A Highly Enantioselective Alkene Methoxycarbonylation Enables a Concise Synthesis of (S)-Flurbiprofen

Article abstract of DOI:10.1002/ejoc.201700791

A highly enantioselective synthesis of (S)-flurbiprofen methyl ester in two steps from commercially available 4-bromo-2-fluoro-1,1′-biphenyl is shown. [PdCl₂((S)-xylyl-phanephos)] catalyst is used to accomplish both Grignard cross-coupling and the highly enantioselective intermolecular methoxycarbonylation reaction.

Full text of DOI:10.1002/ejoc.201700791

A Journal of
Accepted Article
Title: A highly enantioselective alkene methoxycarbonylation enables a
concise synthesis of (S)-flurbiprofen.
Authors: Gavin J. Harkness and Matthew Lee Clarke
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700791
Link to VoR: http://dx.doi.org/10.1002/ejoc.201700791
Supported by

European Journal of Organic Chemistry
10.1002/ejoc.201700791
FULL PAPER
A highly enantioselective alkene methoxycarbonylation enables a
concise synthesis of (S)-Flurbiprofen
[
a]
[a]
Gavin J. Harkness, and Matthew L. Clarke*
Abstract: A highly enantioselective synthesis of (S)-Flurbiprofen
methyl ester in two steps from commercially available 4-bromo-2-
2
fluoro-1,1’-biphenyl is shown. [PdCl ((S)-Xylyl-Phanephos)] catalyst
is used to accomplish both Grignard cross-coupling and the highly
enantioselective intermolecular methoxycarbonylation reaction.
Introduction
Flurbiprofen is one of the “profen” anti-inflammatories and is
[
1]
widely sold as a racemate. However, some applications,
including those that are expanding commercially, require a
Figure 1. Pd-Phanephos catalysts for the hydroxy- / methoxycarbonylation of
alkenes.
[
1b-c, 2]
single enantiomer form of Flurbiprofen.
The enantiomers of
[
1a, 1c, 3]
Flurbiprofen do not undergo significant inversion in vivo.
Catalytic asymmetric syntheses of enantiomerically enriched
Flurbiprofen are relatively rare and generally have some
problems that would prevent scale-up; such as requiring quite a
large number of steps and reagents that are generally not
biphenyl exploiting the same class of Pd-Phanephos catalysts
that are used in carbonylation. However, low yields as well as
forcing conditions made us seek an alternative synthesis
(Scheme 1 (i)). We felt a preferable synthesis might make use of
a vinyl electrophile and a more stable aromatic Grignard
[
4]
preferred at large scale. It has long been recognised that direct
conversion of alkenes to branched carboxylic acid derivatives is
potentially a more attractive procedure for making various
[
10]
reagent.
vinyl chloride have been carried out before.
vinyl tosylate, readily available by the decomposition of
Indeed, large scale syntheses of vinyl arenes from
[
5]
[11]
products, including various profen type drugs have been made
We found that
[
5b, 6]
in this way industrially as racemates.
[
12]
tetrahydrofuran , was an easier to handle vinyl electrophile
than gaseous but cheap vinyl chloride/bromide, and could be
cross-coupled with 2-fluoro-1,1’-biphenyl magnesium bromide
with good efficiency in the presence of 1 mol% (S)-1 mo or (R)-2
mo (Scheme 1 (ii) and Table 1). To the best of our knowledge,
this is the first example of vinyl tosylate being used in a Grignard
cross-coupling reaction.
Hydroxycarbonylation and methoxycarbonylation of vinyl arenes
[
5e-f, 7]
has been a very challenging reaction to develop,
due to difficulties with simultaneous control of enantio- and
most likely
[
5g-i, 8]
regioselectivity.
Phanephos ligands
Palladium catalysts derived from certain
[
9d]
represent leading catalysts for
intermolecular enantioselective alkene carbonylation (Figure
[
9a-c]
[9b]
1
).
an especially suitable catalyst for the methoxycarbonylation of
styrene (typically around 80 e.e. and near perfect
regioselectivity). Other phanephos ligands tend to give similar
enantioselectivities between 70 and 90 in the
2 4
[Pd Cl (F24-Phanephos)] dimer, 2 di, was found to be
%
%
methoxycarbonylation of styrene but with no regiocontrol. In
order to study the use of this catalyst system in the synthesis of
a real target, we have investigated the catalytic synthesis of (S)-
Flurbiprofen, and report these results here.
Results and Discussion
We first required reliable access to the vinyl arene, 3-fluoro-4-
phenylstyrene. This could be made by a Pd-catalysed cross-
coupling of vinyl magnesium bromide with 4-bromo-2-fluoro-1,1’-
Scheme 1. Three routes for the synthesis of vinyl arene, 3-fluoro-4-
phenylstyrene. Reaction conditions: (i) 1 mol% rac-1 mo, 2-MeTHF, 80 °C, 89
h, 44 % yield; (ii) 1 mol% (S)-1 mo, 2-MeTHF, 20 °C, 17 h, up to 99 % yield,
[a]
School of Chemistry, University of St Andrews, EaStCHEM,
St Andrews, Fife, Scotland, UK, KY16 9ST
E-mail: mc28@st-andrews.ac.uk
2 3 2
see Table 1; (iii) 1 mol% rac-1 mo, K CO (3 equiv.), dioxane/H O, 101 °C, 17
h, 59 % isolated yield.
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201700791
FULL PAPER
Isolation of pure product was complicated by the very apolar,
soluble nature of the product and the homocoupling and
(R)-2 mo gave higher enantioselectivity than the dipalladium
complex (R)-2 di. The level of enantioselectivity using (R)-2 di is
significantly lower than that observed with styrene (~ 80 % e.e.).
hydrolysis
by-products,
3’,3’’-difluoro-
[
1,1’;4’,1’’;4’’,1’’’]quarterphenyl and 2-fluorobiphenyl (Table 1,
2
Monomeric [PdCl ((S)-Xylyl-Phanephos)], (S)-1 mo, gave
Entries 2 and 6). However, we felt that these inert impurities
could likely be removed from the final product. An alternative
route involving an adaptation of the Suzuki reaction of 4-bromo-
slightly higher enantioselectivity but low yield. All of the acid
products could be isolated in pure form by simple acid-base
extraction.
[
13]
2
-fluoro-1,1’-biphenyl with vinylboronic acid pinacol ester gave,
after chromatography, pure alkene in 59 % yield using rac-1 mo
Scheme 1 (iii)), which was used to initially investigate the
(
Table 2. Synthesis of Flurbiprofen by enantioselective hydroxycarbonylation
using Pd-Phanephos catalysts.
carbonylation reactions.
Table 1. Pd-Phanephos-catalysed Grignard cross-coupling of vinyl tosylate with
2
-fluoro-4-biphenylylmagnesium bromide.
[
a]
o
[b]
[c]
[d]
Entry
Catalyst
T ( C)
Product
(%)
b/l
e.e.
[
a]
o
[b]
[b]
(%)
56
55
72
47
42
Entry
1
Catalyst
Catalyst
Loading
T ( C)
t (h)
Conversion
(%)
Product
(%)
[
e][f]
1
(S)-1 mo
(S)-1 mo
(S)-1 mo
(R)-2 mo
(R)-2 di
80
80
60
60
60
14 [6]
0.50
0.73
0.96
79
(
mol%)
[
f]
[
c]
2
21 [13]
14 [10]
97 [69]
91 [69]
(S)-1 mo
(S)-1 mo
(S)-1 mo
1
1
20
20
20
17
17
4
> 99
> 99
99
[
d][e]
[f]
3
4
5
2
[90]
3
4
0.25
83
78
83
2
0
> 99
55
(S)-1 mo
(R)-2 mo
(R)-2 mo
0.1
1
50
20
20
3
> 99
> 99
> 99
65
82
[
a]
Reactions were carried out on the scale of vinyl arene (0.25 mmol) in 2-
MeTHF (750 µL) and according to table, equation and ESI, unless otherwise
[
g]
5
19
17
[
b]
1
noted.
methylnaphthalene as an internal standard [yield of isolated product in square
brackets after acid-base extraction].
Conversions and yields were determined by H NMR using 1-
[
d][g][h]
[i]
6
1
[79]
[
c]
1
[d]
b/l ratio determined by H NMR.
[
a]
Enantiomeric excess determined by chiral HPLC. (S)-configured catalysts give
Reactions were carried out on the scale of vinyl tosylate (0.50 mmol), Grignard
[
e]
[f]
(
S)-configured product and vice versa. Reaction performed in 2-butanone.
reagent (0.60 mmol in 2-MeTHF, molarity determined by titration before use), 2-
MeTHF (1.0 mL) in Schlenk flasks under argon, unless otherwise noted.
[
b] 17 h.
ꢀ
1
Conversions and yields were determined by H NMR using 1-methylnaphthalene
as an internal standard [yield of isolated product in square brackets]. Average
[
c]
[
d]
yield of 13 experiments (t 17-21 h) = 92 %, see Table S2, entries 1-14.
internal standard. 0.76 mmol scale. 90 % yield isolated with 2-fluorobiphenyl
No
[
e]
[f]
[
g]
[h]
While the results with the F24-Phanephos catalysts (Table 2,
impurity; total product obtained = 68 %.
performed in a sealed microwave vial with crimp cap. 79 % yield isolated with Entries 4 and 5) are reasonably good in the context of this
0.25 mmol scale.
Reaction
[
i]
2
-fluorobiphenyl impurity; total product obtained = 63 %.
challenging reaction, the moderate enantioselectivity was not
sufficient to be synthetically useful. We therefore checked to see
if methoxycarbonylation could deliver any improvements (Table
3
). In all our previous work, methoxycarbonylation and
In
previous
work
on
hydroxycarbonylation
and
hydroxycarbonylation of a given alkene have tended to give
fairly similar regioselectivity and enantioselectivity. The results in
Table 3 were therefore surprising for several reasons. Most
[
9a, 9b]
methoxycarbonylation of styrene
, [Pd Cl (F24-Phanephos)]
2 4
dimer, 2di, was clearly identified as the best catalyst for this type
of process in terms of productivity, rate, and due to giving very
high regioselectivity. It was therefore examined and compared to
other Pd-Phanephos catalysts in the hydroxycarbonylation of 3-
fluoro-4-phenylstyrene (Table 2). It is clear that, F24-Phanephos
catalysts give the best results in hydroxycarbonylation of 3-
fluoro-4-phenylstyrene. High yields, as well as excellent
regioselectivity towards the branched isomer were observed. In
contrast to previous studies, the monomeric palladium complex
catalysts show very disappointing activity with only [PdCl ((S)-
2
Xylyl-Phanephos)], (S)-1 mo, yielding any considerable product,
with methanol as solvent. On top of this, (S)-1 mo was found to
show excellent enantioselectivity (Table 3, Entries 1-7); this
exceeds the selectivity observed with other styrene derivatives
[
9a,b]
in previous work.
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201700791
FULL PAPER
the lower regioselectivity of the reactions using (S)-1 mo.
Increasing CO pressure increased regioselectivity to branched
ester, but not considerably (Table 3, Entries 2 and 7). The low
yields using F24-Phanephos catalysts (R)-2 mo/di are likely due
to an unfavourable electronic effect retarding some part of the
cycle to a much greater degree here than is observed with
styrene itself. Consistent with this, the essentially isosteric
phanephos based catalysts (R)-3 mo/di with meta
dichlorophenyl groups also gave low yields relative to Xylyl-
Phanephos catalyst (S)-1 mo. Since enantioselection is a subtle
event, the increases in enantioselectivity with this substrate,
while striking, represent very small energy differences, but do
reveal that this substrate is very nicely matched to the chiral
pocket in the Pd/ phanephos catalysts. We have previously
found that the concentration of methanol is significant to both
productivity and selectivity in methoxycarbonylations. Neat
Table 3. Synthesis of prodrug Flurbiprofen methyl ester by enantioselective
methoxycarbonylation using Pd-Phanephos catalysts.
[
a]
o
[b]
[c]
[d]
Entry
1
Catalyst
T ( C)
Product
%)
b/l
e.e.
(
(%)
91
93
92
95
95
96
96
-
[
9]
methanol is beneficial for productivity in previous work. Here
this case is even more extreme, with other solvents using
methanol as a reagent giving no product at all. This is not likely
due to incompatibility in these solvents, since toluene, Me-THF
and butanone have all given some product formation in
(S)-1 mo
(S)-1 mo
(S)-1 mo
(S)-1 mo
(S)-1 mo
(S)-1 mo
(S)-1 mo
(S)-1 mo
(S)-1 mo
(S)-1 mo
(S)-1 mo
(S)-1 di
60
60
60
45
40
40
40
40
40
40
20
40
40
40
40
40
40
98
> 99
59
1.17
1.37
1.27
1.31
1.39
1.54
1.63
-
[
e]
2
[
e][f]
3
[
9c]
carbonylation of another substrate using these catalysts.
In
[
g]
4
83 [78]
addition, successful reactions in methanol tend to be
accompanied by the formation of palladium black, while the
reactions in Table 3, entries 8-10 were homogeneous solutions.
It is quite likely that the active catalyst did not form in these
solvents under these conditions. Some time ago we adopted the
use of PTSA and LiCl as convenient solid sources of acid and
5
81 [71]
[
h]
6
61
81
0
[
e]
7
[
5c]
[
i][j]
chloride; this also gives better results when compared to the
8
use of HCl, MsOH (inactive under these conditions) or Al(OTf)
(Table 3, entry 7 and ESI Table S-4)
3
[
j][k]
9
0
-
-
[
j][l]
1
0
0
-
-
The highly enantioenriched Flurbiprofen methyl ester obtained
was then subjected to acid-catalysed hydrolysis to (S)-
Flurbiprofen in near quantitative yield and without any
1
1
2
3
14
27
8
1.69
1.62
> 100
> 100
> 100
2.78
3.38
98
96
51
58
40
83
74
[
1a]
1
1
considerable loss in enantioselectivity (Scheme 2).
(R)-2 mo
(R)-2 mo
(R)-2 di
[
i]
1
4
5
7
[
i]
1
10
6
1
6
7
(R)-3 mo
(R)-3 di
1
8
[
a]
Reactions were carried out on the scale of vinyl arene (0.25 mmol) in MeOH
Scheme 2. Acid hydrolysis of enantio-enriched Flurbiprofen methyl ester to
desired Flurbiprofen without any significant loss in enantioselectivity. Yield of
isolated product in square bracket.
[
b]
(
750 µL) and according to table, equation and ESI, unless otherwise noted.
1
Conversions and yields were determined by
H
NMR using 1-
methylnaphthalene as an internal standard [yield of isolated product in square
brackets], this includes regioisomerically pure branched products 39 % (entry
[
c]
1
[d]
4
), 32 % (entry 5). b/l ratio determined by H NMR. Enantiomeric excess
determined by chiral HPLC. (S)-configured catalysts give (S)-configured
Attempts were made to try to couple the two processes of cross-
[
e]
[f]
[g]
[h]
product and vice versa.
Al(OTf) (20 mol%) as acid.
butanone solvent. PhMe as solvent.
70 bar CO. No PTSA.H
2
O.
1 mmol scale.
[k]
coupling and carbonylation together in a tandem manner, re-
[
i]
[j]
3
2-MeTHF solvent.
10 equiv. MeOH.
2-
[5b, 6c-f]
[
l]
using the catalyst.
Unfortunately, a one-pot process
involving hydroxycarbonylation failed to give any considerable
product and returned unreacted vinyl arene. Cannula filtration
between the two steps improved yields, with 50 % product
detected (21 % isolated product) over the two steps. Similar
Isolation of pure branched ester (95 % e.e.) was possible by
column chromatography, albeit in only moderate yields due to
issues were encountered with one-pot cross-coupling
-
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201700791
FULL PAPER
o
methoxycarbonylation, with the overall yield of pure branched
bath at 40 C for 17 hours with constant stirring. Upon cooling to room
temperature, the pressure was released slowly into a well-ventilated
isomer over the two steps not exceeding 17 % (see ESI).
fume cupboard. The mixture was analysed by taking a sample, diluting
1
in CDCl
3
, and analysing by H NMR to assess the ratio between SM and
desired product, as well as regioselectivity. Solvent was removed under
reduced pressure and purification via column chromatography on silica
gel (eluent petroleum ether:EtOAc, 100:0 to 90:10) gave branched
methyl 2-(2-fluoro-biphenyl-4-yl)-propionate (20.7 mg, 32 %) as a white
crystalline solid, linear methyl 3-(2-fluoro-biphenyl-4-yl)-propionate (3.6
mg, 6 %) as a colourless oil and a mixture of both regioisomers (21.3 mg,
3
3 %) as a colourless oil. The enantiomeric excess was determined by
-
1
HPLC, using a Chiracel OJ column, 250 x 4.6 mm, 10 µm, 0.5 mL min ,
9
5:5 hexane : iso-propanol, t
46 min.
R R R
[(-)-R] = 23 min, t [(+)-S] = 27 min, t [linear]
=
[
14]
Methyl 2-(2-fluoro-biphenyl-4-yl)-propionate: m.p. 39-40 °C {Lit.
40 °C}; δ (500 MHz, CDCl ): 7.56-7.51 (2H, m, CArH), 7.48-7.33 (4H, m,
ArH), 7.17-7.09 (2H, m, CArH), 3.77 (1H, q, J = 7.2, -CHCH ), 3.71 (3H,
s, -OCH ), 1.54 (3H, d, J = 7.2, -CHCH ); δ (376 MHz, CDCl ): -117.6;
(125 MHz, CDCl ): 174.6 (CO CH ), 159.8 (d, J = 248.3, CArF), 141.9
d, J = 7.7, CAr), 135.6 (CAr), 131.0 (d, J = 3.9, CArH), 129.1 (2C, d, J =
.9, CArH), 128.6 (2C, CArH), 128.0 (d, J = 13.6, CAr), 127.8 (CArH), 123.7
d, J = 3.3, CArH), 115.4 (d, J = 23.6, CArH), 52.4 (-OCH ), 45.1 (-CHCH ),
([M+H] ) requires 259.1129;
: C, 74.40; H, 5.85;
Found: C, 74.51; H, 5.99. These data are consistent with those reported
Scheme 3. Synthesis of Flurbiprofen and prodrug Flurbiprofen methyl ester
from vinyl tosylate. Reaction conditions: (i) Cross-coupling: (R)-2 mo (1
mol%), 19 h, > 99 % conversion, 73 % yield; (i*) Hydroxycarbonylation:
H
3
C
3
3
3
F
3
2 2
Reaction mixture quenched with H O (5 equv.), filtered by cannula, H O (5
δ
C
3
2
3
equiv.) added to filtrate prior to reaction, 60 °C, 65 h, 69 % conversion, 69 %
yield – Total isolated product from vinyl tosylate = 21 %, b:l = 6.08, e.e. = 41 %
(
2
(
R), R = H. (ii) Cross-Coupling: (S)-1 mo (1 mol%), 17 h, > 99 % conversion,
(
3
3
9
6
0 % yield isolated with 2-fluorobiphenyl impurity; total product obtained =
+
+
1
3 2
8.6 (-CHCH ); m/z HRMS (ESI ) C16H16FO
8 %; (ii*) Methoxycarbonylation: Isolated mixture re-charged with (S)-1 mo
found 259.1126 (-1.2 ppm). Anal. Calcd for C16H15FO
2
(
1 mol%), MeOH, 40 °C, 17 h, 73 % conversion, 68 % yield – Total isolated
product from vinyl tosylate = 40 %, b:l = 1.50, e.e. = 96 % (S), this includes
regioisomerically pure branched product 17 %, R = Me.
[
15]
20
[1a]
in literature.
[α]
D
= + 46.2 (c = 1.00, CHCl
3
, e.e. = 95 % (S)) {lit.
2
0
[
α]
D
= - 39.2 (c = 1.50, CHCl
3
, e.e. = 76 % (R))}.
Methyl 3-(2-fluoro-biphenyl-4-yl)-propionate:
485 (w), 1416 (m), 1265 (w) 1196 (m), 1153 (m), 1126 (m), 827 (w), 766
s); δ (500 MHz, CDCl ): 7.56-7.52 (2H, m, CArH), 7.47-7.42 (2H, m,
ArH), 7.40-7.33 (2H, m, CArH), 7.06 (1H, dd, J = 7.8, 1.7, CArH), 7.02 (1H,
), 3.00 (2H, t, J = 7.8, CArCH ),
(376 MHz, CDCl ): -118.2; δ (125
), 159.8 (d, J = 248.0, CArF), 142.2 (d, J =
7.7, CAr), 135.8 (CAr), 130.8 (d, J = 3.9, CArH), 129.0 (2C, d, J = 3.0,
νmax (ATR) 1732 (s),
Conclusions
1
(
H
3
A highly enantioselective synthesis of (S)-Flurbiprofen methyl
C
ester in two steps from commercially available 4-bromo-2-fluoro-
dd, J = 11.5, 1.7, CArH), 3.70 (3H, s, -OCH
.68 (2H, t, J = 7.8, CArCH CH ); δ
MHz, CDCl ): 173.2 (CO CH
3
2
1
2
,1’-biphenyl has been achieved. [PdCl ((S)-Xylyl-Phanephos)],
2
2
2
F
3
C
catalyst (S)-1 mo was used to accomplish both the novel
Grignard cross-coupling of vinyl tosylate and the intermolecular
methoxycarbonylation of vinyl arene. Significantly higher
enantioselectivity is observed in the methoxycarbonylation of
this substrate than styrene.
3
2
3
C
ArH), 128.5 (2C, CArH), 127.7 (CArH), 127.0 (d, J = 13.5, CAr), 124.4 (d, J
3.2, CArH), 116.0 (d, J = 22.8, CArH), 51.9 (-OCH ), 35.4 (CArCH CH ),
Na ([M+Na] ) requires
=
3
2
2
+
+
+
3
2
0.4 (CArCH
2 2 2
CH ); m/z HRMS (ESI ) C16H15FO
81.0948; found 281.0944 (-1.4 ppm).
Experimental Section
Acknowledgements
Example procedure of methoxycarbonylation of 3-fluoro-4-phenylstyrene,
The authors thank all the technical staff in the School of
Chemistry for their assistance, the EPSRC for funding for this
programme from EP/MC038868/1 and via the DTG.
Table 3, Entry 5:
Lithium chloride (2.1 mg, 0.05 mmol), para-toluenesulfonic acid
2
monohydrate (9.5 mg, 0. 50 mmol) and [PdCl ((S)-Xylyl-Phanephos)] (2.2
mg, 0.0025 mmol) were weighed into a microwave vial equipped with a
magnetic stirrer bar. The vial was sealed with a crimp cap and flushed
with argon for 30 minutes. 3-fluoro-4-phenylstyrene (49.6 mg, 0.25 mmol)
and 1-methylnaphthalene (30 µL, 0.21 mmol, internal standard) were
Keywords: Palladium • Asymmetric Catalysis • Carbonylation •
Hydroesterification • Hydroxycarbonylation
[
[
1] a) R. Morrone, G. Nicolosi, A. Patti, M. Piattelli, Tetrahedron: Asymm.
added to
Degassed methanol (750 µL) was then added to the Schlenk flask to
make a solution. A t sample (approximately 10 µL) was taken and
a flame dried Schlenk flask under an inert atmosphere.
1
2
995, 6, 1773-1778; b) B. Hinz, K. Brune, T. Rau, A. Pahl, Pharm. Res.
001, 18, 151-156; c) A. A. M. Abdel-Aziz, A. A. Al-Badr, G. A. Hafez, in
0
Profiles of Drug Substances, Excipients and Related Methodology, Vol.
(Ed.: G. B. Harry), Academic Press, 2012, pp. 113-181; d) H.
Fujisawa, T. Fujiwara, Y. Takeuchi, K. Omata, Chem. Pharm. Bull. 2005,
3, 524-528.
1
3
7
analysed by H NMR (to calibrate the ratio of internal standard to starting
material). The solution containing the alkene and internal standard was
added to the microwave vial via syringe. The crimp cap was pierced with
two needles and quickly placed into an autoclave which had previously
been placed under an argon atmosphere, before being opened under a
flow of argon. The autoclave was sealed, purged three times with CO
and then pressurised to 30 bar. The autoclave was then placed in an oil
5
2] a) M. Arroyo, J. V. Sinisterra, J. Org. Chem. 1994, 59, 4410-4417; b) A.
M. Panico, V. Cardile, F. Vittorio, G. Ronsisvalle, G. M. Scoto, C. Parenti,
B. Gentile, R. Morrone, G. Nicolosi, Il Farmaco 2003, 58, 1339-1344; c)
B. M. Peskar, S. Kluge, B. A. Peskar, S. M. Soglowek, K. Brune,
Prostaglandins 1991, 42, 515-531; d) N. Otsuka, I. Yataba, I. Matsushita,
H. Matsumoto, Y. Hoshino, Y. Terada, Clinical and Experimental
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201700791
FULL PAPER
Nephrology 2017, 1-8; e) M. Sugimoto, Y. Toda, M. Hori, A. Mitani, T.
Ichihara, S. Sekine, T. Hirose, H. Endo, N. Futaki, S. Kaku, N. Otsuka, H.
Matsumoto, Drug Dev. Res. 2016, 77, 20-28; f) M. Sugimoto, Y. Toda, M.
Hori, A. Mitani, T. Ichihara, S. Sekine, S. Kaku, N. Otsuka, H. Matsumoto,
Drug Dev. Res. 2016, 77, 206-211; g) I. Yataba, N. Otsuka, I. Matsushita,
M. Kamezawa, I. Yamada, S. Sasaki, K. Uebaba, H. Matsumoto, Y.
Hoshino, European J. Clin. Pharm. 2016, 72, 53-59; h) I. Yataba, N.
Otsuka, I. Matsushita, H. Matsumoto, Y. Hoshino, Clinical Drug
Investigation 2016, 36, 673-682; i) I. Yataba, N. Otsuka, I. Matsushita, H.
Matsumoto, Y. Hoshino, Mod Rheumatol 2017, 27, 130-136; j) Launch of
the Transdermal Anti-inflammatory Analgesic Patch Formulation
[11] T. Banno, Y. Hayakawa, M. Umeno, J. Organomet. Chem. 2002, 653,
288-291.
[12] T. M. Gøgsig, L. S. Søbjerg, A. T. Lindhardt, K. L. Jensen, T. Skrydstrup,
J. Org. Chem. 2008, 73, 3404-3410.
[13] R. D. Grigg, J. W. Rigoli, R. Van Hoveln, S. Neale, J. M. Schomaker,
Chem. - Eur. J. 2012, 18, 9391-9396.
[14] M. Zaheer, M. Zia-ur-Rehman, N. Jamil, M. N. Arshad, S. Z. Siddiqui, A.
M. Asiri, J. Chem. Res. 2015, 39, 668-673.
[15] J. Pietruszka, M. Schölzel, Adv. Synth. Catal. 2012, 354, 751-756.
LOQOA®
Tape;
can
be
found
under
http://www.taisho-
holdings.co.jp/en/release/2016/2016012001-e.pdf, 2016.
[
3] a) N. M. Davies, Clinical Pharmacokinetics 1995, 28, 100-114; b) W. J.
Wechter, J. Clin. Pharm. 1994, 34, 1036-1042; c) G. Geisslinger, J.
Lotsch, S. Menzel, G. Kobal, K. Brune, Brit. J. Clin. Pharm. 1994, 37,
3
92-394.
[
[
4] a) C. R. Smith, T. V. RajanBabu, J. Org. Chem. 2009, 74, 3066-3072; b)
R. C. Griesbach, D. P. G. Hamon, R. J. Kennedy, Tetrahedron: Asymm.
1
997, 8, 507-510.
5] a) T. Hiyama, N. Wakasa, T. Kusumoto, Synlett 1991, 1991, 569-570; b)
H. Neumann, A. Brennführer, M. Beller, Adv. Synth. Catal. 2008, 350,
2
1
1
2
437-2442; c) A. Seayad, S. Jayasree, R. V. Chaudhari, Org. Lett. 1999,
, 459-462; d) A. Seayad, S. Jayasree, R. V. Chaudhari, Catal. Lett.
999, 61, 99-103; e) S. Jayasree, A. Seayad, R. V. Chaudhari, Org. Lett.
000, 2, 203-206; f) H. Li, K. dong, H. Jiao, H. Neumann, R. Jackstell, M.
Beller, Nat. Chem. 2016, 8, 1159.; g) H. Alper, N. Hamel, J. Am. Chem.
Soc. 1990, 112, 2803-2804; h) K. Yasutoyo, O. Kentaro, N. Kyoko, H.
Tamejiro, Bull. Chem. Soc. Jpn. 2004, 77, 347-355; i) P. Kalck, M.
Urrutigoïty, Inorg. Chim. Acta 2015, 431, 110-121; j) C. Aderne, I. A.
Guzei, G. W. Holzapfel, T. Bredenkamp, ChemCatChem, 2016, 8, 1084-
1
093.
[
6] a) C. Ramminger, D. Zim, V. R. Lando, V. Fassina, A. L. Monteiro, J.
Braz. Chem. Soc. 2000, 11, 105-111; b) A. Zapf, M. Beller, Top. Catal.
2
5
1
002, 19, 101-109; c) T. C. Wu, (Ethyl Corporation), U.S. Patent
322959, 1994; d) T. C. Wu, (Ethyl Corporation), U.S. Patent 5315026,
994; e) T. C. Wu, K. C. Chockalingham, W. D. Klobucar, G. D. Focht,
(
Albemarle Corporation), WO9830522, 1998; f) R. W. Lin, R. C. Herndon,
R. H. Allen, K. C. Chockalingham, G. D. Focht, R. K. Roy, (Albemarle
Corporation), WO 98/30529 1998; g) T. C. Wu, (Albemarle Corporation),
U.S. Patent 5 536 870, 1996; h) V. Ramachandran, T. C. Wu, C. B. Berry,
(
Albemarle Corporation), WO 98/37052, 1998; i) I. Shimizu, Y.
Matsumura, Y. Arai, (Nippon Petrochemicals Co.,Ltd.), US Patent
,922,052, 1990; j) G. P. Stahly, R. M. Starrett, in Chirality in Industry II
Eds.: A. N. Collins, G. N. Sheldrake, J. Crosby), J. Wiley & Sons, 1997,
pp. 19-40.
7] a) I. del Rıo
68; b) I. del Río, C. Claver, Piet W. N. M. van Leeuwen, Eur. J. Inorg.
4
(
[
[
́
, N. Ruiz, C. Claver, Inorg. Chem. Commun. 2000, 3, 166-
1
Chem. 2001, 2001, 2719-2738; c) J. A. Fuentes, A. M. Z. Slawin, M. L.
Clarke, Catal. Sci. Tech. 2012, 2, 715-718; d) H. Ooka, T. Inoue, S.
Itsuno, M. Tanaka, Chem. Commun. 2005, 1173-1175; e) T. O. Vieira, M.
J. Green, H. Alper, Org. Lett. 2006, 8, 6143-6145.
8] a) G. Cometti, G. P. Chiusoli, J. Organomet. Chem. 1982, 236, C31-C32;
́
b) I. del Rıo, N. Ruiz, C. Claver, L. A. van der Veen, P. W. N. M. van
Leeuwen, J. Mol. Catal. A: Chem. 2000, 161, 39-48; c) C. Godard, B. K.
Munoz, A. Ruiz, C. Claver, Dalton Transactions 2008, 853-860; d) C.
Godard, A. Ruiz, C. Claver, Helv. Chim. Acta 2006, 89, 1610-1622; e) E.
Guiu, M. Caporali, B. Muñoz, C. Müller, M. Lutz, A. L. Spek, C. Claver, P.
W. N. M. van Leeuwen, Organometallics 2006, 25, 3102-3104; f) M. D.
Miquel-Serrano, A. Aghmiz, M. Diéguez, A. M. Masdeu-Bultó, C. Claver,
D. Sinou, Tetrahedron: Asymm. 1999, 10, 4463-4467; g) B. Muñoz, A.
Marinetti, A. Ruiz, S. Castillon, C. Claver, Inorg. Chem. Commun. 2005,
8
, 1113-1115; h) B. K. Munoz, C. Godard, A. Marinetti, A. Ruiz, J. Benet-
Buchholz, C. Claver, Dalt. Trans. 2007, 5524-5530; i) S. Oi, M. Nomura,
T. Aiko, Y. Inoue, J. Mol. Catal. A: Chem. 1997, 115, 289-295; j) L. Wang,
W. H. Kwok, A. S. C. Chan, T. Tu, X. Hou, L. Dai, Tetrahedron: Asymm.
2
003, 14, 2291-2295; k) M. L. Clarke, J. A. Fuentes, in C-1 Building
Blocks in Organic Synthesis 1, Vol. 1 (Ed.: P. W. N. M. van Leeuwen),
Thieme, 2014, pp. 229-258; l) J. Li, W. Chang, W. Ren, J. Dai, Y. Shi,
Org. Lett. 2016, 18, 5456-5459; m) T. Bredenkamp, C. Halzapfel, Catal.
Commun. 2017, 96, 74-78.
[
[
9] a) T. M. Konrad, J. A. Fuentes, A. M. Z. Slawin, M. L. Clarke, Angew.
Chem. Int. Ed. 2010, 49, 9197-9200; b) T. M. Konrad, J. T. Durrani, C. J.
Cobley, M. L. Clarke, Chem. Commun. 2013, 49, 3306-3308; c) J. A.
Fuentes, J. T. Durrani, S. M. Leckie, L. Crawford, M. Buhl, M. L. Clarke,
Catal. Sci. Tech. 2016, 6, 7477-7485; d) For original synthesis of
Phanephos, see K. Rossen, P. J. Pye, R. Maliakal, and R. P. Volante, J.
Org. Chem. 1997, 62, 6462-6463.
10] T. Kohei, S. Koji, K. Yoshihisa, Z. Michio, F. Akira, K. Shun-ichi, N. Isao,
M. Akio, K. Makoto, Bull. Chem. Soc. Jpn. 1976, 49, 1958-1969.
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201700791
FULL PAPER
Entry for the Table of Contents (Please choose one layout)
Layout 2:
FULL PAPER
Palladium catalysis
Gavin J. Harkness Matthew L. Clarke*
Page No. – Page No.
A highly enantioselective alkene
methoxycarbonylation enables a
concise synthesis of (S)-Flurbiprofen
An enantioselective synthesis of (S)-Flurbiprofen is described: The same type of Pd
complex has been found to be useful in making the vinyl arene substrate, and as
catalyst for a highly enantioselective alkene carbonylation.
*
one or two words that highlight the emphasis of the paper or the field of the study
This article is protected by copyright. All rights reserved.