Synthesis of highly substituted pyrrolidines via palladium-catalyzed cyclization of 5-vinyloxazolidinones and activated alkenes

Article abstract of DOI:10.1016/j.tet.2008.02.019

N-Tosyl-5,5-divinyloxazolidin-2-one undergoes a palladium-catalyzed decarboxylative cyclization across a range of electrophilic alkenes to give the corresponding pyrrolidine derivatives bearing two contiguous quaternary centres. Alkenes bearing two electron-withdrawing groups are required; pyrrolidines were not formed from mono-activated alkenes. Bulky, electron-rich phosphines promote pyrrolidine formation with less highly electrophilic, doubly activated alkenes, and a dramatic improvement is observed in the presence of iodide.

Full text of DOI:10.1016/j.tet.2008.02.019

Available online at www.sciencedirect.com
Tetrahedron 64 (2008) 3744e3750
www.elsevier.com/locate/tet
Synthesis of highly substituted pyrrolidines via palladium-catalyzed
cyclization of 5-vinyloxazolidinones and activated alkenes
a
a
b
Julian G. Knight a, , Paul A. Stoker , Kirill Tchabanenko , Simon J. Harwood ,
*
Kenneth W.M. Lawrie b
a School of Natural Sciences, Bedson Building, Newcastle University, Newcastle upon Tyne NE1 7RU, UK
b GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK
Received 15 October 2007; received in revised form 18 January 2008; accepted 7 February 2008
Available online 9 February 2008
Abstract
N-Tosyl-5,5-divinyloxazolidin-2-one undergoes a palladium-catalyzed decarboxylative cyclization across a range of electrophilic alkenes to
give the corresponding pyrrolidine derivatives bearing two contiguous quaternary centres. Alkenes bearing two electron-withdrawing groups are
required; pyrrolidines were not formed from mono-activated alkenes. Bulky, electron-rich phosphines promote pyrrolidine formation with less
highly electrophilic, doubly activated alkenes, and a dramatic improvement is observed in the presence of iodide.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
In fact, this approach to the construction of the pyrrolidine
ring by cyclization across a carbonecarbon double bond to
form the NeC1 and C2eC3 bonds has been accomplished
previously using a range of different enophiles. These include
the base-promoted addition of b-chloro-amines to enones;5
addition of allylic amines across electron-rich alkenes medi-
ated by palladium(II)6 or across acrylates mediated by base;7
formation of 3-exomethylenepyrrolidines by cyclization of
propargylic amines across electron poor alkenes mediated by
base,8 copper (I)9 or palladium (0);10 Lewis acid mediated
cyclization of a-amino aldehydes across allyl silanes11 or tan-
dem Knoevenagel reaction of a-amino aldehydes followed by
cyclization of the resulting highly electron-deficient allylic
amines across enol ethers.12
Pyrrolidine-containing compounds display a wide variety
of biological activities.1 Pyrrolidines have also been used
extensively in chiral ligands and auxiliaries for asymmetric
synthesis,2 and as highly effective scaffolds for the develop-
ment of organocatalysts.3 Because of this, the synthesis of
the pyrrolidine ring system has been the subject of much
research. We were interested in developing a one-pot synthesis
of pyrrolidines based on [3þ2] cycloaddition of an activated
alkene with a 1,3-dipole (Fig. 1, path a) as an alternative to
the more commonly used addition of azomethine ylides to
activated alkenes4 (Fig. 1, path b).
We have reported13e15 the decarboxylative carbonylation of
5-vinyloxazolidin-2-ones 1 as a stereocontrolled route to piperi-
dines 2 and have used this reaction as the key step in the synthesis
of polyhydroxylated piperidines such as deoxymannojirimycin
and mannolactam.16 This reaction is proposed to proceed via
a p-allyl palladium(II) cation such as 3, which can be regarded,
after loss of CO2, as an equivalent of the 1,3-dipole 4 (Fig. 2).
This suggested the possibility of cycloaddition to suitably acti-
vated electrophilic alkenes, which would lead to pyrrolidines.
In fact, 2-vinylaziridines 5 (R1¼alkyl) have been shown to
a
b
N
R
N
R
N
R
Figure 1. Construction of the pyrrolidine ring via [3þ2] cycloaddition.
* Corresponding author. Tel./fax: þ44 191 222 7068.
E-mail address: j.g.knight@ncl.ac.uk (J.G. Knight).
0040-4020/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.02.019

J.G. Knight et al. / Tetrahedron 64 (2008) 3744e3750
3745
p-allyl palladium cationic intermediates from hydroxyalkyl
allyl carbonates using Trost’s chiral ligand.25
O
Pd(0) cat.
CO, THF
R1
N
O
R1
O
We have reported26 our preliminary investigation on the
synthesis of highly substituted pyrrolidines via palladium-
catalyzed decarboxylative [3þ2] cycloaddition of 5,5-divinyl
N-tosyloxazolidinones across alkylidene malonate derivatives
and herein present the full details of this work. Recently,
Tunge has reported the very closely analogous decarboxylative
cyclization of 6-vinyloxazinanones with alkylidene malonates
to give the corresponding vinylpiperidines.27
N
Ts
Ts
1
2
PdLn
O
R1
R1
O
N
N
Ts
4
Ts
3
Figure 2. Decarboxylative carbonylation of 5-vinyloxazolidin-2-ones via a
1,3-dipole equivalent.
2. Results and discussion
undergo palladium-catalyzed ring-opening cyclization with a
range of heterocumulenes such as carbodiimides, isothiocya-
nates and isocyanates to give the corresponding five-membered
heterocycles 6 (Fig. 3),17 and this reaction has been used as the
basis for an enantioselective synthesis of imidazolidinones using
a chiral palladium catalyst.18 Yamamoto has reported the synthe-
sis of pyrrolidines 7 by palladium-catalyzed addition of N-tosyl-
2-vinylaziridines 5 (R1¼Ts) to highly electrophilic alkenes19
and, since Ibuka has shown that N-sulfonyl-5-vinyloxazolidin-
2-ones 8 are readily converted to the corresponding vinylazir-
idines 9 by palladium-catalyzed decarboxylation,20 this suggests
that the more easily synthesized oxazolidinones might be used in
place of aziridines for the preparation of pyrrolidine derivatives.
In a similar way, Takemoto has reported the use of N-sulfonylox-
azolidinones in place of the corresponding aziridines in a palla-
dium-catalyzed synthesis of g-amino alcohols.21
As the synthesis of pyrrolidines 7 from vinylaziridines 5 is
reported to occur with low diastereoselectivity,19 we chose to
use the achiral 5,5-divinyloxazolidinone 10, which avoids this
issue as long as the two electron-withdrawing groups on the
alkene are identical. Oxazolidinone 10 was prepared in three
steps from N-Boc glycine methyl ester (Scheme 1). Treatment
of the amino ester with excess vinyl magnesium bromide gave
the bisallylic alcohol 11, which, without purification, was cy-
clized to the oxazolidinone 12 by treatment with potassium
tert-butoxide. Tosylation of the oxazolidinone nitrogen pro-
duced 10 in good yield.
a
BocHN
11
BocHN
CO2Me
OH
Pd(OAc)2/PPh3
R1N
b
c
HN
O
TsN
O
R1N
NR2
6
R2N
C Y
O
Y = NR2, S, O
5
O
Y
12
10
Scheme 1. Reagents and conditions: (a) CH2CHMgBr (2.5 equiv), THF,
ꢁ78 ꢀC to 20 ꢀC, 4 h; (b) KOtBu, THF, 0 ꢀC, 3 h, 45% for two steps; (c)
NaH, THF, 0 ꢀC, then TsCl, 90%.
Z
Z
R1=Ts
R2
R1N
R2
Z
Pd2(dba)3, (4-FC6H4)3P
Z
7
The benzylidene Meldrum’s acid derivative 13a was used
to investigate the optimum conditions for the reaction. We
were pleased to find that treatment of the oxazolidinone 10
with palladium tetrakis(triphenylphosphine) (10 mol %) fol-
lowed by the alkene 13a at 40 ꢀC gave the corresponding
pyrrolidine 14a albeit in low yield (23%, Table 1, entry 1).
In our work on carbonylation of N-tosyl 5-vinyloxazolidinones
we found that a reduction in the phosphine/palladium ratio was
tolerated such that yields were essentially unchanged when
just one phosphine per palladium was used.28 The results in
Table 1 (entries 1e5) show that this is true here also. The yield
of pyrrolidine 14a was essentially unchanged as the phospho-
rus/palladium ratio was reduced from 4:1 to 1:1, although no
reaction was observed when triphenylphosphine was omitted
altogether. It can also be seen that the yields are relatively in-
dependent of the nature of the palladium precursor: Pd(PPh3)4
(entry 1), Pd2(dba)3 plus PPh3 (entry 5) and Pd2(dba)3$CHCl3
plus PPh3 (entries 2e4) all giving similar yields of pyrrolidi-
none (Scheme 2).
R2
R2
R1O2SN
(Ph3P)4Pd cat.
THF, 0 °C
R1O2SN
O
O
8
9
Figure 3. Palladium-catalyzed reactions involving vinylaziridines.
In choosing a suitable dipolarophile, we were guided by the
extensive reports of palladium-catalyzed tandem additions of a
range of nucleophile/electrophile combinations to highly elec-
tron-deficient alkylidene malonate derivatives.22 Balme has re-
ported the synthesis of exomethylene tetrahydrofurans and
pyrrolidines by palladium-mediated cyclization of propargylic
alcohols and amines across alkylidene malonates23 and has ex-
tended this to three-component couplings terminated by metal-
catalyzed arylation to give benzylidene pyrrolidines from
propargylic amines.10b,f Yamamoto has used the palladium-
catalyzed addition of vinyloxiranes to alkylidene malonates
to form tetrahydrofurans24 and has reported an enantioselec-
tive variant based on the generation of similar hydroxyalkyl
A range of phosphines of varying steric and electronic prop-
erties were screened (entries 6e11). Tributylphosphine and the

3746
J.G. Knight et al. / Tetrahedron 64 (2008) 3744e3750
Table 1
Palladium-catalyzed decarboxylative cyclization of 5,5-divinyloxazolidin-2-one 10 with Michael acceptors 13 (Scheme 2)
Entry
Michael acceptor
Phosphine
P:Pda
Additive
Product
Yieldb
1
13a
13a
13a
13a
13a
13a
13a
13a
13a
13a
13a
13a
13a
13a
13a
13a
PPh3
PPh3
4c
4
2
1
1e
4
4
4
4
4
4
4
4
4
4
4
d
d
14a
14a
14a
14a
14a
14a
14a
14a
14a
14a
14a
14a
14a
14a
14a
14a
23d
24d
21d
23d
18d
0
2
3
PPh3
PPh3
d
d
4
5
PPh3
Bu3P
TMPPf
d
d
6
7
O
O
O
d
d
35
0
TsN
O
8
dppb
dppf
Ph
O
Ph
O
9
d
d
d
0
O
10
11
12
13
14
15
16
2-Ph(C6H4)PCy2 (15a)
2-Ph(C6H4)PtBu2 (15b)
O
36
11
0
PPh3
PPh3
PPh3
PPh3
PPh3
Bu4NF
Bu4NCl
Bu4NBr
Bu4NI
Bu4NOAc
0
67
77
42
O
CN
O
O
17
18
19
20
13b
13b
13b
13b
PPh3
PPh3
PPh3
PPh3
1
1
4
4
d
14b
14b
14b
14b
38
60
63
78g
CN
Bu4NI
Bu4NI
Bu4NI
N
O
Ts
21
22
23
24
13c
13c
13c
13c
PPh3
PPh3
1
4
4
4
d
14c
14c
14c
14c
65
62
73g
72
CN
CO2Et
TsN
Ph
Bu4NI
Bu4NI
Bu4NI
Ph
PPh3
2-Ph(C6H4)PCy2 (15a)
CO2Et
CN
25
26
27
13d
13d
13d
PPh3
PPh3
PPh3
1
4
4
d
Bu4NI
Bu4NI
14d
14d
14d
95
68
35g
CN
CN
TsN
Ph
Ph
CN
CN
MeO
28
29
30
13e
13e
13e
PPh3
PPh3
PPh3
1
4
4
d
Bu4NI
Bu4NI
14e
14e
14e
97
84
53g
TsN
CN
CN
CN
CN
4-MeOC6H4
31
32
33
13f
13f
13f
PPh3
PPh3
PPh3
1
4
4
d
Bu4NI
Bu4NI
14f
14f
14f
82
58
43g
TsN
O
CN
CN
CN
CN
O
a
Ratio of phosphorus/palladium in catalyst used.
Isolated yield.
b
c
d
e
f
Pd(PPh3)4 (10 mol %) was used in this case.
NMR yield, see Section 3 for details.
Pd2(dba)3 (5 mol %) was used in this case.
TMPP¼trimethylolpropane phosphite.
Reaction time was 18 h in this case.
g
chelating diphosphines dppb and dppf gave no product (the ox-
azolidinone was the major component visible in the NMR of the
crude product mixture). Improvements in the yield of pyrrol-
idine were observed using the phosphite TMPP (entry 7) and
the bulky electron-rich 2-(dicyclohexylphosphino)biphenyl
15a (entry 10), introduced by Buchwald29 for amination reac-
tions. The even more bulky 2-(di-tert-butylphosphino)biphenyl
15b gave a poorer result (entry 11). Although the improvements
in yield were encouraging, the relatively high cost of TMPP and
15a in comparison to triphenylphosphine makes these less
attractive.
The influence of added halide and acetate ions was then ex-
amined using triphenylphosphine as the ligand (entries 12e16).
Both fluoride and chloride ions inhibited the reaction and none
of the pyrrolidine was observed (entries 12 and 13). A dramatic
improvement was observed when tetrabutylammonium
Z1
Ar
Z2
TsN
TsN
13
O
10
Z2
O
Z1
Ar
14
Scheme 2. Reagents and conditions: Pd2(dba)3$CHCl3 (5 mol %), PPh3, 13
(1.5 equiv), additive (2.0 equiv), THF, 40 ꢀC, 2 h.

J.G. Knight et al. / Tetrahedron 64 (2008) 3744e3750
3747
2
I
L4Pd
- 2L
LPd PdL
I
TsN
Ar
Z
+ I
Z
L2Pd
L2PdI
14
TsN
O
+ L
O
oxidative
addition
10
TsN
Ar
TsN
Ar
+ I
PdLI
TsN
+ I
TsN
O
PdL
Z
PdL2I
Z
Z
21
Z
O
O
O
PdL2
20
17
16
- CO2
+ I
-L
Z
Ar
13
TsN
Ar
TsN
Ar
+ I
TsN
Z
TsN
PdL2I
PdL2I
conjugate
addition
PdL2
Z
Z
Z
Z
PdL2
18
19
Scheme 3. Proposed catalytic cycle.
bromidewas used (67%, entry 14) and this was increased further
still with iodide (77%, entry 15). Acetate ions also promoted the
reaction, but to a lesser extent than either bromide or iodide
(42%, entry 16).
The more highly activated arylidene malononitrile deriva-
tives 13def gave excellent yields of the corresponding pyrro-
lidines 14def (entries 25, 28, 31) and in these cases the
addition of iodide led to lower yields (entries 26, 29, 32),
which dropped even further with prolonged reaction times (en-
tries 27, 30, 33). The benzylidene malononitrile 13d was re-
covered unchanged after treatment with tetrabutylammonium
iodide in THF either in the presence or absence of Pd2(dba)3
and triphenylphosphine. The reason for the detrimental effect
of iodide in these cases is unclear but probably involves fur-
ther reactions of the initially formed pyrrolidine on extended
reaction times.
Having established the effective reaction conditions, we
then investigated a variety of different electron-deficient coup-
ling partners. The 3-cyanochromone 13b behaved in a similar
way to the Meldrum’s acid derivative 13a in that cyclization
occurred to give the corresponding pyrrolidine 14b in moder-
ate yield (38%, entry 17). In the presence of iodide, the yield
was improved to 60% (entry 18) and use of a P:Pd ratio of 4
gave a slightly better yield than a ratio of 1 (63%, entry 19).
The best yield (78%) was obtained by extending the reaction
time to 18 h (entry 20). The use of a more electrophilic alkene,
ethyl E-2-cyanocinnamate 13c gave the pyrrolidine 14c in
65% yield, essentially as a single diastereoisomer (entry 21).
In this case the addition of iodide produced an almost identical
yield (62%, entry 22) with a reaction time of 2 h, but this was
improved (73%, entry 23) after 18 h. The yield was not further
increased by using the bulky phosphine 15a (72%, entry 24).
The stereochemistry of the pyrrolidine 14c was assigned on
the basis of comparison of the chemical shift of the pyrrolidine
2-proton (5.51 ppm), which was much closer to the value
(5.76 ppm) in the Meldrum’s acid derived product 14a in
which the 2-H is syn to an ester than to that of the correspond-
ing malononitrile-derived products 14def (5.18e4.97 ppm),
in which the 2-H is necessarily syn to a nitrile group. The
stereochemical outcome can be explained on the basis of mini-
mizing the steric interaction between the phenyl ring and
the substituents (CO2Et and CN) on the 3-position of the pyr-
rolidine but would also arise if the cyclization occurred by
a concerted syn-addition across the dipolarophile.
Attempts to use less activated Michael acceptors such as
ethyl cinnamate, ethyl acrylate, acrylonitrile, maleic anhy-
dride, phenyl vinyl sulfone, b-nitrostyrene and dimethyl acetyl-
enedicarboxylate were all unsuccessful.
A possible catalytic cycle is shown in Scheme 3. Failure of
the reaction when chelating diphosphines dppb and dppf were
used suggests that at some stage of the mechanism palladium
carries only one phosphine ligand. This may also be supported
by the success of the reaction even when the phosphorus/
palladium ratio is reduced from 4:1 to 1:1 and also by the
improvement when the very bulky phosphine 15a was used,
since this ligand favours mono-phosphine p-allyl palla-
dium(II) complexes.30 Electron-rich phosphines, such as 15a
are expected to accelerate the rate of the oxidative addition
step and bulky ligands facilitate reductive elimination.29,31
Halide ions are well known to affect the outcomes of transition
metal-catalyzed processes, including reactions involving
p-allyl palladium(II) species.32 Acceleration of the oxidative
addition step to form a p-allyl palladium(II) intermediate
may result from the increased nucleophilicity of (Ph3P)nPdXꢁ

3748
J.G. Knight et al. / Tetrahedron 64 (2008) 3744e3750
species.32 Halide ions are known to add to p-allyl palla-
dium(II) cations to set up an equilibrium with the corresponding
h1-bonded allyl complexes.32 In this case, decarboxylation of
the p-allyl cation 16 may be slow due to a favourable intramo-
lecular interaction between the palladium and the carbamate
anion. Iodide-induced conversion of 16 into the s-allyl 17
may facilitate the subsequent decarboxylation by disrupting
this interaction. In a similar way, the conjugate addition of
the p-allyl cation 18 to the electrophile 13 may be retarded
by stabilization of the amide anion by palladium; this interac-
tion would also be reduced by formation of the corresponding
s-allyl complex 19. It is likely that the final, cyclization step
occurs from a p-allyl cation, such as 20, rather than the less
electrophilic s-allyl 21. In our case, iodide proved to be the
most effective halide additive, and this was especially evident
in reactions of less reactive alkenes (13aec) and chloride ions
were found to inhibit the present reaction completely (Table 1,
entry 13). Given the improvement found using the bulky elec-
tron-rich phosphine 15a and iodide, steric factors may be
important, either in favouring ligand dissociation or dissociation
of coordinated carbamate oxygen (from a species such as 16),
which will facilitate decarboxylation or reductive elimination
in the cyclization step.
The failure of reactions using less electrophilic alkenes
suggests that the nucleophilicity of the nitrogen-based anion
is important. While the strongly electron-withdrawing tosyl
group assists in the decarboxylation step by stabilizing the
resulting anion on nitrogen, this same stabilization will reduce
the nucleophilicity of the anion and slow down the subsequent
conjugate addition step. It may therefore be useful to explore
less powerfully electron-withdrawing substituents on nitrogen.
Indeed, Yamamoto has recently reported a very effective inter-
molecular aminoallylation of activated alkenes using allyl
carbamates in which the nitrogen atom bears a less electron-
withdrawing alkoxycarbonyl group.33
Flash column chromatography was performed on Fluorochem
LC3025 silica gel (40e63 mm). All reactions were carried out
under an atmosphere of nitrogen in pre-dried glassware unless
otherwise stated. Where necessary, solvents were dried prior to
use. Dichloromethane was distilled from calcium hydride un-
der nitrogen immediately prior to use. Ethanol was distilled
˚
from magnesium under nitrogen and stored over 4 A molecu-
lar sieves. Ether and tetrahydrofuran were distilled from
sodium/benzophenone ketyl immediately prior to use. All
chemicals were purchased from the Aldrich, Fluka, Sigma,
Strem or Lancaster chemical companies and were used as sup-
plied except where indicated. The benzylidene Meldrum’s acid
derivative 13a was prepared as previously described.34
3.2. 5,5-Divinyloxazolidin-2-one 12
To a stirred solution of N-(tert-butoxycarbonyl)glycine
methyl ester (10.06 g, 53.2 mmol) in THF (500 mL) was added
vinyl magnesium bromide (212 mL, 1 M solution in THF,
212 mmol) dropwise and the mixture was stirred at room tem-
perature for 2 h. The reaction was quenched with saturated
aqueous ammonium chloride (100 mL) and the mixture was
extracted with EtOAc (3ꢂ100 mL). The combined organic
layers were washed with brine (2ꢂ100 mL), dried (MgSO4),
filtered and the solvent removed under reduced pressure to
give the crude bisallylic alcohol 11 as a light brown oil
(10.89 g), which was used without further purification.
For the crude product 11: dH (300 MHz, CDCl3) 5.88 (2H,
dd, J¼10.7, 17.3 Hz, CH]CH2), 5.41 (2H, d, J¼17.3 Hz,
CH]CH2), 5.20 (2H, d, J¼10.7 Hz, CH]CH2), 3.25 (2H,
t
d, J¼6.2 Hz, NCH2), 1.43 (9H, s, Bu).
To a stirred solution of the bisallylic alcohol 11 (10.89 g,
51.1 mmol) in THF (500 mL) at 0 ꢀC was added KOtBu
(6.87 g, 61.3 mmol) and the reaction mixture was stirred for
15 h. The solvent was removed under reduced pressure and
the residue dissolved in ethyl acetate. The solution was
washed with brine until the brine layer was clear. The organic
layer was dried (MgSO4), filtered and the solvent was removed
under reduced pressure. The crude product was purified by
flash column chromatography (petrol/EtOAc, 1:1) to give the
oxazolidinone 12 as a light brown oil (3.33 g, 45% over two
steps). dH (300 MHz, CDCl3): 6.18 (1H, br s, NH), 5.88
(2H, dd, J¼10.7, 17.1 Hz, CH]CH2), 5.35 (2H, d,
J¼17.1 Hz, HC]CHH), 5.24 (2H, d, J¼10.7 Hz, HC]CHH),
3.49 (2H, s, NCH2); dC (75 MHz, CDCl3): 159.2, 136.8, 116.2,
83.5, 50.6; nmax/cmꢁ1 (film): 3292, 2989, 1754; m/z (EIþ): 140
(Mþ, 11%), 112 (20), 98 (8), 94 (24), 83 (77), 68 (54), 55 (90),
43 (19), 39 (100). Anal. Calcd for C7H9NO2: C, 60.42; H,
6.52; N, 10.07%, found: C, 60.96; H, 6.45; N, 9.62%.
In summary, we have developed an effective palladium-
catalyzed cyclization of the 5,5-divinyloxazolidinone 10
across a range of electron-deficient alkenes. Iodide promotes
the reaction with less highly activated electrophiles and the
cyclization generates pyrrolidines 14 bearing two contiguous
quaternary carbon atoms in good yields.
3. Experimental
3.1. General
Melting points were determined on a Linkham TC92 hot
stage and are uncorrected. Infrared spectra were recorded on
a Nicolet 20 PCIR instrument. Mass spectra were recorded
on Micromass Autospec M and Kratos MS80 RF spectrome-
1
ters in electron impact (EI) mode. H NMR spectra were re-
3.3. 3-(para-Toluenesulfonyl)-5,5-divinyloxazolidin-2-one 10
corded on Bruker WM 300 (300 MHz), JEOL LA 500
(500 MHz) and Bruker AMX 500 (500 MHz) spectrometers
at ambient temperature. 13C NMR was recorded on Bruker
WM 300 (75 MHz) and JEOL LA 500 (125 MHz) spectrome-
ters at ambient temperature. Thin layer chromatography was
performed on EM reagent 0.25 mm silica gel 60-F plates.
To a suspension of sodium hydride (1.153 g, 60% dispersion
in oil, 28.8 mmol) in THF (14 mL) and DMF (36 mL) at
0 ꢀC were added 5,5-vinyloxazolidin-2-one 12 (2.005 g,
14.4 mmol) and p-toluenesulfonyl chloride (3.571 g,
18.7 mmol) and the mixture was stirred overnight. The reaction

J.G. Knight et al. / Tetrahedron 64 (2008) 3744e3750
3749
mixture was cooled to ꢁ78 ꢀC, quenched with saturated ammo-
nium chloride (50 mL) and extracted with ether (2ꢂ75 mL).
The combined organic layers were washed with hydrochloric
acid (50 mL, 2.0 M), saturated aqueous sodium hydrogen
carbonate (50 mL), water (50 mL) and brine (100 mL), dried
(MgSO4), filtered and the solvent was removed under reduced
pressure. The crude mixture was purified by flash column
chromatography (petrol/EtOAc, 19:1, 9:1, 4:1) to give the
oxazolidinone 10 as a white solid (2.188 g, 90%); mp 85e
87 ꢀC; dH (300 MHz, CDCl3): 7.95 (2H, d, J¼8.3 Hz, two of
MeC6H4SO2), 7.41 (2H, d, J¼8.3 Hz, two of MeC6H4SO2),
5.91 (2H, dd, J¼17.2, 10.8 Hz, CH]CH2), 5.43 (2H, d,
J¼17.2 Hz, HC]CHH), 5.36 (2H, d, J¼10.8 Hz, HC]CHH),
3.95 (s, 2H, NCH2), 2.48 (s, 3H, CH3); dC (75 MHz, CDCl3):
151.3, 146.2, 135.4, 134.3, 130.3, 128.6, 118.3, 81.9, 54.2,
22.1; nmax/cmꢁ1 (KBr): 2923, 1776, 1363, 1169; m/z (EIþ):
229 (Mþꢁ64, 36%), 174 (8), 157 (6), 149 (83), 139 (30), 119
(11), 108 (19), 91 (100), 79 (21), 65 (66), 56 (87), 39 (24).
Anal. Calcd for C14H15NO4S: C, 57.32; H, 5.15; N, 4.77%,
found: C, 57.40; H, 5.16; N, 4.78%.
dd, J¼17.1, 10.5 Hz, CH]CH2), 5.39 (1H, d, J¼11.1 Hz,
CH]CHH), 5.18 (1H, d, J¼17.4, CH]CHH), 5.13 (1H, d,
J¼17.1 Hz, CH]CHH), 5.04 (1H, d, J¼10.5 Hz, CH]CHH),
4.51 (1H, d, J¼10.9 Hz, NCH2), 4.02 (1H, d, J¼10.9 Hz,
NCH2), 2.41 (3H, s, ArCH3), 1.51 (3H, s, CH3), 0.89 (3H, s,
CH3); dC (125 MHz, CDCl3): 165.2, 163.0, 143.8, 136.9,
136.4, 135.3, 133.9, 129.7, 129.5, 128.8, 128.3, 128.1,
120.0, 117.4, 105.6, 71.44, 68.1, 58.1, 56.9, 30.4, 28.3, 21.7;
nmax/cmꢁ1 (KBr): 2924, 1774, 1742; m/z (EIþ): 482 (Mþ,
55%), 449 (50), 349 (96), 305 (100), 261 (54); found: (Mþ)
482.1623, C23H28NO6S requires: 482.1637.
3.4.2. 1,2,3,3a,4,9a-Hexahydro-4-oxo-1-(para-toluene-
sulfonyl)-3,3-divinylchromeno[2,3-b]pyrrole-3a-carbo-
nitrile 14b
White solid; mp 145e148 ꢀC; dH (300 MHz, CDCl3): 7.80e
7.70 (3H, m, ArH), 7.50 (1H, apparent t, J¼7.8 Hz, ArH), 7.29
(2H, d, J¼7.8 Hz, ArH), 7.02 (1H, t, J¼7.8 Hz, ArH), 6.94 (1H,
d, J¼8.4 Hz, ArH), 6.17 (1H, dd, J¼17.4, 10.8 Hz, CH]CH2),
6.08 (1H, s, NCH), 5.69 (1H, dd, J¼17.4, 10.8 Hz, CH]CH2),
5.33 (1H, d, J¼10.8 Hz, CH]CHH), 5.09 (1H, d, J¼17.4 Hz,
CH]CHH), 5.06 (1H, d, J¼17.4 Hz, CH]CHH), 4.93 (1H, d,
J¼10.8 Hz, CH]CHH), 3.74 (1H, d, J¼9.6 Hz, NCH2), 3.60
(1H, d, J¼9.6 Hz, NCH2), 2.36 (3H, s, CH3); dC (125 MHz,
CDCl3): 182.8, 159.3, 145.1, 138.2, 135.3, 135.2, 134.2,
130.3, 128.2, 128.0, 127.7, 123.6, 120.1, 119.8, 119.2, 114.7,
91.33, 60.3, 57.0, 54.2, 21.8; nmax/cmꢁ1 (KBr): 2247, 1638,
1644; m/z (EIþ): 421 (Mþ, 20%), 208 (50); found: (MþþH)
421.1230, C23H21N2O4S requires: 421.1222.
3.4. Typical procedure for palladium-catalyzed pyrrolidine
formation
Pd2(dba)3$CHCl3 (41.4 mg, 0.04 mmol) was added to a
stirred solution of the oxazolidinone 10 (234 mg, 0.8 mmol),
phosphine (0.08e0.32 mmol, depending on the reaction) and
tetrabutylammonium salt (1.6 mmol, added in some cases,
see table) in THF (10 mL). The mixture was stirred at 40 ꢀC
for 20 min and then a solution of the electrophilic alkene 13
(1.2 mmol) in THF (4 mL) was added dropwise. The resulting
solution was stirred for 2 h, filtered through a plug of Celite,
washed with dichloromethane and the solvent was removed
under reduced pressure. Purification by flash column chroma-
tography (SiO2) eluting with petrol/EtOAc (5:1) gave the
pyrrolidine 14.
3.4.3. 1-(para-Toluenesulfonyl)-3-cyano-3-ethoxycarbonyl-
2-phenyl-5,5-divinylpyrrolidine 14c
White prisms; mp 102e103 ꢀC; dH (300 MHz, CDCl3): 7.40
(2H, d, J¼6.6 Hz, ArH), 7.30e7.10 (7H, m, ArH), 6.24 (1H, dd,
J¼17.4, 10.8 Hz, CH]CH2), 5.52 (1H, dd, J¼17.1, 10.8 Hz,
CH]CH2), 5.51 (1H, s, NCH), 5.45 (1H, d, J¼10.8 Hz,
CH]CHH), 5.38 (1H, d, J¼17.1 Hz, CH]CHH), 5.28 (2H,
m, CH]CH2), 4.15 (1H, d, J¼11.5 Hz, NCH2), 4.25e4.00
(2H, m, OCH2CH3), 3.95 (1H, d, J¼11.5 Hz, NCH2), 2.31
(3H, s, ArCH3), 1.18 (3H, t, J¼7.1 Hz, OCH2CH3); dC
(125 MHz, CDCl3): 163.7, 144.1, 136.6, 135.2, 134.9, 133.7,
129.8, 129.2, 128.8, 128.4, 127.7, 120.0, 119.9, 115.4, 66.8,
65.1, 63.9, 56.4, 55.7, 21.5, 14.4; nmax/cmꢁ1 (KBr): 2244,
1745, 1342, 1270, 1164, 1095, 1000; m/z (EIþ): 450 (Mþ,
8%), 295 (95), 118 (100), 91 (65); found: (Mþ) 450.1607,
C25H26N2O4S requires: 450.1613.
For the initial comparative study of Pd(PPh3)4 and Pd2(dba)3
1
with varying amounts of PPh3, yields were measured by H
NMR as follows: the crude product was filtered through Celite,
washed with CH2Cl2 (30 mL) and then the solvent was removed
under reduced pressure. The resulting oil was dissolved in
CDCl3 (2.0 mL). Two hundred and fifty microlitres of this solu-
tion was placed into an NMR tube and 250 mL of a solution of
1,3-dinitrobenzene [0.8 mmol in CDCl3 (2.0 mL)] was added.
The resulting mixture was diluted with CDCl3 and the 1H NMR
spectrum was recorded. The NMR yield was calculated from the
relative integrals of the signals from 1,3-dinitrobenzene (d 9.00,
1H, H-2; d 8.50, 2H, H-4) and the pyrrolidine product 14a (d
5.18e5.04, 3H, vinyl-H; d 4.51, 1H, H-5; d 4.02, 1H, H-5). In
the case of Table 1, entry 5, purification of the product resulted
in an isolated yield of 18%, close to the NMR yield of 23%.
3.4.4. 1-(para-Toluenesulfonyl)-3,3-dicyano-2-phenyl-5,5-
divinylpyrrolidine 14d
White prisms; mp 99e101 ꢀC; dH (300 MHz, CDCl3):
7.40e7.10 (9H, m, ArH), 6.04 (1H, dd, J¼17.4, 10.8 Hz,
CH]CH2), 5.96 (1H, dd, J¼17.4, 10.8 Hz, CH]CH2), 5.67
(1H, d, J¼17.4 Hz, CH]CHH), 5.62 (1H, d, J¼10.8 Hz,
CH]CHH), 5.55 (1H, d, J¼10.8 Hz, CH]CHH), 5.40 (1H,
d, J¼17.4 Hz, CH]CHH), 5.05 (1H, s, NCH), 4.45 (1H, d,
J¼11.7 Hz, NCH2), 3.80 (1H, d, J¼11.7 Hz, NCH2), 2.32
(3H, s, CH3); dC (125 MHz, CDCl3): 143.0, 134.7, 133.4,
3.4.1. 8,8-Dimethyl-1-phenyl-2-(para-toluenesulfonyl)-4,4-
divinyl-7,9-dioxa-2-azaspiro[4.5]decane-6,10-dione 14a
White solid; mp 144e146 ꢀC; dH (300 MHz, CDCl3): 7.58
(2H, d, J¼8.4 Hz, ArH), 7.30e7.15 (7H, m, ArH), 5.76 (1H, s,
NCH), 5.72 (1H, dd, J¼17.4, 11.1 Hz, CH]CH2), 5.62 (1H,

3750
J.G. Knight et al. / Tetrahedron 64 (2008) 3744e3750
Weinheim, 2005; (b) Longbottom, D. A.; Franckevicius, V.; Ley, S. V.
ꢀ
Chimia 2007, 61, 247; (c) Sulzer-Mosse, S.; Alexakis, A. Chem. Commun.
130.7, 130.5, 129.7, 129.5, 128.6, 128.3, 127.2, 126.8, 126.1,
120.9, 120.3, 67.9, 54.5, 52.7, 52.3, 21.7; nmax/cmꢁ1 (KBr):
2359, 2339, 1345, 1166; m/z (EIþ): 403 (Mþ, 45%), 248
(27), 118 (100), 91 (60); found: (Mþ) 403.1372,
C23H21N3O2S requires: 403.1354.
´
2007, 3123; (d) Bolm, C.; Rantanen, T.; Schiffers, I.; Zani, L. Angew.
Chem., Int. Ed. 2005, 44, 1758.
4. For a recent review, see: Pandey, G.; Banerjee, P.; Gadre, S. R. Chem. Rev.
2006, 106, 4484.
5. Dolfini, J. E.; Dolfini, D. M. Tetrahedron Lett. 1964, 2103.
6. (a) Fugami, K.; Oshima, K.; Uchimoto, K. Tetrahedron Lett. 1987, 28,
809; (b) Fugami, K.; Oshima, K.; Utimoto, K. Bull. Chem. Soc. Jpn.
1989, 62, 2050; (c) Scarborough, C. C.; Stahl, S. S. Org. Lett. 2006, 8,
3251; (d) Larock, R. C.; He, Y.; Leong, W. W.; Han, X.; Refvik, M. D.;
Zenner, J. M. J. Org. Chem. 1998, 63, 2154.
7. (a) Barco, A.; Benetti, S.; Casolari, A.; Pollini, G. P.; Spalluto, G.
Tetrahedron Lett. 1990, 31, 4917; (b) Barco, A.; Benetti, S.; Casolari,
A.; Pollini, G. P.; Spalluto, G. Tetrahedron Lett. 1990, 31, 3039.
8. Dumez, E.; Rodriguez, J.; Dulcere, J.-P. Chem. Commun. 1997, 1831.
9. Clique, B.; Monteiro, N.; Balme, G. Tetrahedron Lett. 1999, 40, 1301.
10. (a) Clique, B.; Vassiliou, S.; Monteiro, N.; Balme, G. Eur. J. Org. Chem.
2002, 1493; (b) Azoulay, S.; Monteiro, N.; Balme, G. Tetrahedron Lett.
2002, 43, 9311; (c) Clique, B.; Fabritius, C.-H.; Couturier, C.; Monteiro,
N.; Balme, G. Chem. Commun. 2003, 272; (d) Liu, G.; Lu, X. Tetrahedron
Lett. 2002, 44, 467; (e) Clique, B.; Anselme, C.; Otto, D.; Monteiro, N.;
Balme, G. Tetrahedron Lett. 2004, 45, 1195; (f) Martinon, L.; Azoulay,
S.; Monteiro, N.; Kuendig, E. P.; Balme, G. J. Organomet. Chem. 2004,
689, 3831.
3.4.5. 1-(para-Toluenesulfonyl)-3,3-dicyano-2-(4-methoxy-
phenyl)-5,5-divinylpyrrolidine 14e
White prisms; mp 98e99 ꢀC; dH (300 MHz, CDCl3) 7.40
(2H, d, J¼8.4 Hz, ArH), 7.04e7.02 (4H, m, ArH), 6.75 (2H,
d, J¼8.7 Hz, ArH), 6.04 (1H, dd, J¼17.4, 10.8 Hz,
CH]CH2), 5.95 (1H, dd, J¼17.1, 10.8 Hz, CH]CH2), 5.65
(1H, d, J¼17.1 Hz, CH]CHH), 5.61 (1H, d, J¼10.8 Hz,
CH]CHH), 5.54 (1H, d, J¼10.8 Hz, CH]CHH), 5.40 (1H,
d, J¼17.4 Hz, CH]CHH), 4.97 (1H, s, NCH), 4.31 (1H, d,
J¼11.8 Hz, NCH2), 3.82 (1H, d, J¼11.8 Hz, NCH2), 3.69
(3H, s, OCH3), 2.32 (3H, s, ArCH3); dC (125 MHz, CDCl3)
165.2, 161.1, 144.7, 133.2, 132.3, 129.4, 128.8, 127.7, 124.4,
124.0, 122.4, 121.8, 114.9, 113.8, 69.2, 55.9, 55.7, 54.4, 53.8,
21.9; nmax/cmꢁ1 (KBr): 2225, 1513, 1278, 1180; m/z (EIþ):
433 (Mþ, 50%), 278 (59), 184 (41), 148 (100), 121 (38), 91
(41); found: (Mþ) 433.1472, C24H23N3O3S requires: 433.1460.
11. (a) Dikshit, D. K.; Goswami, L. N.; Singh, V. S. Synlett 2003, 1737; (b)
Kiyooka, S.-i.; Shiomi, Y.; Kira, H.; Kaneko, Y.; Tanimori, S. J. Org.
Chem. 1994, 59, 1958.
3.4.6. 1-(para-Toluenesulfonyl)-3,3-dicyano-2-(2-furyl)-5,5-
divinylpyrrolidine 14f
12. (a) Tietze, L. F.; Evers, H.; Topken, E. Angew. Chem., Int. Ed. 2001, 40, 903;
(b) Tietze, L. F.; Evers, H.; Topken, E. Helv. Chim. Acta 2002, 85, 4200.
13. Knight, J. G.; Ainge, S. W.; Harm, A. M.; Harwood, S. J.; Maughan, H. I.;
Armour, D. R.; Hollinshead, D. M.; Jaxa-Chamiec, A. A. J. Am. Chem.
Soc. 2000, 122, 2944.
White prisms; mp 102e104 ꢀC; dH (300 MHz, CDCl3): 7.45
(2H, d, J¼8.1 Hz, ArH), 7.30e7.20 (3H, m, ArH), 6.44 (1H, d,
J¼3.3 Hz, ArH), 6.32 (1H, dd, J¼3.3, 1.8 Hz, ArH), 6.07 (1H,
dd, J¼17.4, 10.8 Hz, CH]CH2), 5.97 (1H, dd, J¼17.4,
10.5 Hz, CH]CH2), 5.64 (1H, d, J¼17.4 Hz, CH]CHH),
5.64 (1H, d, J¼10.5 Hz, CH]CHH), 5.55 (1H, d, J¼10.8 Hz,
CH]CHH), 5.41 (1H, d, J¼17.4 Hz, CH]CHH), 5.18 (1H,
s, NCH), 4.21 (1H, d, J¼11.4 Hz, NCH2), 3.82 (1H, d,
J¼11.4 Hz, NCH2), 2.37 (3H, s, CH3); dC (125 MHz, CDCl3):
144.9, 144.3, 135.6, 132.7, 131.9, 130.2, 129.7, 127.3, 122.0,
121.7, 112.7, 111.4, 111.3, 111.0, 62.9, 55.8, 52.8, 51.3, 21.6;
nmax/cmꢁ1 (KBr): 2356, 2339, 1357, 1164; m/z (EIþ): 393
(Mþ, 7%), 238 (22), 108 (100), 91 (29); found: (Mþ)
393.1152, C21H19N3O3S requires: 393.1147.
14. Knight, J. G.; Tchabanenko, K. Tetrahedron 2002, 58, 6659.
15. Anderson, T. F.; Knight, J. G.; Tchabanenko, K. Tetrahedron Lett. 2003,
44, 757.
16. Knight, J. G.; Tchabanenko, K. Tetrahedron 2003, 59, 281.
17. Butler, D. C. D.; Inman, G. A.; Alper, H. J. Org. Chem. 2000, 65, 5887.
18. Trost, B. M.; Fandrick, D. R. J. Am. Chem. Soc. 2003, 125, 11836.
19. Aoyagi, K.; Nakamura, H.; Yamamoto, Y. J. Org. Chem. 2002, 67, 5977.
20. Ibuka, T.; Mimura, N.; Aoyama, H.; Akaji, M.; Ohno, H.; Miwa, Y.; Taga,
T.; Nakai, K.; Tamamura, H.; Fujii, N. J. Org. Chem. 1997, 62, 999.
21. Anzai, M.; Yanada, R.; Fujii, N.; Ohno, H.; Ibuka, T.; Takemoto, Y.
Tetrahedron 2002, 58, 5231.
22. For a review, see: Patil, N. T.; Yamamoto, Y. Synlett 2007, 1994.
23. Marat, X.; Monteiro, N.; Balme, G. Synlett 1997, 845.
24. Shim, J.-g.; Yamamoto, Y. J. Org. Chem. 1998, 63, 3067.
25. Sekido, M.; Aoyagi, K.; Nakamura, H.; Kabuto, C.; Yamamoto, Y. J. Org.
Chem. 2001, 66, 7142.
Acknowledgements
26. Knight, J. G.; Tchabanenko, K.; Stoker, P. A.; Harwood, S. J. Tetrahedron
Lett. 2005, 46, 6261.
We thank the EPSRC and GlaxoSmithKline for funding.
References and notes
27. Wang, C.; Tunge, J. A. Org. Lett. 2006, 8, 3211.
28. Knight, J. G.; Lawson, I. M.; Johnson, C. N. Synthesis 2006, 227.
29. (a) Wolfe, J. P.; Buchwald, S. L. Angew. Chem., Int. Ed. 1999, 38, 2413;
(b) Aranyos, A.; Old, D. W.; Kiyomori, A.; Wolfe, J. P.; Sadighi, J. P.;
Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 4369; (c) Gunda, P. Synlett
2006, 1621.
1. (a) Bellina, F.; Rossi, R. Tetrahedron 2006, 62, 7213; (b) Daly, J. W.;
Spande, T. F.; Garraffo, H. M. J. Nat. Prod. 2005, 68, 1556; (c) O’Hagan,
D. Nat. Prod. Rep. 2000, 17, 435 and references therein; (d) The Alka-
loids: Chemistry and Biology; Cordell, G. A., Ed.; Academic Press: San
Diego, CA, 2000; Vol. 54.
30. See e.g.: Faller, J. W.; Sarantopoulos, N. Organometallics 2004, 23, 2179.
~
31. Hartwig, J. F.; Richards, S.; Baranano, D.; Paul, F. J. Am. Chem. Soc.
1998, 118, 3626.
32. (a) For a review, see: Fagnou, K.; Lautens, M. Angew. Chem., Int. Ed.
2002, 41, 27; (b) Jutand, A. Appl. Organomet. Chem. 2004, 18, 574; (c)
2. Chiral auxiliaries or ligands, e.g.: (a) Ahern, T.; Muller-Bunz, H.; Guiry,
¨
P. J. J. Org. Chem. 2006, 71, 7596; (b) Pugin, B.; Blaser, H.-U. Adv. Synth.
Catal. 2006, 348, 1743; (c) Rao, H.; Jin, Y.; Fu, H.; Jiang, Y.; Zhao, Y.
Chem.dEur. J. 2006, 12, 3636; (d) Fache, F.; Schultz, E.; Tomasino,
M. L.; Lemaire, M. Chem. Rev. 2000, 100, 2159; (e) Whitesell, J. K.
Chem. Rev. 1989, 89, 1581.
~
Cantat, T.; Agenet, N.; Jutand, A.; Pleixats, R.; Moreno-Manas, M. Eur.
J. Org. Chem. 2005, 4277; (d) Fristrup, P.; Jensen, T.; Hoppe, J.; Norrby,
P.-o. Chem.dEur. J. 2006, 12, 5352.
33. Patil, N. T.; Huo, Z.; Yamamoto, Y. J. Org. Chem. 2006, 71, 6991.
34. Hu, Y.; Wei, P.; Huang, H.; Le, Z.-g.; Chen, Z.-c. Synth. Commun. 2005,
35, 2955.
3. (a) Berkessel, A.; Groger, H. Asymmetric Organocatalysis: From Biomi-
¨
metic Concepts to Applications in Asymmetric Synthesis; Wiley-VCH: