Quinoxalines XV. convenient synthesis and structural study of pyrazolo[1,5-a]quinoxalines

Article abstract of DOI:10.1021/jo802398g

A series of aryloxymethylquinoxaline oximes, hitherto unknown and synthesized from the corresponding aldehydes, afforded in only one step pyrazolo[1,5-a]quinoxalines in the presence of acetic anhydride at high temperatures. A formal [3,5]-sigmatropic rear

Full text of DOI:10.1021/jo802398g

Quinoxalines XV. Convenient Synthesis and Structural Study of
Pyrazolo[1,5-a]quinoxalines
Gerhard Sarodnick,† Torsten Linker,*,† Matthias Heydenreich,‡ Andreas Koch,‡
Ines Starke,‡ Sylvia Fu¨rstenberg,‡ and Erich Kleinpeter*,‡
Department of Chemistry, UniVersity of Potsdam, Karl-Liebknecht-Str. 24-25, D-14476 Potsdam, Germany
linker@chem.uni-potsdam.de; kp@chem.uni-potsdam.de
ReceiVed October 28, 2008
A series of aryloxymethylquinoxaline oximes, hitherto unknown and synthesized from the corresponding
aldehydes, afforded in only one step pyrazolo[1,5-a]quinoxalines in the presence of acetic anhydride at
high temperatures. A formal [3,5]-sigmatropic rearrangement was proposed as the mechanistic rationale
for this unprecedented transformation. Saponification with potassium hydroxide furnished the free phenol
derivatives which were studied by NMR spectroscopy and accompanying theoretical DFT calculations,
establishing intramolecular hydrogen bonding and the spatial magnetic properties. Additionally, mass
spectrometric fragmentation was investigated by B/E-linked scans and collision-induced dissociation
experiments. The fragmentation pattern devoted a new gas phase rearrangement process, which proved
to be unique and characteristic for pyrazolo[1,5-a]quinoxalines.
SCHEME 1. Synthetic Strategies to Heterocycles 2 and 43,4
Introduction
Heterocycles are of current interest for biological and medical
studies, and new synthetic strategies are a challenging task for
organic chemists.1 For instance, nitrogen-containing tricyclic
compounds were obtained from quinolines by a radical meth-
odology very recently.2 In general, tricyclic heteroaromatic
compounds have found various applications as fungicides or
herbicides and are potential enzyme inhibitors. Common
structures are 1H-pyrazolo[3,4-b]quinoxalines (flavazoles) 2,
which can be easily synthesized by oxidative cyclization of the
corresponding quinoxaline hydrazones 1 and are nowadays well-
established.3 Interestingly, the structurally related pyrazolo[1,5-
a]quinoxalines 4 were studied less intensively and were obtained
in only low yields as byproduct from the photodecomposition
of azides 3 (Scheme 1).4 This is surprising since such hetero-
cycles 4 exhibit important properties as HIV integrase inhibitors
and in vivo antitumor activities, which were discovered only
very recently.5 Herein we present a new and convenient
synthetic strategy to pyrazolo[1,5-a]quinoxalines 4, which
proceeds presumably by an interesting [3,5]-sigmatropic rear-
† Organische Chemie.
‡ Analytische Chemie.
(1) (a) Chemistry of Heterocyclic Compounds; Springer: New York, 2008;
Vol. 44. (b) AdVances in Heterocyclic Chemistry; Katritzky, A. R., Ed.; Elsevier:
London, 2008; Vol. 96.
(2) Aulenta, F.; Wefelscheid, U. K.; Bru¨dgam, I.; Reissig, H.-U. Eur. J. Org.
Chem. 2008, 2325–2335.
(3) (a) Kim, H. S.; Chung, J. Y.; Kim, E. K.; Park, Y. T.; Hong, Y. S.; Lee,
M. K.; Kurasawa, Y.; Takada, A. J. Heterocycl. Chem. 1996, 33, 1855–1858.
(b) Makino, K.; Kim, H. S.; Kurasawa, Y. J. Heterocycl. Chem. 1999, 36, 321–
328. (c) Sarodnick, G.; Linker, T. J. Heterocycl. Chem. 2001, 38, 829–836. (d)
Sarodnick, G.; Heydenreich, M.; Linker, T.; Kleinpeter, E. Tetrahedron 2003,
59, 6311–6321. (e) Heydenreich, M.; Koch, A.; Sarodnick, G.; Kleinpeter, E.
Tetrahedron 2005, 61, 2373–2385. (f) El Ashry, E. S. H.; Atta, K. F.; Aboul-
Ela, S.; Beldi, R. J. Carbohydr. Chem. 2007, 26, 1–16.
(4) (a) Albini, A.; Bettinetti, G.; Minoli, G. J. Chem. Soc., Perkin Trans. 1
1983, 2491–2494. (b) Albini, A.; Bettinetti, G.; Minoli, G. J. Am. Chem. Soc.
1997, 119, 7308–7315. (c) Albini, A.; Bettinetti, G.; Minoli, G. J. Am. Chem.
Soc. 1999, 121, 3104–3113. (d) Carra, C.; Bally, T.; Albini, A. J. Am. Chem.
Soc. 2005, 127, 5552–5562.
1282 J. Org. Chem. 2009, 74, 1282–1287
10.1021/jo802398g CCC: $40.75 2009 American Chemical Society
Published on Web 01/02/2009

Quinoxalines XV
SCHEME 2. Synthesis of Oximes 8
SCHEME 3. Synthesis of the Pyrazolo[1,5-a]quinoxalines 4a-f
rangement. Additionally, we focus on the physical organic
properties of these rarely available pyrazolo[1,5-a]quinoxalines
and studied this heterocyclic ring system in detail by an
experimental and theoretical study. In particular, the aromaticity
of the various ring units subject to spatial magnetic properties,
intramolecular hydrogen bonding, steric hindrance within the
molecules, and the unique and characteristic mass spectrometric
fragmentation of the pyrazolo[1,5-a]quinoxalines will be reported.
The formation of the pyrazolo[1,5-a]quinoxalines 4 is un-
precedented and significant from the mechanistic point of view.
Obviously, a C-O bond is broken in favor of a newly formed
N-N bond, with the driving force being aromatization to the
pyrazole ring. In the first step, the acetylation to the O-
acetyloximes 9 in the presence of acetic anhydride is likely.
Such compounds are very reactive in Beckmann rearrange-
ments,7 and even adjacent amines can form a N-N bond with
the oxime.8 Therefore, we propose a nucleophilic attack of the
quinoxaline nitrogen under cleavage of the C-O bond (Scheme
4). Formally, this transformation is a [3,5]-sigmatropic rear-
rangement, which is rarely described in literature, but was
observed during the reaction of arylhydrazones.9 The resulting
enamines 10 undergo intramolecular vinylogous Michael ad-
ditions to the activated enone, regenerating the aromatic
phenolate 11. Finally, tautomerization and elimination of acetic
acid affords the phenols 4d-f, which react with acetic anhydride
to the acetates 4a-c. This trapping step is in accordance to the
reaction of similar zwitterionic intermediates with trimethylsi-
lylcyanide, observed during the photodegradation of merocya-
nines.10 Overall, the formation of a conjugated aromatic system
and the entropically favorable elimination in the last step should
provide enough energy for this unusual [3,5]-sigmatropic
rearrangement.
Results and Discussion
Synthesis of Pyrazolo[1,5-a]quinoxalines 4. During the
course of our investigations on synthetic transformations of
quinoxalines,3c-e we developed an easy entry to the benzyl
ethers 7 from the corresponding benzyl bromides 5 and
commercially available salicylaldehydes 6.6 The reaction of the
aldehydes 7 with hydroxylamine hydrochloride proceeded
smoothly, and the hitherto unknown oximes 8a-c were isolated
in analytically pure form and excellent yields by simple
crystallization (Scheme 2).
Treatment of the oximes 8 with an excess of acetic anhydride
in the presence of sodium acetate at high temperatures afforded
directly the pyrazolo[1,5-a]quinoxalines 4a-c in moderate
yields. Finally, the free phenols 4d-f, which were of interest
from the possibility of intramolecular hydrogen bonding, were
obtained by saponification of the acetates with potassium
hydroxide (Scheme 3).
Structural Study of the Pyrazolo[1,5-a]quinoxalines 4.
1
Most interesting in the H NMR spectra of the free phenol
(7) Review: Gawley, R. E. Org. React. 1988, 35, 1–420.
(8) Review: (a) Narasaka, K.; Kitamura, M. Eur. J. Org. Chem. 2005, 21,
4505–4519. Very recent example: (b) Counceller, C. M.; Eichmann, C. C.; Wray,
B. C.; Stambuli, J. P Org. Lett. 2008, 10, 1021–1023.
(9) Fusco, R.; Sannicolo, F. J. Org. Chem. 1981, 46, 83–89.
(10) Malatesta, V.; Neri, C.; Wis, M. L.; Montanari, L.; Millini, R. J. Am.
Chem. Soc. 1997, 119, 3451–3455.
(5) (a) Wai, J. S.; Williams, P. D.; Langford, H. M. PCT Int. Appl. WO
2005120516, 2005; Chem. Abstr. 2005, 1328397. (b) Moarbess, G.; Deleuze-
Masquefa, C.; Bonnard, V.; Gayraud-Paniagua, S.; Vidal, J.-R.; Bressolle, F.;
Pinguet, F.; Bonnet, P.-A. Bioorg. Med. Chem. 2008, 16, 6601–6610.
(6) Starke, I.; Sarodnick, G.; Ovcharenko, V. V.; Pihlaja, K.; Kleinpeter, E.
Tetrahedron 2004, 60, 6063–6078.
J. Org. Chem. Vol. 74, No. 3, 2009 1283

Sarodnick et al.
SCHEME 4. Proposed Mechanism for the Formation of Pyrazolo[1,5-a]quinoxalines 4a-f
stable conformer which is completely planar. Planarity was
obtained also for the structure of the 180° phenyl rotamer C.
This conformer C, however, was found to be 4.3 kcal mol-1
(in water) and 4.9 kcal mol-1 (in chloroform) less stable than
conformer A; the same energy amount as molecular stabilization
energy of the pyrazolo[1,5-a]quinoxalines 4d-f due to the
intramolecular hydrogen bond can be suggested. The structure
of the pyrazolo[1,5-a]quinoxaline conformer without H-bond
B proves to be even less stable (7.7 kcal mol-1 in water and
8.3 kcal mol-1 in chloroform) than the 180° rotamer C. In
addition, the phenyl moiety is twisted from the plane of the
pyrazolo[1,5-a]quinoxaline moiety by ca. 40°. The additional
potential energy of B with respect to C (3.4 kcal mol-1 in water
and 3.3 kcal mol-1 in chloroform) can be assigned to steric
destabilization subject to H · · ·H contacts of pyrazolo[1,5-
a]quinoxaline and phenyl moieties.
The NH tautomers of pyrazolo[1,5-a]quinoxalines 4e were
also calculated; only the 180° rotamer D was found as a local
minimum on the potential energy surface (PES) but was 27.6
kcal mol-1 less stable than A. The corresponding NH tautomer
similar to A, but NH at the pyrazol and CdO at the phenyl
moiety, could not be identified as a minimum on the PES (the
calculation starting with the corresponding initial structure
delivered A as the energy minimum). Therefore, potential
tautomers of A in the pyrazolo[1,5-a]quinoxalines 4d-f can
be disregarded.
Along the DFT calculations, the spatial magnetic properties
of the pyrazolo[1,5-a]quinoxalines 4d-f were calculated as
through-space NMR shieldings (TSNMRS)12 which had been
successfully applied to visualize and qualitatively inform about
the aromaticity of potential aryl compounds.13 The TSNMRS
of the pyrazolo[1,5-a]quinoxalines 4e, thus obtained, are visual-
ized as iso-chemical-shielding surfaces (ICSS) of different size
and direction and are given for the preferred conformer A in
Figure 2.
FIGURE 1. Structures of the pyrazolo[1,5-a]quinoxaline derivative 4e
[global minimum (A), without H-bonding (B), 180° rotamer (C), and
NH tautomer (D)].
derivatives 4d-f is the low field position of the OH protons (δ
10.25-10.70) pointing to the existence of an intramolecular
hydrogen bond to the nitrogen atom of the pyrazol ring moiety;
variation in both solution concentration and temperature are
supportive of this assumption. Thus, initially this structure A,
the one without hydrogen bond B, and also the 180° phenyl
rotamer C were theoretically calculated employing the DFT
theory at the B3LYP/6-311G** level. Both water and chloro-
form were considered as NMR solvents applying the self-
consistent reaction field (SCRF) method and the self-consistent
isodensity polarized continuum model (SCIPCM).11 Structures,
thus obtained, and their relative energies are given for compound
4e in Figure 1.
As expected, a thorough conjugated aromatic π-system is
existent: the spatial magnetic properties of pyrazolo[1,5-
a]quinoxalines 4e as TSNMRS, visualized as common deshield-
The structure of the pyrazolo[1,5-a]quinoxaline 4e with the
intramolecular H-bond A as suggested proves to be the most
(12) Kleinpeter, E.; Klod, S.; Koch, A. J. Mol. Struct. (THEOCHEM) 2007,
811, 45–60, and references therein.
(11) Foresman, J. B.; Keith, A. T.; Wiberg, K. B.; Snoonian, J.; Frisch, M. J.
J. Phys. Chem. 1996, 100, 160098–161104.
(13) Klod, S.; Kleinpeter, E. J. Chem. Soc., Perkin Trans. 2 2001, 1893–
1898.
1284 J. Org. Chem. Vol. 74, No. 3, 2009

Quinoxalines XV
FIGURE 2. TSNMRS of pyrazolo[1,5-a]quinoxaline derivative 4a visualized (a,b) as ICSS -0.1 ppm (deshielding, red), +0.1 ppm (shielding,
yellow), +0.5 ppm (green), +1 ppm (green-blue-cyan), +2 ppm (cyan), and +5 ppm (blue) and (c) as visualized as ICSS of 5 ppm (blue) only.
ing [-0.1 ppm (red)] and shielding ICSS [+0.1 ppm (yellow)
and +0.5 ppm (green)], spectacularly confirm the implication.
Incipient with the shielding ICSS of +1 ppm (green-blue) and
increasingly at the shielding ICSS of +2 ppm (cyan) and + 5
ppm (blue), respectively, the TSNMRS, however, inform
qualitatively about the different aromaticity of the four aromatic
moieties of the pyrazolo[1,5-a]quinoxaline ring system (cf.
Figure 2c): while the aromaticity of the two benzene rings
together with the five-membered pyrazole unit proves obviously
to be similar, the corresponding value of the pyrazine ring
moiety is declining. This result can be construed only by a
preferred π-electron conjugation between the two terminal
benzene rings via the N-NdC connection and much less via
the wider NdCH-CdC-C link changing the local aromaticity
hereby.
The application of the same theoretical method for the
corresponding acetates 4a-c added up to four local minima on
the PES, which are near in relative energy and similar in
structure; these structures, relative energies, and, in order to
show also the similarity in the twist dihedral angles between
pyrazolo[1,5-a]quinoxaline and phenyl moieties and between
the phenyl ring plane and the O-OC(O)Me group, respectively,
the corresponding dihedral angles are given for 4b in Figure 3.
The theoretical study reveals the global minimum structure E
to have a dihedral angle of 21.4° only and the ester group in
ring-out conformation; this group in ring-in conformation
(structure H) destabilizes the molecule by 2.9 kcal mol-1 but
reduces the twist between the two aromatic moieties to 17.1°
only.
Beyond the OH protons in the 1H NMR spectra, both proton
and 13C chemical shifts are not further informative with respect
to the structural assignment of the pyrazolo[1,5-a]quinoxaline
derivatives 4. 1H and 13C chemical shifts of the aromatic protons/
carbon atoms are so similar that a detailed assignment proves
useless; in addition, simultaneous theoretical calculation of the
δ values employing the GIAO perturbation method14 did not
bring the assignment procedure really forward.
FIGURE 3. Structures of the pyrazolo[1,5-a]quinoxaline derivative 4b
[global minimum (E) and local minima structures (F-H); dihedral
angles for the twist of the phenyl substituent (N-C-C(i)-C(o)) and
of the OCOCH3 moiety (C(i)-C(o)-O-C(dO)) are given (i ipso; o
ortho).
The final structural proof of the pyrazolo[1,5-a]quinoxaline
derivatives 4 rendered the mass spectra, most important peaks
in the EI mass spectra of the pyrazolo[1,5-a]quinoxalines 4 and
of the oximes 8 hitherto unknown; the elemental composition
of the ions was determined by accurate mass measurements,
and the fragmentation pathways were clarified by B/E-linked
scans and collision-induced dissociation. The corresponding data
are given in Table S1 in the Supporting Information and Table
1.
Common fragment ions for the free phenol derivatives 4d-f
•
are compatible with losses of CH3 , OH•, and CHO, respectively,
in the corresponding acetates 4a-c, the characteristic [M -
CH3CO]+ ion could be detected. The EI mass spectra of the
studied compounds 4 are characterized further by the presence
of the ions C15H11N2 and C15H10N2 at m/z 219 and 218,
respectively; in case of the pyrazolo[1,5-a]quinoxalines with
R1 ) Ph (4c and 4f), the ion C15H10N2 at m/z 218 proves to be
even the base peak in the mass spectrum. The latter ions together
with C14H9N2 at m/z 205, C10H7N2 at m/z 155, and C9H7N2 at
(14) Ditchfield, R. Mol. Phys. 1974, 27, 789–807.
J. Org. Chem. Vol. 74, No. 3, 2009 1285

Sarodnick et al.
TABLE 1. Characteristic Fragment Ions of Compounds 4d-f as Proved by Linked Scan Measurements
compound no
result of the linked scans m/z
4d B/E m/z 275
260 [M - CH3]+, 258 [M - OH]+, 246 [M - CHO]+, 173 [M - Ph
- CN]+
4e B/E m/z 353
4f B/E m/z 337
336 [M - OH]+, 324 [M - CHO]+, 173 [M - Ph - CN - Br]+
244 [M - Ph - OH]+, 235 [Ph - CN]+
SCHEME 5. Fragmentation of the Pyrazolo[1,5-a]quinoxaline Derivatives 4d-f
m/z 143 are well-known from the fragmentation patterns of
simple quinoxalines and their alkyl and aryl derivatives,
published already previously.15
Conclusions
We developed a new, short and convenient synthesis of
pyrazolo[1,5-a]quinoxalines from simple quinoxalines. The key
step was the reaction of an oxime with acetic anhydride, which
proceeded under formation of a N-N bond and cleavage of a
C-O bond. A mechanistic rationale was provided by an unusual
[3,5]-sigmatropic rearrangement with the driving force of
aromatization. Both the acetates 4a-c and the free phenols 4d-f
of the pyrazolo[1,5-a]quinoxalines were theoretically calculated
employing the DFT theory at the B3LYP/6-311G** level.19-22
The free phenols form intramolecular hydrogen bonds to the
pyrazol nitrogen atom (both the stabilizing molecular energy
of this H-bond and the steric hindrance between pyrazol and
ortho-phenyl protons could be determined quantitatively). The
corresponding acetates form a number of preferred conformers
with the planes of pyrazolo[1,5-a]quinoxaline and phenyl
moieties slightly twisted and the ester group either in ring-in
or ring-out conformation.
Furthermore, the aromaticity of the four different ring moieties
of the pyrazolo[1,5-a]quinoxalines 4 were estimated qualitatively
by calculating TSNMRS and visualizing23 the latter as ICSS of
different size and direction. The aromaticity of the two benzene
rings together with the five-membered pyrazole unit of the
molecules proves to be similar, and the corresponding value of
the pyrazine ring moiety is declining as a consequence of the
preferred π-conjugation between the two terminal benzene rings
viatheN-NdClinkandmuchlessviathewiderNdC-CdC-C
connection changing the local aromaticity hereby. Finally, the
Additionally, in the EI mass spectra of the pyrazolo[1,5-
a]quinoxalines with R1 ) CH3 (4a,b,d,e), the ion C10H9N2O at
m/z 173 with RA (30-70%) was observed. On the basis of the
linked scan B/E experiments, this fragment ion had to be
attributed to the loss of Ph-CN and Ph-CN-Br, respectively,
directly from the molecular ion (cf. Table 1). Also in the mass
spectra of the analogues with R1 ) Ph (4c,f), a similar ion
C15H11N2O at m/z 235 was detected. In the latter two com-
pounds, the loss of Ph-CN can in principle originate from the
phenyl substituent R1 or from the one located on the pyrazolo
ring moiety, due to similar rearrangement processes in the gas
phase. In order to prove, for comparison purposes also the two
chloro-labeled compounds (R1 ) p-C6H4Cl instead of C6H5 in
4c,f) have been synthesized and EI-MS studied: in the corre-
sponding mass spectra, the ion [M - Ph - CN]+ was found,
indicating that the fragment Ph-CN indeed is not originating
from the quinoxaline unit of 4c,f but rather from the pyrazolo
unit.
The ions [C10H9N2O] at m/z 173, [C15H11N2O] at m/z 235,
and of the complementary Ph-CN species in the mass spectra
of the free phenol pyrazolo[1,5-a]quinoxaline derivatives 4d-f
originate from a fragmentation mechanism proximal to a back-
reaction, which is given in Scheme 5. The splitting of Ph-CN
directly from the molecular ion can only be explained by this
gas phase rearrangement process, which proves similar to the
Claisen rearrangement or to a [3,5]-sigmatropic rearrangement
reaction. In any case, this fragmentation mechanism of elimina-
tion of Ph-CN from the molecular ion is unique and very
characteristic for the pyrazolo[1,5-a]quinoxalines 4d-f studied.
Similar rearrangement reactions in the gas phase, for example,
the Claisen rearrangement and the sigmatropic rearrangement,
have been observed and well-documented.16-18
(19) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.;
Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci,
B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada,
M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.;
Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, P.;
Cross, J. B.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev,
O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.;
Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.;
Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck,
A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.;
Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz,
P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng,
C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen,
W.; Wong, M. W.; Gonzalez, C; Pople, J. A. Gaussian 03, revision C.02;
Gaussian, Inc.: Wallingford, CT, 2004.
The ions [C10H9N2O] at m/z 173 and [C15H11N2O] at m/z 235
have been observed in the mass spectra of the acetyl-substituted
pyrazolo[1,5-a]quinoxaline derivatives 4a-c, as well.
(15) Porter, Q. N. Mass Spectrometry of Heterocyclic Compounds, 2nd ed.;
John Wiley: New York, 1985.
(16) Kingston, E. E.; Beynon, J. H.; Liehr, J. G.; Meyrant, P.; Flammang,
R.; Maquestiau, A. Org. Mass Spectrom. 1985, 20, 351–359.
(17) Ramana, D. V.; Sudha, M. S. J. Chem. Soc., Perkin Trans. 2 1993,
675–678.
(20) Becke, A. D. J. Chem. Phys. 1993, 98, 5648–5652.
(21) Lee, C.; Yang, W.; Parr, R. G. Phys. ReV. B 1988, 37, 785–789.
(22) Hehre, W. J.; Radom, L.; Schleyer, P. v. R.; Pople, J. A. Ab Initio
Molecular Orbital Theory; Wiley: New York, 1986.
(18) Eichinger, P. C. H.; Bowie, J. H.; Hayes, R. N. J. Org. Chem. 1987,
52, 5224–5228.
(23) SYBYL 7.3; Tripos Inc.: 1699 South Hanley Road, St. Louis, MO 63144.
1286 J. Org. Chem. Vol. 74, No. 3, 2009

Quinoxalines XV
showed complete conversion. If starting material remained, the
mixture was heated at 130 °C for an additional 10 min. After cooling
to rt, the crude product was precipitated at 4 °C for 12 h, and the
pyrazolo[1,5-a]quinoxaline 4 was purified by recrystallization from
2-propanol.
structure of the pyrazolo[1,5-a]quinoxalines 4 was proved by
EI mass spectrometry via a unique and characteristic fragmenta-
tion pattern.
Experimental Section
2-(4-Methylpyrazolo[1,5-a]quinoxalin-2-yl)phenyl acetate
(4a): The compound was obtained from the oxime 8a in 43% yield,
mp 169-170 °C; IR 3050 (C-H); 1H NMR (CDCl3) δ 8.39 (1Η,
dd, J ) 8.0, 1.0 Hz), 7.97 (1Η, dd, J ) 8.0, 1.6 Hz), 7.94 (1Η, dd,
J ) 9.0, 0.9 Hz), 7.53 (1Η, t, J ) 7.1 Hz), 7.48 (1H, t, J ) 8.1 z),
7.39 (1H, dt, J ) 7.5, 1.6 Hz), 7.32 (1H, dt, J ) 7.4, 1.2 Hz), 7.17
(1Η, dd, J ) 7.8,1.0 Hz), 6.99 (1H, s), 2.73 (3H, s), 2.35 (3H, s);
13C NMR (CDCl3) δ 169.2, 152.2, 149.4, 147.9, 135.8, 133.8, 129.8,
129.5, 128.9, 128.3, 128.0, 126.2, 126.1, 125.4, 123.3, 114.4, 100.4,
22.2, 21.2; MS m/z (%) 275 (100), 260 (7), 258 (8), 246 (13), 219
(8), 205 (10), 173 (30). Anal. Calcd for C19H15N3O2 (317.12 g/mol):
C, 71.91; H, 4.76; N, 13.24. Found: C, 71.84; H, 4.96; N, 13.17.
HRMS: m/z calcd for C19H15N3O2* 317.1164, found 317.1154.
For 4b to 4f, see the Supporting Information.
General Procedure for the Synthesis of Oximes 8a-c: The
aldehyde 7 (20 mmol) was dissolved in ethanol (100 mL) at 60
°C, and a solution of hydroxylamine hydrochloride (1.74 g, 25
mmol) and sodium acetate trihydrate (4.08 g, 30 mmol) in water
(50 mL) was added at this temperature. After heating under reflux
for 1 h, the mixture was cooled to rt, and the oximes 8 were
precipitated at 4 °C for 12 h.
2-(3-Methylquinoxalin-2-ylmethoxy)benzoxime (8a): The com-
pound was obtained from the aldehyde 7a in 87% yield, mp 185
1
°C; IR 3240 (O-H), 3008 (C-H), 1626, 1602 (CdO); H NMR
(CDCl3) δ 8.49 (1H, s), 8.08 (2H, m), 7.76 (3H, m), 7.35 (1H, dt,
J ) 8.3, 1.6 Hz), 7.16 (1H, d, J ) 8.2 Hz), 6.99 (1H, t, J ) 7.5
Hz), 5.45 (2H, s), 2.87 (3H, s); 13C NMR (CDCl3) δ 56.3, 153.8,
150.0, 146.1, 142.0, 140.5, 131.2, 130.4, 129.3, 129.1, 128.4, 126.8,
121.6, 121.2, 112.6, 71.1, 22.3; MS m/z (%) 276 (27), 174 (10),
157 (100). Anal. Calcd for C17H15N3O2 (293.12 g/mol): C, 69.61;
H, 5.15; N, 14.33. Found: C, 69.44; H, 5.25; N, 14.31. HRMS:
m/z calcd for C17H15N3O2* 293.1164, found 293.1170.
Supporting Information Available: Experimental section,
copies of the 1H and 13C NMR spectra of the studied compounds
(4 and 8), and the coordinates and absolute energies at the
B3LYP/6-311G** level of theory for compounds 4e(A-H).
This material is available free of charge via the Internet at
http://pubs.acs.org.
For 8b and 8c, see the Supporting Information.
General Procedure for the Synthesis of the Pyrazolo[1,5-
a]quinoxalines 4a-c: A mixture of the oxime 8 (10 mmol),
anhydrous sodium acetate (1.64 g, 20 mmol), and acetic anhydride
(15.3 g, 150 mmol) was heated at 100 °C for 0.5-3 h until TLC
JO802398G
J. Org. Chem. Vol. 74, No. 3, 2009 1287