Cycloisomerization alkenes

Another useful class of palladium-catalyzed cycloisomerizations is based on the general mechanistic pathway shown in Scheme 13. In this chemistry, a hydridopalladium acetate complex is regarded as the catalytically active species.27b-29 According to this pathway, coordination of a generic enyne such as 59 to the palladium metal center facilitates a hydropalladation reaction to give intermediate 60. With a pendant alkene, 60 can then participate in a ring-form-... 

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). 

Gycloisomerization of a disubstituted alkyne sometimes required activation of the alkyne by the addition of a conjugated carbonyl and performing the reaction at a higher temperature as in Equation (38). The geometry of the alkene determines the regioselectivity of the /3-hydride elimination, as ( )-60 gave predominantly 61 (Equation (38)), while 62 was the major product of the cycloisomerization of (Z)-60 (Equation (39)). 

As the steric bulk of the propargylic substituents increased, the preference for the formation of the seven-membered ring increased as well. Formation of a ruthenacyclopentene intermediate with sterically hindered substrates involves a large amount of A(1,3) strain, leading to preferential formation of a 7r-allyl species. This novel cycloisomerization process is very sensitive to alkene substitution the requirement for a m-methyl group was evidenced by the failure of 70 to give... 

Stereoinduction was observed, as in the formation of 74 (Equation (46)) as a single diastereomer 1,3-stereo-induction was not successful. Most substrates contained only methyl-substituted olefins, leading to terminal alkenes. In the case of the cycloisomerization of an //-propyl-substituted enyne, a modicum of selectivity with respect to olefin geometry was exhibited 73 was produced in an isomeric ratio of 1 3.5. The authors do not specify whether the (E)- or (Z)-geometry was preferred. 

Weinreb86 has reported the Alder-ene cyclization of enallenes under thermal conditions (Equation (85)). Varying the substitution pattern of alkene and allene groups had little effect on the yield of cyclized product. One exception was a,/ -unsaturated ester 130(Equation (86)) cycloisomerization under thermal conditions led to the formation of the Alder-ene product 131 and the unexpected hetero-Diels-Alder product 132 in a 3 1 ratio. 

Enantioselective hydrogenation of 1,6-enynes using chirally modified cationic rhodium precatalysts enables enantioselective reductive cyclization to afford alky-lidene-substituted carbocycles and heterocycles [27 b, 41, 42]. Good to excellent yields and exceptional levels of asymmetric induction are observed across a structurally diverse set of substrates. For systems that embody 1,2-disubstituted alkenes, competitive /9-hydride elimination en route to products of cycloisomerization is observed. However, related enone-containing substrates cannot engage in /9-hydride elimination, and undergo reductive cyclization in good yield (Table 22.12). 

Cycloisomerizations are one of the most popular methods for the formation of carbo- and heterocyclic compounds [1, 2], Although in most cases alkenes and/or alkynes are still involved, there now exist a significant number of similar applications of allenes which benefit from the higher reactivity of the allene-unit. 

The first example involving a rhodium catalyst in an ene reaction was reported by Schmitz in 1976. An intramolecular cyclization of a diene occurred to give a pyrrole when exposed to rhodium trichloride in isobutanol (Eq. 2) [15]. Subsequently to this work, Grigg utilized Wilkinson s catalyst to effect a similar cycloisomerization reaction (Eq. 3) [16]. Opplozer and Eurstner showed that a n -allyl-rhodium species could be formed from an allyl carbonate or acetate and intercepted intramolecularly by an alkene to afford 1,4-dienes (Eq. 4). Hydridotetrakis(triphenylphosphine)rhodium(l) proved to be the most efficient catalyst for this particular transformation. A direct comparison was made between this catalyst and palladium bis(dibenzylidene) acetone, in which it was determined that rhodium might offer an additional stereochemical perspective. In the latter case, this type of reaction is typically referred to as a metallo-ene reaction [17]. 

Tab. 8.1 summarizes the various substrates that were subjected to the rhodium-catalyzed reaction using a Rh-dppb catalyst system. Only ds-alkenes were cycloisomerized under these conditions, because the trans-alkenes simply did not react. Moreover, the formation of the y-butyrolactone (Tab. 8.1, entry 8) is significant, because the corresponding palladium-, ruthenium-, and titanium-catalyzed Alder-ene versions of this reaction have not been reported. In each of the precursors shown in Tab. 8.1 (excluding entry 7), a methyl group is attached to the alkene. This leads to cycloisomerization products possessing a terminal alkene, thus avoiding any stereochemical issues. Also,... 

Under optimized conditions, cycloisomerizations of a number of functionalized hept-l-en-6-ynes took place in good-to-excellent yields (Table 9.3). Heteroatom substitution was tolerated both within the tether and on its periphery. Alkynyl silanes and selenides underwent rearrangement to provide cyclized products in moderate yield (entries 6 and 7). One example of seven-membered ring formation was reported (entry 5). Surprisingly, though, substitution was not tolerated on the alkene moiety of the reacting enyne. The authors surmize that steric congestion retards the desired [2 + 2]-cycloaddition reaction to the point that side reactions, such as alkyne dimerization, become dominant. 

On the other hand, Takacs and coworkers added organometallic reducing agents to the reaction mixture and promoted the formation of low-valent iron(O) bipyridine complexes. The mechanism of the low-valent iron-catalyzed Alder-ene reaction involves coordination of the two starting materials within the ligand sphere of the iron, which makes the Woodward-Hoffmann rules for such reactions obsolete [11]. Thereby, the scope of the reactions was broadened so that alkenes and 1,3-dienes could also be used as educts in a formal [4 + 4]-cycloisomerization (Scheme 9.3) [12]. Intriguingly, the diastereoselectivity of the cydopentane products can be influenced by either the application of the 2Z-isomer 3 or the 2 E-isomer 4. Especially the E-isomers 4 gave almost exclusive cis selectivity [13]. 

Cyclohexyldienyl complexes, with Ti(IV), 4, 327 Cyclohexylisocyanides, with gold(I) halides, 2, 281 Cyclohexylphosphine, for semiconductor growth, 12, 9 Cyclohexyl selenides, preparation, 9, 480 Cyclohydrocarbonylation alkenes, 11, 515 alkynes, 11, 522 dienes, 11, 522 overview, 11, 511-555 for ring expansion, 11, 527 Cycloisomerizations, via silver catalysts, 9, 558 Cyclomanganation, product types, 5, 777-778 Cyclometallated azobenzenes, liquid crystals, 12, 251 Cyclometallated complexes for OLEDs... 

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],... 

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... 

Considering the mechanistic rationales of the transition metal-catalyzed enyne cycloisomerization, different catalytic pathways have been proposed, depending on the reaction conditions and the choice of metal catalyst [3-5, 45], Complexation of the transition metal to alkene or alkyne moieties can activate one or both of them. Depending on the manner of formation of the intermediates, three major mechanisms have been proposed. The simultaneous coordination of both unsaturated bonds to the transition metal led to the formation of metallacydes, which is the most common pathway in transition metal-catalyzed cycloisomerization reactions. Hydrometalation of the alkyne led to the corresponding vinylmetal species, which reacts in turn with olefins via carbometalation. The last possible pathway involves the formation of a Jt-allyl complex which could further react with the alkyne moiety. The Jt-allyl complex could be formed either with a functional group at the allylic position or via direct C-H activation. Here the three major pathways will be discussed in a generalized form to illustrate the mechanisms (Scheme 8). 

Compared with cycloisomerization, enyne metathesis as a bond reorganization of an alkene and an alkyne to produce a 1,3-diene is less studied. A recent review by Diver and Giessert highlights some recent advances in synthetic applications, and mechanistic features [60]. 

Heterocyclization reactions with saturated moieties (alcohols, amines, thiols, etc.) or acids on unsaturated counterparts (alkenes, allenes, alkynes, etc.) are not covered in this chapter since they are addition, and not isomerization, reactions. Silver is also widely used as an activating agent for producing highly reactive metallic cations (anion metathesis), which, in turn, may catalyze cycloisomerization reactions. This aspect is covered only when the silver control experiments give substantial positive results. 

Few examples of ene-yne cycloisomerization reactions are seen in the literature. The first results for ene-yne cycloisomerizations were with systems bearing an heteroatom (amine or oxygen) next to the alkene counterpart (forming an enamine or an enol ether). Indeed, Dake s group reported the cyclization of enesulfonamides on alkynes (69-70, Scheme 5.30) under catalysis by platinum and silver salts.85 Catalysis using AgOTf (1 1 mol%) was particularly efficient with systems such as 69 (Scheme 5.30)... 

The photocycloaddition of (cyclic) a,(B-unsaturated ketones to alkenes affording cyclobutanes as products comprises the four reaction types shown in Sch. 1, i.e., (a) intermolecular enone + alkene cycloaddition (b) cycloisomerization of alkenylsubstituted enones (c) photocyclodimerization of enones, one ground state enone molecule acting as alkene and (d) cycloisomerization of fe-enones. 

The first such reaction published in 1908 by Ciamician and Silber was the light induced carvone —> carvonecamphor isomerization, corresponding to type b [1]. Between 1930 and 1960 some examples of photodimerizations (type c) of steroidal cyclohexenones and 3-alkylcyclohexenones were reported [2-5]. In 1964, Eaton and Cole accomplished the synthesis of cubane, wherein the key step is again a type b) photocycloisomerization [6]. The first examples of type a) reactions were the cyclopent-2-enone + cyclopentene photocycloaddition (Eaton, 1962) and then the photoaddition of cyclohex-2-enone to a variety of alkenes (Corey, 1964) [7,8]. Very soon thereafter the first reviews on photocycloaddition of a,(3-unsaturated ketones to alkenes appeared [9,10]. Finally, one early example of a type d) isomerization was communicated in 1981 [11]. This chapter will focus mainly on intermolecular enone + alkene cycloadditions, i.e., type a), reactions and also comprise some recent developments in the intramolecular, i.e., type b) cycloisomerizations. 

In contrast to these intermolecular enone + alkene photocycloadditions, the regioselectivity in the corresponding intramolecular cycloisomerizations of alkenylcycloalkenones is controlled primarily by... 

Besides enyne metathesis [66] (see also the chapter Recent Advances in Alkenes Metathesis in this volume), which generally produces 1-vinylcyclo-alkenes, ruthenium-catalyzed enyne cycloisomerization can proceed by two major pathways via hydrometallation or a ruthenacycle intermediate. The RuClH(CO)(PPh3)3 complex catalyzed the cyclization of 1,5- and 1,6-enynes with an electron-withdrawing group on the alkene to give cyclized 1,3-dienes, dialkylidenecyclopentanes (for n=2), or alkylidenecyclopentenes (for n= 1) [69,70] (Eq. 51). Hydroruthenation of the alkyne can give two vinylruthenium complexes which can undergo intramolecular alkene insertion into the Ru-C bond. 

Intramolecular variants of the Alder-ene type couplings between alkynes and alkenes have been extensively explored by means of palladium catalysis [73]. Recently, such a cycloisomerization of enynes was also accomplished with ruthenium catalysis (Scheme 4.32) [74]. 

A mechanism which involved the allylic carbon-hydrogen bond activation of the alkene moiety was proposed for the cycloisomerization of 1,6-diyne to alkylidenecy-cloheptene on the basis of stereochemical consideration and deuterium labeling experiment (Scheme 12.7). 

Analogously, intramolecular hydrosilation reactions have been carried out with alkenes cyclization of alkenyloxy-silanes catalyzed by thiols <1998J(P1)467> and by Pt <1996TL827> has been described. In addition, intramolecular temporary silicon-tethered rhodium-catalyzed [4- -2- -2]-cycloisomerization reactions have been carried out by Evans and Bawn (Equation 50) <2004JA11150>. 

The success of cycloisomerization reactions of this type is critically dependent on factors that influence the conformational mobility of the side chain bearing the alkene moiety. Additionally, functional groups which are able to serve as ligands at palladium may also be of importance. As an example, neither the (E)- nor the (Z)-crotonate derivative ( -IS or (Z)-13 gives rise to the formation of bicyclic products on treatment with bis(dibenzylideneacetone)palladium/tri-isopropyl phosphite. Instead, the corresponding isomeric substituted butadienes, methyl (2E or 2Z,6 )-7,8-dimethylnona-2,6,8-trienoate (14) and methyl (2E or 2Z)-8-methyl-7-methyl-enenona-2,8-dienoate (15), are formed. 

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