Nucleophilic addition reactions with oxygen nucleophiles

Both dienyl- and 7r-allylmetal complexes of Fe,492 Mo,493,494 and W374 have also been prepared and undergone similar reactions with oxygen nucleophiles. One pertinent example is the reaction of 7r-allylmolybdenum complexes with internal alcohols leading to THFs (Equation (128)) 493 additional examples of this chemistry have appeared in a... 

The number of reports about addition reactions of oxygen nucleophiles to acceptor-substituted dienes is rather limited. Coffman111 and Kurtz17 examined the reaction of 2,4-pentadienenitrile with sodium methoxide and isolated the 2 1 adduct 3,5-dimethoxypen-tanenitrile formed by successive 1,6- and 1,4-additions (equation 34). Analogous treatment... 

On the other hand, some evidence for the longer life-time of the intermediate formed with amines may be inferred from the formation of small amounts of (116a) from piperidine and /J-chloroacrylonitrile, in addition to the main substitution product. (116a) is also the sole substitution product with aniline (R1=Ph, R2 = H) but no such products were reported for reactions with oxygen or sulphur nucleophiles. For formation of (116a) the initially-formed carbanion should be long-lived enough as to attack another j8-chloroacrylonitrile molecule (Scotti and Frazza, 1964). 

Aldehydes and ketones undergo nucleophilic addition-elimination reactions with oxygen and nitrogen nucleophiles. 

Functionalization of pyridine. Regioselective reaction with oxygen, sulfur, and nitrogen nucleophiles and with carbon nucleophiles at C-2 occurs via an addition-elimination pathway. 

The second set of examples involves the use of thionium ions as electrophiles in inter- and intramolecular processes to obtain a-substituted sulfides (see 24 25, Scheme 20.7T which is the most common type of Pummerer reaction. Applications of this classical Pummerer rearrangement are exemplified in the synthesis of trans-solamin, the synthesis of indolizidine alkaloids, and the synthesis of the CDE ring of erinacine E. The first exanple fScheme 20.10 uses Pummerer chemistry in the generation of a thionium ion, which reacts in an intermolecular tin-mediated ene reaction the second one fScheme 20.11 uses Pummerer chemistry to introduce a nitrogen-containing heterocycle by intramolecular addition to form the coniceine core and the third example fScheme 20.12 is an intramolecular silicon-induced Pummerer reaction with oxygenated nucleophiles applied to the synthesis of a precursor of erinacine. Details of these Pummerer-based strategies are discussed below. 

V. Nucleophilic Addition Reactions with Loss of the Carbonyi Oxygen... 

As inert as the C-25 lactone carbonyl has been during the course of this synthesis, it can serve the role of electrophile in a reaction with a nucleophile. For example, addition of benzyloxymethyl-lithium29 to a cold (-78 °C) solution of 41 in THF, followed by treatment of the intermediate hemiketal with methyl orthoformate under acidic conditions, provides intermediate 42 in 80% overall yield. Reduction of the carbon-bromine bond in 42 with concomitant -elimination of the C-9 ether oxygen is achieved with Zn-Cu couple and sodium iodide at 60 °C in DMF. Under these reaction conditions, it is conceivable that the bromine substituent in 42 is replaced by iodine, after which event reductive elimination occurs. Silylation of the newly formed tertiary hydroxyl group at C-12 with triethylsilyl perchlorate, followed by oxidative cleavage of the olefin with ozone, results in the formation of key intermediate 3 in 85 % yield from 42. 

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). 

With a-alkyl-substituted chiral carbonyl compounds bearing an alkoxy group in the -position, the diastereoselectivity of nucleophilic addition reactions is influenced not only by steric factors, which can be described by the models of Cram and Felkin (see Section 1.3.1.1.), but also by a possible coordination of the nucleophile counterion with the /J-oxygen atom. Thus, coordination of the metal cation with the carbonyl oxygen and the /J-alkoxy substituent leads to a chelated transition state 1 which implies attack of the nucleophile from the least hindered side, opposite to the pseudoequatorial substituent R1. Therefore, the anb-diastereomer 2 should be formed in excess. With respect to the stereogenic center in the a-position, the predominant formation of the anft-diastereomer means that anti-Cram selectivity has occurred. 

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