Rhodaelectro-catalyzed chemo-divergent C–H activations with alkylidenecyclopropanes for selective cyclopropylations

Abstract

Herein, we report on selectivity control in C–H activations with alkylidenecyclopropanes (ACPs) for the chemo-selective assembly of cyclopropanes or dienes. Thus, unprecedented rhodaelectro-catalyzed C–H activations were realized with diversely decorated ACPs with a wide substrate scope and electricity as the sole oxidant.

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Throughout the last decade, C–H activation has emerged as an increasingly powerful tool in molecular syntheses.¹ In sharp contrast, strategies for transition metal-catalyzed C–C activation remain comparably underdeveloped.² In recent years, major advances, in particular in ring-strain release-promoted C–C cleavages, have been achieved by Dong,³Bower,⁴ and Marek,⁵ among others.⁶ Alkylidenecyclopropanes⁷ (ACPs) have previously been recognized as a versatile platform for C–H/C–C functionalizations. However, their application within a bifurcated mechanistic manifold for the selective introduction of cyclopropane⁸ or 1,3-dienes⁹ motifs has thus far proven elusive, although they represent crucial structural scaffolds in a variety of pharmaceuticals, biologically active molecules and natural products. While a single example of rhodium-catalyzed dienylation was realized with chemical oxidants,¹⁰ cyclopropylations are as of yet not available.

The use of electricity to drive chemical reactions has recently witnessed a remarkable renaissance.¹¹ Significant momentum was particularly gained by the merger of metallaelectrocatalysis and C–H activation to avoid often toxic and expensive oxidants.^1b,12 With our continued interest in rhodaelectro-catalyzed C–H activation,¹³ we have now developed a bifurcated C–H activation with alkylidenecyclopropanes that can be conducted under sustainable and operationally-simple electrochemical conditions. Salient features of our strategy include (a) full control of selectivity within a bifurcated manifold for C–H cyclopropylations versus dienylations via β-H over β-C elimination, (b) detailed mechanistic insights by means of experiment and computation, (c) absence of external chemical oxidants, (d) water as the reaction medium, and (e) a user-friendly undivided cell setup without additional electrolyte (Fig. 1).

Fig. 1 Cyclopropylation and dienylation enabled by rhodaelectro-catalysis.

We initiated our studies with indole 1a and ACP 2a to evaluate C–H dienylations and cyclopropylations in a user-friendly undivided cell setup with a graphite felt (GF) anode and a platinum cathode (Table 1). The dienylated product 3aa was obtained in 72% yield in the presence of 2.5 mol% [Cp*RhCl₂]₂, using 1,4-dioxane/H₂O (1 : 1) as the solvent. After examination of different bases, NaO₂CAd led to the best result, delivering diene 3aa in 85% yield with an Z/E ratio of 4.5/1 (entries 1–5). The indispensable roles of electricity and the rhodium catalyst were further confirmed by control experiments (entries 6 and 7). A variation of the current did not result in an improved performance (entries 8 and 9). We also tested different acids and found that cyclopentanecarboxylic acid proved beneficial (entries 10 and 11). With an increased amount of NaO₂CAd, the product was obtained in a higher Z/E ratio, albeit with a small decrease in efficiency (entry 12). A higher reaction temperature improved the efficacy. Importantly, the novel cyclopropylated product 5aa was obtained in high yield when using benzyl ACP 4a.¹⁴

Table 1 Electrochemical C–H dienylation of indole^a

Entry	Base	Acid	Yield (%)	Z/E
a Undivided cell, graphite felt anode (GF), platinum plate cathode (Pt), 1a (0.1 mmol) 2a (0.16 mmol), [Cp*RhCl2]2 (2.5 mol%), base (20 mol%), acid (10 mol%), 1,4-dioxane/H2O (1 : 1, 4.0 mL), 85 °C, CCE @ 3.0 mA, under air, 4.0 h, yield of isolated product, Z/E ratio determined by ^1H NMR spectroscopy, CypCO2H = cyclopentanecarboxylic acid. b Without electricity, 12 h. c Without [Cp*RhCl2]2. d CCE @ 2.0 mA, 6.0 h. e CCE @ 4.0 mA, 3.0 h. f NaO2CAd (40 mol%). g 0.2 mmol scale, 1,4-dioxane/H2O (1 : 1, 8.0 mL), CCE @ 5.0 mA, 3.0 h. h 95 °C. i 4a instead of 2a under the conditions of entry 14.
1	NaOAc	CypCO2H	72	3.9/1
2	NaOPiv	CypCO2H	78	3.5/1
3	NaO2CMes	CypCO2H	60	4.0/1
4	NaO2CPh	CypCO2H	82	3.6/1
5	NaO2CAd	CypCO2H	85	4.5/1
6^b	NaO2CAd	CypCO2H	24	2.4/1
7^c	NaO2CAd	CypCO2H	—	—
8^d	NaO2CAd	CypCO2H	87	3.8/1
9^e	NaO2CAd	CypCO2H	72	3.2/1
10	NaO2CAd	MesCO2H	78	3.8/1
11	NaO2CAd	PivOH	82	3.3/1
12^f	NaO2CAd	CypCO2H	82	6.0/1
13^f^g	NaO2CAd	CypCO2H	87	6.5/1
14	NaO 2 CAd	CypCO 2 H	89	7.0/1
15	NaO 2 CAd	CypCO 2 H	95 (5aa)	<1/20

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With the optimized reaction conditions for the electrochemical C–H dienylation in hand, its versatility was explored with substituted indoles 1 (Scheme 1). 3-, 5- or 7-Methyl indoles 1 delivered the desired products 3ba, 3ea and 3oa, while the 3-methyl indole 1b gave an improved selectivity. Fluorine- and methoxy-substituted indoles 1 were efficiently transformed, but 6-substituted indoles 1k and 1m displayed a slightly lower efficiency. Various functional groups were tolerated by the rhodium electrocatalyst, such as chloro, bromo and cyano substituents. Interestingly, indole 1n with an ester functionality at the 6-position delivered diene 3na in high yield. The dienylation protocol was also amenable to pyrrole 3pa.¹⁵

Scheme 1 Electrocatalytic C–H dienylation of indoles 1.

Next, the robustness of the rhodaelectro-catalyzed C–H dienylation was evaluated with a variety of functionalized cyclopropanes (Scheme 2). Substrates containing bromide groups delivered chemo-selectively the products 3ae and 3am. In contrast to previous studies, electron-deficient heteroarenes showed an inherent high reactivity.¹³ However, electron-rich substrates also performed well in the electrocatalysis. The connectivity of diene 3ap was unambiguously confirmed by single-crystal X-ray analysis.‡

Scheme 2 Electrochemical C–H dienylation with ACPs 2.

Thereafter, we turned our attention to the versatility of the unprecedented electrochemical C–H cyclopropylation of indoles 1 (Scheme 3). We found that an otherwise reactive hydroxyl was fully tolerated, despite being in close proximity (5ca). Halogen-containing indoles, even the reactive iodo-substituent, were likewise viable substrates. Indoles containing electron-withdrawing or electron-donating groups selectively underwent this transformation. For 7-methyl indole, the cyclopropylation showed a higher efficiency as compared to the dienylation (5oaversus3oa). The rhodaelectrocatalysis proved also applicable to pyrroles, while the structure of the cyclopropylated product 5pa was confirmed by single-crystal X-ray analysis.‡ It is noteworthy that, 2-phenyl pyridine could also be employed for the electrocatalysis to deliver arene 5qa. The tryptamine-derived substrate 1r delivered the challenging ring-opening product 5ra′.

Scheme 3 Electrocatalyzed C–H cyclopropylation of indoles 1, arenes and pyrroles.

Next, we explored the C–H cyclopropylation with differently substituted ACPs 4 (Scheme 4). Substrate 4c bearing an iodo-substituent gave the desired product 5ac with a small amount of the deiodinated product (5aa:5ac 1/3). The aqueous conditions were compatible with linear or branched alkyl-derived cyclopropanes (5ad–5af). The challenging cyclopropane 4g bearing a terminal alkene was also found to be a viable substrate, affording product 5ag in 79% yield. The transformation was also tolerant to changes in the backbone of the cyclic alkanes and generated the desired products 5ah and 5ai. Indeed, the structurally more complex, natural product citronellol-derived starting material 4j was chemo-selectively converted to the desired product 5aj.

Scheme 4 Rhodaelectro-catalyzed C–H cyclopropylation with ACPs 4.

To gain insights into the reaction mechanism, control experiments were performed. The independently prepared cyclometalated complex 9¹⁶ was found to serve as a catalytically competent species (Scheme 5a). Under the standard conditions but without electricity, H/D exchange of indole 1a with D₂O was observed with significant deuterium incorporation at the position C2 (Scheme S2 in the ESI†). However, a significant deuterium-incorporation into product 3aa was not observed, when 1a was reacted with 2a under the electrochemical conditions using D₂O as the cosolvent (Scheme S3 in the ESI†). A kinetic isotope effect (KIE) study was next conducted. Parallel independent reactions resulted in a value of k_H/k_D ≈ 1.4 (Scheme 5b), indicating that the C–H cleavage step is likely not involved in the rate-determining step.¹⁴

Scheme 5 Summary of key mechanistic findings.

In order to further understand the catalyst's mode of action, we became interested in studying the rhodaelectro-catalyzed C–H cyclopropylation of indole 1a with ACP 4a by density functional theory (DFT). Geometry optimizations and frequency calculations were performed at the TPSS-D3(BJ)/def2-SVP level of theory, while single point energies were calculated at the PW6B95-D3(BJ)/def2-TZVP+SMD(1,4-dioxane) and PBE0-D3(BJ)/def2-TZVP+SMD(1,4-dioxane) level of theory.¹⁴ All energies reported here were calculated at the PW6B95-D3(BJ)/def2-TZVP+SMD(1,4-dioxane)//TPSS-D3(BJ)/def2-SVP level of theory.¹⁴ Our calculations indicated that after the migratory insertion of ACP 4a, β-H elimination occurs from the intermediate DviaTS(D-E) (Fig. S1, ESI†) with a barrier of 1.1 kcal mol⁻¹. Moreover, β–H elimination from the intermediate D results in the regioselective formation of the E-isomer as the major product, while the generation of Z-isomer is energetically not favourable.¹⁴

Based on our studies, we propose a plausible catalytic cycle for the unprecedented rhodaelectro-C–H-cyclopropylation, which is initiated by the formation of a catalytically competent mononuclear cationic Cp*Rh(III) species. As shown in Fig. 2, coordination of indole 1a to Cp*Rh(III) and facile subsequent cyclorhodation at the 2-position affords rhodacycle A. Then, the insertion of alkene 4a occurs to furnish intermediate D, which undergoes β-H elimination to generate the cyclopropylated product 5aa along with a rhodium(I) intermediate. Finally, the Cp*Rh(III) species is regenerated by rate-limiting reoxidation of rhodium(I) at the anode, while generating molecular hydrogen as the byproduct at the cathode and completing the catalytic cycle. In terms of the dienylation, intermediate D undergoes β-C elimination to form intermediate G (Fig. S10 in the ESI†). Final β-H elimination then delivers the dienylated indole 3aa.

Fig. 2 Proposed mechanism for electro-C–H cyclopropylation with ACPs 4.

In conclusion, we have reported on a versatile rhodaelectro-catalyzed C–H activation with alkylidenecyclopropanes under aqueous conditions, devoid of stoichiometric amounts of chemical oxidants. Our unique strategy allowed for the control of selectivity within a bifurcated mechanistic pathway by the judicious choice of β-H over β-C elimination. Detailed studies by experiment and calculation provided key insights into the catalyst's mode of action, revealing β-H elimination as the key selectivity-determining process for an unprecedented C–H cyclopropylation. The reactive catalyst can be regenerated in a sustainable manner by anodic oxidation, yielding hydrogen as the sole stoichiometric byproduct. Thereby, a wealth of heteroarenes was functionalized with excellent chemo-, position- and diastereoselectivity.

Generous support by the DFG (Gottfried-Wilhelm-Leibniz award to L. A.) and the CSC (fellowship to Z. S.) is gratefully acknowledged. We thank Dr Christopher Golz (Göttingen University) for assistance with the X-ray diffraction analysis.

Conflicts of interest

There are no conflicts to declare.

Notes and references

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14. Detailed information is given in the ESI†.
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Footnotes

† Electronic supplementary information (ESI) available. CCDC 2025011 (3ap) and 2025012 (5pa). For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/d0cc08123j

‡ Deposition numbers 2025011 (3ap) and 2025012 (5pa) contain the supplementary crystallographic data for this paper.

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