Of lactim ethers

A. Synthesis of Lactim Ethers from Piperazine-2,5-diones. 254... 

This section deals mainly with the metalation of lactim ethers and subsequent reaction with electrophiles to generate new C—C bonds at position 3 or 6. Hydrolysis of the products leads to new amino acid esters. The chief attraction of this synthetic route is the high degree of stereoselectivity in the carbon—carbon bond-forming step. It is known as the Schollkopf method for the chiral synthesis of amino acids. 

The chemical properties of lactim ethers have been briefly reviewed.8, 9 The present review surveys the reactions and use of lactim ethers in syntheses. 

A detailed study of the action of dialkyl sulfates on caprolactam (1) was undertaken by Benson and Cairns.16 They found that the outcome depended on the molecular proportions of the reactants. Slow addition of the alkylating agent increased the yield of lactim ethers (2), whereas excess dialkyl sulfates decreased the yield because of the preferential formation of N-alkyl derivatives (3). Benson and Cairns proposed that 3 was formed via 2 and 4 as follows. 

No comparison between trialkyloxonium fluoroborates and dialkyl sulfates has been made, but analysis of available data shows that oxonium salts are more generally applicable reagents for the preparation of lactim ethers. The alkylation of 3-carbethoxypiperid-2-one (7)25 and morpholin-3-one (8)32 with dimethyl sulfate failed, but with triethyloxonium fluoroborate these compounds gave 2-ethoxy-3-carbethoxy-3,4,5,6-tetrahydropyridine (9) and 3-ethoxy-3,4-dehydro-morpholine (10) in excellent yield. The selective character of triethyloxonium fluoroborate is shown in its reaction with 3,3-diethyl-5-methylpiperidine-2,4-dione (11 ).25 Reaction of 11 with the calculated quantity of dimethyl sulfate resulted in alkylation of the carbonyl group in position 4 with formation of 12, but reaction of 11 with triethyloxonium fluoroborate gave the lactim ether (13). 

Trialkyloxonium fluoroborates give better yields of lactim ethers than other alkylating agents because of the selectivity of these reagents in the O-alkylation of lactams. This was borne out by Meerwein at al.,42 who arranged carbonyl compounds according to their capacity to undergo alkylation with oxonium salts as follows lactams > acyclic amides > lactones > carboxylic esters > ketones > aldehydes. 

An important method for the preparation of lactim ethers is the transformation of lactams to imidochlorides followed by treatment with alcohols. Thus, the reaction of caprolactam with phosphoryl chloride followed by methanol resulted in O-methylcaprolactim (2, R = Me)43 (Scheme 2). 

Another example of the preparation of lactim ethers from lactams and phosphoryl chloride is the transformation of tetrahydro-/ -carbolin-l-one (19) to l-alkoxy-3,4-dihydro-/3-carboline (20)46,47 (Scheme 3). 

Presumably, the synthesis of lactim ethers from lactams and acylat-ing agents, including phosgene and ethyl chloroformate, proceeds via intermediate imidochlorides5 5 57 (Scheme 4). 

A synthesis of lactim ethers based on the action of hydrazoic acid on cyclic ketones in the presence of alcohols has been developed [Eq. (I)].60... 

Individual methods for the synthesis of lactim ethers also depend on the nature of the starting materials, e.g., the transformation of 2,3-dimethyl-3-cyanomethylindolenine (28) to the tricyclic lactim ether (29) in the presence of sodium ethoxide61 (Scheme 6). 

The reactions of lactim ethers involving the lactim ether part may be classified into two groups. 

Reactions involving loss of the entire alkoxyl group (Scheme 8). The thermal rearrangement of lactim ethers to iV-alkyl lactams is a... 

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