High-Pressure

Article pubs.acs.org/OPRD

Continuous Flow Synthesis under High-Temperature/High-Pressure Conditions Using a Resistively Heated Flow Reactor Ahmed Adeyemi,† Joakim Bergman,‡ Jonas Brånalt,‡ Jonas Sav̈ marker,§ and Mats Larhed*,∥ †

Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, Uppsala Biomedical Center, §The Beijer Laboratory for Drug Discovery, Department of Medicinal Chemistry, Uppsala Biomedical Center, ∥Department of Medicinal Chemistry, Science for Life Laboratory, Uppsala Biomedical Center, Uppsala University, P.O. Box 574, SE-751 23 Uppsala, Sweden ‡ Department of Medicinal Chemistry, Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Pepparedsleden 1, Mölndal, 431 83, Sweden S Supporting Information *

ABSTRACT: A cheap, easy-to-build, and effective resistively heated reactor for continuous flow synthesis at high temperature and pressure is herein presented. The reactor is rapidly heated directly using an electric current and is capable of rapidly delivering temperatures and pressures up to 400 °C and 200 bar, respectively. High-temperature and high-pressure applications of this reactor were safely performed and demonstrated by selected transformations such as esterifications, transesterifications, and direct carboxylic acid to nitrile reactions using supercritical ethanol, methanol, and acetonitrile. Reaction temperatures were between 300 and 400 °C with excellent conversions and good to excellent isolated product yields. Examples of Diels−Alder reactions were also carried out at temperatures up to 300 °C in high yield. No additives or catalysts were used in the reactions.

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INTRODUCTION Continuous flow (CF) synthesis has evolved into a very important tool in modern organic and pharmaceutical chemistry.1−3 The unique advantages offered by flow chemistry compared to batch process reactions have the potential to simplify modern organic synthesis. These advantages include faster reactions, controlled and quicker optimization, cleaner products, in-line monitoring, and ease of scale up.1−5 Moreover, flow chemistry enables the safe handling of reactions that involve explosive and toxic intermediates.5−8 Active pharmaceutical ingredients (APIs) have also been synthesized using continuous flow, further underlining the importance of flow chemistry.3−5 The applicability of flow chemistry can be put down to its ability to meet different and challenging reaction conditions. Thus, the type and applicability of a CF system are dependent on specific reaction conditions. In handling different reaction temperatures, CF reactors have been reported which employ water baths, oil baths, heating mantles, microwave heating, and even gas chromatography ovens (GC ovens), as heat sources.2,9−12 The choice of a heating methodology is sometimes dictated by the temperature limit attainable.1 A water bath is unsuitable for reactions above 100 °C. An oil bath is inappropriate at temperatures above 300 °C due to its low convenience, slow heating rate, and safety concerns.13 Microwave (MW) systems and GC ovens have been reported as heating sources in CF for temperatures up to 350 °C.14,15 However, MW heating is limited to MW absorbing reaction mixtures or reactors, while temperature control in GC ovens can be time-consuming with respect to the rate of heating and cooling. The number of flow systems that handle reactions above 300 °C are limited despite the advantages offered by hightemperature and high-pressure conditions.8,16b,c The few available systems are expensive and require a degree of © 2017 American Chemical Society

expertise to operate. Heat transfer is an important consideration when using CF synthesis at high temperatures. Effective heat transfer between the heat source and the reactor is necessary to attain the temperature inside the reactor, except in the case of MW heating with MW transparent reactors. One heating option that is suitable for high temperature and pressure is the application of direct resistive heating. Direct resistive heating involves the use of the electrical resistance in the reactor itself to generate heat. Kunz and co-worker reported a directly heated CF reactor, albeit operational at a lower temperature than the commercially available reactors.13 The heating rates were remarkably higher than by using a GC oven as heat source. An indirect conductively heated batch reactor was also recently reported by Obermayer and co-workers.17 They were able to demonstrate a batch reactor operational at temperature up to 250 °C and 20 bar using indirect conductive heating. Overall, compared to the traditional batch heater, the resistively heated CF reactors may offer a promising alternative for organic synthesis.11,13,14,16a,18 We have previously reported on systems that use microwaves as a heating method in CF synthesis.15a We have also reported on the use of MW-heated silicon carbide reactors to overcome the problem of metal precipitation, hotspot formation, and reactor failures in metal-catalyzed reactions.15c The success of the silicon carbide reactors has prompted us to develop simpler systems that can provide direct heating to the reactor, with cheaper materials. Herein we present a CF reactor, directly heated by electric resistance, capable of delivering temperatures up to 400 °C and pressures up to 200 bar. Safety concerns and cost issues are addressed, with solutions proffered with the resistively heated CF reactor. The resistively heated reactor is Received: February 27, 2017 Published: June 15, 2017 947

DOI: 10.1021/acs.oprd.7b00063 Org. Process Res. Dev. 2017, 21, 947−955

Organic Process Research & Development

Article

Figure 1. Schematic overview of the resistively heated CF reactor system. A potential difference is applied between two ends of the steel reactor. The power source regulates the voltage applied. A thermostat (in orange) sits on the reactor is connected to the power supply to regulate and record temperature relative to the current and voltage input. The power supply is capable of up to 320 W (maximum current of 20 A and maximum voltage of 42 V). Backpressure regulator (BPR) controls the pressure and is capable of providing up to 200 bar pressure.

Figure 2. Photographs of the 6 mL resistively heated CF reactor (left) with a potential difference created by the two wires (black and red) connected to the two ends of the reactor. On the right is the 6 mL CF reactor placed in an insulated casing to minimize temperature loss during experiments.

Figures 1 and 2). Direct current was passed through the coil using a direct current (DC) power source. The power source used is capable of supplying a current of 20 A and voltage of 42 V and generating a maximum power output of 320 W. One open end of the resistively heated reactor is connected to a standard liquid chromatography (LC) pump using capillary tubing. The other end is attached to a backpressure regulator (BPR) which is then linked to a collection outlet. Pressure is controlled by the BPR that is connected to the exit end of the reactor, and the processed liquid is collected after the BPR. The BPR used in this study has been previously reported in earlier works within our group.15 It is water cooled when attached to the resistively heated CF reactor and capable of maintaining a pressure of up to 200 bar within the reactor. The temperature of the reactor was measured by connecting a thermostat to the top end of the reactor coil. The thermostat was then coupled to the power source so that it can be controlled by the voltage input. This allowed for precise temperature control by regulating the current and voltage (see Figure 1) and subsequent rapid heating of the reactor. The reactor was placed in an insulated enclosure to minimize heat loss. When the reactor is operational, a closed system is in place, with an insulated lid covering the insulated enclosure

relatively cheap and energy-efficient. Three high-temperature transformations that involve supercritical ethanol, methanol, and acetonitrile were selected to validate the reactor effectiveness in esterification, transesterification, and direct conversion of carboxylic acids to nitriles, respectively. Furthermore, a Diels−Alder reaction involving electrondeficient dienophiles was successfully carried out at high temperatures using the resistively heated CF reactor.

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RESULTS AND DISCUSSION Reactor Design. We set out to design a low-cost, simple, robust, and effective CF reactor using a material suitable for high temperature and high-pressure. In addition, the material had to be chemically inert and resistant to corrosion over a reasonable period. The reactor should also be easily replaceable, preferably at lower expense relative to other similar CF reactors designed for high temperature and pressure conditions. Steel was an obvious material of choice as it fulfilled the aforementioned requirements, especially the ability to withstand temperatures up to 400 °C and pressure up to 200 bar. A steel coil with both ends open was thus constructed (6 mL volume). A potential difference was created at the two ends of the coil by connecting opposing charges to both ends (see 948



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Figure 3. Heating rate with acetonitrile passing through the system. A thermostat located near the exit of the reactor recorded temperature according to Figures 1 and 2.

shown in Figure 2. Once the target temperature is reached, very little oscillation was observed around the set temperature (maximum 5 °C). Initial tests to investigate the heating rate with organic solvents flowing through the directly heated flow system showed the heating rate was about 100 °C/min. The tests were conducted with three different solvents: methanol, ethanol, and acetonitrile flowing through the reactor at a constant flow rate of 0.5 mL/min. The reactor was heated from room temperature to 400 °C using the maximum power input of about 320 W in less than 5 min. The results for acetonitrile shown in Figure 3 are similar to the results obtained with the other two solvents: methanol and ethanol flowing through the reactor. Cooling rates were also measured by disconnecting the power supply and removing the reactor insulators. Cooling from 400 to 100 °C was done in 4 min at room temperature without external cooling devices. Further cooling from 100 °C to room temperature took an extra 6−10 min across all three solvents. The rapid heating and cooling rates are important in optimization reactions requiring temperature control “on the fly”. This rapid heating is of great importance in CF reactor design. As these CF reactors are designed for frequent usage, replacement should be possible. Precipitation within the reactor can also necessitate the need for reactor replacement. Steel tubings are commercially available at relatively low cost and can be cut into desired length (volume). Creating a potential difference on the reactor to generate heat is simple and can be easily done. The size of the reactor and the required temperature influences the amount of voltage/current applied. The larger the size of the reactor, the higher the required input of voltage/current needed to heat the reactor. Similarly, the reactor size also influences the heating and cooling rates. Reactors with smaller sizes tend to heat up and cool down at a faster rate than larger sized reactors. This can be particularly useful in optimization studies that require rapid heating and cooling. This set up allows for great flexibility as the system will accept various dimensions (volumes) of the reactor coil. A 6 mL coil reactor was fabricated and used in all reactions reported in this paper. The residence time of a CF process is a function of the flow rate (in mL/min) and the volume of the reactor. However, as this system was designed for high temperature and high

pressure usage, it was important to take into account solvent expansion and higher diffusion rate that occur at high temperature. The effect of solvent expansion and diffusion of reagents within the reactor were taken into consideration by estimating the average residence time of reactants within the reactor. This was investigated using three test solvents: methanol, ethanol, and acetonitrile, using benzoic acid as a test substrate. Benzoic acid was dissolved in each test solvents and passed through the reactor at different temperatures. The residence time was determined by spotting the output on a thin layer chromatography (TLC) paper and recorded to the nearest 30 s. It was discovered that, relative to room temperature, there was a 2-fold decrease in residence time at 300 °C, while the residence time decreased up to four-fold at 400 °C (see SI for data). For a reaction in ethanol with a flow rate of 0.5 mL/min in a 6 mL resistively heated CF reactor, the residence times were estimated as 6 and 3 min if the reactions were carried out at 300 and 400 °C, respectively. There was no solvent expansion observed when toluene was used as the solvent. Validation of the Resistively Heated Reactor. Supercritical Solvent Reactions. One class of chemical processes that can best demonstrate the advantages of high temperature and pressure are reactions involving common solvents at supercritical states. Ethanol, methanol, and acetonitrile reach supercritical states at temperatures between 250 and 400 °C, at pressures above 70 bar.19 At supercritical state, these solvents exhibit properties not obtainable at ambient temperatures. Hence, we decided to investigate reactions involving supercritical ethanol, methanol, and acetonitrile using the resistively heated reactor system. These reactions do otherwise require the use of additional reagents or catalysts to be carried out at lower temperatures. The time taken to react under supercritical conditions is also remarkably decreased.14,16a Supercritical Ethanol. Esterification. Ethanol attains supercritical state when compressed to pressures above 65 bar and heated above 250 °C.19,20 The previous use of supercritical ethanol in high temperature CF synthesis was reported for the catalyst free transformation of carboxylic acids to the corresponding ethyl esters in good yields.16a This reaction class has been extensively utilized for biodiesel production on an industrial scale.21 Previously reported esterification of benzoic acid using supercritical ethanol was done at 300 °C and 100 bar.16a We attempted to achieve these 949



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acts as a nucleophile rather than an inert solvent that it is at room temperature. These properties are utilized in the transesterification reactions of supercritical methanol. As with supercritical ethanol, this direct transesterification reaction can be important in late stage functionalization in organic synthesis.16a Ethyl-3-phenylpropanoate 3a was chosen as test compound, having being previously reported in similar transesterification reaction to its methyl ester 4a (Table 3).16a With temperatures at 400 °C and pressure up to 180 bar, this experiment afforded a chance to assess the effectiveness as well as the safety and ease of handling of the resistively heated CF system at extreme conditions. Using the same resistively heated CF reactor and procedures as in earlier esterification reactions, the conversion and yield of transesterification reaction was investigated at different temperatures and residence times. The results are presented in Table 3, with isolated yield recorded for the highest conversion entries only. In all compounds examined, improved conversion (and yield) was observed at higher temperatures. The decomposition of starting material or products inside the reactor was not observed, from the high yields and 1H NMR data. The yields were generally higher than the supercritical ethanol esterification reactions. As the flow rate was kept constant, the residence time decreased with increasing temperature. This decreased residence time did not however affect conversion or isolated yield. Ethyl esters 3a, 3b, and 3d gave isolated yields of 90% and above at 400 °C. Other substrates such as benzoic anhydride 3c and allyl ester 3e also gave good conversions and isolated yield at 400 °C (Table 3, entries 3 and 5). Supercritical Acetonitrile. Direct Conversion of Carboxylic Acids to Nitriles. Supercritical acetonitrile is attained at temperatures above 275 °C and 48 bar.23 Chemical reactions utilizing supercritical acetonitrile have previously been reported.23 The direct conversion of carboxylic acids to nitriles is yet an additional example of a valuable high temperature and pressure organic transformation.14 As a further test of reactor capabilities at elevated temperature and pressure, the reaction was attempted using the resistive heated CF reactor. As previously observed by Kappe, the residence time could not be directly estimated from the flow rate and reactor volume since solvent expansion of acetonitrile within capillary reactor at supercritical conditions was experienced.14 In our case, acetonitrile expansion between 250 and 350 °C and 100 bar was between 1.7 and 3 fold (see SI). This was taken into consideration in estimating the residence time reported in Table 4. The conversion of 2-methoxybenzoic acid 5a to its corresponding nitrile 6a was attempted using the 6 mL resistively heated reactor (Table 4). The pressure was kept constant at 100 bar. As there are no easily distinguishable protons between the starting acid and product, characterization and conversion estimation by 1H NMR were avoided. GC-MS analysis was selected for characterization and conversion estimation, using naphthalene as an internal standard. Naphthalene was chosen as internal standard due to its stability at temperatures between 300 and 400 °C.24 Temperature and residence times were investigated, and the results are presented in Table 4. The most productive conditions were found to be 0.25 mL/min at 350 °C (entry 6). The results obtained were similar to results previously reported using a GC-oven powered CF systems.14 Conversion recorded using the resistively heated CF reactor was slightly better (100% vs 98%) than that achieved when a GC-oven

supercritical conditions as a test of our newly build CF reactor. Using the resistively heated CF reactor, steady state parameters were reached by pumping absolute ethanol through the reactor at the desired temperature and pressure for about 10 min. The flow rate and temperature were used for the estimation of residence time as earlier discussed, thus taking solvent expansion at high temperature in the 6 mL CF reactor into consideration (see SI). Benzoic acid, 1a, was dissolved in absolute ethanol to make a solution of concentration 40 mg/mL. The solution was pumped into the reactor under different conditions as depicted in Table 1. By collecting a known volume of eluent, the reacting Table 1. Effect of Temperature and Residence Time on the Esterification of Benzoic Acid to Ethyl Benzoate Using Supercritical Ethanol in a Resistively Heated CF Reactor

entry

temperature (°C)

flow rate (mL/min)

residence timea (min)

conversionb (%)

yieldc (%)

1 2 3 4 5 6

300 300 300 325 350 375

1.0 0.5 0.25 0.5 0.5 0.5

3 6 12 6 4 4

55 85 84 79 90 100

51 82 74 71 76 40

a

The residence time is reported after adjusting for solvent expansion at supercritical conditions. bConversion is reported as the percentage of carboxylic acid that was transformed and estimated by 1H NMR. c Isolated yield. The purity of isolated product in all instances was more than 95% as estimated by NMR.

mass can be calculated as the concentration was kept constant. The isolated yield for benzoic acid esterification (Table 1) is similar to the yield reported with similar reaction using a commercially available flow system.16a Conversion was determined by 1H NMR, quantitatively from the percentage of carboxylic acid reacted to ethyl ester formed. Pressure was maintained at 120 bar, and concentration was constant throughout the experiment. The highest yield was achieved at 300 °C and in 6 min (flow rate 0.5 mL/min). Increasing the temperature or lowering the flow rate did not give higher yield, although conversion was marginally improved. Increasing the temperature above 300 °C was unfavorable for the esterification, as can be seen in Table 1. At 375 °C, entry 6 in Table 1, the extensive decomposition of the benzoic acid was detected, an observation previously seen by Kappe et al.14,16a The reaction scope was further investigated with additional carboxylic acids (Table 2), and similar good yields were generally observed. The flow rate was kept at 0.5 mL/min which translates to a residence time of 6 min, after considering solvent expansion at 300 °C. Derivatives of benzoic acid such as carboxylic acids 1b, 1c, and 1d were converted to their corresponding esters in good yield at 300 °C. Other heterocyclic carboxylic acids such as furan-3-carboxylic acid 1f and thiophene-3-carboxylic acid 1g gave low conversion at 300 °C, but near full conversion at 350 °C. Supercritical Methanol. Transesterification Reactions. Methanol reaches a supercritical state when compressed to about 140 bar, at temperatures above 300 °C.22 At this state, the nucleophilic properties of methanol are enhanced, and it 950



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Table 2. Scope of Esterification Reactions Using Different Carboxylic Acids and Supercritical Ethanol in a Resistively Heated CF Reactorb

a The isolated yield is recorded in which purity was over 95% as determined by 1H NMR. bConditions: a 6 mL reactor was used. The flow rate was 0.5 mL/min. Residence time is reported after adjusting for solvent expansion at supercritical conditions.

powered CF reactor was used. The isolated yield was however lower with the resistively heated CF reactor (82% vs 98%), although 82% yield was achieved in shorter residence time with the resistively heated system (8 min vs 25 min). Although increasing the temperature resulted in increased transformation, there was no corresponding increase in isolated yield. Increasing the residence time also increased the conversion, but 350 °C was preferred to minimize compound decomposition. N-Heterocyclic nitriles are valuable intermediates in medicinal chemistry projects, often used in cyclization reactions to form heterocycles.25 Due to low solubility of some Nheterocyclic carboxylic acids in acetonitrile, N-methyl-2pyrrolidone (NMP) was used as a cosolvent (up to 20% v/ v). Acetylpiperidyl carboxylic acid 5c was selected to investigate the effect of cosolvents on the direct conversion of carboxylic acids to nitriles using supercritical acetonitrile. The best conditions for the conversion to nitrile when using NMP as cosolvent were investigated, and the results are presented in Table 5. We decided to quantify the outcome as a ratio of the product peak to that of the internal standard. The reaction was still clean, with only the peaks of the cosolvent, product, and/or starting material observed in most cases. In these test situations, the conversion of the carboxylic acids to nitriles was quite high, above 85% in all instances. The isolated yields were, however, below 65%, in contrast to the over 75% observed with non N-heterocyclic nitrile 6a.

Having identified appropriate CF conditions for the conversion of 5c to 6c with NMP as a cosolvent, the transformation was further screened with different carboxylic acids. In all compounds listed in Table 6, there was a conversion of over 90% observed. The isolated yields of 6 with aromatic and aliphatic carboxylic acid starting materials were between 77% to 85% in entries 1, 2, 6, and 7. However, the outcome was lesser for N-heterocyclic nitriles 6c, 6d, and 6e (entries 3−5). Some N-heterocyclic carboxylic acids such as pyrrole-based acids preferentially gave the decarboxylative elimination products (not included). High-Temperature Diels−Alder Reactions. As a further validation of the reactor, Diels−Alder cyclizations were carried out at elevated temperature. The reaction of diene 7a with electron-deficient dienophile 8a has been reported to take 5 days to completion at 100 °C and 20 min at 250 °C with microwave heating.26 The reaction (residence) time was further reduced to 2 min using CF processing at 280 °C and 130 bar. We investigated this reaction using the resistively heated CF reactor at different temperatures and flow rates (Table 7). The pressure was kept constant at 90 bar, and no catalysts or additives were used in the reaction. Unlike ethanol, methanol, and acetonitrile, solvent expansion was not noticed in toluene. The flow rate was directly translated to the residence time within the reactor by using the reactor volume (6 mL). The results shown in Table 7 show that the conversion of the diene 7a to cyclohexyl 9a increased with increasing temperature and 951



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Table 3. Scope of Transesterification To Form Methyl Esters Directly Using a Resistively Heated CF Reactor

a c

Time is reported as the residence time after adjusting for solvent expansion at supercritical conditions. bConversion was estimated using 1H NMR. Isolated yield is recorded for the highest conversion entries only, and the purity was over 95% as determined by 1H NMR.

reducing flow rate (increasing residence time). Full conversion to the cyclized product 9a was achieved at 200 °C with a residence time of 6 min (entry 4, Table 7). By using the hightemperature performance of the system, it was possible to reduce the residence time to 2 min at 300 °C (entry 5, Table 7), with full conversion. The transformation was also repeated with dienophile 8b, and similar results were obtained (Scheme 1). However, the transformation was slower than the reaction in Table 7, and full conversion was obtained after 6 min at 300 °C, with a slightly higher yield.

reactor were safely performed and demonstrated by selected transformations such as esterifications, transesterifications, and direct carboxylic acid to nitrile reactions using supercritical ethanol, methanol, and acetonitrile. Diels−Alder reactions were also safely done at 200−300 °C, providing high yields. Although, applying direct current to a reactor raises safety concerns, the insulated enclosure minimizes contact and prevents heat loses. This CF reactor stands out particularly for its rapid heating rate, even up to 400 °C. The cooling rate is also rapid, and its ability to heat and cool safely is impressive. Residual solvent volume of up to 6 mL can be contained in the reactor at a particular time. The connection of the heater with a thermostat enables high process control, even at high temperatures. In addition, bypassing a secondary heat transfer minimizes the power required. The current and voltage applied is enough to heat up the reactor, while also unlikely to trigger electrochemical reactions. In summary, the resistively heated reactor is a viable option for CF synthesis over a range of temperature and pressure conditions. The simplicity to assemble and the user friendliness

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CONCLUSION We have demonstrated a highly effective, yet simple flow system suitable for organic synthesis requiring conditions up to 400 °C and 200 bar. Assembling the resistively heated CF reactor is considerably cheaper and easier than alternative reactors with similar efficiency. The material used for the reactor is readily available and replacement and cleaning easily done. High-temperature and high-pressure applications of this 952



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flow conditions. Carboxylic acid (1.20 g) was dissolved in 30 mL of absolute ethanol to get a 40 mg/mL reaction mixture. The reaction mixture was ultrasonicated for 15 min to get a completely homogeneous solution. Reaction conditions such as temperature and pressure were preset on the resistively heated CF system. Absolute ethanol was first pumped through the system at a flow rate of 0.5 mL/min until steady state (ca. 15 min). The reaction mixture was then pumped into the resistively heated reactor at the preset flow rate. The collection of the processed solution was started after processing of 10 mL following constant pumping in of the carboxylic acid. Some of the product mixture (0.5 mL) was collected, dried with N2, and analyzed for conversion. The conversion of the carboxylic acid to ethyl ester was estimated from the ethyl ester protons ratio using 1H NMR. Processing was continued, and 10 mL of the processed mixture was collected and dried in vacuo. The processed mixture was then dissolved in 15 mL of ethyl acetate and washed twice with saturated Na2CO3 (10 mL). The organic phase was dried with Mg2SO4 and concentrated in vacuo to get the crude product, needing no further purification. The ethyl ester formed was then characterized by NMR. General Procedure 2. Transesterification reactions were completed using supercritical methanol under continuous flow conditions. The starting ester (1.20 g) was dissolved in 30 mL of laboratory grade methanol to get a 40 mg/mL solution (unless otherwise stated). The solution was ultrasonicated for 15 min. Reaction conditions such as temperature and pressure were preset on the flow system. Methanol was pumped through the system at the desired flow rate until steady state was reached (ca. 15 min). The starting ester solution was then pumped into the resistively heated reactor at the desired flow rate. The collection of the processed solution was started after processing of 10 mL following constant pumping in of the starting ester. Some of the processed solution (0.5 mL) was collected, dried with N2, and analyzed for conversion. The conversion of the starting material was estimated from the methyl ester formation using 1H NMR. Processing was continued, and 10 mL of the processed solution was collected and dried in vacuo to afford the methyl ester. The methyl ester formed was characterized by NMR, with purity over 95%, thus needing no further purifications. In instances where purity was below 95%, purification by column chromatography was carried out. General Procedure 3. The direct conversion of carboxylic acids to nitriles was completed using supercritical acetonitrile under continuous flow conditions. Carboxylic acid (0.30 g) was dissolved in 30 mL of acetonitrile to get a 10 mg/mL solution. The solution was ultrasonicated for 15 min. Reaction conditions such as temperature and pressure were preset on the flow system. Acetonitrile was first pumped through the system at the desired flow rate until steady state was reached (ca. 15 min). The acid solution was then pumped into the resistively heated reactor at the desired flow rate. Collection of the processed solution was started after processing of 10 mL following constant pumping in of the carboxylic acid. Processing was continued, and 10 mL of the processed solution was collected and dried in vacuo. The product was then dissolved in 15 mL of ethyl acetate and washed twice with saturated Na2CO3 (10 mL). The organic phase was dried with Mg2SO4 and concentrated in vacuo to get the crude product, needing no further purification.

Table 4. Direct Transformation of 2-Methoxybenzoic Acid 5a to Nitrile 6a Using Supercritical Acetonitrile in a Resistively Heated CF Reactor

entry

temperature (°C)

flow rate (mL/min)


conversionb (%) [isolated yield]

1 2 3 4 5 6 7

250 300 325 350 350 350 375

0.5 0.5 0.5 0.5 1.0 0.25 0.5

8 6 6 4 2 8 4

49 76 74 82 66 100 [82]c 100

a

The residence time is reported after adjusting for solvent expansion at supercritical conditions. bConversion is reported as the percentage of carboxylic acid that reacted. It was determined from the ratio of nitrile product to carboxylic acid peak areas in the GC-MS. cThe isolated yield is recorded in which purity was over 95% as determined by 1H NMR.

Table 5. Direct Conversion of 1-Acetylpiperidine-4carboxylic Acid 5c to Nitrile 6c Using Supercritical Acetonitrile and NMP as a Cosolvent in a Resistively Heated CF Reactor

entry

temperature (°C)

flow rate (mL/min)


conversionb (%)

product/ internal standardc

1 2 3 4 5 6 7 8 9 10

250 250 300 300 325 325 350 350 375 375

0.5 0.25 0.5 0.25 0.5 0.25 0.5 0.25 0.5 0.25

8 16 6 12 6 12 4 8 4 8

86 91 92 98 98 99 100 100 100 100

0.24 2.23 2.16 2.81 3.02 3.24 3.38 [63%] 3.36 3.36 3.32

a

The residence time is reported after adjusting for solvent expansion at supercritical conditions. bConversion is determined by GC-MS, with naphthalene as an internal standard. cThe relative yield was quantified as a ratio of the product to internal standard.

of the resistively heated reactor makes it a promising alternative for continuous flow synthesis in both academia and industry. More so, the resistively heated CF reactor system can potentially be used in demonstrating CF synthesis in educational and research establishments. Overall, a robust, easy-to-use, cheap, fast, and effective continuous flow reactor has been presented and validated for high-temperature and high-pressure reactions.

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EXPERIMENTAL SECTION General Procedure 1. The esterification of carboxylic acids was completed using supercritical ethanol under continuous 953



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Table 6. Conversion of Carboxylic Acids to Corresponding Nitriles Using Supercritical Acetonitrile

Residence time was estimated by adjusting the flow rate with solvent expansion at high temperature (see SI for detailed information). bThe yield is reported as isolated yield with a purity over 95% according to NMR. a

Table 7. Effect of Temperature and Residence Time on the Diels−Alder Reaction between Diene 7a and Dienophile 8a in the Resistively Heated CF Reactora

entry

temperature (°C)

flow rate (mL/min)

residence time (min)

conversionb (%)

1 2 3 4 5

100 200 200 200 300

1 3 2 1 3

6 2 3 6 2

0.3 10 85 100 [87]c 100 [84]c

Scheme 1. Diels−Alder Reaction with Butyl Acrylate Carried out in 6 min Using the Resistively Heated CF Reactor

Where N-methyl pyrillidone (NMP) was used as a cosolvent, the workup procedure was slightly changed. In this case, 10 mL of processed product was collected and dried in vacuo. The product was then dissolved in 20 mL of ethyl acetate and washed twice with saturated sodium carbonate. The organic phase was further washed with brine until NMP was removed (5−7 times). The organic phase was dried with Mg2SO4 and concentrated in vacuo to get the crude product. The nitrile formed was analyzed by NMR. For nitriles 6a and 6c, some of the processed product (0.1 mL) was collected and dissolved in dichloromethane (DCM). GC-MS analysis was carried out to

a

The pressure was kept constant at 90 bar. bConversion is reported as the percentage of diene that reacted. It was determined from the ratio of proton alpha to nitrile group in 9a to allylic protons in the diene. c The isolated yield is recorded in which purity was over 95% as determined by 1H NMR.

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establish the conversion. Conversion was estimated from the peak area, with naphthalene used as an internal standard. General Procedure 4. A Diels−Alder reaction was completed under continuous flow conditions. 2,3-Dimethyl1,3-butadiene (3.3 g, 40 mmol) and dienophile (80 mmol, 2 equiv) were added together and the volume made to 30 mL by adding toluene. The mixture was ultrasonicated for 5 min. Toluene was pumped into the reactor at the set temperature and flow rate until steady state was reached (ca. 10 min). The prepared mixture was pumped into the reactor at the set flow rate and temperature. Processed products were collected and evaporated in vacuo to afford the crude cyclized product needing no further purification. Conversion was estimated by 1 H NMR.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.oprd.7b00063. Detailed continuous flow instrument setup and reactor parameters, experimental procedures, 1H NMR and 13C NMR spectra for products (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Fax: +46 18 471 4374. Telephone: +46 18-471 4667. ORCID

Mats Larhed: 0000-0001-6258-0635 Funding

We acknowledge ARIADME, a European FP7 ITN Community’s Seventh Framework Programme under Grant Agreement No. 607517. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We wish to acknowledge Magnus Fagrell for help developing the flow instrumentation. We are grateful to AstraZeneca, Mölndal Sweden for the opportunity to carry out continuous flow chemistry on site. We thank Uppsala University for support.

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ABBREVIATIONS CF, continuous flow; MW, microwave; Pd, palladium; SiC, silicon carbide; BPR, backpressure regulator REFERENCES

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