Micelle-Enabled Suzuki–Miyaura Cross-Coupling ... - ACS Publications

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Micelle-Enabled Suzuki-Miyaura Cross-coupling of Heteroaryl Boronate Esters Pengfei Guo, Hao Zhang, Jianguang Zhou, Fabrice Gallou, Michael Parmentier, and Hui Wang J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00257 • Publication Date (Web): 25 May 2018 Downloaded from http://pubs.acs.org on May 25, 2018

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The Journal of Organic Chemistry

Micelle-Enabled Suzuki-Miyaura Cross-coupling of Heteroaryl Boronate Esters Pengfei Guo*†, Hao Zhang†, Jianguang Zhou†, Fabrice Gallou‡, Michael Parmentier‡, and Hui Wang† †Chemical & Analytical Development, Suzhou Novartis Pharma Technology Company Limited, Changshu, Jiangsu 215537, China ‡Chemical & Analytical Development, Novartis Pharma AG, 4056 Basel, Switzerland

ABSTRACT: Here we report a micellar protocol for Suzuki-Miyaura cross-coupling of heteroaryl boronic esters with aryl or heteroaryl halides. The micellar catalysis enables this coupling reaction to run under mild condition, which avoids the decomposition of heteroaryl boronate esters and allows for high chemo-selectivity for cross coupling reaction with 6-chloropridine-2-boronic ester. The micellar protocol expands the scope of cross-coupling reaction with challenging heteroaryl boronic esters and well complements the existing cross-coupling methods for construction of heterobiaryl building blocks.

Heterobiaryl rings are not only important structural motifs frequently found in physiologically active compounds, including complex natural products, drug candidates and clinically used drugs;1 but also versatile building blocks for construction of various ligands2 in a variety of transition-metal catalyzed processes such as cross coupling reactions, asymmetric conjugate addition, asymmetric hydroboration and C-H activation. In connection with an ongoing synthesis of an early phase drug candidate, we have been interested in the cross-coupling of heteroaryl boronate esters with aryl or heteroaryl halides. However, as reported, heteroaryl boronate esters, especially 2-pyridyl boronate esters, are particularly challenging substrates for Suzuki-Miyaura cross coupling reactions because the boronate esters placed next to basic nitrogen tend to undergo proto-deborylation under standard Suzuki coupling conditions and result in moderate yields.3 To address the proto-deborylation issue, besides the long-existing alternative methods4 such as use of 2-pyridylzinc bromides (Negishi cross-coupling), 2-trimethylsilylpyridine (Hiyama cross-coupling) and 2-(tributylstannyl) pyridine as nucleophiles (Stille cross-coupling), several methods focusing on boron-related nucleophiles have been well developed, including use of 2-pyridyl N,Ndiethanolamine boronate esters,5 lithium triisopropyl 2-pyridinyl boronates,6 potassium 2-pyridyl trifluoroborates,7 tetrabutylammonium 2-pyridyltriolborate salts8 or N-methylimino diacetic acid (MIDA) boronates as nucleophiles, as we even tried ourselves using the micellar conditions9. Despite all these advances, the Suzuki coupling of heteroaryl boronic esters remains a significant challenge

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because each of the existing methods has certain limitations, such as in-situ or tedious preparation of nucleophiles, use of toxic reagents, limited reaction scopes or functional groups tolerance. During our stability assessment of 2-heteroaryl boronic esters, we observed that lower temperature could greatly minimize the protodeborylation side reaction. In recent years, Professor Lipshutz’s group discovered that the non-ionic surfactant TPGS-750-M in water could form micelles, which can partially “solubilize” organic substrates in an aqueous medium and allows a variety of chemical transformations under much milder conditions.10 We envisioned the Suzuki cross-coupling of 2-heteroaryl boronate ester might be enabled under mild conditions thanks to the micellar environment. Such an environment indeed allows the reaction to work at lower reaction temperature, thus minimizing the proto-deborylation and other side reactions, and leading to a high-yielding reaction. Following this thought and our previous experience with this technology,11 we developed a general micellar protocol for Suzuki-Miyaura cross-coupling reaction of heteroaryl boronic esters, which gives high yields and great chemo-selectivity. Table 1. Micellar Protocol Optimization for 6-Chloropyridine-2-boronic ester a,b

First, we examined the coupling of commercially available 6-chloro-2-pyridyl boronate ester 2a with 2-bromopyridine 1a. Our systematic studies showed that PdCl2(dtbpf)/Et3N/THF/2%TPGS-750-M water system at 40 oC could minimize the potential protodeborylation side reaction to about 4%, although it gave desired product 3a in only 68% (relative HPLC ratio), bis-suzuki side product 3a-1 in 13% (relative HPLC ratio) and some des-bromo side product (Table 1, entry 1). Lower reaction temperature (20 oC) significantly minimized all side reactions and improved not only the yield of 3a (91% isolated yield after column separation) but also the chemo-selectivity --- no bis-suzuki side product 3a-1 was observed (entry 2). It is noteworthy that both TPGS-750-M surfactant and THF co-solvent are required in this reaction because absence of either one slowed down the reaction rate and gave incomplete conversion (entry 3, 4 and 5). Presumably, this was ascribed to the micellar catalysis effect.12 Also, other readily available palladium catalysts were not as efficient as PdCl2(dtbpf) (entry 6 and 7). The scope of heteroaryl or aryl bromides was investigated by subjecting 6-chloro-2-pyridyl boronate ester 2a and a range of commercially available heteroaryl or aryl bromides to the optimized reaction conditions (Table 2). Both electron-deficient pyridyl bromides at 2, 3 or 4 positions (3a to 3g) and electron-rich phenyl bromides (3h to 3j) coupled with 6-chloro-2-pyridyl boronic ester 2a to give good yields and good chemo-selectivity. Besides, this condition also worked well for imidazole bromide (3l) and

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The Journal of Organic Chemistry thiazole bromide (3k). A variety of functional groups are well tolerated, such as chloride (3c, 3i), methoxy group (3e), cyano group (3i) and amino group (3j). It is also notable that due to the good chemo-selectivity, the remaining chloride could be very useful for further functionalization. The low yield of product 3d is likely due to the relatively electron-rich property and strong metalcoordination property, which might result in a slow reaction rate and palladium catalyst deactivation. Table 2. Micellar Suzuki-Miyaura Coupling: Scope of Heteroaryl/Aryl bromides a,b,d

With a broad range of heteroaryl or aryl bromides established, we further examined the scope of heteroaryl boronate esters (Table 3). Boronate esters at either meta- or para-positions of pyridine gave the corresponding products (5a, 5b and 5c) in good yield. In addition, this micellar protocol also worked smoothly for boronate esters of commonly used and practically useful heteroaryl rings, such as pyrimidine, imidazole, thiazole and pyrazole (5d to 5g). Table 3. Micellar Suzuki-Miyaura Coupling: Scope of Heteroaryl boronate esters a,b,c

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In conclusion, we have developed a general and practical micellar protocol for the Suzuki-Miyaura coupling of challenging heteroaryl boronic esters. This new protocol expands the scope of the well-known Suzuki-Miyaura coupling. Thus, newly developed chemo-selective and high-yielding micellar condition for heteroaryl boronate esters well complements the existing cross-coupling methods for construction of heterobiaryl building blocks. We expect this new protocol for rapid access to heterobiaryl rings will have many applications in synthetic organic chemistry and medicinal chemistry, allowing for environmentally friendly reaction conditions and reduction of organic wastes.

Experimental Section Unless otherwise noted, all reactions were carried out under nitrogen atmosphere. All reagents and solvents were obtained from commercial suppliers and used without further purification. Standard column chromatography was performed on 300–400 mesh silica gel using flash column chromatography techniques. 1H NMR and 13C NMR spectra were recorded on Bruker 400 UltraShieldTM spectrometer.

General Experimental

procedure: To a 25 mL three necked flask was added bromide (1.0 mmol), boronate (1.25 mmol), TEA (2.0 mmol),

PdCl2(dtbpf) (0.05 mmol), 8 mL of THF and 12 mL of 2% TPGS aqueous solution at room temperature. The reaction mixture was degassed with nitrogen. Then the reaction mixture was stirred at reaction temperature (20 oC to 50 oC) until the TLC indicated all of the bromide was consumed, and the resulting mixture was diluted with 50 mL of MTBE. The organic layer was collected, dried over Na2SO4 and filtered. The filtrate was concentrated, and the concentrated residue was purified by flash column chromatography to afford the product. Or the solid product crystallized out from the reaction mixture and direct filtration gave the desired product (for example 3i). 6-Chloro-2,2'-bipyridine (3a)13. Purification by flash column chromatography (hexane/EtOAc=4:1) to provide 3a (0.44 g, 91% yield) as an

off white solid: mp 62-64 oC; 1H NMR (400 MHz, DMSO) δ7.51 (dd, J=8.0 8.0 Hz, 1 H ), 7.59 (d, J=8.0 Hz, 1 H), 8.06-7.95 (m, 2 H), 8.30 (d, J=8.0 Hz, 1 H), 8.37 (d, J=8.0 Hz, 1 H), 8.72 (d, J=8.0 Hz, 1 H); 13C NMR (100 MHz, DMSO)δ156.6, 156.0, 150.4, 150.0, 141.4, + 138.1, 125.3, 125.1, 121.2,120.0; HRMS (ESI, Quadrupole-TOF) m/z: (MH ) calcd for C10H8ClN2 191.0371, 193.0341, Found 191.0392, 193.0347. 6'-Chloro-3-(trifluoromethyl)-2,2'-bipyridine (3b). Purification by flash column chromatography (hexane/EtOAc=4:1) to provide 3b (0.4g, 87% yield) as a brown viscous oil. 1H NMR (400 MHz, DMSO) δ7.67 (d, J=8.1 Hz, 1 H), 7.72 - 7.87 (m, 2 H), 8.07 (dd, J=8.1, 7.8 Hz, 1 H) 8.39 (d, J=8.1Hz, 1 H), 8.96 (d, J=4.7 Hz, 1 H); 13C NMR (100 MHz, DMSO) δ157.2, 154.4, 152.9, 149.4, 141.0, 136.4, 125.1, 124.6, 124.2 (q, J=32.3 Hz, CCF3), 123.9 (q, J=273.7 Hz, CF3), 123.4; HRMS (ESI, Quadrupole-TOF) m/z: (MH ) calcd for C11H7ClF3N2 259.0244, 2610215, Found 259.0260, 261.0244. +

5,6'-Dichloro-2,2'-bipyridine (3c). Purification by flash column chromatography (hexane/EtOAc=4:1) to provide 3c (0.42 g, 90% yield) as a white solid: mp 134-136 oC; 1H NMR (400 MHz, CDCl3) δ7.34 (d, J=8.0 Hz, 1 H), 7.70 - 7.84 (m, 2 H), 8.31 (d, J=8.0 Hz, 1 H), 8.37 (d, J=8.6 Hz, 1 H), 8.60 (d, J=2.3 Hz, 1 H); 13C NMR (100 MHz, CDCl3)δ155.8, 152.7, 151.0, 148.1, 139.6, 136.7, 124.5, 122.2, 119.4; HRMS (ESI, Quadrupole-TOF) m/z: (MH ) calcd for C10H7Cl2N2 224.9981, 226.9951, Found 224.9997, 226.9963. +

5-Methoxy-2'-(trifluoromethyl)-2,4'-bipyridine (3e) Purification by flash column chromatography (hexane/EtOAc=4:1) to provide 3e (0.44 g, 81% yield) as a brown solid: mp 70-72 oC; 1H NMR (400 MHz, DMSO) δ7.57 (d, J=8.8 Hz, 1 H), 8.27 (d, J=8.8 Hz, 1 H), 8.31 (d, J=5.1 Hz, 1 H), 8.39 - 8.52 (m, 2 H), 8.83 (d, J=5.1 Hz, 1 H); 13C NMR (100 MHz, DMSO) δ157.0, 151.4, 147.8, 147.8 (q, J=34.3 Hz, CCF3), 144.4, 138.8, 123.7, 123.0, 122.3 (q, J=275.7 Hz, CF3), 121.6, 117.1, 56.4; HRMS (ESI, Quadrupole-TOF) m/z: (MH ) calcd for C12H10F3N2O 255.0740, Found 255.0764. +

6-Chloro-2,3'-bipyridine(3f)14. Purification by flash column chromatography (hexane/EtOAc=4:1) to provide 3f (0.42 g, 87% yield) as an

off-white solid: mp 55-57 oC; 1H NMR (400 MHz, DMSO) δ7.54 - 7.59 (m, 2 H), 8.0 (dd, J=8.0, 7.7 Hz, 1 H), 8.11 (d, J=7.7 Hz, 1 H), 8.42 (d, J=8.0 Hz, 1 H), 8.68 (d, J=4.8 Hz, 1 H), 9.25 (s, 1 H); 13C NMR (100 MHz, DMSO)δ155.1, 151.0, 148.3, 141.5, 134.6, 133.0, 124.4, 124.2, 120.3; HRMS (ESI, Quadrupole-TOF) m/z: (MH ) calcd for C10H8ClN2 191.0371, 193.0341, Found 191.0392, 193.0348. +

6-Chloro-2,4'-bipyridine (3g)15. Purification by flash column chromatography (hexane/EtOAc=6:1) to provide 3g (0.41g, 84% yield) as a

white solid: mp 121-123 oC; 1H NMR (400 MHz, DMSO) δ7.61 (d, J=7.8 Hz, 1 H), 7.98 - 8.08 (m, 3 H), 8.15 (d, J=7.7 Hz, 1 H), 8.73-

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The Journal of Organic Chemistry 8.75 (m, 2 H); 13C NMR (100 MHz, DMSO) δ154.7, 151.0, 150.9, 144.3, 141.6, 125.3, 121.1, 120.7; HRMS (ESI, Quadrupole-TOF) m/z: (MH ) calcd for C10H8ClN2 191.0371, 193.0341, Found 191.0383, 193.0343. +

2-Chloro-6-phenylpyridine (3h)16. Purification by flash column chromatography (hexane/EtOAc=8:1) to provide 3h (0.42 g, 87% yield) as a yellow solid: mp 30-32 oC; 1H NMR (400 MHz, DMSO) δ7.47 - 7.61 (m, 4 H), 7.93 - 8.06 (m, 2 H), 8.07 - 8.15 (m, 2 H); 13C NMR (100 MHz, DMSO)δ157.4, 150.7, 141.3, 137.4, 130.3, 129.4, 127.1, 123.4, 119.2; HRMS (ESI, Quadrupole-TOF) m/z: (MH ) calcd for C11H9ClN 190.0418, 192.0389, Found 190.0421, 192.0393. +

2-Chloro-4-(6-chloropyridin-2-yl)benzonitrile (3i). Purification by crystallization from MTBE to provide 3i (0.32 g, 87% yield) as a brown solid: mp 148-150 oC; 1H NMR (400 MHz, DMSO) δ7.59 (d, J=7.6 Hz, 1H), 7.94-8.24 (m, 4H), 8.25-8.55 (m, 1H), 8.34 (s, 1H); 13C NMR (100 MHz, DMSO) δ153.8, 150.9, 143.2, 141.7, 136.6, 135.6, 128.0, 126.3, 125.4, 121.2, 116.3, 113.0, 70.2; HRMS (ESI, Quadrupole-TOF) m/z: (MH ) calcd for C12H7Cl2N2 248.9981, 250.9951, Found 248.9997, 250.9962. +

3-(6-Chloropyridin-2-yl)aniline (3j). Purification by flash column chromatography (hexane/EtOAc=8:1) to provide 3j (0.43 g, 90% yield)

as a yellow solid: mp 96-98 oC; 1H NMR (400 MHz, DMSO) δ5.06 - 5.57 (bs, 2 H), 6.58 - 6.83 (m, 1 H), 7.12 - 7.24 (m, 2 H), 7.33 7.39 (m, 1 H), 7.47 (d, J=7.7 Hz, 1H), 7.82 - 7.99 (m, 2 H); 13C NMR (100 MHz, DMSO)δ158.2, 150.5, 149.7, 141.1, 138.0, 129.9, 122.9, 119.4, 115.9, 114.6, 112.3; HRMS (ESI, Quadrupole-TOF) m/z: (MH ) calcd for C11H10ClN2 205.0527, 207.0498, Found 205.0553, 207.0507. +

5-(6-Chloropyridin-2-yl)-2-methylthiazole 3k. Purification by flash column chromatography (hexane/EtOAc=6:1) to provide 3k (0.35 g, 79% yield) as an off-white solid. 1H NMR (400 MHz, DMSO) δ2.68 (s, 3 H), 7.41 (d, J=7.3 Hz, 1 H), 7.84 - 8.00 (m, 2 H), 8.36 (s, 1 H); 13C NMR (100 MHz, DMSO) δ168.6, 151.3, 150.4, 141.6, 141.1, 138.1, 123.2, 118.9, 19.6; HRMS (ESI, Quadrupole-TOF) m/z: (MH ) calcd for C9H8ClN2S 211.0091, 213.0032, Found 211.0097, 213.0068. +

3-(Trifluoromethyl)-2,3'-bipyridine (5a). Purification by flash column chromatography (hexane/EtOAc=8:1) to provide 5a (0.3 g, 75%

yield) as a brown oil. 1H NMR (400 MHz, DMSO) δ7.54 (dd, J=7.9, 4.8 Hz, 1 H), 7.72 (dd, J=7.9, 4.8 Hz, 1 H), 7.90 (d, J=7.8 Hz, 1 H), 8.35 (d, J=7.8 Hz, 1 H), 8.66 (s, 1 H), 8.70 (d, J=4.8 Hz, 1 H), 8.96 (d, J=4.8 Hz, 1 H); 13C NMR (100 MHz, DMSO) δ154.9, 153.2, 150.3, 149.2, 136.5, 135.8, 135.3, 124.3 (q, J=30.3 Hz, CCF3), 122.6 (q, J=273.7 Hz, CF3), 123.7, 123.5; HRMS (ESI, Quadrupole-TOF) m/z: (MH ) calcd for C11H8F3N2 225.0634, Found 225.0658. +

3-(Trifluoromethyl)-2,4'-bipyridine (5b). Purification by flash column chromatography (hexane/EtOAc=8:1) to provide 5b (0.28 g, 71%

yield) as a brown solid: mp 80-83 oC; 1H NMR (400 MHz, DMSO) δ 7.48 (d, J=8.0 Hz, 2H), 7.75 (dd, J=7.8, 4.4 Hz, 1 H), 8.38 (d, J=7.8 Hz, 1 H) 8.72 (d, J=8.0 Hz, 2 H), 8.96 (d, J=4.4 Hz, 1 H); 13C NMR (100 MHz, DMSO) δ155.3, 153.2, 149.9, 146.8, 135.9, 124.2 (q, J=31.3 Hz, CCF3), 124.1, 123.9 (q, J=274.7 Hz, CF3), 123.7; HRMS (ESI, Quadrupole-TOF) m/z: (MH ) calcd for C11H8F3N2 +

225.0634, Found 225.0652. 2',3-Bis(trifluoromethyl)-2,4'-bipyridine (5c). Purification by flash column chromatography (hexane/EtOAc=6:1 to 3:1) to provide 5c (0.43 g, 83% yield) as a brown solid: mp 51-53 oC; 1H NMR (400 MHz, DMSO) δ7.80 (dd, J=8.0, 5.1 Hz, 1 H), 7.85 (d, J=5.1 Hz, 1 H), 8.02 (s, 1 H), 8.42 (d, J=8.0 Hz, 1H), 8.91 - 9.09 (m, 2 H); 13C NMR (100 MHz, DMSO) δ153.8, 153.4, 150.8, 149.0, 147.0 (q, J=34.3 Hz, CCF3), 136.0, 127.3, 124.6, 124.2 (q, J=32.3 Hz, CCF3), 123.8 (q, J=274.7 Hz, CF3), 122.0 (q, J=275.7 Hz, CF3), 120.8; HRMS (ESI, Quadrupole-TOF) m/z: (MH ) calcd for C12H7F6N2 293.0508, Found 293.0535. +

Methyl 3-amino-6-(pyridin-2-yl)pyrazine-2-carboxylate (5d). Purification by flash column chromatography (hexane/EtOAc =4:1 to 2:1) to provide 5d (0.53 g, 73% yield) as a yellow solid: mp 188-190 oC; 1H NMR (400 MHz, DMSO) δ3.92 (s, 3 H), 7.39 (dd, J=8.0, 8.0 Hz, 1 H), 7.64 (br s, 2H), 7.92 (dd, J=8.0, 4.7 Hz, 1 H), 8.11 (d, J=8.0 Hz, 1 H), 8.63 (d, J=4.7 Hz, 1 H), 9.18 (s, 1 H); 13C NMR (100 MHz, DMSO)δ166.7, 156.1, 154.2, 149.6, 146.1, 139.2, 146.1, 139.8, 123.8, 122.1, 119.6; HRMS (ESI, Quadrupole-TOF) m/z: (MH ) calcd for C11H11N4O2 231.0877, Found 231.0881. +

2-(2-Chloro-1-methyl-1H-imidazol-5-yl)-3-(trifluoromethyl)pyridine (5e). Purification by column chromatography (hexane/EtOAc= 8:1) to provide 5e (0.36 g, 78% yield) as a colorless oil. 1H NMR (400 MHz, DMSO) δ3.53 (s, 3 H), 7.10 (s, 1 H), 7.71 (dd, J=8.1, 4.8 Hz, 1 H), 8.37 (dd, J=8.1 Hz, 1 H), 8.99 (d, J=4.8 Hz, 1 H); 13C NMR (100 MHz, DMSO) δ153.3, 146.7, 136.1, 134.0, 130.6, 129.5, 125.4 (q, J=30.3 Hz, CCF3), 124.0, 123.8 (q, J=273.7 Hz, CF3), 32.5; HRMS (ESI, Quadrupole-TOF) m/z: (MH ) calcd for C10H8ClF3N3 262.0353, 264.0324, Found 262.0364, 264.0332. +

5-(3-(Trifluoromethyl)pyridin-2-yl)thiazole (5f). Purification by flash column chromatography (hexane/EtOAc=8:1) to provide 5f (0.3 g, 74% yield) as an off-white solid: 98-99 oC; 1H NMR (400 MHz, DMSO) δ7.66 (dd, J=8.1, 4.8 Hz, 1 H), 8.21 (s, 1 H), 8.35 (dd, J=8.1 Hz, 1 H), 8.90 (d, J=4.8 Hz, 1 H), 9.18 - 9.39 (s, 1 H); 13C NMR (100 MHz, DMSO) δ157.8, 153.4, 148.0, 143.1, 137.1, 136.3, 124.0 (q, J=274.7 Hz, CF3), 123.8, 122.9 (q, J=32.3 Hz, CCF3); HRMS (ESI, Quadrupole-TOF) m/z: (MH ) calcd for C9H6F3N2S 231.0198, Found 231.0206. +

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2-(1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)-3-(trifluoromethyl)pyridine (5g). Purification by flash column chromatography (hexane/EtOAc=10:1 to 4:1) to provide 5g (0.42 g, 80% yield) as a colorless oil. 1H NMR (400 MHz, DMSO) δ1.28 - 1.66 (m, 3 H), 1.80 2.06 (m, 2 H), 2.20 - 2.38 (m, 1 H), 3.12 - 3.26 (m, 1 H), 3.61 (m, 1 H), 5.40 (m, 1 H), 6.50 (d, J=1.7 Hz, 1 H), 7.61 (d, J=1.7 Hz, 1 H), 7.74 (dd, J=8.0, 4.9 Hz, 1 H), 8.36 (d, J=8.0 Hz, 1 H) 8.97 (d, J=4.9 Hz, 1 H); 13C NMR (100 MHz, DMSO) δ153.1, 148.2, 138.9, 138.4, 135.8, 125.5 (q, J=32.3 Hz, CCF3), 124.3, 123.6 (q, J=273.7 Hz, CF3), 109.0 84.0, 66.2, 29.2, 25.0, 21.9; HRMS (ESI, Quadrupole-TOF) m/z: (MH -THP) calcd for C9H7F3N3 214.0587, Found 214.0593. +

ASSOCIATED CONTENT Supporting Information 1

H and 13C spectra for all new compounds. This material is available, free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION Corresponding author Email: [email protected]

ACKNOWLEDGMENT We thank Mr. Huanqing Jia and Mr. Weiyong Kong for some preliminary work and Dr. Jianwei Bian for some fruitful discussion. We thank analytical team in Novartis for instrumental support for collection of high resolution mass data and NMR data.

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