Thermal Ring-Opening of Pyrazolo[3,4-d][1,2,3]triazin-4-ones: An Experimental and Theoretical Study

Article abstract of DOI:10.1002/ejoc.201701538

Several 3-pyrazolylcarbonyl-pyrazolo[3,4-d][1,2,3]triazin-4-ones have been prepared from 5-amino-1H-pyrazole-4-carbonitriles through a simple sequence. In the first step, diazotization of the corresponding aminopyrazoles afforded pyrazolo[3,4-d][1,2,3]triazin-4-ones. Next, thermal rearrangement of these compounds through nitrogen elimination gave the final products. The proposed mechanism for the ring-opening of the pyrazolotriazinones to give the pyrazolylcarbonyl-pyrazolotriazinones involves the generation of an iminoketene intermediate, which reacts with a second molecule of pyrazolotriazinone. The complete mechanism of product formation involving the iminoketene intermediate, and all other reasonable pathways, have been explored in detail through DFT calculations. Furthermore, additional experiments to corroborate the presence of the iminoketene intermediate were carried out.

Full text of DOI:10.1002/ejoc.201701538

A Journal of
Accepted Article
Title: Thermal ring opening of pyrazolo[3,4-d][1,2,3]triazin-4-ones: an
experimental and theoretical study
Authors: Juan Pablo Colomer, María Lourdes Sciú, Cristina Ramirez,
Silvia Soria Castro, Domingo Mariano Vera, and Elizabeth
Laura Moyano
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701538
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10.1002/ejoc.201701538
European Journal of Organic Chemistry
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Thermal ring opening of pyrazolo[3,4-d][1,2,3]triazin-4-ones: an
experimental and theoretical study
Juan P. Colomer,† [a] María L. Sciú,†[a] Cristina L. Ramirez,[b] Silvia M. Soria-Castro,[a] D. Mariano A.
Vera*[b] and Elizabeth L. Moyano*[a]
Concerning to the chemical reactivity of azole-annelated
[1,2,3]triazinones it can be found modifications at the carbonyl
group to give 4-substituted azolo-triazines,[2,4,7] alkylations at N-
Abstract: Several 3-pyrazolecarbonyl-pyrazolo[3,4-d][1,2,3]triazin-4-
3[8] and opening of the triazine ring with elimination of nitrogen to
ones were prepared from 5-amino-1H-pyrazole-4-carbonitriles
afford pyrazole derivatives[9–12] or (pyrazolyl)pyrazolo-oxazinones
through a simple sequence. In a first step, diazotization of
via dimerization of an iminoketene intermediate.[11,12] However,
aminopyrazole afforded pyrazolo[3,4-d][1,2,3]triazin-4-ones. Next, a
the study of nitrogen loss reactions in azolotriazines as an
thermal rearrangement of these compounds through a nitrogen
approach to prepare new heterocycles has not been so much
elimination gave the final products. The proposed mechanism for the
explored, despite of the synthetic potential of the precursors.
ring opening of pyrazolotriazinones to give the pyrazolecarbonyl-
Following our studies of azolotriazines compounds, in this
pyrazolotriazinones includes the generation of an iminoketene
work we reported the thermally induced elimination of nitrogen
intermediate, which reacts with
a
second molecule of
from
pyrazolo[3,4-d][1,2,3]triazin-4-ones
to
give
3-
pyrazolotriazinone. The complete and detailed mechanism of product
formation involving the iminoketene intermediate and all other
reasonable pathways as well, were explored with DFT calculations.
Furthermore, additional experimental studies to corroborate the
presence of iminoketene intermediate were carried out.
(pyrazolecarbonyl)-pyrazolotriazinones in a simple protocol. A
mechanism for the formation of the new pyrazolotriazinone
amides is proposed based on a detailed exploration of the
complex potential energy surfaces of all reasonable pathways
using first principles quantum chemical calculations. Also, a novel
microwave-assisted preparation of aminopyrazole precursors of
pyrazolo[3,4-d][1,2,3]triazin-4-ones is described.
Introduction
Results and Discussion
Many structural analogues of the naturally occurring purine
bases have attracted attention due to their broad spectrum of
biological activity.[1] In particular azole-annelated [1,2,3]triazines
possess activity as antivirals, antitubercular agents, inhibitors of
protoporphyrinogen oxidase, herbicides, pesticides, among
others.[2–4] In view of the important biological activity of purine
analogues, our research interests have been focused on the
synthesis of pyrazolo[3,4-d][1,2,3]triazin-4-ones and imidazo[4,5-
d][1,2,3]triazin-4-ones establishing a convenient method to
access a broad range of these derivatives through the one-pot
First, the synthesis of 5-amino-1H-pyrazole-4-carbonitrile
(3a-g), as precursors of pyrazolotriazinones (4a-g), was carried
out applying focused microwave irradiation. As background
information about the application of microwave methodology,
should be mentioned the flow microwave synthesis of this type of
aminopyrazoles in very good yield.[13] In our approach compounds
3a-g were prepared from ethoxymethylenemalononitrile (1) and
hydrazines (2) using ethanol as solvent, temperature of 100 °C
and irradiation times of 2-7 min operating at 300 W (Scheme 1).
The addition of triethylamine as base was required for
neutralization of acid salts of hydrazines. According to the results,
in several cases, the application of microwaves improved the
pyrazoles yields in comparison to the conventional synthesis;
however, the main advantage was the significant reduction of
reaction times from hours to minutes (Table 1).[5,6] In particular,
for the synthesis of 3b, the replacement of part of ethanol by water
improved yields. It was found that the optimum ratio (in volume)
of water: ethanol was 1:3. When water amount was increased the
yield decreased. In the case of the reaction performed in equal
amounts of both solvents, the yield of 3b diminished to 59% and
when only water was used the yield of pyrazole was only 20%.
diazotization
reaction
of
5-amino-azole-4-carbonitrile
precursors.[5,6] We found that the stability and transformations of
the diazonium ion intermediate was strongly dependent on the
type of azole ring and, to a lesser extent, the nature of
substituents at N-1.[6]
[a]
[b]
INFIQC – Department of Organic Chemistry – School of Chemical
Sciences – National University of Córdoba, Córdoba, Argentine.
E-mail: lauramoy@fcq.unc.edu.ar
QUIAMM-INBIOTEC- Dept. of Chemistry – School of Exact and
Natural Sciences – National University of Mar del Plata, Mar del
Plata, Argentine
E-mail: dmavera@yahoo.com
† These authors contributed equally to this publication
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201701538
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The structure of the tautomer 3H-pyrazolotriazinones was
confirmed by NMR and IR experiments and the spectral
information agreed with previous results.[5,6,10]
Scheme 1. Microwave assisted synthesis of 5-amino-1H-pyrazole-4-
carbonitriles 3a-g.
Table 1. Synthesis of 5-amino-1H-pyrazole-4-carbonitriles in conventional
and microwave methodologies.
Compound
R
Conventional (%)[a]
Microwave (%)[b]
69
3a
3b
3c
3d
3e
3f
H
45
63
69
97
51
91
27
Scheme 2. Synthesis of pyrazolotriazinones 4 and 5 from aminopyrazoles 3.
Ph
67(74[c],88[d]
)
The thermal treatment of 4b-g in boiling benzene afforded
new
compounds
3-(5-amino-pyrazole-4-carbonyl)-
p-OMe-C6H4
p-F-C6H4
m-F-C6H4
o-F-C6H4
Pyridin-2-yl
72
79
74
81
48
pyrazolotriazinones 5b-g. Regarding the reactivity of different
triazinones 4 towards the formation of compounds 5, it was
noticeable that pyridinyl precursor (4g) did not react to give
product 5g in considerable amounts (only 9 %). This result would
indicate that the feasibility of triazine ring opening strongly
depends on the N-7 pyrazole substitution. In this sense, a
stabilization of the triazine ring could be obtained when pyridinyl
group was present in the fused pyrazole ring.
3g
Table 2. Yields of pyrazolotriazinones (4b-g and 5b-g)
[a] EtOH reflux, N(Et)3, time: 2-6 h. Isolated yields. [b] EtOH, N(Et)3,
100 °C, time: 2-7 min, 300 W. [c] EtOH: H2O equal to 2:1, 100 °C, time:
2 min, 300 W. [d] EtOH: H2O equal to 3:1, 100 °C, time: 2 min, 300 W.
R
Compd.
Yield (%)[a]
Compd.
Yield (%)[a]
H
4a
4b
4c
4d
4e
4f
-
-
-
Following, 3a-g were subjected to diazotization conditions
to prepare pyrazolo[3,4-d][1,2,3]triazin-4-ones 4a-g using the
protocol previously described (Scheme 2).[5,6] Yields of
compounds 4 were good, apart from the pyridinyl-derivative 4g
and the impossibility to afford the 7-unsubstituted
pyrazolotriazinone 4a (Table 2). In the case of 4g, the depleted
yield can be attributed to difficulties in the purification of this
product from the reaction mixture. The unsuccessful conversion
of 3a to 4a could be explained by less stability of diazo group in
the pyrazole diazonium intermediate, which avoid the formation of
triazinone ring. It is known that reactivity and stability of diazonium
cation is strongly dependent on the substituents, electron-
withdrawing groups, generally increase the electrophilic
properties of the diazo group while electron-donating substituents
stabilize the diazonium cation reducing the electrophilicity of diazo
group.[14] In the case of cyclization reaction to form the triazinone
ring, the diazonium cation should be electrophilic and stable
enough to attack the nitrile group minimizing other competitive
reactions.
Ph
77
88
70
52
64
39
5b
5c
5d
5e
5f
67
46
62
51
66
9[b]
p-OMe-C6H4
p-F-C6H4
m-F-C6H4
o-F-C6H4
Pyridin-2-yl
4g
5g
[a] Isolated yields. [b] Determined by 1H NMR.
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10.1002/ejoc.201701538
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Scheme 3. Possible reaction ways to form pyrazolotriazinone 5.
The identity of these new pyrazolotriazinones 5 was
unambiguously confirmed by NMR, IR and high-resolution mass
1
spectra. For example, the H NMR spectrum of 5b (Figure 1),
showed the presence of a characteristic singlet for the pyrazole
H-13 proton (7.74 ppm), a typical singlet for the triazine H-5 proton
(8.54 ppm) and a broad signal for amino protons (6.94 ppm). Also,
a characteristic doublet for the ortho-aromatic protons of phenyl
group attached to N-7 in triazine ring could be assigned (8.19
ppm). The analysis of 13C NMR spectra and 2D experiments
allowed the assignment of both carbonylic carbons, one belonged
to the triazinone ring (152.9 ppm) and the other linked triazine with
pyrazole ring (163.6 ppm) and olefinic carbons 16 (153.2 ppm), 5
(136.5 ppm), 13 (142.6 ppm), 5a (109.4 ppm), 7a (148.6 ppm) and
12 (100.7 ppm) (see Figure 1).
In addition, IR analysis showed the presence of two bands
corresponding to stretching of both C=O bonds at 1716 and 1692
cm-1 and a typical N-H stretching vibration at 3461 cm-1.
Optionally, pyrazolotriazinone 4, either intact or after ring
opening, can suffer a nucleophilic addition at the amide carbonyl
group by another molecule of pyrazolotriazinone. The ring
opening of polycyclic 1,2,3-triazines with nucleophiles has been
described in literature, in which the triazinone suffers a
nucleophilic attack at the exposed and reactive C-4 position by a
further molecule of triazinone.[15,16,24] In particular, in the
thermolysis of 1,2,3-benzotriazin-4-one an unstable aryl-triazene
intermediate has been also postulated in the ring opening
reactions to give o-aminobenzoyl derivatives.[15]
In addition, reaction of pyrazolotriazinones
4
(via
iminoketene or direct nucleophilic attack) to form
pyrazolecarbonyl-triazinones 5 was favored over the simple
dimerization of iminoketenes to give oxazinone derivatives as it
was previously observed in thermolysis of pyrrolediones,[25]
benzotriazinones[15] and pyrazolotriazinones.[11] In this last work,
phosphorus pentoxide was required for the thermal
transformation of triazinones to pyrazolo-oxazinones.
Figure 1. NMR data: assignment of main protons, carbons and correlations for
5b.
In order to explore the formation of 5, different pathways
were considered. The proposed mechanistic puzzle for the
formation of pyrazolecarbonyl-pyrazolotriazinones 5b-g is
depicted in the Scheme 3.
Considering
the
literature
of
thermolysis
of
pyrazolotriazinones analogues, different mechanistic proposals
would arise depending mainly on when the nitrogen molecule is
released and the possibility of the formation of the iminoketene 6.
In view of the mechanistic richness in obtaining of 5 from 4, all
reasonable mechanistic pathways (in terms of free energy) were
considered in a detailed ab initio exploration of the free energy
surfaces. Five main possibilities will be discussed and labeled as
Path A to E (Scheme 4). The computational procedure here
applied was done at the CAM-B3LYP/6-311+G(d,p) level of
theory, which was successfully proved in a related heterocyclic
mechanistic study.[22] The potential energy surface exploration for
the formation of compounds 5b (R = Ph) and 5c (R = p-OMe-
C6H4), taken as representatives, was performed. As additional
examination, energy calculations at the MP2, MP3 and
MP4(DQ)/6-311+G(d,p) were carried out to all stationary points
found for the derivative 5b (see SI, Table S2). The relative
standard free energy at 298.15 K is shown below each structure
for R = Ph and between parenthesis for R = p-OMe-C6H4. These
relative free energies are referred to zero -by definition- for the
reactants 4b and 4c, respectively.
The formation of 5b-g could be probably analogous to the
thermal conversion of 1,2,3-benzotriazin-4(3H)-one to give
anthraniloyl-benzotriazinone, via an elimination of molecular
nitrogen, to give quinazolino[3,2-c][1,2,3]benzotriazin-8-one.[15,16]
It should be mentioned that the anthraniloyl-benzotriazinone
(analogue to the pyrazoyl-pyrazolotriazinones here described)
was not isolated and for this reason was postulated as
intermediate in that reaction. Subsequently, this intermediate
could afford a cyclodehydration reaction in diethylene glycol
dimethyl ether reflux to give the quinazolino-fused derivative.
Pyrazolotriazinone 4 could give nitrogen extrusion via a
retro Diels-Alder reaction, as it was proposed for the thermolysis
of pyrrolotriazines 9 or sequentially, following the ring opening, as
it was proposed for the photochemical reactions of
benzotriazinones.[17] Elimination of nitrogen from 4 could lead to
the imidoylketene 6 or even an azetinone intermediate which can
coexist in equilibrium.[15,18–22] These intermediates could react
with a nucleophile, in this case a second molecule of 4 or a better
suited tautomer of it, to get the final product 5. Similar nucleophilic
reactions have been already reported for benzoazetinones to get
aminobenzamides and anthranilate esters.[23]
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Scheme 4. Summary of the computational mechanistic study. Relative standard free energies below each structure label are indicated along the different
mechanistic pathways for the reaction 4b → 5b (and for 4c → 5c in parenthesis). All energies in kcal/mol referred to the energy of two equivalents of the reactants
4b/4c taken as zero.
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First, from the three different tautomers of 4 (4, 4i, and 4ii),
only 4i (13.3 and 13.2 kcal/mol above 4b or 4c, respectively)
would be able to productively release N2 at the beginning of the
process. Hereafter, no further attention will be paid to the
tautomers interconversion, since fast tautomeric equilibria are
expected in the reaction conditions. Indeed, the double proton
transfer (DPT) for 4 with another molecule of itself or another
intermediate would be one of the possible mechanism for
tautomer interconversion. Bovarets et al. have extensively studied
this kind of DPT in DNA base pairs and found to have
interconversion barriers between 8 and 13 kcal/mol for thymine
tautomerization assisted by another thymine (canonical and enol
pair) and for guanine-thymine pairs (canonical pair to enol pair),
respectively.[26,27] These values are considerably lower than the
energies required to proceed through the proposed reaction paths
form 4, as shown later (either 28.5 or 49.5 kcal/mol through the
different pathways).
Figure 3. Molecular electrostatic potential of 6b colored from red (-0.1 a.u.) to
blue (+0.1 a.u.) on an isodensity surface (electron density of 0.01 a.u.).
The relative free energy of the transition state for the earlier
nitrogen release, TS4i-6b / TS4i-6c was found to be 28.3 kcal/mol,
practically the same in both cases, leading to the iminoketene
intermediate 6b/c, which is considerably stable (-24.9 and -24.8
kcal/mol, respectively) (see structure of TS4i-6b as
representative on Figure 2).
Figure 2. Structure of the transition state TS4i-6b for the concerted nitrogen
molecule released from 4ib. Vectors indicate the imaginary frequency xyz
displacement vectors.
This earlier nitrogen release is the initial step of four variants
(Path A, B, C and D) which are based on the intermediacy of
iminoketene 6. As can be noted by inspecting its molecular
electrostatic potential (Figure 3), this intermediate 6 proves to be
a very strong electrophile, which can attack either a nucleophilic
nitrogen of the triazine ring of 4 (or one of its tautomers) or,
intramolecularly, its own imino nitrogen.
Paths A and B consider the attack of iminoketene 6 to a
nucleophilic nitrogen of the triazine ring of 4 (or one of its
tautomers). Among them, direct reaction of 6 with a molecule of 4
for giving the new C-N bond between the ketene carbon and N-3
from 4 is clearly disregarded, since this nitrogen is not nucleophilic
at all (N-3 is signaled with a yellow arrow on Figure 4); essentially
N-2 and N-1 are much more nucleophilic than N-3, as it can be
noted by inspection of the electrostatic potential of 4c on Figure
4. Thus, an encounter with 4 will couple the ketene carbon with
one of the other nitrogens, as shown later, the lowest energy
transition state for an encounter with 4 will couple with its N-2.
Figure 4. Molecular electrostatic potentials for the tautomers postulated to react
with 6c: 4c, 4ic and 4iic as representatives (similar charge distribution for
4b,4ib and 4iib). The nitrogen forming the C-N bond in the final product 5c (N-
3) is indicated with a yellow arrow. It appears as slightly electrophilic in 4c and
as a fine nucleophile in the case of both 4ic and 4iic. In the case of 4iic, despite
the similar colors for N-3 and N-2, N-3 is the most nucleophilic with an ESP fitted
charge of -0.615 against -0.560 on N-2 (A similar pattern was found for 4iib with
-0.598 on N-3 and -0.539 on N-2). Colors and scale as in Figure 3.
Either in the case of 6b or 6c, Path A proceeds through the
encounter with a molecule of the tautomer 4ii of the reactive
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passing through a transition state TS4ii-5ii (shown on SI
Figure S1) for giving 5ii, which is a tautomer of the final product 5
(Scheme 4). This TS is the lowest of the four possible alternatives
Paths A-D available for 6 in the case of the phenyl (0.66 kcal/mol
of relative free energy) and the second lowest in the case of the
anisyl derivative (at 1.35 kcal/mol).
In the case that 6 coupled with triazinone 4, it will lead to
another intermediate (8i) which will continue reacting with further
rearrangements to give 5, as it can be seen in the Path B.
Another direct coupling of the ketene electrophile with N-3
of triazines to directly yield 5 is possible from the tautomer 4i, this
approach proceeds through Path C (Scheme 4). As shown in
Figure 4, the N-3 of 4ic (yellow arrow) is the most nucleophilic one
and it will readily couple to the ketene C of 6c. The same is
expected for the case of 4iic and, in contrast to what was found
for 4c where N-3 looks rather like another electrophile.
Along Path B, the alternative considered for 6 is to react
directly with 4 generating a newC-N bond to the N-2 of the triazine
ring, passing through TS6-8ib/c (at a relative free energy of 1.46
and 1.13 kcal/mol, respectively) for reaching the intermediate 8i,
which readily tautomerizes to 8ii, the latter being the most stable
intermediate. Then, 8ii isomerizes via a three-membered ring TS,
TS8ii-5, which leads to the final product 5. The transition state
TS8ii-5b is notably lower in energy (9.0 kcal/mol) than the
counterpart TS8ii-5c (see Figure 5). In this case the effect of the
electron donor group changes the electron distribution on the π
systems of both the pyrazole and triazine rings. This confers to
TS8ii-5c a more bound character, turning it harder to rearrange
than TS8ii-5b, as confirmed through the NBO analysis depicted
on the Figure S2 of the SI, where the Wiberg bond orders are
summarized for the two TSs.
The third possible intermolecular reaction of 6 is the
encounter with the tautomer 4i of the reactant as it is depicted in
the Path C (Scheme 4). An encounter complex between 6 and 4i
yields the intermediate 5i, passing through the transition state
TS6-5i at a relative energy of about 2.5 kcal/mol (similar for R =
Ph and R = p-OMe-C6H4). This TS lies at a relative energy slightly
higher than either TS6-8i or TS4ii-5ii (Path A, discussed earlier)
(between 1 and 2.5 kcal/mol above those for the reaction of 6+4ii
via Path A and 6+4 via Path B, respectively). However, 5i still lies
at a relative high free energy and, once formed, it readily
tautomerizes to the final product 5 without the irreversible
formation of the stable isomer 8ii, as in the case of Path B.
Path D considers the isomerization of 6 to the fused
azetinone intermediate 9 via the intramolecular attack of its
ketene C to its imine N. This intermediate could directly attack the
nitrogen N-3 of 4, since it initiates the adduct formation by
transferring its proton, turning N-3 nucleophilic at the time it
approaches the amide carbonyl group. The TS9-5, which is at 5.8
and 9.8 kcal/mol of relative free energy for 9b and 9c respectively,
finally leads to the final product 5 (figures S4). In this case the
electron densities drawn by each different substituent make a
small difference in energy (about 4 kcal/mol).
All paths discussed so far start from an earlier nitrogen
molecule release. However, different possibilities can be
considered for a later N2 release. One of them, with the lowest
free energy, was labeled as Path E and is discussed with
illustrative purposes. However, it would be extremely unlikely in
comparison to the alternatives arisen from the earlier N2 release
and the intermediacy of iminoketene 6 (Paths A-D). A comparison
of the different free energy profiles for paths A to E is shown on
Figure 6 for R = Ph and Figure 7 for R = p-OMe-C6H4.
Along Path E, 4 would first open the ring (alone or concerted
with the association to other molecule of 4, not shown) to form 7,
a ketene nucleophile with retention of all the nitrogen atoms of the
broken triazine. This azoketene 7 later couples with 4 to give
adduct 10i. Next up, this adduct tautomerizes to 10ii and finally
releases a molecule of N2 thus yielding the intermediate 5ii, a
tautomer of the product 5. It should be clearly remarked than all
the TS and even the most stable intermediate within pathway E
are always fairly at higher free energies than the energy of the
highest TS in the pathways based on the earlier N2 release (A, B,
C and D) (Scheme 4, Figures 6 and 7).
The comparison of Figures 6 and 7 reveals that the phenyl
and anisyl derivatives follow very similar pathways always
passing through the iminoketene key intermediate 6. However,
the possibility of certain control of the kinetics after the irreversible
formation of the isomer 8ii seems to be more likely to happen in
the case of the 4c→ 5c reaction, as shown in the previous
discussion and Figure 5.
Figure 5. Structure and main geometry features of the TSs for the N-2 →N-3
rearrangement for giving products 5b / 5c through the Path B. a) TS8ii-5b;
b) TS8ii-5c. Vectors indicate the imaginary frequency xyz displacement vectors.
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Figure 6. Free energy profiles for the mechanistic pathways of the 4b→ 5b
reaction. Colors codes correspond to the Paths A-E, as in Scheme 4.
Scheme 5. Reactions of pyrazolotriazinone 4b under different conditions.
On the other hand, it has been reported that chlorination of
pyrazolotriazinones with phosphorus oxychloride gives pyrazole-
4-carbonyl chlorides [11] by reaction of the iminoketene
intermediate with the chlorinated agent. When we treated 4b with
refluxing SOCl2 and DMF in catalytic amounts, the pyrazole-4-
carboxylic acid 11 was isolated as main product (52% yield),
instead of the pyrazole-4-carbonyl chloride which surely
hydrolyzes under reaction conditions.
To confirm the importance of nucleophilic species in the
reaction, the nitrogen elimination reaction of pyrazolotriazinone
4b was carried out in the presence of two amino compounds, p-
toluidine and aminopyrazole 3b. Reaction with toluidine afforded
amide 13 in 59% yield, while in the reaction with 3b, an attractive
pyrazolyl-pyrazole carboxamide 14 was formed (59% yield).
Pyrazolotriazinone 5b was not detected in any case in the
reaction mixture. These findings would support that the
intermediates formed from 4b can react with other nucleophilic
species (amines or water) faster than with other triazinone 4b to
give amides or acid products.
Figure 7. Free energy profiles for the mechanistic pathways of the 4c→ 5c
reaction. Colors codes correspond to the Paths A-E, as in Scheme 4.
Following, several experiments were proposed in order to
clarify the reaction mechanism and verify the presence of the
reaction intermediates. First, thermolysis of 4b was carried out in
a mixture of benzene/water as solvent (Scheme 5). It is known
that ketenes like 6 in the presence of water easily form carboxylic
acids.[19] Analysis of the reaction mixture showed the presence of
the amino-acid derivative 11 (63% yield) and the aminopyrazole
12 (11% yield). The formation of 12 can be rationalized by
decarboxylation of 11, subjected to solvent refluxing for many
hours.[28]
Conclusions
A
novel thermal transformation of 7-aryl/heteroaryl-
pyrazolo[3,4-d][1,2,3]triazin-4-ones was studied. The
combination of one molecule of pyrazolotriazinone with the
iminoketene produced by nitrogen elimination from the other
molecule of pyrazolotriazinone, could explain the formation of
attractive 3-(pyrazole-carbonyl)-pyrazolotriazinone derivatives. In
this case the nucleophilic substitution of ketene is carried out by
the N-3 of the triazinone moiety to form the amide product. The
reaction was carried out for 7-aryl-substituted pyrazolotriazines
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10.1002/ejoc.201701538
European Journal of Organic Chemistry
FULL PAPER
filtration and washed with cold ethanol. The spectral characteristics of
while the pyridinyl derivative was almost un-reactive, perhaps
because of the stability of the triazinone ring, regarding the
nitrogen extrusion reaction.
compounds 3a-d,f correspond to literature values.[5,6,29]
5-Amino-1-(3-fluorophenyl)-1H-pyrazole-4-carbonitrile (3e):
This
The mechanistic study undoubtedly discarded the possibility
of nitrogen molecule release at any stage different from the very
first step of the mechanism (TS4i-6, Scheme 4 and Figure 2),
leading to the iminoketene intermediate 6. The iminoketene was
found as the key intermediate for continuing through the four
reasonable pathways, all of them with TSs and intermediates
below the energy of TS4i-6. Once 6 is formed, it can either
isomerize to the azetinone 9, before coupling with the reactant 4
as in Path D, or directly react with 4 (Path B) or one of its
tautomers, either 4i (Path C) or 4ii (Path A). The fate of the phenyl
derivative would clearly be rate-controlled by the N2 release
following the preferred Path A. Similar behavior would be
expected for the anisyl derivative, except that in this case, once
6c is formed the smaller barrier for proceeding would conduct
Path B, which further involves an irreversible reaction producing
an isomer of the final product which slowly isomerizes.
compound was obtained as a yellow solid in a 74% yield (149 mg). 1H NMR
(400 MHz, (CD3)2CO, 25°C): δ= 7.71 (s, 1H, 3-H), 7.60 (td, J = 8.2, 6.5 Hz,
1H, 12-H), 7.46 (ddd, J = 8.1, 1.7, 0.8 Hz, 1H, 13-H), 7.40 (br. dt, J = 9.8,
2.1 Hz, 1H, 9-H), 7.23 (tdd, J = 8.6, 2.5, 0.9 Hz, 1H, 11-H), 6.25 (br. s, 2H,
7-H) ppm. 13C NMR δ= 163.7 (d, J = 245.8 Hz, C10), 152.2 (C5), 142.5
(C3), 140.3 (d, J = 10.2 Hz, C8), 132.1 (d, J = 9.2 Hz, C12), 120.9 (d, J =
3.1 Hz, C13), 115.7 (d, J = 21.2 Hz, C11), 114.4 (C6), 112.4 (d, J = 25.0
Hz, C9), 76.1 (C4) ppm.
5-Amino-1-(pyridin-2-yl)-1H-pyrazole-4-carbonitrile
(3g):
This
compound was obtained as a yellow solid in a 48% yield (88 mg). 1H NMR
(400 MHz, (CD3)2SO, 25°C): δ= 8.47 (ddd, J = 4.9, 1.7, 0.7 Hz, 1H, 10-H),
8.11 (br. s, 2H,7-H), 8.02 (ddd, J = 8.5, 7.4, 1.9 Hz, 1H, 12-H), 7.89 (s, 1H,
2-H), 7.85 (br. d, J = 8,4 Hz, 1H, 13-H), 7.35 (ddd, J = 7.4, 5.0, 1.0 Hz, 1H,
11-H). 13C NMR (101 MHz, (CD3)2SO, 25°C): δ= 153.2 (C8), 153.0 (C5),
147.1 (C10), 142.5 (C3), 139.9 (C12), 121.2 (C11), 114.4 (C6), 113.3
(C13), 73.3 (C4) ppm.
In agreement with calculations, reactions of phenyl-derivative 4b
would endorse the presence of an iminoketene intermediate 6 in
the ring opening of triazinone in the same way as in previously
reactions described for benzotriazinones.
The synthesis of amides like 5, 13 or 14 through the application
of this simple methodology opens a range of possibilities to get
General procedure for the synthesis of pyrazolo[3,4-d][1,2,3]triazin-
4-ones (4b-g): Aqueous NaNO2 (0.124 g, 1.8 mmol, 1 mL) was added to
a stirred and cooled solution (0–5 °C) of pyrazole 3 (1 mmol) in a mixture
of HCl:AcOH (3:1, 20 mL) over a period of 10 min. The reaction mixture
was allowed to warm at room temperature and was stirred for 20 h. The
precipitate of pyrazolotriazinone was then filtered off, and the residue was
diluted with water (20 mL), extracted with dichloromethane (3 x 30 mL),
and dried with anhydrous MgSO4. The resulting solution was concentrated
to dryness, and the solid was then subject to chromatographic column
separation with dichloromethane and dichloromethane/ethyl acetate in
different proportions. The spectral characteristics of compounds 4b-d,f
correspond to literature values. [5,6]
heterocyclic
amides
containing
both
pyrazolyl
and
pyrazolotriazinyl substituents.
Experimental Section
General: All reagents obtained from commercial sources were used
without further purification. Microwave experiments were carried out in a
CEM-Discovery Labmate monomode equipment. NMR spectra were
recorded on a 400 MHz Bruker spectrometer (1H at 400.16 MHz and 13C
at 100.62 MHz) at ambient temperature. Solutions were typically prepared
in either deuterochloroform (CDCl3), deuteroacetone ((CD3)2CO) or
deuterated dimethylsulfoxide (DMSO-d6) with chemical shifts referenced
to deuterated solvent as an internal standard. 1H NMR data are reported
indicating the chemical shift (δ), the multiplicity (s, singlet; d, doublet; t,
triplet; q, quartet; m, multiplet; br, broad; dd, doublet of doublets, etc.), the
coupling constant (J) in Hz and the integration (e.g. 1H). HRMS were
recorded by using the electrospray ionization (ESI) technique and Q-TOF
detection. FT-IR spectra where realized using Nicolet iN10 system
(Thermo Scientific, USA) with MCT (mercury cadmium telluride) detector
and Ominc Picta workstation. Spectra were collected in high-resolution (8
cm-1) mode and 64 scans.
7-(3-Fluorophenyl)-4H-pyrazolo[3,4-d][1,2,3]triazin-4-one (4e): This
1
compound was obtained as a white powder in a 52% yield (120 mg). H
NMR (400 MHz, (CD3)2SO, 25°C): δ= 15.39 (s, 1H, 5-H), 8.65 (s, 1H, 3-H),
8.00 ─ 7.93 (m, 2H, 8, 12-H), 7.70 (dt, J = 8.3, 6.6 Hz, 1H, 11-H), 7.38 (tdd,
J = 8.5, 2.5, 0.8 Hz, 1H, 10-H) ppm. 13C NMR (101 MHz, (CD3)2SO, 25°C):
δ= 162.1 (d, J = 244.5 Hz, C9), 153.7 (C4), 148.3 (C7a), 138.8 (d, J = 10.7
Hz, C13), 135.8 (C3), 131.5 (d, J = 9.1 Hz, C11), 118.3 (d, J = 3.0 Hz, C12),
115.1 (d, J = 20.9 Hz, C10), 109.7 (d, J = 26.6 Hz, C8), 108.1 (C3a) ppm.
HRMS (ESI+): calculated for C10H7N5OFH+ 232.06291; found 232.06279.
7-(Pyridin-2-yl)-4H-pyrazolo[3,4-d][1,2,3]triazin-4-one
(4g):
This
compound was obtained as yellow crystals in a 39% yield (83 mg). 1H NMR
(400 MHz, (CD3)2SO, 25°C): δ= 8.64 (ddd, J = 4.8, 1.8, 0.7 Hz, 1H, 9-H),
8.49 (s, 1H, 3-H), 8.14 (td, J = 7.6, 1.9 Hz, 1H, 10-H), 7.82 (dt, J = 8.2, 0.8
Hz, 1H, 12-H), 7.63 (ddd, J = 7.5, 4.8, 1.0 Hz, 1H, 11-H) ppm. 13C NMR
(101 MHz, (CD3)2SO, 25°C): δ= 149.7 (C4), 148.6 (C9), 143.4 (C3), 139.9
(C10), 133.4 (C7a), 125.0 (C11), 119.0 (C12), 111.7 (C13), 94.4 (C3a)
ppm.
General procedure for the synthesis of 5-amino-1H-pyrazole-4-
carbonitrile (3a-g): Ethoxymethylenemalononitrile 1 (0.122 g, 1 mmol),
and triethylamine (0.14 mL, 1.2 mmol) were added to a mixture of
hydrazine 2 (1.2 mmol) in ethanol (2 mL) and heated using microwave
irradiation for 2-7 minutes at 100 °C, 300 W, in a closed system. To obtain
compound 3a the hydrazine sulfate salt was used, while for compounds
3b-g hydrazine hydrochloride was employed. In case of 3b and 3g, the
solid obtained was isolated by filtration and washed with cold water. For
compounds 3a, 3c-f, the residue was extracted with chloroform (3 x 5 mL)
and dried with anhydrous MgSO4. The resulting solution was concentrated
to dryness and the solid was recrystallized from ethanol, isolated by
General procedure for the synthesis of 3-(5-amino-pyrazole-4-
carbonyl)-pyrazolo[3,4-d][1,2,3]triazin-4-ones (5b-g): Benzene (10 mL)
was added to pyrazolotriazines 4 (0.25 mmol), stirred and heated to reflux
for 2-6 h. The solvent was then evaporated and the solid obtained was
purified by chromatographic column with dichloromethane/ethyl acetate in
different proportions.
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10.1002/ejoc.201701538
European Journal of Organic Chemistry
FULL PAPER
3-(5-Amino-1-phenyl-1H-pyrazole-4-carbonyl)-7-phenyl-3,7-dihydro-
4H-pyrazolo[3,4-d][1,2,3]triazin-4-one (5b): This compound was
obtained as a white solid in a 67% yield (66 mg), m.p. 189.2 ºC (dec.). 1H
NMR (400 MHz, (CD3)2CO, 25°C): δ= 8.54 (s, 1H,3-H), 8.20 – 8.17 (m, 2H,
8, 12-H), 7.74 (s, 1H, 3’-H), 7.71-7.64 (m, 4H, 9,11,8’, 12’-H), 7.61 – 7.54
(m, 3H, 10, 9’, 11’-H), 7.48 (tt, J = 7.3, 1.3 Hz, 1H, 10’-H), 6.94 (s, 2H, 5’-
H) ppm. 13C NMR (101 MHz, (CD3)2CO, 25°C): δ= 163.6 (C6’), 153.2 (C5’),
152.9 (C4), 148.6 (C7a), 142.6 (C3’), 138.9 (C13), 138.3 (C7’), 136.5 (C3),
130.6 (C9’, 11’), 130.4 (C9, 11), 129.4 (C10), 129.3 (C10’), 125.2 (C8’, 12’),
123.7 (C8, 12), 109.4 (C3a), 100.7 (C4’) ppm. MS (EI): m/z (%) = 399 (7)
[M + 1]+, 398 (8) [M]+, 370 (30), 328 (12), 213 (45), 186 (77), 156 (11), 91
3-(5-Amino-1-(2-fluorophenyl)-1H-pyrazole-4-carbonyl)-7-(2-
fluorophenyl)-3,7-dihydro-4H-pyrazolo[3,4-d][1,2,3]triazin-4-one (5f):
This compound was obtained as a white solid, with 66% yield (71 mg), m.p.
193.4 ºC (dec.). 1H NMR (400 MHz, (CD3)2SO, 25°C): δ= 8.82 (s, 1H, 3-
H), 7.85 (td, J = 7.8, 1.6 Hz, 1H, 11’-H), 7.80 (s, 1H, 3’-H), 7.76 – 7.70 (m,
1H, 12’-H), 7.67 – 7.64 (m, 1H, 9’-H), 7.62 – 7.58 (m, 2H, 11, 12-H), 7.55
– 7.46 (m, 2H, 9, 10’-H), 7.44 (br. s, 2H, 5’-H), 7.41 – 7.37 (m, 1H, 10-H)
ppm. 13C NMR (100 MHz, (CD3)2SO, 25°C): δ= 161.6 (C6’), 157.0 (J =
251.1 Hz, C8), 155.9 (J = 252.6 Hz, C8’), 153.4 (C5’), 152.0 (C4), 148.5
(C7a), 142.6 (C3’), 136.9 (C3), 132.3 (J = 7,8 Hz, C12’), 131.6 (J = 7.8 Hz,
C12), 129.4 (C11), 128.9 (C11’), 125.5 (J = 3.9 Hz, C10’), 125.4 (J = 3.9
Hz, C10), 124.3 (J = 13.4 Hz, C13), 124.2 (J = 11.7 Hz, C7’), 117.2 (J =
19.0 Hz, C9’), 117.1 (J = 18.9 Hz, C9), 107.6 (C3a), 98.3 (C4’) ppm. MS
(EI): m/z (%)= 435 (9) [M + 1]+, 434 (9) [M]+, 407 (19), 406 (18), 365 (10),
364 (10), 231 (19), 204 (100), 184 (30), 161 (14), 149 (12), 137 (19), 123
(21), 109 (39), 95 (91), 75 (44), 52 (23). HRMS (ESI+): calculated for
C20H12N8O2F2Na+ 457.0949; found 457.0943.
+
(32), 77 (100), 51 (42). HRMS (ESI+): calculated for C20H15N8O2
399.13187; found 399.1321. IR (KBr): 3434.83 cm-1 (υN-H), 1712.84 cm-1
(υC=O ketone), 1686.35 cm-1 (υC=O amide), 1609.81 cm-1 (υC=C
aromatic).
3-(5-Amino-1-(4-methoxyphenyl)-1H-pyrazole-4-carbonyl)-7-(4-
methoxyphenyl)-3,7-dihydro-4H-pyrazolo[3,4-d][1,2,3]triazin-4-one
(5c): This compound was obtained as a yellow solid in a 46% yield (52 mg),
m.p. 190.5 ºC (dec.). 1H NMR (400 MHz, (CD3)2SO, 25ºC): δ= 8.72 (s, 1H,
3-H), 7.95 (d, J = 9.0 Hz, 2H, 8, 12-H), 7.73 (s, 1H, 3’-H), 7.47 (d, J = 8.9
Hz, 2H, 8’, 12’-H), 7.23 (d, J = 9.1 Hz, 2H, 9’, 11’-H), 7.18 (br. s, 2H, 5’-H),
7.11 (d, J = 8.9 Hz, 2H, 9, 11-H), 3.87 (s, 3H, 13-H), 3.83 (s, 3H, 13’-H)
ppm. 13C NMR (100 MHz, (CD3)2SO 25ºC): δ= 162.0 (C6’), 159.3 (C10),
159.1 (C10’), 152.1 (C5’), 152.0 (C4), 147.2 (C7a), 141.8 (C3’), 135.8 (C3),
130.3 (C7’), 129.7 (C14), 126.4 (C8’, 12’), 124.7 (C8, 12), 114.8 (C9, 11,
9’, 11’), 107.7 (C3a), 99.1 (C4’), 55.6 (C13), 55.5 (C13’) ppm. MS (EI): m/z
(%)= 430 (58), 388 (7), 243 (60), 216(77), 215 (100), 206 (19), 199 (18),
185 (10), 172 (17), 132 (16), 120 (36), 106 (33), 93 (30), 76 (61), 63 (62),
51 (70), 43 (83). HRMS (ESI+): calculated for C22H19N8O4+ 459.1529; found
459.1529.
Synthesis of 5-amino-1-phenyl-1H-pyrazole-4-carboxylic acid (11):
Method 1: Pyrazolotriazinone 4b (0.051 g, 0.24 mmol) was treated with
refluxing SOCl2 (3 mL) and catalytic amounts of DMF for 2h. After that time,
the mixture was evaporated under reduced pressure, and the resultant
solid was washed three times with dichloromethane (15 mL) to facilitate
the elimination of remaining SOCl2. This solid was purified by column
chromatography, using CH2Cl2/ PhMe/MeOH (8:1:1) as solvent mixture, to
1
give 11 (52 %) as a yellow solid: H-RMN (400 MHz, CD3)2SO, 25°C): δ=
6,28 (broad singlet, 2H), 7,39-7,43 (m, 1H 7,51-7,56 (m, 4H), 7,68 (s, 1H),
12,07 (broad singlet, 1H) ppm. 13C-RMN (100MHz, (CD3)2SO): δ= 95,30;
123,44; 127,38; 129,43; 137,99; 140,51; 149,86; 165,26 ppm. MS (EI): m/z
(%) = 204 (68) [M + 1]+, 203 (79) [M]+, 185 (96), 184 (84), 156 (21), 130
(7), 119 (7), 103 (12), 91 (57), 77 (100), 65 (18), 54 (20), 53 (61), 52 (54),
41 (20).
3-(5-Amino-1-(4-fluorophenyl)-1H-pyrazole-4-carbonyl)-7-(4-
fluorophenyl)-3,7-dihydro-4H-pyrazolo[3,4-d][1,2,3]triazin-4-one (5d):
This compound was obtained as a yellow solid in a 62% yield (67 mg), m.p.
182.2 ºC (dec.). 1H NMR (400 MHz, (CD3)2SO, 25°C): δ= 8,76 (s, 1H, 3-
H), 8.13-8.09 (m, 2H, 8, 12-H), 7.75 (s, 1H, 3’-H), 7.63-7.59 (m, 2H, 8‘, 12’-
H), 7.54 (br. t, J = 8.8 Hz, 9, 11-H), 7.41 (br. t, J = 8.8 Hz, 9’, 11’-H), 7.34
(br. S, 2H, 5’-H) ppm. 13C NMR (100 MHz, (CD3)2SO, 25°C): δ= 161.8 (C6’),
161.6 (J = 246.3 Hz, C10), 161.5 (J = 245.4 Hz, C10’), 152.2 (C5’), 152.1
(C4), 147.5 (C7a), 142.2 (C3’), 136.2 (C3), 133.7 (J = 2.9 Hz, C13), 133.3
(J = 2.8 Hz, C13’), 127.2 (J = 9.1 Hz, C8’, 12’), 125.3 (J = 8.9 Hz, C8, 12),
116.6 (J = 23.3 Hz, C9, 11), 116.5 (J = 23.1 Hz, C9’, 11’), 108.1 (C3a),
99.2 (C4’) ppm. MS (EI): m/z (%)= 434 (2) [M]+, 433 (2), 405, (10), 363 (4),
231 (20), 204 (41), 174 (6), 149 (7), 132 (7), 121 (13), 109 (37), 95 (100),
75 (52), 52 (33). HRMS (ESI+): calculated for C20H12N8O2F2Na+ 457.0949;
found 457.0949.
Method 2: A mixture of 4b (0.047 g, 0.22 mmol), benzene (7.2 mL) and
water (0.8 mL) was refluxed by 6 h. The reaction was then cooled and a
white solid was obtained, it was filtered and submitted to analysis. This
solid was identified as 1-phenyl-1H-pyrazol-5-amine (12) and all spectral
characteristics correspond to literature values. 27 The aqueous-organic
mixture recovered from the filtration was separated, the organic phase was
dried (MgSO4), filtered and the filtrate was evaporated under reduce
pressure to give a yellow solid. Then, this solid was redissolved in acetone
and analyzed by GC-MS. The analysis showed the presence of 11 (63%
yield) as main product and traces of 12 (11% yield).
Synthesis
of
5-amino-1-phenyl-N-(p-tolyl)-1H-pyrazole-4-
carboxamide (13): Benzene (4 mL) was added to a mixture of
pyrazolotriazine 4b (0.023 g, 0.11 mmol) and p-toluidine (0.027 g, 0.25
mmol), stirred and heated to reflux for 5 h. The solution was kept at room
temperature and a white solid was formed after 24 h. The precipitate was
then filtered off, washed with cold water and dried to give 13 (19 mg, 59%
3-(5-Amino-1-(3-fluorophenyl)-1H-pyrazole-4-carbonyl)-7-(3-
fluorophenyl)-3,7-dihydro-4H-pyrazolo[3,4-d][1,2,3]triazin-4-one (5e):
This compound was obtained as a yellow solid in a 51% yield (55 mg), m.p.
1
yield) as a yellow solid. H NMR (400 MHz, (CD3)2CO, 25°C): δ= 8.91 (s,
1
148.3 ºC (dec.). H NMR (400 MHz, (CD3)2CO, 25°C): δ= 8.80 (s, 1H, 3-
1H, 14-H), 8.01 (s, 1H, 3-H), 7.64 – 7.62 (m, 4H, 9-13-16-20-H), 7.54 (br.
t, J = 7.9 Hz, 2H, 10-12-H), 7.40 (br. t, J = 7.4 Hz, 1H, 11-H), 7.12 (d, J =
8.2 Hz, 2H, 17-19-H), 6.30 (br. s, 2H, 6-H), 2.28 (s, 3H, 21-H) ppm. 13C
NMR (101 MHz, (CD3)2CO, 25°C): δ= 163.9 (C7), 150.8 (C5), 139.5 (C8),
138.7 (C3), 138.0 (C15), 133.1 (C18*), 133.1 (C18*), 130.3 (C10, 12),
129.9 (C17, 19), 128.2 (C11), 124.3 (C9, 13), 120.8 (C16*, 20*), 120.7
(C16*, 20*), 98.9 (determined by HMBC correlation, C4), 20.8 (C21) ppm.
*Mixture of interconverting rotational isomers with respect to the amide
bond. IR (KBr): 3464.60- 3313.64 cm-1 (υN-H), 1642.15 cm-1 (υC=O
amide).
H), 8.05 – 7.97 (m, 2H, 8, 12-H), 7.80 (s, 1H, 3’-H), 7.77 – 7.67 (m, 1H, 11-
H), 7.64 – 7.59 (m, 1H, 11’-H), 7.48 – 7.31 (m, 6H, 10, 5’, 8’,10’, 12’-H).
13C NMR (101 MHz, (CD3)2CO, 25°C): δ= 162.1 (d, J = 244.9 Hz, C9, 9‘),
161.7 (C6‘), 152.1 (C5‘), 151.9 (C4), 147.7 (C7a), 142.5 (C3‘), 138.5 (d, J
= 10.1 Hz, C13), 138.3 (d, J = 10.5 Hz, C13‘), 136.6 (C3), 131.6 (d, J = 9.0
Hz, C11), 131.3 (d, J = 9.2 Hz, C11‘), 120.4 (d, J = 2.5 Hz, C12‘), 118.6 (d,
J = 2.6 Hz, C12), 115.4 (d, J = 21.0 Hz, C10), 115.1 (d, J = 20.9 Hz, C10‘),
111.8 (d, J = 24.6 Hz, C8‘), 109.9 (d, J = 26.7 Hz, C8), 108.5 (C3a), 99.2
(C4‘) ppm. HRMS (ESI+): calculated for C20H13N8O2F2+ 435.11240; found
435.11201.
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10.1002/ejoc.201701538
European Journal of Organic Chemistry
FULL PAPER
Synthesis of 5-amino-N-(4-cyano-1-phenyl-1H-pyrazol-5-yl)-1-phenyl-
1H-pyrazole-4-carboxamide (14): A mixture of pyrazolotriazinone 4b
(0.107 g, 0.50 mmol) and 5-amino-1-(phenyl)-1H-pyrazole-4-carbonitrile
(3b) (0.092 g, 0.50 mmol) in benzene (15 mL) was refluxed for 3 h. After
that time, the solvent was evaporated and the solid residue was purified
by column chromatography (dichloromethane: ethyl acetate, 9:1) to give
14 as a yellow solid (109 mg, 59% yield): 1H-RMN (400 MHz, CD3)2SO,
25°C): δ= 6.50 (br.s, 2H, 6-H), 7.38-7.49 (m, 2H), 7.52–7.60 (m, 8H), 8.00
(s, 1H,3´-H), 8.34 (s, 1H, 3-H), 10.32 (br. s, 1H, 6´-H) ppm. 13C-RMN (100
MHz, (CD3)2SO): δ= 90.8 (C4´); 96 (C4); 113.0 (C7´); 123.6 (C9,13,9´,13´);
123.7 (C9,13,9´,13´); 127.6 (C11´); 128.8 (C11); 129.5 (C10,12,10´,12´);
129.6 (C10,12,10´,12´); 137.6 (C8); 137.7 (C8´); 138.7 (C5); 141.2 (C5´);
142.4 (C3); 150.1 (C3´); 162.6 (C7) ppm. MS (EI): m/z (%)= 369 (M+, 2);
368 (M-1, 2); 206 (2); 186 (100); 131 (10); 77 (54); 51 (24).
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Computational Procedure: The potential energy surface exploration was
carried out using the Gaussian 09 package for the DFT calculations.[30] All
the relevant stationary points along the main paths, reactants, TSs,
intermediates, and products were fully calculated using the range
separated correction of the B3LYP functional, CAM-B3LYP (CAM,
Coulomb Attenuating Method) with 6-311+G(d,p) basis set.[31] The
obtained stationary points were characterized by means of the Hessian
diagonalization and further harmonic frequencies analyses for obtaining
zero point and thermal corrections to the energy, enthalpy and free energy.
In relevant cases, IRC simulations were started from the TS computed
modes, using mass weighted coordinates and maximum step size ranging
from 0.014 to 0.045 atomic units.[22] A summary of IRC simulations for most
cases are included as figures S7 to S16, showing the electronic energy
(relative to the TS energy) against the range of the intrinsic reaction
coordinate explored and 3D structures of intermediates and TSs. All
optimizations and frequencies analyses were done within the IEFPCM
model for benzene, [32] the solvent used in the synthesis of 5b-c starting
for 4b-c. For the case of the 4b  5b mechanism, the structures of all
stationary points found were also subjected to single point energy
calculations at the MP2, MP3 and MP4(DQ)/6-311+G(d,p) levels of
theory,[33] also in IEFPCM benzene as solvent. The results are summarized
on Table S2. The free energy profiles obtained at the MP2, MP3, MP4 and
CAM-B3LYP levels of theory are superimposed for each of the individual
paths A-E in the figure S6 which show a general good agreement between
the DFT and MP4 ab initio results. Visualization and graphics rendering
were done with Molden and VMD 1.8.9.[34] The relative free energies
reported on Scheme 4 were obtained by taken the standard free energy
from the normal analysis of reactants 4b and 4c as reference, i.e. two
equivalents of the reactants as zero. The electronic energies in Hartrees,
zero point energy and thermal corrections are available as SI table S1, as
well as the whole set of cartesian coordinates of all stationary points (SI,
Part 3).
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This work was supported by SECYT-UNC together with the
National Research Council of Argentina (CONICET). M. L. Sciú
acknowledges the receipt of a scholarship from the CONICET.
The authors also thank Dr. Novruz Akhmedov (West Virginia
University, USA) for his valuable contribution in the structural
elucidation of pyrazolotriazine compounds.
Keywords: pyrazolotriazine • nitrogen extrusion • iminoketene •
quantum-chemical calculations • diazotization
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10.1002/ejoc.201701538
European Journal of Organic Chemistry
FULL PAPER
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This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701538
European Journal of Organic Chemistry
FULL PAPER
FULL PAPER
Azolotriazines
Juan P. Colomer, María L. Sciú, Cristina
L. Ramirez, Silvia M. Soria-Castro, D.
Mariano A. Vera* and Elizabeth L.
Moyano*
Page No. – Page No.
The thermal ring opening of pyrazolotriazinones affords pyrazolecarbonyl-
pyrazolotriazin-4-ones in one pot reaction. Experimental and computational
investigations explain the mechanism operating in this reaction.
A straightforward synthesis of 3-
pyrazolecarbonyl-pyrazolo[3,4-
d][1,2,3]triazin-4-ones: an
experimental and theoretical study
This article is protected by copyright. All rights reserved.