaporated in vacuo and the crude product was purified by
flash chromatography with an automated flash chromatography system
(using a gradient of 0−30% AcOEt/Hexane) to obtain the title
compounds 11a−11d.
3-Butyl-5-methoxy-N-phenyl-1H-indazole-2(3H)-carbox-
amide (11a). Orange oil, 44 mg, 54% yield; Rf = 0.45 (silica gel, 25%
AcOEt/Hexane); 1H NMR (400 MHz, CDCl3) δ 8.77 (s, 1H), 7.61−
7.49 (m, 2H), 7.35−7.26 (m, 2H), 7.14−6.98 (m, 5H), 6.61 (t, J = 5.4
Hz, 1H), 3.83 (s, 3H), 2.35−2.14 (m, 2H), 1.56−1.38 (m, 2H), 1.40−
1.26 (m, 2H), 0.93 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3)
δ 159.7, 152.9, 143.7, 143.6, 138.7, 131.0, 128.9, 128.0, 122.8, 119.0,
115.3, 55.5, 55.4, 32.2, 28.6, 22.3, 13.9; [M + H]+ = 326; HRMS (ESI)
m/z calculated for C19H24N3O2 [M + H]+ = 326.18630; found
326.18621.
7.91 (s, 1H), 7.48 (dd, J = 10.3, 2.1 Hz, 1H), 7.21−7.15 (m, 2H), 6.96
(m, 1H), 6.61 (m, 1H), 6.30 (d, J = 10.3 Hz, 1H), 3.81 (s, 3H), 3.09
(td, J = 14.1, 5.4 Hz, 2H), 2.21 (d, J = 14.7 Hz, 2H), 2.07−1.87 (m,
3H), 1.73−1.56 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 160.2,
150.2, 142.7, 139.4, 135.3, 130.4, 129.6, 128.2, 128.2, 111.4, 109.1,
104.8, 85.5, 55.3, 33.3, 23.1, 21.8; [M + H]+ = 384; HRMS (ESI) m/z
calculated for C19H22N5O4 [M + H]+ = 384.16663; found 384.16655.
3-Butyl-N-phenyl-[1,2,4]triazolo[4,3-a]pyrazine-2(3H)-
carboxamide (9e). Orange solid, 45 mg, 61% yield; mp 153−155 °C
; Rf = 0.33 (silica gel, 25% AcOEt/Hexane); 1H NMR (400
MHz,CDCl3) δ 8.01 (s, 1H), 7.75 (s, 1H), 7.48 (d, J = 8.6 Hz,
2H), 7.30 (s, 1H), 7.04 (t, J = 7.4 Hz, 1H), 6.89 (d, J = 4.7 Hz, 1H),
6.68 (d, J = 4.0 Hz, 1H), 6.30 (t, J = 3.7 Hz, 1H), 1.47−1.19 (m, 7H),
0.91 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 152.3, 143.3,
142.4, 142.4, 138.2, 129.0, 123.1, 122.1, 119.0, 34.3, 24.2, 22.3, 14.0;
[M + H]+ = 298; HRMS (ESI) m/z calculated for C16H20N5O [M +
H]+ = 298.16624; found 298.16632.
3-Isopropyl-N-phenylbenzo[4,5]thiazolo[2,3-c][1,2,4]-
triazole-2(3H)-carboxamide (9f). Brown solid, 40 mg, 47% yield;
mp 155−157 °C; Rf = 0.25 (silica gel, 20% AcOEt/Hexane); 1H NMR
(400 MHz, CDCl3) δ 11.29 (s, 1H), 8.56 (d, J = 4.7 Hz, 1H), 7.82−
7.76 (m, 2H), 7.61−7.59 (m, 1H), 7.39−7.29 (m, 5H), 7.14 (d, J = 0.7
Hz, 1H), 1.29−1.27 (m, 6H), 1.17−1.15 (m, 1H); 13C NMR (100
MHz, CDCl3) δ 169.6, 150.5, 149.9, 137.9, 132.5, 129.4, 129.2, 126.3,
124.3, 124.0, 121.3, 121.1, 120.6, 33.0, 31.6, 19.9, 19.4; [M + H]+ =
339; HRMS (ESI) m/z calculated for C18H19N4OS [M + H]+
339.12013; found 339.12019.
=
General Procedure for the Synthesis of Triazolo-azines
Carbothiamides 9g−9i. To a stirring solution of 2-hydrazinyl-
pyridine (1.0 equiv, 0.25 mmol) in DCE (1 mL) were added the
aldehyde (1.0 equiv, 0.25 mmol) and the isothiocyanate (5.0 equiv,
1.25 mmol), followed by the addition of calcium chloride (0.1 equiv).
The reaction was heated by microwave irradiation for 60 min at 120
°C. Upon reaction completion (monitored by LC/MS and TLC), the
solvent was evaporated in vacuo and the crude product was purified
with an automated flash chromatography purification system (using a
gradient of 0−30% AcOEt/Hexane) to obtain title compounds, 9g−9i.
3-Butyl-N-ethyl-6-nitro-[1,2,4]triazolo[4,3-a]pyridine-2(3H)-
carbothioamide (9g). Brown oil, 36 mg, 47% yield; Rf = 0.57 (silica
1
gel, 25% AcOEt/Hexane); H NMR (400 MHz, CDCl3) δ 8.29−8.20
(m, 1H), 7.62 (ddd, J = 10.3, 2.2, 0.8 Hz, 1H), 6.99 (s, 1H), 6.83−6.66
(m, 1H), 6.36 (d, J = 10.3 Hz, 1H), 3.74−3.60 (m, 2H), 2.71 (m, J,
1H), 1.37 (m, 4H), 1.25 (dd, J = 7.2, 0.6 Hz, 3H), 1.00−0.93 (m, 1H),
0.90 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 174.3, 146.4,
133.6, 131.2, 129.6, 111.0, 79.3, 39.3, 34.3, 23.8, 22.2, 14.5, 13.9; [M +
H]+ = 310; HRMS (ESI) m/z calculated for C13H20N5O2S [M + H]+
= 310.13322; found 310.13315.
5-Methoxy-N-(3-methoxyphenyl)-3-phenethyl-1H-indazole-
2(3H)-carboxamide (11b). Brown oil, 65 mg, 64% yield; Rf = 0.53
(silica gel, 40% AcOEt/Hexane); 1H NMR (400 MHz, CDCl3) δ 8.67
(s, 1H), 7.42 (s, 1H), 7.28 (d, J = 7.5 Hz, 2H), 7.23−7.12 (m, 4H),
7.06 (d, J = 9.0 Hz, 2H), 6.99 (d, J = 9.0 Hz, 2H), 6.92 (ddd, J = 8.0,
2.0, 0.8 Hz, 1H), 6.65 (t, J = 5.1 Hz, 1H), 6.60 (ddd, J = 8.3, 2.5, 0.9
Hz, 1H), 3.82 (s, 3H), 3.78 (s, 3H), 2.84 (t, J = 7.6 Hz, 2H), 2.68−
2.54 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 160.3, 159.9, 152.9,
142.6, 140.6, 139.9, 130.9, 129.4, 128.5, 128.3, 127.8, 126.3, 115.4,
111.1, 109.4, 104.2, 55.5, 55.2, 34.0, 32.8; [M + H]+ = 404; HRMS
(ESI) m/z calculated for C24H26N3O3 [M + H]+ = 404.19687; found
404.19776.
N-(3-Chlorophenyl)-3-ethyl-5-methoxy-1H-indazole-2(3H)-
carboxamide (11c). Beige solid, 33 mg, 40% yield; mp 146−147 °C;
Rf = 0.34 (silica gel, 20% AcOEt/Hexane); 1H NMR (400 MHz,
CDCl3) δ 8.79 (s, 1H), 7.51 (d, J = 8.9 Hz, 2H), 7.25 (d, J = 8.9 Hz,
2H), 7.16−6.90 (m, 4H), 6.65 (t, J = 5.0 Hz, 1H), 3.83 (s, 3H), 2.30
(qd, J = 7.5, 5.0 Hz, 2H), 1.09 (t, J = 7.5 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 160.0, 153.0, 144.9, 137.5, 131.1, 129.0, 127.8, 127.7,
120.3, 115.5, 55.6, 26.0, 10.8; [M + H]+ = 332; HRMS (ESI) m/z
calculated for C17H19ClN3O2 [M + H]+ = 332.11603; found
332.11637.
6-Bromo-N-ethyl-3-isopropyl-[1,2,4]triazolo[4,3-a]pyridine-
2(3H)-carbothioamide (9h). Orange solid, 30 mg, 36% yield; mp
1
122−123 °C; Rf = 0.28 (silica gel, 20% AcOEt/Hexane); H NMR
(400 MHz, CDCl3) δ 7.09−7.04 (m, 1H), 6.92 (dd, J = 9.9, 1.9 Hz,
2H), 6.53 (d, J = 2.0 Hz, 1H), 6.31 (d, J = 9.9 Hz, 1H), 3.66 (qd, J =
7.3, 5.6 Hz, 2H), 2.92−2.81 (m, 1H), 1.25 (d, J = 7.2 Hz, 3H), 1.10 (d,
J = 7.3 Hz, 3H), 0.87 (d, J = 6.9 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 174.3, 139.2, 131.1, 113.1, 96.6, 83.3, 39.3, 33.5, 29.8, 18.4,
14.8, 14.7; [M + H]+ = 329; HRMS (ESI) m/z calculated for
C12H18BrN4S [M + H]+ = 329.04299; found 329.04395.
N-(Benzo[d][1,3]dioxol-4-yl)-3-ethyl-8-(trifluoromethyl)-
[1,2,4]triazolo[4,3-a]pyridine-2(3H)-carbothioamide (9i). Or-
ange oil, 65 mg, 66% yield; Rf = 0.12 (silica gel, 20% AcOEt/
1
Hexane); H NMR (400 MHz, CDCl3) δ 8.62 (m, 1H), 7.40−7.30
(m, 1H), 7.15 (q, J = 5.4 Hz, 2H), 6.89−6.71 (m, 3H), 5.97 (s, 2H),
2.76 (qd, J = 7.4, 3.9 Hz, 1H), 2.03−1.92 (m, 1H), 1.26 (t, J = 7.1 Hz,
1H), 1.00−0.80 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 172.5,
147.4, 145.6, 136.0, 134.0, 132.5, 118.7, 107.8, 107.5, 103.7, 101.4,
79.3, 26.9, 6.1; [M + H]+ = 397; HRMS (ESI) m/z calculated for
C17H16F3N4O2S [M + H]+ = 397.09406; found 397.09461.
5-Methoxy-3-(2-(methylthio)ethyl)-N-(4-(trifluoromethoxy)-
phenyl)-1H-indazole-2(3H)-carboxamide (11d). Beige solid, 71
mg, 66% yield; mp 133−135 °C; Rf = 0.22 (silica gel, 20% AcOEt/
Hexane); 1H NMR (400 MHz, CDCl3) δ 8.86 (s, 1H), 7.59 (d, J = 9.1
Hz, 2H), 7.21−6.86 (m, 5H), 6.66 (t, J = 4.8 Hz, 1H), 3.84 (s, 3H),
2.71 (td, J = 6.7, 1.1 Hz, 2H), 2.65−2.54 (m, 2H), 2.14 (s, 3H), 1.59
(br s, 1H); 13C NMR (100 MHz, CDCl3) δ 160.1, 152.9, 144.5, 141.6,
General Procedure for the Synthesis of N-Tosyl Triazolo-
pyridine-carboxamide 9j. To a stirring solution of 2-hydrazinyl-
H
dx.doi.org/10.1021/jo500723d | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
137.6, 131.0, 127.6, 121.9, 120.1, 115.6, 55.7, 32.2, 31.3, 16.0; [M +
H]+ = 428; HRMS (ESI) m/z calculated for C19H21F3N3O3S [M +
H]+ = 428.12502; found 428.12561.
3.5 Hz, 1H), 2.22−1.93 (m, 1H), 1.02 (t, J = 7.4 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 165.6, 146.8, 133.8, 133.0, 131.7, 129.8, 129.2,
128.1, 111.8, 77.9, 26.3, 6.1; [M + H]+ = 299; HRMS (ESI) m/z
calculated for C15H15N4O3 [M + H]+ = 299.11387; found 299.11410.
2-Methyl-1-(3-phenethyl-8-(trifluoromethyl)-[1,2,4]triazolo-
[4,3-a]pyridin-2(3H)-yl)propan-1-one (16b). Brown oil, 35 mg,
General Procedure for the Synthesis of Triazolopyridine
Carboxylic Acids 14a−d. To a stirring solution of the corresponding
2-hydrazinylpyridine (1.0 equiv, 0.25 mmol) in DCE (1 mL) were
added the aldehyde (1.0 equiv, 0.25 mmol) and the corresponding
cyclic anhydride (1.0 equiv, 0.25 mmol). The reaction was stirred for
30 min at room temperature. Upon reaction completion (monitored
by LC/MS and TLC), the solvent was evaporated in vacuo and the
crude product was purified by flash chromatography (using a gradient
0−20% AcOET/DCM) to obtain compounds of generic structure 14.
(E)-2-Bromo-4-(3-butyl-8-chloro-[1,2,4]triazolo[4,3-a]-
pyridin-2(3H)-yl)-4-oxobut-2-enoic Acid (14a). Orange crystals,
77 mg, 79% yield; mp 154−155 °C ; Rf = 0.28 (silica gel, 5% AcOEt/
DCM); 1H NMR (400 MHz, CDCl3) δ 8.21 (s, 1H), 7.19 (dd, J = 7.1,
0.9 Hz, 1H), 7.07 (dd, J = 6.8, 0.9 Hz, 1H), 6.46 (t, J = 3.4 Hz, 1H),
6.06 (t, J = 7.0 Hz, 1H), 2.56−2.32 (m, 1H), 1.94 (m, 1H), 1.33 (m,
4H), 1.15 (m, 1H), 0.89 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 160.5, 158.3, 150.5, 136.1, 128.6, 128.5, 117.4, 110.1, 106.5,
79.3, 31.7, 23.9, 22.2, 13.9; [M + H]+ = 388; HRMS (ESI) m/z
calculated for C14H16BrClN3O3 [M + H]+ = 388.00581; found
388.00505. Single crystal structure for X-ray analysis was obtained
from a mixture of AcOEt/Hexane (1:3) by means of slow
evaporation.19
1
39% yield; Rf = 0.23 (silica gel, 40% AcOEt/Hexane); H NMR (400
MHz, CDCl3) δ 7.46−7.01 (m, 6H), 6.84 (d, J = 6.9 Hz, 1H), 6.30 (t,
J = 3.3 Hz, 1H), 5.63 (t, J = 6.8 Hz, 1H), 3.38−3.15 (m, 1H), 2.82−
2.40 (m, 3H), 2.23−2.05 (m, 1H), 1.23 (d, J = 6.9 Hz, 3H), 1.13 (d, J
= 6.9 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 174.6, 144.7, 140.4,
135.0, 135.1, 133.9, 129.0, 128.7, 128.6, 128.7, 126.3, 123.2, 102.4,
75.6, 34.5, 31.5, 28.7, 19.1, 18.2; [M + H]+ = 364; HRMS (ESI) m/z
calculated for C19H21F3N3O [M + H]+ = 364.16312; found 364.16318.
Furan-2-yl(3-(2-(methylthio)ethyl)-6-nitro-[1,2,4]triazolo-
[4,3-a]pyridin-2(3H)-yl)methanone (16c). Red oil, 41 mg, 49%
yield; Rf = 0.19 (silica gel, 40% AcOEt/Hexane); 1H NMR (400 MHz,
CDCl3) δ 8.40 (d, J = 2.1 Hz, 1H), 7.83−7.51 (m, 3H), 6.62 (t, J = 3.6
Hz, 1H), 6.55 (dd, J = 3.5, 1.7 Hz, 1H), 6.46 (d, J = 10.3 Hz, 1H),
2.83−2.58 (m, 2H), 2.61−2.45 (m, 1H), 2.36 (ddq, J = 11.3, 7.4, 4.4,
3.7 Hz, 1H), 2.12 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 163.5,
147.1, 145.9, 145.0, 133.9, 129.9, 119.5, 111.8, 111.7, 110.0, 76.4, 33.2,
27.5, 15.7; [M + H]+ = 335; HRMS (ESI) m/z calculated for
C14H15N4O4S [M + H]+ = 335.08085; found 335.08122.
1-(3-Ethyl-8-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-
2(3H)-yl)ethanone (16d). Red oil, 26 mg, 40% yield; Rf = 0.14 (silica
gel, 40% AcOEt/Hexane); 1H NMR (400 MHz, CDCl3) δ 7.20 (d, J =
6.8 Hz, 1H), 7.09−6.85 (m, 1H), 6.28 (t, J = 3.4 Hz, 1H), 5.79 (t, J =
6.8 Hz, 1H), 2.32 (m, 1H), 2.27 (s, 3H), 1.85 (ddd, J = 15.0, 7.5, 3.2
Hz, 1H), 0.91 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
168.0, 135.3, 135.2, 134.1, 133.9, 123.2, 102.5, 76.5, 26.3, 21.2, 6.3; [M
+ H]+ = 260; HRMS (ESI) m/z calculated for C11H13F3N3O [M +
H]+ = 260.10052; found 260.10073.
(E)-2-Bromo-4-(3-ethyl-8-(trifluoromethyl)-[1,2,4]triazolo-
[4,3-a]pyridin-2(3H)-yl)-4-oxobut-2-enoic Acid (14b). Orange
1
oil, 57 mg, 58% yield; Rf = 0.15 (silica gel, 5% AcOEt/DCM); H
NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 7.45 (d, J = 6.8 Hz, 1H),
7.32 (d, J = 1.0 Hz, 1H), 6.41 (t, J = 3.3 Hz, 1H), 6.12 (t, J = 6.9 Hz,
1H), 2.51 (m, 1H), 2.06−1.93 (m, 1H), 0.91 (t, J = 7.4 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 160.6, 158.4, 147.8, 137.3, 136.2, 134.1,
128.7, 120.1, 113.3, 104.9, 78.0, 25.0, 5.9; [M + H]+ = 394; HRMS
(ESI) m/z calculated for C13H10BrF3N3O3 [M − H]− = 391.98630;
found 391.98622.
(3-Fluorophenyl)(3-phenethyl-8-(trifluoromethyl)-[1,2,4]-
triazolo[4,3-a]pyridin-2(3H)-yl)methanone (16e). Brown oil, 59
1
mg, 57% yield; Rf = 0.15 (silica gel, 40% AcOEt/Hexane); H NMR
2-(3-Ethyl-8-(trifluoromethyl)-2,3-dihydro-[1,2,4]triazolo-
(400 MHz, CDCl3) δ 8.12−7.83 (m, 2H), 7.38 (td, J = 8.1, 5.8 Hz,
1H), 7.33−7.07 (m, 7H), 6.94 (d, J = 6.5 Hz, 1H), 6.55 (t, J = 3.1 Hz,
1H), 5.73 (t, J = 6.8 Hz, 1H), 2.94−2.75 (m, 2H), 2.64 (m, 1H),
2.47−2.09 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 163.2, 140.0,
139.9, 129.1, 128.6, 128.19, 128.17, 128.16, 126.3, 126.1, 118.3, 118.1,
117.6, 117.3, 113.1, 102.9, 76.7, 33.8, 28.6; [M + H]+ = 416; HRMS
(ESI) m/z calculated for C22H18F4N3O [M + H]+ = 416.13805; found
416.13867.
[4,3-a]pyridine-2-carbonyl)benzoic Acid (14c). Brown oil, 54 mg,
1
59% yield; Rf = 0.5 (silica gel, 10% AcOEt/DCM); H NMR (400
MHz, CDCl3) δ 10.95 (br. s, 1H), 8.14 (m,1H), 8.07−7.78 (m, 3H),
7.62 (d, J = 7.0 Hz, 1H), 7.64−7.46 (m, 2H), 6.99 (t, J = 6.9 Hz, 1H),
3.17 (q, J = 7.6 Hz, 2H), 1.50 (t, J = 7.6 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 166.3, 151.7, 136.2, 134.7, 131.7, 130.9, 129.8, 128.7,
125.8, 125.7, 124.1, 116.6, 112.5, 52.9, 29.8, 18.2, 11.0; [M + H]+ =
366; HRMS (ESI) m/z calculated for C17H13F3N3O3 [M − H]−
364.09145; found 364.09153.
=
(3-(2-(Methylthio)ethyl)-8-(trifluoromethyl)-[1,2,4]triazolo-
[4,3-a]pyridin-2(3H)-yl)(p-tolyl)methanone (16f). Brown oil, 30
2-(3-(2-(Methylthio)ethyl)-8-(trifluoromethyl)-2,3-dihydro-
[1,2,4]triazolo[4,3-a]pyridine-2-carbonyl)benzoic Acid (14d).
Orange oil, 52 mg, 51% yield; Rf = 0.22 (silica gel, 10% AcOEt/
1
mg, 31% yield; Rf = 0.13 (silica gel, 40% AcOEt/Hexane); H NMR
(400 MHz, CDCl3) δ 8.10 (d, J = 8.2 Hz, 2H), 7.22 (d, J = 8.4 Hz,
3H), 7.21−6.97 (m, 1H), 6.60 (t, J = 3.6 Hz, 1H), 5.84 (t, J = 6.8 Hz,
1H), 2.84−2.61 (m, 1H), 2.59 (m, 1H), 2.60−2.47 (m, 1H), 2.39 (s,
3H), 2.33−2.20 (m, 1H), 2.12 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 164.3, 145.1, 141.9, 135.4, 135.3, 134.1, 130.5, 130.1, 128.5, 123.1,
120.4, 102.9, 76.1, 33.2, 27.8, 21.7, 15.8; [M + H]+ = 382; HRMS
(ESI) m/z calculated for C18H19F3N3OS [M + H]+ = 382.11954;
found 382.12005.
1
DCM); H NMR (400 MHz, CDCl3) δ 8.11−7.67 (m, 3H), 7.62−
7.37 (m, 2H), 7.10 (m, 2H), 5.66 (t, J = 6.8 Hz, 1H), 2.74 (m, 1H),
2.65−2.41 (m, 2H), 2.34−2.23 (m, 1H), 2.12 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 166.2, 162.7, 145.6, 136.0, 134.6, 129.7, 128.2, 125.7,
124.0, 116.4, 114.2, 110.0, 75.5, 33.7, 31.6, 31.4, 27.6, 15.6; [M + H]+
= 412; HRMS (ESI) m/z calculated for C18H15F3N3O3S [M − H]− =
410.07917; found 410.07967.
General Procedure for the Synthesis of Acyl-triazolo-
pyridines 16a−f. To a stirring solution of the corresponding 2-
hydrazinyl-pyridine (1.0 equiv, 0.25 mmol) and aldehyde (1.0 equiv,
0.25 mmol) dissolved in DCE (1 mL) was added acyl chloride (1.0
equiv, 0.25 mmol), and the reaction was heated via microwave
irradiation for 30 min at 120 °C. After reaction completion (monitored
by LC/MS and TLC), solvent was evaporated in vacuo and the crude
product was purified with an automated flash chromatography system
(using a gradient of 0−40% AcOEt/Hexane) to obtain compounds of
generic structure 16.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra for compounds of generic structure 6,
9, 11, 14, 16 and CIF files/ORTEP diagrams for compounds
6c, 9c, and 14a (Figures S1, S3, and S5, respectively). This
material is available free of charge via the Internet at http://
pubs.acs.org.
(3-Ethyl-6-nitro-[1,2,4]triazolo[4,3-a]pyridin-2(3H)-yl)-
(phenyl)methanone (16a). Brown oil, 31 mg, 42% yield; Rf = 0.20
(silica gel, 40% AcOEt/Hexane); 1H NMR (400 MHz, CDCl3) δ 8.28
(d, J = 2.1 Hz, 1H), 7.97 (dd, J = 8.4, 1.4 Hz, 2H), 7.66−7.33 (m, 4H),
6.60 (s, 1H), 6.37 (dd, J = 10.4, 0.5 Hz, 1H), 2.59 (ddd, J = 15.2, 7.5,
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: hulme@pharmacy.arizona.edu.
I
dx.doi.org/10.1021/jo500723d | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Carrillo, R.; Delgado, J.; Marcaccini, S.; Marcos, C. Mol. Diversity 2011,
15, 529−539.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
Financial support from the National Institute of Health (Grant
P41GM086190 to C.H.) and CONACyT/University of
Arizona (Doctoral Fellowship 215981/311412 for G.M.A.)
are gratefully acknowledged. We also thank Dr. Sue Roberts for
X-ray analysis and the mass spectroscopy facility for HRMS
analysis.
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