Biphasic Aqueous Reaction Conditions for Process-Friendly

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Biphasic Aqueous Reaction Conditions for Process-Friendly Palladium-Catalyzed C−N Cross-Coupling of Aryl Amines Subhash Pithani,† Marcus Malmgren,† Carl-Johan Aurell,† Grigorios Nikitidis,† and Stig D. Friis*,‡ †

Early Chemical Development, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden Medicinal Chemistry, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden

‡

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S Supporting Information *

rates, ultimately leading to reproducibility issues on a large scale.12,13 As a consequence, significant research efforts have gone into avoiding the use of these bases (Figure 1). On a small scale,

ABSTRACT: We herein describe a method for palladium-catalyzed C−N cross-coupling of aryl amines and aryl halides in a biphasic reaction medium composed of 2methyltetrahydrofuran (MeTHF) and water. By effective solubilization of the inorganic base used, common challenges associated with the scalability of Buchwald− Hartwig aminations using inorganic bases were circumvented. The mildly basic nature of the reaction conditions was highlighted by the facile coupling of a base-sensitive substrate, which could be converted to the corresponding product with a high level of crude purity. The method is operationally simple and displays an improved safety and sustainability profile compared with many alternative strategies for large-scale Buchwald−Hartwig amination. Relying on a commonly available dialkylbiarylphosphine ligand, this approach was applied to three clinically relevant C−N cross-coupling reactions on the hecto- to kilogram scale. KEYWORDS: C−N cross-coupling, process chemistry, green chemistry, weak base, palladium catalysis

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INTRODUCTION

Figure 1. Strategies to avoid insoluble bases in palladium-catalyzed C−N cross-coupling.20

Over the last 25 years, Buchwald−Hartwig amination has become an increasingly important strategy for the construction of C−N bonds.1−5 The C(sp2)−N bond is ubiquitous in drug discovery, and while classical strategies to forge this bond, such as SNAr reactions, the Curtius rearrangement, and coppermediated couplings, are still important transformations,6 their limited scope restricts broad applicability. More modern approaches, including photoredox/nickel catalysis,7 electrochemical,8 and C−H activation-dependent strategies have emerged in recent years,9,10 but the palladium-catalyzed Buchwald−Hartwig amination remains the gold standard for this transformation. Conditions under which this reaction takes place generally feature either a strong organic base such as tBuONa or LiHMDS or a weaker inorganic base such as Cs2CO3 or K3PO4.11 While the partially or fully soluble organic bases generally provide stirrable reaction mixtures, their strong basicity may cause reduced functional group tolerance, and their moisture-sensitive nature makes them challenging to handle on scale. On the other hand, the insoluble nature of the milder inorganic bases in common organic solvents may result in inconsistent mixing, poor mass transfer, and varying reaction © XXXX American Chemical Society

phosphazene bases have been reported to facilitate a broad range of palladium-catalyzed C−N cross-coupling reactions under mild conditions.14,15 However, the high cost and moisture-sensitive nature of this class of organic bases limit their applicability in large-scale synthesis. In 2018, Buchwald and co-workers reported that when a specialized triaryldialkylphosphine (AlPhos)-ligated palladium catalyst was employed, the amination of a broad scope of (pseudo)aryl halides could be realized using the common and inexpensive base 1,8diazabicyclo[5.4.0]undec-7-ene (DBU).16 While the ability to use DBU as the base, the homogeneous nature of the reaction mixture, and the overall mild reaction conditions are attractive features, the high cost and limited supply of the employed catalyst makes this strategy less attractive for multigram-scale C−N bond formations. Special Issue: Honoring 25 Years of the Buchwald-Hartwig Amination Received: May 21, 2019

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DOI: 10.1021/acs.oprd.9b00237 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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Table 1. Comparison of Conditions for C−N Cross-Coupling toward 3

conversiona to entry

base (equiv)

solvent

1b

3a

3b

amenable to large scale?

1 2 3 4 5 6 7

tAmylOK (4) tAmylOK (4) tAmylOK (4) iPr2NEt (4) K2CO3 (4) Cs2CO3 (4) Cs2CO3 (2)

dioxane THF DMF DMF DMF DMF MeTHF/waterd

63% 62% 10% 33% 3% − −

− − 61% − 35% 18% 90%

− − − − 52% 59% −

− − nob,c − nob,c nob,c yes

a

Conversion to product by LCMS using uncorrected UV response; the remainder of the mass balance is due to 1a. bInadequate crude purity. Prone to emulsification during workup. dMeTHF and water in a 2:1 ratio by volume.

c

1 and 2). When the solvent was switched to DMF, moderate conversion to the desired product 3a was observed along with significant N−S bond cleavage to form 1b (Table 1, entry 3). Using a milder organic or inorganic base did not remove the problem of tosyl deprotection but instead caused the reaction to fail or form undesired 3b as the major product (Table 1, entries 4−6). Furthermore, the aqueous workup, which was required to remove DMF, resulted in the formation of an emulsion on scale, thus eliminating the possibility of using this solvent. To address several issues at once, a mixture of 2methyltetrahydrofuran (MeTHF) and water was examined as the solvent in combination with Cs2CO3 as the base. This ensured smooth dissolution of the inorganic base and eliminated the need for an aqueous DMF containing workup, thus making these conditions amendable for scaled-up synthesis. At the same time, these conditions provided sufficient solubility of 1a in the heated reaction mixture to allow clean conversion to 3a with no detection of side products arising from cleavage of the tosyl group (Table 1, entry 7).24 Notably, no phase-transfer catalyst or surfactant was required for the reaction to proceed smoothly, and no major side products that could be attributed to the aqueous nature of the reaction mixture were observed.25−27 Concomitant with the initial identification of the biphasic aqueous reaction conditions as a key to the success of the C− N bond formation to provide intermediate 3a, further medicinal chemistry efforts had shown the corresponding 5fluoropyrimidine analogue 5 to ultimately provide a more attractive clinical candidate.22 Little reactivity difference between the substrates was observed, and the optimal conditions (Table 1, entry 7) could be applied directly to the multigram-scale synthesis of 5 (Scheme 1), albeit with a reduced catalyst loading. Starting from 194 g of 4, 2.9 L of a 2:1 mixture of MeTHF and water served as a practical and green reaction medium, ultimately enabling the isolation of 5 in 81% yield. Key to the success of this chemical step was the clean conversion to 5, which precipitated from the biphasic reaction mixture upon cooling.24 This allowed the product to be isolated by simple filtration and carried on to the next step without further purification.28 As a testament to the scalability of this strategy, similar reaction conditions have since been used to access 5 on a 10 kg scale.

To mitigate some of the challenges associated with scaling up palladium-catalyzed C−N cross-coupling reactions and as part of our continuous effort toward employing greener solvents, we speculated that large-scale Buchwald−Hartwig aminations could be performed in a biphasic aqueous medium. In combination with a common inorganic base, this should provide a mildly basic homogeneous biphasic reaction mixture, thus eliminating some of the scalability challenges associated with other strategies. Previous work on a milligram scale demonstrated the potential viability of this strategy, as simple model substrates could be coupled using strongly basic aqueous sodium or potassium hydroxide solutions.17−19

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RESULTS AND DISCUSSION As part of an ongoing project toward a Janus kinase (JAK) inhibitor, we became interested in exploring the scalability of Buchwald−Hartwig aminations in high-polarity solvents and solvent mixtures.21,22 Initial efforts were prompted by the poor solubility in common organic solvents displayed by the electrophilic coupling partner 1a and product 3a. This limited the amount of material that could be delivered by applying the strategy developed during the medicinal chemistry campaign. The reaction conditions, which relied on N,N-dimethylformamide (DMF) as the solvent, provided moderate conversion to the desired product along with the formation of the tosyldeprotected substrate (1b) and product (3b) as the major side products.23 Initial studies had shown that the use of 1b resulted in significantly slower catalytic turnover compared with 1a, ultimately necessitating several catalyst charges for the reaction to go to completion. Furthermore, as a direct consequence of the poor solubility displayed by 3a, a high level of crude purity was required to avoid purification by column chromatography, which was unfeasible on a multigram scale. With these challenges in mind, we set out to explore alternative reaction conditions to realize this C−N bondforming reaction (Table 1). During the medicinal chemistry campaign, a catalyst based on Pd2(dba)3 and DavePhos had been identified and used for milligram- to gram-scale synthesis of 3a. Applying this catalytic system, but with potassium tertamyl oxide as the base in an ethereal solvent, caused a complete shutdown of the desired amination reaction, presumably due to the poor solubility of 1a (Table 1, entries B

DOI: 10.1021/acs.oprd.9b00237 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

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to the product after 1 week in refluxing isopropanol with ptoluenesulfonic acid as the catalyst. On a milligram scale, the C−N bond had been forged using a XantPhos-ligated palladium catalyst in dioxane with Cs2CO3 as the base. However, performing the reaction on a multigram scale, with an overhead stirrer in place of a magnetic stir bar, resulted in a significant decrease in reaction rate and ultimately caused the reaction to stall. Speculating that this poorer performance was caused by the lack of grinding of the insoluble base effected by the magnetic stir bar on a small scale, we turned our attention toward rendering the reaction mixture homogeneous. This approach was further encouraged by the observation that addition of water (1 vol %) to a stalled reaction caused productive C−N cross-coupling to resume. Upon application of the Pd2(dba)3/DavePhos-based biphasic aqueous reaction conditions, this time using a 9:1 ratio of MeTHF to water, the reaction showed consistently high and clean conversion to the desired product even on a hectogram scale (Scheme 3).24,31

Scheme 1. C−N Cross-Coupling in an Aqueous Biphasic Reaction Mixture as a Key Step toward a Potent JAK Inhibitor

More often than not, early process chemistry teams are under significant time pressure to deliver hecto- to kilogram quantities of complex molecules and thus allow little time for route scouting and reaction optimization. As a consequence, it is key to have robust and process-friendly bond-forming methodologies that allow important molecular disconnections employed by medicinal chemists.29 As part of an ongoing project, we needed to access 2,6-difunctionalized pyridine 8, and a synthetic strategy including palladium-catalyzed C−N cross-coupling of 6 and 7 was identified as the most viable. Saving valuable time, the aqueous biphasic reaction conditions previously described could be applied directly (Scheme 2).

Scheme 3. Late-Stage C−N Cross-Coupling To Access ERK Inhibitor 11, Applying a Biphasic Aqueous Reaction Mixture

Scheme 2. C−N Cross-Coupling in an Aqueous Biphasic Reaction Mixture To Access an Early Intermediate

Attempts to further optimize the reaction by switching the organic component of the solvent to dioxane or MeCN were not fruitful, and the catalyst loading could not be reduced below 8 mol % Pd on this scale. For consistently high conversion to be obtained, the reaction had to be well-stirred, presumably to ensure a high contact area between the phases. Upon completion of the reaction, the basic aqueous phase was removed, and a mild acidic wash served to efficiently remove excess 10. Subsequently, the palladium level could be significantly reduced by applying a silica-based scavenger. Purification by preparative supercritical fluid chromatography (SFC) afforded 11 in 70% yield starting from 0.2 mol of 9. Subsequent campaigns to supply material for late preclinical studies have since applied similar biphasic aqueous reaction conditions to prepare 2.8 kg of 11, which was transformed into the final active pharmaceutical ingredient by a simple salt formation. The development and application of greener and more sustainable reaction conditions that are at the same time competitive in terms of reaction performance, safety, and process operations are key to rendering the drug development industry less resource-intensive. In a number of Buchwald− Hartwig aminations, we have been able to show that the substitution of classic organic solvents like DMF and dioxane for a mixture of water and MeTHF can provide milder and more scalable reaction conditions, often leading to an improved yield and better impurity profile.32 In addition to the attractive safety profile of MeTHF, this solvent is

Interestingly, an initial screening for suitable reaction conditions had shown that multiple charges of an XPhosbased catalyst were required for the reaction to go to completion when toluene was used as the solvent. On the other hand, with the biphasic aqueous reaction conditions, no secondary addition of catalyst was required. In contrast to the synthesis of 5, both the starting materials and the product of this cross-coupling displayed ample solubility in the reaction mixture at room temperature. Heating to gentle reflux for 13 h ensured complete and clean conversion to the desired product 8.24 After cooling, the crude product could be collected by precipitation with heptane and simple filtration. Redissolution of the crude product followed by treatment with a palladium scavenger and activated carbon set the stage for a recrystallization from EtOAc to afford analytically pure 8 in 92% yield on a 112 g scale. Subsequent batches of increasing size have since applied C−N cross-coupling in this biphasic aqueous reaction medium to access 8 on a >50 kg scale, thus truly highlighting the scalability and process-friendly nature of this chemistry. The 11-step early process route toward 11, a potent inhibitor of the extracellular signal-regulated kinase (ERK), features a Buchwald−Hartwig amination as the last step prior to a final salt formation.30 Initial efforts to eliminate the need for transition metal catalysis, instead relying on an SNAr mechanism, proved inefficient under both basic and acidic conditions. The latter provided a maximum of 50% conversion C

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114.7, 114.7, 43.7, 21.2. 19F NMR (376 MHz, DMSO-d6): δ (ppm) −120.1 (s, 1F), −146.1 (s, 1F). HRMS: calcd for C26H19F2N5O6S2 ([M + H]+), 600.0818; found, 600.0844. 1-(6-((4-Methylthiazol-2-yl)amino)pyridin-2-yl)pyrrolidin-2-one (8). A dry 5 L reactor under nitrogen was charged with 4-methylthiazol-2-amine (56.1 g, 482 mmol, 99% purity), 1-(6-bromopyridin-2-yl)pyrrolidin-2-one (106.7 g, 438.2 mmol, 99% purity), tris(dibenzylideneacetone)dipalladium(0) (12.0 g, 13.1 mmol), 2-(dicyclohexylphosphino)-2′-(N,N-dimethylamino)biphenyl (10.4 g, 26.3 mmol), and cesium carbonate (286 g, 876 mmol). Subsequently, degassed 2-methyltetrahydrofuran (800 mL) and water (400 mL) were added, and the reactor was subjected to five cycles of vacuum and nitrogen backfill. The reaction mixture was heated to gentle reflux (approximately 72 °C internal temperature) under agitation by an overhead stirrer. After 13 h, LCMS showed complete consumption of the starting material, and the reaction mixture was cooled to 10 °C. Heptane (1.6 L) was added, and the mixture was stirred for 1 h. The solid was collected by filtration and washed with water (3 × 500 mL) and heptane (500 mL) to give the crude product (170 g) as a gray solid. The crude material was dissolved in a 9:1 mixture of CH2Cl2 and MeOH (2.0 L) before the metal scavenger Silicycle SiliaMetS Thiol, loading 1.42 mmol/g (30.0 g) was added along with DARCO G-60, -100 mesh activated carbon powder (10.0 g). The mixture was stirred at room temperature. After 16 h, the mixture was filtered through a pad of silica (d = 10 cm, l = 4 cm), eluting with a 9:1 mixture of CH2Cl2 and MeOH (1.0 L). The volatiles were removed in vacuo to afford a beige solid (116 g). This material was recrystallized from EtOAc, collected by filtration, washed with EtOAc (500 mL), and dried under vacuum at 45 °C to afford the title compound (112.0 g, 99 wt % purity by 1H NMR, 92% corrected yield) as a beige solid. 1 H NMR (400 MHz, DMSO-d6): δ (ppm) 11.18 (s, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.66 (t, J = 8.0 Hz, 1H), 6.70 (d, J = 7.8 Hz, 1H), 6.44−6.62 (m, 1H), 4.19 (t, J = 7.1 Hz, 2H), 2.57 (t, J = 8.1 Hz, 2H), 2.18−2.28 (m, 3H), 2.08 (quintet, J = 7.8 Hz, 2H). 13C NMR (100 MHz, DMSO-d6): δ (ppm) 174.5, 158.7, 150.6, 149.8, 146.5, 139.2, 105.3, 105.2, 104.5, 48.3, 33.1, 17.2, 17.0. HRMS: calcd for C13H14N4OS ([M + H]+), 275.0961; found, 275.0956. (S)-7-(3,4-Difluorobenzyl)-5-(methoxymethyl)-2-(5methyl-2-((1-methyl-1H-pyrazol-5-yl)amino)pyrimidin4-yl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one (11). A dry 2 L reactor under nitrogen was charged with (R)-2-(2chloro-5-methylpyrimidin-4-yl)-7-(3,4-difluorobenzyl)-6-(methoxymethyl)-6,7-dihydroimidazo[1,2-a]pyrazin-8(5H)-one (104.7 g, 225.6 mmol, 93.5% purity), 1-methyl-1H-pyrazol-5amine (33.5 g, 338.5 mmol, 98% purity), and cesium carbonate (147.0 g, 451.3 mmol). Degassed 2-methyltetrahydrofuran (1.2 L) and water (120 mL) were added, and the reactor was subjected to six cycles of vacuum and nitrogen backfill. Subsequently, tris(dibenzylideneacetone)dipalladium(0) (8.27 g, 9.0 mmol) and 2-(dicyclohexylphosphino)-2′-(N,Ndimethylamino)biphenyl (7.10 g, 18.1 mmol) were added, and the reactor was subjected to another six cycles of vacuum and nitrogen backfill. The reaction mixture was heated to gentle reflux (approximately 72 °C internal temperature) under agitation by an overhead stirrer (500 rpm). After 21 h, the mixture was cooled to 40 °C and washed with water (500 mL), 1 M aqueous citric acid (400 mL + 200 mL), and water (200 mL). The organic layer was treated with the metal

considered renewable and features a significantly reduced lifecycle carbon footprint compared with many other organic solvents.33,34 Furthermore, the use of these biphasic aqueous reaction conditions eliminates the need for a potentially exothermic quench of any excess base after reaction completion, thus minimizing the risk of impurity formation and further improving process safety.

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CONCLUSION We have developed a new set of mildly basic aqueous biphasic reaction conditions for palladium-catalyzed C−N crosscoupling. This general strategy, which features a combination of MeTHF and water as the solvent, was applied to three diverse C−N cross-coupling reactions related to ongoing drug development projects and thus enabled the Buchwald− Hartwig aminations to be performed on a hecto- to multikilogram scale. Consistently high yields were obtained with no observation of diminishing reaction rates as the transformations progressed, and no impurities related to the aqueous nature of the reaction medium were identified. Highlighting the mildly basic nature of the conditions, aryl chloride 4 could be coupled without compromising the basesensitive protecting group, thus avoiding catalyst poisoning and enabling good process control. We envision that the broad applicability and ease of implementation associated with these biphasic aqueous reaction conditions will allow their widespread use in other process chemistry departments as a green and scalable alternative to currently available strategies.

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EXPERIMENTAL SECTION

5-Fluoro-N-(2-fluoro-3-(methylsulfonyl)phenyl)-4-(7nitro-1-tosyl-1H-indol-3-yl)pyrimidin-2-amine (5). A dry 5 L reactor under nitrogen was charged with 3-(2-chloro-5fluoropyrimidin-4-yl)-7-nitro-1-tosyl-1H-indole (194.3 g, 417.7 mmol, 96% purity), 2-fluoro-3-(methylsulfonyl)aniline hydrochloride salt (113.0 g, 500.8 mmol), tris(dibenzylideneacetone)dipalladium(0) (19.9 g, 21.7 mmol), and 2-(dicyclohexylphosphino)-2′-(N,N-dimethylamino)biphenyl (17.1 g, 43.5 mmol). Subsequently, degassed 2methyltetrahydrofuran (2.0 L) and cesium carbonate (298.0 g, 913.2 mmol) in water (0.9 L) were added, and the reactor was subjected to six cycles of vacuum and nitrogen backfill. The reaction mixture was heated to gentle reflux (approximately 72 °C internal temperature) under agitation by an overhead stirrer. After 16 h, heptane (2.0 L) was added, and the reaction mixture was cooled to 5 °C and stirred for 30 min. The solid was collected by filtration, washed with heptane (500 mL), water (2 × 1.0 L), 2-methyltetrahydrofuran (600 mL), and heptane (600 mL), and then dried under vacuum at 40 °C to afford the title compound (254.4 g, 80 wt % purity by 1H NMR, 81% corrected yield) as a brown solid, which was used in the next step without further purification. 1 H NMR (400 MHz, DMSO-d6): δ (ppm) 9.78 (s, 1H), 8.82 (d, J = 7.9 Hz, 1H), 8.68 (d, J = 3.0 Hz, 1H), 8.60 (d, J = 1.4 Hz, 1H), 8.12 (t, J = 7.1 Hz, 1H), 7.95 (d, J = 7.8 Hz, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.64 (t, J = 6.3 Hz, 1H), 7.43−7.54 (m, 4H), 3.31 (s, 3H), 2.40 (s, 3H). 13C NMR (100 MHz, DMSO-d6) (complex spectrum due to C−F splitting, all signals given): δ (ppm) 156.6, 156.5, 153.2, 151.3, 150.7, 148.8, 146.8, 146.7, 146.7, 146.5, 146.2, 138.4, 134.9, 134.7, 134.1, 131.4, 131.3, 131.0, 130.1 (2C), 129.3, 129.2, 139.1, 128.9, 128.5, 127.2, 127.0 (2C), 124.8, 124.7, 124.7, 124.7, 123.6, 121.8, D

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(4) Louie, J.; Hartwig, J. F. Palladium-catalyzed synthesis of arylamines from aryl halides. Mechanistic studies lead to coupling in the absence of tin reagents. Tetrahedron Lett. 1995, 36, 3609−3612. (5) Ruiz-Castillo, P.; Buchwald, S. L. Applications of PalladiumCatalyzed C−N Cross-Coupling Reactions. Chem. Rev. 2016, 116, 12564−12649. (6) Monnier, F.; Taillefer, M. Catalytic C−C, C−N, and C−O Ullmann-Type Coupling Reactions. Angew. Chem., Int. Ed. 2009, 48, 6954−6971. (7) Corcoran, E. B.; Pirnot, M. T.; Lin, S.; Dreher, S. D.; DiRocco, D. A.; Davies, I. W.; Buchwald, S. L.; MacMillan, D. W. C. Aryl Amination Using Ligand-Free Ni(II) Salts and Photoredox Catalysis. Science 2016, 353, 279−283. (8) Li, C.; Kawamata, Y.; Nakamura, H.; Vantourout, J. C.; Liu, Z.; Hou, Q.; Bao, D.; Starr, J. T.; Chen, J.; Yan, M.; Baran, P. S. Electrochemically Enabled, Nickel-Catalyzed Amination. Angew. Chem., Int. Ed. 2017, 56, 13088−13093. (9) Park, Y.; Kim, Y.; Chang, S. Transition Metal-Catalyzed C−H Amination: Scope, Mechanism, and Applications. Chem. Rev. 2017, 117, 9247−9301. (10) Ruffoni, A.; Juliá, F.; Svejstrup, T. D.; McMillan, A. J.; Douglas, J. D.; Leonori, D. Practical and regioselective amination of arenes using alkyl amines. Nat. Chem. 2019, 11, 426−433. (11) Surry, D. S.; Buchwald, S. L. Biaryl Phosphane Ligands in Palladium-Catalyzed Amination. Angew. Chem., Int. Ed. 2008, 47, 6338−6361. (12) Schlummer, B.; Scholz, U. Palladium-Catalyzed C−N and C− O Coupling − A Practical Guide from an Industrial Vantage Point. Adv. Synth. Catal. 2004, 346, 1599−1626. (13) Meyers, C.; Maes, B. U. W.; Loones, K. T. J.; Bal, G.; Lemière, G. L. F.; Dommisse, R. A. Study of a New Rate Increasing “Base Effect” in the Palladium-Catalyzed Amination of Aryl Iodides. J. Org. Chem. 2004, 69, 6010−6017. (14) Buitrago Santanilla, A.; Christensen, M.; Campeau, L.-C.; Davies, I. W.; Dreher, S. D. P2Et Phosphazene: A Mild, Functional Group Tolerant Base for Soluble, Room Temperature Pd-Catalyzed C−N, C−O, and C−C Cross-Coupling Reactions. Org. Lett. 2015, 17, 3370−3373. (15) Ahneman, D. T.; Estrada, J. G.; Lin, S.; Dreher, S. D.; Doyle, S. G. Predicting reaction performance in C−N cross-coupling using machine learning. Science 2018, 360, 186−190. (16) Dennis, J. M.; White, N. A.; Liu, R. Y.; Buchwald, S. L. Breaking the Base Barrier: An Electron-Deficient Palladium Catalyst Enables the Use of a Common Soluble Base in C−N Coupling. J. Am. Chem. Soc. 2018, 140, 4721−4725. (17) Kuwano, R.; Utsunomiya, M.; Hartwig, J. F. Aqueous Hydroxide as a Base for Palladium-Catalyzed Amination of Aryl Chlorides and Bromides. J. Org. Chem. 2002, 67, 6479−6486. (18) Wüllner, G.; Jänsch, H.; Kannenberg, S.; Schubert, F.; Boche, G. Palladium-catalyzed amination of aromatic halides in watercontaining solvent systems: A two-phase protocol. Chem. Commun. 1998, 1509−1510. (19) Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.; Buchwald, S. L. Expanding Pd-Catalyzed C−N Bond-Forming Processes: The First Amidation of Aryl Sulfonates, Aqueous Amination, and Complementarity with Cu-Catalyzed Reactions. J. Am. Chem. Soc. 2003, 125, 6653−6655. (20) Many competent conditions for palladium-catalyzed C−N cross-couplings have been described. The term “Standard Conditions” represents a set of mildly basic conditions that are frequently presented in the literature. (21) Grimster, N. P.; Anderson, E.; Alimzhanov, M.; Bebernitz, G.; Bell, K.; Chuaqui, C.; Deegan, T.; Ferguson, A. D.; Gero, T.; Harsch, A.; Huszar, D.; Kawatkar, A.; Kettle, J. G.; Lyne, P.; Read, J. A.; Rivard Costa, C.; Ruston, L.; Schroeder, P.; Shi, J.; Su, Q.; Throner, S.; Toader, D.; Vasbinder, M.; Woessner, R.; Wang, H.; Wu, A.; Ye, M.; Zheng, W.; Zinda, M. Discovery and Optimization of a Novel Series of Highly Selective JAK1 Kinase Inhibitors. J. Med. Chem. 2018, 61, 5235−5244.

scavenger Silicycle SiliaMetS Thiol, loading 1.42 mmol/g (50 g), stirring at 40 °C for 3 h. The solid was filtered off, and the filtrate was further treated with Silicycle SiliaMetS Thiol, loading 1.42 mmol/g (100 g), stirring at 40 °C for 16 h. The solid was filtered off, and the volatiles were removed in vacuo to give the crude product (211 g), which was purified by preparative SFC using a Kromasil DIOL column (10 μm, 250 mm × 50 mm), eluting with 25−35% EtOH/NH3 (99.5/0.5) in scCO2 (140 bar, 40 °C, 280 nm) at a flow rate of 450 mL/ min. The resulting residue was coevaporated with MeCN (2 × 500 mL) to give the title compound (90.0 g, 87 wt % purity by 1 H NMR, including 4.5 wt % MeCN, 70% corrected yield) as a dry foam. 1 H NMR (400 MHz, DMSO): δ (ppm) 9.20 (s, 1H), 8.31 (s, 1H), 7.93 (s, 1H), 7.44−7.52 (m, 1H), 7.36−7.43 (m, 1H), 7.33 (d, J = 1.9 Hz, 1H), 7.21−7.30 (m, 1H), 6.30 (d, J = 1.9 Hz, 1H), 5.08 (d, J = 15.4 Hz, 1H), 4.41−4.57 (m, 2H), 4.38 (d, J = 15.5 Hz, 1H), 3.99−4.07 (m, 1H), 3.70 (s, 3H), 3.40 (dd, J = 10.1, 5.0 Hz, 1H), 3.27−3.32 (m, 1H), 3.17 (s, 3H), 2.51 (s, 3H). 13C NMR (100 MHz, DMSO-d6): δ (ppm) 160.8, 158.3, 156.9, 155.8, 150.3 (dd, JC−F = 72.5, 12.8 Hz), 147.8 (dd, JC−F = 71.6, 12.7 Hz), 141.6, 138.6, 137.6, 137.2, 135.6 (dd, JC−F = 5.4, 3.7 Hz), 124.5 (dd, JC−F = 6.5, 3.4 Hz), 123.9, 117.5 (d, JC−F = 17.0 Hz), 117.5, 116.7 (d, JC−F = 17.4 Hz), 97.9, 70.9, 58.6, 54.3, 47.5, 44.1, 35.4, 16.6. 19F NMR (376 MHz, DMSO-d6): δ (ppm) −138.7 (d, JF−F = 22.6 Hz, 1F), −140.9 (d, JF−F = 22.6 Hz, 1F). HRMS: calcd for C24H24F2N8O2 ([M + H]+), 495.2063; found, 495.2074.

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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.9b00237. NMR spectra for compounds 5, 8, and 11 (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Stig D. Friis: 0000-0003-4330-5173 Funding

S.D.F. acknowledges the AstraZeneca PostDoc Program for their financial support. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors gratefully acknowledge Dr. Hans Emtenäs and Dr. Magnus J. Johansson for advice on the preparation of this article as well as Anna Jonson for purification support.

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REFERENCES

(1) Guram, A. S.; Buchwald, S. L. Palladium-Catalyzed Aromatic Aminations with in Situ Generated Aminostannanes. J. Am. Chem. Soc. 1994, 116, 7901−7902. (2) Paul, F.; Patt, J.; Hartwig, J. F. Palladium-Catalyzed Formation of Carbon-Nitrogen Bonds. Reaction Intermediates and Catalyst Improvements in the Hetero Cross-Coupling of Aryl Halides and Tin Amides. J. Am. Chem. Soc. 1994, 116, 5969−5970. (3) Guram, A. S.; Rennels, R. A.; Buchwald, S. L. A Simple Catalytic Method for the Conversion of Aryl Bromides to Arylamines. Angew. Chem., Int. Ed. Engl. 1995, 34, 1348−1350. E

DOI: 10.1021/acs.oprd.9b00237 Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development

Communication

(22) An article describing the development of this Janus kinase inhibitor is in preparation. (23) Liu, Y.; Shen, L.; Prashad, M.; Tibbatts, J.; Repic, O.; Blacklock, T. J. A Green N-Detosylation of Indoles and Related Heterocycles Using Phase Transfer Catalysis. Org. Process Res. Dev. 2008, 12, 778− 780. (24) The cross-coupling generally proceeded with clean conversion (>90% of the LCMS UV peak area could be attributed to the substrate or product, excluding signals arising from the palladium source or supporting ligand) and no formation of any single major impurity (