Functional cross metathesis

This review focuses on the cross-metathesis reactions of functionalised alkenes catalysed by well-defined metal carbene complexes. The cross- and self-metath-esis reactions of unfunctionalised alkenes are of limited use to the synthetic organic chemist and therefore outside the scope of this review. Similarly, ill-defined multicomponent catalyst systems, which generally have very limited functional group tolerance, will only be included as a brief introduction to the subject area. 

The reaction tolerated a variety of functionality, including ester and ether groups on the alkyl-substituted alkene at least two carbons away from the double bond, and raefa-nitro or para-methoxy substituents on the styrene. As expected, cross-metathesis occurred selectively at the less hindered monosubsti-tuted double bond of dienes also containing a disubstituted alkene (Eq. 8). 

With the development of an analogous ruthenium benzylidene catalyst 17 by Grubbs and co-workers in 1995, a ruthenium carbene catalyst suitable for the cross-metathesis reaction was in place [34]. Benzylidene 17 exhibited the same impressive tolerance of air and moisture, and the same stability towards functional groups as its predecessor 4, but benefited from easier preparation [35,36] and much improved initiation rates. 

For the cross-metathesis of functionalised alkenes the ill-defined classical catalyst systems currently offer very few advantages (cost and heterogeneous catalysis) over the more functional group tolerant Schrock and Grubbs alkylidene... 

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. 

McNaughton, B. R. Bucholtz, K. M. Camaano-Moure, A. Miller, B. L. Self-selection in olefin cross metathesis The effect of remote functionality. Org. Lett. 2005, 7, 733-736. 

The cross-metathesis of terminal alkenes and functionalized alkenes is shown in Table 6.2. In each case, a CM product is obtained in high yield and an -isomer is formed predominantly. ... 

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 ... 

Table A. Functionalized homoallylic alcohols from olefin cross metathesis and subsequent allylboration reactions with benzaldehyde...

As indicated by the examples, ruthenium catalysts 5-7 can be used for compounds containing a broad range of functional groups, especially those containing oxygen, and they are also tolerant to water. The greater challenge is the use of these catalysts for cross-metathesis for which SHOP (Eq. 15) is one example, and Eq. 19" represents a recent success. 

With the discovery by Grubbs of ruthenium carbene complexes such as Cl2(PCy3)2Ru=CHR, which mediate olefin metathesis under mild reaction conditions and which are compatible with a broad range of functional groups [111], the application of olefin metathesis to solid-phase synthesis became a realistic approach for the preparation of alkenes. Both ring-closing metathesis and cross-metathesis of alkenes and alkynes bound to insoluble supports have been realized (Figure 5.12). 

Where there is no spacer group between the C=C bond and the functional group, productive self-metathesis does not occur, but cross-metathesis reactions with other olefins are still possible. Recent impressive examples of this are the cross-metathesis reactions of acrylonitrile (equation 19). The reaction occurs with a wide variety of R groups. For 15 different compounds the yield of the new nitrile after 3 h at room temperature is 40-90%, with the cis isomer always strongly preferred (75-90%). Only minor amounts of RCH2CH=CHCH2R are formed, and no NCCH=CHCN182. The fact that acrylonitrile... 

The utility of Ru-catalyzed cross-metathesis in multicomponent coupling strategies has also been demonstrated. For instance, one-pot cross-metathesis/allylboration sequences have been reported by Miyaura [170] and by Goldberg and Grubbs [171]. Pinacol allyl boronate 174 was reacted with a series of functionalized olefins, which include symmetrically 1,2-disubstituted olefins as well as hindered olefins and styrenes, in the presence of catalyst 175 to produce intermediate allyl boro-nates (e.g. 176). The latter may then be reacted in situ with aldehydes to produce functionalized homoallylic alcohols with high levels of anti-selectivity (Scheme 8.80). 

Cross-metathesis of two different alkenes 11 and 42 usually produces a mixture of products 6 and 15. However, depending on the functional groups R1 and R2, the cross-product 6 is obtained with high selectivity rather than the homoproduct 15 from 11 and 42. Some terminal alkenes, such as allylstannane [16], acrylonitrile [17,18] and allylsilane [19], undergo clean cross-metathesis to give cross-products 6 as the main product, rather than homoproducts 15. Cross-metathesis of the cyclic alkenes 43 with terminal alkenes 42 can be used for the synthesis of dienes 44. 

The functionalization of SAMs via ruthenium-catalyzed cross metathesis of vinyl-terminated SAMs has been reported by Lee et al.76 to install a variety of acrylic derivatives on SAMs bearing vinyl groups on their outer surface. The major drawback of this approach is the intra-SAM metathesis which causes the formation of a mixture of surface-bound products, limiting the reproducibility of the method. The formation of urethanes by the reaction of diisocyanates77 or isothiocyanates78 with hydroxyl- and amino-terminated SAMs has been reported as well. The reaction of hydroxyl-terminated SAMs with diisocyanates, allowed the preparation of isocyanate SAMs that proved to be reactive towards amines, alcohols, and water, displaying the standard chemistry of the isocyanate groups.77... 

Cleavage of polymer-bound allyl esters with palladium catalysts provides general access to 7i-allyl complexes, which can react with a variety of nucleophiles. This has been used in the development of re-allyl-based linkers. Ene-yne cross metathesis and subsequent cleavage in the presence of different nucleophiles yields the corresponding functionalized dienes 93 [93] (Scheme 6.1.19). 

The ruthenium-catalyzed olefin cross-metathesis to the preparation of functionalized allyl boronates has resulted in a one-pot three-component coupling procedure for the synthesis of functionalized homoallylic alcohols.617,618 The utility of the protocol was demonstrated in asymmetric allylboration using a tartrate ester (Equation (152)).617... 

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). 

RCM and CM provide convenient access to a range of intricate products of relevance to the pharmaceutical, agrochemical and fragrance industries. While RCM can effectively create the functionalized carbo- and hetero-cyclic structures common in many such products, cross metathesis is a simple way of introducing often difficult combinations of functional groups. 

It was recognized early that efficient olefin cross metathesis could provide new methods for the synthesis of complex molecules. However, neither (la) nor (2a) were very effective at intermolecular cross metathesis owing to poor reaction selectivity (cross vs. intramolecular metathesis) and low E. Z ratios see (E) (Z) Isomers) The advent of more active and functional group tolerant olefin metathesis catalysts recently made cross metathesis a viable route for constructing a large variety of fimctionalized acyclic alkenes. 

Grubbs used (4a) to efficiently install functional groups that might otherwise be added via C H activation or allylic oxidation pathways (Scheme 12). Among the breadth of compound types accessible through these cross metathesis strategies were substituted vinyl-phosphonic, boronic, and carbonyl esters, which were synthesized in good to excellent yields. ... 

Several examples of the use of (4a) catalyzed cross metathesis of protected allylic sugars, or vinyl substituted heterocycles or vinylated functional groups have been reported. Vinylphosphonate-linked nucleotide dimers were synthesized by cross metathesis using complex (4a), achieving products with E Z ratios of >20 1 in moderate to good yields (equation 17). A metal-mediated route to acyclic nucleosides developed by Agrofoglio and coworkers produced nucleosides in two steps from parent pyrimidines and purines. ... 

Grubbs found that (4 a) ring-opened cyclic olefins, and then react with an acrylate to produce end functionalized linear olefins, giving a ring-opened cross metathesis product (ROCM) with two olefins with differing reactivity (equation 19). Key to the distribution of products was the relative rates of ring-opening and cross metathesis with the functionalized olefin. 

A later report describes AROM/CM of norbomyl alkenes and styrene coupling partners to create asymmetrically functionalized cyclopentanes with alkenyl groups that can be further elaborated. High yields (>98%) of trans (>98) cross metathesis products (predominantly the desired ring-opened, A-B metathesis product) can be achieved using (97a) (equation 22). 

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