3-Ketosulfoxides

To a solution of p-ketosulfoxide (2 mmol) in THF (20mmol) at -78°C was added dropwise a 1 m solution of DIBAH in hexane (2.2 ml, 2.2 mmol). After 1 h at -78°C the reaction mixture was quenched by adding methanol (20 ml). The solvent was evaporated and the residue was diluted with water and extracted with dichloromethane. The organic layer was washed with a 5% sodium hydroxide solution, dried and evaporated. Chromatography on silica gel (ether/hexane 60 40) afforded (R,S)-(3a) in an 80% yield, m.p. 124-126°C, diastereoisomeric ratio (R,S)I(R,R) 95 5 (NMR). 

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This ester is converted in high yield to the y -ketosulfoxide by means of the dimethyl sulfoxide anion. Heating in acetic acid then produces a hemi-mercaptal acetate, which on treatment with Raney nickel gives the desired 21-acetoxy-20-ketone in a 50-70% overall yield from the -ketosulfoxide. A 17a-hydroxyl may also be present during the sequence. 

A 1.5 to 2 M solution of methylsulfinyl carbanion in dimethyl sulfoxide is prepared under nitrogen as above from sodium hydride and dry dimethyl sulfoxide. An equal volume of dry tetrahydrofuran is added and the solution is cooled in an ice bath during the addition, with stirring, of the ester (0.5 equivalent for each 1 equivalent of carbanion neat if liquid, or dissolved in dry tetrahydrofuran if solid) over a period of several minutes. The ice bath is removed and stirring is continued for 30 minutes. The reaction mixture is then poured into three times its volume of water, acidified with aqueous hydrochloric acid to a pH of 3-4 (pH paper), and thoroughly extracted with chloroform. The combined extracts are washed three times with water, dried over anhydrous sodium sulfate, and evaporated to yield the jS-ketosulfoxide as a white or pale yellow crystalline solid. The crude product is triturated with cold ether or isopropyl ether and filtered to give the product in a good state of purity. 

Schneider and Simon82 prepared / -ketosulfoxides 47a and 47b by sulfinylation of the dianions of the methyl acetoacetates 48a and 48b with sulfinate ester 19 followed by decarboxylation of the intermediate products (Scheme 2). Apparently this avoids racemiz-ation experienced by others in the direct synthesis of these compounds9. /J-Ketosulfoxides are also available from the reaction of the anion derived from methyl p-tolyl sulfoxide with esters (see Section II.E). They can also be obtained, in some cases, through the hydrolysis of a-sulfinylhydrazones whose synthesis is described below. Mention has already been made of the synthesis of 2-p-tolylsulfinylcycloalkanones such as 32. 

Methyl 2-phenylsulfmylacetate 96 and /S-ketosulfoxides have been used for the syntheses of various ketones and derivatives of carboxylic acids131"133. For example, cu-(methylsulfinyl)acetophenone 97 have been converted to the corresponding ketone or to y- and <5-ketoesters134. 

Desulfurization of /1-ketosulfoxides with Zn/AcOH134 or aluminium amalgam133 can lead to the corresponding ketones. Other related reactions may be those shown in Scheme 3146 147. 

Enantiomerically pure /J-keto sulfoxides are prepared easily via condensation of a-lithiosulfinyl carbanions with esters. Reduction of the carbonyl group in such /J-keto sulfoxides leads to diastereomeric /J-hydroxysulfoxides. The major recent advance in this area has been the discovery that non-chelating hydride donors (e.g., diisobutylaluminium hydride, DIBAL) tend to form one /J-hydroxysulfoxide while chelating hydride donors [e.g., lithium aluminium hydride (LAH), or DIBAL in the presence of divalent zinc ions] tend to produce the diastereomeric /J-hydroxysulfoxide. The level of diastereoselectivity is often very high. For example, enantiomerically pure /J-ketosulfoxide 32 is reduced by LAH in diethyl ether to give mainly the (RR)-diastereomer whereas DIBAL produces exclusively the (.S R)-diastereomer (equation 30)53-69. A second example is shown in... 

A similar complementarity has been observed in LAH vs. DIBAL reduction of / -ketosulfoxides in which the keto group is also part of a conjugated enone system (equation 32)69. After reductive cleavage (Li, EtNH2) of the alkyl-sulfur bond, 3-alken-2-ols of high enantiomeric purity are produced59. 

When both the carbonyl group and the sulfinyl group of a /J-ketosulfoxide are attached to the same carbon atom of a carbon-carbon double bond, then addition of nucleophiles can occur at the electrophilic -carbon atom (i.e., 1,4-addition, conjugate addition) and/or... 

Majeti11 has studied the photochemistry of simple /I-ketosulfoxides, PhCOCH2SOCH3, and found cleavage of the sulfur-carbon bond, especially in polar solvents, and the Norrish Type II process to be the predominant pathways, leading to both 1,2-dibenzoylethane and methyl methanethiolsulfonate by radical dimerization, as well as acetophenone (equation 3). Nozaki and coworkers12 independently revealed similar results and reported in addition a pH-dependent distribution of products. Miyamoto and Nozaki13 have shown the incorporation of protic solvents into methyl styryl sulfoxide, by a polar addition mechanism. 

Reaction of the y9-ketosulfoxide 1201 with TMSOTf 20/DlPEA affords, in 100% yield, the diene 1202, which readily undergoes Diels-Alder reactions, e.g. with methyl acrylate [26] (Scheme 8.9). 

Sila-Pummerer reaction of the /1-ketosulfoxide 1257 with the enol silyl ether of acetophenone 653 in the presence of BSA 22 a and stannous triflate affords the C-substituted sulfide 1258 in 82% yield and HMDSO 7 [52]. The allylic sulfoxide 1259 reacts with 653 in the presence of TMSOTf 20/DIPEA to give the unsaturated sulfide 1260 in 62% yield or, with the enol silyl ether of cyclohexanone 107a , the unsaturated sulfide 1261 in 63% yield and HMDSO 7 [53] (Scheme 8.21). 

Dimsyl anion 88 reacts with esters of aromatic carboxylic acids and aliphatic acids which do not have a readily transferable proton, to give -ketosulfoxides . There are not many cases in which acyl chlorides were used However, the reaction... 

Carbanions derived from optically active sulfoxides react with esters, affording generally optically active )S-ketoesters ° . Kunieda and coworkers revealed that treatment of (-t-)-(R)-methyl p-tolyl sulfoxide 107 with n-butyllithium or dimethy-lamine afforded the corresponding carbanion, which upon further reaction with ethyl benzoate gave (-l-)-(R)-a-(p-tolylsulfinyl)acetophenone 108. They also found that the reaction between chiral esters of carboxylic acids (R COOR ) and a-lithio aryl methyl sulfoxides gave optically active 3-ketosulfoxides The stereoselectivity was found to be markedly influenced by the size of the R group of the esters and the optical purity reached to 70.3% when R was a t-butyl group. 

Ketosulfoxides are subject to chelation control when reduced by DiBAlH in the presence of ZnCl2.141 This allows the use of chirality of the sulfoxide group to control the stereochemistry at the ketone carbonyl. 

Workup gives back the (3-ketosulfoxide. This part of the mechanism is directly analogous to a Claisen condensation. 

The optically active sulfoxides 39 and 40 were formed in optical yields up to 20% and with opposite configurations at sulfur. The reaction of the carbanion derived from racemic methyl p-tolyl sulfoxide (41) with 0.5 molar equivalent of (-)-menthyl carboxylates 42 was found (70) to occur asymmetrically to give the corresponding optically active -ketosulfoxide 43 and methyl p-tolyl sulfoxide 41, having opposite configurations at sulfur. The degree of stereo-... 

The use of a chiral sulfoxide group as the stereoinducing element is at the center of Solladie s approach to the smaller fragment [44] and a C(8)-C(18) segment [44,45] of the larger fragment of lb (Scheme 27). jS-Ketosulfoxide 200 was obtained from S-ketoester 198 via carbonyl protection and condensation with chiral sulfoxide 199. Two completely diastereoselective reductions of 200... 

Diazomethane has been used to transfer methylene with high diastereoselec-tivity to the carbonyl group of a series of jS-ketosulfoxides, (Rs)-jo-tolyl-S(0)-CHR—CO—CHj F3,Cl2, giving the corresponding epoxides." ... 

Sulfur-containing groups serve as acceptors successfully. /1-Ketosulfoxides and /1-ketosulfones 68 form aminopyrans 69 with UNs... 

Due to their inherent polarizability, a-halo-/3-ketosulfoxides may be used as electrophilic partners in desulfination reaction to generate metal enolate. Therefore, treatment of a-halo-/3-ketosulfoxides with EtMgBr gives magnesium enolates. Trapping these reagents with various electrophiles allows the preparation of a-haloketones (equation 79, Table 10). 

In constrat to a-halo-/3-ketosulfoxides, I-chloroalkyl aryl sulfoxides react with Grignard reagents to give /3-oxido carbenoids. The rearrangement of these intermediates leads... 

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