Preparation of 2H-spiro[Benzo[d]isothiazole-3,3′ -pyrazole]-1, l-dioxide-2′ (4′ H)-carboxylates from Dilithiated C(α ), N-carboalkoxyhydrazones and methyl 2-(Aminosulfonyl)benzoate

Article abstract of DOI:10.1002/jhet.50

A variety of substituted spiro(benzoisothiazole-pyrazoles) have been prepared by the condensation of dilithiated C(α ),N-carboalkoxyhydrazones with lithiated methyl 2-(aminosulfonyl)benzoate followed by the cyclization of intermediates with acetic anhydri

Full text of DOI:10.1002/jhet.50

March 2009
Preparation of 2H-spiro[Benzo[d]isothiazole-3,30-pyrazole]-1,
1-dioxide-20(40H)-carboxylates from Dilithiated C(a),
231
N-Carboalkoxyhydrazones and Methyl 2-(Aminosulfonyl)benzoate
Anna C. Dawsey,a Chandra Potter,a John D. Knight,a Zachary C. Kennedy,a
Ellyn A. Smith,a Amanda M. Acevedo-Jake,a Andrew J. Puciaty,a
Clyde R. Metz,a Charles F. Beam,a* William T. Pennington,b
and Donald G. VanDerveerb
aDepartment of Chemistry and Biochemistry, College of Charleston, Charleston,
South Carolina 29424
bDepartment of Chemistry, Clemson University, Clemson, South Carolina 29634
*E-mail: beamc@cofc.edu
Received August 20, 2008
DOI 10.1002/jhet.50
Published online 13 April 2009 in Wiley InterScience (www.interscience.wiley.com).
A variety of substituted spiro(benzoisothiazole-pyrazoles) have been prepared by the condensation of
dilithiated C(a),N-carboalkoxyhydrazones with lithiated methyl 2-(aminosulfonyl)benzoate followed by
the cyclization of intermediates with acetic anhydride, which also resulted in spiro N-acetylated prod-
ucts when carbomethoxyhydrazones or carboethoxyhydrazones were used, and spiro NH products when
carbo-tert-butoxyhydrazones were used.
J. Heterocyclic Chem., 46, 231 (2009).
INTRODUCTION
spiro(BID-isoxazoles) 3 [5]; with dilithiated b-ketoesters
4 (R ¼ OMe or OEt) to afford BID-b-ketoesters 5 (R ¼
OMe or OEt); with dilithiated b-diketones 4 (R ¼ Ar)
to afford BID-b-diketones 5 (R ¼ Ar); or with trilithi-
ated b-ketoamides 4 (R ¼ NLiC6H5) resulting in BID b-
ketoamides 5 (R ¼ NHC6H5) [6].
Pyrazoles [1] and benzoisothiazole dioxides [2] have
been prepared and studied because of their biological
potential, serving as intermediate compounds in other
syntheses, spectral studies, theoretical studies, and other
uses. Various spiro pyrazoles have been investigated [3],
and spiro benzoisothiazoles dioxides (BIDs) have
received limited study [4]. There are no reports concern-
ing the preparation of spiro(benzoisothiazole-pyrazole)
dioxides.
N-Phenyl-, or NH- pyrazolebenzenesulfonamides 7
resulted [7,8] when dilithiated phenylhydrazones (R1 ¼
Ph) or dilithiated carbo-tert-butoxyhydrazones (R1 ¼ t-
Bu) were condensed-cyclized (also hydrolysis-decarboxy-
lation for 7, NH-) with 10 (from 1).
In this laboratory, BIDs and pyrazoles have been syn-
thesized by the condensation-cyclization of polylithiated
intermediates, prepared in excess lithium diisopropyla-
mide (LDA), with methyl 2-(aminosulfonyl)benzoate 1,
Scheme 1. Specifically, anionic electrophile 10 has been
condensed-cyclized with dilithiated oximes 2 to afford
RESULTS AND DISCUSSION
During the current investigation dilithiated carbo-
alkoxyhydrazones 6a–l (6f, trilithiated) or 9a–c were
C
V
2009 HeteroCorporation

232
A. C. Dawsey, C. Potter, J. D. Knight, Z. C. Kennedy, E. A. Smith, A. M. Acevedo-Jake, A. J.
Puciaty, C. R. Metz, C. F. Beam, W. T. Pennington, and D. G. VanDerveer
Vol 46
Scheme 1. Condensation-cyclization syntheses with methyl 2-
(aminosulfonyl)benzoate.
Figure 1. ORTEP diagram (50% ellipsoids for non-hydrogen atoms),
C
20H19N3O5S 8a [9].
hydrazone 6f (R3 ¼ 2-LiOC6H4) was condensed with 10,
and intermediates were cyclized to afford O-acetylation
and N-acetylation spiro product 8f. The N-acetylation
process did not occur when dilithiated carbo-tert-butoxy-
hydrazone intermediates were used instead, and only
NH spiro(BID-pyrazoles) 8g–l and 10c were isolated.
N-Acetylated spiro(BID-pyrazoles) 8a–f were not
originally anticipated, and an X-ray single crystal analy-
sis was determined for spiro product 8a resulting from
condensed-cyclized with lithiated methyl 2-(aminosulfo-
nyl)benzoate 10 (from 1) to afford spiro(BID-pyrazoles)
8a–l or 10a–c and not pyrazole-benzenesulfon-amides 7
Scheme 2.
Specifically, 6a–l or 9a–c underwent an anion-anion
condensation with 10 to form intermediate compounds
that were isolated but not characterized followed by
cyclization and N-acetylation with acetic anhydride to
afford N-acetyl spiro(BID-pyrazoles) 8a–f, 10a, and
10b. Trilithiated 20-hydroxyacetophenone carbomethoxy-
the condensation-cyclization of 6a (R1 ¼ Et, R3
¼
C6H5) with 10.
The molecular structure of 8a is shown in Figure 1
(atoms assigned numbers), and selected bond distances
and angles are listed in Table 1. The bond lengths agree
with the assignment of the double bond shown between
C9 and N2. Because the unit cell of each compound is
centrosymmetric, both enantiomorphic structures about
the C1 chiral center are present.
Scheme 2. Reactants/products.
The least squares best planes representing the fused
rings are nearly coplanar with angles of 1.52ꢀ between
Table 1
ꢀ
˚
Selected bond distances (A) and angles ( ), C20H19N3O5S 8a.
C1-C2
C2-C3
C3-S1
1.524(3)
1.376(3)
1.742(2)
1.690(2)
1.491(3)
1.475(2)
1.399(2)
1.288(3)
1.500(3)
1.550(3)
1.472(3)
1.371(3)
1.206(3)
1.342(3)
C1-C2-C3
C2-C3-S1
C3-S1-N3
S1-N3-C1
N3-C1-C2
115.4(2)
112.0(2)
92.8(1)
S1-N3
N3-C1
C1-N1
N1-N2
N2-C9
C9-C8
C8-C1
C9-C13
N1-C12
C12-O4
C12-O5
115.6(1)
104.1(2)
103.1(2)
114.0(2)
107.8(2)
113.7(2)
100.5(2)
172.8(2)
176.8(2)
ꢁ4.1(3)
C1-C8-C9
C8-C9-N2
C9-N2-N1
N2-N1-C1
N1-C1-C8
C14-C13-C9-N2
C13-C9-N2-N1
N2-N1-C12-O4
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2009 Preparation of 2H-spiro[Benzo[d]isothiazole-3,30-pyrazole]-1,1-dioxide-20(40H)-carboxylates
from Dilithiated C(a),N-Carboalkoxyhydrazones and Methyl 2-(Aminosulfonyl)benzoate
233
Scheme 3. Mechanistic Details.
group hindering further reaction at the BIDs nitrogen
with acetic anhydride, and its success was dependant on
the strong cyclization ability of acetic anhydride/
pyridine.
EXPERIMENTAL
Melting points were obtained with a Mel-Temp II melting
point apparatus in open capillary tubes and are uncorrected.
Entry compounds, C(a),N-carboalkoxy-hydrazones were pre-
pared from C(a),O-ketones in a 1:1 condensation with methyl,
ethyl, or tert-butyl carbazate [11]. The tetrahydrofuran (THF)
was distilled from sodium (benzophenone ketyl as an indicator
of dryness) prior to use, and organic chemicals were obtained
from Aldrich Chemical Co. Infrared spectra were obtained
with a Nicolet Impact 410 FT-IR. Proton and 13C NMR spec-
tra were obtained with a Varian Associates Mercury Oxford
300 MHz nuclear magnetic resonance spectrometer, and chem-
ical shifts were recorded in d ppm downfield from an internal
tetramethylsilane standard. Combustion analyses were per-
formed 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 vol-
ume; 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.
2H-spiro[Benzo[d]isothiazole-3,30-pyrazole]-1,1-dioxide-20
(40H)-carboxylates (8a–l) and (10a–c). LDA (0.0788 mol or
0.0945 mol for 8f) was prepared by the addition of 49 mL (or
59 mL for 8f) of 1.6M n-butyllithium 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 8.02 g or 9.54 g for 8f (0.0788 mol or 0.0945 mol
for 8f) of diisopropylamine, dissolved in 25–30 mL of dry
THF, was added from the addition funnel at a fast dropwise
rate during a 5 min period (0ꢀC, nitrogen). The solution was
stirred for an additional 15–20 min, and then 0.0150 mol of
the carboalkoxyhydrazone dissolved in 50 mL of THF was
added at a fast dropwise rate during 5–10 min. After 1 hr (2 h
for 8f), 3.39 g (0.0158 mol) of methyl 2-(aminosulfonyl)ben-
zoate 1, dissolved in 25-35 mL of THF was added, during
5 min, to the polylithiated intermediate, and the solution was
stirred and condensed for 1 h. Finally, 100 mL of 3M hydro-
chloric acid was added quickly followed by 100 mL of solvent
grade ether, then stirring the two-phase mixture for 5 min, fol-
lowed 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 fil-
tered. The aqueous layer was extracted with ether or THF
(2 ꢂ 75 mL), and the organic fractions were combined, filtered,
evaporated, and the solid organic materials were air-dried.
them. The two five-member rings in each molecule are
nearly perpendicular with an angle of 89.54ꢀ. The rings
connected by C9 and C13 are nearly coplanar with
angles of 9.19ꢀ, which allows for extended pi bonding
between these rings and possibly with the atoms in the
C12 carboxylate group.
In addition to single crystal X-ray analysis leading to
results illustrated in the ORTEP diagram, Figure 1, other
representative characterization parameters supported the
spiro structure, such as DEPT clearly identifying CH2 or
1
CH in appropriate products. The H-NMR CH2 absorp-
tion for 8a–l were noted as a pair of doublets d 3.54–
3.66 and d 3.97–4.04 ppm, J ¼ 18.0–18.7 Hz; N-acetyl
singlet proton absorptions were displayed at d 2.52–
2.64, usually 2.63 or 2.64 ppm in products 8a–f, 10a
and 10b and absent in products 8g–l and 10c. The 13C
NMR for all products displayed the spiro carbon absorp-
tion from d 80.4–84.0 ppm. Combustion analysis indi-
cated incorporation of water (methanol in 8k) [10] in
the analytical crystalline products 8a, 8c, 8d, 8j, and 8l.
LCMS for most of the products contained the expected
(M þ H)þ; for 8i and 8j it was not detected. Base ions
for each of these products may be explained by loss of
a carbo-tert-butoxy fragment.
Mechanistic details, Scheme 3, to explain the forma-
tion of products may involve dilithiated carboalkoxyhy-
drazone and monolithiated ester-sulfonamide 10, leading
to intermediates 11 and/or 12 (e.g., from acetophe-
nones), with each having potential for difficulty in
cyclodehydration. Attempts to isolate saccharin from
treatment of 1 (to 10) with LDA under the same reaction
conditions were unsuccessful.
Products 8g–l and 10c were only formed from cycli-
zation and not accompanied by N-acetylation, which
may be attributed to the larger size of the tert-butoxy
The twofold cyclization and acetylation required 6 mL of
acetic anhydride and 4 mL of pyridine for each 1 g of dry
intermediate(s) compound(s) [12]. Each gram of solid inter-
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

234
A. C. Dawsey, C. Potter, J. D. Knight, Z. C. Kennedy, E. A. Smith, A. M. Acevedo-Jake, A. J.
Puciaty, C. R. Metz, C. F. Beam, W. T. Pennington, and D. G. VanDerveer
Vol 46
mediate(s) was dissolved in pyridine followed by the dropwise
addition of acetic anhydride. The solution was stirred at room
temperature for 1 h. The addition of ca. 80 g of ice usually
resulted in a precipitate, which was collected by filtration, washed
with water and recrystallized from methanol or ethanol.
Table 2
Crystallographic data, C20H19N3O5S 8a.
CCDC deposit number [17]
Color/shape
689213
Yellow/Parallelopiped
0.36 ꢂ 0.36 ꢂ 0.31
C20H19N3O5S
413.44
Ethyl2-acetyl-50-phenyl-2H-spiro[benzo-[d]isothiazole-3,30-
Crystal dimensions (mm)
Formula
pyrazole]-1,1-dioxide-20(40H)-carboxylate
(8a). Compound
Formula mass
T (ꢀC)
Crystal system
Space Group
8a was obtained in 69% yield, mp 179–182ꢀC (methanol),
from the two-step procedure for the condensation-cyclization
of dilithiated acetophenone carboethoxyhydrazone and 10. IR:
ꢁ120(2)
Monoclinic
P21/c
12.372(3)
1709 and 1727 cmꢁ1 1H NMR (deuteriochloroform): d 1.67
.
˚
a (A)
˚
(m, 3H), 2.64 (s, 3H, CH3), 3.68–4.06 (m, 4H) [13], and 7.41–
7.68, 7.71–7.91 (m, 9H, ArH). 13C NMR (deuteriochloroform):
d 14.8, 23.7, 49.5 (DEPT CH2), 53.6, 81.2, 121.2, 122.9,
127.6, 128.9, 129.2, 131.3, 132.5, 133.5, 135.3, 137.1, 147.7,
151.0 and 166.9. LCMS, exact mass, 413.10: (M þ H)þ,
b (A)
17.490(4)
9.655(2)
˚
c (A)
b (ꢀ)
107.12(3)
1996.6(7)
3
˚
V (A )
Z
4
1.375
0.71073
0.199
dcalc (g cmꢁ3
)
.
414.04. Anal. Calcd for C20H19N3O5S 1= H O: C, 57.47; H,
4
2
˚
k (A)
4.70; N, 10.05. Found: C, 57.47; H, 4.63; N, 10.08.
l (mmꢁ1
F(000)
)
Single crystal X-ray structure determination. Yellow
crystals of C20H19N3O5S 8a were recrystallized from ethanol
in order to give satisfactory crystals for X-ray determination.
Crystal data for X-ray studies were collected at ꢁ120ꢀC on a
Mercury CCD area detector coupled with a Rigaku AFC8 dif-
fractometer with graphite monochromated Mo-K radiation.
Data were collected in 0.50ꢀ oscillations in x with 20 s expo-
sures. A sweep of data was done using x oscillations from
ꢁ40.0ꢀ to 90.0ꢀ at v ¼ 45.0ꢀ and u ¼ 0.0ꢀ; a second sweep
was performed using x oscillations from ꢁ30.0ꢀ to 80.0ꢀ at
v ¼ 45.0ꢀ and u ¼ 90.0ꢀ. The crystal-to-detector distances
were 27.7147 mm. Details of the data collection is reported in Ta-
ble 2. Data were collected, processed, and corrected for Lorentz
polarization and for absorption using CrystalClear (Rigaku) [15].
The non-hydrogen atoms were refined anisotropically. Ideal
hydrogen atom coordinates were calculated and the hydrogen
atoms were allowed to ride on their respective carbon atoms.
The temperature factors of all hydrogen atoms were varied iso-
tropically. Structure solution, refinement, and the calculation of
derived results were performed using the SHELX-97 [16] package
of computer programs. Neutral atom scattering factors were those
of Cromer and Waber [16], and the real and imaginary anoma-
lous dispersion corrections were those of Cromer [17].
864
3.45–25.15
3952
y range (ꢀ)
Reflections collected
Miller indices
ꢁ14 ꢃ h ꢃ 14, 0 ꢃ k ꢃ 20,
0 ꢃlꢃ 11
3,544
Unique reflections
Unique reflections I > 2r (I)
Max and min transmission
Data, restraints, parameters
Final R indices I > 2r (I)
3,121
0.9408, 0.9317
3544, 0, 264
R1 ¼ 0.0515
wR2 ¼ 0.1243
R1 ¼ 0.0585
wR2 ¼ 0.1305
1.098
R indices all data
Goodness of fit on F2
Largest diff peak and hole (e A
ꢁ3
˚
)
0.245, ꢁ0.373
chloroform): d 2.64 (s, 3H, CH3), 3.66 (d, 1H, J ¼ 18.6 Hz),
3.74 (s, 3H, CH3O), 3.97 (d, 1H, J ¼ 18.6 Hz), 6.51–6.53 (m,
13
1H), 6.87 (s br, 1H), 7.47–7.54 (m, 1H), 7.69–7.83 (m, 3H,
ArH) and 7.89 (d, 1H, J ¼ 7.5 Hz).
C NMR (deuterio-
chloroform): d 23.9, 48.6 (DEPT CH2), 53.7, 80.9, 112.2,
112.7, 121.4, 123.0, 131.5, 132.6, 135.5, 137.2, 144.0, 144.9,
145.8, 151.2, and 167.0. LCMS exact mass, 389.07: (M þ
H)þ, 389.94. Anal. Calcd for C17H15N3O6S. 1= H O: C, 51.25;
Methyl
2-acetyl-50-(4-chlorophenyl)-2H-spiro-[benzo[d]
isothiazole-3,30-pyrazole]-1,1-dioxide-20(40H)-carboxylate
(8b). Compound 8b was obtained in 74% yield, mp 181ꢀC dec
(benzene/hexanes), from the two-step procedure for the con-
densation-cyclization of dilithiated 40-chloroacetophenone car-
2
2
H, 4.05; N, 10.55. Found: C, 51.30; H, 3.91; N, 10.33.
Ethyl 2-acetyl-50-(2-furanyl)-2H-spiro-[benzo[d]-isothiazole-
3,30-pyrazole]-1,1-dioxide-20(40H)-carboxylate (8d). Compound
1
bomethoxyhydrazone and 10. IR: 1705 cmꢁ1. H NMR (deuter-
8d was obtained in 40% yield, mp 145–147 C (ethanol), from
the two-step procedure for the condensation-cyclization of dili-
ꢀ
iochloroform): d 2.64 (s, 3H, CH3), 3.67(d, 1H, J ¼ 18.7 Hz),
3.74 (s, 3H, CH3O), and 3.99 (d, 1H) and 7.39–7.50, 7.68–
7.82 (m, 7H, ArH) and 7.90 (d, 1H, J ¼ 7.5 Hz). 13C NMR
(deuteriochloroform): d 24.0, 49.0 (DEPT CH2), 53.9, 81.6,
121.5, 123.1, 128.2, 129.3, 131.6, 132.7, 135.6, 136.9, 151.1.
LCMS, exact mass, 433.05: (M þ H)þ, 433.99; (M ꢁ H)ꢁ,
432.10. Anal. Calcd for C19H16 Cl N3O5S: C, 52.60; H, 3.72;
N, 9.69. Found: C, 52.75; H, 3.64; N, 9.70.
thiated 2-acetylfuran carboethoxyhydrazone and 10. IR: 1712
cmꢁ1 1H NMR (DMSO-d6): d 1.06 (t, 3H), 2.50 (s, 3H),
.
3.43–3.46 (m, 1H), 3.88–3.96 (m, 3H), 6.67–6.69 (m, 1H),
6.94 (d, 1H, J ¼ 3.6 Hz), 7.76–7.92 (m, 5H), and 8.14 (d, 1H,
J ¼ 7.8 Hz). 13C NMR (DMSO-d6): d 23.4, 48.1, 61.7, 80.8,
112.2, 113.6, 121.0, 123.9, 131.6, 135.8, 143.9, 145.6, and
166.1. LCMS, exact mass, 403.08: (M þ H)þ, 403.95; (M ꢁ
.
Methyl 2-acetyl-50-(2-furanyl)-2H-spiro-[benzo[d]isothia-
zole-3,30-pyrazole]-1,1-dioxide-20(40H)-carboxylate (8c). Com-
pound 8c was obtained in 44% yield, mp 177–178ꢀC (ben-
zene/hexanes), from the two-step procedure for the condensa-
tion-cyclization of dilithiated 2-acetylfuran carbomethoxyhy-
H)ꢁ, 402.11. Anal. Calcd for C18H17N3O6S 7/8 H2O: C,
51.58; H, 4.51; N, 10.02. Found: C, 51.48; H, 3.38; N, 9.95.
Methyl 2-acetyl-50-(4-methylphenyl)-2H-spiro-[benzo[d]-
isothiazole-3,30-pyrazole]-1,1-dioxide-20(40H)-carboxylate
(8e). Compound 8e was obtained in 40% yield, mp 166–
168ꢀC (methanol), from the two-step procedure for the
1
drazone and 10. IR: 1709 and 1728 cmꢁ1. H NMR (deuterio-
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

March 2009 Preparation of 2H-spiro[Benzo[d]isothiazole-3,30-pyrazole]-1,1-dioxide-20(40H)-carboxylates
from Dilithiated C(a),N-Carboalkoxyhydrazones and Methyl 2-(Aminosulfonyl)benzoate
235
condensation-cyclization of dilithiated 40-methylacetophenone
carbomethoxyhydrazone and 10. IR: 1709 and 1728 cmꢁ1 1H
form): d 1.25 (s, 9H, CH3), 3.66 (d, 1H, J ¼18.3 Hz), 4.04 (d,
.
1Hz, J ¼ 18.3 Hz), 5.78 (s, 1H), and 7.39–7.41, 7.61–7.82 (m,
9H). 13C NMR (deuteriochloroform): d 27.7, 50.5 (DEPT
CH2), 81.4, 83.6, 121.1, 122.8, 126.8, 128.3, 128.8, 130.2,
130.4, 130.7, 133.8, 136.2, and 151.9. LCMS, exact mass,
399.13: LCMS, (M þ H)þ not detected, base peak 299.07.
Anal. Calcd for C20H21N3O4S: C, 60.13; H, 5.30; N, 10.52.
Found: C, 59.98; H, 5.37; N, 10.50.
NMR (deuteriochloroform): d 2.39 (s, 3H), 2.63 (s, 3H), 3.65–
4.03 (m, 5H) [13], 7.21–7.28, 7.46–7.48, and 7.63–7.90 (m,
8H). 13C NMR (DMSO-d6): d 21.7, 24.1, 48.9 (DEPT CH2),
53.4, 82.0, 121.4, 124.5, 127.4, 128.5, 130.0, 132.2, 136.4,
137.5, 140.1, 151.2, 153.1, and 166.7. LCMS, exact mass,
413.10: (M þ H)þ, 414.08. Anal. Calcd for C20H19N3O5S: C,
58.10; H, 4.63; N, 10.16. Found: C, 58.06; H, 4.70; N, 9.97.
Methyl 2-acetyl-50-(2-acetoxyphenyl)-2H-spiro-[benzo[d]-
isothiazole-3,30-pyrazole]-1,1-dioxide-20(40H)-carboxylate
(8f). Compound 8f was obtained in 58% yield, mp 218–220ꢀC
(benzene/hexanes) from the two-step procedure for the conden-
sation-cyclization of trilithiated 20-hydroxyacetophenone carbo-
1,1-Dimethylethyl 50-(4-methylphenyl)-2H-spiro-[benzo-
[d]isothiazole-3,30-pyrazole]-1,1-dioxide-20(40H)-carboxylate
(8j). Compound 8j was obtained in 33% yield, mp 181.5–
182ꢀC (methanol), from the two-step procedure for the con-
densation-cyclization of dilithiated 40-methylacetophenone
carbo-t-butoxyhydrazone and 10. IR: 1697 and ꢄ3100 broad
1
methoxyhydrazone and 10. IR: 1703 and 1728 cmꢁ1. H NMR
cmꢁ1 1H NMR (deuteriochloroform): d 1.17 (s, 9H, CH3),
.
(deuteriochloroform): d 2.39 (s, 3H), 2.63(s, 3H), 3.65–3.71
(m, 4H), 4.02 (d, 1H, J ¼ 18.3 Hz), 7.18 (d, 1H, J ¼ 7.8 Hz),
7.26–7.31 (m, 1H), 7.42–7.49 (m, 2H), 7.69–7.80 (m, 3H), and
7.87 (d, 1H, J ¼ 7.8 Hz). 13C NMR (deuteriochloroform): d
22.3, 23.8, 50.2, 53.4 (DEPT CH2), 80.6, 121.2, 123.0, 123.3,
124.9, 126.3, 129.5, 131.4, 132.5, 135.5, 137.2, 148.8, 149.0,
151.1, 166.9, and 170.1. LCMS, exact mass, 457.09: (M þ
H)þ, 457.93. Anal. Calcd for C21H19N3O7S: C, 58.10; H, 4.63;
N, 10.16. Found: C, 58.06; H, 4.70; N, 9.97.
2.37 (s, 3H, CH3), 3.62 (d, 1H, J ¼ 18.0 Hz), 3.99 (d, 1H,
CH3, J ¼ 18.0 Hz), 5.84 (s), 7.20 (d, 1H, J ¼ 8.0 Hz), 7.47
(d, 1H, J ¼ 7.8 Hz), 7.59–7.72 (m, 5H), and 7.81 (d, 1H, J ¼
7.8 Hz). 13C NMR (deuteriochloroform): d 21.7, 27.8, 50.7,
81.5, 83.6, 121.3, 123.0, 127.0, 127.4, 127.6, 129.7, 130.5,
133.8, 136.3, 141.4, 141.7, 150.3, and 152.1. LCMS, exact
mass, 413.14: (M þ H)þ not detected, base peak 314.00. Anal.
Calcd for C21H23N3O5S. 1= H O: C, 60.34; H, 5.67; N, 10.05.
4
2
Found: C, 60.28; H, 5.70; N, 10.05.
1,1-Dimethylethyl 50-(4-methoxyphenyl)-2H-spiro-[benzo-
[d]isothiazole-3,30-pyrazole]-1,1-dioxide-20(40H)-carboxylate
(8g). Compound 8g was obtained in 92% yield, mp 190–
191ꢀC (methanol), from the two-step procedure for the con-
densation-cyclization of dilithiated 40-methoxyacetophenone
1,1-Dimethylethyl
50-(4-chlorophenyl)-2H-spiro-[benzo-
[d]isothiazole-3,30-pyrazole]-1,1-dioxide-20(40H)-carboxylate
(8k). Compound 8k was obtained in 35% yield, mp 152–
155ꢀC (methanol), from the two-step procedure for the con-
densation-cyclization of dilithiated 40-chloroacetophenone
carbo-t-butoxyhydrazone and 10. IR: 1693 and 3438 broad
1
carbo-t-butoxyhydrazone and 10. IR: 1696 and 3128 cmꢁ1. H
1
cmꢁ1. H NMR (deuteriochloroform): d 1.15 (s, 9H), 3.54 (d,
NMR (DMSO-d6): d 1.03 (s, 9H, CH3), 3.68–3.91 (m, 2H,
CH2), 3.82 (s, 3H, OCH3), 7.04 (d, 2H, J ¼ 9.0 Hz), 7.63–
7.88 (m, 6H), and 9.18 (s, NH). 13C NMR (DMSO-d6): d 27.2,
49.3 (DEPT CH2), 55.4, 80.6, 80.9, 114.2, 120.6, 123.5, 123.9,
128.2, 130.3, 133.6, 135.5, 139.8, 149.9, 151.3, and 160.8.
LCMS, exact mass, 429.14: (M þ H)þ, 429.67. Anal. Calcd
for C21H23N3O5S: C, 58.73; H, 5.40; N, 9.78. Found: C,
58.41; H, 5.49; N, 9.65.
1H, J ¼ 18.0 Hz), 4.00 (d, 1H, J ¼ 18.3 Hz), 7.38 (d, 2H, J ¼
8.7 Hz), 7.49 (d, 1H, J ¼ 7.5 Hz), 7.63–7.70 (m, 4H), and
7.79 (d, 1H, J ¼ 6.9 Hz). 13C NMR (deuteriochloroform): d
27.9, 50.6, 51.0, 81.7, 83.9, 121.5, 123.1, 128.3, 129.1, 129.4,
130.7, 134.1, 136.3, 137.0, 141.3, 150.4, and 151.1. LCMS,
exact mass, 433.09: (M þ H)þ, 433.75. Anal. Calcd for
.
C20H20 Cl N3O4S 5/4 CH3OH [10]: C, 53.74; H, 5.52; N,
1,1-Dimethylethyl 50-(3,4-dimethoxyphenyl)-2H-spiro-[be
nzo[d]isothiazole-3,30-pyrazole]-1,1-dioxide-20(40H)-carboxy-
late (8h). Compound 8h was obtained in 38% yield, mp 200–
203ꢀC (ethanol), from the two-step procedure for the conden-
sation-cyclization of dilithiated 30,40-dimethoxyacetophenone
8.85. Found: C, 53.88; H, 5.19; N, 8.94.
1,1-Dimethylethyl 50-(3,4-dimethylphenyl)-2H-spiro-[ben-
zo[d]isothiazole-3,30-pyrazole]-1,1-dioxide-20(40H)-car-boxy-
late (8l). Compound 8l was obtained in 31% yield, mp 197–
201ꢀC (methanol), from the two-step procedure for the con-
densation-cyclization of dilithiated 30,40-dimethylacetophenone
1
carbo-t-butoxyhydrazone and 10. IR: 1727 and 3231 cmꢁ1. H
carbo-t-butoxyhydrazone and 10. IR: 1712 and 3415 cmꢁ1. H
1
NMR (deuteriochloroform): d 1.17 (s, 9H, CH3), 3.65 (d, 1H,
J ¼ 15.0 Hz), 3.90 (s, 3H, OCH3), 3.91 (s, 3H, OCH3), 3.95
(d, 1H, J ¼ 18.3 Hz), 6.81 (d, 1H, J ¼ 8.4 Hz), 7.01 (dd, 1H,
J ¼ 8.1 Hz), 7.39 (d, 1H, J ¼ 2.1 Hz), 7.51 (d, 1H, J ¼ 7.8
Hz), 7.61–7.74 (m, 2H), and (7.81 and 7.83 singlets broad,
1H). 13C NMR (deuteriochloroform): d 27.8, 50.5 (DEPT
CH2), 81.3, 83.4, 108.6, 110.6, 120.7, 121.3, 123.9, 123.3,
130.5, 133.9, 136.1, 141.3, 149.1, 150.3, 151.3, and 151.6.
LCMS, exact mass, 459.15: (M þ H)þ, 459.64. Anal. Calcd
for C22H25N3O6S: C, 57.50; H, 5.48; N, 9.14. Found: C,
57.26; H, 5.55; N, 9.03.
NMR (deuteriochloroform): d 1.18 (s, 9H, CH3), 2.28 (s, 3H,
CH3), 2.30 (s, 3H, CH3), 3.64 (d, 1H, J ¼ 18.3 Hz), 4.01(d,
1H, CH3, J ¼ 18.0 Hz), 5.7 (s), 7.17 (d, 1H, J ¼ 8.1 Hz),
7.42–7.59 (m, 2H), 7.60–7.73 (m, 4H), and 7.81 (d, 2H, J ¼
7.8 Hz). 13C NMR (deuteriochloroform): d 19.7, 19.9, 27.7,
50.7 (DEPT CH2), 81.3, 83.4, 107.4, 121.1, 122.8, 124.4,
127.7, 127.9, 130.0, 130.3, 133.8, 136.2, 137.2, 140.0, and
152.2. LCMS, exact mass, 427.16: (M þ H)þ, 427.70. Anal.
Calcd for C22H25N3O4S.1H2O: C, 59.31; H, 6.11; N, 9.43.
Found: C, 59.69: H, 6.26; N, 9.07.
1,1-Dimethylethyl 50-phenyl-2H-spiro-[benzo[d]-isothiazole-
3,30-pyrazole]-1,1-dioxide-20(40H)-carboxylate (8i). Compound
8i was obtained in 59% yield, mp 193–197ꢀC (methanol),
from the two-step procedure for the condensation-cyclization
of dilithiated acetophenone carbo-t-butoxyhydrazone and 10.
Ethyl 2-acetyl-30-(4,5-dihydrobenz[g]indazinyl)-2H-spiro-
[benzo[d]isothiazole-3,30-pyrazole]-1,1-dioxide-20(40H)-car-
boxylate (10a). Compound 10a was obtained in 60% yield,
mp 257–259ꢀC dec (methanol), from the two-step procedure
for the condensation-cyclization of dilithiated 1-tetralone car-
1
IR: 1701, 1728, and 3195 cmꢁ1
;
1H NMR (deuteriochloro-
boethoxyhydrazone and 10. IR: 1703 and 1739 cmꢁ1. H NMR
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

236
A. C. Dawsey, C. Potter, J. D. Knight, Z. C. Kennedy, E. A. Smith, A. M. Acevedo-Jake, A. J.
Puciaty, C. R. Metz, C. F. Beam, W. T. Pennington, and D. G. VanDerveer
Vol 46
ocyclic Syst 2002, 6, 52; (c) Makino, K.; Kim, H. S.; Kurasawa, Y. J
Heterocyclic Chem 1998, 35, 489; (d) Elguero, J. In Comprehensive
Heterocyclic Chemistry II; Shinkai, I., Ed.; Elsevier: Oxford, UK,
1996; Vol. 3, pp 1–75, 817–932.
(deuteriochloroform): d 0.91 (m, 1H), 1.27 (m, 3H), 1.80–1.84
(m, 1H), 2.03–2.05 (m, 1H), 2.52 (s, 3H, CH3), 3.70–3.91 (m,
3H, OCH3), 7.16–7.18 (m, 1H), 7.29–7.37 (m, 3H), 7.61–7.90
(m, 4H), and 8.22–8.24 (m, 1H). 13C NMR (deuteriochloro-
form): d 14.3, 22.1 (DEPT CH2), 24.1 (CH3 DEPT), 29.5
(CH2 DEPT), 59.1 (DEPT CH), 62.9, 84.0, 121.4, 123.4,
125.9, 126.4, 127.2, 129.2, 131.0, 131.3, 132.6, 135.3, 138.9,
152.9, and 167.6. LCMS, exact mass, 439.12: (M þ H)þ,
439.99. Anal. Calcd for C22H21N3O5S: C, 60.12; H, 4.82; N,
9.56. Found: C, 59.82; H, 4.54; N, 9.95.
[2]
(a) Eissa, A. M. F. Heterocyclic Commun 2003, 9, 181;
(b) Dopp, D. Int J Photoenergy 2001, 3, 41; (c) Bethell, D.; Page, P.
C. B.; Vahedi, H. J Org Chem 2000, 65, 6756.
[3]
(a) Elkanzi, N. A. A. Phosphorus, Sulfur, Silicon, Relat
Elements 2008, 183, 2040; (b) Ren, Z.; Cao, W.; Chen, J.; Chen, Y.;
Deng, H.; Shao, M.; Wu, D. Tetrahedron 2008, 64, 5156; (c) Padma-
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Compd 2007, 43, 76; (f) Padmavathi, V.; Balaiah, A.; Ravisankar, N.;
Sarma, M. R.; Padmaja, A. J Ecotoxicol Environ Monitoring 2006, 16,
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Methyl 2-acetyl-30-(4,5-dihydrobenz[g]indazinyl)-2H-spi-
ro[benzo[d]isothiazole-3,30-pyrazole]-1,1-di-oxide-20(40H)-car-
boxylate (10b). Compound 10b was obtained in 71% yield,
mp 209ꢀC dec (ethanol), from the two-step procedure for the
condensation-cyclization of dilithiated 1-tetralone carbometh-
oxyhydrazone and 10. IR: 1701 cmꢁ1 1H NMR (deuterio-
.
chloroform): d 1.80–1.85 (m, 1H), 2.03–2.06 (m, 1H), 2.63 (s,
3H, CH3), 2.75–2.98 (m, 2H), 3.60–3.82 (m, 4H, CH and
OCH3), 7.16–7.39, 7.57–7.90 (m, 7H), and 8.21 (d, 1H, J ¼
6.6 Hz). 13C NMR (deuteriochloroform): d 22.1, 24.1, 29.5,
53.9 (DEPT CH2), 59.2, 84.0, 121.5, 123.3, 125.8, 127.3,
129.2, 131.1, 131.4, 131.7, 132.7, 135.4, 139.1, 152.0, 153.2,
and 167.8. LCMS, exact mass, 425.10: (M þ H)þ, 426.05.
Anal. Calcd for C21H19N3O5S: C, 59.28; H, 4.50; N, 9.88.
Found: C, 58.94; H, 4.63; N, 9.60.
[4] Wrobel, J.; Dietrich, A. Heterocycles 1994, 38, 1823.
[5] Grant, B. J.; Kramp, C. R.; Knight, J. D.; Meierhoefer, M.
A.; Vella, J. H.; Sober, C. L.; Jones, S. S.; Metz, C. R.; Beam, C. F.;
Pennington, W.T.; VanDerveer, D. G.; Camper, N. D. J Heterocyclic
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(a) Dunn, S. P.; Hajiaghamohseni, L. M.; Lioi, S. B.;
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G.; Camper, N. D. J Heterocyclic Chem 2005, 42, 1095.
1,1-Dimethylethyl
30-(4,5-dihydrobenz[g]indazinyl)-2H-
spiro[benzo[d]isothiazole-3,30-pyrazole]-1,1-dioxide-20(40H)-
carboxylate (10c). Compound 10c was obtained in 39 %
yield, mp 187–188ꢀC (methanol), from the two-step procedure
for the condensation-cyclization of dilithiated 1-tetralone
carbo-t-butoxyhydrazone and 10. IR: 1689 and 3183 broad
cmꢁ1 1H NMR (DMSO-d6): d 1.05 (s, 9H, CH3), 1.70–1.74
.
[8] Knight, J. D.; Brown, J. B.; Overby, J. S.; Beam, C. F.;
Camper, N. D. J Heterocyclic Chem 2008, 45, 189.
(m, 1H of CH2), 1.91–1.99 (m, 1H of CH2), 2.69–3.00 (m, 2H,
CH2), 3.85 (dd, 1H, CH, J ¼ 4.4, 13.2 Hz), 7.29–7.42 (m,
13
[9] Farrugia, L. J Appl Cryst 1997, 30, 565.
3H), and 7.67–7.92 (m, 4H), 7.93 (d, 1H, J ¼ 7.2 Hz), and
[10] Knight, J. D.; Kramp, C. R.; Hilton, E. J.; Vella, J. H.;
Grant, B. J.; Hajiaghamohseni, L. M.; Meierhoefer, M. A.; Dunn, S.
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Compound 7b in this study incorporated methanol.
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Classe Sci Fis Mat e Nat 1952, 12, 583; (b) Mirone, P.; Vampiri, M.
Chem Abstr 1952, 46, 9423.
9.27 (s, NH).
C NMR (DMSO-d6): d 21.9, 27.8, 28.9, 56.3
(DEPT CH), 81.3, 83.9, 121.2, 124.5, 124.7, 127.47, 127.52,
129.9, 139.9, 131.1, 133.9, 136.3, 139.9, 140.2, 150.9, and
153.0. LCMS, exact mass, 425.14: (M þ H)þ, 425.74. Anal.
Calcd for C22H23N3O4S: C, 62.10; H, 5.45; N, 9.88. Found: C,
62.14; H, 5.52; N, 9.78.
[12] Johnson, A. L.; Sweetser, P. B. J Org Chem 1976, 41, 110.
[13] Multiplets in 8a and 8e were poorly resolved but each con-
tained a distinguishable doublet, each with J ¼ 18.6 Hz.
Acknowledgments. The authors thank the following sponsors:
the Research Corporation, the National Science Foundation
grants CHE # 9708014 and # 0212699 for Research at Undergrad-
uate Institutions, and the United States Department of Agricul-
ture, NRICGP # 2003-35504-12853. The College of Charleston
awarded single summer grants through its Summer Undergradu-
ate Research Forum (SURF-2006 through 2008) to J. D. Knight,
A. C. Dawsey, E. A. Smith, A. M. Acevedo-Jake, A. J. Puciaty,
and Z. C. Kennedy.
[14] (a) Rigaku Corporation. CrystalClear; Rigaku Corporation:
Danvers, MA, 1999; (b) Jacobson, R. A. REQABS v 1.1; Molecular
Structure Corp: Texas, 1998.
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System–Windows Version; University of Gottingen: Germany, 1997.
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International Tables for X-Ray Crystallography, Vol IV:
Tables 2.2 B and 2.3.1; Kluwer Academic Publisher: Dordrecht,
1974.
[17] CCDC
# 689213 contains the supplementary crystallo-
REFERENCES AND NOTES
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from the Cambridge Crystallographic Data Centre via www.ccdc.
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