Zinc Mediated Cyclopropanation

Reaction of alkenes with diiodomethane in the presence of a zinc/copper couple produces cyclopropanes by methylene transfer from an organozinc species. This is the established method of synthesising cyclopropanes. However, the procedure requires activation of the zinc by use of Zn/Cu, Zn/Ag couples, I2 or lithium metal. The first of these is most commonly used, but the sensitivity of the system to air makes the results irreproducible and erratic. Furthermore, the reaction which follows has an induction period of indeterminate length and can be extremely violent. Both these factors contribute to making large scale reactions fickle and dangerous. 

In 1982 Repic and Vogt [138] discovered that chemical activation was unnecessary in the presence of ultrasound and yields of cyclopropanated olefins were considerably higher than could be obtained using conventional methods. The reaction was carried out under nitrogen in refluxing dimethoxy-ethane, taking care to ensure that all traces of iodine were removed from the diiodomethane prior to its use. Under these conditions reaction was instantaneous and was found to proceed smoothly and rapidly with extremely crude forms of zinc, e.g. rods, foils and mossy zinc. Examination of the reaction with methyl oleate in the presence and absence of ultrasound clearly demonstrates the rate increase obtained by sonication of the reaction mixture this is shown in Fig. 22. Furthermore, switching off the ultrasound source reduces the rate of reaction to that of the stirred reaction. 

The same reaction was scaled up and run in a 50-gallon bath at 100 °C [139]. The reaction gave 0.5 kg (82%) of the cyclopropane after 2.25 h. In this case the zinc was cast as two 800 g lumps (using 125-ml conical flasks as moulds ). This increased the degree of control possible as the surface 

Recently published work [141] showed that the less reactive dibromo-methane could be used for cyclopropanation although the prior activation of the zinc was necessary. The reaction has a long induction period and yields are somewhat lower than those reported using diiodomethane. 

In 1977 Isobe et al. reported that RjZnLi 2 LiCl species would add con-jugatively to a-enones in a 1,4 fashion. Transfer of the alkyl groups proceeded in high yield, although neither phenyl nor acetylenic substrates could be persuaded to react at all [142]. 

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This review outlines developments in zinc-mediated cyclopropanation from the initial reports in the 1950s through to the current state of the art methods. The presentation will rely heavily on how the evolution of mechanistic understanding aided in the rationalization and optimization of each new advance in the asymmetric process. 

Recently, many efforts have focused on the development of the enantioselective (iodomethyl)zinc-mediated cyclopropanation of allylic alcohols. Kobayashi and co-workers reported that moderate to good enantioselectivities were observed if a C2-symmetric chiral disulfonamide was added. To reduce the rate of uncatalyzed... 

Recently, many efforts have been focused on the development of the enantioselective (iodomethyl)zinc-mediated cyclopropanation of allylic alcohols. Kobayashi and co-workers reported that moderate to good enantioselectivities were observed if a Ci-symmetric chiral disulfonamide was added. " To reduce the rate of uncatalyzed process responsible for decrease of enantioselectivity, Charette and Brochu studied the effect of addition of Lewis acid, and proved that TiCU accelerates the reaction. The addition of the chiral titanium catalyst 548 allowed the conversion of 3-aryl and 3-heteroaryl-substituted allylic alcohols to the corresponding cyclopropane derivatives in enantiomeric ratios up to 97 3 (Scheme 2-154, eq. (a)). The dioxaborolane ligand 549 is an efficient chiral reagent for the enantioselective cyclopropanation not only of allylic alcohols but also of unconjugated and conjugated... 

Methylene difluorocyclopropanes are relatively rare and their rearrangement chemistry has been reviewed recently [14]. In addition, electron deficient alkenes such as sesquiterpenoid methylene lactones may be competent substrates. Two crystal structures of compounds prepared in this way were reported recently [15,16]. Other relatively recent methods use dibromodifluoromethane, a relatively inexpensive and liquid precursor. Dolbier and co-workers described a simple zinc-mediated protocol [17], while Balcerzak and Jonczyk described a useful reproducible phase transfer catalysed procedure (Eq. 6) using bromo-form and dibromodifluoromethane [18]. The only problem here appears to be in separating cyclopropane products from alkene starting material (the authors recommend titration with bromine which is not particularly amenable for small scale use). Schlosser and co-workers have also described a mild ylide-based approach using dibromodifluoromethane [19] which reacts particularly well with highly nucleophilic alkenes such as enol ethers [20], and remarkably, with alkynes [21] to afford labile difluorocyclopropenes (Eq. 7). 

Scheme 8 Zinc-mediated preparation of cyclopropanes from functionalised iodobutenes...

The organoaluminum-mediated cyclopropanation had unique selectivity not observable in Simmons-Smith type reactions [95], Treatment of geraniol with i-Bu3Al (2 equiv.)-methylene iodide (1 equiv.) in CH2CI2 at room temperature for 5 h produced cyclopropanation products in 75 % combined yields in the ratio 76 1 4. Consequently, methylene transfer by the aluminum method occurs almost exclusively at the C(6)-C(7) olefinic site far from the hydroxy group of geraniol and the C(2) -C(3) ole-finic bond was left intact. In sharp contrast, the zinc method resulted in the opposite regioselectivity via hydroxy-assisted cyclopropanation, as shown in Sch, 62. 

The nucleophilic carbanion can also be generated from a,a-dihalomalonates or malonitriles and a suitable metal. Examples have been reported of zinc metal, magnesium metal, indium metal,dialkyltelluride, trialkylstibene, trialkylarsane, and trialkylbithmuthane mediated cyclopropanations of Michael acceptors. These reactions are closely related to the examples mentioned above. 

Cyclopropanated allylboration reagents have been used to homoallylate and homocrotylate aldehydes. A zinc-mediated a-prenylation of aldehydes and ketones has been reported conventional conditions have yielded mainly the y-adduct to date. " A racemic allene has been hydroborated in an enantioconvergent manner the enantioenriched crotylborane then reacts with aldehydes in high ee to give ( j-stannyl-homoallylic alcohols. A copper-catalysed y-selective and stereospecific allylic alkylation of ketene silyl acetals has been reported. ... 

The zinc homoenolates from cyclopropanes 15. react in the presence of MejSiCl/HMPA with a,[3-unsaturated ketones to give good yields of 1,6-D systems, by a copper-mediated (CuBr-Me2S) Michael-type addition (Table 5.4). 

Cyclopropanation mediated by zinc organometallics 2. Stereoselective cyclopropanation of acyclic alkenes... 

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