Ir(III)-catalyzed synthesis of isoquinolines from benzimidates and α-diazocarbonyl compounds

Abstract

We report herein a tandem Ir(III)-catalyzed C–H activation and annulation reaction for the synthesis of isoquinolines by using readily available substituted benzimidates and α-diazocarbonyl compounds under mild conditions. The catalytic reaction exhibits excellent tolerance to different functional groups and the corresponding isoquinolines were obtained in good to excellent yields. This novel method affords an alternative strategy for the construction of diverse and useful isoquinoline derivatives.

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Introduction

N-heterocycles are ubiquitous in natural products, pharmaceuticals and biologically active molecules.¹ The isoquinoline core as the structural backbone in naturally occurring alkaloids, can display unique biological functions.² Traditional approaches to isoquinolines include Bischler–Napieralski reaction,³ Pomeranz–Fritsch reaction⁴ and Pictet–Spengler reaction⁵ which are usually carried out under harsh conditions or using complicated substitutes. Recently, many processes have been developed to synthesize isoquinolines by employing transition-metal catalyzed C–N coupling and C–H activation. In regard to these two strategies, approaches via transition-metal catalyzed C–N coupling comprise of Ullmann-type reactions and Buchwald–Hartwig reactions among others, which involve using aryl halides as the substrates.⁶ On the contrast, C–H activation approaches have, to some extent, taken precedence over the former due to their high atom economy and contribution in green chemistry. Among these protocols, Rh and Pd catalysts were mainly used to catalyze the sequential C–H activation/annulation of aromatic oximes,⁷ imines,⁸ benzamides,⁹S-aryl sulfoximines¹⁰ and azides¹¹ with internal alkynes, alkenes and α-diazocarbonyl compounds to get access to substituted isoquinolines. For example, very recently, the Patel group reported an elegant example of a Ir(III)-catalyzed intermolecular annulation reaction using aryloximes and diazo compounds for the synthesis of isoquinoline N-oxides,¹² and the Glorius group reported the first example of a Co(III)-catalyzed C–H bond activation of imines with diazo compounds for the synthesis of isoquinolin-3-ones.¹³

Benzimidates which are readily available from benzonitriles are good starting materials for building N-heterocycles via transition-metal catalyzed C–H activation. Recently, there are a lot of approaches using this kind of substrates to construct different N-heterocycles like indazoles, quinazolines and isoquinolines.¹⁴ Among these reactions, in 2013 Glorius reported one example for synthesis of isoquinolines by using a benzimidate.¹⁵ However, investigations on the mechanism of such a transformation and finding an alternative catalyst system to carry out this reaction are still needed. Motivated by these and in continuation of our interest in heterocycle building, herein, we report an efficient Ir(III)-catalyzed approach to synthesize multisubstituted isoquinolines via cascade reaction of readily available substituted benzimidates and α-diazocarbonyl compounds under mild conditions (Scheme 1).

Scheme 1 Ir(III)-catalyzed approach to synthesize multisubstituted isoquinolines.

Results and discussion

At the outset of this study, the reaction of ethyl benzimidate (1a) and ethyl 2-diazo-3-oxobutanoate (2b) was chosen as the model to optimize reaction conditions including the solvents, temperature, and catalyst systems. The initial experiments were performed with ethyl benzimidate (1a) (0.25 mmol) and ethyl 2-diazo-3-oxobutanoate (2b) (0.3 mmol) in the presence of [Cp*IrCl₂]₂ (5 mol%) and AgNTf₂ (20 mol%) as the catalyst system at 60 °C under nitrogen atmosphere in EtOH (2 mL) for 12 h, as given in Table 1. Fortunately, the desired product 3aa was obtained in 60% yield under these conditions. The structure of 3aa was confirmed by ¹H and ¹³C NMR spectroscopy and high-resolution mass spectrometry (HRMS). Stimulated by this result, first, the effect of solvents was investigated (compare entries 1–3), and MeOH gave the best result, as the yield of 3aa increased to 69% yield (Table 1, entry 2). No target product was obtained by using AgSbF₆ as the catalyst (entry 4). Other transition metals were also screened (entries 5–8), and the transformation did not occur by using these catalysts other than Cu(OAc)₂, but the yield of 3aa sharply declined to 16% (entry 5). The use of [Cp*IrCl₂]₂/AgSbF₆ as the catalyst afforded a slightly lower yield to those obtained using the [Cp*IrCl₂]₂/AgNTf₂ catalyst system (Table 1, compare entries 9 and 11). To avoid byproducts and the decomposition of imidate, lower temperatures and longer reaction time were also tested. The yield declined to 54% when the reaction time was changed to 24 h (entry 10), and the best yield was obtained when the temperature was 50 °C (entry 11). It is a balance between the reactivity and the substrate decomposition.

Table 1 Ir(III)-catalyzed synthesis of ethyl 1-ethoxy-3-methylisoquinoline-4-carboxylate (3aa) via cascade reaction of ethyl benzimidate (1a) and ethyl 2-diazo-3-oxobutanoate (2a): optimization of conditions^a

Entry	Catalyst system	Solvent	Temp (°C)	Yield^b (%)
a Reaction conditions: ethyl benzimidate (1a) (0.25 mmol), ethyl 2-diazo-3-oxobutanoate (2b) (0.3 mmol), cat. (5 mol%/20 mol%), 12 h, solvent (2 mL) under nitrogen atmosphere. b Isolated yield. c Reaction time is 24 h.
1	[Cp*IrCl2]2/AgNTf2	EtOH	60	60
2	[Cp*IrCl2]2/AgNTf2	MeOH	60	69
3	[Cp*IrCl2]2/AgNTf2	THF	60	48
4	AgSbF6	MeOH	60	Trace
5	Cu(OAc)2	MeOH	60	16
6	Pd(OAc)2	MeOH	60	Trace
7	Cu(acac)2	MeOH	60	Trace
8	[(p-Cymene)RuCl2]2/AgSbF6	MeOH	60	Trace
9	[Cp*IrCl2]2/AgSbF6	MeOH	50	62
10	[Cp*IrCl2]2/AgNTf2	MeOH	60	54^c
11	[Cp*IrCl 2 ] 2 /AgNTf 2	MeOH	50	73
12	[Cp*IrCl2]2/AgNTf2	MeOH	30	50

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Additionally, inspired by other reports, we compared the catalytic performance of three group IX metal catalyst, including [Cp*IrCl₂]₂, Cp*Co(CO)I₂ and [Cp*RhCl₂]₂. The reactions of ethyl benzimidate (1a) with ethyl 2-diazo-3-oxobutanoate (2b) and methyl 2-diazo-3-oxobutanoate (2c) were chosen as the model reactions. As shown in Tables S1 and S2 (see the ESI†), the transformations did not occur employing Cp*Co(CO)I₂/AgSbF₆ as the catalyst, even though the temperature was increased to 120 °C. These results demonstrated that the catalytic performance of [Cp*IrCl₂]₂ and [Cp*RhCl₂]₂ is very similar, and the yields of corresponding products varied slightly.

Under the optimum reaction conditions above, as shown in Table 2, the substrate scope of the cascade reactions was investigated, and the examined substrates provided moderate to good yields. Benzimidates bearing substituents at the para-position with electron-donating substituents (e.g. Me, OMe), showed higher reactivity than substrates with strong electron-withdrawing groups (e.g. CF₃) at the same position, affording products 3ea, 3eb and 3ef in lower yields respectively. The chloro-substituted arylimidates also performed well to afford the corresponding products in good yields (3da, 3db, 3de and 3df). Some meta-substituted arylimidates demonstrated the excellent regioselectivity, affording products 3ha, 3hc and 3ic in good yields. Moreover, imidates with other alkyl ester groups (3fb, 3fc, 3ga and 3gb), and even a protic benzophenone imine (3kb) all showed good reactivity, delivering desired products in good yields. In addition, ethyl thiophene-3-carbimidate (1j) also afforded the corresponding product (3jc) in satisfactory yield (71%).

Table 2 Ir(III)-catalyzed synthesis of isoquinolines from benzimidates and α-diazocarbonyl compounds^a

3, yield^b

a Reaction conditions: benzimidates (1a) (0.25 mmol), α-diazocarbonyl compounds (2b) (0.3 mmol), [Cp*IrCl₂]₂ (5 mol%), AgNTf₂ (20 mol%), 12 h, 50 °C, MeOH (2 mL) under nitrogen atmosphere. b Isolated yield.

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Furthermore, we investigated the reactions of various diazo compounds with 1. As shown in Table 2, diazo substrates bearing substituents such as ketone, ester, alkyl, and phenyl afforded the corresponding isoquinolines in 65–89% yield. For substrate 2, the substituents in which R³ is t-butyl ester could lead to lower yield (3af, 3cf, 3df and 3ef).

Based on the literature reports, a plausible mechanism was proposed (Scheme 2). The first step is the generation of a cationic Ir(III) species from the [Cp*IrCl₂]₂ and AgNTf₂, then the benzimidates reacts with Cp*Ir(III) through directed C–H cleavage to form intermediate I. Following that, I coordinates with the diazo compound, generate the Ir(III)–carbene II. Subsequently, migratory insertion of the carbene into the Ir–C bond leads to intermediate III. Next, protonolysis of III delivers the alkylated product IV, and releases the Ir(III) catalyst, which participates a new catalytic cycle. Then tautomerization of intermediate IV generates in situ enol intermediate, which undergoes dehydration via nucleophilic cyclization to give the final product 3.

Scheme 2 Possible mechanism for Ir(III)-catalyzed synthesis of multisubstituted isoquinolines (3).

Conclusions

In summary, we have developed a convenient and efficient cascade Ir(III)-catalyzed C–H activation and annulation reactions for the synthesis of isoquinolines. The protocol uses readily available substituted benzimidates and α-diazocarbonyl compounds as the starting materials, [Cp*IrCl₂]₂/AgNTf₂ as the catalyst system. The reactions were performed under mild conditions, providing target products in good yields, while no extra additive were required. This easy approach affords an alternative strategy for the construction of diverse and useful isoquinoline derivatives.

Acknowledgements

This work was supported by the National Natural Science Foundation of China (21402126), Natural Science Foundation of Liaoning Province (20141090), the Program for Excellent Talents in University of Liaoning Province (LJQ2014121), Doctoral Fund of Shenyang Normal University, Director Fund of Ecological and Environmental Research Centre of Shenyang Normal University (EERC-G-201403).

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6ra10045g

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