Replacement by oxygen nucleophiles

Difluoropyridines. 2,4-Difluoropyridine can be prepared (26% yield) from 2,4-dichloropyridine and potassium fluoride in sulfolane and ethylene glycol initiator (403). The 4-fluorine is preferentially replaced by oxygen nucleophiles to give 2-fluoro-4-hydroxypyridine derivatives for herbicidal apphcations (404). 

Ruonne atoms in aromatic nitrogen heterocycles are readily replaced by oxygen nucleophiles [77] Bistnfluoromethyl hydroxylarmne anion is an mterest-ing nucleophile for the mtroduction of oxygen mto perfluoropyndine Rearrangement of the product occurs at 125 °C [18] (equation 12)... 

The discussion to this point has focused entirely on the epoxidation of allylic (and homoallylic) alcohols catalyzed by the Ti(OR)2(tartrate) complex. The role of the olefin as a nucleophile toward the activated peroxide oxygen in this reaction has been established (see discussion of mechanism). If the olefin of the allylic alcohol is replaced by another nucleophilic group then, in principle, oxidation of that group may occur (Eq. 6A.6) [141 ]. 

Now, you saw a similar insertion5 reaction earlier in the chapter, and the mechanism here is not dissimilar. Both peracids and diazomethane contain a nucleophilic centre that carries a good leaving group, and addition of peracid to the carbonyl group gives a structure that should remind you of a semipinacol intermediate with one of the carbon atoms replaced by oxygen. 

Substitution (SnI or Sn2) is the major reaction of nucleophiles in which one functional group is replaced by another (nucleophilic aliphatic substitution). Nucleophiles can also form a new bond to an acyl carbon (nucleophilic acyl addition). Both of these retrosynthetic transforms are represented by the C-Nuc species, where Nuc = CN , AcQ-, RO , N3-, CO2-, etc. and X = Cl, Br, I, OAc, OSO2R, and so on for Sn2 reactions. In nucleophilic acyl substitutions, the nucleophile is usually a carbon, nitrogen or oxygen species. 

The hydride nucleophile may be replaced by carbon nucleophiles from allyltrimethylsilane or silyl enol ethers, giving the corresponding sulfide derivatives in moderate to good yields. This is consistent with the proposed formation of a sulfonium intermediate from the direct Lewis acid interaction of the silicon of TMSCl, activated by InCl3, with the oxygen of OTMS instead of the alkylthio moiety... 

The replacement of a substituent on an aromauc nng by a nucleophile is termed arylaUon. This chapter considers the replacement by nucleophihc oxygen, sulfur, nitrogen, and carbon of aromatic fluonne atoms, which are often activated by electron-withdrawing groups. 

The reactions shown above are nucleophilic substitutions that involve replacement of bromine by oxygen. The reactions may or may not proceed by similar mechanisms. 

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 bis(morpholino)phosphinoyloxy group in the benzodiazepine 36 (Ar = Ph) is readily replaced by nitrogen and oxygen nucleophiles.233... 

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