Ylides methylene transfer

The 1,3-dipolar cycloaddition of the carbonyl ylide (31) to the aldimine (32) produces the adduct (33), which has been used to synthesize the taxol C(13) side-chain (34), which is known to be required for the antitumour activity of taxol (Scheme 9).35 The dirhodium tetraacetate-catalysed decomposition of l-diazo-5-phenylpentane-2,5-dione (35) yields the carbonyl ylide (36), which cycloadds to methylenecyclopropanes (37) to produce spirocyclopropanated 8-oxabicyclo[3.2.1]octan-2-ones [(38)-(40)] in 6-75% yields (Scheme 10).36 The 1,3-dipolar cycloadditions of aliphatic or alicyclic thiocarbonyl ylides with thiobenzophenone produce both regioisomeric 1,3-dithiolanes as expected. However, in the case of highly sterically hindered thiocarbonyl ylides, methylene transfer leads to the formation of 4,4,5,5-tetraphenyl-l,3-dithiolane.37,38... 

Attempts at making epoxycyclopropanes (595) from a -unsaturated ketones and cyclopropyl ketones with ylide methylene-transfer reagents have been reported. " However, compounds were isolated which are believed to be products of rearrangement of the unisolable epoxycyclopropanes. 

Due to the high reactivity of sulfonium ylide 2 for a,P-unsaturated ketone substrates, it normally undergoes methylene transfer to the carbonyl to give the corresponding epoxides. However, cyclopropanation did take place when 1,1-diphenylethylene and ethyl cinnamate were treated with 2 to furnish cyclopropanes 53 and 54, respectively. 

Corey s ylide (1), as the methylene transfer reagent, has been utilized in ring expansion of epoxide 75 and arizidine 77 to provide the corresponding oxetane 76 and azetidine 78, respectively. 

Dimethylsulfoxonium methylide (DMSY, also referred to as Corey s reagent) is a convenient methylene transfer reagent. It appears to be the most used sulfur ylide and a Tetrahedron Report [455] covers most of its chemistry (345 references). In contrast to dimethylsulfonium methylide, which must be used as soon as it is formed, DMSY is much more stable and can be stored for several days at room temperature. It is the reagent of choice in many instances. However, with a,(3-unsaturated ketones the two reagents react in different ways, as shown for cyclohexenone. 

Dialkyl sulphides are converted into trialkylsulphonium salts by treatment with an alkyl halide (the bromide or iodide is usually the reactant of choice). An important example of this group is trimethylsulphonium iodide, which is used as a methylene transfer reagent by virtue of its being converted in the presence of base into a sulphur ylide, which is a nucleophilic carbene equivalent. 

Hi. MIRC reactions mth ylides. Numerous cyclopropane derivatives have been synthesized via methylene transfer generated from sulphur ylides, such as dimethylsulpho-xonium methylide, to electron-deficient alkenes. This is shown in the examples in... 

Sulfurylides as methylene transfer reagents were not suitable in every case. Sulfoxonium ylide (178) and the pyridyl derivative (164, R= pyridyl) formed the cyclopropane (176) , but the same reagent generated an acylated sulfoxonium ylide (177) with a phenyl compound (164, R = phenyl) (Scheme 2). The less reactive sulfonium ylide (179) and... 

The methylene transfer reaction from ylides to ketones has been developed as a convenient synthetic method for obtaining oxiranes [24]. However, the experimental procedure is complex. For example, a THF solution of dimethylsulfonium-methylide (61) is obtained by treatment of trimethylsulfonium iodide (60) with BuLi in THF at 0°C, and after addition of the ketone the mixture is heated at 50-55 °C under nitrogen to yield the oxirane. Throughout the reaction and separation of the product, the organic solvent is essential [25]. 

Cyclopropanated 1,3-disubstituted 1,2-dihydropentalenes 12 were prepared from 1,2-di-hydropen talenes 11 by methylene transfer from trimethyloxosulfonium iodide in dimethyl sulfoxide using sodium hydride at room temperature. The phenyl substituent at Cl completely shields the ryn-side of the reactive C3 to C4 double bond against attack by the ylide reagent. Compounds 12 serve as starting materials for hexahydroindene derivatives by acid-catalyzed ring-expansion reactions. 

Interestingly, the methylene transfer can also be effected in the solid state. Thus leaving a mixture of ( )- -aryl-2-benzoylethenes 18 with trimethyloxosulfonium iodide and potassium hydroxide at room temperature for 3 hours in the solid state gave the trans-cyclopropanated compounds 19 selectively in good yield (79-91 The reaction in the solid state is a much improved procedure compared with the ylide generation normally carried out and does not require dry solvent.Enantioselective solid state methylene transfer has also been reported however, a low enantiomeric excess was obtained. 

Methylene transfer (compare Dimethyloxosulfonium methylide, 1, 314-315 2, 169-171 this volume). The ylide reacts with electrophilic olefins to yield cyclopropanes. Thus it reacts with benzalacetophenone to give an essentially quantitative yield of trans-1 -benzoyl-2-phenyIcyclopropane (2), and with dimethyl maleate to give the trans-adduct (3) in 75% yield. 

The copper-catalyzed methylene transfer from sulfonium ylidcs to electron-rich olefins proceeds stereospecifically and probably involves a methylene copper complex15. Sulfonium, sulfoxonium, and (dialkylamino)sulfoxonium ylides are nucleophilic species and, in uncatalyzed reactions, only good Michael acceptors are attacked16 (see also Vol. IV/3, p 139 and Vol. E 11 2, p 1422). The cyclopropanation proceeds stepwise via a zwitterion, and therefore the olefin configuration is not necessarily reflected in the cyclopropane stereochemistry. Thus, both dimethyl ( )- or (Z)-2-butenedioate react with dimethylamino(phenyl)sulfoxonium methylide to give the //ww-substituted cyclopropane 4 only1. ... 

The reaction is most often used for epoxide synthesis via methylene transfer. An important point concerns the difference in reactivity of sulfonium versus phosphonium ylides. The former gives three-membered rings the latter gives alkenes via the Wittig reaction. Thermodynamics is believed to account for a good deal of this difference the P+-0 bond in a phosphine oxide (BDE 544 kJ/mol) is much stronger than the S+-0 bond in DMSO (BDE for DMSO DMS + O 389 kJ/mol), which would form if the sulfonium ylide reaction resulted in an alkene. 

Sulfur ylides are usually used in methylene-transfer cyclo-propanation, and an alkylidene-transfer reaction is rather difficult because the generation of an alkylidene ylide is typically difficult. Taylor and coworkers developed a new alkylidene-transfer cyclopropanation reaction using a triiso-propylsulfoxonium ylide, which was readily generated from triisopropylsulfoxonium tetrafluoroborate (Scheme 1.26) [45]. They successfully prepared gem-dimethylcyclopro-panes from electron-deficient alkenes. The obtained cyclopropanes usually contained trani-configuration. 

Sulfur ylides can also transfer substituted methylene units, such as isopropylidene (Entries 10 and 11) or cyclopropylidene (Entries 12 and 13). The oxaspiropentanes formed by reaction of aldehydes and ketones with diphenylsulfonium cyclopropylide are useful intermediates in a number of transformations such as acid-catalyzed rearrangement to cyclobutanones.285... 

Methylene difluorocyclopropanes are relatively rare and their rearrangement chemistry has been reviewed recently [14]. In addition, electron deficient alkenes such as sesquiterpenoid methylene lactones may be competent substrates. Two crystal structures of compounds prepared in this way were reported recently [15,16]. Other relatively recent methods use dibromodifluoromethane, a relatively inexpensive and liquid precursor. Dolbier and co-workers described a simple zinc-mediated protocol [17], while Balcerzak and Jonczyk described a useful reproducible phase transfer catalysed procedure (Eq. 6) using bromo-form and dibromodifluoromethane [18]. The only problem here appears to be in separating cyclopropane products from alkene starting material (the authors recommend titration with bromine which is not particularly amenable for small scale use). Schlosser and co-workers have also described a mild ylide-based approach using dibromodifluoromethane [19] which reacts particularly well with highly nucleophilic alkenes such as enol ethers [20], and remarkably, with alkynes [21] to afford labile difluorocyclopropenes (Eq. 7). 

Dimethyloxosulfonium methylide reacts with the triketone (212) to give the fused 2-hydroxymethylenedihydropyran (213) (76H(4)1755). The reaction is thought to proceed through a zwitterion and the epoxide as indicated in Scheme 41. Intramolecular nucleophilic attack leads to the dihydropyran and the overall process may be regarded as a transfer of methylene from the sulfur ylide. 

The biosynthesis of the cyclopropane ring in natural products can occur through transfer of a methylene group from an ylide derived from S-adenosyl methionine to an unactivated olefin such as an oleic ester [468] via a copper(i) carbcne complex [469]. 

Both reagents transfer a methylene group in efficient and selective pathways. So it is not surprising that sulfur ylides have been widely used as synthetic tools for the preparation of epoxides. The reactions can make use of sulfonium salts under phase transfer catalytic conditions, and the cheap and easily accessible trimethyl sulfonium methyl sulfate and triethylsulfonium ethyl sulfate were found to show a high reactivity under such conditions [450]. 

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