Seyferth-Gilbert Alkyne Synthesis

Seyferth-Gilbert Alkyne Synthesis

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]

Aldehydes and ketones can be converted into alkynes with one carbon homologation using the α-diazophosphonate compound called the Gilbert reagent.

When Y=H, the reaction needs a strong base such as tBuOK to proceed and base sensitive reactants are inevitably incompatible. However, with the modified reagent in which Y=Ac, milder bases such as potassium carbonate can be used, so the substrate scope is wider (the Ohira-Bestmann modification).

The Seyferth–Gilbert homologation

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 vinyldiazo-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
gilbert_alkyne_2.gif

Bestmann modification

Ohira–Bestmann reagent
Ohira-bestmann reagent 2d-skeletal.png
Identifiers
CAS number 90965-06-3
PubChem 11106189
ChemSpider 9281325
Jmol-3D images Image 1
Properties
Molecular formula C5H9N2O4P
Molar mass 192.11
Except where noted otherwise, 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]

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]

  • Examples

Lithiated TMS diazomethane also works for the same transformation.[1] Shown below is an example where it is used in the synthesis of (+)-Ambruticin.[2]

gilbert_alkyne_3.gif

An example in the context of bryostatin synthesis.[3]

gilbert_alkyne_4.gif

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-potProcedure for the Synthesis of Alkynes from Aldehydes”. Synlett 1996 (06): 521–522.doi:10.1055/s-1996-5474.
    1. 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.
    2. 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
    3.  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.
  • General References

・Seyferth, D.; Hilbert, P.; Marmor, R. S. J. Am. Chem. Soc. 1967, 89, 4811; J. Org. Chem. 1971, 36, 1379. doi:10.1021/jo00809a014
・Gilbert, J. C.; Weerasooriya, U. J. Org. Chem. 1979, 44, 4997; ibid. 1982, 47, 1837. doi:10.1021/jo00349a007

<Ohira-Bestmann Modification>
・Ohira, S. Synth. Commun. 1989, 19, 561.
・Müller, S.; Liepold, B.; Roth, G. J.; Bestmann, H. J. Synlett 1996, 521. doi:10.1055/s-1996-5474
・Roth, G. J.; Liepold, B.; Muller, S. G.; Bestmann, H. J. Synthesis 2004, 59. doi:10.1055/s-2003-44346

<Preparation>
・Callant, P.; D’haenens, L.; Vandewalle, M. Synth. Commun. 1984, 14, 155.
・Brown, D. G.; Velthuisen, E. J.; Commerford, J. R.; Brisbois, R. G.; Hoye, T. R. J. Org. Chem. 1996, 61, 2540. doi:10.1021/jo951944n

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