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Cite this: Org. Biomol. Chem., 2014, 12, 4594 Received 6th May 2014, Accepted 22nd May 2014

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Towards aryl C–N bond formation in dynamic thin films† Michael N. Gandy,a Colin L. Raston*b and Keith A. Stubbs*a

DOI: 10.1039/c4ob00926f www.rsc.org/obc

C–N bond forming reactions are important in organic chemistry. A thin film microfluidic vortex fluidic device (VFD) operating under confined mode affords N-aryl compounds from 2-chloropyrazine and the corresponding amine, without the need for a transition metal catalyst.

The development of useful methodologies in organic chemistry is fundamental to finding new and more efficient ways to prepare targeted molecules for biological and materials applications. An area of intense research is in developing new bond-forming reactions, notably in forming C–N bonds which are common in nature, including in natural products, and in synthetic compounds. Indeed, many drugs and drug candidates contain C–N bonds1 and therefore the development of efficient, cheap, scalable and environmentally friendly methods to form such synthons is of growing importance. Flow chemistry involving microfluidic platforms is gaining attention as a paradigm for the controlled synthesis of organic molecules.2–9 Most of these platforms use conventional microfluidics where the liquid is confined within channels, under laminar flow conditions, and where scaling up of the reactions requires arrays of such channels.4 Other microfluidic platforms instead function by passing liquids over rotating surfaces, where the dynamic thin films generated are typically under turbulent flow conditions.6,9 Here scaling up is achieved by simply running the same microfluidic platform for longer times under the same conditions. We recently developed a thin film microfluidic vortex fluidic device (VFD), which is an efficient platform for preparing organic molecules, in controlling chemical reactivity and selectivity.6,10,11 The VFD is also effective in a number of other scientific endeavours, including the top-down and bottom-up syntheses of nanomaterials,12–14 highlighted for example in a School of Chemistry and Biochemistry, The University of Western Australia, Crawley, WA 6009, Australia. E-mail: [email protected] b School of Chemical and Physical Sciences, Flinders University, Bedford Park, SA 5042, Australia. E-mail: [email protected] † Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ob00926f

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the exfoliation of graphene from graphite15 and the synthesis of superparamagnetic nanoparticles,16 controlling the formation of calcium carbonate polymorphs,17 room temperature synthesis of mesoporous silica,18 and the disassembly of self organised systems.19 These applications of the VFD relate to the device delivering a constant form of ‘soft’ mechanoenergy within dynamic thin films,6 rather than more intense forms of mechanoenergy, for example sonication and ball milling. Within a VFD a tube is rotated at high speed to generate a centrifugal force, and if it is tilted above the horizontal orientation (>0° tilt angle) then the ensuing thin film experiences shearing forces for which the intensity thereof depends on the various operational parameters. This includes the diameter of the tube which is typically a 10 mm6,10–19 or 20 mm18 diameter NMR tube. The shear forces act on the liquid contained in the tube when operating in either the confined mode, which is for a finite volume of liquid, or the continuous flow mode of operation.6 For the former the liquid flow is upwards at the internal surface of the rotating tube, and downwards close to the liquid surface (Stewartson/Ekman layers).15 For the continuous flow mode, jet feeds direct reacting liquids to the base of the tube. Here there is intense uniform micro-mixing with additional shear associated with the viscous drag as the liquids whirls along the tube. Thus, the VFD facilitates both scaling up under continuous flow mode, and small scale synthesis typically encountered at the research level, in the confined mode, with the latter featuring in the present study, for a 10 mm diameter tube. In addition, the confined mode lends itself to robotic control for scaling up for a large number of sequential reactions of small aliquots of a reacting liquid. We report on the use of the VFD in forming C–N bonds for a variety of different amines reacting with 2-chloropyrazine as an archetypal aryl halide (Scheme 1). This work is part of a program towards developing more efficient and alternative synthetic protocols for targeted organic reactions using the VFD, where the intense shear ensures that the reactions are beyond diffusion control. Typically, the formation of aryl C–N bonds is achieved using nucleophilic aromatic substitution-based chemistry,20

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Scheme 1 (A) General palladium-catalysed reaction of 2-chloropyrazine and organic amines. (B) Model reaction for investigating the utility of the VFD in avoiding the use of a transition metal catalyst.

Ullmann-type couplings21 and more recently Buchwald– Hartwig-based conditions,22 with the latter being by far the most efficient. Given the high cost of palladium and recent push toward greener syntheses, and with the products being devoid of trace amounts of any metal catalyst,23 recent efforts have highlighted some C–N bond forming reactions that avoid the use of transition metal-based catalysis. Our attention was drawn to the known C–N bond forming reaction involving 2-chloropyrazine and an amine, which typically involves palladium-mediated catalysis (Scheme 1), but where the use of palladium has been avoided, although this uses potassium fluoride24 which is potentially an issue in avoiding the use of toxic reagents and glass etching material. A significant development would be to ascertain whether this chemistry could be undertaken in the VFD, which circumvents the inefficient mixing and heat transfer associated with traditional batch processing.6 Furthermore, batch processing often has limitations with respect to the yield, scalability, reproducibility from one batch to another, and the nature of the protocol involved, for example the order of addition of the reagents. In the first instance, we chose to study the coupling of 2-chloropyrazine and morpholine in the confined mode of operation of the VFD as a model reaction, given that this reaction could be directly compared to the aforementioned batch method.24 For this mode of operation of the VFD the shear at high speed arises from the cross vector of centrifugal force and gravity.15 At the outset, our general procedure involved using the VFD at standard operating conditions (7000 rpm, 45° tilt angle6) to couple 2-chloropyrazine and morpholine in the presence of aqueous K2CO3 solution at 100 °C for 12 h. Gratifyingly, the yield of the reaction was 62%, which is consistent with that found in the literature when conducted at the same temperature, but importantly the time to achieve this yield was reduced dramatically, by 35%. With this result in hand we attempted to further investigate whether the processing time could be reduced, as well as ascertaining if there were any effects from using different bases. A selection of bases was chosen that had differing characteristics and we used two reaction times (6 and 12 hours). We found that the best base was K3PO4 with the yield of 64% using the standard operating

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Fig. 1 Variation in isolated yield for the reaction between 2-chloropyrazine and morpholine when varying the choice of base, for the VFD operating at 7000 rpm, and a tilt angle of 0°, at 100 °C for 12 hours. All reactions were conducted in triplicate with the average shown. Errors were within ±3%.

conditions, but the time required for maximum yield was still 12 hours (Fig. 1). A unique feature of the VFD is that variation in the rotational speed and angle of inclination is possible and importantly, changing these parameters have been shown previously to affect the outcome of organic reactions. This relates to the presence of different angular and speed dependent shear regimes.6,10,11 Indeed, in this work the systematic variation of rotational speed and tilt angle greatly affected the yield (Fig. 2). Changing the tilt angle for a specific rotational speed affected the yield in line with previous observations for other organic reactions6,10,11 with lower speeds also generally giving better outcomes. Overall, optimal conditions for this reaction favour lower rotational speeds, which translates to thicker films of liquid in the tube, noting that the average liquid film thickness for 1 mL of solvent in the 10 mm NMR tube inclined at 45° and rotating speed at 7000 rpm is ca. 230 μm whereas at 3500 rpm it is ca. 450–230 μm.6,15 In previous studies, a tilt angle of 45° where the cross vector of gravity and centrifugal

Fig. 2 Variation in isolated yield for the reaction between 2-chloropyrazine and morpholine when varying the rotational speed and tilt angle of the VFD. The optimisation procedure used aqueous K3PO4 solution at 100 °C for 12 hours. All reactions were conducted in triplicate with the average shown. Errors were within ±3%.

Org. Biomol. Chem., 2014, 12, 4594–4597 | 4595

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Table 1 Synthesis of various alkylaminopyrazines using the VFD operating at 3500 rpm and 45° tilt angle at 100 °C for 12 h in confined mode. Literature yields for the batch reaction conducted at 100 °C, for 17 h using aqueous KF as base are shown in brackets24

Published on 23 May 2014. Downloaded by Vanderbilt University on 12/10/2014 21:27:06.

Entry

Product

Isolated yield (lit. yield)24 (%)

1

76 (70)

2

91 (76)

3

78

4

82 (52)

5

9

6

74

7

81 (81)

8

55

9

12

10

29

11

20 (28)

12

32

13

38 (47)

14

55 (58)

force is at a maximum, results in higher conversions relative to other tilt angles ≤75°.6,15 In the present case, for lower speeds ca. 3500 rpm and a tilt angle of 60° and 30° resulted in similar

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yields to that observed at 45° (Fig. 2). At higher speeds (7000 rpm), a 60° tilt resulted in the highest yield, which is dramatically different relative to a 30° tilt. This demonstrates that the choice of tilt angle and speed is important in optimising specific reactions on the VFD. Other reactions thus far studied include Diels–Alder reaction,6,11 condensation of phenols with aldehydes in forming calixarenes,10 and sequential aldol condensation and Michael addition reactions.6 With suitable reaction conditions established, we sought to explore this system further to prepare a series of alkylaminopyrazines. In all cases the yields were comparable to literature preparations of respective compounds, but achieved in a considerably shorter time, and avoiding the use of KF (Table 1). We note that the use of continuous flow mode of operation of the VFD was limited as the lowest practical flow rate (0.1 mL min−1) deliverable by the jet feeds does not afford sufficient residence time to complete the reaction. In conclusion, we have established a novel method for the synthesis of alkylaminopyrazines using a VFD operating in the confined mode. The yields of the compounds can be controlled by varying the rotational speed and tilt angle of the tube in the VFD, with a reduction in reaction time. Moreover, this is without the addition of a transition metal catalyst, and the scene is now set to explore the utility of the VFD in avoiding the use of a catalyst for a plethora of chemical reactions. Also of note is that the operating parameters of the VFD are more specific for a particular reaction, in judgement relative to earlier studies, and it appears different shear rates effect different reactions in different ways and this will feature in further research. The fluid dynamics in the VFD are inherently complex for tilt angles >0° and

Towards aryl C-N bond formation in dynamic thin films.

C-N bond forming reactions are important in organic chemistry. A thin film microfluidic vortex fluidic device (VFD) operating under confined mode affo...
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