On the Chemistry of the Resveratrol Diastereomers

On the Chemistry of the Resveratrol Diastereomers

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MoChem_Template_Vers 3.2May 2011

Solvent-free cascade assembling of salicylaldehydes and cyanoacetates: fast and efficient approach to medicinally relevant 2-amino-4H-chromene scaffold

Michail N. Elinson* ● Ruslan F. Nasybullin ●Fedor V. Ryzhkov ● Tatiana A. Zaimovskaya ● Mikhail P. Egorov

Supplementary material

Experimental

All melting points were measured with a Gallenkamp melting point apparatus. 1H and 13CNMR spectra were recorded in DMSO-d6 and CDCl3 with a Bruker Avance II 300 spectrometer at ambient temperature. Chemical shift values are relative to Me4Si. IR spectra were recorded with a Bruker ALPHA-T FT-IR spectrometer in KBr pellets. All chemicals used in this study were commercially available

General procedure

Salicylaldehyde (5 mmol), cyanoacetate (10 mmol), and sodium acetate or potassium fluoride (0.5mmol) were stirred in a flask equipped with a magnetic stirrer at 20°C for 30 min (method A) or grinded in mortar for 15 min (method B). After the reaction was finished, 2 cm3 of EtOH was added to obtain homogeneous suspension after stirring. Then ethanol was dried under reduced pressure. The solid was then rinsed on filter with water (2 x 5 cm3) and dried.

Methyl 2-amino-4-(1-cyano-2-methoxy-2-oxoethyl)-4H-chromene-3-carbo-xylate (3a)

Yield 98%; m.p. 121-123 ºC (Ref.[1] 120-122 ºC); major diastereoisomer: lH NMR (300 MHz, DMSO-d6): δ= 3.79 (s, 3H, OCH3), 3.81 (s, 3H, OCH3), 4.00 (d, 1H, CH, J = 3.8 Hz), 4.71 (d, 1H, CH, J = 3.8 Hz), 7.05 - 7.91 (m, 6H, Ar and NH2); minor diastereoisomer: lH NMR (300 MHz, DMSO-d6): δ= 3.68 (s, 3H, OCH3), 3.77 (s, 3H, OCH3), 3.95 (d, 1H, CH, J = 3.5 Hz), 4.62 (d, 1H, CH, J = 3.5 Hz), 7.05 - 7.91 (m, 6H, Ar and NH2).

Ethyl 2-amino-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carbo-xylate (3b)

Yield 94%; m.p. 141-143ºC (Ref.[2] 142-143 ºC); major diastereoisomer: lH NMR (300 MHz, DMSO-d6): δ= 1.17 (t, 3H, CH3, J = 7.3 Hz), 1.25 (t, 3H, CH3, J = 7.3 Hz), 3.98-4.22 (m, 4H, two OCH2), 4.33 (d, 1H, CH, J = 3.7 Hz), 4.59 (d, 1H, CH, J = 3.7 Hz), 7.02 – 7.45 (m, 4H, Ar), 7.80 (s, 2H, NH2); minor diastereoisomer: lH NMR (300 MHz, DMSO-d6): δ= 1.11 (t, 3H, CH3, J = 7.4 Hz), 1.22 (t, 3H, CH3, J = 7.4 Hz), 3.97-4.22 (m, 5H, two OCH2 and СН), 4.54 (d, 1H, CH, J = 3.7 Hz), 7.02 – 7.45 (m, 4H, Ar), 7.80 (c, 2H, NH2).

Ethyl 2-amino-4-(1-cyano-2-ethoxy-2-oxoethyl)-6-methyl-4H-chromene-3-carboxylate (3c)

Yield 92%; m.p. 109-111 ºC (Ref.[3] 110-112 ºC); major diastereoisomer: lH NMR (300 MHz, DMSO-d6): δ=1.23 (t, 3H, CH3, J = 7.3 Hz), 1.26 (t, 3H, CH3, J = 7.3 Hz), 2.24 (s, 3H, CH3), 3.97-4.23 (m, 4H, two OCH2), 4.35 (d, 1H, CH, J = 3.6 Hz), 4.51 (d, 1H, CH, J = 3.6 Hz), 6.84 (s, 1H, Ar), 6.98 (d, 1H, Ar, J = 8.5 Hz), 7.28 (d, 1H, Ar, J = 8.5 Hz), 7.74 (s, 2H, NH2); minor diastereoisomer: lH NMR (300 MHz, DMSO-d6): δ=1.14 (t, 3H, CH3, J = 7.3 Hz), 1.18 (t, 3H, CH3, J = 7.3 Hz), 2.27 (s, 3H, CH3), 3.97-4.25 (m, 5H, two OCH2 and CH), 4.47 (d, 1H, CH, J = 3.1 Hz), 6.96 (s, 1H, Ar), 7.03 (d, 1H, Ar, J = 8.3 Hz), 7.15 (d, 1H, Ar, J = 8.3 Hz), 7.80 (s, 2H, NH2).

Methyl 2-amino-4-(1-cyano-2-methoxy-2-oxoethyl)-8-methoxy-4H-chro-mene-3-carboxylate (3d)

Yield 91%; m.p. 155-157 ºC (Ref.[1] 150-153 ºC); major diastereoisomer: lH NMR (300 MHz, DMSO-d6): δ= 3.67 (s, 3H, OCH3), 3.71 (s, 3H, OCH3), 3.81 (s, 3H, OCH3), 4.38 (d, 1H, CH, J = 3.8 Hz), 4.50 (d, 1H, CH, J = 3.8 Hz), 6.56 (d, 1H, Ar J = 8.8 Hz), 7.00-7.18 (m, 2Н, Ar), 7.88 (s, 2H, NH2); minor diastereoisomer: lH NMR (300 MHz, DMSO-d6): δ= 3.57 (s, 3H, OCH3), 3.65 (s, 3H, OCH3), 3.80 (s, 3H, OCH3), 4.14 (d, 1H, CH, J = 3.7 Hz), 4.51 (d, 1H, CH, J = 3.7 Hz), 6.91 (d, 1H, Ar J = 8.8 Hz), 7.00-7.18 (м, 2Н, Ar), 7.90 (s, 2H, NH2).

Ethyl 2-amino-4-(1-cyano-2-ethoxy-2-oxoethyl)-8-methoxy-4H-chromene-3-carboxylate (3e)

Yield 90%; m.p. 124-126 ºC (Ref.[2] 126-127 ºC); major diastereoisomer: lH NMR (300 MHz, DMSO-d6): δ= 1.17 (t, 3H, CH3, J = 7.3 Hz), 1.20 (t, 3H, CH3, J = 7.3 Hz), 3.81 (s, 3H, OCH3), 3.98-4.21 (m, 4Н, two OCH2) 4.30 (d, 1H, CH, J = 3.7 Hz), 4.52 (d, 1H, CH, J = 3.7 Hz), 6.59 (d, 1H, Ar, J = 8.6 Hz), 7.00-7.18 (m, 2Н, Ar), 7.85 (s, 2H, NH2). minor diastereoisomer: lH NMR (300 MHz, DMSO-d6): δ = 1.10 (t, 3H, CH3, J = 7.3 Hz), 1.21 (t, 3H, CH3, J = 7.3 Hz), 3.81 (s, 3H, OCH3), 3.98-4.21 (m, 5Н, two OCH2 and CH), 4.50 (d, 1H, CH, J = 3.7 Hz), 6.93 (d, 1H, Ar, J = 8.8 Hz), 7.00-7.18 (m, 2Н, Ar), 7.85 (s, 2H, NH2).

Methyl 2-amino-4-(1-cyano-2-methoxy-2-oxoethyl)-8-ethoxy-4H-chro-mene-3-carboxylate (3f)

Yield 92%; m.p. 149-151 °C.MS (EI, 70 eV): m/z (%): 346 ([M]+, 3), 247 (25), 216 (8), 187 (100), 159 (59), 132 (6), 119 (8), 105 (16), 76 (41), 68 (81). IR (KBr): ν = 3439, 3320, 2980, 2248, 1738, 1683, 1527, 1436, 1341, 1094; Anal. calcd. for C17H18N2O6: C, 58.96; H, 5.24; N, 8.09. Found: C, 58.82; H, 5.31; N, 7.94. Major diastereoisomer: 1H NMR (300 MHz, DMSOd6): δ = 1.38 (t, J = 7.2 Hz, 3H, CH3), 3.68 (s, 3H, OCH3), 3.73 (s, 3H, OCH3), 4.08-4.15 (m, 2H, OCH2), 4.38 (d, J = 3.8 Hz, 1H, CH), 4.52 (d, J = 3.8 Hz, 1H, CH), 6.55-6.58 (m, 1H, Ar), 7.02-7.06 (m, 2H, Ar), 7.86 (s, 2H, NH2); 13C NMR (75 MHz, DMSO-d6): δ = 14.6, 36.5, 46.9, 50.8, 53.0, 64.3, 71.1, 113.3, 116.1, 118.9, 119.6, 124.4, 139.7, 146.4, 162.6, 165.6, 167.7.Minor diastereoisomer: 1H NMR (300 MHz, DMSO-d6): δ = 1.35 (t, J = 7.2 Hz, 3H, CH3), 3.59 (s, 3H, OCH3), 3.66 (s, 3H, OCH3), 4.08-4.17 (m, 3H, OCH2 and CH), 4.54 (d, J = 3.4 Hz, 1H, CH), 6.93 (d, J = 7.4 Hz, 1H, Ar), 7.10-7.15 (m, 2H, Ar), 7.88 (s, 2H, NH2); 13C NMR (75 MHz, DMSO-d6): δ = 14.4, 36.8, 47.3, 50.6, 52.8, 64.1, 70.3, 113.1, 116.2, 121.2, 123.5, 124.7, 139.5, 146.1, 162.7, 165.4, 167.9.

Methyl 2-amino-6-chloro-4-(1-cyano-2-methoxy-2-oxoethyl)-4H-chro-mene-3-carboxylate (3g)

Yield 93%; m.p. 126-128 °C.MS (EI, 70 eV): m/z (%): 338 ([M]+, 1), 336 ([M]+, 3), 240 (35), 238 (71), 206 (37), 177 (20), 152 (12), 114 (35), 88 (22), 68 (51), 52 (100). IR (KBr): ν = 3430, 3312, 2955, 2249, 1745, 1686, 1639, 1522, 1231, 1078. Anal. calcd. for C15H13ClN2O5: C, 53.50; H, 3.89; Cl, 10.53; N, 8.32. Found: C, 53.24; H, 3.96; Cl, 10.74; N, 8.13. Major diastereo-isomer: 1H NMR (300 MHz, DMSO-d6): 3.68 (s, 3H, OCH3), 3.74 (s, 3H, OCH3), 4.42 (d, J = 3.8 Hz, 1H, CH), 4.56 (d, J = 3.8 Hz, 1H, CH), 7.09 (d, J = 2.1 Hz, 1H, Ar), 7.17 (d, J = 8.5 Hz, 1H, Ar), 7.40 (dd, J1 = 8.5 Hz, J2 = 2.1 Hz, 1H, Ar), 7.87 (s, 2H, NH2); 13C NMR (75 MHz, DMSO-d6): δ = 36.1, 46.6, 50.8, 53.0, 70.6, 115.9, 117.9, 127.6, 128.4, 129.0, 129.2, 148.9, 162.3, 165.5, 167.4.Minor diastereoisomer: 1H NMR (300 MHz, DMSO-d6): 3.60 (s, 3H, OCH3), 3.67 (s, 3H, OCH3), 4.29 (d, J = 3.2 Hz, 1H, CH), 4.58 (d, J = 3.2 Hz, 1H, CH), 7.13 (d, J = 8.6 Hz, 1H, Ar), 7.43 (dd, J1 = 8.6 Hz, J2 = 2.0 Hz, 1H, Ar), 7.53 (d, J = 2.0 Hz, 1H, Ar), 7.89 (s, 2H, NH2); 13C NMR: δ = 36.3, 46.8, 50.7, 52.9, 69.9, 116.0, 117.6, 122.4, 123.7, 128.0, 128.2, 148.7, 162.5, 165.3, 167.6.

Methyl 2-amino-6-bromo-4-(1-cyano-2-methoxy-2-oxoethyl)-4H-chro-mene-3-carboxylate (3h)

Yield 93%; m.p. 125-127 ºC (Ref.[4] 126-127 ºC); major diastereoisomer: lH NMR (300 MHz, DMSO-d6): δ= 3.65 (s, 3H, OCH3), 3.72 (s, 3H, OCH3), 4.40 (d, 1H, CH, J = 3.6 Hz), 4.52 (d, 1H, CH, J = 3.6 Hz), 7.08 (d, 1H, Ar, J = 8.7 Hz), 7.18 (s, 1H, Ar), 7.57 (d, 1H, Ar, J = 8.7 Hz), 7.91 (s, 2H, NH2); minor diastereoisomer: lH NMR (300 MHz, DMSO-d6): δ= 3.57 (s, 3H, OCH3), 3.62 (s, 3H, OCH3), 4.26 (d, 1H, CH, J = 3.0 Hz), 4.55 (d, 1H, CH, J = 3.0 Hz), 7.05 (d, 1H, Ar, J = 8.5 Hz), 7.52 (d, 1H, Ar, J = 8.5 Hz), 7.62 (s, 1H, Ar), 7.89 (s, 2H, NH2).

Ethyl 2-amino-6-bromo-4-(1-cyano-2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (3i)

Yield 90%; m.p. 106-108 ºC (Ref.[2] 104-105 ºC); major diastereoisomer: lH NMR (300 MHz, DMSO-d6): δ= 1.18 (t, 3H, CH3, J = 7.3 Hz), 1.22 (t, 3H, CH3, J = 7.3 Hz), 4.02-4.23 (m, 4H, two OCH2), 4.37 (d, 1H, CH, J = 3.8 Hz), 4.54 (d, 1H, CH, J = 3.8 Hz), 7.08 (d, 1H, Ar, J = 8.6 Hz), 7.20 (s, 1H, Ar), 7.55 (d, 1H, Ar, J = 8.6 Hz), 7.84 (s, 2H, NH2); minor diastereoisomer: lH NMR (300 MHz, DMSO-d6): δ= 1.12 (t, 3H, CH3, J = 7.3 Hz), 1.24 (t, 3H, CH3, J = 7.3 Hz), 4.02-4.23 (m, 5H, two OCH2 and СН), 4.53 (d, 1H, CH, J = 3.0 Hz), 7.02 (d, 1H, Ar, J = 8.4 Hz), 7.55 (d, 1H, Ar, J = 8.4 Hz), 7.62 (s, 1H, Ar), 7.89 (s, 2H, NH2).

Methyl 2-amino-4-(1-cyano-2-methoxy-2-oxoethyl)-6-nitro-4H-chromene-3-carboxylate (3k)

Yield 92%; m.p. 155-157 ºC (Ref.[5] 156 ºC); major diastereoisomer: lH NMR (300 MHz, DMSO-d6): δ= 3.70 (s, 3H, OCH3), 3.75 (s, 3H, OCH3), 4.48 (d, 1H, CH, J = 3.7 Hz), 4.67 (d, 1H, CH, J = 3.7 Hz), 7.33 (d, 1H, Ar, J = 8.9 Hz), 7.91 (s, 3H, Ar and NH2), 8.20 (d, 1H, Ar, J = 8.9) Hz; minor diastereoisomer: lH NMR (300 MHz, DMSO-d6): δ= 3.65 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 4.32 (d, 1H, CH, J = 3.7 Hz), 4.65 (d, 1H, CH, J = 3.7 Hz), 7.30 (d, 1H, Ar, J = 8.9 Hz), 7.91 (s, 3H, Ar и NH2), 8.25 (d, 1H, Ar, J = 8.9Hz).

Ethyl 2-amino-4-(1-cyano-2-ethoxy-2-oxoethyl)-6-nitro-4H-chromene-3-carboxylate (3l)

Yield 91%; m.p. 133-135 ºC(Ref.[4] 134-135 ºC); major diastereoisomer: lH NMR (300 MHz, DMSO-d6): δ= 1.23 (t, 3H, CH3, J = 7.3 Hz), 1.28 (t, 3H, CH3, J = 7.3 Hz), 4.05-4.27 (m, 4H, two OCH2), 4.47 (d, 1H, CH, J = 3.7Hz), 4.75 (d, 1H, CH, J = 3.7 Hz), 7.39 (d, 1H, Ar, J = 9.1 Hz), 7.93 (s, 2H, NH2), 8.02 (s, 1H, Ar), 8.28 (d, 1H, Ar, J = 9.1 Hz); minor diastereoisomer: lH NMR (300 MHz, DMSO-d6): δ= 1.07 (t, 3H, CH3, J = 7.3 Hz), 1.16 (t, 3H, CH3, J = 7.3 Hz), 4.05-4.27 (m, 4H, two OCH2), 4.33 (d, 1H, CH, J = 3.0 Hz), 4.74 (d, 1H, CH, J = 3.0 Hz), 7.34 (d, 1H, Ar, J = 8.5 Hz), 7.91 (s, 2H, NH2), 8.26 (d, 1H, Ar, J = 8.5 Hz), 8.41 (s, 1H, Ar).

References

1. Roudier JF, Foucaud A (1984) Synthesis 159

2. Fujimoto A, Sakurai A (1977) Synthesis1977:871.

3. Doshi JM, Tian D, Xing C (2006) J Med Chem 49:7731

4. ElinsonMN, DorofeevAS, FeducovichSK, Nasybullin RF, Gorbunov SV, Stepanov NO, NikishinGI (2006) Tetrahedron Lett 47:7629.

5. Curini M, Epifano F, Chimichi S, Montanari F, Nocchettic M, Rosatia O (2005) Tetrahedron Lett 46:3497

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