Seyferth–Gilbert homologation

Reaction mechanism

Deprotonation of the Seyferth–Gilbert reagent A gives an anion B, which reacts with the ketone to form the oxaphosphetane 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

The dimethyl (diazomethyl)phosphonate carbanion can be generated in situ from dimethyl-1-diazo-2-oxopropylphosphonate (also called the Ohira-Bestmann reagent) by reaction with methanol and potassium carbonate as the base by cleavage of the acetyl group as methyl acetate. Reaction of Bestmann's reagent with aldehydes gives terminal alkynes often in very high yield and fewer steps than the Corey–Fuchs reaction.

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

Traditional syntheses of the Ohira−Bestmann reagent use the rather explosive tosyl azide, but better diazo transfer agents are available.

Other modifications

Another modification for less reactive aldehydes is made by replacement of potassium carbonate with caesium carbonate in MeOH and results in a drastic yield increase.

References

References

1. D. Seyferth. (1971). "Reactions of dimethylphosphono-substituted diazoalkanes. (MeO)2P(O)CR transfer to olefins and 1,3-dipolar additions of (MeO)2P(O)C(N2)R". J. Org. Chem..
2. (1982). "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". [[J. Org. Chem.]].
3. D. G. Brown. (1996). "A Convenient Synthesis of Dimethyl (Diazomethyl)phosphonate (Seyferth/Gilbert Reagent)". J. Org. Chem..
4. S. Müller. (1996). "An Improved One-pot Procedure for the Synthesis of Alkynes from Aldehydes". [[Synlett]].
5. G. Roth. (2004). "Further Improvements of the Synthesis of Alkynes from Aldehydes". [[Synthesis (journal).
6. Jepsen, T.H, Kristensen, J.L. ''J. Org. Chem.'' '''2014''', "''In Situ'' Generation of the Ohira–Bestmann Reagent from Stable Sulfonyl Azide: Scalable Synthesis of Alkynes from Aldehydes". http://pubs.acs.org/doi/abs/10.1021/jo501803f
7. (2004). "Cyclophanes. Part LII:1 Ethynyl[2.2]paracyclophanes – New Building Blocks for Molecular Scaffolding". [[Synthesis (journal).