Solvent-Free Synthesis of α-Amino Ketones from α-Hydroxyl Ketones via A Novel Tandem Reaction Sequence Based on Heyns Rearrangement

Abstract

Heyns rearrangement have been famous for carbohydrate chemists for several decades. However, this reaction was underrated as a useful method for synthetic chemists due to preparative shortcomings. Herein we developed an efficient method for the synthesis of pharmaceutically important α-amino ketones from readily available α-hydroxy ketones and secondary amines through a tandem reaction sequence based on Heyns rearrangement. The reaction smoothly proceeded by using catalytic PTSA as catalyst without solvent. Primary and secondary α-hydroxy ketones were readily used and regioselectively afforded the correspondingly α-amino ketones with moderate yield.

Key words

Heyns rearrangement - α-amino ketone - solvent-free - α-hydroxyl ketone - tandem reaction

• References and Notes

• 1a Smith AB, Beauchamp TJ, LaMarche MJ, Kaufman MD, Qiu Y, Arimoto H, Jones DR, Kobayashi K. J. Am. Chem. Soc. 2000; 122: 8654
• 1b Trost BM, Knopf JD, Brindle CS. Chem. Rev. 2016; 116: 15035
• 1c Allred TK, Manoni F, Harran PG. Chem. Rev. 2017; 117: 11994
• 2a Walsh PJ, Li H, de Parrodi CA. Chem. Rev. 2007; 107: 2503
• 2b Martins MA. P, Frizzo CP, Moreira DN, Buriol L, Machado P. Chem. Rev. 2009; 109: 4140
• 3 Wang, Z. Heyns Rearrangement, In Comprehensive Organic Name Reactions and Reagents; John Wiley & Sons, Inc., 2010.
• 4a Wrodnigg TM, Stütz AE. Angew. Chem. Int. Ed. 1999; 38: 827
• 4b Shan Y, Oulaidi F, Lahmann M. Tetrahedron Lett. 2013; 54: 3960
• 4c Guzi TJ, Macdonald TL. Tetrahedron Lett. 1996; 37: 2939
• 4d Miyairi S, Maeda K, Oe T, Kato T, Naganuma A. Steroids 1999; 64: 252
• 5 Miyairi S, Ichikawa T, Nambara T. Tetrahedron Lett. 1991; 32: 1213
• 6a Melis N, Secci F, Boddaert T, Aitken DJ, Frongia A. Chem. Commun. 2015; 51: 15272
• 6b Melis N, Ghisu L, Guillot R, Caboni P, Secci F, Aitken DJ, Frongia A. Eur. J. Org. Chem. 2015; 4358
• 6c Gallas K, Pototschnig G, Adanitsch F, Stutz AE, Wrodnigg TM. Beilstein. J. Org. Chem. 2012; 8: 1619
• 6d Frongia A, Secci F, Capitta F, Piras PP, Sanna ML. Chem. Commun. 2013; 49: 8812
• 6e Frongia A, Melis N, Serra I, Secci F, Piras PP, Caboni P. Asian J. Org. Chem. 2014; 3: 378
• 6f Aitken DJ, Caboni P, Eijsberg H, Frongia A, Guillot R, Ollivier J, Piras PP, Secci F. Adv. Synth. Catal. 2014; 356: 941
• 7 Li G, Tang L, Liu H, Wang Y, Zhao G, Tang Z. Org. Lett. 2016; 18: 4526
• 8a Blough BE, Landavazo A, Partilla JS, Baumann MH, Decker AM, Page KM, Rothman RB. ACS Med. Chem. Lett. 2014; 5: 623
• 8b Aarde SM, Huang PK, Creehan KM, Dickerson TJ, Taffe MA. Neuropharmacology 2013; 71: 130
• 8c Aarde SM, Angrish D, Barlow DJ, Wright MJ. Jr, Vandewater SA, Creehan KM, Houseknecht KL, Dickerson TJ, Taffe MA. Addict. Biol. 2013; 18: 786
• 9a Myers MC. W, Iera JA, Bang J.-K, Hara T, Saito S. i, Zambetti GP, Appella DH. J. Am. Chem. Soc. 2005; 127: 6152
• 9b Meltzer PC, Butler D, Deschamps JR, Madras BK. J. Med. Chem. 2006; 49: 1420
• 9c Carroll FI, Blough BE, Abraham P, Mills AC, Holleman JA, Wolckenhauer SA, Decker AM, Landavazo A, McElroy KT, Navarro HA, Gatch MB, Forster MJ. J. Med. Chem. 2009; 52: 6768
• 9d Bouteiller C, Becerril-Ortega J, Marchand P, Nicole O, Barré L, Buisson A, Perrio C. Org. Biomol. Chem. 2010; 8: 1111
• 10a Xie L, Wu Y, Yi W, Zhu L, Xiang J, He W. J. Org. Chem. 2013; 78: 9190
• 10b Tanemura K, Suzuki T, Nishida Y, Satsumabayashi K, Horaguchi T. Chem. Commun. 2004; 470
• 10c Perrine DM, Ross JT, Nervi SJ, Zimmerman RH, Short A. J. Chem. Ed. 2000; 77: 1479
• 10d Jiang Q, Sheng W, Guo C. Green Chem. 2013; 15: 2175
• 10e Arbuj SS, Waghmode SB, Ramaswamy AV. Tetrahedron Lett. 2007; 48: 1411
• 11 Evans RW, Zbieg JR, Zhu S, Li W, MacMillan DW. J. Am. Chem. Soc. 2013; 135: 16074
• 12 Jiang Q, Xu B, Zhao A, Jia J, Liu T, Guo C. J. Org. Chem. 2014; 79: 8750
• 13 Guha S, Rajeshkumar V, Kotha SS, Sekar G. Org. Lett. 2015; 17: 406
• 14a Kotha SS, Sekar G. Tetrahedron Lett. 2015; 56: 6323
• 14b Kotha SS, Chandrasekar S, Sahu S, Sekar G. Eur. J. Org. Chem. 2014; 7451
• 14c Sahoo SC, Nath U, Pan SC. Eur. J. Org. Chem. 2017; 4434
• 15 Preparation of 2-[Methyl(phenyl)amino]-1-phenylethan-1-one (3j) – General Procedure 2-Hydroxyacetophenone (0.1 mmol) and morpholine (0.1 mmol) were added in a reaction vessel followed by catalytic PTSA (0.005 mmol). The reaction mixture was stirred under nitrogen atmosphere overnight at 50 ℃. After full conversion of the starting material, the reaction mixture was cooled down to room temperature and purified by silica gel flash column directly (eluent: petroleum ether/ethyl acetate = 3:1); colorless oil, 14.2 mg (63%). ¹H NMR (400 MHz, CDCl₃): δ = 8.11–7.96 (m, 2 H), 7.64 (t, J = 7.4 Hz, 1 H), 7.52 (t, J = 7.6 Hz, 2 H), 7.24 (dd, J = 8.7, 7.4 Hz, 2 H), 6.83–6.59 (m, 3 H), 4.81 (s, 2 H), 3.13 (s, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 196.48 (s), 149.20 (s), 135.46 (s), 133.55 (s), 129.21 (s), 128.82 (s), 127.81 (s), 117.12 (s), 112.28 (s), 77.34 (s), 77.03 (s), 76.71 (s), 58.99 (s), 39.58 (s). HRMS (ESI): C₁₅H₁₅NO neutral mass: 225.11536; observed [M + H]⁺: 226.12296.
• 16 Preparation of 2-(Indolin-1-yl)-1-phenylpropan-1-one (4i) The reaction executed with general procedure, 24 h at 80 °C; brown oil, 11.3 mg (45%). ¹H NMR (400 MHz, CDCl₃): δ = 8.12–8.04 (m, 2 H), 7.64–7.53 (m, 1 H), 7.53–7.39 (m, 2 H), 7.19–7.07 (m, 2 H), 6.70 (dd, J = 10.7, 3.9 Hz, 1 H), 6.58 (d, J = 7.7 Hz, 1 H), 5.22–5.10 (m, 1 H), 3.47 (dd, J = 18.2, 9.5 Hz, 1 H), 3.32 (td, J = 8.9, 5.2 Hz, 1 H), 3.01–2.85 (m, 2 H), 1.40 (t, J = 7.4 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 199.23 (s), 150.03 (s), 135.78 (s), 133.24 (s), 130.16 (s), 128.54 (s), 127.38 (s), 124.71 (s), 117.80 (s), 106.31 (s), 55.04 (s), 47.65 (s), 28.26 (s), 10.15 (s). HRMS (ESI): C₁₇H₁₇NO₂ neutral mass: 251.13101; observed [M + H]⁺: 252.13811.
• 17 Preparation of 1-(4-Bromophenyl)-2-morpholinobutan-1-one (4n) The reaction executed with the general procedure; yellow oil, 17.1 mg (55%). ¹H NMR (400 MHz, CDCl₃): δ = 8.07–7.86 (m, 2 H), 7.75–7.56 (m, 2 H), 3.81 (dd, J = 9.3, 4.7 Hz, 1 H), 3.68 (dd, J = 10.8, 6.2 Hz, 4 H), 2.75–2.63 (m, 2 H), 2.62–2.48 (m, 2 H), 1.97–1.70 (m, 2 H), 0.92–0.84 (m, 4 H). ¹³C NMR (101 MHz, CDCl₃): δ = 198.59 (s), 131.82 (s), 130.21 (s), 77.33 (s), 77.02 (s), 76.70 (s), 70.99 (s), 67.31 (s), 50.28 (s), 19.06 (s), 10.97 (s), 1.02 (s). HRMS (ESI): C₁₄H₁₈BrNO₂ neutral mass: 311.05209; observed [M + H]⁺: 312.05453.
• 18 Sánchez-Viesca F. Am. J. Chem. 2015; 5: 86