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Synlett 2009(7): 1162-1166  
DOI: 10.1055/s-0028-1088115
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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

Jinlong Wua, Yong Jianga, Wei-Min Dai*a,b
a Laboratory of Asymmetric Catalysis and Synthesis, Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. of China
Fax: +86(571)87953128; e-Mail: chdai@zju.edu.cn;
b Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong SAR, P. R. of China
Fax: +85223581594; e-Mail: chdai@ust.hk;
Further Information

Publication History

Received 2 February 2009
Publication Date:
26 March 2009 (online)

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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 (SNAr), 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.

1

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

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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.

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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.