Deoxygenative functionalization of alcohols, ethers, and carbonyl compounds by chromium catalysis

Wendi Chang; Tenggang Jiao; Changpeng Chen; Feijiang Zhou; Xiaogai Li; Shuya Wang; Jingxia Wang; Jinwei Zhang; Jing Liu; Ying Cao; Xiaoming Zeng; Xuefeng Cong

doi:10.1126/sciadv.aeg4594

. 2026 Sep 25;12(39):eaeg4594. doi: 10.1126/sciadv.aeg4594

Deoxygenative functionalization of alcohols, ethers, and carbonyl compounds by chromium catalysis

Wendi Chang ^1,^†, Tenggang Jiao ^1,^†, Changpeng Chen ^2,^*,^†, Feijiang Zhou ¹, Xiaogai Li ¹, Shuya Wang ¹, Jingxia Wang ¹, Jinwei Zhang ¹, Jing Liu ¹, Ying Cao ¹, Xiaoming Zeng ^3,^*, Xuefeng Cong ^1,^4,^*

PMCID: PMC13614368 PMID: 42789705

Abstract

The development of an efficient and unified methodology for converting ubiquitous alcohols, ethers, carbonyls, and esters into value-added products via the activation of C−O single and double bonds is of great interest and importance but remains a challenging goal. Herein, we report an efficient and general chromium-catalyzed strategy for the deoxygenative functionalization of alcohols, ethers, and carbonyl compounds with a number of electrophiles. This general strategy couples these oxygenated functional groups with a number of electrophiles, providing an efficient route for the synthesis of a broad range of synthetically appealing organosilicon, organogermanium, organostannane, and organoboron compounds. Moreover, this chromium-catalyzed strategy is demonstrated to be readily scalable and applicable to the late-stage functionalization of various biorelevant molecules. Mechanistic investigations suggest that this deoxygenative functionalization was initiated by two-electron oxidative addition of the C−O bond to a highly active, low-valent chromium species, generating an organochromium intermediate that reacts with a number of electrophiles to construct C−Si, C−Ge, C−Sn, and C−B bonds.

INTRODUCTION

Alcohols, ethers, carbonyls, and esters are fundamental structural motifs in a large number of natural products, bioactive molecules, and pharmaceuticals (Fig. 1A) (1, 2). They are also among the most accessible and versatile feedstock chemicals in synthetic organic chemistry. Therefore, the development of efficient and selective methods for converting these oxygen-containing groups into value-added functionalities via the direct activation and functionalization of C−O single and double bonds is of great interest and much importance. Among various deoxygenative functionalization (3–8), silylation of these oxygenated motifs is of particular interest as it provides an efficient and straightforward route for the synthesis of structurally diverse organosilanes, which represent a valuable class of synthetic linchpins with broad applications in organic synthesis, functional materials, and bioactive molecules (9–18). Remarkable advances have been recently made in transition metal–catalyzed deoxygenative silylation of alcohol derivatives with diverse silicon nucleophiles (Fig. 1B) (19–27). Very recently, Xu (28) and Lundberg (29) independently developed an efficient electrochemical method for the deoxygenative silylation of alcohols or ketones with hydrosilanes, substantially expanding access to functionalized organosilanes. However, the analogous deoxygenative silylation using silicon electrophiles, especially with readily accessible chlorosilanes that are raw materials for producing silicon nucleophiles and hydrosilanes, has remained underdeveloped. In particular, achieving this transformation directly from free alcohols and carbonyls presents a substantial and persistent challenge. Recent breakthroughs were achieved by Shu (30–37) and Oestreich (38, 39), realizing the deoxygenative silylation of alkenyl triflates and activated alkyl triflates with chlorosilanes (Fig. 1C, top). Subsequently, the reductive coupling with chlorosilanes has attracted growing interest (40–49). One important example in this regard was reported by Nakao and coworkers, who demonstrated rhodium/indium heterobimetallic catalysis for the reductive C(sp³)–O silylation of ethers (Fig. 1C, bottom) (42). Very recently, Lin and coworkers developed an elegant two-stage, one-pot electrochemical protocol that enables the direct deoxygenative silylation of alcohols and carbonyl compounds with chlorosilanes via electrochemical reduction of in situ–generated silyl ethers (50, 51), further highlighting the growing interest in this research field. Nevertheless, this electrochemical strategy has seen limited application in the deoxygenative silylation of propargyl alcohols and requires excess hydrosilane (e.g., methyldimethoxysilane) to generate silyl ethers. Consequently, the development of a unified and efficient catalytic strategy for the deoxygenative silylation of alcohols, ethers, and carbonyl compounds using readily available chlorosilanes remains highly desirable.

Fig. 1. — (A) Represent natural products and pharmaceuticals containing alcohols and carbonyl groups. (B) Deoxygenative silylation of preactivated alcohol derivatives with silyl nucleophiles by transition metal catalysts. (C) Deoxygenative silylation of alkenyl and activated alkyl triflates and ethers with chlorosilanes by nickel and rhodium/indium catalysis. (D) Deoxygenative functionalization of alcohols, ethers, and carbonyl compounds with diverse electrophiles by chromium catalysis (this work).

Chromium catalysis has recently emerged as a powerful tool for the activation and transformation of strong chemical bonds (52–68). In particular, low-valent chromium catalysts have demonstrated unique activity and selectivity in the activation and functionalization of unactivated C–O bonds of phenol and alcohol derivatives (54, 55). This capability has enabled various challenging transformations (69–75), including the chemoselective cross-coupling of two distinct C(aryl)–O bonds (70), the reductive coupling between C(aryl)–N and C(aryl)–O bonds (71), and the multicomponent coupling of geminal C–O and C–H bonds in benzyl ethers with arylmagnesium reagents and electrophiles (72). Inspired by these achievements, we envisioned chromium catalysis as an efficient platform for the deoxygenative functionalization of alcohols, ethers, and carbonyls with diverse electrophiles. Herein, we report an efficient and general chromium-catalyzed strategy for the deoxygenative functionalization of alcohols, ethers, and carbonyl compounds with a number of electrophiles (Fig. 1D). This strategy couples these oxygenated functional groups with electrophiles via a two-electron oxidative addition process for the C–O bond activation, providing efficient access to a broad range of synthetically appealing organosilicon, organogermanium, organostannane, and organoboron building blocks. Moreover, this chromium-catalyzed protocol is demonstrated to be readily scalable and applicable to the direct functionalization and late-stage modification of various biorelevant molecules.

RESULTS

Screening of reaction conditions

We commenced our study by examining the reaction of 2-naphthylmethyl 2-pyridyl ether 1a with chlorotrimethylsilane 2a (Fig. 2A) as the pyridyl group can promote the C−O bond cleavage and stabilize the metalloalkane intermediates (72, 76–78). Evaluation of transition metal catalysts revealed that the low-cost CrCl₃, combined with ethylmagnesium bromide (EtMgBr) as the reductant, showed good activity for the deoxygenative silylation of 1a with 2a, affording the corresponding product 3a in 80% yield at room temperature (Fig. 2A, entries 1 to 3, and see the Supplementary Materials). In contrast, the reaction of 2-naphthylmethyl methyl ether 1a′ with 2a did not occur under the same conditions (Fig. 2A, entry 4), highlighting the essential role of the pyridyl group. This result prompted us to explore the use of external pyridyl ligands to facilitate the reaction of 1a′ with 2a. As anticipated, 4,4′-di-tert-butyl-2,2′-dipyridyl (dtbpy) allowed the deoxygenative silylation of 1a′ with 2a to occur at room temperature, albeit giving the product 3a in 26% yield (Fig. 2A, entry 5). Other dipyridyl ligands such as 4,4′-dimethyl-2,2′-bipyridyl, 6,6′-di-methyl-2,2′-dipyridyl, and 2,2′-bipyridine showed less efficiency in promoting the silylation of 1a′ (Fig. 2A, entries 6 to 8). Pyridine (0.8 equiv) also facilitated the silylation of 1a′, affording 3a in 30% yield (Fig. 2A, entry 9). The use of terpyridine (tpy) afforded 3a in 26% yield (Fig. 2A, entry 10). Replacing tpy with the tert-butyl–substituted analog ^tBu₃-tpy increased the yield of 3a to 36% (Fig. 2A, entry 11). Gratifyingly, conducting the reaction of 1a′ with 2a at 70°C in the presence of ^tBu₃-tpy increased the yield of 3a to 52% (Fig. 2A, entry 12). Increasing the loading of CrCl₃ and ^tBu₃-tpy to 20 mol % further enhanced the yield of 3a to 83% (Fig. 2A, entry 13). Notably, the reaction of 2-naphthylmethanol 1a″ with 2a at 70°C in the presence of ^tBu₃-tpy also occurred, affording 3a in 45% yield, along with the benzyl trimethylsilyl ether in 46% yield (Fig. 2A, entry 14).

We next examined the analogous reactions of cinnamyl alcohol and its ether derivatives (Fig. 2B). The deoxygenative silylation of the cinnamyl 2-pyridyl ether 4a with 2a proceeded efficiently at room temperature using CrCl₃ as the catalyst and EtMgBr as the reductant, affording the corresponding cinnamyltrimethylsilane 5a in 78% yield (Fig. 2B, entry 1). The silylation of cinnamyl methyl ether 4a′ with 2a also took place but gave a lower yield (Fig. 2B, entry 2). Gratifyingly, the use of dtbpy ligand substantially accelerated the reaction of 4a′ with 2a, affording the desired product 5a in 95% yield (Fig. 2B, entry 3). Notably, the deoxygenative silylation of cinnamyl alcohol 4a″ with 2a also underwent smoothly under the same conditions, yielding 5a in 95% yield (Fig. 2B, entry 4). In the absence of dtbpy, the reaction of 4a″ with 2a gave 5a in 50% yield along with the cinnamyl trimethylsilyl ether 4a-Si in 49% yield (Fig. 2B, entry 5). The reaction of 4a-Si with 2a in the presence of dtbpy worked well to afford 5a in 95% yield (Fig. 2B, entry 6). These results indicated that the cinnamyl trimethylsilyl ether 4a-Si should be a key intermediate in the silylation of alcohol 4a″ with 2a. Subsequently, the analogous reactions of propargyl alcohol and its ether derivatives were examined (Fig. 2C). Similar to 4a, the reaction of the propargyl 2-pyridyl ether 6a with 2a also worked well at room temperature, affording the tetrasubstituted silylallene 7a in 85% yield (Fig. 2C, entry 1). The analogous methyl ether 6a′ afforded 7a in a relatively lower yield (Fig. 2C, entry 2). As observed for 4a′, the dtbpy ligand also dramatically increased the yield of 7a to 95% in the reaction of 6a′ (Fig. 2C, entry 3). The reaction of propargyl alcohol 6a″ showed a similar performance with that of 6a′, giving 7a in 95% yield in the presence of dtbpy but a relatively lower yield of 7a in the absence of dtbpy (Fig. 2C, entries 4 and 5).

Substrate scope

Having established the deoxygenative silylation of 2-naphthylmethyl alcohol and its ether derivatives 1a–1a″ with 2a, we then investigated the silylation reactions of various (hetero)arylmethyl alcohol and their ether derivatives 1–1″ with chlorosilanes 2. Some representative results are summarized in Fig. 3. In addition to 1a, 1-naphthylmethyl 2-pyridyl ether also reacted well with 2a, affording the desired product 3b in 78% yield. A wide range of substituted benzyl 2-pyridyl ethers also underwent the deoxygenative silylation with 2a smoothly, affording the corresponding products 3c to 3af in 50 to 88% yields. Function groups such as OMe (3k), OPh (3e and 3l), F (3h and 3x), Cl (3aa and 3ac), styryl (3i), CF₃ (3n), OCF₃ (3z), SiMe₃ (3r), and aromatic heterocycles (3o, 3p, 3u, 3v, and 3w) were all well tolerated. Double C–O silylation of 1,4-bis[(pyridin-2-yloxy)methyl]benzene with 2a furnished the disilylated product 3ag in 63% yield. Heteroarylmethyl 2-pyridyl ethers such as benzo[b]thiophen-3-ylmethyl, thiophen-3-ylmethyl, and (1-methyl-1H-pyrazol-4-yl)methyl analogs were also suitable substrates, affording the corresponding products 3ah to 3aj in 63-to 78% yields. Notably, secondary 2-naphthylmethyl and benzyl 2-pyridyl ethers were also compatible, affording the desired products 3ak to 3aq in 35 to 70% yields. The sterically demanding tertiary 2-phenylpropan-2-yl 2-pyridyl ether also proved to be suitable substrate for the reaction with 2a, affording the desired product 3ar in 55% yield. Besides 2-pyridyl ethers, arylmethyl methyl ethers 1′ also reacted well with 2a by CrCl₃ in the presence of ^tBu₃-tpy at 70°C, affording the corresponding arylmethyl-substituted silanes in good yields. This catalytic system was also compatible with diverse functional groups such as alkyl, aryl, SiMe₃, OMe, CF₃, F, OCF₃, and aromatic heterocycles. Several examples of arylmethyl alcohols 1″ were also tested, affording the desired products in moderate yields, along with the formation of the corresponding arylmethyl trimethylsilyl ethers.

Fig. 3. — Reaction condition A: 1 (0.2 mmol), 2 (0.8 mmol), CrCl₃ (10 mol %), EtMgBr (1.0 mmol), and THF (2.0 ml), room temperature, 12 hours, isolated yields. Reaction condition B: 1′ (0.2 mmol), 2 (0.8 mmol), CrCl₃ (20 mol %), ^tBu₃-bpy (20 mol %), EtMgBr (1.0 mmol), and THF (2.0 ml), room temperature, 12 hours, isolated yields. ^a70°C, 24 hours. ^bAlcohols 1″ (0.2 mmol), 2a (1.0 mmol), CrCl₃ (25 mol %), dtbpy (25 mol %), EtMgBr (1.2 mmol), and THF (2.0 ml), 70^oC, 48 hours.

The substrate scope of chlorosilanes 2 was then investigated. A series of alkyl-, phenyl-, and vinyl-substituted chlorosilanes proved to be effective for the reaction with 1a and 1a′, affording the corresponding silylation products 3as to 3aaa in good yields. Chloro(chloromethyl)dimethylsilane was also a suitable substrate for the reaction with 1a, affording the desired product 3aab in 40% yield. However, the reactions of chlorodimethylsilane and chloro(trimethoxy)silane with either 1a or 1a′ were unsuccessful probably because of the electronic effect. Notably, in the reactions of dichlorosilanes with 1a, one Si–Cl bond coupled selectively with the C–O bond, while the other Si–Cl bond reacted with EtMgBr, affording the 2-naphthylmethyl–substituted ethylsilanes 3aae and 3aaf in 75 and 50% yields, respectively.

Figure 4 summarizes the analogous deoxygenative silylation of allyl alcohols 4″ and propargyl alcohols 6″ with chlorosilanes 2 by CrCl₃/dtbpy. Cinnamyl alcohols bearing diverse substituents at benzene ring all worked well with 2a, affording the corresponding allylsilanes 5a–5h in 70 to 87% yields with high stereoselectivity. Function groups such as OMe (5c, 5g, and 5h), SMe (5d), F (5f), and Cl (5e) were compatible. The α-methyl (5i and 5j) and -n-pentyl (5k) substituents did not hamper the reaction with 2a, affording 5i to 5k in 89 to 95% yields. The secondary allylic alcohol (E)-4-phenylbut-3-en-2-ol also reacted efficiently with 2a, affording the corresponding product 5l in 82% yield with regioselectivity (3:1) favoring the less hindered site. In addition to 2a, chlorotriethyl-, tert-butylchlorodimethyl-, n-butylchlorodimethyl, and allylchlorodimethylsilanes were also compatible for the reactions with 4a, affording the corresponding products 5m to 5p in 80 to 88% yields. The reaction of 1-vinyl–substituted alcohols or their methyl ethers occurred selectively at the less hindered site, yielding the corresponding terminal allylsilanes 5a and 5q to 5t in 85 to 95% yields. (E)-1,3-Diphenylprop-2-en-1-ol also reacted well with 2a to give 5u in 86% yields. The analogous reactions of propargyl alcohols 6″ with 2 were then examined. A series of propargyl alcohols with diverse substitution at the alkynyl or propargyl positions reacted well with 2a to furnish tetra- and trisubstituted silylallenes 7a to 7m in 72 to 91% yields. Chlorotriethyl-, chlorodimethylphenyl, tert-butylchlorodimethyl- and allylchlorodimethylsilanes were also suitable for the reaction with 6a″, affording 7n to 7q in 86 to 89% yields. The reaction of primary propargyl alcohol 3-phenylprop-2-yn-1-ol with 2a gave the corresponding propargyl silane 7r′ as the major product, probably because of steric effect.

Fig. 4. — Reaction conditions: alcohols 4″ or 5″ (0.2 mmol), 2 (1.0 mmol), CrCl₃ (10 mol %), dtbpy (10 mol %), EtMgBr (1.2 mmol), and THF (2.0 ml), room temperature, 12 hours, isolated yields.

This chromium-catalyzed silylation methodology could be applicable to the direct functionalization and late-stage modification of natural products, pharmaceuticals, and their derivatives, as demonstrated with adapalene, tonalid, celestlide, donepezil, piperonyl alcohol, perillyl aldehyde, linalool, myrtenal, geranyl linalool, β-ionone, and dihydro-β-ionone (Fig. 5A). To further highlight the practical value of the present protocol, some gram-scale reactions were carried out (Fig. 5B). The reactions of 10 mmol of allylic methyl ethers derived from linalool and dihydro-β-ionone with 2a afforded the desired products 5w and 5aa in 85 and 80% yields, respectively. Similarly, the reactions of 10 mmol of propargyl alcohol 6b with 2a under the standard conditions yielded the tetrasubstituted silylallene 7b in 91% yield. The reaction of 10 mmol of 1a with 2a under standard conditions proceeded efficiently to afford the desired product 3a in 75% yield. Compound 3a was readily converted into secondary amine (3a-1), secondary alcohol (3a-2), methyl 2-(naphthalen-2-yl)acetate (3a-3), and 2-naphthyl(trimethylsilyl)methanone (3a-4).

Fig. 5. — (A) Deoxygenative silylation of biorevelent derivatives. (B) Gram-scale reactions and transformations of 3a. For detailed conditions regarding the silylation of biorelevant derivatives and gram-scale reactions, see the Supplementary Materials. Reaction conditions for transformations of 3a: (a) 3a (0.2 mmol), (E)-N,1-diphenylmethanimine (0.15 mmol), TBAF (5 mol %), 4-Å MS (100 mg), and THF (1 ml), 80°C, 12 hours; (b) 3-Methoxybenzaldehyde (0.4 mmol), TBAT (5 mol %), and THF (1 ml), 80°C, 6 hours; (c) CO₂ (1 atm), CsF (0.6 mmol), DMF (1 ml), 100°C, 4 hours, and then MeI (2 equiv), Cs₂CO₃ (2 equiv), r.t., 30 min; (d) NBS (0.4 mmol), AIBN (5 mol %), benzene (1 ml), 80°C, 12 hours, bad then AgOAc (0.4 mmol), H₂O:Acetone:EtOH = 1:2:3 (2 ml), r.t., 24 hours.

The analogous deoxygenative functionalization of alcohols and its ether derivatives with other electrophiles was then investigated (Fig. 6). As shown in Fig. 6A, chlorotrimethylgermane and chlorotrimethylstannane were also suitable electrophiles for the present deoxygenative functionalization, affording the corresponding organogermanium and organostannane compounds in 42 to 75% yields. However, boron electrophiles such as methyl pinacolyl borate (MeOBpin) and pinacolboane (HBpin) were incompatible for the deoxyborylation with 1a under CrCl₃/EtMgBr conditions (Fig. 6B, entries 1 and 2). To our delight, the deoxyborylation of 1a with HBpin was successfully achieved by switching the reductant from EtMgBr to Mg, affording the corresponding product 9a in 81% yield (Fig. 6B, entry 3). The reaction of the analogous methyl ether 1a′ with HBpin also worked well in the presence of dtbpy ligand and Mg reductant (79, 80), giving the desired product 9a in 91% yield; however, no product was formed in its absence (Fig. 6B, entries 4 and 5). The direct deoxyborylation of the free alcohol 1a″ with HBpin was also achieved, delivering 9a in 78% yield (Fig. 6B, entry 6), albeit over a longer reaction time. Notably, this chromium-catalyzed deoxyborylation protocol is scalable and can be applied to the gram-scale synthesis of 9a (see the Supplementary Materials).

As shown in Fig. 6C, the deoxyborylation of various alcohols and ethers with HBpin was also examined. A wide range of arylmethyl 2-pyridyl ethers reacted well with HBpin, affording the corresponding deoxyborylation products 9b to 9y in 40 to 92% yields. Function groups such as OMe (9w), OEt (9l), OH (9p), F (9j and 9n), Cl (9o and 9u), CF₃ (9g), OCF₃ (9m), Bpin (9h), and heterocycles (9s and 9v) were compatible. Notably, the reactions of secondary benzyl and 2-naphthylmethyl 2-pyridyl ethers also underwent smoothly to afford the desired borylation products 9z to 9ab in 63 to 88% yields. Moreover, arylmethyl methyl ethers and alcohols are also compatible, affording the corresponding borylation products in good yields. This borylation methodology was also applicable to the late-stage functionalization of biorelevant molecules such as adapalene (9ac), celestolide (9ad), and tonalid (9ae). The reactions of allyl methyl ethers and alcohols also worked well, yielding the corresponding allyl boronic esters 9af to 9aj in good yields with excellent stereoselectivity (81–86).

Building on the insight that in situ–generated borate ester intermediate ROBpin is a key intermediate for the deoxyborylation of alcohols with HBpin (87, 88), we extended this chromium-catalyzed strategy to the deoxyborylation of aldehydes, ketones, and esters using HBpin as both an in situ–activating reagent and electrophile (Fig. 7A) (89–94). As anticipated, 2-naphthaldehyde and methyl 2-naphthoate proved to be suitable substrates, affording the corresponding deoxyborylation product 9a in 78 and 45% yields, respectively. The deoxyborylation of 2-acetylnaphthalene 10c and celestolide 10d also worked well, giving the desired borylated product 9ab and 9ad in 58 and 54% yields, respectively. The methyl ester derived from adapalene was also converted to the corresponding borylated product 9ac in 50% yield. Furthermore, substituted cinnamaldehydes were also compatible with this chromium-catalyzed deoxyborylation protocol, affording the corresponding allyl boronic esters 9af to 9aj in synthetic useful yields.

Fig. 7. — (A) Deoxygenative borylation of aldehydes, ketones, and esters. (B) Deoxygenative silylation of carbonyls. For detailed conditions, see the Supplementary Materials.

We subsequently explored the deoxygenative silylation of diverse aldehydes by leveraging their in situ conversion into reactive silyl ether intermediates (Fig. 7B). Using a B(C₆F₅)₃-catalyzed hydrosilylation to generate silyl ethers in situ, the deoxygenative silylation of cinnamaldehydes was successfully achieved, affording the corresponding allylsilanes 5a to 5g in good yields. The reaction of acrylaldehyde with chlorosilanes in the presence of EtMgBr or ⁿHexylMgBr proceeded efficiently to afford the deoxygenative silylation products 5af and 5ag in 84 and 85% yields, respectively. This reaction proceeds through nucleophilic addition of EtMgBr or ⁿHexylMgBr to the carbonyl group, generating a silyl ether intermediate in situ. Similarly, cinnamaldehyde also reacted well with 2a, affording the corresponding product 5ah in 60% yield with moderate regio- and stereoselectivity. Notably, the deoxygenative silylation of aromatic and aliphatic aldehydes with 2a using vinyl magnesium bromide instead of EtMgBr also underwent smoothly via in situ generation of 1-vinyl–substituted silyl ethers, affording the corresponding allylsianes 5a to 5am in good yields. Enhanced activity was achieved by using 1.2 equiv of vinylMgBr as an initiator, followed by the addition of EtMgBr (5ai, 48 versus 80% and 5q, 30 versus 78%). Similarly, the reaction of 2-acetylnaphthalene 10c with 2a also worked well by using 1.2 equiv of vinylMgBr as an initiator, followed by the addition of EtMgBr as the reductant, affording the desired product 5am in 58% yield.

Mechanistic investigations

To gain information on the reaction mechanism, several mechanistic experiments were conducted. The reaction of CrCl₃ with EtMgBr at room temperature for 2 hours released ethylene and hydrogen gas, as detected by gas chromatography–mass spectrometry (Fig. 8A, top). No substantial silylation was observed between 1a and 2a when using MeMgBr as the reductant (Fig. 8A, bottom). These observations indicate that a low-valent chromium species might be formed via transmetalation of CrCl₃ followed by β-hydride elimination and hydride reduction (95). The radical clock experiments were then conducted to determine whether a radical pathway was involved in this deoxygenative functionalization reaction (Fig. 8B). The reactions of α-cyclopropyl–substituted 2-naphthylmethyl ethers afforded the corresponding silylation and borylation products 3aan and 9ak in 45 and 38% yields, respectively, with no observed ring-opening products. These results indicate that a single-electron transfer pathway might be not involved in this chromium-catalyzed deoxygenative functionalization. Treatment of 1a with 0.2, 0.5, or 1.0 equiv of CrCl₃ and 4.0 equiv of EtMgBr, followed by quenching with D₂O, gave the corresponding deuterated product 11-D in 13, 34, and 65% yields, respectively (Fig. 8C, top). The stoichiometric reaction of 1a with 1.0 equiv of CrCl₃ and 2.0 equiv of Mg at 80°C gave 2-methylnaphthalene 12 in 40% yield (Fig. 8C, bottom). These results suggest that an organochromium species might be generated in this chromium-catalyzed deoxygenative functionalization. In the reaction of chlorodimethyl(phenyl)silane with EtMgBr catalyzed by CrCl₃/dtbpy, no deuterated dimethyl(phenyl)silane was observed (Fig. 8D), suggesting that a silyl magnesium reagent might be not generated in this reaction. The treatment of CrCl₃ with EtMgBr, followed by addition of chlorodimethyl(phenyl)silane and subsequent quenching with D₂O, did not yield deuterated dimethyl(phenyl)silane. This result indicates that a silyl chromium species might not be involved in this deoxygenative silylation reaction.

Fig. 8. — (A) Exploring the formation of active low-valent chromium species. (B) Radical clock experiments. (C) Investigating the formation of benzyl chromium species. (D) Investigating the formation of silyl magnesium or silyl chromium species. (E) Plausible mechanisms for the deoxygenative silylation and borylation of 2-pyridyl ether 1a. (F) Plausible mechanisms for the deoxygenative silylation of allylic and propargylic alcohol **4a″** and **6a″** via in situ generation of silyl ethers.

On the basis of the above experimental results and previous reports (58, 65, 72, 73), possible mechanisms for the deoxygenative silylation and borylation of 2-pyridyl ether 1a, and silylation of allylic and propargylic alcohol 4a″ and 5a″ are proposed as shown in Fig. 8. The coordination of the pyridyl species in 1a to the low-valent chromium species, which was generated from the reduction of CrCl₃ with EtMgBr or Mg, followed by two-electron oxidative addition of the C–O bond of 1a by low-valent chromium would form an alkyl chromium intermediate II. The substitution reaction between II and 2a via a transition state TSI would generate the product 3a and a chromium species III (48, 72). The reduction of III with EtMgBr followed by the coordination to 1a would yield the intermediate I to restart the catalytic cycle (Fig. 8E). In the case of borylation with HBpin, the σ-bond metathesis between II and HBpin via a transition state TSII would occur to yield the product 9a and a chromium-hydride species IV (Fig. 8E). The chromium hydride species IV was further validated by the formation of deoxygenative protonation byproducts from certain incompatible substrates (see the Supplementary Materials). For substrate 1a′, ^tBu₃-tpy and dtbpy promoted the deoxygenative silylation and borylation by stabilizing the alkyl chromium intermediate (see the Supplementary Materials for the possible reaction mechanisms of the silylation and borylation of methyl ether 1a′). In the reaction of cinnamyl alcohol 4a″, the C−O bond cleavage of in situ–generated silyl ether by a dtbpy-ligated low-valent chromium species would give a π-allyl chromium intermediate IV (96, 97). The substitution reaction between IV and 2a favored at less steric site, affording the product 5a (Fig. 8F). In the case of propargyl alcohol 5a″, the C−O bond cleavage of in situ–generated silyl ether by a dtbpy-ligated low-valent chromium species would yield a propargyl chromium species VI, which would undergo a reversible 1,3-metal migration to give an allenyl chromium species VII (96). The substitution reaction between the allenyl chromium species VII and 2a would selectively take place because of the steric reason, giving the desired allenylsilane product 7a (Fig. 8F).

DISCUSSION

In summary, we have developed an efficient, concise, and general chromium-catalyzed strategy for the deoxygenative functionalization of alcohols, ethers, carbonyls, and esters with a number of electrophiles. This strategy couples these oxygenated functionalities with a number of electrophiles, providing an efficient and straightforward route for the synthesis of a broad range of synthetically valuable organosilicon, organogermanium, organostannane, and organoboron building blocks. The utility of this efficient chromium-catalyzed protocol has also been demonstrated by reaction scale-up and the direct functionalization and late-stage modification of various biorelevant molecules. Mechanistic studies indicate that this deoxygenative functionalization reaction proceeds through two-electron oxidative addition of the C–O bond to a low-valent chromium species, generating an organochromium intermediate that subsequently undergoes reaction with a number of electrophiles to forge C–Si, C–Ge, C–Sn, and C–B bonds. This work not only establishes an efficient and unified platform for converting ubiquitous oxygenated compounds into diverse organosilicon, organogermanium, organostannane, and organoboron building blocks but also opens up a promising frontier for the study of chromium catalysis. Further studies on low-valent chromium catalysis are in progress.

MATERIALS AND METHODS

General procedure for the deoxygenative silylation of arylmethyl 2-pyridyl ethers with chlorosilanes by chromium

A dried Schlenk tube was charged with 2-pyridyl ethers (0.2 mmol), CrCl₃ (10 mol %), and chlorosilanes (0.8 mmol), followed by adding a freshly distilled tetrahydrofuran (THF, 1 ml) by syringe under atmosphere of nitrogen. After stirring at room temperature for 5 min, EtMgBr (1.0 M in THF, 1 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 12 hours. After being quenched by aqueous NH₄Cl (2 ml), the crude product was extracted with ethyl acetate (3 × 10 ml). The combined organic phases were dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was purified by flash chromatography on silica gel to give the desired product.

General procedure for the deoxygenative silylation of arylmethyl methyl ethers with chlorosilanes by chromium in the presence of ligand

A dried Schlenk tube was charged with methyl ethers (0.2 mmol), CrCl₃ (20 mol %), ligand (20 mol %), and chlorosilanes (0.8 mmol), followed by adding a freshly distilled THF (1 ml) by syringe under atmosphere of nitrogen. After stirring at room temperature for 5 min, EtMgBr (1.0 M in THF, 1 mmol) was added dropwise, and the reaction mixture was stirred at 70°C for 24 hours. After being cooled to room temperature and quenched by aqueous NH₄Cl (2 ml), the crude product was extracted with ethyl acetate (3 × 10 ml). The combined organic phases were dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was purified by flash chromatography on silica gel to give the desired product.

General procedure for the deoxygenative silylation of arylmethyl alcohols with by chromium in the presence of ^tBu₃-tpy

A dried Schlenk tube was charged with arylmethyl alcohols (0.2 mmol), CrCl₃ (25 mol %), ^tBu₃-tpy (25 mol %), and chlorosilanes (1.0 mmol), followed by adding a freshly distilled THF (0.8 ml) by syringe under atmosphere of nitrogen. After stirring at room temperature for 5 min, EtMgBr (1.0 M in THF, 1.2 mmol) was added dropwise, and the reaction mixture was stirred at 70°C for 24 hours. After being cooled to room temperature and quenched by aqueous NH₄Cl (2 ml), the crude product was extracted with ethyl acetate (3 × 10 ml). The combined organic phases were dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was purified by flash chromatography on silica gel to give the desired product.

General procedure for the deoxygenative silylation of allyl and propargyl alcohols with by chromium in the presence of dtbpy

A dried Schlenk tube was charged with allyl and propargyl alcohols (0.2 mmol), CrCl₃ (10 mol %), dtbpy (10 mol %), and chlorosilanes (1.0 mmol), followed by adding a freshly distilled THF (0.8 ml) by syringe under atmosphere of nitrogen. After stirring at room temperature for 5 min, EtMgBr (1.0 M in THF, 1.2 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 12 hours. After being quenched by aqueous NH₄Cl (2 ml), the crude product was extracted with ethyl acetate (3 × 10 ml). The combined organic phases were dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was purified by flash chromatography on silica gel to give the desired product.

General procedure for the deoxyborylation of 2-pyridyl ethers with HBpin by chromium

A dried Schlenk tube was charged with 2-pyridyl ethers (0.2 mmol), CrCl₃ (10 mol %), Mg (0.4 mmol), and HBpin (0.6 mmol), followed by adding a freshly distilled THF (2 ml) by syringe under atmosphere of nitrogen. The reaction mixture was stirred at 80°C for 12 hours. After being cooled to room temperature, ethyl acetate (2 ml) was added into the reaction mixture and concentrated under vacuum. The residue was purified by flash chromatography on silica gel to give the desired product.

General procedure for the deoxyborylation of methyl ethers or alcohols with HBpin by chromium in the presence of dtbpy

A dried Schlenk tube was charged with methyl ethers or alcohols (0.2 mmol), CrCl₃ (10 mol %), dtbpy (10 mol %), Mg (0.4 mmol), and HBpin (0.6 mmol), followed by adding a freshly distilled THF (2 ml) by syringe under atmosphere of nitrogen. The reaction mixture was stirred at 80°C for 48 hours. After cooled room temperature, ethyl acetate (2 ml) was added into the reaction mixture and concentrated under vacuum. The residue was purified by flash chromatography on silica gel to give the desired product.

Acknowledgments

Funding:

This work was financially supported by the National Natural Science Foundation of China (grants 22571224 to X.C. and 22125107 to X.Z.), Shandong Provincial Natural Science Foundation (ZR2026MS0094 to C.C.), and the Haihe Laboratory of Sustainable Chemical Transformations (24HHWCSS00009 to X.C.).

Author contributions:

Conceptualization: C.C., X.Z., and X.C. Methodology: W.C., T.J., and C.C. Investigation: W.C., T.J., C.C., F.Z., X.L., S.W., J.W., J.Z., J.L., and Y.C. Supervision: C.C., X.Z., and X.C. Writing—original draft: X.C. Writing—review and editing: X.Z. and X.C. Funding acquisition: C.C., X.Z., and X.C.

Competing interests:

The authors declare that they have no competing interests.

Data, code, and materials availability:

All data and code needed to evaluate and reproduce the results in the paper are present in the paper and/or the Supplementary Materials. This study did not generate new materials.

Supplementary Materials

This PDF file includes:

Supplementary Text

Tables S1 to S8

Figs. S1 and S2

NMR Spectra

References

sciadv.aeg4594_sm.pdf^{(25MB, pdf)}

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Text

Tables S1 to S8

Figs. S1 and S2

NMR Spectra

References

sciadv.aeg4594_sm.pdf^{(25MB, pdf)}

Data Availability Statement

All data and code needed to evaluate and reproduce the results in the paper are present in the paper and/or the Supplementary Materials. This study did not generate new materials.

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PERMALINK

Deoxygenative functionalization of alcohols, ethers, and carbonyl compounds by chromium catalysis

Wendi Chang

Tenggang Jiao

Changpeng Chen

Feijiang Zhou

Xiaogai Li

Shuya Wang

Jingxia Wang

Jinwei Zhang

Jing Liu

Ying Cao

Xiaoming Zeng

Xuefeng Cong

Roles

Abstract

INTRODUCTION

Fig. 1. Background and reaction design.

RESULTS

Screening of reaction conditions

Fig. 2. Optimization of reaction conditions.

Substrate scope

Fig. 3. Deoxygenative silylation of (hetero)arylmethyl ethers and alcohols.

Fig. 4. Deoxygenative silylation of allylic and propargylic alcohols.

Fig. 5. Deoxygenative silylation of biorelevant derivatives, gram-scale reactions, and transformations of 3a.

Fig. 6. Deoxygenative germanylation, stannylation, and borylation of ethers and alcohols.

Fig. 7. Deoxygenative silylation and borylation of carbonyl compounds.

Mechanistic investigations

Fig. 8. Mechanistic studies.

DISCUSSION

MATERIALS AND METHODS

General procedure for the deoxygenative silylation of arylmethyl 2-pyridyl ethers with chlorosilanes by chromium

General procedure for the deoxygenative silylation of arylmethyl methyl ethers with chlorosilanes by chromium in the presence of ligand

General procedure for the deoxygenative silylation of arylmethyl alcohols with by chromium in the presence of tBu3-tpy

General procedure for the deoxygenative silylation of allyl and propargyl alcohols with by chromium in the presence of dtbpy

General procedure for the deoxyborylation of 2-pyridyl ethers with HBpin by chromium

General procedure for the deoxyborylation of methyl ethers or alcohols with HBpin by chromium in the presence of dtbpy

Acknowledgments

Funding:

Author contributions:

Competing interests:

Data, code, and materials availability:

Supplementary Materials

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REFERENCES

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

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General procedure for the deoxygenative silylation of arylmethyl alcohols with by chromium in the presence of ^tBu₃-tpy