Ketene A,0-acetals

N-Methylation of 139 with iodomethane in nitromethane afforded 2,3,4,4,6-pentamethyl-5,6-dihydro-4/7-oxazi-nium iodide 140. Deprotonation of 140 with sodium hydride resulted in formation of the cyclic ketene-A, 0-acetal derivative tetrahydro-l,3-oxazine 141 (Scheme 21) <2006JC0262>. 

A study of ketene A, O-acetals has shown that such compounds derived from lactam acetals may be used in the preparation of larger heterocyclic systems via reaction with a 1,3-dipolar species, the initial cycloadducts stabilizing their structures by aromatization. Pyrrolo[2,3-i/]-l,2,3-triazole derivatives, however, do not undergo such elimination reactions and stable cycloadducts may be obtained. Thus, the lactam acetals (133) give the ketene A,0-acetals (134), which on reaction with p-nitrophenyl azide yield substituted pyrrolo[2,3-d]-l,2,3-triazole derivatives (135) <86CB359l>. 

Non-catalyzed aldol reactions via hypervalent silicon species have also been studied. An aldol reaction between aldehydes and silyl enol ethers of amides was reported by Myers [105]. The reaction can be conducted under mild conditions to produce anti aldol without Lewis acid or base catalysts (Sch. 62). Asymmetric induction was particularly high when the (Z)-silyl ketene A/,0-acetal derived from prolinol was used. 

The [4-1-2] cycloaddition of dimethyl-1,2,4,5-tetrazine-3,6-dicarboxylate 41 with ketene A,0-acetals or cyanamide yielded tetrafunctionalized pyridazines 42 or 1,2,4-triazine 43 respectively. Treatment of 42-43 with zinc dust in AcOH afforded pyrrole 44 or imidazole 45 derivatives <06S 1513>. 

The 3,3-sigmatropic shift of ketene A, 0-acetals, first developed by Eschenmoser, preceded studies of the ynamine-Claisen rearrangement, where the reactive intermediate is formed at ambient tempera-... 

Ketene 0-acetals are converted to 1,1-enediamines when reacted with amines. For example, compound 45 has been prepared by substitution of the methoxy with amine (equation 16). Symmetric 1,1-enediamines are obtained when both the alkoxy and the amino substituents are displaced by the amine employed In this way, the reaction between ketene 0-acetals 50 and piperidine leads to 1,1-dipipetidinoethylene (35) (equation 17) Alternatively, 35 can be prepared from the reaction of piperidine with triethyl orthoacetate or with ethoxyacetylene , reactions which probably proceed via a ketene A, 0-acetal intermediate. 

Allyl A -phenylimidates are known to undergo thermal rearrangement to y.d-unsaturated anilides via their ketene A 0-acetal isomers250,231. The palladium(II)-mediated rearrangement preferentially leads to T -double-bond geometry, but decreased selectivities are observed in the case of an electron-donating substituent in position 2 of the pericyclic system, as in the rearrangement of 1361 and 2126. 

Holmes has also reported an interesting route to synthesise ketene a 0-acetals starting with phenylselenyl acetal 286. In the example, transacetalization of 285 with aminoalcohol derivative 284 results phenylselenyl A, 0-acetal 286. Selenoxide formation and syn-elimination... 

Vinyl sulfoxides containing an a-trimethylsilyl group, for example as 1197, rearrange on heating in benzene to give the vinyl sulfoxide 1198 in up to 19% yield, the acetylene 1199 in 37% yield, and the ketene-S,0-acetal 1200 in 32% yield [25] (Scheme 8.8). 

Cycloaddition of dimethyl l,2,4,5-tetrazine-3,6-dicarboxylate with EWG-substituted primary ketene N,0-acetals provides a tetrasubstituted pyridazine, methyl 4-amino-5,7-dioxo-6,7-dihydro-5/7-pyrrolo[3,4-4pyridazine-3-carboxylate <200681513>. 

Decomposition of a-diazo ketoamides 208 in the presence of substituted propiolic esters gives spirocyclic oxiranes 209. The reaction involves intramolecular addition of a rhodium carbenoid onto the oxygen atom of the amide group to yield the carbonyl ylide, which, after 1,4-H-migration, produces a cyclic ketene N,0-acetal 210. The latter further reacts with the activated triple bond of the dipolarophile to form a zwitterionic intermediate and, finally, a spirocycloadduct (Scheme 26) (90JA2037). 

Investigation of the reaction of l,l-bis(dimethylamino)ethylene 4, ketene IV,S- or iV,0-acetals, with 1,2,4-triazines and 1,2,4,5-tetrazines has been conducted by Muller and Sauer Unlike ketene, N,S- or A, 0-acetals, 1,1-enediamine 4 leads to both... 

Due to the interaction between the two amino groups, 1,1-enediamine 4 would adopt a perpendicular conformation which impairs attack on the 7i-system from both sides of 4. If 1,1-enediamine 4 would have a planar configuration, it would show greater reactivity than ketene N,S- or JV,0-acetals. This has been convincingly demonstrated by comparing the reactivity of l,3-dimethyl-2-(methylene)imidazoline (3) with 4, and with ketene N,S- or A, 0-acetals. 

Under kinetic control 1-(diethylamino)-l-propyne preferentially adds alcohols syn to hydrogen. If the reaction is carried out at room temperature in the presence of a Lewis acid, fast equilibration of ketene A2,0-acetals occurs and the rearrangement proceeds via the thermodynamically favored (Z)-isomer. Slow addition of allylic alcohols at 140 °C suppresses the rapid equilibration thus making the rearrangement of the kinetic ketene, Y,0-acetal intermediate competitive with cisitrans isomerization to the thermodynamically more stable intennediate, e.g.. formation of 14 and 15 (Table 9). 

Allyl W-phenylimidates rearrange upon heating in refluxing decalin at 190 °C to give ,<5-unsat-urated anilides in moderate diastereoselectivitics, probably due to nonstereoselective formation of the ketene /V,0-acetal intermediates, e.g., formation of 1 and 2250. The diastereoselectivities are opposite to those observed in Vleerwein- Eschenmoser rearrangements (cf. p 3406). Products with a syn relationship predominate in the rearrangement of allyl W-phenylimidates derived from. E-allylic alcohols. 

Alkoxythioenolethers a, P-Ethylenesulfoxides Ketene S,0-acetals a-Sulfoniooxo compds. 

The Meerwein-Eschenmoser-Claisen rearrangement is one of the most useful pericyclic reactions. In its basic form, it involves the conversion of an allylic alcohol 1 to a ketene N, 0-acetal 2, which undergoes rapid [3,3]-sigmatropic rearrangement to yield a y,d-unsaturated amide 3 (Scheme 7.1). In accordance with the general electronic effects observed in Claisen rearrangements, the presence of an electron-donating amino substituent on the ketene acetal intermediate substantially increases the rate of the pericydic step. 

Several variants of the Meerwein-Eschenmoser-Claisen rearrangement have been reported, which mostly differ in the way the ketene N,0-acetal intermediate is formed. Following a review of this aspect, the regjo- and stereoselectivity of the reaction is discussed. Finally, the usefulness of the reaction in the synthesis of complex target molecules is highlighted using selected examples, mostly from natural product syntheses. 

Shortly after Meerwein s and Eschenmoser s original reports, Ficini disclosed the use of ynamines as suitable precursors of aUyhc ketene N,0-acetals (Scheme 7.8) [10, 17]. AUyhc alcohols add to ynamines (15) either in the presence of catalytic amounts of a Lewis acid, for instance BFj-OEtj, or at elevated temperatures. This addition presumably proceeds through the intermediacy of a keteniminium ion 16. The resulting ketene N,0-acetals then undergo the sigmatropic rearrangement to yield the corresponding amides. 

The issue of simple diastereoselectivity arises when both the allyl and vinyl moieties of the ketene N,0-acetal intermediate 2 are substituted at their terminus, leading to vicinal stereocenters in the products (Scheme 7.22). In analogy to the aldol reaction, the stereochemical outcome can be predicted in terms of a Zimmermann-Traxler type chair-shaped transition state. Accordingly, the synlanti ratio of the products depends on double bond geometry. Whereas the geometry of the unsaturated alcohol is pre-determined and usually not subject to equilibration, the geometry of the ketene N,0-acetal moiety depends on the reaction conditions that lead to its in situ formation. 

In the case of substituted ketene N,0-acetals formed through equilibria, for instance under the classical Eschenmoser conditions, the thermodynamically more stable (Z)-ketene N,0-acetal 61a is preferentially formed to avoid aUyUc strain between residue R and the bulky dimethylamine moiety (Scheme 7.22). Invoking a chair-shaped transition state, the anti-isomer is then formed from an (E)-allylic alcohol in the course of the sigmatropic rearrangement. Note that transition states 61a and 61b are diastereomers and not conformational isomers. 

Scheme 7.23 illustrates the diastereoselectivities observed under various conditions in the synthesis of 2,3-dimethyl pent-5-enamides from ( )-2-buten-l-ol [11, 14, 25, 26, 47]. The anti isomer usually predominates with the exception of the thermal Ficini-Claisen variant (Scheme 7.23, Eq. 2) [18]. In this case, slow addition of the allylic alcohol to the ynamine at elevated temperatures resulted in a 1 2 mixture of aniv.syn products. This result can be explained by assuming that addition of the alcohol to the ketene iminium intermediate (cf 16, Scheme 7.9) occurs from the less hindered side and results in the preferential formation of the (E)-ketene N,0-acetal. This kinetic intermediate then undergoes rearrangement...

In the light of the emergence of morpholine amides as substitutes of Weinreb amides, a direct incorporation of the former in the Eschenmoser-Claisen product is strategically attractive for synthesis. Traimer and coworker have treated allylic alcohol 290 with jV,jV-morpholine acetal 289 at high temperature, generating in situ the ketene iV, 0-acetal which smoothly rearranged to morpholine amide 291. ° ... 

Tsunoda has rationalized a role for chelation with preferential formation of the Z-enolate 397 from Y-crotyl glycolamide 395 and glycinamide 396. At elevated temperature, the (. -ketene iV, 0-acetal 397 exhibits a facile aza-Claisen rearrangement with excellent syn selectivity. ... 

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