Metathesis cross

The reaction of two acyclic olefins to produce a mix of new products is finding use in organic synthesis. The reaction under many circumstances produces the statistical mixture of products. High yields of the cross product can sometimes be obtained by either stoichiometric control or by the use of functional groups. When unfunctionalized olefins are used in the reaction, all the products are of similar stability and reactivity. Under these conditions, a 1 2 1 mixture of olefins will lead to only a 50% yield of the cross product. However, as shown below, if an excess of one of the olefins is used, the percentage yield based on the minor olefin may be much higher (Eq. 6.14) [1]. 

Although the desired product is often produced in low yield, cross metathesis does not result in the loss of double bonds, and the olefin fragments remain intact hence, the byproducts can be recycled. Recycling is demonstrated in the application below, where cross metathesis is used to prepare an insect pheromone for the peach twig borer, an insect that attacks a variety of fruits (Eq. 6.15). The pheromone can be used to control the population of the insect through disruption of the insect s mating process [35]. 

In this application, the byproducts can be recycled to produce very high yields of the desired products (Eq. 6.16). Unlike RCM, cross metathesis is favored by high concentrations of substrates, and consequently lower catalyst loadings are generally required for cross metathesis. In many cases, the reactions are best run without solvents. 

In many complex syntheses, good yields can be obtained by combining a sterically hindered olefin with a readily available cross partner, and allyl silanes have proven to be very valuable cross partners in such processes [36]. 

The tolerance of ruthenium catalysts to a variety of functionality, and the efficiency of the reaction, have led to cross metathesis being used to prepare a variety of highly functionalized molecules. The examples in Eq. 6.17 demonstrate the array of functionality that can be tolerated [37]. 

The treatment of equivalent amounts of two different alkenes with a metathesis catalyst generally leads to the formation of complex product mixtures [925,926]. There are, however, several ways in which cross metathesis can be rendered synthetically useful. One example of an industrial application of cross metathesis is the ethenolysis of internal alkenes. In this process cyclic or linear olefins are treated with ethylene at 50 bar/20 80 °C in the presence of a heterogeneous metathesis catalyst. The reverse reaction of ADMET/RCM occurs, and terminal alkenes are obtained. 

Much more challenging is the targetted introduction of carbon substituents at terminal olefins by means of cross metathesis. Because of the mild reaction conditions under which alkene metathesis proceeds, cross metathesis could become an extremely valuable tool for the synthetic chemist if the critical parameters for productive cross metathesis between different, functionalized olefins were understood. 

The examples listed in Table 3.21 illustrate the synthetic possibilities of cross metathesis. In many of the procedures reported, advantage is taken of the fact that some alkenes (e.g. acrylonitrile, styrenes) undergo slow self metathesis only. Interestingly, it is also possible to realize cross metathesis between alkenes and alkynes (Table 3.21, Entries 11-13), both in solution and on solid supports [927,928]. 

Experimental Procedure 3.2.9. Cross Metathesis with a Molybdenum Catalyst in Homogeneous Phase (E)- -Phenyl-1-octene [929] 

The molybdenum complex 1 (342 mg, 0.45 mmol, 1%) is added to a mixture of dichloromethane (90 mL), 1-octene (5.0 g, 44.6 mmol) and styrene (9.29 g, 89.2 mmol). The resulting mixture is stirred at room temperature for 1 h and then filtered through a pad of silica gel. After rinsing with dichloromethane the combined filtrates are concentrated and the crude product is purified by column chromatography (silica gel). 7.9 g (94%) of the title compound is obtained as a colorless oil. 

Application of these principles even allows selectivity when one component has two alkenes (schemes 8.90,8.91).  

Cross-metathesis was employed to couple the two sides of the molecule in a synthesis of nupharamine 

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As stated above, olefin metathesis is in principle reversible, because all steps of the catalytic cycle are reversible. In preparatively useful transformations, the equilibrium is shifted to one side. This is most commonly achieved by removal of a volatile alkene, mostly ethene, from the reaction mixture. An obvious and well-established way to classify olefin metathesis reactions is depicted in Scheme 2. Depending on the structure of the olefin, metathesis may occur either inter- or intramolecularly. Intermolecular metathesis of two alkenes is called cross metathesis (CM) (if the two alkenes are identical, as in the case of the Phillips triolefin process, the term self metathesis is sometimes used). The intermolecular metathesis of an a,co-diene leads to polymeric structures and ethene this mode of metathesis is called acyclic diene metathesis (ADMET). Intramolecular metathesis of these substrates gives cycloalkenes and ethene (ring-closing metathesis, RCM) the reverse reaction is the cleavage of a cyclo-... 

Scheme 2 Different modes of the olefin metathesis reaction cross metathesis (CM), ringclosing metathesis (RCM), ring-opening metathesis (ROM), acyclic diene metathesis polymerization (ADMET), and ring-opening metathesis polymerization (ROMP)...

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 resulting carbene complex 41b bears a hetero substituent and shows activity in the ring-opening/cross metathesis of strained bicyclic alkenes and... 

The E/Z selectivity problem is restricted to cross metathesis and RCM leading to macrocycles (macro-RCM). Both aspects have recently been covered in reviews by Blechert et al. [8d] and by Prunet [44]. E/Z selectivity can be influenced by reaction temperature, solvent or substitution pattern of the substrate. Here, we will only discuss the influence of the precatalyst. 

A first evaluation of complex 71a by Blechert et al. revealed that its catalytic activity differs significantly from that of the monophosphine complex 56d [49b]. In particular, 71a appears to have a much stronger tendency to promote cross metathesis rather than RCM. Follow-up studies by the same group demonstrate that 71a allows the cross metathesis of electron-deficient alkenes with excellent yields and chemoselectivities [50]. For instance, alkene 72 undergoes selective cross metathesis with 3,3,3-trifluoropropene to give 73 in excellent yield and selectivity. Precatalyst 56d, under identical conditions, furnishes a mixture of 73 and the homodimer of 72 (Scheme 17) [50a]. While 56d was found to be active in the cross metathesis involving acrylates, it failed with acrylonitrile [51]. With 71a, this problem can be overcome, as illustrated for the conversion of 72—>74 (Scheme 17) [50b]. 

An alternative approach to phosphine-free ruthenium precatalysts is based on pyridine complex 70 [48], which has been established by Grubbs et al. as a valuable precursor for other mixed NHC-phosphine complexes (cf. Scheme 15). Complex 70 is only moderately active in the cross metathesis of allylbenzene... 

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 cross metathesis of vinylsilanes is catalyzed by the first-generation ruthenium catalyst 9. This transformation has been extensively investigated from both preparative and mechanistic points of view by Marciniec et al. [86]. Interestingly, the same vinylsilanes obtained from cross metathesis may also result from a ruthenium-hydride-catalyzed silylative coupling and there might be some interference of metathesis and nonmetathesis mechanisms [87]. 

Few reports describe the cross metathesis of allyl halides [88]. First-generation catalyst 9 does not seem to be sufficiently reactive to promote this reaction in preparatively useful yields and acceptable catalyst loadings, but second-generation catalyst 56d gives good results for allyl chloride. Cross-metathesis... 

Olefin metathesis of vinylboronates [102] and allylboronates [103, 104] has been investigated over the past few years because organoboranes are versatile intermediates for organic synthesis. Cross metathesis of vinylboronate 108 and 2-butene 109, for example, yields the boronate 110, which can be converted to the corresponding vinyl bromide 111 with high Z selectivity. Vinyl iodides can be obtained analogously. It should be noted that vinyl bromides and vinyl... 

Allylboronates are attractive reagents for the highly diastereoselective ally-lation of carbonyl compounds. A sequential cross-metathesis-allylation reaction has recently been developed by Grubbs et al. [88c] and by Miyaura et al. [103]. The sequence is illustrated in Scheme 23 for the formation of homoallylic alcohol 114 from allylboronate 112, acetal 113, and benzaldehyde [88c]. 

Enyne metathesis starting either from acetylenic boronates and homoallylic alcohols [104a,c] or from propargyl alcohols and allylboronates [104b] has recently been described. The resulting boronated dienes can be converted to allenes or cycloaddition products. The cross metathesis of vinylcyclopropyl-boronates directed toward the total synthesis of natural products has very recently been investigated by Pietruszka et al. [104d]. 

Bent ansa-metallocenes of early transition metals (especially Ti, Zr, Hf) have attracted considerable interest due to their catalytic activity in the polymerization of a-olefins. Ruthenium-catalyzed olefin metathesis has been used to connect two Cp substituents coordinated to the same metal [120c, 121a] by RCM or to connect two bent metallocenes by cross metathesis [121b]. A remarkable influence of the catalyst on E/Z selectivity was described for the latter case while first-generation catalyst 9 yields a 1 1 mixture of E- and Z-dimer 127, -127 is the only product formed with 56d (Eq. 19). 

Enyne Cross Metathesis and Ring-Closing Enyne Metathesis.348... 

Alkyne cross metathesis Acyclic diene metathesis Asymmetric ring-closing metathesis Asymmetric ring-opening metathesis Cross metathesis... 

Fig. la—d Typical alkene metathesis reactions ring-closing (RCM) and ring-opening (ROM) metathesis (a), diene cross metathesis (CM, b), ROM-RCM (c), and ROM-double RCM (d) sequences (ring-rearrangement reactions, RRM)... 

Fig. 2a-c Typical enyne metathesis reactions ring-closing enyne metathesis (a) enyne cross metathesis (b and c)... 

Fig. 3a,b Typical diyne metathesis reactions ring-closing alkyne metathesis (RCAM, a) diyne cross metathesis (ACM, b)... 

The reversible nature of cross metathesis is of synthetic importance because, by the use of a sufficiently active metathesis catalyst, it generally ensures the preferential formation of the most thermodynamically stable product. This results in the transformation of terminal olefins into internal ones, and we have seen that undesired self-metathesis products can be recycled by exposing them to a second CM process. 

Ring-Closing Alkyne Metathesis (RCAM) and Alkyne Cross Metathesis (ACM)... 

Olefin cross metathesis starts to compete with traditional C=C bondforming reactions such as the Wittig reaction and its modifications, as illustrated by the increasing use of electron-deficient conjugated alkenes for the ( )-selective construction of enals and enoates. 

For a discussion on the beneficial effect of using homodimers of one CM substrate in cross metathesis reactions, see Blackwell HE, O Leary DJ, Chatterjee AK, Washenfelder RA, Bussmann DA, Grubbs RH (2000) J Am Chem Soc 122 58... 

The alkene groups in TsICH = CH2]s have allowed a wider variety of chemistry to be carried out than for either TsHs or TsPhs. For example, Feher s group have prepared a variety of unsaturated POSS molecules via olefin cross-metathesis... 

Table 12 Compounds TsRs obtained by cross- -metathesis or silylative coupling of T8[CH = CH2]8 w ith alkenes ... 

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