Organozirconium-mediated solution- and solid-phase synthesis of 3-benzyl pyrrolidines and other potentially neuroactive amines

Article abstract of DOI:10.1055/s-2006-951553

An efficient route to 3-benzylpyrrolidines using a zirconium-mediated cyclisation both in solution and on a solid support is reported. 3-Benzylidine-pyrrolidines, 3-aryl-pyrrolidines and 4-arylpiperidines were also synthesised. Georg Thieme Verlag Stuttga

Full text of DOI:10.1055/s-2006-951553

3314
LETTER
Organozirconium-Mediated Solution- and Solid-Phase Synthesis of 3-Benzyl
Pyrrolidines and Other Potentially Neuroactive Amines
S
ynthesis of 3-Be
u
nzyl Pyrroli
p
dines and oth
e
er Potentia
r
lly Neur
t
oactive
Amin
A
es . Hunter, Donald P. S. Macfarlane, Richard J. Whitby*
School of Chemistry, University of Southampton, Southampton, Hants SO17 1BJ, UK
Fax +44(2380)593781; E-mail: rjw1@soton.ac.uk
Received 29 August 2006
phase. The usual route, alkylation of an allylamine with a
Abstract: An efficient route to 3-benzylpyrrolidines using a zirco-
nium-mediated cyclisation both in solution and on a solid support is
reported. 3-Benzylidine-pyrrolidines, 3-aryl-pyrrolidines and 4-
arylpiperidines were also synthesised.
cinnamyl bromide, works well in solution but the large ex-
cess needed to drive the reaction to completion on a solid
phase would lead to over-alkylation. It is also not suitable
for library synthesis as the substituted cinnamyl bromides
require multistep synthesis. Our route thus started with the
cinnamic acids 1a–e, readily available commercially or by
Knoevenagal condensation13 (Scheme 1 and Table 1).
Key words: zirconium, neuroactive, pyrrolidine, solid-phase, li-
brary
The cinnamic acids 1a–e were converted to their acid
chlorides followed by addition of allylamine in aqueous
NaOH to give the corresponding N-allyl cinnamides 2a–
e, isolated by recrystallisation from ethanol in moderate to
good yields. The secondary amides were benzylated to
give 3a–e. Carbonyl reduction of 3a with LiAlH414 failed
to give 4a cleanly but reduction with 1.3 equivalents of
AlH3 in THF,15 generated using the procedure of Yoon,15a
was found to work well and was applied to give the bisal-
lylic amines 4a–e in moderate yield.
Efficient synthesis of nitrogen heterocycles, both in solu-
tion and on the solid phase, is important for the provision
of compounds for drug discovery. Nitrogen heterocycles
which contain an aryl ring b or g to the nitrogen are par-
ticularly relevant in the search for neuroactive compounds
as they are conformationally constrained analogues of
neurotransmitters such as dopamine and serotonin as well
as known ligands for opiate receptors.1 Compounds con-
taining a pyrrolidine motif display activity in many bio-
logical systems and a particularly interesting class of
pyrrolidine pharmacophores are the 3-benzyl pyrrolidines
which exhibit potent activity as antagonists for the NK-3
receptor2 and dopamine receptor3 and also as protein ki-
nase C inhibitors.4 Zirconocene-mediated bicyclisation of
p-components to the corresponding zirconacycles was
first reported by Negishi and Nugent5 and these have
proven valuable synthetic intermediates for elaboration in
many ways.6 Zirconocene induced co-cyclisation has
been reported as a route to nitrogen heterocycles.7,8 We
now report its application to the synthesis of potentially
neuroactive amines, particularly 3-benzyl pyrrolidines for
which efficient synthetic routes are lacking.9 An addition-
al aim of the work reported below was to develop a syn-
thetic route which could be used for library synthesis, and
to demonstrate the first use of zirconocene mediated co-
cyclisations on resin bound systems. Solid-phase synthe-
sis of pyrrolidines via palladium-catalysed cyclisation–
cleavage has been reported10 and several late transition-
metal-mediated p-component cyclisations on the solid
phase are also known including Pauson–Khand reaction11
and olefin metathesis–cleavage.12
Dienes 4a–e were cyclised using Negishi’s reagent, zir-
conocene(1-butene),16 generated in situ from dibutylzir-
conocene. An extended time at room temperature was
used to isomerise the initially formed 1:1 mixture of
trans- to cis-fused zirconacycles 5 to a 5:1 mixture in
favour of the former. Protonolysis gave the pyrrolidines
6a–e as inseparable 5:1 trans- to cis-mixtures.17 The ste-
reochemistry of the major and minor isomers was clear
from the 13C NMR shifts of the methyl groups (typically
O
i. oxalyl chloride, catalytic DMF,
CH2Cl2, 0 °C to r.t., overnight.
O
Ar
Ar
HN
Ar
HO
ii. NaOH (aq), allylamine, 0 °C to r.t.,
20 min
1
2
O
NaH, BnBr,
r.t., overnight
AlH3, THF, 0 °C,
BnN
30 min
Ar
BnN
3
4
The key step in our 3-benzylpyrrolidine synthesis was to
be the zirconocene-mediated co-cyclisation of 1-aryl-4-
aza-1,6-dienes 4. We needed a synthesis of 4, which was
reasonable for library synthesis, including on a solid
Cp2ZrCl2,
Ar
MeOH,
NaHCO3 (aq),
Ar
nBuLi (2.0 equiv)
BnN
BnN
ZrCp2
r.t., 2 h
–78 °C to r.t.
then r.t., 8 h
5
6
SYNLETT 2006, No. 19, pp 3314–3318
0
1
.1
2
.2
0
0
6
Scheme 1 Solution-phase synthesis of 3-benzylpyrrolidines.
Advanced online publication: 23.11.2006
DOI: 10.1055/s-2006-951553; Art ID: D25506ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 3-Benzyl Pyrrolidines and other Potentially Neuroactive Amines
3315
Table 1 Solution-Phase Synthesis of 3-Benzylpyrrolidines
Series
Ar
Yield of 2 (%)
Yield of 3 (%)
Yield of 4 (%)
Yield of 6 (%)
a
b
c
d
e
Ph
50
59
87
89
59
97
99
57
55
51
50
50
91
81
54
76
70
4-MeC6H4
4-MeOC6H4
4-F-C6H4
3,4-(OCH2O)C6H3
100
53
82
dC = 19.4 and 15.2 ppm, respectively), the upfield shift in complete conversion to 8, and monitoring over 36 hours
the cis-isomer being due to the g-gauche effect (steric showed slow conversion of the initial 1:1 trans:cis isomer
compression).18
mixture to 2:1, isolated in 86% yield, based on the expect-
ed loading of the resin.
We now sought to develop a solid-phase approach to the
demonstrated zirconocene-mediated 3-benzylpyrrolidine We now sought to apply our solid-phase conditions to the
synthesis. To test the key zirconocene-mediated cyclisa- synthesis of a small library of 3-benzylpyrrolidines.
tion of a resin-supported diene Merrifield resin was heated
Reaction of Merrifield resin with allylamine in refluxing
with diallylamine in N-methylpyrrolidinone (NMP) over-
THF generated the resin-bound amine 10. Coupling of 10
night at 120 °C to furnish immobilised diallyl amine 7
with cinnamic acids 1a–e using 1-hydroxybenzotriazole
(Scheme 2).19 The resin was washed thoroughly with
(HOBT) and 1,3-diisopropylcarbodiimide (DIC) failed to
give 11a–e in CH2Cl2 (indicated by the resins giving a
freshly distilled THF and dried under 0.1 mmHg vacuum
to ensure no moisture remained for the zirconocene-medi-
positive chloranil test)22 but was quantitative in DMF.
ated cyclisation. It should be noted that dichloromethane
Resin-bound amides 11a–e were reduced with 1.3 equiv-
alents AlH3 to give 12a–e. Subsequent addition of three
equivalents of dibutylzirconocene, overnight agitation
should not be used to swell or wash the resin as we have
shown that zirconocene(1-butene) reacts rapidly with it.20
The resin was suspended in THF at –78 °C and treated
and MeOH–NaHCO3 (aq) quench gave resin-bound pyr-
with one equivalent of dibutylzirconocene, prepared in a
rolidines 13a–e. Cleavage from the resin using ethylchlo-
roformate generated carbamates 14a–e each as a 2:1 ratio
of trans- to cis- isomers in moderate yield (25–57% over
separate flask. After warming to room temperature, and
shaking for three hours, quenching with MeOH–NaHCO3
(aq) (shaking overnight), washing and drying the resin,
five steps from the starting Merrifield resin; Scheme 3,
then cleaving with ethylchloroformate21 gave a 2:1 mix-
Table 2).23 The pyrrolidines were obtained in 85–98%
ture of the required pyrrolidine 8 and ethyl diallylcarbam-
ate 9, the latter resulting from cleavage of the uncyclised
material. Use of two equivalents dibutylzirconocene gave
O
NH
N
Ar
b
Cl
a
diallylamine,
NMP,
N
Cp2ZrBu2
120 °C, 14 h
–78 °C to r.t.
10
11a–e
7
N
N
Ar
c, d
Ar
MeOH,
NaHCO3
aq
N
N
12a–e
13a–e
Ph
ZrCp2
16 h
O
e
e
O
N
N
Ar
Ar
O
O
EtOCOCl
CH2Cl2
EtO
N
14a–e
6a–e
O
N
+
reflux, 2 h
Scheme 3 Solid-phase synthesis of 3-benzylpyrrolidines. Reagents
and conditions: a) ArCHCHCO2H, HOBT, DIC, DMF; b) AlH3,
THF, 0.5 h, 0 °C; c) Cp2ZrBu2, THF, –78 °C to r.t., then r.t. 16–24 h;
d) MeOH, NaHCO3 (aq), r.t., 16 h; e) EtOCOCl, CH2Cl2, reflux, 2 h.
8
9
Scheme 2 Model studies on solid-phase synthesis.
Synlett 2006, No. 19, 3314–3318 © Thieme Stuttgart · New York

3316
R. A. Hunter et al.
LETTER
Ph
Ph
16a R = Me, 58%
Table 2 Solid- and Solution-Phase Synthesis of 14a–e
i. Cp2ZrBu2
Series
Ar
Yield and
Yield of 14
from 6 (%)
MeN
MeN
ii. MeOH,
NaHCO3 aq
16b R = SiMe3, 61%
(purity) of 14
from 10 (%)
R
R
15a R = Me; 15b R = SiMe3
a
b
c
Ph
41 (95)
57 (90)
32 (95)
34 (95)
25 (85)
63
72
57
74
44
MeN
i. Cp2ZrBu2
4-MeC6H4
4-MeOC6H4
4-F-C6H4
MeN
ii. MeOH,
NaHCO3 aq
OMe
OMe
17
18, 64%
Ph
d
e
Ph
i. Cp2ZrBu2
ii. MeOH,
3,4-(OCH2O)C6H3
MeN
RN
MeN
20, 78%
NaHCO3 aq
19
Ph
purity as determined by 1H NMR comparison with analyt-
ically pure samples prepared from 6a–e.24 The observed
difference in diastereoisomeric product ratios of 6 be-
tween the solution- and solid-phase routes is interesting
and suggests that the resin environment either inhibits
isomerisation to the trans-zirconacycle, or thermodynam-
ically favours the cis-isomer compared with solution.
Ph
i. Cp2ZrBu2
22a R = Me, 78%
22b R = Bn, 52%
RN
ii. MeOH,
NaHCO3 aq
21a R = Me; 21b R = Bn
Ph
Ph
i. Cp2ZrBu2
Finally, we briefly examined the potential for zir-
conocene-induced cyclisations to provide access to other
heterocycles containing the important b- and g-aryl-amine
pharmacophores. 3-Benzylpyrrolidines 16 with an alke-
nylidene group on the 4-position were formed by zirconi-
um-mediated co-cyclisation of the enynes 15. Likewise
co-cyclisation of enyne 17 and diyne 19 formed the 3-ben-
zylidenepyrrolidines 18 and 20 (Scheme 4), the latter with
great potential for further elaboration by Diels–Alder cy-
cloadditions. We were pleased to find that cyclisation of
the dienes 21 and enyne 23 provided a useful entry to 3-
arylpyrrolidines,7d structures which were initially investi-
gated for analgesic properties, and recently shown to be
good ligands for a range of receptors including m-opioid
and dopamine.25 Finally, zirconium-mediated co-cyclisa-
tion of the 1,7-dienes 25 formed the 4-phenylpiperidines
26 in poor yield. 4-Arylpiperidines, including 3,4-dimeth-
yl-substituted examples, are potent ligands for the m-opio-
id receptor26 and the basis for several commercial drugs.
24, 51%
BnN
RN
BnN
ii. MeOH,
NaHCO3 aq
23
H
i. Cp2ZrBu2
RN
26a R = Me, 12%
26b R = Bn, 15%
ii. MeOH,
NaHCO3 aq
Ph
Ph
25a R = Me; 25b R = Bn
Scheme 4 Synthesis of potentially neuroactive amines.
References and Notes
(1) (a) Kane, B. E.; Svensson, B.; Ferguson, D. M. AAPS
Journal 2006, 8, E126. (b) Glennon, R. A.; Ismaiel, A. M.;
Smith, J. D.; Yousif, M.; El-Ashmawy, M.; Herndon, J. L.;
Fischer, J. B.; Howie, K. J. B.; Server, A. C. J. Med. Chem.
1991, 34, 1855.
(2) Horwell, D. C.; Naylor, D.; Willems, H. M. G. Bioorg. Med.
Chem. Lett. 1997, 7, 31.
(3) Thomas, C.; Ohnmacht, U.; Niger, M.; Gmeiner, P. Bioorg.
Med. Chem. Lett. 1998, 8, 2885.
(4) (a) Defauw, J. M.; Murphy, M. M.; Jagdmann, G. E.; Hu, H.;
Lampe, J. W.; Hollinshead, S. P.; Mitchell, T. J.; Crane, H.
M.; Heerding, J. M.; Mendoza, J. S.; Davis, J. E.; Darges, J.
W.; Hubbard, F. R.; Hall, S. E. J. Med. Chem. 1996, 39,
5215. (b) Jagdmann, G. E.; Defauw, J. M.; Lampe, J. W.;
Darges, J. W.; Kalter, K. Bioorg. Med. Chem. Lett. 1996, 6,
1759.
(5) (a) Negishi, E.; Holmes, S. J.; Tour, J. M.; Miller, J. A. J.
Am. Chem. Soc. 1985, 107, 2568. (b) Nugent, W. A.; Taber,
D. F. J. Am. Chem. Soc. 1989, 111, 6435.
Overall, the synthesis of the 3-benzyl-4-methyl pyrroli-
dine pharmacophore has been explored by both solution-
and solid-phase methods, the latter giving higher overall
yields. The use of AlH3 to form allylamines from cin-
namyl amides, and the first report of a zirconium-mediat-
ed cyclisation on a solid phase, are particular highlights.
Zirconium-based routes to a variety of other aryl-substi-
tuted heterocycles which will be of biological interest
have also been demonstrated.
Acknowledgment
(6) Dixon, S.; Fillery, S. M.; Kasatkin, A.; Norton, D.; Thomas,
E.; Whitby, R. J. Tetrahedron 2004, 60, 1401; and references
therein.
We thank Merck Sharpe and Dohme, Neuroscience Research Cen-
tre and Eli Lilly for funding this work.
Synlett 2006, No. 19, 3314–3318 © Thieme Stuttgart · New York

LETTER
Synthesis of 3-Benzyl Pyrrolidines and other Potentially Neuroactive Amines
3317
(7) Pyrrolidines: (a) Rousset, C. J.; Swanson, D. R.; Lamaty, F.;
Negishi, E. Tetrahedron Lett. 1989, 30, 5105. (b) Uesaka,
N.; Saitoh, F.; Mori, M.; Shibasaki, M.; Okamura, K.; Date,
T. J. Org. Chem. 1994, 59, 5633. (c) Saitoh, F.; Mori, M.;
Okamura, K.; Date, T. Tetrahedron 1995, 51, 4439.
(d) Mori, M.; Kuroda, S.; Zhang, C. S.; Sato, Y. J. Org.
Chem. 1997, 62, 3263. (e) Campbell, A. D.; Raynham, T.
M.; Taylor, R. J. K. J. Chem. Soc., Perkin Trans. 1 2000,
3194.
(8) Piperidines: (a) Kemp, M. I.; Whitby, R. J.; Coote, S. J.
Synthesis 1998, 557. (b) Kemp, M. I.; Whitby, R. J.; Coote,
S. J. Synthesis 1998, 552. (c) Mori, M.; Imai, A. E.; Uesaka,
N. Heterocycles 1995, 40, 551. (d) Bird, A. J.; Taylor, R. J.
K.; Wei, X. Synlett 1995, 1237. (e) Azepanes: Macfarlane,
D. P. S.; Norton, D.; Whitby, R. J.; Tupper, D. Synlett,
submitted.
(EI): m/z (%) = 279 (59) [M], 187 (87), 173 (76), 158 (83).
HRMS (ES+): m/z calcd for C20H26N+ [M + H+] 280.2060;
found: 280.2057.
(18) (a) Whitesell, J. K.; Minton, M. A. Stereochemical Analysis
of Alicyclic Compounds by C-13 NMR Spectroscopy;
Chapman and Hall: London, New York, 1987, 37–55.
(b) Ando, T.; Kusa, K.; Uchiyama, M.; Yoshida, S.;
Takahashi, N. Agric. Biol. Chem. 1983, 47, 2849.
(19) A carbamate linker could not be used as Cp2Zr(1-butene)
caused cleavage of the allyl–nitrogen bond rather than
cyclisation.
(20) Norton, D. PhD Thesis; University of Southampton: UK,
2004.
(21) Sasakura, K.; Adachi, M.; Sugasawa, T. Synth. Commun.
1988, 18, 265.
(22) Vojkovsky, T. Peptide Res. 1995, 8, 236.
(9) Zhou, Z.-L.; Keana, J. F. W. J. Org. Chem. 1999, 64, 3763.
(10) Brown, R. C. D.; Fisher, M. Chem. Commun. 1999, 1547.
(11) (a) Bolton, G. L. Tetrahedron Lett. 1996, 37, 3433.
(b) Bolton, G. L.; Hodges, J. C.; Rubin, J. R. Tetrahedron
1997, 53, 6611. (c) Spitzer, J. L.; Kurth, M. J.; Schore, N. E.
Tetrahedron 1997, 53, 6791.
(12) Brown, R. C. D.; Castro, J. L.; Moriggi, J. D. Tetrahedron
Lett. 2000, 41, 3681.
(13) Jones, G. Org. React. 1967, 15, 204.
(23) Solid-Phase Route to 14b.
Merrifield resin (18.75 g, 1.6 mmol/g, 30 mmol), allylamine
(600 mmol, 45 mL) in THF (120 mL) were heated at 75 °C
overnight. The resin was filtered and washed with dry
distilled THF (10 × 60 mL) then dried in a vacuum oven at
40 °C for 5 d to give resin-bound N-allylamine 10 as a white
solid (19.5 g). IR: 3082 (w), 3025 (w), 2919 (m), 2848 (w),
1601 (w), 1510 (m), 1493 (m), 1452 (s) cm–1. 4-Methyl
cinnamic acid (3.24 g, 20 mmol) and HOBT (2.70 g, 20
mmol) were stirred for 15 min in DMF (30 mL). The
reaction flask was cooled to 0 °C before DIC (3.1 mL, 20
mmol) was added. The flask was warmed to r.t. before
stirring for a further 15 min. The reaction mixture was then
poured into a plastic filter vessel containing 10 (3.25 g,
5 mmol), suspended in DMF (30 mL). The reaction was
agitated for 1 week, filtered and washed with hot DMF,
MeOH, CH2Cl2 and Et2O. The resin was dried using a
vacuum oven at 40 °C for 2 d to give the pale yellow resin-
bound(E)-N-allyl-3-(4-methylphenyl)acrylamide(11b, 3.38
g). IR: 3024 (w), 2924 (m), 1650 (s), 1605 (s), 1512 (m),
1452 (s), 1411 (s), 1200 (s) cm–1. In a dry peptide tube, 11b
(0.338 g, 0.5 mmol) was suspended in THF (40 mL). Then,
AlH3 (1.2 mL of a 0.55 M solution in THF, 0.65 mmol, 1.3
equiv) was added under an argon atmosphere. The reaction
was shaken overnight, filtered and the resin washed under
argon with dry THF and Et2O, and dried under vacuum for 2
h to afford resin-bound N-allyl-N-[(E)-3-(4-methyl-
phenyl)prop-2-enyl]amine (12b). IR: 3025 (w), 2921 (w),
1644 (w), 1602 (w), 1493 (m), 1452 (m), 1067 (m) cm–1.
Cp2ZrCl2 (0.438 g, 1.5 mmol, 3 equiv) in THF (10 mL)
was cooled to –78 °C before BuLi (1.2 mL of 2.5 M solution,
3 mmol) was added. The reaction was stirred for 30 min at
–78 °C before being added via cannular to resin 12b (0.5
mmol) suspended in THF (40 mL). The reaction was
warmed to r.t. and shaken for 20 h. The resulting burgundy-
coloured resin mixture was quenched with MeOH (5 mL)
and sat. NaHCO3 (5 mL), shaken overnight, filtered and
washed with hot H2O, MeOH, CH2Cl2 and Et2O before
drying under vacuum for 2 h to afford resin-bound 3-methyl-
4-(4-methylbenzyl)pyrrolidine (13b). IR: 2923 (w), 1567
(m), 1493 (w), 1451 (w), 1367 (m), 1020 (w) cm–1. Resin
13b (0.5 mmol) was suspended in dry CH2Cl2 (10 mL), ethyl
chloroformate (0.15 mL, 1.5 mmol) added and the mixture
boiled under reflux for 2 h. The resin was filtered, washed
with CH2Cl2 (3 × 50 mL) and the washings were con-
centrated in vacuo to give ethyl 3-methyl-4-(4-methyl-
benzyl)pyrrolidine-1-carboxylate (14b) as a colourless oil
(74 mg, 57% based on resin used) in >90% purity based on
a comparison with the NMR spectra of the pure carbamate
prepared by the solution-phase cleavage of 6b.24
(14) Akamatsu, H.; Kusumoto, S.; Fukase, K. Tetrahedron Lett.
2002, 43, 8867.
(15) (a) Yoon, N. M.; Brown, H. C. J. Am. Chem. Soc. 1968, 90,
2927. (b) Matecka, D.; Rothman, R. B.; Radesca, L.; de
Costa, B. R.; Dersch, C. M.; Partilla, J. S.; Pert, A.; Glowa,
J. R.; Wojnicki, F. H. E.; Rice, K. C. J. Med. Chem. 1996,
39, 4704. (c) Shah, J. H.; Kline, R. H.; Geter-Douglass, B.;
Izenwasser, S.; Witkin, J. M.; Newman, A. H. J. Med. Chem.
1996, 39, 3423.
(16) (a) Negishi, E.; Holmes, S. J.; Tour, J. M.; Miller, J. A.;
Cederbaum, F. E.; Swanson, D. R.; Takahashi, T. J. Am.
Chem. Soc. 1989, 111, 3336. (b) Negishi, E.; Cederbaum, F.
E.; Takahashi, T. Tetrahedron Lett. 1986, 27, 2929.
(17) Synthesis of 1-Benzyl-3-methyl-4-(4-methyl-
benzyl)pyrrolidine.
Cp2ZrCl2 (0.35 g, 1.2 mmol) in THF (5 mL) was cooled to
–78 °C before BuLi (0.96 mL of 2.5 M solution in hexane,
2.4 mmol) was added slowly. The reaction was stirred for
20 min at –78 °C before N-allylbenzyl[(E)-3-(4-methyl-
phenyl)allyl]amine (0.277 g, 1 mmol) in THF (5 mL) was
added slowly. The reaction was warmed to r.t. and stirred for
24 h. MeOH (5 mL) and sat. aq NaHCO3 solution (5 mL)
were added and mixture stirred overnight. Extractive work-
up and chromatography (SiO2, 1% Et3N, in 40:60 PE) gave
the title pyrrolidine as a 5:1 mixture of trans- to cis-dia-
stereoisomers as a colourless oil (226 mg, 81%). 1H NMR
(300 MHz, CDCl3): d = 7.25–7.10 (5 H, m), 7.00–6.94 (4 H,
m), 3.57–3.50 (1 H, m), 3.48–3.39 (1 H, m), 2.94 (1 Hcis, m),
2.75–2.61 (2 H, m), 2.57–2.25 (3 H, m), 2.22 (3 H, s), 2.13–
2.04 (1 H, m), 2.02–1.96 (1 Hcis, m), 1.93–1.76 (2 Htrans, m),
0.91 (3 Hcis, d, J = 7.3 Hz), 0.85 (3 Htrans, d, J = 6.5 Hz) ppm.
13C NMR (75 MHz, CDCl3): d (trans-isomer): 139.59 (C),
138.42 (C), 135.33 (C), 129.09 (CH), 128.87 (CH), 128.82
(CH), 128.31 (CH), 126.90 (CH), 62.36 (CH2), 60.87 (CH2),
60.30 (CH2), 48.00 (CH), 40.49 (CH2), 38.96 (CH), 21.16
(CH3), 19.41 (CH3) ppm; d (cis-isomer): 139.70 (C), 138.65
(C), 135.26 (C), 129.14 (CH), 128.87 (CH), 128.65 (CH),
128.32 (CH), 126.90 (CH), 62.62 (CH2), 61.12 (CH2), 59.84
(CH2), 41.95 (CH), 35.35 (CH2), 34.50 (CH), 21.16 (CH3),
15.17 (CH3) ppm. IR: 3025 (w), 2952 (m), 2915 (m), 2782
(m), 1514 (m), 1453 (s), 1376 (m), 1028 (m) cm–1. LRMS
Synlett 2006, No. 19, 3314–3318 © Thieme Stuttgart · New York

3318
R. A. Hunter et al.
LETTER
(24) Solution-Phase Route to 14b.
solution- and solid-phase routes, respectively) = 155.58 (C),
137.52 / 137.47 (C), 135.72 / 135.69 (C), 129.33 (CH),
128.65 (CH), 60.98 (CH2), 53.35 (CH2), 49.44 / 49.09 (CH2),
43.89 / 43.24 (CH), 35.45 / 34.74 (CH), 33.88 / 33.84 (CH2),
21.13 CH3), 15.02 (CH3), 13.71 / 13.64 (CH3) ppm. IR: 2931
(w), 2870 (w), 1695 (s), 1515 (w), 1420 (s), 1349 (m)
cm–1. LRMS (EI): m/z (%) = 261 (33) [M+], 216 (8), 156
(79), 105 (100). Anal. Calcd (%) for C16H23NO2: C, 73.53;
H, 8.87; N, 5.36. Found: C, 73.29; H, 8.78; N, 5.40.
(25) (a) Bishop, D. C.; Selway, R. A.; Webb, N. E.; Winder, C.
V.; Welford, M.; Cavalla, J. F. J. Med. Chem. 1965, 1, 316.
(b) Lyles-Eggleston, M.; Altundas, R.; Xia, J.; Sikazwe, D.
M. N.; Fan, P.; Yang, Q.; Li, S.; Zhang, W.; Zhu, X.;
Schmidt, A. W.; Vanase-Frawley, M.; Shrihkande, A.;
Villalobos, A.; Borne, R. F.; Ablordeppey, S. Y. J. Med.
Chem. 2004, 47, 497. (c) Sonesson, C.; Wikstrom, H.;
Smith, M. W.; Svensson, K.; Carlsson, A.; Waters, N.
Bioorg. Med. Chem. Lett. 1997, 7, 241.
N-Benzyl-3-methyl-4-(4-methylbenzyl)pyrrolidine (6b,
0.14 g, 0.5 mmol) and ethylchloroformate (0.15 mL, 1.5
mmol) in CH2Cl2 (10 mL) were heated at 65 °C for 3 h. The
CH2Cl2 was removed in vacuo and the resulting brown oil
purified by column chromatography (SiO2, Et2O–PE, 1:1).
Kugelrohr distillation (0.1 mmHg, 220 °C) gave 14b as a
colourless oil (94 mg, 72%). 1H NMR (400 MHz, CDCl3):
d = 7.18–7.06 (4 H, m), 4.21–4.10 (2 H, m), 3.77–3.62 (1
Htrans, m), 3.49 (1 H, m), 3.31–2.86 (4 H + 1Hcis, m), 2.81–
2.71 (2 Hcis, m), 2.58–2.41 (2 Htrans, m), 2.38 (3 H, s), 2.36–
2.29 (2 Hcis, m), 2.10–1.88 (2 Htrans, m), 1.33–1.23 (3 H, m),
1.11 (3 Htrans, d, J = 7 Hz), 1.07 (3 Hcis, d, J = 7 Hz) ppm.
13C NMR (100 MHz, CDCl3; where signals are separated by
‘/’ they correspond to rotomers due to the carbamate
group): d (trans-isomer) = 155.23 (C), 137.13 / 136.99 (C),
135.80 (C), 129.29 (CH), 128.74 / 128.71 (CH), 60.95
(CH2), 53.45 / 53.21 (CH2), 51.73 / 51.35 (CH2), 47.70 /
46.99 (CH), 38.66 / 37.98 (CH2), 37.71 / 37.61 (CH), 21.13
(CH3), 16.46 (CH3), 15.02 (CH3) ppm; d (cis-isomer; derived
from comparison of 5:1 and 2:1 trans:cis isomer mixed from
(26) Leander, D. J.; Cantrell, B. E.; Reel, J. K.; Snoddy, J.;
Laurane, M. G.; Johnson, B. G.; Mitch, C. H.; Zimmerman,
D. M. J. Med. Chem. 1993, 36, 2833.
Synlett 2006, No. 19, 3314–3318 © Thieme Stuttgart · New York