A concise synthesis of carpanone using solid-supported reagents and scavengers

Article abstract of DOI:10.1039/b203388g

The synthesis of the natural product carpanone by utilization of polymer supported reagents, eliminating the need for conventional purification techniques was reported. The synthesis and crystal structure of a polymer-supported iridium catalyst for isomerization was also reported. The observations showed that isomerization of electron-rich aromatic compounds by the catalyst resulted in products with predominantly trans alkene geometry. However, the electron-poor derivatives were found to be less prone to rearrangement.

Full text of DOI:10.1039/b203388g

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A concise synthesis of carpanone using solid-supported reagents
and scavengers
Ian R. Baxendale, Ai-Lan Lee and Steven V. Ley*
1
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge,
UK CB2 1EW. E-mail: svl1000@cam.ac.uk; Fax: ϩ44 (0) 1223 336442;
Tel: ϩ44 (0) 1223 336398
Received (in Cambridge, UK) 5th April 2002, Accepted 26th June 2002
First published as an Advance Article on the web 18th July 2002
Polymer-supported reagents have been applied to the synthesis of the natural product carpanone resulting in a clean
and efficient synthesis without the requirement for conventional purification techniques. A new polymer-supported
transition metal isomerisation catalyst is also reported.
Table 1 Claisen rearrangement of substrate 4
Introduction
The utilisation of solid-supported reagents in chemical
synthesis has been shown to markedly improve productivity in
many critical aspects of the generation of new chemical entities
and complex target molecules. The potential to configure the
reactions in both a serial and convergent fashion offers many
distinct advantages compared to solid-phase synthesis. In
addition the simple removal of spent reagents through filtration
enables reactions to be driven to completion through the
addition of excess reagents and for lower yielding reactions to
be cleaned-up using scavenger resins.
Microwave at 220 ЊC
Conversion (%)
3 × 15 min
30 min continuous
45 min continuous
2 ϩ 2 ϩ 2 ϩ 1 ϩ 1 ϩ 15 ϩ 15 ϩ 15 min
97
78
86
85
We have previously reported on the use of these concepts in
the sequential multi-step synthesis of various natural products
using solid-supported reagents and scavengers to effect all the
individual steps.1 As a consequence, no chromatographic
purification procedures were necessary and all stages proceeded
with simple and rapid optimisation. Here we report in full on
the concise preparation of carpanone 2 using these methods
and also describe the development of two new solid-supported
reagents used in the synthesis.2,3
The natural product carpanone 2 was first isolated from the
bark of the carpano tree from the island of Bouganville in the
Pacific Ocean.4 Carpanone is a hexacyclic molecule with five
contiguous stereogenic centres, no formal element of symmetry
and shows no optical activity. The elegant biomimetic synthesis
of carpanone (Scheme 1) was first accomplished by Chapman
and occurs through a diastereoselective oxidative dimerization
of 1 using PdCl2 followed by rapid exo-selective inverse
electron demand Hetero-Diels–Alder cycloaddition.5 More
recently, Shair and co-workers have synthesised carpanone-like
molecules on solid-support using the same biomimetic
approach.6
Scheme 1 Synthetic pathway to ( )-carpanone.
Results and discussion
microwave well system8 (3 × 15 min) at 220 ЊC. The reaction
proceeded smoothly to give 5 in 97% conversion and the ionic
liquid was removed by a simple filtration through a plug of
silica. It was interesting to note that neither a 1 × 45 min burst
nor many short bursts of microwave irradiation at the same
temperature (220 ЊC) managed to give better conversions (86
and 85% respectively, Table 1). However, the reaction was found
to be sensitive to concentration. A clean conversion was only
obtained with a concentration of ∼0.2 mmol mlϪ1 of substrate
in toluene. When the concentration was increased to 0.6 mmol
mlϪ1, the reaction gave a complex mixture of products.
The synthesis begins from commercially available sesamol 3†
which is readily allylated in acetonitrile containing a small
quantity of dimethylformamide, using allyl bromide and a
polymer-supported phosphazene base (PS–BEMP)7 to give the
aryl ether 4 in 98% yield (Scheme 2). The product 4 was then
subjected to Claisen rearrangement. This was best achieved
using a toluene–ionic liquid (1-ethyl-3-methyl-1H-imidazolium
hexafluorophosphate) biphasic system and heating in a focused
† The IUPAC name for sesamol is 3,4-(methylenedioxy)phenol.
1850
J. Chem. Soc., Perkin Trans. 1, 2002, 1850–1857
This journal is © The Royal Society of Chemistry 2002
DOI: 10.1039/b203388g

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Table 2 Isomerisation of substrate 5 to 1
Reagents
Conditions
Time
Results
PS-Wilkinson’s catalyst
PS-Wilkinson’s catalyst
Wilkinson’s catalyst
NaOEt–EtOH
PS–BEMP
TFA
Reflux in THF
24 h
15 min
2 h
30 min
30 min
2 h
No reaction
No reaction
No reaction
No reaction
No reaction
No reaction
Microwave in THF, 100 ЊC
DABCO, ethanol (eq), reflux
Microwave 140 ЊC
Microwave in MeCN 130 ЊC
Reflux in CH2Cl2
Heat to 80 ЊC in aq. ethanol
30 min
No reaction
Microwave at 85 ЊC in aq. ethanol
20 min
No reaction
RhCl3ؒnH2O
Ethanol, RT
Microwave at 100 ЊC
Activated with H2, THF, RT
2.5 h
15 min
1 h
10% conversion
3 : 1 mixture of trans–cis products
85–88% isolated yield, 127 : 1 trans–cis ratio
KOtBu–DMSO
Ir(COD)(PPh2Me)2PF6
Scheme 2 Synthesis of carpanone using polymer-supported reagents and scavengers.
The isomerisation of 5 to 1 proved to be more difficult than
initially anticipated. Polystyrene-supported RhCl3-quarternary
ammonium ion pair catalyst,9 Wilkinson’s catalyst, polymer-
supported Wilkinson’s catalyst,10 PS–BEMP and TFA all failed
to effect the isomerisation. RhCl3ؒnH2O gave a maximum of
10% conversion while the KOtBu–DMSO system gave a low
3 : 1 trans–cis selectivity (Table 2). Felkin’s iridium catalyst,11
which is formed by bubbling hydrogen through a THF
suspension of [Ir(COD)(PPh2Me)2]PF6, was discovered to be an
excellent reagent for this selective transformation. In addition
the conditions are mild compared to traditional base induced
isomerisations and the trans–cis ratio was an excellent 127 : 1
for the isomerisation of 5. We therefore developed a polymer-
supported version of the Felkin iridium catalyst.
Scheme 3 Preparation of catalyst 6.
polymer-supported triphenylphosphine and [(COD)IrCl]2. This
batch was found to be less active despite having a higher iridium
Scheme 3 shows the synthesis and proposed structure of the
polymer-supported iridium catalyst, 6.6 A 6 : 1 molar ratio of
polymer-supported triphenylphosphine12 and [(COD)IrCl]2
was agitated in THF at room temperature for 24 h. Addition of
ammonium hexafluorophosphate as a solution in THF and
agitation for a further 24 h produced a red polymer with the
proposed structure 8.13 Elemental analysis indicated 12.5%
iridium, corresponding to a theoretical loading of 0.65 mmol
loading of 1 mmol gϪ1
.
The catalyst 6 was also tested on various aryl allylic
derivatives and aryl ethers (Table 3). In general the isomerisa-
tion of electron-rich aromatic compounds by catalyst 6 results in
products with predominantly the trans alkene geometry (entries
1–7). However, electron-poor derivatives (entries 13 and 14) are
substantially less prone to rearrangement. Isomerisations of
aryl ethers (entries 9–12) also proceeded smoothly, though
these were not trans selective. However, catalyst 6 may still find
an application in allyl ether deprotections where trans selec-
tivity is not relevant.14
g
Ϫ1. Hydrogen activation of catalyst 8 produces a chrome
yellow polymer of suggested structure 6 which isomerised
substrate 5 at room temperature to give an 11 : 1 trans–cis ratio
of 1. Catalyst 8 was also prepared using a 2 : 1 molar ratio of
J. Chem. Soc., Perkin Trans. 1, 2002, 1850–1857
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Table 3 Isomerisations using reagent 6
Entry
1
Substrate
Producta
Trans–cis ratiob
>95% trans
2
>95% trans
3
4
>97% trans
>96% trans
5
6
trans only
>98% trans
7
8
∼92% trans
∼92% trans
9
Mixture of trans and cis products
10
11
12
13
1 : 1
1 : 1
1 : 1
—
Recovered starting material with <4% isomerised product
14
15
50% conversion
—
—
Recovered starting material
1
a Recovered yields are essentially quantitative although H-NMR analysis indicate up to 4% of the hydrogenated alkene product present in small
scale reactions. b Determined by 1H-NMR.
In another experiment we determined whether the isomerisa-
tions were solely due to 6 or to a species that may have leached
into the solution from the support during the course of the
reaction. To test this, the reaction with dillapiole‡ (entry 6) was
stopped after 15 minutes of reaction by filtration. Analysis
showed a 60% conversion to the desired product. The filtrate
was then allowed to stir for a further 12 h. No further
‡ The IUPAC name for dillapiole is 1-allyl-2,3-dimethoxy-4,5-
(methylenedioxy)benzene.
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Table 4 Oxidative coupling of 1 to form carpanone, 2
Entry
Oxidising agent
eq.
TLC monitoring
Yielda
Conditions
Solvent
1
2
3
4
5
6
7
8
9
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PS–PhI(OAc)2(soluble)
PS–PhI(OAc)2(soluble)
PS–PhI(OAc)2(soluble)
PS–PhI(OAc)2(insoluble)
PhI(OCOCF3)
PS–PhI(OCOCF3)
TPAP, O2
1.1
1.1
0.5
45%
52%
26%
low
∼7%
17%
low
RT
TFEd
Ϫ40 ЊC to RT
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
TFE and CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Ϫ40 ЊC O/Nc
∼2
∼2
Mixture of products
Mixture of products
Mixture of products
RT
Ϫ40 ЊC to RT
Ϫ40 ЊC to RT
Ϫ28 ЊC to Ϫ20 ЊC O/N
Ϫ40 ЊC O/N
RT
RT
RT
RT
∼1.1
∼1.3
Complex mixture of products
Complex mixture of products
Complex mixture of products
Complex mixture of products
2 is main product
∼1.0
∼1.0
low
10
11
12
Catalytic
Catalytic
Catalytic
Co(salen), O2
Co(salen), chiral, O2
78%
2 is main product
85%b
a Together with carpanone, a small amount of another product, which is likely to be a configurational isomer, was formed. This has been reported
previously.16 b [α]D = 0. c O/N = overnight reaction. d TFE = 2,2,2-trifluoroethanol.
reaction was observed, suggesting that the active catalyst
remains associated with the support during the course of the
reaction.
In an attempt to show that 6 can be recycled, we carried out a
sequence of reactions on allylbenzene. The recovered polymer
from the first conversion was reactivated with hydrogen and
reused for a further three runs.15 The conversion dropped from
quantitative to 95%, 91% and 75% in each subsequent run,
suggesting some degradation of the catalyst (the cis–trans ratio
remained constant). A recycling test was also carried out on
dillapiole (entry 6) since this substrate required a shorter
reaction time of 1.5 h for each run. The sequence proceeded
from quantitative to 91% to 70%. The reaction did however
proceed to completion on the fourth run after it was allowed to
react overnight.
As a further investigation, the catalytic potential of 6 was
tested using the dimethoxy substrate (entry 2). Employing
catalyst 6 (2 mol%) for the isomerisation of 800 mg of the
substrate resulted in 77% conversion after 24 h. Subsequent
monitoring over an additional 3 day period showed a slow but
steady progression to 84% conversion (day 2; 80%, day 3; 82%).
The addition of a further batch of freshly prepared catalyst
(1 mol%) allowed the reaction to proceed to completion over
a further 48 h period.
Felkin’s catalyst was reported to be selective towards primary
allyl ethers and so far only primary allyl ethers and aryls have
been tested. To test the selectivity of catalyst 6, the non-primary
allyl aryl (entry 15) was subjected to isomerising conditions
with 6. No isomerisation was observed, suggesting that catalyst
6 is also selective towards primary allyls.
Scheme 4 Preparation of the Co(salen) catalyst 7.
Finally, the coupling of 1 to form carpanone 2 was carried
out using hypervalent iodine reagents (Table 4). The transform-
ation was successful using solution phase PhI(OAc)2, yielding
carpanone in 52% after chromatographic purification (entry 2).
The reaction proceeded within minutes at room temperature
but was found to give much cleaner transformations at lower
temperatures. Encouraged by this result, the insoluble16a and
soluble16b polymer-supported PhI(OAc)2 were used to attempt
this coupling under various conditions (entries 4–9). Although
these reactions did form carpanone, the isolated yields were
generally low and the reactions were not clean, and therefore
were not acceptable.
of these three starting materials produced a mixture of
ligands. The hydroxy-terminated ligands were selectively
captured by addition of hydroxymethylpolystyrene, derivatised
as the corresponding 4-nitrophenyl carbonate, while the
non-hydroxy-terminated ligand was washed away from the
polymer-bound product. Finally, cobalt complexation was
achieved by the addition of Co(OAc)2ؒ4H2O. Elemental
analysis indicated 2.2% Co which corresponds to a theoretical
loading of 0.37 mmol gϪ1
.
Reagent 7 was used in catalytic amounts to transform 1 to
carpanone 2 successfully by agitating a suspension of 7 and 1
in CH2Cl2 at room temperature under an atmosphere of O2
(Scheme 2). However, a minor side product, the aldehyde 10
formed in this reaction. This side product was scavenged from
the reaction mixture using polymer-supported trisamine
scavenger. This procedure successfully converted 1 to carpa-
none in 80% yield and 98% HPLC purity without any aqueous
work up or chromatographic purification. When a crude
mixture of 11 : 1 trans–cis 1 and 4,5-methylenedioxy-2-
propenylphenol was used, a further step was necessary to
In 1981, Matsumoto and Kuroda successfully synthesised
carpanone in excellent yield (94%) by the oxidation of 1
with molecular oxygen in the presence of Co(salen).17
A
polymer-supported version of Co(salen) was therefore
synthesised using a slight modification of Anis and Jacobsen’s
method for making polymer-supported chiral Co(salen)
complexes for hydrolytic kinetic resolution of terminal epoxides
(Scheme 4).18 The synthesis starts from readily available
salicylaldehyde, gentisaldehyde and diethylamine. The reaction
J. Chem. Soc., Perkin Trans. 1, 2002, 1850–1857
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remove the unreacted phenol. This was achieved using polymer-
supported Na2CO3 to give carpanone in 70% yield.
was placed in a sealed tube heated with stirring at 220 ЊC for 3 ×
15 min using microwave radiation. The mixture was cooled to
RT in the microwave using a stream of pressurised (4 bar)
nitrogen before filtration through a pad of silica using Et2O as
the eluent. The filtrate was concentrated in vacuo to yield 5 as a
yellow solid (97% conversion); νmax/cmϪ1 3235 (OH), 1636
(C᎐C), 1504 (Ar C᎐C), 1205 & 1054 (C–O); δ (400 MHz,
᎐
᎐
H
CDCl3) 6.58 (1H, s, H-2), 6.43 (1H, s, H-5), 5.96 (1H, m,
CH2CHCHHЈ), 5.88 (2H, s, OCH2O), 5.16 (1H, m, CH2CH-
CHHЈ), 5.13 (1H, m, CH2CHCHHЈ), 4.68 (1H, s, OH ), 3.35
(2H, dt, J 6.22, 1.46, CH2CHCHHЈ); δC(CDCl3) 149.05, 147.16,
141.91, 136.81ϩ, 117.20, 116.77Ϫ, 109.49ϩ, 101.38Ϫ, 99.08ϩ,
35.43Ϫ.
In summary, the work reported above illustrates further the
power of using immobilised systems in a multi-step fashion to
produce complex products without the need for conventional
work-up methods.
Experimental
Polymer-supported iridium isomerisation catalyst (8)
Unless otherwise specified, all reactions involving polymers
were carried out on a laboratory shaker IKA 125 at 250 rpm.
All moisture sensitive reactions were carried out under an
argon atmosphere using oven-dried glassware. All commercially
available resins were washed and dried in vacuo prior to use.
Diethyl ether (Et2O) and tetrahydrofuran (THF) were distilled
from sodium benzophenone ketyl; acetonitrile, benzene,
dichloromethane, methanol and toluene from calcium hydride.
All other solvents and reagents were used as supplied unless
otherwise specified. Analytical TLC was performed using
precoated glass-backed plates (Merck Kieselgel 60 F254) and
visualised by ultra-violet radiation, acidic ammonium molyb-
date() or potassium permanganate. Infra-red spectra were
obtained on Perkin–Elmer Spectrum One FT-IR spectrometer.
Single-bead infra-red spectra were recorded on a Perkin–Elmer
Autoimage system with a spectrum 1000 IR bench. Samples
for single bead IR spectroscopy were flattened using a Specac
Triphenylphosphine on polymer support (Fluka, 3 mmol gϪ1
,
1.49 g, 4.47 mmol) was added to a suspension of chloro-
(cycloocta-1,5-diene)iridium()dimer (500 mg, 0.744 mmol) in
THF (10 ml). The resulting suspension was agitated under an
atmosphere of argon at RT for 24 h. The polymer turned dark
red–brown. A solution of ammonium hexafluorophosphate
(970 mg, 5.95 mmol) in THF (14 ml) was then added and the
resulting suspension was agitated under an atmosphere of
argon at RT for 24 h. The resulting red–brown polymer was
washed sequentially with MeOH and CH2Cl2 and dried in
vacuo. Elemental analysis indicated 12.5% iridium was present,
corresponding to a theoretical loading of 0.65 mmol gϪ1
.
Preparation of trans-6-propenylbenzo[1,3]dioxol-5-ol (1)2
Solution phase. An oven dried Schlenk flask was charged with
a suspension of [Ir(COD)(PPh2Me)2]PF6 (138 mg, 0.16 mmol)
in THF (10 ml). Hydrogen gas was bubbled through the
solution until the red catalyst dissolved completely to give a
pale yellow catalyst solution of [Ir(THF)2H2(PPh2Me)2]PF6.
The flask was evacuated and filled with argon 3 times. A
solution of 5 (0.97 g, 5.4 mmol) in THF (10 ml) was cannulated
into the catalyst solution and the resulting mixture was stirred
under an atmosphere of argon for 1 h. The reaction was
quenched with a buffer solution (pH 7), the organic layer
extracted with Et2O, dried (MgSO4) and evaporated under
reduced pressure. The residue was chromatographed (SiO2, 3 : 2
petroleum ether–diethyl ether) to give 1 (0.82 g, 85%) as a pale
yellow solid; νmax/cmϪ1 3324 (OH), 1635 (C᎐C), 1508 (Ar C᎐C),
1
diamond compression cell. H-NMR spectra were recorded in
CDCl3 on a Bruker Advance DPX-400 spectrometer at 400
MHz with residual chloroform as the internal reference (δH
=
7.26 ppm) and J values are given in Hz. 13C-NMR spectra
were recorded in CDCl3 on the same spectrometer at 100 MHz
with the central peak of chloroform as the internal reference
(δC = 77.0 ppm). DEPT 135 and two-dimensional (COSY,
HMQC and HMBC) NMR spectroscopy were used, where
appropriate, to aid in the assignment of signals in the 1H-NMR
and 13C-NMR spectra. Mass spectra were obtained using
electrospray techniques on a Bruker BIOAPEX 4.7 T FTICR
spectrometer at the Department of Chemistry, University of
Cambridge. Microanalyses were performed by Medac Ltd.,
Surrey. X-Ray crystal structures were determined at the
Department of Chemistry, Lensfield Road, Cambridge. The
microwave used was a prototype Smith Synthesizer supplied
by Personal Chemistry, Sweden.
᎐
᎐
1245 & 1032 (C–O); δH(400 MHz, CDCl3) 6.76 (1H, s, H-2),
6.48 (1H, dd, J 15.73, 1.83, CHCHCH3), 6.39 (1H, s, H-5), 6.02
(1H, dq, J 15.73, 6.59, H-8), 5.88 (2H, s, OCH2O), 4.90 (1H, s,
OH ), 1.881 (3H, dd, J 6.59, 1.83, CH3); δC(CDCl3) 147.23,
147.00, 128.10, 126.39ϩ, 124.90ϩ, 117.43, 105.88ϩ, 101.01Ϫ,
98.19ϩ, 18.70ϩ.
Preparation of 5-allyloxybenzo[1,3]dioxole 4
Using polymer-supported reagent 8. An oven-dried flask was
charged with catalyst 8 (150 mg) and THF (3 ml). Hydrogen gas
was bubbled through the resulting suspension until the polymer
turned from red to chrome yellow. The suspension was flushed
with argon before a solution of 5 (35 mg, 0.20 mmol) in THF
(1.5 ml) was cannulated into it. The resulting suspension was
agitated under an atmosphere of argon at RT for 24 h. The
polymer was removed via filtration and washed sequentially
with Et2O and CH2Cl2. The filtrate was concentrated in vacuo
and filtered through a plug of silica to give 1 with a trans–cis
ratio of 11 : 1, and a small amount (<3%) of the hydrogenated
product, 4,5-methylenedioxy-2-propenylphenol. Mass recovery
was essentially quantitative.
A solution of sesamol (1 g, 7.24 mmol) in acetonitrile–DMF 9 :
1 (40 ml) was added to PS–BEMP (Fluka, 2.2 mmol base gϪ1
,
9.87 g, 21.7 mmol). Allyl bromide (0.876 g, 7.24 mmol) was
added and the resulting mixture agitated under an argon
atmosphere at RT for 3 h. The polymer was removed by
filtration and the resulting filtrate was filtered through a plug of
silica and concentrated in vacuo to yield 4 as a colourless oil
(1.27 g, 7.1 mmol, 98%); νmax/cmϪ1 1630 (C᎐C), 1501 (Ar C᎐C),
᎐
᎐
1242 & 1038 (C–O); δH(400 MHz, CDCl3) 6.69 (1H, d, J 8.42,
H-3), 6.51 (1H, d, J 2.56, H-6), 6.36 (1H, dd, J 8.42, 2.56, H-2),
6.00 (1H, m, CH2CHCHHЈ), 5.91 (2H, s, OCH2O), 5.39 (1H,
dd, J 17.2, 1.83, CH2CHCHЈH ), 5.27 (1H, dd, J 10.25, 1.83,
CH2CHCHЈH), 4.47 (2H, d, J 5.49, OCH2CH); δC(CDCl3)
154.15, 148.27, 141.76, 133.50ϩ, 117.45Ϫ, 107.89ϩ, 106.01ϩ,
101.08Ϫ, 98.31ϩ, 69.73Ϫ.
Polystyrene-bound 4-nitrophenyl carbonate18
Hydroxymethyl polystyrene (Advanced Chemtech, 1% cross-
linked, 1 mmol gϪ1, 1.0 g), 4-nitrophenyl chloroformate (0.81 g,
4 mmol) and DMAP (0.12 g, 1 mmol) were combined, CH2Cl2
(14 ml) was added, and the resulting suspension agitated at
RT for 1.5 h. Filtration and rinsing with anhydrous CH2Cl2
Preparation of 6-allylbenzo[1,3]dioxol-5-ol (5)19
A mixture of 4 (200 mg, 1.12 mmol), 1-ethyl-3-methyl-1H-
imidazolium hexafluorophosphate (280 mg) and toluene (3 ml)
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followed by drying in vacuo yielded white beads; νmax (single
bead)/cmϪ1 1768 (C᎐O), 1527 (C–NO ).
When using a crude mixture of 11 : 1 trans–cis 1 and 4,5-
methylenedioxy-2-propenylphenol, a further step was required
to scavenge out the phenolic impurities: polymer-supported
carbonate (Fluka, 3.5 mmol gϪ1, 40 mg) and CH2Cl2 (2 ml) were
added to the crude product and the resulting suspension was
agitated at RT for 3 h. The polymer was removed by filtration
and filtrate was concentrated in vacuo to give carpanone (24 mg,
70%) as a white solid.
᎐
2
Dissymmetric salen ligand (9a, 9b, 9c)
Ethylenediamine (0.39 g, 6.4 mmol) was added to a solution of
salicylaldehyde (1.17 g, 9.6 mmol) and 2,5-dihydroxy-
benzaldehyde (0.44 g, 3.2 mmol) in CH2Cl2 (50 ml). The
reaction mixture was stirred under an atmosphere of argon at
RT for 24 h, then concentrated in vacuo to yield a yellow solid.
This product was used without further purification in the
synthesis of 7 by resin-capture. The expected statistical yield of
9b in this step is 2.4 mmol assuming equal reactivity of the two
General procedure for isomerisation reactions using reagent 8
An oven-dried flask was charged with catalyst 8 (150 mg) and
THF (2.5 ml). Hydrogen gas was bubbled through the resulting
suspension until the polymer turned from red to chrome yellow.
The suspension was flushed with argon before a solution of the
aryl allylic derivative or allyl ether (0.25 mmol) in THF (2.5 ml)
was cannulated into it. The resulting suspension was agitated
under an atmosphere of argon at RT for 24 h. The polymer
was removed via filtration and washed sequentially with THF
and CH2Cl2. The filtrate was concentrated in vacuo. Crude
mass recovery was essentially quantitative and 1H NMR
spectroscopy was used to determine the trans–cis ratio. In these
small scale reactions, 1H NMR analysis also indicates up to 4%
hydrogenated alkene product.
aldehydes, based on work by Jacobsen and co-workers;18 νmax
/
cmϪ1 3284 (OH), 1633 (C᎐N).
᎐
Polystyrene-bound salen ligand
Dissymmetric salen ligand 9 (0.225 g, 0.3 mmol), DMAP
(25 mg, 0.2 mmol) and diisopropyl ethylamine (DIPEA)
(50 mg, 0.4 mmol) was added to a suspension of polystyrene-
bound 4-nitrophenyl carbonate (0.250 g, ∼0.2 mmol) in
anhydrous DMF (5 ml). The resulting orange–yellow
suspension was agitated at RT for 3 h, then filtered and rinsed
sequentially with DMF, CH2Cl2, MeOH, CH2Cl2 and dried in
vacuo to yield the product as yellow beads; νmax (single bead)/
cmϪ1 1763 (C᎐O), 1635 (C᎐N). The absorbance at 1527
Preparation of 2-methoxy-6-(E )-prop-2-enylphenol.20 Follow-
ing the procedure above, o-eugenol¶ (41 mg, 0.25 mmol) was
isomerised by reagent 8 to give the title compound as a yellow
solid with a 19 : 1 trans–cis selectivity; νmax/cmϪ1 3416 (OH),
᎐
᎐
(C–NO2) has disappeared completely.
Polystyrene-bound Co(salen) complex (7)
1656 (C᎐C), 1612, 1586, 1475 (Ar C᎐C), 1270, 1064 (C–O–C),
᎐
᎐
A solution of Co(OAc)2ؒ4H2O (99 mg, 0.4 mmol) in 1 : 1
MeOH–toluene (4 ml) was added to the polystyrene-bound
salen ligand (0.25 g) with agitation at RT. After 2 h, the beads
were filtered, rinsed sequentially with MeOH and CH2Cl2 and
dried in vacuo to yield dark brown beads; νmax (single bead)/
cmϪ1 1763 (C᎐O), 1635 (C᎐N). Elemental analysis indicated
973 (trans HC᎐CH); δ (400 MHz, CDCl ) 6.98 (1H, d, J 7.68,
᎐
H
3
Ar–H3), 6.85–6.70 (2H, m, Ar–H), 6.68 (1H, dq, J 17.56, 1.83,
CH᎐CHCH ), 6.29 (1H, dq, J 17.56, 6.59, CH᎐CHCH ), 5.82
᎐
᎐
3
3
(1H, s, OH ), 3.87 (3H, s, OCH3), 1.90 (3H, dd, J 6.59, 1.83,
CH᎐CHCH ); δC(CDCl3) 146.63, 142.57, 126.87, 125.12,
᎐
3
᎐
᎐
124.34, 119.37, 118.85, 108.71, 56.06, 18.87.
2.2% Co corresponding to a loading of 0.37 mmol gϪ1
.
Preparation of 1,2-dimethoxy-4-(E )-prop-2-enylbenzene.21
Following the procedure above, 4-allyl-1,2-dimethoxybenzene
(45 mg, 0.25 mmol) was isomerised by reagent 8 to give the
title compound as a colourless liquid with a 19 : 1 trans–cis
Preparation of carpanone (2)1,2
Polystyrene-bound Co(salen) 7 (49 mg) was added to a solution
of 6-propenylbenzo[1,3]dioxol-5-ol 1 (34 mg, 0.19 mmol) in
CH2Cl2 (2.5 ml). The resulting suspension was agitated under
an atmosphere of oxygen at RT for 3 h. The polymer was
removed by filtration and washed sequentially with CH2Cl2 and
Et2O. The filtrate was concentrated in vacuo and the resulting
residue was dissolved in CH2Cl2 (2.5 ml). Polymer-supported
trisamine (90 mg) was added and the resulting suspension
agitated under an atmosphere of argon at RT for 2 h. The
polymer was removed by filtration and the filtrate was filtered
through a plug of silica with Et2O as eluent. The solvent was
evaporated in vacuo to yield carpanone (27 mg, 80%, HPLC
purity, 98.10%) as a white solid. Recrystallisation from carbon
tetrachloride gave white crystals; mp 185 ЊC [lit.2 mp 185 ЊC];
δH(400 MHz, CDCl3) 7.02 (1H, ddd, J 2.3, 0.9, 5.0, H-7Ј), 6.80
(1H, s, H-6), 6.33 (1H, s, H-3), 5.90 (1H, d, J 1.5, OCaHHO),
5.87 (1H, d, J 1.5, OCaHHO), 5.69 (1H, s, H-3Ј), 5.67 (1H, s,
OCbHHO), 5.63 (1H, s, OCbHHO), 3.28 (1H, dd, J 7.4, 2.1,
H-7), 3.17 (1H, ddd, J 7.4, 2.3, 2.3, H-6Ј), 2.52 (1H, m, H-8),
2.22 (1H, m, H-8Ј), 1.14 (3H, d, J 7.2, H-9), 0.71 (3H, d, J 7.6,
H-9Ј); Found (ESI): [M ϩ Na]ϩ 377.1001, C20H18O6Na requires
377.1001. Data are consistent with those reported previously.1,2
Crystal data§: C20H18O6, M = 354.34, monoclinic, a = 8.3846
(4), b = 27.9562 (17), c = 7.1987(4), β = 107.629(3)Њ, U =
1608.14(15) Å3, T = 180(2) K, space group P21, Z = 4, µ = 0,109
mmϪ1, 8235 reflections collected, 2752 independent reflections
(Rint = 0.0463). The final wR(F 2) was 0.0873.5
selectivity; νmax/cmϪ1 1603, 1583, 1512 (Ar C᎐C), 1230, 1026
᎐
(C–O–C), 962 (trans HC᎐CH); δ (400 MHz, CDCl ) 6.69–6.83
᎐
H
3
(3H, m, Ar–H), 6.26 (1H, dq, J 15.73, 1.83, CH᎐CHCH ), 6.02
᎐
3
(1H, dq, J 15.73, 6.59, CH᎐CHCH ), 3.81 (3H, s, OCH ), 3.78
᎐
3
3
(3H, s, OCH ), 1.79 (3H, dd, J 6.59, 1.83, CH᎐CHCH );
᎐
3
3
δC(CDCl3) 148.97, 148.16, 131.15, 130.58, 123.72, 118.62,
111.22, 108.52, 55.87, 55.73, 18.28; Found (ESI): [M ϩ Na]ϩ
201.0892, C11H14O2Na requires 201.0891.
Preparation
of
1-methoxy-4-(E )-prop-2-enylbenzene.22
Following the procedure above, 4-allylanisole (37 mg, 0.25
mmol) was isomerised by reagent 8 to give the title compound
as a colourless liquid with a 97 : 3 trans–cis selectivity; δH(400
MHz, CDCl3) 7.27 (2H, d, J 8.78, Ar–H), 6.84 (2H, d, J 8.78,
Ar–H), 6.36 (1H, dq, J 15.72, 1.83, CH᎐CHCH ), 6.10 (1H, dq,
᎐
3
J 15.73, 6.59, CH᎐CHCH ), 3.80 (3H, s, OCH ), 1.87 (3H, dd,
᎐
3
3
J 6.59, 1.83, CH᎐CHCH ); δ (CDCl ) 158.58Ϫ, 130.82Ϫ,
᎐
3
C
3
130.34ϩ, 126.85ϩ, 123.44ϩ, 113.89ϩ, 55.24ϩ, 18.35ϩ; Found
(ESI): [M]ϩ 148.08942, C10H12O1 requires 148.08878.
Preparation of 2,6-dimethoxy-4-(E )-prop-2-enylphenol.23
Following the procedure above, 4-allyl-2,6-dimethoxyphenol
(49 mg, 0.25 mmol) was isomerised by reagent 8 to give the title
compound as a yellow liquid with a 24 : 1 trans–cis selectivity;
νmax/cmϪ1 3470 (OH), 1653 (C᎐C), 1603, 1516 (Ar C᎐C), 961
᎐
᎐
(trans HC᎐CH); δ (400 MHz, CDCl ) 6.55 (2H, s, Ar–H), 6.29
᎐
H
3
§ CCDC reference number 187437. See http://www.rsc.org/suppdata/
p1/b2/b203388g for crystallographic files in .cif or other electronic
format.
¶ The IUPAC name for o-eugenol is 2-allyl-6-methoxyphenol.
J. Chem. Soc., Perkin Trans. 1, 2002, 1850–1857
1855

View Online
(1H, dq, J 15.73, 1.83, CH᎐CHCH ), 6.07 (1H, dq, J 15.73,
Preparation of (3-propenyloxyprop-2-enyl)benzene. Following
᎐
3
6.59, CH᎐CHCH ), 5.46 (1H, s, OH ), 3.87 (6H, s, OCH ), 1.85
the procedure above, (3-allyloxypropenyl)benzene (25 mg, 0.14
mmol) was isomerised by reagent 8 (70 mg) to give the title
compound as a colourless liquid with as a mixture of 1 : 1
trans–cis isomers; δH(400 MHz, CDCl3) 7.40–7.42 (10H, m,
Ar–H), 6.62 (2H, dq, J 16.10, 1.83, H-1), 6.33–6.22 (3H, m,
᎐
3
3
(3H, dd, J 6.59, 1.83, CH᎐CHCH ); δ (CDCl ) 147.07, 134.00,
᎐
3
C
3
130.92, 129.57, 123.76, 102.67, 56.19, 18.22.
Preparation of (E )-prop-2-enylbenzene.24 Following the
procedure above, allylbenzene (30 mg, 0.25 mmol) was
isomerised by reagent 8 to give the title compound as a
H-2, OCH᎐CHCH -trans), 6.02 (1H, dq, J 6.22, 1.46, OCH᎐
᎐
᎐
3
CHCH -cis), 4.87 (1H, m, CH᎐CHCH -trans), 4.43 (1H, m,
᎐
3
3
colourless liquid; νmax/cmϪ1 1598, 1578, 1496 (Ar C᎐C), 960
CH᎐CHCH -cis), 4.41 (2H, dd, J 16.10, 1.83, H-3-cis), 4.33
᎐
3
᎐
(2H, dd, J 16.10, 1.83, H-3-trans), 1.62 (3H, dd, J 5.12, 1.83,
CH3-cis), 1.56 (3H, dd, J 6.59, 1.46, CH3-trans).
(trans HC᎐CH); δ (400 MHz, CDCl ) 7.47–7.20 (5H, m,
᎐
H
3
Ar–H), 6.46 (1H, dq, J 15.73, 1.46, CH᎐CHCH ), 6.28 (1H, dq,
᎐
3
J 15.73, 6.59, CH᎐CHCH ), 1.93 (3H, dd, J 6.59, 1.46, CH᎐
CHCH3); δC(CDCl3) 137.94, 131.05, 128.44, 126.70, 125.81,
125.62, 18.44.
᎐
᎐
3
Acknowledgements
We gratefully acknowledge the financial support from the
Cambridge Commonwealth Trust, The British Council, The
committee of Vice-Chancellors and Principals and Astra-
Zeneca for PhD funding (to ALL), Pfizer Central Research for
a Postdoctoral Fellowship (to IRB), the BP endowment and the
Novartis Research Fellowship (to SVL). We thank Dr Andrew
D. Bond for the X-ray structure determination.
Preparation of 4,5-dimethoxy-(E )-prop-2-enylbenzo[1,3]-
dioxole.25 Following the procedure above, dillapiole (56 mg,
0.25 mmol) was isomerised by reagent 8 to give the title
compound as a colourless oil with a 39 : 1 trans–cis selectivity;
δH(400 MHz, CDCl3) 6.61 (1H, s Ar–H), 6.59 (1H, dq, J 15.73,
1.83, CH᎐CHCH ), 6.05 (1H, dq, J 15.73, 6.59, CH᎐CHCH ),
᎐
᎐
3
3
5.85 (2H, s, OCH2O), 4.00 (3H, s, OCH3), 3.74 (3H, s, OCH3),
1.86 (3H, dd, J 6.59, 1.83, CH᎐CHCH ); δ (CDCl ) 145.04,
References
᎐
3
C
3
143.92, 137.53, 136.49, 125.17, 124.91, 124.84, 101.14, 98.34,
61,43, 60.02, 18.66; Found (ESI): [MH]ϩ 223.09750, C12H15O4
requires 223.0970.
1 (a) S. V. Ley, O. Schucht, A. W. Thomas and P. J. Murray, J. Chem.
Soc., Perkin Trans. 1, 1999, 1251; (b) J. Habermann, S. V. Ley and
J. S. Scott, J. Chem. Soc., Perkin Trans. 1, 1999, 1253; (c)
I. R. Baxendale and S. V. Ley, Bioorg. Med. Chem. Lett., 2000, 10,
1983; (d ) I. R. Baxendale, G. Brusotti, M. Matsuoka and S. V. Ley,
J. Chem. Soc., Perkin Trans. 1, 2002, 143; (e) I. R. Baxendale,
S. V. Ley and C. Puitti, Angew. Chem., Int. Ed., 2002, 41, 2194, in
press; ( f ) S. V. Ley, I. R. Baxendale, R. N. Bream, P. S. Jackson,
A. G. Leach, D. A. Longbottom, M. Nesi, J. S. Scott, R. I. Storer
and S. J. Taylor, J. Chem. Soc., Perkin Trans. 1, 2000, 3815; (g)
S. V. Ley, I. R. Baxendale, G. Brusotti, M. Caldarelli, A. Massi and
M. Nesi, Il Farmaco, 2002, 57, 321; (h) S. V. Ley and I. R. Baxendale,
Chem. Rec., 2002 in press.
2 (a) I. R. Baxendale, A.-L. Lee and S. V. Ley, Synlett, 2001, 1482;
(b) I. R. Baxendale, A.-L. Lee and S. V. Ley, Synlett, 2001, 2004.
3 I. R. Baxendale, A.-L. Lee and S. V. Ley, Synlett, 2002, 516.
4 G. C. Brophy, J. Mohandas, M. Slaytor, S. Sternhell, T. R. Watson
and L. A. Wilson, Tetrahedron Lett., 1969, 5159.
5 O. L. Chapman, M. R. Engel, J. P. Springer and J. C. Clardy, J. Am.
Chem. Soc., 1971, 6696.
6 C. W. Lindsey, L. K. Chan, B. C. Goess, R. Joseph and M. D. Shair,
J. Am. Chem. Soc., 2000, 122, 422.
7 The reagent polymer-supported 2-tert-butylimino-2-diethylamino-
1,3-dimethylperhydro-1,3,2-diazaphosphorine (PS–BEMP) had a
loading of 2. 3 mmol gϪ1 and was purchased from Fluka: Cat. No.
20026.
8 A fully automated Coherent Synthesis System microwave
machine was used. This was supplied by Personal Chemistry:
Hamnesplanaden 5, SE-753 19 Uppsala, Sweden; www.
personalchemistry.com.
Preparation of prop-2-enyloxybenzene.26 Following the
procedure above, allyl phenyl ether (20 mg, 0.15 mmol) was
isomerised by reagent 8 to give the title compound as a
colourless liquid as a mixture of 1 : 1 trans–cis isomers;
δH(400 MHz, CDCl3) 7.22 (4H, m, Ar–H), 6.92 (6H, m, Ar–H),
6.34 (1H, dq, J 12.08, 1.46, OCH᎐CHCH -trans), 6.30 (1H, dq,
᎐
3
J 6.22, 1.83, OCH᎐CHCH -cis), 5.29 (1H, dq, J 12.08, 6.95,
᎐
3
CH᎐CHCH -trans), 4.79 (1H, dq, J 6.22, 6.95, OCH᎐CHCH -
᎐
᎐
3
3
cis), 1.64 (3H, dd, J 6.95, 1.83, CH3-cis), 1.59 (3H, dd, J 6.95,
1.46, CH3-trans).
Prop-2-enyloxymethylbenzene.27 Following the procedure
above, allyl benzyl ether (30 mg, 0.20 mmol) was isomerised by
reagent 8 to give the title compound as a colourless liquid as
a mixture of 1 : 1 trans–cis isomers; δH(400 MHz, CDCl3)
7.34–7.16 (10H, m, Ar–H), 6.24 (1H, dq, J 12.44, 1.46, OCH᎐
᎐
CHCH -trans), 5.96 (1H, dq, J 6.22, 1.83, OCH᎐CHCH -cis),
᎐
3
3
4.82 (1H, dq, J 6.59, 12.44, CH᎐CHCH -trans), 4.72 (2H, s,
᎐
3
PhCH O), 4.63 (2H, s, PhCH O), 4.37 (1H, m, OCH᎐CHCH -
᎐
2
2
3
cis), 1.83 (3H, dd, J 5.12, 1.83, CH3-cis), 1.49 (3H, dd, J 6.59,
1.46, CH3-trans).
9 M. Setty-Fichman, J. Blum and Y. Sasson, Tetrahedron. Lett., 1994,
35, 781.
10 Tris(triphenylphosphine)rhodium() chloride polymer bound was
purchased from Fluka: Cat. No. 93407.
(3-Allyloxy-(E )-prop-2-enyl)benzene.28 Sodium hydride (60%
w/w dispersion in oil) was added to a solution of cinnamyl
alcohol (300 mg, 2.24 mmol) in dry DMF (5 ml) at 0 ЊC. The
mixture was allowed to stir under argon for 30 min. Allyl
bromide (0.23 ml, 2.68 mmol) was added dropwise and the
reaction mixture was allowed to stir for a further 3 h. The
reaction mixture was diluted with ether, quenched with water
and the organic layer extracted with ether. The combined
organic layers were washed with brine and dried (MgSO4).
The crude product was purified by column chromatography
(4 : 1 petroleum ether–diethyl ether) to yield the title compound
as a colourless liquid (324 mg, 83%); νmax/cmϪ1 1647, 1599, 1495
11 (a) D. Baudry, M. Ephritikhine and H. Felkin, J. Chem. Soc., Chem.
Commun., 1978, 694; (b) R. H. Crabtree, H. Felkin and G. E. Morris,
J. Chem. Soc., Chem. Commun., 1976, 716; (c) R. Yamamoto,
N. Fujikawa and N. Miyanra, Synth. Commun., 2000, 30, 2383.
12 Triphenylphosphine on polymer-support had a loading of 3 mmol
g
Ϫ1 and was purchased from Fluka; Cat. No. 93093.
13 Proposed structure of the active species 6 and 8 is based on the
solution-phase analogue (a) L. M. Haines and E. Singleton, J.
Chem. Soc., Dalton, 1972, 1891; (b) see ref. 11c.
14 (a) J. H. Kloosterman, J. H. Van Boom, P. Chatelard, P. Boullanger
and G. Descotes, Tetrahedron Lett., 1985, 5045; (b) J. J. Oltroovt,
C. A. A. van Boeckel, J. H. de Koning and J. H. Van Boom,
Synthesis, 1981, 305.
15 All reactions were stopped after 16 h and the reaction mixture
analysed directly.
16 (a) H. Togo, G Nogami and M. Yokoyama, Synlett, 1998, 534;
S. V. Ley, A. W. Thomas and H. Finch, J. Chem. Soc., Perkin
Trans. 1, 1999, 669; (b) H. Tohma, H. Morioka, S. Takizawa,
M. Arisawa and Y. Kita, Tetrahedron, 2001, 57, 345; G.-P. Wang
and Z.-C. Chen, Synth. Commun., 1999, 29, 2859.
(Ar C᎐C), 1071 (C–O), 965 (RCH᎐CHR-trans), 921 (RCH᎐
᎐
᎐
᎐
CH2); δH(400 MHz, CDCl3) 7.24–7.45 (5H, m, Ar–H), 6.65
(1H, d, J 16.10, H-1), 6.33 (1H, dt, J 16.10, 5.85, H-2), 5.99
(1H, m, CH᎐CH ), 5.34 (1H, ddt, J 17.2, 1.46, 1.46, CH ᎐
᎐
᎐
2
2
CHHЈ), 5.23 (1H, ddt, J 10.25, 1.46, 1.46, CH ᎐CHHЈ), 4.19
᎐
2
(2H, dd, J 5.85, 1.46, H-3), 4.07 (2H, ddd, J 5.85, 1.46, 1.46,
OCH2CH); δC(CDCl3) 136.74, 134.74, 132.38, 128.52, 127.62,
126.46, 126.07, 117.07, 71.11, 70.70.
1856
J. Chem. Soc., Perkin Trans. 1, 2002, 1850–1857

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20 J. Arnarp, J. Bielawski, B.-N. Dahlin, O. Dahlman, C. R. Enzell and
T. Pettersson, Acta. Chem. Scand., 1989, 44.
23 A. F. A. Wallis, Aust. J. Chem., 1973, 26, 585.
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Soc., 1993, 115, 6065.
25 J. Jakupovic and F. Eid, Phytochemistry, 1987, 2427.
26 A. Annuziata, C. Galli, M. Marinelli and T. Pau, Eur. J. Org. Chem.,
2001, 7, 1323.
21 T. Yamashita, Tetrahedron, 1994, 50, 9275.
22 I. N. N. Namboothiri and A. Hassner, J. Organomet. Chem., 1996,
69.
27 J. Otera and Y. Niibo, Bull. Chem. Soc. Jpn., 1986, 59, 3977.
28 S. Torii, S. Takagishi, T. Inokuchi and H. Okumoto, Bull. Chem.
Soc. Jpn., 1987, 60, 775.
J. Chem. Soc., Perkin Trans. 1, 2002, 1850–1857
1857