A rapid flow strategy for the oxidative cyanation of secondary and tertiary amines via C-H activation

An efficient continuous flow protocol has been developed for bond C-H activation which promotes the α-cyanation of secondary and tertiary amines using magnetic nano-ferrites.


Synthesis and characterization of catalyst
Magnetic nano-ferrites (Fe 3 O 4 ) were synthesized according to reported methods 26 and further characterized by X-ray powder diffraction (XRD), scanning electron microscope (SEM), energy dispersive X-ray analysis (EDX) and X-ray photoelectron spectroscopy (XPS). The XRD (Fig. 1) and SEM (Fig. 2) confirmed the formation of single-phase Fe 3 O 4 nanoparticles. The presence of iron further supported by XPS ( Figure S2) and EDX ( Figure S3).

Results and Discussion
The magnetic nano-ferrites (Fe 3 O 4 ) were then employed for C-H bond activation and resulting cyanation of amines in a 1/16″ (i.d. 0.8mm and 10m in length) stainless steel coiled tube flow reactor (5.03mL total internal dead volume). The coil reactor is totally immersed in a Paratherm ® NF mineral oil bath. The oil bath was set upon a magnetic hot plate and continuously stirred to maintain a uniform temperature. The temperature attained by the oil bath facilitates efficient heating of the coiled reactor allowing transfer of heat via a thin film of reaction mixture flowing within the coiled tube. This allows for the reaction mixture (i.e., thin-film), coupled with the nano-ferrite catalyst, to rapidly attain the needed the reaction's activation energy. The reaction mixture was pumped through the pre-heated coil via the inlet port using a peristaltic pump. This facilitated not only the lateral movement of the reaction mixture within the heated reaction zone, but also creates a consistent and well-mixed reaction fluid within the reactor. The reaction output was then collected at the exit port.   Several experimental trials for the cyanation of N, N-dimethylaniline were performed to establish optimized reaction conditions. All reactions were conducted in the presence of magnetic nano-ferrites (Fe 3 O 4 ) by varying temperature and flow rate respectively (Table 1, entries 1-15). A reaction mixture was first prepared by dissolving N, N-dimethylaniline in a water and methanol solution (1:1 ratio). Further, 25mg of Fe 3 O 4 catalyst, NaCN (1.1 mmol) and 30% (aq) hydrogen peroxide (1 mmol) were added (Fig. 3). This mixture was then pumped through the coil reactor at room temperature and ambient pressure. Several reactions were performed at the room temperature while varying the flow rate (and subsequently the residence time) ( Table 1, [13][14][15]. Upon optimizing the reaction conditions, the scope of the reaction was explored using a variety of tertiary and secondary amines ( Table 2, entries 1-6). Importantly, the presence of an electron withdrawing (e.g. bromo group on ortho-and para-position; Table 2, entries 2-3) and an electron donating group (e.g. methyl group on ortho-and para-position; Table 2, entries 4-5) did not affect the reaction rate and delivered the full conversion to desired products.
A plausible mechanism has been proposed for the oxidative cyanation of amines wherein the reaction follows an oxidative and reductive mechanism. Iron (II), 1, reacts with H 2 O 2 leading to the formation of reactive oxo-iron (IV) species, 2 which subsequently reacts with a tertiary amine to give an iminium ion, 4. This intermediate, 4, reacts with in-situ generated HCN and delivers the corresponding α-aminonitrile (Fig. 4) 19 .

Conclusions
Magnetic nano-ferrites coupled with a continuous flow reactor provides a protocol that has been used to arrive at a more sustainable approach for the synthesis of α-aminonitriles via C-H activation. This efficient method generates the desired products in less than 10 min of reaction. This strategy offers major improvements over previously reported methods which often require longer reaction times and higher temperatures rendering it more attractive in term of efficiency and ease of synthesis. Moreover, this approach is further simplified as the nano-ferrites can be easily separated using external magnet upon completion of the reaction. The recycled nano-ferrites can then be reused again without any demonstrated loss of its catalytic activity (Supplementary Information). Therefore, qualitatively speaking in terms of costs and energy, the developed protocol is more appealing and is an improved alternative over the conventional methods for the C-H activation.
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