Ethers, Thioethers

Both ethers and thioethers are hydrolyzed via acid-catalysis to the alcohol or thiol, but are reasonably stable at neutral and basic conditions. Hydrolysis of ethers and thioethers is usually only observed if attached to an aryl group or other cationic stabilizing groups (e.g., API cefamandole nafate thiother hydrolysis [16]). 

Secondary thiol (R—S—R ) oxidizes to R—SO—R, which further oxidizes to sulfone (R—SO2—R ) (e.g., fluphenazine enanthate thioether [17]). 

1 Sulfonamides, Sulfonylureas, Epoxides, and Aziridines. Sulfonamides (RS02NR 2) are susceptible to acid hydrolysis (RS02NR 2 -1- water -1-acid RSO2OH), but not basic hydrolysis. Primary alcohols react rapidly only with A,A -disubstituted sulfonamides to yield sulfonic esters (RS02NR 2 -1-R OH -I- acid RSO2OR + NHR y. Sulfonamides are not susceptible to oxidation because the sulfur is already fuUy oxidized. 

Sulfonylureas (R—SO2—NH—CO—NHR ) undergo hydrolysis (acid plus water) to form RSO2NH2 -1- CO2 -1- H+. An example of sulfonylurea hydrolysis is Glibenclamide [18]. 

Epoxides undergo nucleophilic attack by water (hydrolysis to form diol) or other nuclophiles. The oxirane ring contains significant ring-strain and ring opening relieves this strain. 

---

Figure 9. Graph of Standard Free Entropy against Standard Free Enthalpy for an Ether, Thioether and Amine...

The preparation of novel triazole-containing 20-22 membered macrocyclic azacrown ether-thioethers was reported <96JCR(S)182> and the first selective synthetic method fra the synthesis of dicyanotriazolehemiporhyrazines was published <96JOC6446>. 1,2,4-Triazole-containing polyimide beads were prepared and employed as Mo(VI) epoxidation catalyst supports, liie 1,2,4-nitronyl nitroxide 29 was also synthesized and found to have remarkable magnetic properties <96AM60>. 

When n electron donors are involved, the XB is preferentially along the axis of the donated lone pair on D. For instance, XBs around ethers, thioethers, and amines feature a tetrahedral arrangement with preferential axial directions for the XBs around hexacyclic amines, and equatorial directions for hexacyclic thioethers [16,17,124,139-142] (Fig. 6). 

H and 13C NMR Data. The examples in Scheme 3.23 provide characteristic proton and carbon chemical shift and coupling constant data for fluorinated alcohols, ethers, thioethers, sulfoxides, and sul-fones. An ether substituent serves to deshield the carbon of a CH2F by about 20 ppm. This can be compared to the 40-ppm deshielding generally observed in a nonfluorinated ether system. Thus, the fluorine substituent seems to have a damping effect on the usual effects of other substituents. 

Returning to the higher member of the homologous series but nevertheless changing the sulfonate type and solvent as compared to the above case of the cyclobutane-1,1,2,2-tetratosylate 37 the corresponding tetramesylate 18 affords the dithioether 45 instead of the ether-thioether 43 (dioxan/ethanol 77%). 

Wipf has shown that this method is quite general and tolerates several functional groups, such as ethers, thioethers, silanes, halides, aromatic rings, and olefins. The iodoalkyne 64 is readily carbometalated and after treatment with the dialkynylcuprate 59 furnishes the functionalized copper reagent 65, which smoothly undergoes 1,4-addition reactions with enones. Thus, in the case of 2-cyclohexenone, the functionalized ketone 66 is produced in 85% yield (Scheme... 

Carboxylic esters, thiol esters, and amides can be made, respectively, by acid-catalyzed hydration of acetylenic ethers, thioethers,162 and ynamines, without a mercuric catalyst 163... 

Figure 68 Ether, thioether hydrolysis under acidic conditions.

The Mitsunobu Reaction allows the conversion of primary and secondary alcohols to esters, phenyl ethers, thioethers and various other compounds. The nucleophile employed should be acidic, since one of the reagents (DEAD, diethylazodicarboxylate) must be protonated during the course of the reaction to prevent from side reactions. 

The rates of SnI and Sn2 reactions are usually strongly enhanced when atoms with an unshared electron pair are directly attached to the reaction center, as in a-halo-methyl ethers, thioethers, or amines (Scheme 4.30). Only the halogens do not lead to an enhancement of Sn2 reactivity, but to inhibition of bimolecular substitution reactions (Scheme 4.30). In SnI reactions, however, a-halogens can both increase or reduce the rate of substitution [127]. 

F. Leroux, P. Jeschke, M. Schlosser, a-Fluorinated ethers, thioethers, and amines anomerically biased species, Chem. Rev. 105 (2005) 827-856. 

The C-C bonding in R2 has been replaced by ether, thioether, amide or ester bond without losing sweetness. Rx is a small side chain such as a methyl, ethyl, isopropyl, or hydroxymethyl group, or an ester having a small substituent. The exact chemical nature of these groups is not crucial. 

In contrast to the 5-endo-trig anionic cyclization reactions, rarely observed, there are several examples in which 5-endo-dig processes are involved. Hence 2,3-disubstituted benzofurans, benzothiophenes and indoles 374 have been synthesized starting from triflu-oroethyl ethers, thioethers and anilines 373, respectively, and alkyllithium compounds. A 5-endo-dig carbolithiation reaction on 375, generated by two successive eliminations, one substitution and one ortho-lithiation reactions, is proposed to account for the formation of the corresponding 2-lithiated heterocycles. Further reaction of these intermediates with electrophiles affords compounds 374 (Scheme 98)159. In the case of thioether 373 (X = S) a bromine substituent must be present at the ortho position. 

Phenoxycarbonyl)phenol, Phenyl salicylate Aliphatic, Cycloaliphatic and Aromatic Ethers, Thioethers, and Acetals 41.9 0.346... 

---