Azomethine ylides cycloaddition” sequence

The reaction mechanism proposed for the LiBr/NEta induced azomethine ylide cycloadditions to a,p-unsaturated carbonyl acceptors is illustrated in Scheme 11.10. The ( , )-ylides, reversibly generated from the imine esters, interact with acceptors under frontier orbital control, and the lithium atom of ylides coordinates with the carbonyl oxygen of the acceptors. Either through a direct cycloaddition (path a) or a sequence of Michael addition-intramolecular cyclization (path b), the cycloadducts are produced with endo- and regioselectivity. Path b is more likely, since in some cases Michael adducts are isolated. 

Like other 1,3-dipoles, azomethine ylides were mostly utilized in the ring construction of five-membered nitrogen heteroaromatics by a sequence of cycloadditions to acetylenes and formal oxidation. Thus, azomethine ylides were employed as the synthetic equivalents of nitrile ylides. Other synthetic applications of azomethine ylides, especially the intended utilization of stereochemical characteristics of the azomethine ylide cycloadditions, were quite rare. 

Spirooxindoles, such as, for example ( )-coerulescine (101) have been prepared employing a sequence starting from 2-fluoronitrobenzene, which was initially subjected to treatment with the anion of dimethyl malonate, followed by decarboxylation and concomitant installation of the methylene group using formaldehyde in the presence of potassium carbonate to produce the intermediate 102 in good yield. This material readily underwent dipolar cycloaddition with the azomethine ylide generated from sarcosine and formaldehyde, followed by a reductive cyclization of adduct 103 to furnish the natural product 101 <02TL9175>. 

Surprisingly, the indolizidine aziridine 39 was synthesized in 88% yield, but was found to be an uncatalyzed reaction, providing the product upon diazo-transfer at 0°C to oxime 37. Two plausible mechanisms are invoked for this carbene reaction sequence (1) a carbenoid insertion process or (2) collapse of the azomethine ylide formed upon addition of the diazoamide. The uncatalyzed process is likely due to a dipolar cycloaddition of the diazo and pendent oxime. 

Achiwa reported a short synthesis of pyrrolizidine derivatives by the cycloadditions using a nonstabilized azomethine ylide 23 (m = 1) (82CPB3167). When the trimer of 1-pyrroline is treated with a silylmethyl triflate, N-alkylation of the 1-pyrroline takes place. Then the resulting iminium salt is desilylated with fluoride ion in the presence of ethyl acrylate to give ethyl pyrrolizidine-l-carboxylate 295 as a mixture of stereoisomers (28%). After the epimerization of 295 with LDA, the ester moiety is reduced with lithium aluminum hydride in ether to provide (+ )-trachelanthamidine (296). A double bond can be introduced into 295 by a sequence of phenyl-selenylation at the 1-position, oxidation with hydrogen peroxide, and elimination of the selenyl moiety. The 1,2-dehydropyrrolizidine-l-carboxylate 297 is an excellent precursor of (+ )-supinidine (298) and (+)-isoretronecanol (299). Though in poor yield, 297 is directly available by the reaction of 23 with ethyl 3-chloropropenoate. 

One of the most appealing aspects of these multicomponent syntheses is the reactivity of the components. Often, the reaction sequence commences without the aid of external catalysts and still preserves selectivity. However, sometimes the reactive center is created in situ, which does require the assistance of an external catalyst. Transition metals, for instance, can be effectively used to induce reactivity, like in the synthesis of another viral protein inhibitor. The work of Garner and coworkers provided a new route to the core of a novel influenza neuramidase inhibitor in one pot [38]. The [C -I- NC -I- CC] coupling reaction proceeds via a metalated azomethine ylide by condensation of the amine 134 and aldehyde 132, which undergoes a [3 -l- 2] cycloaddition with activated dipolarophile 133 (Scheme 14.17). 

Zhang et al. (2006) have reported an advance fluorous synthesis of hydantoin-, piperazinedione-, and benzodiazepinedione-fused tricyclic and tetracyclic ring systems using a sequence of microwave-assisted, fluorous multicomponent reactions (F-MCRs) and fluorous solid-phase extractions (F-SPEs). They used microwave-assisted one pot, three-component [3+2] cycloaddition of azomethine ylides with... 

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