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

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

• 1a Fretz H. Tetrahedron Lett.  1996,  37:  8479 
• 1b Boussie TR. Murphy V. Hall KA. Coutard C. Dales C. Petro M. Carlson E. Turner HW. Powers TS. Tetrahedron  1999,  55:  11699 
• 2 An earlier report described a mixed benzoin condensation on a solid support yielding benzils in trace amounts (4-6%) only. However, further reaction of the resin-bound benzils towards heterocycles was not reported. See: Lenzhoff CC. Wong JY. Can. J. Chem.  1973,  51:  3756 
• 3a Cironi P. Tulla-Puche J. Barany G. Albericio F. Álvarez M. Org. Lett.  2004,  6:  1405 
• 3b Cironi P. Manzanares I. Albericio F. Álvarez M. Org. Lett.  2003,  5:  2959 
• 3c Bräse S. Köbberling J. Griebenow N. Organopalladium Reactions in Combinatorial Chemistry, In Handbook of Organopalladium Chemistry for Organic Synthesis   Vol. 2:  Negishi E. John Wiley and Sons; New York: 2002.  p.3031 
• 3d Ljungdahl N. Bromfield K. Kann N. Top. Curr. Chem.  2007,  278:  89 
• 3e Nelson JC. Young JK. Moore JS. J. Org. Chem.  1996,  61:  8160 
• 3f Erdélyi M. Gogoll A. J. Org. Chem.  2003,  68:  6431 
• 4 The solid-phase oxidation of aromatic TMS-protected acetylenes to α-ketocarboxylic acids with OsO₄ and NMO has been reported recently. See: Le Quement ST. Nielsen TE. Meldal M. J. Comb. Chem.  2008,  10:  546 
• 5 Mousset C. Provot O. Hamze A. Bignon J. Brion J.-D. Alami M. Tetrahedron  2008,  64:  4287 
• 6a Yusubov MS. Filimonov VD. Synthesis  1991,  131 
• 6b Yusubov MS. Filimonov VD. Vasilyeva VP. Chi K.-W. Synthesis  1995,  1234 
• 7 Chi K.-W. Yusubov MS. Filimonov VD. Synth. Commun.  1994,  24:  2119 
• 8 Wolfe S. Pilgrim WR. Garrard TF. Chamberlain P. Can. J. Chem.  1971,  49:  2941 
• 9 Sieber P. Tetrahedron Lett.  1987,  28:  6147 
• 13a Debus H. Liebigs Ann. Chem.  1858,  107:  199 
• 13b Radziszewski B. Ber. Dtsch. Chem. Ges.  1882,  15:  2706 
• Trimethyl orthoformate was used instead of molecular sieve as the dehydrating reagent. See:
• 14a Look GC. Murphy MM. Campbell DA. Gallop MA. Tetrahedron Lett.  1995,  36:  2937 
• 14b Quinoxaline synthesis using molecular sieve: Ott S. Faust R. Synthesis  2005,  3135 
• 15 Sarshar S. Siev D. Mjalli AMM. Tetrahedron Lett.  1996,  37:  835 
• 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 

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.