Preparation and reductive transformations of vinylogous sulfonamides (β-sulfonyl enamines), and application to the synthesis of indolizidines

Article abstract of DOI:10.1039/b413379j

Condensation between the methiodide salts of 1-alkylpyrrolidine-2-thiones and ethyl [(4-methylphenyl)sulfonyl]acetate or 1-[(4-methylphenyl)sulfonyl]propan-2-one afforded several 2-{[(4-methylphenyl)sulfonyl]methylene}pyrrolidines in good yield. These β-sulfonyl enamines are sufficiently nucleophilic for cyclisation with internal electrophiles to give sulfone-substituted indolizines, potentially useful scaffolds for alkaloid synthesis. The carbon-carbon double bond in vinylogous sulfonamides was reduced stereoselectively either by catalytic hydrogenation or by treatment with sodium borohydride to yield β-sulfonyl amines. The sulfone group in β-acyl-β-sulfonyl enamines could be removed by hydrogenolysis with sodium amalgam in THF-methanol to give enaminones.

Full text of DOI:10.1039/b413379j

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A R T I C L E
Preparation and reductive transformations of vinylogous
sulfonamides (b-sulfonyl enamines), and application to the synthesis
of indolizidines
Joseph P. Michael,* Charles B. de Koning, Tshepo J. Malefetse and Ibrahim Yillah
Molecular Sciences Institute, School of Chemistry, University of the Witwatersrand,
Johannesburg, P.O. Wits 2050, South Africa. E-mail: jmichael@aurum.wits.ac.za;
Fax: +27 (0)11 717-6749; Tel: +27 (0)11 717-6753
Received 2nd September 2004, Accepted 4th October 2004
First published as an Advance Article on the web 4th November 2004
Condensation between the methiodide salts of 1-alkylpyrrolidine-2-thiones and ethyl
[(4-methylphenyl)sulfonyl]acetate or 1-[(4-methylphenyl)sulfonyl]propan-2-one afforded several
2-{[(4-methylphenyl)sulfonyl]methylene}pyrrolidines in good yield. These b-sulfonyl enamines are sufficiently
nucleophilic for cyclisation with internal electrophiles to give sulfone-substituted indolizines, potentially useful
scaffolds for alkaloid synthesis. The carbon–carbon double bond in vinylogous sulfonamides was reduced
stereoselectively either by catalytic hydrogenation or by treatment with sodium borohydride to yield b-sulfonyl
amines. The sulfone group in b-acyl-b-sulfonyl enamines could be removed by hydrogenolysis with sodium amalgam
in THF–methanol to give enaminones.
sation with relatively acidic compounds such as nitromethane
Introduction
or 1,3-dicarbonyl compounds 4 (Y, Z = CO2Rꢀ, COMe, CN,
Enaminones (b-acylated enamines; vinylogous amides, ure-
NO2) to produce b-substituted enamines.13 We envisaged that
=
=
thanes and ureas) of general structure N–C C–C O are readily
prepared intermediates that have found widespread application
in organic synthesis because of their versatile reactivity both as
nucleophiles and as electrophiles.1 We ourselves have described
several applications of these systems in the synthesis of alkaloids
this method could be applied to the synthesis of vinylogous
sulfonamides 1 (Y = SO2Ar, Z = H) by using the anions of
suitable a-sulfonyl esters or a-sulfonyl ketones 4 (Y = SO2Ar,
Z = CORꢀ) as nucleophilic partners, followed by removal of the
carbonyl-containing substituent (Scheme 1). A related conden-
sation, involving the reaction of phenylsulfonylacetonitrile with
1-methylpyrrolidine-2-thione in the presence of silver carbonate,
has been reported by Brillon and Sauve´.14
and other nitrogen heterocycles.2–4 Related systems N–C C–Z
=
(Z = CN, NO2) have also featured in our work,2,5 and we have
recently started to explore the applicability of vinylogous sul-
fonamides (Z = SO2Ar) in alkaloid synthesis. By incorporating
the sulfone group into our systems, we intend to take advantage
of two of its most valuable properties: its ability to form a-
sulfonyl anions that one can exploit in a variety of synthetically
useful transformations; and its ready removal by reductive
or, less commonly, oxidative methods once it has served its
purpose.6 While the chemistry of vinylogous sulfonamides and
their tautomers has received limited attention in the literature,7,8
uses in the synthesis of alkaloids are rare. They feature most
prominently in several syntheses of pyrrolidine, piperidine,
indolizidine, quinolizidine and quinolinone alkaloids by Back
and co-workers, where they are encountered as intermediates
formed by the conjugate addition of amines to alkynylsulfones.9
In this article we describe model studies on the synthesis of
vinylogous sulfonamides such as 1, their cyclisation to form
indolizidines, a common motif in alkaloid systems,10 and several
further transformations of the products.
Scheme 1
The thiolactams chosen for these model studies, prepared
from the corresponding lactams by thionation with phos-
phorus pentasulfide, included 1-methylpyrrolidine-2-thione15
5, 3-(2-thioxopyrrolidin-1-yl)propyl acetate16 6 and ethyl 3-
(2-thioxopyrrolidin-1-yl)propanoate4 7. The nucleophilic part-
ners, ethyl [(4-methylphenyl)sulfonyl]acetate17 8 and 1-[(4-
methylphenyl)sulfonyl]propan-2-one18 9, were prepared in 89%
and 98% yields, respectively, by reaction of sodium 4-
methylbenzenesulfinate with ethyl bromoacetate or chloroace-
tone according to reported procedures. Treating the thiolactams
with an excess of iodomethane in dry tetrahydrofuran followed
by removal of the solvent in vacuo afforded the moisture-sensitive
methiodide salts, which were used without further purification.
The salts were then treated with the sulfones in the presence
of base at room temperature (Scheme 2). Optimal yields were
obtained with triethylamine as base and dichloromethane as
solvent, and reactions generally went to completion if left for
ca. 72 h.
Results and discussion
In view of our long-term interest in indolizidine alkaloid
synthesis, the vinylogous sulfonamides chosen as models for
the present studies incorporate the pyrrolidine motif, as shown
in 1 (n = 1; Y = SO2Ar; Z = H). Whereas analogous
enaminones 1 (n = 1, 2; Y = COR, COAr, CO2R; Z = H)
are readily prepared by Eschenmoser condensation (sulfide
contraction) between the corresponding thiolactams 2 (n = 1,
2) and a-halomethylcarbonyl compounds,11 this method fails
with a-halomethylsulfones, which react unusually poorly with
nucleophiles.12 However, if thiolactams are activated by pre-
treatment with electrophiles such as iodomethane, the resulting
thioiminium salts 3 can then undergo Knoevenagel-like conden-
Excellent yields of products 10 and 11 (>90%) were ob-
tained from the reaction of the sulfonyl ester 8 with thiones
5 and 6, respectively. The products were obtained as sin-
gle geometric isomers—probably, for steric reasons, the (E)-
isomers as illustrated, although efforts to establish the geometry
3 5 1 0
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 5 1 0 – 3 5 1 7
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
©

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Scheme 3 Reagents and conditions: i, K2CO3, MeOH, rt, 1 h (96%); ii,
LiAlH4, THF, rt, 15 h (94%); iii, PPh3, Im, I2 MeCN, reflux, 2 h (80%); iv,
KOH, EtOH, reflux, 30 min, then HCl; v, K2CO3, Ac2O, MeCN, 50 ◦C,
2 h, rt, 21 h (71% over 2 steps).
Scheme 2 Reagents and conditions: i, MeI, THF, 0 ◦C, 1–17 h; ii, add 8
or 9, NEt3, CH2Cl2, rt, 72 h (yields: 10, 90%; 11, 95%; 12 + 15, 11% +
81%; 13 + 16, 5% + 81%; 14 + 17, 5% + 70%); iii, TFA, 80–90 ◦C,
30 min (yields: 15, 85%; 16, 87%; 17, 92%).
When the alcohol was treated with iodine, triphenylphosphine
and imidazole in boiling acetonitrile for 2 h,21 the desired
bicyclic product, 8-[(4-methylphenyl)sulfonyl]-1,2,3,5,6,7-hexa-
hydroindolizine 20, was obtained via the detectable but un-
isolated iodoalkyl intermediate as a crystalline solid in 80%
yield. For the acylative cyclisation, the ester group of 17 was
hydrolysed with ethanolic potassium hydroxide solution, and
the crude potassium carboxylate was heated with acetic an-
hydride in acetonitrile at 50 ◦C. Cyclisation of the mixed anhy-
dride intermediate gave 8-[(4-methylphenyl)sulfonyl]-2,3,5,6-
tetrahydroindolizin-7(1H)-one 21 in 71% overall yield.
by NMR spectroscopic methods gave ambiguous results.
However, attempts to remove the ester group by hydrolysis
and decarboxylation failed. With the keto sulfone 9, the
expected products 12–14, formed as single geometric isomers
and again assumed to be (E) for steric reasons, were always
accompanied by the vinylogous sulfonamides 15–17, reflecting
spontaneous deacetylation under the reaction conditions. The
relative amounts of the two products varied from reaction to
reaction, the amount of deacylated product increasing with
time. However, the combined yield of the products was in
general high. Spontaneous deacetylation has previously been
observed with related products derived by condensing lactim
ethers with ethyl acetoacetate or acetylacetone,19,20 and can in
fact be promoted by treatment with trifluoroacetic acid. In our
hands, the acetyl groups could also be removed easily and cleanly
from compounds 12–14 by treating them with trifluoroacetic
If vinylogous sulfonamides are to be effective intermediates for
alkaloid synthesis, then two additional transformations require
=
investigation: the reduction of the C C double bond, and
the removal of the sulfonyl substituent. We have previously
achieved the reduction of various enaminones by catalytic
hydrogenation or upon treatment with complex metal hydrides.2
In the present work, we found that catalytic hydrogenation of the
simple monocyclic compounds 15 and 16 required some forcing,
eventually being accomplished at a pressure of 7.5–10 atm in
glacial acetic acid over platinum dioxide. The tertiary amines
22 and 23 were isolated in yields of 84% and 98%, respectively.
Reduction of 15 with sodium borohydride in methanol also gave
22, but in 68% yield, whereas the reduction of the acetoxypropyl
compound 16 under these rather basic conditions not only
reduced the alkene bond but also cleaved the acetate from the
side chain to give alcohol 24 in 85% yield.
◦
acid at 80–90 C for 30 min. The overall yields of compounds
15–17 by this two-step condensation–deacetylation process were
in the range 74–90%. More conveniently but less efficiently, if
the mixture of products from the condensation reaction was not
separated, but instead treated immediately with trifluoroacetic
acid, the overall yields of 15–17 were 5–10% lower. In addition, if
the condensation between 9 and the methiodide salts was carried
out in dichloromethane with potassium carbonate as base, the
deacylated products were isolated almost exclusively, although
also in diminished yield. The illustrated (E)-geometry of the
deacylated products 15–17 was inferred from the chemical shift
of the ring protons at C-3 (ca. d 3.0), the downfield shift of about
0.5 ppm relative to a (Z)-analogue7 arising from the anisotropic
deshielding effect of the sulfonyl group. This phenomenon is
With potential alkaloid precursors such as the sulfonylated
indolizines 20 and 21, the reduction of the double bond must be
stereoselective, especially if additional substituents are present
on the bicyclic nucleus. Our previously published work includes
examples of stereocontrolled reduction of analogous bicyclic
vinylogous urethanes22 and cyanamides.5 We found that the
expected cis-selective hydrogenation of bicyclic vinylogous sul-
fonamide 20 under similar conditions to those described above
afforded compound 25, a crystalline solid, in 65% yield. In the 1H
NMR spectrum, the signals for the two methine hydrogen atoms
showed a mutual coupling constant of ca. 4.6 Hz, confirming
that they do not share a trans-diaxial relationship. Somewhat
surprisingly in view of our experience with vinylogous urethanes,
the identical product was obtained in 75% yield when the reduc-
tion was performed with sodium borohydride in methanol. In
this case, however, the trans-dihydrogenated diastereomer 26 was
also obtained as a minor product (7%). Interestingly, in a single
attempt at oxidative removal of the sulfone from 25 by treatment
with n-butyllithium and bis(trimethylsilyl) peroxide,23 only the
trans-product 26 was recovered in 84% yield, indicating an easy
base-induced epimerisation. We have previously experienced
similar epimerisations with alkyl indolizidine-8-carboxylates4,22
and quinolizidine-1-carbonitrile.5 The equatorial disposition
11a
well precedented with related (E)- and (Z)-enaminones. It
should be noted that attempts to purify the acetyl products
12–14 were usually pointless, as further handling encouraged
decomposition; lactams 18 were frequently detected in the NMR
spectra after attempted purification.
With compounds 16 and 17 in hand, the next objective was
to examine whether the vinylogous sulfonamide unit displayed
sufficient “enamine” character to participate in intramolecular
cycloalkylation and cycloacylation, respectively, to produce
hexahydroindolizine systems. However, because the acetate
substituent of the former was not expected to function as a
leaving group, an alternative was sought. Hydrolysis of 16 with
potassium carbonate in methanol afforded the corresponding
alcohol 19 as a brownish oil in 96% yield (Scheme 3). Compound
19 could also be obtained in 94% yield by reducing ethyl
3-((2E)-2-{[(4-methylphenyl)sulfonyl]methylene}pyrrolidin-
1-yl)propanoate 17 with lithium aluminium hydride in THF
at room temperature for 15 h; remarkably, the vinylogous
sulfonamide was not reduced under these conditions (vide infra).
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 5 1 0 – 3 5 1 7
3 5 1 1

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of the sulfone substituent in 26 presumably makes this the
thermodynamically preferred isomer.
(conventional columns) or Whatman Partisil Prep 40, particle
size 0.040–0.063 mm (flash columns). FTIR spectra were
recorded on Bruker Vector 22 or Bruker IFS 25 spectrometers.
NMR spectra were recorded on a Bruker AC-200 spectrometer
The oxoindolizidine 21 proved to be completely resistant to
catalytic hydrogenation. However, with sodium borohydride in
methanol, a single diastereomeric product was isolated as a
clear oil in 64% yield, the ketone also undergoing reduction
under these conditions. It was not possible to assign the stereo-
chemistry unambiguously from the NMR spectrum because of
overlapping signals, but thermodynamic considerations suggest
structure 27, in which the substituents on the trans-fused
indolizidine nucleus occupy equatorial positions.
1
(200.13 MHz for H, 50.32 MHz for 13C) or a Bruker DRX
1
400 (400.132 MHz for H, 100.625 MHz for 13C). CDCl3 was
used as solvent and TMS as internal standard. DEPT and CH-
correlated spectra were routinely used for assignment of signals.
J values are given in Hz. High-resolution mass spectra were
recorded at 70 eV on a VG 70 SEQ mass spectrometer with a
MASPEC II data system.
While reductive removal of sulfones from saturated carbon
sites is a common synthetic transformation,24 there are fewer
reported examples of the hydrogenolysis of alkenylsulfones, and
apparently none involving vinylogous sulfonamides. Although
we explored several methods for removing the sulfone group
from several of our vinylogous sulfonamides, the most suc-
cessful involved treatment with sodium amalgam and disodium
hydrogen phosphate in THF–methanol at ambient temperature,
according to a procedure devised by Trost et al.25 Under these
conditions 10 and 21 yielded the corresponding desulfonylated
products 28 and 29 in yields of 86% and 77%, respectively,
while the acetate 11 underwent concomitant ester hydrolysis
to give the alcohol 30 in 87% yield. Products 28 and 30 were
once again obtained as (E)-isomers; but this finding implies
nothing about the geometry of precursors 10 and 11, since
it is known that stereochemistry is not necessarily preserved
in the desulfonylation of vinylsulfones with metal amalgams.26
In these three examples, the products are all comparatively
stable enaminones, the spectroscopic data for which agreed
with those published elsewhere. Some attempts to desulfonylate
vinylogous sulfonamides not bearing the additional stabilising
substituent (e.g., 20) gave ambiguous results, probably because
of the susceptibility of the unstabilised enamine product to
hydrolysis.
General procedure for the preparation of vinylogous sulfonamides
To a stirred solution of 1-alkylpyrrolidine-2-thione (ca. 2–
11 mmol scale) in distilled THF (5–10 cm3) was added excess
iodomethane (1.7–2.0 equiv.) at 0 ◦C. In some cases the a-
(methylthio)iminium salt precipitated out almost immediately,
but in general the reaction was allowed to proceed until TLC
showed complete consumption of the thiolactam (1–17 h). The
solvent and other volatiles were removed by evaporation, and
the residue was dissolved in CH2Cl2 (10–20 cm3). A solution of
the sulfones 8 or 9 (1 equiv.) and dry distilled NEt3 (2 equiv.)
in CH2Cl2 (5–20 cm3) was added, and the reaction mixture was
stirred at ambient temperature for 72 h. The resulting solution
was then washed with water (ca. 50 cm3), and the aqueous phase
was extracted with further portions of CH2Cl2 (3 × 40 cm3).
The combined organic phases were dried (Na2SO4 or MgSO4),
filtered and evaporated in vacuo. The resulting crude products
were when purified by chromatography on silica gel with hexane–
EtOAc mixtures as eluent. The following results were recorded.
Ethyl [(4-methylphenyl)sulfonyl](1-methylpyrrolidin-2-ylid-
ene)acetate 10 (3.17 g, 90%) was obtained from 1-methyl-
pyrrolidine-2-thione 5 (1.26 g, 10.9 mmol) and iodomethane
(2.65 g, 18.7 mmol) in THF (10 cm3) stirred at 0 ◦C for 1 h,
followed by evaporation of the solvent, dissolution in CH2Cl2
(20 cm3) and addition of ethyl [(4-methylphenyl)sulfonyl]acetate
8 (2.64 g, 10.9 mmol) and NEt3 (2.22 g, 21.9 mmol) in CH2Cl2
(20 cm3); needles, mp 102–104 ◦C (from EtOAc–hexane) (Found:
C, 59.0; H, 6.6; N, 4.0. C16H21NO4S requires C, 59.4; H, 6.5; N,
4.3%); Rf 0.24 (EtOAc); mmax (KBr)/cm−1 2983 (m), 2940 (m),
1741 (s), 1684 (s), 1597 (m), 1327 (s), 1303 (m), 1152 (s), 1086
(m), 1026 (m) and 816 (m); dH (200 MHz; CDCl3; Me4Si) 7.79
(2H, d, J 8.3, Ar 2-H/6-H), 7.24 (2H, d, J 8.3, Ar 3-H/5-
H), 4.02 (2H, q, J 7.1, OCH2CH3), 3.67 (2H, t, J 7.2, NCH2),
=
3.41 (2H, t, J 7.8, CH2C ), 2.97 (3H, s, NCH3), 2.39 (3H, s,
ArCH3), 2.08 (2H, quintet, J ca. 7.3, CH2CH2CH2) and 1.09
(3H, t, J 7.1, OCH2CH3); dC (50 MHz; CDCl3; Me4Si) 170.2
=
=
(C O), 163.6 (NC C), 142.5 and 142.0 (ArC), 128.8 and 126.8
=
(ArCH), 94.8 (NC C), 60.2 (OCH2CH3), 57.6 (NCH2), 39.6
In conclusion, we have demonstrated that vinylogous sulfon-
amides of the type that might be suitable for use in alkaloid
synthesis are readily accessible, and are sufficiently nucleophilic
for reaction with internal electrophiles to give useful indolizidine
scaffolds for further elaboration. The carbon–carbon double
bond can be reduced in a stereocontrolled fashion, and the
sulfone group can be removed hydrogenolytically under suitable
conditions. Investigations into the application of these results in
the synthesis of several alkaloids are now under way.
=
(NCH3), 36.2 (CH2C ), 21.4 (ArCH3), 20.3 (CH2CH2CH2) and
14.0 (OCH2CH3); m/z 323 (1%, M+), 178 (16), 155 (47), 105
(19), 91 (100) and 65 (12) (Found: M+, 323.1196. C16H21NO4S
requires 323.1191).
Ethyl [1-(3-acetoxypropyl)pyrrolidin-2-ylidene][(4-methyl-
phenyl)sulfonyl]acetate 11 (1.93 g, 95%) was obtained from 3-
(2-thioxopyrrolidin-1-yl)propyl acetate 6 (1.00 g, 4.97 mmol)
and iodomethane (1.25 g, 8.81 mmol) in THF (10 cm3) stirred
at 0 ◦C for 1 h, followed by evaporation of the solvent,
dissolution in CH2Cl2 (20 cm3) and addition of ethyl [(4-
methylphenyl)sulfonyl]acetate 8 (1.09 g, 4.50 mmol) and NEt3
(1.04 g, 9.29 mmol) in CH2Cl2 (5 cm3); straw-coloured oil; Rf
0.20 (EtOAc–hexane, 1 : 1); mmax (film)/cm−1 2985 (m), 2942
(m), 1741 (s), 1597 (m), 1327 (s), 1303 (m), 1152 (m), 1085 (m),
1026 (m) and 815 (m); dH (400 MHz; CDCl3; Me4Si) 7.77 (2H,
d, J 8.2, Ar 2-H/6-H), 7.24 (2H, d, J 8.1, Ar 3-H/5-H), 4.07
(2H, q, J 7.1, OCH2CH3), 3.99 (2H, t, J 6.1, CH2OAc), 3.60
(2H, t, J 7.2, NCH2), 3.36 (2H, t, J 7.5, NCH2), 3.27 (2H, t,
Experimental
All solvents used for reactions and chromatography were
distilled before use. Tetrahydrofuran (THF) was distilled from
Na/benzophenone, and dichloromethane, acetonitrile and tri-
ethylamine from CaH2. Commercially available chemicals were
used as received. Melting points, recorded on a Reichert
hot-stage microscope apparatus, are uncorrected. TLC was
performed on aluminium-backed Alugram Sil G/UV254 plates
pre-coated with 0.25 mm silica gel 60. Column chromatography
was carried out on silica gel 60, particle size 0.063–0.200 mm
=
J 7.8, CH2C ), 2.38 (3H, s, ArCH3), 1.99 (3H, s, O2CCH3),
2.02–1.91 (4H, m, 2 × CH2CH2CH2) and 1.15 (3H, t, J 7.1,
3 5 1 2
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 5 1 0 – 3 5 1 7

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=
OCH2CH3); dC (100 MHz; CDCl3; Me4Si) 169.9 and 167.2 (2 ×
CDCl3; Me4Si) 189.1 ( CCOCH3), 174.5 (OCOCH3), 170.7
(NC C), 142.4 and 142.3 (ArC), 129.4 and 125.6 (ArCH),
=
=
=
C
O), 163.5 (NC C), 142.0 and 141.3 (ArC), 128.2 and 126.0
=
=
(ArCH), 95.0 (NC C), 61.0 (OCH2CH3), 59.7 (CH2OAc), 54.1
(ring NCH2), 47.3 (chain NCH2), 35.4 (CH2C ), 24.8 and 20.6
104.0 (NC C), 61.5 (CH2OAc), 55.0 (ring NCH2), 49.5 (chain
=
=
=
NCH2), 37.3 (CH2C ), 30.1 ( CCOCH3), 25.1 (CH2CH2OAc),
21.2, 20.7 and 20.1 (ArCH3, OCOCH3 and ring C-4); m/z
(EI) 379 (<1%, M+), 276 (11), 213 (17), 187 (25), 186 (100),
185 (15), 155 (22), 148 (31), 144 (18), 142 (14), 127 (19), 126
(99), 125 (95), 124 (18), 112 (25), 110 (10), 105 (20), 99 (31), 98
(96), 97 (24) and 91 (64) (Found: M+, 379.1448. C19H25NO5S
requires 379.1453). Compound 16: colourless needles, mp
92–93 ◦C (from EtOAc–hexane) (Found: C, 60.5; H, 6.9; N,
4.0. C17H23NO4S requires C, 60.5; H, 6.9; N, 4.15%); Rf 0.29
(EtOAc–hexane, 1 : 1); mmax (CHCl3)/cm−1 3014 (w), 2974 (w),
1736 (m), 1582 (s), 1230 (s), 1132 (m), 1082 (m), and 576 (m);
dH (400 MHz; CDCl3; Me4Si) 7.75 (2H, d, J 8.2, Ar 2-H/6-H),
(2 × CH2CH2CH2), 20.0 and 19.6 (ArCH3 and O2CCH3) and
13.3 (OCH2CH3); m/z (EI) 409 (1.3%, M+), 364 (11), 350 (46),
254 (14), 210 (12), 194 (24), 169 (11), 168 (100), 122 (28), 120
(12) and 91 (16) (Found: M+, 409.1546. C20H27NO6S requires
409.1559).
1-[(4-Methylphenyl)sulfonyl]-1-(1-methylpyrrolidin-2-ylidene)
propan-2-one 12 (0.33 g, 11%) and (2E)-1-methyl-2-{[(4-
methylphenyl)sulfonyl]methylene}pyrrolidine 15 (2.03 g, 81%)
were obtained from 1-methylpyrrolidine-2-thione 5 (1.15 g,
9.98 mmol) and iodomethane (1.52 g, 10.71 mmol) in THF
(10 cm3) stirred at 0 ◦C for 1.5 h, followed by evaporation of
the solvent, dissolution in CH2Cl2 (10 cm3) and addition of
1-[(4-methylphenyl)sulfonyl]propan-2-one 9 (2.12 g, 10.0 mmol)
and NEt3 (2.02 g, 20.0 mmol) in CH2Cl2 (10 cm3). The
compounds were separated by chromatography on silica gel
with hexane–EtOAc mixtures as eluent. Compound 12: clear
oil, Rf 0.52 (EtOAc–hexane, 1 : 1), decomposing on attempted
purification; mmax (film)/cm−1 2926 (w), 1720 (m), 1676 (s),
1598 (m), 1424 (m), 1402 (m), 1320 (s), 1302 (s), 1146 (s), 1086
(m) and 670 (m); dH (200 MHz; CDCl3; Me4Si) discernible
signals at 7.73 (2H, d, J 8.2, Ar 2-H/6-H), 7.28 (2H, d, J 8.2,
Ar 3-H/5-H), 3.78 (2H, t, J 7.4, NCH2), 3.31 (2H, t, J 7.6,
=
7.25 (2H, d, J 8.2, Ar 3-H/5-H), 4.94 (1H, s, CH), 4.04 (2H,
t, J 6.1, CH2OAc), 3.36 (2H, t, J 7.0, NCH2), 3.20 (2H, t, J
7.2, NCH2), 3.00 (2H, t, J 7.8, CH2C ), 2.40 (3H, s, ArCH3),
=
2.05 (3H, s, O2CCH3) and 1.95–1.85 (4H, overlapping quintets,
J ca. 7.2, 2 × CH2CH2CH2); dC (100 MHz; CDCl3; Me4Si)
=
=
170.8 (C O), 161.3 (NC CH), 143.2 and 141.8 (ArC), 129.2
=
and 125.9 (ArCH), 86.8 (NC CH), 61.5 (CH2OAc), 52.6
=
(ring NCH2), 43.1 (chain NCH2), 31.1 (CH2C ), 25.1 (chain
CH2CH2CH2), 21.3 (ArCH3) and 20.8 (OCOCH3) and 20.7
(ring C-4); m/z (EI) 337 (4%, M+), 279 (13), 278 (76), 182(14),
168 (23), 138 (15), 123 (24), 122 (41), 108 (14) 97 (10), 96
(100) and 91 (20) (Found: M+, 337.1336. C17H23NO4S requires
337.1348).
Ethyl 3-(2-{1-[(4-methylphenyl)sulfonyl]-2-oxopropylidene}
pyrrolidin-1-yl)propanoate 14 (28 mg, 5%) and ethyl 3-((2E)-
2-{[(4-methylphenyl)sulfonyl]methylene}pyrrolidin-1-yl)propa-
noate 17 (350 mg, 70%) were obtained from ethyl 3-(2-
=
CH2C ), 2.95 (3H, s, NCH3), 2.40 (3H, s, ArCH3), 2.31 (3H, s,
COCH3) and 2.07 (2H, quintet, J ca. 7.2, CH2CH2CH2); dC
=
=
(50 MHz; CDCl3; Me4Si) 189.3 (C O), 174.4 (NC C), 142.7
=
and 142.3 (ArC), 129.5 and 125.8 (ArCH), 104.0 (NC C),
=
58.2 (NCH2), 40.5 (NCH3), 36.9 (CH2C ), 30.3 (COMe), 21.4
(ArCH3), 20.1 (ring C-4); m/z 293 (<1%, M+), 212 (17), 169
(31), 155 (58), 148 (31), 122 (17), 107 (10), 105 (23), 92 (14), 91
(100) and 89 (11) (Found: M+, 293.1078. C15H19NO3S requires
293.1086). Compound 15: colourless spars, mp 80–81 ◦C
(from EtOAc–hexane); Rf 0.24 (EtOAc–hexane, 1 : 1); mmax
(CHCl3)/cm−1 3012 (w), 2926 (w), 2860 (w), 1588 (s), 1300
(m), 1282 (m), 1132 (m) and 1082 (m); dH (200 MHz; CDCl3;
Me4Si) 7.82 (2H, d, J 8.3, Ar 2-H/6-H), 7.30 (2H, d, J 8.3,
thioxopyrrolidin-1-yl)propanoate
7 (300 mg, 1.49 mmol)
and iodomethane (230 mg, 1.62 mmol) in THF (10 cm3)
stirred at 0 ◦C for 17 h, followed by evaporation of the
solvent, dissolution in CH2Cl2 (15 cm3) and addition of 1-[(4-
methylphenyl)sulfonyl]propan-2-one 9 (320 mg, 1.51 mmol) and
NEt3 (260 mg, 2.57 mmol). The compounds were separated by
chromatography on silica gel with hexane–EtOAc mixtures as
eluent. Compound 14: yellow oil; Rf 0.86 (EtOAc–hexane, 1 : 1),
decomposing on attempted purification; mmax (film)/cm−1 2976
(w), 2938 (w), 2872 (w), 1664 (s), 1606 (s), 1376 (m), 1300
(m), 1268 (m), 1248 (m), 1204 (m), 1144 (s) and 1056 (s); dH
(200 MHz; CDCl3; Me4Si) discernible signals at 7.73 (2H, d,
J 8.2, Ar 2-H/6-H), 7.28 (2H, d, J 8.2, Ar 3-H/5-H), 4.16 (2H,
q, J 7.2, OCH2CH3), 3.78 (2H, t, J 7.3, NCH2), 3.63 (2H, t,
=
Ar 3-H/5-H), 4.87 (1H, s, CH), 3.40 (2H, t, J 7.1, NCH2),
3.05 (2H, t, J 7.8, CH2C ), 2.79 (3H, s, NCH3), 2.43 (3H, s,
ArCH3) and 1.95 (2H, quintet, J ca. 7.4, CH2CH2CH2); dC
(50 MHz; CDCl3; Me4Si) 161.9 (NC CH), 143.4 and 141.8
=
=
=
(ArC), 129.3 and 126.1 (ArCH), 86.7 (NC CH), 54.5 (NCH2),
=
33.2 (NCH3), 31.0 (CH2C ), 21.4 (ArCH3) and 20.8 (ring
C-4); m/z (EI) 252 (12%, M+ + 1), 251 (68, M+), 187 (21), 186
(18), 160 (6), 112 (9), 105 (12), 96 (100), 94 (14) and 91 (12)
(Found: M+, 251.0968. C13H17NO2S requires 251.0980).
=
J 6.7, NCH2), 3.27 (2H, t, J 7.8, CH2C ), 2.72 (2H, t,
J 6.7, CH2CO2Et), 2.41 (3H, s, ArCH3), 2.31 (3H, s, COCH3),
2.08–2.03 (2H, m, J ca. 7.5, CH2CH2CH2) and 1.28 (3H, t,
J 7.2, OCH2CH3); dC (50 MHz; CDCl3; Me4Si) 189.4 (COCH3),
174.1 (CO2Et), 170.7 (NC C), 142.4 and 142.3 (ArC), 129.4
and 125.7 (ArCH), 104.4 (NC C), 60.9 (OCH2CH3), 55.6
3-(2-{1-[(4-Methylphenyl)sulfonyl]-2-oxopropylidene}pyrro-
lidin-1-yl)propyl acetate 13 (50 mg, 6%) and 3-((2E)-2-{[(4-
methylphenyl)sulfonyl]methylene}pyrrolidin-1-yl)propyl acetate
16 (710 mg, 81%) were obtained from 3-(2-thioxopyrrolidin-
1-yl)propyl acetate 6 (525 mg, 2.60 mmol) and iodomethane
=
=
=
(ring NCH2), 47.8 (chain NCH2), 37.3 (CH2C ), 30.3 and 30.2
◦
(740 mg, 5.21 mmol) in THF (10 cm3) stirred at 0 C for 1 h,
(CH2CO2Et and COCH3), 21.3 (ArCH3), 20.1 (CH2CH2CH2)
and 14.0 (OCH2CH3). Compound 17: clear oil, hardening to a
low-melting wax (Found: C, 60.3: H, 6.7; N, 3.9. C17H23NO4S
requires C, 60.5; H, 6.97; N, 4.15%); Rf 0.80 (EtOAc); mmax
(film)/cm−1 2982 (m), 2936 (w), 1728 (s), 1678 (s), 1598 (m), 1496
(m), 1464 (m), 1444 (m), 1426 (m), 1376 (m), 1320 (s), 1292 (s),
1256 (m), 1190 (s), 1156 (s) and 1086 (m); dH (200 MHz; CDCl3;
Me4Si) 7.75 (2H, d, J 8.2, Ar 2-H/6-H), 7.27 (2H, d, J 8.2, Ar
followed by evaporation of the solvent, dissolution in CH2Cl2
(15 cm3) and addition of 1-[(4-methylphenyl)sulfonyl]propan-
2-one 9 (550 mg, 2.59 mmol) and NEt3 (530 mg, 5.24 mmol)
in CH2Cl2 (5 cm3). The compounds were separated by
chromatography on silica gel with hexane–EtOAc mixtures as
eluent. Compound 13: clear oil, Rf 0.56 (EtOAc–MeOH, 10 :
1), 0.31 (EtOAc), decomposing on attempted purification; mmax
(film)/cm−1 2956 (w), 2930 (w), 1738 (s), 1684 (s), 1464 (m),
1428 (m), 1366 (m), 1320 (m), 1290 (m), 1242 (s), 1154 (m), 1086
(m) and 1046 (m); dH (400 MHz; CDCl3; Me4Si) discernible
signals at 7.72 (2H, d, J 8.3, Ar 2-H/6-H), 7.27 (2H, d, J 8.3,
Ar 3-H/5-H), 4.05 (2H, t, J 6.1, CH2OAc), 3.78 (2H, t, J 7.3,
=
3-H/5-H), 4.93 (1H, s, CH), 4.11 (2H, q, J 7.2, OCH2CH3),
3.43 and 3.39 (4H, overlapping t, J ca. 7.0, 2 × NCH2), 2.99
=
(2H, t, J 7.8, CH2C ), 2.54 (2H, t, J 6.9, CH2CO2Et), 2.39
(3H, s, ArCH3), 1.89 (2H, quintet, J ca. 7.4, CH2CH2CH2) and
1.24 (3H, t, J 7.2, OCH2CH3); dC (50 MHz; CDCl3; Me4Si)
=
=
=
NCH2), 3.42 (2H, t, J 6.9, NCH2), 3.29 (2H, t, J 7.8, CH2C ),
2.41 (3H, s, ArCH3), 2.31 (3H, s, CCOCH3), 2.17–2.04 and
171.1 (C O), 160.9 (NC CH), 143.1 and 141.9 (ArC), 129.3
=
=
and 126.0 (ArCH), 87.3 (NC CH), 60.9 (OCH2CH3), 52.9
=
2.06 (5H, overlapping m and s, CH2CH2OAc and O2CCH3)
and 2.01-1.81 (2H, m, ring CH2CH2CH2); dC (100 MHz;
(ring NCH2), 42.0 (chain NCH2), 31.0 and 30.8 (CH2C
and CH2CO2Et), 21.3 (ArCH3), 20.9 (CH2CH2CH2) and 14.1
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 5 1 0 – 3 5 1 7
3 5 1 3

View Online
(OCH2CH3); m/z (EI) 337 (28%, M+), 250 (9), 183 (10), 182
(100), 172(11), 171 (47), 154 (16), 136 (12), 110 (43), 109 (16),
108 (57), 96 (11), 94 (11), 92 (11) and 91 (64) (Found: M+,
337.1341. C17H23NO4S requires 337.1348).
(b) A solution of ethyl 3-((2E)-2-{[(4-methylphenyl)sulfonyl]
methylene}pyrrolidin-1-yl)propanoate 17 (1.50 g, 4.45 mmol)
in THF (20 cm3) was stirred at room temperature with LiAlH4
(0.25 g, 6.59 mmol) under nitrogen for 15 h. Water (0.5 cm3),
aq. NaOH solution (2.0 M; 0.5 cm3) and water (1.5 cm3) were
then sequentially added to the reaction mixture. The solids
were removed by filtration through celite and washed with
CH2Cl2 (20 cm3). Evaporation of the filtrate gave a brown oil,
which was purified by column chromatography with EtOAc
as eluting solvent. 3-((2E)-2-{[(4-Methylphenyl)sulfonyl]
methylene}pyrrolidin-1-yl)propan-1-ol 19 was obtained as a pale
brown oil (1.24 g, 94%); characterisation as described above.
General procedure for the deacetylation of acetylated vinylogous
sulfonamides
A solution of the acetylated vinylogous sulfonamides 12–14 in
trifluoroacetic acid (4 cm3 per mmol of reactant) was heated
at reflux for 30 minutes at 80 ◦C. The reaction mixture was
cooled, made basic with aq. Na2CO3 solution (10%), extracted
with dichloromethane (3 × 30 cm3), dried (MgSO4) and filtered.
The solvent was removed on the rotary evaporator to give the
desired vinylogous sulfonamides as chromatographically pure
compounds. The yields of products 15–17 were 85%, 87% and
92%, respectively. Characterisation of these compounds was
dealt with in the previous section.
1,2,3,5,6,7-Hexahydroindolizin-8-yl 4-methylphenyl sulfone 20
3-((2E)-2-{[(4-Methylphenyl)sulfonyl]methylene}pyrrolidin-
1-yl)propan-1-ol 19 (200 mg, 0.68 mmol) was dissolved in freshly
distilled acetonitrile (10 cm3), to which was added triphenyl-
phosphine (530 mg, 2.02 mmol, 3.0 equiv.), imidazole (230 mg,
3.38 mmol, 5.0 equiv.) and iodine (340 mg, 1.34 mmol, 2.0
equiv.) at about 5 min intervals. This mixture was heated at reflux
under nitrogen for 2 h. The solvent was then removed in vacuo,
and the residue was partitioned between water (30 cm3) and
CH2Cl2 (30 cm3). The aqueous phase was separated and back-
extracted with dichloromethane (2 × 30 cm3). The combined
organic phases were dried (MgSO4) and evaporated to yield
a viscous oil, which was purified by column chromatography
on silica gel with CHCl3–EtOH (5 : 1) as eluent. The
cyclised product, 1,2,3,5,6,7-hexahydroindolizin-8-yl 4-methyl-
phenyl sulfone 20 (150 mg, 80%), was obtained as colourless
needles, mp 105–106 ◦C; Rf 0.35 (EtOAc–hexane, 1 : 1); mmax
(CHCl3)/cm−1 2949 (m), 2849 (m), 1593 (s), 1295 (s), 1143 (m),
1123 (m), 1078 (m), 1000 (w), 811 (m), 660 (m), 590 (m) and
535 (m); dH (400 MHz; CDCl3; Me4Si) 7.69 (2H, d, J 8.2, Ar
2-H/6-H), 7.24 (2H, d, J 8.2, Ar 3-H/5-H), 3.27 (2H, t, J 7.0,
3-H), 3.12–3.09 (4H, m, 1-H and 5-H), 2.39 (3H, s, ArCH3),
2.32 (2H, t, J 6.1, 7-H), 1.92 (2H, quintet, J ca. 7.5, 2-H) and
1.81 (2H, br quintet, J ca. 6.1, 6-H); dC (50 MHz; CDCl3; Me4Si)
155.6 (C-8a), 141.8 and 141.7 (ArC), 129.2 and 126.1 (ArCH),
92.5 (C-8), 52.8 (C-3), 44.6 (C-5), 31.2 (C-1), 22.0, 21.4 and 21.2
3-((2E)-2-{[(4-Methylphenyl)sulfonyl]methylene}pyrrolidin-1-
yl)propyl acetate 16: representative one-pot procedure
A solution of 3-(2-thioxopyrrolidin-1-yl)propyl acetate 6 (0.50 g,
2.48 mmol) in THF (10 cm3) was stirred with iodomethane
(0.63 g, 4.44 mmol) at ice-bath temperature for 1 h. The solvent
was removed in vacuo, and the resulting salt was dissolved
in acetonitrile (15 cm3). 1-[(4-Methylphenyl)sulfonyl]propan-
2-one 9 (0.55 g, 2.59 mmol) and NEt3 (0.52 g, 5.14 mmol)
were added, and the solution was stirred under nitrogen at
room temperature for 14 h. The solvent was removed in vacuo,
and the residue was heated in trifluoroacetic acid (10 cm3) at
80–90 ◦C for 1 h. The reaction mixture was cooled, made
basic with aq. Na2CO3 solution (10%), then extracted with
CH2Cl2 (3 × 30 cm3). The combined organic phases were
dried (MgSO4), filtered and evaporated in vacuo. The residue
was purified by column chromatography on silica gel with
EtOAc–MeOH (10 : 1) as eluent to give 3-((2E)-2-{[(4-
methylphenyl)sulfonyl]methylene}pyrrolidin-1-yl)propyl acetate
16 (0.54 g, 65%) as colourless needles, mp 92–93 ◦C; characteri-
sation as described above.
(C-2, C-6, C-7) and 20.9 (ArCH3); m/z (EI) 278 (13%, M+
+
1), 277 (71, M+), 153 (11), 122 (80), 121 (100), 120 (55) and 91
(8) (Found: M+, 277.1131. C15H19NO2S requires 277.1136).
3-((2E)-2-{[(4-Methylphenyl)sulfonyl]methylene}pyrrolidin-1-yl)
propan-1-ol 19
8-[(4-Methylphenyl)sulfonyl]-2,3,5,6-tetrahydroindolizin-7(1H)-
one 21
(a) A solution of 3-((2E)-2-{[(4-methylphenyl)sulfonyl]methyl-
ene}pyrrolidin-1-yl)propyl acetate 16 (180 mg, 0.53 mmol) in
methanol (15 cm3) containing K2CO3 (1.07 g, 7.74 mmol) was
stirred for 1 h at ambient temperature. Inorganic solids were
removed by filtration and the solvent was evaporated in vacuo.
The dark viscous residue was dissolved in CHCl3 (25 cm3),
and the resulting solution was washed with saturated aq. NaCl
solution (10 cm3). The phases were separated, and the aqueous
layer was back-extracted with CHCl3 (3 × 10 cm3). The organic
extracts were then combined, dried (MgSO4) and evaporated in
vacuo to give the title compound 19 as a chromatographically
pure pale brown oil (150 mg, 96%); Rf 0.23 (EtOAc); mmax
(film)/cm−1 3483 (br m), 2944 (m), 2930 (w), 2876 (w), 1584 (s),
1290 (s), 1276 (s), 1128 (s), 1080 (s) and 846 (m); dH (400 MHz;
CDCl3; Me4Si) 7.74 (2H, d, J 8.2, Ar 2-H/6-H), 7.24 (2H, d,
A
solution of ethyl 3-((2E)-2-{[(4-methylphenyl)sulfonyl]
methylene}pyrrolidin-1-yl)propanoate 17 (300 mg, 0.89 mmol)
in ethanolic KOH solution (1.0 M; 20 cm3) was heated at
reflux under nitrogen for 30 min. The solvent was removed in
vacuo, and the residue was partitioned between water (40 cm3)
and CH2Cl2 (40 cm3). The aqueous phase was washed with
CH2Cl2 (2 × 40 cm3), then acidified to pH 5 with conc. aq.
HCl and extracted with CH2Cl2 (3 × 40 cm3) and EtOAc
(40 cm3). The combined organic phases were dried (Na2SO4)
and evaporated in vacuo to afford 3-((2E)-2-{[(4-methylphenyl)
sulfonyl]methylene}pyrrolidin-1-yl)propanoic acid as a viscous
yellow oil. This oil and acetic anhydride (0.10 g, 1.02 mmol) were
dissolved in acetonitrile (20 cm3), K2CO3 (130 mg, 0.94 mmol)
was added, and the mixture was stirred at 50 ◦C for 2 h and at
room temperature for a further 21 h. The solvent was removed
in vacuo, and the residue was partitioned between water (40 cm3)
and CH2Cl2 (2 × 30 cm3). The organic fractions were combined,
dried (MgSO4) and evaporated to give a brown oil, which was
purified by column chromatography on silica gel with EtOAc–
MeOH (4 : 1) as eluent. 8-[(4-Methylphenyl)sulfonyl]-2,3,5,6-
tetrahydroindolizin-7(1H)-one 21 (183 mg, 71%) was obtained
as a chromatographically pure off-white solid, mp 243–244 ◦C;
Rf = 0.44 (EtOAc–MeOH, 4 : 1); mmax (film)/cm−1 1638 (s), 1573
(s), 1460 (m), 1364 (m), 1299 (m), 1185 (m), 1143 (s), 1080 (m),
=
J 8.2, Ar 3-H/5-H), 4.97 (1H, s, CH), 3.62 (2H, t, J 5.9,
CH2OH), 3.37 (2H, t, J 7.0, NCH2), 3.25 (2H, t, J 7.2, NCH2),
=
2.97 (2H, t, J 7.5, CH2C ), 2.45 (1H, br s, OH), 2.39 (3H, s,
ArCH3), 1.89 (2H, quintet, J ca. 7.4, ring CH2CH2CH2) and
1.77 (2H, quintet, J ca. 7.5, chain CH2CH2CH2); dC (100 MHz;
=
CDCl3; Me4Si) 161.6 (NC CH), 143.3 and 141.7 (ArC), 129.3
=
and 125.9 (ArCH), 85.9 (NC CH), 59.5 (CH2OH), 52.8 (ring
=
NCH2), 43.2 (chain NCH2), 31.2 (CH2C ), 28.7 (CH2CH2OH),
21.3 (ArCH3) and 20.8 (ring C-4); m/z (EI) 295 (2%, M+), 140
(10), 126 (11), 111 (90), 97 (9), 96 (100) and 91 (12) (Found: M+,
295.1240. C15H21NO3S requires 295.1242).
3 5 1 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 5 1 0 – 3 5 1 7

View Online
1040 (w), 666 (m) and 598 (m); dH (400 MHz; CDCl3; Me4Si) 7.89
(2H, d, J 8.2, Ar 2-H/6-H), 7.24 (2H, d, J 8.2, Ar 3-H/5-H), 3.60
(2H, t, J 7.3, 3-H), 3.53 and 3.48 (4H, overlapping t, J ca. 7.7, 1-H
and 5-H), 2.47 (2H, t, J 7.8, 6-H), 2.37 (3H, s, ArCH3) and 2.16
(2H, quintet, J ca. 7.5, 2-H); dC (50 MHz; CDCl3; Me4Si) 184.5
7.5 atm for 24 h. After work-up and chromatography with
EtOAc–MeOH (10 : 1) as eluent, the product was isolated
as colourless needles, mp 101–102 ◦C (from EtOAc–hexane)
(Found: C, 64.0; H, 7.6; N, 4.9; S, 11.3. C15H21NO2S requires
C, 64.5; H, 7.6; N, 5.0; S, 11.5%); Rf 0.33 (EtOAc–MeOH,
10 : 1); mmax (CHCl3)/cm−1 2963 (m), 1597 (s), 1300 (s), 1146
(s), 1085 (m) and 817 (m); dH (400 MHz; CDCl3; Me4Si) 7.78
(2H, d, J 8.1, Ar 2-H/6-H), 7.35 (2H, d, J 8.1, Ar 3-H/5-H),
3.57 (1H, dt, J 9.7 and ca. 4.6, CHSO2; assignment confirmed
by HETCORR), 3.12 (1H, ddd, J 10.9, 6.6 and ca. 4.6, 8a-H;
assignment confirmed by HETCORR), 2.86 (1H, ddd, J 11.0,
6.6 and 4.8, 3-Heq), 2.63 (1H, br dt, J ca. 11.6 and 9.0, 3-Hax),
2.50–2.40 and 2.45 (5H, overlapping m and s, 5-H and ArCH3),
2.15–1.95, 1.95–1.80 and 1.80–1.65 (7H, clusters of m, 1-H,
2-H, 6-H, 7-Heq) and 1.50 (1H, m, 7-Hax?); dC (100 MHz; CDCl3;
Me4Si) 144.4 and 135.8 (ArC), 129.6 and 128.3 (ArCH), 62.1
(C-8; assignment confirmed by DEPT), 58.9 (C-8a; assignment
confirmed by DEPT), 53.9 (C-3), 48.0 (C-5), 23.7, 22.1, 21.4,
21.3 (ArCH3) and 20.1.
=
(C O), 170.4 (C-8a), 142.6 and 141.0 (ArC), 128.8 and 127.4
(ArCH), 106.8 (C-8), 54.6 (C-3), 43.8 (C-5), 34.9 and 34.0 (C-1,
C-6), 21.4 (ArCH3) and 21.0 (C-2); m/z (EI) 291 (1.6%, M+), 227
(21), 226 (100) and 91 (4) (Found: M+, 291.0927. C15H17NO3S
requires 291.0929).
Catalytic hydrogenation of vinylogous sulfonamides: general
procedure
The vinylogous sulfonamide was dissolved in absolute ethanol
containing a suspension of platinum dioxide catalyst (10–15% by
mass of starting material). The mixture was then stirred under
a blanket of hydrogen at a pressure of 7.5–10 atm until TLC
indicated complete consumption of starting material (12–48 h).
The catalyst was removed by filtration through celite, and the
filtrate was evaporated under reduced pressure to afford the
crude product, which was purified by column chromatography
on silica gel. The following results were recorded.
Reduction of vinylogous sulfonamides with sodium borohydride:
general procedure
4-Methylphenyl (1-methylpyrrolidin-2-yl)methyl sulfone 22
(210 mg, 84%) was obtained by hydrogenating (2E)-1-methyl-2-
{[(4-methylphenyl)sulfonyl]methylene}pyrrolidine 15 (250 mg,
0.99 mmol) in absolute ethanol (20 cm3) over PtO2 (25 mg) at 10
atm for 48 h. After work-up and chromatography with EtOAc–
MeOH (10 : 1) as eluent, the product was isolated as colourless
spars, mp 77–78 ◦C (Found: C, 62.1; H, 7.6; N, 5.55; S, 12.9.
C13H19NO2S requires C, 61.6; H, 7.6; N, 5.5; S, 12.7%); Rf 0.35
(EtOAc–MeOH, 10 : 1); mmax (CHCl3)/cm−1 3424 (br, OH), 2967
(m), 2792 (m), 1645 (m), 1598 (m), 1456 (m), 1302 (s), 1148 (s),
1087 (m), 820 (m), 773 (m), 664 (m) and 563 (m); dH (400 MHz;
CDCl3; Me4Si) 7.79 (2H, d, J 8.2, Ar 2-H/6-H), 7.36 (2H, d,
J 8.2, Ar 3-H/5-H), 3.37 (1H, dd, J 14.0 and 2.5, CHaHbSO2),
3.03 and ca. 2.99 (2H, dd, J 14.0 and 9.6, and m, CHaHbSO2
and NCHaHb), 2.61-2.56 (1H, m, NCH), 2.46 (3H, s, ArCH3),
2.24 (3H, s, NCH3), 2.15 (1H, distorted td, J ca. 9.2 and 8.1,
NCHaHb), 2.11–2.01, 1.78–1.66 and 1.65–1.56 (1H, 2H and 1H,
3 × m, remaining H); dC (100 MHz; CDCl3; Me4Si) 144.6 and
137.0 (ArC), 129.9 and 127.9 (ArCH), 60.6 (CH2SO2), 60.2 (C-
2), 56.1 (C-5), 40.2 (NCH3), 31.5 (C-3), 22.5 (ArCH3) and 21.6
(C-4).
3-(2-{[(4-Methylphenyl)sulfonyl]methyl}pyrrolidin-1-yl)pro-
pyl acetate 23 (357 mg, 98%) was obtained by hydrogenating
3-((2E)-2-{[(4-methylphenyl)sulfonyl]methylene}pyrrolidin-1-
yl)propyl acetate 16 (360 mg, 1.07 mmol) in absolute ethanol
(30 cm3) over PtO2 (36 mg) at 7.5 atm for 24 h. After work-up
and chromatography with EtOAc as eluent, the product was
isolated as a yellow oil; Rf 0.39 (EtOAc); mmax (film)/cm−1 2961
(m), 2812 (m), 1738 (s), 1598 (m), 1368 (m) and 1303 (m); dH
(400 MHz; CDCl3; Me4Si) 7.71 (2H, d, J 8.3, Ar 2-H/6-H),
7.29 (2H, d, J 8.3, Ar 3-H/5-H), 3.98 (2H, br t, J 6.3 with fine
coupling, CH2OAc), 3.23 (1H, dd, J 13.3 and 2.3, CHaHbSO2),
3.00–2.90 (2H, m, CHaHbSO2 and ring NCHaHb), 2.78–2.72
(1H, m, NCH), 2.62 (1H, dt, J 12.1 and 8.0, chain NCHaHb),
2.38 (3H, s, ArCH3), 2.30–1.70 and 1.95 (7H, overlapping m
and s, ring and chain NCHaHb and O2CCH3, among others)
and 1.70–1.52 (4H, m, remaining H); dC (100 MHz; CDCl3;
A solution of the vinylogous sulfonamide in methanol (15 cm3
per mmol of reactant) was stirred with sodium borohydride (1–
1.5 equiv.) under nitrogen at ambient temperature until TLC
indicated consumption of the starting material. The reaction
mixture was acidified with aq. HCl (1.0 M), filtered through
celite and evaporated in vacuo. The residue was partitioned be-
tween aq. Na2CO3 solution (10%; 50 cm3) and dichloromethane
(3 × 40 cm3). The organic fractions were combined, washed
with water (20 cm3), dried (MgSO4), filtered and concentrated
in vacuo to afford the crude product, which was purified by
column chromatography on silica gel. The following results were
recorded.
4-Methylphenyl (1-methylpyrrolidin-2-yl)methyl sulfone 22
(170 mg, 68%) was obtained by reducing (2E)-1-methyl-2-
{[(4-methylphenyl)sulfonyl]methylene}pyrrolidine 15 (250 mg,
0.99 mmol) in methanol (15 cm3) with sodium borohydride
(59 mg, 1.56 mmol) for 30 min. After work-up and chro-
matography on silica gel with EtOAc–MeOH (10 : 1) as eluent,
the product was isolated as colourless needles, mp 77–78 ◦C;
characterisation as described above.
3-(2-{[(4-Methylphenyl)sulfonyl]methyl}pyrrolidin-1-yl)pro-
pan-1-ol 24 (270 mg, 85%) was obtained by reducing 3-((2E)-
2-{[(4-methylphenyl)sulfonyl]methylene}pyrrolidin-1-yl)propyl
acetate 16 (360 mg, 1.07 mmol) in methanol (20 cm3) with
sodium borohydride (47 mg, 1.24 mmol) for 1 h. After work-up
and chromatography on silica gel with EtOAc–MeOH (10 : 1)
as eluent, the product was isolated as a yellow oil; Rf 0.25
(EtOAc); mmax (film)/cm−1 3417 (br m), 2956 (m), 1644 (m), 1597
(m), 1304 (m), 1147 (s), 1086 (m) and 1064 (m); dH (400 MHz;
CDCl3; Me4Si) 7.79 (2H, d, J 8.2, Ar 2-H/6-H), 7.37 (2H, d, J
8.2, Ar 3-H/5-H), 3.75–3.67 (3H, m, CH2OH and CHaHbSO2),
3.39 (1H, dd, J 13.9 and 2.5, CHaHbSO2), 3.19 (1H, ddd, J 9.6,
6.2 and 3.6, chain NCHaHb), 3.07 (1H, dd, J 13.9 and 9.5, ring
NCHaHb), 2.90–2.84 (2H, m, NCH and NCHaHb), 2.46 (4H,
overlapping s, OH and ArCH3), 2.16 (1H, distorted td, J ca.
9.0 and 7.8, chain NCHaHb), 2.05 (1H, ddd, J 15.7, 12.5 and
7.9, ring 3-Ha), 1.83-1.71 (4H, m, ring 4-H and CH2CH2OH)
and 1.70-1.52 (1H, m, ring 3-Hb); dC (100 MHz; CDCl3;
Me4Si) 144.7 and 136.9 (ArC), 129.9 and 127.8 (ArCH), 63.8
(CH2OH), 60.8 (CH2SO2), 59.2 (NCH), 54.1 and 53.0 (2 ×
NCH2), 31.1 and 29.4 (ring C-3 and CH2CH2OH), 22.7 (ring
C-4) and 21.5 (ArCH3); m/z (EI) 297 (1%, M+), 252 (34),
142 (9), 141 (6), 129 (8), 128 (100), 98 (6), 97 (32), 96 (23), 91
(18) and 84 (21) (Found: M+, 297.1387. C15H23NO3S requires
297.1399).
=
Me4Si) 170.8 (C O), 144.5 and 136.9 (ArC), 129.7 and 127.6
(ArCH), 62.2 (CH2OAc), 60.9 (CH2SO2), 58.6 (NCH), 52.6
and 50.3 (2 × NCH2), 30.9 (ring C-3), 27.5 (CH2CH2OAc), 22.7
(ring C-4), 21.4 (ArCH3) and 20.7 (O2CCH3); m/z (EI) 339
(7%, M+), 254 (7), 253 (16), 252 (100) and 170 (40) (Found: M+,
339.1500. C17H25NO4S requires 339.1504).
(8R*,8aR*)-8-[(4-Methylphenyl)sulfonyl]octahydroindolizine
25 (130 mg, 65%) was obtained by hydrogenating 1,2,3,5,6,7-
hexahydroindolizin-8-yl 4-methylphenyl sulfone 20 (200 mg,
0.72 mmol) in absolute ethanol (5 cm3) over PtO2 (30 mg) at
(8R*,8aR*)-8-[(4-Methylphenyl)sulfonyl]octahydroindolizine
25 (150 mg, 75%) and (8R*, 8aS*)-8-[(4-methylphenyl)
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 5 1 0 – 3 5 1 7
3 5 1 5

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sulfonyl]octahydroindolizine 26 (14.8 mg, 7%) were obtained
by reducing 1,2,3,5,6,7-hexahydroindolizin-8-yl 4-methylphenyl
sulfone 20 (200 mg, 0.72 mmol) in methanol (10 cm3) with
sodium borohydride (34 mg, 0.90 mmol) for 24 h. After work-up
and chromatography on silica gel with EtOAc–MeOH (10 :
1) as eluent, the major product 25 was isolated as colourless
needles, mp 101–102 ◦C; characterisation as described above.
The minor product 27 was a clear oil; Rf 0.38 (EtOAc); mmax
(film)/cm−1 2965 (m), 1710 (m), 1597 (m), 1376 (m), 1300
(s), 1150 (s), 1088 (m) and 1036 (m); dH (400 MHz; CDCl3;
Me4Si) 7.75 (2H, d, J 8.2, Ar 2-H/6-H), 7.35 (2H, d, J 8.2, Ar
3-H/5-H), 3.06–3.01 (2H, m, CHSO2 and 8a-H), 2.94 (1H, ddd,
J 12.8, 9.5 and 3.3, 3-Heq?), 2.46 (3H, s, ArCH3), 2.24–1.91 and
1.80–1.55 (2 × 5H, clusters of m, ring CH2) and 1.43 (1H, qd,
J 12.8 and 4.3, 7-Hax?); dC (50 MHz; CDCl3; Me4Si) 144.6 and
135.1 (ArC), 129.6 and 128.7 (ArCH), 66.6 (C-8), 62.5 (C-8a),
53.4 (C-5), 51.6 (C-3), 29.9 (C-1), 25.6, 24.5, 21.5 (ArCH3) and
20.7; m/z (EI) 279 (14%, M+), 278 (62), 277 (11), 172 (16), 149
(17), 124 (39), 123 (100), 122 (46), 97 (30), 96 (36) and 91 (43)
(Found: M+, 279.1289. C15H21NO2S requires 279.1293).
(7R*,8R*,8aR*)-8-[(4-Methylphenyl)sulfonyl]octahydroin-
dolizin-7-ol 27 (130 mg, 64%) was obtained by reducing 8-[(4-
methylphenyl)sulfonyl]-2,3,5,6-tetrahydroindolizin-7(1H)-one
21 (200 mg, 0.69 mmol) in MeOH–CHCl3 (1 : 1; 10 cm3) with
sodium borohydride (39 mg, 1.03 mmol) for 1 h. After work-up
and chromatography on silica gel with EtOAc as eluent, the
product, a single diastereomer, was isolated as a clear oil; Rf
0.53 (EtOAc); mmax (film)/cm−1 3420 (br m), 2970 (m), 1635 (m),
1570 (m), 1461 (m), 1366 (m), 1300 (m), 1144 (s), 1081 (m) and
666 (m); dH (400 MHz; CDCl3; Me4Si) 7.79 (2H, d, J 8.3, Ar
2-H/6-H), 7.37 (2H, d, J 8.3, Ar 3-H/5-H), 4.16 (1H, d?, J ca.
2?, CHOH), ca. 3.45 (1H, br s, OH), 3.07–2.98 (2H, m, 8-H and
8a-H), 2.84–2.74 (2H, m, 3-Heq and 5-Heq), 2.55 (1H, td, J 11.9
and 2.8, 3-Hax), 2.46 (3H, s, ArCH3), 2.23 (1H, br quintet, J ca.
9.1, 5-Hax), 2.22–2.04, ca. 1.89 and 1.87–1.51 (1H + 1H + 4H,
clusters of m, ring CH2); dC (100 MHz; CDCl3; Me4Si) 145.1
and 135.8 (ArC), 129.9 and 128.3 (ArCH), 70.1 (C-8), 63.6
(C-7), 56.5 (C-8a), 52.9 (C-3), 45.7 (C-5), 32.4, 29.6, 21.6 and
20.8 (ArCH3); m/z (EI) 295 (4%, M+), 278 (6), 266 (14), 265
(40), 264 (16), 140 (30), 139 (78), 138 (25), 137 (46), 123 (10),
122 (100), 97 (42), 96 (31) and 91 (11) (Found: M+, 295.1241.
C15H21NO3S requires 295.1242).
temperature under nitrogen until TLC indicated consumption of
the reactant. After removal of solids by filtration, the filtrate was
evaporated in vacuo, and the residue was partitioned between
water and CH2Cl2. The combined organic fractions were dried
(MgSO4), filtered and purified where necessary. The following
results were recorded.
Ethyl (2E)-(1-methylpyrrolidin-2-ylidene)acetate 28 (90 mg,
86%) was obtained by treating ethyl [(4-methylphenyl)sulfonyl]
(1-methypyrrolidin-2-ylidene)acetate 10 (200 mg, 0.62 mmol)
with sodium amalgam (6%; 2.0 g) and Na2HPO4 (280 mg,
1.97 mmol) in THF–MeOH (1 : 1; 10 cm3) for 14 h. The product,
a clear oil, was chromatographically pure. Rf 0.41 (EtOAc–
hexane 3:7); mmax (film)/cm−1 2978 (m), 2943 (m), 1686 (s), 1595
(s), 1410 (m) and 1377 (m); dH (200 MHz; CDCl3; Me4Si) 4.46
=
(1H, s, CH), 4.09 (2H, q, J 7.2, OCH2CH3), 3.39 (2H, t, J 7.0,
NCH2), 3.13 (2H, t, J 7.8, CH2C ), 2.80 (3H, s, NCH3), 1.95
=
(2H, br quintet, J ca. 7.3, CH2CH2CH2) and 1.25 (3H, t, J 7.2,
OCH2CH3); dC (50 MHz; CDCl3; Me4Si) 169.1 (C O), 165.3
(NC CH), 77.4 (NC CH), 57.8 (OCH2CH3), 54.0 (NCH2),
32.8 (CH2C ), 32.1 (NCH3), 20.7 (CH2CH2CH2) and 14.4
(OCH2CH3). Data accord with those published elsewhere in the
literature.27 Picrate salt: mp 87.5–88.5 ◦C (from EtOAc) (Found:
C, 45.5; H, 4.4; N, 14.6. C9H15NO2·C6H3N3O7 requires C, 45.2;
H, 4.55; N, 14.1%).
=
=
=
=
2,3,5,6-Tetrahydroindolizin-7(1H)-one 29 (73 mg, 77%)
was obtained by treating 8-[(4-methylphenyl)sulfonyl]-2,3,5,6-
tetrahydroindolizin-7(1H)-one 21 (200 mg, 0.69 mmol) with
sodium amalgam (2.0 g) and Na2HPO4 (200 mg, 1.41 mmol)
in THF–MeOH (1 : 1; 20cm3) for 14 h. The product, a clear oil,
was chromatographically pure. Rf 0.29 (EtOAc–MeOH 10 : 1);
mmax (film)/cm−1 2964 (m), 2870 (m), 1616 (m), 1568 (s), 1506
(m), 1369 (m) and 1319 (m); dH (200 MHz; CDCl3; Me4Si) 4.97
(1H, s, 8-H), 3.48 (2H, t, J 7.9, 5-H), 3.42 (2H, t, J 6.9, 3-H), 2.70
(2H, t, J 7.7, 1-H), 2.50 (2H, t, J 7.9, 6-H) and 2.08 (2H, quintet,
J ca. 7.3, 2-H); dC (50 MHz; CDCl3; Me4Si) 190.4 (C-7), 169.0
(C-8a), 92.5 (C-8), 52.9 (C-3), 44.8 (C-5), 34.6 (C-6), 31.5 (C-1)
and 20.9 (C-2). Data accord with those published elsewhere in
the literature.28
Ethyl (2E)-1-[(3-hydroxypropyl)pyrrolidin-2-ylidene]acetate
30 (91 mg, 87%) was obtained by treating ethyl [1-(3-acetoxy-
propyl)pyrrolidin-2-ylidene][(4-methylphenyl)sulfonyl]acetate
11 (200 mg, 0.49 mmol) with sodium amalgam (6%; 2.0 g) and
Na2HPO4 (210 mg, 1.48 mmol) in THF–MeOH (1 : 1; 10cm3)
for 14 h. The product, purified by chromatography on silica
gel with EtOAc as eluent, was obtained as a yellow oil (lit.,4
Attempted oxidative desulfonylation of (8R*,8aR*)-8-[(4-methyl-
phenyl)sulfonyl]octahydroindolizine 25
◦
mp 62–63 C); Rf 0.45 (EtOAc); mmax (film)/cm−1 3419 (br m),
n-Butyllithium (1.28 M in hexane; 2.0 cm3, 2.56 mmol) was
added by syringe to a solution of the title compound 25 (0.25 g,
0.89 mmol) in dry THF (10 cm3), cooled under nitrogen to
−78 ◦C. The resulting yellow solution was stirred for 15 min
before the addition of neat bis(trimethylsilyl) peroxide (0.19 g,
1.07 mmol). The reaction mixture was stirred overnight at
ambient temperature before being quenched with ice-cold aq.
saturated NaHCO3 solution (20 cm3). After extraction with
diethyl ether (2 × 30 cm3), the combined organic fractions
were dried (MgSO4), filtered and evaporated in vacuo to
give a brown oil. After column chromatography on silica
gel with EtOAc–hexane (1 : 1) as eluent, (8R*,8aS*)-8-[(4-
methylphenyl)sulfonyl]octahydroindolizine 26 (0.21 g, 84%) was
isolated as a clear oil; characterisation as described above.
2977 (m), 2945 (w), 2874 (w), 1658 (m), 1586 (s), 1148 (m) and
=
1067 (m); dH (200 MHz; CDCl3; Me4Si) 4.54 (1H, s, CH), 4.07
(2H, q, J 7.1, OCH2CH3), 3.65 (2H, t, J 6.0, CH2OH), 3.41
(3H, overlapping br s and t, J 7.1, OH and chain NCH2), 3.31
=
(2H, t, J 7.2, ring NCH2), 3.13 (2H, t, J 7.7, CH2C ), 1.94
(2H, quintet, J ca. 7.4, ring CH2CH2CH2), 1.81 (2H, quintet,
J ca. 6.7, CH2CH2OH) and 1.24 (3H, t, J 7.1, OCH2CH3); dC
=
=
(50 MHz; CDCl3; Me4Si) 169.6 (C O), 164.9 (NC CH), 77.0
=
(NC CH), 59.4 and 58.0 (CH2OH, OCH2CH3), 52.5 (ring
=
NCH2), 42.9 (chain NCH2), 32.5 (CH2C ), 28.7 (CH2CH2OH),
20.7 (ring C-4) and 14.4 (OCH2CH3); m/z (EI) 213 (37%, M+),
196 (15), 182 (15), 170 (10), 169 (100), 168 (83), 155 (13), 154
(9), 126 (23), 125 (12), 110 (26), 108 (13), 97 (80), 96 (87) and 80
(9) (Found: M+, 213.1369. C11H19NO3 requires 213.1365). Data
accord with those published elsewhere in the literature.4
Reductive desulfonylation of vinylogous sulfonamides: general
procedure
Sodium amalgam (6%) was prepared by carefully heating a
mixture of sodium (1.50 g) and mercury (25.0 g) over an open
flame until there was an ignition. The amalgam was stored
under nitrogen until required. The amalgam (excess; ca. 2 g)
was added to a solution of vinylogous sulfonamide (0.5–1 mmol
scale) in THF–MeOH (1 : 1; 10–20 cm3) containing a suspension
of Na2HPO4 (3 equiv.), and the mixture was stirred at ambient
Acknowledgements
This work was supported by grants from the National Re-
search Foundation, Pretoria, (grant number 2053652) and
the University of the Witwatersrand. We are grateful to Mrs
S. Heiss (University of the Witwatersrand) and Dr P. R. Boshoff
(formerly of the Cape Technikon) for recording NMR spectra
3 5 1 6
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 5 1 0 – 3 5 1 7

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and mass spectra, respectively, and to Mr M. Philpott (ISCW,
Pretoria) for performing microanalyses.
pp. 91–258; (c) For annual reports on progress in the chemistry of
indolizidine and quinolizidine alkaloids, see J. P. Michael, Nat. Prod.
Rep., 2004, 21, 625–649, and earlier reviews in this series.
11 (a) M. Roth, P. Dubs, E. Go¨tschi and A. Eschenmoser, Helv. Chim.
Acta, 1971, 54, 710–734; (b) K. Shiosaki, in Comprehensive Organic
Synthesis, ed. B. M. Trost, Pergamon Press, Oxford, 1991, vol. 2, pp.
865–892.
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O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 5 1 0 – 3 5 1 7
3 5 1 7