Organic compounds -- part of the class 532-570 series – Organic compounds – Boron containing
Reexamination Certificate
2002-09-06
2004-03-16
Saeed, Kamal (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Boron containing
Reexamination Certificate
active
06706925
ABSTRACT:
Aromatic boronic acids have become indispensible in the synthesis of complex organic molecules. They make it possible to produce many structures which are otherwise obtainable only with difficulty.
Many examples of such Suzuki reactions are reported in the chemical literature. Among these, C—C coupling reactions in which aliphatic or olefinic boronic acids are used are relatively rare.
One reason for this is the usually challenging synthesis of new nonaromatic boronic acids which are of interest for research. Such boronic acids would allow the introduction of interesting substructures which cannot be achieved or achieved only with difficulty by means of classical synthesis.
Aliphatic and olefinic boronic acids are usually prepared by means of hydroboration of alkenes and alkynes or else via conversion of haloolefins into Grignard compounds and addition of the resulting organomagnesium compounds onto esters of boric acid. However, these reactions frequently display only low chemoselectivities and regioselectivities. Examples are the reaction of catecholborane with styrenes or the reaction of alkylmagnesium halides with boric esters.
The handling of boranes on an industrial scale, in particular, is often an obstacle because of their hazardous properties.
The present invention describes a simple, direct route to alkylboronic and alkenylboronic acids via the corresponding bis(allyl)boranes which gives good yields and can be carried out in a single vessel.
The present invention accordingly provides a process for preparing bis(allyl)boranes of the formula (I) by reacting a diene with sodium borohydride in the presence of an oxidant in an inert solvent, with the borane generated in situ reacting selectively with the diene to form the bis(allyl)borane of the formula (I). The first step of the reaction generates borane which dimerizes in the absence of the diene to form diborane but reacts with the diene to form the corresponding bis(allyl)borane highly selectively.
This route to bis(allyl)boranes is novel and was thus not to be expected since the reaction of borane with dienes is described in the literature as largely unselective, giving predominantly borolanes as main products (Dokl. Akad. Nauk. SSSR, Ser. Khim. 1964, 155, 141; Izv. Akad. Nauk. SSSR, Ser. Khim. 1965, 2111). Bis(allyl)boranes have hitherto been prepared in the literature via thermal disproportionation reactions.
In a preferred embodiment, the diene used is 2,5-dimethylhexa-2,4-diene (R
1
, R
2
, R
5
, R
6
=methyl, R
3
, R
4
=H).
The alkene or alkyne is added to the bis(allyl)borane which has been generated in this way and is reacted therewith. This reaction proceeds highly regioselectively and chemoselectively. The alkylbis(allyl)borane (V) or alkenylbis(allyl)borane (III) is selectively oxidized in the same vessel to the corresponding bisallyl boronate. The bis(allyl) ester can be isolated as such or converted into a derivative.
The bis(allyl)boranes and bis(allyl) esters produced can be used in the same vessel in C—C coupling reactions, for example Suzuki reactions. Isolation of the boronic acid can be circumvented. This is particularly useful when the boronic acid is very sensitive to oxidation, heat or hydrolysis.
In the first reaction step, diborane is generated in situ from sodium borohydride by reaction with an oxidant (Ox), e.g. with substituted or unsubstituted C
1
-C
8
-, in particular C
1
-C
4
-alkyl halides or dialkyl sulfates, preferably with alkyl iodides or bromides or dialkyl sulfates, particularly preferably with dimethyl sulfate, diethyl sulfate, benzyl bromide or iodoethane, in an inert solvent at temperatures of from −20 to +30° C., preferably from −5 to +10° C., and this then reacts selectively with the diene present in the reaction mixture to form the corresponding bis(allyl)borane I.
Suitable solvents are, for example, various ethers or hydrocarbons, in particular C
1
-C
10
hydrocarbons or mixtures thereof, preferably ethers such as end-proteceted oligoglycol or polyglycol ethers or THF, particularly preferably diglyme, which are inert toward the reactants.
The radicals R
1
-R
6
are H, aryl or C
1
-C
4
-alkyl, substituted or unsubstituted, and may be closed to form a cyclic system, e.g. via the radicals R
1
and R
5
to form a six-membered ring, preferably H and methyl. In a particularly preferred embodiment, 2,5-dimethylhexa-2,4-diene (R
1
, R
2
, R
5
, R
5
=methyl, R
3
, R
4
=H) are employed. The diene is used in an amount of from 1 to 10 molar equivalents based on sodium borohydride, preferably 2-3 molar equivalents. The concentration of the bis(allyl)borane formed is from 0.1 to 5 mol/l, preferably from 0.5 to 2 mol/l.
The present invention further provides a process for preparing boronic acids by reaction of a diene with sodium borohydride in the presence of an oxidant to form the corresponding bis(allyl)borane of the formula (I) and further reaction of the borane (I) with an appropriate alkene (II) or alkyne (IV) to give the alkylbis(allyl)borane (III) or alkenylbis(allyl)borane (V) which is oxidized directly in the presence of an oxidant to form the corresponding bisallyl alkylboronate or alkenylboronate and, if desired, subsequent conversion into a derivative.
The bis(allyl)borane (I) produced in this way is reacted in the same vessel with a substituted alkene (II) or alkyne (IV) at temperatures in the range from −10 to 100° C., preferably from 0 to 50° C., particularly preferably from 0 to 25° C., to form the alkylbis(allyl)borane (III) or alkenylbis(allyl)borane (V), which can advantageously be employed in C—C coupling reactions, in particular in Suzuki coupling reactions.
The radicals R
7
to R
12
are, in particular, aryl, substituted or unsubstituted, alkyl-(C
1
-C
8
), which may be branched and/or substituted, alkoxy-(C
1
-C
8
), acyloxy-(C
1
-C
8
), Ophenyl, fluorine, chlorine, NO
2
, NH
2
, NHalkyl-(C
1
-C
8
), Nalkyl
2
-(C
1
-C
8
), CN, CHO, SO
3
H, SO
3
R, SO
2
NH
2
, SO
2
N(alkyl-(C
1
-C
8
))
2
, SO
2
-alkyl-(C
1
-C
8
), COO-alkyl-(C
1
-C
8
), CONH
2
, CO-alkyl-(C
1
-C
8
), NHCHO, CF
3
, 5-membered heteroaryl or 6-membered heteroaryl. Two radicals can also form a cyclic system which may contain heteroatoms.
The range of alkenes and alkynes which can be used is very wide. The examples given for substituents are only an illustrative selection from the possible range and do not restrict the process of the invention to these.
To avoid selectivity problems in the oxidation, for example in the oxidation of bis(cyclohexyl)boranes to bis(cyclohexyloxy)boronic acids by means of N-oxides as described in the literature (Synthesis, 1988, 103), keto compounds are used according to the invention for the oxidation in the third reaction step after the hydrolysis. It is possible to use, for example, formaldehyde, acetone, glyoxal, diacetyl, preferably formaldehyde and diacetyl.
The oxidation takes place at temperatures of from 0 to 100° C., preferably from 10 to 40° C. The keto compounds are added in a molar ratio of 1-2 based on sodium borohydride used.
The oxidation of alkenylbis(allyl)boranes (V) by means of formaldehyde gives boronic esters of the formula (VI), while that by means of diacetyl gives esters of the formula (VII).
The boronic esters which result from the oxidation of the alkylbis(allyl)boranes (III) have an analogous structure, with the only difference being that the alkyl substituent on the boron is different.
The boronic esters produced in this way can be converted into the appropriate derivatives by known methods. For example, hydrolysis gives the free boronic acids (Q1, Q2=OH), reaction with pinacol gives the corresponding pinacol esters (Q1, Q2=—OC(CH
3
)
2
—C(CH
3
)
2
O—) and reaction with diethanolamine gives the corresponding diethanolamine esters (Q1, Q2=—OCH
2
CH
2
NHCH
2
CH
2
O—).
In principle, any desired derivatives can be prepared without problems, for example simple alkyl esters (Q1, Q2=Oalkyl) or cyclic esters derived from ethylene glycol or catecholborane.
The process de
Kalinin Alexei
Scherer Stefan
Snieckus Victor
Clariant GmbH
Hanf Scott E.
Saeed Kamal
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