Iridium catalysts with bicyclic pyridine-phosphinite ligands: Asymmetric hydrogenation of olefins and furan derivatives

Article abstract of DOI:10.1002/anie.200601529

(Chemical Equation Presented) Superior bicyclics: Iridium catalysts as 1 derived from pyridine-phosphinite ligands considerably extend the scope of asymmetric hydrogenation. In addition to various unfunctionalized and functionalized olefins, furans, and benzofurans, for which no catalysts were known before, are also hydrogenated with high enantioselectivity (see scheme).

Full text of DOI:10.1002/anie.200601529

Communications
of these catalysts. In these studies, we also found that the
choice of solvent and anion is crucial as only in weakly
coordinating solvents like dichloromethane or toluene with a
virtually non-coordinating anion such as BArF (tetrakis[bis-
3,5-(trifluoromethyl)phenyl]borate) could high turnover
numbers (> 5000) be obtained.[1a,5] Although high enantiose-
lectivities were obtained in the hydrogenation of certain
trisubstituted aryl alkenes such as (E)-methylstilbene, the
application range of Ir-phox catalysts proved to be limited.
However, subsequent work has led to new classes of N,P
ligands, which have broadened the scope of Ir-catalyzed
hydrogenation considerably.[1,6,7]
Asymmetric Hydrogenation Catalysts
DOI: 10.1002/anie.200601529
Among the many structures we investigated, oxazoline-
phosphinites such as 3[1,6a,b] and certain imidazoline ana-
logues[6c] proved to be particularly efficient, giving high
enantiomeric excesses with a wide range of unfunctionalized
as well as certain functionalized olefins. With the intention of
mimicking the coordination sphere of the Crabtree catalysts
more closely, we also examined a series of pyridine- and
quinoline-derived ligands 4 and 5.[8] As the results were quite
encouraging, we decided to extend our studies to bicyclic
analogues of type 6 because we thought that the more rigid
conformation imposed by the additional ring could result in
even higher enantioselectivities. Here we report the syntheses
of a series of pyridyl–phosphinites 6 and their evaluation as
ligands for Ir-catalyzed asymmetric hydrogenation.
Iridium Catalysts with Bicyclic Pyridine–
Phosphinite Ligands: Asymmetric Hydrogenation
of Olefins and Furan Derivatives**
Stefan Kaiser, Sebastian P. Smidt, and Andreas Pfaltz*
Iridium complexes with chiral N,P ligands have established
themselves as efficient catalysts for the asymmetric hydro-
genation of olefins, with largely complementary scope to Rh
and Ru diphosphane complexes.[1] In contrast to Rh and Ru
catalysts, they do not require a coordinating polar group next
=
to the C C bond. Initial experiments with cationic phospha-
As shown in the schemes below, ligands of this type are
readily accessible from simple, commercially available start-
ing materials via the corresponding pyridyl alcohols. By
changing the substituents at the pyridine ring and the P atom,
or altering the size of the carbocyclic ring, the steric and
electronic properties of these ligands and the coordination
geometry can be optimized for a specific substrate.
nyloxazoline (phox)[2] complexes ([Ir(1)(cod)]+XÀ) (cod =
cyclooctadiene) showed that these catalysts are highly active
in the hydrogenation of unfunctionalized tri- and even
tetrasubstituted olefins.[3] In this respect, they resemble
Crabtreeꢀs catalyst, [(Cy3P)(pyridine)Ir(cod)]PF6 (Cy = cy-
clohexyl),[4] which provided the stimulus for the development
Ligands with unsubstituted backbones (6, R1 = H) were
synthesized from commercially available precursors 12–14 via
pyridyl alcohols 7–9 (Scheme 1). Oxidation to the corre-
Scheme 1. Synthesis of pyridyl alcohols 7–9: a) 0.5–5 mol%MTO
(methyltrioxorhenium), 30%aq. H 2O2 (2 equiv), CH2Cl2, RT; b) TFAA
(trifluoroacetic anhydride) (2.5 equiv), CH2Cl2, 08C to RT, 4 h; 2m
LiOH, CH2Cl2, RT, 3 h.
[*] Dr. S. Kaiser, Dr. S. P. Smidt, Prof. Dr. A. Pfaltz
Department of Chemistry
sponding N-oxides 15–17 with aqueous hydrogen peroxide
and catalytic amounts of methyltrioxorhenium (MTO),[9]
subsequent Boekelheide rearrangement induced by trifluoro-
acetic anhydride (TFAA), and hydrolysis with aqueous LiOH
led to pyridyl alcohols 7–9 in overall yields of 40, 69, and 54%,
respectively.[10] Alternatively, 8 could be prepared from 8-
hydroxyquinoline by hydrogenation with PtO2 in CF3CO2H.
However, the yield of this reaction was only 27%.
University of Basel
St. Johanns-Ring 19, 4056 Basel (Switzerland)
Fax: (+41)61-267-1103
E-mail: andreas.pfaltz@unibas.ch
[**] Financial support from the Swiss National Science Foundation and
the Federal Commission for Technology and Innovation (KTI) is
gratefully acknowledged.
The analogous substituted pyridyl alcohols 10 and 11 were
synthesized from acetophenone by the five-step sequence
Supporting Information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 1: Iridium-catalyzed hydrogenation of (E)-2-(4-methoxyphenyl)-2-
shown in Scheme 2 in overall yields of 30 and 10%,
respectively.[11] In this case, 3-chloroperbenzoic acid gave
better yields of pyridine N-oxides than MTO/H2O2.
butene (27).[a,b]
Catalyst
n
R1
R2
ee [%][c]
26a (R)
26b (R)
26c (R)
26d (R)
26e[d] (R)
26 f (R)
26g (S)
26h (R)
26i (S)
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
2
2
2
3
H
H
H
H
Ph
Ph
Ph
H
H
H
Ph
oTol
Cy
tBu
oTol
Cy
tBu
Ph
oTol
Cy
tBu
furyl
Ph
oTol
Cy
tBu
Ph
78 (R)
74 (R)
68 (R)
72 (R)
>99 (R)
97 (R)
>99 (S)
82 (R)
83 (S)
70 (R)
75 (S)
71 (S)
86 (R)
97 (R)
95 (S)
97 (S)
96 (S)
>99 (S)
89 (R)
96 (S)
82 (S)
26j (R)
26k (S)
26l (S)
H
H
=
Scheme 2. Synthesis of pyridyl alcohols 10 and 11: a) [H2C N(CH3)2]Cl
26m[18] (R)
26n[18] (R)
26o[18] (S)
26p[18] (S)
26q (S)
26r (S)
Me
Me
Me
Me
Ph
Ph
Ph
Ph
H
(1 equiv), acetonitrile, reflux, 1 h; b) cyclopentanone morpholine enam-
ine or cyclohexanone pyrrolidine enamine, dioxane, reflux, 16 h; c) HO-
NH3Cl (1 equiv), ethanol, reflux, 3 h; d) m-CPBA (1.2 equiv), CH2Cl2,
08C to RT, overnight; e) TFAA (2.5 equiv), CH2Cl2, 08C to RT, 4 h; 2m
LiOH, CH2Cl2, RT, 3 h.
oTol
Cy
tBu
Ph
26 s (R)
26t (S)
26u (S)
The racemic pyridyl alcohols 7–11 were resolved by
preparative HPLC on a chiral column.[12] This method proved
to convenient for preparing ligands on a 0.5 to 5.0-g scale.
However, enantioselective routes based on kinetic resolution
or asymmetric reduction of the corresponding ketones are
available.[13,14] The enantiopure alcohols 7–11 were converted
into the corresponding phosphinites 6 either by treatment
with diaryl (N,N-diethylamino)phosphane/4,5-dichloroimida-
zole/NEt3 in CH2Cl2 or by deprotonation with NaH in THF/
DMF (9:1) and subsequent treatment with dialkyl chloro-
phosphane (Scheme 3). The corresponding Ir(cod) complexes
[a] See Equation (1) for conditions and Refs. [1a,3] for experimental
procedures. [b] Conversion was determined by GC.[3] [c] Determined by
chiral HPLC.[3] [d] The diphenylphosphinite analogue formed only
catalytically inactive [IrL2][BArF].
observed enantioselectivities. Introduction of a substituent
next to the pyridine N atom strongly increases the ee obtained
(cf. 26b vs. 26e and 26i vs. 26n and 26r). For catalysts 26m
and 26q, which contain a substituted pyridine ring, the
enantioselectivities rise substantially when the P-phenyl
groups are replaced by ortho-tolyl groups, an effect that has
also been observed for phox ligands.[3] Di-tert-butyl phos-
phinites (in particular 26g and 26t) give better results than
the analogous cyclohexyl phosphinites (26 f and 26s). For
unsubstituted pyridine derivatives 26a, 26h, and 26u the size
of the carbocyclic ring seems to have little influence.
However, for substituted analogues (R1 = Ph) larger differ-
ences are observed between the five- and six-membered ring
derivatives (cf. 26g vs. 26t and 26 f vs. 26 s). In general, the
five-membered ring derivatives induce higher enantioselec-
tivities, although exceptions have been found for other
substrates.[15] Three catalysts (26e, 26g, and 26r) react with
essentially 100% enantioselectivity.
Selected results for differently substituted unfunctional-
ized alkenes 29–33, allylic alcohol 34, and a,b-unsaturated
esters 35–37 are listed in Figure 1. A comparison with the
results obtained with pyridine- and quinoline-derived ligands
4 and 5 clearly demonstrates that the additional carbocyclic
ring improves the enantioselectivity. With the exception of
the terminal olefin 31 and the problematic tetrasubstituted
alkene 33, for which no highly selective Ir catalyst has yet
been reported,[16] the enantiomeric excesses match or, as in
Scheme 3. Synthesis of phosphinite complexes 26a–u: a) Ar2PNEt2/
4,5-dichloroimidazole/triethylamine (1:1:1, 2 equiv), CH2Cl2, 08C to RT,
1 to 9 d; b) Alk2PCl (1 equiv), NaH (1.3 equiv), THF/DMF (9:1), 08C
to RT, 1 to 4 d; c) [Ir(cod)Cl]2 (0.5 equiv), CH2Cl2, 508C, 2 h; NaBArF
(1.3 equiv), RT, 2 min; H2O, RT, 15 min.
26 were obtained following the standard protocol[3] as orange
to red crystalline solids. The absolute configuration of
complexes 26c, 26 f, 26k, 26o, 26t, and 26u was assigned by
X-ray analysis.[13] The absolute configuration of the corre-
sponding phosphinites and pyridyl alcohols was deduced
based on these structures.
Complexes 26a–u were evaluated as catalysts in the
hydrogenation of a series of alkenes that have previously been
used as test substrates.[1] Table 1, which lists a comprehensive
data set for alkene 27, reveals several important trends in the
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tively long reaction times were necessary. The benzofuran
carboxylate ester 42, in particular, reacted only sluggishly,
albeit with virtually perfect enantioselectivity. Overall, cata-
lysts like 26g and 26p open up an attractive enantioselective
route to tetrahydrofuran and benzodihydrofuran systems,
which are structural motifs found in many natural products
and biologically active compounds.
In summary, the results obtained so far indicate a
remarkably broad scope for Ir catalysts derived from
pyridine–phosphinite ligands 6. Moreover, we have recently
found that complexes 26e, 26g, and 26r are also highly
efficient catalysts for the asymmetric hydrogenation of purely
alkyl-substituted olefins.[15] Thus, we are confident that these
catalysts will find many further applications in asymmetric
hydrogenation.
Received: April 18, 2006
Published online: July 5, 2006
Keywords: asymmetric catalysis · hydrogenation · iridium ·
.
ligand design · N,P ligands
Figure 1. Selected hydrogenation results; see Table 1 for reaction
conditions. [a] 30 min, 1 bar H2; [b] 2 mol%catalyst.
the case of substrate 30, surpass the best values reported to
date.[1]
[1]a) A. Pfaltz, J. Blankenstein, R. Hilgraf, E. Hörmann, S.
McIntyre, F. Menges, M. Schönleber, S. P. Smidt, B. Wüstenberg,
N. Zimmermann, Adv. Synth. Catal. 2002, 344, 33 – 44; b) X. Cui,
K. Burgess, Chem. Rev. 2005, 105, 3272 – 3297; c) K. Källström, I.
Munslow, P. G. Andersson, Chem. Eur. J. 2006, 12, 3194 – 3200.
[2]G. Helmchen, A. Pfaltz, Acc. Chem. Res. 2000, 33, 336 – 345.
[3]A. Lightfoot, P. Schnider, A. Pfaltz, Angew. Chem. 1998, 110,
3047 – 3050; Angew. Chem. Int. Ed. 1998, 37, 2897 – 2899.
[4]R. H. Crabtree, Acc. Chem. Res. 1979, 12, 331 – 337.
[5]S. P. Smidt, N. Zimmermann, M. Studer, A. Pfaltz, Chem. Eur. J.
2004, 10, 4685 – 4693.
[6]a) J. Blankenstein, A. Pfaltz, Angew. Chem. 2001, 113, 4577 –
4579; Angew. Chem. Int. Ed. 2001, 40, 4445 – 4447; b) F. Menges,
A. Pfaltz, Adv. Synth. Catal. 2002, 344, 40 – 44; c) F. Menges, M.
Neuburger, A. Pfaltz, Org. Lett. 2002, 4, 4713 – 4716; d) S. P.
Smidt, F. Menges, A. Pfaltz, Org. Lett. 2004, 6, 2023 – 2026; e) R.
Hilgraf, A. Pfaltz, Adv. Synth. Catal. 2005, 347, 61 – 77.
[7]For related work from other research groups, see: a) Y. Fan, X.
Cui, K. Burgess, M. B. Hall, J. Am. Chem. Soc. 2004, 126, 16688 –
16689; b) X. Cui, Y. Fan, M. B. Hall, K. Burgess, Chem. Eur. J.
2005, 11, 6859 – 6868; c) K. Källström, C. Hedberg, P. Brandt, A.
Bayer, P. G. Andersson, J. Am. Chem. Soc. 2004, 126, 14308 –
14309; d) C. Hedberg, K. Källström, P. Brandt, L. K. Hansen,
P. G. Andersson, J. Am. Chem. Soc. 2006, 128, 2995 – 3001; e) D.
Liu, W. Tang, X. Zhang, Org. Lett. 2004, 6, 513 – 516; f) T.
Bunlaksananusorn, K. Polborn, P. Knochel, Angew. Chem. 2003,
115, 4071 – 4073; Angew. Chem. Int. Ed. 2003, 42, 3941 – 3943;
g) T. Focken, G. Raabe, C. Bolm, Tetrahedron: Asymmetry 2004,
15, 1693 – 1706; h) P. G. Cozzi, F. Menges, S. Kaiser, Synlett 2003,
833 – 836.
Subsequent screening of other potential substrates
showed that these catalysts also allow the asymmetric
reduction of furan derivatives, a class of substrate for which
no efficient enantioselective catalysts were known. In pre-
vious studies of furyl-substituted alkenes, we had found that
with certain Ir complexes derived from oxazoline–dialkyl-
=
phosphinite ligands 3, both the olefinic C C bond and the
furan p system were reduced.[17] The stereoselectivities were,
however, moderate. Catalysts 26g and 26p proved to be more
efficient and induced good to excellent enantioselectivities in
the hydrogenation of a series of substituted furans and
benzofurans (Figure 2). As expected, the benzene ring of
substrates 40 and 42 was not reduced. Ligands with bulky
electron-rich (tBu)2P groups were found to be best suited for
this class of substrate. Ligands with cyclohexyl substituents at
the P atom gave lower conversion and ee, whereas catalysts
with analogous diphenylphosphinite ligands showed essen-
tially no activity. Because of the low reactivity of the furan
and benzofuran p systems, elevated temperatures and rela-
[8]a) W. J. Drury III, N. Zimmermann, M. Keenan, M. Hayashi, S.
Kaiser, R. Goddard, A. Pfaltz, Angew. Chem. 2004, 116, 72 – 76;
Angew. Chem. Int. Ed. 2004, 43, 70 – 74; b) for other pyridine-
derived N,P ligands, see the review: G. Chelucci, G. Orrœ, G. A.
Pinna, Tetrahedron 2003, 59, 9471 – 9515, and ref. [7f].
[9]C. CopØret, H. Adolfsson, T. A. V. Khuong, A. K. Yudin, K. B.
Sharpless, J. Org. Chem. 1998, 63, 1740 – 1741.
Figure 2. Representative hydrogenation results for furan and benzo-
furan derivatives. [a] 1 mol%catalyst, 50 bar H 2, 24 h, 408C;
[b] 2 mol%catalyst, 100 bar H 2, 24 h, 408C.
[10]a) V. C. Boekelheide, W. J. Linn, J. Am. Chem. Soc. 1954, 76,
1286 – 1291; b) M. Uchida, S. Morita, M. Chihiro, T. Kanbe, K.
Yamasaki, Y. Yabuuchi, K. Nakagawa, Chem. Pharm. Bull. 1989,
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37, 1517 – 1523; c) C. Fontenas, E. Bejan, H. A. Haddou,
G. G. A. Balavoine, Synth. Commun. 1995, 25, 629 – 633.
[11]a) D. Sielemann, R. Keuper, N. Risch, J. Prakt. Chem. 1999, 341,
487 – 491; b) G. Kinast, L. F. Tietze, Angew. Chem. 1976, 88,
261 – 262; Angew. Chem. Int. Ed. Engl. 1976, 15, 239 – 240.
[12]See the Supporting Information; 9 had to be converted into the
corresponding diastereomeric (1S)-camphanoate before HPLC
separation.
[13]S. Kaiser, Dissertation, University of Basel, 2005.
[14]C. Mazet, S. Roseblade, V. Köhler, A. Pfaltz, Org. Lett. 2006, 8,
1879 – 1882.
[15]S. Bell, B. Wüstenberg, S. Kaiser, F. Menges, T. Netscher, A.
Pfaltz, Science 2006, 311, 642 – 644.
[16]For highly enantioselective Zr catalysts, see: M. V. Troutman,
D. H. Appella, S. L. Buchwald, J. Am. Chem. Soc. 1999, 121,
4916 – 4917.
[17]B. Wüstenberg, A. Pfaltz, published in: B. Wüstenberg, Dis-
sertation, University of Basel, 2003.
[18]For preparation of complexes 26m–p see the Supporting
Information.
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