1-Aryl-5-methoxy-pyrrolones as synthons for 1,3-dipolar cycloadditions

Article abstract of DOI:10.1016/S0040-4020(00)00056-9

A general method is described to convert the title compound into more complex nitrogen heterocyclic systems in a short and attractive pathway. Spiroisoxazolidine 6 was obtained from the reaction of nitrone 3 with ethyl vinyl ether. Chloroformylation of pyrrolone 2 gave 1-aryl-2-chloro-5-methoxy- pyrrol-3-carbaldehyde 4. Substitution of chlorine atom with unsaturated nucleophiles 8a,b and then modifying the aldehyde function into 1,3-dipoles 10 and 14 furnished tricyclic heterocycles 11, 12 and 15 via intramolecular 1,3-dipolar cycloaddition reaction. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00056-9

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 3013±3020
1-Aryl-5-methoxy-pyrrolones as Synthons
for 1,3-Dipolar Cycloadditions
*
Hisham A. Abd El-Nabi
Chemistry Department, Faculty of Science, El-Minia University, El-Minia, A.R. Egypt
Received 15 October 1999; revised 21 December 1999; accepted 13 January 2000
AbstractÐA general method is described to convert the title compound into more complex nitrogen heterocyclic systems in a short and
attractive pathway. Spiroisoxazolidine 6 was obtained from the reaction of nitrone 3 with ethyl vinyl ether. Chloroformylation of pyrrolone 2
gave 1-aryl-2-chloro-5-methoxy-pyrrol-3-carbaldehyde 4. Substitution of chlorine atom with unsaturated nucleophiles 8a,b and then modi-
fying the aldehyde function into 1,3-dipoles 10 and 14 furnished tricyclic heterocycles 11, 12 and 15 via intramolecular 1,3-dipolar
cycloaddition reaction. q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
reported.4 In an effort to explore the scope of these reac-
tions, a number of new pyrrole substrates bearing a 1,3-
dipole unit was prepared and tested for cycloaddition reac-
tions. The model compounds of type 4 are interesting start-
ing materials for two reasons: ®rstly, the chlorine atom is
easily substituted by unsaturated nucleophiles; and secondly
the aldehyde function is ideally suited for conversion into
1,3-dipoles (nitrone and nitrile oxide). By incorporating an
internal 1,3-dipole tethered to a dipolarophile, construction
The chemistry of monocyclic heterocyclic 2,3-diones has in
general been widely explored during the last few decades. In
particular, derivatives of such structures have been found to
serve as versatile synthons in (a) thermolysis reactions1 (b)
cycloaddition reactions2 and (c) reactions with nucleo-
philes.3 Several attempts to change functional groups in
pyrrole- or furan-2,3-diones and related systems have been
Scheme 1.
Keywords: 1,3-dipolar cycloaddition; nitrones; nitrile oxide; pyrrolones.
* Tel.: 12-086-363011; fax: 12-086-342601; e-mail: rumenia@rusys.eg.net
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00056-9

3014
H. A. A. El-Nabi / Tetrahedron 56 (2000) 3013±3020
of spiro and more complex nitrogen heterocyclic systems
has been performed in a short and attractive pathway, start-
ing from simple pyrrolone 2. With this goal in mind, some
model studies were undertaken to determine the facility of
intramolecular cyclization of 1,3-dipoles 3, 10 and 14.
dienophile for a,b-unsaturated carbonyl compounds7 and a
useful dipolarophile with 1,3-dipoles8 (Scheme 2). The IR
spectra of the formed product showed a CvO band but at
frequency higher than that of the starting nitrones which is
attributed to relief of conjugation. This assumption allows
us to exclude the heterodienic product 7 and hence the
reaction must be regarded as a 1,3-dipolar cycloaddition.
Thus, 1-aryl-5-methoxy-pyrrol-2-one 2a±c were easily
synthesized, in 74±82% yield, from the reaction of
N-aryl-acetimidic ester5 with chloroacetyl chloride as
outlined in Scheme 1. Bromination of pyrrolone 2 followed
by treatment with nitrosobenzene at room temperature
furnished the heterocyclic aryl nitrones 3 in 62±73%
yield. Several trials to get 3 from pyrrol-2,3-diones 51b
and phenyl hydroxylamine were unsuccessful. On the
other hand, conversion of pyrrolone 2 into 1-aryl-2-chloro-
5-methoxypyrrol-3-carbaldehyde 4 can be achieved by
chloroformylation of pyrrolone 2 (see Experimental) in a
similar way for chloroformylation of 3-methyl-1-phenyl-
pyrazol-5-one.6
On the other hand, the 13C NMR spectrum of 6a shows
signal at 55.27 which was assigned to the spiro carbon
atom in addition 63.72 for OCH2 which act as strong
1
evidence for the proposed structure. The H NMR spectra
are consistent with the spiroisoxazolidino heterocyclic
structures (see Experimental).
The reaction of 1-aryl-2-chloro-5-methoxypyrrol-3-carb-
aldehyde 4 with alkenylamine 8a in re¯uxing ethanol gave
the corresponding 2-alkenylamino derivatives 9a±c, while
substitution with allenethiolate, generated by basic decom-
position of the allylisothiourea salt, furnished the 2-(allyl-
sulfanyl)pyrrol-3-carbaldehyde 9d±f as shown in Scheme 3.
Treatment of 9a±f with freshly prepared phenyl hydroxyl-
amine, in re¯uxing ethanol for 3 h, gave nitrones inter-
mediates 10 which underwent intramolecular cyclization
to furnish the fused tricyclic system 11 in a good to excellent
yield. None of the isomeric bridged product 12 is produced
despite the preference for that regio-chemistry in the inter-
molecular reaction.9 The structures of 11 was con®rmed
beside the elemental analysis by spectroscopic data (see
Experimental).
The structural conformation of 3a±c was accomplished on
the basis of the analytical data and spectroscopic properties:
the IR spectrum of 3a showed a characteristic absorption
1
band at 1710 cm21 for the CvO group. The H NMR
showed a singlet at 4.45 ppm for 1H at pyrrole C-4 and a
singlet at 3.80 for 3H of OMe, 7.30±8.59 (10H, m, 2 Ph).
The nitrones 3 exist in E or Z isomeric forms. The E isomer
has two protons (ortho) deshielded by the ring carbonyl
but owing to the lack of these signals all nitrones are
presumably formed in the Z con®guration only (Fig. 1).
Finally the aldehydes 9a±f were converted into more
reactive nitrile oxides 14, which were generated in situ by
formation of the oxime 13 which were then oxidized with
sodium hypochlorite.10 Nitrile oxide 14 cyclized
spontaneously to the dihydroisooxazole 15a±f in quanti-
tative yield at room temperature. The oximes 13 were
prepared and characterized in the customary way (see
Experimental).
The reactivity of nitrone 3a±c was examined by allowing it
to react with ethyl vinyl ether, which is known to be a good
Conclusion
In summary, we have demonstrated that 1-aryl-5-meth-
oxy-2-pyrrolone 2 are potential candidates for several
fused heterocycles systems via intramolecular 1,3-dipolar
Figure 1.
Scheme 2.

H. A. A. El-Nabi / Tetrahedron 56 (2000) 3013±3020
3015
Scheme 3.
cycloaddition reactions. Incorporation of the 1,3-dipole unit
on the tether can be achieved by two ways: (a) bromination
of pyrrolone 2 followed by treatment with nitrosobenzene
furnishes heteroaromatic nitrones 3; (b) chloroformylation
spectra were measured with a Perkin±Elmer Model 298
spectrophotometer. H NMR spectra were recorded on a
1
Varian XL-200 spectrometer with CDCl3 as solvent and
TMS as internal reference, chemical shifts are expressed as
d ppm. Analytical data were performed on C,H,N-Elemental
analyzer Carlo Erba 1106. Silica gel 60 (Merck, 230±
400 mesh) was used for ¯ash chromatography.
of
2
gave 1-aryl-2-chloro-5-methoxypyrrole-3-carb-
aldehyde 4. By introducing an unsaturated nucleophile at
position 2 and converting the aldehyde function into a
1,3-dipole (nitrone or nitrile oxide), construction of spiro
and fused tricyclic systems has been performed in a simple
and short way.
1-Aryl-5-methoxy-2,3-dihydro-1H-2-pyrrolone 2a±c
General procedure: A solution of the corresponding N-aryl-
acetimidic ester 1 (0.1 mmol) obtained by heating equimolar
mixtures of alkyl orthoacetate and primary aromatic amine,5
and dry triethylamine (2.02 g, 0.2 mmol) in dry Et2O
(50 mL) is maintained at 08C. A solution of chloroacetyl
chloride (1.34 g, 0.12 mmol) in dry Et2O (10 mL) is added
Experimental
All melting points were determined on a Gallenkamp
melting point apparatus and are uncorrected. Infra-red

3016
H. A. A. El-Nabi / Tetrahedron 56 (2000) 3013±3020
dropwise during 30 min with vigorous stirring. After 2 h at
08C, n-hexane (50 mL) is added, and stirring continued for
30 min. at room temperature. The precipitate is ®ltered and
washed rapidly with ice water (2£30 mL) to remove the
ammonium salt. Recrystallization of the crude colorless
product from ethanol afforded 2 in 74±82% yield.
s, C4-H), 3.80 (3H, s, OMe), 2.28 (3H, s, Me); dC
(100.6 MHz, CDCl3) 166.64, 166.42, 157.21, 147.45,
139.98, 135.20, 131.54, 130.61, 129.22, 127.29, 120.55,
86.42, 54.47, 21.01.
[5-Methoxy-1-(4-methoxyphenyl)-2-oxo-2,3-dihydro-1H-
3-pyrrolyldine](phenyl)ammoniumolate 3c (2.36 g, 73%)
as colorless needles, mp 1588C; [Found: C, 66.37; H, 4.82;
N, 8.45. C18H16N2O4 requires C, 66.66; H, 4.97; N 8.64%];
Rf (toluene/acetone 10: 2) 0.45; nmax (KBr) 1705 cm21; dH
(200 MHz, CDCl3) 6.79±7.82 (9H, m, Ph and Ar), 4.46 (1H,
s, C4-H), 3.80 (3H, s, OMe), 3.69 (3H, s, OMe); dC
(100.6 MHz, CDCl3) 167.42, 167.24, 157.63, 147.45,
134.01, 131.93, 130.61, 129.22, 127.29, 120.55, 118.89,
87.52, 57.30, 54.47.
5-Methoxy-1-phenyl-2,3-dihydro-1H-2-pyrrolone (2a)
(1.4 g, 74%) as colorless needles, mp 112±1148C; [Found:
C, 69.71; H, 5.82; N, 7.32. C11H11NO2 requires C, 69.83; H,
5.86; N, 7.40%]; Rf (toluene/acetone 10: 2) 0.42; nmax (KBr)
1710 cm21; dH (200 MHz, CDCl3) 7.25±7.78 (5H, m, Ph),
3.80 (3H, s, OMe), 3.52 (1H, t, Jˆ6.7 Hz, C4-H), 3.01 (2H,
d, Jˆ6.7 Hz, C3-H); dC (100.6 MHz, CDCl3) 171.82,
152.89, 134.78, 131.27, 127.06, 120.52, 92.62, 54.37, 36.77.
5-Methoxy-1-(4-methyl phenyl)-2,3-dihydro-1H-2-pyrro-
lone (2b) (1.6 g, 78%) as colorless needles, mp 139±1408C;
[Found: C, 70.78; H, 6.32; N, 6.77. C12H13NO2 requires C,
70.92; H, 6.45; N, 6.89%]; Rf (toluene/acetone 10: 2) 0.53;
nmax (KBr) 1715 cm21; dH (200 MHz, CDCl3) 7.15±7.58
(4H, m, Ph), 3.77 (3H, s, OMe), 3.50 (1H, t, Jˆ6.7 Hz,
C4-H), 3.15 (2H, d, Jˆ6.7 Hz, C3-H), 2.28 (3H, s, CH3);
dC (100.6 MHz, CDCl3) 170.95, 152.8, 135.85, 132.99,
131.53, 126.92, 92.81, 54.72, 36.75, 21.16.
1-Aryl-2-chloro-5-methoxy-1H-3-pyrrolcarbaldehyde
4a±c
General method: A similar way for chloroformylation of
3-methyl-1-phenyl-pyrazol-5-one7 was used.
2-Chloro-5-methoxy-1-phenyl-1H-3-pyrrolcarbaldehyde
4a (1.34 g, 57%) as colorless needles, mp 1638C; [Found: C,
60.97; H, 4.06; Cl, 14.79; N, 5.89. C12H10ClNO2 requires C,
61.16; H, 4.28; Cl, 15.04; N, 5.94%]; Rf (toluene/acetone
10: 2) 0.37; nmax (KBr) 1675 cm21; dH (200 MHz, CDCl3)
10.24 (1H, s, CHO), 6.28±7.24 (5H, m, Ph), 6.26 (1H, s, C4-
H), 3.90 (3H, s, OMe); dC (100.6 MHz, CDCl3) 183.92,
158.37, 136.24, 134.13, 130.63, 127.67, 120.61, 111.90,
92.43, 56.80.
5-Methoxy-1-(4-methoxy phenyl)-2,3-dihydro-1H-2-pyrro-
lone (2c) (1.8 g, 82%) as colorless needles, mp 152±1538C;
[Found: C, 65.68; H, 5.87; N, 6.32. C12H13NO3 requires C,
65.74; H, 5.98; N, 6.39%]; Rf (toluene/acetone 10: 2) 0.47;
nmax (KBr) 1715 cm21; dH (200 MHz, CDCl3) 7.20±7.65
(4H, m, Ar), 3.77 (3H, s, OMe), 3.69 (3H, s, OMe), 3.50
(1H, t, Jˆ6.7 Hz, C4-H), 3.01 (2H, d, Jˆ6.7 Hz, C3-H).
2-Chloro-5-methoxy-1-(4-methylphenyl)-1H-3-pyrrolcarb-
aldehyde 4b (1.62 g, 65%) as colorless needles, mp 1788C;
[Found: C, 62.50; H, 4.82; Cl, 13.95; N, 5.44. C13H12ClNO2
requires C, 62.53; H, 4.84; Cl, 14.20; N 5.61%]; Rf (toluene/
acetone 10: 2) 0.39; nmax (KBr) 1670 cm21; dH (200 MHz,
CDCl3) 10.32 (1H, s, CHO), 6.67±7.28 (4H, m, Ar), 6.30
(1H, s, C4-H), 3.80 (3H, s, OMe), 2.38 (3H, s, Me); dC
(100.6 MHz, CDCl3) 184.32, 158.82, 140.65, 136.74,
135.21, 132.38, 120.26, 112.21, 93.03, 56.18, 21.01.
Arylnitrones 3a±c
General procedure: Saturated solution of 1-aryl-3-bromo-5-
methoxypyrrol-2-one (0.05 mmol), was obtained in quanti-
tative yield by brominating of 2 with one mole of bromine in
acetic acid (40 mL) at room temperature. The clear solution
was poured into water (50 mL) to give a white solid which
can be used as or can be crystallized from EtOH, and nitro-
sobenzene (5.35 g, 0.05 mmol) in EtOH (10 mL) are mixed
and stirred at room temperature for 6 h. The product was
collected by suction to give 62±73% yield of 3a±c, which
recrystallize from benzene.
2-Chloro-5-methoxy-1-(4-methoxyphenyl)-1H-3-pyrrol-
carbaldehyde 4c (1.83 g, 69%) as colorless needles, mp
2118C; [Found: C, 58.69; H, 4.52; Cl, 13.10; N, 5.22.
C13H12ClNO3 requires C, 58.77; H, 4.55; Cl, 13.34; N,
5.27%]; Rf (toluene/acetone 10: 2) 0.44; nmax (KBr)
1670 cm21; dH (200 MHz, CDCl3) 10.08 (1H, s, CHO),
6.71±7.78 (4H, m, Ar), 6.35 (1H, s, C4-H), 3.80 (3H, s,
OMe), 3.77 (3H, s, OMe); dC (100.6 MHz, CDCl3)
183.72, 159.08, 145.71, 137.01, 134.82, 129.23, 122.94,
112.87, 92.70, 57.90, 55.78.
[5-Methoxy-2-oxo-1-phenyl-2,3-dihydro-1H-3-pyrrolyl-
dine](phenyl)ammoniumolate 3a (1.82 g, 62%) as color-
less needles, mp 168±1708C; [Found: C, 69.11; H, 4.70; N
9.49. C17H14N2O3 requires C, 69.38; H, 4.79; N, 9.52%]; Rf
(toluene/acetone 10: 2) 0.35; nmax (KBr) 1710 cm21; dH
(200 MHz, CDCl3) 7.27±8.61 (10H, m, 2Ph), 4.46 (1H, s,
C4-H), 3.80 (3H, s, OMe); dC (100.6 MHz, CDCl3) 165.98,
158.07, 156.94, 147.45, 138.91, 132.08, 129.22, 128.33,
127.29, 121.65, 120.55, 86.18, 54.47.
Spiroisoxazolidino-heterocyles 6a±c
General method: A mixture of nitrones 3a±c (1 mmol) and
ethylvinyl ether (7.2 g, 0.1 mol) was allowed to react at
room temperature until the T.L.C. showed the disappear-
ance of the starting nitrone (about 48 h). The excess
of vinylether was evaporated, the residue was simply
crystallized from the EtOH and the spiroisoxazolidino-
heterocyles 6a±c were obtained in nearly quantitative
yield, which recrystallized from EtOH.
[5-Methoxy-1-(4-methylphenyl)-2-oxo-2,3-dihydro-1H-
3-pyrrolyldine](phenyl)ammoniumolate 3b (2.1 g, 68%)
as colorless needles, mp 1788C; [Found: C, 69.97; H, 5.05;
N, 8.95. C18H16N2O3 requires C, 70.12; H, 5.23; N 9.09%];
Rf (toluene/acetone 10: 2) 0.40; nmax (KBr) 1705 cm21; dH
(200 MHz, CDCl3) 7.12±8.60 (9H, m, Ph and Ar), 4.46 (1H,

H. A. A. El-Nabi / Tetrahedron 56 (2000) 3013±3020
3017
3-Ethoxy-8-methoxy-1,7-diphenyl-2-oxa-1,7-diazaspiro-
[4.4]non-8-en-6-one 6a (2.38 g, 65%) as colorless prisms,
mp 1678C; [Found: C, 68.95; H, 6.25; N, 7.73. C21H22N2O4
requires C, 68.84; H, 6.05; N, 7.65%]; Rf (toluene/ace-
tone 10: 2) 0.67; nmax (KBr) 3100, 2890, 1725 cm21; dH
(200 MHz, CDCl3) 7.29±7.84 (10H, m, 2 Ph), 5.69 (1H,
dd, Jˆ3, 6 Hz, C3-H), 3.77 (3H, s, OMe), 3.68 (1H, s, C9-
H), 3.52 (2H, q, Jˆ7 Hz, ester CH2), 2.79±2.94 (2H, dd,
Jˆ3, 6 Hz, CH2), 1.10 (3H, t, Jˆ7 Hz, Me); dC (100.6 MHz,
CDCl3) 171.95, 151.63, 144.82, 134.92, 130.54, 129.67,
127.29, 126.74, 121.29, 120.52, 101.51, 89.59, 63.72,
55.27, 54.77, 41.21, 14.73.
2-[Allyl(methyl)amino]-5-methoxy-1-(4-methylphenyl)-
1H-3-pyrrolecarbaldehyde 9b (2.13 g, 75%) as light
yellow needles, mp 1678C; [Found: C, 71.64; H, 6.91; N,
9.65. C17H20N2O2 requires C, 71.81; H, 7.09; N, 9.85%]; Rf
(toluene/acetone 10: 2) 0.75; nmax (KBr) 1665 cm21; dH
(200 MHz, CDCl3) 9.88 (1H, s, CHO), 6.68±7.21 (4H, m,
Ar), 5.82 (1H, m, CHvCH2), 5.35 (1H, s, C4-H), 5.09, 4.95
(2H, dd, Jˆ17, 5 Hz, CHvCH2), 4.35 (2H, d, Jˆ6.6 Hz,
CH2), 3.87 (3H, s, OMe), 3.02 (3H, s, NMe), 2.35 (3H, s,
Me).
2-[Allyl(methyl)amino]-5-methoxy-1-(4-methoxyphenyl)-
1H-3-pyrrolecarbaldehyde 9c (2.49 g, 83%) as light
yellow needles, mp 1898C; [Found: C, 67.79; H, 6.55; N,
9.12. C17H20N2O3 requires C, 67.98; H, 6.71; N, 9.33%]; Rf
(toluene/acetone 10: 2) 0.77; nmax (KBr) 1665 cm21; dH
(200 MHz, CDCl3) 9.78 (1H, s, CHO), 6.74±7.32 (4H, m,
Ar), 5.90 (1H, m, CHvCH2), 5.25 (1H, s, C4-H), 5.15, 5.04
(2H, dd, Jˆ16, 5 Hz, CHvCH2), 4.25 (2H, d, Jˆ7 Hz,
CH2), 3.85 (3H, s, OMe), 3.72 (3H, s, OMe), 3.12 (3H, s,
NMe).
3-Ethoxy-8-methoxy-7-(methylphenyl)-1-phenyl-2-oxa-
1,7-diazaspiro[4.4]non-8-en-6-one 6b (2.46 g, 70%) as
colorless prisms, mp 1528C; [Found: C, 69.21; H, 6.24; N,
7.28. C22H24N2O4 requires C, 69.46; H, 6.36; N, 7.36%]; Rf
(toluene/acetone 10: 2) 0.70; nmax (KBr) 3100, 2890,
1720 cm21; dH (200 MHz, CDCl3) 7.21±7.89 (9H, m, Ph
and Ar), 5.73 (1H, dd, Jˆ3, 6 Hz, C3-H), 3.79 (s, 3H,
OMe), 3.72 (1H, s, C9-H), 3.52 (2H, q, Jˆ7 Hz, ester
CH2), 2.80±2.94 (2H, dd, Jˆ3, 6 Hz,CH2), 2.20 (3H, s,
Me), 1.15 (3H, t, Jˆ7 Hz, Me); dC (100.6 MHz, CDCl3)
172.75, 151.23, 145.82, 135.72, 130.22, 129.16, 127.29,
126.97, 121.59, 120.45, 96.89, 91.34, 63.52, 56.07, 54.97,
39.57, 21.65, 14.73.
General method for 9d±f
A solution of allyl bromide (6.0 g, 0.05 mol) and thiourea
(3.81 g, 0.05 mol) in ethanol (60 mL) was re¯uxed for 1 h
then a solution of ethanolic NaOH (4 g in 100 mL) was
added and re¯ux was continued for a further 1 h. The chloro-
aldehyde 4 (34 mmol) was added to the mixture which was
then re¯uxed for 30 min. After addition of water (75 mL) to
the mixture it was extracted with diethylether (3£70 mL),
dried (MgSO4) and evaporated to give 9d±f in 60±74%
yield which was crystallized from ethanol.
3-Ethoxy-8-methoxy-7-(methoxyphenyl)-1-phenyl-2-oxa-
1,7-diazaspiro[4.4]non-8-en-6-one 6c (2.97 g, 75%) as
colorless prisms, mp 1838C; [Found: C, 66.48; H, 6.10; N,
7.13. C22H24N2O5 requires C, 66.65; H, 6.10; N, 7.07%]; Rf
(toluene/acetone 10: 2) 0.72; nmax (KBr) 3100, 2900,
1720 cm21; dH (200 MHz, CDCl3) 6.79±7.35 (9H, m, Ph
and Ar), 5.68 (1H, dd, Jˆ3, 6 Hz, C3-H), 3.75 (3H, s,
OCH3), 3.70 (1H, s, C9-H), 3.69 (3H, s, OMe), 3.52 (2H,
q, Jˆ7 Hz, ester CH2), 2.82±2.90 (2H, dd, Jˆ3, 6 Hz, CH2),
1.25 (3H, t, Jˆ7 Hz, Me); dC (100.6 MHz, CDCl3) 173.59,
152.03, 147.62, 136.44, 131.24, 129.86, 128.12, 126.07,
122.32, 121.11, 96.05, 90.07, 63.45, 57.30, 55.25, 54.62,
40.15, 14.33.
2-(Allylsulfanyl)-5-methoxy-1-phenyl-1H-3-pyrrolecarb-
aldehyde 9d (1.63 g, 60%) as light yellow needles, mp
898C; [Found: C, 65.78; H, 5.43; N, 4.98; S, 11.89.
C15H15NO2S requires C, 65.91; H, 5.53; N, 5.12; S,
11.73%]; Rf (toluene/acetone 10: 2) 0.70; nmax (KBr)
1670 cm21; dH (200 MHz, CDCl3) 10.08 (1H, s, CHO),
7.38±7.57 (5H, m, Ph), 5.75 (1H, m, CHvCH2), 5.60
(1H, s, C4-H), 4.95, 4.85 (2H, dd, Jˆ16, 4, CHvCH2),
3.80 (3H, s, OMe), 3.48 (2H, d, Jˆ7 Hz, CH2S); dC
(100.6 MHz, CDCl3) 185.20, 158.32, 157.22, 135.65,
129.81, 129.61, 126.81, 121.39, 120.87, 112.87, 89.72,
56.66, 33.98.
General method for 9a±c
A mixture of chloroaldehyde 4 (13 mmol) and diallylamine
8a (2.49 g, 35 mmol) in ethanol (40 mL) was re¯uxed for
12 h. The ethanol was removed in vacuo and the residue was
poured into water, then extracted with chloroform
(25 mL£3). The organic layer was dried and the chloroform
was evaporated off. The residue was puri®ed by ¯ash
chromatography (n-hexane:chloroform 5:1) to give 9a±c
in 70±83% yield.
2-(Allylsulfanyl)-5-methoxy-1-(4-methylphenyl)-1H-3-
pyrrolecarbaldehyde 9e (1.86 g, 65%) as light yellow
needles, mp 1138C; [Found: C, 66.92; H, 6.03; N, 4.99; S,
11.23. C16H17NO2S requires C, 66.87; H, 5.96; N, 4.87; S
11.16%]; Rf (toluene/acetone 10: 2) 0.74; nmax (KBr)
1665 cm21; dH (200 MHz, CDCl3) 9.91 (1H, s, CHO),
7.01±7.35 (4H, m, Ar), 5.80 (1H, m, CHvCH2), 5.65
(1H, s, C4-H), 4.80, 4.60 (2H, dd, Jˆ17, 6 Hz,
CHvCH2), 3.85 (3H, s, OMe), 3.25 (2H, d, Jˆ7 Hz,
CH2S), 2.38 (3H, s, Me).
2-[Allyl(methyl)amino]-5-methoxy-1-phenyl-1H-3-pyrrole-
carbaldehyde 9a (1.89 g, 70%) as light yellow needles, mp
1428C; [Found: C, 70.88; H, 6.51; N, 10.18. C16H18N2O2
requires C, 71.09; H, 6.71; N, 10.36%]; Rf (toluene/acetone
10: 2) 0.71; nmax (KBr) 1670 cm21; dH (200 MHz, CDCl3)
9.88 (s, 1H, CHO), 6.58±7.37 (5H, m, Ph), 5.82 (1H, m,
CHvCH2), 5.24 (1H, s, C4-H), 5.14, 4.85 (2H, dd, Jˆ18,
5 Hz, CHvCH2), 4.26 (2H, d, Jˆ6.6 Hz, CH2), 3.93 (3H, s,
OMe), 3.02 (3H, s, NMe); dC (100.6 MHz, CDCl3) 184.92,
149.99, 145.14, 134.86, 131.34, 129.91, 126.67, 133.22,
118.49, 103.26, 90.12, 56.98, 55.46, 39.14.
2-(Allylsulfanyl)-5-methoxy-1-(4-methoxyphenyl)-1H-3-
pyrrolecarbaldehyde 9f (2.25g, 74%) as light yellow
needles, mp 1328C; [Found: C, 63.12; H, 5.44; N, 4.43; S,
10.33. C16H17NO3S requires C, 63.35; H, 5.65; N, 4.62; S,
10.57%]; Rf (toluene/acetone 10: 2) 0.80; nmax (KBr)

3018
H. A. A. El-Nabi / Tetrahedron 56 (2000) 3013±3020
1675 cm21; dH (200 MHz, CDCl3) 9.94 (1H, s, CHO),
7.21±7.45 (4H, m, Ar), 5.65 (1H, s, C4-H), 5.55 (1H, m,
CHvCH2), 5.05, 4.75 (2H, dd, Jˆ17, 5 Hz, CHvCH2),
3.90 (3H, s, OMe), 3.18 (2H, d, Jˆ7 Hz, CH2S), 3.65 (3H,
s, OMe).
139.01, 129.52, 129.23, 127.43, 126.82, 132.90, 122.11,
120.55, 108.28, 71.31, 61.76, 55.98, 40.00, 29.71.
7-Methoxy-6-(4-methylphenyl)-1-phenyl-3a,4,6,8b-tetra-
hydro-1H,3H-pyrrolo[30,20:5,6]thiopyrano[4,3-c]isoxazole
11e (2.46 g, 65%) as pale yellow prisms, mp 168±1698C;
[Found: C, 69.66; H, 5.76; N, 7.32; S, 8.31. C22H22N2O2S
requires C, 69.82; H, 5.86; N, 7.40; S, 8.45%]; Rf (toluene/
acetone 10: 2) 0.41; nmax (KBr) 3040, 2980 cm21; dH
(200 MHz, CDCl3) 6.75±7.55 (9H, m, Ph and Ar) 4.69
(1H, d, Jˆ6 Hz, C9-H), 4.50 (1H, s, C8-H), 4.12 (2H, dd,
Jˆ13, 8 Hz, C3-H), 3.90 (3H, s, OMe), 3.24±3.30 (2H, m,
CH2S), 2.45 (1H, m, C3a-H), 2.38 (3H, s, Me).
1-Aryl-7-methoxy-6-phenyl-3,3a,4,5,6,8b-hexahydro-
1H-isoxazolo[3,4-d]pyrolo[2,3-b]pyridine 11a±f
General method: To a stirred solution of aldehyde 9
(1 mmol) in absolute EtOH (15 mL) is added dropwise a
solution of phenylhydroxylamine freshly prepared
(109 mg 1 mmol). The mixture is then re¯uxed gently for
3 h. The solid was ®ltered off, washed with EtOH and dried
to give 11a±f in 60±80% yield.
7-Methoxy-6-(4-methoxyphenyl)-1-phenyl-3a,4,6,8b-tetra-
hydro-1H,3H-pyrrolo[30,20:5,6]thiopyrano[4,3-c]isoxazole
11f (2.64 g, 67%) as pale yellow prisms, mp222±2238C;
[Found: C, 66.80; H, 5.52; N, 7.12; S, 8.01. C22H22N2O3S
requires C, 66.98; H, 5.62; N, 7.10; S, 8.13%]; Rf (toluene/
acetone 10: 2) 0.40; nmax (KBr) 3040, 2980 cm21; dH
(200 MHz, CDCl3) 6.76±7.50 (9H, m, Ph and Ar), 4.68
(1H, d, Jˆ6 Hz, C9-H), 4.50 (1H, s, C8-H), 4.17 (2H, dd,
Jˆ13, 8 Hz, C3-H), 3.88 (3H, s, OMe), 3.20±3.28 (2H, m,
CH2S), 2.53 (1H, m, C3a-H), 3.77 (3H, s, OMe).
7-Methoxy-5-methyl-1,6-diphenyl-3,3a,4,5,6,8b-hexahy-
dro-1H-isoxazolo[3,4-d]pyrolo[2,3-b]pyridine 11a (2.86 g,
79%) as pale yellow prisms, mp 214±2158C; [Found: C,
73.28; H, 6.62; N, 11.89. C22H23N3O2 requires C, 73.11;
H, 6.41; N, 11.63%]; Rf (toluene/acetone 10: 2) 0.45; nmax
(KBr) 3050, 2980 cm21; dH (200 MHz, CDCl3) 6.84±7.75
(10H, m, 2Ph), 4.18 (1H, d, Jˆ5 Hz, C9-H), 3.93 (1H, dd,
Jˆ16, 7 Hz, C3-H), 3.88 (1H, s, C8-H), 3.83 (1H, dd, Jˆ16,
7 Hz, C3-H), 3.80 (3H, s, OMe), 3.67 (1H, dd, Jˆ12, 6 Hz,
C4-H), 3.60 (1H, dd, Jˆ12, 6 Hz, C4-H), 3.29 (3H, s, NMe),
2.75 (1H, m, C3a-H).
1-Aryl-2-[allyl(methyl)amine]-5-methoxy-1H-3-pyrrole-
carbaldehydeoxime 13a±f
7-Methoxy-5-methyl-6-(4-methylphenyl)-1-phenyl-3,3a,4,
5,6,8b-hexahydro-1H-isoxazolo[3,4-d]pyrolo-[2,3-b]pyri-
dine 11b (3 g, 80%) as pale yellow prisms, mp 225±2268C;
[Found: C, 73.78, H, 6.81; N, 11.39. C23H25N3O2 requires C,
73.58; H, 6.71; N, 11.19%]; Rf (toluene/acetone 10: 2) 0.47;
General Method: A solution of the aldehyde 9 (4 mmol) in
ethanol (20 mL) was treated with aqueous NH2OH.HCl and
NaHCO3 (8 mmol each in 10 mL) and stirred overnight at
room temperature. The mixture was extracted with dichloro-
methane (3£25 mL) and the combined extracts were
washed with water (3£25 mL), dried (MgSO4) and evapo-
rated, the residue was crystallized from ethanol to give 65±
70% yield from oxime 13a±f.
n
max (KBr) 3050, 2980 cm21; dH (200 MHz, CDCl3) 6.95±
7.82 (9H, m, Ph and Ar), 4.32 (1H, d, Jˆ5 Hz, C9-H), 4.23
(1H, s, C8-H), 3.97 (1H, dd, Jˆ16, 7 Hz, C3-H), 3.83 (3H, s,
OMe), 3.78 (1H, dd, Jˆ12, 6 Hz, C4-H), 3.76 (1H, dd,
Jˆ16, 7 Hz, C3-H), 3.71 (1H, dd, Jˆ12, 6 Hz, C4-H),
3.35 (3H, s, NMe), 2.75 (1H, m, C3a-H), 2.32 (3H, s, Me).
2-[Allyl(methyl)amine]-5-methoxy-1-Phenyl-1H-3-pyrrole-
carbaldehydeoxime 13a (1.97 g, 69%) as colorless needles,
mp 1258C; [Found: C, 67.11; H, 6.52, N, 14.59. C16H19N3O2
requires C, 67.35; H, 6.71; N, 14.73%]; Rf (toluene/ace-
tone 10: 2) 0.75; nmax (KBr) 3400±3200, 1640 cm21; dH
(200 MHz, CDCl3) 10.76 (1H, bs, OH), 7.23±7.30 (5H, m,
Ph), 7.47 (1H, s, CHvN), 5.94 (1H, m, CHvCH2), 5.02,
5.12 (2H, dd, Jˆ10, 5 Hz, CHvCH2), 4.93 (1H, s, C4-H),
3.90 (2H, d, Jˆ7 Hz, CH2), 3.90 (3H, s, OMe), 3.04 (3H, s,
NMe), dC (100.6 MHz, CDCl3) 149.95, 146.55, 145.58,
135.83, 133.02, 130.52, 128.55, 126.67, 118.79, 113.67,
89.92, 59.10, 53.30, 40.85.
7-Methoxy-6-(4-methoxyphenyl)-5-methyl-1-phenyl-3,3a,
4,5,6,8b-hexahydro-1H-isoxazolo[3,4-d]pyrolo-[2,3-b]-
pyridine 11c (3.12 g, 80%) as pale yellow prisms, mp 205±
2068C; [Found: C, 70.51; H, 6.40; N, 10.70. C23H25N3O3
requires C, 70.57; H, 6.44; N, 10.73%]; Rf (toluene/ace-
tone 10: 2) 0.43; nmax (KBr) 3050, 2980 cm21; dH
(200 MHz, CDCl3) 6.85±7.75 (9H, m, Ph and Ar), 4.41
(1H, d, Jˆ5 Hz, C9-H), 4.29 (1H, s, C8-H), 3.91 (1H, dd,
Jˆ16, 7 Hz, C3-H), 3.86 (3H, s, OMe), 3.80 (1H, dd, Jˆ16,
7 Hz, C3-H), 3.75 (3H, s, OMe), 3.69 (1H, dd, Jˆ12, 6 Hz,
C4-H), 3.67 (1H, dd, Jˆ12, 6 Hz, C4-H), 3.47 (3H, s, NMe),
2.62 (1H, m, C3a-H).
2-[Allyl(methyl)amine]-5-methoxy-1-(4-methylphenyl)-
1H-3-pyrrolecarbaldehydeoxime 13b (2.16 g, 72%) as
colorless needles, mp 1678C; [Found: C, 67.93; H, 6.96;
N, 13.89. C17H21N3O2 requires C, 68.21; H, 7.07; N,
14.04%]; Rf (toluene/acetone 10: 2) 0.77; nmax (KBr)
7-Methoxy-1,6-diphenyl-3a,4,6,8b-tetrahydro-1H,3H-
pyrrolo[30,20:5,6]thiopyrano[4,3-c]isoxazole 11d (2.2 g,
60%) as pale yellow prisms, mp 182±1848C; [Found: C,
68.95; H, 5.45; N, 7.55; S, 8.69. C21H20N2O2S requires C,
69.21; H, 5.53; N, 7.69; S, 8.80%]; Rf (toluene/acetone 10:
2) 0.38; nmax (KBr) 3040, 2980 cm21; dH (200 MHz,
CDCl3) 6.57±7.55 (10H, m, 2Ph), 4.65 (1H, d, Jˆ6 Hz,
C9-H), 4.56 (1H, s, C8-H), 4.0 (2H, dd, Jˆ13, 7.5 Hz,
C3-H), 3.85 (3H, s, OMe), 3.30 (2H, m, CH2S), 2.50 (1H,
m, C3a-H); dC (100.6 MHz, CDCl3) 158.30, 149.61, 146.32,
3400±3200, 1635 cm21
.
2-[Allyl(methyl)amine]-5-methoxy-1-(4-methoxyphenyl)-
1H-3-pyrrolecarbaldehydeoxime 13c (2.06 g, 65%) as
colorless needles, mp 1818C; [Found: C, 64.53; H, 6.63;
N, 13.18. C17H21N3O3 requires C, 64.74; H, 6.71; N,
13.32%]; Rf (toluene/acetone 10: 2) 0.80; nmax (KBr)
3400±3200, 1635 cm21
.

H. A. A. El-Nabi / Tetrahedron 56 (2000) 3013±3020
3019
2-(Allylsulfanyl)-5-methoxy-1-phenyl-1H-3-pyrrolecarb-
aldehydeoxime 13d (1.7 g, 59%) as colorless needles, mp
1428C; [Found: C, 62.53; H, 5.60; N, 9.80; S, 10.89.
C15H16N2O2S requires C, 62.48; H, 5.59; N, 9.71; S,
11.12%]; Rf (toluene/acetone 10: 2) 0.68; nmax (KBr)
prisms, mp 2128C; [Found: C, 62.73; H, 4.79; N, 9.80; S,
10.95. C15H14N2O2S requires C, 62.92; H, 4.93; N, 9.78; S,
11.20%]; Rf (toluene/acetone 10: 2) 0.37; nmax (KBr)
1610 cm21; dH (400 MHz, CDCl3) 6.64±7.42 (5H, m, Ph),
5.48 (1H, s, C8-H), 4.83 (1H, d, Jˆ4 Hz, C3-H), 4.75 (1H,
d, Jˆ9 Hz, C3-H), 4.03 (1H, m, C3a-H), 3.95 (3H, s, OMe),
3.61 (1H, d, Jˆ14 Hz, C4-H), 3.45 (1H, d, Jˆ6 Hz, C4-H);
dC (100.6 MHz, CDCl3) 152.40, 151.48, 151.40, 145.76,
137.70, 129.10, 128.92, 125.87, 121.43, 66.52, 56.30,
47.81, 24.65.
3400±3200, 1640 cm21
.
2-(Allylsulfanyl)-5-methoxy-1-(4-methylphenyl)-1H-3-
pyrrolecarbaldehydeoxime 13e (1.79g, 59%) as colorless
needles, mp 1658C; [Found: C, 63.42; H, 5.92; N, 9.03; S,
10.47. C16H18N2O2S requires C, 63.55; H, 6.00; N, 9.26; S,
10.60%]; Rf (toluene/acetone 10: 2) 0.70; nmax (KBr) 3400±
7-Methoxy-6-(4-methylphenyl)-3a,4-dihydro-3H,6H-
pyrrolo[30,20:5,6]thiopyrano[4,3-c]isoxazole 15e (2.85 g,
95%) as colorless prisms, mp 1858C; [Found: C, 63.86; H,
5.22; N, 9.28; S, 10.52. C16H16N2O2S requires C, 63.98; H,
5.37; N, 9.33; S, 10.67%]; Rf (toluene/acetone 10: 2) 0.43;
nmax (KBr) 1615 cm21; dH (400 MHz, CDCl3) 7.10±7.40
(4H, m, Ar), 5.50 (1H, s, C8-H), 4.85 (1H, d, Jˆ4 Hz, C3-
H), 4.70 (1H, d, Jˆ9 Hz, C3-H), 4.13 (1H, m, C3a-H), 3.90
(3H, s, OMe), 3.55 (1H, d, Jˆ14 Hz, C4-H), 3.40 (1H, d,
Jˆ6 Hz, C4-H), 2.38 (3H, s, Me); dC (100.6 MHz, CDCl3)
153.45, 152.32, 150.30, 147.60, 136.18, 135.47, 131.16,
129.42, 121.50, 66.30, 55.90, 47.75, 24.65, 21.01.
3200, 1640 cm21
.
2-(Allylsulfanyl)-5-methoxy-1-(4-methoxyphenyl)-1H-3-
pyrrolecarbaldehydeoxime 13f (2.17g, 68%) as colorless
needles, mp 1338C; [Found: C, 60.21; H, 5.43; N, 8.89; S,
9.89. C16H18N2O3S requires C, 60.36; H, 5.70; N, 8.80; S,
10.07%]; Rf (toluene/acetone 10: 2) 0.73; nmax (KBr) 3400±
3200, 1640 cm21
.
Aqueous NaOCl (13%, 4 mol) was added dropwise at 08C to
a vigorously stirred solution of the oxime 13 (2.75 mmol) in
chloroform (30 mL). After the mixture had been stirred
overnight at room temperature the organic phase was
separated, dried (MgSO4), and evaporated, the crude
product 15a±f in nearly quantitative yield which then was
crystallized from cyclohexane/chloroform (3:1).
7-Methoxy-6-(4-methoxyphenyl)-3a,4-dihydro-3H,6H-
pyrrolo[30,20:5,6]thiopyrano[4,3-c]isoxazole 15f (3.04 g,
96%) as colorless prisms, mp 2588C; [Found: C, 60.54; H,
4.96; N, 8.80; S, 9.85. C16H16N2O3S requires C, 60.74; H,
5.10; N, 8.85; S, 10.13%]; Rf (toluene/acetone 10: 2) 0.47;
nmax (KBr) 1615 cm21; dH (400 MHz, CDCl3) 6.88±7.22
(4H, m, Ar), 5.55 (1H, s, C8-H), 4.85 (1H, d, Jˆ4 Hz, C3-
H), 4.70 (1H, d, Jˆ9 Hz, C3-H), 4.15 (1H, m, C3a-H), 3.95
(3H, s, OMe), 3.80 (3H, s, OMe), 3.68 (1H, d, Jˆ14 Hz, C4-
H), 3.50 (1H, d, Jˆ6 Hz, C4-H); dC (100.6 MHz, CDCl3)
153.09, 152.67, 151.88, 147.64, 139.56, 130.88, 126.87,
126.72, 123.32, 68.82, 55.85, 48.25, 25.20.
7-Methoxy-5-methyl-6-phenyl-3a,4,5,6-tetrahydro-3H-
isoxazolo[3,4-d]pyrrolo[2,3-b]pyridine 15a (2.64 g, 93%)
as colorless prisms, mp 1558C; [Found: C, 67.63; H, 5.89;
N, 14.68. C16H17N3O2 requires C, 67.83; H, 6.05; N,
14.83%]; Rf (toluene/acetone 10: 2) 0.47; nmax (KBr)
1610 cm21; dH (200 MHz, CDCl3) 7.28±7.75 (5H, m, Ph),
4.95 (1H, s, C8-H), 4.68 (2H, dd, Jˆ14, 8 Hz, C3-H), 3.95
(3H, s, OMe), 3.65 (1H, m, C3a-H), 3.30 (3H, s, NMe), 3.27
(2H, dd, Jˆ8, 3 Hz, C4 -H), dC (100.6 MHz, CDCl3)
152.08, 150.47, 146.10, 140.55, 137.74, 129.10, 126.52,
120.61, 104.27, 72.73, 55.98, 53.42, 43.89, 38.45.
Acknowledgements
The author is deeply grateful to Prof. Dr G. Kollenz,
Institute for Organic Chemistry, Karl-Fransenz University,
Graz, Austria, for valuable discussions and continuous
effective support.
7-Methoxy-5-methyl-6-(4-methylphenyl)-3a,4,5,6-tetra-
hydro-3H-isoxazolo[3,4-d]pyrrolo[2,3-b]pyridine
15b
(2.74 g, 92%) as colorless prisms, mp 1798C; [Found: C,
68.52, H, 6.29; N, 14.00. C17H19N3O2 requires C, 68.67;
H, 6.44; N, 14.13%]; Rf (toluene/acetone 10: 2) 0.50; nmax
(KBr) 1610 cm21; dH (200 MHz, CDCl3) 7.42±7.75 (4H, m,
Ar), 4.90 (1H, s, C8-H), 4.68 (2H, dd, Jˆ14, 7 Hz, C3-H),
3.90 (3H, s, OMe), 3.69 (1H, m, C3a-H), 3.30 (3H, s, NMe),
3.27 (2H, dd, Jˆ8, 3 Hz, C4-H), 2.38 (3H, s, Me).
References
1. (a) El-Nabi, H. A. A.; Kollenz, G.; Monatsh. Chem., 1997, 128,
381±387; (b) Fulloon, B.; El-Nabi, H. A. A.; Kollenz G.;
Wentrup, C., Tetrahedron Lett., 1995 36, 6547±6550.
2. (a) El-Nabi, H. A. A., Tetrahedron, 1997, 53, 1813±1822;
(b) El-Nabi, H. A. A., J. Chem. Res. (S), 1996, 466±467.
3. Review: Kollenz, G.; Heilmayer, W., Trends in Heterocycl.
Chem., 1993, 3, 379±395.
7-Methoxy-6-(4-methoxyphenyl)-5-methyl-3a,4,5,6-tetra-
hydro-3H-isoxazolo[3,4-d]pyrrolo[2,3-b]pyridine
15c
(2.98 g, 95%) as colorless prisms, mp 2038C; [Found: C,
64.89; H, 5.95; N, 13.20. C17H19N3O3 requires C, 65.16;
H, 6.11; N, 13.41%]; Rf (toluene/acetone 10: 2) 0.43; nmax
(KBr) 1610 cm21; dH (200 MHz, CDCl3) 7.40±7.70 (4H, m,
Ar), 4.90 (1H, s, C8-H), 4.65 (2H, dd, Jˆ14, 8 Hz, C3-H),
3.90 (3H, s, OMe), 3.75 (3H, s, OMe), 3.69 (1H, m, C3a-H),
3.32 (3H, s, NMe), 3.27 (2H, dd, Jˆ8, 4 Hz, C4-H).
4. Kollenz, G.; Penn, G.; Theuer, R.; Fabian, W. M. F.; El-Nabi,
H. A. A.; Zhang, X.; Peters, K.; Peters, E. M.; von Schnering, H. G.
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7-Methoxy-6-phenyl-3a,4-dihydro-3H,6H-pyrrolo[30,20:5,6]-
thiopyrano[4,3-c]isoxazole 15d (2.69 g, 94%) as colorless
7. For a review see: Desimoni, G.; Tacconi, G., Chem. Rev. 1975,
75 (6), 651±692.

3020
H. A. A. El-Nabi / Tetrahedron 56 (2000) 3013±3020
8. For a review see: Bianchi, G.; Micheli, C. D. E.; Gandol®, R.,
1,3-Dipolar Cycloadditions Involving XvY Groups, in The
Chemistry of Functional Groups, Supplement A, Patai, S., Ed.;
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Trans. 1, 1988, 607; (b) Oppolzer, W.; Keller, K. Tetrahedron
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Chem. Soc., 1959, 81, 6334±6335.
10. Lee, G. A. Synthesis 1982, 508, 509.
9. (a) Prajapati, D.; Bhuyan, P.; Sandhu J. S. J. Chem. Soc. Perkin