Palladium cyclopropanation

The above procedure was used for the preparation of all compounds except 104p, which was obtained from 104r by palladium-catalyzed coupling with tributylvinyl-stannane followed by palladium-catalyzed cyclopropanation of the resulting vinyl intermediate with diazomethane (Scheme 32) (99BMC3187). 

Whereas the utility of these methods has been amply documented, they are limited in the structures they can provide because of their dependence on the diazoacetate functionality and its unique chemical properties. Transfer of a simple, unsubstituted methylene would allow access to a more general subset of chiral cyclopropanes. However, attempts to utilize simple diazo compounds, such as diazomethane, have never approached the high selectivities observed with the related diazoacetates (Scheme 3.2) [4]. Traditional strategies involving rhodium [3a,c], copper [ 3b, 5] and palladium have yet to provide a solution to this synthetic problem. The most promising results to date involve the use of zinc carbenoids albeit with selectivities less than those obtained using the diazoacetates. 

The catalyst exerts some influence on the bonds broken in hydrogenolysis of saturated cyclopropanes (775), but in vinyl and alkylidene cyclopropanes the effect is pronounced. Platinum or palladium are used frequently. In one case, Nishimura s [124a) catalyst, rhodium-platinum oxide (7 3), worked well where platinum oxide failed (.75). An impressive example of the marked influence of catalyst is the hydrogenation of the spirooctane 42, which,... 

Negishi E, Tan Z (2005) Diastereoselective, Enantioselective, and Regioselective Carbo-alumination Reactions Catalyzed by Zirconocene Derivatives. 8 139-176 Netherton M, Fu GC (2005)Palladium-catalyzed Cross-Coupling Reactions of Unactivated Alkyl Electrophiles with Organometallic Compounds. 14 85-108 NicolaouKC, KingNP, He Y (1998) Ring-Closing Metathesis in the Synthesis of EpothUones and Polyether Natural Products. 1 73-104 Nishiyama H (2004) Cyclopropanation with Ruthenium Catalysts. 11 81-92 Noels A, Demonceau A, Delaude L (2004) Ruthenium Promoted Catalysed Radical Processes toward Fine Chemistry. 11 155-171... 

Recently, Y. Yamamoto reported a palladium-catalyzed hydroalkoxylation of methylene cyclopropanes (Scheme 6-25) [105]. Curiously, the catalysis proceeds under very specific conditions, i.e. only a 1 2 mixture of [Pd(PPh3)4] and P(o-tolyl)3 leads to an active system. Other combinations using Pd(0 or II) precursors with P(o-tolyl)3 or l,3-bis(diphenylphosphino)propane, the use of [Pd(PPh3)4] without P(o-tolyl)3 or with other phosphine ligands were all inefficient for the hydroalkoxylation. The authors assumed a mechanism in which oxidative addition of the alcohol to a Pd(0) center yields a hydrido(alkoxo) complex which is subsequently involved in hydropal-ladation of methylenecyclopropane. 

In 2004, Molander et al. developed another type of chiral sulfur-containing ligands for the intermolecular Heck reaction. Thus, their corresponding novel cyclopropane-based phosphorus/sulfur palladium complexes proved to be active as catalysts for the reaction between phenyltriflate and dihydrofuran, providing at high temperature a mixture of the expected product and its iso-merised analogue (Scheme 7.7). The major isomer C was obtained with a maximum enantioseleetivity of 63% ee. 

Some years ago we began a program to explore the scope of the palladium-catalyzed annulation of alkenes, dienes and alkynes by functionally-substituted aryl and vinylic halides or triflates as a convenient approach to a wide variety of heterocycles and carbocycles. We subsequently reported annulations involving 1,2-, 1,3- and 1,4-dienes unsaturated cyclopropanes and cyclobutanes cyclic and bicyclic alkenes and alkynes, much of which was reviewed in 1999 (Scheme l).1 In recent days our work has concentrated on the annulation of alkynes. Recent developments in this area will be reviewed and some novel palladium migration processes that have been discovered during the course of this work will be discussed. 

Only one report mentions the cyclopropanation with diazodiphenylmethane in the presence of a group VIII metal catalyst. Remarkably enough, the selectivity of the reaction with 5-methylene-bicyclo[2.2.1]hept-2-ene (8) can be reversed completely. With Rh2(OAc)4 as catalyst, the exocyclie double bond is cyclopropanated exclusively (>100 1), whereas in the presence of bis(benzonitrile) palladium(II) chloride the endocyclic C=C bond is attacked with very high selectivity (>50 1)47). 

The dominant role of copper catalysts has been challenged by the introduction of powerful group VIII metal catalysts. From a systematic screening, palladium(II) and rhodium(II) derivatives, especially the respective carboxylates62)63)64-, have emerged as catalysts of choice. In addition, rhodium and ruthenium carbonyl clusters, Rh COJjg 65> and Ru3(CO)12 e6), seem to work well. Tables 3 and 4 present a comparison of the efficiency of different catalysts in cyclopropanation reactions with ethyl diazoacetate under standardized conditions. 

All reactions listed in Tables 5-7 were carried out under a nitrogen atmosphere, but with the rhodium or palladium catalysts no noticeable or only minor reduction in cyclopropane yields was observed when air was present. In contrast, air clearly had a yield-diminishing effect in the CuCl P(0-/-Pr)3-catalyzed reactions, especially with cyclohexene and 3,4-dihydropyran. Cyclohexene was oxidized to 2-cyclohexen-l-one, and 3,4-dihydropyran gave 5,6-dihydro-4-pyrone and 5,6-dihydro-2-pyrone, albeit in yields below 8 % 59). 

The catalytic cyclopropanation of 1,3-dienes leads exclusively or nearly so to mono-cyclopropanation products, as long as no excess of diazocarbonyl compound is applied. The regioselectivity has been tested for representative rhodium, copper and palladium catalysts 59 7 ,72), and the results are displayed in Table 9. 

Cyclopropanation of C=C bonds by carbenoids derived from diazoesters usually occurs stereospeciflcally with respect to the configuration of the olefin. This has been confirmed for cyclopropanation with copper 2S,S7,60 85), palladium 86), and rhodium catalysts S9,87>. However, cyclopropanation of c -D2-styrene with ethyl diazoacetate in the presence of a (l,2-dioximato)cobalt(II) complex occurs with considerable geometrical isomerization88). Furthermore, CuCl-catalyzed cyclopropanation of cis-2-butene with co-diazoacetophenone gives a mixture of the cis- and trans-1,2-dimethylcyclopropanes 89). 

Palladium(II) acetate was found to be a good catalyst for such cyclopropanations with ethyl diazoacetate (Scheme 19) by analogy with the same transformation using diazomethane (see Sect. 2.1). The best yields were obtained with monosubstituted alkenes such as acrylic esters and methyl vinyl ketone (64-85 %), whereas they dropped to 10-30% for a,p-unsaturated carbonyl compounds bearing alkyl groups in a- or p-position such as ethyl crotonate, isophorone and methyl methacrylate 141). In none of these reactions was formation of carbene dimers observed. 7>ms-benzalaceto-phenone was cyclopropanated stereospecifically in about 50% yield PdCl2 and palladium(II) acetylacetonate were less efficient catalysts 34 >. Diazoketones may be used instead of diazoesters, as the cyclopropanation of acrylonitrile by diazoacenaph-thenone/Pd(OAc)2 (75 % yield) shows142). 

Enantioselective carbenoid cyclopropanation can be expected to occur when either an olefin bearing a chiral substituent, or such a diazo compound or a chiral catalyst is present. Only the latter alternative has been widely applied in practice. All efficient chiral catalysts which are known at present are copper or cobalt(II) chelates, whereas palladium complexes 86) proved to be uneflective. The carbenoid reactions between alkyl diazoacetates and styrene or 1,1 -diphenylethylene (Scheme 27) are usually chosen to test the efficiency of a chiral catalyst. As will be seen in the following, the extent to which optical induction is brought about by enantioselection either at a prochiral olefin or at a prochiral carbenoid center, varies widely with the chiral catalyst used. 

Intramolecular oxonium ylide formation is assumed to initialize the copper-catalyzed transformation of a, (3-epoxy diazomethyl ketones 341 to olefins 342 in the presence of an alcohol 333 . The reaction may be described as an intramolecular oxygen transfer from the epoxide ring to the carbenoid carbon atom, yielding a p,y-unsaturated a-ketoaldehyde which is then acetalized. A detailed reaction mechanism has been proposed. In some cases, the oxonium-ylide pathway gives rise to additional products when the reaction is catalyzed by copper powder. If, on the other hand, diazoketones of type 341 are heated in the presence of olefins (e.g. styrene, cyclohexene, cyclopen-tene, but not isopropenyl acetate or 2,3-dimethyl-2-butene) and palladium(II) acetate, intermolecular cyclopropanation rather than oxonium ylide derived chemistry takes place 334 ). 

In order to rationalize the catalyst-dependent selectivity of cyclopropanation reaction with respect to the alkene, the ability of a transition metal for olefin coordination has been considered to be a key factor (see Sect. 2.2.1 and 2.2.2). It was proposed that palladium and certain copper catalysts promote cyclopropanation through intramolecular carbene transfer from a metal carbene to an alkene molecule coordinated to the same metal atom25,64. The preferential cyclopropanation of terminal olefins and the less hindered double bond in dienes spoke in favor of metal-olefin coordination. Furthermore, stable and metastable metal-carbene-olefin complexes are known, some of which undergo intramolecular cyclopropane formation, e.g. 426 - 427 415). 

In the presence of nickel(0), tethered diene-VCPs react to produce eight- and five-membered ring products (Scheme 2). Palladium(O) and cobalt(m) were also tried but produced only decomposition products. However, in the presence of Wilkinson s catalyst (RhCl(PPh3)3), tethered diene-VCP 1 was cleanly converted to triene 4 in 91% yield. Although the desired cycloaddition reaction was not obtained, the cleavage of the cyclopropane ring was encouraging.22... 

Bis-silylation of bicyclopropylidene in the presence of the palladium-isocyanide catalyst with hexamethyldisilane and phenylpentamethyldisilane gives 1,2-addition products in good yields at 70 °C vide supra). No G-G bond cleavage takes place with the bis-silylation reaction. In contrast to this example, in which both the cyclopropane rings are... 

Silaboration of bicyclopropylidene proceeds via proximal G-G bond cleavage at 130 °C in the presence of the palladium// r/-alkyl isocyanide catalyst (Equation (88)). In contrast to the aforementioned silaboration of methylene cyclopropanes, vinylsilane products are obtained with high regioselectivity.102... 

Grigg extended this alkyne cyclization to trapping with stannanes to give 3-exo-dienes [347], alkynes to afford tetracycles [338, 348], and alkenes leading to cyclopropanes [349], an example of which is illustrated. In his studies Grigg and co-workers have found that thallium and silver salts suppress direct capture of these palladium intermediates prior to capture [350]. 

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. 

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