Cyclopropanation of Michael acceptors

Sulfur ylides are most frequently employed in this methodology. The cyclopropanations of Michael acceptors with arsenic252, selenium253 and tellurium ylides254 have also been... 

Asymmetric cyclopropanations of Michael acceptors with ylides have been explored for a number of substrates modified with chiral auxiliaries. The reactions of 47 with Ph3P=CMe2,48 (equation 119)259 and of 49 with 50 (equation 120)260-261 proceed with excel-... 

The nucleophilic carbanion can also be generated from a,a-dihalomalonates or malonitriles and a suitable metal. Examples have been reported of zinc metal, magnesium metal, indium metal,dialkyltelluride, trialkylstibene, trialkylarsane, and trialkylbithmuthane mediated cyclopropanations of Michael acceptors. These reactions are closely related to the examples mentioned above. 

Other examples of cyclopropanation with stabilized 5-ylides, i.e. alkyl- or aryl-(dimeth-ylamino)oxosulfonium alkanides/ " are presented in Table 15. 5-Ylides stabilized by an anion-stabilizing group at the nucleophilic carbon atom have also been successfully utilized for the cyclopropanation of Michael acceptors. The stabilizing group was a ketone/ " ester/carboxylate anion/ phosphonate diester/ or a cyano function (Table 16). 

Oxosulfonium ylides as well as sulfonium ylides stabilized by an electron-withdrawing group, such as an acyl , an alkoxycarbonyP , a cyano " and one of their vinylogues satisfactorily cyclopropanate a variety of Michael acceptors (e.g., equation 81) . In these reactions, the 1,2-addition is usually a minor pathway. Ylides stabilized by two... 

A wide variety of Michael acceptors have been reacted with sulfoxonium methylides, e.g. a,p-unsaturated ketones, nitriles, sulfones, sulfonamides and nitro compounds, to give good yields of the corresponding cyclopropane derivatives.1,2a Steric hindrance may decrease the rate of reaction but need not prevent reaction for example, the very hindered compound 4,6,6-trimethyl-3-hepten-2one (61) reacts with dimethylsulfoxonium methylide (33) to give the cyclopropane (62) (Scheme 24). 

Alkenes susceptible to Michael additions react with sulfur ylides to form cyclopropanes. Examples of typical ylides used in the cyclopropanation reaction of Michael acceptors are presented in Scheme 4. Best results were obtained with stabilized ylides, i.e. ylides of type C, D or E, and yields were enhanced with increase of the electron-withdrawing capacity of the anion stabilizing group in the alkene. The mechanism of the cyclopropanation reaction (Scheme 5) is known, and proceeds in a nonstereospecific manner. The E/Z geometry of the alkene is frequently retained in the product and a high degree of asymmetric induction can be achieved with optically active Michael acceptors or ylides. 

The reaction of Michael acceptors with dimethyloxosulfonium methanide has been extensively explored. " In addition to carbene (or carbenoid) additions (Section 1.2.1.) and the Simmons-Smith method, " (see also Section 1.2.1.1.) this is the most widely utilized method for the introduction of a cyclopropane ring, in good to excellent yield, to a,)S-unsaturated... 

Sulfur ylides are useful as nucleophilic alkylidene transfer agents in reactions with electron-deficient functional groups, forming epoxides with carbonyls, and either undergoing carbonyl addition with epoxide formation or conjugate addition with cyclopropanation with Michael acceptors, depending on the structure of the Michael acceptor [113]. 

Asymmetric allylic C-H activation of more complex substrates reveals some intrinsic features of the Rh2(S-DOSP)4 donor/acceptor carbenoids [135, 136]. Cyclopropanation of trans-disubstituted or highly substituted alkenes is rarely observed, due to the steric demands of these carbenoids [16]. Therefore, the C-H activation pathway is inherently enhanced at substituted allylic sites and the bulky rhodium carbenoid discriminates between accessible secondary sites for diastereoselective C-H insertion. As a result, the asymmetric allylic C-H activation provides alternative methods for the preparation of chiral molecules traditionally derived from classic C-C bond-forming reactions such as the Michael reaction and the Claisen rearrangement [135, 136]. 

Syntheses of cyclopropanes and oxiranes of high optical activity could be achieved [480] through reactions of anions derived from optically active sulfoximines or sulfoxides, respectively, with Michael acceptors or aldehydes, separation of the diastereoisomeric adducts and conversion of these to the cyclized products. 

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... 

Michael acceptors which carry a good leaving group at the a-carbon atom or whose electron-withdrawing group itself can serve as the leaving group may be cyclopropanated by active methylene compounds under basic conditions via a prototropic shift subsequent to the Michael addition as outlined in equation 139. Thus, the basicity of the carbanions involved must be balanced to allow the requisite prototropic shift otherwise, the reaction will be very slow or will not work. 

Another type of chiral Michael acceptor, the oxazepine derivatives (47), is prepared by condensation of the (-)-ephedrine-derived malonic acid derivative (46) with aldehydes (Scheme 18).51 52 Treatment of (47) with a variety of Grignard reagents in the presence of NiCh affords, after hydrolysis and decarboxylation, the 3-substituted carboxylic acids (48), in most cases with more than 90% ee. Diastereoselective Michael additions to (47) were also used for the preparation of optically active cyclopropane derivatives (49)53 and P-substituted-y-butyrolactones (50 Scheme 18).54 A total synthesis of indolmycin is based on this methodology.55... 

Only a limited number of examples have been reported. The reactivity of sulfonium ylide 98a, prepared by the reaction of thiepine 96 and dimethyl diazomalonate (Section 13.03.6.1), was examined <20060BC2218>. The reactivity of the stabilized sulfonium ylide 98a was restricted to the highly reactive Michael acceptor, tetracya-noethylene 152 (the ylide failed to react with benzaldehyde or dicyanoethylene). Reaction of ylide 98a with tetracyanoethylene 152 led to the consumption of the ylide 98a (Equation 22). Thiepine 96 was produced in the reaction and the formation of cyclopropane 153 was suggested. 

Addition of dimethylsulfonium methylide (122) to various Michael acceptors (121), followed by alkylation, has been reported to produce functionalized 1-substituted alkenes (124), arising via the unprecedented elimination (123), rather than the usual cyclopropanation products. In silyl substituted substrates, where a facile Peterson-type olefination is possible from the adduct, elimination took place instead. Aryl-substituted Michael acceptors (121 R1 = Ar) underwent a similar olefination to give 1-substituted styrene derivatives with moderate yields along with a side product, which arose by nucleophilic demethylation from the adduct of dimethylsulfonium methylide and arylidene malonates. Hammett studies revealed that selectivity for olefination versus demethylation increases as the aryl substituent becomes more electron deficient.164... 

Why does the stabilized ylid prefer to react with the double bond In order to understand this, let s consider first the reaction of a simple, unstabilized ylid with an unsaturated ketone. The enone 1 has two electrophilic sites, but from Chapters 10 and 23, in which we discussed the regioselectivity of j attack of nucleophiles on Michael acceptors like this, you would expect that direct 1,2-attack on the i ketone is the faster reaction. This step is irreversible, and subsequent displacement of the sulfide i leaving group by the alkoxide produces an epoxide. It s unimportant whether a cyclopropane prod- uct would have been more stable ihe epoxide forms faster and is therefore the kinetic product. 

An interesting feature of Michael addition reactions is that Michael acceptors with a leaving group (mostly halides) in y-position can be used for the synthesis of cyclopropanes. The so-called Michael-initiated ring closure reaction (MIRC reaction) starts with an addition of a nucleophile to the a,/3-unsaturated carbonyl, and afterwards the intermediate enolate displaces the leaving group to give the desired cyclopropanes. ... 

When carbon nucleophiles carrying a leaving group at the a-position are allowed to react with Michael acceptors, the resultant intermediate anions will be capable of undergoing an intramolecular displacement to produce cyclopropanes (equation 85). Some reactions described in Section III. A may actually proceed in this way. 

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