Synthesis of Pyrimidine‐Fused Benzazepines from 5‐Allyl‐4,6‐dichloropyrimidines

Abstract

A detailed examination of the synthesis of functionalized 6,11‐dihydro‐5H‐benzo[b]pyrimido[5,4‐f]azepines 4 is described. Base‐promoted aromatic nucleophilic substitution of 5‐allyl‐4,6‐dichloropyrimidines 1a–c with different N‐substituted anilines and indoline gave the corresponding aminolysis products 3a–p, which on acid‐promoted intramolecular Friedel–Crafts cyclization produced the target polysubstituted 6,11‐dihydro‐5H‐benzo[b]pyrimido[5,4‐f]azepines 4a–p in moderate to very high yields.

Five closely related 4-chloro-6,11-dihydro-5H-benzo[b]pyrimido[5,4-f]azepines: similar molecular structures but different supramolecular assemblies

“…Compounds (I)-(IV) were prepared according to the published method of Acosta-Quintero et al (2015). Colourless crystals of each, suitable for single-crystal X-ray diffraction, were grown by slow evaporation, at ambient temperature and in the presence of air, of solutions in heptane-ethyl acetate (4:1 v/v).…”

“…Accordingly, we have recently developed (Acosta-Quintero et al, 2015) a new synthetic approach (see Scheme 1) based on our previous work on intramolecular Friedel-Crafts alkylation as the key step in the construction of azepine ring systems containing different nitrogen-containing heterocycles (Palma et al, 2004(Palma et al, , 2010Yé pez et al, 2006). Accordingly, we have recently developed (Acosta-Quintero et al, 2015) a new synthetic approach (see Scheme 1) based on our previous work on intramolecular Friedel-Crafts alkylation as the key step in the construction of azepine ring systems containing different nitrogen-containing heterocycles (Palma et al, 2004(Palma et al, , 2010Yé pez et al, 2006).…”

An integrative study to identify novel scaffolds for sphingosine kinase 1 inhibitors

“…Synthesis of compounds 2–12 , 14 and 15 have not been previously reported in the literature, and thus their characterization is now described (compounds 7–9 were reported only as moderate antimicrobial and/or antioxidant agents, but without their synthesis and analytical data [49–51]). Synthesis and characterization of compounds 1 , 13 and 16 have been previously reported [52–54]. …”

“…Compound 2 was synthesized in two steps from synthetically available 4-chloro-6,11-dimethyl-6,11-dihydro-5H-benzo[ b ]pyrimido [5,4-f]azepine [52] by treatment with excess of hydrazine monohydrate and subsequent condensation of the resulted hydrazinyl derivative with p-chlorobenzaldehyde. Both the above precursor of compound 1 and compound 2 were prepared following the general procedure shown in Scheme 1, which starts from the corresponding 5-allyl-4,6-dichloropyrimidine that suffers aminolysis by reaction with a substituted N-methylaniline to afford the corresponding 5-allyl-4-arylamino-4-chloropyrimidine which under a strong acid media provokes intramolecular Friedel-Crafts cyclization to afford the corresponding 6,11–dihydro–5H–benzo [ b ]pyrimido [5,4–f]azepine; in the case of starting from p -methoxy-N-methylaniline, the demethylation of the methoxy group is observed in the cyclization step and so rendering the compound 1 .…”

“…Hydrazine monohydrate (0.15 mL, 3.0 mmol) was added to a stirred solution of 4-chloro-6,11-dihydro-5 H -benzo[ b ]pyrimido[5,4- f ]azepine (100 mg, 0.39 mmol) [52] in ethanol (10 mL). The mixture was heated at reflux for 24 h, and then ethanol and excess of hydrazine were removed under reduced pressure.…”