3-Nitrochromene Derivatives as 2π Components in 1,3-Dipolar Cycloadditions of Azomethine Ylides

Abstract

The 1,3-dipolar cycloaddition of 2-aryl-3-nitrochromenes with various azomethine ylides has been investigated. The structure and stereochemistry of cycloadducts were studied in detail by NMR spectroscopic methods.

Key words

azomethine ylids - chromenes - cycloadditions - pyrroles

References

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11

General Procedure: A mixture of sarcosine (2.5 equiv) or N-benzyl-glycine (2.5 equiv), paraformaldehyde (6 equiv), and the corresponding 3-nitrochromene derivatives (3a-e, 1 equiv) was heated under reflux in toluene (10 mL for 1 mmol of dipolarophile). The water formed was removed by the aid of a Dean-Stark trap. After completion of the reaction (judged by TLC) the reaction mixture was filtered through a pad of Celite and the solvent was evaporated in vacuo. The residue crystallized from Et₂O to give 4a-j. The reaction times and yields (based on the dipolarophiles) are summarized in Table [1] . All new compounds afforded correct elemental analyses and spectroscopic data, for example: 2-Methyl-3a-nitro-4-phenyl-benzopirano[3,4- c ]-pyrrolidine ( 4a): ¹H NMR (250 MHz, CDCl₃): δ = 7.44 (5 H, m, Ph-H), 7.23 (2 H, m, Ar-H), 7.04 (2 H, m, Ar-H), 5.01 (1 H, s, H-4), 4.03 (1 H, t, J = 8.5 Hz, H-9b), 3.62 (1 H, d, J = 11.4 Hz, H-3), 3.50 (1 H, t, J = 8.5 Hz, H-1), 2.85 (1 H, d, J = 11.4 Hz, H-3), 2.71 (1 H, t, J = 8.5 Hz, H-1), 2.41 (3 H, s, NMe). ¹³C NMR (62.5 MHz, CDCl₃): δ = 154.0 (q, C-5a), 134.0 (Ph-1′C), 129.4 (CH, C-7), 128.5 (2 × CH, Ph-2′ and 6′C), 128.3 (CH, C-9), 127.8 (CH, Ph-4′C), 126.8 (2 × CH, Ph-3′ and 5′C), 122.6 (q, C-9a), 122.5 (CH, C-8), 117.6 (CH, C-6), 95.9 (q, C-3a), 80.1 (CH, C-4), 62.8 (CH₂), 61.8 (CH₂), 43.3 (CH, H-9b), 41.3 (NCH₃). IR (KBr): 2976, 2947, 2823, 1535, 1489, 1479, 1452, 1371, 1254, 1238, 1149, 1045, 1024 cm^-1.
2-Benzyl-4-(4-chlorophenyl)-3a-nitro-benzopirano[3,4- c ]-pyrrolidine ( 4f): ¹H NMR (250 MHz, CDCl₃): δ = 7.37-7.23 (8 H, m, Ar-H), 7.21 (1 H, t, J = 7.5 Hz, H-7), 7.16 (2 H, d, J = 8.5 Hz, Ar⁴-3′ and 5′H), 7.02 (1 H, t, J = 7.5 Hz, H-8), 7.00 (1 H, d, J = 7.5 Hz, H-6), 5.03 (1 H, s, H-4), 3.97 (1 H, t, J = 8.4 Hz, H-9b), 3.71 (1 H, d, J = 12.9 Hz, CH₂Ph), 3.57 (1 H, d, J = 12.9 Hz, CH₂Ph), 3.46 (1 H, t, J = 8.4 Hz, H-1), 3.41 (1 H, d, J = 11.4 Hz, H-3), 2.87 (1 H, d, J = 11.4 Hz, H-3), 2.86 (1 H, t, J = 8.4 Hz, H-1). ¹³C NMR (62.5 MHz, CDCl₃): δ = 154.0 (q, C-5a), 137.6 (Bn-1′C), 135.5 (q, Ar⁴-4′C), 132.8 (q, Ar⁴-1′C), 128.9 (2 × CH), 128.8 (2 × CH), 128.7 (2 × CH), 128.4 (2 × CH), 128.1 (CH, C-9), 127.8 (Bn-4′C), 123.1 (CH, C-8), 122.9 (q, C-9a), 117.8 (CH, C-6), 94.9 (q, C-3a), 79.6 (CH, C-4), 60.7 (CH₂), 59.2 (CH₂), 59.1 (CH₂), 42.6 (CH, H-9b). IR (KBr): 3061, 3025, 2968, 2920, 2824, 1537, 1490, 1455, 1380, 1260, 1233, 1210, 1153, 1092, 1057, 1014 cm^-1.

15

General Procedure: The corresponding 3-nitrochromene derivatives (3a-e, 10 mmol) were dissolved in dry toluene (50 mL) and ethyl (4-chlorobenzylideneamino)acetate (2.47 g, 11 mmol) or methyl 2-(4-chlorobenzylideneamino)-3-phenyl-propionate (3.32 g, 11 mmol), silver acetate (2.50 g, 15 mmol), and Et₃N (1.11 g, 1.6 mL, 11 mmol) was added. The reaction mixture was stirred at r.t. for 12 h. After the completion of the reaction (judged by TLC) aq NH₄Cl solution (25 mL) was added to the reaction mixture and this was washed with H₂O (2 × 20 mL) and brine (20 mL). The organic layer was dried over MgSO₄, evaporated and the residue was trituated with Et₂O. The crystallized product was collected to yield a white powder, which could be recrystallized from EtOH to give 6a-j. The reaction times and yields (based on the dipolarophiles) are summarized in Table [2] . Selected data for representative examples:
Ethyl 3-(4-chlorophenyl)-3a-nitro-4-phenyl-benzopirano[3,4- c ]-pyrrolidine-1-carboxylate ( 6a): ¹H NMR (250 MHz, CDCl₃): δ = 7.51 (d, 1 H, J = 7.6 Hz, H-9), 7.35 (2 H, d, J = 8.7 Hz, Ar³-3′ and 5′H), 7.27 (2 H, d, J = 8.7 Hz, Ar³-2′ and 6′H), 7.12 (7 H, m, Ar-H), 6.77 (d, 1 H, J = 7.5 Hz, H-6), 5.48 (1 H, s, H-4), 4.88 (1 H, br m, H-3), 4.74 (1 H, d, J = 3.6 Hz, H-9b), 4.43 (2 H, q, J = 7.1 Hz, OCH₂), 4.05 (1 H, br s, H-1), 2.99 (1 H, br s, H-2), 1.41 (3 H, t, J = 7.1 Hz, CH₂CH₃). ¹³C NMR (62.5 MHz, CDCl₃): δ = 171.8 (q, C=O), 149.7 (q, C-5a), 135.4 (q, Ar³-4′C), 134.7 (q, Ar³-1′C), 129.1 (2 × CH, Ar³-2′ and 6′C), 129.0 (CH, C-7), 128.9 (CH, C-9), 128.8 (CH, Ar⁴-1′C), 128.5 (2 × CH, Ar³-3′ and 5′C), 128.4 (q, C-9a), 128.3 (2 × CH, Ar⁴-2′ and 6′C), 128.2 (2 × CH, Ar⁴-3′ and 5′C), 124.8 (CH, Ar⁴-4′C), 123.2 (CH, C-8), 118.2 (CH, C-6), 96.4 (q, C-3a), 75.5 (CH, C-4), 69.4 (CH, C-3), 68.3 (CH, C-1), 62.2 (CH₂), 45.6 (CH, H-9b), 14.3 (CH₃). IR (KBr): 3334, 2979, 1733, 1586, 1540, 1487, 1453, 1368, 1298, 1228, 1212, 1114, 1094, 1015 cm^-1.
Methyl 1-benzyl-3,4- bis -(4-chlorophenyl)-3a-nitro-benzopirano[3,4- c ]-pyrrolidine-1-carboxylate ( 6f): ¹H NMR (250 MHz, CDCl₃): δ = 7.76 (1 H, dd, J = 1.7 and 7.8 Hz, H-9), 7.35 (2 H, d, J = 8.6 Hz, Ar³-3′ and 5′H), 7.27 (2 H, d, J = 8.6 Hz, Ar³-2′ and 6′H), 7.15 (4 H, m, Bn-H and H-7), 7.14 (2 H, d, J = 8.5 Hz, Ar⁴-3′ and 5′H), 7.10 (1 H, dt, J = 1.7 and 7.8 Hz, H-8), 7.05 (2 H, d, J = 8.5 Hz, Ar⁴-2′ and 6′H), 6.96 (2 H, m, Bn-H), 6.76 (1 H, dd, J = 1.7 and 7.8 Hz, H-6), 5.55 (1 H, s, H-4), 5.10 (1 H, s, H-9b), 5.09 (1 H, d, J = 7.8 Hz, H-3), 3.78 (3 H, s, OMe), 2.94 (1 H, br d, J = 7.8 Hz, H-2), 2.81 (1 H, d, J = 13.7 Hz, α-CH₂), 2.37 (1 H, d, J = 13.7 Hz, β-CH₂). ¹³C NMR (125 MHz, CDCl₃): δ = 174.4 (q, C=O), 152.1 (q, C-5a), 136.0 (q, Bn-1′C), 135.4 (q, Ar³-4′C), 134.9 (q, Ar⁴-4′C), 133.3 (q, Ar³-1′C), 132.9 (q, Ar⁴-1′C), 130.6 (CH, C-9), 129.9 (2 × CH, Bn-2′ and 6′C), 129.6 (2 × CH, Ar⁴-2′ and 6′C), 129.3 (CH, C-7), 129.2 (2 × CH, Ar³-3′ and 5′C), 128.5 (2 × CH, Bn-3′ and 5′C), 128.3 (2 × CH, Ar⁴-3′ and 5′C), 128.1 (2 × CH, Ar³-2′ and 6′C), 127.0 (CH, Bn-4′C), 123.1 (CH, C-8), 122.2 (q, C-9a), 118.7 (CH, C-6), 98.5 (q, C-3a), 77.0 (CH, C-4), 72.2 (q, C-1), 67.4 (CH, C-3), 52.7 (OCH₃), 49.8 (CH, C-9b), 42.2 (CH₂). IR (KBr): 3341, 3031, 1751, 1601, 1542, 1491, 1456, 1436, 1239, 1208, 1130, 1111, 1096, 1079, 1042, 1014, 1006 cm^-1.

17

General Procedure for the Preparation of Compounds 8: The corresponding 3-nitrochromene (3, 0.80 mmol) and 6,7-dimethoxy-(2-methoxycarbonylmethyl)-3,4-dihydro-isoquinolinium bromide (0.29 g, 0.85 mmol) was dissolved in dry MeOH (10 mL) and Et₃N (0.14 mL, 0.10 g, 1.00 mmol) was added under argon atmosphere. The reaction mixture was stirred at r.t. for 24 h. The solvent was removed in vacuo, the residue was suspended in Et₂O (20 mL). The ethereal solution was washed with H₂O (10 mL) and brine (5 mL), dried over MgSO₄ and evaporated in vacuo to yield a white solid, which was recrystallized from EtOH to give 8a,b,d. The reaction times and yields are summarized in Table [4] . Selected data for representative example:
Methyl 8,9-dimethoxy-6a-nitro-6-(4-methoxyphenyl)-6a,6b,11,12,14,14a-hexahydro-6 H -chromeno[3′,4′:3,4]pyrrolidino[2,1- a ]isoquinoline-14-carboxylate ( 8b): ¹H NMR (500 MHz, CDCl₃): δ = 7.18 (1 H, t, J = 7.5 Hz, H-3), 7.06 (1 H, d, J = 7.5 Hz, H-1), 6.93 (1 H, d, J = 7.5 Hz, H-4), 6.90 (1 H, t, J = 7.5 Hz, H-2), 6.85 (2 H, d, J = 8.2 Hz, Ar⁶-2′ and 6′H), 6.51 (1 H, s, H-10), 6.46 (2 H, d, J = 8.2 Hz, Ar⁶-3′ and 5′H), 6.10 (1 H, s, H-7), 5.77 (1 H, s, H-6), 4.86 (1 H, s, H-6b), 4.12 (1 H, d, J = 11.3 Hz, H-14a), 4.11 (1 H, d, J = 11.3 Hz, H-14), 3.83 (3 H, s, OMe), 3.70 (3 H, s, OMe), 3.36 (3 H, s, OMe), 3.32 (3 H, s, OMe), 3.18 (1 H, m, H-11), 3.01 (1 H, m, H-12), 2.70 (1 H, m, H-12), 2.62 (1 H, m, H-11). ¹³C NMR (125 MHz, CDCl₃): δ = 170.4 (q, C=O), 159.6 (q, Ar⁶-4′C), 153.6 (q, C-4a), 147.8 (q, C-9), 146.7 (q, C-8), 129.9 (2 × CH, Ar⁶-2′ and 6′C), 129.4 (CH, C-1), 128.8 (CH, C-3), 128.0 (q, Ar⁶-1′C), 127.5 (q, C-10a), 127.4 (C-14b), 123.4 (C-6c), 120.5 (CH, C-2), 116.2 (CH, C-4), 113.2 (C-10), 112.9 (2 × CH, Ar⁶-3′ and 5′C), 109.8 (CH, C-7), 90.4 (q, C-6a), 75.8 (CH, C-6), 67.7 (CH, C-14), 65.7 (C-6b), 55.8 (OMe), 55.2 (OMe), 54.6 (OMe), 51.7 (OMe), 47.2 (CH, C-14a), 46.8 (C-12), 29.7 (C-11). IR (KBr): 2990, 2945, 2913, 2835, 1749, 1612, 1585, 1552, 1519, 1490, 1459, 1437, 1353, 1249, 1212, 1193, 1150, 1117, 1076, 1042, 1021 cm^-1.