The Intramolecular Alder Ene Reaction

In comparison to the intramolecular Diels-Alder reaction, the intramolecular Alder ene reaction has been little studied (1,2). All examples in the hterature through mid-1981 are included in the Tables at the end of this chapter. 

For the purpose of this chapter, the ene reaction is considered to be the transfer of a proton from an ene donor to an ene acceptor, with concomitant formation of a bond between them. In the intramolecular case, R and R will be joined [1]. The aim of this chapter is to present the scope and limitations of the intramolecular ene reaction as they now stand, and to suggest directions to be explored that might make this reaction even more useful than it has been in organic synthesis. 

Formally, the ene reaction is a concerted, six-electron process. In practice, as with some examples (see Chapter Two) of the intramolecular Diels-Alder reaction, nonsynchronous bond formation may play an important role [2]. With some exceptions (3), free radical inhibitors have no effect on the reaction 

Electron withdrawing substituents on the ene acceptor accelerate the reaction, and this effect is accentuated by Lewis acid catalysis. The corollary, that electron-donating substituents on the ene donor could also accelerate the reaction, has not been explored. 

Depending on the positioning of the bridge linking the ene donor and acceptor, three orientations are possible for the intramolecular ene reaction. These have been described by Oppolzer (1) as Types I, II, and III. Snider (5) has observed, in addition. Type IV [3]. Type I reactions are by far the most studied, especially for five- and six-membered ring forming reactions. It is conceivable, especially as activated ene systems are developed, that Types II-IV will become more important. 

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The Alder-ene reaction has traditionally been performed under thermal conditions—generally at temperatures in excess of 200 °C. Transition metal catalysis not only maintains the attractive atom-economical feature of the Alder-ene reaction, but also allows for regiocontrol and, in many cases, stereoselectivity. A multitude of transition metal complexes has shown the ability to catalyze the intramolecular Alder-ene reaction. Each possesses a unique reactivity that is reflected in the diversity of carbocyclic and heterocyclic products accessible via the transition metal-catalyzed intramolecular Alder-ene reaction. Presumably for these reasons, investigation of the thermal Alder-ene reaction seems to have stopped almost completely. For example, more than 40 papers pertaining to the transition metal-catalyzed intramolecular Alder-ene reaction have been published over the last decade. In the process of writing this review, we encountered only three recent examples of the thermal intramolecular Alder-ene reaction, two of which were applications to the synthesis of biologically relevant compounds (see Section 10.12.6). 

The intramolecular Alder-ene reaction (enyne cydoisomerization reaction) with alkynes as the enophiles has found wide application compared with diene systems. The reason may be the ready chemo-differentiation between alkene and alkyne functionality and the more reactive alkyne moiety. Furthermore, the diene nature of the products will promote further applications such as Diels-Alder reactions in organic synthesis. Over the past two decades the transition metal-catalyzed Alder-ene cycloisomerization of l,n-enynes (typically n= 6, 7) has emerged as a very powerful method for constructing complicated carbo- or heterocydic frameworks. The transition metals for this transformation indude Pd, Pt, Co, Ru, Ni-Cr, and Rh. Lewis acid-promoted cydoisomerization of activated enynes has also been reported [11],... 

Diastereomeric control in the intramolecular Alder ene reaction, influence of a chiral acceptor 70... 

Inter- and intramolecular ruthenium-catalyzed Alder-ene reactions were utilized to synthesize the proposed structures of amphidinolide A.98 Conversion of dienyne 163 into pentaene 164 was accomplished in 46% yield with the products obtained as a 3.5 1 mixture of the branched to linear forms (Scheme 39). It is notable that the Cp variant of the ruthenium catalyst 64 was used for the intermolecular Alder-ene reaction. Conversion of 164 into protected amphidinolide A was performed using high dilution conditions with the normal catalyst to give a 58% yield of the macrolide which was then deprotected to provide the natural product. 

In the same manner, the natural products (—)-protometinol analogue [16] (Scheme 9.6) and (—)-gibboside [17] were synthesized utilizing an intramolecular Alder-ene reaction in the key step. However, the synthesis of the cyclization... 

A ruthenium based catalytic system was developed by Trost and coworkers and used for the intermolecular Alder-ene reaction of unactivated alkynes and alkenes [30]. In initial attempts to develop an intramolecular version it was found that CpRu(COD)Cl catalyzed 1,6-enyne cycloisomerizations only if the olefins were monosubstituted. They recently discovered that if the cationic ruthenium catalyst CpRu(CH3CN)3+PF6 is used the reaction can tolerate 1,2-di- or tri-substituted alkenes and enables the cycloisomerization of 1,6- and 1,7-enynes [31]. The formation of metallacyclopentene and a /3-hydride elimination mechanism was proposed and the cycloisomerization product was formed in favor of the 1,4-diene. A... 

Highly enantioselective Rh-catalyzed intramolecular Alder-ene reactions for the synthesis of chiral 3-alkylidene-4-vinyltetrahydrofurans were reported by Zhang, as illustrated below <02AG(E)3457>. Metallic indium was also shown to mediate the intramolecular cyclization of tethered allyl bromides onto terminal alkynes to afford 3-methylene-4-vinyltetrahydrofurans in 50-62% yield <02SL2068>. 

There has been a report of the use of ionic liquids to expedite the metal catalyzed intramolecular Alder-Ene reaction. In this work, an Ir catalyst was used, the yields for the conversion of 146 into 147 were high and the use of the ionic liquid served to reduce the temperature required by... 

The third chapter is devoted to the all-carbon intramolecular Alder ene reaction. The tables in that chapter summarize all examples that could be found in the literature through 1981, with several additional examples from 1982. Leading references to heterocyclic ene reactions are also included in this chapter. 

Petit L, Banwell MG, Willis AC (2011) The total synthesis of the crinine alkaloid hamayne via a pd[0]-catalyzed intramolecular alder-ene reaction. Org Lett 13 5800-5803... 

Intramolecular Alder-ene reactions of 1,6-enynes have been reported to proceed in the presence of the 18-electron iron(O) complexes [CpFe(C2H4)2][Li(tmeda)] for cyclic enynes or [CpFe(cod)][Li(dme)] for acyclic enynes (Scheme 4-317). 

Trost and others have extensively studied the ruthenium-catalyzed intermolecular Alder-ene reaction (see Section 10.12.3) however, conditions developed for the intermolecular coupling of alkenes and alkynes failed to lead to intramolecular cycloisomerization due the sensitivity of the [CpRu(cod)Cl] catalyst system to substitution patterns on the alkene.51 Trost and Toste instead found success using cationic [CpRu(MeCN)3]PF6 41. In contrast to the analogous palladium conditions, this catalyst gives exclusively 1,4-diene cycloisomerization products. The absence of 1,3-dienes supports the suggestion that the ruthenium-catalyzed cycloisomerization of enynes proceeds through a ruthenacycle intermediate (Scheme 11). 

The proposed catalytic cycle of the ruthenium-catalyzed intermolecular Alder-ene reaction is shown in Scheme 21 (cycle A) and proceeds via ruthenacyclopentane 100. Support for this mechanism is derived from the observation that the intermediate can be trapped intramolecularly by an alcohol or amine nucleophile to form the corresponding five-or six-membered heterocycle (Scheme 21, cycle B and Equation (66)).74,75 Four- and seven-membered rings cannot be formed via this methodology, presumably because the competing /3-hydride elimination is faster than interception of the transition state for these substrates, 101 and 102, only the formal Alder-ene product is observed (Equations (67) and (68)). 

An intramolecular palladium-catalyzed cycloisomerization of enyne 170 was used to access the antifungal agent, chokol C (Scheme 43).102 The choice of ligand and catalyst was essential to the efficiency of the Alder-ene reaction. Enone 171 was obtained as a single olefinic isomer resulting from migration of only Ha during the cycloisomerization reaction. 

Substrates possessing an allene that participate in the Alder-ene reaction are less common, but a few examples are known. Malacria [11] and Livinghouse [12] have independently used cobalt to effect intramolecular allenic Alder-ene reactions but the scope of these reactions was not investigated. Sato has performed an allenic Alder-ene reaction to form five-membered rings, using stoichiometric amounts of titanium [13], and Trost has shown that 1,3-dienes can be prepared via an intermolecular Alder-ene reaction between allenes and enones using a ruthenium(II) catalyst [14]. 

Brummond [28] was the first to illustrate that cross-conjugated trienes could be obtained via an allenic Alder-ene reaction catalyzed by [Rh(CO)2Cl]2 (Eq. 14). Selective formation of the cross-conjugated triene was enabled by a selective cycloisomerization reaction occurring with the distal double bond of the aUene. Typically directing groups on the allene, differential substitution of the aUene termini, or intramolecularization are required for constitutional group selectivity. However, rhodium(f), unlike other transition metals examined, facihtated selective cyclization with the distal double bond of the allene in nearly aU the cases examined. 

The cross-conjugated trienes have potential in many different types of diversification strategies. For example, the triene clearly lends itself to inter- and intramolecular Diels-Alder reactions. Incorporation of the hydroxymethyl group on the tether allows attachment of functionality suitable for reactions subsequent to the Alder-ene reactions. As depicted in Scheme 8.5, propargyl tosylamides A, alkynyl silanes B, acrylate esters C, and propargyl ethers D can all be readily prepared from 39... 

Esteruelas and coworkers reported the stoichiometric Diels-Alder type addition of dienes to the Cp-Cy double bond of allenylidene complexes to give the corresponding substituted vinylidene complexes (Equation 7.7) [33]. The results of this stoichiometric reaction prompted us to investigate the diruthenium complex-catalyzed allenylidene-ene reaction between alkenes and the Cp-Cy double bond of an allenylidene moiety. Results of inter- and intramolecular allenylidene-ene reactions providing novel coupling products between alkynes and alkenes are described in this section [34]. 

A stereocontrolled route to the trisubstituted pyrrolidine 146 is achieved using either a concurrent Chugaev-ene reaction or a retro-Diels-Alder-ene reaction <20000L3181, 2001TL4523>, both approaches giving the pyrrolidine in good yields and with complete stereoselectivity. Thus, the thermolysis of either 147 or 148 produces a common intermediate which subsequently undergoes intramolecular ene reaction under the reaction conditions (Scheme 10). 

Intramolecular examples of iron-catalyzed formal Alder-ene reactions, which are also denoted cycloisomerization reactions, were described in the late 1980s by the groups of Tietze and Takacs in reactions directed towards cyclopentane [6, 7], cyclohexane [8], piperidine [9] and tetrahydropyran derivatives [10]. 

The intramolecular iron-catalyzed Alder-ene reaction of enynes in the carbocy-clization reaction was recently reported by Furstner et al. (Scheme 9.8) [20], A low-valent cyclopentadienyliron catalyst, specifically the [CpFe(C2H4)2][Li(tmeda)] complex, is a reactive catalyst for enyne cydoisomerization reactions. Bicyclic products, also incorporating large ring systems, are thereby accessible, and the Thorpe-Ingold effect seems to be helpful for these types of reactions. 

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