Metal-catalysed radical cyclisations leading to N-heterocycles: New approaches to gabapentin and pulchellalactam

Article abstract of DOI:10.1016/S0040-4020(03)01030-5

The copper(I) or ruthenium(II)-mediated radical cyclisation of halo-amides has been utilised to afford functionalised pyrrolidinones via 5-endo-trig or 5-exo-trig radical cyclisation pathways. This methodology has been applied to novel and concise syntheses of the anti-epileptic drug gabapentin and the biologically active natural product pulchellalactam.

Full text of DOI:10.1016/S0040-4020(03)01030-5

Tetrahedron 59 (2003) 6221–6231
Metal-catalysed radical cyclisations leading to N-heterocycles:
new approaches to gabapentin and pulchellalactam
Justin S. Bryans,a Nicola E. A. Chessum,b Nathalie Huther,b Andrew F. Parsonsb
,
*
and Franco Ghelfic
aPfizer Global Research and Development, Sandwich, Kent CT13 9NJ, UK
bDepartment of Chemistry, University of York, Heslington, York YO10 5DD, UK
´
Dipartimento di Chimica, Universita degli Studi di Modena e Reggio Emilia, Via Campi 183, I-41100 Modena, Italy
c
Received 8 May 2003; revised 5 June 2003; accepted 30 June 2003
Abstract—The copper(I) or ruthenium(II)-mediated radical cyclisation of halo-amides has been utilised to afford functionalised
pyrrolidinones via 5-endo-trig or 5-exo-trig radical cyclisation pathways. This methodology has been applied to novel and concise syntheses
of the anti-epileptic drug gabapentin and the biologically active natural product pulchellalactam.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
The formation of 5-membered nitrogen heterocycles using
radical cyclisation reactions has attracted the attention of
synthetic chemists for many years. A wide range of
N-heterocycles have been prepared from unsaturated
organohalides using a variety of radical cyclisation
methods, the most popular of which involves reductive
cyclisation using tributyltin hydride.1 The high toxicity of
Scheme 1.
organotin derivatives and the difficulty of removing
organotin halide derivatives from organic products has
recently led to the development of alternative radical
reagents to organotin derivatives.
nitrogen heterocycles although most studies have concen-
trated on the use of 4-exo-trig or 5-exo-trig radical
cyclisation reactions to prepare substituted b-lactams or
pyrrolidinones, respectively.3 More recently, however,
attention has turned towards the use of ‘disfavoured’
One particularly useful alternative method involves treat-
5-endo-trig radical cyclisations.4 Our group and others
ment of unsaturated organohalides with copper(I) or
have shown that haloenamide precursors can undergo
ruthenium(II) complexes in atom transfer radical cyclisation
cyclisation to form functionalised pyrrolidinones in excel-
(ATRC) reactions.2 In these oxidative cyclisations, abstrac-
lent yield and suitable metal catalysts include copper(I)
tion of a halogen atom by for example, CuCl is followed by
chloride/bipyridine or dichlorotris-(triphenylphosphine)-
radical cyclisation (Scheme 1). The resulting cyclic carbon-
ruthenium(II).5 Following on from these studies we now
centred radical can then abstract a halogen-atom from the
wish to report for the first time, the application of ATRC
CuCl2 to form the cyclic organohalide and CuCl, which can
continue the chain reaction. There are a number of attractive
reactions to the formal synthesis of gabapentin 1 and the
total synthesis of pulchellactam 2 (Fig. 1). The key-step in
features of this approach including the fact that functiona-
these syntheses involves an ATRC of a halo-enamide
lised cyclic products are formed using catalytic amounts of
precursor.
easily recovered and inexpensive metal complexes.
ATRC reactions have been used to prepare a variety of
Keywords: amino acids; cyclisations; nitrogen heterocycles; radical
reactions.
*
Corresponding author. Tel.: þ44-1904-432608; fax: þ44-1904-432516;
e-mail: afp2@york.ac.uk
Figure 1.
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)01030-5

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J. S. Bryans et al. / Tetrahedron 59 (2003) 6221–6231
2. Results and discussion
prone to hydrolysis on silica and so the crude reaction
mixture was filtered through a celite plug to remove the
copper complex. Spirocycle 4 was then reacted with
tributyltin hydride (3.3 Equiv.) in order to remove all
three chlorine atoms. Surprisingly, hydrolysis rather than
reduction of the chlorine atom a- to nitrogen occurs to give
the hydroxy-pyrrolidinone 5 in a reasonable yield of 42%
over the two steps.11 Hydroxy-pyrrolidinone 5 was also
formed when tributyltin hydride (3.3 Equiv.) was added
directly to the crude cyclisation product (containing the
copper complex).12 This may be explained by the presence
of residual water in the reaction mixture. It should also be
noted that hydroxy-pyrrolidinone 5 is formed in moderate
yield (26%) on reaction of 3.3 Equiv. of tributyltin hydride
with trichloro-enamide 3 and so even under these reducing
conditions a chlorine ATRC can take place.13 The hydroxy
group in 5 was however, easily removed using trifluoro-
acetic acid and triethylsilane14 to give pyrrolidinone 6 in
55% yield. Finally, oxidative deprotection of the PMB
group was achieved using 10 Equiv. of cerium(IV)
ammonium nitrate to provide the desired spirocycle 7 in
83% yield. When the number of equivalents of cerium(IV)
ammonium nitrate was reduced to 3, some starting material
was recovered (13%) and 7 was isolated in a lower yield of
53%. The approach shown in Scheme 2 involves hydrolysis
of spirocycle 7 to form the hydrochloride salt of gabapentin
1 (in 71% yield) and so this completes a new formal
synthesis of 1.
Gabapentin 1, sold under the name neurontinw, is an anti-
epileptic drug marketed by Pfizer. Although originally
designed as a lipophilic GABA analogue, it has been shown
that it does not interact with any of the enzymes on the
GABA metabolic pathway. It also does not directly interact
with either the GABAA or GABAB receptors.6 Instead,
gabapentin 1 has been shown to bind with high affinity to a
binding site of a calcium channel and it is thought that
gabapentin 1 exerts its biological activity through inter-
action at this site.7 Gabapentin 1 can be prepared from
cyclohexanone by the short 4-step sequence shown in
Scheme 2.8 Good yields are observed for each step apart
from the Michael-addition step and the overall yield of 1 is
25%. The main problem with this approach is that it cannot
be used to access a wide range of analogues. Hence,
although a variety of different groups have been introduced
at different sites of the cyclohexane ring, it is not easy to
introduce substituents at the 2 and 4 positions of 1.9 As a
consequence, an alternative and potentially more flexible
approach to 1 was designed as described below.
Scheme 2.
The formation of the intermediate trichloride 4 offers a
potentially flexible approach to a range of gabapentin 1
analogues. Substitution of the chlorine atoms could allow
the selective introduction of a variety of substituents at the 2
and 4 positions of gabapentin 1 (e.g. reaction of the
N-benzyl analogue of 4 with methanol leads to selective
substitution of the chlorine adjacent to the nitrogen, the
resulting methoxy derivative is presumably formed via an
intermediate N-acyl iminium ion5b). The convergent nature
of the 5-endo cyclisation approach also allows the rapid
preparation of a range of substituted precursors. For
example, reaction of the imine derived from cyclohexane
carboxaldehyde and p-methoxybenzylamine with 2-bromo-
isobutyryl bromide affords bromo-enamide 8 in 64% yield
(Fig. 2). Reaction of 8 with tributyltin hydride (added over
5 h) affords pyrrolidinone 9 in 45% yield (together with
46% of the simple reduced product), which on N-deprotec-
tion gives the dimethylated compound 10 (in 88% yield).
Cyclisation of 8 using copper(I) chloride/bipyridine was
also successful and spirocycle 9 was isolated after reduction
of the intermediate cyclic product using triethylsilane and
trifluoroacetic acid (in 11% overall yield from 8). The
copper(I)-mediated cyclisation gave 11 (in 21% yield) as an
inseparable mixture with the b-lactam by-product 12 (in
Initially, trichloro-enamide 3 was prepared (in 15% yield)
by reaction of cyclohexane carboxaldehyde with
4-methoxybenzylamine under Dean–Stark conditions fol-
lowed by immediate N-acylation of the crude imine using
trichloroacetyl chloride at 08C (Scheme 3). Enamide 3 was
then heated with copper(I) chloride/bipyridine in order to
affect the desired 5-endo-trig radical cyclisation.10 This
afforded the desired trichlorinated spirocycle 4, which was
Scheme 3.
Figure 2.

J. S. Bryans et al. / Tetrahedron 59 (2003) 6221–6231
6223
36% yield), which is derived from a competitive 4-exo
radical cyclisation3d,15—this is not surprising as the 5-endo
cyclisation requires the formation of two adjacent and
sterically hindered quaternary centres in 11.
in the formation of the unsaturated pyrrolidinone pulchella-
lactam 2. Pulchellalactam 2 has recently been isolated from
the marine fungus Corollospora pulchella and is a potent
inhibitor of a protein tyrosine phosphatase, CD45, which
has an important role in the activation of B and T cells.20
This makes it a therapeutic target for autoimmune and
chronic anti-inflammatory diseases.
Although the 5-endo approach offers an alternative strategy
to gabapentin 1 and related compounds the overall yield of 1
from the copper(I) catalysed approach (Scheme 3) is only
2% primarily because of the inefficient formation of
trichloroenamide 4. In order to develop a more efficient
synthesis of 1, an alternative 5-exo radical cyclisation
approach was also investigated as shown in Scheme 4. The
key step in this approach involved the radical cyclisation of
the cyclohexene derivative 13, which bears an N-dimethyl-
amino protecting group.3a
Previous work within our group21 and elsewhere5 has shown
that unsaturated pyrrolidinones can be isolated from some
copper(I)- or ruthenium(II)-mediated 5-endo ATRC reac-
tions if the intermediate cyclic halides can undergo
elimination of HX. As a consequence, it was proposed
that on heating the N-protected enamide 16 with a copper(I)
or ruthenium(II) complex the intermediate cyclic dichloride
17 would undergo elimination to form the core ring system
of pulchellalactam 2 (Scheme 5). Model studies supported
this hypothesis as reaction of dichloride 18 (formed in 75%
yield as a single unassigned enamide isomer from reaction
of 3-pentanone, benzylamine and dichloroacetyl chloride)
with copper(I) chloride/bipyridine (1 Equiv.) afforded
conjugated dienone 20 in 34% yield as a 1:1 mixture of
double bond isomers (Fig. 3). Interestingly, when the same
reaction was carried out in the presence of RuCl2(PPh3)3
(0.5 Equiv.) dienone 20 was isolated in an excellent 94%
yield (as a 1:1 mixture of isomers). Cyclisation of the
corresponding trichloroenamide 19 also showed that the use
of RuCl2(PPh3)3 was more effective than copper(I) chloride/
bipyridine, the corresponding chloro-dienone 21 was
isolated in 67 and 34% yields, respectively.
Scheme 4.
The cyclohexyl precursor 13 was prepared (in 69% yield)
from condensation of dimethylhydrazine with cyclohex-1-
ene carbaldehyde, followed by reduction of the imine and
N-acylation of the resulting hydrazine.16 On treatment of
trichloride 13 with copper(I) chloride and TMEDA3a the
desired spirocycle 14 was formed in 73% yield as a 3.3:1
mixture of separable diastereoisomers.17 Using bipyridine
as the ligand in place of TMEDA resulted in a lower yield of
14 (around 41%) and the formation of reduced by-products.
Heating trichloride 14 with Raney nickel at 1108C resulted
in the formation of spirocycle 15 in a crude yield of around
90% - there was no evidence for cleavage of the N–N
hydrazide bond.3a However, the nitrogen protecting group
could be efficiently removed on treatment of 15 with
magnesium monoperoxyphthalate in methanol.18 This
afforded spirocycle 7 in 81% yield and this completes a
second formal synthesis of gabapentin 1. The overall yield
of gabapentin 1 prepared via this 7-step approach is 26%,
which is the same yield as that reported for the synthesis
shown in Scheme 2. Importantly, this new approach
involves the formation of 14, which has chlorine atoms
adjacent to the lactam carbonyl and within the cyclohexane
ring. These chlorine atoms could be used to further
functionalise the cyclohexane ring and the C-2 position of
gabapentin 1.19
Scheme 5.
Figure 3.
Our studies towards the synthesis of 2 started with the
formation of the precursor dichloro-enamide 23 (Scheme 6).
On reaction of ketone 22 with p-methoxybenzylamine
followed by dichloroacetyl chloride, enamide 23 was
formed together with regioisomer 24 as an inseparable
mixture (after column chromatography) in a combined yield
1
of 32%. The H NMR spectrum indicated a 1.7:1 ratio of
enamides 23:24, respectively and this mixture was then
heated with RuCl2(PPh3)2 in toluene (under the same
conditions as for the model system). Reaction with the
Ru(II) catalyst afforded the desired pyrrolidinone 25 as a
1:1.2 mixture of cis-:trans-isomers in a combined yield of
76% from enamide 23. The trans-pyrrolidinone isomer
26 was also formed from cyclisation of enamide 24 in 51%
yield. N-Deprotection of the double bond isomers of 25 was
Following the successful formation of spirocyclic com-
pounds using copper(I)-mediated ATRC reactions, our
attention turned to the use of a similar 5-endo cyclisation

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J. S. Bryans et al. / Tetrahedron 59 (2003) 6221–6231
respectively. Dienones 29 and 30 could be isolated
separately on column chromatography and these were
subjected to a variety of deprotection conditions. Surpris-
ingly, oxidative deprotection using cerium(IV) ammonium
nitrate or alternatively dipotassium hydrogen phosphate and
potassium persulfate23 was unsuccessful and both gave rise
to complex reaction mixtures. However, stirring 29 in neat
TFA at rt resulted in clean N-deprotection and the formation
of pulchellalactam 2 in 66% yield. A similar reaction of the
trans-double bond isomer 30 gave the trans-isomer of
pulchellalactam, namely compound 33, in 83% yield. A
trace amount (,5%) of pulchellalactam 2 was also observed
1
in the H NMR spectrum and this was presumably derived
from isomerisation of the double bond in 33. The spectro-
scopic data for both 2 and 33 was consistent with that
recently reported by Li and co-workers.24
Although the overall yield of (Z)- and (E)-pulchellalactam 2
and 33 is modest (10% from ketone 22) this represents a
very quick and convergent route to 2 and structurally related
compounds, which could possess a variety of interesting
biological properties. Variation of the ketone precursor
followed by enamide formation and then radical cyclisation,
under the mild reaction conditions, could therefore be used
to rapidly access a range of analogues.
Scheme 6.
then attempted using CAN (under a variety of conditions)
but this resulted in the formation of a complicated mixture
of products presumably derived from oxidation of the
protecting group and the diene. Heating 25 with TFA22 in
chloroform was also unsuccessful and so the synthesis was
restarted using an alternative nitrogen protecting group.
3. Experimental
3.1. General
IR spectra were recorded on an ATI Mattson Genesis FT IR
spectrometer. 1H and 13C NMR spectra were recorded on a
Jeol EX 270 spectrometer. The carbon spectra were
assigned using DEPT experiments. Coupling constants (J)
were recorded in Hertz to the nearest 0.5 Hz. Mass spectra
were recorded on a Fisons Instruments VG Analytical
Autospec Mass Spectrometer. Thin layer chromatography
(tlc) was performed on Merck aluminium-backed silica gel
plates. Compounds were visualised under a UV lamp, using
alkaline potassium permanganate solution and/or iodine.
Column chromatography was performed using silica gel
(Matrix Silica 60, 70–200 mm Fisons or ICN flash silica 60,
32–63 mm).
The 2,4-dimethoxybenzyl group was chosen as the
N-protecting group because this particularly electron-rich
benzyl group has been shown to be especially susceptible to
oxidative deprotection.23 Hence, reaction of 2,4-dimethoxy-
benzylamine with ketone 22 followed by dichloroacetyl
chloride produced an inseparable 1.5:1 mixture of the
enamide regioisomers 27 and 28 respectively, in 32% yield
(Fig. 4). On heating this mixture with RuCl2(PPh3)3
(0.5 Equiv.) in toluene, enamide 27 gave the desired
dienones 29 and 30 in 32 and 41% yield while the
alternative enamide 28 gave the cyclic products 31 and 32
(tentatively assigned) in much lower yields of 17 and 14%,
3.1.1. Representative formation of an enamide pre-
cursor: formation of 2,2,2-trichloro-N-(cyclohexylidene-
methyl)-N-(4-methoxybenzyl)acetamide (3). Cyclohexane
carboxaldehyde (1.56 g, 1.68 mL, 13.9 mmol) and
p-methoxybenzylamine (1.97 g, 1.88 mL, 14.4 mmol)
were combined in toluene (50 mL) and heated to reflux
under nitrogen in a Dean–Stark apparatus overnight. The
solvent was then removed in vacuo. The imine residue was
re-dissolved in dry toluene (5 mL) and slowly added to a
stirring solution of trichloroacetyl chloride (2.88 g,
1.77 mL, 15.84 mmol) in dry toluene (50 mL) at 08C
under nitrogen. The reaction was allowed to stir for 1 h
with warming to rt, after which time the reaction was cooled
back to 08C and Et3N (4.37 g, 6.02 mL, 43.2 mmol) was
added. The reaction was allowed to stir for a further 2 h with
warming to rt before saturated aqueous Na2CO3 (50 mL)
was added and the reaction left to stir for 48 h, after which
time the aqueous and organic layers were separated and the
Figure 4.

J. S. Bryans et al. / Tetrahedron 59 (2003) 6221–6231
6225
aqueous layer extracted with ether (3£50 mL). The
combined organic extracts were dried (MgSO4) and
concentrated in vacuo. Column chromatography (silica;
9:1, petroleum ether–EtOAc) gave enamide 3 as a white
solid (798 mg, 15%); mp 53–548C; Rf 0.2 (9:1, petroleum
ether–EtOAc); (Found: C, 54.2; N, 3.7; H, 5.4.
were then separated and the organic layer washed with
water (20 mL), brine (20 mL), dried (MgSO4) and concen-
trated in vacuo. Column chromatography (silica; 3:1,
petroleum ether–EtOAc) gave the product 5 (68 mg,
42%) as a yellow oil. Rf 0.2 (2:1 petroleum ether–
EtOAc); nmax/cm21 (CH3Cl) 3588 (w, OH), 3027 (m),
2933 (m), 2856 (m), 1686 (s, CvO), 1612 (w), 1513 (s),
1451 (m), 1246 (s), 1033 (m); dH (270 MHz, CDCl3) 7.25–
7.10 (2H, m, 2£CHvCOMe, aromatics), 6.90–6.85 (2H,
m, 2£CHvCCH2N, aromatics), 4.81 (1H, d, J¼15.0 Hz,
CHAHBAr), 4.51 (1H, s, CHOH), 4.01 (1H, d, J¼15.0 Hz,
CHAHBAr), 3.75 (3H, s, OCH3), 2.35 (1H, d, J¼17.0 Hz,
CHAHBCO), 2.22 (1H, d, J¼17.0 Hz, CHAHBCO), 1.90–
1.10 (10H, m, 5£CH2-cyclohexane ring); dC (67.5 MHz,
CDCl3) 174.5 (CvO), 158.8 (COMe), 129.4 (2£CHCOMe,
aromatics), 128.6 (CvCH, aromatic), 113.9 (2£
CHvCCH2N, aromatics), 88.6 (CHOH), 55.2 (OCH3),
42.9 (CH2Ar), 40.9 (CH2CO), 40.4 (CCHOH), 35.1, 31.5,
25.6, 22.8, 22.1 (5£CH2-cyclohexane ring); m/z (CI, NH3)
290 (MþHþ, 100%), 272 (100), 152 (17), 136 (7), 121 (20);
HRMS found 290.1748. C17H23NO3 requires for MH,
290.1756.
C17H20Cl3NO2 requires C, 54.2; N, 3.7; H, 5.4%); nmax
/
cm21 (CHCl3) 3010 (m), 2937 (s), 2856 (m), 1679 (s,
CvO), 1612 (m), 1511 (s), 1252 (s); dH (270 MHz, CDCl3)
7.20 (2H, d, J¼9.0 Hz, 2£CHvCOMe, aromatics), 6.85
(2H, d, J¼9.0 Hz, 2£CHvCCH2N, aromatics), 6.01 (1H, s,
CHvC), 4.64 (2H, s, CH2Ar), 3.78 (3H, s, OCH3), 2.15–
2.00 (4H, m, 2£CH2-cyclohexane ring), 1.60 (6H, m,
3£CH2-cyclohexane ring); dC (67.5 MHz, CDCl3) 160.6,
159.1 (CvO and COMe), 143.5 (CvCH), 129.9 (2£
CHvCOMe, aromatics), 128.0 (CvCH), 120.1 (NCH),
113.8 (2£CHvCCH2N, aromatics), 93.4 (CCl3), 56.0
(CH2Ar), 55.1 (OCH3), 32.8, 28.7, 27.3 (3£CH2-cyclo-
hexane ring), 26.0 (2£CH2-cyclohexane ring); m/z (CI,
NH3) 376 (35MþHþ, 100%), 342 (10), 306 (60), 272 (10),
215 (7), 121 (100), 35 (7); HRMS found 376.0637.
C17H20Cl3NO2 requires for 35MH, 376.0638.
3.1.2. Representative copper(I)-mediated cyclisation of
an enamide: formation of 1,4,4-trichloro-2-(4-methoxy-
3.1.4. 2-(4-Methoxybenzyl)-2-azaspiro[4.5]decan-3-one
(6). Triethylsilane (1 mL) and trifluoroacetic acid (1 mL)
were added to a stirred solution of alcohol 5 (68 mg,
0.23 mmol) in anhydrous dichloromethane (1 mL) at rt
under nitrogen. The reaction was allowed to stir for 0.5 h,
after which time the reaction was diluted with dichloro-
methane (15 mL) and washed with water (15 mL). The
organic layer was dried (MgSO4) and concentrated in vacuo.
Column chromatography (silica; 1:1 petroleum ether–
EtOAc) afforded the required product 6 (34 mg, 55%) as a
benzyl)-2-azaspiro[4.5]decan-3-one
(4).
Copper(I)
chloride (28 mg, 0.28 mmol) and 2,20-bipyridine (44 mg,
0.28 mmol) were added to a stirred solution of enamide 3
(211 mg, 0.56 mmol) in dry, degassed toluene (6 mL) under
nitrogen. The mixture was heated to reflux for 11 h, after
which time the solvent was removed in vacuo. The sample
was then dissolved in toluene and filtered through celite to
remove the catalyst complex, which afforded crude 4
(0.21 g) as a brown semi-solid and this was used directly in
colourless oil. Rf 0.2 (1:1 petroleum ether–EtOAc); nmax
/
the subsequent reaction. Rf 0.1 (dichloromethane); nmax
/
cm21 (thin film) 2925 (s), 2850 (m), 1685 (s, CvO), 1511
(m), 1245 (s), 1033 (m); dH (270 MHz, CDCl3) 7.16 (2H, d,
J¼9.0 Hz, 2£CHvCOMe, aromatics), 6.84 (2H, d,
J¼9.0 Hz, 2£CHvCH2N, aromatics), 4.36 (2H, s,
CH2Ar), 3.79 (3H, s, OCH3), 2.69 (2H, s, CH2N), 2.28
(2H, s, CH2CO), 1.60–1.40 (10H, m, 5£CH2-cyclohexane
ring); dC (67.5 MHz, CDCl3) 173.9 (CvO), 158.9 (COMe),
129.4 (2£CHvCOMe, aromatics), 128.6 (CvCH,
aromatic), 113.9 (2£CHvCH2N, aromatics), 57.9
(CH2Ar), 55.2 (OCH3), 45.8 (CH2N), 44.1 (CH2CO), 36.8
(2£CH2-cyclohexane ring), 36.0 (C(CH2)4), 25.5 (1£CH2-
cyclohexane ring), 22.7 (2£CH2-cyclohexane ring); m/z (CI,
NH3) 274 (MþHþ, 100%), 166 (5), 121 (25), 49 (7); HRMS
found 274.1808. C17H23NO2 requires for MH, 274.1807.
cm21 (CH3Cl) 3019 (m), 2935 (s), 2859 (m), 1787 (w), 1727
(s, CvO), 1612 (m), 1513 (m), 1247 (s), 1084 (m), 1033
(m); dH (270 MHz, CDCl3) 7.28–7.14 (2H, m, 2£
CHvCOMe, aromatics), 6.92–6.80 (2£CHvCCH2N,
aromatics), 4.92 (1H, d, J¼14.5 Hz, CHAHBAr), 4.77 (1H,
s, CHCl), 4.14 (1H, d, J¼14.5 Hz, CHAHBAr), 3.78 (3H, s,
OCH3), 2.58–2.22 (1H, m, cyclohexane ring), 2.10–0.90
(9H, m, cyclohexane ring); dC (67.5 MHz, CDCl3) 166.2
(CvO), 159.3 (COMe), 130.0 (2£CHvCOMe, aromatics),
128.1 (CvCH, aromatic), 114.1 (2£CHvCH2N,
aromatics), 91.2 (CCl2), 83.0 (CHCl), 55.2 (OCH3), 50.0
(CCCl2), 44.6 (CH2Ar), 32.6, 26.1, 25.1, 22.1, 21.5
(5£CH2-cyclohexane ring); m/z (CI, NH3) 393
(35MþNHþ4 , 15%), 375 (15), 358 (30), 324 (65), 306
(100), 272 (95), 121 (90); HRMS found 393.0903.
C17H20Cl3NO2 requires for 35MþNH4, 393.0899.
3.1.5. 2-Azaspiro[4.5]decan-3-one (7). Cerium(IV)
ammonium nitrate (0.60 g, 1.1 mmol) was added to a
solution of lactam 6 (30 mg, 0.11 mmol) in acetonitrile
(5 mL) and water (1 mL). The reaction was left to stir at rt
overnight and the aqueous layer was diluted with brine
(15 mL) and the aqueous and organic layers separated. The
aqueous layer was then extracted with EtOAc (3£30 mL),
the combined organic layer was dried (MgSO4) and
concentrated in vacuo. Column chromatography (silica;
diethyl ether) afforded product 78 (14 mg, 83%) as an oil. Rf
0.1 (diethyl ether); nmax/cm21 (CH3Cl) 3228 (w, NH), 2925
(m), 2854 (w), 1697 (s, CvO), 1450 (w), 1313 (w), 1251
(w), 1068 (w); dH (270 MHz, CDCl3) 5.80 (1H, br s, NH),
3.16 (2H, s, CH2N), 2.19 (2H, s, CH2CO), 1.62–1.37 (10H,
3.1.3. Representative tributyltin hydride-mediated
reduction: formation of 1-hydroxy-2-(4-methoxy-
benzyl)-2-azaspiro[4.5]decan-3-one (5). Bu3SnH (0.54 g,
0.50 mL, 1.85 mmol) and AIBN (28 mg, 0.17 mmol) were
added to a stirred solution of g-lactam 4 (0.21 g, 0.56 mmol)
in dry, degassed toluene (20 mL) under nitrogen. The
reaction was heated to reflux for 0.75 h, after which time the
solvent was removed in vacuo. The resultant residue was re-
dissolved in diethyl ether (20 mL) and stirred vigorously
with an aqueous potassium fluoride solution (10% by
weight, 20 mL) overnight. The organic and aqueous layers

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J. S. Bryans et al. / Tetrahedron 59 (2003) 6221–6231
m, 5£CH2-cyclohexane ring); m/z (CI, NH3) 154 (MþHþ,
100%); HRMS found 154.1232. C9H15NO requires for MH,
154.1231.
(m, NH), 3013 (m), 2938 (m), 2857 (m), 1694 (s, CvO),
1490 (m), 1448 (m), 1313 (w), 970 (m), 674 (m); dH
(270 MHz, CDCl3) 6.67 (1H, br s, NH), 3.19 (2H, s, CH2N),
1.71–1.50 (5H, m, CH2-cyclohexane ring), 1.30–1.10 (5H,
m, CH2-cyclohexane ring), 0.98 (6H, s, 2£CH3); dC
(67.5 MHz, CDCl3) 183.5 (CvO), 46.8 (CH2N), 46.1
(CMe2), 44.3 (CCMe2), 30.3 (2£CH2-cyclohexane ring),
26.3 (CH2-cyclohexane ring), 23.1 (2£CH2-cyclohexane
ring), 19.5 (2£CH3); m/z (CI, NH3) 182 (MþHþ, 100%);
HRMS found 182.1540. C11H19NO requires for MH,
182.1544.
3.1.6. N-Benzyl-2-bromo-N-(cyclohexylidenemethyl)-2-
methylpropanamide (8). Following the same procedure
as for the preparation of 3, cyclohexane carboxaldehyde
(1.56 g, 1.68 mL, 13.9 mmol), p-methoxybenzylamine
(1.97 g, 1.88 mL, 14.4 mmol) and 2-bromoisobutyryl
bromide (2.88 g, 1.96 mL, 15.8 mmol) were reacted to
give enamide 8 as a yellow oil (3.52 g, 64%). Rf 0.2 (9:1
petroleum ether–EtOAc); nmax/cm21 (thin film) 2929 (s),
2854 (m), 1637 (s, CvO), 1511 (m), 1245 (m), 1174 (m),
1108 (m), 1035 (m); dH (270 MHz, CDCl3) 7.18 (2H, d,
J¼9.0 Hz, 2£CHvCOMe, aromatics), 6.84 (2H, d,
J¼9.0 Hz, 2£CHvCCH2N, aromatics), 6.25 (1H, s,
CvCH), 4.61 (2H, s, CH2Ar), 3.79 (3H, s, OCH3), 2.15–
2.00 (4H, m, 2£CH2-cyclohexane ring), 1.97 (6H, s,
2£CH3), 1.65–1.40 (6H, m, 3£CH2-cyclohexane ring); dC
(67.5 MHz, CDCl3) 170.4 (CvO), 158.7 (COMe), 141.0
(CvCH), 129.4, 129.3 (CvCH and 2£CHvCOMe,
aromatics), 122.6 (CvCH), 113.7 (2£CHvCCH2N,
aromatics), 58.5 (CBrMe2), 55.1 (OCH3), 54.3 (CH2N),
32.8 (CH2-cyclohexane ring), 32.3 (2£CH3), 28.5, 27.4,
26.2, 26.0 (4£CH2-cyclohexane ring); m/z (CI, NH3) 382
(81MþHþ, 50%), 380 (79MþHþ, 50), 300 (33), 121 (100);
HRMS found 380.1225. C19H26BrNO2 requires for 79MH,
380.1231.
3.1.9. Copper(I)-mediated cyclisation of enamide (8).
Following the procedure used for the formation of 4,
copper(I) chloride (37 mg, 0.37 mmol) and 2,20-bipyridine
(58 mg, 0.37 mmol) were heated with enamide 8 (280 mg,
0.74 mmol) in toluene (7 mL) for 27 h. Column chroma-
tography (silica; 2:1 petroleum ether–EtOAc) afforded an
inseparable mixture of 11 (50 mg, 21%) and 12 (43 mg,
36%) as an oil. 1-Hydroxy-2-(4-methoxybenzyl)-4,4-
dimethyl-2-azaspiro[4.5]decan-3-one 11. The presence of
this compound was indicated by 1H NMR spectroscopy and
mass spectrometry; Rf 0.3 (2:1 petroleum ether–EtOAc); dH
(270 MHz, CDCl3) 7.20 (2H, d, J¼8.5 Hz, 2£CHvCOMe,
aromatics), 6.83 (2H, d, J¼8.5 Hz, 2£CHvCCH2N,
aromatics), 4.83 (1H, s, CHOH), 4.77 (1H, d, J¼14.5 Hz,
CHAHBN), 4.18 (1H, d, J¼14.5 Hz, CHAHBN), 3.78 (3H, s,
OCH3), 2.02–1.88 (2H, m, CH2-cyclohexane ring), 1.20
(3H, s, CH3), 0.98 (3H, s, CH3), 1.80–1.05 (8H, m, 4£CH2-
cyclohexane ring); m/z (CI, NH3) 318 (MþHþ, 33%).
4-Cyclohexyl-1-(4-methoxybenzyl)-3,3-dimethylazetidin-
2-one 12. The presence of this compound was indicated by
1H NMR spectroscopy and mass spectrometry; Rf 0.3 (2:1
petroleum ether–EtOAc); dH (270 MHz, CDCl3) 7.15 (2H,
d, J¼9.0 Hz, 2£CHvCOMe, aromatics), 6.85 (2H, d,
J¼9.0 Hz, 2£CHvCCH2N, aromatics), 5.56 (1H, br s,
CvCH), 4.76 (1H, d, J¼15.0 Hz, CHAHBN), 3.79 (1H, d,
J¼15.0 Hz, CHAHBN), 3.79 (3H, s, OCH3), 3.32 (1H, s,
CHN), 2.14–2.03 (2H, m, CH2-cyclohexane ring), 1.86–
1.49 (6H, m, 3£CH2-cyclohexane ring), 1.23 (3H, s, CH3),
1.04 (3H, s, CH3); m/z (CI, NH3) 300 (MþHþ, 100%), 136
(46), 121 (63).
3.1.7. Tributyltin hydride-mediated cyclisation of
enamide (8): preparation of 2-(4-methoxybenzyl)-4,4-
dimethyl-2-azaspiro[4.5]decan-3-one (9).
A solution
(0.014 M) of tributyltin hydride (215 mg, 0.20 mL,
0.74 mmol) and AIBN (11 mg, 0.07 mmol) in dry, degassed
toluene (53 mL) was slowly added (over 5 h) to a stirred,
refluxing solution (0.024 M) of enamide 8 (253 mg,
0.67 mmol) in dry degassed toluene (28 mL) under nitrogen.
Following the same workup procedure as for the preparation
of
5
afforded N-benzyl-N-(cyclohexylidenemethyl)-2-
methylpropanamide (92 mg, 46%) as a colourless oil and
g-lactam 9 (90 mg, 45%) as a colourless oil after column
chromatography. g-Lactam 9: Rf 0.2 (1:1 petroleum ether–
EtOAc); nmax/cm21 (CH3Cl) 2932 (s), 2852 (s), 1681 (s,
CvO), 1512 (s), 1445 (m), 1247 (s); dH (270 MHz, CDCl3)
7.13 (2H, d, J¼7.0 Hz, 2£CHvCOMe, aromatics), 6.85
(2H, d, J¼7.0 Hz, 2£CHvCCH2N, aromatics), 4.37 (2H, s,
CH2Ar), 3.79 (3H, s, OCH3), 2.97 (2H, s, CH2N), 1.70–0.90
(10H, m, 5£CH2-cyclohexane ring), 0.98 (6H, s, 2£CH3);
dC (67.5 MHz, CDCl3) 180.0 (CvO), 159.0 (COMe), 129.5
(2£CHvCOMe, aromatics), 129.0 (CvCH, aromatic),
114.0 (2£CHvCCH2N, aromatics), 55.2 (OCH3), 51.3
(CH2Ar), 47.5 (CMe2), 46.2 (CH2N), 42.1 (CCMe2), 33.6
(2£CH2-cyclohexane ring), 26.0 (CH2-cyclohexane ring),
23.0 (2£CH2-cyclohexane ring), 19.6 (2£CH3); m/z (CI,
NH3) 302 (MþHþ, 100%); HRMS found 302.2114.
C19H28NO2 requires for MH, 302.2115.
3.1.10. Copper(I)-mediated cyclisation of enamide (8)
followed by reduction using triethylsilane. Following the
procedure used for the formation of 4, copper(I) chloride
(59 mg, 0.60 mmol) and 2,20-bipyridine (94 mg, 0.60 mmol)
were heated with enamide 8 (398 mg, 1.05 mmol) in toluene
for 6 days. The crude product was filtered through celite, the
solvent evaporated and dichloromethane (4 mL) followed
by triethylsilane (4 mL) and trifluoroacetic acid (4 mL)
added. After stirring at rt for 2.5 h, further dichloromethane
(20 mL) was added and the mixture was washed with water
(20 mL) and then brine (20 mL). The organic phase was
dried (MgSO4), evaporated and column chromatography
(silica; 19:1, petroleum ether–EtOAc) gave 11 (37 mg,
11%) as a colourless oil.
3.1.8. 4,4-Dimethyl-2-azaspiro[4.5]decan-3-one (10).
According to the procedure described for the deprotection
of 6, the reaction of cerium(IV) ammonium nitrate (1.59 g,
2.9 mmol) with g-lactam 9 (87 mg, 0.29 mmol) in MeCN/
H2O (5:1, 18 mL) gave 10 (46 mg, 88%) as a white solid;
mp 102–1038C; Rf 0.2 (EtOAc); nmax/cm21 (CHCl3) 3441
3.1.11. N-Cyclohex-1-enylmethyl-N0,N0-dimethylhydra-
zine, trichloroacetylated (13). Dimethylamino-borane
(0.094 g, 1.6 mmol) and 1-cyclohexen-1-carboxaldehyde
N,N-dimethylhydrazone (0.152 g, 1 mmol), obtained quan-
titatively by condensation of dimethylhydrazine with

J. S. Bryans et al. / Tetrahedron 59 (2003) 6221–6231
6227
cyclohex-1-ene carbaldehyde,16 were weighed in a screw
capped Schlenk tube equipped with a septum. Then, under
argon and at 08C, diethyl ether (2 mL) and a solution of
anhydrous p-toluenesulfonic acid (1.033 g, 6 mmol) in
diethyl ether (2 mL), both cooled to 08C, were added.
After 3 h, the reaction mixture was quenched with Na2CO3
(10% w/v, 6 mL), under an inert atmosphere. The organic
phase (ether) was cannulated into another Schlenk tube,
evaporated and dichloromethane (2 mL) added. After
cooling to 08C, triethylamine (0.12 g, 0.17 mL, 1.2 mmol)
and trichloroacetyl chloride (0.20 g, 0.12 mL, 1.1 mmol)
were introduced. After overnight stirring, the mixture was
diluted with NaOH (5% w/v, 6 mL), and extracted with
dichloromethane. The combined organic layers were dried
over MgSO4 and concentrated. Column chromatography of
the crude product on silica gel, using a petroleum
ether/diethyl ether gradient, gave 0.23 g of a yellow semi-
solid. This product was an 89/11 mixture of 13 0(69%) and
trichloroacetylated N-[(cyclohexyl)-methyl]-N0,N -dimethyl-
1.16 (5H, m, CH2-cyclohexane ring), 0.94–0.77 (2H, m,
CH2-cyclohexane ring); dC (67.5 MHz, CDCl3) 157.6
(CvO), 77.8 (CCl2), 62.0 (CHCl), 50.6 (CCCl2), 46.5
(CH2N), 43.7 (2£CH3), 34.2, 33.8, 30.3, 25.6 (4£CH2-
cyclohexane ring); m/z (CI, NH3) 299 (35MþHþ, 5%), 277
(30), 262 (80), 245 (100).
3.1.13. 2-(Dimethylamino)-2-azaspiro[4.5]decan-3-one
(15). Wet Raney nickel (2.3 g) was added to a solution of
lactam 14 (88 mg, 0.3 mmol) in ethanol (10 mL) and the
mixture was heated to reflux overnight. The reaction was
filtered through celite to remove the nickel catalyst and
1
concentrated in vacuo. A H NMR spectrum of the crude
product suggested 15 was formed in around 90% yield and
this was immediately reacted with MMPP·H2O. A pure
sample of 15 could be obtained by filtration of the crude
product through a silica plug (19:1 diethyl ether–methanol);
oil; Rf 0.2 (19:1 diethyl ether–methanol); nmax/cm21
(CH3Cl) 2981 (m), 2928 (m), 2857 (m), 1691 (s, CvO),
1452 (m) 1248 (m); dH (270 MHz, CDCl3) 3.13 (2H, s,
CH2N), 2.60 (6H, s, 2£CH3), 2.15 (2H, s, CH2CO), 1.44
(10H, app br s, 5£CH2-cyclohexyl ring); dC (67.5 MHz,
CDCl3) 172.5 (CvO), 51.2 (CH2N), 43.9 (2£CH3), 37.4
(CH2CO), 35.5 (CCH2), 26.1 (2£CH2-cyclohexyl ring),
23.2 (3£CH2-cyclohexyl ring); m/z (CI, NH3) 197 (MþHþ,
100%); HRMS found 197.1654. C11H20N2O requires for
MH, 197.1654.
1
hydrazine (8%) as indicated by the H NMR spectrum. Rf
0.4 (5:1 petroleum ether–EtOAc); nmax/cm21 (thin film)
2927 (s), 2859 (m), 2834 (m), 1690 (s, CvO), 1457 (m),
1400 (m), 1269 (m), 1152 (m), 1111 (m); dH (270 MHz,
CDCl3) 5.57 (1H, app. quin., J¼2.0 Hz, CHvC), 3.97 (2H,
s, CH2N), 2.64 (6H, s, 2£CH3), 1.60–1.40 (4H, m, 2£CH2-
cyclohexane ring), 1.75–1.45 (4H, m, 2£CH2-cyclohexane
ring); dC (67.5 MHz, CDCl3) 187.1 (CvO), 162.4
(CvCH), 133.7 (CCl3), 123.8 (CvCH), 47.0 (CH2N),
44.6 (2£CH3), 26.5, 25.6, 23.1, 22.8 (4£CH2-cyclohexane
ring); m/z (CI, NH3) 299 (35MþHþ, 98%), 265 (20), 95 (30);
HRMS found 299.0485. C11H17Cl3N2O requires for 35MH,
299.0485.
3.1.14. Deprotection of hydrazide (15) using MMPP.
Magnesium monoperoxyphthalate hexahydrate (0.46 g,
0.93 mmol) was added to a solution of hydrazide 15
(62 mg, 0.31 mmol) in methanol (0.8 mL) and the reaction
was allowed to stir at rt for 3 h. The solvent was removed in
vacuo and the resulting residue re-dissolved in ethyl acetate
(20 mL). The organic layer was washed with water (15 mL),
brine (15 mL) and dried (MgSO4). Column chromatography
(silica; diethyl ether) gave 7 as an oil (39 mg, 81%).
3.1.12. 4,4,6-Trichloro-2-(dimethylamino)-2-azaspiro-
[4.5]decan-3-one (14). Copper(I) chloride (7 mg,
0.07 mmol) and TMEDA (0.02 mL, 0.14 mmol) were
added to a solution of enamide 13 (204 mg, 0.68 mmol) in
dry, degassed toluene (7 mL) under nitrogen. The reaction
was heated to 608C for 24 h, after which time the solvent
was removed in vacuo. Column chromatography (silica; 1:1
pentane–EtOAc) gave product 14 (150 mg, 73%) as a 3.3:1
mixture of diastereomers. Major diastereoisomer; white
3.1.15. (E or Z)-3-(N-Benzyl-2,2-dichloroethanamido)-
pent-2-ene (18). The same procedure as for the synthesis of
19 was used, but at 08C dichloroacetyl chloride (0.98 mL,
10.23 mmol)
then
N,N-diethylaniline
(1.63 mL,
solid; mp 76–778C; Rf 0.6 (1:1 pentane–EtOAc); nmax
/
10.23 mmol) were added. After 3 h, the mixture was
worked-up and purified by column chromatography (silica,
petroleum ether–ethyl acetate, 20:1) to afford 18 (2.00 g,
75%) as a yellow gum; Rf 0.3 (petroleum ether–ethyl
acetate, 20:1); nmax (thin film) 2973 (m), 1679 (s, CvO),
1455 (w), 1401 (m), 1204 (w), 806 (m), 757 (m), 699 (m),
469 (vs) cm21; dH (270 MHz, CDCl3) 7.39–7.23 (5H, m,
aromatics), 6.39 (1H, s, CHCl2), 5.23 (1H, q, J¼7 Hz,
CHCH3), 4.61 (2H, s, CH2Ph), 2.31 (2H, q, J¼7.5 Hz,
CH2CH3), 1.59 (3H, d, J¼7 Hz, CHCH3), 1.01 (3H, t,
J¼7.5, CH2CH3); dC (67.5 MHz, CDCl3) 164.2 (NCO),
138.8 (CvCHCH3), 135.8 (CvCHCH3), 127.8 (CvCH),
127.9, 127.4, 126.8 (5£CHvC), 63.9 (CHCl2), 49.4
(CH2Ph), 21.2 (CH2CH3), 12.5 (CH3CH), 11.2 (CH3CH2);
m/z (CI, NH3) 303 (35MþNH4þ, 47%), 286 (35MþHþ, 100),
250 (93), 216 (46), 200 (6), 174 (8), 108 (7), 91 (15); HRMS
found 286.0763. C14H17Cl2NO requires for 35MH,
286.0765.
cm21 (thin film) 2943 (m), 2863 (m), 2785 (w), 1732 (s,
CvO), 1447 (m), 1402 (m), 1282 (m), 921 (m), 851 (m); dH
(270 MHz, CDCl3) 4.28 (1H, dd, J¼11.5, 4.0 Hz, CHCl),
3.60 (1H, d, J¼10.0 Hz, CHAHBN), 3.26 (1H, d, J¼10.0 Hz,
CHAHBN), 2.74 (6H, s, 2£CH3), 2.39 (1H, br dq, J¼14.0,
3.5 Hz, CH-cyclohexyl-ring), 2.32–2.20 (1H, m, CH-
cyclohexyl ring), 1.97–1.75 (3H, m, CH-cyclohexyl ring),
1.59 (1H, td, J¼13.5, 3.5 Hz, CH-cyclohexyl ring), 1.49–
1.09 (2H, m, CH-cyclohexyl-ring); dC (67.5 MHz, CDCl3)
164.2 (CvO), 91.4 (CCl2), 63.6 (CHCl), 50.3 (CCCl2), 46.9
(CH2N), 42.7 (2£CH3), 34.6, 32.9, 25.6, 22.0 (4£CH2-
cyclohexyl ring); m/z (CI, NH3) 317 (35MþNH4þ, 40%), 299
(35MþHþ, 100); HRMS found 299.0479. C11H17Cl3N2O
requires for 35MH, 299.0479. Minor diastereoisomer; semi-
solid; Rf 0.1 (1:1 pentane–EtOAc); nmax/cm21 (thin film)
2923 (s), 2853 (m), 1720 (s, CvO), 1650 (w), 1449 (m),
1320 (m), 963 (m), 816 (w); dH (270 MHz, CDCl3) 4.19
(1H, dd, J¼12.0, 4.0 Hz, CHCl), 3.91 (1H, d, J¼11.0 Hz,
CHAHBN), 3.46 (1H, d, J¼11.0 Hz, CHAHBN), 2.85 (6H, s,
2£CH3), 2.25–2.15 (1H, m, CH-cyclohexane ring), 1.89–
3.1.16. (E or Z)-3-(N-Benzyl-2,2,2-trichloroethanamido)-
pent-2-ene (19). A solution of benzylamine (1.00 g,

6228
J. S. Bryans et al. / Tetrahedron 59 (2003) 6221–6231
9.3 mmol) and pentan-3-one (0.8 g, 9.3 mmol) in toluene
(45 mL) with a catalytic amount of p-toluenesulfonic acid
(10 mg) was refluxed in a Dean–Stark apparatus for 15 h.
The reaction was cooled to 08C and trichloroacetyl chloride
(1.14 mL, 10.23 mmol) followed by triethylamine
(1.68 mL, 10.23 mmol) was added dropwise. After 2 h,
the solvent was removed in vacuo and the residue was
worked-up as described in the representative procedure for
3. The crude product was purified by column chromato-
graphy (silica, petroleum ether–ethyl acetate, 20:1) to
afford 19 (3.67 g, 62%) as a yellow oil; Rf 0.3 (petroleum
ether–ethyl acetate, 20:1); nmax (CHCl3) 2975 (m), 1665 (s,
CvO), 1495 (w), 1454 (m), 1433 (w), 1393 (s), 1355 (w),
1275 (w), 1243 (m), 824 (s), 739 (w), 700 (m) cm21; dH
(270 MHz, toluene-d8, 808C) 7.34–7.12 (5H, m, aromatics),
5.42 (1H, q, J¼7 Hz, CHCH3), 4.83 (2H, s, CH2Ph), 2.31
(2H, q, J¼7.5 Hz, CH2CH3), 1.52 (3H, d, J¼7 Hz, CHCH3),
1.12 (3H, t, J¼7.5 Hz, CH2CH3); dC (67.5 MHz, CDCl3)
160.2 (NCO), 138.2 (CvCHCH3), 135.3 (CvCHCH3),
128.7 (CvCH), 127.8, 127.3, 126.9 (5£CHvC), 92.9
(CCl3), 53.4 (CH2Ph), 24.2 (CH2CH3), 12.4 (CH3CH), 11.2
(CH3CH2); m/z (CI, NH3) 320 (35MþHþ, 100%), 286 (34),
250 (30), 214 (36), 202 (14), 174 (14), 105 (50), 91 (93);
HRMS found 320.0379. C14H16Cl3NO requires for 35MH,
320.0376.
a 1.2:1 mixture of alkene isomers. Z-isomer: 30%; Rf 0.33
(dichloromethane–diethyl ether, 30:1); nmax (thin film)
3019 (s), 2382 (w), 1698 (m, CvO), 1215 (vs) cm21; dH
(270 MHz, CDCl3) 7.34–7.24 (5H, m, aromatics), 5.40 (1H,
q, J¼8 Hz, CHCH3), 5.11 (2H, s, CH2Ph), 2.14 (3H, s,
CCH3), 1.82 (3H, d, J¼8 Hz, CHCH3); dC (67.5 MHz,
CDCl3) 165.9 (NCO), 141.3 (CCl), 138.0 (NCCH), 137.7
(CCCH3), 128.7 (CvCH), 127.1, 125.7, 122.6 (5£CHvC),
109.5 (CCHCH3), 45.1 (CH2Ph), 12.7 (CH3C), 10.3
(CH3CH); m/z (CI, NH3) 248 (35MþHþ, 100%), 91 (31);
HRMS found 248.0838. C14H14ClNO requires for 35MH,
248.0842. E-isomer: 37%; Rf 0.27 (dichloromethane–
diethyl ether, 30:1); nmax (thin film) 3015 (s), 2371 (w),
1691 (m, CvO), 1220 (s) cm21; dH (270 MHz, CDCl3)
7.31–7.15 (5H, m, aromatics), 5.44 (1H, q, J¼8 Hz,
CHCH3), 4.85 (2H, s, CH2Ph), 2.31 (3H, s, CCH3), 1.96
(3H, d, J¼8 Hz, CHCH3); dC (67.5 MHz, CDCl3) 164.7
(NCO), 139.2 (CCl), 137.5 (NCCH), 137.0 (CCCH3), 128.6
(CvCH), 127.2, 126.9, 123.1 (5£CHvC), 112.0
(CCHCH3), 41.6 (CH2Ph), 12.0 (CH3C), 11.5 (CH3CH);
m/z (CI, NH3) 248 (35MþHþ, 100%), 214 (6), 91 (22);
HRMS found 248.0836. C14H14ClNO requires for 35MH,
248.0842.
3.1.19. (E or Z)-3-(N-4-Methoxybenzyl-2,2-dichloro-
ethanamido)-5-methyl-hex-2-ene (23). Following the
same procedure as for the preparation of 3, a solution of
2-methyl-hexan-3-one 2225 (1.00 g, 8.76 mmol) and
4-methoxybenzylamine (1.14 mL, 8.76 mmol) was refluxed
in toluene (45 mL) for 15 h and then, at 08C, dichloroacetyl
chloride (0.93 mL, 9.64 mmol) was added dropwise fol-
lowed by the addition of N,N-diethylaniline (1.53 mL,
9.64 mmol). After 4 h, the mixture was worked-up and
purified by column chromatography (silica, petroleum
ether–ethyl acetate, 11:2) to afford 23 (0.61 g, 20%) as an
inseparable mixture with 24 (0.36 g, 12%) as an oil.
Enamide 23: Rf 0.3 (petroleum ether–ethyl acetate, 11:2);
nmax (thin film) (as a mixture with 24; 23:24¼63:37) 3040
(br, w), 2958 (br, m), 1680 (m, CvO), 1613 (w), 1526 (m),
1249 (m), 1177 (m), 698 (br, m), 469 (s) cm21; dH
(270 MHz, CDCl3) 7.19 (2H, d, J¼9 Hz, aromatics), 6.81
(2H, d, J¼9 Hz, aromatics), 6.40 (1H, s, CHCl2), 5.29 (1H,
q, J¼7 Hz, CHCH3), 5.10 (1H, d, J¼14 Hz, CHAr), 4.10
(1H, d, J¼14 Hz, CHAr), 3.77 (3H, s, OCH3), 2.10 (1H, d,
J¼7 Hz, CH2CH), 1.64 (3H, d, J¼7 Hz, CHCH3), 1.21 (1H,
m, CH2CH), 0.94 (6H, br m, (CH3)2CH); dC (67.5 MHz,
CDCl3) 165.2 (NCO), 160.6 (COCH3), 139.2 (CvCHCH3),
137.4 (CvCH), 131.7, 131.2 (CHvC), 114.9
(CvCHCH3), 65.7 (CHCl2), 55.6 (OCH3), 50.4 (NCH2C),
39.0 (CH2CH), 27.5 (CH2CH), 23.0, 14.0 (CvCHCH3 and
CH(CH3)2); m/z (CI, NH3) 361 (35MþNH4þ, 4%), 344
(35MþHþ, 33), 274 (27), 230 (4), 150 (11), 121 (100);
HRMS found 344.2795. C17H23Cl2NO2 requires for 35MH,
3.1.17. (E/Z)-N-Benzyl-4-methyl-5-ethylidene-3-pyrro-
lin-2-one (20). A solution of enamide 18 (100 mg,
0.35 mmol) and RuCl2(PPh3)3 (167 mg, 0.17 mmol) was
heated in dry degassed toluene (2.8 mL) until complete
consumption of starting material. Evaporation of the solvent
in vacuo followed by column chromatography (dichloro-
methane–diethyl ether, 30:1) afforded 20 (70 mg, 94%) as a
1:1 mixture of alkene isomers. Z-isomer: 47%; Rf 0.21
(dichloromethane–diethyl ether, 30:1); nmax (thin film)
3088 (w), 2926 (w), 1682 (s, CvO), 1438 (s), 757 (m)
cm21; dH (270 MHz, CDCl3) 7.30–7.08 (5H, m, aromatics),
5.96 (1H, s, CHCO), 5.31 (1H, q, J¼8 Hz, CHCH3), 5.05
(2H, s, CH2Ph), 2.11 (3H, s, CCH3), 1.77 (3H, d, J¼8 Hz,
CHCH3); dC (67.5 MHz, CDCl3) 171.3 (NCO), 148.8
(CCCH3), 140.5 (CvCH), 138.3 (NCCH), 128.6, 126.9,
125.6 (5£CHvC), 118.4 (COCH), 108.4 (CCHCH3), 44.1
(CH2Ph), 12.5 (CH3C), 10.9 (CH3CH); m/z (CI, NH3) 214
(MþHþ, 100%), 91 (6); HRMS found 214.1224. C14H15NO
requires for MH, 214.1231. E-isomer: 47%; Rf 0.19
(dichloromethane–diethyl ether, 30:1); nmax (thin film)
3011 (m), 2926 (w), 1679 (s, CvO), 1216 (m), 758 (s)
cm21; dH (270 MHz, CDCl3) 7.31–7.11 (5H, m, aromatics),
6.01 (1H, s, CHCO), 5.36 (1H, q, J¼8 Hz, CHCH3), 4.80
(2H, s, CH2Ph), 2.39 (3H, s, CCH3), 1.95 (3H, d, J¼8 Hz,
CHCH3); dC (67.5 MHz, CDCl3) 169.0 (NCO), 146.7
(CCCH3), 139.7 (CvCH), 137.6 (NCCH), 128.5, 127.0,
126.6 (5£CHvC), 122.8 (COCH), 110.8 (CCHCH3), 42.3
(CH2Ph), 17.1 (CH3C), 12.9 (CH3CH); m/z (CI, NH3) 214
(MþHþ, 100%).
344.2797. The presence of 24 was indicated by 1H and 13
C
NMR spectroscopy: dH (270 MHz, CDCl3) 6.31 (1H, s,
CHCl2), 5.20 (1H, br d, J¼14.5 Hz, CHAr), 4.85 (1H, d,
J¼10.2 Hz, CHCH(CH3)2), 3.95 (1H, br d, J¼14.5 Hz,
CHAr), 1.05 (3H, t, J¼8 Hz, CH2CH3); dC (67.5 MHz,
CDCl3) 164.3 (NCO), 159.0 (COCH3), 140.4 (CvCHCH),
137.7 (CvCH), 135.7, 129.9 (CHvC), 113.7 (CvCHCH),
63.9 (CHCl2), 55.1 (OCH3), 48.8 (NCH2C), 27.0
(CH(CH3)2), 22.1 (CH2CH3), 14.1 (CH(CH3)2), 7.8
(CH2CH3).
3.1.18. (E/Z)-N-Benzyl-3-chloro-4-methyl-5-ethylidene-
3-pyrrolin-2-one (21). A solution of enamide 19 (200 mg,
0.62 mmol) and RuCl2(PPh3)3 (296 mg, 0.31 mmol) was
heated in dry degassed toluene (5.6 mL) until complete
consumption of starting material. Evaporation of the solvent
in vacuo followed by column chromatography (dichloro-
methane–diethyl ether, 30:1) afforded 21 (103 mg, 67%) as

J. S. Bryans et al. / Tetrahedron 59 (2003) 6221–6231
6229
3.1.20. (E/Z)-N-(4-Methoxy-benzyl)-4-methyl-5-
isobutylidene-3-pyrrolin-2-one (25). solution of
CHvC, aromatic), 6.45–6.33 (2H, m, CH-aromatic), 6.41
(1H, s, CHCl2), 5.29 (1H, q, J¼7.0 Hz, CHCH3), 5.05 (1H,
br d, J¼13.5 Hz, CHAHBN), 4.32 (1H, br d, J¼13.5 Hz,
CHAHBN), 3.78 (3H, s, OCH3), 3.74 (3H, s, OCH3), 2.07
(2H, m, CH2CH(CH3)2), 1.70 (1H, app. quin., J¼7.0 Hz,
CH(CH3)2), 1.59 (3H, d, J¼7.0 Hz, CHCH3), 0.94 (6H, d,
J¼6.5 Hz, 2£CH3); dC (67.5 MHz, CDCl3) 165.3, 161.2
(CvO and 2£COMe, aromatic), 139.7 (CH, aromatic),
138.7 (CvCN), 131.5 (CH, aromatic), 127.2 (CH, aromatic
or CHCH3), 117.6 (CCH2N), 104.8 (CH, aromatic or
CHCH3), 98.6 (CH aromatic), 65.1 (CHCl2), 55.9
(2£OCH3), 44.3 (CH2Ar), 38.4 (CH2CH(CH3)2), 27.1
(CH(CH3)2), 22.7, 12.7 (CHCH3 and C(CH3)2); m/z (CI,
NH3) 374 (35MþHþ, 32%), 301 (15), 151 (100); HRMS
found 374.1291. C18H25Cl2NO3 requires for 35MH,
374.1289. The presence of compound 28 was indicated by
1H NMR spectroscopy; Rf 0.5 (5:1 petroleum ether–
EtOAc); dH (270 MHz, CDCl3) 4.88 (1H, d, J¼10.0 Hz,
CHCH(CH3)2), 2.48–2.31 (1H, m, CH(CH3)2), 2.13–2.03
(2H, m, CH2CH3), 1.23 (3H, t, J¼7.0 Hz, CH2CH3).
A
enamides 23 and 24 (1.7:1, 189 mg, 0.55 mmol) and
RuCl2(PPh3)3 (268 mg, 0.28 mmol) was heated in dry
degassed toluene (8 mL) until complete consumption of
starting material. Evaporation of the solvent in vacuo
followed by column chromatography (dichloromethane–
diethyl ether, 30:1) afforded E-25 (39 mg, 41% from 23) and
an inseparable mixture of Z-25 and 26 (33 mg, 35% from
23; 28 mg, 51% from 24) in a 1:1.2 ratio from the 1H NMR
spectrum. Z-25: 35%; Rf 0.15 (dichloromethane–diethyl
ether, 30:1); nmax (thin film) 2963 (m), 2927 (m), 1687 (s,
CvO), 1530 (s), 1266 (s), 758 (s) cm21; dH (270 MHz,
CDCl3) 7.00 (2H, d, J¼9 Hz, aromatics), 6.84 (2H, d,
J¼9 Hz, aromatics), 5.95 (1H, s, CHCO), 4.96 (1H, d,
J¼11 Hz, CH–CH(CH3)2), 4.94 (2H, s, CH2Ph), 3.78 (3H,
s, OCH3), 2.79 (1H, m, CH(CH3)2), 2.11 (3H, s, CCH3),
0.82 (6H, d, J¼6 Hz, CH(CH3)2); dC (67.5 MHz, CDCl3)
170.9 (NCO), 158.5 (COCH3), 149.3 (CCH3), 137.0
(NCH2C), 130.1 (N–CvC), 126.8 (2£CHvC), 121.2
(COCH), 119.0 (CHCH(CH3)2), 113.9 (2£CHCOCH3),
55.2 (OCH3), 43.6 (CH2Ar), 26.1 (CH(CH3)2), 23.3, 12.6
(CH(CH3)2 and CCH3); m/z (CI, NH3) 272 (MþHþ, 100%),
152 (7), 121 (25); HRMS found 272.1646. C17H21NO2
requires for MH, 272.1650. E-25: 41%; Rf 0.1 (dichloro-
methane–diethyl ether, 30:1); nmax (thin film) 3012 (m),
2928 (m), 1680 (s, CvO), 1513 (m), 1215 (m), 758 (s)
cm21; dH (270 MHz, CDCl3) 7.11 (2H, d, J¼9 Hz,
aromatics), 6.83 (2H, d, J¼9 Hz, aromatics), 5.98 (1H, s,
CHCO), 5.14 (1H, d, J¼11 Hz, CH(CH3)2), 4.73 (2H, s,
CH2Ph), 3.77 (3H, s, OCH3), 2.99 (1H, m, CH(CH3)2), 2.29
(3H, s, CCH3), 0.99 (6H, d, J¼6 Hz, CH(CH3)2); dC
(67.5 MHz, CDCl3) 168.9 (NCO), 158.0 (COCH3), 146.0
(CCH3), 136.9 (NCH2C), 129.7 (N–CvC), 128.0
(2£CHvC), 124.4 (COCH), 123.3 (CHCH(CH3)2), 113.7
(2£CHCOCH3), 55.2 (OCH3), 41.6 (CH2Ar), 26.3
(CH(CH3)2), 23.6, 16.6 (CH(CH3)2 and CCH3); m/z (CI,
NH3) 272 (MþHþ, 100%), 152 (6), 121 (27). The presence
of (5E)-5-ethylidene-4-isopropyl-N-(4-methoxy-benzyl)-3-
pyrrolin-2-one 26 was indicated by NMR spectroscopy. dH
(270 MHz, CDCl3) 6.92 (2H, d, J¼7 Hz, aromatics), 6.75
(2H, d, J¼7 Hz, aromatics), 5.80 (1H, s, COCH), 5.29 (1H,
q, J¼7.8 Hz, CvCHCH3), 4.80 (2H, s, CH2Ar), 3.70 (3H, s,
CH3O), 2.71 (1H, m, CHMe2), 1.75 (3H, d, J¼8 Hz,
CvCHCH3), 1.14 (6H, d, J¼6.8 Hz, CH(CH3)2); dC
(67.5 MHz, CDCl3) 170.9 (NCO), 158.4 (COCH3), 149.3
(CvCHCO), 137.0, 130.1 (NCvCH and NCH2CvC),
126.8 (2£CHvC), 115.4 (COCH), 113.8 (2£CHvC),
107.5 (CHCH3), 55.1 (CH3O), 43.6 (ArCH2), 30.8
(CH(CH3)2), 22.9, 12.5 (CH(CH3)2 and CHCH3).
3.1.22. Ruthenium(II)-mediated cyclisation of enamides
(27) and (28). Enamides 27 and 28 (1.5:1, 457 mg,
1.22 mmol), and RuCl2(PPh3)3 (585 mg, 0.61 mmol) were
combined in dry, thoroughly degassed toluene (12 mL) and
heated to reflux under nitrogen for 4 days to give 31 as a
brown solid (17 mg, 12%), a mixture of 31 (9 mg, 5%) and
29 (19 mg, 10%) as a semi-solid, a mixture of 29 (42 mg,
22%) and 32 (27 mg, 14%) as an oil and 30 (90 mg, 41%) as
an
oil.
(5Z)-1-(2,4-Dimethoxybenzyl)-4-methyl-5-(2-
methylpropylidene)-3-pyrrolin-2-one 29; Rf 0.3 (2:1
petroleum ether–EtOAc); nmax/cm21 (thin film) 2999 (w),
2959 (m), 2925 (m), 2866 (w), 1688 (s, CvO), 1615 (m),
1590 (m), 1507 (m), 1458 (m), 1260 (m), 1207 (m); dH
(270 MHz, CDCl3) 6.67 (1H, d, J¼8.5 Hz, CHvC,
aromatic), 6.44 (1H, d, J¼2.5 Hz, CH-aromatic), 6.37
(1H, dd, J¼8.5, 2.5 Hz, CH-aromatic), 5.94 (1H, s,
CHCO), 4.96 (1H, d, J¼11.0 Hz, CHCH(CH3)2), 4.89
(2H, s, CH2Ar), 3.83 (3H, s, OCH3), 3.76 (3H, s, OCH3),
2.82–2.54 (1H, m, CH(CH3)2), 2.11 (3H, s, CHCH3), 0.81
(6H, d, J¼6.5 Hz, CH(CH3)2); dC (67.5 MHz, CDCl3) 171.5
(CvO), 160.1, 157.4 (2£COMe, aromatics), 149.4 (CCH3),
137.6 (CCN), 127.0 (CHvC, aromatic), 121.8 (NCOCH),
119.6, 119.5 (NCvCH and NCH2C), 104.4, 98.6
(2£CHvC, aromatic), 55.7 (2£OCH3), 39.4 (CH2Ar),
23.9 (2£CH3), 26.1 (CH(CH3)2), 13.0 (CH3); m/z (CI,
NH3) 302 (MþHþ, 100%), 151 (20); HRMS found
302.1759. C18H23NO3 requires for MH, 302.1756. (5E)-1-
(2,4-Dimethoxybenzyl)-4-methyl-5-(2-methylpropylidene)-
3-pyrrolin-2-one 30; Rf 0.3 (1:1 petroleum ether–EtOAc);
n
max/cm21 (thin film) 2963 (m), 2926 (m), 2839 (w), 1686 (s,
3.1.21. 2,2-Dichloro-N-(2,4-dimethoxybenzyl)-N-[(1E or
Z)-1-isobutylprop-1-enyl]acetamide (27). Following the
representative procedure for the preparation of 3, ketone 22
(2.18 g, 19.1 mmol), 2,4-dimethoxybenzylamine (3.19 g,
2.87 mL, 19.1 mmol) and dichloroacetyl chloride (3.10 g,
2.02 mL, 21.0 mmol) in the presence of triethylamine
(5.80 g, 7.99 mL, 57.3 mmol) were reacted to give an
inseparable mixture of 27 (1.40 g, 19%) and 28 (0.92 g,
13%) as a yellow oil. Rf 0.5 (5:1 petroleum ether–EtOAc);
CvO), 1615 (m), 1590 (m), 1508 (m), 1438 (m), 1352 (m);
dH (270 MHz, CDCl3) 6.88 (1H, d, J¼8.0 Hz, CHvC,
aromatic), 6.42 (1H, d, J¼2.0 Hz, CH-aromatic), 6.37
(1H, dd, J¼8.0, 2.0 Hz, aromatic), 5.96 (1H, s, CHCO),
5.26 (1H, d, J¼10.5 Hz, CHCH(CH3)2), 4.71 (2H, s, CH2Ar),
3.84 (3H, s, OCH3), 3.75 (3H, s, OCH3), 3.09–2.91 (1H, m,
CH(CH3)2), 2.27 (3H, s, CH3), 0.98 (6H, d, J¼6.5 Hz,
2£CH3); dC (67.5 MHz, CDCl3) 169.5 (CvO), 160.2, 157.6
(2£COMe, aromatics), 146.5 (CCH3), 137.4 (NCvCH),
129.1 (CHvC, aromatic), 124.9, 123.8 (NCOCH and
NCvCH), 118.5 (NCH2C), 104.5, 98.4 (2£CHvC, aro-
matics), 55.6 (2£OCH3), 36.6 (CH2Ar), 29.6 (CH(CH3)2),
n
max/cm21 (CHCl3) 3008 (m), 2962 (s), 2871 (m), 1673 (s,
CvO), 1613 (m), 1507 (m), 1402 (m), 1158 (m), 1038 (m).
Enamide 27: dH (270 MHz, CDCl3) 7.21 (1H, d, J¼8.0 Hz,

6230
J. S. Bryans et al. / Tetrahedron 59 (2003) 6221–6231
24.1 (2£CH3), 17.0 (CH3); m/z (CI, NH3) 302 (MþHþ,
100%), 167 (10), 151 (40); HRMS found 302.1754.
C18H23NO3 requires for MH, 302.1756. (5E)-1-(2,4-
Dimethoxybenzyl)-5-ethylidene-4-isopropyl-3-pyrrolin-2-
one 31; mp 124–1268C; Rf 0.3 (2:1 petroleum ether–
EtOAc); nmax/cm21 (CHCl3) 3014 (m), 2968 (m), 1680 (s,
CvO), 1655 (m), 1507 (m), 1261 (m), 1157 (m), 1038 (m),
843 (w); dH (270 MHz, CDCl3) 6.67 (1H, d, J¼8.0 Hz,
CHvC aromatic), 6.44 (1H, d, J¼2.5 Hz, CH-aromatic),
6.39 (1H, dd, J¼8.0, 2.5 Hz, CH-aromatic), 5.92 (1H, s,
CHCO), 5.36 (1H, q, J¼8.0 Hz, CHCH3), 4.92 (2H, s,
CH2Ar), 3.81 (3H, s, OCH3), 3.76 (3H, s, OCH3), 2.78 (1H,
sept, J¼7.0 Hz, CH(CH3)2), 1.74 (3H, d, J¼8.0 Hz,
CHCH3), 1.21 (6H, d, J¼7.0 Hz, CH(CH3)2); dC
(67.5 MHz, CDCl3) 172.0 (CvO), 160.3, 159.9, 157.6
(2£COMe, aromatics and CCH(CH3)2), 139.8 (NC), 127.0
(CH, aromatic), 119.6 (CHCO), 116.2 (NCH2C), 108.3
(CHCH3), 104.6 (CH aromatic), 98.9 (CH, aromatic), 55.9
(2£CH3O), 39.9 (CH2Ar), 26.0 (CH(CH3)2), 23.6 (CH3),
12.5 (2£CH3); m/z (CI, NH3) 302 (MþHþ, 100%), 151 (20);
HRMS found 302.1754. C18H23NO3 requires for MH,
302.1756. (5Z)-1-(2,4-Dimethoxybenzyl)-5-ethylidene-4-
isopropyl-3-pyrrolin-2-one 32; the presence of this com-
pound was indicated by 1H NMR spectroscopy; Rf 0.3 (2:1
petroleum ether–EtOAc); dH (270 MHz, CDCl3)6.81(1H, d,
J¼8.0 Hz, CHvC, aromatic), 6.47–6.33 (2H, m, CH
aromatics), 6.03 (1H, s, CHCO), 5.40 (1H, qd, J¼8.0,
1.5 Hz, CHCH3), 4.72 (2H, s, CH2Ar), 3.81 (3H, s, OCH3),
3.76 (3H, s, OCH3), 3.09–2.96 (1H, m, CH(CH3)2), 1.97 (3H,
d, J¼8.0 Hz, CHCH3), 1.23 (6H, d, J¼7.0 Hz, CH(CH3)2).
ether–EtOAc); nmax/cm21 (CHCl3) 3456 (m, NH), 2967
(m), 2928 (m), 2870 (m), 1685 (s, CvO), 1464 (m), 1347
(w), 1174 (w), 976 (w), 842 (m); dH (270 MHz, CDCl3) 9.28
(1H, br s, NH), 5.94 (1H, s, CHCO), 5.41 (1H, d,
J¼10.5 Hz,
CHCH(CH3)2),
3.10–2.90
(1H,
m,
CH(CH3)2), 2.29 (3H, s, CH3) 1.08 (6H, d, J¼6.5 Hz,
CH(CH3)2); dC (67.5 MHz, CDCl3) 147.8 (CCH3), 137.0
(CCN), 127.0 (CHCH(CH3)2), 121.8 (CHCO), 27.3
(CH(CH3)2), 24.0, 16.8 (3£CH3); m/z (CI, NH3) 152
(MþHþ, 100%), 136 (70); HRMS found 152.1074.
C9H13NO requires for MH, 152.1075.
Acknowledgements
We would like to thank Parke-Davis/Pfizer and the BBSRC
for funding and David Sharpe for preliminary work on the
pulchellalactam project.
References
1. (a) Bowman, W. R.; Fletcher, A. J.; Potts, B. S. J. Chem. Soc.,
Perkin Trans. 1 2002, 2747. (b) Parsons, A. F. An Introduction
to Free Radical Chemistry; Blackwell Science: Oxford, 2000.
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2. (a) Clark, A. J. Chem. Soc. Rev. 2002, 31, 1. (b) Iqbal, J.;
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Ghirardini, G.; Grandi, R.; Libertini, E.; Montemaggi, M. C.;
Pagnoni, U. M.; Pinetti, A.; De Buyck, L.; Parsons, A. F.
Tetrahedron 1999, 55, 5839. (c) Ghelfi, F.; Ghirardini, G.;
Libertini, E.; Forti, L.; Pagnoni, U. M. Tetrahedron Lett. 1999,
40, 8595. (d) Clark, A. J.; Battle, G. M.; Bridge, A.
Tetrahedron Lett. 2001, 42, 4409.
3.1.23. (5Z)-4-Methyl-5-(2-methylpropylidene)-3-pyrro-
lin-2-one or (Z)-pulchellalactam (2). Trifluoroacetic acid
(4.6 mL) was added to lactam 29 (32 mg, 0.11 mmol) and
the reaction left to stir at rt under nitrogen for 0.25 h. The
reaction was observed to turn dark red/purple in colour
almost immediately. The reaction was then diluted with
CHCl3 (15 mL) and the trifluoroacetic acid was
co-evaporated with the CHCl3 to give a purple/brown
residue. Column chromatography (silica; 1:1, petroleum
ether–EtOAc) gave 224 as a crystalline solid (11 mg, 66%).
Rf 0.2 (1:1 petroleum ether–EtOAc); nmax/cm21 (CHCl3)
3462 (w, NH), 2965 (m), 2928 (m), 1685 (s, CvO), 1462
(m), 1347 (m), 843 (m), 672 (m); dH (270 MHz, CDCl3)
8.71 (1H, br s, NH), 5.86 (1H, d, J¼1.5 Hz, CHCO), 5.12
(1H, d, J¼9.5 Hz, CHCH(CH3)2), 2.80–2.60 (1H, m,
CH(CH3)2), 2.07 (3H, s, CH3) 1.10 (6H, d, J¼6.5 Hz,
CH(CH3)2); dC (67.5 MHz, CDCl3) 173.0 (CvO), 149.3
(CCH3), 138.1 (CCN), 121.5 (CHCH(CH3)2), 120.7
(CHCO), 28.1 (CH(CH3)2), 23.4, 12.4 (3£CH3); m/z (CI,
NH3) 169 (MþNHþ4 , 20%), 152 (MþHþ, 100); HRMS
found 169.1338. C9H13NO requires for MNH4, 169.1340.
4. For a review see: (a) Ishibashi, H.; Sato, T.; Ikeda, M.
Synthesis 2002, 695. (b) Chatgilialoglu, C.; Ferreri, C.; Guerra,
M.; Timokhin, V.; Froudakis, G.; Gimisis, T. J. Am. Chem.
Soc. 2002, 124, 10765.
´
5. (a) Parsons, A. F. C. R. Acad. Sci. Ser. IIc: Chim. 2001, 4, 391.
(b) Bryans, J. S.; Chessum, N. E. A.; Parsons, A. F.; Ghelfi, F.
Tetrahedron Lett. 2001, 42, 2901. (c) Clark, A. J.; Dell, C. P.;
´
McDonagh, J. P. C. R. Acad. Sci. Ser. IIc: Chim. 2001, 4, 1.
6. Taylor, C. P. Neurology 1994, 44, 510.
7. Sutton, K. G.; Snutch, T. P. Drug Dev. Res. 2002, 54, 167.
8. Bryans, J. S.; Morrell, A. I. Int. Pat. Appl. WO 99/14184,
1999; Chem. Abstr., 1999, 130, 223583.
9. (a) Bryans, J. S.; Davies, N.; Gee, N. S.; Dissanayake, V. U.
K.; Ratcliffe, G. S.; Horwell, D. C.; Kneen, C. O.; Morrell,
A. I.; Oles, R. J.; O’Toole, J. C.; Perkins, G. M.; Singh, L.;
Suman-Chauhan, N.; O’Neill, J. A. J. Med. Chem. 1998, 41,
1838. (b) Receveur, J.-M.; Bryans, J. S.; Field, M. J.; Singh,
L.; Horwell, D. C. Bioorg. Med. Chem. Lett. 1999, 9, 2329.
(c) Bryans, J. S.; Horwell, D. C.; Ratcliffe, G. S.; Receveur,
J.-M.; Rubin, J. R. Bioorg. Med. Chem. 1999, 7, 715.
(d) Griffiths, G.; Mettler, H.; Mills, L. S.; Previdoli, F. Helv.
Chim. Acta 1991, 74, 309.
3.1.24. (5E)-4-Methyl-5-(2-methylpropylidene)-3-pyrro-
lin-2-one or (E)-pulchellalactam (33). Trifluoroacetic acid
(13 mL) was added to lactam 30 (81 mg, 0.31 mmol) and
the reaction left to stir at rt under nitrogen for 2 h. The
reaction was observed to turn dark red/purple in colour over
time. The reaction was then diluted with CHCl3 (20 mL)
and the trifluoroacetic acid was co-evaporated with the
CHCl3 to give a purple/brown residue. Column chromato-
graphy (silica; 1:1, petroleum ether–EtOAc) gave 3324 as a
white crystalline solid (34 mg, 83%). Rf 0.2 (1:1 petroleum
10. For a similar cyclisation mediated by nickel in AcOH/iPrOH
see: Cassayre, J.; Quiclet-Sire, B.; Saunier, J.-B.; Zard, S. Z.
Tetrahedron 1998, 54, 1029.

J. S. Bryans et al. / Tetrahedron 59 (2003) 6221–6231
6231
11. Heating the corresponding N-benzyl protected enamide 3 with
RuCl2(PPh3)3 in toluene gave 2-benzyl-4,4-dichloro-1-
hydroxy-2-azaspiro[4.5]decan-3-one in only 20% yield
(together with b-lactam products in 28% yield).
12. Copper(I) hydride can be generated from copper(I) chloride
and tributyltin hydride: Tanaka, H.; Yamaguchi, Y.; Sumida,
S.-I.; Kuroboshi, M.; Mochizuki, M.; Torii, S. J. Chem. Soc.,
Perkin Trans. 1 1999, 3463.
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