Organic compounds -- part of the class 532-570 series – Organic compounds – Heavy metal containing
Reexamination Certificate
1999-03-01
2001-02-06
Padmanabhan, Sreeni (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heavy metal containing
C556S129000, C556S118000, C568S433000, C568S458000
Reexamination Certificate
active
06184404
ABSTRACT:
This invention relates to a process for the selective alkylation of aldehydes by means of organozinc compounds.
Organozinc compounds R—Zn—X or R
2
Zn (R=alkyl, aryl, x=Cl, Br, I) are easy-to-handle organometallic reagents, which in the synthesis can be used for selective CC cross-linking reactions, where due to the low reactivity of the zinc species the transfer of the residue R requires the presence of a further transition metal compound, e.g. a copper, palladium, cobalt or titanium compound. A particular advantage of the zinc-organic chemistry consists in the fact that the above-mentioned organic residues R can also have a functional group FG, such as an ester, amine or nitrile function. (A good survey is provided by P. Knochel and R. D. Singer in Chem. Rev. 1993, 93, 2117-2188).
Of particular importance is the transfer of functionalized organic residues (R-FG) to aldehydes, as this reaction takes place enantioselectively in the presence of suitable chiral auxiliaries (ligands):
In this way, functionalized secondary alcohols can in general be produced with good yields and very good enantiomeric purities (>90%). This excellent selectivity is paid for with a relatively poor reactivity of the Zn species. The latter leads to the fact that the zinc compound must generally be used with a two- or threefold excess, i.e. from the amounts (R-FG) used only about 15 to 30% are transferred to the aldehyde in the final analysis. The rest is lost during processing. The same is true for the titanium compound used as co-reagent, which must preferably be used in about equimolar amounts (based on the Zn compound).
To increase the utilization of the zinc-bound alkyl residue, there were used recently mixed zinc compounds of the type
(FG-R)-Zn—CH
2
Si(CH
3
)
3
[C. Lutz, P. Knochel, J. Org. Chem. 1997, 62, 7895]. It was found that the H
2
C—Si(CH
3
)
3
residue (“TMSM”) is not transferred to carbonyl compounds and thus a desired chemoselective transfer of the functionalized alkyl residue (R-FG) is ensured.
In this way, the residue (R-FG) to be transferred is required in considerably lower amounts. This is of high interest in particular for valuable functionalized residues. For technical applications, the TMSM residue is, however, less suited because of a lack of availability and because of the high price of its precursor compound Cl—CH
2
—Si(CH
3
)
3
.
It is therefore the object underlying the invention to eliminate the disadvantages known from the prior art and in particular create a process for the (enantioselective) alkylation of aldehydes by means of zinc-organic compounds, wherein the alkyl residue to be transferred can be present in a functionalized form and saturates only one valency each of the zinc, and the second zinc compound is saturated by an easily accessible and in expensive residue (“dummy ligand”) which does not disturb the alkylation.
It is a further object of the invention to create novel compounds, by means of which the (enantioselective) alkylation of aldehydes can be performed to a particular advantage corresponding to the inventive process.
Despite the prejudice described in the literature [Steven H. Bertz et al., J. Am. Chem. Soc. 1996, 118, 10906], which postulates that for stabilizing the Zn dummy bond (and thus the non-transfer of the dummy ligand) an Si atom in &bgr;-position with respect to the Zn atom (&bgr;-silyl effect with respect to metal centers) is required as in the case of the above-mentioned TMSM residue, it was surprisingly found out that also a number of simple, silicon-free, organic residues of the type
are likewise able to act as dummy ligands in the above-described zinc-organic compounds. There are preferably used alkyl residues with 1 to 8 C atoms and phenyl residues which can optionally carry in addition one or more alkyl substituents, in particular dummy ligands with R
2
=phenyl and R
3
, R
4
=methyl, or with R
2
, R
3
, R
4
=methyl. The essential features of the inventive process are stated in claim
1
. Sub-claims
2
to
10
disclose features which develop the inventive process. Claims
11
and
12
refer to a new group of dialkylzinc compounds by means of which the chemoselective transfer of (functionalized) alkyl residues in accordance with the inventive process takes place particularly easily.
For performing the inventive process basically all aldehydes and in particular the following aldehydes may be used: saturated aldehydes with n-alkyl chains and branched alkyl chains, aromatic and heteroaromatic aldehydes, benzaldehyde, substituted benzaldehyde, such as anisaldehyde, pyridine-2-carbaldehyde, pyridine-3-carbaldehyde, pyridine-4-carbaldehyde, quinoline-3-carbaldehyde, quinoline-4-carbaldehyde, isoquinoline-4-carbaldehyde and further heteroaromatic aldehydes, unsaturated aldehydes, cinnamic aldehyde and derivatives, alkenals, 1-cyclopentene-1-carbaldehyde, 1-cyclohexene-1-carbaldehyde, alkinals, functionalized aldehydes, aminoaldehydes and hydroxyaldehydes.
As a reaction for the (enantioselective) alkylation of aldehydes by means of such zinc-organic compounds, whose one ligand consists of the (functionalized) residue (R-FG) to be transferred chemoselectively, and whose other ligand consists of an easily accessible and inexpensive dummy, the following reaction was chosen:
Yield
x
isolated
1:2
1)
ee1
2)
R
2
,R
3
,R
4
= Me
(neopentyl)
2.4
82%
100:0
89%
R
2
,R
3
= Me,
R
4
= Ph
(neophyl)
2.4
82%
100:0
89%
R
2
,R
3
= Me,
R
4
= H
(i-Bu)
2.4
—
95:5
94%
R
5
= Me
(i-Pr)
2.4
—
82:18
rac.
1)
Determined by a) GC column and b) HPLC analysis; a) Chrompack Chirasil CB, carrier gas H
2
, 100 kPa; b) Chiracel OD; UV detector, 215 nm.
2
Determined by chiral HPLC analysis, Chiracel OD.
ee = percentage excess of the enantiomer with respect to the racemate.
In this case, the catalyst system for the addition of mixed (partly functionalized) dialkylzinc compounds to aldehydes consists of (R,R)-1,2-bis-(trifluoromethanesulfonamido)cyclohexane as chiral ligand and titanium tetraisopropylate as Lewis acid. As can be seen from the results of the test reaction indicated in the above table, in the case of the neopentyl (dummy) ligand (R
2
,R
3
,R
4
=Me) and of the neophyl (dummy) ligand (R
2
,R
3
=Me, R
4
=Ph) only the desired residue (R-FG), in this case 4-pivaloxybutyl, is transferred to the aldehyde, namely largely enantioselectively. A change to sterically less demanding dummy ligands, such as isobutyl (R
2
,R
3
=Me, R
4
=H) and isopropyl (R
5
=Me), leads to a partial transfer of the dummy ligand to the aldehyde (5% or 18%). Nevertheless, the desired reaction product 1 is still obtained in a clear excess with respect to the undesired product 2.
Thus, it has been shown that by means of the inventive process the residue (R-FG) to be transferred is transferred chemoselectively from the dialkylzinc compound to the aldehyde, where the dummy ligand of the dialkylzinc compound consists of easily accessible and inexpensive organic residues. Furthermore, with this novel process there can in general also be achieved good enantiomeric purities.
When the residue (R-FG) to be transferred consists of simple, non-functionalized alkyl residues (C
1
-C
12
), the addition of the mixed dialkylzinc reagent can be reduced from x=2.4 to x=1.6 equivalents. In general, these dialkylzinc reagents are more reactive than dialkylzinc compounds in which (R-FG) is a functionalized alkyl residue.
For performing the inventive process, 1 to 40 mol-%, preferably 2 to 20 mol-% (based on the aldehyde) of a chiral ligand (e.g. (R,R)-1,2-bis-(trifluoromethanesulfonamido)cyclohexane or (S,S)-1,2-bis-(trifluoromethanesulfonamido)cyclohexane) in a solvent such as a hydrocarbon (C
5
-C
12
), an aromatic hydrocarbon (preferably toluene), an ether (preferably diethyl ether) or a chlorinated hydrocarbon (preferably dichloromethane) are suspended or dissolved at room temperature. Subsequently, 0.1 to 2.0 equivalents, preferably 0.6 to 1.2 equ
Knochel Paul
Lutz Christian
Fulbright & Jaworski LLP
Metallgesellschaft Aktiengesellschaft
Padmanabhan Sreeni
LandOfFree
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