Electrochemical synthesis of 4-quinazolinone derivatives mediated by acetic acid

The acid-catalyzed cyclization of 2-aminobenzamides into 4-quinazolines was achieved using a combination of carbon and aluminum electrodes under electrochemical conditions. Overall, the method offers large substrate scope with good functional group tolerance using acetic acid as an inexpensive electrolyte. Quinazolin-4(3 H )- one and 2-methylquinazolin-4(3 H )-one derivatives were also prepared under similar electrochemical conditions. The transformations occurred at room temperature with moderate to good yields. A few of the quinazolin-4(3 H )-one cores were successfully transformed into compounds similar to known anticancer drugs.


Introduction
[12] Figure 1.Active pharmaceutical agents and natural products containing quinazolinone structures.
There are various chemical methods known in the literature to prepare quinazolinone starting from 2aminobenzamides, but each process has their own limitations, like high temperatures and the use of transition metals.A few electrochemical methods have also been reported for the synthesis of 4-quinazolinones starting from 2-aminobenzamides (See scheme 1).Recently, Chen et al. have reported the electrochemical synthesis of 4-quinazolinones, but there are a very few reports of utilization of the said method to prepare quinazolin-4(3H)-ones and 2-methylquinazolin-4(3H)-ones which are important scaffolds in anticancer drugs. 13Yao et al. have also utilized various substituted benzyl chlorides to couple with 2-amino benzamides to prepare 4quinazolinones at high temperatures. 14In addition, Wang et al. have described the synthesis of quinazolinone derivatives at high reaction temperatures. 15We thus envisioned the synthesis of 4-quinazolinones from 2aminobenzamides by using an aluminum and carbon electrode system and acetic acid as an electrolyte though an oxidative cyclization in an undivided cell.To our pleasant surprise, it worked well to provide several valuable heterocyclic systems.This electrochemical method is thus quite useful to synthesize quinazolin-4(3H)one and 2-methylquinazolin-4(3H)-one derivatives in very good yields at room temperature and under mild reaction conditions.© AUTHOR(S) Scheme 1.[15]

Results and Discussion
7][18] Performing research on similar lines we electrochemically reacted benzaldehyde (1a) and 2-aminobenzamide (2a) in acetonitrile and after 3 h obtained 41% conversion (as per LCMS analysis).Encouraged by this result we screened a number of solvents (as listed in Table-1).We observed that polar protic solvent like methanol and ethanol facilitated the reaction and that increasing the ratio of methanol in the presence of acetonitrile led to a decrease in reaction time.
We have observed that by using acetonitrile as a solvent, the reaction did not move to full conversion, even after stirring for 24 h (entry 1a).Of interest was that an increase in the ratio of methanol to acetonitrile, appeared to improve the conversion rate.We also screened some polar aprotic solvents like DMSO, tetrahydrofuran and acetone, but did not observe any conversion in DMSO and tetrahydrofuran, whereas only 7% conversion was observed in acetone (entries 2-9).Furthermore, we obtained 86% conversion after 3 h, when methanol was used exclusively as a solvent (entry 10).The polar solvent would appear to facilitate the Schiff base formation leading to better conversion. 19Apart from methanol, promising results were also observed in ethanol for which 69% conversion was attained; however, by decreasing the polarity of the alcohols by using propanol only 39% conversion was observed after 3 h.Another advantage of having a polar solvent was the better solubility of the starting materials.All these electrochemical conversions were carried out through an electrochemical reactor prepared from a 5v mobile phone charger.In addition, a carbon rod (0.2 mm diameter) and aluminum wires were used as electrodes.Furthermore, a current of 0.35 A/cm -2 was passed through the reaction for 3h to carry out these electrochemical conversions in good yield.As a control reaction, we reacted 1a and 2a in methanol, using aluminum as cathode and carbon as anode with 5 equivalents of acetic acid without passing electric current through the system.After stirring this reaction for 3 h, the majority of non-cyclized starting materials were observed in the reaction.When we did the reaction without using acetic acid, we again observed mostly starting materials after 3 hours, with no trace of cyclized product being formed.Thus, it was confirmed that electric current and acetic acid were both required for the reaction to initiate.Acetic acid was used both as an accelerant for the Schiff base formation and an electrolyte and could easily be removed from the reaction mixture through a simple workup after the reaction was deemed complete.

Page 5 of 14 © AUTHOR(S)
With these optimized conditions in hand, we next turned our attention to exploring the substrate scope and generality of the method with differently substituted 2-aminobenzamides and aldehydes.As a result, we synthesized various substituted 4-quinazolinone in 58-87% yields (see Table 2).All these reactions were performed with equimolar ratio of aldehyde and 2-aminobenzamides.For example, aromatic aldehydes were coupled with 2-aminobenzamides to yield 3a and 3c, both in 85% yield, and 3b in 87% yield respectively.Heteroaromatic aldehydes also successfully participated in the electrochemical reaction to yield 3d and 3e in 83% and 80% respectively.It should be noted that 4-and 5-substituted 2-aminobenzamides are very commonly utilized in the synthesis of anticancer drugs. 20To this end, 4-methoxy-2-aminobenzamide, 5methoxy-2-aminobenzamide and 4,5-dimethoxy-2-aminobenzamide were coupled with benzaldehyde to give as outcome products 3f, 3g and 3h which were isolated in 86%, 82% and 84% yield respectively.Although the yield of 3f was found to be slightly greater than the 3g and 3h, it would be difficult to attribute this to the electron-rich benzamide system (as compared to 3g and 3h) as the yield difference falls within experimental error.
We then turned our attention to the synthesis of quinazolin-4(3H)-one and 2-methylquinazolin-4(3H)-one derivatives.To this end, 1, 3, 5-trioxane and paraldehyde were coupled with 2-amino benzamides to afford 3i and 3j in 60% and 70% yield respectively.Substituted 2-amino-benzamides were also coupled with 1,3,5trioxane to afford substituted quinazolin-4(3H)-one derivatives compounds 3k, 3l and 3p, 3q in 59%, 57%, 58% and 62% yield, respectively.Similarly, chloro-substituted 2-aminobenzamide was coupled with paraldehyde to provide substituted 2-methylquinazolin-4(3H)-one 3o, and 2-amino-N-methylbenzamide was reacted with paraldehyde and 1,3,5-trioxane to synthesize 3m and 3n in 61% and 71% yield respectively.We observed that in the reactions where we coupled 1,3,5-trioxane or paraldehyde with different 2-aminobenzamides it was required to increase the reaction time to 5 h to allow the reactions to go to completion.This increase in reaction time might be because of the use of the stable trimer forms of formaldehyde and acetaldehyde which require a longer time for Schiff base formation followed by cyclization.
We also tried to demonstrate in a few examples how the products could be further utilized to prepare various anti-cancer drug molecules.To this goal, utilizing the same electrochemical method, we synthesized substituted N-phenyl-7-methoxyquinazolin-4-amines 4 and 5 (from 3k and 3q as shown in Scheme-2) as compounds which are similar in structure to the marketed drugs, Gefitinib and Vantetinib.To this end, 3k and 3q were heated at reflux in POCl3 for 3 hours to give chloro intermediates (4' and 5') which were reacted with different anilines at 90 o C in isopropanol solvent to give 4 and 5 in 81% and 80% yield over two steps respectively.
Scheme 2. Extension of materials 3k and 3q into 4 and 5 bearing resemblance to common anticancer drugs.
We have also carried out scale up reactions by reacting benzaldehyde (1a) and 2-amino benzamide (1b) to prepare compound 3a' in 5 g scale.While we increased the scale of the reaction, no drastic change in yield was experienced; however, the reaction time was increased to 5 h to ensure the reaction went to completion.This process proved well across variety of substrates and scale of reactions.
Finally, in terms of an overall reaction sequence, the process is thought to begin with the acid-catalyzed reaction between the substituted 2-aminobenzamide 1 and a differently substituted aldehyde 2 to form hemiaminal intermediate 6, which dehydrates under the acidic conditions to provide imine intermediate 7. © AUTHOR(S) Imine 7 and cyclized compound 8 are interconvertible, with 8 then finally undergoing anodic oxidation to afford the desired product 3.

Conclusions
An easy, scalable and robust electrochemical method is developed to synthesize various 4-quinazolinone derivatives by reacting various (benz)aldehydes with substituted 2-aminobenzamides using acetic acid as an electrolyte.This method was utilized to synthesize substituted quinazolin-4(3H)-one and 2-methylquinazolin-4(3H)-one derivatives.All these moieties are very important in the recent drug discovery because of their pharmacological importance.Scale up of the reaction was also carried out to check the feasibility and scalability of reactions.

Experimental Section
General Method.All reagents were purchased from commercial sources (Sigma-Aldrich, Angene and TCI) and were used without further purification.Acetonitrile was dried over P2O5 before use.Methanol was used without drying.The reactions were monitored using pre-coated thin-layer chromatography (TLC) plates (Merck, silica gel 60 F254, 0.25 mm) and compounds were visualized either under ultraviolet light (254 nm) or by staining with iodine.Silica gel (100 -200 and 230-400 mesh) was used for column chromatography. 1 H and 13 C NMR spectra were recorded on Bruker Advance 400 instrument operating at 400 MHz ( 1 H), 101 MHz ( 13 C).Chemical shifts (δ) in and referenced to TMS as an internal standard (δ 0.00 for 1 H NMR) or DMSO-d6/CDCl3 (δ 77.0 ppm for 13 C NMR); coupling constants (J) are quoted in Hz.All 1 H-NMR had moisture observed at δ 1.5 -1.6 for CDCl3 and δ 3.3 for DMSO-d6.LCMS was recorded on WATERS ACQUETY H Class with PDA and SQ DETECTOR instrument.

Synthesis of compounds 4 and 5 4-Chloro-7-methoxyquinazoline (4').
To a solution of 7-methoxyquinazolin-4(3H)-one (200 mg, 1.14 mmol) in POCl3 (4 mL) was cool to 0 o C. Reaction mixture was refluxed for 3 h.The progress of the reaction was monitored by TLC.After completion of reaction, the reaction mixture was evaporated under reduced pressure and residue was co-evaporated twice with dichloromethane and dried under reduced pressure to afford 4chloro-7-methoxyquinazoline as brown liquid, which was utilized in next step without any purification.