Seyferth–Gilbert homologation

Seyferth–Gilbert homologation
Named after Dietmar Seyferth
John C. Gilbert
Reaction type Homologation reaction
Identifiers
Organic Chemistry Portal seyferth-gilbert-homologation
RSC ontology ID RXNO:0000387

The Seyferth–Gilbert homologation is a chemical reaction of an aryl ketone 1 (or aldehyde) with dimethyl (diazomethyl)phosphonate 2 and potassium tert-butoxide to give substituted alkynes 3.[1][2] Dimethyl (diazomethyl)phosphonate 2 is often called the Seyferth–Gilbert reagent.[3]

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 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

Ohira–Bestmann reagent
Names
IUPAC name
dimethyl (1-diazo-2-oxopropyl)phosphonate
Identifiers
90965-06-3
ChemSpider 9281325
Jmol interactive 3D Image
PubChem 11106189
Properties
C5H9N2O4P
Molar mass 192.11
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Infobox references

Dimethyl (diazomethyl)phosphonate can be generated in situ from dimethyl-1-diazo-2-oxopropylphosphonate (also called the Ohira-Bestmann reagent) by reaction with methanol and potassium carbonate. Reaction of Bestmann's reagent with aldehydes gives terminal alkynes often in very high yield.[4][5]

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

Improved in situ generation of the Ohira-Bestmann reagent

Safe and scalable synthesis of alkynes from aldehydes

Recently a safer and more scalable approach has been developed for the synthesis of alkynes from aldehydes. This protocol takes advantage of a stable sulfonyl azide, rather than tosyl azide, for the in situ generation of the Ohira−Bestmann reagent.[6]

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.[7]

See also

References

  1. ↑ D. Seyferth, R. S. Marmor and P. Hilbert (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. 36 (10): 1379–1386. doi:10.1021/jo00809a014.
  2. ↑ J. C. Gilbert and U. Weerasooriya (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. 47 (10): 1837–1845. doi:10.1021/jo00349a007.
  3. ↑ D. G. Brown, E. J. Velthuisen, J. R. Commerford, R. G. Brisbois and T. H. Hoye (1996). "A Convenient Synthesis of Dimethyl (Diazomethyl)phosphonate (Seyferth/Gilbert Reagent)". J. Org. Chem. 61 (7): 2540–2541. doi:10.1021/jo951944n.
  4. ↑ S. Müller, B. Liepold, G. Roth and H. J. Bestmann* (1996). "An Improved One-pot Procedure for the Synthesis of Alkynes from Aldehydes". Synlett 1996 (06): 521–522. doi:10.1055/s-1996-5474.
  5. ↑ G. Roth, B. Liepold, S. Müller and H. J. Bestmann (2004). "Further Improvements of the Synthesis of Alkynes from Aldehydes". Synthesis 2004 (1): 59–62. doi:10.1055/s-2003-44346.
  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. ↑ Lidija Bondarenko, Ina Dix, Heino Hinrichs, Henning Hopf* (2004). "Cyclophanes. Part LII:1 Ethynyl[2.2]paracyclophanes – New Building Blocks for Molecular Scaffolding". Synthesis 2004 (16): 2751–2759. doi:10.1055/s-2004-834872.
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