INDOLPhos: novel hybrid phosphine-phosphoramidite ligands for asymmetric hydrogenation and hydroformylation

Article abstract of DOI:10.1039/b709956h

Hybrid bidentate phosphine-phosphoramidite ligands are prepared in a modular 2-step sequence and their rhodium complexes display high selectivity in rhodium catalysed hydrogenation and hydroformylation reactions. The Royal Society of Chemistry.

Full text of DOI:10.1039/b709956h

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www.rsc.org/dalton | Dalton Transactions
INDOLPhos: novel hybrid phosphine-phosphoramidite ligands for
asymmetric hydrogenation and hydroformylation†
Jeroen Wassenaar and Joost N. H. Reek*
Received 2nd July 2007, Accepted 13th July 2007
First published as an Advance Article on the web 27th July 2007
DOI: 10.1039/b709956h
Hybrid bidentate phosphine-phosphoramidite ligands are
prepared in a modular 2-step sequence and their rhodium
complexes display high selectivity in rhodium catalysed hy-
drogenation and hydroformylation reactions.
high degree of rigidity (Fig. 1). The ridigity is expressed by large
phosphine-phosphoramidite couplings in the P NMR spectra
3
1
of ligands 2a–d (up to 250 Hz, see ESI†), which is also observed
8c,15
for other rigid small bite angle ligands.
Therefore, INDOLPhos
can be considered as a hybrid analogue of the successful DuPHOS
in terms of bite-angle and rigidity, but variation of substituents is
far more facile in the current ligand facilitating the synthesis of
large and diverse ligand libraries.
Enantioselective transition metal catalysis has emerged as a unique
tool for the introduction of chirality in pharmaceuticals and
fine chemical intermediates. Asymmetric catalytic hydrogenation
has become particular important as many different building
1
blocks with a variety of functional groups becomes accessible.
2
Traditionally, chiral bidentate phosphine ligands have dominated
3
4
this field until more recently Feringa and De Vries, Reetz
5
and Pringle introduced the use of monodentate phosphites and
phosphoramidites. Due to their more simple structure, their
synthesis is generally much less elaborate enabling the preparation
of large ligand libraries, which are required to rapidly find new
catalysts that enable asymmetric conversion of new substrates.
Although these monodentate based catalyst have been successful
for many reactions, bidentate ligands, and heterobidentates in
particular, will always be required to achieve high activity,
selectivity and stability for a number of transformations. Therefore
there is a need to develop novel bidentate ligands, preferentially
with straightforward synthetic procedures. A recent advancement
Fig. 1 Calculated (DFT, B3LYP, 6–31G*) structure of INDOLPhos 2b
(
green = C, white = H, blue = N, red = O, yellow = P).
We have optimised the synthesis of indolylphosphines by using
CO
2
as a protecting and directing group resulting in a one-pot
6,7
in this area is the use of supramolecular bidentate ligands
11
protocol. Deprotonation of the indolyl NH by n-BuLi is followed
by carboxylation to yield the protected 1-carboxyl-3-methylindole
in situ. Addition of t-BuLi results in selective deprotonation at the
ortho-position of the carboxyl group to yield the 2-lithiated inter-
mediate, which is reacted with the corresponding chlorophosphine.
The carboxyl protecting group is removed by mild acidic work-
up to give indolylphosphines 1 in good yield. Initial condensation
attempts of 1 with bisnaphthol phosphorchloridites in the presence
of weak bases such as triethylamine failed, probably due to the
low nucleophilicity of the indolyl NH. Deprotonation using a
strong base such as n-BuLi proved to be effective and INDOLPhos
ligands 2a–d are obtained in high yield (Scheme 1).
which form by assembly of functionalised simple monodentate
building blocks. Alternatively, one could devise simple modular
synthetic strategies that should lead to easy access to bidentate
ligands. Here we present a series of hybrid bidentate phosphine-
phosphoramidite ligands 2a–d that are accessible by a two-step
synthetic sequence from cheap commercially available building
blocks. ‡ The new ligands display unusual coordination properties
and are highly active and selective in the rhodium catalysed
hydrogenation and hydroformylation.
8
Browning and co-workers have introduced indolylphosphines
1, which are appealing to us as they are easily prepared in one
step from cheap starting materials and offer further phosphorus
The coordination properties of ligands 2a–d to cationic rhodium
10
functionalisation through the indolyl nitrogen. The novel biden-
tate phosphine-phosphoramidite ligand (INDOLPhos) contains
a two-atom bridge leading to the formation of five-membered
coordination cycles as opposed to the frequently reported six-
1
31
were investigated by H and P NMR spectroscopy. Mixing ligand
a with one equivalent of [Rh(nbd) ]BF in CDCl led to the
formation of a 1 : 4 mixture of the expected [Rh(2a)(nbd)]BF and
2
2
4
3
4
ꢀ
ꢀ
a second species exhibiting a complicated AA XX multiplet in the
9
membered cycles. In addition, molecular modelling indicates that
31
P NMR spectrum (Fig. 2). The second species could be identified
2
the backbone is completely sp hybridised thereby enforcing a
as [Rh(2a)
2
]BF where phosphines and phosphoramidites of the
4
two ligands are in mutual cis position as indicated by the large
JPN,PC of 389 Hz (Fig. 3). To our knowledge this is the second report
of such a bis-ligated species for hybrid bidentate phosphorus
ligands. Importantly, when changing the steric properties of the
ligand to more bulky substituents on either the phosphine (2b)
Van’t Hoff Institute for Molecular Sciences, University of Amsterdam,
Nieuwe Achtergracht 166, 1018 WV Amsterdam, The Netherlands.E-mail:
reek@science.uva.nl; Fax: +31 20 5256422; Tel: +31 20 5256437
12
†
Electronic supplementary information (ESI) available: Ligand syn-
thesis, experimental details and additional NMR spectra. See DOI:
0.1039/b709956h
1
or bisnaphthol (2c), only mono-ligated species [Rh(2b)(nbd)]BF
4
3
750 | Dalton Trans., 2007, 3750–3753
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3
1
1
Fig. 2 Calculated (top) and measured (bottom) P{ H} NMR spectra for [Rh(2a)
2
]BF
4
. Coupling constants used for the simulated spectrum: JPN,Rh
=
2
25 Hz, JPC,Rh = 124 Hz, JPN,PN = 26 Hz, JPC,PC = 17 Hz, JPN,PC(cis) = −62 Hz, JPN,PC(trans) = 389 Hz. The additional double doublet in the measured spectrum
4
stems from [Rh(2a)(nbd)]BF .
31
2 4
Fig. 3 Structure of [Rh(2a) ]BF (left) and assignment of P NMR
coupling constants (right).
hydrogenation of benchmark substrates dimethyl itaconate (A)
and methyl 2-acetamidoacrylate (B) using ligands 2a–d was
studied (Table 1). To our surprise it was observed that ligand
2a, although it forms unreactive bis-ligated species, was able to
hydrogenate A and B to full conversion, inducing a considerable
amount of ee (entries 1 and 5). It is proposed that the minor
mono-ligated species performs most of the catalysis along with
the achiral Rh-precursor which lowers the ee. Control experiments
showed that ligand free [Rh(nbd)
2
]BF was able to fully convert A
4
Scheme 1 Synthesis of INDOLPhos ligands.
and B within 12 h. The more bulky ligand 2c bearing trimethylsilyl
groups in ortho-position on the bisnaphthol preventing bis-ligated
species results in similar activities compared to ligand 2a as full
conversion is obtained. However, the selectivity obtained with the
catalyst based on 2c was rather low (36% and lower entries 3 and 7).
Interestingly, full conversion and high selectivities were obtained
when the steric bulk was introduced on the phosphine moiety (2b,
up to 98% entries 2 and 6). For MAA (B), the enantioselectivity
could be further enhanced by introducing methyl substituents in
and [Rh(2c)(nbd)]BF
factors disfavouring bis-ligated species in the case of 2b and 2d are
4
were formed (Fig. S2–S4 ESI†). Additional
the lack of p-stacking interactions and the stronger trans-effect of
alkyl phosphines.
The special coordination properties of ligands 2a–d prompted
us to investigate their influence on the catalytic performance
in the Rh-catalysed hydrogenation and hydroformylation. The
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Table 1 Rhodium catalysed asymmetric hydrogenation of dimethyl ita-
using a hybrid phosphine-phosphoramidite ligand derived from
NOBIN. Initial results were disappointing as the application
a
conate and methyl 2-acetamidoacrylate
8f
of parent ligand 2a gave rise to low conversion (entry 1). Since
the hydroformylation reaction is carried out in the presence of
excess ligand with respect to rhodium, this low activity can
be explained by the formation of inactive complexes with two
ligands 2a coordinated to rhodium, as was also observed in the
NMR experiments (vide supra). Indeed, introduction of sterically
more demanding groups suppresses the formation of such species.
Instead active catalysts are formed that provide the product with
moderate to good ee’s with a maximum of 72% ee (ligand 2d
entry 5). A very high selectivity for the branched product with an
b/l ratio of 17 was obtained using ligand 2b (entry 2). We expect
that further optimization of this ligand will lead to a catalyst that
will give both high regio- and enantio-selectivity.
In summary, we have developed a new set of hybrid biden-
tate phosphine-phosphoramidite ligands based on the indole
backbone. Their coordination mode to Rh is controlled by the
steric properties of the ligand which has been shown to play a
major role in the asymmetric hydrogenation and hydroformy-
lation. High enantioselectivities (up to 98% ee) are obtained
with ligands 2b and 2d in the hydrogenation. A high selectivity
for the branched aldehyde along with good ee (up to 72%) is
reached in the hydroformylation of styrene. The modular synthetic
sequence allows for easy derivatization of the ligand enabling high-
throughput screening of a INDOLPhos library to convert more
challenging substrates. We are currently exploring this strategy
along with elucidating the true origin of the ligand-size dependent
enantioselection in the hydrogenation of B.
Entry
Ligand
Substrate
% conv.
% ee (config)
1
2
3
4
5
6
7
8
2a
2b
A
A
A
A
B
B
B
B
100
100
100
100
100
100
100
100
73 (S)
98 (S)
12 (S)
92 (S)
13 (S)
86 (R)
36 (R)
97 (R)
b
2c
2d
2a
2b
b
2c
2d
a
Reactions were performed in CH
00, 10 bar of H
Rh(2c)(cod)]BF was used instead of the in situ generated catalyst.
2
Cl
2
, Rh/L = 1 : 1.1, Rh/substrate = 1 :
]BF as metal precursor.
◦
1
2
, at 25 C for 16 h using [Rh(nbd)
2
4
b
[
4
ortho-position of the bisnaphthol moiety (2d, up to 97% entries 4
and 8).
In all ligands the absolute configuration of the bisnaphthol,
the only source of chirality in the molecule, was identical. It is
therefore surprising that 2a gives the opposite enantiomer of the
product compared to 2b–d in the hydrogenation of B (entries 5–
). This result suggests that a different mechanism is operating
in the case of 2a. Jug e´ et al. have described a similar effect
when changing substituents on their hybrid aminophosphine–
phosphinite system. They observed a reversal of enantioselec-
tivity when aryl substituents were replaced by alkyl, which is
explained by steric effects in the intermediate olefin complexes
forcing the substrate to coordinate with the other prochiral face.
A similar explanation is likely for the origin of the effects we
observe as the change in substituents is comparable.
8
13
14
Acknowledgements
We gratefully acknowledge NRSCC for financial support.
After the promising results obtained in the hydrogenation
we investigated the catalytic properties of ligands 2a–d in the
more challenging hydroformylation of styrene (Table 2). We were
encouraged by the results of Zhang and co-workers who obtained
complete enantioselection in the hydroformylation of styrene
Notes and references
‡
Prices for starting materials according to the 2007–2008 Aldrich cata-
−1
−1
logue: 3-methylindole, 2.16 € g ; chlorodiphenylphosphine, 0.69 € g
;
(S)-BINOL, 3.14 € g− ; phosphorus trichloride, < 0.02 € g
1
−1
.
1
For an exhaustive review on homogeneous hydrogenation see: The
Handbook of Homogeneous Hydrogenation, ed. J. G. de Vries, C. J. El-
sevier, Wiley-VCH, Weinheim, 2007.
a
Table 2 Rhodium catalysed asymmetric hydroformylation of styrene
2
3
For a recent review see: W. Tang and X. Zhang, Chem. Rev., 2003, 103,
3
029 and references cited therein.
M. van den Berg, A. J. Minnaard, E. P. Schudde, J. van Esch, A. H. M.
de Vries, J. G. de Vries and B. L. Feringa, J. Am. Chem. Soc., 2000, 122,
1
1539.
4
5
6
M. T. Reetz and G. Mehler, Angew. Chem., Int. Ed., 2000, 39,
3
889.
C. Claver, E. Fernandez, A. Gillon, K. Heslop, D. J. Hyett, A. Martorell,
A. G. Orpen and P. G. Pringle, Chem. Commun., 2000, 961.
◦
b
c
d
Entry
T/ C
Ligand
% conv.
b/l
% ee
(a) V. F. Slagt, P. W. N. M. van Leeuwen and J. N. H. Reek, Chem.
Commun., 2003, 2474; (b) V. F. Slagt, P. W. N. M. van Leeuwen and
J. N. H. Reek, Angew. Chem., Int. Ed., 2003, 42, 5619; (c) V. F. Slagt,
M. R o¨ der, P. C. J. Kamer, P. W. N. M. van Leeuwen and J. N. H. Reek,
J. Am. Chem. Soc., 2004, 126, 4056; (d) J. N. H. Reek, M. R o¨ der, P. E.
Goudriaan, P. C. J. Kamer, P. W. N. M. van Leeuwen and V. F. Slagt,
J. Organomet. Chem., 2005, 605, 4505; (e) X.-B. Jiang, L. Lefort, P. E.
Goudriaan, A. H. M. de Vries, P. W. N. M. van Leeuwen, J. G. de Vries
and J. N. H. Reek, Angew. Chem., Int. Ed., 2006, 45, 1223; (f) A. J.
Sandee, A. M. van der Burg and J. N. H. Reek, Chem. Commun., 2007,
864; (g) M. Kuil, P. E. Goudriaan, P. W. N. M. van Leeuwen and J. N. H.
Reek, Chem. Commun., 2006, 4679.
e
1
2
60
40
60
60
40
60
2a
2b
2b
2c
2d
2d
3
84
55
99
96
97
2
17
6
12
10
7
0
50
51
9
72
61
f
3
4
5
6
a
−1
−1
[
Rh(acac)(CO)
2
] = 1.0 mmol l in toluene, [ligand] = 4.0 mmol l
,
b
styrene/rhodium = 1000, pressure = 10 bar (CO/H
2
= 1/1). Percentage
c
conversion; the reaction was stopped after 19 h. Ratio of branched to
d
linear product. In all cases the R enantiomer of the product was formed.
e
f
7 (a) B. Breit and W. Seiche, J. Am. Chem. Soc., 2003, 125, 6608; (b) B.
Breit and W. Seiche, Angew. Chem., Int. Ed., 2005, 44, 1640; (c) B. Breit
4
8 h. 65 h.
3
752 | Dalton Trans., 2007, 3750–3753
This journal is © The Royal Society of Chemistry 2007

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and W. Seiche, J. Am. Chem. Soc., 2003, 125, 6608; (d) F. Chevallier and
B. Breit, Angew. Chem., Int. Ed., 2006, 45, 1599; (e) J. M. Takacs, D. S.
Reddy, S. A. Moteki, D. Wu and H. Palencia, J. Am. Chem. Soc., 2004,
Tetrahedron: Asymmetry, 2006, 17, 2726; (k) K. A. Vallianatou, I. D.
Kostas, J. Holz and A. B o¨ rner, Tetrahedron Lett., 2006, 47, 7947.
9 A flexible two-atom bridged hybrid phosphine-phosphite bidentate has
been reported by Faraone et al.: C. G. Arena, F. Faraone, C. Graiff and
A. Tiripicchio, Eur. J. Inorg. Chem., 2002, 711.
10 J. O. Yu, E. Lam, J. L. Sereda, N. C. Rampersad, A. J. Lough, C. S.
Browning and D. H. Farrar, Organometallics, 2005, 24, 37.
11 A. R. Katritzky and K. Akutagawa, Synth. Commun., 1988, 18, 1151.
12 A similar species has been detected for hybrid phosphine-phosphite
ligands by Pizzano et al.: M. Rubio, S. Vargas, A. Su a´ rez, E. A´ lvarez
and A. Pizzano, Chem.–Eur. J., 2007, 13, 1821.
13 For a recent review on the mechanism of Rh-catalysed asymmetric
hydrogenation see: I. D. Gridnev and T. Imamoto, Acc. Chem. Res.,
2004, 37, 633.
1
26, 4494; (f) P. A. Duckmanton, A. J. Blake and J. B. Love, Inorg.
Chem., 2005, 44, 7708.
For other examples of hybrid phosphine-phosphoramidite ligands see:
8
(
3
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2
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2
4
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19; (i) J.-D. Huang, X.-P. Hu, Z.-C. Duan, Q.-H. Zeng, S.-B.
14 C. Darcel, D. Moulin, J.-C. Henry, M. Lagrelette, P. Richard, P. D.
Harvey and S. Jug e´ , Eur. J. Org. Chem., 2007, 2078.
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4
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