A new cyclization to fused pyrazoles tunable for pericyclic or pseudopericyclic route: An experimental and theoretical study

Article abstract of DOI:10.1021/jo800483a

(Chemical Equation Presented) 2-Pyrazinyl (2) and 3-pyridazinylketone arylhydrazones (6) and their benzologues undergo a ring closure reaction to yield pyrazolo[3,4-b]pyrazines (4) and pyrazolo[4,3-c]pyridazines (7), respectively, in acceptable to good yi

Full text of DOI:10.1021/jo800483a

A New Cyclization to Fused Pyrazoles Tunable for Pericyclic or
Pseudopericyclic Route: An Experimental and Theoretical Study
´
La´szlo´ Fila´k, Tibor Andra´s Rokob, Gyo¨ngyve´r Agnes Vasko´, Orsolya Egyed,
´
Agnes Go¨mo¨ry, Zsuzsanna Riedl, and Gyo¨rgy Hajo´s*
Chemical Research Center, Hungarian Academy of Sciences, Pusztaszeri u´t 59-67,
H-1025 Budapest, Hungary
ghajos@chemres.hu
ReceiVed February 29, 2008
2-Pyrazinyl (2) and 3-pyridazinylketone arylhydrazones (6) and their benzologues undergo a ring closure
reaction to yield pyrazolo[3,4-b]pyrazines (4) and pyrazolo[4,3-c]pyridazines (7), respectively, in acceptable
to good yields. The reaction was found to be accelerated by using acidic or basic conditions. Quantum
chemical calculations suggest the key step of the mechanism to be a direct cyclization; analysis of
aromaticity based on computed magnetic properties revealed its medium-dependent pericyclic or
pseudopericyclic character. The cyclization reaction has also been extended for the synthesis of related
ring systems (9, 12, 14).
Introduction
Some years ago we reported1 that [1,2,3]triazolo[1,5-a]py-
razinium salt c (Figure 1), accessible by oxidative cyclization
of the 4-chlorophenylhydrazone (b) obtained from the appropri-
ate ketone (a), easily undergoes thermal rearrangement to yield
the reactive valence bond isomeric diazaallenium cation (d),
which species spontaneously cyclizes either on the phenyl
substituent or the pyrazine ring. Thus, accordingly, formation
of an indazole (e) and pyrazolo[3,4-b]pyrazine (f) has been
experienced.
In the course of detailed experimental research of these
transformations, chromatographic analysis of the reaction
mixture of transformation afb indicated, quite unexpectedly,
the presence of f as a side product in variable amounts. Careful
isolation and comparison of this side product formed besides b
and one of the main products (f) obtained from c via d
unambiguously supported their structural identity, and thus,
further investigation of the transformation aff seemed of
particular interest.
FIGURE 1. Chart of different reaction pathways leading to pyra-
zolo[3,4-b]pyrazines (f).
Results and Discussion
Results of experiments with transformation 1f2 carried out
under various reaction conditions revealed that under the earlier
established conditions (sodium acetate in ethanol) the hydrazone
(2) is the main product, whereas under acidic conditions a
* To whom correspondence should be addressed. Phone: +36-1-4381110.
Fax: +36-1-4381145.
(1) Be´res, M.; Hajo´s, Gy.; Riedl, Zs.; Soo´s, T.; Tima´ri, G.; Messmer, A. J.
Org. Chem. 1999, 64, 5499.
3900 J. Org. Chem. 2008, 73, 3900–3906
10.1021/jo800483a CCC: $40.75 2008 American Chemical Society
Published on Web 04/18/2008

New Cyclization to Fused Pyrazoles
SCHEME 1
dramatic change occurs and the fused pyrazole 4 is only formed
in moderate to good yields (Scheme 1). When some selected
hydrazones were treated under acidic conditions, that is, with
application of the same conditions as that used with the
successful synthesis of 4 from 1, the same pyrazolo[3,4-
b]pyrazines were obtained, which strongly supports the fact that
hydrazones 2 are intermediates along the pathway 1-4. This
cyclization provides a simple, general approach to pyrazolo[3,4-
b]pyrazine derivatives, which were earlier available only by
more sophisticated methods.1,2
Concerning the reaction mechanism of this ring closure,
several possibilities can be outlined. The fact that the pyrazole
ring closure is successful in the presence of acid suggests that
the main ring closing step might be a nucleophilic attack of the
hydrazone-N atom at the pyrazine ring activated by protonation
to give the dihydro intermediate 3 (which can exist in some of
the possible tautomeric forms, e.g. 3, 3′, or 3′′),3 and then areal
oxidation could lead to the heteroaromatic product (4). Similar
activation at the hydrazone site of the molecule was also found
successful: when 2a or 2b was treated with DBU and, thus, a
powerful negatively charged nitrogen nucleophile was formed,
the same ring closure took place and 4a or 4b, respectively,
was obtained in good yield.
reacted with arylhydrazines in the presence of acid, gave rise
to pyrazolo[4,3-c]pyridazines (7a, 7b). To the best of our
knowledge, only a few representatives of this ring system have
been synthesized before by using different approaches.4 Similar
to the analogous pyrazine derivatives, also this transformation
proceeds via formation of the hydrazones (6), which can be
isolated when 5 is reacted with an arylhydrazine under buffered
conditions. Transformation of 6 to 7 under thermal conditions
has also been accomplished: heating 6c in dichlorobenzene (at
140 °C) for 12 h gave rise to formation of 7c in medium yield.
Our efforts to carry out analogous pyrazole-fusion to pyrim-
idines, unfortunately, failed and only decomposition was
experienced.
SCHEME 2
Although all of these mechanistic considerations seemed to
be in accordance with the experimental finding, another
explanation should also be considered: inspection of the double
bonds and lone pair of the hydrazone-nitrogen atom in 2 reveals
that these three electron pairs could also interact in a pericyclic
manner. To find experimental support for this supposition,
hydrazone 2a was heated in pure 1,2-dichlorobenzene without
the presence of any acid or base. Under somewhat more forced
conditions (at 140 °C, for 12 h), the ring closure was successful,
and 4a was obtained in the same yield as under acidic
conditions.
The ring closure methodology was also successfully extended
for pyridazines (Scheme 2). Thus, pyridazinyl ketone (5a), when
After the successful cyclizations with two diazines, the
question arose if similar transformation could also be carried
out with pyridinylhydrazones. In the case of 2-pyridylketone
hydrazone, the reactivity of position 3 against a nucleophile is
obviously much less than that of diazines; however, the
pericyclic route could, in principle, be realized. In accordance
with these considerations, treatment of the hydrazone 8 either
with acid or with base did not result in any ring closure. Heating
(2) (a) Chien, T.-C.; Smaldone, R. A.; Townsend, L. B. Tetrahedron Lett.
2004, 45, 4105. (b) Sicker, D.; Mann, G.; Hofmann, J. J. Pract. Chem. 1990,
586, 381. (c) Cecchi, L.; Constanzo, A.; Vettori, L. P.; Auzzi, G.; Bruni, F.;
Sio, F. Farmaco Ed. Sci. 1982, 37, 116. Starting from substituted pyrazine: (d)
Foks, H.; Pancechowska-Ksepko, D.; Kedzia, A.; Zwolska, Y.; Janowiec, M.;
Augistynowicz-Kopec, E. Farmaco 2005, 60, 513. (e) Elgemeie, G. E. H.;
Elfahhan, H. A.; Ghozlan, S. A. S.; Elnagdi, M. H. Bull. Chem. Soc. Jpn. 1984,
57, 1650. (f) Kocevar, M.; Tisler, M.; Stanovnik, B. Heterocycles 1982, 19,
339. (g) Kocevar, M.; Vercek, B.; Stanovnik, B.; Tisler, M. Monatsh. Chem.
1982, 113, 731.
(4) (a) Baig, G. U.; Stevens, M. F. G. J. Chem. Soc., Perkin Trans. 1 1981,
1424. (b) Tretyakov, E. V.; Knight, D. W.; Vasilevsky, S. F. J. Chem. Soc.,
Perkin Trans. 1 1999, 3721.
(3) Our efforts to detect the intermediate formation of this dihydro species
by NMR spectrosopy, unfortunately, failed.
J. Org. Chem. Vol. 73, No. 10, 2008 3901

Fila´k et al.
FIGURE 2. Proposed reaction mechanism and energetics for the cyclization of 2e in apolar solvent. (Inset) Arbitrary atom numbering used in text.
in dichlorobenzene at 190 °C, in turn, proved to be suitable for
the cyclization, and 9 was isolated in medium yield (Scheme
3).5
hydrogen bond, the ring closure can therefore proceed directly
from the most stable conformer having C3-H· · ·N9 contact.
Protonation of 2e can occur at several positions but the N4
protonated form is predicted to be most stable and to have the
lowest cyclization barrier. For both acid and base catalysis, the
energy profile of the reaction is similar to the neutral case, but
the ring closure requires significantly less activation free energy
(24.8 kcal/mol in acidic, 21.7 kcal/mol in basic medium), in
accordance with experimental results. Cyclization of the neutral
2e to B is endothermic, with late transition state as predicted
by the Hammond postulate. In this step, catalytic effect of both
acids and bases is therefore mainly based on stabilizing the
zwitterionic product B as compared to the respective form of
the hydrazone. Acid catalysis is most effective at N4, which is
expected and has been indeed calculated to be the most basic
site in B.
The investigated ring closure proceeds via reorganization of
electrons around the perimeter of the forming heterocycle. Such
reactions may have cyclic orbital overlap in their transition
states, in which case they follow appropriate stereochemistry
to achieve aromaticity with the given number of electrons
(pericyclic reactions).7,8 However, ring atoms (usually heteroa-
toms) may participate with more than a single orbital in the
reaction, which means disconnection in the cyclic overlap, and
therefore, absence of aromaticity and stereochemical require-
ments (pseudopericyclic reactions).9–14 The nonuniqueness of
the MO picture can make distinction based on involved orbitals
ambigous;10,11 therefore, other means have been proposed to
classify reactions as pericyclic or pseudopericyclic. Among
SCHEME 3
To unravel the mechanism of the ring closure, quantum
chemical calculations have been carried out for the cyclization
of 2e.6 As the investigated hydrazones are air-stable compounds,
it was assumed that ring closure precedes oxidation. The latter,
being probably an exergonic, multistep radical reaction with
molecular oxygen, has not been studied; neither has the
formation of the Z geometric isomer of the hydrazone required
for the cyclization.
In apolar solvents, the most stable form of the Z-hydrazone
is predicted to be the one having an internal N9-H· · ·N1
hydrogen bond, which must be broken to achieve the conforma-
tion A suitable for the ring closure (Figure 2). Direct cyclization
to intermediate B is feasible; the overall barrier of this process
is high (39.5 kcal/mol), which explains the need for elevated
temperature to accomplish this transformation. B is thermody-
namically unstable, lying 34.3 kcal/mol above 2e, but its
rearomatization to 3′e or 3′′e via tautomerization might be the
next step rendering already the ring closure exergonic; the above
proposed structure 3e might be an intermediate here. An
alternative route might start with the formation of the zwitte-
rionic tautomer C, which can then cyclize through a slightly
lower barrier (36.7 kcal/mol) to another unstable intermediate
D. Oxidation might proceed directly from intermediates B or
D, or from any one of their tautomers (including 3e, 3′e, and
3′′e).
(7) (a) Evans, M. G.; Warhurst, E. Trans. Faraday. Soc. 1938, 34, 614. (b)
Woodward, R. B.; Hoffmann, R. Angew. Chem., Int. Ed. Engl. 1969, 8, 781. (c)
Zimmerman, H. E. Acc. Chem. Res. 1971, 4, 272. (d) Dewar, M. J. S. Angew.
Chem., Int. Ed. Engl. 1971, 10, 761. (e) See special issue 5 dedicated to
aromaticity: Chem. ReV. 2001, 101.
(8) Herges, R.; Jiao, H.; Schleyer, P. v. R. Angew. Chem., Int. Ed. Engl.
1994, 33, 1376.
(9) Ross, J. A.; Seiders, R. P.; Lemal, D. M. J. Am. Chem. Soc. 1976, 98,
4325.
For the catalyzed cases only (de)protonated species were
compared to each other. Deprotonation of the attacking N9
nitrogen atom of 2e precludes the formation of the N9-H· · ·N1
(10) Snyder, J. P.; Halgren, T. A. J. Am. Chem. Soc. 1980, 102, 2861.
(11) Birney, D. M.; Wagenseller, P. E. J. Am. Chem. Soc. 1994, 116, 6262.
(12) Cabaleiro-Lago, E. M.; Rodr´ıguez-Otero, J.; Varela-Varela, S. M.; Pen˜a-
Gallego, A.; Hermida-Ramo´n, J. M. J. Org. Chem. 2005, 70, 3921.
(13) Fabian, W. M. F.; Bakulev, V. A.; Kappe, C. O. J. Org. Chem. 1998,
63, 5801.
(5) (a) Soo´s, T.; Hajo´s, Gy.; Messmer, A. J. Org. Chem. 1997, 62, 1136. (b)
Foster, E. H.; Hurst, J. J. Chem. Soc., Perkin Trans. 1 1976, 507. (c) Foster,
E. H.; Hurst, J. J. Chem. Soc., Perkin Trans. 1 1973, 2901.
(14) Subbotina, J. O.; Bakulev, V. A.; Herges, R.; Fabian, W. M. F. Int. J.
Quantum Chem. 2006, 106, 2229.
(6) For detailed energetics, see Supporting Information.
3902 J. Org. Chem. Vol. 73, No. 10, 2008

New Cyclization to Fused Pyrazoles
SCHEME 4
FIGURE 3. NICS values calculated along the IRC paths.
others,13,15 characteristic magnetic properties of aromatic sys-
tems have been shown to be useful for this purpose.8,16,17 For
instance, strong magnetic shielding caused by aromatic ring
currents can be detected by calculating nucleus independent
chemical shift (NICS) values18 near the center of the forming
ring.
Following literature recommendations, we calculated NICS
values at the center of the ring as well as 0.5 Å and 1 Å above
and below along the intrinsic reaction coordinate (IRC) path of
the ring closure step.12,19 Presence of a minimum with large
negative values in these curves points to enhancement of
aromaticity, characteristic for pericyclic reactions. After observ-
ing atomic motions along the IRC, for drawing conclusions we
have chosen the data calculated 1 Å away from the center on
the side from which the pyrazine ring is attacked, as cyclic
overlap of the p orbitals is supposed to be the largest, influence
of localized σ bonds the smallest here.12,19,20 All calculated
curves are given in the Supporting Information.
Geometric and magnetic aspects (Figure 3) both support that
cyclization of the neutral molecule is a pericyclic disrotatory
electrocyclization, which is a thermally allowed process for such
10e- systems according to the Woodward-Hoffmann rules.
Cyclization of the N4 protonated form has less expressed
pericyclic character. While both HOMO and LUMO of the
neutral system spread to both the aromatic ring and the hydra-
zone side chain, protonation causes the HOMO to be more
localized on the side chain, LUMO on the pyrazine ring (see
Figure 4). Electrocyclization character is therefore decreased
in favor of aromatic nucleophilic addition. However, removing
the proton from N9 (either via deprotonation by base or in
tautomerization to the zwitterionic C) leads to a completely
different picture. One of its two lone pairs can remain conjugated
with the π system during the whole course of the cyclization,
whereas the other one attacks the carbon atom. Involvement of
two orbitals of N9 suggests orbital disconnection preventing
aromatization, which is clearly demonstrated by the NICS curve.
These reaction routes can therefore be classified as pseudoperi-
cyclic.
The relatively mild reaction conditions and the acceptable
yields supported the preparative importance of the experienced
ring closure and, thus, extension of this methodology for
benzologues of the above-discussed azines has been decided.
Our literature survey indicated that similar ring closure with
quinoxalines have been described: Boguslavskiy et al.21 de-
scribed that treatment of 2-quinoxalylketone hydrazones with
diluted sulfuric acid on air resulted in fused pyrazoles, whereas
Sarodnick et al. carried out similar ring closure in xylene at
high temperature in the presence of chloranil.22
In one of our recent publications,23 we have reported on
difficulties with transformation of 3-cinnolylketones (10) to
hydrazones, and only the 4-nitrophenyl derivative (11) could
be isolated. We have now found that with treatment of the
majority of these ketones with arylhydrazines, a spontaneous
ring closure to pyazolo[4,3-c]cinnolines (12) occurs (Scheme
4). The facile cyclization found under acidic conditions is
obviously caused by the enhanced sensitivity of position 4
against nucleophiles due to the presence of the fused benzene
ring. A different ring closure starting from 4-hydroxy substituted
cinnolinylketone hydrazones to related substances has also been
reported.24
Presence of the fused benzene ring in 3-isoquinolinylketone
hydrazones was found not effective enough to facilitate the
pyrazole formation and treatment of 3-isoquinolylketones with
arylhydrazines under acidic conditions gave only hydrazones.
Application of the thermal ring closure technique, however,
(15) Subbotina, J. O.; Sadchikova, E. V.; Bakulev, V. A.; Fabian, W. M. F.;
Herges, R. Int. J. Quantum Chem. 2007, 107, 2479.
(16) Chen, Z.; Wannere, C. S.; Corminboeuf, C.; Puchta, R.; Schleyer, P. v.
R. Chem. ReV. 2005, 105, 3842 and references therein.
(17) Geuenich, D.; Hess, K.; Ko¨hler, F.; Herges, R. Chem. ReV. 2005, 105,
3758 and references therein.
(21) Boguslavskiy, A. M.; Ponizowskiy, M. G.; Kodess, M. I.; Charushin,
V. N. Russ. Chem. Bull., Int. Ed. 2003, 52, 2175.
(22) Sarodnick, G.; Heydenreich, M.; Linker, T.; Kleinpeter, E. Tetrahedron
2003, 59, 6311.
(18) Schleyer, P. v. R.; Maerker, C.; Dransfeld, A.; Jiao, H.; Hommes, N. J. R.
v. E. J. Am. Chem. Soc. 1996, 118, 6317.
(19) Schleyer, P. v. R.; Manoharan, M.; Wang, Z.; Kiran, B.; Jiao, H.; Puchta,
R.; Hommes, N. J. R. v. E. Org. Lett. 2001, 3, 2465.
´
(23) Vasko´, Gy. A.; Riedl, Zs.; Egyed, O.; Hajo´s, Gy. ArkiVoc 2008, iii, 25.
(20) de Lera, A. R.; Alvarez, R.; Lecea, B.; Torrado, A.; Coss´ıo, F. P. Angew.
Chem., Int. Ed. 2001, 40, 557.
(24) Youssef, M. S. K.; El-Dean, A. M. K.; Abbady, M. S.; Hassan, K. M.
Collect. Czech. Chem. Commun. 1991, 56, 8.
J. Org. Chem. Vol. 73, No. 10, 2008 3903

Fila´k et al.
FIGURE 4. Molecular orbitals of various forms of Z-2e at d(C3-N9) ) 2.21 Å.
SCHEME 5
unscaled frequencies, using standard formulas in the ideal gas
approximation as implemented in Gaussian, and refer to 298.15 K
and 1 atm. Relative electronic energies were determined using
single-point spin component scaled MP2 (SCS-MP2) method28
employing the aug-cc-pVTZ basis set29 with the resolution of
identity (RI) integral approximation.30 Free energies of solvation
were estimated31 from the conductor-like polarizable continuum
model32 (CPCM) with HF wave function and the 6-31+G** basis
set,27,33 using the in vacuo optimized geometries and van der Waals
radii from Bondi.34 Toluene, ethanol, and THF were used as solvent
for the neutral case, acid, and base catalysis, respectively. Reported
energy values refer to relative Gibbs free energies of solvated
species. Transition states were further analyzed by intrinsic reaction
coordinate (IRC) calculations35 at the B3LYP/6-31G* level. These
usually failed before reaching the respective minima, but they
revealed a significant portion of the path. Aromaticity was studied
using NICS values16,18 calculated at the geometrical centers of the
forming rings, as well as 0.5 and 1 Å above and below. The GIAO-
B3LYP/6-31+G* method36 was used for this purpose.
proved to be successful: heating of hydrazone 13 in dichlo-
robenzene for 6 h resulted in formation of the pyrazolo[4,3-
c]isoquinoline derivative 14 (Scheme 5). This tricyclic product
proved to be identical with those obtained by us earlier via a
different reaction pathway.
Conclusion
Our findings reveal that azinyl and diazinyl ketone hydrazones
are suitable starting materials for ring closure to fused pyrazoles.
Quantum chemical calculations reveal that the mechanism of
these cyclizations specifically depend on the applied reaction
conditions: under thermal conditions, the transformation is
clearly of pericyclic nature, and under acidic conditions, where
the nucleophilic character of the hydrazone side chain is
obviously decisive, the pericyclic character of the cyclization
is still present. In the presence of a strong base, the ring closure
can also be carried out, and the calculations suggest that
pseudoelectrocyclization takes place in this case.
Syntheses of 2-(4-chlorobenzoyl)pyrazine38 (1a), acetylpyrazine38
(1b), 3-(4-chlorobenzoyl)pyridazine (5a),37 3-acetylpyridazine (5b),37
2-(4-chlorobenzoyl)pyridine39 (E)-2-((2-(4-bromophenyl)hydrazono)-
(4-chlorophenyl)methyl)pyrazine (2a),38 (E)-2-(1-(2-(4-bromophenyl)-
hydrazono)ethyl)pyrazine (2d),38 3- (E)-[2-(4-bromophenyl)hydrazi-
nylidene](4-chlorophenyl)methyl]pyridazine (6a),37 (E)-3-(1-(2-(4-
bromophenyl)-hydrazono)ethyl)pyridazine (6c),37 1-(4-bromophenyl)-
3-(4-chlorophenyl)-1H-pyrazolo[3,4-b]pyrazine(4a),38andcinnolylketones
(10)40 have been published earlier.
General Procedure for Hydrazones 2, 6, and 8. A mixture of
the appropriate ketone (1, 5 or 2(4-Cl-benzoyl)pyridine 5 mmol),
substituted phenylhydrazine hydrochloride (6.1 mmol), and NaOAc
(4.9 g, 60 mmol) was stirred in a mixture of ethanol (15 mL) and
Experimental Section
724. (b) Hehre, W. J.; Ditchfield, R.; Pople, J. A. J. Chem. Phys. 1972, 56,
2257. (c) Hariharan, P. C.; Pople, J. A. Theor. Chim. Acta 1973, 28, 213.
(28) (a) Møller, C.; Plesset, M. S. Phys. ReV. 1934, 46, 618. (b) Grimme, S.
J. Chem. Phys. 2003, 118, 9095.
Computational Details. The Gaussian and Turbomole software
packages25 were used throughout this study. Stationary points of
the potential energy surface were located at the B3LYP/6-31G*
density functional level of theory,26,27 and their nature (minimum
or first-order saddle point) was confirmed by harmonic vibrational
analysis at the same level (having 0 and 1 imaginary frequency,
respectively). Thermodynamic corrections were estimated from
(29) (a) Dunning, T. H., Jr J. Chem. Phys. 1989, 90, 1007. (b) Kendall, R. A.;
Dunning, T. H., Jr.; Harrison, R. J. J. Chem. Phys. 1992, 96, 6796.
(30) (a) Feyereisen, M.; Fitzgerald, G.; Komornicki, A. Chem. Phys. Lett.
1993, 208, 359. (b) Weigend, F.; Ha¨ser, M. Theor. Chem. Acc. 1997, 97, 331.
(31) Takano, Y.; Houk, K. N. J. Chem. Theory Comput. 2005, 1, 70.
(32) (a) Klamt, A.; Schu¨u¨rmann, G. J. Chem. Soc., Perkin Trans. 2 1993,
799. (b) Andzelm, J.; Ko¨lmel, C.; Klamt, A. J. Chem. Phys. 1995, 103, 9312.
(c) Barone, V.; Cossi, M. J. Phys. Chem. A 1998, 102, 1995. (d) Cossi, M.;
Rega, N.; Scalmani, G.; Barone, V. J. Comput. Chem. 2003, 24, 669.
(33) Clark, T.; Chandrasekhar, J.; Spitznagel, G. W.; Schleyer, P. v. R.
J. Comput. Chem. 1983, 4, 294.
(25) (a) Frisch, M. J.; et al. Gaussian 03, revision B.05; Gaussian, Inc.:
Wallingford, CT, 2004. (b) Ahlrichs, R.; et al. TURBOMOLE, version 5.9.1;
Universita¨t Karlsruhe: Karlsruhe, Germany, 2007. Full references are given in
Supporting Information.
(26) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648. (b) Lee, C.; Yang, W.;
Parr, R. G. Phys. ReV. B 1988, 37, 785. (c) Stephens, P. J.; Devlin, F. J.;
Chabalowski, C. F.; Frisch, M. J. J. Phys. Chem. 1994, 98, 11623.
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(34) Bondi, A. J. Chem. Phys. 1964, 68, 441.
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8251 and references therein.
3904 J. Org. Chem. Vol. 73, No. 10, 2008

New Cyclization to Fused Pyrazoles
chloroform (10 mL) at rt. The progress of the reaction was
monitored by TLC. After disappearance of the starting material,
water (100 mL) and saturated NaHCO3 solution (pH ) 7-8) were
added. The organic layer was separated, and the aqueous phase
was extracted with chloroform (3 × 30 mL). The combined organic
layer was dried over Na2SO4 and evaporated. The crude product
was subjected to flash chromatography over silica by using hexane/
EtOAc ) 4:1 as eluent. The product was recrystallized from ethanol.
General Procedure for the Synthesis of Pyrazoles 4 and 7
from Ketones under Acidic Conditions. A mixture of the
appropriate ketone (10 mmol), arylhydrazine (12 mmol), saturated
HCl in ethanol (0.5 mL), and ethanol (30 mL) was refluxed for
4-24 h. The progress of the reaction was monitored by TLC. After
disappearance of the starting material water (50 mL) was added,
and the solution was made basic (pH ) 8) with 1 M NaOH. The
reaction mixture was extracted with chloroform, and the organic
layer was dried over Na2SO4 and evaporated. The residue was flash
chromatographed over silica by using chloroform as eluent. The
product was recrystallized from acetonitrile.
3-(4-Chlorophenyl)-1-(4-nitrophenyl)-1H-pyrazolo[3,4-b]pyra-
zine (4c). This compound was obtained from 2-(4-chloroben-
zoyl)pyrazine (1a, 10 mmol, 2.19 g) and (4-nitrophenyl)hydrazine
hydrochloride (12 mmol, 2.27 g) to give the title compound (1.93
g, 55%) as brown crystals, mp 182-184 °C;. IR (KBr) νmax: 1596,
1515, 1503, 1401, 1342, 1201, 1111, 1091, 958, 854 cm-1; 1H NMR
(CDCl3) δ (ppm): 7.52 (2H, m, H3′+H5′), 8.41 (2H, m, H3′′+H5′′),
8.55 (2H, m, H2′+H6′), 8.72 (2H, m, H2′′+H6′′), 8.64 + 8.77
(2H, 2×d, J ) 2.2 Hz, H5+H6); 13C NMR (CDCl3) δ (ppm): 120.0
(C2′′+C6′′), 125.4 (C3′′+C5′′), 129.0 (C2′+C6′), 129.4 (C3′+C5′),
129.5 (C3a), 135.0 (C1′), 135.9 (C4′), 142.4 (C5), 143.5 (C6), 144.1
(C7a), 144.2 (C4′′), 145.2 (C1′′), 145.3 (C3). Anal. Calcd for
C17H10ClN5O2 (351.05): C, 58.05; H, 2.87; N, 19.91; Found: C,
58.12; H, 2.65; N, 19.67.
3-(4-Chlorophenyl)-1-p-tolyl-1H-pyrazolo[3,4-b]pyrazine (4b).
This compound was obtained from 2-(4-chlorobenzoyl)pyrazine (1a,
10 mmol, 2.19 g) and p-tolylhydrazine hydrochloride (12 mmol,
1.91 g) to give 1.98 g of the product (62%) as yellow crystals, mp
160-161 °C.
1-(4-Bromophenyl)-3-(4-chlorophenyl)-1H-pyrazolo[3,4-b]pyra-
zine (4a). This compound was obtained from 2-(4-chloroben-
zoyl)pyrazine (1a, 10 mmol, 2.19 g) and (4-bromophenyl)hydrazine
hydrochloride (12 mmol, 2.68 g) to give 4a (2.35 g, 61%) as orange
crystals, mp 202-203 °C.
(E)-2-((4-Chlorophenyl)(2-p-tolylhydrazono)methyl)pyra-
zine (2b). This compound was obtained from 2-(4-chloroben-
zoyl)pyrazine (1a, 5.0 mmol, 1.10 g) and 4-methylphenylhydrazine
hydrochloride (6.1 mmol, 0.95 g) to give the title compound (1.20
g, 75%) as yellow crystals, mp 184-185 °C; IR (KBr) νmax: 3163,
1
3031, 1512, 1402, 1248, 1011, 814 cm-1; H NMR (CDCl3) δ
(ppm): 2.29 (3H, s, CH3), 7.00-7.18 (4H, m, H2′′+H3′′+H5′′+H6′′),
7.32 (2H, m, H3′+H5′), 7.58 (2H, m, H2′+H6′), 7.86 (1H, s, NH),
8.36 (2H, m, H5+H6), 9.45 (1H, d, J ) 1.1 Hz, H3);. 13C NMR
(CDCl3) δ (ppm): 20.6 (CH3′′), 113.4 (C2′′+C6′′), 129.9 (C3′′+C5′′),
130.0 (C2′+C6′), 130.8 (C3′+C5′), 135.6 (C4′′), 139.6 (C1′′), 141.0
(C6), 141.6 (C3), 142.0 (C5), 142.9 + 143.0 (C1′+C4′), 145.7
(CdN), 151.8 (C2). Anal. Calcd for C18H15ClN4 (322.10): C, 66.98;
H, 4.68; N, 17.36; Found: C, 66.97; H, 4.71; N, 17.20.
(E)-2-((4-Chlorophenyl)(2-(4-nitrophenyl)hydrazono)meth-
yl)pyrazine (2c). This compound was obtained from 2-(4-chlo-
robenzoyl)pyrazine (1a, 5.0 mmol, 1.10 g) and 4-nitrophenylhy-
drazine hydrochloride (6.1 mmol, 1.15 g) to give 1.42 g of product
(81%) as yellow crystals; mp 210-215 °C.
(E)-2-(1-(2-p-Tolylhydrazono)Ethyl)Pyrazine (2e). This com-
pound was obtained from acetylpyrazine (1b, 5.0 mmol, 0.61 g)
and p-tolylhydrazine hydrochloride (6.1 mmol, 0.95 g) to give
0.96 g of the product (85%) as deep-red crystals, mp 155 °C.
(E)-3-((4-Chlorophenyl)(2-p-tolylhydrazono)methyl)py-
ridazine (6b). This compound was obtained from 3-p-chloroben-
zoylpyridazine (5a, 5.0 mmol, 1.10 g) and p-tolylhydrazine
hydrochloride (6.1 mmol, 0.95 g) to give 1.24 g of the product
1-(4-Bromophenyl)-3-methyl-1H-pyrazolo[3,4-b]pyrazine (4d).
This compound was obtained from acetylpyrazine (1b, 10 mmol,
1.22 g) and (4-bromophenyl)hydrazine hydrochloride (12 mmol,
2.68 g) to give 1.67 g of the product (58%); orange crystals, mp
134-136 °C.
(77%) as pale-yellow crystals, mp 187-192 °C; IR (KBr) νmax
:
3278, 1613, 1558, 1519, 1430, 1252, 1141, 1090, 1013 cm-1; H
NMR (DMSO-d6) δ (ppm): 2.20 (3H, s, CH3′′), 7.05 (2H, m,
H2′′+H6′′), 7.23 (2H, m, H3′′+H5′′), 7.38 (2H, m, H3′+H5′), 7.60
(2H, m, H2′+H6′), 7.66 (1H, dd, J ) 6.0 + 3.2 Hz, H5), 8.35
(1H, d, J ) 6.0 Hz, H4), 9.04 (1H, d, J ) 3.2 Hz, H6), 9.53 (1H,
s, NH); 13C NMR (DMSO-d6) δ (ppm): 21.2 (CH3′′), 114.6
(C2′′+C6′′), 124.4 (C4), 127.7 (C5), 129.9 (C3′′+C5′′), 130.1
(C4′′), 130.3 (C3′+C5′), 131.9 (C4′), 132.6 (C2′+C6′), 134.3 (C1′),
139.2 (C1”), 143.3 (CdN), 151.0 (C6), 159.8 (C3). HRMS (EI):
M+, found 322.0983. C18H15ClN4 requires 322.0985.
1
3-Methyl-1-p-tolyl-1H-pyrazolo[3,4-b]pyrazine (4e). This com-
pound was obtained from acetylpyrazine (1b, 10 mmol, 1.22 g) to
and p-tolylhydrazine hydrochloride (12 mmol, 1.91 g) to give 1.32 g
of the product (59%) as brown crystals, mp 83-84 °C.
1-(4-Bromophenyl)-3-(4-chlorophenyl)-1H-pyrazolo[4,3-c]py-
ridazine (7a). This compound was obtained from 3-(4-chloroben-
zoyl)pyridazine (5a, 10 mmol, 2.19 g) and (4-bromophenyl)hydra-
zine hydrochloride (12 mmol, 2.68 g) to give 2.63 g (68%) of 7a
as pale-yellow crystals, mp 212-214 °C; IR (KBr) νmax: 3079, 2919,
1589, 1574, 1492, 1394, 1093, 1072, 824 cm-1; 1H NMR (CDCl3)
δ (ppm): 7.52 (2H, m, H3′+H5′), 7.65 (2H, m, H3′′+H5′′), 7.72
(2H, m, H2′′+H6′′), 7.78 (1H, d, J ) 6.2 Hz, H7), 8.50 (2H, m,
H2′+H6′), 9.22 (1H, d, J ) 6.2 Hz, H6); 13C NMR (CDCl3) δ
(ppm): 106.3 (C7), 121.3 (C4′′), 123.4 (C2′′+C6′′), 128.8 (C3a),
129.1 (C2′+C6′), 129.2 (C3′+C5′), 131.5 (C1′), 133.0 (C3′′+C5′′),
136.0 (C4′), 137.7 (C7a), 145.2 (C3), 145.6 (C6), 147.1 (C1′′). Anal.
Calcd for C17H10BrClN4 (383.98): C, 52.95; H, 2.61; N, 14.53;
Found: C, 52.95; H, 2.49; N, 14.25.
(E)-2-((2-(4-Bromophenyl)Hydrazono)(4-chlorophenyl)meth-
yl)pyridine (8). This compound was obtained from 2-(4-chloroben-
zoyl)pyridine (5.0 mmol, 1.08 g) and (4-bromophenyl)hydrazine
hydrochloride (6.1 mmol, 1.35 g) to give 1.58 g (82%) of 8; yellow
crystals, mp 186-190 °C; IR (KBr) νmax: 3277, 1592, 1560, 1494,
1
1426, 1242, 1132, 1070, 829 cm-1; H NMR (CDCl3) δ (ppm):
7.00 (2H, m, H3′+H5′), 7.17 (1H, m, H5), 7.31 (2H, m, H2′′+H6′′),
7.36 (2H, m, H3′′+H5′′), 7.56 (2H, m, H2′+H6′), 7.68 (1H, s, NH),
7.72 (1H, m, H4), 8.15 (1H, d, J ) 8.1 Hz, H3), 8.48 (1H, d, J )
4.2 Hz, H6); 13C NMR (CDCl3) δ (ppm): 112.8 (C4′′), 114.8
(C2′′+C6′′), 120.6 (C3), 122.5 (C5), 128.5 (C1′), 129.9 (C2′+C6′),
130.7 (C3′+C5′), 132.1 (C3′′+C5′′), 135.4 (C4), 136.1 (C4′), 143.0
(C1′′), 143.7 (CdN), 148.9 (C6), 155.9 (C2). Anal. Calcd for
C18H13BrClN3 (385.00): C, 55.91; H, 3.39; N, 10.87; Found: C,
55.77; H, 3.33; N, 10.86.
3-(4-Chlorophenyl)-1-p-tolyl-1H-pyrazolo[4,3-c]pyridazine (7b).
This compound was obtained from 3-p-chlorobenzoylpyridazine
(5a, 10 mmol, 2.19 g) p-tolylhydrazine hydrochloride (12 mmol,
1.91 g) to give 2.28 g of the product (71%) as yellow crystals, mp
185-187 °C.
General Procedure for the Synthesis of 4 and 7 under Basic
Medium. A mixture of the appropriate hydrazone (0.5 mmol), DBU
(1 mL), and THF (20 mL) was refluxed for 4-8 h. The progress
of the reaction was monitored by TLC. After disappearance of the
starting material, water (50 mL) was added, the solution was
extracted with chloroform, and the organic layer was dried over
(37) Riedl, Zs.; Hajo´s, Gy.; Messmer, A. J. Heterocyclic Chem. 1993, 30,
819.
(38) Be´res, M.; Hajo´s, Gy.; Riedl, Zs.; Tima´ri, G.; Messmer, A.; Holly, S.;
Schantl, J. G. Tetrahedron 1997, 53, 9393.
(39) Corey, E. J.; Helal, C. J. Tetrahedron Lett. 1996, 37, 5675.
(40) Al-Awadi, N. A.; Elnagdi, M. H.; Ibrahim, Y. A.; Kaul, K.; Kumar, A.
Tetrahedron 2001, 57, 1609.
J. Org. Chem. Vol. 73, No. 10, 2008 3905

Fila´k et al.
Na2SO4 and evaporated. The residue was flash chromatographed
over silica by using hexane/EtOAc ) 4:1 as eluent.
General Procedure of Preparation of Pyrazolo[4,3-c]cinno-
lines (12). A mixture of the appropriate cinnolinylketone (10, 5.0
mmol) ethanol (50 mL), (4-bromophenyl)hydrazine hydrochloride
or p-tolylhydrazine hydrochloride (1.67 g, or 1.20 g, respectively,
7.5 mmol), and 5N hydrochlorid acid in ethanol (1.27 mL) was
refluxed for 4.5 h. The mixture was cooled, and the precipitated
solid was collected. The crystals were suspended in water and
extracted with chloroform, and the organic layer was dried over
Na2SO4, filtered, and evaporated. The residue was boiled in ethanol
(20 mL), the mixture was cooled, and the crystalline product was
filtered off and recrystallized from dimethyl formamide.
3-(4-Nitrophenyl)-1-p-tolyl-1H-pyrazolo[4,3-c]cinnoline (12d).
This compound was obtained from cinnolin-3-yl(4-nitrophenyl)-
methanone (10d, 1.40 g), and p-tolylhydrazine hydrochloride to
give 0.97 g (51%) of 12d as pale-yellow crystals, mp 288-289
°C; νmax: 3073, 2922, 1600, 1509, 1346, 836, 764 cm-1; 1H NMR
(CDCl3) δ (ppm): 2.6 (3H, s, Me), 7.5 (2H, m, H3′+H5′), 7.62
(2H, m, H2′+H6′), 7.77 (2H, m, H8+ H9), 7.95 (1H, m, H7), 8.38
(2H, m, H2′′+ H6′′), 8.76 (1H, d, J ) 8.0 Hz, H6), 9.0 (2H, m,
H3′′+H5′′); 13C NMR (CDCl3) δ (ppm): 21.4 (CH3), 112.9 (C9a),
120.8 (C9), 123.8 (C2′′+C6′′), 126.4 (C2′+C6′), 128.5 (C3′′+C5′′),
128.6 (C3a), 130.1 (C7), 130.5 (C3′+C5′), 131.0 (C6), 131.5 (C8),
137.2 (C3), 137.4 (C1′), 139.3 (C1a), 140.6 (C4′), 143.2 (C4′′),
146.3 (C5a), 147.8 (C1′′); Anal. Calcd for C22H15N5O2 (381.39):
C, 69.28; H, 3.96; N, 18.36; Found: C, 69.28; H, 3.96; N, 18.36.
1-(4-Bromophenyl)-3-phenyl-1H-pyrazolo[4,3-c]cinnoline (12a).
This compound was obtained from cinnolin-3-yl(phenyl)methanone
(10a, 1.17 g), and (4-bromophenyl)hydrazine hydrochloride to give
1.0 g (45%) of product as white crystals, mp 287-289 °C.
1-(4-Bromophenyl)-3-(4-chlorophenyl)-1H-pyrazolo[4,3-c]cin-
noline(12b).Thiscompoundwasobtainedfrom(4-chlorophenyl)(cin-
nolin-3-yl)methanone (10b, 1.34 g) and (4-bromophenyl)hydrazine
hydrochloride to give 1.12 g (52%) of product as white crystals,
mp > 300 °C.
1-(4-Bromophenyl)-3-(4-chlorophenyl)-1H-pyrazolo[3,4-b]pyra-
zine (4a). This compound was obtained from (E)-2-((2-(4-bro-
mophenyl)hydrazono)(4-chlorophenyl)methyl)pyrazine (2a) (0.5
mmol, 0.193 g) to give 0.139 g (72%) of product. Physical and
spectroscopic data (mp, IR, NMR) of this product were identical
with 4a, which was earlier isolated from 2-(4-chlorobenzoyl)pyra-
zine and (4-bromophenyl)hydrazine hydrochloride under acidic
conditions.
3-(4-Chlorophenyl)-1-p-tolyl-1H-pyrazolo[3,4-b]pyrazine (4b).
This compound was obtained from (E)-2-((4-chlorophenyl)(2-p-
tolylhydrazono)methyl)pyrazine (2b) (0.5 mmol, 0.162 g) to give
4b (0.121 g, 76%). Physical and spectroscopic data (mp, IR, NMR)
of this product were identical with 4b, which was earlier isolated
from 2-(4-chlorobenzoyl)pyrazine and p-tolylhydrazinehydrochlo-
ride under acidic conditions.
3-(4-Chlorophenyl)-1-p-tolyl-1H-pyrazolo[4,3-c]pyridazine
(7b). This compound was obtained from (E)-3-((4-chlorophenyl)(2-
p-tolylhydrazono)methyl)pyridazine (6b) (0.5 mmol, 0.162 g) to
give title compound 7b (0.114 g, 70%). Physical and spectroscopic
data (mp, IR, NMR) of this product were identical with 7b, which
was earlier isolated from 2-(4-chlorobenzoyl)pyridazine and p-
tolylhydrazine hydrochloride under acidic conditions.
General Procedure for Pyrazole Formation from Hydra-
zones in 1,2-Dichlorobenzene. A mixture of the appropriate
hydrazone (2, 6, 8, and 13, 1 mmol) and 1,2-dichlorobenzene (15
mL) was stirred at 140 °C for 12-18 h. The progress of the reaction
was monitored by TLC. After disappearance of the starting material,
the reaction mixture was evaporated under reduced pressure at 140
°C and the residue was flash chromatographed over silica by using
hexane/EtOAc ) 4:1 as eluent.
1-(4-Bromophenyl)-3-(4-chlorophenyl)-1H-pyrazolo[3,4-b]pyra-
zine (4a). This compound was obtained from (E)-2-((2-(4-bromophe-
nyl)hydrazono)(4-chlorophenyl)methyl)pyrazine (2a) (1 mmol, 0.388
g) to give 0.251 g (65%) of 4a. Physical and spectroscopic data (mp,
IR, NMR) of this product were identical with 4a, which was earlier
isolated from 2-(4-chlorobenzoyl)pyrazine and (4-bromophenyl)hy-
drazine hydrochloride under acidic reaction conditions.
1,3-Bis(4-bromophenyl)-1H-pyrazolo[4,3-c]cinnoline (12c).
This compound was obtained from (4-bromophenyl)(cinnolin-3-
yl)methanone (10c, 1.57 g), and (4-bromophenyl)hydrazine hydro-
chloride to give 1.0 g (42%) of product as white crystals, mp >
300 °C.
1-(4-Bromophenyl)-3-methyl-1H-pyrazolo[4,3-c]pyridazine (7c).
This compound was obtained from (E)-3-(1-(2-(4-bromophenyl)-
hydrazono)ethyl)pyridazine (6c) (0.345 mmol, 0.1 g) to give 0.078
g of product (79%) as brown crystals, mp 192-196 °C.
1-(4-Bromophenyl)-3-(4-chlorophenyl)-1H-pyrazolo[4,3-b]py-
ridine (9). This compound was obtained from (E)-2-((2-(4-
bromophenyl)hydrazono)(4-chlorophenyl)methyl)pyridine (8, 2 mmol,
0.77 g), at 190 °C to give 0.340 g (44%) of 9 as white crystals, mp
159-162 °C; IR (KBr) νmax: 3064, 1589, 1494, 1425, 1399, 1302,
1-(4-Bromophenyl)-3-(4-methoxyphenyl)-1H-pyrazolo[4,3-
c]cinnoline (12e). This compound was obtained from cinnolin-3-
yl(4-methoxyphenyl)methanone (10e, 1.32 g), and (4-bromophe-
nyl)hydrazine hydrochloride to give 1.18 g (55%) of product as
yellow crystals, mp 255-260 °C.
Acknowledgment. T.A.R. gratefully acknowledges fruitful
discussions with Imre Pa´pai and Andra´s Stirling. This work was
partially supported by the Hungarian Research Fund (OTKA
Grant No. K-60549) and project GVOP-3.2.1-2004-04-0311/
3.0.
1
1090, 947, 825 cm-1; H NMR (CDCl3) δ (ppm): 7.38 (1H, dd, J
) 8.4, 4.2 Hz, H6), 7.48 (2H, m, H3′+H5′), 7.68 (4H, m,
H3′′+H5′′, H2′′+H6′′), 8.03 (1H, d, J ) 8.4 Hz, H7), 8.57 (2H,
m, H2′+H6′), 8.72 (1H, d, J ) 4.2 Hz, H5); 13C NMR (CDCl3) δ
(ppm): 118.3 (C6), 120.4 (C4′′), 121.5 (C7), 123.6 (C2′′+C6′′),
128.7 (C2′+C6′), 128.9 (C3′+C5′), 130.2 (C1′), 132.8 (C3′′+C5′′),
134.6 (C4′), 138.7 (C7a), 140.0 (C3), 141.1 (C1′′), 144.1 (C3a),
146.3 (C5). Anal. Calcd for C18H11BrClN3 (382.98): C, 56.20; H,
2.88; N, 10.92; Found: C, 56.23; H, 2.64; N, 10.92.
1-(4-Bromophenyl)-3-(4-chlorophenyl)-1H-pyrazolo[4,3-c]iso-
quinoline (14). This compound was obtained from (E)-3-((2-(4-
bromophenyl)hydrazono)(4-chlorophenyl)methyl)isoquinoline (13,
1 mmol, 0.435 g) to give title compound 14 (0.273 g, 63%) as
white crystals. All physical and spectroscopic data of this product
were identical with the literaturic data.
Supporting Information Available: More detailed informa-
1
tion, copy of NMR spectra of all compounds, H NMR data
(Tables S1-3), elemental analysis (Table S4), and data of
computation; full references of software packages, all calculated
NICS curves (Figure S1); detailed energetics for the cyclization
of 2e (Tables S5-7); total electronic energies (Tables S8-10);
Cartesian coordinates of all calculated stationary points. This
material is available free of charge via the Internet at http://pubs.
acs.org.
JO800483A
3906 J. Org. Chem. Vol. 73, No. 10, 2008