Cyclopropanations and C-H Insertion Reactions

Carbenes and carbenoids constitute a class of reactive intermediates traditionally intimately associated with the synthesis of cyclopropanes, and more recently with products derived from C-H insertion processes. The reactions of diazoacetic acid esters with aromatic hydrocarbons such as toluene to give cyclopropanes with the liberation of N2, date back to the seminal experiments by Buchner and Curtius reported in 1885 [11]. Much later, in 1942, Meerwein reported that carbenes generated from diazomethane undergo insertion into C-H bonds [12], Seminal experiments that had significant impact for the utilization of such reactions in synthesis were performed by Stork, who demonstrated that carbenes prepared by photolysis of diazoketones participated in stereospecific intramolecular cycloadditions with al-kenes to form bicyclic cyclopropanes (Equations 1 and 2) [13]. Julia reported that intramolecular C-H insertion reactions of a chiral substrate 5 including a stereogenic methine center proceeded stereospecifically with retention of configuration (Equation 3) [14]. 

B In its new meaning (collabora-tively conceived by W. von E. Doering, S. Winstein and R. B. Woodward in a nocturnal Chicago taxi and later delivered diurnally in Boston) carbene is synonymous with one of the several definitions of methylene and has already begun to find use in the chemical literature  

Classics in Stereoselective Synthesis. Erick M. Carreira and Lisbet Kvaerno Copyright 2009 WILEY-VCH Verlag GmbH Co. KGaA, Weinheim ISBN 978-3-527-32452-1 (Hardcover) 

The fact that carbenes are characterized by their stereospecific transformations has effectively paved the way for numerous innovative developments. The discovery that rhodium acetate can function as a catalyst for carbene generation from diazoacetates [15, 16] with much higher efficiency than copper salts, which had been traditionally used, provided an opening into the vast possibilities offered by transition metal catalysis. The increasing number of novel, stereoselective reactions of carbenoid species have become an indispensable toolbox for the modern practitioner of chemical synthesis [17-22], 

The seemingly limited number of available methods to access cyclopropanes by standard transformations in the laboratory are a result of the inherent ring strain of these systems. The fact that carbenes are intrinsically high-energy species renders them unique in the construction of numerous natural and nonnatural products that include cyclopropanes (Sections 15.2-15.5). However, there have been recent developments in methods that provide access to cyclopropanes via alternative intermediates and mechanistic pathways that are strikingly efficient (Section 15.6). Additionally, carbene and carbenoid intermediates have been reported to partake in a variety of stereoselective C-H insertions (Sections 15.7-15.8). 

---

The carbenoid fragment reacts as an electron-deficient carbon centre. Substituents both at rhodium and at the carbene centre can make it more electron-deficient. If the carbenoid is given the choice between a cyclopropanation and C-H insertion reaction, the preference for C-H insertion increases with the electron deficiency [19], Figure 17.10. 

For the rhodium-catalyzed cyclopropanation of olefin substrates with activated allylic C—H groups, the selectivity between cyclopropanation and C—H insertion is sometimes unsatisfactory. Very recently, Davies and Thompson (128) reported a selective silver-catalyzed cyclopropanation of olefins to give predominately cyclopropane products. Aryldiazoacetates were used as carbene precursors with the aryl groups helping to stabilize the carbene intermediate and facilitate the reaction. Notably, phenallyldiazoacetate with different olefins also gave cyclopropane products (Fig. 26). 

Carbene)iron complexes are often only labile intermediates that undergo followup reactions as usually observed in carbene chemistry such as C-H insertion or cyclopropanation. Intramolecular C-H insertion reaction of (rj -cyclopentadienyl)-dicarbonyliron-carbene complexes provides bicyclic cyclopentanes (Scheme 4-60). The reaction has been applied for the synthesis of the fungal metabolite ( )-sterpurene and ( )-pentalenene. ... 

Calculations performed for cyclopropanation with Fischer-type carbene complexes [28] indicate that the electrophilic attack of the carbene complex at the alkene and the final ring closure are concerted. Extrapolation from this result to the C-H insertion reaction (in which a a-bond instead of a 7i-bond is cleaved) suggests that C-H bond cleavage and the formation of the new C-C and C-H bonds might also be concerted (Figure 3.38). 

Although C—H insertion reactions rarely occur in intermolecular reactions with diazoacetates, these are common side reactions with diazomalonates3132 (equation 10) and diazo ketones (with a-allyl vinyl ethers).33 Several mechanistic pathways are available to generate the products of an apparent direct C—H insertion reaction and these include dipolar intermediates, ir-allyl complexes and ring opening of cyclopropanes.1 Oxidative problems due to the presence of oxygen are common with copper catalysts, but these are rarely encountered with rhodium catalysts except in systems where the carbenoid is ineffectively captured.34... 

In these C-H insertion reactions, the similarity with cyclopropane formation by intramolecular cycloadditions to alkenes is clear, and the mechanisms mirror one another quite closely. As with the cyclopropanation reactions, the path of the reaction differs according to whether the carbene is a singlet or triplet. Singlet carbenes can insert in a concerted manner, with the orbitals overlapping constructively provided the carbene approaches side-on. 

Copper powder, copper bronze, Cu O, CuO, CuSO, CuCl and CuBr were the first catalysts which were used routinely for cyclopropanation of olefins as well as of aromatic and heteroaromatic compounds with diazoketones and diazoacetates. Competing insertion of a ketocarbene unit into a C—H bond of the substrate or solvent remained an excpetion in contrast to the much more frequent intramolecular C—H insertion reactions of appropriately substituted a-diazoketones or diazoacetates Reviews dealing with the cyclopropanation chemistry of diazo-acetic esters (including consideration of the efficiency of the copper catalysts mentioned above) and diazomalonic esters as well as with intramolecular cyclopropanation reactions of diazoketones have appeared. 

In a useful extension of this methodology for enantioselection in intramolecular cyclopropanation, Doyle s group have used chiral rhodium (II) carbox-amidates to effect enantiomer differentiation in reactions of racemic secondary allylic diazoacetates [47]. The catalyst-enantiomer matching approach has also been applied very successfully to intramolecular C-H insertion reactions vide infra). The (R)- and (S)-enantiomers, (10) and (11), respectively, of cyclohex-2-en-1 -yl diazoacetate are displayed in Scheme 7. On exposure to Rh2(4i -MEOX)4 the (R)-enantiomer (10) undergoes cyclopropanation to form tricyclic ketone... 

Enantioselective C-H insertion reactions have been successfully performed by various rhodium catalysts over a broad range of substrates in both an intramolecular and an intermolecular manner. Of the many examples reported, a few are highhghted here. McKervey and coworkers have obtained good diastereoselectivity and enantioselectivity in the C-H insertion reaction of compound (9.91) catalysed by rhodium complex (9.92). Intramolecular cyclopropanation is not competitive in this case, since the alkene moiety is too remote. 

Tosylhydrazone salts could also be deconposed into the corresponding diazo compounds in the presence of a phase transfer catalyst. The addition of late transition metal complexes leads to the formation of metal carbenoid species which undergo various reactions such as cyclopropanation, aziridination, epoxidation, and C-H insertion. While both cyclopropanation and aziridination work equally well in the presence of the sodium and lithium tosylhydrazone salts, it was established that the sodium salt provided higher yields and selectivities in the reaction with aldehydes which led to the formation of epoxides (eq 28). ... 

Bis(methoxycarbonyl)(phenyliodinio)methanide (778), the most common iodonium ylide derived from malonate methyl ester, has found synthetic applications in the C—H insertion reactions [1044-1048] and the cyclopropanation of alkenes [1049-1055], including enantioselective cyclopropanations in the presence of chiral rhodium complexes [1056-1058], Representative examples of these reactions are shown in Scheme 3.306 and include the BFs-catalyzed bis(carbonyl)alkylation of 2-alkylthiophenes 777 [1045] and the optimized procedure for rhodium-catalyzed cyclopropanation of styrene 779 [1052]. 

The use of ylides as carbene precursors constitutes a novel original approach to control or extend carbenic reactions. The thiophenium ylide XXVIII prepared by catalytic decomposition of methyl diazomalonate in the presence of dichloro-2,5-thiophene has been successfully applied as a carbene equivalent or precursor to the cyclopropanation of olefins, the OH insertion and the C-H insertion reaction in activated arenes [112, 113] the catalyst being rhodium(II) acetate or copper(II) acetylaceto-nate. 

Introducing a second metal also opens the way to bimetallic redox synergy, which has been observed in paddlewheel binuclear rhodiumfll) catalysts. These chiral binuclear complexes are able to promote a variety of catalytic reactions like cyclopropanation [50], cyclopropenation [51], and C-H insertion [52-54] reactions achieving very high enantioselectivities (Scheme 12) (for reviews, see [55-57]). In addition to contributing to the paddle wheel structure of the complex, the role of the second rhodium is to stabilize its rhodium(II) neighbor that accounts for the high catalytic activity. 

---