Molecular diversity from the three-component reaction of 2-hydroxy-1,4-naphthaquinone, aldehydes and 6-aminouracils: a reaction condition dependent MCR

Abstract

The three-component reaction of 2-hydroxy-1,4-naphthaquinone, aldehydes, and 6-aminouracil derivatives in acetic acid/water (1 : 1; v/v) under microwave heating conditions provides 1,4-dihydropyridines fused with naphthaquinone and pyrimidines. On the other hand the same reaction combinations under conventional reflux conditions provide acyclic trisubstituted methane derivatives. Using these tuneable reaction conditions a series of polycyclic fused N-heterocycles has been synthesized. The notable features of this methodology are a simple metal-free one-pot operation, easy purification process, use of the green solvent water, short reaction time and good to moderate yields of the products.

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Introduction

One-pot multicomponent reactions (MCRs) have emerged as an efficient tool for benign synthesis of functionalized heterocycles by virtue of their convergence, productivity, facile execution, and generation of highly diverse and complex products from easily available starting materials in a single operation.¹ MCRs are very useful to access “privileged medicinal scaffolds”, especially, for synthesizing various N-heterocyclic compounds which are key constituents of a wide range of both natural and synthetic bioactive compounds.^2,3 Microwave assisted multicomponent reactions have drawn remarkable attention from organic and medicinal chemists considering their green features. MW irradiation provides enhanced reaction rates, higher yields of products, better selectivity, rapid optimization of reactions and several ecofriendly advantages.⁴ Further, in comparison with organic solvents, water is a non-toxic, non-corrosive, non-explosive and is readily available solvent. These properties along with the network of hydrogen bonds, large surface tension, high polarity and high specific heat capacity make it both economical and environmentally friendly and thus suitable as a green solvent.^5,6 According to the current synthetic requirements and from green perspective, environmentally benign multicomponent procedures employing microwave methodology in aqueous medium are particularly welcome. Polycyclic fused N-heterocycles have attracted much attention due to their presence in biologically active natural products and pharmaceuticals. They display a wide range of biological activities such as antifungal, antibacterial, antineoplastic, anticancer, antiplasmodial, and as DNA intercalators.⁷ The presence of several functional groups in one molecule often proves useful to find better bioactivities of compounds. Further, literature survey shows that fused polycyclic N-heterocycles containing naphthaquinone,^8–10 1,4-dihydro pyridine^11–13 and pyrimidine¹⁴ moieties are important in discovering new bioactive compounds due to their fascinating molecular structure and remarkable pharmacological efficiency. This class of building blocks are useful for treating Alzheimer's disease¹⁵ and also exhibit anti-tumor,¹⁶ antimicrobial,¹⁷ anti-diarrhea,¹⁸ and anti-cancer activities.¹⁹ Some of the pharmacologically active fused polycyclic N-heterocycles are shown in Fig. 1.

Fig. 1 Examples of pharmaceutically important fused polycyclic N-heterocycles and their activities.

6-Aminouracil is considered as a very popular and useful starting material for the synthesis of heterocyclic scaffolds using multicomponent reaction.²⁰ Recently various research groups have explored 6-amino uracil in multicomponent reactions to construct fused heterocycles.²¹

Considering the importance of fused polycyclic N-heterocycles having naphthaquinone, 1,4-DHP and pyrimidine moieties in pharmaceutical and chemical domains, and also as a part of our continuous effort on the synthesis of highly functionalized or fused heterocycles,^22–24 we turned our attention to design a thee component reaction of 2-hydroxy-1,4-naphthaquinone (1), 6-aminouracils (2) and aldehydes (3). In acetic acid/water (1 : 1) under reflux conditions we ended with acyclic products 5 (Scheme 1). Interestingly, when we carried out the same reaction under microwaves in acetic acid/water (1 : 1), we ended with fused polycyclic N-heterocycles 4 (Scheme 1). It consists of three important bioactive moieties naphthaquinone, 1,4-dihydropyridine and pyrimidine (Fig. 2).

Scheme 1 Formation of 4 and 5 in different reaction conditions from the three component reactions.

Fig. 2 Product having three important bioactive moieties.

Results and discussion

For the preliminary investigation, reaction of 2-hydroxy-1,4-naphthaquinone 1, 1,3-dimethyl-6-aminouracil 2a and 4-methyl benzaldehyde 3c was chosen as model reaction. In the presence of acetic acid under the reflux conditions, this combination provided 75% of acyclic product 5ac within 5 h (Table 1, entry 1) and we did not get our desired three component cyclic product 4ac under this reaction conditions. Next, we attempted to get the cyclized product by varying various parameters of the reaction, such as using microwave heating, solvent etc. Interestingly, the same model reaction provided 77% yield of the corresponding fused polycyclic N-heterocyclic product 4ac and 12% of acyclic product 5ac, after microwave heating at 130 °C for 15 minutes in acetic acid medium (Table 1, entry 2). The product 4ac was fully characterized by recording IR, ¹H & ¹³C NMR as well as HRMS. Encouraged by this positive result, the same set of reaction was performed in various solvents under microwave heating and the results are summarized in Table 1 (entries 3–6). Interestingly, it has been observed that when the reaction was performed in the presence of protic solvents like AcOH, H₂O, and EtOH it gives cyclic product 4ac as major and acyclic product 5ac as minor product (Table 1 entries 2–4). But when the reaction was performed in DMSO and PEG-400, only acyclic product 5ac was observed (Table 1, entries 5 and 6). To further investigate, we also performed the same model reaction using mixed solvent like acetic acid and other solvent (1 : 1) under reflux as well as microwave reaction conditions (Table 1, entries 7–12). Among them, acetic acid/water (1 : 1) under microwave heating was found as optimum reaction conditions in terms of yield obtained (Table 1, entry 9).

Table 1 Optimization of reaction conditions^a

Entry	Solvent	Reaction conditions	Yield^b (%) 4ac/5ac	Time (h/min)
a Reactions were carried out in 1.0 mmol scale with 1 : 1 : 1 ratio of 2-hydroxy-1,4-naphthaquinone, 1,3-dimethyl-6-aminouracil and 4-methyl benzaldehyde in 2 ml solvent.b Isolated yields.
1	AcOH	Reflux	0/75	5 h
2	AcOH	MW	77/12	15 min
3	H2O	MW	66/15	15 min
4	EtOH	MW	51/12	15 min
5	DMSO	MW	0/53	15 min
6	PEG-400	MW	0/72	15 min
7	AcOH/H2O (1 : 1)	Reflux	0/80	5 h
8	AcOH/EtOH (1 : 1)	MW	76/15	15 min
9	AcOH/H2O (1 : 1)	MW	90/8	15 min
10	AcOH/DMF (1 : 1)	MW	56/21	15 min
11	AcOH/CH3CN (1 : 1)	MW	68/14	15 min
12	AcOH/DMSO (1 : 1)	MW	48/40	15 min

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In order to explore the scope of this multicomponent reaction, a wide variety of aldehydes 3a–r were reacted with 2-hydroxy-1,4-naphthaquinone 1 and aminouracil derivatives 2a–b under the optimized reaction conditions and the results are summarized in Table 2. It is notable that the characteristics of 2a–b and 3a–r had an important influence on the final products. In most of the cases when 2a was employed, cyclic product 4 was obtained as major and acyclic product 5 as minor product (Table 2, entries 1–7 and 9). However, in the cases of 2-chlorobenzaldehyde 3h, naphthaldehyde 3j and 2-methoxybenzaldehyde 3k, we obtained exclusively cyclic product and no acyclic product (Table 2, entries 8, 10 and 11) was observed. Further, when 6-aminouracil 2b was tested with 1 and different substituted aldehydes 3(a, d–e, g–i, k–o) only cyclic products were observed (Table 2, entries 12–22). Next we examined some aliphatic aldehydes such as cyclohexyl carboxaldehyde 3q and butyraldehyde 3r. Unfortunately, they provided acyclic product only (Table 2, entries 23 and 24). However, when 4-cyanobenzaldehyde 3o and 3-nitrobenzaldehyde 3p were used, we obtained 6ao and 6ap along with 4ao and 4ap (Table 3, entries 1 and 2) respectively.

Table 2 Scope of the reaction^a

Entry	R	R1	% yield^b of 4		% yield^b of 5^c
a Reactions were carried out in 1.0 mmol scale with 1 : 1 : 1 ratio of 2-hydroxy-1,4-naphthaquinone, 1,3-dimethyl-6-aminouracil and 4-methylbenzaldehyde in acetic acid/water (1 : 1) in microwave.b Isolated yields.c For full characterization of compounds 5, please see ref. 22.
1	CH3	C6H5	4aa	79	5aa	13
2	CH3	4-ClC6H4	4ab	87	5ab	10
3	CH3	4-CH3C6H4	4ac	90	5ac	8
4	CH3	4-OCH3C6H4	4ad	85	5ad	10
5	CH3	4-CH(CH3)2C6H4	4ae	82	5ae	12
6	CH3	4-NO2C6H4	4af	64	5af	32
7	CH3	4-FC6H4	4ag	71	5ag	25
8	CH3	2-ClC6H4	4ah	90	5ah	—
9	CH3	3-BrC6H4	4ai	78	5ai	18
10	CH3	Naphthyl	4aj	85	5aj	—
11	CH3	2-OCH3C6H4	4ak	92	5ak	—
12	H	C6H5	4ba	89	5ba	—
13	H	4-OCH3C6H4	4bd	91	5bd	—
14	H	4-CH(CH3)2C6H4	4be	87	5be	—
15	H	4-FC6H4	4bg	89	5bg	—
16	H	2-ClC6H4	4bh	87	5bh	—
17	H	3-BrC6H4	4bi	92	5bi	—
18	H	2-OCH3C6H4	4bk	96	5bk	—
19	H	2-CH3C6H4	4bl	93	5bl	—
20	H	2,6-DiCH3C6H3	4bm	87	5am	—
21	H	4-BrC6H4	4bn	87	5bn	—
22	H	4-CNC6H4	4bo	78	5bo	—
23	CH3	Cyclohexyl	4aq	—	5aq	81
24	CH3	Butyl	4ar	—	5ar	79

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Table 3 Scope of the reaction^a

Entry	R	R1	% yield^b of 4		% yield^b of 6
a Reactions were carried out with 1 : 1 : 1 ratio of 2-hydroxy-1,4-naphthaquinone, 1,3-dimethyl-6-aminouracil and 4-methylbenzaldehyde in acetic acid/water (1 : 1) under microwave irradiation.b Isolated yields.
1	CH3	4-CNC6H4	4ao	38	6ao	52
2	CH3	3-NO2C6H4	4ap	35	6ap	58

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All the products were fully characterized by IR, ¹H NMR, ¹³C NMR spectroscopy as well as HRMS. The formation of 4 and 5 were ascertained from NMR spectroscopy with compound 4ac and 5ac (Fig. 3). As a representative case, ¹H NMR of 4ac was interpreted by the presence of a singlet at 8.82 for –NH proton, 8.08–7.00 ppm for eight Ar-H protons, and singlet at 5.22 for CH proton. While, ¹H NMR of 5ac was characterized by the presence of a singlet at 13.28 for –OH proton, 8.26–7.77 and 7.15–6.90 ppm for eight Ar-H proton and two singlets at 7.19 and 5.79 for –NH₂ and –CH protons respectively. From this it is clear that the product 4ac is the fused polycyclic N-heterocycle whereas the acyclic product is 5ac where free –NH₂ and –OH groups are present.

Fig. 3 Comparison of ¹H NMR spectra of cyclic product 4ac with acyclic product 5ac.

The formation of product 4, can be explained by the proposed mechanism, as shown in Scheme 2. The reaction is initiated by a acetic acid assisted aldol condensation to provide A which transforms to B after elimination of water molecule. Then B reacts with 6-aminouracil derivatives 2a–b in a Michael-type fashion and gave C which undergoes intramolecular condensation followed by tautomerization to give the corresponding product (4).

Scheme 2 Proposed mechanism.

Next, we attempted to convert acyclic product which we obtained under reflux conditions to the corresponding cyclic products. For that we have treated the acyclic product 5ac in acetic acid/water (1 : 1) under MW heating for 15 min and the corresponding cyclic product 4ac was obtained in 78% yield (Scheme 3).

Scheme 3 Synthesis of cyclic product from the acyclic one.

Finally, we explored cinnamaldehyde an α,β-unsaturated aldehyde in this three component reaction under the similar reaction conditions. To our surprise, this aldehyde did not provide expected acyclic product 5as or cyclic product 4as, instead of these a novel unexpected cyclic product 7as was obtained as shown in Scheme 4.

Scheme 4 Synthesis of unexpected product 7as from the reaction of cinnamaldehyde, 2-hydroxy-1,4-naphthaquinone and 2a.

Conclusions

In conclusion, we have demonstrated the effects of reaction conditions on the formation of two types of products from the three-component reaction of 2-hydroxy-1,4-naphthaquinone, aldehydes and 6-aminouracils. This method is a green tool for the synthesis of fused polycyclic N-heterocycles in acetic acid/water under microwave heating. The main advantages of this method are (i) easy purification process of the products avoiding column chromatographic purification, (ii) high atom economy of the reaction (iii) use of water as solvent, (iv) short reaction time, (v) good yields of the products and (vi) environmentally benign procedures. Considering the presence of naphthaquinone and pyrimidine moiety fused with 1,4-DHPs, it is expected that these products will exhibit promising bioactivities.

Acknowledgements

We are grateful to NIT Patna and IIT Patna for providing general research facilities to carryout this work. T. P. is thankful to SERB-DST, India for financial support with Sanction No. EMR/2016/000960. The authors are also thankful to SAIF-Panjab University and SAIF-IIT Patna for providing the analytical facilities for characterization of products.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: General experimental procedure, characterization data, with copies of ¹H, ¹³C NMR spectrum. See DOI: 10.1039/c6ra18828a

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