Toluene and its Derivatives as Atom-Efficient Benzylating Agents for Secondary Amines

Abstract

Toluene as a replacement for common N-benzylating agents, such as benzyl bromide, can be an atom-efficient alternative reagent. Under nickel catalysis and mildly oxidative conditions, it is possible to activate toluene efficiently and use it directly for the benzylation of different 2-aminopyridines. The transformation is not restricted to simple toluene, but also substituted derivatives give the desired product in good yields. Effective cleavage of the pyridine moiety is presented.

Key words

C–H functionalization - benzylation - nickel catalysis - toluene activation - amines

• References and Notes

• 1 Greene's Protective Groups in Organic Synthesis. 4th ed. Wuts PG. M, Greene TW. John Wiley and Sons; Hoboken, NJ: 2006
• 2 Hickinbottom WJ. J. Chem. Soc. 1930; 992
• 3 Aranapakam V, Davis JM, Grosu GT, BakerEllingboe J, Zask A, Levin JI, Sandanayaka VP, Du M, Skotnicki JS, DiJoseph JF, Sung A, Sharr MA, Killar LM, Walter T, Jin G, Cowling R, Tillett J, Zhao W, McDevitt J, Xu ZB. J. Med. Chem. 2003; 46: 2376
• 4 Kerwin JF, Hall GC, Milnes FJ, Witt IH, McLean RA, Macko E, Fellows EJ, Ullyot GE. J. Am. Chem. Soc. 1951; 73: 4162
• 5 Abdel-Magid AF, Carson KG, Harris BD, Maryanoff CA, Shah RD. J. Org. Chem. 1996; 61: 3849
• 6 Sato S, Sakamoto T, Miyazawa E, Kikugawa Y. Tetrahedron 2004; 60: 7899
• 7 Lane CF. Synthesis 1975; 135
• 8 Zhang Y, Qi X, Cui X, Shi F, Deng Y. Tetrahedron Lett. 2011; 52: 1334
• 9 Kawahara R, Fujita K.-I, Yamaguchi R. J. Am. Chem. Soc. 2010; 132: 15108
• 10 Aihara Y, Tobisu M, Fukumoto Y, Chatani N. J. Am. Chem. Soc. 2014; 136: 15509
• 11 Curto JM, Kozlowski MC. J. Am. Chem. Soc. 2015; 137: 18
• 12 Zhang HJ, Su F, Wen TB. J. Org. Chem. 2015; 80: 11322
• 13 Qin G, Chen X, Yang L, Huang H. ACS Catal. 2015; 5: 2882
• 14 Soni V, Khake SM, Punji B. ACS Catal. 2017; 7: 4202
• 15 Zhou S.-L, Guo L.-N, Duan X.-H. Eur. J. Org. Chem. 2014; 8094
• 16 Sattar M, Kumar S. Org. Lett. 2017; 19: 5960
• 17 Xue Q, Xie J, Li H, Cheng Y, Zhu C. Chem. Commun. 2013; 49: 3700
• 18 Kubo T, Aihara Y, Chatani N. Chem. Lett. 2015; 44: 1365
• 19 Sha S.-C, Tcyrulnikov S, Li M, Hu B, Fu Y, Kozlowski MC, Walsh PJ. J. Am. Chem. Soc. 2018; 140: 12415
• 20 Wang Z, Zheng Z, Xu X, Mao J, Walsh PJ. Nat. Commun. 2018; 9: 3365
• 21 Pandey G, Laha R. Angew. Chem. Int. Ed. 2015; 54: 14875
• 22 Vasilopoulos A, Zultanski SL, Stahl SS. J. Am. Chem. Soc. 2017; 139: 7705
• 23 Powell DA, Fan H. J. Org. Chem. 2010; 75: 2726
• 24 Yang Y, Lan J, You J. Chem. Rev. 2017; 117: 8787
• 25 Girard SA, Knauber T, Li CJ. Angew. Chem. Int. Ed. 2014; 53: 74
• 26 Standard Procedure for N-Benzylation A flame-dried microwave vial was charged with starting material (100 mg, 1.0 equiv) and solid reactants, NaHCO₃ (2.0 equiv), PPh₃ (0.1 equiv), and Ni(OTf)₂ (0.1 equiv), and transferred into an argon-filled glove box. Then solvent (2 mL, ca. 35 equiv) and 2-iodoperfluoropropane (2.0 equiv) were added in this order to avoid evaporation of the later and the vessel was sealed. The vial was placed in a heater previously set to 140 °C and magnetically stirred at 750 rpm for 23 h. The reaction mixture was filtered over Celite and its solid remains were set in an ultrasonic bath with DCM and also fitered. The combined organic solutions were concentrated under reduced pressure giving the crude product, which was purified by column chromatography using light petrol and ethyl acetate. N,N-Dibenzyl-3-methyl-2-pyridinamine (3) N-Benzyl-3-methyl-2-pyridinamine (1, 53.4 mg, 269.3 μmol) was used as starting material with toluene as solvent and treated according to the general procedure for N-benzylation. After workup 110 mg crude material were purified by column chromatography. After purification the desired product 3 (50.1 mg, 173.2 μmol, 65%) was obtained as yellow oil. R_f = 0.40 (LP/EtOAc, 10:1) GC/MS: STD 10 min; r.t, 7.82 min; 288.2 (M, 0.5), 197.1 (100), 91.0 (50), 79.0 (26), 65.0 (50). ¹H NMR (400 MHz, CDCl₃): δ = 8.13 (ddd, J = 4.88, 1.96, 0.71 Hz, 1 H), 7.40 (ddd, J = 7.35, 1.87, 0.89 Hz, 1 H), 7.26 (m, 10 H), 7.20 (m, 2 H), 6.82 (dd, J = 7.34, 4.81 Hz, 1 H), 4.32 (s, 4 H), 2.38 (s, 3 H) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 161.5, 145.4, 139.6, 139.1, 128.4, 128.3, 126.9, 125.8, 118.2, 54.6, 18.9 ppm. HRMS for C₂₀H₂₀N₂: m/z [M + H]⁺ calcd: 289.1705; found: 289.1626.
• 27 Dastbaravardeh N, Kirchner K, Schnürch M, Mihovilovic MD. J. Org. Chem. 2013; 78: 658
• 28 Xu ZY, Jiang YY, Yu HZ, Fu Y. Chem. Asian J. 2015; 10: 2479
• 29 Probst A, Vonwerner K. J. Fluorine Chem. 1990; 47: 163
• 30 Xu T, Cheung CW, Hu X. Angew. Chem. Int. Ed. 2014; 53: 4910
• 31 Dastbaravardeh N, Schnürch M, Mihovilovic MD. Org. Lett. 2012; 14: 1930