A Straightforward Entry to γ-Trifluoromethylated Allenamides and Their Synthetic Applications

Abstract

γ-Trifluoromethylated allenamides were obtained in good to excellent yields through a base-induced isomerization from the corresponding protected trifluoromethylated propargylic amines. This method, which simply required the treatment of the starting propargylic amines with sodium hydroxide in THF, was found to be fairly general and tolerates various alkyl and aryl substituents and a range of protecting groups on the nitrogen atom. The reactivity of the γ-trifluoromethylated allenamides was explored and they were found to be excellent substrates for radical- and gold(I)-catalyzed cyclizations yielding fluoro-alkylated nitrogen heterocycles.

Key words

allenamides - trifluoromethyl - copper-mediated reaction - isomerization - radical reaction - gold(I) catalysis

• References and Notes

• 1a Modern Allene Chemistry . Krause N, Hashmi SK. Wiley-VCH; 2008
• 1b Zimmer R, Dinesh CU, Nandanan E, Khan FA. Chem. Rev. 2000; 100: 3067
• 1c Hashmi AS. K. Angew. Chem. Int. Ed. 2000; 39: 3590
• 1d Aubert C, Fensterbank L, Garcia P, Malacria M, Simonneau A. Chem. Rev. 2011; 111: 1954
• 1e Yu S, Ma S. Angew. Chem. Int. Ed. 2012; 51: 3074
• 1f Lledo A, Pla-Quintana A, Roglans A. Chem. Soc. Rev. 2016; 45: 2010

For a recent (and rare) use of allene as a ligand scaffold, see:
• 1g Vanitcha A, Damelincourt C, Gontard G, Vanthuyne N, Mouries-Mansuy V, Fensterbank L. Chem. Commun. 2016; 52: 6785
• 2a Wei L.-L, Xiong H, Hsung RP. Acc. Chem. Res. 2003; 36: 773
• 2b Lu T, Lu Z, Ma ZX, Zhang Y, Hsung RP. Chem. Rev. 2013; 113: 4862
• 3 Yang X, Toste FD. Chem. Sci. 2016; 7: 2653
• 4a Wang Y, Zhang P, Liu Y, Xia F, Zhang J. Chem. Sci. 2015; 6: 5564
• 4b Faustino H, Varela I, Mascarenas JL, Lopez F. Chem. Sci. 2015; 6: 2903
• 4c Hernández-Díaz C, Rubio E, González JM. Eur. J. Org. Chem. 2016; 265
• 5 Wang Y, Zhang P, Qian D, Zhang J. Angew. Chem. Int. Ed. 2015; 54: 14849

Reviews:
• 6a Yang W, Hashmi AS. K. Chem. Soc. Rev. 2014; 43: 2941
• 6b Pflasterer D, Hashmi AS. K. Chem. Soc. Rev. 2016; 45: 1331
• 6c Fernandez-Casado J, Nelson R, Mascarenas JL, Lopez F. Chem. Commun. 2016; 52: 2909
• 7a Demmer CS, Benoit E, Evano G. Org. Lett. 2016; 18: 1438
• 7b Zhang G, Xiong T, Wang Z, Xu G, Wang X, Zhang Q. Angew. Chem. Int. Ed. 2015; 54: 12649
• 8a Han HY, Kim MS, Son JB, Jeong IH. Tetrahedron Lett. 2006; 47: 209
• 8b Yamazaki T, Yamamoto T, Ichihara R. J. Org. Chem. 2006; 71: 6251
• 9a Johnson D, Rodriguez A, Kennedy GD, Krishnan G. J. Heterocycl. Chem. 1994; 31: 871
• 9b Hanzawa Y, Kawagoe K.-i, Yamada A, Kobayashi Y. Tetrahedron Lett. 1985; 26: 219
• 9c Li P, Liu Z.-J, Liu J.-T. Tetrahedron 2010; 66: 9729
• 10a Watanabe Y, Yamazaki T. Synlett 2009; 3352
• 10b Ikawa K, Hioki Y, Mikami K. Org. Lett. 2010; 12: 5716
• 11 Liu J, Liu Z, Wu N, Liao P, Bi X. Chem. Eur. J. 2014; 20: 2154
• 12a Shimizu M, Higashi M, Takeda Y, Jiang G, Murai M, Hiyama T. Synlett 2007; 1163
• 12b Sakamoto T, Takahashi K, Yamazaki T, Kitazume T. J. Org. Chem. 1999; 64: 9467
• 13a Burton DJ, Hartgraves GA, Hsu J. Tetrahedron Lett. 1990; 31: 3699
• 13b Bouillon J.-P, Maliverney C, Merenyi R, Viehe HG. J. Chem. Soc., Perkin Trans. 1 1991; 2147
• 13c Zhao TS. N, Szabó KJ. Org. Lett. 2012; 14: 3966
• 13d Miyake Y, Ota S.-i, Shibata M, Nakajima K, Nishibayashi Y. Chem. Commun. 2013; 49: 7809
• 13e Ji Y.-L, Kong J.-J, Lin J.-H, Xiao J.-C, Gu Y.-C. Org. Biomol. Chem. 2014; 12: 2903
• 13f Ambler BR, Peddi S, Altman RA. Synthesis 2014; 46: 1938
• 13g Ambler BR, Peddi S, Altman RA. Org. Lett. 2015; 17: 2506
• 13h Ji Y.-L, Luo J.-J, Lin J.-H, Xiao J.-C, Gu Y.-C. Org. Lett. 2016; 18: 1000
• 14 Tresse C, Guissart C, Schweizer S, Bouhoute Y, Chany A.-C, Goddard M.-L, Blanchard N, Evano G. Adv. Synth. Catal. 2014; 356: 2051
• 15 Navarro-Vázquez A. Beilstein J. Org. Chem. 2015; 11: 1441
• 16 Typical Procedure for the Synthesis of Trifluoromethylated Alkyne 2 from Terminal Alkyne 1 The reaction of 1a is representative. A 50 mL round-bottom flask was charged with CuI (143 mg, 0.75 mmol, 1.5 equiv), K₂CO₃ (207 mg, 1.5 mmol, 3.0 equiv), TMEDA (112 μL, 0.75 mmol, 1.5 equiv), and DMF (2.3 mL). The resulting deep blue mixture was vigorously stirred at room temperature under air atmosphere for 20 min. TMSCF₃ (148 μL, 1.00 mmol, 2.0 equiv) was added, and the resulting deep green mixture was stirred for an additional 15 min under air atmosphere, then cooled to 0 °C. A solution of terminal alkyne 1 (0.50 mmol, 1 equiv) and TMSCF₃ (148 μL, 1.00 mmol, 2.0 equiv) in DMF (2.3 mL), previously cooled to 0 °C, was then added in one portion. The reaction mixture was stirred at 0 °C for 30 min, under air atmosphere, and allowed to warm to room temperature and stirred for 24 h. At the end of the reaction, H₂O was added and the aqueous layer was extracted with Et₂O (three times). The combined organic layers were washed with H₂O (three times), brine, dried over MgSO₄, filtered, and concentrated under vacuum. The crude product was then purified by flash column chromatography on silica gel to afford the desired trifluoromethylated alkyne 2. t-Butyl Dodecyl(4,4,4-trifluorobut-2-yn-1-yl)carbamate (2a) This product was obtained following the general procedure from tert-butyl dodecyl(prop-2-yn-1-yl)carbamate (1a, 250 mg, 0.77 mmol) to afford the desired product (226 mg, 0.58 mmol, 75%) as a yellow oil. Solvent system for flash chromatography: pentane–Et₂O (9:1). ¹H NMR (300 MHz, CDCl₃): δ = 4.28–3.95 (m, 2 H), 3.28 (t, J = 7.3 Hz, 2 H), 1.58–1.50 (m, 2 H), 1.47 (s, 9 H), 1.34–1.21 (m, 18 H), 0.88 (t, J = 6.4 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 155.0 (br s), 114.0 (q, J = 257.1 Hz), 84.5 (br s), 80.8, 70.4 (q, J = 50.9 Hz), 47.3 (br s), 36.5 and 35.7 (br s, rot.), 32.0, 29.77, 29.75, 29.70 (2 C), 29.5, 29.4, 28.4 (3 C), 28.2, 26.8, 22.8, 14.2. ¹⁹F NMR (376 MHz, CDCl₃): δ = –51.3 (br s, 3 F). IR (ATR): ν_max = 2924, 2859, 2283, 1696, 1457, 1402, 1283, 1152, 870, 750 cm^–1. HRMS (APCI): m/z calcd for C₂₁H₃₆F₃NaNO₂ [M + Na]⁺: 414.2590; found: 414.2583.
• 17 Huang J, Xiong H, Hsung RP, Rameshkumar C, Mulder JA, Grebe TP. Org. Lett. 2002; 4: 2417
• 18 Liu H, Leow D, Huang K.-W, Tan C.-H. J. Am. Chem. Soc. 2009; 131: 7212
• 19 Yamazaki T, Watanabe Y, Yoshida N, Kawasaki-Takasuka T. Tetrahedron 2012; 68: 6665
• 20 Typical Procedure for the Synthesis of γ-Trifluoromethylated Allenamide 3 from Trifluoromethylated Alkyne 2 The reaction of 2a is representative. To a stirred solution of the trifluoromethylated propargyl amide 2 (0.15 mmol) in THF (2.40 mL) was added NaOH (1.20 mL, 1.20 mmol, 1 M in H₂O, 8 equiv), and the reaction was stirred at 40 °C for 24 h. After completion of the reaction, the crude mixture was quenched with a sat. aq NH₄Cl solution, and the aqueous layer was extracted with Et₂O (three times). The combined organic layers were washed with water (twice), brine, dried with MgSO₄, filtered, and concentrated under vacuum. The crude was purified by flash column chromatography on silica gel to afford the desired γ-trifluoromethylated allenamide 3. tert-Butyl Dodecyl(4,4,4-trifluorobuta-1,2-dien-1-yl)carbamate (3a) This product was obtained from tert-butyl dodecyl(4,4,4-trifluorobut-2-yn-1-yl)carbamate (2a, 50 mg, 0.13 mmol) to afford the desired product 3a (46 mg, 0.12 mmol, 92%) as a colorless oil. Solvent system for flash chromatography: cyclohexane–EtOAc–Et₃N (100:1:1). ¹H NMR (300 MHz, CDCl₃): δ = 7.65 and 7.47 (br s, 1 H, rot.), 5.95 (app. quint, J = 5.5 Hz, 1 H), 3.28 (t, J = 6.5 Hz, 2 H), 1.55–1.45 (m, 11 H), 1.25 (s, 18 H), 0.88 (t, J = 6.9 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 199.9 and 198.4 (br s, rot.), 152.7 and 152.0 (br s, rot.), 121.7 (q, J = 271.3 Hz), 107.1 (br s), 95.4 (q, J = 39.6 Hz), 82.0 (br s), 46.2 and 45.7 (rot.), 32.1, 29.8 (2 C), 29.69, 29.66, 29.5, 29.4, 28.3 (3 C), 27.4 (br s), 26.8, 22.8, 14.2. ¹⁹F NMR (376 MHz, CDCl₃): δ = –63.1 (dd, J = 5.3, 3.3 Hz, 3 F). IR (ATR): ν_max = 2935, 2856, 1707, 1467, 1370, 1283, 1141, 870 cm^–1. HRMS (APCI): m/z calcd for C₂₁H₃₆F₃NaNO₄ [M + Na]⁺: 414.2590; found: 414.2588.
• 21 Sulfonamides were not tolerated in this process, the highly electrophilic tosyl iminium intermediate being hydrolyzed over time. This is a clear indication that a one-pot trifluoromethylation–isomerization sequence is feasible, although such a process was not systematically explored in this work.
• 22 We currently do not have a sound explanation for this lack of reactivity. Along the same lines, it was noticed that the oxidative copper-mediated trifluoromethylation reaction of terminal alkynes was inhibited with certain classes of substrates such as N-propargyl phthalimide or substrates possessing a phenyl group in the propargylic position.
• 23 Shen L, Hsung RP. Org. Lett. 2005; 7: 775
• 24a Krause N, Winter C. Chem. Rev. 2011; 111: 1994
• 24b Hashmi AS. K, Schwarz L, Choi J.-H, Frost TM. Angew. Chem. Int. Ed. 2000; 39: 2285
• 25a Manzo AM, Perboni AD, Broggini G, Rigamonti M. Tetrahedron Lett. 2009; 50: 4696
• 25b Singh S, Elsegood MR. J, Kimber MC. Synlett 2012; 23: 565
• 25c De Sousa Fonseca FC, Araujo FM, Nagem TJ, de Oliveira TT, Roque D, Correia C, Taylor JG. Synth. Commun. 2013; 43: 758
• 25d Bernal-Albert P, Faustino H, Gimeno A, Asensio G, Mascarenas JL, Lopez F. Org. Lett. 2014; 16: 6196
• 25e Slater NH, Brown NJ, Elsegood MR. J, Kimber MC. Org. Lett. 2014; 16: 4606

For related gold-catalyzed anellations, see:
• 26a Pflästerer D, Dolbundalchok P, Rafique S, Rudolph M, Rominger F, Hashmi AS. K. Adv. Synth. Catal. 2013; 355: 1383
• 26b Pflästerer D, Rettenmeier E, Schneider S, de Las Heras Ruiz E, Rudolph M, Hashmi AS. K. Chem. Eur. J. 2014; 20: 6752
• 26c Pflästerer D, Schumacher S, Rudolph M, Hashmi AS. K. Chem. Eur. J. 2015; 21: 11585
• 26d Fazeli A, Pflästerer D, Rudolph M, Hashmi AS. K. J. Organomet. Chem. 2015; 795: 68
• 27 For the generation of α,β-unsaturated N-acyliminiums from N,O-acetals using Sn(II)-catalysis, see: Kinderman SS, Wekking MM. T, van Maarseveen JH, Schoemaker HE, Hiemstra H, Rutjes FP. J. T. J. Org. Chem. 2005; 70: 5519
• 28a Berry CR, Hsung RP, Antoline JE, Petersen ME, Challeppan R, Nielson JA. J. Org. Chem. 2005; 70: 4038
• 28b Navarro-Vázquez A, Rodríguez D, Martínez-Esperón MF, García A, Saá C, Domínguez D. Tetrahedron Lett. 2007; 48: 2741
• 28c Manoni E, Gualandi A, Mengozzi L, Bandini M, Cozzi PG. RSC Adv. 2015; 5: 10546