LAS DOCE REGLAS

The increased reactivity of donor-acceptor (DA) cyclopropanes 113 results from the vicinal relationship between both donor and acceptor groups, which work in a synergistic manner to activate the C-C bond for cleavage.80, 101 The activated vicinal DA cyclopropanes serve as synthetically useful

1,3-dipolar synthons 114, via the push-pull effect, to promote a variety of reactions

Scheme 1.27. C-H arylation of cyclopropylanilines via ring opening.

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with nucleophiles, electrophiles, or dipolarphiles (Figure 1.8). The dual activation of vicinal substituents further enhances the synthetic applications of cyclopropanes by combining both homo-Michael and homo-enolate equivalents into one synthon. In addition, the acquired umplung reactivity is advantageous to achieve transformations that are challenging by previous routes. One of the approaches to ring opening reactions of DA cyclopropanes is nucleophilic addition by heteroatom nucleophiles or electron rich arenes, usually mediated by a Lewis acid. The carbanion 154 bearing the acceptor group can then be protonated to provide 1,3-

bifunctionalized acyclic derivatives, which are found in biologically active small molecules . A ring opening strategy by Charette reported a nucleophilic addition of primary or secondary amine nucleophiles to enantiomerically enriched DA cyclopropanes (methyl 1-

nitrocyclopropanecarboxylates 157) catalyzed by Ni(ClO4)2 as a Lewis acid (Scheme 1.28).102

The amino-functionalized products 158 were achieved in good yields (63-94%) with complete retention of enantiomeric excess at C-4. The doubly activated cyclopropanes were employed again in a similar ring opening strategy using a variety of phenol derivatives as nucleophiles to provide the 1,3-bifunctional adducts 159 (53-84%), in the presence of Cs2CO3 as the base.103

This method enabled quick access to 3-aryl-3-phenoxypropane motifs, which are found in numerous monoamine reuptake inhibitors, such as Strattera.

Another approach to ring opening of DA cyclopropanes proceeds through reactions with electrophiles to yield 1,3-substituted acyclic systems, analogous to the transformed adducts

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Scheme 1.29. Ring-opening reactions of DA cyclopropanes with electrophiles.

mentioned with nucleophiles. Recent developments introduced transition metals to promote the ring cleavage, while employing acceptor-substituted vinylcyclopropanes as suitable substrates to undergo the transformation. The key nucleophilic π-allyl-metal species formed thus enables an inverse of polarity and reactivity of DA cyclopropanes by the observed electrophilic trapping at the donor site. In contrast to the normal polarity, the nucleophilic reactivity at the donor site arises as a result of the umpolung reactivity. In 2011, the Krische group investigated a DA cyclopropane-mediated carbonyl allylation catalyzed by a cyclometalated iridium complex (Scheme 1.29).104 The enantioselective C-C coupling process tolerated alcohols or aldehyde oxidation levels as effective carbonyl electrophiles to provide the desired enantiomerically enriched products 161. Moreover, further conversion to disubstituted δ-lactones 162 was successfully realized.

In addition to the nucleophilic and electrophilic approaches to ring opening of activated DA cyclopropanes, cycloadditions with various dipolarophiles have been commonly exploited as a pathway to ring-opening cyclization. Cycloadditions has become a prominent tool for the construction of highly functionalized and complex polycyclic structures, produced in one single step. The bond breaking and bond forming event (stepwise or concerted) provides the ability to

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control the stereochemical outcome of the reaction. Moreover, high regioselectivity is attained by the preferential addition of the partially charged centers in the dipolarophiles with the 1,3- dipole cyclopropane. Both inter- and intramolecular cycloadditions of DA cyclopropanes have been widely investigated and have continued to showcase its applicability in organic synthesis and natural products. For instance, numerous reports by Johnson,105 Waser,106 Yang,107 and others described aldehyde compounds undergoing [3+2] cycloadditions with DA cyclopropanes 163 for the formation of tetrahydrofuran (THF) derivatives (Scheme 1.30, Eq. 1). Alkyl- and aryl-substituents were susceptible donor groups on the cyclopropane while the acceptor groups were limited to geminal ester substituents. Successfully catalyzed by various Lewis-acids, cycloadditions with neutral or electron-deficient aldehydes resulted in high stereoselectivity for the preferred 2,5-cis-configured tetrahydrofuran adducts 165. Likewise, amino-substituted tetrahydrofuran derivatives were synthesized by replacing the donor group with an amine substituent (i.e. Nphth) on cyclopropane 163. Notably, the stereochemical outcome of the cycloaddition was highly influenced by the choice of aldehyde as 2,5-trans products 166 were observed with electron-rich aryl aldehydes.

Scheme 1.30. Ring-opening cycloaddition of DA cyclopropanes with aldehydes, imines, and nitrones.

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Analogous to the carbonyl systems are imines and nitrones which have been reported to participate in the cycloadditions with DA cyclopropanes to provide tetrahydropyrroles/

pyrrolidines and 1,2-oxazines, respectively (Scheme 1.30, Eq. 2). The Kerr group investigated the preparation of 2,5-cis-pyrrolidines 167 from a [3+2] cycloaddition of aldimines and 1,1- cyclopropanediesters 163 catalyzed by a mild Lewis-acid, Yb(OTf)3.108 The diastereoselectivity

was rationalized by model 167a, similar to Johnson’s, illustrating a Mannich-type ring closure in which the diaxial interaction between substituent (R1) of the imine and ester of the cyclopropane was minimized. Under the same Lewis acidic conditions or promoted by magnesium iodide (MgI2), the authors revealed a [3+3] cycloaddition of nitrones with 1,1-cyclopropanediester to

yield tetrahydro-1,2-oxazines 168, as the cis isomer exclusively.109 Upon generating the nitrone in situ, via an aldehyde and hydroxylamine, the oxygen anion produced is proposed to open the cyclopropane ring in a nucleophilic fashion (see 168a). Further mechanistic evidences supported a stepwise pathway rather than a concerted pathway. While much intermolecular ring opening cyclizations of DA cyclopropanes have been well-documented, examples involving an

intramolecular transformation have become more frequent.110 Likewise, the required acid needed to activate the ring cleavage has lead to the ongoing development of various catalytic procedures. Major advantages of the intramolecular route include increased and controllable reactivity to achieve high selectivities, as well as rapid formation of complex polycycles and natural products.

The modes of activation for cyclopropanes have allowed development of various ring- opening strategies to further showcase its broad utility in organic transformations. The

susceptibility to C-C bond cleavage has permitted substituted cyclopropanes to serve as valuable substrates in synthetic applications. Among the activated cyclopropanes, cyclopropanols have

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been most frequently investigated as donor-substituted cyclopropanes. However, ring-opening strategies with aminocyclopropanes remain less explored. Successful cycloadditions with DA cyclopropanes have sparked the interest of investigating cycloadditions with

aminocyclopropanes as an effective ring-opening strategy for donor-substituted cyclopropanes. To the best of our knowledge, no reports of aminocyclopropane undergoing cycloaddition, mediated by visible light photocatalysis, has been documented prior to our group’s discovery of the [3+2] annulation of cyclopropylanilines.