Alkenyl halides are some of the most useful building blocks for synthesizing small organic molecules. A catalyst has now allowed their direct preparation from widely available alkenes using the cross-metathesis reaction. See Article p.459
The development of synthetic methods for chemical transformations is an ongoing challenge. Advances in this field have far-reaching effects on everyday life, because new transformations can streamline the preparation of pharmaceuticals, agrochemicals and materials. On page 459 of this issue, Hoveyda and colleagues1 describe just such an advance: a reaction that allows direct access to cis-substituted vinyl fluorides, chlorides and bromides, members of the alkenyl halide family of compounds that are of great value in organic synthesis.
Organic molecules that contain halogen atoms, such as alkenyl halides — characterized by the C = C – X group, where X is a halogen atom such as fluorine, chlorine or bromine — have a central role in the rapid construction of organic molecules in general. This is because many of the most useful synthetic reactions are catalysed by transition metals, which insert into carbon–halogen bonds and thus enable the carbon atom to form bonds with other atoms2. Certain alkenyl fluorides, chlorides and bromides are also essential structural motifs for the biological activities of drugs and naturally occurring compounds3,4.
However, some alkenyl halides are not easy to prepare. Olefination reactions are known that form carbon–carbon double bonds (C = C bonds) with halogens attached, but these frequently produce substantial amounts of side products5. Not all alkenyl halides can be obtained in this way, and even when this approach is successful, the products are often isolated as an undesirable mixture of cis- and trans-isomers (in cis-isomers, the groups are on the same side of the double bond and point in the same direction, but in trans-isomers they are on different sides of the double bond and point in opposite directions). Alkenyl halides can also be made by reacting a positively charged halogen species with alkenes (hydrocarbons that incorporate double bonds) containing boron6, silicon7 or tin atoms8, but the preparation of these alkenes is cumbersome.
An alternative synthetic strategy that could convert readily available alkenes to their corresponding alkenyl halides is cross-metathesis, a variant of the olefin metathesis transformation. Olefin metathesis is a fundamental organic reaction that redistributes C = C bonds, providing a simple route to a wide range of compounds; cross-metathesis involves the redistribution of double bonds between two different alkene molecules (Fig. 1a). Advances in olefin metathesis have greatly expanded the chemist's toolbox of carbon–carbon bond-forming reactions9 because of the versatility of this process, and because of the abundance of alkenes.
But, so far, efforts to use cross-metathesis to convert alkenes to alkenyl halides have met with little success. Such reactions require different alkenyl halides to be used as starting materials, but these compounds tend to deactivate metathesis catalysts by forming several species that drastically slow down, or even stop, the catalytic cycle. For example, attempts to use standard ruthenium-based catalysts in such reactions result in the formation of species (carbenes and carbides) that are catalytically inactive10.
Hoveyda and colleagues have circumvented this problem by exploring the use of catalysts based on tungsten and molybdenum in high oxidation states. The authors report that a molybdenum-based catalyst has outstanding activity in cross-metathesis reactions, and delivers high yields of a range of vinyl halides (Fig. 1b).
Most alkenyl halides are toxic gases at ambient conditions, so the researchers instead used commercially available liquid 1,2-dihaloethene reagents — alkenyl halides in which a halogen is attached at both ends of a C = C bond — as reactants to convert alkenes to vinyl chlorides and bromides (Fig. 1b). This protocol is a great advance because it makes the process operationally convenient and safe. The authors also used Z-bromo-fluoroethene to make vinyl fluorides, a reaction that could, in principle, also produce vinyl bromides as side products. Impressively, the reactions generated vinyl fluorides selectively, especially for molecules in which the C = C bond is close to a bulky group. The authors propose that steric effects (associated with the spatial crowding of chemical groups) and electronic factors account for this remarkable selectivity.
Furthermore, all the vinyl halides made in the authors' reactions were prepared with high cis-selectivity, a characteristic feature of this type of molybdenum catalyst that Hoveyda's group established previously11. The highest cis-selectivities were obtained in reactions of alkenes that contain bulky groups, but alkenes with linear chains also yielded synthetically useful cis:trans ratios of products. Finally, the authors showcased their chemistry by using it to convert a cyclic alkene — a ring of eight carbons that includes one C = C bond — into a linear molecule with a vinyl bromide at either end (see Fig 3. of the paper1). This compound has been used12 in the synthesis of tetrahydrosiphonodiol, a natural product that has antitumour activity.
Hoveyda and colleagues' transformation offers a powerful strategy for preparing cis-alkenyl halides, especially given that alkenes are abundant motifs in fine chemicals such as pharmaceuticals and agrochemicals. In addition, the tolerance of the reaction to a broad range of chemical groups could inspire synthetic chemists to apply this reaction in more complex molecular settings: for example, in intermediates prepared during the late stages of synthetic routes to drug candidates, or in natural-product synthesis.
It should be noted that the air-sensitive catalyst is not commercially available at present, nor easy to synthesize. However, the authors say that paraffin capsules containing the catalyst will become commercially available and could be used outside the nitrogen-filled boxes commonly required for handling air-sensitive reagents, which would greatly simplify the catalyst's use. Further mechanistic insights will be needed to explain why the monohalomethylidene species formed as catalytic intermediates in the reactions are so much more reactive than those formed in previous attempts at these reactions. However, there is little doubt that the influence of this transformation will further increase the already widespread application of cross-metathesis in chemical synthesis.
Koh, M. J., Nguyen, T. T., Zhang, H., Schrock, R. R. & Hoveyda, A. H. Nature 531, 459–465 (2016).
Jana, R., Pathak, T. P. & Sigman, M. S. Chem. Rev. 111, 1417–1492 (2011).
Silverman, R. B., Bichler, K. A. & Leon, A. J. J. Am. Chem. Soc. 118, 1253–1261 (1996).
Renner, M. K., Jensen, P. R. & Fenical, W. J. Org. Chem. 63, 8346–8354 (1998).
Hodgson, D. M. & Arif, T. J. Am. Chem. Soc. 130, 16500–16501 (2008).
Brown, H. C., Hamaoka, T. & Ravindran, N. J. Am. Chem. Soc. 95, 6456–6457 (1973).
Pawluć, P., Hreczycho, G., Szudkowska, J., Kubicki, M. & Marciniec, B. Org. Lett. 11, 3390–3393 (2009).
Nicolaou, K. C., Veale, C. A., Webber, S. E. & Katerinopoulos, H. J. Am. Chem. Soc. 107, 7515–7518 (1985).
Nicolaou, K. C., Bulger, P. G. & Sarlah, D. Angew. Chem. Int. Edn 44, 4490–4527 (2005).
Macnaughtan, M. L., Johnson, M. J. A. & Kampf, J. W. J. Am. Chem. Soc. 129, 7708–7709 (2007).
Meek, S. J., O'Brien, R. V., Llaveria, J., Schrock, R. R. & Hoveyda, A. H. Nature 471, 461–466 (2011).
López, S., Fernández-Trillo, F., Midón, P., Castedo, L. & Saá, C. J. Org. Chem. 70, 6346–6352 (2005).