Regioselective electrochemical cascade C–H sulfonylation–bromination of indolizines to access difunctionalized indolizines

Abstract

Regioselective electrochemical C–H sulfonylation–bromination between indolizines, sodium sulfinates, and KBr has been established in an undivided cell, in which KBr serves as both the brominating agent and electrolyte. This consecutive C3–H sulfonylation and C1–H bromination protocol enables the synthesis of difunctionalized indolizine derivatives under catalyst- and oxidant-free conditions. Moreover, electrochemical C–H sulfonylation–thiocyanation/selenylation/thiolation of indolizines was realized via a two-step process. This protocol features excellent regioselectivity and environmentally friendly electrolysis.

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The past two decades have witnessed the flourishing development of electrochemical organic synthesis. As an environmentally friendly, practical, and selectivity tunable synthetic method, electrochemistry has been recognized as a powerful and sustainable tool in various organic transformations.^1,2 Recently, electrochemical C–H sulfonylation³ and bromination reactions⁴ have been well established. However, to the best of our knowledge, research studies on highly selective electrochemical C–H sulfonylation and halogenation at different sites of the same parent molecule are very rare, although this strategy will simultaneously introduce both sulfonyl and halogen groups into a parent molecule.

Indolizines are privileged scaffolds owing to their biological activities and fluorescence properties in synthetic pharmaceuticals and materials science (Scheme 1).^5,6 As a consequence, several methods for the preparation of functionalized indolizines have been developed.⁷ Among these cases, selective C–H functionalization is regarded as an ideal strategy for the modification of indolizine rings due to no need for prefunctionalization of precursors and a higher atom- and step-economy.⁸ Traditionally, C–H functionalization mainly occurs at the C3 position; for example, we have realized a variety of C3–H thiolation, dicarbonylation, carboxamidation, dithiocarbamation, and disulfuration reactions (Scheme 2a, eqn (1)).⁹ In addition, we have also discovered selective C3–H and C1–H dithiolation and electrochemical diselenylation to introduce two of the same group into indolizines (Scheme 2a, eqn (2)).¹⁰ However, introducing two different functional groups via selective C3–H and C1–H difunctionalization is challenging and vary rare. Very recently, we have successfully implemented an electrochemical phosphorothiolation and 1,4-S → C phospho-Fries rearrangement to access phosphorothiolated and mercapto-phosphono substituted indolizines (Scheme 2a, eqn (3)).¹¹ This success inspired us to further explore the selective C3–H and C1–H difunctionalization of indolizines. As part of our continuous interest in indolizines and electrochemistry,¹² we report herein a regioselective electrochemical C–H sulfonylation–bromination from indolizines, sodium sulfinates, and KBr to efficiently incorporate a sulfonyl and a Br atom at the C3 and C1 sites, respectively. Notably, KBr serves as both the brominating agent and electrolyte (Scheme 2b).

Scheme 1 Biologically active molecules and the fluorescent core skeleton.

Scheme 2 Selective C–H functionalization of indolizines.

To investigate the regioselective electrochemical C–H sulfonylation–bromination, our initial study started with 2-phenylindolizine 1a and sodium p-toluenesulfonate 2a as model substrates. Gratefully, when electrolysis was carried out using KBr as the electrolyte, Cs₂CO₃ and S₈ as additives, and MeCN/H₂O (v/v = 4/1) as the co-solvent, 65% yield of the selective sulfonylation–bromination product 3a was afforded at 10 mA constant current in 10 h (Table 1, entry 1). Further exploration revealed that the electrolyte was sensitive to the transformation, and almost no target product 3a was detected when ⁿBu₄NBr was used instead of KBr as the electrolyte (entry 2). The reaction proceeded to achieve the cascade C–H functionalization when other bases such as Et₃N, DBU, and K₂CO₃ were added (entries 3–5). Cs₂CO₃ was found to be the most efficient base for this transformation. Subsequently, reaction solvents were screened. MeCN/H₂O as the solvent gave the best result compared to DMF/H₂O and THF/H₂O (entries 6 and 7). Furthermore, when the current was increased to 15 mA or reduced to 8 mA, a reduced yield of 3a was observed (entries 8 and 9). The reaction provided 3a in 56% yield without the addition of Cs₂CO₃ (entry 10). Moreover, product 3a was not detected in the absence of S₈ or electricity, which illustrated that both are crucial for the transformation (entries 11 and 12).

Table 1 Optimization of the reaction conditions^a

Entry	Deviation from standard conditions	3a/yield^b (%)
a Reaction conditions: vitreous carbon plate anode, platinum plate cathode, constant current = 10 mA, 1a (0.3 mmol), 2a (2 equiv.), electrolyte (1.2 mmol), base (1 equiv.), S8 (2.5 equiv.), solvents (5.0 mL, v/v = 4 : 1), undivided cell, r.t., 10 h. b Isolated yield.
1	None	65
2	^nBu4NBr instead of KBr	—
3	Et3N instead of Cs2CO3	18
4	DBU instead of Cs2CO3	27
5	K2CO3 instead of Cs2CO3	38
6	DMF/H2O as the solvent	26
7	THF/H2O as the solvent	21
8	Constant current = 15 mA	32
9	Constant current = 8 mA	37
10	No Cs2CO3	56
11	No S8	—
12	No electricity	—

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After optimizing the electrolysis conditions, we then turned our attention to exploring the substrate scope of this electrochemical C–H sulfonylation–bromination of indolizines. Various indolizine derivatives were first evaluated under the optimal conditions, and the results are shown in Scheme 3. 2-Phenylindolizines with substituents such as –Me, –OMe, –Et, and –Br on the pyridine ring smoothly delivered the dual C–H functionalization products 3b–3f in 36–61% yields. When the ortho-substituent of the phenyl in 2-phenylindolizine was occupied by the electron-withdrawing group –F, the reactions provided the desired product 3g in 63% yield. Next, the effect of the substituent at the para position of the phenyl in 2-phenylindolizines was examined. The 2-phenylindolizines bearing substituents such as –OMe, –F, –Cl, –CN, and –CF₃ at the para position offered the corresponding products 3h–3k in 52–78% yields. The structure of product 3i was determined by single-crystal X-ray analysis (CCDC number: 2305723†). When the substituents (–F, –Cl, and –Br) occupied the meta position, it was found that the reactivity was slightly affected, furnishing the functional indolizine products 3l–3n in 42–58% yields. Notably, 2-(4-fluoro-3-methylphenyl)indolizine was also found to be effective for the electrochemical C–H sulfonylation–bromination (3o). In addition, disubstituted indolizines were tolerated in this electrochemical reaction as well, giving the expected sulfonylated–brominated indolizine derivatives 3p–3r in acceptable yields.

Scheme 3 Substrate scope of indolizines. Reaction conditions: 1 (0.3 mmol), 2a (0.6 mmol), KBr (1.2 mmol), Cs₂CO₃ (0.3 mmol), S₈ (0.75 mmol), MeCN/H₂O = 4 mL/1 mL, 10 mA, r.t., 10 h. Isolated yield.

Next, the scope of the reaction with respect to the sodium sulfinate reactants was investigated with 2-phenylindolizine as the substrate (Scheme 4). Under the optimized conditions, the electroneutral substrate sodium benzenesulfinate allowed the preparation of product 4a in 73% yield. Meanwhile, satisfactory yields of the target products could also be obtained for the substrates bearing electron-withdrawing substituents including sodium 4-fluorobenzenesulfinate, sodium 4-chlorobenzenesulfinate, and even sodium 3-chloro-4-fluorobenzenesulfinate (4b–4d). Moreover, aliphatic sulfinates such as sodium methanesulfinate and sodium ethanesulfinate proved to be suitable reaction partners, providing the desired sulfonylbrominated indolizines in 63–68% yields (4e and 4f). However, sodium trifluoromethanesulfinate and sodium hydroxymethanesulfinate did not convert to the desired products (4g and 4h).

Scheme 4 Substrate scope of sodium sulfinates. Reaction conditions: 1a (0.3 mmol), 2 (0.6 mmol), KBr (1.2 mmol), Cs₂CO₃ (0.3 mmol), S₈ (0.75 mmol), MeCN/H₂O = 4 mL/1 mL, 10 mA, r.t., 10 h. Isolated yield.

Encouraged by the above success, we wondered whether diverse functional groups such as –SCN, –SeR, and –SR could be selectively introduced into indolizines.^12a,13 If possible, it would widely expand the applications of this electrochemical C3–H and C1–H difunctionalization protocol. However, we did not detect the desired products when 2-phenylindolizine 1a, sodium p-toluenesulfonate 2a, and NH₄SCN were used under the optimal electrochemical conditions. Interestingly, this aim could be realized via a two-step process. Electrochemical selective C3–H sulfonylation occurred first, which gave the C3-sulfonated indolizine 5a (Scheme 5, eqn (1)). C3-sulfonated indolizines further underwent electrochemical C1–H thiocyanation to furnish the products 6. For example, a variety of indolizines led to the formation of sulfonylation–thiocyanation products 6a–6c in good yields (Scheme 5). This strategy was extended to the electrochemical synthesis of the sulfonylation–selenylation products 7a–7c and they were obtained in excellent yields (Scheme 6). The diaryl diselenide and dialkyl diselenide were both efficient coupling partners. Moreover, diaryl disulfide could also participate in the electrochemical selective sulfonylation–thiolation, providing the desired product 7d in 81% yield.

Scheme 5 Electrochemical selective sulfonylation–thiocyanation of indolizines. Reaction conditions: 5 (0.2 mmol), NH₄SCN (0.6 mmol), Bu₄NBF₄ (0.8 mmol), MeCN = 5.0 mL, 10 mA, r.t., 10 h. Isolated yield.

Scheme 6 Electrochemical selective sulfonylation–selenylation/thiolation of indolizines. Reaction conditions: 5 (0.2 mmol), (RSe)₂ or (RS)₂ (0.6 mmol), KI (0.8 mmol), MeCN/H₂O = 4 mL/1 mL, 10 mA, r.t., 10 h. Isolated yield.

In addition, a scale-up reaction of 1a and 2a was performed in an undivided cell, resulting in the generation of the difunctional indolizine derivative 3a in 61% isolated yield (Scheme 7, eqn (2)). To gain insights into the mechanism of the electrochemical C–H sulfonylation–bromination of indolizines, control experiments and cyclic voltammetry (CV) tests were carried out (Schemes 7 and 8). First, 3-sulfonylated indolizine 5a was detected via electrochemical cross-coupling reactions between 2-phenylindolizine 1a and sodium sulfinate 2a (Scheme 5, eqn (1)). The 3-sulfonylated indolizine 5a further underwent the electrochemical C–H bromination to afford the final difunctionalized product 3a in 81% yield, which indicated that 5a was likely to be an effective intermediate in the reaction (Scheme 7, eqn (3)). Meanwhile, we also noticed that the desired product 3a could not be observed in the absence of S₈ or electric current, which confirmed the important role of S₈ and electric current in the bromination reaction (Table 1, entry 11 and eqn (3)). Moreover, the addition of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) inhibited the model reaction completely (Scheme 7, eqn (4)). This suggested that the reaction possibly proceeded via a radical pathway. Finally, we explored the redox behavior of 2-phenylindolizine 1a, p-toluenesulfinate 2a, and KBr by CV to understand the possible mechanism. The oxidation peaks of 1a and 2a were observed at 1.19 V and 1.20 V, respectively.^8b The very close oxidation potentials between 1a and 2a likely induced the radical–radical cross-coupling reaction. Meantime, KBr showed an oxidation peak at 1.22 V. Thus, 1a and 2a exhibited a lower oxidation potential and were preferentially oxidized at the anode.

Scheme 7 Scale-up reaction and mechanistic experiments.

Scheme 8 CV experiments.

Based on the experimental results and literature reports,^4a,8b,13 two plausible reaction mechanisms for the electrochemical C–H sulfonylation–bromination of indolizines were proposed, as shown in Scheme 9. In path A, p-toluenesulfinate 2a first loses one electron at the anode to generate a sulfonyl radical. 2-Phenylindolizine 1a is also oxidized at the anode to produce the radical species I. Subsequently, the radical–radical cross-coupling reaction between the sulfone radical and radical species I gives the intermediate II, which undergoes deprotonation to provide 3-sulfonylated indolizine 5a. On the other hand, Br₂ was formed via the electrochemical oxidization at the anode. The formed Br₂ was quickly captured by S₈ to give the complex III,¹⁴ which further reacted with 3-sulfonylated indolizine 5a to yield the active bromonium ion intermediate IV. Next, a ring-opening reaction occurred to give the intermediate V, which was followed by deprotonation to give the final product 3a. In path B, 3-sulfonyl indolizine 5a was generated according to path A. The electrochemical oxidation of 5a to its corresponding radical cation VI occurs; meanwhile the bromine radical is formed at the anode. Then the radical cation VI and the bromine radical undergo “radical–radical” coupling to give the intermediate V. Finally, product 3a was obtained via the deprotonation of intermediate V.

Scheme 9 Proposed mechanism pathways.

Conclusions

In conclusion, we have demonstrated an environmentally friendly electrochemical regioselective C–H sulfonylation–bromination from indolizines and sodium sulfinates with readily available KBr as the halogenating agent and electrolyte. This selective electrochemical sulfonylation–bromination protocol allows for the construction of difunctionalized indolizine derivatives under catalyst- and oxidant-free conditions. Moreover, electrochemical C–H sulfonylation–thiocyanation/selenylation/thiolation of indolizines was also achieved via a two-step process. Finally, a series of control experiments and CV examinations were conducted to clarify the reaction mechanism.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was supported by the National Natural Science Foundation of China (22001045) and the Start-up Grant from Guangdong Pharmaceutical University (51304043005 and 51304035006).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 2305723. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d4qo00035h

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