Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2002-02-14
2004-02-03
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
Reexamination Certificate
active
06686498
ABSTRACT:
TECHNICAL FIELD
The present invention relates to the field of organic synthesis and more specifically to a process for the preparation of Michael-adducts, as defined below, by reacting a &bgr;,&bgr;- or a &agr;,&bgr;-disubstituted, or a &agr;,&bgr;,&bgr;-trisubstituted, &agr;,&bgr;-unsaturated ketone (I) with a &bgr;-ketoester or a &bgr;-diketone (II) in presence of a suitable catalyst of formula M(X)
n
, according to scheme 1:
PRIOR ART
To the best of our knowledge, no reaction according to scheme 1 involving a &agr;,&bgr;-disubstituted, or a &agr;,&bgr;,&bgr;-trisubstituted, &agr;,&bgr;-unsaturated ketone with a &bgr;-ketoester or a &bgr;-diketone has been reported in the prior art.
Various processes involving addition reactions between &bgr;,&bgr;-disubstituted &agr;,&bgr;-unsaturated ketones and &bgr;-ketoester or a &bgr;-diketone in the presence of a base have been reported before. However, they all provide a product which is the result of a so-called Robinson annulation, e.g. as described in J. D. Surmatis et al.,
J Org. Chem.,
(1970), 1053.
The coupling of a &bgr;,&bgr;-disubstituted enone with an alkyl &bgr;-ketoester in the presence of 5% of a metal/acac complex (acac being 2,4-pentanedione) and 5% of a Lewis or a Broënsted acid (P. Kocovsky et al.,
Tetrahedron Lett.,
(1986), 5015 or P. Kocovsky et al.,
Coll. Czech. Chem. Commun.,
(1988), 2667) has also been tried, but the &bgr;,&bgr;-disubstituted enones used by these authors proved to be inert under a variety of conditions.
Similarly, the direct coupling of the same type of compounds under high pressures (W. G. Dauben et al,
Tetrahedron Lett.,
(1983), 3841), has shown that a Michael-adduct can only be obtained if a highly reactive &bgr;,&bgr;-disubstituted enone, such as the 3,4,5,6-tetrahydro-1(2H)-pentalenone, is used. Another example of the synthesis of a Michael-adduct, by using highly activated &bgr;,&bgr;-disubstituted &agr;,&bgr;-unsaturated ketones, possessing a C═C double bond moiety as part of a bycyclic ring, is described in A. M. El-Gendy et al.
Asian. J. Chem.;
(1990), 2, 168.
U.S. Pat. Nos. 4,939,143 and 4,900,754 report the synthesis of 3,3-dimethyl-2-(4-fluoro-3-methylbenzoyl)-5-oxohexanoate. In said synthesis a &bgr;,&bgr;-disubstituted enone is reacted with a &bgr;-ketoester in presence of a stoechiometric amount of BF
3
·OEt
2
at 0° C. However, this method has the major drawback to need a stoechiometric amount of an expensive, strong and reactive Lewis acid. Furthermore, said method, which has been reported only for the specific reaction described in the US patents, cannot be considered as a general method because if a &bgr;-diketone is used instead of &bgr;-ketoester then the reaction leads directly to the Robinson annulation product, as described in A. Fernandez-Mateos et al.
J. Org. Chem.;
(1998), 63, 9440.
Y. L. Chow;
Can. J. Chem.,
(1993), 71, 846 teaches about the photochemical reaction between a &bgr;,&bgr;-disubstituted enone and a B(acac)F
2
complex. Nevertheless, said reaction leads to the formation of several by-products and, additionally, needs a steochiometric amount of BF
3
.
Although compounds of formula (III) are interesting intermediates in a number of synthesis, and can also be precursors of &bgr;,&bgr;-disubstituted-&dgr;-diketonic or &agr;,&bgr;-disubstituted-&dgr;-diketonic compounds, to the best of our knowledge, none of the methods reported for their preparation is of general or of simple application.
DESCRIPTION OF THE INVENTION
In order to overcome the difficulties aforementioned, the present invention relates to a simple and general process, aimed at the synthesis of the compounds of formula (III) in a single step.
In this process, the preparation of a compound of formula (III):
wherein
Q represents a R′ group, a OR′ group, or a NH
2
, NHR′ or NR′
2
group;
R
1
, R′ and R″ represent, independently from each other, an aromatic ring possibly substituted, or a linear or branched C
1
-C
8
alkyl or alkenyl group, possibly substituted;
R′″ represents a hydrogen atom or a linear or branched C
1
-C
4
alkyl or alkenyl group;
R
2
, R
3
, R
4
, represent, independently from each other, a hydrogen atom or an aromatic ring possibly substituted, or a linear, branched or cyclic C
1
-C
8
alkyl or alkenyl group, possibly substituted, provided that at least two of said R
2
, R
3
and R
4
groups do not represent simultaneously an hydrogen atom; or
two of the groups R
1
to R
4
are bonded together to form a ring having 5 to 15 carbon atoms, said ring being possibly substituted;
characterized in that a &bgr;,&bgr;- or a &agr;,&bgr;-disubstituted, or a &agr;,&bgr;,&bgr;-trisubstituted, &agr;,&bgr;-unsaturated ketone (I)
wherein R
1
, R
2
, R
3
and R
4
have the same meaning as in formula (III),
is reacted with a &bgr;-ketoester or a &bgr;-diketone (II)
wherein Y, R″ and R′″ have the same meaning as in formula (III),
in the presence of a catalyst of formula M(X)
n
, M representing a metal or a group containing a metal, n representing an integer from 1 to 4 and X representing a weakly coordinating or non-coordinating mono-anion.
As non-limiting examples, groups which are possible substituents of R
1
, R
2
, R
3
, R
4
, R′, R″ and of the ring, which two of said R′ to R
4
may form together, are C
1
-C
7
alkyl, alkenyl or alkoxy groups, C
5
-C
7
cycloalkyl or cycloalkenyl groups, or aromatic rings possibly substituted by a C
1
-C
8
alkyl or alkoxy group or a halide atom.
Preferably,
Q represents a R′ or a OR′ group;
R′, R′ and R″ represent, independently from each other, a linear C
1
-C
5
alkyl or alkenyl group, possibly substituted;
R′″ represents a hydrogen atom or a linear or branched C
1
-C
3
alkyl group;
R
2
, R
3
and R
4
represent a hydrogen atom or a linear C
1
-C
5
alkyl or alkenyl group, possibly substituted, provided that at least two of said R
2
, R
3
and R
4
groups do not represent simultaneously an hydrogen atom; or
two of the groups R
1
to R
4
are bonded together to form a ring having 5 to 8 carbon atoms, said ring being possibly substituted.
As non-limiting examples, groups which are possible substituents of R
1
, R
2
, R
3
, R
4
, R′, R″ and of the ring, which two of said R
1
to R
4
may form together, are C
1
-C
4
alkyl, alkenyl or alkoxy groups, C
5
-C
6
cycloalkyl or cycloalkenyl groups or aromatic groups possibly substituted by a C
1
-C
6
linear or branched alkyl or alkoxy group or a halide atom.
More preferably, the compound of formula (I) is 4-methyl-3-penten-2-one or 3-methyl-3-penten-2-one, and the compound of formula (JI) is 2,4-pentanedione or a C
1
-C
4
alkyl ester of the 3-oxo-butanoate.
Preferred catalysts of formula M(X)
n
are those wherein M is selected from the group consisting of the 3d transition metals, the lanthanides, the trimethylsilane group (Me
3
Si), the vanadyl group (VO
3+
), the alkaline metals, Sc, Y, Sn, Pb, Al and Bi;
n is an integer from 1 to 3; and
X is selected from the group consisting of CF
3
SO
3
−
, RSO
3
−
, SbF
6
−
, PF
6
−
, ClO
4
−
, [BF
3
(RCOCRCOR)]
−
, [BF
3
(RCOCRCO
2
R)]
−
, [BF
3
(RCOO)]
−
, [BF
3
(RO)]
−
, BZ
4
−
, Z being a fluoride atom or an alkyl or aryl group possibly substituted, and R representing an C
1
-C
10
aromatic, alkylaromatic or alkyl group, possibly substituted.
Groups which are possible substituents of Z and R are, for example, halides atomts, C
1
to C
6
alkyl or alkoxy groups or non-coordinatng nitrogen containing groups.
More preferably M is selected from the group consisting of Cu, Zn, Y and Yb;
n is an integer from 1 to 3; and
X is selected from the group consisting of CF
3
SO
3
−
, C
6
H
5
SO
3
−
, CH
3
C
6
H
4
SO
3
−
, CH
3
SO
3
−
, SbF
6
−
, PF
6
−
, ClO
4
−
, [BF
3
(acac)]
−
(acac representing CH
3
COCHCOCH
3
−
), [BF
3
(CH
3
COO)]
−
, BF
4
Firmenich SA
Reyes Hector M
Rotman Alan L.
Winston & Strawn LLP
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