Acyclic enamines

Dimethyl acetylenedicarboxylate (80) undergoes initial 1,2 cycloaddition with acyclic enamines to form cyclobutene intermediates which immediately decompose into acyclic dienaminodiesters (94,95). When an acyclic n/c-enediamine is used instead of a simple acyclic enamine, a dienediamino-diester is produced via a cyclobutene intermediate (95a). A cyclization reaction of dimethyl acetylenedicarboxylate with an acyclic enaminoketone... 

The reaction of methyl propiolate (82) with acyclic enamines produces acyclic dienamines (100), as was the case with dimethyl acetylenedicarboxylate, and the treatment of the pyrrolidine enamines of cycloheptanone, cyclooctanone, cycloundecanone, and cyclododecanone with methyl propiolate results in ring enlargement products (100,101). When the enamines of cyclohexanone are allowed to react with methyl propiolate, rather anomalous products are formed (100). The pyrrolidine enamine of cyclopentanone forms stable 1,2-cycloaddition adduct 83 with methyl propiolate (82). Adduct 83 rearranges to the simple alkylation product 84 upon standing at room temperature, and heating 83 to about 90° causes ring expansion to 85 (97,100). 

Many acyclic enamines form thioamides when they are allowed to react with elemental sulfur at room temperature in dimethylformamide solvent 138). They also produce cyclic 1,3-dithiole by-products, which become main products at higher temperatures 135). For example, the reaction of l-(N-morpholino)-l-phenylethene (106) and sulfur in dimethylformamide solvent yields 1,3-dithiole 107. 

The reduction of enamides (62-73) has been applied primarily to the synthesis of cyclic enamines (74-76), but also to acyclic enamines (77). 

The addition of secondary amines to acetylenes is most applicable to the synthesis of conjugated acyclic enamines (50,171,172). Particularly the addition to acetylenic esters and sulfones has been investigated (173-177) and it appears that an initial trans addition is followed by isomerization to more stable products where the amine and functional group are in a trans orientation (178). Enamines have also been obtained by addition of secondary amines to allenes (179). 

Thus the reactions of cyclic or acyclic enamines with acrylic esters or acrylonitrile can be directed to the exclusive formation of monoalkylated ketones (3,294-301). The corresponding enolate anion alkylations lead preferentially to di- or higher-alkylation products. However, by proper choice of reaction conditions, enamines can also be used for the preferential formation of higher alkylation products, if these are desired. Such reactions are valuable in the a substitution of aldehydes, which undergo self-condensation in base-catalyzed reactions (117,118). Monoalkylation products are favored in nonhydroxylic solvents such as benzene or dioxane, whereas dialkylation products can be obtained in hydroxylic solvents such as methanol. The difference in products can be ascribed to the differing fates of an initially formed zwitterionic intermediate. Collapse to a cyclobutane takes place in a nonprotonic solvent, whereas protonation on the newly introduced substitutent and deprotonation of the imonium salt, in alcohol, leads to a new enamine available for further substitution. 

Additions to acyclic enamines (337,343), to 1,1-dipiperidinoethylene (344), and to the analogous ethoxydimethylaminoethylene (344) gave products derived from ring cleavage of an initially formed cyclobutene adduct. 

This catalytic system can be used for the kinetic resolution of di-substituted 1-pyrrolines, for which high ee-values are achieved for both the amine and the recovered materials, especially when they are substituted in positions 2 and 5 (Table 6.6) [111]. Moreover, it should be noted that acyclic enamines are converted with high ee-values into their corresponding amines (89-98% ee Table 6.7), which is in sharp contrast to what is obtained for acyclic imines (vide supra) [112]. 

Scheme 15 Asymmetric hydrogenation of cyclic and acyclic enamines...

Guertler et al. (1996) described a wide range of cycloaddition reaction between 2-vinyl indoles acting as heterodienes and cyclic or acyclic enamines bearing acceptor groups in (3 positions. The reaction was induced by the formation of 2-vinylindole cation-radicals through anodic oxidation. The synthesis of 4a-carbomethoxy-6-cyano-5,7-dimethylindolo[l,2-a]-l,2,3,4,4a,12a-hexahydro-1,8-naphthyridine can serve as an example (Scheme 7.24). 

Salicylaldehyde also reacts with enamines to form chromans, although these have not usually been isolated but rather have been oxidized directly to a chromone (66JOC1232). The synthesis has been applied to both cyclic and acyclic enamines and to 2-hydroxy-1-naphthaldehyde. The initial intermediate undergoes an intramolecular cyclization involving participation of the neighbouring hydroxyl group. 

TABLE 1. 13C NMR chemical shifts [<5TMS (PPm)] for primary and tertiary acyclic enamines... 

TABLE 7. 15N-NMR chemical shifts [<5CH315N02 (ppm)] for acyclic enamines in 80% v/vC6D6... 

The proton chemical shifts and coupling constants for a number of simple acyclic enamines are collected in Tables 11 and 12, respectively. Data collected in previous reviews that will be useful when discussing more complex enamines have been included. 

TABLE 10. Coupling constants, J (in Hz), from 15N-NMR spectra of simple acyclic enamines... 

The addition of ynamines to unsaturated systems provides access to a variety of cyclic and acyclic enamine systems232-234 (equation 13). 

Carlson and Rappe229-232 have studied the bromination of unsymmetrical acyclic enamines and a number of interesting facts have emerged. At — 78°C the enamines are converted rapidly into the a-bromoiminium salts (92 and 97) which are stable towards further bromination consequently the yields of dibromoketone are low at this temperature and hydrolysis gives a-bromoketones (94 and 100). At room temperature, or in the presence of added base (Me3N), dehydrobromination occurs to give bromoenamines (93 and 98) and, after further bromination, gives a,a- and a,a -dibromoketones (95 and 102). The yield of 94 far exceeds the amount of the less substituted enamine (91a) present in the equilibrium mixture of enamines, and is even formed (to the extent of 14%) when a pure sample of the more substituted enamine (91b) is brominated. This result was explained, not by displacement of the enamine equilibrium (91a 91b), but by de-... 

The most remarkable feature of this method is that even acyclic enamines undergo reductive alkylation with good diastereoselectivity. The reaction of propiophenone enamines 31-33 with primary carbon-centered radicals substituted by different electron-... 

Acyclic enamines give diazetidines with dimethyl diazenedicarboxylate, e.g., formation of 9. when hydrogen abstraction and ene reaction can be suppressed18, but from the less nucleophilic A -vinylpyrrolidinone the oxadiazine 10 is obtained16. 

It is clear that the considerable limitations noted by Verboom and Rein-houdt were largely due to the constraints imposed by the benzene or enami-nic ring. In Viehe s work on acyclic enamine reactions, the broad range of enamine bases, the ease of cyclization even in the absence of a-EWG groups, and the variation in product stereochemistry, all would appear to be the result of removing these constraints. Clearly, much remains to be done to exploit these observations fully. 

---