Review of Seyferth-Gilbert Homologation Reaction (Carbon-Adding Reaction)

1. Discovery and Development of the Reaction

In 1973, British chemists E. W. Colvin and B. J. Hamill first reported a novel organic transformation reaction in the Journal of the Chemical Society. Under basic conditions, using trimethylsilyl diazomethane (TMSCHN2) or dimethylphosphoryldiazomethane as reagents, this reaction can convert aldehydes and ketones into corresponding alkyne derivatives in one step. Notably, the dimethylphosphoryldiazomethane reagent used by these researchers was synthesized and characterized for the first time by American chemist D. Seyferth.

In subsequent studies, Colvin's research group found that this transformation reaction had significant substrate limitations; specifically, it was only applicable to non-enolizable carbonyl compound systems including diaryl ketones and aromatic aldehydes with strong electron-withdrawing groups. This limitation severely restricted its application value in complex molecular synthesis.

In 1979, J.C. Gilbert’s team at Purdue University made groundbreaking improvements to this reaction by developing new reaction conditions utilizing α-diazophosphate as a key reagent under mild basic conditions for broader carbonyl compound transformations. This improved method not only simplified operations but also allowed various carbonyl compounds to be efficiently converted into terminal or internal alkynes via a “one-pot” approach. To honor the contributions of both pioneers, this series of reactions has been officially named Seyferth-Gilbert homologation reactions (also known as carbon-adding reactions).

2. Characteristics and Operating Conditions of the Reaction

2.1 Traditional Operating Method In Gilbert's initial reaction scheme developed earlier on, diakyl phosphonydiazomethane (DAMP) was required as a key reagent; although not directly available commercially, it could be prepared through standard organic synthesis methods involving strict anhydrous anaerobic conditions with strong bases like n-butyllithium or potassium tert-butoxide for deprotonation treatment at low temperatures (-78°C). The final product is obtained after conventional aqueous workup. However, traditional methods have notable limitations due to harsh operating conditions leading many base-sensitive functional groups unable to withstand them resulting in strictly limited substrate applicability while requiring high technical demands on experimental equipment within controlled inert atmospheres restricting routine synthetic applications significantly. 2.2 Ohira-Bestmann Improvement Method In 1989 Japanese chemist Ohira along with German chemist Bestmann independently reported important modifications improving upon said reactions wherein they utilized dimethyl-1-diazo-2-oxopropyl phosphonate alongside potassium carbonate acting mildly alkaline solvent methanol enabling successful room temperature processes yielding high yields after simple aqueous processing post stirring several hours further exhibiting compatibility across most common functionalities without inducing racemization phenomena observed during optical active substrates’ transformations demonstrating exceptional tolerance towards acidic C-H bonds whilst maintaining operational simplicity negating stringent moisture-free requirements encountered previously though selectivity constraints remain present regarding α ,β-unsaturated aldehyde substrates failing expected enyne formation instead producing propargyl methyl ester side products possibly related intermediate stability concerning pathways involved throughout conversion steps taken subsequently examined extensively receiving broad recognition from peers alike.

3 Mechanistic Studies

involving detailed examinations recognized widely categorized primarily four critical stages: after nucleophilic attack initiated under alkaline environments methoxy ions react against reagent molecules facilitating decarboxylative events generating highly reactive carbanion intermediates possessing pronounced nucleophilic characteristics before attacking target carbonylic centers forming oxaphosphetanes resembling classical Horner-Wadsworth–Emmons olefination mechanisms followed lastly culminating intramolecular rearrangements yielding thermodynamically stable alkyne products defining regioselectivity stereochemical features governing entire process outcomes effectively establishing groundwork understanding crucial interactions taking place therein enhancing future explorations avenues likely lead innovative methodologies expanding horizons chemical syntheses pursuits globally speaking! and more...​