Tandem cyclisation and [2,3]-Stevens rearrangement to 2-substituted pyrrolidines

Article abstract of DOI:10.1016/S0040-4039(01)02286-9

Reaction of N-methylallylamine with diethyl meso-2,5-dibromoadipate in DMF at ambient temperature in the presence of potassium carbonate led directly to the two diastereomers of diethyl 2-allyl-N-methylpyrrolidine-2,5-dicarboxylate. The reaction proceeds via a [2,3]-sigmatropic Stevens rearrangement, which occurred spontaneously under the reaction conditions. This gave a higher yield under milder conditions than the traditional Stevens reaction of diethyl N-allylpyrrolidine-2,5-dicarboxylate with iodomethane. The sequence was a key step in the synthesis of a series of analogues of the alkaloid stemofoline.

Full text of DOI:10.1016/S0040-4039(01)02286-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 899–902
Tandem cyclisation and [2,3]-Stevens rearrangement to
2-substituted pyrrolidines
Stephen C. Smith* and Philip D. Bentley
Discovery Chemistry, Syngenta, Jealott’s Hill International Research Centre, Bracknell, Berkshire RG42 6EY, UK
Received 2 October 2001; revised 14 November 2001; accepted 30 November 2001
Abstract—Reaction of N-methylallylamine with diethyl meso-2,5-dibromoadipate in DMF at ambient temperature in the presence
of potassium carbonate led directly to the two diastereomers of diethyl 2-allyl-N-methylpyrrolidine-2,5-dicarboxylate. The
reaction proceeds via a [2,3]-sigmatropic Stevens rearrangement, which occurred spontaneously under the reaction conditions.
This gave a higher yield under milder conditions than the traditional Stevens reaction of diethyl N-allylpyrrolidine-2,5-dicarboxyl-
ate with iodomethane. The sequence was a key step in the synthesis of a series of analogues of the alkaloid stemofoline. © 2002
Elsevier Science Ltd. All rights reserved.
Stemofoline 1 is an alkaloid isolated from the plant
Stemona japonica.1 It has attracted wide interest
because of its reported insecticidal activity2 and syn-
thetically challenging structure.3
the piperazine offers a handle for coupling with
tetronate equivalents and the acylated nitrogen can
inductively lower the pKa of the basic nitrogen.
Appropriate tetronate4 3 (X=O) and tetramate5 3 (X=
NR) coupling partners were readily prepared as both
the E and Z acids using one of several effective litera-
ture routes.
As part of a programme to synthesise structurally-sim-
plified insecticidal compounds based on stemofoline,
the fused piperazine analogues 2 were designed with
three key objectives in mind (Fig. 1): (i) maintain the
structural rigidity of the natural product and a good
3-D overlay of functionality; (ii) ensure the pKa is kept
close to the unusually low measured value of 6.8 for
stemofoline; and (iii) incorporate an alkyl substituent to
mimic the n-butyl side chain. The second nitrogen of
Synthesis of the 3,8-diazabicyclo[3.2.1]octane ring sys-
tem in coupling partner 4 was accomplished using
modified literature procedures6,7 (Scheme 1). Starting
with diethyl meso-2,5-dibromoadipate 5, reaction with
benzylamine gave first the pyrrolidine via ring closure
Figure 1.
Keywords: [2,3]-sigmatropic; Stevens rearrangement; stemofoline.
* Corresponding author. Fax: +44(0)1344 455629; e-mail: steve.smith@syngenta.com
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02286-9

900
S. C. Smith, P. D. Bentley / Tetrahedron Letters 43 (2002) 899–902
Scheme 1. Reagents and conditions: (i) (a) benzylamine, 3.1 equiv., toluene, 85°C, (b) filter, then evaporate; (ii) benzylamine,
xylene, reflux, 71% over two steps; (iii) 230°C, neat, distil off EtOH, 73%; (iv) H2, 1 atm, Pd/C, MeOH, HCl, 85%; (v) LiAlH4,
Et2O, 0°C–reflux; (vi) (Boc)2O, DCM, rt, 60% over two steps; (vii) H2, 1 atm, Pd/C, MeOH, 72%.
and then the mono amide 6. The minor trans diester
was removed at this stage by column chromatogra-
phy. Cyclisation was achieved by heating 6 neat to
230°C and removing ethanol.6 Reduction with lithium
aluminium hydride, t-butyloxycarbonyl (Boc) protec-
tion and removal of the benzyl group7 gave 7 in a
reasonable overall yield.
Scheme 3. Reagents and conditions: (i) iodomethane,
K2CO3, 55°C, 48 h, 2% product by GC–MS.
It was envisaged that the route to 7 could be adapted
to make 1-alkyl-3,8-diazabicyclo[3.2.1]octanes 4 (R2=
alkyl) by making use of the [2,3]-sigmatropic Stevens
rearrangement8 of a suitable intermediate. Thus, fol-
lowing similar initial steps, the N-allyl pyrrolidine 8
was prepared (Scheme 2) as a 3:1 cis:trans mixture of
diesters.9 Pyrrolidine 8 was treated under standard
Stevens rearrangement conditions8a using excess
iodomethane and potassium carbonate in DMF at
55°C for 48 h, giving a modest 42% yield of the
2-allyl pyrrolidine 9 as a 4:1 cis:trans mixture of
diesters after purification. A small amount of starting
material 8 was recovered, although most was con-
sumed as polar by-products. It was postulated that
the product 9 was just as likely to quaternise with
iodomethane under the reaction conditions as the
starting material 8, thus lowering the overall yield.
allylamine to give the cyclised and [2,3]-Stevens-rear-
ranged product 9 directly in one pot.10 The [2,3]-
Stevens reaction proceeds more rapidly and at lower
temperature than via the quaternisation route.
The 2-allyl pyrrolidine 9 was taken on to the 1-alkyl-
3,8-diazabicyclo[3.2.1]octane following similar steps to
those described to make compound 7. The key cycli-
sation to 1211 was found to proceed much more
cleanly with the n-propyl derivative than the allyl, so
this was reduced prior to cyclisation. Only the major
cis isomer was observed to undergo subsequent cycli-
sation, with isolation of the minor undesired trans
by-product, thus confirming the initial stereochem-
istry. Reduction and debenzylation provided 1312
which was then readily coupled with a number of
tetronic and tetramic acid derivatives 3, for example
14 as shown in Scheme 5 to give the stemofoline
mimic 15.13
Perhaps not surprisingly, the bicyclic system 10 gave
only 2% of the [2,3]-Stevens rearrangement product
11 as well as mostly starting material, presumably
because the bridgehead anion does not form very
readily (Scheme 3).
In summary, it has been demonstrated that an
intramolecular cyclative approach to the key quater-
nary intermediate required for the [2,3]-Stevens rear-
A significant improvement in the [2,3]-Stevens rear-
rangement was achieved by considering an alternative
route to the key N-allyl quaternary ammoniumylide
via an intramolecular cyclisation rather than inter-
molecular quaternisation which appears to be a rate
limiting step with less reactive nitrogen centres
(Scheme 4). Thus, compound 5 reacts with N-methyl-
rangement enables
a more rapid reaction under
milder conditions, leading to a significantly higher
overall yield. It is expected that this reaction will find
general applications in the synthesis of other 2-substi-
tuted pyrrolidines and derivatives of cyclic amines
such as proline.
Scheme 2. Reagents and conditions: (i) allylamine, 3.1 equiv., toluene, 8°C, 80% as a 3:1 cis:trans mixture of diesters by GC; (ii)
iodomethane, K2CO3, DMF, 55°C, 48 h, 42% as a 4:1 cis:trans mixture by GC.

S. C. Smith, P. D. Bentley / Tetrahedron Letters 43 (2002) 899–902
901
Scheme 4. Reagents and conditions: (i) N-methylallylamine, K2CO3, DMF, 0°C–rt, 58%, as a 13:5 cis:trans mixture by GC after
column chromatography; (ii) benzylamine, xylene, reflux, 48 h, 55%; (iii) H2, Pd/C, 1 atm EtOH, quant.; (iv) 230°C, neat, distil
off EtOH, 71%; (v) LiAlH4, Et2O, 0°C–reflux, 79%; (vi) H2, 6.5 bar, Pd/C, EtOH, 35 h, 94%.
Scheme 5. Reagents and conditions: (i) (a) 14, oxalyl chloride, THF, DMF (cat.), rt, 1 h; (b) 13, Et3N, rt, 4 h, 57%.
J.; Coldham, I.; Middleton, M. L. Synlett 2000, 236–238;
(d) Glaeske, K. W.; West, F. G. Org. Lett. 1999, 1,
31–33.
References
1. (a) Irie, H.; Masaki, N.; Ohno, K.; Osaki, K.; Taga, T.;
Uyeo, S. J. Chem. Soc. D 1970, 17, 1066; (b) Masaki, N.
Kagaku No Ryoiki, 1971, 25(4), A-25 (CA75(8):54716e).
2. Sakata, K.; Aoki, K.; Change, C-F.; Sakurai, A.;
Tamura, S.; Murakoshi, S. Agric. Biol. Chem. 1978, 42
(2), 457–463.
3. For synthetic approaches to stemofoline and related
structures, see: (a) Kende, A. S.; Smalley, T. L., Jr.;
Huang, H. J. Am. Chem. Soc. 1999, 121, 7431–7432; (b)
Kercher, T.; Livinghouse, T. J. Am. Chem. Soc. 1996,
118, 4200–1; (c) Beddoes, R. L.; Davies, M. P. H.;
Thomas, E. J. J. Chem. Soc., Chem. Commun. 1992,
538–40.
4. (a) Doyle, I. R.; Massy-Westropp, R. A. Aust. J. Chem.
1982, 35, 1903–1911; (b) Price, M. F.; Massy-Westropp,
R. A. Aust. J. Chem. 1980, 33, 333–341.
5. (a) Gill, G. B.; James, G. D.; Oates, K. V.; Pattenden, G.
J. Chem. Soc., Perkin Trans. 1 1993, 2567–2579; (b)
James, G. D.; Mills, S. D.; Pattenden, G. J. Chem. Soc.,
Perkin Trans. 1 1993, 2581–2584.
6. (a) Cignarella, G.; Nathansohn, G. J. Org. Chem. 1961,
26, 1500–1504; (b) Cignarella, G.; Nathansohn, G.;
Occelli, E. J. Org. Chem. 1961, 26, 2747–2750; (c) Black-
man, S. W.; Baltzly, R. J. Org. Chem. 1961, 26, 2750–
2755.
7. Barlocco, D.; Cignarella, G.; Tondi, D.; Vianello, P.;
Villa, S.; Bartolini, A.; Ghelardini, C.; Galeotti, N.;
Anderson, D. J.; Kuntzweiler, T. A.; Colombo, D.;
Toma, L. J. Med. Chem. 1998, 41, 674–681.
8. (a) Coldham, I.; Middleton, M. L.; Taylor, P. L. J.
Chem. Soc., Perkin Trans. 1 1997, 20, 2951; (b) Kaiser, G.
V.; Ashbrook, C. W.; Baldwin, J. E. J. Am. Chem. Soc.
1971, 93, 2342; (c) Arbore, A. P. A.; Cane-Honeysett, D.
9. The stereochemistry of the inseparable cis and trans
diesters of pyrrolidine (8) was confirmed empirically by
the observation that only the cis isomer was able to lead
on to cyclisation to give the 3,8-diazabicyclo[3.2.1]octane
skeleton in subsequent steps. It was possible to isolate the
unreacted trans materials after the cyclisation reaction.
10. Typical experimental procedure for tandem intramolecular
cyclisation and Stevens rearrangement. Preparation of
compound 9. Diethyl meso-2,5-dibromoadipate (11.5 g,
31.7 mmol) was dissolved in dry DMF (25 ml) and
K2CO3 (8.75 g, 63 mmol) was added. The mixture was
cooled under N2 to 0°C (ice/water bath) with stirring and
N-methylallylamine (2.25 g, 3.04 ml, 31.7 mmol) was
added in one portion. The reaction was mildly exother-
mic and required cooling for 1 h, after which time it was
allowed to warm to ambient temperature (25°C). After
stirring for 16 h, the reaction was poured into a mixture
of ether (100 ml) and water (100 ml). The aqueous phase
was re-extracted with ether (100 ml). The combined
organic phases were washed with water (×2), brine and
dried (MgSO4). Evaporation and purification by flash
chromatography on silica, eluting with ethyl acetate in
hexane (gradient 15–25%) gave 9 (as a 13:5 mixture of
1
cis:trans diester isomers) as an oil 4.94 g (58%). H NMR
(270 MHz, CDCl3): l (ppm) 1.21–1.32 (6H, m), 1.70–1.82
(1H, m), 1.85–2.04 (1H, m), 2.04–2.16 (1H, m), 2.16–2.26
(1H, m), 2.36 (trans) and 2.56 (cis) (3H, 2s), 2.40–2.50
(1H, m), 2.61–2.74 (1H, m), 3.48–3.55 (trans) and 3.57–
3.64 (cis) (1H, 2m), 4.07–4.20 (4H, m), 5.03–5.16 (2H, m),
5.60–5.76 (cis) and 5.78–5.92 (trans) (1H, 2m); calcd for
C14H24NO4 (MH+) 270.1705, found 270.1698.

902
S. C. Smith, P. D. Bentley / Tetrahedron Letters 43 (2002) 899–902
11. Compound 12: 1H NMR (270 MHz, CDCl3): l (ppm)
0.98 (3H, t, J=7.1 Hz), 1.22–1.55 (2H, m), 1.55–1.67
(1H, m), 1.74 (1H, d, J=9.2 Hz), 1.81 (1H, d, J=9.2
Hz), 1.86–2.00 (1H, m), 2.10–2.30 (2H, m), 2.23 (3H,
s), 3.83 (1H, d, J=7.1 Hz), 4.87 (2H, s), 7.20–7.47 (5H,
m); (MS (ES+) 287 (MH+); calcd for C17H23N2O2
(MH+) 287.1760, found 287.1760.
(2H, m), 3.10 (1H, d, J=12.1 Hz), 3.31–3.39 (2H, m),
6.70 (1H, v br s); MS (ES+) 169 (MH+).
13. Compound 15: 1H NMR (270 MHz, CDCl3): l (ppm)
(2:1 rotameric isomers) 0.89–0.98 (3H, m), 1.24–1.75
(7H, m), 1.90–2.02 (1H, m), 2.11 and 2.12 (3H, 2s),
2.34 (3H, s), 2.84 (0.65H, d, J=12.8 Hz), 3.07–3.34
(2.7H, m), 3.58 (0.65H, d, J=12.8 Hz), 4.20–4.13 (1H,
m), 4.17 and 4.18 (3H, 2s), 5.73 (1H, s) MS (ES+) 335
(MH+); calcd for C18H27N2O4 (MH+) 335.1971, found
335.1979.
12. Compound 13: 1H NMR (270 MHz, CDCl3): l (ppm)
0.93 (3H, t, J=7.1 Hz), 1.20–1.63 (4H, m), 1.73–1.87
(1H, m), 1.94–2.20 (3H, m), 2.42 (3H, s), 2.70–2.80