Synthesis and Application of Chiral Phosphino-Imidazoline Ligands: Ir-Catalyzed Enantioselective Hydrogenation

Article abstract of DOI:10.1021/ol027253c

(Matrix Presented) A series of chiral phosphino-imidazolines (PHIM ligands) 1a-j with different substituents at the stereogenic center, the nitrogen atom of the imidazoline ring, and at the phosphorus atom were synthesized. Iridium complexes derived from

Full text of DOI:10.1021/ol027253c

ORGANIC
LETTERS
2002
Vol. 4, No. 26
4713-4716
Synthesis and Application of Chiral
Phosphino-Imidazoline Ligands:
Ir-Catalyzed Enantioselective
Hydrogenation
Frederik Menges, Markus Neuburger,† and Andreas Pfaltz*
Department of Chemistry, UniVersity of Basel, St. Johanns-Ring 19,
CH-4056 Basel, Switzerland
andreas.pfaltz@unibas.ch
Received November 8, 2002
ABSTRACT
A series of chiral phosphino-imidazolines (PHIM ligands) 1a−j with different substituents at the stereogenic center, the nitrogen atom of the
imidazoline ring, and at the phosphorus atom were synthesized. Iridium complexes derived from these ligands have been evaluated as catalysts
for the enantioselective hydrogenation of unfunctionalized olefins. In several cases, higher enantiomeric excesses were observed than with
analogous phosphino-oxazoline ligands.
Phosphino-oxazolines 2 (PHOX ligands) are versatile chiral
ligands that have found a wide range of applications in
asymmetric catalysis.1 Cationic iridium complexes derived
from these ligands have proven to be highly effective
catalysts for the enantioselective hydrogenation of imines
and olefins, including unfunctionalized alkenes.2 The modular
nature of the ligand structure made it possible to vary the
backbone, the oxazoline part, and the phosphorus substituents
extensively. This led us to several related ligand classes such
as the pyrrolyl-derived phosphino-oxazolines 33 and the
phosphinite-oxazolines 4,4 which have considerably expanded
the scope of Ir-catalyzed hydrogenation.5,6
Analogous imidazoline-derived P,N-ligands such as 5 have
not received attention so far, although they can be easily
prepared from readily available chiral precursors such as
diamines or amino alcohols.7 This is surprising, because the
additional nitrogen atom provides a handle for tuning the
(4) (a) Blankenstein, J.; Pfaltz, A. Angew. Chem., Int. Ed. 2001, 40,
4445-4447. (b) Menges, F.; Pfaltz, A. AdV. Synth. Catal. 2002, 344, 40-
44.
(5) 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. In press.
(6) For related phosphino-oxazolines and carbene-oxazoline ligands,
see: (a) Hou, D.-R.; Reibenspies, J. H.; Burgess, K. J. Org. Chem. 2001,
66, 206-215. (b) Hou, D.-R.; Reibenspies, J.; Colacot, T. J.; Burgess, K.
Chem. Eur. J. 2001, 7, 5391-5400. (c) Jones, G.; Richards, C. J.
Tetrahedron Lett. 2001, 42, 5553-5555. (d) Powell, M. T.; Hou, D.-R.;
Perry, M. C.; Cui, X.; Burgess, K. J. Am. Chem. Soc. 2001, 123, 8878-
8879.
(7) We have found only one publication on imidazoline-phosphine
ligands: Bussaca, C. (Boehringer Ingelheim Pharmaceuticals), US Patent
Application, US6316620, 2001. Ligands of this type are also under
investigation in the laboratory of Dr. Mike Casey, University College Dublin
(Casey, M. Personal communication).
† Laboratory for Chemical Crystallography.
(1) Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000, 33, 336-345.
(2) (a) Schnider, P.; Koch, G.; Pre´toˆt, R.; Wang, G.; Bohnen, F. M.;
Kru¨ger, C.; Pfaltz, A. Chem. Eur. J. 1997, 3, 887-892. (b) Lightfoot, A.;
Schnider, P.; Pfaltz, A. Angew. Chem., Int. Ed. 1998, 37, 2897-2899.
Blackmond, D. G.; Lightfoot, A.; Pfaltz, A.; Rosner, T.; Schnider, P.;
Zimmermann, N. Chirality 2000, 12, 442-449.
(3) Cozzi, P. G.; Zimmermann, N.; Hilgraf, R.; Schaffner, S.; Pfaltz, A.
AdV. Synth. Catal. 2001, 343, 450-454.
10.1021/ol027253c CCC: $22.00 © 2002 American Chemical Society
Published on Web 12/03/2002

electronic and conformational properties of the ligand by
proper choice of the R3 group. Moreover, this group could
also serve as a linker for attaching the ligand to a solid
support. Therefore, we felt that phosphino-imidazolines could
be a valuable addition to the known phosphino-oxazolines
and decided to synthesize a series of imidazoline derivatives
5a-j in order to evaluate their scope as ligands in the Ir-
catalyzed enantioselective hydrogenation.
Table 1. Hydrogenation of trans-R-Methylstilbene
catalyst
R1
R2
Ph
Ph
Ph
Ph
R3
conversiona (%) eeb (%)
1a
1b
1c
1d
1e
1f
1g
1h
1i
iPr
iPr
iPr
iPr
tBu Ph
tBu Ph
tBu Ph
tBu Ph
iPr
Cy
Bn
Ph
Ph
>99
>99
>99
>99
>99
98
>99
92
>99
96
63
65
60
74
76
69
73
74
94
85
97
pMeO-C6H4
pCF3-C6H4
pTol
tBu oTol Ph
tBu oTol Bn
1j
Ir -2c
tBu oTol
-
>99
a Determined by GC. b Determined by HPLC (see ref 2b). c Entry taken
from ref 2b.
Starting from easily accessible â-hydroxyamides 6, the
2-phenylimidazolines 7 were conveniently prepared, using
an efficient method recently reported by Casey et al. (Scheme
1).8 Subsequent ortho-lithiation, followed by reaction with
Crystalline BArF (tetrakis[3,5-bis(trifluormethyl)phenyl]-
borate) salts are air and moisture stable and could be purified
by chromatography on silica gel without special precautions.
Crystal structures of PHIM complex 1i and the corre-
sponding PHOX complex Ir-2, bearing the same substituents
at the phosphorus atom (o-Tol) and the stereogenic center
(tBu), closely resemble each other (Figure 1). However, the
Scheme 1. Preparation of [Ir(P∧N)(COD)]BArF Complexes
a Reaction conditions: (a) SOCl2, 85 °C, 4 h, then TEA, R3NH2,
Et2O, 3 h, rt, 38-86%; (b) secBuLi, TMEDA, pentane, from -78
°C to room temperature, then ClPR2 , 12 h at room temperature,
2
9-79%; (c) [Ir(COD)Cl]2, CH2Cl2, 2 h, 40 °C, then NaBArF, H2O,
rt (71-94%).
different diaryl-chlorophosphines led to phosphino-imida-
zolines 5a-j (R1, R2, R3, see Table 1). The yields in this
step varied from 9 (5h) to 79% (5e).
The corresponding iridium complexes 1a-j, having dif-
ferent substituents at the stereogenic center and the phophorus
and nitrogen atoms, were obtained in high yields using the
standard protocol developed for Ir-PHOX complexes.2b
Figure 1. Structure of PHIM complex 1i9 in the solid state and an
analogous PHOX complex (Ir-2).10 Anions and cyclooctadienes
have been omitted.
torsion angles (τ) between the central phenyl ring and the
five-membered heterocycle differ by 20° (C-C-C-O angle
) -11° vs C-C-C-N angle ) -31°). The Ir-P distances
(2.3009(12) in 1i vs 2.3055(17) Å in Ir-2) and the Ir-N
distances (2.080(5) vs 2.106 (3) Å) are almost identical,
indicating that the electron densities on the coordinating
nitrogen atoms are similar.
(8) Boland, N. A.; Casey, M.; Hynes, S. J.; Matthews, J. W.; Smyth, M.
P. J. Org. Chem. 2002, 67, 3919-3922.
(9) Single crystals of 1i obtained with PF6- instead of BArF- gave better
results in the refinement. Crystallographic data has been deposited under
CCDC 197021. Further details can be found in Supporting Information.
(10) Smidt, S. P.; Mukherje, P.; Pfaltz, A.; Neuburger, M. Unpublished
results.
4714
Org. Lett., Vol. 4, No. 26, 2002

Table 2. Hydrogenation of (E)-2-(4-Methoxyphenyl)-2-butene
Table 4. Hydrogenation of
6-Methoxy-1-methyl-3,4-dihydronaphthalene
catalyst
R1
R2
Ph
Ph
Ph
Ph
R3
conversiona (%) eeb (%)
catalyst
R1
R2
Ph
Ph
Ph
Ph
R3
conversiona (%) eeb (%)
1a
1b
1c
1d
1e
1f
1g
1h
1i
iPr
iPr
iPr
iPr
tBu Ph
tBu Ph
tBu Ph
tBu Ph
iPr
Cy
Bn
Ph
Ph
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
45
45
46
69
82
81
78
80
81
90
81
1a
1b
1c
1d
1e
1f
1g
1h
1i
iPr
iPr
iPr
iPr
tBu Ph
tBu Ph
tBu Ph
tBu Ph
iPr
Cy
Bn
Ph
Ph
>99
>99
82
5
rac
rac
52
76
72
75
73
91
67
72
>99
>99
>99
>99
97
pMeO-C6H4
pCF3-C6H4
pTol
pMeO-C6H4
pCF3-C6H4
pTol
tBu oTol Ph
tBu oTol Bn
tBu oTol
1j
Ir -2c
tBu oTol Ph
tBu oTol Bn
tBu oTol
>99
87
-
1j
Ir -2c
a Determined by GC. b Determined by HPLC (see ref 2b). c Entry taken
from ref 5.
-
>99
a Determined by GC. b Determined by HPLC (see ref 2b). c Entry taken
from ref 2b.
In the hydrogenation of trans-R-methylstilbene (8), dif-
ferent catalysts 1a-j gave ee values between 60 and 94%
(Table 1). The results show that the substituents at the
imidazoline nitrogen atom have a distinct influence on the
enantioselectivity, with N-aryl groups (1d-i) being superior
to analogous N-alkyl groups (1a-c, 1j). The effect of a
π-donor or π-acceptor substituent in the para position of the
N-aryl group is small (1e-h). Complex 1i proved to be
almost as selective as the coresponding Ir-PHOX complex
Ir-2 (94 vs 97% ee).
Similar trends were observed for the hydrogenation of (E)-
2-(4-methoxyphenyl)-2-butene (9) within the series 1a-d
and 1e-h (Table 2). However, with catalysts 1i and 1j, the
selectivity order between N-phenyl and N-benzyl observed
with alkene 8 and other substrates (Tables 3 and 4) was
reversed (R3 ) Bn, 90% ee; R3 ) Ph, 81% ee). With this
substrate, the PHOX complex Ir-2 was less selective than
the best imidazoline-derived catalyst 1j (81 vs 90% ee).
In the hydrogenation of the (Z)-alkene 10, catalyst 1i with
a N-phenyl-substituted ligand produced the highest enantio-
meric excess (88%), whereas the N-benzyl analogue gave a
somewhat lower selectivity of 83% ee (Table 3). The PHOX-
derived catalyst Ir-2 was significantly less selective in this
case.
Essentially the same selectivity order between catalysts
1a-j was observed for the hydrogenation of dihydronaph-
thalene derivative 11 (Table 4).
Again, PHIM complex 1i was the most selective catalyst,
outperforming the Ir-PHOX complex Ir-2 (91 vs 72% ee).
Table 5. Hydrogenation of 2-(4-Methoxyphenyl)-1-butene
Table 3. Hydrogenation of (Z)-2-(4-Methoxyphenyl)-2-butene
catalyst R1 R2
R3
T (°C) conversiona (%) eeb (%)
catalyst
R1
R2
Ph
Ph
Ph
Ph
R3
conversiona (%) eeb (%)
1e
1e
1f
1f
1g
1g
1h
1i
tBu Ph Ph
tBu Ph Ph
25
0
>99
48
50
47
52
50
54
44
53
54
18
52
24
60
1a
1b
1c
1d
1e
1f
1g
1h
1i
iPr
iPr
iPr
iPr
tBu Ph
tBu Ph
tBu Ph
tBu Ph
iPr
Cy
Bn
Ph
Ph
>99
>99
>99
>99
97
16
13
12
58
86
82
87
84
88
83
63
tBu Ph pMeO-C6H4
tBu Ph pMeO-C6H4
tBu Ph pCF3-C6H4
tBu Ph pCF3-C6H4
tBu Ph pTol
25
0
>99
65
25
0
25
25
0
>99
>99
>99
42
pMeO-C6H4
pCF3-C6H4
pTol
98
>99
92
tBu oTol Ph
1i
tBu oTol Ph
4
tBu oTol Ph
tBu oTol Bn
tBu oTol
>99
>99
>99
1j
tBu oTol Bn
25
0
74
13
1j
Ir -2c
1j
tBu oTol Bn
-
Ir -2c tBu oTol
-
25
>99
a Determined by GC. b Determined by HPLC (see ref 2b). c Entry taken
from ref 5.
a Determined by GC. b Determined by HPLC (see ref 2b). c Entry taken
from ref 5.
Org. Lett., Vol. 4, No. 26, 2002
4715

As previously observed4 in the hydrogenation of the
terminal alkene 12, the best enantioselectivities were obtained
at ambient pressure (Table 5). In this case, the ee values
were somewhat lower than with the Ir-PHOX catalyst Ir-
2. Lowering the temperature to 0 °C resulted in slower
reaction rates and inferior enantioselectivities, especially in
the case of catalysts 1i and 1j.
ligands 2,1 further studies of phosphino-imidazoline ligands
5 seem to be worthwhile.
Acknowledgment. Financial support from the Swiss
National Science Foundation, the Federal Commission for
Technology and Innovation (KTI Project No. 5189.2 KTS),
and Solvias AG, Basel, is gratefully acknowledged. F.M.
thanks the Fonds der chemischen Industrie, Frankfurt, and
the German Federal Ministry for Science and Technology
(BMBF) for a Kekule´ Fellowship.
The results obtained with phosphino-imidazoline ligands
5 are encouraging. In several cases, the enantioselectivities
were higher than with phosphino-oxazolines 2. As iridium
complexes of phosphinite-oxazolines 4 have often proven
to be superior to PHOX-derived catalysts,4 we plan to
synthesize analogous phosphinite-imidazolines and evaluate
the corresponding iridium complexes as catalysts. Moreover,
in view of the wide range of applications found for PHOX
Supporting Information Available: Experimental pro-
cedures, analytical data for all new compounds, and X-ray
data for 1i. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL027253C
4716
Org. Lett., Vol. 4, No. 26, 2002