Methylenecyclopentanes

Versatile [3 + 2]-cydoaddition pathways to five-membered carbocydes involve the trimethylenemethane (= 2-methylene-propanediyl) synthon (B.M. Trost, 1986). Palladium(0)-induced 1,3-elimination at suitable reagents generates a reactive n -2-methylene-l,3-propa-nediyl complex which reacts highly diastereoselectively with electron-deficient olefins. The resulting methylenecyclopentanes are easily modified, e. g., by ozonolysis, hydroboration etc., and thus a large variety of interesting cyclopcntane derivatives is accessible. 

Chemoselectivity in the cycloaddition of 2-methylenecycloheptenone (174) changes on addition of In(acac)3. The allylic carbonate 175 reacts with the ketone 174 in the presence of In(acac)3 to give the methylenetetrahydrofuran 176, and the methylenecyclopentane 177 is obtained in its absence[l 13], The cycloaddition of ynones to produce the methylenetetrahydrofuran proceeds smoothly only in the presence of In(acac)3 (10 mol%)[114]. 

The TT-allylpalladium complexes 241 formed from the ally carbonates 240 bearing an anion-stabilizing EWG are converted into the Pd complexes of TMM (trimethylenemethane) as reactive, dipolar intermediates 242 by intramolecular deprotonation with the alkoxide anion, and undergo [3 + 2] cycloaddition to give five-membered ring compounds 244 by Michael addition to an electron-deficient double bond and subsequent intramolecular allylation of the generated carbanion 243. This cycloaddition proceeds under neutral conditions, yielding the functionalized methylenecyclopentanes 244[148], The syn-... 

The intramolecular carbopalladation (or insertion) of the triple bond in dimethyl 4-pentynylmalonate (215) with Pd—H species and malonate anion as shown by 216 proceeds in the presence of f-BuOK and 18-crown ether, affording the methylenecyclopentane derivatives 217 and 218, the amounts of which depend on the reaction conditions. The Pd—H species may be formed... 

Methylenecyclopentane has the less substituted double bond and is the major product The reported isomer distribution is 91% methylenecyclopentane and 9% 1 methylcyclopentene ... 

Assign the chemical shifts 8 1.6, priate protons of methylenecyclopentane... 

The discovery of palladium trimethylenemethane (TMM) cycloadditions by Trost and Chan over two decades ago constitutes one of the significant advancements in ring-construction methodology [1]. In their seminal work it was shown that in the presence of a palladium(O) catalyst, 2-[(trimethylsilyl)methyl]-2-propen-l-yl acetate (1) generates a TMM-Pd intermediate (2) that serves as the all-carbon 1,3-di-pole. It was further demonstrated that (2) could be efficiently trapped by an electron-deficient olefin to give a methylenecyclopentane via a [3-1-2] cycloaddition (Eq. 1). 

The TMM [4-1-3] cycloaddition to pyrone has been employed in a synthetic study of a novel biologically active diterpene pseudolaric acid B (106), in which the formation of the bridged adduct (107) from the 2-pyrone (108) is the key step in the sequence (Scheme 2.29). A mixture of the other isomer (109) and the methylenecyclopentane (110) was also isolated from the reaction. It is important to point out that the presence of a tin co-catalyst is critical in effecting the reaction. This is the first example a "tin-effect observed in a [4-1-3] cycloaddition [40]. 

For example, Piers and Marais demonstrated that keto iodo alkene 32 can be converted to bicyclic keto alkene 35 in one pot21 (see Scheme 7). In this interesting methylenecyclopentane annulation method, it is presumed that intermediate 33, produced by sequential oxidative addition and deprotonation reactions, undergoes conver-... 

Scheme 7. Piers s palladium-catalyzed methylenecyclopentane annulation method.

The annulation of a methylenecyclopentane ring has a peculiarity Lewis acids are ineffective as catalysts the reaction, however, takes place in the presence of fluoride42. 

These methylenecyclopentane annulations may also be applied to conjugated dienones, e.g., 4-methyl-4-[2-(trimethylsilylmethyl)-2-propeny[]-3-vinyl-2-cyclohexenones43 44. Again, fluoride ion was used successfully to generate either octahydro-5//-inden-5-ones or hexahydro-2( 1H (-pentalenones. 

One limitation of this methodology is that unprotected terminal alkynes are incompatible with the strongly basic ethyl zinc reagents required for this reaction. Iivinghouse and coworkers found that a similar Ti(IV)tetra-aryloxide/cyclohexylmagnesium chloride system catalytically cycloisomer-ized dienes to methylenecyclopentanes 63 with the formation of some reduced product 64 (Eq. 8) [35]. 

Cationic palladium complex 121 reductively coupled enynes (Eq. 20) using trichlorosilane as the stoichiometric reductant [71]. This combination of catalyst and silane afforded silylated methylenecyclopentanes such as 122 in good yield from enynes such as 123. Attempts to develop an enantioselective version of this reaction were not successful [71]. When enediyne 124 was cyclized in the presence of trichlorosilane, the reaction favored enyne cycli-zation 126 by a 3 1 ratio over diyne cyclization to 125 (Eq. 21). In contrast, when the more electron-rich dichloromethylsilane was used as the reductant, diyne cyclization product 125 was preferred in a ratio of 4 1 [71]. Selectivities of up to 10 1 for enyne cyclization were observed, depending on the substrate employed [72],... 

In the presence of formic acid, Pd(OAc)2 and PPI13, 1,6-enyne 129a is re-ductively coupled to provide methylenecyclopentane 131, along with 132 and 133 (Eq. 24) [75,77]. The reaction tolerated substitution at either the 1- or 2-positions of the alkene and the terminal position of the alkyne. 1,7-Enynes gave methylenecyclohexane products. This catalytic system gave regioiso-meric products depending on the reaction conditions (Scheme 26). When the... 

Attempts to extend this reaction to the five-membered ring olefins 1-methylcyclopentene and norbomene resulted in 1-methylcyclopentane and methylenecyclopentane for the former and products (43)-(48) for the latter(80) ... 

While 2-arylsubstituted methylenecyclopropanes reacted with tetracyano-ethylene (131, TCNE) to give [3 + 2] adducts, i.e. methylenecyclopentanes [37], via cleavage of the cyclopropyl CC bond, benzylidenecyclopropanes 156 and 157 behaved as dienes toward TCNE (Scheme 23). 

The cycloadditions in entries 1-3 are still believed to occur via a diradical stepwise pathway, as confirmed by obtaining a thermodynamic 78 22 trans/cis mixture of dispirooctanes 536 from frans-dicyanoethylene (533) (entry 3) [13b, 143], The cycloaddition to tetracyanoethylene (131) in the absence of oxygen gives only low yields of the [2 + 2] adduct, due to the simultaneous formation of products 542 and 543 (Scheme 74) [13b]. Still, the formation of the cyclobutanes 537 and 542 is noteworthy, since the reactions of TCNE with phenyl substituted MCPs exclusively afford methylenecyclopentane derivatives [37,144], The reaction is thought to occur via dipolar intermediates 539-541 formed after an initial SET process (Scheme 74) [13b]. The occurrence of intermediates 540 and 541 has been confirmed by trapping experiments [13b]. 

The second termination reaction is alkyl chain end transfer from the active species to aluminium [155]. This termination becomes major one at lower temperatures in the catalyst systems activated by MAO. XH and 13CNMR analysis of the polymer obtained by the cyclopolymerization of 1,5-hexadiene, catalyzed by Cp ZrCl2/MAO, afforded signals due to methylenecyclopentane, cyclopentane, and methylcyclopentane end groups upon acidic hydrolysis, indicating that chain transfer occurs both by /Miydrogen elimination and chain transfer to aluminium in the ratio of 2 8, and the latter process is predominant when the polymerization is carried out at — 25°C [156]. The values of rate constants for Cp2ZrCl2/MAO at 70°C are reported to be kp = 168-1670 (Ms) 1, kfr = 0.021 - 0.81 s 1, and kfr = 0.28 s-1 [155]. 

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

See, for example, R. S. Hosmane and J. F. Liebman, Tetrahedron Lett., 33, 2303 (1992). We additionally note that in the absence of any conjugative interaction, the difference of the enthalpies of formation of fulvene (vide infra) and benzene would very nearly equal the difference of the enthalpies of formation of methylenecyclopentane and cyclohexene. The former difference is 161 kJ mol-1 while the latter difference is but 17 kJ mol-1. 

This is by analogy to cyclopentane, cyclopentene and methylenecyclopentane, all from References 17 by Greenberg and Liebman. 

Diisobutylaluminium hydride catalyses the ring-closure of various dienes. It is proposed that the process involves addition of the aluminium hydride to a terminal double bond, followed by ring-closure and, finally, elimination of the catalyst (equation 106). Thus 1,5-hexadiene gives methylenecyclopentane (213) (equation 107), 1,6-heptadiene gives methylenecyclohexane (214) (equation 108), 4-vinylcyclohexene gives bicyclo[3.2.1]oct-2-ene (215) (equation 109) and the spiro compound 217 is obtained from 5-methylene-l,8-nonadiene (216) (equation 110)112. 

The diester 226 undergoes ring-closure to the methylenecyclopentane derivative 227 in the presence of a catalytic amount of chlorotris(triphenylphosphine)rhodium in boiling chloroform saturated with hydrogen chloride. In contrast, if the reaction is catalysed by palladium(II) acetate, the isomeric cyclopentene 228 is produced (equation 115)118. 

Sunlamp irradiation of butynyl iodide (6) in the presence of hexabutylditin generates an alkyl radical that reacts with an electron-deficient alkene (7) to form an (iodomethylene)cyclopentene (8) in moderate yield. This product can be reduced by Bu3SnH (AIBN) to the methylenecyclopentane (9).2... 

Cyclization of a 1,6-enyne to a methylenecyclopentane can be effected with a Pd(0) catalyst complexed with a phosphine ligand in combination with a trialkyl-silane as a hydride donor (equation I).4 Under these conditions a 1,7-enyne can be cyclized to a methylenecyclohexane. 

Cycloaddition to aldehydes. In the presence of a Pd(0) catalyst, 1 adds to electron-poor alkenes to give methylenecyclopentanes. It also adds to aldehydes to form methylenetetrahydrofurans when tributyltin acetate is used as a cocatalyst.1... 

Depending on the substrate, the enallenes 213 react with a ruthenium-hydrido catalyst to give either the initial product the methylenecyclopentanes 214 with a 1,4-diene substructure or to the conjugated vinylcyclopentenes 215. The latter are formed by a subsequent ruthenium-catalyzed isomerization of the initial cycization product 214 (Scheme 15.69) [136]. 

Another rhodium-catalyzed isomerization, by Makino and Itoh [137], allows the conversion of enallenes 216 and 218 to either five-membered methylenecyclopentanes 217 or, under a CO atmosphere in dioxane, seven-membered alkylidenecyclo-heptenes 218 (Scheme 15.70). With one more carbon in the bridge (in 220), methy-lenecyclohexane 221 was accessible, but as much as 20 mol% of catalyst was necessary. A more recent paper also covers this reaction [138]. 

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