Assessing the scope of the tandem Michael/intramolecular aldol reaction mediated by secondary amines, thiols and phosphines

doi:10.1016/S0040-4020(01)00744-X

Tetrahedron

Volume 57, Issue 36, 3 September 2001, Pages 7771-7784

https://doi.org/10.1016/S0040-4020(01)00744-X Get rights and content

Abstract

The outcome of a tandem Michael/intramolecular aldol reaction which is mediated by secondary amines, thiols and phosphines has been found to be highly substrate dependent, with the best results being obtained for the formation of 5 and 6-membered rings using thiol or thiolate nucleophiles. Amine and phosphine mediated cyclisations were found to be problematic in several cases but were still effective methods for the formation of 5–7 membered rings.

Introduction

In our preliminary communications,¹ we described the ability of a range of nucleophiles, including secondary amines, thiols and phosphines to effect a tandem intramolecular Michael/aldol cyclisation of enones 1 leading to either the adducts 2 or the eliminated Baylis–Hillman type product 3¹ (Scheme 1).

Following these preliminary studies we were keen to assess the scope of this reaction taking into account such variables as the nature of the nucleophile and the group R and the potential for variations in the ring size of the product formed. We were also interested in studying the mechanistic aspects of this reaction and this paper brings together our preliminary findings on these matters and our further studies on the process.

Section snippets

Preparation of aldehydes 1

The substrates (1a–j) for the investigation were prepared by reaction of a suitable phosphorus ylid with a dialdehyde prepared by either hydrolysis of 2,5-dimethoxytetrahydrofuran in the case of succinaldehyde (method A),² ozonolysis of a cycloalkene (method B) or using an aqueous solution of glutaraldehyde (method C) (Table 1). The crude products are purified by column chromatography and a bis-enone, obtained by double Wittig reaction on the dialdehyde, is generally obtained as a by-product of

Reactions involving secondary amines

Our preliminary investigation stemmed from the observations that a suitable catalyst for effecting the conversion of the substrate 1a into the cyclised product 3a was the secondary amine piperidine. We thus performed a preliminary study of the reaction of other amines and it was apparent that piperidine was by far the superior choice of catalyst for effecting this transformation. The results in Table 2 illustrate that, with the exception of the hindered amine 2,6-dimethylpiperidine, all the

Systematic modification of substrates and catalyst

With these preliminary studies in hand, we next embarked upon a systematic study of the cyclisation process and chose to investigate the use of different electron withdrawing groups in the Michael substrate and to couple these modifications with variation in ring size and the use of other nucleophiles. This decision was based upon literature reports that metal thiolates and selenates,⁶ or metallated amines⁷ can be used in tandem Michael-aldol reactions, including some cyclisations,⁸ and that

Conclusion

It is apparent from these results that the amine catalysed cyclisations are limited in scope to the 5- and 6-membered cyclisations with enones as the Michael acceptors; yields for the tandem processes being high in both cases. Yields for the formation of the eliminated products using a catalytic amount of piperidine are satisfactory with enone substrates, however, enoate and thioenoate examples lead only to decomposition. The phosphine mediated cyclisations work best for the 6- and 7-membered

Experimental

Reagents: All reagents were obtained from commercial suppliers and were used without further purification.

Solvents: Solvents were purified when necessary using standard methods, in particular, dichloromethane (DCM) was distilled over calcium hydride. Petrol refers to the fraction of petroleum spirit boiling in the range 40–60°C. Chromatography: The purity of compounds was assessed by thin layer chromatography (TLC). Unless otherwise stated, all new compounds were homogeneous as indicated by

Acknowledgements

Thanks are given to the EPSRC (PMB, GR/M50584), the ERASMUS scheme (F. D., S. F.), the European Social Fund (E. L. R.) and to the University of Wales for funding. The EPSRC Mass spectrometry centre at Swansea is also acknowledged.

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