Isothiazoles. Part 12: Isothiazolylphosphonates, a new class of isothiazole dioxides

Article abstract of DOI:10.1016/S0040-4020(01)00448-3

We describe a mild and efficient method to prepare 3-amino-4,5-dihydro-5-isothiazolylphosphonates from 3-amino-5-unsubstituted isothiazole dioxides. Starting from 3-amino-5-bromo-isothiazole dioxides either 3-amino-5-isothiazolylphosphonates or 5-diethoxyphosphoryl-4,5-dihydro-4-isothiazolylphosphonates were prepared. Isothiazolylphosphonates represent a new class of isothiazole dioxides. Some preliminary investigations on the reactivity with 1,3-dipoles were reported.

Full text of DOI:10.1016/S0040-4020(01)00448-3

TETRAHEDRON
Pergamon
Tetrahedron 57 72001) 5455±5459
Isothiazoles. Part 12: Isothiazolylphosphonates, a new class of
isothiazole dioxides
Francesca Clerici,p Maria Luisa Gelmi, Elena Pini and Marinella Valle
Á
Facolta di Farmacia e Centro Interuniversitario di Ricerca sulle Reazioni Pericicliche e Sintesi di Sistemi Etero e Carbociclici,
Á
Istituto di Chimica Organica, Universita di Milano, Via Venezian 21, 20133 Milano, Italy
Received 22 February 2001; revised 4 April 2001; accepted 20 April 2001
AbstractÐWe describe a mild and ef®cient method to prepare 3-amino-4,5-dihydro-5-isothiazolylphosphonates from 3-amino-5-
unsubstituted isothiazole dioxides. Starting from 3-amino-5-bromo-isothiazole dioxides either 3-amino-5-isothiazolylphosphonates or
5-diethoxyphosphoryl-4,5-dihydro-4-isothiazolylphosphonates were prepared. Isothiazolylphosphonates represent a new class of isothiazole
dioxides. Some preliminary investigations on the reactivity with 1,3-dipoles were reported. q 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
The structure of compound 3 was con®rmed by analytical
and spectroscopic data showing the characteristic signals
associated with the ethoxy groups linked to the phosphorus
atom 7two overlapped triplets at 1.35 d associated with
the methyl groups, two quartets at 4.15, 4.25 d associated
with the CH2O groups) and two double doublets at 3.70
and 4.75 d associated with H-4 and H-5, respectively
7JH4±Pˆ16.5 Hz; JH5±Pˆ17.8 Hz). The small coupling
constant 7JH±Hˆ3.3 Hz) indicates a trans con®guration
according to the less steric hindrance between the bulky
aromatic and phosphonate groups. The 13C NMR spectrum
is mainly characterized by a singlet at 52.5 d which is asso-
ciated with C-4 and by a doublet at 64.9 d 71JC±Pˆ141.2 Hz)
associated with C-5. A long range coupling with phosphorus
It is known that the phosphono group is largely present in
natural compounds, frequently regulating very important
biological functions. Furthermore, several phosphonate
derivatives exhibit various pharmaceutical and phyto-
pharmaceutical activities, as well as rheological properties
of interest for different industrial applications. Thus a large
number of new phosphonic acids and their derivatives have
been prepared hitherto with special attention to heterocyclic
compounds.1±4 In consideration with this fact and in
continuing our research on the reactivity of 3-amino-4-
aryl-isothiazole 1,1-dioxides,5,6 we attempted to prepare
isothiazol 1,1-dioxides functionalized with the phosphonate
group and to study their reactivity.
3
was observed also for C-3 7166.2 d, JC±Pˆ5.5 Hz). The
correctassignmentwas con®rmed by performing 13C±1H
correlation experiments which showed an evident relation
between the signals at 4.75 and 3.70 d with those at 64.9 and
52.5 d, respectively.
2. Results and discussion
3-Diethylamino-4-74-methoxyphenyl)isothiazol 1,1-dioxide
1a was reacted with triethylphosphite 7TEP, 2) as t he
solventat100 8C to give compound 3 as the sole reaction
productin 50% yield 7Scheme 1).
Compound 3 is formed through nucleophilic attack of TEP
on C-5 that has been previously demonstrated to be the more
electrophilic center of the isothiazole dioxide ring.7
When the reaction was performed on 1b in toluene and with
an equimolecular amountof TEP 7 2) compound 4 was
obtained through an addition±elimination process. This
latter was transformed into 5 by reacting with TEP 72) as
the solvent at 1108C. The same product, i.e. could be
obtained directly by heating 1b in TEP 72) as the solvent
at110 8C for 4 h 7Scheme 2).
Scheme 1.
The structures of compounds 4 and 5 were con®rmed by
analytical and spectroscopic data. Particularly for
Keywords: isothiazoles; phosphonates; sulfur heterocycles; cycloaddition
reactions.
Corresponding author. Tel.: 139-2-706-303-48; fax: 139-2-706-384-73;
e-mail: francesca.clerici@unimi.it
1
compound 5 H NMR and 13C NMR analyses were very
helpful to ascertain the correct regiochemistry of the TEP
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020701)00448-3

5456
F. Clerici et al. / Tetrahedron 57 -2001) 5455±5459
were performed to ascertain the regiochemistry of the
cycloaddition and the conclusion con®rmed by safe deter-
mination of the structure of the transformation products 7see
later). It is worth noting that unsubstituted, alkyl- and aryl-
substituted-isothiazole dioxides are known to react with
diazomethane in a highly sito- and regio-selective manner,
affording the pyrazoline with a opposite regiochemistry
compared to 7 and 8.8 Both the theoretical and practical
results of cycloadditions of diazoalkanes to electron-
de®cient double bonds suggest that in most cases the simple
rules hold that the dipolar carbon links to the dipolarophile
site having the greater electron de®ciency. In line with this,
our results suggest that in the isothiazolylphosphonate ring a
charge distribution exists according to which the more
electrophilic center is located on C-4. It has to be noted
that this picture ®ts well with the formation of compound
5, nucleophilic addition of TEP 72) occurring atC-4 of 4.
Scheme 2.
addition. In the 1H NMR spectrum a double doublet at 4.6 d,
showing two coupling constants approximately in the same
Those results prompted us to investigate another class of
1,3-dipoles, viz. the nitrile oxides 7Scheme 4). Previously,
we demonstrated that 5-unsubstituted 3-amino-isothiazole
dioxides actas good dipolarophiles in cycloaddiiotn
reactions with nitrile oxides affording isothiazolo[5,4-d]-
isoxazole derivatives.9 In this case, the cycloaddition
reaction was performed with 4-methoxybenzonitrile oxide
9a and 4-chlorobenzonitrile oxide 9b which were generated
in situ according to literature method.10,11 The structures of
compounds 10 were con®rmed by analytical and spectro-
scopic data which allowed to assign the correct regio-
chemistry. In this case, the products 10a and 10b showed
a regiochemistry in accordance with a charge-controlled
cycloaddition reaction. The reaction is highly regioselective
only one regioisomer 10a or 10b being detected at least at
the detection limits 71H NMR, TLC on the whole reaction
mixture).
3
range 72JH±Pˆ19.4 Hz, JH±Pˆ23 Hz), was associated with
H-5. This signal appeared as a singletin hte
decoupled specrtum. The mostrelevantfeaut res in ht e
1H±31P
13C
NMR spectrum are two doublets at 64.0 and at 64.8 Hz both
showing a very large coupling constant 13C±31P 71Jˆ138,
152 Hz, respectively) which is consistent with a coupling
via one bond with the phosphorus con®rming that both
carbons were directly linked to a phosphonate group. The
stereochemistry was assigned on the basis of NOE experi-
ments taking into account the lack of Overhauser effects
between H-5 and the hydrogens of the 4-methoxysubstituted
aryl group.
Compound 5 was evidently formed by virtue of a nucleo-
philic attack of TEP on C-4 in the intermediate 4, showing a
reversal of the regiochemistry of the nucleophilic addition
compared with 1a and 1b and, in general, of 3-amino-
isothiazole dioxides. This result prompted us to investigate
the reactivity of 4 in 1,3-dipolar cycloaddition reaction.
Compounds 8 and 10 were stable at room temperature but
underwent rapid decomposition when heated with bases
7ethanolic KOH at re¯ux or DBU at 1008C). Compound 8
Isothiazolylphosphonate 4 readily reacted with an ethereal
solution of diazomethane 76) affording a mixture of the two
tautomeric 1- and 2-pyrazolines 7 and 8 7Scheme 3). The
1-pyrazoline 7, which is the primary cycloadduct,
tautomerizes at a slower rate into the more stable 2-pyrazo-
line 8. This latter was obtained in high yield in pure form
while 7 was obtained in minor amount and always in
mixture with 8. This result gives good evidence that the
cycloaddition reaction is easy and highly regioselective.
The structure of compounds 7 and 8 were con®rmed by
analytical and spectroscopic data. NOESY experiments
Scheme 4.
Scheme 3.

F. Clerici et al. / Tetrahedron 57 -2001) 5455±5459
5457
Scheme 5.
Scheme 6.
afforded pyrazolylphosphonate 11 through a base-catalyzed
elimination reaction of SO2 and diethylcyanamide with
cleavage of the isothiazole dioxide ring according to a docu-
mented general trend 7Scheme 5).12±14 10a treated with
DBU afforded a complex mixture of intractable tars. By
treatment with an excess of ethanolic KOH compounds 12
was found. The transformation to isoxazole 12 occurred
through initial elimination of the phosphonate group leading
to 13.9 This was con®rmed by reacting 10a with an equi-
molecular amount of ethanolic KOH: in this conditions only
13 was isolated from the reaction mixture which was trans-
formed into 12 by reacting with an excess of the base
7Scheme 6).
3.1. Data for compounds
3.1.1. [3-Diethylamino-4-,4-methoxyphenyl)-1,1-dioxo-
4,5-dihydro-1H-isothiazol-5-yl]-phosphonic acid diethyl
ester 3. Compound 1a 73.4 mmol) was suspended in
7EtO)3P 2 710 mL) and heated under stirring at 1008C
until disappearance of the starting material 74 h, TLC
AcOEt/toluene 9:1). The solvent was evaporated i.v. and
the residue chromatographed on silica gel 7cyclohexane/
AcOEt100:0 ot 0:100) affording 3. Yield 50%. Mp 1068C
7white powder from diethyl ether). IR 7nujol) cm21 1590
1
7CvN), 1260±1240 7PvO), 1050 7P±O); H NMR 0.87
7t, 3H, Jˆ7.2 Hz, CH3); 1.20 7t, 3H, Jˆ7.2 Hz, CH3); 1.30
72t, Jˆ7.1 Hz, 6H, CH3); 3.06±3.19 7m, 1H, CH2); 3.38±
3.45 7m, 1H, CH2); 3.62±3.68 7m, 2H, CH2); 3.70 7dd, 1H,
JH±Hˆ3.3 Hz, JH4±Pˆ16.5 Hz, H4); 3.80 7s, 3H, OCH3);
4.15, 4.25 72q, Jˆ7.1 Hz, 4H, CH2); 4.75 7dd, 1H,
JH±Hˆ3.3 Hz, JH5±Pˆ17.8 Hz, H5); 6.8 7AB syst.,
JABˆ8.7 Hz, 2H, aryl-H); 7.2 7AB syst., 2H, JABˆ8.7 Hz,
aryl-H). 13C NMR 12.1, 13.4, 16.6±16.8, 43.5, 45.0, 52.5,
55.7, 63.7, 64.8, 64.9, 115.4, 128.7, 129.7, 160.0, 166.2.
31P NMR 15.90. Calcd for C18H29N2O6PS 7432.47) C
49.99 H 6.76 N 6.48, found C 50.36 H 6.80 N 6.18. m/z
433 7M1).
By a simple and mild method we made available
compounds 3, 4, 5 which displayed an isothiazole dioxide
moiety substituted with one or two phosphono groups
that appeared to be new classes of isothiazole 1,1-dioxides.
On this basis, we planned a study of the chemical reactivity
of these new class of compounds. Compound 4 was
demonstrated to be a good partner in 1,3-dipolar cyclo-
addition reactions with diazomethane and nitrile-oxides,
affording byciclic systems which are susceptible to
cleavage to pyrazolylphosphonate and isoxazolylsulfona-
mide, respectively.
3.1.2. [3-Diethylamino-4-,4-methoxyphenyl)-1,1-dioxo-
1H-isothiazol-5-yl]-phosphonic acid diethyl ester 4.
Compound 1b 70.27 mmol) was suspended in toluene
75 mL) and 7EtO)3P 2 70.81 mmol, 135 mL) was added
and the mixture heated at re¯ux until disappearance of the
starting material 72 h, TLC AcOEt/toluene 9:1). The solvent
was evaporated under reduced pressure and the residue
slowly crystallized from diethylether affording 4. Yield
90%. Mp 968C 7pale yellow powder from diethyl ether).
IR 7nujol) cm21 1603, 1570 7CvC, CvN), 1245 7PvO),
1055 7P±O); 1H NMR 0.87±0.89 7m, 3H, CH3); 1.20±1.41
7m, 9H, CH3); 2.97±3.17 7m, 2H, CH2); 3.50±3.75 7m, 2H,
CH2), 3.86 7s, 3H, OCH3); 4.06±4.24 7m, 4H, CH2); 6.8 7AB
syst., 2H, JABˆ8.7, aryl-H,); 7.2 7AB syst., 2H, JABˆ8.7,
3. Experimental
1H NMR spectra were obtained in CDCl3 as the solvent with
Bruker AC 200, Bruker Avance 300 and Varian Gemini 200
instruments. Melting points were determined using a BuÈchi
510 7capillary) or an Electrothermal 9100 apparatus. IR
spectra were recorded on a Jasco IR report 100 spectro-
photometer. Compounds 1a,15 b,16 617 have already been
described. Nitrile oxide 9a was generated in situ according
to published procedures.10 4-Chlorobenzonitrile oxide 9b
was obtained by dehydrohalogenation of the hydroximoyl
chloride in diethyl ether 7colorless crystals, mp 82±838C).11

5458
F. Clerici et al. / Tetrahedron 57 -2001) 5455±5459
aryl-H,). 13C NMR 11.7, 14.2, 16.1±16.2, 44.0, 47.5, 55.4,
63.8, 114.3, 122.3, 128.7, 132.8, 146.0, 159.0, 160.8. 31P
NMR 1.93. Calcd for C18H27N2O6PS 7430.46) C 50.22 H
6.32 N 6.51 found C 50.80 H 6.73 N 6.60.
JH±Pˆ13.9 Hz); 5.85 7dd, 1H, Jˆ20.2 Hz, JH±Pˆ16 Hz);
13C NMR 70.7 7C6a); 31P NMR 14.29.
3.1.7. [6-Diethylamino-3a,6a-dihydro-4,4-dioxo-3,6a-di-
,4-methoxyphenyl)-isothiazolo-[5,4-d]-isoxazol-3a-yl]-
phosphonic acid diethyl ester 10a. Compound 4
3.1.3.
[5-,Diethoxy-phosphoryl)-3-diethylamino-4-,4-
methoxyphenyl)-1,1-dioxo-4,5-dihydro-isothiazol-4-yl]
phosphonic acid diethyl ester 5. Method A: Compound 1b
70.27 mmol) was suspended in 7EtO)3P 2 75 mL) and heated
under stirring at 1008C until disappearance of the starting
material 74 h, TLC AcOEt/toluene 9:1). The solvent was
evaporated i.v. and the residue chromatographed on silica
gel 7cyclohexane/AcOEt100:0 ot 0:100) affording 5. Yield
53%. Method B: Compound 4 70.22 mmol) was suspended
in 7EtO)3P 2 75 mL) and heated under stirring at 1108C until
disappearance of the starting material 74 h, TLC AcOEt/
toluene 9:1). The solvent was evaporated i.v. and the residue
chromatographed on silica gel 7cyclohexane/AcOEt 100:0
to 0:100) affording 5. Yield 63%. Mp 1518C 7white powder
from diethylether). IR 7nujol) cm21 1570 7CvN); 1250
70.96 mmol) was dissolved in ethanol 710 mL) and
4-methoxybenzaldoxime 70.96 mmol) and chloramine T
71.5 mmol) were added in one portion. The mixture was
re¯uxed until disappearance of the starting materials 72 h,
TLC AcOEt). The solvent was evaporated under reduced
pressure and the residue chromatographed on silica gel
7cyclohexane/AcOEt100:0 ot 0:100) affording pure 10a.
Yield 65%. Mp142±1438C 7white powder from diethyl
ether). IR 7nujol) cm21 1610, 1520; 1260 7PvO);
10507P±O); 1H NMR 0.95, 1.05, 1.14, 1.26 74t, 12H,
Jˆ7 Hz, CH3); 2.90±3.05 7m, 2H, CH2); 3.20±3.45 7m,
2H, CH2); 3.65±4.20 7m, 4H, CH2); 3.86 7s, 3H, OCH3);
3.87 7s, 3H, OCH3); 6.87±7.02 7m, 2H, aryl-H); 6.92 7d,
AB syst., 2H, JABˆ8.8 Hz, aryl-H); 7.10±7.20 7m, 1H,
aryl-H); 7.65±7.80 7m, 1H, aryl-H); 8.30 7d, AB syst., 2H,
JABˆ8.8 Hz, aryl-H). 13C NMR 11.14, 12.93, 16.00, 43.64,
45.27, 55.31, 55.44, 63.50, 63.65, 64.51, 64.65, 84.14,
101.80, 113.23, 113.75, 113.92, 119.77, 123.99, 128.47,
128.76, 132.55, 155.15, 161.20, 165.40. 31P NMR 8.93.
Calcd for C26H34N3O8PS 7579.60) C 53.88 H 5.91 N 7.25,
found 54.20 H 6.28 N 6.90.
1
7PvO); 10207P±O); H NMR 0.85, 1.13, 1.23, 1.26, 1.36,
1.45 76t, 18H, Jˆ7 Hz, CH3); 3.05, 3.31, 3.50, 3.65 74m, 4H,
2CH2); 3.79 7s, 3H, OCH3); 3.70±3.99, 4.15±4.30 72m, 6H,
,
2
3CH2); 4.45 7q, 2H, Jˆ7 Hz, CH2); 4.60 7dd, JH±Pù3JH±P
19.34 and 22.95 Hz, 1H, H-5,); 6.87 7d, AB syst., 2H,
Jˆ8.8 Hz, aryl-H); 7.25 7bs, 1H, aryl-H); 7.60 7bs, 1H,
aryl-H). 13C NMR 11.6, 13.0, 16.4±16.18, 46.0, 46.1,
55.7, 63.3, 64.0, 64.6, 64.7, 64.8, 114.0, 124.0, 129.7,
160.0, 163.7. 31P NMR 12.0 7d, 1P, JP±Pˆ11.9), 19.0 7d,
1P, JP±Pˆ11.9). Calcd for C22H38N2O9 P2S 7568.56) C
46.67 H 6.74 N 4.93, found C 47.02 H 6.42 N 4.74.
3.1.8. [3-,4-Chlorophenyl)-6-diethylamino-3a,6a-dihy-
dro-4,4-dioxo-6a-,4-methoxyphenyl)-isothiazolo-[5,4-d]-
isoxazol-3a-yl]-phosphonic acid diethyl ester 10b. A
benzene solution of the hydroximoyl chloride 70.23 mmol)
was dropped into a stirred solution of triethylamine
70.23 mmol) in the same solvent at 08C. After a few minutes
the mixture was allowed to warm to room temperature and a
solution of 4 70.23 mmol) in benzene 72 mL) and dichloro-
methane 71 mL) was added dropwise. At the end of the
addition the mixture was re¯uxed until disappearance of
the reactants 7about 8 h, TLC AcOEt/toluene 9:1). The
solvent was evaporated under reduced pressure and the
residue was chromatographed on silica gel 7cyclohexane/
AcOEt100:0 ot 0:100) affording 10b. Yield 65%. Mp
1308C 7white powder from diethyl ether). IR 7nujol) cm21
1610, 1520; 1260 7PvO); 10507P±O); 1H NMR 0.95, 0.96,
1.05, 1.14 74t, 12H, Jˆ6.9 Hz, CH3); 2.85±3.10, 3.15±3.45,
3.60±4.10 73m, 8H, 4CH2); 3.87 7s, 3H, OCH3); 6.90±7.05
7m, 2H); 7.10±7.20 7m, 1H); 7.37 7d, AB syst., 2H,
JABˆ8.8); 7.69±7.80 7m, 1H); 8.28 7d, AB syst., 2H,
JABˆ8.8). 13C NMR 11.14, 12.91, 15.96, 16.07, 43.69,
45.34, 55.46, 63.58, 63.72, 64.70, 64.81, 84.00, 102.18,
113.90, 123.55, 126.02, 128.04, 128.36, 128.70, 132.18,
136.86, 154.85, 161.08, 165.10. Calcd for C25H31N3ClO7PS
7584.02) C 51.41 H 5.35 N 7.19, found C 51.48 H 5.19 N
7.35.
3.1.4. Cycloaddition reaction of 4 and diazomethane 6.
Compound 4 70.23 mmol) was dissolved in toluene 75 mL)
and a ethereal solution of diazomethane 6 was slowly
dropped in under stirring at room temperature. After 1 h
the reagent has completely disappeared 7TLC AcOEt/
toluene 9:1). Evaporation of the solvent and crystallization
from diethyl ether afforded 7 and 8 in mixture. By stirring
the mixture in chloroform solution, 7 was completely trans-
formed into 8. Total yield 7718) 85%.
3.1.5. [3-Diethylamino-3a-,4-methoxyphenyl)-1,1-dioxo-
3a,6a-dihydro-pyrazolo[4,3-d]isothiazol-6a-yl] phospho-
nic acid diethyl ester 8. Mp 141±1438C 7white powder
from diethyl ether). IR 7nujol) cm21 3280±3230 7NH);
1
1586 7CvN); 1236 7PvO); 10237P±O); H NMR 0.90 7t,
3H, Jˆ7.1 Hz, CH3); 1.10±1.22 7m, 9H, CH3); 2.89±3.15
7m, 2H, CH2); 3.34±3.54 7m, 2H, CH2); 3.82 7s, 3H, OCH3);
3.84±4.05 7m, 4H, CH2); 6.47 7d, JH±Pˆ2.61 Hz, NH);
6.88±7.00 7m, 3H, aryl-H1H-4); 7.16 7d, AB syst., 1H,
JABˆ8.8 Hz, aryl-H); 7.73 7d, AB syst., JABˆ8.8 Hz, 1H,
aryl-H). 13C NMR 11.3, 12.6, 16.1±16.3, 43.1±44.8, 55.4,
64.0, 64.1, 81.5, 83.3, 114.1, 124.7, 128.3, 129.5, 137.4,
160.6, 166.0. 31P NMR 8.8. Calcd for C19H29N4O6PS
7472.50) C 48.30 H 6.19 N 11.86 found C 48.46 H 6.15 N
11.54.
3.1.9.
4-,4-Methoxyphenyl)-1H-pyrazol-3,5)-yl)phos-
phonic acid diethyl ester 11. Compound 8 70.21 mmol)
was heated at 1008C with an equimolecular amount of
DBU 70.21 mmol, 31 mL) and the reaction checked by
TLC 71 h, AcOEt/toluene 9:1). The reaction mixture was
taken up with dichloromethane and washed with HCl
10%71 mL) and then with water 72£1 mL). The organic
layer was separated, dried over Na2SO4, ®lterd and the
3.1.6. [3-Diethylamino-3a-,4-methoxyphenyl)-1,1-dioxo-
3a,4-dihydro-pyrazolo[4,3-d]isothiazol-6a-yl]phospho-
nic acid diethyl ester 7. Compound 7 was always obtained
in mixture with 8. In t he1H NMR spectrum of the
mixture signi®cant signals are: 5.40 7dd, 1H, Jˆ20.2 Hz,

F. Clerici et al. / Tetrahedron 57 -2001) 5455±5459
5459
solventevaporaetd under reduced pressure affording 11.
Yield 54%. Mp 848C 7pale yellow powder from pentane).
IR 7nujol) cm21 3100±3000 7NH); 1610; 1245 7PvO); 1010
AcOEt/cyclohexane 1:1 or CH2Cl2/MeOH 10:1). The
solventwas evaporated under reduced pressure and the resi-
due acidi®ed with 10% HCl to Congo red and extracted in
dichloromethane 75 mL). The organic phase was washed
with water 72£2.5 mL), separated, dried with Na2SO4,
®ltered and the solvent evaporated under reduced pressure
affording 13. Yield: 80%. Mp 1688C 7lit.9 169±1708C).
1
7P±O). H NMR 1.23 7t, 6H, Jˆ7.1 Hz, CH3); 3.87 7s, 3H,
OCH3); 4.06 7q, 4H, Jˆ7.1 Hz, CH2); 6.97 7d, AB syst., 2H,
JABˆ8.8 Hz, aryl-H); 7.77 7d, AB syst., 2H, JABˆ8.8 Hz,
aryl-H); 7.98 7s, 1H, CH); 8.83 7bs, 1H, NH, exch. D2O).
13C NMR 16.1, 16.2, 55.3, 62.1, 62.2, 103.5, 113.9, 123.1,
129.1, 141.6, 150.2, 160.3. 31P NMR 16.09. Calcd for
C14H19N2O4P 7310.29) C 54.19 H 6.17 N 9.03 found C
53.42 H 6.08 N 8.80.
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5. Beccalli, E. M.; Clerici, F.; Gelmi, M. L. Tetrahedron 2000,
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55, 14975±14984.
7. Beccalli, E. M.; Clerici, F.; Gelmi, M. L. Tetrahedron 1999,
55, 2001±2012.
8. Clerici, F.; Ferrario, T.; Gelmi, M. L.; Marelli, R. J. Chem.
Soc., Perkin Trans. 1 1994, 2533±2536.
9. Clerici, F.; Ferraris, F.; Gelmi, M. L. Tetrahedron 1995, 51,
12351±12362.
1
10. Hassner, A.; Rai, K. M. L. Synthesis 1989, 1, 57±59.
11. Grundman, C.; GruÈnanger, P. In The Nitrile Oxides; Springer:
Berlin, 1971; pp 44.
7NH). H NMR 7DMSO) 3.78 7s, 3H, CH3); 3.81 7s, 3H,
CH3); 5.84 7s, 1H, H-5); 6.30±6.40 7bm, 3H, NH1NH2,
exch. D2O); 6.90 7d, AB syst., 2H, JABˆ8.8 Hz, aryl-H);
7.00 7d, AB syst., 2H, JABˆ8.8 Hz, aryl-H); 7.45 7d, AB
syst., 2H, JABˆ8.8 Hz, aryl-H); 7.75 7d, AB syst., 2H,
JABˆ8.8, aryl-H). 13C NMR 7DMSO) 55.01, 55.28, 72.38,
113.5, 113.8, 121.0, 126.4, 128.4, 129.4, 137.0, 155.1,
159.0, 160.6. Calcd for C17H18N2O5S 7362.40) C 56.34 H
5.01 N 7.73, found C 56.47 H 4.95 N 7.99.
12. Baggi, P.; Clerici, F.; Gelmi, M. L.; Mottadelli, S.
Tetrahedron 1995, 51, 2455±2466.
13. Clerici, F.; Galletti, F.; Pocar, D.; Roversi, P. Tetrahedron
1996, 52, 7183±7200.
14. Clerici, F.; Gelmi, M. L.; Soave, R.; Valle, M. Tetrahedron
1998, 54, 11285±11296.
15. Clerici, F.; Marazzi, G.; Taglietti, M. Tetrahedron 1992, 48,
3227±3238.
3.1.11. [6-Diethylamino-3a,6a-dihydro-3a,6a-di-,4-meth-
oxyphenyl)-isothiazolo-[5,4-d]-isoxazole]-4,4-dioxide 13.
Compound 10a 70.18 mmol) was dissolved in ethanol
75 mL) and a solution of KOH 710.1 mg, 0.18 mmol) in
ethanol 71.0 mL) was added in one portion and stirred
until disappearance of the starting material 73 h, TLC
16. Clerici, F.; Erba, E.; Gelmi, M. L.; Valle, M. Tetrahedron
1997, 53, 15859±15866.
17. Vogel, A. In Textbook of Practical Organic Chemistry; 4th ed.,
Longman: New York, 1978; pp 291.