Cyclopropanes functionalized

The nature of vinylcyclopropane radical cations was elucidated via the electron transfer induced photochemistry of a simple vinylcyclopropane system, in which the two functionalities are locked in the anri-configuration, viz., 4-methylene-l-isopropylbicyclo[3.1.0]hexane (sabinene, 39). Substrates, 39 and 47 are related, except for the orientation of the olefinic group relative to the cyclopropane function trans for 39 versus cis for 47. The product distribution and stereochemistry obtained from 39 elucidate various facets of the mechanism and reveal details of the reactivity and structure of the vinylcyclopropane radical cation 19 . 

Methylene-l-isopropylbicyclo[3.1.0]hexane (sabinene, 34) contains an alkene and a cyclopropane function locked in the anti orientation. CIDNP effects for 34 support a radical cation, in which the electron spin is delocalized between the olefinic 7t-system and the internal cyclopropane bond. The results are compatible with a vinylcyclopropane radical cation, 34 , with one weakened cyclopropane bond, which has retained the steric integrity of the parent molecule [219]. 

Abstract The present work describes a comprehensive review of the functionalization of cyclopropyl C-H bonds via transition-metal catalysis. Compared to the enormous number of publications related to direct sp and sp bond transformations in the last two decades, the first full account of direct cyclopropyl C(sp )-H bond functionalization was only disclosed in 2011. Both intra- and intermolecular transformations are detailed in the review, including asymmetric reactions. In addition, mechanistic aspects of various Pd-catalyzed cyclopropane functionalizations are discussed. 

Scheme 1 Cyclopropane functionalization via (a) amide-directed metalation and (b) Pd-catalyzed diastereoselective iodination...

Scheme 4 Cyclopropane functionalization reactions from the Sanfind group (a) iodination, (b)...

Scheme 25 Enantioselective cyclopropane functionalization promoted by NHC ligand 94...

Whenever functional groups are connected with a C=C double bond, their reactivity is often relayed through that double bond. Analogous rules can be applied to the corresponding cyclopropane derivatives. 

Trifluoromethylzinc compounds can be prepared via the direct reaction of dihaloditluoromethane with zinc powder in DMF [J5] (equation 24) In this reaction, the DMF functions both as solvent and reactant Mechanistic experiments support a difluorocarbene reaction intermediate Indeed, a mixture of zinc and difluorodibromomethane in THF has been used for the synthesis of gewi-difluo-ro-cyclopropane derivatives [34 (equaUon 25)... 

The behavior of strained,/Zuorimiret/ methylenecyelopropanes depends upon the position and level of fluorination [34], l-(Difluoromethylene)cyclopropane is much like tetrafluoroethylene in its preference for [2+2] cycloaddition (equation 37), but Its 2,2-difluoro isomer favors [4+2] cycloadditions (equation 38). Perfluoromethylenecyclopropane is an exceptionally reactive dienophile but does not undergo [2+2] cycloadditions, possibly because of stenc reasons [34, 45] Cycloadditions involving most possible combinations of simple fluoroalkenes and alkenes or alkynes have been tried [85], but kinetic activation enthalpies (A/f j for only the dimerizations of tetrafluoroethylene (22 6-23 5 kcal/mol), chlorotri-fluoroethylene (23 6 kcal/mol), and perfluoropropene (31.6 kcal/mol) and the cycloaddition between chlorotnfluoroethylene and perfluoropropene (25.5 kcal/mol) have been determined accurately [97, 98] Some cycloadditions involving more functionalized alkenes are listed in Table 5 [99. 100, 101, 102, 103]... 

Whereas the utility of these methods has been amply documented, they are limited in the structures they can provide because of their dependence on the diazoacetate functionality and its unique chemical properties. Transfer of a simple, unsubstituted methylene would allow access to a more general subset of chiral cyclopropanes. However, attempts to utilize simple diazo compounds, such as diazomethane, have never approached the high selectivities observed with the related diazoacetates (Scheme 3.2) [4]. Traditional strategies involving rhodium [3a,c], copper [ 3b, 5] and palladium have yet to provide a solution to this synthetic problem. The most promising results to date involve the use of zinc carbenoids albeit with selectivities less than those obtained using the diazoacetates. 

Upon removal of the auxiliary, an enantioenriched product could be obtained. The application of chiral auxiliary-based methods to Simmons-Smith cyclopropanation not only provided a useful synthetic strategy, but it also served to substantiate earlier mechanistic hypotheses regarding the directing influence of oxygen-containing functional groups on the zinc reagent [6dj. 

The cyclopropane cyclizations by elimination of triflinic acid (CF3S02H) are readily effected by basic treatment of triflones (trifluoromethyl alkyl sulfones) with activated /-protons (equations 46 and 47)39. The cyclopropane diesters 45 are formed on treatment of 44 with potassium hydride in DMSO or sodium methoxide in methanol (equation 48). In contrast, the monoester 46 failed to give the desired cyclopropane40. Addition of carbanions derived from /f, y-unsaturated phenyl sulfones to a, /i-unsaturated carboxylic esters and subsequent elimination of benzenesulfinate ion give cyclopropanes possessing the unsaturated side chain and the ester function in trans positions (equation 49)41. 

These reactions serve as a link in understanding selectivity differences between inter- and intramolecular cyclopropanation reactions, and they have been useful in defining the mechanism of addition as a function of catalyst [50,69,70]. 

Pyrazolines (51) can be converted to cyclopropane and N2 on photolysis""" or pyroiysis. The tautomeric 2-pyrazolines (52), which are more stable than 51 also give the reaction, but in this case an acidic or basic catalyst is required, the function of which is to convert 52 to 51." In the absence of such catalysts, 52 do not react/ In a similar manner, triazolines (53) are converted to aziridines." Side reactions are frequent with both 51 and 53, and some substrates do not give the reaction at all. However, the reaction has proved synthetically useful in many cases. In general, photolysis gives better yields and fewer side reactions than pyrolysis with both 51 and 53. S/Z-Pyrazoles" " (54) are stable to heat, but in some cases can be converted to... 

D.K. Taylor and co-workers investigated thoroughly a new route to diastere-omerically pure functionalized cyclopropanes utilizing stabilized phosphonium ylides and y-hydroxyenones derived from 1,2-dioxines (Scheme 7) [34-38]. 

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]. 

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