Additive-Free Copper-Catalyzed Benzylic C(sp³)–H Carbamation: Simple Preparation of Primary Benzylic Amines

Abstract

A simple and practical method for the synthesis of primary alkylamines by direct functionalization of hydrocarbons is described. The N-Boc-protected alkylamines are readily prepared from tert-butyl (trimethylsilyl)carbamate and N-fluorobenzenesulfonimide in the presence of a Cu(I) catalyst at low catalyst loadings. Advantageously, this process proceeds free of any additive such as auxiliary bases/acids, requires only one equivalent of the substrate, and does not require ligand synthesis. This operationally simple C–H carbamation method shows high site selectivity and good functional-group tolerance, and uses a commercially available Cu precatalyst and oxidant to furnish N-Boc protected alkylamines in yields of 16–83%. The products can be simply deprotected under mild acidic conditions to generate primary benzylic amines. This practical method was subsequently used for the synthesis of the active pharmaceutical ingredients cinacalcet and sertraline.

Key words

copper catalysis - fluorobenzenesulfonimide - amination - alkylamines - benzylic amines

Publication History

Received: 23 August 2023

Accepted after revision: 07 September 2023

Accepted Manuscript online:
07 September 2023

Article published online:
12 October 2023

• References and Notes

• 1 Hili R, Yudin AK. Nat. Chem. Biol. 2006; 2: 284
• 2 Amino Group Chemistry: From Synthesis to the Life Sciences. Ricci A. Wiley-VCH; Weinheim: 2008
• 3 Shi Y, Rong N, Zhang X, Yin Q. Synthesis 2023; 55: 1053
• 4 Park Y, Kim Y, Chang S. Chem. Rev. 2017; 117: 9247
• 5 Hazelard D, Nocquet P.-A, Compain P. Org. Chem. Front. 2017; 4: 2500
• 6 Trowbridge A, Walton SM, Gaunt MJ. Chem. Rev. 2020; 120: 2613
• 7 Liu Y, You T, Wang H.-X, Tang Z, Zhou Z.-Y, Che C.-M. Chem. Soc. Rev. 2020; 49: 5310
• 8 Darses B, Rodrigues R, Neuville L, Mazurais M, Dauban P. Chem. Commun. 2017; 53: 493
• 9 Gephart RT. III, Warren TH. Organometallics 2012; 31: 7728
• 10 Ju M, Schomaker JM. Nat. Rev. Chem. 2021; 5: 580
• 11 Chu JC. K, Rovis T. Angew. Chem. Int. Ed. 2017; 57: 62
• 12 Hayashi H, Uchida T. Eur. J. Org. Chem. 2020; 909
• 13 Zard SZ. Chem. Soc. Rev. 2008; 37: 1603
• 14 Song L, Zhang L, Luo S, Cheng J.-P. Chem. Eur. J. 2014; 20: 14231
• 15 Takeda Y, Hayakawa J, Yaano K, Minakata S. Chem. Lett. 2012; 41: 1672
• 16 Trammell R, Rajabimoghadam K, Garcia-Bosch I. Chem. Rev. 2019; 119: 2954
• 17 Ma J.-l, Zhou X.-m, Chen J.-l, Shi J.-x, Cheng H.-c, Guoa P.-h, Ji H.-b. Org. Biomol. Chem. 2022; 20: 7554
• 18 Du Bois J. Org. Process Res. Dev. 2011; 15: 758
• 19 Li Z, Capretto DA, Rahaman R, He C. Angew. Chem. Int. Ed. 2007; 46: 5184
• 20 Alonso E, Ramón DJ, Yus M. Tetrahedron 1997; 53: 14355
• 21 Lefenfeld M, Dye JL, Nandi P, Jackson J. WO 2007095276 2007
• 22 Milburn RR, Snieckus V. Angew. Chem. Int. Ed. 2004; 43: 892
• 23 Knowles HS, Parsons AF, Pettifer RM, Rickling S. Tetrahedron 2000; 56: 979
• 24 Uchiyama M, Matsumoto Y, Nakamura S, Ohwada T, Kobayashi N, Yamashita N, Matsumiya A, Sakamoto T. J. Am. Chem. Soc. 2004; 126: 8755
• 25 Nyasse B, Grehn L, Ragnarsson U. Chem. Commun. 1997; 1017
• 26 Ankner T, Hilmersson G. Org. Lett. 2009; 11: 503
• 27 Wolfe JP, Åhman J, Sadighi JP, Singer RA, Buchwald SL. Tetrahedron Lett. 1997; 38: 6367
• 28 Mao R, Balon J, Hu X. Angew. Chem. Int. Ed. 2018; 57: 9501
• 29 Kramer S. Org. Lett. 2019; 21: 65
• 30 Chen X, Lian Z, Kramer S. Angew. Chem. Int. Ed. 2023; 62: e202217638
• 31 Jayasooriya IU, Bakhoda A, Palmer R, Ng K, Khachemoune NL, Bertke JA, Warren TH. Chem. Sci. 2021; 12: 15733
• 32 Ghosh SK, Hu M, Comito RJ. Chem. Eur. J. 2021; 27: 17601
• 33 Liu S, Achou R, Boulanger C, Pawar G, Kumar N, Lusseau J, Robert F, Landais Y. Chem. Commun. 2020; 56: 13013
• 34 Murugesan K, Wei Z, Chandrashekhar V, Jiao H, Beller M, Jagadeesh RV. Chem. Sci. 2020; 11: 4332
• 35 Zhang Z, Chen P, Liu G. Chem. Soc. Rev. 2022; 51: 1640
• 36 Wang F, Chen P, Liu G. Acc. Chem. Res. 2018; 51: 2036
• 37 Golden DL, Suh S.-E, Stahl SS. Nat. Rev. Chem. 2022; 6: 405
• 38 Muñoz-Molina JM, Belderrain TR, Pérez PJ. Synthesis 2021; 53: 51
• 39 Javorskis T, Orentas E. J. Org. Chem. 2017; 82: 13423
• 40 Gibson FS, Bergmeier SC, Rapoport H. J. Org. Chem. 1994; 59: 3216
• 41 Poremb KE, Kadunce NT, Suzuki N, Cherney AH, Reisman SE. J. Am. Chem. Soc. 2017; 139: 5684
• 42 Takuya H, Kumiko Y, Keiji M. Chem. Lett. 2011; 40: 326
• 43 Copper-Catalyzed Benzylic C–H Carbamation; General Procedure On the benchtop, a disposable 4 mL glass vial equipped with a Teflon-coated stirrer bar was charged with TMSNHBoc (0.5 mmol, 95 mg, 2 equiv) and NFSI (0.75 mmol, 236.5 mg, 2.5 equiv). Solid R–H substrates (0.25 mmol, 1 equiv) were weighed and added to the vial. The vial was then sealed with a PTFE-lined pierceable cap. BOX (L1; 0.015 mmol, 4.5 mg, 6 mol%) was weighed into a second vial equipped with a Teflon stirrer bar. Both vials were then transferred to a purged glovebox under an atmosphere of dry N₂. In the glovebox, CuI·Me₂S (0.018 mmol, 4.5 mg, 5 mol%) was weighed into the vial containing the BOX ligand, and MeCN (2.0 mL) and the R–H substrate (if liquid) were added. The mixture was then stirred for 30 min under N₂ to form a dull-purple Cu catalyst solution. This was then added to the vial containing the other reaction components, and the mixture was stirred at 40 °C for 24 h.
• 44 tert-Butyl (5-Methyl-2,3-dihydro-1H-inden-1-yl)carbamate (2l) Prepared by the general procedure, with purification by flash column chromatography (silica gel, 0–20% gradient EtOAc–hexanes) to give a white solid; yield: 53 mg (76%). ¹H NMR (400 MHz, CDCl₃): δ = 7.21 (d, J = 7.6 Hz, 1 H), 7.02 (d, J = 11.0 Hz, 2 H), 5.13 (q, J = 7.8 Hz, 1 H), 4.78 (d, J = 8.8 Hz, 1 H), 2.90 (ddd, J = 16.0, 8.8, 3.9 Hz, 1 H), 2.78 (dt, J = 16.1, 8.1 Hz, 1 H), 2.62–2.44 (m, 1 H), 2.33 (s, 3 H), 1.85–1.71 (m, 1 H), 1.49 (s, 9 H). ¹³C NMR (121 MHz, CDCl₃): δ = 155.8, 143.5, 140.8, 137.7, 127.6, 125.5, 123.9, 79.4, 55.8, 34.6, 30.1, 28.7, 21.4. GC/MS (EI): m/z = 247.1. HRMS (TOF-ESI): m/z [M + 1]⁺ calcd for C₁₅H₂₃NO₂: 248.1651; found: 248.1657.