We thank the Research Training Group ‘Chemical Bond Activation’ (GRK 2226) funded by the Deutsche Forschungsgemeinschaft for financial support of this project.
Carbon–carbon bond-forming hydroaminoalkylation reactions between trimethylamine and alkynes, alkenes, allenes, or a methylenecyclopropane (MCP) are achieved in the presence of titanium catalysts. The reactions take place by C–H bond activation at the methyl group of trimethylamine and therefore offer flexible and direct methods for the C–H functionalization of trimethylamine. The importance of the developed procedures for the synthesis of pharmaceutically relevant dimethylaminomethyl-substituted products is underlined by a straightforward synthesis of the antidepressant butriptyline.
11 CCDC 2278262 ((E)-7a·HCl), 2278260 (21·HCl), 2278261 (23·HCl), and 2278263 (29·HCl) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www. ccdc.cam.ac.uk/data request/cif
12
Thye H,
Fornfeist F,
Geik D,
Schlüschen LL,
Schmidtmann M,
Doye S.
Synthesis 2023; in press
14aHydroaminoalkylation Reactions with Trimethylamine; Typical Synthesis for Butriptyline (21): In a glovebox under N2-atmosphere, a 5 mL ampoule with magnetic stirring bar was charged with TiBn4 (41.2 mg, 0.10 mmol, 10 mol%), LH2 (36.5 mg, 0.10 mmol, 10 mol%), and toluene (1.1 mL). To this solution, trimethylamine (0.4 mL, c = 2.5 molL–1 in toluene, 1.0 mmol) and 5-allyl-10,11-dihydro-5H-dibenzo[a,d][7]annulene (20, 352 mg, 1.5 mmol) were added. Additional toluene (3.0 mL) was used to transfer [Ph3C][B(C6F5)4] (73.8 mg, 0.08 mmol, 8 mol%) as a suspension to the reaction mixture. The ampoule was sealed with a natural gas/O2 torch14b and heated in an oil bath to 70 °C for 24 h. After the reaction mixture had cooled to room temperature and diluted with EtOAc (25 mL), the solvents were removed under reduced pressure and the residue was purified by flash column chromatography (hexanes/EtOAc/MeOH/HNEt2 = 10:10:1:0.042, Rf = 0.12) to give butriptyline (21, 230 mg, 0.78 mmol, 78 %) as a slightly yellow oil. 1H NMR (500 MHz, CDCl3): δ = 1.01 (d, J = 6.5 Hz, 3 H), 1.45–1.62 (m, 1 H), 1.73 (ddd, J = 14.2, 8.5, 6.1 Hz, 1 H), 2.06–2.12 (m, 1 H), 2.14 (s, 6 H), 2.21 (ddd, J = 11.8, 7.0, 4.4 Hz, 1 H), 2.37–2.49 (m, 1 H), 2.92–3.16 (m, 2 H), 3.27–3.54 (m, 2 H), 4.06–4.29 (m, 1 H), 7.08–7.14 (m, 6 H), 7.17–7.22 (m, 2 H). 13C{1H} NMR (125 MHz, DEPT, CDCl3): δ = 18.7 (CH3), 29.0 (CH), 33.1 (CH2), 33.5 (CH2), 45.6 (CH3), 45.7 (CH), 66.9 (CH2), 126.0 (CH), 126.1 (CH), 126.4 (CH), 126.6 (CH), 130.2 (CH), 130.7 (CH), 139.2 (C), 139.9 (C), 141.8 (C), 142.4 (C).
