Synthesis of carboxamides from the catalyzed reaction of...

Details Synthesis of carboxamides from the catalyzed reaction of... Synthesis of carboxamides from the catalyzed reaction of...

2000-07-28

2002-01-15

Nazario-Gonzalez, Porfirio (Department: 1621)

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

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

C544S391000, C556S021000, C564S182000, C564S183000, C564S184000, C564S185000

Reexamination Certificate

active

06339157

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to a process for the synthesis of amides from the reaction of an aldehyde with a primary or secondary amine in the presence of a catalyst and suitable additives and solvents. The catalyst is a metal complex, which may be in the form of a metal-ligand complex or metal precursor/ligand composition.
BACKGROUND OF THE INVENTION
Carboxamides represent important synthetic intermediates for a variety of applications in pharmaceutical, chemical, and polymer industries. Generally, carboxamides are molecules that have a covalent bond between a carboxyl carbon and a nitrogen atom, i.e., C(O)—N.
Carboxamides are known to be synthesized from the reactions of acids, acid halides and esters with amines. The synthesis of carboxamides from the reaction of aryl halides or alkyl halides or alkenes with carbon monoxides and amines (amidocarbonylation) is also known in the art. Many different process conditions and catalysts have been developed for these transformations. These reactions however, do not use readily available aldehydes.
In contrast, methods for carboxamide synthesis from aldehydes are fairly limited. One carbon higher homologous amides can be synthesized from the reaction of aldehydes with carbon monoxide and amines (amidocarbonylation; see, e.g., Beller et al.,
Angew. Chem. Int. Ed
., 2000, 39, 1010-1027, incorporated herein by reference, for a recent review) in presence of suitable catalysts. Carboxamides can also be synthesized from aldehydes in a multiple step (4 step) synthetic sequence (Boche, et al.,
Tetrahedron Lett
. 1982, 23, 3255), but this process involves industrially undesirable reagents and process conditions. Other highly specific methods for the synthesis of specific carboxamides from the reaction of specific aldehydes and amines include the Angelini-Rimini synthesis of hydroxamic acids from the reaction of aidehydes and N-sulfonylhydroxylamine (Hassner et al. Tetrahedron Organic Chemistry Series Volume 11: Organic Syntheses Based On Named and Unnamed Reactions, Pergamon 1994, p. 4), and the is Passerini synthesis of &agr;-hydroxycarboxamides from the reaction of an aldehyde or ketone with an isocyanide (Hassner et al., Id., p. 289). These methods are of limited scope and are not applicable for the general direct synthesis of carboxamides from aldehydes.
Thus, given the ready availability of aldehydes, it is desirable to have an industrially viable, general, and direct method for the synthesis of carboxamides from the reaction of aldehydes and amines.
SUMMARY OF THE INVENTION
This invention provides a new method for the synthesis of carboxamides from the metal precursor complex—ligand composition catalyzed reaction of aldehydes and amines, and alleviates many of the problems associated with the current methods for the synthesis of carboxamides from aldehydes. This invention offers the benefit of direct and economical conversion of aldehyde to carboxamides. This invention offers the additional benefit of higher functional group compatibility. The method utilizes industrially viable reagents and solvents.
The present invention offers a process for the synthesis of carboxamides by reacting a mixture of an aldehyde, an amine, an oxidant and a base in the presence of metal-ligand complex or composition as a catalyst and a suitable solvent. The products are the result of the formation of the carbon-nitrogen bond from the amine/aldehyde combination. The invention identifies process conditions, which surprisingly result in the selective and predominant formation of the carboxamide rather than aryl amines resulting from the reaction of amines with halobenzene (oxidant).
In another embodiment, this invention provides for the synthesis of carboxamides from an alcohol and an amine. The reaction proceeds by oxidizing the alcohol to the corresponding aldehyde and subsequent reaction of the aldehyde product with an amine to form the carboxamide. The embodiment can proceed as a one-pot synthesis with sequential or substantially concurrent (e.g., simultaneous) addition of reactants and catalyst.
Thus, it is an object of this invention to provide a process for the formation of a carboxamide from the reaction of an amine and an aldehyde.
It is another object of this invention to provide a process for the formation of a carboxamide from the metal precursor complex—ligand catalyzed reaction of an amine and an aldehyde.
It is a further object of this invention to provide a process for the formation of a carboxamide from the reaction of an amine and an aldehyde where the amine and/or aldehyde comprises other reactive functionalities.
It is yet a further object of this invention to form a carboxamide from the reaction of an amine and an aldehyde under mild, and economically and/or environmentally sound conditions.
It is still a further object of this invention to form a carboxamide in a one-pot synthesis reaction starting from an alcohol substrate and an amine.
These and other objects of the invention are accomplished through a reaction using suitable metal-ligand compositions or complexes that can be generated in situ or separately by adding suitable ligands to suitable precursor metals. Suitable ligands of this process can be characterized by the general formulas PR
3
, NR
3
, SR
2
, OR
2
, or :CR
2
(carbenes) wherein each R is independently selected from the group consisting of hydrocarbyl (e.g., alkyl, alkenyl, alkynyl, aryl, alkaryl, aralkyl, etc.), substituted hydrocarbyl (e.g., substituted alkyl, alkenyl, alkynyl, aryl, aralkyl, alkaryl, etc.), heteroatom-containing hydrocarbyl (e.g., heteroatom-containing alkyl, alkenyl, alkynyl, aryl, aralkyl, alkaryl, etc.) and substituted heteroatom-containing hydrocarbyl (e.g., substituted heteroatom-containing alkyl, alkenyl, alkynyl, aryl, aralkyl, alkaryl, etc.). Suitable precursor metal complexes can be characterized by the form ML
n
wherein M is a transition metal, preferably Pd, Ni, Ru, Rh, Co, Ir, and most preferably Pd and Ni and L is a suitable neutral or charged organic or inorganic fragment or solid support. Suitable bases of this process can be organic and inorganic compounds such as amines, alkali and alkaline earth metal carbonates, phosphates, alkoxides, hydroxides and fluorides. Suitable solvents include hydrocarbons, ethers, ketones, alcohols, and nitriles.
Further aspects of this invention will be evident to those of skill in the art upon review of this specification.
DETAILED DESCRIPTION OF THE INVENTION
It is to be understood that unless otherwise indicated this invention is not limited to specific reactants, catalyst compositions (including heteroatom-containing activators and acids), or synthetic methods. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting.
As used in this specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, reference to “a reagent” includes mixtures of reagents, “a base” includes mixtures of bases, “a catalyst composition” includes mixtures of catalyst compositions, and the like.
In describing and claiming the present invention, the following terminology will be used in accordance with the definitions set out below. A named R group will generally have the structure that is recognized in the art as corresponding to R groups having that name. For the purposes of illustration, representative R groups as enumerated above are defined herein. These definitions are intended to supplement and illustrate, not preclude, the definitions known to those of skill in the art.
The following definitions pertain to chemical structures, molecular segments and substituents:
As used herein, the phrase “having the structure” is not intended to be limiting and is used in the same way that the term “comprising” is commonly used. The term “independently selected from the group consisting of” is used herein to indicate that the recited elements, e.g., R groups or the l

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