Lactimization

A) Keto or lactam form. (B) Enol or lactim form. 

Lactones, l xictides, iMciams, and Lactims. When the hydroxy acid from which water may be considered to have been eliminated has a trivial name, the lactone is designated by substituting -olactone for -ic acid. Locants for a carbonyl group are numbered as low as possible, even before that of a hydroxyl group. 

Lactides, intermolecular cyclic esters, are named as heterocycles. Lactams and lactims, containing a —CO—NH— and —C(OH)=N— group, respectively, are named as heterocycles, but they may also be named with -lactam or -lactim in place of -olide. For example. 

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). 

This compound represents the unstable pseudo- or lactam-foim, and passes into the stable or lactim-foim (Baeyer),... 

The aromaticity of the pyrimidine and purine ring systems and the electron-rich nature of their —OH and —NHg substituents endow them with the capacity to undergo keto-enol tautomeric shifts. That is, pyrimidines and purines exist as tautomeric pairs, as shown in Figure 11.6 for uracil. The keto tautomer is called a lactam, whereas the enol form is a lactim. The lactam form vastly predominates at neutral pH. In other words, pA) values for ring nitrogen atoms 1 and 3 in uracil are greater than 8 (the pAl, value for N-3 is 9.5) (Table 11.1). 

According to the triazine nomenclature, 5-azauracil is 2,4-dioxo-l,2,3,4-tetrahydro-l,3,5-triazine (2). The subject index of Chemical Abstracts prefers s-triazine-2,4(lH,3H)-dione. Furthermore, some authors use a name derived from the lactim structure, 2,4-dihydroxy-s-triazine (3). The numbering of the substituents is the same for all these types of nomenclature. 

A detailed investigation of the tautomeric structure of 6-azauracil was carried out by Jona and Gut and by Horak and Gut. They measured the UV and IR spectra and compared similar systems and their derivatives in which the lactam or lactim configuration was fixed by A - or 0-substitution (as will be seen later no 0-alkyl deriva-... 

During methylation of 6-azauracil with a theoretical amount of diazomcthane, the 3-methyl derivative (63) was obtained in very good yield. Excess reagent produces the dimethyl derivative (64). During none of the alkylation reactions was it possible to observe the formation of 0-alkyl derivatives of 6-azauracil. This can be taken as evidence that 6-azauracil does not react in the lactim form (e.g., Section II,B, b). 

According to the systematic nomenclature these substances were first named l-f-triazolo[d] pyrimidines in compliance with the general principles of the Ring Index/ More recent papers and Chemical Abstracts indexes use the term i -triazolo[4,5-d]pyrimidine (147) in accord with the lUPAC nomenclature. The numbering of substituents when using the last-mentioned name is different from that of the 8-aza analogs. For the formulas of oxygen and sulfur derivatives names derived from the lactim or thiolactim form are almost exclusively in use (in common with the purine derivatives). These derivatives are thus described as hydroxy and mercapto derivatives, respectively. The name 1,2,3,4,6-pentaazaindene is used only rarely for this system. 

The TJV spectra were measured for practically all the numerous derivatives. Beside the analytical application of these to demonstrate the position of the substituent no detailed interpretation was attempted, however. On the whole, they are similar to the spectra of analogous purine derivatives and also display a similar dependence on Despite the fact that the question of structure with regard to the lactim-lactam (or thiolactim-thiolactam) tautomerism has not been studied in detail, it can be assumed that oxygen and sulfur derivatives, at variance with the conventional way of writing the formulas, possess a lactam or thiolactam structure. This is in agreement with the views on the analogous purine derivatives. 

The lactam-lactim tautomerism of hydroxyquinazolines is reflected in their chemical reactivity. Thus they are chlorinated to 4-chloro-quinazolines (see Section VI,A), and both 0- and A-methylation have been observed. When a substituent is already present on a nitrogen atom, as in 3-methyl-4(3i7)quinazolinone, chlorination gives 4-chloroquinazoline with loss of the methyl group (see la). 2-... 

Syntheses of phthalimidines (e.g., 30) do not in themselves constitute syntheses of isoindoles or isoindolenines, since the lactam from shows no tendency to tautomerize, as discerned from spectroscopic evidence, to lactim forms (31 and 32). However, phthalimidines are... 

Similar considerations apply to nitrogen-containing heterocycles carrying acidic groups, for example 2-hydroxypteridine, but the situation is further complicated by lactam-lactim tautomerism in the neutral species. Thus, hydroxypteridines exist predominantly as lactams, such as 6, in dynamic equilibrium with small amounts of lactims, such as 7. There is, in consequence, a decrease in the aromatic... 

Acylation of l,2,4-triazolo[l,5-c]quiiiazoliii-5-oiie (141) with ethyl chlo-roformate occurred at N6 to afford the 6-ethoxycarboiiyl derivative 142 (75CB3799) (Scheme 55). Tliis result indicates that the amide tautomer (lactam tautomer) 141 prevailed over the corresponding imidic acid tautomer (lactim tautomer). 

Tlie infrared spectra revealed the dominance of the 2-oxo (153) and 5-0X0 (157) structures (amide or lactam tautomers) over the 2-hydroxy (154) and the 5-hydroxy (192) structures (imidic acid or lactim tautomers)... 

Racemic and chiral syntheses of some indolo[2,3-<2]quinolizidine alkaloids through a lactim ether route 98H(47)525. 

Treatment of bis-lactim ether 420 with BuLi, then with cw-l,4-dichloro-2-butene in the presence of Nal afforded 3,4,9,9n-tetrahydro-6//-pyrido[l,2-fl]pyrazin-4-one (421) with 96% diastereomeric excess (97TA1855). Reaction of l,2-diphenyl-6-methyl-quinoxaline with 1,4-dichlorobutane in THF in the presence of Na at —78°C afforded a 3 1 mixture of 4a,5-diphenyl-9-methyl-l,2,3,4-tetrahydro-4a//-pyrido[l,2-n]quinoxaline and 4-(4-chlorobutyl)-2,3-diphenyl-6-methyl-1,4-dihydroquinoxaline (98JHC1349). 

Only brief reference is made in this section to azepinones as there is scant evidence for the existence of their azepinol tautomers. 1 //-Azepin-3(2//)-ones, e.g. 12, exist exclusively as the nonconjugated, nonplanar 3-oxo forms in a wide range of solvent systems.43 44 All attempts to generate the enolates have failed. Likewise, l//-azepin-2(3//)-ones, for which lactim and enol tautomers are possible, prefer the amide form 13.45... 

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. 

Fig. 14. Dimeric 38 is a cis-lactim derivative, while tetrameric 40 and oligomeric 35 are trans-lactim derivatives with a partially delocalized N—C—O central moiety. 36 and 39 are monomeric complexes...

Azadienes undergo Diels-Alder reactions to form pyridine, dihydro- and tetrahydropyridine derivatives. N-Vinyl lactim ethers undergo Diels-Alder reactions with a limited set of dienophiles. " Thioketones react with dienes to give Diels-Alder cycloadducts. The carbonyl group of lactams have also been shown to be a dienophile. Certain heterocyclic aromatic rings (among them furans) can also behave as dienes in the Diels-Alder reaction. Some hetero dienes that give the reaction are -C=C-C=0, 0=C-C=0, and N=C-C=N. ... 

The high simple diastereoselectivities observed running the [4-1-3] cycloadditions raised the question concerning the induction of chirality. Preliminary experiments involving chiral menthyloxy Fischer carbenes 169 (R = (-)-men-thyl) resulted in the formation of the diastereomeric lactim ethers 173-1 and 173-2 in a 7 3 ratio, which could be separated by means of a crystallization. A final acidic hydrolysis gave the enantiomerically pure e-caprolactams 175 and ent-175 and the acyclic esters, respectively. No signs of racemization have been detected,Eqs. (18,19) [39b]. 

Imino ethers and, in particular, lactim ethers [141] such as O-ethylpyrrolidone 384a [142] or O-trimethylsilylcaprolactam 384b, which is formed, in equilibrium with N-trimethylsilylcaprolactam, on treatment of caprolactam with HMDS 2, condense readily with activated methylene compounds such as methyl or ethyl cyanoacetate to the y9-enamino esters 385 a and 385 b [140] whereas O-alkylureas such as 2-methoxyimidazoline 386 [143-146] afford products such as 387. 

Molecules in real solvents can exist in one or more tautomeric forms. The use of different tautomers in calculations can lead to significant variation in the estimated log P values (Pig. 15.1). Accurate prediction of the dominant tautomer requires ah initio calculahons. Due to speed limitations such calculations are not feasible for virtual screening and prediction of large compound collections. Moreover, the interpretation of the results can also be difficult, for example, the lacton-lactim (Pig. 15. IB) is the stable form of maleic hydrazide in the gas phase but the difference between this and the dilacton form (Pig. 15.1C and D) disappears in solution... 

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