Transition Metal Catalyzed Cyclopropanations

Historically, copper-based catalysts have played a prominent role in the in situ generation of metal carbenes (or carbenoids) from diazo compounds. In the 1970s, new transition metal complexes were discovered that widened the range 

Rhodium(II)-mediated reactions have found many applications. The literature up to 1985 in intramolecular and intermolecular cyclopropanations, including choice of catalysts and mechanistic aspects, has been thoroughly reviewed by Maas [9]. More recent reviews are available that focus on the ligand effects and mechanism [10], and on their utilization in fine organic synthesis as well as in natural product synthesis [11]. All of these reviews, and in particular McKervey s comprehensive review [11a] on organic synthesis with a-diazocarbonyl compounds, deal with the utilization of functionalized diazo compounds as carbenoid precursors. Herrmann et al. surveyed the organometallic chemistry of diazoalkanes [11c, lid]. 

In contrast to the wealth of chemistry reported for catalyzed reactions of diazocarbonyl compounds, there are fewer applications of diazomethane as a carbenoid precursor. Catalytic decomposition of diazomethane, CH2N2, has been reported as a general method for the methylenation of chemical compounds [12]. The efficacy of rhodium catalysts for mediating carbene transfer from diazoalkanes is poor. The preparative use of diazomethane in the synthesis of cyclopropane derivatives from olefins is mostly associated with the employment of palladium cat- 

The available literature data support the assertion that the outcome of the methylene cycloadditions depends to a large extent on the ability of the olefin to be coordinated to the palladium center. In that respect, the mechanism of palladium-catalyzed cyclopropanation appears to differ significantly from that of rho-dium(ll)-catalyzed cyclopropanations. One advantage of using palladium catalysts with diazomethane is associated with the possibility of synthesizing polycyclopropane adducts, a topic of current interest (vide infra) which has no general satisfactory solution with other diazo compound/catalyst combinations. This point is exemplified below for the cyclopropanation of the esters of trans-polyunsaturated acids. Moreover, the reactivity of the double bonds depends both on their position in the linear hydrocarbon chain and on their configuration (eq. (f)). 

While the only double bond cyclopropanated in the arachidonic ester 1 is that next to the ester group, both trans double bonds of the unsaturated ester 2 are cyclopropanated in good yield (eq. (2)) [12]. 

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The detailed mechanism of transition metal-catalyzed cyclopropanation using diazo compounds as a carbene source is still covered by clouds of controversy, but it is generally accepted that the reaction proceeds through metal-carbenoid complexes,17-21 and the valency of the metal ions (M) changes with carbenoid formation (Scheme 85). 

The transition metal-catalyzed cyclopropanation of alkenes is one of the most efficient methods for the preparation of cyclopropanes. In 1959 Dull and Abend reported [617] their finding that treatment of ketene diethylacetal with diazomethane in the presence of catalytic amounts of copper(I) bromide leads to the formation of cyclopropanone diethylacetal. The same year Wittig described the cyclopropanation of cyclohexene with diazomethane and zinc(II) iodide [494]. Since then many variations and improvements of this reaction have been reported. Today a large number of transition metal complexes are known which react with diazoalkanes or other carbene precursors to yield intermediates capable of cyclopropanating olefins (Figure 3.32). However, from the commonly used catalysts of this type (rhodium(II) or palladium(II) carboxylates, copper salts) no carbene complexes have yet been identified spectroscopically. 

The transition metal-catalyzed cyclopropanation of alkenes with diazomethane is a valuable alternative to Simmons-Smith methodology [645]. Because of the mild reaction conditions under which this reaction takes place, diazomethane is the reagent of choice if sensitive olefins are to be cyclopropanated [646-648]. 

Most electrophilic carbene complexes with hydrogen at Cjj will undergo fast 1,2-proton migration with subsequent elimination of the metal and formation of an alkene. For this reason, transition metal-catalyzed cyclopropanations with non-acceptor-substituted diazoalkanes have mainly been limited to the use of diazomethane, aryl-, and diaryldiazomethanes (Tables 3.4 and 3.5). 

Table 3.5. Transition-metal-catalyzed cyclopropanations with diazoalkanes.

With respect to the large number of unsaturated diazo and diazocarbonyl compounds that have recently been used for intramolecular transition metal catalyzed cyclopropanation reactions (6-8), it is remarkable that 1,3-dipolar cycloadditions with retention of the azo moiety have only been occasionally observed. This finding is probably due to the fact that these [3+2]-cycloaddition reactions require thermal activation while the catalytic reactions are carried out at ambient temperature. A7-AUyl carboxamides appear to be rather amenable to intramolecular cycloaddition. Compounds 254—256 (Scheme 8.61) cyclize intra-molecularly even at room temperature. The faster reaction of 254c (310) and diethoxyphosphoryl-substituted diazoamides 255 (311) as compared with diazoacetamides 254a (312) (xy2 25 h at 22 °C) and 254b (310), points to a LUMO (dipole) — HOMO(dipolarophile) controlled process. The A -pyrazolines expected... 

SCHEME 92. Transition metal-catalyzed cyclopropanation of olefins with diazoalkanes. 

R. Paulissen, A. J. Hubert, and Ph. Teyssie (1972) Transition metal-catalyzed cyclopropanation of olefins, Tetrahedron Lett 15 1465-1466... 

Similarly, the transition metal catalyzed cyclopropanation of alkenes or arenes with diazo compounds, in general, involves short-lived metal-carbene complexes which react with the alkene with concomitant reductive elimination of the metal fragment. Although not involving free carbenes, such reactions are covered fully in this section. 

Therefore, only the important features concerning the scope and limitations of transition metal catalyzed cyclopropanation reactions will be discussed here for further examples and references, the reader should consult the Houben-Weyl volumes mentioned above. 

Table 8. Transition Metal Catalyzed Cyclopropanation of Alkenes and 1,3-Dienes with Ethyl Di-...

A detailed description of the numerous examples of vinylcyclopropropanes used in transition metal mediated organic synthesis is far beyond the scope of this section and can be found in several reviews. Prominent examples are conversions to open-chain products, as well as formation of four-, five-, six- and seven-membered rings via ring expansion or incorporation of other substrates such as carbon monoxide, alkenes or alkynes. Thus divinylcyclopropanes, obtainable via transition metal catalyzed cyclopropanation reactions, undergo a facile thermal Cope rearrangement to form cycloheptadienes. ... 

Scheme 6.30. Catalytic cycle for the transition metal-catalyzed cyclopropanation of olefins by diazoalkanes (after [112] and [113]).

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 ... 

Transition metal-catalyzed cyclopropane-based cycloadditions provide efficient strategies for the construction of (poly)cyclic structures. More importantly, the cycloadditions feature atom- and step-economy, good regio- and stereoselectivity, and excellent functional group tolerance. More and more total syntheses of natural products benefit fi om the rich cycloaddition chemistry of VCPs and MCPs. To date, numerous total syntheses of natural products have been accomplished utilizing these methodologies as key steps. Listed in Fig. 4 are some selected examples. 

The reactions of three-membered ring carbocycles have been exhaustively investigated for decades they are still the subject of active research. As described in this chapter, the inclusion of transition-metal-catalyzed cyclopropane ring-opening reactions is a powerful method for producing useful molecules that are otherwise difficult or impossible to obtain. Alkynes, alkenes, and carbon monoxide can participate in ring-expanding annulation with three-membered carbocycles. 

With diazo esters, the regioselectivity in transition metal-catalyzed cyclopropanation of dienes and trienes was generally... 

In contrast to the aforementioned diazoalkanes and aryldiazomethanes, whose instability and high explosiveness have diminished their general utility as a monomer for polymer synthesis, diazocarbonyl compounds have been known to be rather stable and frequently used as a reagent for organic synthesis [35, 36], In particular, transition metal catalyzed cyclopropanation of diazocarbonyl compounds with C=C double bonds has been extensively investigated and established as a very useful method for the formation of cyclopropane frameworks, where application for asymmetric synthesis using various optically active ligands has been successfully achieved. 

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