Syntheses of enantiopure 3,4-diamino-1-substituted pyrrolidines

Article abstract of DOI:10.1055/s-2005-924769

A convenient and general route to enantiopure 3,4-di-amino-1-substituted pyrrolidines has been devised. 1-Alkyl, 1-alkanoyl, 1-cycloalkyl and 1-aryl-3,4-diaminopyrrolidines of the (3R,4R)-configurations have all been prepared, the cycloalkyl and (mono)ary

Full text of DOI:10.1055/s-2005-924769

PAPER
247
Syntheses of Enantiopure 3,4-Diamino-1-Substituted Pyrrolidines
S
ynthese
s
of Ena
h
ntiopure Pyr
a
rolidines rles M. Marson,*a Robert C. Mellingb
a
Department of Chemistry, University College London, Christopher Ingold Laboratories, 20 Gordon Street, London WC1H 0AJ, UK
Fax +44(020)76797463; E-mail: c.m.marson@ucl.ac.uk
Department of Chemistry, Queen Mary and Westfield College, University of London, London E1 4NS, UK
b
Received 5 July 2005
substituted 3,4-diaminopyrrolidines and their related 3,4-
disubstituted derivatives is limited, and a general route
has not yet been demonstrated. A particular limitation has
been observed in attempted two-fold displacements of the
Abstract: A convenient and general route to enantiopure 3,4-di-
amino-1-substituted pyrrolidines has been devised. 1-Alkyl, 1-al-
kanoyl, 1-cycloalkyl and 1-aryl-3,4-diaminopyrrolidines of the
(3R,4R)-configurations have all been prepared, the cycloalkyl and
(mono)aryl being novel derivatives. A previous difficulty in the corresponding pyrrolidine-trans-3,4-dimesylates with so-
synthesis of such compounds is the observation that dimesylates un-
dium azide; for example, 3,4-diazido-1-dodecylpyrroli-
dergo two-fold displacement with sodium azide in very poor yields
dine could be obtained in no more than 10% yield by the
(<10%), if at all. However, use of lithium azide permits satisfactory
use of sodium azide, either in DMF, HMPA, or under two-
yields of the diazides 5 and hence the corresponding diamines 6 and
phase conditions using phase-transfer catalysis.12 An al-
their derivatives, and avoids the generation and use of hydrazoic ac-
ternative procedure involves the generation of the highly
toxic and explosive hydrazoic acid and its use under Mit-
sunobu conditions (e.g. with diethylacetylene dicarboxyl-
ate and triphenylphosphine),10,12 but this method has been
chiefly applied only to the 1-benzyl compound and has
limitations (other sources of azide failed and a reverse or-
der of addition was necessary).12 Here, we describe con-
venient routes via the dimesylates 4 to a variety of
enantiopure 3,4-disubstituted pyrrolidines including the
diazides 5, the vicinal diamines 6 and 9, the bis(methane-
sulfonamides) 7, and the diamides 8 (Scheme 1).
id, as previously required in a Mitsunobu procedure.
Key words: enantioselective synthesis, pyrrolidines, vicinal di-
amines, two-fold inversions, lithium azide
Enantiopure trans-vicinal diamino compounds have at-
tracted much interest, such C2-symmetric diamines occu-
pying a central role in catalytic asymmetric synthesis.1
Whereas cyclohexane-1,2-diamine and its derivatives are
well described and in enantiopure forms have found ex-
tensive use as catalysts in asymmetric synthesis,2 1,2-di-
amines on a five-membered ring are much less well-
known, including 3,4-diaminopyrrolidine and its deriva-
tives. Many amino-substituted pyrrolidines possess sig-
In a representative procedure, (3R,4R)-diacetoxysuccinic
anhydride (1)13 was reacted with one equivalent of a pri-
mary amine in THF at 0 °C, and the intermediate amido
acid formed was treated directly with thionyl chloride (24
hours, 20 °C) to give the diacetoxypyrrolidin-2,5-dione 2
in good yields. The pyrrolidin-2,5-diones 2 were reduced
with NaBH4–I2 in THF,12 but with a modification of the
published procedure for the hydrolytic work-up:14 a two-
stage work-up involved stirring with acetic acid–hydro-
chloric acid 1:1 solution (10 M) for 10 hours, followed by
washing with methanolic KOH solution (4 M)
(Scheme 1). Detailed preparations of the compounds 2
and 3 have been described elsewhere.15
nificant
pharmacological
properties,3
including
antibacterial activity,4a and antagonistic activity toward
the melanin-concentrating hormone receptor.4b They have
also found use in catalytic asymmetric synthesis.5 3-Ami-
nopyrrolidines have served as templates for the introduc-
tion of essential pharmacophoric groups,6 and present a
relatively conformationally rigid framework suitable for
incorporation into anti-filarial agents.7
trans-3,4-Diaminopyrrolidines have found use in the as-
sembly of numerous systems of specific molecular
recognition8 and as catalysts in enantioselective alkyla-
tions,9 functions that make use of their C2 symmetry.
trans-3,4-Diaminopyrrolidines are also well-suited to de-
velopment in the context of combinatorial chemistry10 and
have formed the basis of some C-nucleosides.11 Substitut-
ed 3,4-diaminopyrrolidines occupy a niche that is difficult
to replace, since a wide variety of 1-substituents may be
introduced without losing the essential C2 symmetry of
the molecule. A suitable 1-substituent would also permit
attachment to polymeric resins or beads. Despite these ap-
plications and advantages, the literature on enantiopure 1-
Mesylation of the diols 3 employed methanesufonyl chlo-
ride (2.2 equiv) and triethylamine (2.2 equiv), giving the
dimesylates 4 that underwent two-fold displacement with
lithium azide20 to give the diazides 5. Hydrogenolysis
over 10% palladium on carbon afforded the diamines 6,
which could be isolated or derivatised as the dimesylates
7, the diamides 8, or the secondary amines 9. Using this
protocol, 1-alkyl-, 1-cycloalkyl-, and 1-aryl-substituted
pyrrolidines 3–9 could be consistently and reliably pre-
pared, even in quantities up to 2 g. The relevance of the se-
quence to 1-aryl substituents is noteworthy, partly
because there is no general route to such monocyclic aro-
matic systems,16 and partly because condensation of aryl-
amines with tartaric acid does not appear to be viable.
SYNTHESIS 2006, No. 2, pp 0247–0256
x
x
.
x
x
.2
0
0
5
Advanced online publication: 21.12.2005
DOI: 10.1055/s-2005-924769; Art ID: P09205SS
© Georg Thieme Verlag Stuttgart · New York

248
C. M. Marson, R. C. Melling
PAPER
O
ysed coupling at the ortho-position. Catalytic
hydrogenation of 11 could not be accomplished using
10% palladium on carbon, but proceeded in 79% yield in
the presence of palladium black (Scheme 2). Subsequent
reactions proceeded uneventfully: mesylation afforded
dimesylate 4e (81%), and two-fold displacement of the
latter with lithium azide afforded 5e (45%), which was hy-
drogenolysed in ethanol using 10% palladium on carbon
to give the diamine 6e in 84% yield. N-Substituents were
added to 6e by acylation and subsequent reduction: reac-
tion of 6e with 3,3-dimethylbutanoyl chloride and
triethylamine afforded diamide 8h (86%), which under-
went reduction by the borane–dimethylsulfide complex
Me2S·BH3, giving the secondary amine 9h in 80% yield.
The secondary amine 9g was prepared analogously, by
acylation of 6b to give 8g (92%) and reduction in 72%
yield with Me2S·BH3, affording 9g.
O
OAc
OAc
OAc
i) RNH2
NaBH4, I2
R
N
O
THF, reflux
ii) SOCl2
OAc
O
O
1
2
OH
OH
OMs
OMs
LiN3, DMF
CH3SO2Cl,
Et3N
R
R
N
R
R
N
N
3
5
4
N3
N3
NH2
NH2
H2, 10% Pd-C
ethanol
CH3SO2Cl,
Et3N
N
N
6
A convenient and general route to enantiopure 3,4-diami-
nopyrrolidines with a variety of 1-substitutents has been
devised, proceeding via the dimesylates of the readily
preparable pyrrolidine-3,4-diols 3. Access to the 1-aryl
substituents is notable, since to our knowledge 1-
monoarylated derivatives of enantiopure 3,4-diaminopyr-
rolidines have not been hitherto prepared, a significant ad-
vance considering their advantages of crystallinity and
potential for attachment to solid supports. The use of lith-
ium azide permits satisfactory two-fold displacements of
the dimesylates 4, furnishing the diazides 5, from which
the corresponding diamines 6 and their derivatives can be
obtained, while avoiding the generation and use of the
very hazardous hydrazoic acid, currently the only alterna-
tive satisfactory procedure.
NHCOR1
NHCOR1
NHCH2R1
NHMs
NHMs
R
R
N
R
N
NHCH2R1
7
8
9
g R = cyclohexyl, R1 = 2,2-dimethylpropyl
h R = 1,1'-biphenyl-2-yl, R1 = 2,2-dimethylpropyl
a R = n-octyl
b R = cyclohexyl
c R = phenyl
d R = 4-iodophenyl
e R = 1,1'-biphenyl-2-yl
f R = octanoyl
Scheme 1
A 1-alkanoyl substituent was conveniently introduced by
hydrogenolysis of (3S,4S)-1-benzylpyrrolidin-2,5-diol17
to give (3S,4S)-pyrrolidin-2,5-diol, which underwent
acylation in situ with octanoyl chloride, giving 3f in 29%
yield for the two steps. Subsequent reactions proceeded
smoothly: mesylation afforded dimesylate 4f (73%), and
two-fold displacement of the latter with lithium azide af-
forded 5f (55%), which was hydrogenolysed in ethanol,
using 10% palladium on carbon to give the N-acylated di-
amine 6f in 31% yield.
Analytical thin-layer chromatography (TLC) was performed on
Merck 0.25 mm thick pre-coated, aluminium-backed silica gel
plates, visualized by UV illumination or iodine vapour, or devel-
oped by heating with one of: (a) 5% anisaldehyde soln in EtOH–
CH3CO2H–H2SO4, 95:5:1; (b) 2% vanillin soln in EtOH–H2SO4,
98:2; (c) 1% KMnO4 in aq 0.5 M K2CO3 soln; or (d) 2.0 M H2SO4,
sat. with Ce(SO4)2. Flash column chromatography was performed
on alumina (Merck 90, 63–200 mm; 60G neutral type E) or silica gel
(Merck 40–63 mm, 230–400 mesh). Melting points were determined
on a Reichert hot stage apparatus and are uncorrected. Optical rota-
tions were recorded on an Optical activity AA-100 digital polarim-
In order to prepare 1-biphenyl-substituted pyrrolidines,
diol 3d17 was benzylated to give the ether 10 (79%) when
reacted with sodium hydride (3 equiv) and benzyl bro-
mide (2 equiv) in THF. Reaction of ether 10 under
Negishi conditions18,19 led not to the expected [1,1¢-biphe-
nyl-4-yl]pyrrolidine, but instead to the [1,1¢-biphenyl-2-
yl]pyrrolidine 11 (28%) and also the deiodinated amine
(3S,4S)-3,4-bis(oxybenzyl)-1-phenylpyrrolidine (53%).
Evidently, lithiation ortho to the pyrrolidine ring had oc-
curred, followed by transmetalation and palladium-catal-
1
eter using the Na-D line. H NMR spectra were recorded at 250
MHz and 13C NMR spectra were recorded at 62 MHz, both in
CDCl3 and on a Bruker AM 250 instrument, unless otherwise stat-
ed, using TMS as the internal standard. IR spectra were recorded as
KBr plates, CHCl3 soln, or neat as liquid films. Mass spectra were
obtained either as electron impact or fast atom bombardment. All
reactions were performed under an atmosphere of dry N2, except for
OBn
OBn
H2, palladium black
1. n-BuLi, ZnCl2
3e
I
N
N
2. Ni(acac)2, DIBAL-H,
PhBr, Ph3P
ethanol
OBn
OBn
10
11
Scheme 2
Synthesis 2006, No. 2, 247–256 © Thieme Stuttgart · New York

PAPER
Syntheses of Enantiopure Pyrrolidines
249
those reactions conducted in aq media. Solvents were rigorously
dried and purified prior to use. Solvent was transferred via cannula-
tion (stainless steel double-tipped needle) under positive atmo-
spheric pressure. Evaporation of solvent refers to removal under
reduced pressure. The NH3 used had a relative density of <0.880 at
15 °C in water. Petroleum ether (PE) used had the boiling range 40–
60 °C.
J = 13.0 Hz, NCHH), 2.24 (t, 2 H, J = 7.5 Hz, CH2CO), 1.59 (quin,
2 H, J = 6.5 Hz, CH2CH2CO), 1.20 [m, 8 H, (CH2)3CH3], 0.89 (t, 3
H, J = 7.0 Hz, CH3).
13C NMR (62 MHz, CDCl3): d = 173.5 (CO), 75.4 (CHOH), 74.0
(CHOH), 52.5 (CH2N), 51.6 (CH2N), 34.6 (CH2CH2N), 31.8, 29.5,
29.1, 24.9, 22.7 (CH2CH3), 14.1 (CH3).
MS (FAB) m/z (%) = 231 (13) [M + 2 H]+, 230 (100) [M + H]+, 229
(2) [M+].
(3S,4S)-1-[1,1¢-Biphenyl-2-yl]pyrrolidine-3,4-diol (3e)
HRMS–FAB: m/z [M + H]+ calcd for C12H24NO3: 230.1756; found:
230.1770.
To a three-necked, 100 mL flask, equipped with a two-way vacuum
tap, rubber septum, and magnetic stirring bead was added a mixture
of [1,1¢-biphenyl-2-yl]pyrrolidine 11 (2.07 g, 4.76 mmol), MeOH
(40 mL), CH3CO2H (1 mL), TFA, and Pd black (0.25 g). The vessel
was cooled to 0 °C, evacuated to 15 mmHg, and purged with H2 at
positive atmospheric pressure. After three successive evacuation–
purging cycles the vessel was allowed to warm to 40 °C and stirring
was continued over 16 h at this temperature under an atmosphere of
fresh H2. Filtration, washing with EtOH (4 × 10 mL), and evapora-
tion gave a residue that was adsorbed onto neutral alumina and the
impregnated dispersion was applied to the top of a pre-packed col-
umn of silica gel and eluted with EtOAc–Et2O (1:19). The appropri-
ate fractions were combined, filtered through a glass-wool plug, and
the eluent was evaporated to give 3e (0.96 g, 79%) as a buff solid.
An analytical sample was obtained by dropwise addition of n-hex-
ane to a soln in CHCl3 at 0 °C; [a]D32 +1.5° (c 4.6, CHCl3).
General Procedure A: (3S,4S)-3,4-Bis(methanesulfonyloxy)-1-
octylpyrrolidine (4a)
To a stirred soln of (3S,4S)-1-octylpyrrolidine-3,4-diol15 (0.185 g,
0.860 mmol) and Et3N (0.19 g, 1.9 mmol) in CH2Cl2 (30 mL) at
0 °C was added dropwise a soln of MsCl (0.22 g, 1.9 mmol) in
CH2Cl2 (8 mL). After allowing the mixture to warm slowly to
20 °C, stirring was continued for 25 min under an atmosphere of dry
N2. H2O (30 mL) was added and the aq layer was extracted with
CH2Cl2 (3 × 15 mL). The combined extracts were washed with H2O
(15 mL), aq 2.0 M citric acid (15 mL), sat. aq NaHCO3 soln (15
mL), then with brine (2 × 15 mL), and dried over MgSO4. Filtration
and evaporation gave a residue that was adsorbed onto silica gel and
the impregnated dispersion applied to a column of silica gel and
eluted with EtOAc–PE (3:7) to give 4a (0.23 g, 71%) as a semi-
crystalline solid; mp 51 °C. An analytical sample crystallised from
IR (film): 3355, 3060, 3020, 2915, 1600, 1590, 1585, 1560 cm–1.
1H NMR (250 MHz, CDCl3): d = 7.46–7.18 (m, 7 H, 4,6-aryl and
2¢,6¢-aryl), 6.98 (t, 1 H, J = 7.5 Hz, 5-aryl), 6.93 (d, 1 H, J = 7.5 Hz,
3-aryl), 4.04 (t, 2 H, J = 3.0 Hz, CHOH), 3.30 (dd, 2 H, J = 10.0, 5.0
Hz, NCHH), 2.83 (dd, 2 H, J = 10.0, 3.3 Hz, NCHH), 1.90 (br s, 2
H, CHOH).
13C NMR (62 MHz, CDCl3): d = 146.8 (2-aryl), 142.4 (1¢-aryl),
132.2 (6-aryl), 131.7 (1-aryl), 129.1 (2¢,6¢-aryl), 128.4 (3¢,5¢-aryl),
128.2 (4-aryl), 126.8 (4¢-aryl), 120.1 (5-aryl), 115.6 (3-aryl), 76.5
(CHOH), 56.6 (NCH2).
30
CHCl3–n-hexane as opaque prisms; mp 51–52 °C; [a]D +41° (c
0.9, CHCl3).
IR (nujol): 1465, 1375, 1175 cm–1.
1H NMR (250 MHz, CDCl3): d = 5.18 (t, 2 H, J = 5.0 Hz, CHOMs),
3.20 (dd, 2 H, J = 11.0, 5.0 Hz, NCHHCHOMs), 3.13 (s, 6 H,
SO2Me), 2.89 (dd, 2 H, J = 11.0, 4.0 Hz, NCHHCHOMs), 2.54 (m,
2 H, NCH2CH2), 1.53 (quin, 2 H, J = 7.0 Hz, NCH2CH2), 1.29 [m,
10 H, (CH2)5CH3], 0.88 (t, 3 H, J = 7.0 Hz, CH3).
13C NMR (62 MHz, CDCl3):
(NCH2CHOMs), 55.7 (CH2CH2N), 38.5 (SO2Me), 31.6, 29.4, 29.2,
27.7, 27.3, 22.7 (CH2CH3), 14.1 (CH3).
d = 82.0 (CHOMs), 58.2
MS (EI, 70 eV): m/z (%) = 257 (1) [M + 2 H]+, 256 (13) [M + H]+,
255 (72) [M+], 218 (3), 194 (100), 77 (5).
HRMS (EI): m/z calcd for C16H17NO2: 255.1259; found: 255.1259.
MS (FAB): m/z (%) = 372 (100) [M + H]+, 272 (32), 180 (59), 154
(7), 136 (3).
(3S,4S)-1-n-Octanoylpyrrolidine-3,4-diol (3f)
HRMS–FAB: m/z [M + H]+ calcd for C14H30NO6S2: 372.1515;
found: 372.1530.
A Parr hydrogenation vessel was charged with (3S,4S)-1-ben-
zylpyrrolidine-3,4-diol (0.70 g, 3.6 mmol), CH3OH (40 mL),
CH3CO2H (1 mL), and 10% Pd on carbon (0.30 g). The vessel was
evacuated to 55 mmHg and purged with H2 at approximately 40 psi.
After three successive evacuation–purge cycles the vessel was
capped with fresh H2 and vigorously oscillated for 72 h at 10 °C
(ambient temperature) under a blanket of H2 at approximately 40
psi. The mixture was filtered through celite 545 and the filter cake
was washed with EtOH (4 × 20 mL) and evaporated. The residue
was dissolved in THF (35 mL), cooled to 0 °C, and 3 M aq Na2CO3
soln was added dropwise until the soln came to pH 10. A soln of N-
octanoyl chloride (0.88 g, 5.4 mmol) in THF (3 mL) was then added
dropwise. The mixture was then warmed to 20 °C with stirring at
that temperature for 1 h, while maintaining pH at 9–10. The mixture
was extracted with EtOAc (30 mL) and the organic layer was sepa-
rated and retained. The aq layer was extracted with EtOAc (3 × 25
mL). All the EtOAc extracts were combined, washed with brine
(2 × 25 mL), and dried over MgSO4. The soln was filtered and evap-
orated, and the residue was purified by flash column chromatogra-
phy on silica gel, using EtOAc–MeOH (19:1) to give 3f (0.24 g,
29%) as a colourless oil; [a]D32 –1.75° (c 1.0, CHCl3).
Anal. Calcd for C16H31Cl6NO6S2 (an inclusion compound of
C14H29NO6S2 with 2 CHCl3): C, 31.49; H, 5.12; N, 2.30. Found: C,
31.96; H, 5.53; N, 2.49.
(3S,4S)-3,4-Bis(methanesulfonyloxy)-1-phenylpyrrolidine (4c)
To a stirred suspension of (3S,4S)-1-phenylpyrrolidine-3,4-diol20
(0.36 g, 2.0 mmol) and Et3N (0.41 g, 4.10 mmol) in 40 mL of
CH2Cl2 at 0 °C was added a soln of MsCl (0.47 g, 4.10 mmol) in
CH2Cl2 (5 mL) dropwise. The reaction mixture was allowed to
warm slowly to 20 °C and stirring was continued at that temperature
for 45 min under an atmosphere of dry N2. The mixture was worked
up as in General Procedure A, but replacing citric acid with 4 M HCl
soln. The residue was adsorbed onto neutral alumina and the im-
pregnated dispersion was applied to a column of silica gel, which
was eluted with EtOAc–PE (3:7) to give 4c (0.51 g, 76%) as a pur-
ple powder; mp 114 °C. An analytical sample crystallised from ben-
32
zene as light purple prisms; mp 125 °C; [a]D +53.1° (c 1.7,
CH2Cl2).
IR (KBr): 3055, 2900, 1600, 1505, 1370, 1170 cm–1.
IR (CHCl3): 3500–3200, 3000, 2850, 1625 cm–1.
1H NMR (250 MHz, CDCl3): d = 7.26 (t, 2 H, J = 8.0 Hz, m-aryl),
6.80 (t, 1 H, J = 8.0 Hz, p-aryl), 6.59 (d, 2 H, J = 8.0 Hz, o-aryl),
5.35 (m, 2 H, CHOMs), 3.85 (dd, 2 H, J = 11.5, 5.5 Hz, NCHH-
1H NMR (250 MHz, CDCl3): d = 4.78 (br s, 2 H, CHOH), 4.22 (br
s, 1 H, CHOH), 4.14 (br s, 1 H, CHOH), 3.75 (dd, 1 H, J = 13.0, 6.0
Hz, NCHH), 3.65 (dd, 1 H, J = 13.0, 5.0 Hz, NCHH), 3.42 (t, 2 H,
Synthesis 2006, No. 2, 247–256 © Thieme Stuttgart · New York

250
C. M. Marson, R. C. Melling
PAPER
CHOMs), 3.60 (dd, 2 H, J = 11.5, 3.0 Hz, NCHHCHOMs), 3.11 (s,
6 H, SO2Me).
(3S,4S)-3,4-Bis(methanesulfonyloxy)-1-n-octanoylpyrrolidine
(4f)
Following General Procedure A, diol 3f (0.22 g, 0.97 mmol) was re-
acted with MsCl and Et3N. Work-up gave a residue that was ad-
sorbed onto neutral alumina and the impregnated dispersion was
applied to a column of silica gel and eluted with EtOAc–PE (9:1) to
give 4f (0.27 g, 73%) as an off-white powder; mp 76 °C. An analyt-
ical sample crystallised from EtOAc–n-hexane (1:1) as white
plates; mp 76 °C; [a]D32 +0.68° (c 1.1, CHCl3).
13C NMR (62 MHz, CDCl3): d = 146.4 (ipso-aryl), 129.5 (m-aryl),
118.1 (p-aryl), 112.4 (o-aryl), 80.0 (CHOMs), 51.7 (NCH2), 38.6
(SO2Me).
MS (FAB): m/z (%) = 342 (23) [M+], 286 (25), 144 (100), 136 (35),
120 (27), 106 (60).
Anal. Calcd for C12H17NO6S2: C, 42.97; H, 5.11; N, 4.18. Found: C,
43.08; H, 5.08; N, 4.09.
IR (CHCl3): 3040, 2930, 1655, 1460, 1340, 1185 cm–1.
1H NMR (250 MHz, CDCl3): d = 5.31 (m, 1 H, CHOMs), 5.21 (m,
1 H, CHOMs), 3.95 (dd, 2 H, J = 14.0, 4.5 Hz, NCHHCHOMs),
3.83 (d, 2 H, J = 14.0 Hz, NCHHCHOMs), 3.15 (s, 3 H, SO2Me),
3.13 (s, 3 H, SO2Me), 2.28 (t, 2 H, J = 7.5 Hz, CH2CO), 1.65 (quin,
2 H, J = 5.2 Hz, CH2CH2CO), 1.30 [m, 8 H, (CH2)4CH3], 0.88 (t, 3
H, J = 7.0 Hz, CH3).
13C NMR (62 MHz, CDCl3): d = 172.2 (CO), 79.6 (CHOMs), 78.4
(CHOMs), 50.2 (NCH2), 49.2 (NCH2), 38.7 (SO2Me), 38.6
(SO2Me), 34.6 (COCH2), 31.7, 29.4, 29.1, 24.6, 22.6 (CH2CH3),
14.1 (CH3).
(3S,4S)-1-(4-Iodophenyl)-3,4-bis(methanesulfonyloxy)pyrroli-
dine (4d)
Following General Procedure A, diol 3d15 (0.49 g, 1.6 mmol) was
reacted with MsCl and Et3N. After work-up, the residue was ad-
sorbed onto neutral alumina and the impregnated dispersion was ap-
plied to the top of a column of silica gel and eluted with EtOAc–PE
(3:7). After evaporation of the solvent the residue was dissolved in
Et2O, filtered, and evaporated to give 4d (0.62 g, 84%) as a white
amorphous powder; mp 150 °C. An analytical sample crystallised
32
from EtOAc as small colourless needles; mp 151–151.5 °C; [a]D
+15.8° (c 1.5, DMSO).
MS (FAB): m/z (%) = 386 (100) [M + H]+, 382 (55), 260 (16), 167
(16).
IR (KBr): 3050, 2900, 1590, 1490, 1420, 1365, 1175 cm–1.
1H NMR (250 MHz, CDCl3): d = 7.48 (d, 2 H, J = 7.5 Hz, m-aryl),
6.49 (d, 2 H, J = 7.5 Hz, o-aryl), 5.42 (d, 2 H, J = 5.0 Hz, CHOMs)
3.75 (dd, 2 H, J = 13.0, 5.0 Hz, NCHHCHOMs), 3.53 (d, 2 H,
J = 13.0 Hz, NCHHCHOMs), 3.37 (s, 6 H, OSO2Me).
13C NMR (62 MHz, CDCl3): d = 146.4 (ipso-N-aryl), 137.6 (m-ar-
yl), 115.0 (o-aryl), 80.4 (CHOMs), 78.3 (ipso-iodo-aryl), 51.4
(NCH2), 38.0 (OSO2Me).
HRMS–FAB: m/z [M]+ calcd for C14H27NO7S2: 385.1229; found:
385.1240.
Anal. Calcd for C14H27NO7S2: C, 43.62; H, 7.06; N, 3.63. Found: C,
43.76; H, 7.12; N, 3.41.
Reactions with Lithium Azide. CAUTION: All reactions em-
ploying azides were conducted in a fume-hood with a lowered
sash and a reinforced blast-shield. Where it was necessary to
conduct certain azide displacements on a multigram scale, the
appropriate precautions necessary for large-scale working with
explosive reagents were observed. Caution must also be exer-
cised when recording melting points because detonation some-
times occurred.
MS (EI, 70 eV): m/z (%) = 461 (3) [M + H]+, 460 (15) [M+], 395 (8),
335 (26), 254 (74), 144 (100), 77 (28).
HRMS (EI): m/z calcd for C12H16INO6S2: 460.9464; found:
460.9461.
Anal. Calcd for C12H16INO6S2: C, 31.18; H, 3.71; N, 3.03. Found:
C, 31.46; H, 3.42; N, 2.86.
DMF was redistilled from CaH2 under reduced pressure (1.5–2.0
mmHg/45–50 °C) and collected over CaH2 for immediate use. A
stainless steel double-tipped needle or syringe was used to transfer
solvent. LiN321 was freshly prepared and dried over P4O10 in a vac-
uum desiccator at 1.5–2.0 mmHg for 12–16 h prior to use. Larger
scale wet extractions of DMF media were best performed using
continuous extraction. TLC analyses of reaction extent were con-
ducted by extracting an aliquot by partitioning between Et2O and 4
M aq NaOH soln.
(3S,4S)-3,4-Bis(methanesulfonyloxy)-1-[1,1¢-biphenyl-2-yl]pyr-
rolidine (4e)
Following General Procedure A, diol 3e (0.93 g, 3.65 mmol) was re-
acted with MsCl and Et3N. Chromatography gave a yellow oil that
was dissolved in Et2O (45 mL), filtered, and evaporated. The crude
residue (1.21 g, 81% yield) was triturated with pentane at 0 °C to
give 4e as a yellow solid (0.92 g, 61%); mp 104–111 °C. An analyt-
ical sample crystallised from EtOAc by the slow diffusion of sur-
rounding pentane vapour at 5 °C as long needles, mp 128–129 °C;
[a]D32 +47.3° (c 4.7, CH2Cl2).
Lithium azide
The following is a modification of the literature procedure.21 To a
stirred soln of Li2SO4·H2O (2.82 g, 22.0 mmol) and NaN3 (2.60 g,
40.0 mmol; CAUTION) in distilled H2O (20 mL) at 40 °C, behind
a robust shield was added EtOH (80 mL, technical grade 96%) in a
narrow stream by means of a pressure-equalising addition funnel.
The mixture was allowed to cool slowly to 20 °C and stirring was
continued at 20 °C for 30 min to 1 h. (For larger runs a longer diges-
tion period gave a purer product; in the original procedure21 a stir-
ring time of only 10 min was indicated). The soln was filtered
through a sintered glass funnel and the filtrate was evaporated (on a
Büchi rotary-vacuum, in a fume-hood with the sash down) to near
dryness: CAUTION. The white paste was dried over P4O10 in a vac-
uum desiccator at 1.5–2.0 mmHg for 12–16 h prior to use, affording
LiN321 as white plates (1.05 g, 54%; CAUTION).
IR (KBr): 3025, 2935, 1592, 1500, 1360, 1180 cm–1.
1H NMR (250 MHz, CDCl3): d = 7.50–7.20 (m, 7 H, aryl-H4,6 and
aryl-H2¢-6¢), 7.05 (dt, 1 H, J = 7.5, 1.0 Hz, aryl-H5), 6.89 (d, 1 H,
J = 8.5 Hz, aryl-H3), 5.07 (t, 2 H, J = 3.0 Hz, CHOMs), 3.42 (dd, 2
H, J = 12.5, 5.2 Hz, NCHHCHOMs), 3.10 (dd, 2 H, J = 12.5, 4.0
Hz, NCHHCHOMs), 3.00 (s, 6 H, SO2Me).
13C NMR (62 MHz, CDCl3): d = 145.2 (aryl-C2), 141.4 (aryl-C1¢),
132.6 (aryl-C1), 132.1 (aryl-C6), 129.0 (aryl-C2¢,6¢), 128.6 (aryl-
C3¢,5¢), 128.3 (aryl-C4), 127.1 (aryl-C4¢), 121.8 (aryl-C5), 116.3 (aryl-
C3), 81.1 (CHOMs), 54.3 (NCH2), 38.5 (SO2Me).
MS (EI, 70 eV): m/z (%) = 412 (2) [M + H]+, 411 (10) [M+], 218
(100), 180 (7), 109 (12).
General Procedure B: (3R,4R)-1-n-Octyl-3,4-diazidopyrroli-
dine (5a)
To a stirred soln of dimesylate 4a (0.19 g, 0.51 mmol) in DMF (5
mL) at 0 °C was added LiN3 (0.25 g, 5.1 mmol; CAUTION) by
HRMS (EI): m/z calcd for C18H21NO6S2: 411.0810; found:
411.0811.
Synthesis 2006, No. 2, 247–256 © Thieme Stuttgart · New York

PAPER
Syntheses of Enantiopure Pyrrolidines
251
means of a solid addition funnel equipped with a side-arm. The mix-
ture was stirred and allowed to warm slowly to 100 °C, then kept
stirring at that temperature for 16 h under an atmosphere of dry N2.
Aq 2 M LiCl soln (15 mL) was added, and the organic layer was
separated and retained. The aq layer was extracted with Et2O
(5 × 10 mL). The combined ethereal extracts were added to the orig-
inal organic layer and the whole was washed with brine (2 × 10 mL)
and dried over MgSO4. The soln was filtered and evaporated. Col-
umn chromatography of the residue on silica gel, using EtOAc–PE
(1:49) afforded 5a (85 mg, 63%) as a pale, mobile oil. An analytical
purity was obtained by preparative alumina-plate thin-layer chro-
matography [three plate elutions with CHCl3–n-hexane (1:99), elut-
ed at 20 °C in the dark]. The appropriate band was excised and
extracted with MeOH, filtered through a sintered glass micro-fun-
nel, and the filtrate was evaporated under reduced pressure and the
residue was redissolved in CHCl3. This soln was filtered through a
fluted paper and the filtrate was evaporated to give 5a as a grey, mo-
bile oil; [a]D32 –74.6° (c 1.3, CH2Cl2).
(3R,4R)-3,4-Diazido-1-phenylpyrrolidine (5c)
To a stirred suspension of dimesylate 4c (0.46 g, 1.4 mmol) in DMF
(3 mL) at 0 °C was added LiN321 (0.68 g, 13.8 mmol; CAUTION)
by means of a solid addition funnel equipped with a side-arm. The
vessel was allowed to warm slowly to 60 °C and stirring was con-
tinued at that temperature for 5 d under an atmosphere of dry N2.
The mixture was worked up as for General Procedure B, except that
the aq layers were extracted with Et2O (5 × 10 mL), then with
EtOAc (10 mL). Further work-up and column chromatography on
silica gel (EtOAc–hexane, 1:49) gave 5c (98 mg, 31%) as white
plates; mp 78 °C. An analytical sample crystallised from n-hexane
as transparent prisms; mp 78 °C; [a]D32 –83.2° (c 1.2, CHCl3).
IR (KBr): 3050, 2985, 2100, 1610, 1500 cm–1.
1H NMR (250 MHz, CDCl3): d = 7.24 (t, 2 H, J = 8.0 Hz, m-aryl),
6.78 (t, 1 H, J = 8.0 Hz, p-aryl), 6.55 (d, 2 H, J = 10.0 Hz, o-aryl),
4.11 (t, 2 H, J = 4.0 Hz, CHN3), 3.85 (dd, 2 H, J = 10.5, 5.2 Hz,
CHHCHN3), 3.34 (dd, 2 H, J = 10.5, 4.0 Hz, CHHCHN3).
13C NMR (62 MHz, CDCl3): d = 146.5 (ipso-aryl), 129.4 (m-aryl),
117.4 (p-aryl), 112.0 (o-aryl), 64.3 (CHN3), 50.7 (CH2CHN3).
MS (FAB): m/z (%) = 229 [M]+ (31), 154 (100), 137 (47), 136 (54)
and 120 (15).
HRMS–FAB: m/z [M]+ calcd for C10H11N7: 229.1076; found:
229.1090.
IR (film): 2925, 2855, 2795, 2100, 1465 cm–1.
1H NMR (250 MHz, CDCl3): d = 3.87 (t, 2 H, J = 3.5, Hz, CHN3),
2.96 (dd, 2 H, J = 11.0, 6.0 Hz, CHHCHN3), 2.59 (dd, 2 H, J = 11.0,
5.0 Hz, CHHCHN3), 2.43 (m, 2 H, NCH2CH2), 1.47 (t, 2 H, J = 6.3
Hz, NCH2CH2), 1.28 [m, 10 H, (CH2)5CH3], 0.89 (t, 3 H, J = 7.5 Hz,
CH3).
13C NMR (62 MHz, CDCl3): d = 65.7 (CHN3), 57.9 (CH2CHN3),
55.6 (CH2CH2N), 31.9 (CH2CH2N), 29.5, 29.3, 28.2, 27.4, 22.7
(CH2CH3), 14.1 (CH3).
Anal. Calcd for C10H11N7: C, 52.39; H, 4.84; N, 42.77. Found: C,
52.68; H, 4.90; N, 42.60.
MS (FAB): m/z (%) = 266 (100) [M + H]+, 223 (9), 180 (34), 166
(3R,4R)-3,4-Diazido-1-(4-iodophenyl)pyrrolidine (5d)
To a stirred soln of dimesylate 4d (0.58 g, 1.26 mmol) in DMF (8
mL) at 0 °C was added LiN3 (0.62 g, 12.6 mmol; CAUTION) in
portions via a solid addition funnel equipped with a side-arm. The
mixture was allowed to warm slowly to 60 °C and stirring was con-
tinued at that temperature for 5 d under an atmosphere of dry N2.
Since the reaction had hardly proceeded, additional LiN3 (0.62 g,
12.6 mmol; CAUTION) in DMF (5 mL) was added and heating was
continued with stirring under an atmosphere of dry N2 for an addi-
tional 5 d. The mixture was worked up as for General Procedure B
and column chromatography on silica gel (EtOAc–PE, 1:49) gave
5d (0.20 g, 45%) as a white, flocculent solid; mp 113 °C. An ana-
lytical sample crystallised from CHCl3 (by the slow diffusion of
surrounding n-hexane vapour at 5 °C in the dark) as white, velvety
plates; mp 113–114 °C; [a]D29 –49.2° (c 1.2, CHCl3).
(33), 154 (20), 142 (22).
HRMS–FAB: m/z [M + H]+ calcd for C12H24N7: 266.2093; found:
266.2070.
(3R,4R)-3,4-Diazido-1-cyclohexylpyrrolidine (5b)
To a stirred suspension of (3S,4S)-3,4-bis(methanesulfonyloxy)-1-
cyclohexylpyrrolidine15 (13.1 g, 38.5 mmol) in 45 mL of DMF at
0 °C was added LiN321 (1.89 g, 38.5 mmol, CAUTION) by means
of a solid addition funnel equipped with a side-arm. The vessel was
allowed to warm slowly to 100 °C (CAUTION) and stirring was
continued at that temperature for 16 h under an atmosphere of dry
N2. When cool, the amount of DMF was reduced by repeated co-
evaporation with benzene (4 × 20 mL) under reduced pressure, us-
ing a bath temperature of approximately 35 °C (CAUTION). The
residue was suspended in sat. aq LiCl soln (90 mL) and continuous-
ly extracted for 16 h with Et2O–EtOAc (1:1). The organic layer was
dried over MgSO4, filtered through a sintered glass funnel, and
evaporated. The residue was adsorbed onto silica gel and the im-
pregnated dispersion was applied to the top of a silica column,
which was eluted with EtOAc–PE (1:39) to give 5b (3.8 g, 42%) as
a clear, mobile liquid; [a]D32 –84.0° (c 0.4, CHCl3).
IR (KBr): 3060, 3040, 2900, 2850, 2100, 1595, 1505, 1480 cm–1.
1H NMR (250 MHz, CDCl3): d = 7.50 (d, 2 H, J = 9.0 Hz, aryl-H3,5),
6.34 (d, 2 H, J = 9.0 Hz, aryl-H2,6), 4.12 (quin, 2 H, J = 3.5 Hz,
CHN3), 3.67 (dd, 2 H, J = 10.5, 5.3 Hz, CHHCHN3), 3.31 (dd, 2 H,
J = 10.5, 4.5 Hz, CHHCHN3).
13C NMR (62 MHz, CDCl3): d = 138.0 (aryl-C3,5), 114.2 (aryl-C2,6),
64.2 (CHN3), 50.7 (NCH2), (ipso-aryl resonances not detected).
IR (film): 2925, 2850, 2790, 2095, 1470, 1450 cm–1.
MS (EI, 70 eV): m/z (%) = 335 (28) [M+], 343 (40), 305 (14), 229
(81), 222 (34), 180 (7), 144 (13), 105 (100).
1H NMR (250 MHz, CDCl3): d = 3.83 (t, 2 H, J = 4.7 Hz, CHN3),
3.05 (dd, 2 H, J = 10.0, 6.7 Hz, CHHCHN3), 2.66 (dd, 2 H, J = 10.0,
4.7 Hz, CHHCHN3), 2.15 (m, 1 H, cyclohexylCH-N), 1.90–1.10
[m, 10 H, (CH2)5].
HRMS (EI): m/z calcd for C10H10IN7: 355.0042; found: 355.0048.
(3R,4R)-3,4-Diazido-1-[1,1¢-biphenyl-2-yl]pyrrolidine (5e)
To a stirred suspension of dimesylate 4e (1.18 g, 2.87 mmol) in dry
DMF (25 mL) at 0 °C under an atmosphere of dry N2 was added
LiN3 (1.41 g, 28.7 mmol; CAUTION) by means of a solid addition
funnel equipped with a side-arm. The mixture was allowed to warm
slowly to 50 °C and stirring was continued at 50 °C for 5 d under an
atmosphere of dry N2. Since the reaction had hardly proceeded, ad-
ditional LiN3 (1.41 g, 28.7 mmol; CAUTION) in DMF (10 mL) was
added, and heating was continued with stirring under an atmosphere
of dry N2 for an additional 5 d. When cool, the amount of DMF was
reduced by repeated co-evaporation with benzene (4 × 20 mL) un-
13C NMR (62 MHz, CDCl3): d = 65.4 (CHN3), 62.0 (C1HN), 55.0
(CH2CHN3), 31.2 (CH2CHN), 31.0 (CH2CHN), 26.0 (C4), 24.7
(C3,5).
MS (FAB): m/z (%) = 236 (100) [M + H]+, 235 (50) [M+], 192 (18),
150 (41), 136 (15), 125 (32), 112 (22).
HRMS–FAB: m/z [M + H]+ calcd for C10H18N7: 236.1624; found:
236.1610.
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252
C. M. Marson, R. C. Melling
PAPER
der reduced pressure, using a bath temperature of approximately
35 °C (CAUTION). The residue was worked up as for General Pro-
cedure B and column chromatography on silica gel (EtOAc–PE,
1:99) gave a brown syrup that upon trituration with n-hexane–Et2O
(1:1) afforded 5e (0.40 g, 45%) as an amorphous white solid; mp
91–95 °C. An analytical sample crystallised from CH2Cl2 (by the
slow diffusion of surrounding n-hexane vapour at 5 °C in the dark),
giving 5e as needles; mp 96.5 °C; [a]D32 –114.3° (c 1.4, CHCl3).
N2. The THF soln was dried over KOH pellets, decanted, and the fil-
trate was evaporated. The crude product was adsorbed onto neutral
alumina and the impregnated dispersion was applied to the top of a
pre-packed column of silica gel, which was eluted with MeOH–
NH3–Et3N (18:10:1). The appropriate fractions were combined, fil-
tered through a fluted paper, and the eluent was evaporated. The res-
idue was dissolved in THF and stirred over powered KOH. The soln
was filtered and evaporated to give 6a (33 mg, 63%) as a brown oil.
An analytical sample was obtained by preparative alumina thin-lay-
er chromatography [two plate elutions with NH3–MeOH (1:199) at
20 °C]. The appropriate band was excised and extracted with
MeOH, filtered through a sintered glass micro-funnel, the filtrate
was evaporated, and the residue redissolved in CHCl3. This soln
was filtered through a fluted paper and the filtrate was evaporated
to give 6a as a clear oil; [a]D32 –12.5° (c 0.2, CHCl3).
IR (KBr): 3060, 2920, 2850, 2105, 1592, 1500, 1475 cm–1.
1H NMR (250 MHz, CDCl3): d = 7.50–7.20 (m, 7 H, aryl-H4,6 and
aryl-H2¢-6¢), 6.98 (dt, 1 H, J = 7.0, 0.5 Hz, aryl-H5), 6.88 (dd, 1 H,
J = 8.5, 0.5 Hz, aryl-H3), 3.81 (m, 2 H, CHN3), 3.32 (dd, 2 H,
J = 10.0, 5.0 Hz, CHHCHN3), 3.10 (dd, 2 H, J = 10.0, 4.0 Hz,
CHHCHN3).
13C NMR (62 MHz, CDCl3): d = 145.8 (aryl-C2), 141.9 (aryl-C1¢),
132.3 (aryl-C6), 131.8 (aryl-C1), 129.1 (aryl-C2¢,6), 128.5 (aryl-
IR (film): 3495, 3480, 3010, 2925, 2850, 2855 cm–1.
1H NMR (250 MHz, CDCl3): d = 3.10 (t, 2 H, J = 4.5 Hz, CHNH2),
2.93 (dd, 2 H, J = 10.0, 6.0 Hz, CHHCHNH2), 2.70 (br s, 4 H,
CHNH2), 2.40 (m, 2 H, CH2CH2N), 2.35 (dd, 2 H, J = 10.0, 5.0 Hz,
CHHCHNH2), 1.43 (quin, 2 H, J = 5.5 Hz, CH2CH2N), 1.35–1.22
[m, 10 H, (CH2)5CH3], 0.89 (t, 3 H, J = 5.0 Hz, CH3).
C3¢,5¢), 128.1 (aryl-C4), 127.0 (aryl-C4¢), 120.7 (aryl-C5), 115.3 (aryl-
C3), 64.4 (CHN3), 53.7 (CH2CHN3).
MS (EI, 70 eV): m/z (%) = 306 (20) [M + H]+, 305 (100) [M+], 218
(76), 194 (95), 180 (80), 152 (37).
13C NMR (62 MHz, CDCl3): d = 62.0 (CHNH2), 60.4 (CHCH2NH2),
56.5 (CH2CH2N), 31.6 (CH2CH2N), 29.5, 29.2, 28.4, 27.5, 22.6
(CH2CH3), 14.1 (CH3).
MS (FAB): m/z (%) = 214 (78) [M + H]+, 195 (88), 180 (100), 156
(25), 142 (27), 109 (32).
HRMS (EI): m/z calcd for C16H15N7: 305.1389; found: 305.1388.
Anal. Calcd for C16H15N7: C, 62.94; H, 4.95; N, 32.11. Found: C,
62.82; H, 4.82; N, 32.24.
(3S,4S)-3,4-Diazido-1-n-octanoylpyrrolidine (5f)
To a stirred soln of dimesylate 4f (0.24 g, 0.62 mmol) in DMF (5
mL) at 0 °C was added LiN3 (0.30 g, 6.2 mmol; CAUTION) in por-
tions via a solid addition funnel, equipped with a side-arm. The mix-
ture was allowed to warm slowly to 20 °C and stirring was
continued at that temperature for 20 h under an atmosphere of dry
N2. Since the reaction had hardly proceeded, the mixture was heated
under an atmosphere of dry N2 with stirring to 80 °C (CAUTION)
and maintained at 80 °C for 4 d. When cool, the mixture was
worked up as for General Procedure B and column chromatography
on silica gel (EtOAc–PE, 1:4) gave 5f (96 mg, 55%) as a clear, mo-
bile oil; [a]D25 –22.9° (c 1.0, CHCl3).
HRMS–FAB: m/z [M + H]+ calcd for C12H28N3: 214.2283; found:
214.2270.
General Procedure C: (3R,4R)-3,4-Diamino-1-cyclohexyl-
pyrrolidine (6b)
To a three-necked 50 mL flask, equipped with a two-way vacuum
tap, rubber septum, and magnetic stirring bar was added diazide 5b
(3.68 g, 15.7 mmol), EtOH (80 mL) and 10% Pd on carbon (3.0 g).
The vessel was cooled to 0 °C, evacuated at 15 mmHg, and purged
with H2 at positive atmospheric pressure. After three successive
evacuation–purge cycles the vessel was allowed to warm to 20 °C
and stirring was continued at that temperature for 16 h under H2 at
atmospheric pressure. Upon completion, IR spectroscopy con-
firmed the absence of azide (nmax 2100 cm–1). The mixture was fil-
tered through celite 545 and the filter cake was washed with EtOH
(4 × 15 mL) and evaporated. The crude product was adsorbed onto
basic alumina and the impregnated dispersion was applied to the top
of a pre-packed column of silica gel, which was eluted with NH3–
MeOH (1:49). The appropriate fractions were combined, filtered
through a fluted paper, and the eluent was evaporated. The residue
was dissolved in THF (30 mL) and stirred over powered K2CO3.
The soln was filtered and evaporated to give 6b (1.92 g, 67%) as a
brown oil. An analytical sample was obtained by preparative alumi-
na thin-layer chromatography [five plate elutions with NH3–MeOH
(1:199) at 20 °C]. The appropriate band was excised and extracted
with MeOH, filtered through a sintered glass micro-funnel, and the
filtrate was evaporated under reduced pressure and the residue re-
dissolved in CHCl3. This soln was filtered through a fluted paper
and the filtrate was evaporated to give 6a as a clear oil; [a]D32 –19.5°
(c 0.7, CHCl3).
IR (CHCl3): 3150, 2935, 2855, 2110, 1650, 1460 cm–1.
1H NMR (250 MHz, CDCl3): d = 4.05 (m, 2 H, CHN3), 3.81 (t, 1
H, J = 6.0 Hz, CHHCHN3), 3.76 (d, 1 H, J = 6.0 Hz, CHHCHN3),
3.63 (dd, 1 H, J = 12.5, 3.5 Hz, N3CHCHH), 3.47 (dd, 1 H, J = 12.5,
3.5 Hz, N3CHCHH), 2.24 (t, 2 H, J = 7.5 Hz, COCH2), 1.66 (quin,
2 H, J = 6.5 Hz, COCH2CH2), 1.40–1.25 [m, 8 H, (CH2)4CH3], 0.88
(t, 3 H, J = 6.0 Hz, CH3).
13C NMR (62 MHz, CDCl3): d = 172.1 (CO), 64.3 (CHN3), 62.8
(CHN3), 49.3 (CH2CHN3), 48.4 (CH2CHN3), 34.6 (COCH2), 31.7,
29.4, 29.1, 24.8, 22.6 (CH2CH3), 14.1 (CH3).
MS (FAB): m/z (%) = 280 (100) [M + H]+, 196 (34), 154 (16), 136
(23), 127 (18).
HRMS–FAB: m/z [M + H]+ calcd for C12H22N7O: 280.1886; found:
280.1870.
(3R,4R)-1-n-Octyl-3,4-diaminopyrrolidine (6a)
To a stirred suspension of LiAlH4 (52 mg, 1.54 mmol) in THF (10
mL) at 0 °C was injected a soln of diazide 5a (65 mg, 0.24 mmol)
in THF (1 mL). The stirred mixture was heated slowly to reflux and
kept at reflux for 2 h under an atmosphere of dry N2. Upon comple-
tion, IR spectroscopy confirmed the absence of azide (nmax 2100
cm–1). The mixture was cooled to 0 °C and H2O was added drop-
wise, until effervescence ceased. The mixture was repeatedly co-
evaporated with toluene (5 mL portions) until a greyish powder re-
mained. This powder was placed in a micro soxhlet thimble and
continuously extracted with THF for 16 h under an atmosphere of
IR (film): 3350, 3300, 2925, 2850, 2095, 1450 cm–1.
1H NMR (250 MHz, CDCl3): d = 2.98 (m, 4 H, CHNH2 and
CHHCHNH2) 2.38 (dd, 2 H, J = 11.0, 5.0 Hz, CHHCHNH2), 2.02
(m, 1 H, CHN), 1.93 (br m, 4 H, CHNH2), 1.90–1.05 [m, 10 H,
(CH2)5].
13C NMR (62 MHz, CDCl3): d = 62.8 (CHN), 60.2 (CHNH2), 59.3
(CH2CHNH2), 31.2 (C2,6), 26.0 (C4), 24.8 (C3,5).
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Syntheses of Enantiopure Pyrrolidines
253
MS (EI, 70 eV): m/z (%) = 183 (24) [M+], 166 (57), 150 (20), 144
(30), 140 (38), 126 (23), 112 (14), 98 (46), 82 (100), 71 (21), 56
(47), 44 (46).
HRMS (EI): m/z calcd for C10H14IN3 303.0232; found: 303.0214.
(3R,4R)-3,4-Diamino-1-[1,1¢-biphenyl-2-yl]pyrrolidine (6e)
Following General Procedure C, diazide 5e (0.37 g, 1.2 mmol) was
hydrogenated over 10% Pd on carbon. After work-up and column
chromatography eluting with NH3–MeOH (1:99), the residue was
dissolved in CHCl3 (40 mL) and stirred over powered K2CO3. The
soln was filtered and evaporated to give 6e (0.26 g, 84%) as a yel-
low oil, which became turbid upon exposure to air. An analytical
sample obtained by preparative silica plate thin-layer chromatogra-
phy (as in General Procedure C, but only two plate elutions) gave
6e as a clear, viscous oil; [a]D32 –75.4° (c 0.52, CHCl3).
HRMS (EI): m/z calcd for C10H21N3: 183.1735; found: 183.1735.
(3R,4R)-3,4-Diamino-1-phenylpyrrolidine (6c)
Following General Procedure C, diazide 5c (74 mg, 0.32 mmol) was
hydrogenated over 10% Pd on carbon. After work-up and column
chromatography, the residue was dissolved in THF (45 mL) and
stirred over powered K2CO3. The soln was filtered and evaporated
to give 6c (37 mg, 65%) as a white powder; mp 125 °C. An analyt-
ical sample crystallised from DMF by the slow diffusion of sur-
rounding pentane vapour at 5 °C, giving small prisms; mp 125 °C;
[a]D30 –39.4° (c 0.8, DMF).
IR (film): 3395, 3350, 3155, 2990, 2950, 1600, 1592, 1495 cm–1.
1H NMR (600 MHz, CDCl3): d = 7.42 (dd, 2 H, J = 7.8, 1.0 Hz,
2¢,6¢-aryl), 7.36 (t, 2 H, J = 7.3 Hz, 3¢,5¢-aryl), 7.27 (t, 1 H, J = 7.0
Hz, 4¢-aryl), 7.24 (dt, 1 H, J = 7.8, 1.7 Hz, 4-aryl), 7.18 (dd, 1 H,
J = 7.5, 1.5 Hz, 6-aryl), 6.89 (dt, 1 H, J = 7.3, 1.0 Hz, 5-aryl), 6.86
(d, 1 H, J = 8.5 Hz, 3-aryl), 3.23 (dd, 2 H, J = 9.0, 5.0 Hz,
CHHCHNH2), 2.95 (t, 2 H, J = 5.0 Hz, CHNH2), 2.69 (dd, 2 H,
J = 9.0, 5.5 Hz, CHHCHNH2), 1.30 (br s, 4 H, NH2).
1H NMR (600 MHz, ROESY spectrum recorded in CDCl3);
through-space coupling pairs: 7.42, 7.36; 7.42, 7.27; 7.42, 7.18;
7.42, 3.23; 7.42, 2.69; 6.86, 3.23; 6.86, 2.69; 7.36, 7.27; 7.24, 6.89;
7.24, 6.86; 7.18, 6.89.
IR (KBr): 3410, 3340, 3050, 2910, 2845, 1600, 1570, 1505 cm–1.
1H NMR (250 MHz, CDCl3): d = 7.23 (t, 2 H, J = 6.5 Hz, m-aryl),
6.69 (t, 1 H, J = 6.5 Hz, p-aryl), 6.54 (dd, 2 H, J = 8.5, 1.0 Hz, o-
aryl), 3.68 (dd, 2 H, J = 9.5, 5.5 Hz, CHHCHNH2), 3.19 (m, 2 H,
CHNH2), 3.03 (dd, 2 H, J = 9.5, 6.5 Hz, CHHCHNH2), 1.40 (br s,
4 H, CHNH2).
13C NMR (62 MHz, CDCl3): d = 147.7 (ipso-aryl), 129.3 (m-aryl),
116.0 (p-aryl), 111.4 (o-aryl), 59.3 (CHNH2), 54.7 (CH2CHNH2).
MS (EI, 70 eV): m/z (%) = 178 (6) [M + H]+, 177.1 (61) [M+], 160
(22), 144 (9), 134 (49), 120 (48), 106 (94), 91 (100), 77 (47), 71
(12), 56 (18).
13C NMR (62 MHz, CDCl3): d = 147.2 (2-aryl), 142.7 (1¢-aryl),
132.3 (6-aryl), 132.10 (1-aryl), 129.1 (2¢,6¢-aryl), 128.2 (3¢,5¢-aryl),
128.0 (4-aryl), 126.5 (4¢-aryl), 119.2 (5-aryl), 114.7 (3-aryl), 59.1
(CHNH2), 57.9 (CH2CHNH2).
HRMS (EI): m/z calcd for C10H15N3: 177.1266; found: 177.1267.
The dipicrate (C10H15N3 + C6H33O7 × 2) crystallised from EtOH
with inclusion of one molecule of EtOH.
MS (EI, 70 eV): m/z (%) = 254 (8) [M + H]+, 253 (40) [M+], 210
(34), 194 (100), 183 (58), 181 (55), 159 (70), 77 (13).
Anal. Calcd for C24H27N9O15: C, 42.30; H, 3.99. Found: C, 41.73;
H, 4.38.
HRMS (EI): m/z calcd for C16H19N3: 253.1579; found: 253.1579.
(3S,4S)-3,4-Diamino-1-(4-iodophenyl)pyrrolidine (6d)
(3S,4S)-3,4-Diamino-1-octanoylpyrrolidine (6f)
Aspects of the Staudinger procedure used by Vaultier et al.22 were
used in this preparation. To a stirred soln of diazide 5d (115 mg,
0.320 mmol) in THF (5 mL) at 0 °C was injected a soln of PPh3
(0.255 g, 0.970 mmol) in THF (3 mL). After a rapid effervescence,
the mixture was allowed to warm slowly to 20 °C and stirring was
continued at 20 °C for 16 h under an atmosphere of dry N2. Distilled
H2O (2 mL) was then added and the mixture stirred for an additional
16 h under an atmosphere of N2. Upon completion, IR spectroscopy
confirmed the absence of azide (nmax 2100 cm–1). Sat. aq NH4Cl soln
(10 mL) was added and the organic layer separated and kept. The aq
layer was extracted with CHCl3 (4 × 10 mL). All the extracts were
combined with the original organic layer and the whole was washed
with brine (2 × 5 mL) and dried over powdered KOH. The soln was
filtered and evaporated. The residue was applied as an alumina dis-
persion to a column of silica gel and eluted with NH3–MeOH (1:49)
to give a solid that was dissolved in THF (15 mL) and stirred over
powered K2CO3. The soln was filtered and evaporated to give 6d
(63 mg, 64%) as white plates; mp 134 °C. An analytical sample was
obtained by preparative alumina-plate thin-layer chromatography
[four plate elutions with NH3–MeOH (1:99) at 20 °C] as described
in General Procedure C to give 6d as a white solid; mp 134 °C;
[a]D30 –36.2° (c 0.9, DMF).
Following General Procedure C, diazide 5f (63 mg, 0.23 mmol) was
hydrogenated over 10% Pd on carbon (30 mg). After work-up and
column chromatography eluting with NH3–MeOH (1:99), the resi-
due was dissolved in THF (15 mL) and stirred over powered K2CO3.
The soln was filtered and evaporated to give 6f (16 mg, 31%) as
brown gum. An analytical sample was obtained by preparative sili-
ca plate thin-layer chromatography (as in General Procedure C, but
only three plate elutions) as a white wax; [a]D –32.5° (c 0.25,
CH2Cl2).
IR (KBr): 3410, 3360, 2925, 2850, 1630, 1460 cm–1.
1H NMR (250 MHz, CDCl3): d = 4.0–3.2 (m, 2 H, CH2CHNH2),
3.2–3.0 (m, 2 H, CHNH2), 2.80 (d, 1 H, J = 13.0 Hz, CHHN), 2.40
(d, 1 H, J = 13.0 Hz, CHHN), 2.22 (quin, 2 H, J = 6.0 Hz, COCH2),
1.85–1.50 (m, 2 H, COCH2CH2 and br s, 4 H, CHNH2), 1.36–1.05
[m, 8 H, (CH2)4CH3], 0.87 (t, 3 H, J = 6.5 Hz, CH3).
MS (EI, 70 eV): m/z (%) = 227 (5) [M+], 225 (32), 223 (2), 185 (66),
151 (15), 99 (12), 83 (100).
25
HRMS (EI): m/z [M – 4H]+ calcd for C12H21N3O: 223.1685; found:
223.1671.
(3R,4R)-3,4-Bis(methanesulfonamido)-1-phenylpyrrolidine (7c)
To a stirred soln of diaminopyrrolidine 6c (20 mg, 0.11 mmol) and
Et3N (24 mg, 0.24 mmol) in CH2Cl2 (6 mL) at 0 °C was injected a
soln of MsCl (27 mg, 0.24 mmol) in CH2Cl2 (1 mL). The mixture
was allowed to warm slowly to 20 °C and stirring was continued at
20 °C for 45 min under an atmosphere of dry N2. H2O (5 mL) was
added and the organic layer was separated and kept. The aq layer
was extracted with CH2Cl2 (3 × 5 mL). All the extracts were com-
bined with the original organic layer and the whole was washed
with brine (2 × 5 mL) and dried over Na2SO4. The soln was filtered
IR (KBr): 3340, 3290, 2900, 2845, 1650, 1595, 1505, 1480 cm–1.
1H NMR (250 MHz, CDCl3): d = 7.40 (d, 2 H, J = 9.5 Hz, 3,5-aryl),
6.34 (d, 2 H, J = 9.5 Hz, 2,6-aryl), 4.79 (s, 4 H, CHNH2), 3.60 (dd,
2 H, J = 9.5, 5.5 Hz, CHHCHNH2), 3.24 (m, 2 H, CHNH2), 3.02
(dd, 2 H, J = 9.5, 6.0 Hz, CHHCHNH2).
13C NMR (62 MHz, CDCl3): d = 148.7 (1-aryl), 138.8 (3,5-aryl),
115.2 (2,6-aryl), 77.4 (4-aryl), 59.0 (CHNH2), 54.6 (CH2CHNH2).
MS (EI, 70 eV): m/z (%) = 303 (68) [M+], 151 (32), 96 (45), 42 (38).
Synthesis 2006, No. 2, 247–256 © Thieme Stuttgart · New York

254
C. M. Marson, R. C. Melling
PAPER
and evaporated. Column chromatography of the residue on silica
gel, eluting with EtOAc–PE (11:9), afforded a gum that was recrys-
tallised from EtOH to give 7c (20 mg, 52%) as needles; mp 125 °C;
[a]D31 –68.5° (c 0.4, acetone).
IR (KBr): 3296, 2955, 2870, 1645, 1540 cm–1.
1H NMR (250 MHz, CDCl3): d = 7.30–7.10 (m, 7 H, aryl), 6.92 (dt,
1 H, J = 6.5, 1.0 Hz, 5-aryl), 6.73 (d, 1 H, J = 8.0 Hz, 3-aryl), 6.45
(br s, 2 H, NHCO), 4.28 (sext, 2 H, J = 7.0, 1.0 Hz, CHN), 3.20 (dd,
2 H, J = 11.0, 7.0 Hz, CHHCHN), 2.75 (dd, 2 H, J = 11.0, 7.0 Hz,
CHHCHN), 1.99 (s, 4 H, COCH2), 0.97 (s, 18 H, t-Bu).
13C NMR (62 MHz, CDCl3): d = 172.7 (NHCO), 146.7 (2-aryl),
142.2 (1¢-aryl), 132.2 (6-aryl), 131.0 (1-aryl), 129.1 (2¢,6¢-aryl),
128.1 (3¢,5¢-aryl), 128.0 (4-aryl), 126.5 (4¢-aryl), 119.9 (5-aryl),
114.9 (3-aryl), 54.6 (NHCOCH2), 53.6 (CHN), 50.2 (CH2CHN),
30.9 (CMe3), 29.9 (CMe3).
IR (KBr): 3405, 3220, 2900, 1600, 1510, 1450, 1321, 1145 cm–1.
1H NMR (250 MHz, CDCl3): d = 7.62 (br s, 2 H, NHSO2), 7.16 (t,
2 H, J = 8.0 Hz, m-aryl), 6.63 (t, 1 H, J = 8.0 Hz, p-aryl), 6.56 (d, 2
H, J = 8.0 Hz, o-aryl), 3.89 (quin, 2 H, J = 5.5 Hz, CHNHMs), 3.67
(dd, 2 H, J = 10.5, 5.5 Hz, CHHCHNHMs), 3.08 (dd, 2 H, J = 10.5,
5.5 Hz, CHHCHNHMs), 3.05 (s, 6 H, SO2Me).
13C NMR (62 MHz, DMSO-d6): d = 147.3 (ipso-aryl), 129.3 (m-ar-
yl), 116.3 (p-aryl), 111.8 (o-aryl), 56.9 (CHNHMs), 51.6
(CH2CHNHMs), 41.7 (SO2Me).
MS (EI, 70 eV): m/z (%) = 450 (1) [M + H]+, 449 (3) [M+], 434 (8),
334 (8), 219 (100) 180 (13), 152 (4), 57 (24).
MS (EI, 70 eV): m/z (%) = 334 (5) [M + H]+, 333 (36) [M+], 283 (6),
HRMS (EI): m/z calcd for C28H39N3O2: 449.3042; found: 449.3035.
144 (23), 106 (100), 79 (39), 69 (47).
Anal. Calcd for C28H39N3O2: C, 74.80; H, 8.74; N, 9.35. Found: C,
75.14; H, 8.92.
HRMS (EI): m/z calcd for C12H19N3O4S2: 333.0817; found:
333.0817.
(3R,4R)-1-Cyclohexyl-3,4-bis(3,3-dimethylbutylamino)pyrroli-
dine (9g)
(3R,4R)-1-Cyclohexyl-3,4-bis(3,3-dimethylbutanamido)pyrroli-
dine (8g)
To a stirred soln of diamide 8g (3.43 g, 9.05 mmol) in THF (55 mL)
at 0 °C was added dropwise Me2S·BH3 (22.6 mL, 45.3 mmol; 2.0
M)12 in THF. The stirred mixture was brought slowly to reflux and
was kept at reflux for 16 h under an atmosphere of dry N2. Upon
completion, IR spectroscopy confirmed the absence of a carbonyl
group. The mixture was cooled to 0 °C and MeOH was added drop-
wise until effervescence ceased. The mixture was acidified to pH 2–
3 by dropwise addition of 10 M HCl soln–MeOH (1:1; CAUTION)
and then heated at reflux for 1 h. The mixture was cooled and ad-
justed at pH 9 by dropwise addition of 4 M methanolic KOH soln at
0 °C. Sat. aq NH4Cl soln (30 mL) was added and the organic layer
was separated and kept. The aq layer was extracted with CHCl3
(3 × 30 mL). All the extracts were combined with the original or-
ganic layer and the whole was washed with brine (2 × 25 mL) and
dried over K2CO3. The soln was filtered and evaporated. The resi-
due was adsorbed onto neutral alumina and the impregnated disper-
sion was applied to the top of a pre-packed column of silica gel and
eluted with MeOH–CHCl3 (1:49). The appropriate fractions were
combined, filtered and evaporated to give a residue that was dis-
solved in CH2Cl2 (30 mL) and stirred and dried over K2CO3. The
soln was filtered and evaporated to give 9g (2.29 g, 72%) as a pale
yellow oil. An analytical sample was obtained by preparative silica
plate thin-layer chromatography [as in General Procedure C, but
only three plate elutions with MeOH–CHCl3 (1:99) at 20 °C], fol-
lowed by recrystallisation from CH2Cl2–hexane, as an opaque wax;
[a]D31 –28.3° (c 1.2, CHCl3).
To a stirred soln of diaminopyrrolidine 6b (1.84 g, 10.0 mmol) and
Et3N (2.14 g, 21.1 mmol) in CH2Cl2 (55 mL) at –85 °C was injected
3,3-dimethylbutanoyl chloride (2.84 g, 21.1 mmol). The mixture
was allowed to warm slowly to 20 °C and stirring was continued at
that temperature for 4 h under an atmosphere of dry N2. Sat. aq
NaHCO3 soln (35 mL) was added and the organic layer was sepa-
rated and kept. The aq layer was extracted with CH2Cl2 (3 × 25
mL). All the extracts were combined with the original organic layer
and the whole was washed with brine (2 × 25 mL) and dried over
Na2SO4. The soln was filtered and evaporated. The residue was ad-
sorbed onto neutral alumina and the impregnated dispersion was ap-
plied to the top of a pre-packed column of silica gel and eluted with
MeOH–CHCl3 (1:99) to give 8g (3.5 g, 92%) as white plates; mp
approx. 200 °C. An analytical sample crystallised from acetone as
plates; mp 219 °C, clearing at 224 °C; [a]D32 –22.9° (c 3.6, CHCl3).
IR (KBr): 3290, 3080, 2900, 2780, 1635, 1545 cm–1.
1H NMR (250 MHz, CDCl3): d = 6.34 (br s, 2 H, CONH), 4.18 (sext,
2 H, J = 6.5 Hz, CHNH), 3.80 (t, 2 H, J = 76.5 Hz, CHHCHNH),
2.62 (dd, 2 H, J = 10.5, 6.5 Hz, CHHCHNH), 2.22 (m, 1 H, CHN),
2.02 (s, 4 H, COCH2), 1.90–1.50 [br m, 10 H, (CH2)5], 1.01 (s, 18
H, t-Bu).
13C NMR (62 MHz, CDCl3): d = 172.5 (NHCO), 63.0 (CHN), 55.9
(CH2CHNH), 55.6 (CHNH), 50.3 (COCH2), 31.0 (CMe3), 30.9
(C2,6), 29.9 (CMe3), 25.9 (C4), 24.8 (C3,5).
IR (film): 3250, (NH), 2970, 2795, 1470, 1450 cm–1.
MS (EI, 70 eV): m/z (%) = 380 (5) [M + H]+, 379 (13) [M+], 365
1H NMR (250 MHz, CDCl3): d = 2.94 (m, 4 H, CHNH and
CHHCHN), 2.58 (t, 4 H, J = 8.0 Hz, NHCH2), 2.45 (dd, 2 H,
J = 14.0, 9.5 Hz, CHHCHN), 2.05 (m, 1 H, CHN), 1.95–1.55 (m, 7
H, cyclohexyl and 2 × CHNH), 1.40 (t, 4 H, J = 9.0 Hz,
NHCH2CH2) 1.30–1.10 (m, 5 H, cyclohexyl), 0.89 (s, 18 H, t-Bu).
13C NMR (62 MHz, CDCl3): d = 64.4 (CHNH), 63.3 (CHN), 57.3
(CH2CHN), 44.6 (NHCH2), 44.4 (NHCH2CH2), 31.2 (C2,6), 29.9
(CMe3), 29.6 (CMe3), 26.1 (C4), 25.0 (C3,5).
(24), 364 (100), 308 (8), 205 (3), 149 (9), 99 (3), 57 (10).
HRMS (EI): m/z calcd for C22H41N3O2: 379.3199; found: 379.3199.
An inclusion compound was formed with acetone. Anal. Calcd
C22H41N3O2·3C3H6O: C, 67.23; H, 10.74. Found: C, 67.44; H,
10.35.
(3R,4R)-3,4-Bis(3,3-dimethylbutanamido)-1-[1,1¢-biphenyl-2-
yl]pyrrolidine (8h)
MS (EI, 70 eV): m/z (%) = 380 (5) [M + H]+, 379 (13) [M+], 365
(24), 364 (100), 308 (8), 205 (3), 149 (9), 99 (3), 57 (10).
To a stirred soln of diaminopyrrolidine 6b (0.235 g, 0.930 mmol)
and Et3N (0.20 g, 2.0 mmol) in CH2Cl2 (5 mL) at –85 °C was inject-
ed 3,3-dimethylbutanoyl chloride (0.264 g, 2.00 mmol). Work-up as
for 8g afforded a residue that on column chromatography over silica
gel, eluted with MeOH–CHCl3 (1:99), gave 8h (0.36 g, 86%) as
grey plates, mp 200–210 °C. An analytical sample was obtained by
preparative silica plate thin-layer chromatography (as in General
Procedure C, but only four plate elutions with CH2Cl2), followed by
recrystallisation from CH2Cl2–hexane, as needles; mp 225–228 °C;
[a]D34 –82.7° (c 1.5, CHCl3).
HRMS (EI): m/z calcd for C22H45N3: 351.3613; found: 351.3611.
(3R,4R)-3,4-Bis(3,3-dimethylbutylamino)-1-[1,1′-biphenyl-2-
yl]pyrrolidine (9h)
To a stirred soln of 8h (0.34 g, 0.75 mmol) in THF (5 mL) at 0 °C
was added dropwise Me2S·BH3 (1.9 mL, 3.8 mmol; 2.0 M)12 in
THF. Work-up and column chromatography as for 9g but using an
Synthesis 2006, No. 2, 247–256 © Thieme Stuttgart · New York

PAPER
Syntheses of Enantiopure Pyrrolidines
255
eluent of MeOH–CHCl3 (1:99) afforded an oil that was dissolved in
CH2Cl2 (5 mL) and dried over K2CO3. The soln was filtered and
evaporated to give 9h (0.25 g, 80%) as a yellow oil. An analytical
sample was obtained by preparative silica plate thin-layer chroma-
tography (as in General Procedure C, but only four plate elutions
with CHCl3 at 5 °C in the dark) as a mobile oil; [a]D –54.9° (c
1.5, CHCl3).
IR (film): 3303, 3020, 2950, 2910, 2860, 1590, 1565, 1500 cm–1.
1H NMR (250 MHz, CDCl3): d = 7.50–7.18 (m, 7 H, 4,6-aryl and
2¢,6¢-aryl), 6.92 (t, 1 H, J = 7.0 Hz, 5-aryl), 6.90 (d, 1 H, J = 8.5 Hz,
3-aryl), 3.15 (dd, 2 H, J = 9.5, 5.5 Hz, CHHCHN), 2.93 (quin, 2 H,
J = 4.0 Hz, CHNH) 2.73 (dd, 2 H, J = 8.5, 4.5 Hz, CHHCHN), 2.47
(dd, 4 H, J = 10.5, 7.0 Hz, NHCH2), 1.60 (br s, 2 H, NHCH2), 1.30
(m, 4 H, NHCH2CH2), 0.86 (s, 18 H, t-Bu).
13C NMR (62 MHz, CDCl3): d = 147.3 (2-aryl), 142.5 (1¢-aryl),
132.0 (1-aryl), 131.9 (2,6-aryl), 129.0 (2¢,6¢-aryl), 128.2 (3¢,5¢-aryl),
128.1 (4-aryl), 126.6 (4¢-aryl), 119.9 (5-aryl), 115.7 (3-aryl), 63.6
(CHNH), 55.9 (CH2CHN), 44.5 (NHCH2), 44.3 (NHCH2CH2), 29.9
(CMe3), 29.7 (CMe3).
To a separate stirred soln of freshly prepared Ni(acac)223 (133 mg,
0.520 mmol) and PPh3 (0.545 g, 2.08 mmol) in THF (65 mL) at
–85 °C was injected DIBAL-H (0.7 mL, 1.04 mmol; 1.5 M soln in
dry toluene). The mixture was stirred at this temperature for 20 min
before the introduction of a soln of bromobenzene (3.26 g, 20.8
mmol) in THF (20 mL). This stirred mixture was allowed to warm
slowly to 20 °C and stirring was continued for 30 min. Both flasks
were cooled to –85 °C and the content of the first flask was trans-
ferred dropwise to the second flask over a period of approximately
1 h. The stirred mixture was allowed to warm slowly to 20 °C and
stirred for 16 h under an atmosphere of dry N2.
31.5
Sat. aq NH4Cl soln (70 mL) was added and the organic layer was
separated and kept. The aq layer was extracted with CHCl3 (3 × 60
mL). All the extracts were combined with the original organic layer
and the whole was washed with brine (2 × 60 mL) and dried over
Na2SO4. The soln was filtered and evaporated. The residue was ad-
sorbed onto neutral alumina and the impregnated dispersion was ap-
plied to the top of a pre-packed column of silica gel and eluted with
toluene–hexane (1:1) to give (3S,4S)-3,4-bis(oxybenzyl)-1-phe-
nylpyrrolidine (3.29 g, 53%) as a glass, followed by 11 (2.11 g,
28%) as an oil. An analytical sample was obtained by preparative
silica plate thin-layer chromatography [as in General Procedure C,
but only three plate elutions with toluene–hexane (1:4) at 20 °C] as
a viscous syrup; [a]D29 +34.2° (c 1.6, CHCl3).
MS (EI, 70 eV): m/z (%) = 422 (3) [M + H]+, 421 (9) [M+], 350 (14),
294 (100) 220 (10), 174 (53), 169 (73), 112 (8), 56 (37).
HRMS (EI): m/z calcd for C28H43N3: 421.3457; found: 421.3456.
(3S,4S)-3,4-Bis(oxybenzyl)-1-(4-iodophenyl)pyrrolidine (10)
To a stirred soln of diol 3d15 (6.74 g, 22.1 mmol) and NaH (1.59 g,
66.3 mmol, as a 60% dispersion in paraffin oil) in THF (120 mL) at
0 °C was added dropwise a soln of benzyl bromide (7.94 g, 46.4
mmol) in THF (30 mL). The stirred mixture was brought slowly to
reflux and was kept at reflux for 4 h under an atmosphere of dry N2.
Sat. aq NH4Cl (60 mL) was added and the organic layer was sepa-
rated and kept. The aq layer was extracted with EtOAc (3 × 50 mL).
All the extracts were combined with the original organic layer and
the whole was washed with brine (2 × 25 mL) and dried over
MgSO4. The soln was filtered and evaporated. The residue was ad-
sorbed onto neutral alumina and the impregnated dispersion was ap-
plied to the top of a pre-packed column of silica gel and eluted with
EtOAc–PE (1:19) to give 10 (8.47 g, 79%) as buff-coloured plates;
mp 102–107 °C. From one of the chromatographic fractions an an-
alytical sample crystallised as pale blue prisms; mp 108–110 °C;
[a]D27 +22.7° (c 0.7, CH2Cl2).
(3S,4S)-3,4-bis(oxybenzyl)-1-phenylpyrrolidine
1H NMR (250 MHz, CDCl3): d = 7.40–7.20 (m, 12 H, CH2Ph and
3,5-aryl), 6.55 (dt, 1 H, J = 6.5, 1.0 Hz, 4-aryl), 6.44 (dd, 2 H,
J = 8.7, 1.0 Hz, 2,6-aryl), 4.53 (s, 4 H, CH2Ph), 4.06 (t, 2 H, J = 5.0
Hz, CHOBn), 3.47 (dd, 2 H, J = 11.0, 4.0 Hz, CHHCHOBn), 3.08
(d, 2 H, J = 11.0 Hz, CHHCHOBn);
(3S,4S)-3,4-Bis(oxybenzyl)-1-[1,1¢-biphenyl-2-yl]pyrrolidine
(11)
IR (film): 3060, 3025, 2920, 2860, 1590, 1565, 1540, 1450 cm–1.
1H NMR (250 MHz, CDCl3): d = 7.50 (dd, 2 H, J = 7.5, 1.0 Hz,
2¢,6¢-aryl), 7.40–7.20 (m, 15 H, CH2Ph, 4,6-aryl and 3¢,4¢,5¢-aryl),
6.93 (d, 1 H, J = 6.5, 1.0 Hz, 5-aryl), 6.87 (d, 1 H, J = 6.5 Hz, 3-
aryl), 4.41 (s, 4 H, CH2Ph), 3.99 (t, 2 H, J = 3.5 Hz, CHOBn), 3.23
(dd, 2 H, J = 10.5, 6.0 Hz, CHHCHOBn), 2.98 (dd, 2 H, J = 10.5,
5.0 Hz, CHHCHOBn).
13C NMR (62 MHz, CDCl3): d = 147.2 (2-aryl), 142.6 (1¢-aryl),
138.3 (CH2Ph1), 132.3 (6-aryl), 131.4 (1-aryl), 129.2 (2¢,6¢-aryl),
128.6 (CH2Ph3,5), 128.4 (3¢,5¢-aryl), 128.1 (4-aryl), 127.8
(CH2Ph2,4,6), 126.6 (4¢-aryl), 119.8 (5-aryl), 115.5 (3-aryl), 81.9
(CHOBn), 71.5 (CH2Ph), 54.4 (CH2CHOBn).
IR (film): 3050, 2980, 2915, 2855, 1590, 1495 cm–1.
1H NMR (250 MHz, CDCl3): d = 7.43 (d, 2 H, J = 9.0 Hz, 3,5-aryl),
7.30 (m, 10 H, arylCH2), 6.28 (d, 2 H, J = 9.0 Hz, 2,6-aryl), 4.55 (s,
4 H, PhCH2O), 4.20 (d, 2 H, J = 4.5, 3.0 Hz, CHOBn), 3.55 (dd, 2
H, J = 10.0, 4.5 Hz, CHHCHOBn), 3.30 (dd, 2 H, J = 10.0, 3.0 Hz,
CHHCHOBn).
13C NMR (62 MHz, CDCl3): d = 147.2 (1-aryl), 137.9 (1-PhCH2),
137.7 (3,5-aryl), 128.6 (3,5-PhCH2), 128.0 (4-PhCH2), 127.8 (2,6-
PhCH2), 114.2 (2,6-aryl), 81.0 (CHOBn), 76.9 (4-aryl), 71.8
(PhCH2), 51.6 (CH2CHOBn).
MS (EI, 70 eV): m/z (%) = 437 (3) [M + 2 H]+, 436 (18) [M + H]+,
435 (53) [M+], 252 (7), 222 (11), 182 (100), 152 (10), 91 (100).
HRMS (EI): m/z calcd for C30H29NO2: 435.2198; found: 435.2211.
Acknowledgment
MS (EI, 70 eV): m/z (%) = 487 (1) [M + 2 H]+, 486 (13) [M + H]+,
485 (51) [M+], 359 (24), 267 (3), 146 (4), 91 (100).
Support of this work by the Engineering and Physical Sciences
Research Council as a ROPA studentship (to R.C.M.) is gratefully
acknowledged.
HRMS (EI): m/z calcd for C24H24INO2: 485.0852; found: 485.0853.
(3S,4S)-3,4-Bis(oxybenzyl)-1-[1,1¢-biphenyl-2-yl]pyrrolidine
(11)
References
Some aspects of this coupling were derived from the procedure of
Larson and Raphael.18 To a stirred soln of 10 (8.39 g, 17.3 mmol) in
THF (80 mL) at –85 °C was injected n-BuLi (13.6 mL, 21.8 mmol;
1.6 M in dry hexane). After stirring at –85 °C for 30 min, anhyd
ZnCl2 (2.83 g, 20.8 mmol) was added in one portion. The stirred
mixture was allowed to warm slowly to 20 °C and was then stirred
for 1 h under an atmosphere of dry N2.
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