3.2. General Experimental Procedure for the Synthesis of Michael Type Addition Products 2
In a round-button flask and under argon, the corresponding iminoester 1 (0.5 mmol) in toluene (1.5 mL), and the catalyst dimethylphenylphosphine (0.05 mmol) were added. Then a solution of electrophilic alkene (1 mmol) in toluene (1 mL) was added dropwise during 30 minutes using an addition pump, then, the mixture was stirred at room temperature for 24 hours. Solvent was removed under reduced pressure, to afford the corresponding final product 2.
Dimethyl (E)-2-(benzylideneamino)pentanedioate (2a): Pale yellow oil (118.2 mg, 96%, 92% purity). IR (neat) νmax: 1735, 1643, 1438, 1253, 1199, 1164, 755, 694 cm-1. 1H NMR (400 MHz) δ 8.29 (s, 1H, HC=N), 7.82 – 7.72 (m, 2H, ArH), 7.48 – 7.37 (m, 3H, ArH), 4.07 (dd, J = 8.1, 5.0 Hz, 1H, NCHCO2Me), 3.74 (s, 3H, CO2CH3), 3.65 (s, 3H, CO2CH3), 2.43 – 2.38 (m, 2H, CH2), 2.36 – 2.23 (m, 2H, CH2). 13C NMR (101 MHz) δ 173.3, 171.9 (C=O), 164.3 (C=N), 135.5(CAr), 131.3(CHAr), 128.6 (4x CHAr), 71.8 (CH), 52.2, 51.6 (CH3), 30.2, 28.3 (CH2). MS (EI) m/z: 263 (M+, 11%), 204 (74), 203 (38), 190 (43), 144 (100), 130 (29), 117 (31), 104 (39), 90 (21). HRMS (ESI): m/z calcd for C14H17NO4 [M+] 263.1158; found: 263.1159.
5-Butyl 1-methyl (E)-2-(benzylideneamino)pentanedioate (2b): Pale yellow oil (146 mg, 96%, 91% purity). IR (neat) vmax: 1731, 1643, 1438, 1390, 1168, 1068, 732, 694 cm-1. 1H NMR (400 MHz) δ 8.26 (s, 1H, HC=N), 7.90 – 7.66 (m, 2H, ArH), 7.51 – 7.21 (m, 3H, ArH), 4.37 – 3.92 (m, 3H, NCHCO2Me, CO2CH2CH2CH2CH3 ), 3.86 – 3.55 (m, 3H, CO2CH3), 2.34 (d, J = 2.0 Hz, 2H, NCHCH2CH2), 2.33 – 1.88 (m, 2H, NCHCH2CH2), 1.70 – 1.41 (m, 2H, CO2CH2CH2CH2CH3), 1.41 – 1.19 (m, 2H, CO2CH2CH2CH2CH3), 1.07 – 0.68 (m, 3H, CO2CH2CH2CH2CH3). 13C NMR (101 MHz) δ 172.88 (C=O), 171.90 (C=O), 164.25 (C=N), 135.53 (CAr), 131.26 (CHAr), 128.59 (CHAr x4), 71.81 (CH), 64.34 (CH2), 52.19 (CH3), 30.61 (CH2), 30.41 (CH2), 28.33 (CH2), 19.09 (CH2), 13.66 (CH3). MS (EI) m/z: 305 (M+, 17%), 246 (66), 232 (38), 190 (81), 144 (100). HRMS (ESI): m/z calcd for C17H23NO4 [M+] 305.1627; found: 305.1622.
Dimethyl (E)-2-((4-methylbenzylidene)amino)pentanedioate (2c): Pale yellow oil (119.4 mg, 86%, 95% purity). IR (neat) νmax: 1735, 1643, 1438, 1253, 1199, 1168, 813 cm-1. 1H NMR (300 MHz) δ 8.25 (s, 1H, HC=N), 7.66 (d, J = 8.1 Hz, 2H, ArH), 7.22 (d, J = 7.7 Hz, 2H, ArH), 4.04 (dd, J = 8.0, 4.9 Hz, 1H, NCHCO2Me), 3.74 (s, 3H, CO2CH3), 3.64 (s, 3H, CO2CH3), 2.39 (s, 3H, CH3Ar), 2.38 – 2.22 (m, 4H, CH2-CH2). 13C NMR (101 MHz) δ 173.5 (C=O), 172.3 (C=O), 164.2 (C=N), 141.7 (CAr), 132.9 (CH3CAr), 129.3 (CHAr), 128.6 (CHAr), 71.8 (CH), 52.2, 51.6 (CH3), 30.1, 28.3 (CH2), 21.5 (CH3CAr). MS (EI) m/z: 277 (M+, 17%), 218 (64), 217 (32) 204 (48), 158 (100), 144 (34), 131 (28), 130 (24), 118 (40). HRMS (ESI): m/z calcd for C15H19NO4 [M+] 277.1314; found: 277.1322.
Dimethyl (E)-2-[(naphth-2-ylmethylene)amino)]pentanedioate (2d): Pale yellow prisms (147.2 mg, 90%, 92% purity). mp: 78-79 ºC (n-hexane:AcOEt). IR (neat) νmax: 1727, 1639, 1434, 1176, 1095, 829, 752 cm-1. 1H NMR (300 MHz) δ 8.46 (s, 1H,HC=N), 8.10 (s, 1H, ArH), 8 .03 (dd, J = 8.6, 1.4 Hz, 1H, ArH), 7.94 – 7.81 (m, 3H, ArH), 7.59 – 7.47 (m, 2H, ArH), 4.15 (dd, J = 7.7, 5.0 Hz, 1H, NCHCO2Me), 3.78 (s, 3H,CO2CH3), 3.66 (s, 3H, CO2CH3), 2.49 – 2.42 (m, 2H, CH2), 2.41 – 2.28 (m, 2H,CH2). 13C NMR (101 MHz) δ 173.3 (C=O), 171.9 (C=O), 164.3 (C=N), 134.9 (C=CCH=N), 133.2, 133.0 (PhC), 130.7, 128.7, 128.5, 127.9, 127.6, 126.6, 124.0 (PhCH), 71.8 (NCH), 52.2, 51.6 (CH3), 30.2, 28.4 (CO2CH3). MS (EI) m/z: 313 (M+, 31%), 254 (100), 240 (61), 222 (28), 194 (99), 180 (69), 167 (66), 154 (57), 140 (30), 139 (51), 127 (24). HRMS (ESI): m/z calcd for C18H19NO4 [M+] 313.1314; found: 313.1331.
Dimethyl (E)-2-[(4-methoxybenzylidene)amino]pentanedioate (2e): yellow oil (141.9 mg, 87%, 92% purity). IR (neat) νmax: 1735, 1249, 1164, 1025, 833 cm-1. 1H NMR (400 MHz) δ 8.21 (s, 1H, HC=N), 7.75 – 7.69 (m, 2H, ArH), 6.95 – 6.90 (m, 2H, ArH), 4.02 (dd, J = 8.1, 5.0 Hz, 1H, NCHCO2Me), 3.84 (s, 3H,CO2CH3), 3.74 (s, 3H,CO2CH3), 3.64 (s, 3H, CH3OAr), 2.45 – 2.15 (m, 4H, CH2-CH2). 13C NMR (75 MHz) δ 173.34 (C=O), 172.13 (C=O), 163.54 (C=N), 162.15 (OCH3CAr), 130.26 (2xCHAr), 128.52 (CAr), 114.00 (2xCHAr), 71.75(CH), 55.38 (OCH3CAr), 52.19, 51.58 (CO2CH3), 30.22, 28.39 (CH2). MS (EI) m/z: 293 (M+, 25%), 262 (21), 234 (69), 233 (41), 220 (62), 174 (100), 160 (29), 147 (23), 134 (40). HRMS (ESI): m/z calcd for C15H19NO4 [M+] 293.1263; found: 293.1262.
5-(Tert-butyl) 1-methyl (E)-2-[(2-bromobenzylidene)amino]pentanedioate (2f): Pale yellow oil (196.6 mg, 88%, 91% purity). IR (neat) νmax: 1727, 1149, 752, 686 cm-1. 1H NMR (300 MHz) δ 8.65 (s, 1H, HC=N), 8.08 (dd, J = 7.6, 2.0 Hz, 1H, ArH), 7.60 – 7.55 (m, 1H, ArH), 7.38 – 7.28 (m, 2H, ArH), 4.19 – 4.08 (m, 1H, NCHCO2Me), 3.76 (s, 3H, CH3), 2.37 – 2.22 (m, 4H, CH2-CH2), 1.44 (s, 9H, (CH3)3). 13C NMR (101 MHz) δ 172.02 (C=O2tBu), 171.85 (CO2Me), 163.16 (CH=N), 134.01 (CAr), 133.03 (CHAr), 132.37 (CHAr), 129.27 (CHAr), 127.63(CHAr), 125.36 (BrCAr), 80.54 (C(CH3)3), 71.83(NCHCO2Me), 52.29 (CH3), 31.49 (CH2), 28.45 (CH2), 28.11 (C(CH3)3). MS (EI) m/z: 384 (M+, 1%), 329 (47), 327 (48), 312 (38), 310 (38), 276 (93), 269 (44), 268 (100), 224 (41), 222 (37), 184 (41), 89 (50), 57 (66). HRMS (ESI): m/z calc for C17H22BrNO4 [M+] 383.073; found: 385.0694.
5-(Tert-butyl) 1-methyl (E)-2-[(3-bromobenzylidene)amino]pentanedioate (2g): Pale yellow oil (215.3 mg, 93%, 92% purity). IR (neat) νmax: 1727, 1369, 1149, 752, 682 cm-1. 1H NMR (400 MHz) δ 8.22 (s, 1H, HC=N), 7.98 (t, J = 1.8 Hz, 1H, ArH), 7.66 – 7.62 (m, 1H, ArH), 7.58 – 7.54 (m, 1H, ArH), 7.28 (t, J = 7.8 Hz, 1H, ArH), 4.09 – 4.04 (m, 1H, NCHCO2Me), 3.74 (s, 3H, CO2CH3), 2.30 – 2.15 (m, 4H, CH2-CH2), 1.43 (s, 9H, CO2(CH3)3). 13C NMR (101 MHz) δ 172.0 (C=O), 171.8 (C=O), 162.5 (CH=N), 137.4 (CAr), 134.1 (CHAr), 131.0 (CHAr), 130.1 (CHAr), 127.5 (CHAr), 122.9 (BrCAr), 80.5 (C(CH3)3), 71.7 (NCHCO2Me), 52.3 (CO2CH3), 31.5 (CH2), 28.4 (CH2), 28.1 [(CH3)3]. MS (EI) m/z: 384 (M+, 7%), 329 (43), 327 (45), 310 (38, 268 (100), 224 (43), 222 (40), 184 (42), 116 (36), 89 (50), 57 (93). HRMS (ESI): m/z calc for C17H22BrNO4 [M+] 383.073; found: 383.0737.
Dimethyl (E)-2-[(4-bromobenzylidene)amino]pentanedioate (2h): Pale yellow oil (151.3 mg, 88%, 93% purity). IR (neat) νmax: 1731, 2116, 1068, 1010, 821, 732 cm-1. 1H NMR (300 MHz) δ 8.24 (s, 1H, HC=N), 7.68 – 7.61 (m, 2H, ArH), 7.59 – 7.52 (m, 2H, ArH), 4.15 – 3.98 (m, 1H, NCHCO2Me), 3.75 (s, 3H, CO2CH3 ), 3.65 (s, 3H, CO2CH3), 2.47 – 2.14 (m, 4H, CH2-CH2). 13C NMR (101 MHz) δ 173.24 (C=O), 171.69 (C=O), 163.07 (C=N), 134.39 (BrCAr), 131.9, 129.9 (CHAr), 125.8 (CAr), 71.6 (CH), 52.3, 51.6 (CH3), 30.1, 28.2 (CH2). MS (EI) m/z: 342 (M+, 4%), 282 (87), 268 (55), 222 (100), 184 (54), 143 (42), 116 (40), 89 (88). HRMS (ESI): m/z calcd for C14H16BrNO4 [M+] 341.0263; found: 341.0265.
5-(Tert-butyl) 1-methyl (E)-2-[(4-bromobenzylidene)amino]pentanedioate (2i): Pale yellow oil (139.1 mg, 93%, 93% purity). IR (neat) νmax: 1727, 1369, 1149, 825 cm-1. 1H NMR (300 MHz) δ 8.23 (s, 1H, HC=N), 7.65 (d, J = 8.5 Hz, 2H, ArH), 7.56 (d, J = 8.5 Hz, 2H, ArH), 4.10 – 4.02 (m, 1H, NCHCO2Me), 3.75 (s, 3H, CO2CH3), 2.34 – 2.15 (m, 4H, CH2-CH2), 1.43 (s, 9H, C(CH3)3). 13C NMR (101 MHz) δ 172.2 (C=O), 172.0 (C=O), 163.0 (C=N), 134.5 (BrCAr), 132.0 (CHAr), 130.1 (CHAr), 125.9 (CAr), 80.6 [C(CH3)3], 71.9 (CH), 52.4 (CO2CH3), 31.7 (CH2), 28.6 (CH2), 28.2 [CO2C(CH3)3]. MS (EI) m/z: 383(M+, 3%), 327 (49), 312 (42), 268 (100), 224 (48), 184 (40), 89 (63), 57(92). HRMS (ESI): m/z calc for C17H22BrNO4 [M+] 383.0730; found: 383.0720.
Dimethyl (E)-2-[(pyridin-3-ylmethylene)amino]pentanedioate (2j): Pale yellow oil (214.7 mg, 93%, 90% purity). IR (neat) νmax: 1731, 1434, 1172, 806, 709 cm-1. 1H NMR (300 MHz) δ 8.86 (dd, J = 2.1, 0.7 Hz, 1H, ArH), 8.65 (dd, J = 4.8, 1.7 Hz, 1H, ArH), 8.32 (s, 1H, HC=N), 8.15 (dt, J = 7.9, 1.9 Hz, 1H, ArH), 7.34 (dd, J = 7.9, 4.8 Hz, 1H, ArH), 4.10 (dd, J = 7.7, 5.0 Hz, 1H, NHCO2Me), 3.73 (s, 3H, CH3), 3.63 (s, 3H, CH3), 2.42 – 2.19 (m, 4H, CH2-CH2). 13C NMR (101 MHz) δ 173.2 (C=O), 171.5 (C=O), 161.6 (C=N), 152.1 (CHAr), 150.6 (CHAr), 134.9 (CHAr), 131.1 (CAr), 123.6 (CHAr), 71.7 (CH), 52.3 (CH3), 51.7 (CH3), 30.1 (CH2), 28.2 (CH2). MS (EI) m/z: 264 (M+, 7%), 205 (74), 204 (43), 191 (26), 145 (100), 118 (27), 105 (38). HRMS (ESI): m/z calcd for C13H16N2O4 [M+] 264.111; found: 264.1108.
5-(Tert-butyl) 1-methyl (E)-2-[(pyridin-3-ylmethylene)amino]pentanedioate (2k): Pale yellow oil (241.7 mg, 83 %, 89% purity). IR (neat) νmax: 1727, 1369, 1253, 1153, 802, 709 cm-1. 1H NMR (300 MHz) δ 8.88 – 8.86 (m, 1H, ArH), 8.66 (dd, J = 4.8, 1.7 Hz, 1H, ArH), 8.32 (s, 1H, HC=N), 8.16 (dt, J = 7.9, 1.9 Hz, 1H, ArH), 7.34 (dd, J = 7.7, 4.8 Hz, 1H, ArH), 4.13 – 4. 06 (m, 1H, NHCO2Me), 3.74 (s, 3H, CH3), 2.38 – 2.10 (m, 4H, CH2-CH2), 1.42 (s, 9H, [(CH3)3]. 13C NMR (75 MHz) δ 171.9 (C=O), 171.67(C=O), 161.3 (C=N), 152.0 (CHAr), 150.6 (CHAr), 134.9 (CHAr), 131.1 (CAr), 123.6 (CHAr), 80.5 [C(CH3)3], 71.8 (CH), 52.2 (CO2CH3), 31.4 (CH2), 28.3 (CH2), 28.0 [C(CH3)3]. MS (EI) m/z: 306 (M+, 1%), 250 (69), 233 (38), 191 (100), 145 (54), 118 (28), 105 (22), 57 (33). HRMS (ESI): m/z calcd for C16H22N2O4 [M+] 306.158; found: 306.1579.
5-(Tert-butyl) 1-methyl (E)-2-[(thien-2-ylmethylene)amino]pentanedioate (2l): Pale yellow oil (147.2 mg, 90%, 91% purity). IR (neat) νmax: 1727, 1627, 1249, 1211, 1153, 713 cm-1. 1H NMR (400 MHz) δ 8.39 (s, 1H, HC=N), 7.46 (d, J = 5.0 Hz, 1H, Thienyl-H), 7.38 (dd, J = 3.6, 1.0 Hz, 1H, Thienyl-H), 7.10 (dd, J = 4.9, 3.7 Hz, 1H, Thienyl-H), 4.04 (dd, J = 8.5, 4.1 Hz, 1H, NCHCO2Me), 3.75 (s, 3H, CO2CH3), 2.43 – 2.16 (m, 4H, CH2-CH2), 1.45 [s, 9H, C(CH3)3]. 13C NMR (101 MHz) δ 172.1, 171.9 (C=O), 157.1 (C=N), 141.6 (SCC=N), 131.6, 129.8, 127.4 (ArC), 80.4 [C(CH3)3], 71.4 (NCH), 52.2 (CH3), 31.6, 28.3 (CH2), 28.1 [C(CH3)3]. MS (EI) m/z: 311 (M+, 6%), 255 (93), 238 (64), 195 (100), 194 (95), 150 (71), 123 (35), 112 (44), 110 (29), 96 (44), 57 (51), 43 (36), 41 (23). HRMS (ESI): m/z calcd for C15H21NO4S[M+] 311.1196; found: 311.119.
5-Butyl 1-methyl (E)-2-(benzylideneamino)-2-methylpentanedioate (2m): Pale yellow oil (152 mg, 95%, 86% purity). IR (neat) vmax: 1729, 1643, 1452, 1378, 1174, 1114, 730, 694 cm-1. 1H NMR (400 MHz) δ 8.24 (s, 1H, HC=N), 7.76 – 7.71 (m, 2H, ArH), 7.40 – 7.36 (m, 3H ArH), 4.02 (m, J = 6.7, 0.8 Hz, 2H, CO2CH2CH2CH2CH3), 3.71 (s, 3H, CO2CH3), 2.45 (m, J = 9.6, 7.9, 5.7 Hz, 2H, NCH3CH2CH2), 2.33 (m, J = 13.7, 10.1, 5.6 Hz, 1H, NCH3CH2CH2), 2.19 – 2.10 (m, 1H, NCH3CH2CH2), 1.55 (m, J = 8.2, 7.0, 6.0 Hz, 2H, CO2CH2CH2CH2CH3), 1.49 (s, 3H, NCCH3), 1.39 – 1.26 (m, 2H, CO2CH2CH2CH2CH3), 0.89 (t, J = 7.4 Hz, 3H, CO2CH2CH2CH2CH3). 13C NMR (101 MHz) δ 174.14 (C=O), 173.53 (C=O), 159.81 (C=N), 136.27 (CAr), 130.97 (CHAr), 128.53 (CHAr x2), 128.35 (CHAr x2), 67.52 (CH), 64.32 (CH2), 52.21 (CH3), 35.06 (CH2), 30.64 (CH2), 29.64 (CH2), 23.40 (CH3), 19.11 (CH2), 13.69(CH3). MS (EI) m/z: 319 (M+, >1%), 260 (100), 158 (38). HRMS (ESI): m/z calcd for C17H22NO4 [M+ - CH3] 304.1549; found: 304.1545.
Dimethyl (E)-2-[(4-bromobenzylidene)amino]-2-methylpentanedioate (2n): Pale yellow oil (110.2 mg, 90%, 90% purity). IR (neat) νmax: 1731, 1438, 1245, 1172, 1114, 821 cm-1. 1H NMR (300 MHz) δ 8.22 (s, 1H, HC=N), 7.65 – 7.59 (m, 2H, ArH), 7.57 – 7.51 (m, 2H, ArH), 3.74 (s, 3H, CH3), 3.64 (s, 3H, CH3), 2.58 – 2.26 (m, 4H, CH2-CH2), 1.50 (s, 3H, CH3). 13C NMR (101 MHz) δ 173.9 (C=O), 173.8 (C=O), 158.7 (C=N), 135.1 (CAr), 131.8 (2xCHAr), 129.78 (2xCHAr), 125.4 (BrCAr), 67.5 (NCCO2Me), 52.3 (CH3), 51.6 (CH3), 35.0 (CH2), 29.4 (CH2), 23.3 (CH3CN). MS (EI) m/z: 356 (M+, <1%), 298 (97), 296 (100), 236 (27), 184 (19), 89 (32). HRMS (ESI): m/z calc for C13H15BrNO2 [M+-CO2CH3] 296.0286; found: 296.0286.
5-Butyl 1-methyl (E)-2-[(4-bromobenzylidene)amino]-2-methylpentanedioate (2o): Pale yellow oil (191 mg, 96%, 91% purity). IR (neat) Vmax: 1729, 1643, 1438, 1170, 1114, 1066, 821, 744 cm-1. 1H NMR (400 MHz) δ 8.18 (s, 1H, NH), 7.58 (ddd, J = 8.4, 5.8, 2.7 Hz, 2H, ArH), 7.49 (dt, J = 12.4, 4.7 Hz, 2H, ArH), 4.00 (td, J = 6.7, 2.9 Hz, 2H, CO2CH2CH2CH2CH3), 3.68 (s, 3H CH3), 2.41 (dqt, J = 9.1, 6.5, 3.2 Hz, 2H, CH2CO2nBu), 2.36 – 2.23 (m, 1H, NCCH2), 2.12 (dddd, J = 12.0, 8.3, 6.0, 2.3 Hz, 1H, NCCH2), 1.53 (dt, J = 12.7, 6.8 Hz, 2H, CO2CH2CH2CH2CH3), 1.45 (s, 3H, CH3), 1.39 – 1.24 (m, 2H, CO2CH2CH2CH2CH3), 0.87 (tt, J = 6.2, 3.2 Hz, 3H, CH3).13C NMR (101 MHz) δ 173.86 (C=O), 173.38 (C=O), 158.61 (HC=N), 135.16 (CAr), 131.73 (CHAr x2), 129.76 (CHAr x2), 125.37 (CAr), 67.60 (C), 64.32 (CH2), 52.24 (CH3), 35.01 (CH2), 30.62 (CH2), 29.62 (CH2), 23.36 (CH3), 19.10 (CH2), 13.68 (CH3). ). MS (EI) m/z: 398 (M+, >1%), 338 (100), 238 (31). HRMS (ESI): m/z calcd for C17H21BrNO4 [M+ - CH3] 382.0654; found: 382.0647.
5-(Tert-butyl) 1-methyl (E)-2-[(4-bromobenzylidene)amino]-2-methylpentanedioate (2p): Pale yellow oil (104.5 mg, 77%, 88% purity). IR (neat) νmax: 2981, 1727, 1643, 1589, 1249, 1153, 1114, 821 cm-1. 1H NMR (400 MHz) δ 8.20 (s, 1H, HC=N), 7.64 – 7.59 (m, 2H, ArH), 7.55 – 7.50 (m, 2H, ArH), 3.72 (s, 3H, CH3), 2.45 – 2.34 (m, 2H, CH2), 2.32 – 2.22 (m, 2H, CH2), 1.48 (s, 3H CH3), 1.42 [s, 9H, C(CH3)3]. 13C NMR (75 MHz) δ 174.0 (C=O), 172.6 (C=O), 158.5 (C=N), 135.2 (CAr), 131.7 (2xCHAr), 129.8 (2xCHAr), 125.3 (BrCAr), 80.3 (C(CH3)3), 67.6 (NCCO2Me), 52.2 (CO2CH3), 34.9 (CH2), 30.7 (CH2), 28.0 [C(CH3)3], 23.3 (CH3). MS (EI) m/z: 398 (M+, <1 %), 284 (97), 282 (100), 268 (100), 238 (20), 236 (20), 184 (20), 160 (48), 89 (35), 57 (31), 43(24). HRMS (ESI): m/z calc for C12H13BrNO2 [M+-C6H11O2] 284.0102; found: 284.0102.
Dimethyl (E)-2-benzyl-2-[(4-bromobenzylidene)amino]pentanedioate (2q): Pale yellow oil (201.2 mg, 90%, 90% purity). IR (neat) νmax: 1731, 1438, 1172, 1083, 821, 740, 701 cm-1. 1H NMR (300 MHz) δ 7.97 (s, 1H, HC=N), 7.60 – 7.51 (m, 4H, ArH), 7.24 – 7.14 (m, 5H, ArH), 3.74 (s, 3H, CH3), 3.62 (s, 3H, CH3), 3.35 – 3.10 (m, 2H, CH2Ar), 2.45 – 2.23 (m, 4H, CH2-CH2). 13C NMR (75 MHz) δ 173.7 (C=O), 172.8 (C=O), 160.5 (C=N), 135.8 (CAr), 135.1 (CArCH2), 131.8 (2xCHAr), 130.6 (2xCHAr), 129.7 (2xCHAr), 128.1 (2xCHAr), 126.9 (CHAr), 125.4 (BrCAr), 71.6 (NCCO2Me), 52.0 (CH3), 51.6 (CH3), 44.3 (PhCH2), 32.9 (CH2), 29.5 (CH2). MS (EI) m/z: 432 (M+, <1 %), 372 (18), 342 (98), 340 (100), 254 (25), 91 (45). HRMS (ESI): m/z calc for C19H19BrNO2 [M+- CO2CH3] 372.0599; found: 372.0605.
Methyl (E)-2-[(4-bromobenzylidene)amino]-5-(dimethylamino)-5-oxopentanoate (2u): Pale yellow oil (153.1 mg 90%, 86% purity). IR (neat) νmax: 1735, 1639, 1203, 1168, 1064, 821 cm-1. 1H NMR (300 MHz) δ 8.24 (s, 1H, HC=N), 7.65 – 7.59 (m, 2H, ArH), 7.55 – 7.49 (m, 2H, ArH), 4.19 – 4.13 (m, 1H, NCHCO2Me), 3.71 (s, 3H, CO2CH3), 2.93 (s, 3H, NCH3), 2.89 (s, 3H, NCH3), 2.40 – 2.29 (m, 4H, CH2-CH2). 13C NMR (101 MHz) δ 172.1 (C=O), 171.9 (C=O), 162.9 (CH=N), 134.5 (CAr), 131.8 (CHAr), 129.9 (CHAr), 125.6 (BrCAr), 71.6 (NCHCO2Me), 52.2 (CO2CH3), 37.1 (NCH3), 35.9 (NCH3), 28.9 (CH2), 28.7 (CH2). MS (EI) m/z: 354 (M+, 5 %), 270 (30), 268 (32), 224 (35), 222 (31), 173 (24), 100 (26), 89 (31), 87 (100), 72 (35), 45 (25). HRMS (ESI): m/z calc for C15H19BrN2O3 [M+] 354.0579; found: 354.0565.
Methyl (E)-2-[(4-bromobenzylidene)amino]-4-cyano-2-(2-cyanoethyl)butanoate (6v): Pale yellow oil (117.0 mg, 90%, 84% purity). IR (neat) νmax: 1727, 1369, 1149, 825 cm-1. 1H NMR (300 MHz) δ 8.24 (s, 1H, HC=N), 7.65 – 7.59 (m, 2H, ArH), 7.55 – 7.49 (m, 2H, ArH), 4.19 – 4.13 (m, 1H, NCHCO2Me), 3.71 (s, 3H, CO2CH3), 2.93 (s, 3H, NCH3), 2.89 (s, 3H, NCH3), 2.40 – 2.29 (m, 4H, CH2-CH2). 13C NMR (101 MHz) δ 172.1 (C=O), 171.9 (C=O), 162.9 (CH=N), 134.5 (CAr), 131.8 (CHAr), 129.9 (CHAr), 125.7 (BrCAr), 71.6 (NCHCO2Me), 52.2 (CO2CH3), 37.1 (NCH3), 35.3 (NCH3), 28.9 (CH2), 28.7 (CH2). MS (EI) m/z: 354 (M+, 5 %), 270 (30), 268 (32), 224 (35), 222 (31), 173 (24), 100 (26), 89 (31), 87 (100), 72 (35), 45 (25). HRMS (ESI): m/z calc for C15H19BrN2O3 [M+] 354.0579; found: 354.0565.
3.3. General Procedure for the Synthesis of Pyroglutamate Derivatives
To a solution of NaBH4 (0.8 mmol, 2 eq) in Methanol (4 mL) at 0°C a solution of corresponding adduct 2 in Methanol (2mL) was added and the reaction was refluxed at 80 °C for 2 hours. After that, the solvent was removed and the crude was redissolved in AcEOt (4 mL) followed by the addition of SiO2 and refluxed again for 24 hours. Then, the mixture was filtered and removed the solvent under vacuum. Finally, the crude was purified by flash column chromatography on silica gel (Hexane/AcEOt, 3:1) to afford the corresponding cycloadducts 8.
Methyl 5-oxo-1-(pyridin-3-ylmethyl)pyrrolidine-2-carboxylate (8a): Pale yellow oil (93 mg, 60%). IR (neat) νmax: 1689, 1411, 1211, 1025, 794, 721 cm-1. 1H NMR (300 MHz) δ 8.48 (dd, J = 4.7, 1.2 Hz, 1H, ArH), 8.41 (d, J = 1.2 Hz, 1H, ArH), 7.54 (dt, J = 7.8, 2.0 Hz, 1H, ArH), 7.27 – 7.18 (m, 1H, ArH), 4.90 (d, J = 15.1 Hz, 1H, CH2NC=O), 4.04 (d, J =15.1 Hz, 1H, CH2NC=O), 3.94 (dd, J = 9.0, 3.2 Hz, 1H, NCHCO2Me), 3.62 (s, 3H, CH3), 2.56 – 2.45 (m, 1H, CH2), 2.43 – 2.34 (m, 1H, CH2), 2.27 – 2.17 (m, 1H, CH2), 2.11 – 1.99 (m, 1H, CH2). 13C NMR (101 MHz) δ 175.2 (NC=O), 171.9 (C=O), 149.6 (NCHAr), 149.3 (NCHAr), 136.3 (CHAr), 131.6 (CAr), 123.7 (CHAr), 58.8 (NCHCO2), 52.6 (CH3), 43.2 (CH2N), 29.3 (CH2), 22.8 (CH2). MS (EI) m/z: 234 (M+, 14%), 175 (98), 92 (100), 65(17). HRMS (ESI): m/z calc for C12H14N2O3 [M+] 234.1004; found: 234.0998.
Methyl 1-(4-bromobenzyl)-2-methyl-5-oxopyrrolidine-2-carboxylate (8b): Pale yellow oil (49.1 mg, 42%). IR (neat) νmax: 2360, 1735, 1689, 1392, 1168 cm-1. 1H NMR (400 MHz) δ 7.44 – 7.38 (m, 2H, ArH), 7.19 – 7.11 (m, 2H, ArH), 4.52 (d, J = 15.6 Hz, 1H, ArCH2N), 4.29 (d, J = 15.5 Hz, 1H, ArCH2N), 3.51 (s, 3H, CO2CH3), 2.57 (dt, J = 17.0, 9.8 Hz, 1H, NC=OCH2), 2.46 (ddd, J = 17.0, 9.7, 2.7 Hz, 1H, NC=OCH2), 2.34 (ddd, J = 12.9, 9.3, 2.7 Hz, 1H, NCCH2), 1.90 (dt, J = 13.2, 9.9 Hz, 1H, NCCH2), 1.41 (s, 3H, CH3). 13C NMR (101 MHz) δ 175.8 (C=O), 173.7 (C=O), 136.6 (CAr), 131.8 (2xCHAr), 129.9 (2xCHAr), 121.2 (BrCAr), 66.0 (NCCH3), 52.4 (CO2CH3), 43.9 (ArCH2N), 32.1 (C=OCH2), 29.5 (CCH2), 23.2 (NCCH3). MS (EI) m/z: 325 (M+, 7%), 268 (72), 266 (73), 171 (95), 169 (100), 90 (28), 89 (22). HRMS (ESI): m/z calc for C14H16BrNO3 [M+] 325.0314; found: 325.0306.
Methyl 2-benzyl-1-(4-bromobenzyl)-5-oxopyrrolidine-2-carboxylate (8c): Colorless needles (77 mg, 63%). Mp: 78-79 ºC (n-hexane/AcOEt). IR (neat) νmax: 1689, 1392, 1261, 1184, 1068, 806, 732, 701 cm-1. 1H NMR (300 MHz) δ 7.46 – 7.40 (m, 2H, ArH), 7.30 – 7.24 (m, 3H, ArH), 7.23 – 7.17 (m, 2H, ArH), 7.10 – 7.04 (m, 2H, ArH), 4.81 (d, J = 15.5 Hz, 1H, HCN), 4.40 (d, J = 15.5 Hz, 1H, HCN), 3.38 (s, 3H, CH3), 3.27 (d, J = 14.0 Hz, 1H, NCCHPh), 3.00 (d, J = 14.0 Hz, 1H, NCCHPh), 2.46 – 2.23 (m, 2H, NCOCH2), 2.10 – 1.84 (m, 2H,NCCH2). 13C NMR (75 MHz) δ 176.0 (C=O), 172.2 (C=O), 136.5 (CAr), 134.4 (CAr), 131.4 (2xCHAr), 130.0 (2xCHAr), 129.9 (2xCHAr), 128.6 (2xCHAr), 127.3 (CHAr), 121.2 (BrCAr), 69.2 (NCCO2Me), 52.2 (CH3), 44.0 (PhCH2N), 40.4 (CCH2Ph), 29.2 (CH2C=O), 27.5 (NCCH2). MS (EI) m/z: 402 (M+, 1%), 312 (67), 310 (68), 171 (97), 169 (100), 91 (22), 90 (27). HRMS (ESI): m/z calc for C20H20BrNO3 [M+] 401.0627; found: 401.0619.
Methyl 2-[(1H-indol-3-yl)methyl]-1-(4-bromobenzyl)-5-oxopyrrolidine-2-carboxylate (8d): Purple oil (105.6 mg, 45%). IR (neat) vmax: 1735, 1673, 1434, 1394, 1257, 1070, 736 cm-1. 1H NMR (400 MHz) δ 8.29 (s, 1H, NH), 7.56 (dt, J = 7.7, 1.0 Hz, 1H, ArH), 7.46 – 7.41 (m, 2H, ArH), 7.35 (dt, J = 8.1, 1.0 Hz, 1H, ArH), 7.27 – 7.11 (m, 4H, ArH), 6.77 (s, 1H, CHNH), 4.85 (d, J = 15.3 Hz, 1H, H2CN), 4.36 (d, J = 15.2 Hz, 1H, H2CN), 3.52 (d, J = 15.2 Hz, 1H, CH2CCHNH), 3.37 (s, 3H, CO2CH3), 3.18 (d, J = 15.3 Hz, 1H, CH2CCHNH), 2.44 (ddd, J = 16.2, 9.8, 5.5 Hz, 1H, NCOCH2), 2.30 – 2.20 (m, 1H, NCOCH2CH2), 2.13 – 1.97 (m, 2H, NCOCH2, NCOCH2CH2). 13C NMR (101 MHz) δ 176.76 (C=O), 173.09 (C=O), 136.39 (CAr), 135.85 (CAr), 131.60 (CHAr), 130.40 (CHAr), 128.43 (CAr), 123.19 (CHAr), 122.44 (CHAr), 121.48 (CAr), 119.95 (CHAr), 118.38 (CHAr), 111.47 (CHAr), 108.49 (CAr), 69.72 (C), 52.36 (CH3), 44.18 (CH2), 29.68 (CH2), 29.57 (CH2), 27.90 (CH2). MS (EI) m/z: 441 (M+, >1%), 310 (21), 252 (26), 168 (100), 126 (20), 90 (26). HRMS (ESI): m/z calcd for C22H21BrN2O3 [M+] 440.0736; found: 440.0712.
Methyl 2-[(benzyloxy)methyl]-1-(4-bromobenzyl)-5-oxopyrrolidine-2-carboxylate (8e): Colorless liquid (107.2 mg, 46%) IR (neat) vmax: 1739, 1693, 1432, 1392, 1166, 1070, 736, 698 cm-1. 1H NMR (400 MHz) δ 7.57 – 7.23 (m, 5H, ArH), 7.23 – 7.01 (m, 4H, ArH), 4.59 (d, J = 15.5 Hz, 1H, H2CN), 4.34 (d, J = 15.5 Hz, 1H, H2CN), 4.23 (q, J = 12.0 Hz, 2H, CCH2OCH2Ph), 3.68 (d, J = 10.0 Hz, 1H, CCH2OCH2Ph), 3.58 (s, 3H, CO2CH3), 3.46 (d, J = 10.0 Hz, 1H, CCH2OCH2Ph), 2.55 – 2.45 (m, 2H, CH2C=O), 2.20 (m, J = 13.2, 7.3, 5.8 Hz, 1H, CH2CCO2Me), 2.10 (m, J = 13.1, 9.5 Hz, 1H CH2CCO2Me). 13C NMR (101 MHz) δ 176.32 (C=O), 172.30 (C=O), 137.30 (CAr), 137.10 (CAr), 131.33 (CHAr), 129.95 (CHAr), 128.54 (CHAr), 128.00 (CHAr), 127.75 (CHAr), 121.04 (C), 73.40 (CH2), 71.29 (CH2), 69.63 (C), 52.60 (CH3), 44.71 (CH2), 29.32 (CH2), 27.11 (CH2). MS (EI) m/z: 432 (M+, 2%), 310 (66), 169 (100), 91 (73). HRMS (ESI): m/z calcd for C21H22BrNO4 [M+] 431.0732; found: 433.0723.
Methyl 1-(4-bromobenzyl)-2-[2-(methylthio)ethyl]-5-oxopyrrolidine-2-carboxylate (8f): Pale yellow oil (65.8 mg, 42%). IR (neat) vmax: 1733, 1689, 1432, 1390, 1160, 1070, 732 cm-1. 1H NMR (400 MHz) δ 7.41 (d, J = 8.4 Hz, 2H, ArH), 7.16 (d, J = 8.4 Hz, 2H ArH), 4.51 – 4.29 (m, 2H, H2CN), 3.45 (s, 3H, CO2CH3), 2.61 (dt, J = 17.0, 9.6 Hz, 1H, CCH2CH2SCH3), 2.53 – 2.36 (m, 2H, CCH2CH2SCH3, CCH2CH2SCH3), 2.35 – 2.25 (m, 2H, CCH2CH2SCH3, NCCH2CH2CO), 2.23 – 2.10 (m, 1H, NCCH2CH2CO), 2.01 (s, 3H, SCH3), 1.98 – 1.87 (m, 2H, NCCH2CH2CO, NCCH2CH2CO). 13C NMR (101 MHz) δ 176.19 (C=O), 172.80 (C=O), 136.24 (CAr), 131.68 (CHAr x2), 130.32 (CHAr x2), 121.61 (CAr), 68.58 (C), 52.56 (CH3), 44.14 (CH2), 35.00 (CH2), 29.62 (CH2), 28.06 (CH2), 27.92 (CH2), 15.75 (CH3). MS (EI) m/z: 386 (M+, 13%), 328 (64), 169 (100), 90 (23), 61 (30). HRMS (ESI): m/z calcd for C16H20BrNO3S [M+] 385.0347; found: 387.0328.