Divergent electrosynthesis of diketopiperazines and amides

Abstract

The development of convenient and practical synthetic strategies for constructing bioactive diketopiperazines (DKPs) and amide scaffolds without metal residues is of great interest in organic synthesis. Herein, we report a straightforward and scalable P(V)/I⁻-co-mediated divergent electrosynthesis of bioactive DKPs and amides from readily available amino acids, coupled with favorable green metrics such as a low E-factor (1.07) and PMI (2.07). Mechanistic studies confirmed that the phosphate ester intermediate formed via anodic oxidation serves as a pivotal species in enabling this divergent electrochemical transformation.

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Green foundation

1. We established an electrochemical platform for synthesizing bioactive DKPs and amides without protecting groups, replacing toxic P(III)/high temperature methods (up to 145 °C) with traceless electrons and stable P(V) at room temperature.

2. A straightforward and scalable electrosynthesis method was developed, enabling gram-scale production (76% yield) without metal residues or multi-step protection/deprotection while simultaneously achieving favorable green metrics (E-factor: 1.07; PMI: 2.07).

3. Future work will be aimed at further reducing the catalytic loading of NaI and developing a flow electrochemical synthesis.

Diketopiperazines (DKPs) are privileged structural motifs in bioactive natural products, exhibiting broad pharmacological activities,¹ including antitumor,² antiviral,³ antifungal,⁴ antibacterial,⁵ and antifouling⁶ properties (Scheme 1A). Beyond serving as bitter flavor compounds in foods like coffee, cacao, chocolate, and beer, they also function as organic catalysts for hydrocyanation of imine.⁷ The traditional synthetic routes to these heterocycles typically rely on thermal cycloamidation or multi-step protection/deprotection strategies.⁸ While protection/deprotection cyclization mitigates thermodynamic instability in amino acid precursors, its step inefficiency and harsh reagents contradict green chemistry principles (Scheme 1B, route-a).⁹ Although the strategy using P(III)/microwave radiation enables the synthesis of both symmetrical and asymmetrical DKPs from various natural amino acids, it requires toxic and flammable P(III) and temperatures as high as 145 °C, violating green chemistry principles (Scheme 1B, route-b).¹⁰ Therefore, developing a direct, efficient, and green synthetic method for DKP derivatives is imperative.

Scheme 1 Content of this work.

Over the past decade, organic electrosynthesis has emerged as a powerful green chemistry platform, replacing traditional redox reagents with traceless electrons to enable sustainable synthetic transformations.¹¹ To the best of our knowledge, the P(V)/I⁻-co-mediated divergent electrosynthesis of bioactive DKPs scaffolds has not yet been developed. Previously, we developed versatile photochemical and electrochemical strategies for the decarboxylative functionalization of N-arylglycines (Scheme 1C).¹² Leveraging our established expertise in electrochemical synthesis,¹³ we herein designed an innovative divergent electrosynthetic platform for the efficient construction of bioactive DKPs and amide scaffolds, mediated by a novel P(V)/I⁻ system (Scheme 1D). The proposed mechanism initiates with anodic oxidation of iodide to generate I₃⁻ and I₂ species, which rapidly react with phosphorus oxides to form the highly reactive phosphinic iodide (Int-A). This electrophilic species then undergoes nucleophilic attack by the amino acids, yielding the phosphate ester intermediate. Ultimately, phosphate ester intermediate undergoes nucleophilic cyclization with another molecule of Int-B or amines, affording recoverable high-value building blocks such as diphenylphosphinic acid and the desired products. This mechanistic design not only facilitates the development of a sustainable platform for the programmable assembly of structurally diversified DKPs, but also extends its applicability to amide architectures. Notably, the promising green credentials of our electrosynthetic method for DKPs are substantiated by a comprehensive set of six quantitative metrics, with the low E-factor (1.07) and PMI (2.07) underscoring its efficient resource utilization and minimized environmental footprint.

Based on the reaction design, we initiated our investigation by employing phenylglycine (1a) as the benchmark substrate for comprehensive reaction parameter optimization (Table 1). Initially, the model reaction conducted at room temperature using diphenylphosphine oxide (1b) as the deoxygenation reagent in a mixed solvent system of acetonitrile and ethyl acetate containing amounts of Et₃N and NaI, under constant current electrolysis (10 mA cm⁻²) for 3 hours, afforded the desired product 1c in 75% yield (Table 1, entry 1). Notably, the diphenylphosphinic acid generated from diphenylphosphine oxide as the deoxygenating reagent could be efficiently recovered in 85% yield through a simple acidification step. The control experiments showed that current, 1b, Et₃N, and NaI are all necessary conditions for this transformation (Table 1, entries 2 and 3). Lower yields were observed when ethyl acetate was replaced by DMA, DCE, 1,4-dioxane, or when acetonitrile was used as the sole solvent (Table 1, entries 4 and 5). However, the yield of the desired product was not enhanced when alternative quaternary ammonium salts were employed as electrolytes (Table 1, entries 6 and 7). The evaluation of alternative iodide sources (KI, NH₄I, ⁿBu₄NI) proved counterproductive, as a decrease in yield was observed in all cases compared to NaI (Table 1, entry 8). While the underlying cause is not definitively established, we speculate that it may be related to dependent effects on solubility. Notably, deviating from the optimal loading of NaI, by either increasing or decreasing it, led to a lower yield of product 1c (Table 1, entry 9). Similarly, in the study of base variations, the product yield slightly decreased either with Et₃N substitution or at different Et₃N loadings (Table 1, entries 10 and 11). Additionally, we examined the impact of current and electrode materials on the product yield. The results showed that altering the charge load quantity, whether increased or decreased, did not lead to an enhancement in yield (Table 1, entry 12). Investigation of electrode materials revealed that a carbon rod anode paired with a platinum plate cathode constituted the optimal combination (Table 1, entry 13). Finally, a systematic evaluation of various phosphorus oxides (2b–5b) or P^III derivatives (6b) revealed that compound 1b exhibited superior performance as the optimal choice for this transformation (Table 1, entry 14).

Table 1 Optimization of the reaction conditions^a

Entry	Variation	Yield^b/%
DIPEA = N,N-diisopropylethylamine, Py = pyridine, EA = ethyl acetate, DCE = 1,2-dichloroethane, DMA = dimethylacetamide.a Reaction conditions: carbon rods (diameter = 6 mm) as the anode, Pt (1.0 × 1.0 cm^2), 2.24 F mol^−1, 1a (0.5 mmol), b (0.5 mmol), Et3N (0.8 mmol), ^nBu4NBF4 (0.5 mmol), NaI (50 mol%), CH3CN/EA (3 mL, v = 2/1), air, r.t.b GC yield with 4-methylaniline as the internal standard (isolated yields).
1	None	75 (72)
2	Without current	0
3	Without 1b, or Et3N, or NaI	0
4	DMA, DCE, 1,4-dioxane instead of EA	51, 50, 41
5	CH3CN	51
6	^nBu4NPF6 instead of ^nBu4NBF4	64
7	^nBu4NOAc, ^nBu4NNO3, ^nBu4NClO4	0, 44, 33
8	KI, NH4I, ^nBu4NI instead of NaI	35, 39, 55
9	NaI (20 mol%, 60 mol%, 70 mol%)	27, 73, 61
10	Py, DIPEA instead of Et3N	53, 55
11	Et3N (0.5 mmol, 1.0 mmol)	62, 48
12	0.28 F mol^−1, 0.84 F/mol	23, 57
13	Pt (+)|C (−), Pt (+)|Pt (−), C (+)|C (−)	35, 66, 25

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With the optimized conditions in hand, the scope and limitations of the electrochemical synthesis of bioactive symmetrical and asymmetrical DKPs scaffolds from various readily available N-aryl glycines (a) were evaluated (Scheme 2). Firstly, under the standard reaction conditions, we explored the scope of amino acids applicable to the synthesis of symmetrical DKP derivatives. To our delight, various N-aryl glycines bearing either electron-donating (2c–5c) or electron-withdrawing (6c–11c) groups underwent the reaction smoothly under the established conditions, affording the corresponding products in moderate to excellent yields. Moreover, indoline-2-carboxylic acid was also capable of delivering the corresponding product 12c in 60% yield under the established reaction conditions. Notably, N-Fmoc glycine also afforded the corresponding product 13c under the standard conditions, albeit in a reduced yield.

Scheme 2 Synthesis of DKPs. Reactions conducted on a 0.5 mmol scale. Reaction conditions: carbon rods (diameter = 6 mm) as the anode, Pt (1.0 × 1.0 cm²), 2.24 F mol⁻¹, a (0.5 mmol), 1b (0.5 mmol), Et₃N (0.8 mmol), ⁿBu₄NBF₄ (0.5 mmol), NaI (50 mol%), CH₃CN/EA (3 mL, v = 2/1), air, r.t., isolated yields, FE = Faraday efficiency.

Unfortunately, the reaction did not yield the desired product (14c and 14c′) when proline or glycine was used. We speculate that this can be attributed to the insufficient stability of the corresponding phosphoester intermediate formed during the reaction. This hypothesis was validated through asymmetric DKP synthesis, where compounds 15c and 7c were furnished in 64% and 22% yields, respectively. Furthermore, our strategy can be effectively utilized for the selective synthesis of asymmetric DKP derivatives, yielding moderate product outputs (16c–18c).

Subsequently, guided by our designed reaction protocol, we examined the substrate scope of amines as stronger nucleophilic reagents, employing N-phenylglycine (1a) as a benchmark compound for the synthesis of amide derivatives (Scheme 3). Notably, both aromatic and alkyl primary amines proved compatible under the standard conditions, affording the corresponding products in moderate-to-excellent yields (1e–9e). Similarly, representative secondary amines reacted effectively under the standard conditions, affording target products in moderate yields (10e–13e). Overall, the developed P(V)/I⁻-co-mediated electrosynthesis strategy provided a divergent, sustainable platform for synthesizing bioactive DKPs and amides.

Scheme 3 Synthesis of amides. Reactions conducted on a 0.5 mmol scale. Reaction conditions: carbon rods (diameter = 6 mm) as the anode, Pt (1.0 × 1.0 cm²), 2.24 F mol⁻¹, 1a (0.5 mmol), 1b (0.5 mmol), d (0.5 mmol), Et₃N (0.8 mmol), ⁿBu₄NBF₄ (0.5 mmol), NaI (50 mol%), CH₃CN/EA (3 mL, v = 2/1), air, r.t., isolated yields, FE = Faraday efficiency.

To validate the proposed reaction mechanism, we carried out a series of mechanistic experiments (Scheme 4). First, the cyclic voltammetry (CV) experiments were performed, and the results are summarized in Scheme 4A and B. Iodide ions are oxidized at the anode to generate I₃⁻ (0.41 V) and I₂ (0.74 V vs. Ag/AgCl, saturated KCl).¹⁴ Direct electron transfer between the in situ-generated iodine species (I₂/I₃⁻) and substrate 1b is revealed by the electrochemical analysis of their mixture (Scheme 4A). However, such electron transfer was not observed between the I₂/I₃⁻ species and substrate 1a (Scheme 4B).

Scheme 4 Mechanism studies.

To probe the role of I⁻ in the reaction, a stoichiometric experiment using I₂ was performed (Scheme 4C). These results indicated that the anodic oxidation of I⁻ to I₃⁻, and the subsequent dissociation of I₃⁻ into I₂ and I⁻ was essential for product formation. Next, we investigated the potential intermediates involved in the reaction pathway. Given the high reactivity and inherent instability of the in situ generated diphenylphosphinic iodide (A), diphenylphosphinic chloride (7b) was employed as a more stable alternative. This modification led to the formation of the desired product in 65% yield, suggesting that the in situ generated diphenylphosphinic iodide (A) was a possible intermediate (Scheme 4D). In contrast, no product was observed when 2-(phenylamino)acetaldehyde (1a′) was used as the starting material (Scheme 4E). Besides, the in situ phosphate ester intermediate (B) that we speculated would be generated could be verified by GC-MS (Fig. S2). Notably, the reaction converted diphenylphosphine oxide (1b) into diphenylphosphinic acid, which served as a high-value building block and was recovered in 85% yield (Fig. S1). Even with the addition of three equivalents of the radical scavenger (TEMPO, BHT, or 1,1-diphenylethylene), the desired product was still obtained (Scheme S1). This strongly suggests that the transformation does not proceed via a radical mechanism. The observed decrease in yield was attributed to the scavenger consuming both coulombs and key iodine species (I₃⁻/I₂) in the system (detailed explanations are provided in the SI).

Based on the aforementioned experimental results and previous reports, a possible mechanism has been hypothesized (Scheme 5).¹⁵ The process begins with the oxidation of iodide ions at the anode to produce I₃⁻ or I₂. These species then react with diphenylphosphine oxide (1b) to generate a highly reactive intermediate A. Next, the crucial intermediate B is generated in situ by the reaction of A with 1a, and releases HI. In this directional electrochemical synthesis, the amine nucleophile's strength dictates the reaction pathway. In the presence of an amine more nucleophilic than B, the latter reacts preferentially with the amine to generate the amide 1e. Meanwhile the absence of amine generates the amide 1c through an intermolecular nucleophilic cyclization (INC) of B. The liberated diphenylphosphinic acid can be isolated by acidifying the reaction solution, a process that is readily achieved and facilitates its recovery. The corresponding cathodic half-reaction proceeds at the cathode, where H⁺ is reduced to molecular hydrogen.

Scheme 5 Proposed mechanistic pathway.

The synthetic applicability of the present protocol was evaluated through gram-scale reactions employing 1a/1b and 8a/1b systems, which afforded the desired products 1c and 8c under standard conditions. As shown in Scheme 6, the reaction could afford 1c and 8c in 76% and 54% yields, respectively. The obtained product 1c further reduced to access compound 1f with a yield of 75%. Similarly, compound 8c could undergo further functionalization to afford 2f with a yield of 56%. Notably, we evaluated six quantitative green metrics for our gram-scale electrosynthesis of diketopiperazines (Table S1), including environmental factor (E-factor = 1.07), atom economy (AE = 87.2%), reaction mass efficiency (RME = 48.2%), process mass intensity (PMI = 2.07), carbon efficiency (CE = 93.3%), and atom efficiency (66.3%). These metrics collectively attest to the promising green credentials of our method, particularly its efficient resource utilization and reduced environmental footprint, as reflected in the low E-factor and PMI values.

Scheme 6 Gram-scale synthesis and application. (a) 0.25 mmol scale, LiAlH₄ (4.0 equiv.), N₂, 0 °C (10 min) to r.t., 3 h. (b) 0.25 mmol scale, PhNHNH₂ (2.5 mmol), toluene, 100 °C, air, 12 h.

Conclusions

In summary, we have developed a novel P(V)/I⁻-co-mediated divergent electrosynthesis of bioactive DKPs and amides from readily available amino acids. This novel electrochemical synthesis strategy overcomes the key limitations of traditional methods, including (1) mandatory amino acid protection/deprotection sequences, (2) high temperatures, and (3) dependence on toxic dichloro(methoxy)phosphane. Starting from readily available amino acids, our methodology establishes a divergent and green platform for synthesizing biologically active DKPs and amide derivatives, showing a low environmental impact, as reflected by a lower E-factor of 1.07 and a PMI of 2.07. Mechanistic evidence supports the reaction design and the proposed mechanistic pathway.

Conflicts of interest

There are no conflicts to declare.

Data availability

The data supporting this article have been included as part of the supplementary information (SI). Supplementary information: Experimental details, characterization data for new compounds, and copies of NMR spectra (PDF). See DOI: https://doi.org/10.1039/d5gc05648a.

Acknowledgements

This work is supported by the Natural Science Foundation of Shandong Province (No. ZR2025MS110), the Natural Science Foundation of China (No. 22301313), Jiangxi Chengguang New Materials Co., Ltd (No. kj2025hx148), and Qufu Normal University (No. 6132 and 6125).

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Footnote

† These authors contributed equally to this work.

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