Assembly of 1,3-Dihydro-2H-3-benzazepin-2-one Conjugates via Ugi Four-Component Reaction and Palladium-Catalyzed Hydroamidation [¹]

Abstract

The Ugi four-component reaction (U-4CR) of a number of 2-aminophenols was carried out with 2-alknylbenzaldehydes, benzyl isocyanide, and 2-chloro-5-nitrobenzoic acid in MeOH under microwave heating (MW, 80 ˚C, 20 min). The reaction mixture was then directly treated with aqueous K₂CO₃ (MW, 100 ˚C, 10 min) to promote an intramolecular nucleophilic aromatic substitution (S_NAr), resulting in the formation of highly functionalized dibenz[b,f][1,4]oxazepin-11(10H)-ones. The N-benzyl amide and arylalkynyl moieties, derived from benzyl isocyanide and 2-alkynylbenzaldehydes, allow for further assembly of 1,3-dihydro-2H-3-benzazepin-2-one scaffold via an intramolecular 7-endo-dig hydroamidation catalyzed by 10 mol% Pd(PhCN)₂Cl₂ (THF, 60 ˚C, 24 h, 61-74%). This new post-Ugi annulation enables an expeditious access to the C-N bond-linked conjugates of two benzannulated seven-membered-ring heterocycles.

Key words

alkynes - hydroamidation - microwaves - palladium - Ugi four-component reaction

1

Part 12. Chemistry of Aminophenols. For part 11, see ref. 9d.

References and Notes

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1

Part 12. Chemistry of Aminophenols. For part 11, see ref. 9d.

17

General Procedure for the Synthesis of 10a-g A 10 mL pressurized process vial was charged with 0.25 mmol each of 2-aminophenol 5, 2-alknylbenzaldehyde 6, 2-chloro-5-nitrobenzoic acid (7), and benzyl isocyanide (8), and MeOH (2 mL). The loaded vial was then sealed with a cap containing a silicon septum, and put into the microwave cavity, and heated at 80 ˚C for 20 min. Then, an aq soln of K₂CO₃ (1 mL, 0.30 mmol) was added to the reaction vial through a syringe followed by heating at 100 ˚C for 10 min in the microwave cavity. Water was added to the reaction mixture, and the organic layer was extracted with EtOAc (3 × 10 mL). The combined organic layer was washed with brine, dried over anhyd Na₂SO₄, and evaporated under reduced pressure. The residue was purified by column chromatography over SiO₂ with elution by 20% EtOAc in PE (60-90 ˚C) to afford 10. The structures and yields of the products 10a-g are given in Table  [¹] .
Characterization Data for Compound 10c White crystalline solid; mp 149-151 ˚C (CH₂Cl₂-hexane). R _f  = 0.45 (20% EtOAc-hexane). IR (KBr): 3399, 3322, 2964, 2230, 1651, 1529, 1345, 1272, 1225 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 8.84 (d, J = 2.4 Hz, 1 H), 8.28 (dd, J = 8.4, 2.4 Hz, 1 H), 7.59-7.55 (m, 1 H), 7.45 (br s, 1 H), 7.37-7.25 (m, 7 H), 7.18-7.12 (m, 2 H), 7.04 (d, J = 8.8 Hz, 1 H), 7.00 (dd, J = 8.8, 2.4 Hz, 1 H), 6.41 (br s, 1 H), 6.35 (t, J = 5.6 Hz, 1 H), 4.66 and 4.59 (ABqd, J = 14.8, 6.0 Hz, 2 H), 2.21 (t, J = 7.2 Hz, 2 H), 1.48-1.37 (m, 2 H), 1.11 (s, 9 H), 0.88 (t, J = 7.6 Hz, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 168.9, 165.4, 165.2, 151.9, 148.9, 144.7, 137.8, 135.4 (br), 132.4, 129.7 (br), 129.0, 128.6 (2×), 128.4, 128.3, 127.6 (2×), 127.5, 127.4, 127.2, 124.9, 124.2, 121.1, 120.2, 97.4, 77.6, 66.6, 43.9, 34.4, 31.0 (3×), 21.9, 21.4, 13.5 (two aromatic carbons were not seen). MS (+ESI): m/z (%) = 624 (100) [M + Na⁺]. Anal. Calcd for C₃₇H₃₅N₃O₅: C, 73.86; H, 5.86; N, 6.98. Found: C, 73.85; H, 5.83; N, 7.01.

18

General Procedure for the Synthesis of 13a-g A 10 mL flask was charged with 10 (0.25 mmol) and Pd(PhCN)₂Cl₂ (2.5 ¥ 10^-² mmol, 10 mol%). The flask was evacuated and backfilled with N₂ (repeated three times). To the degassed flask was added degassed anhyd THF (2.5 mL) followed by heating at 60 ˚C for 24 h. Water was added to the reaction mixture, and the aqueous layer was extracted with EtOAc (3 × 10 mL). The combined organic layer was washed with brine, dried over anhyd Na₂SO₄, and evaporated under reduced pressure. The residue was purified by flash column chromatography over SiO₂ with elution by 20% EtOAc in PE (60-90 ˚C) to give 13. The structures and yields of 13a-g are given in Table  [³] . Full characterization data for compounds 13a,b and 13d-g can be found in the Supporting Information.
Characterization Data for Compound 13c White crystalline solid; mp 223-225 ˚C (CH₂Cl₂-hexane). R _f  = 0.47 (20% EtOAc-hexane). IR (KBr) 2961, 1661, 1529, 1346, 1274 cm^-¹. ^¹H NMR (500 MHz, DMSO-d ₆, 80 ˚C): δ = 8.63 (s, 1 H), 8.39 (dd, J = 8.5, 2.0 Hz, 1 H), 7.58 (d, J = 9.0 Hz, 2 H), 7.37-6.90 (m, 9 H), 6.75 (d, J = 7.0 Hz, 2 H), 6.42 (br s, 1 H), 6.27 (br s, 1 H), 5.02 (br s, 1 H), 4.55 (br s, 1 H), 2.30-2.10 (m, 2 H), 1.50-1.30 (m, 2 H), 1.01 (s, 9 H), 0.78 (br s, 3 H). ^¹³C NMR (125 MHz, DMSO-d ₆, 80 ˚C): δ = 165.1, 164.6, 163.6, 151.8, 148.2, 144.7, 140.0(br), 137.8, 133.5, 130.8, 130.0(br), 129.1, 128.1, 127.9 (3× ), 127.7, 126.6, 126.5 (2×), 126.2, 124.3 (br), 124.0, 121.9, 120.2, 116.6 (br), 67.4 (br), 46.90, 35.9, 34.2, 30.8 (3×), 20.2, 13.7 (two aromatic carbons were not seen). MS (+ESI): m/z (%) = 624 (32) [M + Na⁺], 602 (100) [M + H⁺]. Anal. Calcd for C₃₇H₃₅N₃O₅: C, 73.86; H, 5.86; N, 6.98. Found: C, 73.86; H, 5.91; N, 6.86.