Quinaphos and dihydro-quinaphos phosphine-phosphoramidite ligands for asymmetric hydrogenation

Article abstract of DOI:10.1002/chem.201000063

New derivatives of the Quinaphos ligands and the related Dihydro-Quinaphos ligands based on the more flexible 1,2,3,4-tetrahydroquinoline backbone have been prepared and fully characterised. A general and straightforward separation protocol was devised, which allowed for the gram-scale isolation of the R _a,S_c and S_a,R_c diastereomers. These new phos-phine-phosphoramidite ligands have been applied in the Rh-catalysed asymmetric hydrogenation of functionalised olefins with the achievement of excel-lent enantioselectivities (≥99%) in most cases and turnover frequency (TOF) values of up to ≥ 20000 h^-1. These results substantiate the practical utility of readily accessible Quinaphostype ligands, which belong to the most active and selective category of ligands for Rh-catalysed hydrogenation known to date.

Full text of DOI:10.1002/chem.201000063

FULL PAPER
DOI: 10.1002/chem.201000063
Quinaphos and Dihydro-Quinaphos Phosphine–Phosphoramidite Ligands for
Asymmetric Hydrogenation
Thomas Pullmann,[a] Barthel Engendahl,[a] Ziyun Zhang,[a] Markus Hçlscher,[a]
Antonio Zanotti-Gerosa,[b] Alan Dyke,[b] Giancarlo Franciꢀ,*[a] and Walter Leitner*[a]
Dedicated to Professor Felice Faraone, for his inspiration in the development of Quinaphos, on the occasion of his retirement
Abstract: New derivatives of the Qui-
naphos ligands and the related Dihy-
dro-Quinaphos ligands based on the
more flexible 1,2,3,4-tetrahydroquino-
line backbone have been prepared and
phine–phosphoramidite ligands have
been applied in the Rh-catalysed asym-
metric hydrogenation of functionalised
olefins with the achievement of excel-
lent enantioselectivities (ꢀ99%) in
most cases and turnover frequency
(TOF) values of up to ꢀ20000 hÀ1.
These results substantiate the practical
utility of readily accessible Quinaphos-
type ligands, which belong to the most
active and selective category of ligands
for Rh-catalysed hydrogenation known
to date.
fully characterised.
A general and
Keywords: asymmetric catalysis
bidentate ligands · enantioselectivi-
ty hydrogenation phosphor-
amidites
·
straightforward separation protocol
was devised, which allowed for the
gram-scale isolation of the Ra,Sc and
Sa,Rc diastereomers. These new phos-
·
·
AHCTUNGTRENNUNG
Introduction
tronically unsymmetrical P,P’-ligands, the phosphine–phos-
phite BINAPHOS, was reported by Nozaki in 1993.[3] This
hybrid phosphorus ligand and its derivatives were success-
fully applied in Rh-catalysed asymmetric hydroformylation[4]
and hydrogenation[5] reactions, as well as in Pd-catalysed co-
polymerisation[6] and hydrophosphorylation reactions.[7]
More recently, several phosphine–phosphoramidite li-
gands[2,8] have been synthesised and used in asymmetric hy-
drogenation[9,10] and hydroformylation[9a,11] reactions with
the production of good to excellent enantioselectivities. In
some cases, mixtures of monodentate chiral phosphorami-
dites and achiral phosphines can mimic the corresponding
bidentate ligands. This can lead to improved enantioselectiv-
ity and catalyst activity in hydrogenation reactions with re-
spect to the use of chiral monodentate phosphoramidites
only.[12]
In 2000, we reported the first example of a chiral phos-
phine–phosphoramidite ligand (Quinaphos) and showed the
high potential of this class of ligands in asymmetric cataly-
sis.[9a,10l,13] Quinaphos is based on the 1,2-dihydroquinoline
backbone and is obtained through a modular synthetic ap-
proach as a diastereomeric mixture. The two diastereomers
(Ra,Rc)-nBu-Quinaphos ((Ra,Rc)-5a) and (Ra,Sc)-nBu-Quina-
phos ((Ra,Sc)-5a) were separated by column chromatogra-
phy and a strong cooperation between the two stereo-ele-
ments was observed in asymmetric catalysis.[9] The relative
Asymmetric hydrogenation with transition-metal complexes
is one the most efficient methods for the synthesis of enan-
tio-enriched compounds and the development of chiral
phosphorus ligands plays a determining role for progress in
this area.[1] Among the vast structural variety of ligands, bi-
dentate-chelating P,P’-ligands with electronically different P-
donor groups offer interesting potential for fine-tuning in
transition-metal-catalysed asymmetric reactions.[2] Very suc-
cessful hetero-combinations are those with one phosphino
group combined with a less-electron-rich phosphoramidite
or phosphite unit. A prominent representative of such elec-
[a] Dr. T. Pullmann, B. Engendahl, Z. Zhang, Dr. M. Hçlscher,
Dr. G. Franciꢀ, Prof. Dr. W. Leitner
Institut fꢁr Technische und Makromolekulare Chemie
RWTH Aachen University, Worringerweg 1
520274 Aachen (Germany)
Fax : (+49)241-80-22177
E-mail: francio@itmc.rwth-aachen.de
leitner@itmc.rwth-aachen.de
[b] Dr. A. Zanotti-Gerosa, Dr. A. Dyke
Johnson Matthey, Unit 28, Cambridge Science Park
Cambridge, CB4 0FP (UK)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000063.
Chem. Eur. J. 2010, 16, 7517 – 7526
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Table 1. 31P NMR chemical shifts and coupling constants of Quinaphos
derivatives (C6D6).
stereochemistry (Ra,Rc)-5a was found to correspond to the
matched diastereomer for the enantioselective Rh-catalysed
hydrogenation of olefins and led to excellent enantioselec-
tivities and activities.[9a]
In the present study, we have investigated structural varia-
tions within the Quinaphos-family focusing on the group at
the 2-position (R), the aryl group at the phosphine moiety
(PAr2) and the olefinic double bond within the heterocyclic
backbone (Scheme 1).
R/Ar
Diastereomer
configuration[a] NP(O)2 PAr2
d (31P) [ppm]
JACHTUNGTRENNUNG
1
2
3
4
5
6
nBu/Ph
nBu/Ph
Ph/Ph
Ph/Ph
1-Naph/Ph
1-Naph/Ph
5a
5a
6a
6a
7a
7a
A (Ra,Rc)
B (Ra,Sc)
A (Ra,Sc)
B (Ra,Rc)
A (Ra,Sc)
B (Ra,Rc)
137.5
143.6
132.8
141.2
138.1
140.6
137.7
141.5
À17.8 191.7
À16.4 131.2
À18.6 192.1
À21.3 140.5
À18.4 209.6
À20.9 151.5
À18.9 204.9
À20.3 158.2
7[b] 1-Naph/Xylyl 7b Aent (Sa,Rc)
8[b] 1-Naph/Xylyl 7b Bent (Sa,Sc)
[a] Due to priority change (CIP rules) the stereodescriptors of entries 1,
3, 5 and 2, 4, 6 correspond to the same spatial arrangement, A and B, re-
spectively. [b] Measured in CDCl3.
Scheme 1. Modifications to the Quinaphos-ligand framework.
The assignment of signals to the corresponding diastereo-
mers relies on the distinctive value of the P,P’-coupling con-
stants. It is important to note that (Ra,Rc)-5a has the same
spatial arrangement (A) as (Ra,Sc)-6a and (Ra,Sc)-7a be-
cause of the priority change in accordance with the Cahn–
Ingold–Prelog (CIP) rules. Diastereomers B are character-
ised by smaller coupling constants (J=130–160 Hz), whereas
significantly larger splittings (J=190–210 Hz) are observed
for the corresponding diastereomers A.[9c]
All ligands have been fully characterised in solution. The
structure of a free ligand and of a rhodium complex in the
solid state has been determined by single-crystal X-ray anal-
ysis. The new ligands have been applied in the Rh-catalysed
asymmetric hydrogenation of functionalised olefins and give
excellent enantioselectivities (ꢀ99% in almost all cases)
and turnover frequency (TOF) values up to 21600 hÀ1.
Attempts to separate the diastereomeric mixtures of 6a
and 7a by column chromatography, both on silica gel and
on aluminium oxide, failed with a variety of eluent mixtures.
Very poor separation and/or extensive decomposition were
always observed. In contrast, we succeeded to separate the
diastereomers of 7a very readily by crystallisation. The addi-
tion of ethanol to a solution of 7a in toluene led to the se-
lective precipitation of the Ra,Sc diastereomer as a colourless
powder with a diastereomeric excess (de) of 93–95%. The
mother liquor contained the Ra,Rc diastereomer with a simi-
lar diastereomeric purity, together with other side products.
Diastereomerically pure (Ra,Sc)-7a, inclusive of 5–10% of
toluene, was obtained after a second precipitation using the
same solvent combination. Precipitation from CH2Cl2/n-pen-
tane afforded solvent-free (Ra,Sc)-7a with an overall yield of
62%. Since (Ra,Sc)-7a (diastereomer A) has the matched
relative configuration for the Rh-catalysed hydrogenation,[9a]
the isolation of the other diastereomer (Ra,Rc)-7a was not
pursued in the present work.
Results and Discussion
Synthesis of Quinaphos derivatives: Phosphine–phosphor-
ACHTUNGTRENNUNG
a
Scheme 2. The organolithium reagents PhLi and 1-naphthyl-
lithium (3) were added to 8-diarylphosphinoquinoline (1) to
result in the formation of the corresponding lithium amides
2. The dark-red solutions were reacted directly with the
enantiopure phosphorochloridite 4[13a] and led to the selec-
tive formation (>90% by 31P NMR spectroscopy) of the de-
sired ligands as 1:1 mixtures of the corresponding (Ra,Rc)
and (Ra,Sc) diastereomers. 31P NMR chemical shifts and the
P, P’-coupling constants for the different Quinaphos deriva-
tives are summarised in Table 1.
Notably, the simple procedure described above for isolat-
ing pure (Ra,Sc)-7a could be applied successfully for the
gram-scale separation of other 1-naphthyl-substituted Qui-
naphos derivatives. Starting from bis(3,5-xylyl)-substituted
phosphine 1b, the corresponding derivative (Xyl2P,1-Naph)-
Quinaphos (7b) was synthesised from (S)-4 (Scheme 2).
Chemically and diastereomerically pure (Sa,Rc)-7b could be
obtained after three recrystallisation steps (1.5 g, 56% over-
all yield).
Scheme 2. Synthetic route to Quinaphos ligands.
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Phosphine–Phosphoramidite Ligands for Asymmetric Hydrogenation
FULL PAPER
the phosphine oxide was carried out with trichlorosilane in
the presence of NEt3 to afford phosphine 12a in 63% yield.
In the final step, compound 12a was deprotonated with phe-
nyllithium and the resultant lithium amide intermediate was
treated with phosphorochloridite (Ra)-4 to afford Dihydro-
Quinaphos 13a with a high selectivity of 95% (as deter-
mined by 31P NMR spectroscopy). It is interesting to note
that the deprotonation in this last step could only be carried
out successfully by using strong bases, such as phenyllithium
or butyllithium. Neither the use of triethylamine or 4-(dime-
thylamino)pyridine (as HCl scavengers) nor stronger bases,
for example, sodium hydride, led to the formation of the de-
sired product 13a. Similar observations were recently re-
ported for the synthesis of IN-
Synthesis of Dihydro-Quinaphos: The quinoline backbone
of the Quinaphos-ligand family features an olefinic double
bond, which may itself be subject to hydrogenation under
catalytic conditions.[14] This would lead from an essentially
planar arrangement to a more flexible backbone and, hence,
to a change in coordination properties. To investigate this in
more detail, we set out to synthesise saturated analogues,
3,4-dihydro-Quinaphos, for direct comparison.
Initial attempts to obtain Dihydro-Quinaphos 13a directly
from 7a by hydrogenation of the C-3=C-4 double bond over
Pd/C were not successful. Hence, we envisaged an alterna-
tive multi-step procedure as shown in Scheme 3. Firstly, 1-
DOLPhos.[10h]
Again, the separation of the
diastereomers of 13a was car-
ried out by the precipitation
procedure described above for
ligands 7a and 7b, which con-
firmed the generality of this ap-
proach. Accordingly, diastereo-
merically pure and solvent free
(Ra,Sc)-13a was obtained in
57% overall yield.
Solid-state structure of ligand
(Ra,Sc)-13a·CHCl3: Single crys-
tals of (Ra,Sc)-13a·CHCl3 suita-
ble for X-ray analysis could be
obtained by slow diffusion from
CHCl3/Et2O at room tempera-
ture (Figure 1).[16] Table 2 con-
tains selected bond lengths and
angles. The absolute configura-
tion at C-40 was confirmed as
Scheme 3. Synthetic route to Dihydro-Quinaphos derivative 13a.
S, which validated the initial as-
naphthyl-lithium (3) was added to 8-(diphenylphosphino)-
quinoline (1a) to give the intermediate 2a, which was subse-
quently quenched with water to give the phosphinoamine
8a. Again, Pd/C hydrogenation of the free phosphinoamine
8a failed to afford 12a (route A). This indicated that the
phosphino group should be protected to prevent strong co-
ordination to the palladium catalyst and, hence, catalyst de-
activation. A reaction sequence of phosphine oxidation, het-
erocycle hydrogenation, followed by phosphine reduction
was devised to circumvent this problem (route B).
signment based on the P,P’-coupling constants and chemical
shifts within the Quinaphos family.[9] The six-membered het-
The oxidation of 8a with H2O2 led to the formation of
1,2-dihydroquinoline 9a together with the re-aromatised
quinoline 10a in a ratio of 70:30, respectively. This mixture
was completely oxidised in situ, over Pd/C in the presence
of air, to 10a with an overall yield of 76%.[15] The subse-
quent hydrogenation of 10a was carried out over the same
catalyst batch used for the dehydrogenation (Pd/C) to give
the corresponding 1,2,3,4-tetrahydroquinoline 11a in 91%
yield. These transformations can be monitored conveniently
by means of in situ 31P NMR spectroscopy. The reduction of
Figure 1. ORTEP representation of (Ra,Sc)-13a·CHCl3 (50% probability
level; hydrogen atoms and CHCl3 are omitted for clarity).
Chem. Eur. J. 2010, 16, 7517 – 7526
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7519

G. Franciꢀ, W. Leitner et al.
Table 2. Selected bond lengths, angles and dihedral angles of 13a in crys-
tals of 13a·CHCl3.
Distances
[ꢃ]
Angles
[8]
À
P1 N1
À
P1 O1
1.6725(17)
1.6679(15)
1.6679(15)
1.8371(21)
1.8264(20)
1.8410(20)
1.4823(25)
1.4242(25)
1.487(3)
O2-P1-O1
C41-N1-C40
C41-N1-P1
C40-N1-P1
C8-C9-C11-C12
C40-N1-P1-O2
C39-C40-C42-C43
C27-P2-C33-C34
97.36(7)
118.71(16)
117.35(13)
122.96(13)
57.1
47.2
95.5
47.7
À
P1 02
À
P2 C33
À
P2 C21
À
P2 C27
À
N1 C40
À
N1 C41
À
C9 C11
Scheme 4. Synthesis of Rh-complexes from a [RhACTHNUGRTENNU(G acac)CAHTUNGTNER(NUGN cod)] precursor.
erocycle of the 1,2,3,4-tetrahydroquinoline backbone adopts
a boat conformation and the carbon atoms C-39 and C-40
reside out of the plane defined by the aromatic carbon
atoms of the heterocyclic backbone. This puckered arrange-
ment is significantly different from the parent Quinaphos
backbone, as expected.[9]
plings (Table 3). Interestingly, a considerable coordination
shift of d=40–43 ppm was observed for the phosphine moi-
eties, whereas no significant change in the chemical shift
was noticeable for the phosphoramidite moieties. Moreover,
a large decrease of the P,P-coupling constants from around
200 to about 62 Hz occurred upon coordination for all li-
gands, due to the change of the coupling mode from
through-space to through-bond coupling.
The nitrogen atom has a trigonal planar arrangement with
an angle sum of 3598, indicative of pronounced sp2 charac-
À
ter. The quite short P N distance of 1.6725(17) ꢃ hints at a
partial double-bond character and confirms sp2 hybridisation
of the nitrogen atom. The phosphoramidite phosphorus
atom, P1, is located slightly out of the plane defined by the
aromatic carbon atoms of the 1,2,3,4-tetrahydroquinoline
backbone (dihedral angle P1-N1-C41-C33=51.28), probably
to minimize repulsion with the 1-naphthyl substituent.
The free electron pairs at the phosphorus atoms point in
approximately the same direction, already in good align-
ment for metal chelation. Moreover, the through-space dis-
tance between the two phosphorus atoms of 3.19 ꢃ supports
that the P,P’-coupling is caused by a through-space interac-
tion rather than a through-bond coupling.[17] The torsion
angle of the binaphthyl moiety is in the expected range
(57.18).
Table 3. 31P NMR chemical shifts and coupling constants of [Rh
(P,P’)] complexes (CDCl3).
ACHTUNGTRENNUNG(cod)-
AHCTUNGTRENNUNG
Complex
d (31P) [ppm]
PAr2 NP(O)2
J [Hz]
Rh,NP(O)2
Rh,PAr2
P, P’
14
15
16
24.8
23.7
22.7
138.3
138.0
136.9
135.9
135.8
133.4
258.4
259.5
252.6
61.3
62.0
62.4
Solid-state structure of 14·CH2Cl2: Single crystals of [Rh-
(cod){(Ra,Sc)-7a}][BF4]·CH2Cl2 (14·CH2Cl2) suitable for X-
A
R
ACHTUNGTRENNUNG
ray diffraction analysis were obtained by slow diffusion
Synthesis of rhodium-Quinaphos complexes: Addition
from CH2Cl2/Et2O at room temperature.[16] Figure 2 shows
1 equiv of (Ra,Sc)-7a to [Rh
diene) in CH2Cl2 or THF led to a mixture (ꢁ20:1) of the
desired compound [Rh(cod){(Ra,Sc)-7a}][BF4] (14) and the
homoleptic complex [Rh{(Ra,Sc)-7a}2]
[BF4].[18] In contrast,
the addition of 1 equiv of the ligand to a solution of [Rh-
(cod)(thf)2][BF4] in THF (generated in situ by protonation
of [Rh(acac)(cod)] (acac=acetylacetonate) with
ACHUTGTNERN(NGU cod)2]ACHTUGNTREN[NUGN BF4] (cod=1,5-cycloocta-
A
R
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
A
R
ACHTUNGTRENNUNG
A
ACHTUNGTRENNUNG
HBF4·Et2O) resulted in the exclusive formation of 14 in
59% yield after recrystallisation from CH2Cl2/Et2O
(Scheme 4). This reactivity is in line with the observation
that Quinaphos-type ligands typically exhibit better catalytic
performance in isolated precursors or systems generated in
situ from [Rh
[Rh(cod)2][BF4] precursor.
By using the same procedure, the complexes [Rh
{(Sa,Rc)-7b}][BF4] (15) and [Rh(cod){(Ra,Sc)-13a}][BF4] (16)
ACHTUNGTRENNUNG(acac)ACHTUNGTRENNUNG(cod)]/HBF4 compared with use of the
A
ACHTUNGTRENNUNG
AHCTUNGTRENGN(UN cod)-
A
E
E
N
ACHTUNGTRENNUNG
were obtained in 49 and 65% yield, respectively. As expect-
ed, two signals were present in each of the 31P NMR spectra,
both as doublet of doublets due to the P,P’- and Rh,P-cou-
Figure 2. ORTEP representation of [Rh
(30% probability level; hydrogen atoms, the BF4 anion and CH2Cl2 are
omitted for clarity).
G
G
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Phosphine–Phosphoramidite Ligands for Asymmetric Hydrogenation
FULL PAPER
the molecular structure of the cationic metal complex and
Table 4 contains selected bond lengths and angles.
drogen pressures between 30 and 70 bar. Dichloromethane
was the solvent of choice, except for the hydrogenation of
a-acetamido cinnamic acid (21), for which methanol was
used for solubility reasons, and for hydrogenation of trifluor-
omethylvinyl acetate (29), for which no additional solvent
was added. The results are summarised in Table 5.
Table 4. Selected bond lengths and angles of complex 14 in crystals of
14·CH2Cl2.
Bond
[ꢃ]
Angle
[8]
In the presence of complex 14 (0.1 mol%), both dimethyl-
À
Rh1 P1
2.1984(13)
2.2939(14)
2.263(5)
2.315(5)
2.271(6)
2.228(6)
1.375(8)
1.369(9)
1.662(4)
1.805(6)
1.512(8)
P1-Rh1-P2
C32-N1-C28
C32-N1-P1
C28-N1-P1
C8-C7-C11-C18
C28-N1-P1-O1
C27-C28-C27-C21
C42-P2-C33-C34
84.97(5)
115.9(4)
120.8(3)
119.8(4)
64.6
52.5
131.1
118.5
AHCTUNGTREGiNNNU taconate (17) and acetamidomethylacrylate (19) were hy-
À
Rh1 P2
drogenated quantitatively within 30 min with almost perfect
enantioselectivity (>99% ), which corresponds to a TOF of
ꢀ2000 hÀ1 (Table 5, entries 1 and 7). Full conversion of sub-
strates 17 and 19, within 30 min and with excellent enantio-
selectivities (>99%), was also obtained with ligand 7b (at a
catalyst loading of 0.1 mol%), which bears the sterically
more demanding bis(3,5-xylyl)phosphino group (Table 5, en-
tries 4 and 8). A broad range of substrates can be hydrogen-
ated with these ligands with uniformly excellent levels of
enantioselectivity. The cinnamic acid derivative 21 was con-
verted quantitatively in methanol to 22 with 97% ee, which
demonstrated that the catalyst is stable towards free acid
(Table 5, entry 10). The corresponding methyl ester 23 and
the more bulky benzoyl-protected derivative 25 could be hy-
À
Rh1 C57
À
Rh1 C45
À
Rh1 C44
À
Rh1 C54
À
C44 C54
À
C45 C57
À
P1 N1
À
P2 C33
À
C7 C11
The rhodium centre displays a typical square-planar ge-
ometry and the bite angle of the two phosphorus donors
amounts to 84.97(5)8. As already observed for another phos-
phine–phosphoramidite rhodi-
um complex,[10j] the phosphor-
ACHTUNGTRENNUNG
Table 5. Asymmetric hydrogenation of functionalised olefins with Quinaphos-type ligands in catalysts [Rh-
[BF4].[a]
AHCTUNGTREGNU(NN cod)ACHTUNREGTG(NNUN P,P’)]CAHTNUGTRENNUGN
phine–rhodium
(2.1984(13)
bond
versus
2.2939(14) ꢃ, respectively). The
two phenyl rings at phosphorus
atom P2 adopt the characteris-
tic face–edge conformation.
The dihedral angle of the bi-
naphthyl moiety in the phos-
phoramidite portion is approxi-
mately 64.68. The 1-naphthyl
substituent at the stereogenic
C28 is quite far from the rhodi-
um centre, which is in line with
the observation that the sub-
stituents in this position only
have a moderate influence on
the stereocontrol exerted by
Quinaphos ligands.[13d] The co-
Substrate
P,P’ ligand
(Ra,Sc)-7a
(Ra,Sc)-7a
(Ra,Sc)-7a
(Sa,Rc)-7b
(Ra,Sc)-13a
(Ra,Sc)-13a
(Ra,Sc)-7a
(Sa,Rc)-7b
(Ra,Sc)-13a
(Ra,Sc)-7a
(Ra,Sc)-7a
(Ra,Sc)-7a
(Ra,Sc)-7a
(Sa,Rc)-7b
t [min]
S/C[b]
Conversion [%]
TOF [hÀ1
]
ee[c] [%]
1
17
17
17
17
17
17
19
19
19
21
23
25
27
29
U
30
45
30
30
3
30
30
30
5
30
60
60
30
240
1000
10000
20000
1000
1000
20000
1000
1000
1000
1000
1000
1000
1000
1000
>99
94
25
>99
>99
54
>99
>99
99
>99
>99
>99
>99
>99
ꢀ2000
12600
10000
ꢀ2000
ꢀ20000
21600
ꢀ2000
ꢀ2000
11900
ꢀ2000
ꢀ1000
ꢀ1000
ꢀ2000
ꢀ250
>99 (R)
>99 (R)
>99 (R)
>99 (S)
>99 (R)
>99 (R)
99 (S)
99 (R)
99 (S)
97 (S)
>99 (S)
99 (S)
2[d]
3
ordinated
1,5-cyclooctadiene
ligand shows a clockwise twist
of about 138.
4[e]
5
6
Asymmetric
Complexes 14, 15, 16 and [Rh-
(cod){(Sa,Rc)-7b}][BF4], gener-
hydrogenation:
7
8[e]
9
A
R
ACHTUNGTRENNUNG
10[f]
11
12[f]
13
14[g]
ated in situ by the procedure
described above, were applied
in the asymmetric hydrogena-
tion of functionalised olefins.
The reactions were carried out
>99 (S)
98 (R)
[a] CH2Cl2 (2 mL), RT, 30 bar H2, 500 rpm. [b] Substrate/catalyst ratio. [c] ee=enantiomeric excess. [d] 70 bar
at room temperature under hy- H2. [e] Catalyst generated in situ. [f] MeOH used as solvent. [g] Reaction performed neat.
Chem. Eur. J. 2010, 16, 7517 – 7526
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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7521

G. Franciꢀ, W. Leitner et al.
drogenated quantitatively with enantioselectivities ꢀ99%
(Table 5, entries 11 and 12, respectively). Full conversion
after 30 min with >99% ee was also achieved in the hydro-
genation of enamide 27 (Table 5, entry 13). The hydrogena-
tion of trifluoromethylvinyl acetate 29 was carried out in the
neat substrate with complex 15 as the catalyst. The hydro-
genated product 30 was obtained in 98% ee (Table 5,
entry 14).
To estimate the activity of complex 14, the hydrogenation
of 17 was carried out with a reduced catalyst loading of
0.01 mol%. At 70 bar of H2, product 18 was formed almost
quantitatively (conversion=94%) in >99% ee within
45 min, which corresponded to a TOF of 12600 hÀ1 (Table 5,
entry 2). A further reduction of the catalyst loading shows
that this represents an upper limit for the TOF of this
system (Table 5, entry 3). Compared with ligand (Ra,Rc)-
5a,[9a] complex 14 leads to very similar activities and enan-
tioselectivities in the hydrogenation of 17.
The Dihydro-Quinaphos derivative (Ra,Sc)-13a, the more
flexible analogue of (Ra,Sc)-7a, was tested in the hydrogena-
tion of itaconate 17 and acrylate 19. Again, excellent enan-
tioselectivities ꢀ99% were obtained. At a substrate/catalyst
ratio of 1000, full conversion was achieved after 3 and 5 min
(equivalent to TOF values of ꢀ20000 and 11900 hÀ1), re-
spectively (Table 5, entries 5 and 9). To evaluate the activity
of complex 16 more precisely and to have a direct compari-
son with 14, a hydrogenation experiment was carried out
with 16 under exactly the same conditions used in Table 5,
entry 3 for 14. At a catalyst loading of 0.005 mol%, the re-
action was stopped after 30 min by venting the autoclave.
Relative to 14, catalyst 16 led to almost two-fold conversion
(54%), which corresponds to a TOF of 21600 hÀ1 (Table 5,
entries 6 versus 3). These results show clearly that the satu-
ration modification of the double bond in the heterocyclic
part of the backbone causes a significant increase of the cat-
alyst activity,[14] without a negative effect on the enantiose-
lectivity.
droamino acid derivatives (including a free acid) and enam-
ides. In almost all cases ee values ꢀ99% were obtained,
combined with TOF values of up to 12600 hÀ1. A two-fold
enhancement of catalyst activity, TOF values ꢀ20000 hÀ1
and the same excellent level of enantioselectivity were ob-
served when using the Dihydro-Quinaphos ligand (Ra,Sc)-
13a compared with the corresponding Quinaphos ligand
(Ra,Sc)-7a. These results substantiate the practical utility of
readily accessible Quinaphos-type ligands, which belong to
the most active and selective ligands for the rhodium-cata-
lysed hydrogenation known to date.
Experimental Section
General: All reactions and manipulations were performed by using stan-
dard Schlenk techniques or in a glove box (M. Braun MB 150B-G) under
an inert argon atmosphere unless otherwise noted. Argon 4.6 was pur-
chased from Messer and traces of water and oxygen were removed with
an M. Braun MB 100-HP apparatus. 1H, 13C and 31P NMR spectra were
recorded on a Bruker AV 600 (600, 150 and 243 MHz, respectively) or a
Bruker DPX-300 spectrometer (300, 75 and 121 MHz, respectively).
Chemical shifts (d) were referenced to residual solvent peaks (1H NMR,
13C NMR) or to external standard 85% H3PO4 (31P NMR). Mass spectra
were recorded on a Varian 1200L Quadrupole GC-MS, Finnigan MAT
8200 (MS and HRMS-EI) or a Bruker FTICR-Apex III spectrometer
(HRMS-ESI). IR spectra were recorded on a Perkin–Elmer PE-1760 FT
or a Thermo Electron Avatar 380 spectrometer. Optical rotations were
measured on a Jasco P-1020 polarimeter. The concentrations used for
measuring specific rotations are given as g/100 mL. THF, toluene and n-
pentane were dried over alumina with a solvent purification system from
Innovative Technology. Et2O, MeOH and EtOH were distilled and then
dried over molecular sieves. All other organic solvents were purged with
argon for 2 h prior to use. Deuterated solvents were degassed through
freeze–pump–thaw cycles and stored over molecular sieves. The following
substances were been synthesised according to literature procedures:
(cod)],[20] phosphorochloridite (Ra)-4 and (Sa)-4,[13a] enamide
[RhACTHNUGRTENNUG(acac)ACHTUGNTRENNUGN
(29)[21] and N-benzoylamino cinnamic acid (27).[22] For the synthesis of 1a
and 1b see the Supporting Information. 8-Bromoquinoline was purchased
from Frontier Scientific Europe. All other chemicals were purchased
from Sigma–Aldrich, Acros or Alfa Aesar and used as received.
Ligand (Ra,Sc)-7a: A solution of 1-naphthyllithium (1 equiv, 17.5 mL, c=
0.385m in THF) was added slowly with a syringe at À208C to a solution
of 1a (2.112 g, 6.741 mmol) in THF (50 mL). The reaction mixture was
stirred for 1 h at 08C and then cooled to À208C before phosphorochlori-
dite (R)-4 (1 equiv, 6.741 mmol, 2.364 g) in THF (20 mL) was added
dropwise. The mixture was allowed to warm to RT and stirred for 1 h.
The solvent was removed under reduced pressure and the resulting solid
was extracted with toluene (80 mL). The extracted phase was filtered
through a plug of alumina (25 mL), concentrated under reduced pressure
and the resulting solid was dried in vacuo (4.808 g). A portion of this
solid (1.873 g) was dissolved in toluene (11 mL) and ethanol (37 mL) was
added dropwise, whereupon a colourless solid (821.6 mg) precipitated (in
some cases the precipitation was delayed and the mixture was allowed to
stir overnight), which contained (Ra,Sc)-7a (95–97%) and (Ra,Rc)-7a (3–
5%). This solid was recrystallised from toluene/ethanol (10:50 mL) to
afford diastereomerically pure (Ra,Sc)-7 with included toluene. Solvent-
free (Ra,Sc)-7a was obtained as a colourless powder after recrystallisation
of (Ra,Sc)-7 from CH2Cl2/n-pentane (5:30 mL). Yield: 62% (496.2 mg);
Conclusion
We have reported the synthesis of new ligands of the Quina-
phos family, which include the first examples of Dihydro-
Quinaphos ligands based on the conformationally more flex-
ible 1,2,3,4-tetrahydroquinoline backbone. Exploiting
a
modular synthetic approach to Quinaphos, a 1-naphthyl sub-
stituent was introduced at C-2, which significantly affects
the solubility profile of the diastereomers and enables a
facile separation. Hence, a general, simple and reliable pro-
tocol was developed and allowed the isolation of pure Ra,Sc
and Sa,Rc diastereomers on a gram scale.[20] This procedure
could be applied successfully to all derivatives with a 1-
naphthyl group, irrespective of the nature of the phosphine
group and of the dihydro- or tetrahydroquinoline backbone.
The new Quinaphos-type ligands showed remarkably high
enantioselectivities and activities in the rhodium-catalysed
asymmetric hydrogenation of functionalised olefins, dehy-
1
[a]2D0 =À6948 (c=0.5 in CHCl3); H NMR (600 MHz, CDCl3): d=8.18 (d,
J=8.7 Hz, 1H; Ar), 8.13 (d, J=8.2 Hz, 1H; Ar), 7.89 (d, J=8.8 Hz, 1H;
Ar), 7.86 (d, J=8.2 Hz, 1H; Ar), 7.71 (d, J=8.7 Hz, 1H; Ar), 7.62–7.53
(m, 6H; Ar), 7.46–7.28 (m, 14H; Ar), 7.24 (m, 1H; Ar), 7.17–7.12 (m,
2H; Ar), 7.07–7.03 (m, 2H; Ar), 6.56 (d, J=9.6 Hz, 1H; H-4), 6.41 (m,
1H; Ar), 6.35 (d, J=8.5 Hz, 1H; Ar), 5.97 (dd, J=9.6, 5.8 Hz 1H; H-3),
5.88 ppm (m, 1H; H-2); 13C NMR (150 MHz, CDCl3): d=150.71 (m; Cq),
7522
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Chem. Eur. J. 2010, 16, 7517 – 7526

Phosphine–Phosphoramidite Ligands for Asymmetric Hydrogenation
FULL PAPER
149.51 (Cq), 143.76 (dd, J=24.1, 20.5 Hz; Cq), 140.47 (t, J=18.1 Hz; Cq),
138.62 (Cq), 137.73 (CH), 137.13 (d, J=5.6 Hz; Cq), 133.55 (Cq), 133.53
(CH), 133.50 (CH), 133.39 (CH), 133.37 (CH), 133.22 (Cq), 132.72 (Cq),
131.59 (Cq), 130.99 (Cq), 130.59 (CH), 130.50 (CH), 129.60 (CH), 128.50
(2CH), 128.50 (Cq), 128.47 (CH), 128.45 (2CH), 128.42 (CH), 128.40
(CH), 128.34 (Cq), 128.30 (CH), 128.29 (Cq), 128.27 (CH), 128.23 (CH),
127.66 (CH), 127.43 (CH), 126.98 (CH), 126.58 (CH), 126.27 (CH),
125.68 (CH), 125.52 (CH), 125.11
264 (38), 254 (15), 252 (27); HRMS (ESI): m/z: calcd for C55H44NO2P2:
812.284182 [M+H]+; found: 812.284121.
Compound 10a: Hydrogen peroxide (8 mL, 35% w/w) was added slowly
at 08C to a solution of 8a (1.504 g, 3.407 mmol) in CH2Cl2 (25 mL). The
reaction mixture was stirred overnight at RT. The mixture was cooled
with an ice bath and Pd on charcoal (10% w/w, 750 mg) was added in
small portions while excess H2O2 was decomposed. The suspension was
stirred for 3 d at RT. The solid was allowed to settle and the supernatant
was filtered through basic Celite (25 mL). The organic phase was separat-
ed, dried over anhydrous Na2SO4 and concentrated under reduced pres-
sure. The remaining solid was dried under vacuum at 608C. Compound
10a was obtained as a yellow solid. Yield: 1.175 g (2.579 mmol, 76%);
1H NMR (600 MHz, CDCl3): d=8.77 (ddd, J=13.8, 7.1, 1.5 Hz, 1H; H-
7), 8.25 (dd, J=8.5, 1.7 Hz, 1H; Ar), 8.10 (dt, J=8.1, 1.2 Hz, 1H; Ar),
7.89 (m, 2H; Ar), 7.81–7.73 (m, 6H; Ar), 7.67 (d, J=8.4 Hz, 1H; Ar),
7.46 (m, 1H; Ar), 7.41–7.33 (m, 3H; Ar), 7.23–7.15 (m, 5H; Ar),
6.82 ppm (dd, J=7.1, 1.2 Hz, 1H; Ar); 13C NMR (150 MHz, CDCl3): d=
158.64 (Cq), 147.75 (d, J=6.0 Hz; Cq), 137.96 (d, J=6.5 Hz; C-7), 137.78
(Cq), 136.29 (CH), 133.78 (d, J=108.5 Hz; 2Cq), 133.75 (Cq), 132.64 (d,
J=10.6 Hz; 4CH), 132.58 (CH), 131.47 (d, J=101.1 Hz; Cq), 131.22 (d,
J=3.0 Hz; 2CH), 130.80 (Cq), 129.16 (CH), 128.54 (CH), 128.46 (CH),
127.91 (d, J=12.6 Hz; 4CH), 127.00 (d, J=7.5 Hz; Cq), 126.60 (CH),
126.41 (d, J=12.5 Hz; CH), 125.88 (CH), 125.27 (CH), 125.25 (CH),
(CH), 125.06 (CH), 125.02 (CH),
124.07 (CH), 124.00 (CH), 123.76 (d,
J=5.0 Hz; Cq), 123.40 (CH), 123.35
(CH), 122.32 (CH), 122.25 (CH),
122.09 (Cq), 51.10 ppm (CH); 31P NMR
(243 MHz, CDCl3): d=137.9 (d, J=
205.6 Hz; NP(O)2), À18.8 ppm (d, J=
205.6 Hz; PPh2); HRMS (ESI): m/z:
calcd for C51H35NNaO2P2: 778.203530
[M+Na]+; found: 778.204537.
Ligand (Sa,Rc)-7b: A solution of 1-naphthyllithium (1 equiv, 21.8 mL, c=
0.301m in THF) was slowly added with a syringe at À208C to a solution
of 1b (2.471 g, 6.693 mmol) in THF (50 mL). The reaction mixture was
stirred for 1 h at 08C and then cooled to À208C. Phosphorochloridite
(Sa)-4 (1 equiv, 6.693 mmol, 2.348 g) in THF (20 mL) was added drop-
wise. After stirring overnight at RT, the volatile compounds were re-
moved under reduced pressure and the remaining solid was dried in
vacuo. Toluene (24 mL) and ethanol (5 mL) were added to the obtained
solid and the resulting mixture was heated to 408C to give a clear solu-
tion. After cooling to RT, ethanol (85 mL) was added slowly with a sy-
ringe, whereupon a colourless solid precipitated containing (Sa,Rc)-7b
with approximately 93% de (as determined by 31P NMR spectroscopy).
The obtained solid was filtered off and dissolved in hot (70–808C) tolu-
ene (70 mL). Ethanol (60 mL) was added and resulted in the formation
of a colourless powder that contained (Sa,Rc)-7b in diastereomerically
pure form (as determined by 31P NMR spectroscopy). The obtained solid
included residual toluene, which could not be removed, even by heating
in vacuo overnight. Solvent-free (Sa,Rc)-7b was obtained after precipita-
tion from CH2Cl2/n-pentane (11:70 mL). After removal of the mother
liquor, the solid was dried in vacuo at 608C to give (Sa,Rc)-7b as a white
powder. Yield: 56% (1.53 g, 1.88 mmol); >99% de; [a]2D0 =+5768 (c=0.5
in CHCl3); 1H NMR (600 MHz, CDCl3): d=8.17 (d, J=8.7 Hz, 1H; Ar),
8.11 (d, J=8.2 Hz, 1H; Ar), 7.87 (d, J=8.9 Hz, 1H; Ar), 7.85 (d, J=
8.2 Hz, 1H; Ar), 7.70 (d, J=8.7 Hz, 1H; H-3A), 7.60–7.51 (m, 4H; Ar),
7.42–7.29 (m, 6H; Ar), 7.22 (m, 1H; Ar), 7.17–7.07 (m, 4H; Ar), 7.05 (m,
1H; Ar), 7.00 (t, J=7.5 Hz, 1H; Ar), 6.93 (s, 1H; Ar), 6.91 (s, 1H; Ar),
6.90 (s, 2H; Ar), 6.54 (d, J=9.6 Hz, 1H; H-4), 6.38 (m, 1H; Ar), 6.33 (d,
J=8.6 Hz, 1H; H-8’), 5.96 (dd, J=9.6, 5.7 Hz, 1H; H-3), 5.85 (m, 1H; H-
2), 2.27 (s, 6H; CH3), 2.26 ppm (s, 6H; CH3); 13C NMR (150 MHz,
CD2Cl2): d=151.20 (m; Cq), 149.80 (Cq), 144.06 (dd, J=24.3, 20.6 Hz;
Cq), 140.91 (dd, J=17.4, 16.8 Hz; Cq), 139.21 (Cq), 138.40 (Cq), 138.38
(CH), 138.36 (2Cq), 138.31 (Cq), 137.05 (d, J=3.5 Hz; Cq), 134.04 (Cq),
133.65 (Cq), 133.16 (Cq), 132.17 (Cq), 131.78 (CH), 131.64 (CH), 131.61
(d, J=2.5 Hz; CH), 131.56 (Cq), 131.49 (d, J=2.3 Hz; CH), 131.08 (CH),
130.62 (CH), 130.60 (CH), 130.54 (CH), 130.34 (CH), 129.05 (Cq), 128.98
(CH), 128.96 (CH), 128.89 (CH), 128.78 (CH), 128.70 (2Cq), 128.18
(CH), 127.63 (CH), 127.19 (CH), 127.06 (CH), 126.80 (CH), 126.29 (CH),
125.87 (CH), 125.72 (CH), 125.58 (CH), 125.57 (CH), 124.68 (CH),
124.47 (d, J=4.9 Hz; Cq), 124.35 (CH),
123.70 ppm
(CH);
31P NMR
(243 MHz, CDCl3): d=28.5 ppm; MS
(EI): m/z (%): 456 (20), 455 (76), 454
(100), 377 (8), 376 (29), 330 (5), 328
(9), 300 (8), 254 (11), 253 (13), 252
(9); HRMS (ESI): m/z; calcd for
C31H23NOP: 456.151175 [M+H]+;
found: 456.150816.
Compound 11a: A suspension of 10a (219.3 mg, 0.481 mmol) and Pd on
charcoal (50 mg, 5% w/w) in CH2Cl2 (4 mL) was placed in a 10 mL stain-
less-steel autoclave equipped with a glass inlet and a magnetic stirrer.
Hydrogen was added (30 bar) and the reaction mixture was stirred for
16 h. The autoclave was vented and the reaction mixture was filtered
through a plug of basic Celite. The filter material was washed with
CH2Cl2 (5 mL) and the combined organic filtrates were concentrated
under reduced pressure. The remaining solid was dried under vacuum at
608C. Compound 11a was obtained as a yellow solid. Yield: 201.3 mg
(0.438 mmol, 91%); 1H NMR (600 MHz, CDCl3): d=7.99–7.95 (m, 1H;
Ar), 7.86–7.82 (m, 1H; Ar), 7.76–7.66 (m, 5H; Ar), 7.60 (dt, J=7.3,
1.2 Hz, 1H; Ar), 7.56 (dt, J=7.3, 1.2 Hz, 1H; Ar), 7.54–7.43 (m, 6H;
Ar), 7.23 (brs, 1H; NH), 7.18 (t, J=7.7 Hz, 1H; Ar), 7.11 (d, J=7.2 Hz,
1H; Ar), 7.07 (d, J=7.2 Hz, 1H; Ar), 6.71 (m, 1H; Ar), 6.51 (dt, J=7.5,
2.8 Hz, 1H; Ar), 5.40 (m, 1H; H-2), 2.87 (m, 1H; HA-4), 2.63 (m, 1H;
HB-4), 2.29 (m, 1H; HA-3), 1.99 ppm (m, 1H; HB-3); 13C NMR
(150 MHz, CDCl3): d=149.97 (d, J=2.3 Hz; Cq), 139.83 (C-1’), 133.90
(Cq), 132.95 (d, J=103.3 Hz; Cq), 133.18 (d, J=2.2 Hz; CH), 132.51 (d,
J=104.4 Hz; Cq), 132.31 (d, J=9.7 Hz; 4CH), 132.00 (d, J=2.9 Hz; CH),
131.92 (d, J=2.9 Hz; CH), 131.77 (d, J=11.2 Hz; CH), 130.18 (C-8a),
129.05 (CH), 128.58 (d, J=12.1 Hz; 4CH), 127.45 (CH), 126.00 (CH),
125.60 (CH), 125.41 (CH), 123.62 (CH), 122.63 (CH), 121.84 (d, J=
7.9 Hz; Cq), 114.57 (d, J=13.8 Hz; CH), 110.60 (d, J=105.9 Hz; Cq),
51.71 (C-2), 28.01 (C-3), 26.09 ppm (C-4); 31P NMR (243 MHz, CDCl3):
d=35.9 ppm; MS (EI): m/z (%): 461
(6), 460 (33), 459 [M]+ (100), 458 (20),
333 (17), 332 (73), 331 (15), 330 (12),
305 (10), 255 (5), 254 (23), 230 (11),
201 (9), 199 (5), 191 (7), 152 (5), 141
123.80 (CH), 123.63 (CH), 122.68
(CH), 122.38 (CH), 122.35 (Cq), 51.57
(d, J=3.2 Hz; C-2), 21.76 (2CH3),
21.73 ppm
(2CH3);
31P NMR
(6); HRMS (ESI): m/z: calcd for
(243 MHz, CDCl3): d=137.7 (d, J=
204.9 Hz; NP(O)2), À18.9 ppm (d, J=
204.9 Hz; PXyl2); MS (EI): m/z (%):
813 (18), 812 (55), 811 (100), 810 (26),
707 (45), 706 (88), 685 (38), 684 (76),
527 (39), 526 (98), 496 (22), 495 (12),
406 (22), 391 (33), 390 (33), 316 (23),
315 (76), 284 (15), 269 (16), 268 (70),
C31H22NNaOP: 482.164421 [M+Na]+;
found: 482.164413.
Compound 12a: Trichlorosilane was added with a syringe to a solution of
11a (5.002 g, 10.98 mmol) and triethylamine (24.16 mmol, 2.2 equiv,
2.43 mL) in toluene (120 mL) under vigorous stirring and the reaction
mixture was heated at reflux temperature for 3 h. The mixture was al-
lowed to cool to RT and a solution of aqueous NaOH (37 mL, 4m) was
Chem. Eur. J. 2010, 16, 7517 – 7526
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7523

G. Franciꢀ, W. Leitner et al.
added. The organic phase was diluted with ethyl acetate (50 mL) and the
aqueous phase separated. The organic layer was washed with brine
(50 mL), dried over anhydrous Na2SO4 and evaporated to dryness under
reduced pressure. The obtained solid was dissolved in CH2Cl2 (50 mL)
and the solution was filtered through a plug of silica (25 mL). The filter
cake was eluted with additional CH2Cl2 (3ꢄ50 mL) and the combined or-
ganic layers were evaporated under reduced pressure. The remaining
solid was dried in vacuo to afford 12a as a bright yellow solid. Yield:
3.183 g (65%); 1H NMR (600 MHz, CDCl3): d=8.01 (d, J=8.2 Hz, 1H;
H-8’), 7.87 (d, J=8.1 Hz, 1H; Ar), 7.73 (d, J=8.1 Hz, 1H; Ar), 7.51–7.34
(m, 12H; Ar), 7.29 (m, 1H; Ar), 7.24 (m, 1H; Ar), 7.07 (d, J=7.4 Hz,
1H; H-5), 6.72 (m, 1H; Ar), 6.62 (t, J=7.5 Hz, 1H; Ar), 5.34 (m, 1H; H-
2), 5.12 (d, J=7.3 Hz, 1H; NH), 2.97 (m, 1H; H-4), 2.74 (dt, J=16.2,
5.5 Hz, 1H; H-4), 2.34 (m, 1H; H-3), 2.08 ppm (m, 1H; H-3); 13C NMR
(150 MHz, CDCl3): d=147.49 (d, J=17.1 Hz; Cq), 139.97 (C-1’), 135.76
(d, J=7.0 Hz; CPh,ipso), 135.54 (d, J=7.3 Hz; CPh,ipso), 134.16 (CH), 134.03
(CH), 133.97 (CH), 133.93 (Cq), 133.85 (CH), 132.46 (d, J=3.3 Hz; CH),
130.53 (C-5), 130.37 (C-8’a), 129.09 (CH), 128.99 (CH), 128.83 (CH),
128.72 (2CH), 128.67 (2CH), 127.67 (CH), 126.13 (CH), 125.68 (CH),
125.56 (CH), 123.51 (CH), 122.75 (C-8’), 120.58 (d, J=3.0 Hz; Cq), 117.87
(d, J=7.4 Hz; Cq), 116.68 (d, J=3.0 Hz; CH), 52.45 (C-2), 28.89 (C-4),
26.51 ppm (C-3); 31P NMR (243 MHz,
122.30 (CH), 122.16 (Cq), 122.05 (CH), 51.99 (d, J=3.1 Hz; C-2), 34.73
(C-3), 27.86 ppm (C-4); 31P NMR (243 MHz, CDCl3): d=138.2 (d, J=
184.9 Hz; NP(O)2), À19.9 ppm (d, J=184.9 Hz; PPh2); MS (EI): m/z
(%): 759 (5), 758 (16), 757 [M]+ (29), 682 (12), 681 (50), 680 (100), 617
(8), 603 (6), 527 (12), 526 (32), 472 (7), 458 (5), 379 (11), 365 (14), 335
(17), 334 (5), 318 (5), 315 (5), 302 (7), 301 (9), 268 (7), 252 (15), 242 (6),
240 (6); HRMS (ESI): m/z: calcd for C51H37NNaO2P2: 780.219180
[M+Na]+; found: 780.218943.
Compound (Ra,Rc)-13a: 31P NMR (121 MHz, CDCl3): d=141.1 (d, J=
151.5 Hz; NP (O)2), À18.7 ppm (d, J=151.5 Hz; PPh2).
Complex 14: HBF4·Et2O (1.2 equiv, 0.294 mmol, 40 mL) was added to a
solution of (acetylacetonato)-(1,5-cyclooctadiene)-rhodium(I) (75.9 mg,
0.245 mmol) in dry THF (10 mL). After stirring for 10 min, a solution of
(Ra,Sc)-7a (1 equiv, 0.294 mmol, 185.0 mg) in THF (5 mL) was added,
whereupon the colour of the solution turned from yellow to orange.
After stirring for 30 min, the mixture was concentrated to half of the
volume under reduced pressure. n-Pentane (25 mL) was added, where-
upon a yellow solid formed, which was separated from the mother liquor.
To remove included THF, this solid was dissolved in CH2Cl2 (8 mL) and
precipitated by adding Et2O (25 mL). The mother liquor was removed
and the remaining yellow solid was dried under reduced pressure at 508C
to give 14. Yield: 151.7 mg (59%); 1H NMR (600 MHz, CDCl3): d=8.35
(d, J=8.9 Hz, 1H; Ar), 8.22 (d, J=8.8 Hz,1H; Ar), 8.10 (d, J=8.1 Hz,
1H; Ar), 8.06 (d, J=8.2 Hz, 1H; Ar), 7.81 (d, J=8.9 Hz, 1H; Ar), 7.70
(d, J=7.2 Hz, 1H; Ar), 7.69 (d, J=7.8 Hz, 1H; Ar), 7.63 (d, J=8.8 Hz,
1H; Ar), 7.60 (m, 1H; Ar), 7.54–7.48 (m, 5H; Ar), 7.43–7.26 (m, 10H;
Ar), 7.26–7.20 (m, 3H; Ar), 7.06 (m, 1H; Ar), 6.67 (t, J=7.8 Hz, 1H;
Ar), 6.63 (d, J=9.4 Hz, 1H; H-4), 6.35–6.30 (m, 2H; Ar), 6.20 (d, J=
8.7 Hz, 1H; Ar), 5.91 (t, J=6.8 Hz, 1H; CHcod), 5.81 (t, J=7.0 Hz, 1H;
CHcod), 5.77 (t, J=7.1 Hz, 1H; H-2), 5.61 (dd, J=9.4, 6.1 Hz, 1H; H-3),
4.21 (m, 1H; CHcod), 3.68 (m, 1H; CHcod), 2.85 (m, 1H; CH2), 2.69–2.48
(m, 3H; CH2), 2.01 (m, 1H; CH2), 1.95–1.82 (m, 2H; CH2), 1.35–
1.18 ppm (m, 1H; CH2); 31P NMR (243 MHz, CDCl3): d=138.3 (dd,
CDCl3): d=À20.9 ppm; MS (EI): m/z:
445 (5), 444 (33), 443 [M]+ (100), 442
(14), 316 (13), 290 (9), 258 (6), 238
(13), 222 (7), 221 (6), 183 (10); HRMS
(ESI): m/z: calcd for C31H27NP:
444.187565
444.187779.
[M+H]+;
found:
Ligand (Ra,Sc)-13a: A solution of phosphine 12a (1.729 g, 3.898 mmol) in
THF (40 mL) was cooled to À208C and phenyllithium (1 equiv, 2.12 mL,
c=1.84m in di-n-butylether/cyclohexane, 30:70) was added slowly with a
syringe. After complete addition, the reaction mixture was stirred for 1 h
at 08C and then cooled to À208C. Phosphorochloridite (R)-4 (1 equiv,
7.8 mL, c=0.5m in toluene) was added slowly and the mixture was al-
lowed to warm to RT. After stirring for 1 h at RT the mixture was con-
centrated under reduced pressure and the remaining solid was dried in
vacuo (4.256 g). Toluene (40 mL) and ethanol (2 mL) were added to a
portion of this solid (3.915 g) and the resulting mixture was heated to
408C, which resulted in a clear solution. After cooling to RT, ethanol
(48 mL) was added slowly with a syringe, whereupon a colourless solid
precipitated that contained (Ra,Sc)-13a with approximately 93% de (as
determined by 31P NMR spectroscopy). The obtained solid was filtered
off and dissolved in hot (40–808C) toluene (32 mL). Ethanol (50 mL)
was added and resulted in the formation of a colourless powder that con-
tained (Ra,Sc)-13a in diastereomerically pure form (as determined by
31P NMR spectroscopy). The obtained solid included residual toluene,
which could not be removed, even by heating in vacuo overnight. Sol-
vent-free (Ra,Sc)-13a was obtained after precipitation from CH2Cl2/n-
pentane (50:70 mL). After removal of the mother liquor, the solid was
dried in vacuo at 608C to yield (Ra,Sc)-13a as a white powder. Yield:
57% (774.5 mg, 1.022 mmol); >99% de; [a]2D0 =À2568 (c=0.5 in CHCl3);
1H NMR (600 MHz, CDCl3): d=8.25 (d, J=8.8 Hz, 1H; H-4A), 8.16 (d,
J=8.16 Hz, 1H; H-5A), 7.84 (d, J=8.8 Hz, 2H; Ar), 7.80 (d, J=8.70 Hz,
1H; H-3A), 7.60–7.52 (m, 4H; Ar), 7.51–7.35 (m, 9H; Ar), 7.35–7.25 (m,
8H; Ar), 7.22 (m, 1H; Ar), 7.13 (m, 1H; Ar), 7.06–6.99 (m, 2H; Ar),
6.16 (d, J=8.5 Hz, 1H; H-8’), 6.11 (m, 1H; Ar), 5.66 (m, 1H; H-2), 3.14
(m, 1H; HA-4), 2.77 (m, 1H; HB-4), 2.64 (m, 1H; HA-3), 1.60 ppm (m,
1H; HB-3); 13C NMR (150 MHz, CDCl3): d=151.48 (t, J=4.1 Hz; Cq),
149.62 (Cq), 146.92 (dd, J=24.6, 20.4 Hz; Cq), 142.58 (C-1’), 140.46 (m;
Cq), 138.17 (d, J=7.1 Hz; Cq), 136.46 (CH), 136.09 (m; Cq), 133.58 (CH),
133.51 (d, J=3.1 Hz; CH), 133.46 (CH), 133.46 (Cq), 133.39 (d, J=
3.1 Hz; CH), 133.27 (Cq), 132.64 (Cq), 131.45 (Cq), 130.69 (Cq), 130.38
(CH), 130.01 (C-4A), 129.66 (dd, J=8.6, 4.9 Hz; Cq), 129.33 (Cq), 129.10
(CH), 128.55 (d, J=6.0 Hz; 2CH), 128.41 (CH), 128.36 (d, J=6.5 Hz;
2CH), 128.28 (CH), 128.25 (CH), 128.24 (CH), 128.12 (CH), 127.68
(CH), 126.97 (CH), 126.52 (CH), 126.36 (CH), 126.09 (CH), 125.35 (CH),
125.15 (CH), 124.93 (CH), 124.85 (CH), 124.81 (CH), 124.08 (CH),
123.76 (d, J=5.2 Hz; Cq), 123.48 (d, J=3.7 Hz; CH), 122.41 (C-3A),
J
P, P ’ =61.3 Hz,
JACTHNGUTREN(NUG Rh,P)=258.4 Hz; NP(O)2), 24.8 ppm (dd, JACHTUNGTRENNUNG(P,P’)=
61.3 Hz, JACTHUGNTNR(NEUG Rh,P)=135.9 Hz; PPh2); HRMS (ESI): m/z: calcd for
C59H47NO2P2Rh: 966.212458 [M]+ ; found: 966.211939.
Complex 15: HBF4·Et2O (1.2 equiv, 0.144 mmol, 20 mL) was added to a
solution of (acetylacetonato)(1,5-cyclooctadiene)rhodium(I) (37.4 mg,
0.120 mmol) in dry THF (5 mL). After stirring for 10 min a solution of
(Sa,Rc)-7b (1 equiv, 0.120 mmol, 98.0 mg) in THF (5 mL) was added. The
resulting orange solution was stirred for 30 min and then concentrated to
half volume under reduced pressure. n-Pentane (30 mL) was added,
whereupon a yellow solid formed, which was separated from the mother
liquor by filtration. To remove included THF, the solid was dissolved in
CH2Cl2 (1 mL) and precipitated by adding Et2O (15 mL). The mother
liquor was removed and the remaining yellow solid was dried under re-
duced pressure at 508C to afford 15. Yield: 65.9 mg (49%). 1H NMR
(400 MHz, CDCl3): d=8.24 (d, J=8.9 Hz, 1H; Ar), 8.16 (d, J=8.9 Hz,
1H; Ar), 8.05 (d, J=8.1 Hz, 1H; Ar), 8.01 (d, J=8.1 Hz, 1H; Ar), 7.73
(d, J=8.9 Hz, 1H; Ar), 7.58–7.51 (m, 2H; Ar), 7.50–7.43 (m, 2H; Ar),
7.41 (m, 1H; Ar), 7.36–7.24 (m, 6H; Ar), 7.23–7.16 (m, 4H; Ar), 7.09 (s,
1H; Ar), 7.03 (t, J=7.3 Hz, 1H; Ar), 6.86 (s, 1H; Ar), 6.80 (d, J=
11.3 Hz, 2H; Ar), 6.52–6.43 (m, 2H; Ar), 6.30 (t, J=8.0 Hz, 1H; Ar),
6.15 (d, J=8.5 Hz, 1H; Ar), 6.09 (d, J=7.5 Hz, 1H; Ar), 5.86 (m, 1H),
5.78–5.71 (m, 2H; CHcod), 3.92 (m, 1H; CHcod), 3.60 (m, 1H; CHcod),
2.75–2.61 (m, 2H; CH2), 2.54–2.47 (m, 2H; CH2), 2.27 (s, 6H; CH3), 2.15
(s, 6H; CH3) 2.03–1.89 (m, 2H; CH2), 1.77–1.72 ppm (m, 2H; CH2);
31P NMR (162 MHz, CDCl3): d=138.0 (dd, J
ACTHUNRTGENN(GU P,P)=62.0 Hz, JACHTUNGTRENNUNG(P,Rh)=
7524
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Chem. Eur. J. 2010, 16, 7517 – 7526

Phosphine–Phosphoramidite Ligands for Asymmetric Hydrogenation
FULL PAPER
259.5 Hz; NP(O)2), 23.7 ppm (dd, J
(P,P)=62.0 Hz, J
E
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PXyl2); HRMS (ESI): m/z: calcd for C63H55NO2P2Rh: 1022.27576 [M]+
found: 1022.27660.
Complex 16: HBF4·Et2O (1.2 equiv, 0.120 mmol, 16 mL) was added to a
solution of (acetylacetonato)(1,5-cyclooctadiene)rhodium(I) (31.0 mg,
0.100 mmol) in dry THF (5 mL). After stirring for 10 min, a solution of
(Ra,Sc)-13a (1 equiv, 0.100 mmol, 75.8 mg) in THF (5 mL) was added.
The resulting orange solution was stirred for 30 min and then concentrat-
ed to half of the volume under reduced pressure. n-Pentane (30 mL) was
added, whereupon a yellow solid formed, which was separated from the
mother liquor. To remove included THF, the solid was dissolved in
CH2Cl2 (3 mL) and precipitated by the addition of Et2O (30 mL). The
mother liquor was removed by filtration and the remaining yellow solid
was dried under reduced pressure at 508C to give 16. Yield: 61.1 mg
(65%); 1H NMR (600 MHz, CDCl3): d=8.24 (d, J=8.8 Hz, 1H; Ar),
8.21 (d, J=9.0 Hz, 1H; Ar), 8.15 (d, J=8.2 Hz, 1H; Ar), 7.98 (d, J=
8.0 Hz, 1H; Ar), 7.83 (m, 2H; Ar), 7.69 (m, 2H; Ar), 7.66–7.61 (m, 2H;
Ar), 7.61–7.56 (m, 2H; Ar), 7.53–7.49 (m, 4H; Ar), 7.47–7.28 (m, 8H;
Ar), 7.28–7.23 (m, 1H; Ar), 7.21–7.15 (m, 2H; Ar), 7.11 (d, J=8.5 Hz,
1H; Ar), 7.02 (t, J=7.5 Hz, 1H; Ar), 6.62 (t, J=7.6 Hz, 1H; Ar), 6.13
(m, 2H), 5.92 (m, 2H), 5.72–5.61 (m, 2H), 4.16 (m, 1H), 3.59 (m, 1H),
2.76 (m, 1H), 2.56–2.44 (m, 4H), 2.38 (m, 1H), 1.99 (m, 1H), 1.89–1.77
(m, 2H), 1.61 (m, 1H), 0.99 ppm (m, 1H); 31P NMR (243 MHz, CDCl3):
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127.
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metry 2008, 19, 1862–1866; l) M. Eggenstein, A. Thomas, J. Theuer-
kauf, G. Franciꢀ, W. Leitner, Adv. Synth. Catal. 2009, 351, 725–732;
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d=136.9 (dd, JP, P’ =62.4 Hz, JACHTUNTRGNEU(GN Rh,P)=252.6 Hz; NP(O)2), 22.7 ppm (dd,
JACHTUNGTRENNUNG(P,P)=62.4 Hz, JACHTUNGTRENNUNG(Rh,P)=133.4 Hz; PPh2); HRMS (ESI): m/z: calcd for
C59H49NO2P2Rh: 968.228808 [M]+; found: 968.230606.
General procedure for asymmetric hydrogenation: A 10 mL stainless-
steel autoclave equipped with a glass inlet and a magnetic stirring bar
was charged under an argon atmosphere with the substrate (1 mmol).
The desired Rh complex (1 mmol) was added by syringe as a stock solu-
tion in CH2Cl2 or MeOH. The total amount of solvent was adjusted to
2 mL by the addition of the appropriate quantity of the same solvent and
the autoclave was pressurised with hydrogen (see Table 5 for details).
The reaction was started by switching on the stirrer. The reaction mixture
was stirred at RT for the desired reaction time then the pressure was
carefully released. The conversion was determined by 1H NMR spectros-
copy of the concentrated reaction mixture. The ee value was determined
by chiral GC or HPLC analysis after filtration through a plug of silica.
The absolute configurations of the hydrogenation products were assigned
by comparison of the sign of optical rotation to those reported in the lit-
erature.
Acknowledgements
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University) for the measurement of NMR spectra, Brigitte Pꢁtz (Organic
Department, RWTH Aachen University) for the measurement of HRMS
data, Prof. Dr. Ulli Englert and Yutian Wang (Inorganic Department,
RWTH Aachen University) for the acquisition of X-ray diffraction raw
data, Umicore for a generous gift of precious-metal complexes and the
German Federal Ministry for Education and Research (BMBF) for finan-
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step as the reduction of both compounds results in the desired
1,2,3,4-tetrahydroquinoline 11a.
[16] CCDC-749795 (13a·CHCl3) and 749794 (14·CH2Cl2) contain the
supplementary crystallographic data for this paper. These data can
Chem. Eur. J. 2010, 16, 7517 – 7526
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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7525

G. Franciꢀ, W. Leitner et al.
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[19] Induction time in asymmetric hydrogenation of prochiral olefins has
not been taken into account; see for instance: H.-J. Drexler, W.
Baumann, A. Spannenberg, C. Fischer, D. Heller, J. Organomet.
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Received: January 11, 2010
Published online: May 17, 2010
7526
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