P-chirogenic diphosphazanes with axially chiral substituents and their use in rh-catalyzed asymmetric hydrogenation

Article abstract of DOI:10.1021/acs.joc.0c01108

A convenient synthesis of enantiopure P-chirogenic diphosphazanes incorporating bulky bisphenol and 1,1′-bi-2-naphtholderived substituents via the functionalization of a readily accessible enantiopure lithium phosphinoamide with chlorophosphoridites was developed. Since the product requires no subsequent deprotection, the protocol provides an easy, convenient synthesis of P-chirogenic ligands on the gram scale. The ligands were applied in the Rh-catalyzed asymmetric hydrogenation of benchmark substrates furnishing enantiomeric excess values up to 96%.

Full text of DOI:10.1021/acs.joc.0c01108

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Article
P-chirogenic Diphosphazanes with Axially Chiral Substituents
and their Use in Rh-catalyzed Asymmetric Hydrogenation
Jan-Ole Moritz, Soumyadeep Chakrabortty, Bernd H. Müller, Anke Spannenberg, and Paul C.J. Kamer
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.0c01108 • Publication Date (Web): 14 Sep 2020
Downloaded from pubs.acs.org on September 14, 2020
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P-chirogenic Diphosphazanes with Axially Chiral Substituents and their
Use in Rh-catalyzed Asymmetric Hydrogenation
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‡
‡
Jan-Ole Moritz, Soumyadeep Chakrabortty, Bernd H. Müller, Anke Spannenberg, Paul C. J.
Kamer*
Leibniz-Institut für Katalyse e.V., Albert-Einstein-Straße 29a, 18059 Rostock, Germany
Keywords: P-chirogenic, asymmetric catalysis, Rhodium, hydrogenation
th
Dedicated to Prof. Dr. Uwe Rosenthal on the occasion of his 70 birthday.
Abstract
A convenient synthesis of enantiopure P-chirogenic diphosphazanes incorporating bulky
bisphenol and BINOL-derived substituents via functionalization of a readily accessible
enantiopure lithium phosphinoamide with chlorophosphoridites was developed. Since the
product requires no subsequent deprotection, the protocol provides an easy, convenient
synthesis of P-chirogenic ligands on gram-scale. The ligands were applied in Rh-catalyzed
asymmetric hydrogenation of benchmark substrates furnishing ee’s up to 96%.
Introduction
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Chiral diphosphines are ubiquitous in asymmetric catalysis. The incorporation of a chiral center
or axially chiral fragments into ligand scaffolds is well described in literature.1,2 However, in
most of the catalysts used in this field, the chiral information is located on a carbon and not on
the coordinating phosphorus. After the success of Knowles and co-workers in asymmetric
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hydrogenation with PAMP and DiPAMP, P-chirogenic ligands have gathered more attention.
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The work of Jugé, Imamoto, Horner, Börner and others have set milestones in the synthesis
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of P-chirogenic compounds. In the last two decades, examples like MaxPHOS, MaxPHOX,
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ThaxPHOS, QuinoxP*, or TCFP shined light on the potential of ligands incorporating P-
chirogenic moieties in asymmetric catalysis. In addition, the development of ligands like BINAP
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by Noyori and the phosphoramidite MonoPhos by De Vries and Feringa gave rise to the
use of axially chiral ligands in asymmetric catalysis. Another family of P-stereogenic N-
phosphine-phosphinite ligands have been developed by Diéguez et al. based on readily
available (1R,2S)-(−)-ephedrine and applied in asymmetric hydrogenation with very promising
enantioselectivities up to >99%.13b To the best of our knowledge, the potential of the
incorporation of P-chirogenic components in combination with axially chiral motifs has not been
well explored. The design concept described in here takes this into account (Figure 1) where
we combine the successful application of MaxPHOS with the powerful performance of axially
chiral BINOL-based phosphites.13a,c This concept is based on the work by Krishnamurthy and
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co-workers, who described the synthesis of diphosphazanes with an axially chiral BINOL-
derived P-component.14
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Figure 1 General structure of a PNP ligand incorporation a P-chirogenic center as well as an axially chiral structure
compared to previous work by De Vries, Feringa and Krishnamurthy.
To gain simple access to this motif, a convenient synthesis of an enantiopure and easily
functionalizable nucleophilic PN-synthon is needed. Two of such PN building blocks were
described by Riera and Verdaguer.8,15
Herein, we report a convenient two-step synthesis of both enantiomers of an enantiopure
lithium phosphinoamide, useable as nucleophilic PN-synthon, on multi-gram-scale and its
functionalization towards diphosphazanes. The ligands have been applied in the Rh-catalyzed
asymmetric hydrogenation of alkenes and the cooperativity between the two chiral modules
has been investigated.
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Results and Discussion
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Preparation of the PN-synthon
Kolodyazhnyi et al. described that the base-assisted nucleophilic substitution of (tert-
butyl)phenylchlorophosphine with enantiopure (S)-1-phenylethylamine furnishes
a
diastereomeric mixture of the corresponding phosphazane 1 with diastereomeric ratios up to
90:10 (Scheme 1). The use of (R)- instead of (S)-1-phenylethylamine leads to the
corresponding opposite diastereomeric mixture.16
Scheme 1 Synthesis of P-chirogenic phosphazanes as diastereomeric mixture according to Gryshkun and co-
workers.16
Reaction of the diastereomeric mixture of (R ,S)-1 (major) and (S ,S)-1 (minor) with n-BuLi in
P
P
the presence of TMEDA in n-heptane at – 78 °C furnished a bright yellow precipitate, which
can be dissolved completely upon immediate heating to 80 °C. After cooling down to
recrystallize the compound, diastereomerically pure crystals of (R ,S)-2 were obtained
P
(Scheme 2).
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Scheme 2 Synthesis of enantiopure lithium phosphinoamide. Both enantiomers are available.
The molecular structure of (R ,S)-2 in the solid state revealed the (R)-configuration of the
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phosphorus atom (Figure S 63, for thermal ellipsoid plots of all molecular structures, crystal
parameters and refinement metrics see ESI). As intended with the addition of TMEDA, no
aggregates were observed and the lithium phosphinoamide forms a well-defined monomeric
species (for comparison of lithiation with TMEDA and without see Figures S48 vs S49).
In order to access the enantiomer of (R ,S)-2, (S ,R)-2, the diastereomeric mixture consisting
P
P
of (S ,R)-1 (major) and (R ,R)-1 (minor) is used as starting material for the previously
P
P
described reaction sequence.
Synthesis of PNP-ligands and Coordination Behavior
Generally, 2 can provide easy access to a wide variety of bidentate ligands and was reacted
with phosphorochloridites containing bisphenol and BINOL-moieties. Additionally, reaction
with 2-chloro-1,3,2-dioxaphospholane was also performed to study the interaction of the P-
chirogenic center and the axially chiral BINOL-fragment (Scheme 3). All further modifications
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in the ligand backbone, run smoothly at – 78 °C in toluene and the desired product is obtained
in high purity after separation from LiCl and the removal of the solvent. All the PNP ligands
(L1-L5) are characterized by NMR and mass
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Scheme 3 Synthesized set of optically pure ligands for Rh-catalyzed asymmetric hydrogenation utilizing stereopure
lithium phosphinoamide as PN-building block. Reaction conditions: a) 1.) – 78 °C, 1 eq. of chlorophosphoridite
P P
dissolved in toluene is added to 1 eq. of (R ,S)-2 or (S ,R)-2 (crude) dissolved in toluene; 2.) filtration and removal
of solvent.
spectrometry. 31P{ H} NMR of the ligands shows two signals (doublets) for the phosphine
1
within the range of 55-58 ppm and for the P(OR) of 141-147 ppm (Figure S 45). The coupling
2
constant is also in accordance to the 2JP-P constant in the range of 32-38 Hz. Additionally, the
thermal stability of the ligands was also investigated. The P-chirogenic moiety is stable at room
temperature but tends to epimerize above 80°C, which results in the formation of the other
diastereomer as the P(OR) moiety and the substituent at the amine remain stereo-chemically
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fixed (Figure S 46 and S 47).
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The crystal structure of (R ,S)-L1 reveals (R)-configuration of P1 (Figure S 64). Crystals
P
suitable for X-ray analysis of (S ,R)-L1 (Figure S 65) were obtained applying the synthetic
P
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procedure with (S ,R)- instead of (R ,S)-2 and used for confirmation of the configuration. As
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expected, the molecular structures of (R ,S)-L1 and (S ,R)-L1 are enantiomeric and bond
P
P
lengths and angles differ just slightly. Hence, only the structure of (R ,S)-L1 is discussed
P
herein.
The geometrical environment of N1 is planar as indicated by the sum of the relevant bond
angles (ΣN1 = 359.6(2)°). Additionally, P1-N1 bond distance (1.7304(16) Å) is longer than the
P2-N1 bond (1.6860(16) Å).
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The P{ H} NMR spectrum of the mixture of one equivalent of (R ,S)-L1 (dissolved in CH Cl )
P
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and one equivalent of [Rh(nbd) ]BF (also dissolved in CH Cl ) indicates a 2:1 complex with
2
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an AA’XX’ spin system in which J(AX) and J(AX’) are almost equal as main component (Figure
2). A similar behavior was observed by Vidal-Ferran and co-workers for Rh(I) species ligated
17
by two P-OP ligands. An experiment with a 2:1 ligand to Rh ratio furnished an almost identical
NMR spectrum and the AA’XX’ spin system was confirmed by simple spin system simulation
with coupling constants J(AX) and J(AX’) of 43.1 Hz and 45.0 Hz, respectively.
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X'
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simulated spectrum
with AA'XX' spin system
c)
b)
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ppm
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Figure 2 in situ 31P{ H} NMR spectra of reaction mixtures with [Rh(nbd)
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]BF
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P
: (R ,S)-L1 ratios of 1:1 (a) and 1:2 (b)
1
in CH
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Cl
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and simulated 31P{ H} NMR AA’XX’ spectrum (MestReNova 14, spectrometer frequency: 161 MHz) (c).
Crystals suitable for X-ray diffraction were obtained from the reaction mixture with a
[
Rh(nbd) ]BF : (R ,S)-L1 ratio 1:2 in CH Cl via gas diffusion of Et O into the solution. The
2
4
P
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crystal structure reveals a homoleptic bis-diphosphine complex of rhodium exhibiting a
distorted square planar complex geometry (Figure S 66). The ligand bite angles in the complex
are 69.63(3)° and 69.91(3)°, respectively, and in good accordance with bite angles enforced
by examples of similar PNP ligands coordinated to Rh(I) in a 1:1 fashion8c,18 or 2:1 fashion.19
However, the coordination chemistry of ligand and metal described here does not necessarily
reflect the actual situation during the catalytic reaction as solvents and concentrations are
different.20
Application in Rh-catalyzed asymmetric hydrogenation
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We evaluated the catalytic activity of these P-chirogenic PNP ligands in the asymmetric
hydrogenation of alkenes. In general, the complexes were prepared in situ by the addition of
corresponding PNP ligands to the metal precursor, [Rh(cod) ]BF prior to the catalysis.
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Tables 1 and 2 show the results of the asymmetric hydrogenation of substrates 1 to 4 using
chiral PNP ligands. L1-L5, have been tested in Rh-catalyzed enantioselective hydrogenation
of the benchmark substrate methyl (Z)-α-acetamidocinnamate (S1) in a series of catalytic
experiments. Hydrogenation of the C-C double bond occurred in MeOH at 10 bar of H2
pressure (catalyst/substrate =1:100) at room temperature (25 °C) with complete conversion
but with moderate ee up to 46% (Table 1, entries 1-2, S1, MeOH).
21
MeOH can be a detrimental solvent for P-N as well as P-O bonds. However, when mimicking
the conditions of the catalyst formation in MeOH, only minor decomposition of the ligand was
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1
observed (based on the P{ H} NMR spectrum, Figure S50). In addition, the reactions with S1
were performed in dichloromethane in order to check whether there is any notable solvent
effect or not. No significant differences in ee’s have been observed (Table 1, entries 1-2, S1,
CH Cl ). As we could afford to use MeOH, since the ligands are unexpectedly stable in this
2
2
environmentally more benign solvent, further experiments were performed in MeOH.
To investigate the influence of chirality in the ligand backbone atropoisomerically flexible
biphenyl ligands (R ,S)-L2 was applied in the hydrogenation of S1 leading to moderate
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enantiomeric excess (Table 1, entry 3). The stereoselectivity of the hydrogenation could be
increased up to 20% upon modification on the biaryl part. The ortho-di-substituted biphenyl
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(R ,S)-L3 ligand gave rise to 51% ee (Table 1, entry 4) following the same reaction condition.
P
Finally, the effect of a fixed axial chirality in the P(OR) motif was studied in the catalytic
2
performance using (S) and (R)-BINOL moiety. (R ,S,S )-L4 was applied in the hydrogenation
P
ax
of S1 leading to high enantiomeric excess of 94% (entry 5, table 1). As expected, application
of (S ,R,R )-L4 resulted in formation of the opposite S-enantiomer of the product with similar
P
ax
ee of 96% (Table 1, entry 6). Changing the configuration of the BINOL moiety, forming the
diastereomeric ligand (R ,S,R )-L5, resulted in the formation of S-product albeit in lower ee of
P
ax
78%. Clearly, L4 is the matched diastereomer for the asymmetric hydrogenation of S1, where
L5 represents the mismatched combination of chiral entities.22
Table 1. ee (%) in Rh-catalyzed asymmetric hydrogenation using L1-L5 and S1 in MeOH and
CH Cl
2
2
NHAc
NHAc
H2

[
Rh]/L*
Ph
COOMe
Ph
COOMe
S1
Entry
Ligand
S1 (MeOH)
S1 (CH Cl )
2
2
1
(R ,S)-L1
46% (R)
46% (R)
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(S ,R)-L1
40% (S)
30% (R)
51% (R)
94% (R)
38% (S)
33% (R)
50% (R)
94% (R)
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(R ,S)-L2
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2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(R ,S)-L3
P
(R ,S,S )-
P
ax
L4
6
7
8
(S ,R,R )-
96% (S)
78% (S)
80% (R)
94% (S)
78% (S)
82% (R)
P
ax
L4
(R ,S,R )-
P
ax
L5
(S ,R,S )-
P
ax
L5
Reaction condition: In a stainless steel autoclave, Rh:substrate =1:100 , Rh/L = 1: 1.1,
[
Rh(cod) ]BF (0.005 mmol) as metal precursor, H (10 bar),12 h, appropriate solvent (2mL), T =
2 4 2
2
5 °C, all reactions are performed in duplicate, full conversion was achieved in all cases as
determined by GC. Enantiomeric excess of the product was determined by chiral HPLC (absolute
configuration drawn in parenthesis).
Similarly, (Z)-α-acetamido cinnamic acid (S2) and methyl 2-acetamidoacrylate (S3) were also
asymmetrically hydrogenated (Table 2, entries 1-8 ). The enantiomeric pairs of (R ,S)-
P
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
L1/(S ,R)-L1 and the PNP-BINOL ligands (R ,S,S )-L4/(S ,R,R )-L4 and (R ,S,R )-
P
P
ax
P
ax
P
ax
L5/(S ,R,S )-L5 were tested. Again, both enantiomers of L1 resulted in low ee for S2 and even
P
ax
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
lower for S3. In comparison, enantioselectivity was also increased in the case of S2 and S3
using (R ,S)-L2 and (R ,S)-L3 (Table 2, entry 3 vs entry 4). The (S )-BINOL derivatives
P
P
ax
(
(R ,S,S )-L4 and (S ,R,S )-L5) give rise to (R)-enantiomer (entries 5 and 8, Table 1 and 2)
P
ax
P
ax
and (R )-BINOL moiety (R ,S,R )-L5 and (S ,R,R )-L4) produces the (S)-enantiomer (entries
ax
P
ax
P
ax
6 and 7, Table 1 and 2) in asymmetric hydrogenation of both S2 and S3. A similar matched-
mismatched effect22 as for S1 was observed for these substrates as the degree of
enantioselection again largely depends on the chiral information in the BINOL moiety. The
matched combinations gave up to 30% higher ee than the mismatched ones, as illustrated by
(
R ,S,S )-L4 and (R ,S,R )-L5 for S3. In addition to that, the match effect has also been
P
ax
P
ax
observed in the hydrogenation of dimethyl itaconate (S4) under the same reaction condition
(Table 2, entry 5 and 6 vs 7 and 8). The intrinsic additional chirality (axially chiral BINOL moiety)
in the PNP-ligand backbone apparently plays a pivotal role to achieve high enantioselectivity
in asymmetric hydrogenation.
Table 2. ee (%) in Rh-catalyzed asymmetric hydrogenation using L1-L5 and S2-S4 in MeOH.
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R3

R3
H2
[
Rh]/L*
R1
COOR2
R1
COOR2
MeOH
S2: R = Ph, R = H, R = NHAc
S3: R = H, R = Me, R = NHAc
S4: R = H, R = Me, R = CH COOMe
1
2
3
1
2
3
1
2
3
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Entry
Ligand
S2
S3
S4
-
1
2
3
4
5
6
7
8
(R ,S)-L1
23% (R) 20% (R)
16% (S) 10% (S)
14% (R) 14% (R)
22% (R) 32% (R)
P
(S ,R)-L1
-
P
(R ,S)-L2
nda
nda
P
(R ,S)-L3
P
(R ,S,S )-L4
88% (R) 92% (R) 32% (R)
92% (S) 92% (S) 28% (S)
P
ax
(S ,R,R )-L4
P
ax
(R ,S,R )-L5
84% (S) 60% (S)
80% (R) 72% (R)
-
-
P
ax
(S ,R,S )-L5
P
ax
Reaction condition: In a stainless steel autoclave, Rh:substrate =1:100 , Rh/L = 1: 1.1, [Rh(cod) ]BF
2
4
(0.005 mmol) as metal precursor, H (10 bar),12 h, MeOH (2 mL), T = 25 °C, all reactions are
2
performed in duplicate, full conversion was achieved in all cases as determined by GC.
Enantiomeric excess of the product was determined by chiral HPLC (absolute configuration drawn
a
in parenthesis). Not determined.
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
From the results of the present set of ligands it is clear that steric bulk on the diol part of the
phosphoramidite moiety contributes to improved enantioselectivity but fixing the biaryl axis in
the matched position has the highest impact. Obvious next step is to introduce bisnaphthol
moieties with increasing steric bulk at ortho-positions. This approach has been reported
previously23 and is currently being pursued by us (for further testing of substrates cf. reference
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
26)
.
Conclusions
A series of P-chirogenic diphosphazanes incorporating diol, bisphenol and BINOL-derived
substituents has been prepared on gram-scale. The incorporation of bulky, axially chiral
BINOL-derived moiety into the ligand structure leads to a significant increase of the
enantioselectivity of the catalyst. Additionally, the sole change from (R )- to (S )-configurated
ax
ax
BINOL-fragments is sufficient to invert the stereoselectivity of the reaction, which reveals a
dominant role of the axially chiral part of the ligand in the presented cases. However, the P-
chirogenic fragment is still of importance in this matter, indicated by the observed match-
mismatched interaction. Careful arrangement of both chirogenic sites of the presented system
is required to achieve high enantioselectivity.
Experimental Section
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9
All synthetic work was performed under oxygen- and moisture free conditions using standard
Schlenk and glovebox techniques. All reagents were purchased from commercial sources and
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
used as received, unless otherwise stated. TMEDA, NEt , (S)-1-phenylethylamine, (R)-1-
3
phenylethylamine, CD Cl and CD Cl were dried over CaH , distilled prior to use, and
3
2
2
2
degassed with three freeze-pump-thaw cycles. THF was distilled from Na/benzophenone.
Toluene and CH Cl (amylene stabilized (50 ppm)) were bought from Acros Organics with
2
2
99.85% purity, <0.005% water content and stored under inert atmosphere over molecular
sieves. n-Heptane and C D were dried over Na/benzophenone and tetraglyme and distilled
6
6
24
prior to use. n-Pentane was purified using Grubbs-type column system Pure Solv MD-5. 2-
Chloro-1,3,2-dioxaphospholidine was bought from TCI and degassed via freeze-pump-thaw
cycles. (R)- and (S)-BINOL were bought from Merck and used as received. Samples for mass
spectrometry were prepared in the glove box and measured on a Finnigan MAT 95-XP
(Thermo Electron) or Kratos MS-50 spectrometer and measurements were carried out in
HRMS (ESI-TOF) mode. Fragment signals are given in mass per charge number (m/z). NMR
1
13
31
spectra were recorded on Bruker Avance 300 ( H: 300, C: 75, P: 121 MHz), Bruker Fourier
1
1
3
00 ( H: 300, 13C: 75, 31P: 121 MHz) or Avance 400 ( H: 400, 13C: 100, 31P: 161 MHz)
instruments operating at the denoted spectrometer frequency given in Megahertz (MHz) for
the specified nucleus. Samples for measurement of melting points were prepared under argon
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
in a capillary tube sealed with grease. The measurements were conducted on a Mettler-Toledo
MP-70 melting point apparatus. Optical rotations were measured on an Anton Paar MCP 200.
Experimental details of the X-ray single crystal analysis are described in the ESI.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Synthesis of (R ,S)-1/(S ,S)-1 (diastereomeric mixture) A 50 mL Schlenk-tube was filled with
P
P
(S)-1-phenylethylamine (0.9 mL, 7.07 mmol), which was subsequently dissolved in toluene
(
20 mL). After addition of NEt (1.0 mL, 7.17 mmol), tert-butylphenylchlorophosphine (1.3 mL,
3
6.90 mmol) was added dropwise into the mixture. Upon heating in an oil bath to 90 °C (16 h),
a white precipitate was formed. The supernatant was filtered off and the precipitate was
washed with toluene (2.5 mL). The solvent was completely removed from the filtrate, yielding
1
1 as colorless oil (1.8 g, 6.31 mmol). Yield: 91%. H (300 MHz, CD Cl ): δ 7.51-7.18 (m, 10H,
2
2
ArH), 4.32-4.16 (m, 1H, CH), 2.16 (m, 1H, NH), 1.56 (major) and 1.47 (minor) (d, 2JHH = 6.6
3
Hz, 3H [integrated as one signal], CH ), 0.99 (major) and 0.95 (minor) (d, J = 12.8 Hz, 9H
3
PH
13
1
3
[
integrated as one signal], (CH ) ); C{ H} NMR (75 MHz, CD Cl ): δ 147.9 (d, J = 3.8 Hz,
3
3
2
2
PC
ipso-NPh, major), 147.6 (d, 3JPC = 5.2 Hz, ipso-NPh, minor), 140.9 (d, 1JPC = 28.5 Hz, ipso-
PPh, minor), 140.4 (d, 1JPC = 25.0 Hz, ipso-PPh, major), 131.5, 131.2, 128.6, 128.4, 127.9 (d,
J = 6.6 Hz, ArC), 127.8 (d, J = 6.7 Hz, ArC), 127.1 – 126.5 (m, ArC), 57.4 (d, 2JPC = 26.7 Hz,
CH, major), 57.1 (d, 2JPC = 25.6 Hz, CH, minor) 31.5 (d, J = 7.4 Hz), 31.3 (d, J = 6.0 Hz), 26.2
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3
31
1
(
d, 1JPC = 14.9 Hz, C(CH ) ), 25.8 (d, J = 8.1 Hz, NCH ); P{ H} (121 MHz, CD Cl ): δ 48.22
3 3
PC
3
2
2
(minor, 17%), 47.58 (major, 83 %)
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Analytical data match previously reported data.16
The opposite product (S ,R)-1/(R ,R)-1 (diastereomeric mixture) was obtained in the same
P
P
31
1
way: P{ H} (121 MHz, CD Cl ): δ = 48.21 (minor, 17%), 47.58 (major, 83 %)
2
2
Analytical data match previously reported data.16
Synthesis of phosphorochloridites
The synthesis was carried out according to the general procedure for phosphorochloridites
formation and the analytical data matched with the reported procedure.25
2
,2′-biphenol phosphochloridite
A solution of 2,2′-biphenol (1.61g, 8.75 mmol ) in THF (25mL) was slowly added to a mixture
of PCl (1.0 mL, 11.4 mmol) and Et N ( 2.7 mL, 19.25 mmol) in THF (10 mL) at 0 °C. After 22
3
3
h, the reaction mixture was filtered under inert atmosphere and the solvent was evaporated to
yield the white-yellowish powder (1.75g, 80%).
1
13
1
H NMR (300 MHz, C D ): δ 7.1-7.0 (m, 2H), 6.9-6.8 (m, 6H). C{ H} NMR (75 MHz, C D ): δ
6
6
6
6
31
1
1
49.8, 131.4, 130.8, 129.7, 126.3, 122.5. P{ H} NMR (122 MHz, C D ): δ 180.1.
6
6
3,3',5,5'-tetra-tert-butyl-[1,1'-biphenyl]-2,2'-diol phosphochloridite
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
A solution of 3,3',5,5'-tetra-tert-butyl-[1,1'-biphenyl]-2,2'-diol (3.5g, 8.75 mmol ) in THF (25mL)
was slowly added to a mixture of PCl (1.0 mL, 11.4 mmol) and Et N ( 2.7 mL, 19.25 mmol) in
3
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
THF (10 mL) at 0 °C. After 22 h, the reaction mixture was filtered under inert atmosphere and
the solvent was evaporated to yield the white-yellowish powder (3.30g, 82%).
1
13
1
H NMR (400 MHz, CDCl ): δ 7.4 (s, 2 H), 7.1 (s, 2 H), 1.4 (s, 18H), 1.3 (s, 18H). C{ H} NMR
3
(
101 MHz, CDCl ): δ 147.7, 145.7, 140.6, 133.7, 128.2, 128.0, 127.7, 126.9, 124.5, 35.7, 34.9,
3
31
1
3
1.7. P { H} NMR (162 MHz, CDCl ): δ 171.6.
3
(S)/(R)-BINOL-phosphorochloridites
A solution of (S) or (R)-1,1’-bi-2-naphthol (2.5 g, 8.75 mmol) in THF (25mL) was slowly added
to a mixture of PCl (1.0 mL, 11.4 mmol) and Et N ( 2.7 mL, 19.25 mmol) in THF (10 mL) at 0
3
3
°
C. After 22 h, the reaction mixture was filtered under inert atmosphere and the solvent was
evaporated to yield the white-yellowish powder (2.60g, 85%).
1
13
1
H NMR (300 MHz, CDCl ): δ 8.07-7.98 (m, 4H), 7.58-7.30 (m, 8H) ppm. C{ H} NMR (75
3
MHz, CDCl ): δ 148.0, 147.5, 132.3, 131.7, 131.1, 130.2, 128.6, 128.2, 127.9, 127.6, 127.2,
3
31
1
1
27.1, 126.7, 126.6, 125.9, 125.6, 121.8, 121.3 ppm. P{ H} NMR (121 MHz, CDCl ): δ 178.4
3
ppm.
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Synthesis of PNP ligands
(
R ,S)-L1. (R ,S)-1/(S ,S)-1 (diastereomeric mixture (83:17); 1.74 g; 6.09 mmol) was dissolved
P
P
P
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
in heptane (38 mL). TMEDA (1.00 mL, 6.70 mmol) was added and subsequently the solution
was cooled down to –78 °C. Next, nBuLi (2.5 M in n-hexane; 2.44 mL) was added dropwise
into the mixture. Immediately after addition, a yellow precipitate occurred and the cooling bath
was removed, allowing the solution to reach room temperature. Upon heating in an oil bath to
80 °C the yellow solid was dissolved and recrystallized at room temperature overnight.
Afterwards, the supernatant was removed via cannula followed by drying of the yellow crystals
in vacuo and the solid was weighed (1.64 g, 4.02 mmol). The yellow solid was dissolved in
toluene (30 mL) and brought to reaction with 2-chloro-1,3,2-dioxaphospholidine (536 mg, 4.20
mmol) leading to formation of a white precipitate. The solid was filtered off and the solvent was
removed in vacuo. The obtained white solid was dissolved again in toluene (35 mL) to remove
the last percentage of insoluble compounds. Again, the solids were filtered off and the solvent
were completely removed in vacuo. A white powder was obtained, which was washed with n-
pentane at –78 °C. Upon drying, 1.09 g (2.90 mmol) of the optically pure product (R ,S)-L1
P
was received as a colorless powder. Crystals suitable for X-ray analysis were collected from
the washing solution at 6 °C. Yield: 48% (1.09 g). M.p. 121°C. [훼]2 = + 28.2° (푐 0.5, CH Cl )
98
퐷
2
2
1
H NMR (400 MHz, C D ): δ 8.02-7.95 (m, 2H), 7.63-7.55 (m, 2H), 7.28-7.18 (m, 4H), 7.14-
6
6
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
7
.02 (m, 2H), 4.76-4.64 (m, 1H), 3.87-3.76 (m, 1H), 3.69-3.60 (m, 1H), 3.52-3.36 (m, 2H), 1.5
dd, 3H, 3JHH = 7.02 Hz, J = 0.86 Hz), 1.06 (d, 9H, J = 13.77 Hz). C{ H} NMR (100 MHz,
3
13
1
(
0
1
2
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8
9
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1
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3
4
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
C D ): δ 142.6 (d, J = 3.5 Hz), 140.5 (dd, J = 30.3 Hz), 132.9 - 132.0 (m), 129.4 (d, J = 2.8 Hz),
6
6
128.3 - 126.9 (m), 126.8, 64.4, 64.0 (d, J = 8.5 Hz), 53.0 (dd, J = 27.0 Hz, J = 2.1 Hz), 32.7
15
(dd, J = 18.6 Hz, J = 4.3 Hz), 29.0 (dd, J = 17.5 Hz, J = 9.7 Hz), 20.2 (d, J = 14.5 Hz); N (30
31
1
2
2
MHz, C D ): δ = –279.6 (m); P{ H} (161 MHz, C D ): δ 146.30 (d, J = 33 Hz), 54.38 (d, J =
6
6
6
6
33 Hz). HRMS (ESI-TOF): m/z calculated for C H NO P : 376.1595 [M+H]+; observed
20
27
2
2
376.1595. EA: Anal. calcd. for C H NO P : C: 63.99, H: 7.25, N: 3.73. Found: C: 63.93, H:
20
27
2
2
7.46, N:3.79
(S ,R)-L1. (S ,R)-L1 was synthesized according to the procedure described for (R ,S)-L1.
P
P
P
Crystals suitable for X-ray analysis were collected from the washing solution at 6 °C. Yield:
7% (0.84 g). M.p. 121°C. [훼] 2퐷 98 = ― 28.8° (푐 0.5, CH Cl ) H NMR (400 MHz, C D ): δ 8.03-
1
3
7
3
2
2
6
6
.96 (m, 2H), 7.64-7.55 (m, 2H), 7.28-7.18 (m, 4H), 7.14-7.01 (m, 2H), 4.76-4.64 (m, 1H), 3.85-
.76 (m, 1H), 3.69-3.60 (m, 1H), 3.52-3.36 (m, 2H), 1.5 (dd, 3H, 3JHH = 7.06 Hz, J = 0.88 Hz),
3
13
1
1.06 (d, 9H, J = 13.80 Hz ); C{ H} NMR (100 MHz, C D ) δ 142.6, 140.5, 132.5, 129.8, 125.7,
6
6
31
1
2
64.4, 64.0, 53.0, 32.7, 29.0, 20.2; P{ H} NMR (161 MHz, C D ): δ 146.22 (d, J = 32.9 Hz),
6
6
2
54.38 (d, J = 32.8 Hz). HRMS (ESI-TOF): m/z calculated for C H NO P : 376.1595 [M+H]+;
20
27
2
2
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observed 376.1596. EA: Anal. calcd. for C H NO P : C: 63.99, H: 7.25, N: 3.73. Found: C:
20
27
2
2
64.06, H: 7.26, N: 3.85
1
1
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(
R ,S)-L2. Optically pure (R ,S)-2 was prepared according the previously mentioned protocol
P
P
and used as crude material. A solution of pure 2,2′-biphenol phosphochloridite (0.36 mmol, 90
mg) dissolved in toluene (10 mL) was slowly added to (R ,S)-2 (0.36 mmol, 150 mg) in toluene
P
(10 mL) at - 78 °C. The mixture was allowed to reach room temperature and stirred for 10 h.
The resulting solution was filtered, and the solvent was removed in vacuo. A white solid was
formed, which was again washed with n-pentane to obtain (R ,S)-L2 in optically pure form.
P
Yield: 54% (0.098g). M.p. 153°C. [훼]2 = + 90.8° (푐 0.5,CH Cl ) H NMR (300 MHz, C D ): δ
98
1
퐷
2
2
6
6
8.11 (m, 2H), 7.67 (d, 2H, J = 8.7 Hz), 7.31-7.19 (m, 8H), 7.12- 6.92 (m, 6H), 5.30- 5.23(m,
13
1
1
H), 1.58 (d, 3H, J = 7 Hz), 1.09 (d, 9H, J = 14 Hz). C{ H} NMR (75 MHz, C D ): δ 133.6
6
6
(ArC), 133.3 (ArC), 132.7 (ArC), 130.6 (ArC), 130.4 (ArCH), 130.1 (ArCH), 129.8 (ArC), 129.7
(ArC), 129.4 (ArCH), 129.0 (ArCH), 127.3 (ArCH), 125.4 (ArCH), 124.4 (ArCH), 122.9 (ArCH),
31
1
1
20.7 (ArCH), 53.9 (NCCH ), 34.0 (PC(CH ) ), 29.2 (PC(CH ) ), 20.8 (NCCH ). P{ H} NMR
3
3 3
3 3
3
2
2
(122 MHz, C D ) δ 142.7 (d, J = 37.9 Hz), 54.9 (d, J = 37.9 Hz). HRMS (ESI-TOF): m/z
6
6
+
calculated for C H NO P : 500.1908 [M+H] ; observed 500.1900.
30
31
2
2
(R ,S)-L3 was synthesized following the same protocol as mentioned for (R ,S)-L2 using
P
P
3
,3',5,5'-tetra-tert-butyl-[1,1'-biphenyl]-2,2'-diol phosphochloridite and crude (R ,S)-2. Yield:
P
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6
3% (0.138 g). M.p. 175°C. [훼] 2퐷 98 = 124.5° (푐 0.5, CH Cl ) H NMR (400 MHz, CDCl ): δ 7.91
1
5
2
2
3
(
m, 2H), 7.35- 7.29 (m, 3H),7.24- 7.20 (m, 3H), 7.13 (m, 1H), 7.07- 6.94 (m, 5H), 4.70 (m, 1H),
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1.36 (s, 9H), 1.24 (s, 9H), 1.17 (s, 9H), 1.14 (d, 3H, J = 8 Hz) , 0.89 (s, 9H), 0.72 (d, 9H, J =
13
1
14 Hz). C{ H} NMR (101 MHz, CDCl ): δ 148.0 (ArC), 147.9 (ArC), 147.5 (ArC), 146.1 (ArC),
3
1
45.8 (ArC), 144.1 (ArC), 140.6 (ArC), 139.5 (ArC), 133.3 (ArCH), 132.2 (ArCH), 130.2 (ArCH),
29.6 (ArC), 129.2 (ArC), 128.4 (ArCH), 128.2 (ArCH), 128.0 (ArCH), 127.7 (ArCH), 127.4
1
(
ArCH), 127.0 (ArCH), 125.8 (ArCH), 125.5 (ArCH), 124.4 (ArCH), 124.3 (ArCH),
55.6(NCCH ), 35.3 C(CH ) , 34.8(PC(CH ) ), 33.6 (C(CH ) ), 31.7 (C(CH ) ), 31.1 (C(CH ) ),
3
3 3
3 3
3 3
3 3
3 3
31
1
2
28.3(PC(CH ) ), 21.6 (NCCH ). P{ H} NMR (162 MHz, CDCl ) δ 145.9 (d, J = 34.1 Hz), 53.9
3
3
3
3
2
+
(
d, J = 36.5 Hz). HRMS (ESI-TOF): m/z calculated for C H NO P : 724.4412 [M+H] ;
46
63
2
2
observed 724.4419.
(
R ,S,S )-L4. Optically pure (R ,S)-2 was prepared according the previously mentioned
P
ax
P
protocol and used as crude material. A solution of optically pure (S)-BINOL phosphochloridite
(
0.36 mmol, 133 mg) dissolved in toluene (10 mL) was slowly added to (R ,S)-2 (0.36 mmol,
P
150 mg) in toluene (10 mL) at - 78 °C. The mixture was allowed to reach at room temperature
and stirred for 10 h. The resulting solution was filtered, and the solvent was removed in vacuo.
A white solid was formed, which was again washed with pentane to obtain (R ,S,S )-L4 in
P
ax
optically pure form. Yield: 49% (0.105 g). M.p. 147°C. [훼] 2퐷 98 = +188.1° (푐 0.5, CH Cl ) H NMR
1
2
2
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(
400 MHz, CDCl ): δ 8.06 (d, 1H, J = 8.74 Hz), 7.99-7.93 (m, 3H), 7.88 (d, 1H, J = 8.97), 7.81
3
(d, 1H, J = 8.29 Hz), 7.57-7.28 (m, 16H), 4.90 (m, 1H), 1.51 (d, 3H, J = 6.12 Hz), 1.00 (d, 9H,
13
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
J = 14.04 Hz) ppm. C{ H} NMR (100 MHz, CDCl ): δ 151.0 (ArC), 149.0 (ArC), 143.3 (ArC),
3
133.3 (ArC), 133.1 (ArC), 132.6 (ArC), 130.8 (ArCH), 130.5 (ArCH), 129.9 (ArC), 129.2 (ArC),
1
28.7 (ArCH), 128.5 (ArCH), 128.3 (ArCH), 128.2 (ArCH), 128.0 (ArCH), 128.0 (ArCH), 127.7
(
ArCH), 127.5 (ArCH), 127.4 (ArCH), 127.0 (ArCH), 126.5 (ArCH), 126.4 (ArCH), 126.1
ArCH), 125.1(ArCH), 124.6 (ArCH), 122.5 (ArC), 122.2 (ArC), 54.6(NCCH ), 34.2 (PC(CH ) ),
(
3
3 3
31
1
2
29.4(PC(CH ) ) , 21.9 (NCCH ) ppm. P{ H} NMR (161 MHz, CDCl ): δ 144.63 (d, J = 37 Hz),
3
3
3
3
2
58.64 (d, J = 37 Hz) ppm. HRMS (ESI-TOF): m/z calculated for C H NO P : 600.2221
38
35
2
2
+
[
M+H] ; observed 600.2236.
(S ,R,R )-L4. (S ,R,R )-L4 was synthesized following the same protocol as mentioned for
P
ax
P
ax
(R ,S,S )-L4 using (R)-BINOL phosphochloridite and crude (S ,R)-2. Yield: 39% (0.083 g).
P
ax
P
M.p. 148°C. [훼]2 = ―188.7° (푐 0.5, CH Cl ) H NMR (400 MHz, CDCl ): δ 7.90 (d, 1H,
98
1
퐷
2
2
3
J = 8.08 Hz) , 7.84-7.75 (m, 3H), 7.71 (d, 1H, J = 7.70 Hz), 7.65 (d, 1H, J = 9.33 Hz), 7.42-7.07
13
1
(m, 16H), 4.73 (m, 1H), 1.27 (d, 3H, J = 6.02 Hz), 1.01 (d, 9H, J = 12.91 Hz) ppm. C{ H} NMR
(100 MHz, CDCl ): δ 151.2 (ArC), 149.4 (ArC), 142.8 (ArC), 134.4 (ArC), 133.0 (ArC), 131.6
3
(ArC), 130.8 (ArCH), 130.5 (ArCH), 129.9 (ArC), 129.2 (ArC), 128.7 (ArCH), 128.5 (ArCH),
1
28.2 (ArCH), 128.0 (ArCH), 127.7 (ArCH), 127. 5 (ArCH), 127.0 (ArCH), 126.4 (ArCH), 125.1
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2
2
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2
2
2
2
3
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(
ArCH), 124.6 (ArCH), 122.5 (ArCH), 122.2 (ArC), 120.1 (ArC), 54.4 (NCCH ), 34.3
3
31
1
(PC(CH ) ), 29.3 (PC(CH ) ), 21.8 (NCCH ) ppm. P{ H} NMR (161 MHz, CDCl ): δ 144.63
3
3
3 3
3
3
2
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
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8
9
0
1
2
3
4
5
6
7
8
9
0
(d, J = 36.96 Hz), 58.64 (d, J = 37.05 Hz) ppm. HRMS (ESI-TOF): m/z calculated for
+
C H NO P : 600.2221 [M+H] ; observed 600.2223.
38
35
2
2
(R ,S,R )-L5. (R ,S,R )-L5 was synthesized following the same protocol as mentioned for
P
ax
P
ax
(R ,S,S )-L4 using (R)-BINOL phosphochloridite and crude (R ,S)-2 adduct. Yield: 50%
P
ax
P
0.107 g). M.p. 156°C. [훼] 2퐷 98 = ―167.2° (푐 0.5, CH Cl ) H NMR (400 MHz, CDCl ): δ 7.94 (d,
1
(
2
2
3
1
H, J = 8.56 Hz), 7.87-7.83 (m, 3H), 7.78 (d, 1H, J = 8.56 Hz), 7.61 (d, 1H, J = 9.10 Hz ), 7.40-
13
1
7
.05 (m, 16H) , 4.65 (m, 1H), 1.53 (d, 3H, J = 6.73 Hz) , 1.00 (d, 9H, J = 13.04 Hz) ppm. C{ H}
NMR (100 MHz, CDCl ): δ 150.4 (ArC), 149.5 (ArC), 142.2 (ArC), 133.01 (ArC), 133.0 (ArC),
3
1
32.9 (ArC), 131.5 (ArCH), 131.4 (ArCH), 129.7 (ArC), 129.6 (ArC), 129.1 (ArCH), 128.6
(ArCH), 128.4 (ArCH), 128.2 (ArCH), 128.1 (ArCH), 127.9 (ArCH), 127.2 (ArCH), 126.9
(ArCH), 126.3 (ArCH), 126.2 (ArCH), 125.0 (ArCH), 124.7 (ArCH), 122.2 (ArC), 122.0 (ArC),
31
1
5
3.8 (NCCH ), 33.4 (PC(CH ) ), 28.8 (PC(CH ) ), 21.0 (NCCH ) ppm. P{ H} NMR (161 MHz,
3
3 3
3 3
3
2
2
CDCl ): δ 141.83 (d, J = 38 Hz) , 55.33 (d, J = 38 Hz) ppm. HRMS (ESI-TOF): m/z calculated
3
+
for C H NO P : 600.2221 [M+H] ; observed 600.2232.
38
35
2
2
(S ,R,S )-L5. (S ,R,S )-L5 was synthesized following the same protocol as mentioned for
P
ax
P
ax
(R ,S,S )-L4 using (S)-BINOL phosphochloridite and crude (S ,R)-2. Yield: 40% (0.085 g).
P
ax
P
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M.p. 155°C. [훼]2 = +167.9° (푐 0.5, CH Cl ) H NMR (400 MHz, CDCl ): δ 8.03 (d, 1H,
98
1
퐷
2
2
3
J = 9.02 Hz), 7.99 (m, 3H), 7.93-7.90 (m, 1H), 7.62 (d, 1H, J = 7.76 Hz), 7.53-7.17 (m, 16H),
13
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1.52 (d, 3H, J = 8.05 Hz), 1.00 (d, 9H, J = 14.81 Hz) ppm. C{ H} NMR (100 MHz, CDCl ): δ
3
151.0 (ArC), 149.2 (ArC), 141.8 (ArC), 138.6 (ArC), 134.5 (ArC), 132.9 (ArC), 131.5 (ArCH),
1
30.7 (ArCH), 129.8 (ArC), 129.7 (ArC), 128.7 (ArCH), 128.5 (ArCH), 128.3 (ArCH), 128.2
(
ArCH), 128.0 (ArCH), 127.7 (ArCH), 127.6 (ArCH), 127.3 (ArCH), 127.0 (ArCH), 126.4
ArCH), 126.2 (ArCH), 125.5 (ArCH), 125.1 (ArCH), 124.8 (ArCH), 122.3 (ArC), 122.1 (ArC),
(
31
1
53.8 (NCCH ), 33.7 (PC(CH ) ), 29.2 (PC(CH ) , 21.2 (NCCH ) ppm. P{ H} NMR (161 MHz,
3
3 3
3 3
3
2
2
CDCl ): δ 141.83 (d, J = 38 Hz), 55.33 (d, J = 38 Hz) ppm. HRMS (ESI-TOF): m/z calculated
3
+
for C H NO P : 600.2221 [M+H] ; observed 600.2228.
38
35
2
2
General procedure for asymmetric hydrogenation
All the hydrogenation experiments were performed in stainless steel autoclave charged with
an insert suitbale for up to 8 reaction vessels (4 mL) with teflon mini stirring bars. In a typical
experiment, a reaction vessel is charged with [Rh(cod) ]BF (1.9 mg, 5µmol) and ligand
2
4
(
5.5µmol, M/L= 1/1.1) and stirred for 10-15 mins in the appropiate solvent (2 mL). Then the
desired substrates (0.5 mmol) were added to the reaction vessel maintaining the inert
atmosphere and the vessels were placed in a high pressure autoclave. First the autoclave was
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purged two times with nitrogen and three times with hydrogen. Finally it was pressurized at 10
bar of H pressure at 25 ° C for 12 hrs. After the desired reaction time, the autoclave was
2
0
1
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3
4
5
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7
8
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0
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0
depressurized and the reaction vessels were diluted with EtOAc and filtered through a short
pad of silica. The conversion was determined by GC measurement and the enantiomeric exess
was measured by chiral HPLC.
31
1
In situ P{ H} NMR experiments of (R ,S)-L1 and [Rh(nbd) ]BF
P
2
4
To a solution of (R ,S)-L1 (0.20 mmol, 70 mg) in CH Cl (10 mL) a solution of [Rh(nbd) ]BF
P
2
2
2
4
(
0.05 M) in CH Cl (1.8 mL for M:L ratio 1:2; 3.4 mL for 1:1 ratio) was added at room
2
2
temperature. After 1h, a sample was taken (0.4 mL) and submitted for NMR measurement
(
solvent: 0.2 mL CD Cl ).
2
2
ASSOCIATED CONTENT
Supporting information
NMR spectra, detailed structural information of the synthesized compounds and HPLC traces,
thermal ellipsoid plots, crystal data and refinement metrics of reported crystal structures. This
material is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
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Paul C. J. Kamer - Leibniz-Institut für Katalyse e.V. Albert-Einstein-Straße 29a 18059 Rostock,
Germany;
Email: Paul.Kamer@catalysis.de
Authors
Jan-Ole Moritz - Leibniz-Institut für Katalyse e.V. Albert-Einstein-Straße 29a 18059 Rostock,
Germany.
Soumyadeep Chakrabortty - Leibniz-Institut für Katalyse e.V. Albert-Einstein-Straße 29a
18059 Rostock, Germany.
Bernd H. Müller - Leibniz-Institut für Katalyse e.V. Albert-Einstein-Straße 29a 18059 Rostock,
Germany.
Anke Spannenberg - Leibniz-Institut für Katalyse e.V. Albert-Einstein-Straße 29a 18059
Rostock, Germany.
Notes
The authors declare no competing financial interest.
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Author Contributions
‡J.-O.M. and S.D.C. contributed equally.
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Acknowledgement
We thank Deutsche Forschungsgemeinschaft e.V. (KA 2936/1-1) for financial support. We
would also like to thank Prof. Johannes G. de Vries for fruitful discussions and LIKAT for the
analytical facilities.
References
(1) Börner, A., Ed. Phosphorus Ligands in Asymmetric Catalysis - Synthesis and Application;
Wiley-VCH: Weinheim, 2008.
(2) McCarthy, M.; Guiry, P. J. Axially chiral bidentate ligands in asymmetric catalysis.
Tetrahedron 2001, 57, 3809.
(3) Knowles, W. S.; Sabacky, M. J.; Vineyard, B. D.; Weinkauff, D. J. Asymmetric
hydrogenation with a complex of rhodium and a chiral bisphosphine. J. Am. Chem. Soc. 1975,
97, 2567.
(4) a) Jugé, S.; Stephan, M.; Laffitte, J. A.; Genet, J. P. Efficient asymmetric synthesis of
optically pure tertiary mono and diphosphine ligands. Tetrahedron Lett. 1990, 31, 6357. b)
Dutartre, M.; Bayardon, J.; Jugé, S. Applications and stereoselective syntheses of P-chirogenic
phosphorus compounds. Chem. Soc. Rev. 2016, 45, 5771.
(5) a) Imamoto, T.; Oshiki, T.; Onozawa, T.; Kusumoto, T.; Sato, K. Synthesis and reactions
of phosphine-boranes. Synthesis of new bidentate ligands with homochiral phosphine centers
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The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
via optically pure phosphine-boranes. J. Am. Chem. Soc. 1990, 112, 5244. b) Imamoto, T.;
Watanabe, J.; Wada, Y.; Masuda, H.; Yamada, H.; Tsuruta, H.; Matsukawa, S.; Yamaguchi,
K. P-Chiral Bis(trialkylphosphine) Ligands and Their Use in Highly Enantioselective
Hydrogenation Reactions. J. Am. Chem. Soc. 1998, 120, 1635.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(6) Horner, L.; Jordan, M. Zur Stereochemie und zum chemischen Verhalten optisch aktiver
Amidophosphoniumsalze und optisch aktiver Phosphinigsaureamide. Phosphorus Sulfur
Relat. Elem. 1980, 8, 225.
(7) Dubrovina, N. V.; Börner, A. Enantioselective Catalysis with Chiral Phosphine Oxide
Preligands. Angew. Chem. Int. Ed. 2004, 43, 5883.
(8) a) Revés, M.; Ferrer, C.; León, T.; Doran, S.; Etayo, P.; Vidal-Ferran, A.; Riera, A.;
Verdaguer, X. Primary and Secondary Aminophosphines as Novel P-Stereogenic Building
Blocks for Ligand Synthesis. Angew. Chem. Int. Ed. 2010, 49, 9452. b) Grabulosa, A.; Doran,
S.; Brandariz, G.; Muller, G.; Benet-Buchholz, J.; Riera, A.; Verdaguer, X. Nickel(II) and
Palladium(II) Complexes of the Small-Bite-Angle P-Stereogenic Diphosphine Ligand
MaxPHOS and Its Monosulfide. Organometallics 2014, 33, 692. c) Cristóbal-Lecina, E.;
Constantino, A. R.; Grabulosa, A.; Riera, A.; Verdaguer, X. Rhodium-Catalyzed Pauson–
Khand Reaction Using a Small-Bite-Angle P-Stereogenic C -Diphosphine Ligand.
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Organometallics 2015, 34, 4989 d) the MaxPHOS-family was recently reviewed in Cabré, A.;
Riera, A.; Verdaguer, X. P-Stereogenic Amino-Phosphines as Chiral Ligands: From Privileged
Intermediates to Asymmetric Catalysis. Acc. Chem. Res. 2020, 53, 676.
(9) a) Orgué, S.; Flores-Gaspar, A.; Biosca, M.; Pámies, O.; Dieguez, M.; Riera, A.; Verdaguer,
X. Stereospecific S(N)2@P reactions: novel access to bulky P-stereogenic ligands. Chem.
Commun. 2015, 51, 17548. b) Orgué, S.; León, T.; Riera, A.; Verdaguer, X. Asymmetric
Intermolecular Cobalt-Catalyzed Pauson-Khand Reaction Using a P-Stereogenic Bis-
Phosphane. Org. Lett. 2015, 17, 250.
(10) Imamoto, T.; Sugita, K.; Yoshida, K. An Air-Stable P-Chiral Phosphine Ligand for Highly
Enantioselective Transition-Metal-Catalyzed Reactions. J. Am. Chem. Soc. 2005, 127, 11934.
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