Synthesis of C2-symmetric analogues of 4-(pyrrolidino)pyridine: New chiral nucleophilic catalysts

Article abstract of DOI:10.1039/b004704j

The syntheses of a series of enantiomerically pure C₂-symmetric 4-(pyrrolidino)pyridine (PP Y) derivatives by S_NAr of 4-halo-/4-phenoxypyridines and by cyclocondensation from 4-aminopyridine are described. Preliminary results pertaining to their use as catalysts for acylative kinetic resolution of 1-phenylethanol are also presented. A single-crystal X-ray analysis of PPY If is reported. The Royal Society of Chemistry 2000.

Full text of DOI:10.1039/b004704j

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Synthesis of C2-symmetric analogues of 4-(pyrrolidino)pyridine:
new chiral nucleophilic catalysts
Alan C. Spivey,*a Adrian Maddaford,a Tomasz Fekner,†a Alison J. Redgraveb and
Christopher S. Frampton‡c
1
a Department of Chemistry, University of Sheffield, Brook Hill, Sheffield, UK S3 7HF
b GlaxoWellcome Medicines Research Centre, Gunnels Wood Road, Stevenage,
Hertfordshire, UK SG1 2NY
c Roche Discovery Welwyn, 40 Broadwater Road, Welwyn Garden City, Hertfordshire,
UK AL7 3AY
Received (in Cambridge, UK) 13th June 2000, Accepted 21st August 2000
First published as an Advance Article on the web 6th October 2000
The syntheses of a series of enantiomerically pure C2-symmetric 4-(pyrrolidino)pyridine (PPY) derivatives by
SNAr of 4-halo-/4-phenoxypyridines and by cyclocondensation from 4-aminopyridine are described. Preliminary
results pertaining to their use as catalysts for acylative kinetic resolution of 1-phenylethanol are also presented.
A single-crystal X-ray analysis of PPY If is reported.
Preliminary results pertaining to the use of PPYs I as catalysts
for KR of 1-phenylethanol are also described.
Introduction
4-(Dimethylamino)pyridine (DMAP)1,2 and 4-(pyrrolidino)-
pyridine (PPY)3 are potent nucleophilic catalysts for acyl
transfer and related transformations.3–7 In the last four years
we8–10 and others11–24 have reported chirally modified deriv-
atives of these structures as novel catalysts for enantioselective
acyl transfer.25 A number of such derivatives, notably Fu’s
planar-chiral DMAP 1,15–22 Fuji’s chiral PPY 2,14 and our
axially chiral DMAP 38–10 offer practically useful levels of
stereoselectivity in acylative kinetic resolutions (KRs)26 or
asymmetric desymmetrisations (ADs)27 of alcohols. Prompted
by a recent disclosure by Kotsuki28 on the synthesis of (S)-
prolinol-derived chiral PPY catalysts by pressure-promoted
nucleophilic aromatic substitution (SNAr) of 4-chloropyridine,
we report here on the syntheses of a series of trans-2,5-
disubstituted pyrrolidine-based C2-symmetric PPY catalysts
of general structure I, either by SNAr of 4-halo-/4-phenoxy-
pyridines or by cyclocondensation from 4-aminopyridine.
Our interest in trans-2,5-disubstituted pyrrolidine-based
C2-symmetric PPYs I as potential asymmetric acyl transfer
catalysts arose from consideration of essentially two design
tenets: the requirement for a DMAP derivative capable of exert-
ing strict stereocontrol over the approach of a nucleophile (e.g.
secondary alcohol) to the carbonyl of a derived acyl pyridinium
salt, and the need to realise this without compromising the
nucleophilicity, hence catalytic activity, of the pyridine nitro-
gen. These tenets constitute a dilemma as the introduction
of stereogenic elements ortho to the pyridyl nitrogen, and thus
proximal to the acyl pyridinium carbonyl group, strongly
attenuate catalytic activity in acyl transfer processes.5,11,29
However, Fuji et al. have shown that chiral PPY 2 can catalyse
KR of certain cis-diol derivatives14 and has proposed that
ordering of the acyl pyridinium salt by face–face π–π inter-
actions30 between the 2-naphthyl substituent and the electron
deficient acyl pyridinium ring§ is responsible for effective
chirality transfer. Following molecular modelling studies, we
envisaged that similar ordering influences, between the aryl
ethers and the acyl pyridinium ring, might operate for
C2-symmetric PPYs I.31 The decision to target structures with
C2 symmetry followed from the expectation that the presence of
a C2 axis of symmetry would serve to reduce the possible
number of competing diastereomeric transition states available
during acylative KR or AD processes.32
Results and discussion
Our first approach to the synthesis of C2-symmetric chiral
PPYs
I involved an SNAr reaction between trans-2,5-
disubstituted pyrrolidines and pyridines containing a leaving
group at the 4-position. Although the thermal reaction of
2,5-dimethylpyrroline (of unspecified stereochemistry) with 4-
chloropyridine hydrochloride has been reported (21% yield,
no experimental details provided),3 highly substituted amines
are known to be poorly nucleophilic and reluctant to partici-
pate in SNAr reactions.33 Using pyrrolidines 7 and 8 (>98%
† Present address: Department of Chemistry, The Ohio State Uni-
versity, 100 West 18th Ave., Columbus, OH 43210, USA.
‡ Author to whom correspondence regarding single-crystal X-ray
analysis should be addressed.
§ As evidenced by 1H NMR chemical shift and NOE data for the
acylated and non-acylated forms of this catalyst.
3460
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This journal is © The Royal Society of Chemistry 2000
DOI: 10.1039/b004704j

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Table 1 SNAr coupling between 4-substituted pyridines and trans-2,5-
disubstituted pyrrolidines
% Yield (product)
Pyrrolidine
Method Aa
Method Bb
Method Cc
7
8
~50d (9)
—
~80d (9)
0 (Ia)
~90,d 50e (9)
<10d (Ia)
a Conditions: pyridine 4–pyrrolidine 7–K2CO3 (1:1.5:2), 110 ЊC, 15 h.
b Conditions: pyridine 5–pyrrolidine (7/8)–K2CO3 (1:1.7:1), DMF,
95 ЊC, 22 h. c Conditions: pyridine 6–pyrrolidine (7/8) (1:1.3), 200 ЊC,
22 h. d By NMR integration. e Isolated by distillation.
ee34,35 and >95% ee,36 respectively), a series of exploratory
thermal reactions was carried out (Table 1). The best procedure
for the synthesis of chiral PPY 9 from pyrrolidine 7 involved
heating 4-phenoxypyridine 6 at 200 ЊC in a bomb (~90% by 1H
NMR, 50% isolated following distillation). However, under
identical conditions pyrrolidine 8 gave just traces of coupled
product Ia, presumably because the alkoxy substituents induct-
ively decrease its nucleophilicity relative to pyrrolidine 7. An
alternative route to the desired chiral PPYs I was therefore
sought.
Scheme 1
I
an efficient synthesis of enantiomerically pure tetrol
11a56,57,62 was required. We employed an established route
from -mannitol (5 steps, 42% overall yield)|| in preference
to one from hexa-1,5-diene involving isomer separation.57
Selective protection of the primary hydroxy groups in tetrol
11a with benzyl,55,56,67 TBS,68,69 TBDPS,55 benzoyl,66 and
pivaloyl66 groups has been reported previously. We initially
opted to protect tetrol 11a as the 1,6-dibenzyl ether via
the bis(dibutylstannylene) acetal**67 and to activate the
2,5-hydroxy groups as mesylates to give cyclocondensation
precursor 11c67 (Scheme 1). Reaction of mesylate 11c with the
dianion of 4-aminopyridine under the conditions optimised
for mesylate 10 gave the desired chiral PPY Ib in 40% yield,
along with 52% of the meso-tetrahydrofuran derivative 13.
This transformation defied our attempts at optimisation. The
corresponding nosyl derivative 11d (nosyl = 4-nitrophenyl-
sulfonyl) cyclocondensed to give exclusively tetrahydrofuran 13
Thermal extrusion of SO2 from pyridine-4-sulfonamides
was briefly explored. Analogous extrusions of SO2 from pyr-
idine-4-sulfonyl chloride,37 pyridine-4-sulfonohydrazides,38
4-(N-methylsulfonyl)-2,3,5,6-tetrachloropyridine,39
N-alkyl-
2,4-dinitrobenzenesulfonamides,40 but not N,N-dialkyl-
sulfonamides41–43 are known. Disappointingly, SO2 extrusion
from 4-(pyrrolidinosulfonyl)pyridine43 could not be induced
under any of the conditions explored [(a) mesitylene
TMSOTf (1 eq.), reflux; (b) DMSO, 150 ЊC; (c) ethylene
glycol, reflux; (d) AcOH H2O2 (2 eq.), reflux].
We also explored Pd(0)-catalysed amination44,45 of 4-bromo-
pyridine as a number of unhindered secondary amines (e.g.
morpholine,46 dibutylamine,47 diallylamine48 and N-methyl-
aniline49) have been successfully coupled to 4-halopyridines in
this manner. We were able to readily reproduce Buchwald’s46
Pd(OAc)2-catalysed coupling of morpholine with 4-bromo-
pyridine to give 4-(N-morpholino)pyridine in 95% yield, but
attempts to couple the more sterically demanding pyrrolidine
7 using these conditions failed.
Next we explored the construction of the chiral pyrrolidine
around the exocyclic nitrogen of 4-aminopyridine. The
synthesis of N-substituted 2,5-bis(alkoxymethyl)pyrrolidines
(and isostructural borolanes50 and phospholanes51–53) from
enantiomerically pure 1,4-dimesylates,54,55 1,4-ditosylates,55–57
1,4-ditriflates,55,58,59 and 1,4-cyclic sulfates51 by cycloconden-
sation with primary amines is well known.60 The feasibility
of employing poorly nucleophilic 4-aminopyridine was first
established by a cyclocondensation reaction between 2,5-bis-
(methylsulfonyloxy)hexane 10 and the disodium salt of 4-
aminopyridine61 to give a ~1:1 mixture of PPYs ( )-9 and 12
in 98% yield (Scheme 1).¶ For the synthesis of chiral PPYs
|| Synthesis of tetrol 11a from -mannitol. 1) Formation of 1,2:5,6-
bis(acetonide) using 2,2-dimethoxypropane–TsOH (60%).63 2) Conver-
sion to the 3,4-thiocarbonate using thiophosgene–DMAP (87%).64 3)
Corey–Winter type alk-3(4)-ene formation using P(OEt)3 by a modifi-
cation of the method of Haines (91%).65 Complete hydrolysis of excess
P(OEt)3 following this reaction requires refluxing the crude reaction
product with 6 M NaOH for 48 h (cf. prolonged stirring at rt). 4)
Alkene hydrogenation using H2 over Rh–Al2O3 by a modification of the
methods of Marzi56 and Kibayashi66 (95%). The use of H2 (1 atm)
in THF66 results in the formation of a number of unidentified by-
products, particularly on a large scale. This can be circumvented by
the use of H2 (70 atm) in EtOH. The use of recrystallised alkene
for this hydrogenation is also crucial as traces of phosphite, or
phosphite-derived impurities, result in the formation of significant
quantities of by-products. 5) Acetonide hydrolysis in refluxing 2 M HCl
(~93%).66
** The duration of the reaction between the in-situ formed bis-
(stannylene) acetal and BnBr–Bu4NBr is critical to the ratio of 1,6-
di-:1,2,6-tri-benzylated products obtained. Reaction times of 1–1.5 h
(cf. Kibayashi, 1 h)67 reproducibly give the desired 1,6-dibenzylated
product 11b in 50–60% yield [with 10–30% 1,2,6-tribenzylated product
which can be readily recycled to tetrol 11a by hydrogenation: 10%
Pd–C, THF, H2 (1 atm)] whereas longer periods (cf. Marzi, 24 h)55
result in almost exclusive tribenzylation. An improved work-up for
this reaction incorporates an extraction with 3 M NaOH to remove
tin-containing by-products70 thereby facilitating subsequent
chromatography.
¶ A ratio of 5:2:1, NaH–4-aminopyridine–mesylate 10, is required in
this reaction. This appears to be due to the inability of NaH to form
more than 50% of the disodium salt of 4-aminopyridine as judged by
monitoring the evolution of H2 during deprotonation in THF.
J. Chem. Soc., Perkin Trans. 1, 2000, 3460–3468
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Table 2 Catalysis of acylation of hindered alcohol, 1-methylcyclo-
hexanol, with Ac2O–Et3N
under analogous conditions. In contrast, cyclic sulfate 11e gave
the desired chiral PPY Ib in 52% yield, although the overall
yield from tetrol 11a was very similar to that via mesylate 11c,
a consequence of the slightly lower yield of cyclic sulfate
formation.
Given the rather moderate efficiency of the mesylate and
cyclic sulfate cyclocondensations, we explored alternative pro-
tecting group regimes. Although TBS ether 11f 67and benzoyl
ester 11h††73 failed to give any cyclised products,‡‡ the trityl
ether 11j cyclocondensed to give chiral PPY Ic in 42% yield.
Since this did not represent a significant improvement over the
cyclocondensation using benzyl ether protected mesylate 11c,
we chose to concentrate our efforts towards the target aryl ether
PPYs from benzyl ether Ib.
Benzyl ether hydrogenolysis of chiral PPY Ib with purifi-
cation using an isolute-SCX ion-exchange cartridge afforded
diol Id in 94% yield.§§ The synthesis of aryl ether derivatives Ie–
Ih under Mitsunobu conditions was then explored (Scheme 2).74
Ratio of alcohol:acetate by GC
Catalyst
After 10 h
After 24 h
No catalyst
DMAP
PPY
99:1
10:90
7:93
7:93
34:66
90:10
98:2
2:98
1:99
2:98
24:76
80:20
(Ϫ)-9
(ϩ)-If
(ϩ)-Ih
Fig. 1 X-Ray crystal structure of bis(phenyl ether) If.
mined by single-crystal X-ray analysis (Fig. 1). There are no
intramolecular face–face π–π interactions between the phenyl
groups and the pyridine ring in the crystal lattice. This may be
due to the competition provided by intermolecular π–π inter-
actions between interleaved phenyl groups (i.e. crystal packing
forces), but intramolecular stacking prior to pyridinium salt
formation was in any case not expected.3
Representative PPYs (Ϫ)-9, (ϩ)-If, and (ϩ)-Ih were shown to
catalyse the acetylation of 1-methylcyclohexanol with Ac2O
under standard conditions (Table 2).76 The catalytic activity of
PPY (Ϫ)-9 is comparable to that of DMAP but PPYs (ϩ)-If
and (ϩ)-Ih show diminished activity. Since the rate-determining
step for DMAP-catalysed acylation is the reaction of the
alcohol with the acylpyridinium salt, the observed rate is a
function of the concentration and reactivity of the acyl-
pyridinium salt in solution.76 It seems likely in these cases that
the observed rate differences reflect primarily the respective
acylpyridinium salt concentrations in solution, as PPYs (ϩ)-If
and (ϩ)-Ih both displayed poor solubility under the test
conditions.
PPYs (Ϫ)-9, (ϩ)-Ib, (ϩ)-Ic and (ϩ)-Ie–h have also been
subject to preliminary screening for their ability to effect KR
of 1-phenylethanol with Ac2O under standard conditions
(Table 3). The selectivity factors obtained (s = 1.1–1.8)77 are
significantly lower than the accepted threshold of s = 7 required
for a synthetically useful KR reaction.26 Furthermore, given
that the selectivities displayed by the aryl ether containing
catalysts (ϩ)-Ie–h are comparable to that of catalyst (Ϫ)-9,
lacking aryl ether appendages, it is clear that the desired
ordering interactions within the former either are not taking
place or are ineffective for chirality transfer. Studies are on-
going using these and structurally related catalysts to address
these issues and to delineate more efficient KR conditions.
In summary, a series of novel chiral C2-symmetric PPYs have
been prepared and shown to catalyse the acylation of secondary
alcohols. The efficient KR of secondary alcohols using these
catalysts has not yet been achieved, however studies towards
this goal are ongoing.
Scheme 2 Reagents: i, Pd–C, H2; ii, p-NO2C6H4OH, DEAD, PPh3; iii,
PhOH, ADDP, PBu3; iv, 2-naphthol, ADDP, PBu3; v, p-MeOC6H4OH,
TMAD, PBu3.
Ether Ie was prepared from diol Id and p-nitrophenol in 88%
yield using standard DEAD–PPh3-based Mitsunobu coupling
conditions. Ethers If and Ig were prepared from phenol and
2-naphthol in 81 and 83% yields respectively, using Tsunoda’s
ADDP–PBu3 REDOX system (ADDP = 1,1Ј-(azodicarbonyl)-
dipiperidine).75 Ether Ih was prepared from p-methoxyphenol
in 83% yield using Tsunoda’s TMAD–PBu3 REDOX system
(TMAD = N,N,NЈ,NЈ-tetramethylazocarboxamide).14
The structure of phenyl ether If was unequivocally deter-
†† Mesylate 11h was prepared using a variant of the method of
Kibayashi67 employing just catalytic quantities of tin.71,72
‡‡ Marzi has noted that the corresponding di-OTBDPS ditosylate fails
to undergo thermal cyclisation with benzylamine and attributed this
failure to steric effects.55 However, in view of the successful cyclisation
of the ditrityl derivative 11j we believe that the failure of di-OTBS
derivative 11f to cyclise under our conditions is due to deprotection of
these silyl groups during the reaction as 11f is not recovered following
work-up.
§§ These contain sulfonic acid-derivatised silica and are available from
International Sorbent Technology Ltd., IST House, Duffryn Industrial
Estate, Hengoed, Mid Glamorgan, UK CF82 7R3.
3462
J. Chem. Soc., Perkin Trans. 1, 2000, 3460–3468

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acidified with 1 M HCl (10 cm3). The aqueous phase was
Table 3 KR of 1-phenylethanol using C2-symmetric PPYs
washed with Et2O (2 × 20 cm3), basified with 10% NaOH
(10 cm3) and extracted with Et2O (3 × 30 cm3). The combined
organic extracts were dried over MgSO4 and concentrated
in vacuo. The resulting brown oil was purified by distillation
(160 ЊC/0.3 mmHg) to give pyridine 9 as a clear yellow oil
(0.537 g, 50%). Rf 0.40 (NH3 saturated MeOH–CH2Cl2, 1:19);
[α]D25 Ϫ119 (c 5.0 in CHCl3); νmax/cmϪ1 (CHCl3) 1644, 1596, 1552,
1537, 1461, 1410, 1382, 1338, 1239, 1164; δH (CDCl3) 1.20 (6H,
d, J = 7.0 Hz, 2 × CH3), 1.60–1.75 (2H, m, CH2), 2.16–2.30
(2H, m, CH2), 3.93–4.07 (2H, m, 2 × CH), 6.35 (2H, d, J = 6.5
Hz, 2 × CH), 8.12 (2H, d, J = 6.5 Hz, 2 × CH); δC (CDCl3)
17.80 (2 × CH3), 30.03 (2 × CH2), 52.85 (2 × CH), 108.43
(2 × CH), 149.35 (2 × CH) and 149.84 (Cq); m/z (EIϩ)
(rel. intensity) 176 (Mϩ, 24%), 161 (100) and 78 (15). HRMS
calcd. for C11H16N2 (Mϩ) 176.1313, found 176.1311.
(R)-Alcohol
(S)-Acetate
Catalyst
T/min
Ca (%)
EeA (%)b
EeE (%)b
s
(Ϫ)-9
120
328
120
330
120
330
120
445
120
520
120
526
120
510
68.9
75.5
45.8
50.5
35.4
40.8
9.5
18.6
17.6
45.4
15.8
38.5
25.4
31.0
15.7c
21.7c
18.0
20.2
1.9
3.0
1.8
3.3
4.2
8.3
3.2
9.9
3.3
6.6c
4.9c
14.5
14.2
2.9
1.3
1.3
1.8
1.8
1.1
1.1
1.4
1.4
1.6
1.3
1.5
1.5
1.3
1.5
(ϩ)-Ib
(ϩ)-Ic
(ϩ)-Ie
(ϩ)-If
(ϩ)-Ig
(ϩ)-Ih
2.4
16.7
13.3
15.9
14.3
17.0
16.3
15.7
16.8
trans-3,4-Didehydro-3,4-dideoxy-1,2:5,6-di-O-isopropylidene-D-
threo-hexitol65,80
A solution of 1,2:5,6-di-O-isopropylidene-3,4-O-thioxocarb-
onyl--mannitol65 (52 g, 0.17 mol) and triethyl phosphite
(265 cm3) was heated at reflux for 17 h. The mixture was cooled
to room temperature and 6 M NaOH (400 cm3) added drop-
wise. After 2 days heating at reflux the reaction mixture was
cooled and extracted with CH2Cl2 (3 × 300 cm3). The combined
organic extracts were washed with water (2 × 500 cm3), dried
over MgSO4, filtered, and concentrated in vacuo. Recrystallis-
ation from n-pentane gave the title compound as clear colourless
needles (35.7 g, 91%). Mp 82–83 ЊC [lit.,65 80–82 ЊC (petrol)];
Rf 0.65 (EtOAc–petrol, 3:7); [α]D20 ϩ68.6 (c 1.0 in CHCl3) [lit.,80
[α]D20 ϩ58.8 (c 1.02 in CHCl3)]; δH (CDCl3) 1.39 (6H, s, 2 × CH3),
1.43 (6H, s, 2 × CH3), 3.6 (2H, t, J = 7.9 Hz, CH2), 4.1 (2H, dd,
J = 7.9, 6.3 Hz, CH2), 4.45–4.57 (2H, m, 2 × CH), 5.76–5.84
(2H, m, CH); m/z (EIϩ) (rel. intensity) 228 (Mϩ, 21%), 213 (79),
95 (67) and 72 (100).
6.8
a Conversion by (HPLC) mass balance. b By HPLC using a Chiralcel
OD column. c (S)-Alcohol and (R)-acetate obtained as major enantio-
mers.
Experimental
General
All reactions were performed under anhydrous conditions and
an inert atmosphere of nitrogen in flame-dried glassware. Yields
refer to chromatographically and spectroscopically (1H NMR)
homogeneous materials, unless otherwise indicated. Reagents
were used as obtained from commercial sources or purified
according to known procedures.78 Flash chromatography was
carried out using Merck Kieselgel 60 F254 (230–400 mesh)
silica gel. Only distilled solvents were used as eluents. Thin
layer chromatography (TLC) was performed on Merck DC-
Alufolien or glass plates pre-coated with silica gel 60 F254 which
were visualised either by quenching of ultraviolet fluorescence
(λmax = 254 nm) or by charring with 5% w/v phosphomolybdic
acid in 95% EtOH, 10% w/v ammonium molybdate in 1 M
H2SO4, or 10% KMnO4 in 1 M H2SO4. Observed retention
factors (Rf) are quoted to the nearest 0.05. All reaction solvents
were distilled before use and stored over activated 4 Å mole-
cular sieves, unless otherwise indicated. Anhydrous CH2Cl2
was obtained by refluxing over CaH2. Anhydrous THF and
Et2O were obtained by distillation, immediately before use,
from sodium–benzophenone ketyl under an inert atmosphere
of nitrogen. Anhydrous DMF was obtained by distillation from
CaH2 under reduced pressure. Petrol refers to the fraction of
light petroleum boiling between 40 and 60 ЊC. High resolution
3,4-Dideoxy-1,2:5,6-di-O-isopropylidene-D-threo-hexitol56,66
To a solution of trans-3,4-didehydro-3,4-dideoxy-1,2:5,6-di-O-
isopropylidene--threo-hexitol (12.6 g, 55.3 mmol) in absolute
EtOH (100 cm3) was added 5% Rh–Al2O3 (0.32 g, 2.5% w/w).
The mixture was stirred vigorously under hydrogen (1 atm) for
10 h. The mixture was then filtered through a Celite pad, con-
centrated in vacuo, and distilled to give the title compound as a
clear colourless oil (12.1 g, 95%). Rf 0.60 (EtOAc–petrol, 3:7);
[α]D20 ϩ10.0 (c 2.0 in MeOH) [lit.,66 [α]D23 ϩ17.5 (c 5.78 in MeOH)];
δH (CDCl3) 1.3 (6H, s, 2 × CH3), 1.35 (6H, s, 2 × CH3), 1.45–
1.75 (4H, m, 2 × CH2), 3.48–3.52 (2H, m, CH2), 3.96–4.15 (4H,
m, CH2 ϩ 2 × CH); m/z (CIϩ) (rel. intensity) 231 (MHϩ, 93%),
215 (100), 173 (80), 157 (84) and 72 (75).
(2S,5S)-1,6-Bis(benzyloxy)hexane-2,5-diol 56,67 11b and (2S,5S)-
1,2,6-tris(benzyloxy)hexan-5-ol
Tetrol 11a67 (21.8 g, 0.145 mol) was placed in a round
bottomed flask (1 l) fitted with a Dean–Stark trap. Toluene
(450 cm3) and dibutyltin oxide (72 g, 0.29 mol) were added and
the mixture was heated at reflux for 17 h. The reaction mixture
was allowed to cool to room temperature and treated with
tetrabutylammonium bromide (46.9 g, 0.145 mol) followed by
benzyl bromide (73 cm3, 0.61 mol). The mixture was heated to
reflux for 75 min, cooled and poured into water (500 cm3). After
2 h, the reaction mixture was filtered through a Celite pad.
The organic phase was separated, washed with 3 M NaOH
(500 cm3), dried over MgSO4, filtered, and concentrated in
vacuo. Purification by flash chromatography eluting with ethyl
acetate–petrol (1:3) gave the following compounds.
mass spectrometry (HRMS) measurements are valid to
5
ppm. GC was performed on a Perkin-Elmer series 8600 instru-
ment employing air/helium as carrier gas and using flame ion-
isation detection. HPLC was performed on a Hewlett-Packard
series 1100 instrument using UV detection (monitoring at
211 8 nm and referenced to 525 50 nm). 4-Fluoropyridine
5 was prepared according to the method of Desai.79 4-(Pyrrol-
idinosulfonyl)pyridine43 was prepared from 4-mercaptopyrid-
ine according to the method of Talik and Plazek.41
4-[(2R,5R)-2,5-Dimethylpyrrolidino]pyridine 9
An intimate mixture of 4-phenoxypyridine hydrochloride
63 (1.4 g, 6.1 mmol) and (2R,5R)-2,5-dimethylpyrrolidine34
(0.786 g, 7.94 mmol) was heated in a sealed tube at 200 ЊC for
24 h. The reaction was cooled, diluted with Et2O (20 cm3), and
Diol 11b.67 (23.5 g, 49%) As a clear colourless oil. Rf 0.20
(EtOAc–petrol, 1:1); [α]D21 Ϫ10.0 (c 1.0 in MeOH) [lit.,56 [α]D25
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Ϫ5.9 (c 1.0 in MeOH)]; δH (CDCl3) 1.55–1.65 (4H, m, 2 × CH2),
3.35 (2H, dd, J = 9.4, 7.6 Hz, CH2), 3.50 (2H, t, J = 7.0 Hz,
CH2), 3.77–3.91 (2H, m, 2 × CH), 4.54 (4H, s, 2 × CH2), 7.26–
7.39 (10Harom, m); m/z (EIϩ) (rel. intensity) 330 (Mϩ, 14%), 191
(53) and 91 (100).
(4H, m, 2 × CH2), 2.0–2.25 (4H, m, 2 × CH2), 3.75–3.90 (2H,
m, 2 × CH), 3.93–4.05 (2H, m, 2 × CH), 6.34–6.43 (4H, m,
4 × CH), 8.07–8.21 (4H, m, 4 × CH); m/z (EIϩ) (rel. intensity)
176 (Mϩ, 24%), 161 (100) and 78 (15). HRMS calcd. for
C11H16N2 (Mϩ) 176.1313, found 176.1311.
(2S,5S)-1,2,6-Tris(benzyloxy)hexan-5-ol. (16.5 g, 27%) As a
clear colourless oil. Rf 0.35 (EtOAc–petrol, 3:7); [α]D21 Ϫ4.1
(c 2.4 in CHCl3); νmax/cmϪ1 (CHCl3) 3005, 2913, 2855, 1450 and
1093; δH (CDCl3) 1.45–1.85 (4H, m, 2 × CH2), 3.30–3.85 (6H,
m, 2 × CH2 ϩ 2 × CH), 4.55–4.75 (6H, m, 3 × CH2), 7.26–7.39
(15Harom, m); δC (CDCl3) 27.81 (CH2), 28.92 (CH2), 70.22 (CH),
71.96 (CH2), 72.09 (CH2), 72.70 (2 × CH2), 73.37 (CH2), 77.74
(CH), 127.59 (CH), 127.70 (CH), 127.81 (CH), 127.91 (CH),
128.38 (CH), 128.44 (CH), 128.51 (CH), 138.09 (Cq), 138.36
(Cq) and 138.76 (Cq); m/z (CIϩ) (rel. intensity) 421 (Mϩ, 52%),
191 (42) and 91 (100). HRMS calcd. for C27H33O4 (Mϩ)
421.2379, found 421.2366.
4-[(2R,5R)-2,5-Bis(benzyloxymethyl)pyrrolidino]pyridine Ib and
meso-2,5-bis(benzyloxymethyl)oxolane 13. Method I
Sodium hydride (60% dispersion in mineral oil, 0.99 g,
25 mmol) was washed with hexane (3 × 10 cm3) and the volatile
components were removed in vacuo. A solution of 4-amino-
pyridine (1.16 g, 12.4 mmol) in THF (20 cm3) was added and
the mixture stirred for 3 h. Mesylate 11c (3.0 g, 6.2 mmol) in
THF (10 cm3) was added and the mixture heated at reflux for
20 h. The reaction was cooled to room temperature, carefully
quenched with 1 M NH4OH (150 cm3), and extracted with
CH2Cl2 (2 × 300 cm3). The combined organic extracts were
dried over MgSO4, filtered, and concentrated in vacuo. Purifi-
cation by flash chromatography eluting with petrol–EtOAc
(2:1) and then EtOH gave the following compounds.
Hydrogenolysis of (2S,5S)-1,2,6-tris(benzyloxy)hexan-5-ol to
give (2S,5S)-hexane-1,2,5,6-tetrol67 11a
To a solution of (2S,5S)-1,2,6-tris(benzyloxy)hexan-5-ol (6.2 g,
15 mmol) in THF (25 cm3) was added 10% Pd–C (0.6 g, 10%
w/w). The mixture was stirred vigorously under hydrogen
(1 atm) for 20 h, filtered through a Celite pad, and concentrated
in vacuo to give tetrol 11a (2.2 g, 99%) as a white amorphous
solid. Mp 92–94 ЊC [lit.,67 92–94 ЊC (MeOH)]; [α]D20 Ϫ17.8 (c 1.7
in MeOH) [lit.,67 [α]D26 Ϫ24.0 (c 1.69 in MeOH)]; δH (D2O) 1.15–
1.6 (4H, m, 2 × CH2), 3.4–3.8 (6H, m, 2 × CH ϩ 2 × CH2);
m/z (CIϩ) (rel. intensity) 168 (MNH4ϩ, 42%), 151 (MHϩ, 100%)
and 101 (42).
Pyridine Ib. As a pale yellow oil (0.96 g, 40%). Rf 0.40 (NH3
saturated MeOH–CH2Cl2, 1:19); [α]D17 ϩ89 (c 1.6 in CHCl3);
νmax/cmϪ1 (CHCl3) 2930, 1592, 1503, 1454, 1377, 1093 and 1004;
δH (CDCl3) 1.97–2.19 (4H, m, 2 × CH2), 3.22 (2H, dd, J = 9.5,
8.2 Hz, CH2), 3.53 (2H, dd, J = 9.5, 3.1 Hz, CH2), 3.92–4.04
(2H, m, 2 × CH), 4.47 (4H, s, 2 × CH2), 6.35 (2H, d, J = 5.8 Hz,
2 × CH), 7.23–7.39 (10Harom, m), 8.10 (2H, d, J = 5.8 Hz,
2 × CH); δC (CDCl3) 26.75 (2 × CH2), 57.24 (2 × CH), 68.17
(2 × CH2), 73.32 (2 × CH2), 108.64 (2 × CH), 127.68 (4 × CH),
127.83 (2 × CH), 128.47 (4 × CH), 137.96 (2 × Cq), 149.77
(2 × CH) and 150.00 (Cq); m/z (EIϩ) (rel. intensity) 388 (Mϩ,
25%), 267 (100) and 91 (81). HRMS calcd. for C25H28O2N2
(Mϩ) 388.2151, found 388.2143.
(2S,5S)-1,6-Bis(benzyloxy)-2,5-bis(methylsulfonyloxy)hexane67
11c
To a solution of diol 11b (11 g, 0.033 mol) in CH2Cl2 (150 cm3)
was added Et3N (18 cm3, 0.13 mol). The mixture was cooled
to 0 ЊC and methanesulfonyl chloride (7.7 cm3, 0.099 mol)
added dropwise. After 90 min the reaction mixture was washed
with water (2 × 100 cm3). The organic phase was dried over
MgSO4, filtered, and concentrated in vacuo. Purification by
flash chromatography eluting with CH2Cl2–EtOAc (4:1) gave
mesylate 11c as an amorphous white powder (16.0 g, 99%).
Rf 0.25 (EtOAc–petrol, 3:7); [α]D20 ϩ8.5 (c 1.2 in CHCl3);
δH (CDCl3) 1.76–1.83 (4H, m, 2 × CH2), 3.02 (6H, s, 2 × CH3),
3.42–3.67 (4H, m, 2 × CH2), 4.51 (2H, d, J = 11.6 Hz, CH2),
Oxolane 13. As a pale yellow oil (1.00 g, 52%). Rf 0.20
(EtOAc–petrol, 1:9); νmax/cmϪ1 (CHCl3) 2864, 1719, 1703,
1600, 1493, 1149, 1231 and 1085; δH (CDCl3) 1.63–1.78 (2H, m,
CH2), 1.87–2.01 (2H, m, CH2), 3.42–3.56 (4H, m, 2 × CH2),
4.07–4.20 (2H, m, 2 × CH), 4.50–4.63 (4H, m, 2 × CH2), 7.25–
7.38 (10Harom, m); δC (CDCl3) 27.99 (2 × CH2), 72.88 (2 × CH2),
73.36 (2 × CH2), 78.68 (2 × CH), 127.58 (2 × CH), 127.72
(4 × CH), 128.37 (4 × CH) and 138.39 (2 × Cq); m/z (CIϩ) (rel.
intensity) 330 (MNH4ϩ, 26%), 313 (MHϩ, 10%), 221 (67) and
91 (100). HRMS calcd. for C20H25O3 (Mϩ) 313.1804, found
313.1789.
4.56 (2H, d, J = 11.6 Hz, CH2), 4.86–4.97 (2H, m, 2 × CH),
7.25–7.48 (10Harom, m); m/z (EIϩ) (rel. intensity) 504 (MNH4
,
ϩ
95%), 331 (58), 318 (76) and 91 (100).
(2S,5S)-1,6-Bis(benzyloxy)-2,5-bis(p-nitrophenylsulfonyloxy)-
hexane 11d
( )-4-(2,5-Dimethylpyrrolidino)pyridine ( )-9 and meso-4-(2,5-
To a solution of diol 11b (0.45 g, 1.4 mmol) in CH2Cl2 (10 cm3)
was added Et3N (0.76 cm3, 5.5 mmol). The mixture was cooled
to 0 ЊC and p-nitrobenzenesulfonyl chloride (0.91 g, 4.1 mmol)
was added portionwise with stirring over 15 min. The mixture
was stirred for 3 h at 0 ЊC and for 30 min at room temperature,
diluted with CH2Cl2 (10 cm3), and washed with 1 M HCl (20
cm3) and water (20 cm3). The organic phase was dried over
MgSO4, filtered, and concentrated in vacuo. Purification by
flash chromatography eluting with CH2Cl2–petrol (7:3) gave
nosylate 11d as an amorphous yellow powder (0.66 g, 69%).
dimethylpyrrolidino)pyridine 12
Sodium hydride (60% dispersion in mineral oil, 0.53 g,
13 mmol) was washed with hexane (3 × 15 cm3) and volatiles
were removed in vacuo. A solution of 4-aminopyridine (0.50 g,
5.3 mmol) in THF (20 cm3) was added and the mixture stirred
for 3 h. After addition of a solution of 2,5-bis(methyl-
sulfonyloxy)hexane [~1:1 ( )-:meso]35 (0.73 g, 2.7 mmol) in
THF (10 cm3), the reaction mixture was heated at reflux for
20 h. The reaction mixture was cooled to room temperature,
carefully quenched with 1 M NH4OH and extracted with
CH2Cl2 (3 × 100 cm3). The combined organic extracts were
dried over MgSO4, filtered, and concentrated in vacuo. Purifi-
cation by flash chromatography eluting with absolute ethanol
gave a mixture of pyridines ( )-9 and 12 (~1:1 by 1H NMR) as
a brown oil (0.46 g, 98%). Rf 0.40 (NH3 saturated MeOH–
CH2Cl2, 1:19); νmax/cmϪ1 (CHCl3) 1644, 1596, 1552, 1537,
1461, 1410, 1382, 1338, 1239, 1164; δH (CDCl3) 1.10 (6H, d,
J = 7.0 Hz, 2 × CH3), 1.25 (6H, d, J = 7.0 Hz, 2 × CH3), 1.6–1.8
Rf 0.50 (EtOAc–petrol, 3:7); [α]D19 ϩ31.1 (c 2.2 in CHCl3); νmax
/
cmϪ1 (CHCl3) 2868, 1532, 1349, 1182, 1099 and 912; δH (CDCl3)
1.79–1.96 (4H, m, 2 × CH2), 3.48 (4H, d, J = 7.0 Hz, 2 × CH2),
4.17–4.38 (4H, m, 2 × CH2), 4.87–5.03 (2H, m, 2 × CH), 7.03–
7.12 (4Harom, m), 7.21–7.32 (6Harom, m), 7.92–8.03 (4Harom, m)
and 8.04–8.14 (4Harom, m); δC (CDCl3) 26.70 (2 × CH2), 71.12
(2 × CH2), 73.30 (2 × CH2), 82.70 (2 × CH), 123.97 (4 × CH),
127.79 (4 × CH), 128.17 (2 × CH), 128.41 (4 × CH), 129.08
(4 × CH), 136.91 (2 × Cq), 142.59 (2 × Cq) and 150.34 (2 × Cq).
3464
J. Chem. Soc., Perkin Trans. 1, 2000, 3460–3468

View Article Online
Found: C, 54.94; H, 4.67; N, 3.71. Calcd. for C32H32N2O12S2:
C, 54.85; H, 4.60; N, 3.71%.
Ϫ8.4 (c 2.04 in CHCl3)]; δH (CDCl3) 1.59–2.20 (4H, m,
2 × CH2), 3.97–4.14 (1H, m, CH), 4.21–4.63 (4H, m, 2 × CH2),
5.52–5.65 (1H, m, CH), 7.32–7.60 (9Harom, m) and 7.92–8.08
(6Harom, m); m/z (CIϩ) (rel. intensity) 462 (Mϩ, 15%), 327 (10),
219 (37), 205 (32) and 105 (100).
(2S,5S)-1,6-Bis(benzyloxy)hexane-2,5-diyl cyclic sulfate 11e
To a solution of diol 11b (0.23 g, 0.70 mmol) in CH2Cl2 (5 cm3)
was added Et3N (0.39 cm3, 2.8 mmol) and the mixture cooled
to 0 ЊC. Thionyl chloride (0.25 g, 2.1 mmol) was added drop-
wise and the reaction mixture stirred for an additional 30 min.
The mixture was diluted with Et2O (10 cm3) and the ethereal
solution washed with brine (3 × 5 cm3) and dried over MgSO4.
The organic phase was concentrated in vacuo and the residue
dissolved in a mixture of CCl4 (4 cm3), MeCN (4 cm3) and
water (6 cm3). To the reaction mixture was added NaIO4 (0.3 g,
1.4 mmol), followed by RuCl3ؒxH2O (1 mg) with stirring at 0 ЊC
for 2 h. The mixture was then extracted with Et2O (3 × 10 cm3)
and the combined extracts were washed with brine (5 cm3),
dried over MgSO4, filtered, and concentrated in vacuo. Purifi-
cation by flash chromatography eluting with petrol–EtOAc
(3:1) gave cyclic sulfate 11e as a clear colourless oil (0.24 g,
87%). Rf 0.30 (EtOAc–petrol, 3:7); [α]D20 Ϫ26.5 (c 9.0 in CH2-
Cl2); νmax/cmϪ1 (CHCl3) 1391, 1190, 1098, 964, 952 and 915;
δH (CDCl3) 1.98–2.08 (4H, m, 2 × CH2), 3.54–3.72 (4H, m,
2 × CH2), 4.58 (4H, s, 2 × CH2), 4.72–4.84 (2H, m, 2 × CH),
7.25–7.40 (10Harom, m); δC (CDCl3) 29.04 (2 × CH2), 70.93
(2 × CH2), 73.94 (2 × CH2), 82.75 (2 × CH), 127.78 (4 × CH),
127.97 (2 × CH), 128.54 (4 × CH) and 137.44 (2 × Cq); m/z
(EIϩ) (rel. intensity) 392 (Mϩ, 14%), 301 (67) and 91 (100).
HRMS calcd. for C20H24O6S (Mϩ) 392.1294, found 392.1289.
(2S,5S)-1,6-Bis(benzoyloxy)-2,5-bis(methylsulfonyloxy)hexane67
11h
To a solution of diol 11g (0.21 g, 0.59 mmol) in CH2Cl2 (5 cm3)
was added Et3N (0.33 cm3, 2.4 mmol). The mixture was cooled
to 0 ЊC and methanesulfonyl chloride (0.14 cm3, 1.8 mmol) was
added dropwise. The reaction mixture was stirred at 0 ЊC for
30 min and at room temperature for 1 h. The mixture was then
diluted with CH2Cl2 (5 cm3) and washed sequentially with 1 M
NaOH (10 cm3) and 2 M HCl (10 cm3). The organic phase was
dried over MgSO4, filtered, and concentrated in vacuo. Purifi-
cation by flash chromatography eluting with CH2Cl2–EtOAc
(1:1) gave mesylate 11h as an amorphous white powder (0.26 g,
86%). Mp 109–111 ЊC (CH2Cl2–petrol) [lit.,67 108–109 ЊC
(CH2Cl2–hexane)]; [α]D19 ϩ15.4 (c 1.1 in CHCl3) [lit.,67 [α]D28 ϩ14.3
(c 1.13 in CHCl3)]; δH (CDCl3) 1.97–2.06 (4H, m, 2 × CH2),
3.05 (6H, s, 2 × CH3), 4.45 (2H, dd, J = 12.2, 6.6 Hz, CH2), 4.55
(2H, dd, J = 12.5, 3.2 Hz, CH2), 7.4–8.1 (10Harom, m); m/z (CIϩ)
(rel. intensity) 359 (23, Mϩ), 223 (74) and 105 (100).
(2S,5S)-1,6-Bis(triphenylmethyloxy)hexane-2,5-diol 11i
To a solution of tetrol 11a67 (0.45 g, 3.0 mmol) in pyridine (20
cm3) was added DMAP (0.04 g, 0.3 mmol) and trityl chloride
(1.8 g, 6.5 mmol), and the mixture stirred for 24 h. The solution
was concentrated in vacuo, dissolved in CH2Cl2 (30 cm3), and
washed with water (3 × 25 cm3). The organic phase was dried
over MgSO4, filtered, and concentrated in vacuo. Purification by
flash chromatography eluting with EtOAc–petrol (1:2) gave
diol 11i as an amorphous white powder (1.29 g, 69%). Rf 0.70
(EtOAc–petrol, 1:1); mp 157–159 ЊC (EtOAc–petrol); [α]D18 ϩ4.0
(c 2.5 in CHCl3); νmax/cmϪ1 (CHCl3) 3594, 3058, 1957, 1596,
1490, 1442, 1234, 1202 and 1008; δH (CDCl3) 1.40–1.52 (4H,
m, 2 × CH2), 2.97–3.17 (4H, m, 2 × CH2), 3.69–3.83 (2H, m,
2 × CH), 7.1–7.5 (30Harom, m); δC (CDCl3) 29.63 (2 × CH2),
67.59 (2 × CH2), 70.90 (2 × CH), 86.64 (2 × Cq), 127.10 (6 ×
CH), 127.87 (12 × CH), 128.65 (12 × CH) and 143.84 (6 × Cq).
HRMS calcd. for C44H42O4 634.3083, found 634.3088.
4-[(2R,5R)-2,5-Bis(benzyloxymethyl)pyrrolidino]pyridine Ib.
Method II
Sodium hydride (60% dispersion in mineral oil, 0.11 g,
2.7 mmol) was washed with hexane (3 × 5 cm3) and the volatile
components were removed in vacuo. A solution of 4-amino-
pyridine (0.10 g, 1.1 mmol) in THF (5 cm3) was added and the
mixture stirred for 3 h. A solution of cyclic sulfate 11e (0.21 g,
0.54 mmol) in THF (5 cm3) was added and the reaction was
heated at reflux for 20 h. The reaction was cooled to room
temperature, carefully quenched with 1 M NH4OH (25 cm3)
and extracted with CH2Cl2 (2 × 25 cm3). The combined organic
extracts were dried over MgSO4, filtered, and concentrated
in vacuo. Purification by flash chromatography eluting with
petrol–EtOAc (2:1) and then ethanol gave pyridine Ib as a pale
yellow oil (0.11 g, 52%). Spectroscopic data as above.
(2S,5S)-1,6-Bis(triphenylmethyloxy)-2,5-bis(methylsulfonyloxy)-
hexane 11j
(2S,5S)-1,6-Bis(benzoyloxy)hexane-2,5-diol67 11g and (2S,5S)-
To a solution of diol 11i (0.43 g, 0.68 mmol) in CH2Cl2 (10 cm3)
was added Et3N (0.38 cm3, 2.7 mmol). The mixture was cooled
to 0 ЊC and methanesulfonyl chloride (0.16 cm3, 2.0 mmol)
added dropwise. After 90 min at 0 ЊC, the reaction mixture was
washed with water (2 × 10 cm3). The organic phase was dried
over MgSO4, filtered, and concentrated in vacuo. Purification
by flash chromatography eluting with petrol–EtOAc (4:1) gave
mesylate 11j as an amorphous white powder (0.51 g, 94%).
Rf 0.45 (EtOAc–petrol, 3:7); mp 149–151 ЊC (EtOAc–petrol);
[α]D21 ϩ9.2 (c 2.2 in CHCl3); νmax/cmϪ1 (CHCl3) 3594, 3058, 1486,
1446, 1328 and 1008; δH (CDCl3) 1.55–1.80 (4H, m, 2 × CH2),
3.00 (6H, s, 2 × CH3), 3.19 (2H, dd, J = 10.7, 6.6 Hz, CH2), 3.35
(2H, dd, J = 10.7, 4.0 Hz, CH2), 4.82–4.92 (2H, m, 2 × CH),
7.20–7.45 (30Harom, m); δC (CDCl3) 27.08 (2 × CH2), 38.84
(2 × CH3), 65.29 (2 × CH2), 81.54 (2 × CH), 87.37 (2 × Cq),
127.40 (6 × CH), 128.11 (12 × CH), 128.67 (12 × CH) and
143.32 (6 × Cq). Found: C, 69.14; H, 6.04; S, 8.07. Calcd. for
C46H46O8S2: C, 69.85; H, 5.86; S, 8.11%.
1,2,6-tris(benzoyloxy)hexan-5-ol67
To a solution of tetrol 11a67 (0.20 g, 1.4 mmol) in tert-amyl
alcohol (10 cm3) was added dimethyltin dichloride (0.006 g,
0.03 mmol), K2CO3 (0.38 g, 2.7 mmol) and benzoyl chloride
(0.38 cm3, 3.3 mmol). The reaction mixture was stirred for
20 h and then concentrated in vacuo. The residue was diluted
with water (25 cm3) and extracted with CH2Cl2 (2 × 25 cm3).
The combined organic extracts were dried over MgSO4, filtered,
and concentrated in vacuo. Purification by flash chromato-
graphy, eluting with petrol–EtOAc (2:1), gave the following
compounds.
Diol 11g. (0.24 g, 49%) As an amorphous white powder.
Mp 110–112 ЊC (CH2Cl2–petrol) [lit.,67 110.5–111.5 ЊC (CHCl3–
hexane)]; Rf 0.30 (EtOAc–petrol, 1:1); [α]D18 ϩ3.7 (c 2.7 in
CHCl3) [lit.,67 [α]D27 ϩ2.5 (c 2.69 in CHCl3)]; δH (CDCl3) 1.65–
1.90 (4H, m, 2 × CH2), 3.30 (2H, br s, 2 × OH), 3.92–4.09 (2H,
m, 2 × CH), 4.20–4.48 (4H, m, 2 × CH2), 7.35–7.59 (6Harom, m),
8.03 (4Harom, m); m/z (CIϩ) (rel. intensity) 359 (MHϩ, 93%), 219
(100), 205 (71) and 105 (90).
4-[(2R,5R)-2,5-Bis(triphenylmethyloxymethyl)pyrrolidino]-
pyridine Ic
(2S,5S)-1,2,6-Tris(benzoyloxy)hexan-5-ol. (0.037 g, 6%) As an
amorphous white solid. [α]D21 Ϫ9.9 (c 2.0 in CHCl3) [lit.,67 [α]D29
Sodium hydride (60% dispersion in mineral oil, 0.10 g, 2.5
mmol) was washed with hexane (3 × 5 cm3) and the volatile
J. Chem. Soc., Perkin Trans. 1, 2000, 3460–3468
3465

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components were removed in vacuo. A solution of 4-amino-
pyridine (0.09 g, 1.0 mmol) in THF (7.5 cm3) was added and the
mixture stirred for 4 h. The mixture was brought to reflux and
mesylate 11j (0.4 g, 0.5 mmol) in THF (5 cm3) added. After 17 h
heating at reflux, the reaction mixture was cooled to room
temperature, carefully quenched with sat. NH4OH (25 cm3)
and extracted with CH2Cl2 (3 × 25 cm3). The combined organic
extracts were dried over MgSO4, filtered, and concentrated
in vacuo. Purification by flash chromatography eluting with
MeOH saturated with NH3–CH2Cl2 (0.03:1) gave pyridine Ic
as a clear colourless oil (0.15 g, 42%). Rf 0.65 (NH3 saturated
MeOH–CH2Cl2, 1:19); [α]D17 ϩ35 (c 1.7 in CHCl3); νmax/cmϪ1
(CHCl3) 2952, 2872, 1592, 1509, 1489, 1445, 1382, 1227 and
1073; δH (CDCl3) 2.04–2.20 (4H, m, 2 × CH2), 3.05 (2H,
dd, J = 9.5, 7.9 Hz, CH2), 3.21 (2H, dd, J = 9.5, 3.1 Hz, CH2),
3.85–3.97 (2H, m, 2 × CH), 5.92 (2H, d, J = 6.4 Hz, 2 × CH),
7.15–7.45 (30Harom, m), 7.92 (2H, d, J = 6.4 Hz, 2 × CH);
δC (CDCl3) 26.62 (2 × CH2), 50.55 (2 × CH), 61.37 (2 × Cq),
86.96 (2 × CH2), 108.52 (2 × CH), 127.11 (6 × CH), 127.85
(12 × CH), 128.59 (12 × CH), 143.92 (6 × Cq), 149.02 (2 × CH)
and 150.20 (Cq); m/z (CIϪ) (rel. intensity) 449 (Mϩ Ϫ C(C6H5)3,
30%), 259 (100) and 243 (35). Found: C, 85.41; H, 6.59; N, 3.78.
Calcd. for C49H44N2O2: C, 84.94; H, 6.40; N, 4.04%.
298 (100) and 159 (14). HRMS calcd. for C23H22O6N4 (Mϩ)
450.1539, found 450.1528.
4-[(2R,5R)-2,5-Bis(phenoxymethyl)pyrrolidino]pyridine If
To a solution of pyridine Id (0.1 g, 0.5 mmol) in THF (10 cm3)
were added phenol (0.27 g, 2.9 mmol) and tributylphosphine
(0.48 cm3, 1.9 mmol). The mixture was cooled to 0 ЊC and a
solution of ADDP74 (0.49 g, 1.9 mmol) in THF (5 cm3) was
added dropwise with vigorous stirring. The reaction mixture
was warmed to room temperature, stirred for 24 h, and diluted
with petrol (10 cm3). The reaction mixture was then filtered
through a Celite pad and concentrated in vacuo. The residue
was dissolved in MeOH and loaded onto an SCX ion-exchange
column (2 g). The column was washed with MeOH (20 cm3)
and the product eluted with MeOH saturated with NH3
(25 cm3). Evaporation and further purification by flash chrom-
atography eluting with MeOH saturated with NH3–CH2Cl2–
EtOAc (0.14:6:1) gave a white amorphous solid. Recrystallis-
ation from MeOH gave pyridine If as white needles (0.14 g,
81%). Mp 163–164 ЊC (MeOH); Rf 0.45 (NH3 saturated
MeOH–CH2Cl2, 1:19); [α]D17 ϩ153 (c 1.4 in CHCl3); νmax/cmϪ1
(CHCl3) 1596, 1499, 1470, 1377, 1239 and 1211; δH (CDCl3)
2.14–2.40 (4H, m, 2 × CH2), 3.71 (2H, t, J = 9.2 Hz, CH2), 4.08
(2H, dd, J = 9.2, 2.7 Hz, CH2), 4.26–4.38 (2H, m, 2 × CH), 6.57
(2H, dd, J = 5.2, 1.8 Hz, 2 × CH), 6.80–7.35 (10Harom, m), 8.22
(2H, dd, J = 5.2, 1.8 Hz, 2 × CH); δC (CDCl3) 26.70 (2 × CH2),
56.97 (2 × CH), 65.68 (2 × CH2), 108.89 (2 × CH), 114.51
(4 × CH), 121.24 (2 × CH), 129.61 (4 × CH), 149.89 (Cq),
150.27 (2 × CH) and 158.53 (Cq); m/z (EIϩ) (rel. intensity) 360
(Mϩ, 11%), 253 (100). HRMS calcd. for C23H24O2N2 (Mϩ)
360.1838, found 360.1834.
4-[(2R,5R)-2,5-Bis(hydroxymethyl)pyrrolidino]pyridine Id
To a solution of pyridine Ib (1.0 g, 2.6 mmol) in a mixture of
absolute EtOH (9 cm3) and 1 M HCl (3 cm3) was added 10%
Pd–C (0.1 g, 10% w/w). The mixture was stirred vigorously
under hydrogen (1 atm) for 4 h, filtered through a Celite pad,
and concentrated in vacuo. The residue was dissolved in MeOH
and loaded onto an SCX ion-exchange column (10 g). The col-
umn was washed with MeOH (3 × 25 cm3) and the product
eluted with MeOH saturated with NH3 (25 cm3). Evaporation
and crystallisation from MeOH gave pyridine Id as clear colour-
less needles (0.45 g, 84%). Mp 197–198 ЊC (MeOH); Rf 0.05
(NH3 saturated MeOH–CH2Cl2, 1:19); [α]D17 ϩ39 (c 1.3 in
MeOH); νmax/cmϪ1 (Nujol) 3326, 1600, 1533, 1374 and 1038;
δH (CD3OD) 2.03–2.25 (4H, m, 2 × CH2), 3.33–3.41 (2H, m,
CH2), 3.62 (2H, dd, J = 11.0, 2.7 Hz, CH2), 3.92–4.04 (2H, m,
2 × CH), 6.64 (2H, dd, J = 6.4, 1.4 Hz, 2 × CH) and 8.04 (2H,
d, J = 6.4 Hz, 2 × CH); δC (CD3OD) 27.03 (2 × CH2), 60.68
(2 × CH), 60.99 (2 × CH2), 110.20 (2 × CH), 149.57 (2 × CH)
and 152.48 (Cq); m/z (EIϩ) (rel. intensity) 208 (Mϩ, 12%), 177
(100). HRMS calcd. for C11H16O2N2 (Mϩ) 208.1212, found
208.1215.
4-[(2R,5R)-2,5-Bis(2-naphthyloxymethyl)pyrrolidino]pyridine Ig
To a solution of pyridine Id (0.512 g, 2.46 mmol) in THF
(60 cm3) were added 2-naphthol (2.13 g, 14.8 mmol) and tri-
butylphosphine (2.5 cm3, 9.8 mmol). The mixture was cooled
to 0 ЊC and ADDP (2.5 g, 9.8 mmol) in THF (15 cm3) added
dropwise with vigorous stirring. The reaction was warmed to
room temperature, stirred for 18 h and diluted with petrol (15
cm3). The reaction mixture was then filtered through a Celite
pad and concentrated in vacuo. The residue was triturated with
MeOH (30 cm3) to give pyridine Ig as an amorphous solid (380
mg, 34%). The mother liquor was concentrated in vacuo and
loaded onto an SCX ion-exchange column (10 g). The column
was washed with MeOH (3 × 20 cm3) and the product eluted
with MeOH saturated with NH3 (50 cm3). Evaporation and
further purification by flash chromatography eluting with
MeOH saturated with NH3–CH2Cl2–EtOAc (0.1:5:1) gave an
additional amount of pyridine Ig as an amorphous white solid
(560 mg, 49%; total yield 0.94 g, 83%). Mp >225 ЊC (MeOH);
Rf 0.75 (NH3 saturated MeOH–CH2Cl2, 1:19); [α]D17 ϩ207 (c 1.6
CHCl3); νmax/cmϪ1 (CHCl3) 1596, 1508, 1467, 1388 and 1226;
δH (CDCl3) 2.20–2.48 (4H, m, 2 × CH2), 3.88 (2H, t, J = 8.5 Hz,
CH2), 4.23 (2H, m, CH2), 4.37–4.47 (2H, m, 2 × CH), 6.65
(2H, d, J = 6.4 Hz, 2 × CH), 7.05–7.80 (14Harom, m), 8.26 (2H,
d, J = 6.4 Hz, 2 × CH); δC (CDCl3) 26.78 (2 × CH2), 56.99
(2 × CH), 65.81 (2 × CH2), 106.77 (2 × CH), 108.94 (2 × CH),
118.65 (2 × CH), 123.92 (2 × CH), 126.59 (2 × CH), 126.77
(2 × CH), 127.69 (2 × CH), 129.14 (2 × Cq), 129.60 (2 × CH),
134.44 (2 × Cq), 149.94 (Cq), 150.34 (2 × CH) and 156.46
(2 × Cq); m/z (EIϩ) (rel. intensity) 460 (Mϩ, 11%), 303 (100) and
159 (22). HRMS calcd. for C31H28O2N2 (Mϩ) 460.2151, found
460.2147.
4-[(2R,5R)-2,5-Bis(p-nitrophenoxymethyl)pyrrolidino]pyridine
Ie
To a solution of pyridine Id (0.054 g, 0.26 mmol) in THF
(4 cm3) was added p-nitrophenol (0.15 g, 1.0 mmol) and tri-
phenylphosphine (0.27 g, 1.0 mmol). The mixture was cooled
to 0 ЊC and DEAD (0.16 cm3, 1.0 mmol) added dropwise
with vigorous stirring. After 2 h, the mixture warmed to room
temperature, stirred for an additional 18 h, and concentrated in
vacuo. The residue was dissolved in MeOH and loaded onto an
SCX ion-exchange column (2 g). The column was washed with
MeOH (20 cm3) and the product eluted with MeOH saturated
with NH3 (25 cm3). Evaporation and crystallisation from
MeOH gave pyridine Ie as a pale yellow solid (0.11 g, 88%). Mp
86–88 ЊC (MeOH); Rf 0.45 (NH3 saturated MeOH–CH2Cl2,
1:19); [α]D16 ϩ12.6 (c 1.4 in CHCl3); νmax/cmϪ1 (CHCl3) 1588,
1515, 1466, 1373, 1340, 1255, 1211 and 1109; δH (CDCl3) 2.14–
2.47 (4H, m, 2 × CH2), 3.86 (2H, dd, J = 9.2, 7.9 Hz, CH2), 4.12
(2H, dd, J = 9.2, 2.7 Hz, CH2), 4.33–4.45 (2H, m, 2 × CH),
6.59 (2H, d, J = 6.1 Hz, 2 × CH), 6.84–6.93 (4Harom, m), 8.09–
8.20 (2CH ϩ 4Harom, m); δC (CDCl3) 26.75 (2 × CH2), 56.67
(2 × CH), 66.52 (2 × CH2), 108.94 (2 × CH), 114.47 (4 × CH),
125.97 (4 × CH), 141.89 (2 × Cq), 149.73 (Cq), 150.09 (2 × CH)
and 163.29 (2 × Cq); m/z (EIϩ) (rel. intensity) 450 (Mϩ, 7%),
4-[(2R,5R)-2,5-Bis(p-methoxyphenoxymethyl)pyrrolidino]-
pyridine Ih
To a solution of pyridine Id (0.21 g, 1.0 mmol) in THF
(10 cm3) was added p-methoxyphenol (0.74 g, 6.0 mmol) and
3466
J. Chem. Soc., Perkin Trans. 1, 2000, 3460–3468

View Article Online
tributylphosphine (1.0 cm3, 4.0 mmol). The mixture was cooled
to 0 ЊC and TMAD75 (0.69 g, 4.0 mmol) in THF (5 cm3) added
dropwise with vigorous stirring. The reaction was warmed to
room temperature, stirred for 18 h and diluted with petrol
(5 cm3). The reaction mixture was then filtered through a Celite
pad and concentrated in vacuo. The residue was triturated with
MeOH (30 cm3) to give pyridine Ih as a white amorphous solid
(270 mg, 65%). The mother liquor was concentrated in vacuo
and loaded onto an SCX ion-exchange column (2 g). The
column was washed with MeOH (25 cm3) and the product
eluted with MeOH saturated with NH3 (25 cm3). Evaporation
and further purification by flash chromatography eluting with
MeOH saturated with NH3–CH2Cl2–EtOAc (0.1:5:1) gave an
additional amount of pyridine Ig as a white amorphous solid
(80 mg, 19%). Recrystallisation of the combined product
batches from MeOH gave white needles (total yield 0.34 g,
82%). Mp 193 ЊC (MeOH); Rf 0.40 (NH3 saturated MeOH–
CH2Cl2, 1:19); [α]D16 ϩ134 (c 1.6 in CHCl3); νmax/cmϪ1 (CHCl3)
1592, 1503, 1466, 1377, 1235 and 1036; δH (CDCl3) 2.15–2.35
(4H, m, 2 × CH2), 3.67 (2H, t, J = 8.9 Hz, CH2), 3.77 (6H, s,
2 × CH3), 4.04 (2H, dd, J = 8.9, 2.7 Hz, CH2), 4.22–4.34 (2H,
Å3, Z = 4, Dc = 1.256 g cmϪ1, µ = 0.080 mmϪ1 (Mo-Kα, λ =
0.71073 Å), F(000) = 768, T = 123(1) K. Bruker AXS SMART
CCD area-detector diffractometer, crystal size, plate, 0.20 ×
0.20 × 0.05 mm, θmax 26.35Њ, 19928 reflections measured, 3905
unique, 100% complete (Rint = 0.0285). Structure solution by
direct methods, full-matrix least-squares refinement on F2 with
2
weighting wϪ1 = σ2(Fo ) ϩ (0.0590P)2, where P = (Fo2 ϩ 2Fc2)/3,
anisotropic displacement parameters, riding hydrogen atoms
with Uiso free, no absorption correction, absolute structure
2
not determined. Final Rw = {Σ[w(Fo2 Ϫ Fc2)2]/Σ[w(Fo )2]1/2} =
0.0806 for all data, conventional R = 0.0298 on F values of
3531 reflections with I > 2σ(I), S = 1.002 for all data and 268
parameters. Final difference map between ϩ0.15 and Ϫ0.16
e ÅϪ3. Programs: Bruker AXS, SMART, SAINT and SADABS
control and integration software,81 SHELXTL structure
solution and refinement.82
Acknowledgements
Grateful acknowledgement is made to the ESPRC, Glaxo-
Wellcome, and the Leverhulme Trust for financial support and
Dr Vipulkumar K. Patel (GlaxoWellcome) for providing the
ion-exchange purification protocol.
m, 2 × CH), 6.54 (2H, d, J = 5.8 Hz, 2 × CH), 6.75–6.9 (8Harom
,
m), 8.24 (2H, d, J = 5.8 Hz, 2 × CH); δC (CDCl3) 26.63
(2 × CH2), 55.75 (2 × CH3), 56.97 (2 × CH), 66.44 (2 × CH2),
108.82 (2 × CH), 114.71 (4 × CH), 115.44 (4 × CH), 149.90
(Cq), 150.17 (2 × CH), 152.64 (2 × Cq) and 154.15 (2 × Cq);
m/z (EIϩ) (rel. intensity) 420 (Mϩ, 8%) and 283 (100). HRMS
calcd. for C25H28O4N2 (Mϩ) 420.2049, found 420.2063.
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