1-Aryl-5-methoxypyrrolones as synthons for fused heterocycles

Article abstract of DOI:10.1016/S0040-4020(01)01029-8

3-Di(methylsulfonyl)methylene-pyrrol-2-one and 2-(1-aryl-5-methoxy-2-oxo-2,3-dihydro-1H-3-pyrrolylidene)malononitrile were obtained from 1-aryl-5-methoxypyrrolones. Aziridine and hydroxylamine reacted with pyrrol-2-one to afford 2,7-diazaspiro[4.4]nona-3,6-diene and oxime derivatives, respectively. Pyrrolo[2,3-c]isoxazoles or pyrrolo[2,3-c]isothiazole were formed in high yield from oximes depending upon the reaction conditions employed for ring closure. Treatment of pyrrolylidene malononitrile with N¹,N²-di(4-chlorophenyl)acetamidine in ethyl acetate furnished azepine derivatives in 70-75% yield.

Full text of DOI:10.1016/S0040-4020(01)01029-8

TETRAHEDRON
Pergamon
Tetrahedron 58 (2002) 135±141
1-Aryl-5-methoxypyrrolones as synthons for fused heterocycles
Hisham A. Abd El-Nabip
Department of Chemistry, Faculty of Science, El-Minia University, El-Minia, A. R. Egypt
Received 14 June 2001; revised 20 September 2001; accepted 11 October 2001
AbstractÐ3-Di(methylsulfonyl)methylene-pyrrol-2-one and 2-(1-aryl-5-methoxy-2-oxo-2,3-dihydro-1H-3-pyrrolylidene)malononitrile
were obtained from 1-aryl-5-methoxypyrrolones. Aziridine and hydroxylamine reacted with pyrrol-2-one to afford 2,7-diazaspiro[4.4]-
nona-3,6-diene and oxime derivatives, respectively. Pyrrolo[2,3-c]isoxazoles or pyrrolo[2,3-c]isothiazole were formed in high yield from
oximes depending upon the reaction conditions employed for ring closure. Treatment of pyrrolylidene malononitrile with N1,N2-di(4-
chlorophenyl)acetamidine in ethyl acetate furnished azepine derivatives in 70±75% yield. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
the synthesis of 3-di(methylsulfanyl)methylene-pyrrol-2-
one 2a±c and 2-(1-aryl-5-methoxy-2-oxo-2,3-dihydro-1H-
3-pyrrolylidene)malononitrile 4a±c have been investigated.
The reactivity of these compounds were examined towards
aziridine, hydroxylamine and N1,N2-di(4-cholorophenyl)-
acetamidine in order to obtain fused heterocyclic systems
in a clean and direct synthesis.
Pyrrolones have received considerable attention1 as a result
of the presence of the lactam ring in some antibiotics, in bile
pigments2 and in the natural alkaloid jatropham, which
shows inhibitory activity towards P-388 Lymphocytic
leukemia.3 Pyrrole-2,3-diones have proved to be good
synthons for different heterocycles.4±8 Several attempts to
modify the functional groups in pyrrole-2,3-diones have
been made: transformation of carbonyl groups into the
corresponding CvS moieties using Lawesson's reagent,9
or to furnish nitrones, aldehydes10 o r CvC double bonds
instead of CvO functionalities via the Wittig reaction.11
Therefore, in order to extend our investigation on such
1-aryl-5-methoxypyrrolones10 1a±c as potential precursors,
2. Results and discussion
It is well known that active methylenes of heterocyclic
compounds react with carbon disul®de in the presence of
base.12±14 Thus, treatment of 1-aryl-5-methoxypyrrol-2-
ones10 1a±c with carbon disul®de followed by treatment
Scheme 1.
Keywords: pyrrolones; malononitrile; aziridine; hydroxylamine; N1,N2-di(4-chlorophenyl)-acetamidine.
Tel.: 12-86-363011; fax: 12-86-342601; e-mail: rumenia@rusys.eg.net
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0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(01)01029-8

136
H. A. A. El-Nabi / Tetrahedron 58 (2002) 135±141
Scheme 2.
with dimethyl sulfate in the presence of sodium hydroxide
and dimethyl sulfoxide gave 3-di(methylsulfonyl)methyl-
enepyrrol-2-one 2a±c as pale yellow needles in 68±79%
yield. The structure of the product was con®rmed beside
elemental analysis by spectroscopic measurements that
supported the suggested structure (Section 4). On the
other hand, 2-(1-aryl-5-methoxy-2-oxo-2,3-dihydro-1H-3-
pyrrolylidene)malononitriles 4a±c were obtained in good
yield 58±67% by re¯uxing equimolar amounts of pyrrole-
2,3-diones8 3a±c and malononitrile in acetonitrile with a
catalytic amount of triethylamine. The structures of 4a±c
were con®rmed by analytical and spectroscopic measure-
ments and by synthesis of the same products from 1-aryl-
5-methoxypyrrolones10 1a±c with tetracyanoethylene as
shown in Scheme 1. These results are in good agreement
with a similar ®nding with 3-methyl-1-phenyl-2-pyrazoline-
4,5-diones.15,16
since they decomposed during puri®cation, but their
formation was established by heating in xylene for 2 h
which gave either compounds 6 or 7 as pale yellow powders
in 60±65% yield (Scheme 2). Structure 7 was excluded
based on spectroscopic measurements which characterized
the product as 2,7-diazaspiro[4.4]nona-3,6-dien-1-one
6a±c. The IR spectra of 6a±c showed characteristic absorp-
tion bands between 1685 and 1675 cm21 for CvO, and
1
between 1635 and 1630 cm21 for CvN group. The H
NMR spectra showed
a singlet between 2.43 and
2.47 ppm for SCH3, and between 2.35±2.50 and 3.80±
3.96 ppm for CH2 and NCH2, respectively. Final con-
®rmation of structures 6a±c were derived from their 13C
NMR spectra. The assignment of all ring carbons of 6a
brought a signi®cant con®rmation of the 2,7-diazaspiro-
[4.4]nona-3,6-diene ring system: 171.85 (CO), 161.47
(C-6), 147.43 (C-3), 90.46 (C-4), 59.87 (spirocarbon C-5),
53.69 (OCH3), 44.87 (NCH2) and 34.95 (CH2). The
chemical shift value of the spiro carbon was found in the
region usually known for such spiro ring system.10,18
The a-oxoketene dithioacetal functionality has proven to be
a versatile three-carbon synthon17 which is useful in the
synthesis of heterocyclic compounds. Thus, thio-aziridine-
methylene derivatives 5a±c were easily obtained from 2a±c
on treatment with aziridine in diethyl ether at 0±58C.
Attempts toisolate 5a±c in pure form were unsuccessful
On the other hand, treatment of 2a±c with hydroxylamine in
aqueous ethanol heated to re¯ux gave the corresponding
oximes 8a±c stereoselectively and in excellent yield. The

H. A. A. El-Nabi / Tetrahedron 58 (2002) 135±141
137
Scheme 3.
oxime, in general, is formed as a mixture of syn/anti geo-
metrical isomers, the syn or anti geometry of oxime is
readily determined from 13C NMR spectroscopy since the
a-carbons syn to the oxime hydroxyl group are shifted
up®eld relative tothe anti a-carbons as a result of the
yielding route to pyrrolo[2,3-c]isoxazole and pyrrolo[2,3-c]-
isothiazole derivatives.
Finally, N1,N2-di(4-chlorophenyl)acetamidine 11 reacted
with 4a±c in ethyl acetate at re¯ux for 8 h to give novel
pyrrolo[2,3-d]azepines 15a±c in 70±75% yield (Scheme 3).
The formation of 15a±c is suggested toproceed via initial
nucleophilic attack by N2 of 11 on one nitrile carbon of 4a±c
gives rise to 12a±c which must exist in equilibrium with
tautomers 13a±c. These tautomers, being ketene aminals,
exhibit nucleophilic character at the terminal methylene
carbon atom attacking either carbonyl carbon or C-3 of
4a±c to furnish either pyrrolo[2,3-d]azepines 15 or spiro
derivatives 16. However, the shift difference observed in
the methylene signals and the number of signals attributable
to aryl-carbon atoms linked to hydrogen excluded a spiro
structure for compound 16.18,21 The IR spectra of 15a±c
showed strong absorptions between 3310 and 3315 cm21
for OH and between 3240 and 3235 cm21 for NH with
further bands in the range 2190±2195 cm21 for CN and
g-effect.19 The allylic carbon Cg o r C chemical shift
d
remains fairly constant for a series of a-oxoketene dithio-
acetals and vinylogous thiol esters20 and serves as a
reference point in assignment of chemical shifts. The
geometry of 8 is assumed tobe syn. The geometrical assign-
ment of 8a±c in the absence of mixtures must be viewed as
tentative. Structures 8a±c were in agreement with elemental
analysis and spectroscopic measurements. In a clean and
direct pathway oximes, 8a±c can be converted into either
9a±c or 10a±c by heating in xylene for 2 h or on treatment
with thionyl chloride and pyridine as shown in Scheme 2.
The results of analytical and spectroscopic measurements
clearly revealed 9a±c and 10a±c as pyrrolo[2,3-c]isoxa-
zoles and pyrrolo[2,3-c]isothiazoles, respectively. The IR
spectrum of 9a showed absorption bands at 3050 and
1640 cm21 for aromatic-H and CvN, respectively, 1H
NMR spectrum showed single at 2.65 ppm for SCH3, 3.95
for OCH3, 4.78 for C4-H and 7.05±7.52 for aromatic-H;
while 13C NMR spectrum showed signals at 156.19 (C-5),
150.63 (C-6a), 136.16 (C-3), 117.76 (C-3a), 86.16 (C-4),
55.46 (OCH3), 20.64 (SCH3) and aromatic carbons at
139.80, 131.12, 122.10, 121.35 in support of the proposed
structure. This procedure provided a convenient high
1
1630±1640 cm21 for CvN. H NMR spectra AB patterns
with dA in the range 3.55±3.62 and dB between 3.72 and
3.75 with (2J) values between 16.24 and 16.85 Hz are
assigned tothe C-8 methylene group adjacent tothe chiral
carbon atom C-8a. The presence of this methylene group is
alsoevident from the 13C-DEPT-spectra exhibiting negative
signals at d 32.28 and 34.48. The broad-band 1H-decoupled
13C NMR spectra of 15a,b showed signals at d 92.30 and

138
H. A. A. El-Nabi / Tetrahedron 58 (2002) 135±141
93.85 for C-8a bearing the hydroxy group and one signal
each at d 116.40 and 118.40 for the cyano group.
58.42; H, 5.43; N, 4.42, S, 20.74. C15H17NO2S2 requires
C, 58.60; H, 5.57; N, 4.56; S, 20.86%); Rf (benzene/acetone,
10:2) 0.42; nmax (KBr) 1685 cm21; dH (200 MHz, CDCl3,
TMS) 7.07±7.70 (m, 4H, Ar), 5.28 (s, 1H, C4-H), 3.70
(s, 3H, OCH3), 2.67 (s, 6H, 2SCH3), 2.28 (s, 3H, CH3).
dC (100 MHz, CDCl3, TMS) 160.12, 154.02, 139.65,
137.82, 133.37, 133.15, 128.37, 123.22, 95.45, 52.78,
21.23, 17.35.
3. Conclusion
In summary, we have proved that 1-aryl-5-methoxypyrro-
lones 1a±c are good synthons for fused heterocyclic
nitrogen compounds via converting them into 3-di(methyl-
sulfonyl)methylene-pyrrol-2-ones 2a±c and 2-(1-aryl-5-
methoxy-2-oxo-2,3-dihydro-1H-3-pyrrolylidene)malono-
nitriles 4a±c. Aziridine and hydroxylamine reacted with
2a±c to afford 2,7-diazaspiro[4.4]nona-3,6-dienes 6a±c
and oxime derivatives 8a±c, respectively. On the other
hand, pyrrolo[2,3-c]isoxazoles 9a±c and pyrrolo[2,3-c]-
isothiazoles 10a±c were obtained from oximes 8a±c
depending upon the reaction conditions employed for ring
closure. Azepine derivatives 15a±c were established as
the sole products from reaction of 4a±c with N1,N2-di(4-
chlorophenyl)acetamidine 11 in ethyl acetate.
4.1.4. 3-[Di(methylsulfanyl)methylene]-5-methoxy-1-(4-
methoxyphenyl)-2,3-dihydro-1H-2-pyrrolone (2c). 25.5 g,
79%; as pale yellow needles mp 157±1588C (Found: C,
55.54; H, 5.11; N, 4.22; S, 19.71. C15H17NO3S2 requires
C, 55.71; H, 5.30; N, 4.33; S, 19.83%); Rf (benzene/acetone,
10:2) 0.45; nmax (KBr) 1680 cm21; dH (200 MHz, CDCl3,
TMS) 6.79±7.59 (m, 4H, Ar), 5.28 (s, 1H, C4-H), 3.72
(s, 3H, OCH3), 3.65 (s, 3H, p-OCH3), 2.60 (s, 6H,
2SCH3); dC (100 MHz, CDCl3, TMS) 161.45, 154.73,
139.95, 131.85, 116.29, 129.69, 159.09, 120.70, 95.75,
58.30, 52.85, 17.55.
4.1.5.
2-(1-Aryl-5-methoxy-2-oxo-2,3-dihydro-1H-3-
4. Experimental
4.1. General
pyrrolylidene) malononitrile 4a±c. Method A. Dione
3a±c (0.01 mol) was dissolved in dry acetonitrile (30 mL)
and malononitile (0.01 mol) was added with two drops of
TEA. The reaction mixture was heated at re¯ux on a water
bath for 30 min, whereby a black precipitate was formed.
This was ®ltered washed with cold ethanol and dried.
Crystallization from ethanol/petroleum ether (1:1) furnished
4a±c in 58±67% yield.
All melting points were determined on a Gallenkamp
melting point apparatus and are uncorrected. Infrared
spectra were measured with a Perkin±Elmer Model 298
1
spectrophotometer. H NMR spectra were recorded on a
Varian XL-200 spectrometer with CDCl3 as solvent and
TMS as internal reference, chemical shifts are expressed
as d ppm. Analytical data were determined on C,H,N-
Elemental Analyzer CarloErba 1106. Silica gel 60
(Merck, 230±400 mesh) was used for ¯ash chromatography.
Method B. 1-Aryl-5-methoxypyrrolone 1a±c (0.01 mol)
was dissolved in ethyl acetate (30 mL) and teteracyanoethyl-
ene (0.01 mol) was added. The reaction mixture was
re¯uxed for 2 h a black precipitate was formed. Treatment
as in Method A gave 4a±c in 45, 49 and 52% yield,
respectively.
4.1.1. 1-Aryl-3-[di(methylsulfanyl)methylene]-5-methoxy-
2,3-dihydro-1H-2-pyrrolone (2a±c). To a solution of 1a±c
(0.1 mol) in Me2SO (100 mL), concentrated NaOH (10 g of
NaOH in 30 mL of H2O) was added under stirring and CS2
(0.1 mol) was then added slowly dropwise under stirring
over a period of 30 min while the temperature of the mixture
was maintained at 5±108C. The reaction mixture was stirred
for 1 h and Me2SO4 (35 g) was added dropwise with cooling
over a period of 20 min. The mixture was stirred for 2 h
and poured into ice water. The precipitate was collected
by ®ltration, washed with 5% NaOH and with H2O, and
recrystallized from benzene to give 2a±c as pale yellow
needles in 68±79% yield.
4.1.6. 2-(5-Methoxy-2-oxo-1-phenyl-2,3-dihydro-1H-3-
pyrrolylidene) malononitrile 4a. 1.45 g, 58%; as deep
red ¯akes mp 211±2128C (Found: C, 66.71; H, 3.58; N,
16.60. C14H9N3O2 requires C, 66.93; H, 3.61; N, 16.72%);
Rf (benzene/chloroform, 10:3) 0.29; nmax (KBr) 2200, 1680
and 1620 cm21; dH (200 MHz, CDCl3, TMS) 7.30±7.74 (m,
5H, Ph), 4.73 (s, 1H, C4-H), 3.79 (s, 3H, OCH3). dC
(100 MHz, CDCl3, TMS) 164.87, 162.78, 144.21, 136.91,
133.79, 131.56, 120.53, 115.57, 94.20, 83.91, 54.45.
4.1.7.
2-[5-Methoxy-1-(4-methylphenyl)-2-oxo-2,3-di-
hydro-1H-3-pyrrolylidene] malononitrile (4b). 1.64 g,
62%; as deep red ¯akes mp 227±2288C (Found: C, 67.74;
H, 4.02; N, 15.63. C15H11N3O2 requires C, 67.92; H, 4.18;
N, 15.84%); Rf (benzene/chloroform, 10:3) 0.33; nmax (KBr)
2200, 1675 and 1620 cm21; dH (200 MHz, CDCl3, TMS)
7.12±7.73 (m, 4H, Ar), 4.65 (s, 1H, C4-H), 3.71 (s, 3H,
OCH3), 2.34 (s, 3H, CH3). dC (100 MHz, CDCl3, TMS)
165.96, 163.58, 145.31, 137.45, 133.0, 132.94, 131.02,
114.32, 94.83, 84.35, 54.89, 22.12.
4.1.2.
3-[Di(methylsulfanyl)methylene]-5-methoxy-1-
phenyl-2,3-dihydro-1H-2-pyrrolone (2a). 19.2 g, 68%;
as pale yellow needles mp 127±1288C (Found: C, 57.03;
H, 4.98; N, 4.63; S, 21.63. C14H15NO2S2 requires C, 57.31;
H, 5.15; N, 4.77; S, 21.85%); Rf (benzene/acetone, 10:2)
0.37; nmax (KBr) 1680 cm21; dH (200 MHz, CDCl3, TMS)
7.26±7.69 (m, 5H, Ph), 5.24 (s, 1H, C4-H), 3.68 (s, 3H,
OCH3), 2.63 (s, 6H, 2SCH3). dC (100 MHz, CDCl3, TMS)
160.06, 152.93, 138.77, 136.74, 131.37, 129.39, 126.55,
120.70, 94.72, 51.56, 16.95.
4.1.8. 2-[5-Methoxy-1-(4-methoxyphenyl)-2-oxo-2,3-di-
hydro-1H-3-pyrrolylidene] malononitrile (4c). 1.88 g,
67%; as deep red ¯akes mp 243±2448C (Found: C, 63.90;
H, 3.93; N, 14.77. C15H11N3O3 requires C, 64.05; H, 3.94;
4.1.3. 3-[Di(methylsulfanyl)methylene]-5-methoxy-1-(4-
methylphenyl)-2,3-dihydro-1H-2-pyrrolone (2b). 22.4 g,
73%; as pale yellow needles mp 142±1438C (Found: C,

H. A. A. El-Nabi / Tetrahedron 58 (2002) 135±141
139
N, 14.94%); Rf (benzene/chloroform, 10:3) 0.36; nmax (KBr)
2200, 1675 and 1620 cm21; dH (200 MHz, CDCl3, TMS)
7.23±7.84 (m, 4H, Ar), 4.79 (s, 1H, C4-H), 3.80 (s, 3H,
OCH3), 3.62 (s, 3H, p-OCH3). dC (100 MHz, CDCl3,
TMS) 166.07, 164.78, 158.92, 145.84, 134.26, 132.25,
116.47, 116.11, 95.20, 84.94, 57.30, 56.65.
temperature, ethanol was removed in vacuo, and the concen-
trated reaction mixture was then poured into a separatory
funnel containing ice cold water (100 mL) and methylene
chloride (100 mL). The organic layer was separated and
dried over anhydrous MgSO4. Filtration and concentration
in vacuogave 8a±c in 85±93% yields.
4.1.9. 7-Aryl-8-methoxy-1-(methylsulfanyl)-2,7-diaza-
spiro[4.4]nona-1,8-dien-6-one (6a±c). A mixture of 2a±c
(1 mmol) and aziridine (5 mmol) in dry diethyl ether
(100 mL) was stirred at 0±58C for 2±4 h. Removal of the
solvent under reduced pressure yielded 5a±c. The isomeri-
zation of 5a±c to 6a±c was achieved by heating in xylene
for 2 h yielded the spiro compounds 6a±c in 60±65% yield
which then recrystallized from ethanol.
4.1.14. 3-[Di(methylsulfanyl)methylene]-5-methoxy-1-
phenyl-2,3-dihydro-1H-2-pyrrolone oxime (8a). 0.261 g,
85%; as colorless needles mp 186±1878C (Found: C, 54.28;
H, 5.02; N, 8.89; S, 20.61. C14H16N2O2S2 requires C, 54.52;
H, 5.23; N, 9.08; S, 20.79%); Rf (petroleum ether/ether, 1:1)
0.22; nmax (KBr) 3500±3300 cm21; dH (200 MHz, CDCl3,
TMS) 9.98 (s, 1H, OH), 7.18±7.57 (m, 5H, Ph), 5.76 (s, 1H,
C4-H), 3.52 (s, 3H, OCH3), 2.55 (s, 6H, 2SCH3). dC
(100 MHz, CDCl3, TMS) 156.52, 153.75, 147.91, 140.14,
137.85, 131.12, 123.84, 122.10, 87.96, 52.87, 17.64.
4.1.10. 3-Methoxy-6-(methylsulfanyl)-2-phenyl-2,7-di-
azaspiro[4.4]nona-3,6-dien-1-one (6a). 0.187 g, 65%; as
pale yellow powder mp 166±1678C (Found: C, 62.34; H,
5.52; N, 9.63; S, 10.89. C15H16N2O2S requires C, 62.48; H,
5.59; N, 9.71; S, 11.12%); Rf (benzene/acetone, 10:2) 0.32;
nmax (KBr) 1685 and 1630 cm21; dH (200 MHz, CDCl3,
TMS) 7.31±7.72 (m, 5H, Ph), 3.80±3.86 (m, 2H, NCH2),
3.77 (s, 3H, OCH3), 4.29 (s, 1H, C4-H), 2.35±2.50 (m, 2H,
CH2), 2.45 (s, 3H, SCH3). dC (100 MHz, CDCl3, TMS)
171.85, 161.47, 147.43, 134.68, 131.89, 127.58, 120.52,
90.46, 59.87, 53.69, 44.87, 34.95, 13.62.
4.1.15. 3-[Di(methylsulfanyl)methylene]-5-methoxy-1-
(4-methylphenyl)-2,3-dihydro-1H-2-pyrroloneoxime (8b).
0.289 g, 90%; as colorless needles mp 186±1878C (Found:
C, 55.63; H, 5.42; N, 8.52; S, 19.67. C15H18N2O2S2 requires
C, 55.88; H, 5.63; N, 8.69; S, 19.89%); Rf (petroleum ether/
ether, 1:1) 0.24; nmax (KBr) 3500±3300 cm21; dH (200
MHz, CDCl3, TMS) 10.05 (s, 1H, OH), 7.22±7.78 (m,
4H, Ar), 5.64 (s, 1H, C4-H), 3.48 (s, 3H, OCH3), 2.50 (s,
6H, 2SCH3), 2.28 (s, 3H, CH3). dC (100 MHz, CDCl3, TMS)
157.60, 154.21, 148.12, 140.35, 138.90, 135.65, 130.58,
123.66, 88.15, 53.13, 21.01, 17.85.
4.1.11. 3-Methoxy-2-(4-methylphenyl)-6-(methylsulfanyl)-
2,7-diazaspiro[4.4]nona-3,6-dien-1-one (6b). 0.181 g,
60%; as pale yellow powder mp 142±1438C (Found: C,
63.32; H, 5.87; N, 9.11; S, 10.32. C16H18N2O2S requires
C, 63.55; H, 6.00; N, 9.26; S, 10.60%); Rf (benzene/acetone,
10:2) 0.35; nmax (KBr) 1675 and 1630 cm21. dH (200 MHz,
CDCl3, TMS) 7.23±7.58 (m, 4H, Ar), 3.84±3.90 (m, 2H,
NCH2), 3.81 (s, 3H, OCH3), 4.31 (s, 1H, C4-H), 2.37±2.48
(m, 2H, CH2), 2.43 (s, 3H, SCH3), 2.28 (s, 3H, CH3). dC
(100 MHz, CDCl3, TMS) 172.19, 162.42, 148.55, 135.72,
132.99, 131.86, 128.91, 91.88, 60.69, 55.73, 45.67, 35.59,
21.01, 13.58.
4.1.16. 3-[Di(methylsulfanyl)methylene]-5-methoxy-1-
(4-methoxyphenyl)-2,3-dihydro-1H-2-pyrrolone oxime
(8c). 0.314 g, 93%; as colorless needles mp 162±1638C
(Found: C, 53.00; H, 5.09; N, 8.00; S, 18.74.
C15H18N2O3S2 requires C, 53.23; H, 5.36; N, 8.28; S,
18.95%); Rf (petroleum ether/ether 1:1) 0.26; nmax (KBr)
3500±3300 cm21; dH (200 MHz, CDCl3, TMS) 9.95 (s,
1H, OH), 7.03±7.68 (m, 4H, Ar), 5.76 (s, 1H, C4-H), 3.69
(s, 3H, p-OCH3), 2.55 (s, 6H, SCH3), 2.52 (s, 3H, OCH3). dC
(100 MHz, CDCl3, TMS) 158.90, 158.49, 154.53, 149.21,
142.25, 133.31, 124.70, 116.03, 88.45, 57.30, 53.25, 17.85.
4.1.12. 3-Methoxy-2-(4-methoxyphenyl)-6-(methylsul-
fanyl)-2,7-diazaspiro[4.4]nona-3,6-dien-1-one (6c). 0.2 g,
63%; as pale yellow powder mp 186±1878C (Found: C,
60.12; H, 5.57; N, 8.71; S, 9.86. C16H18N2O3S requires C,
60.36; H, 5.70; N, 8.80; S, 10.07%); Rf (benzene/acetone,
10:2) 0.41; nmax (KBr) 1675 and 1635 cm21. dH (200 MHz,
CDCl3, TMS) 7.08±7.45 (m, 4H, Ar), 3.92±3.96 (m, 2H,
NCH2), 3.79 (s, 3H, OCH3), 3.69 (s, 3H, p-OCH3), 4.29 (s,
1H, C4-H), 2.40±2.47 (m, 2H, CH2), 2.47 (s, 3H, SCH3). dC
(100 MHz, CDCl3, TMS) 173.25, 163.32, 159.75, 149.54,
131.54, 128.91, 116.45, 92.43, 59.47, 56.37, 57.30, 45.88,
36.31, 14.24.
4.1.17. 6-Aryl-5-methoxy-3-(methylsulfanyl)-6H-pyrrolo-
[2,3-c]isoxazole (9a±c). Heating of oxime 8a±c (1 mmol)
in dry xylene (30 mL) tore¯ux and stirred for 2±3 h. The
progress of reaction was monitored by TLC and worked
up when starting material had completely disappeared.
Removal of the solvent in vacuo afforded crude isoxazoles
9a±c as a pale yellow powder in 90±95% yields. The crude
products were relatively clean. Analytical pure samples
were obtained by ¯ash chromatography using toluene/
acetone (10:1).
4.1.18.
5-Methoxy-3-(methylsulfanyl)-6-phenyl-6H-
4.1.13. 1-Aryl-3-[di(methylsulfanyl)methylene]-5-methoxy-
2,3-dihydro-1H-2-pyrrolone oxime (8a±c). An aqueous
ethanol hydroxylamine solution was generated from
hydroxylamine hydrocloride (3.46 g, 5 mmol), KOH
(2.8 g, 5 mmol) in water (10 mL), and 95% ethanol
(50 mL). The clear solution was neutral to litmus paper.
To this hydroxylamine solution was added 1 mmol of the
appropriate ketene dithioacetal. The solution was heated to
re¯ux and stirred for 24 h. The solution was cooled to room
pyrrolo[2,3-c]isoxazole (9a). 0.234 g, 90%; as colorless
needles mp 198±1998C (Found: C, 59.69; H, 4.42; N,
10.46; S, 12.11. C13H12N2O2S requires C, 59.98; H, 4.65;
N, 10.76; S, 12.32%); Rf (petroleum ether/ether, 1:1) 0.27;
nmax (KBr) 3050, 1640 cm21; dH (200 MHz, CDCl3, TMS)
7.05±7.52 (m, 5H, Ph), 4.78 (s, 1H, C4-H), 3.95 (s, 3H,
OCH3), 2.65 (s, 3H, SCH3). dC (100 MHz, CDCl3, TMS)
156.19, 150.63, 139.80, 136.16, 131.12, 122.10, 121.35,
117.76, 86.16, 55.46, 20.64.

140
H. A. A. El-Nabi / Tetrahedron 58 (2002) 135±141
4.1.19.
5-Methoxy-6-(4-methylphenyl)-3-(methylsul-
135.65, 130.88, 129.87, 121.12, 123.71, 88.09, 53.43,
21.31, 20.23.
fanyl)-6H-pyrrolo[2,3-c]isoxazole (9b). 0.254 g,93%; as
colorless needles mp 212±2138C (Found: C, 60.98; H,
4.97; N, 10.01; S, 11.49. C14H14N2O2S requires C, 61.29;
5.14; N, 10.21; S, 11.69%); Rf (petroleum ether/ether, 1:1)
0.31; nmax (KBr) 3050, 1635 cm21; dH (200 MHz, CDCl3,
TMS) 7.35±7.75 (m, 4H, Ar), 4.86 (s, 1H, C4-H), 3.95 (s,
3H, OCH3), 2.62 (s, 3H, SCH3), 2.38 (s, 3H, CH3). dC
(100 MHz, CDCl3, TMS) 159.10, 152.45, 140.88, 138.32,
135.65, 130.58, 120.80, 119.45, 88.36, 56.15, 21.75, 21.01.
4.1.24. 5-Methoxy-6-(4-methoxyphenyl)-3-(methylsul-
fanyl)-6H-pyrrolo[2,3-c]isothiazole (10c). 0.260 g, 85%;
as colorless needles mp 247±2488C (Found: C, 54.72; H,
4.58; N, 9.00; S, 20.77. C14H14N2O2S2 requires C, 54.88; H,
4.61; N, 9.14; S, 20.93%); Rf (petroleum ether/ether, 1:1)
0.42; nmax (KBr) 3050, 1645 cm21; dH (200 MHz, CDCl3,
TMS) 7.12±7.65 (m, 4H, Ar), 5.23 (s, 1H, C4-H), 3.90 (s,
3H, OCH3), 3.66 (s, 3H, p-OCH3), 2.63 (s, 3H, SCH3). dC
(100 MHz, CDCl3, TMS) 157.49, 146.81, 149.83, 136.23,
135.10, 123.12, 121.72, 116.44, 89.41, 58.89, 52.78, 20.63.
4.1.20. 5-Methoxy-6-(4-methoxyphenyl)-3-(methylsul-
fanyl)-6H-pyrrolo[2,3-c]isoxazole (9c). 0.275 g, 95%; as
colorless needles mp 237±2388C (Found: C, 57.84; H,
4.63; N, 9.47; S, 10.85. C14H14N2O3S requires C, 57.92;
H, 4.86; N, 9.65; S, 11.04%); Rf (petroleum ether/ether,
1:1) 0.31; nmax (KBr) 3050, 1635 cm21; dH (200 MHz,
CDCl3, TMS) 7.12±7.51 (m, 4H, Ar), 4.86 (s, 1H, C4-H),
3.84 (s, 3H, OCH3), 3.77 (s, 3H, p-OCH3), 2.73 (s, 3H,
SCH3). dC (100 MHz, CDCl3, TMS) 160.49, 158.49,
151.53, 137.46, 133.31, 124.70, 117.76, 116.03, 88.45,
57.30, 53.25, 20.64.
4.2. Reaction of N1,N2-di(4-chlorophenyl)acetamidine 11
with 4a±c to give 15a±c
To a stirred solution of the amidine 11 (1 mmol) in ethyl
acetate (5 mL) a solution of 4a±c (1 mmol) in ethyl acetate
(20 mL) was added dropwise at room temperature. Heating
the reaction mixture at re¯ux for 8 h, the reaction was moni-
tored by TLC until all starting materials were consumed,
ethyl acetate was removed in vacuo and the concentrated
residue were subjected to ¯ash chromatography using
benzene/ethanol (10:3) to give 15a±c in 70±75% yield.
4.1.21. 6-Aryl-5-methoxy-3-(methylsulfanyl)-6H-pyrrolo-
[2,3-c]isothiazole (10a±c). Dry methylene chloride (25
mL) was cooled to 0±58C. Thionyl chloride (1.25 mmol)
was added dropwise and the solution was stirred for
10 min. Pyridine (1.25 mmol) was added to the thionyl
chloride solution, which was stirred for an additional
15 min at 08C. The oxime (1 mmol) in dry methylene
chloride was added dropwise to the solution over a period
of 10 min. The solution was stirred for 1 h at 08C, warmed to
room temperature, and then stirred for another 8±10 h.
When TLC showed complete disappearance of oxime, the
reaction mixture was diluted with 60 mL of diethyl ether
and washed with 10% HCl (3£30 mL), saturated sodium
bicarbonate (2£30 mL) and distilled water. The organic
phase was dried over anhydrous MgSO4. Filtration and
removal of solvent in vacuo afforded crude isothiazoles
10a±c in high yields (83±86%). Analytically pure samples
were obtained by ¯ash chromatography using benzene/
acetone (10:2).
4.2.1. 6-(4-Chlorophenyl)-7-[(4-chlorophenyl)imino]-8a-
hydroxy-5-imino-2-methoxy-1-phenyl-1,5,6,7,8,8a-hexa-
hydropyrrolo[2,3-d]azepin-4-yl-cyanide 15a. 0.386 g,
73%; as colorless powder mp 267±2688C (Found: C,
63.25; H, 3.87; Cl, 13.18; N, 13.00. C28H21Cl2N5O2 requires
C, 63.41; H, 3.99; Cl, 13.37; N, 13.20%); Rf (benzene/
ethanol, 10:3) 0.35; nmax (KBr) 3310±3240, 2190 and
1630 cm21; dH (200 MHz, CDCl3, TMS) 7.81 (broad s,
2H, NH and OH), 6.95±7.75 (m, 13H, Ph and 2Ar), 4. 65
(s, 1H, C4-H), 3.64 (s, 3H, OCH3), 3.62(d, 1H, Jˆ13.85 Hz,
CHAHB), 3.72 (d, 1H, Jˆ13.85 Hz, CHAHB); dC (100 MHz,
CDCl3, TMS) 163.34, 154.90, 149.62, 149.0, 137.63,
133.41, 127.55, 121.39, 116.40, 92.30, 85.77, 84.42,
55.67, 34.48.
4.2.2. 6-(4-Chlorophenyl)-7-[(4-chlorophenyl)imino]-8a-
hydroxy-5-imino-2-methoxy-1-(4-methylphenyl)-1,5,6,7,
8,8a-hexahydropyrrolo[2,3-d]azepin-4-yl-cyanide (15b).
0.408 g, 75%; as colorless powder mp 254±2558C (Found:
C, 63.76; H, 4.21; Cl, 12.87; N, 12.64. C29H23Cl2N5O2
requires C, 63.98; H, 4.26; Cl, 13.02; N, 12.86%); Rf
(benzene/ethanol, 10:3) 0.38; nmax (KBr) 3320±3235,
2190 and 1635 cm21; dH (200 MHz, CDCl3, TMS) 7.79
(broad s, 2H, NH and OH), 6.85±7.72 (m, 12H, 3Ar),
4.72 (s, 1H, C4-H), 3.70 (s, 3H, OCH3), 3.59 (d, 1H, Jˆ
13.85 Hz, CHAHB), 3.74 (d, 1H, Jˆ13.85 Hz, CHAHB), 2.24
(s, 3H, CH3). dC (100 MHz, CDCl3, TMS) 164.84, 155.62,
152.23, 150.15, 140.76, 131.68, 130.42, 126.08, 118.40,
93.85, 88.02, 86.81, 57.21, 32.28, 19.20.
4.1.22.
5-Methoxy-3-(methylsulfanyl)-6-phenyl-6H-
pyrrolo[2,3-c]isothiazole (10a). 0.229 g, 83%; as colorless
needles mp 256±2578C (Found: C, 56.43; H, 4.38; N, 9.89;
S, 22.95. C13H12N2OS2 requires C, 56.50; H, 4.38; N, 10.14;
S, 23.20%); Rf (petroleum ether/ether, 1:1) 0.33; nmax (KBr)
3045, 1635 cm21; dH (200 MHz, CDCl3, TMS) 7.15±7.58
(m, 5H, Ph); 5.11 (s, 1H, C4-H), 3.90 (s, 3H, OCH3), 2.59 (s,
3H, SCH3). dC (100 MHz, CDCl3, TMS) 148.44, 144.12,
138.90, 131.52, 129.07, 123.89, 122.10, 119.41, 86.88,
52.79, 19.52.
4.1.23. 5-Methoxy-6-(4-methylphenyl)-3-(methylsulfanyl)-
6H-pyrrolo[2,3-c]isothiazole (10b). 0.249 g, 86%; as
colorless needles mp 225±2268C (Found: C, 57.72; H,
4.80; N, 9.45; S, 21.87. C14H14N2OS2 requires C, 57.90;
H, 4.86; N, 9.65; S, 22.08%); Rf (petroleum ether/ether,
1:1) 0.38; nmax (KBr) 3050, 1640 cm21; dH (200 MHz,
CDCl3, TMS) 7.21±7.82 (m, 4H, Ar), 5.19 (s, 1H, C4-H),
3.82 (s, 3H, OCH3), 2.55 (s, 3H, SCH3), 2.45 (s, 3H, CH3).
dC (100 MHz, CDCl3, TMS) 149.52, 146.32, 139.98,
4.2.3. 6-(4-Chlorophenyl)-7-[(4-chlorophenyl)imino]-8a-
hydroxy-5-imino-2-methoxy-1-(4-methoxyphenyl)-1,5,6,
7,8,8a-hexahydropyrrolo[2,3-d]azepin-4-yl-cyanide (15c).
0.392 g, 70%; as colorless powder mp 287±2888C (Found:
C, 61.89; H, 4.00; Cl, 12.44; N, 12.33. C29H23Cl2N5O3
requires C, 62.15; 4.14; Cl, 12.65; N, 12.50%); Rf (benzene/
ethanol, 10:3) 0.41; nmax (KBr) 3315±3235, 2195 and

H. A. A. El-Nabi / Tetrahedron 58 (2002) 135±141
141
1640 cm21; dH (200 MHz, CDCl3, TMS) 7.83 (broad s, 2H,
NH and OH), 6.90±7.78 (m, 12H, 3Ar), 4.74 (s, 1H, C4-H),
3.74 (s, 3H, OCH3), 3.55 (d, 1H, Jˆ13.85 Hz, CHAHB), 3.70
(d, 1H, Jˆ13.85 Hz, CHAHB), 3.63 (s, 3H, OCH3).
11. Review:Maercker, A. The Wittig-Reaction; Organic
Reactions, Vol. 14; ,1965; pp 270±490.
12. Jensen, K. A.; Henriksen, L. Acta Chem. Scand. 1968, 22 (4),
1107±1128.
13. (a) Edwards, H. D.; Kendall, J. D. Chem. Abstr. 1951, 45,
4052h. (b) Papini, P.; Ridi, M. Gazz. Chem. Ital. 1959, 89,
526±539. (c) Papini, P.; Auzzi, G. Gazz. Chem. Ital. 1966, 96
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1965, 3315. (e) Philipe, R.; Jean, V. Bull. Soc. Chim. Fr. 1965,
3312±3315. (f) Matolcsy, G.; Sohar, P.; Bordas, B. Chem.
Ber. 1971, 104, 1155±1158.
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