Seyferth-Gilbert homologation

The Seyferth-Gilbert homologation is a the chemical reaction of an aryl ketone 1 (or aldehyde) with dimethyl (diazomethyl)phosphonate 2 and potassium tert-butoxide to give substituted alkynes 3.cite journal | author = D. Seyferth, R. S. Marmor and P. Hilbert | title = Reactions of dimethylphosphono-substituted diazoalkanes. (MeO)2P(O)CR transfer to olefins and 1,3-dipolar additions of (MeO)2P(O)C(N2)R | year = 1971 | journal = J. Org. Chem. | volume = 36 | issue = 10 | pages = 1379–1386 | doi = 10.1021/jo00809a014] cite journal | author = J. C. Gilbert and U. Weerasooriya | title = Diazoethenes: their attempted synthesis from aldehydes and aromatic ketones by way of the Horner-Emmons modification of the Wittig reaction. A facile synthesis of alkynes | year = 1982 | journal = J. Org. Chem. | volume = 47 | issue = 10 | pages = 1837–1845 | doi = 10.1021/jo00349a007] Dimethyl (diazomethyl)phosphonate 2 is often called the Seyferth-Gilbert reagent.cite journal | author = D. G. Brown, E. J. Velthuisen, J. R. Commerford, R. G. Brisbois and T. H. Hoye | title = A Convenient Synthesis of Dimethyl (Diazomethyl)phosphonate (Seyferth/Gilbert Reagent) | year = 1996 | journal = J. Org. Chem. | volume = 61 | issue = 7 | pages = 2540–2541 | doi = 10.1021/jo951944n]

This reaction is called a "homologation" because the product has exactly one additional carbon more than the starting material.

Reaction mechanism

Deprotonation of the Seyferth-Gilbert reagent A give an anion B which reacts with the ketone to form the oxaphosphatane D. Elimination of dimethylphosphate E gives the vinyl diazo-intermediate Fa and Fb. The generation of nitrogen gas gives a vinyl carbene G which via a 1,2-migration forms the desired alkyne H.

Bestmann modification

Dimethyl (diazomethyl)phosphonate can be generated in situ from dimethyl-1-diazo-2-oxopropylphosphonate (also called Bestmann's reagent) by reaction with methanol and potassium carbonate. Reaction of Bestmann's reagent with aldehydes gives terminal alkynes often in very high yield.cite journal | author = S. Müller, B. Liepold, G. Roth and H. J. Bestmann* | title = An Improved One-pot Procedure for the Synthesis of Alkynes from Aldehydes | year = 1996 | journal = Synlett | volume = | issue = 06 | pages = 521–522 | doi = 10.1055/s-1996-5474] cite journal | author = G. Roth, B. Liepold, S. Müller and H. J. Bestmann | title = Further Improvements of the Synthesis of Alkynes from Aldehydes | year = 2004 | journal = Synthesis | volume = | issue = 1 | pages = 59–62 | doi = 10.1055/s-2003-44346]

The use of the milder potassium carbonate makes this procedure much more compatible with a wide variety of functional groups.

References

ee also

*Corey-Fuchs reaction
*Horner-Wadsworth-Emmons reaction
*Wittig reaction