Facile Synthesis of Azetidine Nitrones and Diastereoselective Conversion into Densely Substituted Azetidines

Abstract

An electrocyclization route to azetidine nitrones from N-alkenylnitrones was discovered that provides facile access to these unsaturated strained heterocycles. Reactivity studies showed that these compounds undergo a variety of reduction, cycloaddition, and nucleophilic addition reactions to form highly substituted azetidines with excellent diastereoselectivity. Taken together, these transformations provide a fundamentally different approach to azetidine synthesis than traditional cyclization by nucleophilic displacement and provide novel access to a variety of underexplored strained heterocyclic compounds.

Facile Synthesis of Azetidine Nitrones and Diastereoselective Conversion into Densely Substituted Azetidines

“…Oximes with unsymmetrical substituents at the electrophilic position gave single diastereomers of 4 ( Table 2, entries 13 and 14). [17] These results show that the process described in Table 2tolerates avariety of substrates for the preparation of azetidine nitrones 4.…”

“…As shown in entries 1-3, activation of 4a with Meerweinss alt facilitated the addition of asilyl enol ether,asilyl ketene acetal, and an allylstannane to give N-ethoxyazetidines 13 a-13 c in good yields and excellent diastereoselectivity.T he cis relationship between the phenyl and the ethyl groups was verified by an X-ray crystal structure of 13 a. [17] Further exploration of the alkylation of 4a was investigated with ab enzoyl triflate electrophile generated in situ from BzCl and AgOTf (Table 3, entries 4-6). While these transformations exhibited similar reactivity with the same nucleophiles to give azetidines 14 a-14 c,t he diastereoselectivity of these processes was low to moderate.I nterestingly,h igh diastereoselectivities were regained for alkylations of the less sterically hindered benzoyl-activated azetidine nitrone 9 when using as ilyl ketene acetal and an allylstannane ( Table 3,…”

“…Thes tructure of 4a was verified by X-ray crystallography. [17] Additionally,n itrone 3a was converted into azetidine 4a in good yield when heated at 40 8 8Ci n DMSO,DCE, and MeCN,but only moderate yields in toluene and iPrOAc (Table 1, entries 1a nd 6-9). Nitrone 3b was converted into azetidine 4b in only moderate yields when heated at 40 8 8Ci nD MSO,D CE, or MeCN,a nd low yields when heated in toluene or iPrOAc.…”

“…Zuschriften gave 9,which was reduced under hydrogenation conditions to give N-hydroxyazetidine 10 in good yield and high diastereoselectivity for the mutually trans isomer. [17] Further exposure of azetidines 8 and 10 to reducing conditions gave the corresponding ring-opened amino esters 11 and 12. [22] These results illustrate the diversity of azetidines that are easily accessible from azetidine nitrones 4.…”

Cycloaddition of Benzyne with Alkoxy-Substituted Pyrroline-N-oxides­: Unexpected Rearrangement to an N-Phenylpyrrole

“…7,8 Following the seminal work of Kaliappan's goup, 4 we studied the cycloaddition of dialkoxypyrroline N-oxides with benzyne as another entry to radicamine or codonopsinine analogues. In particular, the lack of substitution on C-5 of the nitrone could allow the introduction of various substituents by following the well-known alkylation of the nitrone following the oxidative opening of the hexahydropyrrolo[1,2-b]isoxazolidine ring.…”