Rh(II)-Catalyzed Synthesis of 1,3-Diols via 5-endo-trig Cyclization of Silyl Radicals

Abstract

1,3-Diols, which are a frequent motif in biologically active molecules, can be prepared from readily available allylic alcohols via formal anti-Markovnikov hydration. The commonly employed hydroboration–oxidation sequence for the synthesis of terminal alcohols is challenging for allylic alcohols, and O-protection of the alcohol can be necessary. To increase atom economy, we explored the use of silane protecting groups that can be engaged in intramolecular hydrosilylation. Oxidative cleavage of the cyclized product yields the desired 1,3-diol and obviates the need for super-stoichiometric borane reagents. Based on a detailed study of O-silylation conditions, a protocol is presented that furnishes quantitative yields of a wide range of O-silylated alcohols which contain Si–H bonds for further functionalization. We show that a MOF-based Rh(II) porphyrin can furnish efficient intramolecular hydrosilylation, while the corresponding homogeneous analogue proved unreactive. Radical trapping studies suggest that silyl radicals constitute key intermediates in Rh(II)-catalyzed intramolecular hydrosilylation. Preferential 5-endo-trig versus 6-exo-trig cyclization and 5-exo-trig versus 6-endo-trig cyclization of the silyl radical intermediates led to chemoselective 1,3-diol formation for substrates containing multiple olefins.

Despite the need for at least one stoichiometric reagent other than water and olefin, indirect anti-Markovnikov hydration reactions remain important preparative methods. No general anti-Markovnikov hydration reaction that requires only water and olefin in stoichiometric quantities has been reported, so that less atom-efficient synthetic sequences are required for many substrate classes.[1] [2] [3] The most frequently employed synthetic approach to convert terminal olefins into terminal alcohols consists of olefin hydroboration followed by oxidation, which is a reliable tool for many types of olefins.[4–6] Allylic alcohols, however, constitute a problematic substrate class for hydroboration because of the possibility of interactions between the borane reagent and the hydroxyl group.[7–10] In 2019, Wang and co-workers reported a copper-catalyzed O-silylation–hydroboration-oxidation sequence that furnished the desired 1,3-diols in high diastereoselectivity and good yields (Scheme [1]).[9] We speculated that a silane protecting group that contains a Si–H bond could fulfill the roles of both boron and silicon in an analogous indirect hydration reaction and thus improve the atom economy by obviating the need for super-stoichiometric amounts of borane. Previous examples of alcohol-directed hydrosilylation followed by oxidation reported the formation of cis-1,3-diols, trans-1,3-diols, 1,4-diols, and 1,3,5-triols in good to excellent diastereoselectivity.[11] [12] [13] [14] Both platinum and rhodium catalysts have been found to promote directed hydrosilylation, although the loadings of rhodium catalysts commonly exceed 2 mol%.[11] [12] [13] [14] All known directed hydrosilylation methods have been proposed to proceed via an organometallic mechanism in which the rhodium catalyst oxidatively inserts into the O-bound Si–H bond, and then undergoes olefin migratory insertion followed by reductive elimination.

We were inspired to test whether an alternative one-electron mechanism would effectively furnish alcohol-directed hydrosilylation in our earlier work with Rh(II) porphyrin catalysts, where a recyclable Rh(II) catalyst (0.37 mol%) proved sufficient to achieve olefin hydrosilylation.[15] Rh(II) porphyrin complexes contain an unpaired spin that is largely localized in the dz² orbital on the Rh center.[16] The resulting reactivity, which resembles that of an organic radical, leads to Rh(II) porphyrins being sometimes referred to as ‘metalloradicals’.[17] Notably, Sanford and Groves reported stoichiometric anti-Markovnikov hydration with Rh(II) porphyrin complexes in 2004 (Scheme [1]).[18] The authors showed that while each step of their proposed catalytic cycle could be achieved, olefin migratory insertion proved incompatible with the reaction conditions required for subsequent reaction steps. Catalytic transformations involving Rh(II) porphyrins are generally rare, which we attribute to the challenge of re-forming Rh(II) from stable Rh(III)–X intermediates generated during the catalytic cycle.[19] [20] [21] [22] [23] [24] The first of two existing examples of the catalytic conversion of silanes via porphyrin Rh(II) catalysis was disclosed in 2015 by Fu and co-workers, and involves the generation of H₂ from silanes alongside the formation of silanols (Scheme [1]).[20] We have recently found that olefin hydrosilylation can be efficiently catalyzed by Rh(II) porphyrins that are elaborated into the linker of a metal-organic framework (MOF).[15] Site-isolation of Rh(II) porphyrins in a MOF alters the mode in which the Rh(II) center engages with substrates such as silanes and olefins and it eliminates side reactions that obstruct turnover for the homogeneous hydrosilylation catalyst.[25] [26] Considering the low loadings of Rh(II) sufficient for efficient silane conversion and the recyclable nature of the heterogeneous catalyst, we set out to investigate whether an atom-efficient indirect anti-Markovnikov hydration protocol could be developed based on a Rh(II)-catalyzed silyl radical cyclization reaction (Scheme [1]).

The initial challenge in the proposed work rested in the development of an efficient protocol for the installation of a protecting group that contains a Si–H moiety. The limited hydrolytic stability of silyl ethers in which the silicon center is sterically accessible precludes purification of the silylated allylic alcohol via column chromatography on deactivated silica or alumina. We were thus desirous to identify an O-silylation procedure that would furnish a wide range of silylated allylic alcohols in sufficient purity to permit direct use in subsequent cyclization reactions. Ideally, the reaction conditions for O-silylation, intramolecular hydrosilylation, and oxidation could furthermore be chosen so that all transformations required for the formal anti-Markovnikov hydration can be achieved in an efficient three-step-one-pot sequence. We thus identified dihydrosilanes H₂SiR₂ as promising reagents, because dehydrogenative silylation of allylic alcohols would only furnish H₂ alongside the desired hydrosilyl ether. Limited success could be achieved for NaOH catalysis, which has been reported for the dehydrosilylation of alcohols with tertiary silanes.[27] Only an isolated example of selective monofunctionalization of a bulky secondary silane has been reported, and, with one exception [see Supporting Information (SI), Figure S2], attempted dehydrosilylation of allyl alcohols with H₂SiEt₂ gave rise to mixture of mono- and difunctionalized products. Selective monofunctionalization of secondary silanes with alcohols has previously been demonstrated by the Kunai group in the presence of catalytic amounts of either PdCl₂ or NiCl₂.[28] While no reactivity could be observed for attempted dehydrosilylation with allylic alcohols in the presence of NiCl₂, the use of 0.2 mol% PdCl₂ in benzene at room temperature furnished monofunctionalized silanes in up to 85% yield (see SI, Figure S2). For our proposed indirect anti-Markovnikov hydration reaction sequence, however, an iridium-catalyzed protocol reported by Hartwig and co-workers proved more appealing, since it would permit us to carry out dehydrogenative silylation in THF, which is also a suitable solvent for Tamao–Fleming oxidation reactions. A variety of allylic alcohols were thus subjected to H₂SiEt₂ in the presence of [Ir(COD)(OMe)]₂ (0.05–0.5 mol%) at room temperature. Clean conversion to the desired O-silylation product could be observed for all allylic alcohols tested except S11–S14 (see SI, Figure S1). For a number of substrates (6, 8, 10, 13, S8–S10) an increase in the reaction temperature to 60 °C was required to achieve full conversion, but primary, secondary, and tertiary alcohols were efficiently transformed (see SI, Figure S1).

With the required O-silylated allylic alcohols in hand, we tested the performance of homogeneous and heterogeneous Rh(II) catalysts in promoting intramolecular olefin hydrosilylation. Since the active Rh(II) catalyst is air-sensitive, the corresponding air-stable Rh(III)-Me precatalysts 1, 2, or 3 (see Scheme [1]) were employed. We have shown previously that conversion of 1, 2, and 3 to the corresponding Rh(II) porphyrins takes place upon irradiation with a 390 nm LED light source via release of methyl radicals that are trapped by the solvent.[15] A loading of 0.2 mol% of one of 1, 2, or 3 was able to provide complete conversion of [(2,3-dimethylbut-3-en-2-yl)oxy]diethylsilane (4a) to the product of intramolecular hydrosilylation, 2,2-diethyl-4,5,5-trimethyl-1,2-oxasilolane (4b), within 16 hours. In the absence of light, no conversion of 4a was observed, which is consistent with the inability of closed-shell Rh(III) pre-catalysts to promote the generation of silyl radicals, the presumed key intermediate in the intramolecular hydrosilylation reaction. Since we assumed that an O-bound silyl radical is the key reaction intermediate that gives rise to the observed cyclization, we compared the performance of Rh-based catalysts with other reported transition-metal-catalyzed methods for the generation of silyl radicals. However, neither a manganese [Mn₂(CO)₁₀ (1 mol%), 140 °C] nor a copper-catalyzed [CuCl (5 mol%), TBHP (3 equiv), 110 °C] protocol was able to furnish the desired product 4b.[29] [30]

Several additional O-silylated allyl alcohol derivatives underwent cyclization via intramolecular hydrosilylation in the presence of 1 (0.2 mol%). Subsequent treatment of the cyclized intermediates with H₂O₂ in the presence of base furnished the expected 1,3-diol products 5c–9c (Scheme [2]). Notably, however, a number of additional side reactions were observed when the 3-step-1-pot anti-Markovnikov hydration sequence was applied to allylic alcohols 10–13 (Scheme [2]). Olefin hydrogenation (10a, 11a, 13a), double bond isomerization (12b), and ester reduction (13a) constitute unexpected reaction outcomes for a transformation catalyzed by a Rh(II) porphyrin catalyst. We carried out a number of control experiments that confirmed that 1 was unable to promote ester reduction in the presence of either H₂SiEt₂ or diethyl(pentan-3-yloxy)silane (see SI, Figure S8). On the other hand, the olefin-ligated Ir(I) catalyst [(Ir(COE)₂Cl)₂] (COE = cyclooctene) has been reported to promote the controlled reduction of esters to aldehydes via silyl acetal intermediates.[31] Furthermore, productive hydrosilylation catalysis with molecular Rh(II) porphyrin catalyst 1 was unexpected based on our experience with the intermolecular hydrosilylation reaction, where reversible catalyst deactivation led to very sluggish transformations for non-MOF catalysts.[15] Since substrates 4–13 were prepared via iridium-catalyzed dehydrogenative silylation, we suspected that residual iridium present in the intermediates subjected to the intramolecular hydrosilylation reaction gave rise to the unexpected outcomes. All efforts to remove iridium prior to the cyclization reaction proved unsuccessful due to the limited hydrolytic stability of the O-silylated allylic alcohol intermediates (see SI, Figures S6 and S7).

To determine if the presence of iridium residues was not only responsible for the observation of unexpected reaction outcomes, but also promoted the desired intramolecular hydrosilylation reaction, we carried out test reactions in the absence of Rh(II) porphyrin 1. Efficient intramolecular hydrosilylation could be observed when a solution of 4a, 5a, or 6a prepared via iridium-catalyzed dehydrogenative silylation was irradiated with 390 nm light for 16 h. Since no notable decrease in reaction rates was observed in the absence of 1, we concluded that 1 did not constitute an active catalyst and cyclization of 4a proceeded via an iridium-catalyzed process. We thus attribute the results shown in Scheme [2] to an iridium-catalyzed process that was promoted either by light or enabled by local heating due to irradiation of the reaction mixture. Iridium-promoted cyclization does not require the presence of light, however, because intramolecular­ hydrosilylation in the presence of [Ir(COD)OMe]₂ was likewise observed in the dark when the reaction mixture was heated at 60 °C for 16 h.

Since 1 was catalytically inactive and iridium catalysis furnished an unselective transformation, we aimed to understand whether selective intramolecular hydrosilylation could be elicited by structural alterations of the Rh(II) porphyrin. In order to determine the fate of 1 under the reaction conditions of intramolecular hydrosilylation of iridium-containing 4a (Figure [1]A), we observed the reaction mixture by ¹H NMR spectroscopy during irradiation with a 456 nm fibre-coupled LED (Figure [1]B).

Structural assignment of the rhodium-containing intermediates observed over the course of the reaction (Figure [1]C) was carried out by repeating the conversion of 4a to 4b with a catalyst loading of 10 mol% to permit better signal resolution and thus the structural assignment of rhodium-containing intermediates. Conversion of pre-catalyst 1 to rhodium-containing species that participate in the catalytic cycle was largely complete after 4 h (Figure [1]C), and a relatively steady concentration of Rh(III)-H intermediate Rh(III)H-1 could be observed over the course of the reaction. After full conversion of 4a had been achieved, 4 was the dominant Rh-containing species present in the reaction mixture, and a characteristic ¹H NMR signal for porphyrin Rh(III)–H at –37.8 ppm could be observed (see SI, Figure S12).

Additionally, low concentrations of species Rh(III)[Si]-1, which we tentatively attribute to Rh(III) porphyrin carrying an axial silyl ligand (Figure [1]D), was also observed. Silicon-bound ethyl groups were detected with chemical shifts of –3.2 ppm (–Si–CH_a H_b–CH₃), –2.9 ppm (–Si–CH_a H_b –CH₃) and –1.3 ppm (–Si–CH_aH_b–CH₃ ), which are characteristic of the Rh–SiEt₂R moiety, but definite assignment of the R substituent bound to silicon was not possible. The silyl-substituted rhodium species detected suggests that Si–H cleavage of the silane either proceeded by a cooperative action of two Rh(II) porphyrins, or that silyl radical intermediates are trapped by Rh(II) prior to undergoing intramolecular cyclization. Considering the low concentration of Rh(II) porphyrin present in solution under the reaction conditions, we suspect that cooperative Si–H bond cleavage had taken place and the desired silyl radical intermediates had not been formed. We previously showed that the formation of silyl radicals and Rh(III)–H was favored by the incorporation of Rh(II) porphyrins in a MOF matrix where cooperative Si–H bond activation is prevented by geometric frustration.[25] In order to probe whether MOF-based Rh(II) catalysts 2 and 3 are able to promote chemoselective cyclization of O-silylated allylic alcohols, an iridium-free protocol for their preparation was required, however.

Hydrosilyl ether protection groups have the potential to serve as useful traceless direction groups for alcohol functionalization reactions.[32] [33] [34] [35] Since all our attempts to purify allylic alcohols containing a hydrosilyl protecting group met with full or partial decomposition, their application would be substantially aided by a transition-metal-free preparation route which furnishes the protected alcohol in sufficient purity for direct use in follow-up transformations. To this end, we turned to commercially available hydrochlorosilanes HClSiR₂ (R = Me) as reaction precursors, which have previously been used in transition-metal-free alcohol protection reactions.[36] [37] [38] Notably, differentially substituted precursors could readily be accessed from dihydrosilanes via a recently reported direct photo HAT protocol that relies on dichloromethane as a chloride source.[39] We tested the performance of different base promoters [K₂CO_3­, TMDS (1,1,3,3-tetramethyldisilazane), NEt₃, and NMe₃] in the O-silylation reaction of trans,trans-hexa-2,4-dien-1-ol (14) in dichloromethane at room temperature. While NEt₃ furnished promising results, a maximum yield for the O-silylated derivative of 87% could be achieved when different reagent ratios, addition modes, or reaction temperatures were evaluated (see SI, Figures S14 and S15). During a systematic comparison of different solvents, bases, and reaction temperatures, we found that installation of the HSiR₂ protecting group in quantitative yield could reproducibly be achieved in the presence of triethylamine in diethyl ether. To establish the generality of the conditions, we tested a variety of primary, secondary, and tertiary allylic alcohols (Scheme [3]). Full conversion to the desired product could be achieved in all cases and spectroscopic data indicated that the unpurified reaction products were sufficiently pure to warrant their direct use in follow-up transformations. A particular focus was placed on substrates containing multiple double bonds to probe whether alcohol-directed intramolecular hydrosilylation could ensure a chemoselective hydration of only one of the olefins present in the substrate. A number of representative dienes and trienes containing the OSiHMe₂ moiety were therefore selected to compare the performance of molecular and MOF-based Rh(II) porphyrins with known catalysts for intramolecular hydrosilylation (Scheme [4]). B(C₆F₅)₃ has previously been reported to achieve the regio- and stereoselective synthesis of cyclic siloxanes from unsaturated alkoxysilane,[40] but no reaction was observed for O-silylated dienes or trienes 14a–18a. Molecular Rh(II) porphyrin 1 likewise proved inactive in the attempted intramolecular hydrosilylation of O-silylated allylic alcohols that had been prepared via the transition-metal-free route described in Scheme [4]. [Ir(cod)OMe]₂ efficiently promoted intramolecular hydrosilylation of 15a and 16a, but substrates 14a and 18a proved unreactive. For both MOF-supported Rh(II) porphyrins, however, cyclization via intramolecular hydrosilylation was observed for all five substrates subjected to the reactivity comparison. Notably, however, an O-silylated derivative of allylic alcohol 14 prepared via a PdCl₂-catalyzed dehydrosilylation with H₂SiEt₂ failed to undergo intramolecular hydrosilylation with 2. Since intermolecular hydrosilylation catalyzed by 2 proceeds effectively for a variety of alkyl- and aryl-substituted silanes,[15] we suspect that the lack of reactivity was due to the presence of palladium residues in the silylated reaction intermediate. A general O-silylation procedure that does not give rise to transition metal contamination thus appears crucial for the effective use of tertiary silanes as a traceless directing group for subsequent functionalization reactions. Pre-catalysts 2 and 3 are based on the MOF structures PCN-224 and PCN-222, respectively.[41] [42] Both are assembled from identical organic linkers and metal nodes, but differ in their topology, so that 2 contains 1.9 nm cubic cages and 3 contains trigonal pores as well as hexagonal channels with a diameter of 3.7 nm. MOF-based catalysts 2 and 3 showed almost identical performance with conversions for different substrates ranging from 78% to 99%, which suggest that no substantial mass transfer limitations were present for the substrates under investigation.

MOF-based Rh(II) porphyrin catalysts were able to promote intramolecular hydrosilylation of both terminal and internal double bonds, although a mixture of diastereomers was obtained in the cyclization of 17a (Scheme [4]). Interestingly, the choice of MOF topology had a noticeable effect on the diastereomeric outcome, which suggests that the degree of confinement of the radical intermediates influences stereochemical outcomes. In the case of diene 16a, clean conversion to 16b was observed, even though the presumed carbon-centered radical intermediate would have the opportunity to undergo a second cyclization to form a five-membered ring and a stabilized tertiary radical.[43] [44] The hex-5-enyl radical cyclization proceeds with a rate of 1.0 × 10⁵ s^–1 at 25 °C,[45] and dimethyl substitution is computationally predicted to lead to a four-fold increase in the cyclization rate.[46] Since the rate of radical cyclization reactions are not notably influenced by the choice of solvent,[47] HAT between the initially formed carbon-centered radical intermediate and Rh(III)–H must proceed with a rate of >4 × 10⁵ s^–1 to account for the exclusive formation of 16b.

As the most efficient catalyst for the cyclization of O-silylated dienes and trienes, 2 was used for the exploration of directed hydration via a three-step-one-pot sequence (Scheme [5]). To probe the practicality of the developed protocol, we also performed the O-silylation reaction on a 1.5 g scale, which quantitatively furnished O-silylated derivative 16a. When Rh(II)-catalyzed cyclization of 16a was carried out on gram-scale, full conversion was observed after irradiation with a single LED lamp for 20 h. Notably, Wu and co-workers previously demonstrated that photocatalytic transformations that proceed via silyl radical intermediates could successfully be carried out on 100 g scales through the use of a microfluidic setup.[39] [48] [49]

The use of allylic alcohol substrates in the hydroxyl-directed hydration reaction furnished the corresponding terminal alcohols, whereas homoallylic alcohol 17a introduced a hydroxyl group at the non-terminal position of the olefin (Scheme [5]). We attribute the observed reaction outcome for 17c to a preference of the intermediate silyl radical for 5-exo-trig over 6-endo-trig cyclization. Interestingly, the reaction outcomes for 14c, 15c, 16c, and 18c are consistent with 5-endo-trig cyclization, which is a disfavored process according to Baldwin’s rules.[50] [51] The increased length of an O–Si versus an O–C bond has previously been observed to alleviate orbital overlap constraints and permit the cyclization of silicon-centered radicals via a 5-endo-trig process.[52] [53] [54] Interestingly, highly selectively hydration of the terminal double bond was observed for 18c, despite the fact that 18a contains two distinct sites at which intramolecular hydrosilylation could take place via a 5-endo-trig process (Scheme [4]). We attribute the high regioselectivity to silyl radical intermediates frequently displaying a strong preference for attack of the terminal carbon of electron-rich olefin substrates.[15] [43] [49] Formation of 17b highlights, however, that attack of the silyl radical at an internal position in a 5-endo-trig cyclization reaction is preferred over a 6-endo-trig cyclization in which the silyl radical attacks the terminal position of the olefin.

To substantiate the intermediacy of the proposed silicon-centered radical intermediates, we carried out Rh(II)-porphyrin-catalyzed cyclization reactions of 14a in the presence of the persistent radical TEMPO. When intramolecular hydrosilylation catalyzed by 2 (0.37 mol%) was attempted in the presence of either 0.2, 1, or 10 equivalents of TEMPO, a species with the sum formula C₁₇H₃₄N₁O₂Si₁ could be detected by HRMS analysis of the reaction mixture. The mass of the detected intermediate is consistent with the TEMPO adduct of the proposed silicon-centered and the proposed carbon-centered radical intermediate, which are compositionally identical (Scheme [6]A). In an effort to assign the structure of the detected TEMPO adduct, we verified that Rh(II)-catalyzed cyclization of 14a also proceeded efficiently in benzene (see SI, Figure S24), and carried out additional radical trapping studies in benzene-d ₆. HRMS analysis confirmed that 31 and/or 32 were likewise formed during Rh(II)-catalyzed cyclization of 14a in benzene in the presence of different amounts of TEMPO.

No useful NMR data could be obtained when a reaction mixture containing TEMPO (10 equiv) was analyzed, but a decrease in the amount of stable radical permitted the collection of NMR data. We found that the conversion of 14a to 14b was reduced to 40% by the presence of TEMPO (0.2 equiv) (see SI, Figure S24). Upon addition of TEMPO (1 equiv), only a trace of cyclized product 14b was formed, which is consistent with the participation of radical intermediates in the reaction mechanism. While other silicon-containing species could be observed in the reaction mixture, their low concentration and the broadening observed in NMR spectra of TEMPO-containing reaction mixtures did not permit us to determine whether the TEMPO adduct observed by HRMS corresponded to 31, 32, or a mixture of both species. We propose that Rh(II) porphyrin metalloradical Rh(II)-2 and Rh(III)H-2 are interconverted during the catalytic cycle via hydrogen atom transfer with 14a and a carbon-centered radical which is generated upon cyclization of the silicon-centered radical (Scheme [6]B). To confirm that Rh(II)-2 participates in the catalytic cycle, we isolated Rh(II)-2 and tested its ability to promote cyclization of 14a. While the molecular metalloradical Rh(II)-1 rapidly forms the poorly soluble dimer via Rh–Rh bond formation, site isolation within the MOF stabilizes the metalloradical via geometric frustration so that it can readily be isolated and stored. Replacement of the pre-catalyst Rh(III)Me-2 with the presumed active catalyst Rh(II)-2 furnished 14b with undiminished efficiency, which substantiates that Rh(II)-2 participates in the catalytic cycle. We propose that, while Rh(II) centers generated from molecular precatalyst 1 engage in a cooperative Si–H activation process to furnish Rh(III)–H and Rh(III)–silyl (Figure [1]), the MOF-based Rh(II) centers react with O-silylated intermediates to furnish Rh(III)–H and silyl radical intermediates that undergo cyclization (Scheme [6]). The crucial role of the MOF in the proposed mechanism thus lies in ensuring a spatial separation between the Rh(II) centers. Notably, a combination of 1 and PCN-224, a rhodium-free version of MOF catalyst 2, failed to promote the cyclization reaction, which rules out a crucial contribution of the zirconium-based MOF nodes to the transformation. On the other hand, 17% conversion of 16a to 16b could be achieved with a combination of molecular catalyst 1 and ZrO₂ (50 mg; see SI, Figure S26). We attribute the partial conversion observed to the adhesion of 1 to the surface of the ZrO₂ support (see SI, Figure S27), which gives rise to a number of spatially isolated Rh(II) centers that are able to promote the cyclization reaction of 16a.

In summary, we showed an efficient transition-metal-free protocol for the protection of allylic alcohols with silanes featuring a Si–H bond. A subsequent intramolecular hydrosilylation reaction catalyzed by MOF-supported Rh(II) porphyrins takes place via 5-endo-trig or 5-exo-trig cyclization of a silyl radical intermediate. The silane functions as a traceless directing group in a three-step-one-pot olefin hydration sequence, so that the introduction of the hydroxyl substituent takes place in a predictable and selective manner even for substrates containing multiple double bonds. The significance of a transition-metal-free route for the synthesis of the hydrolytically labile O-silylated reaction intermediate is illustrated by the ability of iridium or palladium residues to promote undesired reactions or inhibit follow-up transformations.

Unless otherwise indicated, chemicals and solvents were obtained from commercial suppliers and used as received. Deuterated solvents were obtained from Eurisotop. The 4 Å molecular sieves were activated at 300 °C under dynamic vacuum (5 × 10⁻⁶ mbar) for 1 d prior to use. All liquid alcohols were degassed using the freeze–pump–thaw method, dried over activated 4 Å molecular sieves, and then stored in a glovebox prior to use. Anhydrous and degassed THF was dried by distillation from an appropriate drying agent in the technical laboratories of the Max-Planck-Institut für Kohlenforschung and stored in Schlenk flasks under argon. VWR silica gel (40–63 μm) was used for filtration and separation. Anhydrous argon was purchased from Air Liquide with >99.5% purity. A QExactive instrument from Thermo Fisher Scientific with direct injection to the sprayer was used for ESI-MS measurements. NMR data were recorded on a Bruker AVas 500 MHz (for LED NMR), AVIII HD 300 MHz or Bruker AVNeo 600 MHz NMR spectrometer. ¹H and ¹³C chemical shifts are referenced to the deuterated solvent as internal standard. Attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR) (diamond crystal) was measured by using an Agilent Cary 630 FTIR. Spectra were recorded between 4000 and 650 cm^–1 (4 cm^–1 resolution, 128 scans per spectrum) at rt. All reactions with purple light were carried out by using an LED Kessil® PR160L-390 nm as a light source. The vials were cooled by in-house compressed air flow to ensure that the temperature of the reaction mixture was not noticeably elevated above rt. A fiber-coupled ultra-high-power LED from Prizmatix Ltd. (Israel) was used as light source (LED head: UHP-T-450 SR, peak wavelength λ = 450 nm). The length of the fiber cable was approximately 6 m. Argon was used as the glovebox atmosphere with O₂ <0.1 ppm and H₂O <0.1 ppm. Rh(II) porphyrins 1–3 were synthesized according to reported procedures.[15]

1,3-Diols 5c–9c; General Procedure

In an argon-filled glovebox, one of alcohols 4–9 (1.0 mmol) was placed in an 8 mL screw-capped glass vial containing a stir bar. THF (2 mL) was added, followed by a freshly prepared solution of [Ir(cod)OMe]₂ (0.5–5.0 μmol, 0.05–0.5 mol%) in THF (0.50 mL) and Et₂SiH₂ (1.20 mmol, 1.20 equiv). The vial was capped with a Teflon-lined screw cap, and the resulting solution was stirred in the glovebox at rt or 60 °C until complete conversion to the corresponding diethyl(hydrido)silyl ether was observed, as determined by TLC or ¹H NMR analysis. The reaction mixture was concentrated, and 1 (2.0 μmol, 0.2 mol%) and anhydrous THF (4 mL) were added to the same vial. The reaction mixture was stirred at 500 rpm at rt and irradiated with a 390 nm purple LED for 16 h while the reaction mixture was cooled by in-house compressed air flow. Finally, KF (2.0 mmol, 2.0 equiv), KHCO₃ (2.0 mmol, 2.0 equiv), and 30% aq H₂O₂ (12.0 mmol, 12.0 equiv) were added to the same vial, along with sufficient amounts of MeOH to achieve a THF/MeOH (1:1) mixture, before the reaction mixture was stirred at 60 °C for 5 h. Subsequently, the reaction mixture was left to cool to rt and all volatiles were removed under reduced pressure. The residue obtained was dissolved in CH₂Cl₂ (3–4 mL), and the resulting solution was transferred to a separatory funnel followed by the addition of brine. The combined extract from three extractions with CH₂Cl₂ was dried over Na₂SO₄ and concentrated. The residue was purified by preparatory TLC (MeOH/CH₂Cl₂) to afford the title compounds. Compounds 10a, 11a,b, 12a,b, and 13a were also obtained by following the general procedure outlined for the synthesis of 1,3-diols 5c–9c.

2-(Hydroxymethyl)cyclododecan-1-ol (5c)

Yellow solid; yield: 46%; mp 71±0.5 °C.

FTIR (ATR): 3298, 3209, 2934, 2903, 2863, 2849, 1467, 1439, 1019, 725 cm^–1.

¹H NMR (600 MHz, CD₂Cl₂): δ = 3.84 (ddd, J = 8.8, 5.1, 4.1 Hz, 1 H), 3.75 (dd, J = 11.0, 3.2 Hz, 1 H), 3.62 (dd, J = 10.4, 2.8 Hz, 1 H), 2.75 (s, 1 H), 2.28 (s, 1 H), 1.78–1.71 (m, 1 H), 1.71–1.58 (m, 2 H), 1.53–1.45 (m, 1 H), 1.46–1.22 (m, 15 H), 1.18–1.06 (m, 1 H), 0.99–0.85 (m, 1 H).

¹³C NMR (151 MHz, CD₂Cl₂): δ = 74.87, 66.43, 40.78, 32.33, 25.34, 25.08, 24.83, 24.21, 23.57, 23.53, 23.43, 23.13, 20.00.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₃H₂₆O₂: 237.182499; found: 237.182520; deviation: –0.09 ppm.

1-(p-Tolyl)propane-1,3-diol (6c)

Brown liquid; yield: 38%.

FTIR (ATR): 3322, 2921, 2879, 1515, 1412, 1047, 1020, 814 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 7.29–7.24 (m, 2 H, 5), 7.20–7.14 (m, 2 H, 6), 4.94 (dd, J = 8.9, 3.7 Hz, 1 H, 3), 3.90–3.82 (m, 2 H, 1), 2.35 (s, 3 H, 8), 2.21 (bs, 2 H), 2.03 (dddd, J = 14.2, 8.9, 6.8, 5.3 Hz, 1 H, 2′), 1.96–1.89 (m, 1 H, 2′′).

¹³C NMR (151 MHz, CDCl₃): δ = 141.5, 137.5, 129.4, 125.7, 74.5, 61.7, 40.6, 21.2.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₀H₁₄O₂: 189.08860; found: 189.08886; deviation: –1.38 ppm.

1-(2-Hydroxyethyl)cyclooctan-1-ol (7c)

Brown solid; yield: 72%; mp 48±0.5 °C.

FTIR (ATR): 3331, 3260, 2919, 2849, 1737, 1144, 1024, 870 cm^–1.

¹H NMR (600 MHz, CD₂Cl₂): δ = 3.87–3.73 (m, 2 H), 2.62 (s, 1 H), 2.33–2.08 (m, 1 H), 1.82 (dddd, J = 14.1, 9.9, 1.9, 0.6 Hz, 2 H), 1.73–1.68 (m, 2 H), 1.68–1.53 (m, 8 H), 1.51–1.44 (m, 3 H), 1.44–1.37 (m, 2 H).

¹³C NMR (151 MHz, CD₂Cl₂): δ = 76.50, 60.00, 41.65, 36.67, 28.56, 25.41, 22.54.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₀H₂₀O₂: 195.13555; found: 195.13554; deviation: 0.05 ppm.

1-(4-Methoxyphenyl)propane-1,3-diol (8c)

Yellow liquid; yield: 63%.

FTIR (ATR): 3327, 2940, 2841, 1610, 1510, 1242, 1174, 1030, 828 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.35–7.27 (m, 2 H), 6.93–6.85 (m, 2 H), 4.93 (dd, J = 8.8, 3.8 Hz, 1 H), 3.86 (dd, J = 6.4, 4.6 Hz, 2 H), 3.81 (s, 3 H), 2.11–1.99 (m, 1 H), 1.97–1.85 (m, 1 H).

¹³C NMR (75 MHz, CDCl₃): δ = 159.21, 136.64, 127.05, 114.03, 74.14, 61.63, 55.44, 40.58.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₀H₁₄O₃: 205.083514; found: 205.083560; deviation: –0.22 ppm.

1-(2-Hydroxyethyl)-5-methyl-2-(prop-1-en-2-yl)cyclohexan-1-ol (9c)

Reaction mixture was irradiated with 390 nm purple LED for 3 d.

Yellow liquid; yield: 61%.

FTIR (ATR): 3388, 2926, 2869, 1735, 1720, 1459, 1035, 752 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 4.89 (dtt, J = 2.5, 1.8, 1.1 Hz, 1 H), 4.76 (dq, J = 2.2, 0.7 Hz, 1 H), 3.99 (dddd, J = 11.0, 10.1, 3.8, 0.8 Hz, 1 H), 3.75 (ddd, J = 11.0, 5.4, 4.2 Hz, 1 H), 2.02–1.94 (m, 4 H), 1.88 (dd, J = 12.8, 3.3 Hz, 2 H), 1.82 (dt, J = 1.5, 0.7 Hz, 3 H), 1.48–1.44 (m, 2 H), 1.41 (dtd, J = 14.6, 4.1, 0.7 Hz, 2 H), 0.92–0.90 (m, 5 H).

¹³C NMR (151 MHz, CD₂Cl₂): δ = 74.47, 69.53, 57.67, 51.63, 50.20, 40.66, 35.75, 30.82, 27.95, 23.59, 22.34, 19.94.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₂H₂₂O₂: 221.15120; found: 221.15127; deviation: –0.32 ppm.

Diols 14c–18c; General Procedure

In an argon-filled glovebox, one of alcohols 14–18 (0.5 mmol, 1.0 equiv) was placed in an 8 mL screw-capped glass vial containing a stir bar. A freshly prepared solution of Et₃N (1.0 mmol, 2.0 equiv) in Et₂O was added to the reaction vial at 0 °C under inert atmosphere, followed by the addition of a solution of HClSiMe₂ (0.75 mmol, 1.5 equiv) in Et₂O. The resulting solution was stirred at rt inside a glovebox. After overnight stirring, the white solid that had formed (Et₃N·HCl) was removed by filtration over filter paper that had been dried in an oven at 120 °C for 2 d. The resulting solution was concentrated and an aliquot of it was subjected to ¹H NMR analysis (C₆D₆) to confirm complete consumption of the starting material. To the same vial, 2 (1.85 μmol, 0.37 mol%), air (1 mL; see Note below), and anhydrous THF (4 mL) was added. The reaction mixture was stirred at 500 rpm at rt and irradiated with a 390 nm purple LED for 16 h (a reaction time of 20 h was used for 5 mmol scale) while it was cooled by in-house compressed air flow. Finally, KF (2.0 mmol, 2.0 equiv), KHCO₃ (2.0 mmol, 2.0 equiv), and 30% aq H₂O₂ (12.0 mmol, 12.0 equiv) were added to the same vial, along with sufficient amounts of MeOH to achieve a THF/MeOH (1:1) mixture, before the reaction mixture was stirred at 60 °C for 5 h. Subsequently, the reaction mixture was left to cool to rt and all volatiles were removed under reduced pressure. The residue obtained was dissolved in CH₂Cl₂ (3–4 mL), and the resulting solution was transferred to a separatory funnel followed by the addition of brine. The combined extract from three extractions with CH₂Cl₂ was dried over Na₂SO₄ and concentrated. The residue was purified by preparatory TLC (MeOH/CH₂Cl₂) to afford the title compounds.

Note: For small-scale reaction (≤25 mg), intramolecular hydrosilylation catalyzed by 2 or 3 proceeded efficiently under an inert atmosphere. However, for allylic alcohol scales of ~100 mg, the introduction of limited amounts of oxygen are essential for the reaction to proceed efficiently. We assume that the small amount of residual oxygen that remains present after the reaction mixture was purged with argon was sufficient for small-scale reactions, but deliberate addition of small amounts of air was necessary for larger reaction scales. To address this, air (1 mL) was introduced into the reaction vessel via a syringe after the addition of catalyst 2. We had observed a similar oxygen effect for Rh(II)-porphyrin-catalyzed intermolecular hydrosilylation and elucidated the mechanistic role of oxygen in the transformation.[25] For intramolecular hydrosilylation on a larger scale (1.06 g), the addition of air (20 mL) was necessary to ensure efficient cyclization.

Hex-4-ene-1,3-diol (14c)

Transparent oil; yield: 35%.

FTIR (ATR): 3331, 2939, 2921, 2882, 1674, 1438, 1055, 963, 921 cm^–1.

¹H NMR (600 MHz, C₆D₆): δ = 5.51–5.44 (m, 1 H), 5.36 (ddt, J = 15.3, 6.4, 1.5 Hz, 1 H), 4.11–4.06 (m, 1 H), 3.62 (dddd, J = 10.5, 6.1, 4.7, 1.1 Hz, 1 H), 3.56–3.51 (m, 1 H), 1.62–1.55 (m, 1 H), 1.50 (ddd, J = 6.3, 1.9, 1.1 Hz, 3 H), 1.49–1.45 (m, 1 H).

¹³C NMR (151 MHz, C₆D₆): δ = 134.79, 125.46, 72.49, 61.15, 39.24, 17.65.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₆H₁₂O₂: 139.07295; found: 139.07298; deviation: –0.22 ppm.

3,7,11-Trimethyldodeca-6,10-diene-1,3-diol (15c)

Note that the starting material used in the reaction consisted of the commercially available E/Z mixture.

Transparent oil; yield: 56%; E/Z 1.5:1.

FTIR (ATR): 3364, 2968, 2929, 1719, 1448, 1376, 1109, 1059, 1032 cm^–1.

¹H NMR (600 MHz, C₆D₆): δ (E-isomer) = 5.24 (m, 1 H), 5.24 (m, 1 H), 3.64 (m, 2 H), 2.18 (q, 2 H), 2.09 (t, 2 H), 2.07, (m, 2 H), 1.70 (q, 3 H), 1.61 (m, 3 H), 1.57 (m, 3 H), 1.56 (m, 1 H), 1.48 (m, 1 H), 1.42 (m, 1 H), 1.35 (m, 1 H), 1.05 (s, 3 H).

¹³C NMR (151 MHz, C₆D₆): δ (E-isomer) = 135.14, 131.33, 125.16, 124.89, 73.24, 59.83, 42.90, 42.08, 40.21, 27.17, 26.75, 25.89, 23.00, 17.78, 16.06.

¹H NMR (600 MHz, C₆D₆): δ (Z-isomer) = 5.24 (m, 1 H), 5.21 (m, 1 H), 3.64 (m, 2 H), 1.58 (m, 1 H), 1.38 (m, 1 H), 1.49 (m, 1 H), 1.43 (m, 1 H), 2.09, (m, 2 H), 2.14 (m, 2 H), 2.15 (m, 2 H), 1.68 (m, 3 H), 1.58 (m, 3 H), 1.06 (s, 3 H), 1.72 (q, 3 H).

¹³C NMR (151 MHz, C₆D₆): δ (Z-isomer) = 135.15, 131.51, 126.00, 124.86, 73.17, 59.83, 43.28, 42.06, 32.31, 27.06, 26.75, 25.91, 23.63, 22.90, 17.73.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₅H₂₈O₂: 263.19815; found: 263.19834; deviation: –0.72 ppm.

3,7-Dimethyloct-6-ene-1,3-diol (16c)

Since incomplete conversion was observed when the Tamao–Fleming oxidation was carried out according to the standard procedure, another protocol was employed instead, which furnished complete conversion.[55]

A solution of KH (0.9 g, 6.8 mmol, 13.6 equiv) in DMF was prepared in a round-bottom flask, and 5–6 M t-BuOOH in decane (1.50 mL, 9.0 mmol, 18.0 equiv) was added, followed by a reaction mixture of 16b in DMF. After 10 min, CsF (0.5 g, 3.0 mmol, 6.0 equiv) was added and the reaction mixture was heated to 70 °C. After 17 h, the reaction mixture was cooled to rt and Et₂O (20 mL) and sat. aq LiCl (50 mL) were added. The layers were separated and the aqueous layer was extracted with Et₂O (3 × 20 mL). The combined organic layers were dried with Na₂SO₄ and concentrated in vacuo. The compound was isolated by using column chromatography (silica gel, MeOH/CH₂Cl₂ 2:98).

Transparent oil; yield: 74%.

FTIR (ATR): 3343, 2971, 2924, 1711, 1671, 1438, 1374, 1118, 1062, 1028 cm^–1.

¹H NMR (600 MHiiz, C₆D₆): δ = 5.18 (tdq, J = 7.2, 2.9, 1.4 Hz, 1 H), 3.70–3.62 (m, 2 H), 2.11–1.98 (m, 2 H), 1.67 (q, J = 1.3 Hz, 3 H), 1.57 (br s, 3 H), 1.60–1.36 (m, 4 H), 1.07 (s, 3 H).

¹³C NMR (151 MHz, C₆D₆): δ = 131.26, 125.23, 73.30, 59.81, 42.92, 41.95, 26.67, 25.85, 23.09, 17.68.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₀H₂₀O₂: 195.135549; found: 195.135660; deviation: –0.57 ppm.

6,10-Dimethylundeca-5,9-diene-2,4-diol (17c)

Transparent oil; yield: 53%.

FTIR (ATR): 3352, 2967, 2930, 2861, 1735, 1668, 1447, 1375, 1297, 1129, 1066, 829 cm^–1.

¹H NMR (600 MHz, C₆D₆): δ (syn-diastereomer) = 5.19 (dd, 1 H), 5.12 (dtq, 1 H), 4.53 (ddd, 1 H), 3.94 (dqd, 1 H), 2.05 (m, 4 H), 1.65 (3 H), 1.63 (d, 3 H), 1.59 (d, 3 H), 1.51 (d, 3 H), 1.37 (ddd, 2 H), 1.11 (d, 3 H).

¹³C NMR (151 MHz, C₆D₆): δ (syn-diastereomer) = 137.37, 132.20, 129.87, 124.54, 69.32, 68.30, 46.02, 32.56, 26.88, 25.78, 24.36, 23.30, 17.67.

¹H NMR (600 MHz, C₆D₆): δ (anti-diastereomer) = 5.34 (dq, 1 H), 5.14 (ddd, 1 H), 4.68 (ddd, 1 H), 4.08 (ddtd, 1 H), 2.05 (m, 4 H), 1.65 (d, 3 H), 1.61 (m, 3 H), 1.58 (m, 2 H), 1.53 (m 3 H), 1.11 (d, 3 H).

¹³C NMR (151 MHz, C₆D₆): δ (anti-diastereomer) = 137.22, 132.15, 129.72, 124.53, 66.04, 65.18, 45.62, 32.53, 26.90, 25.81, 23.91, 23.38, 17.69.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₃H₂₄O₂: 235.166849; found: 235.166710; deviation: 0.59 ppm.

(E)-3-Methyl-5-(2,6,6-trimethylcyclohex-1-en-1-yl)pent-4-ene-1,3-diol (18c)

Transparent oil; yield: 55%.

FTIR (ATR): 3348, 2962, 2928, 1932, 1653, 1454, 1370, 1360, 1092, 1051, 974 cm^–1.

¹H NMR (600 MHz, C₆D₆): δ = 6.27 (dtq, J = 16.0, 2.0, 1.0 Hz, 1 H), 5.38 (d, J = 16.0 Hz, 1 H), 3.73 (ddd, J = 10.8, 9.1, 3.6 Hz, 1 H), 3.56 (ddd, J = 10.8, 5.6, 4.2 Hz, 1 H), 1.95 (tdd, J = 6.3, 2.0, 1.0 Hz, 2 H), 1.72 (q, J = 1.0 Hz, 3 H), 1.68 (ddd, J = 14.4, 9.0, 4.2 Hz, 1 H), 1.63–1.57 (m, 2 H), 1.49–1.47 (m, 2 H), 1.44 (ddd, J = 14.4, 5.6, 3.6 Hz, 1 H), 1.20 (s, 3 H), 1.10 (s, 3 H), 1.09 (s, 3 H).

¹³C NMR (151 MHz, C₆D₆): δ = 140.69, 137.70, 127.79, 125.52, 74.21, 60.48, 43.04, 39.78, 34.33, 32.98, 29.67, 29.06, 28.98, 21.68, 19.82.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₅H₂₆O₂: 261.182499; found: 261.182340; deviation: 0.61 ppm.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

The authors would like to thank Dr. Markus Leutzsch for providing LED NMR data and Markus Kochius and Dr. Markus Leutzsch for carrying out structural assignments and analyses of reaction mixtures. We also thank Dr. Maurice van Gastel for carrying out a UV-VIS measurement of 1 as well as the members of the mass spectrometry and chromatography departments at the Max-Planck-Institut für Kohlenforschung. Open Access Funding was provided by Project Deal.

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Corresponding Author

Publication History

Received: 14 March 2025

Accepted after revision: 29 April 2025

Accepted Manuscript online:
05 May 2025

Article published online:
02 June 2025

© 2025. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

Georg Thieme Verlag KG
Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

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