Azetidine ring

A number of 2-acylazetidines have been prepared by reaction of 1,3-dihaloacyl compounds with amino derivatives (Section 5.09.2.3.l(m)). This is illustrated for azetidine 2-carboxylic acid (56), the only known naturally occurring azetidine. Ring expansion of activated aziridines (43) and contraction of 4-oxazolines (55) has also found limited use (Section 5.09.2.3.2(f) and Hi)). 

A structurally unrelated agent is tazadolene (40). The synthesis of tazadolene begins with P-keto ester 37 and subsequent enamine formation with 3-amino-1-propanol followed by hydrogenolysis to give 38. This phenylhydroxymethyl compound is then dehydrated with hydrochloride acid to form olefin 39. Treatment with bromine and triphenylphosphine effects cycliza-tion to form the azetidine ring of tazadolene [10]. 

Azetidine ring is an important structure because it is present in many compounds of pharmaceutical interest however, its manipulation must be done very carefully owing to the reactivity of these heterocycles of small size. An interesting application of the use ofbiocatalytic processes is the resolution of azetidine esters (Scheme 7.11). The procedure to choose for the resolution of these compounds is the enzymatic ammonolysis of the corresponding N-substituted azetidines [26]. 

Vicinal coupling constants of azetidine ring protons show that the two trans... 

The rotational barriers of A-nitroso-, A-formyl and A-(A,A-dimethylcarbamoyl)-azetidines, compared with those of analogous acyclic amides, suggest that amide conjugation is weaker when the nitrogen is part of an azetidine ring (87KGS912). 

The four-membered azetidine ring remains unaffected by sodium in liquid ammonia, 94 methanolic ammonia, 95 5M barium hydroxide at 100 °C for 24 hours, 87 sodium hydroxide under ester saponification conditions, 87 HC1 at room temperature, 96,97 catalytic hydrogenation under normal conditions, 87,95 and ozonolysisJ87 Correspondingly, as observed for proline, the azetidine-2-carboxylic acid (2) raises no particular difficulties in the synthesis of related peptides. 

The generation of four-membered ring systems can be accomplished by a cycloaddition process under photochemical conditions or with special substrates under thermal conditions. Iron-vinylidene complexes belong to such a class of special substrates where a thermal [2 + 2]-cycloaddition is possible. If imines are used, a hetero-[2 + 2]-cycloaddition with an iron-vinylidene complex leads to an iron-carbene complex attached to an azetidine ring system, as reported by Barrett and coworkers (Scheme 9.20) [46, 47]. The oxidation of these iron-carbene complexes leads to [3-lactams 27. Interestingly, the application of 2-thiazolines generates penam... 

The azetidine ring is stable during a variety of transformations of the functional groups present on the ring carbon(s). The reaction of l-ethoxycarbonyl-3-(bromomethyl)-3-chloroazetidines 85 with l,8-diazobicyclo[5.4.0]undec-7-ene (DBU),... 

The action of A-chlorosuccinimide, or a source of positive fluorine such as Selectfluor , in aqueous acetonitrile on the alkene 138 (R1 = Me) is to open the azetidine ring by attack at the allylic position to yield the cyclobuten-3-ol 139 (R OH, R2 = H, R3 = Me) <2003JOC5292>. Chlorosulfonyl isocyanate (CSI) reacts with 138 (R = Et) to give both a chlorobutene 139 (R1 = Cl R2 = CONH2 R3 = Et) and the bicyclic reduced pyrimidone 140 (R1 = Et). However, the action of CSI on the more substituted 2-azabicyclo[2.2.0]hex-5-ene 141 provided the reduced mono-cyclic pyrimidone 142 <2003JOC1626>. 

Bicyclic complexes containing an azetidine ring and a palladium atom 525 have been shown to be effective catalysts in Suzuki coupling reactions with bromobenzenes and with the generally less reactive chlorobenzenes. The catalyst was stable in air for several months without loss of activity and the catalyst loading in the reaction could be lowered to 0.1% without a decrease of yield in the reactions studied <2005JOM2306>. 

---