The chemical synthesis of a plethora of molecular structures remains a central objective in the study and exploitation of their properties. Over the last decades focus has shifted towards improving the sustainability of such synthesis campaigns in view of resourcefulness, cost efficiency and waste avoidance [1,2,3]. Crucially this approach encompasses academic and industrial chemists alike aiming to introduce more atom and step economic routes to yield desired products. The choice of solvents and reagents thereby plays a key role in designing improved syntheses, and guidelines towards better sustainability are commonly exploited today [4]. In addition to replacing undesirable reagents and solvents several strategies are employed to improve process metrics and provide for greener chemical synthesis. These may include the use of bioderived solvents such as 2-MeTHF or cyrene [5, 6] as well as a variety of biorenewable chemical building blocks such as carbohydrates and amino acid derivatives [7]. In addition, transition metal-based catalysts can often be replaced by enzymes that are non-toxic and biodegradable [8]. Recent years have furthermore witnessed an uptake of modern enabling technologies to bring about the cleaner and oftentimes more efficient synthesis of target compounds. Amongst these, continuous flow chemistry plays an important part as its advantages over batch synthesis directly address challenges commonly faced in the fine chemical industry. As such flow chemistry offers improved heat and mass transfer through reactor miniaturisation which leads to small footprint systems whose modular configuration provides for additional flexibility [9]. Modern flow reactors have been developed with integrated in-line analysis [10] and purification [11] tools to facilitate the safe and automatable operation of synthetic sequences providing robust access to numerous structures of interest for academic and industrial applications. Unsurprisingly, flow technology has been exploited for the use of biorenewable building blocks [12] and biocatalysts [13] leading to many attractive applications as reviewed recently. Whilst these efforts are ongoing, new approaches are much needed to relinquish our dependence on petrol-based commodities and realise advances towards a fully sustainable chemical workflow.

As part of our interest in developing effective and environmentally attractive entries into drug-like heterocyclic targets, we have previously reported on using carbohydrates to prepare thioimidazole derivatives (3) via the Marckwald multicomponent reaction (MCR) [14] as well as the flow-based desulfurisation of these structures yielding drugs such as the analgesic etomidate and its analogues [15]. More recently, we described a bio-based route towards various cinnolines (7) and dihydrocinnolines (9) [16] via reaction of glucose with phenyl hydrazine. In this current work we wish to report on a flow-assisted approach for the preparation of phenyl glucosazone 6 which is an attractive building block for the azide-free synthesis of functionalised 1,2,3-triazoles, specifically the less explored 2-phenyl-1,2,3-triazole scaffold (8, Scheme 1).

Scheme 1
scheme 1

Use of carbohydrates towards drug-like heterocycles

Phenyl glucosazone (6) is formed when reacting glucose with an excess of phenyl hydrazine in the presence of acid at elevated temperature. This material has long been known amongst carbohydrate chemists and its formation can be used as a test for carbohydrates due to the intense yellow colour of this insoluble product [17]. The condensation reaction features the formal oxidation of the glucose scaffold leading to two phenyl hydrazone moieties embedded in the glucosazone structure [18] (6, Scheme 1) for which mechanistic rationales have been reported [16, 19]. In addition to generating glucosazone in good yields of 40–50%, a small portion of a cinnoline side-product (7, ca. 20%) can be isolated in these reactions which has been derivatised into valuable cinnoline building blocks as outlined in our earlier works [16]. Amongst the synthetic uses of glucosazone itself, its oxidative transformation into 2-phenyl-1,2,3-triazoles stands out. This process became a focal point in one of our recent efforts aimed at generating this type of heterocycle via a carbohydrate-based route that would not necessitate the use of azides or other unstable nitrogenous building blocks. Upon scaling the glucosazone forming reaction in batch mode to decagram quantities we noticed issues due to stirring of the viscous reaction mixture which resulted in prolonged reaction times and a tedious work-up protocol necessitating multiple washes of the solid product which required large amounts of solvent. Seeking a more efficient process that would not suffer from these limitations, we turned to continuous flow processing as small reactor set-ups can be exploited at scale through continuous operation which would avoid the handling large inventories of material at any given time.

Results and Discussion

Our study commenced by selecting an appropriate reactor set-up that would facilitate the formation of the solid glucosazone product in a continuous manner. To minimise risks of reactor blockages, we opted to use wider tubing (PFA, 2.4 mm ID, 15 mL) that was coiled and submerged into a heated water bath. Collection of the crude product was achieved in a glass bottle without using a backpressure regulator. A Vapourtec E-series flow module in combination with peristaltic pumps was used for all subsequent flow experiments (Scheme 2).

Scheme 2
scheme 2

Set-up of initial flow optimisation studies

Initially, we opted to use the same stoichiometries (phenyl hydrazine/glucose 3.3:1 molar ratio, 0.5 M wrt glucose) as employed in prior batch experiments (Table 1, entry 1). Upon passing the reaction mixture through the heated reactor coil (maintained at 85 °C) a colour change from light brown to yellow was noted which was accompanied by formation of a yellow solid within 20 min. Interestingly, the solid did not form uniformly within the tubing but instead nucleation and bridging was observed [20]. This led to built-up of solid material inside the coil and eventually caused blocking after ca. 1 h. To reduce the risk of reactor fouling by blocking, the concentration of the stock solution was reduced from 0.5 M to 0.15 M. This was effective as the formation of solid product was delayed and the suspended material could be pumped through the set-up without further problems. However, the isolated yield was modest indicating that dilution of the mixture slowed down product formation (entry 2). To resolve this, we opted to increase the residence time from 30 to 45 min (entry 3) keeping all other parameters as before. Though this increased the yield slightly, this approach would reduce the reaction throughput. Therefore, it was decided that a slightly increased concentration would be beneficial when using higher residence times (entry 4). This set of conditions initially proved effective; however, some solid product was retained in the tubing indicating that reactor fouling and pressure built-up would eventually become an issue. These results indicated that a lower concentration was needed to mitigate fouling, yet slow flow rates would at the same time favour settling of particles as well as bridging. To increase mixing and at the same time avoid settling of the solid product, we next trialled a segmented flow approach whereby the stock solution containing glucose (1 equiv.), phenyl hydrazine (3.3 equiv.) and acetic acid (5.8 equiv.) in water was combined with a stream of air using the peristaltic pumps of our flow set-up. This segmented flow regime would firstly provide for micro-mixing via Taylor flow [21], and secondly would introduce oxygen which would facilitate the oxidative step in the glucosazone formation (i.e., oxidation at C2).

Table 1 Summary of flow optimisation studies

Several experiments with different flow rates of the two streams (substrate solution and air) quickly revealed that this approach was effective and that equal flow rates provide for a stable slug flow pattern. Problems via product sedimentation and blockages were avoided due to the biphasic system allowing for increased concentrations which generated the desired glucosazone product in acceptable yield (entry 5). To improve this further a larger reactor coil (30 mL, 2.4 mm ID) was constructed to provide for longer residence times of the liquid phase whilst maintaining high flow rates. Under the optimised conditions (45 min residence time, 85 °C) a 4 h run was performed under steady state conditions which gave the desired product in a high yield of 53% without reactor blockages. Isolation of the pure glucosazone product was achieved by simple vacuum filtration and did not require additional washes as experienced in the scaled batch experiments.

Having developed an efficient access to the glucosazone building block we next evaluated its conversion to 2-phenyl-1,2,3-triazoles via an oxidative cyclisation process. Different literature reports highlight that both copper(II) sulfate [22] and manganese dioxide [23] can be used as stoichiometric oxidants at elevated temperature. Our own batch studies confirmed this and showed a preference for the copper(II) sulfate system as the alternative required careful quench of the strongly acidic reaction mixture (sulfuric acid/MnO2). Heating the heterogeneous reaction mixture at reflux for 3 h thus gave the desired triazole species in high yield (Scheme 3). This product was initially obtained as a brown powder along with an embedded red solid which we assigned to be CuO. Recrystallisation from diethyl ether yielded the desired triazole material as an off-white powder. Using an acetone/water solvent system provided suitable single crystals to verify the structure of this product via X-ray diffraction studies [24]. With multigram quantities of this material at hand we studied its conversion to the corresponding aldehyde species 10 using NaIO4 which was uneventful [22]. This aldehyde product is a valuable drug-like building block that can easily be derivatised into other materials exploiting the aldehyde moiety as exemplified by its reaction with Meldrums acid. The resulting condensation product was isolated in high chemical yield and its crystalline nature allowed for confirmation of the structure and connectivity of the triazole core via single crystal X-ray diffraction experiments [24].

Scheme 3
scheme 3

Route from phenyl glucosazone to 2-phenyl-1,2,3-triazole building blocks 8, 10 and 11


In summary, a continuous flow approach was developed for the generation of phenyl glucosazone from glucose and phenyl hydrazine in the presence of acetic acid. Reactor fouling and blockage was initially observed due to the insolubility of the reaction product that adhered to the reactor surface. To prevent reactor fouling, a slug flow approach was trialled whereby a stream of air was mixed with the reaction mixture and pumped through the heated reactor coil (85 °C). This was met with success generating the phenyl glucosazone target in high yield during a scale-up run (4 h, 53%, 4.5 g isolated). This material was subsequently transformed into a 2-phenyl-1,2,3-triazole core via a CuSO4-mediated oxidative cyclisation. Further diol cleavage using NaIO4 rendered a valuable triazole carbaldehyde building block on multigram scale that can be subjected to aldol condensation processes.