Oxidant- and metal-free synthesis of 4(3H)-quinazolinones from 2-amino-N-methoxybenzamides and aldehydes via acid-promoted cyclocondensation and elimination

Abstract

A series of biologically important 4(3H)-quinazolinones were readily synthesized in good to excellent yields from 2-amino-N-methoxybenzamides and aldehydes via a cascade reaction consisting of AcOH-promoted cyclocondensation and elimination. The current method sets itself apart from the conventional approach utilizing anthranilamide derivatives and aldehydes as building blocks, by its unique features, other than the high yields and one-pot procedure, including the absence of an oxidant, the elimination of a heavy-metal catalyst, and the formation of a non-toxic ester byproduct.

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Quinazolinones are an important class of nitrogen-containing heterocycle (azaheterocycles) which exhibit a range of biological and pharmaceutical properties,¹ including but not limited to antihypertensive,² anticancer,³ anti-inflammatory,⁴ antimalarial⁵ and antimicrobial⁶ activities. In addition to their occurrence in natural products, they also frequently appear in pharmaceutical agents for their applications as potent antagonistic receptors.⁷ For example, Pegamine, isolated from Peganum harmala, has been found to possess cytotoxic activity,⁸ and NPS 53574, a new calcilytic template for blocking calcium receptor (CaR) activity, is proven to be capable of treating osteoporosis (Fig. 1).⁹ Both of these two biologically active compounds possess the common quinazolinone skeleton in their respective structure.

Fig. 1 Representative quinazolinones in natural products and pharmaceutical agents.

Considering the significance of this class of compounds, many efforts have been devoted to explore the methodologies for the construction of 4(3H)-quinazolinone skeletons. The representative methods involve cyclization of o-acylaminobenzamide,¹⁰ amination of benzoxazin-4-one,¹¹ multicomponent reactions (MCRs) among isatoic anhydride, amine with aldehyde,¹² benzyl halide¹³ or orthoester.¹⁴ In addition, transition metal catalysts such as copper,¹⁵ ruthenium,¹⁶ iridium¹⁷ and palladium¹⁸ have also been applied to the synthesis of quinazolinones through a one-pot oxidative cyclization of primary alcohols with o-aminobenzamides as well as through a domino process of N-arylation followed by condensative cyclization. Another extensively studied strategy was a sometimes metal-free, one-pot protocol which involves a cyclocondensation of anthranilamides with aldehydes followed by a subsequent oxidant-mediated dehydrogenation process (Scheme 1, eqn (1)).¹⁹ Various non-metal oxidants such as DDQ,^19a I₂,^19f O₂²⁰ as well as metal ones such as CuCl₂,^19c KMnO₄,^19e have been applied to realize the second oxidative step. Although this last strategy has some practical advantages and potential applications, many of the existing methods have the disadvantages such as harsh conditions, unsatisfactory yields and most seriously, the use of the stoichiometric oxidants or heavy-metal reagents. To the best of our knowledge, there are few reports, if any, describing the dehydrogenation step that does not require the participation of an oxidant or a heavy-metal catalyst.²¹ In this communication, we report a novel green protocol for the synthesis of 4(3H)-quinazolinone compounds 3, that is free of oxidant or catalyst and was carried out in a convenient one-pot reaction between 2-amino-N-methoxybenzamides 1 and various aldehydes 2, going through an intermediate of 3-methoxy-2,3-dihydroquinazolin-4(1H)-one A (Scheme 1, eqn (2)). It is worthy to note that the generated MeOH was converted to a nontoxic ester as a byproduct in this approach.²²

Scheme 1 Strategies of synthesis of 4(3H)-quinazolinones.

In our previous work,²³ we found that the reaction of 2-amino-N-methoxybenzamides 1 with aldehydes 2 conveniently afforded 3-methoxy-2,3-dihydroquinazolin-4(1H)-ones A in the presence of catalytic amount of TsOH. We envisaged that the treatment of 3-methoxy-2,3-dihydroquinazolin-4(1H)-one A with a suitable acid might trigger an acid-promoted demethanolization and thereafter give 4(1H)-quinazolinone B, which should quickly isomerize into 4(3H)-quinazolinone 3 (Scheme 2). To our pleasant surprise, we found that by heating the isolated 3-methoxy-2,3-dihydroquinazolin-4(1H)-one A₁ in refluxed TFA for 55 minutes, the desired 4(3H)-quinazolinone 3a was obtained in 84% yield (Scheme 3).

Scheme 2 Proposed route to access 4(3H)-quinazolinones.

Scheme 3 Conversion of A₁ into 3a through acid-promoted elimination of MeOH.

Considering the fact the formation of 3-methoxy-2,3-dihydroquinazolin-4(3H)-one A was also realized under acidic conditions, we next focused on designing a cascade reaction which entails developing a one-pot protocol for the synthesis of 3 from 1 and 2. We selected 2-amino-N-methoxybenzamide 1a and benzaldehyde 2a as model substrates. To our delight, after heating the two starting materials in TFA for 1 h, the reaction afforded the desired product 3a in 81% yield (Table 1, entry 1). Various acids were used as solvent to further screen for the more favorable reaction conditions (Table 1, entries 2–7). Judging by the yield of the desired product, acetic acid was concluded as the best solvent (Table 1, entry 7). By increasing the reaction temperature from 80 °C to 100 °C, the reaction time was cut down by half, from 3 h to 1.5 h, and the yield was slightly increased (Table 1, entry 8). However, operating the reaction at even higher temperature did not improve the product yield, although the reaction time was further shortened to 1 h (Table 1, entry 9). Study on the concentration of the reactant 1a showed neither higher nor lower concentration was beneficial to the reaction as negative consequences such as more byproducts (therefore less desired product) or lengthened reaction time were observed, respectively (Table 1, entries 10–11).

Table 1 Optimization of reaction conditions^a

Entry	Solvent	T (°C)	Time (h)	Yield^b (%)
a Reaction conditions: substrate 1a (1.0 mmol) and aldehyde 2a (1.1 mmol) in solvent (4 mL).b Isolated yields.c The concentration of the reaction was 0.5 mol L^−1, based on substrate 1a.d The concentration of the reaction was 0.20 mol L^−1, based on substrate 1a.
1	TFA	Reflux	1	81
2	PivOH	80	8	0
3	CHCl2COOH	80	1.5	70
4	TfOH	80	12	ND
5	HCl	80	3	12
6	HCO2H	80	12	34
7	AcOH	80	3	88
8	AcOH	100	1.5	93
9	AcOH	110	1	89
10^c	AcOH	100	1.5	82
11^d	AcOH	100	4	92

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With the optimal reaction conditions in hand, the scope and generality of this new one-pot protocol was investigated, the results of which are summarized in Table 2. By reacting 2-amino-N-methoxybenzamide 1a with substituted aldehydes 2b–e, bearing electron-withdrawing groups, the desired products 3b–e were conveniently achieved in satisfactory to excellent yields (Table 2, entries 2–5) in each case. One slight exception was the reaction between 1a and 2e, which was completed in a much longer 4.5 h and afforded the desired product 3e in relatively lower yield. This was obviously due to the steric hindrance brought by the o-substituted bulky trifluoromethyl group in aldehyde 2e (Table 2, entry 5). The method was equally well applicable to the benzaldehydes bearing electron-rich substituent (Table 2, entries 6–8). In the case of di-substituted benzaldehydes, bearing either electron-withdrawing or electron-donating group, the desired products were obtained in even better yields (Table 2, entries 9–10). Each of the substrates, containing either an electron-deficient or electron-rich substituent on the benzene ring of 2-amino-N-alkoxybenzamide, was converted to the corresponding 4(3H)-quinazolinone products 3k–m in good to excellent yields (Table 2, entries 11–13). Further study revealed that the aromatic aldehydes could also be replaced with aliphatic aldehydes, rendering the method applicable to the synthesis of 2-alkyl-4(3H)-quinazolinones 3n–q in good to excellent yields (Table 2, entries 14–17). Furthermore, we were pleased to find that (E)-2-(1-phenylprop-1-en-2-yl)quinazolin-4(3H)-one 3r could also be obtained in good yield, which indicated that this method was also compatible with the aldehydes bearing an α,β-unsaturated double bond (Table 2, entry 18).

Table 2 Synthesis of 4(3H)-quinazolinones via AcOH-promoted cyclocondensation and elimination^a

Entry	1		2		Product 3	Time (h)	Yield^b (%)
	R^1		R^2
a Reaction conditions: substrate 1a (1.0 mmol) and aldehyde 2a (1.1 mmol) in solvent (4 mL).b Isolated yields.c 3 equiv. of aldehyde was used.
1	H	1a	Ph	2a	3a	1.5	93
2	H	1a	p-Br-Ph	2b	3b	1	95
3	H	1a	p-F-Ph	2c	3c	0.5	95
4	H	1a	m-Cl-Ph	2d	3d	0.3	82
5	H	1a	o-CF3-Ph	2e	3e	4.5	81
6	H	1a	p-Me-Ph	2f	3f	1	87
7	H	1a	p-MeO-Ph	2g	3g	1	73
8	H	1a	p-OH-Ph	2h	3h	2	92
9	H	1a	2,6-diCl-Ph	2i	3i	2	95
10	H	1a	3,4-diMeO-Ph	2j	3j	1	98
11	5-Br	1b	Ph	2a	3k	0.3	93
12	3-Me	1c	Ph	2a	3l	0.5	80
13	4-MeO	1d	Ph	2a	3m	0.5	98
14	H	1a	n-propyl	2k	3n	1	79
15	6-Cl	1e	n-propyl	2k	3o	1	75
16^c	4-F	1f	Me	2l	3p	5	95
17^c	4-MeO	1d	i-propyl	2m	3q	3	80
18	H	1a	(E)-Ph-CH=C(Me)	2n	3r	3	82

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Unfortunately, when 4-nitrobenzaldehyde 2o and 2-amino-N-methoxy-4-nitrobenzamide 1g were applied, the reaction only gave 3-methoxy-2-(4-nitrophenyl)-2,3-dihydroquinazolin-4(1H)-one A₂ and 3-methoxy-7-nitro-2-phenyl-2,3-dihydroquinazolin-4(1H)-one A₃ as the only products, rather than the expected 4(3H)-quinazolinones even at reflux temperature for 14 h. To our delightful surprise, treating the obtained compound A₂ and A₃ with KOH in DMSO could also trigger the elimination and finally afforded the desired 4(3H)-quinazolinone products 3s and 3t in satisfactory yields (Scheme 4).

Scheme 4 Another way to synthesize nitro-substituted 4(3H)-quinazolinones.

To further demonstrate the potential applications of this novel acid-promoted synthesis of 4(3H)-quinazolinones, we directed our efforts toward the synthesis of the naturally occurring Pegamine. The required substrate aldehyde 2p can be easily prepared from butane-1,4-diol according to the reported procedures.²⁴ To our delight, subjecting 1a and 2p to our optimized reaction conditions afforded the 4(3H)-quinazolinone 3u in a satisfactory 86% yield. After deprotecting the benzyl group of 3u by hydrogenation over Pd/C, the desired natural product Pegamine was obtained in 88% yield (Scheme 5).

Scheme 5 Application of the method to the synthesis of natural product Pegamine.

Conclusions

In summary, we have developed an efficient green approach which allows for rapid construction of the 4(3H)-quinazolinone skeleton from 2-amino-N-methoxybenzamides 1 and aldehydes 2 through a novel one-pot AcOH-promoted cyclocondensation and elimination process. This is a successful example of synthesizing the biologically important 4(3H)-quinazolinone compounds obviating the participation of either an oxidant or a heavy-metal catalyst. The method has proven to apply to a broad scope of substrates and to afford the desired 4(3H)-quinazolinone in satisfactory to excellent yields. The numerous attractive properties such as the oxidant-free and environmental benignancy characteristics, the one-pot protocol, and simple setup and work-up procedure, altogether promise this method many potentially useful applications in organic synthesis.

Acknowledgements

We acknowledge the National Natural Science Foundation of China (#21072148), Foundation (B) for Peiyang Scholar-Young Core Faculty of Tianjin University (2013XR-0144), the Innovation Foundation of Tianjin University (2013XJ-0005) and, especially, the National Basic Research Project (2014CB932201) for financial support.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: NMR data. See DOI: 10.1039/c4ra04331f

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