N-Methyl dicyclohexylamine → Dicyclopentadienyltitanium

Temperature

0 °C

General Note: The reaction was run in such a way as to minimize exposure to light. Reactions were run under a layer of foil to block light and the lab lights were turned off while manipulating the reaction mixtures. To a suspension of titanocenedichloride (4.33 g, 17 mmol) in toluene (141 mL) at 0° C. was added methyllithium (1.6M in diethyl ether, 26.5 mL, 42.5 mmol) dropwise. The reaction was stirred at 0° C. for 1 h. The reaction was quenched by addition of 70 mL of a 6% ammonium chloride solution. The resulting heterogeneous mixture was vigorously stirred for 15 min at 0° C. prior to separation of the layers. The heterogeneous mixture was filtered through a course frit and added to the sep funnel. The layers were separated and the organic layer dried over magnesium sulfate. The solution was filtered and treated with (1-(tert-butoxycarbonyl)-4-(4-fluorophenyl)piperidin-4-yl)methyl 5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole-7-carboxylate (3.5 g, 5.7 mmol) and N-cyclohexyl-N-methylcyclohexanamine (0.61 mL, 2.8 mmol) and the mixture concentrated to ˜⅓ its volume. The bath temperature was maintained at 30° C. while reaction mixture was being concentrated. The reaction flask was flushed with a stream of nitrogen and fitted with a reflux condenser (which had also been flushed with a stream of nitrogen for some time) and the resulting solution was placed in an oil bath preheated to 80° C. The bath temperature was set to 80° C. and stirred at that temperature (start=11 AM). After 9 h, heating was discontinued and the reaction allowed to stir at room temperature overnight. The reaction was concentrated to remove ˜½ of the toluene. The reaction was diluted with 100 mL of hexanes to precipitate some of the titanocenes with stirring. To decompose the remaining titanocene, silica gel (10 g) was added as a solid with vigorous stirring to the suspension at 0° C. The ice bath was removed and stirring continued for 15 min. The resulting suspension was filtered and the resulting pad washed with 25% ethyl acetate/n-hexane. The mother liquor was concentrated and loaded onto a silica gel column (10% ethyl acetate/n-hexane). After several volumes at 10%, the gradient was ramped to 25% ethyl acetate/n-hexane to give the product with significant levels of titanocene byproducts by TLC. All of the fractions that contained product were concentrated and repurified by column chromatography (10% ethyl acetate/n-hexane→25% ethyl acetate/n-hexane) to give 3.06 g (88%) as a very faint yellow solid. 1H-NMR (CDCl3, 500 MHz) δ 8.05 (s, 1H), 7.58 (d, J=1.8 Hz, 1H), 7.44 (dd, J=8.9, 5.5 Hz, 2H), 7.33 (d, J=1.8 Hz, 1H), 7.10 (dd, J=8.9, 8.5 Hz, 2H), 5.95 (d, J=2.1 Hz, 1H), 5.69 (s, 2H), 4.59 (d, J=2.1 Hz, 1H), 3.83 (s, 2H), 3.80 (bs, 2H), 3.64 (t, J=8.6 Hz, 2H), 3.10 (m, 2H), 2.31 (m, 2H), 1.99 (m, 2H), 1.45 (s, 9H), 0.93 (t, J=8.2 Hz, 2H), −0.04 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 161.6 (d, J=246 Hz), 155.0, 144.3, 138.21, 138.19, 128.9 (d, J=8.6 Hz), 127.8, 126.9, 124.7, 123.6, 122.4, 119.2, 115.5 (d, J=20 Hz), 90.0, 82.0, 79.6, 75.8, 67.8, 41.1, 40.2 (br), 32.5, 28.6, 17.9, −1.4. Mass spec.: 616.36 (MH)+.

1. customthe reaction mixtures
2. customThe reaction was quenched by addition of 70 mL of a 6% ammonium chloride solution
3. stirringThe resulting heterogeneous mixture was vigorously stirred for 15 min at 0° C.
4. customto separation of the layers
5. filtrationThe heterogeneous mixture was filtered through a course frit
6. additionadded to the sep funnel
7. customThe layers were separated
8. dry with materialthe organic layer dried over magnesium sulfate
9. filtrationThe solution was filtered
10. concentrationthe mixture concentrated
11. temperatureThe bath temperature was maintained at 30° C. while reaction mixture
12. concentrationwas being concentrated
13. customThe reaction flask was flushed with a stream of nitrogen
14. customfitted with a reflux condenser (which
15. customhad also been flushed with a stream of nitrogen for some time) and the resulting solution
16. customwas placed in an oil bath
17. custompreheated to 80° C
18. customwas set to 80° C.
19. stirringstirred at that temperature (start=11 AM)
20. waitAfter 9 h
21. temperatureheating
22. stirringto stir at room temperature overnight
23. concentrationThe reaction was concentrated
24. customto remove ˜½ of the toluene
25. additionThe reaction was diluted with 100 mL of hexanes
26. customto precipitate some of the titanocenes
27. stirringwith stirring
28. additionwas added as a solid
29. stirringwith vigorous stirring to the suspension at 0° C
30. customThe ice bath was removed
31. stirringstirring
32. waitcontinued for 15 min
33. filtrationThe resulting suspension was filtered
34. washthe resulting pad washed with 25% ethyl acetate/n-hexane
35. concentrationThe mother liquor was concentrated

ORD record

ord-1651819d440249e6bbc75439faad82c4

Source dataset

uspto-grants-2011_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08026257B2