Efficient, selective, and green: Catalyst tuning for highly enatioselective reactions of ethylene

Article abstract of DOI:10.1021/ol800395m

Fine tuning of the biaryl and amino moieties of Feringa's phosphoramidite ligands yields structurally simpler, yet more efficient and selective, ligands for asymmetric hydrovinylation of vinylarenes and acylic 1,3-dienes. The enantioselectivities and yields observed in the formation of the 3-arylbutenes are among the highest for all asymmetric catalytic processes reported to date for the synthesis of intermediates for the widely used antiinflammatory 2-arylpropionic acids including naproxen, ibuprofen, fenoprofen, and flurbiprofen.

Full text of DOI:10.1021/ol800395m

ORGANIC
LETTERS
2008
Vol. 10, No. 8
1657-1659
Efficient, Selective, and Green: Catalyst
Tuning for Highly Enantioselective
Reactions of Ethylene
Craig R. Smith and T. V. RajanBabu*
Department of Chemistry, The Ohio State UniVersity, 100 West 18th AVenue,
Columbus, Ohio 43210
rajanbabu.1@osu.edu
Received February 20, 2008
ABSTRACT
Fine tuning of the biaryl and amino moieties of Feringa’s phosphoramidite ligands yields structurally simpler, yet more efficient and selective,
ligands for asymmetric hydrovinylation of vinylarenes and acylic 1,3-dienes. The enantioselectivities and yields observed in the formation of
the 3-arylbutenes are among the highest for all asymmetric catalytic processes reported to date for the synthesis of intermediates for the
widely used antiinflammatory 2-arylpropionic acids including naproxen, ibuprofen, fenoprofen, and flurbiprofen.
The asymmetric hydrovinylation (HV) of an alkene, viz.,
addition of ethylene as a vinyl group and a hydrogen across
a double bond with concomitant generation of an asymmetric
center, is one of the oldest asymmetric carbon-carbon bond-
forming reactions.1 Since ethylene is a cheap, abundantly
available feedstock carbon source, and the resulting vinyl
group in the product readily transformed into a variety of
other common functional groups, this reaction has huge
potential as a scalable, environmentally benign method for
the preparation of valuable chemical intermediates.
primary products, and attendant oligomerization of the
starting alkenes.
Recently, several protocols for the reaction have been
described in which nearly quantitative yields of the desired
products can be obtained using only catalytic amounts of
metal complexes, most notably those of nickel (eq 1).2 Yet,
practical levels of enantioselectivity (i.e., enantiomeric excess
>95%) have been achieved only for limited substrates, often
at the cost of incomplete conversions, isomerization of the
Conspicuously absent among the more successful sub-
strates are Ar-substituted vinylarenes, best exemplified3 by
(2) Ni: (a) Nomura, N.; Jin, J.; Park, H.; RajanBabu, T. V. J. Am. Chem.
Soc. 1998, 120, 459. (b) RajanBabu, T. V.; Nomura, N.; Jin, J.; Nandi, M.;
Park, H.; Sun, X. J. Org. Chem. 2003, 68, 8431. Ru: (c) He, Z.; Yi, C. S.;
Donaldson, W. A. Org. Lett. 2003, 5, 1567. Co: (d) Grutters, M. M. P.;
Mu¨ller, C.; Vogt, D. J. Am. Chem. Soc. 2006, 128, 7414. Pd: (e) Englert,
U.; Haerter, R.; Vasen, D.; Salzer, A.; Eggeling, E. B.; Vogt, D.
Organometallics 1999, 18, 4390. (f) Shi, W.-J.; Xie, J.-H.; Zhou, Q.-L.
Tetrahedron: Asymmetry 2005, 16, 705.
(1) (a) Bogdanovic´, H. B.; Meister, B.; Pauling, H. Angew. Chem., Int.
Ed. Engl. 1972, 11, 1023. (b) For a recent review, see: RajanBabu, T. V.
Chem. ReV. 2003, 103, 2845.
10.1021/ol800395m CCC: $40.75
© 2008 American Chemical Society
Published on Web 03/20/2008

4-isobutylstyrene (current best: ∼95% yield, 91% ee) and
6-methoxy-2-vinylnaphthalene (73% yield; 86% ee), potential
precursors of antiinflammatory 2-arylpropionic acids, (S)-
ibuprofen and (S)-naproxen, the latter a hugely successful
commercial drug (Aleve) currently produced by classical
resolution.4 Since binaphthol-derived phosphoramidites5 were
introduced for asymmetric HV of vinylarenes,6a under our
originally reported conditions,2a these ligands have been used
with varying degree of success for HV of a variety of
substrates including norbornene,6b 1,3-dienes,6c and 1-sub-
stituted styrenes.6d,e Asymmetric HV of similar substrates is
the starting point for several total synthesis efforts (e.g.,
pseudopterosins and related compounds (see eq 1)) in our
group; therefore, we decided to explore the scope of ligand
tuning in this highly versatile, modular ligand system, and
the results are reported in this paper. Ligands L1-L10 (Figure
1), readily prepared7,8 from the corresponding bisphenols,
of all-carbon quaternary centers.6d The results are tabulated
in Table 1. A sample of the racemic compound was prepared
Table 1. Asymmetric Hydrovinylation of 4-Methoxystyrenea,b
ligand
(mol %)
conv
(%)
selec.
(%)
entry
% eec
confd
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
L1 + L2/0.7
L1/0.7
L2/0.7
L3/0.7
L4/0.7
L5/0.7
L5/2.0
L6/0.7
L6/2.0
L7/2.0
L8/0.7
L8/1.0
L8/2.0
L9/0.7
L9/1.0
L9/2.0
>99
>99
>99
>99
0
23
87
21
>99
14
2
2
21
73
>99
>99
>99
>99
>99
>99
>99
-
>99
>99
>99
95
>99
>99
>99
>99
>99
91
0
94
>95
94
-
76
78
90
92
16
86
85
87
91
88
87
98
-
S
R
S
-
S
S
S
S
S
S
S
S
S
S
S
S
65
>99
L
10/0.7
a
See Supporting Information for full experimental details. b Conversions
and selectivities determined by GC analysis. c GC on Cyclodex-B column.
d
Configuration assigned by comparison of GC retention times of known
compounds.3
in a reaction of p-methoxystyrene with ethylene (1 atm) in
the presence of a catalytic amount of [(allyl)NiBr]2, a racemic
ligand (a 1:1 mixture of L1 and L2), and sodium tetrakis-
[(3,5-trifluoromethyl)phenyl]borate [NaBARF] (Table 1,
entry 1).
Among the ligands examined, in addition to the original
Feringa ligand L3, two others stand out.8 The ligand L1 (or
its enantiomer L2), which has only a lowly biphenyl
backbone instead of a chiral binaphthyl unit and is signifi-
cantly cheaper, still yields similar selectivities and conver-
sions (entries 2 and 3). The ligand L10, in which the (S)-N-
R-methylbenzyl groups are replaced with achiral benzyl and
chiral (S)-R-methyl-1-naphthyl groups, is by far the best
ligand for this exacting reaction,9 yielding nearly quantitative
yield and selectivity (entry 17). Surprisingly, ligands prepared
from achiral dibenzylamine and enantiopure 2,2′-binaphthol
(not shown) gave no conversion.8
Figure 1. Selected phosphoramidite ligands.
PCl3, and various chiral amines, were used for this study.
The feasibility of ligand control in the hydrovinyl-
ation was initially investigated using p-methoxystyrene, an
electron-rich model substrate that consistently had given
one of the poorest reactions (80% yield, 73% ee)
among vinylarenes tested previously. We started
these investigations using a modified protocol (eq 1, R )
4-OMe) that had originally been developed for the generation
(3) Zhang, A.; RajanBabu, T. V. Org. Lett. 2004, 6, 1515.
(4) For a review of synthesis of 2-arylpropionic acids, see: Stahly, G.
P.; Starrett, R. M. In Chirality in Industry II; Collins, A. N., Sheldrake, G.
N., Crosby, J., Eds.; John Wiley: Chichester, 1997.
(5) (a) Feringa, B. L. Acc. Chem. Res. 2000, 33, 346. (b) Arnold, L. A.;
Imbos, R.; Mandoli, A.; de Vries, A. H. M.; Naasz, R.; Feringa, B. L.
Tetrahedron 2000, 56, 2865.
(6) (a) Francio´, G.; Faraone, F.; Leitner, W. J. Am. Chem. Soc. 2002,
124, 736. (b) Kumareswaran, R.; Nandi, N.; RajanBabu, T. V. Org. Lett.
2003, 5, 4345. (c) Zhang, A.; RajanBabu, T. V. J. Am. Chem. Soc. 2006,
128, 54. (d) Zhang, A: RajanBabu, T. V. J. Am. Chem. Soc. 2006, 128,
5620. (e) Shi, W.-J.; Zhang, Q.; Xie, J.-H.; Zhu, S.-F.; Hou, G.-H.; Zhou,
Q.-L. J. Am. Chem. Soc. 2006, 128, 2780.
(7) For representative examples of finely tuned phosphoramidites from
various research groups, see: (a) Alexakis, A.; Polet, D.; Rosset, S.; March,
S. J. Org. Chem. 2004, 69, 5660. (b) Bernsmann, H.; van den Berg, M.;
Hoen, R.; Minnaard, A. J.; Mehler, G.; Reetz, M. T.; De Vries, J. G.;
Feringa, B. L. J. Org. Chem. 2005, 70, 943. (c) Streiff, S.; Welter, C.;
Schelwies, M.; Lipowsky, G.; Miller, N.; Helmchen, G. Chem. Commun.
2005, 2957. (d) Leitner, A.; Shekhar, S.; Pouy, M. J.; Hartwig, J. F. J. Am.
Chem. Soc. 2005, 127, 15506. (e) Yu, R. T.; Rovis, T. J. Am. Chem. Soc.
2006, 128, 12370. (f) Du, H.; Yuan, W.; Zhao, B.; Shi, Y. J. Am. Chem.
Soc. 2007, 129, 11688.
Hydrovinylation of other vinylarenes, 1-alkylvinyl-
arenes, and an open-chain diene was attempted under
(9) To the best of our knowledge, this ligand has not been described in
the literature.
(10) For the best asymmetric routes to date, Naproxen via Ru-catalyzed
asymmetric hydrogenation of 2-arylacrylic acids: (a) Ohta, T.; Takaya, H.;
Kitamura, M; Nagai, K.; Noyori, R. J. Org. Chem. 1987, 52, 3174 (98%
ee). Ni-catalyzed asymmetric hydrocyanation: (b) RajanBabu, T. V.;
Casalnuovo, A. L. J. Am. Chem. Soc. 1996, 118, 6325 and references cited
therein (95% ee). Ibuprofen via Ru-catalyzed hydrogenation: (c) Uemura,
T.; Zhang, X.; Matsumura, K.; Sayo, N.; Kumobayashi, H.; Ohta, T.; Nozaki,
K.; Takaya, H. J. Org. Chem. 1996, 61, 5510 (97% ee). Rh-catalyzed
asymmetric hydroformylation: (d) Nozaki, K.; Sakai, N.; Nanno, T.;
Higashijima, T.; Mano, S.; Horiuchi, T.; Takaya, H. J. Am. Chem. Soc.
1997, 119, 4413 (92% ee). Hydrovinylation: ref 3 (91%). No useful catalytic
asymmetric methods are known for other (S)-2-arylpropionic acid precursors.
(8) See Supporting Information for experimental details and a more
complete list of ligands.
1658
Org. Lett., Vol. 10, No. 8, 2008

optimal conditions, and the results are shown in
Table 2. The enantioselectivities obtained for the precursors
highest oVerall selectiVity obtained to date for any Viable
intermediates for these important compounds.10 In one case
where we have further optimized the reaction, the hydrovi-
nylation of 4-i-butylstyrene can be accomplished with
0.00014 equiv of catalyst (substrate/catalyst ratio ) 7142)
in 4.67 h at 0 °C. For the biphenyl-derived ligands L1 and
L2, the configuration of the amine determines the sense of
asymmetric induction. With the S-chiral moiety in the amine
portion of the ligand, the product configuration in all cases
is also S. As seen in entries 1-5, the lack of axial chirality
in the ligand leads to little erosion of ee, suggesting that for
simple substrates a more elaborate (and expensive) binaph-
thol-based phosphoramidite is not necessary to achieve high
stereoselectivity. In all cases examined, L10 yielded the best
results in terms of overall yield and selectivity.
Table 2. Asymmetric Hydrovinylation of Vinylarenes and a
1,3-Dienea
Although for the vinylarenes, including 1-alkylstyrenes
(entries 7 and 8), which yield all-carbon quaternary centers
in the product, less rigid catalytic complexes from biphenols
are adequate, for more challenging substrates such as an
acyclic 1,3-diene,11 a binaphthyl backbone is essential for
high selectivities (entry 6). Previous attempts to effect
asymmetric hydrovinylation of acylic 1,3-dienes resulted in
less than 5% ee.6c,12 Although 1-methylenetetralin undergoes
hydrovinylation easily to afford 8 in excellent ee, the
substrate underwent significant isomerization (∼30%) of the
starting material to 1-methyl-3,4-dihydronaphthalene, which
is a major distraction from this otherwise useful reaction.
Expansion of the scope of this reaction to heteroaromatic
compounds, cyclic vinylarenes, and acyclic dienes and
applications of these reactions in natural product synthesis
will be reported in due course.
Acknowledgment. Financial assistance for this research
by the NSF (CHE-0610349) and NIH (General Medical
Sciences, R01 GM075107) is gratefully acknowledged.
Supporting Information Available: Full experimental
details of synthesis of ligands, hydrovinylation reactions, and
spectroscopic and chromatographic data for characterization
of compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
a
See eq 1 and Supporting Information for further experimental details.
b
c
Conversion and selectivities determined by GC analysis.
Yields
OL800395M
determined by isolated mass after column purification. d Selectivity for HV
product. e Determined by GC, except for 5, which was determined by HPLC.
(11) Except for Diels-Alder reactions, asymmetric catalyzed C-C bond-
forming reactions of acyclic 1,3-dienes give only moderate regio- and
enantioselectivities. See, for example: (a) cyclopropanation: Doyle, M. In
Catalytic Asymmetric Synthesis; Ojima, I., Ed.; Wiley-VCH: New York,
2000. (b) ene reaction: Terada, M.; Mikami, K. J. Chem. Soc., Chem.
Commun. 1995, 2391. (c) Hydroformylation: Horiuchi, T.; Ohta, T.;
Shirakawa, E.; Nozaki, K.; Takaya, H. Tetrahedron 1997, 53, 7795. (d)
Hydrocyanation: Saha, B.; RajanBabu, T. V. Org. Lett. 2006, 8, 4657.
(12) He, Z.; Yi, C. S.; Donaldson, W. A. Synlett 2004, 1312.
f
25
Configuration assigned by comparison of known GC data and [R]D
values.3,6c,d 5 mol % of catalyst used. Rest isomerized product from
g
h
starting material, 1-methyl-3,4-dihydronaphthalene.
4-7 for enantiopure arylpropionic acids ibuprofen, naproxen
flurbiprofen, and fenoprofen (entries 2-5) represent the
Org. Lett., Vol. 10, No. 8, 2008
1659