Facile and general electrochemical deuteration of unactivated alkyl halides

ABSTRACT Herein, a facile and general electroreductive deuteration of unactivated alkyl halides (X = Cl, Br, I) or pseudo-halides (X = OMs) using D2O as the economical deuterium source was

reported. In addition to primary and secondary alkyl halides, sterically hindered tertiary chlorides also work very well, affording the target deuterodehalogenated products with excellent

efficiency and deuterium incorporation. More than 60 examples are provided, including late-stage dehalogenative deuteration of natural products, pharmaceuticals, and their derivatives, all

with excellent deuterium incorporation (up to 99% D), demonstrating the potential utility of the developed method in organic synthesis. Furthermore, the method does not require external

catalysts and tolerates high current, showing possible use in industrial applications. SIMILAR CONTENT BEING VIEWED BY OTHERS PD-CATALYZED DEUTERATION OF ARYL HALIDES WITH DEUTERIUM OXIDE

Article Open access 16 March 2025 ORGANOPHOTOCATALYTIC SELECTIVE DEUTERODEHALOGENATION OF ARYL OR ALKYL CHLORIDES Article Open access 17 May 2021 ELECTROCHEMICAL HALOGEN-ATOM TRANSFER

ALKYLATION VIA Α-AMINOALKYL RADICAL ACTIVATION OF ALKYL IODIDES Article Open access 26 October 2023 INTRODUCTION Compounds with D-labeling play an important role in the realm of chemistry,

mechanistic studies, and pharmaceutical science1,2,3,4,5,6,7,8,9. Dehalogenative deuteration from organic halides is a straightforward way to obtain deuterated target compounds. However,

major studies focused on dehalogenative deuteration of aryl halides and activated alkyl halides10,11,12,13,14,15,16,17,18,19,20. In contrast, corresponding reports on unactivated alkyl

halides, particularly on unactivated alkyl chlorides, have not been well elucidated. Several realizations have been reported but suffer from a number of problems, such as limiting to alkyl

iodides using radical initiators21,22, the usage of a stoichiometric metal reductant23, long reaction time, and low reactivity of tertiary alkyl halides using photocatalysis24, etc.

Therefore, the development of simple, efficient, and environmentally-friendly approaches to access deuterated compounds from unactivated alkyl halides with high D-incorporation is highly

desirable. Meanwhile, organic electrochemistry has become a powerful tool for sustainable synthesis by employing electron instead of stoichiometric amounts of redox reagents in the past

decade25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44. Organic halides are important players in traditional organic chemistry as well as promising electrochemistry, owing to

their versatile reactivity and readily available properties. Thus, impressive electrochemical progress of organic halides has been made, such as reductive bifunctionalization of

alkenes45,46,47,48, reductive coupling with halides49,50,51,52,53,54,55,56, and others57,58,59,60,61,62,63,64,65,66,67,68. Hence, electrochemical deuteration of organic halides could be a

straightforward and promising route for valuable deuterated compounds, which has gained increasing attention69,70,71. However, current research and success in electrochemical deuteration

have been focused on aryl halides. In sharp contrast, electrochemically driven dehalogenative deuteration of unactivated halides has proven elusive (Fig. 1a). Direct electrochemical

deuteration of unactivated alkyl halides is challenging due to their extremely negative reduction potential19,72,73,74, and likelihood of competitive undesired side reactions50. Herein, we

report our effort in developing this dehalogenative deuteration of unactivated alkyl halides, making it a general, economically and environmentally approach through electrochemistry (Fig.

1b). Notable features of this strategy include: (a) broad scope and excellent D-incorporation, including unsatisfactory tertiary chlorides in previous studies, (b) D2O as an economical

deuterium source, (c) external catalysts-free and the use of electricity as an environmentally-friendly reductant, (d) catalytic amounts of electrolyte and no sacrificial anode, (e)

tolerance with high current (up to 500 mA), making it potentially applicable in industrial production, (f) late-stage deuteration of complex natural products and drug derivatives. RESULT

OPTIMIZATION OF ELECTROREDUCTIVE DEHALOGENATION DEUTERATION Initially, we started our investigation using D2O as the economical deuterium source, unactivated alkyl bromide 1 as the

substrate, and DMF as the solvent. After careful optimization, the corresponding product 2 was finally obtained in excellent yield and D-incorporation under 30 mA constant current with

carbon felt (CF) and Pb as electrodes, in the presence of DIPEA as well as the catalytic amount of TBAI as the electrolyte in an undivided cell at room temperature for 10 hours (Table 1,

entry 1). The control experiment revealed that the electricity was essential for the observed reactivity (entry 2). The reaction still worked well in the absence of DIPEA with 60% yield

(entry 3), which showed that DMF could also be oxidized on anode. In addition, reducing the current to 20 mA led to lower yield and D-incorporation (entry 4). Surprisingly, the desired

transformation proceeded smoothly with a higher current at 100 mA in 60 min (entry 5). It is notable that even under an extremely high current at 500 mA, the reaction still proceeded well to

give the target product in only 15 min, without diminishing the yield and D-labeling level, showing potential usage in industrial amplification (entry 6). DMSO was proven to be a poor

solvent for this transformation (entry 7), while MeCN gave a comparable yield but lower D-incorporation (entry 8). The reaction also worked well when _n_Bu4NBF4 was used as the electrolyte,

albeit in a slightly lower yield (entry 9). Finally, different electrodes were tested but none of the results surpassed entry 1 (entries 10-13). SUBSTRATE SCOPE With the optimized reaction

conditions in hand, we probed the generality of this electroreductive deuteration reaction. Firstly, various alkyl bromides were screened (Fig. 2A). Alkyl bromides with different lengths of

carbon chains worked well to afford the corresponding products with excellent D-incorporation (2-7). Substituents with electron-withdrawing or donating properties were compatible and showed

little effect on the reaction (8-13). Besides, other aromatic rings, including naphthalene, indole, and dihydrobenzofuran (15-17), were all well tolerated. The success of this procedure

could be confirmed by the excellent compatibility of a wide range of functionalities, such as terminal ether (18), ester (19), and thioether (20), unprotected lactam (21-23), Boc-protected

amine (24), terminal olefin (25), tetrahydropyran (26), as well as internal ester (27). Interestingly, for substrates containing both Br and Cl, it was found that the C-Br bond was easier to

cleave (28). Besides, alkyl iodides also worked smoothly in this protocol, affording the corresponding products with excellent deuterium incorporation (Fig. 2B, 29-31). We were pleased to

find that OMs could be a suitable leaving group to give the target product in 64% yield and 99% D-incorporation (32). Next, we turned our attention to a more challenging target, unactivated

alkyl chlorides (Fig. 2C). To our delight, primary alkyl chlorides took part in the reaction with a broad range of functionalities and showed similar results to alkyl bromides, yielding the

corresponding products in good efficiency and D-incorporation (33-45). Furthermore, other alkyl chlorides, especially tertiary substrates that did not work well in previous studies24,

yielded the desired products unquestionably in satisfactory D-incorporation using this method (46-49). To further demonstrate the generality, and environmentally-friendly nature of the

developed method, as well as its application in bioactive molecules and drug discovery, the late-stage deuteration was conducted using a series of natural products, pharmaceuticals, and

their derivatives (Fig. 2D). The dehalogenative deuteration of pharmaceuticals including Estrone (50), Pregnenolone (52), DL-Menthol (53), Phytol (57), and Triclosan (58) was successfully

achieved in 77–83% yield with 97-98% D-incorporation. Pharmaceutical intermediates ethynyl estradiol (51) and dihydro cuminyl alcohol (54) containing unsaturated bonds can also be used in

this protocol. Ibuprofen (55) and naproxen (56), which are commonly used for the ease of pain, afforded the corresponding deuterated compounds in good yields (67%, 88%) with excellent

deuterium incorporation (both 98% D). Furthermore, amino acid and glucose derivatives that widely exist in organisms can also be deuterated smoothly with high levels of D-incorporation

(59−64, 97−99%). In addition, the tolerance of the reaction system to tertiary chlorides can be extended to complex substrates (65, 66). ELECTROCHEMICAL DEHALOGENATIVE DEUTERATION OF ALKYL

BROMIDES WITH 500 MA CURRENT As high current density has a key impact on the amplification of reaction scales, we further explored the practicability of some representative substrates at a

current of 500 mA. To our delight, the reactions were complete during a much shorter reaction time (in only 15 minutes). Simple alkyl bromides with a variety of functional groups (2, 16, 23,

and 26) as well as complex alkyl bromides derived from ibuprofen (55), L-phenylalanine (59), Diacetonefructose (61), and D-mannofuranose (63) were all amenable. level of D-incorporation has

not changed at all (Fig. 3). Alkyl chloride was also well tolerated and the corresponding product 37 was obtained in 15 min. In addition, this electrochemical reduction protocol could be

applied to the gram-scale preparation of deuterated product 8 under 500 mA constant current (Fig. 4a). MECHANISTIC STUDIES Several mechanistic studies were conducted to gain insight into the

reaction mechanism. Firstly, 2 equiv. of TEMPO was added to the reaction system and in the absence of D2O, the TEMPO adduct was obtained in 64% yield (67), together with hydrodehalogenated

product 2-H in 28% yield (Fig. 4b, eq 1). Then, repeat the reaction with 2 equiv. of D2O resulted in the TEMPO adduct in 21% yield and deuterodehalogenated product 2 in 75% yield with 55%

D-incorporation (Fig. 4b, eq 2). These results indicated that the alkyl radical might be involved in the electrochemical system. Then, we sought to gain further insight into the reaction

mechanism through cyclic voltammetry (CV) experiments. A reduction peak of alkyl bromides 1 at −3.40 V (vs Ag/Ag+ in CH3CN) was observed (Fig. 5a, the red line), and no obvious reduction

peak of D2O was observed (Fig. 5a). At the same time, the oxidation potential of TBAI (Fig. 5b, pink line, 1.0 V) was very close to that of DIPEA (Fig. 5b, blue line, 1.1 V). Thus we

inferred that both TBAI and DIPEA might act as the electron donors in this reaction. Notably, the anodic oxidation of alkyl bromide 1 was also indicated with higher potential than that of

DIPEA (green line). This might explain the improved yield once external DIPEA was added by inhibiting the undesired oxidation or decomposition of the starting material (Table 1, entries 1

and 3). In addition, during the reaction system without TBAI, an increase in current can be clearly observed, indicating the electrolysis of DIPEA incorporated with formed bromo anion may

further generate conductive substances (Fig. 5c). Based on the mechanistic studies and previous literature5,48, a plausible mechanism is proposed (Fig. 6). The reaction was initiated by the

anodic oxidation of DIPEA and/or TBAI or DMF and the direct reduction of alkyl halides on the cathode to form the corresponding alkyl radical I and halide anions. The radical I continued to

be reduced to an alkyl anion II at the cathode. Finally, intermediate II reacted with deuterated water to provide the expected product III. At the same time, iminium ion intermediate IV

generated from DIPEA on the anode might combine with the released halogen anions to form ammonium salt, a possible conductive species. DISCUSSION In conclusion, we have developed a general

dehalogenative deuteration of unactivated alkyl (pseudo)halides (X = Cl, Br, I, OMs) driven by electrochemical force with high reactivity, selectivity, and excellent D-incorporation. D2O was

used as an efficient and economical deuterium source. A wide range of unactivated alkyl halides containing diverse functionalities are well tolerated, as well as the extension to late stage

deuteration of natural products, pharmaceuticals, and their derivatives. We envisage that the native features, including tolerance of high current and environmentally-friendly conditions,

will bring further opportunity in its application to organic synthesis, drug discovery and modification, and even industrial production. Further electrochemical transformations of

unactivated alkyl halides are currently ongoing in our laboratory. METHODS GENERAL PROCEDURE OF THE ELECTROCHEMICAL DEHALOGENATIVE DEUTERATION OF ALKYL BROMIDE, IODIDE OR PSEUDO-HALIDES The

electrocatalysis was carried out in an undivided cell with a carbon felt anode (10 mm × 15 mm × 5 mm) and a lead cathode (10 mm × 15 mm × 0.3 mm). To a 15 mL pre‐dried undivided

electrochemical cell (15 mL) equipped with a magnetic bar were added alkyl bromide, iodide or pseudo-halides (0.5 mmol, 1 equiv), TBAI (36.9 mg, 0.1 mmol, 20 mol%), and DMF (5.0 mL). Then

D2O (25 mmol, 50 equiv) and DIPEA (1.5 mmol, 3.0 equiv) were added via a syringe. The electrocatalysis was performed at room temperature with a constant current of 30 mA maintained for 10 h.

The carbon felt anode was washed with EtOAc (3 × 5 mL) in an ultrasonic bath. H2O (20 mL) was added to the system, and the resulting mixture was extracted with EtOAc (3 ×20 mL). The

combined organic phase was dried with anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography to furnish the desired product. GENERAL

PROCEDURE OF THE ELECTROCHEMICAL DEHALOGENATIVE DEUTERATION OF ALKYL CHLORIDES The electrocatalysis was carried out in an undivided cell with a graphite felt anode (10 mm × 15 mm × 5 mm) and

a lead cathode (10 mm × 15 mm × 0.3 mm). To a 15 mL pre‐dried undivided electrochemical cell (15 mL) equipped with a magnetic bar were added alkyl chloride (0.5 mmol, 1 equiv), TBAI (36.9 

mg, 0.1 mmol, 20 mol%) and DMF (5.0 mL). Then D2O (25 mmol, 50 equiv) and DIPEA (1.5 mmol, 3.0 equiv) were added via a syringe. The electrocatalysis was performed at room temperature with a

constant current of 50 mA maintained for 10 h. The carbon felt anode was washed with EtOAc (3 × 5 mL) in an ultrasonic bath. H2O (20 mL) was added to the system, and the resulting mixture

was extracted with EtOAc (3 × 20 mL). The combined organic phase was dried with anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography

to furnish the desired product. GENERAL PROCEDURE OF THE ELECTROCHEMICAL DEHALOGENATIVE DEUTERATION OF ALKYL BROMIDES AND CHLORIDE WITH 500 MA CURRENT The electrocatalysis was carried out

in an undivided cell with a carbon felt anode (or graphite felt) (10 mm × 15 mm × 5 mm) and a lead cathode (10 mm × 15 mm × 0.3 mm). To a 15 mL pre‐dried undivided electrochemical cell (15 

mL) equipped with a magnetic bar were added alkyl bromide or chloride (0.5 mmol, 1 equiv), TBAI (36.9 mg, 0.1 mmol, 20 mol%) and DMF (5.0 mL). Then D2O (25 mmol, 50 equiv) and DIPEA (1.5 

mmol, 3.0 equiv) were added via a syringe. The electrocatalysis was performed at room temperature with a constant current of 500 mA maintained for 15 min (reaction system exothermic). The

carbon felt anode was washed with EtOAc (3 × 5 mL) in an ultrasonic bath. H2O (20 mL) was added to the system, and the resulting mixture was extracted with EtOAc (3 × 20 mL). The combined

organic phase was dried with anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography to furnish the desired product. GRAM-SCALE

SYNTHESIS OF 8 To an undivided reaction flask (diameter: 40 mm, length: 130 mm, volume: 200 mL) equipped with a teflon-coated magnetic stirring bar and teflon cap, a carbon felt anode (25 mm

× 50 mm × 5 mm), and a lead cathode (25 mm × 50 mm × 0.3 mm) were added (4-bromobutoxy)benzene (3.44 g, 15 mmol), TBAI (1.11 g, 3.0 mmol), DMF (100 mL), D2O (15 mL, 0.75 mol) and DIPEA

(5.80 g, 45 mmol). The electrocatalysis was performed at room temperature with a constant current of 500 mA maintained for 4 h (the reaction system was exothermic). The carbon felt anode was

washed with EtOAc (3 × 20 mL) in an ultrasonic bath. H2O (200 mL) was added to the system, and the resulting mixture was extracted with EtOAc (3 × 200 mL). The combined organic phase was

dried with anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography to furnish the desired product. DATA AVAILABILITY The authors

declare that the data supporting the findings of this study are available within the article and its Supplementary Information files. Extra data are available from the author upon request.

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143, 12985–12991 (2021). Article  CAS  PubMed  Google Scholar  Download references ACKNOWLEDGEMENTS Financial support from the Fundamental Research Funds for the Central Universities (No.

63213063), Frontiers Science Center for New Organic Matter, Nankai University (Grant No. 63181206) and Nankai University are gratefully acknowledged. AUTHOR INFORMATION AUTHORS AND

AFFILIATIONS * State Key Laboratory and Institute of Elemento-Organic Chemistry, Frontiers Science Center for New Organic Matter, College of Chemistry, Nankai University, 94 Weijin Road,

Tianjin, 300071, China Pengfei Li, Chengcheng Guo, Siyi Wang, Dengke Ma, Tian Feng, Yanwei Wang & Youai Qiu Authors * Pengfei Li View author publications You can also search for this

author inPubMed Google Scholar * Chengcheng Guo View author publications You can also search for this author inPubMed Google Scholar * Siyi Wang View author publications You can also search

for this author inPubMed Google Scholar * Dengke Ma View author publications You can also search for this author inPubMed Google Scholar * Tian Feng View author publications You can also

search for this author inPubMed Google Scholar * Yanwei Wang View author publications You can also search for this author inPubMed Google Scholar * Youai Qiu View author publications You can

also search for this author inPubMed Google Scholar CONTRIBUTIONS Y.Q. and P.L. conceived and designed the study and wrote the manuscript. P.L, C.C.G, S.W, D.M, T.F, Y.W, Y.Q. performed the

experiments, mechanistic studies and revised the manuscript. All authors contributed to the analysis and interpretation of the data. CORRESPONDING AUTHOR Correspondence to Youai Qiu. ETHICS

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electrochemical deuteration of unactivated alkyl halides. _Nat Commun_ 13, 3774 (2022). https://doi.org/10.1038/s41467-022-31435-9 Download citation * Received: 29 January 2022 * Accepted:

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