Reconfiguration of a Continuous Flow Platform for Extended Operation

Sep 19, 2014 - Reconfiguration of a Continuous Flow Platform for Extended Operation: Application to a Cryogenic Fluorine-Directed ortho-Lithiation Rea...
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Reconfiguration of a Continuous Flow Platform for Extended Operation: Application to a Cryogenic Fluorine-Directed orthoLithiation Reaction James A. Newby,† D. Wayne Blaylock,‡ Paul M. Witt,‡ Richard M. Turner,† Patrick L. Heider,‡ Bashir H. Harji,§ Duncan L. Browne,† and Steven V. Ley*,† †

Whiffen Laboratory, Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, U.K. Dow Chemical Company, Midland, Michigan 48674, United States § Cambridge Reactor Design, Unit D2, Brookfield Business Centre, Cottenham, Cambridgeshire CB24 8PS, U.K. ‡

S Supporting Information *

ABSTRACT: A flow platform for preparing various aromatic scaffolds using a low-temperature fluorine-directed ortho-lithiation reaction has been successfully reconfigured to allow large-scale processing over extended reaction periods. During the course of this work several key factors have resulted in the development of new technology such as stainless steel y-piece fittings capable of hosting a thermocouple at the point of mixing which directly controls the power output of a cryogenic cooling device. These developments have enabled the continuous processing of an industrially relevant product, where adequate mixing, cooling, and exotherm control are important for successful operation. The configuration culminates in a large-scale campaign where the flow platform is utilised to process over 100 g of pure product over 7 h, in a yield of 80% after workup.

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INTRODUCTION Ortho-lithiation plays a key strategic role in the preparation of functionalized aromatic building blocks.1 In particular, the value derives from a wide variety of known directing groups and compatibility with a range of electrophilic quenching agents. This approach is particularly valuable for installing functionality to aromatic species to enable cross coupling reactions.2 Most relevant to this discussion is the known propensity for a fluorine substituent to direct ortho-lithiation and be subsequently quenched by boron electrophiles.3 A relevant example of fluorine-directed cryogenic lithiation is the conversion of 2-chloro-6-fluoroanisole (2,6-CFA) into (4chloro-2-fluoro-3-methoxyphenyl)boronic acid (PBA) as part of a synthesis strategy.4 As shown in Scheme 1, this reaction proceeds through two key synthetic steps and is complicated by the thermally unstable nature of the lithiated intermediate. The instability of the lithiated intermediate motivated the development of a flow process in lieu of traditional batch processing. Here we detail our findings, culminating in design modifications to a 5-coil flow chemistry platform technology4 to provide material at a rate of 15.1 g/h. In general terms 2,6-CFA can be converted into PBA by selective deprotonation using n-butyllithium at low temperature. The resulting lithiated species is treated with a trimethylborate solution to give the dimethyl ester of PBA (PBA-diMe) or the corresponding lithium salt in organic solution. This solution can be treated with aqueous potassium hydroxide to hydrolyse the methyl esters and form the potassium boronate of PBA (PBAK), which subsequently partitions into the aqueous phase. The organic phase is removed, and the aqueous solution is acidified by the addition of hydrochloric acid to give the free acid PBA that is recovered from solution by extraction using an organic solvent. In competition with this desired reaction process is © XXXX American Chemical Society

Scheme 1. Considerations for the conversion of 2,6-CFA to PBA

ortho-elimination of lithium fluoride to generate a highly reactive benzyne intermediate capable of participating in exothermic decomposition reactions. It was also noted that, at sufficiently low temperatures, borylation of the lithiated intermediate is favored, whereas at elevated temperatures the undesired Special Issue: Organometallic Carbanions in Practical Organic Synthesis Received: July 8, 2014

A

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benzyne formation is dominant. Furthermore, the generated exotherm is sufficiently vigorous to lead rapidly to thermal runaway unless efficient cooling is applied. Continuous flow chemistry methods were anticipated to provide an attractive solution to the hazards posed by the exothermic decomposition of the lithiated intermediate.

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RESULTS In order to design a process where borylation is favored over decomposition, we initially set out to establish the appropriate temperature to maintain the Li 2,6-CFA prior to and during the addition of the boron electrophile. The point at which the Li 2,6-CFA would degrade in an exothermic fashion was determined through a combination of analytical techniques. This temperature was then used as a maximum value in all subsequent reaction runs in order to avoid a runaway reaction. This benchmark value was achieved by two methods. The first used cold differential scanning calorimetry (DSC), through which the heat of reaction from Li 2,6-CFA decomposition was monitored in real time via a temperature ramp. The results of this cold-DSC investigation are shown in Figure 1.

Figure 2. Decomposition of Li 2,6-CFA observed measurement. The decrease in Li-2,6-CFA at 15 accompanied by an exotherm or an increase in decomposition product. We believe that the small artifact from baseline drift.

via in situ IR min was not signal of the decrease is an

reasonably long processing times. Instead, the results indicated that the second DSC-detected decomposition region, in excess of −26 °C, is a better measure of the point at which observable bulk decomposition is detected on time scales relevant to the reaction. Based on the data, batch operations have been largely limited to temperatures colder than −50 °C. This value provides a safety barrier of approximately 20 °C before the reaction pot would be in danger of losing containment due to an exothermic runaway. In addition to this safety barrier, concentrations were such that an adiabatic temperature rise (calculated from DSC data) would not result in solvent loss or pressurisation. An example of such a batch reaction is shown in Figure 3, as monitored by in situ IR measurement. In order to gain a better understanding of the relative rates of lithiation and borylation, a series of “shot”addition lithiation and borylation reactions were carried out. Note that at lower concentrations of 2,6-CFA (0.2 equiv) the rate of lithiation appears to slow down (seen as curvature in the graph). This is not seen in the borylation reaction (no curvature in the graph), and therefore we conclude that the borylation step is significantly faster than lithiation. These batch reactions were carried out in 1,2-dimethoxyethane (DME) solvent. While investigating potential solvents for the batch process, it was noted that tetrahydrofuran (THF) resulted in a difficult-to-stir viscous phase during the borylation reaction, which raised concerns that poor mixing could lead to pooling of unreacted trimethylborate in the reactor and the potential for exothermic runaway should all of the unreacted material suddenly break through, rapidly mixing and reacting. Given this limitation of THF, DME was chosen as a more suitable solvent for batch processing. With this understanding of the reaction in batch we decided to investigate alternative flow chemistry methods, primarily aimed at reducing the in-process volume of the highly unstable lithiated intermediate while maintaining sufficiently low temperature to avoid decomposition. Flow chemistry is ideally suited to be coupled with organometallic reactions and especially where the control of reaction temperature and mixing is clearly paramount to the success of the process.5 We were also mindful that attempts to run this reaction in our flow systems would challenge our current equipment and therefore would lead to useful developments of the tools and techniques. Additionally, we were intrigued by the possibility of using one flow platform that could generate new analogues and then be used to scale-up

Figure 1. Cold DSC plot of Li 2,6-CFA under a nitrogen atmosphere. The green line shows data obtained, and the red line indicates the boundary of the area of integration.

The integrated heat of reaction listed in Figure 1 is computed on a per gram of solution basis. Correcting for the concentration of Li 2,6-CFA in the sample, the Li 2,6-CFA decomposition was found to have a heat of reaction of ≈ −226 kJ/mol under a N2 atmosphere. The onset of exothermic degradation appears around −48 °C; however, the rate of decomposition is detected to accelerate rapidly at −26 °C. Bulk decomposition was also observed via in situ IR measurement in order to better understand the onset of significant Li 2,6-CFA decomposition relevant to the time scale of the lithiation and borylation reactions. Wavelengths corresponding to both the Li 2,6-CFA and the decomposition products concentrations were observed (C−F stretch around 1000 cm−1). In this experiment, the temperature of the reaction solution was slowly raised until decomposition products were observed. The experiment revealed that detectable bulk decomposition began at approximately −26 °C as shown in Figure 2. Therefore, while the DSC-detected onset of Li 2,6CFA decomposition is −48 °C, the results of the IR measurements indicated that decomposition in this region is sufficiently slow that it is not readily observable, even with B

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Figure 3. In situ IR monitoring of a series of shot-addition lithiation and borylation reactions at −65 °C.

mandrels and these y-pieces was suspended in the air giving rise to poor temperature control and a lack of robustness; this led us to develop an improved system. Our first solution (generation 2 design) was to submerge the y-pieces into the center of the reactor to maintain contact with the internal copper coil (Scheme 2). This improved the temperature readings measured at the y-pieces. With this setup and while maintaining a temperature set-point of −40 °C, we could now secure a 73% yield of the desired PBA product. Nevertheless this was again accompanied by some discoloring of the output stream, indicating suboptimal temperature control within the reactor. Further improvements were possible by moving the reactor set point to −50 °C which provided a 92% yield and more importantly, no discoloring of the flow stream. A plot of the live thermocouple data during this reaction (Figure 4) highlights that the temperature control at y-piece 1 was

the production of these compounds to give useful quantities for more detailed evaluation in a versatile and flexible manner. We began the study by employing a newly developed five-coil flow reactor setup,4 whereby reagent loops were loaded with CFA in DME, n-BuLi in hexanes and trimethylborate in DME and a carrying solvent stream of pure DME. The initial reaction under these conditions was conducted at −60 °C, where a precipitate formed in the n-BuLi stream that blocked in the precooling coil. This result was confirmed by an offline batch test where addition of DME to a cooled solution of n-BuLi in hexanes also resulted in the formation of a fine precipitate that redissolved upon standing, suggesting that this solvent combination was incompatible for a segmented-flow setup whereby the n-BuLi mixes/diffuses with DME at the front and back ends of the reaction segment prior to entering the cooled zone and hence results in a blockage inside the narrow channels (1.0 mm i.d.). Replacing DME with THF circumvented this issue and permitted investigations under segmented-flow conditions as a precipitate did not form in the n-BuLi precooling loop. Initially we set out to correlate the reactor output with the various coil and cooling cycles. At the higher temperature of −40 °C the reaction produced no desired product; rather it formed a darkly colored solution/slurry, indicative of decomposition of the aryllithium species via a benzyne intermediate (Schemes 2, part 1). We hypothesized that reaction failure under these conditions was largely due to inadequate temperature control. To test this we used thermocouples with flowing streams of THF (no reagents) to record the actual temperature at various positions along the cooled reactor. This was achieved using a data logging device6 where the thermocouples were secured in position initially by either tie-wraps or sticky-tape (Scheme 2). The data shows that the supplied cooling was adequate at points in direct contact with the cooled copper coil and chrome-coated heat exchanger and reactor mandrels. However, any part of the system that was not in direct contact with the cooled metal varied dramatically from the set point temperature. Indeed, our positioning of y-pieces in preliminary runs was not sufficient to guarantee effective cooling at the point of mixing. Furthermore, the tubing between the cooled

Figure 4. Thermocouple data for segmented reaction under generation 2 design; y-piece 1 was exotherm controlled, y-piece 2 was exotherm poorly controlled.

sufficient, whereas a significant temperature deviation developed at y-piece 2. While this large deviation did not lead to degradation in segmented flow at small reactant volumes, it was indicative that insufficient cooling was available for a fully continuous process. In light of this data and given our aims of securing a robust and continuous processing unit that could perform this reaction at larger scales we decided to re-evaluate the cooling methods as C

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Scheme 2. Details of preliminary problems encountered and the identification of a solution (PC = pre-cooling loop; RX = reaction loop)

improvement would (a) provide better heat transfer to facilitate continuous operation and (b) allow feedback and temperature management at the point of mixing. The modified design (generation 3) consisted of the metal mixer mounted on a mandrel that was modified to hold a wider bore tubing to permit greater throughput (2.44 mm ID × 3.26 mm OD) (Scheme 4). The generation 3 design resulted in vastly improved temperature control at y-piece 2 (Figure 5), and most notably the process could be operated continuously over a 3 h period while containing the potential exotherm. With this setup a 50% conversion to product was observed, with no discoloring of the reaction solution. Working on the hypothesis that the reaction rates had been significantly slowed by the improved temperature control we decided to increase the set point temperature of the reactor to −40 and −35 °C, again observing similar conversions and no discoloration (Scheme 4).

it relates to the second y-piece. We started by examining the way in which the temperature was currently being managed by the system. The device consists of an adiabatic refrigeration unit where the maximum cooling of the device can reach −90 °C (Scheme 3, part 1). Once the user sets the desired temperature, the cooler switches on to maximum power, and the temperature begins to drop. As the machine reaches the set point, as determined by feedback from a thermocouple positioned in a receiving hole in the wall of the chrome-coated cylinder, the machine initiates secondary control via an offsetting heater. The power supplied to the heater can then be varied and used to control the fine-tuning of the temperature with a great deal of accuracy at the point where the feedback thermocouple resides. With this understanding, and the desire to maintain a modular system, we designed a metal mixing unit that could additionally encompass a thermocouple placed in the process stream. This D

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Scheme 3

Figure 5. Thermocouple data for continuous reaction using the generation 3 metal tee-piece with thermocouple feedback control design; y-piece 1 is exotherm controlled, and y-piece 2 is exotherm controlled (controlling thermocouple).

phenomenon was witnessed in flow. In the flow case however an intermittent gel appears to form. As the gel builds the pressure drop in the system also rises, until a point where the gel is pushed out of the reactor, the pressure drop decreases, and the outlet flow returns to the liquid phase. Owing to this, we used a Teledyne ISCO dual syringe pump (two 100D pumps and a controller) which could pump the butyllithium reliably and work at the pressures created by the flowing gel. Running on one working day for a 7 h period (after allowing 30 min to reach steady-state) provided 106 g of the desired PBA product following an offline workup (see Scheme 6). The thermocouple results for this process show control within a few degrees at both mixers for the duration of the reaction (Figure 6).

As increasing the temperature failed to improve the yield, we hypothesized that the mixing of the THF stream (containing 2,6-CFA) and the hexane stream (containing BuLi) was slow relative to the residence time in the reaction coil and was therefore limiting the lithiation step (Reynolds number ≈5). We therefore looked at the inclusion of stirrer bars and an agitating motor at the outlet of the mixer, as dynamic mixing has been shown to improve mixing efficiency at flow rates around 1.5 mL/min.7 In order to achieve this, the outlet tubing from the mixer was changed from 2.44 to 4.0 mm ID so that a series of stirrer bars could be introduced into the tubing (generation 4 design). A stepper motor with an added spinning disc carrying a magnet was positioned in proximity to the stirrer bars (Scheme 5). We were pleased to find that by improving the mixing we could also improve the yields, suggesting that the mixing limitation issues were improved or solved. With this system, we then turned attention to performing a continuous reaction over the period of a working day. For this we had to identify appropriate pumps which could reliably deliver the nbutyllithium solution. This was complicated by some complex (and reproducible) phase behavior within the flow reactor setup. Analogous to the batch tests in THF where the reaction becomes extremely viscous during borylation, a similar

Figure 6. Thermocouple data for 7 h continuous reaction using generation 4 design with thermocouple feedback control; y-piece 1 is exotherm controlled, y-piece 2 is exotherm controlled (controlling thermocouple).

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CONCLUSION In conclusion we have applied our multicoil cryogenic flow reactor to a challenging problem of industrial relevance, where adequate mixing, cooling, and exotherm control are paramount to limiting a highly exothermic degradation process. This collaborative approach has driven important developments to the mesoscale flow systems, culminating in inventive solutions and improvements. For example we maintained a set temperature during a highly exothermic reaction by controlling the power output of the cooler based on temperature measurements E

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Scheme 4. Generation 3 design employing a mixing unit with in-stream thermocouple providing feedback control and its use in an early continuous run

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EXPERIMENTAL DETAILS General Procedures. Reagents and solvents were commercial grade and were used as supplied. 1H NMR and 13C NMR data were recorded on a Bruker Avance (400 MHz for 1H and 100 MHz for 13C NMR) spectrometer using the residual solvent peak as the internal reference (d6-DMSO = 2.50 ppm for 1H and 39.4 ppm for 13C). To simplify the 1H NMR of PBA a drop of D2O was added to the NMR sample (in d6-DMSO) to convert the boroxine trimer to free PBA. NMR data are reported as follows: chemical shift in ppm (δ), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, m = multiplet, br = broad signal, or combinations of thereof), coupling constant (Hz), integration. Infrared spectra were obtained on a PerkinElmer Spectrum One FT-IR spectrometer, and absorptions are reported in reciprocal centimeters. Solutions were pumped continuously using a Uniqsis FlowSyn device (2,6-CFA stream and trimethyl borate stream) and a Teledyne-Isco syringe pump (two 100 D cylinders with a controller operating in continuous mode). The reactor tubing was wrapped around deep-grooved mandrels purchased from either Uniqsis or CambridgeReactorDesign. Three precooling loops of 1.5 m volume were prepared in-house from commercially available PFA tubing (2.44 mm i.d., 3.26 mm o.d., 0.32 m tube length). The first reactor loop of 20 mL volume was assembled in-house using commercially available PFA tubing (4.0 mm i.d., 4.5 mm o.d., 1.6 m tube length) and fitted with five magnetic stirrer bars.The second reactor loop of 20 mL volume was also assembled in house from commercially available PFA tubing (2.44 mm i.d., 3.26 mm o.d., 4.28 m tube length). The tubing was fitted with Swagelok stainless steel nuts and ferrules and connected to the tee-piece fittings supplied by CambridgeReactorDesign. The tee-piece fittings were attached to a mandrel, and each mandrel placed over the cooled cylinder

Scheme 5. Results using generation 4 design with different tubing i.d. and setup for in situ stirring and agitation (reactor dome removed for clarity)

at the point of mixing, measured inside the flowing liquid stream. A method for improving mixing limitations is reported by incorporating a series of in-line agitated stirrer bars. Finally, by coupling these changes with the appropriately sized coils and pumps we were able to process the reaction continuously to provide greater than 100 g of material within a 7 h working period on the same cooling device used previously for the preparation of 20 analogues at one gram scale,4 thus representing the applicability of flow devices to behave as early discovery and process development tools. F

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Scheme 6. Setup of generation 4 apparatus for a 7 h continuous run (reactor dome removed for clarity of picture)

thin film) 1440, 1040, 920, 750; 1H NMR (400 MHz, d6DMSO) δ 7.26−7.20 (2H, m), 3.91 (3H, s) ppm; 13C NMR (100 MHz, d6-DMSO) δ 160.4, 158.0, 143.8 (d JC−F = 246.5 Hz), 130.1 (d JC−F = 10.5 Hz), 129.1 (d JC−F = 3.5 Hz), 125.5 (d JC−F = 3.0 Hz), 61.7 (d JC−F = 4.0 Hz) ppm; 19F NMR (400 MHz, d6-DMSO) δ −120.8 ppm. HRMS (TOF+) found 205.0244, C7H8BClFO3H+ requires 205.0239. The boronic acid has a strong tendency to dry under the workup conditions to give the boroxine trimer. The unreported signal at ∼3.6 ppm in 1H NMR is from residual H2O from adding D2O added to shift the equilibrium towards the free boronic acid.

block. K-type thermocouples were fitted inside each tee-piece, and the thermocouple in the second tee was connected to the cryo-flow unit to act as a controlling temperature: The reactor assembly was fitted to the pumps using 1.0 mm i.d. PFA tubing of approximately 1 m length and solvent flowed through the reactor at 2 mL/min per pump until all tubing was completely filled. A glass dome was placed over the cylinder block, and a motor fitted with a magnetic disc was placed near to the stirrer bars in the first reactor loop. The magnet was rotated at a sufficient velocity to agitate the stirrer bars. The cryo-flow unit was set to a temperature of −40 °C and allowed to reach temperature (achieved after 1 h). While cooling, solvent was flowed at 0.5 mL/min per pump. 2.5 L solutions of CFA (1 M in THF) and B(OMe)3 (1.5 M in THF) were prepared, and n-butyllithium was used (1 M in hexanes) directly from an 800 mL bottle. When the reactor had reached the set temperature, both CFA and B(OMe)3 streams were pumped at 1.5 mL/min for 10 min, and then n-butyllithium was pumped using the syringe pump under a positive pressure of argon. The collected solution was sent to waste for 45 min to allow the system to reach steady state. After this time the output of the reactor was collected in a 1 L bottle that was replaced at 2 h intervals. The collected material was subjected to a batch workup where 250 mL of crude solution was added to 250 mL of 1 M potassium hydroxide solution and 250 mL of hexane. The mixture was subjected to extraction and the layers separated. The lower aqueous layer was acidified to pH 1 with 200 mL of 3 M hydrochloric acid upon which a white precipitate was formed. 250 mL ethyl acetate was added, dissolving the precipitate, and the combined layers were extracted. The upper organic layer was collected, dried with magnesium sulfate, and reduced under vacuum to yield the desired product as a white solid.

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ASSOCIATED CONTENT

S Supporting Information *

1

H, 13C, and 19F NMR spectra for PBA. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare the following competing financial interest(s): Dr. Bashir Harji is the director of Cambridge Reactor Design Ltd (registered number 2550086).

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ACKNOWLEDGMENTS The authors would like to thank the Dow Chemical Company (J.A.N., D.W.B., P.M.W., and P.L.H), the department of chemistry, University of Cambridge (R.M.T.) and the EPSRC (award no. EP/F069685/1, D.L.B. and S.V.L.) Florin Dan, Jossian Oppenheimer, and Andrew Pastzor Jr. (ret.) of the Dow Chemical Company are acknowledged for their generation of the cold DSC data as well as Mark Rickard for assistance in processing the in situ IR data presented here.

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ANALYTICAL DATA (4-Chloro-2-fluoro-3-methoxyphenyl)boronic Acid (PBA). Isolated as a white solid. Mpt 236−238 °C. IR (cm−1, G

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