Synthesis of pharmaceutical drugs from cardanol derived from cashew nut shell liquid

Article abstract of DOI:10.1039/c8gc03823f

Cardanol from cashew nut shell liquid extracted from cashew nut shells was successfully converted into various useful pharmaceutical drugs, such as norfenefrine, rac-phenylephrine, etilefrine and fenoprofene. 3-Vinylphenol, the key intermediate for the synthesis of these drugs, was synthesised from cardanol by ethenolysis to 3-non-8-enylphenol followed by isomerising ethenolysis. The metathesis reaction worked very well using DCM, but the greener solvent, 2-methyl tetrahydrofuran, also gave very similar results. Hydroxyamination of 3-vinylphenol with an iron porphyrin catalyst afforded norfenefrine in over 70% yield. Methylation and ethylation of norfenefrine afforded rac-phenylephrine and etilefrine respectively. A sequence of C-O coupling, isomerising metathesis and selective methoxycarbonylation afforded fenoprofene in good yield. A comparison of the routes described in this paper with some standard literature syntheses of 3-vinylphenol and of the drug molecules shows significant environmental advantages in terms of precursors, yields, number of steps, conditions and the use of catalysts. The Atom Economy of our processes is generally similar or significantly superior to those of the literature processes mainly because the side products produced during synthesis of 3-vinylphenol (1-octeme, 1,4-cyclohexadiene and propene) are easily separable and of commercial value, especially as they are bio-derived. The E Factor for the production of 2-vinylphenol by our process is also very low compared with those of previously reported syntheses.

Full text of DOI:10.1039/c8gc03823f

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Synthesis of pharmaceutical drugs from cardanol
derived from cashew nut shell liquid†‡
Cite this: DOI: 10.1039/c8gc03823f
Yiping Shi,
Paul C. J. Kamer § and David J. Cole-Hamilton
*
Cardanol from cashew nut shell liquid extracted from cashew nut shells was successfully converted into
various useful pharmaceutical drugs, such as norfenefrine, rac-phenylephrine, etilefrine and fenoprofene.
3-Vinylphenol, the key intermediate for the synthesis of these drugs, was synthesised from cardanol by
ethenolysis to 3-non-8-enylphenol followed by isomerising ethenolysis. The metathesis reaction worked
very well using DCM, but the greener solvent, 2-methyl tetrahydrofuran, also gave very similar results.
Hydroxyamination of 3-vinylphenol with an iron porphyrin catalyst afforded norfenefrine in over 70%
yield. Methylation and ethylation of norfenefrine afforded rac-phenylephrine and etilefrine respectively. A
sequence of C–O coupling, isomerising metathesis and selective methoxycarbonylation afforded feno-
profene in good yield. A comparison of the routes described in this paper with some standard literature
syntheses of 3-vinylphenol and of the drug molecules shows significant environmental advantages in
terms of precursors, yields, number of steps, conditions and the use of catalysts. The Atom Economy of
our processes is generally similar or significantly superior to those of the literature processes mainly
because the side products produced during synthesis of 3-vinylphenol (1-octeme, 1,4-cyclohexadiene
and propene) are easily separable and of commercial value, especially as they are bio-derived. The
E Factor for the production of 2-vinylphenol by our process is also very low compared with those of pre-
viously reported syntheses.
Received 7th December 2018,
Accepted 15th January 2019
DOI: 10.1039/c8gc03823f
rsc.li/greenchem
has versatile applications, and it can be used for a wide range
of chemical modifications to produce useful monomer precur-
Introduction
Cashew nut shell liquid (CNSL) is a natural oil and a byproduct sors. CNSL derived material can be used as chemical inter-
of cashew nut manufacture. Around 30–35% of the shell mediates, additives,4,5 stabilizers,6 lubricants,7 diesel engine
weight is CNSL,1 and about ∼1 M tonnes of CNSL is produced fuel alternatives,8 anti-oxidants,9 anticorrosive paints, sodium
annually worldwide.2 Presently, in the cashew nut industry, cardanol sulfate detergent,10 coating, brake linings11 and
cashew nut shells are disposed of as furnace materials, and resins.12 Although there is a large number of applications of
are burnt in a semi-open pit for thermal energy generation for cashew nut shell liquid (CNSL) and its components, anacardic
roasting the nuts. They are also burnt for cooking applications, acid and cardanol, there are very few examples of the trans-
which is a quick and cheap way for disposal. However, these formation of cashew nut shell liquid and its components into
applications have very low combustion efficiency.3
small value-added molecules. The examples predominantly
CNSL contains a mixture of products including anacardic focused on the metathesis of the double bonds in anacardic
acid, 1, cardanol, 2, cardol, 3, and 2-methylcardol, 4, which
contain different functional groups, the aromatic ring, the
hydroxyl group, the carboxylic acid and the double bonds in
the alkyl chain (Fig. 1). For this reason, cashew nut shell liquid
EaStChem, School of Chemistry, University of St. Andrews, Fife, KY16 9ST Scotland,
UK. E-mail: djc@st-and.ac.uk
†Dedicated to Ernesto Carmona, and outstanding chemist and great friend, on
the occasion of his 70th birthday.
‡Electronic supplementary information (ESI) available. See DOI: 10.1039/
c8gc03823f
§Current address: Bioinspired Homo-
& Heterogeneous catalysis, Leibniz
Institute for Catalysis, Albert-Einstein-Straβe 29 a, 18059 Rostock, Germany.
Fig. 1 Components of CNSL.
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acid and cardanols using either homogeneous or hetero- which do not compete with food. An inedible by-product from
geneous catalysis (the latter with Ru catalysts supported on food processing, in this case cashew nut shell liquid, is there-
mesoporous molecular sieve SBA-15).13
fore a very good starting material. The aromatic and olefin
Metathesis reactions of anacardic acid and cardanol for the functional groups make cardanol suitable for this purpose.
synthesis of fine chemicals and new hybrid functional After searching through the drug database, five drugs (feno-
materials have been reviewed.14 Cardanol porphyrins, cardanol profen, 5, norfenefrine, 6, phenylephrine, 7, etilefrine, 8, and
phthalocyanines and cardanol fullerenes can all be produced metaraminol, 9) were found to be of potential interest. The
by metathesis of cardanol derivatives.14 These interesting importance and the current synthesis of these drugs will be
studies enabled the synthesis of challenging molecules. discussed in detail later. Their general structures, containing a
However, it would be more interesting to synthesise products meta-hydroxyl group, are similar to the ones in cardanol, 2, or
with practical use. It has previously been reported in our group anacardic acid, 1, from CNSL (highlighted in red, Scheme 1).
that the tsetse fly attractants, 3-ethyl phenol and 3-propyl Only a few steps of modification are needed to convert food by-
phenol can both be produced selectively in good yields (>80%) products into high value and important medicines, which will
from cardanol.15
be discussed in detail later.
We have also used homogeneous metathesis,16–18 isomeris-
ing metathesis,15 methoxycarbonylation18 and isomerisa-
tion17,19 to make higher added value chemicals such as
Results and discussion
3-nonylphenol,16,17
1-octene,16,17
1,3-cyclohexadiene,16,17
The initial retrosyntheses of the target drugs are summarised
in Scheme 1, from which it can be concluded that 3-vinyl-
phenol, 10, is the key intermediate for the synthesis of the rele-
vant drugs. Therefore, the initial study was focused on convert-
ing CNSL and derivates (e.g. anacardic acid and cardanol) into
3-vinylphenol, 10.
which allows ethenolysis using simple first generation meta-
thesis catalysts,16,20 potential monomers containing hydroxy
and carboxyl groups,18 fused bicyclic compounds19 and large
ring macrocyles.18 To the best of our knowledge, the only
report of converting CNSL, anacardic acid or cardanol into
pharmaceutical drugs is the synthesis of ginkgolic acid, a tyro-
sinase inhibitor, from anacardic acid, which appeared while
this manuscript was under review.21 although we have reported
3-vinylphenol
the synthesis of a substituted isochromen-1-one which has 3-Vinylphenol, 10, could be obtained by an ethenolysis of
some structural similarities to massoia lactone from anarcar- cardanol acid to give 3-(non-8-enyl)phenol, 11, as the intermedi-
dic acid.19 Pharmaceutical drugs are mainly synthesised from ate, which was followed by a one-pot isomerising ethenolysis.15
fossil fuels by stoichiometric reactions, and in some cases Following a similar reaction procedure previously reported in
toxic reagents such as cyanide are involved, which renders the our group,15 3-(non-8-enyl)phenol, 11, was obtained in 96%
synthesis environmentally unfriendly. Our target was to syn- yield after ethenolysis of cardanol with HG1 catalyst, 12
thesise pharmaceutical drugs from renewable feedstocks (Table 1, entry 1). The yield was slightly lower with G1 catalyst,
Scheme 1 Retrosynthesis of target drugs, with the relationship to cardanol, 2.
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Table 1 Metathesis of anacardic acid and cardanol to 3-(non-8-enyl)
studies in our group showed that the [Pd2(dba)3]/DTBPMB/
MSA system, which is active for the isomerising methoxycarbo-
nylation of methyl oleate,22 and is a good isomerisation cata-
lyst in the absence of CO, is effective for isomerising cardanol,
although the yield of benzylic alkene was only 40%. This is the
thermodynamic maximum. Although the styrene will be the
most thermodynamically favoured isomer, the conjugation
energy is insufficient to overcome the entropic advantage of
having the double bond in other positions in the chain com-
pletely. Therefore, the cardanol was shortened by ethenolysis
to produce 3-(non-8-enyl)phenol, 11, with the method pre-
viously mentioned (96% yield, Table 1, entry 1). 3-(Non-8-enyl)
phenol, 11, was isomerized with [Pd2(dba)3]/DTBPMB/MSA in
toluene at 80 °C, after 64 hours, the benzylic product, 3-(non-
1-en-1-yl)phenol, 17, was obtained in 68% selectivity over all
the other isomers (Table 2, entry 1). Heating at 80 °C for
96 hours led to 71% selectivity of 17 (Table 2, entry 2).
Isomerisation of 3-(non-8-enyl)phenol with Pd catalyst can also
be carried out in other solvents. Very similar results were
obtained in DCM, THF or in a greener solvent, 2-MeTHF
(Table 2, entries 3–8). [Rh(acac)(CO)2] together with DTBPMB
ligand is known to be effective in isomerising hydroformyla-
tion of cardanol,23 therefore, it was interesting to find out
whether [Rh(acac)(CO)2]/DTBPMB is effective in the isomeriza-
tion reaction in the absence of CO/H2 gas. However, no
benzylic alkene was observed after 64 hours, and only 28% of
the terminal alkene was converted to other internal alkenes
(Table 2, entry 9).
phenola
Entry
Substrate
Catalyst
Yield (%)
1
2
Cardanol
Cardanol
Cardanol
Cardanol
Anacardic acid
Anacardic acid
HG1
G1
HG2
HG1
HG2
HG1
96
85
11
93
<1
1
3
4b
5
6
a Reagents and conditions: Substrate (3 mmol), catalyst (0.3 mol%),
anhydrous DCM (7.5 mL), ethene (10 bar), 24 h, r.t. b 2-Methyl THF
(7.5 mL) instead of DCM.
13 (85%, Table 1, entry 2), and only 11% yield of 3-(non-8-enyl)
phenol, 11, was obtained when cardanol was metathesized
with HG2 catalyst, 14 (Table 1, entry 3). Very similar results
were obtained when the greener solvent, 2-methyl THF, was
used (Table 1, entry 4). However, when anacardic acid, 1, was
used as substrate, very poor conversions were observed using
either HG1, 12, or HG2 catalysts, 14 (Table 1, entries 5 and 6).
Reproduction of the isomerizing metathesis of 11 was carried
out using ruthenium (M1, 15) and palladium dimer, 16,
the desired 3-vinylphenol, 10, was obtained in 78% yield
(Scheme 2), which is consistent with the literature results.15
The synthesis of 3-vinylphenol, 10, could also, in principle,
be carried out by a two-step synthesis: isomerisation of carda-
nol to the benzylic cardanol followed by ethenolysis. Previous
After isomerization of 3-(non-8-enyl)phenol, 11, the meta-
thesis reaction was then carried out on the crude product from
the isomerisation step (71% of 17, Table 2, entry 2). The crude
product was metathesized using M1 catalyst, 15, and 3-vinyl-
phenol, 10, was obtained in 65% yield by GC-FID together with
alkenyl phenols with longer chain lengths (Scheme 3).
Table 2 Optimisation of alkene isomerisationa
T
t
Sel. (benzylic alkene/
Entry Cat prec.
solvent
(°C) (h) others)b (%)
1
2
3
4
5
6
7
8
9
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
[Pd2(dba)3]
Toluene
Toluene
DCM
DCM
THF
THF
2-MeTHF 80
2-MeTHF 80
80
80
40
40
70
70
64 68
96 71
64 68
96 70
64 62
96 62
64 63
96 63
[Rh(acac)(CO)2] Toluene
80
64
0
a Reagents and conditions: Substrate (50 mg, 0.2 mmol, 1 equiv.), cata-
lyst (5 mol%) DTBPMB (0.5 equiv.), MSA (0.7 equiv.), solvent (1 mL).
b Selectivity calculated by quantitative 1H NMR.
Scheme 2 Synthesis of 3-vinyl phenol by isomerising metathesis using
a palladium dimer (isomerisation) and M1 (metathesis) catalyst.
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Synthesis of norfenefrine
form. Norfenefrine, 6, plays a role as a minor neurotransmitter
in the brain and regulates blood pressure in acute hypotensive
states.25
Norfenefrine, 6, is an adrenergic agent used as a sympathomi-
metic drug, which is pharmaceutically active in its racemic
As presented in Scheme 1, 3-vinylphenol, 10, which was
successfully obtained from cardanol by ethenolysis followed by
isomerising metathesis, could possibly be used as an inter-
mediate for the synthesis of norfenefrine, 6, by a hydroxyami-
nation reaction on the double bond. Morandi reported a reac-
tion of this kind which converts 1-methoxy-3-vinylbenzene, 18,
to 2-amino-1-(3-methoxyphenyl)ethan-1-ol, 19, in 70% yield
using an iron catalyst and O-pivaloylhydroxylammonium tri-
flate (Scheme 4, Reaction A).24 We employed a similar method
using 3-vinylphenol, 10, as substrate, and the desired norfene-
frine, 6, which is also known as 3-(2-amino-1-hydroxyethyl)
phenol, was obtained in 71% isolated yield (Scheme 4,
Reaction B).
Scheme 3 Synthesis of 3-vinylphenol in two steps from 3-non-8-enyl
phenol.
Synthesis of metaraminol
Metaraminol, 9, which is used in the prevention and treatment
of hypotension,26 has a very similar structure as norfenefrine,
6. It is active in its enantiopure form. It is interesting to inves-
tigate if the hydroxyamination reaction used for the synthesis
of norfenefrine, 6, would work when using 3-(prop-1-en-1-yl)
phenol, 20, as substrate. According to literature data, hydroxy-
amination of styrene, 21, occurs in 74% yield, while using
β-methyl styrene, 22, as substrate gave around 20% yield
(Scheme 5, Reaction A).24 The extra methyl group on the side
chain led to a dramatic decrease of the yield. A reaction using
the same hydroxyamination conditions as for 3-vinylphenol
was carried out on 3-(prop-1-en-1-yl)phenol, 20. The desired
racemic metaraminol, 9, was obtained in 24% NMR yield in
this case (Scheme 4, Reaction B). This is in line with the
results from the literature.
Synthesis of racemic phenylephrine
Phenylephrine which has a similar structure to that of norfe-
nefrine, is a sympathomimetic, vasoconstrictor, mydriatic and
cardiotonic agent. It can be used as decongestant, pupil
dilator, vasopressor and in the treatment of hemorrhoids and
priapism, to dilate the pupil or to increase the blood pressure,
Scheme 4 Hydroxyamination of styrene type substrate. (A) Literature
hydroxyamination of 1-methoxy-3-vinylbenzene, 18.24 (B) Experimental
synthesis of norfenefrine, 6, from 3-vinylphenol, 10.
Scheme 5 Synthesis of metaraminol, 9, and related literature results.24
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it is active as the L-isomer.25 Selective methylation of norfenefr-
ine, 6, could result in the formation of racemic phenylephrine,
7. However, there are three active sites for the direct alkylation,
both of the hydroxy groups and the amine groups are readily
available for the reaction.
When reacting norfenefrine, 6, with methyl iodide in the
presence of a base, a rather complicated mixture of products
was obtained, which might be because of methylation on
alcohol, mono- and dimethylated products, and selective
methylation was not achieved by this method (Table 3, entries Scheme 6 Synthesis of etilefrine, 8 from norfenefrine, 6.
1 and 2). It has been reported that 1,1,1,3,3,3-hexafluoro-2-
propanol (HFIP) is a good solvent for the selective alkylation of
amines, producing a high proportion of mono-alkylated pro-
ducts over di-alkylated products.22 Methylation of norfenefrine
with methyl iodide in HFIP in the absence of base gave very
poor conversion, and low yield of the desired phenylephrine
(Table 3, entry 3). By changing the methylation agent from
methyl iodide to methyl triflate, much higher conversion was
observed, and the desired phenylephrine, 7, was obtained in
79% yield (Table 3, entry 4).
ethyl triflate in HFIP led to a higher yield of the desired etilefr-
ine (79%) compared to the reductive amination, together with
17% of the diethylated product after 1 hour at room tempera-
ture (Scheme 7).
Synthesis of fenoprofen
Another drug, which contains a meta-hydroxy phenyl group
similar to CNSL, is fenoprofen, 5, which is a nonsteroidal anti-
inflammatory drug (NSAID) and is marketed in the USA as
Nalfon, which is also pharmaceutically active in its racemic
form. The current cost for its oral capsules (400 mg) is around
$256 for a supply of 90 capsules.28 It is effective for the treat-
ment of fever, pain and swelling caused by inflammation.
A few synthetic pathways have been tested (ESI, section
S1‡). The best reaction pathway is to convert cardanol to the
O-Ph cardanol, 24, firstly, which could avoid the complexity of
the C–O coupling with unstable intermediates (e.g. styrene
intermediate 10 in Scheme S1‡).
Cardanol, 3, was therefore reacted with bromobenzene first
in the presence of anhydrous potassium tert-butoxide under
literature conditions for the C–O coupling of the phenol
(Step A, Scheme 8).29 Only about 30% of cardanol was con-
verted to the O-Ph product, 24, at 45 °C. Increasing the tem-
perature increased the conversion, and at 100 °C, the starting
material was fully converted. Preparative scale gave similar
results, and the O-Ph cardanol, 24, was successfully syn-
thesised in 82% yield.
Synthesis of etilefrine
Another drug with a similar structure to that of norfenefrine,
6, is etilefrine, 8, which is a cardiac stimulant, and is used as
an antihypotensive. Etilefrine is pharmaceutically active in its
racemic form. Etilefrine can increase cardiac output, stroke
volume, venous return and blood pressure by intravenous infu-
sion.27 It is also an analeptic and sympathomimetic agent.25
Reductive amination was used for the selective alkylation of
nitrogen over the oxygen. When reacting norfenefrine, 6, with
acetaldehyde in the presence of sodium borohydride, both the
desired etilefrine, 8, and the side diethylated product 23 were
obtained, and they were easily separated by flash column
chromatography. The expected etilefrine, 8, was obtained in
54% yield, and the diethylated product was obtained in 35%
yield (Scheme 6).
Due to the success of the methylation procedure for the
selective mono-methylation of norfenefrine, we employed
these conditions in the synthesis of etilefrine using ethyl tri-
flate as the ethyl source. The ethylation of norfenefrine with
After obtaining O-Ph cardanol, 24, 1-phenoxy-3-vinyl-
benzene, 25, can be synthesized in two steps (Step B and C in
Scheme 8). Firstly, the O-Ph cardanol, 24, was metathesized to
the corresponding 1-(non-8-en-1-yl)-3-phenoxybenzene, 26,
using HG1 catalyst in high yield (97%) with 1-octene as the
side product. 1-(Non-8-en-1-yl)-3-phenoxybenzene, 26, was
then converted to 1-phenoxy-3-vinylbenzene, 25, by the isomer-
Table 3 Methylation of norfenefrinea
Entry MX
Solvent
T (°C) t (h) Conv.b (%) Yieldb (%)
1c
2c
3
MeI
MeI
MeI
Acetone
DMSO
HFIP
60
100
25
2
16
24
1
100
100
4
n.d.
n.d
2
4
MeOTf HFIP
25
84
79
a Conditions: Norfenefrine (1 mmol), MeX (1.5 mmol), HFIP (1 mL).
b Conversions and yields were calculated by 1H NMR spectroscopy.
c KOH (2 equiv.).
Scheme 7 Ethylation of norfenefrine using ethyl triflate.
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Scheme 8 The synthesis of fenoprofen.
ising metathesis reaction with palladium dimer and M1 cataly- acid (rac-BNPA) afforded the desired product 28 in 82% yield
sis, as discussed earlier for the synthesis of 3-vinylphenol. A together with 12% of the linear product, methyl 3-(3-phenoxy-
one-pot isomerising metathesis of 1-(non-8-en-1-yl)-3-phenoxy- phenyl)propanoate, 29 (Scheme 10). Hydrolysis of 28 in 1,4-
benzene, 26, first afforded a mixture of 1-phenoxy-3-vinyl- dioxane afforded fenoprofen, 5, in 91% yield. The hydrolysis of
benzene, 25, and 1-phenoxy-3-(prop-1-en-1-yl)benzene, 27. The 28 can also be carried out in DMSO, which afford the desired
crude mixture was filtered through a plug of silica, and fenoprofen, 5, in 92% yield. However, the hydrolysis reaction
metathesized again with M1 catalyst. The desired 1-phenoxy-3- in 2-MeTHF did not give the desired product at all. With this
vinylbenzene, 25, was successfully obtained in 80% yield method, biomass is successfully converted to fenoprofen drug
(Scheme 9).
The next step is the synthesis of the branched ester 28 (Step
in good yield (47.5% overall yield from cardanol, 2).
Enantioselective synthesis of the branched ester 28, from
D, Scheme 8). Branch selective methoxycarbonylation with Pd/ 1-phenoxy-3-vinylbenzene, 25, was also performed using a cata-
DTBPMB system in the presence of racemic BINOL-phosphoric lyst developed by Clarke,30 30 (Scheme 11). After 17 h, 44%
Scheme 9 Synthesis of 1-phenoxy-3-vinylbenzene by isomerising metathesis.
Scheme 10 Synthesis of fenoprofen from 1-phenoxy-3-vinylbenzene.
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by pyrolysis of cardanol31,32 or from fossil fuel derived cyclo-
hexanone.33 We note that the first step of our synthesis, ethe-
nolysis of cardanol produces products as shown in Fig. 2.
It is clear from analysis of Table 4 that our route is superior
to pyrolysis because of the low temperatures used, the high
yield and the side products. 1-Octene (from ethenolysis of car-
danol containing 1 double bond is a valuable chemical used
as a co-monomer for polyethylene and is required on 500 000
tonne per year in the US alone at a value of $1–2000 per
tonne.34,35 1,4-Cyclohexadiene (self-metathesis of cardanol
containing 3 double bonds; note that this does not require
ethene) is a useful organic synthon and hydrogen donor or
acceptor36 and we have shown that it can allow ethenolysis of a
number of alkenes including methyl oleate to proceed cleanly
using cheap first-generation ruthenium-based metathesis cata-
lysts.16,37 Indeed, it is essential for the clean ethenoylsis of car-
danol in the first step of the synthesis of 3-vinylphenol dis-
cussed here. Both 1-octene and cyclohexanone can be separ-
ated easily from one another and from 3-(non-8-enyl)phenol by
distillation. The second step of the synthesis of 3-vinylphenol
produces propene (>94%)15 as the by-product. This is also a
valuable commodity chemical (∼100 000 tonnes per year) used
for making polymers and plasticisers and in the cumarin
process for the manufacture of phenol.38 The price of
propene39 is similar to that of ethene40 per mol, so making it
as a side product in this way is an attractive proposition.
Scheme 11 Enantioselective methoxycarbonylation of 1-phenoxy-3-
vinylbenzene. Reagents: 1-Phenoxy-3-vinylbenzene (0.55 mmol), LiCl
(2 mol%), para-toluenesulfonic acid monohydrate (2 equiv.), 30 (1 mol%),
MeOH (0.75 mL), CO (30 bar), 40 °C, 17 h.30
conversion was observed, with 69% branched to linear selecti-
vity and 88% ee.
Comparisons with literature processes
3-Vinylphenol. We have reported the synthesis of four
important drug molecules from cardanol, a readily available
byproduct of food manufacture, in this case cashew nuts. In
most cases yields are high and only a few steps are involved.
Although making drugs from renewable resources which do
not compete for land with food is attractive in its own right, it
is also important to compare our syntheses with others based
on fossil fuel or other bioderived feedstocks.
As the demand for bio derived polymers rises, bio-1-octene
and bio-propene will also be essential. The first step of our
process produces 1-octene with 87.5% of the C derived from
bioresources. If the ethenolysis were carried out using bio-
ethene, from bioethanol, the 1-ocetene would be 100% bio-
derived. Similarly, if bio-ethene were used for the isomerising
metathesis, 100% bio-propene would be the by-product.
On the basis of atom economy, the synthesis of 3-vinyl-
phenol from 3-vinylcyclohex-2-enone33 looks attractive. However,
the oxidant is dimethylsulphoxide, which gives no useful side
The main platform chemical for this study is 3-vinylphenyl,
which we have synthesised from cardanol in 75% isolated
yield after two steps. 3-Vinylphenol has been made in one step
Fig. 2 Products from the ethenolysis of each component of cardanol. The percentage figures on the right refer to the amount of each component
in the batch used in this study.
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Table 4 Comparisons with literature process for the synthesis of 3-vinylphenol
Metathesis of cardanol
Pyrolysis of cardanol31,32
1
From 3-vinylcyclohex-2-enone33
Number of steps
2
1
Step 1
C2H4
25
Step 2
C2H4
40–80
70
6 from benzene
DMSO
100
Other reagents
Temperature /°C
Isolated yield/%
Side products
None
540–600
12–15
96
45% (final step)
1-Octene, 1,4-cyclohexadiene Propene 3-Ethylphenol, 3-methylphenol, Unknown
Small amount of volatile
hydrocarbons from cardanol
with 2 double bonds.
phenol, alkenes and alkanes
(C2–4 and higher), high boiling
residue
Atom economy42,43
65
31
92
92
47
Overall atom economy
Atom economy (all usable products)
Over all atom economy (all usable
products
40
40
76
59.4
59.4
100
E Factor44,45/kg (waste) kg (products)−1 0.09
0.1
products and the yield is only 45%. For a direct comparison, taking into account useable side products, which is higher
we need to look at the synthesis from basic building blocks. than that for the published reaction. In addition, fewer steps
3-Vinylcyclohex-2-enone is derived from benzene, a non renew- are required, fossil fuel resources are not used and it only
able resource in six steps via cumarin, cumarin peroxide, consist of three steps, all catalytic from cardanol.
phenol, cyclohexan-2-one (Birch reduction) and finally 3-vinyl
cyclohex-2-enone.41 Many of these steps are atom inefficient from benzaldehyde in 8 steps. Benzaldehyde can be extracted
and or involve stoichiometric metal reagents. from bitter almond oil. Nitration of benzaldehyde with oxalyl
Phenylephrine. Phenylephrine is industrially synthesised
Thus, on the basis of simplicity, mild conditions (important chloride, dimethyl formamide and KNO3 affords 3-nitrobenz-
because 3-vinylphenol is unstable), yield, renewable resources aldehyde,51 which can then be hydrogenated to 3-aminobenz-
that are of low value and not used in food and the value of the aldehyde with molecular hydrogen and palladium on Fe(OH)x
side products, the synthesis of 3-vinylphenol from cardanol solid support.52 3-Aminobenzaldehyde is converted to
seems to be very much more attractive than other available 3-hydroxybenzaldehyde with sodium nitrite and sulfuric
syntheses.
acid.53 3-Hydroxybenzaldehyde was protected by methoxy-
Norfenefrine. Norfenefrine can be synthesised in 5 steps ethoxymethyl chloride and diisopropyl ethyl amine. The methoxy-
from benzene (Scheme 12). Acetophenone synthesised from ethoxymethyl ether was treated with dimethyloxosulfonium
the benzene by a Friedel–Crafts reaction,46 was reacted with methylide, which generated the racemic epoxide. Kinetic
bromine fluoride to form the 1-(3-bromophenyl)ethan-1-one.47 resolution by hydrolysis with (R,R)-N,N′-bis(3,5-di-tert-butyl-
The bromide was converted to 1-(3-hydroxyphenyl)ethan-1-one salicylidene)-1,2-cyclohexanediaminocobalt acetate complex
by using a Pd/tBuPhos system.48 2-Bromo-1-(3-bromophenyl) provided the (S)-diol along with the unreacted (R)-epoxide,
ethan-1-one was then formed by using Montmorillonite K10, which were then separated by column chromatography.
aluminium chloride and bromine.49 And finally, hexamethyl- Opening of the desired (R)-epoxide with methanolic methyl-
enetetramine was used to convert 2-bromo-1-(3-bromophenyl) amine gave amino alcohol. Finally, removal of the methox-
ethan-1-one to the desired norfenefrine.50 The atom efficiency yethoxymethyl group by refluxing in methanolic HCl afforded
is 24%. The total atom efficiency of our process is 36% when the desired compound as the HCl salt (Scheme 13).54 The syn-
thesis of phenylephrine has an atom economy of 39% to the
hydrochloride. Using NaOH to give the free phenylephrine
would reduce the atom economy to 30%. Our method starting
from cashew nut shell liquid has an atom economy of 22%
when taking useful products into account, but it does not
involve protection and deprotection.
Etilefrine. The synthesis of etilefrine can be achieved start-
ing from benzene, 1-(3-hydroxyphenyl)ethan-1-one is obtained
using the same initial pathway to the synthesis of
norfenefrine.46–48 1-(3-Hydroxyphenyl)ethan-1-one was then
converted to 3-acetylphenyl acetate using magnesium perchlor-
ate as catalyst,55 and a bromination of 3-acetylphenyl acetate
afforded 3-(2-bromoacetyl)phenyl acetate,56 which was then
converted to the etilefrine with ethylamine, sodium boro-
Scheme 12 Synthesis of the norfenefrine in literature.
hydride and water (Scheme 14).57 The atom efficiency of this
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Scheme 13 Original synthesis of phenylephrine.
fossil fuel based synthetic method is 28%, which is slightly then brominated to 1-(1-bromoethyl)-3-phenoxybenzene, by
higher than our synthetic method starting from cashew nut phosphorous tribromide. The bromide is converted to a nitrile
shell liquid, 22%.
group using sodium cyanide. Finally, 2-(3-phenoxyphenyl)pro-
Fenoprofen. Fenoprofen is traditionally synthesised from pionitrile, is hydrolyzed to the desired fenoprofen.58 This well-
3-hydroxyacetophenone by stoichiometric reactions in 5 steps known reaction pathway requires environmentally unfriendly
including the use of sodium cyanide and phosphorus tribro- stoichiometric conditions in most of the steps. It also involves
mide (Scheme 15).58 3-Hydroxyacetophenone, is C–O coupled sodium cyanide, which is dangerous to handle. Our method
by bromobenzene using potassium carbonate and copper cata- omitted the unpleasant cyanide step and converted bio-
lyst to 3-phenoxyacetophenone. The ketone is reduced using derived cardanol into fenoprofen. The atom efficiency of our
sodium borohydride to the corresponding alcohol, which is method (taking usable side products into account) is 68%
which is higher than the atom efficiency of the reported
method (30%) shown in Scheme 15. In addition, although
3-hydroxyacetophenone can be bio-derived as a component of
castoreum, the exudate from the castor sacs of the mature
beaver, it seems unlikely that this could be a commercially
viable source, so further steps may be required for the pro-
duction of fenoprofen by this route.
Although we have demonstrated significant advantages of
the routes to certain pharmaceuticals described in this paper
over conventional synthetic processes, we acknowledge that
the synthesis of drugs and their precursors is tightly controlled
by the United Nations Convention59 against illicit drugs and
psychotropic substances, 1988 and EU60 legislation and that
the high purity required of the final products is also enforced
under the International Convention on Harmonisation (ICH)
Guidelines.61 Further work on the process engineering by qua-
lified API or drug manufacturers will be required before these
Scheme 14 The original synthesis of etilefrine.
routes from cardanol can be fully implemented.
Scheme 15 Original synthesis of fenoprofen.
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Green Chemistry
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Conclusions
Relatively inexpensive cardanol, an inedible component
cashew nut shell liquid has been successfully converted to
important and high-value medicinal drugs, such as norfenefr-
ine, phenylephrine, etilefrine and fenoprofen in good yields by
mostly catalytic reactions. For fenoprofen, the key methoxy-
carbonylation step has been demonstrated with good enantio-
selectivity. The greener solvent, 2-methyl THF, gave very good
results for the metathesis of cardanol. Our methods start from
a readily available and relatively cheap bio-based resource, gen-
erally use catalytic reactions, have fewer steps and avoid
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1,4-cyclohexadiene (from triunsaturated cardanol) are signifi-
cant products of the first ethenolysis reaction and propene is
the side product of the isomerising metathesis step. These
valuable side products make the E factor for synthesis of
B. P. N. Tamtama, P. P. Sari, P. L. Sari, S. Ichsan,
Y. R. Kristiawan and F. N. Aini, IOP Conference Series:
Materials Science and Engineering, International Conference
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UNSP 012051.
3-vinylphenol by our route very low compared with those of 12 Y. C. Guo, G. Mele, F. Martina, E. Margapoti, G. Vasapollo
previously reported syntheses.
and W. J. Xiao, J. Organomet. Chem., 2006, 691, 5383.
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Conflicts of interest
15 S. Baader, P. E. Podsiadly, D. J. Cole-Hamilton and
L. J. Goossen, Green Chem., 2014, 16, 4885.
16 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.
17 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.
18 J. E. Mgaya, S. A. Bartlett, E. B. Mubofu, Q. A. Mgani,
A. M. Z. Slawin, P. J. Pogorzelec and D. J. Cole-Hamilton,
ChemCatChem, 2016, 8, 751.
19 J. E. Mgaya, E. B. Mubofu, Q. A. Mgani, D. B. Cordes,
A. M. Slawin and D. J. Cole-Hamilton, Eur. J. Lipid Sci.
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There are no conflicts to declare.
Acknowledgements
We thank James Mgaya for the cashew nut shells and Dr José
A. Fuentes for providing catalyst 30. We also thank the EPSRC
for the critical mass grant ‘Clean Catalysis for Sustainable
Development’ (EP/J018139/1), Sasol Technology, UK for a case
studentship (Y. S.) and the EPSRC UK National Mass
Spectrometry Facility at Swansea University for mass spectro-
metric analysis. We are grateful to the referees of an earlier
version of this paper for suggesting the comparisons of our
processes with standard literature methods for synthesis of the
same compounds.
20 J. Julis, S. Bartlett and D. J. Cole-Hamilton, WO 2015114323
A1, 2015.
21 J. Pollini, V. Bragoni and L. J. Gooßen, Beilstein J. Org.
Chem., 2018, 14, 2737.
22 M. R. L. Furst, R. Le Goff, D. Quinzler, S. Mecking,
C. H. Botting and D. J. Cole-Hamilton, Green Chem., 2012,
14, 472.
23 S. Pandey, D. R. Shinde and S. H. Chikkali, ChemCatChem,
2017, 9, 3997.
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