The Regiospecific C-Benzylation of Heterocyclic Ketene Aminals with Ethyl 2-(Bromomethyl)benzoate: A Simple Route to 1H-Imidazo[1,2-b][2]benzazepin-5-one Derivatives

Abstract

Heterocyclic ketene aminals reacted with ethyl 2-(bromomethyl)benzoate in refluxing acetonitrile to afford the C-benzylated products that underwent intramolecular cyclocondensation reaction to produce e-lactam fused heterocyclic compounds. The heterocyclic ring size effect on the reaction was discussed.Key words: heterocyclic ketene aminals, ethyl 2-(bromomethyl)benzoate, 1H-imidazo[1,2-b][2]benzazepin-5-one Heterocyclic ketene aminals are powerful and versatile intermediates in heterocyclic synthesis. 1 Owing to the conjugation effect of the electron donating amino groups and electron withdrawing aroyl substituents, the aroyl substituted heterocyclic ketene aminals show an intriguing ambident nucleophilic reactivity. Thus, nucleophilic reaction may take place selectively on the enaminic carbon (a-carbon), 2 the secondary amino nitrogen 3 and the aroyl oxygen 4 depending on the electrophilic reagents and reaction conditions employed. One of the noticeable applications of heterocyclic ketene aminals is the preparation of fused heterocycles through their annulation reactions utilizing a-carbon and secondary amino nitrogen with bis electrophilic reagents. So far a range of bis electrophiles such as a,b-unsaturated compounds, 5 ethyl bromoacetate, 2b,6 a-bromoacetophenone, a-bromoacetone 7 and dimethyl oxalate 8 have been applied to construct various fused heterocycles including g-and d-lactam fused 1,3-diazaheterocyclic compounds. However, the synthesis of azepinone fused heterocycles has not been explored until now. Because of interesting biological activities, azepinone derivatives have attracted considerable attention both from synthetic and medicinal chemists. Our recent success in the regiospecific benzylation reaction of heterocyclic ketene aminals has led us to attempt the synthesis of e-lactam fused 1,3-diazaheterocyclic compounds from the reaction with ethyl 2-(bromomethyl)benzoate.To begin our study, we first examined the reaction of the five membered heterocyclic ketene aminals 1a-d with ethyl 2-(bromomethyl)benzoate 4. In refluxing acetonitrile, the reaction proceeded efficiently to give the C-benzylated compounds 5a-d as the sole products in high yield. Under identical conditions, the six and seven membered heterocyclic ketene aminal analogs 2 and 3 underwent the similar regiospecific C-benzylation reaction to afford the protonated amidinium salts 6 and 7 in most cases. The amidinium salts appeared very stable and could be purified by silica gel column chromatography. Under treatment with a solution of saturated potassium carbonate the six membered hexahydropyrimidinium salts 6b-d convert into the corresponding free bases 8b-d. No dehydrobromination reaction was observed for the seven membered intermediates 7a-d. Various reaction conditions were applied to promote intramolecular cyclocondensation reaction between the secondary amino group and the ester function. When the reaction was performed in ethanolic potassium hydroxide at room temperature, the five membered compounds 5a-d were transformed into th...

Design, Synthesis, Crystal Structure Analysis, and Insecticidal Evaluation of Phenylazoneonicotinoids

“…The double bond on the cyclic 1,1-enediamine bears the characteristic of high polarization resulting from the conjugation effect of an electron-withdrawing substituent and a strong electron-donating amino group . The α-carbon is the first reaction site when the intermediate is attacked by the electrophilic reagents owing to the delocalization effect of the lone pair electron on the nitrogen atom. , Various adducting reactions of methyleneimidazolidine with electrophiles such as heterocyclic aldehyde, benzyl bromide, ethyl propiolate, diphenylnitrile imine, and diazonium salt proceed smoothly and have been reported previously, ,− which proved to us the possibility of synthesizing the phenylazoneonicotinoids by reaction with different substituted diazonium salts (Scheme ).…”