Ultrasound-assisted condensation cyclization reaction: fast synthesis of quinazolinones from o-aminobenzamides and aldehydes under ambient conditions

Abstract

In this work, a facile and efficient ultrasound-assisted fast synthesis of quinazolinones from o-aminobenzamides and aldehydes is reported. The reaction proceeds smoothly under ambient temperature and pressure conditions without the need for a metal catalyst in just 15 minutes. In addition, this approach exhibits broad substrate tolerance and provides a series of quinazolinones with moderate to excellent yields. The results reported here reveal an important new application of ultrasound-assisted synthesis in the fast synthesis of valuable organic products.

---

Quinazolinones are an important class of nitrogen-containing heterocycles that have been found to exhibit a broad spectrum of biological and pharmacological activity, including anti-inflammatory,¹ antitumor,² antimicrobial,³ antifungal⁴ and antiviral activities.⁵ They are core structures commonly existing in a variety of natural products and pharmaceutical candidates, and a number of quinazolinone-based drugs have been approved (Fig. 1). For example, rutaecarpine from a Chinese herbal drug is used to treat anti-inflammatory and gastrointestinal disorders, cholera and headache.^6,7 Raltitrexed has played an important role in the treatment of advanced colorectal cancer where 5-fluorouracil (5-FU) is not tolerated or inappropriate, and has single-agent activity in a variety of advanced solid tumours.^8,9 Idelalisib is a potent small-molecule PI3K inhibitor that abrogates PI3K/Akt signaling and promotes apoptosis.^10,11 Albaconazole is a novel triazole antifungal drug with a potent broad spectrum of antifungal activity, favorable pharmacokinetics and high oral bioavailability.^12,13

Fig. 1 Selected examples of quinazolinone-based drugs.

In view of their importance as privileged scaffolds, a number of different synthetic approaches have been developed to synthesize quinazolinones over the past several decades.^14–21 Although many approaches have been used to synthesize quinazolinones to date, the most classical and versatile approach is the condensation reaction of o-aminobenzamides with aldehydes, alcohols, amines, or carboxylic acid derivatives (Scheme 1). Sreenivasa et al. revealed a protocol for the synthesis of quinazolinones via reaction between o-aminobenzamides and aldehydes using mesoporous ZrO₂-supported Cu₂O (Cu₂ZrO₃) as catalyst.²² Paul et al. reported a metal–ligand cooperative approach to achieve dehydrogenative functionalization of alcohols to quinazolinones.²³ Yi et al. disclosed a ruthenium-catalyzed synthesis of quinazolinones from the dehydrogenative and deaminative coupling reactions of o-aminobenzamides with amines.²⁴ Zhou et al. realized a strategy for the iron-catalyzed aerobic oxidative functionalization of sp³ C–H bonds for the construction of quinazolinones from o-aminobenzamides and carboxylic acid derivatives.²⁵ Despite the merits of these approaches, some of them suffer from limitations such as corrosive or environmentally unfriendly catalysts, special prefunctionalized reagents, long reaction time and harsh reaction conditions. Therefore, the pursuit of alternative approaches for the synthesis of quinazolinones in a facile, efficient and green way is still urgently needed.

Scheme 1 General approaches for the synthesis of quinazolinones.

Over the past decades, several novel technologies have emerged as powerful operating tools for organic synthesis, with the following being the most commonly used: visible light irradiation,^26–29 electrochemical technique,^30,31 microwave irradiation^32,33 and ultrasound irradiation.^34,35 Due to the uniqueness of ultrasound irradiation in accelerating organic reactions, its application has been widely reported.^36–38 Compared to conventional heating approaches, it not only reduces the reaction time but also improves the reaction rate and yield. In addition, ultrasound irradiation facilitates the reaction under ambient conditions, eliminating the need for high temperature, high pressure and metal catalyst.

Owing to these benefits, ultrasound irradiation offers an attractive alternative to achieve chemical transformations which are usually difficult to attain under mild conditions. Herein, we present an ultrasound-assisted fast synthesis of quinazolinones from the condensation cyclization reaction of o-aminobenzamides and aldehydes (Scheme 2). The reaction is carried out under ambient temperature and pressure conditions without the need for a metal catalyst. We believe that the present strategy not only represents a facile and efficient approach for the synthesis of quinazolinones but also exhibits promising prospects in organic synthesis.

Scheme 2 Our work for synthesis of quinazolinones.

The model reaction was initiated by choosing o-aminobenzamide 1a and benzaldehyde 2a as substrates in CH₃OH under ultrasound irradiation at 150 W and 60 °C for 30 min. As expected, the desired product 3aa was obtained with 55% yield (Table 1, entry 1). First, different solvents, such as C₂H₅OH, CH₃CN, DMF, THF and H₂O, were screened. Compared with CH₃OH, a similar yield was obtained by using C₂H₅OH as the solvent (Table 1, entry 2), and CH₃CN provided a lower yield (Table 1, entry 3). Besides, other solvents were not suitable for this reaction (Table 1, entries 4–6). Subsequently, various oxidants, such as DDQ, TBHP and DTBP, were evaluated and it was found that the best yield, as high as 80%, of the desired product 3aa was obtained when DDQ was used as the oxidant (Table 1, entry 7), while other oxidants such as TBHP or DTBP did not affect the yield of 3aa significantly (Table 1, entries 8 and 9).

Table 1 Optimization of the reaction conditions^a

Entry	Solvent	Oxidant (equiv.)	Power (W)	Temp (°C)	Time (min)	Yield^b (%)
a Reaction conditions: o-aminobenzamide 1a (1.0 mmol) and benzaldehyde 2a (1.0 mmol) as substrates, oxidant based on 1a, solvent (10.0 mL), under ultrasound irradiation. b Isolated yield.
1	CH3OH	—	150	60	30	55
2	C2H5OH	—	150	60	30	53
3	CH3CN	—	150	60	30	36
4	DMF	—	150	60	30	Trace
5	THF	—	150	60	30	Trace
6	H2O	—	150	60	30	N.R.
7	CH3OH	DDQ (1.0)	150	60	30	80
8	CH3OH	TBHP (1.0)	150	60	30	68
9	CH3OH	DTBP (1.0)	150	60	30	60
10	CH3OH	DDQ (1.2)	150	60	30	90
11	CH3OH	DDQ (1.5)	150	60	30	90
12	CH3OH	DDQ (1.2)	120	60	30	90
13	CH3OH	DDQ (1.2)	90	60	30	90
14	CH3OH	DDQ (1.2)	60	60	30	90
15	CH3OH	DDQ (1.2)	30	60	30	61
16	CH3OH	DDQ (1.2)	60	50	30	90
17	CH3OH	DDQ (1.2)	60	rt	30	90
18	CH3OH	DDQ (1.2)	60	rt	15	90
19	CH3OH	DDQ (1.2)	60	rt	10	83

---

Remarkably, the yield of 3aa increased from 80% to 90% with the DDQ loading increased to 1.2 equiv. (Table 1, entry 10). However, when the DDQ loading increased to 1.5 equiv., the yield of 3aa was not significantly improved (Table 1, entry 11). Next, the effect of different powers of ultrasound irradiation on the reaction was investigated. It was observed that the reaction afforded the best result with 90% yield under ultrasound irradiation with power of 60 W, and increase in the power from 60 W to 150 W did not affect the yield of the desired product 3aa (Table 1, entries 12–14). Further decrease in power to 30 W gave the desired product 3aa with only 61% yield (Table 1, entry 15). Then, the effect of temperature on the reaction was further explored. It was clear that increasing the reaction temperature had no effect on the reaction yield (Table 1, entry 16). We observed the formation of the desired product 3aa in an excellent yield of 90% when the reaction was carried out at room temperature (Table 1, entry 17). Finally, experiments with different reaction times were performed and it was found that the optimal reaction time could be reduced to 15 min (Table 1, entry 18). A decrease in yield was observed when the reaction time was reduced from 15 min to 10 min (Table 1, entry 19). In summary, the optimal reaction conditions were found to be o-aminobenzamide 1a (1.0 mmol), benzaldehyde 2a (1.0 mmol), DDQ (1.2 mmol), CH₃OH (10 mL) under ultrasound irradiation at 60 W for 15 min at room temperature.

Having identified the optimal reaction conditions, we explored the applicability of the reaction scope of diversely substituted aldehydes (Table 2). First, monosubstituted aromatic aldehydes bearing groups with different electronic effects at the para-, ortho- or meta-position were successively subjected to the conditions, and the desired products were obtained in moderate to good yields (3aa–3aq). Generally, aromatic aldehydes with electron-withdrawing substituents (–F, –Cl, –Br, –CF₃, –CN) provided higher yields of the desired products (3ab–3af, 3aj–3al, 3ao–3ap), mostly around 90%, while the desired products of electron-donating substituents (–CH₃, –OCH₃) were acquired in slightly lower yields of 80–85% (3ag–3ai, 3am–3an, 3aq). Also, the positions of the substituents on the aromatic aldehydes had little influence on the reaction. Multi-substituted aromatic aldehydes also worked well to afford the corresponding products 3ar and 3as in 89% and 80% yield, respectively. Next, heteroaromatic aldehydes with pyridinyl and thienyl groups were examined, and the corresponding products 3at and 3au were successfully acquired in 88% and 81% yield, respectively. In addition, it is important to note that aliphatic aldehydes were also tolerated and led to the corresponding products (3av–3ax) in acceptable yields of 75–78%.

Table 2 Reaction scope for aldehydes^a

a Reaction conditions: o-aminobenzamide 1a (1.0 mmol), aldehyde 2 (1.0 mmol), DDQ (1.2 mmol), CH₃OH (10 mL), ultrasound irradiation, 60 W, 15 min, rt.

---

To further supplement the substrate scope, we investigated the scope of o-aminobenzamides with benzaldehyde 2a as the reaction partner under optimal reaction conditions. To our pleasure, a range of o-aminobenzamides bearing various substitution patterns were tolerated in this reaction, thus giving the corresponding products in moderate to good yields (Table 3). Primary o-aminobenzamides bearing either an electron-withdrawing group or an electron-donating group at different positions of the phenyl ring proceeded smoothly to afford the desired products (3ba–3ea) in 82–90% yields. Moreover, 2-amino-N-methylbenzamide 1f was also compatible and afforded the corresponding product 3fa in 79% yield under optimal reaction conditions.

Table 3 Reaction scope for o-aminobenzamides^a

a Reaction conditions: o-aminobenzamide 1 (1.0 mmol), benzaldehyde 2a (1.0 mmol), DDQ (1.2 mmol), CH₃OH (10 mL), ultrasound irradiation, 60 W, 15 min, rt.

---

Based on the relevant literature,^39–43 a plausible reaction mechanism for the ultrasound-assisted synthesis of quinazolinones from the reaction of o-aminobenzamides and aldehydes is presented in Scheme 3. Initially, the condensation reaction between o-aminobenzamide 1a and benzaldehyde 2a afforded the imine intermediate A under ultrasound irradiation. Subsequently, the intramolecular cyclization of intermediate A occurred to generate the aminal intermediate B. Finally, the aminal intermediate B was prone to be oxidized to the desired product 3aa in the presence of DDQ which may be converted to the by-product DDQH₂. It is supposed that oxidation of the substrate occurs by hydride transfer from the substrate via anomeric-based oxidation to DDQ, thereby forming an ion pair adduct. The substrate-cation/DDQH ion pair may convert to the desired product and DDQH₂.

Scheme 3 A plausible reaction mechanism.

Conclusions

In summary, we successfully developed a facile and efficient approach for the fast synthesis of quinazolinones via ultrasound-assisted condensation cyclization reaction of o-aminobenzamides and aldehydes. The approach was performed with CH₃OH as the solvent and DDQ as the oxidant under ultrasound irradiation at 60 W for 15 min at room temperature. The reactions proceeded smoothly, affording the corresponding quinazolinones in moderate to excellent yields with good functional group tolerance. The present approach significantly improved conventional approaches, giving way to obvious advantages including ease of operation, short reaction time, metal-free and mild reaction conditions. Moreover, a plausible reaction mechanism for the ultrasound-assisted synthesis of quinazolinones was proposed based on the relevant literature. The application of this approach to the preparation of other valuable organic products is underway in our laboratory.

Data availability

The authors confirm that the data supporting the findings of this study are available within the article and/or its ESI.†

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

The authors are grateful for the support from the Tangshan Science and Technology Plan Project (No. 24130220C), the Basic Research Fund of Provincial Universities in Hebei Province (No. JJC2024037) and the Natural Science Foundation of Hebei Province of China (No. B2021209007).

Notes and references

1. A. Kumar and C. S. Rajput, Eur. J. Med. Chem., 2009, 44, 83–90.
2. M. A. Mohamed, R. R. Ayyad, T. Z. Shawer, A.-M. Alaa and A. S. El-Azab, Eur. J. Med. Chem., 2016, 112, 106–113.
3. S. K. Pandey, U. Yadava, A. Upadhyay and M. L. Sharma, Bioorg. Chem., 2021, 108, 104611.
4. W. Ettahiri, R. Salim, M. Adardour, E. Ech-Chihbi, I. Yunusa, M. M. Alanazi, S. Lahmidi, A. E. Barnossi, O. Merzouki and A. Iraqi Housseini, Molecules, 2023, 28, 5340.
5. M. Ashraf-Uz-Zaman, X. Li, Y. Yao, C. B. Mishra, B. K. Moku and Y. Song, J. Med. Chem., 2023, 66, 10746–10760.
6. K. M. Tian, J. J. Li and S. W. Xu, Pharmacol. Res., 2019, 141, 541–550.
7. X. Li, J. Ge, Q. Zheng, J. Zhang and R. Liu, Phytomedicine, 2020, 68, 153180.
8. E. Van Cutsem, D. Cunningham, J. Maroun, A. Cervantes and B. Glimelius, Ann. Oncol., 2002, 13, 513–522.
9. C. Kelly, N. Bhuva, M. Harrison, A. Buckley and M. Saunders, Eur. J. Cancer, 2013, 49, 2303–2310.
10. D. A. Fruman and L. C. Cantley, N. Engl. J. Med., 2014, 370, 1061–1062.
11. A. Markham, Drugs, 2014, 74, 1701–1707.
12. G. Aperis and E. Mylonakis, Expert Opin. Invest. Drugs, 2006, 15, 579–602.
13. R. M. Guillon, F. Pagniez, C. Picot, D. Hédou, A. Tonnerre, E. Chosson, M. Duflos, T. Besson, C. D. Logé and P. Le Pape, ACS Med. Chem. Lett., 2013, 4, 288–292.
14. F. Teng, T. Yu, Y. Peng, W. Hu, H. Hu, Y. He, S. Luo and Q. Zhu, J. Am. Chem. Soc., 2021, 143, 2722–2728.
15. X. Yang, G. Cheng, J. Shen, C. Kuai and X. Cui, Org. Chem. Front., 2015, 2, 366–368.
16. X. Jiang, T. Tang, J. M. Wang, Z. Chen, Y. M. Zhu and S. J. Ji, J. Org. Chem., 2014, 79, 5082–5087.
17. Z. Xie, J. Lan, H. Zhu, G. Lei, G. Jiang and Z. Le, Chin. Chem. Lett., 2021, 32, 1427–1431.
18. Z. Bie, G. Li, L. Wang, Y. Lv, J. Niu and S. Gao, Tetrahedron Lett., 2016, 57, 4935–4938.
19. S. R. Vemula, D. Kumar and G. R. Cook, Tetrahedron Lett., 2018, 59, 3801–3805.
20. T. Ahl el haj, K. E. Mejdoubi, K. Sadraoui, B. C. El Idrissi and B. Sallek, Kinet. Catal., 2022, 63, 707–715.
21. B. Dutta, R. P. Borah, L. Bahsis, A. Dutta, B. Sarma, K. Singh, A. Kumar and D. Sarma, Eur. J. Org. Chem., 2024, e202400789.
22. L. Parashuram, S. Sreenivasa, S. Akshatha, V. U. Kumar and S. Kumar, Asian J. Org. Chem., 2017, 6, 1755–1759.
23. S. Das, S. Sinha, D. Samanta, R. Mondal, G. Chakraborty, P. Brandao and N. D. Paul, J. Org. Chem., 2019, 84, 10160–10171.
24. P. T. Kirinde Arachchige and C. S. Yi, Org. Lett., 2019, 21, 3337–3341.
25. X. Chen, T. Chen, F. Ji, Y. Zhou and S. F. Yin, Catal. Sci. Technol., 2015, 5, 2197–2202.
26. D. M. Schultz and T. P. Yoon, Science, 2014, 343, 1239176.
27. L. Marzo, S. K. Pagire, O. Reiser and B. König, Angew. Chem., Int. Ed., 2018, 57, 10034–10072.
28. M. Zhang, Q. Y. Fu, G. Gao, H. Y. He, Y. Zhang, Y. S. Wu and Z. H. Zhang, ACS Sustainable Chem. Eng., 2017, 5, 6175–6182.
29. J. Q. Di, M. Zhang, Y. X. Chen, J. X. Wang, S. S. Geng, J. Q. Tang and Z. H. Zhang, Green Chem., 2021, 23, 1041–1049.
30. Y. Jiang, K. Xu and C. Zeng, Chem. Rev., 2017, 118, 4485–4540.
31. M. Yan, Y. Kawamata and P. S. Baran, Chem. Rev., 2017, 117, 13230–13319.
32. Á. Díaz-Ortiz, P. Prieto and A. De La Hoz, Chem. Rec., 2019, 19, 85–97.
33. A. De la Hoz, A. Diaz-Ortiz and A. Moreno, Chem. Soc. Rev., 2005, 34, 164–178.
34. B. Banerjee, Ultrason. Sonochem., 2017, 35, 1–14.
35. G. Cravotto and P. Cintas, Chem. – Eur. J., 2007, 13, 1902–1909.
36. G. Brahmachari, N. Nayek, M. Mandal, A. Bhowmick and I. Karmakar, Curr. Org. Chem., 2021, 25, 1539–1565.
37. S. Saranya, S. Radhika, C. M. Afsina Abdulla and G. Anilkumar, J. Heterocyclic Chem., 2021, 58, 1570–1580.
38. S. Puri, B. Kaur, A. Parmar and H. Kumar, Curr. Org. Chem., 2013, 17, 1790–1828.
39. S. Rachakonda, P. S. Pratap and M. V. B. Rao, Synthesis, 2012, 44, 2065–2069.
40. S. H. Siddiki, K. Kon, A. S. Touchy and K.-i. Shimizu, Catal. Sci. Technol., 2014, 4, 1716–1719.
41. Q. Wang, M. Lv, J. Liu, Y. Li, Q. Xu, X. Zhang and H. Cao, ChemSusChem, 2019, 12, 3043–3048.
42. N. Ghorashi, Z. Shokri, R. Moradi, A. Abdelrasoul and A. Rostami, RSC Adv., 2020, 10, 14254–14261.
43. V. T. Nguyen, H. Q. Ngo, D. T. Le, T. Truong and N. T. Phan, Chem. Eng. J., 2016, 284, 778–785.

---

Footnote

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d4re00479e

---