Sulfoxides ketosulfoxides

Sulfoxides Ketosulfoxide derivatives (10.19), where R is an alkyl or a phenyl group, exhibit two cleavage processes [34] one in the triplet state (lifetime 7.5 ns for R = methyl) and another in the singlet state (lifetime 3 ns). 

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. 

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... 

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. 

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). 

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. 

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... 

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... 

The first report of reactions of this kind of dipoles with racemic vinyl sulfoxides was published in 1973 [162]. Benzonitrile oxide reacts smoothly with sodium salts of some /3-ketosulfoxides, 204, to give the corresponding 4-methylsulfinyl isoxazoles 205 in good yields. The isoxazoline intermediates were not isolated in any case. To our knowledge, this was the first paper reporting the use of vinyl sulfoxides as dipolarophiles and revealed the strong tendency of the resulting isoxazoline to be transformed into aromatic isoxazoles. The reaction of nitrili-mine 206 with sulfinyl enolates 204 to obtain sulfinyl pyrazoles 207 was also reported in this paper (Scheme 97). 

The presence of a chiral sulfoxide group in the P-position allows the highly selective reduction of imines by Li 5-BU3BH or LiBEt3H [482, 1120] (Figure 6.20). Reduction of P-sulfonylimines with DIBAH/ZnCl2 at -78°C is also very efficient, and produces nonracemic amines after Raney nickel desulfurization [1121, 1122] (Figure 6.20). A chelated complex that is similar to the one involved in the reduction of p-ketosulfoxides ( 6.1.2.2) is proposed as a reaction intermediate. 

In some of the more complex molecules, there are instances in which the low energy chromophore is probably not localized on the sulfoxide, yet the sulfinyl (SO) group is involved in the observed transformations. Some attempt will be made to differentiate photochemical reactions of molecules that merely happen to contain a sulfinyl group and those for which the sulfoxide is the critical functional group and/or chromophore. Section IX is reserved for the chemistry of ketosulfoxides in which the chemistry is clearly carbonyl but the reaction involves of sulfinyl site. The photochemistry of sulfenic esters (R-S-0-R ) appears throughout the text, particularly in Section III—the discussion of sulfoxide a-cleavage reactions. A short additional section on these sulfoxide isomers is also included at the end. 

An important group of reactions occur in (usually P-) ketosulfoxides, in which it is clear that the ketone is the chromophore and the sulfoxide merely an important actor in subsequent chemistry. A few of these have been seen already, such as the extrusion of SO from 146 [140]. The most common reaction of the P-ketosulfoxides is S-C cleavage, typically P to the ketone and a to the sulfoxide, as is common for other ketones with good P-leaving groups. 

The required ketosulfoxide 69 (Scheme 15) was obtained in two steps in a one-pot procedure from 1,4-dimethoxybenzene (66). Ortho Hthiation of 66, lithium-copper exchange, and addition to methyl acrylate gave ester 67. Reaction of the anion obtained from (R)-methyl(p-tolyl)sulfoxide (68) [89] by treatment with LDA, with ester 67 afforded ketone 69. Diastereoselective addition of diethylaluminum cyanide to the carbonyl group of 69 [90] furnished sulfinylcyanohydrin 70 as the sole product. The (S) configuration of the new stereogenic center was inferred from the previous studies of acycUc P-ketosulfoxides [91,92]. 

Solladie and Hunt [96] proposed an interesting synthesis of this segment whereby the five chiral centers were constructed by successive stereocontrolled transformations from chiral sulfoxide 133 (Scheme 17), prepared by a previously described method [98]. Dibal reduction [98] of R-P-ketosulfoxide 133 afforded the R,R-hydroxy sulfoxide 134 (94% de). This sulfoxide was then reduced to... 

Another class of synthetic intermediates are the /3-ketosulfoxides, which are prepared by acylation of the dimethyl sulfoxide anion with esters... 

Over the past decade, the stereocontrolled reduction of enantiomerically pure P-ketosulfoxides by hydride reagents, particularly within the Solladid research group, has sparked considerable interest, as an approach to many synthetically important intermediates and biologically active molecules of defined chirality. The applications described below outline the effectiveness of the chiral sulfoxide moiety as a stereocontrol element, and highlight the ready removal of the sulfoxide group after its contribution to the synthetic scheme. In all cases, the sense of stereochemical induction can be rationalized and predicted on the basis of steric, stereoelectronic and/or chelation control factors. 

In 1982, Solladi reported a highly efficient, asymmetric synthesis of both enantiomers of methyl carbinols based on the stereoselective reduction of an enantiomerically pure P-ketosulfoxide [1], Prior to this work, only low to moderate levels of enantiomeric purity had been observed by Cinquini [2] and Johnson [3] in similar studies. The P-ketosulfoxides used in Solladie s study were prepared by condensation of the a-sulfinyl carbanion of (J )-methyl p-tolyl sulfoxide with esters (Scheme 4.1). 

Michael addition of scalemic /3-ketosulfoxides R1COCH2S (0)To1 (chiral at sulfur) to O, /3-unsaturated aldehydes R CH=CHCHO, catalysed by proline derivatives, has been shown to exhibit complete control of configuration at the two newly constructed chiral centres. The configuration at the a-position of the moiety originating from the nucleophile is controlled by the sulfoxide group, whereas the configuration at the -position of the Michael acceptor is controlled by the catalyst, which allows the preparation of all possible diastereoisomers in an enantiomericaUy pure form. Theoretical calculations suggest that enolates, rather than enols, are the active reactants. " ... 

The reaction of biaryl lactones with C-nucleophiles was interesting since it allowed an extension of the carbon framework. For the condensation of the chiral lithiated sulfoxide depicted in Scheme 5.10, a 1 1 mixture of the two diastereomeric /i-ketosulfoxides was formed due to the interconversion of the... 

A chiral precursor of a special type is sulfoxide 48, used in a synthesis of (+)-boronolide (Scheme 2.10) [33aj. Acylation of its hthium anion with conjugated ester 49 gave P-ketosulfoxide 50, which was stereoselectively reduced under chelation control to P-hydroxy sulfoxide 51. Oxidative funtionahzation of the olefinic bond (five steps) furnished triacetate 52, stiU containing the stereogenic sulfoxide moiety. The latter was eliminated by means of a Pummerer reaction, which afforded... 

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