Ketene addition, nucleophilic additions

A differentiation between 8.100 and 8.101 is possible on the basis of theoretical investigations on the addition of water to ketenes. Such nucleophilic additions were... 

Nucleophilic Addition. Reagents with labile hydrogen atoms, such as alcohols, thiols, phenols, carboxyHc acids and amines, add to ketenes giving the corresponding carboxyHc acid derivatives (1) as shown ia Figure 1 (38). Not many are of practical importance, as there are better ways to such... 

Ketenes undergo rapid addition by nucleophilic attack at the sp-carbon atom. The reaction of tertiary amines and acyl halides, in the absence of nucleophiles, is a general preparation for ketenes. ... 

Photodriven reactions of Fischer carbenes with alcohols produces esters, the expected product from nucleophilic addition to ketenes. Hydroxycarbene complexes, generated in situ by protonation of the corresponding ate complex, produced a-hydroxyesters in modest yield (Table 15) [103]. Ketals,presumably formed by thermal decomposition of the carbenes, were major by-products. The discovery that amides were readily converted to aminocarbene complexes [104] resulted in an efficient approach to a-amino acids by photodriven reaction of these aminocarbenes with alcohols (Table 16) [105,106]. a-Alkylation of the (methyl)(dibenzylamino)carbene complex followed by photolysis produced a range of racemic alanine derivatives (Eq. 26). With chiral oxazolidine carbene complexes optically active amino acid derivatives were available (Eq. 27). Since both enantiomers of the optically active chromium aminocarbene are equally available, both the natural S and unnatural R amino acid derivatives are equally... 

The cycloaddition between a nitrilimine 319 and an aroyl substituted heterocyclic ketene aminal 318 has been found to be stepwise, involving an initial nucleophilic addition of 318 to 319 followed by intramolecular cyclocondensation of the intermediate 320 providing fully substituted pyrazole 321 (Eq. 36) [92]. When Ar was the 2,4-dinitrophenyl group, the intermediate 320 was isolable and required forcing conditions (xylene, reflux, 10 h) to undergo cyclization ... 

Addition of Ketene Acetals and Enoles In recent years, much attention has been given to the synthesis of optically active nitrogen-containing compounds, with the key step being the highly stereoselective nucleophilic addition of ketene silyl acetals to nitrones (Scheme 2.174). Similar to nitrone cyanations, in ketene silyl acetal reactions one observes an accelerating effect with thiourea derivatives (633). 

As demonstrated in a series of kinetic experiments by Wittkopp and Schreiner, nitrone N-benzylideneanihne N-oxide can be activated for 1,3-dipolar cycloadditions through double hydrogen-bonding 9 [Ij. Takemoto and co-workers, in 2003, published the nucleophilic addition of TMSCN and ketene silyl acetals to nitrones and aldehydes proceeding in the presence of thiourea organocatalyst 9 (Figure 6.4) [147]. 

Reaction of crowded chromium alkenyl Fischer carbene (50) with bulky ketene acetals provides an interesting entry to 3-substituted pent-l-ynoate (53)45 Formation of the alkyne can be rationalized by a 1,4-nucleophilic addition of the ketene on the unsaturated carbene complex (crowded complexes will not undergo potential 1,2-addition), following by oxonium (51) formation and fragmentation to a vinylidene carbene complex (52), which undergoes a 1,3-shift to the alkynylchromium complex leading the alkyne after reductive elimination. 

The molecular mechanisms for the nucleophilic addition of lithium enolates and silyl ketene acetals to nitrones in the absence and in the presence of a Lewis acid catalyst to give isoxazolidin-5-ones or hydroxylamines have been investigated by DFT methods at the B3LYP/6-31G level.13 An analysis of the global electrophilicity of the reagents accounts for the strong electrophile activation of the Lewis acid-coordinated nitrone, (g) and the analysis of the local indices leads to an explanation for the experimentally observed regioselectivity. 

A nucleophilic addition of bis(TMS) ketene acetals to pyridines (223), aided by acylation of the pyridine nitrogen with methyl chloroformate, has been reported to produce the 1,4-adduct (224).264... 

Regioselectivity control in the double nucleophilic addition of ketene silyl acetals to a-unsaturated imines has been reported.85... 

The regioselectivity of the double nucleophilic addition of ketene silyl acetals to a,/3-unsaturated imines has been found to be highly dependent on the subtle difference in the reactivities of the ketene silyl acetals the factors are mainly derived from the ability of the ketene silyl acetals to undergo the silicon-aluminium exchange reaction, where the aluminium enolate preferentially undergoes 1,4-addition.209... 

We must here anticipate a little and use some concepts developed in the following chapters. If the reaction is considered as a nucleophilic addition of the alkene to the ketene, the alkene should attack the central atom of the ketene, making an obtuse angle with C=0 (p. 144). If it is considered as an electrophilic addition of ketene on the alkene, the central atom of the ketene should attack the double bond on its center... 

Intermolecular addition of carbon nucleophiles to the ri2-pyrrolium complexes has shown limited success because of the decreased reactivity of the iminium moiety coupled with the acidity (pKa 18-20) of the ammine ligands on the osmium, the latter of which prohibits the use of robust nucleophiles. Addition of cyanide ion to the l-methyl-2//-pyr-rolium complex 32 occurs to give the 2-cyano-substituted 3-pyrroline complex 75 as one diastereomer (Figure 15). In contrast, the 1-methyl-3//-pyrrolium species 28, which possesses an acidic C-3-proton in an anti orientation, results in a significant (-30%) amount of deprotonation in addition to the 2-pyrroline complex 78 under the same reaction conditions. Uncharacteristically, 78 is isolated as a 3 2 ratio of isomers, presumably via epimerization at C-2.17 Other potential nucleophiles such as the conjugate base of malononitrile, potassium acetoacetate, and the silyl ketene acetal 2-methoxy-l-methyl-2-(trimethylsiloxy)-l-propene either do not react or result in deprotonation under ambient conditions. 

The use of substituted pyridines in organic synthesis has broad application. The activation of the pyridine ring toward nucleophilic attack is well known in the literature. The products of such reactions are often dihydropyridines which can serve as intermediates in more complex synthetic strategies. Rudler and co-workers have reported on the nucleophilic addition of bis(trimethylsilyl)ketene acetals to pyridine (26). The 1,4-addition product 27 was then cyclized with iodine to afford bicycle 28 in 90% overall yield <02CC940>. Yamada has elegantly shown that facial selectivity can be achieved and chiral 1,4-dihydropyridines accessed in high yield and de (29—>30) <02JA8184>. 

Crotyltins react regioselectively with a-alkylimines to give exclusively branched products with an excellent syn/anti selectivity up to 30 1, when the imine activation is conducted at —78 °C prior to the addition of the crotyltin. This selectivity which is consistent with an acyclic transition state is rapidly fading when operating at a higher temperature. This would be the result of an equilibrium between the two imine/Lewis acid complexes (equation 14). There are very few examples with a, /3-unsaturated aldimines, but it has to be noted that under TiCU activation, they are able to undergo a double nucleophilic addition of ketene silyl acetal and allyltributyltin to give the homoallylic amine in a reasonable yield . 

The chemistry of iron vinylidene complexes is dominated by the electrophilicity of the carbon atom adjacent to the iron organometallic unit. While addition of water leads to an acyl complex (i.e., the reverse of the dehydration shown in equation 10), addition of an alcohol leads to a vinyl ether complex. Similarly, other iron vinyl complexes can be prepared by the addition of thiolate, hydride, or an organocuprate (Scheme 33). " The nucleophilic addition of imines gave enaminoiron intermediates that could be further elaborated into cyclic aminocarbenes. This methodology has been used to provide access to /3-lactams and ultimately penicillin analogs, and good diastereoselectivities were observed (6 1-15 1) (Scheme 34). 04 Iso, vinylidene complexes are intermediates in cyclizations of alkynyl irons with substituted ketenes, acid chlorides, and related electrophiles an example is shown (equation 11). These cyclizations led to the formation of a series of isolable and characterizable cyclic vinyl iron complexes. 

The (dienyl)iron cations of type (248) and (265) are susceptible to reaction with nucleophiles. For the (cyclohexadienyl)iron cations, nucleophilic attack always occurs at a terminal carbon, on the face of the ligand opposite to the metal, to afford / -cyclohexadiene products. Typical nucleophiles used are malonate anions, amines, electron-rich aromatics, silyl ketene acetals, enamines, hydrides, and aUyl silanes intramolecular nucleophilic addition is also possible. The addition of highly basic organometaUic nucleophiles (Grignard reagents, organolithiums) is often problematic this may be overcome by replacing one of the iron carbonyl... 

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