Alkoxides, intramolecular addition

It is interesting to note that the oxa-analogous Michael addition was reported for the first time in 1878 by Loydl et al. [19] in their work on the synthesis of artificial malic acid, which was five years ahead of the discovery of the actual Michael reaction described first by Komnenos [20], Claisen [21], and later Michael in 1887 [22] as one of the most important methods for C—C bond formation. In continuation of the early work on the oxa-Michael addition [23], the inter- and intramolecular additions of alkoxides to enantiopure Michael acceptors has been investigated, leading to the diastereo- and enantioselective synthesis of the corresponding Michael adducts [24]. The intramolecular reaction has often been used as a key step in natural product synthesis, for example as by Nicolaou et al. in the synthesis of Brevetoxin B in 1989 [25]. The addition of oxygen nucleophiles to nitro-alkenes was described by Barrett et al. [26], Kamimura et al. [27], and Brade and Vasella [28]. 

For less acidic alcohols, nucleophilic participation is ineffective because of the low tendency for such alcohols to function as leaving groups. The tetrahedral intermediate formed by intramolecular addition simply returns to starting material because the carboxylate is a much better leaving roup than the alkoxide. In contrast to aspirin itself, acetyl salicylates with electron-withdrawing groups (o- and p-nitro analogs) hydrolyze via the nucleophilic catalysis mechanism. ... 

Cross [3+2] annulation of cyclopropyl ketones with enones occurred under similar conditions when using titanium(IV) alkoxides as additives (Scheme 2.82). Cyclopropyl aldimines also underwent analogous annulation [135]. Intramolecular cyclopropyl ketone-alkene [3+2] annulation was achieved using a photocatalytic system comprising Ru(bpy)3 (bpy = 2,2 -bipyridyl), La(OTf)3 (Tf = trrfluoromethanesulfonyl, and TMEDA (tetramethylethylenediamine) [136]. 

The TT-allylpalladium complexes 241 formed from the ally carbonates 240 bearing an anion-stabilizing EWG are converted into the Pd complexes of TMM (trimethylenemethane) as reactive, dipolar intermediates 242 by intramolecular deprotonation with the alkoxide anion, and undergo [3 + 2] cycloaddition to give five-membered ring compounds 244 by Michael addition to an electron-deficient double bond and subsequent intramolecular allylation of the generated carbanion 243. This cycloaddition proceeds under neutral conditions, yielding the functionalized methylenecyclopentanes 244[148], The syn-... 

Another method for the synthesis of epoxides is through the use of halo-hydrins, prepared by electrophilic addition of HO—X to alkenes (Section 7.3). When halohydrins are treated with base, HX is eliminated and an epoxide is produced by an intramolecular Williamson ether synthesis. That is, the nucleophilic alkoxide ion and the electrophilic alkyl halide are in the same molecule. 

The intramolecular Michael addition11 of a nucleophilic oxygen to an a,/ -unsaturated ester constitutes an attractive alternative strategy for the synthesis of the pyran nucleus, a strategy that could conceivably be applied to the brevetoxin problem (see Scheme 2). For example, treatment of hydroxy a,/ -unsaturated ester 9 with sodium hydride furnishes an alkoxide ion that induces ring formation by attacking the electrophilic //-carbon of the unsaturated ester moiety. This base-induced intramolecular Michael addition reaction is a reversible process, and it ultimately affords the thermodynamically most stable product 10 (92% yield). 

On the other hand, in the case of a-halogenoethyl sulphoxides 503 an SN2-type displacement occurs with mercaptide anions and leads to a-alkylthioethyl sulphoxides 504, while the elimination-addition mechanism is operative with alkoxide anions, affording jS-alkoxyethyl sulphoxides577,596 505 (equation 306). Finally, the reaction of 1-halogeno-l-methylethyl derivatives with both nucleophiles mentioned above occurs via the elimination-addition mechanism596 (equation 307). The substitution reaction can also take place intramolecularly (equation 308) and it proceeds very easily (cf. Section IV.A.2.C)484,600. 

The key cyclization in Step B-2 was followed by a sequence of steps that effected a ring expansion via a carbene addition and cyclopropyl halide solvolysis. The products of Steps E and F are interesting in that the tricyclic structures are largely converted to tetracyclic derivatives by intramolecular aldol reactions. The extraneous bond was broken in Step G. First a diol was formed by NaBH4 reduction and this was converted via the lithium alkoxide to a monomesylate. The resulting (3-hydroxy mesylate is capable of a concerted fragmentation, which occurred on treatment with potassium f-butoxide. 

The mechanism of [3 + 2] reductive cycloadditions clearly is more complex than other aldehyde/alkyne couplings since additional bonds are formed in the process. The catalytic reductive [3 + 2] cycloaddition process likely proceeds via the intermediacy of metallacycle 29, followed by enolate protonation to afford vinyl nickel species 30, alkenyl addition to the aldehyde to afford nickel alkoxide 31, and reduction of the Ni(II) alkoxide 31 back to the catalytically active Ni(0) species by Et3B (Scheme 23). In an intramolecular case, metallacycle 29 was isolated, fully characterized, and illustrated to undergo [3 + 2] reductive cycloaddition upon exposure to methanol [45]. Related pathways have recently been described involving cobalt-catalyzed reductive cyclo additions of enones and allenes [46], suggesting that this novel mechanism may be general for a variety of metals and substrate combinations. 

The most studied catalyst family of this type are lithium alkyls. With relatively non-bulky substituents, for example nBuLi, the polymerization of MMA is complicated by side reactions.4 0 These may be suppressed if bulkier initiators such as 1,1-diphenylhexyllithium are used,431 especially at low temperature (typically —78 °C), allowing the synthesis of block copolymers.432,433 The addition of bulky lithium alkoxides to alkyllithium initiators also retards the rate of intramolecular cyclization, thus allowing the polymerization temperature to be raised.427 LiCl has been used to similar effect, allowing monodisperse PMMA (Mw/Mn = 1.2) to be prepared at —20 °C.434 Sterically hindered lithium aluminum alkyls have been used at ambient (or higher) temperature to polymerize MMA in a controlled way.435 This process has been termed screened anionic polymerization since the bulky alkyl substituents screen the propagating terminus from side reactions. 

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