Cyclopropanations with Carbene Equivalents

Enantiomerically pure iron carbene complexes have been used for carbene transfer reactions to alkenes, e.g. vinyl acetate and styrene, at low temperature to furnish cyclopropanes with moderate cis/trans selectivity in high optical yield (75-95% ee). A two-step reaction mechanism has been proposed to explain the origin of enantioselectivity.  

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Reaction of Electrondeficient Olefins with Donor-Carbene-Equivalents One interesting application of Fischer-type carbene complexes in organic synthesis is their addition to acceptor olefins affording methoxy substituted cyclopropanes 65 (Eq. 20). 

Because of these and other useful molecules containing three-membered rings, methods to make them are important as well as interesting. Most chemical syntheses of compounds containing cyclopropyl groups make use of the addition of a carbene, or carbene equivalent, to an aikene. What do we mean by carbene equivalent Usually, this is a molecule that has the potential to form a carbene, though it may not actually react via a carbene intermediate. One such example is a zinc carbenoid formed when diiodomethane is reacted with zinc metal it reacts with alkenes just as a carbene would—it undergoes addition to the 7t bond and produces a cyclopropane. 

Heteroatom-containing ene analogues react with imine or carbene equivalents to give heterocycles in reactions similar to [2-1-1] carbene/alkene cyclopropanation. Alkylidenoaminoboranes R2N=B=CR 2 react slowly with various azides with loss of N2 to form azaboriridines 36 in poor yield. An example appears in Equation (21) (R = PhCH2 or Ph) <1985AGE416, 1989CB595>. 

All disconnections are the same on cyclopropane, requiring a carbene equivalent which will add to an unactivated double bond. Diazomethane will do this, but one of the best carbene sources is CH2I2 with a zinc-copper couple (the Simmons-Smith reaction ). This works particularly well on allylic alcohols (31), no doubt because of hydrogen bonding between the OH group and the reagent. The reaction is then totally stereoselective. 

The formation of substituted cyclopropane rings by the reaction of alkenes with Fischer carbenes has been known for some time [58]. More recently, cyclopropyl groups have been produced as parts of bicyclic and tricyclic ring systems by, formally, the reaction of Fischer carbenes with one equivalent of alkene and one equivalent of alkyne. Indeed, this reaction type proceeds through alkene trapping of a metal carbene generated in situ. The various methodologies that have been developed may be divided into three classes the intermolecular reaction of a,co-enynes with Fischer carbenes, the partially intramolecular reaction of Fischer carbene-tethered alkynes with alkenes, and the fully intramolecular reactions of Fischer carbene-tethered enynes. No fiilly intramolecular version of this reaction has been reported. 

One of the most important applications of EDA and of other diazo compounds with electron-withdrawing a-suhstituents (denoted EWG in the equation below) is as carbene equivalents in transition-metal-catalyzed cyclopropanation reactions ... 

In considering catalyzed olefin-cyclopropane interconversions, an important question arises concerning thermodynamic control and the tendency (or lack thereof) to attain a state of equilibrium for the system. Mango (74) has recently estimated the expected relative amounts of ethylene and cyclopropane for various reaction conditions and concluded that the reported results were contrary to thermodynamic expectation. In particular, the vigorous formation of ethylene from cyclopropane (16) at -78°C was stated to be especially unfavored. On the basis of various reported observations and considerations, Mango concluded that a reaction scheme such as that in Eq. (26) above (assuming no influence of catalyst) was not appropriate, because the proper relative amounts of cyclopropanes and olefins just do not occur. However, it can be argued that the role of the catalyst is in fact an important element in the equilibration scheme, for the proposed metal-carbene and [M ] species in Eq. (26) are neither equivalent nor freely interconverted under normal reaction conditions. Consequently, all the reaction pathways are not simultaneously accessible with ease, as seen in the published literature, and the expected equilibria do not really have an opportunity for attainment. In such a case, absence of thermodynamic control should not a priori deny the validity of Eq. (26). 

A few specific examples of cyclopropanation using the above methods are shown in Scheme 2.134. The naturally occurring insecticide /ra -chrisanthemic acid 396 served as an obvious target to check the viability of carbene addition as a preparative method. This compound was first synthesized (in the mixture with the cis isomer) by the monocyclopropanation of 2,5-dimethyl-2,4-hexadiene. Since then, numerous analogs of 396 were prepared by similar reactions. Some of the analogs are now widely used as efficient and ecologically safe pesticides. The formation of the tricyclic hydrocarbon 397 from 1,5-hexadiene proceeds as a sequence of inter- and intramolecular carbene transfer reactions. An initial carbene precursor, CHBr3, is actually employed here as an equivalent of a unique tetradentate Ci synthon The preparation of 398 via intramolecular [2 + 1] photocycloaddition is a typical example of the efficiency of this route for the construction of the polycyclic framework frequently encountered in the structures of natural compounds. 

When the donor character of the amino substituent at the transition-metal-carbene carbon atom is reduced, it should be possible to influence the thermal stability and reactivity in favor of the desired cyclopropanation process. Indeed, pyrrol-1 -ylcarbene complexes 18 of chromium, molybdenum and tungsten do exhibit the desired reactivity. In the last step, the pyrrole ring of 19 can be converted to the NH2 function in 20 after oxidative cleavage with ozone.In this respect, the pyrrole heterocycle represents a synthetic equivalent of the amino function. 

This section describes methods for the cyclopropanation of alkenes with silicon-, germanium-, tin-, or lead-substituted carbenes and their equivalents. 

Muller chose to examine cyclohexene and 1,4-cyclohexadiene (ten equivalents relative to diazo compound) as model systems, and screened a variety of carbenoid precursors and catalysts (Scheme 24, left). All reactions were conducted in DCM at 25 °C. The results with 1,4-cyclohexadiene were quite clear-cut. With acceptor-substituted carbenes, selectivity was >95 5 in favor of cyclopropanation 108 for Cu° or Rh2(OAc)4 catalysts. For acceptor/acceptor carbenoid precursors, CuCl still favored cyclopropanation >95 5, but with Rh2(OAc)4 insertion 109 now became... 

Totally intramolecular enyne metathesis Diels-Alder sequences have been demonstrated (e.g., the conversion of 244 into 246). Enyne RCM of substrate 247 affords stereochemically pure 248 due to kinetic resolution during metathesis.A process equivalent to enyne metathesis that proceeds through a non-carbene mechanism has been demonstrated using platinum chloride as a catalyst. In addition to routine observations, some other interesting side-reactions have been noted (Scheme 29). Competitive cross-metathesis with ethylene and intramolecular enyne metathesis were observed in the treatment of substrate 249 with catalyst 16 and ethylene.Cyclopropane ring opening was observed in the attempted enyne metathesis of substrate 253, resulting in alkylidenecyclopentene 254. 

Extrusion of nitrogen from arylchlorodiazirines formally gives a carbene. In the presence of an olefin, a sonochemical cyclopropanation occurs smoothly under neutral conditions (Eq. 6). The authors state that the procedure is "extraordinarily simple" a diazirine and an olefin are sonicated in a bath in hexane at 40 C, a temperature at which the compounds are thermally stable.66 The reaction occurs in yields equivalent to the photochemical process, but with much greater ease. Good yields are obtained from allyl bromide, 2,3-dimethyl-2-butene, or diethyl... 

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