Chiral diphosphites and diphosphoramidites as cheap and efficient ligands in Rh-catalyzed asymmetric olefin hydrogenation

Article abstract of DOI:10.1039/b601638c

Chiral diphosphites and diphosphoramidites derived from BINOL or diphenylprolinol are efficient ligands in asymmetric Rh-catalyzed olefin hydrogenation, provided the proper achiral backbone is chosen. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b601638c

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Chiral diphosphites and diphosphoramidites as cheap and efficient
ligands in Rh-catalyzed asymmetric olefin hydrogenation
Manfred T. Reetz,* Gerlinde Mehler and Oleg Bondarev
Received (in Cambridge, UK) 3rd February 2006, Accepted 5th April 2006
First published as an Advance Article on the web 2nd May 2006
DOI: 10.1039/b601638c
Chiral diphosphites and diphosphoramidites derived from
BINOL or diphenylprolinol are efficient ligands in asymmetric
Rh-catalyzed olefin hydrogenation, provided the proper achiral
backbone is chosen.
Several years ago it was reported that BINOL-derived mono-
dentate phosphites,1 phosphonites2 and phosphoramidites3 are
efficient ligands in Rh-catalyzed olefin hydrogenation (90–99% ee).
These observations were surprising, because it had been accepted
that chelating bidentate P-ligands are generally necessary for high
levels of enantioselectivity, probably due to restricted rotations in
the respective Rh-complexes.4 Recently, we published a mechan-
istic study which showed that two monodentate phosphites are
attached to rhodium with formation of defined conformers, and
that the lock-and-key mechanism holds in which the major Rh/
olefin diastereomer leads to the product (anti-Halpern).5 Oddly
enough, the analogous diphosphites and diphosphoramidites
having achiral backbones appear not to be well suited. In fact,
up to 1999 the highest ee-value in any olefin hydrogenation using
chiral diphosphites had been reported not to exceed 34%.6 At that
time we described a BINOL-derived diphosphite with a chiral
backbone (dianhydro-D-mannitol) as the first case of high
efficiency (ee up to 96%).7 However, although BINOL constitutes
one of the cheapest chiral auxiliaries, the chiral diol used as the
backbone is not readily available. Therefore, such diphosphites are
not practical. In the case of diphosphoramidites, ethane- and
propane-diamine as backbones lead to only 70–72% ee.3 All of
these observations suggest that chiral diphosphites and dipho-
As a model reaction for testing the performance of ligands 1–5
in Rh-catalyzed olefin hydrogenation, we chose the transformation
of itaconate 6 to methyl succinate 7. The standard procedure, used
sphoramidites having achiral backbones are not suited for efficient
olefin hydrogenation. Here we report that this is not the case.
previously in related cases,1,3,7 was applied in which [Rh(cod)2]BF4
Based on our mechanistic study regarding the efficiency of
is treated with one equivalent of a bidentate ligand leading to the
BINOL-derived monophosphites,5 we thought that it might be
respective precatalyst in which one 1,5-cyclooctadiene (cod) has
possible to design analogous diphosphites which might in fact be
been replaced.
well suited for Rh-catalyzed olefin hydrogenation. We suspected
that the nature of the achiral backbone may be crucial, and
therefore prepared bidentate ligands having different spacers
between the two phosphorus centers. Diphosphites 1 and 2 and
diphosphoramidites 3 and 4 were easily prepared by phosphor-
ylating the corresponding diols or diamines using standard
procedures1,3 (yields: 75–95%).
We also considered combining the functional moieties of
Table 1 shows some remarkable trends. Conversion and ee
depend much on the nature of the achiral backbone. If the
backbone is short as in the ligands derived from ethylene glycol
(1a), 1,3-propane diol (1b), ethylene diamine (3a) or 1,3-propane
diamine (3b), enantioselectivity is poor to mediocre and conversion
varies greatly (Table 1, entries 1, 2, 9, 10). In contrast, longer
backbones such as those in 1c, 2a, 2c and 3c lead to 93–97% ee
BINOL-derived phosphites and phosphoramidites in a new class
of bidentate ligands, as in 5 prepared by phosphorylating
commercially available 4-hydroxypiperidine (non-optimized yield:
55%).
Max-Planck-Institut fu¨r Kohlenforschung, D-45470, Mu¨lheim/Ruhr,
Germany. E-mail: reetz@mpi-muelheim.mpg.de; Fax: +49 208 306 2985
2292 | Chem. Commun., 2006, 2292–2294
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Table 1 Rh-catalyzed asymmetric hydrogenation of itaconate 6a
Table 2 Rh-catalyzed asymmetric hydrogenation of N-acyl amino
acrylate 8aa
Entry
Ligand
Conversion (%)
ee (%)
Entry
Substrate
Ligand
ee (%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
2a
2b
2c
2d
2e
3a
3b
3c
3d
4a
4b
5
99
44
96
97
10–40
97
73
38
93
97
50–90
96
66–77
88
89
33
1
2
3
4
5
6
7
8
9
a
8a
8a
8a
8a
8a
8a
8a
8a
8a
1c
2a
3a
3b
3c
3d
4a
4b
5
70
79
80
50
96
98
99
99
95
23
50
100
100
100
100
100
100
100
10
11
12
13
14
15
a
93
90
96
99
Same conditions as in Table 1; 100% conversion in all cases; (S)-
BINOL-derived ligands afford (R)-9a.
96
alcohols have been described previously.9
Rh:substrate = 1 : 1000; 1.3 bar H2; CH2Cl2; 22 uC; 20 h. (S)-
BINOL-derived ligands provide (S)-6.
(Table 1, entries 3, 4, 6, 11). The ligands derived from tri- and
pentaethylene glycol provide results which appear not to be
reproducible, which may be due to the presence of small amounts
of water. Remarkably, the diphosphoramidites derived from
piperazine (4a) and homopiperazine (4b) result in 96–99% ee
(entries 13, 14), which stands in contrast to the mediocre results
obtained from the structurally related ethano-bridged ligand 3a3
(entry 9). The phosphite/phosphoramidite 5 is also a high
performance ligand (ee = 96%; entry 15).
The ligands were then tested in the hydrogenation of 6 and 8a,b.
Table 3 shows that 12a results in low enantioselectivity in all cases
(entries 1, 4, 7), whereas 12b and 12c with longer backbones lead to
high levels of asymmetric induction. Thus, an effect analogous to
the previous observation regarding ligands 1–5 is operating.
The results provoke the question whether well defined Rh-
chelates are formed or whether dinuclear species or oligomers are
involved. An unambiguous answer is difficult because we were able
to obtain data only of the pre-catalysts in which one of the
cyclooctadiene (cod) ligands has been replaced by a bidentate
P-ligand. It is well known that as hydrogenation is initiated, the
second cod ligand is hydrogenated with formation of the reactive
catalyst.4 All attempts to obtain spectroscopic data of the latter
failed. An ESI-MS study of the Rh-precatalysts derived from 3, 4
and 12 clearly shows the existence of the respective Rh-chelates, in
which one cyclooctadiene (cod) is bonded to the metal. Although
we searched intensely in the higher mass region, no evidence for
possible dinuclear or oligomeric complexes was found. The NMR
spectra of the complexes at 100-fold higher concentrations relative
to hydrogenation conditions (and about 10 times higher than
The ligands were then tested in the Rh-catalyzed hydrogenation
of N-acyl amino acrylate 8a. Table 2 shows that many of them are
again well suited, the diphosphoramidites 4a,b once more being
particularly noteworthy (entries 7, 8).
In order to determine whether BINOL can be replaced by other
chiral auxiliaries, several ‘‘standard’’ diols such as (R,R)-hydro-
benzoin were employed. Such bidentate ligands resulted in poor
enantioselectivity. In sharp contrast, bidentate P-ligands derived
from commercially available (S)-a,a-diphenylprolinol 10 turned
out to be surprisingly efficient, provided the correct achiral
backbone is chosen. The synthesis of this new type of ligand
involves diastereoselective phosphorylation of 10 by PCl3 with
exclusive formation of (S,RP)-11 followed by standard phosphor-
ylation of achiral diols such as ethylene glycol, 1,4-butane diol or
diethylene glycol. The conclusion regarding the relative configura-
tion of 12 is based on the X-ray structure of an analogous
compound produced by phosphorylation of a phenol by (S,RP)-
11).8 Structurally related P-heterocycles derived from amino
Table 3 Rh-catalyzed asymmetric hydrogenation of 6 and 8a,b
Entry
Substrate
Ligand
ee (%)
1
2
3
4
5
6
7
8
9
a
6
6
6
8a
8a
8a
8b
8b
8b
12a
12b
12c
12a
12b
12c
12a
12b
12c
2 (R)
92 (R)
90 (R)
32 (S)
91 (S)
89 (S)
10 (S)
94 (S)
86 (S)
Same conditions as in Table 1; 100% conversion in all cases.
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monodenate ligands in general: (i) F. Lagasse and H. B. Kagan, Chem.
Pharm. Bull., 2000, 48, 315–324.
2 (a) M. T. Reetz and T. Sell, Tetrahedron Lett., 2000, 41, 6333–6336; (b)
C. Claver, E. Fernandez, A. Gillon, K. Heslop, D. J. Hyett,
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under MS-conditions) also show the presence of the expected
complexes. However, under these conditions (concentrations
higher than when hydrogenating) about 10–20% of species appear
which may be dinuclear or oligomeric. The influence of
concentration, e.g., in the range 0.05–0.2 M, on ee was tested in
several cases, e.g., 4a and 12a. No appreciable effect was observed.
Thus, bidentate-Rh species are probably involved, although other
intermediates under the actual reaction conditions cannot be
excluded with certainty at this time. Finally, the effect of varying
the Rh : ligand ratio was studied using two different dipho-
sphoramidites. In the case of 3a, doubling the Rh : 3a ratio from
1 : 1 to 1 : 2 shuts down the reaction, as does a 1 : 3 ratio. In the
case of 3d, the rate also decreases when using more ligands, but not
as drastically. At Rh:3d ratios of 1 : 2 and 1 : 3, only 44 and 12%
conversion at low enantioselectivity, 58 and 25% ee, respectively,
are observed. These results show that binding more than one
bidentate ligand to rhodium is detrimental.
In summary, we have shown, inter alia, that BINOL-derived
diphosphites and diphosphoramidites, which had previously been
thought to be ligands leading to low or mediocre levels of
enantioselectivity in Rh-catalyzed olefin hydrogenation, may in
fact be very efficient. A prerequisite is the proper choice of the
achiral backbone. In general, it needs to be fairly long, allowing for
an optimal degree of flexibility. The piperazine- and homopiper-
azine-derived ligands (4a,b) appear to constitute exceptions to this
guideline. The present findings open the door for industrial
applications10 because BINOL is one of the cheapest chiral
auxiliaries currently available. Moreover, our concept of using
mixtures of two different monodentate P-ligands11 can now be
used as a basis to design corresponding bidentate ligands, most
likely with sufficiently long achiral backbones.
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J. M. Brown, in Comprehensive Asymmetric Catalysis, ed. E. N.
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ch. 5.1.
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8 M. T. Reetz, O. Bondarev and R. Goddard, unpublished.
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S. E. Lyubimov, A. A. Shiryaev, S. V. Zheglov, O. G. Bondarev,
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This work was supported by the Fonds der Chemischen
Industrie. O.B. thanks the Alexander von Humboldt Foundation
for a research fellowship.
10 M. T. Reetz and G. Mehler, DE Pat., A 10 2005 044 355.9, 2005.
11 (a) M. T. Reetz, T. Sell, A. Meiswinkel and G. Mehler, Angew. Chem.,
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M. T. Reetz, G. Mehler and A. Meiswinkel, Tetrahedron: Asymmetry,
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Notes and references
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(Angew. Chem., Int. Ed., 2000, 39, 3889–3890); (b) M. T. Reetz,
G. Mehler, A. Meiswinkel and T. Sell, Tetrahedron Lett., 2002, 43,
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and X. Li, Synthesis, 2005, 3183–3185; reviews : (e) M. T. Reetz, Chim.
Oggi, 2003, 21, 10/11, 5–8; (f) T. Jerphagnon, J.-L. Renaud,
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2294 | Chem. Commun., 2006, 2292–2294
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