Cyclopropane, trisubstituted

Cyclopropanes, 1,2,3-trisubstituted, 205, 206 Cyclopropanols, nucleophilic addition cylization, 249-50 Cyclopropylcarbinyl-homoaUyl... 

The carbenoid generated from diiodomethane/diethylzinc is often found to be more reactive than the conventional Simmons-Smith reagent. Thus, in the case of 1-alkenylboronic acid esters, where diazomethane failed to cyclopropanate trisubstituted derivatives (Section 1.2.1.1.1.) diiodomethane/diethylzinc gave good yields of the required products 16. ... 

Tertiary bismuthines appear to have a number of uses in synthetic organic chemistry (32), eg, they promote the formation of 1,1,2-trisubstituted cyclopropanes by the iateraction of electron-deficient olefins and dialkyl dibromomalonates (100). They have also been employed for the preparation of thin films (qv) of superconducting bismuth strontium calcium copper oxide (101), as cocatalysts for the polymerization of alkynes (102), as inhibitors of the flammabihty of epoxy resins (103), and for a number of other industrial purposes. 

Alkenylcarbene complexes react with in situ-generated iodomethyllithium or dibromomethyllithium, at low temperature, to produce cydopropylcarbene complexes in a formal [2C+1S] cycloaddition reaction. This reaction is highly diastereoselective and the use of chiral alkenylcarbene complexes derived from (-)-8-phenylmenthol has allowed the enantioselective synthesis of highly interesting 1,2-disubstituted and 1,2,3-trisubstituted cyclopropane derivatives [31] (Scheme 9). As in the precedent example, this reaction is supposed to proceed through an initial 1,4-addition of the corresponding halomethyllithium derivative to the alkenylcarbene complex, followed by a spontaneous y-elimi-nation of lithium halide to produce the final cydopropylcarbene complexes. 

Only a few results are available concerning competitive cyclopropanation of non-conjugated dienes. The case of 1,4-hexadiene72 (mixture of Z and E isomers) illustrates the reactivity difference between a monosubstituted and a 1,2-disubstituted double bond, whereas in limonene (24)47, a 1,1-disubstituted and a trisubstituted double bond compete for the carbenoid derived from ethyl diazoacetate. In both cases, the less substituted double bond reacts preferentially (Scheme 8). 

Aziridines have been synthesized, albeit in low yield, by copper-catalyzed decomposition of ethyl diazoacetate in the presence of an inline 260). It seems that such a carbenoid cyclopropanation reaction has not been realized with other diazo compounds. The recently described preparation of 1,2,3-trisubstituted aziridines by reaction of phenyldiazomethane with N-alkyl aldimines or ketimines in the presence of zinc iodide 261 > most certainly does not proceed through carbenoid intermediates rather, the metal salt serves to activate the imine to nucleophilic attack from the diazo carbon. Replacement of Znl2 by one of the traditional copper catalysts resulted in formation of imidazoline derivatives via an intermediate azomethine ylide261). 

The second Had synthesis provided a route to 2,3,4-trisubstituted pyrroles <06CC2271>. Mixing cinnamaldehyde 27 with aminocarbene complex 28 in the presence of molecular sieves (MS) gave pyrrole 29. The authors proposed a mechanism that included a cyclopropane intermediate and subsequent fragmentation and intramolecular condensation. 

These catalysts were shown to have some generality beyond trisubstituted alke-nes. In particular, Z-menthyl diazoacetate leads to moderately selective cyclopropane formation with a number of alkenes. These are illustrated in Table I. 

Reipig (39,40), Pfaltz (41), and Andersson and their co-workers (42) independently showed that these catalysts are capable of effecting the selective cyclopropanation of enol ethers and enolsilanes. Methyl vinyl ketone and acetophenone enolsilanes provide high selectivities in the cyclopropane products, but both isomers are formed equally. The trisubstituted dihydropyran 65 leads to cyclopropane adducts in high diastereoselectivities and enantioselectivities using 55c CuOTf as catalyst. 

Lowenthal and Masamune (44) investigated the cyclopropanation of trisubsti-tuted alkenes leading to a chrysanthemic acid synthesis. They found that ligand 50c provided poor selectivities in this case (24% de for the trans isomer). Substitution in the 5 position of the oxazolines leads to increased selectivities, with excellent results provided by the BHT ester (94 6, 94% ee), Eq. 32. This ligand proved to be applicable to other trisubstituted and several cis-disubstituted alkenes, providing the corresponding cyclopropanes in ee values of 82-95%. These authors note that catalysts generated from CuOTf, CuOf-Bu, and Cu(II) precursors (with activation) provided similar yields and enantioselectivities. 

In addition, if this reaction was run in the presence of trimethylborate, a usual zinc-boron exchange led to the cyclopropylboron derivative that could be used in Suzuki coupling to give rise to trisubstituted cyclopropanes (equation 64) . 

Interestingly, cyclopropane and benzene have the same number of isomers for a given number of identical substituents ignoring optical isomers, cyclopropane and benzene have one type of monosubstituted derivative, three types of disubstituted, three types of trisubstituted, three types of tetrasubstituted and one type apiece of penta- and hexasubstitution. But does this seemingly accidental counting equivalence have any thermochemical consequences ... 

Cyclopropanes 1,1,2-trisubstituted with electron-withdrawing groups are prepared by treating electron-deficient alkenes with dibromomalonic ester or related active methylene dibromides in the presence of trialkylstibine (equation 132))290 291, dibutyl telluride292 or... 

Steric factors, in some cases, are the key to the regiocontrol in intermolecular cyclopropanation reactions. The inertness of trisubstituted double bonds to palladium catalysed cyclopropanation may explain the extremely regoselective cyclopropanation observed with FK 506 (equation 10)20. 

A related allylic C-H insertion that has considerable promise for strategic organic synthesis is the reaction with enol silyl ethers [23]. The resulting silyl-protected 1,5-dicarbonyls would otherwise typically be formed by means of a Michael addition. Even though with ethyl diazoacetates vinyl ethers are readily cyclopropanated [l],such reactions are generally disfavored in trisubstituted vinyl ethers with the sterically crowded donor/acceptor carbenoids [23]. Instead, C-H insertion predominates. Again, if sufficient size differentiation exists at the C-H activation site, highly diastereoselective and enantioselective reactions can be achieved as illustrated in the reaction of 20 with 17 to form 21 [23]. 

However, structural effects from the olefin on stereoselection are relatively minor, and only with trisubstituted olefins do diastereoisomer ratios exceed 95 5. 5-Halo-2-pentenes (entries 7 and 8) are exceptional in this series with both an inverted preference for formation of the cw-cyclopropane derivative and the high selectivity for this stereoisomer. Only one other... 

A novel method for enantioselective organocatalytic cyclopropanation has been developed, using a new class of iminium intermediates and based on the concept of directed electrostatic activation (DEA). This novel organocatalytic mechanism exploits dual activation of ylide (153) and enal (152) substrates through the formation of the iminium intermediate (155) and electrostatic activation (156). The resulting (g) trisubstituted cyclopropanes (157) were obtained with high levels of enantio- and diastereo-control.180... 

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