Lactim-ethers, cyclic

Cyclic lactim ethers (465, n = 0 and 1, R2 = see below, R5 = OMe) were condensed with Meldrum s acid (421) in the presence of a catalytic... 

The five- and six-membered isopropylidene 2-azacycloalkylidenemalo-nates (468, n = 0 and 1, R2 = R4 = H) were prepared in 94% and 76% yields, respectively, in the reactions of Meldrum s acid (421) and the appropriate cyclic lactim ether (465, n = 0 and 1, R2 = H, R5 = OMe) in the presence of triethylamine in boiling benzene overnight (79JOC3089). Under these conditions, caprolactim methyl ether did not react, but if the latter reaction was carried out in the presence of acetic acid and piperidine in boiling benzene overnight, a seven-membered cyclic compound (468, n = 2, R2 = R4 = H) was obtained in 58% yield (79JOC3089). 

With lactam acetals (98), cyclic imidic chlorides (99) (X = Cl), lactim ethers (99) (X = OMe), or certain iminium salts (100) amidoximes form 5-(aminoalkyl) substituted oxadiazoles (Scheme 37)... 

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). 

An alternative protocol towards pyrazino 2,l-b]quinazolines 79 relied on cyclocondensation of diketopiperazine-derived lactim ethers with anthranilic acid. Microwave dielectric heating in a domestic oven (600 W irradiation power) furnished heterocycles 79 within 3-5 min, while the corresponding reaction in an oil-bath required 2 hours heating at 120-140 °C [129]. The use of N-protected co-amino acids 83 in the microwave-assisted reaction with anthranilic acid 71 furnished pyrrolo 2, -b]quinazolines 85 via transannu-lar cyclization of the intermediate cyclic diamide 84 [126]. Subsequent in situ condensation with a variety of aldehydes furnished isaindigotone 86 and analogues, possessing cytotoxic activity (Scheme 51). 

This article deals with results achieved with the 2,5-dimethoxy-3,6-dihydropyra-zines, the heterocycles of type I. Results obtained with the imidazolinones III are discussed elsewhere 6). At first glance the heterocycles I look rather esoteric. However, the yare nothing but the bis-lactim ethers of the well known 2,5-diketopiperazines, the cyclic dipeptides. — At first, experiments with the symmetrical bis-lactim-ether (6) of cyclo(L-Ala-L-Ala) (5) are described and then results with several mixed bis-lactimethers. Symmetrical bis-lactimethers — i.e. those, build up from two identical amino acids — do have one disadvantage, inherent in the system, namely, only one half of the chiral auxiliary is recovered, the other half is incorporated in the product. But they are easily prepared and, hence, are good models to commence a study. 

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... 

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. 

Common synthetic methods for the preparation of cyclic 8-enamino esters are the condensation between a lactim ether and benzyl cyanoacetate followed by hydrogenolytic decarboxylation, or the imino ester carbon-carbon condensation with tert-butyl cyanoacetate followed by a trifluoroacetic acid treatment. The use of a thiolactam condensed with ethyl bromoacetate gives, after sulfur extrusion by triphenylphosphine, cyclic 8-enamino esters. Compared with these methods, the Meldrum s acid condensation followed by the monodecarboxylating transesterification described here is more convenient and practical. An extension of this procedure permits preparation of smaller... 

The alkylation of a-aminoacids has been performed by Schfillkopf and coworkers (154, 261, 861] via cyclic lactim ethers 1.114 formed from (S)-valine (R = /-Pr) or (S)-ferf-leucine (R = fert-Bu). In this method, one aminoacid acts as a dural auxiliary for alkylation of another. Deprotonation of 1.114 (R = H or Me) by -BuLi in THF takes place on the least hindered carbon leading to an anionic spedes 538 whose upper face is hindered by the R group. Alkylation is carried out at -78°C and takes place on the carbon bearing R substituent, from the lower face (Figure 5.25). Acid hydrolysis leads to a-alkyl substituted aminoacids with a high enantiomeric excess. However, when R = H, some unwanted epimerization can occur. 

Reaction of dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate with 6-methoxy-l,2,3,4-tetrahy-dropyridine gives dimethyl l,2,3,4-tetrahydropyrido[2,3-<5f]pyridazine-5,8-dicarboxylate. Apparently the lactim ether is in tautomeric equilibrium with the corresponding cyclic ketene A,O-acetal, which acts as the dienophile, the final step being the elimination of methanol.73 For a related synthesis, see ref 74. 

Cyclic ketene 7V,S-aminals (187) with different ring sizes were used by Marcelis and van der Plas to form (188) (Equation (5)) <87JHC545>. Cyclic lactim ethers (189) and donor substituted 2,5-dihydropyrazines (191) react in their tautomeric ketene (9,A -aminal forms (190) and (192) (194) and (193) are accessible as has been shown in a number of examples (Scheme 34) <77AP(310)936, 90AP(323)89>. The sulfur analogue reacts in the same way. Finally, lactam acetals (195) can be used as an in situ source of cyclic ketene 0,A -aminals (196) and form pyridazines (197) on reaction with... 

Reactions of lactim ethers 22 with active methylene compounds in EtaN/ CHCI3 afford enaminones 23, generally in high yields. Thermolysis or base-catalyzed hydrolysis then leads to the enaminones 24, Scheme 7 (79JOC3089 81TL963 83S195). This method is particularly useful for cyclic... 

Common synthetic methods for the preparation of cyclic B-enamino esters are the condensation between a lactim ether and benzyl cyanoacetate followed... 

The cyclic diamides formed by the cyclodehydration of a-amino acids are known trivially as 2,5-diketopiperazines, and are the important element of an asymmetric synthesis of a-methyl substituted amino acids developed by Schollkopf.Ii l The anion (55) resulting from deprotonation of the bis-lactim ether of a diketopiperazine undergoes alkylation with very high diastereofacial selection, especially if the chiral auxiliary is derived from (5)-valine. 

Cyclic imidic esters (lactim alkyl ethers) are also readily converted into cyclic amidine by amines826 or amino acids.827... 

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