Methylenecyclopentanes, synthesis

Parallel to the development of the TMM-Pd synthon for methylenecyclopentane synthesis has been the investigation of an alternative procedure aimed at similar functionality. It involves the use of methylenecyclopropanes in the presence of transition metal catalysts (either Ni(0)- or Pd(O)-based)32. In contrast to the conjunctive reagents described earlier, two different synthon types may be generated from methylenecyclopropanes that are both capable of [3 + 2] cycloaddition. This is outlined in the following scheme, where distal C —C bond cleavage leads to cycloaddition products denoted as type A and proximal ring opening leads to type B products. 

Vinylsilanes also find use as intermediates for cyclopentenone annulation of a, (3-unsaturated acid chlorides under Lewis acid conditions.One such example is shown in Scheme A novel methylenecyclopentane synthesis depends on... 

The cleavage of the intermediate 1,4-diradical can also become the major path as in the synthesis of methylenecyclopentane (4.8) 408). 

Methylenecyclopentane-1,3-diyls 14 Synthesis and ESR Properties. The first member of the 2-methylenecyclopentane-l,3-diyl series to be synthesized was the 2-isopropylidene derivative 14b, (Scheme 5.2) followed by a number of others (14a, 14c-f), including the unsubstituted methylene compound... 

Methylenecyclopentanes.2 Trost and Curran have used 1 as an electrophilic synthon for trimethylenemethane. Thus 1 reacts with the anion of 2 to give 3 in 72% yield. This product was oxidized to the disulfone, which was then cyclized to 4 by F. Various transformations are possible for the exocyclic methylene group. For the synthesis of coriolin (6), the group was converted to a pem-dimethyl group by cyclopropanation and hydrogenolysis. The product (5) was converted in several more steps into 6. 

On the basis of preceding experience in the synthesis of methylenecyclopentanes, Curran discovered a cascade reaction proceeding via a 4 + 1 radical annulation mechanism that led to a new synthesis of cyclopenta-fused quinolines [60] (Scheme 16.15). 

Reductive dehalogenation is an efficient method of synthesis of cyclopropanes spiroannulated to five- and higher-membered carbocycles (i.e. compounds in which spiroannulation does not result in accumulation of extra strain) . The required gem-(dihalomethyl)cycloalkanes are usually prepared by halogenation of the precursor diols (equation 1). The cyclization is most efficiently accomplished in the Zn-alcohol-water system . For example, spiro[2.5]octane 7 was prepared in 91% yield using this procedure. This method is useful even for a one-step preparation of bis-spirocyclopropyl compounds as exemplified in equation 2. However, the application of the reductive dehalogenation method to the synthesis of more strained SPC (i.e. spirohexane or spiropentane) often leads to rearranged products. For example, methylenecyclopentane was the only product obtained from bis(bromomethyl)cyclobutane (equation 3) ... 

Considering the industrial importance of cyclopropanes in the pesticide field, it is not surprising that chiral ferrocenylphosphines have been applied as control ligands for the palladium-catalyzed enantioselective formation of cyclopropanes from the dicarbonate of 2-butene-1,4-diol and malonates, leading to 70% ee (Fig. 4-32e) [179]. Ferrocenylphosphines also induce chirality in the reaction of sulfonyl-substituted propenyl carbonates and acrylic esters to methylenecyclopentanes (up to 78% ee (Fig. 4-321)) [180], with potential applications in natural product synthesis. These examples show that the synthetic potential of chiral ferrocene derivatives is not yet fully exploited, and one may look forward to new applications. 

The two Pd(0) or Ni(0) catalyzed [3+2]-cycloadditions starting with the readily accessible trimethylenemethane -precursors [2-(acetoxymethyl)-3-allyl]trimethyl-silan, methylenecyclopropane, and their substituted derivatives are important new methods for the synthesis of methylenecyclopentanes. Because of the simplicity with which many problems of cyclopentane-syntheses can be solved in a convenient one pot reaction this new methodology may be compared with the synthesis of six-membered rings by the powerful 4+2]-cycloaddition of the Diels-Alder reaction. 

Cycloaddition.2 In the presence of this nickel catalyst, methylenecyclo-propanes undergo an unusual cycloaddition across carbon-carbon double bonds. Thus methylenecyclopropane (1) when heated in a sealed tube (60°, 48 hrs.) with excess methyl acrylate in the presence of bis(acrylonitrile)nickel(0) gives the 1 1 adduct, methyl 3-methylenecyclopentanecarboxylate (2), in 82% yield. Methyl vinyl ketone or acrylonitrile is also a suitable substrate. The reaction provides a useful synthesis of methylenecyclopentane derivatives. 

These reactions proceed smoothly at 20-40 °C with high regio- and stereoselectivity. For example, dimethyl maleate forms largely the cw-fused cyclopentane. This process has been used to excellent effect in the synthesis of optically active, methylenecyclopentanes by employing chirally modified acrylate acceptors (sec Section 1.6.1.2.3.3). 

Singleton has developed an intermolecular [3+2] addition strategy for the synthesis of functionalized cyclopentane rings using strained methylenecyclopropanes as radical traps (Scheme 22) [53]. The success of methylenecyclopropane 27 with electron-rich and unactivated alkenes arises from the ready formation of the highly stable electrophilic radicals 28b. Thus, this reaction works well with equimolar amounts of unactivated and electron-rich alkenes but does not work with electron-poor alkenes. The reagent 29 and 30 are prepared by the structural modification of 27. Furthermore, [3+2] methylenecyclopentane annulations of electron-poor alkenes can be carried out with unactivated methylenecyclopropane 31 and 32 [54]. 

Cyclization. An efficient synthesis of methylenecyclopentanes from 1,6-dienes is by Ru catalysis. 

Bromo methallyl sulfone, prepared from methallyl phenyl sulfone, has proven to be a good substrate for stereoselective synthesis of trisubstituted methylenecyclopentanes with a variety of different Michael receptors. For example, the trans trans-trisubstituted methylenecyclopentane was efficiently prepared in 93% yield by a cascade Michael addition/cyclization beginning with ethyl ( )-crotonate (eq 22). The phosphonate sulfone reagent, readily available from methallyl phenyl sulfone, was used for the selective synthesis of 1,3-dienes. The synthesis included... 

Total syntheses of diterpenoid hydrokempenones have been accomplished by Paquette et al.,f using the Pd-catalyzed [3 + 2] cycloaddition methodology. One example is outlined on Scheme 43 and describes the synthesis of an isomeric compound 208 of 3/3-hydroxy-7/3-kemp-8(9)-en-6-one, a defense secretion agent of the neotropical species Nasutitermes octopilis. 3-AUcoxy-2-cyclohexenone 204 was efficiently functionalized and transformed to bicylic adduct 205 via a Robinson annulation reaction. Reduction of the double bond followed by condensation of dimethyl carbonate and oxidation gave the keto ester 206, which was treated with [2-(acetoxymethyl)-3-allyl]trimethylsilane, palladium acetate, and triisopropyl phosphite in refluxing tetrahydrofuran to afford a 98% yield of 207. Substituted methylenecyclopentane 207 was then functionalized by stereoselective reduction and protections, and final closure was done under basic conditions after an ozonolysis step. A modified Barton-McCombie reaction produced the desired tetracyclic adduct 208. 

The strategy used for the formation of methylenecyclopentanes was applied to the one-pot synthesis of various 3-methylenetetrahydrofurans. The methodology was based on an oxygen nucleophile initiated Michael addition of propargyl alcohols to alkylidene or arylidenemalonates followed in situ by a Pd-mediated cyclization. ° ... 

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