Synthesis of N-Heteropolycyclic Compounds Including Quinazolinone Skeleton Using Friedel–Crafts Alkylation

Abstract A simple method to synthesize N-heteropolycyclic quinazolinones was developed including Knoevenagel condensation of quinazolines and aldehydes and Friedel–Craft alkylation as key steps. Knoevenagel reaction of 2-methyl-3-phenylquinazolin-4(3H)-one proceeded smoothly under a basic condition and subsequent Friedel–Craft alkylation with Brønsted acid gave the N-heteropolycyclic quinazolinones in good yields. Furthermore, these new polycyclic compounds were converted into organic molecules having a long π-conjugation system by treatment of 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) to utilize them as organic dyes. GRAPHICAL ABSTRACT


RESULTS AND DISCUSSION
We prepared a starting quinazolinone substrate (4a,b) from 2-nitrobenzoic acid (5a,b) via the following synthetic routes. At first, 5a,b was converted into 2-nitrobenzoyl chloride by oxalyl chloride, and a catalytic amount of N,N-dimethylformamide (DMF) in dichloroethane (DCE) and subsequent treatment of aniline gave the amide coupling product. After a reduction in the presence of palladium-charcoal catalysts under a hydrogen atmosphere, the amine product 6a,b was obtained in good yield. Finally, the acetylated product 7a,b was converted into 4a,b (Scheme 2) without any difficulties.
From the quinazolinone substrate (4) and aldehydes, the condensation product 3 was prepared in good yields by Knoevenagel reactions. The reaction proceeded smoothly in quite simple acidic or basic conditions. Various internal alkenyl products 3 having different electronic properties were synthesized under acidic conditions (Scheme 4).
With these Knoevenagel condensation products (3a-e), we tried to synthesize cyclization products by Friedel-Crafts reaction. The reaction conditions were screened with a quinazolinone 3c to optimize Brønsted acids or Lewis acids, solvents, and temperatures ( Table 1). Because of a harsh condition without solvent, methanesulfonic acid (MeSO 3 H), the reaction resulted in a lower yield (entry 1). A reduced amount of MeSO 3 H in dicholoroethene (DCE) gave good results at both 120°C and 150°C, but reaction time was long (entries 2 and 3). Eventually, trifluoromethanesulfonic acid (CF 3 SO 3 H) was found to be the best acid in our reaction conditions (entry 4). Phosphoric acid (H 3 PO 4 ) afforded cyclization product in 50% yield (entry 5). Lewis acids, such as AlCl 3 , FeCl 3 , BF 3 •OEt 2 , and TiCl 4 were not effective acid for this reaction (entries 6-9).  With these optimized conditions in hands, we were able to synthesize polycyclic compounds 2 containing quinazolinone skeleton (Scheme 5) for application to organic dyes.
Because 2 did not have a fully conjugated π system, we tried to convert them into 1 by aromatization. Thus, the fully conjugated product 1 was successfully synthesized by treatment of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) with 2 (Scheme 6). More complicated compounds 8 having longer π conjugation were also synthesized utilizing palladium-catalyzed cross-coupling reactions. For example, 1c was reacted with o-tolylboronic acid and styrene to give the corresponding cross-coupling product 8a and 8b, respectively (Scheme 7) in good yields.

CONCLUSIONS
In summary, we developed a methodology to produce heteropolycyclic compounds by simple Friedel-Crafts alkylation of quinazolinone derivatives. The fully conjugated quinazolinone derivatives are anticipated to be utilized as organic dyes. Spectroscopic analyses of our heteropolycyclic compounds are now in progress.

SUPPORTING INFORMATION
Supplemental data for this article can be accessed on the publisher's website.

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