Alkylation of sulfoxides

Five- and six-membered sulfoxides were shown to be alkylated with high stereoselecti-vities70,76. Marquet and coworkers137 applied this reaction to synthesize di-biotin 105 by stereoselective alkylation of sulfoxide 104. 

Johnson and McCants (161) were the first to show that the alkaline hydrolysis of alkoxysulfonium salts, obtained by 0-alkylation of sulfoxides, proceeds with inversion of configuration at sulfur. This method was employed to interconvert (/ )- and (5)-benzyl p-tolyl sulfoxides 37 as shown in Scheme 21. In contrast to the hydroxide anion, the chloride, bromide, and iodide anions as well as the nitrogen atom of pyridine react with chiral ethoxydiarylsulfonium salts, not at sulfur but at the a-carbon atom of the ethoxy group, yielding the starting sulfoxide with retained configuration (284). On the other hand, the nucleophilic attack of the fluoride anion is directed at sulfur as in the case of the hydroxide anion (285). 

Alkylation of sulfoxides. The last steps in a recent synthesis of biotin (4) are shown in equation (I). The sulfide 1 was converted into the sulfoxide 2 since alkylation of sulfoxides is highly stereoselective, leading to substitution trans to the S O bond. Alkylation of the carbanion of 2, generated with CHsLi in THF,... 

The reduction of alkoxysulfonium salts (formed by alkylation of sulfoxides with methyl fluorosulfonate) with sodium cyanohydridoborate in dichloromethane is catalyzed by 18-crown-6 [32] (see Eq. 13.24). By this method, dibutyl, diphenyl, dibenzyl, and tetramethylene sulfoxides are reduced to the corresponding sulfides in 85%, 77%, 91%, and 87% yields, respectively. 

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). 

Replacement of the methyl ketone moiety in 78 by a phenyl sulfoxide, interestingly, leads to a relatively potent uricosuric agent with diminished antiinflammatory action. This effect in lowering serum levels or uric acid leads to the use of this drug in the treatment of gout. Alkylation of diethyl malonate with the chlorosulfide, 79, gives the intermediate, 80. The pyrazolodione (81) is prepared in the usual way by condensation with hydrazobenzene. Careful oxidation of the sulfide with one equiv-... 

Replacement of the terminal nitrogen of the piperazine by carbon is said to enhance the antiemetic activity of the phenothiazines at the expense of the other pharmacologic effects. The simplest compound in this series, pipamazine (88), is prepared by alkylation of nipecotamide (87) with the chloropropyl phenothiazine (58). Preparation of the analogous sulfoxide begins with acetylation of the thiomethyl compound, 89 [prepared by a route... 

C ( propyl) N phenylmtrone to N phenylmaleimide, 46, 96 semicarbazide hydrochloride to ami noacetone hydiochlonde, 46,1 tetraphenylcyclopentadienone to diphenyl acetylene, 46, 44 Alcohols, synthesis of equatorial, 47, 19 Aldehydes, aromatic, synthesis of, 47, 1 /3-chloro a,0 unsaturated, from ke tones and dimethylformamide-phosphorus oxy chloride, 46, 20 from alky 1 halides, 47, 97 from oxidation of alcohols with dimethyl sulfoxide, dicyclohexyl carbodumide, and pyndimum tnfluoroacetate, 47, 27 Alkylation, of 2 carbomethoxycyclo pentanone with benzyl chloride 45,7... 

Attempts to prepare 5-vinyl-5F7-dibenz[b,/]azepine by alkylation of 5i/-dibenz[b,/]azepine with 2-chloroethyl-p-toluenesulfonate followed by dehydrochlorination, or by direct vinylation with acetylene under pressure in toluene or in dimethyl sulfoxide, have failed.194 Also, 5H-dibenz[b,/]azepine fails to react with acryloyl chloride, although the 5-acryloyl derivative 8 (R = COCH = CH2 mp 122 — 123 C) has been prepared in 65% yield by condensing dibenz-azepine 5 with 3-chloroacryloyl chloride, followed by dehydrochlorination of the product with l,8-diazabicyclo[5.4.0]undec-7-ene in dimethyl sulfoxide at 80-90°C.194... 

Besides simple alkyl-substituted sulfoxides, (a-chloroalkyl)sulfoxides have been used as reagents for diastereoselective addition reactions. Thus, a synthesis of enantiomerically pure 2-hydroxy carboxylates is based on the addition of (-)-l-[(l-chlorobutyl)sulfinyl]-4-methyl-benzene (10) to aldehydes433. The sulfoxide, optically pure with respect to the sulfoxide chirality but a mixture of diastereomers with respect to the a-sulfinyl carbon, can be readily deprotonated at — 55 °C. Subsequent addition to aldehydes afforded a mixture of the diastereomers 11A and 11B. Although the diastereoselectivity of the addition reaction is very low, the diastereomers are easily separated by flash chromatography. Thermal elimination of the sulfinyl group in refluxing xylene cleanly afforded the vinyl chlorides 12 A/12B in high chemical yield as a mixture of E- and Z-isomers. After ozonolysis in ethanol, followed by reductive workup, enantiomerically pure ethyl a-hydroxycarboxylates were obtained. 

Similar conclusions were reached for sulfoxides 157. Conformation 158 was preferred for (RS/SR)-157 but with some contribution from conformer 159. The (RR/SS) dias-tereomers preferred the reverse conformer 161 was preferred to 160161. An attractive force between Ph/Ar and Ph/R was thought to be the primary factor in determining the conformational preference of sulfoxides 152 and 157. MM2 calculations were carried out on a series of molecules of general structure PhCHR—X—R with X equal to CHOH, C=0, S and S=0151. The main conformers of these molecules have the Ph (or aryl) and R (alkyl) groups gauche. The calculations supported the existence of CH-tr attractive interactions with minor contributions from other effects. 

All attempts to prepare other [2 + 4] cycloadducts of sulfoxides 115 with dienophiles such as maleic anhydride, ethyl azodicarboxylate, etc., have failed60. A method for preparing ordinary alkyl-substituted thiirene oxides (e.g. 18 R1 = R2 = alkyl) is still lacking. 

In the case of diaryl sulfoxides the formation of both the aryl radical and the hydroxycyclohexadienyl radical was observed optically. Veltwisch and coworkers45 studied also the reaction of OH radicals from radiolysis of aqueous solutions of mixed (alkyl phenyl) sulfoxides (PhSOR). They found the formation of both alkylsulfinic and phenylsulfinic acids. 

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). 

---