Preparation of 2-(1H-pyrazol-5-yl)benzenesulfonamides from polylithiated C(α),N-carbo-tert-butoxyhydrazones and methyl 2-(aminosulfonyl)benzoate

Article abstract of DOI:10.1002/jhet.5570450122

(Chemical Equation Presented) Select C(α), N-carbo-tert- butoxyhydrazones were dilithiated with excess lithium diisopropylamide followed by condensation with methyl 2-(aminosulfonyl)benzoate, acid cyclization, hydrolysis, and decarboxylation to afford new

Full text of DOI:10.1002/jhet.5570450122

Jan-Feb 2008
189
Preparation of 2-(1H-Pyrazol-5-yl)Benzenesulfonamides from
Polylithiated C(ꢀ),N-Carbo-tert-Butoxyhydrazones and Methyl
2-(Aminosulfonyl)benzoate
John D. Knight, Jordan B. Brown, Jason S. Overby, and Charles F. Beam*
Department of Chemistry and Biochemistry, College of Charleston, Charleston, SC 29424
N. Dwight Camper
Department of Entomology, Soils, and Plant Diseases, Clemson University, Clemson, SC 29634
Received May 23, 2007
O
O
1. 5 or 6 equiv. LDA
2. ester-sulfonamide
3. 3 M / 6 M HCl
S
R4
R3
H2N
CH2
C
H
N
OC(CH3)3
R4
N
C
O
N
H
R3
N
Select C(ꢀ), N-carbo-tert-butoxyhydrazones were dilithiated with excess lithium diisopropylamide
followed by condensation with methyl 2-(aminosulfonyl)benzoate, acid cyclization, hydrolysis, and
decarboxylation to afford new 2-(1H-pyrazol-5-yl)benzenesulfonamides, [NH-pyrazolyl-ortho-benzene-
sulfonamides].
J. Heterocyclic Chem., 45, 189 (2008).
oxazinones) [8], or lithiated ethyl oxanilate (dilithiated
phenylhydrazones gives pyrazolecarboxamides) [9]. Our
continuing efforts have demonstrated the large potential for
the 1,4-multiple anion synthesis of pyrazoles, especially
NH-pyrazoles [10] and other heterocyclic compounds.
Methyl 2-(aminosulfonyl)benzoate 1 is well docu-
mented for the preparation of important compounds used
in agriculture [11]. The vast majority of the reactions
involving this compound take advantage of the synthetic
potential of the sulfonamide group. One major use for the
carbomethoxy ester group has been for its reaction with
the ortho-substituted sulfonamide group to afford
saccharin-related compounds, whose synthetic, biological,
and agricultural potentials are documented [12].
In two introductory investigations, we explored the
synthetic potential for the condensation of lithiated ester-
sulfonamide 1' (from 1), an anionic electrophile, with
polylithiated nucleophiles such as dilithiated ꢁ-ketoesters
or dilithiated ortho-toluic acids, which are anionic nucleo-
philes, for the preparation of new heterocyclic
compounds, benzoisothiazole dioxides [13] and fused ring
benzoisothiazole dioxide-isoquinolinones [14].
INTRODUCTION
A distinct group of heterocyclic compounds with
biological and agricultural potential and use are
substituted 1H-pyrazoles and related compounds with a
pyrazole component such as indazoles and dihydrobenz-
indazoles [1]. In addition to the general characteristics of
pyrazoles, their properties and uses may be modified
based on the nature of the atoms or pendant groups
bonded to the carbons or nitrogen of the pyrazole ring
system. Specifically, several reports deal with the
benzenesulfonamide pendant group bonded to a 1H-
pyrazole; para-benzenesulfonamides are documented as
herbicidal sulfonamides [2]; ortho-benzenesulfonamides
have potential as chymase inhibitors [3]. The methods of
preparation for these specific compounds, however, are
rather limited.
Pyrazoles in general, especially 1H-pyrazoles, have been
prepared by several key procedures such as the
condensation-cyclization of ꢁ-dicarbonyl compounds with
hydrazines or the 1,3-dipolar addition of nitrilimines with
alkynes [1]. One of our synthetic interests and endeavors
has been the condensation-cyclization of polylithiated
C(ꢀ),N-hydrazones with aromatic esters and related
reagents [4-6] for the preparation of pyrazoles. A part of
our developing studies has been the condensation of these
1,4-dilithiated hydrazone intermediates with routine or
challenging anionic electrophilic reagents such as lithiated
ethyl benzoylacetate (dilithiated phenylhydrazones give
phenacylpyrazoles) [7], lithiated methyl salicylates
(dilithiated carboalkoxyhydrazones give pyrazolobenz-
The initially planned preparation of isoxazole-ortho-
benzenesulfonamides
4
and pyrazole-ortho-benzene-
sulfonamides 5 by the condensation-cyclization of 1,4-
dilithiated oximes 2' (from oxime 2) or 1,4-dilithiated
phenylhydrazones 3' (from phenyl hydrazone 3) with 1'
was expected to offer a challenge (Figure 1). The
anticipated C-acylated intermediates could be more
difficult to cyclize to 4 or 5 as a result of the ortho-
benzenesulfonamide moiety bonded to the carbonyl

190
J. D. Knight, J. B. Brown, J. S. Overby, C. F. Beam and N. D. Camper
Vol 45
O
S
substituted NH-pyrazoles or spiro(BID-pyrazoles) ana-
logous to 5 and/or 7. This is due to the bonding location
and restrictive properties/features of the sulfonamide
group and the BOC group.
Also, we have been successful in preparing other BOC-
pyrazoles by acid cyclization of the appropriate C-
O
O
S
CH2Li
xs LDA
HN
OCH3
NHLi
+
C
OLi
R3
N
then acid
O
O O
R3
N
6
4
X
1'
2'
O O
S
H2N
1
2
O
O
O
R3
N
S
LiHN
R
R
4
3
CHLi
C
N
Li
N
O
1'
C
CLi
C
OC(CH )
3 3
O O
S
O
S
R
R
C
O
4
R4
R3
Li
N
CHLi
C
N
H2N
R4
OCH3
NHLi
xs LDA
Li
OC(CH )
3 3
N
N
C
O
+
3
8'
C6H5
then acid
13'
N
O O
1'
C6H5
R3
N
O
X
3'
3
1'
5
X
O
O
O
O
O
N
S
S
HN
S
N
HN
R
H N
4
2
R4
R3
1
R
4
N
N
H
R
N
3
C6H5
N
OC(CH )
3 3
C
O
R
3
16
7
14
Figure 1. Methyl 2-(aminosulfonylbenzoate) and azole-ortho-
benzenesulfonamides or spiro(benzisothiazole-azole)dioxides.
O
O
N
O
O
N
S
N
S
N
H N
2
H N
2
R
4
R
4
carbon. Unexpectedly, spiro(benzoisothiazole-isoxazole)-
dioxides 6 [15] resulted and not the projected isoxazole-
ortho-benzenesulfonamides 4. Intermediates resulting
from condensation-cyclization of dilithiated phenyl-
hydrazones 3' with lithiated ester-sulfonamide 1' (from 1)
resulted in N-phenylpyrazolyl-ortho-benzenesulfonamides
5 [16]. Products 5 and 6 may be explained with plausible
intermediates resulting from inductive and/or resonance
effect arguments.
-CO2
OH
C
O
R
3
H
R
3
15
9-11
O
S
O
OCH
NHLi
3
NLi
O
S
O
O
O
1'
12'
In comparison to the 1,4-dilithiated N-phenylhydrazone
3' system, the condensation of 1' and 1,4-dilthiatiated N-
carbo-tert-butoxyhydrazones (BOC-hydrazones) 8' (from
BOC hydrazone 8) have the potential to go to either
Figure 3. Reaction details.
acylated intermediates usually possessing an ortho- or
para- electron donating phenyl substituents and not a
sulfonamide group [17]. Initial attempts to affect a
general procedure for acid hydrolysis-decarboxylation of
BOC pyrazoles gave inconsistent results.
O
O
R4
R3
S
N
1. 5 or 6 equiv. LDA
2. ester sulfonamide 1
3. 3M/6M HCl
CH2
C
H2N
R4
H
N
OC(CH3)3
N
C
O
While all of the targeted new NH-pyrazoles 9-11 would
have considerable developmental potential, their prepar-
ation is additionally challenging as a result of all of these
steric, inductive and resonance factors.
N
H
O
R3
8
9
N
9a. R3= 3,4-(CH3O)2C6H3 9a.-h.,
N
H
O
RESULTS AND DISCUSSION
9b. R3= 4-HOC6H4
9c. R3= 4-FC6H4
9d. R3= 4-CH3OC6H4
9e. R3= 4-ClC6H4
9f. R3= C6H5
R4= H
S
NH2
BOC-hydrazones 8 and ester-sulfonamide 1 were used
in this investigation; 8 is easily prepared [18] as needed in
multi-gram quantities by the straightforward 1:1
condensation of C(ꢀ)-ketones with tert-butyl carbazate
(BOC-hydrazine), and 1 is readily available. The BOC-
hydrazones 8 were easily purified by recrystallization
from methanol (new: 8a, 95%; 8b, 56%; 8c, 95%; 8d,
92%) and chromatographic separations were unnecessary
[19].
10
9g. R3= 2-naphthyl
9h. R3= 2-HOC6H4
N
N
H
O
O
S
NH2
11
Figure 2. Overall reaction summary.

Jan-Feb 2008
Preparation of 2-(1H-Pyrazol-5-yl)Benzenesulfonamides
191
During the current study, NH-pyrazolyl-ortho-benzene-
sulfonamides 9a-h, 10, and 11 were prepared (Figure 2).
BOC-hydrazones 8 were dilithiated to 8' with excess
lithium diisopropylamide (LDA) [hydrazone:LDA: ester-
sulfonamide 1:6:1 for 9b and 9h, 1:5:1 for others] [20],
condensed with 1, which was presumed to be at least
monolithiated to 1' [21], or cyclized to the lithiated
reactions. The yields of products ranged from 36-89 %;
9b and 9h were prepared from trilithiated and not
dilithiated intermediates. The yields obtained for these
products [50% and 44%] are relatively good when
compared to other hydroxyphenyl-containing compounds
in strong-base preparations. Since 9-11 were prepared by
a general procedure, the yields reported here may not be
the optimum possible for a particular compound. While
all NH-pyrazoles are gaining in importance, it further
demonstrates the use of methyl 2-(aminosulfonyl)-
benzoate 1 for Claisen-type condensations with polylithi-
ated systems and subsequent cyclization to new products
of varying structure that have agricultural, other
biological, synthetic, spectral studies, and other develop-
mental potential.
saccharin salt 12' [22].
The presumed C-acylated
intermediates 13 (from acification of 13'), resulting from
the condensation of 8' with 1', were not isolated but acid-
cyclized directly with 3 M hydrochloric acid to BOC-
pyrazole 14 [17]. This was followed by the addition of
concentrated hydrochloric acid until the total concen-
tration of acid was brought to 6 M. The mixture was
stirred at room temperature and under no other special
conditions [12a]. Cyclodehydration to 14 would be
followed by hydrolysis to cleave the tert-butyl ester group
to N-carboxylic acid 15, and then decarboxylation,
resulting in the targeted NH-pyrazoles, 9-11. It is likely
that cyclization would occur before the hydrolysis and
decarboxylation of the ester [16].
EXPERIMENTAL
Melting points were obtained with a Mel-Temp II melting point
apparatus in open capillary tubes and are uncorrected. Fourier
Transform infrared spectra were obtained with a Nicolet Impact 410
FT-IR and a Mattson Genesis II FT-IR with Specac Golden Gate
Accessory. 1H, 13C and 19F (for 8c and 9c) magnetic resonance
spectra were obtained with a Varian Associates Mercury Oxford
300 MHz nuclear magnetic resonance spectrometer, and chemical
We established that 9a-h (10 is a dihydrobenzindazole)
and 11 are pyrazoles and not potential isomeric spiro-
(benzoisothiazole-pyrazole) dioxides 16 using absorption
spectra, including DEPT, and liquid chromatography
mass spectrometry (LCMS). The IR of the products
indicated several NH/NH2 absorptions, 3257-3387 cm-1,
with the lack of absorptions for the carboxyl group. The
shifts are recorded in
ꢀ ppm downfield from an internal
tetramethylsilane (TMS) standard. Combustion analyses were
performed by Quantitative Technologies, Inc., P.O. Box 470, Salem
Industrial Park, Bldg. 5, 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; 2-4 mg samples were prepared in 2 mL/L
of acetonitrile; 10 μL 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 MS modes. Data were
collected at full scan from 100 to 650 amu.
1,1-Dimethylethyl 2-[1-(3,4-Dimethoxyphenyl)ethylidene]-
hydrazinecarboxylate (8a). To a 250 mL Erlenmeyer flask
containing a magnetic stirrer was added 10.0 g (0.0555 mol) of
3',4'-dimethoxyacetophenone and 7.70 g (0.0568 mol) of tert-
butyl carbazate followed by 100-150 mL of methanol and 8-10
drops of formic acid. Stirring was initiated to dissolve the
ketone and hydrazide, and the solution was slowly brought to the
boiling point. It was allowed to continue boiling slowly until
approximately 50 mL of methanol remained in the flask. The
flask was cooled, and the resulting solid was filtered to give
15.54 g (95%) of hydrazone 8a, mp 149-152 °C (methanol), as
white crystals. IR: 3207, 1727, and 1694 cm-1. 1H NMR:
(deuteriochloroform): ꢀ 1.55 (s, 9H), 2.18 (s, 3H), 3.88 (s, 3H),
3.93 (s, 3H), 6.82 (d, 1H, J = 9.0 Hz), 7.19 (d, 2H, J = 9.0 Hz),
7.55 (s, 1H), and 7.97 (s, NH). 13C NMR (DMSO-d6): ꢀ 12.5,
28.3, 55.8, 81.1, 108.8, 110.2, 119.3, 131.1, 147.2, 148.9, 150.1,
153.1. LCMS, mw, 294.4; exact mass, 294.2: (M+H)+, 295.0.
Anal. Calcd for C15H22N2O4: C, 61.21; H, 7.53; N, 9.52. Found:
C, 61.27; H, 7.54; N, 9.46.
1H-NMR usually displayed the NH-pyrazole from ꢀ
13
12.67-13.94 ppm. Also, DEPT, 1H, and
C-NMR
immediately ruled out the spiro isomer 16 with the
absence of methylene carbon 9a-h, or methyne carbon
absorptions in 10 and 11. Many of the analytical samples
contained incorporated water and other solvent molecules
(e.g., for product 9c, C16H15N3O3S·ꢀ H2O) [23]. Since
this occurrence was higher than normal for us, Liquid
Chromatography Mass Spectroscopy (LCMS) was used
for all samples to verify the [M+H]+ molecular ion for
each compound (and [M-H]- for 9b and 9h) without
incorporated solvent molecules interfering.
The current procedure affords examples for
a
regioselective multi-gram preparation of NH-pyrazolyl-
ortho-benzenesulfonamides, 9-11, starting with readily
prepared carbo-tert-butoxyhydrazones 8, using the
straightforward application of a well documented earlier
procedure for 8, including rapid purification [18]. All of
the products 9-11 are new, and it may difficult to prepare
them by traditional procedures or even by a simple
adaptation of the developed procedure for N-phenyl-
pyrazolyl-benzenesulfonamides 5 [16]. The use of 3 and
6 M hydrochloric acid to bring about cyclization,
hydrolysis [12a], and decarboxylation proved to be a
simple yet effective choice where other acid procedures
have given less consistent results because of side
1,1-Dimethylethyl 2-[1-(4-Hydroxyphenyl)ethylidene]-
hydrazinecarboxylate (8b). Hydrazone 8b was prepared in the

192
J. D. Knight, J. B. Brown, J. S. Overby, C. F. Beam and N. D. Camper
Vol 45
same manner as 8a using 8.80 g (0.0646 mol) of 4'-hydroxy-
acetophenone and 8.99 g (0.0681 mol) of tert-butyl carbazate,
and yielded 9.03 g (56%) of product, mp 128-129 °C
(methanol), as white crystals. IR: 3341, 3196, 1727, and 1693
cm-1. 1H NMR (DMSO-d6): ꢀ 1.45 (s, 9H), 2.11 (s, 3H), 6.80 (d,
2H, J = 9.0 Hz), 7.55 (d, 2H, J = 9.0 Hz), 7.56 (s, 1H), 9.60 (s,
NH), and 9.66 (s, OH). 13C NMR (DMSO-d6): ꢀ 14.3, 28.8, 79.8,
115.6, 128.1, 130.1, 149.3, 153.9, 158.9. LCMS, mw, 250.3;
exact mass, 250.1: (M+H)+, 250.7, (M-H)-, 249.7. Anal. Calcd
for C13H18N2O3: C, 62.37; H, 7.25; N, 11.19. Found: C, 62.19;
H, 7.20; N, 11.18.
1,1-Dimethylethyl 2-[1-(4-Fluorophenyl)ethylidene]hydra-
zinecarboxylate (8c). Hydrazone 8c was prepared in the same
manner as 8a using 10.0 g (0.0724 mol) of 4'-fluoro-
acetophenone and 10.04 g (0.0760 mol) of tert-butyl carbazate,
and yielded 17.36 g (95%) of product, mp 168-171 °C
(methanol), as white crystals. IR: 3280, 1733 cm-1. 1H NMR
(deuteriochloroform): ꢀ 1.46 (s, 9H), 2.16 (s, 3H), 7.14-7.21 (m,
1H), 7.73-7.78 (m, 2H), and 9.82 (s, NH). 13C NMR (deuterio-
chloroform): ꢀ 12.8, 28.3, 81.4, 115.2 (d, JCF = 21.7 Hz), 128.1
(d, JCF = 8.3 Hz), 134.4 (d, JCF = 3.1 Hz), 147.8, 153.8, 163.4 (d,
JCF = 247.1 Hz). 19F NMR (deuteriochloroform): ꢀ -113.8 (b, m).
LCMS, mw, 252.3; exact mass, 252.1: (M+H)+, 252.9. Anal.
Calcd for C13H17FN2O2: C, 61.89; H, 6.79; N, 11.10. Found: C,
61.77; H, 6.76; N, 10.99.
1,1-Dimethylethyl 2-Cyclododecylidenehydrazinecarbox-
ylate (11d). Hydrazone 8d was prepared in the same manner as
8a using 3.0 g (0.0165 mol) of cyclododecanone and 2.25 g
(0.0173 mol) of tert-butyl carbazate, and yielded 4.55 g (92%)
of product, mp 155-157 °C (methanol), as white crystals. IR:
3241, 1677 cm-1. 1H NMR (deuteriochloroform): ꢀ 1.35 (s, 9H),
1.50 (s broad, 14H), 1.61 (m, 2H), 1.70 (m, 2H), 2.22 (t, 2H, J =
6.8 Hz), 2.33 (t, 2H, J = 6.9 Hz), and 7.85 (s, NH). 13C NMR
(deuteriochloroform): ꢀ 22.4, 23.1, 23.6, 24.5, 24.8, 25.0, 25.1,
26.9, 28.2, 28.3, 32.9, 80.5, 153.4, 155.9. LCMS, mw, 296.5;
exact mass, 296.3: (M+H)+, 296.9. Anal. Calcd for C17H32N2O2:
C, 68.88; H, 10.88; N, 9.45. Found: C, 68.50; H, 10.86; N, 9.54.
General Procedure for the Preparation of 2-(1H-Pyrazol-
5-yl)benzenesulfonamides). (Ratio of reagents – BOC
hydrazone: LDA: ester, 1:5-6:1) In a typical reaction sequence,
LDA was prepared by the addition of 49-50 mL (60 mL for 9b
and 9h) of 1.60 M n-butyllithium (0.0788 mol/0.0945 mol for 9b
and 9h) in hexanes 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 8.01 g (0.0791 mol) or
9.76 g (0.0961 mol for 9b and 9h) of diisopropylamine (99.5% -
Aldrich Chem. Co.), dissolved in 25-35 mL of dry THF (freshly
distilled from sodium-benzophenone ketyl) was added from the
addition funnel at a fast drop wise rate during a 5 min (0 °C, N2)
period. The solution was stirred for an additional 15-20 min,
and then treated via the addition funnel, during 5 min, with BOC
hydrazone [17] (0.015 mol) dissolved in 40-60 mL of THF.
After 45-60 min [or 2-2.5 hr for 9b and 9h], a solution of 3.47 g
(0.0158 mol – 5% molar excess) of methyl 2-(aminosulfonyl)-
benzoate 1 dissolved in 50 mL of THF, was added, during 5
min, to the dilithiated or trilithiated intermediate, and the
solution was stirred overnight (N2) at room temp. Finally, 100
mL of 3 M hydrochloric acid was added all at once, followed by
an additional 100 mL of reagent grade THF, and the two-phase
mixture was well-stirred and heated under reflux for
approximately 30-40 min. The mixture was cooled to room
temp. and was followed by the addition of 50 mL of conc.
hydrochloric acid. Vigorous stirring was conducted at room
temp. for 24 hr. At the end of this period, the mixture was
poured into a large flask (ca. 1 or 2 L) containing 100 mL of
reagent grade ethyl ether. The mixture was then neutralized
with solid sodium bicarbonate, and the layers separated. If a
solid appeared at this point, reagent grade THF could be added
to induce dissolution, or the precipitate could be filtered. The
aqueous layer was extracted with ethyl ether (2 x 50 mL), and
the organic fractions were combined, not dried, evaporated
under reduced pressure, and recrystallized from common
solvents to afford products 9-11.
2-(3-(3,4-Dimethoxyphenyl)-1H-pyrazol-5-yl))benzene-
sulfonamide (9a). This compound was obtained as pale yellow
crystals, mp 135-139 °C (benzene/methanol), in 65% yield (3.56
g) using the general procedure from the condensation-
cyclization of dilithiated 3',4'-dimethoxyacetophenone BOC-
hydrazone 8a and ester-sulfonamide 1. IR: 3277, 3250 cm-1. 1H
NMR (DMSO-d6): ꢀ 3.78 (s, 3H), 3.85 (s, 3H), 7.03 (s, 1H),
7.05 (s, 1H), 7.37-7.82 (m, 5H), 8.10 (d, 1H, J = 7.8 Hz), and
13.59 (s, NH). 13C NMR (DMSO-d6): ꢀ 56.2, 56.3, 103.2, 109.9,
112.8, 118.7, 122.3, 128.3, 128.7, 132.3, 132.7, 132.8, 141.7,
143.9, 149.8, and 152.3. LCMS, mw, 359.4; exact mass, 359.1:
(M+H)+, 360.0. Anal. Calcd for C17H17N3O4S•1/4 H2O: C,
56.11; H, 4.85; N, 11.55. Found: C, 56.11; H, 4.54; N, 11.27.
2-(3-(4-Hydroxyphenyl)-1H-pyrazol-5-yl))benzenesulfonamide
(9b). This compound was obtained as pale yellow crystals, mp 278
°C (xylenes/DMF), in 50% yield (2.38 g) using the general procedure
from the condensation-cyclization of trilithiated 4'-hydroxyaceto-
phenone BOC-hydrazone 8b and ester-sulfonamide 1. IR: 3382,
1
3351 cm-1. H NMR (DMSO-d6): ꢀ 6.95 (s, 1H), 6.93 (d, 1H, J = 6.3
Hz), 7.54-7.83 (m. 5H), 8.10 (d, 1H, J = 7.5 Hz), 9.82 (s, OH), and
13.50 (s, NH). 13C NMR (DMSO-d6): ꢀ 102.7, 116.6, 120.6, 127.6,
128.3, 128.7, 132.3, 132.7, 141.7, 144.1, 151.3, and 158.5. LCMS,
mw, 315.4; exact mass, 315.1: (M+H)+, 316.0; (M-H)- 314.0. Anal.
Calcd for C15 H12N3O3S: C, 57.13; H, 4.16; N, 13.33. Found: C,
56.86; H, 3.84; N, 13.12.
2-(3-(4-Fluorophenyl)-1H-pyrazol-5-yl))benzenesulfon-
amide (9c). This compound was obtained as dark yellow crystals,
mp 214-216 °C (xylenes), in 68% yield (3.25 g) using the general
procedure from the condensation-cyclization of dilithiated 4'-fluoro-
acetophenone BOC-hydrazone 8c and ester-sulfonamide 1. IR: 3300
sh, 3284, 3275 sh cm-1. 1H NMR (DMSO-d6): ꢀ 7.09 (s, 1H), 7.34
(d, 2H, J = 8.7 Hz), 7.58-7.73 (m. 3H), and 7.92- 7.94 (m, 2H), and
8.11 (d, 1H, J = 7.5 Hz). 13C NMR (DMSO-d6): ꢀ 104.1, 116.7 (d,
JCF = 21.6 Hz), 126.0, 128.2 (d, JCF = 7.5 Hz), 128.3, 128.9, 129.6,
129.7, 131.5, 132.8 (d, JCF = 7.5 Hz), 142.0, 144.1, 149.3, and 162.7
(d, JCF = 245.5 Hz). 19 F NMR (DMSO-d6): ꢀ -113.6 (m, b). LCMS,
mw, 317.3; exact mass, 317.1: (M+H)+, 318.0. Anal. Calcd for
C15H12 FN3O2S•1/8 C8H10 [23]: C, 58.13; H, 4.04; N 12.71. Found:
C. 58.17; H, 4.02; N, 12.54.
2-(3-(4-Methoxyphenyl)-1H-pyrazol-5-yl))benzenesulfon-
amide (9d). This compound was obtained as pale white
crystals, mp 212 °C (benzene/methanol), in 64% yield (3.19 g)
using the general procedure from the condensation-cyclization
of dilithiated 4'-methoxyacetophenone BOC-hydrazone 8 and
ester-sulfonamide 1. IR: 3363, 3302 cm-1. 1H NMR (DMSO-
d6): ꢀ 3.79 (s, 3H), 6.96 (s, 1H), 7.05 (d, 2H, J = 8.6 Hz), 7.66-
7.73 (m, 5H), 8.06 (d, 1H, J = 7.5 Hz), and 13.59 (s, NH). 13C
NMR (DMSO-d6): ꢀ 55.9, 103.0, 115.2, 122.1, 127.5, 128.3,
128.7, 132.3, 132.7, 132.8, 141.7, 143.6, 151.3, and 160.1.
LCMS, mw, 329.4; exact mass, 329.1: (M+H)+, 329.9. Anal.

Jan-Feb 2008
Preparation of 2-(1H-Pyrazol-5-yl)Benzenesulfonamides
193
Calcd for C16H15N3O3S•1/4 H2O: C, 57.56; H, 4.68; N, 12.59.
Found: C, 57.70; H, 4.59; N, 12.28.
233 °C (benzene/methanol), in 36% yield (2.13 g) using the general
procedure from the condensation-cyclization of dilithiated 1-cyclodo-
decaone BOC-hydrazone 8d and ester-sulfonamide 1. IR: 3272,
3372 sh cm-1. 1H NMR (DMSO-d6): ꢀ 1.07-1.41 (m, 13H), 1.76 (s
broad, 2H), 2.42-2.64 (m, 4H), 3.40 (s, 1H), 7.39-7.64 (m, 3H),
8.01(d. 1H, J = 7.86 Hz) and 12.67 (s, 1H). 13C NMR: (DMSO-d6): ꢀ
19.2, 20.5, 22.0, 22.2, 24.0, 24.2, 24.5, 26.9, 27.2, 115.8, 127.1,
127.8, 131.8, 132.9, 141.1, 142.0, and 148.1. LCMS, mw, 361.5;
exact mass, 361.2: (M+H)+, 362.1. Anal. Calcd for C19H27N3O2S: C,
63.13; H, 7.53; N, 11.62. Found: C, 62.98; H, 7.60; N, 11.43.
2-(3-(4-Chlorophenyl)-1H-pyrazol-5-yl))benzenesulfon-
amide (9e). This compound was obtained as pale orange crystals,
mp 216 °C (xylenes/DMF), in 46% yield (2.30 g) using the general
procedure from the condensation-cyclization of dilithiated 4'-chloro-
acetophenone BOC-hydrazone 8 and ester-sulfonamide 1. IR: 3289
sh cm-1. 1H NMR (DMSO-d6): ꢀ 7.21 (s, 1H), 7.34 (d, 2H, J = 8.6
Hz), 7.58-7.84 (m. 5H), and 7.97-7.99 (m, 2H), and 8.17 (d, 1H, J =
7.8 Hz). 13C NMR (DMSO-d6): ꢀ 104.0, 125.7, 127.4, 128.1, 128.5,
129.2, 129.4, 130.6, 132.4, 133.5, 142.0 and 151.4. LCMS, mw,
333.3; exact mass, 333.0: (M+H)+, 333.9. Anal. Calcd for C15H12
ClN3O2S•1/8 C8H10 [23]: C, 55.37; H, 3.85; N 12.11. Found: C,
55.23; H, 3.64; N, 11.96.
Acknowledgements. We wish to thank the following
sponsors: the Research Corporation, the National Science
Foundation grants CHE # 9708014 and # 0212699 for Research
at Undergraduate Institutions, the United States Department of
Agriculture, NRICGP # 2003-35504-12853, and Donors of the
Petroleum Research Fund, Administered by the American
Chemical Society. The College of Charleston LCMS facility was
funded by NIH grant #P20 RR-016461 from the National Center
for Research Resources. The College of Charleston awarded
summer grants through its Summer Undergraduate Research
with Faculty program (SURF-2006) to J. D. Knight and J. B.
Brown.
2-(3-(Phenyl-1H-pyrazol-5-yl))benzenesulfonamide (9f). This
compound was obtained as yellow crystals, mp 197-200 °C (benzene/
methanol), in 63% yield (2.80 g) using the general procedure from the
condensation-cyclization of dilithiated acetophenone BOC-hydrazone
1
8 and ester-sulfonamide 1. IR: 3308 sh cm±1. H NMR (DMSO-d6): ꢀ
3.79 (s, 3H), 6.99 (s, 1H), 7.08 (d, 2H, J = 8.6 Hz), 7.38-7.84 (m. 8H),
8.07 (d, 1H, J = 7.8 Hz), and 13.69 (s, NH). 13C NMR (DMSO-d6): ꢀ
103.3, 125.3, 127.5, 128.1, 128.6, 128.8, 129.2, 131.5, 132.1, 132.2,
141.1, 143.0, and 150.7. LCMS, mw, 299.4; exact mass, 299.1:
(M+H)+, 300.0. Anal. Calcd for C15H13N3O2S: C, 60.18; H, 4.38; N,
14.04. Found: C, 60.19; H, 4.21; N, 13.93.
REFERENCES
2-(3-(2-Naphthyl)-1H-pyrazol-5-yl))benzenesulfonamide (9g).
This compound was obtained as white crystals, mp 241-243 °C
(xylenes/isobutanol), in 89% yield (4.65 g) using the general
procedure from the condensation-cyclization of dilithiated 2-aceto-
naphthone BOC-hydrazone 8 and ester-sulfonamide 1. IR: 3281 sh
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(s, 1H) and 13.94 (s, NH). 13 C NMR (DMSO-d6): ꢀ 104.0, 123.6,
124.0, 126.5, 126.8, 127.9, 127.8, 128.1, 128.3, 128.7, 132.1, 132.2,
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4.14; N, 11.82. Found: C, 64.48; H, 4.21; N, 11.87.
2-(3-(2-Hydroxyphenyl)-1H-pyrazol-5-yl))benzenesulfonamide
(9h). This compound, was obtained as pale yellow crystals, mp 178-
179 °C (toluene/1-propanol), in 44% yield (2.10 g) using the general
procedure from the condensation-cyclization of dilithiated 2'-
hydroxyacetophenone BOC-hydrazone 8 and ester-sulfonamide 1.
IR: 3375, 3277 cm-1. 1H NMR (DMSO-d6): ꢀ 6.87-7.02 (m, 2H),
7.14-7.25 (m, 1H), 7.47-7.67 (m, 5H), 8.13 (d, 1H, J = 7.5 Hz), 10.3
(s, OH), 12.7 (s, NH). 13C NMR (DMSO-d6): ꢀ 103.9, 115.5, 116.2,
119.2, 126.9, 127.5, 128.8, 131.5, 131.6, 141.0, 148.6 and 154.1.
LCMS, mw, 315.3; exact mass, 315.1: (M+H)+, 316.0; (M-H)-,
314.0. Anal. Calcd for C15 H12N3O3S•1 H2O: C, 54.04; H, 4.54; N,
12.60. Found: C, 54.05; H, 4.42; N, 12.48.
2-(4,5-Dihydro-2H-benz[g]indazol-3-yl)benzenesulfonamide
(10). This compound was obtained as light orange crystals, mp 266-
268 °C (toluene/1-propanol), in 66% yield (3.24 g) using the general
procedure from the condensation-cyclization of dilithiated 1-tetralone
BOC-hydrazone 8 and ester-sulfonamide 1. IR: 3338, 3357 sh cm-1.
1H NMR (DMF-d7): ꢀ 2.94-2.99 (m, 2H), 3.15-3.20 (m, 2H), 7.30-
7.39 (m, 3H), 7.65-7.77 (m, 3H), 7.86-7.90 (m, 1H), 8.20-8.23 (m,
1H), and 13.90 (s, NH). 13C NMR (DMSO-d6): ꢀ 19.6, 29.8, 115.2,
122.0, 125.7, 127.2, 128.2, 128.4, 129.0, 131.6, 132.4, 132.7, 134.7,
140.2, 142.7, 147.3, and 162.2 [24]. LCMS, mw, 325.4; exact mass,
325.1: (M+H)+, 326.0. Anal. Calcd for C17H13N3O2S: C, 62.75; H,
4.65; N, 12.91. Found: C, 62.69; H, 4.46; N, 12.69.
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[23] During previous investigations, several analytical samples
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[24] The 13C spectrum was taken at a frequency of 75 MHz, which
does not provide a high enough resolution to distinguish several of the
aromatic carbons in this molecule.
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