A New Synthesis of Benzo[b]acridones

Abstract

A novel and efficient route for the synthesis of new benzo[b]acridones has been described. It involves the Diels-Alder reaction of N-substituted-4-quinolone-3-carbaldehyde with ortho-benzoquinodimethanes giving benzo[b]-1,6,6a,12a-tetrahydroacridones, which are the result of a cycloaddition reaction followed by an in situ deformylation. The oxidation of these tetrahydroacridones in dimethyl sulfoxide using a catalytic amount of iodine gives the new benzo[b]acridone derivatives. It was demonstrated that the ­cycloaddition reaction is only efficient if an electron-withdrawing N-protecting group is present.

Key words

4-quinolone-3-carbaldehydes - benzo[b]acridones - Diels-Alder reactions - oxidation - N-protecting groups.

References and Notes

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20

Optimized Experimental Procedure
A mixture of 1-methyl-4-quinolone-3-carbaldehyde (1, 121.7 mg, 0.65 mmol) and 1,3-dihydrobenzo[c]thiophene 2,2-dioxide (2a) in 1,2,4-trichlorobenzene (TCB, 6 mL) was refluxed under a variety of reaction conditions (see Table  [¹] ). After cooling to r.t., the reaction mixture was purified by silica gel column chromatography; the TCB solvent was removed using light PE as eluent, and then the cycloadducts were eluted with a mixture of light PE-EtOAc (4:1). The solvent was evaporated to dryness and the mixture of diastereomers was separated by preparative thin-layer chromatography using a mixture of light PE-EtOAc (9:1). The 7-methylbenzo[b]-1,6,6a,12a-tetrahydroacridones 4 and 5 and the benzo[b]acridone(6) were obtained as yellow compounds.

21

Physical Data for cis -7-Methylbenzo[ b ]-1,6,6a,12a-tetrahydroacridone (4) ^¹H NMR (300.1 MHz, CDCl₃): δ = 2.80-3.02 (m, 3 H, 1 × H-1, 2 × H-6), 3.11 (s, 3 H, NCH₃), 3.31-3.36 (m, 1 H, H-12a), 3.81 (dd, 1 H, J = 1.6, 17.3 Hz, H-1), 3.95 (dt, 1 H, J = 5.5, 11.0 Hz, H-6a), 6.69 (d, 1 H, J = 8.6 Hz, H-8), 6.71 (ddd, 1 H, J = 0.9, 7.3, 7.6 Hz, H-10), 6.96 (d, 1 H, J = 7.4 Hz, H-5), 7.06 (dt, 1 H, J = 1.5, 7.4 Hz, H-4), 7.13 (dt, 1 H, J = 1.3, 7.4 Hz, H-3), 7.20 (d, 1 H, J = 7.4 Hz, H-2), 7.41 (ddd, 1 H, J = 1.7, 7.3, 8.6 Hz, H-9), 7.86 (dd, 1 H, J = 1.7, 7.6 Hz, H-11). ^¹³C NMR (75.47 MHz, CDCl₃): δ = 26.1 and 26.6 (C-1 and C-6), 37.6 (NCH₃), 45.1 (C-12a), 60.4 (C-6a), 113.1 (C-8), 116.6 (C-10), 118.8 (C-11a), 125.8 (C-4), 126.4 (C-3), 127.9 (C-11), 129.1 and 129.2 (C-2 and C-5), 133.0 (C-5a), 133.8 (C-1a), 135.6 (C-9), 150.0 (C-7a), 194.1 (C-12). ESI⁺-MS: m/z (%) = 264 (100) [M + H]⁺, 286 (93) [M + Na]⁺, 302 (8) [M + K]⁺, 549 (47) [2 M + Na]⁺. HRMS (EI, 70 eV): m/z calcd for C₁₈H₁₇NO: 263.1310; found: 263.1309.

22

Physical Data for trans -7-Methylbenzo[ b ]-1,6,6a,12a-tetrahydroacridone (5) ^¹H NMR (300.1 MHz, CDCl₃): δ = 2.80-2.90 (m, 1 H,
H-12a), 2.91-3.01 (m, 1 H, H-1), 3.07 (s, 3 H, NCH₃), 3.11-3.16 (m, 1 H, H-6), 3.49-3.56 (m, 2 H, H-1, H-6), 3.57-3.63 (m, 1 H, H-6a), 6.81 (ddd, 1 H, J = 0.9, 7.3, 7.6 Hz, H-10), 6.90 (d, 1 H, J = 8.7 Hz, H-8), 7.18-7.25 (m, 4 H, H-2 to
H-5), 7.46 (ddd, 1 H, J = 1.8, 7.3, 8.7 Hz, H-9), 7.96 (dd, 1 H, J = 1.8, 7.6 Hz, H-11). ^¹³C NMR (75.47 MHz, CDCl₃): δ = 29.1 (C-1), 34.1 (NCH₃), 36.6 (C-6), 46.8 (C-12a), 59.0 (C-6a), 113.9 (C-8), 117.5 (C-10), 119.6 (C-11a), 126.2 and 126.6 (C-3 and C-4), 127.9 (C-1), 128.9 and 129.0 (C-2 and C-5), 132.9 (C-5a), 134.4 (C-1a), 135.7 (C-9), 152.7 (C-7a), 194.6 (C-12). ESI⁺-MS: m/z (%) = 264 (100) [M + H]⁺, 286 (25) [M + Na]⁺, 549 (19) [2 M + Na]⁺. HRMS (EI, 70 eV): m/z calcd for C₁₈H₁₇NO: 263.1310; found: 263.1312.

24

Physical Data for 7-Methylbenzo[ b ]acridone (6)
^¹H NMR (300.1 MHz, CDCl₃): δ = 3.95 (s, 1 H, NCH₃), 7.26 (ddd, 1 H, J = 0.8, 6.8, 7.9 Hz, H-10), 7.43 (ddd, 1 H, J = 1.2, 6.7, 8.1 Hz, H-3), 7.50 (d, 1 H, J = 8.6 Hz, H-8), 7.57 (ddd, 1 H, J = 1.3, 6.7, 8.2 Hz, H-4), 7.74 (ddd, 1 H, J = 1.7, 6.8, 8.6 Hz, H-9), 7.81 (s, 1 H, H-6), 7.90 (d, 1 H, J = 8.2 Hz,
H-5), 8.05 (d, 1 H, J = 8.1 Hz, H-2), 8.57 (dd, 1 H, J = 1.7, 7.9 Hz, H-11), 9.13 (s, 1 H, H-1). ^¹³C NMR (75.47 MHz, CDCl₃): δ = 33.8 (NCH₃), 110.5 (C-6), 114.4 (C-8), 120.5 (C-10), 121.3 (C11a), 122.6 (C-12a), 124.5 (C-3), 126.9
(C-5), 127.9 (C-1a), 128.0 (C-11), 128.7 (C-4), 129.0 (C-1), 129.5 (C-2), 134.4 (C-9), 136.4 (C-5a), 139.7 (C-6a), 143.6 (C-7a), 179.4 (C-12). ESI⁺-MS: m/z (%) = 260 (100) [M + H]⁺, 282 (33) [M + Na]⁺, 541 (54) [2 M + Na]⁺. HRMS (EI, 70 eV): m/z calcd for C₁₈H₁₃NO: 259.0997; found: 259.0999.

25

Although the cycloaddition reactions were carried out under nitrogen to avoid moisture, the reaction medium was not deoxygenated, the residual oxygen presumably being the oxidant.

28

Optimized Experimental Procedure Iodine (4%) was added to a solution of the appropriate
7-ethoxycarbonylbenzo[b]-1,6,6a,12a-tetrahydroacridones 10a-c (0.16 mmol) in DMSO (3 mL). The solution was heated at 170-180 ˚C or at reflux, for 50 min. After cooling to r.t., the reaction mixture was poured onto ice (10 g) and H₂O (10 mL), a small amount of Na₂S₂O₃ was added to eliminate the remaining traces of iodine, and the reaction mixture was stirred for some minutes. The yellow solid obtained was filtered off, washed with H₂O (2 × 20 mL), dissolved in EtOAc (20 mL), and washed with H₂O (2 × 20 mL). The solvent was evaporated to dryness and the residue was purified by silica gel column with a mixture of light PE-EtOAc (4:1 to 2:1). The 7-ethoxycarbonylbenzo[b]acridones 12a-c were obtained as yellow solids and the benzo[b]acridones 13a-c were obtained as orange solids. When the reactions were carried out 170-180 ˚C; the results were as follows: 12a, 37%; 13a, 49%; 12b, 25%; 13b, 37%; 12c, 25%; 13c, 45%. When the reactions were carried in refluxing DMSO, the yields were: 12a, 2%; 13a, 59%; 12b, 2%; 13b, 59%; 12c, 4%; 13c, 82%.

29

Physical Data for 7-Ethoxycarbonylbenzo[ b ]-acridone (12a) Mp 118-120 ˚C. ^¹H NMR (300.1 MHz, CDCl₃): δ = 1.42 (t, 3 H, J = 7.1 Hz, NCO₂CH₂CH ₃), 4.47 (q, 2 H, J = 7.1 Hz, NCO₂CH ₂CH₃), 7.39 (ddd, 1 H, J = 1.1, 7.4, 7.7 Hz, H-10), 7.52 (ddd, 1 H, J = 1.2, 6.8, 8.1 Hz, H-3), 7.62 (ddd, 1 H, J = 1.3, 6.8, 8.2 Hz, H-4), 7.66 (ddd, 1 H, J = 1.7, 7.4, 8.4 Hz, H-9), 7.86 (d, 1 H, J = 8.4 Hz, H-8), 7.92 (d, 1 H, J = 8.2 Hz, H-5), 8.04 (d, 1 H, J = 8.1 Hz, H-2), 8.31 (dd, 1 H, J = 1.7, 7.7 Hz, H-11), 8.37 (s, 1 H, H-6), 8.85 (s, 1 H, H-1). ^¹³C NMR (75.47 MHz, CDCl₃): δ = 14.1 (NCO₂CH₂ CH₃), 64.2 (NCO₂ CH₂CH₃), 119.8 (C-6), 122.6 (C-8), 124.6
(C-10), 125.4 (C-12a), 125.8 (C-11a), 126.1 (C-3), 126.8
(C-11), 127.7 (C-5), 128.0 (C-1), 128.9 (C-4), 129.5 (C-2), 129.9 (C-1a), 133.0 (C-9), 135.2 (C-5a), 135.9 (C-6a), 140.8 (C-7a), 153.8 (NCO₂CH₂CH₃), 181.0 (C-12). ESI⁺-MS: m/z (%) = 318 (75) [M + H]⁺, 340 (31) [M + Na]⁺, 356 (11)
[M + K]⁺, 657 (100) [2 M + Na]⁺, 974 (30) [3 M + Na]⁺. HRMS (EI, 70 eV): m/z calcd for C₂₀H₁₅NO₃: 317.1052; found: 317.1053.

30

Physical Data for Benzo[ b ]acridone (13a) Mp >300 ˚C. ^¹H NMR (300.1 MHz, CDCl₃): δ = 7.22 (ddd, 1 H, J = 0.8, 6.9, 8.0 Hz, H-10), 7.44 (ddd, 1 H, J = 0.9, 7.1, 7.9 Hz, H-3), 7.55 (d, 1 H, J = 8.4 Hz, H-8), 7.60 (ddd, 1 H, J = 1.1, 7.1, 8.2 Hz, H-4), 7.76 (ddd, 1 H, J = 1.5, 6.9, 8.4 Hz, H-9), 7.96 (s, 1 H, H-6), 8.01 (d, 1 H, J = 8.2 Hz, H-5), 8.17 (d, 1 H, J = 7.9 Hz, H-2), 8.26 (dd, 1 H, J = 1.5, 8.0 Hz, H-11), 8.94 (s, 1 H, H-1), 11.75 (s, 1 H, NH). ^¹³C NMR (75.47 MHz, CDCl₃): δ = 112.0 (C-6), 117.0 (C-8), 118.9 (C-11a), 120.2 (C-10), 121.2 (C-12a), 124.1 (C-3), 126.4
(C-11), 126.5 (C-5), 127.3 (C-1), 127.7 (C-1a), 128.5 (C-4), 129.7 (C-2), 134.3 (C-9), 135.9 (C-5a), 137.9 (C-6a), 142.1 (C-7a), 178.2 (C-12). ESI⁺-MS: m/z (%) = 246 (100) [M + H]⁺. HRMS (EI, 70 eV): m/z calcd for C₁₇H₁₁NO: 245.0841; found: 245.0842.