Ethers neighbouring group participation

Ether groups in the side-chain were found to stabilize primary alkoxycarbenium ions via neighbouring group participation (Scheme ll).92 This allowed these intermediates to react with carbon nucleophiles in Sn reactions, giving alkylated products in moderate to good yields. The second step of these reactions was rate determining. Since the five- and six-membered ring intermediates were the most stable, they reacted slowest with the carbon nucleophile. 

Using tetrafluoroboric acid, several unsaturated acids and nitriles were thus made reactive and were converted into acetoxy lactones [3]. Tosyloxy-, phosphoryloxy-and iodomethyl lactones as well as cyclic ethers resulting from analogous neighbouring group participation will be discussed in connection with other hypervalent iodine reagents. 

The mechanism by which they speed up the reactions is known as neighbouring group participation. Compare the reaction of this ether and this sulfide with an alcohol. 

You ve already met the most important ones—sulfides, esters, carboxylates. Ethers and amines (you will see some of these shortly) can also assist substitution reactions through neighbouring group participation. The important thing that they have in common is an electron-rich heteroatom with a lone pair that can be used to form the cyclic intermediate. Sulfides are rather better than ethers—this sulfide reacts with water much faster than rc-PrCl but the ether reacts with acetic acid four times more slowly than rc-PrOSC Ar. 

An unusual substitution with neighbouring-group participation occurred when the 3o -chloro-2)S,19-oxido compound (51) was treated with either zinc metal or sodium acetate in acetic acid. ° j8-Face participation by the ether oxygen (52) led to nucleophilic attack at the 2a- and 3a-positions, forming both the 3a-acetoxy-2j8,19-oxido- (53) and the 2a-acetoxy-3) ,19-oxido-compounds (54). 

By 1903, Emil Fischer had already appreciated that a proximate nucleophile can accelerate the rate of cleavage of an otherwise unreactive amide. Adaptation of such neighbouring group participation to relay deprotection is easy all that is required is a protecting group with a latent hydroxyl or amino function within easy bonding distance of the amide carbonyl, as illustrated in Scheme 8.27 by the reduction of the o-nitrophenylacetamide 27,1. The theme is capable of extensive variation. For example, 2-((/er/-butyldiphenylsilyloxy)methyl]benz-amides (27.2), 2-(acetoxymethyl)benzamides (273) and 3-methyl-3-(2,4,5-tri-methyl-3,6-dioxo-cycIohexa-l,4-dienyl) butyramides (27.4) all have latent hydroxyl nucleophiles that are released by silyl ether cleavage, ester hydrolysis and quinone reduction, respectively. 

Gimstone, F.D., and B.S. Perera, The Halogenation of Some Long-Chain Hydroxy Alkenes with Special Reference to the Possibility of Neighbouring Group Participation Leading to Cyclic Ethers and Lactones, Chem. Phys. Lipids 11 43-65 (1973). 

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