Cyclopropyl substrates

When the reaction step R—X R- takes place at a chiral carbon, racemization is almost always observed because free radieals do not retain configuration. Exceptions to this rule are found at cyclopropyl substrates, where both inversion and retention of eonfiguration have been reported, and in the reactions mentioned on page 899. 

We have previously seen (p. 437) that this is the reason nucleophilic substitutions are not feasible at a cyclopropyl substrate. The reaction is often used to convert... 

Cyclic substrates. Cyclopropyl substrates are extremely resistant to nucleophilic attack.285 For example, cyclopropyl tosylate solvolyzes about 106 times more slowly than cyclobutyl tosylate in acetic acid at (WC.286 When such attack does take place, the result is generally not normal substitution (though exceptions are known,287 especially when an a stabilizing group such as aryl or alkoxy is present) but ring opening 288... 

This concerted ionization and disrotatory ring-opening of cyclopropyl substrates has been an area of continuing interest . It can be prohibited by steric or conjugative interactions . For instance, 1-cyclopropylcyclopropyl chloride (3a) or tosylate (3b) lead to unrearranged solvolysis products, i.e. 1-cyclopropylcyclopropanol (4), and to cyclopropylethyl ketone (5) arising from homoketonization (equation 4). 

IV. CYCLOPROPYL SUBSTRATES AND SUBSTRATE ANALOGS USES AS PROBES OF ENZYMATIC MECHANISMS. 

Cyclopropyl substrates 1 with nearly all possible halogen combinations have been studied in this reaction. Some of the more informative work is cited as references in the table below. 

In 2013, Babu et al. [39] and Charette et al. [40] disclosed the direct arylation of cyclopropanes employing the aminoquinolamide and picolinamide auxiliaries, respectively. Thus, the Babu group showed that the methylene C-H bond of cyclopropyl substrate 63 can be functionalized with excess aryl iodide in the presence of catalytic Pd(OAc)2 and stoichiometric AgOAc (Scheme 17) [39]. 2-Methylthioanilide 67 could also be employed as auxiliary however the arylated cyclopropanes 68 and 69 were obtained in lower yields. Monoarylated cyclopropanes 64-66 and 68-69 were obtained as the cis-diastereomer moreover, cis-diarylated cyclopropanes can be obtained when excess (8 equiv.) aryl iodide is employed. It is also possible to access mixed triarylated cyclopropylcarboxamides... 

The aminoquinolinamide auxiliary was also shown to mediate the construction of 1,1,2-trisubstimted arylcyclopropanes [43]. Substrate 78, bearing a cis-substituted cyclopropyl moiety, reacted smoothly with a variety of (hetero)aryl iodides in a Pd-catalyzed, Ag-mediated transformation (Scheme 21). Notably, substituents such as an aldehyde, a hydroxyl, or an unprotected indole were tolerated under the reaction conditions. Additionally, the reactivity of trans-cyclopropyl substrate 79 was investigated (Scheme 21). The challenge here was... 

A system consisting of a chiral NHC ligand and a Pd(0) catalyst was shown to activate racemic cyclopropyl substrate 91 in a publication by Kiindig et al. [51]. The reaction was not selective as a 1 1 mixture of products arising from the reaction of... 

Further evidence to exclude the triplet radical pathway includes the use of cyclopropyl substrates, which serve as a radical clock. In all cases, the reaction proceeds with no indication of ring fragmentation. The nature of the transition state of the C—H insertion step has been analyzed, via a Hammett study of the intermo-lecular C—H amination with p-substituted benzenes. A negative q value of 0.73 is obtained for the intermolecular reaction with trichloroethylsulfamate [71]. Such data indicate that there is a small, but significant, preference for electron-rich substrates, thus the resonance does contribute to the stabilization of a partial positive charge at the insertion carbon in the transition state. A kinetic isotope value of 1.9 is observed for competitive intramolecular C—H amination with a deuterated substrate (Eq. (5.21)). 

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