Alkylation, by oxonium salts

Alkylations by oxonium salts have added several new weapons to the synthetic chemist s armamentarium. For example, the O-alkylated products from amides [R1C(OR)=NR2R3]+ (R == CH3 or C2H5) may be hydrolyzed under mild conditions to amines and esters,14-34 reduced to the amines RjCH-jNRaRa by sodium borohydride,13 converted to amide acetals RiC(OR)2NR2R3 by alkoxides,4-16 and (for R3 = H) deproton-ated to the imino esters R1C(OR)=NR2.16-18 Amide acetals and imino esters are themselves in turn useful synthetic intermediates. Indeed, oxonium salts transform the rather intractable amide group into a highly reactive and versatile functionality, a fact elegantly exploited in recent work on the synthesis of corrins.34... 

Only those 1.1-diphenyl-X -phosphorins in which the phosphorin ring is unsubstituted could be alkylated or acylated at the ring (see p. 77). The 2.4.6-tri-phenylated 1.1-disubstituted A -phosphorins cannot be alkylated by oxonium salts or acylated by acylchlorides under normal conditions. 

A/-Acylimino compounds are converted by oxonium salts to iminium salts, which can be regarded as azaallenium salts. " A lot of lactams have been alkylated by oxonium salts at the carbonyl oxygen to give salts of type (70 equation 43)7-i0.199-207... 

Alkylation, by oxonium salts, 51,144 intramolecular to form cyclopropanes, 52, 35 of acids, 50, 61 of lithium enolates, 52, 39 of malonitrile, 53, 24 with benzyl chloromethyl ether,... 

That ethylene oxide can react directly with oxonium ions is shown by its reaction with triethyl oxonium borofluoride but this reaction, because of its complexity, does not shed much light on the polymerization. The sole product is dioxane and the vinyl ether colors appear only after all epoxide has reacted. Initial rates suggest first order in catalyst but the first order plots of monomer disappearance are flat S-curves suggesting a rate which first falls off, then tends towards zero order. The first step in the reaction is most probably a simple bimolecular alkylation of the epoxide by oxonium salt but the subsequent steps are obscure. The simplest path would be... 

Trialkyloxonium fluoroborates give better yields of lactim ethers than other alkylating agents because of the selectivity of these reagents in the O-alkylation of lactams. This was borne out by Meerwein at al.,42 who arranged carbonyl compounds according to their capacity to undergo alkylation with oxonium salts as follows lactams > acyclic amides > lactones > carboxylic esters > ketones > aldehydes. 

The action of trialkyloxonium salts on aliphatic ethers leads to exchange of alkyl groups. Sulfoxides,212 nitriles,213 and disulfides214 can be alkylated smoothly by oxonium salts. Saturated aldehydes and ketones can be alkylated only if, like pinacolin and camphor, they contain a tertiary alkyl group neighboring the carbonyl group. Then for instance, the carboxonium salts obtained can be readily converted by alkali alkoxides into acetals and orthoesters which are difficult to obtain in other ways. 

Direct alkylation or acylation of the oxygen of THF by exchange or addition occurs with the use of trialkyl oxonium salts, carboxonium salts, super-acid esters or anhydrides, acyhum salts, and sometimes carbenium salts. 

Examples of polyfunctional carboxylic acids esterified by this method are shown in Table I. Yields are uniformly high, with the exception of those cases (maleic and fumaric acids) where some of the product appears to be lost during work-up as a result of water solubility. Even with carboxylic acids containing a second functional group (e.g., amide, nitrile) which can readily react with the oxonium salt, the more nucleophilic carboxylate anion is preferentially alkylated. The examples described in detail above illustrate the esterification of an acid containing a labile acetoxy group, which would not survive other procedures such as the traditional Fischer esterification. 

Alkyl halides can be alkylated by ethers or ketones to give oxonium salts, if a very weak, negatively charged nucleophile is present to serve as a counterion and a Lewis... 

O -Alkylations of azepin-2-ones, and benzazepin-2-ones, are most efficiently brought about by trialkyloxonium tetrafluoroborates (Meerwein s reagents) (B-69MI51600,73JOC1090, 81HCA373). S-Alkylation of the thiones is effected similarly. These oxonium salts have also proved useful for the alkylation of azepinedione precursors of azatropones and azatropolones (72JOC208) (see also Section 5.16.3.1.2). 5//-Dibenz[f>,e]azepine-6,11 -dione with triethyloxonium tetrafluoroborate O-ethylates at the amide carbonyl and not at the ketonic carbonyl as was first proposed (72AJC2421). 

In contrast to pyridine derivatives, aryl- and alkyl-substituted A -phosphorins cannot be protonated by strong, non-oxidizing acids such as trifluoroacetic acid. Addition of trifluoroacetic acid to cyclohexane solutions of various A -phosphorins fails to produce any change in the UV spectra Similarly, alkylation by such strong agents as oxonium salts or acylation by acylchlorides cannot be induced at the P atom or any ring C atom. This behavior has also been discussed theoretically 55a)... 

The course of the alkylation was investigated in detail by Markl and Merz It was found that alkyl iodides attack by an SnI mechanism, primarily at the phosphorus, to form 144, while oxonium salts prefer the C—2 position. Nonpolar solvents favor SN2-alkylation at C—2 to 145. The X -phosphorins 144 are thermodynamically more stable than the isomeric 1,2-dihydro-X -phosphorins... 

At lower temperatures the oxonium salt or the alkyl hydrogen sulfate may react by an SN displacement mechanism with excess alcohol in the reaction mixture, thereby forming a dialkyl ether. Although each step in the reaction is reversible, ether formation can be enhanced by distilling away the ether as fast as it forms. Diethyl ether is made commercially by this process ... 

The preparation and properties of the oxonium salts have been considered here in some detail because of their great importance in the polymerization of cyclic ethers by Friedel Crafts catalysts. From the point of view of this review the most important reactions of these salts are those with ethers and alcohols with ethers they exchange alkyl groups in an equilibrium process,... 

In many cases, the main step in the syntheses of trialkyloxonium salts is the alkylation of a dialkyl ether with a reactive intermediate oxonium ion formed in situ. Thus, the most widely used method for preparing trialkyloxonium tetrafluoroborates by the reaction of epichlorohydrin and BF3 is based on the intermediacy of the inner oxonium salt 3291 95 97 [Eq. (4.19)]. 

Non-deprotonated amides are weak nucleophiles and are only alkylated by trialkyl -oxonium salts or dimethyl sulfate at oxygen or by some carbocations at nitrogen [16, 83]. Alkylation with primary or secondary alkyl halides under basic reaction conditions is usually rather difficult, because of the low nucleophilicity and high basicity of deprotonated amides. Non-cyclic amides are extremely difficult to N-alkylate, and few examples of such reactions (mainly methylations, benzylations, or allyla-tions) have been reported (Scheme 6.21). 4-Halobutyramides, on the other hand, can often be cyclized to pyrrolidinones in high yield by treatment with bases (see Scheme 1.8) [84—86]. 

If Kd = 10 6 mol/L, free ions will dominate when the concentration of carbenium ions is less than 10" 6 mol/L. However, dissociation is strongly suppressed by adding salts with common ions. For example, addition of 10 3 mol/L of salt with common anion decreases the concentration of free ions from approximately I0-6-10 9 mol/L. Ion pair dissociation may also be suppressed by the counterions of adventitious oxonium ions formed by alkylation or protonation of impurities such as moisture. Even 10 5 mol/L of such oxonium ions reduces the concentration of free ions considerably. 

The preparation of (C2Hs)30 SbFg and oxonium salts with higher alkyl groups can readily by achieved by a one-step nthesis. 

In the first step of this reaction sequence, the primary alcohol 21 is oxidized to the corresponding aldehyde 38 in a Parikh-Doering oxidation which is related to the Swern oxidation. In general, this type of oxidation is conveniently carried out by addition of a solution of pyridine-SOs complex in DMSO to a mixture of the alcohol, DMSO and NEts. It can be assumed that dimethyl sulfoxide and sulfur trioxide react to form 0-dimethylsulfoxonium sulfate 40, which then further reacts with primary alcohol 39 to give 0-alkyl dimethylsulf-oxonium intermediate 41. Then, sulfonium salt 42 is formed and subsequently deprotonated by NEts to give sulfonium ylide 43. Finally, an intramolecular p-elimination occurs to provide the desired aldehyde 44 and dimethyl sulfide. 

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