ortho-Naphthoquinone-catalyzed aerobic oxidation of amines to fused pyrimidin-4(3H)-ones: a convergent synthetic route to bouchardatine and sildenafil

A facile access to fused pyrimidin-4(3H)-one derivatives has been established by using the metal-free ortho-naphthoquinone-catalyzed aerobic cross-coupling reactions of amines. The utilization of two readily available amines allowed a direct coupling strategy to quinazolinone natural product, bouchardatine, as well as sildenafil (Viagra™) in a highly convergent manner.


1) Synthesis of 2-Amino-aryl Benzamides (Method A for 1d, 1e, 1f and 1m)
Benzonitrile compounds (1.0 mmol) and Cs2CO3 (1.0 equiv) were added into a 10 mL microwave reaction vial and 8.5 mL of deionized water was added. After irradiation under microwave at 150  C for 25 min-2 h, the reaction mixture was cooled down and concentrated under reduced pressure. The residue was dissolved in acetone, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluent: 2-5% MeOH in DCM) to give 1d-1f, 1m in 70-90% yields.

2) Synthesis of 2-Amino-aryl Benzamides (Method B for 1g-1i)
To a flask charged with anthranilic acid (1.0 mmol) and 1,1'-carbonyldiimidazole (1.0 equiv), was added 4 mL of anhydrous DMF under argon. The reaction was stirred at 40  C for 12 h. After cooling down to ambient temperature, amine (1.0 equiv) was added and reaction was further stirred for 2 h. The reaction mixture was extracted with ethyl acetate (20 mL x 3) and washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (eluent: 20% ethyl acetate in hexanes) to give 1g-1i in 67-92% yields.

3) Characterization of Aryl Benzamide Starting Materials:
2-Amino-5-methylbenzamide (1d): The product 1d was prepared by the Method A using 2amino-5-methylbenzonitrile (132.1 mg, 1.0 mmol). The pure product was obtained by column chromatography on silica gel using 3% MeOH in CH2Cl2 as eluent. 130.4 mg (80%); Pale yellow solid; The 1 H and 13 C NMR spectra for this compound are consistent with the previously reported literature. 5

2-Amino-4-chlorobenzamide (1e):
The product 1e was prepared by the Method A using 2amino-4-chlorobenzonitrile (152.5 mg, 1.0 mmol). The pure product was obtained by column chromatography on silica gel using 2% MeOH in CH2Cl2 as eluent. 153.5 mg (90%); Pale yellow solid; The 1 H and 13 C NMR spectra for this compound are consistent with the previously reported literature. 6

2-Amino-4-methylbenzamide (1f):
The product 1f was prepared by the Method A using 2-amino-4-methylbenzonitrile (132.1 mg, 1.0 mmol). The pure product was obtained by column chromatography on silica gel using 3% MeOH in CH2Cl2 as eluent. 112.5 mg (75%); White solid; The 1 H and 13 C NMR spectra for this compound are consistent with the previously reported literature. 7

2-Amino-N-benzylbenzamide (1h):
The product 1h was prepared by the Method B using anthranilic acid (137.1 mg, 1.0 mmol) and benzylamine (109 L, 1.0 mmol). The pure product was obtained by column chromatography on silica gel using 20% ethyl acetate in hexanes as eluent. 203.6 mg (90%); White solid; The 1 H and 13 C NMR spectra for this compound are consistent with the previously reported literature. 8

Preparation of ortho-Naphthoquinones Catalysts:
ortho-Naphthoquinone catalysts were prepared by the previously reported method. 9

General Procedure A for the Synthesis of Fused Pyrimidin-4(3H)-ones:
To a dried flask charged with catalyst o-NQ1 (0.01 mmol, 5 mol%), aryl benzamide (0.2 mmol), aryl benzylamine (0.24 mmol) were added 1.0 mL of DMSO followed by TFA (0.04 mmol, 20 mol%). The reaction was stirred under O2 balloon at 100-120  C for 12-36 h. The reaction mixture was cooled down to ambient temperature, diluted with 10 mL of water, and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: 30-40% acetone in hexanes or 20-40% ethyl acetate in hexanes) to give the desired products 4a-4zh in 23-97% yields.

mmol Scale Reaction
To a dried flask charged with catalyst o-NQ1 (11.7 mg, 0.05 mmol, 5 mol%), benzamide (136.2 mg, 1.0 mmol), benzylamine (131 L, 1.2 mmol) were added 5.0 mL of DMSO followed by TFA (15 L, 0.2 mmol, 20 mol %). The reaction was stirred under O2 balloon at 100  C for 36 h. The reaction mixture was cooled down to ambient temperature, diluted with 20 mL of water, and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: 30% Acetone in hexanes) to give the desired product 6a in 85% yield (186 mg). Table 1, Scheme 2 and 3 2-Phenyl-2,3-dihydroquinazolin-4(1H)-one (3a): The product 3a was prepared by the General Procedure A (CH3CN was used as solvent instead of DMSO) using 1a (27.2 mg, 0.2 mmol) and 2a (26 L, 0.24 mmol). The pure product was obtained by column chromatography on silica gel using 30% acetone in hexanes as eluent. 35.8 mg (80%); white solid; The 1 H NMR and 13 C NMR spectra for this compound are consistent with previously reported literature data. 10
46 mg (97%); white solid; The 1 H NMR and 13 C NMR spectra for this compound are consistent with previously reported literature data. 12
35 mg (58%); white solid; The 1 H NMR and 13 C NMR spectra for this compound are consistent with previously reported literature data. 13

2-(m-Tolyl)quinazolin-4(3H)-one (4g):
The product 4g was prepared by the General Procedure A using 1a (27.2 mg, 0.2 mmol) and 2g (30 L, 0.24 mmol). The pure product was obtained by column chromatography on silica gel using 20% acetone in hexanes as eluent. 42 mg (90%) white solid; The 1 H NMR and 13 C NMR spectra for this compound are consistent with previously reported literature data. 13

1) Synthesis of Benzyamine Derivative 2r
Step 1: To a flask charged with 3 mL of chlorosulfonic acid and 1 mL of Thionyl chloride was added 2ethoxybenzamide (1.65 g, 10 mmol) at 0  C under argon. The reaction mixture was stirred for 12 h below 20  C. After reaction was complete by TLC, the reaction mixture was poured into chopped ice and the resulting product was extracted with dichloromethane (50 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure.
The crude product was dissolved in 20 mL of dry dichloromethane and 1-methylpiperazine (2.44 mL, 20 mmol) was added to the mixture. The reaction was stirred for 30 min at 0  C and then continued to stir at ambient temperature for 1 h. After the reaction was complete by TLC, 10 mL of water and 20 mL of saturated NH4Cl were added, respectively.

2r-Benzamide (2-Ethoxy
10% Pd/C (120 mg) was added at ambient temperature under argon. The reaction atmosphere was then changed from argon to hydrogen and the solution was stirred for 48 h. After which, the reaction mixture was basified by adding the 1M NaOH solution (20 mL) and diluted with ethyl acetate (30 mL) and filtered through Celite. The filtrate was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: 3% NH4OH+15% CH3CN in DCM) to give the compound 2q in 60% yield.