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Related Reactions
Corey-Fuchs Reaction
Wittig Reaction
Synthesis of alkynes

Seyferth-Gilbert Homologation
Bestmann-Ohira Reagent

The Seyferth-Gilbert Homologation is the base-promoted reaction of dimethyl (diazomethyl)phosphonate with aldehydes and aryl ketones at low temperatures, and provides a synthesis of alkynes. The Ohira-Bestmann modification using dimethyl 1-diazo-2-oxopropylphosphonate allows the conversion of base-labile substrates such as enolizable aldehydes, which would tend to undergo aldol condensation under the Seyferth-Gilbert conditions:

Mechanism of the Seyferth-Gilbert Homologation

The mechanism is described in detail in a report by Gilbert (J. Org. Chem., 1982, 47, 1837-1845. Abstract).

The deprotonated Seyferth-Gilbert reagent adds to the carbonyl compound forming an alkoxide that closes to give an oxaphosphetane:

Comparable to the Wittig Reaction, a cycloelimination yields a stable dimethyl phosphate anion and a diazoalkene:

Upon warming of the reaction mixture to room temperature, loss of nitrogen gives a vinylidene carbene that yields the desired alkyne after 1,2-migration of one of the substituents:

For substrates with substituents that have low migratory aptitudes, such as 4-nitrobenzaldehyde, the existence of the nitrene can be demonstrated by adding an excess of amine or alcohol to the reaction mixture, which yields the products of insertion reactions:

An alternative mechanism would involve nitrogen loss at an earlier stage of the mechanism, prior to the cycloelimination; i.e. N2 loss and rearrangement would occur from the oxaphosphetane to yield an oxaphosphete, to be followed by the cycloelimination:

The failure of several attempts to use Wittig-like reactions for the direct synthesis of alkynes tends to rule out this alternative mechanism. One could argue that the generation of alkynes is very fast, but this possibility can be excluded through comparison with similar structures. The Seyferth-Gilbert reagent should be more stable than a comparable alkyl azide. Ring strain is expected not to be important, since diazocyclobutane is still stable at -40°C and its decomposition to the azine is slow even at 0°C. The diazooxaphosphetane should have a similar molecular geometry in addition to a stabilizing neighbor group effect, so that a fast reaction cannot be anticipated.

The dimethyl (diazomethyl)phosphonate anion can also be generated by mild acyl cleavage of dimethyl diazo-2-oxopropylphosphonate.

Here the gentle reaction conditions allow the conversion of even enolizable aldehydes in good yields:

S. Müller, B. Liepold, G. J. Roth, H. J. Bestmann, Synlett, 1996, 521-522.

Originally, a single example of the conversion of an n-alkylaldehyde under basic methanolysis of the reagent was reported in 1986 by Ohira (Synth. Commun., 1986, 19, 561. DOI). The scope and limitations of the reaction were later examined by Bestmann, who obtained several alkynes in good to excellent yields and in pure form after simple work-up. Dimethyl diazo-2-oxopropylphosphonate is also referred as Bestmann-Ohiro Reagent.

Note: the reaction of ketones yield methyl enol ethers in the presence of methanol due to trapping of the intermediate carbene.

Both the Seyferth-Gilbert reagent and the Bestmann-Ohira reagent can conveniently be prepared by using diazo transfer reagents. An in situ generation of the Bestmann-Ohira reagent can be found in the recent literature section.

Recent Literature

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. C. Gilbert, U. Weerasooriya, J. Org. Chem., 1982, 47, 1837-1845.

An Improved One-pot Procedure for the Synthesis of Alkynes from Aldehydes
S. Müller, B. Liepold, G. J. Roth, H. J. Bestmann, Synlett, 1996, 521-522.

In Situ Generation of the Ohira-Bestmann Reagent from Stable Sulfonyl Azide: Scalable Synthesis of Alkynes from Aldehydes
T. H. Jepsen, J. L. Kristensen, J. Org. Chem., 2014, 79, 9423-9426.

Further Improvements of the Synthesis of Alkynes from Aldehydes
G. J. Roth, B. Liepold, S. G. Müller, H. J. Bestmann, Synthesis, 2004, 59-62.

One-pot conversion of activated alcohols into terminal alkynes using manganese dioxide in combination with the Bestmann-Ohira reagent
E. Quesada, R. J. K. Taylor, Tetrahedron Lett., 2005, 46, 6473-6476.

A convenient scalable one-pot conversion of esters and Weinreb amides to terminal alkynes
H. D Dickson, S. C. Smith, K. W. Hinkle, Tetrahedron Lett., 2004, 45, 5597-5599.

Sequential Seyferth-Gilbert/CuAAC Reactions: Application to the One-Pot Synthesis of Triazoles from Aldehydes
D. Luvino, C. Amalric, M. Smietana, J.-J. Vasseur, Synlett, 2007, 3037-3041.