Why are benzimidazoles efficiently acylated with esters? Identification of a tetrahedral hemiacetal alkoxide intermediate

Tetrahedron Letters

Volumn 46, Issue 30, 2005, Pages 5081-5084

  Asakawa, Ken Ichi ^b   Dannenberg, J J ^c   Fitch, Kenneth J ^a   Hall, Stan S ^d   Kadowaki, Chie ^b   Karady, Sandor ^a   Kii, Satoshi ^b   Maeda, Kenji ^b   Marcune, Benjamin F ^a   Mase, Toshiaki ^b   Miller, Ross A ^a   Reamer, Robert A ^a   Tschaen, David M ^a  

^a MERCK RESEARCH LABORATORIES   (United States)

^b BANYU PHARMACEUTICAL CO LTD   (Japan)

^c CITY UNIVERSITY OF NEW YORK   (United States)

^d RUTGERS UNIVERSITY   (United States)

Author keywords

Acylation; Benzimidazole; Hemiacetal alkoxide; Ketones; Tetrahedral intermediate

Indexed keywords

ACETAL DERIVATIVE; BENZIMIDAZOLE DERIVATIVE; ESTER DERIVATIVE; LACTAM DERIVATIVE; LACTONE DERIVATIVE;

ACYLATION; ARTICLE; CHEMICAL STRUCTURE; LOW TEMPERATURE; NUCLEAR MAGNETIC RESONANCE;

EID: 20544441249     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/j.tetlet.2005.05.068     Document Type: Article

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20. Dimethoxymethyl benzimidazole 1a was prepared as follows: A solution of benzimidazole (10 g), and benzenesulfonic acid (0.3 g) in trimethyl orthoformate (50 ml) was heated to reflux for 10 h followed by slow distillation for 2 h. The product was isolated by fractional distillation bp: 120-125°C and 3 mm. N-Methyl benzimidazole was the major byproduct contaminating all fractions. Alt 1a can be generated in situ and acylated without isolation as follows: the solution of benzimidazole (6.6 g), trimethyl orthoformate (23 ml) and benzenesulfonic acid (0.3 g) in toluene (60 ml) was heated to reflux then slowly distilled to remove half of the solvent. Toluene (60 ml) was added again and 40 ml was removed by slow distillation. The cooled solution was neutralized with 0.8 ml of diisopropylamine, THF (60 ml), and methyl benzoate (8.4 g) were added. The mixture was cooled to -78°C and LDA solution (34 ml, 2 M, in THF/heptane) was added dropwise. After aging for 2 h at that temperature, and warming to room temperature, 2 N HCl (57 ml) was added and the mixture was agitated for an hour. The pH was adjusted to 9 with 50% NaOH, 15 g NaCl was added and the layers were separated. The organic layer was washed with 10% sodium bicarbonate solution and concentrated to produce the ketone 5a in 76% yield.
21. Same procedure as described above starting with o-phenylenediamine and triethyl orthoformate.
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