Ultrasound mediated efficient synthesis of spironaphthoquinolines

Abstract

An atom-economical synthesis of spironaphthoquinolines from a mixture of 2-aminoanthracene, aldehyde and a Knoevenagel condensation product was developed. The association of the method with the use of ultrasound and its procedural simplicity makes it an attractive protocol for the formation of novel and important heterocycles.

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Introduction

Organic synthesis requires the use of energy, chemical ingredients, catalysts, ligands and covers operations from separation to distribution after the end of the reaction. Chemists or industrial workers face many questions related to health and safety during these processes. Additionally, the use of chemicals and their disposal as waste also raises the level of environmental problems. In this scenario, the practices of ‘safety in academic/industrial chemistry laboratories’ and/or ‘sustainable chemistry’ have attracted attention and become alluring topics for discussion in both scientific as well as governmental sectors of society.¹ Ultrasound-assisted organic synthesis (UAOS) has proven to be a particularly significant discipline for meeting goals to tackle environmental problems, by minimizing waste production and energy consumption.² The ultrasonic physical and chemical effects arise from the phenomenon of ‘bubble formation and collapse’, referred to as ‘cavitation’, which produces extremely favorable conditions locally and consequently induces the formation of chemical species not easily achieved in conventional conditions.³ Thus, UAOS has attracted extensive interest with beautiful characteristics such as selectivity, reaction time, catalyst and solvent recyclability and operational simplicity.⁴ These advantages make acoustic radiation treatment an interesting alternative technique to synthesize essential organic compounds.⁵

The nucleus of naphthoquinoline is one of the appealing heterocyclic compounds, and draws considerable attention from chemists together with biologists for its medicinal importance. For example, in a recent report, Carrigan’s group synthesized naphthoquinoline dicarboxylic acids which were able to inhibit vesicular glutamate transporters.^6a Compounds containing the naphthoquinoline moiety were found to inhibit apoptosis signal-regulating kinase 1 (ASK1).^6b Dzieduszycka^6c and Bu’s^6d,e laboratories also carried out successful experiments and concluded with a positive note on the antitumor activities of naphthoquinolines. It can also be mentioned that dynemicin A, an enediyne antibiotic, has provided indications about the antitumor nature of naphthoquinoline templates.^6f These discoveries have inspired us to develop efficient synthetic routes for the generation of naphthoquinoline-containing heterocyclic scaffolds.

We have recently found that 1-aminonaphthalene is useful for the foundation of desired products with good yields.^7a We believe that the fusion of aromatic ring/rings and/or modification at the position of the amino group may lead to products which will provide an informative set of structure–activity relationships (SARs) for their growth-inhibitory properties in tumor cells. Moreover, our expected products, i.e. naphtho[2,3-f]quinolines, are promising candidates for organic electroluminescent media, with their luminescent properties in the blue region.^7b In addition, our interest in UAOS has been piqued by the production of 7-methyl-substituted pyrido[4,3-d]pyrimidines.^7c Amalgamation of these facts ignited us to consider 2-aminoanthracene as an aromatic amine to construct products under sonochemical conditions. As a consequence of our practice to synthesize novel and complex heterocyclic compounds,^7a,c–e we describe herein a facile synthesis of spironaphthoquinoline derivatives (Scheme 1). To the best of our knowledge, this is the first report on the preparation of spironaphthoquinoline derivatives using sonochemistry with 2-aminoanthracene as one of the starting materials.

Scheme 1 Sonochemical synthesis of spironaphthoquinolines.

Results and discussion

In our reaction strategy, the utilization of an ethanolic solution of a 1 : 1 : 1 mixture of 2-aminoanthracene (1), 4-bromobenzaldehyde (2a) and 5-(4-bromobenzylidene)-1,3-dimethylpyrimidine-2,4,6-trione (3a) under sonochemical conditions afforded 1,3-bis(4-bromophenyl)-1′,3′-dimethyl-3,4-dihydrospiro[naphtho[2,3-f]quinoline-2,5′-pyrimidine]-2′,4′,6′-trione (4a) after work-up, in a very excellent yield (87%). The work-up procedure for the reaction was very simple. The reaction mixture was allowed to settle at room temperature after ultrasound irradiation for 45 min. The pure product was obtained by simple Buchner filtration of the heavy precipitate which was formed by the addition of cold distilled water into the reaction mixture treated with ultrasound. The product was further purified by washing with cold ethanol. The structure of the compound was then established from different spectroscopic analyses. The ¹H NMR spectrum of compound 4a showed the presence of one NH proton at δ 4.64 ppm and two tertiary CH protons at δ 4.92 and 5.69 ppm as singlets. The characteristic signal for two N-methyl groups appeared at δ 2.81 and 3.14. The IR spectrum showed the presence of the NH group at 3393 cm⁻¹. The cis orientation of two C–H protons of compound 4a was found by recording its bidimensional NOE NMR spectrum.

Although a detailed mechanistic study of this reaction remains to be fully performed, the formation of compound 4a can be explained by Scheme 2. We assume that an imine (A) is formed between 2-aminoanthracene (1) and 4-bromobenzaldehyde (2a), which then undergoes a cycloaddition reaction with 5-(4-bromobenzylidene)-1,3-dimethylpyrimidine-2,4,6-trione (3a) to form the final product (4a). To verify our proposed mechanism, a two-component reaction was carried out between a pre-formed imine, N-(4-bromobenzylidene)anthracen-2-amine (A) and 5-(4-bromobenzylidene)-1,3-dimethylpyrimidine-2,4,6-trione (3a) under the same reaction conditions (Scheme 3). As expected, the derivative 4a was obtained in a comparable yield (82%). We further confirmed our mechanistic postulate by monitoring the model reaction at different time intervals (by thin layer chromatography), observing that an intense spot appeared with a R_f value of 0.71 (ethyl acetate : hexane 3 : 7) within 8 minutes, which was accompanied by enhancement of the temperature of the reaction mixture (100 °C; the temperature remained constant till the conclusion of the reaction). After 10 minutes, we stopped the reaction, allowed the reaction mixture to settle down at room temperature, and isolated the compound responsible for the spot, the NMR spectrum of which corresponded to A. These consequences showed that the experimental results were highly consistent with the proposed mechanism.

Scheme 2 Mechanistic postulate for the formation of 4a.

Scheme 3 Two-component synthesis of 4a.

Our initial effort on this reaction in order to achieve suitable reaction conditions was made with the ultrasound treatment of a 1 : 1 : 1 mixture of 2-aminoanthracene (1), 4-bromobenzaldehyde (2a) and 5-(4-bromobenzylidene)-1,3-dimethylpyrimidine-2,4,6-trione (3a) under a variety of solvent systems for 30 minutes. The starting compound, 5-(4-bromobenzylidene)-1,3-dimethylpyrimidine-2,4,6-trione (3a), can easily be obtained following Knoevenagel condensation between 1,3-dimethylpyrimidine-2,4,6-trione and 4-bromobenzaldehyde.⁸ It was found that when water was used as the reaction medium without any external template, the yield of product was very low. The scheme was found to be favourable in all solvents tested such as DCM, DCE, THF, ethanol, methanol, dioxane, toluene, DMF and DMSO under ultrasound conditions, and provided good yields. However, reflection about the toxic effects from most of the organic solvents encouraged us to consider ethanol as the solvent for all further reactions. An increase in the time duration of ultrasound irradiation (45 min) improved the yield of the product, but a further increase in time (60 min) did not indicate any enhancement in the yield of the product (Table 1). Therefore, ultrasound irradiation for 45 minutes in an ethanolic medium were found to be the optimized reaction conditions to give the best yield of the desired product.

Table 1 Optimization studies for the synthesis of 4a^a

Entry	Solvent	Time	Yield^b (%)
a Reaction conditions: a mixture of 2-aminoanthracene (1, 1 mmol), 4-bromobenzaldehyde (2a, 1 mmol), and Knoevenagel condensed product (3a, 1 mmol) was dissolved in different solvents (10 mL) and ultrasonicated for an appropriate time.b Isolated yield.
1	Water	30 min	Trace
2	DCM	30 min	45
3	DCE	30 min	48
4	THF	30 min	45
5	EtOH	30 min	83
6	MeOH	30 min	84
7	Dioxane	30 min	67
8	Toluene	30 min	72
9	DMF	30 min	70
10	DMSO	30 min	65
11	EtOH	45 min	87
12	EtOH	60 min	87

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The feasibility of the reaction scheme was then verified for library production of spironaphthoquinoline derivatives employing different aromatic, heteroaromatic and conjugated aromatic aldehydes, and the results are summarized in Table 2. During our generalization studies, we were satisfied to find that the reaction was effective with aldehydes bearing electron-withdrawing and -donating substituents on the aromatic ring. It can be stated here that in most of the cases, aldehydes with electron-withdrawing groups on the aromatic ring gave better yields of products in comparison to aromatic aldehydes with electron-donating groups. It is also noteworthy that aromatic aldehydes containing para-substituted functionality gave better yields than a meta-substituted one (Table 2, entries 4 and 7) and that this, in turn, gave a better yield than an ortho-substituted counterpart (Table 2, entries 7 and 8). Applications of heteroaromatic and conjugated aromatic aldehydes gratified our methodology, indicating their excellent impacts on the yields of desired products (Table 2, entries 10–12). These findings stimulated our group to further generalize the reaction by varying the aldehydes and Knoevenagel condensed molecules, and the results obtained are summarized in Table 2, entries 13–22. The yield of the reaction was found to be satisfactory in all cases. We were excited to notice that Knoevenagel condensed molecules with electron-withdrawing and -donating substituents on the aromatic ring underwent the reaction smoothly. On the other hand, we were unfortunate not to obtain our desired products using aliphatic aldehydes, even after prolonged reaction times. All the products obtained were characterized by spectroscopic analyses.

Table 2 Direct synthesis of spironaphthoquinolines 4a–x^a

Entry	R^1	R^2	Product	Yield^b (%)
a Reaction conditions: 2-aminoanthracene (1, 1 mmol), aldehyde (2, 1 mmol) and a Knoevenagel condensed product (3, 1 mmol) were dissolved in ethanol (10 ml) and ultrasonicated for 45 min.b Isolated yield.
1	4-Br (2a)	4-Br (3a)	4a	87
2	4-CH3 (2b)	4-OCH3 (3b)	4b	86
3	4-Br (2a)	4-OCH3 (3b)	4c	89
4	4-Cl (2c)	4-OCH3 (3b)	4d	88
5	4-F (2d)	4-OCH3 (3b)	4e	88
6	4-NO2 (2e)	4-OCH3 (3b)	4f	88
7	3-Cl (2f)	4-OCH3 (3b)	4g	86
8	2-Cl (2g)	4-OCH3 (3b)	4h	84
9	2-CH3 (2h)	4-OCH3 (3b)	4i	81
10	C6H5CH=CH (2i)	4-OCH3 (3b)	4j	85
11	C4H3O (2j)	4-OCH3 (3b)	4k	83
12	C4H3S (2k)	4-OCH3 (3b)	4l	83
13	4-OCH3 (2l)	4-OCH3 (3b)	4m	88
14	4-Br (2a)	4-Cl (3c)	4n	88
15	4-Br (2a)	4-F (3d)	4o	87
16	4-Br (2a)	4-NO2 (3e)	4p	87
17	4-Br (2a)	2-CH3 (3f)	4q	85
18	2-CH3 (2h)	4-Br (3a)	4r	83
19	2-CH3 (2h)	4-F (3d)	4s	83
20	4-CH3 (2b)	4-NO2 (3e)	4t	82
21	4-CH3 (2b)	4-Cl (3c)	4u	81
22	4-CH3 (2b)	2-CH3 (3f)	4v	80

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We extended our study to examine the scope of the reaction scheme in a conventional heating process. Thus, a 1 : 1 : 1 mixture of 2-aminoanthracene (1), 4-bromobenzaldehyde (2a) and 5-(4-bromobenzylidene)-1,3-dimethylpyrimidine-2,4,6-trione (3a), when refluxed in ethanol for 5 hours, yielded 1,3-bis(4-bromophenyl)-1′,3′-dimethyl-3,4-dihydrospiro[naphtho[2,3-f]quinoline-2,5′-pyrimidine]-2′,4′,6′-trione (4a) in a yield of 75%. Further increase in reaction time resulted in decomposition of products, thereby leading to lower yields. It can be added that no exciting results were obtained when the reaction mixture was refluxed for less than 5 hours, where N-(4-bromobenzylidene)anthracen-2-amine (A) was obtained in higher amounts (72%) than product 4a (60%). We also performed a set of reactions for different reaction times under classical conditions, highlighted in Table 3. These observations made it clear that the reaction is assisted by ultrasound radiation, which leads to more favorable reaction times.

Table 3 A set of comparative studies of yield vs. time under different heating conditions^a

Entry	R^1	R^2	Product	Time (h)	Yield^b (%)
a Reaction conditions: 2-aminoanthracene (1, 1 mmol), aldehyde (2, 1 mmol) and a Knoevenagel condensed product (3, 1 mmol) were refluxed without catalyst in ethanol (10 mL).b Isolated yield.
1	4-Br	4-Br	4a	5/4	75/60
2	4-Br	4-OCH3	4c	6/4	72/61
3	C4H3O	4-OCH3	4k	5/4	66/50
4	4-Br	4-Cl	4n	5/3	73/55
5	4-CH3	4-NO2	4t	5/4	70/57

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Conclusions

In summary, we have demonstrated the first catalyst-free synthesis of spironaphthoquinolines through the application of ultrasound-assisted organic synthesis. Excellent yields of products can be obtained from this atom-economical procedure, without the requirement of the traditional purification techniques of column chromatography and recrystallization. The filtrate, which contained the solvent ethanol, was successfully utilized for the second batch of the reaction. Overall, our developed methodology can be regarded as a valuable protocol for production of bioactive nitrogen-containing compounds, and will create interest among chemists towards sustainable chemistry.

Acknowledgements

We are grateful to CSIR, New Delhi for providing financial support to this work under network project ORIGIN. We also thank the Director, CSIR-NEIST, Jorhat for his keen interest and constant encouragement.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5ra13793d

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