Highly enantioselective hydroformylation of dihydrofurans catalyzed by hybrid phosphine-phosphonite rhodium complexes

Article abstract of DOI:10.1039/b924046b

Unprecedented regio- and enantioselectivities (>91%) are reported for the Rh-catalyzed asymmetric hydroformylation of 2,3- and 2,5-dihydrofuran using tunable hybrid phosphine-phosphonite ligands.

Full text of DOI:10.1039/b924046b

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Highly enantioselective hydroformylation of dihydrofurans catalyzed
by hybrid phosphine–phosphonite rhodium complexesw
Samir H. Chikkali,ab Rosalba Bellini,a Guillaume Berthon-Gelloz,a
Jarl Ivar van der Vlugt,a Bas de Bruina and Joost N. H. Reek*a
Received (in Cambridge, UK) 17th November 2009, Accepted 4th January 2010
First published as an Advance Article on the web 18th January 2010
DOI: 10.1039/b924046b
Unprecedented regio- and enantioselectivities (491%) are
reported for the Rh-catalyzed asymmetric hydroformylation
of 2,3- and 2,5-dihydrofuran using tunable hybrid phosphine–
phosphonite ligands.
the intermediate A to afford 2, which subsequently hydro-
formylates to 4.
So far non-C2 symmetric bidentate ligands such as
BINAPHOS5 and sugar based diphosphites5 provide the most
selective rhodium catalysts for the hydroformylation of 1 and
2. Based on these results, we anticipated that a tunable hybrid
phosphine–phosphonite scaffold could result in an active and
selective catalyst; so far such ligands have not been reported in
the asymmetric hydroformylation of heterocyclic olefins.
Herein we report on the syntheses and successful application
of xanthene based hybrid phosphine–phosphonite ligands in
the Rh-catalyzed asymmetric hydroformylation of 2,3- and
2,5-dihydrofuran, leading to unprecedented regioselectivities
and the highest enantioselectivities (91%) ever reported for
these challenging substrates.
Asymmetric hydroformylation is a powerful synthetic tool to
construct a plethora of enantiomerically enriched compounds,
and it has found several applications.1 Traditionally, vinyl
aromatics have been the most extensively explored substrates,2
while asymmetric hydroformylation of heterocyclic olefins
such as dihydrofuran, dihydropyran and pyrroline is scarcely
investigated.3 The carbaldehydes of dihydrofuran and pyrroline
display a wide range of biological activities, functioning as
antitumor and antibacterial agents, and are recognized as
influential motifs in pharmaceutical compounds.4 The asymmetric
hydroformylation of these heterocyclic olefins would provide
an efficient and atom economic protocol to prepare the
respective carbaldehydes. Control over the stereo-selectivity
is principally the key challenge in asymmetric hydroformylation
reactions, but for the current dihydrofuran substrates also
chemo- and regioselectivity are crucial issues to be addressed,
as isomerization often takes place under hydroformylation
conditions (Scheme 1). Although compound 3 is the expected
hydroformylation product of 2,5-dihydrofuran 1, generally
significant amounts of compound 2 and 4 are also formed.
The isomerization occurs via b-hydride elimination of
Wide bite angle diphosphines such as xantphos have been
successfully applied in e.g. Rh-catalyzed hydroformylation,
leading to good regioselectivities whilst suppressing undesirable
isomerization reactions.6 We anticipated that chiral ligands
with inequivalent P-donors5,7 based on the xanthene backbone
may address both the stereoselectivity and the chemoselectivity
issues involved in the hydroformylation of dihydrofurans, and
therefore we set out to prepare xanthene based phosphine–
phosphonite ligands 7a–c.z The s-donating phosphine group
and p-accepting phosphonite fragment, bearing a chiral
auxiliary, are anticipated to induce a highly asymmetric environ-
ment around the catalytic center. Ligand modifications are
relatively straightforward, giving rise to a set of similar ligands
using analogous synthetic schemes.
Our approach involves a simple, two step synthetic protocol
starting from the reported monophosphine 5.8 Lithiation of 5
followed by the addition of aminochlorophosphine yielded
intermediate 6 (see Scheme 2) in 85% isolated yield.w The
31P NMR spectrum of 6 in C6D6 at room temperature
indicates an AB spin system with doublets at 92.4 and
ꢀ15.1 ppm (6JP–P coupling of 17.1 Hz), assigned to the
aminophosphine and diphenyl phosphine moieties, respectively.9
The desired hybrid phosphine–phosphonite ligands 7a–c were
readily prepared upon reaction of 6 with the BINOL derivatives
a–c (Scheme 2).10 The individual reactions were generally
carried out in toluene at 120 1C and the products were isolated
nearly quantitatively after purification by flash silica
chromatography.10 Typically, the 31P NMR spectra of 7a–c
at ambient temperature displayed a doublet in the range
of 181–167 ppm (phosphonite) and one between ꢀ13
Scheme 1 Proposed isomerization mechanism in hydroformylation
of 1.
a Supramolecular and Homogeneous Catalysis,
van’t Hoff Institute For Molecular Science,
University of Amsterdam, Nieuwe Achtergracht 166, 1018 WV,
Amsterdam, The Netherlands. E-mail: J.N.H.Reek@uva.nl;
Fax: +31 20 5255604
b Dutch Polymer Institute DPI, PO Box 902, 5600 AX, Eindhoven,
The Netherlands
w Electronic supplementary information (ESI) available: Experimental
procedures, spectroscopic and analytical data 6, 7a–c, 8 and 9. See
DOI: 10.1039/b924046b
6
and ꢀ18 ppm (phosphine) with JP–P couplings of approx.
30–34 Hz. The chemical shift of the phosphonite fragment is
ꢁc
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various reaction conditions. Preliminary screening with 7c
pointed to a much better performance of the rhodium
complexes based on this ligand as ee’s around 90% were
obtained. Increasing the reaction temperature from 25 1C
to 40 1C led to significantly higher conversions without
jeopardizing the selectivity (Table 1, run 6 vs. 7 and 8).
Furthermore, prolonged reaction time increased the conver-
sion to aldehyde 3, whilst retaining high regio- and stereo-
selectivity (Table 1, run 10). At 45 1C regioselectivity reached
499.95% for 3-carbaldehyde 3 with 91% ee at 90% conver-
sion (run 8). Performing the reaction at 50 1C led to a drop
in both regio- and enantioselectivity and substantial iso-
merization (15%) to 2,3-dihydrofuran was observed (run 9).
We attribute the dramatically decreased regio- and enantio-
selectivity to the parallel hydroformylation of 2,3-dihydro-
furan, generated in situ via isomerization (Scheme 1), which
results in the opposite enatiomer of carbaldehyde 3 (vide infra).
As can be seen from runs 13–19 (vide infra), hydroformylation
of 2 by the same catalyst produces two regioisomeric products.
Importantly the opposite enantiomer of carbaldehydes 3 is
formed when this substrate is converted, indicating that iso-
merization of 1 to 2 and subsequent hydroformylation
dramatically lowers the overall ee. We therefore performed
an experiment at 30 bars of H2/CO, to further suppress
Scheme 2 General methodology displaying the synthesis of ligands
7a–c; (i) ꢀ78 1C, 2 equiv. tert-BuLi, 1.1 equiv. ClP(NEt2)2; (ii) 1.1 equiv.
BINOL derivatives a–c, 120 1C reflux in toluene.
similar to those reported previously.9 All new ligands were
characterized by a combination of analytical techniques (ESIw).
The coordination behaviour of the hybrid ligand 7c was
studied by mixing 2 equivalents of 7c with 1 equivalent of
[Rh(m-Cl)(CO)2]2 in dichloromethane, and the complex
formation was monitored by 31P NMR spectroscopy. The
reaction proceeded readily at ambient temperature and after
2 h complex 8 [Rh(7c)(CO)Cl] was formed in quantitative
yield. The 31P NMR spectrum of 8 displays two doublets of
doublets at 162.2 ppm (1JRh–P = 202 Hz, 2JP–P = 532 Hz) and
20.6 ppm (1JRh–P = 127.5 Hz, 2JP–P = 532 Hz), clearly indicating
the coordination of two chemically inequivalent phosphorus
atoms to the rhodium in mutual trans-disposition (ESIw).
Table 1 Rhodium catalyzed asymmetric hydroformylation of 1 and 2
using ligands 7a–ca
In our pursuit to identify the catalytic species we investi-
gated the coordination mode of 7c under catalytic conditions.
Stoichiometric amounts of 7c and Rh(acac)(CO)2 were mixed
under 5 bars of syngas. The 31P high pressure (HP) NMR
spectrum of this solution revealed two doublets of doublets,
centered at 173.9 ppm (with 1JRh–P = 203 Hz, 2JP–P = 95 Hz)
Ligand/ L/Rh
Run sub
Regio
%
Convc
%ee
3
ratio Time/h Temp/1C (3/4)b
1i
2d
3e
4
5
6
7a/1
7b/1
7b/1
7c/1
7c/1
7c/1
7c/1
7c/1
7c/1
7c/1
7c/1
2.1
4.7
4.7
2
15
15
18
15
15
15
15
40
15
48
48
16
18
16
15
15
40
20
60
60
40
40
25
25
25
40
45
50
45
45
25
60
40
50
40
25
25
45
85 : 15 60
99 : 1 35
100 : 00 20
100 : 00 5–8
100 : 00
100 : 00
100 : 00 40
100 : 00 90
96 : 4
100 : 00 97
100 : 00 86
93 : 7
75 : 25 34
81 : 19
75 : 25 18
4
B5
47
89 (S)
90 (S)
91 (S)
91 (S)
91 (S)
32 (S)
90 (S)
90 (S)
90 (S)
19
55 (R)
87 (R)
88 (R)
91 (R)
90 (R)
81 (R)
3
5
5
1
2
and 19.5 ppm (with JRh–P = 130.6 Hz, JP–P = 95 Hz). The
corresponding 1H HP-NMR spectrum of this solution dis-
played a doublet of doublets of doublets in the hydride region,
at ꢀ9.0 ppm (1JRh–H = 4.1 Hz, 2JP*–H = 35 and 2JP–H = 8 Hz).
Coupling patterns were verified with various 1D- and
4.7
4.7
4.7
4.7
4.7
5.5
4.7
2.1
4.7
4.7
4.7
4.7
4.7
4.7
7
8f
9g
10
11
75
2
12h 7c/1
n.d.
2D-NMR spectroscopic techniques. The fairly small JP–H
13j
14k 7b/2
7a/2
couplings are characteristic for a complex with predominantly
bis-equatorial (ee) coordination mode of the two phosphorus
donors, which is in line with data for xanthene based
diphosphonites,11 but is rather unusual for a hybrid bidentate
bisphosphorus ligand (ESIw).12 In the estimated 20% ea
complex present in solution, the phosphonite is positioned
trans to the hydride.
7
15
16
17l
7c/2
7c/2
7c/2
79 : 21
80 : 20
81 : 19 n.d.
77 : 23 69
7
5
18m 7c/2
19n 7c/2
Rh(acac)(CO)2 (1.9 ꢂ 10ꢀ6 mol), S/Rh = 200, p(CO/H2) = 20 bars,
T = 25 1C, t = 15 h, toluene = 0.75 mL, no hydrogenation or
isomerization product could be observed. Regio- and enantio-
a
The performance of the phosphine–phosphonite ligands
7a–c in the asymmetric hydroformylation of 2,5-dihydrofuran
was evaluated and the representative catalytic data are
summarized in Table 1. The catalysts were prepared in situ
by mixing an appropriate amount of 7 and Rh(acac)(CO)2 as a
catalyst precursor. The catalyst based on the ligands
with chiral binol derivatives 7a and 7b displayed very poor
performance (runs 1–3). Only a moderate ee of 47% could be
obtained using the ligand 7b, even after extensive screening of
b
c
selectivity measured by chiral GC. Total conversion determined by
d
1H NMR. S/Rh = 400. p(CO/H2) = 55 bars, S/Rh = 400.
e
f
Isomerization to 2,3-dihydrofuran was detected by NMR (5%).
Isomerization to 2,3-dihydrofuran was detected by NMR (15%).
g
h
i
j
p(CO/H2) = 30 bars, S/Rh = 400. S/Rh = 400. L/Rh = 2.1,
k
S/Rh = 400. p(CO/H2) = 40 bars, S/Rh = 400. p(CO/H2) =
l
m
n
25 bars. p(CO/H2) = 15 bars, S/Rh = 400. Rh(acac)(CO)2
(3.9 ꢂ 10ꢀ6 mol).
ꢁc
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isomerization,5 but this instead decreased the regioselectivity
while the enantioselectivity was retained (run 12). To our
knowledge, the enantiomeric excess for the hydroformylation
of 2,5-dihydrofuran obtained with ligand 7c (91%) is the
highest ever reported, and importantly, it coincides with
excellent regioselectivity (499.95%).
Notes and references
z A simple PM3 model suggested that the 3,30 position on the
(octahydro)binol in 7 should be the most influential position to
control the selectivity and that increasing steric bulk around this
position might induce high enantioselectivities. Based on these
leads we designed the tuneable, hybrid phosphine–phosphonite
ligands 7a–c.
Riding high on the excellent catalyst performance, we
set out to assess the ligands 7a–c in the asymmetric hydro-
formylation of 2,3-dihydrofuran. The important findings are
also summarized in Table 1. Overall, substrate 2 was found to
be less reactive than 1 and the regioselectivity in all cases
stayed almost constant at 80 : 20 (3/4). Ligands 7a and 7b were
again outperformed by 7c (runs 13–15). Further optimization
was performed using ligand 7c, and the conversion improved
significantly at higher temperatures, although at the expense of
a slightly lower enantioselectivity (runs 15–17). Next, the effect
of syngas pressure was studied. An excellent enantioselectivity
(91%) with the best regio-control (80 : 20) was achieved at
25 bars (run 17), while either lower or higher pressures resulted
in decreased selectivities (runs 15, 16 and 18, 19). Prolonged
reaction times at 45 1C improved the conversion to 69%,
although the enantioselectivity dropped to 81% (run 19).
Interestingly, the sense of enantioselection in 1 and 2 is
opposite in nature, i.e. the absolute configuration of the
predominant enantiomer obtained from 1 is S, while that
obtained from 2 is R (ESIw). This is important as it explains
why isomerization side reactions can directly deteriorate the ee
of the product that is formed.
1 K. Nozaki, Comprehensive Asymmetric Catalysis, Springer,
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In conclusion, we report a new class of xanthene based,
hybrid phosphine–phosphonite ligands that are easy to modify.
In situ high pressure NMR spectroscopy showed that the two
phosphorus nuclei predominantly occupy bis-equatorial posi-
tions, in contrast to most related chiral hybrid bidentate
ligands such as BINAPHOS. On the other hand, this mode
of coordination is in line with previous xanthene based
ligands.11 The performance of the novel ligands was evaluated
in the asymmetric hydroformylation of notoriously difficult
2,3- and 2,5-dihydrofuran substrates. The hybrid ligand 7c was
undoubtedly the best among the three and displayed excellent
performance. Employing 7c, an unprecedented high enantio-
meric excess (91%) was obtained in the hydroformylation of 1
along with excellent regio-selectivities. Similarly, an ee of
91% and good regioselectivity (80 : 20) was obtained in the
asymmetric hydroformylation of 2 using ligand 7c, which
clearly outperforms other systems reported for this substrate.
A remarkable observation is that both enantiomers of product
3 are accessible using the same catalyst, simply by changing the
substrate from 2,5- to 2,3-dihydrofuran. In addition, this
phenomenon implies the necessity to suppress isomerization,
as this will lead to a dramatic decrease in selectivity. We are
currently further exploring the substrate scope of this new
class of catalysts.
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9 Similar chemical shifts for xanthene based bis-aminophosphines
and diphosphonites have been previously reported; W. Goertz,
P. C. J. Kamer, P. W. N. M. van Leeuwen and D. Vogt,
Chem.–Eur. J., 2001, 7(8), 1614; J. I. van der Vlugt,
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¨
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10 Synthesis of 7a and 7b proceeds smoothly, whereas a catalytic
amount of tetrazole as a protonating agent was necessary to
prepare 7c, see ESIw.
This work is part of the Research Program of the Dutch
Polymer Institute DPI, projectnr. #656 and is also financially
supported by the European Commission [RTN Network (R)
Evolutionary Catalysis MRTN-CT-2006035866].
11 J. I. van der Vlugt, R. Sablong, P. C. M. M. Magusin, A. M. Mills,
A. Spek and D. Vogt, Organometallics, 2004, 23, 3177.
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ꢁc
This journal is The Royal Society of Chemistry 2010
1246 | Chem. Commun., 2010, 46, 1244–1246