Metal complexes of functionalized sulfur-containing ligands: Part XIX. Synthesis and reactions of new pyrroloisothiazoles

Article abstract of DOI:10.1002/hlca.200390200

The title compounds were prepared starting from the dihydropyrrolones 4-6. Nucleophilic displacement and ring closure yielded the 1H-pyrrolo[3,2-c]isothiazol-5(4H)-ones 8 and 10. The fused systems formed salts with strong acids and electrophiles (15, 16), as well as with bases. Oxidation led either to S(2)-oxides (18a, 20a) or to the corresponding bicyclic sultams (18b, 20b), depending on the reaction conditions. The sulfinamide 18a was also obtained from the known 1,2-dithiolopyrrolone S-oxide 21 by a ring-opening/ring-closure reaction sequence. O-Methylation of 8 furnished the 'azafulvene' 17. The oxidative addition of [Pt(η²-C ₂H₄)L₂] (24a: L = Ph₃P,24b: L = 1/2 dppf. 24c: L = 1/2 (R,R)-diop) to 18a and 20a led to the cis-amido-sulfenato Pt complexes 25 and 26a-c, respectively.

Full text of DOI:10.1002/hlca.200390200

Helvetica Chimica Acta Vol. 86 (2003)
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Metal Complexes of Functionalized Sulfur-Containing Ligands
Part XIX
Synthesis and Reactions of New Pyrroloisothiazoles
by Hans-Dietrich Stachel*a), Elisabeth Immerz-Winklera), Hermann Poschenriedera), Andreas Windta),
Wolfgang Weigand*b), Norbert Drescherc), and Ralf W¸nschc)
a) Department Pharmazie/Zentrum f¸r Pharmaforschung, Universit‰t M¸nchen, Butenandtstr. 7, D-81377
M¸nchen (fax: ‡ 4989218077994; e-mail: hdsta@cup.uni-muenchen.de)
b) Institut f¸r Anorganische und Analytische Chemie, Friedrich-Schiller-Universit‰t Jena,
August-Bebel-Strasse 2, D-07743, Jena (fax: ‡ 493641948102; e-mail: wolfgang.weigand@uni-jena.de)
c) Department Chemie, Universit‰t M¸nchen, Butenandtstr. 9, D-81377 M¸nchen
Dedicated to Professor Heinrich Nˆth on the occasion of his 75th birthday
The title compounds were prepared starting from the dihydropyrrolones 4 6. Nucleophilic displacement
and ring closure yielded the 1H-pyrrolo[3,2-c]isothiazol-5(4H)-ones 8 and 10. The fused systems formed salts
with strong acids and electrophiles (15, 16), as well as with bases. Oxidation led either to S(2)-oxides (18a, 20a)
or to the corresponding bicyclic sultams (18b, 20b), depending on the reaction conditions. The sulfinamide 18a
was also obtained from the known 1,2-dithiolopyrrolone S-oxide 21 by a ring-opening/ring-closure reaction
sequence. O-Methylation of 8 furnished the −azafulvene× 17. The oxidative addition of [Pt(h2-C2H4)L2] (24a:
L ˆ Ph3P, 24b: L ˆ 1/2 dppf, 24c: L ˆ 1/2 (R,R)-diop) to 18a and 20a led to the cis-amido-sulfenato Pt complexes
25 and 26a c, respectively.
Introduction. The natural antibiotics holomycin (1, R ˆ H) and thiolutin (R ˆ
Me) have been known for a long time [1]. Thiolutin was found to suppress tumor-
induced angiogenesis and may be of value in antitumor therapy [2].
Recently, we reported the synthesis and chemistry of differently substituted 1,2-
dithiolopyrrolones of the general formula 2, which are structurally related to the
natural substances [3]. In spite of the disulfide partial structure, these heterocyclic
compounds proved to be very stable due to marked resonance, so that the
zwitterionic structure of 2 reflects their properties best, as corroborated by high dipole
moments.
We describe here the synthesis and some reactions of 1H-pyrrolo[3,2-c]isothiazol-
5(4H)-ones (3), which may also be regarded as 2-thia-1,4-diazapentalene derivatives.
As aza-analogs of 1,2-dithiolo[4,3-b]pyrrol-5(4H)-ones 2, these novel products
represent stable cyclic sulfenamides thanks to mesomerism, as expressed by the
resonance structure 3.
Results and Discussion. The synthesis started from the tetramic acid derivative
(Z)-4 [4]. With MeNH2, nucleophilic displacement occurred selectively at the MeO
group to furnish enamine 5 (Michael-type reaction). Upon reaction with a solution of
Na2S, the red sodium thiolate 7 was obtained. This salt could not be isolated in

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analytically pure form because of its tendency to be oxidized by air. After completing
the oxidation in aqueous solution with I2 or H2O2, the poorly soluble pyrroloisothiazole
8 was obtained in good yield. Similarly, the cyano anolog 10 was prepared from (E/Z)-6
[5] and H2S in the presence of Et3N, followed by oxidation with I2.
Due to considerable NH acidity, compounds 8 and 10 formed sparingly soluble K
salts with 3n KOH in MeOH. The salts were stable for at least 24 h at room
temperature in aqueous solutions and reacted with MeI to yield the corresponding N-
methylated compounds 9 and 11, respectively. The stabilities of 8 and 9 toward strong
alkali, in contrast to other sulfenamides [6], opened the possibility to saponify the ester
groups. While 8 was fully recovered after heating with methanolic KOH for 3 h, 9 was
saponified under the same conditions to afford the carboxylic acid 12. The latter was
decarboxylated in the presence of Cu and quinoline at 1508. The resulting product 13
easily underwent electrophilic substitution in 6-position with NaNO2 and AcOH to
yield the nitro derivative 14. Interestingly, and quite in contrast to 8 and 9, compound 13
decomposed when dissolved in trifluoroacetic acid at room temperature, as well as in
AcOH upon short heating, presumably due to cleavage of the sulfenamide bond and
ensuing reactions [7]. However, the new heterocycles showed low basicity.
From compound 8 and HClO4 in AcOH, the crystalline perchlorate 15 was
obtained, which hydrolyzed immediately upon contact with H2O. Analogously, reaction
of 8 with methyl fluorosulfonate gave the pyrroloisothiazolium salt 16, the hydrolysis of
which (NaHCO3) led to the imino ester 17, which may be regarded as an −azafulvene×
[8], and which was also obtained by reacting 8 with diazomethane in nearly quantitative
yield. The preferential O-methylation of lactams is usually interpreted as a hint of the
weakened double-bond character of the CˆO group due to resonance [9].
The pyrroloisothiazolones 8 10 were oxidized stepwise with H2O2 in AcOH at
ambient temperature to afford first the corresponding sulfinamides 18a 20a, and then
the sulfonamides 18b 20b, depending on reaction time. Compound 18a has been
prepared earlier by −S/N-exchange× with MeNH2 in the presence of I2 from 21 [3]. The
sulfinamides 18a 20a underwent thermal disproportionation at temperatures just
.
‡
‡
below their melting points. Their mass spectra showed both the M and [M À O]
signals. The most prominent peak in the MS fragmentation of 8/9 and 18a/19a was that
of the thiobenzoyl ion (m/z 121). MS fragmentation of 18b followed another pathway,
‡
the [M À SO2] fragment being the predominant peak.
Similar to the parent compound, 18a/18b formed sparingly soluble salts with KOH
in MeOH, but reacted with MeI to the corresponding N-methylated derivatives 19a/
19b. In aqueous solution, the K salt of 18a decomposed within 1 h at room temperature.
However, the potassium salt of 18b was found to be stable in aqueous solution at room

Helvetica Chimica Acta Vol. 86 (2003)
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Scheme 1
temperature for 3 d. Upon heating with strong alkali, 18b was reversibly transformed to
the sultam 22 by cleavage of the lactam ring. Differing in basicity and nucleophilicity
from the parent compounds (X ˆ S), the S-oxides 18a/18b did not react with HClO4 or
methyl fluorosulfonate. Both compounds were converted to the N-methylated
derivatives 19a/19b exclusively upon treatment with CH2N2.
The different degrees of resonance stabilization in the pyrroloisothiazolones
mentioned above are mirrored in the 1H-NMR chemical shifts of the N-Me H-atoms of
1
the isothiazole ring. Whereas H-NMR signals in N-methylated open-chain or cyclic

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Scheme 2
sulfenamides are usually found below 3.0 ppm [10], the corresponding resonances in
the spectra of 8, 9, and 14 appeared between 4.06 and 4.21 ppm. This downfield shift
may be attributed to a strongly deshielding effect caused by a positive partial charge on
the N-atom, as depicted in the zwitterionic resonance structure 3. As expected, the N-
1
Me H-NMR signal of the perchlorate 15 was found in the same range (4.05 ppm).
1
However, there was an exception: in the H-NMR spectrum of 13, the N-Me signal
appeared at 3.48 ppm. This strong upfield shift relative to the corresponding signals of
8 and 9 can be rationalized by the loss of the acceptor substituent in 6-position, which
reduces the resonance energy and, consequently, the chemical stability of 13. The lesser
degree of resonance stabilization of 18a/19a in comparison to 8/9 as apparent also
from the chemical behavior was also reflected by the N-Me signals in the NMR
spectra (a shift to higher field of more than 0.4 ppm). The assignments of the N- vs. O-
1
Me H-NMR signals were achieved by CH-COSY measurements.
The longest-wavelength UV-absorptions of 8 and 9 in MeOH, MeCN, and dioxane
showed −negative solvatochromy×. Such behavior is in agreement with a marked dipolar
character [11]. In contrast, solvatochromy was observed neither in the UV spectra of
the nitriles 10 and 11, nor in those of 18 and 19.
The sulfenamides 8 and 9 were reduced by NaBH4. The red color of the solutions
obtained indicated the formation of sodium thiolate 7 or its N-methylated analog,
respectively. Oxidative recyclization to 8 and 9 was promoted by air (O2) or I2.
Likewise, 8 and 9 were obtained by executing the same reduction/oxidation sequence
with 18a/19a. Analogously, 20a was reduced to 10. Boronhydride reduction of the more-

Helvetica Chimica Acta Vol. 86 (2003)
2475
stable bicyclic sulfonamide 18b afforded only the trans-dihydrogenated sultam
derivative 23. As expected, hydrogenation took place at the activated C(6)ˆC(6a)
double bond. The N-Me signal was shifted markedly upfield relative to that of the
starting compound 18b. NOE Experiments confirmed the neighbourhood of the N-Me
group and HÀC(6a). The latter coupled with HÀC(6) (J ˆ 9 Hz), and the signal for
HÀC(6) disappeared upon H/D-exchange. In the IR spectrum, hydrogenation caused a
shift of the two CˆO absorption bands of 18b at 1720 and 1710 cmÀ1 to shorter
wavelengths (1760 and 1735 cmÀ1).
Previous work in our laboratory with [(Ph3P)2Pt(h2 C2H4)] (24a) showed that it is
possible to activate NÀS(O) bonds in N-(alkyl- and arylsulfinyl)phthalimides to yield
sulfinato platinum(II) complexes [12]. This paper extends the study of Pt complexes
formed between 24a (L ˆ Ph3P), 24b (L ˆ 1/2 dppf), or 24c (L ˆ 1/2 (R,R)-diop)1),
and 18a or 20a, respectively. Slowly heating 18a or 20a with 24a c in toluene at 1008
(18a) or 658 (20a), respectively, afforded the complexes 25 and 26a c via insertion of
Pt0 into the NÀS(O) bond. When chiral 24c was treated with 2 equiv. of 20a, two
products in a 1:1 ratio were observed by 31P-NMR spectroscopy. Their structures were
assigned on the basis of spectral similarities as the diastereoisomers (R*SO,R,R)-26c; no
diastereoselectivity was observed in this thermodynamically controlled reaction.
Scheme 3
The 31P-NMR spectra of 25 and 26a,b display the typical AB pattern for cis-amido-
sulfenato platinum(II) complexes [12] with two doublets and 195Pt satellites (1J(Pt,P) ˆ
2217 2490 Hz for P trans to S(O), and 1J(Pt,P) ˆ 3588 3646 Hz for P trans to N). This
is in accordance with our previous observation that the sulfenato group in cis-
[(dppe)Pt[S(O)C4H9](Nphth)]1) exhibits a stronger −trans-influence× than the amido
group [12]. The 31P-NMR spectrum of (R*SO,R,R)-26c displays two well-defined AB-
1
spin patterns and the expected 195Pt/31P couplings. In the H-NMR spectra of 26a c,
the signals of the N-Me H-atoms are shifted upfield by 0.7 ppm compared with those of
20a. In 26a c, the 4J(P,H) coupling constants are 3.4 3.9 Hz. Moreover, the 13C-NMR
resonances of the C-atoms directly bonded to the S-atom, and of the sp2 C-atoms
bonded to the N-atoms are shifted upfield by 2.4 2.9 and 4.0 3.3 ppm, respectively,
compared with those of 20a. In contrast, a significant downfield shift of ca. 14 ppm is
observed for the Me C-atom bonded to the amido N-atom.
1
)
Abbreviations: dppf ˆ 1,1'-bis(diphenylphosphino)ferrocene, diop ˆ 4,5-bis[(diphenylphosphino)methyl]-
2,2-dimethyl-1,3-dioxolane, dppe ˆ 1,2-bis(diphenylphosphino)ethane, Nphth ˆ N-phthalimide.

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The IR spectra of 25 and 26a c exhibit weak n(SO) bands at 980 1000 cmÀ1, in
agreement with those of other sulfenato complexes [12][13]. These IR bands are
shifted by ca. 65 85 cmÀ1 to lower wavenumbers relative to those of the corresponding
sulfinamides 18a and 20a, respectively. Analogously, shifts of the CˆO (25) and the
CꢀN (26a c) IR absorptions to lower wavenumbers are observed.
In conclusion, we have demonstrated that it is possible to activate a NÀS(O) bond
in the pyrroloisothiazolone S-oxides 18a and 20a by oxidative addition of the Pt0
complexes 24a c. The products isolated and characterized were the cis-amido-
sulfenato platinum(II) complexes 25 and 26a c. Compared with the analogous
reactions of the isoelectronic 1,2-dithiolo[4,3-b]pyrrolone S-oxide (21) [14] with Pt0
complexes, higher reaction temperatures were necessary.
Experimental Part
General. M .p.:B¸chi melting-point apparatus; uncorrected. IR Spectra: Perkin-Elmer PARAGON 1000;
KBr pellets; in cmÀ1. UV/VIS Spectra: Kontron Uvikon-810 Anakomp-220 or Perkin-Elmer Lambda-20; lmax in
nm (log e), in MeOH soln., unless stated otherwise. 1H-NMR Spectra: JEOL GSX-400; d in ppm rel. to Me4Si
as internal standard, J in Hz, solvent A ˆ (D6)DMSO, B ˆ CD2Cl2, unless indicated otherwise. 13C-NMR
Spectra: JEOL EX-400; d in ppm rel. to Me4Si as internal standard, J in Hz, solvents A or B, unless indicated
otherwise. 31P-NMR Spectra: JEOL GSX-270; d in ppm rel. to 85% aq. H3PO4 as external standard, J in Hz,
solvent B, unless indicated otherwise. MS: Hewlett-Packard 5989A, 70 eV. Flash chromatography (FC): 250 ml
column (Baker), silica gel (0.040 0.063 mm; Merck). Elemental analysis: Heraeus CHNO-Rapid Analyser or
carried out by I. Beetz, Mikroanalytisches Laboratorium; Kronach, Germany.
Methyl (Z)-5-[(Bromo)(phenyl)methylene]-2,5-dihydro-4-(methylamino)-2-oxo-1H-pyrrole-3-carboxylate
(5). A soln. of 1.01 g (3 mmol) of (Z)-4 [4] in MeOH (25 ml) was heated with 0.5 ml of an aq. soln. (40%) of
MeNH2 at 508 for 5 min. The volatile components were removed under reduced pressure, and the residue was
recrystallized from MeOH. Yield: 670 mg (66%). Yellow crystals. M.p. 1708. UV: 325 (4.312), 227 (3.981). IR:
3360, 3240, 3020, 2955, 1740, 1715, 1670, 1595. 1H-NMR (CDCl3): 7.43 (s, 5 H); 3.85 (s, 3 H); 2.28 (d, J ˆ 5.1,
.
‡
3 H). MS: 338/336 (M ). Anal. calc. for C14H13BrN2O3 (337.17): C 49.87, H 3.89, N 8.31; found: C 49.93, H 3.99,
N 8.37.
Sodium (1,5-dihydro-4-(methoxycarbonyl)-3-(methylamino)-5-oxopyrrol-2-ylidene)phenylmethanethiolate
(7). A soln. of 1.35 g (4 mmol) of 5 and 1.2 g (5 mmol) of Na2S ¥ 5 H2O in MeOH (20 ml) was stirred at r.t. for
12 h. The red soln. obtained was evaporated in vacuo to dryness. The soln. of the residue in AcOEt (25 ml) was
filtered through a column with silica gel and evaporated. The salt was obtained in almost pure form. Yield:
930 mg (75%). Orange crystals. UV: 332 (3.916), 294 (3.876), 226 (4.191). IR: 3420, 2980, 2940, 1685, 1575.
1H-NMR (A): 12.15 (d, J ˆ 5.1, 1 H); 7.38 (s, 1 H); 7.30 (s, 5 H); 3.65 (s, 3 H); 2.98 (d, J ˆ 5.1, 3 H).
Methyl 4,5-Dihydro-1-methyl-5-oxo-3-phenyl-1H-pyrrolo[3,2-c]isothiazole-6-carboxylate (8). An aq. soln.
(5 ml) of H2O2 (3%) was added dropwise to a stirred soln. of 0.93 g (3 mmol) of 7 in H2O (20 ml). After 10 min,
the precipitate was collected and recrystallized from MeOH. Yield: 575 mg (65%). Yellow crystals. M.p. 282
2848 (MeOH). UV: 365 (4.226), 330 (3.825), 258 (sh), 243 (3.907). IR: 3120, 3000, 2940, 1660, 1570. 1H-NMR
(A): 10.36 (s, 1 H); 7.58 7.43 (m, 5 H); 4.08 (s, MeN); 3.69 (s, M eO). 13C-NMR (A): 172.1 (C(5)); 163.8
(COOMe); 158.4 (C(6a)); 134.4 (C(3a)); 129.7 127.3 (Ph), 124.5 (C(3)); 120.4 (C(6)); 50.2 (MeO); 38.6
.
‡
(MeN). MS: 288 (M ), 121. Anal. calc. for C14H12N2O3S (288.32): C 58.32, H 4.20, N 9.72, S 11.12; found: C
58.39, H 4.24, N 9.80, S 11.04.
Methyl 4,5-Dihydro-1,4-dimethyl-5-oxo-3-phenyl-1H-pyrrolo[3,2-c]isothiazole-6-carboxylate (9). A soln.
of 0.29 g (1 mmol) of 8 in anh. DMF (5 ml) was stirred with 33 mg (1.1 mmol) of NaH (80%) for 1 h at r.t. After
addition of MeI (2 ml), stirring was continued for another hour. The soln. was diluted with CH2Cl2 (20 ml) and
then extracted twice with H2O. The combined org. layers were dried (Na2SO4) and evaporated to dryness. The
residue was recrystallized from MeOH. Yield: 130 mg (43%). Yellowish crystals. M.p. 195 1968. UV: 355
1
(4.368), 248 (3.970). IR: 3050, 2920, 1660, 1640, 1585. H-NMR (A): 7.47 (s, 5 H); 4.18 (s, 3 H); 3.75 (s, 3 H);
.
‡
3.01 (s, 3 H). MS: 302 (M ), 121. Anal. calc. for C15H14N2O3S (302.35): C 59.59, H 4.67, N 9.27, S 10.61; found: C
59.68, H 4.64, N 9.34, S 10.41.

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Ethyl 6-Cyano-4,5-dihydro-1-methyl-5-oxo-1H-pyrrolo[3,2-c]isothiazole-3-carboxylate (10). H2S was
passed slowly through a soln. of 0.60 g (2 mmol) of (E/Z)-6 [5] and 0.30 g (3 mmol) of Et3N in anh. MeCN
(50 ml) at r.t. for 5 min. The volatile components were removed in vacuo. A MeOH soln. of the red residue
(5 ml) was titrated with a 0.1n soln. of I2 (20 ml). The precipitate was collected after 4 h and recrystallized from
AcOEt. Yield: 206 mg (41%). Yellow powder. M.p. 2108 (dec.). Yellow fluorescence at 365 nm. UV: 328
(4.226), 310 (4.104), 231 (3.940), 207 (4.322). IR: 3112, 2984, 2722, 2207, 1688, 1673, 1608. 1H-NMR (A): 11.21
.
‡
(s, 1 H); 4.32 (q, J ˆ 7.1, 2 H); 3.81 (s, 3 H); 1.30 (t, J ˆ 7.1, 3 H). MS: 251 (M ). Anal. calc. for C10H9N3O3S
(251.26): C 47.80, H 3.61, N 16.72, S 12.76; found: C 47.61, H 3.70, N 16.57, S 12.70.
Ethyl 6-Cyano-4,5-dihydro-1,4-dimethyl-5-oxo-1H-pyrrolo[3,2-c]isothiazole-3-carboxylate (11). This prod-
uct was prepared analogously to 9 from 0.25 g (1 mmol) of 10. 240 mg (91%). Yellow crystals. M.p. 200 2028
(MeOH/diisopropyl ether 1:1). Yellow fluorescence at 365 nm. UV: 379 (4.307), 335 (3.980), 235 (4.128), 207
(4.227). IR: 2977, 2209, 1703, 1636 1608. 1H-NMR (A): 4.31 (q, J ˆ 7.1, 2 H); 3.87 (s, 3 H); 3.54 (s, 3 H); 1.31
.
‡
(t, J ˆ 7.1, 3 H). MS: 265 (M ). Anal. calc. for C11H11N3O3S (265.29): C 49.80, H 4.18, N 15.84, S 12.09; found: C
49.85, H 4.13, N 15.65, S 11.87.
4,5-Dihydro-1,4-dimethyl-5-oxo-3-phenyl-1H-pyrrolo[3,2-c]isothiazole-6-carboxylic Acid (12). A soln. of
0.30 g (1 mmol) of 9 in MeOH (6 ml) was refluxed with aq. 3n KOH (5 ml) for 3 h. After cooling (08), the
potassium salt of 12 precipitated. The aq. soln. was acidified with dilute HCl, and the precipitate was crystallized
from H2O. Yield: 190 mg (66%). Faintly yellow crystals. M.p. 260 2638. UV: 348 (4.197), 326 (sh), 244 (4.305).
.
‡
IR: 3060, 3020, 2920, 1705, 1630, 1590. 1H-NMR (A): 7.57 (s, 5 H); 3.50 (s, 3 H); 3.00 (s, 3 H). MS: 288 (M ),
121. Anal. calc. for C14H12N2O3S (288.32): C 58.32, H 4.20, N 9.72, S 11.12; found: C 60.02, H 5.37 N 8.65, S 10.08.
1,4-Dimethyl-3-phenyl-1H-pyrrolo[3,2-c]isothiazol-5(4H)-one (13). A soln. of 0.58 g (2 mmol) of 12 in
quinoline (3 ml) was heated with a small amount of powdered Cu until the evolution of CO2 ceased. The cooled
mixture was brought on a silica-gel column and eluted first with petroleum ether and then with Et2O. The latter
fraction was evaporated, and the residue was crystallized from Et2O. Yield: 78 mg (16%). Dark yellow crystals.
M.p. 262 2648. UV: 352 (sh), 318 (4.391), 266 (sh), 248 (4.176). IR: 3050, 2920, 1660, 1590. 1H-NMR (A): 7.50
.
‡
(s, 5 H); 4.90 (s, 1 H); 3.48 (s, 3 H); 3.13 (s, 3 H). MS: 244 (M ); 121. Anal. calc. for C13H12N2OS (244.31): C
63.91, H 4.95, N 11.47, S 13.12; found: C 63.85, H 4.99, N 11.49, S 13.15.
1,4-Dimethyl-6-nitro-3-phenyl-1H-pyrrolo[3,2-c]isothiazol-5(4H)-one (14). A mixture of 0.29 g (1 mmol)
of 12 and 0.35 g (5 mmol) of NaNO2 in AcOH (15 ml) was stirred at r.t. for 15 min. Shortly after a clear soln. was
obtained, a brownish intermediate product began to precipitate. After 15 min, the precipitate was collected and
suspended in AcOH (10 ml). To this mixture, 3n HNO3 (2 ml) was added while stirring. After 10 min, the yellow
soln. obtained was diluted with H2O (100 ml) and extracted twice with AcOEt. The combined org. layers were
dried (Na2SO4), the solvent was evaporated, and the residue was crystallized from diisopropyl ether/EtOH 1:1.
Yield: 153 mg (53%). Yellowish powder. M.p. 2508 (dec.). UV: 383 (4.336), 285 (4.199). IR: 3052, 2940, 1678,
.
‡
1
1570, 1390. H-NMR (A): 7.55 7.58 (m, 5 H); 4.21 (s, 3 H); 2.95 (s, 3 H). MS: 289 (M ), 121. Anal. calc. for
C13H11N3O3S (289.31): C 53.97, H 3.83,N 14.52, S 11.08; found: C 53.68, H 3.76, N 14.30, S 10.82.
5-Hydroxy-6-(methoxycarbonyl)-1-methyl-3-phenyl-4H-pyrrolo[3,2-c]isothiazolium Perchlorate (15).
Upon addition of 0.16 g (1.1 mmol) of HClO4 (70%) to a soln. of 0.29 g (1 mmol) of 8 in AcOH (5 ml), the
product precipitated spontaneously. Yield: 280 mg (72%). Nearly colorless crystals. M.p. 224 2268 (AcOH).
UV (HClO4): 320 (4.155), 248 (3.911), 214 (4.067). IR: 3000, 1725, 1625, 1570. 1H-NMR (A): 8.45 (s, l H); 7.51
(m, 5 H); 4.05 (s, 3 H); 3.65 (s, 3 H).
5-Methoxy-6-(methoxycarbonyl)-1-methyl-3-phenyl-4H-[3,2-c]isothiazolium Fluorosulfonate (16). A soln.
of 0.29 g (1 mmol) of 8 in anh. 1,2-dimethoxyethane (10 ml) and 0.5 ml (4 mmol) of methyl fluorosulfonate was
refluxed for 15 min. The soln. was concentrated to half of the initial volume. The salt precipitated while cooling
and was used immediately for the synthesis of 17.
Methyl 5-Methoxy-1-methyl-3-phenyl-1H-pyrrolo[3,2-c]isothiazole-6-carboxylate (17). a) Compound 16
was stirred with a sat. aq. soln. of NaHCO3 (50 ml) and then extracted with CH2Cl2 (3Â). The combined org.
layers were dried (Na2SO4), and the solvent was removed. Yield: 227 mg (76%).
b) An ethereal soln. of CH2N2 (excess) was added to a stirred suspension of 0.29 g (1 mmol) of 8 in Et2O
(10 ml). A clear soln. was obtained after stirring for 2 h. After removal of the volatile components, the product
was isolated in nearly quant. yield. Faintly yellow crystals. M.p. 1518 (MeOH). UV: 341 (4.210), 258 (4.329). IR:
2940, 1680, 1595. 1H-NMR (A): 8.13 7.90 (m, 2 H); 7.65 7.47 (m, 3 H); 4.18 (s, 3 H); 4.07 (s, 3 H); 3.70
.
‡
(s, 3 H). MS: 302 (M ); 121. Anal. calc. for C15H14N2O3S (302.35): C 59.59, H 4.67, N 9.27, S 10.61; found: C
59.73, H 4.58, N 9.14, S 10.60.
Methyl 4,5-Dihydro-1-methyl-2,5-dioxo-3-phenyl-1H-2l4-pyrrolo[3,2-c]isothiazole-6-carboxylate (18a). A
soln. of 0.29 g (1 mmol) of 8 in AcOH (10 ml) and 3 ml of an aq. soln. of H2O2 (30%) were mixed and kept at r.t.

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Helvetica Chimica Acta Vol. 86 (2003)
for 12 h. The product precipitated. Yield: 101 mg (33%). Yellowish crystals. M.p. 241 2448 dec. (MeOH). UV:
370 (sh), 334 (4.245), 232 (4.107). IR: 3170, 3050, 2950, 1720, 1700, 1665, 1610, 1075. 1H-NMR (A): 10.92
(s, l H); 7.66 7.42 (m, Ph); 3.75 (s, MeO), 3.67 (s, M eN).13C-NMR (A): 171.5 (C(5)); 162.0 (COOMe); 158.3
.
‡
(C(6a)); 135.7 (C(3a)); 129.5 127.9 (Ph, C(3)); 122.0 (C(6)); 51.2 (MeO); 32.8 (MeN). MS: 304 (M ), 121.
Anal. calc. for C14 H12N2O4S (304.32): C 55.25, H 3.97, N 9.21, S 10.54; found: C 55.41, H 3.93, N 9.18, S 10.64.
Methyl 4,5-Dihydro-1-methyl-2,2,5-trioxo-3-phenyl-1H-2l6-pyrrolo[3,2-c]isothiazole-6-carboxylate (18b).
A soln. of 0.29 g (1 mmol) of 8 in AcOH (30 ml) and 3 ml of an aq. soln. of H2O2 (30%) were mixed and kept at
r.t. for 7 d. The product precipitated upon dilution with H2O (250 ml). Yield: 61 mg (19%). Faintly yellow
crystals. M.p. 252 2548 (MeOH). UV: 370 (sh), 324 (4.214), 233 (4.105). IR: 3240, 3080, 2960, 1720, 1710, 1680,
1625, 1320, 1160. 1H-NMR (A): 11.36 (s, l H); 7.75 7.50 (m, Ph); 3.79 (s, MeO); 3.56 (s, M eN).13C-NMR (A):
169.1 (C(5)); 161.4 (COOMe); 149.6 (C(6a)); 133.8 (C(3a)); 130.1 127.3 (Ph, C(3)); 124.8 (C(6)); 51.7 (MeO);
.
‡
29.6 (MeN). MS: 320 (M ). Anal. calc. for C14H12N2O5S (320.32): C 52.49, H 3.78, N 8.75, S 10.01; found: C
52.46, H 3.74, N 8.80, S 9.97.
Methyl 4,5-Dihydro-1,4-dimethyl-2,5-dioxo-3-phenyl-1H-2l4-pyrrolo[3,2-c]isothiazole-6-carboxylate (19a).
The product was prepared analogously to 9 from 0.30 g (1 mmol) of 18a. Yield: 162 mg (51%). Yellowish
crystals. M.p. 1908 (MeOH). UV: 320 (4.213), 249 (3.879). IR: 2950, 2920, 1720, 1700, 1670, 1605, 1070.
.
‡
1H-NMR (A): 7.53 (s, Ph); 3.76 (s, MeO); 3.66 (s, M eÀN(1)); 2.92 (s, M eÀN(4)). MS: 318 (M ). 121. Anal.
calc. for C15H14N2O4S (318.35): C 56.59, H 4.43, N 8.80, S 10.07; found: C 56.67, H 4.52, N 8.85, S 10.12.
Methyl 4,5-Dihydro-1,4-dimethyl-2,2,5-trioxo-3-phenyl-1H-2l6-pyrrolo[3,2-c]isothiazole-6-carboxylate
(19b). The product was prepared analogously to 9 from 0.32 g (1 mmol) of compound 18b. Yield: 117 mg
(35%). Yellowish crystals. M.p. 210 2128 (MeOH). UV: 308 (4.297), 249 (3.911). IR: 2960, 2920, 1740, 1705,
1690, 1635, 1310, 1150. 1H-NMR (A): 7.60 (s, 5 H); 3.77 (s, MeO); 3.55 (s, M eÀN(1)); 2.83 (s, M eÀN(4)). MS:
.
‡
334 (M ). Anal. calc. for C15H14N2O5S (334.35): C 53.88, H 4.22, N 8.38, S 9.59; found: C 53.94, H 4.25, N 8.46, S
9.41.
Ethyl 6-Cyano-4,5-dihydro-1-methyl-2,5-dioxo-1H-2l4-pyrrolo[3,2-c]isothiazole-3-carboxylate (20a). The
product was prepared analogously to 18a from 0.25 g (1 mmol) of compound 10. Yield: 200 mg (76%). Yellow
powder. M.p. 2358 (AcOEt). UV: 380 (sh), 306 (4.625), 209 (4.353). IR: 3190, 3002, 2225, 1740, 1687, 1636, 1070.
.
‡
1H-NMR (A): 11.85 (s, 1 H); 4.30 (q, J ˆ 7.1, 2 H); 3.49 (s, 3 H); 1.28 (t, J ˆ 7.1, 3 H). MS: 267 (M ). Anal. calc.
for C10H9N3O4S (267.26): C 44.94, H 3.39, N 15.72, S 12.00; found: C 45.14, H 3.46, N 15.66, S 11.78.
Ethyl 6-Cyano-4,5-dihydro-1-methyl-2,2,5-trioxo-1H-2l6-pyrrolo[3,2-c]isothiazole-3-carboxylate (20b). A
soln. of 0.25 g (1 mmol) of 10 in AcOH (10 ml) and 3 ml of an aq. soln. of H2O2 (30%) were mixed and heated
to 808 for 4 h. After cooling, the soln. was diluted with H2O (150 ml) and extracted with CH2Cl2 (3Â). The
combined org. layers were washed with NaHSO3 soln. and H2O, dried (Na2SO4), and the solvent was
evaporated. The residue was purified by FC (AcOEt/cyclohexane 2 :1). 72 mg (26%). Yellow powder. Rf (0.51).
M.p. 200 2028 (AcOEt/cyclohexane). UV: 370 (3.272), 303 (4.380), 206 (4.195). IR: 3253, 2225, 1765, 1715
.
‡
1
1687, 1655, 1310, 1160. H-NMR (A): 4.33 (q, J ˆ 7.1, 2 H); 3.40 (s, 3 H); 1.29 (t, J ˆ 7.1, 3 H). MS: 283 (M ).
Anal. calc. for C10H9N3O5S (283.26): C 42.40, H 3.20, N 14.83, S 11.32; found: C 42.46, H 3.29, N 14.69, S 11.12.
Monomethyl (Z)-2-(2,3-Dihydro-2-methyl-4-(methylamino)-1,1-dioxo-5-phenyl-1l6-isothiazol-3-ylidene)-
malonate (22). A suspension of 0.67 g (2 mmol) of 19b in MeOH (10 ml) was heated with 1.0 ml (3 mmol)
of 3n KOH at reflux for 10 min. The potassium salt of 22 precipitated during cooling. The aq. soln. was acidified
with HCl and extracted with CH2Cl2 (2Â). The combined org. layers were dried with Na2SO4, and the solvent
was evaporated. Yield: 834 mg (80%). Colorless crystals. M.p. 1318 (CH2Cl2). UV: 304 (4.200), 242 (4.087). IR:
3320, 3230, 2950, 2920, 1755, 1740, 1695, 1625, 1260, 1170. 1H-NMR (A): 8.63 (s, 1 H); 8.15 (d, J ˆ 6, 1 H); 7.53
.
‡
(s, 5 H); 3.83 (s, 3 H); 2.85 (d, J ˆ 6, 3 H); 2.51 (s, 3 H). MS: 352 (M ). Anal. calc. for C15H16N2O6S (352.36): C
51.13, H 4.58, N 7.95, S 9.10; found: C 51.31, H 4.67, N 7.99, S 9.01.
Methyl (6R*,6aR*)-4,5,6,6a-Tetrahydro-1-methyl-2,2,5-trioxo-3-phenyl-1H-2l6-pyrrolo[3,2-c]isothiazole-6-
carboxylate (23). To a stirred soln. of 0.32 g (1 mmol) of 18a in MeOH (10 ml) were added 0.38 g (10 mmol) of
NaBH4. After 10 min, the solvent was removed in vacuo. An aq. soln. of the residue was acidified with HCl and
extracted with CH2Cl2 (3Â). The combined org. layers were washed with H2O, dried (Na2SO4), and the solvent
was evaporated. Yield: 177 mg (55%). Colorless crystals. M.p. 1818 (diisopropyl ether/EtOH). UV: 272 (4.253).
IR: 3200, 3070, 2930, 1760, 1735, 1680, 1595, 1295, 1135. 1H-NMR (A): 11.80 (s, 1 H); 7.50 (m, Ph); 4.61 (d, J ˆ 9,
.
‡
HÀC(6a)); 4.14 (d, J ˆ 9, HÀC(6), H/D-exchange with D2O); 3.82 (s, MeO); 2.70 (s, MeN). MS: 322 (M ).
Anal. calc. for C14H14N2O5S (322.34): C 52.17, H 4.38, N 8.69, S 9.95; found: C 52.12, H 4.43, N 8.76, S 9.85.
Methyl 3,3-[(Ferrocen-1,1'-diyl)bis(diphenylphosphino)]-1-methyl-4,8-dioxo-5-phenyl-4-thia-2,7-diaza-3-
platinabicyclo[4.3.0]nona-1(9),5-diene-9-carboxylate (25). A mixture of 24b (78 mg, 0.1 mmol; [15]) and 18a
(30 mg, 0.1 mmol) in 10 ml of toluene was heated slowly with stirring to 1008; the color of the resulting soln.

Helvetica Chimica Acta Vol. 86 (2003)
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changed from orange to red. The soln. was stirred at this temp. for 0.5 h, and an orange solid began to separate.
At this point, the heating was stopped and the mixture was cooled to r.t. After stirring for 1 h, the soln. was
concentrated in vacuo to 5 ml. Addition of hexane (20 ml) caused precipitation of the crude material, which was
collected by centrifugation, washed with Et2O (2 Â 20 ml), and dried in vacuo. Yield: 71 mg (67%). Orange-
brown powder. M.p. 205 2068. IR: 3282w, 1695 (sh), 1670s, 1000m. 1H-NMR (B): 9.98 (s, NH); 7.14 8.03
(m, 25 arom. H); 3.43 4.51 (m, 8 H, Cp); 4.36 (s, CO2Me); 3.53 (s, NM e). 31P-NMR: 9.73, 9.86 (1J(Pt,P) ˆ
2490, 3646, 2J(P,P) ˆ 30.5). Anal. calc. for C48H40FeN2O4P2PtS (1053.10): C 54.70, H 3.80, N 2.66, S 3.04; found:
C 53.85, H 4.05, N 2.65, S 3.59.
Methyl 1-Methyl-4,8-dioxo-5-phenyl-3,3-bis(triphenylphosphino)-4-thia-2,7-diaza-3-platinabicyclo[4.3.0]-
nona-1(9),5-diene-9-carboxylate (26a). Compound 20a (27 mg, 0.1 mmol) was added to a soln. of 24a
(75 mg, 0.1 mmol; [16]) in toluene (10 ml). The mixture was heated with stirring to 60 708, leading to a clear
soln. The color changed from orange to red. The soln. was stirred at this temp. for 1 h and then cooled to r.t. An
orange solid began to separate. The soln. was concentrated in vacuo to 5 ml, and addition of hexane (20 ml)
afforded an orange-ochre precipitate, which was collected by centrifugation. The crude material was washed
with Et2O (2 Â 10 ml) and dried in vacuo. Yield: 79 mg (80%). Orange-ochre powder. M.p. 210 2118. IR: 3405
(br.), 2199m, 1706m, 1661s, 980w. 1H-NMR (B): 8.86 (s, NH); 7.13 7.58 (m, 30 arom. H); 4.01 (m, CHaHbMe);
3.67 (m, CHaHbMe); 2.83 (d, J ˆ 3.4, NMe); 0.90 (m, CH2Me). 13C-NMR (B): 170.97; 167.10 (J ˆ 7.4); 161.43;
155.08; 127.5 134.7; 117.19; 109.34 (J ˆ 3.7); 70.53; 61.41; 44.64 (J ˆ 3.7); 13.75. 31P-NMR: 11.48, 15.99
(1J(Pt,P) ˆ 2217, 3588, 2J(P,P) ˆ 26.9). Anal. calc. for C46H39N3O4P2PtS (986.93): C 55.98, H 3.98, N 4.26, S 3.25;
found: C 55.37, H 3.86, N 4.05, S 3.53.
Ethyl 9-Cyano-3,3-[(ferrocen-1,1'-diyl)bis(diphenylphosphino)]-1-methyl-4,8-dioxo-4-thia-2,7-diaza-3-
platinabicyclo[4.3.0]nona-1(9),5-diene-5-carboxylate (26b). Preparation similar to that of 26a, but with 78 mg
(0.1 mmol) of 24b and 27 mg (0.1 mmol) of 20a. Yield: 75 mg (74%). Orange-ochre solid. M.p. 187 1898. IR:
3436 (br.), 2198m, 1704s, 1666m, 999w. 1H-NMR (B): 8.85 (s, NH); 7.15 8.85 (m, 20 arom. H); 3.59 4.99
(m, 8 H, Cp); 4.13 (m, CHaHbMe); 3.78 (m, CHaHbMe); 2.94 (d, J ˆ 3.9, NMe); 1.16 (m, CH2Me). 31P-NMR:
9.99, 16.93 (1J(Pt,P) ˆ 2285, 3662, 2J(P,P) ˆ 31.7). Anal. calc. for C44H37FeN3O4P2PtS (1016.76): C 51.98, H 3.67,
N 4.13, S 3.15; found: C 51.08, H 3.85, N 3.87, S 3.49.
Ethyl 9-Cyano-3,3-[(2,2-dimethyl-1,3-dioxolan-4,5-diyl)bis(diphenylphosphino)]-1-methyl-4,8-dioxo-4-
thia-2,7-diaza-3-platinabicyclo[4.3.0]nona-1(9),5-diene-5-carboxylate (26c). Preparation similar to that of
26a, but with 72 mg (0.1 mmol) of 24c [17] and 27 mg (0.1 mmol) of 20a. 1:1 Mixture of two diastereoisomers
1
(DS I/DS II). Yield: 44 mg (46%). M.p. 194 1968. IR: 3436, 3385 (br.), 2198m, 1703s, 1666s, 995w. H-NMR
(B): 9.00; 8.90 (s, NH); 7.28 8.08 (m, 20 arom. H); 3.81 4.24 (m, CH2Me); 3.84 3.96 (m, CHO); 2.76; 2.74
(s, NMe); 1.00 1.19 (m, CH2Me). 13C-NMR (B): 171.49/171.40; 167.86/167.79; 162.06/161.88 (J ˆ 4.3); 155.66/
155.60; 117.60/117.48; 110.12/109.37; 109.93/109.42 (J ˆ 3.6); 71.15/71.11; 62.07/61.87; 44.85/44.81 (J ˆ 2.7); 26.91;
26.87/26.82; 26.36; 14.29/14.09. 31P-NMR: 4.57, 0.78/1.17, À 6.78 (1J(Pt,P) ˆ 2064, 3411, 2J(P,P) ˆ 27.2/1J(Pt,P) ˆ
2042, 3387, 2J(P,P) ˆ 29.3). Anal. calc. for C41H41N3O6P2PtS (962.92): C 51.25, H 4.30, N 4.37, S 3.34; found:
C 50.74, H 4.53, N 4.07, S 3.54.
We gratefully acknowledge financial support of the Deutsche Forschungsgemeinschaft and the Fonds der
Chemischen Industrie.
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Received March 4, 2003