Organic compounds -- part of the class 532-570 series – Organic compounds – Amino nitrogen containing
Reexamination Certificate
1999-09-23
2001-09-18
Padmanabhan, Sreeni (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Amino nitrogen containing
C564S392000, C568S715000, C568S813000, C568S822000, C568S828000, C568S832000, C568S835000
Reexamination Certificate
active
06291713
ABSTRACT:
DESCRIPTION
The present invention relates to a process of transferring &agr;,&bgr;-unsaturated alkyl groups (i.e. the allyl residue or substituted allyl residues or substituted and unsubstituted benzyl compounds) to electrophilic organic compounds subsequently referred to as electrophiles.
The transfer of allyl groups and allied residues to an organic molecule by means of organometallic reagents is a method of synthesis known for a long time. There are used for instance &agr;,&bgr;-unsaturated alkyl compounds of magnesium, lithium or zinc. The same are generally prepared by reacting a metal with an unsaturated organohalogen compound. In this synthesis a certain amount of homocoupling product is formed in a secondary reaction by a so-called “Wurtz coupling”:
The yield is thereby reduced and the processing and cleaning of the desired product is rendered more difficult.
The amount of homocoupling product (a 1,5-diene) depends on the nature of the metal and the specific reaction conditions. In general, a decrease in the reaction temperatures leads to an improved yield of organometal. However, low temperatures generally decrease the reaction rate and rarely are economic, as they can only be maintained by a high consumption of energy.
The transfer of compounds substituted in the allyl position to an electrophile constitutes a particular problem. In this case, an undesired rearrangement occurs in general by forming the thermodynamically more stable isomer substituted in the olefin position, so that product mixtures or only the resultant isomerization product are obtained:
In the “anionic” transfer of substituted allyl groups to an electrophile, poor regioselectivities are observed in general. For instance, when reacting E-2-butenyl zinc bromide with benzaldehyde a 1:1 mixture of the two diastereoisomers is obtained.
It is the object of the invention to eliminate the disadvantages of the prior art and create a process which allows to stereoselectively transfer &agr;,&bgr;-unsaturated alkyl groups to an electrophile without isomerization.
This object is solved by the process indicated in claim
1
. Claims
2
to
8
constitute a further development of the indicated process.
For transferring an &agr;,&bgr;-unsaturated alkyl group (A)
there is used a zinc enolate (B) substituted in a sterically exacting way (i.e. R
1
and R
2
are voluminous substituents) or the zinc alkyl (C), which is in equilibrium with this zinc enolate and is reacted with an electrophile (E) to obtain the desired product (D):
with R′=H, alkyl and R″=alkyl and R′″=Alkyl,
R
2
=R
1
or phenyl,
R
3
, R
4
=independent of each other H, alkyl, aryl, heteroaryl,
R
5
=H, alkyl, aryl, a functional group (ether, ester, nitrile, C═C double bond),
R
4
and R
5
or R
3
and R
5
may be connected with each other via a cyclization,
X=Cl, Br, J, alkyl or O—C(R
1
,R
2
)—A and
E=electrophile=aldehyde, ketone, nitrile, imine, alkyne.
The invention is based on the surprising observation that sterically exacting zinc enolates of the type (B) are not stable in contrast to the enolates of other metals, but fragment by forming a sterically exacting ketone and an allyl zinc compound (C). The system (B,C), subsequently referred to as “masked zinc alkyl”, can react with an electrophile (E) by forming a valuable product (D).
The masked zinc alkyl (B,C) can be prepared by transmetallation of a compound (F), which includes the &agr;,&bgr;-unsaturated alkyl group (A), in accordance with the following equation:
In general, the masked zinc alkyl (B,C) is not isolated, but formed in situ and immediately reacted with the electrophile (E).
Expediently, the molar ratio of the used metal enolate (F) to the electrophile (E) is largely stoichiometric (1:(0.8 to 3.0), preferably 1:(1.0 to 1.2), whereas the zinc salt ZnHal
2
can be used in an amount of 0.1 to 1.5 mol, based on 1 mol of the starting compound (F). An amount of 0.1 to 0.5 mol is preferred.
The metal enolate (F) can for instance be prepared in a known manner, as follows:
The access to the metal enolate (F) most favorable for the individual case results for instance from the individual availability of the precursors.
The masked zinc alkyl (B,C) can also be prepared by metallation of a compound (G), which includes the &agr;,&bgr;-unsaturated alkyl group (A), by means of a dialkyl zinc compound ZnR
2
in accordance with the following equation:
This reaction can easily be performed e.g. with diethyl zinc.
With this process variant, too, the masked zinc alkyl (B,C) is generally not isolated, but formed in situ and immediately reacted with the electrophile (E).
All reactions described so far are performed in an aprotic solvent. As aprotic solvent there may be used ethers, amides or hydrocarbons or mixtures of these solvents. As ethers, there may for instance be used diethyl ethers, tetrahydrofuran (THF) or 2-methyl-THF, as amide there may for instance be used hexamethylphosphoric triamide (HMPT), N-methyl-2-pyrrolidinone (NMP), N,N-dimethylformamide (DMF) or 1,3-dimethyltetrahydro-2(1H)-pyrimidinone (DMPU), and as hydrocarbon there may for instance be used toluene, hexane, heptane or cyclohexane.
It was observed that the speed of the fragmentation (B)→(C) is influenced by the donor power of the solvent. The more polar the solvent, the faster the breakdown, i.e. the more the reaction temperature can be decreased. The second factor which determines the speed of the fragmentation is the specific substitution pattern of the zinc enolate (B). The following Table 1 indicates the respectively recommended temperature range for the allyl transfer reaction (I):
TABLE 1
Typical reaction
Typical
Substituent
temperature
reaction
No.
Solvent
R
1
R
2
R
3
R
4
R
5
(° C.)
time
1
THF/hexane
t
Bu
t
Bu
H
H
H
0 to 40
min - 2 hrs.
2
THF/hexane
i
Pr
i
Pr
H
H
H
40 to 100
10 hrs.
3
THF/HMPT
i
Pr
i
Pr
H
H
H
40 to 100
5 hrs.
4
THF/hexane
t
Bu
t
Bu
alkyl
H
H
−80 to −20
min
5
THF/hexane
t
Bu
t
Bu
H
cyclo
*
40 to 100
5 hrs.
C
4
H
4
6
THF
t
Bu
t
Bu
H
alkyl
H
20 to 100
a few hours
7
THF
t
Bu
t
Bu
H
H
alkyl
0 to 40
a few hours
* = benzyl (R
3
and R
4
are connected via cyclization),
t
Bu = tert-butyl,
i
Pr = iso-propyl
When the masked zinc alkyl (B,C) is prepared from the alcohol precursor in accordance with reaction (III), there are basically no restrictions with respect to the residue R, but the more reactive zinc compounds with short-chain residues (C
1
to C
4
are preferred. Diethyl zinc, which is commercially available, is particularly recommended. The reaction is effected in strongly coordinating solvents (e.g. a mixture of THF and DMPU) at a temperature in the range between about 0 and 70° C. in the presence of the electrophile. Due to the low reactivity of dialkyl zinc compounds with respect to alcohols, the reaction takes a few to many hours.
On the other hand, the metal exchange in the reaction of metal elonates (F) with zinc halides in accordance with reaction (II) is much faster, so that even at low temperatures (e.g. −78° C.) short reaction times are observed. This variant is preferred as compared to the above-described mode of formation from alcohol and dialkyl zinc compound. This is particularly true for those &agr;,&bgr;-unsaturated alkyl groups (A) and/or electrophiles (E) which can isomerize at higher temperatures in an undesired way.
The metal/zinc exchange (II) can accordingly be performed at temperatures which are adapted to the respective structures. The exchange preferably takes place in the presence of the electrophilic recipient molecule (E) by observing the reaction temperatures indicated in the above table. In the case of isomerization-stable &agr;,&bgr;-unsaturated alkyl groups (A), the electrophile (E) can also be added upon termination of the metal/zinc exchange. For this case, however, the required reaction times are prolonged correspondingly.
A further advantage of the inventive process consists in that substituted allyl groups (A) (R
3
&
Jones Philip
Knochel Paul
Fulbright & Jaworski LLP
Metallgesellschaft Aktiengesellschaft
Padmanabhan Sreeni
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