An immense effort has been made to develop efficient strategies for the direct functionalization of C H bonds using transition-metal catalysis. For the most part, ruthenium-, rhodium-, and palladium-based catalysts have been applied to effect either C C or C Het (Het= heteroatom) bond formation by replacement of a C H bond. Few examples have been described that employ copper as catalysts, which is particular attractive due to its low cost and low toxicity. Herein, we disclose a new Cu(OAc)2catalyzed synthesis of benzimidazoles from amidines through a C H functionalization/C N bond-forming process that uses oxygen as the oxidant and generates water as the only direct waste product. Recently, we reported that carbazoles could be formed by intramolecular C H bond functionalization. We were eager to extend our approach to the synthesis of other classes of heterocycles, such as benzimidazoles, which are of considerable importance in medicinal chemistry. Brain0s palladiumcatalyzed N-arylation of (ortho-bromophenyl)amidines to give benzimidazoles inspired us to use amidines as our starting materials. The cyclization of amidines by oxidative means had been reported earlier. However, the use of stoichiometric amounts of reagents, such as Pb(OAc)4 [9] and iodine(III) compounds, and a rather narrow functionalgroup scope—only examples with Me, Cl, and Br substituents were reported—are major disadvantages. NaOCl is known to promote the cyclization as well via N-chlorinated amidines. Although the low cost of NaOCl is an appealing feature, low to moderate yields were obtained for amidines bearing functional groups, and as mentioned in one report, chlorinated side products might be anticipated when this method is applied. Altogether, these drawbacks prompted us to reinvestigate this transformation. We started our study by examining the conversion of Nphenylbenzamidine (1) into 2-phenylbenzimidazole (2). After an initial screen of palladium and copper catalysts, solvents, and reaction temperatures, we found that the use of 15 mol% Cu(OAc)2 in DMSO at 100 8C under an oxygen atmosphere produced 2 after 18 h in 19% yield with a low conversion of 1 (Table 1, entry 1). Using 5 equivalents of pyridine or triethylamine as a basic additive, the conversion was enhanced, but

C-H functionalization/C-N bond formation: copper-catalyzed synthesis of benzimidazoles from amidines.

N,N′-Chelating biheteroaromatic ligands; a survey

A simple and efficient procedure for the synthesis of benzimidazoles using air as the oxidant

Synthesis and potent antimicrobial activity of some novel methyl or ethyl 1H-benzimidazole-5-carboxylates derivatives carrying amide or amidine groups.

Protection for the Amino Group

Benzoxazoles, benzothiazoles and benzimidazoles having substituents on the azole and benzene nuclei were synthesized evaluated for antifungal, insecticidal and herbicidal activities. It was found that benzimidazoles tended to exhibit antifungal activity while benzothiazoles tended to show herbicidal activity. Chloro, trifluoromethyl, methoxy and ethoxy groups at the 5 position were potent substituents, and the 2-pyridyl group at the 2 position is a common structural unit. Among several active derivatives, 7-chloro-2-(2-pyridyl) benzimidazole and 2-(2-pyridyl)-5-trifluoromethylbenzothiazole exhibited significant activity against Panonycus citri.

Synthesis of Benzoxazoles, Benzothiazoles and Benzimidazoles and Evaluation of Their Antifungal, Insecticidal and Herbicidal Activities

Acidic Properties of Benzimidazoles and Substituent Effects. IV. Relationship between the Acidities of N'-(Substituted Phenyl) arylamidines and Ring Closures to Imidazole

The preparation of series of 2-pyridyl-4(3H)-quinazolinones is described. Some of them showed a hypnotic action in mice when given orally. Studies on the structure-activity relationship demonstrated that 2-pyridyl, 3-pyridyl, and 4-pyridyl substitution at 2 position of quinazolinone ring, and o-, m-, and p-substitution of the aromatic ring at 3 position are suitable for manifestation of hypnotic activity. The order of potency of activities produced by the difference in the position of substitution of substituents at 2 and 3 position decreased in the order of 4-pyridyl, o-tolyl>3-pyridyl, o-tolyl>2-pyridyl, o-tolyl. The anthranilates of these 4(3H)-quinazolinones were inactive. A maximum hypnotic effect accompanied with other potent pharmacological properties was observed in 2-(4-pyridyl)-3-o-tolyl-4(3H)-quinazolinone (14), the potency of which was equal to or stronger than Methaqualone in mice.

Syntheses and Pharmacological Activities of 2-Heterocyclic Substituted 4(3H)-Quinazolinone Derivatives

The reaction of 2, 3-lutidine N-oxide (I) with phenyl isocyanate (IIa) in dimethyl-formamide at 110°C gave a 1 : 2 adduct (IIIa). Under reflux in ethanolic potassium hydroxide, IIIa readily lost a component of IIa and was converted to 5-methyl-6-N-phenylcarbamoylmethyl-3-pyridinol (IVa) in 95% yield. 2-Phenylpyridine N-oxides (V-VII) reacted with phenyl isocyanates (II) to afford 1 : 1 cycloadducts (IX-XI and XII-XIV). The reaction of 2-(p-nitrophenyl) pyridine N-oxide (VIII) with IIa directly afforded 2-anilino-6-(p-nitrophenyl) pyridine derivatives (XIVa and XVa).

Masataka Ichikawa

Papers

Synthesis of Benzoxazoles, Benzothiazoles and Benzimidazoles and Evaluation of Their Antifungal, Insecticidal and Herbicidal Activities

Acidic Properties of Benzimidazoles and Substituent Effects. IV. Relationship between the Acidities of N'-(Substituted Phenyl) arylamidines and Ring Closures to Imidazole

Syntheses and Pharmacological Activities of 2-Heterocyclic Substituted 4(3H)-Quinazolinone Derivatives

Reaction of Aromatic N-Oxides with Dipolarophiles. V. 1,3-Cycloaddition of 2-Substituted Pyridine N-Oxides with Phenyl Isocyanates

Acidic properties of benzimidazoles and substituents effects. I. Correlation between acid dissociations and hydrogen bondings of some benzimidazoles.