Ghosez keteniminium-olefin cyclization

What is Ghosez keteniminium-olefin cyclization?

The synthesis of cyclobutanones from the reaction of alkenes and keteniminium ions was first reported by Ghosez in 1972. The keteniminium ions are typically produced from tertiary amides by reacting with triflic anhydride and a hindered pyridine base, or by dechlorinating 1-chloro-N,N,2-trimethyl-1-propylenamine with AgBF4 followed by hydrolyzing the resulting iminium salts under biphasic conditions. This reaction is referred to as Ghosez keteniminium-olefin cyclization or Ghosez [2+2] keteniminium-olefin cycloaddition, and the Ghosez reagent is 1-chloro-N,N,2-trimethyl-1-propylenamine, which is generated from the treatment of N,N-dimethyl 2-methylpropionamide with phosgene and triethylamine.

Ghosez keteniminium-olefin cyclization - general reaction scheme - Ghosez [2+2] keteniminium-olefin cycloaddition
Ghosez keteniminium-olefin cyclization

The keteniminium salt is a ketene equivalent that is superior to ketene in [2+2] cycloaddition due to its higher electrophilicity and lack of dimerization resulting from charge-charge repulsion. Compared to ketenes, the reaction conditions for keteniminium salt are mild, and yields are typically satisfactory. Additionally, the use of a chiral inducer on the carbon atom of the keteniminium salt often leads to the formation of cyclobutanone with a configuration following the known chirality of the inducer.

Despite the fact that the combination of a keteniminium salt with 1,1-disubstituted alkenes leads to very limited product yields due to intermolecular reactions, the intramolecular cycloaddition can occur with tethers of three, four, five, and seven atoms. This is in contrast to the corresponding reaction of ketenes, which usually only proceed with three or four-atom tethers.

It is worth noting that Ghosez had previously reported the [2+2] cycloaddition between keteniminium and imines to create β-lactams as early as 1970. This cycloaddition can generate azetidiniminium salts, which can be transformed into various molecules apart from β-lactams, including 2-acetidinethiones, azetidinimines, oxazolidin-2-ones, and 2-amino-1-azetines, as well as 1,2-amino alcohols and α-amino acids.

The keteniminium salts can be easily created from N,N-dialkyl amides using phosgene, with the resulting N,N-dialkyl-2-chloroiminium chloride taking three possible routes to produce azetidiniminium salts. Path a, which involves a direct reaction with imine in the presence of triethylamine, is the most practical, but only path c provides 4-alkyl azetidiniminium salts. Chiral iminium salts typically produce chiral azetidiniminium salts with high optical purity, but the diastereoselectivity of the reaction is mostly determined by the large α-substituents on the carboxyl moiety, while it is comparatively independent of the substituents on the corresponding imines.

When treated with base (e.g., hydroxide) followed by acidic hydrolysis, azetidiniminium salts can produce either β-lactams or β-amino amides via exocyclic or endocyclic C-N bond cleavage. The ratio of β-lactams to β-amino amides is determined by the relative rate of protonation on the exocyclic and endocyclic nitrogen atom of the tetrahedral intermediate. Additionally, thiolysis or aminolysis by reacting azetidiniminium salts with sodium hydrosulfide or primary amines (including ammonia and hydroxylamine) can produce the corresponding azetidinethiones or azetidinimines. However, azetidiniminium salts with hydrogen at the α-carbon yield a much lower product yield, in which case the corresponding azetidinimines can be produced by creating azetidine-2-thione and subsequently reacting it with amine in the presence of mercuric acetate.

Finally, the Baeyer-Villiger oxidation of azetidiniminium salts generates oxazolidinones, and the oxidation of azetidiniminium salts with bis-trimethylsilyl peroxide in the presence of fluoride generates five-membered carbamates, which can then be hydrolyzed to aminoalcohols.