Highly regio- and enantioselective asymmetric hydroformylation of olefins mediated by 2,5-disubstituted phospholane ligands

Article abstract of DOI:10.1002/anie.200501478

(Chemical Equation Presented) Off the shelf: The commercially available ligand (R,R)-1,2-bis(2,5-diphenylphospholano)ethane ((R,R)-Ph-bpe) has been identified as an excellent ligand for asymmetric hydroformylation. State-of-the-art regio- and enantioselectivities are obtained for reactions with styrene, allyl cyanide, and vinyl acetate as substrates while high reaction rates (> 4000 turnovers h^-1) are maintained (see scheme; Ac = acetate, b/l = branched/linear).

Full text of DOI:10.1002/anie.200501478

Communications
Asymmetric Catalysis
the regio- and enantioselectivities simultaneously, and c) lim-
ited substrate scope for any single ligand.
DOI: 10.1002/anie.200501478
The reaction rates of Rh-catalyzed hydroformylations are
commonly slower than those of asymmetric hydrogenations
that are conducted near ambient temperature. Commercially
viable rates in AHF can be achieved at 80–1208C (turnover
rates of several thousand per hour); however, lower regio-
and enantioselectivities are usually observed at these high
temperatures. Thus, the most desired characteristic of the new
generation of AHF ligands should be the ability to produce
optically active aldehydes at high temperatures without
compromising product selectivity.
Highly Regio- and Enantioselective Asymmetric
Hydroformylation of Olefins Mediated by 2,5-
Disubstituted Phospholane Ligands**
Alex T. Axtell, Christopher J. Cobley, Jerzy Klosin,*
Gregory T. Whiteker, Antonio Zanotti-Gerosa, and
Khalil A. Abboud
Only a few chiral ligands have been successfully applied in
AHF reactions (Scheme 1). Among the most effective are
(2R,4R)-chiraphite (1)[3] and its analogues,[4] which exhibit
enantioselectivities of up to 90% ee for the hydroformylation
of styrene at low temperatures; (R,S)-binaphos (2),[5] which
shows high enantioselectivities for the hydroformylation of
many structurally diverse olefins; (S,S)-kelliphite (3), which is
effective for the hydroformylation of allyl cyanide[6] and vinyl
acetate;[7] and (S,S)-esphos (5), which displays a high enan-
tioselectivity for the hydroformylation of vinyl acetate.[8]
Asymmetric hydroformylation (AHF) is a powerful synthetic
methodology that allows conversion of olefins into optically
active aldehydes in a single step [Eq. (1)].[1] The aldehyde
[9]
Together with Landis and co-workers, we recently reported
group is one of the most versatile functional groups and can
be readily transformed into a variety of high-value-added
chiral chemicals, such as amines, imines, alcohols, and acids.[2]
Even though AHF offers great promise to the fine-chemical
industry, this reaction has not been utilized on a commercial
scale because of several remaining technical challenges;
among the most important to overcome are a) low reaction
rates at low temperatures for reactions in which good
selectivities are usually observed, b) difficulties in controlling
the application of diazaphospholane ligands 4 in AHF
reactions which showed outstanding hydroformylation rates
and very high enantioselectivities for reactions with styrene
and allyl cyanide substrates. Diazaphospholane 4 is especially
selective for vinyl acetate at 808C (96% ee, b/l = 35). This
ligand family is structurally related to 1,2-bis(2,5-dialkylphos-
pholano)benzene (duphos; 6–8), 1,2-bis(2,5-dialkylphospho-
lano)ethane[10] (bpe; 9–11), and especially the recently
reported
(R,R)-1,2-bis(2,5-diphenylphospholano)ethane
((R,R)-Ph-bpe; 12) Scheme 2).[11] The duphos and bpe
ligands[12] have been proven to be exceptional ligands for
the asymmetric hydrogenation[13] of dehydroamino acids and
mono- and disubstituted itaconates, among numerous other
applications, but their use has not been reported for AHF
reactions.
[*] A. T. Axtell, Dr. J. Klosin
Chemical Sciences
The Dow Chemical Company
1776 Building, Midland, MI 48674 (USA)
Fax: (+1)989-638-6225
E-mail: jklosin@dow.com
Herein, we report that 12 is an excellent ligand for the
rhodium-catalyzed AHF of styrene, allyl cyanide, and vinyl
acetate at high temperatures (80–1008C). (R,R)-Ph-bpe (12)
displays the best regio- and enantioselectivities reported to
date for the hydroformylation of styrene and allyl cyanide and
the second best for the hydroformylation of vinyl acetate. The
reaction rates obtained at these elevated temperatures render
this catalytic system amenable to industrial applications.
The hydroformylation reactions were carried out at 808C
and 1.034 MPa CO/H2 pressure with substrate/catalyst molar
ratios of 5000:1 and a catalyst concentration of 0.37 mm.
Phospholane and phosphetane ligands 6–16 (Scheme 2) and
previously reported ligands 1–4 were evaluated under iden-
tical conditions for comparison. Active catalysts were pre-
pared by combining [Rh(acac)(CO)2] (acac = acetylaceto-
nate) with 1.2 equivalents of each bidentate ligand (2.1 equiv
for 16) in toluene followed by pressurizing the resulting
solution with syngas (CO/H2, molar ratio of 1:1). Styrene, allyl
cyanide, and vinyl acetate underwent simultaneous hydro-
formylation under constant pressure, with the gas uptake
being monitored continuously. Olefin conversion, together
Dr. C. J. Cobley, Dr. A. Zanotti-Gerosa[+]
Dowpharma
Chirotech Technology Limited
321 Cambridge Science Park, Cambridge CB40WG (UK)
Dr. G. T. Whiteker
Chemical Sciences
The Dow Chemical Company
740 Building, South Charleston, WV 25303 (USA)
Dr. K. A. Abboud
Department of Chemistry
University of Florida
Gainesville, FL 32611 (USA)
[+] Current address:
Johnson Matthey Catalysts
28 Cambridge Science Park
Cambridge CB40FP (UK)
[**] We thank Dr. Mark Jackson for providing a sample of the Ph-bpe
ligand, Prof. Clark Landis from the University of Wisconsin—
Madison, and Dr. Cynthia Rand, Dr. Ian Lennon, and Dr. Guy Casy
from Dowpharma for helpful discussions.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Scheme 1. Chiral ligands that have been successfully applied in AHF reactions.
ferrocenyl phospholane and phosphetane[14] ligands
13–15 (Table 1, entries 12–14). (R,R)-Ph-bpe (12)
exhibits an average turnover frequency of 1139 hÀ1,
which is about five times more active than the second
fastest phospholane 11 and only about two times
slower than 1 and 2. The most likely reason for the
increased activity of 12 compared with the other
phospholane ligands is the presence of the electron-
withdrawing phenyl rings that reduce the overall
basicity of the phosphine moiety. The IR spectroscopic
data nCO obtained for [Mo(CO)4{(S,S)-Me-bpe}],
[Mo(CO)4{(S,S)-iPr-bpe}], and [Mo(CO)4{(R,R)-Ph-
bpe}] (2012, 2011, and 2015 cmÀ1, respectively)[15]
support the assertion that (R,R)-Ph-bpe is the least
basic phosphine amongst the bpe ligands. It is well
established that electron-poor phosphines lead to
more active catalysts in Rh-catalyzed hydroformylation.[1a]
The olefin conversion and regio- and enantioselectivity
data for the ligands investigated in this study are summarized
in Table 1. The olefin conversion data are in close agreement
with the syngas uptake curves and clearly demonstrate that 12
exhibits the fastest hydroformylation rates of all the phos-
pholane and phosphetane ligands in this study
(Table 1, entry 11 versus entries 6–10 and 12–15).
The enantioselectivity data show that bpe and
duphos ligands with larger substituents in the 2,5-
positions of the phospholane rings (iPr and Ph versus
Me and Et) lead to noticeably higher enantioselectiv-
ities. Importantly, the selectivities observed for sty-
rene, allyl cyanide, and vinyl acetate are comparable
for a given phospholane ligand, thus suggesting the
potential for broad applicability of phospholane
ligands to a wide range of substrates. Monodentate
ligand 16 has a very poor activity and selectivity, which
indicates that the bidentate nature of the ligand is
necessary for achieving high regio- and enantioselec-
tivities. Phospholane 12 is the most enantioselective
ligand in this study giving 94, 90, and 82% ee for the
Scheme 2. Phospholane and phosphetane ligands.
with the regio- and enantioselectivities of the products, was
determined by using gas chromatography on a chiral sta-
tionary phase, as previously described.[7] The syngas uptake
curves demonstrate that all the phospholane ligands screened
exhibited low hydroformylation rates except for 12 (Figure 1).
The lowest hydroformylation rates were observed for the
Figure 1. Syngas-uptake curves for reactions performed with a olefin/catalyst
ratio of 5000:1 (at 808Cin toluene with 1.034 MPa of CO/H (1:1) and a L/Rh
ratio of 1.2:1).
2
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Table 1: Percentage conversion (conv.), branched/linear ratio (b/l), and enantioselectivities of the hydroformylation reactions of styrene, allyl cyanide,
and vinyl acetate.
Entry
Ligand
Styrene
b/l
Allyl cyanide
b/l
Vinyl acetate
b/l
conv. [%]
ee [%]
conv. [%]
ee [%]
conv. [%]
ee [%]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
(2R,4R)-chiraphite (1)
(R,S)-binaphos (2)
(S,S)-kelliphite (3)
diazaphospholane 4
(R,R)-Me-duphos (6)
(R,R)-Et-duphos (7)
(S,S)-iPr-duphos (8)
(R,R)-Me-bpe (9)
(S,S)-Et-bpe (10)
(S,S)-iPr-bpe (11)
(R,R)-Ph-bpe (12)
(R,R)-iPr-5-Fc (13)
89
96
82
100
10
14
15
8
10
11
57
9
9.1:1
4.5:1
8.4:1
50 (R)
82 (R)
3 (S)
98
98
98
100
42
49
55
36
40
48
96
28
31
28
30
5.8:1
2.1:1
9.9:1
4.1:1
6.6:1
7.8:1
7.2:1
5.8:1
6.2:1
6.7:1
7.1:1
3.9:1
5.3:1
2.3:1
3.5:1
14 (R)
72 (R)
68 (S)
87 (R)
32 (S)
35 (S)
82 (S)
37 (S)
49 (R)
83 (S)
90 (R)
49 (R)
73 (R)
53 (S)
7 (R)
76
72
83
100
26
27
29
23
23
28
52
22
23
22
17
246:1
8.2:1
65:1
49 (R)
48 (S)
72 (R)
96 (S)
51 (R)
66 (R)
74 (R)
59 (R)
66 (S)
70 (R)
82 (S)
29 (R)
27 (R)
39 (R)
8 (S)
6.6:1
82 (R)
44 (S)
52 (S)
83 (S)
43 (S)
55 (R)
82 (S)
94 (R)
15 (R)
55 (R)
18 (S)
11 (R)
37:1
15.7:1
13.7:1
11.3:1
14.0:1
11.3:1
9.5:1
45.0:1
3.2:1
1.7:1
176:1
371:1
322:1
97:1
152:1
142:1
340:1
94:1
(R,R)-tBu-ferrotane (14)
(R,R)-Me-ferrotane (15)
(R,R)-iPr-phospholane (16)
10
9
11
29:1
8.5:1
21:1
3.6:1
4.4:1
[a] All the reactions were performed at 808Cin toluene with 1.034 MPa of CO/H (1:1), L/Rh=1.2:1 (2.1:1 for 16), substrate/Rh=5000:1, catalyst
2
concentration of 0.037 mol%, and a reaction time of 3 h.
reactions of styrene, allyl cyanide, and vinyl acetate,
respectively.[16] Phospholane 12 is not only the most
enantioselective ligand for the hydroformylation of
styrene (including previously reported ligands 1–4),
but it also gives an unprecedented high regioselectivity
(b/l = 45:1). Under identical conditions, 2, for example,
exhibits a significantly lower regioselectivity (b/l =
4.5:1). The ability of a ligand to give high regioselectiv-
ities in AHF (high ratio of branched to linear isomers) is
a very important attribute as any amount of achiral
linear isomer can be regarded as an additional impurity
Figure 2. Syngas-uptake curves for reactions were performed with a ratio of
that must be separated from the desired chiral product.
olefin/catalyst=30000:1 (at 808Cin toluene with 1.034 MPa of CO/H (1:1)
2
To put the regioselectivities of the styrene products into and a L/Rh ratio of 1.2:1).
perspective, the amount of the undesired linear isomer
formed with (R,R)-Ph-bpe (12) is 2.2% (b/l = 45:1),
whereas with (R,S)-binaphos (2) it is 18.2% (b/l = 4.5:1;
Table 1, entries 11 and 2). Phospholane 12 also gives the
highest enantioselectivity (90% ee, b/l = 7.1:1) in the case of
the hydroformylation of allyl cyanide. Under the same
conditions, diazaphospholane 4 gives a similar enantioselec-
tivity (87% ee) but a noticeably lower regioselectivity (b/l =
4.1:1). For ligands 1–4, only 3 gives a higher regioselectivity
for the hydroformylation of allyl cyanide (b/l = 9.9:1),
although with a much lower enantioselectivity (68% ee).
Phospholane 12 gives the second best enantioselectivity
(82% ee) for the hydroformylation of vinyl acetate but with
a high regioselectivity (b/l = 340:1) that is unprecedented. The
only ligand that shows higher enantioselectivity for the
hydroformylation of vinyl acetate is the recently reported
diazaphospholane 4 (96% ee, b/l = 37:1).[9]
A second set of hydroformylation reactions was con-
ducted to compare ligand 12 with ligands 1–4 using mixtures
of neat olefins at 808C and 1.034MPa pressure of syngas with
substrate/catalyst molar ratios of 30000:1 and a catalyst
concentration of 0.062 mm. At these very low catalyst
loadings, the rate of hydroformylation with 12 (an average
turnover frequency of 4467 hÀ1) was virtually identical to
those of 1 and 2 and only slower than 3 and 4 (see Figure 2).
The regio- and enantioselectivities achieved under these
conditions were comparable to those obtained at the sub-
strate/catalyst ratio of 5000:1 (see Table 2).
Hydroformylation experiments conducted with the iso-
lated rhodium complex [Rh(acac){(R,R)-Ph-bpe}], prepared
by the reaction of 12 and [Rh(cod)(acac)] (cod = cycloocta-
diene), gave identical results to experiments in which the
rhodium complex was prepared in situ prior to the hydro-
formylation reaction. The solid-state structures of 12 and
[Rh(acac){(R,R)-Ph-bpe}] were determined by single-crystal
X-ray analysis (Figures 3 and 4).[17]
A preliminary investigation into the reaction conditions
(olefin concentration, CO and H2 pressures, and temperature)
reveals that the hydroformylation rate with 12 is first order in
olefin concentration, zero order in ligand concentration
(ligand/Rh = 1:1–5:1), zero order in H2 pressure, and negative
first order in CO pressure. These observations are consistent
with the dissociation of CO from a five-coordinate rhodium
dicarbonyl complex as a pre-equilibrium step prior to the
[18]
À
rate-limiting insertion of the olefin into the Rh H bond.
Interestingly, the enantioselectivities of all the products were
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Table 2: Percent conversion (conv.), branched/linear ratio (b/l), and enantioselectivities of the hydroformylation reactions of styrene, allyl cyanide, and
vinyl acetate.
Entry
Ligand
Styrene
b/l
Allyl cyanide
b/l
Vinyl acetate
b/l
conv. [%]
ee [%]
conv. [%]
ee [%]
conv. [%]
ee [%]
1
2
3
4
5
(2R,4R)-chiraphite (1)
(R,S)-binaphos (2)
(S,S)-kelliphite (3)
diazaphospholane (4)
(R,R)-Ph-bpe (12)
32
35
32
73
33
10.8:1
4.6:1
9.2:1
5.7:1
51 (R)
81 (R)
3 (S)
80 (R)
92 (R)
74
58
99
100
67
5.8:1
2.1:1
10.1:1
3.9:1
7.6:1
13 (R)
68 (R)
66 (S)
80 (R)
90 (R)
34
23
32
92
34
204:1
7.1:1
100:1
47:1
50 (R)
58 (S)
75 (R)
95 (S)
82 (S)
45.0:1
263:1
[a] All the reactions were performed at 808Cin toluene at 1.034 MPa of CO/H 2 (1:1) with L/Rh=1.2:1, substrate/Rh=30000:1, a reaction time of 3 h,
and 4.43 mL of a mixture of styrene/allyl cyanide/vinyl acetate/dodecane (1:1:1:0.3 molar ratio).
unaffected by variations in the syngas pressure (0.345–
3.102 MPa), whereas the regioselectivities were dependent
upon pressure, with b/l ratios of 40:1– 45:1 for the styrene
products and b/l ratios of 1060:1–155:1 for the vinyl acetate
products being observed over these pressures.
In conclusion, (R,R)-Ph-bpe (12) was identified as an
excellent ligand for asymmetric hydroformylation which gives
state-of-the-art regio- and enantioselectivities for styrene,
allyl cyanide, and vinyl acetate, while maintaining commer-
cially viable turnover rates over 4000 hÀ1 at 808C. The
remarkable ability of phospholane-based ligands 12 and 4 to
yield very high enantioselectivities at high temperatures
renders these ligands suitable for large-scale industrial
applications.
Received: April 28, 2005
Published online: August 12, 2005
Keywords: asymmetric catalysis · hydroformylation · P ligands ·
.
Figure 3. Molecular structure of (R,R)-Ph-bpe (12), with the thermal
rhodium
ellipsoids set at 40% probability.
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Communications
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[16] Hydroformylation experiments conducted with individual ole-
fins gave the same selectivities for all three substrates as those
obtained from simultaneous hydroformylations of these olefins,
except for the regioselectivity for the reaction of vinyl acetate,
which was lowered to b/l = 260:1.
[17] X-ray diffraction data for 12: Mr = C34H36P2, T= 173 K, l =
0.71073 Š, monoclinic, C2, a = 19.394(1), b = 18.956(1), c =
24.752(2) Š, b = 104.717(1)8, Z = 12, no. reflections = 14755
(7283 > 2s(I)), refinement on F2, R1(>2s(I)) = 0.0363, R1(all
data) = 0.086, GOF = 0.756; [Rh(acac){(R,R)-Ph-bpe}]: Mr =
C80H89NO4P4Rh2, T= 173 K, l = 0.71073 Š, monoclinic, P21,
a = 10.3863(6),
b = 19.9915(12),
c = 17.8855(10) Š,
b =
105.370(1)8, Z = 2, no. reflections = 14572 (13725 > 2s(I)),
refinement on F2, R1(>2s(I)) = 0.0209, R1(all data) = 0.0229,
GOF = 1.000. CCDC-270008 and -270009 contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge from the Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
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