Cyclopropanations with Ylide Reagents

Asymmetric ylide cyclopropanations have been studied since 1960 and have been intensively discussed and documented in the literature. Besides chiral aminosulfoxonium ylides, chiral sulfonium as well as chiral sulfoxonium ylides have been examined in reagent-controlled asymmetric cyclopropanations. However, asymmetric ylide cyclopropanations with alkenes bearing the chiral inductor proved to be more efficient. 

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The reaction of chloromethyl aryl ethers with nucleophilic reagents has been described by Barber et al Thus, by reaction with thiourea, potassium thiocyanate, or sodium cyanide, there arc obtained aryloxyalkylisothiouronium salts, aryloxyalkyl thiocyanates, and aryloxyalkylacetonitriles, respectively. The reaction of chloromethyl aryl ethers with butyllithium leads to an aryloxycarbene which on reaction with olefins gives aryloxy-cyclopropanes. The ethers react with triphenylphosphine and a base to give phcnoxymethylene ylides which arc useful in con-... 

Reviews have featured epoxidation, cyclopropanation, aziridination, olefination, and rearrangement reactions of asymmetric ylides 66 non-phosphorus stabilized carbanions in alkene synthesis 67 phosphorus ylides and related compounds 68 the Wittig reaction 69,70 and [2,3]-Wittig rearrangement of a-phosphonylated sulfonium and ammonium ylides.71 Reactions of carbanions with electrophilic reagents, including alkylation and Wittig-Homer olefination reactions, have been discussed with reference to Hammett per correlations.72... 

Asymmetric ylide reactions such as epoxidation, cyclopropanation, aziridination, [2,3]-sigmatropic rearrangement and alkenation can be carried out with chiral ylide (reagent-controlled asymmetric induction) or a chiral C=X compound (substrate-controlled asymmetric epoxidations). Non-racemic epoxides are significant intermediates in the synthesis of, for instance, pharmaceuticals and agrochemicals. 

In addition to developments with ylides in asymmetric cyclopropanation reactions, there have been promising reports involving other unrelated cyclopropanation processes. Corey has documented exciting results in a study of the Kulinkovic reaction (Equation 24) [84], This reaction involves the addition of Grignard reagents to esters in the presence of Ti(Oi-Pr)4 to afford cyclopropanols [85]. Corey demonstrated that when the reaction was conducted in the presence of bis(TADDOL)Ti complex 143, enantioenriched products 144 were obtained (up to 78 % ee) [84]. This method provides an important entry point to chiral cyclopropanols, a class of products not otherwise conveniently accessible in optically active form. 

Dimethylsulfonium methylide is both more reactive and less stable than dimethylsulfoxonium methylide, so it is generated and used at a lower temperature. A sharp distinction between the two ylides emerges in their reactions with a, ( -unsaturated carbonyl compounds. Dimethylsulfonium methylide yields epoxides, whereas dimethylsulfoxonium methylide reacts by conjugate addition and gives cyclopropanes (compare Entries 5 and 6 in Scheme 2.21). It appears that the reason for the difference lies in the relative rates of the two reactions available to the betaine intermediate (a) reversal to starting materials, or (b) intramolecular nucleophilic displacement.284 Presumably both reagents react most rapidly at the carbonyl group. In the case of dimethylsulfonium methylide the intramolecular displacement step is faster than the reverse of the addition, and epoxide formation takes place. 

Sulfonium ylides R2S=CR 2 [672,673] and metallated sulfones [674-676] can cyclopropanate simple alkenes upon catalysis with copper and nickel complexes (Table 3.6). Because of the increased nucleophilicity and basicity of these ylides, compared with diazoalkanes, these reagents are prone to numerous side-reactions,... 

Kinetic control and thermodynamic control account, respectively, for epoxide formation and cyclopropanation [204]. Various Michael acceptors have been converted to cyclopropane derivatives with sulfur ylides. Some of the reagents used to transfer CHCOR [456], CHCOOR [457], CHMe... 

A limited number of other anionic species have been employed as Michael donors in tandem vicinal difunctionalizations. In a manner similar to sulfur ylides described above, phosphonium ylides can be used as cyclopropanating reagents by means of a conjugate addition-a-intramolecular alkylation sequence. Phosphonium ylides have been used with greater frequency261-263 than sulfur ylides and display little steric sensitivity.264 Phosphorus-stabilized allylic anions can display regiospecific 7-1,4-addition when used as Michael donors.265... 

Ylides based upon sulfur are the most generally useful in these cyclopropane-forming reactions.133 Early work in this area was done with the simple dimethyloxysulfonium methylide (9) derived from dimethyl sulfoxide. The even simpler dimethylsulfonium methylide (10) was studied at the same time as a reagent primarily for the conversion of carbonyl compounds into epoxides.134 Somewhat later, other types of sulfur ylides were developed, among which the nitrogen-substituted derivatives such as (11) are... 

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 reagent is prepared by heating triethyl phosphite with ethyl bromoacetate and is used in the modified Wittig reaction. Sodium hydride abstracts an activated a-hydrogen atom to give an anion salt (2) which functions Hke an ylide in reacting with an aldehyde or ketone to give an a,j3-un aturated ester (3). 1,2-Dimethoxy-ethane is used as solvent. The anion salt (2) reacts with diphenylketene to form the allene (5) and with styrene epoxide to form the cyclopropane (6). 

A number of cyclopropyl-substituted five-membered heterocycles have been synthesized by addition of various 1,3-dipolar reagents to (alk-l-enyl)cyclopropanes. Most reactions were performed using tricyclo[3.1.0.0 ]hex-3-ene and tricyclo[3.1.0.0 ]hex-3-en-3-yl phenyl sul-fone, giving the corresponding cycloadducts in very good yields on treatment with azides, a carbonyldicobalt complex, nitrile oxides, diphenylni-trilimine, (4-nitrophenyl)benzenecarbonitrile ylide, and diazoalkanes. For example, addition of tricyclo[3.1.0.0 ]hex-3-ene (1) to 4-nitrophenyl azide gave dihydro-1,2,3-triazole 2 in 94 /o yield. ... 

Short-lived carbenes can react with pyridine to form the corresponding pyridinium ylide, which are far more stable than the starting carbenes. For example, pyridinium tungstate 33, prepared from phenyl ethoxy carbene 31 and dihydropyridine 32, serves as an effective cyclopropanation reagent to give products 34 and 35 in a 95 5 ratio and in 35% yield. ... 

Related cyclopropanations have also been reported using sulfonium and telluronium ylides as intermediates. In particular, the cyclopropanation of enones has been carried out employing an allyl bromide as the cyclopropa-nating reagent and sulfonium and telluronium salts 134 and 135 as pre-catalysts (Scheme 7.84). These species, in the presence of a base, generated the corresponding ylide which underwent the cascade Michael/intramolecular nucleophilic substitution and it is in this second step that the real catalytically active species is released, able to interact with another molecule of the allyl bromide and thus regenerating the sulfonium or telluronium salts pre-catalysts, which can afterwards continue in the catalytic cycle. The substitution at the... 

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