Pd-trimethylenemethane

One of the most important classes of Michael initiated ring closure processes in the construction of carbo- and heterocycles are stepwise cycloaddition reactions where a metal induces dipolar behavior in otherwise unreactive organic compounds to be reacted with activated olefins. In this area, Pd-assisted cycloaddition reactions which involve zwitterionic zr-allylPd complexes of type I (linear type), II, or III (Pd-Trimethylenemethane (TMM) type and analogs) as reactive dipole partners are popular methods that provide highly functionalized, saturated ring systems often with high stereocontrol and atom economy (Scheme 1). Discovered in the early 1980s, they have been extensively covered in the review literature [8-16]. 

Trimethylsilylmethyl)allyl acetate (263) is a useful compound, which generates Pd-trimethylenemethane complex (TTM) 264 and undergoes [3 -I- 2] cycloadditions with 265 to afford 266. Also [3 + 3] cycloaddition is possible [97]. The carbonate 267 can be used for similar cycloadditions under neutral conditions [98]. 

TIBAH, Triisobutylaluminum TMDHS, Tetramethyldihydrosiloxane TMEDA, Tetramethylethylenediamine TMM, Trimethylenemethane TMM-Pd, Trimethylenemethane palladium TMOF, Trimethyl orthoformate TMS, Trimethylsilyl TMU, AA A W -Tetramethylurea TOF, Turnover frequency Tol, Tolyl... 

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-... 

Cycloaddition involving the Pd-catalyzed trimethylenemethane (TMM) fragment 63 and the 1.3-diene 61 with an EWG offers a good synthetic method for the hydroazulene skeleton 65. The cydoaddition of trimethylene-... 

Cycloaddition of COj with the dimethyl-substituted methylenecyclopropane 75 proceeds smoothly above 100 °C under pressure, yielding the five-membered ring lactone 76. The regiocheraistry of this reaction is different from that of above-mentioned diphenyl-substituted methylenecyclopropanes 66 and 67[61], This allylic lactone 76 is another source of trimethylenemethane when it is treated with Pd(0) catalyst coordinated by dppe in refluxing toluene to generate 77, and its reaction with aldehydes or ketones affords the 3-methylenetetrahy-drofuran derivative 78 as expected for this intermediate. Also, the lactone 76 reacts with a, /3-unsaturated carbonyl compounds. The reaction of coumarin (79) with 76 to give the chroman-2-one derivative 80 is an example[62]. 

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). 

Construction of the cyclopentane ring was accomplished by utilization of Trosf s Pd-mediated diastereoselective [3+2] trimethylenemethane (TMM) cycloaddition [4] on the cinnamate 5 having an Evans type chiral auxiliary [4b], The resulting diastereomeric mixture (3 1 at best) of 7a and 7b was separated by careful silica gel column chromatography (7a is less polar than 7b under normal phase). Puri-... 

Acetoxymethyl)allyl]trimethylsilane (5) in the presence of a Pd(0) reagent, for instance, acts as an equivalent of trimethylenemethane in cycloadditions to electron-deficient alkenes such as a,p-unsaturated ketones, esters, nitriles, sulphones and lactones [7] (Scheme 6.6). 

The palladium [Pd(Ph3)4]-catalysed 3 + 3-cycloaddition of trimethylenemethane with azomethineimines produced hexahydropyridazine derivatives under mild conditions (40 °C).171 The Lewis acid-catalysed formal oxa-[3 + 3]-cycloaddition of a,f+ unsaturated aldehydes with 6-methyl-4-hydroxy-2-pyrone, 1,3-diketones, and viny-logous silyl esters yielded a variety of pyrones at room temperature.172 Croton-aldehyde has been converted to 6-hydroxy-4-methylcyclohex-l-enecarboxaldehyde by an enantioselective 3 + 3-cycloaddition catalysed by proline. This methodology was used in the synthesis of (—)-isopulegol hydrate, (—)-cubebaol, and (—)-6-hydroxy-4-methylcyclohex-l-ene-1-methanol acetate, an intermediate in the total synthesis of the alkaloid magellanine.173... 

As an approach to the synthesis of piperidines with stereocontrol, multiple functionality, and flexibility, the authors employed a [3+3] cycloaddition reaction of a silylpropenyl acetate with aziridines in the presence of a palladium catalyst. The key intermediate is a palladium-trimethylenemethane (Pd-TMM) complex <03JOC4286>. Optically active aziridines gave enantiomerically pure piperidines. 

Transition metal chemistry provides an especially rich source of methods for the construction of cyclic compounds. The idea to synthesize 297 from precursor 298 comes from the recognition of 298 as an equivalent to the 1,3-bipolar synthon 298a, trimethylenemethane. It was reasoned that intermediates equivalent to 298a might be formed as transient species and stabilized by complexation with transition metals, e.g. Pd(0). With reagents such as Michael acceptors they can be used for an efficient cyclopentanoannulation. ... 

H 2]-Cycloaddition occurs between 3-methoxycarbonyl-2-pyrone 309 and a trimethylenemethane Pd[(/-PrO)3P]4 complex to give the cycloadduct 310 in 71% yield (88JA1602). (See Scheme 59.) Reactions of 309 and 3-acetylcoumarin 236a with cyclopropenone acetal derivative 312 afford regioselectivity the cyclopentenone acetal compound 313 and 314, respectively (92JA5523). 

Methylenecyclopentanes The intramolecular Pd-catalyzed cycloaddition of trimethylenemethane to electron-deficient aUcenes uses McjSnOAc as a cocatalyst. 

As the proceeding chapters demonstrate, Ni(0)- and Pd(0)-catalyzed [3-1-21-cycloadditions of methylenecyclopropanes with alkenes open a new, simple, and useful route to a number of substituted methylenecyclopentanes. This catalytic generation of a trimethylenemethane synthon and its addition to olefinic double bonds not only lead to five-membered rings but also introduce an exocyclic methylene group, which is a useful functionality for further structural elaboration. 

Theoretical studies 225>226> as well as preparative work strongly indicate that the reactive palladium organic intermediate in Reaction 115b and 115c is an unsym-metrical, zwitterionic trimethylenemethane-palladium (TMM-Pd) complex, as formulated in Eq. 117. Moreover, cycloaddition with a cyclic TMM-Pd-precursor revealed that the electron-deficient olefin attacks the TMM-Pd unit from the side away from the metal. This demonstrates that complexation of the olefin with the metal does not occur prior to C—C bond formation 183>. 

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. 

Participation of heterocycles in Pd-catalyzed cycloadditions involving trimethylenemethane and its analogs 02MI6. 

When the reaction of active methine compounds with methylenecyclopro-pane was carried out in the presence of Pd(PPh3)4 as the catalyst, two types of ring-opening product were obtained (Eq. 72) [146]. This observation suggests that the reaction does not proceed through the trimethylenemethane-palladium intermediate, from which one ring-opening product would be formed predominantly [147]. 

The oxidative addition of an allylic acetate having an allylsilane structure (18) to a Pd(0) complex provides a (trimethylenemethane)palladium species (19), which undergoes [3+2] cycloaddition to a variety of electron-deficient olefins (eqs (115) and (116)) [146]. 

Acetoxymethyl-3-allyltrimethylsilane is a bifunctional or conjunctive reagent that provides an efficient and versatile means of synthesizing methylenecyclopentanes via [3 + 2] cy-cloaddition18 In the presence of catalytic amounts of an appropriate palladium(O) complex, the combination of the allyl acetate and allylsilane functionalities results in the formation of a metal-stabilized trimethylenemethane unit (TMM-Pd). This is able to undergo Smooth [3 + 2] cyeloaddition reactions with electron-deficient olefins. 

The success of this carboxylative trimethylenemethane cycloaddition extends to the addition to cyclohexenone. In contrast to the poorly yielding process involving the unsubstituted TMM -Pd complex, a respectable yield of 49 % is obtained here. This is explained by the reduced basicity of the silylated complex, thus leading to fewer side reactions. The reaction is also considered to have a greater degree of concertedness and this becomes apparent in the discussion of chiral Z- and f-olefins in Section 1.6.1.2.3.2. The failure of in situ derived palladium complexes to yield the desired product is attributed to the basic conditions employed which result in double-bond migrations to the endocyclic, conjugated system. 

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