Trimethylenemethane cycloaddition reactions

The presence of five-membered rings such as cyclopentanes, cyclopentenes, and dihydrofurans in a wide range of target molecules has led to a variety of methods for their preparation. One of the most successful of these is the use of the trimethylenemethane (TMM) [3 + 2] cycloaddition, catalysed by palladium(O) complexes. The TMM unit in these reactions is derived from 2-[(trimethylsilyl)methyl]-2-propen-l-yl acetate 39. Formation of the palladium TT-allyl complex is followed by removal of the trimethylsilyl group and nucleophilic attack of the resulting acetate ion, thus producing a zwitterionic palladium complex 40. 

Normally this is reacted with an alkene bearing electron withdrawing substituents, which make the substrate prone to Michael-type 1,4-addition. The resulting cyclisation product, exemplified by 41, has an exo methylene functionality. The mechanism is thought to be stepwise, consisting of nucleophilic attack at carbon followed by attack of the resulting enolate on the ir-allyl palladium unit. 

The cause of this remarkable selectivity switch is thought to be due to the relative stability of the two intermediates. Normal 1,4-addition leads to an enolate anion, the charge of which may be delocalised away from the oxygen centre. The presence of indium(III), however, stabilises the 1,2-addition product (an alkoxide), presumably forming an ate complex. As the initial reaction of the TMM palladium complex with the a,p-unsaturated substrate is reversible, stabilisation of the 1,2-addition intermediate biases the equilibrium in favour of the eventual 1,2-cyclisation product. 

Protocol 7, chosen for this reaction, is representative of the method described. Cycloaddition of the unsaturated diester gives the 1,4-cycloaddition product, with complete exo selectivity. 

Preparation of encfo-2,6-dimethoxy carbonyl-4-methylenetricyclo [5.2.1.0 ] decane (Structure 45) 

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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... 

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 addition of simple ester or ketoenolates to TT-allylpalladium complexes may constitute the second step of an ingenious [3 + 2] cycloaddition reaction. One substrate that undergoes this process is 2-(tri-methylsilylmethyl)allyl acetate (5). The mechanism proposed involves initial formation of a 2-(tri-methylsilylmethyl)allylpalladium cation followed by desilylation by the acetate liberated in the oxidative addition (Scheme 1). The dipolar intermediate can be envisioned as an T]3-trimethylenemethane-PdL2 species (6) or, less likely, an -complex (7). 

The addition of the trimethylenemethane-palladium complex to alkenes may proceed by a concerted process or via a stepwise mechanism in which the anion of the 1,3-dipole attacks Michael-fashion to generate an intermediate anion which collapses to form a five-membered ring by attack on the allylpalla-dium complex. This [3 + 2] cycloaddition reaction has been reviewed.128 A number of additional reports of its use have appeared recently.129-134... 

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]. 

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]. 

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. 

Cyclopropene, methylenecyclopropane and their derivatives have proved to be valuable reagents in transition metal-catalyzed cycloaddition reactions. Small and medium carbocycles can be prepared by this method. The chemoselectivity observed in some of these reactions is quite remarkable. In addition, high degree of regio- and stereoselectivity is obtained in most cases. In particular the new [3+2] cycloaddition described here and which involves methylenecyclopropane and its derivatives as trimethylenemethane synthones, shows great synthetic promise as a method for constructing fivemembered rings. 

The involvement of trimethylenemethane diradicals in deazetization of diazoalkane-allene adducts or trimethylene diradicals in the deazetization of the adducts of acyclic alkenes often leads to mixture of regioisomers and stereoisomers and from the standpoint of cyclopropane syntheses, this is undesirable. Far fewer problems of this type attend deazetization of the adducts of cyclic or polycyclic alkenes and, furthermore, even a modest amount of strain in the system activates the alkene to diazoalkane addition so that there is no need for activating substituents on the double bond. Cyclopropene is highly reactive towards diazoalkanes (see also Section 1.1.5.1.5.3.1.) and cycloaddition reactions of this type provide a ready entry into the bi-cyclo[1.1.0]butane series. The addition of diphenyldiazomethane to cyclopropene gave 4,4-diphenyl-2,3-diazabicyclo[3.1.0]hex-2-ene (1), which on photolysis gave a mixture of 2,2-diphenylbicyclo[1.1.0]butane (2) and 1,1-diphenylbuta-l,3-diene (3). ... 

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. 

Cycloaddition reactions. The aminophosphite Hg-2C derived from octahydro-BINOL is found to promote the [3+3]cycloaddition of nitrones and trimethylenemethane derivatives to furnish 1,2-oxazines. Remarkable ligand effects have been observed in the spiroannulation of oxindoles products possessing opposite configuration at the spirocyclic center arise by changing the naphthyl substituents on the pyrrolidine ring (7A [a-Np] vs. 7B [P-Np])."... 

The use of trimethy1enemethane in [3+2] cycloaddition reactions has been developed extensively. Cycloadditions using methyl 1-(trimethyl silyl)-2-[ (trimethylsilyl)methyl]prop-l-en-3-yl carbonate as the trimethylenemethane precursor produce carboxylated adducts (Scheme 46). Reaction of trimethylenemethane with... 

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)). 

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). 

Another example of the trimethylenemethane type of compound is provided by the tricarbonyliron complex of heptafulvene. This complex undergoes a cycloaddition reaction with methyl acetylenedicarboxylate and the product can be converted into 1,2-dicarbomethyoxyazulene [Eq. (163) (Kerber and Ehntholt, 1973)]. 

In reactions where palladium(O) is required to start the catalytic process, formation of the active complex may be achieved in situ by the reduction of a suitable palladium(II) complex, e.g. Pd(OAc)2- ITiis process also has the advantage that any phosphine may be used in the reaction, without the need to synthesise and isolate the corresponding palladium(0) phosphine complex. Using this method, only 2-3 equiv of phosphine may be used, rendering the resulting palladium(O) complex coordinatively unsaturated and therefore very reactive. A good example of this is the use of Pd(OAc)2/P(o-tolyl)3 in the protocol for the Heck reaction (Protocol 1 in this chapter). Another method for the in situ reduction of palladium(II) is the use of DIBAL-H as the reductant. This has been used by Trost in trimethylenemethane (TMM) [3 + 2] cycloaddition reactions, an example of which is also given in this chapter (I otocol 7). 

There have been reports of a number of reactions of CPNA 73 that result in cleavage of the strained C—C o-bond under thermal conditions. The formed reactive intermediate 74 undergoes insertion and cheletropic [1+2]-, [3+2]-, and [3-1-4] cycloaddition reactions under thermal conditions (Scheme 6.13a). The reactivity profiles reported to date are consistent with such a a-delocalized singlet species 74 that can react either as a 1,1- or as a 1,3-dipole. Moreover, the 2-alkylidenecyclopropanone acetal 75 derived from a CPNA 76 is a useful precursor of dialkoxy trimethylenemethane (TMM) 77. MUd thermolysis of 75 in the presence of an electrophile generates 77, which undergoes a [3+2] cycloaddition to form cyclopentane derivative 78 (Scheme 6.13b). These results were reviewed by Nakamura and coworkers [32]. 

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). 

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