Utilizing Native Directing Groups: Mechanistic Understanding of a

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Utilizing Native Directing Groups: Mechanistic Understanding of a Direct Arylation Leads to Formation of Tetracyclic Heterocycles via Tandem Intermolecular, Intramolecular C−H Activation Steven R. Wisniewski,*,† Scott A. Savage,† Evan O. Romero,† Martin D. Eastgate,† Yichen Tan,† Eric M. Simmons,† R. Erik Plata,‡,§ John R. Sowa, Jr.,‡,∥ and Donna G. Blackmond‡ †

Chemical and Synthetic Development, Bristol-Myers Squibb, One Squibb Drive, New Brunswick, New Jersey 08903, United States Department of Chemistry, Scripps Research, 10550 North Torrey Pines Road, La Jolla, California 92037, United States

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‡

S Supporting Information *

ABSTRACT: A mechanistic study on a direct arylation using a native picolylamine directing group is reported. Kinetic studies determined the concentration dependence of substrates and catalysts, as well as catalyst degradation, which led to the development of a new set of reaction conditions capable of affording a robust kinetic profile. During reaction optimization, a small impurity was observed, which was determined to be a dual C−H activation product. A second set of conditions were found to flip the selectivity of the C−H activation to form this tetracycle in high yield. A catalytic cycle is proposed for the intermolecular/intramolecular C−H activation pathway.

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INTRODUCTION Direct arylation1 is a powerful tool for the rapid installation of aryl groups, building molecular complexity without prefunctionalization. Recently, we disclosed our proposed commercial route to the active pharmaceutical ingredient (API) of an IKur inhibitor, BMS-919373 (Figure 1), which utilized a direct arylation to install the phenyl ring, directed by the 2picolylamine side chain.2

Scheme 1. Route Utilizing Suzuki Cross-Coupling To Install Arene

bromoisatin itself is 1,2,3-substituted, its traditional synthesis from bromoaniline is nontrivial. In contrast, installing the phenyl group through a C−H activation enabled the use of isatoic anhydride (Scheme 2), shortening the route to the tertbutyl-protected API (2) by two steps, driving significant gains in efficiency and dramatically lowering the cost of the heterocycle starting material. The challenges associated with this reaction required detailed mechanistic studies to optimize and develop this C−H functionalization process, the results of which are reported herein. Although there are no previous examples of the C5-direct arylation of quinazoline systems, Qi and Daugulis reported the C8-direct arylation of naphthalenes, directed by picolinamide,4 utilizing palladium catalysis. Since those initial reports, C−H activation at the C8 position has been demonstrated to afford a library of functionalized naphthalenes.5 Based on this precedent, we were confident about the utilization of the C− H activation in our route to BMS-919373.

Figure 1. Structure of BMS-919373.

Several routes were investigated during the route scouting phase of this project, including the installation of the key C5phenyl ring through cross-coupling early in the synthesis. The direct arylation in the synthetic route required significant optimization and mechanistic understanding to develop a robust, scalable process. However, the important advantages of employing a C−H activation as the key disconnection justified these scientific endeavors, the most significant being its impact on the synthetic strategy. It is a simplifying strategy, enabling the use of feedstock chemicals as starting materials. In the previous route,3 a 1,2,3-trisubstituted arene was synthesized from bromoisatin in three steps, the last of which was a Suzuki coupling, in 19% overall yield (Scheme 1). Given that © 2019 American Chemical Society

Received: March 24, 2019 Published: May 22, 2019 7961

DOI: 10.1021/acs.joc.9b00823 J. Org. Chem. 2019, 84, 7961−7970

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The Journal of Organic Chemistry Scheme 2. Route Utilizing Direct Arylation To Install Arene

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RESULTS AND DISCUSSION Optimization of the direct arylation required a careful choice of metal and arene source. Even though Rh6 and Ru7 are capable of performing direct arylations, we chose palladium for optimization based on the literature precedent and improved sustainability. The use of a halobenzene would allow a simple, inexpensive arene source, which is preferred to an oxidative direct arylation with phenylboronic acid,8 as it would require functionalization of the halobenzene. Further, although effective in many direct arylations, the use of diaryliodonium salts9 introduces thermal stability concerns in addition to a significant amount of waste. There, we sought to develop a palladium-catalyzed C−H activation with a halobenzene. Throughout the optimization process, each variable (palladium source, solvent, ligand, base, arene source) in the reaction mixture was investigated to determine the optimal reaction conditions (Table 1).10 Similar to the reported

complete conversion to a product. Anisole was chosen as the solvent because of its higher boiling point and lower toxicity.11 Attempts to increase solubility by use of high boiling, polar, aprotic solvents such as dimethylformamide (DMF), dimethylacetamide (DMAc), and N-methyl-2-pyrrolidone (NMP) completely shut down the reaction. The variable that had the most significant impact on the reaction was the base. The nature of the base proved to be critical as moving to fully soluble organic bases, such as triethylamine, 2,6-lutidine, and 1,8-diazabicyclo[5.4.0]undec-7ene inhibited the desired transformation (Table 1). Furthermore, strong inorganic bases, such as KOt-Bu and NaOMe, were ineffective in the transformation, as were weak bases such as CsF and KF. Potassium phosphate bases were not effective in this transformation. Carbonate, bicarbonate, and acetate bases were also tested in the direct arylation. Unlike many similar C−H functionalizations, the addition of a catalytic amount of acid, such as acetic acid, pivalic acid, or 2phenylbenzoic acid12 with KHCO3 as the base, did not improve the reaction profile relative to the inorganic base alone. Sodium salts of these bases did not afford conversion to the product. However, increasing the equivalents of the potassium and cesium salts of these bases had a drastic effect on the impurity profile as significant levels of a new impurity were observed (Figure 2). Note that the temperature was increased to 120 °C to improve reaction robustness.2 Characterization of this new impurity showed that it was a novel tetracycle13 (3a), which could be formed by the product undergoing a second C−H activation of the ortho C−H bond on the newly installed aromatic ring. Modeling of the product−palladium complex computationally showed this H atom in close proximity to the empty coordination site on Pd,

Table 1. Summary of HTE Optimization

change from above conditions

RAP 2:RAP 1

none NMP, DMAc, or DMF as solvent NEt3 as base 2,6-lutidine as base addition of PPh3 (no anisole) bromobenzene instead of PhI phenyltriflate instead of PhI

91:9 2:98 4:96 17:83 14:86 0:100 0:100

conditions, iodobenzene was the optimal source of the arene, as bromobenzene and phenyltriflate were unreactive under an array of reaction conditions. KHCO3 was effective although complete conversion was not observed at 110 °C. Several other interesting trends were observed during reaction optimization. First, no significant difference in yield or conversion was observed across a variety of palladium precursors (Pd(OAc)2, (MeCN)2PdCl2, Pd2dba3). The addition of a ligand (monodentate and bidentate phosphines, phosphites, diketocompounds, substituted pyridines) inhibited the reaction. Further screening revealed that the use of pyridine as a ligand in a 1:1 L/M ratio slowed the rate of the reaction but still resulted in complete conversion. Because of the high reaction temperature, only high boiling solvents (>100 °C) were tested in the direct arylation, of which only dioxane and anisole provided

Figure 2. Effect of base equivalents on the generation of new impurity, 3a. 1 (1.0 equiv), base (1.0−3.0 equiv), Pd(OAc)2 (0.05 equiv), PhI (12.0 equiv), anisole (5 mL/g), 120 °C. 7962

DOI: 10.1021/acs.joc.9b00823 J. Org. Chem. 2019, 84, 7961−7970

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The Journal of Organic Chemistry presumably allowing for a facile second C−H activation event (Figure 3).

Figure 3. Dual C−H activation product (3a) and calculated structure of the putative precursor product−Pd complex (key: gray = C, white = H, aqua = H, blue = N, turquoise = Pd, purple = I).

Figure 4. Same excess and product addition experiments. Standard reaction conditions as in Scheme 1. Same excess: [1]0 = 0.14 M; [PhI] = 3.16 M. Product addition: [1]0 = 0.14 M; [PhI] = 3.16 M; [2]0 = 0.14 M.

In selecting the base for this process, there is a balance between reaction profile (conversion and impurity formation) and robustness. If a reaction generates 5% of an impurity that can be easily removed during the isolation, these reaction conditions would be preferred to a set of reaction conditions where there is a significant risk of a reaction failing because of catalyst degradation (for example). Therefore, analysis of the bases tested in the direct arylation quickly eliminated KHCO3 (1.0 equiv) and KOAc (1.0−3.0 equiv). Potassium acetate at any equivalent was unable to give full reaction conversion, as did equimolar amounts of KHCO3. Higher equivalents (1−3) of KHCO3 increase the formation of 3a. Moving to a stronger base, K2CO3, also promotes this second C−H activation. KOPiv is promising as increasing the amount of base to 3.0 equiv has little effect on the formation of 3a. In regard to the cesium bases, both perform well at 1.0 equiv, with ∼1.3 AP14 of 3a formed under these conditions, whereas 2.0−3.0 equiv results in significant impurity formation. CsOPiv is significantly less hygroscopic than CsOAc, and therefore, the top two options for the C−H activation are KOPiv and CsOPiv. With a wider tolerance of base charge, KOPiv was chosen for the initial set of conditions for the direct arylation of 1, and kinetic studies of the reaction were carried out to understand reaction driving forces and catalyst robustness using reaction progress kinetic analysis.15 Standard reaction conditions are shown in Scheme 3. “Same excess” experiments15 (“excess” for Scheme 3. Standard Reaction Conditions for Kinetic Studies

a reaction. A + B → C is defined as [B]0 − [A]0) noted the presence of catalyst deactivation and no product inhibition (Figure 4). The results of this experiment are concerning for process developmentthe reason behind catalyst deactivation must be understood and remedied to ensure a robust process is developed, thereby mitigating any risk of reaction failure. Concentration dependences of reaction components were obtained from initial rate measurements to avoid the complication of the catalyst decay on the rate over the course of reaction progress. Figure 5 shows that the rate is zero order in [1], first order in [PhI], and zero order in base. Figure 6

Figure 5. Initial rate dependences on 1 (top), PhI (middle), and KOPiv (bottom). See the Supporting Information for reaction conditions.

shows that the reaction is first order in [Pd].16 These results suggest that the Pd catalyst is saturated with 1 and that the subsequent oxidative addition of [PhI] may be ratedetermining. To further understand the catalytic system, a series of experiments were then completed to investigate catalyst 7963

DOI: 10.1021/acs.joc.9b00823 J. Org. Chem. 2019, 84, 7961−7970

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The Journal of Organic Chemistry

during the crystallization of the product (and the resultant KI formed in the reaction), which would sequester Pd from the reaction, leading to catalyst deactivation. To address this issue, we investigated the reaction with CsOPiv, which had already been demonstrated to be effective and minimize the formation of the cyclized impurity. In practice, CsOPiv was formed in situ from the reaction of Cs2CO3 (0.51 equiv) and pivalic acid (1.05 equiv). The kinetics of the reaction under these conditions afforded the desired linear reaction profile expected when PhI is in large excess, and the catalyst is stable (Figure 8). Figure 6. Order in Pd determined via variable time normalization analysis,16 where linearity with x-axis = time × Pdx, where x = 1 indicates first order in [Pd]. See the Supporting Information for reaction conditions.

degradation. Because an inorganic iodide salt (KI) is generated as a byproduct of the reaction, an insoluble PdI2 species could form,17 which, in turn, could lead to a decay in the rate of the reaction. To test this hypothesis, a spiking study with tetrabutylammonium iodide (TBAI) was conducted with 0− 2.3 equiv of TBAI (Figure 7). As little as 0.3 equiv TBAI Figure 8. Kinetic study of the direct arylation with CsOPiv (1 (1.0 equiv), Pd(OAc)2, (5 mol %), Cs2CO3 (0.51 equiv), PivOH (1.05 equiv), PhI (12 equiv), anisole (5 mL/g), 120 °C, average of 4 runs).

Under the optimized conditions, similar in-process yields of ∼95% and low levels of cyclized impurity 3a ( 250 °C. 1H NMR (500 MHz, d7DMF): δ 9.75 (s, 1H), 9.23 (s, 1H), 9.15 (d, J = 1.5 Hz, 1H), 8.68 (d, J = 1.2 Hz, 1H), 8.55−8.50 (m, 1H), 8.45−8.39 (m, 1H), 8.13−8.07

substituted arenes resulted in complete regioselectivity in the intramolecular C−H activation, presumably controlled by steric interactions (entries 2, 6). 3,5-Dichloroiodobenzene was unreactive in the dual C−H activation, resulting in only the C−H activation product, presumably due to the steric hindrance of the arene. Also, 3-iodopyridine gave a mixture of regioisomers in the intramolecular C−H activation step.26 In summary, we have determined the key steps in the catalytic cycle for the late-stage palladium-catalyzed C−H arylation directed by picolylamine. Investigations into the impurities generated in the reaction led to the discovery of a dual C−H activation byproduct resulting from an intramolecular, intermolecular C−H activation pathway. A methodology that exploits this side product formation to afford novel tetracycles efficiently in one step was developed.

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EXPERIMENTAL SECTION

General Considerations. All reagents were purchased from commercial sources. Standard benchtop techniques were employed for handling air-sensitive reagents. Melting points (°C) are uncorrected. NMR spectra were recorded on a 400 or 500 MHz spectrometer. Data are presented as follows: chemical shift (ppm), multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet, br = broad), coupling constant J (Hz), and integration. Analytical thinlayer chromatography (TLC) was performed on TLC silica gel plates (0.25 mm) precoated with a fluorescent indicator. Visualization of the TLC plates was effected with ultraviolet light. Standard flash chromatography procedures were followed using 100−200 mesh silica gel. High resolution mass spectrometry (HRMS) samples were run on the Thermo LTQ-Orbitrap with an Acquity Classic inlet. Procedure for Initial KOPiv Conditions. To a 40 mL scintillation vial with stir bar was added N-(tert-butyl)-5-(4((pyridin-2-ylmethyl)amino)quinazolin-2-yl)pyridine-3-sulfonamide (2.0 g, 4.46 mmol), Pd(OAc)2 (50 mg, 0.05 equiv), potassium pivalate (1.87 g, 3.0 equiv), iodobenzene (12 equiv), and anisole (10 mL). The vial was capped with a pressure relief septa. The reaction mixture was heated to 110 °C in a pie block until complete conversion was observed, as judged by ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS) (∼16 h). Procedure for Inorganic Salt Spiking Study. To a 40 mL scintillation vial with stir bar was added N-(tert-butyl)-5-(4-((pyridin2-ylmethyl)amino)quinazolin-2-yl)pyridine-3-sulfonamide (2.0 g, 4.46 mmol), Pd(OAc)2 (50 mg, 0.05 equiv), potassium pivalate (1.87 g, 3.0 equiv), iodobenzene (12 equiv), and anisole (10 mL). TBAI, TBAOTf, KPF6, KOTf, and KI (0.3 equiv) were then spiked into the reaction. The vial was capped with a pressure relief septa. The reaction mixture was heated to 110 °C in a pie block. Aliquots were taken and subjected to liquid chromatography analysis to determine the rate of starting material consumption. Procedure for Palladacycle Formation (4). Under ambient conditions, 1 (30 mg, 0.067 mmol) was dissolved in anhydrous THF. One equivalent of Pd(OAc)2 (15 mg, 0.067 mmol) was added with stirring. A yellow noncrystalline precipitate formed after 30 min. The solution was cooled to −78 °C and layered with 20 mL of hexanes. Then, 5 equiv of pyridine (27 μL, 0.34 mmol) was added to the hexane layer. The reaction tube was placed in a dewar packed with dry ice and allowed to warm to room temperature. After 3 days, goldenyellow, needle-shaped crystals formed at the hexanes/THF interface. The remaining product was isolated to give 17 mg of 4 as the monoTHF solvate in 44% yield. Preparation of N-(tert-Butyl)-5-(5-phenyl-4-((pyridin-2ylmethyl)amino)quinazolin-2-yl)pyridine-3-sulfonamide (2). To a 250 mL reactor were added iodobenzene (220.2 g, 1058 mmol) and anisole (202.5 g, 1870 mmol), which was degassed by bubbling N2 for 30 min. Then, 1 (40.17 g, 85.98 mmol), cesium carbonate (14.24 g, 43.70 mmol), pivalic acid (9.3 g, 90 mmol), and palladium(II) acetate (963.5 mg, 4.29 mmol) were added, and the reaction was heated to 120 °C via a circulating Huber chiller under N2 7967

DOI: 10.1021/acs.joc.9b00823 J. Org. Chem. 2019, 84, 7961−7970

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(m, 1H), 8.03 (s, 1H), 7.91−7.77 (m, 3H), 7.73−7.67 (m, 1H), 7.64−7.61 (m, 2H), 7.35−7.28 (m, 1H), 6.34−6.03 (br s, 2H), 1.22 (s, 9H); 13C{1H} NMR (125.8 MHz, d7-DMF): δ 170.7, 159.4, 157.8, 157.3, 152.9, 152.1, 150.5, 149.6, 142.1, 138.5, 138.2, 135.8, 135.1, 134.2, 131.4, 127.7, 125.1, 124.7, 123.7, 123.0, 120.5, 117.9, 117.6, 115.5, 55.2, 49.6, 22.0; IR (neat) 3312, 3289, 3159, 2971, 1584, 1417, 1333, 1149, 679 cm−1; HRMS (ESI) m/z: 601.1016 calcd for C29H26BrN6O2S [M + H]+, found 601.0990. Preparation of N-(tert-Butyl)-5-(9-fluoro-7-(pyridin-2-ylmethyl)7H-pyrimido[4,5,6-gh]phenanthridin-5-yl)pyridine-3-sulfonamide (3c). The title compound was obtained as an off-white solid in 72% yield (1.74 g). Mp > 250 °C. 1H NMR (500 MHz, d7-DMF): δ 9.72 (s, 1H), 9.21 (s, 1H), 9.16 (s, 1H), 8.52 (br d, J = 4.6 Hz, 1H), 8.45 (br s, 1H), 8.16 (d, J = 7.4 Hz, 1H), 8.03 (s, 1H), 7.98 (t, J = 7.8 Hz, 1H), 7.88 (s, 1H), 7.80 (t, J = 7.8 Hz, 1H), 7.71 (br d, J = 7.9 Hz, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.48 (br d, J = 11.6 Hz, 1H), 7.30 (t, J = 6.2 Hz, 1H), 7.15 (br t, J = 8.2 Hz, 1H), 6.05 (br s, 1H), 1.24 (s, 9H); 13C{1H} NMR (125.8 MHz, d7-DMF): δ 169.7, 158.4, 156.8, 156.3, 151.9, 151.1, 149.5, 148.6, 141.1, 137.5, 137.2, 134.8, 134.1, 133.2, 133.2, 130.4, 126.7, 124.1, 123.7, 122.7, 122.0, 119.4, 116.9, 116.5, 114.5, 54.2, 48.6, 20.9; IR (neat) 3243, 3070, 2983, 2861, 1599, 1316, 1139, 678 cm−1; HRMS (ESI) m/z: 553.2016 calcd for C29H29N6O3S [M + H]+, found 553.1991. Preparation of N-(tert-Butyl)-5-(9-methoxy-7-(pyridin-2-ylmethyl)-7H-pyrimido[4,5,6-gh]phenanthridin-5-yl)pyridine-3-sulfonamide (3d). The title compound was obtained as an off-white solid in 76% yield (1.87 g). Mp 220−222 °C. 1H NMR (500 MHz, d7-DMF): δ 9.76 (s, 1H), 9.24 (s, 1H), 9.15 (s, 1H), 8.56 (br d, J = 4.6 Hz, 1H), 8.34 (d, J = 8.9 Hz, 1H), 8.12 (d, J = 7.6 Hz, 1H), 8.05−8.04 (m, 1H), 8.04−8.03 (m, 1H), 8.03 (s, 1H), 7.98 (t, J = 7.8 Hz, 1H), 7.87 (s, 1H), 7.78 (t, J = 7.8 Hz, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.61 (d, J = 7.9 Hz, 1H), 7.31 (t, J = 6.2 Hz, 1H), 7.16 (s, 1H), 6.96 (br d, J = 8.5 Hz, 1H), 6.34−5.74 (br s, 2H), 3.86 (s, 3H), 1.23 (s, 9H); 13C{1H} NMR (125.8 MHz, d7-DMF): δ 169.7, 158.2, 157.1, 156.8, 151.9, 151.2, 149.5, 148.4, 141.1, 139.4, 137.3, 134.7, 134.2, 133.2, 132.0, 125.6, 122.8, 122.1, 122.0, 115.2, 114.9, 113.6, 110.7, 102.1, 55.4, 54.2, 48.7, 21.0; IR (neat) 3356, 3062, 2979, 1575, 1519, 1331, 1143, 998, 801 cm −1 ; HRMS (ESI) m/z: 593.1288 calcd for C29H27Cl2N6O2S [M + H]+, found 593.1268. Preparation of N-(tert-Butyl)-5-(9-methyl-7-(pyridin-2-ylmethyl)7H-pyrimido[4,5,6-gh]phenanthridin-5-yl)pyridine-3-sulfonamide (3e). The title compound was obtained as an off-white solid in 80% yield (1.91 g). Mp > 250 °C. 1H NMR (500 MHz, d7-DMF): δ 9.73 (s, 1H), 9.22 (s, 1H), 9.14 (s, 1H), 8.54 (br d, J = 4.9 Hz, 1H), 8.24 (br d, J = 11.3 Hz, 2H), 8.04−8.00 (m, 1H), 7.84 (br s, 1H), 7.78− 7.72 (m, 2H), 7.54−7.49 (m, 2H), 7.33−7.28 (m, 2H), 6.27−5.79 (br s, 2H), 2.42 (s, 3H), 1.23 (s, 9H); 13C{1H} NMR (125.8 MHz, d7DMF): δ 169.7, 158.2, 156.7, 156.5, 151.9, 151.2, 149.5, 148.4, 141.1, 137.1, 135.8, 134.6, 134.2, 133.5, 133.2, 131.6, 131.6, 124.1, 123.1, 122.6, 121.8, 121.4, 117.1, 116.0, 114.3, 54.2, 48.5, 21.0, 20.0; IR (neat) 3239, 2972, 1584, 1324, 1145, 804, 683 cm−1; HRMS (ESI) m/z: 537.2043 calcd for C30H29N6O2S [M + H]+, found 537.2067. Preparation of N-(tert-Butyl)-5-(10-methyl-7-(pyridin-2-ylmethyl)-7H-pyrimido[4,5,6-gh]phenanthridin-5-yl)pyridine-3-sulfonamide (3f). The title compound was obtained as an off-white solid in 59% yield (1.41 g). Mp 235−237 °C. 1H NMR (500 MHz, d7-DMF): δ 9.72 (s, 1H), 9.21 (s, 1H), 9.14 (s, 1H), 8.53 (br d, J = 4.9 Hz, 1H), 8.32 (d, J = 7.9 Hz, 1H), 8.21 (d, J = 7.9 Hz, 1H), 8.04−8.00 (m, 3H), 7.86 (s, 1H), 7.77 (t, J = 7.6 Hz, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.56 (d, J = 7.9 Hz, 1H), 7.50 (s, 1H), 7.29 (t, J = 6.2 Hz, 1H), 7.18 (d, J = 8.2 Hz, 1H), 6.10 (br s, 2H), 2.37 (s, 3H), 1.23 (s, 9H); 13 C{1H} NMR (125.8 MHz, d7-DMF): δ 158.4, 157.0, 156.9, 152.1, 151.3, 149.7, 148.6, 141.2, 141.2, 138.2, 137.3, 134.8, 134.4, 133.3, 132.0, 125.1, 124.2, 122.9, 122.8, 121.9, 119.3, 117.5, 115.9, 114.2, 54.3, 48.6, 21.2, 21.1; IR (neat) 3179, 2967, 2937, 1631, 1417, 1335, 1147, 661 cm−1; HRMS (ESI) m/z: 537.2041 calcd for C30H29N6O2S [M + H]+, found 537.2067.

Article

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.9b00823. X-ray crystallography data for 4 (CIF) Optimization of the C−H activation, computational study, crystal structure of palladacycle, competency of the palladacycle in the C−H activation, product inhibition study, kinetic study, NMR spectra for 2 and 3a−f (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Steven R. Wisniewski: 0000-0001-6035-4394 Scott A. Savage: 0000-0002-7823-0696 Martin D. Eastgate: 0000-0002-6487-3121 Eric M. Simmons: 0000-0002-3854-1561 John R. Sowa, Jr.: 0000-0003-2388-3830 Donna G. Blackmond: 0000-0001-9829-8375 Present Addresses §

Department of Chemistry, University of Texas Rio Grande Valley, Edinburg, Texas 78539, United States (R.E.P.). ∥ Department of Chemistry, Governors State University, University Park, Illinois 60484, United States (J.R.S.). Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Mike Peddicord is acknowledged for helping obtain HRMS data. Robert Wethman, John Wasylyk, and Ming Huang are acknowledged for helping obtain IR data. David Ayers is acknowledged for the NMR work to determine the structure of the tetracycle. Charles Pathirana is acknowledged for obtaining NMR data for several compounds. Neil Strotman is acknowledged for insightful conversation. The authors thank Arnold Rheingold (UCSD) for acquiring the X-ray structure of the palladacycle. The BMS Senior Leadership Team is acknowledged for support of this manuscript.

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REFERENCES

(1) For recent reviews of direct arylation, see: (a) Lei, A.; Zhang, H. Transition Metal-Catalysed Direct Arylation of Unactivated Arenes with Aryl Halides. In C−H and C−X Bond Functionalization: Transition Metal Mediation; Ribas, X., Ed.; Royal Society of Chemistry: London, 2013; pp 310−327. (b) Sharma, U.; Modak, A.; Maity, S.; Maji, A.; Maiti, D. Direct Arylation via C−H Activation In New Trends in Cross-Coupling: Theory and Applications. Colacot, R., Ed.; Royal Society of Chemistry: London, 2015; pp 551−609. (c) Rossi, R.; Bellina, F.; Lessi, M.; Manzini, C. Cross-Coupling of Heteroarenes by C−H Functionalization: Recent Progress towards Direct Arylation and Heteroarylation Reactions Involving Heteroarenes Containing One Heteroatom. Adv. Synth. Catal. 2014, 356, 17−117. (2) Wisniewski, S. R.; Steven, J. M.; Yu, M.; Fraunhoffer, K. J.; Romero, E. O.; Savage, S. A. Utilizing Native Directing Groups: Synthesis of a Selective IKur Inhibitor, BMS-919373, via a Regioselective C−H Arylation. J. Org. Chem. 2019, 84, 4704. (3) Gunaga, P.; Lloyd, J.; Mummadi, S.; Banerjee, A.; Dhondi, N. K.; Hennan, J.; Subray, V.; Jayaram, R.; Rajugowda, N.; Reddy, K. U.; Kumaraguru, D.; Mandal, U.; Beldona, D.; Adisechen, A. K.; Yadav, 7968

DOI: 10.1021/acs.joc.9b00823 J. Org. Chem. 2019, 84, 7961−7970

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(11) Prat, D.; Wells, A.; Hayler, J.; Sneddon, H.; McElroy, C. R.; Abou-Shehada, S.; Dunn, P. J. CHEM21 selection guide of classicaland less classical-solvents. Green Chem. 2016, 18, 288−296. (12) For examples of an inorganic base and carboxylic acid additive, see: (a) Lafrance, M.; Fagnou, K. Palladium-Catalyzed Benzene Arylation: Incorporation of Catalytic Pivalic Acid as a Proton Shuttle and a Key Element in Catalyst Design. J. Am. Chem. Soc. 2006, 128, 16496. (b) Kim, J.; Hong, S. H. Ligand-Promoted Direct C−H Arylation of Simple Arenes: Evidence for a Cooperative Bimetallic Mechanism. ACS Catal. 2017, 7, 3336. (c) Stephens, D. E.; LakeyBeitia, J.; Atesin, A. C.; Atesin, T. A.; Chavez, G.; Arman, H. D.; Larinov, O. V. Palladium-Catalyzed C8-Selective C−H Arylation of Quinoline N-Oxides: Insights into the Electronic, Steric, and Solvation Effects on the Site Selectivity by Mechanistic and DFT Computational Studies. ACS Catal. 2015, 5, 167. For selected reviews on carboxylate ligands in transition-metal-catalyzed C−H functionalization reactions, see: (d) Lapointe, D.; Fagnou, K. Overview of the Mechanistic Work on the Concerted Metallation−Deprotonation Pathway. Chem. Lett. 2010, 39, 1118. (e) Ackermann, L. Overview of the Mechanistic Work on the Concerted Metallation−Deprotonation Pathway. Chem. Rev. 2011, 111, 1315. (13) Scifinder search in December 2018 yielded no hits for this tetracyclic core. (14) AP is the area percent of product relative to all other nonsolvent peaks in a liquid chromatography chromatogram. AP values are uncorrected for the difference in the LC response factors for the starting material versus the C−H activation product. In the case of this direct arylation, the in-process yield is within 5% of the AP of 2. (15) (a) Blackmond, D. G. Reaction Progress Kinetic Analysis: A Powerful Methodology for Mechanistic Studies of Complex Catalytic Reactions. Angew. Chem., Int. Ed. 2005, 44, 4032−4320. (b) Mathew, J. S.; Klussmann, M.; Iwamura, H.; Valera, F.; Futran, A.; Emanuelsson, E. A. C.; Blackmond, D. G. Investigations of PdCatalyzed ArX Coupling Reactions Informed by Reaction Progress Kinetic Analysis. J. Org. Chem. 2006, 71, 4711−4722. (c) Blackmond, D. G. Kinetic Profiling of Organic Catalytic Reactions as a Mechanistic Tool. J. Am. Chem. Soc. 2015, 137, 10852−10866. (16) Burés, J. A Simple Graphical Method to Determine the Order in Catalyst. Angew. Chem. Int. Ed. 2016, 55, 16084−16087. (17) Wang, X.-C.; Hu, Y.; Bonacorsi, S.; Hong, Y.; Burrell, R.; Yu, J.Q. Pd(II)-Catalyzed C−H Iodination Using Molecular I2 as the Sole Oxidant. J. Am. Chem. Soc. 2013, 135, 10326. (18) For example utilizing MOTf, see: Lovinger, G. J.; Aparece, M. D.; Morken, J. P. Pd-Catalyzed Conjunctive Cross-Coupling between Grignard-Derived Boron “Ate” Complexes and C(sp2) Halides or Triflates: NaOTf as a Grignard Activator and Halide Scavenger. J. Am. Chem. Soc. 2017, 139, 3153. (19) The mass of the palladacycle (5d) was observed by LC-MS but attempts to crystallize it were unsuccessful. (20) See SI for X-ray characterization. (21) Comparison of this complex to the standard reaction conditions with the addition of 1.0 equiv pyridine relative to catalyst. (22) See SI for computational study. (23) (a) Davies, D. L.; Donald, S. M. A.; Macgregor, S. A. Computational Study of the Mechanism of Cyclometalation by Palladium Acetate. J. Am. Chem. Soc. 2005, 127, 13754−13755. (b) García-Cuadrado, D.; Braga, A. A. C.; Maseras, F.; Echavarren, A. M. Proton Abstraction Mechanism for the Palladium-Catalyzed Intramolecular Arylation. J. Am. Chem. Soc. 2006, 128, 1066−1067. (c) Davies, D. L.; Macgregor, S. A.; McMullin, C. L. Computational Studies of Carboxylate-Assisted C−H Activation and Functionalization at Group 8−10 Transition Metal Centers. Chem. Rev. 2017, 117, 8649−8709. (d) Gorelsky, S. I.; Lapointe, D.; Fagnou, K. Analysis of the Concerted Metalation-Deprotonation Mechanism in PalladiumCatalyzed Direct Arylation Across a Broad Range of Aromatic Substrates. J. Am. Chem. Soc. 2008, 130, 10848. (e) Sun, H.-Y.; Gorelsky, S. I.; Stuart, D. R.; Campeau, L.-C.; Fagnou, K. Mechanistic Analysis of Azine N-Oxide Direct Arylation: Evidence for a Critical 7969

DOI: 10.1021/acs.joc.9b00823 J. Org. Chem. 2019, 84, 7961−7970

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The Journal of Organic Chemistry Role of Acetate in the Pd(OAc)2 Precatalyst. J. Org. Chem. 2010, 75, 8180. (f) Gorelsky, S. I.; Lapointe, D.; Fagnou, K. Analysis of the Palladium-Catalyzed (Aromatic)C−H Bond Metalation−Deprotonation Mechanism Spanning the Entire Spectrum of Arenes. J. Org. Chem. 2012, 77, 658. (24) For examples of domino C−H activation/C-N bond formation in the synthesis of phenanthridinones, see: (a) Wang, G.-W.; Yuan, T.-T.; Li, D.-D. One-Pot Formation of C-C and C-N Bonds through Palladium-Catalyzed Dual C−H Activation: Synthesis of Phenanthridinones. Angew. Chem., Int. Ed. 2011, 50, 1380. (b) Saha, R.; Sekar, G. Stable Pd-nanoparticles catalyzed domino CH activation/ CN bond formation strategy: An access to phenanthridinones. J. Catal. 2018, 366, 176. (c) Jaiswal, Y.; Kumar, Y.; Pal, J.; Subramanian, R.; Kumar, A. Rapid synthesis of polysubstituted phenanthridines from simple aliphatic/aromatic nitriles and iodo arenes via Pd(II) catalyzed domino C−C/C−C/C−N bond formation. Chem. Commun. 2018, 54, 7207. (25) For examples of homocoupling of aryl halides, see: (a) Hennings, D. D.; Iwama, T.; Rawal, V. H. Palladium-Catalyzed (Ullmann-Type) Homocoupling of Aryl Halides: A Convenient and General Synthesis of Symmetrical Biaryls via Inter- and Intramolecular Coupling Reactions. Org. Lett. 1999, 1, 1205. (b) Wang, L.; Zhang, Y.; Liu, L.; Wang, Y. Palladium-Catalyzed Homocoupling and Cross-Coupling Reactions of Aryl Halides in Poly(ethylene glycol). J. Org. Chem. 2006, 71, 1284. (26) The goal of Table 1 was to show the dual C−H activation applied to more complicated aryl iodides than iodobenzene. An extensive screening of aryl iodides was outside of the scope of this manuscript.

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DOI: 10.1021/acs.joc.9b00823 J. Org. Chem. 2019, 84, 7961−7970