Synthesis and Application of N-Methylbenzamide

General description

N-Methylbenzamide, a pale yellow or white solid with a burning point of 74°C, is an important pesticide intermediate. N-Methylbenzamide is a potent phosphodiesterase 10A (PDE10A) inhibitor. N-Methylbenzamide has anticancer activity.

Fig. 1 The structure of N-Methylbenzamide.

Synthetic routes

Fig. 2 The synthetic method 1 of N-Methylbenzamide.

Weigh N-methoxy-N-methylbenzamide (45 mg, 0.30 mmol, 1.0 equiv.), 2, 4, 5, 6-tetra (9H-carbazol-9-yl) isophthalonitrile (5 mol%) and LiBF₄ (2.0 equiv.) in round bottom flask. Seal the flask, evacuate and purge with argon. Add degassed MeCN (0.1 M) and diisopropylethylamine (1.0 equiv.). Stir the reaction mixture for 16 h under light irradiation (402 nm). Remove the solvent in vacuo. Purify the crude residue by column chromatography (60% EtOAc in n-pentane). 1H NMR (400 MHz, DMSO-d₆): δ (ppm) = 8.42 (s, 1H), 7.86 .-. 7.79 (m, 2H), 7.54 .-. 7.48 (m, 1H), 7.48 .-. 7.42 (m, 2H), 2.78 (d, J= 4.6 Hz, 3H) HRMS exact mass calculated for [M+Na]⁺(C8H9NONa⁺): 158.0576; found 158.0574 [1].

Fig. 3 The synthetic method 2 of N-Methylbenzamide.

Add benzoic acid (977 mg, 8 mmol), dry DCM (20 mL) and catalytic amount of DMF in a 100 mL round-bottom flask. Cool the reaction mixture to 0°C and stir for 5 minutes. Add (COCl)₂ (0.89 mL, 1.3 equiv.) dropwise to the reaction mixture and stir at room temperature for 4 hours. Concentrate the resulting mixture under reduced pressure to obtain acid chloride. Add catalytic amount of 4-dimethylaminopyridine, dry DCM (15 mL), MeNH₂ (2 (M) in THF) (5.19 mL, 1.3 equiv.) and Et₃N (1.56 mL, 1.4 equiv.) to the mixture in a 100 mL round-bottom flask. Cool the reaction mixture to 0°C. Add acid chloride (1.0 equiv.) dropwise at 0°C. Stir the reaction mixture at room temperature for 12 hours. Add water (40 mL) and seperate the organic layer. Extract the aqueous layer with DCM (3 x 30 mL). Wash the combined organic layer with saturated aqueous NaHCO₃ (30 mL) solution followed by water (30 mL). Dry the organic layer over Na₂SO₄ and concentrated under reduced pressure. Purify the crude mass by silica gel column chromatography (20% ethyl acetate in hexane as eluent) to obtain N-methylbenzamide [2].

Fig. 4 The synthetic method 3 of N-Methylbenzamide.

Charge a 10 mL crimp vial, equipped with a magnetic stirring bar with methylene blue trihydrate (3.7 mg, 10 mol%), sodium dodecyl laurate (72 mg, 0.25 mmol), 2-bromo-N-benzyl-N-methylbenzamide (30.4 mg, 0.1 mmol) and distilled water (5 mL). Degas the resulting mixture via five pump-argon cycles. Add n-BuNH₂ (0.30 mmol) to the reaction mixture under argon. Degas the mixture again via two short pump-argon cycles. Irradiate the reaction mixture with 7 W 455 nm LEDs through the plane bottom side. Stir the reaction mixture intensely for 20 h. Maintain the temperature at 40°C to 42°C by cooling with the built-in cooling fan. Open the vial. Transfer the crude reaction mixture to a separatory funnel. Add saturated solution of K₂CO₃ (5 mL) and brine (20 mL) to the reaction mixture. Extract the mixture with AcOEt (3 x 20 mL). Wash the combined organic fractions with fresh brine. Dry the combined organic fractions over MgSO₄. Filter the combined organic fractions. Concentrate the filtrate in vacuo. Purify the crude product by flash column chromatography on silica gel (AcOEt:n-hexane 20%) to obtain N-methylbenzamide [3].

Application

Preparation of Dinuclear organoplatinum(II) complexes

The preparation and characterization of cationic, dinuclear complexes of the type trans-[Pt(PPh3)(2)(sigma-C₆H₄NHMe)-mu-L-Pt(PPh₃)(2)(sigma-C₆H₄NHMe)](OTf)(2) (L = 4,4'-bipyridine, 4,7-phenanthroline, 4,4'-dipyrazolylmethane, and 1,1'-diphenyl-4,4'-dipyrazolylmethane; OTf = trifluoromethanesulfonate (triflate)) containing two C-3-N-methylbenzamide ligands are described. The key structural feature of the cationic complexes is the presence of two convergent amide groups that may allow for charge-assisted, H-bonding interactions in solution with suitable heteroaromatic guest molecules such as nucleobases [4].

As phosphodiesterase 10A (PDE10A) inhibitors

PDE10A is a recently identified phosphodiesterase with a quite remarkable localization since the protein is abundant only in brain tissue. Based on this unique localization, research has focused extensively on using PDE10A modulators as a novel therapeutic approach for dysfunction in the basal ganglia circuit including Parkinson's disease, Huntington's disease, schizophrenia, addiction and obsessive compulsive disorder. Medicinal chemistry efforts identified the N-methyl-N-[4-(quinolin-2-ylmethoxy)-phenyl]-isonicotinamide (8) as a nanomolar PDE10A inhibitor. A subsequent Lead-optimization program identified analogous N-methylanilides and their corresponding N-methylbenzamides (29) as potent PDE10A inhibitors, concurrently some interesting and unexpected binding modes were identified [5].

References

[1] Soika J, McLaughlin C, Nevesely T, et al. Organophotocatalytic N–O Bond Cleavage of Weinreb Amides: Mechanism-Guided Evolution of a PET to ConPET Plat-form[J]. 2022.

[2] Hoque M E, Bisht R, Unnikrishnan A, et al. Iridium‐Catalyzed Ligand‐Controlled Remote para‐Selective C? H Activation and Borylation of Twisted Aromatic Amides[J]. Angewandte Chemie, 2022: e202203539.

[3] Cybularczyk-Cecotka M, Predygier J, Crespi S, et al. Photocatalysis in Aqueous Micellar Media Enables Divergent C–H Arylation and N-Dealkylation of Benzamides[J]. ACS Catalysis, 2022, 12(6): 3543-3549.

[4] Crisp M G, Rendina L M. Dinuclear organoplatinum (II) complexes containing N-methylbenzamide[J]. Canadian Journal of Chemistry, 2009, 87(1): 212-216.

[5] Kilburn J P, Kehler J, Langg?rd M, et al. N-Methylanilide and N-methylbenzamide derivatives as phosphodiesterase 10A (PDE10A) inhibitors[J]. Bioorganic & medicinal chemistry, 2013, 21(19): 6053-6062.

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