Alkenes cross-metathesis, enyne

Diynes are also used to perform intermolecular enyne metathesis. With the objective of producing functionalized hetero- and carbocycles, a cascade diyne-alkene cross metathesis leading to five-membered cyclic products has recently been proposed [27] (Scheme 13). 

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... 

S.S. SaUm, R.K. Bellingham, R.C.D. Brown, One-pot ring-closing metathesis-alkene cross metathesis reactions of sulfemide-Unked enynes, Eur. J. Qrg. Chem. (2004) 800-806. 

The relay strategy has also been applied to selective alkene cross metathesis (CM). Very recently, Kim and coworkers reported the total synthesis of (+)-3-(Z)-isolaureatin (64) via this strategy (Fig. 20) [65]. The crucial cross metathesis of alkene for stereoselective introduction of the (Z)-enyne unit was successfully realized in 76% yield in the presence of Grubbs catalyst (67) using Lee s protocol. The relay precursor, enyne (66), was subjected to the reaction mixture to initiate the desired process. 

We will focus on the development of ruthenium-based metathesis precatalysts with enhanced activity and applications to the metathesis of alkenes with nonstandard electronic properties. In the class of molybdenum complexes [7a,g,h] recent research was mainly directed to the development of homochi-ral precatalysts for enantioselective olefin metathesis. This aspect has recently been covered by Schrock and Hoveyda in a short review and will not be discussed here [8h]. In addition, several important special topics have recently been addressed by excellent reviews, e.g., the synthesis of medium-sized rings by RCM [8a], applications of olefin metathesis to carbohydrate chemistry [8b], cross metathesis [8c,d],enyne metathesis [8e,f], ring-rearrangement metathesis [8g], enantioselective metathesis [8h], and applications of metathesis in polymer chemistry (ADMET,ROMP) [8i,j]. Application of olefin metathesis to the total synthesis of complex natural products is covered in the contribution by Mulzer et al. in this volume. 

The cross metathesis of acrylic amides [71] and the self metathesis of two-electron-deficient alkenes [72] is possible using the precatalyst 56d. The performance of the three second-generation catalysts 56c,d (Table 3) and 71a (Scheme 16) in a domino RCM/CM of enynes and acrylates was recently compared by Grimaud et al. [73]. Enyne metathesis of 81 in the presence of methyl acrylate gives the desired product 82 only with phosphine-free 71a as a pre-... 

The success of the cross-metathesis reactions involving styrene and acrylonitrile led to an investigation into the reactivity of other Ji-substituted terminal alkenes [27]. Vinylboranes, enones, dienes, enynes and a,p-unsaturated esters were tested, but all of these substrates failed to undergo the desired cross-metathesis reaction using the molybdenum catalyst. 

Cross-metathesis of enynes having various functional groups on the alkyne and an alkene gives dienes having useful functional groups such as vinyl silane or enol ether as the sole product ... 

Enynes without the cycloalkene moiety can also react with electron-deficient alkenes by a cascade ring-closing metathesis-cross metathesis (RCM-CM) process [23] (Scheme 10). The use of Hoveyda s catalyst is necessary, not to stop the reaction at the RCM step, but to perform the subsequent CM step. Indeed, the organic product arising from the RCM is first formed and then reacts with the alkene in the presence of the ruthenium complex to give the CM reaction. 

The intermolecular enyne cross metathesis, and consecutive RCM, between a terminal alkyne and 1,5-hexadiene produces cyclohexadienes, by cascade CM-RCM reaction, and trienes, formed during the sole CM step. Studies of various parameters of the reaction conditions did not show any improvement of the ratio of desired cyclohexadiene product [25] (Scheme 12). The reaction with cyclopentene instead of hexadiene as the alkene leads to 2-substituted-l,3-cycloheptadienes [26]. After the first cyclopentene ROM, the enyne metathesis is favored rather than ROMP by an appropriate balance between cycloalkene ring strain and reactivity of the alkyne. 

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... 

The general reaction equation for alkene metathesis in a simple system, cross-metathesis of two different disubstituted alkenes, is depicted in Scheme 1. In this reaction, a transition metal catalyst establishes equilibrium between the starting alkenes, the ( )- and (Z)-stereoisomers of all possible substituent combinations, and ethylene. Related reaction processes have also been reported for alkynes (aikyne metathesis) and for combinations of alkenes and alkynes (enyne metathesis). Aikyne metathesis is less well developed compared to alkene metathesis and enyne metathesis. This review has been organized according to the basic modes of metathesis depicted in Scheme 2. Alkene metathesis is the more developed process and numerous examples of all the variants have been reported. Aikyne metathesis is less well developed and three variants exist aikyne cross-metathesis, aikyne metathesis polymerization, and ring-closing aikyne metathesis. 

A tandem (domino) cross-metathesis reaction between an enyne and 3 equivalents of a conjugated alkene proceeds in dichloromethane at 40 °C for 12 h with a high yield in the presence of the same ruthenium-carbene flve-membered ring compound 8.53, as shown in Eq. (8.21) [54, 55]. 

Royer F, Vilain C, EUcaiem L, Grimaud L. Selective domino ring-closing metathesis-cross-metathesis reactions between enynes and electron-deficient alkenes. Org. Lett. 2003 5 2007-2009. 

Blechert reported a skillful method of cross-enyne metathesis. Solid-supported alkyne 139 is reacted with alkene in the presence of Ic to give 140. For cleavage of 1,3-diene from solid-supported product 140 having an allyl acetate moiety, palladium-catalyzed allylic substitution is used. Thus, 140 is treated with Pd(PPh3)4 in the presence of methyl malonate to afford three-component coupling product 141 in good yield ... 

Cross-enyne metathesis has also been applied to solid-phase synthesis by immobilizing either the alkyne or the alkene (498,499). By combination with a Diels-Alder reaction, this process has been used to create a combinatorial library of various six-membered ring structures (500). Within this theme, intermolecular enyne metathesis is the integral synthetic method used to produce novel amino acid derivatives (501, 502). To this end, the aromatic ring of highly substituted phenylalanines was synthesized through enyne crossmetathesis and cycloaddition. 

Cross-Enyne Metathesis/Diels-Alder MCRs Ruthenium-based complexes are known to catalyze the metathesis between alkynes and alkenes to afford 1,3-dienes. Fnstero, del Pozo et al. further exploited this cross-enyne metathesis (CEYM) by trapping the 1,3-diene with a dieno-phile via an intermolecnlar Diels-Alder reaction [198]. Thns, the Ru-catalyzed MCR between alkynes 220-221 and 1,7-octadiene as an in situ sonrce of ethylene by RCM generates a 1,3-diene that can snbseqnently nndergo a Diels-Alder reaction with a wide variety of dienophiles 222... 

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