Synthesis of Lactim Ethers

The direct alkylation methods include the reaction of lactams with diazomethane14 and the alkylation of metal salts of lactams with alkyl halides.15 These two methods are not often used nowadays, because the alkylation can more conveniently be carried out with dialkyl sulfates or triethyloxonium fluoroborate. 

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. 

In recent years the alkylation of lactams has been achieved using tertiary oxonium salts, particularly triethyloxonium fluoroborate.19,20 This reaction proceeds via cation formation (cf. 5). Treatment of the salt with base leads to the lactim ether. 

The oxonium salts give better results than other alkylating agents.21 Numerous examples of the application of oxonium salts for the alkylation of lactams21-27 show that no A-alkyl derivatives could be isolated because of the high selectivity of oxonium salts in similar reactions. 

Harley-Mason and T. J. Leeney, Proc. Chem. Soc. (London), 368 (1964). 

---

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

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). 

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 reaction of lactim ethers with hydrazine and its derivatives proceeds readily. The resulting compounds are highly reactive and can be used in different reactions involving the side chain and the cyclic nitrogen atom.5,54,76> 80-82 For example, the treatment of caprolactam hydrazone (40) with nitrous acid results in pentamethyl-enetetrazole (41),54,80,81 and the use of diiferent lactim ethers gives other tetrazoles.32,35 The synthesis of polymethylenetetrazoles from lactim ethers and HN3,83 and also84 from HN3 and O-acyl lactims (or imidochlorides of lactams), obtained from lactams and sulfochlorides or phosphoryl chloride, may be mentioned. 

The readiness of amidine formation in reactions of lactim ethers with amines has been used in the synthesis of 8,9-poly methylene-purines.97 Attempts to condense 2 (R = Me) with uramil and l,3-dimethyl-4,5-diaminouracil failed.97 Lactim ethers were also found not to react with derivatives of 5-aminouracil, probably due to the low basicity of the latter.97... 

Thus the application of lactim ethers in organic synthesis is of practical and theoretical importance. Numerous heterocycles, including new heterocyclic systems interesting both from biological and chemical standpoints have been obtained. The wide choice of readily available starting materials makes the use of lactim ethers profitable in synthetic organic chemistry. 

The only recorded synthesis of this type from a pyridazine involves the [4 + 2] cycloaddition of the lactim ether (374) with l,2,4,5-tetrazine-3,6-dicarboxylic ester, which proceeds with loss of nitrogen and methanol from the intermediate adduct to give the pyrido[2,3-t/]pyridazine (375) (77AP936). 

An excellent method for the diastereoselective synthesis of substituted amino acids is based on optically active bislactim ethers of cyclodipeptides as Michael donors (Schollkopf method, see Section 1.5.2.4.2.2.4.). Thus, the lithium enolates of bislactim ethers, from amino acids add in a 1,4-fashion to various a,/i-unsaturated esters with high diastereofacial selectivity (syn/anti ratios > 99.3 0.7-99.5 0.5). For example, the enolate of the lactim ether derivative 6, prepared from (S)-valine and glycine, adds in a highly stereoselective manner to methyl ( )-3-phenyl-propenoate a cis/trans ratio of 99.6 0.4 and a syn/anti ratio of 91 9, with respect to the two new stereogenic centers, in the product 7 are found105, los. 

Excellent reviews covering the enantioselective synthesis of non-proteinogenic amino acids via metallated his-lactim ethers of cyclic dipeptides (2,5-diketopiperazines) (187) have been compiled by Schollkopf188). 

Subsequently, the asymmetric synthesis of stereospecifically monodeu-terated 1-aminocyclopropane-l-carboxylic acids (IS, 2R) and (IS, 2S) has also been achieved by a modification of the above route (89JOC270). The essential step involves an intramolecular alkylation on a lactim ether anion (Scheme 64). 

An enantioselective synthesis of CR)-amino acids has been developed which utilizes L-valine as the chiral auxiliary (81AG(E)798). The diketopiperazine cycZo-(L-Val-Gly) (780) was converted to its bis-lactim ether (781) by methylation with Meerwein s salt, and the ether metallated in the glycine portion by n-butyllithium. Alkylation of the delocalized... 

---