Iminium-enamine approaches

In fact, this intramolecular version shortly preceded the intermolecular one discussed above, since the first example was disclosed by Kunz and MacMillan in 2005 [89], shortly followed by Jprgensen and co-workers [90]. This approach has proved to be highly versatile, leading to practical enantioselective syntheses of chiral cyclopropanes [89, 91], epoxides [90], and aziridines [92]. Finally, the use of bifunctional synthons in sequential iminium/enamine catalysis provides a very general entry to carbo- and heterocyclic compounds [93]. 

It has been shown in this chapter that combined iminium-enamine catalyzed approaches offer the potential to achieve complex (multistep) transformations in a single operational step, thus giving access to high structural complexity combined with excellent effectivity. In addition, it was pointed out also that organocatalysis can be used successfully when combined with metal catalysis e.g. metathesis). Although these complex approaches have been pursued only for the last few years, the results obtained so far are very promising and thus this methodology should be applied more widely in the future (Table 3). 

ReaxFF, a reactive force-field approach, has been used to model the iminium-enamine conversion in the proline-catalysed self-aldol of propanol. " " Quantum mechanical methods have been used to study the same step in the proline-catalysed aldol. " ... 

Jprgensen and coworkers exploited an approach in 2005 by designing a three-component reaction involving iminium/enamine activation (Scheme 2.23). They demonstrated that thiols 84 can initiate the sequence by a thia-Michael addition to... 

Our theoretical investigation regarding the understanding of the conversion of iminium into enamine in the framework of a proline-catalyzed aldol reaction emphasizes that the reactive force field (FF), ReaxFF, used in combination with molecular dynamics (MD) simulations is a relevant method to investigate the mechanism of proton transfers in iminium-enamine conversions. This approach should be extended to model other steps of proline-catalyzed... 

According to the proposed transition state model of the reaction, the enamine approaches the iminium cation from the opposite side of the bulky diphenyl-Trimethylsilyloxy (OTMS) group (Figure 40.17). 

Other classical synthetic approaches to 2-furanamine have failed, including the Curtius method and Beckmann rearrangement of 2-benzoylfuran oxime. However, hydrazinolysis of AT-(2-furyl)phthalimide, obtained from phthalimide and 2,5-dimethoxy-2,5-dihy-drofuran, gives 2-furanamine which was not isolated but detected by GLC-MS and H NMR spectroscopy. The latter reveals the absence of imino tautomers (75AP713). The chemistry of 2-dialkylamino-5-phenylfurans is typical of enamines protonation occurs on carbon to produce iminium salts. They are stable to base but afford 5-phenylfuran-2(3//)-one on hydrolysis with dilute acid. 2-Morpholino-5-phenylfuran couples with diazonium salts and affords Diels-Alder adducts with maleic anhydride and IV-phenylmaleimide (73JCS(P1)2523). 

Indeed, the iminium formate intermediates are approached by hydride from the more accessible side of the molecule. A similar result had been obtained by Noyce and Bachelor203 for the enamines of 2-methylcyclohexanone. 

In 1996, the same group 87) reported further work on the synthesis of indole analogues of the cephalotaxine ring system (Scheme 52). The key intermediate in this ring-expansion approach, bromoiminium ion 300, was prepared in three steps from tryptamine and the chloro diester 298 via enamine 299. On treatment with several bases, the iminium ion 300 underwent rearrangement, presumably via the intermediate alkoxide 301, to give the azepinone derivative 302, which was reduced with sodium borohydride to a mixture of isomeric alcohols 303. The alcohols 303 underwent rapid intramolecular cyclization when treated with a 95% solution of sulfuric acid to yield pentacyclic ketone 304. 

Another classical approach to 3-carbolines involves Bischler-Napieralski reaction of indoles, the intramolecular cyclization of iminium chlorides derived from tryptamides. Triphenylphosphite proved to be a mild reagent capable of promoting this reaction <05SL661>. The cyclization of ketene iV,S-acetals derived from tryptamine produced push-pull P-carboline enamines <05SL309>. 

When reviewed in CHEC-I some examples of cyclization y to the heteroatom had been described for the synthesis of pyridazines, but the method was of most importance in the synthesis of cinnolines. Examples of pyridazine syntheses included cyclization of ketazines with EDA, and intramolecular Wittig reactions of phosphoranes derived from phosphacumuleneneylides and the hydrazones produced from 1,3-dicarbonyl compounds and aryldiazonium salts. Synthetically useful approaches to cinnolines given include the intramolecular Friedel-Crafts acylation of the diacid chlorides derived from the condensation products of aryldiazonium salts and diethyl malonate to give 4(l//)-cinnolinones, and thermal cyclization of iminium hydrazones obtained from enamine esters and aryldiazonium salts. 

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