Anchimeric process

No sooner than Wharton s landmark publications did Dodson of G. D. Searle discover a side reaction of the Wharton reaction.7 Treatment of 16a,17-epoxypregnenolone (9) with hydrazine hydrate resulted in not only the expected allylic alcohol 10 (ca. 25% yield), but also a small amount of pyrazole 11 (ca. 10% yield) as well. It was speculated that the mechanism involved an intramolecular Sn2 displacement of the epoxide by the diazene (the anchimeric process) followed by dehydration.8... 

This would render an overall process of Sn2 addition in an inverted fashion. In addition, from the model, it appeared that if such an anchimeric assistance indeed existed, Sn2 addition could proceed faster, whereas the SN2 addition pathway could be slowed or even suppressed because the ct c o (of the oxonium bond) is not aligned with the system of the C5a-C5 exo-cyclic olefin in the conformation assumed by 90 (see model). The following experiment would actually support this assertion. 

The direct interaction of the reaction center of a molecular entity with a lone pair of electrons of an atom within that same molecular entity that is not associated with the reaction center or, interaction of the reaction center with the reaction center nor conjugated with the reaction center. Rate acceleration by such a process is referred to as anchimeric assistance. See Intramolecular Catalysis Synartetic Acceleration. 

Halogen displacement from 2-halo-tetrahydropyrans and -hexahydropyrimidines is extremely easy, being assisted, in the SnI process, by the electron pairs on the heteroatom (equation 124). 3-Halohexahydropyridines can also show accelerated halogen displacement (anchimeric assistance from nitrogen equation 125). Apart from these and other (normal) substitutions, eliminations of H—Hal are also commonly found. 

Such a rearrangement is not observed with glycine, alanine, 2-aminobutanoic acid or 2-amino-3-cyclohexylpropanoic acid, occurs partially with valine and isoleucine, but is complete with phenylalanine, tyrosine and threonine. By analogy with previous dediazoniation studies on 2-amino acids in acidic media,309 this rearrangement has been explained by the anchimeric assistance of alkyl (Val, lie), aryl (f he, Tyr) or hydroxy (Thr) groups during the dediazoniation process 306 for example, in the case of phenylalanine (4). 

The second step (glycosylation step) should consist of a sterically uniform, high-yielding glycosyl transfer to the acceptor however, by a truly catalytic process, where diastereocontrol may be derived from the glycosyl donor anomeric configuration (by inversion or retention), by anchimeric assistance, by influence of the solvent, by thermodynamics, or by any other effects. 

The glycosylation is supposed to operate via a l,3-0-(/7-methoxy)-benzoxoniumion 37. This approach may be characterized as a 1,3-anchimeric assisted process in which the configuration at C-3 is responsible for the anomeric orientation. 

The solvolysis product distribution and the kinetic data (solvent effect33) m = 0.583 — 0.505, substituent effect34) q = —2.98) were clearly consistent with a SNj ionization process involving the anchimeric assistance of the triple bond (kA) 35) leading to the resonance stabilized cation 63 with its positive charge delocalized through the adjacent triple bond into the aryl (or cyclopropyl) group 13). 

The homogeneous unimolecular decomposition of o-hydroxy-2-phenvlethyl chloride yielded mainly benzodihydrofuran, HC1 and much less o-hydroxystyrene. The rate was significantly higher than that of phenylethyl chloride and ethyl chloride (Table 28). According to the nature of the product formation and the kinetic data, the OH provided anchimeric assistance in the elimination process. The mechanism proposed is described in equations 87 and 88. 

The stereochemical course of solvolysis of a diastereomeric /3-bromo-silane, which was found to be trans elimination, as well as the observation of 1,2-silyl group migration in a process of substitution at the 0 carbon 143) are evidence of anchimeric assistance of the silyl group in ionization of the bond to the /3 carbon. It was further noticed 144) that after quenching the solvolysis reaction of /3-bromo-/3-dideuterioethylsilane the substrate recovered is a mixture of a and /3 deuterated isomers [Eq. (33)]. These... 

Another way to obtain chiral clusters is to use mixed-metal systems (see Section II,A). Addition of acid to one of the two diastereomers of [WCo(/i-HC2CH(OH)Et)(CO)5Cp] leads to formation of two propargylium cations which do not isomerize in solution on the NMR time scale.75 Similarly, protonation of the separate diastereomers of [MoCo(/i-2-propynylborneol) (CO)5Cp] leads to formation of propargylium cations which are nonflux-ional. It has been shown that the diastereomer ratios for metal-stabilized cationic clusters can be directly correlated with the ionization process, and it is proposed that the elimination of water is anchimerically assisted by... 

Enamines are readily available ketone derivatives." Exposure of these compounds to certain transition metal salts has been shown to produce a-oxygenated imines which are rapidly hydrolyzed to their ketone counterparts. Thus, for example, morpholino enamines, prepared in situ, are a-acetoxylated on treatment with thallium triacetate. The process is thought to involve either direct nucleophilic extraction of an acetate unit or the intermediacy of an organothallium species which subsequendy undergoes anchimerically assisted intramolecular acetoxy migration to generate the a-acetoxyimine (Scheme IS). 

Substitution of complexed dienols (244) or dienol acetates with carbon or heteroatom nucleophiles, in the presence of a Lewis acid, occurs with retention of configuration (Scheme 69). (Alkyl aluminum reagents act as both nucleophile and Lewis acid in this process). This reaction is believed to proceed via stereospecific ionization, with anchimeric assistance from the iron, to generate the transoid pentadienyl cation (247) followed by attack of the weak nucleophile on the face opposite to iron. The cross-conjugated pentadienyl cation can also be generated the substitution of (2-acetoxymethyl-l,3-butadiene)Fe(CO)3 (193) has previously been discussed (Section 6.1.1). 

The Lewis acid catalyzed process is not applicable to aryl ketones, where ester products have been observed through aryl migration. Furthermore, anchimeric and solvent effects have been noted during oxidation of a 3-carboxy steroidal ketone. a-Oxygenation, although not inhibited, was altered. Despite the frequently disappointing yields the reagent has been widely used, particularly in the steroid field, and remains a useful, if not first choice , procedure. 

Intramolecular reactions are much faster than intermolecular reactions, and the anchimeric assistance, measured by the ratio of the rate constant of the unimolecular reaction to that of the analogous bimolecular reaction, depends strongly on the size of the ring that should be formed in the unimolecular process. The ratio of these constants can reach values of up to 10 mol/L. Thus, intramolecular trapping confirms the presence of radicals as short-lived intermediates but does not prove that chain growth proceeds via radical coupling. 

Exposure of this intermediate to potassium carbonate would first generate a carboxylate anion (VI), which in turn would be strategically located to interact with the very proximal axial proton, thus providing anchimeric assistance to the anti-dehydrobromination that ensues. The final consolidation of the lactone ring may be achieved by a 8 2 process that would cause the migration of the C=C bond to its final location. Moral Never underestimate the complexity of any reaction mechanism. Often, its intricacy will be directly proportional to the available experimental data. 

We have depicted the pinacol rearrangement as a two-step process with an actual carbonium ion as intermediate. There is good evidence that this is so, at least when a tertiary or benzylic cation can be formed. Evidently the stability of the incipient cation in the transition state permits (SNl-lihe) loss of water without anchimeric assistance from the migrating group. This is, we note, in contrast to what happens in migration to electron-deficient nitrogen or oxygen. 

Reaction of the cis tosylate is much slower than that of cyclohexyl tosylate, and this we can readily understand powerful electron-withdrawal by acetoxy slows down formation of the carbonium ion in the SnI process. Reaction of the trans tosylate, although much faster than that of its diastereomer, is still somewhat slower than that of cyclohexyl tosylate. But should not the anchimerically assisted reaction be much faster tlian the unassisted reaction of the unsubstituted tosylate The answer is, not necessarily. We must not forget the electronic effect of the acetoxy substituent. Although SN2-like, attack by acetoxy has considerable SnI character (see Sec. 17.15) deactivation by electron withdrawal tends to offset activation by anchimeric assistance. The cis tosylate is electronically similar to the trans, and is a much better standard by which to measure anchimeric assistance. (This point will be discussed further in the next section.)... 

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