Polycyclic N-Heterocyclic Compounds. Part 60: Reactions of 3-(2-Cyanophenyl)quinazolin-4(3H)-ones with Primary Amines

Abstract

3-Substituted-quinazolin-4(3H)-ones are prominent structures in the fields of medicinal and natural product chemistry. 2)Their related analogues are, therefore, attractive for potential pharmaceutical applications.In our previous paper, 1,3) we described that fused 3-(2-bromoethyl)pyrimidin-4(3H)-ones (1) can react with primary alkylamines to afford abnormal rearranged products (fused 3-alkyl-4-alkyliminopyrimidines (2)) in addition to substituted 3-(2-alkylaminoethyl) derivatives (Fig. 1). The abnormal rearranged products seemed to be as a result of a new type of Dimroth rearrangement. We also showed that one of the rearranged products had considerable antidepressant activity, comparable to that of imipramine.In 2000, W. Szczepankiewicz and J. Suwinski reported the one-pot reaction of 2-aminobenzonitrile and formic acid to form 3-(2-cyanophenyl)quinazolin-4(3H)-one (3), instead of quinazolin-4(3H)-one, which was the anticipated product. 4)We, therefore, wondered if a Dimroth-type rearrangement with primary alkylamines could be applied to substrate 3 to afford 3-alkyl-4-alkyliminoquinazolines. Another possibility was that an addition of the nucleophile, ring opening, and ring closure (ANRORC) reaction could occur to give 3-alkylquinazolin-4(3H)-ones (4). There have already been shown that N 1 -(2,4-dinitrophenyl (or 4-nitrophenyl))inosines with primary alkylamines afford N 1 -alkyl inosines via an ANRORC mechanism.5-9) Here we have described the reaction of 3 with primary alkylamines in detail.First, we tested the reaction of 3 with methylamine in N,N-dimethylformamide (DMF) at room temperature. The product 4a in 56% yield was obtained with 2-aminobenzonitrile as a side product, as confirmed by TLC (Chart 1). In the 1 H-NMR spectrum of 4a, one methyl group appeared at 3.61 ppm, one proton singlet of the pyrimidine ring appeared at 8.06 ppm, and four aromatic region signals of the 2-cyanophenyl moiety of 3 disappeared. In the IR spectrum of 4a, the appearance of a lactam carbonyl band at 1670 cm Ϫ1 and disappearance of the nitrile band were observed. These results suggested that an ANRORC reaction had occurred in the reaction of 3 with methylamine. Similar results were seen when ethylamine was used to give the product 4b in 52% yield.In addition, a reaction between 3 and n-propylamine did not proceed at room temperature, as shown by TLC analysis. Contrary to the reactions with methylamine or ethylamine, which were added as methanol or aqueous solutions, respectively, n-propylamine was used as a neat in DMF solution; we therefore assumed that a protic solvent was necessary to allow this ANRORC reaction. Addition of methanol as a cosolvent with DMF was tested to give the desired product 4c in 51% yield. We also tested combining 3 with tert-butylamine in the presence of methanol in DMF; however, no reaction occurred. Perhaps, steric hindrance of the tert-butyl group prohibited nucleophilic attack of amino functionality to 3. Furthermore, the reaction of 3 with dimethylamine did not proceed at all. We theorized that ...

Palladium‐Catalyzed Tandem Reaction of Quinazolinone‐Based Nitriles with Arylboronic Acids: Synthesis of 2‐(4‐Arylquinazolin‐2‐yl)anilines

“…To gain insight into the reaction mechanism, further experimental studies were performed under the standard conditions as shown in Scheme . Our initial attempts to perform the reaction in the absence of arylboronic acid failed to give the desired ring‐cleaved 2‐amino‐ N ‐(2‐cyanophenyl) benzamide ( 5 a ) (Scheme a) . In addition, the product 3 a could not be detected when the reaction of 5 a with 2 a (Scheme b).…”

Efficient Synthesis and Computational Studies of Useful Guanylating Agents: 1H‐Benzotriazole‐1‐carboximidamides

“…Compounds 2 a-e further stirred with hydroxylamine hydrochloride in dry methanol at room temperature for 2 h to afford the corresponding oximes (3 a-e) in good yields. [26] We optimized the reaction conditions by using various reagents to obtain the targeted products (Table 1) and we got 1H-benzotriazole-1-carboximidamides (4 a-e) when we treated compounds 3 a-e with acyl benzotriazole in presence of triethylamine in THF at 0°C for 6 h (Scheme 1). We isolated the pure products by using column chromatography.…”

N3-Alkylation during formation of quinazolin-4-ones from condensation of anthranilamides and orthoamides

“…9,10 These quinazolin-4-ones can then be readily alkylated at 3-N with alkyl halides and potassium hydroxide in methanol 11 or under phase-transfer conditions. 10 Less-used routes to N 3 -alkylquinazolin-4-ones include replacement of the whole [N 3 -Ar] unit of 3-(2-cyanophenyl)quinazolin-4-ones with primary alkylamines (by initial nucleophilic attack on the carbonyl), 12 copper(I)-catalysed reaction of N-alkyl-2iodobenzamides with formamidine, 13 photochemical rearrangements of 2-alkylcinnolinium-4-olates 14 and condensation of anthranilic acid with primary amines and orthoesters under Lewis acid catalysis 15, 16 and with alkylisocyanides. 17 The way is therefore open to examine whether 1a and its homologues can be used as a source of electrophilic one-carbon units to convert anthranilamides to 3-unsubstituted quinazolin-4-ones under milder conditions than required for the corresponding reaction with formamide; this study also included the effect of a diversity of substituents at the 3-position of the anthranilamide to test sensitivity to steric bulk ortho to the amine and to electronwithdrawing or electron-donating substituents which influence the nucleophilicity of this amine.…”