Synthesis of a New Class of Conformationally Rigid Phosphino-oxazolines: Highly Enantioselective Ligands for Ir-Catalyzed Asymmetric Hydrogenation

Article abstract of DOI:10.1021/ol0362717

(Equation presented) A new class of conformationally rigid phosphino-oxazoline ligands were synthesized from readily available enantiopure phenyl glycinol. Ir complexes with these ligands are air-stable and highly enantioselective catalysts for asymmetric

Full text of DOI:10.1021/ol0362717

ORGANIC
LETTERS
2004
Vol. 6, No. 4
513-516
Synthesis of a New Class of
Conformationally Rigid
Phosphino-oxazolines: Highly
Enantioselective Ligands for Ir-Catalyzed
Asymmetric Hydrogenation
Duan Liu, Wenjun Tang, and Xumu Zhang*
Department of Chemistry, The PennsylVania State UniVersity,
UniVersity Park, PennsylVania 16802
xumu@chem.psu.edu
Received November 20, 2003
ABSTRACT
A new class of conformationally rigid phosphino-oxazoline ligands were synthesized from readily available enantiopure phenyl glycinol. Ir
complexes with these ligands are air-stable and highly enantioselective catalysts for asymmetric hydrogenation of aryl alkenes and r,â-
unsaturated esters in up to 99% ee.
Among the most commonly used transition metal catalysts
for asymmetric hydrogenation, Ir-based systems are relatively
underdeveloped compared to Rh- or Ru-based systems.1 One
well-known Ir complex is the Crabtree catalyst,2 which is
highly efficient for hydrogenation of unfunctionalized polysub-
stituted olefins, a type of substrate remaining difficult to
reduce with Rh or Ru catalysts.3 The high reactivity of the
Crabtree catalyst was attributed to its unique structure
containing a phosphorus donor and a nitrogen donor. Pfaltz
et al. used optically active phosphino-oxazoline ligands 1
(PHOX) (Figure 1) to mimic a chiral version of the Crabtree
catalyst and obtained up to 99% enantiomeric excesses for
some functionalized and unfunctionalized olefins.4 Following
this discovery, a number of chiral P,N-containing ligands
emerged and were successfully applied to the Ir-catalyzed
asymmetric hydrogenation of olefins.5 Burgess also reported
asymmetric hydrogenation of aryl alkenes with novel chiral
carbene-oxazoline ligands.6 However, most of these catalysts
suffered from high substrate dependence and relatively low
TON (few exceeded 1000). Thus, the development of new
efficient chiral ligands for Ir-catalyzed hydrogenation is still
needed and challenging. Herein, we report a new class of
easily accessible chiral phosphino-oxazoline ligands 2 and
(1) For recent reviews, see: (a) Ohkuma, T.; Kitamura, M.; Noyori, R.
In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima, I., Ed.; Wiley: New
York, 2000. (b) ComprehensiVe Asymmetric Catalysis; Jacobsen, E. N.,
Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 1999; Vol. 1. (c) Noyori,
R. Asymmetric Catalysis in Organic Synthesis; Wiley-Interscience: New
York, 1994.
(2) Crabtree, R. Acc. Chem. Res. 1979, 12, 331.
(3) Forman, G. S.; Ohkuma, T.; Hems, W. P.; Noyori, R. Tetrahedron
Lett. 2000, 41, 9471.
Figure 1. Chiral P,N ligands for asymmetric hydrogenation.
10.1021/ol0362717 CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/21/2004

their application to Ir-catalyzed asymmetric hydrogenation.
Versatile methods have been developed for making these
ligands from the inexpensive phenyl glycinol.
needed. Although the R-N,N-dimethyl amino group is
commonly used as an ortho directing group for metalation
of aromatic rings,12 direct use of primary amines for such a
purpose was much less explored and not used to construct
chiral ligands.13 Polniaszek et al. prepared (2-chloro- or 2,6-
dichlorophenyl)ethylamine from phenylethylamine via ortho
lithiation directed by the in situ-generated N-lithiosilyl-
amine.14 After modification of their method, we successfully
carried out, for the first time, an ortho lithiation of silyl-
protected phenyl glycinol. Subsequent reaction with I2 or
different phosphine chlorides efficiently gave rise to (2-iodo
or 2-phosphino)phenyl glycinol derivatives, which are novel
and highly modular chiral synthons for ligand synthesis. On
the basis of this method, two slightly different routes were
developed for making ligands 2 (Scheme 1). In route A, (R)-
The conformational rigidity of a chiral ligand has been
demonstrated to be an important factor for high enantio-
selectivity in asymmetric catalysis.7 Bidentate ligands with
a more rigid linker between the two coordinating sites can
form a more rigid metallocycle with fewer available con-
formations and thus enhance the enantiofacial differentiation.
JM-Phos 3, reported by Burgess, exhibited very good
enantioselectivities in Pd-catalyzed allylic alkylation reac-
tions8 and Ir-catalyzed hydrogenation of several olefins.5g
However, the ethylene linker between the phosphine and
oxazoline moieties is too flexible to deliver the maximal
asymmetric induction from the chiral ligand. In the studies
of closely related ligands 4,9 Pfaltz found that both diaster-
eomers of 4b induced significantly higher enantioselectivities
than ligands 4a for a number of hydrogenation substrates.
One possible explanation for such an observation is that the
additional substituent (R4 ) Me) on the oxazoline ring
restricts the conformational flexibility of the five-membered
ring and improves the overall enantiofacial differentiation
of the chiral catalyst. On the basis of these considerations,
we envision that ligands 2 might be superior to JM-Phos
due to their more rigid 1,2-phenyl linker. Furthermore, X-ray
studies have shown that Ir complexes with 35g and 49b have
significantly different chiral environments from those in Ir
complexes with PHOX 1. Since ligands 2 are structurally
closer to PHOX than 3 and 4, they would provide a more
direct comparison with PHOX in their catalytic behavior.
The inexpensive enantiopure phenyl glycinol is widely
used as a building block in chiral ligand synthesis.5,10
However, ortho-substituted phenyl glycinol derivatives are
rarely used due to the lack of efficient synthesis.11 One of
the most direct ways to make ligands 2 would be based on
ortho substitution of phenyl glycinol. Thus, developing an
efficient method of ortho substitution of phenyl glycinol was
Scheme 1
(4) Lightfoot, A.; Schnider, P.; Pfaltz, A. Angew. Chem., Int. Ed. 1998,
37, 2897.
(5) (a) For a recent review of hydrogenation of olefin with P,N ligands,
see: Pfaltz, A.; Blankenstein, J.; Hilgraf, R.; Hormann, E.; McIntyre, S.;
Menges, F.; Schonleber, M.; Smidt, S. P.; Wustenberg, B.; Zimmermann,
N. AdV. Synth. Catal. 2003, 345, 33 and references therein. (b) Bunlak-
sananusorn, T.; Polborn, K.; Knochel, P. Angew. Chem., Int. Ed. 2003, 42,
3941. (c) Xu, G.; Gilbertson, S. R. Tetrahedron Lett. 2003, 44, 953. (d)
Brauer, D. J.; Kottsieper, K. W.; Bossenbach, S.; Stelzer, O. Eur. J. Inorg.
Chem. 2003, 1748. (e) Tang, W.; Wang, W.; Zhang, X. Angew. Chem.,
Int. Ed. 2003, 42, 943. (f) Menges, F.; Neuburger, M.; Pfaltz, A. Org. Lett.
2002, 4, 4713. (g) Hou, D.; Reibenspies, J.; Colacot, T. J.; Burgess, K.
Chem. Eur. J. 2001, 7, 5391.
(6) (a) Perry, M. C.; Cui, X.; Powell, M. T.; Hou, D.; Reibenspies, J.
H.; Burgess, K. J. Am. Chem. Soc. 2003, 125, 113. (b) Powell, M. T.; Hou,
D.; Perry, M. C.; Cui, X.; Burgess, K. J. Am. Chem. Soc. 2001, 123, 8878.
(7) (a) Zhang, X. Enantiomer 1999, 4, 541. (b) Brown, J. M.; Chaloner,
P. A. Homogeneous Catalysis with Metal Phosphine Complexes; Pignolet,
L. H., Ed.; Plenum: New York, 1983; p 137.
phenyl glycinol 5 was protected with TBSCl to give
intermediate 6, which was directly subjected to ortho
lithiation with 3 equiv of n-BuLi. Subsequent iodination
followed by aqueous workup afforded aryl iodide 7. Oxazo-
line formation using literature methods4 gave the key
intermediate 8. Lithium-halogen exchange of 8 with t-BuLi
followed by reaction with Ph2PCl afforded the desired ligand
2a. Presumably, variation of the phosphine chloride in the
(8) (a) Hou, D.; Reibenspies, J. H.; Burgess, K. J. Org. Chem. 2001, 66,
206. (b) Hou, D.; Burgess, K. Org. Lett. 1999, 1, 1745.
(9) (a) Menges, F.; Pfaltz, A. AdV. Synth. Catal. 2002, 344, 40. (b)
Blankenstein, J.; Pfaltz, A. Angew. Chem., Int. Ed. 2001, 40, 4445.
(10) (a) Jiang, Y.; Jiang, Q.; Zhang, X. J. Am. Chem. Soc. 1998, 120,
3817. (b) Davies, I. W.; Gerena, L.; Cai, D.; Larsen, R. D.; Verhoeven, T.
R.; Reider, P. J. Tetrahedron Lett. 1997, 38, 1145. (c) Evans, D. A.; Lectka,
T.; Miller, S. J. Tetrahedron Lett. 1993, 34, 7027.
(12) (a) Ireland, T.; Grossheimann, G.; Wieser-Jeunesse, C.; Knochel,
P. Angew. Chem., Int. Ed. 1999, 38, 3212. (b) Almena Perea, J. J.; Bo¨rner,
A.; Knochel, P. Tetrahedron Lett. 1998, 39, 8073. (c) Gschwend, H. W.;
Rodriguez, H. R. Org. React. (N.Y.) 1979, 26, 1.
(13) Burns, S. A.; Corriu, R. J. P.; Huynh, V.; Moreau, J. J. E. J.
Organomet. Chem. 1987, 333, 281.
(11) O’Brien, P.; Osborne, S. A.; Parker, D. D. J. Chem. Soc., Perkin
Trans. 1 1998, 2519.
(14) (a) Polniaszek, R. P.; Lichti, C. F. Synth. Commun. 1992, 22, 171.
(b) Polniaszek, R. P.; Kaufman, C. R. J. Am. Chem. Soc. 1989, 111, 4859.
514
Org. Lett., Vol. 6, No. 4, 2004

last step would allow a facile tuning of the phosphine site.
In route B, a phosphine chloride, instead of I2, was used as
the electrophile after the ortho lithiation step. Subsequent
protection of the phosphine with sulfur followed by aqueous
workup generated phosphine sulfide 9, which could be
converted into a series of oxazolines 10 with various R2
substituents by reaction with essentially unlimited carboxylic
acids. Reduction of 10 with Raney Ni15 afforded ligands 2b-
e. The combination of both routes provided convenient ways
of tuning on either the phosphine site or the oxazoline site
from intermediates 8 or 9. This is useful when building a
ligand set to search for the best one for a particular reaction
or substrate.
Increasing the H2 pressure dramatically improved the conver-
sion, while the enantioselectivity did not change significantly.
Performing the reaction at an elevated temperature also
resulted in a great increase in conversion. Pfaltz et al.
reported that the formation of inactive hydride-bridged Ir
trimers during the catalytic cycle might be one of the major
reasons for the deactivation of catalyst and isolated a trimeric
Ir(PHOX)-hydride complex after treating the corresponding
Ir complex with H2 (Figure 2).5a On the basis of this
To evaluate the catalytic properties of ligands 2 in
asymmetric catalysis, their Ir complexes 11 were prepared
according to a literature procedure, in which a weakly
coordinating group BARF (tetrakis[3,5-bis(trifluoromethyl)-
phenyl]borate) was used as the counterion. These complexes
are air-stable and can be stored in air for months without
losing their catalytic properties. Methylstilbene 12a, a typical
substrate for Ir-catalyzed asymmetric hydrogenation of
unfunctionallized olefins, was initially tested with complexes
11a-e under 50 bar of H2 pressure at room temperature in
CH2Cl2. As shown in Table 1, all the catalysts gave excellent
Figure 2. Formation of a hydride-bridged Ir trimer
hypothesis and our observations, we suppose the following:
(1) a relatively larger R2 substituent on the oxazoline ring
might be beneficial not only for the enantioselectivity but
also for the reactivity; (2) more electron-donating ligands
might form more reactive catalyst or more stable catalytic
species by preventing the formation of the hydride-bridged
Ir trimer, presumably through a trans effect; (3) increasing
the H2 pressure might accelerate the desired catalytic cycle
relative to the formation of the Ir trimer; (4) a higher reaction
temperature might either accelerate the desired catalytic cycle
or possibly decelerate the formation of the Ir trimer. These
hypotheses can give us some guidance for further ligand
modification and optimization of reaction conditions for a
particular substrate, though more experimental data and
detailed mechanistic studies are needed. Another methyl-
stilbene derivative 12b was then examined with a few of
the best catalysts (11a, 11d, and 11e). Complete conversions
and very high enantioselectivities were obtained with 11a
and 11d (entries 10 and 11), while 11e, the most reactive
catalyst, gave a slightly lower selectivity (entry 12). Thus,
the overall results for asymmetric hydrogenation of biaryl
alkenes with ligands 2 compare favorably with those obtained
with JM-Phos 3 (95% ee for 12a and 93% ee for 12b).5g
Table 1. Asymmetric Hydrogenation of Methylstilbene
Derivatives with 11a
H2
conversion
[%]b
ee
[%]c
entry substrate catalyst pressure temp
1
2
3
4
5
6
7
8
9
12a
12a
12a
12a
12a
12a
12a
12a
12a
12b
12b
12b
11a
11a
11a
11a
11b
11c
11d
11e
11e
11a
11d
11e
10 bar rt
50 bar rt
90 bar rt
50 bar 50 °C
50 bar rt
50 bar rt
50 bar rt
50 bar rt
100 bar rt
100 bar rt
100 bar rt
100 bar rt
31
64
94
98
77
98
98
97
98
83
97
97
99
98
97
97
90
68
98
>99
>99
>99
>99
>99
10
11
12
Scheme 2
a See Supporting Information for experimental details. b Conversions were
determined by GC. c Enantiomeric excesses were determined by chiral
HPLC (Chiralcel OJ-H), and the absolute configuration was assigned by
comparison of the retention times of two enantiomers with reported data.
enantioselectivity (97-99% ee), except for 11b (83% ee).
Although the conversions were not satisfactory with 11a,
11b, and 11c, high conversions were obtained with 11d and
11e (entries 7 and 8). Pressure and temperature effects were
examined with 11a on the same substrate (entries 1-4).
Asymmetric hydrogenation of â-methyl cinnamic esters,
(15) Gilbertson, S. R.; Fu, Z. Org. Lett. 2001, 3, 161.
Org. Lett., Vol. 6, No. 4, 2004
followed by reduction of the ester function, can efficiently
515

substrates with the air-stable catalysts 11. Methyl-(E)-â-
methyl cinnamate 14a was initially selected as the substrate
to screen ligands and reaction conditions. Complete conver-
sions and extremely high enantioselectivities were observed
with complexes 11a and 11d under 100 bar at room
temperature (entries 1-3). The ee values are significantly
higher than with PHOX as a ligand (84% ee). However, when
substrate 14b having a para-fluoro substituent on the phenyl
ring was subjected to hydrogenation, the conversion was not
complete even at elevated temperature. The highest enantio-
selectivity and conversion for 14b were obtained with 11d
at 50 °C under 100 bar (entry 7). We therefore used 11d as
a catalyst and these optimized conditions for hydrogenation
of several other aryl-(E)-â-methylcinnamic esters 14c-g.
Excellent ee values (94-99%) were obtained regardless of
the substitution pattern on the phenyl ring, which were
comparable to the best reported to date.5a,e The reactivities
seemed quite substrate dependent. However, no obvious trend
could be observed.
In conclusion, we have developed a novel and efficient
synthesis of ortho-substituted phenyl glycinol, which has led
to a new class of conformationally rigid phosphino-oxazoline
ligands. Their catalytic potential has been demonstrated in
the highly enantioselective Ir-catalyzed hydrogenation of
olefins. Further modification of the ligands and more
applications of this new class of ligands in asymmetric
catalysis are in progress.
Table 2. Asymmetric Hydrogenation of â-Methylcinnamic
Esters with 11a
H2
conversion ee
entry
substrate
14a R ) H
14a R ) H
14a R ) H
14b R ) p-F
14b R ) p-F
14b R ) p-F
14b R ) p-F
14a R ) H
catalyst pressure temp
[%]b
[%]c
1
2
3
4
5
6
7
8
9
11a
11d
11e
11a
11d
11e
11d
11d
11d
11d
11d
11d
100 bar rt
100 bar rt
100 bar rt
100 bar rt
100 bar rt
100 bar rt
100 bar 50 °C
100 bar 50 °C
100 bar 50 °C
100 bar 50 °C
100 bar 50 °C
100 bar 50 °C
100 bar 50 °C
>99
>99
>99
32
58
94
90
>99
87
>99
>99
96
98
99
91
89
91
85
96
99
98
98
99
94
95
14c R ) p-Cl
10 14d R ) p-CH3
11 14e R ) m-CH3
12 14f R ) p-OCH3
13 14g R ) p-OCF3 11d
84
a See Supporting Information for experimental details. b Conversions were
determined by GC. c Enantiomeric excesses were determined by chiral
HPLC (Chiralcel OJ-H) or chiral GC (Chiralselect 1000). Absolute
configuration was assigned by comparison of the retention times of two
enantiomers with reported data.
form chiral 3-arylbutanols, which are important intermediates
for the synthesis of aromatic sesquiterpenes of the bisabolane
family.16 Few systems have been reported to be highly
selective for this type of substrate.5a,e We were certainly
interested in examining these important hydrogenation
Acknowledgment. This work was supported by the
National Institutes of Health.
Supporting Information Available: Experimental details
and spectroscopic data for all the new compounds and a
general hydrogenation procedure. This material is available
free of charge via the Internet at http://pubs.acs.org.
(16) (a) Fuganti, C.; Serra, S.; Dulio, A. J. Chem. Soc., Perkin Trans. 1
2000, 3758. (b) Fuganti, C.; Serra, S.; Dulio, A. J. Chem. Soc., Perkin Trans.
1 1999, 279. (c) Meyers, A. I.; Stoianova, D. J. Org. Chem. 1997, 62, 5219.
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