Elsevier

Tetrahedron

Volume 62, Issue 51, 18 December 2006, Pages 12064-12070
Tetrahedron

Synthesis and isomerization of N-α-aza-heteroaryl-β-lactams

https://doi.org/10.1016/j.tet.2006.09.075Get rights and content

Abstract

The [2+2] carbonylative cycloaddition of N-α-aza-heteroaryl substituted imines with allyl bromide led partially to β-lactams, which underwent isomerization to the more stable α,β-unsaturated carbonyl compound. Pyrimidinone derivatives together with doubly unsaturated amides represent the remaining isolated products. The strong electron-withdrawing effect of the two α-aza-heterocycles linked to the nitrogen atom and to the C4 of the 2-azetidinone structure could give a ring expansion, through a 2-azetinone intermediate that affords the pyrimidinone compounds. The substituted amides, instead, should result from a ring-opening reaction of the β-lactam.

Introduction

β-Lactams show a wide range of pharmacological activities and synthetic routes to such compounds continue to be developed.1, 2, 3, 4 The use of 2-azetidinones as starting materials in organic synthesis is based on the impressive variety of transformations that can be derived from this system. For instance, Alcaide and Almendros described the selective bond cleavage and rearrangement of the β-lactam nucleus with applications in the stereocontrolled synthesis.5 Thus, compounds such as alkaloids,6, 7 carbohydrates8, 9 and different kinds of heterocycles10, 11, 12, 13, 14 have been produced from β-lactams. Recently, we reported the stereoselective synthesis of β-lactams by an improved Pd-catalyzed [2+2] carbonylative cycloaddition of allyl halides with various imines,15 where the catalytic species involved was Pd(0)16 (Scheme 1). Moreover, we found that the presence of an α-aza-heterocycle attached to the iminic carbon, for example, where Ar=2-benzothiazole or 2-thiazole or 2-pyridine, led partially to β-lactams having a vinylic moiety conjugated to the carbonyl group.16 The high electron-withdrawing effect of the α-aza-heterocycle should increase the acidity of the proton linked to C3, favouring isomerization in the presence of Et3N.

The deprotonation and the stereoselective functionalization of the C3 carbon atom of β-lactams have been also reported by us.17 It has been shown that the deprotonation of the C4 carbon could be achieved only with a structure showing no protons at C3 and having an α-aza-heterocycle linked at C4, which increased the acidity of the directly attached hydrogen (Scheme 2).

In order to thoroughly investigate the electron-withdrawing effect of various heterocycles linked at the different positions of the β-lactam nucleus, we thought to perform, under the same conditions, the [2+2] carbonylative cycloaddition of N-α-aza-heteroaryl substituted imines with allyl bromide.

Section snippets

Results and discussion

The reacting N-α-aza-heteroaryl imines 17 were prepared by coupling reactions of the appropriate amines with the corresponding aldehydes according to the Taguchi's methodology (Scheme 3).18

According to previous results,15 the [2+2] carbonylative cycloaddition of the imines 17 with allyl bromide under CO pressure, in the presence of Et3N and Pd(OAc)2/Ph3P, should afford β-lactams A (Scheme 4).

Surprisingly, such structures were not obtained but, from the reaction mixtures compounds 821 listed

Conclusion

In summary, we have prepared N-α-aza-heteroaryl β-lactams, which underwent isomerization. Novel α,β-unsaturated 2-azetidinones were prepared together with new pyrimidinone derivatives and doubly unsaturated amides. The pyrimidinone compounds seem to be produced from ring expansion of the rearranged β-lactams through a 2-azetinone intermediate. This behaviour has been observed only for structures showing two heterocyclic moieties linked to the nitrogen atom and to the C4 carbon, respectively.

General

THF, triethylamine, palladium(II)acetate, triphenyl-phosphine, allyl bromide, 4-formylmorpholine, 2-pyridinecarboxaldehyde, 2-aminothiazole, 2-aminopyridine, 3-aminopyridine, 4-methyl-thiazole, 2-aminothiophenol, glycolic acid and all other chemicals were of commercial grade (Aldrich) and were used without further purification. Benzaldehyde and allyl bromide of commercial grade (Aldrich), were purified by distillation prior to use. Petroleum ether refers to the 40–60 °C boiling fraction. The 1H

Acknowledgements

We like to thank the MIUR, Rome, and the University of Lecce (Italy) for financial support.

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