Synthesis of oxazepin-quinoxaline bis-heterocyclic scaffolds via an efficient three component synthetic protocol

Abstract

An efficient protocol has been developed to access a series of novel highly complex bis-heterocyclic oxazepin-quinoxaline derivatives. The new bifunctional compounds were synthesized via a one-pot three component reaction between 2-(2-formylphenoxy)acetic acid, an amine and 6-hydroxybenzo[f]quinoxaline-2,3-dicarbonitrile in toluene under reflux conditions without using any catalyst in good to excellent yields.

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Oxazepines as a “privileged scaffold” are a well-known class of seven-membered heterocycles with two heteroatoms. The molecular properties of this pharmaceutically important nucleus have been extensively studied due to its presence in some natural products and biologically active compounds.¹ Among the biological activities, it is worth mentioning antithrombotic,² antiepileptic,³ anticonvulsant,⁴ anti-inflammatory,⁵ progesterone agonist,⁶ antifungal,⁷ antagonist and analgesic,⁸ antipsychotic,⁹ anxiolytics,¹⁰ antihistaminic,¹¹ antiaggregating,¹² and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitory¹³ activities. Moreover, among compounds containing this fragment, Sintamils (I)¹⁴ and its derivatives as antidepressants and Ioxapine¹⁵ because of its potential clozapine-like properties were reported (Fig. 1).¹⁶

Fig. 1 Examples of medicinal oxazepines.

As a result of the above-mentioned properties of oxazepine frameworks, a variety of methods have been introduced for the preparation of these compounds.¹⁷ For example, a synthesis via a copper-catalyzed cascade reaction has been reported by Nakamura.¹⁸ Reiser and co-workers achieved combinatorial liquid-phase synthesis of [1,4]oxazepine-7-ones via the Baylis–Hillman reaction.¹⁹ Menendez and co-workers reported syntheses of oxazepine scaffolds through a CAN-catalyzed four-component reaction.²⁰ In addition, the use of a novel modification of four-component Ugi condensation for synthesis of oxazepines has been reported by Ivachtchenko.²¹

Nowadays, the combination of several functional groups in one molecule seems as a useful tool to optimize properties of biological compounds. Quinoxaline frameworks have attracted considerable attention due to their presence in a large variety of physiologically active compounds, with applications varying from medicinal to agricultural.²² Besides, this chemical-building block has been used to generate different materials to be used in the field of new technologies.²³ Accordingly, the incorporation of quinoxalines into oxazepines may potentially provide a class of novel drug candidates with unusual biological activities.

Inspired by the above investigation and our continued interest in the development of new synthetic methods for generation of heterocyclic compounds,²⁴ herein we wish to report synthesis of oxazepin-quinoxaline bis-heterocyclic scaffold 4 by a one-pot three-component condensation reaction of 2-(2-formylphenoxy)acetic acid 1 as a bifunctional building block,²⁵ amines 2 as a N-resource and 6-hydroxybenzo[f]quinoxaline-2,3-dicarbonitrile 3 as a nucleophilic reagent in toluene under reflux conditions without using any catalyst (Table 2).

Table 1 Solvent optimization^a,c

Entry	Solvent	Temp. (°C)	Time (h)	Yield^b (%)
a Reaction conditions: 2-(2-formylphenoxy)acetic acid 1 (1 mmol), benzyl amine 2a (1 mmol), 6-hydroxybenzo[f]quinoxaline-2,3-dicarbonitrile 3 (1 mmol), solvent (5 mL).b Isolated yields.c NR (no reaction).
1	MeOH	64 °C	24	Trace
2	EtOH	78 °C	24	Trace
3	CH3CN	81 °C	24	80
4	H2O	100 °C	24	NR
5	AcOH	118 °C	24	Trace
6	Toluene	110 °C	24	96
7	H2O/AcOH (2 : 1, v/v)	100 °C	24	10
8	EtOH/AcOH (2 : 1, v/v)	78 °C	24	15

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Table 2 Synthesis of oxazepin-quinoxaline bis-heterocyclic scaffolds

Entry	R	Product	Yield of 4 (%)	m. p. (°C)
4a	C6H5CH2 2a		96	220 dec.
4b	4-CH3C6H4CH2 2b		85	218 dec.
4c	2-ClC6H4CH2 2c		90	216–217
4d	CH3CH2CH2 2d		94	229 dec.
4e	CH3(CH2)4CH2 2e		84	221 dec.
4f	CH3 2f		95	210 dec.
4g	CH3CH2CHCH3 2g		95	197 dec.
4h	(CH3)2CHCH2 2h		94	211 dec.

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In a pilot experiment, 2-(2-formylphenoxy)acetic acid 1, benzyl amine 2a and 6-hydroxybenzo[f]quinoxaline-2,3-dicarbonitrile 3, which was prepared according to our previously reported method,²⁶ were refluxed in toluene. The progress of reaction was monitored by TLC. After 24 h, the reaction was completed and 5-(4-benzyl-3-oxo-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-5-yl)-6-hydroxybenzo[f]quinoxaline-2,3-dicarbonitrile 4a was obtained in 96% yield (Scheme 1).

Scheme 1 Synthesis of compound 4a.

In order to obtain the best media, the reaction was investigated in various solvents of different polarity and viscosity. As indicated in Table 1, the efficiency and the yield of the reaction in toluene were higher than those obtained in other solvents.

With the optimized reaction conditions in hand, we began to evaluate the substrate scope of structurally various amines. As indicated in Table 2, the one-pot three component reactions proceeded very efficiently under reflux conditions to produce the corresponding 2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-5-ylbenzo[f]quinoxaline-2,3-dicarbonitrile derivatives 4a–h in good to excellent yields.

The structures of compounds 4a–h were deduced from their IR, mass, ¹H NMR, and ¹³C NMR spectral data. The spectroscopic data of desired products were in accordance with the assigned structures. For example, the ¹H NMR spectrum of 4a exhibited two ABq for CH₂ of benzyl and OCH₂ at δ = 4.25 and 4.80, a singlet at δ = 6.43 for CH and a multiplet and two doublet at δ = 6.78–8.92 for H-aromatic and OH. The ¹H-decoupled ¹³C NMR spectrum of 4a showed 28 distinct resonances in agreement with the proposed structure. The mass spectra of these compounds displayed molecular ion peaks at the appropriate m/z values.

It is worth noting that we also investigated the reaction between different nucleophilic reagents 5, 2-(2-formylphenoxy)acetic acid 1 and benzyl amine 2a under the previous-mentioned optimized conditions. As indicated in Table 3, only the reaction carried out very well with indole 5a affording the desired product 6aa in 85% yield. In the case of entries 6ab–ae, imine formation, did not proceed in the presence of nucleophiles 5b–5e. Presumably, these observations may be due to the low nucleophilicity of these nucleophiles in comparison with indole. In view of the success of the mentioned reaction, we explored the scope and limitations of this reaction, by extending the procedure to various amines 2, 2-(2-formylphenoxy)acetic acid 1 and indole 5a. As shown in Table 3, the products 6aa, 6ba, 6da and 6fa were produced in 72–85% yields and the structures of them were identified by its IR and ¹H NMR and mass spectral data.

Table 3 Effect of different nucleophilic reagent for the formation of oxazepine ring

Entry	R	NuH	Product	Yield (%) NP (no product)
6aa	C6H5CH2 2a			85
6ba	4-CH3C6H4CH2 2b			72
6da	CH3CH2CH2 2d			75
6fa	CH3 2f			84
6ab	C6H5CH2 2a			NP
6ac	C6H5CH2 2a			NP
6ad	C6H5CH2 2a			NP
6ae	C6H5CH2 2a			NP

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On the basis of experimental results, a suggested mechanism for the formation of 2,3,4,5-tetrahydrobenzo[f][1,4]oxazepin-5-ylbenzo[f]quinoxaline-2,3-dicarbonitrile derivatives 4a–h is presented in Scheme 2. It is conceivable that the initial event in this reaction is the nucleophilic attack of amines 2 to formyl group to afford the imine intermediate 7,^25a,b which subsequently reacts with 3 to form intermediate 8. Finally, intermediate 8 undergoes an intramolecular cyclization^25a,b to give the final product 4.

Scheme 2 Proposed pathway for the formation of compound 4.

Conclusions

In summary, we have successfully demonstrated a novel and highly efficient one-pot strategy for the synthesis of complex bis-heterocyclic oxazepin-quinoxalines which are two important pharmacological and biological scaffolds through three component reactions of 6-hydroxybenzo[f]quinoxaline-2,3-dicarbonitrile, 2-(2-formylphenoxy)acetic acid and structurally diverse amines in good to excellent isolated yields. Moreover, it is worth mentioning that this operationally simple, practical, and scalable method allows C–C bond and C–N bond formation with excellent scope. The potential uses of this protocol in synthetic and medicinal chemistry may be remarkable, since the products share structural and functional group properties of the biologically active molecules.

Experimental

General procedure

A mixture of 2-(2-formylphenoxy)acetic acid 1 (0.18 g, 1 mmol), amines 2 (1 mmol), and 6-hydroxybenzo[f]quinoxaline-2,3-dicarbonitrile 3 (0.25 g, 1 mmol) in toluene (5 mL) was refluxed for 24 h. After completion of the reaction, as indicated by TLC (ethyl acetate/n-hexane, 3/1), the precipitate was filtered and washed with toluene. The products were further purified by recrystallization in acetone.

Acknowledgements

We gratefully acknowledge financial support from the Iran National Science Foundation (INSF) and Research Council of Shahid Beheshti University.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra08486a

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