Reagent of the month – March – Seyferth-Gilbert and Bestmann-Ohira reagents

Reagent of the month – March – Seyferth-Gilbert and Bestmann-Ohira reagents

Dimethyl(1-diazomethyl)phosphonate (Seyferth–Gilbert reagent, Figure 1) is a homologation reagent used to convert aryl ketones and some aldehydes into alkynes elongated by one carbon atom coming from the reagent itself in the Seyferth–Gilbert homologation (Figure 2).

Figure 1: Structure of the Seyferth–Gilbert reagent.

Reaction mechanism

First, the acidic proton of the Seyferth–Gilbert reagent (1) is deprotonated with a strong base (potassium tert-butoxide is usually used) giving the carbanion 2. Then, a mechanism similar to that of Horner–Wadsworth–Emmons reaction proceeds, leading to the formation of the corresponding diazoalkane 5. This intermediate then decomposes upon warming the reaction mixture giving the carbene intermediate 7 with a loss of nitrogen. Finally, the carbene undergoes a rearrangement giving the final alkyne 8. (Original publication: 10.1021/jo00349a007)

Figure 2: Seyferth–Gilbert homologation reaction mechanism.

Limitations and updates

Due to the use of a strong base in the initial step, Seyferth–Gilbert homologation cannot be performed with base labile carbonyl compounds such as enolizable aldehydes, which would undergo aldol condensation reactions under basic conditions.

This problem has been overcome by a different way of generating the carbanion 2 in the reaction mixture. Methanolysis of dimethyl diazo-2-oxopropylphosphonate was first used by Susumu Ohira from the Okayama university to perform the analogous homologation reaction using a weaker base (

Later, the reaction conditions were developed further by Bestmann et al. to run using just potassium carbonate as a base, making the reaction usable also for the synthesis of terminal alkynes from enolizable aldehydes (DOI: 10.1055/s-1996-5474, doi:10.1055/s-2003-44346). Dimethyl diazo-2-oxopropylphosphonate (Figure 3.) is called Ohira–Bestmann reagent.

Figure 3: Methanolysis of Ohira–Bestmann reagent leads to the formation of carbanion 2 under milder conditions. The methoxide anion can be generated in small quantities by weak bases such as K2CO3.

Preparation of the Ohira–Bestmann reagent

The Ohira–Bestmann reagent can be easily prepared in-situ by diazo transfer reagents such as sulfonyl azides (Figure 4.,

Figure 4: In-situ generation of Ohira–Bestmann reagent.

Application in synthesis

One pot tandem procedures combining Ohira–Bestmann homologation with reactions of terminal alkynes, such as sonogashira coupling or CuAAC reactions, were recently developed (Figure 5.,, DOI: 10.1055/s-2007-990877).

Figure 5: Tandem Ohira–Bestmann/Sonogashira and Ohira–Bestmann/CuAAC reactions.

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