Iridium-catalyzed asymmetric hydrogenation of fluorinated olefins using N,P-ligands: A struggle with hydrogenolysis and selectivity

Article abstract of DOI:10.1021/ja0686763

To broaden the substrate scope of asymmetric iridium-catalyzed hydrogenation, fluorine-functionalized olefins were synthesized and hydrogenated with iridium complexes. Preliminary results showed high levels of fluorine elimination together with low selectivity. The loss of vinylic fluorine at first seemed difficult to handle, but further studies revealed that a catalyst with an azanorbornyl scaffold in the ligand gave more promising results. With this in mind, a new ligand was developed. This gave among the best results published to date for fluorine asymmetric hydrogenation, yielding high conversion and very high ee's with very little fluorine elimination. Further increasing the selectivity, the trials also revealed that tetrasubstituted fluorine-containing olefins can be hydrogenated with high ee's, despite that this class of compounds has usually shown low reactivity in this reaction type. Copyright

Full text of DOI:10.1021/ja0686763

Published on Web 03/22/2007
Iridium-Catalyzed Asymmetric Hydrogenation of Fluorinated Olefins Using
N,P-Ligands: A Struggle with Hydrogenolysis and Selectivity
Mattias Engman, Jarle S. Diesen, Alexander Paptchikhine, and Pher G. Andersson*
Department of Biochemistry and Organic Chemistry, Uppsala UniVersity, Box 576, S-751 23 Uppsala, Sweden
Received December 4, 2006; E-mail: pher.andersson@biorg.uu.se
Table 1. Hydrogenation of Fluorine-Containing Olefinsa
The enantioselective hydrogenation of olefins is one of the most
powerful and studied transformations in asymmetric catalysis. The
reaction is typically accomplished using complexes of chiral P,P-
or N,P-chelating ligands with metals like ruthenium and rhodium.1
In the past decade, iridium complexes have proven to be efficient
catalysts for the enantioselective hydrogenation of olefins.2 The
iridium catalyst developed by Crabtree in 19773 was modified by
Pfaltz in 1998 to give an iridium-phosphanodihydrooxazole (PHOX)
catalyst that could hydrogenate tri- and tetrasubstituted olefins with
enantiomeric excesses (ee’s) up to 98%.4 Since then, several other
stereoselective iridium-based N,P-ligand catalysts have been re-
ported for the hydrogenation of a limited range of substrates.5
Organofluorine compounds are increasing in popularity within
the pharmaceutical industry, and a growing number of active
pharmaceutical products now contain fluorine, such as top selling
antidepressants like Fluoxetine and Paroxetine.6 Fluorine can alter
the properties of a molecule significantly7 and “smuggling fluorine
into a lead structure enhances the probability of landing a hit almost
10-fold.”8 However, the synthetic methods available for introducing
a fluorine-containing stereocenter are still few, and most involve
asymmetric fluorination of â-keto esters or â-keto phosphonates.9
MethodsforcreatingaCHF-bearingstereocenterbyasymmetrichydrog-
enation are even rarer.10 In a recent patent, Nelson et al. reported
on the asymmetric hydrogenation of cyclic vinylfluorides using Rh-
Walphos.11 We therefore wanted to evaluate our newly developed
a General conditions: 0.5-2.0 mol % catalyst, room temp to 40 °C, dry
CH2Cl2, 20-100 bar H2. Ratio and conversion were determined by 1H NMR.
iridium catalysts in the asymmetric hydrogenation of vinylic fluorine
compounds to explore the ability of these catalysts to create
stereocenters bearing fluorine atoms. Surprisingly, the hydrogena-
tion of fluorine-containing olefins has only been reported a few
times. The reason for this might be the ability of vinylic fluorine
to be cleaved off.12 Herein, we report for the first time the successful
asymmetric hydrogenation with ee’s up to 99% of vinyl fluorides
utilizing iridium-based catalysis (Table 1, entries 2 and 3).
To develop this hydrogenation reaction, we first confronted the
problem of hydrogenolysis. There are two plausible pathways for
the loss of fluorine (Scheme 1). One possibility is that the vinyl
fluoride initially undergoes hydrogenation and the fluorine atom is
lost from the formed product. A second possibility is that the
fluorine atom is first lost from the fluorinated olefin, forming 3,
which is subsequently hydrogenated to compound 4. The latter route
is the most probable, because the vinylic fluorine is more unstable
than its saturated counterpart.
Hydrogenation of an E/Z mixture of ester 1 shows V5i removes
fluorine from the substrate efficiently. This is particularly pro-
nounced in R,R,R-trifluorotoluene solution, with 62% defluorination
being observed. When the solvent was changed to CH2Cl2,
defluorination could be decreased to 40% (Chart 1, complex V),
but the reaction proceeded slowly. We prepared the racemate of 2,
and subjected it to hydrogenation with complex V. Only 2 could
be detected, indicating that the loss of fluorine, as expected, follows
the latter proposed path shown in Scheme 1.
b Details are given in the Supporting Information.
Scheme 1. The Plausible Defluorination/Hydrogenation and
Hydrogenation/Defluorination Routes to 4.
Similar disappointing results were observed using the analogous
thiazole complex IV. However, the use of iridium complexes based
on the azanorbornyl scaffold (I-III)5j,m resulted in less defluori-
nation. Complex I gave the best results, concerning both the level
of defluorination and conversion. It was chosen for further
evaluation with some trisubstituted substrates (Table 1). The ester
(entry 1) required high pressures (100 bar) and elevated tempera-
tures (40 °C) to undergo hydrogenation, whereas the acetate (entry
2) and the alcohol (entry 3) reacted more readily. The highest
reaction rates and conversions were observed for the alcohol (entry
3). Full conversion was reached with 20 bar H2, 0.5 mol % catalyst,
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10.1021/ja0686763 CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Chart 1. Overview of Conversions and C-F Bond Cleavage in
the Hydrogenations of 1a
We have shown that asymmetric hydrogenation of fluorinated
olefins with iridium complexes is possible, often with low catalyst
loadings and with low levels of defluorination. Further studies to
prepare and evaluate other substrates, and to design complexes that
are able to hydrogenate a broader range of fluorinated olefins, are
ongoing in our group.
Acknowledgment. The article is dedicated to Prof. Miguel Yus
on the occasion of his 60th birthday. The Swedish Research Council
(VR), Astra&Zeneca, and Ligbank (activity 3, Contract FP6-
505267-1) supported this work. We also would like to thank Dr. I.
J. Munslow and Dr. T. Church for careful reading of the manuscript,
and Assoc. Prof. A. Gogoll for the help with the 1H-19F NOE
experiments.
Supporting Information Available: Experimental details and
spectral data for the preparation of the reported compounds. This
material is available free of charge via the Internet at http://pubs.acs.org.
a Conditions: 100 Bar H2, 72 h, 40 °C in CH2Cl2.
References
(1) (a) Brown, J. M. In ComprehensiVe Asymmetric Catalysis; Jacobsen, E.
N., Pfaltz, A., Yamamoto, H., Eds.; Springer-Verlag: Berlin, 1999; Vol.
I, pp 121-182. (b) Review: Cui, X.; Burgess, K. Chem. ReV. 2005, 105,
3272-3296.
and 24 h at room temp. The ee’s varied from poor (29%, entry 1)
to good (87% for entry 2 and 80% for entry 3).
Catalysts I-III all have a nitrogen atom as the linker between
the ligand backbone and the phosphorus-containing group, whereas
IV and V have a methylene group and an oxygen atom, respectively.
Given that the azanorbornyl-ligand-based complexes I-III dis-
played overall better activity and caused less defluorination than
complexes IV and V, we reasoned that an oxazole or thiazole
scaffold containing an amine linker would be an interesting
candidate to be evaluated in this type of reactions. Because thiazole-
based catalysts have generally performed better than the oxazole-
based catalysts for olefin hydrogenation,5i,k thiazole was used as
the backbone for the new amine-linked ligand. The synthesis of
complex VI is outlined in Scheme 2.
(2) Ka¨llstro¨m, K.; Munslow, I.; Andersson, P. G. Chem.sEur. J. 2006, 12,
3194-3200.
(3) Crabtree, R. H.; Felkin, H.; Morris, G. E. J. Organomet. Chem. 1977,
141, 205-215.
(4) Lightfoot, A.; Schnider, P.; Pfaltz, A. Angew. Chem. 1998, 110, 3047-
3050; Angew. Chem., Int. Ed. 1998, 37, 2897-2899.
(5) (a) Blankenstein, J.; Pfaltz, A. Angew. Chem., Int. Ed. 2001, 40, 4445-
4447. (b) Menges, F.; Neuburger, M.; Pfaltz, A. Org. Lett. 2002, 4, 4713-
4716. (c) Hou, D.-R.; Burgess, K. Org. Lett. 1999, 1, 1745-1747. (d)
Tang, W.; Wang, W.; Zhang, X. Angew. Chem., Int. Ed. 2003, 42, 943-
946. (e) Xu, G.; Gilbertson, S. R. Tetrahedron Lett. 2003, 953-955. (f)
Bunlaksananurson, T.; Polborn, K.; Knochel, P. Angew. Chem., Int. Ed.
2003, 42, 3941-3943. (g) Pfaltz, A.; Blankenstein, J.; Hilgraf, R.;
Ho¨rmann, E.; McIntyre, S.; Menges, F.; Scho¨nleber, M.; Smidt, S. P.;
Wu¨stenberg, B.; Zimmermann, N. AdV. Synth. Catal. 2003, 345 (1, 2),
33-43. (h) Durry, W. J., III; Zimmerman, N.; Keenan, M.; Hayashi, M.;
Kaiser, S.; Goddard, R.; Pfaltz, A. Angew. Chem., Int. Ed. 2004, 43, 70-
74. (i) Ka¨llstro¨m, K.; Hedberg, C.; Brandt, P.; Bayer, A.; Andersson, P.
G. J. Am. Chem. Soc. 2004, 126, 14308-14309. (j) Trifonova, A.; Diesen,
J. S.; Andersson, P. G. Chem.sEur. J. 2006, 12, 2318-2328. (k) Hedberg,
C.; Ka¨llstro¨m, K.; Brandt, P.; Hansen, L. K.; Andersson, P. G. J. Am.
Chem. Soc. 2006, 128, 2995-3001. (l) Hou, D.-R.; Reibenspies, J.;
Burgess, K. J. Org. Chem. 2001, 66, 206-215. (m) Trifonova, A.; Diesen,
J. S.; Chapman, C. J.; Anderson, P. G. Org. Lett. 2004, 6, 3825-3827.
(6) (a) Patrick, G. L. An Introduction to Medicinal Chemistry, 3rd ed.; Oxford
University Press: Oxford, U.K., 2005; Chapter 9. (b) Review: Butler,
M. S. J. Nat. Prod. 2004, 67, 2141-2153.
Scheme 2. Synthesis of Complex VIa
(7) Quotation by M. Schlosser in the article “Fabulous Fluorine” by Thayer,
A. M. Chem. Eng. News 2006, June 5, 15-24.
(8) (a) Review: Patani, G. A.; LaVoie, E. J. Chem. ReV. 1996, 96, 3147-
3176. (b) Minireview Ojima, I. Chem. Bio. Chem. 2004, 5, 628-635. (c)
Minireview Bo¨hm, H.-J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.;
Mu¨ller, K.; Obst-Sander, U.; Stahl, M. ChemBioChem 2004, 5, 637-643.
(9) (a) Hintermann, L.; Togni, A. Angew. Chem., Int. Ed. 2000, 39, 4359-
4362. (b) Kim, D. Y.; Park, E. J. Org. Lett. 2002, 4, 545-547. (c) Ma,
J.-A.; Cahard, D. Tetrahedron: Asymmetry 2004, 15, 1007-1011. (d)
Shibata, N.; Ishimaru, T.; Nagai, T.; Kohno, J.; Toru, T. Synlett 2004,
10, 1703-1706. (e) Huang, Y.; Walji, A. M.; Larsen, C. H.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2005, 127, 15051-15053. (f) Hamashima,
Y.; Suzuki, T.; Shimura, Y.; Shimizu, T.; Umebayashi, N.; Tamura, T.;
Sasamoto, N.; Sodeoka, M. Tetrahedron Lett. 2005, 46, 1447-1450. (g)
Brochu, M. P.; Brown, S. P.; MacMillan, D. W. C. J. Am. Chem. Soc.
2004, 126, 4108-4109. (h) Beeson, T. D.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2005, 127, 8826-8828.
a Conditions and reagents: See Supporting Information.
Complex VI was screened with the trisubstituted substrates and
showed excellent selectivity, ee g 99% (entries 2 and 3).
Despite that tetrasubstituted olefins have proven difficult to hy-
drogenate catalytically, tetrasubstituted fluoroolefins underwent
hydrogenation (100 bar, 40 °C, 72 h) with >99% diastereomeric
excess (de). Selectivity is increased from 29 to 57% ee (entries 1
and 4) for complex I when a methyl group is added to the substrate.
For complex VI, the selectivities were surprisingly lower with the
methylated substrates. Oddly, it did not catalyze the reaction of
entry 1, whereas the tetrasubstituted equivalent (entry 4) gave 30%
conversion. Hydrogenations of the tetrasubstituted olefins all
proceeded via a clean syn-addition of H2 across the double bond.
(10) Review: Mikami, K.; Itoh, Y.; Yamanaka, M. Chem. ReV. 2004, 104,
1-16.
(11) Nelson, T. D.; Kress, M. H.; Krska, S. W.; Mitten, J. V.; Sun, Y. PCT
Int. Appl. 2006, WO 2006069287 A1, CAN 145:103564.
(12) Allmendinger, T.; Dandois, C.; Walliser, B. Tetrahedron Lett. 1991, 24,
2735-2736.
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