Ethers by nucleophilic substitution

Halogenation is a useful tool because it adds a functional group to a previously unfunctionalized molecule, making an alkyl halide. These alkyl halides can then be converted to alkenes by elimination. and to alcohols and ethers by nucleophilic substitution. 

Scheme 2.174 Generation of perfluoroalkoxide anions and their use to generate aliphatic perfluoroalkyl ethers by nucleophilic substitution of a suitable leaving group (TAS+ — tris(dimethylamino)sulfonium pip = 1,1,2,2,6,6-hexamethylpiperidinium) [20, 22, 23, 25b].

Williamson s synthesis A method for the preparation of mixed ethers by nucleophilic substitution. A haloalkane is refluxed with an alcoholic solution of sodium alkoxide (from sodium dissolved in alcohol) ... 

The activating influence of the ring nitrogen provides an important versatility for the synthesis of pyridones, pyridinols, and pyridine ethers, by nucleophilic substitution at the 2- and 4- and even the 3-position. Further, the potential of accomplishing these substitutions via pyridine W-oxides contributes to the scope of this method. 

A long standing method for the preparation of ethers is the Williamson ether synthesis Nucleophilic substitution of an alkyl halide by an alkoxide gives the carbon-oxygen bond of an ether... 

The cleavage of carbon-oxygen bonds in ethers or esters by nucleophilic substitution is frequently a useful synthetic transformation. 

Dibenzopyrrocolines have been prepared by intramolecular addition of benzyne intermediates and by nucleophilic substitutions, as shown in Scheme 6 with the synthesis of ( )-cryptowoline (2) and the related dehydro base 39 by Bennington and Morin (7). ( )-6 -Bromotetrahydroisoquinoline 37, prepared by standard procedures, when heated with copper powder in dimethylformamide afforded dibenzopyrrocoline 38 in low yield, and 39 was formed when 37 was allowed to react with potassium amide in liquid ammonia. Compound 39 was converted to ( )-cryptowoline iodide (2) by hydrogenolysis of O-benzyl ether 39 and quartemization with methyl iodide. 

Alkyl azides. Sodium azide as such is of little use for preparation of alkyl azides by nucleophilic substitution reactions because of solubility problems. The reaction can be carried out under phase-transfer conditions with methyltrioctylam-monium chloride/NaN3.3 An even more effective polymeric reagent can be obtained by reaction of NaN3 with Amberlite IR-400.4 This reagent converts alkyl bromides, iodides, or tosylates into azides at 20° in essentially quantitative yield. The solvents of choice are CH3CN, CHC13, ether, or DMF. 

Methoxymethyl derivatives of polysilanes, which cannot be obtained from the corresponding chloromethyl compounds by nucleophilic substitution because of intramolecular rearrangement, are prepared successfully by the reaction of chloropolysilanes with monochloromethyl ether in the presence of magnesium in tetrahydrofuran. 

Nucleophilic displacement of anomeric sulfones. 2-Benzenesulfonyl cyclic ethers undergo nucleophilic substitution with various organozinc reagents, particularly with those formed by reaction of ZnBr2 with Grignard reagents, rather than an alkyllithium. 

Reaction of the benzylic bromide 1195 with silylenol ether 1196 in the presence of TBAI and Gingras salt ([//-If 111 ][I h SnF2]) affords the isochroman-4-one 1197 in poor yield. The product can be explained by the 1,2-addition of the enolate to the top side chain, followed by nucleophilic substitution of the benzylic bromide (Equation 459) <2000CEJ3887>. 

Functional Group Transformation Alcohols can be prepared by nucleophilic substitution of alkyl halides, hydrolysis of esters, reduction of carboxylic acids or esters, reduction of aldehydes or ketones, electrophilic addition of alkenes, hydroboration of alkenes, or substitution of ethers. 

In many cases, crown ether-assisted nucleophilic substitution reactions in nonpolar solvents are faster than similar reactions in polar aprotic solvents, even though polar aprotic solvents enhance nucleophilicity by solvating anions poorly. 

Scheme 2 shows the analogous preparation of the (3-alkoxypropyl)diethoxymethylsilanes, starting with the catalytic addition of dichloromethylsilane to the corresponding alkoxy allyl ethers followed by nucleophilic substitution of the chlorine atoms by ethoxy groups. 

On constant current electrolysis (0.27 mAcm +180-600 mV V5. SCE) in AC2O containing ethyl vinyl ether, 4,5-dimethoxy-2-methylphenol (108) was converted to two cyclohexa-2,4-dienones 109 and 110 and cyclohexa-2,5-dienone 111, in 29, 18 and 8% yields, respectively (Scheme 20). The product 110 is formed by nucleophilic substitution at the C-6 position followed by acetal formation with EtOH molecule generated initially from the ethyl vinyl ether while the C-4 position is attacked by ethyl vinyl ether to yield 111. 

Scheme 2.136 Perfluoroalkylation with MeaSiCFa and its homologue Me3SiC2F5 by nucleophilic substitution of alkyl triflates (glyme = ethyleneglycol dimethyl ether) [90].

Reactions of Alcohols and Ethers with Hydrogen Halides Reaction of the C-0 Bond by Nucleophilic Substitution... 

Avoidance by choice of oxygenated starting materials Oxidation through Lithiation and Ort/ro-Lithiation Hydroxylation of Pyridines by ortho-Lithiation Synthesis of Atpenin B Introducing OH by Nucleophilic Substitution Part II - Oxidation of Enols and Enolates Direct Oxidation without Formation of a Specific Enol Selenium dioxide Nitrosation with nitrites Nitrosation with stable nitroso compounds Indirect Oxidation with Formation of a Specific Enol Enone Formation Pd(II) oxidation ofsilyl enol ethers Bromination of enols in enone formation Sulfur and selenium compounds in enone formation Asymmetric Synthesis of Cannabispirenones... 

Alkoxy derivatives in the electrophilic positions are readily available by nucleophilic substitution reactions as discussed for the oxo derivatives above. 2,4-Dialkoxyquinazolines can be prepared by boiling 2,4-dichloroquinazolines with two equivalents of alkali alkoxide in the appropriate alcohol. Mixed ethers (137) are possible because of the great difference in positional reactivity the first substitution is in the 4-position (136). 4-Chloro- and 2,4-dichloro-quinazoline very readily suffer alcoholysis in the 4-position with acid catalysis, presumably via 4-adduct formation as in the facile hydrolysis discussed above. 

Synthesis of Crown Ethers. - The fundamental approach to the syntheses (cyclization by nucleophilic substitution of the separate halves of the ring) remains unchanged. The metal-catalysed cyclization of (60) to form benzo-... 

A novel approach to spiro-linked crown ethers was devised in which (76) was used as the basic building unit. Protection of (76) as (77) was followed by nucleophilic substitution to form the crown (78), which incorporates a diol moiety which can condense with other glycols to yield "multiloop crown compounds". 

In the second step, a distillation-reaction system is appHed to prevent hydrolysis of epichlorohydrin, by removing epichlorohydrin and water as an azeotropic mixture from the top of the distillation column. This operation is known as steam-stripping. In addition to being used in the synthesis of epichlorohydrin, AC is also used as a raw material for synthesizing other aHyl compounds such as aHyl esters, aHyl ethers, and aUylamines by nucleophilic substitution, utilizing the easily substituting property of its chloride group. 

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