Palladium catalysed bis- and tris-cyclisations furnishing fused cyclopropyl carbo/heterocycles

Article abstract of DOI:10.1016/j.tet.2006.07.100

Catalytic bis- and tris-cyclisation of a series of acyclic carbo- and heterocyclic precursors results in formation of two or three rings, two or three C-C bonds and two asymmetric tetrasubstituted C-centres regio- and stereoselectively in excellent yield.

Full text of DOI:10.1016/j.tet.2006.07.100

Tetrahedron 62 (2006) 9523–9532
Palladium catalysed bis- and tris-cyclisations furnishing fused
cyclopropyl carbo/heterocycles
*
Ronald Grigg, Uthai Sakee, Visuvanathar Sridharan, Sukanthini Sukirthalingam and
Ravishanker Thangavelauthum
Molecular Innovation Diversity and Automated Synthesis (MIDAS) Centre, School of Chemistry,
Leeds University, Leeds LS2 9JT, UK
Received 26 May 2006; revised 7 July 2006; accepted 27 July 2006
Available online 21 August 2006
Abstract—Catalytic bis- and tris-cyclisation of a series of acyclic carbo- and heterocyclic precursors results in formation of two or three rings,
two or three C–C bonds and two asymmetric tetrasubstituted C-centres regio- and stereoselectively in excellent yield.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
cyclisation
Pd(0)
X
R
PdX
R
Palladium catalysed cascade reactions provide valuable
strategies for the constructions of fused, bridged and spiro
carbo/heterocyclic systems.1,2 Furthermore such cascades
have demonstrated their utility for the construction of small
strained rings. We and others have reported palladium
catalysed cyclisations leading to di-, tri- and tetracyclic
compounds containing fused cyclopropane rings.3–10 Addi-
tionally palladium catalysed tandem cyclisation–cyclopro-
panation is a novel way of assembling a variety of carbo/
heterocyclic skeletons with concomitant engineering of con-
siderable additional molecular complexity not available via
classical methods for the formation of cyclopropanes such
as the reaction of diazo compounds with alkenes catalysed
by Rh,11a–e Ru,11f Cu,12 Pd13 and Pt14 complexes, and Pt15a
and Au15b catalysed cycloisomerisation.
PdX
oxidative
addition
R
X = Br, I, OTf
A
B
R = H
R= H
/
3-exo-trig
β-hydride
elimination
PdX
R
C
D
R
Scheme 1.
2. Bis-cyclisation cascades
2.1. 5-exo-trig/3-exo-trig Cascades
In this paper we report full details of palladium catalysed
bis- and tris-cyclisation cascades affording fused/spiro
cyclopropyl carbo/heterocycles.3a–c A general palladium
catalysed bis-cyclisation cascade is shown in Scheme 1.
2.1.1. Carbocyclic systems. Enol triflates 3a–c were pre-
pared (Scheme 2) to explore palladium catalysed 5-exo-trig/
3-exo-trig cascades forming tricyclic cyclopropanes. Thus
1a–c were treated with 1.1 mol equiv BuOK in BuOH
and 4-iodo-2-methylbut-3-ene to give 2a–c in good yields.
Subsequent treatment of 2a–c with Comins triflating agent16
in the presence of LDA at ꢀ78 ꢁC afforded enol triflates
3a–c in 77–81% yields.
t
t
Oxidative addition of Pd(0) to the carbon–halide/triflate
bond gives a vinyl palladium(II) species A. Cyclisation of
A onto a proximal alkene gives the alkyl palladium(II) inter-
mediate B. When R¼H then B may undergo a b-hydride
elimination to give C. If RsH a second cyclisation occurs
to form the tricyclic cyclopropane D.
When enol triflate 3awas reacted in the presence of 10 mol %
Pd(OAc)2, 20 mol % PPh3, Na2CO3 (2 mol equiv), Et4NCl
(1 mol equiv) in boiling acetonitrile it afforded 4 as a single
diastereoisomer in 88% yield. The bond forming sequence
is detailed in Scheme 3. The relative stereochemistry of 4
was established by NOE studies on 5, which was prepared
* Corresponding author. Tel.: +441133436501; fax: +441133436530;
e-mail: r.grigg@leeds.ac.uk
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.07.100

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R. Grigg et al. / Tetrahedron 62 (2006) 9523–9532
O
3/5/6-ring systems. It would be expected that addition of
O
CO2R (i)tBuOK, tBuOH
(ii)
Ag+ or Tl+ salts17,18 would suppress double bond isomerisa-
tion (vide infra 21, 22). Indeed addition of TlOAc (1.2 mol
equiv) and reducing the reaction time to 5 h afforded 9
(76%) as the sole product.
CO R
( )
n
2
( )
n
2 a-c
78-87%
I
a. n = 1, R = Me
b. n = 2, R = Et
c. n = 3, R = Me
1
83 °C, 12h
Cl
The vinyl triflate 12 was prepared in 70% yield from b-tetra-
lone in three steps by carboxymethylation, alkylation and
triflation (Scheme 5) in order to study the formation of a
tetracyclic cyclopropyl system. Cyclisation of 12 under the
same conditions as described above afforded 13 in 90%
yield. The relative stereochemistry of 13 was also estab-
lished by LiAlH4 reduction to give 14 followed by NOE
studies. Irradiation of both of the diastereotopic Hc protons
(d 3.45) resulted in enhancement (2.5%) of the signal for
Ha (d 0.90) thus establishing their cis-relationship.
LDA, - 78 °C, 1h
Tf
N
Tf
N
3h
OTf
CO2R
( )
n
3 a-c
77-81%
Scheme 2.
LPd
OTf
Pd(0)
PdL
5-exo-trig
CO2Me
oxidative
addition
MeO2C
CO2Me
CO2Me
3a
(i) NaH, Dimethyl carbonate
THF,60 °C
O
O
6
(ii) tBuOK, tBuOH
3-exo-trig
LDA, - 78 °C
THF, Comins's
reagent
β-hydride
elimination
LPd
CO2Me
CO2Me
MeO2C
4
OTf
Scheme 3.
12 80%
by LiAlH4 reduction of 4. Thus irradiation of both of the dia-
stereotopic protons Hc (d 3.45) resulted in 3% enhancement
of the signal for the proton Ha (d 0.90) showing that the cyclo-
propane ring and the –CH2OH group are cis-related.
Scheme 5.
Hc
Hc
HOC
MeO2C
Hb
Ha
Ha
Hb
CO2Me
Ha
Hb
CO2Et
13
14
COH
Hc
COH
Hc Hc
Hc
8
7
4
5
2.1.2. Heterocyclic systems. Enol triflate 16 was synthes-
ised in three steps in good yield (Scheme 6). Methyl 4-oxo-
piperidine-3-carboxylate was N-acetylated in the presence
of Et3N in CH2Cl2. The alkyl side chain was then introduced
in the presence of tBuOK as base. Triflation of 15 was carried
out using McMurry’s method19 to afford 16 in 64% yield.
In a similar manner the analogous six-membered enol triflate
3b underwent consecutive stereo- and regiospecific 5-exo-
trig and 3-exo-trig cyclisations to give the 3/5/6-ring system
7 in 73% yield. The relative stereochemistry was established
by NOE studies on 8, which was obtained by LiAlH4 reduc-
tion of 7. Irradiation of both of the diastereotopic protons Hc
(d 3.45) resulted in 2.5% enhancement of the signal for Ha
(d 1.05).
Enol triflate 16 successfully underwent a palladium catalysed
5-exo-trig/3-exo-trig cyclisation cascade to give 17 as a
single stereoisomer in 62% yield.
A further heterocyclic precursor, vinyl bromide 18, was
prepared from 2,3-dibromocyclohexene and 2-methyl-2-
propen-1-ol in 68% yield. It cyclised in the presence of
5 mol % PdCl2(PPh3)2, Et4NCl (1 mol equiv) and Zn dust
The seven-membered ring enol triflate 3c cyclised under
similar conditions to afford a 2:1:1 mixture of 9, 10 and 11
in 75% yield (Scheme 4). In this case double bond isomerisa-
tion proved more facile than in the case of the 3/5/5- and
Pd(OAc)2 / PPh3
Na2CO3
Et4NCl
OTf
+
+
CO2Me
:
CO2Me
70%
CO2Me
CO2Me
MeCN, 80 °C, 8h
9
10
11
3c
2
1
:
1
Scheme 4.

R. Grigg et al. / Tetrahedron 62 (2006) 9523–9532
9525
O
O
N
CO2Me
(i) Ac2O, Et3N, CH2Cl2
(ii) tBuOK, tBuOH ∆ 19h
Br
CO2Me
N
H
N
N
H
COMe
COMe
23
COMe
24
15 45%
I
(i) NaH, THF, 0 °C
(ii) PhNTf2
All the foregoing cyclopropyl forming cyclisations proceed
regio- and stereoselectively and involve the formation of
two rings, two C–C bonds and two chiral tetrasubstituted
C-centres.
rt to 60 °C 8h
OTf
Pd(OAc)2
Na2CO3
2.2.1. Mechanism. Cyclopropanation as an integral part of
palladium catalysed cascades is often concealed by rear-
rangement of a cyclopropylcarbinylpalladium intermediate
with accompanying ring expansion in appropriate cases.
This process was first identified and explained, essentially si-
multaneously, by Torii21 and Negishi.22 Negishi formalised
the rearrangement in terms of type I 25 and type II 29 sub-
strates (Scheme 7).22 The key difference is that a type I sub-
strate is processed via intermediate 27 in which the required
syn alignment of bonds b to the palladium only allows either
equilibration with 26 or b-H elimination to form 28. In con-
trast type II substrates 29 proceed via 31, which can equili-
brate with 30 but additionally now possess a rotatable bond
CO2Me
CO2Me
Et4NCl
MeCN, 80 °C, 8h
N
N
17
COMe
COMe
64%
62%
16
Scheme 6.
(2 mol equiv) in MeCN at 80 ꢁC to afford 19 in 50% yield.
There are twopotential roles for the Zn dust: (a) as a reductant
of Pd(II) to Pd(0) and (b) as a halogen sink20 promoting
formation of a more reactive, coordinatively unsaturated
palladium intermediate. The relative stereochemistry of 19
was established by NOE studies. Thus irradiation of proton
Ha (d 3.92) effected enhancement (2%) of the signal of Hb
(d 1.10) establishing that the cyclopropane ring and Ha
are cis-related.
31 (
) allowing the palladium to attain a syn alignment
with either cyclopropyl bond a or b. syn Alignment with
bond b triggers a cyclopropylcarbinylpalladium ring expan-
sion affording 32 and subsequently 33 (or double bond iso-
mer) in which the diagnostic olefinic geometry (R1/R2) has
been inverted.23 For very elegant examples of stereochemical
control of such processes see Torii et al.21 Solvent effects on
type II processes have been interpreted in terms of equilibra-
tion of 31 and 32.24
Hb
Hc
Br
O
O
Ha
19
18
Type I
R
R
R
R
2.2. 6-exo-trig/3-exo-trig Cascades
H
H
( )
n
PdLn
R1
26
PdLn
R
Vinyl halide 20 was synthesised in 55% yield from 2-hy-
droxyacetophenone and 2,3-dibromocyclohex-1-ene in boil-
ing THF, followed by a Wittig reaction. Under standard
palladium catalysed cyclisation conditions 20 gave a 10:1
mixture of 21 and 22 in 71% yield via successive 6-exo-
trig and 3-exo-trig cyclisations. The isomeric product 22
was suppressed by using modified reaction conditions previ-
ously developed by us.18 Thus when the reaction was
repeated with 10 mol % Pd(OAc)2, 20 mol % PPh3 and
1.2 mol equiv TlOAc in boiling MeCN, 21 was obtained
as the sole product in 76% yield.
R1
R1
28
LnPd
25
27
Type II
R
R
R
( )
n
( )
( )
PdLn
R2
n
n
b
PdLn
R2
a
PdLn
1 R2
R
31
R1
30
R1
29
R
R
PdLn
( )
( )
n
n
Br
R1
32
R1
33
R2
R2
O
O
22
O
21
H
H
Scheme 7.
20
We briefly looked at the N-analogue of 20. Compound 23
was prepared in 70% yield from N-acetyl-2-isopropenyl-
aniline in two steps by acetylation followed by alkylation.
Cyclisation of 23 under our standard conditions over 8 h
afforded 24 in a disappointing 37% yield. However, addition
of Zn dust (2 mol equiv) improved the yield from 37 to 72%
and reduced the reaction time to 3 h.
A stereochemical feature not heretofore discussed is the
influence of an allylic stereocentre in the type I substrates,
which is present in 3a–c, 16, 20 and 23 in this work. The
fusion of a new five- or six-membered ring onto an existing
5–7-membered ring in these examples always results in
a cis-arrangement of the allylic substituent and the

9526
R. Grigg et al. / Tetrahedron 62 (2006) 9523–9532
cyclopropyl ring (vide infra). Mechanistically the initial
cyclisation pre-ordains all the subsequent cascade stereo-
chemistry (Scheme 8) and is controlled by the four-centre
C–Pd/alkene transition state 34, ease of coordination of the
alkene and (presumably) tether length. The reaction then
proceeds via a second four-centre transition state 35 to prod-
uct. The initial cyclisation 34/35 places the CH2PdX
group on the exo face of a bowl shaped transition state min-
imising steric interactions. The second cyclisation affords
36, which lacks the rotatable C–C bond necessary to effect
a syn relationship between the Pd–C bond and the cyclo-
propyl ‘a’ bond in 36.
hydride ion capture e.g. 42/44. This process results in
formation of three rings, three C–C bonds, and two chiral
tetrasubstituted C-centres.
CO2Me
LnIPd
CO2Me
CO2Me
CO2Me
I
Pd(0)
5-exo-dig
N
N
Ac
Ac
40
39
5-exo-trig
CO2Me
CO2Me
CO2Me
CO2Me
XPd
LnIPd
a
H
XPd
XPd
Product
R
R
Pd(0)
Pd(0)
( )
( )
n
n
N
Ac
N
Ac
H
36
35
favoured
44
41
formic acid
piperidine
R
XPd
( )
n
X
3-exo-trig
34
R
CO2Me
CO2Me
CO2Me
CO2Me
( )
n
disfavoured
LnIPd
β-hydride
elimination
Scheme 8.
N
N
Ac
Ac
43
Scheme 10.
42
2.3. Tris-cyclisation cascades
Tris-cyclisation substrate 39 was prepared in two steps via
sequential alkylation procedures in good yield (Scheme 9).
3. Summary
Br
We have demonstrated novel regio- and stereoselective pal-
ladium catalysed bis- and tris-cyclisation cascades allowing
access to polyclic cyclopropyl carbo- and heterocycles,
regio- and stereoselectively in good yields. The stability of
the cyclopropyl products arises by suppression of the cyclo-
propylcarbinyl palladium(II) rearrangement due to lack of
a rotatable C–C bond, which prevents a syn alignment be-
tween the Pd–C bond and the relevant cyclopropyl C–C
bond. Related cyclisations7–10 were reported subsequent to
our preliminary communications.3
(i) NaOMe, MeOH
(ii)
BrH2CC CCH2Br
MeO2C CO2Me
37
MeO2C CO2Me
38
I
nBuLi,
NH
Ac
THF, -60°C to rt
CO2Me
CO2Me
4. Experimental
4.1. General
I
N
Ac
39
Melting points were determined on a Reichert hot-stage
apparatus and are uncorrected. Mass spectral data were ob-
tained from a VG Autospec instrument operating at 70 eV
(EI and FAB) or ZD 2000 electrospray instrument (ES).
Accurate molecular masses were obtained from the EPSRC
Swansea Mass Spectroscopy service using perfluorotributyl-
amine or polyethylenimine as an internal standard. Micro-
analyses were obtained using a Carbo Erba MOD11016
instrument. IR spectra were determined on a Nicolet Magna
FT-IR 560 spectrometer. The IR samples were prepared as
thin films by evaporation of a solution of the compound in
DCM onto a germanium plate. Nuclear magnetic resonance
spectra were recorded on QE 300 and Bruker 400 instru-
ments operating at, 300 and 400 MHz, respectively. Solvents
Scheme 9.
Under our standard palladium catalysed conditions 39 un-
dergoes an initial 5-exo-dig cyclisation to give a vinyl palla-
dium intermediate 40, followed by a 5-exo-trig cyclisation
process forming an alkyl palladium intermediate 41, which
then undergoes a 3-exo-trig cyclisation followed by b-hy-
dride elimination to give 44 in 62% yield (Scheme 10).3a Ad-
dition of formic acid and piperidine as hydride ion source
in place of Na2CO3 also afforded 44. This indicates that
all three cyclisation processes: 5-exo-dig, 5-exo-trig and
3-exo-trig are faster than hydride ion capture processes
and also that b-hydride elimination 42/43 is faster than

R. Grigg et al. / Tetrahedron 62 (2006) 9523–9532
9527
were dried according to established methods, unless pur-
chased dry from Aldrich in sure-seal bottles. Palladium ace-
tate was supplied by Johnson Matthey and used as received.
The term ether refers to diethyl ether and the term petrol re-
fers to the 40–60 ꢁC boiling point fraction of petroleum
ether.
in THF (10 ml) while maintaining the temperature between
ꢀ30 and ꢀ20 ꢁC. The resulting solution was stirred at that
temperature for 0.5 h. Compound 2b (5 g, 0.02 mol) in
THF (10 ml) was added dropwise at ꢀ78 ꢁC and the solution
was stirred at ꢀ78 ꢁC for 1 h. N-(5-Chloro-2-pyridyl)trifli-
mide (8.24 g, 0.02 mol) in THF (15 ml) was then added
dropwise at ꢀ78 ꢁC and the resulting mixture maintained
at ꢀ78 ꢁC for 3 h. The solvent was then removed under re-
duced pressure and the residue partitioned between water
(100 ml) and dichloromethane (150 ml). The water layer
was extracted with dichloromethane (100 ml) and the com-
bined dichloromethane extracts dried (MgSO4) and evapo-
rated. The residue was purified by flash chromatography
(SiO2) eluting with 1:1 v/v ether–petroleum ether to afford
the product (6.5 g, 83%) as a pale yellow oil, bp 96–
102 ꢁC/0.02 mmHg. Found: C, 48.75; H, 5.70; S, 8.60; F,
15.25; C15H21F3O5S requires: C, 48.65; H, 5.65; S, 8.65;
F, 15.4%; dH: 1.27 (t, 3H, J 6 Hz, Me), 1.73 (s, 3H,
]CMe), 1.31–2.47 (m, 10H, 5ꢂCH2), 4.23 (m, 2H,
OCH2), 4.71 (m, 2H, ]CH2) and 5.91 (m, 1H, ]CH); m/z
(%): 370 (M+, 1), 325 (5), 302 (100), 221 (11), 69 (93), 55
(63) and 41 (47); nmax (film): 1735, 1425, 1220, 1150,
4.2. General procedure for alkylation of 2-oxocyclo-
alkane carboxylates
2-Methyl-4-iodo-1-butene (1 mmol) was added to a stirred
solution of methyl 2-oxocycloalkane carboxylate (1 mmol)
and KOtBu (1 mmol) in ButOH (10 ml). The solution was
slowly heated to boiling and maintained under reflux for
19 h. After cooling, the mixture was treated with water
to dissolve precipitated salts and extracted with ether
(3ꢂ25 ml). The combined ether extracts were washed with
saturated brine, dried (MgSO4) and evaporated in vacuo to
leave an oil, which was purified by column chromatography
or kugelrohr distillation.
4.2.1. Methyl 1-(3-methyl-3-butenyl)-2-oxocyclopentane
carboxylate (2a). 2-Methyl-4-iodo-1-butene (6.89 g,
35 mmol), methyl 2-oxocyclopentane carboxylate (5.0 g,
35 mmol) and 1 M potassium tert-butoxide in tert-butanol
(42 ml) were reacted by the general method. Workup in
the usual way followed by distillation afforded the product
(6.0 g, 81%) as a colourless oil, bp 77–79 ꢁC/0.03 mmHg.
Found: C, 68.35; H, 8.40; C12H18O3 requires C, 68.55; H,
8.50%; dH: 1.75 (s, 3H, Me), 1.91–2.30 (m, 10H, 5ꢂCH2),
3.75 (s, 3H, OMe), 4.70 (s, 2H, ]CH2); m/z (%): 210
(M+, 1), 151 (4), 142 (100), 110 (89), 55 (36) and 41 (28);
1100, 1040, 920, 840 and 775 cmꢀ1
.
4.2.4. Methyl 1-(3-methyl-3-butenyl)-2-oxocycloheptane
carboxylate (2c). Prepared from 2-methyl-4-iodo-1-butene
(12.6 g, 0.06 mol) and methyl 2-oxocycloheptane carboxyl-
ate (10 g, 0.058 mol) in 1 M potassium tert-butoxide in
tert-butanol (70 ml) by the general procedure. The yellow so-
lution was heated slowly to reflux and maintained there for
19 h. The solvent was then removed under reduced pressure
and the residue partitioned between water (150 ml) and di-
chloromethane (200 ml). The water layer was extracted
with dichloromethane (100 ml) and the combined dichloro-
methane extracts dried (MgSO4) and evaporated. The residue
was purified by flash chromatography (SiO2) eluting with 1:4
v/v ether–petroleum ether to afford the product (12.2 g, 87%)
as a colourless oil, bp 90–93 ꢁC/0.03 mmHg. Found: C,
70.35; H, 9.20; C14H22O3 requires: C, 70.60; H, 9.25%; dH:
1.72 (s, 3H, Me), 1.43–2.61 (m, 14H, 7ꢂCH2), 3.71 (s, 3H,
OMe), 4.70 (m, 2H, ]CH2); m/z (%): 238 (M+, 1), 207 (5),
170 (100), 138 (95), 110 (37) and 55 (18); nmax (film):
nmax: 1770, 1680, 1485, 1280, 1190 and 930 cmꢀ1
.
4.2.2. 1-(3-Methyl-3-butenyl)-1-methoxycarbonyl-2-cy-
clopentenol triflate (3a). n-Butyllithium (19.64 ml, 1.6 M
solution in hexane, 0.03 mol) was added slowly via a syringe
to a stirred solution of diisopropylamine (4.4 ml, 0.031 mol)
in freshly distilled THF (10 ml) while maintaining the tem-
perature between ꢀ30 and ꢀ20 ꢁC. The resulting solution
was stirred at that temperature for 0.5 h. Compound 2a
(6 g, 0.028 mol) in THF (10 ml) was added dropwise at
ꢀ78 ꢁC and the resulting solution stirred at ꢀ78 ꢁC for 1 h.
N-(5-Chloro-2-pyridyl)triflimide (12.3 g, 0.031 mol) in
THF (15 ml) was then added dropwise at ꢀ78 ꢁC and the re-
sulting solution maintained at that temperature for 3 h. After
allowing the reaction mixture to come to room temperature,
water was added, the mixture extracted with ether, washed
with 10% NaOH and the organic extracts dried (MgSO4)
and evaporated. The residual oil was distilled under vacuum
to afford the product (7.5 g, 77%) as a colourless oil, bp 82–
85 ꢁC/0.03 mmHg. Found: C, 45.80; H, 5.00; S, 9.50; F,
16.60; C13H17F3O5S requires: C, 45.60; H, 4.95; S, 9.35; F,
16.65%; dH: 1.72 (s, 3H, Me), 1.92–2.54 (m, 8H, 4ꢂCH2),
3.72 (s, 3H, OMe), 4.75 (d, 2H, J 10 Hz, ]CH2), 5.78 (s,
1H, CH]C); m/z (%): 342 (M+, 1), 273 (100), 149 (7), 133
(50), 108 (94), 69 (80), 55 (47) and 41 (56); nmax (film):
2900, 1730, 1450, 1220 and 910 cmꢀ1
.
4.2.5. 1-(3-Methyl-3-butenyl)-1-methoxycarbonyl-2-
cycloheptenol triflate (3c). n-Butyllithium (28.9 ml, 1.6 M
solution in hexane, 0.046 mol) was added slowly via a
syringe to a stirred solution of diisopropylamine (6.46 ml,
0.046 mol) in THF (15 ml) while maintaining the tempera-
ture between ꢀ30 and ꢀ20 ꢁC and stirring continued at
this temperature for a further 0.5 h. Compound 2c (10 g,
0.04 mol) in THF (10 ml) was then added dropwise at
ꢀ78 ꢁC, and the solution was stirred at ꢀ78 ꢁC for 1 h.
N-(5-Chloro-2-pyridyl)triflimide (16.48 g, 0.04 mol) in THF
(15 ml) was added dropwise at ꢀ78 ꢁC and the resulting
mixture maintained at ꢀ78 ꢁC for 3 h. The solvent was
then removed under reduced pressure and the residue
partitioned between water (200 ml) and dichloromethane
(240 ml). The water layer was extracted with dichloro-
methane (100 ml) and the combined dichloromethane extracts
dried (MgSO4) and evaporated. The residue was purified
by flash chromatography (SiO2) eluting with 1:16 v/v
ether–petroleum ether to afford the product (12.8 g, 81%)
2880, 1700, 1610, 1380, 1200, 1190 and 820 cmꢀ1
.
4.2.3. 1-(3-Methyl-3-butenyl)-1-ethoxycarbonyl-2-cyclo-
hexenol triflate (3b). n-Butyllithium (14.44 ml, 1.6 M solu-
tion in hexane, 0.023 mol) was added slowly via a syringe to
a stirred solution of diisopropylamine (3.23 ml, 0.023 mol)

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R. Grigg et al. / Tetrahedron 62 (2006) 9523–9532
as a pale yellow oil, bp 102–104 ꢁC/0.02 mmHg. Found: C,
48.50; H, 5.65; S, 8.70; F, 15.10; C15H21F3O5S requires: C,
48.65; H, 5.65; S, 8.65; F, 15.40%; dH: 1.70 (s, 3H,
Me), 1.88–2.18 (m, 12H, 6ꢂCH2), 3.75 (s, 3H, OMe), 4.7
(m, 2H, C]CH2), 6.01 (m, 1H, ]CH); m/z (%): 370
(M+, 1), 302 (51), 152 (77), 69 (100) and 55 (43); nmax
(film): 3300, 2900, 1740, 1410, 1210, 1170, 1000 and
The water layer was extracted with dichloromethane
(60 ml) and the combined dichloromethane extracts dried
(MgSO4) and evaporated. The residue was purified by flash
chromatography (SiO2) eluting with 1:16 v/v ether–petro-
leum ether to afford the product (0.12 g, 71%) as a colourless
oil. Found: C, 76.20; H, 9.15; C14H20O2 requires: C, 76.35;
H, 9.10%; dH: 0.52 (d, 1H, J 6 Hz, cyclopropyl H), 1.03 (s,
3H, Me), 1.21 (t, 3H, J 6 Hz, Me), 1.23–2.07 (m, 9H,
4ꢂCH2 and cyclopropyl H), 4.05 (m, 2H, OCH2), 5.23 and
5.72 (2ꢂm, 2ꢂ1H, 2ꢂ]CH); m/z (%): 220 (M+, 3), 147
(100), 131 (31), 105 (61) and 91 (62); nmax (film): 2900,
1740, 1650, 1460, 1400, 1380, 1280, 1200, 1090, 1050,
890 cmꢀ1
.
4.2.6. Methyl 1a-methyl-1,1a,2,3-tetrahydrocyclo-
propa[c]pentalene-3a(4H)-carboxylate (4). Enol triflate
2a (0.3 g, 0.87 mmol) was added to a stirred suspension
of Pd(OAc)2 (0.019 g, 0.087 mmol), PPh3 (0.046 g,
0.175 mmol), Na2CO3 (0.185 g, 1.75 mmol) and Et4NCl
(0.145 g, 0.87 mmol) in acetonitrile (8 ml). The resulting
mixture was boiled under reflux under a nitrogen atmosphere
for 8 h. The solvent was then removed under reduced pres-
sure and the residue partitioned between water (50 ml) and
dichloromethane (50 ml). The water layer was extracted
with dichloromethane (50 ml) and the combined dichloro-
methane extracts dried (MgSO4) and evaporated. The residue
was purified by flash chromatography (SiO2) eluting with
1:16 v/v ether–petroleum ether to afford the product
(0.15 g, 89%) as a colourless oil; dH: 0.95 and 1.00 (2ꢂd,
2ꢂ1H, J 6 Hz, cyclopropyl H), 1.08 (s, 3H, Me), 1.80–2.14
(m, 4H, 2ꢂCH2), 2.36 and 2.92 (2ꢂd, 2ꢂ1H, J 16 Hz,
CH2), 3.54 (s, 3H, OMe), 5.43 and 5.75 (2ꢂm, 2ꢂ1H,
2ꢂ]CH); m/z (%): 192 (M+, 15), 133 (100), 115 (16), 91
(49) and 39 (19); nmax (film): 1720, 1600, 1445, 1380,
975 and 700 cmꢀ1
.
4.2.9. (1a-Methyl-1,1a,2,3,4,5-hexahydro-3a-cyclopro-
pa[c]inden-3a-yl) methanol (8). Compound 7 (0.1 g,
0.454 mmol) in dry ether (8 ml) was added dropwise to
a stirred suspension of LiAlH4 (0.018 g, 0.454 mmol) in
ether (8 ml). The resulting suspension was boiled under re-
flux for 2 h, cooled and the excess LiAlH4 destroyed by suc-
cessive addition of H2O (1 ml), 15% NaOH (1 ml) and H2O
(2 ml). After the addition was complete, the solution was
stirred for 1 h, filtered and the precipitate washed with ether
(2ꢂ15 ml). The combined ether layers were dried (MgSO4),
concentrated in vacuo and the residue purified by column
chromatography eluting with 1:4 v/v ether–petroleum ether
to afford the product (0.063 g, 78%) as a colourless oil.
Found: C, 81.00; H, 10.20; C12H18O requires: C, 80.90; H,
10.10%; dH: 0.35 and 1.02 (2ꢂd, 2ꢂ1H, J 5 Hz, cyclopropyl
H), 1.16 (s, 3H, Me), 1.30–2.12 (m, 9H, 4ꢂCH2 and OH),
3.46 and 3.75 (2ꢂd, 2H, J 10 Hz, OCH2), 5.19 and 5.23
(2ꢂbr s, 2ꢂ1H, CH]CH); m/z (%): 178 (M+, 9), 147
(100), 117 (27), 105 (43), 91 (64), 77 (18) and 41 (16);
1300, 1260, 1200, 1080, 800 and 735 cmꢀ1
.
4.2.7. (1a-Methyl-1,1a,2,3-tetrahydro-cyclopropa[c]pen-
talen-3a(4H)-yl) methanol (5). Compound 4 (0.15 g,
0.781 mmol), in dry ether (9 ml) was added dropwise to
the stirred suspension of LiAlH4 (0.03 g, 0.781 mmol) in
ether (6 ml). The resulting suspension was boiled under re-
flux for 2 h, cooled and the excess LiAlH4 decomposed by
successive addition of H2O (1 ml), 15% NaOH (1 ml) and
H2O (2 ml). After the addition was complete, the solution
was stirred for 1 h, filtered and the precipitate washed with
ether (2ꢂ20 ml). The combined ether layers were dried
(MgSO4), concentrated in vacuo and the residue purified
by column chromatography eluting with 1:2 v/v ether–
petroleum ether to afford the product (0.102 g, 80%) as a
colourless oil. Found: C, 80.50; H, 10.00; C11H16O requires:
C, 80.50; H, 9.75%; dH: 0.821 and 0.952 (2ꢂd, 2ꢂ1H,
J 6 Hz, cyclopropyl H), 1.06 (s, 3H, Me), 1.30–1.84
(m, 5H, 2ꢂCH2 and OH), 2.28 and 2.43 (2ꢂd, 2H, J
16 Hz, CH2), 3.41 and 3.49 (2ꢂd, 2H, J 10 Hz, OCH2) and
5.49 and 5.75 (2ꢂbr s, 2ꢂ1H, ]CH2); m/z (%): 164 (M+,
8), 133 (100), 105 (50), 91 (61), 79 (16), 55 (14) and 41
(17); nmax (film): 3475, 1730, 1485, 1290, 1180 and
nmax (film): 3330, 1480, 1390, 1045 and 940 cmꢀ1
.
4.2.10. Methyl 1a-methyl-1,1a,2,3,5,6-hexahydrocyclo-
propa[c]azulene-3a(4aH)-carboxylate (9). (a) Enol triflate
3c (0.2 g, 0.54 mmol) was added to a suspension of Pd(OAc)2
(0.012 g, 0.054 mmol), PPh3 (0.028 g, 0.l08 mmol), Na2CO3
(0.114 g, 1.08 mmol) and Et4NCl (0.089 g, 0.54 mmol) in
acetonitrile (6 ml). The resulting mixture was boiled under
reflux under a nitrogen atmosphere for 9 h. The solvent
was then removed under reduced pressure and the residue
partitioned between water (50 ml) and dichloromethane
(50 ml). The water layer was extracted with dichloro-
methane (60 ml) and the combined dichloromethane extracts
dried (MgSO4) and evaporated. The residue was purified by
flash chromatography (SiO2), eluting with 1:16 v/v ether–pe-
troleum ether, to afford 9 (0.035 g, 30%), and a 1:1 mixture
of 10 and 11 (0.053 g, 45%) as colourless oils. Found (mixed
isomers): C, 76.20; H, 9.15; C14H20O2 requires: C, 76.35; H,
9.05%; 9 dH: (500 MHz): 0.42 and 1.00 (2ꢂd, 2ꢂ1H, J
5.0 Hz, cyclopropyl H), 1.14 (s, 3H, Me), 1.5–2.2 (m, 10H,
5ꢂCH2), 3.68 (s, 3H, OMe), 5.10 (dd, 1H, J 12.0, 2.6 Hz,
]CH) and 5.7 (ddd, 1H, J 12.0, 6.8, 3.0 Hz, ]CH); 10
and 11 (1:1 mixture) dH: 0.02 and 0.73 (2ꢂd, 2H, J 5 Hz,
cyclopropyl H), 0.08 and 0.54 (2ꢂd, 2H, J 5 Hz, cyclopropyl
H), 1.12 and 1.23 (2ꢂs, 6H, 2ꢂMe), 1.43–2.42 (m, 20H,
10ꢂCH2), 3.16 (d, 1H, J 3 Hz, ]CH), 3.64 and 3.65 (2ꢂs,
6H, 2ꢂOMe), 5.63 (m, 2H, HC]CH), 5.98 (m, 1H,
]CH); m/z (%): 220 (M+, 22), 161 (100), 160 (50), 145
(42), 105 (95) and 77 (17); nmax (film): 1730, 1650, 1450,
760 cmꢀ1
.
4.2.8. Ethyl 1a-methyl-1,1a,2,3,4,5-hexahydro-3aH-
cyclopropa[c]indene-3a-carboxylate (7). Enol triflate 3b
(0.3 g, 0.81 mmol) was added to a suspension of Pd(OAc)2
(0.018 g, 0.081 mmol), PPh3 (0.042 g, 0.l62 mmol), Na2CO3
(0.171 g, 1.62 mmol) and Et4NCl (0.134 g, 0.81 mmol) in
acetonitrile (8 ml). The resulting mixture was boiled under
reflux under a nitrogen atmosphere for 8 h. The solvent was
then removed under reduced pressure and the residue parti-
tioned between water (60 ml) and dichloromethane (60 ml).
1250, 1200, 1110, 1080, 1020 and 840 cmꢀ1
.

R. Grigg et al. / Tetrahedron 62 (2006) 9523–9532
9529
(b) Repeating the reaction but with a reaction time of 5 h and
the addition of TlOAc (0.315 g, 1.2 mmol) afforded 9 (76%)
as the sole product.
ether to afford a solid, which was crystallised from ether–
petroleum ether to give the product (0.17 g, 90%) as colour-
less prisms, mp 59–61 ꢁC. Found: C, 80.35; H, 7.15;
C17H18O2 requires: C, 80.30; H, 7.10%; dH: 0.77 and 1.25
(2ꢂd, 2ꢂ1H, J 5 Hz, cyclopropyl H), 1.11 (s, 3H, Me),
1.58–2.56 (m, 4H, 2ꢂCH2), 3.58 (s, 3H, OMe), 5.59 and
6.53 (2ꢂd, 2ꢂ1H, J 9 Hz, ]CH), 7.08–7.35 (m, 4H, ArH);
m/z (%): 254 (M+, 12), 195 (100), 179 (32), 165 (37) and
4.2.11. Methyl 1-(3-methyl-3-butenyl)-2-tetralone-1-
carboxylate (12). 2-Methyl-4 iodo-1-butene (2.05 g,
10.7 mmol) was added to a stirred solution of 1-carbo-
methoxy-2-tetralone (2 g, 9.8 mmol) and KOtBu (1.21 g,
10.7 mmol in 1 M solution of tBuOH). The pale yellow solu-
tion was boiled under reflux for 10 h, cooled, water added to
dissolve the precipitate and extracted with ether (3ꢂ20 ml).
The combined ether extracts were washed with saturated
brine (50 ml), dried (MgSO4) and evaporated in vacuum to
leave an oil, which was distilled under reduced pressure to
afford the product (1.5 g, 57%) as a colourless oil, bp 120–
122 ꢁC/0.01 mmHg. Found: C, 74.75; H, 7.60; C17H20O3
requires: C, 75.00; H, 7.35%; dH: 1.61 (s, 3H, Me), 2.29–3.19
(m, 8H, 4ꢂCH2), 3.6 (s, 3H, OMe), 4.60 and 4.46 (2ꢂs,
2ꢂ1H, ]CH2), 7.21–7.24 (m, 4H, ArH); m/z (%): 272
(M+, 1), 204 (46), 172 (100), 129 (22), 115 (34), 77 (6) and
65 (3); nmax (film): 1780, 1700, 1550, 1505, 1440, 1410,
77 (3); nmax (film): 750, 1500, 1410, 1260 and 750 cmꢀ1
.
4.2.14. (6a-Methyl-5,6,6a,7-tetrahydro-4bH-cyclo-
propa[2,3] cyclopenta[1,2-a] naphthalen-4b-yl) metha-
nol (14). Compound 13 (0.045 g, 0.177 mmol) in dry ether
(8 ml) was added dropwise to a stirred suspension of LiAlH4
(0.0068 g, 0.177 mmol) in ether (6 ml). The resulting sus-
pension was boiled under reflux for 2 h, cooled, and the
excess LiAlH4 destroyed by careful successive addition of
H2O (0.5 ml), 15% NaOH (0.5 ml) and H2O (1 ml). After
the addition was complete, the solution was stirred for 1 h, fil-
tered and the precipitate washed with ether (2ꢂ20 ml). The
combined ether layers were dried (MgSO4), concentrated
in vacuo and the residue subjected to column chromato-
graphy eluting with 1:8 v/v ether–petroleum ether to afford
the product (0.033 g, 82%) as a colourless oil. Found:
226.1355; C16H18O requires: 226.1357; dH: 0.78 and 1.42
(2ꢂd, 2H, J 5 and 4 Hz, cyclopropyl H), 1.26 (s, 3H, Me),
1.5–2.48 (m, 5H, 2ꢂCH2+OH), 3.64 and 3.75 (2ꢂd, 2H, J
11 Hz, OCH2), 5.70 and 6.67 (2ꢂd, 2H, J 9 Hz, 2ꢂ]CH),
7.25–7.45 (m, 4H, ArH); m/z (%): 226 (M+, 25), 195 (100),
77 (8), 65 (4) and 43 (4).
1370, 1280, 1140 and 960 cmꢀ1
.
4.2.12. Methyl 1-(3-methylbut-3-enyl)-2-trifluoromethyl-
sulfonyloxy-1,4-dihydronaphthalene-1-carboxylate (12).
1-Carbomethoxy-1-(3-methylbut-3-enyl)-2-tetralone (1.15 g,
4.2 mmol) in THF (8 ml) was added dropwise at ꢀ78 ꢁC
to a stirred solution of lithium diisopropylamide [from
n-BuLi (3.17 ml, 1.6 M solution in hexane, 5.0 mmol) and
diisopropylamine (0.71 ml, 5.0 mmol)] in THF (10 ml).
The resulting solution was stirred at ꢀ78 ꢁC for 1 h and
N-(5-chloro-2-pyridyl)triflimide (1.74 g, 4.86 mmol) in
THF (10 ml) was then added dropwise with stirring and
the resulting mixture stirred at ꢀ78 ꢁC for 3 h. The solvent
was then removed under reduced pressure and the residue
partitioned between water (100 ml) and dichloromethane
(150 ml). The water layer was extracted with dichloro-
methane (100 ml), the combined dichloromethane extracts
dried (MgSO4) and evaporated. The residue was purified
by flash chromatography (SiO2) eluting with 1:4 v/v ether–
petroleum ether to afford the product (1.1 g, 65%) as a col-
ourless oil. Found: C, 53.04; H, 4.70; S, 8.00; F, 14.30;
C18H19F3O5S requires: C, 53.45; H, 4.70; S, 7.90; F,
14.1%; dH: 1.44–2.27 (m, 6H, 3ꢂCH2), 1.63 and 3.70
(2ꢂs, 2ꢂ3H, 2ꢂMe), 4.62 and 4.65 (2ꢂs, 2ꢂ1H, ]CH2),
6.23–6.26 (m, 1H, ]CH), 7.19–7.33 (m, 4H, ArH); m/z
(%): 404 (M+, 1), 345 (4), 289 (100), 255 (12), 69 (69)
and 41 (45); nmax (film): 1780, 1450, 1270, 1175, 1060,
4.2.15. Methyl 1-acetyl-3-(3-methyl-3-butenyl)-4-oxo-
piperidine-3-carboxylate (15). Methyl 1-acetyl-4-oxopi-
peridine-3-carboxylate (2.00 g, 10.05 mmol) was added to
a stirred solution of KOtBu (1.17 g, 10.42 mmol) in DMSO
(20 ml). The resulting solution was stirred at room tempera-
ture for 1 h, when 2-methyl-4-iodo-1-butene (2.00 g,
10.2 mmol) was added and stirring continued at room tem-
perature for a further 14 h. The solution was then diluted
with water (30 ml) and extracted with EtOAc (3ꢂ30 ml).
The combined ethyl acetate extracts were washed with satu-
rated brine (50 ml), dried (MgSO4) and evaporated under
reduced pressure. The residual oil was purified by column
chromatography (SiO2) eluting with 10:1 v/v ether–petro-
leum ether to afford the product (1.25 g, 46%) as a pale
yellow oil. Found: C, 62.70; H, 8.05; N, 5.25; C14H21NO4
requires: C, 62.90; H, 7.90; N, 5.25%; dH: 1.61–2.37 (m,
10H, 5ꢂCH2), 1.65 (s, 3H, ]CMe), 2.18 (s, 3H, COMe),
3.49 (s, 3H, OMe), 4.8 (s, 2H, ]CH2); m/z (%): 267 (M+,
4), 239 (27), 199 (78), 69 (36), 55 (51) and 43 (100); nmax
1000, 930, 840 and 740 cmꢀ1
.
4.2.13. Methyl 7a-methyl-6b,7,7a,8-tetrahydrocyclo-
propa[3,4] cyclopenta[1,2-a] naphthalene (13). Enol tri-
flate 12 (0.3 g, 0.742 mmol) was added to a stirred
suspension of Pd(OAc)2 (0.016 g, 0.074 mmol), PPh3
(0.038 g, 0.148 mmol), Na2CO3 (0.157 g, 1.48 mmol) and
Et4NCl (0.122 g, 0.742 mmol) in CH3CN (10 ml). The re-
sulting mixture was boiled under reflux for 8 h. The solvent
was then removed under reduced pressure and the residue
partitioned between water (50 ml) and dichloromethane
(50 ml). The water layer was extracted with dichloromethane
(50 ml), the combined dichloromethane extracts dried
(MgSO4) and evaporated. The residue was subjected to flash
chromatography (SiO2) eluting with 1:4 v/v ether–petroleum
(film): 2800, 1720, 1690, 1500, 1410 and 1290 cmꢀ1
.
4.2.16. Methyl 1-acetyl-3-(3-methyl-3-butenyl)-4-tri-
fluoromethylsulfonyloxy piperidine-3-carboxylate (16).
Compound 15 (0.2 g, 0.75 mmol) in THF (5 ml) was added
dropwise to a suspension of NaH (0.043 g, 1.8 mmol) in
freshly distilled THF (10 ml) at 0 ꢁC. The resulting mixture
was allowed to warm to room temperature and then PhNTf2
(0.28 g, 0.786 mmol) in THF (6 ml) was added dropwise and
the mixture heated at 60 ꢁC for 8 h. The solvent was then re-
moved under reduced pressure and the residue partitioned
between water (50 ml) and dichloromethane (50 ml). The
water layer was extracted with dichloromethane (50 ml)

9530
R. Grigg et al. / Tetrahedron 62 (2006) 9523–9532
and the combined dichloromethane extracts dried (MgSO4)
and evaporated. The residue was purified by flash chromato-
graphy (SiO2) eluting with 1:8 v/v ether–petroleum ether to
afford the product (0.19 g, 64%) as a colourless oil. Accurate
mass: 399.0961; C15H20F3N06S requires: 399.0963; dH:
1.11–4.3 (m, 8H, 4ꢂCH2), 1.66 (s, 3H, ]CMe), 2.16 (s,
3H, COMe), 3.69 (s, 3H, CO2Me), 4.63 and 4.7 (2ꢂs, 2H,
]CH2), 5.8 (br s, 1H, ]CH); m/z (%): 399 (M+, 7), 368
(12), 331 (40), 266 (76), 198 (47), 166 (100), 69 (72) and
43 (83); nmax (film): 3400, 1800, 1700, 1480, 1260, 1200,
Me), 1.43–2.13 (m, 4H, 2ꢂCH2), 3.61 and 3.72 (2ꢂd, 2H,
J 8.1 Hz, OCH2), 3.87–3.93 (m, 1H, OCH), 5.15–5.19 (m,
1H, ]CH), 5.69–5.72 (m, 1H, ]CH); m/z (%): 150 (M+,
34), 135 (27), 91 (100), 55 (23) and 41 (31); nmax (film):
1750, 1500, 1090 and 740 cmꢀ1
.
4.2.20. 6-(2-Acetylphenoxy)-l-bromocyclohexene. 2-Hy-
droxyacetophenone (1.8 g, 0.013 mol) in freshly distilled
THF (15 ml) was added to a stirred suspension of NaH
(0.634 g, 60% dispersion in oil, 0.013 mol) in freshly dis-
tilled THF (10 ml) at 0 ꢁC. The resulting mixture was stirred
for 1 h at room temperature when 2,3-dibromohexene (3.2 g,
0.013 mol) was added and the resulting mixture was boiled
under reflux for 8 h. The solvent was then removed under re-
duced pressure and the residue partitioned between water
(70 ml) and dichloromethane (100 ml). The water layer
was extracted with dichloromethane (100 ml) and the com-
bined dichloromethane layers dried (MgSO4) and evapo-
rated. The residue was distilled under reduced pressure to
give the product (1.9 g, 49%) as a colourless oil, bp 140–
148 ꢁC/0.03 mmHg. Found: C, 56.90; H, 5.20; Br, 27.30;
C14H15BrO2 requires: C, 56.95; H, 5.05; Br, 27.10%; dH:
1.05–2.21 (m, 6H, 3ꢂCH2), 2.66 (s, 3H, COMe), 4.8 (br s,
1H, OCH), 6.39–6.41 (m, 1H, ]CH), 6.95–7.75 (m, 4H,
ArH); m/z (%): 296 (M+, 2), 294 (M+, 2), 215 (13), 160
(23), 121 (21), 79 (100) and 43 (22); nmax (film): 2900,
1140 and 930 cmꢀ1
.
4.2.17. Methyl 2-acetyl-5a-methyl-1,2,5,5a,6,7-hexahy-
dro-7aH-cyclopropa[2,3] cyclopenta[1,2-c] pyridine-7a
carboxylate (17). The enol triflate 16 (0.13 g, 0.325 mmol)
was added to a stirred suspension of Pd(OAc)2 (0.007 g,
0.0325 mmol), PPh3 (0.017 g, 0.065 mmol), Na2CO3
(0.069 g, 0.651 mmol) and Et4NCl (0.053 g, 0.325 mmol)
in CH3CN (8 ml). The resulting mixture was stirred and
boiled under reflux for 8 h. Standard workup followed by col-
umn chromatography eluting with 4:1 v/v ether–petroleum
ether afforded the product (0.05 g, 62%) as a colourless oil.
Found: C, 67.50; H, 7.80; N, 5.50; C14H19NO3 requires: C,
67.50; H, 7.65; N, 5.60%; dH: 0.6 and 1.2 (d, 2H, J 5 Hz, cy-
clopropyl H), 1.12 (s, 3H, Me), 1.1–1.8 (m, 6H, 3ꢂCH2), 2.02
(s, 3H, COMe), 3.63 (s, 3H, OMe) and 6.62 and 7.27 (2ꢂm,
2ꢂH, 2ꢂ]CH); m/z (%): 249 (M+, 33), 206 (93), 189 (77),
146 (100) and 43 (57); nmax (film): 1720, 1450, 1375, 1250,
1700, 1630, 1510, 1480, 1330, 1270, 1000 and 780 cmꢀ1
.
1110, 1080 and 1040 cmꢀ1
.
4.2.21. 2-Bromocyclohex-2-en-1-yl 2-isopropenylphenyl
ether (20). n-Butyllithium (5.16 ml, 1.6 M solution in
hexane, 8.27 mmol) was added to a stirred suspension of methyl-
triphenylphosphonium bromide (2.95 g, 8.27 mmol) in
ether (40 ml) under nitrogen and stirring continued at room
temperature for an hour. 6-(2-Acetylphenoxy)-l-bromo-
cyclohexene (1.22 g, 4.13 mmol) in ether (20 ml) was added
dropwise over 30 min. The resulting mixture was stirred for
15 h, then diluted with water (20 ml) and extracted with
ether (3ꢂ20 ml). The combined ether extracts were dried
(MgSO4), evaporated in vacuo and the residue distilled to
afford the product (0.64 g, 53%) as colourless oil, bp 100–
110 ꢁC/0.02 mmHg. Found: C, 61.45; H, 5.85; Br, 27.30;
C15H17BrO requires: C, 61.45; H, 5.80; Br, 27.30%; dH:
1.65–2.03 (m, 6H, 3ꢂCH2), 2.06 (s, 3H, Me), 4.69 (br s,
1H, CH), 4.96, 5.02 (2ꢂs, 2ꢂ1H, ]CH2), 6.26 (m, 1H,
]CH) and 6.84–7.14 (m, 4H, ArH); m/z (%): 294 (M+, 3),
292 (M+, 3), 213 (21), 134 (100), 91 (30) and 79 (93).
4.2.18. 2-Bromocyclohex-2-en-1-yl 2-methylprop-2-en-1-
yl ether (18). 2-Methyl-2-propen-1-ol (0.546 g, 7.57 mmol)
in THF (5 ml) was added to a stirred suspension of NaH
(0.45 g, 60% dispersion in oil, 9 mmol) in freshly distilled
THF (10 ml) at 0 ꢁC and stirring continued for 1 h at room
temperature. 2,3-Dibromocyclohexene (2 g, 8.7 mmol) was
then added and stirring continued for a further 8 h at room
temperature at which time the solvent was removed under re-
duced pressure and the residue partitioned between water
(50 ml) and dichloromethane (50 ml). The water layer was
extracted with dichloromethane (50 ml) and the combined
dichloromethane extracts dried (MgSO4) and evaporated.
The residue was distilled under reduced pressure to afford
the product (1.2 g, 68%) as a colourless oil, bp 62–65 ꢁC/
0.25 mmHg. Accurate mass: 230.0305; C10H15BrO requires:
230.0306; dH: 1.50–2.05 (m, 6H, 3ꢂCH2), 1.74 (s, 3H, Me),
3.79 (br s, 1H, OCH), 3.98 (m, 2H, OCH2), 4.82 and 4.94
(2ꢂs, 2ꢂlH, ]CH2), 6.14–6.16 (m, 1H, ]CH); m/z (%):
232 (M+, 1), 230 (M+, 1), 175 (31), 151 (35), 79 (100), 55
(34) and 41 (15); nmax (film): 3200, 1670, 1470, 1350, 1100
4.2.22. 10b-Methyl-1,5,5a,10b-tetrahydro-4H-cyclopro-
paxanthene (21). Vinyl bromide 20 (0.15 g, 0.508 mmol)
was added to a stirred suspension of Pd(OAc)2 (0.011 g,
0.0508 mmol), PPh3 (0.026 g, 0.101 mmol) and TlOAc
(0.162 g, 0.616 mmol) in CH3CN (8 ml). The resulting mix-
ture was stirred and boiled under reflux for 5 h. The solvent
was then removed under reduced pressure and the residue
partitioned between water (50 ml) and dichloromethane
(50 ml). The water layer was extracted with dichloro-
methane (50 ml) and the combined dichloromethane extracts
dried (MgSO4) and evaporated. The residue was purified by
flash chromatography (SiO2) eluting with 1:2 v/v ether–
petroleum ether to afford the product 21 (0.074 g, 76%)
as a pale yellow oil. Accurate mass: 212.1209; C15H16O
requires: 212.1209; dH: 0.872 and 1.36 (2ꢂd, 2H, J 5 Hz, cy-
clopropyl H), 1.40 (s, 3H, Me), 1.18–2.23 (m, 4H, 2ꢂCH2),
and 910 cmꢀ1
.
4.2.19. 1a-Methyl-1a,2,4,5-tetrahydro-1H,3aH-cyclo-
propa[c] [1] benzofuran (19). Vinyl bromide 18 (0.05 g,
0.216 mmol) was added to a stirred suspension of
PdC12(PPh3)2 (0.015 g, 0.0216 mmol), Zn dust (0.028 g,
0.432 mmol) and Et4NCl (0.035 g, 0.216 mmol) in CH3CN
(5 ml) and the resulting mixture was stirred and boiled under
reflux for 2 h. Standard workup followed by column chroma-
tography eluting with 1:4 v/v ether–petroleum ether afforded
the product (0.016 g, 50%) as a colourless oil. Accurate mass:
150.1045; C10H14O requires: 150.1044; dH: 0.529 and 0.964
(2ꢂd, 2ꢂ1H, J 4.4 and 4.5 Hz, cyclopropyl H), 1.1 (s, 3H,

R. Grigg et al. / Tetrahedron 62 (2006) 9523–9532
9531
4.27 (m, 1H, OCH), 5.35 and 5.70 (2ꢂm, 2ꢂ1H, 2ꢂ]CH),
6.70–7.24 (m, 4H, ArH); m/z (%): 212 (M+, 21), 197 (42), 91
(18), 77 (13) and 32 (100); nmax (film): 1620, 1505, 1470,
bp 105–110 ꢁC/0.1 mmHg. Found: C, 49.30; H, 5.45;
C13H17BrO4 requires: C, 49.23; H, 5.40%; dH: 2.90, 2.83
and 1.66 (3ꢂs, 2H, 2H and 3H, C]CCH2, CH2 and
C]CCH3), 3.75 and 3.88 (2ꢂs, 2H and 3H, CH2Br and
OCH3), 4.85 and 4.92 (2ꢂd, 2ꢂ1H, J 1.3 Hz, C]CH2); m/z
(%): 319 and 317 (1.6), 177 (100), 145 (16), 117 (40), 59
1240 and 770 cmꢀ1
.
4.2.23. N-Acetyl-N-(2-bromocyclohex-2-enyl)-2-isopro-
penylaniline (23). N-Acetyl-2-isopropenylaniline (1.74 g,
0.01 mol) in freshly distilled THF (15 ml) was added to
a stirred suspension of NaH (0.58 g, 0.0l2 mol, 60% disper-
sion in oil) in THF (10 ml) at 0 ꢁC. The resulting mixture
was stirred for 1 h at room temperature when 2,3-dibromo-
cyclohexene (2.77 g, 0.011 mol) was added and stirring con-
tinued for further 8 h. The solvent was then removed under
reduced pressure and the residue partitioned between water
(100 ml) and dichloromethane (150 ml). The water layer
was extracted with dichloromethane (100 ml) and the com-
bined dichloromethane extracts dried (MgSO4) and evapo-
rated. The residual pale yellow solid was crystallised from
ether–petroleum ether to give the product (2.32 g, 70%) as
pale yellow prisms, mp 86–88 ꢁC. Found: C, 61.00; H,
6.00; N, 4.05; Br, 24.10; C17H20BrNO requires: C, 61.05;
H, 5.95; N, 4.20; Br, 23.95%; dH: 1.15–2.08 (m, 6H,
3ꢂCH2), 1.80 (s, 3H, ]CMe), 2.02 (s, 3H, COMe), 4.94
and 5.14 (2ꢂs, 2ꢂ1H, ]CH2), 5.61–5.73 (m, 1H, NCH),
6.15–6.23 (m, 1H, ]CH), 7.20–7.34 (m, 4H, ArH); m/z
(%): 335 (M+, 1), 333 (M+, 1), 254 (100), 212 (12), 174
(17), 91 (51) and 43 (39); nmax (Nujol): 3400, 3050, 1790,
(28); nmax (film): 2237, 1735, 1434, 1276, 1206, 1183 cmꢀ1
.
4.2.26. Dimethyl {4-[acetyl (2-iodophenyl) amino] but-2-
yn-1-yl}(2-methylprop-2-en-1-yl) malonate (39). n-BuLi
(4.2 ml of 1.6 M solution in hexane, 0.0066 mol) was added
from a syringe to a cooled solution (0–4 ꢁC) of N,N-diisopro-
pylamine (0.84 ml, 0.006 mol) in dry THF (25 ml) under an
atmosphere of N2 and stirring and cooling continued for
15 min. The reaction mixture was then cooled to ꢀ60 ꢁC,
a solution of 2-iodoacetanilide (1.56 g, 0.006 mol) in dry
THF (10 ml) was added and the mixture stirred at ꢀ60 ꢁC
for 15 min. A solution of 38 (1.903 g, 0.006 mol) in THF
(5ml) was added next and the mixture allowed to warm to
room temperature with stirring over 15 h. The mixture was
then quenched with a saturated solution of NH4Cl (20 ml)
and extracted with ether (3ꢂ25 ml). The combined ether
layers were dried over anhydrous MgSO4, evaporated and
the residue purified by flash column chromatography, eluting
with 7:3 v/v ether–petroleum ether to give the product
(1.44 g, 49%), which crystallised as colourless plates from
ether–petroleum ether, mp 63–65 ꢁC. Found: C, 50.60; H,
4.85; N, 2.70; I, 25.70; C21H24INO5 requires: C, 50.70; H,
4.86; N, 2.82; I, 25.52%; dH: 1.52 and 1.71 (2ꢂs, 2ꢂ3H,
COCH3 and C]CCH3), 2.6 5 and 2.71 (2ꢂs, 2ꢂ2H,
2ꢂCH2), 3.62 and 3.63 (2ꢂs, 2ꢂ3H, 2ꢂCOOCH3), 4.63
and 4.78 (2ꢂs, 2ꢂ1H, C]CH2), 3.70 and 4.96 (2ꢂdd,
2ꢂ1H, J 17.2 and 2 Hz, NCH2), 7.06 and 7.39 (2ꢂm, 2H
and 1H, ArH), 7.87 (dd, 1H, J 7.8 and 1.7 Hz, ArH); m/z
(%): 497 (M+, 42), 482 (50), 370 (22), 366 (92), 312 (25),
244 (100), 177 (28); 43; nmax (KBr): 1736, 1666, 1469,
1480, 1320, 1080 and 820 cmꢀ1
.
4.2.24. 6-Acetyl-10b-methyl-1,4,5,5a,6,10b-hexahydro-
cyclopropa[1]acridine (24). Vinyl bromide 23 (0.05 g,
0.0149 mmol) was added to a stirred suspension of
PdCl2(PPh3)2 (0.01 g, 0.0149 mmol), Zn dust (0.019 g,
0.299 mmol) and Et4NCl (0.024 g, 0.149 mmol) in CH3CN
(5 ml). The resulting mixture was stirred and boiled under
reflux for 4 h. The solvent was then removed under reduced
pressure and the residue partitioned between water (30 ml)
and dichloromethane (30 ml). The water layer was extracted
with dichloromethane (30 ml) and the combined dichloro-
methane layers dried (MgSO4) and evaporated. The residue
was purified by flash chromatography (SiO2) eluting with
1:4 v/v ether–petroleum ether to afford the product
(0.0275 g, 73%) as a pale yellow oil. Found: C, 80.65; H,
7.60; N, 5.25; C17H19NO requires: C, 80.65; H, 7.50; N,
5.55%; dH: 0.96 and 1.36 (2ꢂd, 2ꢂ1H, J 6 Hz, cyclopropyl
H), 1.46 (s, 3H, Me), 2.14 (s, 3H, COMe), 1.1–2.4 (m, 4H,
2ꢂCH2), 5.10 and 5.49 (2ꢂd, 2H, J 11 Hz, ]CH), 5.75–
5.8 (m, 1H, NCH), 6.95–7.43 (m, 4H, ArH); m/z (%): 253
(M+, 35), 238 (7), 210 (61), 160 (100), 77 (19) and 43
1280, 1206, 1194 cmꢀ1
.
4.2.27. Dimethyl 1-(1-acetyl-1H-indol-3-yl)-5-methylbi-
cyclo [3.1.0] hexane-3,3-dicarboxylate (43). A mixture of
39 (0.248 g, 0.0005 mol), Pd(OAc)2 (0.011 g, 10 mol %),
PPh3 (0.026 g, 20 mol %), Na2CO3 (0.046 g, 0.0005 mol)
and Et4NCl (0.082 g, 0.0005 mol) in dry acetonitrile (7 ml)
was heated at 70 ꢁC for 0.5 h. The palladium residue was fil-
tered off, the solvent evaporated, the residue dissolved in
EtOAc (15 ml) and washed with water (15 ml). The organic
layer was separated, dried over anhydrous MgSO4 and evap-
orated to leave a brown solid, which was purified by prepar-
ative TLC, eluting with 3:2 v/v ether–petroleum ether to give
the product (0.12 g, 65%) as a colourless solid, which be-
came an amorphous pale yellow solid when exposed to air.
Found: C, 66.85; H, 6.30; N, 3.45; C21H23NO5$0.5H2O re-
quires: C, 66.65; H, 6.39; N, 3.70%; dH: 0.66 (br s, 2H,
CH2), 0.93 and 2.52 (2ꢂs, 2ꢂ3H, COCH3 and CH3), 2.57
(d, 1H, J 13.7 Hz), 2.85 (m, 3H), 3.66 and 3.67 (2ꢂs,
2ꢂ3H, 2ꢂCH3), 7.13 –7.29 (m, 2H, ArH), 7.50 and 8.34
(2ꢂd, 2ꢂlH, J 7.2 Hz, ArH); m/z (%): 369 (M+, 100), 327
(25), 250 (29), 208 (70), 49 (57), 47 (43), 43 (37).
(25); nmax (Nujol): 3000, 1690, 1490, 1410 and 750 cmꢀ1
.
4.2.25. Dimethyl 4-bromobut-2-ynyl-2-methylprop-
2-enylmalonate (38). Dimethyl 2-methylprop-2-enylmalo-
nate (9.31 g, 0.05 mol) was slowly added to a methanolic
solution of sodium methoxide [prepared from Na (1.15 g) and
absolute MeOH (25 ml)] and stirred the mixture at room
temperature for 15 min. 1,4-Dibromobut-2-yne (12.71 g,
0.06 mol) was then added and stirring continued at room tem-
perature for a further 16 h when water (25 ml) was added and
the mixture extracted with ether (3ꢂ40 ml). The combined
ether layers were washed with brine, dried over anhydrous
MgSO4 and evaporated. The residual oil was distilled
to give the product as a pale yellow liquid (5.0 g, 32%),
Acknowledgements
We thank Leeds University and the EU for a Marie Curie
fellowship (for U.S.) and the EPSRC for support.

9532
R. Grigg et al. / Tetrahedron 62 (2006) 9523–9532
2005, 5109–5111; (c) Gao, M. Z.; Wang, B.; Kong, D.;
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