A versatile and high-yielding indium trichloride mediated cyclization reaction of silylated homoallylic alcohols, thiols, or amines with aldehydes or epoxides is described as a rapid route to a range of unsaturated heterocycles. The excellent diastereoselectivity observed offers a method of wide scope and generality.
The development of a Lewis acid-promoted aza-Prins reaction to form piperidines and pyrrolidines is described. Indium trichloride has been found to be a highly successful and mild Lewis acid for promoting this reaction. A thorough mechanistic investigation is described, including the factors that influence the formation of the 5- or 6-membered ring product(s).
Reaction of 4-trimethylsilyl-3-butenyl-1-amines with aldehydes under mild Lewis acid conditions gives substituted tetrahydropyridines in excellent yields and with excellent trans diastereoselectivity.The piperidine ring is widespread in nature and there have been numerous accounts of the synthesis of piperidines and their wide range of biological activities. Nevertheless, synthetic methodologies for the synthesis of nitrogen containing heterocycles continue to be of immense importance.The use of silanes in the termination of cyclisation reactions is now a popular synthetic methodology, and the area has been extensively reviewed. 1 Furthermore, there are now many examples of natural product total syntheses that have incorporated this methodology as a key step. 1 We have recently added to this wealth of methodology by reporting the facile indium trichloride mediated cyclisation of Z-4-trimethylsilyl-3-buten-1-ols with aldehydes or epoxides to give good yields of substituted dihydropyrans -the silyl-Prins reaction (Scheme 1). 2 The reaction demonstrates exclusive cis-diastereoselectivity across the oxygen atom.It occurred to us that it would be interesting to explore the application of the silyl-Prins reaction to the synthesis of the tetrahydropyridine ring. Despite Overman's impressive work on the acid-catalysed vinylsilane-iminium ion cyclisation to azacycles, 3 to the best of our knowledge, there are no examples of Lewis acid mediated Prins-type cyclisations to give tetrahydropyridines. The acid-promoted cyclisation reaction of vinylsilanes to give tetrahydropyridines, however, continues to be of considerable interest, and the recent work reported by Tanner 4 prompts us to report our findings in this area.The desired substrates for our initial studies were a range of N-substituted Z-4-trimethylsilyl-3-buten-1-ylamines 1 (Scheme 2). Initially these were prepared via a four step sequence starting from either 3-butyn-1-ol or 4-pentyn-2-ol. Silylation using n-butyllithium/trimethylsilyl chloride followed by DIBAL-H reduction gave 4-trimethylsilyl-3-buten-1-ol in 85-90% overall yield. Tosylation of the alcohol and displacement with a range of amines gave the desired cyclisation precursors 1a-f.Initially a range of Lewis acids were screened. 5 No reaction was observed for the reaction of 1b with either benzaldehyde or hexanal using any Lewis acid in dry dichloromethane at low or room temperature (Table 1, entries 1, 3 and 5). Increasing the temperature to refluxing dichloromethane did, however, by GC-analysis, suggest traces of product formation. The solvent therefore was switched to a higher boiling solvent -acetonitrile. Several Lewis acids now proceeded to promote the reaction and Scheme 2 Synthesis of 4-trimethylsilyl-3-butenyl-1-amines OH TMS R R OH 1. 2n-BuLi, -78 °C, THF 2. 2TMS-Cl, -78 °C to r.t. 3. DIBAL-H, Et 2 O, reflux 1. TsCl, DMAP, Et 3 N CH 2 Cl 2 , 0 °C, >90% 2. R 1 NH 2 , EtOH, reflux NHR 1 TMS R 85-90% a) R = H, R 1 = Ph 40% b) R = H, R 1 = Bn 62% c) R = H, R 1 = n-Pr 89% d) R = Me, R 1 = Ph 70% e) ...
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