Synthesis of exocyclic enamides via stereocontrolled allylic isomerization and 1,3-transposition

Article abstract of DOI:10.1081/SCC-100104405

In the presence of pyridinium para-toluenesulfonate (PPTS) an allylic alcohol moiety exocyclic to a lactam ring undergoes allylic isomerisation, or if the solvent is nucleophilic, 1,3-transposition can occur. All the rearrangements occurred with stereocon

Full text of DOI:10.1081/SCC-100104405

This article was downloaded by: [University of Hong Kong Libraries]
On: 10 November 2014, At: 19:06
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number:
1072954 Registered office: Mortimer House, 37-41 Mortimer Street,
London W1T 3JH, UK
Synthetic Communications:
An International Journal
for Rapid Communication of
Synthetic Organic Chemistry
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
SYNTHESIS OF
EXOCYCLIC ENAMIDES VIA
STEREOCONTROLLED ALLYLIC
ISOMERIZATION AND 1,3-
TRANSPOSITION
Afzal Khan a , Charles M. Marson b & Rod A. Porter
a Department of Chemistry , Queen Mary &
Westfield College , Mile End Road, London, E1
4NS, U.K.
b Department of Chemistry , University College
London, Christopher Ingold Laboratories , 20
Gordon Street, London, WC1H OAJ, U.K.
Published online: 09 Nov 2006.
To cite this article: Afzal Khan , Charles M. Marson & Rod A. Porter (2001)
SYNTHESIS OF EXOCYCLIC ENAMIDES VIA STEREOCONTROLLED ALLYLIC
ISOMERIZATION AND 1,3-TRANSPOSITION, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry,
31:11, 1753-1764, DOI: 10.1081/SCC-100104405
To link to this article: http://dx.doi.org/10.1081/SCC-100104405
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all
the information (the “Content”) contained in the publications on our

platform. However, Taylor & Francis, our agents, and our licensors
make no representations or warranties whatsoever as to the accuracy,
completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of
the authors, and are not the views of or endorsed by Taylor & Francis.
The accuracy of the Content should not be relied upon and should be
independently verified with primary sources of information. Taylor and
Francis shall not be liable for any losses, actions, claims, proceedings,
demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in
relation to or arising out of the use of the Content.
This article may be used for research, teaching, and private study
purposes. Any substantial or systematic reproduction, redistribution,
reselling, loan, sub-licensing, systematic supply, or distribution in any form
to anyone is expressly forbidden. Terms & Conditions of access and use
can be found at http://www.tandfonline.com/page/terms-and-conditions

SYNTHETIC COMMUNICATIONS, 31(11), 1753–1764 (2001)
SYNTHESIS OF EXOCYCLIC ENAMIDES
VIA STEREOCONTROLLED ALLYLIC
ISOMERIZATION AND
1,3-TRANSPOSITION
Afzal Khan,1 Charles M. Marson,1, and Rod A. Porter2
*
1Department of Chemistry, Queen Mary & Westfield
College, Mile End Road, London, E1 4NS, U.K.
2SmithKline Beecham Pharmaceuticals, New Frontiers
Science Park, Third Avenue, Harlow, CM 19 5AW, U.K.
ABSTRACT
In the presence of pyridinium para-toluenesulfonate (PPTS)
an allylic alcohol moiety exocyclic to a lactam ring undergoes
allylic isomerisation, or if the solvent is nucleophilic, 1,3-
transposition can occur. All the rearrangements occurred
with stereocontrol.
Acyclic enamides are valuable precursors for asymmetric reduction to
chiral nitrogen compounds,1 among other uses in synthesis. However, cyclic
enamides, in which the double bond is exocyclic, are less common,2 and
perhaps in consequence have been used relatively little in synthesis. Most of
those that have been prepared possess an alkoxycarbonyl group attached to
* Corresponding author. Current address: Department of Chemistry, University
College London, Christopher Ingold Laboratories, 20 Gordon Street, London
WC1H OAJ, U.K.
1753
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

1754
KHAN, MARSON, AND PORTER
the exocyclic double bond,3 formed for example at high temperatures by the
condensation of stabilised ylides with cyclic imides.4 We here report mild
and stereocontrolled routes to enamides containing an hydroxymethyl,
hydroxyalkyl, or bromomethyl group.
We reasoned that the ability of allylic alcohols to undergo allylic iso-
merisation or 1,3-transposition reactions5 (Scheme 1) could be exploited in
the context of the lactams 1. The intramolecular transpositions frequently
occur with excellent stereocontrol owing to sigmatropic rearrangements.6,7
On the other hand, intermolecular 1,3-transpositions can be troublesome;
early work showed that mineral acids often gave equilibrium mixtures or
were incompatible with other functional groups.8 Such 1,3-transpositions
have been improved by the use of a catalytic combination of tetrabutyl-
ammonium perrhenate and para-toluenesulfonic acid,9 but even so tertiary
allylic alcohols underwent dehydration rather than isomerisation.
Scheme 1. Modes of reactions of an allylic alchol.
We report here some allylic isomerisations and 1,3-transpositions of
tertiary allylic alcohols of type 1 with a catalytic amount of pyridinium
para-toluenesulfonate (PPTS)10 to give primary allylic alcohols and allylic
ethers (Table 1). An acyliminium species 2, an excellent electrophile,11 is
believed to be formed, followed by nucleophilic attack (Scheme 2). By
other means, peroxides and allyl bromides can be prepared. For all of the
above reactions, NMR data were consistent with the presence of only one
alkene isomer, and in one case (bromide 6, Scheme 4), that was shown by
nOe experiments to have the E-configuration, as in 3.
Table 1 shows some allylic isomerisations and 1,3-transpositions of
the tertiary allylic alcohols 1. Non-nucleophilic solvents such as
dichloromethane (entry 1) have been used to effect allylic isomerisation.12
Scheme 2. Stereocontrolled rearrangements of allylic alcohols.

SYNTHESIS OF EXOCYCLIC ENAMIDES
Table 1. Reaction of Allylic Alcohols with PPTS
1755
It was hoped that the use of vinyl acetate as the solvent would generate the
vinyl ether, prior to a [3,3]-sigmatropic rearrangement; however, only allylic
isomerisation was observed (entry 2). The use of alcohols as solvents gave
allylic ethers in all cases (entries 3–5). Treatment of 5-hydroxy-1-(2-hydroxy-
ethyl)-5-vinyl-2-pyrrolidinone with PPTS in dichloromethane induced
decomposition, no intramolecular 1,3-transposition (with or without cycli-

1756
KHAN, MARSON, AND PORTER
Scheme 3.
Diperoxide formation involving a 1,3-transposition.
sation) being observed, so that protection of the hydroxy group as 1c proved
necessary.
Reaction of 1b with an alkyl peroxide nucleophile was also effective; in
tin (IV) chloride (10 mol%) in the presence of tert-butyl hydroperoxide (2.3
mol equiv.) gave the a,g-diperoxide 4 (Scheme 3). Formation of the perox-
ides 4 and 5 is believed to involve acyliminium cations generated by attack
of SnCl4 on the hydroxy group of 1b and subsequent expulsion of an oxo-tin
moiety.
Treatment of allylic alcohol 1b with N-bromosuccinimide in aqueous
THF also induced 1,3-transposition, affording the allylic bromide 6
(Scheme 4) as a single diastereoisomer.9 The bromide 6 underwent displace-
ment with malonate anion to give esters 7 and 8, showing that the functio-
nalised allylic lactams can be used in C–C bond formation.
In conclusion, allylic isomerisations and transpositions have been
shown to occur with PPTS under mild conditions, compatible with sensitive
functionality. The formation of free hydroxyl groups is notable, and was not
directly achievable via rearrangements of unsaturated esters.7 The stereo-
controlled formation of an exocyclic allylic alcohol unit is well-suited to
Scheme 4. Oxidative transposition followed by alkylation of malonate.

SYNTHESIS OF EXOCYCLIC ENAMIDES
1757
further functionalisation, e.g. asymmetric epoxidation, and hence may find
use in total synthesis. The uses of other nucleophiles such as thiols or amines
for these 1,3-transposition reactions are to be investigated.
EXPERIMENTAL
General. All melting points were determined on a microscope hot-stage
apparatus. 1H and 13C NMR spectra were run on a Bruker AM-250 instru-
ment at 250 and 68.8 MHz respectively. Combustion analyses were carried
out using a Perkin Elmer 2400 CHNelemental analyzer. Mass spectra were
obtained on a Kratos MS-50 RF spectrometer. Infrared spectra were
recorded on a Perkin Elmer FT-IR 1720 instrument. Thin-layer chromato-
graphy was performed on Merck 0.2 mm aluminium-backed silica gel
60 F254 plates and visualized using an alkaline KMnO4 spray or by
ultraviolet light. Flash column chromatography was performed using
Merk 0.040 to 0.063 mm, 230 to 400 mesh silica gel. Petroleum ether
(40–60ꢀC fraction) and ethyl acetate were distilled before use; tetrahydro-
furan was distilled from sodium and benzophenone; dichloromethane was
distilled from calcium hydride. Evaporation refers to the removal of solvent
under reduced pressure.
The following compounds were prepared by literature procedures:
5-hydroxy-1-methyl-5-vinyl-2-pyrrolidinone;13 and 1-(2-hydroxyethyl)-2,5-
pyrrolidinedione.14
N-Methylsuccinimide. A mixture of succinimide (5.0 g, 50.5 mmol),
methyl iodide (7.88 g, 55.5 mmol) and anhydrous potassium cabonate
(8.37 g, 60.6 mmol) was heated at reflux in anhydrous acetone (75 ml) for
4 h and give a fine precipitate of potassium bromide. After cooling to 20ꢀC
the mixture was filtered and the acetone evaporated to give a solid, to which
a
small amount of dichloromethane was added. Filtration gave
N-Methylsuccinimide as a white solid (5.59 g, 98%); mp 68–70ꢀC (ethyl
acetate/petroleum ether), lit.15 mp 64ꢀC.
N-Benzylsuccinimide. A mixture of succinimide (2.0 g, 20.2 mmol),
benzyl bromide (3.80 g, 22.2 mmol) and anhydrous potassium carbonate
(3.35 g, 24.2 mmol) was heated at reflux in anhydrous acetone (30 ml) for
2.5 h, and gave a fine white precipitate of potassium bromide. After cooling
to 20ꢀC the mixture was filtered and the acetone evaporated to give a pale
orange solid which was recrystallised from ethyl acetate/light petroleum
ether to give N-benzylsuccinimide as white platelets (3.06 g, 94%); mp
103–104ꢀC, lit.16 mp 100–103ꢀC; H NMR (CDCl3) d 7.45–7.10 (5H, m,
1
Ar), 4.61 (2H, s, CH2Ph), 2.64 (4H, s, CH2CO); 13C NMR (CDCl3) d
176.9 (s), 135.8 (s), 128.9 (d), 128.6 (d), 128.0 (d), 42.4 (t) 28.2 (t).

1758
KHAN, MARSON, AND PORTER
5-Hydroxy-1-(2-hydroxyethyl)-5-vinylpyrrolidin-2-one. To stirred
a
solution of 1-(2-hydroxyethyl)pyrrolidine-2,5-dione (2.0 g, 14.0 mmol) in
THF (100 ml), cooled to ꢁ78ꢀC, was added vinylmagnesium bromide
(34.9 ml, 34.9 mmol, 1 M solution in THF) dropwise. The cooling bath
was then removed and the mixture stirred at 20ꢀC for 1.5 h. It was then
poured onto saturated ammonium chloride (40 ml), the layers separated and
the aqueous layer extracted with ether (2 ꢂ 20 ml). The combined organic
extracts were dried (MgSO4) and evaporated to give an orange oil. This was
purified by column chromatography (95:5 ethyl acetate: 40–60ꢀC petroleum
ether) to give 5-hydroxy-1-(2-hydroxyethyl)-5-vinylpyrrolidin-2-one as a
colourless oil (0.39 g, 16%); IR, ꢀmax (thin film): 3340 cmꢁ1 1H N MR
;
(CDCl3) d 5.85 (1H, dd, J ¼ 15.5 Hz, J ¼ 8.0 Hz, ¼ CH), 5.40 (1H, dd,
J ¼ 15.5 Hz, J ¼ 1.3 Hz, ¼ CH2), 5.33 (1H, dd, J ¼ 8.0 Hz, J ¼ 1.3 Hz,
¼ CH2), 5.05–3.40 (4H, m), 2.40–2.05 (4H, m); 13C NMR (CDCl3) d 176.1
(s), 139.2 (d), 117.3 (t), 98.3 (s), 39.4 (t), 65.5 (t), 30.4 (t), 28.3 (t); m/z (EI):
171 (M+, 37%), 155 (16%), 145 (20%), 115 (39%), 82 (41%), 55 (100%);
HRMS, M+ found 171.0903, C8H13NO3 requires 171.0895.
1-[2-(Tetrahydropyran-2-yloxy)ethyl]pyrrolidine-2,5-dione. To 1-(2-
hydroxyethyl)pyrrolidine-2,5-dione (3.0 g, 21.0 mmol) in dichloromethane
(150 ml) was added dihydropyran (2.64 g, 31.4 mmol) then pyridinium
para-toluenesulfonate (0.53 g, 2.10 mmol) and the mixture heated at reflux
for 40 min. It was then cooled, washed with half-saturated brine, dried
(MgSO4) and evaporated. The residue was purified by column chromato-
graphy (60:40 ethyl acetate: 40–60ꢀC petroleum ether) to give 1-[2-(tetrahy-
dropyran-2-yloxy)ethyl]pyrrolidine-2,5-dione as a white microprisms (4.42 g,
93%); mp 82–84ꢀC (ethyl acetate/petroleum ether); IR, ꢀmax (nujol mull):
1
1700 cmꢁ1; H NMR (CDCl3) d 4.80 (1H, m, OCHO), 3.90–3.40 (6H, m),
2.71 (4H, s, COCH2), 1.85–1.40 (6H, 3); 13C NMR (CDCl3) d 177.1 (s), 98.2
(d), 63.0 (t), 62.3 (t), 38.3 (t), 30.4 (t), 28.2 (t), 25.4 (t), 19.3 (t); m/z (EI): 227
(M+, 100%), 207 (56%), 186 (22%), 155 (32%), 108 (72%); HRMS, M+
found 227.1146, C11H17NO4 requires 227.1157.
1-Benzyl-5-hydroxy-5-vinylpyrrolidin-2-one (1b). N-benzylsuccinimide
(2.0 g, 10.6 mmol) in THF (80 ml) was cooled in an ice-salt mixture and
treated dropwise with vinylmagnesium bromide (15.9 ml, 15.9 mmol,
1M solution in THF). When the addition was complete the mixture
was allowed to stir at 0ꢀC for 1.5 h. It was then poured onto saturated
aqueous ammonium chloride (40 ml), the layers separated and the aqueous
layer extracted with diethyl ether (3ꢂ15 ml). The combined organic extracts
were dried (MgSO4), evaporated, and the residue purified by column
chromatography (55:45 ethyl acetate: 40–60ꢀC petroleum ether) to give
1b as an oily solid (2.14 g, 93%); IR, ꢀmax (thin film): 3330,
1
1670, 1500 cmꢁ1; H NMR (CDCl3) d 7.35–7.10 (5H, m, Ar), 5.66 (1H,

SYNTHESIS OF EXOCYCLIC ENAMIDES
1759
dd, J ¼ 17.0 Hz, J ¼ 11.0 Hz, ¼ CH), 5.42 (1H, dd, J ¼ 17.0 Hz, J ¼ 1.0 Hz,
¼ CH2), 5.17 (1H, dd, J ¼ 11.0 Hz, J ¼ 1.0 Hz, ¼ CH2), 4.35 (2H, s, NCH2),
2.70–1.90 (4H, m); 13C NMR (CDCl3) d 175.7 (s), 139.2 (d), 138.2 (s), 128.4
(d), 128.3 (d), 127.1 (d), 116.6 (t), 91.3 (s), 43.0 (t), 34.3 (t), 29.1 (t); m/z (EI):
217 (M+, 22%), 199 (89%), 170 (60%), 146 (11%), 106 (62%), 91 (100%),
84 (42%), 65 (62%); HRMS, M+ found 217.1102, C13H15NO2 requires
217.1103.
5-Hydroxy-1-[2-(tetrahydropyran-2-yloxy)ethyl]-5-vinylpyrrolidin-2-one
(1c). To a solution of 1-[2-(tetrahydropyran-2-yloxy)ethyl]pyrrolidine-
2,5-dione (2.0 g, 8.80 mmol) in THF (70 ml), cooled to ꢁ78ꢀC, was added
vinylmagnesium bromide (13.2 ml, 13.2 mmol, 1M solution in THF) drop-
wise. When the addition was complete the mixture was stirred at 20ꢀC for
4 h. It was then poured onto saturated ammonium chloride (30 ml), the
layers separated and the aqueous layer extracted with diethyl ether
(2ꢂ20 ml). The combined organic extracts were dried (MgSO4) and evapo-
rated to give an orange oil which was purified by column chromatography
(70:30 ethyl acetate: 40–60ꢀC petroleum ether) to give 1c as a colourless oil
1
(1.24 g, 55%), IR, ꢀmax (thin film): 3330, 1680 cmꢁ1; H NMR (CDCl3) d
5.82 (1H, m, ¼ CH), 5.64–5.50 (1H, m, ¼ CH2), 5.44–5.30 (1H, m, ¼ CH2),
4.64 (1H, m, OCHO), 4.00–3.35 (6H, m), 3.20–3.04 (1H, m), 2.80–2.55 (1H,
m), 2.45–2.25 (1H, m), 2.20–1.30 (7H, m); 13C NMR (CDCl3) d 176.7 (s),
176.6 (s), 139.9 (d), 117.5 (t), 117.3 (t), 98.9 (d), 98.8 (d), 90.1 (s), 65.6 (t),
65.2 (t), 62.5 (t), 62.3 (t), 40.1 (t), 39.7 (t), 34.0 (t), 33.8 (t), 30.1 (t), 29.3 (t),
25.2 (t), 25.0 (t), 19.4 (t), 19.2 (t); m/z (FAB): 278 (MNa+, 32%), 256 (20%),
238 (70%), 172 (32%), 154 (100%), 111 (28%); HRMS, MNa+ found
278.1380, C13H21NO4Na requires 278.1368.
5-(2-Hydroxyethylidene)-1-methylpyrrolidin-2-one (3a). To a solution
of 5-hydroxy-1-methyl-5-vinylpyrrolidin-2-one13 (0.20 g, 1.42 mmol) in etha-
nol free dichloromethane (10 ml) was added pyridinium para-toluenesulfo-
nate (36 mg, 0.14 mmol). The mixture was then stirred at 20ꢀC for 2 h,
diluted with diethyl ether, washed with half-saturated brine and the organic
layer dried (MgSO4) and evaporated to give an oil which was purified
by column chromatography (90:10 ethyl acetate: 40–60ꢀC petroleum
ether) to give 3a as a colourless oil (142 mg, 71%); IR, ꢀmax (thin
film): 3380, 1690 cmꢁ1
;
1H NMR (CDCl3) d 4.84 (1H, tt, J ¼ 7.5 Hz,
J ¼ 2.0 Hz, ¼ CH2) 3.98 (2H, d, J ¼ 7.5 Hz, CH2OH), 2.88 (3H, s, CH3),
2.70 (2H, m, CH2CO), 2.45 (2H, m, ¼ CCH2); 13C NMR (CDCl3) d 175.8
(s), 145.8 (s), 96.4 (d), 65.5 (t), 28.6 (t), 26.6 (q), 21.2 (t); m/z (EI) 141 (M+,
48%), 124 (100%), 119 (13%), 114 (47%), 98 (42%), 88 (33%), 84 (69%),
68 (59%), 57 (79%); HRMS, M+ found 141.0783, C7H11NO2 requires
141.0790.

1760
KHAN, MARSON, AND PORTER
1-Benzyl-5-(2-hydroxyethylidene)pyrrolidin-2-one (3b). To a solution of
1b (0.1 g, 0.46 mmol) in vinyl acetate (5 ml) was added pyridinium para-
toluenesulfonate (13 mg, 0.046 mmol) and the solution stirred at 20ꢀC for
0.5 h. Sodium hydrogen carbonate (0.2 g) was added and the solution
filtered and evaporated. The residue was purified by column chromato-
graphy (80:20 ethyl acetate: 40–60ꢀC petroleum ether) to give 3b as a
clear oil (40 mg, 40%); IR, ꢀmax (thin film): 3380, 1690 cmꢁ1 1H N MR
;
(CDCl3) d 7.50–7.00 (5H, m, Ar), 4.82 (1H, tt, J ¼ 7.5 Hz, J ¼ 2 Hz,
¼ CH ), 4.68 (2H, s, CH2Ph), 8.83 (2H, d, J ¼ 7.5 Hz, CH2OH), 2.70–2.40
(4H, m); 13C NMR (CDCl3) d 175.9 (s), 144.2 (s), 136.0 (s), 128.7 (d), 127.4
(d), 127.3 (d), 97.7 (d), 65.0 (t), 43.9 (t), 28.6 (t), 21.3 (t); m/z (FAB): 218
(M+, 72%), 197 (32%), 182 (62%), 160 (100%), 139 (25%); HRMS, MH+
found 218.1181, C13H16NO2 requires 218.1190.
5-(2-Benzyloxyethylidene)-1-methylpyrrolidin-2-one (3c). A mixture of
5-hydroxy-1-methyl-5-vinylpyrrolidin-2-one13 (0.20 g, 1.42 mmol) and
benzyl alcohol (4.0 g, 37 mmol) in THF (15 ml) was cooled to 0ꢀC and
then treated with a catalytic quantity of pyridinium para-toluenesulfonate.
The mixture was then stirred at 20ꢀC for 2 h, diluted with diethyl ether
(20 ml) and washed with half-saturated brine. The organic layer was dried
(MgSO4) and evaporated to give an oil which was purified by Kugelrohr
distillation (90ꢀC/0.2 mm Hg) followed by column chromatography
(30:70 ethyl acetate: 40–60ꢀC petroleum ether) to give 3c as a light orange
oil (0.25 g, 81%); IR, ꢀmax (thin film): 1690, 1100 cmꢁ1; 1H NMR (CDCl3) d
7.30 (5H, m, Ar), 4.90 (1H, tt, J ¼ 7.5 Hz, J ¼ 2.0 Hz, ¼ CH ) 4.52 (2H, s,
CH2Ph), 4.05 (2H, d, J ¼ 7.5 Hz, CH2OBn), 2.95 (3H, s, CH3), 2.80–2.60
(2H, m, CH2CO), 2.55–2.40 (2H, m, ¼ CCH2); 13C
N
MR
(CDCl3) d 175.8 (s), 145.9 (s), 138.2 (s), 128.4 (d), 127.9 (d), 127.7 (d),
96.5 (d), 72.2 (t), 65.4 (t), 28.6 (t), 26.6 (q), 21.2 (t); m/z (FAB): 232
(MH+, 35%), 212 (100%), 98 (42%), 67 (49%); HRMS, MH+ found
232.1348, C14H18NO2 requires 232.1357.
5-(2-Ethoxyethylidene)-1-methylpyrrolidin-2-one (3d). To a solution of
5-hydroxy-1-methyl-5-vinylpyrrolidin-2-one13 (0.20 g, 1.42 mmol) in ethanol
(15 ml) at 20ꢀC was added a catalytic quantity of pyridinium para-toluene-
sulfonate. The mixture was then stirred for 30 min at 20ꢀC and the ethanol
evaporated at 30ꢀC to give an oil which was purified by column chromato-
graphy (70:30 ethyl acetate: 40–60ꢀC petroleum ether) to give 3d as an
1
orange oil (0.17 g, 71%); IR, ꢀmax (thin film) 1690, 1100 cmꢁ1; H N MR
(CDCl3) d 5.84 (1H, tt, J ¼ 7.5 Hz J ¼ 2.0 Hz, ¼ CH), 3.98 (2H, d,
J ¼ 7.5 Hz, CH2OEt), 3.48 (2H, q, J ¼ 7.5 Hz), 2.88 (3H, s, CH3), 2.70
(2H, m, CH2CO), 2.45 (2H, m, ¼ CCH2), 1.16 (3H, t, J ¼ 7.5 Hz,
OCH2CH3); 13C NMR (CDCl3) d 175.8 (s), 145.5 (s), 96.7 (d), 65.6 (t),
28.6 (t), 26.5 (q), 21.1 (t), 15.3 (q); m/z (EI): 169 (Mþ, 25%), 140 (18%),

SYNTHESIS OF EXOCYCLIC ENAMIDES
1761
124 (100%), 114 (54%), 96 (21%), 68 (20%), 55 (15%); HRMS, Mþ found
169.1093, C9H15NO2 requires 169.1103.
5-(2-Ethoxyethylidene)-1-[2-(tetrahydropyran-2-yloxy)ethyl]-pyrrolidin-
2-one(3e) . To solution of 5-hydroxy-1-[2-(tetrahydropyran-2-yloxy)ethyl]-5-
vinylpyrrolidin-2-one (0.24 g, 0.94 mmol) in ethanol (8 ml) at 20ꢀC was added
pyridinium para-toluenesulfonate (24 mg, 0.094 mmol). The mixture was then
stirred for 0.5 h and quenched by adding solid sodium hydrogen carbonate.
It was then filtered and evaporated at 20ꢀC. The residue was purified by
column chromatography (65:35 ethyl acetate: 40–60ꢀC petroleum ether) to
give 3e as a light orange oil (0.26 g, 98%): IR, ꢀmax (thin film): 1690,
1
1100 cmꢁ1; H NMR (CDCl3) d 5.06 (1H, tt, J ¼ 7.5 Hz, J ¼ 2.1 Hz ¼ CH),
4.62 (1H, t, J ¼ 3.5 Hz, OCHO), 4.02 (2H, d, J ¼ 7.5 Hz, CH2OCH2CH3),
3.85–3.40 (8H, m), 2.76 (2H, t, J ¼ 7.5 Hz, CH2CO), 2.49 (2H, m, ¼ CCH2),
1.90–1.40 (6H, m), 1.22 (3H, t, J ¼ 7.5 Hz, OCH2CH3); 13C N MR
(CDCl3) d 175.7 (s), 144.1 (s), 98.4 (d), 97.0 (d), 65.7 (t), 65.3 (t), 63.1 (t),
61.9 (t), 39.6 (t), 30.4 (t), 28.5 (t), 25.4 (t), 21.3 (t), 19.1 (t), 15.2 (q); m/z
(FAB): 154 (74%), 136 (100%), 126 (41%); HRMS, Mþ found 283.1776,
C15H25NO4 requires 283.1784.
Reaction of 1-Benzyl-5-hydroxy-5-vinylpyrrolidin-2-one (1b) with tert-
Butyl Hydroperoxide and with tin (IV) Chloride. Caution: care should be
exercised and correct procedures followed17when handling with tert-butyl
hydroperoxide and the alkyl peroxide products. A solution 1b (0.3 g,
1.38 mmol) in dichloromethane (20 ml) was cooled to ꢁ78ꢀC and treated
dropwise with tin (IV) chloride (37 mg, 0.14 mmol, 10 mol %) followed by
tert-butyl hydroperoxide (Caution: 0.52 ml, 3.18 mmol, 6.08 M solution in
dichloromethane). The mixture was then stirred atꢁ78ꢀC for 2 h, poured
onto ice (15 g) and the layers separated. The aqueous layer was extracted
with dichloromethane (3 ꢂ 10 ml) and the combined organic extracts dried
(MgSO4) and evaporated to give an oil which was purified by column chro-
matography (14:86 ethyl acetate: 40–60ꢀC petroleum ether) to give the
diperoxide 4 as a colourless oil (69 mg, 13%); IR, ꢀmax (thin film):
1705 cmꢁ1 1H NMR (CDCl3) d 7.35–7.10 (5H, m, Ar), 4.79 (1H, d,
;
J ¼ 15.5 Hz, CH2Ph), 4.12 (1H, d, J ¼ 15.5 Hz, CH2Ph), 3.87 (2H, t,
t
J ¼ 7.0 Hz, CH2OO), 2.70–1.70 (6H, m), 1.20 (9H, s, Bu), 1.15 (9H, s,
tBu); 13C NMR (CDCl3) d 177.0 (s), 138.6 (s), 128.4 (d), 127.7 (d), 127.0
(d), 98.2 (s), 80.1 (s), 79.9 (s), 69.8 (t), 42.8 (t), 34.7 (t), 30.2 (t), 28.7 (t), 26.5
(q), 26.3 (q); m/z (FAB): 380 (MHþ, 100%), 290 (90%), 234 (14%), 216
(16%), 190 (65%); HRMS, MHþ found 380.2450, C21H34NO5 requires
380.2437; and the peroxide 5 as a colourless oil (136 mg, 33%); IR, ꢀmax
(thin film): 1705 cmꢁ1; 1H NMR (CDCl3) d 7.40–7.20 (5H, m, Ar), 5.62 (1H,
d, J ¼ 17.5 Hz, J ¼ 11.0 Hz, ¼ CH), 5.35 (1H, dd, J ¼ 17.5 Hz, J ¼ 1.5 Hz
¼ CH2), 5.16 (1H, dd, J ¼ 11.0 Hz, J ¼ 1.5 Hz, CH2), 4.63 (1H, d, J ¼

1762
KHAN, MARSON, AND PORTER
15.5 Hz, CH2Ph), 4.16 (1H, d, J ¼ 15.5 Hz, CH2Ph), 2.55–2.35 (2H, m,
t
CH2CO), 2.20–2.00 (2H, m, CH2) 1.15 (9H, s, Bu); 13C NMR (CDCl3) d
177.0 (s), 138.5 (s), 136.2 (d), 128.6 (d), 127.9 (d), 127.3 (d), 117.7 (d), 97.6
(s), 80.0 (s), 43.4 (t), 32.0 (t), 30.7 (t), 26.6 (q); m/z (FAB): 290 (MHþ,
100%), 234 (18%), 216 (31%), 190 (67%); HRMS, MHþ found 290.1770,
C17H24NO3 requires 290.1756.
1-Benzyl-5-(2-bromoethylidene)-3-pyrrolidin-2-one (6). A solution of 1b
(0.2 g, 0.92 mmol) in THF (5 ml) and water (1 ml) was cooled to 0ꢀC and
treated portion-wise with N-bromosuccinimide (0.18 g, 1.01 mmol). When
the addition was complete the mixture was stirred at 20ꢀC for 20 h.
Diethyl ether (5 ml) and water (5 ml) were then added, and the layers sepa-
rated. The aqueous layer was extracted with diethyl ether (2 ꢂ 4 ml),
the combined organic extracts washed throughly with saturated aqueous
sodium hydrogen carbonate (8 ml) then brine (5 ml), and dried (MgSO4).
Evaporation gave a residue which was purified by column chromatography
(50:50 ethyl acetate: 40–60ꢀC petroleum ether) to give 6 as a dark red
solid (156 mg, 61%), mp 82–84ꢀC (ethyl acetate/petroleum ether); IR,
1
ꢀmax (nujol mull): 1705, 1680, 1645 cmꢁ1; H NMR (CDCl3) d 7.40–7.05
(6H, m), 6.35 (1H, dd, J ¼ 6.0 Hz, J ¼ 2.0 Hz, ¼ CHCO), 5.51 (1H, dt,
J ¼ 9.0 Hz, J ¼ 2.0 Hz, ¼ CHCH2Br), 4.82 (2H, s, CH2Ph), 4.18 (2H,
d, J ¼ 9.0 Hz, CH2Br); 13C NMR (CDCl3) d 169.9 (s), 142.3 (s), 136.6
(s), 132.0 (d), 128.7 (d), 127.5 (d), 126.8 (d), 125.6 (d), 109.2 (d), 42.7
(t), 26.7 (t); m/z (EI): 277 (Mþ, 79Br, 13%), 233 (11%), 198 (100%), 91
(78%), 65 (11%); HRMS, Mþ found 277.0105, C13H12NO79Br requires
277.0102
Reaction of 1-Benzyl-5-(2-bromoethylidene)-3-pyrrolin-2-one (6) with
Diethyl Sodiomalonate. Sodium hydride (24 mg, 0.79 mmol, 80% dispersion
in oil) was washed twice with THF, then THF (10 ml) was added. The
mixture was cooled to 0ꢀC and treated dropwise with diethyl malonate
(0.13 g, 0.79 mmol) in THF (5 ml). It was then stirred at 0ꢀC for 0.5 h and
a solution of 6 (0.20 g, 0.72 mmol) in THF (5 ml) was added dropwise. When
the addition was complete the mixture was stirred 20ꢀC for 3 h, poured onto
saturated aqueous ammonium chloride (10 ml) and the layers separated. The
aqueous layer was exracted with ether (2 ꢂ 5 ml) and the combined organic
extracts dried (MgSO4) and evaporated. The residue was purified by column
chromatography (30:70 then 40:60 ethyl acetate: 40–60ꢀC petroleum ether)
to give 7 as a dark red oil (91 mg, 35%); IR, ꢀmax (thin film): 1735,
1690 cmꢁ1
;
1H NMR (CDCl3) d 7.40–7.10 (6H, m), 6.27 (1H, dd,
J ¼ 6.0 Hz, J ¼ 1.5 Hz, ¼ CHCO), 5.28 (1H, t, J ¼ 8.5 Hz, ¼ CHCH2), 4.80
(2H, s, CH2Ph), 4.12 (4H, q, J ¼ 7.0 Hz, OCH2), 3.36 (1H, t, J ¼ 7.5 Hz,
COCHCO), 2.84 (2H, dd, J ¼ 8.5 Hz, J ¼7.5 Hz ¼ CHCH2), 1.21 (6H, t,
J ¼ 7.0 Hz, CH3); 13C NMR (CDCl3) d 170.1 (s), 168.3 (s), 141.3 (s), 137.1

SYNTHESIS OF EXOCYCLIC ENAMIDES
1763
(s), 132.9 (d), 128.6 (d), 127.3 (d), 126.9 (d), 124.8 (d), 110.1 (d), 61.7 (t), 52.0
(t), 51.7 (d), 26.9 (t), 14.0 (q); m/z (FAB): 358 (MHþ, 100%), 342 (62%),
305 (31%), 276 (48%), 243 (56%); HRMS, MHþ found 358.1660,
C20H24NO5 requires 358.1654; and 8 as a dark red oil (226 mg, 60%); IR,
1
ꢀmax (thin film): 1735, 1690 cmꢁ1; H NMR (CDCl3) d 7.40–7.05 (10H, m,
Ar), 6.67 (2H, dd, J ¼ 5.5 Hz, J ¼ 2.0 Hz, CH¼ CHCO), 6.12 (2H, dd,
J ¼ 5.5 Hz, J ¼ 2.0 Hz, ¼ CHCO), 5.02 (2H, J ¼ 8.0 Hz, ¼ CHCH2), 4.76
(4H, s, CH2Ph), 4.09 (4H, q, J ¼ 7.0 Hz, OCH2CH3), 2.58 (4H, d, J ¼
8.0 Hz, ¼ CHCH2), 1.17 (6H, t, J ¼ 7.0 Hz, 2CH3); 13C NMR (CDCl3) d
170.0 (s), 169.8 (s), 141.5 (s), 137.2 (s), 132.3 (d), 128.7 (d), 127.5 (d),
127.2 (d), 124.8 (d), 107.9 (d), 61.8 (t), 57.6 (s), 42.6 (t), 30.7 (t), 14.0 (q);
m/z (FAB): 555 (MHþ, 100%), 464 (21%), 371 (31%), 308 (41%), 296
(34%), 284 (24%), 262 (21%), 218 (45%), 210 (39%); HRMS, MHþ
found 555.2488, C33H35N2O6 requires 555.2495.
ACKNOWLEDGMENTS
We are grateful to the Engineering and Physical Sciences Research
Council and SmithKline Beecham for a CASE award (to A.K.).
REFERENCES
1. Burk, M.J.; Allen, J.G.; Kiesman, W.F. J. Am. Chem. Soc. 1998, 120,
657.
2. Kolocouris, N. Bull. Soc. Chim. Fr. 1973, 1057.
3. Abell, A.D.; Oldham, M.D.; Taylor, J.M. J. Org. Chem. 1995, 60,
1214; Orr, D.E.; Synthesis, 1984, 7, 614; Kapron, P.; Lhommet, G.;
Maitte, P. Tetrahedron Lett. 1981, 22, 2255.
4. Hart, D.J. J. Org. Chem., 1981, 46, 367.
5. Altenbach, D.-J. in Comprehensive Organic Synthesis, Eds. Trost, B.
M. and Fleming, I. Pergamon Press, Oxford, 1991, vol. 6, pp. 829–844.
6. (a) Grieco, P.A.; Tathill, P.A.; Slam, H.L. J. Org. Chem., 1981, 46,
5005. (b) Overman, L. E. Angew. Chem. Int. Ed. Engl. 1984, 23, 579.
7. Babler, J.H.; Olsen, J.O. Tetrahedron Lett. 1974, 351.
8. (a) Braude, E.A. Quart. Rev., 1950, 404. (b) Bruun, D.S.; Heilbron,
I.M.; Weedon, A.C.; Woods, P. J. Chem. Soc. 1950, 633.
9. Narasaka, K.; Kusama, H.; Hayashi, Y. Tetrahedron 1992, 48, 2059.
10. Miyashita, N.; Yoshikoshi, A.; Grieco, P.A. J. Org. Chem. 1977, 42,
3772.
11. Speckamp, W.N.; Hiemstra, H. Tetrahedron 1985, 41, 4367.

1764
KHAN, MARSON, AND PORTER
12. Kitagawa, Y.; Hashimoto, S.; Iemura, S.; Yamamoto, H.; Nozaki, H.
J. Am. Chem. Soc. 1976, 98, 5030.
13. Drage, J.S.; Earle, R.A.; Vollhardt, K.P.C. J. Heterocycl. Chem. 1982,
19, 701.
14. Nagao, Y.; Dai, W.-M.; Ochai, M.; Shiro, M. Tetrahedron 1990, 46,
6361.
15. Katritzky, A.R.; Liso, G.; Lunt, E.; Patel, R.C.; Thind, S.S.; Zia, A. J.
Chem. Soc., Perkin Trans. 1 1980, 849.
16. Barry, J.E.; Finkelstein, M.; Moore, W.M.; Ross, S.D.; Eberson, L.;
Jonsson, L. J. Org. Chem. 1982, 47, 1292.
¨
17. Hanson, R.M.; Sharpless, K.B. J. Org. Chem. 1986, 51, 1922.
Received in the UK September 22, 1999