Hydroboronation process

Details Hydroboronation process Hydroboronation process

2001-08-13

2004-01-20

Vollano, Jean F. (Department: 1623)

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

Organic compounds

Borate esters

C544S229000, C546S013000, C549S004000, C548S110000

Reexamination Certificate

active

06680401

ABSTRACT:

This invention relates to a process for preparing organoboron compounds which involves reacting an appropriately substituted organic compound with a substituted borane. In particular the invention relates to the synthesis of aryl or vinyl borates using disubstituted monohydroboranes and related species. These organoborates, and their corresponding boronic acids, are useful reactants in organic coupling reactions. They are particularly useful in the synthesis of new and known organic molecules and have application in the synthesis of pharmaceuticals, pesticides and other useful organic compounds. The compounds represent useful intermediates and building blocks for organic synthesis and are useful in combinatorial chemistry.
Processes for forming covalent bonds between organic compounds, both inter- and intra-molecular, are of particular importance to the synthetic organic chemist. Many such reactions are known, each requiring its own special reaction conditions, solvents, catalysts, activating groups etc. Some known types of coupling reactions involving olefinic moieties include the Michael reaction and reactions described in the following references: Transition Metals in the Synthesis of Complex Organic Molecules (L. S. Hegedus, University Science Books, 1994, ISBN 0-935702-28-8); Handbook of Palladium Catalysed Organic Reactions (J. Malleron, J. Fiaud and J. Legros, Academic Press, 1997, ISBN 0-12-466615-9); Palladium Reagents and Catalysts (Innovations in Organic Synthesis by J. Tsuji, John Wiley & Sons, 1995, ISBN 0-471-95483-7); and N. Miyuara and A. Suzuki, Chem Rev. 1995, 95, 2457-2483.
Catalysts of palladium, its complexes and its salts are well recognised for activation of C—H bonds towards coupling reactions. In this regard the Heck reaction of an alkene with an aryl or vinyl halide in the presence of palladium derivatives has been the subject of intensive study. Other Group VIII metal catalysts, such as platinum, have also been used to activate such carbon bonds.
The success of the Heck reaction depends to a large extent on the substrates and the reaction conditions. When two &bgr;-hydrogens are present in the alkene the reaction generally leads to the formation of the (E)-alkenes which are often contaminated with the corresponding (Z)-alkenes.
Although alkene borates (alkenylborates) can be reacted with a variety of organic molecules to give coupled products via the formation of new carbon-carbon bonds (See for example the references above) the process for the preparation of the alkenylborates by the commonly used hydroboration reaction of alkynes is limited because of the difficulties that are encountered through the lack of regiochemistry and/or chemoselectivity (such as the reduction of a number of different functional groups) (See N. Miyuara and A. Suzuki, Chem Rev. 1995, 95, 2457-2483). Improved methodologies are thus required for the synthesis of alkene borates.
Substituted bi- and tri-aryl compounds are of great interest to the pharmaceutical and agrochemical industries. A great number of these compounds have been found to possess pharmaceutical activity, while others have been found to be useful pesticides. There is also interest from the polymer industry in polymers prepared by the linking together of aromatic ring compounds.
Conventional methods for covalently linking aromatic rings, such as by reaction of an appropriate Grignard reagent, involve harsh conditions and are not suitable for aromatic rings with active hydrogen containing substituents. Substituents with active hydrogen atoms also can become involved in unwanted side reactions leading to undesirable products. Such substituents need to be protected prior to reaction. Boronic acid derivatives required for the Suzuki reaction are traditionally synthesized through highly reactive organonietallic intermediates.
In view of the severity of the reaction conditions the range of substituents which could be present during the formation of the boronic acid derivatives was considerably limited, and the range of useful reaction media (solvents) was restricted.
It has now been found that aryl and alkene borates can be synthesised from particular substituted olefinic or aromatic ring compounds under mild conditions and in the presence of a range of substituents. This process overcomes or at least alleviates one or more of the limitations encountered in the use of the conventional hydroboration methodology and is fundamentally different, in the case of the preparation of alkene borates, in that the starting material is an alkene and not an alkyne.
Accordingly the invention provides a process for the synthesis of an alkene or aryl borate which comprises reacting:
(i) an olefinic compound having a halogen or halogen-like substituent in a vinylic substitution position, or
(ii) an aromatic ring compound having a halogen or halogen-like substituent in a ring substitution position, said aromatic ring compound also having at least one substituent selected from the group consisting of hydroxy, amino, imino, acetyleno, carboxy (including carboxylato), carboximidyl, sulfo, sulfinyl, sulfinimidyl, sulfinohydroximyl, sulfonimidyl, sulfondiimidyl, sulfonohydroximyl, sultamyl, phosphinyl, phosphinimidyl, phosphonyl, dihydroxyphosphanyl, hydroxyphosphanyl, phosphono (including phosphonato), hydrohydroxyphosphoryl, allophanyl, guanidino, hydantoyl, ureido, and ureylene
with a disubstituted monohydroborane, in the presence of a Group 8-11 metal catalyst and a suitable base, such that a borane residue is introduced at the substitution position.
For convenience, the reaction described above will be referred to as the “boronation reaction”.
The term “disubstituted monohydroborane” refers to a monoboron compound having two non-hydrogen substituents and one hydrogen substituent.
The term “borane residue” refers to a disubstituted monohydroborane moiety after breakage of the B—H bond. An example of a borane residue is the moiety (RO)
2
B— where R is as defined below.
This process is fundamentally different from the conventional hydroboration processes in that substitution occurs rather than addition. Accordingly a completely different mechanism is involved.
According to conventional hydroboration processes, alkyl 3 and alkeneboronic esters 5 are prepared from the corresponding alkenes 2 and alkynes 4 as shown below with pinacol borane:
These reactions formally add one hydrogen and a boronic acid ester across the respective substrates. No base is required and although the reactions may be catalysed by transition metal species these are not essential. With monoalkyl alkynes the reactions yield the (E)-pinacol (1-alkenyl)boronates 5 as the major stereoisomer. The other two isomers 5a and 5b are difficult to obtain using this methodology.
However the present invention provides a convenient route to these difficult to obtain isomers. Instead of addition across a double bond as described above the present invention results in the replacement of a halide or halogen-like substituent in the vinylic position with a borane residue. Accordingly the location of the borane residue in the product is governed by the location of the halide.
Aromatic compounds do not hydroboronate with the use of the reagent 1.
The process according to the present invention also provides advantages over other processes for activating carbon atoms towards coupling reactions. According to the present process it is possible to synthesise a wide range of substituted aryl and alkene borates, without the need for the prior protection of a wide variety of functional groups, including active hydrogen functionalities.
It is possible to generate the disubstituted monohydroborane in situ by reaction of a borane with an appropriate alcohol or amine. In a particularly preferred embodiment the borane ester so prepared can be used without isolation in the boronation reaction. This process can be used to generate esters, as well as ester/amides or diamides. This process surprisingly allows the generation and reaction of disubstituted monohydroboranes which cannot be isolated in the

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