Synthesis and separation of two stereoisomers of deuterated tetrasubstituted allylic alcohols via consecutive dual 1,2-metallate shifts

Abstract

Herein, we report an efficient strategy for the synthesis and stereoisomer separation of deuterated tetrasubstituted allylic alcohols from alkynyl tetracoordinate boron species using readily available D₂O as the deuterium source in a single vessel system. This transformation proceeds via consecutive dual 1,2-metallate shifts, achieving efficient construction of both isomeric deuterated allylic alcohols without the requirement for condition optimization or the selection of special reagents and substrates upon oxidation. And the method features quantitative deuterium incorporation (>99%), broad substrate scope, and direct access to pharmaceutically relevant scaffolds under mild conditions.

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Introduction

Transformations of alkynes into alkenes are a cornerstone reaction in organic synthesis, providing a versatile route to construct carbon–carbon double bonds with defined stereochemistry.^1–3 Achieving precise control over the geometry (E/Z) of these alkenes is paramount, as it profoundly influences the molecule's physical properties, biological activity, and subsequent reactivity.^4–9 Nevertheless, exercising this control remains a significant and ongoing challenge. Additionally, a mixture of isomers is of limited value, since the distinct properties of each stereoisomer are often essential for downstream applications or biological evaluation. Consequently, the formation of a mixture poses a formidable challenge for separation due to the nearly identical physicochemical properties (e.g., polarity, boiling point) of the (E)- and (Z)-isomers, making many techniques largely ineffective. This inherent difficulty underscores the critical need for developing novel synthetic strategies that can either achieve high stereoselectivity or provide a means for the straightforward separation of the resulting isomeric products.

Deuterated molecules represent a significant class of high value-added compounds. In pharmaceutical chemistry, the strategic incorporation of deuterium atoms into organic molecules can modulate key pharmacokinetic properties, including absorption, distribution, metabolism, and excretion (ADME).^10–12 Consequently, deuterium-containing drugs are increasingly employed in clinical settings. Within synthetic chemistry, deuterium-labeled molecules serve as indispensable tools for elucidating hydrogen sources in reaction systems, tracing reaction pathways, and measuring kinetic isotope effects (KIE) to probe reaction mechanisms.¹³ Deuterated olefins, a prominent subset of deuterium compounds, are prevalent structural motifs in both natural products and synthetic pharmaceuticals (Scheme 1a).^14–17 Current synthetic strategies for accessing deuterated olefins exhibit limitations. Traditional ionic approaches, employing strong acids (e.g., DCl, D₂SO₄) or bases (e.g., NaOD) and organometallic reagents to facilitate H/D exchange, often suffer from poor functional group compatibility and low chemoselectivity.¹⁸ Transition metal catalysis (utilizing Ir, Pd, Pt, Ru, Rh, etc.) via C–H activation offers an alternative, but typically requires expensive catalysts and ligands under demanding reaction conditions.^18–21 Single-electron transfer processes provide another route, although they encompass diverse reaction types with varying efficiencies. Despite these advances, the development of novel, robust, and practical methodologies for assembling deuterated olefins from readily accessible substrates under mild conditions remains highly desirable.^16,18,22

Scheme 1 Significance of deuterated olefins and approaches to allylborons. (a) Representative containing-deuterium alkenyl moiety pharmaceuticals and applications for allylboronates; (b) representative methods for the construction of allylboronates; (c) challenge in the stereoselective synthesis of allylboronates from alkynes; (d) synthesis of deuterated tetrasubstituted allylboronates via consecutive dual 1,2-metallate shift (this work).

Organoboron compounds represent a vital class of synthetic intermediates with broad applications in pharmaceutical chemistry and materials science.^23–26 Among these, allylboronates have garnered increasing attention as versatile precursors for constructing diverse allylic compounds through metal-catalyzed reactions,^27–30 radical transformations,³¹ and migration processes.^32–35 Despite their utility, synthetic access to allylboronates remains limited. Representative advances include Morkens' report³⁶ of a palladium-catalyzed enantioselective conjunctive cross-coupling to access terminal and internal α-chiral allylboronates (Scheme 1b, left). Separately, Yin's group^37–39 achieved allylboronate synthesis via nickel- or palladium-catalyzed reactions of undirected alkenes.

B₂pin₂, and alkenyl halides or triflates (Scheme 1b, right). Notably, tetracoordinate boron species—characterized by transmetalation and migration capabilities—have emerged as key motifs within the organoboron family.²⁶ Building on our sustained interest in this field, our group has developed novel metallate shift transformations.^40–44 Recently, we disclosed four distinct alkynyl tetracoordinate boron migrations involving dual 1,2-aryl or 1,2/1,3-aryl shifts to access tetrasubstituted olefins.⁴⁵ Additionally, we achieved photo-induced trifunctionalization of bromostyrenes through remote radical migrations of tetracoordinate boron species.^46,47 However, a key limitation in the synthesis of allylboronates from alkynes is the inherent formation of a mixture of configurational isomers (Scheme 1c). As established, such mixtures are of limited practical value, and their separation remains a major challenge due to the nearly identical physicochemical properties of the isomers. Consequently, this system presents two inherent challenges: (1) How to ensure the reaction proceeds efficiently; (2) How to achieve the separation of configurational isomers (Scheme 1c).

We herein report a strategy for the efficient synthesis and separation of both configurational isomers of deuterated tetrasubstituted allylboron compounds, derived from alkynyl tetracoordinate boron precursors. The transformation proceeds via consecutive dual 1,2-metallate shifts, mediated by commercially available ICH₂Bpin and readily accessible D₂O as a convenient deuterium source (Scheme 1d). Notably, both stereoisomeric deuterated allyl alcohols can be selectively obtained through straightforward oxidation of the resulting allylboronates followed by silica gel chromatography. This method achieves quantitative deuteration (>99% D-incorporation) and exhibits a broad substrate scope, unprecedented consecutive double 1,2-migrations, and direct access to two valuable deuterated stereodefined architectures.

Our investigation into the synthesis of deuterated tetrasubstituted allylboronates commenced with alkynyl tetracoordinate boron 1a, ICH₂Bpin (2) and D₂O in anhydrous DCM at 90 °C. To our delight, the target product 3a was obtained in 82% yield and corresponding Z/E-configurations were detected in 37% and 45% yields, respectively. Initial solvent screening identified anhydrous DCM as optimal, outperforming THF, CH₃CN as well as DMF (Table 1, entries 1–4). Subsequent temperature optimization (entries 5 and 6) established 90 °C as ideal, while the lower (60 °C) and higher (100 °C) temperatures afforded product 3a in diminished yields. Besides, different reaction time for this process was explored, suggesting that the best reasonable reaction time is 12 h. The desired product was obtained in 63% yield (3a-Z: 30%; 3a-E: 33%) when reaction time is decreased to 6 h. (see SI for details). Upon replacing ICH₂Bpin by BrCH₂Bpin or ClCH₂Bpin, the yield of 3a significantly dropped (entries 9 and 10). Therefore, the optimal reaction conditions of this reaction were believed as: alkyne tetracoordinate boron tetramethylammonium hept-1-yn-1-yltriphenylborate 1a (1.5 equivalents), ICH₂Bpin (1 equivalent) and D₂O (20 equivalents) in 1 mL DCM, at 90 °C for 12 hours under argon atmosphere. Then, the corresponding alcohols 4a-Z and 4a-E were afforded by the oxidation of 3a-Z and 3a-E, and could be isolated respectively through column chromatography.

Table 1 Reaction condition optimizations^a

Entry	Variation from standard conditions	Yield of 3a^b	Yield of 4a-Z^b	Yield of 4a-E^b
a Reaction conditions: the reaction was carried out with 1a (0.24 mmol), ICH2Bpin 2 (0.2 mmol), D2O (20 equiv.), in 1 mL dry DCM at 90 °C for 12 h. b Yields were determined by gas chromatography (GC) using n-decane as the internal standard. c Isolated yield of corresponding alcohols products 4a-Z and 4a-E by oxidation. Unless otherwise specified, the deuterium incorporation for product exceeds 99%.
1	None	82% (73%)^c	37% (34%)^c	45% (39%)^c
2	Dry THF as solvent	11%	3%	8%
3	Dry MeCN as solvent	48%	36%	12%
4	Dry DMF as solvent	4%	2%	2%
5	At 60 °C	50%	25%	25%
6	At 100 °C	54%	25%	29%
7	6 h instead of 12 h	63%	30%	33%
8	18 h instead of 12 h	82%	40%	42%
9	X = Cl	9%	4%	5%
10	X = Br	63%	33%	30%

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After determining the optimal reaction conditions, we turned our attention to investigate the substrate scope. As showed in Scheme 2, the scope of the long chain alkyl substituted tetracoordinate alkynyl borons was first investigated, affording the target product (4a–4d) with good yields. And a scale-up reaction of 1a was performed to give the target products 4a in 63% yield (Scheme 2). Reaction of tetramethylammonium (3-cyclohexylprop-1-yn-1-yl)triphenylborate (1e) with ICH₂Bpin occurred to produce the target products 4e in 67% yield (4e-Z, 27% yield and 4e-E, 40% yield). Besides, tetramethylammonium triphenyl(3-phenylprop-1-yn-1-yl)borate (1f) was also suitable for this system, providing the wanted products 4f in good yields and deuteration. Subsequently, various phenylethyl-containing substrates (1g–1k) were tested under the standard reaction conditions, providing the target products 4g–4k in moderate to good yield. In addition, (Z/E)-4-(naphthalen-2-yl)-2-(phenylmethylene-d)butan-1-ol (4l) was formed by the reaction of tetramethylammonium (4-(naphthalen-2-yl)but-1-yn-1-yl)triphenylborate (1l) with 2a under the same reaction conditions. Subsequently, various ether-containing aliphatic tetracoordinate alkynyl borons were investigated for exploring the reaction scope, in general, the reaction tolerated an array of substituents with different steric and electronic properties. The para-substituted group on the aromatic ring were investigated, both electron-withdrawing groups including cyano (4m) and halo (4n) and electronic-donating groups including phenyl (4o), methoxyl (4p) and isopropyl (4q) were compatible with this reaction conditions with good results. 2-Substituted substrates (1r and 1s) could form the desired products 4r and 4s in 72% (Z-type: 34% yield, E-type, 38% yield) and 52% yields (Z-type: 25% yield, E-type: 27% yield), respectively with excellent deuteration. The substrate tetramethylammonium (5-(3-methoxyphenoxy)pent-1-yn-1-yl)triphenylborate (1t) underwent the standard reaction conditions to obtain the products 4t in 55% yield with >99% deuteration. The reaction conditions were also compatible with disubstituted substrates (1u–1y), which afford the target products 4u–4y with good results. The trisubstituted substrates (1z) worked well in this system, providing the 5-(4-bromo-3,5-dimethylphenoxy)-2-(phenylmethylene-d)pentan-1-ol (4z) in 75% yield (Z-type: 30% yield, E-type, 45% yield) with excellent deuteration. And fortunately, the absolute structure of 4z-E was unequivocally confirmed by X-ray crystallographic analysis (see SI for the details). Notably, fused ring, such as naphthalene ring (1aa), and aza-containing substrates, such as indole (1ab) underwent the above reaction conditions access to the corresponding products (4aa and 4ab) in 39% and 50% yield with beautiful deuteration. In addition, other ether-containing substrates, such as tetramethylammonium (5-(benzyloxy)pent-1-yn-1-yl)triphenylborate (1ac) and tetramethylammonium (6-phenoxyhex-1-yn-1-yl)triphenylborate (1ad), could also generate the target products 4ac–4ad in 61% and 73% yield, correspondingly, with >99% deuteration. We next tested whether other boronic ester enable to induce 1,2-migration of the alkynyl tetracoordinated borons. Different α-iodoboronates were tested under the standard reaction conditions, unfortunately, this transformation could not proceed smoothly (Scheme 2).

Scheme 2 Substrate scope^aReaction conditions: the reaction was carried out with 1 (0.24 mmol), compound 2 (0.2 mmol), D₂O (20 equiv.), in 1 mL dry DCM at 90 °C for 12 h, then 3 and NaBO₃·H₂O (3 equiv.) in 2 mL THF, 1 mL H₂O at room temperature for 4 h. Isolated yields, Z/E were determined by ¹H NMR. ^bYield of 4a-Z and 4a-E.

Moreover, this protocol enables the direct deuteration of complex pharmaceuticals. Employing an estrone derivative (1ae) as the substrate afforded deuterated product 4ae in 52% yield with quantitative deuterium incorporation (>99% D) (Scheme 3, eq. 1). Importantly, this protocol also worked well by a one-pot process from terminal alkynes to access the corresponding products (Scheme 3, eq. 2). We subsequently examined the compatibility of alternative migratory groups beyond phenyl, including alkyl and diverse aryl substituents, via a one-pot synthesis protocol (Scheme 3, eq. 3). The ethyl group demonstrated successful migration, affording product 4af in 42% yield. This result confirms the feasibility of accessing complex deuterated architectures from commercially available alkyne precursors in a single transformation.

Scheme 3 Exploration of migratory group. ^aReaction conditions: terminal alkyne (1.5 equiv.), n-BuLi (1.5 equiv.) in 8 mL THF at −78 °C for 30 min; BEt₃·THF (1.5 equiv.), under argon, 1 h; ICH₂Bpin (1 mmol), D₂O (20 equiv.), at 60 °C, overnight; then NaBO₃·H₂O (3 equiv.), 4 mL H₂O at rt for 4 h. Isolated yields.

To demonstrate the synthetic utility of this methodology, we performed derivatizations of the products (Scheme 4). A gram-scale reaction (1.2 g) of tetramethylammonium (5-([1,1′-biphenyl]-4-yloxy)pent-1-yn-1-yl)triphenylborate afforded deuterated product 4o in 68% yield. Selective oxidation of deuterated allylic alcohol 4o-E yielded α,β-unsaturated aldehyde 5 in 90% yield with quantitative deuterium retention (>99% D). Similarly, epoxidation of 4o-Z provided epoxide 6 in 78% yield and >99% deuterium incorporation. Furthermore, we applied this approach to late-stage diversification of pharmaceuticals. Esterification of probenecid and naproxen with deuterated intermediates afforded products 7 and 8 in 98% and 82% yields, respectively, with quantitative deuteration.

Scheme 4 Transformations of the product. Unless otherwise specified, the deuterium incorporation for all products exceeds 99%.

To elucidate the migration mechanism between alkynyl tetracoordinate boron species and ICH₂Bpin under optimized conditions, we conducted mechanistic investigations (Scheme 5). Radical trapping experiments using 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) or 1,1-diphenylethylene revealed no trapped intermediates, excluding a single-electron transfer (SET) pathway. Control experiments substituting ICH₂Bpin with 1-iodopropane (9) or iodocyclohexane (10) under standard conditions yielded no 1,2-migration product, demonstrating that the initial migration requires Lewis acidic activation by the boronic ester (Scheme 5b). Substrate scope studies revealed significantly diminished yield for 4af. Further analysis indicated that proximal oxygen atoms (within two carbons of the triple bond) inhibit reactivity, whereas substrates with distal oxygen (4ad, 4ae) or no oxygen (4f) perform optimally (Scheme 2). This suggests competitive coordination of ICH₂Bpin to oxygen, impeding boronic ester-directed migration. When sterically hindered substrate 1ag was employed, the diphenylboron-retained product 11 was isolated in 22% yield, implying deuteration occurs via protonation by the diphenylboron moiety (Scheme 5c). Based on these findings and precedent literature,^34,48 we propose a mechanistic pathway (Scheme 5d): ICH₂Bpin acts as a Lewis acid to activate the alkyne, triggering stereorandom initial 1,2-migration to form intermediates I/II. Subsequent Matteson-type 1,2-migrations⁴⁹ afford tetrasubstituted allylboronates III/IV, which undergo deuteration via D₂O to yield final products A/B.

Scheme 5 Mechanistic studies and proposed mechanism.

Conclusions

In summary, we have developed a novel strategy for synthesizing two different isomers of deuterated tetrasubstituted allylboronates. Oxidation of these compounds provides access to valuable deuterated allylic alcohols as separable stereoisomers. This approach constructs sterically congested deuterated architectures from commercially accessible terminal alkynes using operationally simple deuteration with benign D₂O under mild conditions. Mechanistic studies establish that dual sequential 1,2-migration reactions, enabled by commodity reagent ICH₂Bpin, govern the transformation.

Author contributions

Q. S. and X. M. conceived and designed the experiments. P. L. and Y. Y. performed experiments and analyzed the data. Q. S. and X. M. wrote the paper. All authors discussed the results and commented on the manuscript.

Conflicts of interest

There are no conflicts to declare.

Data availability

The data supporting the findings of this article are available within the paper and its Supplementary Information.

CCDC 2247992 contains the supplementary crystallographic data for this paper.⁵⁰

Supplementary information: [experimental procedures and characterization data]. See DOI: https://doi.org/10.1039/d5sc06886j.

Acknowledgements

Financial support from National Key R&D Program of China (2023YFF0723900), National Natural Science Foundation of China (22501046, 22271105), Open Research Fund of Hubei Key Laboratory of Pollutant Analysis & Reuse Technology Open Foundation (PA240102), State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University and Open Research Fund of School of Chemistry and Chemical Engineering, Henan Normal University are gratefully acknowledged.

Notes and references

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