Bismuth(III) Chloride: An Efficient Catalyst for the One-Pot Stereoselective Synthesis of Octahydroacridines

Abstract

A one-pot procedure for the stereocontrolled preparation of octahydroacridine derivatives is reported, which involves the intramolecular hetero-Diels-Alder reaction of N-arylimines produced in situ from citronellal and aromatic amines. The temperature of the reaction medium plays a key role in determination of the trans/cis ratio.Octahydroacridine derivatives are an important class of compounds with interesting pharmacological activity. 2-4 Therefore, many synthetic methods have been reported for the preparation of the octahydroacridine skeleton, such as catalytic hydrogenation of acridines, 5 amino-claisen rearrangement of geranyl aniline, 6 Beckman rearrangement of oxime sulfonates, 7 and acid-catalyzed condensation of aniline with isophorone. 8 The intramolecular hetero-Diels-Alder reaction of N-arylimines with nonactivated olefins tethered to the diene system is the most powerful synthetic tool for constructing nitrogen heterocyclic compounds. For this transformation a variety of strong Lewis or Brönsted acids were used. 9 However, the above mentioned syntheses have drawbacks like the use of harsh conditions, longer reaction times, non-availability of raw materials, and the requirement of low temperatures (-78°C), especially due to the lack of stereocontrol of the ring fusion. Recently, solid-phase synthesis 10 of these derivatives has been reported using Yb(OTf) 3 . Bi(III) derivatives have been used for several organic transformations, 11 such as for Mukaiyama aldol and Michael reactions, 12 in the carbonyl-and aza-Diels-Alder reactions, 13 acylation reactions, 14 and as effective halogenating agents by association with halogenosilanes, 15 because they are regarded as the least toxic of the heavy elements 16 and this new interest in bismuth is easily justified by its friendly ecological behavior. 16 In our continuing effort on the use of BiCl 3 as an efficient catalyst for various reactions, 17 we have recently reported the preparation of tetrahydro[4,3-b]chromanoquinolines 18 by intramolecular hetero-Diels-Alder reaction using BiCl 3 . In this report, we describe a novel, highly efficient and stereoselective synthesis of octahydroacridines in one-pot from the reaction of citronellal and amines with a catalytic amount of BiCl 3 at 0°C in acetonitrile (Scheme).The cyclization was carried out by the addition of BiCl 3 (5 mol%) to a cooled solution of citronellal (2) and aniline (1a) in acetonitrile, which resulted in the formation of octahydroacridine 3a exclusively as a single product in high yield. The reaction was instantaneous as followed by TLC, and found to be highly diastereoselective. The isolated product was purified using silica gel chromatography and characterized by 1 H NMR data as the transisomer. Since the imines are hygroscopic and moisture sensitive it is desirable to carry out the reaction in a onepot procedure without the need of preformation of the imines. Although it can be considered that the product formation involves the intramolecular hetero-Diels-Alder reaction of N-arylimines, genera...

Brønsted and Lewis Solid Acid Catalysts in the Valorization of Citronellal

“…An efficient synthesis of OHAs starts from citronellal and N-arylamines [13,14] (Scheme 2). This Lewis-acid catalyzed imino Diels-Alder reaction is the most atom-economic way to OHAs, with high yields and, in some cases, high stereoselectivity.…”

Heterogeneous Catalysts for the One-Pot Synthesis of Chemicals and Fine Chemicals

“…[58][59][60] Particularly, 1,2,3,4,4a,9,9a,10-octahydroacridines (Scheme 6) are compounds of pharmacological interest due to their activity as gastric acid secretion inhibitors. 61,62 Among the different methodologies described for the synthesis of the OHA skeleton, the most atom-economic process, is the twostep Lewis acid catalyzed reaction involving the reaction between an unsaturated aldehyde and an aniline derivative forming the corresponding imine (an azadiene) followed by hetero-Diels-Alder cyclization (Scheme 6) [58][59][60] giving the corresponding OHA in high yields, and in some cases 100% stereoselectivity. However, the main drawbacks of this approach are the long time required, low temperatures, expensive Lewis acid, and the use of hazardous organic solvents.…”

Highly Diastereoselective Synthesis of New trans-Fused Octahydro­acridines via Intramolecular Cationic Imino Diels–Alder Reaction of N-Protected Anilines and Citronellal or Citronella Essential Oil

“…Another diastereoselective approach involves control of the reaction temperature at 0 °C to obtain almost exclusively the trans isomer in very high yields when anilines and citronellal were used. 15 Further modifications to the imino Diels-Alder reaction include the use of ionic liquids and trifluoroethanol as catalyst and solvent simultaneously, 3,16,17 glycerol as reusable solvent, 18 and microwave irradiation over solid supports; 19 all of these routes afford the desired products in a cis/trans ratio close to 1:1.…”