Keto-sulfones, alkylation

Among other methods for the preparation of alkylated ketones are (1) the Stork enamine reaction (12-18), (2) the acetoacetic ester synthesis (10-104), (3) alkylation of p-keto sulfones or sulfoxides (10-104), (4) acylation of CH3SOCH2 followed by reductive cleavage (10-119), (5) treatment of a-halo ketones with lithium dialkyl-copper reagents (10-94), and (6) treatment of a-halo ketones with trialkylboranes (10-109). 

Alkylation of sodium tolylsulhnate with bromomethyl or chloromethyl ketones (la-c) under reflux for 2 h in ethanol gave 3-keto sulfones (2a-c) in 62-90% yields after crystallization. (Adapted from Swenson et ah, 2002)... 

Desulfuration a-alkylation of -keto sulfones.1 Reductive alkylation of sul-fones is routinely carried out by a-alkylation of the enolate followed by desulfuration (Al/Hg). It can also be effected in one pot by desulfuration with lithium in liquid ammonia, which generates an enolate that can be alkylated. The yield is markedly enhanced by conversion of the lithium enolate to an alkylstannyl enolate by addition of Bu3SnCl with HMPT as cosolvent. 

Resin-bound 7-keto sulfones, prepared in a straightforward, three-step process comprising alkylation of a resin-bound sulfinate salt, alkylation of a sulfone-supported anion with an epoxide, and Jones oxidation of the 7-hydroxy sulfone, provided a source of structurally diverse three-carbon fragments <2004JC0928>. Reaction with a phenylenediamine to give the 1,5-benzodiazepine presumably occurs via initial imine formation followed by expulsion of the resin-bound sulfone, which acts as a traceless linker (Scheme 73). Yields for this process are a modest 10-38%. 

Salts of sulfinic acids ace converted to sulfones by the action of pri-lary/ secondary, and benzyl halides, alkyl sulfates, and aryl halides in which the halogen atoms are activated by nitro groups in the ortbo or para positions. The reaction fails with t-amyl halide. The yields vary widely, depending upon the nature of the reactants. From salts of benzenesulfinic acid and simple alkylating agents, sulfones are produced in 50-90% yields. Satisfactory results have been obtained when the aryl sulfinic acid contains nitro, cyano, and acetamido groups. Keto sulfones are made in 48-62% yields by alkylation with a-halo ketones. ... 

More complex products are obtained from cyclizations in which the oxidizable functionality and the alkene are present in the same molecule. y9-Keto esters have been used extensively for Mn(III)-based oxidative cyclizations and react with Mn(OAc)3 at room temperature or slightly above [4, 10, 11, 15], They may be cyclic or acyclic and may be a-unsubstituted or may contain an a-alkyl or chloro substituent. Cycloalkanones are formed if the unsaturated chain is attached to the ketone. y-Lactones are formed from allylic acetoacetates [10, 11]. Less acidic /3-keto amides have recently been used for the formation of lactams or cycloalkanones [37]. Malonic esters have also been widely used and form radicals at 60-80 °C. Cycloalkanes are formed if an unsaturated chain is attached to the a-position. y-Lactones are formed from allylic malonates [10, 11]. yff-Diketones have been used with some success for cyclizations to both alkenes and aromatic rings [10, 11]. Other acidic carbonyl compounds such as fi-keto acids, /3-keto sulfoxides, j8-keto sulfones, and P-nitro ketones have seen limited use [10, 11]. We have recently found that oxidative cyclizations of unsaturated ketones can be carried out in high yield in acetic acid at 80 °C if the ketone selectively enolizes to one side and the product cannot enolize... 

An alternative chemoselective monohalogenation of -keto sulfones using potassium halide and hydrogen peroxide could be employed to afford the desired halomethyl sulfone reagents. Furthermore, direct alkylation of sulfinate salts with methylene bromide afforded cr-bromosutfones in moderate yields. ... 

Reaction of the metalated sulfones with esters, lac-tones, amides and carbonates leads to the corresponding /3-keto sulfone (eq 9). The /3-keto sulfones thus formed display chemistry reminiscent of /3-keto esters in their enhanced acidity and tendency to undergo C- and 0-alkylation and acylation. 

In a related study, the annulation is combined with a ring expansion reaction. The reaction utilizes a -keto sulfone as the two-carbon component along with an allylic mesylate as the bifunctional reagent. The alkylation/cyclization process is outlined in eq 4. The subsequent ring expansion appears to be a general process except for cases involving fused six- and seven-membered ring systems (eq 5). 

PdLX complex undergoing insertion of the coordinated double bond into the a-Pd-carbon bond to form a Pd-alkyl intermediate. With 1,4-penta-diene and 1,5-hexadiene, cyclic keto esters are formed in MeOH and a similar cyclic mechanism is suggested involving insertion of the coordinated double bond into the acyl Pd complex intermediate (16). Although CO pressures of 1000 atm were used, these cyclic ketones were produced also at 250 atm in the presence of p-toluene sulfonic acid, but no details were reported. 

A useful preparation of A-acylureas initiated by the addition of A-halo amides to isocyanides was described (equation 35)53. / -Keto-a-(phenylthio)alkyl p-tolyl sulfones in... 

The free base 3a was further converted to the mandelate salt, a white crystalline product. The cyclobutyl analog 3b was similarly prepared from 8 and converted to the crystalline mandelate salt. The (S ) A-tetrahydrofurfuryl derivative 3c was prepared from (S) tetrahydrofurfuryl (1/f) camphor-10-sulfonate (10) as previously reported (Mertz et al., 1997). The 10-keto morphinans were prepared by the oxidation (Michne and Albertson, 1972) of the morphi-nan 7 with Cr03/H2S04 followed by alkylation with cyclopropyl methyl bromide and 0-demethylation to yield 4b (Scheme 1). O-Demethylation of 11 to form 13 followed by alkylation with (S) tetrahydrofurfuryl (I R) camphor-10 sulfonate (10), led to 4a. The assignment of the stereochemistry of 4a was based on the work of Merz and Stockhaus (1979). 

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