Synthesis of tsetse fly attractants from a cashew nut shell extract by isomerising metathesis

Article abstract of DOI:10.1039/c4gc01269k

Starting from a purified cashew nut shell extract containing mostly anacardic acid derivatives, the tsetse fly attractants 3-ethyl- and 3-propylphenol were selectively synthesised. The mixture was first converted into 3-(non-8-enyl)phenol in 98% purity via ethenolysis and distillation with concomitant decarboxylation. The olefinic side chain was then shortened by isomerising cross-metathesis with short-chain olefins in the presence of a [Pd(μ-Br)(^tBu₃P)]₂ isomerisation catalyst and a second-generation Hoveyda-Grubbs catalyst, and the synthesis was completed by a hydrogenation step.

Full text of DOI:10.1039/c4gc01269k

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Synthesis of tsetse fly attractants from a cashew
nut shell extract by isomerising metathesis†
Cite this: DOI: 10.1039/c4gc01269k
S. Baader,a P. E. Podsiadly,a D. J. Cole-Hamilton*b and L. J. Goossen*a
Starting from a purified cashew nut shell extract containing mostly anacardic acid derivatives, the tsetse
fly attractants 3-ethyl- and 3-propylphenol were selectively synthesised. The mixture was first converted
into 3-(non-8-enyl)phenol in 98% purity via ethenolysis and distillation with concomitant decarboxylation.
The olefinic side chain was then shortened by isomerising cross-metathesis with short-chain olefins in
the presence of a [Pd(µ-Br)(tBu3P)]2 isomerisation catalyst and a second-generation Hoveyda–Grubbs
catalyst, and the synthesis was completed by a hydrogenation step.
Received 7th July 2014,
Accepted 27th August 2014
DOI: 10.1039/c4gc01269k
www.rsc.org/greenchem
Tsetse flies, the main vector of African sleeping sickness
(trypanosomiasis), inhabit sub-Saharan Africa, the region
Introduction
Cashew nut shell liquid (CNSL) is a by-product of cashew nut where CNSL is predominantly produced in Africa (Nigeria,
processing, and is available on a scale of 450 000 tonnes per Ivory Coast, and Tanzania).6 Traps charged with the kairo-
year.1 It is an excellent representative of an unused, non- mones (2 and 3) are used as a sustainable and eco-friendly way
eatable natural resource for which no competition occurs to control the tsetse fly population. Both kairomones are
between land use for food or raw material production.2 When worthwhile synthetic targets, because each works best to
CNSL is extracted from the cashew nut shells via cold-press or attract a certain type of vector tsetse fly, 2 for Glossina morsi-
solvent extraction, it consists predominantly of anacardic acids tans morsitans, and 3 for G. pallidipes.7
(1a–d) and other phenolic compounds such as cardanol
Various strategies for the synthesis of 3-propylphenol (3)
(3-pentadecenylphenol) and cardol (5-pentadecenylbenzene- have been reported. These include multi-step reactions with
1,3-diol).3 Each of these has a 15-carbon side chain with a waste-intensive key steps, e.g. Wittig and Grignard reactions of
varying degree of saturation, located in the meta-position rela- 3-hydroxybenzaldehyde.8 3 has also been synthesised from car-
tive to the hydroxy group. Anacardic acids (1) are promising danol via isomerisation of the double bond into the benzylic
substrates for various decarboxylative and decarbonylative position, followed by metathesis with 2-butene.9 However, the
transformations.4 Upon distillation, they are known to decarb- isomerisation step resulted in a mixture of isomers, among
oxylate with formation of cardanol and other phenols. The which the desired product with the double bond conjugated
structurally related kairomones 3-ethyl- (2) and 3-propylphenol with the aromatic ring made up for only 40%. As a conse-
(3) are potent tsetse fly attractants (Fig. 1).5
quence, the overall yield of 3-propylphenol (3) remained un-
satisfactory (11% based on cardanol).
More efficient syntheses of 3-propyl- (3) and 3-ethylphenol
(2) directly from CNSL would, thus, be highly desirable. We
envisioned that isomerising olefin metathesis could be the key
technology to access kairomones from CNSL, either as a
mixture of 2 and 3 that might directly be usable in the fly
traps, or in pure form.
Our strategy was to start with a basic extraction of CNSL,
which would serve to remove side components such as the
resorcinolic derivative cardol and lead to anacardic acids (1), a
mixture of salicylic acids 1a–d with saturated, mono-, di- and
tri-unsaturated C15 side chains in the 6-position of the aromatic
ring (Scheme 1).3 Since the side-chain double bond closest to
the ring is positioned at C8 in all unsaturated isomers, it should
be possible to convert this mixture into a reasonably pure single
compound by ethenolysis followed by crack distillation with
Fig. 1 Kairomones used as tsetse fly attractants.
aFachbereich Chemie, Organische Chemie, TU Kaiserslautern, Erwin-Schrödinger-
Straße 54, 67663 Kaiserslautern, Germany. E-mail: goossen@chemie.uni-kl.de;
Fax: +49 (631) 205-2046; Tel: +49 (631) 205-3921
bEaStCHEM, School of Chemistry, University of St. Andrews, St. Andrews, Fife,
KY16 9ST Scotland, UK. E-mail: djc@st-andrews.ac.uk
†Electronic supplementary information (ESI) available: General methods and
spectroscopic data. See DOI: 10.1039/c4gc01269k
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tion, which led to 52 g (58 wt% based on the ethereal extract)
of the acid mixture 1.
Next, we investigated the ethenolysis step. As a starting
point, we used the Ru-1 catalyst, and stirred a solution of 1
and Ru-1 in dichloromethane under 10 bar ethene pressure at
23 °C (Table 1, entry 1). These conditions had previously been
shown to work well for the ethenolysis of the decarboxylated
derivative cardanol.10 However, for the anacardic acids 1,
ethenolysis proceeded with unsatisfactory yields even at a rela-
tively high catalyst loading of 1 mol% Ru-1.
We started optimising the ethenolysis by testing numerous
ruthenium-based catalysts (Fig. 2), with a focus on complexes
known to promote ethenolysis.11 These include first- and
second-generation Grubbs- and Hoveyda-type catalysts (Ru-2,12
Ru-3,13 Ru-4,14 and Ru-515), and the indenylidene-ruthenium
complexes Ru-616 and Ru-7.17
Scheme 1 Selective conversion of anacardic acids (1) to 3-(non-8-
enyl)phenol (5).
As can be seen from Table 1, other phosphine-ligated cata-
lysts (Ru-2 and Ru-3) were more efficient than Ru-1, and near-
quantitative yield was achieved with the first-generation
Hoveyda–Grubbs catalyst Ru-3 (entries 2 and 3). Among the
NHC-ligated catalysts, the second-generation Grubbs catalyst
Ru-4 was most effective, giving 77% yield of 4 (entries 4–7). In
contrast, a low yield of the desired product 4 was obtained using
Ru-5 (entry 5). Second-generation indenylidene catalysts were
inferior (Ru-7; entry 6) or completely inactive (Ru-6; entry 7).
With the best ruthenium catalyst Ru-3, it was possible to
reduce the loading to 0.05 mol% and still achieve good yields
of the desired product 5 (entries 8–10). The finding that phos-
phine-based metathesis catalysts outperform modern NHC
systems is remarkable but not unprecedented, since Ru-3
has been reported to be optimal also for the ethenolysis of
2-methoxy-6-pentadecenylbenzoic acid methyl esters.10
Scheme 2 From 3-(non-8-enyl)phenol (5) to the tsetse fly attractants
2 and 3.
concomitant decarboxylation. Regardless of the number of
double bonds on the far side of C8, the ethenolysis would
shorten all unsaturated side chains to ω-nonenyl groups. In the
distillation, the carboxylate group would be removed and the
main product 3-(non-8-enyl)phenol (5) separated from the low-
boiling olefins formed during ethenolysis, as well as the higher-
boiling saturated cardanol derivative 3-pentadecylphenol (1d).
Subsequent isomerising ethenolysis of 5 would shorten the
olefinic side chain stepwise in a statistical fashion (Scheme 2).
Depending on the ethene pressure and catalyst system, the
side-chain-length distribution of the resulting product mixture
should be adjustable so that a mixture of 6 and 7 is obtained
reasonably free of other components, which could be hydro-
genated in situ to the kairomones 2 and 3.
Table 1 Selective ethenolysis of anacardic acids (1)
An additional, non-isomerising cross-metathesis step with
pure ethene or 2-butene prior to hydrogenation should allow
directly accessing either product 6 or 7 in pure form, since the
thermodynamically favoured conjugated double-bond isomers
6 and 7 should be the main components in the equilibrated
isomerising metathesis mixture. Subsequent hydrogenation
would give access to pure 2 or 3.
Entry
Ru-cat.
Loading/mol%
Yield 4/%
Conversion 1/%
1
2
3
4
5
6
7
8
9
10
Ru-1
Ru-2
Ru-3
Ru-4
Ru-5
Ru-6
Ru-7
Ru-3
Ru-3
Ru-3
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.5
0.1
0.05
46
78
92
77
21
0
70
83
>94
83
82
Results and discussion
Ethenolysis of anacardic acids
87
47
56
71/89a
65
81/99a
76
Based on these considerations, we approached the synthetic
procedure starting from the cashew nut shells. An extraction of
400 g of nut shells with diethyl ether yielded 90 g of CNSL
(23 wt% based on the nut shells). The acids were separated
from other phenolic components by precipitation of their
calcium salts using calcium hydroxide followed by acidifica-
61
71
Conditions: 0.25 mmol 1, 1 mol% metathesis catalyst, 1 mL DCM, 10
bar ethene, 23 °C, 16 h. Yields were determined by GC analysis. In the
GC injector, 4 quantitatively decarboxylates to 5, which was quantified
using n-hexadecane as an internal standard. a Preparative-scale
reaction (2.50 g, 7.30 mmol).
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[5]·9)/([5] + [ethene]), calculated from the concentration of
each alkene substrate and its respective chain length. This
standard formula for the calculation of an arithmetic mean
only roughly approximates the reaction outcome. The chain
length distribution is more accurately assessed using the simu-
lation program described in ref. 19.
In search for an effective catalyst system, we stirred a THF
solution of 3-(non-8-enyl)phenol (5) under 6 bar ethene
pressure (corresponding to an ethene/5 ratio of roughly 22 : 1
and an expected mean chain length of 2.3) with the Pd-based
isomerisation catalyst and a Ru-metathesis catalyst for 16 h at
50 °C. For 1.5 mol% Ru-5 and 1.5 mol% Pd-1, a system that
had been reported to be optimal for the isomerising etheno-
lysis of allyl arenes, 24% 3-hydroxstyrene (6) and 53% 3-(prop-
1-enyl)phenol (7) were obtained along with minor quantities of
longer-chain homologues. However, the mean chain length of
3.2, which was calculated from the GC-integrals, indicates that
the reaction did not go to completion (Table 2, entry 1).
Phosphine-based first-generation catalysts and NHC-based
indenylidene complexes were found to be ineffective, which is
understandable from their low activity in non-isomerising
styrene cross-metatheses.22 With the second-generation
Grubbs catalyst Ru-4, only unsatisfactory yields were obtained,
which can be explained by a release of phosphine from the
pre-catalyst, which is known to inhibit the isomerisation cata-
lyst Pd-1.19,21 Best results were obtained with the Hoveyda-
type NHC catalyst Ru-8 (entries 3–4). After slightly increasing
the catalyst loading to 2 mol%, the desired ethenyl- and
propenylarenes 6 and 7 were almost exclusively formed within
16 h along with only trace amounts of longer-chain derivatives
(entry 4). The mean chain length was found to be 2.4. One
would expect that the low solubility of ethene in the reaction
solvent leads to an accumulation of more soluble longer-chain
Fig. 2 Isomerisation and metathesis catalysts.
The results were even better on a preparative scale (2.50 g,
7.30 mmol). In the presence of 0.5 mol% Ru-3, compound 4
was formed in near-quantitative yield. Upon distillation at
above 140 °C,18 4 decarboxylated quantitatively to 3-(non-8-
enyl)phenol (5) which was isolated in 89% yield and 98%
purity while the saturated compound 1d remained in the dis-
tillation residue. This corresponds to an overall yield of 7 wt%
of 5 based on the cashew nut shells.
Isomerising ethenolysis of 3-(non-8-enyl)phenol
The key step in our synthesis of the tsetse fly attractants 2 and
3 is the shortening of the olefinic side chains by isomerising
cross-metathesis. We have recently demonstrated that iso-
merising metathesis is a valuable synthetic concept for the
valorisation of oleic acid derivatives and of naturally occurring
allylarenes.19 In this context, the dimeric palladium(I) complex
[Pd(µ-Br)(tBu3P)]2 (Pd-1)20 had proven to be a uniquely effective
isomerisation catalyst, fully compatible with state-of-the-art
ruthenium metathesis catalysts.21
Table 2 Isomerising ethenolysis of 3-(non-8-enyl)phenol (3)
In an isomerising cross-metathesis, the olefinic substrates
are continuously converted into an equilibrium mixture of
double-bond isomers, which constantly undergo olefin meta-
thesis until olefin blends with a homogeneous chain-length
distribution are formed. The mean chain length is determined
by the average number of side chain carbons for each substrate
weighted with its molar equivalents.
Thus, in the isomerising cross-metathesis of 3-(non-8-enyl)-
phenol (5) with ethene, an equilibrium mixture of non-volatile
aryl alkenes and volatile unsubstituted alkenes with an identi-
cal chain length distribution should ideally form. If all double-
bond isomers had the same thermodynamic stability and reac-
tivity, their mean chain length should equal ([ethene]·2 +
Yield/%
Entry
Ru-cat./mol%
C2H4/bar
6
7
R ≥ CH3
1
2
3
Ru-5 (1.5)
Ru-4 (1.5)
Ru-8 (1.5)
Ru-8 (2.0)
Ru-8 (2.0)
Ru-8 (2.0)
Ru-8 (2.0)
Ru-8 (2.0)
6
6
6
6
6
6
2
1
24
0
53
17
56
40
23
58
54
67
23
82
23
Traces
Traces
4
Traces
5
22
56
77
37
45
27
4
5a
6b
7
8
Conditions: 0.5 mmol 5, 1.5 mol% Pd-1, metathesis catalyst (amount
given), 2 mL THF, 50 °C, 16 h. Yields were determined by GC using
n-decane as an internal standard. a 4 mL THF. b 8 h.
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olefins in the liquid phase, thus shifting the solution equili-
brium towards longer chains.23
Indeed, GC analysis revealed that the relative ratio of ethene/
propene/butene is 3.5/2.2/1 in the gas phase and 1/2.8/4.6 in
the liquid phase of the equilibrated reaction mixture. Upon
increasing the amount of solvent and thereby reducing the gas-
phase and increasing the liquid-phase volume, the equilibrium
concentration of 6 and 7 changed to 77% and 23%, respectively,
which corresponds to a mean chain length of 2.2 (entry 5).
Control experiments revealed that it takes more than 8 h until
this equilibrium concentration is reached (entry 6).
When lowering the ethene excess to 9 : 1 (2.0 bar ethene,
calculated mean chain length: 2.7), 7 was obtained as the
main product and the mean chain length increased to 2.6
(entry 7). At only 6 : 1 ethene/5 ratio (1.0 bar ethene, calculated
mean chain length: 3.0), the mean chain length was found to
be 2.8 but the concentration of the longer-chain homologues
increased to an undesirably high level (entry 8).
Scheme 3 Preparative-scale one-pot synthesis of the kairomone 3.
viously reported isomerisation/butenolysis/hydrogenation
sequence.9
3-Ethylphenol (2) was also synthesised in pure form from
the mixture of 6 and 7 that was obtained in the isomerising
metathesis step. The synthetic strategy is identical to the one
outlined for the 3-propylphenol (3), only that the 2-butene
used in the terminal cross-metathesis step was replaced by
ethene. This way, 2 was obtained in an overall yield of 84%.
Synthesis of an 3-ethyl- and 3-proylphenol mixture
When performing the isomerising ethenolysis using the opti-
mal catalyst system and substrate ratio (1.0 mmol 5, 1.5 mol%
Pd-1, 2.0 mol% Ru-8, 4 mL THF, 50 °C, 16 h, approx. 9 : 1
ethene/5, 5.0 bar ethene),24 a mixture of the ethenylarene 6
(43%) and the propenylarene 7 (56%) was formed. Upon
exchanging the olefin atmosphere above the reaction mixture
for hydrogen (3.0 bar) and adding charcoal to prevent agglom-
eration of the metal catalyst, the product mixture was directly
hydrogenated to the corresponding saturated kairomones,
which were isolated in a combined 85% yield (2/3 = 1 : 1.3).
Isomerising butenolysis of 3-(non-8-enyl)phenol
We also tried whether performing the isomerising metathesis
using a vast excess of 2-butene would lead to formation of 3 in
satisfactory selectivity. However, even when stirring 5 with
approx. 50 equivalents 2-butene (2.0 bar), 3 was formed in only
64% yield along with the higher homologues butenyl- and
pentenylphenol. We also attempted to shorten the reaction
sequence by performing an isomerising ethenolysis of the ana-
cardic acids (1). Unfortunately, the isomerisation catalyst quickly
lost its activity for this rather impure substrate. It could not yet
be determined which impurity is responsible for this effect.
Selective synthesis of the tsetse fly attractants 3-propyl- and
3-ethylphenol
Since both kairomones target different tsetse flies, this
approach, which produces 2 and 3 in similar amounts, should
be advantageous for the application in fly traps. For the selec-
tive synthesis of the widely used kairomone 3, an additional
butenolysis step is required. Thus, the isomerising ethenolysis
of 5 was first allowed to reach its equilibrium. After 16 h, the
metathesis catalyst was still fully active, but the isomerisation
Experimental
General methods
catalyst had lost most of its reactivity. At this stage, the reac- All reactions were performed in oven-dried glassware contain-
tion mixture, which consisted mostly of the conjugated ing a Teflon-coated stirring bar. Solvents were purified, dried
isomers of 3-propenylphenol and of 3-ethenylphenol, was by standard procedures, and degassed by three freeze–pump–
purged with 2-butene (approx. 50 : 1 ratio 2-butene/6 +7, 2.0 thaw cycles prior to use. All reactions were monitored by GC
bar) and stirred for another 16 h at 50 °C. This way, 7 was using n-hexadecane or n-decane as an internal standard.
obtained in 92% overall yield and 95% purity.
Response factors of the products with regard to n-(hexa-)decane
For a preparative-scale (4.0 mmol), one-pot synthesis of were obtained experimentally by analysing known quantities of
3-propylphenol (3), the isomerising ethenolysis was performed the substances. GC analyses were carried out using a HP6890
using only a 7 : 1 ethene/5 ratio (7.5 bar, the pressure limit of with an HP-5 capillary column (phenyl methyl siloxane 30 m ×
the reactor). After 16 h, the gas phase was first exchanged for 320 × 0.25, 100/2.3-30-300/3) and a time program beginning
2-butene (approx. 50 equiv., 2.0 bar) and after 16 h for hydro- with 2 min at 60 °C, followed by a 30 °C min−1 ramp to 300 °C,
gen (5.0 bar). This way, the desired kairomone 3 was obtained then 3 min at this temperature. Headspace GC analyses were
in 78% yield (Scheme 3). This one-pot synthesis of 3-propyl- carried out using a Perkin Elmer AutoSystem XL with Supelco
phenol (3), which does not require purification of intermedi- packed column (80/100 Poropak, 6 FT × 1/8 In. S.S.). Commer-
ates and delivers the desired product 3 in 69% yield based on cial substrates were used as received unless otherwise stated.
anacardic acids (1a–d), compares favourably even with the pre- The metathesis catalysts used herein are available commercially,
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for example, from Sigma-Aldrich or Umicore. But-2-ene was (5 cm3). Removal of the solvent yielded the desired product 3
obtained from Apollo Scientific Ltd as a mixture of E/Z-isomers as a bright yellow oil (425 mg, 3.12 mmol, 78%). The analytical
(purity: 99% by GC, ratio of E/Z-isomers: 68%/31%) and ethene data matched those reported in the literature.8
from Air Liquide GmbH (purity: 99.9%).
Synthesis of 3-ethylphenol (2) from 3-(non-8-enyl)phenol (5)
Extraction of anacardic acids (1) from cashew nut shells
In a glove box, an oven-dried 35 mL Fisher-Porter vessel with a
Cashew nut shells (400 g) were ground into ∼1 mm small par-
ticles which were than extracted in a Soxhlet apparatus with
Et2O (500 mL) for 6 h. Removal of the solvent in vacuo resulted
in a highly viscous brown oil (90.0 g, 23 wt%). 40 g of this crude
extract were dissolved in 5% aqueous methanol (240 mL), and
calcium hydroxide (20.0 g, 259 mmol) was added in portions
under stirring. The temperature of the reaction mixture was
then raised to 50 °C, and stirring was continued for 2.5 h
leading to precipitation of calcium anacardate. The precipitate
was filtered off and washed with methanol (200 mL). It was
then suspended in distilled water (200 mL), and the anacardic
acids were liberated by treatment with HCl (30 mL, 12 M) and
stirring for 1 h at RT. The mixture was then extracted with
EtOAc (2 × 200 mL) and the combined organic phases were
washed with distilled water (100 mL), dried over MgSO4 and
concentrated under reduced pressure to yield a mixture of ana-
cardic acids as a viscous, dark brown oil (23.1 g, 58 wt%).
stirring bar was charged with Pd-1 (10.0 mg, 13.0 µmol), Ru-8
(13.2 mg, 20.0 µmol), THF (4 mL) and 3-(non-8-enyl)phenol (5)
(250 mg, 1.00 mmol). The vessel was removed from the glove-
box and pressurised with ethene (5.0 bar). The mixture was
stirred at 50 °C for 16 h. After cooling to −78 °C, the pressure
was slowly released. The reaction mixture was then filtered
through a plug of silica gel and the solvent removed in vacuo.
Under inert conditions, Ru-8 (13.2 mg, 20.0 mmol) and THF
(4 mL) were added to the mixture of 3-ethenyl- (2) and 3-(prop-
2-enyl)phenol (3) (∼1 : 1) in a Fisher-Porter vessel, which was
pressurised with ethene (4.0 bar). The mixture was allowed to
stir overnight at 50 °C. Subsequently, the reaction mixture was
cooled to 0 °C and the pressure was slowly released. Hydrogen-
ation was performed by adding methanol (5 mL) and activated
charcoal (100 mg), and stirring the reaction mixture for 3 h at
50 °C under hydrogen pressure (5.0 bar). After slowly releasing
the pressure, the mixture was filtered through Celite (1 cm3), the
solvent was removed by distillation over a Vigreux column, the
residue was dissolved in Et2O and filtered through a plug of
silica gel (5 cm3). Removal of the solvent yielded the desired
product 2 as a colourless oil (101 mg, 0.84 mmol, 84%). The
analytical data matched those reported in the literature.25
Preparative scale synthesis of 3-(non-8-enyl)phenol (5) from
anacardic acids (1)
In a glovebox, a PTFA-lined steel autoclave with a stirring bar
was charged with the metathesis catalyst Ru-3 (21.6 mg, 36.0
µmol), dichloromethane (30 mL), and the anacardic acid
mixture (1) (2.50 g, 7.30 mmol). The autoclave was then purged
with ethene three times and pressurised to 10 bar. The resulting
mixture was stirred for 16 h at RT. Then, the solvent was
removed in vacuo. Crack distillation of the crude product mixture
in a Kugelrohr (120 °C, 10−2 mbar) yielded 3-(non-8-enyl)phenol
(5) as light yellow oil (1.41 g, 6.46 mmol, 89%, GC-purity: >98%).
The analytical data matched those reported in the literature.10
Conclusions
Isomerising olefin cross-metathesis enabled the synthesis of
the tsetse fly attractants 3-ethylphenol (2) and 3-propylphenol
(3) from an anacardic acid mixture (1) extracted from cashew
nut shells. The key towards providing a uniform substrate is
the ethenolysis of the anacardic acids followed by thermal de-
carboxylation. This way, mono-, di- and tri-unsaturated side
chains are all shortened to nine carbons, and the 3-(non-8-
enyl)phenol is separated from derivatives with saturated side
chains. A one-pot sequence consisting of isomerising etheno-
lysis followed by an optional butenolysis or ethenolysis and
hydrogenation of the olefinic side chain, all effectively
mediated by a combination of the isomerisation catalyst [Pd(µ-
Br)(tBu3P)]2 and a second-generation Hoveyda–Grubbs meta-
thesis catalyst, furnishes the desired 3-ethylphenol (2) and
3-propylphenol (3) either in pure form or as a mixture. This
concise reaction sequence underlines the high potential of iso-
merising cross-metathesis as a key technology in the chemical
valorisation of non-food, renewable resources.
Preparative scale synthesis of 3-proplyphenol (3) from
3-(non-8-enyl)phenol (5)
In a glove box, an oven-dried 70 mL Fisher-Porter vessel with a
stirring bar was charged with Pd-1 (40.4 mg, 52.0 µmol), Ru-8
(52.5 mg, 80.0 µmol), THF (16 mL) and 3-(non-8-enyl)phenol
(5) (950 mg, 4.00 mmol). The vessel was removed from the
glovebox and pressurised with ethene (7.5 bar). The mixture
was stirred at 50 °C for 16 h. After cooling to −78 °C, the
pressure was slowly released under inert conditions. The vessel
was warmed to 0 °C and 2-butene (11.2 g, 200 mmol) was con-
densed in. The mixture was allowed to stir overnight at 50 °C.
Subsequently, the reaction mixture was cooled to 0 °C and the
pressure was slowly released. Hydrogenation was performed by
adding methanol (25 mL) and activated charcoal (300 mg),
and stirring the reaction mixture for 3 h at 50 °C under hydro-
gen pressure (5.0 bar). After slowly releasing the pressure, the
Acknowledgements
mixture was filtered through Celite (1 cm3), the solvent was We thank NanoKat, the Collaborative Research Centre SFB/
removed by distillation over a Vigreux column, and the residue TRR 88 “3MET”, Carl Zeiss (RCR) and the Deutsche Bundes-
was dissolved in Et2O, filtered through a plug of silica gel stiftung Umwelt (fellowship to S.B.) for financial support, and
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Umicore AG for the donation of chemicals. We also thank
Mark Niebergall for technical assistance, Christian Schneider
and Denise Scherbl for HPLC analysis.
9 J. A. Mmongoyo, Q. A. Mgani, S. J. M. Mdachi,
P. J. Pogorzelec and D. J. Cole-Hamilton, Eur. J. Lipid Sci.
Technol., 2012, 114, 1183–1192.
10 J. Julis, S. A. Bartlett, S. Baader, N. Beresford, E. J. Routledge,
C. S. J. Cazin and D. J. Cole-Hamilton, Green Chem., 2014,
16, 2846–2856. For recent publication on cardanol ethenoly-
sis, see: T. Shinde, V. Varga, M. Polášek, M. Horáček,
N. Žilková and H. Balcar, Appl. Catal., A, 2014, 478, 138–145.
11 C. Thurier, C. Fischmeister, C. Bruneau, H. Olivier-Bourbi-
gou and P. H. Dixneuf, ChemSusChem, 2008, 1, 118–122;
R. M. Thomas, B. K. Keitz, T. M. Champagne and
R. H. Grubbs, J. Am. Chem. Soc., 2011, 133, 7490–7496;
K. A. Burdett, L. D. Harris, P. Margl, B. R. Maughon,
T. Mokhtar-Zadeh, P. C. Saucier and E. P. Wasserman,
Organometallics, 2004, 23, 2027–2047; G. S. Forman,
A. E. McConnell, M. J. Hanton, A. M. Z. Slawin, R. P. Tooze,
W. J. van Rensburg, W. H. Meyer, C. Dwyer, M. M. Kirk and
D. W. Serfontein, Organometallics, 2004, 23, 4824–4827.
Notes and references
1 A. Velmurugan and M. Loganathan, World Acad. Sci. Eng.
Technol., 2011, 5, 738–743.
2 V. S. Balachandran, S. R. Jadhav, P. K. Vemula and G. John,
Chem. Soc. Rev., 2013, 42, 427–438; C. S. K. Lin,
L. A. Pfaltzgraff, L. Herrero-Davila, E. B. Mubofu,
S. Abderrahim, J. H. Clark, A. A. Koutinas, N. Kopsahelis,
K. Stamatelatou, F. Dickson, S. Thankappan, Z. Mohamed,
R. Brocklesby and R. Luque, Energy Environ. Sci., 2013, 6,
426–464; R. L. Quirino, T. F. Garrison and M. R. Kessler,
Green Chem., 2014, 16, 1700–1715.
3 R. Paramashivappa, P. Phani Kumar, P. J. Vithayathil and
A. Srinivasa Rao, J. Agric. Food Chem., 2001, 49, 2548–2551; 12 P. Schwab, M. B. France, J. W. Ziller and R. H. Grubbs,
P. Phani Kumar, R. Paramashivappa, P. J. Vithayathil, Angew. Chem. Int. Ed., 1995, 34, 2039–2041.
P. V. Subba Rao and A. Srinivasa Rao, J. Agric. Food Chem., 13 J. P. A. Harrity, D. S. La, D. R. Cefalo, M. S. Visser and
2002, 50, 4705–4708. A. H. Hoveyda, J. Am. Chem. Soc., 1998, 120, 2343–2351.
4 L. J. Gooßen, F. Collet and K. Gooßen, Isr. J. Chem., 2010, 14 M. Scholl, S. Ding, C. W. Lee and R. H. Grubbs, Org. Lett.,
50, 617–629; S. Bhadra, W. I. Dzik and L. J. Gooßen, J. Am. 1999, 1, 953–956.
Chem. Soc., 2012, 134, 9938–9941; L. J. Gooßen, L. Winkel, 15 S. B. Garber, J. S. Kingsbury, B. L. Gray and A. H. Hoveyda,
A. Dohring, K. Ghosh and J. Paetzold, Synlett, 2002, 1237– J. Am. Chem. Soc., 2000, 122, 8168–8179.
1240; L. J. Gooßen and J. Paetzold, Adv. Synth. Catal., 2004, 16 S. Monsaert, R. Drozdzak, V. Dragutan, I. Dragutan and
346, 1665–1668. F. Verpoort, Eur. J. Inorg. Chem., 2008, 2008, 432–440.
5 M. L. A. Owaga, Int. J. Trop. Insect Sci., 1985, 6, 561–566; 17 F. W. C. Verpoort and C. B. De, WO Pat., 2003062253, 2003.
M. L. A. Owaga, A. Hassanali and P. G. McDowell, 18 I. Risfaheri, T. T. Irawadi, M. A. Nur and I. Sailah,
Int. J. Trop. Insect Sci., 1988, 9, 95–100; M. Okech and
A. Hassanali, Int. J. Trop. Insect Sci., 1990, 11, 363–368.
6 M. P. Barrett, R. J. Burchmore, A. Stich, J. O. Lazzari,
A. C. Frasch, J. J. Cazzulo and S. Krishna, Lancet, 2003, 362,
1469–1480; P. P. Simarro, G. Cecchi, J. R. Franco, M. Paone,
A. Diarra, J. A. Ruiz-Postigo, E. M. Fèvre, R. C. Mattioli and
J. G. Jannin, PLoS Negl. Trop. Dis., 2012, 6, e1859;
P. G. Kennedy, Lancet Neurol., 2013, 12, 186–194;
B. I. Williams, African trypanosomiasis, in The Wellcome
Trust illustrated history of tropical diseases, The Wellcome
Indones. J. Agric., 2008, 2, 11–22.
19 D. M. Ohlmann, N. Tschauder, J.-P. Stockis, K. Gooßen,
M. Dierker and L. J. Gooßen, J. Am. Chem. Soc., 2012, 134,
13716–13729; L. J. Gooßen, D. M. Ohlmann and
M. Dierker, WO Pat., 2012143067, 2012; S. Baader,
D. M. Ohlmann and L. J. Gooßen, Chem. – Eur. J., 2013,
19, 9807–9810; related isomerising functionalisations:
D. M. Ohlmann, L. J. Gooßen and M. Dierker, Chem. – Eur.
J., 2011, 17, 9508–9519; L. J. Gooßen, D. M. Ohlmann and
M. Dierker, Green Chem., 2010, 12, 197–200.
Trust, London, United Kingdom, 1996; WHO, Fact sheet N° 20 V. Durà-Vilà, D. M. P. Mingos, R. Vilar, A. J. P. White and
259,
http://www.who.int/mediacentre/factsheets/fs259/en
D. J. Williams, J. Organomet. Chem., 2000, 600, 198–205.
21 P. Mamone, M. F. Grünberg, A. Fromm, B. A. Khan and
L. J. Gooßen, Org. Lett., 2012, 14, 3716–3719.
22 A. K. Chatterjee, T.-L. Choi, D. P. Sanders and
R. H. Grubbs, J. Am. Chem. Soc., 2003, 125, 11360–11370;
J. Spekreijse, J. Le Nôtre, J. van Haveren, E. L. Scott and
J. P. M. Sanders, Green Chem., 2012, 14, 2747–2751.
(accessed June 2014).
7 E. Bursell, A. J. E. Gough, P. S. Beevor, A. Cork, D. R. Hall
and G. A. Vale, Bull. Entomol. Res., 1988, 78, 281–291.
8 Grignard: I. Ujváry and G. Mikite, Org. Process Res. Dev.,
2003, 7, 585–587. Wittig: D. R. Magnin, S. A. Biller,
J. K. Dickson, Jr., R. M. Lawrence and R. B. Sulsky, US Pat.,
5470845 A1, 1995; Y. L. Bigot, M. Delmas and A. Gaset, 23 M. Atiqullah, H. Hammawa and H. Hamid, Eur. Polym. J.,
Tetrahedron, 1986, 42, 339–350. For further synthetic 1998, 34, 1511–1520.
approaches, see: W. H. Hartung and F. S. Crossley, J. Am. 24 An identical 5/ethene ratio now translates to a different
Chem. Soc., 1934, 56, 158–159; S. Landa and J. Macák,
Collect. Czech. Chem. Commun., 1958, 23, 1322–1329;
pressure since the same reaction vessels are used as for the
0.5 mmol scale reactions.
G. Ciamician and P. Silber, Ber. Dtsch. Chem. Ges., 1890, 23, 25 R. Shen, T. Chen, Y. Zhao, R. Qiu, Y. Zhou, S. Yin, X. Wang,
1159–1164; C. F. Carvalho and M. V. Sargent, J. Chem. Soc.,
Perkin Trans. 1, 1984, 1621–1626.
M. Goto and L.-B. Han, J. Am. Chem. Soc., 2011, 133,
17037–17044.
Green Chem.
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