Asymmetric NHC-catalyzed synthesis of α-fluoroamides from ... Asymmetric NHC-catalyzed...

Click here to load reader

  • date post

    24-Jan-2021
  • Category

    Documents

  • view

    0
  • download

    0

Embed Size (px)

Transcript of Asymmetric NHC-catalyzed synthesis of α-fluoroamides from ... Asymmetric NHC-catalyzed...

  • Asymmetric NHC-catalyzed synthesis of α-fluoroamides from readily accessible α-fluoroenals. Philip Wheeler, Harit U. Vora and Tomislav Rovis*

    Department of Chemistry, Colorado State University, Fort Collins, CO.

    General methods S-2 NHC-redox acylation of amine hydrochlorides with enals S-3 Preparation of α-fluoroenals S-7 Asymmetric NHC-catalyzed synthesis of α-fluoroamides S-11 Derivatization of α-fluoroamides S-17 Spectral data S-19

    S-1

    Electronic Supplementary Material (ESI) for Chemical Science This journal is © The Royal Society of Chemistry 2013

  • General methods

    All reactions were carried out under an atmosphere of argon in flame dried glassware with magnetic stirring. Toluene was degassed with argon and passed through two columns of neutral alumina. Column chromatography was performed on SiliCycle®SilicaFlash® P60, 40-63µm 60A. Thin layer chromatography was performed on SiliCycle® 250µm 60A plates. Visualization was accomplished with UV quench, KMNO4, or aqueous ceric ammonium molybdate dips followed by heating.

    1H and 13C spectra were recorded on a Varian 400 MHz spectrometer at ambient temperature. 1H NMR data are reported as follows: chemical shift is parts per million (δ, ppm) for chloroform (CHCl3) taken as 7.26 ppm, integration, multiplicity (s = singlet, br s = broad singlet, d = doublet, t = triplet, q = quartet, and m = multiplet), and coupling constants (Hz). 13C NMR data are reported in ppm from CDCl3 taken as 77.0 ppm. Low resolution mass spectra were obtained on an Agilent Technologies 6130 Quadropole Mass Spec and high resolution mass spectra were obtained on a Fisions VG Autospec. Infrared Spectra were obtained on a Bruker Tensor 27 FT-IR spectrometer.

    Anhydrous HOAt was purchased from Advanced Chem Tech and used as received. N,O- dimethylhydroxylamine hydrochloride, glycine methyl ester hydrochloride, L-alanine methyl ester hydrochloride, and L-phenylalanine methyl ester hydrochloride were purchased from Aldrich Chemical Co. and used without further purification. Benzylamine hydrochloride, piperidine hydrochloride, piperazine 1-carboxylic acid ethyl ester hydrochloride, L- phenethylamine hydrochloride and D-phenethylamine hydrochloride were prepared by treatment of the corresponding amine with an equimolar amount of anhydrous hydrogen chloride in ether (purchased from Aldrich Chemical Co. and used as received) followed by filtration. 3-((tert- butyldimethylsilyl)oxy)propanal was prepared according to known procedures. Other aldehydes were obtained from Aldrich Chemical Co. and used without further purification.

    Racemic products were obtained by treating the corresponding fluoroenal with amine hydrochloride and HOAt in the presence of sodium pivalate and achiral triazolium salt in toluene. Enantiomeric ratio was determined by high pressure liquid chromatography on an Agilent Technologies 1100 Series using Daicel™ chiral columns.

    S-2

    Electronic Supplementary Material (ESI) for Chemical Science This journal is © The Royal Society of Chemistry 2013

  • NHC-redox acylation of amine hydrochlorides with enals

    Ph N H

    O

    CO2Me

    General procedure for acylation of amine hydrochlorides. To a 25 mL round-bottom flask equipped with a magnetic stir bar was added ca. 200 mg of molecular sieves (4Å). The sieves were flame activated under vacuum, and the vessel was purged with argon. Glycine methyl ester hydrochloride (50 mg, 0.4 mmol, 1.0 eq.), triazolium catalyst 1b (30 mg, 0.08 mmol, 0.2 eq.), and 1-hydroxy-7-azabenzotriazole (10.8 mg, 0.08 mmol, 0.2 eq.) were weighed into the flask, which was then evacuated and flushed with argon. Toluene (8 mL) was added, and the reaction vessel was heated to 70 °C. Trans-cinnamaldehyde (75 µL, 0.6 mmol, 1.5 eq.) was added, followed by diisopropylethylamine (104 µL, 0.6 mmol, 1.5 eq.), and the reaction was stirred at 70 °C for 3h. The crude reaction mixture was loaded directly onto silica gel, and the product isolated by column chromatography (3:2 hexanes:ethyl acetate) yielding 7b as a yellow oil (82 mg, 93% yield). 1H-NMR (400 MHz, CDCl3) δ (ppm) 7.27-7.15 (m, 5H); 6.04 (br s, 1H); 4.54 (d, 2H, J = 5.2 Hz); 3.71 (s, 3H); 2.95 (dd, 2H, J1 = 7.5 Hz , J2 = 8.1 Hz); 2.53 (dd, 2H, J1 = 7.5 Hz, J2 = 8.1 Hz); 13C-NMR (100 MHz, CDCl3) δ (ppm) 172.56; 170.66; 140.83; 128.72; 128.49; 126.46; 52.58; 41.42; 38.14; 31.62.

    Ph N H

    O

    CO2Me

    Me

    1H-NMR (400 MHz, CDCl3) δ (ppm) 7.26-7.15 (m, 5H); 6.13 (br s, 1H); 4.54 (dq, 1H, J1 = 7.2 Hz, J2 = 1.7 Hz); 3.67 (s, 3H); 2.95 (t, 2H, J = 7.9 Hz); 2.54-2.41 (m, 2H); 1.29 (d, 3H, J = 7.2 Hz); 13C-NMR (100 MHz, CDCl3) δ (ppm) 173.7; 171.9; 140.9; 128.7; 128.5; 126.4; 52.6; 48.1; 38.3; 31.7; 18.6; IR (cm-1) 3299.0; 3028.6; 2952.7; 1746.1; 1650.1; 1542.0; 1497.3; 1453.9; 1378.3; 1210.2; 1167.2; HR-MS (ESI-APCI): Calc’d (m+h): 236.1208; Found (m+h): 236.1279.

    Ph N H

    O

    CO2Me

    Bn

    1H-NMR (400 MHz, CDCl3) δ (ppm) 7.28-7.16 (m, 7H); 6.92-6.90 (m, 2H); 5.80 (br d, 1H, J = 7.5 Hz); 4.86 (dt, 1H, J1 = 7.8 Hz, J2 = 5.6 Hz); 3.68 (s, 3H); 3.04 (d, 2H, J = 5.6 Hz); 2.94-2.89 (m, 2H); 2.54-2.39 (m, 2H) 13C-NMR (100 MHz, CDCl3) δ (ppm) 172.1; 171.6; 140.8; 135.9; 129.4; 128.7; 128.6; 127.3; 126.5; 53.1; 52.5; 38.4; 38.1; 31.6; IR (cm-1) 3028.9; 2951.6; 1745.5; 1650.1; 1604.0; 1536.6; 1497.0; 1453.9; 1371.2; 1213.7; 1121.0; 1077.6; 1029.9; HR- MS (ESI-APCI): Calc’d (m+h): 312.1521; Found (m+h): 312.1594.

    S-3

    Electronic Supplementary Material (ESI) for Chemical Science This journal is © The Royal Society of Chemistry 2013

  • Ph N H

    O

    CO2Me

    i-Pr

    1H-NMR (400 MHz, CDCl3) δ (ppm) 7.24-7.16 (m, 5H); 5.99 (br d, 1H, J = 8.2 Hz); 4.52 (ddd, 1H, J1 = 8.7 Hz, J2 = 5.0 Hz, J3 = 1.8 Hz); 3.67 (s, 3H); 2.94 (t, 2H, J = 9.7 Hz); 2.55-2.50 (m, 2H); 2.07-2.01 (m, 1H), 0.82-0.77 (m, 6H); 13C-NMR (100 MHz, CDCl3) δ (ppm) 172.8; 172.2; 140.8; 128.7; 128.5; 126.4; 57.1; 52.3; 38.4; 31.8; 31.4; 19.0; 17.9; IR (cm-1) 3028.9; 2965.1; 1744.7; 1651.5; 1540.0; 1497.7; 1454.2; 1436.4; 1373.1; 1310.8; 1265.3; 1206.7; 1156.3; 1076.9; 1024.4; HR-MS (ESI-APCI): Calc’d (m+h): 264.1521; Found (m+h): 264.1592.

    Ph N H

    O

    NHAc

    CO2Me

    1H-NMR (400 MHz, CDCl3) δ (ppm) 7.26-7.22 (m, 2H); 7.16 (dd, 3H, J1 = 7.2 Hz, J2 = 5.1 Hz); 6.31 (br d; J = 7.6 Hz); 5.70 (br s, 1H); 4.49 (dt, 1H, J1 = 8.0 Hz, J2 = 4.0 Hz); 3.69 (s, 3H); 2.92 (t, 2H, J = 7.7 Hz); 2.43 (t, 2H, J = 7.7 Hz); 1.98 (s, 3H); 1.77-1.73 (m, 1H); 1.63 (ddt, 1H, J1 = 8.1 Hz, J2 = 3.9 Hz, J3 = 14.5 Hz); 1.46-1.38 (m, 2H); 1.29-1.20 (m, 2H); 13C-NMR (100 MHz, CDCl3) δ (ppm) 173.2; 172.6; 170.3; 141.0; 128.7; 128.5; 126.4; 52.6; 52.0; 38.9; 38.6; 32.0; 32.0; 29.0; 23.3; 22.4; IR (cm-1) 3278.6; 3064.7; 2949.4; 2862.7; 2364.2; 1745.0; 1648.1; 1547.1; 1497.1; 1436.8; 1373.4; 1263.0; 1210.6; 1176.6; 1146.5; 1074.8; 1006.0; HR-MS (ESI- APCI): Calc’d (m+h): 335.1983; Found (m+h): 335.1971.

    Ph N

    O

    O 1H-NMR (400 MHz, CDCl3) δ (ppm) 7.26-7.14 (m, 5H); 3.57 (s, 4H) 3.52 (t, 2H, J = 5.5 Hz); 3.30 (t, 2H, J = 5.5 Hz); 2.94 (t, 2H, J = 8.0 Hz), 2.57 (t, 2H, J = 8.0 Hz); 13C-NMR (100 MHz, CDCl3) δ (ppm) 171.04; 141.25; 128.72; 126.46; 67.02; 66.64; 46.15; 42.13; 35.00; 31.68; IR (cm-1) 3483.9; 3061.23; 3026.6; 2962.2; 2920.4; 2856.7; 1652.6; 1495.3; 1433.8; 1361.5; 1300.5; 1271.5; 1226.7; 1115.5; 1069.6; 1025.8; HR-MS (ESI-APCI): Calc’d (m+h): 220.1259; Found (m+h): 220.1330.

    Ph N

    O

    S

    1H-NMR (400 MHz, CDCl3) δ (ppm) 7.29-7.16 (m, 10H, rotamers A and B); 4.56 (s, 2H, rotamer A); 4.33 (s, 2H, rotamer B); 3.82 (t, 2H, J = 6.4 Hz, rotamer B); 3.57 (t, 2H, J = 6.2 Hz, rotamer A); 3.05-2.86 (m, 8H, rotamers A and B); 2.68-2.51 (m, 4H, rotamers A and B); 13C- NMR (100 MHz, CDCl3) δ (ppm) 170.7; 170.4; 141.2; 128.7; 128.6; 126.5; 49.2; 48.7; 48.4; 37.4; 37.1; 31.3; 31.2; 29.8; IR (cm-1) 3059.9; 3026.2; 2394.7; 2873.5; 1650.1; 1495.7; 1418.3; 1339.3; 1261.0; 1077.6; 1029.7; HR-MS (ESI-APCI): Calc’d (m+h): 222.0874; Found (m+h): 222.0942.

    S-4

    Electronic Supplementary Material (ESI) for Chemical Science This journal is © The Royal Society of Chemistry 2013

  • N H

    O

    CO2Me

    O2N 1H-NMR (400 MHz, CDCl3) δ (ppm) 8.06 (d, 2H, J = 8.4 Hz); 7.32 (d, 2H, J = 8.4 Hz); 6.22 (br s, 1H); 3.96 (d, 2H, J = 5.2 Hz); 3.68 (s, 3H); 3.02 (t, 2H, J = 7.7 Hz); 2.56 (t, 2H, J = 7.7Hz); 13C-NMR (100 MHz, CDCl3) δ (ppm) 171.6; 170.5; 142.0; 146.7; 129.5; 123.9; 52.6; 41.4; 37.0; 31.2; IR (cm-1) 3287.2; 3092.8, 2955.8; 1742.6; 1649.2; 1598.4; 1554.3; 1515.0; 1431.9; 1386.6; 1344.2; 1215.6; 1108.0; 1021.7; HR-MS (ESI-APCI): Calc’d (m+h): 267.0903; Found (m+h): 267.0979.

    N H

    O

    CO2Me

    OHC 1H-NMR (400 MHz, CDCl3) δ (ppm) 9.93 (s, 1H) 7.68 (s, 1H); 7.67 (d, 2H, J = Hz); 7.46-7.38 (m, 2H); 6.11 (br s, 1H); 3.98 (d, 2H, J = 5.2 Hz); 3.69 (s, 3H); 3.03 (t, J = 7.5 Hz); 2.55 (t, 2H J = 7.5 Hz); 13C-NMR (100 MHz, CDCl3) δ (ppm) 192.7; 171.9; 170.5; 142.0; 136.8; 134.9; 129.5; 129.4; 128.2; 52.6; 41.4; 37.5; 31.1; IR (cm-1) 3310.3; 3066.7; 2953.7; 2850.4; 2736.4; 1750.0; 1697.8; 1604.8; 1585.8; 1543.6; 1438.7; 1408.9; 1374.5; 1209.9; 1144.5; 1083.4; 1037.8; 1010.4; HR-MS (ESI-APCI): Calc’d (m+h): 250.1001; Found (m+h): 250.1076.

    N H

    O

    CO2Me

    O

    Me

    1H-NMR (400 MHz, CDCl3) δ (ppm) 7.83 (d, 2H, J = 8.3 Hz); 7.25 (d, 2H, J = 8.2 Hz); 6.07 (br s, 1H); 3.98 (d, 2H, J = 5.2 Hz); 3.70 (s, 3H); 3.00 (t, J = 7.7 Hz); 2.55-2.51 (m, 5H); 13C-NMR (100 MHz, CDCl3) δ (