Microtiter Plate (MTP) Reaction Screening and Optimization of

Oct 2, 2018 - A screening method to evaluate Suzuki–Miyaura and Buchwald–Hartwig coupling reactions under aqueous surfactant conditions has been ...
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Microtiter Plate (MTP) Reaction Screening and Optimization of Surfactant Chemistry: Examples of Suzuki−Miyaura and Buchwald− Hartwig Cross-Couplings in Water Cara E. Brocklehurst,*,† Fabrice Gallou,‡ J. Constanze D. Hartwieg,† Marco Palmieri,† and Dominik Rufle† †

Global Discovery Chemistry, Novartis Institutes for Biomedical Research, Novartis Pharma AG, Basel, Switzerland Chemical and Analytical Development, Novartis Pharma AG, Basel, Switzerland

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S Supporting Information *

order to rapidly gain information about a reaction, we foresaw that rapidly screening for 96 discrete reaction conditions at once, while using minimal starting material would be highly advantageous and could be an enabling technology for identifying optimal conditions for further investigation. Our experiments have shown that reactions using surfactant are highly dependent on the geometry of the reaction vessel and the scale on which they are performed. We set out to generate a high quantity of data using minimal starting material and in as small a reaction vessel as possible. Indeed, significant challenges were encountered due to homogeneity and mixing problems in glass HPLC vials containing stirrer bars. Building on recent observations that addition of an organic solvent to a micellar reaction mixture leads to improved homogeneity, we included a percentage of cosolvent to our reactions.6,7 Ultimately after optimizing our screening procedures we found that, provided that the reaction solvents were thoroughly degassed before use, reactions would smoothly and reliably take place in 50 μL of reaction media in a plastic MTP, albeit not always to full conversion. We have demonstrated that with just 2 μmol of substrate per reaction (approximately 75−100 mg per plate), and were able to rapidly identify conditions for validation and further investigation on larger scale. Our screening plate was designed to contain 12 catalysts (a range of bench stable Buchwald-Pd-G3 and PEPPSi premade ligand/Pd combinations), four bases and two cosolvents. The reaction solvent was 2% TPGS-750-M aqueous solution. Solutions were distributed into the MTP using an Eppendorf EP-Motion pipetting robot, the plate sealed and shaken at 40 °C overnight. The wells were then analyzed by UPLC-MS (2 min analytical method, analytical plates were complete in 4 h) and then the best results validated on approximately 50−100 mg scale in a round bottomed flask. We typically observe higher conversion on larger scale provided the reaction is degassed and rapidly stirred. Low yielding Suzuki−Miyaura reactions in which both the bromide and boronate are sterically hindered is a challenge that is faced by a number of our medicinal chemistry programs. Our teams have demonstrated that many Suzuki−Miyaura reactions can benefit from being run under surfactant conditions at mild temperatures.8−12 However, the range of

ABSTRACT: A screening method to evaluate Suzuki− Miyaura and Buchwald−Hartwig coupling reactions under aqueous surfactant conditions has been established, leading to high yielding and highly selective Suzuki− Miyaura and Buchwald−Hartwig reactions under mild reaction temperatures and ecologically improved conditions. The screening method highlighted the utility of Buchwald−Hartwig third generation precatalysts for unprecedented high conversion Buchwald−Hartwig C− N coupling reactions in water. KEYWORDS: Surfactant, micelle, screening, MTP

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INTRODUCTION High throughput reaction optimization of highly functionalized drug leads has been demonstrated by a number of industrial groups,1−4 and Merck in particular have elegantly shown how reaction screening on μmol scale can give a wealth of information about reactions, while avoiding the depletion of precious substrate stores. Professor Lipshutz,5 and others have demonstrated that coupling reactions can be performed in water containing surfactants at moderate temperatures with improved purity profiles. Herein we describe the combination of 96-well microtiter plate (MTP) screening to find optimal conditions for C−C and C−N coupling reactions in water, and how we solve the technical challenges associated with this recent technology. Under surfactant conditions (e.g., 2% TPGS-750-M in water) [CAS: 1309573-60-1] it is thought that the reaction takes place at high concentration inside the micellar structure (see Figure 1). Surfactant reactions can be run at lower temperatures (typically 20−45 °C), show fewer byproducts, avoid using nonecological solvents, and often the product can be removed from the reaction mixture by simple filtration. All of these criteria are highly advantageous when developing a green process for chemical scale up and tap into the urgency to find alternatives to reprotoxic polar aprotic solvents.

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RESULTS AND DISCUSSION

In our hands, such coupling reactions in surfactants can often be capricious. and we are far from fully understanding all of the parameters that can affect such reactions in aqueous media. In © XXXX American Chemical Society

Received: June 17, 2018 Published: October 2, 2018 A

DOI: 10.1021/acs.oprd.8b00200 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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Figure 1. TPGS-750-M aligned in spherical micelles.

catalysts that has been used to affect this transformation in micelle media is limited; traditionally Pd(dtbpf)Cl2 [Pd-118, CAS: 95408-45-0] is used. We have experienced that for sterically hindered couplings of the type shown in Figure 2(a), screening a range of ligands can be crucial for finding high yielding conversions. In order to validate our screening methodology, the trisubstituted C−C coupling model reaction between pinacol borane 1 and bromide 2 was screened using the plate lay-out detailed in Figure 2b. The heat-map shows integrated product peak areas from UPLC-MS plotted against 96 MTP wells A1 to H12. Three reactions showing the highest conversion were chosen and validated on 100 mg scale. The first reaction, using RuPhos-Pd-G3, potassium phosphate and 5% THF as cosolvent (Figure 2c, entry i) showed >95% conversion after just 5.5 h. With this result, we were able to show that Buchwald precatalysts can be used for high conversion Suzuki−Miyaura reactions under surfactant conditions. The second reaction we validated, using Pd(dtbpf)Cl2, potassium phosphate and 5% THF as cosolvent (Figure 2c, entry ii), showed that full conversion was not obtained after 18h at 40 °C. The third example, using SPhos-Pd-G3 and triethylamine (Figure 2c, entry iii) also showed incomplete conversion. Few Buchwald−Hartwig surfactant aminations exist in the literature; those examples which have been published often use [allyl)PdCl]2 as palladium source and cBRIDP as the ligand.13−15 To validate the surfactant reaction screening for the Buchwald−Hartwig reaction, we chose the coupling between aromatic bromide 4 and Boc-carbamate 5 shown in Figure 3a; a reaction which did not show any product in our hands when using traditional coupling conditions with bulky, electron-rich ligands such as TrixiePhos or XantPhos in organic solvents at 80−90 °C. Experience in surfactant Buchwald−Hartwig reactions told us that using higher concentrations of cosolvent typically led to better reaction homogeneity 10% of cosolvent was used in this case (compared to only 5% for the Suzuki−Miyaura screen). Practically, this translated into avoidance of gummy residues or other inhomogeneities in the reaction mixture that led to deviation (incomplete conversion or reduced purity). Screening identified only a few reactions which showed conversion; those using BrettPhos-Pd-G3 and tBuXPhos-Pd-G3. Literature suggests that tBuXPhos is a water stable ligand which can be used for Buchwald−Hartwig aminations in aqueous media,16 but, to date, it has not been used in palladacycle format. Three conditions using tBuXPhos-Pd-G3 were chosen for validation in combination with K3PO4 or Cs2CO3 and 10% THF or acetone (Figure 3c, entries i−iii). The first two examples

Figure 2. (a) Suzuki−Miyaura coupling between aromatic-BPin 1 and bromide 2; (b) heat-map of UPLC-MS conversion to C−C coupled product 3 across the MTP on 2 μmol/well scale (green = high product formation, red = low product formation, and gray = no product); (c) validation of three conditions (labeled on heat-map) on the 525 μmol scale.

showed full conversion in just 1.5 h (Figure 3c, entries i and ii). The reaction with THF as cosolvent was slightly faster than with acetone as cosolvent. In this particular example, the surfactant conditions enabled a high conversion whereas our previous trials with more traditional solvents at high temperatures failed. B

DOI: 10.1021/acs.oprd.8b00200 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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Figure 4. (a) Buchwald−Hartwig coupling between aniline 7 and chloride 8; (b) optimization conditions on 50 mg scale.

increasing the percentage of THF cosolvent to 40% (Figure 4b, entry 3). If the catalyst loading of tBuXPhos-Pd-G3 was reduced to 1 mol %, the conversion dropped to 14% (Figure 4b, entry 4) however at the higher THF cosolvent percentage, the conversion remained high with near equal equivalents of aniline 7 (Figure 4b, entry 5). Testing the reaction in the absence of surfactant led to incomplete conversion in all cases (Figure 4b, entries 6−8) showing that the micelles are essential to the reaction in order to see high conversions. A scale up reaction, using approximately 35 mmol of chloride 8, and optimized conditions from Figure 4b, entry 5, resulted in a 91% isolated yield, and chromatography was avoided. The reaction was complete in less than 3 h, and after reaction evaporation of THF, Me-THF workup to remove excess amine followed by trituration with TBME (to remove des-chloro and carbazole byproducts), a purity of >98% by UPLC was obtained.

Figure 3. (a) Suzuki−Miyaura coupling between bromide 4 and Boccarbamate 5; (b) heat-map of UPLC-MS conversion to C−N coupled product 6 across the MTP on 2 μmol/well scale (green = high product formation, red = low product formation, gray = no product); (c) validation of three conditions (labeled on heat-map) on 240 μmol scale.

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The same optimized reaction conditions (tBuXPhos-Pd-G3 and THF as cosolvent) have been applied to wide scope of other Buchwald−Hartwig reactions from drug discovery programs are particularly useful in a medicinal chemistry workflow as they provide rapid access to high quality products. Further optimization is typically done in process to further streamline and improve the process. One such example is outlined in Figure 4a in which the coupling between aniline 7 and chloride 8, a reaction in which many byproducts were formed using standard coupling conditions (Pd2(dba)3, BINAP, Cs2CO3, Et3N, dioxane, 100 °C 16 h). The observed conversion by UPLC is full but the reaction results in number of lower polarity impurities visible in the UPLC. Subsequent purification is challenging and several columns were necessary to obtain sufficient purity. The final isolated yield was just 39% on 10 g scale. The coupling reaction between aniline 7 and chloride 8 has been subjected to our surfactant screening protocol and was subsequently further optimized using the range of conditions on 50 mg scale listed in Figure 4b. Reaction conversion by UPLC was boosted slightly by increasing the equivalents of aniline 7 to 1.5 (Figure 4b, entry 2) and further again by

CONCLUSIONS In conclusion, a screening methodology has been developed in which a range of precatalysts can be easily and rapidly screened for Suzuki−Miyaura and Buchwald−Hartwig reactions under surfactant conditions. To the best of our knowledge this is the only technical solution to reliably and rapidly screen for micelle mediated transformations. The simple MTP screen setup allows for easy variation of reaction parameters (e.g., ligand, base, cosolvent, and percentage of cosolvent) to rapidly generate knowledge about a range of other surfactant transformations.

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EXPERIMENTAL SECTION Equipment and MPT Design. Liquid handling was performed using an Eppendorf EP Motion which has been shown to accurately pipet down to 1 μL volumes. Liquids can be transferred either with single tips or with the eight channel pipet for rapid plate preparation. The precatalysts were dissolved in THF and pipetted across to plastic MTP’s. The THF was evaporated before blanketing under argon and sealing for storage in the fridge; a method which allowed C

DOI: 10.1021/acs.oprd.8b00200 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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with 10 μL of stock solution D; rows B1−B12 and F1−F12 were filled with 1.3 μL of Et3N and 8.7 μL water (stock solution E); rows C1−C12 and G1−G12 were filled with 10 μL of stock solution F; rows D1−D12 and H1−H12 were filled with 10 μL of stock solution G. After the pipetting, the plate was flushed again with argon (with low pressure to avoid evaporation of the cosolvent) and sealed with self-adhesive PPfoil. The loaded and sealed MTP was shaken overnight at 40 °C and 900 rpm. The finished reaction was diluted for analysis by UPLC-MS. The sealing was opened carefully and each well diluted with 150 μL MeCN/H2O/DMSO (8:1:1) and mixed eight times by the robot in the pipet tips (with aspirating/ dispensing). For each well, 40 μL of the quenched reaction solution was pipetted into a new analytical MTP with the same coordinates. To each well was added 160 μL MeCN/H2O/ DMSO (8:1:1) and mixed 6 times in the tips. The analytical MTP was sealed with self-adhesive PP-foil and the UPLC-MS run overnight. Results were visualized in a heat map (Figure 3b) or 3D plot of the MTP (see Supporting Information) in which the peak area from HPLC is plotted against the plate positions. Validation Experiments: Suzuki−Miyaura. To three argon flushed 5 mL flat bottomed vials were added 2-(2-(1,1difluoroethyl)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (196 mg, 0.68 mmol), degassed 2% aqueous TPGS750-M (2000 μL), degassed cosolvent (PEG or THF, 400 μL), and base (K3PO4, 335 mg, 1.58 mmol or Et3N neat 220 μL, 1.58 mmol). The resulting white emulsion/suspension was degassed with argon for 1 min. To this emulsion was added catalyst (3 mol %, 0.016 mmol), and the now dark brown reaction mixture was heated to 40 °C. After 15 min 2-bromo-3fluoroaniline (100 mg, 0.53 mmol) was added as liquid. The resulting dark brown emulsion was again degassed with argon and was stirred vigorously at 40 °C. Validation Experiments: Buchwald−Hartwig. To three argon flushed 5 mL flat bottomed vials were added 8-bromo1,6-naphthyridine (50 mg, 0.24 mmol), tert-butyl carbamate (56 mg, 0.48 mmol), degassed 2% aqueous TPGS-750-M (2000 μL), degassed cosolvent (acetone or THF, 400 μL), and base (K3PO4 or Cs2CO3 both 1 M 1196 μL, 1.58 mmol). The resulting white emulsion/suspension was degassed with argon for 1 min. To this emulsion was added catalyst (10 mol %, 0.024 mmol), and the reaction was then stirred vigorously at 50 °C. Scale up Experiment: Buchwald−Hartwig Example. A double-jacketed 200 mL reactor was flushed with argon to which chloride 8 (35.4 mmol) and 6-methylpyridin-2aminutee (4.02 g, 37.2 mmol) were added. Degassed THF (10 mL) was used to rinse the materials into the reactor and 2% aqueous TPGS-750 M (105 mL) was added with stirring. To the resulting white suspension was added dropwise triethylamine (24.7 mL, 177 mmol) within 10 min using a 25 mL dropping funnel resulting in a weak exotherm (which was held between 20 and 25 °C by the reactor system, internal temperature set to 20 °C). The reactor was evacuated to 200 mbar and flushed with argon. tBuXPhos-Pd-G3 (2.82 g, 3.54 mmol) was added and degassed THF (60 mL). The resulting yellow-brown suspension was stirred for 10 min and a slight exotherm was observed. The reaction mixture was warmed to an internal temperature of 40 °C, over a 20 min period, and held at this temperature for 3 h, after which time there was no remaining chloride 8 visible by UPLC-MS.

preparation of multiple plates at a time. The plate layout is shown in the Supporting Information and was applied to both Suzuki−Miyaura and Buchwald−Hartwig screens for convenience. The reactions contain 20 mol % catalyst and 5 equiv of base. Suzuki−Miyaura Screen. Stock solution A: 2-Bromo-3fluoroaniline (45.6 mg, 0.24 mmol) and 2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (89 mg, 0.31 mmol) were dissolved in THF (1200 μL) to give a clear solution (sufficient material for 120 wells, of which 96 will be used). All wells were filled with 10 μL of SM stock solution A (containing 2 μmol 2-bromo-3-fluoroaniline and 2.6 μmol 2-(2-(1,1-difluoroethyl)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane). The THF was evaporated in the drying oven at room temperature and full vacuum for 30 min and then expanded with argon. Stock solution B: 6.25% PEG in 2% aqueous TPGS-750-M (2400 μL) degassed. Stock solution C: 6.25% THF in 2% aqueous TPGS-750-M (2400 μL) degassed. Rows A1-D12 (48 wells) were filled with 40 μL of stock solution B and rows E1H12 (48 wells) were filled with 40 μL of stock solution C. Stock solution D: Cs2CO3 1 M aqueous (250 μL). Stock solution E: Et3N neat (immiscible with water) (250 μL). Stock solution F: K3PO4 1 M aqueous (250 μL). Stock solution G: Na2CO3 1 M aqueous (250 μL). Rows A1−A12 and E1−E12 were filled with 10 μL of stock solution D; rows B1−B12 and F1−F12 were filled with 1.3 μL of Et3N and 8.7 μL water (stock solution E); rows C1−C12 and G1-G12 were filled with 10 μL of stock solution F; rows D1−D12 and H1−H12 were filled with 10 μL of stock solution G. After the pipetting, the plate was flushed again with argon (with low pressure to avoid evaporation of the cosolvent) and sealed with self-adhesive PPfoil. The loaded and sealed MTP was shaken overnight at 40 °C and 900 rpm. The finished reaction was diluted for analysis by UPLC-MS. The sealing was opened carefully and each well diluted with 150 μL MeCN/H2O (9:1) and mixed eight times by the robot in the pipet tips (with aspirating/dispensing). For each well, 40 μL of the quenched reaction solution was pipetted into a new analytical MTP with the same coordinates. To each well was added 160 μL MeCN/H2O (9:1) and mixed 6 times in the tips. The analytical MTP was sealed with selfadhesive PP-foil and the UPLC-MS run overnight. Results were visualized in a heat map (Figure 2b) or 3D plot of the MTP (see Supporting Information) in which the peak area from HPLC is plotted against the plate positions. Buchwald−Hartwig Screen. Stock solution A: 8-Bromo1,6-naphthyridine (50.2 mg, 0.24 mmol) and tert-butyl carbamate (56 mg, 0.48 mmol) were dissolved in THF (1200 μL) to give a clear solution (sufficient material for 120 wells, of which 96 will be used). All wells were filled with 10 μL of SM stock solution A (containing 2 μmol 8-bromo-1,6naphthyridine and 4 μmol tert-butyl carbamate). The THF was evaporated in the drying oven at room temperature and full vacuum for 30 min and then expanded with argon. Stock solution B: 12.5% acetone in 2% aqueous TPGS-750-M (2400 μL) degassed. Stock solution C: 12.5% THF in 2% aqueous TPGS-750-M (2400 μL) degassed. Rows A1-D12 (48 wells) were filled with 40 μL of stock solution B and rows E1H12 (48 wells) were filled with 40 μL of stock solution C. Stock solution D: Cs2CO3 1 M aqueous (250 μL). Stock solution E: Et3N neat (immiscible with water) (250 μL). Stock solution F: K3PO4 1 M aqueous (250 μL). Stock solution G: Na2CO3 1 M aqueous (250 μL). Rows A1−A12 and E1−E12 were filled D

DOI: 10.1021/acs.oprd.8b00200 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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pyridinyl-1H-benzimidazole Diacylglycerol Acyltransferase 1 Inhibitors. J. Med. Chem. 2017, 60, 3594−3605. (4) Perera, D.; Tucker, J. W.; Brahmbhatt, S.; Helal, C. J.; Chong, A.; Farrell, W.; Richardson, P.; Sach, N. W. A platform for automated nanomole-scale reaction screening and micromole-scale synthesis in flow. Science 2018, 359, 429−434. (5) Lipshutz, B. H.; Ghorai, S. Transitioning organic synthesis from organic solvents to water. What’s your E Factor? Green Chem. 2014, 16, 3660−3679. (6) Gallou, F.; Guo, P. F.; Parmentier, M.; Zhou, J. G. A General and Practical Alternative to Polar Aprotic Solvents Exemplified on an Amide Bond Formation. Org. Process Res. Dev. 2016, 20, 1388−1391. (7) Gabriel, C. M.; Lee, N. R.; Bigorne, F.; Klumphu, P.; Parmentier, M.; Gallou, F.; Lipshutz, B. H. Effects of Co-solvents on Reactions Run under Micellar Catalysis Conditions. Org. Lett. 2017, 19, 194− 197. (8) Isley, N. A.; Gallou, F.; Lipshutz, B. H. Transforming SuzukiMiyaura Cross-Couplings of MIDA Boronates into a Green Technology: No Organic Solvents. J. Am. Chem. Soc. 2013, 135, 17707−17710. (9) Handa, S.; Wang, Y.; Gallou, F.; Lipshutz, B. H. Sustainable Feppm Pd nanoparticle catalysis of Suzuki-Miyaura cross-couplings in water. Science 2015, 349, 1087−1091. (10) Gallou, F.; Isley, N. A.; Ganic, A.; Onken, U.; Parmentier, M. Surfactant technology applied toward an active pharmaceutical ingredient: more than a simple green chemistry advance. Green Chem. 2016, 18, 14−19. (11) Handa, S.; Andersson, M. P.; Gallou, F.; Reilly, J.; Lipshutz, B. H. HandaPhos: A General Ligand Enabling Sustainable ppm Levels of Palladium-Catalyzed Cross-Couplings in Water at Room Temperature. Angew. Chem., Int. Ed. 2016, 55, 4914−4918. (12) Isley, N. A.; Wang, Y.; Gallou, F.; Handa, S.; Aue, D. H.; Lipshutz, B. H. A Micellar Catalysis Strategy for Suzuki-Miyaura Cross-Couplings of 2-Pyridyl MIDA Boronates: No Copper, in Water, Very Mild Conditions. ACS Catal. 2017, 7, 8331−8337. (13) Isley, N. A.; Dobarco, S.; Lipshutz, B. H. Installation of protected ammonia equivalents onto aromatic & heteroaromatic rings in water enabled by micellar catalysis. Green Chem. 2014, 16, 1480− 1488. (14) Lipshutz, B. H.; Chung, D. W.; Rich, B. Aminations of Aryl Bromides in Water at Room Temperature. Adv. Synth. Catal. 2009, 351, 1717−1721. (15) Salome, C.; Wagner, P.; Bollenbach, M.; Bihel, F.; Bourguignon, J. J.; Schmitt, M. Buchwald-Hartwig reactions in water using surfactants. Tetrahedron 2014, 70, 3413−3421. (16) Wagner, P.; Bollenbach, M.; Doebelin, C.; Bihel, F.; Bourguignon, J. J.; Salome, C.; Schmitt, M. t-BuXPhos: a highly efficient ligand for Buchwald-Hartwig coupling in water. Green Chem. 2014, 16, 4170−4178.

The reaction mixture was cooled to room temperature and the brown/beige suspension was transferred to a 500 mL round bottomed flask. The reactor was rewashed with THF (50 mL), and the THF was removed on a rotary evaporator at 50 °C, under vacuum (not lower than 100 mbar) to give a brown/beige residue. To the beige/brown solid were added Me-THF (400 mL) and water (400 mL) and the reaction stirred for 2 min at 40 °C to ensure dissolution. The Me-THF layer was separated and the aqueous layer re-extracted with Me-THF (300 mL) at 40 °C. The combined organic phases were concentrated on a rotary evaporator at 50 °C and under vacuum. The solid was suspended with TBME (80 mL) and stirred overnight with a magnetic stirrer after which time the beige suspension was removed by filtration, washed with the mother liquor and twice with TBME (2 × 20 mL). The wet material was dried in a drying cabinet at 40° and under vacuum (for 18 h) to give a beige/brown solid (32.1 mmol, 91% yield).

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.oprd.8b00200.

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Details on MTP design, screening setup and validation experiments along with alternative visualizations and graphics to represent the screening results (PDF)

AUTHOR INFORMATION

Corresponding Author

*(C.E.B.) E-mail: [email protected]. ORCID

Cara E. Brocklehurst: 0000-0002-0484-5540 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors would like to thank the Open Access Analytical team and in particular Daniel Schmid and Franziska Schneider for analytical support. Michael Parmentier’s advice on the application of surfactants is also gratefully acknowledged. Thank you also goes to Alan Abrams for his delightful micelle graphic.

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REFERENCES

(1) Buitrago Santanilla, A.; Regalado, E. L.; Pereira, T.; Shevlin, M.; Bateman, K.; Campeau, L. C.; Schneeweis, J.; Berritt, S.; Shi, Z. C.; Nantermet, P.; Liu, Y.; Helmy, R.; Welch, C. J.; Vachal, P.; Davies, I. W.; Cernak, T.; Dreher, S. D. Nanomole-scale high-throughput chemistry for the synthesis of complex molecules. Science 2015, 347, 49−53. (2) Boga, S. B.; Christensen, M.; Perrotto, N.; Krska, S. W.; Dreher, S.; Tudge, M. T.; Ashley, E. R.; Poirier, M.; Reibarkh, M.; Liu, Y.; Streckfuss, E.; Campeau, L. C.; Ruck, R. T.; Davies, I. W.; Vachal, P. Selective functionalization of complex heterocycles via an automated strong base screening platform. React. Chem. Eng. 2017, 2, 446−450. (3) Cernak, T.; Gesmundo, N. J.; Dykstra, K.; Yu, Y.; Wu, Z. C.; Shi, Z. C.; Vachal, P.; Sperbeck, D.; He, S. W.; Murphy, B. A.; Sonatore, L.; Williams, S.; Madeira, M.; Verras, A.; Reiter, M.; Lee, C. H.; Cuff, J.; Sherer, E. C.; Kuethe, J.; Goble, S.; Perrotto, N.; Pinto, S.; Shen, D. M.; Nargund, R.; Balkovec, J.; DeVita, R. J.; Dreher, S. D. Microscale High-Throughput Experimentation as an Enabling Technology in Drug Discovery: Application in the Discovery of (Piperidinyl)E

DOI: 10.1021/acs.oprd.8b00200 Org. Process Res. Dev. XXXX, XXX, XXX−XXX