Application of a Preformed Pd-BIDIME Precatalyst to Suzuki-Miyaura

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Application of a Preformed Pd-BIDIME Precatalyst to Suzuki-Miyaura Cross-Coupling Reaction in Flow Joshua D. Sieber, Frederic Buono, Andrew Brusoe, Jean-Nicolas Desrosiers, Nizar Haddad, Jon C. Lorenz, Yibo Xu, Hao Wu, Li Zhang, Zhengxu S. Han, Frank Roschangar, Jinhua J. Song, Nathan K. Yee, and Chris H. Senanayake J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b03040 • Publication Date (Web): 04 Feb 2019 Downloaded from http://pubs.acs.org on February 5, 2019

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The Journal of Organic Chemistry

Application of a Preformed Pd-BIDIME Precatalyst to SuzukiMiyaura Cross-Coupling Reaction in Flow Joshua D. Sieber,*, †,§ Frederic Buono,*, † Andrew Brusoe, † Jean-Nicolas Desrosiers,† Nizar Haddad,† Jon C. Lorenz,† Yibo Xu,† Hao Wu,† Li Zhang,† Zhengxu Steve Han,† Frank Roschangar,† Jinhua J. Song,† Nathan K.Yee,† Chris H. Senanayake† †

Chemical Development US, Boehringer Ingelheim Pharmaceuticals, Inc. 900 Ridgebury Road, Ridgefield, CT 06877, USA current address: Department of Chemistry and Department of Chemical and Life Science Engineering, Virginia Commonwealth University, 601 W. Main St., Richmond, VA 23220, USA §

KEYWORDS: homogeneous catalysis, flow chemistry, Suzuki-Miyaura cross-coupling, (BIDIME)Pd 3rd generation.

ABSTRACT: The application of a Buchwald’s 3rd generation palladacycle containing a dihydrobenzooxaphosphole based ligand (e.g., BI-DIME) was reported in the Suzuki cross-coupling reaction. Using flow technology, high yield and reproducible Suzuki cross-coupling reaction for one of our key intermediates was achieved with Pd-loadings as low as 0.5 mol %. This continuous flow approach overcomes catalyst deactivation and scale dependence issues that can be a problem in some traditional batch-mode operations and responds to the challenge of improving process greenness.

In recent years, there has been an increasing interest to develop syntheses of biologically active compounds and active pharmaceutical ingredients (APIs) using flow chemistry techniques to enable continuous processing strategies.1 The benefit to this type of synthetic approach is that process parameters can be more well controlled which allows for better quality control of the final product. 1 Due to this quality benefit, the US FDA has recently recommended the use of continuous processing for pharmaceutical manufacturing.2 This has led to increased research efforts by both academic and industrial labs on the development of new flow chemistries and techniques to enable continuous manufacturing.

its use in continuous manufacturing of the desired API. In this regard, there have been several reports of the application of the Suzuki-Miyaura reaction in flow.6,7 More importantly, however, for the Pd-catalyzed Suzuki-Miyaura reaction to be practical to flow procedures, a robust catalyst system must be employed to enable fast reaction rates (i.e. for short residence times) and to allow for low catalyst charges (i.e. high TONs) due to the high cost of Pd and the requirement for removal of the toxic transition metal from the final API.

Our group has been interested in the development of new ligands (Scheme 1) for Pd-catalyzed Suzuki-Miyaura cross coupling reactions and has reported on a series of tunable dihydrobenzooxaphosphole (1)8 and dihydrobenzoazaThe Pd-catalyzed Suzuki-Miyaura3,4 cross coupling reaction phosphole (2)9 ligands with excellent activity in both represents one of the most extensively used C-C bond 5 standard Suzuki-Miyaura8a-c,9 and asymmetric8d-h Suzukiforming reactions in the pharmaceutical industry. Miyaura cross-coupling reactions enabling the use of low Therefore, implementation of the Suzuki-Miyaura reaction Pd-loadings (< 1 mol %). Therefore, we became interested under flow conditions would be highly desirable to enable to determine if our catalytic system could be utilized to ACS Paragon Plus Environment

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perform Suzuki-Miyaura cross coupling reactions in flow with Pd-loadings of < 1 mol %. Towards this end, we chose to investigate the application of our most general ligand for Suzuki-Miyaura cross coupling reactions: BIDIME to the Suzuki-Miyaura cross coupling in flow. The results of this investigation are disclosed herein. Scheme 1. Dihydrobenzooxaphosphole and Dihydrobenzoazaphosphole Ligands for Suzuki-Miyaura Cross Coupling

Previously, our ligands (1, 2, BI-DIME) have been applied to Pd-catalyzed cross-coupling reactions by generating the active catalyst in situ by mixing the ligand with a Pdprecatalyst such as Pd(OAc)2 or Pd2(dba)3 with excellent results.8,9 However, in recent years there has been extensive development of the preparation of ligand-derived preformed palladacycles to be applied in Pd-catalyzed processes in batch10 and also in flow.11 The benefits of utilizing the preformed ligand-derived palladacycles over generating the catalyst system in situ are: (a) the palladacycles often have improved stability and shelf-life and can be handled in air; (b) the reaction setup is streamlined; (c) the palladacycles are designed to enable facile formation of stoichiometric, monoligated Pd (0), which is likely the most active catalytic species.10g,i These features often enable lower Pd-loadings to be employed when using the ligand-derived palladacycles over generating the catalyst in situ from the ligand and a Pdprecatalyst. Because of these desirable properties of the ligand-derived preformed palladacycles, we chose to investigate use of rac-BI-DIME as a ligand in a derived palladacycle for application to Pd-catalyzed SuzukiMiyaura cross-coupling (4, Scheme 2). Buchwald’s10d 3rd generation palladacycle (4) was prepared employing racBI-DIME for this purpose. Scheme 2. Preparation of (BI-DIME)Pd 3rd Gen. (4)12

Application of palladacycle 4 in the Suzuki-Miyaura crosscoupling between 2-chloropyridine 5 and phenolic boronic

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acid 6 was first analyzed in batch and compared to the use of in situ catalyst formation employing Pd2(dba)3 and racBI-DIME (Scheme 3). After a solvent survey,13 it was identified that a mixed solvent system (IPA/DME/H2O) was needed to insure the full solubility of the coupling partners that will be a requirement for future development using flow technology. Under these experimental conditions (Scheme 3), improved reactivity was observed with the pre-formed palladacycle over generating the catalyst in situ. However, in both cases, the reaction did not proceed to full conversion using 1 mol % Pd-loading, and only 85 % conversion was observed after 24 hours at 80 oC for (BI-DIME)Pd 3rd Gen. catalyzed reaction. Furthermore, both reactions had clean reaction profiles, and unreacted 5 and 6 remained at the end of the reaction. De-halogenation of 2-chloropyridine 5 and protodeboronation of boronic acid 6 was not a significant side-reaction. These results suggested that deactivation of the catalyst was the main cause of incomplete reaction in the batch process. Scheme 3. Comparison of Preformed Palladacycle 4 with that of In Situ Generated Catalyst in Batch Modea

a Reaction conditions: Chloropyridine 5 (0.824 g, 12.6 wt% in 83/17 IPA/DME, 0.500 mmol), boronic acid 6 (0.600 mmol), K2CO3 (1.0 mmol), Pd2(dba)3 (2.3 mg, 0.0025 mmol), rac-BIDIME (1.8 mg, 0.0054 mmol), 4 (3.5 mg, 0.0050 mmol), 80 oC. Conversion to the desired product was measured by HPLC at 220 nm and corrected by the response factor of 7 vs 5.

We next sought to examine the cross-coupling reaction in Scheme 4 under flow conditions (Table 1) using palladacycle 4 as catalyst. Due to the advantage that flow procedures can be run under high pressure to enable heating above the solvent boiling point, we hoped that increasing the reaction temperature above 80 oC would

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The Journal of Organic Chemistry allow for full conversion in the desired cross-coupling by increasing the rate of the coupling reaction relative to catalyst deactivation.14 Using a Uniqsis flow screening system, a solution of 5 and 0.5 mol % of palladacycle 4 in 83/17 IPA/DME13 and a solution of boronic acid 6 and K2CO3 in 85/15 H2O/IPA were mixed in a T-mixer followed by a 1.8 ml microchip equipped with a 100 psi back-pressure regulator. Scheme 4. Reaction Flow Screening Parameters

Finally, full conversion in the reaction could be achieved by performed the reaction at higher concentration and utilizing 2 equiv. of boronic acid 6 (entry 9). The flow conditions identified in Table 1, entry 9 were next tested using 2.3 g of 2-chloropyridine 5 (Scheme 5). The experimental setup was modified slightly to include introduction of EtOAc after the reactor chip to prevent crystallization of 7 and clogging of the reactor. The flow reaction was run for more than 50 min to process the solution of 5 to afford an 89% yield of 7 after workup (batch mode) and isolation. It was observed that the steady state was reached quickly after a few minutes (e.g. 2 reactor volumes) to get a consistent conversion throughout the run time (Graph 1). This system was further utilized in the cross-coupling reactions to form pyridine 9 from chloropyridine 8 with comparable results (Scheme 6). Scheme 5. Flow Suzuki-Miyaura Cross-Coupling

a

Table 1. Pd/BI-DIME Catalyzed Suzuki Cross-Coupling entry

Tem. (oC)

Res.Time (min)

Equiv. 5

Conv.(%)

1

80

1.5

1.2

25

2

100

1.5

1.2

60

3

120

1.5

1.2

81

4

135

1.5

1.2

79

5

120

2.0

1.2

86

6

120

2.0

1.5

91

7b

120

2.0

1.5

94

b

120

2.5

1.5

92

9b

120

2.0

2.0

98

8

Graph 1: Conversion vs. Time for synthesis of 7 and 9 in flow

a

Reaction conditions: Solution 1: 5 + 4 (0.5 mol %) in 6.3 vol. of 83/17 IPA/DME ([5] : 0.75 M); Solution 2: 6 + K2CO3 (1:1.67 molar ratio) in 10 vol. of 85/15 H2O/IPA (8.4 wt% 6). bSolution of 5 was prepared using 4 vol. of 50/50 DME/IPA (24 wt% 5).

Using this set-up, up to 81% conversion could be achieved using 0.5 mol % of palladacycle 4 by increasing the temperature from 80 to 120 oC (entries 1 – 3). Further increasing the temperature to 135 oC did not improve conversion (entry 4); however, increasing the residence time from 1.5 min to 2 min gave a slight improvement in conversion (entry 5). In all cases, there were only trace amounts of protodeboronation of 6 or de-halogenation of 5. This again suggested that incomplete conversion was due to catalyst deactivation; therefore, increased boronic acid charge was tested in an effort to further increase the rate of cross-coupling relative to catalyst deactivation (entries 6 – 9). Reaction conversion could be improved to 91% by increasing the boronic acid charge to 1.5 equiv. (entry 6).

Scheme 6: Formation of pyridine 9 in flow

In conclusion, we have reported the application of BIDIME in the preparation of Buchwald’s 3 rd generation palladacycle utilizing this ligand. Use of this palladacycle

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for Suzuki-Miyaura cross coupling reactions to prepare one of our key intermediate under flow conditions could be achieved with Pd-loadings as low as 0.5 mol %. Using flow technology, this reaction features higher yields, reproducibility and scalability at low catalyst loadings. Current continuous flow approach overcomes the catalyst deactivation, which could be observed in some traditional batch mode and responds to the challenge to improve process greenness.

EXPERIMENTAL SECTION General Methods. Unless otherwise stated, all reactions were carried out using oven- or flame-dried glassware under an inert atmosphere of N2 or Ar. Solvents were purchased from SigmaAldrich as ACS reagent grade. 1H NMR spectra were recorded on Bruker 400 MHz or 500 MHz spectrometers. Chemical shifts are reported in ppm from tetramethylsilane with the solvent resonance as an internal standard (CDCl3: 7.26 ppm). Data are reported as follows: chemical shift, integration, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, p = pentet, h = hextet, hept = heptet, br = broad, m = multiplet), and coupling constants (Hz). 13 C NMR was recorded on a Bruker 400 MHz (100 MHz) instrument with complete proton decoupling. Chemical shifts are reported in ppm with the solvent as the internal standard (CDCl3: 77.0 ppm). 31P NMR spectra were recorded on a Bruker 400 MHz (162 MHz) instrument and chemical shifts are reported relative to 85% H3PO4. High-resolution mass spectroscopy (HRMS) was performed on a TOF instrument with ESI and positive and negative ionization modes. Liquid chromatography was performed using forced flow (flash chromatography) on a Biotage® system using KP-SIL Biotage® SNAP cartridges, or using silica gel grade 60 (230 – 400 mesh) from Fisher Scientific. Thin layer chromatography (TLC) was performed on EMD silica gel F254 2.5x7.5 cm plates. Visualization was achieved using UV light potassium permanganate in water followed by heating. All other reagents were purchased from Sigma-Aldrich, substrates 5 and 8 were purchased from Combi-Blocks and used as received. General flow reactor setup. Flow reactions were performed using a FlowSynTM system with integrated HPLC pumps from Uniqsys. The Suzuki-Miyaura cross-coupling reactions were carried out using a microchip reactor with 1.6 mL of channel (1 mm id.) designed for turbulent mixing with a 1.8 mL total reactor volume. Reagent solutions were mixed just before the chip using a tee-mixer. The outlet stream was then combined with EtOAc using a tee-mixer and an HPLC pump followed by a 100 psi backpressure regulator at the end of the tubing chain. Palladacycle 4. The catalyst synthesis was adapted from the literature.10d To a flask with magnetic stir-bar was charged 7.39 g (9.99 mmol) of -OMs dimer 310d and 6.6 g (20.0 mmol) of BIDIME. The flask was sealed with a septa and inerted using vacuum-purge cycles (3x). CH2Cl2 (100 mL) was then charged and the mixture was agitated for 6 h. Analysis of an aliquot by 31P NMR spectroscopy showed complete consumption of the freephosphine to a new compound. The mixture was then

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concentrated in vacuo to ~14 mL, and 200 mL of MTBE was then charged. The resultant slurry was then agitated at rt for ~ 1 h, and the solid was collected by filtration and dried under vacuum to provide 13.9 g (99%) of palladacycle 4 as a beige-grey solid. 1H NMR (400 MHz, CDCl3): δ 7.54 – 7.60 (m, 1H), 7.42 – 7.51 (m, 2H), 7.39 (t, J = 7.9 Hz, 1H), 7.32 (d, J = 7.9 Hz, 1H), 7.17 – 7.27 (m, 2H), 7.06 – 7.11 (m, 1H), 6.95 (dd, J = 6.7 Hz, J = 3.4 Hz, 1H), 6.89 (d, J = 7.9 Hz, 1H), 6.79 – 6.86 (m, 3H), 6.60 (d, J = 9.0 Hz, 1H), 4.33 (dd J = 12 Hz, J = 2.9 Hz, 1H), 4.24 – 4.32 (m, 1H), 4.02 (s, 1H), 3.70 (s, 3H), 3.64 – 3.71 (m, 1H), 2.59 (s, 3H), 0.88 (d, J = 16 Hz, 9H); 13C{1H}NMR (100 MHz, CDCl3): δ 165.0 (d, JC-P = 6.9 Hz), 158.0, 157.4, 144.5, 139.5 (d, JC-P = 10 Hz), 139.0, 137.4, 136.0 (d, JC-P = 9.7 Hz), 135.5 (d, JC-P = 3.2 Hz), 133.0, 130.1, 128.5 (d, JC-P = 4.0 Hz), 128.5, 127.2, 126.5, 126.0 (d, JC-P = 7.6 Hz), 125.9, 125.4, 120.8, 118.2, 113.7 (d, JC-P = 38 Hz), 110.6 (d, JC-P = 3.8 Hz), 104.8, 103.6, 68.3 (d, JC-P = 24 Hz), 56.3, 55.4, 39.8, 34.4 (d, JC-P = 18 Hz), 25.7 (d, JC-P = 5.6 Hz); 31PNMR (162 MHz, CDCl3): δ 38 ppm. HRMS (DART) m/z calcd for C31H33O3NPPd [M – OMs]+: 604.1227; Found: 604.1226. 2-(6-(3,5-dimethyl-1H-pyrazol-1-yl)pyridine-2-yl)-6methylphenol (7). To a tared bottle with magnetic stir-bar was charged 3.0 g (14.4 mmol) of chloropyridine 5, 50.5 mg (0.072 mmol) of palladacycle 4, and 12 mL of 50/50 IPA/DME. The mixture was agitated until homogeneous and then degassed by Arsparge for ~15 min to provide a 23.4 wt% solution of chloropyridine 5 with a density of 0.93 g/cm3. To a second tared bottle with magnetic stir-bar was charged 5.00 g (24.1 mmol) of boronic acid 6, 7.6 g (55 mmol) of K2CO3, and 50 mL of 85/15 H2O/IPA. The mixture was agitated until homogeneous and then degassed by Ar-sparge for ~15 min to provide an 8.3 wt% solution of boronic acid 6/K2CO3 with a density of 1.16 g/cm3. These two solutions were then maintained at 25 oC and pumped through the microchip reactor at 120 oC with a 2 min residence time (0.21 mL/min flow rate of solution 5 and 0.70 mL/min flow rate of solution 6). The outlet stream at the end of the chip was then combined with EtOAc using a 0.5 mL/min flow rate of EtOAc. After reaching steady-state (~6 min), the outlet stream was collected for a total of 52 min (theoretical yield of 7 = 3.0 g). The phases were then separated, and the aqueous layer was extracted 1x with 20 mL of EtOAc. The combined organics were dried with Na2SO4, and volatiles were removed in vacuo. The crude residue was then dry-loaded onto silica gel using CH2Cl2 and then purified by flash chromatography (gradient, hexanes to 15% EtOAc/hexanes) to afford 2.68 g (89%) of coupling product 7 as a white solid. Mp 77 – 79 oC; 1H NMR (500 MHz, CDCl3): δ 12.99 (s, 1H), 7.94 (t, J = 8.1 Hz, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.68 (d, J = 8.3 Hz, 1H), 7.65 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 7.3 Hz, 1H), 6.85 (t, J = 7.6 Hz, 1H), 6.05 (s, 1H), 2.59 (s, 3H), 2.32 (s, 3H), 2.31 (s, 3H); 13C{1H}NMR (100 MHz, CDCl3): δ 157.0, 156.5, 150.6, 150.3, 140.7, 140.0, 132.7, 127.2, 124.6, 118.6, 118.4, 117.4, 115.2, 109.3, 16.2, 13.63, 13.60. HRMS (DART) m/z calcd for C17H18ON3 [M + H]+: 280.1444; Found: 280.1445. 2-methyl-6-(6-(5-(trifluoromethyl)-1H-pyrazol-1-yl)pyridine2-yl)phenol (9). To a tared bottle with magnetic stir-bar was charged 4.0 g (16.2 mmol) of chloropyridine, 8, 6.5 mg (0.081 mmol) of palladacycle 4, and 14 mL of 50/50 IPA/DME. The

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The Journal of Organic Chemistry mixture was agitated until homogeneous and then degassed by Arsparge for ~15 min to provide a 26.1 wt% solution of 2chloropyridine with a density of 0.99 g/cm3. To a second tared bottle with magnetic stir-bar was charged 6.00 g (39.5 mmol) of boronic acid 6, 9.1 g (66 mmol) of K2CO3, and 60 mL of 85/15 H2O/IPA. The mixture was agitated until homogeneous and then degassed by Ar-sparge for ~15 min to provide an 8.3 wt% solution of boronic acid 6/K2CO3 with a density of 1.15 g/cm3. These two solutions were then maintained at 25 oC and pumped through the microchip reactor at 120 oC with a 2 min residence time (0.21 mL/min flow rate of 2-chloropyridine solution and 0.70 mL/min flow rate of solution 6). The outlet stream at the end of the chip was then combined with EtOAc using a 0.5 mL/min flow rate of EtOAc. After reaching steady-state (~6 min), the outlet stream was collected for a total of 54 min (theoretical yield of 9 = 3.78 g). The phases were then separated, and the aqueous layer was extracted 1x with 20 mL of EtOAc. The combined organics were dried with Na2SO4, and volatiles were removed in vacuo. The crude residue was then dry-loaded onto silica gel using CH2Cl2 and then purified by flash chromatography (gradient, hexanes to 10% EtOAc/hexanes) to afford 3.14 g (83%) of coupling product 9 as a white solid. Mp 111 – 113 oC; 1H NMR (500 MHz, CDCl3): δ 12.33 (s, 1H), 8.02 (t, J = 7.9 Hz, 1H), 7.96 (d, J = 8.1 Hz, 1H), 7.79 (s, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.23 (d, J = 7.3 Hz, 1H), 6.91 (s, 1H), 6.87 (t, J = 7.7 Hz, 1H), 2.31 (s, 3H); 13C{1H}NMR (100 MHz, CDCl3): δ 157.8, 157.0, 148.7, 140.7, 140.1, 133.1, 132.6 (q, JC-F = 40 Hz), 127.5, 124.8, 119.6 (q, JC-F = 267 Hz), 120.3, 118.8, 118.1, 116.5, 110.6 (q, JC-F = 2.6 Hz), 16.2. 19F NMR (376 MHz, CDCl3): δ – 57 ppm. HRMS (DART) m/z calcd for C16H13ON3F3 [M + H]+: 320.1005; Found: 320.1005.

ASSOCIATED CONTENT Supporting Information. Copies of 1H and 13C NMR spectra of the compounds are available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding Author * E-mail for F.B.: [email protected] * E-mail for J.S.: [email protected]

Notes The authors declare no competing financial interest.

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Rosemeyer, M. An Automated Intermittent Flow Approach to Continuous Suzuki Coupling. Org. Process Res. Dev. 2016, 20, 820 – 830. (e) Konda, V.; Rydfjord, J.; Savmarker, J.; Larhed, M. Safe Palladium-Catalyzed Cross-Couplings with Microwave Heating Using Continuous-Flow Silicon Carbide Reactors. Org. Process Res. Dev. 2014, 18, 1413 – 1418. (f) Lee, C. K. Y.; Holmes, A. B.; Ley, S. V.; McConvey, I. F.; Al-Duri, B.; Leeke, G. A.; Santos, R. C. D.; Seville, J. P. K. Efficient batch and continuous flow Suzuki cross-coupling reactions under mild conditions, catalysed by polyurea-encapsulated palladium (II) acetate and tetra-n-butylammonium salts. Chem. Commun. 2005, 2175 – 2177. 8. (a) Tang, W.; Capacci, A. G.; Wei, X.; Li, W.; White, A.; Patel, N. D.; Savoie, J.; Gao, J.; Rodriguez, S.; Qu, B.; Haddad, N.; Lu, B. Z.; Krishnamurthy, D.; Yee, N. K.; Senanayake, C. H. A General and Special Catalyst for Suzuki–Miyaura Coupling Processes. Angew. Chem. Int. Ed. 2010, 49, 5879 – 5883. (b) Zhao, Q.; Li, C.; Senanayake, C. H.; Tang, W. An Efficient Method for Sterically Demanding Suzuki–Miyaura Coupling Reactions. Chem. Eur. J. 2013, 19, 2261 – 2265. (c) Qu, B.; Haddad, N.; Rodriguez, S.; Sieber, J. D.; Desrosiers, J. –N.; Patel, N. D.; Zhang, Y.; Grinberg, N.; Lee, H.; Ma, S.; Ries, U. J.; Yee, N. K.; Senanayake, C. H. Ligand-Accelerated Stereoretentive Suzuki–Miyaura Coupling of Unprotected 3,3′-Dibromo-BINOL. J. Org. Chem. 2016, 81, 745 – 750. (d) Tang, W.; Patel, N. D.; Xu, G.; Xu, X.; Savoie, J.; Ma, S.; Hao, M. –H.; Keshipeddy, S.; Capacci, A. G.; Wei, X.; Zhang, Y.; Gao, J.; Li, W.; Rodriguez, S.; Lu, B. Z.; Yee, N. K. Senanayake, C. H. Efficient Chiral Monophosphorus Ligands for Asymmetric Suzuki–Miyaura Coupling Reactions. Org. Lett. 2012, 14, 2258 – 2261. (e) Xu, G.; Fu, W.; Liu, G.; Senanayake, C. H.; Tang, W. Efficient syntheses of korupensamines A, B and michellamine B by asymmetric Suzuki-Miyaura coupling reactions. J. Am. Chem. Soc. 2014, 136, 570 – 573. (f) Fandrick, K. R.; Li, W.; Zhang, Y.; Tang, W.; Gao, J. Rodriguez, S.; Patel, N. D.; Reeves, D. C.; Wu, J. –P.; Sanyal, S.; Gonnella, N.; Qu, B.; Haddad, N.; Lorenz, J. C.; Sidhu, K.; Wang, J.; Ma, S.; Grinberg, N.; Lee, H.; Tsantrizos, Y.; Poupart, M. –A.; Busacca, C. A.; Yee, N. K.; Lu, B. Z.; Senanayake, C. H. Concise and Practical Asymmetric Synthesis of a Challenging Atropisomeric HIV Integrase Inhibitor. Angew. Chem. Int. Ed. 2015, 54, 7144 – 7148. (g) Haddad, N.; Mangunuru, H. P. R.; Fandrick, K. R.; Qu, B.; Sieber, J. D.; Rodriguez, S.; Desrosiers, J. –N.; Patel, N. D.; Lee, H.; Kurouski, D.; Grinberg, N.; Yee, N. K.; Song, J. J.; Senanayake, C. H. Reengineered BI-DIME Ligand Core Based on Computer Modeling to Increase Selectivity in Asymmetric Suzuki–Miyaura Coupling for the Challenging Axially Chiral HIV Integrase Inhibitor. Adv. Synth. Catal. 2016, 358, 3522 – 3527. 9. Zhang, Y.; Lao, K. S.; Sieber, J. D.; Xu, Y.; Wu, L.; Wang, X. –J.; Desrosiers, J. –N.; Lee, H.; Haddad, N.; Han, S.; Yee, N. K.; Song, J. J.; Howell, A. R.; Senanayake, C. H. Modular Dihydrobenzoazaphosphole Ligands for Suzuki–Miyaura CrossCoupling. Synthesis 2018, 50, 4429-4434. 10. (a) Biscoe, M. R.; Fors, B. P.; Buchwald, S. L. A New Class of Easily Activated Palladium Precatalysts for Facile C–N Cross-Coupling Reactions and Low Temperature Oxidative Addition of Aryl Chlorides. J. Am. Chem. Soc. 2008, 130, 6686 – 6687. (b) Kinzel, T.; Zhang, Y.; Buchwald, S. L. A new palladium precatalyst allows for the fast Suzuki-Miyaura coupling reactions of unstable polyfluorophenyl and 2-heteroaryl boronic acids.. J.

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Am. Chem. Soc. 2010, 132, 14073 – 14075. (c) Dufert, M. A.; Billingsley, K. L.; Buchwald, S. L. Suzuki-Miyaura CrossCoupling of Unprotected, Nitrogen-Rich Heterocycles: Substrate Scope and Mechanistic Investigation. J. Am. Chem. Soc. 2013, 135, 12877 – 12885. (d) Bruno, N. C.; Tudge, M. T.; Buchwald, S. L. Design and Preparation of New Palladium Precatalysts for C-C and C-N Cross-Coupling Reactions. Chem. Sci. 2013, 4, 916 – 920. (e) Bruno, N. C.; Niljianskul, N.; Buchwald, S. L. Nsubstituted 2-aminobiphenylpalladium methanesulfonate precatalysts and their use in C-C and C-N cross-couplings. J. Org. Chem. 2014, 79, 4161 – 4166. (f) Bruneau, A.; Roche, M.; Alami, M.; Messaoudi, S. 2-Aminobiphenyl Palladacycles: The “Most Powerful” Precatalysts in C–C and C–Heteroatom CrossCouplings. ACS Catal. 2015, 5, 1386 – 1396. (g) Li, H.; Johansson Seechurn, C. C. C.; Colacot, T. J. Development of Preformed Pd Catalysts for Cross-Coupling Reactions, Beyond the 2010 Nobel Prize. ACS Catal. 2012, 2, 1147 – 1164. (h) DeAngelis, A. J. Gildner, P. G.; Chow, R.; Colacot, T. J. Generating Active “L-Pd(0)” via Neutral or Cationic π-Allyl palladium Complexes Featuring Biaryl/Bipyrazolylphosphines: Synthetic, Mechanistic, and Structure–Activity Studies in Challenging Cross-Coupling Reactions J. Org. Chem. 2015, 80, 6794 – 6813. (i) Gildner, P. G.; Colacot, T. J. Reactions of the 21st Century: Two Decades of Innovative Catalyst Design for Palladium-Catalyzed Cross-Couplings. Organometallics 2015, 34, 5497 – 5508. 11. (a) Noël, T.; Kuhn; S; Musacchio, A. J.; Jensen, K. V.; Buchwald, S. L. Suzuki–Miyaura Cross‐Coupling Reactions in Flow: Multistep Synthesis Enabled by a Microfluidic Extraction. Angew. Chem. Int. Ed. 2011, 50, 5943-5946. (b) Shu, W.; Buchwald, S. L. Use of precatalysts greatly facilitate palladiumcatalyzed alkynylations in batch and continuous-flow conditions. Chem. Sci. 2011, 2, 2321-2325. (c) Noël, T.; Musacchio, A. J. Suzuki–Miyaura Cross-Coupling of Heteroaryl Halides and Arylboronic Acids in Continuous Flow. Org.Lett. 2011, 13, 51805183 12. Desrosiers, J.-N., Fandrick, D. R., Haddad, N., Li, G., Patel, N. D., Qu, B., Rodriguez, S., Senanayake, C.H.; Sieber, J. D., Tan, Z., Wang, X. –J., Yee, N. K., Zhang, L. , Zhang, Y. Novel Chiral Dihydrobenzooxaphosphole Ligands and Synthesis Thereofus US 2018/0155375 Al. 13. Screening of solvents was driven by the requirement of high solubility of reagents to avoid clogging during flow operations and high reactivity. Chloropyridine 5 is not soluble in IPA, and soluble in DME. After careful solubility study, a solution mixture of 83/17 IPA/DME at [5]: 0.75 M was identified. In order to increase solubility for higher throughput, ratio of DME/ IPA was adjusted to 50/50 ([5]: 1.2 M). Boronic acid 6 is insoluble in IPA, IPA/DME, H2O and H2O/IPA. High solubility in IPA/water was obtained when K2CO3 was added. 14. For similar approach using flow technology see: (a) Porta, R.; Benaglia, M.; Puglisi, A. Flow Chemistry: Recent Developments in the Synthesis of Pharmaceutical Products. Org. Process Res. Dev., 2016, 20 (1), 2 – 25 (b) Buono, F. G.; Zhang, Y.; Tan, Z.; Brusoe, A.; Yang, B.-S.; Lorenz, J. C.; Giovannini, R.; Song, J. J.; Yee, N. K.; Senanayake, C. H. Efficient Iron‐ Catalyzed Kumada Cross‐Coupling Reactions Utilizing Flow Technology under Low Catalyst Loadings Eur. J. Org. Chem. 2016, 15, 2599 – 2602.

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Application of a Preformed Pd-BIDIME Precatalyst to Suzuki-Miyaura

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