Electrochemically assisted deprotection of acetals, ketals, and dithioacetals under neutral conditions

Abstract

Electroorganic synthesis (EOS) enables unattainable molecular transformations that cannot be achieved through conventional acid/base or thermal reactions to be realized by exploiting molecular redox capabilities. The use of acetals as protecting groups for the carbonyl functionality is a pivotal component of natural product synthesis and drug discovery. Acetal deprotection typically requires aqueous acid hydrolysis. Herein, we present the development of an electrochemical deprotection reaction for cyclic acetal, ketal, and dithioacetal derivatives, with a diverse range of such aromatic and aliphatic substrates deprotected in yields of between 55% and quantitative. Mechanistic investigations provided insight into the electro-deprotection process involving acetals. Lithium perchlorate (LiClO₄) plays a dual role, functioning as both the electrolyte and the oxygen source for the carbonyl moiety, with the electro-deprotection reaction proceeding to afford carbonyl products. Moreover, reaction efficiency was markedly enhanced by the addition of 1,3,5-trioxane, which acts as a Li activator.

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Green foundation

1. This study has led to the development of a novel electrochemical approach for the deprotection of acetals, ketals and dithioacetals. The reaction is optimised when driven by a catalytic amount of electrical input. This approach reduces the costs and risks associated with neutralisation processes while achieving high atomic and energy efficiency.

2. This electrochemical deprotection method has been shown to achieve high reaction efficiency under acid/base-free conditions, yielding valuable carbonyl compounds. The reaction is carried out using inexpensive graphite electrodes. These advantages make the methodology a practical and sustainable conversion reaction from a green chemistry perspective.

3. Applying the electrochemical process to continuous flow systems could also improve scalability and cost efficiency. By using renewable energy for the electrochemical recycling of polymers, this approach has the potential to achieve complete carbon neutrality in the future.

Introduction

Electroorganic synthesis (EOS) has garnered considerable attention as a formidable technique for the direct oxidation or reduction of organic compounds.¹ The capacity of EOS to selectively transform specific molecules and functional groups has positioned it as a singularly efficacious synthetic technique, as evidenced by its use in the synthesis of natural products,² drug derivatives,³ and functional materials.⁴ Consequently, further innovative EOS advancements are expected to elicit reactions that are not attainable through conventional methods in both academic and industrial-manufacturing settings.^1a,5–7

Acetals are representative protecting groups for carbonyl groups in organic synthesis.⁸ Typically, acetals are deprotected under acidic conditions using Brønsted or Lewis acid catalysts in the presence of water as the carbonyl oxygen source (Scheme 1A).^8–11 Nevertheless, the use of acidic aqueous conditions necessitates caution and careful consideration that potentially result in the emergence of synthetic limitations. Kita, Fujioka, and their colleagues devised an effective approach for deprotecting acetals under non-acidic conditions via the generation of pyridinium-type salts (Scheme 1B).¹² Liu and colleagues developed a method for transforming ketals into lithium enolates by cleaving the ketal ring under anhydrous, strongly basic conditions with lithium 2,2,6,6-tetramethylpiperidide (LTMP); the generated lithium enolate was then treated with water to convert it into the ketone (Scheme 1C).¹³ The carbonyl oxygen in the product originates from the ketal moiety, and the substrate scope is limited to ketals. Although the reaction mechanisms associated with the transformations depicted in Scheme 1A–C are distinct, they all require the use of stoichiometric quantities of water. Consequently, the development of deprotection reactions for acetals and ketals that do not require the addition of water is of paramount importance from the standpoint of functional group tolerance and substrate applicability. Nevertheless, the development of widely applicable deprotection methods that do not require the deliberate addition of water is significantly challenging, despite the high synthetic demand.

Scheme 1 Acetal deprotection under various conditions.

Herein, we report a versatile method for the electro-deprotection of acetal, ketal, and dithioacetal derivatives (Scheme 1D). The deprotection process is conducted efficiently by combining LiClO₄, which serves as both the electrolyte and the oxygen source, with 1,3,5-trioxane, which acts as the Li activator.

Results and discussion

Optimizing the reaction conditions

The reaction conditions were optimized by applying a constant voltage to graphite electrodes (Table 1). The deprotection reaction was complete within 1 h when a solution of benzaldehyde cyclic acetal 1a in acetonitrile (MeCN) was electrolyzed in the presence of LiClO₄ (as the electrolyte) and potassium carbonate (K₂CO₃) to afford aldehyde 2a in 95% isolated yield (entry 1). The use of NaClO₄ and Mg(ClO₄)₂ also afforded 2a in 78 and 94% yields, respectively, along with oxidized byproduct 3a (entries 2 and 3). In contrast, electrolytes containing tetrabutylammonium as the countercation or an ionic liquid were ineffective (entries 4–7). Deprotection proceeded in the absence of K₂CO₃ to afford 2a in 99% yield within 15 min (entry 8). Details of the reaction-condition investigation are provided in the ESI (Tables S1 and S2†).

Table 1 Optimizing the reaction conditions^a

Entry	Electrolyte	Yield^b (%)
		1a	2a	3a
a Reaction conditions: 1a (0.20 mmol), K2CO3 (1.0 eq.), and the electrolyte (0.20 M) in MeCN (5.0 mL) were reacted in an undivided cell fitted with a graphite carbon cathode and anode (both 1 × 0.8 × 0.1 cm) at a constant voltage of 2.0 V, unless otherwise noted. The potential was maintained using a Ag/AgNO3 reference electrode. b Determined by ^1H NMR analysis using 1,1,2,2-tetrachloroethane as the internal standard. c For 40 min. d Isolated yield. e Without K2CO3. f For 15 min.
1^c	LiClO4	Trace	98 (95)^d	Trace
2	NaClO4	11	78	7
3	Mg(ClO4)2	0	94	4
4	TBAClO4	52	9	0
5	TBACl	92	0	0
6	TBABF4	70	0	0
7	EMIMBF4	56	4	8
8^e^,^f	LiClO4	0	99 (96)^d	Trace

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Control experiments

Control experiments were used to gain further insight into the deprotection reaction (Table 2), which revealed that the reaction does not proceed in the absence of an electric current, confirming that electricity is required for the deprotection reaction to progress (entries 1 vs. 2). Deprotection did not occur when a sacrificial magnesium (Mg) electrode was used as the anode (entry 3 and Tables S3 and S4†);¹⁴ consequently, an anodic oxidation mechanism involving the graphite electrode operates in this reaction (entry 4). Furthermore, the addition of water or oxygen gas facilitated oxidation to afford undesired 3a (entries 4 and 5 and Table S5†).

Table 2 Control experiments^a

Entry	Deviation from the standard conditions	Yield^b (%)
		1a	2a	3a
a Reaction conditions: 1a (0.20 mmol) and LiClO4 (0.20 M) in MeCN (5.0 mL) were reacted in an undivided cell fitted with a graphite carbon cathode and an anode (both 1 × 0.8 × 0.1 cm) at a constant voltage of 2.0 V, unless otherwise stated. The potential was maintained using a Ag/AgNO3 reference electrode. b Determined by ^1H NMR analysis using 1,1,2,2-tetrachloroethane as the internal standard. c Isolated yield.
1	None (Table 1, entry 8)	0	99 (96)^c	Trace
2	No electricity	99	1	0
3	Mg anode instead of graphite carbon anode	>99	0	0
4	Addition of H2O (5 eq.)	0	94	6
5	Under O2	3	65	15

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Mechanistic investigations

We conducted further mechanistic experiments in which electro-deprotection was carried out using a divided cell in which each electrode was separated by a glass frit (Fig. 1A-1 and A-2). While efficient deprotection was observed (A-1) when 1a was added to the anodic cell, no deprotection occurred when 1a was added to the cathodic cell. Accordingly, the deprotection reaction involves anodic oxidation. Moreover, NMR analysis of the reaction mixture revealed that 83% of the ethylene glycol remained in the reaction mixture at the end of the reaction (Fig. 1B). Taken together, these results indicate that the aldehydic oxygen atom does not originate from the ethylene glycol. The white solid formed on the cathode surface during the reaction was examined by XPS, which revealed Cl(I) and Cl(VII) peaks that correspond to LiCl and residual LiClO₄, respectively, which suggests that LiClO₄ is reduced at the cathode (Fig. 1C, S2–S4†).¹⁵ A time-course study showed that the deprotection reaction was complete within 5 s and that 2a was correspondingly generated. The ester-type oxidation product 3a began to gradually form after 900 s (15 min) had elapsed from the start of the reaction, as shown in Fig. 1D. Additional control experiments involving pre-electrolysis (Table S6†) revealed that the electrogenerated acid (EGA; HClO₄)¹⁶ produced by the reaction between LiClO₄ on the anode surface during electrolysis and the trace amounts of moisture present in the reaction mixture partially promoted the deprotection reaction, even in the absence of a base. Cyclic voltammetry (CV) experiments involving 1a and 2a (Fig. 1E) revealed that almost identical oxidation peaks were observed for 1a (at 1.37 and 1.68 V vs. Fc/Fc+, blue trace), and 1a with LiClO₄ (at 1.42 and 1.72 V vs. Fc/Fc+, purple trace). The second oxidation potential of 1a (at 1.68–1.72 V) was found to correspond to the first oxidation potential of 2a (at 1.68 V vs. Fc/Fc+, green trace), which indicates that the addition of LiClO₄ does not affect the first and second oxidation potentials of 1a and 2a.¹⁷

Fig. 1 Mechanistic studies.

Effect of additives

In light of the information gleaned from the mechanistic studies, we investigated the potential of adding cyclic ethers to facilitate the deprotection reaction (Table 3). The yield of 2b did not improve when 1b was deprotected in the presence of 1a (entry 1 vs. 2). In addition, the use of 1,3-dioxolane as the additive did not affect the yield (entry 3). Conversely, the incorporation of 1,3,5-trioxane markedly augmented the deprotection reaction to afford 2b in 94% yield (entry 4). While the addition of 12-crown-4 led to a slightly higher deprotection yield (48%, entry 5), 1,4-dioxane and tetrahydropyran were ineffective (entries 6 and 7, respectively). 1,3,5-Trioxane can potentially coordinate with Li⁺ to enhance its Lewis acidity¹⁸ as well as the solubility of LiClO₄ and the nucleophilicity of ClO₄⁻.

Table 3 The effect of additives on the reaction^a

Entry	Additive		Yield^b (%)
			1b	2b	3b
a Reaction conditions: 1b (0.20 mmol), LiClO4 (0.20 M), and the additive (1.0 eq.) in MeCN (5.0 mL) were reacted in an undivided cell fitted with a graphite carbon cathode and an anode (both 1 × 0.8 × 0.1 cm) at a constant voltage of 2.5 V unless otherwise noted. The potential was maintained using a Ag/AgNO3 reference electrode. b Determined by ^1H NMR analysis using 1,1,2,2-tetrachloroethane as the internal standard. c Isolated yield.
1	None		50	35	8
2	1a		80	16	0
3	1,3-Dioxolane		55	39	3
4	1,3,5-Trioxane		0	94 (94)^c	0
5	12-Crown-4		46	48	4
6	1,4-Dioxane		55	35	3
7	Tetrahydropyran		65	34	1

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Proposed reaction mechanism

The following reaction mechanisms (Fig. 2, routes 1 and 2) were proposed based on the aforementioned experimental outcomes. Initially, acetal 1 undergoes one-electron oxidation on the anode to form reactive radical cation intermediate Avia route 1. The trioxane-solvated Li⁺ complex [Li]⁺ coordinates with the acetal oxygen, thereby activating the acetal moiety and generating oxocarbenium intermediate B, which is then smoothly nucleophilically attacked by perchlorate-derived species (ClO₃⁻, ClO₂⁻ or ClO⁻),¹⁹ resulting in the formation of intermediate C. One-electron reduction from 1 then generates radical cation intermediate A, which facilitates cleavage of the Cl–O bond in C and the formation of aldehyde 2. Ester 3 is generated from Cvia anodic oxidation or oxidation by LiClO that is made in situ, which is a relatively slow and minor reaction pathway. The perchlorates and their derived species (ClO_m⁻) are reduced on the counter electrode to form ClO_m−1⁻, which repeatedly undergoes nucleophilic attack on B and ultimately precipitates as LiCl on the cathode surface.¹⁵ During the reduction process on the cathode, protons are abstracted from the solvent, generating water. Trace amounts of in situ-generated EGA ([H]⁺)^9,16 from the produced water can also function as a catalyst to directly activate the acetal, albeit with poor reaction efficiency (route 2).

Fig. 2 Proposed reaction mechanism.

Substrate scope

We subsequently investigated the substrate scope of the electro-deprotection method, the results of which are presented in Table 4.²⁰ Aromatic acetals 1c–1f, which are substituted with nitro-, iodo-, and methoxycarbonyl groups, respectively, naphthaldehyde cyclic acetals 1g and 1h, and benzaldehyde acyclic acetal 1i were converted into their corresponding aldehydes 2c–2i in excellent yields (82%–quant.), irrespective of the electronic nature of the substituent or its position. Deprotection of neopentyl and pinacol acetals 1j and 1k also yielded 2a in yields of 86% and 84%, respectively, while 1l was selectively deprotected to form 2l in 96% yield. Notably, the alkene moiety is retained throughout this process. The deprotection of aromatic ketal 1m was conducted under both constant voltage and constant current conditions, yielding 2m in 90% and 87% yields, respectively. Acetal-bearing heteroaromatics 1n and 1o were converted into their corresponding aldehydes in yields of 88% and 90%, respectively. The electro-deprotection method was used to synthesize carbonyl products 2p–2s from aliphatic acetals and ketals 1p and 1q, as well as phenylmethyl acetals 1r and 1s, with yields ranging between 55 and 96%. In the course of the study, it was established that estrone derivative 1t, in which the ketone in the steroid skelton was ketal protected, was also readily deprotected to give 2t (estrone) in 78% yield as a hormone therapy drug. Deprotection of 1u, which possesses both acetal and ketal moieties, afforded carbonyl compound 2u in 97% yield. While dithioacetals are typically deprotected using hazardous and highly toxic reagents, such as mercury and peroxides,²¹1v was deprotected to afford 2a in 85% yield. This method is applicable to drug derivatives, with the deprotection of the benzylidene-acetal-protected atorvastatin precursor 1w proceeding in 51% yield to give 2w, while retaining its stereochemistry.

Table 4 Substrate scope^a,b

a Reaction conditions: 1 (0.20 mmol), 1,3,5-trioxane (1.0–5.0 eq.), and LiClO₄ (0.20 M) in MeCN (5.0 mL) were reacted in an undivided cell fitted with a graphite carbon cathode and an anode (both 1 × 0.8 × 0.1 cm), and the voltage was set to 1.5, 2.0, 2.5, or 2.8 V, depending on the substrate, unless otherwise noted. The potential was maintained using an Ag/AgNO₃ reference electrode. b Isolated yield. c GC yield. d K₂CO₃ (1.0 eq.) was added. e Without 1,3,5-trioxane. f Constant current of 5.0 mA.

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Conclusions

In conclusion, we developed an efficient method for deprotecting cyclic acetals, ketals, and dithioacetal derivatives, which proceeds in a redox-neutral manner driven by electricity, with LiClO₄ serving as the electrolyte and carbonyl oxygen source. 1,3,5-Trioxane was found to activate LiClO₄ by coordinating with the Li⁺ to enhance reaction efficiency. Notably, the reaction proceeded without the need to deliberately add water under basic-to-partially acidic conditions because EGA is generated from LiClO₄. As a result, we anticipate that this robust molecular transformation will be used to synthesize pharmaceuticals and functional materials that cannot be achieved using conventional reactions.

Author contributions

Y. Abe: writing – original draft, investigation, data curation; T. Yamada: writing – review & editing, conceptualization, data curation, validation; T. Yamamoto, Y. Esaka: formal analysis, resources; T. Ikawa: data curation, validation; H. Sajiki: supervision, writing – review & editing, data curation, project administration, funding acquisition.

Data availability

The data supporting this article have been included as part of the ESI.†

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We thank Editage (https://www.editage.jp) for English language editing.

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Footnotes

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d4gc06348a

‡ Current address: Faculty of Pharmaceutical Sciences, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.

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