(46b) Investigation into the Preparation of Synthetically Useful a-Aminonitriles Under Continuous Flow

Abstract: Building on an array of synthetic transformations reported within micro fabricated systems, we present an evaluation of a borosilicate glass micro reactor, suitable for conducting multi-component reactions. Introduction: With interest in the preparation of non-proteinogenic ?Ñ-amino acids growing, there are increasing demands for novel and efficient techniques that enable the synthesis of such non-naturally occurring compounds. Although many synthetic procedures have been reported, few are suitable for the incorporation of alkyl imine substrates, often resulting in low yields and selectivities. One synthetic approach however is the Strecker reaction, which as Scheme 1 illustrates is a Lewis acid-catalysed three-component reaction between an aldehyde, amine and a cyanide source. The resulting ?Ñ-aminonitrile is then hydrolysed and deprotected, providing a viable synthetic route to an array of non-natural amino acids. In addition, the reaction also provides a useful route to diamines, imidazoles and thiaimidazoles. Although the Strecker reaction has been shown to be suitable for aliphatic imines, the use of expensive Lewis acid catalysts, harsh reaction conditions, extended reaction times and the somewhat variable yields (due to competing cyanohydrin formation (Scheme 2)) all make this route undesirable. With these factors in mind, it is proposed that by conducting the multi-component reaction within a single, integrated micro reactor, continuous flow operation will enable increased reaction efficiency, affording an array of ?Ñ-aminonitriles in both excellent yield and purity. In the first step towards this goal, a general procedure for the synthesis of aliphatic imines and the subsequent nucleophilic addition of CN- is described, along with the synthesis of 25 ?Ñ-aminonitriles. Experimental: As Figure 1 illustrates, the borosilicate glass micro reactor (3.0 cm x 3.0 cm x 0.6 cm) employed consisted of a °¥T' intersection at which the aldehyde and amine are introduced and reacted within a central channel (150 ?Ým (wide) x 50 ?Ým (deep) x 4.5 cm (long)) to afford the respective imine. Subsequent introduction of the cyanide source, in this case TMSCN, enables the reagents to pre-mix (over 4.5 cm) prior to reaction within the packed bed (0.25 cm (wide) x 300 ?Ým (deep) x 2.1 cm (long)), containing polymer-supported ethylenediaminetetraacetic acid ruthenium (III) chloride (PS-RuCl3) or scandium trifluoromethanesulfonate (PS-Sc(OTf)2) (Figure 2), where nucleophilic addition of CN- to the imine occurs, affording the desired ?Ñ-aminonitrile. Results and Discussion: Prior to evaluating the performance of the micro reactor for a multi-component reaction, the reaction conditions required to enable efficient imine synthesis were firstly investigated. To achieve this, solutions of amine (1.0 M in MeCN) and aldehyde (1.0 M in MeCN) were introduced from separate inlets into the micro channel network, under pressure-driven flow (5.0 to 100.0 ?Ýl min-1), where they were reacted for a designated period of time prior to off-line analysis by GC-MS. Employing the optimal reaction conditions, the pre-formed imines (0.5 M) were subsequently mixed with TMSCN (1.0 eq.), passed through a packed-bed of PS-RuCl3 (at 5.0 ?Ýl min-1) and collected at the outlet. In the case of benzyl-(4-bromobenzylidene)-amine, evaporation of the reaction solvent afforded benzylamino-(4-bromophenyl)-acetonitrile as a pale yellow solid (throughput 0.03 mmol hr-1), analysis of the resulting compound by NMR confirmed product purity (Figure 3). Although this result demonstrated the ability to perform multi-component reactions under continuous flow, it was desirable to increase the productivity of the reactor, consequently a second Lewis acid catalyst was evaluated. As Table 1 illustrates, compared to the previous system PS-Sc(OTf)2 was found to be a more active catalyst, affording quantitative conversions at double (10 ?Ýl min-1) the optimal flow rate previously obtained, affording a throughput of 0.06 mmol hr-1. Consequently, all subsequent investigations were performed using PS-Sc(OTf)2 and as summarised in Table 2, the methodology was successfully extended to the synthesis of 25 ?Ñ-aminonitriles in excellent yield and purity, affording the synthesis and characterisation of 10 previously unknown compounds. Conclusions: As described herein, initial steps have been taken to develop an integrated micro reactor capable of performing multi-component reactions consisting of both solution phase and polymer-assisted steps. Future work will therefore concentrate on the extending the investigation to the reaction of aliphatic aldehydes and the synthesis of ketoimines.