Synthesis of Venlafaxine from Azadiene via a Hetero-Diels-Alder Approach: New Microwave-Assisted Transketalization and Hydroxymethylation Reactions

Abstract

Hetero-Diels-Alder (HDA) methodology has been applied to the synthesis of Venlafaxine taking advantage of a novel MW-assisted transketalization and hydroxymethylation reaction.2-Azadienes 1 have been demonstrated to be versatile intermediates in hetero-Diels-Alder (HDA) reactions 2 with aldehydes to furnish perhydroxazin-4-ones. The latter have been utilized for the production of the 1,3-hydroxyamino moiety, or skeleton, of different biologically active compounds and of important chiral auxiliaries/ ligands in asymmetric organic synthesis. 3 In the course of our studies on these interesting intermediates, we have reported on the preparation of biologically active CNSdrugs, Prozac and Duloxetine, in racemic and optically pure form as well, presenting a scaffold of an 1,3-aminol unsubstituted in the 2-position and a secondary hydroxy functionality. 4 In this paper we report our attempts to apply this strategy to the synthesis of (±)-Venlafaxine (1) 5 characterized by the presence of a substituent (4-methoxyphenyl group) in the 2-position of the 1,3-aminol skeleton ( Figure 1) and a tertiary hydroxy functionality. The importance of 1 resides in the fact that, among a large number of chemical structures found to exhibit antidepressant activity with diminished cardiovascular and anticholinergic liability, this compound has been proven to be the most potent antidepressant agent and has been approved by the drug agencies of many countries for the treatment of depression thanks to its faster onset of action and increased efficiency. From synthetic point of view, the choice of this particular target was dictated by our attempts of rendering the HDA protocol, developed in our laboratories, suitable for the preparation of a library of variably functionalized compounds presenting the 1-hydroxy-3-amino functionalities with or without further substitutions in the backbone chain identified by 1,3-aminol moiety and using as carbonyl-dienophile a ketone. Previous results showed that perhydroxazin-2-ones may be prepared from an 2-aza-1,3-diene variably substituted in the position 1 but unsubstituted in position 4, and a ketone as dienophile, including hindered ones such as menthone. 6 These results were very interesting since the poor reactivity of ketones compared to aldehydes in heteroDiels-Alder reactions is well known, owing to both steric and electronic reasons. As a matter of fact, until recently, only a very few examples of HDA reactions of ketones have been reported. 7 Having in hand this information, we started our studies by preparing the intermediate azadiene 4 from (4-methoxyphenyl)acetyl chloride (2) and the trimethylsilylbenzaldimine 3 according to an existing protocol 1a,8 (Scheme 1).

Schiff Bases: A Short Survey on an Evergreen Chemistry Tool

“…They have been found synthetic applications in the last few decades as relatively stable analogues of the corresponding Schiff bases. Their elaborations to azadiene have been fully explored by the Barluenga [60,61,62], Ghosez [63,64] and Panunzio groups [65,66,67,68,69]. Generally speaking, they are monomeric compounds reasonably stable under anhydrous conditions.…”

Hetero‐Diels–Alder (HDA) Strategy for the Preparation of 6‐Aryl‐ and Heteroaryl‐Substituted Piperidin‐2‐one Scaffolds: Experimental and Theoretical Studies

“…[1][2][3][4] In this area, we and other research group [5][6][7][8][9] have been interested in the use of functionalized azadiene system 1 (Scheme 1) for the preparation of heterocyclic compounds, such as β-lactam rings, by a two-step Staudinger reaction, [10][11][12] as well as tetramic acid scaffolds, [13] perhydrooxazin-2-ones, cyclic intermediates in the synthesis of α-amino β-hydroxy acids, [14,15] β-hydroxycarboxylic acids, [16] and 1,3-aminols, through a hetero-Diels-Alder (HDA) approach. [17][18][19][20] Some processes have been performed by taking advantage of microwave-assisted organic synthesis (MAOS) technology. [21][22][23] More recently, the HDA-approach has been used for the synthesis of conhydrine, which is a poisonous alkaloid present in Conium maculatum and characterized by a piperidine scaffold.…”