Azaruthena(II)-bicyclo[3.2.0]heptadiene: Key Intermediate for Ruthenaelectro(II/III/I)-catalyzed Alkyne Annulations.

A ruthenium-catalyzed electrochemical dehydrogenative annulation reaction of imidazoles with alkynes has been established, enabling the preparation of various bridgehead N-fused [5,6]-bicyclic heteroarenes through regioselective electrochemical C-H/N-H annulation without chemical metal oxidants. Novel azaruthenabicyclo[3.2.0]heptadienes were fully characterized and identified as key intermediates. Mechanistic studies are suggestive of an oxidatively induced reductive elimination pathway within a ruthenium(II/III) regime.

Introduction

Transition‐metal‐catalyzed C−H activations have emerged as a transformative platform,1 with applications to drug design,2 natural product synthesis,3 and material sciences.4 As a consequence, a plethora of transition‐metal‐catalyzed C−H/Het−H activation/alkyne annulations have emerged as useful tools for the preparation of heterocycles.5 However, these methods generally require a stoichiometric amount of organic or metal‐based oxidant, such as toxic and/or expensive copper(II) or silver(I) salts. In recent years, the use of electricity as a formal redox agent to empower chemical reactions has been recognized as an increasingly viable, environmentally friendly strategy.6 Significant recent impetus was gained by the merger of electrocatalysis with oxidative C−H activation, thus avoiding the use of toxic and expensive metal oxidants.7

Despite considerable progress,8 the development of new catalytic manifolds is hampered by a lack of mechanistic understanding. This holds especially true for ruthenaelectrocatalysis, which continues to be underdeveloped. Thus, a plethora of ruthenium‐catalyzed C−H activations with chemical oxidants9 are contrasted by only a few examples of ruthenaelectrocatalysis.10 Within our program on electrochemical C−H activation,11 we have now developed a ruthenium‐catalyzed electrochemical dehydrogenative alkyne annulation by imidazoles that assembles a variety of bridgehead N‐fused [5,6]‐bicyclic heteroarenes (Figure 1). Notably, a novel azaruthena(II)‐bicyclo[3.2.0]heptadiene was identified as the key intermediate, which undergoes oxidation‐induced reductive elimination. This motif provides the first structural proof for an unprecedented mechanistic manifold for annulations—even beyond the generally accepted metallalkenyl, metallacyclopropene, and recently proposed metallallylcarbenoid intermediates.12 Salient features of our findings include:

Figure 1

Novel mechanism for electrooxidative C−H activation by azaruthena(II)‐bicyclo[3.2.0]heptadienes. CV=cyclic voltammetry, DFT=density functional theory, GF=graphite felt.

ruthenaelectrocatalytic alkenylic8c and aryl C−H functionalization,

alkyne annulations for N‐fused [5,6]‐bicyclic heteroarenes,

isolation and full characterization of a novel azaruthena(II)‐bicyclo[3.2.0]heptadiene, and

mechanistic insights into oxidation‐induced reductive elimination13 at ruthenium(II) by experiments and calculation.

Results and Discussion

At the outset of our studies, we explored various reaction conditions for the envisioned ruthenium‐catalyzed electrooxidative C−H/N−H activation of alkenyl imidazole 1 a with alkyne 2 a in an operationally simple, undivided cell setup equipped with a GF (graphite felt) anode and a Pt cathode (Table 1 and see Table S‐1 in the Supporting Information).14 After considerable preliminary experimentation, we observed that the desired product 3 aa was indeed obtained through the use of catalytic amounts of [RuCl2(p‐cymene)]2, along with KPF6 as the optimal catalytic additive, while among various solvents, the best results were observed in DMF (entries 1–5). The yield was reduced when sodium salts were used, such as NaCl and NaPF6 (entries 6 and 7). Gratifyingly, reducing the reaction time to 8 h led to the same yield of product 3 aa (entry 8). A reaction conducted with a Pt anode instead of GF resulted in a sharp drop in yield (entry 10). The addition of 1,4‐benzoquinone as a redox mediator did not improve the performance of the ruthenium catalyst (entries 11 and 12). Control experiments verified the essential role of the electricity, the additive, and the ruthenium catalyst (entries 13–15). A set of otherwise typical transition metal catalysts was also probed, but gave none or significantly reduced amounts of product 3 aa (entries 16–20).

Table 1

Optimization of ruthenaelectrocatalyzed annulation.[a]

Entry	Catalyst	Additive	Solvent	Yield [%][b]
1	[RuCl2(p‐cymene)]2	KPF6	MeOH	10[c]
2	[RuCl2(p‐cymene)]2	KPF6	t‐AmOH/H2O	12[d]
3	[RuCl2(p‐cymene)]2	KPF6	DMA	33
4	[RuCl2(p‐cymene)]2	KPF6	NMP	10
5	[RuCl2(p‐cymene)]2	KPF6	DMF	75
6	[RuCl2(p‐cymene)]2	NaCl	DMF	50
7	[RuCl2(p‐cymene)]2	NaPF6	DMF	66
8	[RuCl2(p‐cymene)]2	KPF6	DMF	75[e]
9	[RuCl2(p‐cymene)]2	KPF6	DMF	56[f]
10	[RuCl2(p‐cymene)]2	KPF6	DMF	46[g]
11	[RuCl2(p‐cymene)]2	KPF6	DMF	33[h]
12	[RuCl2(p‐cymene)]2	KPF6	DMF	28[i]
13	[RuCl2(p‐cymene)]2	KPF6	DMF	10[j]
14	[RuCl2(p‐cymene)]2	–	DMF	50
15	–	KPF6	DMF	–
16	Ru(p‐cymene)(OAc)2	KPF6	DMF	53
17	Co(OAc)2⋅4 H2O	KPF6	DMF	–
18	[Cp*RhCl2]2	KPF6	DMF	36
19	[Cp*IrCl2]2	KPF6	DMF	10
20	Pd(OAc)2	KPF6	DMF	–

[a] Reaction conditions: Undivided cell, 1 a (0.40 mmol), 2 a (0.80 mmol), catalyst (5.0 mol %), additive (20 mol %), solvent (4.0 mL), 140 °C, 16 h, constant current at 4.0 mA, GF anode, Pt‐plate cathode. CCE=concstant current electrolysis [b] Yield of isolated product. [c] 60 °C. [d] t‐AmOH/H2O=1/1, 100 °C. [e] 8 h. [f] 5 h. [g] Pt‐plate as anode. [h] BQ (10 mol %). [i] BQ (10 mol %), 100 °C. [j] No electricity. t‐AmOH=2‐methylbutan‐2‐ol, BQ=1,4‐benzoquinone, Cp*=pentamethylcyclopentadienyl, DMA=dimethylacetamide, DMF=N,N‐dimethylformamide, NMP=N‐methyl‐2‐pyrrolidone.

[RuCl

KPF

[RuCl

KPF

–

–

–

–

–

Having identified the optimal reaction conditions, we explored the versatility of our electrochemical annulation with diversely decorated alkynes 2 (Scheme 1). Alkynes 2 with electron‐rich as well as electron‐deficient aromatic moieties were amenable to the ruthenaelectrocatalyzed C−H functionalizations. Thereby, a variety of synthetically useful electrophilic functional groups, such as chloro (3 af), cyano (3 ag) and bromo (3 al) substituents, were fully tolerated, which should prove invaluable for late‐stage manipulation.

Scheme 1

Electrochemical C−H/N−H activation with alkynes 2.

We next turned our attention to diversified alkenyl imidazoles 1 (Scheme 2). Imidazoles 1 b–f bearing a range of substituents at different sites on the alkene or the imidazole were effectively transferable to deliver products 3 ba–3 fa. In addition, benzimidazole substrates with a β‐methyl group (1 g) and without a β‐substituent on the alkene (1 h) were effective for C−H/N−H activation. Notably, thiophenyl‐substituted benzimidazole 1 i also was a competent substrate, giving the corresponding annulation product 3 ia with high efficacy.

Scheme 2

Electrochemical alkyne annulation by alkenyl imidazoles 1.

The ruthenaelectrocatalyzed dehydrogenative alkyne annulation regime was not restricted to alkenyl imidazoles 1. Indeed, we next investigated the generality of the metallaelectrocataylsis by the assembly of the benzimidazoisoquinoline skeleton 5 (see Table S2 for optimization) through annulation of alkynes 2 by 2‐arylimidazoles 4 (Scheme 3). Substrates with substitution at the 2‐aryl group (4 b–4 i) and the benzimidazole (4 l–4 m) gave the desired benzimidazoisoquinolines. Likewise, 2‐naphthylbenzimidazole (4 j) and 2‐phenylnaphthoimidazole (4 k) also afforded the corresponding products. The unsymmetrical 1‐phenyl‐1‐propyne 2 m gave the product 5 am with high levels of regioselectivity. Importantly, chloro, bromo, ester, amide, and enolizable ketone substituents were thereby fully tolerated.

Scheme 3

Electrooxidative C−H activation of benzimidazoles 4.

Intrigued by the ruthenaelectrocatalyzed C−H/N−H functionalization, we decided to delineate the catalyst's mode of action. To this end, reactions with isotopically labeled solvent were suggestive of a fast C−H cleavage, occurring by the formation of an organometallic C−Ru bond (Scheme 4 a). Intermolecular competition experiments revealed a slight preference for electron‐poor alkynes 2 and electron‐rich arenes 4 (Scheme 4 b). Molecular H2 is generated as the by‐product through cathodic proton reduction, which was confirmed by head‐space GC analysis.14

Scheme 4

Summary of key mechanistic experiments.

Next, we probed the isolation of intermediates by stoichiometric experimentation. Thus, we first selectively prepared the ruthenacycle Ru‐II (Scheme 5 a). Second, the ruthenacycle Ru‐II delivered upon stoichiometric reaction with alkynes 2 the unprecedented azaruthena(II)‐bicyclo[3.2.0]heptadienes Ru‐IVa and Ru‐IVb, which were unambiguously characterized by X‐ray diffraction analysis. Notably, the metallacycles Ru‐II and Ru‐IV proved to be competent under catalytic reaction conditions also (Scheme 5 b). It is noteworthy that the azaruthena(II)‐bicyclo[3.2.0]heptadiene Ru‐IVa was stable, but gave the product 3 aa upon electrolysis, which is suggestive of an oxidation‐induced reductive elimination within a ruthenium(II/III) manifold (Scheme 5 c).

Scheme 5

X‐ray crystal structure analysis (thermal ellipsoids at 50 % probability) and applications.16 Selected bond lengths [Å]: Ru‐II: Ru1‐N1 2.086(3), Ru1‐C3 2.083(3), N1‐C1 1.340(4), C1‐C2 1.446(4), C2‐C3 1.356(4); Ru‐IVa: Ru1‐N1 2.101(2), Ru1‐C14 2.172(3), Ru1‐C15 2.171(3), Ru1‐C16 2.222(3), N1‐C13 1.326(4), C12‐C13 1.481(4), C12‐C14 1.577(4), C12‐C16 1.564(4), C14‐C15 1.442(4), C15‐C16 1.449(4); Ru‐IVb: Ru1‐N1 2.094(3), Ru1‐C13 2.220(3), Ru1‐C14 2.185(3), Ru1‐C15 2.174(3), N1‐C11 1.333(4), C11‐C12 1.477(4), C12‐C13 1.557(4), C12‐C15 1.587(4), C13‐C14 1.446(5), C14‐C15 1.449(5).

Furthermore, we probed the electrochemical C−H activation by means of cyclovoltammetric analysis of the well‐defined ruthenacycles (Figure 2). Thus, we observed at ambient temperature an irreversible oxidation of the ruthenium(II) complex Ru‐II at E p=0.60 V vs. SCE. The azaruthena(II)‐bicyclo[3.2.0]heptadiene Ru‐IVa featured a considerably higher oxidation wave at E p=1.20 V vs. SCE, both of which could be rationalized by an oxidation‐induced reductive elimination within a ruthenium(II/III) regime.

Figure 2

Cyclic voltammetry in DMF with 100 mm KPF6 under N2 at RT with 100 mV s−1 of Ru‐II (5 mm) and Ru‐IVa (5 mm).

Further, we have compared the direct reductive elimination at the azaruthena(II)‐bicyclo[3.2.0]heptadiene Ru‐IV with the oxidatively induced reductive elimination at ruthenium(III) Ru‐V at the PBE0‐D3(BJ)/6‐311++G(d,p),def2‐TZVP(Ru), SDD(Ru)+SMD(DMF)//TPSS‐D3(BJ)/6‐31G(d),def2‐SVP(Ru), SDD(Ru) level of theory (Figure 3). Thus, our computational findings confirmed the preferential reductive elimination at ruthenium(III), which is indicative of a ruthenium(II/III/I) manifold.

Figure 3

Relative Gibbs free energy profile in kcal mol−1 comparing the direct reductive elimination and oxidatively induced reductive elimination pathways at the PBE0‐D3(BJ)/6‐311++G(d,p),def2‐TZVP(Ru),SDD(Ru)+SMD(DMF)//TPSS‐D3(BJ)/6‐31G(d),def2‐SVP(Ru),SDD(Ru) level of theory. Non‐participating hydrogen atoms are omitted for clarity. The bond lengths in the transition states are given in Ångström.

Based on our mechanistic studies, we propose the catalytic cycle to commence by a fast organometallic C−H activation (Scheme 6). Thereby, ruthena(II)cycle Ru‐II is generated.15 Thereafter, alkyne coordination and migratory insertion furnish the azaruthenabicyclo[3.2.0]heptadiene Ru‐IV, which undergoes anodic oxidation to deliver the ruthenium(III) complex Ru‐V. Subsequent pericyclic ring opening yields ruthenium(III) complex Ru‐VI. Oxidation‐induced reductive elimination forms ruthenium(I) complex Ru‐VII, which is anodically reoxidized.

Scheme 6

Proposed catalytic cycle.

Conclusion

In conclusion, we have reported on the electrocatalytic organometallic C−H/N−H functionalization of imidazoles. Novel azaruthenabicyclo[3.2.0]heptadienes were identified as the key intermediate, setting the stage for alkyne annulations from synthetically meaningful alkenyl and aryl imidazoles with ample scope. The C−H activation employed electricity as the only oxidant and generated molecular hydrogen as the sole byproduct. Mechanistic studies by experiment and DFT provided strong support for an oxidation‐induced reductive elimination of azaruthenabicyclo[3.2.0]heptadienes by environmentally benign electricity. These findings should prove instrumental for the mechanistic understanding and catalyst design of ruthenium(II)‐catalyzed oxidative C−H activations.

Conflict of interest

The authors declare no conflict of interest.

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Supplementary

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