J Chem Crystallogr (2010) 40:296–301
297
dienones; and a pyrazoline derivative of eunicin acetate, a
lengthy name spiro compound [22].
were obtained with a Varian Associates Mercury Oxford
300 MHz nuclear magnetic resonance spectrometer, and
chemical shifts were recorded in ppm downfield from an
internal tetramethylsilane standard. Combustion analyses
were performed by Quantitative Technologies, Inc., P.O.
Box 470, Whitehouse, NJ 08888. LCMS analyses were
measured on a Thermo-Finnigan LCQ Advantage system
with the Surveyor autosampler, Surveyor pump, and LCQ
Advantage Max mass spectral detector using electrospray
ionization; 2 mg samples were prepared in 2 mL/L of
acetonitrile; 10 lL injections were pumped at 1.00 mL/min
isocratically with 70% acetonitrile and 30% water, each
buffered with 0.1% formic acid by volume; 15 min runs
were reproduced in both the positive and negative (when
needed) MS modes. Data were collected at full scan from
100 to 650 amu.
Benzoisothiazole dioxides, (1,2-benzoisothiazole 1,1-
dioxides) (BIDs), have received investigation regarding
their synthesis and uses, with a few reports where BIDs
have also been a part of a spiro-heterocyclic system, and
one supported by an X-ray study [24, 25]. There are no
examples of spiro(BID-pyrazoles).
A developing synthetic method for pyrazoles from this
laboratory involves the condensation-cyclization of numer-
ous polylithiated hydrazones with select electrophilic
reagents, usually esters. In addition to finding the general
reaction parameters for affecting the synthesis of a particular
pyrazole, challenges arise when choosing the substituted
hydrazone along with a satisfactory electrophilic reagent. In
the past trilithiated hydrazones, dilithiated phenylhydraz-
ones, and dilithiated carboalkoxyhydrazones have been
investigated along with their condensation–cyclization with
a variety of esters, many of them being straightforward [26]
and others presenting a substantial challenge [27]. On
occasion, an unexpected reaction occurred, and this led to
new products plus additional investigations [28].
Entry compounds, carbomethoxyhydrazones 3, were
prepared from acetophenone (Ar = phenyl) or 2-acetyl-
thiophene (Ar = 2-thienyl) 1, following their condensation
with methyl hydrazinecarboxylate 2 [30]. The preparation
spiro(BID-pyrazoles) 7 and 8 involved the following pro-
cedure (Scheme 1).1 Lithium diisopropylamide (LDA)
(0.0788 mol) was prepared by the addition of 49 mL of
1.6 M n-butyllithium in hexanes (0.0788 mol) to a three-
neck round-bottomed flask (e.g., 500 mL), equipped with a
nitrogen inlet tube, a side-arm addition funnel (e.g.,
125 mL), and a magnetic stir bar. The flask was cooled in an
ice water bath and 8.02 g (0.0788 mol) of diisopropylamine,
dissolved in 25–30 mL of THF, was added from the addition
funnel at a fast drop wise rate during a 5 min period (0 °C,
nitrogen). The solution was stirred for an additional 15–
20 min, and then 0.0150 mol of the carbomethoxyhydrazone
3 dissolved in 50 mL of THF was added at a fast drop wise
rate during 5–10 min. After 1 h, 3.39 g (0.0158 mol) of
methyl 2-(aminosulfonyl)benzoate 5, dissolved in 25–
35 mL of THF was added, during 5 min, to the dilithiated
intermediate 4, and the solution was stirred and condensed
for 1 h. Finally, 100 mL of 3 M hydrochloric acid was added
quickly followed by 100 mL of solvent grade ether, then
stirring the two-phase mixture for 5 min, followed by careful
neutralization with solid sodium bicarbonate, and the two
liquid phases or solid materials separated. If a solid appeared
at this point, the biphasic mixture could be filtered. The
aqueous layer was extracted with ether or THF (2 9 75 mL),
and the organic fractions were combined, filtered, evapo-
rated, and the solid organic materials were air dried. The
twofold cyclization and acetylation required 1 mL of acetic
anhydride and 6 mL of pyridine for each 1 g of dry
Methyl 2-(aminosulfonyl)benzoate 5 has been the type
of electrophilic reagent used by us that has given rise to
several types of heterocyclic compounds: pyrazoles [27]
and spiro(benzisothiazole-isoxazole)dioxides [24]. For
example, dilithiated phenylhydrazones underwent conden-
sation–cyclization with lithiated methyl 2-(aminosulfo-
nyl)benzoate 6 or saccharin lithium to afford 2-(1-phenyl-
1H-pyrazol-5-yl)benzenesulfonamides [27]; however,
when dilithiated oximes were treated with this ester-sul-
fonamide 5, spiro[benzoisothiazole-isoxazole]dioxides [24]
resulted instead of isoxazole-ortho-benzenesulfonamides.
Another investigation involved the condensation-cycliza-
tion-hydrolysis-decarboxylation of dilithiated N-carbo-tert-
butoxyhydrazones with this ester-sulfonamide 5 to afford
NH-pyrazolyl-ortho-benzenesulfonamides [29].
The last synthesis indicated the possibility of success for
condensation–cyclization of N-carbomethoxyhydrazones 3
with this ester-sulfonamide 5 to form C-acylated intermedi-
ates with potential, although limited, for cyclization to the
N-carbomethoxypyrazole-ortho-benzenesulfonamides. The
difficulty envisioned for cyclization of C-acylated interme-
diates could result from challenging resonance, inductive and/
or steric effects of the ester-sulfonamide moiety.
Experimental Section: Synthesis
Materials and Characterization
1
CCDC for compound 7 (689212) and for compound 8 (689211)
contain the supplementary crystallographic data for this paper. These
data can be obtained free of charge from the Cambridge Crystallo-
Fourier transform infrared spectra were obtained with a
Nicolet Impact 410 FT-IR. Proton and 13C NMR spectra
123
Metz, Clyde R.
