Enamines, structural features

Some enamines with special structural features are those derived from ammonia (19 ) and the quinuclidine enamines (19J). Aminocyclobutenes... 

The formation of enamines from carbonyl compounds and secondary amines usually entails as only questionable structural feature, the possible isomeric position of double bonds in the product. Molecular rearrangements have not presented synthetic limitations. A notable exception is the generation of o-aminophenols on distillation of enamines derived from 2-acylfurans 620,621). 

The preparation and investigation of the thietane oxide system (5a) is largely associated with stereochemical and conformational studies . The investigation of the thietane dioxides (5b) is substantially related to the chemistry of sulfenes , the [2 -I- 2] cycloaddition of which with enamines is probably the method of choice for the synthesis of 5b . The study of the thiete dioxide system (6) evolved, at least in part, from the recognition that the unstable thiete system 183 can be uniquely stabilized when the sulfur in the system is transformed into the corresponding sulfone , and that the thiete dioxide system is very useful in cycloadditions and thermolytic reactions. The main interest in the dithietane oxides and dioxides (7) appears to lie in the synthetic challenge associated with their preparation, as well as in their unique structural features and chemical behavior under thermolytic conditions . ... 

Apart from the role of substituents in determining regioselectivity, several other structural features affect the reactivity of dipolarophiles. Strain increases reactivity norbornene, for example, is consistently more reactive than cyclohexene in 1,3-DCA reactions. Conjugated functional groups usually increase reactivity. This increased reactivity has most often been demonstrated with electron-attracting substituents, but for some 1,3-dipoles, enol ethers, enamines, and other alkenes with donor substituents are also quite reactive. Some reactivity data for a series of alkenes with several 1,3-dipoles are given in Table 10.6 of Part A. Additional discussion of these reactivity trends can be found in Section 10.3.1 of Part A. 

Ethylzinc-enamine (95) undergoes a condensation reaction with aldehydes, affording ethylzinc-aldolates (equation 20). Such ethylzinc-aldolates are dimers, due to bridging of the aldolate-oxygen atoms between two zinc atoms. The structural features of this type of compounds will be discussed elsewhere in this chapter. 

Although it is a generally accepted classification of enamines as (i) primary, (ii) secondary and (iii) tertiary, it was not necessary to form separate sets comprising these types of enamines for two reasons. The first was that (i) contained only 7 and (ii) 18 entries, which are insufficient for statistical analysis in comparison with the tertiary enamines (iii 449 entries). The second reason was a lack of special structural features which would justify such a separate treatment, as it was found that primary and secondary enamines contribute to all the four classes (a)-(d). The structures of the compounds in set S together with their reference codes (REFCOD s) ascribed to crystal structures in CSDS and the appropriate reference are given in the Appendix at the end of this chapter. It should be noted that the number of published crystal structures is less than the number of entries (enamine fragments), because more than one fragment may occur in a particular molecule. 

The vast majority of enamine hydrolyses which have been investigated from the mechanistic point of view fit comfortably the mechanism given in Scheme 1. The sometimes convoluted pH-rate profiles are caused by changes in rate-controlling step from protonation at Cp, to nucleophilic hydration of the intermediate iminium ion, to breakdown of the carbinolamine addition product, probably via a zwitterion. The pH values at which changes in rate-controlling step occur are determined by a combination of structural features of the enamine and, in some cases, by the concentrations of buffer species which might be present these issues are discussed in the text. 

A number of comprehensive reviews of enamine and imine chemistry have appeared. Sections in other volumes of this series will concentrate explicitly on carbon-carbon bond forming reactions that use these species. They will be treated here mainly from the perspectives of methods for their formation and of their unique structural features. 

The reversal of facial selectivity was ensured by two rationally designed structural features i) the methyl substituent at C2, which imposes a fixed enamine conformation (Figure 11.4A) and ii) the distal carbo>ylic acid at C4, which successfully directs the facial-selective approach of the reagents (Figure 11.4B). 

Aldehydes and ketones react with primary amines to form azomethines which are usually known as Schiff bases, or sometimes, if the amine is aromatic, as anils. Stable Schiff bases are formed with aromatic aldehydes and with aliphatic and aromatic ketones, those formed from ahphatic aldehydes are often subject to aldol-type polymerization and are not suitable for group protection. The Schiff bases formed from aliphatic ketones are potentially tautomeric with the corresponding enamines, but they exist as azomethines unless there is some other structural feature present to stabilize the enamine form (section 2.1.3.2). The condensation reaction by which these derivatives are formed is acid-catalyzed and easily reversible, thus this method of oup protection is only applicable under neutral or alkaline conditions. The condensation using aromatic aldehydes or aliphatic ketones take place readily without solvent or in refluxing ethanol, those with aryl-alkyl or diaryl ketones may require catalysis or azeotropic removal of the water formed in the reaction. 

It is believed that monofunctional imidazolidinones are optimal for iminium catalysis but without the necessary structural features to participate in bifunctional enamine catalysis (e.g., activation of electrophiles via electrostatic interaction). Conversely, proline has proved to be an enamine catalyst for which bifunctional activation is a standard mode of operation aCTOss a variety of transformation types, yet it is generally ineffective as an iminium catalyst with enals or enones. Therefore, a combination of imidazoUdinone and proline may provide a dual-catalyst system that could fully satisfy the chemoselectivify requirements for cycle-specific catalysis [136]. 

Bifunctional nucleophilic reagents, such as ketones, enamines, / -diketones and their derivatives, amidines, thioureas, thioamides, dithiocar-bamates, and others, are very often employed in cyclizations with azine derivatives, resulting in the formation of annelated five-membered cycles (84UK1648 85KGS1011). The structure of all these 1,3-dinucleophiles feature a double bond conjugated with an anionic center or with a heteroatom bearing the lone pair of electrons (Scheme 5). 

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