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Entry to Highly Hindered Chiral β-Amino Triazoles Bearing a gem-Diaryl Group by Azide-alkyne Click Chemistry

  • Sadu, Venkata Subbaiah (Green Chemistry Division, Korea Research Institute of Chemical Technology) ;
  • Roy, Harendra Nath (Green Chemistry Division, Korea Research Institute of Chemical Technology) ;
  • Arigala, Pitchaiah (Green Chemistry Division, Korea Research Institute of Chemical Technology) ;
  • Hwang, In-Taek (Green Chemistry Division, Korea Research Institute of Chemical Technology) ;
  • Lee, Kee-In (Green Chemistry Division, Korea Research Institute of Chemical Technology)
  • Received : 2014.01.07
  • Accepted : 2014.02.01
  • Published : 2014.06.20
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Abstract

Copper(I)-catalyzed Huisgen cycloaddition of terminal alkynes with unmasked azidoamines derived from amino acids is described. The reported strategy provides a new entry to highly hindered ${\beta}$-amino 1,2,3-triazole derivatives bearing a gem-diaryl group, which are potentially valuable entities as molecular catalysts for asymmetric transformations.

Keywords

Introduction

‘Click chemistry’ is a powerful technique to generate sub-stances quickly and reliably by joining small units together as earlier described by K. Barry Sharpless in 2001.1 Certain-ly, the key requirements could be highly efficient and wide in scope, stereospecific, and the process is to be environ-mentally benign and economically attractive. After the indepen-dent discovery by Meldal and Sharpless that copper(I) catalyzes Huisgen azide-alkyne cycloaddition,2 this became one of the most popular prototype click reactions to date, leading to a plethora of triazole chemistry with an exploding diversity. The exceptional stability and the ready accessi-bility of 1,2,3-triazoles have enabled multilateral mani-pulation of this unique class of heterocycles in medicinal chemistry, chemical biology, and material science.3 Interest-ingly, chiral triazoles have been recently exploited as useful surrogates such as triazole-modified amino acids4 and gly-cosyl triazoles,5 and triazole-incorporated heterocycles.6

On the other hand, asymmetric organocatalytic reaction mediated by small organic molecules is definitely one of the most powerful and versatile tool for the rapid construction of valuable chiral molecules. Since the seminal work of List and MacMillan, a variety of chiral α-amino acid derivatives have been successfully developed as efficient and versatile catalysts for various kinds of asymmetric transformations (Fig. 1(a)).7 They are proven to be excellent organocatalyst pools for a variety of asymmetric transformations resulting in exceptionally high enantioselectivities.8 Indeed, the struc-tural motif of amino acids facilitates a highly pre-organized transition state during the reaction pathway. Chiral amino acids available in both enantiomeric forms have played the key roles in the development of organocatalysis because of their cost-effectiveness and ready availability. The strategies used for the modification of amino acids mainly focused on varying the electronic and/or steric properties of the amino and carboxylic groups. Recently disclosed proline-based molecules such as pyrrolidine-tetrazole,9 -pyridine,10 -imida-zole, 11 and -triazole conjugates,12 are also proven to be useful as asymmetric catalysts for Michael additions and aldol reactions (Fig. 1(b)).

Figure 1.Representative examples of (a) amino acid-based organocatalysts and (b) proline-conjugates.

In the light of the above, we designed a new class of β-amino triazole conjugates by the incorporation of a gem-diaryl moiety adjacent to a stereogenic center. Remarkably, quaternary carbon centers containing a geminal diaryl group have attracted particular interest when they are incorporated into a chiral 1,2-aminoalcohol functionality, and they serve as important structural motifs in the asymmetric transfor-mations. 13 For example, diarylprolinol derivatives are of great importance as the privileged structures in asymmetric catalysis, such as Corey’s oxazaborolidines13a and Jørgensen/Hayashi catalyst.13e We thus envisaged that highly hindered β-amino triazoles would provide a viable strategy for asym-metric transformations because they are more efficient for space shielding against an incoming substrate. In addition, two aryl groups are diastereotopic and might exert a great contribution to an enhanced facial selectivity due to their stereoelectronic effects. Until now there have been no signi-ficant reports on the synthesis of highly hindered β-amino triazoles derived from natural amino acids. Herein we would like to report a new entry to β-amino triazole derivatives bearing a gem-diaryl group using copper-catalyzed cyclo-addition of terminal alkynes and 2,2-diaryl-2-azidoamines, as illustrated in Scheme 1.

Scheme 1.Entry to sterically hindered β-amino triazoles derived from 1,1-diaryl-2-aminoethanols.

 

Experimental Section

General Procedure for the Synthesis of β-Amino Tri-azoles. To a stirred solution of azide (1 mmol), CuSO4·5H2O (10 mol %) and sodium ascorbate (20 mol %) in a 1/1 mixture of water and acetonitrile (5 mL), acetylene (1.2 equiv.) was added under argon atmosphere. The reaction went to completion after stirring at room temperature for 4 h. The reaction mixture was extracted with EtOAc (2 × 10 mL). The combined extracts were washed with water (5 mL) and brine (5 mL), dried over anhydrous Na2SO4, and then evaporated under reduced pressure. The crude was purified by column chromatography on a silica gel (3% MeOH/ CH2Cl2) to give a β-amino triazole.

(S)-1,1-Diphenyl-1-(4-phenyl-1H-1,2,3-triazol-1-yl)pro-pan- 2-amine (2a). Yield: 294.2 mg (83%); Pale yellow oil; = 75.2 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.77-7.74 (m, 2H), 7.49 (s, 1H), 7.40-7.18 (m, 13H), 4.94 (q, 1H, J = 6.5 Hz), 1.76 (brs, 1H), 1.13 (d, 3H, J = 6.6 Hz); 13C NMR (75 MHz, CDCl3) δ = 146.6, 141.0, 138.8, 130.4, 129.0, 128.7, 128.6, 128.3, 128.2, 128.2, 128.1, 125.6, 121.9, 78.8, 52.5, 19.7; HRMS (ESI): m/z [M+H]+ calcd for C23H23N4: 355.1923; found 355.1925.

(S)-Ethyl-1-(2-amino-1,1-diphenylpropyl)-1H-1,2,3-tri-azole-4-carboxylate (2b). Yield: 262.8 mg (75%); Pale yellow oil; = 19.3 (c 1.2, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.88 (s, 1H), 7.40-7.28 (m, 8H), 7.17-7.14 (m, 2H), 4.92-4.90 (m, 1H), 4.38 (q, 2H, J = 7.1 Hz), 1.73 (brs, 2H), 1.37 (t, 3H, J = 7.1 Hz), 1.12 (d, 3H, J = 6.5 Hz); 13C NMR (75 MHz, CDCl3) δ 160.8, 140.6, 139.1, 138.5, 129.8, 128.9, 128.7, 128.5, 128.4, 128.3, 128.1, 79.3, 61.2, 52.1, 19.7, 14.2; HRMS (ESI): m/z [M+H]+ calcd for C20H23N4O2: 351.1794; found 351.1816.

(S)-2-(1-(2-Amino-1,1-diphenylpropyl)-1H-1,2,3-triazol-4-yl)ethanol (2c). Yield: 280.5 mg (87%); Pale brown oil; = 9.3 (c 1.5, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.38-7.29 (m, 8H), 7.14-7.11 (m, 3H), 4.87-4.85 (m, 1H), 3.86 (t, 2H, J = 6.2 Hz), 2.86 (t, 2H, J = 6.1 Hz), 2.31 (brs, 3H), 1.07 (d, 3H, J = 6.5 Hz); 13C NMR (75 MHz, CDCl3) δ 144.4, 141.1, 138.8, 128.9, 128.5, 128.2, 128.19, 128.16, 128.08, 127.8, 123.8, 77.8, 61.3, 52.3, 28.7, 19.6; HRMS (ESI): m/z [M+H]+ calcd for C19H23N4O: 323.1872; found 323.1872.

(S)-1,1-Diphenyl-1-(4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)propan-2-amine (2d). Yield: 275.0 mg (83%); Pale brown oil; = 79.4 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 8.50-8.49 (m, 1H), 8.21 (d, 1H, J = 7.9 Hz), 7.94 (s, 1H), 7.79-7.73 (m, 1H), 7.41-7.29 (m, 8H), 7.23-7.16 (m, 3H), 4.96-4.94 (m, 1H), 1.67 (brs, 2H), 1.14 (d, 3H, J = 6.0 Hz); 13C NMR (75 MHz, CDCl3) δ 150.2, 149.3, 147.1, 140.9, 138.7, 136.9, 129.0, 128.5, 128.3, 128.2, 128.1, 124.3, 122.8, 120.2, 78.9, 52.3, 19.7; HRMS (ESI): m/z [M+H]+ calcd for C22H22N5: 356.1875; found 356.1869.

(S)-3-Methyl-1,1-diphenyl-1-(4-phenyl-1H-1,2,3-triazol-1-yl)butan-2-amine (2e). Yield: 313.4 mg (82%); Trans-parent oil; = 77.8 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.77 (d, 2H, J = 7.3 Hz), 7.62 (s, 1H), 7.39-7.31 (m, 13H), 4.76 (s, 1H), 2.15-2.11 (m, 1H), 1.4 (brs, 2H), 1.24 (d, 3H, J = 6.8 Hz), -0.04 (d, 3H, J = 6.6 Hz); 13C NMR (75 MHz, CDCl3) δ = 146.7, 140.6, 140.0, 130.5, 129.0, 128.7, 128.5, 128.4, 128.3, 128.2, 128.1, 127.9, 125.6, 121.5, 78.8, 59.3, 28.4, 23.7, 15.2; LC/MS (ESI): m/z = 405 [M+Na]+.

(S)-Ethyl-1-(2-amino-3-methyl-1,1-diphenylbutyl)-1H- 1,2,3-triazole-4-carboxylate (2f). Yield: 336.6 mg (89%); Pale brown oil; = −24.6 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 8.09 (s, 1H), 7.44-7.34 (m, 10H), 4.82 (s, 1H), 4.45 (q, 2H, J = 7.1 Hz), 2.16-2.11 (m, 1H), 1.55 (brs, 2H),1.50 (t, 3H, J = 7.1 Hz), 1.30 (d, 3H, J = 6.7 Hz), −0.02 (d, 3H, J = 6.7 Hz); 13C NMR (75 MHz, CDCl3) δ 166.9, 140.2, 139.4, 129.5, 129.0, 128.6, 128.5, 128.5, 128.1, 128.0, 79.4, 61.3, 59.0, 28.4, 23.6, 15.1, 14.3; LC/MS (ESI): m/z = 401 [M+Na]+.

(S)-2-(1-(2-Amino-3-methyl-1,1-diphenylbutyl)-1H-1,2,3- triazol-4-yl)ethanol (2g). Yield: 259.3 mg (74%); Transparent liquid; = 23.4 (c 1.1, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.42-7.34 (m, 11H), 4.67 (s, 1H), 3.97 (t, 2H, J = 5.7 Hz), 2.95 (t, 2H, J = 5.7 Hz), 2.18-2.11 (m, 1H), 1.30 (d, 3H, J = 6.7 Hz), −0.02 (d, 3H, J = 6.7 Hz); 13C NMR (75 MHz, CDCl3) δ 144.6, 140.8, 139.9, 129.0, 128.4, 128.2, 128.0, 127.8, 123.5, 78.6, 61.5, 59.3, 28.7, 28.3, 23.7, 15.0; HRMS (ESI): m/z [M+H]+ calcd for C21H27N4O: 351.2185: found 351.2180.

(S)-3-Methyl-1,1-diphenyl-1-(4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)butan-2-amine (2h). Yield: 333.6 mg (87%); Pale yellow oil; = 153.2 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 8.59-8.57 (m,1H), 8.27 (d, 1H, J = 7.9 Hz), 8.16 (s, 1H), 7.85-7.80 (m, 1H), 7.45-7.37 (m, 10H), 7.28-7.24 (m, 1H), 4.84 (s, 1H), 2.22-2.16 (m, 1H), 1.53 (brs, 2H), 1.33 (d, 3H, J = 6.8 Hz), −0.01(d, 3H, J = 6.5 Hz); 13C NMR (75 MHz, CDCl3) δ 150.3, 149.3, 147.3, 140.7, 139.8, 136.9, 129.0, 128.5, 128.4, 128.2, 128.1, 127.8, 123.9, 122.8, 120.2, 78.9, 59.2, 28.4, 23.7, 15.1; HRMS (ESI): m/z [M+H]+ calcd for C24H26N5: 384.2188; found 384.2178.

(S)-1,2,2-Triphenyl-2-(4-phenyl-1H-1,2,3-triazol-1-yl)-ethanamine (2i). Yield: 291.6 mg (70%); Transparent oil; = 0.6 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.78-7.70 (m, 2H), 7.58 (s, 1H), 7.40-7.08 (m, 14H), 7.18-7.00 (m, 3H), 6.92-6.90 (m, 2H), 5.79 (s, 1H), 2.17 (brs, 2H); 13C NMR (75 MHz, CDCl3) δ 146.6, 140.1, 138.9, 130.5, 130.2, 128.9, 128.9, 128.6, 128.3, 128.1, 127.8, 127.7, 125.7, 122.8, 79.4, 62.9; HRMS (ESI): m/z [M+H]+ calcd for C28H25N4: 417.2079; found 417.2076.

(S)-Ethyl-1-(2-amino-1,1,2-triphenylethyl)-1H-1,2,3-triazole-4-carboxylate (2j). Yield: 292.9 mg (71%); Pale yellow oil; = 7.8 (c 1.5, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.96 (s, 1H), 7.37-7.20 (m, 9H), 7.15 (m, 2H), 6.90-6.85 (m, 4H), 5.83 (brs, 1H), 4.38 (q, 2H, J = 7.1 Hz), 1.92 (brs, 2H), 1.38 (t, 3H, J = 7.1 Hz); 13C NMR (125 MHz, CDCl3) δ 160.8, 139.5, 139.0, 138.5, 130.5, 129.9, 129.8, 129.7, 128.7, 128.6, 128.4, 128.2, 128.1, 128.0, 127.9, 127.8, 127.6, 79.7, 62.25, 61.3, 14.2; LCMS (ESI): m/z = 413 [M+H]+, 412, 411, 409.

(S)-2-(1-(2-Amino-1,1,2-triphenylethyl)-1H-1,2,3-triazol-4-yl)ethanol (2k). Yield: 280.7 mg (73%); Transparent oil; = −9.6 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.36-7.21 (m, 7H), 7.19-7.13 (m, 4H), 6.99-6.93 (m, 2H), 6.86-6.84 (m, 2H), 5.73 (s, 1H), 3.89 (t, 2H, J = 6.0 Hz), 2.88 (t, 2H, J = 6.0 Hz), 2.4 (brs, 2H); 13C NMR (75 MHz, CDCl3) δ 144.4, 140.1, 139.0, 138.8, 130.1, 130.0, 128.7, 128.4, 128.1, 127.9, 127.6, 127.6, 124.6, 78.9, 62.7, 61.6, 28.6; HRMS (ESI): m/z [M+H]+ calcd for C24H25N4O: 385.2028; found 385.2018.

(S)-1,2,2-Triphenyl-2-(4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)ethanamine (2l). Yield: 354.9 mg (85%); Pale yellow oil; = −7.8 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 8.49-8.49 (m, 1H), 8.23-8.20 (m, 1H), 8.01 (s, 1H), 7.79-7.74 (m, 1H), 7.33-7.00 (m, 14H), 6.92-6.89 (m, 2H), 5.82 (brs, 1H), 2.12 (brs, 2H); 13C NMR (75 MHz, CDCl3) δ 150.3, 149.3, 147.0, 140.0, 139.7, 138.8, 136.9, 130.0, 128.9, 128.4, 128.2, 127.8, 127.7, 127.6, 127.6, 125.1, 122.8, 120.3, 79.4, 62.6; HRMS (ESI): m/z [M+H]+ calcd for C27H24N5: 418.2032; found 418.2035.

(S)-1,1,3-Triphenyl-1-(4-phenyl-1H-1,2,3-triazol-1-yl)-propan-2-amine (2m). Yield: 361.7 mg (84%); Transparent oil; = 53.2 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.80-7.75 (m, 2H), 7.50 (s, 1H), 7.42-7.19 (m, 18H), 5.02 (d, 1H, J = 10.2 Hz), 3.36 (d, 1H, J = 13.2 Hz), 2.32 (brs, 2H), 2.16-2.07 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 146.7, 139.8, 130.5, 129.3, 128.8, 128.7, 128.6, 128.5, 128.4, 128.3, 128.2, 126.5, 125.7, 122.0, 78.1, 59.1, 40.4; HRMS (ESI): m/z [M+H]+ calcd for C29H27N4: 431.2236; found 431.2232.

(S)-Ethyl 1-(2-amino-1,1,3-triphenylpropyl)-1H-1,2,3-triazole-4-carboxylate (2n). Yield: 379.6 mg (89%); Trans-parent oil; = 44.0 (c 1.1, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.93 (s, 1H), 7.43-7.33 (m, 8H), 7.28-7.27 (m, 6H), 7.22-7.18 (m, 1H), 4.94 (d, 1H, J = 10.1 Hz), 4.38 (q, 2H, J = 7.1 Hz), 3.29 (d, 1H, J = 13.5 Hz), 1.94 (t, 1H, J = 11.5 Hz), 1.40 (t, 3H, J = 7.1 Hz); 13C NMR (75 MHz, CDCl3) δ 160.9, 139.5, 139.3, 130.0, 129.2, 128.6, 128.6, 128.5, 128.4, 126.6, 78.6, 61.3, 58.8, 40.3, 14.3; HRMS (ESI): m/z [M+H]+ calcd for C26H27N4O2: 427.2134; found 427.2133.

(S)-2-(1-(2-Amino-1,1,3-triphenylpropyl)-1H-1,2,3-tri-azol-4-yl)ethanol (2o). Yield: 322.8 mg (81%); Transparent liquid; = 19.3 (c 1.1, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.37-7.25 (m, 15 H), 7.15 (s, 1H), 4.92 (d, 1H, J = 10.2 Hz), 3.90 (t, 2H, J = 6.0 Hz), 3.29 (d, 1H, J = 13.5 Hz), 2.88 (t, 2H, J = 6.0 Hz), 1.96-1.88 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 144.5, 139.7, 129.2, 129.0, 128.7, 128.5, 128.4, 128.3, 128.2, 126.5, 123.9, 77.8, 61.5, 59.0, 40.2, 28.6; HRMS (ESI): m/z [M+H]+ calcd for C25H27N4O: 399.2185; found 399.2176.

(S)-1,1,3-Triphenyl-1-(4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)propan-2-amine (2p). Yield: 349.5 mg (81%); Oily liquid; = 45.8 (c 1.1, CHCl3); 1H NMR (300 MHz, CDCl3) δ 8.51-8.49 (m, 1H), 8.22-8.19 (m, 1H), 7.98 (s, 1H), 7.95-7.73 (m, 1H), 7.44-7.28 (m, 14H), 7.22-7.17 (m, 2H), 5.03 (d, 1H, J = 10.1 Hz), 3.34 (d, 1H, J = 13.5 Hz), 2.07-1.99 (m, 3H); 13C NMR (75 MHz, CDCl3) δ 150.3, 149.4, 147.2, 139.8, 136.9, 129.3, 128.8, 128.5, 128.5, 128.4, 128.3, 128.3, 126.5, 124.5, 122.8, 120.3, 78.3, 58.9, 40.3; HRMS (ESI): m/z [M+H]+ calcd for C28H26N5: 432.2188; found 432.2189.

(S)-1-(Diphenyl(pyrrolidin-2-yl)methyl)-4-phenyl-1H-1,2,3-triazole (2q). Yield: 304.4 mg (80%); Pale yellow oil; = 39.1 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.79-7.76 (m, 2H), 7.55 (s, 1H), 7.30-7.29 (m, 11H), 7.21- 7.18 (m, 2H), 5.00 (q, 1H, J = 6.8 Hz), 2.98-2.88 (m, 2H), 2.30-2.21 (m, 1H), 1.75-1.57 (m, 2H), 1.35-1.32 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 146.1, 130.6, 129.3, 128.9, 128.7, 128.5, 128.2, 128.1, 127.9, 127.8, 125.7, 125.5, 125.3, 122.1, 64.83, 46.4, 31.54, 29.1, 25.7, 22.6, 14.1; HRMS (ESI): m/z [M+H]+ calcd for C25H25N4: 381.2079; found 381.2076.

(S)-2-(1-(Diphenyl(pyrrolidin-2-yl)methyl)-1H-1,2,3-tri-azol-4-yl)ethanol (2r). Yield: 313.6 mg (90%); Transparent oil; = 7.6 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.32-7.30 (m, 9H), 7.14-7.10 (m, 2H), 4.95-4.90 (q, 1H, J = 6.5 Hz), 3.91 (t, 2H, J = 5.8 Hz), 2.88 (t, 2H, J = 5.8 Hz), 2.84-2.80 (m, 2H) 2.41 (brs, 2H), 2.2-2.14 (m, 1H), 1.72-1.57 (m, 2H), 1.29-1.18 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 144.0, 141.6, 141.0, 129.4, 128.2, 128.1, 128.0, 127.8, 123.9, 64.9, 61.6, 46.4, 29.1, 28.6, 25.7; HRMS (ESI): m/z [M+H]+ calcd for C21H25N4O: 349.2028; found 349.2026.

(S)-2-(1-(Diphenyl(pyrrolidin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyridine (2s). Yield: 354.8 mg (93%); Trans-parent liquid; = 55.6 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 8.51-8.49 (m, 1H), 8.22-8.19 (m, 1H), 7.96 (s, 1H), 7.78-7.73 (m, 1H), 7.40-7.29 (m, 9H), 7.23-7.16 (m, 2H), 5.01 (t, J = 6.5 Hz, 1H), 2.86-2.81 (m, 2H), 2.25-2.15 (m, 2H), 2.12 (bs, 1H), 1.75-1.59 (m, 2H), 1.28-1.20 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 150.5, 149.3, 146.8, 141.4, 140.9, 136.9, 129.5, 128.3, 128.2, 128.1, 128.0, 127.9, 124.5, 122.7, 120.3, 77.2, 64.8, 46.5, 29.2, 25.7; HRMS (ESI): m/z [M+H]+ calcd for C24H24N5: 382.2032; found 382.2032.

(S)-1-(Diphenyl(pyrrolidin-2-yl)methyl)-4-(6-methoxy-naphthalen- 2-yl)-1H-1,2,3-triazole (2t). Yield: 373.1 mg (81%); Pale brown oil; = 121.4 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 8.19 (s, 1H), 7.86-7.83 (d, 1H, J = 8.5 Hz), 7.75-7.72 (d, 2H, J = 9.8 Hz), 7.62 (s, 1H), 7.42-7.33 (m, 8H), 7.24-7.20 (m, 2H), 7.15-7.12 (m, 2H), 5.04 (t, 1H, J = 7.1 Hz), 3.92 (s, 3H), 2.99-2.87 (m, 2H), 2.32-2.19 (m, 1H), 1.79-1.67 (m, 2H), 1.40-1.31 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 157.9, 146.4, 134.3, 129.6, 129.5, 128.9, 128.3, 128.2, 128.1, 127.9, 127.3, 125.9, 124.4, 124.3, 124.2, 122.0, 119.2, 105.8, 65.0, 55.3, 46.5, 29.1, 25.7, 22.7; HRMS (ESI): m/z [M+H]+ calcd for C30H29N4O: 461.2341; found 461.2339.

(S)-4-(2,5-Dimethylphenyl)-1-(diphenyl(pyrrolidin-2-yl)methyl)-1H-1,2,3-triazole (2u). Yield: 310.5 mg (76%); Pale brown oil; = 54.3 (c 1.4, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.57 (s, 1H), 7.44 (s, 1H), 7.40-7.31 (m, 8H), 7.23-7.18 (m, 2H), 7.12 (d, 1H, J = 7.7 Hz), 7.05 (d, 1H, J = 7.7), 5.06 (q, 1H, J = 6.4 Hz), 2.95-2.83 (m, 2H), 2.33 (s, 3H), 2.31 (s, 3H), 2.28-2.21 (m, 1H), 1.77-1.64 (m, 2H), 1.34-1.28 (m, 1H), 1.26 (brs, 1H); 13C NMR (75 MHz, CDCl3) δ 145.7, 135.5, 132.3, 130.8, 129.5, 129.3, 129.2, 128.8, 128.4, 128.3, 128.2, 128.1, 128.0, 124.5, 65.0, 46.5, 28.9, 25.6, 20.8; HRMS (ESI): m/z [M+H]+ calcd for C27H29N4: 409.2392; found 409.2392.

(S)-4-(tert-Butyl)-1-(diphenyl(pyrrolidin-2-yl)methyl)-1H-1,2,3-triazole (2v). Yield: 273.9 mg (76%); Pale brown oil; = 7.8 (c 1.5, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.37-7.28 (m, 8H), 7.13-7.09 (m, 2H), 7.0 (s, 1H), 5.04-4.98 (t, 1H, J = 7.7 Hz), 3.06-2.90 (m, 2H), 2.28-2.19 (m, 1H), 1.83-1.62 (m, 2H), 1.49-1.37 (m, 1H), 1.31 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 156.4, 129.0, 128.5, 128.2, 127.8, 121.6, 75.8, 65.8, 46.48, 30.8, 30.3, 28.7, 25.5; HRMS (ESI): m/z [M+H]+ calcd for C23H29N4: 361.2392; found 361.2388.

Preparation of (S)-1-[Diphenyl(pyrrolidin-2-yl)methyl]-1H-1,2,3-triazole (3). To a stirred solution of 1e (250 mg, 0.9 mmol), potassium carbonate (149 mg, 1.08 mmol), CuSO4·5H2O (44.8 mg, 0.18 mmol), and sodium ascorbate (71.2 mg, 0.36 mmol) in a 1/1 mixture of water and meth-anol (5 mL), trimethylsilylacetylene (132.32 mg, 1.35 mmol) was added under argon atmosphere. The reaction went to completion after stirring at room temperature for 24 h. The reaction mixture was extracted with EtOAc (2 × 10 mL). The combined extracts were washed with water (5 mL) and brine (5 mL), dried over anhydrous Na2SO4, and then evapo-rated under reduced pressure. The residue was dissolved in anhydrous THF (5 mL), TBAF (1 M in THF, 0.45 mL, 0.45 mmol) was added drop wise under argon atmosphere and stirred for 6 h at room temperature. The reaction mixture was evaporated under reduced pressure. The crude was purified by column chromatography (3% MeOH/CH2Cl2) to afford 3 (237 mg, 78%) as a pale brown oil. = 4.8 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.65 (s, 1H), 7.33-7.29 (m, 9H), 7.14-7.12 (m, 2H), 4.95 (t, 1H, J = 7.7 Hz), 2.84-2.80 (m, 2H), 2.23-2.13 (m, 1H), 1.94 (brs, 2H) 1.72-1.59 (m, 2H), 1.29-1.20 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 141.6, 141.0, 132.4, 129.4, 128.3, 128.2, 128.1, 128.0, 127.8, 126.0, 64.9, 46.4, 29.0, 25.6; LC/MS (ESI): m/z = 305 [M+H]+, 304, 236.

CuAAC of 1e with Ethyl Propiolate (Table 2, entry 1). To a stirred solution of 1e (250.0 mg, 0.9 mmol), CuSO4 ⋅5H2O (22.43 mg, 0.09 mmol) and sodium ascorbate (35.58 mg, 0.18 mmol) in a 1/1 mixture of water and acetonitrile (5 mL), ethyl propiolate (105.78 mg, 1.08 mmol) was added under argon atmosphere. The reaction went to completion after stirring at room temperature for 4 h. The reaction mix-ture was extracted with EtOAc (2 × 10 mL). The combined extracts were washed with water (5 mL) and brine (5 mL), dried over anhydrous Na2SO4, and then evaporated under reduced pressure. The crude product was purified by column chromatography (15-30% EtOAc/hexanes) to afford 4a, 4b, and 4c.

(E)-(S)-Ethyl 3-(2-(azidodiphenylmethyl)pyrrolidin-1-yl)acrylate (4a). Transparent oil; = −178.4 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.64 (d, 1H, J = 13.0 Hz), 7.45-7.29 (m, 10H), 4.64-4.61 (m, 1H), 4.5 (d, 1H, J = 13.0 Hz), 4.11 (q, 2H, J = 7.1 Hz), 2.96-2.87 (m, 1H), 2.69-2.62 (m, 1H), 2.24-2.13 (m, 1H), 2.04-1.96 (m, 1H) 1.62- 1.54 (m, 1H), 1.24 (t, 3H, J = 7.1 Hz), 0.84-0.74 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 169.2, 150.2, 139.3, 138.6, 128.9, 128.5, 128.3, 128.2, 128.1, 87.0, 75.9, 68.2, 58.9, 48.6, 28.1, 22.3, 14.5; LC/MS (ESI): m/z = 377 [M+H]+, 334, 236, 158.

(S)-Ethyl-1-(diphenyl(pyrrolidin-2-yl)methyl)-1H-1,2,3-triazole-4-carboxylate (4b). Transparent oil; = 20.7 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.91 (s, 1H), 7.34-7.31 (m, 8H), 7.14-7.13 (m, 2H), 5.0 (t, 1H, J = 7.1 Hz), 4.41 (q, 2H, J = 7.1 Hz), 2.86-2.79 (m, 2H), 2.22-2.12 (m, 1H), 2.0 (brs, 2H), 1.65-1.63 (m, 2H), 1.36 (t, 3H, J = 7.1 Hz), 1.21-1.17(m, 1H); 13C NMR (125 MHz, CDCl3) δ 161.0, 141.1, 140.1, 138.6, 130.0, 129.4, 128.8, 128.7, 128.4, 128.2, 128.1, 128.0, 127.9, 77.7, 64.4, 61.2, 46.45, 29.0, 25.7, 14.3; LC/MS (ESI): m/z = 377 [M+H]+, 237, 236, 275.

(E)-(S)-Ethyl-1-((1-(3-ethoxy-3-oxoprop-1-en-1-yl)pyrro-lidine- 2-yl)diphenylmethyl)-1H-1,2,3-triazole (4c). Off white solid, mp 134-137 °C; = 122.8 (c 1.0, CHCl3); 1H NMR (300 MHz, CDCl3) δ 8.02 (s, 1H), 7.46-7.31 (m, 9H), 7.19-7.16 (m, 2H), 5.82 (d, 1H, J = 8.5 Hz), 4.45 (d, 1H, J = 13.0 Hz), 4.37 (q, 2H, J = 7.1 Hz), 4.08-3.93 (m, 2H) 2.95-2.86 (m, 1H), 2.79-2.72 (m, 1H), 2.55-2.41 (m, 1H), 2.16-2.09 (m, 1H) 1.53-1.42 (m, 1H), 1.37 (t, 3H, J = 7.1 Hz), 1.21-1.16 (t, 3H, J = 7.1 Hz), 0.15-0.04 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 168.5, 160.6, 149.1, 139.6, 138.0, 137.8, 129.4, 129.3, 129.2, 128.7, 128.5, 128.4, 128.3, 89.2, 77.4, 67.3, 61.3, 58.8, 49.6, 29.8, 21.6, 14.4, 14.1; LC/MS (ESI): m/z = 475 [M+H]+, 334, 246.

 

Results and Discussion

In order to address the problems associated with the instal-lation of gem-diaryl moiety, we are particularly interested in the utilization of 1,1-diaryl-2-aminoethanols. We previously developed for an efficient and practical method for a direct azidation of tertiary alcohols including 1,1-diaryl-2-amino-ethanols using sodium azide-sulfuric acid in toluene.14 This prompted us to examine a facile entry to sterically hindered β-amino triazoles via Cu-catalyzed alkyne-azide cycloaddi-tion (CuAAC).

While Cu(I) catalysis provides a reliable means for the assembly of 1,4-disubstituted 1,2,3-triazoles, often is requir-ing anhydrous conditions, and at least an amine base or high temperature to form the Cu-acetylide complexes.15 On the contrary, in situ generation of Cu(I) species by the reduction of Cu(II) salts such as CuSO4 with ascorbate allows the formation of 1,4-triazoles at room temperature and even under aqueous conditions. We first examined the reaction of 1a with phenylacetylene in CH3CN/H2O (1:1) at room temperature. In fact, the 1,3-dipolar cycloaddition was com-pleted within 4 h to give the desired 4-isomer 2a in 83% isolated yield (Table 1, entry 1), in which CuSO4 .5H2O (10 mol %) was used as a cheap copper source and sodium ascorbate (20 mol %) as a reducing agent.

After a successful installation, we next examined the efficacy and scope of the reaction with respect to both azides and alkyne components using the protocol described above. The reaction of alanine derivative 1a with several alkynes afforded the corresponding triazoles in good yields (entries 2-4). After that, the most extensively studied 1,1-diaryl-2-aminoethanol substrates, derived from valine, phenylglycine, phenylalanine, and proline, were included and surveyed within the same protocol. The 2-azidoamine derivatives 1b-1e also smoothly reacted with several kinds of terminal acetylenes to afford β-amino triazoles in good yield, without N-protection of the amino group. So far, the presence of sterically enforced functional groups in the azide partner did not have any significant effect on the product formation. The synthetic procedure was quite straightforward and all reac-tions afforded single isomers as summarized in Table 1. The structures of new triazoles are fully consistent with their 1H, 13C, and MS data. In 1H NMR spectrum, the C(5)-proton of the triazole ring appears as a singlet in the range of δ 7.4-8.2 ppm. The C(4)-carbon resonates between δ 128-148 depend-ing on the substituent present and the C(5)-carbon resonated around δ 128 in 13C NMR spectrum. It is interesting to note that a series of sterically demanding pyrrolidine-triazole conjugates 2q-2v were conveniently prepared from routine Cu-catalyzed cycloaddition reactions, which are potentially valuable entities for organocatalytic transformations. In addi-tion, a monosubstituted triazole 3 was also prepared in 78% yield by the reaction of 1e with (trimethylsilyl)acetylene under the previous reported conditions, followed by a TMS-deprotection (Scheme 2).16

Table 1.aReaction conditions: 1 (1 mmol), alkyne (1.2 equiv), CuSO4 ⋅5H2O (10 mol %), Na ascorbate (20 mol %), MeCN/H2O (1/1, 5 mL)

Scheme 2.CuAAC of 1e with TMS-acetylene to give 3.

An interesting event has been observed during the reaction of 1e with ethyl propiolate featuring a competition between Michael addition and Huisgen cycloaddition. When the reaction was subjected to our standard conditions, it afforded mixtures of products while Michael adducts are predominant (Table 2, entry 1). Meanwhile, the triazole geometry has not changed during the sequential steps, and has been confirmed later by the conversion of 4a to 4c (entry 2). Thus, the reac-tion pathway seems likely that an initially formed Michael adduct 4a may undergo cycloaddition to afford the product 4c. In order to complete this transformation, the addition of an extra ethyl propiolate and high reaction temperature were necessary (entry 3). In addition, X-ray crystal structure of 4c has been solved and shown again that it is a 1,4-disubstituted triazole. Thus, the results clearly show strong 1,4-triazole formation preference even employed with sterically-demand-ing azides.

Table 2.CuAAC of 1e with ethyl propiolate

Figure 2.X-ray crystal structure of 4c.

 

Conclusion

In summary, this investigation has identified a new entry leading to highly hindered chiral β-amino triazoles by azide-alkyne click chemistry. We probed the Cu(II)/sodium as-corbate is preferable and all cycloaddition reactions were performed under aqueous media at room temperature, and using stereo-demanding β-azidoamines as the starting materials. It is interesting to note that almost all reported methods utilized N-protected amino acid precursors for the synthesis of triazole-based amino acids and β-amino triazoles. This protocol provides an economically viable procedure to deliver new chiral triazoles from unmasked 1,1-diaryl-2-amino-ethanols, therefore, and renders as it fulfills many of the prerequisite for green and sustainable chemistry. The highly hindered β-amino triazoles are currently being investigated as potential molecular catalysts.

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