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Synlett 2010(17): 2639-2643  
DOI: 10.1055/s-0030-1258570
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Solid-Phase Synthesis of 1,2-Diketones via Acetylene Oxidation: A Versatile Diversity Platform for the Combinatorial Synthesis of Heterocycles

Nils Griebenow*, Thorsten Meyer
Bayer Schering Pharma AG, Global Drug Discovery, Medicinal Chemistry Wuppertal, Building 460, 42096 Wuppertal, Germany
Fax: +49(202)365866; e-Mail: nils.griebenow@bayerhealthcare.com;
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Publication History

Received 18 June 2010
Publication Date:
23 September 2010 (online)

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Abstract

Investigations towards the solid-phase synthesis of 1,2-diketones via the oxidation of acetylenes and their use in the combinatorial synthesis of heterocycles such as imidazoles and quin­oxalines are described.

Key words

solid-phase synthesis - imidazole - quinoxaline - oxidation - 1,2-diketone

    References and Notes

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  • 16 Representative Experimental Procedure for the Synthesis of Quinoxalines 4-[Oxo(phenyl)acetyl]benzoic acid functionalized Wang resin (4a, 108 mg, 0.10 mmol, loading of 0.93 mmol/g) was suspended in TMOF (3 mL) and charged with 2-amino-aniline (270 mg, 25 equiv, 2.50 mmol). The reaction mixture was shaken at r.t. for 18 h. The resin was filtered off and washed successively with DMF, THF, as well as CH2Cl2. The resin was cleaved with TFA-CH2Cl2 (2 mL, v/v = 1:1) at r.t. for 1 h, filtered, and washed with CH2Cl2 (1 mL). The filtrate was evaporated to dryness providing 22 mg of 4-(3-phenylquinoxalin-2-yl)benzoic acid (6a) in 69% yield.LC-MS: 5.70 min, 88% (210 nm), m/z = 327 [M + H+]. ¹H NMR (400 MHz, DMSO-d 6): δ = 7.36-7.43 (m, 3 H), 7.48-7.50 (m, 2 H), 7.59 (d, J = 8.1, 2 H), 7.90-7.94 (m, 4 H), 8.18-8.20 (m, 2 H), 13.21 (br s, 1 H) ppm. ¹³C NMR (100 MHz, DMSO-d 6): δ = 128.16, 128.86, 128.90, 128.94, 129.54, 129.78, 129.89, 130.61, 130.80, 131.31, 138.44, 140.39, 140.62, 142.76, 152.35, 153.06, 167.05. HRMS: m/z calcd for C21H15O2N2 [M + H+]: 327.1128; found 327.1125. For further analytical data see: van Es T. Backeberg OG. J. Chem. Soc.  1963,  1371 
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10

Purities and product identities were determined by LC-MS analysis using a Hewlett-Packard HP 1100 liquid chroma-tography system coupled to a Micromass ZMD-400 spectrometer equipped with an Intersil column (ODS-3, 50 × 2.1 mm). The mobile phase was H2O (A) and MeCN (B), both containing 0.1% TFA. A gradient was used increasing from 10-95% B in 9 min followed by a hold at 95% B for 1 min and then re-equilibration for 3 min at a flow rate of 0.5 mL/min. The column was maintained at 35 ˚C. Mass spectra were acquired in either the positive or negative ion mode under electrospray ionization (ESI). The compound purity was monitored based on the UV absorbency at 210 nm. The presence of all desired compounds was confirmed by their molecular mass.

11

Yields refer to the crude products and were calculated on the basis of the initial loading of the resin.

12

Representative Experimental Procedure for the Preparation of 1,2-Diketones
Wang resin (6.00 g, 7.14 mmol, loading of 1.19 mmol/g, 1% cross-linking, 100-200 mesh) was suspended in DMF (40 mL). The suspension was charged with 4-idodobenzoic
acid (3.19 g, 1.8 equiv, 12.85 mmol), 2,6-dichlorobenzoyl chloride (2.99 g, 2.0 equiv, 14.27 mmol), and pyridine (1.91 mL, 1.86 g, 3.3 equiv, 23.55 mmol), and the reaction mixture was shaken at r.t. for 18 h. The resin was filtered off and washed successively with DMF, MeOH, THF, as well as CH2Cl2. Residual traces of solvent were removed in vacuo overnight to provide the derivatized resin 2 with a theoretical loading capacity of 0.93 mmol/g based on 100% conversion. Under an atmosphere of argon 4-iodobenzoic acid functionalized Wang resin 2 (3.00 g, 2.80 mmol, loading: 0.93 mmol/g) was suspended in a solution of phenyl-acetylene (3.0 equiv, 858 mg, 8.41 mmol) in DMF-DIPEA (15 mL, v/v = 3:1). Bis(triphenylphosphine)palladium(II) dichloride (197 mg, 0.1 equiv, 0.28 mmol) and copper(I) iodide (213 mg, 0.4 equiv, 1.12 mmol) were added, and the reaction mixture was shaken at r.t. for 18 h. After filtration, the resin was washed with DMF, 50% aq AcOH, MeOH, THF, and CH2Cl2. Residual traces of solvent were removed in vacuo overnight to provide the derivatized resin 3a with a theoretical loading capacity of 0.96 mmol/g based on 100% conversion. An analytical sample of the resin was treated with TFA in CH2Cl2 (v/v = 1:1) for 1 h at r.t. Filtration and evaporation yielded 4-(phenylethynyl)benzoic acid.
LC-MS: 2.52 min, 99% (210 nm), m/z = 221 [M - H-]. ¹H NMR (400 MHz, DMSO-d 6): δ = 7.44-7.49 (m, 3 H), 7.57-7.62 (m, 2 H), 7.66-7.70 (m, 2 H), 7.96-8.00 (m, 2 H) ppm; one proton not observed in this spectrum. HRMS: m/z calcd for C15H11O2 [M + H+]: 223.0754; found: 223.0754.
4-(Phenylethynyl)benzoic acid Wang resin (3a, 209 mg, 0.20 mmol, loading: 0.957 mmol/g) was suspended in anhyd DMSO (2 mL) and charged with iodine (51 mg, 1 equiv, 0.20 mmol). The reaction mixture was heated to 155 ˚C for 1 h. The resin was then filtered off and successively washed with DMF, 50% aq AcOH, MeOH, THF, as well as CH2Cl2. Residual traces of solvent were removed in vacuo overnight to provide the derivatized resin 4a with a theoretical loading capacity of 0.93 mmol/g based on 100% conversion. The resin was cleaved with TFA-CH2Cl2 (2 mL, v/v = 1:1) at r.t. for 1 h, filtered, and washed with CH2Cl2 (1 mL). The filtrate was evaporated to dryness providing 26 mg of 4-[oxo-(phenyl)acetyl]benzoic acid (5a) in 52% yield.
LC-MS: 2.20 min, 95% (210 nm), m/z = 253 [M - H-]. ¹H NMR (400 MHz, DMSO-d 6): δ = 7.63-7.67 (m, 2 H), 7.83 (t, J = 7.60 Hz, 1 H), 7.97 (d, J = 7.72 Hz, 2 H), 8.06 (d, J = 8.16 Hz, 2 H), 8.15 (d, J = 8.16 Hz, 2 H) ppm; one proton not observed in this spectrum. ¹³C NMR (100 MHz, DMSO-d 6): δ = 129.60, 129.86, 129.97, 130.04, 132.21, 135.17, 135.81, 136.41, 166.39, 194.21, 194.25 ppm. HRMS: m/z calcd for C15H11O4 [M + H+]: 255.0652; found: 255.0653.

17

Representative Experimental Procedure for the Synthesis of Imidazoles
4-[Oxo(phenyl)acetyl]benzoic acid functionalized Wang resin (4a, 215 mg, 0.20 mmol, loading of 0.93 mmol/g) was suspended in AcOH (3 mL) and charged with benzaldehyde (420 mg, 20 equiv, 4.00 mmol), and NH4OAc (310 mg, 20 equiv, 4.00 mmol). In case of 7c 40 equiv benzaldehyde, 40 equiv benzylamine, and 1.5 equiv NH4OAc was used. The reaction mixture was heated to 110 ˚C for 16 h. The resin was filtered and washed successively with 50% aq AcOH, DMF, MeOH, THF, as well as CH2Cl2. The resin was cleaved with TFA-CH2Cl2 (2 mL, v/v = 1:1) at r.t. for 1 h, filtered, and washed with CH2Cl2 (1 mL). The filtrate was evaporated to dryness providing 38 mg of 4-(2,5-diphenyl-1H-imidazol-4-yl)benzoic acid (7a) in 56% yield.
LC-MS: 3.83 min, 69% (210 nm), m/z = 341 [M + H+]. ¹H NMR (400 MHz, DMSO-d 6): δ = 7.43-7.51 (m, 3 H), 7.52-7.59 (m 5 H), 7.67 (d, J = 8.60 Hz, 2 H), 7.96 (d, J = 8.60 Hz, 2 H), 8.13 (d, J = 7.45 Hz, 2 H) ppm; two protons not observed in this spectrum. ¹³C NMR (100 MHz, DMSO-d 6): δ = 126.08, 127.64, 128.27, 128.43, 128.54, 128.74, 128.78, 128.89, 129.18, 129.50, 129.63, 129.89, 130.12, 130.99, 145.24, 166.83. HRMS: m/z calcd for C22H17O2N2 [M + H+]: 341.1285; found: 341.1280.