MIRC reactions

An indirect nucleophilic opening is depicted in Scheme 24. The functionalized vinyl aziridine 37 undergoes a Michael-initiated ring closure (MIRC) reaction upon treatment with suitable nucleophiles to give cyclopropanes with concomitant opening of the aziridine ring [34]. 

The optimum results were obtained with Grignard reagents in the presence of 10 mol % of Cu(I)CN. The stereochemical course of this MIRC reaction can be explained by adopting Yamamoto s model for conjugate addition of cyano-cuprates to y-alkoxy-a,)5-unsaturated esters (Fig. 2) [35]. In this model, it is proposed that the larger substituent (L), in our case the tosyl group, will adopt the... 

The cz5-aziridine substrate shows, as expected on the basis of this model, predominant formation of the trans-cyclopropane product. The starting materials for this MIRC reaction can readily be obtained from the aziridine esters by reduction to the corresponding aldehyde and a subsequent Knoevenagel reaction with malonate ester (Scheme 25) [34]. 

Bond constructions similar to those just discussed can be achieved using an alkylidene malonate which is tethered to an alkyl bromide [72]. Of particular interest in this context is the controlled potential reductive cyclization of 263. As illustrated, the method provides a reasonably facile and modestly efficient entry to cyclobutanes 264. Presumably, the process is initiated by reduction of the alkylidene malonate rather than the alkyl halide, since alkyl bromides are more difficult to reduce. The same substrate, when reduced with L-Selectride undergoes conjugate addition of hydride and a subsequent cyclization leading to the five-membered ring 265. The latter transformation constitutes an example of a MIRC reaction [71-73], a process which is clearly complementary to the... 

The Michael addition followed by Intramolecular Ring Closure (MIRC) reactions have been recognized as a general synthetic approach to carbocyclic three-membered ring derivatives [1]. The enhanced Michael reactivity of methyl 2-chloro-2-cyclopropylideneacetate (1-Me) towards thiolates, alkoxides, lithiated amides and cyclohexadienolates (see below) allows one to perform highly efficient assemblies of spiropentane, tricyclo [3.2.1.0 ]octane, bicyclo [2.2.2] octane... 

Scheme 62. Two MIRC reactions of methyl 2-chloro-2-cyclopropylideneacetate (1-Me) [104]...

From a formal point of view, the one-pot heterocyclizations discussed in Sect. 4.2 may be also called MIRC reactions, in the present section this term implies the formation of a cyclopropane ring in accordance with the generally accepted MIRC mechanism [1]... 

In addition, we were able to extend the tandem hetero Michael addition/a-ester-enolate alkylation protocol by an intramolecular variant via a Michael-initiated ring closure (MIRC) reaction leading to diastereo- and enantiomerically pure trans-configured 2-amino-cycloalkanoic acids 30 (Scheme 1.1.7) [14c,d]. 

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. ... 

Rearrangements of complex aziridines can also result in interesting cyclic structures. For example, Zwanenburg and co-workers <1996T12253> have applied the Michael reaction-induced ring-closure (MIRC) reaction to aziridinyl... 

Synthesis and reactivity of electrophilic cyclopropanes b. MIRC reactions with the leaving group in the attacking nucleophile... 

Stereochemical control can be achieved during the MIRC reaction of acrylonitrile with a-chloroacetonitrile producing 1,2-dicyanocyclopropanes. Cis compounds are favoured when a tetraalkylammonium salt is used in a two-phase system. This phenomenon is due to the fact that in the absence of the catalyst, the whole multistep process takes place at the phase boundary, whereas the catalytic reaction occurs inside the organic phase ". ... 

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... 

It is clear that during nucleophilic reactions of allylic halides carrying one EWG various other reaction pathways can occur in addition to MIRC reactions, e.g. addition, substitution, rearrangement and eliminationFor example, reaction of ethyl 4-bromocrotonate (273) with sodium ethoxide in ethanol only affords minor amounts of the 2-ethoxycyclopropane carboxylate (274) in addition to the substitution (276) and the addition-substitution (275) product (equation 83). Nevertheless, a cyclopropane... 

The reaction of vinylsulphonium salts (356) with active methylene functions also gives electrophilic cyclopropanes via the formation of an unstable ylid which undergoes proton shift to an intermediate 1,4-sulphonium betaine (375) followed by expulsion of dimethyl sulphide (equation 115) . In addition MIRC reactions of substrates with... 

Cyclopropanation of steroids (363) at the 1,2-position with malonate in the presence of potassium t-butoxide and tetramethylguanidine takes place with formation of the di(alkoxycarbonyl)cyclopropane derivatives (364) accompanied by steroidal cyano-alkoxycarbonylcyclopropanes (365). When the reaction is carried without tetramethylguanidine only minor amounts of cyclopropyl steroids are isolated The formation of the cyano compound is explained by an initial nucleophilic displacement of bromine by the tetramethylguanidine moiety, followed by several steps (equation 119). Although the reaction of equation 120 cannot be classified as a MIRC reaction sensu strictu the formation of cyclopropa[c]cinnolines (367) via an intramolecular 1,1-cycloaddition of nitrilimines is mentioned here. Treatment of o-vinylphenyl-substituted chloroglyoxylate... 

I.I.3.7.I. MIRC Reactions with the Leaving Group in the Nucleophile... 

Table 9. Examples of MIRC Reactions with a Halogen Atom as Leaving Group...

The yield of the MIRC reaction is mainly determined by the initial Michael addition. Large substituents on the alkene decrease the reaction rate, this trend is illustrated by entries 13-16 in Table 9. 

Generally, MIRC reactions lead to racemic mixtures of cyclopropanes. The stereoselectivity of the reaction is determined by the cyclization step on the in situ formed intermediate Michael adduct. The cisjtrans ratio of the substituents on this newly formed bond depends on the solvent polarity, the degree of anion-cation association and steric interactions. When the reaction takes place under phase-transfer conditions the cisltrans ratio also depends on whether or not a catalyst is used. ... 

Special attention should be given to the MIRC reaction of 2-bromobut-2-enoates with cyclohexenones, e.g. 1 and Table 10. When first cyclohexenone was added to a lithium diiso-propylamide solution, tricyclo[3.2.1.0 ]octan-6-ones were formed in 20-55% yield via double Michael addition, followed by intramolecular displacement. However, when ethyl 2-bro-mobut-2-enoate was first added to a lithium diisopropylamide solution, vinylcyclopropanes were formed in good yield (Table 10, entries 1-2). Other chalcones have also been used to produce vinylcyclopropanes (entries 3-8) with reasonable success. 

Another special case of the MIRC reaction involving a-halocarbanions is the cyclopropanation of hydrazone and oxime anions with methyl a-bromoacrylate to give cyclopropanes 3 and 4, respectively. ... 

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