Reactions of 3-arylmethylene-3H-furan(pyrrol)-2-ones with azomethine ylide: synthesis of substituted azaspirononenes

1,3-Dipolar addition reaction has recently gained importance in the synthesis of spiroheterocyclic compounds [1], [2], [3], [4]. Various heterocyclic systems including biologically active substances can be constructed in one stage [5], [6]. However, the application of this reaction is very limited by a rather weak activation of a multiple bond and unfavorable steric features in the dipolarophilic molecule. Michael’s [7], [8] and Friedel-Krafts’ reactions by the exocyclic C=C bond [9] and bromation reaction by the heterocyclic double bond [10] have previously been carried out in the 3-arylmethylene-3H-furan-2-one series. The reaction of a nucleophilic reagent [9] with diazoacetic ester [11] proceeds through opening of the furanone ring. Spirocompounds from 3-arylmethylene-3H-furan-2-ones and pyrrol-2-one analogs have not been obtained previously.

In this work, the synthesis of the spiro compounds by the reaction between 3-arylmethylene-3H-furan(pyrrol)-2-one and N-benzylidenebenzylamine was carried out by us for the first time. Azomethine ylide was generated in situ by addition of AcOAg/Et₃N to acetonitrile solution of compounds 1a–l and 2 (Scheme 1). The reaction requires an equimolar ratio of the reagents and is completed at room temperature within 2–3 days.

Scheme 1

Starting compounds 1a–l were synthesized by condensation of 4-oxobutyric acids with aromatic aldehydes by using a general procedure [6]. Products 3a–l were obtained with yields up to 72–88%. In the ¹H NMR spectra of 3a–l the two doublets for the vicinal protons at 4.01–4.13 ppm and 4.64–4.79 ppm with a coupling constant J=14.1–14.5 Hz are consistent with trans orientation of these protons. Another proton at the ternary carbon atom adjacent to the nitrogen atom shows as a singlet within 4.28–4.84 ppm. The signal of the proton at the nitrogen atom resonates within 1.84–2.02 ppm. The protons at the sp²-hybridized carbon atoms give an unresolved multiplet in the range of 6.87–7.86 ppm. The chemical shift of the proton Ar₂-C-H depends on the substituent type in the adjacent aromatic ring. Electron donating groups, such as 4-OMe, cause a small upfield shift of the signal (4.62–4.65 ppm) while electron withdrawing substituents, such as 2-Cl, and replacement of the benzene ring by a pyridine leads to downfield shift of the signal (4.72–4.79 ppm) in comparison with the similar signal of spiropyrrolidine with no substitution in its benzene ring (4.66–4.68 ppm). The ¹³C NMR spectra of compounds 3a–l are also fully consistent with the given structures.

A suggested mechanism for the reaction is presented in Scheme 2.

Scheme 2

N-benzylidenebenzylamine is easily deprotonated at one of the methylene groups under the action of triethylamine to form a 2-azaallyl ion stabilized with a silver cation. The metal-organic intermediate keeps its initial spatial structure due to metal coordination and thus provides high stereoselectivity of the process. This reaction is a selective cis-addition proceeding by a single-stage synchronous mechanism with the suggested involvement of complex A, in which the maximum stabilization is achieved due to HOMO overlapping in the dipole with LUMO in the dipolarophile, to produce spiropyrrolidine 3.

The maximum electronic LUMO density is concentrated near the exocyclic C=C bond of an arylmethylene moiety of 3H-furan(pyrrol)-2-one, which favors orbital-controlled cycloaddition of N-benzylidenebenzylamine by this bond. The reaction is highly efficient.