N,N,N',N'-Tetramethylethylenediamine → 1-Cyclopentyl-2-(trifluoromethyl)benzene

To a 30 L jacketed reactor, dry THF (6 L) and magnesium turnings (243.0 g, 10 mol, 1.5 eq.) were added under N2. In a separate flask, FeCl3 (162 g, 1.0 mol, 0.15 eq.) was dissolved in THF (800 mL) (caution, exothermic) under N2. This dark brown solution was cooled to ambient temperature using an ice bath and then added over 35 min to the 30 L reactor contents under N2 at an internal temperature of 10° C. To this yellow/green mixture, TMEDA (1.2 L) was added keeping the internal temperature below 20° C. (slightly exothermic). The resulting rust brown mixture was stirred at 45° C. for 1 h under N2. The reactor content was allowed to cool below 20° C. and a mixture of 1-bromo-2-(trifluoromethyl)benzene (1500 g, 6.67 mol) and bromocyclopentane (1192 g, 8.00 mol, 1.2 eq.) added dropwise under N2 at such a rate as to maintain the internal temperature between 25-30° C. (caution, exothermic). After the addition (333 h) and the exotherm subsided, the reaction mixture was stirred at 25° C. under N2 overnight, allowed to cool to an internal temperature of 0° C. and quenched with 6 N HCL (3 L, 1.5 h) at such a rate as to maintain the internal temperature below 15° C. (caution, very exothermic). After the quench, ethyl acetate (4 L) was added and the reactor content stirred at ambient temperature for 1 h. The phases were separated and the aqueous layer back extracted with ethyl acetate (2.5 L). The combined organic layers were washed with H2O (1 L), brine (1.5 L) and dried (Na2SO4). The solvent was rotary evaporated at 35° C. and the residue fraction distilled under high vacuum (65-70° C., 0.15 Torr) to give 823 g of product (58%, not wt % corrected) as a clear colorless liquid. 1H NMR (Bruker, 400 MHz, DMSO-d6) δ ppm 7.58-7.64 (m, 3H, ArH), 7.34-7.4 (m, 1H, ArH), 3.21-3.29 (m, 1H, —CH), 1.95-2.04 (m, 2H, —CH2), 1.76-1.88 (m, 2H, —CH2), 1.49-1.71 (m, 4H, —CH2).

1. additionadded over 35 min to the 30 L reactor contents under N2 at an internal temperature of 10° C
2. customthe internal temperature below 20° C.
3. temperatureto cool below 20° C.
4. additionadded dropwise under N2 at such a rate as
5. temperatureto maintain the internal temperature between 25-30° C. (caution, exothermic)
6. additionAfter the addition (333 h)
7. temperatureto cool to an internal temperature of 0° C.
8. customquenched with 6 N HCL (3 L, 1.5 h) at such a rate as
9. temperatureto maintain the internal temperature below 15° C. (caution, very exothermic)
10. additionAfter the quench, ethyl acetate (4 L) was added
11. stirringthe reactor content stirred at ambient temperature for 1 h
12. customThe phases were separated
13. extractionthe aqueous layer back extracted with ethyl acetate (2.5 L)
14. washThe combined organic layers were washed with H2O (1 L), brine (1.5 L)
15. dry with materialdried (Na2SO4)
16. customThe solvent was rotary evaporated at 35° C.
17. distillationthe residue fraction distilled under high vacuum (65-70° C., 0.15 Torr)

ORDレコード

ord-84d3dda559624e118c93f57aa86469f7

出典データセット

uspto-grants-2016_09

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US09447041B2