Bismuth-Catalyzed Synthesis of 2-Substituted Quinazolinones

Abstract

The bismuth-catalyzed oxidative condensation of aldehydes with 2-aminobenzamide under aerobic conditions is reported using ethanol as the solvent. Good to excellent isolated yields (68–95%) of the corresponding 2-substituted quinazolinones were obtained under mild reaction conditions with excellent functional group tolerance. The quinazolinones were further functionalized to afford N-allylated quinazolinones, 2-aminopyridine derivatives, and annulated polyheterocyclic compounds via transition-metal catalyzed reactions.

Graphical Abstract

1. Introduction

Quinazoline-4(3H)-ones represent a unique class of heterocycles that has attracted considerable attention due to their wide occurrence in natural products¹ and biologically active compounds (Fig. 1).² They exhibit a wide range of biological and pharmacological activities including antibacterial,^2b antimalarial,^2c antidiabetic,^2d antiallergic,^2e and antifungal properties.^2h In view of the significant value of quinazolinones and their analogs, various methodologies for their synthesis have been developed. Although reported methods are effective in many instances, the development of general, efficient, simple and sustainable approaches is still desirable.

Figure 1.

Selected biologically active quinazolinones

Classical routes for the synthesis of quinazolinones have relied on condensation reactions involving a variety of substrates including, but not limited to, 2-aminobenzamides,^3–9 2-halobenzamides,¹⁰ 2-halobenzonitriles or 2-nitrobenzonitriles,¹¹ amidines¹² and isatoic anhydrides,¹³ among which 2-aminobenzamides are the most explored. As part of our on-going contributions towards benign Lewis acid catalysis^14,17 and sustainable organic synthesis,¹⁸ we wish to report the synthesis of 2-substituted quinazolinones via oxidative cyclocondensation of 2-aminobenzamides with aldehydes catalyzed by a non-toxic and cost-effective bismuth salt in ethanol under mild aerobic conditions.

Synthetic strategies employed for the generation of 2-arylquinazoline-4(3H)-ones from 2-aminobenzamide (1a) can be summarized into three general routes (Scheme 1): (i) oxidative cyclocondensation of 1a with aldehydes,³ alcohols,⁴ and methyl ketones;⁵ (ii) Pd-catalyzed carbonylative reaction of 1a with aryl halides in the presence of carbon monoxide⁶ or isocyanides;⁷ and (iii) copper or hydrogen peroxide-promoted domino oxidative cyclocondensation of 1a with tertiary amines⁸ or benzylamine.⁹ Although most of these methods yield quinazolinones in modest to high yields, they usually require elevated temperatures in excess of 100 °C or a large excess of oxidant and non-renewable solvents.⁴ Recently, an iron nitrate/TEMPO catalyzed approach for the synthesis of quinazolinones was reported by Li and co-workers.^4e Although an improvement over previous methods, it still required stoichiometric amounts of oxidant. Transition metals, for example Ir, Ru, Pd, and Pt, have also been employed for the synthesis of quinazolinones.¹⁹ In 2016, Gao and coworkers reported a VO(acac)₂-catalyzed coupling of 1a with aldehydes or alcohols using O₂ as the oxidant, however DCE was used as the solvent and the reaction was carried out at 80 °C.^4f In 2017, Li and co-workers, utilized an expensive Ir-catalyst for the synthesis of quinazolinones via the dehydrogenative coupling of aminobenzamides and unsaturated aldehydes.^3g At the same time Paul and co-workers utilized a specially designed Ni-catalyst for the synthesis of 2-substituted quinazolinones.^4g Both of these methods, although very effective, require elevated temperatures (120 °C) and non-renewable, toxic solvents (toluene). More recently, in 2018, Sun and co-workers reported a TBHP-mediated oxidative cyclization of 1a with alcohols and aldehydes at 110 °C.^4h Despite these advances, there remains a significant need for simple, efficient and green processes for the synthesis of quinazolinones.²⁰

Scheme 1.

Routes for the synthesis of 2-arylquinazoline-4(3H)-ones from 2-aminobenzamide (1a).

We envisioned that non-toxic and relatively benign bismuth salts¹⁴ under aerobic conditions could function as more sustainable alternatives for the preparation of quinazolinones via oxidative cyclization. To test our hypothesis the cyclocondensation of 1a with benzaldehyde 2a was carried out in the presence of various bismuth salts (10 mol%) at 100 °C in toluene (PhMe) for 12 h (Table 1). We anticipated that the formation of 3a would proceed via intermediate dihydroquinazolinone 3b, hence the reaction mixture was monitored by GC-MS for both 3a and 3b. As expected we observed both in variable amounts under different catalyst conditions.

Table 1.

Investigation of bismuth Lewis acids for the oxidative cyclization of 1a with 2a in toluene.^a

Entry	B1X3	Conversion (%)	3a/3bb	Yield 3a (%)c
1	Bi(OTf)3	>99	85/15	78
2	Bi(NO3)3•5H2O	>99	82/18	75
3	Bi(OAc)3	82	56/44	36
4	Bi(OiPr)3	>99	42/56	31
5	BiF3	92	31/69	18
6	BiBr3	97	78/22	66
7	Ph3Bi	71	36/64	17
8	None	44	20/78	< 5

^aReagents and conditions: 1a (0.5 mmol), 2a (0.75 mmol, 1.5 equiv.), bismuth salt (10 mol%), PhMe (2 mL), 100 °C, 12 h, open air.

^bBased on GC-MS.

^cIsolated yield of 3a.

To our delight, nearly all bismuth(III) salts demonstrated promising potential to promote the oxidative cyclocondensation of 1a with 2a to form 3a via 3b (17–78%; Entries 1–7, Table 1). However, Bi(OTf)₃ and Bi(NO₃)₃•5H₂O were found to be superior for the selective formation of 3a in good isolated yield (78% and 75%, respectively, Entries 1 and 2). Slightly lower selectivity and yields were obtained with Bi(OAc)₃ and BiBr₃ (Entries 3 and 6). Poor selectivity and yield of 3a was obtained in the absence of catalyst (Entry 8). For additional investigation, we opted to employ Bi(NO₃)₃•5H₂O as the catalyst of choice due of its lower cost and toxicity compared to Bi(OTf)₃.²³

To further optimize the reaction for the complete oxidation of intermediate 3b to 3a, and to develop a more sustainable process, we examined the effect of solvents for the oxidative cyclization of 1a with 2a in presence of Bi(NO₃)₃•5H₂O (10 mol%) (Table 2). The reaction was found to be compatible with a diverse range of solvents including hydrocarbon, halogenated hydrocarbon, ethers, protic polar and aprotic polar solvents. However, in general, alcoholic solvents (Entries 8–10) were found to be optimal for maximizing the oxidation of 3b to 3a. Ethanol afforded complete conversion to 3a and was chosen for further studies (Entry 9).

Table 2.

Effect of solvents on the oxidative cyclization of 1a with 2a in the presence of Bi(NO₃)₃•5H₂O.^a

Entry	Solvent	Conversion (%)	3a/3bb	Yield, 3a (%)c
1	PhMe	> 99	84/16	75
2	1,4-Dioxane	> 99	75/25	66
3	DMF	94	60/40	49
4	THF	> 99	82/18	71
5	DCE	> 99	83/17	72
6	DMC	> 99	81/19	70
7	CH3NO2	> 99	95/5	86
8	MeOH	> 99	96/4	88
9	EtOH	> 99	100/0	91
10	iPrOH	> 99	97/3	88

^aReagents and conditions: 1a (0.5 mmol), 2a (0.75 mmol, 1.5 equiv), Bi(NO₃)₃•5H₂O (10 mol%), solvent (2 mL), 100 °C, 12 h, open air.

^bBased on GC-MS.

^cIsolated yield of 3a

In order to further optimize the reaction conditions, the model reaction using Bi(NO₂)₃•5H₂O as catalyst in EtOH was performed while varying other reaction parameters such as the temperature, catalyst loading, and molar equivalent of 2a (Table 3). The most efficient catalyst loading was found to be 10 mol% (Entry 1). No improvement was seen with increased catalyst loading (15 mol%, Entry 2) and the yield of 3b declined significantly with lower catalyst loadings (5 mol%, 62%; 2.5 mol%, 37%; Entries 3 and 4, respectively). Lowering the temperature to 60 °C had no deleterious effect on the reaction (Entries 6 and 7). However, lower temperatures resulted in incomplete oxidation of 3a to the desired 3b (Entries 7 and 8). When the reaction was performed under an inert atmosphere (Entry 11), dihydroquinazolinone was formed as the major product (70% yield), indicating the necessity of air for the oxidation.

Table 3.

Optimization of the reaction parameters^a

Entry	Catalyst (mol%)	T (°C)	2a (equiv)	Yield, 3a (%)c
1	10	100	1.5	91
2	15	100	1.5	91
3	5	100	1.5	62
4	2.5	100	1.5	37
5	10	80	1.5	91
6	10	60	1.5	92
7	10	40	1.5	28c
8	10	rt	1.5	16c
9	10	60	1.2	91
10	10	60	1.0	77
11	10	60	1.2	17d,e
12	none	60	1.2	12

^aReagents and conditions: 1a (0.5 mmol), 2a, Bi(NO₃y5H₂O, EtOH (2 mL), 12 h, open air.

^bIsolated yield of 3a.

^c3b was the major product (GC-MS).

^dreaction carried under N₂,

^e3b was isolated in 70% yield

With the optimized conditions in hand (Table 3, Entry 9), the scope of the oxidative cyclocondensation was explored for the synthesis of a variety of 2-substituted quinazolinones by varying the aldehyde and 2-aminobenzamide reactants (Table 4). Aromatic aldehydes possessing both electron donating and electron withdrawing groups performed well in all cases affording excellent yields of the desired quinazolinones. 1,4-Benzenedialdehyde afforded the mono-quinazolinone product exclusively in high yield (82%, Entry 6). More sterically encumbered aldehydes also reacted well to afford good yields; the yields for these substrates were further improved at slightly higher temperatures (Entries 9, 13, 15, 16 and 17). The reaction also proceeded in good yields with non-aromatic and aliphatic aldehydes. Chloroaminobenzamide (81%, Entry 10) and aminothiophenecarboxamide (70%, Entry 18) were also effective and gave the corresponding products in good yields.

Table 4.

Bismuth nitrate-catalyzed synthesis of 2-susbstituted quinazolinones in EtOH.^a

Entry	Product	Yield (%)b
1	R = H; R1 = H	91
2	R = H; R1 = 4-OMe	90
3	R = H; R1 = 4-NMe2	89
4	R = H; R1 = 4-CF3	78
5	R = H; R1 = 4-Cl	88
6	R = H; R1 = 4-CHO	82
7	R = H; R1 = 4-C(O)Me	78
8	R = H; R1 = 4-CN	77
9	R = H; R1 = 2-F	71 (88)c
10	R = Cl; R1 = H	81
11		88
12		91
13		72 (95)c
14		68c
15		70 (92)c
16		71 (89)c
17d		69 (85)c
18		70

^aReagents and conditions: 2-aminobenzamide (0.5 mmol), aldehyde (0.6 mmol, 1.2 equiv), Bi(NO₃)₃•5H₂O (5 mol%), EtOH (2 mL), 60 °C, 12 h, open air.

^bisolated yield.

^cReaction performed at 100 °C.

^d2.5 equiv. of acetaldehyde was used.

The selective functionalization and derivatization of 2-substituted quinazolinones to generate high value compounds is of significance.²⁰ In this context, we further demonstrated the late-stage functionalization of the cyclocondensation products via transition metal-catalyzed allylations, and annulations.^{18, 2} Thus, the preparation of synthetically useful N-allyl quinazolinone 4, fused quinazolinones 5 and 6, and 2-arylaminopyridine 7 have been demonstrated (Scheme 2).

Scheme 2.

Functionalization of quinazolones. Reagents and conditions: (a) cinnamyl alcohol, Pd(PPh₃)₄ (5 mol%), DMC, 100 °C, 12 h; (b) diphenyl acetylene, [RuCl₂(p-cymene)]₂) (5 mol%), Cu(OAc)₂ (2.2 equiv.), Na₂CO₃ (2.0 equiv.), PhCl, 90 °C, 16 h; (c) diphenyl acetylene, [RuCl₂(p-cymene)]₂) (5 mol%), AgOAc (0.2 equiv.), Cu(OAc)₂ (1 equiv.), TFA (1 equiv.), 1,4-dioxane, 100 °C, 12 h; (d) diphenyl acetylene, [RuCl₂(p-cymene)]₂) (5 mol%), AgOAc (0.2 equiv.), Cu(OAc)₂ (1 equiv.), TFA (1 equiv.), 1,4-dioxane-TFE, 100 °C, 12 h.

Conclusion

In conclusion, we have developed a bismuth-catalyzed protocol for the efficient formation of 2-substituted quinazolinones. The present work demonstrates the first investigation of Bi(III) Lewis acids for the condensation of 2-aminobenzamides with aldehydes under aerobic conditions. Bi(NO₂)₃•5H₂O was found to be a cost effective and nontoxic catalyst that can be used in ethanol as a solvent. The reaction displayed a diverse range of functional group tolerance and the mild conditions afford an efficient and practical method for the synthesis of biologically important functionalized heterocycles.

Highlights:

Sustainable green protocol for the synthesis of quinazolinones.

Bismuth-catalysis for the synthesis of quinazolinones.

Simple and efficient green methodology Biorenewable solvents.

Non-toxic catalysts.