2.3. Synthesis of the But-2-enediamides (3a–k)
To a solution of the substituted acids (2a–k) (2.3 mmol) and diisopropylcarbodiimide (DIC, 0.32 g; 2.5 mmol) in DMF (7 mL), dimethylaminopyridine (DMAP, 0.08 g; 0.65 mmol) was added and the mixture stirred at room temperature for at least 30 min. Benzylamine (0.27 g; 2.5 mmol) was then added and the reaction mixture stirred at room temperature under nitrogen for 12 hrs. A volume of 10 mL of dichloromethane (DCM) was then introduced and the contents stirred for a further 5 min and then washed with brine (3×10 mL), separated, and dried on MgSO4. A precipitate was observed upon cooling the organic layer on ice, which was filtered under suction and washed with DCM, producing the products (3a–k) in pure form.
Compounds 3a and 3i were synthesised previously [22, 23]; however NMR data for 3a are not reported in Bi et al. [22] and are therefore presented below. The 1H and 13C NMR data for 3i (32% yield) was consistent with that reported in Streuff and Muñiz [23].
(2E)-N-Benzyl-
N
′
-phenylbut-2-enediamide (3a).
White powder (35% yield); mp 265–267°C; UV λmax (CH3OH) nm (log ε) 290 (4.31); IR (KBr) υmax (cm−1) 3266 (NH), 3061, 1633 (C=O), 1598, 1542; 1H NMR (DMSO-d6, 400 MHz) δ 10.47 (s, 1H, NH-5), 9.01 (bt, 1H, J=5.9 Hz, NH-6), 7.68 (d, 2H, J=8.1 Hz, H-2′/6′), 7.34–7.36 (m, 4H, H-3′/5′, H-3′′/5′′), 7.28–7.33 (m, 3H, H-2′′/6′′, H-4′′), 7.10–7.12 (m, 1H, H-4′), 7.11 (d, 1H, J=15.1 Hz, H-3), 7.04 (d, 1H, J=15.1 Hz, H-2), 4.41 (d, 2H, J=5.9 Hz, H-7′′); 13C NMR (DMSO-d6, 100 MHz) δ 164.0 (C-1), 162.7 (C-4), 139.4 (C-1′′), 139.3 (C-1′), 134.1 (C-2), 133.7 (C-3), 129.3 (C-3′/5′), 128.9 (C-3′′/5′′), 127.8 (C-2′′/6′′), 127.4 (C-4′′), 124.3 (C-4′), 119.8 (C-2′/6′), 42.9 (C-7′′).
(2E)-N-Benzyl-
N
′
-(2-methoxyphenyl)but-2-enediamide (3b).
White powder (18% yield); mp 260–262°C; UV λmax (CH3OH) nm (log ε) 310 (4.76), 275 (4.92), 240 (5.23); IR (KBr) υmax (cm−1) 3271 (NH), 3034, 1626 (C=O), 1537, 1492; 1H NMR (DMSO-d6, 400 MHz) δ 9.73 (s, 1H, NH-5), 8.95 (bt, 1H, J=5.6 Hz, NH-6), 8.01 (d, 1H, J=7.7 Hz, H-6′), 7.35 (d, 1H, J=15.1 Hz, H-3), 7.33–7.35 (m, 2H, H-3′′/5′′), 7.28–7.30 (m, 3H, H-2′′/6′′, H-4′′), 7.11 (m, 1H, H-5), 7.01 (d, 1H, J=15.1 Hz, H-2), 7.00 (d, 1H, J=7.7 Hz, H-3′), 6.92 (t, 1H, J=7.7 Hz, H-4′), 4.40 (d, 2H, J=5.6 Hz, H-7′′), 3.83 (s, 3H, 2′-OCH3); 13C NMR (DMSO-d6, 100 MHz) δ 164.2 (C-1), 163.0 (C-4), 150.5 (C-2′), 139.4 (C-1′′), 134.1 (C-2), 134.0 (C-3), 128.9 (C-3′′/5′′), 127.8 (C-2′′/6′′), 127.4 (C-4′′), 125.5 (C-5′), 122.8 (C-6′), 120.67 (C-4′), 111.8 (C-3′), 56.15 (2′-OCH3), 42.85 (C-7′′); EIMS (m/z) 310 [M+], 281, 249, 207, 188, 160, 106, 91; HRMS (m/z): 310.1318 (calculated for C18H18N2O3, 310.1315).
(2E)-N-Benzyl-
N
′
-(3-methoxyphenyl)but-2-enediamide (3c).
White powder (65% yield); mp 240-241°C; UV λmax (CH3OH) nm (log ε) 310 (3.88), 280 (3.88), 240 (4.04); IR (KBr) υmax (cm−1) 3266 (NH), 3070, 1633 (C=O), 1602 (NH), 1544, 1492; 1H NMR (DMSO-d6, 400 MHz) δ 10.45 (s, 1H, NH-5), 9.02 (bt, 1H, J=5.8 Hz, NH-6), 7.38 (s, 1H, H-2′), 7.33–7.35 (m, 2H, H-3′′/H-5′′), 7.25–7.29 (m, 3H, H-2′′/6′′, H-4′′), 7.19–7.23 (m, 2H, H-5′,6′), 7.08 (d, 1H, J=15.1 Hz, H-2), 7.02 (d, 1H, J=15.1 Hz, H-3), 6.69 (d, 1H, J=7.8 Hz, H-4′), 4.40 (d, 2H, J=5.8 Hz, H-7′′), 3.73 (s, 3H, 3′-OCH3); 13C NMR (DMSO-d6, 100 MHz) δ 164.0 (C-1), 162.7 (C-4), 160.0 (C-3′), 140.4 (C-1′), 139.3 (C-1′′), 134.2 (C-2), 133.7 (C-3), 130.1 (C-5′), 128.9 (C-3′′/5′′), 127.8 (C-2′′/6′′), 127.5 (C-4′′), 112.2 (C-6′), 109.7 (C-4′), 105.7 (C-2′), 55.5 (3′-OCH3), 42.9 (C-7′′). EIMS (m/z): 310 [M+], 281, 207, 187, 176, 149, 106, 91; HRMS (m/z): 310.1315 (calculated for C18H18N2O3, 310.1315).
(2E)-N-Benzyl-
N
′
-(2-chlorophenyl)but-2-enediamide (3d).
Pale brown powder (24% yield); mp 244-245°C; UV λmax (CH3OH) nm (log ε) 275 (4.36); IR (KBr) υmax (cm−1) 3267 (NH), 3032, 1626 (C=O), 1531, 1494; 1H NMR (DMSO-d6, 400 MHz) δ 10.08 (s, 1H, NH-5), 9.00 (bt, 1H, J=5.9 Hz, NH-6), 7.79 (d, 1H, J=7.9 Hz, H-6′), 7.53 (d, 1H, J=7.9 Hz, H-3′), 7.32–7.35 (m, 2H, H-3′′/5′′), 7.25–7.29 (m, 3H, H-2′′/6′′, H-4′′), 7.07 (d, 2H, J=15.2 Hz, H-2/3), 4.42 (d, 2H, J=5.9 Hz, H-7′′); 13C NMR (DMSO-d6, 100 MHz) δ 164.0 (C-1), 163.1 (C-4), 139.3 (C-1′′), 134.9 (C-2), 134.8 (C-3), 133.1 (C-4′), 130.1 (C-3′), 128.9 (C-3′′/5′′), 127.9 (C-4′′), 127.8 (C-2′′/6′′), 127.4 (C-5′), 126.9 (C-6′), 42.9 (C-7′′); EIMS (m/z): 314 [M+], 281, 207, 187, 138, 106; HRMS (m/z): 314.0820 (calculated for C17H15ClN2O2, 314.0820).
(2E)-N-Benzyl-
N
′
-(3-chlorophenyl)but-2-enediamide (3e).
Pink powder (30% yield); mp 272–274°C; UV λmax (CH3OH) nm (log ε) 290 (4.66), 240 (4.60); IR (KBr) υmax (cm−1) 3265 (NH), 3066, 1633 (C=O), 1592, 1541, 1482; 1H NMR (DMSO-d6, 400 MHz) δ 10.63 (s, 1H, NH-5), 9.03 (bt, 1H, J=5.9 Hz, NH-6), 7.92 (s, 1H, H-2′), 7.51 (d, 1H, J=8.5 Hz, H-4′), 7.36–7.38 (m, 1H, H-5), 7.32–7.34 (m, 2H, H-3′′/5′′), 7.25–7.29 (m, 3H, H-2′′/6′′, H-4′′), 7.17 (d, 1H, J=8.5 Hz, H-6′), 7.06 (s, 2H, H-2/3), 4.41 (d, 2H, J=5.9 Hz, H-7′′); 13C NMR (DMSO-d6, 100 MHz) δ 163.4 (C-1), 162.5 (C-4), 140.2 (C-1′), 138.8 (C-1′′), 134.2 (C-2), 133.1 (C-3), 132.7 (C-3′), 130.5 (C-5′), 128.4 (C-3′′/5′′), 127.3 (C-2′′/6′′), 126.9 (C-4′′), 123.5 (C-6′), 118.8 (C-2′), 117.8 (C-4′), 42.4 (C-7′′). EIMS (m/z) 314 [M+], 281, 207, 180, 153, 138, 117, 106, 91; HRMS (m/z): 314.0826 (calculated for C17H15ClN2O2, 314.0820).
(2E)-N-Benzyl-
N
′
-(3-nitrophenyl)but-2-enediamide (3f).
Cream powder (29% yield); mp 259–261°C; UV λmax (CH3OH) nm (log ε) 275 (5.21); IR (KBr) υmax (cm−1) 3271 (NH), 3038, 1643 (C=O), 1621, 1529; 1H NMR (DMSO-d6, 400 MHz) δ 10.95 (s, 1H, NH-5), 9.07 (bt, 1H, J=5.3 Hz, NH-6), 8.74 (s, 1H, H-2′), 7.97 (d, 2H, J=7.8 Hz, H-4′/6′), 7.67 (t, 1H, J=7.8 Hz, H-5′), 7.33–7.35 (m, 2H, H-3′′/5′′), 7.26–7.29 (m, 3H, H-2′′/6′′, H-4′′), 7.10 (s, 2H, H-2/3), 4.43 (d, 2H, J=5.3 Hz, H-7′′); 13C NMR (DMSO-d6, 100 MHz) δ 163.8 (C-1), 163.4 (C-4), 148.5 (C-3′), 140.4 (C-1′), 139.3 (C-1′′), 135.0 (C-2), 133.0 (C-3), 130.8 (C-5′), 128.9 (C-3′′/5′′), 127.9 (C-2′′/6′′), 127.5 (C-4′′), 125.8 (C-6′), 118.9 (C-4′), 113.9 (C-2′), 42.9 (C-7′′). EIMS (m/z): 325 [M+], 280, 234, 191, 164, 149, 117, 91; HRMS (m/z): 325.1057 (calculated for C18H18N2O3, 325.1060).
(2E)-N-Benzyl-
N
′
-(4-nitrophenyl)but-2-enediamide (3g).
Pale brown powder (12% yield); mp 274–276°C; UV λmax (CH3OH) nm (log ε) 325 (4.90); IR (KBr) υmax (cm−1) 3267 (NH), 3062, 1626 (C=O), 1534, 1492; 1H NMR (DMSO-d6, 400 MHz) δ 11.05 (s, 1H, NH-5), 9.07 (bt, 1H, J=5.9 Hz, NH-6), 8.26 (d, 2H, J=9.1 Hz, H-3′′/5′′), 7.92 (d, 2H, J=9.1 Hz, H-2′′/6′′), 7.29–7.35 (m, 2H, H-3′′/5′′), 7.25–7.27 (m, 3H, H-2′′/6′′, H-4′′), 7.11 (s, 2H, H-2,3), 4.42 (d, 2H, J=5.9 Hz, H-7′′); 13C NMR (DMSO-d6, 100 MHz) δ 163.6 (C-1), 163.3 (C-4), 145.2 (C-1′), 142.9 (C-4′), 139.0 (C-1′′), 135.2 (C-2), 132.7 (C-3), 128.6 (C-3′′/5′′), 127.7 (C-2′′/6′′), 127.3 (C-4′′), 125.3 (C-3′/5′), 119.5 (C-2′/6′), 42.8 (C-7′′); EIMS (m/z): 325, 281, 249, 207, 187, 167, 149, 106; HRMS (m/z): 325.1059 (calculated for C17H15N3O4, 325.1060).
(2E)-N-Benzyl-
N
′
-(pyridin-3-yl)but-2-enediamide (3h).
Brown powder (27% yield); mp 198–200°C; UV λmax (CH3OH) nm (log ε) 270 (4.64), 240 (4.75); IR (KBr) υmax (cm−1) 3268 (NH), 3061, 1625 (C=O), 1532 (NH), 1493; 1H NMR (DMSO-d6, 600 MHz) δ 10.69 (s, 1H, NH-5), 9.04 (bt, 1H, J=5.6 Hz, NH-6), 8.81 (s, 1H, H-2′), 8.31 (d, 1H, J=8.2 Hz, H-6′), 8.14 (d, 1H, J=8.2 Hz, H-4′), 7.38-7.39 (m, H-5′), 7.34–7.36 (m, 2H, H-3′′/5′′), 7.26–7.30 (m, 3H, H-2′′/6′′, H-4′′), 7.10 (d, 1H, J=15.1 Hz, H-3), 7.07 (d, 1H, J=15.1 Hz, H-2), 4.42 (d, 2H, J=5.6 Hz, H-7′′); 13C NMR (DMSO-d6, 150 MHz) δ 163.9 (C-1), 163.2 (C-4), 145.2 (C-6′), 141.4 (C-2′), 139.3 (C-3′), 136.0 (C-1′′), 134.7 (C-2), 133.0 (C-3), 128.9 (C-3′′/5′′), 127.8 (C-2′′/6′′), 127.5 (C-4′′), 126.8 (C-4′), 124.2 (C-5′), 42.9 (C-7′′). EIMS (m/z) 281 [M+], 207, 187, 147, 119, 106, 91; a high resolution mass could not be detected for this compound despite several attempts.
(2E)-N-Benzyl-
N
′
-(3-fluorobenzyl)but-2-enediamide (3j).
White powder (45% yield); mp 298–300°C; UV λmax (CH3OH) nm (log ε) 250 (4.08); IR (KBr) υmax (cm−1) 3275 (NH), 3085, 1626 (C=O), 1591, 1555; 1H NMR (DMSO-d6, 400 MHz) δ 8.94 (t, 1H, J=5.9 Hz, NH-5), 8.93 (t, 1H, J=5.9 Hz, NH-6), 7.30–7.36 (m, 3H, H-5′, H-3′′/5′′), 7.25–7.27 (m, 3H, H-2′′/6′′, H-4′′), 7.05–7.11 (m, 3H, H-2′,4′,6′), 6.93 (s, 2H, H-2/3), 4.39 (d, 2H, J=5.9 Hz, H-7′), 4.37 (d, 2H, J=5.9 Hz, H-7′′); 13C NMR (DMSO-d6, 100 MHz) δ 163.8 (C-4), 163.6 (C-1), 162.2 (d, JCF=242.0 Hz, C-3′), 141.9 (d, JCF=7.2 Hz, C-1′), 138.9 (C-1′′), 132.9 (C-2), 132.6 (C-3), 130.3 (d, JCF=8.4 Hz, C-5′), 128.3 (C-3′′/5′′), 127.3 (C-2′′/6′′), 126.9 (C-4′′), 123.2 (d, JCF=2.7 Hz, C-6′), 113.9 (d, JCF=21.3 Hz, C-2′), 113.6 (d, JCF=20.9 Hz, C-4′), 42.3 (C-7′), 41.8 (C-7′′); 19F-NMR (DMSO-d6, 376.5 MHz) δ −113.46, HRMS (m/z): 312.1270 (calculated for C18H17N2O2F, 312.1272).
(2E)-N-Benzyl-
N
′
-(4-fluorobenzyl)but-2-enediamide (3k).
Pink powder (50% yield); mp 299–301°C; UV λmax (CH3OH) nm (log ε) 250 (4.50); IR (KBr) υmax (cm−1) 3275 (NH), 3084, 1624 (C=O), 1539, 1487; 1H NMR (DMSO-d6, 400 MHz) δ 8.97 (bs, 1H, NH-5), 8.93 (bs, 1H, NH-6), 7.36–7.38 (m, 2H, H-3′′/5′′), 7.31-7.32 (m, 2H, H-2′/6′), 7.26-7.27 (m, 3H, H-2′′/6′′, H-4′′), 7.09–7.11 (m, 2H, H-3′/5′), 6.93 (s, 2H, H-2/3), 4.38 (bs, 4H, H-7′/7′′); 13C NMR (DMSO-d6, 100 MHz) δ 164.2 (C-1), 164.1 (C-4), 161.6 (d, JCF=252.5 Hz, C-4′), 139.4 (C-1′), 135.7 (C-1′′), 133.3 (C-2), 133.2 (C-3), 129.8 (d, JCF=8.0 Hz, C-2′/6′), 128.8 (C-3′′/5′′), 127.8 (C-2′′/6′′), 127.4 (C-4′′), 115.6 (d, JCF=20.9 Hz, C-3′/5′), 42.8 (C-7′), 42.1 (C-7′′); 19F-NMR (DMSO-d6, 376.5 MHz) δ −116.0, HRMS (m/z): 312.1271 (calculated for C18H17FN2O2, 312.1272).