Structural Investigations on Enantiopure P–OP Ligands: A High-Performing P–OP Ligand for Rhodium-Catalysed Hydrogenations

Article abstract of DOI:10.1002/ejoc.201701760

A second generation of phosphine–phosphite (P–OP) ligands, incorporating a more sterically bulky phosphite group than previous P–OP ligand designs, gave very efficient catalysts for the Rh-catalysed asymmetric hydrogenation of a diverse array of substrate

Full text of DOI:10.1002/ejoc.201701760

A Journal of
Accepted Article
Title: Structural Investigations on Enantiopure PꢀOP Ligands:
a Higher Performing PꢀOP Ligand for Rhodium-catalyzed
Hydrogenations
Authors: Héctor Fernández-Pérez, Bugga Balakrishna, and Anton
Vidal-Ferran
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Structural Investigations on Enantiopure POP Ligands: a Higher
Performing POP Ligand for Rhodium-catalyzed Hydrogenations
Héctor Fernández-Pérez,[a] Bugga Balakrishna,[a] and Anton Vidal-Ferran*[a,b]
Dedication ((optional))
Abstract: A second generation of phosphine-phosphite (POP)
ligands, which incorporates a more sterically bulky phosphite group
than previous POP ligand designs, gives very efficient catalysts for
the Rh-catalyzed asymmetric hydrogenation of a diverse array of
substrates (11 examples, from 93% to 99% ee) containing
structurally diverse substituents and chelating groups at the C=C
double bond. The presence of the sterically bulky (Sa)-3,3'-diphenyl-
5,5',6,6',7,7',8,8'-octahydro-[1,1'-binaphthalene]-2,2'-diol-derived
phosphite fragment caused significant increases in the
enantioselectivity (up to ∆ee = 58%) and provided improved results
to those obtained with the first generation of POP-derived rhodium
catalysts (i.e. rhodium complexes incorporating the phosphine-
phosphite ligands with the (Ra)- and (Sa)-BINOL-derived phosphite
groups; BINOL = [1,1'-binaphthalene]-2,2'-diol). Overall, the optimal
ligand L8 provided very high enantioselectivities for an array of
structurally diverse olefins (up to 99% ee).
binaphthalene]-2,2'-diol). Of the two possible configurations of
the BINOL unit, the (Sa)-BINOL-derived POP ligand L6 gives
higher enantioselectivities in the hydrogenation of functionalized
olefins than does (Ra)-BINOL-derived ligand L7. Interestingly, L6
mediates the asymmetric hydrogenation of a vast array of
structurally diverse olefins, including -(acyl)amino acrylates,
itaconic acid derivatives, -aryl enamides, and -substituted
enol esters (60 examples, full conversion, up to 99% ee).[5]
Introduction
As a consequence of their singular electronic and steric
properties, phosphine-phosphite (POP) ligands have emerged
as an efficient class of enantiopure bidentate ligands for several
transition
metal-mediated
enantioselective
catalytic
transformations.[1] For example, BINAPHOS (L1, Figure 1) was
one of the first enantiopure POP ligands to be reported and
provided outstanding catalytic properties in the rhodium-
mediated asymmetric hydroformylation of structurally diverse
olefins.[ 2 ] Furthermore, the rhodium complexes derived from
POP ligands L2L7 (Figure 1) show high performance in the
asymmetric hydrogenation (AH) of functionalized olefins.
Following the seminal work of Ruiz et al., which involved the
application of sugar-derived POP ligand L2 in asymmetric
hydrogenation,[3] a set of structurally diverse enantiopure POP
ligands L3L7 has been developed and applied in asymmetric
hydrogenations.[1,4] Our group has developed a modular ligand
design together with a ligand tuning process that has allowed us
to identify a first generation of efficient POP ligands for
asymmetric hydrogenation (structures L6 and L7 in Figure 1).[5a]
The optimal ligand structures incorporated an anti phosphino
alcohol unit with two stereogenic carbons together with a
phosphite fragment derived from enantiopure BINOL ([1,1'-
Figure 1. Representative enantiopure POP ligands in Rh-mediated AHs.
The wide applicability of L6 has also been demonstrated by
the preparation of advanced synthetic intermediates of active
pharmaceutical ingredients (API’s) through asymmetric
hydrogenation of the appropriate olefin.[6]
The key role of the phosphite fragment of the BINOL-derived
POP ligand was revealed during DFT studies of the rhodium-
catalyzed
asymmetric
hydrogenation
of
methyl
2-
acetamidoacrylate S1.[5b] Firstly, the electronic properties of the
phosphite group were found to favor a cis relationship between
the coordinated olefin (S1) and the phosphite group at the
square planar rhodium center. That is, the right-hand sides of
the quadrant diagrams in Figure 2 are electronically disfavored
towards coordination of the olefin carbon atoms. Secondly, the
naphthyl rings of the BINOL group, in combination with the
phenyl groups of the backbone and phosphine unit, were found
to provide steric blocking that prevents placement of the C=C
bond in one of the two remaining left-hand quadrants (see
Figure 2).
[a]
Institute of Chemical Research of Catalonia (ICIQ) and The
Barcelona Institute of Science and Technology (BIST),
Avgda. Països Catalans 16, 43007 Tarragona, Spain
E-mail: avidal@iciq.cat
https://www.icrea.cat/Web/ScientificStaff/anton-vidal-i-ferran-288
ICREA, Pg. Lluís Companys 23, 08010 Barcelona, Spain
[b]
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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Thus, a combination of steric and electronic effects leaves
the olefin substrate with only one low-energy direction of
approach: towards the lower left quadrant for L6 and the upper
left quadrant for L7.[5b] The (R)-configuration of the
hydrogenation product P1 obtained with ligand L6 is predicted
by placement of the double bond in the lower left quadrant,
coordination of the substrate to the catalyst by the C=O and
C=C groups and delivery of dihydrogen across the C=C bond
from the metal side (the opposite configuration for product P1
obtained with ligand L7 is predicted by placing the substrate in
the upper left quadrant, substrate chelation and delivery of
dihydrogen from the metal side; see Figure 2). Experimental
results have demonstrated that the final configuration of the
hydrogenation products derived from -(acylamino)acrylates,
itaconic acid derivatives and their analogues, -arylenamides,
and -substituted enol esters can always be predicted to be (R)-,
(S)-,[7] (R)-, and (R), respectively when ligand L6 is employed.[5d]
These configurations are obtained following the stereochemical
model indicated above (placement of the double bond in the
lower left quadrant, substrate chelation and delivery of
dihydrogen from the metal side).
have been modified while maintaining the phosphine groups and
carbon backbone design of L6. Metal complexes derived from
these ligands are efficient and highly enantioselective catalysts
in the Rh-mediated hydrogenative kinetic resolution of vinyl
sulfoxides[9] and the Ir-catalyzed asymmetric hydrogenation of
seven-membered C=N-containing heterocyclic compounds.[ 10 ]
The discussion that follows highlights the preparation and
characterization of cationic POP-Rh complexes derived from
L8 and L9 and their use as pre-catalysts in the asymmetric
hydrogenation of an array of structurally diverse functionalized
olefins.
Figure 3. Second generation of enantiopure POP ligands L8 and L9.
Results and Discussion
We initially investigated the preparation of [Rh(nbd)(L8)]BF4
(C1) and [Rh(nbd)(L9)]BF4 (C2) in order to study the
effectiveness of these complexes in asymmetric hydrogenation
reactions. Pre-catalyst C1 has been previously prepared by our
group in
a two-step gram-scale and chromatography-free
procedure.[ 11 ] Complex C2 was prepared in high yield by
reacting stoichiometric amounts of POP ligand L9 with
[Rh(nbd)2]BF4 in DCM (Scheme 1), and was fully characterized
by standard techniques.
Figure 2. Rationalization of the stereochemical outcome of AHs mediated by
rhodium complexes of L6 and L7.
In our quest to develop higher-performing ligands, we have
also reduced the distance between the phosphine and phosphite
groups by one bond.[8] However, enantioselectivities higher than
those afforded by L6 were not obtained.[8] Our most recent
efforts towards higher performing ligands for rhodium mediated
asymmetric hydrogenations are based on modifying the
structure of the [1,1'-biaryl]-2,2'-diol-derived phosphite group by
introducing substituents at the positions more prone to affecting
the steric environment around the rhodium center.
Scheme 1. Preparation of rhodium pre-catalysts C1 and C2 derived from
POP ligands L8 and L9, respectively.
In order to gain information about the structural features of
coordinated POP ligands L8 and L9, single crystals of
complexes C1 and C2 were analyzed by X-ray crystallography.
ORTEP views of the molecular structures of these rhodium
complexes, along with selected bond lengths and angles, are
shown in Figure 4 and Figure 5. Both complexes display square-
planar coordination geometry and both ligands coordinate with
similar bite angles (91.80(5)º and 91.97(3)º for complexes C1
and C2, respectively). The Rh-P distance is shorter for the
phosphite group than for the phosphine group.
Herein, we wish to report the application of ligands L8 and
L9 in Rh-catalyzed AHs,[9] which incorporate a sterically bulky
phosphite fragment derived from 3,3'-diphenyl-5,5',6,6',7,7',8,8'-
octahydro-[1,1'-binaphthalene]-2,2'-diol
(o-Ph-H8-BINOL)
(Figure 3). In these ligands, the substituents at the 3 and 3’
positions of the [1,1'-biaryl]-2,2'-diol-derived phosphite group
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above,[5b] we hypothesized that the rhodium complexes derived
from our second generation of ligands L8 and L9 might provide
higher enantioselectivities than those obtained with their 3,3’-
unsubstituted analogues L6 and L7.
Table 1. AH of functionalized model substrates S2S5 catalyzed by rhodium
complexes derived from POP ligands L6L10[a]
Figure 4. Crystal structure of the Rh-complex C1 (frontal and lateral ORTEP
drawings showing thermal ellipsoids at 30% probability). The H-atoms and
-
BF4 counterion have been omitted for clarity. Selected bond lengths [Å] and
angles [º]: Rh1-P1 = 2.1975(14), Rh1-P2 = 2.3286(14), P1-Rh1-P2 = 91.80(5).
Entry
Lig.
L6
Subs. S2[b]
99% ee (R)
86% ee (S)[c]
99% ee (R)
96% ee (S)
93% ee (S)
Subs. S3[b]
99% ee (S)
97% ee (R)
99% ee (S)
99% ee (R)
92% ee (R)
Subs. S4[b]
98% ee (R)
94% ee (S)
99% ee (R)
98% ee (S)
88% ee (S)
Subs. S5[b]
96% ee (R)
90% ee (S)
99% ee (R)[d]
99% ee (S)
94% ee (S)
1[c]
2
L7
3
L8
4
L9
5
L10
[a] The values shown are the average of at least of two independent runs.
Conversions determined by 1H NMR and
99% unless indicated. [b]
>
Enantiomeric excesses were determined by HPLC or GC analysis on chiral
stationary phases. Absolute configurations were assigned by comparison of
chromatographic elution orders with reported data. [c] Results published in
references 5b and 5d. [d] 96% conversion.
Figure 5. Crystal structure of the Rh-complex C2 (frontal and lateral ORTEP
drawings showing thermal ellipsoids at 30% probability). The H-atoms and
-
BF4 counterion have been omitted for clarity. Selected bond lengths [Å] and
angles [º]: Rh1A-P1A = 2.2014(7), Rh1A-P2A = 2.3214(9), P1A-Rh1A-P2A =
91.97(3).
Analysis of the three-dimensional arrangement of the ligand
in complex C1 indicates that the P-Rh-P coordination plane
roughly bisects the phosphite fragment (see frontal view for
complex C1 in Figure 4). As can also be seen from this view, L8
has a similar orientation to L6. Furthermore, one of the phenyl
groups in the ortho-position is located above the P-Rh-P
coordination plane and is mostly confined to the upper left
quadrant. Ligand L9 takes on a similar three-dimensional
arrangement in complex C2 as ligand L8 does in complex C1;
however, the phenyl group in the ortho-position is now located
below the P-Rh-P coordination plane and is mostly confined to
the lower left quadrant (Figure 5). Overall, the occupation of the
upper left and lower left quadrants in rhodium complexes
derived from ligands L8 and L9, respectively, appears to be
greater than for those of the analogous ligands lacking phenyl
substituents at the 3 and 3’ positions of the [1,1'-biaryl]-2,2'-
diol.[ 12 ] Supported by the computational studies discussed
Catalytic studies to test this hypothesis were performed
under standard catalyst screening conditions (1.0 mol-% of pre-
formed or in situ prepared [Rh(nbd)(POP)] complex as the
catalyst precursor, 20 bar of H2, THF as solvent, room
temperature, and 18 h reaction time).[5d,8] A structurally diverse
array of model substrates was tested: -(acyl)amino acrylate S2,
itaconic acid derivative S3, -aryl enamide S4, and -substituted
enol ester S5. The results of this comparative study are
summarized in entries Table 1, and hydrogenation results from
rhodium pre-catalysts bearing the previously reported first
generation of ligands (i.e., L6 and L7)[5b,d] are included to aid
comparison (entries 1 to 4 in Table 1).
All the rhodium complexes performed very efficiently in
terms of activity, with complete conversion towards the
hydrogenated products P2P5 obtained in almost all cases.
However, as far as enantioselectivity is concerned, the presence
of the o-Ph-H8-BINOL unit in ligands L8 and L9 led to an
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10.1002/ejoc.201701760
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enhancement in the enantioselectivity for all substrates
compared with the results for complexes bearing 3,3’-
unsubstituted ligands L6 and L7 (compare entries 1 with 3 and
entries 2 with 4 in Table 1, respectively). An increase of up to
9% ee was reached in the hydrogenation of substrate S5 using
the rhodium complex derived from ligand L9 (compare entry 2
with entry 4 for substrate S5 in Table 1).
The 5-fluoropyridin-2-yl-substituted vinyl acetamide S11 was
also subjected to hydrogenation using the rhodium catalyst
derived from L8. High enantioselectivity (98% ee, see entry 6 in
Table 2) was observed, but only moderate conversion was
obtained. The resulting hydrogenated product is a valuable
precursor to chiral drugs that are currently in clinical
development for cancer therapy.[17]
To prove that the enhanced enantioselectivities obtained
with the second generation of POP ligands were mainly due to
the introduction of substituents at the 3 and 3’ positions of the
[1,1'-biaryl]-2,2'-diol-derived phosphite, and not due to the
replacement of the binaphthyl group by the 5,5',6,6',7,7',8,8'-
octahydro-binaphthyl motif,[12] we assessed the catalytic
performance of ligand L10[13] in the hydrogenation of substrates
S2S5 (Table 1). Interestingly, slightly lower ee’s were observed
for substrates S3 and S4 with ligand L10 than with ligand L7,
whilst an opposite trend was observed for S2 and S5 (compare
entry 2 with entry 5, Table 1). It is also interesting to note that
the ee’s obtained with L10 for the four model substrates did not
surpass those with L9 (compare entry 4 with entry 5, Table 1),
which proves that the introduction of substituents at the 3 and 3’
positions of the [1,1'-biaryl]-2,2'-diol-derived phosphite plays a
major role in the enhancement of the ee’s in substrates S2S5.
It is noteworthy that the rhodium complex bearing ligand L8
gave perfect enantioselectivities (99% ee) for the four model
substrates (entry 3, Table 1), and is the highest-performing
POP ligand developed by our research group for the Rh-
mediated asymmetric hydrogenation of functionalized olefins.
Encouraged by our results, we decided to assess the
performance of L8 in the asymmetric hydrogenation of a broader
set of structurally diverse functionalized olefins, of which some
underwent hydrogenation with unsatisfactory enantioselectivities
when ligand L6 was employed.[5]
A set of -(acyl)amino acrylates S6S8 was hydrogenated
with excellent enantioselectivities regardless of the substitution
pattern at the aromatic ring (entries 13, Table 2). It should be
noted that the challenging cyclic enamide S9 was hydrogenated
with full conversion and excellent enantioselectivity (96% ee) in
favor of the (R)-configured product (entry 4, Table 2). The
enantioselectivity that we have obtained under mild
hydrogenation conditions is very close to the highest reported
one for enantiopure rhodium(I) catalyst derived from chiral
bidentate phosphorus ligands (98% ee for the rhodium catalyst
derived from Me-PennPhos,[14a] and 96% ee for the rhodium
catalyst derived from Phthalaphos[14b]).
Table 2. AH of functionalized olefins using [Rh(nbd)(L8)]BF4 as catalyst.[a]
p (H2,
bar)
Conv.
[%][b]
Entry
Substrate
ee [%][c]
99 (R)
1
20
> 99
2
3
20
20
> 99
> 99
99 (R)
99 (R)
4
20
> 99
96 (R)
5
6[d]
7
40
80
20
> 99
42 (39)[e]
> 99
93 (R)
98 (R)
99 (R)
[a] The values shown are the average of at least of two independent runs.
Hydrogenations were run in parallel reactor: Reaction conditions:
a
Following
the
same
trend,
the
enantioselective
[Rh(nbd)(L8)]BF4/substrate=1.0:100, r.t., substrate concentration=0.20 M in
THF, 18 h. [b] Conversions determined by 1H NMR. Typical isolated yields
were >90%. [c] Enantiomeric excesses were determined by HPLC analysis on
chiral stationary phases. Absolute configurations were assigned by
comparison of chromatographic elution orders with reported data. [d]
[Rh(nbd)(L8)]BF4/substrate=2.0:100. [e] Isolated yield in parenthesis.
hydrogenation of sterically encumbered N-(1-(naphthalen-1-
yl)vinyl)acetamide S10 provided the hydrogenated product with
complete conversion and a 93% ee (entry 5, Table 2). These
results compete with those of the highest-performing rhodium
catalysts reported in the literature (93% ee for the rhodium
catalyst derived from a phosphine–phosphoramidite ligand,[15a]
and 97% ee for the rhodium catalyst derived from
DioxyBenzP*[15b]). It is interesting to note that the hydrogenation
product of S10 is an advanced intermediate in the synthesis of
cinacalcet hydrochloride, which is used for the treatment of
secondary hyperparathyroidism.[16]
Further interesting substrates for asymmetric hydrogenation
contain an aromatic hydroxyl group that coordinates to rhodium
and assists the hydrogenation reaction. Substrate S12 was
examined as a model substrate for this type of olefin.[18] Perfect
enantioselectivity was obtained with ligand L8, and the
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hydrogenated product was obtained with full conversion (99% ee, the enormous computational capacity required. However,
entry 7, Table 2).
computational studies on the asymmetric hydrogenation of the
simplest possible olefin (methyl 2-acetamidoacrylate, S1) using
the rhodium complexes derived from BINOL-derived POP
ligand L6[5b] paved the way for the rationalization of the results
presented herein. The accepted view for the steric requirements
of these substrates is that, in the transition state, the steric
The results highlighted in Table 3 provide a comparison of
the results obtained for catalysts containing L6 or L8 in the
hydrogenation of a set of structurally diverse substrates. In all
cases the enantioselectivities obtained for the new ligand with
substituents at the 3 and 3’ positions of the (Sa)-[1,1'-biaryl]- 2,2'-
diol-derived phosphite group were either equally high or superior. hindrance appears in the quadrant originally occupied by the
Significant enhancements in the enantioselectivity were obtained
(up to 58% for substrate S12, see entry 9 in Table 3), even for
challenging substrates such as S9 and S10 for which many
reported ligands fail to provide high enantioselectivities (see
entries 6 and 7 in Table 3).[15a,19] The results highlighted in Table
3 also illustrate that the configuration of the hydrogenated
product can be predicted for all substrates: the substrate is
placed in the lower left quadrant, simultaneous coordination of
the C=C bond and the substrate’s chelating group to the
rhodium center occurs, then delivery of dihydrogen across the
C=C double bond from the side of the metal gives the
hydrogenated product. It should be noted that the change to the
(S)-configuration in the hydrogenation products of itaconic acid
derivative S3 is due to an inversion in the CIP priority rules and
not to a breach of the previous rule.
olefin carbon substituted with the chelating group (Cα).[20] There-
Table 3. Comparative table on AHs of a set of functionalized substrates using
rhodium complexes derived from POP ligands L6 and L8.
Entry
Substrate
Ligand L6
Ligand L8
∆ee [%]
Conv. > 99%
99% ee (R)
Conv. > 99%
99% ee (R)
S2
1
2
3
=
=
Conv. > 99%
99% ee (S)
Conv. > 99%
99% ee (S)
S3
S4
Conv. > 99%
98% ee (R)
Conv. > 99%
99% ee (R)
+1
Conv. > 99%
96% ee (R)
Conv. = 96%
99% ee (R)
S5
S6
4
5
6
7
8
9
+3
=
Conv. > 99%
99% ee (R)
Conv. > 99%
99% ee (R)
Conv. > 99%
57% ee (R)
Conv. > 99%
96% ee (R)
S9
+39
+10
=
Conv. = 90%
83% ee (R)
Conv. > 99%
93% ee (R)
S10
S11
S12
Conv. = 50%
98% ee (R)
Conv. = 42%
98% ee (R)
Conv. = 57%
41% ee (R)
Conv. > 99%
99% ee (R)
+58
A computational study on the relative energies of the
transition states of the rate- and stereo-determining step—
oxidative addition of dihydrogen to the ligand-substrate rhodium
complexes[5b] —for all substrates and at a sufficiently high
computational level would certainly allow the experimental
results obtained for ligands L8 and L9 to be rationalized.
Unfortunately, it is not feasible to carry out such a study due to
Figure 6. Three dimensional representation of the oxidative addition transition
states (OATS) for the most favored reaction manifold in the AH of a general
olefin catalyzed by Rh-complexes derived from POP ligand L6 (top) or L8
(bottom). The OATS structure for L6 (top) was already described in ref. [5b].
The depicted OATS structure for L8 (bottom) is the result of the replacement
of ligand L6 for L8 and it does not correspond to an optimized structure.
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use. All manipulations and reactions were run under inert atmosphere
using anhydrous solvents, in either a glove box or with standard Schlenk-
type techniques. All solvents were dried by using a Solvent Purification
System (SPS). Silica gel 60 (230400 mesh) was used for column
chromatography. NMR spectra were recorded in CDCl3 unless otherwise
fore, preferential placement of Cα in the lower-left quadrant of
the two-dimensional representation shown in Figure 2 (or in the
front-lower-left octant in the three-dimensional representation in
Figure 6), places the substrate far from the steric congestion of
the binaphthyl group. This translates into improved
1
noted, using a 400 MHz or 500 MHz spectrometer. H and 13C{1H} NMR
enantioselectivities when the ligands incorporate
configured [1,1'-biaryl]-2,2'-diol-derived phosphite
a
(Sa)-
group.
chemical shifts are quoted in ppm relative to residual solvent peaks,
whereas 31P{1H} chemical shifts are quoted in ppm relative to 85%
phosphoric acid in water. 19F{1H} NMR chemical shifts are quoted in ppm
relative to BF3·OEt2 in CDCl3. High resolution mass spectra (HRMS)
were recorded by using an ESI ionization method in positive mode.
Optical rotations were measured on a Jasco P-1030 polarimeter. Melting
points were measured in open capillaries on a Büchi B-540 instrument
and are uncorrected. Enantiomeric excesses were determined by GC or
HPLC on using chiral stationary phases. GC analyses were performed on
an Agilent 6890N chromatograph equipped with a FID detector. HPLC
analyses were performed on an Agilent 1200 Series chromatograph
equipped with a diode array UV detector.
Assuming that the stereoelectronic effects operating in the
asymmetric hydrogenations involving ligand L6 also apply to
those of L8 (cfr. to the introduction of this manuscript),
increasing the occupancy of the front-upper-left octant, for
instance by introducing substituents at 3 and 3’ positions of the
(Sa)-[1,1'-biaryl]-2,2'-diol-derived phosphite group, should
translate into higher enantioselectivities of the hydrogenation
products. As discussed above, this working hypothesis was
indeed demonstrated at the experimental level: in all cases,
enantioselectivities obtained with L8 equaled or surpassed those
obtained with L6. We are aware that predicting changes to the
enantioselectivity of this complex transformation cannot be
justified solely in terms of the substitution pattern of the [1,1'-
biaryl]-2,2'-diol-derived phosphite group: manifolds involving
placement of the C=C bond in the right-handed octants may also
be intervening at a low extent.[5b] However, we expect that the
work presented herein demonstrates that analysis based on
octant diagrams for a mechanistically well-understood reaction
may prove useful in designing improved ligands. This strategy is
currently being applied to the design and development of new
ligands having better performance in transformations of interest,
such as hydroformylation. The results will be reported in due
course.
General synthetic procedure for the preparation of Rh-pre-catalyst:
A solution of the POP ligand (1.0 mmol) in anhydrous dichloromethane
(5.0 mL) was slowly added via cannula to
a stirred solution of
[Rh(nbd)2]BF4 (0.98 mmol) in anhydrous dichloromethane (5.0 mL). The
reaction was stirred for 2 h at room temperature under argon atmosphere,
after which the dichloromethane solvent was evaporated off until the
mixture had one fourth of its original volume. Anhydrous diethyl ether
(15.0 mL) was slowly added by syringe and the resulting solution was
slowly stirred to yield an orange suspension. The precipitate was filtered
off under inert atmosphere by using a cannula filter and the resulting
solid was washed with anhydrous diethyl ether (2 x 12.0 mL) and dried in
vacuo to afford the pure [Rh(nbd)(POP)]BF4 complex as an orange
powder.
[Rh(nbd)(L8)]BF4 complex (C1): Rhodium complex C1 was prepared by
following the general procedure, starting from POP ligand L8 (0.088 g,
0.106 mmol) and [Rh(nbd)2]BF4 (0.039 g, 0.101 mmol). It was obtained
as an orange powder (0.097 g, 87% isolated yield). The characterization
data of complex C1 has already been published.[11]
Conclusions
The preparation of rhodium pre-catalysts derived from POP
ligands incorporating the sterically bulky o-Ph-H8-BINOL-derived
phosphite is reported. Structural investigations into the
coordination features of the new POP ligands in rhodium pre-
catalysts for asymmetric hydrogenations have provided insight
into the origin of the increased enantioselectivities obtained for
the asymmetric hydrogenations involving these ligands
compared with those for reported POP ligands lacking
substituents at the 3 and 3’ positions of the [1,1'-biaryl]-2,2'-diol-
derived phosphite group. Of the two described ligands, ligand L8,
which incorporates the sterically bulky (Sa)-o-Ph-H8-BINOL-
derived phosphite fragment, provided perfect enantioselectivities
for an array of eleven structurally diverse olefins (ee’s ranging
from 93 to 99% ee, mean ee value of 98% with an standard
deviation of 1.8 % ee).
[Rh(nbd)(L9)]BF4 complex (C2): Rhodium complex C2 was prepared by
following the general procedure, starting from POP ligand L9 (0.197 g,
0.239 mmol) and [Rh(nbd)2]BF4 (0.088 g, 0.234 mmol). It was obtained
as an orange powder (0.227 g, 86% isolated yield). 1H NMR (400 MHz,
CD2Cl2) δ 7.84–7.74 (m, 2H), 7.62–7.39 (m, 9H), 7.37–7.14 (m, 5H),
7.10–6.85 (m, 7H), 6.76–6.71 (m, 2H), 6.35–6.24 (m, 2H), 5.93 (bs, 1H),
5.16 (bs, 1H), 4.52–4.44 (m, 1H), 4.02–3.96 (m, 2H), 3.86 (bs, 1H), 3.61
(bd, J = 14.5 Hz, 1H), 3.13–2.60 (m, 11H), 2.49–2.26 (m, 2H), 1.96–1.54
(m, 10H); 13C{1H} NMR (100 MHz, CD2Cl2) δ 143.4 (C), 143.3 (C), 142.5
(C), 142.4 (C), 139.8 (C), 138.3 (C), 137.9 (C), 137.5 (C), 137.1 (C),
136.7 (C), 135.3 (CH), 135.2 (CH), 132.70 (C), 132.68 (C), 132.4 (C),
132.3 (C), 132.09 (C), 132.07 (C), 131.9 (CH), 131.82 (CH), 131.82 (CH),
131.79 (CH), 131.69 (CH) 131.62 (CH), 131.59 (CH), 131.4 (CH), 130.74
(CH), 130.70 (CH), 130.4 (CH), 130.3 (CH), 129.9 (C), 129.8 (CH), 129.7
(CH), 129.5 (C), 129.4 (C), 129.3 (C), 129.2 (C), 129.1 (CH), 129.0 (CH),
128.94 (CH), 128.88 (CH), 128.77 (CH), 128.3 (CH), 128.2 (C), 128.1 (C),
127.64 (CH), 127.62 (CH), 103.3–102.9 (m, CH), 99.9–99.6 (m, CH),
93.0–92.8 (m, CH), 78.6 (2JC-P = 8.1 Hz, CH), 75.5 (CH), 72.8 (CH2), 71.7
1
(CH2), 59.6 (CH3), 56.3 (CH), 55.3 (CH), 43.7 (d, JC-P = 24.6 Hz, CH),
29.8 (CH2), 29.7 (CH2), 28.4 (CH2), 28.3 (CH2), 23.13 (CH2), 23.1 (CH2),
Experimental Section
1
23.0 (CH2); 31P{1H} NMR (162 MHz, CD2Cl2) δ 131.3 (dd, JRh-P = 265.2
2
1
2
Hz, JP-P = 68.9 Hz, PO), 27.7 (dd, JRh-P = 146.8 Hz, JP-P = 68.9 Hz,
PC). HRMS (ESI+) [Calculated for C61H58O4P2Rh (MBF4)+ 1019.2860;
observed 1019.2833].
General considerations: All syntheses were carried out using chemicals
as purchased from commercial sources, unless otherwise stated.
Glassware was dried under vacuum and heated with a hot air gun before
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10.1002/ejoc.201701760
European Journal of Organic Chemistry
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General procedure for the Rh-mediated asymmetric hydrogenation
of functionalized substrates: A solution of the required amount of
[Rh(nbd)2]BF4 (1.0 mol-%) and POP ligand L8 L9 (1.1 mol-%) and the
corresponding functionalized olefin (0.10 mmol) in anhydrous and
degassed tetrahydrofuran (0.50 mL) was prepared inside a glass vessel
under N2 atmosphere working in a glove box. In all cases, the molar
concentration of a given substrate in the reaction medium was adjusted
to 0.20 M. Once the reaction mixture had been loaded, the glass vessel
was then placed into one of the positions of a steel autoclave reactor
(HEL Cat-24 parallel pressure multireactor). The autoclave was purged
three times with H2 gas (at a pressure not higher than the selected one)
and finally, the autoclave was pressurized under the required pressure of
H2 gas. The reaction mixture was stirred at r.t. for 18 h (overnight
reaction). The autoclave was then slowly depressurized. The reaction
mixture was filtered through a short pad of SiO2 and eluted with ethyl
acetate (1.0 mL). The resulting solution was concentrated under vacuum
and the conversion was determined by 1H NMR. The enantiomeric
excess was determined by GC or HPLC analysis on chiral stationary
phases.
I. J. Munslow, J. Benet-Buchholz, F. Maseras, A. Vidal-Ferran, Chem.
Eur. J. 2010, 16, 6495-6508; c) H. Fernández-Pérez, P. Etayo, J. L.
Núñez-Rico, A. Vidal-Ferran, Chim. Oggi 2010, 28, XXVI-XXVIII; d) J. L.
Núñez-Rico, P. Etayo, H. Fernández-Pérez, A. Vidal-Ferran, Adv.
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The change to the (S)-configuration in the hydrogenation products of
itaconic acid derivatives and analogues is due to an inversion in the
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[8]
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Supporting Information (see footnote on the first page of this article): X-
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[11] For the experimental preparation and characterization data, see the
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[12] Partially hydrogenated binaphthyl motifs in ligands L8 and L9 present
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Acknowledgements
We thank MINECO (CTQ2014-60256-P and Severo Ochoa
Excellence Accreditation SEV-2013-0319), the ICIQ Foundation
for financial support, and Dr. J. Benet-Buchholz for X-ray
crystallographic analysis. B. Balakrishna thanks the AGAUR for
a pre-doctoral fellowship (2013FI-B 00545). We are grateful to
Rosie Somerville for proofreading the manuscript.
[13] The synthesis and characterization data of ligand L10 have been
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C. Gennari, Chem. Eur. J. 2012, 18, 1383-1400.
Keywords: Asymmetric catalysis • Hydrogenation • Rhodium •
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10.1002/ejoc.201701760
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Asymmetric Hydrogenation*
Héctor Fernández-Pérez, Bugga
Balakrishna, Anton Vidal-Ferran*
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Structural Investigations on
Enantiopure POP Ligands: a Higher
Performing POP Ligand for
Rhodium-catalyzed Hydrogenations
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*A second generation of phosphine-phosphite (a.k.a. POP) ligands, which incorporates a more voluminous phosphite group
than in previous POP ligand designs, led to very efficient catalysts for the Rh-catalyzed enantioselective hydrogenation of a
diverse array of substrates (11 examples, from 93% to 99% ee, mean ee value of 98%).
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