Mechanism of the reaction of amine N-oxides with acetic anhydride; The Polonovski reaction
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In connection with their interest in the isolation and medicinal properties of the “gen alkaloids” ( N ‐oxides), Max and Michel Polonovski reported in 1927 their discovery that the treatment of a tertiary amine N ‐oxide with acetic anhydride or acetyl chloride results in a rearrangement in which one of the alkyl groups attached to nitrogen is cleaved, and the N ‐acetyl derivative of the corresponding secondary amine and aldehyde are obtained. As the original work by the Polonovskis was mainly carried out on bicyclic tropane N ‐oxide derivatives, the products of the reaction were the demethylated amides and formaldehyde. The reaction was thus looked upon as a means of effecting N ‐demethylation of tertiary amines. As such it was, and still remains, a viable alternative to the use of cyanogen bromide, alkyl chloroformates, azocarboxylic esters, or nitrous acid for this purpose. These methods often require more drastic conditions and/or promote unwanted side reactions. The central feature of the Polonovski reaction is the transformation of an N ‐oxide to an iminium ion intermediate. Depending on the structure of the substrate and the acid anhydride or other activating reagent employed, iminium ion formation can occur through loss of an α hydrogen, or through fragmentation of a Cαcarbon bond. Again, depending on conditions, the reaction will either stop at this stage and iminium ions become the Polonovski products, or proceed to give enamines or tertiary amides and/or secondary amines and aldehydes. The often close relationship between structure and reaction conditions, which determine both product types and reaction regiochemistry, is discussed. In its initial stages the Polonovski reaction resembles other reactions in which a tertiary amine is oxidized through interaction of the pair of electrons on nitrogen with an agent X followed by elimination of the elements of HX. Reagents like lead tetraacetate, N ‐bromosuccinimide and in particular mercuric acetate have been employed for this purpose. However, the Polonovski reaction can offer certain advantages in selectivity and experimental ease. In principle, any reagent capable of activating the N ‐oxide oxygen could promote the Polonovski reaction. However, three major types of activating agents, acid anhydrides and chlorides (including chloroformate esters), iron salts and complexes, and sulfur dioxide, are usually employed. Perhaps the most important contribution to the use of the Polonovski reaction in modern organic synthesis was the discovery in the 1960s that on replacing acetic anhydride by trifluoroacetic anhydride the reaction could be stopped at the iminium ion stage. Considering the rich chemistry of iminium ions, many applications of this modified, or Polonovski–Potier, reaction have appeared in the literature, the most spectacular of which was the first successful approach to the synthesis of the indole antitumor agents of the vinblastine group. In this chapter the discussion is limited to examples of the Polonovski reaction in which the abovementioned activating reagents are employed. The coverage is restricted to tertiary amine oxides in which at least one of the substituents on nitrogen is an alkyl group. Both acyclic and cyclic amine oxides such as piperidine N ‐oxide fall into this category, whereas heteroaromatic N ‐oxides do not. With the exception of one special case, nitrones are also omitted from the discussion. The literature coverage includes articles appearing before the end of August 1988.
In connection with their interest in the isolation and medicinal properties of the “gen alkaloids” ( N ‐oxides), Max and Michel Polonovski reported in 1927 their discovery that the treatment of a tertiary amine N ‐oxide with acetic anhydride or acetyl chloride results in a rearrangement in which one of the alkyl groups attached to nitrogen is cleaved, and the N ‐acetyl derivative of the corresponding secondary amine and aldehyde are obtained. As the original work by the Polonovskis was mainly carried out on bicyclic tropane N ‐oxide derivatives, the products of the reaction were the demethylated amides and formaldehyde. The reaction was thus looked upon as a means of effecting N ‐demethylation of tertiary amines. As such it was, and still remains, a viable alternative to the use of cyanogen bromide, alkyl chloroformates, azocarboxylic esters, or nitrous acid for this purpose. These methods often require more drastic conditions and/or promote unwanted side reactions. The central feature of the Polonovski reaction is the transformation of an N ‐oxide to an iminium ion intermediate. Depending on the structure of the substrate and the acid anhydride or other activating reagent employed, iminium ion formation can occur through loss of an α hydrogen, or through fragmentation of a Cαcarbon bond. Again, depending on conditions, the reaction will either stop at this stage and iminium ions become the Polonovski products, or proceed to give enamines or tertiary amides and/or secondary amines and aldehydes. The often close relationship between structure and reaction conditions, which determine both product types and reaction regiochemistry, is discussed. In its initial stages the Polonovski reaction resembles other reactions in which a tertiary amine is oxidized through interaction of the pair of electrons on nitrogen with an agent X followed by elimination of the elements of HX. Reagents like lead tetraacetate, N ‐bromosuccinimide and in particular mercuric acetate have been employed for this purpose. However, the Polonovski reaction can offer certain advantages in selectivity and experimental ease. In principle, any reagent capable of activating the N ‐oxide oxygen could promote the Polonovski reaction. However, three major types of activating agents, acid anhydrides and chlorides (including chloroformate esters), iron salts and complexes, and sulfur dioxide, are usually employed. Perhaps the most important contribution to the use of the Polonovski reaction in modern organic synthesis was the discovery in the 1960s that on replacing acetic anhydride by trifluoroacetic anhydride the reaction could be stopped at the iminium ion stage. Considering the rich chemistry of iminium ions, many applications of this modified, or Polonovski–Potier, reaction have appeared in the literature, the most spectacular of which was the first successful approach to the synthesis of the indole antitumor agents of the vinblastine group. In this chapter the discussion is limited to examples of the Polonovski reaction in which the abovementioned activating reagents are employed. The coverage is restricted to tertiary amine oxides in which at least one of the substituents on nitrogen is an alkyl group. Both acyclic and cyclic amine oxides such as piperidine N ‐oxide fall into this category, whereas heteroaromatic N ‐oxides do not. With the exception of one special case, nitrones are also omitted from the discussion. The literature coverage includes articles appearing before the end of August 1988.
The transformation of a tertiary amine oxide into a N , N ‐disubstituted acetamide and an aldehyde by treatment of the tertiary amine oxide with acetic anhydride or acetyl chloride is generally known as the Polonovski reaction. This reaction is also referred to as the Polonovski transformation. It has been reported that under modified condition this reaction can be stopped at the iminium stage, which can be trapped by the addition of cyanide to form an amino nitrile. This reaction is known as the Polonovski–Potier reaction. It has been found that the elimination occurs via an E2 type mechanism and cis ‐elimination has also been observed for nupharidine‐type alkaloids. This reaction has wide application in the transformation of alkaloids.
Die Reaktion des N‐Oxids (I) mit Essigsäureanhydrid wird untersucht.
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