Sulfones, alkylation reduction

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. 

The reduction of sulfones with Sml2 can result in deoxygenation, to give the parent sulfide,59 or carbon-sulfur bond cleavage, depending on the substrate and the reaction conditions employed.60 For example, alkyl and alkenyl phenyl sulfones are reductively cleaved by Sml2 in the presence of HMPA. In the reduction of alkenyl sulfones, competing reduction of the electron-deficient alkene is not observed (Scheme 4.50).60... 

Desulfonylation. Various sulfonyl groups are reductively removed by Mg/MeOH. These include alkenyl sulfones, alkyl tosylates, and A -Boc-arenesulfonamides (p-toluenesulfonhydrazides, V-tosylaziridines ). But when the V-tosylaziridine contains an electron-withdrawing group, ring cleavage to give p-(V-tosylamino) derivatives takes precedence to detosylation. ... 

The Pd-catalyzed, LiHBEt3-mediated reductive desulfonylation of allylic sulfones is also used in the ligand-controlled stereoselective synthesis of dienes191 where it is possible to control the geometry of the diene by a proper selection of the palladium ligand as shown by the distribution of products 1 and 2 (Eq. 115). The method described herein is also applicable to the so-called integrated chemical processes , which allow the preparation of a wide variety of alkenes by combining alkylation of allylic sulfones and reductive desulfonylation in one pot.192,193... 

This Pd-catalyzed LiHBEts reduction is applicable to integrated chanical processes (ICPs), which allows integration of alkylation of allylic sulfones and reductive desulfony-lation under mild basic conditions in one pot to prepare various olefins. ... 

The major sex pheromone component of Drosophila ananassae and D. pallidosa, (Z,Z)-5,25-hentriacondiene 16 and (Z,Z)-5,27-tritriacontadiene 17, respectively, have been synthesized by applying sulfone alkylation and subsequent Sml2-induced reductive removal of the benzenesulfonyl moiety (Scheme 22.5). ... 

The Julia-Lythgoc olefination operates by addition of alkyl sulfone anions to carbonyl compounds and subsequent reductive deoxysulfonation (P. Kocienski, 1985). In comparison with the Wittig reaction, it has several advantages sulfones are often more readily available than phosphorus ylides, and it was often successful when the Wittig olefination failed. The elimination step yields exclusively or predominantly the more stable trans olefin stereoisomer. 

Substitution. Substitution products retain the same nuclear configuration as naphthalene. They are formed by the substitution of one or more hydrogen atoms with other functional groups. Substituted naphthalenes of commercial importance have been obtained by sulfonation, sulfonation and alkah fusion, alkylation, nitration and reduction, and chlorination. 

An asymmetric synthesis of estrone begins with an asymmetric Michael addition of lithium enolate (178) to the scalemic sulfoxide (179). Direct treatment of the cmde Michael adduct with y /i7-chloroperbenzoic acid to oxidize the sulfoxide to a sulfone, followed by reductive removal of the bromine affords (180, X = a and PH R = H) in over 90% yield. Similarly to the conversion of (175) to (176), base-catalyzed epimerization of (180) produces an 85% isolated yield of (181, X = /5H R = H). C8 and C14 of (181) have the same relative and absolute stereochemistry as that of the naturally occurring steroids. Methylation of (181) provides (182). A (CH2)2CuLi-induced reductive cleavage of sulfone (182) followed by stereoselective alkylation of the resultant enolate with an allyl bromide yields (183). Ozonolysis of (183) produces (184) (wherein the aldehydric oxygen is by isopropyUdene) in 68% yield. Compound (184) is the optically active form of Ziegler s intermediate (176), and is converted to (+)-estrone in 6.3% overall yield and >95% enantiomeric excess (200). 

Sulfonic acids are prone to reduction with iodine [7553-56-2] in the presence of triphenylphosphine [603-35-0] to produce the corresponding iodides. This type of reduction is also facile with alkyl sulfonates (16). Aromatic sulfonic acids may also be reduced electrochemicaHy to give the parent arene. However, sulfonic acids, when reduced with iodine and phosphoms [7723-14-0] produce thiols (qv). Amination of sulfonates has also been reported, in which the carbon—sulfur bond is cleaved (17). Ortho-Hthiation of sulfonic acid lithium salts has proven to be a useful technique for organic syntheses, but has Httie commercial importance. Optically active sulfonates have been used in asymmetric syntheses to selectively O-alkylate alcohols and phenols, typically on a laboratory scale. Aromatic sulfonates are cleaved, ie, desulfonated, by uv radiation to give the parent aromatic compound and a coupling product of the aromatic compound, as shown, where Ar represents an aryl group (18). 

Reactions other than those of the nucleophilic reactivity of alkyl sulfates iavolve reactions with hydrocarbons, thermal degradation, sulfonation, halogenation of the alkyl groups, and reduction of the sulfate groups. Aromatic hydrocarbons, eg, benzene and naphthalene, react with alkyl sulfates when cataly2ed by aluminum chloride to give Fhedel-Crafts-type alkylation product mixtures (59). Isobutane is readily alkylated by a dipropyl sulfate mixture from the reaction of propylene ia propane with sulfuric acid (60). 

Such reductive ring contractions of sulfones are formally similar to two other methods capable of supplanting a sulfur atom by a carbon-carbon double bond the Ramberg-Backlundand Stevens rearrangements. The distinguishing feature of this novel approach to cyclobutenes consists in the resultant higher level of alkyl substitution at the sp -hybridized centers. 

The control of chemical reactions (e.g., esterification, sulfonation, nitration, alkylation, polymerization, oxidation, reduction, halogenation) and associated hazards are an essential aspect of chemical manufacture in the CPI. The industries manufacture nearly all their products, such as inorganic, organic, agricultural, polymers, and pharmaceuticals, through the control of reactive chemicals. The reactions that occur are generally without incident. Barton and Nolan [1] examined exothermic runaway incidents and found that the principal causes were ... 

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. 

Besides acylation and alkylation reactions, typical carbonyl reactions, such as reduction and substitution, are known. Thus, the oxo group in position 3 of 8 is attacked by sodium cyanide, resulting in the cyanohydrin in 55% yield. Subsequent dehydration with p-toluene-sulfonic acid and acetylation in position 5 gives 1-benzothiepin 12.90... 

Amides are very weak nucleophiles, far too weak to attack alkyl halides, so they must first be converted to their conjugate bases. By this method, unsubstituted amides can be converted to N-substituted, or N-substituted to N,N-disubstituted, amides. Esters of sulfuric or sulfonic acids can also be substrates. Tertiary substrates give elimination. O-Alkylation is at times a side reaction. Both amides and sulfonamides have been alkylated under phase-transfer conditions. Lactams can be alkylated using similar procedures. Ethyl pyroglutamate (5-carboethoxy 2-pyrrolidinone) and related lactams were converted to N-alkyl derivatives via treatment with NaH (short contact time) followed by addition of the halide. 2-Pyrrolidinone derivatives can be alkylated using a similar procedure. Lactams can be reductively alkylated using aldehydes under catalytic hydrogenation... 

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). 

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