[1-Methyl-1-(pyridin-2-yl)ethyl]amine

Uses

The Shi Auxiliary is a powerful directing group for the hydroxylation of arenes through copper-mediated C-H activation. This useful auxiliary can be removed through acid-mediated hydrolysis and has shown to be done on gram-scale.

General Description

2-(Pyridin-2-yl)isopropyl amine (PIP-amine) is a tertiary amine. A bidentate directing group, useful for the functionalization of C-H bond, has been developed from PIP-amine.

reaction suitability

reagent type: catalyst
reagent type: ligand
reaction type: C-H Activation

Synthesis

General procedure for the synthesis of α,α-dimethyl-2-pyridinemethanamine from 2-cyanopyridine and methyllithium: Anhydrous cerium(III) chloride (35 g, 144 mmol) was mixed with THF (240 mL) under nitrogen protection and stirred for 30 min to form a slurry. The mixture was cooled to -76°C in a dry ice-acetone bath. An ether solution of 1.6 M methyl lithium (90 mL, 144 mmol) was slowly added dropwise, and the rate of dropwise acceleration was controlled to keep the reaction temperature below -60°C. After the dropwise addition was completed, stirring was continued for 30 minutes. The reaction mixture was again cooled to -76 °C, and then a THF (20 mL) solution of 2-cyanopyridine (5 g, 48 mmol) was slowly added, ensuring that the reaction temperature did not exceed -60 °C. The mixture was stirred in a dry ice bath for 15 minutes and then removed from the cooling bath to allow the reaction mixture to slowly warm up to 15 °C. Subsequently, the reaction mixture was placed back in the dry ice bath to cool and ammonium hydroxide (90 mL) was added with stirring. The reaction mixture was allowed to warm to room temperature and stirred overnight. Upon completion of the reaction, the solution was poured out of the mixture and the solids were washed well with THF. The filtrate and washings were combined and the solvent was evaporated to give 1-methyl-1-(pyridin-2-yl)ethylamine in quantitative yield. The structure of the product was confirmed by 1H NMR (400 MHz, CDCl3): δ 8.52 (d, J=4.0 Hz, 1H), 7.60 (td, J=7.7,1.6 Hz, 1H), 7.42 (d, J=7.9 Hz, 1H), 7.15-7.08 (m, 1H), 1.47 (s, 6H).

References

[1] Patent: WO2009/131814, 2009, A2. Location in patent: Page/Page column 43
[2] Journal of the American Chemical Society, 2014, vol. 136, # 33, p. 11574 - 11577
[3] Angewandte Chemie - International Edition, 2013, vol. 52, # 51, p. 13588 - 13592
[4] Angew. Chem., 2013, vol. 125, # 51, p. 13833 - 13837,5
[5] Patent: WO2005/97750, 2005, A1. Location in patent: Page/Page column 147-148