Direct deoxygenative borylation

Metal-catalyzed deoxy-borylation of allylic, benzylic and propargylic alcohols

Considering the difficulty of alcohol direct borylation, the initial exploration in this field focused on some reactive alcohols like allylic alcohols. Pioneered by Szabó and his group, the direct deoxygenative borylation of free allylic alcohol was realized under mild palladium catalysis, among which ligand-free and ligand-enabled conditions were both feasible (Fig. 1A) [47], [48], [49], [50], [51], [52], [53], [54]. For the latter, the PSP- and PSeP-type pincer-type ligands were crucial, managing the desired transformation under mild conditions and controlling linear product formation. In Szabó’s proposed mechanism, the Lewis acidic B₂X₄ was dual-functional, serving as boron sources and activating the –OH in the allylic substrates. Counter anion BF₄⁻ of the palladium catalyst was also non-innocent, which would degrade into F⁻ and BF₃, assisting the transmetallation and activation of alcohols, respectively. The allylboron product could be directly subjected to carbonyl allylation in a one-pot manner.

Fig. 1:

Metal-catalyzed deoxygenative borylation of alcohols. DMSO, dimethylsulfoxide. B₂pin₂, bis(pinacolato)diboron; Bn, benzyl; THF, tetrahydrofuran; DMA, N,N-dimethylacetamide; Acac, acetylacetonate; OAc, acetate; DCPF, 1,1′-bis(dicyclohexylphosphino)ferrocene; MTBE, methyl tert-butyl ether; Xantphos, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.

In collaboration with Aggarwal’s group, they also unveiled a simple Pd-catalyzed protocol with a commercially available palladacyclic catalyst, giving a similar scope of allylboronates with high efficiency [49].

Encouraged by these prior efforts, the more economical iron catalysis was proved viable in the allylic alcohol borylation, as reported by Qu’s and Liu’s groups, respectively (Fig. 1B) [55, 56]. In both cases, primary allylboronates were the major products, while Liu’s conditions were aligned with higher stereocontrol over the alkene geometry due to the Fe-embedded chair transition state. Interestingly, Qu’s protocol required external Brønsted acid, H₃BO₃, for hydroxy group activation; however, a catalytic quantity of Lewis acidic iron was sufficient in the other case.

Recently, a heterogeneous deoxygenative borylation reaction of allylic and benzylic alcohol was accomplished by Shishido, Miura and their colleague by means of TiO₂-supported gold nanoparticles (AuNPs) (Fig. 1C) [57]. Since this AuNP catalyst was designated primarily for acetate borylation, only examples of cinnamyl alcohol and p-anisyl alcohol were shown, which might be converted in situ to the OBpin intermediates via hydrogen evolution to facilitate the C–O borylation.

Comparing the fruitful achievement of allylic alcohol borylation, the same transformation with benzyl alcohols was less investigated until Shi’s 2015 discovery (Fig. 1D) [58]. In their work, a variety of naphthylmethanols were borylated using a simple palladium catalyst and bidentate phosphine. Similar conditions with the addition of Ti(IV) additive could include the less reactive benzyl alcohols in the scope, which constituted one of the rarely known catalytic systems that could manage the direct deoxygenative borylation of benzyl alcohols. Enlightened by Shi’s work, the group of Marder and Szabó uncovered a copper version of benzyl alcohol deoxy-borylation using a chelating phosphine ligand with a large bite angle (Fig. 1E) [59]. Notably, allylic alcohols were also effective substrates with this copper catalyst at lower temperatures.

Similar Cu-catalyzed borylation manifold with the variation of additive, solvent and temperature could lead to a divergent synthesis of alkyl-, vinyl- and allenylboronic acid derivatives from propargyl alcohols, which was reported by the group of Marder and Szabó as well as the one of Ye independently (Fig. 1F) [59], [60], [61]. General mechanistic traits included the formation of a Cu–B complex and a Ti(IV)-coordinated propargyl alkoxide. The reaction outcomes were determined by the specific reaction conditions and partially by the structural properties of the substrates.

Metal-free deoxy-borylation of allylic alcohols

The prosperous development of metal-catalyzed direct deoxygenative borylation brings about the curiosity in metal-free deoxy-borylation [62]. Foreseeably, conditions used to break the alcohol C–O bonds without the assistance of metal catalysts could be harsh. Although the Lewis acidic trivalent boron reagent could alleviate the problem to some extent, substrate scope in this area was still restricted to allylic alcohols only.

In this context, Fernández and Szabó et al. co-developed a base-catalyzed direct deoxygenative borylation reaction of tertiary allylic alcohols, which was promoted by the “ate” complex made of B₂pin₂ and Cs₂CO₃ via S_N2′ fashion (Fig. 2A) [63]. Concurrently, Uchiyama and Hirano et al. [64] found an identical transformation using a stoichiometric amount of NaOMe (Fig. 2A). Density functional theory (DFT) calculation compared the routes of S_N2′ and diborylation followed by boron-Wittig elimination, indicating that the latter might experience a less energetic profile.

Fig. 2:

Metal-free deoxygenative borylation of alcohols. THF, tetrahydrofuran.

Impressively, Fernández’s conditions could also give highly valuable 1,2,3-tris(boronates) products, which presumably originated from the follow-up alkene diborylation with the excessive B₂pin₂ after forming the nascent allylboronate. Moreover, propargyl alcohols could be diborylated with this protocol.

Using H-Bpin as the borylating reagent and catalytic n-BuLi, reductive relay hydroboration of allylic alcohol reaction was accomplished by Shi’s group (Fig. 2B) [65]. The reaction started from the formation of the OBpin borate, which could undertake either a hydroboration/boron Wittig reaction sequence or an S_N2′ hydride attack to give the terminal alkene intermediate. Anti-Markovnikov hydroboration will give the desired product. Such a reductive tandem reaction was complementary to previous approaches that gave allylboronates, resulting in an array of linear-chain aliphatic boronates in good yields.

Deoxy-borylation of phenols

Direct deoxygenative borylation of simple phenols remains hitherto unknown, while many indirect methods have been investigated successfully with some activated derivatives like triflates (Fig. 3) [66, 67]. Classic Miyaura-type aromatic borylation failed with free phenol owing to the strong C(sp²)–O bond (BDE = 111 kcal/mol) and acidic phenolic hydrogen (pKa = 10). Despite these hurdles, Shi and his co-workers realized an unprecedented direct deoxygenative borylation of naphthol under nickel/N-heterocyclic carbene (Ni/NHC) catalysis [58]. Commercially available Ni(0) precursor was bound with a bulky NHC ligand, which borylated the 2-naphthol with B₂pin₂ in the absence of base. Unfortunately, the reaction efficiency was modest and other substrates, especially phenol, were unexplored.

Fig. 3:

Deoxygenative borylation of phenol. COD, 1,5-cyclootadiene; Ad, 1-adamantyl.

Deoxy-borylation of ethers for aromatic boron compound synthesis

Aryl ethers were challenging aromatic electrophiles in organometallic chemistry due to the strong C(sp²)–O bonds and poor leaving ability of alkoxides. For diary ethers, differentiation of sites for metal borylation was proved difficult, which could entail decreased yields and purification problems. To address these issues, Chatani, Tobisu and their co-workers pioneered the field by developing an Rh-catalyzed deoxygenative borylation with aryl 2-pyridyl ethers, wherein the coordination of pyridine nitrogen was found essential for the desired reactivities while minimizing the substrate decomposition (Fig. 4A, upper eq) [68]. Low-valent metal catalyst and electron-rich bulky ligand were the other two parameters that ensured the success of this transformation since they facilitated the C(sp²)–O oxidative addition and enforced the product-forming C(sp²)–B reductive elimination. Such a novel approach provided not only an effective route for arylboronate synthesis but also repurposed the utility of the 2-pyridyloxy group, which was originally designed for metal directionality.

Fig. 4:

Deoxygenative borylation of ethers for aromatic boron compound synthesis. COD, 1,5-cyclootadiene; NHC, N-heterocyclic carbene; DME, 1,2-dimethoxyethane; OAc, acetate; t-BuXPhos, 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl; B₂nep₂, bis(neopentylglycolato)diboron; Cy, cyclohexyl.

Guided by the same logic, Chatani and Tobisu et al. [69] presented another aromatic deoxy-borylation strategy by nickel catalysis (Fig. 4A, middle eq). Simple Ni(II) salt and trialkylphosphine ligand were combined, which afforded a similar scope of aromatic boronates but at a lower reaction temperature and chemical cost. It was worth mentioning that both catalytic methods developed were also applicable to the analogous benzyl ethers.

Inspired by these two elegant precedents, Feng’s group contributed an Fe-catalyzed deoxygenative borylation reaction with the same pyridyl ethers (Fig. 4A, lower eq) [70]. Consistent with the Ni-catalyzed conditions, phosphine ligand and strong base were required. A broad range of ethers, which eventually derived from phenols, could be borylated in Feng’s case, although applying the same conditions to aniline derivatives resulted in unsatisfactory yields of deaminative products.

Anisole and its derivatives could be obtained from lignin depolymerization; therefore, it is conceived as an ideal aromatic electrophile from renewable sources. Toward the direct deoxygenative borylation of aryl methyl ethers, nickel and rhodium stand out again as optimal catalyst options. In 2015, Martin and his colleagues disclosed a ground-breaking direct ipso-borylation reaction for naphthyl or aryl methyl ethers via deoxygenation (Fig. 4B) [71]. A unique promotive effect was observed with HCO₂Na as the base additive, and subtle sterics explained the higher reactivity with B₂(nep)₂ tentatively.

Nakao’s group reported an alternative approach to enable this tough transformation via ligand design (Fig. 4B) [72]. The rhodium was paired with an aluminyl ligand to form a heterobimetallic complex, which catalyzed the deoxy-borylation of different anisoles. A sacrificial trisubstituted alkene was added as the scavenger of HBpin, which was derived from an unidentified side reaction. Interestingly, this rhodium catalysis demonstrated complementary regioselectivity to nickel due to the metal-ligand cooperation in the former. Lewis acidic aluminum and the bulky ligand framework collectively favor the oxidative addition at the less hindered C(sp²)–OR. In the same work, hydrodeoxygenation was also possible with silane as the hydrogen donor.

Deoxy-borylation of ethers for vinylic and aliphatic boron compound synthesis

Deoxygenative borylation of other types of ethers parallels the aromatic ones, which could foster vinylic and aliphatic C-B bonds accordingly.

Taking advantage of nickel catalysis, Ling, Qiu and their group realized the deoxy-borylation of methyl vinyl ethers, giving various vinylboronic acid esters with high E-selectivity (Fig. 5A, upper eq) [73]. Switching to Cu/NHC catalyst, (allenylmethyl) benzyl ethers became viable substrates for vinylboronate preparation, which underwent a formal S_N2′-type borylation via alkoxide elimination (Fig. 5A, middle eq) [74].

Fig. 5:

Deoxygenative borylation of ethers for aliphatic and vinylic boron compound synthesis. Acac, acetylacetonate; Xantphos, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; B₂pin₂, bis(pinacolato)diboron; 4-t-Bu-Py, 4-tert-butylpyridine; Mes, mesityl.

In 2016, Yorimitsu et al. [75] discovered an interesting borylative ring expansion with benzofuran (Fig. 5A, lower eq). Electron-rich NHC/Ni(0) was proposed to insert into the C2–O bond, which was transmetallated with B₂pin₂ and eliminated to form the spirocyclic vinylborates. After hydrolysis, benzoxaborins were produced. Moving such a single-atom editing strategy forward, Dong’s group made another breakthrough in the boron-insertion chemistry with simple ether rings by using dibromoborane and zinc dust (Fig. 5B) [75]. Mechanistically, the initial stage of this novel transformation mimicked the classic dealkylation mechanism enabled by boron trihalides, during which the bromide displacement occurred selectively at the alkyl site with the bulky mesitylborane. Subsequently, nickel catalyzed the reductive borylation and closed the bimetallic cycles by forming oxaborinane. Noticeably, the bulky mesityl group reduced the propensity of dimerization and enhanced products’ stability during purification. Under identical conditions, boron could also slip into C(sp³)–N bond in the N-heterocycles.

Multiboronates are important building blocks in synthetic planning due to the rich boron chemistry. Importantly, it could streamline deborylative transformations sequentially and selectively. Among them, 1,1,3-tris(boronates) remained elusive until the disclosure of Ge’s Co-catalyzed deoxygenative triboration with cinnamyl methyl ethers (Fig. 5C) [76]. The Bpin groups were installed stepwise, during which the allylboronate was believed to be a competent intermediate. Afterward, gem-diboration at the remote position was catalyzed by cobalt, and norbornene behaved as the terminal oxidant.

General methods for deoxy-borylation of aldehydes and ketones

Vicinal diboration of alkenes by diboron is well-established for aliphatic boronate synthesis. In contrast, the analogous 1,2-diboration of carbonyl remained sluggish despite the structural similarity of C=C and C=O bonds. Presumably, this pivotal step could bring a highly activated C,O-diborylated intermediate, which not only reduces the C=O bond order but also facilitates the subsequent C–O cleavage due to the presence of two neighboring trivalent boron atoms.

Based on this assumption, Liu’s and Li’s groups presented two different strategies to achieve the deoxygenative borylation of aldehydes and ketones (Fig. 6). In 2019, Liu and his co-workers established a direct deoxygenative diboration for aldehydes and ketones with simple B₂pin₂ under Cu/NHC catalysis (Fig. 6A) [83]. This novel borylation reaction takes full advantage of the bis-electrophilicity of carbonyl compounds and could also be extended to an unprecedented silylborylation with pinB-SiMe₂Ph. Mechanistically, such a deoxygenative difunctionalization involved a Cu-catalyzed C=O 1,2-diborylation step followed by a borylative migratory substitution assisted by a base. The former step was initially studied by Sadighi et al. [78, 84] and later computed by Lin’s and Marder’s group collaboratively [85], [86], [87]. Harnessing Liu’s conditions, a wide range of gem-diboronates and -silylboronates could be obtained from simple carbonyl starting materials. Impressively, small-molecule ketones (e.g., acetone) were also viable substrates, which remained unfeasible by conventional means.

Fig. 6:

General methods for direct deoxygenative borylation of aldehydes and ketones. B₂pin₂, bis(pinacolato)diboron; DMA, N,N-dimethylacetamide; B₂cat₂, bis(catecholato)diboron. Only key steps in the mechanism were shown. See the original papers for detailed description.

Capitalizing on the same C,O-diboronate, slight condition modification could channel the original diborylation reactivity towards either deoxygenative hydroboration or carboborylation smoothly, further expanding the repertoire of deoxy-borylative transformations of aldehydes and ketones (Fig. 6B and C). However, the latter proceeded at the expense of separate steps of introducing carbon nucleophiles. Very recently, such deoxygenative logic was further enriched by Xu’s group, who combined the Cu-catalyzed aldehyde diborylation and Ni reductive metallaphotoredox cross-couplings for the α,α-dialkyl boronates synthesis [88].

Encouraged by Liu’s elegant studies, particularly the base-mediated migratory substitution of C,O-diboronates, Li and his colleague conceived a similar scenario wherein the first vicinal borylation was under reagent control, therefore, eliminating the metal catalysts from the overall deoxygenative borylation (Fig. 6D) [89]. The key finding in Li’s case was a uniquely enabling diboron reagent, B₂cat₂, which unified the strong Lewis acidity and oxophilicity, promoting the formation of various benzylboronates from substituted benzaldehydes and aryl ketones via deoxygenation [17, 90]. Interestingly, a divergent reaction outcome was observed when subjecting the aliphatic substrates to similar reductive borylation in an anhydrous coordinating solvent, which exclusively gave 1,1,2-tris(boronates) as highly useful products.

In Li’s tentative mechanism, the unique solvent effect led to the assembly of a putative ternary boron complex. Consistent with Liu’s proposal, 1,2-diborylation, migratory bora-substitution and protodeboronation with H₂O will give the monoboration reactivity. Under an analogous mechanistic framework, vinylboronate could be derived via elimination, which was diborylated to deliver the tris(boronate).

Methods for deoxy-borylation of ketones

Ketone deoxygenative borylation could be operated via alkene or enolate by other means. For the former, Zhao’s group launched a systematic study of Rh-catalyzed deoxygenative borylation of ketones, which could offer various mono-, di- and tris(boronates) selectively (Fig. 7A) [91, 92]. By fine-tuning the reaction conditions with ligand choice, borylating reagent and base additive, alkylboronates, vinylboronates, 1,1-vinyldiboronates, and 1,1,2-tris(boronates) could be acquired from simple ketones with high chemo- and regioselectivity, which was governed by the ligated rhodium. In Zhao’s case, the alkene intermediate was validated experimentally and computationally, which resulted from the deoxygenative desaturation under rhodium catalysis. Subsequently, the alkene was borylated under a similar catalytic manifold to provide the desired products.

Fig. 7:

Deoxygenative borylation of ketones. COD, 1,5-cyclootadiene; B₂pin₂, bis(pinacolato)diboron. IPE, 2-isoproproxypropane.

Alternatively, the ketone deoxygenative borylation could be conducted without transition metals. In 2019, Liu’s group contributed a stepwise deoxy-borylation protocol using the ketone-derived enolates (Fig. 7B). Assisted by the Lewis acidic Mg(OMe)₂, which might enhance the polarity of C=O, thereafter, the propensity of boron migration, the enolate was converted into an α,β-borylated alkoxide. This set the stage for a highly stereoselective boron-Wittig reaction and afforded the numerous trisubstituted and tetrasubstituted vinylboronates. Notably, a one-pot deoxygenative borylation reaction of free carboxylic acid was also described in the same work, wherein the acid was transformed into an O-borylated enolate (vinylborate) upon the cooperative action of α,α-diboroalkane and MeLi [93]. Later, the vinylborate was deoxygenated, giving the (Z)-vinylboronate as the major product.