Copper-catalyzed oxidative coupling reaction of α,β-unsaturated aldehydes with amidines: synthesis of 1,2,4-trisubstituted-1H-imidazole-5-carbaldehydes

Abstract

A practical and highly functional group-compatible synthesis of 1,2,4-trisubstituted-1H-imidazole-5-carbaldehydes has been developed via copper-catalyzed oxidative coupling of amidines and α,β-unsaturated aldehydes, which features aldehyde preservation, cheap catalysts, as well as high atom economy and mild conditions.

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Introduction

The imidazole core is an important scaffold that can be found in a large number of natural products (Fig. 1a),¹ pharmaceuticals (Fig. 1b and c),² and advanced materials.³ Thus, the development of synthetic protocols for imidazole derivatives has always been an active area of research.⁴ The Bredereck synthesis,⁵ Van Leusen reaction,⁶ Debus-Radziszewski reaction,⁷ and the reaction of R-haloketones with amidines⁸ are well documented as traditional methods to build imidazole rings. However, these procedures generally involve a strong base or relatively high temperature.

Fig. 1 Examples of compounds with the imidazole skeleton.

With the rapid development of transition metal-catalysis in the past few decades, using simple N-arylated substrates as precursors for the synthesis of various imidazole derivatives has stimulated great research efforts.⁹ Among these, Cu-catalyzed oxidative synthesis of imidazole derivatives has become increasingly popular for their high efficiency.¹⁰ Typically, the group of Chiba has developed a series of strategies to afford various azaheterocycles under Cu-catalyzed oxidative conditions in the past few years.^10b–g

Aldehyde is one of the most important groups in functional group transformation, such as the Aldol and Mannich reactions. As a potentially versatile synthetic intermediate, the aldehyde-substituted imidazoles contain an important reactive center for facile derivatization.¹¹ For example, Qiao's group synthesized novel functional materials, Schiff-base linked polymeric imidazoles (SLPI),¹¹ⁱ which are developed by aldehyde-substituted imidazoles. Based on the previous studies by others and our group,^9j,t,10j,12 we report a copper-catalyzed oxidative coupling of α,β-unsaturated aldehydes with amidines to construct 1,2,4-trisubstituted-1H-imidazole-5-carbaldehydes under mild conditions with H₂O as the sole byproduct.

Results and discussion

We initiated the investigation by using N-phenylbenzamidine (1a) and cinnamaldehyde (2a) as model substrates for optimization of this process, and the effects of all reaction parameters were systematically examined (Table 1). When the reaction was carried out in the presence of CuI (10 mol%), DABCO (1,4-diazabicyclo-[2.2.2]octane) (20 mol%) and PhCl (chlorobenzene) (2 mL) at 100 °C for 36 h under an air atmosphere, the desired product 3aa was isolated in 26% yield (entry 1). It was found that two equivalents of MnO₂ under a N₂ atmosphere increased the reactivity, producing the corresponding product 3aa in 75% yield (entry 3). Other oxidants were inefficient in the presence of N₂ (entries 4–6). Among various copper catalysts that we screened, CuI gave the highest yield (entries 7–9). The replacement of DABCO with other ligands did not promote the efficiency of the reaction (entries 10–12). An evaluation of solvents revealed that PhCl was the optimal choice, while other solvents such as DCE (1,2-dichloroethane), DMF (N,N-dimethylformamide) and 1,4-dioxane showed inferior results (entries 13–15). In addition, lower yields of 3aa were obtained when we attempted to change the ratio of 1a/2a, catalyst loading and temperature (entries 16–19). When varying the amounts of MnO₂, we found that the reaction with two equivalents of MnO₂ offered the best yield (entry 4 vs. entries 20 and 21). The structure of 3aa was confirmed by X-ray crystallography (Fig. 2).¹³

Fig. 2 X-ray structure of 3aa.

Table 1 Optimization of reaction conditions^a

Entry	Catalyst	Ligand	Oxidant	Solvent	Yield^b [%]
a Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), catalyst (10 mol%), ligand (20 mol%), oxidant (2 equiv.), N2, solvent (2 mL), 100 °C, 36 h. b Isolated yield. c Under an air atmosphere. d The ratio of 1a/2a = 1.5 : 1. e CuI (20 mol%), DABCO (40 mol%). f 140 °C. g 70 °C. h MnO2 (1 equiv.). i MnO2 (3 equiv.).
1	CuI	DABCO	Air	PhCl	26
2^c	CuI	DABCO	MnO2	PhCl	48
3	CuI	DABCO	MnO 2	PhCl	75
4	CuI	DABCO	K2S2O8	PhCl	27
5	CuI	DABCO	TBHP	PhCl	20
6	CuI	DABCO	AgCO3	PhCl	15
7	CuBr	DABCO	MnO2	PhCl	20
8	CuBr2	DABCO	MnO2	PhCl	32
9	CuCl2	DABCO	MnO2	PhCl	54
10	CuI	Bipy	MnO2	PhCl	53
11	CuI	TMEDA	MnO2	PhCl	25
12	CuI	PPh3	MnO2	PhCl	21
13	CuI	DABCO	MnO2	DCE	24
14	CuI	DABCO	MnO2	DMF	Trace
15	CuI	DABCO	MnO2	Dioxane	36
16^d	CuI	DABCO	MnO2	PhCl	30
17^e	CuI	DABCO	MnO2	PhCl	68
18^f	CuI	DABCO	MnO2	PhCl	55
19^g	CuI	DABCO	MnO2	PhCl	45
20^h	CuI	DABCO	MnO2	PhCl	59
21^i	CuI	DABCO	MnO2	PhCl	63

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With the optimized conditions in hand, we proceeded to examine the substrate scope (Scheme 1). First, we studied the R¹-substituted arylamidines. Electron-rich-substituted arylamidines such as p-Me and p-OMe gave the reaction products in excellent yields (3ba, 80%; 3ca, 82%). When both aromatic rings were substituted with electron-rich groups, the product was isolated in optimal yield (3na, 88%). Electron-deficient arylamidines bearing halide (F–, Cl–, Br–) and trifluoromethyl groups reacted under the standard conditions to afford the desired products in moderate yields (3da–3ha, 38%–62%).

Scheme 1 The scope of amidines. Isolated yields are given. Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), CuI (10 mol%), DABCO (20 mol%), MnO₂ (2 equiv.), N₂, PhCl (2 mL), 100 °C, 36 h.

We next examined the substrate scope of this reaction using R²-substituted arylamidines. The p-Me-substituted arylamidine delivered 3ja in good yield (81%), while the p-Cl-substituted arylamidine afforded 3ia in lower yield (50%). O-Substituted arylamidines showed slightly lower reactivity than p-substituted arylamidine (3ja, 81%; 3ka, 62%), indicating that steric factors had a negative influence on this conversion. Furthermore, N-(naphthalen-2-yl)benzimidamide, N-(tert-butyl)benzimidamide and N-butylbenzimidamide were tolerated, affording the corresponding products in low yields (3pa, 50%; 3qa, 31%; 3ra, 28%).

The scope of α,β-unsaturated aldehydes was also examined (Scheme 2). Substrates bearing electron-donating groups (methyl and methoxyl) at the aromatic ring produced the corresponding products in good yields (3ab–3ad, 75–87%). The presence of electron-withdrawing substituents (F–, Cl–, Br–) at the para position reduce the efficiency of the reaction, as the corresponding products could be isolated in slightly lower yields (3ae–3ag, 57–65%). Additionally, substrates bearing a furan and an n-propyl were also compatible, albeit providing lower yields (3ai, 36%; 3aj, 34%). Unfortunately, the reaction with p-nitro-substituted α,β-unsaturated aldehyde did not afford the desired product 3ah under the standard reaction conditions. Furthermore, we also tried chalcone with 1a under the standard reaction conditions, which afforded the corresponding product (3ak) in 70% yield.

Scheme 2 The scope of α,β-unsaturated aldehydes. Isolated yields are given. Reaction conditions: 1a (0.2 mmol), 2 (0.4 mmol), CuI (10 mol%), DABCO (20 mol%), MnO₂ (2 equiv.), N₂, PhCl (2 mL), 100 °C, 36 h.

To understand the possible mechanism of this reaction, several control experiments were investigated (Scheme 3). Firstly, the reaction between 1a and 2a without using a catalyst or an oxidant was carried out, but no desired product was detected (Scheme 3, eqn (1) and (2)). Moreover, when 2 equiv. of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) was added into the standard reaction, the isolated yield of 3aa reduced from 75% to 51% (Scheme 3, eqn (3A)), in which it may be the weak oxidizing effect of TEMPO affected the reaction. We also tried other radical traps such as BHT (2,6-di-tert-butyl-4-methylphenol) (Scheme 3, eqn (3B)) and PBN (N-benzylidene-tert-butylamine N-oxide) (Scheme 3, eqn (3C)), which produced 3aa in 60% and 63% yields respectively, indicating that this transformation might not proceed via a radical pathway.

Scheme 3 Controlled experiments.

Based on previous studies and control experiments, a plausible reaction mechanism is proposed as shown in Scheme 4.¹⁴ Initially, a Michael addition of N-arylbenzamidines (1a) to the cinnamaldehyde (2a) took place to form the corresponding Michael adduct A.^14a–d Subsequently, the nitrogen atom that connected to the benzene ring bound with Cu(II) salts to produce intermediate B which simultaneously reacted with the enol to form the cyclic Cu(II) intermediate C.^14e Then intermediate C on oxidation by the oxidant formed intermediate D in which copper was in the +III oxidation state.^14f Finally, intermediate D through reductive elimination afforded intermediate E, which on rapid oxidative aromatization under oxidizing conditions leads to the tandem product 3aa. Reoxidation of the Cu^I to the Cu^II by MnO₂ completed the catalytic cycle.

Scheme 4 Proposed mechanism.

Conclusions

In summary, an efficient copper-catalyzed oxidative coupling of α,β-unsaturated aldehydes with amidines for the synthesis of 1,2,4-trisubstituted-1H-imidazole-5-carbaldehydes was developed, which shows a high atom economy, cheap catalysts and mild conditions. Further studies on the application of this transformation are underway.

Experimental

Typical procedure for the preparation of 3

1 (0.20 mmol), 2 (0.40 mmol), CuI (3.8 mg, 10 mol%), DABCO (4.5 mg, 20 mol%), MnO₂ (34.8 mg, 2.0 equiv.), and PhCl (2 mL) were added to a flask with a magnetic stirring bar under a N₂ atmosphere. The mixture was stirred at 100 °C for 36 h. After cooling to room temperature, the mixture was diluted with ethyl acetate and filtered. The filtrate was removed under reduced pressure to obtain the crude product, which was further purified by silica gel chromatography to give product 3. The identity and purity of the products was confirmed by ¹H NMR and ¹³C NMR spectroscopic analysis.

Acknowledgements

We are grateful for sponsorship of this project by the National Natural Science Foundation of China (no. 21372102 and 21403256).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1409382. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5qo00285k

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