Manfred Schlosser*, Thierry Rausis and Carla Bobbio. Supporting Information

Transcription

1 1 Rerouting the Nucleophilic Attack from the 4-Position to the 2- or 6-Position of 2,4-ihalopyridines and 2,4,6-Trihalopyridines : The Solution to a Long Standing Problem Manfred Schlosser*, Thierry Rausis and Carla Bobbio Supporting Information etails regarding standard operations and abbreviations were explained in previous publications from this laboratory H and 13 C NMR were recorded at 400 and 101 MHz, respectively. The solvent was deuterochloroform or, if marked with an asterisk, perdeuteroacetone. 1. Typical Reaction Sequence 2,4,6-Trifluoro-3-(triethylsilyl)pyridine (9) : At 100 C, butyllithium (0.10 mol) in hexanes (64 ml) was added to a solution of 2,4,6-trifluopyridine (13 g, 0.10 mol) in tetrahydrofuran (0.15 L). After 45 min at 100 C, chlorotriethylsilane (17 ml, 15 g, 0.10 mol) was added. The mixture was allowed to reach 75 C and kept at this temperature for 45 min before adding water (50 ml). The organic phase was separated, dried and the solvents evaporated. istillation afforded 22.5 g (91%) of a colorless liquid; b.p C/1.6 Torr; n H NMR : δ = 6.50 (dd, J = 7.6, 1.9 Hz, 1 H), 0.9 (m, 15 H) ppm. 13 C NMR : δ = (ddd, J = 259, 16, 12 Hz), (ddd, J = 243, 22, 18 Hz), (ddd, J = 245,, 17 Hz), (ddd, J = 50, 35, 6 Hz), 94.8 (ddd, J = 37, 30, 7 Hz), 7.1, 3.8 (t, J = 2.1 Hz) ppm. C 11 H 16 F 3 NSi (247.34) : calcd C 53.42, H 6.52; found C 53.46, H ,6-ifluoro-2-hydrazino-5-(triethylsilyl)pyridine (10) : 2,4,6-Trifluoro-3- (triethylsilyl)pyridine (9; 74 g, 0.30 mol) and hydrazine monohydrate (29 ml, 30 g, 0.60 mol) were heated in tetrahydrofuran (0.10 L) for 2 h at 50 C. After evaporation of the solvent and addition of diethyl ether (75 ml), the organic phase was washed with water (50 ml). Evaporation of the volatiles afforded a yellowish oil; n = ; yield : 76.3 g (98%). 1 H NMR : δ = 6.8 (s, broad, 1 H), 6.33 (d, J = 10.2 Hz, 1 H), 3.8 (s, broad, 2 H), 0.9 (m, 15 H) ppm. 13 C NMR : δ = (dd, J = 253, 17 Hz), (dd, J = 233, 22 Hz), (dd, J =, 15 Hz), 90.8 (dd, J = 51, 36 Hz), 89.3 (dd, J = 29, 5 Hz), 7.1 (3 C), 3.9 (t, J = 2 Hz, 3 C) ppm. C 11 H 19 F 2 N 3 Si (259.37) : calcd. C 50.94, H 7.38; found C 51.21, H 7.31.

2 2 2,4-ifluoro-6-hydrazinopyridine (12) : 4,6-ifluoro-2-hydrazino-5-(triethylsilyl)- pyridine (10; 13 g, 50 mmol) and tetrabutylammonium fluoride trihydrate (16 g, 50 mmol) were mixed in tetrahydrofuran (50 ml) for 2 h at 25 C. The solvent was evaporated and water (25 ml) and diethyl ether (50 ml) were added. After separation of the phases and extraction of the aqueous one with diethyl ether (2 ml), the organic phases reunited were dried, filtered and the solvent evaporated. Trituration from hexanes and filtration afforded 6.21 g (85%) of an orange solid; colorless cotton-like needles (from chloroform and hexanes); m.p C. 1 H NMR : δ = 6.37 (dd, J = 10.0, 1.6 Hz, 1 H), 6.3 (s, broad, 1 H), 5.98 (dt, J = 8.4, 1.7 Hz), 3.8 (s, broad, 2 H) ppm. 13 C NMR : δ = (dd, J = 257, 14 Hz), (dd, J = 236, 17 Hz), (dd, J =, 14 Hz), 89.7 (dd, J = 24, 5 Hz), 86.5 (dd, J = 41, 25 Hz) ppm. C 5 H 5 F 2 N 3 (145.11) : calcd. C 41.39, H 3.47; found C 41.69, H ,4-ifluoropyridine (14): 2,4-ifluoro-6-hydrazinopyridine (17; 15 g, 0.10 mol) and copper(ii) sulfate pentahydrate (50 g, 0. mol) in water (0.45 L) were heated under reflux for 25 min. A steam distillation followed by an ordinary distillation afforded a colorless liquid; b.p C (ref. 4 : 107 C); yield : 5.87 g (51%). 1 H NMR : δ = 8.22 (dd, J = 8.3, 5.8 Hz, 1 H), 6.97 (ddd, J = 7.7, 5.8, 1.9 Hz, 1 H), 6.68 (dt, J = 8.6, 1.9 Hz, 1 H) ppm. 2. Physical Constants, Spectra and Analytical ata of Compounds 1 17 and 23 2-Fluoro-4-hydrazinopyridine (1) : colorless platelets (from tetrahydrofuran and hexanes); m.p C. 1 H NMR*: δ = 9.0 (s, broad, 1 H), 7.79 (d, J = 5.8 Hz, 1 H), 6.85 (dt, J = 5.8, 1.6 Hz, 1 H), 6.57 (d, J = 1.6 Hz, 1 H), 3.0 (s, broad, 2 H) ppm. 13 C NMR* : δ = (d, J = 229 Hz), (d, J = 12 Hz), (d, J = 19 Hz), (d, J = 3 Hz), 91.7 (d, J = 44 Hz) ppm. C 5 H 6 FN 3 (127.12) : calcd. C 47.24, H 4.76; found C 47.15, H ,4-ifluoro-3-iodopyridine (2) : colorless needles (from hexanes); m.p C; 1 H NMR : δ = 8.12 (dd, J = 7.7, 5.8 Hz, 1 H), 6.94 (t, J = 5.8 Hz, 1 H) ppm. 13 C NMR : δ = (dd, J = 262, 7 Hz), (dd, J = 234, 7 Hz), (dd, J = 17, 9 Hz), (dd, J = 21, 6 Hz), 65.3 (dd, J = 47, 27 Hz) ppm. C 5 H 2 F 2 IN (240.98) : calcd. C 24.92, H 0.84; found C 25.07, H ,4-ifluoro-5-iodopyridine (3) : colorless liquid; m.p. 22 C; b.p C/15 Torr; n = H NMR : δ = 8.49 (d, J = 8.8 Hz, 1 H), 6.73 (dd, J = 7.4, 2.5 Hz, 1 H) ppm. 13 C NMR : δ = (dd, J = 262, 13 Hz), (dd, J = 240, 12 Hz), (dd, J = 17, 4 Hz), 98.7 (dd, J = 42, 24 Hz), 76.5 (dd, J = 23, 6 Hz) ppm. C 5 H 2 F 2 IN (240.98) : calcd. C 24.92, H 0.84; found C 25.01, H 0.82.

3 3 2,4-ifluoro-5-(trimethylsilyl)pyridine (4) : colorless liquid; m.p C; b.p C/ Torr; n = H NMR : δ = 8.16 (d, J = 8.9 Hz, 1 H), 6.61 (dd, J = 8.0, 1.6 Hz, 1 H), 0.37 (d, J = 1.0 Hz, 9 H) ppm. 13 C NMR : δ = (dd, J = 258, 12 Hz), (dd, J = 239, 13 Hz), 154.2, (dd, J = 17, 13 Hz), 1.3 (dd, J = 28, 5 Hz), 97.0 (dd, J = 40, 23 Hz), -1.3 (3 C) ppm. C 8 H 11 F 2 NSi (187.27) : calcd. C 51.31, H 5.92; found C 51.04, H Fluoro-2-hydrazino-5-(trimethylsilyl)pyridine (5) : slightly pink prisms (from toluene); m.p C. 1 H NMR : δ = 8.02 (d, J = 9.4 Hz, 1 H), 6.40 (d, J = 10.6 Hz,1 H), 5.9 (s, broad, 1 H), 0.29 (d, J = 0.7 Hz, 9 H) ppm. 13 C NMR : δ = (d, J = 253 Hz), (d, J = 11 Hz), (d, J = 13 Hz), (d, J = 29 Hz), 92.3 (d, J = 26 Hz), -1.0 (3 C) ppm. C 8 H 14 FN 3 Si (199.31) : calcd , H 7.08; found C 48.27, H Fluoro-2-hydrazinopyridine (6) : colorless cotton-like needles (from chloroform and hexanes); m.p C. 1 H NMR : δ = 8.05 (dd, J = 8.7, 5.9 Hz, 1 H), 6.49 (dd, J = 11.2, 2.3 Hz, 1 H), 6.43 (ddd, J = 8.3, 5.8, 2.3 Hz, 1H), 6.2 (s, broad, 1 H), 3.6 (s, broad, 2 H) ppm. 13 C NMR : δ = (d, J = 258 Hz), (d, J = 10 Hz), (d, J = 10 Hz), (d, J = 19 Hz), 93.1 (d, J = 21 Hz) ppm. C 5 H 6 FN 3 (127.12) : calcd , H 4.76; found C 47.21, H Ethoxy-2,6-difluoropyridine (7) : colorless needles (from hexanes); m.p C. 1 H NMR : δ = 6.28 (s, 2 H), 4.11 (q, J = 7.0 Hz, 2 H), 1.45 (t, J = 7.0 Hz, 3 H) ppm. 13 C NMR : δ = (t, J = 12 Hz), (dd, J = 241, Hz, 2 C), 92.4 (symm. m, 2 C), 65.1, 14.2 ppm. C 7 H 7 F 2 NO (159.13) : calcd. C 52.83, H 4.43; found C 52.82, H ,6-ifluoro-4-hydrazinopyridine (8) : colorless platelets (from ethyl acetate); m.p. 0 2 C. 1 H NMR* : δ = 9.3 (s, broad, 1 H), 6.48 (s, 2 H), 3.0 (s, broad, 2 H) ppm. 13 C NMR* : δ = (dd, J = 235, Hz, 2 C), (t, J = 12 Hz), 89.5 (symm. m, 2 C) ppm. C 5 H 5 F 2 N 3 (145.11) : calcd. C 41.38, H 3.47; found C 41.55, H ,4,6-Trifluoro-3-(triethylsilyl)pyridine (9) : colorless liquid; b.p C/1.6 Torr; n H NMR : δ = 6.50 (dd, J = 7.6, 1.9 Hz, 1 H), 0.9 (m, 15 H) ppm. 13 C NMR : δ = (ddd, J = 259, 16, 12 Hz), (ddd, J = 243, 22, 18 Hz), (ddd, J = 245,, 17 Hz), (ddd, J = 50, 35, 6 Hz), 94.8 (ddd, J = 37, 30, 7 Hz), 7.1, 3.8 (t, J = 2.1 Hz) ppm. C 11 H 16 F 3 NSi (247.34) : calcd C 53.42, H 6.52; found C 53.46, H ,6-ifluoro-2-hydrazino-5-(triethylsilyl)pyridine (10) : yellowish oil; n = H NMR : δ = 6.8 (s, broad, 1 H), 6.33 (d, J = 10.2 Hz, 1 H), 3.8 (s, broad, 2 H), 0.9 (m, 15 H) ppm. 13 C NMR : δ = (dd, J = 253, 17 Hz), (dd, J = 233, 22 Hz), (dd, J =, 15 Hz), 90.8 (dd, J = 51, 36 Hz), 89.3 (dd, J = 29, 5 Hz), 7.1 (3 C), 3.9 (t, J = 2 Hz, 3 C) ppm. C 11 H 19 F 2 N 3 Si (259.37) : calcd. C 50.94, H 7.38; found C 51.21, H 7.31.

4 4 2,4-ifluoro-3-(triethylsilyl)pyridine (11) : colorless liquid; b.p C/7 Torr; n H NMR : δ = 8.18 (dd, J = 8.9, 5.5 Hz, 1 H), 6.87 (ddd, J = 7.4, 5.6, 0.7 Hz, 1 H), 0.9 (m, 15 H) ppm. 13 C NMR : δ = (dd, J = 259, 16 Hz), (dd, J = 235, 18 Hz), (dd, J = 19, 12 Hz), (dd, J = 24, 5 Hz), (dd, J = 51, 33 Hz), 7.2, 3.8 (t, J = 2.5 Hz) ppm. C 11 H 17 F 2 NSi (229.35): calcd. C 57.61, H 7.47; found C 57.43, H ,4-ifluoro-6-hydrazinopyridine (12) : colorless cotton-like needles (from chloroform and hexanes); m.p C. 1 H NMR : δ = 6.37 (dd, J = 10.0, 1.6 Hz, 1 H), 6.3 (s, broad, 1 H), 5.98 (dt, J = 8.4, 1.7 Hz), 3.8 (s, broad, 2 H) ppm. 13 C NMR : δ = (dd, J = 257, 14 Hz), (dd, J = 236, 17 Hz), (dd, J =, 14 Hz), 89.7 (dd, J = 24, 5 Hz), 86.5 (dd, J = 41, 25 Hz) ppm. C 5 H 5 F 2 N 3 (145.11) : calcd. C 41.39, H 3.47; found C 41.69, H Bromo-4,6-difluoropyridine (13) : slightly yellow liquid; m.p. 21 to 24 C; b.p C/30 Torr; n = H NMR : δ = 7. (dd, J = 7.1, 2.0 Hz, 1 H), 6.66 (dt, J = 7.9, 1.9 Hz, 1 H) ppm. 13 C NMR : δ = (dd, J = 268, 12 Hz), (dd, J = 246, 14 Hz), (dd, J = 18, 12 Hz), (d, J = 21, 6 Hz), 97.3 (dd, J = 40, 22 Hz) ppm. C 5 H 2 BrF 2 N (193.98) : calcd. C 30.96, H 1.04; found C 31.18, H ,4-ifluoropyridine (14) : colorless liquid; b.p C (ref. 4 : 107 C). 1 H NMR : δ = 8.22 (dd, J = 8.3, 5.8 Hz, 1 H), 6.97 (ddd, J = 7.7, 5.8, 1.9 Hz, 1 H), 6.68 (dt, J = 8.6, 1.9 Hz, 1 H) ppm. 2,3,4,6-Tetrafluoro-5-(trimethylsilyl)pyridine (15) : colorless liquid; b.p C/ Torr (ref. 5 : C/ Torr). 1 H NMR : δ = 0.41 (s, 9 H) ppm. 2,4-ichloro-5-(triethylsilyl)pyridine (16) : colorless liquid; b.p C/2 Torr; n = H NMR : δ = 8.30 (s, 1 H), 7.35 (s, 1 H), 0.9 (m, 15 H) ppm. 13 C NMR : δ = 155.8, 152.9, 152.2, 129.9, 124.4, 7.1 (3 C), 2.9 (3 C) ppm. C 11 H 17 Cl 2 NSi (262.25) : calcd. C 50.38, H 6.53; found C 50.68, H ,4,6-Trichloro-3-(trimethylsilyl)pyridine (17) : colorless liquid; m.p C; b.p C/2.5 Torr. 1 H NMR : δ = 7.27 (s, 1 H), 0.52 (s, 9 H) ppm. 13 C NMR : δ = 156.4, 153.6, 150.7, 131.8, 123.9, 2.0 (3 C) ppm. C 8 H 10 Cl 3 NSi (254.62) : calcd. C 37.74, H 3.96; found C 37.78, H ,4-ichloro-6-hydrazinopyridine () : colorless needles (from ethyl acetate); m.p C. 1 H NMR* : δ = 8.9 (s, broad, 1 H), 7.08 (d, J = 1.6 Hz, 1 H), 6.77 (d, J = 1.6 Hz, 1 H), 3.0 (s, broad, 2 H) ppm. 13 C NMR* : δ = 160.2, 151.2, 147.6, 114.6, ppm. C 5 H 5 Cl 2 N 3 (178.02) : calcd. C 33.73, H 2.83; found C 33.77, H 2.94.

5 5 2,4,5-Trifluoropyridine (21) : colorless liquid; b.p C; n = H NMR : δ = 8.15 (dt, J = 9.6, 1.3 Hz, 1 H), 6.83 (ddd, J = 8.0, 4.8, 2.9 Hz, 1 H) ppm. 13 C NMR : δ = (ddd, J = 237, 11, 2 Hz), (dt, J = 267, 13 Hz), (ddd, J = 254, 11, 6 Hz), (ddd, J = 21, 19, 2 Hz), 99.3 (dd, J = 46, 19 Hz) ppm. C 5 H 2 F 3 N (133.07) : calcd. C 45.13, H 1.51; found C 45.27, H Chloro-3-(triethylsilyl)pyridine (22) : colorless liquid; b.p C/0.5 Torr; n = H NMR : δ = 8.53 (s, 1 H), 8.47 (d, J = 5.1 Hz, 1 H), 7.28 (d, J = 5.1 Hz, 1 H) ppm. 13 C NMR : δ = 156.3, (2 C), 131.1, 124.4, 7.1 (3 C), 3.0 (3 C). ppm. C 11 H 18 ClNSi (227.81) : calcd. C 58.00, H 7.96; found C 58.04, H ,4-ichloropyridine (23) : colorless liquid; b.p C/15 Torr (ref. 6 : C/15 Torr). 1 H NMR : δ = 8.31 (d, J = 5.4 Hz, 1 H), 7.37 (d, J = 1.9 Hz, 1 H), 7.25 (dd, J = 5.4, 1.9 Hz, 1 H) ppm. References (1) Bobbio, C.; Schlosser, M.; Eur. J. Org. Chem. 01, (2) Heiss, C.; Schlosser, M.; Eur. J. Org. Chem. 03, (3) Schlosser, M.; Marull, M.; Eur. J. Org. Chem. 03, (4) Coe, P.L.; Holton, A.G.; Tatlow, J.C.; J. Fluorine Chem. 1982, 21, (5) Coe, P.L.; Rees, A.J.; J. Fluorine Chem. 00, 101, (6) den Hertog, H.J.; Kolder, C.R.; Recl. Trav. Chim. Pays-Bas 1953, 72,