Cu(I)-Catalyzed regioselective synthesis of pyrazolo[5,1- c ]-1,2,4-triazoles

Article abstract of DOI:10.1021/jo300611a

Cycloadditions of terminal alkynes to 1,2,4-triazolium N-imides in the presence of base and Cu(I) afford pyrazolo[5,1-c]-1,2,4-triazoles regioselectively. The scope of alkynes, the influence of the electronic nature of the leaving group, and variations in the 1-alkyl substituent were examined. Quantum chemical calculations were employed to explain the distinct reactivity of the propiolates.

Full text of DOI:10.1021/jo300611a

Note
pubs.acs.org/joc
Cu(I)-Catalyzed Regioselective Synthesis of Pyrazolo[5,1-c]-1,2,4-
triazoles
Davit Jishkariani,‡ C. Dennis Hall,‡ Alexander A. Oliferenko,‡ David Leino,‡ and Alan R. Katritzky*,‡,§
‡Center for Heterocyclic Compounds, Department of Chemistry, University of Florida, Gainesville, Florida 32611-7200, United
States
§Department of Chemistry, King Abdulaziz University, Jeddah, 21589 Saudi Arabia
S
* Supporting Information
ABSTRACT: Cycloadditions of terminal alkynes to 1,2,4-
triazolium N-imides in the presence of base and Cu(I) afford
pyrazolo[5,1-c]-1,2,4-triazoles regioselectively. The scope of
alkynes, the influence of the electronic nature of the leaving
group, and variations in the 1-alkyl substituent were examined.
Quantum chemical calculations were employed to explain the
distinct reactivity of the propiolates.
he diverse applications of pyrazoloazines and pyrazoloa-
zoles with bridgehead nitrogen have aroused interest in
their synthesis. The pyrazolo[5,1-c]-1,2,4-triazole scaffold
endows unique properties, and such compounds have been
studied as azo dyes,1,2 inkjets and color filters,3 photographic
materials,4,5 electrophotographic toners,6 antibacterial agents
with reduced human toxicity7 and antitumor agents.8
Table 1. Synthesis of 1,2,4-Triazoliun N-Imides
T
The limited synthetic methods for such systems fall into
three groups: (i) starting from substituted pyrazolo derivatives
such as 3-amino,9,10 3-hydrazino,1,11−16 3-hydroxy10 or 3-
diazonium salts,17,18 (ii) cyclic condensations of 4-amino-5-
thioxo-1,2,4-triazoles,19 3,4-diamino-1,2,4-triazoles,20,21 3-meth-
ylthio-1,2,4-triazolium salts22 or 4-amino-1,2,4-triazolium salts23
and (iii) ring contraction of [1,2,4]triazolo[3,4-b][1,3,4]-
thiadiazines.24,25
Our continuing interest in the chemistry of heterocyclic
compounds derived from 4-amino-1,2,4-triazole prompted a
study that has resulted in a novel, efficient process for the
regioselective preparation of pyrazolo[5,1-c]-1,2,4-triazole
derivatives. Herein, we report a one-pot, Cu(I)-catalyzed
synthesis of the pyrazolo[5,1-c]-1,2,4-triazole moiety, starting
from 1,2,4-triazolium N-imides and terminal alkynes. We found
no literature reports of such reactions and have now examined
the scope of alkyne substrates together with the effect of
variations in the 1-alkyl substituent and the nature of the
leaving group on the course of the reactions.
entry
R
X
Ar
product
yield (%)
1
2
Bn
Me
Bun
Bn
Me
Bun
Bun
−
Br
I
−
−
−
2a
2b
2c
3a
3b
3c
3d
4
>99
>99
>99
94
3
Br
−
−
−
−
−
−
−
4
4-Me-C6H4
5
4-Me-C6H4
83
6
4-Me-C6H4
88
7
4-NO2−C6H4
91
8
−
−
−
63
9
Bn
5a
5b
57
10
Me
93
the conditions and study the regiochemical outcome of the
reaction (Table 2). The reaction of (1-benzyl-1H-1,2,4-triazol-
4-ium-4-yl)(tosyl)amide 3a with phenylacetylene 6a in the
presence of 5 mol% Cu2Br2 and pyridine (3 equiv) at room
temperature gave 1-benzyl-6-phenyl-1H-pyrazolo[5,1-c][1,2,4]-
triazole 7a as a single regioisomer in 62% yield. In the absence
of catalyst or base, there was either no conversion or a reduced
yield. An increase of catalyst loading had a deleterious effect
(Table 2).
1,2,4-Triazolium N-imides 3a−d and 5a,b were prepared in
83−94% yield via a two-step procedure. Sulfonimids 3a−d were
prepared by the reaction of 4-amino-1,2,4-triazolium salts with
the corresponding arylsulfonyl chlorides.26,27 In the case of N-
nitroimides 5a,b, we first generated 1,2,4-triazolium N-nitro-
imide 4 by nitration28 followed by reaction with the
corresponding alkyl halides29 (Table 1).
Substrate 3a underwent a one-pot, Cu(I)-catalyzed reaction
with phenylacetylene 6a under basic conditions to give 7a. We
then investigated the effects of various parameters to optimize
Received: March 28, 2012
Published: May 21, 2012
© 2012 American Chemical Society
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The Journal of Organic Chemistry
Note
Table 2. Optimization of Reaction Conditions
Scheme 1. Proposed Mechanism for the Cu(I) Mediated
Regioselective Synthesis of Pyrazolo[5,1-c]-1,2,4-triazoles
T (°C)/time
entry solvent
(h)
catalyst
base
7a
7a′
1
2
3
4
5
6
7
8
9
CH2Cl2
CH2Cl2
THF
25/24
40/24
60/24
25/24
25/24
25/24
25/24
25/24
25/24
25/24
40/5
−
−
−
−
−
Et3N
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
a
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
5% Cu2Br2
5% Cu2Br2
20% Cu2Br2
5% Cu2Br2
1% Cu2Br2
pyridine
−
pyridine
62
30
20
Et3N
45
pyridine
25
and HRMS spectral data, it was identified as 8a (Table 4).
Similarly, the reaction with DMAD 6g and ethyl but-2-ynoate
10% CuOAc pyridine
<5
<15
26
10
11
12
10% AgOTf
5% Cu2Br2
5% Cu2Br2
pyridine
pyridine
pyridine
Table 4. Reactions of 1,2,4-Triazolium N-Imides with
Propiolates
60/24
<15
a
Optimized conditions.
Using the optimized conditions, we examined the scope of
this transformation (Table 3). 1,2,4-Triazol-1-ium-amides 3a−
Table 3. Synthesis of Pyrazolo[5,1-c]-1,2,4-triazoles
yield
entry substrates
R
LG
Ts
R1
R2
product (%)
1
3a
3a
5a
5a
3b
3b
5b
5b
3c
3c
3d
3d
3c
3d
3a
3a
6a
6b
6a
6b
6a
6b
6a
6b
6a
6b
6a
6b
6c
6c
6d
6e
Bn
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Ph
Me
Ph
7a
7b
7a
7b
7c
7d
7c
7d
7e
7f
62
65
72
69
54
57
62
73
75
71
78
70
68
77
0
2
Bn
Ts
4-MeO-Ph
Ph
3
Bn
NO2
NO2
Ts
4
Bn
4-MeO-Ph
Ph
5
Me
Me
Me
Me
Bun
Bun
Bun
Bun
Bun
Bun
Bn
6
Ts
4-MeO-Ph
Ph
7
NO2
NO2
Ts
8
4-MeO-Ph
Ph
9
10
11
12
13
14
15
16
Ts
4-MeO-Ph
Ph
Ns
7e
7f
Ns
4-MeO-Ph
4-Me-Ph
4-Me-Ph
Ph
Ts
7g
7g
7h
7i
Ns
Ts
Bn
Ts
Ph
0
d, 5a,b were reacted with terminal or disubstituted alkynes 6a−
e. While terminal alkynes 6a−c gave desired products 7a−g in
62−78% yields, attempts to use disubstituted aromatic alkynes
6d,e resulted in recovery of starting materials.
On the basis of these results, we propose that the copper(I)-
catalyzed formation of intermediate D is followed by a double
bond migration and elimination either of NO2 or the
arylsulfonyl moiety (Scheme 1).
6h furnished compounds 8b,c in 98−99% yields (Table 4). No
catalyst was needed for these reactions, but ethyl acrylate 6i and
fumaronitrile 6j failed to react as dipolarophiles (Table 4). This
outcome is probably the result of extended conjugation
between the nitrogen lone pair and ester moiety in intermediate
I (Scheme 2), which clearly would be absent in the analogous
intermediates from 6i and 6j.
Attempts to synthesize the pyrazolo-1,2,4-triazole moiety by
a Cu(I)-catalyzed one-pot reaction using methyl propiolate 6f
resulted in the regioselective formation of a compound that
contained the N-tosyl moiety. On the basis of 1H and 13C NMR
We propose that a [3 + 2] dipolar cycloaddition of 3a with
6f−h is followed by a ring-opening rearrangement to regenerate
the aromatic 1,2,4-triazole unit,30−32 thus producing ring-
opened products 8a−c (Scheme 2).
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The Journal of Organic Chemistry
Note
differences of total electronic energies) of the two reaction
pathways: one leading to the isolated regioisomer 8a and the
other leading to the hypothetical cyclic structure 8a′. The
energy outcome of pathway I−8a can be evaluated directly by
making a comparison of the total energies of the intermediate I
and the final product 8a, because I and 8a have the same
number of nuclei and electrons. These pathways are displayed
in Scheme 3. It is seen that the total energy of product 8a lies
59.00 kcal/mol lower than the intermediate I. As for the
hypothetical pathway I−8a′, it can only be estimated as an
isodesmic reaction involving two disjoint products: cyclic
structure 8a′ and toluenesulfinic acid. The reaction enthalpy of
this isodesmic reaction was calculated to be −35.6 kcal/mol,
which means that pathway I−8a′ is 23.4 kcal/mol less
energetically favorable than pathway I−8a. Another factor
that can contribute to the higher stability of 8a is an
intramolecular hydrogen bond found between the ring nitrogen
and the hydrogen atom of the NH-Ts moiety in the optimized
structure of 8a (Scheme 3). The quantum chemical calculations
and theoretical reasoning are illustrative enough to demonstrate
the preference to form the ring-opened product 8a as well as to
explain the different regiochemistry of phenylacetylenes 6a−c
and propiolates 6f−h.
In conclusion, a mild, efficient and regioselective one-pot
Cu(I)-mediated synthesis of pyrazolo-1,2,4-triazoles has been
developed. This transformation affords the products at room
temperature under basic conditions. The different regioselec-
tivity of phenylacetylenes and methyl propiolates again
highlights the influence of substitution and electron density
distribution in the dipolarophile. Electrostatic reasons cause
phenylacetylenes to advantageously add to 1,2,4-triazolium N-
imides to afford pyrazolo[5,1-c]-1,2,4-triazole bicyclic systems.
The different reactivity of methyl propiolates (ring-opening) is
explained by utilizing the formalism of model isodesmic
reactions.
Scheme 2. Proposed Mechanism for the Reactions of 1,2,4-
Triazolium N-Imides with Propiolates
To rationalize the different regiochemistry dependent on the
acetylene reactant used (phenylacetylene or methyl propiolate)
and gain further insight into this process, we employed theory
and computations. Table 3 and Table 4 demonstrate that
phenylacetylene adds to 3a−d and 5a,b in a “head-to-tail”
fashion, considering the 1,2,4-triazole ring and the phenyl ring
as the heads in 3a and 6a, respectively. Unlike phenylacetylene,
methyl propiolate 6f adds “head-to-head” to 3a. These two
terminal acetylenes differ mainly in the nature of the
substituent. Methoxycarbonyl is the stronger electron-with-
drawing group, as measured by a larger residual negative charge
remaining on the acetylenic moiety. Molecular structures of the
substrate 3a and the reactants 6a and 6f were optimized using
the Firefly/GAMESS quantum chemical software. Geometry
optimization and SCF energy calculations were done at the
HF/6-31G* level of theory. Mulliken population analysis
(atomic charges) and dipole moments were calculated at the
same level of theory. Atomic charge distributions, starting from
the terminal hydrogen atom, are as follows: 0.297 (H), −0.548
(C1), 0.165 (C2) and 0.314 (H), −0.474 (C1), 0.158 (C2) for
the acetylenic units of 6a and 6f, respectively. Summing up the
charges gives residual negative charges on the acetylenic units
as −0.086 and −0.002 for 6a and 6f, respectively. The gamma-
aromatic system of the carbmethoxy group withdraws a
significant amount of electron density from the acetylenic
unit, thus making 6f a better dipolarophile. Dipole moment
orientation can be another factor of regioselectivity: dipole
moments of the substrate 3a and dipolarophile 6a interact
beneficially only if 3a and 6a are oriented “head-to-tail” with
respect to each other, otherwise a strong dipole repulsion
occurs. In 6f, the dipole moment direction is different, which
affords more beneficial orientations with the 1,3-dipole.
EXPERIMENTAL SECTION
■
Materials and Methods. All reactions were performed in single-
neck round-bottom flasks fitted with rubber septa under positive
pressure of nitrogen. Solvents were freshly distilled and degassed.
Reaction progress was monitored by thin-layer chromatography
(TLC) and visualized by UV light. Melting points were determined
on a capillary point apparatus equipped with a digital thermometer and
are uncorrected. NMR spectra were recorded in CDCl3 or DMSO-d6
with TMS for 1H (300 MHz) and 13C (75 MHz) as an internal
reference. 4-Amino-4H-1,2,4-triazole was purchased from Acros and
used without further purification. Aryl acetylenes and propiolates were
purchased from Sigma-Aldrich and used without further purification.
Elemental analysis was performed on a Carlo Erba-1106 instrument.
General Method for the Preparation of 4-Amino-1,2,4-
triazolium Salts 2a−c. A mixture of 4H-1,2,4-triazol-4-amine (5.00
mmol) and alkyl halide (5.00 mmol, 15.00 mmol in the case of methyl
iodide) in acetonitrile (10 mL) was stirred under reflux for 5 h (rt for
72 h in case of methyl iodide). The solvent and excess alkyl halide was
removed under reduced pressure to give corresponding 1,2,4-
triazolium salts 2a−c. For analytical purity, the residue was
recrystallized from MeOH.
For the reaction of 3a with 6f, assuming the intermediate I as
shown in Scheme 3, we can calculate relative energies (taken as
Scheme 3. Energy Diagram for the Formation of 8a
4-Amino-1-benzyl-1H-1,2,4-triazol-4-ium Bromide (2a). White
crystals (1.26 g, >99%): mp 141.0−142.0 °C (lit.23 mp 141.0−143.0
1
°C); H NMR (DMSO-d6) δ 10.57 (s, 1H), 9.25 (s, 1H), 7.48−7.40
(m, 5H), 7.07 (br s, 2H), 5.67 (s, 2H); 13C NMR (DMSO-d6) δ 145.4,
142.6, 133.3, 128.7, 128.6, 54.6. Anal. Calcd. For C9H11N4Br: C, 42.37;
H, 4.35; N, 21.96. Found: C, 42.40; H, 4.27; N, 22.01.
4-Amino-1-methyl-4H-1,2,4-triazol-1-ium Iodide (2b). Yellow
crystals (1.12 g, >99%): mp 100.0−101.0 °C (lit.33 mp 101.0 °C);
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Note
1H NMR (DMSO-d6) δ 10.16 (s, 1H), 9.18 (s, 1H), 6.95 (br s, 2H),
4.07 (s, 3H); 13C NMR (DMSO-d6) δ 144.9, 142.8, 39.0.
4-Amino-1-butyl-1H-1,2,4-triazol-4-ium Bromide (2c). Low melt-
ing solid (1.09 g, >99%): mp 46.0−47.0 °C (lit.34 mp 47.5−49.0 °C);
1H NMR (CDCl3) δ 10.78 (s, 1H), 8.99 (s, 1H), 6.76 (br s, 2H), 4.48
(t, J = 7.2 Hz, 2H), 2.05−1.89 (m, 2H), 1.52−1.35 (m, 2H), 0.96 (t, J
= 6.9 Hz, 3H); 13C NMR (CDCl3) δ 144.8, 142.6, 52.8, 30.7, 19.4,
13.5.
General Method for the Preparation of 1,2,4-Triazolium N-
Imides 3a−d. Arylsulfonyl chloride (10.00 mmol) was added
portionwise to a solution of corresponding 1,2,4-triazolium salt 2a−c
(5.00 mmol) in pyridine (5 mL), and the mixture was stirred for 1 h at
room temperature. After 1 h, EtOAc (70 mL) was added to the
reaction mixture, which was washed with 10% NaOH solution (3 × 20
mL), dried over anhydrous sodium sulfate, and filtered, and the solvent
was removed under reduced pressure to give corresponding 1,2,4-
triazolium N-imide 3a−d. For analytical purity, the residue was
recrystallized from MeOH.
white crystals (0.62 g, 57%): mp 164.0−165.0 °C (lit.35 mp 164 °C);
1H NMR (DMSO-d6) δ 10.41 (s, 1H), 9.28 (s, 1H), 7.44−7.40 (m,
5H), 5.60 (s, 2H); 13C NMR (DMSO-d6) δ 144.3, 141.5, 133.5, 128.9,
128.9, 128.7, 55.0.
(1-Methyl-1H-1,2,4-triazol-4-ium-4-yl)(nitro)amide (5b). A mix-
ture of sodium hydroxide (0.08 g, 2.00 mmol) and N-(4H-1,2,4-
triazol-4-yl)nitramide 4 (0.26 g, 2.00 mmol) in water (10 mL) was
stirred at room temperature for 1 h and evaporated to dryness under
reduced pressure. The resulting white powder was dissolved in DMF
(5 mL). Methyl iodide (0.71 g, 5.00 mmol) was added in one portion,
and the mixture was stirred at room temperature for 12 h. The
precipitate was removed by filtration, and the filtrate was diluted with
Et2O (100 mL). The resulting precipitate collected by filtration was
dried and recrystallized from EtOH to give corresponding N-
nitroimide 5b as white crystals (0.27 g, 93%): mp 169.0−170.0 °C
(lit.36 mp 169.0−170.0 °C); H NMR (DMSO-d6) δ 10.17 (s, 1H),
1
9.24 (s, 1H), 4.06 (s, 3H); 13C NMR (DMSO-d6) δ 143.7, 141.6, 38.7.
General Method for the Preparation of Pyrazolo[5,1-
c][1,2,4]triazoles 7a−g. Copper(I) bromide (0.03 mmol) was
added to the mixture of 1,2,4-triazolium N-imide (0.50 mmol),
arylacetylene (0.50 mmol), and pyridine (1.50 mmol) in dichloro-
methane (2 mL), and the resulting mixture was stirred for 24 h.
Solvent was removed under reduced pressure, and the residue was
purified by silica-gel column chromatography using EtOAc/hexanes
(1:5) as eluent to afford corresponding pyrazolo[5,1-c][1,2,4]triazoles
7a−g.
(1-Benzyl-1H-1,2,4-triazol-4-ium-4-yl)(tosyl)amide (3a). White
crystals (1.40 g, 85%): mp 170.0−172.0 °C (lit.26 mp 171.0−173.0
1
°C); H NMR (DMSO-d6) δ 9.90 (s, 1H), 8.73 (s, 1H), 7.45−7.35
(m, 5H), 7.29−7.19 (m, 4H), 5.47 (s, 2H), 2.33 (s, 3H); 13C NMR
(DMSO-d6) δ 173.7, 145.6, 142.0, 140.5, 133.8, 129.1, 128.8, 128.6,
128.1, 126.3, 54.5, 20.8.
(1-Methyl-1H-1,2,4-triazol-4-ium-4-yl)(tosyl)amide (3b). White
1
crystals (1.05 g, 83%): mp 203.0−204.0 °C; H NMR (DMSO-d6)
δ 9.72 (s, 1H), 8.64 (s, 1H), 7.45 (d, J = 7.8 Hz, 2H), 7.24 (d, J = 7.8
Hz, 2H), 3.93 (s, 3H), 2.33 (s, 3H); 13C NMR (DMSO-d6) δ 144.9,
142.1, 140.4, 140.1, 129.0, 126.3, 38.5, 20.8. Anal. Calcd. For
C10H12N4O2S: C, 47.61; H, 4.79; N, 22.21. Found: C, 47.82; H,
4.83; N, 22.27.
1-Benzyl-6-phenyl-1H-pyrazolo[5,1-c][1,2,4]triazole (7a). White
1
crystals (85 mg, 62%): mp 113.0−114.0 °C; H NMR (CDCl3) δ
8.25(s, 1H), 7.79(d, J = 6.9 Hz, 2H), 7.41−7.29(m, 8H), 5.70(s, 1H),
5.29(s, 2H); 13C NMR (CDCl3) δ 160.1, 147.2, 134.5, 133.7, 129.0,
128.6, 128.5, 128.2, 128.0, 126.2, 75.1, 54.5. Anal. Calcd. For
C17H14N4: C, 74.43; H, 5.14; N, 20.42. Found: C, 74.31; H, 5.09;
N, 20.44.
(1-Butyl-1H-1,2,4-triazol-4-ium-4-yl)(tosyl)amide (3c). White crys-
tals (1.30 g, 88%): mp 178.0−180.0 °C; 1H NMR (CDCl3) δ 10.00 (s,
1H), 7.85 (s, 1H), 7.63 (d, J = 8.1 Hz, 2H), 7.20 (d, J = 8.1 Hz, 2H),
4.35 (t, J = 7.1 Hz, 2H), 2.38 (s, 3H), 1.96−1.85 (m, 2H), 1.36−1.25
(m, 2H), 0.93 (t, J = 7.4 Hz, 3H); 13C NMR (CDCl3) δ 144.1, 142.5,
141.8, 138.9, 129.4, 127.0, 52.5, 30.8, 21.4, 19.3, 13.3. Anal. Calcd. For
C13H18N4O2S: C, 53.04; H, 6.16; N, 19.03. Found: C, 53.21; H, 6.61;
N, 19.16.
1-Benzyl-6-(4-methoxyphenyl)-1H-pyrazolo[5,1-c][1,2,4]triazole
1
(7b). White crystals (99 mg, 65%): mp 110.0−111.0 °C; H NMR
(CDCl3) δ 8.23 (s, 1H), 7.72 (d, J = 8.7 Hz, 2H), 7.38−7.31 (m, 5H),
6.92 (d, J = 9.0 Hz, 2H), 5.62 (s, 1H), 5.27 (s, 2H), 3.83 (s, 3H); 13C
NMR (CDCl3) δ 159.9, 134.5, 129.9, 129.2, 128.9, 128.5, 128.1, 127.9,
127.4, 126.2, 114.0, 74.6, 55.3, 54.4; HRMS (+ESI-TOF) m/z for
C18H17N4O [M + H]+ calcd. 305.1397, found 305.1403.
(1-Butyl-1H-1,2,4-triazol-4-ium-4-yl)((4-nitrophenyl)sulfonyl)-
1
amide (3d). White crystals (1.48 g, 91%): mp 198.0−200.0 °C; H
1-Methyl-6-phenyl-1H-pyrazolo[5,1-c][1,2,4]triazole (7c). Color-
less crystals (61 mg, 62%): mp 140.0−141.0 °C; 1H NMR (CDCl3) δ
8.22 (s, 1H), 7.88−7.83 (m, 2H), 7.46−7.36 (m, 3H), 6.00 (s, 1H),
3.88 (s, 3H); 13C NMR (CDCl3) δ 160.1, 133.7, 128.7, 128.6, 127.6,
126.2; HRMS (+ESI-TOF) m/z for C11H10N4 [M + H]+ calcd.
199.0978, found 199.0986.
NMR (DMSO-d6) δ 9.81 (s, 1H), 8.79 (s, 1H), 8.29 (d, J = 9.0 Hz,
2H), 7.78 (d, J = 9.3 Hz, 2H), 4.23 (t, J = 6.9 Hz, 2H), 1.80−1.71 (m,
2H), 1.23−1.10 (m, 2H), 0.85 (t, J = 7.2 Hz, 3H); 13C NMR (DMSO-
d6) δ 148.6, 148.5, 145.2, 141.9, 127.7, 124.1, 51.2, 29.9, 18.5, 13.0.
Anal. Calcd. For C12H15N5O4S: C, 44.30; H, 4.65; N, 21.53. Found: C,
44.55; H, 4.98; N, 21.64.
6-(4-Methoxyphenyl)-1-methyl-1H-pyrazolo[5,1-c][1,2,4]triazole
N-(4H-1,2,4-Triazol-4-yl)nitramide (4). Concentrated nitric acid
(70%, 50 mL) was added dropwise to a cooled (0 °C) solution of 4-
amino-1,2,4-triazole (1.68 g, 20.00 mmol) in sulfuric acid (90%, 50
mL). The resulting solution was stirred for 30 min and gradually
warmed up to room temperature. The mixture was stirred for an
additional 1 h and poured into ice water (200 mL). The precipitate
was collected by filtration, washed with cold water, dried, and
recrystallized from MeOH to afford N-(4H-1,2,4-triazol-4-yl)nitramide
4 as colorless needles (1.63 g, 63%): mp 175.0−176.0 °C (lit.28 mp
1
(7d). White crystals (83 mg, 73%): mp 152.0−153.0 °C; H NMR
(CDCl3) δ 8.22 (s, 1H), 7.78 (d, J = 9.0 Hz, 2H), 6.96 (d, J = 8.7 Hz,
2H), 5.91 (s, 1H), 3.86 (s, 3H), 3.85 (s, 3H); 13C NMR (CDCl3) δ
160.1, 160.0, 148.0, 127.6, 127.4, 126.4, 114.1, 73.7, 55.3, 36.7; HRMS
(+ESI-TOF) m/z for C12H12N4O [M + H]+ calcd. 229. 1084, found
229.1092.
1-Butyl-6-phenyl-1H-pyrazolo[5,1-c][1,2,4]triazole (7e). Yelow
1
solid (94 mg, 78%): mp 35.0−40.0 °C; H NMR (CDCl3) δ 8.21,
1
175.0−176.0 °C); H NMR (DMSO-d6) δ 9.66 (s, 2H); 13C NMR
(s, 1H), 7.88−7.84 (m, 2H), 7.46−7.38 (m, 2H), 7.38−7.32 (m, 1H),
5.99 (s, 2H), 4.12 (t, J = 7.2 Hz, 2H), 1.95−1.84 (m, 2H), 1.46−1.33
(m, 2H), 0.97 (t, J = 6.9 Hz, 3H); 13C NMR (CDCl3) δ 160.0, 147.3,
133.9, 128.7, 128.5, 127.4, 126.1, 74.3, 50.2, 30.7, 19.8, 13.6; HRMS
(+APCI-TOF) m/z for C14H17N4 [M + H]+ calcd. 241.1448, found
241.1447.
(DMSO-d6) δ 142.8. Anal. Calcd. For C2H3N5O2: C, 18.61; H, 2.34;
N, 54.26. Found: C, 18.80; H, 2.22; N, 54.09.
(1-Benzyl-4H-1,2,4-triazol-1-ium-4-yl)(nitro)amide (5a). The mix-
ture of sodium hydroxide (0.20 g, 5.0 mmol) and N-(4H-1,2,4-triazol-
4-yl)nitramide 4 (0.65 g, 5.00 mmol) in water (10 mL) was stirred at
room temperature for 1 h and evaporated to dryness under reduced
pressure. The resulting white powder was dissolved in acetonitrile (10
mL). Benzyl bromide (0.86 g, 5.00 mmol) was added in one portion,
and the resulting mixture refluxed for 12 h. After it was cooled to room
temperature, excess solvent was removed under reduced pressure. The
remaining solid was dissolved in EtOAc (50 mL), washed with water
(3 × 20 mL), dried over anhydrous sodium sulfate, and concentrated
under reduced pressure to afford corresponding N-nitroimide 5a as
1-Butyl-6-(4-methoxyphenyl)-1H-pyrazolo[5,1-c][1,2,4]triazole
(7f). Yelow solid (96 mg, 71%): mp 60.0−62.0 °C; 1H NMR (CDCl3)
δ 8.19 (s, 1H), 7.79 (d, J = 8.1 Hz, 2H), 6.95 (d, J = 8.1 Hz, 2H), 5.91
(s, 1H), 4.10 (t, J = 7.1 Hz, 2H), 3.84 (s, 3H), 1.93−1.83 (m, 2H),
1.44−1.32 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H); 13C NMR (CDCl3) δ
160.0, 147.4, 130.0, 129.6, 127.4, 126.5, 114.1, 73.8, 55.3, 50.2, 30.7,
19.8, 13.6; HRMS (+APCI-TOF) m/z for C15H19N4O [M + H]+
calcd. 271.1553, found 271.1551.
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The Journal of Organic Chemistry
Note
1-Butyl-6-(p-tolyl)-1H-pyrazolo[5,1-c][1,2,4]triazole (7g). Yellow
solid (98 mg, 77%): mp 54.0−55.0 °C; H NMR (CDCl3) δ 8.20 (s,
AUTHOR INFORMATION
■
1
Corresponding Author
*E-mail: katritzky@chem.ufl.edu.
1H), 7.75 (d, J = 7.8 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H), 5.96 (s, 1H),
4.12 (t, J = 7.1 Hz, 2H), 2.39 (s, 3H), 1.95−1.85 (m, 2H), 1.46−1.33
(m, 2H), 0.97 (t, J = 7.4 Hz, 3H); 13C NMR (CDCl3) δ 160.1, 147.3,
138.4, 131.0, 129.4, 127.4, 126.0, 50.2, 30.7, 21.3, 19.8, 13.6; HRMS
(+ESI-TOF) m/z for C15H19N4 [M + H]+ calcd. 255.1604, found
255.1607.
Notes
The authors declare no competing financial interest.
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(E)-Methyl-2-(1-benzyl-1H-1,2,4-triazol-5-yl)-3-(4-
methylphenylsulfonamido)acrylate (8a). Methyl propiolate 6f (0.17
g, 2.00 mmol) was added dropwise to a solution of (1-benzyl-1H-1,2,4-
triazol-4-ium-4-yl)(tosyl)amide 3a (0.66 g, 2.00 mmol) in DCM (5
mL) and stirred for 24 h at room temperature. After 24 h, the reaction
mixture was concentrated under reduced pressure to afford pure (E)-
m e t h y l - 2 - ( 1 - b e n z y l - 1 H - 1 , 2 , 4 - t r i a z o l - 5 - y l ) - 3 - ( 4 -
methylphenylsulfonamido)acrylate 8a as colorless microcrystals (0.85
g, >99%): mp 100.0−100.2 °C; 1H NMR (DMSO-d6) δ 8.32 (s, 1H),
8.08 (s, 1H), 7.68 (d, J = 8.1 Hz, 2H), 7.40 (d, J = 7.8 Hz, 2H), 7.23−
7.15 (m, 3H), 7.05 (d, J = 6.0 Hz, 2H), 5.09 (s, 2H), 3.54 (s, 3H), 2.38
(s, 3H); 13C NMR/DEPT-135° (DMSO-d6) δ 165.1 (C), 148.3 (CH),
148.1 (C), 147.8 (CH), 143.2 (C), 137.9 (C), 134.9 (C), 129.7 (CH),
128.1 (CH), 127.6 (CH), 126.2 (CH), 92.1 (C), 52.2 (CH2), 51.4
(CH3), 20.9 (CH3); HRMS (+ESI-TOF) m/z for C20H21N4O4S [M +
H]+ calcd. 413.1278, found 413.1274.
Dimethyl-2-(1-benzyl-1H-1, 2, 4-triazol-5-yl)-3-(4-
methylphenylsulfonamido)maleate (8b). Dimethyl but-2-ynedioate
6g (0.28 g, 2.00 mmol) was added dropwise to a solution of (1-benzyl-
1H-1,2,4-triazol-4-ium-4-yl)(tosyl)amide 3a (0.66 g, 2.00 mmol) in
DCM (5 mL) at −78 °C and stirred for 30 min. After 30 min, the
reaction was allowed to warm up to room temperature and was left for
additional 12 h. The reaction mixture was concentrated under reduced
pressure to afford pure dimethyl2-(1-benzyl-1H-1,2,4-triazol-5-yl)-3-
(4-methylphenylsulfonamido)maleate 8b as white solid (0.95 g,
>99%): mp 45.0−47.0 °C; 1H NMR (DMSO-d6) δ 8.90 (s, 1H),
7.62 (d, J = 8.4 Hz, 2H), 7.32−7.25 (m, 5H), 7.07−7.03 (m, 2H), 4.99
(s, 1H), 3.77 (s, 3H), 3.40 (s, 3H), 2.34 (s, 3H); 13C NMR (DMSO-
d6) δ 165.4, 163.9, 159.3, 149.7, 144.1, 141.5, 140.9, 133.7, 129.0,
128.5, 128.1, 128.0, 125.9, 81.8, 52.7, 52.1, 50.8, 20.8; HRMS (+ESI-
TOF) m/z for C22H22N4O6S [M + H]+ calcd. 471.1333, found
471.1342. Anal. Calcd. For C22H22N4O6S: C, 56.16; H, 4.71; N, 11.91.
Found: C, 56.01; H, 4.87; N, 11.41.
■
(12) Elfahham, H. A.; Sadek, K. U.; Elgemeie, G. E. H.; Elnagdi, M.
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(E)-Ethyl-2-(1-benzyl-1H-1, 2, 4-triazol-5-yl)-3-(4-
methylphenylsulfonamido)but-2-enoate (8c). Ethyl but-2-ynoate 6h
(2.00 g, 2.0 mmol) was added dropwise to the solution of (1-benzyl-
1H-1,2,4-triazol-4-ium-4-yl)(tosyl)amide 3a (0.66 g, 2.0 mmol) in
DCM (5 mL) at room temperature over a period of 10 min. The
resulting mixture was stirred under reflux for additional 12 h. After 12
h, the reaction was allowed to cool to room temperature and
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flash chromatography (EtOAc/hexanes) to afford pure (E)-ethyl 2-(1-
benzyl-1H-1,2,4-triazol-5-yl)-3-(4-methylphenylsulfonamido)but-2-
enoate 8c as white microcrystals (0.85 g, 98%): mp 128.0−130.0 °C;
1H NMR (CDCl3) δ 12.14 (s, 1H), 7.92 (s, 1H), 7.78 (d, J = 8.4 Hz,
2H), 7.34 (d. J = 8.4 Hz, 2H), 7.28−7.23 (m, 3H), 7.16−7.11 (m,
2H), 5.15−5.03 (m, 2H), 4.02 (q, J = 7.2 Hz, 2H), 2.45 (s, 3H), 1.59
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151.0, 149.6, 144.9, 136.9, 134.7, 130.1, 128.7, 128.3, 127.9, 127.4,
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ASSOCIATED CONTENT
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S
* Supporting Information
1H and 13C NMR spectra for 2a−c, 3a−d, 4, 5a,b, 7a−g, and
8a−c and Cartesian coordinates of key intermediate I. This
material is available free of charge via the Internet at http://
pubs.acs.org.
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Note
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