Alkyl-sulfoxides synthesis

A major problem with the sulfoxide synthesis using menthyl sulfmates is its failure to produce optically pure dialkyl sulfoxides. The prerequisite menthyl alkanesulfinates are oils which have resisted separation into the individual epimers. The menthyl phenyl methanesulfmates are an exception the R epimer is crystalline . One solution to this problem, at least for preparing methyl alkyl sulfoxides, was achieved using cholesteryl methanesulfmates (27) . Both epimers were crystalline and could be separated by fractional crystallization, although in poor yield. Treatment of the epimers with n-propyl, n-butyl, isobutyl, p-tolyl and benzyl magnesium halides yielded the respective methyl alkyl sulfoxides (28) in greater than 95% e.e. and in 32 to 53% yields. 

In 2008, Rykowski et al. reported the synthesis of optically active 2,2 -bipyridine alkyl sulfoxides by asymmetric oxidation of their corresponding readily accessible 2,2 -bipyridine alkyl sulfides. These sulfoxides were further evaluated as ligands for the enantioselective addition of ZnEt2 to benzaldehyde, providing only low enantioselectivities of up to 14% ee (Scheme 3.34). 

Alkyl sulfoxides undergo thermal (3-elimination to yield alkenes. This strategy for the preparation of alkenes has also been applied to solid-phase synthesis, but only substrates with a high tendency to undergo elimination (e.g., y-oxo sulfoxides) could be thermally released from the support (Entry 5, Table 3.43). Unactivated sulfoxides could not be cleaved, not even under forcing conditions (199°C [767]). 

Gngnard reagents - [BROMINE COMPOUNDS] (Vol 4) - [ESTERS, ORGANIC] (Vol 9) -from benzene [BENZENE] (Vol 4) -chemiluminescence [LUMINESCENTMATERIALS - CHEMILUMINESCENCE] (Vol 15) -magnesium alkyls from [MAGNESIUM COMPOUNDS] (Vol 15) -reaction of propylene oxides [PROPYLENE OXIDE] (Vol 20) -for silanes [SILICON COMPOUNDS - SILANES] (Vol 22) -for sulfoxide synthesis [SULFOXIDES] (Vol 23)... 

In the mid-1960s Mislow started a research program on the mechanism of the thermal racemization of sulfoxides [97-99]. In the course of these efforts he recognized an enormous racemization rate acceleration for (R)-allyl-p-tolyl sulfoxide ((R)-151) as compared to benzyl or, even more pronounced, to alkyl sulfoxides (Scheme 42). For this compound, prepared by Andersen synthesis [100,101], he found a racemization rate exceeding that of the phenyl-substituted sulfoxide by a factor of 560 000. Based on kinetic measurements Mislow et al. determined the activation parameters to be AH = 22 kcal mor ... 

Anion (63), prepared from an allyl sulfoxide and LDA, reacts with alkyl halides at the a-position to give a-alkylated sulfoxides, which undergo rearrangement upon treatment with a thiophile, resulting in formation of allylic alcohols (Scheme 37).55 This method can be applied to the synthesis of cyclic allylic alcohols (Scheme 38). The reaction of (63) with aldehydes produces a mixture of regioisomers and thus it is less synthetically useful. 

Table 2.12 Synthesis of optically pure t-butyl alkyl sulfoxides from (35)...

CiP was also used in the synthesis of heteroaryl methyl sulfoxides combined with glucose oxidase as a hydrogen peroxide source, as shown in Scheme 6.1 [21]. Optically active heteroaryl alkyl sulfoxides are interesting compounds in organic chemistry, as they present a chelating center that can be used in asymmetric s mthe-sis. Moderate to good results were achieved depending on the substrate structure. The best results were obtained for the oxidation of sulfides with electron-rich heterocycles. 

According to this strategy, a-lithium alkyl sulfoxides I (Scheme 2) have been used as chiral a-hydroxyalkyl carbanion equivalents A, with fluorinated A-protected imines 2, synthetic equivalents of a-amino fluoroalkyl/aryl carbocations B (path 1), to give the target P-fluoroalkyl p-amino alcohols 3. This represents an unprecedented application of lithium alkyl sulfoxides in asymmetric synthesis, which have been... 

The formation of the above anions ("enolate type) depend on equilibria between the carbon compounds, the base, and the solvent. To ensure a substantial concentration of the anionic synthons in solution the pA" of both the conjugated acid of the base and of the solvent must be higher than the pAT -value of the carbon compound. Alkali hydroxides in water (p/T, 16), alkoxides in the corresponding alcohols (pAT, 20), sodium amide in liquid ammonia (pATj 35), dimsyl sodium in dimethyl sulfoxide (pAT, = 35), sodium hydride, lithium amides, or lithium alkyls in ether or hydrocarbon solvents (pAT, > 40) are common combinations used in synthesis. Sometimes the bases (e.g. methoxides, amides, lithium alkyls) react as nucleophiles, in other words they do not abstract a proton, but their anion undergoes addition and substitution reactions with the carbon compound. If such is the case, sterically hindered bases are employed. A few examples are given below (H.O. House, 1972 I. Kuwajima, 1976). 

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). 

Synthesis of aldehydes from pnmary alkyl halides or tosylales, using dimethyl sulfoxide (OMSO). 

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... 

Notable examples of general synthetic procedures in Volume 47 include the synthesis of aromatic aldehydes (from dichloro-methyl methyl ether), aliphatic aldehydes (from alkyl halides and trimethylamine oxide and by oxidation of alcohols using dimethyl sulfoxide, dicyclohexylcarbodiimide, and pyridinum trifluoro-acetate the latter method is particularly useful since the conditions are so mild), carbethoxycycloalkanones (from sodium hydride, diethyl carbonate, and the cycloalkanone), m-dialkylbenzenes (from the />-isomer by isomerization with hydrogen fluoride and boron trifluoride), and the deamination of amines (by conversion to the nitrosoamide and thermolysis to the ester). Other general methods are represented by the synthesis of 1 J-difluoroolefins (from sodium chlorodifluoroacetate, triphenyl phosphine, and an aldehyde or ketone), the nitration of aromatic rings (with ni-tronium tetrafluoroborate), the reductive methylation of aromatic nitro compounds (with formaldehyde and hydrogen), the synthesis of dialkyl ketones (from carboxylic acids and iron powder), and the preparation of 1-substituted cyclopropanols (from the condensation of a 1,3-dichloro-2-propanol derivative and ethyl-... 

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. 

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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