Trimethylenemethane palladium-catalyzed cycloadditions

Recent Advances in Palladium-catalyzed Cycloadditions involving Trimethylenemethane and its Analogs... 

Palladium-catalyzed cycloaddition is one of the most popular and useful reactions for the construction of a variety of cyclic compounds. The first one was the [3 + 2] cycloaddition of 2-[(trimethylsilyl)methyl]aUyl ester with olefins bearing electron-withdrawing groups reported in 1979 (Scheme and later a large number of cycloaddition reactions were studied, where [3 + 2], [3 + 4], [3 + 6], and [1 + 2] cycloaddition reactions were developed (Scheme 2) and applied to natural product synthesis. Most of these catalytic cycloadditions proceed via a trimethylenemethane palladium (TMM-Pd) intermediate or its analogs, oxatrimethylenemethane palladium (OTMM-Pd) and azatrimethylenemelhane palladium (ATMM-Pd) (Scheme 3). 

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 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 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... 

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

A similar pressure effect on regioselectivity was reported for palladium-catalyzed [3-I-2]-cycloadditions [19]. In the reaction of the trimethylenemethane (TMM) precursor 61 with the alkene 62 the two regioisomeric cycloadducts 63 and 64 are possible while 64 is mainly formed at 1 bar, the only product observed at 10 kbar is 63. A possible explanation of this dramatic change in selectivity could be the increased rate of the bimolecular reaction of 65 and 62 to give 63 compared to the unimolecular isomerization of the TMM complexes 65 and 66. Thus, the kineti-cally formed complex 65 is effectively trapped under pressure by the alkene 62. 

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]. 

The palladium-catalyzed [3+2] cycloaddition reaction between enantiomerically pure a,P-unsaturated sulfoxides and trimethylenemethane (266), using the methodology developed by Trost [198], has been reported [199]. Thus, reaction of the sulfoxide (31), 2-acetoxymethyl-3-allyltrimethylsilane (2eq), palladium acetate (5mol%), and triisopropylphosphite (20 eq) in THF under reflux gave the major cycloadduct (267) in 80% yield and 80% de (Scheme 5.87). Moderate to good levels of asymmetric induction were observed for various a,P unsaturated sulfoxides. 

Although the use of 1,3-dipolar cycloaddition reactions that form carbon-heteroatom bonds is fairly common using traditional synthetic methods [2], palladium-catalyzed dipolar cydoaddition reactions of this type are rather rare. However, a few reports have described an interesting and synthetically useful approach to the synthesis of pyrrolidines via Pd-catalyzed [3 + 2] cydoaddition reactions oftrimethylenemethane vdth imines [91]. In very recent studies, Trost has developed an asymmetric variant of these reactions that provides access to enantioenridied pyrrolidine derivatives [92]. For example, treatment of trimethylenemethane precursor 131 with imine 132 proceeds to afford 133 in 84% yield and 91% ee when a catalyst composed of Pd (dba)2 and ligand 134 is used (Eq. (1.53)). 

Trost and coworkers reported a novel palladium-catalyzed [3 + 2] cycloaddition of trimethylenemethane with ketones. This protocol provides access to highly enan-tioenriched tetrahydrofurans bearing a tetrasubstituted stereocenter (Scheme 2.4). In this process, the use of a Cl-symmetric phosphoramidite ligand is critical for establishing this reaction, which demonstrated a uniquely high activity under the reaction conditions [10]. 

Trost, B. M., Bringley, D. A. (2013). Enantioselective synthesis of 2,2-disubstituted tetrahydrofurans palladium-catalyzed [3-1-2] cycloadditions of trimethylenemethane with ketones. Angewandte Chemie International Edition, 52, 4466-4469. 

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). 

Palladium-catalyzed intramolecular [3+2] cycloadditions starting from alkenylidenecyclopropanes have been reported by Mascarenas et al. [44]. For related nickel-catalyzed reactions, the intermediacy of trimethylenemethane complexes has not been invoked [45]. 

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... 

The mode of COj linkage to a methylenccyclopropane involves the intermediate trimethylenemethane, which has also been Implicated in the cycloadditions of mcthylenecyclopropane to alkenes catalyzed by palladium(O). The insertion of COj into this allylic intermediate gives cyclic carboxylate species, which liberate the lactones, as shown in Scheme 11. 

Cyclopropenes and mcthylcnccyclopropanes serve as multifunctional reagents in transition metal catalyzed reactions22. Methylenecyclopropanes, via C-C bond cleavage, are also used as trimethylenemethane precursors in transition metal catalyzed [3 + 2] cycloadditions for selective five-membered-ring formation. Low-valent nickel and palladium complexes are used as catalysts. This method has been extensively reviewed 22 and stereoselective applications are fully described in Section D.1.6.1.2.3. 

In this latter reaction mode, which is observed much more rarely than /3-dehydropal-ladation, a wide variety of ligands can be coupled to each other with the formation of new C—C, C—H, C— N, C—O, and C—Hal bonds. This section does not cover the numerous cascade couplings in which a number of successive intramolecular additions of 2 onto double bonds is eventually completed by /3-dehydropalladationt as well as the numerous [2 -I- 2 -I- 2] and [4 + 2] cyclotri- and cyclodimerizations of alkynes, enynes, and related compounds. " The Pd(0)-catalyzed Cope rearrangement also will not be considered here, as it proceeds via bis(i7 -allyl)palladium(ll) intermediates. The carbopalladation reactions of aUenes, which have been reviewed recently, are covered in Sect. IV.7. (For new examples see also refs. [10]-[12]). On the other hand, the numerous Pd-catalyzed formal [3 + 2] cycloadditions of trimethylenemethane (TMM) complexes may be classified as carbopalladations of alkenes without subsequent dehydropalladation. As the subject of this section has partially been covered in several newly published reviews, " the attention here will be on the most recent and interesting communications. 

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