Catalytic C–H Functionalization of Trimethylamine

Abstract

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.

Key words

amines - C–H activation - hydroaminoalkylation - titanium - trimethylamine

• References

• 1a Weissermel K, Arpe H.-J. Industrial Organic Chemistry . Wiley-VCH; Weinheim: 2003: 51
• 1b Roose P. Methylamines. In Ullmann’s Encyclopedia of Industrial Chemistry. Wiley-VCH; Weinheim: 2015: 1
• 1c Roose P, Turcotte MG. J, Mitchell W. Methylamines . In Kirk-Othmer Encyclopedia of Chemical Technology . J. Wiley & Sons; New York: 2011: 1
• 2 Wieszczycka K. In Chemical Technologies and Processes . Staszak K, Wieszczycka K, Tylkowski B. Walter de Gruyter GmbH; Berlin: 2020: 163
• 3 Corbin DR, Schwarz S, Sonnichsen GC. Catal. Today 1997; 37: 71
• 4a Winthrop SO, Davis MA, Myers GS, Gavin JG, Thomas R, Barber R. J. Org. Chem. 1962; 27: 230
• 4b Guelfi JD, Dreyfus J.-F, Delcros M, Pichot P. Neuropsychobiology 1983; 9: 142

For selected reviews on C–H functionalization reactions, see:
• 5a Dalton T, Faber T, Glorius F. ACS Cent. Sci. 2021; 7: 245
• 5b Lam NY. S, Wu K, Yu J.-Q. Angew. Chem. Int. Ed. 2021; 60: 15767
• 5c Docherty JH, Lister TM, Mcarthur G, Findlay MT, Domingo-Legarda P, Kenyon J, Choudhary S, Larrosa I. Chem. Rev. 2023; 123: 7692

For examples of C–H functionalization reactions of trimethylamine, see:
• 6a Rousselet G, Capdevielle P, Maumy M. Tetrahedron Lett. 1995; 36: 4999
• 6b Sun W, Lin H, Zhou W, Li Z. RSC Adv. 2014; 4: 7491
• 6c Kaper T, Geik D, Fornfeist F, Schmidtmann M, Doye S. Chem. Eur. J. 2022; 28: e202103931

For selected reviews on hydroaminoalkylation chemistry, see:
• 7a Roesky PW. Angew. Chem. Int. Ed. 2009; 48: 4892
• 7b Chong E, Garcia P, Schafer LL. Synthesis 2014; 46: 2884
• 7c Edwards PM, Schafer LL. Chem. Commun. 2018; 54: 12543
• 7d Hannedouche J, Schulz E. Organometallics 2018; 37: 4313
• 7e Schafer LL, Manßen M, Edwards PM, Lui EK. J, Griffin SE, Dunbar CR. Adv. Organomet. Chem. 2020; 74: 405
• 7f Manßen M, Schafer LL. Chem. Soc. Rev. 2020; 49: 6947

For selected pioneering studies in the field of hydroaminoalkylation chemistry, see:
• 8a Clerici MG, Maspero F. Synthesis 1980; 305
• 8b Nugent WA, Ovenall DW, Holmes SJ. Organometallics 1983; 2: 161
• 8c Herzon SB, Hartwig JF. J. Am. Chem. Soc. 2007; 129: 6690
• 8d Kubiak R, Prochnow I, Doye S. Angew. Chem. Int. Ed. 2009; 48: 1153
• 8e Bexrud JA, Eisenberger P, Leitch DC, Payne PR, Schafer LL. J. Am. Chem. Soc. 2009; 131: 2116
• 8f Prochnow I, Zark P, Müller T, Doye S. Angew. Chem. Int. Ed. 2011; 50: 6401
• 9a Nako AE, Oyamada J, Nishiura M, Hou Z. Chem. Sci. 2016; 7: 6429
• 9b Liu F, Luo G, Hou Z, Luo Y. Organometallics 2017; 36: 1557
• 9c Luo G, Liu F, Luo Y, Zhou G, Kang X, Hou Z, Luo L. Organometallics 2019; 38: 1887
• 9d Gao H, Su J, Xu P, Xu X. Org. Chem. Front. 2018; 5: 59
• 9e Su J, Zhou Y, Xu X. Org. Biomol. Chem. 2019; 17: 2013
• 9f Geik D, Rosien M, Bielefeld J, Schmidtmann M, Doye S. Angew. Chem. Int. Ed. 2021; 60: 9936
• 10 For details, see the Supporting Information
• 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
• 13 Han J, Cui Z, Wang J, Liu Z. Synth. Commun. 1985; 10: 855
• 14a Hydroaminoalkylation 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 torch^14b 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, R_f = 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).
• 14b Bielefeld J, Doye S. Angew. Chem. Int. Ed. 2017; 56: 15155

For hydroaminoalkylation reactions of allenes and methylenecyclopropanes with secondary amines, see:
• 15a Bielefeld J, Mannhaupt S, Schmidtmann M, Doye S. Synlett 2019; 30: 967
• 15b Kaper T, Fischer M, Warsitz M, Zimmering R, Beckhaus R, Doye S. Chem. Eur. J. 2020; 26: 14300
• 15c Kaper T, Elma A, Thye H, Knupe-Wolfgang P, Zimmering R, Schmidtmann M, Doye S. Eur. J. Org. Chem. 2022; e202200991
• 16 Thoben N, Kaper T, de Graff S, Gerhards L, Schmidtmann M, Klüner T, Beckhaus R, Doye S. ChemPhysChem 2023; 24: e202300370