Facile synthesis of quinoxaline annulated perfluoroalkylated benzoazepine derivatives

Abstract

Novel perfluoroalkylated benzoazepinoquinoxaline derivatives were synthesized by consecutive intermolecular Michael addition and intramolecular cyclization from 3-(2-aminophenyl)quinoxalin-2(1H)-ones and methyl perfluoroalk-2-ynoates in good yields. This efficient and mild protocol might afford a new pathway for novel drug development.

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Introduction

The versatile quinoxaline ring or benzazepine moiety are found in a large number of bioactive agents that possess a broad spectrum of pharmacological activities such as anti-infective, anti-inflammatory, anticonvulsant, anti-anxiety, anti-seizure, analgesic, sedative, anti-depressive and anticancer activities.^1,2 Thus, both fragments are widely found in bioorganic and medicinal chemistry with applications in drug discovery.

The incorporation of two pharmacophores in a single molecule is one of the techniques being implemented to discover new drugs. Several hybrid molecules have been designed, synthesized and evaluated for their biological activity.³ However, little attention appears to have been paid to such a hybrid molecule that possesses the biologically active quinoxaline ring fused to heterocyclic derivatives of benzazepines. Only a limited number of such compounds have been recorded in the literature.⁴

We have tried to obtain a new library of compounds of high potential value in the drug research field,⁵ and that is why we devoted our attention to develop easily accessible routes to the synthesis of some novel hetero-ring annulated benzazepine derivatives. And on considering that incorporation of fluorine atoms can lead to an increase in bioavailability, lipophilicity, metabolic stability and hydrolytic stability in compounds, in comparison with their non-fluorinated counterparts,⁶ in the present report, we describe the first attempt to prepare a novel class of perfluoroalkylated benzoazepinoquinoxaline derivatives from 3-(2-aminophenyl)quinoxalin-2(1H)-ones and methyl perfluoroalk-2-ynoates.

Results and discussion

At the outset, the reaction of 3-(2-aminophenyl)quinoxalin-2(1H)-one (1a) with methyl 4,4,4-trifluorobut-2-ynoate (2a)⁷ was chosen as a model to optimize reaction conditions (Table 1). The screening began by evaluating the reaction in ethanol at 80 °C in a sealed tube. No transformation occurred within 18 h (Table 1, entry 1). When the reaction was performed in toluene under the same reaction condition, the poor solubility of 1a led to a poor yield of compound 3a (Table 1, entry 2). In order to efficiently obtain a sort of unitary final product, other attempts were also made. Several aprotic solvents (MeCN, DMF, THF, DMSO and 1,4-dioxane) were employed as the reaction media (Table 1, entries 3–7). When the reaction was carried out in 1,4-dioxane at 80 °C for 18 h, the expected product 3a was achieved in 71% yield (Table 1, entry 7). Other solvents also resulted in the formation of the product while they were not as efficient as 1,4-dioxane (Table 1, entries 3–6). By elevating the temperature to about 100 °C, when 1,4-dioxane was under reflux, the reaction provided 3a in 79% yield upon isolation (Table 1, entry 8). At the lower temperature 60 °C, a poor yield of the desired product was obtained (Table 1, entry 9). The effect of the molar ratio of 1a and 2a on this reaction was also investigated, and the ratio 1.0 : 1.2 was found to be suitable (Table 1, entry 10 vs. entries 8 and 11). Moreover, prolonged heating in refluxing 1,4-dioxane decreased the yield (Table 1, entry 12).

Table 1 Screening for the optimum reaction conditions^a

Entry	Molar ratio [1a : 2a]	Solvent	Time [h]	Temp. [°C]	Yield^b [%]
a Reaction conditions: 3-(2-aminophenyl)quinoxalin-2(1H)-one (1a, 1.0 mmol), methyl 4,4,4-trifluorobut-2-ynoate (2a) and solvent (10 mL).b Isolated yield.
1	1.0 : 1.5	EtOH	18	80	0
2	1.0 : 1.5	Toluene	18	80	15
3	1.0 : 1.5	MeCN	18	80	25
4	1.0 : 1.5	DMF	18	80	34
5	1.0 : 1.5	THF	18	80	51
6	1.0 : 1.5	DMSO	18	80	30
7	1.0 : 1.5	1,4-Dioxane	18	80	71
8	1.0 : 1.5	1,4-Dioxane	18	Reflux	79
9	1.0 : 1.5	1,4-Dioxane	18	60	46
10	1.0 : 1.2	1,4-Dioxane	18	Reflux	87
11	1.0 : 2.0	1,4-Dioxane	18	Reflux	81
12	1.0 : 1.2	1,4-Dioxane	24	Reflux	78

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The structure of trifluoromethylated benzoazepinoquinoxaline 3a was elucidated by X-ray crystallographic studies (Fig. 1).⁸ It is clear that 3a exists in the imine form.

Fig. 1 X-ray structure of 3a.

A reasonable mechanism for this transformation is proposed in Scheme 1. Intermediate 4 is generated from a Michael addition between 3-(2-aminophenyl)quinoxalin-2(1H)-ones 1a and methyl 4,4,4-trifluorobut-2-ynoate 2a, followed by an intramolecular cyclization driven by the electron-rich NH group attached to the aromatic ring C in 4 to afford the intermediate 5.⁹ Dehydration and aromatization of the latter leads to the formation of the thermodynamically more stable 3a as the sole product.¹⁰

Scheme 1 Possible reaction mechanism for the generation of trifluoromethylated benzoazepinoquinoxaline 3a.

The best behavior of 1,4-dioxane in the current reaction may be due to its appropriate polarity and solvation compared to all other solvents.¹¹ For example, highly polar aprotic solvents, such as DMSO, DMF and MeCN, can solvate the weakly nucleophilic aromatic amine efficiently, which can be less facile for the Michael addition step. The formation of hydrogen bonding between EtOH and the amine group is averse to the Michael addition step too.

Under the optimized conditions, the substrate scope and limitation of the reaction were explored. As shown in Table 2, the methodology is apparently applicable to a range of 3-(2-aminophenyl)quinoxaline-2(1H)-one derivative (1). Both electron-donating and electron-withdrawing groups (Me-, MeO- and Cl, Br) afforded moderate to good yields. However, compared to electron-withdrawing substituted 1, electron-donating groups afforded slightly higher yields. For example, when the R¹ group attached to aromatic ring C was 5′-methoxy or methyl, products 3d and 3c were isolated in 72 and 66 yields, respectively, higher than product 3b (61%) generated from 5′-Cl substituted 1b. These results can be rationalized from the fact that the electron-donating group at the 5′ position in the aromatic ring C increases the electronic nucleophilicity of NH₂ group, and hence, facilitates the Michael addition with electron-deficient alkyne 2. Furthermore, the cyclization step is triggered more easily. Meanwhile, the R² group at the 6 or 7 position in aromatic ring A was found to have a similar electronic effect on the reaction (Table 2, entries 9 and 10 vs. entry 8).¹⁰

Table 2 Synthesis of 6-perfluoroalkylated benzoazepinoquinoxalines 3^a

Entry	1	2	3	Yield^b [%]
a Reaction conditions: 3-(2-aminophenyl)quinoxalin-2(1H)-ones 1 (1.0 mmol), methyl perfluoroalk-2-ynoates 2 (1.2 mmol), 1,4-dioxane (10.0 mL) under reflux, 18 h.b Isolated yield.c The reaction was incomplete and 1e was recovered.
1		2a		87
2		2a		61
3		2a		66
4		2a		67
5		2a		28^c
6		2a		51
7		2a		55
8		2a		59
9		2a		74
10		2a		64
11		2b		64
12		2b		63
13		2c		45
14		2c		48

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It seemed that the position of the R¹ group in aromatic ring C was also crucial for a successful transformation. Due to the steric hindrance at the 3′-position, which prevents alkyne accessibility for the Michael addition, a much lower yield of product was formed when 3′-Br substituted 1e was employed in the reaction (Table 2, entry 5). 4′ or 5′-Br substituted 1f and 1g gave much better results (Table 2, entries 6 and 7).

With respect to other perfluoroalkylated alkynes other than 2a, sterically differentiated alkynes 2b and 2c were studied. The reaction was compatible with both of them. However, substrates 2b and 2c, featuring increased steric hindrance for the Michael addition, would cause a more severe steric clash in intermediate 4, and thus, leads to a lower yield (see Scheme 1). For example, the anticipated product 3m was isolated only in 45%, much lower than 3k (64%) and 3a (87%). However, if dimethyl acetylenedicarboxylate (DMAD) was used as the alkyne substrate, no desired product was obtained.

Conclusions

We have developed an unprecedented reaction using readily available 3-(2-aminophenyl)quinoxalin-2(1H)-ones and methyl perfluoroalk-2-ynoates as starting materials. This method provides straightforward access to a new class of fascinating 6-perfluoroalkylated benzoazepinoquinoxalines in moderate to good yields. Such a polycyclic nitrogen heterocycle, which possesses two biologically active units in a molecule, is accessible for further investigations towards novel medicinal agents.

Experimental section

General information

Reagents and solvents were purchased from commercially available sources and used without further purification. Methyl perfluoroalk-2-ynoates were prepared according to the known literature. Melting points were recorded on a WRS-1 instrument and are uncorrected. ¹H, ¹⁹F and ¹³C NMR spectra were recorded on a Bruker DRX-500 MHz spectrometer. All chemical shifts are reported in parts per million downfield (positive) of the standard: C₆F₆ for ¹⁹F, TMS for ¹H and ¹³C NMR spectra. IR spectra were obtained on an AVATAR370 FTIR spectrometer. LR-MS (low resolution mass spectroscopy) and HR-MS (high resolution mass spectroscopy) were obtained on a LCMS 2020 and Bruker Daltonics APEXIII 7.0 TESALA FTMS instruments, respectively. X-ray analysis was performed on a Bruker Smart Apex2 CCD spectrometer. Yields reported in this publication refer to isolated compound yields and their purity was determined by ¹H NMR.

General procedure for the preparation of 3-(2-aminophenyl)quinoxalin-2(1H)-ones 1^12,13

A mixture of o-phenylenediamine (5.0 mmol), isatin (5.0 mmol) and PhCO₂H (5.0 mmol) was stirred in 1,4-dioxane (10 mL) at room temperature. Progress of the reaction was monitored by thin-layer chromatography. After completion of the reaction, the precipitate was filtered, washed with 1,4-dioxane and dried to give pure compound 1.

General procedure for the preparation of 6-perfluoroalkylated benzoazepinoquinoxalines 3

A solution of 3-(2-aminophenyl)quinoxalin-2(1H)-ones 1 (1.0 mmol) and methyl perfluoroalk-2-ynoates 2 (1.2 mmol) in 1,4-dioxane (10.0 mL) was stirred for 18 h under reflux. The solvent was removed under vacuum and the residue was purified by column chromatography on silica gel (petroleum ether/ethyl acetate) to give 3.

Acknowledgements

The authors are grateful to the National Natural Science Foundation of China (NSFC) (Grant No. 21542005, 21272152), Yang Fan Program of Science and Technology Commission of Shanghai Municipality (Grant No. 15YF1404200) and Shanghai Municipal Education Commission (Peak Discipline Construction Program) for their financial support.

Notes and references

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Footnotes

† Electronic supplementary information (ESI) available. CCDC 1046307. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra22727a

‡ With equal contribution to this work.

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