Preparation of spiro [benzoisothiazole-isoxazole] dioxides from dilithiated C(α),O-oximes and methyl 2-(aminosulfonyl)benzoate

Article abstract of DOI:10.1002/jhet.5570440318

Several dilithiated C(α),O-oximes were prepared in excess lithium diisopropylamide-tetramethyl-ethylenediamine (LDA/TMEDA) and condensed with methyl 2-(aminosulfonyl)benzoate followed by acid cyclization of intermediates to spiro(benzoisothiazole-isoxazol

Full text of DOI:10.1002/jhet.5570440318

May-Jun 2007
627
Preparation of spiro[Benzoisothiazole-Isoxazole] Dioxides from
Dilithiated C(ꢀ),O-Oximes and Methyl 2-(Aminosulfonyl)benzoate
Bonnie J. Grant, Catherine R. Kramp, John D. Knight, Michelle A. Meierhoefer,
Jarrett H. Vella, Carolyn L. Sober, Stephen S. Jones, Clyde R. Metz,
and Charles F. Beam*
Department of Chemistry and Biochemistry, College of Charleston, Charleston, SC 29424
William T. Pennington and Donald G. VanDerveer
Department of Chemistry, Clemson University, Clemson, SC 29634
N. Dwight Camper
Department of Entomology, Soils, and Plant Diseases, Clemson University, Clemson, SC 29634
Received July 11, 2006
O
O
COOCH3
S
R4
R3
H-N
CHLi
C
R4
R3
SO2NH2
N-OLi
O
xs LDA/acid
N
Several dilithiated C(ꢀ),O-oximes were prepared in excess lithium diisopropylamide-tetramethyl-
ethylenediamine (LDA/TMEDA) and condensed with methyl 2-(aminosulfonyl)benzoate followed by acid
cyclization of intermediates to spiro(benzoisothiazole-isoxazole) dioxides, a new spiro and fused-ring
system. Distortionless enhancement by polarization transfer (DEPT) and liquid chromatography mass
spectrometry (LCMS) for all products, as well as X-ray single crystal analysis on a representative product,
were especially relevant for structure confirmation in this synthesis.
J. Heterocyclic Chem., 44, 627 (2007).
One of our major synthetic endeavors has been the
preparation of substituted isoxazoles [11] and pyrazoles
[12] by employing strong base synthesis methods.
Multiple anion-type intermediates, such as 1,4-dilithiated
oximes 1, or 1,4-dilithiated phenylhydrazones 2 have been
used, beginning with readily available and inexpensive
starting materials, such as substituted acetophenones and
other C(ꢀ)-carbonyl compounds that are transformed into
oximes and hydrazones, and also including a variety of
electrophilic reagents such as substituted aromatic esters,
aldehydes, and ketones.
INTRODUCTION
Isoxazoles and 4,5-dihydroisoxazoles (2-isoxazolines)
are well documented for their methods of preparation,
their usefulness as synthetic intermediates, their biological
potential and activity in both medicine and agriculture,
and for varied spectral and theoretical studies [1]. They
have also been a part of a spiroheterocyclic system with
the spiro link atom between isoxazole and piperidine [2],
isoxazole and indanone [3], isoxazole and flavanone
(benzopyranone) [4], and isoxazole and isoxazole [5].
Benzoisothiazole dioxides, or 1,2-benzoisothiazole 1,1-
dioxides (BIDs) have received less investigation regarding
their synthesis and uses with many of these reports focused
on their biological potential [6] in agriculture and medicine.
A large part of the synthetic effort has focused on placing
pendant groups in the 3-position with a few reports where
BIDs have also been a part of a spiroheterocyclic system:
spiro(BID-oxazolidine dione) [7], and spiro(BID-
oxazolinone) [8].
Recently, we have been successful with carbanionic-
nucleophile anionic-electrophile condensations where
dilithiated intermediates of 1 or 2 were condensed-
cyclized with lithiated methyl thiosalicylate [13], lithiated
ethyl oxanilates [14], lithiated ethyl benzoylacetate [15],
or lithiated methyl 2-(aminosulfonyl)benzoate. The
utilization of the latter ester-sulfonamide 3 led to
preparations of 3-benzoisothiazole dioxide-ꢁ-ketoesters
[16] and benzoisothiazoloisoquinolinone dioxides, the
latter being a new four fused ring heterocyclic system
[17]. The ester-sulfonamide 3 has also been used in the
preparation of pyrazolyl-o-benzenesulfonamides 4 [18]
by the condensation of ester-sulfonamide 3 with
dilithiated phenylhydrazone 2, followed by acid
cyclization of C-acylated intermediates to 4 instead of
spiro(BID-pyrazole) 5.
We have found that methyl 2-(aminosulfonyl)benzoate 3
is especially useful for the synthesis of compounds
containing a benzenesulfonamide or BIDS ring system, and
such compounds have potential for agricultural use and
biological activity [9]. In some instances this resulted when
it has become an ortho-benzenesulfonamide pendant group
of another molecule, usually a heterocycle [10].

628
B. J. Grant, C. R. Kramp, J. D. Knight, M. A. Meierhoefer, J. H. Vella,
C. L. Sober, S. S. Jones, C. R. Metz, and C. F. Beam
Vol 44
CH3
C
1.
CH2Li
C
O
O
O
O
O
R4
R3
S
S
N
Ar
NNH-C6H5
CH2
C
H-N
Ar
N-NLi
H-N
R4
R3
1.- 3.
2
C6H5
N-OH
1. 5 LDA
O
2. methyl 2-(aminosulfonyl)-
benzoate 3
1
N
6-12
1. 5 LDA
R3
3. aq. acid, heat
2. methyl 2-(aminosulfonyl)-
benzoate 2
2., 3.
6, R3= C6H5
7, R3= 4-CH3OC6H4
8, R3= 3,4-(CH3O)2C6H
3. aq. acid, heat
H2N
O
O
S
O
O
O
S
S
N
HN
O
O
H-N
O
O
O
O
S
N
S
N
N
N
H-N
H-N
O
Ar
C6H5
Ar
C6H5
N
N
4
5
O
11
R'
12
Figure 1. N-Phenyl-pyrazolyl-o-benzenesulfonamides.
9, R' = H
10, R'= OCH3
We have also recently used tetramethylethylenediamine
(TMEDA), a lithium chelating agent, in some of our
synthetic endeavors when the original course of a reaction
does not prove satisfactory. TMEDA can improve
reaction yields, increase reaction rates, or even alter the
course of a reaction. Systems involving LDA/TMEDA
have given mixed results [19]. There is one account
involving this complex and dilithiated ꢀ-ketoesters that is
favorable, especially with regard to yield of products [20].
One of our initial projects involving the same type of
dilithiated ꢀ-ketoester intermediates and ester-sulfon-
amide 3 usually improved the products yield or permitted
the reaction to occur [16].
Figure 2. spiro(Benzoisothiazole-Isoxazole) Dioxides,6-12.
extent found in this study [16,18,21,22]. We also obtained
liquid chromatographs with mass spectral detection (LCMS)
for each product. In the positive mode, the expected (M+H)+
molecular ion was found (see experimental).
A representative molecular structure from X-ray analysis
for spiro(BID-isoxazole) 7 is shown in Figure 1. Atomic
positional parameters are listed in Table 2, and selected
bond distances and angles are listed in Table 3. Each
molecule exhibits hydrogen bonding (refer to ORTEP
diagram) between the H atom on the N2 nitrogen atom and
the N1 nitrogen atom on a second molecule and between the
N1 nitrogen atom and the hydrogen atom on the N2 nitrogen
atom on a third molecule.
RESULTS AND DISCUSSION
During the current investigation, dilithiated C(ꢁ),O-
oximes 1 of several substituted acetophenones (for 6-8),
1-tetralones (for 9 and 10), and cycloalkanones (for 11
and 12), were prepared in excess LDA/TMEDA,
condensed with methyl 2-(aminosulfonyl)benzoate 3, and
followed by acid cyclization of intermediates to give
spiro(benzoisothiazole-isoxazole) 6-12 instead of isoxa-
zolyl o-benzenesulfonamides 13 initially expected.
The new spiroheterocycles 6-12 were characterized by
absorption spectra and an X-ray crystallographic analysis of
spiro(BID-isoxazole)dioxide 7. Its ORTEP diagram
illustrated data obtained (Tables 1-3) which displays the
spiro atom link between the two five-member rings, with the
separate ring numbering, C5' of the isoxazole ring and C3 of
the benzoisothiazole dioxide ring in 6-8, and 11 and 12; C3'
and C3 in 9 and 10. Clearly displayed DEPT spectra for 6-8
indicated a methylene carbon at the C4' position, ꢂ 44.8-45.4
ppm, and spectra for 9-12 indicated a methyne carbon, also
isoxazole C4' positions, ꢂ 53.7-56.7 ppm. The DEPT was
compared with the 13C NMR to identify the spiro carbon
atom in each product, and each displayed its 13C NMR
absorption in a narrow range, ꢂ 96.2-97.6 ppm.
Figure 3. ORTEP diagram (50% ellipsoids for non-Hydrogen atoms) for
7, C16H14N2O4S.
Energy calculations (B3YP/6-31G(d)) [23] were
performed on representative products from 6-12 and 14
along with analogous isomers 4 and 5 from an earlier
investigation [18]. The calculations indicate that 14 would
be approximately 9 kcal mol-1 more stable than the spiro
product(s) 6-12, and 4 would be 14.7 kcal mol-1 more stable
than 5. While the heteroaromatic compounds 4 and 14 are
more stable than their respective spiro isomers, 5 and 6-12,
spiroheterocycles 6-12 instead of 14 should be easier to
prepare. In the earlier study [18] 4 was formed and not 5,
and the transformation of 4 to 5 in acid may be more
difficult than the transformation of 14 to 6-12.
Products 7 and 8 had crystals that were free of incorporated
solvents. Recrystallized products 6 and 9-12 contained
solvent molecules. We have previously obtained products
containing solvents included in the crystal, but not to the
Speculative mechanistic considerations may involve one
of two, or both pathways, Claisen and aldol, and they are
presented in a summary manner.
Claisen path A:

May-Jun 2007
Preparation of spiro[Benzoisothiazole-Isoxazole] Dioxides
629
O
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 minute runs were
reproduced in both the positive and negative MS modes. Data
were collected at full scan from 100 to 650 amu.
O
O
O
O
SNH2
R4
R3
S
CH2Li
C
LiN
R4
CH
NOLi
16
O
1
C
OH
R3
N
14
H2NO2S
H3COOC
General Procedure for the Preparation spiro(1,2-
Benzoisothiazole–Isoxazole) 1,1-Dioxdes (6-12). 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, was added 49-50 ml of 1.6 M n-butyllithium (0.0788 mol) in
hexanes (0°) under N2. The flask was cooled in an ice water bath and
8.01 g (0.0788 mol) of diisopropylamine (99.5% - Aldrich Chem.
Co.) dissolved in 25-30 ml of dry THF (freshly distilled from
sodium) was added from the addition funnel at a fast drop rate during
a 5 min (0°, N2) period. The solution was stirred for an additional 15-
20 min, and then treated via the addition funnel, during 5 min, with
oxime [25] (0.015 mol) dissolved in 35-45 ml of THF. After 45-60
min, 7.36 g (0.063 mol) of TMEDA (99.5%) dissolved in 25 ml of
THF was added, and the solution was stirred an additional 10-15 min
Then, 45-60 min later, a solution of 3.47 g (0.0158 mol – 5% molar
excess) of methyl 2-(aminosulfonyl)benzoate 3 dissolved in 25-35 ml
of THF, was added over a period of 5 min, to the dilithiated
intermediate 1, and the solution was stirred overnight (room temp.,
N2). Finally, 100 ml of 3 M hydrochloric acid was added all at once,
followed by an additional 100 ml of solvent grade THF, and the two-
phase mixture was well stirred and heated under reflux for
approximately 45-60 min. At the end of this period, the mixture was
poured into a large flask (ca. 1 or 2 liter) containing ice (ca., 100 g),
followed by the addition of 100 ml of solvent grade ether. The
mixture was then neutralized with solid sodium bicarbonate, and the
layers separated. The aqueous layer was extracted with ether (2x75
ml), and the organic fractions were combined, not dried, filtered,
evaporated, and recrystallized to afford products.
H2N
O
S
O
O
S
O
R4
3
HN
O
O
O
R4
R3
OH
OH
R3
S
N
O
HN
O
H+
C
R4
S
13
N
N
17
O
R3
N
R4
6-12
C
OH
R3
N
15
Figure 4. spiro(Benzoisothiazole-Isoxazole) Dioxides, Mechanism
Considerations
1+3ꢀ14ꢀ15ꢀ6-12; Claisen path B: 1+3ꢀ14ꢀ13ꢀ6-
12; and aldol path: 3ꢀ16+1ꢀ17ꢀ15ꢀ6-12. Two
additional observations related to the mechanism were made
without follow up investigation: (1) if saccharin was used
instead of ester–sulfonamide 3, no products were isolated.
(2) Only a little more than a trace amount of saccharin was
recovered when ester-sulfonamide 3 was treated with excess
LDA under the same conditions employed for lithiation and
condensation and acidification without reflux.
The yields of products ranged from 24-74 %, which may
not be optimal for a given compound. Since TMEDA was
used in this synthesis and not in the synthesis of
pyrazolyl-o-benzenesulfonamides 4 [18], we can state that
it was necessary for the overall success of the synthesis but
further investigation may be necessary to determine its
effect on the direction of the reaction. The reactions are
regioselective, and multi-gram quantities of products can
be obtained following recrystallization from common
solvents. Since select pyrazolyl-o-benzenesulfonamides 4
have given astonishing results in an agricultural assay [24],
the spiro(BID-isoxazole) 6-12 are undergoing related and
appropriate biological testing.
3'-Phenyl spiro[1,2-benzoisothiazole-3,5'(4'H)-isoxazole]
1,1-dioxide (6). Compound 6 was prepared in 65% (3.01 g), mp
195-200° (ethanol/water) using the general procedure for the
condensation-cyclization of dilithiated acetophenone oxime and
1
ester-sulfonamide 3; IR: 3500 cm-1; H NMR (deuteriochloro-
form, DMSO-d6): ꢁ 3.86 (d, 1H, CH, J = 17.1 Hz), 3.95 (d, 1 H,
CH, J = 18.6 Hz), 7.44-7.47, 7.66-7.80, 8.01-8.03 (m, 9H, ArH),
and 9.32 (s broad, NH); 13C NMR (deuteriochloroform, DMSO-
d6): ꢁ 45.1 (DEPT, CH2), 96.4, 129.5, 124.3, 126.7, 128.6,
128.8 (2), 130.6, 131.3, 133.7, 136.6, and 157.1; LCMS, mw,
300.3; exact mass, 300.06: (M+H)+, 300.9; (M-H)-, 298.9. Anal.
Calcd for C15H12N2O3S•1/2H2O [16b,18b,22b]: C, 58.24; H,
4.24; N, 9.05. Found: C, 58.35; H, 3.99; N, 8.67.
EXPERIMENTAL
3'-(4-Methoxyphenyl) spiro[1,2-benzoisothiazole-3,5'(4'H)-
isoxazole] 1,1-dioxide (7). Compound 7 was prepared in 74%
(3.67 g), mp 195-201° (ethanol/benzene) using the general
procedure for the condensation-cyclization of dilithiated
4'-methoxyacetophenone oxime and ester-sulfonamide 3; IR:
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
1
3300 cm-1; H NMR (DMSO-d6): ꢁ 3.79 (d, 1H, J = 17.7 Hz,
Accessory.
Nuclear magnetic resonance (NMR) spectra were
estimate), 3.82 (s, 3H), 4.19 (d, 1H, J = 17.7 Hz), 7.06 (d, 2H, J
= 9.0 Hz), 7.36, 7.79-7.94 (m, 6H), and 9.58 (s broad, NH); 13C
NMR ꢁ (DMSO-d6): ꢁ 45.4 (DEPT, CH2), 56.1, 96.8, 115.1,
121.2, 121.8, 129.0 (2), 129.2, 132.3, 134.6, 137.0, 137.1, 157.7,
and 161.7; LCMS, mw, 330.4; exact mass, 330.07: (M+H)+,
330.9; (M-H)-, 328.9. Anal. Calcd for C16H14N2O4S: C, 58.17;
H, 4.27; N, 8.48. Found: C, 58.42; N, 4.31; N, 8.57.
Single crystal X-ray measurements for crystals of 7,
C16H14N2O4S recrystallization from benzene and dimethylformamide
(DMF) were collected on a Mercury CCD area detector coupled with
obtained with a Varian Mercury-Vx spectrometer in an Oxford
300/54 magnet. Chemical shifts are recorded in ꢁ (ppm) downfield
from internal tetramethylsilane (TMS) reference. 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

630
B. J. Grant, C. R. Kramp, J. D. Knight, M. A. Meierhoefer, J. H. Vella,
C. L. Sober, S. S. Jones, C. R. Metz, and C. F. Beam
Vol 44
a Rigaku AFC8 diffractometer with graphite monochromated Mo-K
(8 = 0.71073 Å) radiation. The data were collected a room
temperature. Data was collected in 0.50° oscillations in ꢀ with 30 s
exposures (two identical scans were performed at each position to
identify detector anomalies). A sweep of data was done using ꢀ
oscillations from -90.0 to 90.0° at ꢁ = 45.0° and ꢂ = 0.0°; a second
sweep was performed using ꢀ oscillations from -30.0 to 30.0° at ꢁ =
45.0° and ꢂ = 90.0°. The crystal-to-detector distance was 27.1 mm.
The detector swing angle was 0.00°. Cell parameters and additional
details of the data collection are reported in Table 1.
(DMSO-d6): ꢄ 3.71-3.86 (m, 7H), 4.19 (d, 1H, J = 18 Hz), 7.06-7.13,
7.26-7.34, 7.47, 7.55, 7.77-7.95, 8.19 (m, 7H), and 9.58 (s, broad,
NH); 13C NMR (DMSO-d6): ꢄ 44.8 (DEPT, CH2), 55.6 (2), 96.2,
103.4, 109.1, 111.9, 119.6, 119.9, 120.6, 120.8, 125.0, 127.9, 130.7,
131.4, 131.6, 133.9, 142.3, and 157.2; LCMS, mw, 360.4; exact mass,
360.08: (M+H)+, 360.9; (M-H)-, 358.9. Anal. Calcd for C17H16N2O5S:
C, 56.66; H, 4.47; N, 7.78. Found: C, 56.77; H, 4.26; N, 7.85.
1,2,3',4'-Tetrahydronaphth[1,2-c]-spiro[1,2-benzoisothiaz-
ole-3,3'(3a'H)-isoxazole] 1,1-dioxide (9). Compound 9 was
prepared in 74% (3.87g), mp 142-146° (methanol/water) using the
general procedure for the condensation-cyclization of dilithiated
1-tetralone oxime and ester-sulfonamide 3; IR: 3332 cm-1; 1H
NMR (deuteriochloroform, DMSO-d6): ꢄ 2.06-2.18 (m, 2H), 2.85-
3.10 (m, 1H), 3.78-3.83 (m, 1H), 7.26-7.40, 7.67-7.82 (m, 7H),
7.99 (d, 1H, J = 6.9 Hz), and 9.00 (s broad, NH); 13C NMR
(deuteriochloroform, DMSO-d6): ꢄ 22.4 (DEPT, CH2), 29.4
(DEPT, CH2), 54.4 (DEPT, CH), 97.6, 120.9, 124.1, 124.9, 125.1,
126.9, 129.2, 131.0, 133.4, 136.0, 137.0, 139.1, and 157.5; LCMS,
mw, 326.4; exact mass, 326.07: (M+H)+, 327.0; (M-H)-, 324.9.
Anal. Calcd for C17H14N2O3S•1/4CH3OH•1H2O [16b,22b]: C,
58.57; H, 4.84; N, 7.93. Found: C, 58.38; H, 4.48, N, 7.94.
Of the 12486 reflections collected, 2640 were unique (Rint
=
0.0491); equivalent reflections were merged. Data were
collected, processed, and corrected for Lorentz-polarization and
for absorption using CrystalClear (Rigaku) [26]. The structures
were solved by direct methods and expanded using Fourier
techniques. The non-hydrogen atoms were refined aniso-
tropically. Ideal hydrogen atom coordinates were calculated and
the hydrogen atoms were allowed to ride on their respective
carbons. The temperature factors of all hydrogen atoms were
varied isotropically. The final cycle of full-matrix least-squares
refinement on F2 converged with R1 = 0.0587 (reflections with I
> 2.00ꢃ(I)), wR2 = 0.1574 (all data). The highest difference
peak was 0.298 and the deepest hole was -0.326.
Structure solution, refinement, and the calculation of derived
results were performed using the SHELX-97 [27] package of
computer programs. Neutral atom scattering factors were those
of Cromer and Waber [28], and the real and imaginary
anomalous dispersion corrections were those of Cromer[29].
7'-Methoxy-1,2,3',4'-tetrahydronaphth[1,2-c]spiro[1,2-benz-
oisothiazole-3,3'(3a'H)-isoxazole] 1,1-dioxide (10). Compound
10 was prepared in 57 % (3.32 g), mp 228-230° (methanol)
using the general procedure for the condensation-cyclization of
dilithiated 6-methoxy-1-tetralone oxime and ester-sulfonamide
1
3; IR: 3543 cm-1, sharp; H NMR (deuteriochloroform): ꢄ 2.00-
2.12 (m,. 2H, CH2), 2.90-2.98 (m, 2H, CH2), 3.37 (s broad),
3.76-3.84 (m, 4H, CH and OCH3), 6.76-6.87 (m, 2H, ArH),
7.67-7.91 (m, 5H, ArH), and 9.19 (s broad, NH). 13C NMR
(deuteriochloroform): ꢄ 22.3 (DEPT, CH2), 29.7 (DEPT, CH2),
49.8, 54.4 (DEPT, CH2), 55.3, 97.3, 113.2, 113.9, 117.4, 120.8,
124.2, 126.7, 131.3, 133.4, 135.9, 137.0, 141.2, 157.2, and
161.6; LCMS, mw, 356.4; exact mass, 356.08: (M+H)+, 356.9;
(M-H)-, 354.9. Anal. Calcd for C18H16N2O4S•CH3OH [22b]: C,
58.90; H, 4.94 N, 7.23. Found: C, 58.69; H, 4.62; N, 7.28.
3',4'-Tetramethylenespiro[1,2-benzoisothiazole-3,5'(4'H)-
isoxazole]1,1-dioxide (11). Compound 11 was prepared in 24 %
(1.01 g), mp 192-196° (ethanol/water) using the general
procedure for the condensation-cyclization of dilithiated
cyclohexanone oxime and ester-sulfonamide 3; IR: 3490 cm-1;
1H NMR (deuteriochloroform): ꢄ 1.35-1.39 (m, 2H), 1.82-2.03
(m, 5H), 2.18-2.35 (m, 1H), 2.80-2.95 (m, 1H,), 3.34-3.40 (m,
1H), 5.69 (s broad, 1H), and 7.58-7.82 (m, 4H); 13C NMR
(deuteriochloroform): ꢄ 24.2, 24.5, 25.4, 25.7, 56.7 (DEPT,
CH), 97.5, 121.1, 124.1, 128.3, 131.2, 133.9, 137.9, and 161.1;
LCMS, mw, 278.3; exact mass, 278.07: (M+H)+, 279.0. Anal.
Calcd for C13H14N2O3S•7/8H2O [16b,18b,21b]: C, 53.08; H,
5.40; N, 9.53. Found: C, 53.25; H, 5.27; N, 9.13.
Table 2
Atomic Positional Parameters for 7, C16H14N2O4S
Atom
x
y
z
U(eq)*
S(1)
0.7056(1)
0.9098(2)
0.6427(2)
0.7322(2)
1.2567(2)
1.0041(2)
0.8150(2)
0.9714(2)
0.8476(2)
0.8188(2)
0.7096(2)
0.6427(2)
0.5401(2)
0.5061(3)
0.5732(3)
0.6757(3)
1.0499(2)
1.0117(2)
1.0836(3)
1.1944(2)
1.2337(2)
1.1620(2)
1.3660(3)
0.8229(1)
0.5387(3)
0.9656(3)
0.8150(3)
0.9273(3)
0.5689(3)
0.7954(4)
0.6509(3)
0.6802(4)
0.6458(4)
0.5571(3)
0.6384(3)
0.5755(4)
0.4257(4)
0.3421(4)
0.4052(4)
0.7113(3)
0.7529(4)
0.8213(5)
0.8516(4)
0.8092(4)
0.7385(4)
0.9821(5)
0.2456(1)
0.2332(1)
0.1971(2)
0.3452(2)
-0.0168(2)
0.2117(2)
0.2235(2)
0.1333(2)
0.0884(2)
0.1729(2)
0.1532(2)
0.1885(2)
0.1795(2)
0.1325(2)
0.0982(3)
0.1080(2)
0.0948(2)
-0.0016(2)
-0.0366(2)
0.0251(2)
0.1201(2)
0.1552(2)
0.0446(3)
0.039(1)
0.045(1)
0.063(1)
0.059(1)
0.050(1)
0.042(1)
0.057(1)
0.036(1)
0.041(1)
0.038(1)
0.037(1)
0.037(1)
0.045(1)
0.054(1)
0.057(1)
0.049(1)
0.036(1)
0.050(1)
0.050(1)
0.039(1)
0.042(1)
0.041(1)
0.059(1)
O(1)
O(2)
O(3)
O(4)
N(1)
N(2)
C(1)
C(2)
C(3)
C(4)
C(5)
C(6)
C(7)
C(8)
C(9)
C(10)
C(11)
C(12)
C(13)
C(14)
C(15)
C(16)
3',4'-Decamethylene spiro[1,2-benzoisothiazole-3, 5'(4'H)-
isoxazole] 1,1-dioxide (12). Compound 12 was prepared in 55
% (2.99 g), mp 186-190° (ethanol/water) using the general
procedure for the condensation-cyclization of dilithiated
cyclododecanone oxime and ester-sulfonamide 3; IR: 3144
1
cm-1; H NMR (DMSO-d6): ꢄ 1.04-1.72 (m, 15 or 16H), 2.25-
*U(eq) defined as one third of the trace of the orthogonalized Uij tensor
2.33 (m, 1H), 2.45-2.54 (m, 1H), 3.42-3.45 (m, 1H), 7.71-7.97
(m, 3H), and 9.40 (s broad, NH). 13C NMR (DMSO-d6): ꢄ 21.9,
22.2, 22.9, 23.3, 23.5, 23.7, 23.8, 24.1, 25.7, 40.1, 40.3, 53.7
(DEPT, CH), 97.4, 120.6, 124.6, 131.6, 133.7, 135.8, 136.4, and
163.3; LC-MS, mw, 362.5; exact mass, 362.17: (M+H)+, 363.1.
Anal. Calcd for C19H26N2O3S•1/2H2O [16b,18b,21b]: C, 61.43;
H, 7.33; N, 7.54. Found: C, 61.12; H, 7.01; N, 7.47.
3'-(3,4-Dimethoxyphenyl)spiro[1,2-benzoisothiazole-3,5'-(4'H)-
isoxazole] 1,1-dioxide (8). Compound 8 was prepared in 46% (2.41
g), mp 215-219° (ethanol/benzene) using the general procedure for
the condensation-cyclization of dilithiated 3',4'-dimethoxyaceto-
phenone oxime and ester-sulfonamide 3; IR: 3367 cm-1; H NMR
1

May-Jun 2007
Preparation of spiro[Benzoisothiazole-Isoxazole] Dioxides
631
Table 3
Selected Bond Distances (Å) and Angles (ꢀ) for 7, C16H14N2O4S
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.
S(1)-O(3)
S(1)-O(2)
S(1)-N(2)
S(1)-C(5)
1.423(2)
1.429(2)
1.621(3)
1.748(3)
1.444(4)
1.521(4)
1.451(3)
1.514(4)
1.374(4)
1.389(4)
1.380(5)
1.376(5)
1.386(5)
1.385(4)
1.427(3)
1.281(4)
1.496(4)
1.467(4)
1.393(4)
1.380(4)
1.388(4)
1.373(4)
1.386(4)
1.392(4)
1.374(3)
1.420(4)
N(2)-C(3)
C(2)-C(3)
O(1)-C(3)
C(3)-C(4)
C(4)-C(5)
C(5)-C(6)
C(6)-C(7)
C(7)-C(8)
C(8)-C(9)
C(4)-C(9)
O(1)-N(1)
N(1)-C(1)
C(1)-C(2)
C(1)-C(10)
C(10)-C(11)
C(11)-C(12)
C(12)-C(13)
C(13)-C(14)
C(14)-C(15)
C(10)-C(15)
O(4)-C(13)
O(4)-C(16)
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117.3(2)
110.8(2)
105.0(2)
107.8(2)
112.6(3)
102.9(2)
117.7(2)
108.2(2)
108.8(2)
113.0(2)
100.6(2)
110.8(2)
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120.5(3)
121.7(3)
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119.6(3)
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120.6(3)
119.7(3)
120.4(3)
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632
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