Iron-catalyzed reductive strecker reaction

Highlights

• A new method to access amino acetonitriles using FeI₂ catalyst.

• Better yields obtained than the use of Ir- or Rh-catalysts.

• One pot synthesis of ¹³C-labelled amino acetonitriles from ¹³C-CO₂.

• Successful application toward modular synthesis of acids, amines, heterocycles, etc.

Abstract

Strecker reaction is widely applied for the synthesis of amino acids from aldehydes, amines and cyanides. Herein, we report the FeI₂-catalyzed reductive Strecker type reaction of formamides instead of aldehydes to produce amino acetonitriles. The challenging capture of carbinolamine intermediates by CN⁻ was achieved via Fe catalysis. This approach afforded better yields than the use of Ir- or Rh-catalysts. The application ability of this methodology is demonstrated by 1) one-pot construction of (¹³C labeled) complex molecules from CO₂ via amino acetonitrile intermediates and 2) convenient production of homologated carboxylic acids from aldehydes.

Introduction

The Strecker reaction is a well-known practical synthetic method for α-aminonitriles, widely used for the preparation of amino acids [1]. The classical Strecker reaction described by the German chemist Adolph Strecker (1822–1871) in 1850, and makes use of aldehydes, amines and hydrogen cyanide as starting materials (Fig. 1a) [2]. Notably, the reaction of formaldehyde with ammonia and cyanide to form amino acids is believed to be the essence of the origin of life [3]. Alternatively and unprecedentedly, substitution of formaldehyde reactant with formamides instead in the presence of reductants, Strecker-type products amino-acetonitriles (AANs) could be generated (Fig. 1b). The challenge is how to rationally design the catalyst and suppress the over-reduction of the active iminium/carbinolamine intermediates.

Aminoacetonitrile is used as the key intermediate to many herbicide and pharmaceuticals. Molecules with at least two functional groups are highly valuable and generally used for diverse syntheses of polymeric materials and bio-active products [4]. Accordingly, AANs are recognized as versatile intermediates in organic synthesis, and can readily be transformed into numerous valuable products such as amino acids, α-amino alcohols, α-amino carbonyl compounds, nitrogen containing thiadiazoles and imidazoles heterocycles [5]. Besides, AANs can easily form carbanion species through C-H deprotonation to give the key intermediate formaldehyde iminium ion with cyanomethyl group regarded as the amine protecting group [6]. Hence, AANs are amenable to further transformation with their structural motif prevalent in an array of transformation with their structural motif prevalent in an array of natural products, pharmaceuticals and drug candidates such as Balicatib, Luliconazole, Girgensohnine (Fig. 1c) [7]. As a consequence, selective construction of amino acetonitriles has received considerable attention in recent years.

Other than the traditional methods via substitution reaction of organic halides, transition-metal-catalyzed direct cyanation of C-H bonds by oxidative cross dehydrogenative coupling methods has emerged as an attractive approach to AANs derivatives [8]. Notable reported examples feature metal-based catalysts such as Ru [9], Fe [10], V [11], Au [12], Mo [13] and metal-organic frameworks [14], in the presence of oxidants O₂, H₂O₂, or TBHP. Furthermore, AANs derivatives have also recently been obtained under photochemical conditions [15]. However, these procedures involve excess use of oxidants and often have problems of limited chemo-selectivity and functional-group tolerance.

Straightforward procedures to prepare AANs derivatives using readily available and more stable starting materials are highly desirable. Recent progress in the reductive cyanation of amides into AANs derivatives has been demonstrated as ideal pathway albeit challenging [16]. Sato group [17] and Huang group [18] have developed cyanations of tertiary amides employing stoichiometric amounts of activating agents (eg. Tf₂O/2-F-Py or [Cp₂ZrHCl]/TFA). Dixon group [19] and Adolfsson group [20] reported the elegant synthesis of α-amino nitriles from tertiary amides catalyzed by IrCl(CO)[P(C₆H₅)₃]₂ (Vaska’s catalysts) and Mo(CO)₆, respectively. Moreover, Huang and co-workers reported the reductive functionalization of secondary amides catalyzed by [IrCl(COE)₂]₂ [21]. However, in these cases, the efficiency for the reactions of formamides was not explored or rather limited [19].

On the other hand, the use of CO₂ as C1 synthon holds promise for sustainable synthesis. Generally employed methods rely largely on the use of organometallic species [22] (Grignard reagents, organoboron, organolithium and organozinc reagents), reductants [23], and unsaturated compounds [24]. These methods exploit the electrophilicity of CO₂ to successfully, prepare alcohols, carboxylic acids and derivatives as well as cyclic compounds [25]. More recently, nucleophilic radical anion CO₂ was generated as key intermediate in photo/electrochemical reductive transformations [26]. Nevertheless, these strategies were mainly based on one-step linear synthesis and only one type of functional group was introduced in the final product. Converting CO₂ into valuable complex molecules is still challenging.

To the best of our knowledge, there is no report on general reductive Strecker cyanation of CO₂-derived formamides to amino acetonitriles. It is well recognized that ligand association and dissociation from metal centers involves significant change in the metal’s coordination sphere. As part of our continuing efforts on transition-metal-catalyzed cyanation reactions and CO₂ utilization [27], we describe here FeI₂-catalyzed reductive cyanation of formamides with TMSCN to access AANs products. Using iodide as the ligand showed unexpected substrate reactivity and selectivity for Fe(II)-catalyzed reductive Strecker reaction of formamides.