The Aza-Silyl-Prins Reaction: A Novel Method for the Synthesis ofTrans-2,6-Tetrahydropyridines

Abstract

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) ...

On the choice of Lewis acids for the Prins reaction; two total syntheses of (±)-Civet

“…This is, we believe, the first example of triflate being trapped in the Prins reaction. Also in contrast to the previous observations, TMSOTf was now by far the highest yielding Lewis acid (Scheme 7 and Table 4), with In(OTf) 3 or any other Lewis triflate-containing Lewis acid (scandium or tin) only giving traces of product, with unreacted starting materials recovered irrespective of temperature (and some decomposition at reflux). Perhaps even more surprising was that the product, as with the chloride-trapped products, was obtained as a single, allcis diastereoisomer.…”

“…Both TMSOTf 42 and TESOTf 43,44 have been utilised in cyclisation reactions where an external nucleophile (to the Lewis acid), such as acetate (from TMSOAc) or acetonitrile has trapped the carbocation, or the cyclisation has been intramolecular and an internal nucleophile has trapped the carbocation, normally forming a second ring. In(OTf) 3 has been used with NH 4 SCN to trap eSCN at the 4-position 45 and also with benzaldehyde or anisole in an ionic liquid in a Prins-FriedeleCrafts reaction 46 and also bismuth triflate catalysed PrinseRitter reactions. 47,34 Both MsOH and TsOH sulfonic acids have been used in the reaction between 2-(arylmethylene)cyclopropylcarbinols and aldehydes to give 3-methylene-5-mesyl(tosyl)-tetrahydropyrans (Scheme 3).…”

“…This mixture was stirred for 5 min before the addition of In(OTf) 3 (1.5 equiv) in one portion. The reaction was allowed to stir at room temperature for 10.5 h before quenching with water.…”

Synthesis of Azabicycles via Cascade Aza-Prins Reactions: Accessing the Indolizidine and Quinolizidine Cores

“…2,[13][14][15][16] Both reactions involve the intermolecular reaction of a carbonyl or related compound (aldehyde, ketone or epoxide) with a secondary homoallylic amine in order to form an iminium ion, which then undergoes intramolecular Prins cyclisation to give either piperidines or tetrahydropyridines, depending on the absence or presence of the silicon moiety on the alkene (Scheme 1). The aza-silyl-Prins reaction is highly tolerant of a range of groups on the secondary amine, but is more limited to a sulfonamide in the aza-Prins reaction.…”

Aliphatic aldehydes in the synthesis of carbo- and heterocycles: Part II. Synthesis of six- and seven-membered rings, bicyclic compounds, and macrocycles

“…According to the authors, the proposed procedure is superior to classical methods, for it ensures preparation of wide series of tri-, tetra-, and pentasubstituted pyridines in high yield. Tetrahydropyridines 77 were synthesized by highly diastereoselective aza-silyl-Prins reaction of aldehydes 1b, 1d, 1h, 1j, and 1l with silylated homoallylamines 76 [80][81][82] [85], or B(C 6 F 5 ) 3 [86] and under microwave [87] or ultrasonic activation [88]. Alkyl-substituted dihydropyridines thus formed were found to exhibit diverse biological activity [89][90][91][92][93][94].…”