Zirconocene-mediated synthesis of 3,4-disubstituted piperidines and reduced isoquinolines

Article abstract of DOI:10.1055/s-1998-5923

Intramolecular cocyclisation of 4-azaocta-1,7-dienes, -1-en-7-ynes, -7- en-1-ynes and -1,7-diynes using 'zirconocene' equivalents affords 3-aza-8- zirconabicyclo[4.3.0]nonanes, -6-enes, -9-enes or -6,9-dienes. Protonolysis, iodinolysis, or carbonylation of these complexes affords 3,4-disubstitued piperidines. Exocyclic 1,3-dienes formed from the coupling/protonolysis of 4- azaocta-1,7-diynes react with activated dienophiles to yield reduced isoquinolines.

Full text of DOI:10.1055/s-1998-5923

SYNTHESIS
April 1998
557
Zirconocene-Mediated Synthesis of 3,4-Disubstituted Piperidines and Reduced
Isoquinolines
Mark I. Kemp,a Richard J. Whitby,*a Steven J. Cooteb
a Department of Chemistry, The University, Southampton, Hants, SO17 1BJ, U.K.
Fax +44(1703)593781; E-mail: rjw1@soton.ac.uk
b Glaxo Wellcome Medicines Research Centre, Gunnels Wood Road, Stevenage, Herts, SG1 2NY, U.K.
Received 22 August 1997
Abstract: Intramolecular cocyclisation of 4-azaocta-1,7-dienes,
-1-en-7-ynes, -7-en-1-ynes and -1,7-diynes using ‘zirconocene’
equivalents affords 3-aza-8-zirconabicyclo[4.3.0]nonanes, -6-
enes, -9-enes or -6,9-dienes. Protonolysis, iodinolysis, or carbony-
lation of these complexes affords 3,4-disubstituted piperidines.
Exocyclic 1,3-dienes formed from the coupling/protonolysis of 4-
azaocta-1,7-diynes react with activated dienophiles to yield
reduced isoquinolines.
clohexanes, but thermal equilibration of the intermediate
zirconabicycles quantitatively forms the trans isomer.6
Heating the initially formed mixture of 2a and 2b at reflux
in tetrahydrofuran caused slow isomerisation to give a 1:1
mixture of 3a and 3b. Unfortunately, byproducts shown to
be the exocyclic alkenes 4 and 5 by GC/MS, NMR, and
independent synthesis of 57 were also formed. A reason-
able mechanism is shown in Scheme 2.
Key words: zirconocene-mediated cyclisation, zirconabicycles,
3,4-disubstituted piperidines, isoquinolines
The intramolecular cocyclisation of 1,n-dienes, -enynes
and -diynes by low valent early transition metals to form
metallabicycles is a useful method of C–C bond formation
between normally unreactive functional groups.1 Efficient
methods for the further elaboration of the carbon–metal
bonds, particularly of zirconacycles, have been devel-
oped,1,2 making zirconacycles versatile intermediates in
organic synthesis. Despite the large number of carbocy-
cles that have been formed in this way, few nitrogen het-
erocycles have been synthesised.3
Scheme 2
Recently Takahashi reported8 that heating a zirconabicy-
cle derived from a 1,4,7-triene at 50°C for 6 h formed an
exocyclic alkene similar to 4 and 5. After 27 hours the ra-
tio 3a:3b:4:5 was 33:33:20:14. The formation of 4 and 5
could be suppressed (<10% in total) by carrying out the
thermolysis in the presence of trimethylphosphine, how-
ever the equilibrium mixture still contained equal
amounts of 3a and 3b, even after 24 hours at 110°C in tol-
uene. The marked difference in stereochemical outcome
in the cyclisation of 1 compared with 1,7-octadiene under
thermodynamic control may be due to reduced 1,3-diaxial
interactions in the cis-fused zirconacycle derived from the
former (Figure 1, B vs. A), although favourable coordina-
tion of the nitrogen to the metal might also be a factor
(Figure 1, C).
We now report full details of the synthesis of 3,4-disubsti-
tuted piperidines by treatment of 4-azaocta-1,7-dienes, -1-
en-7-ynes, -7-en-1-ynes and -1,7-diynes with a source of
zirconocene (‘Cp2Zr’) followed by either protonolysis, io-
dinolysis or carbonylation.4 Scheme 1 shows a typical re-
action sequence.
Scheme 1
Figure 1. Interactions in cis-Fused Zirconabicycles
Addition of diene 1 to dibutylzirconocene in tetrahydrofu-
ran at –78°C and subsequent warming to room tempera-
ture formed a dark red solution of the zirconabicycles 2a
and 2b via ‘Cp2Zr’ transfer from in situ generated zir-
conocene(but-1-ene).5 Hydrolysis gave cis- and trans-N-
benzyl-3,4-dimethylpiperidine (3a and 3b, 4:1) in 91%
overall yield. Under similar conditions, 1,7-octadiene af-
fords an 83:17 mixture of cis- and trans-1,2-dimethylcy-
The stereochemical assignments of 3a and 3b were based
on 1H NMR spectroscopy. Lyle et al.9 report that the ben-
zylic hydrogens of trans-N-benzyl-4-ethyl-3-methyl-pip-
eridine occur as a singlet in the 1H NMR spectrum but in
cis-N-benzyl-3,4-dimethylpiperidine they form an AB
quartet with a 0.1 ppm difference in the chemical shifts.

SYNTHESIS
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558
1
The H NMR spectrum of 3a shows benzylic hydrogens
which differ in their chemical shifts by 0.11 ppm. The
analogous signal for 3b appears as a singlet. The carbon-
13 shifts of the methyl groups are also informative, 14.02
and 16.53 in 3a compared with 17.36 and 19.49 in 3b, the
marked upfield shift of the former being consistent with
the γ-gauche effect expected in the cis isomer.10
Cyclisation of the secondary amine 6 was accomplished
with 2 equivalents of zirconocene(but-1-ene) followed by
aqueous workup and in situ benzylation to give a 50%
yield of the piperidines 3a and 3b (4 : 1). The direct for-
mation of a quaternary center in the cyclisation/protona-
tion of the disubstituted alkene 7 to give the piperidine 8
was notable (Scheme 3). The presence of a nitrogen in the
connecting chain for dienes and enynes has been shown to
allow cyclisations despite substitution of the alkene.2c,3g,11
Scheme 3
We next examined the cyclisation of a range of 4- and 5-
aza-1,7-enynes. Synthesis of the required enyne precur-
sors was unremarkable, with the exception of the prepara-
tion of 11. Reaction of the secondary amine 21 with
formaldehyde and phenylacetylene in the presence of cop-
per acetate gave the expected enyne 1112 together with an
unexpected product 9c, presumably arising via a 2-aza-
Cope rearrangement of the intermediate iminium ion
(Scheme 4).13
further heating did not change the ratio. H–H and C–H
COSY NMR experiments together with coupling-con-
stant and NOE data allowed unambiguous assignment of
the relative stereochemistries (Figure 2). In particular,
proton Hc of 12a appears as a 13 Hz quartet indicating
trans-diaxial couplings to the protons adjacent to both the
methyl and isopropyl groups. For 12b molecular mechan-
Scheme 4
Cyclisation/protonation of the 1,7-enynes using in situ
generated zirconocene(but-1-ene) gave 4- and 3-alkyl-
idene piperidines in good yields (Table). There were a few
points of note.
Cyclisation of 11 gave a separable 40:60 mixture of the
isomeric piperidines 12a and 12b on protic workup. Heat-
ing the intermediate zirconacycle (67°C, 16 h) followed
by protonation gave a 64 : 36 mixture of 12a and 12b, but
Figure 2. Stereochemical Assignments for 12a and 12b

SYNTHESIS
April 1998
559
ics and MOPAC (PM3 and AM1) calculations indicate formed piperidines 25a–c containing a stereodefined exo-
that the conformers A and B are very close in energy. cyclic diene moiety well-suited for further elaboration via
NOE experiments are more consistent with conformer A cycloaddition chemistry (Scheme 6). The protonation
and the coupling constants indicate substantial population with retention of configuration of the C–Zr bonds is
of both forms.
amply supported by precedents, but was proven for 25a by
the observation of 5% NOE’s between the methyl groups
and adjacent piperidine ring methylenes. The formation of
25c was accompanied by small amounts (<3%) of the
product derived from 1,7-enyne cocyclisation.
The successful cyclisation of the tert-butyloxycarbonyl
(BOC) protected amine 18 was gratifying in light of low
yields reported for ester-containing substrates in the zir-
conocene induced cocyclisation due to competitive reduc-
tion.14
Attempted cyclisation of the substrate 13 containing a di-
substituted alkene group using zirconocene(but-1-ene)
gave the piperidine 14 in only 30% yield on protonolysis,
the remainder of the enyne being converted into the three
dimeric compounds 23a–c (1:2:1 ratio, identified by GC/
MS and NMR). The initially formed zirconacyclopropene
22 preferentially carbometallates the alkyne group of an-
other, uncomplexed molecule of 13 rather than the pen-
dant hindered alkene2c (Scheme 5). The problem was
overcome by the slow addition of 13 at room temperature
to a preformed solution of Cp2Zr(DMAP)2 [2 equiv,
DMAP = 4-(dimethylamino)pyridine], a ‘Cp2Zr’ equiva-
lent with moderate thermal stability,15 to give 14 in good
yield with no trace, by gas chromatography, of 23a–c.
Scheme 6
The use of 25a–c in Diels–Alder reactions was briefly in-
vestigated. Reaction of 25a with N-phenylmaleimide and
dimethyl acetylenedicarboxylate (DMAD) gave the re-
duced isoquinolines 26 and 27, respectively, in high yield
(Scheme 7). The cis-endo stereochemistry of 26 is as-
sumed only on the basis of good precedent16 since the sig-
1
nals due to the important CH’s were obscured in the H
NMR spectrum. The proposed structure is supported by
the NMR-derived structure of the very similar tricycle 29
described below.
Scheme 7
Scheme 5
We were particularly interested to see if the thiomethyl
group incorporated in 25b could be directly attacked by
unsymmetrical dienophiles,17 and also facilitate aromati-
sation of the carbocyclic ring.18 Both these aims were re-
alised (Scheme 8). Reaction of 25b with but-3-en-2-one
was complete after two days at room temperature. Con-
centration of the toluene solution and crystallisation gave
the octahydroisoquinoline 28 as white needles in almost
quantitative yield. The regio- and stereochemistry of 28
was proven by NMR including C–H and C–C correlation
The key to efficient use of zirconacycles in organic syn-
thesis is productive elaboration of the carbon–zirconium
bonds. We demonstrated just two examples with these
substrates, carbonylation of the zirconacycle derived from
15 gave the cyclopentenone 17 in moderate yield, and io-
dination of the zirconacycle derived from 18 gave the di-
iodide 20.
Synthesis and Diels–Alder Reactions of 3,4-Dialkyl-
idene Piperidines
1
experiments. H NMR in D6-benzene allowed the key
The Diels–Alder reaction is one of the most useful ring- coupling constants to be determined (Figure 3). Compari-
forming methods available, and early transition metal in- son with models minimised using molecular mechanics
duced cocyclisation of 1,n-diynes is an excellent route to (augmented MM2) for conformational searches, and MO-
stereodefined dienes.1,2c,14,16 To exploit this in the synthe- PAC (PM3) for final minimisations and energy calcula-
sis of reduced isoquinolines we examined the zirconocene- tions confirmed that only the endo stereochemistry was
mediated cocyclisation of 4-azaocta-1,7-diynes. Reduc- consistent with the observed coupling constants (Figure
tive coupling of the diynes 24a–c and protolytic workup 3). The conformer A of the exo-addition product was cal-

SYNTHESIS
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560
culated to be 7 kJ/mol more stable than confomer B – nei- In conclusion we have shown that the zirconium-mediated
ther fit the NMR data. Treatment of 25b with N-methyl- bicyclisation of 4-azaocta-1,7-dienes, -1-en-7-ynes, -7-
maleimide gave the Diels–Alder adduct 29 in good yield. en-1-ynes and -1,7-diynes readily produces bicyclic zir-
1
The endo stereochemistry was confirmed by H NMR conacyclopentanes, -pentenes and -pentadienes in good
combined with molecular modelling. The calculated yield. These zirconabicycles have the potential for ela-
structure for the exo compound gave a dihedral angle be- boration into a wide range of products containing a
tween Ha and Hb of 80°, while for the endo compound it 3,4-disubstituted piperidine substructure. The use of
was 40°, comparing well with the observed 7 Hz coupling. Cp2Zr(DMAP)2 for the successful cyclisation of hindered
Reaction of 25b with DMAD gave an adduct which readi- substrates should be generally useful.
ly eliminated methanethiol (methyl sulphide = Me2S) on
treatment with alumina to afford the 1,2,3,4-tetra-
hydroisoquinoline 30.
Molecular modelling (MM2 and MOPAC with PM3 and/or AM1 pa-
rameter sets) was carried out using CAChe Worksystem Software
version 3.0 (Oxford Molecular) running on a PowerMac 7600. Exten-
sive conformational searches, and molecular dynamics simulations
were used to ensure that true minima were found. MM2 parameters
for the particular arrangement of functional groups in the required
structures are not available so the ‘augmented’ parameter set avail-
able with the above program was used making the results less reliable.
Energies from MOPAC calculations are also rather unreliable. In the
cases examined the predictions of all three methods for conformations
were very close, and the ordering of energies identical.
All reactions involving air sensitive reagents were performed under
an argon or nitrogen atmosphere in oven-dried Schlenk flasks. Nor-
mal workup means that the aqueous and organic layers were sepa-
rated, the aqueous layer extracted twice with more of the specified
Scheme 8
organic solvent, and the combined organic layers dried (K2CO3), fil-
tered, and concentrated by rotary evaporation in vacuo. Et2O, THF,
benzene and toluene were dried and made oxygen-free by distilla-
tion from sodium/benzophenone (the Et2O still also contained tetra-
ethylene glycol dimethyl ether to aid solubility of the benzophenone
ketyl). Petrol refers to the fraction that has a boiling range 40–60°C
and was distilled before use. CH2Cl2 was dried by stirring over P2O5
followed by distillation. Hexamethylphosphoramide (HMPA) was
dried by distilling from CaH2 under reduced pressure (~ 10 Torr).
TLC was performed using Kieselgel 60 G/UV254 precoated alumin-
ium backed plates. Column chromatography was carried out using
Kieselgel 60 230–400 mesh (Merck 9385) silica unless otherwise
specified.
1H and 13C NMR spectra were recorded on Bruker AM360 FT
(360 MHz proton, 90 MHz carbon), Bruker AC300 FT (300 MHz
proton, 75 MHz carbon), Jeol JNM GX270 FT (270 MHz proton, 67.5
MHz carbon) or Bruker AC FT (250 MHz proton, 62.5 MHz carbon)
instruments. The following abbreviations are used to denote multi-
Figure 3. MOPAC/PM3 minimised Conformations of Isomers of 28
Finally, on thermolysis in toluene in the presence of 1%
2,6-di-tert-butyl-p-cresol as a radical inhibitor, the piperi-
dine 25c underwent a slow but high yielding intramolecu-
lar cycloaddition to the pendant unactivated alkene to
afford the tricyclic product 31 as a single isomer (Scheme
9). The stereochemistry shown was not proven, but is ex-
pected from consideration of transition states, and is con-
sistent with a similar cycloaddition reported by Wilson
and Mao19 in which an acyclic 1,3,9-decatriene gave a bi-
cyclic product with >95% trans fusion.
plicity of the signals in the 1H NMR spectra; s, singlet; d, doublet; t,
triplet; q, quartet; br, broad. The abbreviation ‘+ fs’ is used to denote
fine splittings (< 2 Hz) which were not resolved. 13C peaks are noted
with the number of attached hydrogens in parentheses determined by
DEPT 90 and DEPT 135 experiments. Where C–H and/or H–H cor-
relation experiments were performed, the derived assignments are
presented. Infrared spectra were recorded on a Perkin-Elmer 1600 se-
ries FTIR instrument as a thin film on NaCl plates unless otherwise
specified. The peaks are described as strong (s), medium (m), weak
(w) or broad (br). Ultraviolet/visible spectra were recorded on a Per-
kin-Elmer UV/VIS/NIR Lambda 19 spectrometer. Mass spectra were
recorded on a VG Analytical 70-250-SE normal geometry double fo-
cusing mass spectrometer under Electron Impact (EI) ionisation at 70
eV or Chemical Impact (CI) ionisation conditions using ammonia as
the reagent gas. M/e values were measured in atomic mass units, and
the peaks obtained using EI are followed by their intensity relative to
the base peak (100%). Elemental analyses were performed as a ser-
vice by the Physical Sciences department at Glaxo Ware and at Uni-
versity College London.
Scheme 9

SYNTHESIS
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561
Preparation of Cyclization Precursors
N-Benzyl-N-(but-3-enyl)-N-(but-2-ynyl)amine (9a):
N-Allyl-N-benzyl-N-(but-3-enyl)amine (1):
BuLi (2.5 M in hexanes, 0.70 mL, 1.76 mmol) was added dropwise to
a stirred solution of N-benzyl-N-(but-3-enyl)-N-(prop-2-ynyl)amine
(350 mg, 1.76 mmol) in THF (1.5 mL) at –55°C under argon. After
5 min, HMPA (0.3 mL) was slowly added and the solution left for a fur-
ther 5 min. MeI (319 mg, 2.25 mmol) was added and the yellow solu-
tion was warmed to r.t. and stirred for 18 h. Sat. NaHCO3 solution
(8 mL) and Et2O (20 mL) were added, the layers separated, and the
aqueous phase extracted with Et2O (2 × 20 mL), The combined organic
phases were washed with H2O/sat. aq NaHCO3 solution (95:5, 3 ×
20 mL), dried (K2CO3) and solvent removed to give a pale-yellow oil.
The crude product was Kugelrohr distilled (oven temp ~ 120°C/0.6
mbar) to yield 9a as a clear colourless oil (206 mg, 0.965 mmol, 55%).
IR (film): ν = 3061 m, 3025 m, 2974 m, 2917 s, 2821 s, 2269 w, 1640
m, 1600 w, 1584 w, 1493 m, 1452 s, 1364 m, 1327 m, 911 s, 737 s,
698 s cm–1.
Allyl bromide (605 mg, 5 mmol) was added dropwise, with ice cool-
ing, to a stirred mixture of N-benzyl-N-(but-3-enyl)amine21 (807 mg,
5 mmol) and anhyd K2CO3 (690 mg, 5 mmol) in MeCN (2 mL).20 The
mixture was warmed to r.t. and stirred for 48 h. H2O (5 mL) and Et2O
(10 mL) were added, and the mixture worked up as normal to afford
a pale-yellow oil. The crude product was purified using column chro-
matography (petrol/Et2O, 97:3) and Kugelrohr distillation (oven temp
~ 40°C/0.5 mbar) to yield 1 as a clear colourless oil (889 mg,
4.4 mmol, 88%).
IR (film): ν = 3076 m, 3026 m, 2976 m, 2923 m, 2798 s, 1640 m, 1602
w, 1494 m, 1452 m, 1418 w, 1368 w, 915 s, 737 s, 698 s cm–1.
1H NMR (270 MHz, CDCl3): δ = 7.18–7.34 (5 H, m), 5.87 (1 H, ddt,
J = 17, 10, 7 Hz), 5.77 (1 H, ddt, J = 17, 10, 7 Hz), 5.17 (1 H, d + fs,
J = 17 Hz), 5.12 (1 H, d + fs, J = 10 Hz), 5.01 (1 H, d + fs, J = 17 Hz),
4.96 (1 H, d + fs, J = 10 Hz), 3.57 (2 H, s), 3.08 (2 H, dt, J = 7, 1 Hz),
2.52 (2 H, t, J = 7 Hz), 2.23 (2 H, q, J = 7 Hz).
1H NMR (270 MHz, CDCl3): δ = 7.19–7.36 (5 H, m), 5.81 (1 H, ddt,
J = 17, 10, 7 Hz), 5.06 (1 H, d + fs, J = 17 Hz), 4.99 (1 H, d + fs, J =
10 Hz), 3.61 (2 H, s), 3.26 (2 H, q, J = 2 Hz), 2.59 (2 H, t, J = 7 Hz),
2.26 (2 H, q, J = 7 Hz), 1.84 (3 H, t, J = 2 Hz).
13C NMR (67.5 MHz, CDCl3): δ = 139.75 (0), 137.05 (1), 136.09 (1),
128.96 (1), 128.29 (1), 126.92 (1), 117.31 (2), 115.50 (2), 58.11 (2),
56.86 (2), 53.01 (2), 31.70 (2).
13C NMR (67.5 MHz, CDCl3): δ = 139.07 (0), 136.91 (1), 129.18 (1),
128.30 (1), 127.06 (1), 115.56 (2), 80.74 (0), 73.80 (0), 57.86 (2),
52.85 (2), 41.92 (2), 32.21 (2), 3.60 (3).
CI-MS (NH3): m/z = 202 (MH+).
EI-MS: m/z (%) = 213 (M+, <1), 173 (13), 172 (90), 91 (100), 65 (10),
42 (12).
N-Benzyl-N-(but-3-enyl)-N-(2-methylallyl)amine (7):
Prepared from 3-bromo-2-methylpropene (540 mg, 4 mmol) and N-
benzyl-N-(but-3-enyl)amine21 (645 mg, 4 mmol) by the same method
used to form 1. The crude product was purified using column chroma-
tography (petrol/ether 100:0–97:3) and Kugelrohr distillation (oven
temp ~ 75°C/0.7 mbar) to yield 7 as a clear colourless oil (783 mg,
3.64 mmol, 91%).
CI-MS (NH3): m/z = 214 (MH+).
N-Benzyl-N-(but-3-enyl)-N-(3-trimethylsilylprop-2-ynyl)amine
(9b):
BuLi (2.5 M in hexanes, 0.67 mL, 1.69 mmol) was added dropwise to
a solution of N-benzyl-N-(but-3-enyl)-N-(prop-2-ynyl)amine (336
mg, 1.69 mmol) in THF (1.5 mL) at –55°C under argon. After 10 min,
Me3SiCl (238 mg, 2.19 mmol) was slowly added and the solution left
to warm to r.t. After 18 h, sat. NaHCO3 solution (8 mL) and Et2O
(30 mL) were added, the phases separated, and the aqueous phase ex-
tracted with Et2O (2 × 40 mL). The combined organic phases were
dried (K2CO3), filtered, and solvent removed to give a pale-yellow oil.
The crude product was Kugelrohr distilled (oven temp ~ 100°C/0.6
mbar) to afford 9b as a clear colourless oil (454 mg, 1.67 mmol, 98%).
IR (film): ν = 3061 w, 3025 w, 2956 m, 2823 m, 2161 m, 1640 w,
1494 w, 1452 m, 1354 w, 1321 m, 1249 s, 982 s, 844 s, 698 s cm–1.
1H NMR (270 MHz, CDCl3): δ = 7.20–7.35 (5 H, m), 5.83 (1 H, ddt,
J = 17, 10, 7 Hz), 5.07 (1 H, d + fs, J = 17 Hz), 5.01 (1 H, d + fs, J =
10 Hz), 3.62 (2 H, s), 3.32 (2 H, s), 2.62 (2 H, t, J = 7 Hz), 2.28 (2 H,
q, J = 7 Hz), 0.20 (9 H, s, with a superimposed doublet (J = 3 Hz) due
to 5% 29Si).
IR (film): ν = 3072 m, 3024 m, 2975 m, 2939 m, 2793 s, 2716 w, 1640
m, 1601 w, 1493 m, 1451 s, 1369 m, 895 s, 739 s, 697 s cm–1.
1H NMR (270 MHz, CDCl3): δ = 7.17–7.35 (5 H, m), 5.77 (1 H, ddt,
J = 17, 10, 7 Hz), 5.00 (1 H, d + fs, J = 17 Hz), 4.95 (1 H, d + fs, J =
10 Hz), 4.91 (1 H, s), 4.82 (1 H, s), 3.51 (2 H, s), 2.92 (2 H, s), 2.45
(2 H, t, J = 7 Hz), 2.23 (2 H, q, J = 7 Hz), 1.74 (3 H, s).
13C NMR (67.5 MHz, CDCl3): δ = 144.30 (0), 140.22 (0), 137.28 (1),
128.83 (1), 128.27 (1), 126.83 (1), 115.43 (2), 112.71 (2), 61.15 (2),
58.27 (2), 53.04 (2), 31.70 (2), 20.95 (3).
CI-MS (NH3): m/z = 216 (MH+).
N-Benzyl-N-(but-3-enyl)-N-(prop-2-ynyl)amine:
Propargyl bromide (80% wt. in toluene, 1.190 g, 8 mmol) was added
dropwise to a stirred solution of N-benzyl-N-(but-3-enyl)amine21
(2.58 g, 16 mmol ) in anhyd Et2O (8 mL) at r.t.12 After 5 min the clear
solution became cloudy. The mixture was heated to reflux for 1 h and
then cooled to 0°C. The white crystals were filtered off and extracted
with anhyd Et2O (50 mL). The filtrate was concentrated in vacuo to
yield a cloudy oil. The crude product was purified using column chro-
matography (petrol/Et2O, 100:0–95:5) and Kugelrohr distillation (ov-
en temp ~70°C/0.7 mbar) to afford N-benzyl-N-(but-3-enyl)-N-
(prop-2-ynyl)amine as a clear colourless oil (0.714 g, 3.58 mmol,
45%). Virtually all the excess N-benzyl-N-(but-3-enyl)amine was re-
covered by basifying an aqueous solution of the filtered salt with
NaOH (2 M) followed by Et2O extraction and concentration.
IR (film): ν = 3293 s, 3061 m, 3026 m, 2974 m, 2919 m, 2821 s, 2200
w, 1639 m, 1601 w, 1493 m, 1451 m, 1429 m, 1365 m, 1326 m, 913
s, 737 s, 698 s cm–1.
13C NMR (67.5 MHz, CDCl3): δ = 138.88 (0), 136.90 (1), 129.31 (1),
128.42 (1), 127.23 (1), 115.70 (2), 101.03 (0), 90.30 (0), 57.81 (2),
53.01 (2), 42.57 (2), 32.21 (2), 0.34 (3).
CI-MS (NH3): m/z = 272 (MH+).
N-(1-Isopropylbut-3-enyl)-N-propylamine (21):
N-[(E)-2-methylpropylidene]-N-propylamine was prepared from
isobutyraldehyde (7.68 g, 0.13 mol) and propylamine (9.37 g,
0.13 mol) by the method of Campbell et al.22 as a clear colourless oil
(12.6 g, 0.111 mol, 85%); bp 108–115°C/760 Torr (Lit.22 108–
114°C). Allylmagnesium bromide (74 mL of a 1.6 M solution in
Et2O, 0.118 mol) was added dropwise with stirring over 30 min to a
solution of N-[(E)-2-methylpropylidene]-N-propylamine (12.13 g,
0.107 mol) in anhyd Et2O (200 mL) at –78°C. After warming to r.t.
over 3 h sat. NaHCO3 solution (100 mL) was added and the mixture
worked up as normal to yield a clear light-brown oil. Fractional dis-
tillation of the crude product gave the title amine 21 as a clear colour-
less oil (12.45 g, 0.080 mol, 75%; bp 66–69°C/~ 10 mbar).
1H NMR data is consistent with that previously reported.23
IR (film): ν = 3074 w, 2956 s, 2930 s, 2871 s, 2802 m, 1638 m,
1464 m, 1381 m, 1365 w cm–1.
1H NMR (270 MHz, CDCl3): δ = 7.20–7.35 (5 H, m), 5.81 (1 H, ddt,
J = 17, 10, 7 Hz), 5.06 (1 H, d + fs, J = 17 Hz), 5.00 (1 H, d + fs, J =
10 Hz), 3.61 (2 H, s), 3.30 (2 H, d, J = 2 Hz), 2.62 (2 H, t, J = 7 Hz),
2.26 (2 H, q, J = 7 Hz), 2.19 (1 H, t, J = 2 Hz).
13C NMR (67.5 MHz, CDCl3): δ = 138.77 (0), 136.69 (1), 129.14 (1),
128.36 (1), 127.19 (1), 115.70 (2), 78.51 (1), 73.31 (0), 57.73 (2),
52.81 (2), 41.35 (2), 32.18 (2).
EI-MS: m/z (%) = 199 (M+, 1), 159 (11), 158 (71), 92 (9), 91 (100),
65 (9), 39 (8).

SYNTHESIS
Papers
562
1H NMR (270 MHz, CDCl3): δ = 5.74 (1 H, ddt, J = 17, 10, 8 Hz),
5.04 (1 H, d + fs, J = 17 Hz), 5.00 (1 H, d + fs, J = 10 Hz), 2.47 (2 H,
t, J = 8 Hz), 2.26 (1 H, dt, J = 8, 5 Hz), 2.15 (1 H, ddd, J = 16, 8, 5 Hz),
1.95 (1 H, dt, J = 16, 8 Hz), 1.75 (1 H, sextet of d, J = 7, 5 Hz), 1.42
(2 H, sextet, J = 8 Hz), 1.05 (1 H, br s), 0.80–0.90 (9 H, m).
13C NMR (67.5 MHz, CDCl3): δ = 136.91 (1), 116.65 (2), 62.66 (1),
50.09 (2), 35.25 (2), 30.12 (1), 23.63 (2), 18.86 (3), 18.03 (3), 11.89
(3).
13C NMR (67.5 MHz, CDCl3): δ = 140.34 (0), 128.44 (1), 128.16 (1),
126.96 (1), 77.09 (0), 76.93 (0), 53.49 (2), 47.94 (2), 19.87 (2), 3.58
(3).
CI-MS (NH3): m/z = 174 (MH+).
N-Benzyl-N-(2-methylallyl)-N-(pent-3-ynyl)amine (13):
Prepared from N-benzyl-N-(pent-3-ynyl)amine (0.865 g, 5 mmol) and
3-bromo-2-methylpropene (0.675 g, 5 mmol) by the same procedure
used to form 1. The crude product was purified using column chroma-
tography (petrol/Et2O, 100:0–97:3) and Kugelrohr distillation (oven
temp ~ 100°C/0.7 mbar) to yield 13 as a clear colourless oil (1.04 g,
4.6 mmol, 92%).
CI-MS (NH3): m/z = 156 (MH+).
N-(1-Isopropylbut-3-enyl)-N-(3-phenylprop-2-ynyl)-N-propyl-
amine (11) and N-(But-3-enyl)-N-(3-phenylprop-2-ynyl)-N-pro-
pylamine (9c):
IR (film): ν = 3064 w, 3025 w, 2915 s, 2796 s, 1648 w, 1601 w, 1493
According to the procedure developed by Brandsma,12 N-(1-isopro-
pylbut-3-enyl)-N-propylamine (21; 3.24 g, 21 mmol) was added to
powdered paraformaldehyde (0.525 g, 17.5 mmol) in dioxane (2 mL).
The white suspension was stirred at 60°C for 1 h to form a turbid so-
lution. After the addition of Cu(OAc)2•2 H2O (77 mg, 0.385 mmol),
the mixture was warmed to 70°C and phenylacetylene (1.97 g,
19.2 mmol) was introduced dropwise. The bright-yellow suspension
was heated to reflux for 1.5 h. After cooling, H2O (10 mL), sat.
NaHCO3 solution (5 mL) and Et2O (50 mL) were added and the mix-
ture worked up as normal to yield a dark-yellow clear oil. The three
main components of this oil were separated by column chromatogra-
phy (petrol/Et2O, 90:10) to yield 11 (Rf ~ 0.6; 2.23 g, 8.23 mmol,
47%); 9c (Rf ~ 0.2; 0.669 g, 2.97 mmol, 17%) and recovered 21 (Rf ~
0.05; 0.85 g, 5.5 mmol, 26%).
m, 1451 s, 1370 m, 897 s, 738 s, 697 s cm–1.
1H NMR (270 MHz, CDCl3): δ = 7.20–7.35 (5 H, m), 4.92 (1 H, s),
4.83 (1 H, s), 3.54 (2 H, s), 2.94 (2 H, s), 2.57 (2 H, t, J = 7 Hz), 2.27
(2 H, t, J = 7 Hz), 1.73 (6 H, two superimposed singlets).
13C NMR (67.5 MHz, CDCl3): δ = 144.02 (0), 139.96 (0), 128.72 (1),
128.24 (1), 126.86 (1), 112.81 (2), 77.86 (0), 76.24 (0), 60.99 (2),
58.12 (2), 52.72 (2), 20.79 (3), 17.29 (2), 3.58 (3).
CI-MS (NH3): m/z = 228 (MH+).
N-Allyl-N-benzyl-N-(pent-3-ynyl)amine (15):
Prepared from N-benzyl-N-(pent-3-ynyl)amine (957 mg, 5.52 mmol)
by the same method used to form 1. The crude product was purified
using column chromatography (petrol/Et2O, 96:4) and Kugelrohr dis-
tillation (oven temp ~ 55°C/0.6 mbar) to afford 15 as a clear colour-
less oil (966 mg, 4.53 mmol, 82%).
11:
IR (film): ν = 3063 w, 3026 w, 2917 m, 2803 m, 1642 w, 1602 w,
IR (film): ν = 3075 w, 2957 s, 2931 s, 2871 m, 2819 w, 1637 w, 1598
w, 1489 s, 1467 m, 1442 m, 1384 m, 1363 m, 1330 w, 755 s, 690 s
cm–1.
1494 w, 1452 m, 1419 w, 1367 w, 698 s cm–1.
1H NMR (270 MHz, CDCl3): δ = 7.20–7.35 (5 H, m), 5.86 (1 H, ddt,
J = 17, 10, 7 Hz), 5.19 (1 H, d + fs, J = 17 Hz), 5.13 (1 H, d + fs, J =
10 Hz), 3.60 (2 H, s), 3.10 (2 H, d, J = 7 Hz), 2.64 (2 H, t, J = 8 Hz),
2.28 (2 H, tq, J = 8, 3 Hz), 1.75 (3 H, t, J = 3 Hz).
1H NMR (270 MHz, CDCl3): δ = 7.21–7.42 (5 H, m), 5.94 (1 H, ddt,
J = 17, 10, 7 Hz), 5.04 (1 H, d + fs, J = 17 Hz), 4.95 (1 H, d + fs, J =
10 Hz), 3.60 (2 H, s), 2.62 (2 H, t, J = 7 Hz), 2.40–2.55 (2 H, m), 2.23
(1 H, m), 1.82 (1 H, octet, J = 7 Hz), 1.40–1.60 (2 H, sextet, J = 7 Hz),
0.97 (3 H, d, J = 7 Hz), 0.93 (3 H, d, J = 7 Hz), 0.90 (3 H, t, J = 7 Hz).
13C NMR (67.5 MHz, CDCl3): δ = 139.03 (1), 131.65 (1), 128.36 (1),
127.84 (1), 123.95 (0), 115.24 (2), 88.29 (0), 83.62 (0), 68.07 (1),
52.64 (2), 40.90 (2), 33.36 (2), 31.21 (1), 21.90 (2), 20.90 (3), 20.57
(3), 12.03 (3).
13C NMR (67.5 MHz, CDCl3): δ = 139.59 (0), 135.95 (1), 128.92 (1),
128.31 (1), 126.99 (1), 117.47 (2), 77.72 (0), 76.35 (0), 58.07 (2),
56.87 (2), 52.75 (2), 17.40 (2), 3.64 (3).
CI-MS (NH3): m/z = 214 (MH+).
N-Allyl-N-(pent-3-ynyl)amine:
CI-MS (NH3): m/z = 70 (MH+).
5-Bromopent-2-yne (1.47 g, 10 mmol) was added dropwise to reflux-
ing allylamine (1.7 g, 30 mmol). After 6 h the mixture was cooled and
NaOH solution (10 mL, 50% w/v) and Et2O (50 mL) added. The mix-
ture was shaken, the organic layer separated, and the aqueous phase
extracted with Et2O (2 × 50 mL). The combined organic layers were
dried (K2CO3) and distilled to afford the title amine as a clear colour-
less oil (818 mg, 6.64 mmol, 66%; bp 120°C/ ~ 130 mbar).
IR (film): ν = 3311 br, 3077 w, 2920 s, 2820 s, 1644 m, 1456 s, 1330
m, 1119 s, 919 s cm–1.
9c:
IR (film): ν = 3077 w, 2958 s, 2932 s, 2872 m, 2818 m, 1640 w, 1598
w, 1489 s, 1459 m, 1442 m, 1322 m, 755 s, 691 s cm–1.
1H NMR (270 MHz, CDCl3): δ = 7.40–7.45 (2 H, m), 7.25–7.30 (3 H,
m), 5.84 (1 H, ddt, J = 17, 10, 7 Hz), 5.08 (1 H, d + fs, J = 17 Hz),
5.01 (1 H, d + fs, J = 10 Hz), 3.62 (2 H, s), 2.63 (2 H, t, J = 7 Hz), 2.51
(2 H, t, J = 7 Hz), 2.27 (2 H, q, J = 7 Hz), 1.52 (2 H, sextet, J = 7 Hz),
0.92 (3 H, t, J = 7 Hz).
1H NMR (250 MHz, CDCl3): δ = 5.91 (1 H, ddt, J = 17, 10, 6 Hz),
5.20 (1 H, d, J = 17 Hz), 5.10 (1 H, d, J = 10 Hz), 3.28 (2 H, d, J =
6 Hz), 2.72 (2 H, t, J = 7 Hz), 2.34 (2 H, tq, J = 7, 2 Hz), 1.79 (3 H,
t, J = 2 Hz), 1.5 (1 H, br).
13C NMR (67.5 MHz, CDCl3): δ = 136.81 (1), 131.77 (1), 128.30 (1),
127.97 (1), 123.46 (0), 115.66 (2), 85.21 (0), 84.59 (0), 55.89 (2),
53.27 (2), 42.70 (2), 32.16 (2), 20.79 (2), 12.03 (3).
EI-MS: m/z (%) = 227 (M+, <1), 187 (16), 186 (72), 116 (17), 115
(100).
13C NMR (67.5 MHz, CDCl3): δ = 136.49 (1), 116.22 (2), 76.98 (0),
76.88 (0), 51.86 (2), 47.78 (2), 19.71 (2), 3.52 (3).
Thermospray mass spectrum (+ ve ion filament on), m/z = 124
N-Benzyl-N-(pent-3-ynyl)amine:
(MH+).
Prepared from 5-bromopent-2-yne24 (1.10 g, 7.47 mmol) and benzyl-
amine (2.40 g, 22.4 mmol) by the same method used to form 1. The
crude product was distilled through a vacuum-jacketed Vigreux col-
umn at 1.1 mbar. First to distil was the excess benzylamine (bp 30–
32°C/1.1 mbar) followed by the title amine as a clear colourless oil
(1.02 g, 5.90 mmol, 79%; bp 90–92°C/1.1 mbar).
tert-Butyl N-Allyl-N-(pent-3-ynyl)carbamate (18):
Di-tert-butyl dicarbonate (1.4 g, 6.5 mmol) in CH2Cl2 (5 mL) was
added to N-allyl-N-(pent-3-ynyl)amine (663 mg, 5.38 mmol) in
CH2Cl2 (5 mL) at r.t. After stirring for 90 min, the solution was con-
centrated in vacuo and the crude product purified by column chroma-
tography (hexane/Et2O, 95:5) to yield 18 as a clear colourless oil
(1.05 g, 4.70 mmol, 87%).
IR (film): ν = 3309 br, 3061 w, 3026 w, 2917 s, 2834 s, 1603 w, 1494
m, 1453 s, 1359 w, 1329 w, 736 s, 698 s cm–1.
1H NMR (270 MHz, CDCl3): δ = 7.20–7.30 (5 H, m), 3.80 (2 H, s),
2.73 (2 H, t, J = 7 Hz), 2.35 (2 H, tq, J = 7, 3 Hz), 1.77 (3 H, t, J = 3
Hz), 1.7 (1 H, br s).
IR (film): ν = 3082 w, 2977 s, 2921 s, 1700 s, 1645 m, 1541 w, 1462
s, 1407 s, 1367 s, 1250 s, 1170 s, 924 s, 774 s cm–1.

SYNTHESIS
April 1998
563
1H NMR (250 MHz, CDCl3): δ = (signals broadened by presence of
two rotomers) 5.78 (1 H, ddt, J = 17, 10, 6 Hz), 5.15 (1 H, br), 5.10 (1
H, br), 3.88 (2 H, br), 3.30 (2 H, br), 2.33 (2 H, br), 1.77 (3 H, t, J =
2 Hz), 1.46 (9 H, s).
13C NMR (67.5 MHz, CDCl3): δ = 138.67 (0), 129.16 (1), 128.39 (1),
127.23 (1), 88.04 (0), 77.37 (0), 76.49 (0), 76.24 (0), 57.88 (2), 52.72
(2), 43.09 (2), 19.52 (3), 18.15 (2), 3.65 (3).
CI-MS (NH3): m/z = 258 (MH+).
13C NMR (62.5 MHz, CDCl3): δ = (some peaks are doubled up due to
two rotomers) 155.23 (0), 134.20 (1), 116.48 (2)/115.90 (2), 79.56
(0), 76.58 (0), 76.56 (0), 50.38 (2)/49.7 (2), 46.06 (2), 28.35 (3), 18.6
(2), 3.40 (3).
N-Benzyl-N-(non-8-en-2-ynyl)-N-(pent-3-ynyl)amine (24c):
Prepared from N-benzyl-N-(pent-3-ynyl)-N-(prop-2-ynyl)amine (439
mg, 2.03 mmol) by the same procedure used to prepare 9a, except that
6-iodohex-1-ene was used in place of MeI. The crude product was pu-
rified using column chromatography (petrol/Et2O, 100:0–90:10) and
Kugelrohr distillation (oven temp ~ 100°C/0.3 mbar) to yield 24c as
a clear pale-yellow oil (483 mg, 1.65 mmol, 82%).
Thermospray mass spectrum (+ ve ion filament on), m/z = 224 (MH+).
Analysis: calcd for C13H21NO2 (223.3) C, 69.92; H, 9.48; N, 6.27;
found: C, 70.23; H, 9.65; N, 6.50.
N-Benzyl-N-(pent-3-ynyl)-N-(prop-2-ynyl)amine:
IR (film): ν = 3064 w, 3028 w, 2920 s, 2838 m, 1640 w, 1603 w, 1495
m, 1453 m, 1364 m, 1326 m, 699 s cm–1.
Prepared from propargyl bromide (80% by wt. in toluene, 1.49 g,
10 mmol) and N-benzyl-N-(pent-3-ynyl)amine (1.73 g, 10 mmol) by
the same method used to form 1. The crude product was purified us-
ing column chromatography (petrol/Et2O, 100:0–95:5) and Kugelro-
hr distillation (oven temp ~ 80°C/0.8 mbar) to yield the title amine as
a clear colourless oil (1.51 g, 7.15 mmol, 72%).
1H NMR (270 MHz, CDCl3): δ = 7.20–7.35 (5 H, m), 5.82 (1 H, ddt,
J = 17, 10, 7 Hz), 5.03 (1 H, d + fs, J = 17 Hz), 4.97 (1 H, d + fs, J =
10 Hz), 3.64 (2 H, s), 3.30 (2 H, t, J = 2 Hz), 2.70 (2 H, t, J = 7 Hz),
2.33 (2 H, m), 2.24 (2 H, m), 2.09 (2 H, d + fs, J = 7 Hz), 1.77 (3 H,
t, J = 3 Hz), 1.50–1.60 (4 H, m).
13C NMR (67.5 MHz, CDCl3): δ = 138.81 (0), 138.58 (1), 129.06 (1),
128.23 (1), 127.03 (1), 114.62 (2), 85.35 (0), 77.39 (0), 76.18 (0),
74.55 (0), 57.81 (2), 52.64 (2), 41.95 (2), 33.29 (2), 28.43 (2), 28.09
(2), 18.58 (2), 18.02 (2), 3.52 (3).
IR (film): ν = 3288 s, 3060 w, 3026 m, 2915 s, 2830 m, 1600 w, 1493
m, 1452 s, 1358 m, 1327 m, 738 s, 699 s cm–1.
1H NMR (270 MHz, CDCl3): δ = 7.20–7.35 (5 H, m), 3.64 (2 H, s),
3.33 (2 H, d, J = 2 Hz), 2.71 (2 H, t, J = 7 Hz), 2.32 (2 H, tq, J = 7,
3 Hz), 2.23 (1 H, t, J = 2 Hz), 1.76 (3 H, t, J = 3 Hz).
CI-MS (NH3): m/z = 294 (MH+).
13C NMR (67.5 MHz, CDCl3): δ = 138.59 (0), 129.09 (1), 128.36 (1),
127.22 (1), 78.53 (1), 77.29 (0), 76.45 (0), 73.36 (0), 57.73 (2), 52.59
(2), 41.56 (2), 18.12 (2), 3.60 (3).
HRMS (CI, NH3): m/z found 294.2235 (MH+), C21H28N requires
294.2222.
+
CI-MS (NH3): m/z = 212 (MH ).
Zirconocene-Induced Cocyclisations
(3S*,4S*)- and (3S*,4R*)-1-Benzyl-3,4-dimethylpiperidine (3a
and 3b):
N-Benzyl-N-(but-2-ynyl)-N-(pent-3-ynyl)amine (24a):
Prepared from N-benzyl-N-(pent-3-ynyl)-N-(prop-2-ynyl)amine
(10.2 mmol) by the same procedure used to form 9a. The crude prod-
uct was purified using column chromatography (petrol/Et2O, 100:0–
90:10) and Kugelrohr distillation (oven temp ~ 70°C/0.4 mbar) to
yield 24a as a clear colourless oil (1.98 g, 8.81 mmol, 86%).
IR (film): ν = 3062 m, 3028 m, 2918 s, 2830 s, 2271 w, 2195 w, 1602
w, 1586 w, 1494 m, 1453 s, 1364 m, 1329 m, 738 s, 699 s cm–1.
1H NMR (270 MHz, CDCl3): δ = 7.20–7.35 (5 H, m), 3.63 (2 H, s),
3.27 (2 H, q, J = 2 Hz), 2.69 (2 H, t, J = 8 Hz), 2.31 (2 H, tq, J = 8, 2
Hz), 1.84 (3 H, t, J = 2 Hz), 1.76 (3 H, t, J = 2 Hz).
According to the procedure developed by Negishi et al.;2c to a solu-
tion of Cp2ZrCl2 (614 mg, 2.1 mmol) in THF (7 mL) at –78°C under
argon, was slowly added BuLi (2.5 M in hexanes, 1.68 mL, 4.2
mmol). After stirring for 1 h at –78°C, amine 1 (403 mg, 2 mmol) in
THF (3 mL) was added. The yellow solution was warmed to r.t. over
2 h and stirred for a further 2 h to give a solution of the zirconacycles
2a and 2b. MeOH (0.5 mL) was added to the resultant dark-brown so-
lution causing an immediate colour change to yellow. The mixture
was diluted with sat. NaHCO3 solution (5 mL) and Et2O (10 mL), the
layers separated, and the aqueous layer extracted with Et2O (3 × 50
mL). The combined organic extracts were dried (K2CO3) and concen-
trated in vacuo to yield a cloudy yellow oil. Analysis by GC (BP1, 25
m column, 150°C) showed that 3a and 3b were present in an 80:20
ratio. The crude product was purified, and the diastereoisomers par-
tially separated by column chromatography (petrol/Et3N, 97:3). Sub-
sequent Kugelrohr distillation (oven temp ~ 85°C/0.5 mbar) of the
enriched mixtures afforded clear colourless oils (371 mg, 1.82 mmol,
91% combined yield).
13C NMR (67.5 MHz, CDCl3): δ = 138.87 (0), 129.09 (1), 128.29 (1),
127.08 (1), 80.77 (0), 77.45 (0), 76.31 (0), 73.76 (0), 57.88 (2), 52.59
(2), 42.07 (2), 18.04 (2), 3.58 (3), 3.55 (3).
CI-MS (NH3): m/z = 226 (MH+).
HRMS (CI, NH3): m/z found 226.1583 (MH+), C16H20N requires
226.1596.
N-Benzyl-N-(3-methylsulphanylprop-2-ynyl)-N-(pent-3-
ynyl)amine (24b):
BuLi (2.5 M in hexanes, 0.70 mL, 10 mmol) was added dropwise to
a stirred solution of N-benzyl-N-(pent-3-ynyl)-N-(prop-2-ynyl)amine
(2.109 g, 9.98 mmol) in THF (20 mL) at –55°C under argon. After
5 min Me2S2 (1.32 g, 14 mmol, 1.4 equiv) was added, the yellow solu-
IR of a ~ 1:1 mix of two diastereoisomers (film): ν = 3062 w, 3026
w, 2953 s, 2923 s, 2873 s, 2798 m, 2757 m, 1598 w, 1494 w, 1453 m,
1367 m, 698 s cm–1.
3a (obtained pure):
1H NMR (270 MHz, CDCl3): δ = 7.19–7.33 (5 H, m), 3.50 (1 H, d, J
= 13 Hz), 3.38 (1 H, d, J = 13 Hz), 2.55 (1 H, br m), 2.35 (1 H, br m),
2.10–2.30 (2 H, br m), 1.60–1.80 (2 H, m), 1.40–1.60 (2 H, m), 0.89
(3 H, d, J = 7 Hz), 0.85 (3 H, d, J = 7 Hz).
tion warmed to r.t. and stirred for 18 h. Sat. NaHCO solution (8 mL)
3
and Et2O (20 mL) were added, the layers separated, and the aqueous
phase extracted with Et2O (2 × 20 mL). The combined organic phases
were dried (K2CO3) and the solvent removed to give a yellow oil. The
crude product was purified using column chromatography (neutral alu-
minium oxide, Brockmann grade II, petrol/Et2O, 100:0–97:3) and
Kugelrohr distillation (oven temp ~ 100°C/0.5 mbar) to yield 24b as a
clear pale-yellow oil (2.44 g, 9.48 mmol, 95%).
13C NMR (67.5 MHz, CDCl3): δ = 139.29 (0), 128.99 (1), 128.19 (1),
126.82 (1), 63.51 (2), 58.91 (2), 52.45 (2), 33.98 (1), 32.65 (1), 30.65
(2), 16.53 (3), 14.02 (3).
EI-MS: m/z (%) = 203 (M+, 46), 202(47), 126 (27), 112(36), 91 (100).
HRMS (EI): m/z found 203.1668 (M+), C14H21N requires 203.1674.
IR (film): ν = 3062 w, 3028 w, 2918 s, 2829 m, 2172 w, 1602 w, 1494
w, 1453 m, 1432 m, 1358 m, 1324 m, 738 s, 699 s cm–1.
3b (from mixture with 3a):
1H NMR (300 MHz, CDCl3): δ = 3.48 (2H, s), 2.85 (1H, ddt, J = 11,
4, 2 Hz), 2.77 (1H, ddd, J = 11, 4, 2 Hz), 1.90 (1H, ddd, J = 12.5, 11,
3 Hz), 0.82 (3H, d, J = 7 Hz). Other signals obscured by 3a.
1H NMR (270 MHz, CDCl3): δ = 7.20–7.35 (5 H, m), 3.65 (2 H, s),
3.43 (2 H, s), 2.71 (2 H, t, J = 8 Hz), 2.39 (3 H, s), 2.32 (2 H, tq, J =
8, 3 Hz), 1.77 (3 H, t, J = 3 Hz).

SYNTHESIS
Papers
564
13C NMR (67.5 MHz, CDCl3): δ = 138.68 (0), 129.34 (1), 128.23 (1),
126.96 (1), 63.59 (2), 62.00 (2), 54.38 (2), 37.73 (1), 37.63 (1), 34.75
(2), 19.49 (3), 17.36 (3).
product was purified using column chromatography (petrol/Et2O/
Et3N, 100:0:0–90:10:0–85:10:5) and Kugelrohr distillation (oven
temp ~ 50°C/0.5 mbar) to yield 10b as a clear colourless oil (215 mg,
0.787 mmol, 64%).
IR (film): ν = 3086 w, 3064 w, 3028 w, 2955 s, 2846 m, 2796 m, 2748
m, 1619 m, 1496 w, 1455 m, 1389 w, 1376 w, 1339 w, 1248 s, 859 s,
838 s, 698 s cm–1.
Synthesis of 3a and 3b from 6:
BuLi (2.5 M in hexanes, 0.48 mL, 1.20 mmol) was added dropwise to
a solution of Cp2ZrCl2 (173 mg, 0.592 mmol) in THF (2 mL) at
–78°C under argon. After stirring for 1 h at –78°C, N-allyl-N-(but-3-
enyl)amine25 (6; 33 mg, 0.30 mmol) in THF (1 mL) was added and the
mixture was warmed to r.t. After 2 h, the resultant orange solution was
quenched with MeOH (1 mL) containing H2O (40 mg). Benzyl bro-
mide (56 mg, 0.33 mmol) and K2CO3 (80 mg, 0.58 mmol) in MeCN (1
mL) were added and the mixture left to stir overnight. The mixture was
diluted with sat. NaHCO3 solution (5 mL) and Et2O (10 mL), and was
worked up as normal to yield a cloudy yellow oil. Hexamethylbenzene
(7.0 mg, internal NMR standard) was added and the mixture analysed
by 1H NMR spectroscopy. NMR yield 50% (cis/trans, 80:20).
1H NMR (270 MHz, CDCl3): δ = 7.20–7.30 (5 H, m), 5.18 (1 H, d, J
= 2 Hz), 3.59 (1 H, d, J = 12 Hz), 3.37 (1 H, d, J = 12 Hz), 3.36 (1 H,
d, J = 12 Hz), 2.90 (1 H, d + fs, J = 11 Hz), 2.47 (1 H, d, J = 12 Hz),
2.25 (1 H, td, J = 11, 3 Hz), 2.06 (1 H, m), 1.72 (1 H, ddt, J = 13, 5, 4
Hz), 1.38 (1 H, dtd, J = 13, 11, 4 Hz), 1.03 (3 H, d, J = 7 Hz), –0.10
(9 H, s with superimposed doublet (J = 3 Hz) due to 5% 29Si).
13C NMR (67.5 MHz, CDCl3): δ = 157.80 (0), 138.42 (0), 129.74 (1),
128.31 (1), 127.23 (1), 119.89 (1) superimposed upon doublet (J ~ 30
Hz) due to 5% 29Si, 63.68 (2), 58.90 (2), 54.18 (2), 38.30 (1), 34.93
(2), 18.14 (3), 0.33 (3) superimposed upon doublet (J = 26 Hz) due to
5% 29Si.
1-Benzyl-3,3,4-trimethylpiperidine (8):
CI-MS (NH3): m/z = 274 (MH+).
Prepared from 7 (2 mmol) by the same procedure used to form 3. The
zirconabicycle solution became dark brown after 2 h at r.t. After stan-
dard quenching and workup procedures, the resultant cloudy yellow
oil was purified using column chromatography (petrol/Et3N, 100:0–
95:5) and Kugelrohr distillation (oven temp ~ 40°C/0.5 mbar) to yield
8 as a clear colourless oil (320 mg, 1.47 mmol, 70%).
HRMS (CI, NH3): m/z found 274.1982 (MH+), C17H28NSi requires
274.1991.
Analysis: calcd for C17H27NSi (273.5) C, 74.66; H, 9.95; N, 5.12;
found: C, 74.67; H, 10.04; N, 4.76.
4-Methyl-3-[(Z)-phenylmethylene]-1-propylpiperidine (10c):
Prepared from 9c (2 mmol) by the same procedure used to form 3. Af-
ter standard quenching and workup procedures, the cloudy brown oil
was filtered through silica gel (petrol/Et3N, 99:1) and Kugelrohr dis-
tilled (oven temp ~ 60°C/0.4 mbar) to yield 10c as a clear colourless
oil (403 mg, 1.76 mmol, 88%).
IR (film): ν = 3060 w, 3024 w, 2952 s, 2868 m, 2795 m, 2749 m,
1596 w, 1493 m, 1451 m, 1362 m, 737 s, 697 s cm–1.
1H NMR (270 MHz, CDCl3): δ = (all signals were broad) 7.20–7.35
(5 H, m), 3.49 (1 H, d, J = 14 Hz), 3.33 (1 H, d, J = 14 Hz), 2.81 (1 H,
d, J = 11 Hz), 2.37 (1 H, d, J = 11 Hz), 1.91 (1 H, t, J = 11 Hz), 1.63
(1 H, d, J = 11 Hz), 1.40–1.50 (2 H, m), 1.16 (1 H, m), 0.88 (3 H, s),
0.81 (3 H, d, J = 7 Hz), 0.78 (3 H, s).
IR (film): ν = 3055 w, 3022 w, 2957 s, 2930 s, 2872 m, 2800 m, 2756
m, 1654 w, 1599 w, 1490 w, 1459 m, 1380 m, 700 s cm–1.
1H NMR (270 MHz, CDCl3): δ = 7.15–7.32 (5 H, m), 6.30 (1 H, s),
3.72 (1 H, d, J = 12 Hz), 2.88 (1 H, dtd, J = 11.4, 4, 1.5 Hz), 2.51 (1
H, d, J = 12 Hz), 2.2–2.4 (4 H, m), 1.83 (1 H, dtd, J = 12.9, 4.6, 3.3
Hz), 1.4–1.6 (1 H, obscured multiplet), 1.45 (2 H, sextet, J = 7 Hz),
1.17 (3 H, d, J = 7 Hz), 0.85 (3 H, t, J = 7 Hz).
13C NMR (67.5 MHz, CDCl3): δ = 139.66 (0), 128.80 (1), 128.23 (1),
126.79 (1), 67.50 (2), 63.33 (2), 55.17 (2), 39.68 (1), 33.86 (0), 31.34
(2), 27.44 (3), 19.42 (3), 15.76 (3).
EI-MS: m/z (%) = 120 (55), 91 (100) (M+ was not seen).
The maleate salt of 8 was prepared by heating with maleic acid (0.9
equiv), followed by recrystallisation from acetone/Et2O; mp 120–122°C.
Analysis: calcd for C19H27NO4 (333.4) C, 68.44; H, 8.16; N, 4.20;
found C, 68.37; H, 8.11; N > 4.43.
13C NMR (67.5 MHz, CDCl3): δ = 142.45 (0), 138.11 (0), 129.24 (1),
128.11 (1), 126.26 (1), 121.89 (1), 60.97 (2), 54.55 (2), 53.77 (2),
36.91 (1), 35.04 (2), 20.28 (2), 18.21 (3), 12.16 (3).
EI-MS: m/z (%) = 230 (15), 229 (M+, 83), 228 (47), 214 (35), 200
(100), 158 (55), 138 (35).
1-Benzyl-3-[(Z)-ethylidene]-4-methylpiperidine (10a):
Prepared from 9a (0.91 mmol) by the same procedure used to prepare
3. The THF solution of the intermediate zirconabicycle was orange/
brown. Following standard quenching and workup procedures, the
crude product was purified using column chromatography (petrol/
Et2O/Et3N, 100:0:0–90:10:0–85:10:5) and Kugelrohr distillation (ov-
en temp ~ 40°C/0.5 mbar) to yield 10a as a clear colourless oil
(156 mg, 0.727 mmol, 80%).
HRMS (EI): m/z found 229.1822 (M+), C16H23N requires 229.1830.
(2R*,4R*)- and (2R*,4S*)-2-Isopropyl-4-methyl-5[(Z)-phenyl-
methylene]-1-propylpiperidine (12a and 12b):
Prepared from 11 (2 mmol) by the same procedure used to form 3, ex-
cept that the THF solution was stirred at r.t. for only 1 h and became dark
green rather than brown. MeOH (2 mL), sat. NaHCO3 solution (10 mL)
and Et2O (10 mL) were added, and the mixture was worked up as nor-
mal. GC analysis ( 25 m BP1 column, 200°C isothermal) showed that
the crude product contained 12a and 12b in the ratio 40:60. The crude
product was purified, and the diastereoisomers separated by column
chromatography (petrol/Et3N, 99.5:0.5). Subsequent Kugelrohr distilla-
tion (oven temp ~ 110°C/0.5 mbar) afforded 12a (197 mg, 0.73 mmol,
36%) and 12b (295 mg, 1.09 mmol, 55%) as clear colourless oils.
IR of ~ 1:1 mix of diastereoisomers (film): ν = 3055 w, 3022 w, 2957 s,
2931 s, 2870 m, 1648 w, 1598 w, 1492 w, 1458 m, 1381 m, 700 s cm–1.
IR (film): ν = 3060 w, 3022 w, 2954 s, 2924 s, 2869 m, 2842 m, 2791
m, 1602 w, 1493 w, 1452 m, 1364 w, 1343 w, 1304 w, 734 s, 697 s
cm–1.
1H NMR (270 MHz, CDCl3): δ = 7.20–7.35 (5 H, m), 5.23 (1 H, q, J
= 7 Hz), 3.55 (2 H, s), 3.53 (1 H, d, J = 12 Hz), 2.82 (1 H, dt, J = 11,
4 Hz), 2.43 (1 H, d, J = 12 Hz), 2.24 (1 H, td, J = 11, 3 Hz), 2.04 (1
H, m), 1.69 (1 H, dq, J = 13, 4 Hz), 1.54 (3 H, d, J = 7 Hz), 1.33 (1 H,
dtd, J = 13, 11, 4 Hz), 1.03 (3 H, d, J = 7 Hz).
13C NMR (67.5 MHz, CDCl3): δ = 139.34 (0), 138.39 (0), 129.34 (1),
128.21 (1), 127.03 (1), 115.53 (1), 63.13 (2), 53.36 (2), 53.26 (2),
36.31 (1), 34.80 (2), 18.01 (3), 12.80 (3).
12a:
EI-MS: m/z (%) = 215 (M+, 75), 200 (70), 186 (19), 158 (35), 124
(17), 91 (100), 82 (36).
1H NMR (270 MHz, CDCl3): δ = 7.15–7.35 (5 H, m), 6.34 (1 H, s),
3.97 (1 H, d, J = 13 Hz, H-6eq), 2.79 (1 H, d, J = 13 Hz, H-6ax), 2.44
(1 H, ddd, J = 12.8, 9.2, 6.4 Hz, NCH2), 2.29 (2 H, m, H-2 & H-4),
2.20 (1 H, ddd, J = 12.8, 9.2, 6.0 Hz, NCH2), 1.89 (1 H, octet, J = 6.6
Hz, CHMe2), 1.71 (1 H, ddd, J = 12.8, 4.5, 2.7 Hz, H-3eq), 1.20–1.40
HRMS (EI): m/z found 215.1695 (M+), C15H21N requires 215.1674.
1-Benzyl-4-methyl-3-[(Z)-trimethylsilylmethylene]piperidine
(10b):
(2 H, m, NCH CH2Me), 1.17 (3 H, d, J = 7 Hz, C4-CH3), 1.12 (1 H,
2
q, J = 13 Hz, H-3ax), 0.93 [3 H, d, J = 7 Hz, (CH3)2CH], 0.87 [3 H, d,
J = 7 Hz, (CH3)2CH), 0.75 (3 H, t, J = 7 Hz).
Prepared from 9b (1.23 mmol) by the same procedure used to form 3.
Following standard quenching and workup procedures, the crude

SYNTHESIS
April 1998
565
13C NMR (67.5 MHz, CDCl3): δ = 142.71 (0), 138.38 (0), 129.18 (1),
128.07 (1), 126.11 (1), 121.49 (1), 66.91 (1, C-2), 53.16 (2, C-6),
51.95 (2, NCH2Et), 36.90 (1, C-4), 34.65 (2, C-3), 28.61 (1, CHMe2),
20.51 (3), 19.36 (2, MeCH2CH2N), 18.40 (3), 17.43 (3), 12.05 [3,
CH3(CH2)2N].
Analysis: calcd for C15H21N (215.3) C, 83.67; H, 9.83; N, 6.50;
found: C, 83.65; H, 9.50; N, 6.40.
2-Benzyl-2,3,4,6,7,7a-hexahydro-5-methyl-1H-cyclopenta[c]pyri-
din-6-one (17):
EI-MS: m/z (%) = 271 (M+, <1), 228 (100), 143 (17).
To Cp2ZrCl2 (307 mg, 1.05 mmol) in THF (4 mL) at –78°C under ar-
gon, was slowly added BuLi (2.5 M in hexanes, 0.84 mL, 2.1 mmol).
After stirring for 1 h at –78°C, 15 (213 mg, 1 mmol) in THF (1 mL)
was added. The yellow solution was warmed to r.t. over 2 h and
stirred for a further 3 h. The orange/brown THF solution was cooled
to 0°C and the reaction flask was evacuated and refilled 3 times with
CO to a slight positive pressure generated by a double-walled bal-
loon.2c The solution was warmed to r.t. overnight. MeOH (2 mL) was
added and the mixture was concentrated in vacuo to yield a cloudy
yellow oil. Column chromatography (petrol/Et2O, 50:50–0:100) and
Kugelrohr distillation (oven temp ~ 130°C/0.5 mbar) afforded 17 as
a pale-yellow oil (68 mg, 0.28 mmol, 28%).
HRMS (EI): m/z found 271.2300 (M+), C19H29N requires 271.2300.
12b:
1H NMR (300 MHz, CDCl3): δ = 7.10–7.35 (5 H, m), 6.36 (1 H, s),
3.54 (1 H, d, J = 14 Hz, H-6ax), 3.35 (1 H, d, J = 14 Hz, H-6eq), 2.56
(1 H, qdd, J = 7, 6, 4 Hz, H-4), 2.25–2.40 (3 H, m, EtCH2N, H-2), 2.01
(1 H, octet, J = 7 Hz, CHMe2), 1.71 (1 H, ddd, J = 13, 6, 5 Hz, H-3eq),
1.54 (1 H, ddd, J = 13, 8, 4 Hz, H-3ax), 1.10–1.30 (2 H, obscured,
NCH2CH2Me), 1.17 (3 H, d, J = 6 Hz, C4-CH3), 0.98 [3 H, d, J =
7 Hz, (CH3)2CH], 0.90 [3 H, d, J = 7 Hz, (CH3)2CH], 0.73 (3 H, t, J =
7 Hz). Axial and equatorial assignments refer to the confomer with
Me group equatorial, i-Pr group axial (Figure 2).
IR (film): ν = 3060 w, 3026 w, 2945 m, 2919 m, 2798 m, 2758 w,
1701 s, 1656 s, 1494 w, 1453 m, 1410 w, 1385 m, 1353 m, 1329 w,
734 s, 700 s cm–1.
13C NMR (67.5 MHz, CDCl3): δ = 142.71 (0), 138.19 (0), 129.06 (1),
128.07 (1), 126.11 (1), 123.13 (1), 63.10 (1, C-2), 53.40 (2, NCH2Et),
47.80 (2, C-6), 34.50 (1, C-4), 31.93 (2, C-3), 27.94 (1, CHMe2),
20.86 (3), 20.70 (2, MeCH2CH2N), 19.66 (3), 19.49 (3), 11.90 [3,
CH3(CH2)2N].
1H NMR (300 MHz, CDCl3): δ = 7.20–7.50 (5 H, m), 3.61 (1 H, d, J
= 13 Hz, CH2Ph), 3.54 (1 H, d, J = 13 Hz, CH2Ph), 3.21 (1 H, ddd, J
= 11, 6, 2 Hz, H-1), 3.12 (1 H, ddt, J = 12, 6, 2 Hz, H-3), 2.84 (1 H,
br, H-7a), 2.74 (1 H, dt, J = 14, 2 Hz, H-4), 2.48 (1 H, m obscured, H-
4), 2.45 (1 H, dd, J = 18, 7 Hz, H-7), 2.03 (1 H, td, J = 12, 3 Hz, H-
3), 1.87 (1 H, dd, J = 18, 2 Hz, H-7), 1.68 (1 H, m obscured, H-1), 1.68
(3 H, t, J = 1 Hz, CH3).
1-Benzyl-4-[(E)-ethylidene]-3,3-dimethylpiperidine (14):
BuLi (1.6 M in hexanes, 1.25 mL, 2 mmol) was added dropwise to
Cp2ZrCl2 (292 mg, 1 mmol) in THF (3 mL) under N2 at –78°C. After
stirring for 30 min, DMAP (244 mg, 2 mmol) in THF (2 mL) was add-
ed and the mixture was warmed to r.t. After 1 h at r.t., the mixture had
turned from yellow to red/brown.15 A solution of 13 (114 mg,
0.50 mmol) in THF (3 mL) was added over 1 h and the mixture was
stirred for a further 2 h. MeOH (1 mL) was added and the resultant
yellow solution concentrated in vacuo to yield a cloudy yellow oil.
The crude product was purified using column chromatography
(Brockmann grade II neutral alumina, hexane/Et2O, 98:2) and Kugel-
rohr distillation (oven temp ~ 100°C/0.4 mbar) to afford 14 as a pale-
yellow oil (87 mg, 0.38 mmol, 76%).
13C NMR (75 MHz, CDCl3): δ = 208.42 (0), 172.93 (0), 138.02 (0),
133.43 (0), 129.03 (1), 128.36 (1), 127.28 (1), 62.30 (2, CH Ph),
2
60.29 (2, C-1), 53.19 (2, C-3), 39.27 (1, C-7a), 38.28 (2, C-7), 28.43
(2, C-4), 7.67 (3).
EI-MS: m/z (%) = 241 (M+, 88), 198 (16), 164 (28), 150 (37), 91
(100), 65 (17), 42 (32).
HRMS (EI): m/z found 241.1466 (M+), C16H19NO requires 241.1467.
tert-Butyl 4-[(E)-Ethylidene]-3-methylpiperidine-1-carboxylate
(19):
IR (CHCl3): ν = 3064 w, 2961 s, 2929 m, 2866 m, 2800 m, 1621 m,
Prepared from 18 (0.66 mmol) using the same procedure used to form
3, except that the orange zirconabicycle solution was stirred at r.t.
overnight. After adding MeOH (1 mL) the mixture was worked up as
normal to yield a cloudy yellow oil. The crude product was purified
by column chromatography (hexane/Et2O, 90:10) and Kugelrohr dis-
tillation (oven temp ~ 110°C/0.4 mbar) to afford 19 as a clear colour-
less oil (89 mg, 0.40 mmol, 60%).
1495 w, 1465 m, 1455 m, 1435 m, 1361 m cm–1.
1H NMR (250 MHz, CDCl3): δ = 7.20–7.35 (5 H, m), 5.23 (1 H, q, J
= 7 Hz), 3.45 (2 H, s), 2.25–2.45 (4 H, m), 2.07 (2 H, s), 1.57 (3 H, d,
J = 7 Hz), 1.06 (6 H, s).
13C NMR (62.5 MHz, CDCl3): δ = 144.20 (0), 139.52 (0), 128.87 (1),
128.28 (1), 126.89 (1), 113.35 (1), 67.27 (2), 63.04 (2), 55.55 (2),
37.31 (0), 26.67 (3), 25.17 (2), 13.07 (3).
IR (CHCl3): ν = 3008 m, 2965 s, 2929 s, 2865 m, 1680 s, 1467 m,
+
1456 m, 1430 s, 1367 m cm–1.
EI-MS: m/z (%) = 229 (M , 72), 228 (48), 138 (36), 134 (45), 91
1H NMR (250 MHz, CDCl3): δ = (signals broadened by presence of
two rotomers) 5.27 (1 H, q, J = 7 Hz), 3.6 (2 H, br), 3.3 (1 H, br), 3.0
(1 H, br), 2.4 (1 H, dt, J = 13, 5 Hz), 2.23 (1 H, m), 2.05 (1 H, br), 1.61
(3 H, d, J = 7 Hz), 1.48 (9 H, s), 1.02 (3 H, d, J = 6 Hz).
13C NMR (62.5 MHz, CDCl3): δ = (signals broadened by presence of
two rotomers) 155.11 (0), 139.87 (0), 115.67 (1), 79.42 (0), 51.94 (2,
br), 44.47 (2, br), 38.14 (1, br), 28.57 (3), 26.27 (2, br), 16.18 (3, br),
12.77 (3).
(100).
HRMS (EI): m/z found 229.1819 (M+), C16H23N requires 229.1830.
1-Benzyl-4-[(E)-ethylidene]-3-methylpiperidine (16):
Prepared from 15 (2 mmol) by the same procedure used to form 3.
The THF solution of the zirconabicycle became deep red at ~ 0°C.
After standard quenching and workup procedures, the resultant
cloudy yellow oil was purified by column chromatography (petrol/
Et3N, 97:3) and Kugelrohr distillation (oven temp ~ 40°C/0.4 mbar)
to yield 16 as a clear colourless oil (374 mg, 1.74 mmol, 87%).
IR (film): ν = 3062 w, 3026 w, 2956 s, 2900 m, 2795 m, 1670 w, 1602
w, 1494 w, 1464 w, 1453 m, 1358 m, 698 s cm–1.
CI-MS (NH3): m/z = 226 (MH+).
HRMS (CI, NH3): m/z found 226.1815 (MH+), C13H24NO2 requires
226.1807.
1H NMR (270 MHz, CDCl3): δ = 7.20–7.35 (5 H, m), 5.17 (1 H, q, J
= 7 Hz), 3.52 (1 H, d, J = 13 Hz), 3.45 (1 H, d, J = 13 Hz), 2.60–2.70
(2 H, m), 2.51 (1 H, m), 2.3 (1 H, br), 2.00–2.20 (2 H, m), 1.84 (1 H,
dd, J = 10, 9 Hz), 1.58 (3 H, d, J = 7 Hz), 1.00 (3 H, d, J = 7 Hz).
13C NMR (67.5 MHz, CDCl3): δ = 141.11 (0), 138.87 (0), 129.22 (1),
128.29 (1), 127.02 (1), 113.86 (1), 63.12 (2), 62.53 (2), 54.94 (2),
37.50 (1), 27.40 (2), 16.51 (3), 12.84 (3).
tert-Butyl 4-[(Z)-1-Iodoethylidene]-3-iodomethylpiperidine-1-carb-
oxylate (20):
The zirconabicycle was formed from 18 (112 mg, 0.5 mmol) by the
same procedure used to form 2. After stirring the THF solution at r.t.
for 2 h, the solution was cooled to –78°C and I2 (380 mg, 1.5 mmol)
in THF (2 mL) was added. After 1 h at –78°C, the mixture was
warmed to r.t. and stirred for a further 1 h. Sat. NaHCO3 solution
(5 mL) and Et2O (10 mL) were added and the mixture was shaken
well and separated. The aqueous phase was extracted with Et2O
(3 × 10 mL) and the combined organic layers were washed with
EI-MS: m/z (%) = 215 (M+, 86), 214 (58), 138 (36), 124 (53), 91
(100), 42 (34).
HRMS (EI): m/z found 215.1659 (M+), C15H21N requires 215.1674.

SYNTHESIS
Papers
566
Na2S2O3 solution (2 × 10 mL), dried (Na2SO4), filtered and concen-
trated in vacuo to form a light-brown solid. The crude product was pu-
rified using column chromatography (petrol/Et2O, 95:5) to yield 20 as
a white solid (75 mg, 0.15 mmol, 30%). Recrystallisation (hexane)
gave colourless needles; mp 75–78°C.
dard quenching and workup procedures, the crude product was puri-
fied by column chromatography (petrol/Et2O, 95:5) to yield 25c as a
yellow oil (178 mg, 0.602 mmol, 70%).
IR (film): ν = 3063 w, 3027 w, 2926 s, 2856 m, 2795 m, 2753 w, 1640
w, 1494 w, 1454 m, 1358 w, 699 s cm–1.
IR (nujol): ν = 1682 m, 1424 m, 1364 w, 1324 w, 1156 m cm–1.
1H NMR (300 MHz, CDCl3): δ = (All signals were broad due to two
rotomers) 4.35 (1 H, d, J = 16 Hz), 4.1 (1 H, br), 3.2 (3 H, br), 2.97 (1
H, d, J = 16 Hz), 2.70 (2 H, d, J = 15 Hz), 2.58 (3 H, s), 2.10 (1 H, t,
J = 15 Hz), 1.50 (9 H, s).
1H NMR (270 MHz, CDCl3): δ = 7.20–7.35 (5 H, m), 5.78 (1 H, ddt,
J = 17, 10, 7 Hz), 5.50 (1 H, q, J = 7 Hz), 5.44 (1 H, t, J = 8 Hz), 4.97
(1 H, d + fs, J = 17 Hz), 4.92 (1 H, d + fs, J = 10 Hz), 3.57 (2 H, s),
3.06 (2 H, s), 2.54 (2 H, t, J = 6 Hz), 2.32 (2 H, t, J = 6 Hz), 1.90–2.00
(4 H, m), 1.61 (3 H, d, J = 7 Hz), 1.30–1.35 (4 H, m).
13C NMR (75 MHz, CDCl3): δ = 155.14 (0), 139.88 (0), 98.03 (0),
80.44 (0), 52.04 (1, br), 46.53 (2), 43.29 (2, br), 30.02 (3), 28.58 (3),
26.18 (2), 5.67 (2).
13C NMR (67.5 MHz, CDCl3): δ = 139.08 (1), 138.58 (0), 138.45 (0),
137.26 (0), 129.24 (1), 128.29 (1), 127.11 (1), 123.69 (1), 117.26 (1),
114.41 (2), 62.59 (2), 54.24 (2), 53.14 (2), 33.78 (2), 29.34 (2), 28.59
(2), 27.31 (2) - two superimposed peaks, 13.33 (3).
CI-MS (NH3): m/z = 495 (MNH4 ), 478 (MH+).
+
HRMS (CI, NH3): m/z found 477.9739 (MH+), C13H22I2NO2 requires
477.9740.
CI-MS (NH3): m/z = 296 (MH+).
HRMS (EI): m/z found: 295.2280 (M ), C21H29N requires 295.2300.
+
Analysis: calcd for C13H21I2NO2 (477.3) C, 32.72; H, 4.40; N, 2.94;
found: C, 32.45; H, 4.41; N, 2.90.
Cycloaddition Reactions
(3aR*,4S*,9R*,9aS*)-6-Benzyl-2,3,3a,4,5,6,7,8,9,9a-decahydro-4,9-
dimethyl-2-phenyl-1H-pyrrolo[3,4-g]isoquinoline-1,3-dione (26):
Compound 25a (248 mg, 1.10 mmol) in Et2O (1 mL) was added drop-
wise to N-phenylmaleimide (172 mg, 0.99 mmol) in Et2O (5 mL).The
yellow solution was stirred at r.t. for 3 h before concentration in vacuo
to give a light-brown solid. The crude product was purified by column
chromatography (EtOAc/hexane, 80:20) to yield 26 as an unstable or-
ange/brown solid (375 mg, 0.94 mmol, 94%).
1-Benzyl-4-[(E)-ethylidene]-3-[(Z)-ethylidene]piperidine (25a):
Prepared from 24a (9.98 mmol) by the same procedure used to form 3.
The zirconabicycle solution became dark brown as it was warmed to r.t.
After standard quenching and workup procedures, the crude product
was purified by column chromatography (petrol/Et2O/Et3N, 100:0:0–
85:10:5) and Kugelrohr distillation (oven temp ~ 90°C/0.6 mbar) to
yield 25a as a clear pale-yellow oil (1.72 g, 7.56 mmol, 77%).
IR (film): ν = 3027 m, 2951 s, 2914 s, 2859 m, 2795 s, 2755 m, 1656
w, 1604 w, 1494 m, 1454 s, 1379 m, 1356 m, 738 s, 699 s cm–1.
1H NMR (270 MHz, CDCl3): δ = 7.15–7.35 (5 H, m), 5.51 (1 H, q, J
= 7 Hz), 5.49 (1 H, q, J = 7 Hz), 3.56 (2 H, s), 3.08 (2 H, s), 2.52 (2
H, t, J = 6 Hz), 2.30 (2 H, t, J = 6 Hz), 1.59 (3 H, d, J = 7 Hz), 1.55 (3
H, d, J = 7 Hz).
IR (CHCl3): ν = 3027 w, 3011 w, 1709 s, 1600 w, 1500 w, 1457 w,
1385 m cm–1.
1H NMR (250 MHz, CDCl3): δ = 7.10–7.50 (10 H, m), 3.61 (1 H, d,
J = 12 Hz, CH2Ph), 3.54 (1 H, d, J = 12 Hz, CH2Ph), 3.18 (1 H, d, J
= 16 Hz, H-5), 3.12 (2 H, m, H-3a and H-9a), 2.87 (1 H, d, J = 16 Hz,
H-5), 2.50-2.80 (3 H, m, H-7, H-4 and H-9), 2.10–2.30 (3 H, m, H-7,
2 H-8), 1.44 (3 H, d, J = 7 Hz, CH3), 1.40 (3 H, d, J = 7 Hz, CH3).
13C NMR (62.5 MHz, CDCl3): δ = 176.99 (0), 176.94 (0), 138.01 (0),
132.05 (0), 132.02 (0), 131.50 (0), 129.08 (1), 129.04 (1), 128.63 (1),
13C NMR (67.5 MHz, CDCl3): δ = 138.52 (0), 138.45 (0), 137.93 (0),
129.24 (1), 128.27 (1), 127.08 (1), 117.67 (1), 117.18 (1), 62.69 (2),
54.06 (2), 53.03 (2), 27.32 (2), 13.32 (3), 13.17 (3).
EI-MS: m/z (%) = 227 (M+, 20), 212 (27), 198 (24), 91 (100).
The maleate salt of 25a was formed by heating with maleic acid
(0.9 equiv) in acetone, followed by recrystallisation (acetone/Et2O);
mp 136–137°C.
Analysis: calcd for C20H25NO4 (343.4) C, 69.95; H, 7.34; N, 4.08;
found: C, 69.78; H, 7.46; N, 4.17.
128.24 (1), 127.11 (1), 126.70 (1), 62.49 (2, CH Ph), 53.41 (2, C-5),
2
49.70 (2, C-7), 46.04 (1, C-3a or 9a), 45.82 (1, C-3a or 9a), 33.60 (1,
C-4 or 9), 33.08(1, C-4 or 9), 26.61 (2, C-8), 13.69 (3), 13.35 (3).
Thermospray MS (+ ve ion filament on), m/z = 401 (MH+).
HRMS (EI): m/z found 400.2150 (M+), C26H28N2O2 requires
400.2151.
1-Benzyl-4-[(E)-ethylidene]-3-[(Z)-(methylsulphanylmethyl-
ene]piperidine (25b):
Dimethyl (5S*,8R*)-2-Benzyl-1,2,3,4,5,8-hexahydro-5,8-dimeth-
ylisoquinoline-6,7-dicarboxylate (27):
Prepared from 24b (1.54 g, 6.00 mmol) by the same procedure used
to form 3. The zirconabicycle was quenched with MeOH (2 mL) and
the mixture filtered through basic aluminium oxide (Brockmann
grade III) with Et2O. The filtrate was concentrated in vacuo to yield a
cloudy yellow oil. Kugelrohr distillation (oven temp ~ 90°C/
0.2 mbar) of this crude mixture afforded 25b as a yellow/orange oil
(1.20 g, 4.62 mmol, 77%).
Prepared from 25a (248 mg, 1.09 mmol) and dimethyl acetylenedicar-
boxylate (170 mg, 1.19 mmol) by the same procedure used to prepare 26,
except that the reaction mixture was stirred for 24 h. The crude product
was purified by column chromatography (hexane/EtOAc, 60:40) to yield
27 as a viscous orange oil (266 mg, 0.720 mmol, 66%).
IR (CHCl3): ν = 3019 s, 1712 s, 1649 w, 1436 w, 1364 m cm–1.
1H NMR (250 MHz, CDCl3): δ = 7.20–7.40 (5 H, m), 3.78 (3 H, s),
3.76 (3 H, s), 3.65 (1 H, d, J = 12 Hz), 3.56 (1 H, d, J = 12 Hz), 3.10
(1 H, d, J = 16 Hz), 2.88 (2 H, t, J = 7 Hz), 2.77 (1 H, d, J = 16 Hz),
2.59 (2 H, m), 2.35 (1 H, d + fs, J = 16 Hz), 1.93 (1 H, d + fs, J =
16 Hz), 1.25 (3 H, d, J = 7 Hz), 1.21 (3 H, d, J = 7 Hz).
IR (film): ν = 3025 m, 2917 s, 2794 m, 2754 m, 1640 w, 1583 w,
1494 m, 1452 m, 1434 m, 1366 m, 1351 m, 1313 m, 699 s cm–1.
UV (hexane): λmax = 270 nm (ε =17 000 dm3mol–1cm–1).
1H NMR (270 MHz, CDCl3): δ = 7.20–7.35 (5 H, m), 5.99 (1 H, s),
5.53 (1 H, q, J = 7 Hz), 3.59 (2 H, s), 3.19 (2 H, s), 2.51 (2 H, t, J =
6 Hz), 2.31 (2 H, t, J = 6 Hz), 2.27 (3 H, s), 1.62 (3 H, d, J = 7 Hz).
13C NMR (67.5 MHz, CDCl3): δ = 138.26 (0), 136.98 (0), 136.46 (0),
129.37 (1), 128.31 (1), 127.16 (1), 120.22 (1), 118.32 (1), 62.51 (2),
55.57 (2), 52.06 (2), 27.15 (2), 17.71 (3), 13.53 (3).
13C NMR (62.5 MHz, CDCl3): δ = 168.37 (0), 168.10 (0), 139.14 (0),
138.03 (0), 137.98 (0), 129.15 (1), 128.90 (0), 128.76 (0), 128.22 (1),
127.09 (1), 62.56 (2), 54.29 (2), 52.10 (3) - two overlapping peaks,
49.68 (2), 37.44 (1), 35.73 (1), 27.69 (2), 21.17 (3), 20.40 (3).
Thermospray MS (+ ve ion filament on), m/z = 370 (MH+).
HRMS (EI): m/z found 369.1944 (M+), C22H27NO4 requires
369.1940.
EI-MS: m/z (%) = 259 (M+, 9), 244 (48), 212 (85), 125 (17), 91 (100),
65 (11).
HRMS (EI): m/z found 259.1372 (M+), C16H21NS requires 259.1395.
1-[(5R*,7R*,8S*)-2-Benzyl-1,2,3,4,5,6,7,8,-octahydro-5-methyl-
8-(methylsulphanyl)isoquinolin-7-yl]ethan-1-one (28):
But-3-en-2-one (102 mg, 1.46 mmol) was added to 25b (290 mg,
1.12 mmol) in toluene (2 mL), and the mixture was stirred at r.t. After
1-Benzyl-4-[(E)-ethylidene]-3-[(Z)-hept-6-enylidene]piperidine (25c):
Prepared from 24c (0.96 mmol) by the same procedure used to form
3 except that only 0.9 equiv of Cp2ZrBu2 were used. Following stan-

SYNTHESIS
April 1998
567
2 d, the solution was concentrated in vacuo to form an off-white solid.
Recrystallisation (CH2Cl2/Et2O) afforded 28 as white needles (354
mg, 1.08 mmol, 96%); mp 124–126°C.
1H NMR (270 MHz, CDCl3): δ = 7.52 (1 H, s), 7.25–7.40 (5 H, m),
3.93 (3 H, s), 3.84 (3 H, s), 3.68 (2 H, s), 3.62 (2 H, s), 2.78 (4 H, s),
2.16 (3 H, s).
IR (CHCl3): ν = 3010 m, 2960 m, 2923 m, 2807 m, 1708 s, 1603 w,
13C NMR (62.5 MHz, CDCl3): δ = 170.48 (0), 166.38 (0), 139.32 (0),
138.11 (0), 136.26 (0), 133.91 (0), 129.19 (1), 128.52 (1), 127.41 (1),
126.30 (1), 124.75 (0), 62.65 (2), 56.18 (2), 52.58 (3), 52.41 (3), 50.46
(2), 27.87 (2), 15.75 (3) (one aromatic quaternary obscured).
Thermospray MS (+ ve ion filament on), m/z = 354 (MH+).
Analysis: calcd for C21H23NO4 (353.4) C, 71.37; H, 6.56; N, 3.96;
found: C, 71.24; H, 6.52; N, 3.98.
1495 w, 1456 m, 1354 m cm–1.
1H NMR (250 MHz, CDCl3): δ = 7.20–7.40 (5 H, m), 3.67 (1 H, d, J
= 12 Hz, CH2Ph), 3.54 (1 H, d, J = 12 Hz, CH2Ph), 3.40 (1 H, d, J =
12 Hz, H-1), 3.40 (1 H, obscured, H-8), 2.65–2.85 (3 H, m, H-1,H-
7,H-3), 2.30–2.45 (2 H, m, H-3, H-4), 2.20 (3 H, s, SCH3), 1.95–2.15
(2 H, m, H-5, H-6), 2.00 (3 H, s, CH3CO), 1.83 (1 H, m, H-4), 1.55 (1
H, td, J = 13, 11 Hz, H-6), 1.04 (3 H, d, J = 7 Hz, 5-CH3).
1H NMR (360 MHz, C6D6): δ = 7.66 (2 H, d, J = 7 Hz), 7.47 (2 H, t,
J = 7 Hz), 7.38 (1 H, t, J = 7 Hz), 3.794 (1 H, d, J = 13.2 Hz, CH2Ph),
3.79 (1 H, br d, J = 14 Hz, H-1), 3.600 (1 H, d, J = 13.2 Hz, CH2Ph),
3.42 (1 H, br d, J = 4 Hz, H-8), 2.87 (1 H, m, H-3), 2.82 (1 H, dq, J =
14, 2.7 Hz, H-1), 2.509 (1 H, ddd, J = 13.2, 4.4, 2.8 Hz, H-7), 2.45 (1
H, v br d, J 15 Hz, H-4), 2.389 (1 H, ddd, J = 9.3, 8, 3.5 Hz, H-3),
2.099 (3 H, s), 2.06 (1 H, obscured, H-6eq), 2.029 (3 H, s), 1.96 (1 H,
br m, H-5), 1.81 (1 H, td, J = 13, 11 Hz, H-6ax), 1.78 (1 H, br d, J
15 Hz, H-4), 1.07 (3 H, d, J = 7 Hz).
(5R*,6aS*,10aS*)-2-Benzyl-1,2,3,4,5,6,6a,7,8,9,10,10a-dodecahy-
dro-5-methylbenzo[h]isoquinoline (31):
A solution of 2,6-di-tert-butyl-p-cresol (1 mg, 5 µmol) and 25c
(118 mg, 0.40 mmol) in toluene (30 mL) was heated to reflux for 7 d
under argon. After this time, TLC showed complete consumption of
starting material. The reaction mixture was cooled, concentrated in
vacuo and purified by column chromatography (petrol/Et2O, 80:20)
and Kugelrohr distillation (oven temp ~ 130°C/0.3 mbar) to afford 31
as a pale-yellow oil (101 mg, 0.34 mmol, 85%).
13C NMR (62.5 MHz, CDCl3): δ = 209 (0), 138.10 (0), 135.02 (0),
129.15 (1), 128.18 (1), 127.04 (1), 125.66 (0), 62.51 (2, CH2Ph),
55.39 (2, C-1), 52.78 (1, C-7), 49.93 (2, C-3), 45.87 (1, C-8), 33.89
(1, C-5), 29.53 (2, C-6), 28.61 (3, SCH3), 27.76 (2, C-4), 19.35 (3, C5-
CH3), 16.01 (3, COCH3).
IR (film): ν = 3026 w, 2922 s, 2853 m, 2799 m, 1604 w, 1494 w, 1452
m, 1364 m cm–1.
1H NMR (300 MHz, CDCl3): δ = 7.20–7.50 (5 H, m), 3.61 (1 H, d, J
= 11 Hz, CH2Ph), 3.53 (1 H, d, J = 11 Hz, CH2Ph), 2.96 (1 H, d, J =
14 Hz, H-1), 2.8 (1 H, obscured, H-3), 2.78 (1 H, d, J = 14 Hz, H-1),
2.10–2.25 (2 H, m, H-3 and H-4), 2.00 (2 H, m, H-4 and H-5), 1.70–
1.90 (3 H, m), 1.56 (2 H, m, includes H-10a), 1.2–1.5 (5H, m, includes
H-6a), 1.1 (1 H, obscured), 1.04 (3 H, d, J = 7 Hz, CH3), 0.87 (1 H, q
+ fs, J = 9 Hz).
Thermospray MS (+ ve ion filament on), m/z = 330 (MH+).
Analysis: calcd for C20H27NOS (329.5) C, 72.90; H, 8.26; N, 4.25;
found: C, 72.93; H, 8.41; N, 4.29.
(3aR*,4S*,9R*,9aS*)-6-Benzyl-2,3,3a,4,5,6,7,8,9,9a-decahydro-
2,9-dimethyl-4-(methylsulphanyl)-1H-pyrrolo[3,4-g]isoquino-
line-1,3-dione (29):
Formed from 25b (279 mg, 1.08 mmol) and N-methylmaleimide
(155 mg, 1.40 mmol) by the same procedure used to form 28. The
crude product was purified by column chromatography (Brockmann
grade II neutral alumina, Et2O) to yield 29 as a viscous orange oil
(288 mg, 0.778 mmol, 72%).
13C NMR (75 MHz, CDCl3): δ = 138.38 (0), 131.28 (0), 129.51 (1),
129.01 (0), 128.31 (1), 127.12 (1), 63.38 (2, CH Ph), 54.84 (2, C-1),
2
50.11 (2, C-3), 45.71 (1, C-10a), 37.65 (2), 35.88 (1, C-6a), 33.98 (2),
33.05 (1, C-5), 29.38 (2), 29.21 (2, C-4), 27.19 (2), 26.72 (2), 20.30
(3).
HRMS (EI): m/z found 295.2285 (M+), C21H29N requires 295.2300.
A studentship from Glaxo Group Research to MIK is gratefully
acknowledged. We also thank Dr. John Langley for mass spectrome-
try, and Mrs. Joan Street for NMR studies.
IR (CHCl3): ν = 3006 w, 2922 w, 2809 m, 1702 s, 1601 w, 1496 w,
1436 m, 1385 m cm–1.
1H NMR (250 MHz, CDCl3): δ = 7.20–7.40 (5 H, m), 3.63 (1 H, d, J
= 13 Hz, CH2Ph), 3.58 (1 H, d, J = 13 Hz, CH2Ph), 3.39 (1 H, dd, J =
10, 7 Hz, H-3a), 3.31 (1 H, d, J = 7 Hz, H-4), 3.22 (1 H, d, J = 15 Hz,
H-5), 3.11 (1 H obscured, H-9a), 3.06 (1 H, d, J = 15 Hz, H-5), 3.03
(3 H, s, NCH3), 2.55–2.75 (2 H, m, H-7, H-9), 2.44 (1 H, ddd, J = 11,
7, 5 Hz, H-7), 2.26 (3 H, s, SCH3), 2.10–2.20 ( 2 H, m, 2 H-8), 1.24
(3 H, d, J = 7 Hz, C9-CH3).
(1) a) Negishi, E. In Comprehensive Organic Synthesis, 1st ed.,
Vol. 5; Trost, B.M., Ed.; Pergamon: 1991; p1163.
b) Broene, R. D. In Comprehensive Organometallic Chemistry
II; Abel, E.W.; Stone, F.G.A.; Wilkinson, G., Eds.; Pergamon:
Oxford, UK, 1995; Vol. 12; p323.
13C NMR (62.5 MHz, CDCl3): δ = 178.20 (0), 177.07 (0), 137.95 (0),
135.14 (0), 129.18 (1), 128.82 (0), 128.77 (1), 127.15 (1), 62.33 (2,
CH2Ph), 55.02 (2, C-5), 49.64 (2, C-7), 45.54 (1, C-3a), 44.82 (1, C-
4), 42.47 (1, C-9a), 32.04 (1, C-9), 28.92 (2, C-8), 24.61 (3, NCH3),
20.05 (3, SCH3), 17.23 (3, 9-CH3).
c) Negishi, E.; Takahashi, T. Acc. Chem. Res. 1994, 27, 124.
d) Negishi, E.; Ma, S.; Sugihara, T.; Noda, Y. J. Org. Chem.
1997, 62, 1922.
(2) a) Tandem allyl carbenoid/electrophile insertion: Fillery, S. F.;
Gordon, G. J.; Luker, T.; Whitby, R. J. Pure & Appl. Chem.
1997, 69, 633; Gordon, G. J.; Whitby, R. J. Chem. Commun.
1997, 1045, 1321.
Thermospray MS (+ ve ion filament on), m/z = 371 (MH+).
Analysis: calcd for C21H26N2O2S•0.3 H2O (370.5) C, 67.10; H, 7.13;
N, 7.45; found: C, 67.24; H, 7.03; N, 7.20.
b) Tandem isocyanide / rearrangement / insertion: Probert, G. D.;
Whitby, R. J.; Coote, S. J. Tetrahedron Lett., 1995, 36, 4113.
c) Carbonylation: Negishi, E.; Holmes, S.J.; Tour, J.M.; Miller,
J. A.; Cederbaum, F. E.; Swanson, D. R.; Takahashi, T. J. Am.
Chem. Soc. 1989, 111, 3336.
Dimethyl 2-Benzyl-1,2,3,4-tetrahydro-5-methylisoquinoline-6,7-
dicarboxylate (30):
Formed from 25b (229 mg, 0.888 mmol) and dimethyl acetylenedi-
carboxylate (164 mg, 1.15 mmol) by the same procedure used to form
28. The crude product contained around 85% of the non-aromatised
product. Purification by column chromatography on Brockmann
grade II neutral alumina (hexane/Et2O, 50:50) gave a yellow solid
which proved to be the title aromatic compound. Recrystallisation
(CHCl3) afforded 30 as colourless square plates (158 mg,
0.431 mmol, 48%); mp 100–102°C.
d) Aldehyde insertion: Copéret, C.; Negishi, E.; Xi, Z.; Taka-
hashi, T. Tetrahedron Lett. 1994, 35, 695.
e) Metathesis with other elements: Fagan, P. J.; Nugent, W. A.;
Calabrese, J. C. J. Am. Chem. Soc. 1994, 116, 1880.
Cu cat. reactions: f) Kasai, K.; Kotora, M.; Suzuki, N.; Taka-
hashi, T. J. Chem. Soc., Chem. Commun. 1995, 109.
g) Takahashi, T.; Xi, Z.; Kotora, M.; Xi, C.; Nakajima, K.
Tetrahedron Lett. 1996, 37, 7521.
IR (CHCl3): ν = 3027 w, 2953 w, 2805 w, 1723 s, 1603 w, 1577 w,
1495 w, 1436 m, 1393 w, 1369 w, 1301 m cm–1.
h) Lipshutz, B. H.; Segi, M. Tetrahedron 1995, 51, 4407.

SYNTHESIS
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