Methods for producing chiral aldehydes

Details Methods for producing chiral aldehydes Methods for producing chiral aldehydes

2001-05-15

2002-06-04

Padmanabhan, Sreeni (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Oxygen containing

C568S451000, C556S018000

Reexamination Certificate

active

06399834

ABSTRACT:

The present invention relates to methods for producing chiral aldehydes by the enantioselective hydroformylation of prochiral substrates with the aid of a catalyst consisting of a transition metal and a chiral phosphorus-containing ligand which contains aromatic rings substituted with perfluoroalkyl groups.
The addition of hydrogen and carbon monoxide to prochiral C═C double bonds using chiral catalysts (enantioselective hydroformylation) is an efficient method for the synthesis of chiral, non-racemic aldehydes (Catalytic Asymmetric Synthesis, Ed.: I. Ojima, VCH, Weinheim, 1993, p. 273). This reaction type has found great interest, in particular, as a possible access to chiral building blocks for the production of flavoring agents, cosmetics, plant protection agents, food additives (e.g., vitamins), and pharmaceutical agents (Chirality 1991, 3, 355). There may be mentioned, in particular, the preparation of the anti-inflammatory and analgetic drugs ibuprofen and naproxen by the oxidation of the corresponding aldehydes, which can be obtained by enantioselective hydroformylation. Further, chiral aldehydes offer access to &agr;-amino acids, antibiotics based on polyethers and macrocyclic antitumor drugs.
For an efficient enantioselective hydroformylation, the following criteria must be met: 1. high activity of the catalyst; 2. high chemo- and regioselectivity for the formation of the desired aldehyde; 3. high enantioselectivity in favor of the desired enantiomer. The methods known today for enantioselective hydroformylation use catalyst systems which contain a transition metal center in the presence of a chiral coordinated compound (ligand). As the transition metal, rhodium and platinum are mainly used, but other metals including cobalt, iridium or ruthenium also exhibit catalytic activity. As the ligands, chiral phosphorus compounds, above all, have proven useful, the efficiency of the systems being strongly influenced by the structure of the ligands (Chem. Rev. 1995, 95, 2485).
The as yet most efficient catalyst system for enantioselective hydroformylation is based on a rhodium catalyst which contains the ligand (R)-2-(diphenylphosphino)-1,1′-binaphthol-2′-yl (S)-1,1′-binaphthol-2,2′-diyl phosphite, (R,S)-binaphos (Topics in Catalysis 1997, 4, 175; EP 0 614 870 A3) and related ligands (EP 0 684 249 A1, EP 0 647 647 A1). The main drawbacks of the methods relying on this catalyst system include, on the one hand, the limited regioselectivity for the formation of the desired branched isomer in the hydroformylation of vinyl aromatics (see Scheme 1). The regioselectivity with (R,S)-binaphos is, for example, about 88%, and the 12% of linear aldehyde is a worthless by-product which has to be separated off tediously and disposed of. On the other hand, these catalyst systems work with the greatest efficiency only when solvents are used which are toxicologically and ecologically harmful, such as benzene.
TABLE 1
Synthesis of chiral aldehydes by enantioselective hydroformylation.
p
H
2
, CO
T
P
0
total
time t
Conversion
Regioselect.
ee
Ex.
Substrate
S/Rh
Ligand
Solvent
Lig/Rh
[bar]
[° C.]
[bar]
[h]
[%]
[%]
[%]
ref.
styrene
2000
binaphos
benzene(0.5 ml)
4
100
60
—
43
>99
88
94(S)  
1
styrene
2000
(R, S)-1a
benzene(0.5 ml)
4
100
60
—
17
>99
92.7
90.6(S)
2
styrene
1000
(R, S)-1a
hexane(2.0 ml)
4
100
40
—
46
42
95.7
90.0(S)
3
styrene
 786
(R, S)-1a
CO
2
2
40
45
192
16
42.3
93.8
93.0(S)
4
styrene
2000
(R, S)-1a
CO
2
3
40
40
178
66
75.4
94.8
93.6(S)
5
styrene
1000
(R, S)-1a
CO
2
2
20
60
156
16
>99
92.5
90.4(S)
6
styrene
1000
(R, S)-1a
CO
2
2
60
60
242
16
97.6
93.0
92.0(S)
7
styrene
1000
(R, S)-1a
CO
2
2.4
40
36
123
62
91.6
94.8
91.8(S)
8
styrene
1000
(R, S)-1a
CO
2
2.4
40
31
115
62
96.5
95.6
91.8(S)
ref.
p-chlorostyrene
2000
binaphos
benzene(0.5 ml)
4
100
60
—
34
>99
87
93(+)  
9
p-chlorostyrene
1000
(R, S)-1a
CO
2
2
40
40
150
15
89
91.9
88.4(+)
ref.
p-isobutylstyrene
 300
binaphos
benzene(0.5 ml)
4
100
60
—
66
>99
88
92(S)  
10 
p-isobutylstyrene
1000
(R, S)-1a
CO
2
2
40
40
146
16
>99
95.5
90.1(S)
11 
p-isobutylstyrene
1000
(R, S)-1a
CO
2
2
40
29
115
43
61.2
96.1
92.8(S)
ref.: Data from K. Nozaki et al., Topics in Catalysis 1997, 4, 175; J. Am. Chem. Soc. 1997, 119, 4413.
Compressed carbon dioxide in the liquid (liqCO
2
) or supercritical state (ScCO
2
) is an interesting solvent for performing catalytic reactions because it is toxicologically and ecologically safe, in contrast to conventional organic solvents. A survey of catalytic reactions in scCO
2
is found in Science 1995, 269, 1065. To date, liqCO
2
has been employed as a reaction medium only in a few cases, e.g., Angew. Chem. 1997, 109, 2562. However, the ligand (R,S)-binaphos cannot be employed efficiently in compressed carbon dioxide since the enantioselectivity is drastically decreased in the presence of compressed carbon dioxide (S. Kainz, W. Leitner, Catal. Lett., in press).
The use of perfluorinated alkyl chains for increasing the solubility of arylphosphorus ligands in supercritical carbon dioxide and the use of corresponding achiral ligands in the rhodium-catalyzed hydroformylation in scCO
2
has been described in the German Offenlegungsschrift DE 197 02 025 A1. However, an increased regioselectivity in favor of the linear achiral aldehyde is found with the ligands described therein. The use of scCO
2
is a precondition for achieving high reaction rates, while liqCO
2
results in inefficiently slow reactions (D. Koch, W. Leitner, J. Am. Chem. Soc, in press).
We now describe a novel method for producing chiral aldehydes by the enantioselective hydroformylation of prochiral substrates with the aid of a catalyst consisting of a transition metal and a chiral ligand, characterized in that said chiral ligand is a compound of general formula 1
wherein the rings R7-R10 drawn with dotted lines are optional and one or more of rings R1-R6 or R7-R10 are substituted with one or more independently selected substituents of general formula —(CH
2
)
x
(CF
2
)
y
F(x=0-5; y=1-12) or their branched isomers. The synthetic route for such a ligand is shown in Scheme 2, illustrated for the ligand (R,S)1a.
Surprisingly, in the hydroformylation of prochiral substrates, the use of these ligands results in a higher regioselectivity in favor of the branched, chiral aldehyde isomers as compared to a reaction performed with corresponding unsubstituted compounds, but without adversely affecting the enantioselectivity. At the same time, these substituents allow to perform the mentioned processes in compressed carbon dioxide as a reaction medium, whereby the use of toxic or ecologically harmful solvents is avoided. Unexpectedly, the hydroformylation can be performed not only in supercritical CO
2
(scCO
2
), but also in liquid CO
2
(liqCO
2
), which enables working at lower temperatures and pressures during the reaction. Making use of the extractive properties of CO
2
, the products and catalysts can be separated effectively and carefully, and the catalysts are recovered in an active form.
The catalysts for the enantioselective hydroformylation can be either employed in the form of isolated complex compounds which already contain the chiral ligands of formula 1, or they are formed in situ from a ligand of formula 1 and a suitable metal-containing precursor. A detailed description of possible catalyst systems is found, for example, in Chem. Rev. 1995, 95, 2485. In the present method, compounds or salts of transition metals can be employed as metal components. Preferred are catalysts based on the metals Fe, Co, Ir, Ru, Pt, Rh, especially preferred Pt and Rh. Particularly preferred metal components include, for example, RhCl
3
nH
2
O, [Rh
2
(OAc)
4
](OAc=O(O)CCH
3
)], [(L)
2
Rh(&mgr;-Cl)
2
Rh(L)
2
](L=olefin, CO, PR
3
etc.), [(L)
2
Rh(acac)](acac=acetylacetonate) or [(L)
2
PtCl
2
]/SnCl
2
, without

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