Synthesis of novel imidazole-based triheterocycles via a domino Ugi/Michael reaction and silver-catalyzed heteroannulation

Abstract

An efficient and diversity-oriented synthetic strategy for novel triheterocyclic imidazo-pyrrolo-pyrazine/diazepine/diazocine derivatives is elaborated. The process utilizes a domino four-component Ugi reaction/Michael reaction of imidazole-2-carbaldehyde, propargyl amines, 2-alkynoic acids and isonitriles to deliver functionalized imidazole-pyrrolones, which upon a silver-catalyzed heteroannulation in aqueous medium under microwave irradiation furnishes the desired triheterocycles in good to excellent yields.

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Introduction

Nitrogen-containing polyheterocycles are widely present in biologically active natural products¹ and pharmaceuticals.² Among them, substituted imidazoheterocyclic skeletons fused with pyrrolone or pyrazines/diazepines/diazocines represent a class of interesting target molecules due to their potential biological activities such as modulation of the cannabinoid receptors,³ inhibition of the integrin receptor,⁴ antagonist of vasopressin and oxytocin,⁵ anticancer,⁶ antiviral⁷ and insecticidal activities.⁸ However, most of the synthetic routes for polyheterocycles are generally restricted by a multistep procedure, and the preparation of highly functionalized precursors,⁹ driving the synthetic community to develop short and efficient synthetic sequences (Fig. 1).

Fig. 1 Representative examples of bioactive imidazole-based heterocycles.

Isocyanide-based multicomponent reactions (MCRs) have gained considerable popularity for the synthesis of substituted imidazole-based heterocycles.¹⁰ Moreover, the advent of transition-metal catalyzed post-multicomponent reactions (MCR) offers new pathways for the diversity-oriented construction of complex bioactive heterocycles in a few steps.¹¹ Due to their remarkable ability to activate π-systems, especially alkynes, gold¹² and silver¹³ catalysts are widely used for intramolecular heteroannulation and hydroarylation processes to construct carbo- and heterocyclic compounds. In this context, our group has explored several sequential Ugi-four components reaction/transition metal-catalyzed intramolecular heteroannulation and hydroarylation approaches to assemble highly diversified heterocycles such as indolazocines,¹⁴ spiroindolines,¹⁵ imidazodiazepinones¹⁶ pyrroloazepinones and pyrrolopyridinones.¹⁷ Furthermore, the employment of water as solvent for microwave-assisted metal-catalyzed transformations,¹⁸ possesses many advantages like shortened reaction times, increased yields and cleaner processes.

Motivated by the interesting bioactivity of various imidazole-based triheterocycles and as a result of our continuous interest in designing new post-MCR strategies for the generation of novel heterocycles from readily available starting materials, we anticipated that a facile synthesis of functionalized triheterocyclic imidazo-pyrrolo-pyrazines/diazepines/diazocines via a domino Ugi/Michael reaction and subsequent silver-catalyzed heteroannulation would be quite promising (Scheme 1).

Scheme 1 Retrosynthetic analysis for the synthesis of imidazole-based triheterocycles.

Results and discussion

To test the feasibility of our hypotheses, a model substrate model substrate was synthesized via Ugi-4CR¹⁹ of imidazole-2-carbaldehyde (1a), propargyl amine (2a), 2-butynoic acid (3a) and tert-butyl isonitrile (4a) (Table 1). Much to our delight, instead of the formation of the Ugi adduct, this process furnished immediately the imidazo-pyrrolone 5a in 72% yield through a domino Ugi/Michael reaction.²⁰ Then, the intramolecular heteroannulation of the adduct 5a was explored. This reaction proceeded smoothly in the presence of Au(PPh₃)OTf (5 mol%) in chloroform at 70 °C for 4 h affording the desired triheterocycle 6a in an excellent yield of 98% with completely exo-dig selectivity (Table 1, entry 1). Similarly, when different silver salts like AgOTf, AgBF₄, AgNTf₂, AgSbF₆ were used, equally excellent yields were obtained (Table 1, entries 2–5). While with AuCl₃, AuCl and CuCl a slight decreased yield was observed (Table 1, entries 6–8), the reaction met with failure when InCl₃ or PtCl₂ were used (Table 1, entries 9 and 10). The comparatively cheaper and similarly efficient AgSbF₆ was selected to examine the solvent effect. The intramolecular heteroannulation went well in solvents like toluene, THF, MeOH and water (Table 1, entries 11–14). Considering the environmental benign issue and the advantages of microwave-assisted metal-catalyzed transformations in aqueous medium, this transformation was performed under microwave irradiation in water at 120 °C for 0.5 h resulting in the formation of 6a in 89% yield (Table 1, entry 15). When performed under nitrogen atmosphere, 6a was obtained in an excellent yield of 98% (Table 1, entry 16). A lower yield was observed when the catalyst loading was diminished to 2 mol% (Table 1, entry 17).

Table 1 Optimization of the intramolecular heteroannulation^a

Entry	Catalyst	Solvent	T/°C	Time/h	Yield^b of (±)-6a/%
a All the reactions were run on 0.05 mmol scale of 5a with catalyst (5 mol%), solvent (1 mL).b Isolated yields.c The reaction was run under microwave irradiation at a maximum power of 100 W.d Under N2.e 2 mol% of AgSbF6 was used.
1	Au(PPh3)OTf	CHCl3	70	4	98
2	AgOTf	CHCl3	70	4	94
3	AgBF4	CHCl3	70	4	96
4	AgNTf2	CHCl3	70	4	92
5	AgSbF6	CHCl3	70	4	98
6	AuCl3	CHCl3	70	4	88
7	AuCl	CHCl3	70	4	84
8	CuCl	CHCl3	70	4	81
9	InCl3	CHCl3	70	4	18
10	PtCl2	CHCl3	70	4	0
11	AgSbF6	Toluene	70	4	98
12	AgSbF6	THF	70	4	98
13	AgSbF6	MeOH	70	4	94
14	AgSbF6	H2O	110	8	96
15	AgSbF6	H2O	120^c	0.5	89
16^d	AgSbF6	H2O	120^c	0.5	98
17^d^,^e	AgSbF6	H2O	120^c	0.5	62

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With the optimized reaction conditions in hand (Table 1, entry 14), we synthesized diversely substituted Ugi/Michael adducts 5b–o to evaluate the scope and limitations for this regioselective intramolecular heteroannulation process (Table 2). Initial exploration of the scope focused on varying the substitution pattern of 2-alkynoic acid and the isonitrile. Pleasingly, the heteroannulation proceeded smoothly to deliver the imidazo-pyrrolo-pyrazines 6b–j in good to excellent yields. Due to the comparatively poor solubility of the adduct 5j bearing a phenyl substituent on the initial 2-alkynoic acid, a lower yield was observed in the formation of 6j. We next examined the influence of the substituent on propargyl amine. A disubstitution pattern on C-1 was well tolerated yielding the corresponding triheterocycles 6k and 6l in 85% and 55% respectively. The optimized conditions failed to give the desired triheterocycles in the case of Ugi/Michael adducts 5m–o derived from substituted propargyl amines bearing a phenyl substituent on the terminal alkyne, while performing these reactions in chloroform at 70 °C for 12 h give 6m–o in good yields. Additionally, the tricyclic skeleton and geometrical orientations of compound 6a was unambiguously confirmed by X-ray crystallography (Fig. 2).

Table 2 Scope of the intramolecular heteroannulation^a

a The reaction were run on a 0.1 mmol scale of 5a–o with AgSbF₆ (5 mol%), and H₂O (2 mL) in a screw capped vial at 120 °C for 0.5 h under microwave irradiation at a maximum power of 100 W.b The reactions were performed on a 0.1 mmol scale of 5m–o with AgSbF₆ (5 mol%) and CHCl₃ (2 mL) in a screw capped vial at 70 °C for 12 h in an oil bath. TMB = 1,1,3,3-tetramethylbutyl, Cp = cyclopentane.

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Fig. 2 Crystal structure of compound 6a with thermal ellipsoids set at the 50% probability level.²¹

To our satisfaction, the scope of the protocol could be extended to imidazo-pyrrolo-diazepines and -diazocines. The Ugi/Michael adducts 5p–u were prepared from 3-butyn-1-amine or 4-pentyn-1-amine, and subjected to the optimized conditions. The Ag(I)-catalyzed exo-dig cyclization proceeded smoothly resulting in the formation of the triheterocyclic imidazo-pyrrolo-diazepines 6p–r and imidazo-pyrrolo-diazocines 6s–u in moderate to good yield (Table 3). It is notable that the imidazo-pyrrolone-diazocines 6s–u are generated in a lower yields because of enthalpic and entropic reasons in the formation of eight-membered ring.²²

Table 3 Extended scope of the intramolecular heteroannulation^a

a All reactions were run on a 0.1 mmol scale of 5p–u with AgSbF₆ (5 mol%) and H₂O (2 mL) in a screw capped vial at 120 °C for 0.5 h under microwave irradiation at a maximum power of 100 W. TMB = 1,1,3,3-tetramethylbutyl.

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We also evaluated the possibility to run the sequence as a one-pot-three-step fashion. After the Ugi-4CR was performed at r.t. for 24 h, the reaction mixture was heated at 50 °C for 24 h. Subsequently 5 mol% of AgSbF₆ was added and the reaction mixture was heated at 50 °C for 12 h. The desired triheterocycles 6a was generated in an overall yield of 26% (Scheme 2).

Scheme 2 Sequential one-pot process for 6a.

Based on previous investigations,^13,16,23 a plausible mechanism could be proposed (Scheme 3). The generated Ugi adduct 5a′ is undergoing a Michael addition to give the adduct 5a.²⁰ Ag(I)-mediated heteroannulation of 5a delivers intermediate B via an exo-dig process. Finally, deprotonation and protodeauration leads to the formation of the triheterocycle 6a with concomitant regeneration of the silver catalyst.

Scheme 3 Plausible mechanism for the formation of triheterocycles.

Conclusions

In summary, we have elaborated an efficient and green methodology for the rapid construction of novel triheterocyclic imidazo-pyrrolo-pyrazines/diazepines/diazocines starting from readily available building blocks. The domino Ugi-4CR/Michael addition as the first step generates the diversity while the subsequent microwave-assisted Ag(I)-catalyzed heteroannulation in aqueous medium represents an efficient and green protocol resulting in the formation of the new triheterocyclic scaffolds.

Acknowledgements

The authors wish to thank the FWO [Fund for Scientific Research-Flanders (Belgium)] and the Research Fund of the University of Leuven (KU Leuven) for financial support. LVM thank the Hercules Foundation for supporting the purchase of the diffractometer through project AKUL/09/0035. ZL, YZ, GT and YH appreciate the China Scholarship Council (CSC) for providing the financial support in their doctoral studies.

Notes references

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Footnotes

† Electronic supplementary information (ESI) available. CCDC 1500316. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra23180b

‡ Both authors equally contributed.

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