Seyferth–Gilbert homologation

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]

The 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

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.

The mechanism of the Seyferth–Gilbert homologation

Bestmann modification
Ohira–Bestmann reagent
Names
IUPAC name
dimethyl (1-diazo-2-oxopropyl)phosphonate
Identifiers
3D model (JSmol)
ChemSpider
UNII
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]

Bestmann's reagent

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]




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.[7]

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See also

References
  1. D. Seyferth; R. S. Marmor & 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 & 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 & 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 & H. J. Bestmann (1996). "An Improved One-pot Procedure for the Synthesis of Alkynes from Aldehydes". Synlett. 1996 (6): 521–522. doi:10.1055/s-1996-5474.
  5. G. Roth; B. Liepold; S. Müller & 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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