Chiral oxime ethers in asymmetric synthesis. Part 5. Asymmetric synthesis of 2-substituted 5- to 8-membered nitrogen heterocycles by oxime addition-ring-closing metathesis

Article abstract of DOI:10.1039/b207235c

Addition of organometallic reagents to chiral oxime ethers 1 derived from an unsaturated aldehyde, or addition of an alkene containing organometallic to chiral aldoxime ethers 2 results in highly stereoselective formation of the hydroxylamines 6. N-Allylation gives the dienes 7 which undergo ring-closing metathesis (RCM) reaction to give the 5-, 6-, and 7-membered nitrogen heterocycles 8. Likewise, the benzyl carbamates 9, also prepared by stereoselective addition to oxime ethers, were converted into dienes 10, which underwent RCM to give the 5- to 8-membered azacycles 11. The oxime addition-RCM protocol is thus a versatile method for the asymmetric synthesis of nitrogen heterocycles, further exemplified by the conversion of the unsaturated heterocycles into chiral piperidines, including the alkaloid (-)-coniine.

Full text of DOI:10.1039/b207235c

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Chiral oxime ethers in asymmetric synthesis. Part 5.1 Asymmetric
synthesis of 2-substituted 5- to 8-membered nitrogen heterocycles
by oxime addition–ring-closing metathesis
1
James C. A. Hunt, Pierre Laurent and Christopher J. Moody*
School of Chemistry, University of Exeter, Stocker Road, Exeter, UK EX4 4QD
Received (in Cambridge, UK) 23rd July 2002, Accepted 21st August 2002
First published as an Advance Article on the web 2nd October 2002
Addition of organometallic reagents to chiral oxime ethers 1 derived from an unsaturated aldehyde, or addition
of an alkene containing organometallic to chiral aldoxime ethers 2 results in highly stereoselective formation of the
hydroxylamines 6. N-Allylation gives the dienes 7 which undergo ring-closing metathesis (RCM) reaction to give the
5-, 6-, and 7-membered nitrogen heterocycles 8. Likewise, the benzyl carbamates 9, also prepared by stereoselective
addition to oxime ethers, were converted into dienes 10, which underwent RCM to give the 5- to 8-membered
azacycles 11. The oxime addition–RCM protocol is thus a versatile method for the asymmetric synthesis of nitrogen
heterocycles, further exemplified by the conversion of the unsaturated heterocycles into chiral piperidines, including
the alkaloid (Ϫ)-coniine.
the recent past.12,13 The reaction tolerates a wide range of
Introduction
functional groups, and has been used for the synthesis of
The development of methods for the asymmetric synthesis of
nitrogen heterocycles of varying ring size.14–24 The proposed
pyrrolidines, piperidines and ring-fused derivatives such as
combination of oxime addition–RCM is shown in outline in
indolizidines remains an area of current interest due to the
Scheme 2, and we now describe the results of our work in this
presence of such saturated heterocyclic rings in a large range of
area in detail.25
biologically important compounds.2–5 Almost invariably, these
bioactive compounds, and in particular the naturally occurring
derivatives, contain an asymmetric centre adjacent to the ring
nitrogen atom. We have recently shown that such stereocentres
α to nitrogen are readily established by the highly diastereo-
selective addition of organolithium or Grignard reagents to the
C᎐N bond of chiral oxime ethers derived from (R)- and (S )-O-
᎐
(1-phenylbutyl)hydroxylamine (ROPHy/SOPHy) (Scheme 1).
Scheme 2
Scheme 1
Results and discussion
The resulting hydroxylamines are versatile intermediates for
the synthesis of chiral amines,1 including 1-(2-thiazolyl)ethyl-
amine components of thiazole-containing natural products,6,7
α-amino acids,8 β-amino acids,1 and piperidine alkaloids.9
In continuation of our interest in the asymmetric synthesis of
saturated nitrogen heterocycles,9 we decided to investigate the
combination of the highly diastereoselective addition reactions
of ROPHy/SOPHy aldoximes with the ring-closing metathesis
(RCM) reaction as a new route to this class of heterocycle. The
RCM reaction is an extremely powerful synthetic method and,
with the development of practical and reliable catalysts by
Grubbs and others,10,11 has been widely used in synthesis in
As outlined in Scheme 2, the substrates for the RCM reaction
are the chiral dienes 3. These are accessible either by the
addition of an organometallic reagent to an aldoxime ether 1
derived from an unsaturated aldehyde, or by addition of an
alkene containing organometallic reagent to an alkyl or aryl
aldoxime ether 2, followed in both cases by N-allylation of the
resulting hydroxylamine (Scheme 2). Both approaches were
successful. Addition of organolithium reagents to the chiral
oxime ethers 1a and 1b derived by reaction of cinnamaldehyde
with ROPHy or SOPHy respectively,8 and 1c derived from
4-pentenal gave the corresponding hydroxylamines 6a–6e in
2378
J. Chem. Soc., Perkin Trans. 1, 2002, 2378–2389
This journal is © The Royal Society of Chemistry 2002
DOI: 10.1039/b207235c

Table 1
(E)-Oximea
Organometallic addition
Hydroxylamine
Yield/% (de/%)b
R
X
n
Diene
Yield (%)
Heterocycle (configuration)
Yield (%)
1a
1a
1b
1a
1c
2a
2b
(R)-PhCH᎐CHCH᎐NOR*
MeLic
n-BuLic
i-BuLie
PhLic
6a
6b
6c
6d
6e
6f
6g
6g
6h
6i
d(>95)
d(>95)
95 (88)
62 (>95)
d(>95)
d(82)
Me
n-Bu
i-Bu
Ph
Ph
Ph
Ph
Ph
H
H
H
0
0
0
0
2
0
0
7a
7b
7c
7d
7e
7f
72d
66d
83
8a (R)
8b (R)
8c (S )
8d (S )
8e (R)
8f (R)
8g (R)
87
78
74
51
9
35
23
᎐
᎐
(R)-PhCH᎐CHCH᎐NOR*
᎐
᎐
(S )-PhCH᎐CHCH᎐NOR*
᎐
᎐
(R)-PhCH᎐CHCH᎐NOR*
52
᎐
᎐
(S )-H2C᎐CHCH2CH2CH᎐NOR*
PhLi
Ph
74d
34d
28d
᎐
᎐
(S )-BnO(CH2)4CH᎐NOR*
H2C᎐CHMgBr
BnO(CH2)4
(MeO)2CH(CH2)3
᎐
᎐
(S )-(MeO)2CH(CH2)3CH᎐NOR*
H2C᎐CHMgBr
d(79)
7g
᎐
᎐
H2C᎐CHLi
48 (>90)
᎐
2c
2e
(S )-n-PrCH᎐NOR*
H2C᎐CHCH2MgBr
d(87)
n-Pr
Ph
H
H
1
1
7h
7i
39d
57d
8h (R)
8i (R)
90
53
᎐
᎐
(R)-PhCH᎐NOR*
H2C᎐CHCH2MgBrf
d(91)
᎐
᎐
a R* = 1-phenylbutyl; configuration as indicated b In general, the diastereomeric excess (de) of the organometallic addition is determined by integration of the 1H NMR signals of the CHN proton (indicated in 6) for the
two diastereomers. c This addition reaction is reported in ref. 8. d Yield over 2 steps. e The addition to the (R)-enantiomer of the oxime reported in ref. 8. f This addition reaction reported in ref. 1.

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Table 2
Heterocycle
(configuration)
Carbamate
Configuration (ee/%)a
R
X
n
N-allyl carbamate
Yield (%)
Yield (%)
9ab
9bd
9cb
9dg
9eh
9fg
9gh
9hi
S (89c)
R (93e)
R (>95e)
R (90)
S (98)
R (82)
R (90)
S (92)
Me
n-Bu
Ph
n-Pr
4-MeO–C6H4
BnO(CH2)3
Ph
Ph
Ph
Ph
H
H
H
0
0
0
1
1
1
2
3
10a
10b
10c
10d
10e
10f
10g
10h
74
88
63f
90
97
83
89
81
11a (S )
11b (R)
11c (R)
11d (R)
11e (S )
11f (R)
11g (R)
11h (S )
84
77
93
88
91
98
65
19
H
H
n-Pr
a Enantiomeric excess (ee) was determined by HPLC on a chiral phase (ChiralCel OD using hexane–propan-2-ol (9:1) as eluant) by comparison with
the racemate. b The preparation of the enantiomer is described in ref. 8. c Enantiomeric excess (ee) of the N-allyl derivative 10a not 9a. d Prepared as
described in ref. 8. e Refers to the diastereomeric excess (de) of the immediate precursor to 9b. f Allylation using allyl bromide–base caused double
bond migration; prepared using allyl methyl carbonate–Pd(); see text. g Prepared by addition of allylmagnesium bromide to the oxime ether,
followed by cleavage of the N–O bond, and reaction with benzyl chloroformate; stereoselectivity refers to the de before cleavage of the N–O bond.
h Prepared as described in ref. 1. i The preparation of the enantiomer is described in ref. 9.
excellent diastereomeric excess (de) (Table 1). Reaction with
allyl bromide gave the dienes 7a–7e in 32–74% yield over the
two steps. In a similar manner, addition of vinyl or allyl
organometallic reagents to oxime ethers 2a–2c, 2d and 2e gave
hydroxylamines 6f–6i (79–91% de), allylation of which gave the
dienes 7g–7i (28–71% over two steps) (Table 1). The RCM reac-
tion was carried out by heating the dienes 7 in dichloromethane
in the presence of benzylidene bis(tricyclohexylphosphine)-
dichlororuthenium (Grubbs’ catalyst) and gave the expected
heterocycles 8 in varying yield (Table 1). The 5-membered rings
8a–8d were formed in good yield, although the dihydropyrroles
8f and 8g containing an oxygenated substituent were isolated in
significantly poorer yield. The 6-membered rings 8h, 8i were
also readily formed, but the yield of the 7-membered ring 8e
was extremely poor.
recently reported by Grubbs and co-workers,27 although this
possibility was not investigated. Hydrogenation of the tetra-
hydropyridine 8i in methanol–acetic acid resulted in hydrogen-
ation of the double bond and hydrogenolysis of the N–O bond
to give (R)-2-phenylpiperidine isolated initially as its N-tert-
butoxycarbonyl derivative 14. Removal of the Boc-group gave
the known (R)-heterocycle 1528 in good yield confirming the
stereochemistry of the original addition reaction. In a similar
manner, catalytic hydrogenation of the tetrahydropyridine
11d resulted in double bond reduction and removal of the
Cbz-group to give (R)-(Ϫ)-coniine isolated as its hydrochloride
salt 16.29–31 Likewise the tetrahydropyridine 11e and tetra-
hydroazepine 11g were converted into the (S )-piperidine 17 and
known (R)-2-phenylazepane 1828 respectively (Scheme 3).
Although the above results indicate that the basic and nucleo-
philic hydroxylamine nitrogen atoms in 7 are tolerated in the
RCM reaction, we also investigated a set of substrates 10 in
which the nitrogen is rendered non-basic by protection as
its benzyloxycarbonyl (Cbz) derivative. Thus a series of carb-
amates 9, prepared as described previously1,8 or as indicated
in Table 2, was converted into the corresponding N-allyl deriva-
tives 10 by reaction with allyl bromide in the presence of
sodium hydride. In most cases this proved highly satisfactory
and the dienes 10 were obtained in good yield (Table 2). In the
case of 10c, however, double bond migration occurred to give
N-allyl-N-benzyloxycarbonyl-1,3-diphenyl-1-propenylamine in
high yield, and therefore the allyl group was introduced using
the palladium() catalysed reaction of allyl methyl carbonate.26
The RCM reaction proceeded smoothly and gave dihydro-
pyrrole 11a–11c and tetrahydropyridines 11d–11f in excellent
yield (Table 2), although the dihydropyrrole 11a–11c appeared
somewhat unstable and could not be obtained analytically pure.
The yield of the 7-membered ring 11g was somewhat lower,
whilst the 8-membered ring 11h was formed in poor yield.
The versatility of the oxime addition–RCM sequence was
further demonstrated by the subsequent reactions of the
product heterocycles 8 and 11. Thus hydrogenation of the
dihydropyrrole 8c and the tetrahydropyridine 8h over
palladium-on-charcoal in methanol resulted in simple alkene
reduction to give the N-alkoxypyrrolidine 12 and -piperidine
13. In principle, it should be possible to effect both the RCM
reaction and the subsequent reduction of the double bond in
the same reaction vessel using the same ruthenium catalyst as
Experimental
General
Commercially available reagents and solvents were used
throughout without further purification other than those
detailed below. Light petroleum refers to the fraction that boils
between 40 ЊC and 60 ЊC and was distilled from calcium
chloride through a 36 cm Vigreux column before use. Diethyl
ether (ether) and THF were distilled from sodium benzo-
phenone ketyl under nitrogen prior to use. Dichloromethane
was purified and dried by distillation from phosphorus pent-
oxide under nitrogen. Pyridine was distilled from calcium
hydride whilst under nitrogen prior to use.
Analytical thin layer chromatography was carried out using
aluminium or glass backed plates coated with Merck Kieselgel
60 GF254. Developed plates were visualised under ultraviolet
light (254 nm) and/or potassium permanganate or ninhydrin
dip. Flash chromatography was carried out using Merck
Kieselgel 60 H silica. Fully characterised compounds were
chromatographically homogeneous.
IR spectra were recorded on
a Nicolet Magna 550
spectrometer with internal calibration. Spectra were recorded
as thin films on sodium chloride plates, in solution or potassium
bromide discs. NMR spectra were recorded on Bruker AM 300,
or Advance DRX 400 spectrometers at the frequencies stated.
Chemical shifts are recorded in ppm and J values in Hz.
Multiplets less than 0.2 ppm in width were recorded from the
centre, those greater were reported as a range. Chemical shift
2380
J. Chem. Soc., Perkin Trans. 1, 2002, 2378–2389

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(E )-(R)-O-(1-Phenylbutyl)cinnamaldehyde oxime 1a
Prepared as described previously.8
(E )-(S )-O-(1-Phenylbutyl)cinnamaldehyde oxime 1b
Prepared as described for the (R)-enantiomer;8 mp 67 ЊC (lit.,8
(R)-isomer mp 65–67 ЊC (light petroleum)); [α]2D5 Ϫ45.9 (c 1.12,
CH2Cl2) (lit.,8 (R)-isomer [α]2D0 ϩ48.1 (c 1.0, CH2Cl2)).
(S )-O-(1-Phenylbutyl)pent-4-enaldehyde oxime 1c
Prepared as described previously.1
(S )-O-(1-Phenylbutyl)-5-benzyloxypentaldehyde oxime 2a
Prepared from 5-O-benzyloxypentanal32 as a colourless oil
(72%) exactly as described for the (R)-enantiomer;1 [α]2D7 ϩ6.2
(c 1.77, CHCl3).
(S )-O-(1-Phenylbutyl)-5,5-dimethoxypentanaldehyde oxime 2b
Prepared from 5,5-dimethoxypentanal33 as a colourless oil
(E 51% ϩ mixture Z/E 45%); (Found: MHϩ, 294.2063.
C17H27NO3 ϩ H requires 294.2069); [α]2D3 ϩ12.1 (c 0.99, CHCl3);
νmax(film)/cmϪ1 3022, 2950, 2935, 2863, 2827, 1450, 1387, 1358,
1189, 1127, 1061, 922, 758, 697; δH (300 MHz; CDCl3) 7.43
(1 H, t, J 6.2, N᎐CH), 7.29 (5 H, m, ArH), 5.02 (1 H, t, J 6.9,
᎐
OCH), 4.33 (1 H, t, J 5.4, CH(OMe)2), 3.29 (3 H, s,
CH(OMe)(OMe)), 3.28 (3 H, s, CH(OMe)(OMe)), 2.17 (2 H, q,
J 6.2, CH CH᎐N), 1.90 (1 H, m, OCHCHH), 1.76–1.24 (7 H,
᎐
2
m, OCHCHHCH2, CH2CH2), 0.93 (3 H, t, J 7.5, Me); δC (75
MHz; CDCl ) 150.6 (N᎐CH), 142.7 (C), 128.2 (CH), 127.2
᎐
3
(CH), 126.7 (CH), 104.1 (CH), 84.5 (CH), 52.72 (OMe), 52.69
(OMe), 38.4 (CH2), 31.7 (CH2), 29.3 (CH2), 21.8 (CH2), 18.9
(CH2), 14.0 (Me); m/z (CI) 294 (MHϩ, 12%), 162 (76), 149 (32),
133 (82), 130 (100), 112 (59).
(S )-O-(1-Phenylbutyl)butyraldehyde oxime 2c
Prepared as described previously.9
(R)-O-(1-Phenylbutyl)butyraldehyde oxime 2d
Prepared as described previously.1
Scheme 3 (R* = 1-phenylbutyl)
values are referenced against chloroform at 7.27 ppm
for CDCl3, methanol at 3.35 ppm for CD3OD, and DMSO at
2.50 ppm for d6-DMSO, and are accurate to 0.01 ppm (δH)
and 0.10 ppm (δC). High resolution mass spectra (CI and EI)
were either obtained on a Kratos Profile HV3 spectrometer,
on a Micromass GCT-TOF instrument, or at the EPSRC
National Mass Spectrometry Service at the University of
Wales, Swansea. Gas chromatography–mass spectrometry was
carried out on a ThermoQuest Finnigan Trace 2000 series
GCMS, with a 15 m Crossbond® 5% diphenyl–95% dimethyl-
polysiloxane column with a 0.25 mm internal diameter and
CI/EI detection, which was used to obtain some of the low
resolution spectra. Specific rotations were measured on an
AA-1000 polarimeter.
(R)-O-(1-Phenylbutyl)benzaldehyde oxime 2e
Prepared as described previously.1
(S )-O-(1-Phenylbutyl)-4-anisaldehyde oxime 2g
Prepared as described previously.34
(E )-(S )-O-(1-Phenylbutyl)-4-benzyloxybutanaldehyde oxime 2h
Prepared from 4-benzyloxybutanal as a colourless oil (76%);
(Found: MHϩ, 326.2117. C21H27NO2 ϩ H requires 326.2120);
[α]2D6 ϩ6.8 (c 1.46, CHCl3); νmax(film)/cmϪ1 3083, 3058, 3027,
2955, 2930, 2868, 1455, 1358, 1204, 1107, 1030, 927, 733, 702;
δ (300 MHz; CDCl ) 7.46 (1 H, t, J 6.0, N᎐CH), 7.30 (10 H, m,
᎐
H
3
ArH), 5.02 (1 H, t, J 6.8, OCH), 4.43 (2 H, s, CH2Ph), 3.42 (2 H,
t, J 6.4, OCH2), 2.25 (2 H, m, CH2), 1.91 (1 H, m, CHH), 1.73 (3
H, m, CHH, CH2), 1.48–1.24 (2 H, m, CH2), 0.92 (3 H, t, J 7.3,
Me); on standing in CDCl3, slow isomerisation to Z-isomer
occurs; δC (100 MHz; CDCl3) (mixture of E and Z diastereo-
General method for the preparation of O-(1-phenylbutyl) oximes
1 and 2
A suspension of N-(1-phenylbutoxy)phthalimide (3.0 g, 10.17
mmol) in ethanol (50 mL) was heated until the phthalimide
dissolved. Hydrazine hydrate (0.6 mL, 12.4 mmol) was added at
this elevated temperature and the reaction mixture was heated
under reflux for a further 1 h. The solution was then allowed
to cool to room temperature. The carbonyl compound (12 to
30 mmol) was added at room temperature and the reaction
mixture stirred overnight. The solvent was evaporated under
reduced pressure and the residue purified by column chrom-
atography on silica gel eluting with ether:light petroleum (1:20).
isomers) 151.3 (N᎐CH), 150.5 (N᎐CH), 143.0 (C), 142.7 (C),
᎐
᎐
138.5 (C), 138.4 (C), 128.4 (CH), 128.3 (CH), 128.22 (CH),
128.16 (CH), 127.60 (CH), 127.57 (CH), 127.5 (CH), 127.3
(CH), 127.2 (CH), 126.7 (CH), 126.5 (CH), 84.9 (OCH), 84.5
(OCH), 73.0 (OCH2), 72.9 (OCH2), 69.7 (OCH2), 69.3 (OCH2),
38.5 (CH2), 38.4 (CH2), 26.9 (CH2), 26.50 (CH2), 26.46 (CH2),
23.0 (CH2), 18.90 (CH2), 18.86 (CH2), 14.03 (Me), 14.01 (Me);
m/z (CI) 326 (MHϩ, 8%), 193 (100), 166 (84), 150 (60), 106 (36),
70 (38).
J. Chem. Soc., Perkin Trans. 1, 2002, 2378–2389
2381

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General procedure for the addition of organometallic reagents to
oxime ethers
377.2711. C26H35NO requires 377.2718); [α]2D2 ϩ0.1 (c 1.3,
CHCl3); νmax (film)/cmϪ1 3029, 2956, 2927, 2861, 1500, 1456,
970; δH (300 MHz; CDCl3) 7.31 (10 H, m, ArH), 6.36 (1 H, d,
The oxime ether (3.9 mmol) was dissolved in toluene (10 mL)
under nitrogen and cooled to Ϫ78 ЊC. Boron trifluoride etherate
(11.8 mmol) was added and the mixture stirred for 15 min. The
organometallic reagent (11.8 mmol) was added dropwise over
15 min, and the mixture stirred until all starting material was
consumed (typically 2–12 h). The reaction mixture was
quenched at Ϫ78 ЊC with aqueous saturated ammonium
chloride solution (10 mL), and allowed to warm to room
temperature and was extracted with ether (3 × 15 mL), the
extracts were combined, dried (K2CO3), filtered and evap-
orated. The residue was purified by flash chromatography on
silica gel using dichloromethane–light petroleum (1:2) as eluent
to give the hydroxylamine 6.
J 16.1, PhCH᎐), 6.13 (1 H, dd, J 16.1, 8.7, CHCN), 5.86 (1 H,
᎐
m, CH᎐CH ), 5.08 (2 H, m, ᎐CH ), 4.55 (1 H, dd, J 7.6, 6.5,
᎐
᎐
2
2
OCH), 3.38 (3 H, m, NCH, NCH2), 1.99 (1 H, m, CHH),
1.64 (1 H, m, CHH), 1.37–1.14 (8 H, m, 4 × CH2), 0.92 (3 H, t,
J 7.2, Me), 0.86 (3 H, t, J 6.7, Me); δC (100 MHz; CDCl3) 142.8
(C), 137.3 (C), 134.9 (CH), 132.4 (CH), 129.5 (CH), 128.4 (CH),
127.9 (CH), 127.4 (CH), 127.2 (CH), 126.3 (CH), 117.4 (CH2),
85.0 (CH), 67.6 (CH), 58.1 (CH2), 37.6 (CH2), 31.6 (CH2), 28.7
(CH2), 22.7 (CH2), 19.2 (CH2), 14.1 (Me), 14.0 (Me); one ArCH
not observed; m/z (CI) 378 (MHϩ, 1%), 245 (64), 188 (59), 173
(85), 133 (68), 105 (55), 90 (100), 77 (59).
(3S,1ЈS )-N-Allyl-N-(1-phenylbutoxy)-5-methyl-1-phenylhex-1-
en-3-ylamine 7c
The organometallic addition to O-(1-phenylbutyl) oxime ethers
and subsequent N-allylation to give dienes 7
Obtained from the addition of isobutyllithium to the (S )-
cinnamaldehyde oxime ether 1b (95% yield, 88% de) as
described previously for the (R)-enantiomer,8 and subsequent
N-allylation to give the title compound as a colourless oil
(83%); (Found: MHϩ, 378.2795. C26H35NO ϩ H requires
378.2797); [α]2D5 ϩ11.1 (c 1.08, CHCl3); νmax(film)/cmϪ1 3012,
2950, 2925, 2863, 1726, 1209, 927, 758, 666; δH (400 MHz;
The oxime ether (2.84 mmol) was dissolved in toluene (7.2 mL)
under nitrogen and cooled to Ϫ78 ЊC. Boron trifluoride etherate
(8.52 mmol) was added and stirred for 15 min. Organometallic
reagent (8.52 mmol) was added dropwise over 15 min and the
mixture was stirred until all starting material was consumed
(typically 2–12 h). The reaction mixture was quenched at
Ϫ78 ЊC with aqueous saturated ammonium chloride (10 mL),
and allowed to warm to room temperature. The mixture was
extracted with ether (3 × 15 mL), combined, dried (K2CO3),
filtered and evaporated to give the hydroxylamine 6 used in the
next step with no further purification.
The crude hydroxylamine 6 was dissolved in acetonitrile
(14 mL) and potassium carbonate (0.785 g, 5.68 mmol) and
allyl bromide (11.36 mmol) were added to the mixture. The
reaction mixture was heated under reflux for 24 h. The mixture
was cooled to room temperature and the solvent was removed
in vacuo. Water (15 mL) and ether (15 mL) were added to the
mixture and the layers separated. The aqueous layer was further
extracted with ether (2 × 10 mL). The ethereal extracts were
combined, dried (Na2SO4), and evaporated. The residue was
purified by flash chromatography on silica gel using ether:light
petroleum (1:40) as eluent giving the diene 7.
CDCl ) 7.09 (10 H, m, ArH), 6.34 (1 H, d, J 16.0, PhCH᎐CH),
᎐
3
6.11 (1 H, dd, J 16.0, 8.6, PhCH᎐CH), 5.79 (1 H, m, CH᎐CH ),
᎐
᎐
2
5.08 (2 H, m, ᎐CH ), 4.52 (1 H, t, J 6.1, OCH), 3.38 (3 H, m,
᎐
2
NCH, NCH2), 1.94 (1 H, m, NCHCH2CH), 1.64–1.19 (6 H, m,
NCHCH2CH, OCHCH2CH2), 0.89 (3 H, t, J 7.3, Me), 0.84 (3
H, d, J 6.4, Me), 0.76 (3 H, d, J 6.4, Me); δC (100 MHz; CDCl3)
142.7 (C), 137.3 (C), 135.0 (CH), 132.4 (CH), 129.4 (CH), 128.4
(CH), 128.1 (CH), 127.9 (CH), 127.3 (CH), 127.2 (CH), 126.3
(CH), 117.4 (᎐CH ), 85.7 (CH), 85.1 (CH), 65.2 (CH), 58.0
᎐
2
(CH2), 40.7 (CH2), 37.6 (CH2), 24.6 (CH), 23.4 (Me), 21.9 (Me),
19.1 (CH2), 14.1 (Me); m/z (CI) 378 (MHϩ, 70%), 230 (71), 173
(53), 166 (36), 150 (100).
(3S,1ЈR)-N-Allyl-N-(1-phenylbutoxy)-1,3-diphenylprop-1-en-3-
ylamine 7d
Obtained from the addition of phenyllithium the (R)-
cinnamaldehyde oxime ether 1a (62% yield, >95% de) as
described previously,8 and subsequent N-allylation to give the
title compound as a colourless oil (52%); [α]2D2 ϩ28.6 (c 1.05,
CHCl3); νmax(film)/cmϪ1 3063, 3027, 2960, 2920, 2868, 1491,
1445, 963, 912, 733; δH (300 MHz; CDCl3) 7.50–7.18 (15 H, m,
(3R,1ЈR)-N-Allyl-N-(1-phenylbutoxy)-4-phenylbut-3-en-2-
ylamine 7a
Obtained from the addition of methyllithium to the (R)-
cinnamaldehyde oxime ether 1a (>95% de) as described
previously,8 and subsequent N-allylation to give the title com-
pound as a colourless oil (72% over 2 steps); (Found: MHϩ,
336.2329. C23H29NO ϩ H requires 336.2327); [α]2D1 ϩ61.8
(c 2.75, CHCl3); νmax (film)/cmϪ1 3081, 3062, 3027, 2958, 2933,
2871, 1494, 1456, 1070, 970, 917, 748; δH (300 MHz; CDCl3)
ArH), 6.44 (1 H, d, J 15.7, PhCH᎐CH), 6.23–5.87 (2 H, m,
᎐
CH᎐CH , CH᎐CHPh), 5.08 (2 H, m, ᎐CH ), 4.50 (1 H, dd,
᎐
᎐
᎐
2
2
J 18.1, 5.5, NCHH), 4.35 (1 H, t, J 8.0, OCH), 3.42 (1 H, m,
NCH), 3.20 (1 H, dd, J 14.5, 6.9, NCHH), 1.58 (1 H, s,
OCHCHH), 1.43 (1 H, m, OCHCHH), 1.13–0.85 (2 H, m,
CH2), 0.74 (3 H, t, J 7.4, Me); δC (75 MHz; CDCl3) 141.5 (C),
137.0 (C), 133.7 (C), 131.4 (CH), 128.8 (CH), 128.6 (CH), 128.4
(CH), 128.3 (CH), 128.0 (CH), 127.9 (CH), 127.4 (CH), 127.3
7.50–7.23 (10 H, m, ArH), 6.41 (1 H, d, J 16.0, PhCH᎐), 6.05
᎐
(1 H, dd, J 16.0, 7.5, CH᎐CHPh), 5.93 (1 H, m, CH᎐CH ), 5.12
᎐
᎐
2
(2 H, m, ᎐CH ), 4.59 (1 H, t, J 6.6, OCH), 3.58 (1 H, m, NCH),
᎐
2
(CH), 127.2 (CH), 126.5 (CH), 118.3 (᎐CH ), 85.1 (OCH), 73.0
᎐
2
3.38 (2 H, m, CH CH᎐), 2.20–1.97 (1 H, m, CHH), 1.68 (1 H,
᎐
2
(NCH), 58.4 (NCH2), 37.1 (CH2), 18.9 (CH2), 14.0 (Me).
m, CHH), 1.37–1.17 (2 H, m, CH2), 1.24 (3 H, d, J 5.3, Me),
0.93 (3 H, t, J 7.2, Me); δC (100 MHz; CDCl3) 142.7 (C), 137.3
(C), 134.7 (CH), 131.3 (CH), 130.8 (CH), 128.5 (CH), 128.0
(CH), 127.9 (CH), 127.4 (CH), 127.3 (CH), 126.4 (CH), 117.7
(CH2), 85.4 (CH), 62.3 (CH), 57.8 (CH2), 37.6 (CH2), 19.2
(CH2), 17.0 (Me), 14.2 (Me); m/z (FAB) 336 (MHϩ, 13%), 203
(55), 186 (18), 131 (100).
(1R,1ЈS )-N-Allyl-N-(1-phenylbutoxy)-1-phenylpent-4-en-1-
ylamine 7e
Obtained from the addition of phenyllithium to (S )-O-(1-
phenylbutyl)pent-4-enaldehyde oxime 1c (>95% de) as
described above, and subsequent N-allylation to give the title
compound as a colourless oil (74% over 2 steps); (Found: MHϩ,
350.2484. C24H31NO ϩ H requires 350.2484); [α]2D5 Ϫ42.1
(c 1.07, CHCl3); νmax(film)/cmϪ1 3079, 3060, 3027, 2956, 2922,
2865, 1635, 1488, 1450, 1103, 1061, 989, 904, 757, 695; δH (400
(3R,1ЈR)-N-Allyl-N-(1-phenylbutoxy)-1-phenylhept-1-en-3-
ylamine 7b
Obtained from the addition of n-butyllithium to the (R)-
cinnamaldehyde oxime ether 1a (>95% de) as described
previously,8 and subsequent N-allylation to give the title com-
pound as a colourless oil (66% over 2 steps); (Found: Mϩ,
MHz; CDCl ) 7.26 (10 H, m, ArH), 5.75 (2 H, m, 2 × ᎐CH),
᎐
3
5.96 (4 H, m, 2 × ᎐CH ), 4.50 (1 H, t, J 6.5, OCH), 3.68 (1 H,
᎐
2
dd, J 8.7, 5.6, NCH), 3.20 (1 H, m, NCHH), 2.97 (1 H, dd,
J 14.1, 7.7, NCHH), 2.00–1.57 (6 H, m, OCHCH2, NCHCH2-
2382
J. Chem. Soc., Perkin Trans. 1, 2002, 2378–2389

View Article Online
CH2), 1.23 (1 H, m, CHHMe), 1.11 (1 H, m, CHHMe), 0.84 (3
H, t, J 7.3, Me); δC (100 MHz; CDCl3) 142.6 (C), 140.1 (C),
138.5 (CH), 134.5 (CH), 129.4 (CH), 128.1 (CH), 127.92 (CH),
(1 H, m, NCHCHH), 1.88 (1 H, m, OCHCHH), 1.56 (1 H, m,
OCHCHH), 1.41–1.10 (6 H, m, CH2CH2Me, CH2Me), 0.88
(3 H, t, J 7.3, Me), 0.78 (3 H, t, J 6.8, Me); δC (100 MHz;
127.86 (CH), 127.4 (CH), 127.1 (CH), 117.6 (᎐CH ), 114.3
CDCl ) 143.2 (C), 137.5 (᎐CH), 135.8 (᎐CH), 127.8 (CH), 127.7
᎐ ᎐
3
᎐
2
(᎐CH ), 85.4 (CH), 68.5 (CH), 58.0 (CH ), 37.1 (CH ), 32.1
(CH), 127.2 (CH), 116.6 (᎐CH ), 115.5 (᎐CH ), 85.1 (OCH),
᎐ ᎐
2 2
᎐
2
2
2
(CH2), 30.7 (CH2), 19.0 (CH2), 14.1 (Me); m/z (CI) 350 (MHϩ,
63.4 (NCH), 59.9 (NCH2), 37.8 (CH2), 33.3 (CH2), 33.0 (CH2),
19.7 (CH2), 19.1 (CH2), 14.2 (Me), 14.1 (Me); m/z (ES) 302
(MHϩ, 100%), 170 (75), 112 (75), 100 (50).
25%), 218 (34), 200 (79), 145 (42), 133 (100), 107 (26).
(3R,1ЈS )-N-Allyl-N-(1-phenylbutoxy)-7-benzyloxyhept-1-en-3-
ylamine 7f
(1R,1ЈR)-N-Allyl-N-(1-phenybutoxy)-1-phenylbut-3-en-1-
ylamine 7i
Obtained from the addition of vinylmagnesium bromide to (S )-
[O-(1-phenylbutyl)]-5-benzyloxypentaldehyde oxime 2a (82%
de) and subsequent N-allylation to give the title compound as a
colourless oil (34% over 2 steps); (Found: MHϩ, 408.2910.
C27H37NO2 ϩ H requires 408.2902); [α]2D8 Ϫ66.7 (c 1.26, CHCl3);
νmax(film)/cmϪ1 3068, 3027, 2950, 2930, 2858, 1716, 1649, 1450,
1414, 1358, 1102, 1030, 994, 912, 738, 692; δH (400 MHz;
Obtained from the addition of allylmagnesium bromide to (R)-
benzaldehyde oxime ether 2e (91% de) as described previously,1
and subsequent N-allylation to give the title compound as
a colourless oil (57% over 2 steps); (Found: Mϩ, 335.2243.
C23H29NO requires 335.2249); [α]2D2 ϩ8.48 (c 3.3, CHCl3); νmax
(film)/cmϪ1 3064, 3029, 2958, 2954, 2871, 1641, 1494, 1454, 995;
δH(300 MHz; CDCl3) 7.32 (10 H, m, ArH), 5.88 (1 H, m,
CDCl ) 7.31 (10 H, m, ArH), 5.84 (1 H, m, ᎐CH), 5.63 (1 H, br,
᎐
3
NCH CH᎐), 5.56 (1 H, m, NCHCH CH᎐), 5.10–4.89 (4 H, m,
᎐
᎐
᎐CH), 5.22 (1 H, dd, J 10.4, 1.9, ᎐CHH), 5.02 (3 H, m, ᎐CHH,
2
2
᎐
᎐
᎐
2 × ᎐CH ), 4.58 (1 H, dd, J 8.4, 6.0, OCH), 3.84 (1 H, dd, J 9.9,
᎐
᎐CH ), 4.53 (3 H, m, CH Ph, OCH), 3.45 (2 H, t, J 6.5, OCH ),
2
᎐
2
2
2
4.6, NCH), 3.24 (1 H, m, NCHHC᎐), 3.02 (1 H, m, NCHHC᎐),
᎐
᎐
3.24 (1 H, dd, J 13.3, 7.8, NCHH), 3.15 (1 H, m, NCHH), 3.07
(1 H, m, NCH), 1.93 (1 H, m, OCHCHH), 1.75–1.16 (9 H, m,
OCHCHH, 4 × CH2), 0.90 (3 H, t, J 7.3, Me); δC (100 MHz;
2.60 (1 H, m, NCCHHC᎐), 2.53 (1 H, m, NCCHHC᎐), 2.05
᎐
᎐
(1 H, m, CHH), 1.71 (1 H, m, CHH), 1.24 (2 H, m, CH2), 0.93
(3 H, t, J 7.3, Me); δC (100 MHz; CDCl3) 142.6 (C), 140.0 (C),
136.0 (CH), 134.3 (CH), 129.3 (CH), 128.1 (CH), 128.0 (CH),
127.9 (CH), 127.5 (CH), 127.2 (CH), 117.8 (CH2), 116.3 (CH2),
85.5 (CH), 69.0 (CH), 57.4 (CH2), 37.3 (CH2), 36.3 (CH2), 19.1
(CH2), 14.2 (Me); m/z (CI) 335 (Mϩ, 0.4%), 294 (4), 220 (55),
205 (79), 186 (87), 162 (97), 146 (71), 133 (100), 104 (87), 92
(72), 77 (84).
CDCl ) 142.8 (C), 138.7 (C), 136.6 (᎐CH), 134.8 (᎐CH), 128.3
᎐
᎐
3
(CH), 127.92 (CH), 127.88 (CH), 127.6 (CH), 127.5 (CH), 127.4
(CH), 118.0 (᎐CH ), 117.3 (᎐CH ), 85.7 (OCH), 72.8 (OCH ),
᎐
᎐
2
2
2
70.4 (OCH2), 67.6 (NCH), 57.9 (CH2), 37.5 (CH2), 32.0 (CH2),
29.7 (CH2), 23.0 (CH2), 19.3 (CH2), 14.1 (Me); m/z (CI) 408
(MHϩ, 26%), 260 (35), 166 (82), 150 (100).
(3R,1ЈS )-N-Allyl-N-(1-phenylbutoxy)-7,7-dimethoxyhept-1-en-
3-ylamine 7g
General method for the preparation of Cbz-protected amines 9
Zinc dust (140.0 mmol) was added to a solution of hydroxyl-
amine (3.5 mmol) in acetic acid:water (10 mL, 1:1). The
mixture was placed in a sonic bath at 40 ЊC and the reaction was
followed by TLC until completion. The zinc was filtered and
washed with water. The filtrate was basified to pH 8 with
aqueous potassium hydroxide solution (3 M). The solution was
exhaustively extracted with dichloromethane (6 × 15 mL). The
extracts were combined, dried (Na2SO4), filtered and evapor-
ated. Sodium carbonate (7.0 mmol) was added to a solution of
the residue dissolved in THF:water (50 mL, 1:1). The solution
was cooled to 0 ЊC and benzyl chloroformate (3.5 mmol) was
added dropwise. The mixture was allowed to warm to room
temperature and was stirred for 12 h. The THF was evaporated
under reduced pressure and extracted with ether (3 × 10 mL).
The organic extracts were combined, dried (MgSO4), filtered
and evaporated. The residue was purified by flash chrom-
atography on silica gel.
(a) Obtained from the addition of vinylmagnesium bromide to
(S )-O-(1-phenylbutyl) 5,5-dimethoxypentanaldehyde oxime 2b
(79% de) and subsequent N-allylation to give the title com-
pound as a colourless oil (28% of major diastereomer over
2 steps); (Found: MHϩ, 362.2692. C22H35NO3 ϩ H requires
362.2695); [α]2D5 Ϫ71.2 (c 1.04, CHCl3); νmax(film)/cmϪ1 3073,
3027, 2950, 2925, 2873, 2822, 1455, 1189, 1127, 1066, 1045, 999,
917, 758, 697, 666; δH (400 MHz; CDCl3) 7.29 (5 H, m, ArH),
5.84 (1 H, m, NCH CH᎐CH ), 5.60 (1 H, m, NCHCH᎐CH ),
᎐
᎐
2
2
2
5.21 (1 H, dd, J 10.3, 1.9, NCH CH᎐CHH), 5.02 (3 H, m,
᎐
2
NCH CH᎐CHH, NCHCH᎐CH ), 4.51 (1 H, t, J 7.2, OCH),
᎐
᎐
2
2
4.33 (1 H, t, J 5.8, CH(OMe)2), 3.31 (6 H, s, OMe), 3.22 (1 H,
dd, J 13.3, 7.9, NCH), 3.08 (2 H, m, NCH2), 1.91 (1 H, m,
OCHCHH), 1.73–1.12 (9 H, m, OCHCHHCH2, CH2CH2CH2),
0.88 (3 H, t, J 7.4, Me); δC (100 MHz; CDCl3) 142.7 (C),
136.5 (CH), 134.7 (CH), 127.92 (CH), 127.87 (CH), 127.4 (CH),
118.1 (᎐CH ), 117.3 (᎐CH ), 104.4 (CH), 85.6 (CH), 67.5 (CH),
᎐
᎐
2
2
57.8 (CH2), 52.6 (OMe), 52.5 (OMe), 37.5 (CH2), 32.4 (CH2),
32.0 (CH2), 21.5 (CH2), 19.2 (CH2), 14.1 (Me); m/z (CI)
362 (MHϩ, 9%), 330 (39), 227 (14), 198 (39), 180 (56), 149 (26),
133 (100), 107 (34).
(b) Addition of vinyllithium to the above oxime ether
proceded in ca. 90% de, and gave the addition product in 48%
yield (the purified major diasteromer).
(S )-N-Benzyloxycarbonyl-4-phenylbut-3-en-2-ylamine 9a
Prepared as described previously for the (R)-enantiomer in 26%
yield, mp 90–91 ЊC (lit.,8 for (R)-enantiomer mp 89–91 ЊC);
[α]2D3 Ϫ55.4 (c 1.10, CH2Cl2) (lit.,8 for (R)-enantiomer [α]2D0
ϩ48.8 (c 1.0, CH2Cl2)).
(R)-N-Benzyloxycarbonyl-1-phenylhept-1-en-3-ylamine 9b
Prepared as described previously.8
(1R,1ЈR)-N-Allyl-N-(1-phenylbutoxy)hept-1-en-4-ylamine 7h
Obtained from the addition of allylmagnesium bromide to
(S )-O-(1-phenylbutyl)butyraldehyde oxime 2c(87% de) and
subsequent N-allylation to give the title compound as a colour-
less oil (39% over 2 steps); (Found: MHϩ, 302.2478. C20H31NO
ϩ H requires 302.2484); [α]2D2 Ϫ51.3 (c 1.19, CHCl3); νmax(film)/
cmϪ1 3078, 3027, 2955, 2935, 2868, 1639, 1450, 994, 912, 758,
702; δH (400 MHz; CDCl3) 7.27 (5 H, m, ArH), 5.72 (2 H, m,
(R)-N-Benzyloxycarbonyl-1,3-diphenylprop-2-en-1-ylamine 9c
Prepared as described previously for the (S )-enantiomer in 41%
yield, mp 110–112 ЊC (lit.,8 for (S )-enantiomer mp 110–111 ЊC);
[α]2D1 ϩ8.1 (c 1.10, CH2Cl2).
(R)-N-Benzyloxycarbonylhept-1-en-4-ylamine 9d
2 × ᎐CH), 5.02 (4 H, m, 2 × ᎐CH ), 4.49 (1 H, t, J 7.1, OCH),
᎐
᎐
2
3.25 (1 H, dd, J 13.9, 7.2, NCHH), 3.18 (1 H, dd, J 13.9, 5.3,
NCHH), 2.64 (1 H, m, NCH), 2.46 (1 H, m, NCHCHH), 1.98
Addition of allylmagnesium bromide to oxime ether 2c gave
(4R,1ЈS )-N-(1-phenylbutoxy)hept-1-en-4-ylamine 6h as
a
J. Chem. Soc., Perkin Trans. 1, 2002, 2378–2389 2383

View Article Online
colourless oil (51%, >95% de); (Found: MHϩ, 262.2174.
C17H27NO ϩ H requires 262.2171); [α]1D8 Ϫ76.1 (c 0.9, CH2Cl2);
νmax (film)/cmϪ1 3421, 3075, 3029, 2958, 2933, 2874, 1639, 1454,
914; δH (300 MHz; CDCl3) 7.31 (5 H, m, ArH), 5.81 (1 H, m,
(S )-N-Benzyloxycarbonylnon-8-en-4-ylamine 9h
Addition of pent-4-enylmagnesium bromide to the oxime ether
2d gave (6S,1ЈR)-N-(1-phenylbutoxy)non-8-en-4-ylamine as a
colourless oil (88%); [α]2D5 ϩ58.7 (c 0.8, CH2Cl2) (lit.,9 for (R,S )-
isomer [α]2D5 Ϫ61.9 (c 0.62, CH2Cl2)); δH (300 MHz; CDCl3)
᎐CH), 5.29 (1 H, br s, NH), 5.09 (2 H, m, ᎐CH ), 4.56 (1 H, dd,
᎐
᎐
2
J 7.7, 5.8, OCH), 2.85 (1 H, quintet, J 5.9, NCH), 2.34 (1 H, m,
CHHCH᎐), 2.24 (1 H, m, CHHCH᎐), 1.80 (1 H, m, CHH),
7.33 (5 H, m,ArH), 5.84 (1 H, m, ᎐CH), 5.21 (1 H, br s, NH),
᎐
᎐
᎐
5.03 (2 H, m, ᎐CH ), 4.58 (1 H, dd, J 7.9, 5.9, OCH), 2.84 (1 H,
᎐
2
1.57–1.26 (7 H, m, CHH, 3 × CH2), 0.93 (3 H, t, J 7.3, Me), 0.86
(3 H, t, J 7.0, Me); δC(75 MHz; CDCl3) 143.4 (C), 135.7 (CH),
128.3 (CH), 127.3 (CH), 126.6 (CH), 117.1 (CH2), 85.3 (CH),
59.8 (CH), 38.9 (CH2), 36.6 (CH2), 33.5 (CH2), 19.3 (CH2),
19.2 (CH2), 14.2 (Me), 14.1 (Me); m/z (CI) 262 (MHϩ, 15%),
166 (10), 150 (21), 114 (100), 105 (6), 91 (4), 72 (52).
Cleavage of the above hydroxylamine and subsequent protec-
tion gave the title compound as a colourless solid (52%, 90%
ee); mp 53–54 ЊC (from aq. ethanol); (Found: C, 73.0; H, 8.8; N,
5.6. C15H21NO2 requires C, 72.8; H, 8.6; N, 5.7%); (Found:
MHϩ, 248.1649. C15H20NO2 ϩ H requires 248.1649); [α]2D7
ϩ20.7 (c 0.9, CHCl3); νmax (film)/cmϪ1 3309, 3083, 3070, 2952,
1685, 1546, 1465, 1267, 1236; δH (300 MHz; CDCl3) 7.33 (5 H,
m, NCH), 2.10 (2 H, m, CH CH᎐), 1.59–1.31 (12 H, m,
᎐
2
6 × CH2), 0.96 (3 H, t, J 7.3, Me), 0.91 (3 H, t, J 7.0 Me); δC (75
MHz; CDCl3) 143.5 (CH), 138.9 (C), 128.3 (CH), 127.2 (CH),
126.6 (CH), 114.4 (CH2), 85.2 (CH), 60.1 (CH), 38.9 (CH2),
34.1 (CH2), 31.7 (CH2), 25.1 (CH2), 19.3 (CH2), 14.3 (Me), 14.1
(Me).
Cleavage of the above hydroxylamine and subsequent protec-
tion gave the title compound as a colourless oil (88%, 92% ee)
mp 72–74 ЊC (from light petroleum) (lit.,9 for (R)-enantiomer
mp 71–73 ЊC); [α]2D5 ϩ2.3 (c 84, CH2Cl2) (lit.,9 for (R)-
enantiomer [α]2D5 Ϫ1.5 (c 1.0, CH2Cl2); δH (300 MHz; CDCl3)
7.33 (5 H, m, ArH), 5.78 (1 H, m, ᎐CH), 5.13 (2 H, s, CH O),
᎐
2
5.00 (2 H, m, ᎐CH ), 4.48 (1 H, br d, J 9.2, NH), 3.65 (1 H, br s,
᎐
2
m, ArH), 5.77 (1 H, m, ᎐CH), 5.12 (2 H, m, ᎐CH ), 5.09 (2 H, s,
᎐
᎐
2
NCH), 2.04 (2 H, m, CH2) 1.51–1.19 (8 H, m, 4 × CH2), 0.91
(3 H, t, J 6.5, Me); δC (75 MHz; CDCl3) 156.1 (C), 138.6 (CH),
136.7 (C), 128.5 (CH), 128.1 (2 × CH), 114.7 (CH2), 66.5 (CH2),
51.0 (CH), 37.7 (CH2), 34.9 (CH2), 33.6 (CH2), 25.1 (CH2), 19.0
(CH2), 14.0 (Me).
CH2O), 4.57 (1 H, br d, J 8.4, NH), 3.72 (1 H, m, NCH), 2.23 (2
H, m, CH CH᎐), 1.42 (4 H, m, 2 × CH ), 0.91 (3 H, t, J 6.4,
᎐
2
2
Me); δC (75 MHz; CDCl3) 155.7 (C), 142.3 (CH), 137.5 (C),
128.7 (CH), 128.5 (CH), 128.2 (CH), 127.4 (CH), 126.4 (CH),
115.4 (CH2), 66.8 (CH2), 55.0 (CH), 35.8 (CH2), 30.3 (CH2); m/z
(CI) 248 (MHϩ, 14%), 126 (12), 114 (100), 106 (25), 89 (11),
72 (56).
General method for the preparation of dienes 10 by allylation
Sodium hydride (2.040 mmol) was suspended in dry DMF
(1 mL) and cooled to 0 ЊC under nitrogen. A solution of the
Cbz-protected amine 9 (1.020 mmol) in dry DMF (1.5 mL) was
added and the reaction mixture was allowed to warm to room
temperature. After 30 min the reaction mixture was re-cooled to
0 ЊC. Allyl bromide (0.18 mL, 2.040 mmol) was added and the
reaction mixture was allowed to warm to room temperature.
After complete consumption of starting material (TLC) aque-
ous saturated ammonium chloride solution (2 mL) was added
and the mixture was extracted with ether (3 × 10 mL). The
combined organic extracts were washed with water (5 × 10 mL),
dried (Na2SO4) and the mixture was filtered and evaporated.
The residue was purified by column chromatography on silica
gel eluting with light petroleum : ethyl acetate (10:1) to give the
diene 10.
(S )-N-Benzyloxycarbonyl-1-(4-methoxyphenyl)but-3-en-1-
ylamine 9e
Prepared as described previously.1
(R)-7-Benzyloxy-N-benzyloxycarbonylhept-1-en-4-ylamine 9f
Addition of allylmagnesium bromide to oxime 2h gave
(4R,1ЈS )-7-benzyloxy-N-(1-phenylbutoxy)hept-1-en-4-ylamine
(88%, 82% de) as a colourless oil; (Found: MHϩ, 368.2596.
C24H33NO2 ϩ H requires 368.2589); [α]2D4 Ϫ45.2 (c 1.15, CHCl3);
νmax(film)/cmϪ1 3068, 3027, 2955, 2930, 2863, 1460, 1358, 1096,
1025, 912, 738, 692; δH (400 MHz; CDCl3) 7.30 (10 H, m, ArH),
5.78 (1 H, m, ᎐CH), 5.31 (1 H, br s, NH), 5.09 (2 H, m, ᎐CH ),
᎐
᎐
2
4.53 (1 H, m, OCH), 4.47 (2 H, s, CH2Ph), 3.41 (2 H, t, J 6.4,
OCH2), 2.84 (1 H, quintet, J 6.3, NCH), 2.35 (1 H, m,
᎐CHCHH), 2.20 (1 H, m, ᎐CHCHH), 1.86–1.19 (8 H, m, 4 ×
᎐
᎐
CH2), 0.90 (3 H, t, J 7.2, Me); δC (100 MHz; CDCl3) 143.3 (C),
138.6 (C), 135.5 (᎐CH), 128.34 (CH), 128.27 (CH), 127.6 (CH),
(S )-N-Allyl-N-benzyloxycarbonyl-3-phenylbut-2-en-1-ylamine
10a
᎐
127.5 (CH), 127.3 (CH), 126.6 (CH), 117.3 (᎐CH ), 85.3
᎐
2
Obtained from the N-allylation of Cbz-amine 9a as a colourless
oil (74%, 89% ee); (Found: M ϩ NH4, 339.2062. C21H23NO2ϩ
NH4 requires 339.2073); [α]1D8 Ϫ62.1 (c 1.03, CHCl3); νmax(film)/
(OCH), 72.8 (CH2Ph), 70.4 (OCH2), 59.8 (NCH), 38.8 (CH2),
36.6 (CH2), 28.0 (CH2), 26.4 (CH2), 19.2 (CH2), 14.1 (Me); m/z
(CI) 368 (MHϩ, 24%), 166 (100), 150 (82), 110 (76), 58 (54).
Cleavage of the above hydroxylamine and subsequent protec-
tion gave the title compound (91%) as a colourless oil; (Found:
MHϩ, 354.2068. C22H27NO3 ϩ H requires 354.2069); [α]2D5
ϩ13.4 (c 1.42, CHCl3); νmax(film)/cmϪ1 3324 (NH), 3063, 3032,
3001, 2945, 2848, 1701, 1532, 1450, 1360, 1250, 1069, 1020, 907,
738, 692; δH (400 MHz; CDCl3) 7.34 (10 H, m, ArH), 5.78 (1 H,
cmϪ1 3078, 3022, 2970, 2925, 1696 (C᎐O), 1450, 1403, 1250,
᎐
1143, 1020, 963, 912, 748, 687; δH (400 MHz; CDCl3) 7.42–7.18
(10 H, m, ArH), 6.44 (1 H, d, J 15.8, PhCH᎐CH), 6.23 (1 H, dd,
᎐
J 15.9, 5.5, PhCH᎐CH), 5.86 (1 H, m, CH᎐CH2), 5.24–4.71
᎐
᎐
(5 H, m, ᎐CH , CH Ph, NCH), 3.82 (2 H, m, NCH ), 1.38 (3 H,
᎐
2
2
2
d, J 6.9, Me); δC (100 MHz; CDCl ) 156.0 (C᎐O), 136.8 (C),
᎐
3
136.7 (C), 135.6 (CH), 130.6 (CH), 130.2 (CH), 128.6 (CH),
128.4 (CH), 127.9 (CH), 127.8 (CH), 127.6 (CH), 126.4 (CH),
m, ᎐CH), 5.09 (4 H, m, CH Ph, ᎐CH ), 4.68 (1 H, br d, J 8.1,
᎐
᎐
2
2
NH), 4.50 (2 H, s, CH2Ph), 3.74 (1 H, br, NCH), 3.49 (2 H, t,
J 5.6, OCH CH ), 2.25 (2 H, m, ᎐CHCH ), 1.67 (3 H, m,
116.0 (᎐CH ), 67.1 (CH ), 53.2 (CH), 45.7 (CH ), 18.0 (Me); m/z
᎐
2
2
2
᎐
(CI) 339 (M ϩ NH4ϩ, 8%), 322 (MHϩ, 16), 209 (12), 186 (10),
2
2
2
OCH2CH2, CHH), 1.47 (1 H, m, CHH); δC (100 MHz; CDCl3)
131 (100).
156.1 (CO), 138.5 (C), 136.7 (C), 134.2 (᎐CH), 128.5 (CH),
᎐
128.4 (CH), 128.2 (CH), 128.1 (CH),127.7 (CH), 127.6 (CH),
(R)-N-Allyl-N-benzyloxycarbonyl-1-phenylhept-1-en-3-ylamine
10b
118.0 (᎐CH ), 72.9 (CH ), 70.0 (CH ), 66.5 (CH ), 50.5 (CH),
᎐
2
2
2
2
39.6 (CH2), 31.3 (CH2), 26.2 (CH2); m/z (ES) 376 (MϩNa,
100%), 371 (MϩNH4, 50), 354 (MHϩ, 20), 193 (8), 97 (40), 65
(15).
Obtained from the N-allylation of Cbz-amine 9b as a colourless
oil (88%); (Found: MHϩ, 364.2289. C24H29NO2 ϩ H requires
364.2276); [α]2D3 ϩ54.2 (c 0.83, CHCl3); νmax (film)/cmϪ1 3081,
3062, 3029, 2956, 2931, 2871, 1697, 1456, 1407, 1241; δH (300
MHz; CDCl ) 7.31 (10 H, m ArH), 6.49 (1 H, m, CH᎐CH), 6.22
(R)-N-Benzyloxycarbonyl-1-phenylpent-4-en-1-ylamine 9g
Prepared as described previously.1
᎐
3
2384
J. Chem. Soc., Perkin Trans. 1, 2002, 2378–2389

View Article Online
(1 H, m, CH᎐CH), 5.24 (2 H, br s, CH O), 5.15 (2 H, m, ᎐CH ),
(R)-N-Allyl-7-benzyloxy-N-benzyloxycarbonylhept-1-en-4-
᎐
᎐
2
2
4.66 (1 H, m, NCH), 3.85 (2 H, br s, CH CH᎐), 1.62 (2 H, m,
ylamine 10f
᎐
2
CH2), 1.28 (4 H, m, 2 × CH2), 0.91 ( 3 H, br t, J 7.0, Me); δC (75
MHz; CDCl3) 156.2 (C), 136.8 (C), 135.6 (CH), 131.5 (CH),
129.2 (CH), 128.5 (CH), 128.4 (CH), 127.9 (CH), 127.6 (CH),
126.4 (CH), 116.4 (CH2), 67.1 (CH2), 58.5 (CH), 46.5 (CH2),
32.1 (CH2), 28.5 (CH2), 22.5 (CH2), 14.1 (Me); one ArC and
one ArCH not observed; m/z (CI) 364 (MHϩ, 11%), 230 (69),
192 (20), 173 (100), 108 (14), 91 (8).
Obtained from the N-allylation of Cbz-amine 9f and purific-
ation by column chromatography on silica gel eluting with
ether:light petroleum (1:2) as a colourless oil (83%); (Found:
MHϩ, 394.2379. C25H31NO3 ϩ H requires 394.2382); [α]2D2
ϩ11.8 (c 1.02, CHCl3); νmax(film)/cmϪ1 3068, 3027, 2940, 2853,
1690 (CO), 1455, 1409, 1358, 1327, 1230, 1148, 1102, 1030, 989,
912, 769, 738, 697; δH (400 MHz; DMSO, Ϫ10 ЊC) 7.29 (10 H,
m, ArH), 5.80 (1 H, m, ᎐CH), 5.68 (1 H, m, ᎐CH), 5.16–4.95
᎐
᎐
(R)-N-Allyl-N-benzyloxycarbonyl-1,3-diphenylprop-2-en-1-
ylamine 10c
(6 H, m, CH Ph, 2 × ᎐CH ), 4.42 (2 H, s, CH Ph), 3.96 (1 H, br,
᎐
2
2
2
NCH), 3.74 (2 H, m, NCH2), 3.40 (2 H, m, OCH2), 2.26 (2 H,
m, NCHCH2), 1.53 (4 H, m, 2 × CH2); δC (100 MHz; DMSO,
To a solution of Cbz-amine 9c (300 mg, 0.87 mmol) in
anhydrous THF (2 mL), a solution of π-allylpalladium chloride
dimer (3.2 mg, 0.0087 mmol, 1 mol %), triphenylphosphine
(10 mg, 0.039 mmol, 4.5 mol %), and methyl allyl carbonate
(0.21 mL, 1.75 mmol) were added at room temperature.
The reaction mixture was heated under reflux overnight. The
solvent was evaporated in vacuo. The crude product was
purified by column chromatography on silica gel eluting with
ethyl acetate:light petroleum (1:9) to give the title compound
as a colourless oil (140 mg, 63%); (Found: Mϩ, 383.1884.
C26H25NO2 requires 383.1885); [α]2D5 ϩ5.9 (c 2.20, CHCl3);
Ϫ10 ЊC) 156.2 (CO), 139.3 (C), 137.6 (C), 136.2 (᎐CH), 136.1
᎐
(᎐CH), 128.7 (CH), 128.5 (CH), 128.1 (CH), 127.9 (CH), 127.7
᎐
(CH), 127.6 (CH), 117.0 (᎐CH ), 116.6 (᎐CH ), 72.4 (CH ), 69.9
᎐
᎐
2
2
2
(CH2), 66.6 (CH2), 57.0 (NCH), 46.4 (CH2), 37.8 (CH2),
29.5 (CH2), 26.8 (CH2); m/z (ES) 416 (M ϩ Na, 100%), 411
(M ϩ NH4, 45), 394 (MHϩ, 20), 97 (20).
(R)-N-Allyl-N-benzyloxycarbonyl-1-phenylpent-4-en-1-ylamine
10g
Obtained from the N-allylation of Cbz-amine 9g as a colourless
oil (89%); (Found: MHϩ, 336.1952. C22H25NO2 ϩ H requires
336.1963); [α]2D5 ϩ96.8 (c 1.0, CHCl3); νmax (film)/cmϪ1 3066,
3031, 2935, 1697, 1454, 1407, 1321, 1253, 1139, 916; δH (300
νmax(film)/cmϪ1 3058, 3027, 2929, 1696 (C᎐O), 1439, 1399, 1255,
᎐
1143, 968, 912; δH (400 MHz; CDCl3) 7.32 (15 H, m, ArH),
6.53 (2 H, m, PhCH᎐CH), 5.97 (1 H, m, CH ᎐CH), 5.73
᎐
᎐
2
(1 H, m, NCHPh), 5.22 (2 H, AB, J 12.0, OCH2), 5.03 (2 H,
MHz; CDCl ) 7.34 (10 H, m, ArH), 5.86 (1 H, br s, ᎐CH), 5.67
᎐
3
d, J 11.2, ᎐CH ), 4.01 (1 H, dd, J 15.9, 4.4, NCHH), 3.82
(1 H, br s, ᎐CH), 5.43 (1 H, br s, NCH), 5.24 (1 H, d, J 12.5,
᎐
᎐
2
(1 H, dd, J 15.9, 5.8, NCHH); δC (100 MHz; CDCl3) 156.2
CHHO), 5.23 (1 H, d, J 12.5, CHHO), 5.02 (4 H, m, 2 × ᎐CH ),
᎐
2
(C᎐O), 139.8 (C), 136.7 (C), 136.6 (C), 135.1 (CH), 133.3
᎐
3.75 (1 H, m, CHHCH᎐), 3.58 (1 H, dd, J 15.9, 6.7, CHHCH᎐),
᎐ ᎐
(CH), 128.6 (CH), 128.5 (CH), 128.4 (CH), 128.0 (CH),
127.9 (CH), 127.8 (CH), 127.8 (CH), 127.7 (CH), 127.5 (CH),
2.14–1.98 (4 H, m, 2 × CH2); δC (100 MHz; CDCl3) 156.6 (C),
140.1 (C), 137.7 (CH), 136.8 (C), 135.2 (CH), 128.45 (CH),
128.38 (CH), 128.3 (CH), 128.2 (CH), 127.9 (CH), 127.6 (CH),
116.3 (CH2), 115.1 (CH2), 67.2 (CH2), 58.5 (CH), 46.0 (CH2),
30.7 (CH2), 30.3 (CH2); m/z (CI) 336 (MHϩ, 20%), 209 (34),
192 (11), 146 (11), 106 (20), 91 (6).
127.0 (CH), 126.6 (CH), 126.3 (CH), 116.5 (᎐CH ), 67.3 (CH ),
᎐
2
2
61.8 (CH); m/z (CI) 384 (MHϩ, 10%), 248 (8), 209 (35),
193 (100).
(R)-N-Allyl-N-benzyloxycarbonylhept-1-en-4-ylamine 10d
(S )-N-Allyl-N-benzyloxycarbonyl-1-propylhex-5-en-1-ylamine
Obtained from the N-allylation of Cbz-amine 9d as a colourless
oil (90%); (Found: MHϩ, 288.1956. C18H25NO2 ϩ H requires
288.1963); [α]2D1 ϩ15.6 (c 1.0, CHCl3); νmax (film)/cmϪ1 3075,
3033, 2958, 2931, 2871, 1699, 1456, 1409, 1240, 916; δH (300
10h
Obtained from the N-allylation of Cbz-amine 9h as a colourless
oil (81%); (Found: M ϩ NH4ϩ, 333.2543. C20H29NO2 ϩ NH4
requires 333.2542); νmax (film)/cmϪ1 2958, 2931, 2863, 1697,
1456, 1409, 1328, 1238, 995, 912; δH (400 MHz; CDCl3) major
rotamer 7.31 (5 H, m, ArH), 5.95–5.66 (2 H, m, 2 × ᎐CH), 5.29–
4.91 (4 H, m, 2 × ᎐CH ), 5.15 (2 H, s, CH O), 4.12 (1 H, m,
MHz; CDCl ; 60 ЊC) 7.31 (5 H, m, ArH), 5.87 (1 H, m, ᎐CH),
᎐
3
5.73 (1 H, m, ᎐CH), 5.15 (2 H, s, CH O), 5.05 (4 H, m,
᎐
2
᎐
2 × ᎐CH ), 4.08 (1 H, br s, NH), 3.77 (2 H, br s, CH CH᎐), 2.27
᎐
᎐
2
2
᎐
2
2
(2 H, m, CH CH᎐), 1.64–1.29 (4 H, m, 2 × CH ), 0.89 (3 H,
᎐
2
2
NCH), 3.73 (2 H, dd, J 4.4, 17.0, NCH2), 2.03 (2 H, m,
CH CH᎐), 1.51–1.26 (8 H, m, 4 × CH ), 0.89 (3 H, t, J 5.4, Me);
t, J 5.2, Me); δC (100 MHz; CDCl3; 60 ЊC) 156.5 (C),
137.0 (C), 135.9 (CH), 135.5 (CH), 128.4 (CH), 127.9 (CH),
127.6 (CH), 116.9 (CH2), 116.1 (CH2), 66.8 (CH2), 56.4
(CH), 45.8 (CH2), 38.0 (CH2), 34.8 (CH2), 19.2 (CH2), 13.9
(Me); m/z (CI) 288 (MHϩ, 18%), 154 (100), 114 (38), 108 (33),
72 (27).
᎐
2
2
minor rotamer 3.96 (1 H, m, NCH), 0.87 (3 H, t, J 5.7, Me);
δC (100 MHz; CDCl3) major rotamer 156.7 (C), 138.6 (CH),
137.1 (C), 135.9 (CH), 128.4 (CH), 127.8 (CH),127.75 (CH),
116.1 (CH2), 114.6 (CH2), 66.9 (CH2), 56.3 (CH), 45.2 (CH2),
35.5 (CH2), 33.5 (CH2), 32.6 (CH2), 25.7 (CH2), 19.6 (CH2),
13.9 (Me); minor rotamer138.5 (CH), 136.9 (C), 135.4 (CH),
128.2 (CH), 127.8 (CH), 127.68 (CH), 116.3 (CH2), 67.0 (CH2),
45.8 (CH2), 35.8 (CH2), 33.4 (CH2), 32.9 (CH2), 13.8 (Me); m/z
(CI) 333 (M ϩ NH4ϩ, 64%), 316 (100), 300 (5), 272 (5), 182 (19),
125 (2).
(S )-N-Allyl-N-benzyloxycarbonyl-1-(4-methoxyphenyl)but-3-
en-1-ylamine 10e
Obtained from the N-allylation of Cbz-amine 9e as a colourless
oil (97%); (Found: MHϩ, 352.1902. C22H25NO3 ϩ H requires
352.1912); [α]2D7 Ϫ91.1 (c 1.0, CHCl3); νmax (film)/cmϪ1 3075,
3033, 2954, 2935, 2836, 1695, 1513, 1456, 1405, 1249; δH (300
MHz; CDCl3) 7.32 (7 H, m, ArH), 6.86 (2 H, AAЈBBЈ, J 8.5
General method for the preparation of nitrogen heterocycles 8
and 11 via ring-closing metathesis
ArH), 5.79 (1 H, br s, ᎐CH), 5.62 (1 H, br s, ᎐CH), 5.38 (1 H, br
The diene 7 or 10 (0.690 mmol) was dissolved in dry dichloro-
᎐
᎐
s, NCH), 5.20 (2 H, s, CH O), 5.16–4.95 (4 H, m, 2 × ᎐CH ),
methane (4 mL) under nitrogen. To the solution was added
᎐
2
2
3.80 (3 H, s, OMe), 3.71 (1 H, m, CHH), 3.60 ( 1 H, dd, J 15.9,
6.5, CHH), 2.73 (2 H, t, J 7.2, CH C᎐); δ (100 MHz; CDCl )
benzylidene
bis(tricyclohexylphosphine)dichlororuthenium
(0.058 g, 0.0690 mmol, 10 mol%), and the mixture stirred (or
heated under reflux) until complete consumption of starting
material was observed (TLC, typically 2–4 h). The solvent was
removed in vacuo and the residue purified by column chromato-
graphy on silica gel eluting with ethyl acetate:light petroleum
(1:10) to give the azacycle 8 or 11.
᎐
2
C
3
159.0 (C), 156.4 (C), 136.9 (C), 135.3 (CH), 135.0 (CH), 131.7
(C), 129.3 (CH), 128.4 (CH), 128.2 (CH), 127.9 (CH), 117.4
(CH2), 116.2 (CH2), 113.7 (CH), 67.1 (CH2), 58.1 (CH), 55.2
(OMe), 46.0 (CH2), 35.7 (CH2); m/z (CI) 352 (MHϩ, 6%), 218
(32), 209 (12), 178 (9), 161 (100), 108 (8).
J. Chem. Soc., Perkin Trans. 1, 2002, 2378–2389
2385

View Article Online
(2R,1ЈR)-2-Methyl-1-(1-phenylbutoxy)-2,5-dihydro-1H-pyrrole
8a
(2R,1ЈS )-2-Phenyl-1-(1-phenylbutoxy)-2,3,4,7-tetrahydro-1H-
azepine 8e
Obtained from the ring-closing metathesis of diene 7a as a
colourless oil (87%); (Found: Mϩ, 231.1629. C15H21NO requires
231.1623); [α]2D2 ϩ32.1 (c 1.65, CHCl3); νmax (film)/cmϪ1 3064,
3031, 2960, 2929, 2871, 2825, 1454, 1369, 1355, 1027, 761;
δH (300 MHz; CDCl ) 7.31 (5 H, m, ArH), 5.60 (2 H, m, CH᎐
CH), 4.65 (1 H, dd, J 7.8, 5.8, OCH), 4.01 (1 H, m, NCH), 3.52
(2 H, m, NCH2), 1.86 (1 H, m, CHH), 1.62–1.28 (3 H, m, CHH,
CH2), 1.25 (3 H, d, J 6.7, Me), 0.95 (3 H, t, J 7.2, Me); δC (75
MHz; CDCl3) 143.7 (C), 131.7 (CH), 128.1 (CH), 127.3 (CH),
127.2 (CH), 125.3 (CH), 86.1 (CH), 69.0 (CH), 62.6 (CH2), 38.6
(CH2), 19.4 (CH2), 19.2 (Me), 14.1 (Me); m/z (EI) 231 (Mϩ, 1%)
150 (11), 133 (3), 117 (7), 107 (81), 99 (67), 91 (100), 79 (57), 68
(15).
Obtained from the ring-closing metathesis of diene 7e after
purification by column chromatography on silica gel eluting
with ether:light petroleum (3:80) as a colourless oil (9%);
(Found: MHϩ, 322.2171. C22H27NO ϩ H requires 322.2173);
[α]2D5 Ϫ60.0 (c 0.3, CHCl3); νmax(film)/cmϪ1 3063, 3027, 2960,
2925, 2868, 2812, 1731, 1685, 1486, 1450, 1214, 1030, 758, 697,
666; δH (400 MHz; CDCl3) 7.48 (2 H, m, ArH), 7.30 (8 H, m,
᎐
3
ArH), 5.83 (1 H, m, NCH CH᎐CH), 5.38 (1 H, m, NCH CH᎐
᎐
᎐
2
2
CH), 4.22 (1 H, t, J 6.5, OCH), 4.00 (1 H, dd, J 7.2, 4.3, NCH),
3.38 (1 H, dd, J 14.5, 2.1, NCHH), 3.21 (1 H, dd, J 14.5,
7.6, NCHH), 2.29 (1 H, m, NCHCH2CHH), 2.09 (1 H, m,
NCHCH2CHH), 1.93 (1 H, m, NCHCHH), 1.82 (1 H,
m, NCHCHH), 1.35–1.12 (2 H, m, OCHCH2), 0.83 (2 H, m,
CH2Me), 0.54 (3 H, t, J 6.7, Me); δC (100 MHz; CDCl3) 144.8
(C), 142.9 (C), 134.2 (CH), 128.0 (CH), 127.9 (CH), 127.7 (CH),
127.6 (CH), 127.3 (CH), 126.8 (CH), 125.8 (CH), 84.8 (CH),
75.1 (CH), 56.4 (CH2), 37.0 (CH2), 33.2 (CH2), 25.5 (CH2), 18.3
(CH2), 13.8 (Me); m/z (ES) 322 (MHϩ, 20%), 190 (6), 130 (100).
(2R,1ЈR)-2-Butyl-1-(1-phenylbutoxy)-2,5-dihydro-1H-pyrrole 8b
Obtained from the ring-closing metathesis of diene 7b as a
colourless oil (78%); (Found: MHϩ, 274.2176. C18H27NO ϩ H
requires 274.2171); [α]2D2 ϩ28.1 (c 2.35, CH2Cl2); νmax (film)/cmϪ1
2958, 2931, 2871, 1456, 1027, 761; δH (300 MHz; CDCl3) 7.31
(2R,1ЈS )-2-(4-Benzyloxybutyl)-1-(1-phenylbutoxy)-2,5-dihydro-
1H-pyrrole 8f
(5 H, m, ArH), 5.73 (1 H, m, ᎐CH), 5.63 (1 H, m, ᎐CH), 4.64
᎐
᎐
(1 H, dd, J 7.9, 5.7, OCH), 3.95 (1 H, m, NCH), 3.51 (2 H, qq,
J 15.6, 2.0, NCH2), 1.86 (1 H, m, CHH), 1.61–1.29 (9 H, m,
CHH, 4 × CH2), 0.97 (3 H, t, J 7.0, Me), 0.94 (3 H, t, J 7.3, Me);
δC (75 MHz; CDCl3) 143.8 (C), 130.3 (CH), 128.1 (CH), 127.2
(CH), 125.61 (CH), 125.60 (CH), 85.6 (CH), 74.7 (CH), 63.2
(CH2), 38.5 (CH2), 33.3 (CH2), 28.8 (CH2), 22.9 (CH2), 19.4
(CH2), 14.2 (Me), 14.1 (Me); m/z (CI) 274 (MHϩ, 0.1%), 141
(9), 133 (9), 105 (18), 91 (100), 84 (49), (27).
Obtained from the ring-closing metathesis of diene 7f after
purification by column chromatography on silica gel eluting
with ether:light petroleum (1:20) as a colourless oil (35%);
(Found: MHϩ, 380.2587. C25H33NO2 ϩ H requires 380.2589);
[α]2D8 Ϫ81.5 (c 0.54, CHCl3); δH (400 MHz; CDCl3) 7.28 (10 H,
m, ArH), 5.72 (2 H, m, CH᎐CH), 4.58 (1 H, m, OCH), 4.46
᎐
(2 H, m, CH2Ph), 3.95 (1 H, br, NCHH), 3.80 (2 H, m, NCHH,
NCH), 3.29 (2 H, t, J 6.7, OCH2), 1.82 (1 H, m, CHH), 1.55
(1 H, m, CHH), 1.43–0.98 (8 H, m, 4 × CH2), 0.90 (3 H, t, J 7.3,
Me); δC (100 MHz; CDCl3) 143.6 (C), 138.7 (C), 130.8 (CH),
128.3 (CH), 128.0 (CH), 127.6 (CH), 127.45 (CH), 127.37 (CH),
127.2 (CH), 125.2 (CH), 85.3 (OCH), 75.2 (NCH), 72.8
(CH2Ph), 70.3 (OCH2), 63.2 (NCH2), 38.2 (CH2), 32.7 (CH2),
29.7 (CH2), 22.6 (CH2), 19.2 (CH2), 14.0 (Me); m/z (CI) 380
(MHϩ, 18%), 230 (100), 166 (60), 150 (88).
(2S,1ЈS )-2-Isobutyl-1-(1-phenylbutoxy)-2,5-dihydro-1H-pyrrole
8c
Obtained from the ring-closing metathesis of diene 7c after
purification by column chromatography on silica gel eluting
with ether:light petroleum (1:8) as a colourless oil (74%);
(Found: MHϩ, 274.2172. C18H27NO ϩ H requires 274.2171);
[α]2D5 Ϫ28.1 (c 1.35, CHCl3); νmax(film)/cmϪ1 3018, 2955, 1209,
758, 661; δH (400 MHz; CDCl3) 7.28 (5 H, m, ArH), 5.71 (1 H,
(2R,1ЈS )-2-(4,4-Dimethoxybutyl)-1-(1-phenylbutoxy)-2,5-
dihydro-1H-pyrrole 8g
dq, J 6.3, 1.9, CH CH᎐CH), 5.61 (1 H, dq, J 6.3, 1.9, CH CH᎐
᎐
᎐
2
2
CH), 4.66 (1 H, t, J 6.5, OCH), 4.02 (1 H, tt, J 7.2, 1.9, NCH),
3.49 (2 H, m, NCH2), 1.82 (2 H, m, OCHCH2), 1.55–1.25 (5 H,
m, CH2CHMe2, CH2Me), 0.99 (3 H, d, J 6.7, Me), 0.95 (3 H, d,
J 6.6, Me), 0.91 (3 H, t, J 7.3, Me); δC (100 MHz; CDCl3) 143.8
(C), 130.6 (CH), 128.1 (CH), 127.3 (CH), 127.2 (CH), 125.4
(CH), 85.6 (CH), 73.3 (CH), 63.1 (CH2), 43.0 (CH2), 38.4
(CH2), 25.7 (CH), 23.0 (Me), 22.9 (Me), 19.3 (CH2), 14.0 (Me);
m/z (EI) 274 (MHϩ, 100%), 232 (18), 214 (55), 203 (65), 173
(71), 156 (51), 150 (88).
Obtained from the ring-closing metathesis of diene 7g after
purification by column chromatography on silica gel eluting
with ether:light petroleum (1:17) as a colourless oil (23%);
(Found: MHϩ, 334.2394. C20H31NO3 ϩ H requires 334.2382);
[α]2D5 Ϫ126.4 (c 1.25, CHCl3); νmax(film)/cmϪ1 3063, 3022, 2955,
2930, 2868, 2822, 1450, 1383, 1363, 1194, 1127, 1071, 1050,
1020, 953, 907, 758, 697; δH (400 MHz; CDCl3) major diastereo-
isomer 7.29 (5 H, m, ArH), 5.72 (2 H, m, CH᎐CH), 4.57 (1 H,
᎐
t, J 7.5, CH(OMe)2), 4.15 (1 H, t, J 5.8, OCHCH2), 3.94 (1 H,
dd, J 5.8, 1.1, NCHH), 3.78 (2 H, m, NCHH, NCH), 3.26 (3 H,
s, CH(OMe)(OMe)), 3.25 (3 H, s, CH(OMe)(OMe)), 1.89–0.97
(10 H, m, OCHCH2CH2, CH2CH2CH2), 0.90 (3 H, t, J 7.3,
Me); δC (100 MHz; CDCl3) major diastereoisomer 143.7 (C),
130.7 (CH), 128.0 (CH), 127.3 (CH), 127.2 (CH), 125.4 (CH),
104.4 (CH), 85.2 (CH), 75.1 (CH), 63.1 (CH2), 52.6 (OMe), 52.5
(OMe), 32.7 (CH2), 38.2 (CH2), 32.5 (CH2), 21.1 (CH2), 19.3
(CH2), 14.0 (Me); m/z (CI) 334 (MHϩ, 8%), 302 (100), 170 (23),
152 (26), 133 (5), 120 (7).
(2S,1ЈS )-2-Phenyl-1-(1-phenylbutoxy)-2,5-dihydro-1H-pyrrole
8d
Obtained from the ring-closing metathesis of diene 7d after
purification by column chromatography on silica gel eluting
with ethyl acetate:light petroleum (1:50) as a colourless oil
(51%); (Found: MHϩ, 294.1860. C20H23NO ϩ H requires
294.1858); [α]2D2 Ϫ17.7 (c 1.13, CHCl3); νmax(film)/cmϪ1 3053,
3027, 2950, 2925, 2863, 2822, 1450, 1025, 753; δH (400 MHz;
CDCl3) 7.31 (10 H, m, ArH), 5.71 (1 H, dq, J 6.3, 1.9,
(2R,1ЈS )-2-Propyl-1-(1-phenylbutoxy)-1,2,3,6-tetrahydro-
pyridine 8h
PhCHCH᎐CH), 5.64 (1 H, m, PhCHCH᎐CH), 4.97 (1 H, m,
᎐
᎐
NCH), 4.33 (1 H, dd, J 7.7, 5.5, OCH), 3.60 (2 H, m, NCH2),
1.68 (1 H, m, CHH), 1.45–1.02 (3 H, m, CHH, CH2), 0.74 (3 H,
t, J 7.1, Me); δC (100 MHz; CDCl3) 143.8 (C), 142.1 (C), 130.3
(CH), 129.4 (CH), 128.2 (CH), 128.0 (CH), 127.8 (CH), 127.2
(CH), 127.1 (CH), 126.2 (CH), 85.4 (CH), 77.3 (CH), 62.6
(CH2), 38.2 (CH2), 19.1 (CH2), 13.8 (Me); m/z (CI) 294 (MHϩ,
86%), 200 (14), 162 (66), 144 (91), 133 (100).
Obtained from the ring-closing metathesis of diene 7h after
purification by column chromatography on silica gel eluting
with ether:light petroleum (1:50) as a colourless oil (90%);
(Found: MHϩ, 274.2170. C18H27NO ϩ H requires 274.2171);
[α]2D5 Ϫ100.8 (c 1.21, CHCl3); νmax(film)/cmϪ1 3058, 3027, 2955,
2925, 2868, 2822, 1690, 1655, 1496, 1450, 1378, 1194, 1096,
2386
J. Chem. Soc., Perkin Trans. 1, 2002, 2378–2389

View Article Online
1015, 907, 758, 696, 656; δH (400 MHz; CDCl3) 7.30 (5 H, m,
ArH), 5.72 (1 H, m, CH᎐CH), 5.50 (1 H, m, CH᎐CH), 4.55
ϩ120.0 (c 0.75, CHCl3); νmax(film)/cmϪ1 3020, 2981, 2921, 1715
(C᎐O), 1218, 740; δ (400 MHz; CDCl3) major rotamer 7.36–
᎐
᎐
᎐
H
(1 H, t, J 6.5, OCH), 3.24 (2 H, br s, NCH2), 2.79 (1 H, m,
NCH), 2.25–1.85 (3 H, m, CH2, CHH), 1.78–1.50 (2 H, m,
CHH, CHH), 1.44–1.13 (5 H, m, CHH, 2 × CH2), 0.90 (6 H, t,
J 7.3, 2 × Me); δC (100 MHz; CDCl3) 143.5 (C), 128.0 (CH),
6.92 (10 H, m, ArH), 5.91 (1 H, m, CH᎐CHCH ), 5.75 (1 H, dq,
᎐
2
J 6.3, 2.1, CH᎐CHCH ), 5.51 (1 H, q, J 2.1, PhCH), 5.05 (1 H,
᎐
2
d, J 12.6, OCHH), 4.97 (1 H, d, J 12.6, OCHH), 4.78–4.31 (2 H,
m, NCH2); minor rotamer 7.36–6.92 (10 H, m, ArH), 5.91 (1 H,
127.4 (CH), 127.2 (CH), 125.1 (᎐CH), 123.7 (᎐CH), 85.0
m, CH᎐CHCH ), 5.80 (1 H, dq, J 6.3, 2.1, CH᎐CHCH ), 5.59
᎐ ᎐
2 2
᎐
᎐
(OCH), 60.2 (NCH), 53.9 (NCH2), 38.1 (CH2), 34.0 (CH2), 27.2
(CH2), 19.5 (CH2), 19.3 (CH2), 14.2 (Me), 14.1 (Me); m/z (CI)
274 (MHϩ, 90%), 166 (15), 150 (45), 126 (100).
(1 H, q, J 2.1, PhCH), 5.19 (1 H, d, J 12.4, OCHH), 5.03 (1 H,
d, J 12.4, OCHH), 4.78–4.31 (2 H, m, NCH2); δC (100 MHz;
CDCl ) major rotamer 154.6 (C᎐O), 141.8 (C), 136.5 (C), 131.2
᎐
3
(CH), 128.5 (CH), 128.4 (CH), 128.2 (CH), 127.9 (CH),
127.6 (CH), 127.4 (CH), 126.9 (CH), 126.7 (CH), 124.7 (CH),
124.5 (CH), 68.0 (CH), 66.8 (CH2), 54.3 (CH2); minor rotamer
(2R,1ЈR)-2-Phenyl-1-(1-phenylbutoxy)-1,2,3,6-tetrahydro-
pyridine 8i
154.3 (C᎐O), 141.0 (C), 136.9 (C), 131.0 (CH), 128.5
᎐
Obtained from the ring-closing metathesis of diene 7i as a col-
ourless oil (53%); (Found: Mϩ, 307.1934. C21H25NO requires
307.1936); [α]2D5 ϩ85.5 (c 2.0, CHCl3); νmax (film)/cmϪ1 3062,
3031, 2958, 2951, 2871, 2815, 1494, 1454, 757; δH (400 MHz;
(CH), 128.4 (CH), 128.2 (CH), 127.9 (CH), 127.6 (CH), 127.4
(CH), 126.9 (CH), 126.7 (CH), 124.7 (CH), 124.5 (CH), 68.4
(CH), 66.8 (CH2), 53.7 (CH2); a satisfactory mass spectrum
could not be obtained.
CDCl ) 7.55–6.90 (10 H, m, ArH), 5.86 (1 H, m, ᎐CH), 5.68
᎐
3
(1 H, m, ᎐CHCH N), 4.20 (1 H, dd, J 4.9, 9.8, OCH), 3.88
᎐
2
(R)-1-Benzyloxycarbonyl-2-propyl-1,2,3,6-tetrahydropyridine
11d
(1 H, br s, NCH), 3.65 (1 H, br s, NCHH), 2.68–2.37 (1 H,
m, NCHH), 1.94 (1 H, br s, NCHCHH), 1.63 (1 H, m,
NCHCHH), 1.31–0.85 (4 H, m, 2 × CH2), 0.84 (3 H, t, J 5.1,
Me); δC (100 MHz; CDCl3) 141.7 (C), 128.7 (CH), 128.6 (CH),
128.5 (C), 127.9 (CH), 127.8 (CH), 127.7 (CH), 127.4 (CH),
Obtained from the ring-closing metathesis of diene 10d as a
colourless oil (88%); (Found: Mϩ, 259.1568. C16H21NO2
requires 259.1572); [α]1D8 ϩ24.5 (c 2.0, CHCl3); νmax (film)/cmϪ1
3035, 2958, 2931, 2871, 1699, 1421, 1388, 1234, 1116, 1093; δH
127.1 (CH), 124.3 (᎐CH), 124.0 (᎐CH), 84.5 (CH), 66.5 (CH),
᎐
᎐
(400 MHz; CDCl ) 7.34 (5 H, m, ArH), 5.70 (1 H, m, ᎐CH),
᎐
55.8 (CH2), 37.0 (CH2), 34.0 (CH2), 18.9 (CH2), 14.1 (Me); m/z
(EI) 307 (Mϩ, 1%), 175 (96), 133 (19), 121 (57), 105 (21), 91
(100), 77 (27).
3
5.62 (1 H, br s, ᎐CH), 5.17 (1 H, d, J 12.5, CHHO), 5.14 (1 H, d,
᎐
J 12.5, CHHO), 4.39 (2 H, m, NCH2), 3.53 (1 H, br d, J 20,
NCH), 2.41 (1 H, br d, J 17.2, CHHCH᎐), 1.89 (1 H, br d,
᎐
J 17.2, CHHCH᎐), 1.44 (1 H, m, CHH), 1.24 (3 H, m, CHH,
᎐
(S )-1-Benzyloxycarbonyl-2-methyl-2,5-dihydro-1H-pyrrole 11a
CH2), 0.91 (3 H, br s, Me); δC (100 MHz; CDCl3) 155.6 (C),
137.0 (C), 128.4 (CH), 127.9 (CH), 127.8 (CH), 123.3 (CH),
122.9 (CH), 66.9 (CH2), 48.3 (CH), 39.9 (CH2), 29.1 (CH2), 28.9
(CH2), 19.5 (CH2), 14.0 (Me); m/z (EI) 259 (Mϩ, 0.3%), 216
(14), 172 (19), 112 (7), 91 (100), 65 (11), 55 (18).
Obtained from the ring-closing metathesis of diene 10a after
purification by column chromatography on silica gel eluting
with ethyl acetate:light petroleum (1:10) as a colourless oil
(84%); [α]1D6 ϩ35.1 (c 0.57, CHCl3); νmax(film)/cmϪ1 3015, 2960,
2890, 1702 (C᎐O), 1203, 760; δ (400 MHz; CDCl3) two rota-
᎐
H
mers 7.35 (5 H, m, ArH), 5.72 (2 H, m, CH᎐CH), 5.17 (2 H, m,
OCH2Ph), 4.63 (1 H, m, NCH), 4.19 (2 H, m, NCH2), 1.34 (first
rotamer, 1.5 H, d, J 6.4, Me), 1.27 (second rotamer, 1.5 H, d,
᎐
(S )-1-Benzyloxycarbonyl-2-(4-methoxyphenyl)-1,2,3,6-tetra-
hydropyridine 11e
Obtained from the ring-closing metathesis of diene 10e as a
colourless oil (91%); (Found: Mϩ, 323.1514. C20H21NO3
requires 323.1521); [α]1D8 Ϫ95.4 (c 1.3, CHCl3); νmax (film)/cmϪ1
3035, 2954, 2935, 2900, 2836, 1697, 1610, 1513, 1419, 1309,
1249, 1037; δH (300 MHz; CDCl3) 7.33 (7 H, m, ArH), 6.83 (2
J 6.4, Me); δC (100 MHz; CDCl ) two rotamers 154.8 (C᎐O),
᎐
3
154.4 (C᎐O), 137.0 (C), 136.9 (C), 132.0 (CH), 131.8 (CH),
᎐
128.5 (CH), 128.4 (CH),127.9 (CH), 127.8 (CH), 124.2 (CH),
123.9 (CH), 66.8 (OCH2), 66.5 (OCH2), 60.5 (CH), 59.8 (CH),
53.5 (NCH2), 53.1 (NCH2), 20.8 (Me), 19.8 (Me); a satisfactory
mass spectrum could not be obtained.
H, AAЈBBЈ, J 8.3, ArH), 5.92 (1 H, br s, ᎐CH), 5.67 (1 H, m, ᎐
᎐
᎐
CH), 5.64 (1 H, m, NCH), 5.24 (1 H, d, J 12.3, CHHO), 5.20
(1 H, d, J 12.3, CHHO), 4.32 (1 H, br d, J 18.1, NCHH), 3.79
(3 H, s, MeO), 3.40 (1 H, br d, J 18.1, NCHH), 2.72 (1 H, m,
(R)-1-Benzyloxycarbonyl-2-butyl-2,5-dihydro-1H-pyrrole 11b
Obtained from the ring-closing metathesis of diene 10b as a
colourless oil (77%); [α]2D0 Ϫ150.9 (c 0.53, CH2Cl2); νmax (film)/
cmϪ1 3057, 2934, 2902, 1685, 1463, 1255, 1084; δH (400 MHz;
CHHC᎐), 2.54 (1 H, m, CHHC᎐); δ (75 MHz; CDCl3) 158.6
᎐
᎐
C
(C), 155.6 (C), 136.8 (C), 132.6 (C), 128.5 (CH), 128.1 (CH),
128.0 (CH), 127.9 (CH), 124.2 (CH), 123.6 (CH), 113.7 (CH),
67.2 (CH2), 55.2 (Me), 50.4 (CH), 40.3 (CH2), 27.8 (CH2); m/z
(CI) 323 (Mϩ, 2%), 232 (31), 202 (14), 188 (33), 134 (17),
91 (100), 65 (9).
CDCl ) major rotamer 7.33 (5 H, m, ArH), 5.75 (2 H, m, CH᎐
᎐
3
CH), 5.21 (1 H, d, J 12.4, PhCHH), 5.17 (1 H, d, J 12.4,
PhCHH), 4.60 (1 H, m, NCH), 4.27 (1 H, m, NCHH), 4.11
(1 H, dt, J 5.3, 2.0, NCHH), 1.84–1.44 (2 H, m, CH2), 1.35–1.87
(4 H, m, 2 × CH2), 0.89 (3 H, t, J 7.2, Me); minor rotamer 5.14
(1 H, d, J 12.4, PhCHH), 5.12 (1 H, d, J 12.4, PhCHH), 4.07
(1 H, dt, J 5.3, 2.0, NCHH), 0.84 (3 H, t, J 7.3, Me); δC (100
MHz; CDCl3) major rotamer 154.4 (C), 137.1 (C), 130.2 (CH),
128.4 (CH), 128.2 (CH), 127.8 (CH), 124.7 (CH), 66.5 (CH2),
64.8 (CH), 53.6 (CH2), 32.9 (CH2), 26.3 (CH2), 22.8 (CH2), 14.1
(Me); minor rotamer 154.8 (C), 136.9 (C), 130.1 (CH), 125.0
(CH), 66.8 (CH2), 64.0 (CH), 54.1 (CH2), 33.8 (CH2), 26.6
(CH2), 22.7 (CH2), 14.0 (Me); a satisfactory mass spectrum
could not be obtained.
(R)-1-Benzyloxycarbonyl-2-(4-benzyloxypropyl)-1,2,3,6-tetra-
hydropyridine 11f
Obtained from the ring-closing metathesis of diene 10f after
purification by column chromatography on silica gel eluting
with ether:light petroleum (1:2) as a colourless oil (98%, 87%
ee); (Found: MHϩ, 366.2067. C23H27NO3 ϩ H requires
366.2069); [α]2D4 ϩ13.3 (c 1.05, CHCl3); νmax(film)/cmϪ1 3032,
2930, 2853, 1701 (CO), 1419, 1337, 1224, 1112, 1025, 743, 692;
δH (400 MHz; CDCl3) 7.33 (10 H, m, ArH), 5.77–5.56 (2 H, m,
CH᎐CH), 5.14 (2 H, AB, J 12.4, CH Ph), 4.54–4.23 (4 H, m,
᎐
2
CH2Ph, NCH, OCHH), 3.61–3.37 (3 H, m, NCH2, OCHH),
2.44 (1 H, m, CHH), 1.93 (1 H, m, CHH), 1.75–1.44 (4 H, m,
2 × CH2); δC (100 MHz; CDCl3) 155.6 (CO), 138.6 (C), 136.9
(C), 128.5 (CH), 128.4 (CH), 128.0 (CH), 127.9 (CH), 127.6
(CH), 127.5 (CH), 123.3 (᎐CH), 122.8 (᎐CH), 72.9 (CH ), 70.0
(R)-1-Benzyloxycarbonyl-2-phenyl-2,5-dihydro-1H-pyrrole 11c
Obtained from the ring-closing metathesis of diene 10c after
purification by column chromatography on silica gel eluting
with ether:light petroleum (1:10) as a colourless oil (93%); [α]2D5
᎐
᎐
2
J. Chem. Soc., Perkin Trans. 1, 2002, 2378–2389
2387

View Article Online
(NCH2, first rotamer), 69.9 (NCH2, second rotamer), 67.0
(CH2), 48.5 (NCH, first rotamer), 48.0 (NCH, second rotamer),
39.8 (CH2), 29.3 (NCHCH2, first rotamer), 28.7 (NCHCH2,
second rotamer), 28.0 (CH2), 26.6 (CH2); m/z (ES) 753 (2M ϩ
Na, 50%), 748 (2M ϩ NH4, 20), 388 (M ϩ Na, 100), 383 (40),
366 (MHϩ, 25).
the solvent was removed in vacuo to give the title compound
after purification by column chromatography on silica gel
eluting with ether:light petroleum (1:30) as a colourless oil
(30 mg, 91%); (Found: MHϩ, 276.2328. C18H29NO ϩ H
requires 276.2327); [α]2D8 Ϫ74.5 (c 1.06, CHCl3); νmax(film)/cmϪ1
3032, 2955, 2925, 2863, 2822, 1450, 1368, 1091, 1030, 758, 697;
δH (400 MHz; CDCl3) major diastereoisomer 7.26 (5 H, m,
ArH), 4.50 (1 H, t, J 7.0, OCH), 3.41 (1 H, br, NCHH), 2.49
(1 H, br, NCHH), 2.28 (1 H, br, NCH), 1.99 (2 H, m, CHH),
1.70–1.15 (13 H, m, CHH, 6 × CH2), 0.90 (3 H, t, J 7.3, Me),
0.73 (3 H, br, Me); δC (100 MHz; CDCl3) major diastereo-
isomer142.1 (C), 127.9 (CH), 127.6 (CH), 127.2 (CH), 84.5
(OCH), 66.7 (NCH), 57.6 (CH2), 37.5 (CH2), 35.1 (CH2), 30.5
(CH2), 25.8 (CH2), 23.8 (CH2), 19.1 (CH2), 18.6 (CH2), 14.3
(Me), 14.1 (Me); m/z (CI) 276 (MHϩ, 56%), 166 (17), 150 (37),
128 (100).
(R)-1-Benzyloxycarbonyl-2-phenyl-2,3,4,7-tetrahydro-1H-
azepine 11g
Obtained from the ring-closing metathesis of diene 10g as a
colourless oil (65%); (Found: MHϩ, 308.1655. C20H21NO2 ϩ H
requires 308.1650); [α]2D2 ϩ89.3 (c 1.2, CHCl3); νmax (film)/cmϪ1
3062, 3027, 2933, 1699, 1456, 1448, 1415, 1236, 1205, 1116; δH
(300 MHz; CDCl ) 7.31 (10 H, m, ArH), 5.78 (1 H, m, ᎐CH),
᎐
3
5.74 (1 H, m, ᎐CH), 5.54 (1 H, dd, J 12.1, 5.2, NCH), 5.18 (2 H,
᎐
s, CH2O), 4.26 (1 H, dd, J 17.5, 5.8, NCHH), 3.70 (1 H, br d,
J 17.5, NCHH), 2.39–2.18 (4 H, m, 2 × CH2); δC (100 MHz;
CDCl3) 156.9 (C), 141.9 (C), 137.1 (C), 131.6 (CH), 128.5 (CH),
128.4 (CH), 127.9 (CH), 127.6 (CH), 127.5 (CH), 127.1 (CH),
126.2 (CH), 67.1 (CH2), 59.2 (CH), 41.0 (CH2), 31.8 (CH2), 26.9
(CH2); m/z (CI) 308 (MHϩ, 34%), 174 (100), 106 (22), 91 (4).
(R)-1-(tert-Butoxycarbonyl)-2-phenylpiperidine 14
Dehydropiperidine 8i (0.100 g, 0.326 mmol) was dissolved in a
solution of methanol:acetic acid (1:1, 10 mL) and hydrogenated
over palladium on charcoal (25% w/w) for 24 h. The catalyst
was filtered and the solvent was removed in vacuo. The residue
was basified with aqueous saturated sodium hydrogen carbon-
ate solution and exhaustively extracted with dichloromethane
(5 × 5 mL). The combined organic extracts were dried
(Na2SO4), filtered and evaporated. The residue was dissolved in
dichloromethane (5 mL) and di-tert-butyl dicarbonate (0.213 g,
0.978 mmol) and DMAP (cat.) were added and the reaction
mixture stirred overnight. Aqueous saturated sodium
bicarbonate solution was added and the mixture stirred for 10
min. The mixture was extracted with dichloromethane (3 × 5
mL) and the combined organic extracts were dried (Na2SO4),
filtered and evaporated. The residue was purified by column
chromatography eluting with ether:light petroleum (1:10) to
give the title compound as colourless solid (23%); mp 78–80 ЊC
(from n-hexane); (Found: C, 73.1; H, 9.0; N, 5.0. C16H23NO2
requires C, 73.5; H, 8.9; N, 5.4%); (Found: Mϩ, 261.1732.
C16H23NO2 requires 261.1729); [α]2D5 ϩ83.7 (c 0.98, CHCl3); νmax
(KBr)/cmϪ1 2964, 2937, 2859, 1681, 1415, 1159; δH (300 MHz;
CDCl3) 7.29 (5 H, m, ArH), 5.42 (1 H, br d, J 3.8, NCH), 4.05
(1 H, br d, J 13.4, NCHH), 2.77 (1 H, NCH2CHH), 2.31 (1 H,
m, NCHH), 1.88 (1 H, m, NCH2CHH), 1.57 (4 H, m, 2 × CH2),
1.47 (9 H, br s, CMe3); δC (75 MHz; CDCl3) 155.7 (C), 140.4
(C), 128.5 (CH), 126.5 (CH), 126.3 (CH), 79.5 (C), 53.2 (CH),
40.1 (CH2), 28.5 (Me), 28.1 (CH2), 25.5 (CH2), 19.4 (CH2); m/z
(EI) 261 (Mϩ, 7%), 205 (61), 188 (16), 160 (50), 144 (11), 128
(29), 118 (19), 83 (100), 57 (62).
(S )-1-Benzyloxycarbonyl-2-propyl-1,2,3,4,5,8-hexahydroazocine
11h
Obtained from the ring-closing metathesis of diene 10h as a
colourless oil (19%); (Found: Mϩ, 287.1886. C18H25NO2
requires 287.1885); [α]2D0 ϩ77.4 (c 1.24, CHCl3); νmax (film)/cmϪ1
3012, 2956, 2931, 2873, 1697, 1454, 1415, 1236, 1213, 1099, 696;
δH (400 MHz; CDCl3) 7.32 (5 H, m, ArH), 5.56 (2 H, m, 2 ×
᎐CH), 5.19 (1 H, d, J 12.7, PhCHH), 5.14 (1 H, d, J 12.7,
᎐
PhCHH), 4.44–4.17 (2 H, m, NCH2), 3.53 (1 H, dd, J 4.5, 2.3,
NCH), 2.33 (1 H, m, CHHCH᎐), 1.87 (1 H, m, CHHCH᎐),
᎐
᎐
1.53–1.21 (8 H, m, 4 × CH2), 0.91 (3 H, t, J 7.3, Me); δC (100
MHz; CDCl3) 156 (C), 137.3 (C), 129.1 (CH), 128.3 (CH), 128.0
(CH), 127.4 (CH), 126.5 (CH), 126.1 (CH), 66.7 (CH2), 56.1
(CH), 49.9 (CH2), 36.4 (CH2), 28.1 (CH2), 22.9 (CH2), 19.2
(CH2), 14.1 (Me); m/z (EI) 287 (Mϩ, 2%), 244 (3), 200 (16), 152
(6), 116 (24), 91 (100).
Reactions of nitrogen heterocycles
(2R,1ЈS )-2-Isobutyl-1-(1-phenylbutoxy)pyrrolidine 12
Dihydropyrrole 8c (45 mg, 0.22 mmol) was dissolved in meth-
anol (7 mL) and hydrogenated over palladium on charcoal
(6 mg, 10% w/w) for 3 h. The mixture was filtered through
Celite and the solvent was removed in vacuo to give the title
compound after purification by column chromatography on
silica gel eluting with ether : light petroleum (1 : 30) as a colour-
less oil (33 mg, 74%); (Found: MHϩ, 276.2326. C18H29NO ϩ H
requires 276.2327); [α]2D5 Ϫ37.8 (c 0.90, CHCl3); νmax(film)/cmϪ1
3063, 3027, 2945, 2930, 2863, 1465, 1450, 1363, 1102, 1055,
1025, 912, 753, 697; δH (400 MHz; CDCl3) 7.28 (5 H, m, ArH),
4.58 (1 H, t, J 6.6, OCH), 2.92 (1 H, m, NCH), 2.76 (1 H, m,
NCHH), 2.59 (1 H, m, NCHH), 1.86 (2 H, m, OCHCHH,
NCHCHH), 1.71–1.37 (5 H, m, CHMe2, OCHCHH,
NCHCHH, NCH2CH2), 1.26 (4 H, m, NCHCH2, CH2Me),
0.95 (3 H, d, J 6.4, CHMeMe), 0.91 (6 H, m, CHMeMe,
CH2Me); δC (100 MHz; CDCl3) 144.0 (C), 128.0 (CH), 127.15
(CH), 127.09 (CH), 85.1 (OCH), 66.5 (NCH), 56.0 (CH2), 43.2
(CH2), 38.8 (CH2), 27.2 (CH2), 26.0 (CH), 23.8 (Me), 22.4 (Me),
20.2 (CH2), 19.3 (CH2), 14.1 (Me); m/z (ES) 276 (MHϩ, 100%),
144 (100).
(R)-2-Phenylpiperidine 15
(R)-1-(tert-Butoxycarbonyl)-2-phenylpiperidine 14 (0.020 g,
0.077 mmol) was dissolved in dichloromethane (1 mL) and
treated with HCl in ether (1 M, 0.76 mL, 0.766 mmol). After
30 min the reaction mixture was basified with aqueous sodium
hydroxide solution (1 M) to pH 14 and extracted with dichloro-
methane (5 × 5 mL). The combined organic extracts were dried
(Na2SO4), filtered and evaporated to give the title compound as a
colourless oil (82%); [α]2D1 ϩ43.5 (c 0.23, CH2Cl2) (lit.,28 [α]2D2
ϩ49.5 (c 0.2, CH2Cl2); δH (400 MHz; CDCl3) 7.30 (5 H, m,
ArH), 3.61 (1 H, br d, J 8.9, NCH), 3.18 (1 H, br d, J 11.7,
NCHH), 2.85 (1 H, m, NCHH), 1.90 (1 H, br d, J 10.0, CHH),
1.81 (1 H, br d, J 12.2, CHH), 1.68–1.26 (5 H, m, 2 × CHH,
CH2, NH); δC (100 MHz; CDCl3) 144.0 (C), 128.4 (CH), 127.1
(CH), 126.7 (CH), 62.3 (CH), 47.7 (CH2), 34.7 (CH2), 25.7
(CH2), 25.3 (CH2).
(2R,1ЈS )-1-(1-Phenylbutoxy)-2-propylpiperidine 13
(R)-2-Propylpiperidine hydrochloride [(؊)-coniine
hydrochloride] 16
Tetrahydropyridine 8h (33 mg, 0.12 mmol) was dissolved in
methanol (7 mL) and hydrochloride acid (4 M in dioxane)
(1 mL) and hydrogenated over palladium on charcoal (8 mg,
10% w/w) for 4 h. The catalyst was filtered through Celite and
Dehydropiperidine 11d (0.023 g, 0.089 mmol) was dissolved in
methanol (3 mL) and hydrogenated over palladium on charcoal
2388
J. Chem. Soc., Perkin Trans. 1, 2002, 2378–2389

View Article Online
(10% w/w) for 1.5 h. The catalyst was filtered and the filtrate
was treated with HCl in ether (1 M, 0.89 mL, 0.890 mmol) for
5 min. The solvent was removed in vacuo and the residue tri-
turated with ether to give the title compound as a colourless
solid (76%); mp 212–213 ЊC (from CH2Cl2–n-hexane) (lit.,35
217–218 ЊC); [α]2D2 Ϫ4.5 (c 0.66, EtOH) (lit.,35 [α]2D4 Ϫ6.3 (c 0.62,
EtOH); δH (400 MHz; CDCl3) 9.44 (1 H, br s, NH), 9.18 (1 H,
br s, NH), 3.46 (1 H, m, CHN), 2.93 (1 H, m, CHN), 2.81 (1 H,
m, CHN), 2.16–1.41 (10 H, m, 5 × CH2), 0.94 (3 H, t, J 7.3,
Me); δC (100 MHz; CDCl3) 57.2 (CH), 44.8 (CH2), 35.4 (CH2),
28.2 (CH2), 22.4 (CH2), 22.3 (CH2), 18.6 (CH2), 13.7 (Me).
References
1 J. C. A. Hunt, C. Lloyd, C. J. Moody, A. M. Z. Slawin and
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(S )-2-(4-Methoxyphenyl)piperidine 17
Dehydropiperidine 11e (0.042 g, 0.137 mmol) was dissolved in
methanol (53 mL) and hydrogenated over palladium on char-
coal (10% w/w) for 3 h. The catalyst was filtered and the solvent
was removed in vacuo to give the title compound as a colourless
oil (76%); (Found: MHϩ, 192.1389. C12H17NO ϩ H requires
192.1388); [α]2D5 Ϫ73.1 (c 0.41, CH2Cl2); νmax (film)/cmϪ1 3385,
2933, 2852, 1610, 1513, 1452, 1303, 1243, 1037; δH (300 MHz;
CDCl3) 7.27 (2 H, AAЈBBЈ, J 8.3, ArH), 6.84 (2 H, AAЈBBЈ,
J 8.3, ArH), 3.78 (3 H, s, OMe), 3.53 (1 H, dd, J 2.4, 10.1,
NCH), 3.17 (1 H, m, NCHH), 2.77 (1 H, dt, J 11.2, 2.8,
NCHH), 2.10 (1 H, br s, NH), 1.77–1.47 (6 H, m, 3 × CH2);
δC (75 MHz; CDCl3) 158.6 (C), 137.7 (C), 127.7 (CH), 113.7
(CH), 61.7 (CH), 55.2 (CH), 47.8 (CH2), 34.9 (CH2), 25.8
(CH2), 25.4 (CH2); m/z (CI) 192 (MHϩ, 4%), 162 (43), 148 (27),
134 (100), 121 (29), 91 (48), 77 (38).
11 R. H. Grubbs and S. Chang, Tetrahedron, 1998, 54, 4413.
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15 J. Cossy, C. Willis, V. Bellosta and S. BouzBouz, J. Org. Chem., 2002,
67, 1982.
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17 S. M. Ma and B. K. Ni, Org. Lett., 2002, 4, 639.
18 N. Saito, Y. Sato and M. Mori, Org. Lett., 2002, 4, 803.
19 K. B. Lindsay, M. Y. Tang and S. G. Pyne, Synlett, 2002, 731.
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25 Preliminary communication: J. C. A. Hunt, P. Laurent and
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26 F. L. Zumpe and U. Kazmaier, Synthesis, 1999, 1785.
27 J. Louie, C. W. Bielawski and R. H. Grubbs, J. Am. Chem. Soc.,
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28 C. A. Willoughby and S. L. Buchwald, J. Am. Chem. Soc., 1994, 116,
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359.
(R)-2-Phenylazepane 18
Dehydropiperidine 11g (0.045 g, 0.147 mmol) was dissolved in
methanol (5 mL) and hydrogenated over palladium on charcoal
for 3 h. The catalyst was filtered and the was removed in vacuo
to give the title compound as a colourless oil (85%); [α]2D5 ϩ65.6
(c 0.64, CH2Cl2) (lit.,28 [α]2D3 ϩ62.0 (c 4.8, CH2Cl2); νmax (film)/
cmϪ1 3413, 3060, 2952, 2852, 1450, 1143; δH (300 MHz; CDCl3)
7.29 (5 H, m, ArH), 3.75 (1 H, dd, J 9.6, 3.5, NCH), 3.14 (1 H,
m, NCHH), 2.85 (1 H, m, NCHH), 1.98 (1 H, m, NH), 1.86–
1.45 (8 H, m, 4 × CH2); δC (75 MHz; CDCl3) 147.1 (C), 128.4
(CH), 126.7 (CH), 126.4 (CH), 65.0 (CH), 48.3 (CH2), 39.1
(CH2), 30.9 (CH2), 26.9 (CH2), 26.2 (CH2).
31 R. Kumareswaran and A. Hassner, Tetrahedron: Asymmetry, 2001,
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Acknowledgements
6024.
34 P. T. Gallagher, J. C. A. Hunt, A. P. Lightfoot and C. J. Moody,
J. Chem. Soc., Perkin Trans. 1, 1997, 2633.
35 D. Enders and J. Tiebes, Liebigs Ann., 1993, 173.
We thank the EPSRC for support of this work and the EPSRC
Mass Spectrometry Centre at Swansea for mass spectra.
J. Chem. Soc., Perkin Trans. 1, 2002, 2378–2389
2389