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DOI: 10.1055/s-2007-984513
A Two-Carbon Homologation of Aldehydes and Ketones Using Ynamides
Publication History
Publication Date:
25 June 2007 (online)
Abstract
Reactions of ynamides with Lewis acid activated aldehydes, enals, or ketones in the formation of acrylic amides are described here. The overall process is an equivalent of a two-carbon homologation of aldehydes or ketones and is selective for the E-isomer.
Key words
two-carbon homologation - ynamide - torquoselective ring opening - oxetene - E-acrylic amides
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1a
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References and Notes
General Experimental Procedure: To a solution of ynamide 5 (56.0 mg, 0.30 mmol) in CH2Cl2 (30 mL) was added hexanal (0.055 mL, 0.45 mmol, 1.5 equiv). The solution was then cooled to -78 °C and a solution of BF3·OEt2 (0.20 M in CH2Cl2, 0.75 mL, 0.15 mmol) was added carefully dropwise and the reaction was stirred for 10 min at -78 °C. When the TLC analysis showed that the starting ynamide 5 was completely consumed, the reaction mixture was poured into sat aq NaHCO3 (20 mL). The two phases were separated and the aqueous layer was extracted with CH2Cl2 (3 × 20 mL). The organic layers were combined, dried over Na2SO4, and concentrated in vacuo. The resulting crude yellow oil was purified using silica gel flash column chromatography (gradient eluent: 10-20% EtOAc in hexanes) to afford the pure acrylic amide 6 (56.0 mg, 65%) exclusively as the E-isomer and as a colorless oil. 6: R f 0.34 (25% EtOAc in hexanes); [α]D 20 86.0 (c = 0.40, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 0.88 (t, J = 6.8 Hz, 3 H), 1.24-1.34 (m, 4 H), 1.42-1.50 (m, 2 H), 2.25 (dtd, J = 1.2, 6.8, 7.2 Hz, 2 H), 4.27 (dd, J = 4.0, 8.8 Hz, 1 H), 4.81 (dd, J = 4.0, 8.8 Hz, 1 H), 5.48 (dd, J = 4.0, 8.8 Hz, 1 H), 7.10 (dt, J = 7.2, 15.2 Hz, 1 H), 7.25 (dt, J = 1.2, 15.2 Hz, 1 H), 7.30-7.41 (m, 5 H). 13C NMR (125 MHz, CDCl3): δ = 13.9, 22.4, 27.7, 31.3, 32.6, 57.7, 69.9, 120.1, 125.9, 128.6, 129.1, 139.1, 152.3, 153.7, 164.7. IR (film): 2929 (w), 1775 (s), 1686 (w), 1634 (w) cm-1. MS (APCI): m/z (%) = 288.2 (100) [M + H]+.
14For other representative characterizations, see: 7: R
f
0.19 (25% EtOAc in hexanes). 1H NMR (400 MHz, CDCl3): δ = 0.89 (t, J = 6.4 Hz, 3 H), 1.24-1.36 (m, 4 H), 1.44-1.53 (m, 2 H), 2.28 (dt, J = 6.4, 7.2 Hz, 2 H), 4.07 (dd, J = 7.6, 8.4 Hz, 2 H), 4.42 (dd, J = 7.6, 8.4 Hz, 2 H), 7.16 (dt, J = 6.4, 15.6 Hz, 1 H), 7.25 (dt, J = 1.2, 15.6 Hz, 1 H). 13C NMR (125 MHz, CDCl3): δ = 13.8, 22.3, 27.6, 31.2, 32.5, 42.6, 61.9, 119.8, 151.7, 153.4, 165.2. IR (film): 2928 (w), 2859 (w), 1773 (s), 1683 (m), 1643 (w), 1623 (w), 1386 (w), 1359 (m) cm-1. MS (APCI): m/z (%) = 212.2 (100) [M + H]+.
8: R
f
0.35 (25% EtOAc in hexanes); mp 88-91 °C; [α]D
20 -36.9 (c = 0.15, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 4.31 (dd, J = 4.0, 9.2 Hz, 1 H), 4.73 (dd, J = 8.8, 9.2 Hz, 1 H), 5.56 (dd, J = 4.0, 8.8 Hz, 1 H), 7.30-7.41 (m, 6 H), 7.48 (dd, J = 7.6, 7.6 Hz, 1 H), 7.57-7.64 (m, 2 H), 7.79 (d, J = 16.0 Hz, 1 H), 7.94 (d, J = 0.8, 16.0 Hz, 1 H), 8.12 (d, J = 8.4 Hz, 1 H). 13C NMR (100 MHz, CDCl3): δ = 58.1, 70.2, 117.1, 126.2, 128.9, 128.9, 129.1, 129.4, 131.0, 134.7, 139.4, 146.9, 154.1, 165.0. IR (film): 3064 (w), 1775 (s), 1687 (m), 1619 (w) cm-1. MS (APCI): m/z (%) = 294.2 (100) [M + H]+.
9: R
f
0.34 (25% EtOAc in hexanes); [α]D
20 -159 (c = 0.90, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 0.60-0.70 (m, 2 H), 0.94-1.02 (m, 2 H), 1.64-1.74 (m, 1 H), 4.26 (dd, J = 4.0, 8.8 Hz, 1 H), 4.69 (dd, J = 8.8, 8.8 Hz, 1 H), 5.48 (dd, J = 4.0, 8,8 Hz, 1 H), 6.54 (dd, J = 10.4, 15.2 Hz, 1 H), 7.29-7.34 (m, 3 H), 7.34-7.39 (m, 3 H). 13C NMR (100 MHz, CDCl3): δ = 9.5, 9.6, 15.6, 58.0, 70.1, 117.3, 126.2, 128.8, 129.4, 139.5, 154.0, 157.6, 164.7. IR (film): 1770 (s), 2928 (w), 1681 (w), 1623 (w), 1379 (w) cm-1. MS (APCI): m/z (%) = 258.2 (100) [M + H]+.
10: R
f
0.48 (25% EtOAc in hexanes). 1H NMR (400 MHz, CDCl3): δ = 5.22 (s, 2 H), 7.05 (d, J = 15.2 Hz, 1 H), 7.32-7.44 (m, 10 H), 7.71 (d, J = 15.6 Hz, 1 H), 7.92-7.96 (m, 2 H), 8.24-8.27 (m, 2 H). 13C NMR (125 MHz, CDCl3): δ = 50.1, 117.1, 124.3, 128.0, 128.5, 128.7, 129.3, 129.4, 129.7, 131.4, 134.2, 136.3, 145.5, 148.1, 150.7, 166.4. IR (film): 1775 (w), 1683 (m), 1619 (m), 1532 (m), 1350 (s) cm-1. MS (APCI): m/z (%) = 423.1 (100) [M + H]+.
11: R
f
0.43 (25% EtOAc in hexanes); [α]D
20 29.2 (c = 0.15, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 0.84 (t, J = 7.2 Hz, 3 H), 1.20-1.28 (m, 4 H), 1.33-1.41 (m, 2 H), 2.19 (ddd, J = 1.6, 7.6, 15.2 Hz, 2 H), 4.17 (dd, J = 6.8, 9.2 Hz, 1 H), 4.63 (dd, J = 8.8, 8.8 Hz, 1 H), 5.44 (dd, J = 6.8, 8.8 Hz, 1 H), 6.23 (t, J = 7.8 Hz, 1 H), 7.17-7.21 (m, 2 H), 7.27-7.35 (m, 5 H), 7.35-7.42 (m, 3 H). 13C NMR (100 MHz, CDCl3): δ = 13.9, 22.3, 28.5, 28.8, 31.4, 58.1, 69.6, 126.6, 127.6, 127.8, 128.8, 129.0, 129.6, 134.3, 136.1, 137.9, 140.1, 152.6, 169.7. IR (film): 2957 (w), 1787 (s), 1688 (m) cm-1. MS (APCI): m/z (%) = 364.2 (100) [M + H]+.
12: R
f
0.48 (30% EtOAc-hexanes); mp 152-154 °C; [α]D
25 -15.3 (c = 0.60, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 2.20 (d, J = 1.5 Hz, 3 H), 4.34 (dd, J = 7.5, 8.5 Hz, 1 H), 4.80 (t, J = 9.0 Hz, 1 H), 5.59 (dd, J = 7.5, 8.5 Hz, 1 H), 7.11 (s, 1 H), 7.37-7.47 (m, 10 H). 13C NMR (125 MHz, CDCl3): δ = 15.5, 58.7, 70.2, 126.6, 128.6, 128.7, 129.2, 129.5, 129.8, 131.9, 135.8, 137.2, 138.1, 153.7, 171.8. IR (thin film): 3059 (w), 1782 (s), 1678 (s), 1357 (m), 1323 (m) cm-1. MS (APCI): m/z (%) = 308 (100) [M + H]+.
13: R
f
0.40 (20% EtOAc-hexanes); mp 103-105 °C; [α]D
25 -28.3 (c = 0.90, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 0.91-0.96 (m, 3 H), 1.31-1.39 (m, 4 H), 1.47-1.58 (m, 2 H), 1.92 (s, 3 H), 2.19-2.27 (m, 2 H), 4.27 (dd, J = 7.5, 8.5 Hz, 1 H), 4.74 (t, J = 9.0 Hz, 1 H), 5.53 (dd, J = 7.5, 8.5 Hz, 1 H), 6.28 (ddd, J = 1.5, 7.5, 7.5 Hz, 1 H), 7.38-7.53 (m, 5 H). 13C NMR (125 MHz, CDCl3): δ = 13.5, 14.3, 22.8, 28.3, 28.8, 31.8, 58.7, 70.0, 126.6, 129.1, 129.4, 130.7, 138.2, 142.0, 153.8, 171.4. IR (thin film): 2927 (w), 2858 (w), 1789 (s), 1679 (s), 1325 (m) cm-1. MS (APCI): m/z (%) = 302 (100) [M + H]+.
15: R
f
0.34 (25% EtOAc in hexanes); [α]D
20 70.0 (c = 0.90, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 4.20 (dd, J = 7.0, 9.0 Hz, 1 H), 4.65 (dd, J = 9.0, 9.0 Hz, 1 H), 5.39 (dd, J = 1.0, 10.0 Hz, 1 H), 5.47 (dd, J = 6.5, 9.0 Hz, 1 H), 5.57 (dd, J = 1.0, 16.5 Hz, 1 H), 6.55 (ddd, J = 10.0, 11.0, 16.5 Hz, 1 H), 6.69 (d, J = 11.0 Hz, 1 H), 7.20-7.24 (m, 2 H), 7.30-7.36 (m, 5 H), 7.37-7.43 (m, 3 H). 13C NMR (125 MHz, CDCl3): δ = 58.5, 70.0, 125.0, 127.0, 128.2, 128.4, 129.3, 129.4, 130.2, 132.8, 134.3, 136.5, 136.6, 138.0, 152.9, 169.8. IR (film): 1782 (s), 1680 (w) cm-1. MS (APCI): m/z (%) = 320.2 (100) [M + H]+.
16: R
f
0.52 (33% EtOAc in hexanes); mp 146-149 °C; [α]D
25 -59.0 (c = 0.5, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 0.77 (s, 3 H), 1.13 (d, J = 8.0 Hz, 1 H), 1.35 (s, 3 H), 2.13 (s, 1 H), 2.41-2.51 (m, 3 H), 2.66 (t, J = 6.4 Hz, 1 H), 4.27 (dd, J = 3.6, 8.8 Hz, 1 H), 4.69 (dd, J = 8.8, 8.8 Hz, 1 H), 5.51 (dd, J = 3.6, 8.8 Hz, 1 H), 6.08 (s, 1 H), 7.23 (d, J = 15.2 Hz, 1 H), 7.26-7.39 (m, 5 H), 7.42 (d, J = 15.6 Hz, 1 H). 13C NMR (100 MHz, CDCl3): δ = 21.0, 26.3, 31.4, 33.1, 38.0, 40.8, 41.5, 58.1, 70.1, 113.4, 126.1, 128.8, 129.4, 136.8, 139.5, 146.7, 146.8. 154.1, 165.6. IR (neat): 2976 (br m), 1778 (s), 1679 (s), 1494 (s), 1422 (s), 1384 (s) cm-1. MS (APCI): m/z (%) = 338.2 (100) [M + H]+.
17: R
f
0.19 (20% EtOAc-hexanes); [α]D
23 -188.0 (c = 0.25, CH2Cl2). 1H NMR (400 MHz CDCl3): δ = 1.51 (m, 1 H), 1.74 (s, 3 H), 1.92 (ddd, J = 2.4, 5.2, 12.4 Hz, 1 H), 2.15 (m, 2 H), 2.26 (ddd, J = 2.4, 5.2, 12.4 Hz, 1 H), 2.37 (m, 2 H), 4.26 (dd, J = 4.0, 8.8 Hz, 1 H), 4.68 (t, J = 8.8 Hz, 1 H), 4.71 (m, 1 H), 4.75 (t, J = 1.6 Hz, 1 H), 5.51 (dd, J = 4.0, 8.8 Hz, 1 H), 6.22 (t, J = 2.4 Hz, 1 H), 7.23 (d, J = 15.6 Hz, 1 H), 7.30-7.34 (m, 3 H), 7.35-7.39 (m, 2 H), 7.40 (d, J = 15.6 Hz, 1 H). 13C NMR (100 MHz CDCl3): δ = 21.0, 24.8, 27.1, 32.2, 40.8, 58.1, 70.1, 109.4, 114.2, 126.2, 128.8, 129.4, 135.6, 139.5, 140.2, 149.1, 149.8, 154.0, 165.5. IR (neat): 2919 (m), 1773 (s), 1680 (m), 1600 (s), 1383 (m), 1334 (s) cm-1. MS (APCI): m/z (%) = 338.2 (100) [M + H]+.
18: R
f
0.29 (50% EtOAc in hexanes); colorless oil; [α]D
20 -43.8 (c = 0.53, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 2.05 (s, 3 H), 2.07 (s, 3 H), 2.11 (s, 3 H), 4.16 (dd, J = 6.4, 12.1 Hz, 1 H), 4.22 (dd, J = 3.9, 12.1 Hz, 1 H), 4.29 (dd, J = 4.0, 8.9 Hz, 1 H), 4.72 (t, J = 8.9 Hz, 1 H), 5.22 (ddd, J = 3.9, 4.8, 6.5 Hz, 1 H), 5.50 (dd, J = 3.9, 8.8 Hz, 1 H), 5.59 (ddd, J = 1.1, 5.0, 6.3 Hz, 1 H), 6.03 (dd, J = 6.4, 15.4 Hz, 1 H), 6.52 (ddd, J = 1.3, 10.6, 15.4 Hz, 1 H), 7.27-7.43 (m, 7 H). 13C NMR (100 MHz, CDCl3): δ = 20.8, 20.9, 21.0, 57.9, 61.8, 70.2, 71.5, 71.6, 122.3, 126.1, 128.9, 129.4, 132.1, 135.8, 139.0, 144.4, 153.8, 164.5, 169.6, 170.1, 170.6. IR (neat): 3475 (w), 2963 (w), 1775 (m), 1738 (s), 1682 (m), 1606 (m), 1370 (m), 1350 (m), 1330 (m), 1214 (s), 1043 (s), 1013 (s) cm-1. MS (APCI): m/z (%) = 460 (2) [M + H]+, 400 (35) [M - HOAc]+, 340 (100) [M - 2 × HOAc]+, 298 (5), 164 (10).
20a: R
f
0.35 (33% EtOAc-hexanes); mp 128-130 °C; [α]D
25 -181 (c = 0.84, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 1.60-1.75 (m, 4 H), 2.50-2.55 (m, 2 H), 2.69-2.74 (m, 2 H), 4.22 (dd, J = 4.4, 8.8 Hz, 1 H), 4.67 (dd, J = 9.0, 9.0 Hz, 1 H), 5.49 (dd, J = 4.0, 8.8 Hz, 1 H), 7.22 (dddd, J = 2.4, 2.4, 2.4, 2.4 Hz, 1 H), 7.30-7.34 (m, 3 H), 7.35-7.40 (m, 2 H). 13C NMR (125 MHz, CDCl3): δ = 25.6, 26.6, 34.2, 37.1, 57.9, 69.9, 111.0, 126.0, 128.7, 129.4, 139.8, 154.1, 164.5, 174.2. IR (thin film): 3065 (w), 2960 (w), 1772 (s), 1681 (m), 1629 (m), 1378 (s) cm-1. MS (APCI): m/z (%) = 272 (70) [M + H]+, 228 (100), 109 (88). MS (MALDI): m/z calcd for C16H17NO3: 272.1281; found: 272.1280.
20b: R
f
0.49 (25% EtOAc-hexanes); mp 131-133 °C; [α]D
25 -119 (c = 1.50, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 1.44-1.55 (m, 4 H), 1.55-1.63 (m, 2 H), 2.17-2.23 (m, 2 H), 2.55-2.70 (m, 2 H), 4.14 (dd, J = 3.6, 8.8 Hz, 1 H), 4.58 (dd, J = 8.8, 8.8 Hz, 1 H), 5.40 (dd, J = 3.6, 8.8 Hz, 1 H), 6.76 (s, 1 H), 7.21-7.27 (m, 3 H), 7.27-7.33 (m, 2 H). 13C NMR (100 MHz, CDCl3): δ = 26.4, 28.1, 28.9, 31.0, 38.7, 57.9, 70.0, 113.2, 126.1, 128.7, 129.4, 139.7, 153.9, 164.9, 166.6. IR (thin film): 2934 (w), 1777 (s), 1682 (m), 1627 (br s). MS (APCI): m/z (%) = 286.1 (100) [M + H]+.
20c: R
f
0.50 (33% EtOAc-hexanes); mp 134-135 °C; [α]D
25 -191 (c = 0.97, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 1.48-1.53 (m, 4 H), 1.60-1.68 (m, 4 H), 2.47 (br dd, J = 6.0, 6.0 Hz, 2 H), 2.73 (dddd, J = 1.6, 6.0, 6.0, 16.4 Hz, 1 H), 2.82 (dddd, J = 1.6, 6.0, 6.0, 16.4 Hz, 1 H), 4.21 (dd, J = 4.0, 8.8 Hz, 1 H), 4.66 (dd, J = 8.8, 8.8 Hz, 1 H), 5.48 (dd, J = 4.0, 8.8 Hz, 1 H), 6.99 (dddd, J = 1.6, 1.6, 1.6, 1.6 Hz, 1 H), 7.29-7.34 (m, 3 H), 7.36-7.40 (m, 2 H). 13C NMR (125 MHz, CDCl3): δ = 26.5, 28.3, 29.4, 30.0, 33.7, 39.8, 57.9, 69.9, 115.1, 126.0, 128.7, 129.4, 139.8, 154.0, 164.5, 170.8. IR (thin film): 2926 (w), 1779 (s), 1686 (m), 1629 (m), 1377 (s) cm-1. MS (APCI): m/z (%) = 300(35) [M + H]+, 274 (100), 256 (47), 137 (55). MS (MALDI): m/z calcd for C18H21NO3Na: 322.1414; found: 322.1420.
21: R
f
0.41 (33% EtOAc-hexanes); mp 98-99 ºC; [α]D
25 -162 (c = 0.65, CH2Cl2). 1H NMR (500 MHz, CDCl3): δ = 1.01 (dd, J = 7.5, 7.5 Hz, 3 H), 1.12 (dd, J = 7.5, 7.5 Hz, 3 H), 2.25 (qd, J = 1.5, 7.5 Hz, 2 H), 2.46 (dq, J = 7.5, 12.5 Hz, 1 H), 2.54 (dq, J = 7.5, 12.5 Hz, 1 H), 4.22 (dd, J = 4.0, 9.0 Hz, 1 H), 4.67 (dd, J = 9.0, 9.0 Hz, 1 H), 5.49 (dd, J = 4.0, 8.5 Hz, 1 H), 6.91 (dd, J = 1.5, 1.5 Hz, 1 H), 7.30-7.34 (m, 3 H), 7.36-7.40 (m, 2 H). 13C NMR (125 MHz, CDCl3): δ = 12.2, 13.0, 26.6, 31.6, 57.9, 69.9, 113.7, 126.0, 128.7, 129.4, 139.7, 154.0, 164.6, 170.5. IR (thin film): 3035 (w), 2972 (w), 1777 (s), 1685 (m), 1626 (m), 1385 (s) cm-1. MS (APCI): m/z (%) = 274 (8) [M + H]+, 248 (100), 230 (53), 111 (92). MS: (MALDI) m/z calcd for C16H19NO3Na: 296.1257; found: 296.1265.
22a: R
f
0.41 (33% EtOAc-hexanes); clear oil; [α]D
25 +88.4 (c = 1.81, CH2Cl2). 1H NMR (400 MHz, CDCl3; major): δ = 1.94 (m, 2 H), 2.28-2.34 (m, 2 H), 2.36 (m, 2 H), 4.17 (dd, J = 6.8, 8.8 Hz, 1 H), 4.69 (dd, J = 8.8, 8.8 Hz, 1 H), 4.91 (dddd, J = 2.0, 2.0, 2.0, 2.0 Hz, 1 H), 4.99 (dd, J = 6.8, 8.8 Hz, 1 H), 6.07 (s, 1 H), 7.15 (tt, J = 1.2, 7.2 Hz, 1 H), 7.22-7.26 (m, 2 H), 7.30-7.40 (m, 7 H). 1H NMR (400 MHz, CDCl3; minor): δ = 5.95 (s, 1 H). 13C NMR (125 MHz, CDCl3): δ = 21.5, 29.0, 30.8, 59.3, 70.1, 102.7, 111.7, 126.9, 127.3, 128.47, 128.53, 129.2, 129.3, 133.6, 138.0, 139.4, 154.2, 155.9. IR (neat): 3063 (w), 2958 (w), 1761 (s), 1651 (m), 1391 (m), 1364 (m), 1341 (m) cm-1. MS (APCI): m/z (%) = 348 (3) [M + H]+, 296 (100). MS: (MALDI): m/z calcd for C22H21NO3Na: 370.1414; found: 370.1394.
22b: R
f
0.36 (33% EtOAc-hexanes); clear oil; [α]D
25 +174 (c = 1.92, CH2Cl2). 1H NMR (400 MHz, CDCl3; major): δ = 1.49-1.56 (m, 2 H), 1.60-1.78 (m, 4 H), 2.06 (m, 2 H), 2.31 (m, 1 H), 2.38 (m, 1 H), 4.16 (dd, J = 6.8, 8.8 Hz, 1 H), 4.67 (dd, J = 8.8, 8.8 Hz, 1 H), 4.98 (dd, J = 6.8, 8.8 Hz, 1 H), 5.75 (dd, J = 6.4, 6.4 Hz, 1 H), 6.08 (s, 1 H), 7.14 (tt, J = 1.2, 6.4 Hz, 1 H), 7.21-7.25 (m, 2 H), 7.29-7.40 (m, 7 H). 1H NMR (400 MHz, CDCl3; minor): δ = 5.71 (s, 1 H). 13C NMR (125 MHz, CDCl3): δ = 25.3, 26.0, 27.8, 31.6, 31.8, 59.1, 70.0, 106.9, 112.3, 126.8, 127.1, 128.39, 128.41, 129.1, 129.3, 134.0, 138.0, 138.1, 155.3, 155.9. IR (neat): 2981 (w), 1761 (s), 1672 (m), 1391 (m), 1345 (m) cm-1. MS (APCI): m/z (%) = 376 (10) [M + H]+, 296 (100). MS (MALDI): m/z calcd for C24H25NO3Na: 398.1727; found: 398.1709.
23: R
f
0.33 (33% EtOAc-hexanes); clear oil. 1H NMR (400 MHz, CDCl3): δ = 1.13 (t, J = 7.6 Hz, 3 H), 1.59 (d, J = 6.8 Hz, 3 H), 2.23 (dq, J = 7.2, 14.8 Hz, 1 H), 2.30 (dq, J = 7.6, 14.8 Hz, 1 H), 4.12 (dd, J = 6.8, 8.8 Hz, 1 H), 4.66 (dd, J = 8.8, 8.8 Hz, 1 H), 4.89 (q, J = 6.8 Hz, 1 H), 4.93 (dd, J = 6.8, 8.8 Hz, 1 H), 6.12 (s, 1 H), 7.12-7.16 (m, 1 H), 7.20-7.26 (m, 2 H), 7.28-7.40 (m, 7 H). 1H NMR (400 MHz, CDCl3; minor): δ = 0.93 (t, J = 7.2 Hz, 3 H), 1.71 (dt, J = 1.6, 6.8 Hz, 3 H), 2.01-2.20 (m, 2 H), 4.17 (dd, J = 5.6, 8.8 Hz, 1 H), 4.67 (dd, J = 8.8, 8.8 Hz, 1 H), 4.80 (qt, J = 1.2, 6.8 Hz, 1 H), 5.06 (dd, J = 5.6, 8.8 Hz), 5.96 (s, 1 H). 13C NMR (125 MHz, CDCl3): δ = 11.8, 12.3, 22.2, 58.9, 70.1, 98.5, 113.4, 126.7, 127.2, 128.38, 128.41, 129.0, 129.3, 133.9, 137.7, 138.0, 152.5, 156.1. IR (neat): 3062 (w), 2980 (w), 1762 (s), 1661 (w), 1391 (m) cm-1. MS (APCI): m/z (%) = 350 (5) [M + H]+, 296 (100). MS (MALDI): m/z calcd for C22H23NO3Na: 372.1570; found: 372.1566.
24: characterized as an inseparable mixture; R
f
0.49 (25% EtOAc in hexanes); [α]D
20 -80.6 (c = 1.95, CHCl3). 1H NMR (500 MHz, CDCl3; E-isomer): δ = 1.16 (t, J = 7.5 Hz, 3 H), 2.14 (s, 3 H), 2.29 (q, J = 7.5 Hz, 2 H), 4.26 (dd, J = 4.0, 8.5 Hz, 1 H), 4.72 (t, J = 9.0 Hz, 1 H), 5.54 (dd, J = 4.0, 8.5 Hz, 1 H), 7.01-7.03 (m, 1 H), 7.34-7.39 (m, 3 H), 7.40-7.45 (m, 2 H). 1H NMR (500 MHz, CDCl3; Z-isomer): δ = 1.07 (t, J = 7.5 Hz, 3 H), 2.01 (s, 3 H), 2.48-2.56 (m, 1 H), 2.56-2.64 (m, 1 H), 4.24-4.29 (m, 1 H), 4.71 (t, J = 9.0, 1 H), 5.52-5.56 (m, 1 H), 6.97 (br s, 1 H), 7.34-7.39 (m, 3 H), 7.40-7.45 (m, 2 H). IR (neat): 1774 (s), 1684 (m), 1627 (w), 1606 (m) cm-1. MS (APCI): m/z (%) = 260.1 (100) [M + H]+.
25: R
f
0.17 (10% EtOAc in hexanes); [α]D
23 -102.5 (c = 0.80, CHCl3). 1H NMR (400 MHz, CDCl3; E-isomer): δ = 1.22-1.32 (m, 4 H), 1.52-1.82 (m, 6 H), 2.02-2.10 (m, 1 H), 2.07 (s, 3 H), 4.20 (dd, J = 4.0, 8.8 Hz, 1 H), 4.66 (dd, J = 8.8, 8.8 Hz, 1 H), 5.49 (dd, J = 4.0, 8.8 Hz, 1 H), 6.97 (br s, 1 H), 7.28-7.34 (m, 3 H), 7.35-7.40 (m, 2 H). 1H NMR (500 MHz, CDCl3; Z-isomer): δ = 1.22-1.32 (m, 4 H), 1.52-1.82 (m, 7 H), 1.89 (s, 3 H), 4.20 (dd, J = 4.0, 8.8 Hz, 1 H), 4.66 (dd, J = 8.8, 8.8 Hz, 1 H), 5.49 (dd, J = 4.0, 8.8 Hz, 1 H), 6.81 (br s, 1 H), 7.28-7.34 (m, 3 H), 7.35-7.40 (m, 2 H). IR (film): 2926 (m), 2852 (w), 1772 (s), 1680 (m), 1618 (w), 1383 (w) cm-1. MS (APCI): m/z (%) = 314.2 (100) [M + H]+.
26: R
f
0.41 (25% EtOAc in hexanes); [α]D
23 -56.3 (c = 1.45, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 4.31 (dd, J = 4.0, 8.8 Hz, 1 H), 4.73 (d, J = 11.6 Hz, 1 H), 4.74 (d, J = 8.8 Hz, 1 H), 5.03 (d, J = 11.6 Hz, 1 H), 5.55 (dd, J = 4.0, 8.8 Hz, 1 H), 7.33-7.38 (m, 3 H), 7.39-7.44 (m, 5 H), 7.54 (s, 1 H), 7.60-7.64 (m, 2 H). 13C NMR (100 MHz, CDCl3): δ = 40.0, 58.0, 70.3, 119.8, 126.2, 127.3, 129.1, 129.1, 129.5, 130.2, 138.5, 139.1, 153.6, 153.8, 163.9. IR (film): 2923 (w), 1775 (s), 1681 (m), 1615 (w), 1451 (m), 1384 (m) cm-1. MS (APCI): m/z (%) = 342.1 (100) [M + H]+.
We did not rigorously assign the E and Z stereochemistries for the trisubstituted acrylic amides 23, 24 and 25 because of the low ratio and/or yield.
18Authors appreciate the suggestion made by one of the referees to attempt homologations with these unsymmetrical ketones.