Synthesis of highly substituted pyrrolidines via palladium catalysed formal [2+3] cycloaddition of 5-vinyloxazolidin-2-ones to activated alkenes

Article abstract of DOI:10.1016/j.tetlet.2005.07.053

Glycine-derived N-tosyl-5,5-divinyloxazolidin-2-one 10 undergoes a palladium catalysed decarboxylative ring-opening cyclization with strongly electron deficient alkylidenemalonate derivatives to give highly substituted pyrrolidines 14 containing two contiguous quaternary centres.

Full text of DOI:10.1016/j.tetlet.2005.07.053

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 6261–6264
Synthesis of highly substituted pyrrolidines via palladium
catalysed formal [2+3] cycloaddition of 5-vinyloxazolidin-2-ones
to activated alkenes
Julian G. Knight,a,* Kirill Tchabanenko,a Paul A. Stokera and Simon J. Harwoodb
aSchool of Natural Sciences, Bedson Building, Newcastle University, Newcastle upon Tyne NE1 7RU, UK
bGlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK
Received 13January 2005; revised 28 June 2005; accepted 14 July 2005
Abstract—Glycine-derived N-tosyl-5,5-divinyloxazolidin-2-one 10 undergoes a palladium catalysed decarboxylative ring-opening
cyclization with strongly electron deficient alkylidenemalonate derivatives to give highly substituted pyrrolidines 14 containing
two contiguous quaternary centres.
Ó 2005 Elsevier Ltd. All rights reserved.
Transition metal mediated addition of amines to alkenes
is an important method for the synthesis of functional-
ised nitrogen-containing compounds and has found
many applications in the synthesis of biologically impor-
tant species.1 We have reported2–4 the decarboxylative
carbonylation of 5-vinyloxazolidin-2-ones 1 as a stereo-
controlled route to piperidinones 2 and have used this
reaction as the key step in the synthesis of the polyhydr-
oxylated piperidines such as deoxymannojirimycin and
mannolactam.5
This reaction is presumed to proceed via the p-allyl pal-
ladium cation 3, which can be regarded, after loss of
CO2, as an equivalent to the 1,3-dipole 4. This suggests
the possibility of cycloaddition to suitably activated
electrophilic alkenes, which would lead to pyrrolidines.
Pd(OAc)2/PPh3
R1N
R1N
NR2
R2N C
Y
5
Y
6
Y = NR2, S, O
R1=Ts
Z
R2
R1
HN
(Ph3P)2PdCl2 cat.
EtOH, CO (60 atm)
Z
R1N
R2
R1
Z
O
Pd2(dba)3, (4-FC6H4)3P
Z
HN
7
O
O
1
2
In fact, 2-vinylaziridines 5 (R1 = alkyl) are known to
undergo palladium-catalysed ring-opening cyclization
with a range of heterocumulenes such as carbodiimides,
isothiocyanates and isocyanates to give the correspond-
ing five-membered heterocycles 6: imidazolidinone-
imines, imidazolidinethiones, and imidazolidinones,
respectively.6 An enantioselective synthesis of imidazo-
lidinones based on this reaction has been recently
reported using a chiral palladium catalyst.7 In a similar
way, N-tosyl 2-vinylaziridine 5 (R1 = Ts) has been
shown to undergo palladium-catalysed cyclization with
a range of alkylidene malonate derivatives to give pyr-
rolidine derivatives 7.8
PdL2
R1
R1
O
HN
NH
O
4
3
Keywords: Pyrrolidine; Synthesis; Palladium; Catalytic; Cycloaddition.
Corresponding author. Tel./fax: +44 (0)191 2227068; e-mail:
*
j.g.knight@ncl.ac.uk
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.07.053

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J. G. Knight et al. / Tetrahedron Letters 46 (2005) 6261–6264
Ibuka has shown that N-sulfonyl-5-vinyloxazolidin-2-
ones 8 are readily converted to the corresponding vinyl-
aziridines 9 by palladium-catalysed decarboxylation9
and this suggests that the more easily synthesised oxazo-
lidinones 8 might be used in place of aziridines for the
synthesis of pyrrolidine derivatives. Takemoto has
shown that N-sulfonyloxazolidinones can be used in
place of the corresponding aziridines in the palladium
catalysed synthesis of c-amino alcohols.10 In this letter,
we report the successful synthesis of highly substituted
pyrrolidines via palladium-catalysed decarboxylative
cycloaddition of an N-tosyl-5-vinyloxazolidin-2-one to
highly electrophilic alkenes.
14a, albeit in low yield (23% by NMR,11,12 Scheme 2,
Table 1, entry 1). Replacing Pd(PPh3)4 by Pd2(dba)3Æ
CHCl3 and PPh3 (4 equivalents per palladium) had no
significant effect on the yield (entries 1 and 2). The use
of Pd2(dba)3ÆCHCl3 allowed investigation of the effect
of changing the phosphine:palladium ratio (entries 2–
4). In fact, the yield was essentially independent of the
Pd:P ratio. From a practical point of view, the use of less
phosphine made isolation of the product more straight-
forward and so the remaining reactions were conducted
using a palladium:phosphine ratio of 1. Increasing the
reaction time from 2 to 18 h, led to the complete disap-
pearance of the oxazolidinone 10 but without any signif-
icant increase in the yield of the pyrrolidinone 14a. The
use of Pd2(dba)3 gave a similar yield to that obtained
with the corresponding chloroform adduct (entry 5 vs
entry 4).
R2
R1O2SN
R2
(Ph3P)4Pd cat.
THF, 0 oC
R1O2SN
O
8
O
Cyclization of the oxazolidinone 10 with 5 mol %
Pd2(dba)3ÆCHCl3 and 10 mol % of Ph3P in the presence
of the more reactive benzylidinemalononitrile 13b pro-
ceeded to give the pyrrolidine 14b in excellent yield
(Scheme 2, Table 1, entry 6).11 The ease of this reaction
is remarkable considering that the product is formed
with two contiguous quaternary carbons. The results
of other successful cyclizations to give a range of highly
substituted pyrrolidines are shown in Table 1. As can be
seen from Table 1, the pyrrolidine products were pro-
duced in excellent yields from arylidenemalononitriles
(entries 6–8) whereas the yields were reduced when ethyl
E-2-cyanocinnamate 13e (entry 9) or the Meldrumꢀs acid
derivative 13a were used (entry 4). Presumably, in these
latter cases, the lower yields reflect the increasing steric
demand in forming the pyrrolidines. The pyrrolidine
14e formed from ethyl E-2-cyanocinnamate was ob-
tained as a single diastereoisomer. The stereochemistry
was assigned on the basis of the chemical shift
(d = 5.51 ppm) of the proton on the 2-position of the
pyrrolidine, which was much closer to the value ob-
served for the Meldrumꢀs acid derivative 14a (d = 5.35)
than those for the nitrile derivatives 14b (5.09), 14c
(5.00), and 14d (5.10), thus suggesting that H-2 in 14e
is syn to the ester rather than to the cyano group. This
diastereoisomer would be expected to be lower in energy
than the alternative in which the larger ester group is syn
to the phenyl ring. The high stereoselectivity may result
from enhanced steric interactions due to buttressing by
the two adjacent quaternary centres.
9
Yamamoto reported8 low diastereoselectivity in the
addition of vinylaziridines to activated alkenes and so,
in order to avoid this complication, we carried out our
initial investigation on the achiral 5,5-divinyloxazolidin-
one 10. This was prepared in three steps from N-Boc
glycine methyl ester (Scheme 1). Treatment of the amino
ester with excess vinylmagnesium bromide gave the
bisallylic alcohol 11 which, without purification, was
cyclised to the oxazolidinone 12 by treatment with
potassium tert-butoxide. Tosylation of the oxazolidin-
one nitrogen produced 10 in good yield.
The Meldrumꢀs acid benzylidene derivative 13a was used
to investigate the optimum phosphine:palladium ratio.
We were pleased to find that cyclisation of the oxazoli-
dinone 10 with 10 mol % Pd(PPh3)4 in the presence of
the Meldrumꢀs acid derivative 13a gave the pyrrolidine
a
BocHN
11
BocHN
b
CO2Me
OH
c
HN
O
O
TsN
O
O
12
10
Attempts to use less highly activated Michael acceptors
such as ethyl cinnamate, ethyl acrylate, acrylonitrile,
maleic anhydride, and dimethyl acetylenedicarboxylate,
were unsuccessful and approximately 50% of the oxazo-
lidinone 10 was recovered from these reactions.
Scheme 1. Reagents and conditions: (a) CH2CHMgBr (2.5 equiv),
THF, À78 °C to rt, 4 h; (b) KOtBu, THF, 0 °C, 3h, 45% for two steps;
(c) NaH, THF, 0 °C, then TsCl, 90%.
Z1
A possible catalytic cycle is proposed in Scheme 3. Co-
ordination of Pd(0) and ring opening is expected to give
the p-allyl cation 15. Loss of CO2 is no doubt facilitated
by the electron withdrawing tosyl group, which can sta-
bilize the resulting nitrogen anion 16. Coordination of
the nitrogen to the palladium may also help to stabilize
this intermediate. The fact that only 50% of the vinyl-
oxazolidinone was recovered intact when less reactive
Ar
Z2
TsN
TsN
Ar
13
O
Z2
O
Z1
10
14
Scheme 2. Reagents and conditions: Pd2(dba)3ÆCHCl3 (5 mol %),
PPh3, 13 (1.5 equiv), THF, 40 °C, 2 h.11,12

J. G. Knight et al. / Tetrahedron Letters 46 (2005) 6261–6264
6263
Table 1. Palladium catalysed decarboxylative cyclisation of 5,5-divinyloxazolidin-2-one 10 with Michael acceptors 13
Entry
Michael acceptor
Ar
Z1
Z2
P:Pda
Prod.
Yield (%)
O
O
1
13a
4b
14a
23c
Ph
O
O
2
3
4
5
6
7
8
9
13a
13a
13a
13a
13b
13c
13d
13e
4
2
1
1d
1
1
1
1
14a
14a
14a
14a
14b
14c
14d
14e
24c
21c
23c
18c
95e
97e
82e
65e
Ph
CN
CN
CN
CN
CN
CN
CN
CO2Et
4-MeOC6H4
2-Furyl
Ph
a Ratio of Ph3P:Pd.
b Pd(PPh3)4 (10 mol %) was used in this case.
c NMR yield.12
d Pd2(dba)3 (5 mol %) was used in this case.
e Isolated yield.
proach to allokainoids recently reported by Cook and
Sun.13 In that work, a vinyloxazolidinone was reacted
first with a diketene equivalent to make a b-keto-amide,
which subsequently acted as a tethered nucleophile after
palladium catalysed ring-opening and decarboxylation.
TsN
O
TsN
Pd(0)
Z
O
Ar
Z
10
14
In summary, we have developed the palladium catalysed
formal [3+2] cycloaddition of 5,5-divinyloxazolidinone
10 to highly activated Michael acceptors to give pyrrol-
idines 14 bearing two contiguous quaternary centres.
TsN
TsN
Ar
O
O
Further study of the diastereoselectivity of the reactions
of chiral 5,5-divinyloxazolidinones derived from amino
acids other than glycine is currently underway and will
be reported in due course.
PdLn
PdLn
Z
Z
15
17
- CO2
TsN
Z
Ar
Acknowledgements
Z
PdLn
13
16
We thank the EPSRC and GlaxoSmithKline for
funding.
Scheme 3. Proposed catalytic cycle.
References and notes
Michael acceptors were used, and that extended reaction
times led to complete disappearance of the oxazolidin-
one without a corresponding increase in yield of the
pyrrolidine product, suggests that the intermediates 15
or 16 decompose by other pathways in the absence of
reactive Michael acceptors. The presence of the extra
alkene, in conjugation with the p-allyl system, may help
to stabilize 16. Michael addition of the nitrogen nucleo-
phile 16 to the electrophile gives the stabilized carbanion
17. The low nucleophilicity of the N-tosyl anion presum-
ably results in the requirement for highly electrophilic
Michael acceptors and the failure of the cyclisation in
cases where the alkene is activated only by a single elec-
tron withdrawing group.
1. Muller, T. E.; Beller, M. Chem. Rev. 1998, 98, 675–703.
2. 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–
2945.
3. Knight, J. G.; Tchabanenko, K. Tetrahedron 2002, 58,
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7. Trost, B. M.; Fandrick, D. R. J. Am. Chem. Soc. 2003,
125, 11836–11837.
The cyclisation of a tethered carbanion such as 17 onto
the p-allyl cation is similar to that involved in the ap-
8. Aoyagi, K.; Nakamura, H.; Yamamoto, Y. J. Org. Chem.
2002, 67, 5977–5980.

6264
J. G. Knight et al. / Tetrahedron Letters 46 (2005) 6261–6264
9. Ibuka, T.; Mimura, N.; Aoyama, H.; Akaji, M.; Ohno, H.;
129.5, 128.6, 128.3, 127.2, 126.1, 125.8, 120.9, 120.3, 67.9,
54.5, 52.7, 52.3, 21.7; m/z (EI) 403(M +, 45%), 248 (27),
118 (100), 91 (60); Found (M+): 403.1372, C23H21N3O2S
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Takemoto, Y. Tetrahedron 2002, 58, 5231–5239.
12. For the initial comparative study of Pd(PPh)3 and
Pd2(dba)3 with varying amounts of PPh3, yields were
11. Typical procedure: Pd2(dba)3ÆCHCl3 (41.4 mg, 0.04 mmol)
was added to a stirred solution of the oxazolidinone 10
(234 mg, 0.8 mmol) and PPh3 (21 mg, 0.08 mmol) in THF
(10 mL). The mixture was stirred at 40 °C for 20 min and
then a solution of 13b (185 mg, 1.2 mmol) in THF (4 mL)
was added dropwise. The resulting solution was stirred for
2 h, filtered through a plug of Celite and the solvent was
removed under reduced pressure. Purification by flash
column chromatography (SiO2) eluting with petrol/EtOAc
(5:1) gave the pyrrolidine 14b (384 mg, 95%) as white
prisms; mp 99–101 °C; mMAX/cmÀ1 (KBr) 2359, 2339,
1345, 1166; dH (300 MHz, CDCl3) 7.80–7.00 (9H, m, Ar),
6.00–5.76 (2H, m, @CH), 5.61 (1H, d, J 18.7, @CH), 5.54
(1H, d, J 8.9, @CH), 5.50 (1H, d, J 10.8, @CH), 5.39 (1H,
d, J 17.3, @CH), 5.09 (1H, s, H-2), 4.45 (1H, d, J 11.7, H-
5), 3.80 (1H, d, J 11.7, H-5), 2.30 (3H, s, Me); dC
(125 MHz, CDCl3) 143.0, 134.7, 133.4, 130.7, 130.5, 129.7,
1
measured by H NMR as follows: the crude product was
filtered through Celite, washed through with CH2Cl2
(30 mL) and then the solvent was removed under reduced
pressure. The resulting oil was dissolved in CDCl3
(2.0 mL). 250 lL of this solution was placed into an
NMR tube and 250 lL 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-dinitro-
benzene (d 9.00, 1H, H-2; d 8.50, 2H, H-4) and the
pyrrolidine product 14. (d 5.14–4.95, 3H, vinyl-H; d 4.41,
1H, H-5; d 3.95, 1H, H-5). In the case of Table 1, entry 4,
purification of the product resulted in an isolated yield of
17%, close to the NMR yield of 23%.
13. Cook, G. R.; Sun, L. Org. Lett. 2004, 6, 2481–2484.