Trimethylenemethane 4+3 -cycloaddition with

The palladium-catalyzed trimethylenemethane reaction with tropanones was reported in 1987 by Trost and Seoane and is the first example of a [6 + 3]-cycloaddition.130 Chromium-mediated [6 + 3]-cycloadditions of two types have been described-one in which the chromium complex activates the six-carbon component and one in which the chromium complex activates the three-atom component. An example of the first type involves the reaction of a cycloheptatriene-Cr(CO)3 complex with azirines to give cyclic imines in moderate yields (Scheme 40).131... 

The procedures described herein illustrate the preparation of a substituted cyclopropenone acetal and an alkylidene cyclopropanone acetal.The latter compound has been used to generate a dipolar trimethylenemethane (TMM) species that undergoes [3+2] cycloaddition with electron-deficient 2p-electron C=C and C=X compounds. ... 

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>. 

Palladium-Catalyzed Stereoselective [3 + 2 Cycloaddition with Open-Chain Trimethylenemethane Precursors... 

Acetoxymethyl)-3-(trimethylsilyl)propene (1) is used as a trimethylenemethane precursor in palladium(0)-catalvzed [3 + 2] cycloaddition with electron-deficient alkenes, such as enones, acrylonitriles and a,/ -unsaturaled esters23,26. Mechanistically, this reaction, which gives methylenecyclopentane derivatives 2. is interpreted to proceed via trimethylenemethane-palladium complexes 27,28. 

The Trost group has devised a strategy for stereoselective spirocyclic ring installation across 3-alkylidene oxindoles via palladium-catalyzed [3-1-2] cycloaddition with cyano-substituted trimethylenemethane (Scheme 33) [74, 75]. As illustrated, the opposite sense of diastereoselectivity was observed depending on the choice of chiral ligand 125 or 126. Preferential orientation of the benzenoid portion of the oxindole as dictated by the varied steric environments of the naphthyl ring systems on the catalysts has been put forth as a rationale for the observed difference in stereochemical outcomes. Spirooxindoles 127 and 128 were obtained in 92% ee and 99% ee, respectively. A variation of this methodology has been applied in the racemic synthesis of marcfortine B [75]. 

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]. 

Methylene-6-oxabicyclo[3.2.2Inon-8-en-7-ones from 2-pyrones via 4-i-3]-cycloaddition with a trimethylenemethane equivalent... 

Cycloaddition. W-(Diphenylmethylene)-4-methylben-zenesulfonamide (2) has been used as a dienophile in a hetero [3 + 2] cycloaddition. Dipolar trimethylenemethane (TMM, 21), generated by means of thermolysis of methylenecyclopropane (22), undergoes [3 + 2] cycloaddition with the reagent to regio-selectively afford the acetal of the a-methylene-y-lactam product 23. This product is quite acid-sensitive and may he isolated as the corresponding a-alkyhdene-y-amino ester. The cycloadduct serves as a synthetic precursor to y-amino acid derivatives (eq 13). 

The reactivity of trimethylenemethane complexes has not been studied extensively. There are, however, a number of catalytic reactions, for which the intermediacy of trimethylenemethane complexes is plausible albeit not proved in all cases, stepwise processes might also be considered [33]. The most prominent examples in this context are palladium-catalyzed trimethylenemethane cycloadditions [34,35] in the presence of a phosphane or phosphite, starting from 2-acetoxymethyl-3-allyltrimethsilane (33), which have been explored in great depth by Trost et al. [36, 37]. 33 undergoes [3-1-2]- as well as [3-H4]cyclizations with electron-poor alkenes or dienes such as 34, respectively, leading to 35 and 36 (Scheme 10.13). 

It is appropriate to mention that the first reported use of In(III) salts in addition reactions was as a cocatalyst in a cycloaddition protocol. In the paper by Trost et al, the Pd-catalyzed trimethylenemethane cycloaddition reaction proceeded with an initial conjugate addition followed by cyclization to form five-membered rings. Addition of In(acac)3 swings the usual 1,4-addition preference to that of a... 

Developments in the field of stereoselective 1,3-dipolar cycloadditions and their synthetic applications are outlined in Sections 18.2 to 18.4 [22, 23, 28-34]. Subsequently, related [2-i-3]-cycloadditions with 1,3-diradicals and trimethylenemethane equivalents that furnish the corresponding five-membered carbocycles are covered (Section 18.5) [38—41]. The chapter closes with a collection of [2-i-2]-cycloadditions involving ketenes (Section 18.6) [19, 35, 36], photochemical olefin cycloadditions, and Paterno-Biichi reactions (Section 18.7) [36, 37],... 

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]. 

Catalytic asymmetric Diels-Alder reactions are presented by Hayashi, who takes as the starting point the synthetically useful breakthrough in 1979 by Koga et al. The various chiral Lewis acids which can catalyze the reaction of different dieno-philes are presented. Closely related to the Diels-Alder reaction is the [3-1-2] carbo-cyclic cycloaddition of palladium trimethylenemethane with alkenes, discovered by Trost and Chan. In the second chapter Chan provides some brief background information about this class of cycloaddition reaction, but concentrates primarily on recent advances. The part of the book dealing with carbo-cycloaddition reactions is... 

Trimethylenemethane is a special type of alkene that does not exist as the free compound. Various synthetic equivalents to the synthon 43 shown below have been reported. Trost, in particular, has exploited these compounds in 1,3-dipolar cycloaddition reactions.138 139 A metal-bound, isolated trimethylenemethane species was recently reported by Ando (Scheme 6). It resulted from the complexation of an ero-methylenesila-cyclopropene with group 8 carbonyls (Fe, Ru).140,140a The structure was proved by X-ray crystal structure analysis.29Si NMR data were consistent with the -structure shown. 

The palladium-catalyzed hetero-[4 + 3]-cycloadditions reported by Trost and Marrs utilize a metal-complexed trimethylenemethane as the three-carbon component. These complexes react with a,/3-unsaturated imines to produce seven-membered heterocycles in moderate to good yields.84 Two examples of this reaction were reported and are shown in Equations (13) and (14). Only the [4 + 3]-reaction was observed with a,/3-unsaturated imine 76 however, both the [4 + 3]- and the [3 + 2]-modes of reactivity are observed with a,/3-unsaturated imine 79. 

The [3+2] cycloaddition of trimethylenemethane (TMM) on the unsaturated lactam 288 worked efficiently with the use ofPd[P(0 Pr)3]4 (generated in situ from palladium(n) acetate (20mol%) and triisopropyl phosphite (160mol%)). The reaction proceeded cleanly in refluxing toluene to afford exclusively the desired cycloadduct 290 in 80% isolated yield (Equation 48) <2003TL5033>. 

Presumably the reaction takes place via the monoallene 225, which can be made the sole isomerization product if the rearrangement is carried out with sodium methoxide in methanol at 65 °C (yield 60%) [76], The intended intramolecular [2 + 2] cycloaddition to the diradical 227, a hybrid of trimethylenemethane and tetramethy-leneethane, could so far not be detected. 

Stable five-membered ring adducts of Cgg can be synthesized by ]3+2] cycloadditions of trimethylenemethanes (TMM) [13, 195], The TMM intermediates are prepared in situ by thermolysis of 7-alkylidene-2,3-diazabicycloheptene (non-polar TMM) or methylenecyclopropanone ketals (polar TMM). With the mefhylenecyclopropanone ketal addition (Scheme 4.31), 185 and 186 were isolated after chromatography on silica gel. 

Versatile [3 + 2]-cycloaddition pathways to five-membered carbocycles involve the trimethylenemethane (= 2-methylene-propanediyl) synthon (B.M. Trost, 1986). PaIladium(0)-induced 1,3-elimination at suitable reagents generates a reactive n - -methylene-1,3-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 cyclopentane derivatives is accessible. 

The reaction of methylenecyclopropanes with transition metal complexes is well known to promote a catalytic a-ir cycloaddition reaction with unsaturated compounds, in which a trimethylenemethane complex might exist71-76. Recently, much interest has been focused on the interaction of strained silicon-carbon bonds with transition metal complexes. In particular, the reaction of siliranes with acetylene in the presence of transition metal catalysts was extensively investigated by Seyferth s and Ishikawa s groups77-79. In the course of our studies on alkylidenesilirane, we found that palladium catalyzed reaction of Z-79 and E-79 with unsaturated compounds displayed ring expansion reaction modes that depend on the (Z) and (E) regiochemistry of 79 as well as the... 

In trimethylenemethane complexes, the metal stabilizes an unusual and highly reactive ligand which cannot be obtained in free form. Trimethylenemethanetricar-bonyliron (R=H) was the first complex of this kind described in 1966 by Emerson and coworkers (Figure 1.2) [38]. It can be obtained by reaction of bromomethallyl alcohol with Fe(CO)5. Trimethylenemethaneiron complexes have been applied for [3+2]-cycloaddition reactions with alkenes [39]. 

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... 

In a variation on the two-component cycloaddition reaction, a [3+3] strategy was reported whereby reaction of enantiomerically pure aziridines, generated from amino acids, with palladium trimethylenemethane complexes leads to a piperidine (Scheme 114). Yields ranged from 63% to 82% and the efficiency of the methodology was demonstrated by the four-step synthesis of (—)-pseudoconhydrin <2001SL1596>. 

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]. 

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