Enynes, intramolecular metathesis

A further confirmation of the metal carbene mechanism is provided by enyne intramolecular metathesis reactions such as that depicted in equation 61. The C=C bond in the substrate becomes the single bond attaching the alkenyl group to the phenanthrene ring system634,635. 

Enyne intramolecular metathesis reactions, of the type shown in equation 61, can be very useful in organic synthesis. A number of such reactions, catalysed by tungsten or chromium carbene complexes, have been reported634,635,737 - 740. The ruthenium carbene catalysts 18-20 (Table 2) are likely to be increasingly used for this purpose because of their stability, ease of handling and good yields, as in the synthesis of various 5-, 6- and 7-membered heterocycles, e.g. equation 67741. 

Another interesting transformation is the intramolecular metathesis reaction of 1,6-enynes. Depending on the substrates and catalytic species, very different products are formed by the intramolecular enyne metathesis reaction of l,6-enynes[41]. The cyclic 1,3-diene 71 is formed from a linear 1,6-enyne. The bridged tricyclic compound 73 with a bridgehead alkene can be prepared by the enyne metathesis of the cyclic enyne 72. The first step of... 

Reaction of the carbene complex 148 with alkyne affords vinylcarbene 150 via metallacyclobutene 149. In the intramolecular reaction of enyne 152, catalysed by carbene complex 151, the triple bond is converted to vinylcarbene 153 which then reacts with the double bond to give the conjugated diene 154. Generation of 154 is expected by the formation and cleavage of cyclobutene 155 as a hypothetical intermediate. Based on this reaction, Ru-catalysed intramolecular metathesis of enyne 156 gave the N-containing cyclic diene 157, from which (—)-stemoamide (158) was synthesiszed. The reaction can be understood by assuming the formation of the hypothetical cyclobutene 159 from 156 [52],... 

In contrast to the reliable, high-yielding, and selective intramolecular, n-enyne metathesis reaction, intermolecular enyne metathesis (enyne cross-metathesis) has seen less use in the synthesis of complex molecules due to limited selectivity, despite its potential in fragment-coupling processes (404). The most common use of intermolecular enyne metathesis employs ethylene as the alkene component, providing a particularly convenient method for the production of... 

A new three-component organoruthenium catalyst system consisting of [RuClj(p-cymene)], 1,3-bis(mesityl)inidazolium chloride and cesium carbonate was recently utilized in intramolecular metathesis reactions of enynes, from some of which 2,5-dihydrofurans were produced <01SL397>. The same type of precursor also underwent cobalt-mediated cycloisomerization reactions to form 2,5-dihydrofurans, as illustrated <01OL4161>. 

Treatment of an alkyne/alkene mixture with ruthenium carbene complexes results in the formation of diene derivatives without the evolution of byproducts this process is known as enyne cross-metathesis (Scheme 22). An intramolecular version of this reaction has also been demonstrated, sometimes referred to as enyne RCM. The yield of this reaction is frequently higher when ethylene is added to the reaction mixture. The preferred regiochemistry is opposite for enyne cross-metathesis and enyne RCM. The complex mechanistic pathways of Scheme 22 have been employed to account for the observed products of the enyne RCM reaction. Several experiments have shown that initial reaction is at the alkene and not the alkyne. The regiochemistry of enyne RCM can be attributed to the inability to form highly strained intermediate B from intermediate carbene complex A in the alkene-first mechanism. Enyne metathesis is a thermodynamically favorable process, and thus is not a subject to the equilibrium constraints facing alkene cross-metathesis and RCM. In a simple bond energy analysis, the 7r-bond of an alkyne is... 

Under enyne cross-metathesis conditions, the intermolecular reaction of the a,(D-dienes 153, derived from the MBH reaction, with different terminal alkynes 154 afforded triene intermediates that cyclized spontaneously under the reaction conditions to give substituted cis-hexahydro-l/f-indenes 155 (Scheme 4.45), which can be further transformed into steroid analogues via TBS deprotection and oxidation. However, metathesis reactions starting with 156 only furnished trienes 157 [as EfZ) mixtures] and no spontaneous intramolecular cycloaddition occurred. Even at elevated reaction temperatures, trienes 157 cyclized only slowly to give octahydronaphthalene diastereomers. With deprotection of the TBS and subsequent Dess-Martin oxidation, trienes 157 could be converted exclusively into cw-fused 7-substituted 6,7-dehy-drodealone-l-one-lO-carboxylic esters 158 in 50-60% yields. Moreover, c ross-metathesis of TBS-unprotected MBH adduct 159 with alkynes 154 along with treatment with Dess-Martin periodinane (DMP) in one pot could conveniently produce the corresponding bicyclic ketones 160 in moderate yields. ... 

Enyne metathesis is unique and interesting in synthetic organic chemistry. Since it is difficult to control intermolecular enyne metathesis, this reaction is used as intramolecular enyne metathesis. There are two types of enyne metathesis one is caused by [2+2] cycloaddition of a multiple bond and transition metal carbene complex, and the other is an oxidative cyclization reaction caused by low-valent transition metals. In these cases, the alkyli-dene part migrates from alkene to alkyne carbon. Thus, this reaction is called an alkylidene migration reaction or a skeletal reorganization reaction. Many cyclized products having a diene moiety were obtained using intramolecular enyne metathesis. Very recently, intermolecular enyne metathesis has been developed between alkyne and ethylene as novel diene synthesis. 

Metathesis of enynes is another intriguing application in the laboratory. It would seem from the outcome, that it is a completely intramolecular reaction, but if the mechanism involves a metal alkylidene this is not true and the alkylidene group moves on from one substrate molecule to the next, see Figure 16.25. The methylene group moves to the next ring-closed diene. This is a useful tool in organic synthesis [47],... 

On the other hand, it has been shown that ruthenium carbene complexes lb and Ic are also effective for enyne metathesis. Intramolecular reaction of enyne metathesis is now a useful method for synthesizing cyclic compounds having a diene moiety, and intermolecular enyne metathesis has provided a method for synthesis of 1,3-dienes. 

Metathesis of conjugated enyne-enes has been carried out using bispyridine-substituted ruthenium benzylidene catalyst li. An intramolecular version with conjugated enynes affords novel butadienyl cycloalkenes (Equation (8)). The reaction does not proceed with Ic or Ig. 

Yamamoto has proposed a mechanism for the palladium-catalyzed cyclization/hydrosilylation of enynes that accounts for the selective delivery of the silane to the more substituted C=C bond. Initial conversion of [(77 -C3H5)Pd(GOD)] [PF6] to a cationic palladium hydride species followed by complexation of the diyne could form the cationic diynylpalladium hydride intermediate Ib (Scheme 2). Hydrometallation of the less-substituted alkyne would form the palladium alkenyl alkyne complex Ilb that could undergo intramolecular carbometallation to form the palladium dienyl complex Illb. Silylative cleavage of the Pd-G bond, perhaps via cr-bond metathesis, would then release the silylated diene with regeneration of a palladium hydride species (Scheme 2). 

Yttrium-catalyzed enyne cyclization/hydrosilylation was proposed to occur via cr-bond metathesis of the Y-G bond of pre-catalyst Cp 2YMe(THF) with the Si-H bond of the silane to form the yttrium hydride complex Ig (Scheme 8). Hydrometallation of the C=G bond of the enyne coupled with complexation of the pendant G=G bond could form the alkenylyttrium alkyl complex Ilg. Subsequent / -migratory insertion of the alkene moiety into the Y-C bond of Ilg could form cyclopentylmethyl complex Illg. Silylation of the resulting Y-C bond via cr-bond metathesis could release the silylated cycloalkane and regenerate the active yttrium hydride catalyst. Predominant formation of the /ra //j--cyclopentane presumably results from preferential orientation of the allylic substituent in a pseudo-equatorial position in a chairlike transition state for intramolecular carbometallation (Ilg —IHg). 

As seen in the preceding sections, many multicomponent procedures are based on the production of conjugated dienes that are in situ involved in Diels-Alder reactions to obtain polycyclic compounds. In recent years, intramolecular enyne metathesis has become a very popular method by which to access cyclic conjugated dienes [172]. In line with this, Lee [173] has developed a new three-component re-... 

Sequential Grubbs metathesis/Diels-Alder strategies can be used to produce tetrahydroquinolines. For example, intramolecular enyne metathesis followed by reaction with alkynes followed by oxidation serves as a useful route to multisubstituted systems (Scheme 78) <2000CC503>. 

A palladium-catalyzed intramolecular benzannulation of bis-enynes 1135 proceeds chemoselectively to afford dihydroisocoumarins 1136 (Equation 441) <2002JOC2653>. A reaction sequence involving ruthenium-catalyzed yne-ene cross-metathesis of a polystyrene supported undecynoic acid ester followed by a Diels-Alder cycloaddition reaction with DMAD provides the basis for a combinatorial approach to dihydroisocoumarins featuring a variety of side chains at C-6 and C-8 <1999SL1879>. 

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. 

Enyne systems are also capable of impressive multiple RRM transformations. For the first such example see Ref. [119]. The reaction of a ruthenium alkyli-dene with an alkyne produces a new vinyl alkylidene, which can participate in further intramolecular or intermolecular metathesis reactions to form fused ring systems. This has led Grubbs to designate alkynes in such systems as relays . In a noteworthy example, Zuercher et al. [ 120] constructed the four fused rings of the steroid backbone 68 in one efficient step using tandem enyne re-... 

We have found that a combination of intermolecular and intramolecular domino enyne metathesis reactions is also feasible [122]. Reaction between 1,6-heptadiynes 69-72 and allyltrimethylsilane promoted by 2 gave triene cycloadducts 73-76 in moderate-to-good yields (Scheme 22). 

The term intramolecular enyne metathesis describes two types of processes. One involves a [2+2] cycloaddition of a multiple bond and a transition-metal carbene complex and the other is an oxidative cyclization catalyzed by low-valent transition-metal complexes, for example, Pt, Pd and Ru. The latter reaction is also called a skeletal reorganization. Both processes lead to similar products (Eq. 84). 

An intramolecular version of olefin cross-metathesis has been demonstrated in cyclization of a,u -alkadienes 293462 (Equation (85)), cyclization of enyne to provide 1,3-dienylboronic esters 297406 (Equation (86)), and in cyclization of boron-tethered enynes obtained from 1-alkynylboronates and allylic alcohols (298 463 (Equation (87)) or allyl boronates and propargyl alcohols.464... 

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