Sulfones anions, reaction with alkyl halides

As noted above, alkyne anions are very useful in Sn2 reactions with alkyl halides, and in acyl addition reactions to a carbonyl.46 Alkyl halides and sulfonate esters (tosylates and mesylates primarily) serve as electrophilic substrates for acetylides. A simple example is taken from Kaiser s synthesis of niphatoxin B, in which propargyl alcohol (36) is treated with butyllithium and then the OTHP derivative of 8-bromo-1-octanol to give a 47% yield of 37.48... 

Carbanion-enolates are nucleophiles that react with alkyl halides (or sulfonates) by typical S 2 reactions, Carbanion-enolates are best formed using lithium diisopropylamide (lda), (r-Pr)2N Li, in tetrahydrofuran. This base is very strong and converts all the substrate to the anion. Furthermore, it is too sterically hindered to react with RX. 

Alternatively, halide-free 1,3-dialkylimidazolium ILs can be prepared from the five-component reaction (glyoxal, formaldehyde, two different amines and acids. Scheme 2), and those containing alkyl sulfate or trifluoromethane sulfonate anions by simple alkylation of 1-alkylimidazole with the corresponding dialkylsulfate or alkyltrifluoro-methane sulfonate ester, respectively. " ... 

A second method of ester preparation involves the reaction of carboxylate salts with alkyl halides, sulfates, or sulfonates. Because carboxylate ions are relatively weak nucleophiles in protic solvents, this reaction is too slow to be convenient under many circumstances. Use of solvents such as dimethyl sulfoxide and hexamethylphosphoramide, however, which selectively activate anionic nucleophiles, results in much-improved reaction rates. Reaction of carboxylate salts with halides has been found to be a satisfactory preparative reaction in these solvents. The procedure has been found to be particularly useful for certain hindered acids. Scheme 5.4 lists some... 

The reaction of alkoxides with alkyl halides or sulfonates is a useful method for ether synthesis (entries 6-10). Disubstituted sulfides are prepared by reaction of alkyl thiolates with alkylating agents under typical Sn2 reaction conditions (entries 12 and 13). Many small anions can be introduced into organic molecules by nucleophilic substitution. Entries 15 and 16 illustrate the preparation of a nitroal-kane and an alkyl azide, respectively, by displacement reactions. The alkylation of tertiary amines to give quaternary ammonium salts is another example of a synthetically useful nucleophilic substitution process. 

Another class of compounds, known as sulfonate esters (see Figure 11.2), is derived from sulfonic acids RSO3H (see Chapter 16, Section 16.9). The C-0 bond in Figure 11.2 is polarized such that the carbon is electrophilic, analogous to alkyl halides. Sulfonate esters are relatively easy to form, and they react with nucleophiles because the sulfonate anion (RSOg ) is displaced as readily as a halide in this reaction. As with alkyl halides, the nucleophile attacks the 8+ carbon to form a new C-Y bond, while breaking the C-0 bond to form a sulfonate anion, RSOg , which is resonance stabilized. 

Thiols, the sulfur analogs of alcohols, are usually prepared by Sjv 2 reaction of an alkyl halide with thiourea. Mild oxidation of a thiol yields a disulfide, and mild reduction of a disulfide gives back the thiol. Sulfides, the sulfur analogs of ethers, are prepared by an Sk2 reaction between a thiolate anion and a primary or secondary alkyl halide. Sulfides are much more nucleophilic than ethers and can be oxidized to sulfoxides and to sulfones. Sulfides can also be alkylated by reaction with a primary alkyl halide to yield sulfonium ions. 

The Heck reaction is a C-C coupling reaction where an unsaturated hydrocarbon or arene halide/triflate/sulfonate reacts with an alkene in presence of a base and Pd(0) catalyst so as to form a substituted alkene. Kaufmann et al. showed that the Heck reaction carried out in presence of ILs such as tetra-alkyl ammonium and phosphonium salts without the phosphine ligands, resulted in high yields of product. They attributed the activity to the stabilizing effect of ammonium and phosphonium salts on Pd(0) species. Carmichael et al. used ionic liquids containing either A,A -dialkylimidazolium and A-alkylpyridinium cations with anions such as halide, hexafluorophosphate or tetrafiuoroborate to carry out reactions of aryl halide and benzoic anhydride with ethyl and butyl acrylates in presence of Pd catalyst. An example of iodobenzene reacting with ethyl acrylate to give trans-et vy cinnamate is shown in Scheme 14. 

The reduced basicity of phenothiazine nitrogen requires that even acylation proceed via the anion. The amide (34-2) from the methyl thioether (34-1) can be prepared, for example, by sequential reaction with sodium amide and acetic anhydride. Oxidation of that intermediate with peracid proceeds preferentially on the more electron-rich alkyl thioether to give the sulfone this affords the phenothiazine (34-3) on hydrolysis of the amide. Complex side chains are most conveniently incorporated in a stepwise fashion. The first step in the present sequence involves reaction of (34-3) as its anion with l-bromo-3-chloropropane to give (34-4). The use of that halide with alkylate piperidine-4-carboxamide (34-5) affords the antipsychotic agent metopimazine (34-6) [35]. 

The direct a-alkylation of monoketones normally employs reaction of an alkyl halide or sulfonate with the enolate anion produced using a strong base. This method can be satisfactorily used with symmetrical ketones, which are to be dialkylated with a dihalide, and with intramolecular cyclization reactions, where the formation of five- and six-membered rings is often favored over the formation of three-, four-, seven-, and eight-membered rings (M. Mous-seron, 1937 W.S. Johnson, 1963). Regioselective alkylation of dianions according to Hauser s rule (see p. 9f.) is usually also a satisfactory procedure (F.W. Sum, 1979). 

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