200,000+ products from a single source!
sales@angenechem.com
Home > Practical and Scalable Organic Reactions with Flow Microwave Apparatus
Practical and Scalable Organic Reactions with Flow Microwave Apparatus
1.Introduction
Since the pioneering works on microwave-assisted organic reactions reported by Gedye and Giguere in 1986,[1] various types of organic reactions have been actively investigated under microwave conditions.[2] Most applicators used in the initial stage were modified domestic microwave ovens. Subsequently, microwave applicators specialized for chemical synthesis, which are equipped with small scale batch reactors and temperature and pressure control functions, have been developed and are commercially supplied. Nowadays, micro- wave irradiation is authorized as an alternative option for raising the reaction temperature and accelerating the reaction. In contrast to conventional external heating methods that use oil baths, heating blocks, and other apparatus, the microwave heating method enables direct and rapid heating of substrates and solvents to achieve a more uniform heating profile.[2,3] Although microwave irradiation is effective to accelerate the reaction at high temperatures, microwave- assisted synthesis is quite difficult to scale up because of microwaves’ limited penetration depth (e.g. about 1 cm in water at 258C, 2.45 GHz)[3] and limited irradiation power. The straightforward method for the scale-up of microwave reactions is to use a large multimode microwave applicator, although more microwave irradiation power is necessary for elevating the reaction temperature.[4] On the other hand, the stop-flow system recently emerged as an alternative method.[5] In this system, the reaction mixture is automatically pumped into the microwave vessel. The reaction is carried out under microwave irradiation, the product mixture is pumped out from the vessel, and the vessel is cleaned up.
Continuous flow chemistry has attracted much attention from the viewpoint of manufacturing technology, as it is expected to improve safety, reduce energy consumption, and be scalable by protraction of the reaction time.[6] Taking into account the advantage of flow synthesis, the combination of microwave heating and continuous flow technology is expected to overcome the drawback of microwave synthesis.[7] In 1990, Wang and co-workers examined the fundamental organic reactions with their flow microwave applicator composed of a domestic microwave oven.[8] Strauss realized microwave organic reactions under high temperature and pressure conditions using a flow microwave system equipped with a pressure control valve and a monitoring unit of temperature and pressure.[9] Subsequently, some unique systems were developed and their utility in organic and inorganic synthesis was examined.[10]
In parallel, the microwave-to-flow concept reviewed by Kappe, which represents transferring batch microwave reac- tions to continuous flow syntheses with conventional heating methods, has also been investigated.[11] For this purpose, micro- or mesofluidic reactors are normally utilized, because the heat transfer of these reactors is rapid due to a high surface-to-volume ratio. Although this method has been proven to be beneficial in some organic reactions, the scalability is limited owing to the small inner diameter of the reactors.
To overcome these issues, it seems practical to use a tubular reactor with a much larger diameter for microwave heating, since the microwave can penetrate at least 1 cm and heat the reactants and solvent directly without heat transfer from the exterior. Therefore, merging microwave heating with a thick flow reactor would allow for the scale-up of microwave-assisted synthesis. However, a uniform heating profile should be realized in the thick tubular reaction vessel, a technology for which was developed by our research collaborators of SAIDA FDS. They constructed a bench-top flow microwave reactor that uses a much larger reaction vessel compared to standard microreactors (vide infra), the details of which are described in a separate Personal Account by Barham and Yoshimura.[12] To materialize the scale-up of microwave-assisted synthesis, we have investigated some organic reactions using the SAIDA flow microwave appara- tus.[13] In this Personal Account, we summarize our results of scalable microwave-assisted flow synthesis, including new results.
2.Flow Microwave Apparatus
2.1.Features of the Flow Microwave System
The bench-top apparatus for microwave-assisted flow syn- thesis consists of a microwave generator, a resonant cavity (8 cm 3 8 cm 3 20 cm), a helical tubular borosilicate glass reactor (i.d. 3.6 mm, internal volume in the resonant cavity: 5.2–6.2 mL, see: Figure 1b), a pumping system, and a control device (Figure 1a). In particular, highly efficient microwave irradiation can be achieved by generating a uniform electro- magnetic field in its resonant cavity, which makes use of a solid-state device for telecommunications. This is the key to achieving quick and fine adjustment of the irradiation frequency, according to the changes in the electric permittiv- ity of the reaction mixture. This device produces up to 200 W output in a frequency ranging from 2.4 to 2.5 GHz. The flow system is equipped with a backpressure regulator next to the reaction vessel in order to maintain the pressure of the reaction mixture at up to 2.5 MPa. The irradiation power, reflected power, electric field in the cavity, temperature of the reaction mixture at the exit of the reactor (a thermocouple is set inside the helical tube reactor) and the pressure of the reaction mixture are monitored and controlled in real time. All these components are compactly assembled in the space of 160 cm 3 60 cm 3 60 cm.
If the pressure reaches higher than 3.0 MPa or the reaction temperature exceeds 3008C, the microwave applica- tor automatically stops for safety. In addition, the release valve works to decrease the pressure if the pressure becomes accidentally higher than 3.4 MPa. The reaction vessel is coated by a heat shrinkable tube made of a polytetrafluoro- ethylene tubular film and is set in the resonant cavity made by an aluminum alloy A5052 (thickness = 10 mm). There- fore, even in case of the breakage of the reactor, scattering of glass pieces and splashing of the reaction mixture are prevented. Leakage of microwave radiation was measured by ETS-LINDGREN Microwave Survey Meter HI-1501 and the power density was confirmed to be less than 1 mW/cm2 at every position that is within 5 cm from the surface of the microwave applicator.
2.2.Heating Profile of Various Solvents
The temperatures inside the reactor when running common organic solvents were examined under identical conditions (backpressure 2.5 MPa, irradiation power 200 W, flow rate 20 mL/min, reaction vessel: 5.2 mL) (in Table 1). During their passage through the reactor in approximately 16 seconds, all solvents, except for toluene, were heated at higher temperatures than their boiling points under atmospheric conditions. It is likely that the heating profile of each solvent is somewhat related to its boiling point under atmospheric conditions, which is not achieved during external heating. Based on the exit temperature, the solvents examined can be classified into the following four groups: 1) 100–1108C, hydrocarbons such as n-hexane and toluene; 2) close to 1508C, aprotic less polar solvents such as ethyl acetate (EtOAc) and cyclopentyl methyl ether; 3) 180–2008C, protic solvents such as alcohols and acetic acid (AcOH); and 4) above 2108C, aprotic polar solvents such as N,N-dimethyl formamide (DMF) and dimethyl sulfoxide (DMSO). These data are in accordance with the characteristic feature of microwave heating, i.e. the heating profile depends on the physicochemical property of the solvent. It is also worth noting that many solvents were heated to over 1508C in only 16 seconds (residence time) with an irradiation power of 200 W and at a flow rate of 20 mL/min. Again, this rapid heating is achievable owing to the inherent feature of microwave irradiation as well as the quick and fine adjustment ability of this apparatus to generate a uniform electromagnetic field in its resonant cavity.
3.Organic Reactions with Flow Microwave Apparatus
3.1.Fischer Indole Synthesis[13a]
The indole framework can be found in various naturally existing products and important bioactive compounds.[14] Therefore, synthetic methods of indole derivatives were well investigated, and Fischer indole synthesis is one of the most reliable methodologies for the construction of the indole unit.[15] Rapid Fischer indole synthesis has been achieved under microwave irradiation conditions,[16] and continuous flow microwave systems have also been applied to Fischer indole synthesis.[10c,l,17]
To confirm the synthetic utility of the SAIDA flow microwave apparatus, we selected the Fischer indole synthesis as a test reaction (Figure 2, reaction vessel: 5.2 mL). A 1.0 M solution of cyclohexanone (1) in an AcOH (solution A) and a
1.1 M solution of phenylhydrazine (2) in MeCN (solution B) were separately pumped into the reactor at the same flow rate via a mixer installed just before the reactor. The conditions varied in terms of the flow rate of the mixed solution (13– 17 mL/min) and the irradiation power (130–190 W). Each reaction was evaluated using the GC yield of 1,2,3,4- tetrahydro-1H-carbazole (4) measured after the exit temper- ature reached a steady state (Figure 3a). We found that higher yields of 4 were obtained, as the exit temperature became higher. At the same flow rate, a better yield of 4 was obtained by increasing the irradiation power; however, the reaction mixture began to boil at around 2408C, though the BPR was set at 2.5 MPa.
Interestingly, when the concentration of solutions A and B was doubled (2.0 M of solution A and 2.2 M of solution B), higher temperatures and higher yields were achieved compared to the reaction using 1.0 M of solution A even
under the same conditions in terms of the flow rate and irradiation power (Figure 3a and b). These phenomena indicate that the substrates (1 and 2) and/or intermediate 3 absorb microwaves more effectively than MeCN, which may arise from the characteristic feature of direct heating of the compounds by microwave irradiation.
Having established the optimum reaction conditions for the continuous production of 4, we next examined a 100 g scale synthesis. Continuous operation was conducted by pumping a 2.0 M solution of A and a 2.2 M solution of B at a constant rate (total flow rate of 15 mL/min), maintaining the exit temperature at around 2408C, not to exceed the boiling point of the reaction mixture. Consequently, as much as 115 g of 4 was produced during a 1 h operation (75 % yield based on 1). Recently, Mase and Takeda further optimized this reaction using comprehensive reaction analysis and demonstrated higher productivity.[18]
3.2.Biginelli Reaction
Multicomponent reactions to produce complex molecules from simple substrates have been well investigated to shorten the steps of the synthesis. A three-component reaction between an aldehyde, a b-ketoester, and urea to generate dihydropyrimidinone derivatives is called the Biginelli reac- tion. The Biginelli reaction was originally reported in 1893[19] and has been utilized for the synthesis of various bioactive compounds.[20] Since an acid is required to promote this reaction, various Brønsted acids and Lewis acid catalysts have been examined to improve the reaction efficiency.[21] While microwave irradiation has also been applied to the Biginelli reaction,[22] its application to flow continuous system is still rare.[23]
We tried to operate the Biginelli reaction of benzaldehyde (5), methyl acetoacetate (6), and urea (7) using the flow microwave apparatus (Table 2, reaction vessel: 6.0 mL). Toluene sulfonic acid (TsOH) was chosen as an acid catalyst, because the reaction efficiency decreased when other acids, such as AcOH, were used. To dissolve 7 at a higher concentration, MeOH was used as a solvent. Solution C of 5 and 6 (4.25 M) and solution D of TsOH and 7 (2.83 M) were pumped into the reaction vessel in a 2 : 3 ratio, and the final concentrations of all substrates were set at 1.7 M in the reaction vessel (Figure 4). When 5 and 7 were dissolved in the same solution, the corresponding aminal between 5 and 7 precipitated out, which prohibited the desired flow continu- ous operation. This reaction mixture absorbed microwave efficiently, so that the reaction mixture was heated at 1458C quite readily with only 43 W (entry 2). Both the reaction temperature and the reaction time had an effect on the reaction efficiency and their balance seemed to determine the productivity (entries 2–4). With a higher amount of TsOH and higher microwave irradiation power, a maximum yield of 58% yield was obtained at a flow rate of 2.8 mL/min. In this case, the productivity of the reaction step was calculated to be 40 g/h.
200,000+ products from a single source:
© 2019 Angene International Limited. All rights Reserved.