Preparation of Functionalized 2,7-Naphthyridines by Directed Lithiation with (2,2,6,6-Tetramethylpiperidyl)lithium and Their Regioselective Iron-Catalyzed Cross Couplings

Robert Greiner; Romain Blanc; Christian Petermayer; Konstantin Karaghiosoff; Paul Knochel

doi:10.1055/s-0035-1560703

Synlett, Table of Contents

Synlett 2016; 27(02): 231-236
DOI: 10.1055/s-0035-1560703

letter

Preparation of Functionalized 2,7-Naphthyridines by Directed Lithiation with (2,2,6,6-Tetramethylpiperidyl)lithium and Their Regioselective Iron-Catalyzed Cross Couplings

Robert Greiner

Department Chemie, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, 81377 München, Germany Email: Paul.Knochel@cup.uni-muenchen.de

,

Romain Blanc

Department Chemie, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, 81377 München, Germany Email: Paul.Knochel@cup.uni-muenchen.de

,

Christian Petermayer

Department Chemie, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, 81377 München, Germany Email: Paul.Knochel@cup.uni-muenchen.de

,

Konstantin Karaghiosoff

Department Chemie, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, 81377 München, Germany Email: Paul.Knochel@cup.uni-muenchen.de

,

Paul Knochel*

Department Chemie, Ludwig-Maximilians-Universität München, Butenandtstr. 5-13, 81377 München, Germany Email: Paul.Knochel@cup.uni-muenchen.de

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Abstract

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Abstract

We report the regioselective functionalization of 2,7-naphthyridines by using (2,2,6,6-tetramethylpiperidyl)lithium as a base, together with the regioselective iron-catalyzed cross-coupling reactions of the products to give tetraalkylated 2,7-naphthyridines selectively.

Key words

lithiations - Grignard reagents - iron - catalysis - naphthyridines - alkylations

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References

References and Notes

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For a cluster of recent articles on iron-catalyzed reactions, see:

15a Toma Š, Šebesta R. Synthesis 2015; 47: 1683
15b Kuzmina OM, Steib AK, Moyeux A, Knochel P. Synthesis 2015; 47: 1696
15c Shang X, Liu Z.-Q. Synthesis 2015; 47: 1706
15d Tian J.-S, Zhu C.-L, Chen Y.-R, Xu H. Synthesis 2015; 47: 1709
15e Regev A, Shalit H, Pappo D. Synthesis 2015; 47: 1716
15f Bauer G, Cheung C.-W, Hu X. Synthesis 2015; 47: 1726
15g Agata R, Iwamoto T, Nakagawa N, Isozaki K, Hatakeyama T, Takaya H, Nakamura M. Synthesis 2015; 47: 1733
15h Nguyen TB, Ermolenko L, Al-Mourabit A. Synthesis 2015; 47: 1741
15i Savela R, Leino R. Synthesis 2015; 47: 1749
15j Bedford RB, Gallagher T, Pye DR, Savage W. Synthesis 2015; 47: 1761
15k Gopalaiah K, Chandrudu SN, Devi A. Synthesis 2015; 47: 1766
15l Smith SA. M, Morris RH. Synthesis 2015; 47: 1775
15m Tber Z, Hiebel M.-A, Akssira M, Guillaumet G, Berteina-Raboin S. Synthesis 2015; 47: 1780
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18 General: All reactions were carried out under argon in flame-dried glassware. Syringes used to transfer anhyd. solvents or reagents were purged with argon before use. THF was continuously refluxed and freshly distilled from sodium benzophenone ketyl under N₂ and stored over 4 Å MS. Yields refer to isolated yields of compounds estimated to be >95% pure [¹H NMR (25 °C) and capillary GC]. Chemical shifts are reported as δ values in ppm relative to the solvent peak. NMR spectra were recorded in CDCl₃ solution (residual CHCl₃: δ = 7.27 ppm for ¹H NMR and δ = 77.0 ppm for ¹³C NMR). Column chromatography was performed on silica gel (0.040–0.063 mm, 230–400 mesh ASTM; Merck). 1,3,6,8-Tetrahydroxy-2,7-naphthyridine, 1,3,6,8-tetrachloro-2,7-naphthyridine, and 3,6-dichloro-1,8-dimethoxy-2,7-naphthyridine were prepared according to the reported procedures.¹ 1,8-Bis(butylsulfanyl)-3,6-dichloro-2,7-naphthyridine (2c) A dry, argon-flushed, Schlenk flask equipped with a magnetic stirrer bar was charged with a solution of BuSH (1.24 mL, 11.55 mmol, 3.0 equiv) in THF (10 mL). The solution was cooled to 0 °C, and a 2.48 M solution of BuLi in hexane (4.70 mL, 11.7 mmol, 3.05 equiv) was slowly added. The solution was then stirred at 0 °C for 30 min. A second dry, argon-flushed Schlenk flask, equipped with a magnetic stirrer bar was charged with a solution of 1,3,6,8-tetrachloro-2,7-naphthyridine (1; 1.03 g, 3.84 mmol, 1.0 equiv) in THF (10 mL). The solution was cooled to –78 °C, and the freshly prepared 0.72 M solution of BuSLi in THF (13.33 mL, 9.60 mmol, 2.5 equiv) was slowly added. The mixture was stirred at –78 °C for 2 h until the starting material totally disappeared. The reaction was then quenched with sat. aq. NH₄Cl (50 mL), the layers were separated and the aqueous phase was extracted with EtOAc (3 × 50 mL). The combined organic layers were dried (MgSO₄), filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography [silica gel, hexanes–EtOAc (100:1)] to give an off-white solid; yield: 1.24 g (86%); mp 67–69 °C. IR (diamond ATR): 2955, 2931, 2871, 1569, 1492, 1323, 1260, 1118, 1098, 986, 873, 857 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 7.05 (s, 2 H), 3.32 (t, J = 7.3 Hz, 4 H), 1.78 (quin, J = 7.3 Hz, 4 H), 1.53 (sext, J = 7.4 Hz, 4 H), 0.99 (t, J = 7.3 Hz, 6 H). ¹³C NMR (75 MHz, CDCl₃): δ = 163.8, 148.2, 145.9, 120.4, 113.3, 33.3, 30.4, 22.5, 13.9; MS (EI, 70 eV): m/z (%) = 321 (20), 319 (70), 265 (17), 263 (73), 262 (20), 261 (98), 225 (29), 41 (24). HRMS (EI): m/z calcd for C₁₆H₂₀Cl₂N₂S₂: 374.0445; found: 374.0438. Metalation of 1,8-Bis(butylsulfanyl)-3,6-dichloro-2,7-naphthyridine (2c) with TMPLi; General Procedure A dry and argon-flushed Schlenk flask, equipped with a magnetic stirrer bar and a rubber septum was charged with naphthyridine 2c (1.0 equiv) in THF and then cooled to –40 °C. A 1 M solution of TMPLi in THF (1.2 equiv) was slowly added, and the mixture was stirred for 30 min at –40 °C. The appropriate electrophile (1.2 equiv) was added and the solution was stirred at –40 °C until the starting material was completely consumed (GC). 1,8-Bis(butylsulfanyl)-3,6-dichloro-4-(trimethylsilyl)-2,7-naphthyridine (5b) Naphthyridine 2c (250 mg, 0.66 mmol, 1.0 equiv) in THF (2.5 mL) was treated with a 1 M solution of TMPLi in THF (0.79 mL, 0.79 mmol, 1.2 equiv) for 30 min according to the general procedure. Subsequently, TMSCl (0.10 mL, 0.79 mmol, 1.2 equiv) was added at –40 °C and the mixture was continuously stirred for 2 h. The reaction was then quenched with sat. aq. NH₄Cl (5 mL), the layers were separated and the aqueous phase was extracted with EtOAc (3 × 10 mL). The combined organic layers were dried (MgSO₄), filtered and concentrated in vacuo. The residue was purified by flash column chromatography [silica gel, hexanes–EtOAc (100:0.5)] to give a brown solid; yield: 207 mg (73%); mp 42–44 °C. IR (diamond ATR): 2955, 2928, 1563, 1514, 1470, 1263, 1216, 1119, 1023, 892, 845, 822 cm^–1; ¹H NMR (300 MHz, CDCl₃): δ = 7.49 (s, 1 H), 3.36–3.26 (m, 4 H), 1.85–1.71 (m, 4 H), 1.60–1.45 (m, 4 H), 0.99 (t, J = 7.3 Hz, 6 H), 0.54 (s, 9 H). ¹³C NMR (75 MHz, CDCl₃): δ = 164.2, 164.1, 154.6, 150.6, 147.8, 120.2, 120.1, 114.5, 33.3, 33.2, 30.5, 22.4, 13.9, 2.8. MS (EI, 70 eV): m/z (%) = 393 (22), 392 (21), 391 (82), 390 (28), 389 (100), 357 (20), 335 (62), 333 (80), 41 (23). HRMS (EI): m/z calcd for C₁₉H₂₈C_l2N₂S₂Si: 446.0840; found: 446.0844. 4-Allyl-1,8-bis(butylsulfanyl)-3,6-dichloro-2,7-naphthyridine (5e) Naphthyridine 2c (187 mg, 0.5 mmol, 1.0 equiv) in THF (2 mL) was treated with a 1 M solution of TMPLi in THF (0.6 mL, 0.6 mmol, 1.2 equiv) for 30 min by the general procedure. A 1 M solution of CuCN·2LiCl in THF (0.1 mL, 0.1 mmol, 0.2 equiv) was added dropwise at –40 °C, followed by the addition of AllBr (72 mg, 0.6 mmol, 1.2 equiv). The mixture was slowly warmed to r.t. over 1 h and the reaction was quenched with sat. aq NH₄Cl/NH₃ (10:1 v/v, 10 mL). The mixture was extracted with EtOAc (3 × 10 mL) and the combined organic layers were dried (MgSO₄), filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography [silica gel, hexanes–EtOAc (100:0.5)] to give a white solid; 192 mg (93%); mp 61–63 °C; IR (diamond ATR): 2957, 2930, 1573, 1551, 1484, 1454, 1255, 1125, 1081, 908, 889, 830 cm^–1; ¹H NMR (300 MHz, CDCl₃): δ = 7.24 (s, 1 H), 5.99–5.85 (m, 1 H), 5.10 (d, J = 10.0 Hz, 1 H), 4.98 (d, J = 17.1 Hz, 1 H), 3.69 (d, J = 5.3 Hz, 2 H), 3.38–3.26 (m, 4 H), 1.78 (quin, J = 7.3 Hz, 4 H), 1.52 (sext, J = 7.3 Hz, 4 H), 0.99 (t, J = 7.3 Hz, 6 H); ¹³C NMR (75 MHz, CDCl₃): δ = 164.4, 161.2, 148.6, 148.4, 145.0, 133.5, 120.6, 119.9, 117.1, 111.2, 33.4, 33.2, 33.0, 30.5, 30.4, 22.5, 13.9; MS (EI, 70 eV): m/z (%) = 359 (70), 303 (62), 301 (85), 97 (34), 71 (30), 57 (57); HRMS (EI): m/z calcd for C₁₉H₂₄Cl₂N₂S₂: 414.0758; found: 414.0742. Ethyl 1,8-Bis(butylsulfanyl)-3,6-dichloro-2,7-naphthyridine-4-carboxylate (5h) Naphthyridine 2c (207 mg, 0.55 mmol, 1.0 equiv) in THF (2.5 mL) was treated with a 1 M solution of TMPLi in THF (0.66 mL, 0.66 mmol, 1.2 equiv) for 30 min according to the general procedure. A 0.4 M solution of MgCl₂ in THF (1.5 mL, 0.61 mmol, 1.1 equiv) was added at –40 °C. After a further 30 min, EtO₂CCl (0.06 mL, 0.61 mmol, 1.1 equiv) was added and the mixture was warmed to –30 °C and stirred for 5 h until the starting material was completely consumed. The reaction was then quenched with sat. aq. NH₄Cl (20 mL), and the mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were dried (MgSO₄), filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography [silica gel, hexanes–EtOAc (80:1)] to give a yellow solid; yield: 206 mg (84%); mp 72–74 °C. IR (diamond ATR): 2956, 2928, 1729, 1552, 1487, 1218, 1208, 1153, 1122, 1061, 867 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 7.18 (s, 1 H), 4.51 (q, J = 7.1 Hz, 2 H), 3.33 (t, J = 7.2 Hz, 4 H), 1.85–1.72 (m, 4 H), 1.59–1.48 (m, 4 H), 1.45 (t, J = 7.1 Hz, 3 H), 0.99 (t, J = 7.3 Hz, 6 H). ¹³C NMR (75 MHz, CDCl₃): δ = 165.2, 165.1, 164.2, 149.1, 145.1, 142.8, 119.5, 117.6, 110.9, 62.4, 33.3, 33.2, 30.2, 30.1, 22.2, 14.0, 13.7; MS (EI, 70 eV): m/z (%) = 446 (5), 401 (7), 391 (74), 389 (100), 359 (9), 357 (13), 337 (11); 335 (46), 334 (11), 333 (65), 307 (18), 305 (24), 287 (15), 57 (10), 41 (14). HRMS (EI): m/z calcd for C₁₉H₂₄Cl₂N₂O₂S₂: 446.0656; found: 446.0645. 3,6-Dichloro-1,8-dimethyl-2,7-naphthyridine (7) CuI (16.56 g, 87 mmol, 3.0 equiv) was placed in a dry, argon-flushed, round-bottomed Schlenk flask equipped with a magnetic stirrer bar, then dried for 10 min at 450 °C under high vacuum. The flask was refilled with argon and THF (500 mL) was added. The flask was cooled to –40 °C and a 1.51 M solution of MeLi in THF (115 mL, 174 mmol, 6.0 equiv) was slowly added. The mixture was stirred at –40 °C for ~30 min until the solution was completely transparent. Another dry, argon-flushed, round-bottomed Schlenk flask, equipped with a magnetic stirrer bar, was charged with a solution of naphthyridine 2c (10.85 g, 29.0 mmol, 1.0 equiv) in THF (270 mL). The solution was cooled to –40 °C and then slowly added through a cannula to the Me₂CuLi solution. After complete addition, the mixture was stirred at –40 °C for 2 h. The reaction was quenched with sat. aq. NH₄Cl/NH₃ solution (10:1 v/v, 10 mL), the layers were separated and the aqueous phase was extracted with EtOAc (3 × 100 mL). The combined organic layers were dried (MgSO₄), filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography [silica gel, hexanes–EtOAc (8:2)] to give a white solid; yield: 5.5 g (84%); mp 143–145 °C. IR (diamond ATR): 2960, 2932, 1588, 1534, 1454, 1421, 1388, 1323, 1184, 1131, 1048, 891 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 7.43 (s, 2 H), 3.13 (s, 6 H). ¹³C NMR (75 MHz, CDCl₃): δ = 162.0, 148.3, 145.0, 121.7, 116.9, 29.2. MS (EI, 70 eV): m/z (%) = 228 (64), 227 (19), 226 (100), 191 (13), 189 (11), 164 (14), 156 (11), 155 (16), 128 (12), 123 (10), 114 (8), 63 (11). HRMS (EI): m/z calcd for C₁₀H₈Cl₂N₂: 226.0065; found: 226.0071. Iron-Catalyzed Cross-Couplings of Naphthyridine 7; General Procedure A dry, argon-flushed, Schlenk flask, equipped with a magnetic stirrer bar and a rubber septum was charged with naphthyridine 7 (113 mg, 0.50 equiv) and Fe(acac)₃ (5 mol%, 9 mg), followed by anhyd THF (2 mL) [or, in the case of 10e, FeBr₃ (5 mol%, 7.4 mg) and t-BuOMe (2 mL)]. After dropwise addition of the Grignard reagent, the mixture was stirred at r.t. for the indicated time until the starting material was completely consumed (GC). 3,6-Diethyl-1,8-dimethyl-2,7-naphthyridine (10a) Naphthyridine 7 (0.5 mmol, 113 mg, 1.0 equiv) was treated with a 2.4 M solution of EtMgCl in THF (0.44 mL, 1.05 mmol, 2.1 equiv) for 2 h at r.t. according to the general procedure. The reaction was then quenched with sat. aq. NH₄Cl (10 mL). The layers were separated and the aqueous phase was extracted with EtOAc (3 × 10 mL). The combined organic layers were dried (MgSO₄), filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography [silica gel, hexanes–EtOAc (9:1)] to give a red-brown solid; yield: 74 mg (69%); mp 56–57 °C. IR (diamond ATR): 2967, 2925, 1606, 1545, 1456, 1373, 1329, 1062, 963, 915, 895 cm^–1. ¹H NMR (300 MHz, CDCl₃): δ = 7.13 (s, 2 H), 3.06 (s, 6 H), 2.85 (q, J = 7.5 Hz, 4 H), 1.32 (t, J = 7.5 Hz, 6 H). ¹³C NMR (75 MHz, CDCl₃): δ = 158.9, 158.7, 142.7, 120.8, 114.8, 30.9, 29.1, 13.2; MS (EI, 70 eV): m/z (%) = 214 (52), 213 (100), 186 (12), 185 (11), 115 (8), 63 (6), 42 (8). HRMS (EI): m/z calcd for C₁₄H₁₈N₂: 214.1470; found: 214.1470. 3,6-Dicyclohexyl-1,8-dimethyl-2,7-naphthyridine (10d) Naphthyridine 7 (0.5 mmol, 113 mg, 1.0 equiv) was treated with a 0.46 M solution of CyMgBr·LiCl in THF (2.6 mL, 1.2 mmol, 2.4 equiv) for 30 min at r.t. according to the general procedure. The reaction was then quenched with sat. aq NH₄Cl (10 mL). The layers were separated and the aqueous phase was extracted with EtOAc (3 × 10 mL). The combined organic layers were dried (MgSO₄), filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography [silica gel, hexanes–EtOAc (9:1)] to give a white solid; yield: 126 mg (78%); mp 78–79 °C. IR (diamond ATR): = 2922, 2850, 1604, 1540, 1447, 1423, 1328, 939, 900, 876, 849 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.10 (s, 2 H), 3.02 (s, 6 H), 2.74–2.63 (m, 2 H), 2.04–1.92 (m, 4 H), 1.86–1.76 (m, 4 H), 1.74–1.66 (m, 2 H), 1.51–1.32 (m, 8 H), 1.30–1.17 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 161.8, 158.6, 142.7, 121.2, 113.8, 45.9, 32.9, 29.3, 26.6, 26.2. MS (EI, 70 eV): m/z (%) = 322 (38), 321 (20), 293 (15), 281 (16), 268 (25), 267 (100), 254 (29). HRMS (EI): m/z calcd for C₂₂H₃₀N₂: 322.2409; found: 322.2402. 1,8-Dimethyl-3,6-diphenyl-2,7-naphthyridine (10e) Naphthyridine 7 (0.5 mmol, 113 mg, 1.0 equiv) was treated with a 1.78 M solution of PhMgCl in THF (1.12 mL, 2.0 mmol, 4.0 equiv) for 15 min at r.t. according to the general procedure. The reaction was then quenched with sat. aq. NH₄Cl (10 mL), the layers were separated and the aqueous phase was extracted with EtOAc (3 × 10 mL). The combined organic layers were dried (MgSO₄), filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography [silica gel, hexanes–EtOAc (9:1)] to give a white solid; yield: 65 mg (42%); mp 158–160 °C. IR (diamond ATR): 1601, 1547, 1418, 1378, 1026, 893, 774, 763, 695, 682, 644, 579 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.09 (d, J = 7.3 Hz, 4 H), 7.79 (s, 2 H), 7.44 (t, J = 7.5 Hz, 4 H), 7.40–7.32 (m, 2 H), 3.16 (s, 6 H). ¹³C NMR (100 MHz, CDCl₃): δ = 159.7, 152.6, 143.2, 138.8, 129.3, 128.9, 127.3, 121.9, 114.8, 29.6. MS (EI, 70 eV): m/z (%) = 311 (24), 310 (100), 309 (15), 268 (4), 165 (3), 155 (6), 77 (4). HRMS (EI): m/z calcd for C₂₂H₁₈N₂: 310.1470; found: 310.1465.

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Supporting Information