Concept of Ir-catalyzed CH bond activation/borylation by noncovalent interaction

Noncovalent interactions play a fundamental role in molecular biology, crystal engineering, supramolecular chemistry, drug design, sensing applications, and many other research fields in the chemical sciences. Because of this importance, thorough research efforts have been focused on the interpreting and quantifying these interactions, which include H-bonding, electrostatic effects, ππ interaction, cation-π interaction, hydrophobic-hydrophobic interaction, van der Waals forces, and other such type of interactions. However, on the synthetic standpoint, use of these noncovalent interactions are rare, although might be beneficial for the site-selective CH bond activation and functionalization by transition metal catalysis. In this context, iridium-catalyzed CH borylation has gained immense popularity due to the versatility conferred to the CB bonds. Very recently, researchers have started employing these interactions as a governing factor for attaining regioselectivity in arene CH borylation. In this perspective, we will focus on the advancements made so far by the use of various noncovalent interactions in Ir-catalyzed borylations.     

Infrared spectra of B(OMe)3, ClB(OMe)2 and Cl2BOMe species,isolated CH stretching frequencies and bond strengths

Infrared spectra in the gas phase are reported over the range 3100-500 cm⁻¹ for species of B(OMe)₃, ClB(OMe)₂ and Cl₂BOMe, with CH₃, CD₃ and CHD₂ substitution. A detailed analysis of νCH and νCD data in all three species of Cl₂BOMe yields strong evidence for the presence of three kinds of CH bond, two of them weak and one of them strong. The methyl group is then twisted, probably through 10–20°, out of the eclipsed or staggered conformation. The CHD₂ spectra of the di and trimethoxy compounds are less susceptible to analysis, but suggest also the presence of two weak and strong bonds, the former increasing in weakness as the number of methoxy groups increases. This is as expected from the increased competition likely between the lone pair electrons for the empty boron orbital. The spectra of the CD₃ species permit a clear assignment of νBO, δ_sCH₃, δ_sCD₃ and δ_asCD₃ modes. In Cl(COCH₃)₂, ν_sBO lies at 1278 cm⁻¹.     

Radical generation enabled by photoinduced N–O bond fragmentation

Recent advances in synthetic chemistry have seen a resurgence in the development of methods for visible light-mediated radical generation. Herein, we report the development of a photoactive ester based on a quinoline N-oxide core structure, that provides a strong oxidant in its excited state. The heteroaromatic N-oxide provides access to primary, secondary, and tertiary radical intermediates, and its application toward the development of a photochemical Minisci alkylation is reported.

Recent advances in synthetic chemistry have seen a resurgence in the development of methods for visible light-mediated radical generation.

Photoinduced radical generation has become a focal point of contemporary chemical research. Historically, the photochemical formation of radicals has been achieved via the direct irradiation of organic chromophores with high energy UV light, with notable examples including Norrish – type 1 reactions and the photochemical decomposition of azo compounds, peroxides, N-(acyloxy)-pyridones, and xanthates.¹ While a powerful tool, the propensity of organic functional groups to absorb UV light leads to undesired excitation events that ultimately result in uncontrolled, deleterious reactivity.² The use of visible light irradiation to drive reactivity offers a solution to the problems presented by UV light photochemistry, as typical organic functionalities do not absorb in the visible region of the electromagnetic spectrum. In this regard, photoredox catalysis has emerged as a powerful tool for the generation of radical intermediates, as the visible light absorbing catalysts can access high energy excited states that engage organic substrates in redox events.³ While incredibly versatile, the manipulation of substrate oxidation states can limit the scope of reactivity, as functionalities that are predisposed to oxidation (or reduction) may undergo undesired side reactions. To circumvent this limitation, redox auxiliaries are employed to alter the redox properties of the substrate and facilitate reactivity under mild reducing (or oxidizing) conditions.⁴Radical formation via photoinduced dissociation of an auxiliary, or complex, represents a complementary strategy that, in principle, should be tolerant of redox sensitive functionalities. However, despite the ubiquity of this strategy in UV light mediated reaction manifolds, the development of reagents that undergo efficient photodissociation upon visible light irradiation is limited. In 2017, Melchiorre and coworkers reported the dissociation of 4-alkyl-1,4-dihydropyridines (alkyl-DHPs) upon irradiation with 405 nm light (Fig. 1A).⁵ Study of the photoactive alkyl-DHPs revealed that they are reductants in their excited state (D⁺˙/D* = −2.0 V vs. SCE) and, as such, both the dissociative and redox properties of the excited state could be exploited for ipso-substitution of aryl nitriles and nickel catalyzed C(sp²)–C(sp³) cross-coupling reactions.Open in a separate windowFig. 1Overview of photochemical radical generation in synthetic chemistry.In 2020, Ohmiya and colleagues reported that boracene, when reacted with organolithium or Grignard reagents, forms a photoactive alkyl borate salt that liberates an equivalent of an alkyl radical upon irradiation with 440 nm light (Fig. 1B).⁶ Characterization of the boracene-based alkyl borate revealed a strongly reducing excited state (B⁺˙/B* = −2.2 V vs. SCE), and this auxiliary was demonstrated to be effective for nickel catalyzed C(sp²)–C(sp³) cross-coupling reactions with tertiary alkyl radicals.Pioneering work by Barton and coworkers in the 1980''s demonstrated that the thermal or photochemical decomposition of N-(acyloxy)-2-thiopyridones (commonly referred to as Barton esters) could efficiently generate carbon centered radicals, ultimately delivering the corresponding alkane or thioether products.⁷ However, state-of-the-art methods employing pyridine N-oxide or its derivatives as radical precursors have demonstrated limited intermolecular reactivity, as the generated radical intermediates are competitively trapped by the pyridine-based auxiliary.^8,9 To overcome these limitations, we sought to design a pyridine N-oxide based auxiliary that does not undergo undesired alkylation reactions. Inspired by Barton''s work and informed by our previous studies,^8,9 we envisioned that the fast fragmentation of N–O bonds in pyridine N-oxide derivatives could be leveraged in the design of a photocleavable activator that would deliver carbon centered radicals from readily available carboxylic acids as precursors. Importantly, the development of a photoactive ester derived from simple pyridine N-oxide core structure delivers a species that is a strong oxidant in its excited state, complementing the reductive excited states of the previously developed photoactive auxiliaries. Moreover, by using a core structure that is derived from an abundant heteroaromatic building block, the designed photoactive esters will contain highly tunable core structures, allowing for control over the photoexcitation and fragmentation events. Herein, we report the development of a photoactive ester derived from a quinoline N-oxide core structure and its application to achieve an efficient intermolecular Minisci alkylation (Fig. 1C).At the outset of our study, we established several requirements to be satisfied by potential photoactive esters (Fig. 2B): (1) the pyridine N-oxide core structure needed to be preserved, (2) the heteroaromatic core would need to have blocking substituents at the sites of alkylation to slow deleterious functionalization of the ester (i.e. 2-, 4-, and 6-substituted pyridine N-oxide derivatives), (3) the heteroaromatic N-oxide would need to maintain sufficient nucleophilicity to form the activated N-acyloxy pyridinium, (4) the heteroaromatic backbone would need to deliver a sterically accessible N-oxide functionality. Additionally, it was recognized that pyridine N-oxide derivatives bearing alkyl substituents with benzylic C–H bonds were not suitable photoactive esters, as a deleterious Boekelheide reaction occurred upon acylation of the N-oxide functionality. Ultimately, 2,4,6-triphenyl pyridine N-oxide (TPPNO), methyl 2-phenylquinoline-4-carboxylate N-oxide (PQCNO), and methyl acridine-9-carboxylate N-oxide (ACNO) were identified as potential photoactive ester precursors that met all aforementioned requirements.Open in a separate windowFig. 2(A) Comparison of pyridinium esters. (B) Overview of photoactive ester design principles. (C) Photophysical characterization of Ac-TPPNO, Ac-PQCNO, and Ac-ACNO.Initial investigations focused on the photophysical characterization of the three heteroaromatic N-oxides (Fig. 2C). Uv-vis spectroscopy in acetonitrile revealed TPPNO to have two maximum absorbances at 319 nm and 365 nm, with the latter absorbance tailing off beyond 400 nm. PQCNO and ACNO also displayed a strong absorbance feature at 365 nm, however, for ACNO two additional lower energy absorbance features at 418 nm and 444 nm were observed. Addition of acetyl chloride to TPPNO and PQCNO resulted in an increase of intensity for the absorbance features, with no apparent shift in the absorbance maxima. Acylation of the ACNO auxiliary with acetyl chloride caused the maximum at 274 nm to diverge into two distinct sharp absorbance features with maxima at 264 nm and 275 nm. Additionally, the absorbance feature at 364 nm both increased in intensity and became more structured upon acylation, revealing an apparent shoulder at 352 nm. Measurement of the fluorescence spectra for the heteroaromatic N-oxides (irradiated at 361 nm) revealed that Ac-TPPNO, Ac-PQCNO, and Ac-ACNO have emission maxima at 435 nm, 468 nm and 519 nm, respectively (Fig. 3A). In the absence of an acyl equivalent, no emission was observed for the heteroaromatic N-oxides. This finding is consistent with previous reports that pyridine N-oxides and quinoline N-oxides possess non-emissive excited states under basic conditions due to a propensity to undergo a fast rearrangement on the singlet surface.¹⁰Open in a separate windowFig. 3(A) Absorbance and emission spectra for Ac-TPPNO, Ac-PQCNO, and Ac-ACNO. Emission recorded upon irradiation at 361 nm. (B) Fluorescence spectra of Ac-PQCNO monitored over 25 successive scans (excitation 335 nm). (C) Decomposition of Ac-PQCNO upon irradiation by a 427 nm Kessil lamp, monitored by Uv-vis. (D) Proposed mechanism for photochemical decomposition of Ac-PQCNO.Investigation of the photoinduced N–O bond cleavage of Ac-PQCNO revealed that upon successive fluorescence scans (excitation at 335 nm), Ac-PQCNO is observed to decompose steadily with the concomitant appearance of the fluorescence signal corresponding to the generation of deoxygenated quinoline (Fig. 3B). Interrogation of the decomposition by Uv-vis spectroscopy revealed that after 60 s of irradiation of Ac-PQCNO with a 427 nm Kessil lamp, a decrease in the absorbance feature at 365 nm was observed. Upon extending irradiation time out to 30 min, significant degradation of the Ac-PQCNO was observed.Together, the photophysical characterization shows the photoactive esters possess conserved absorption features at 365 nm. Consistent with previous studies on quinoline N-oxide photochemistry, the absorption feature at 365 nm is thought to be π,π* in character and responsible for the observed deoxygenation reactivity.¹¹ The deoxygenation of the aromatic N-oxides is hypothesized to arise from crossing over of the π,π* excited state to a dissociative π,σ* state. Computational evidence in support of the hypothesized mechanism can be found in Fukuda and Ehara''s study on the deoxygenation of structurally related N-hydroxypyridine-2(1H)-thione.¹² Experimental support for this proposed mechanism can be found in Hata and Tanaka''s study of the gas phase photolysis of pyridine N-oxide¹³ as well as Hata''s subsequent translation of this work to the solution phase photodeoxygenation of heteroaromatic N-oxides in the presence of a strong Lewis acid, BF₃·Et₂O.¹⁴Interrogation of the thermal reactivity of Ac-PQCNO revealed there was no deoxygenation of the heteroaromatic N-oxide after heating to 90 °C for 3 hours. This demonstrates that the remarkable reactivity of Ac-PQCNO is due to dissociation of the N–O bond from a low energy photoexcited state.Electrochemical analysis of the heteroaromatic N-oxide photoactive esters using cyclic voltammetry in acetonitrile revealed the Ac-TPPNO, Ac-PQCNO, and Ac-ACNO to have low energy reduction waves, with measured E_1/2 of −0.79 V vs. SCE, − 0.45 V vs. SCE, and −0.47 V vs. SCE. Applying information gathered from absorbance and emission spectroscopy, as well as the electrochemical data, the standard potential for oxidation of Ac-TPPNO, Ac-PQCNO and Ac-ACNO in the excited state was estimated to be +2.30 V [E⁰(T⁺*/T˙)], +2.57 V [E⁰(P⁺*/P˙)], and +2.32 V [E⁰(A⁺*/A˙)] vs. SCE according to the Rehm–Weller approximation (Fig. 2C).¹⁵Due to the mild photolytic conditions for decarboxylative radical generation from N-oxides and characteristics as excited state oxidants, we sought to assess the reactivity of the photocleavable esters towards the development of an intermolecular Minisci alkylation (Fig. 4). Initial studies focused on the addition of the tert-butyl radical to 4-chloroquinoline in acetonitrile. Assessment of reactivity revealed TPPNO and PQCNO to perform identically under unoptimized conditions delivering 27% of the desired 2-tert-butyl-4-chloroquinoline product, while ACNO produced less than 5% of the desired product. Due to the low cost of the parent quinoline and its high yielding N-oxidation,¹⁶ we elected to focus our investigations on the application of PQCNO as a photoactive ester. Degassing the reaction resulted in a substantial increase in yield, providing 90% isolated yield of the desired product. Further investigation of solvents and additives did not result in increased reactivity.Open in a separate windowFig. 4Scope of intermolecular Minisci alkylation. Isolated yields unless otherwise noted. Standard conditions: substrate (0.2 mmol, 1 equiv.), PQCNO (2 equiv.), acyl chloride (2.2 equiv.), CaCl₂ (1 equiv.), MeCN (0.5 mL), N₂ atmosphere, 427 nm Kessil lamp, 30 min. ^aReaction run for 1 hour. ^bReaction run for 2 hours. ^cReaction run for 1 hour with a 1 : 1 mixture of MeCN to DCM as solvent. NMR yield with methyl tert-butyl ether as internal standard, in brackets.Assessment of the scope for the intermolecular Minisci alkylation revealed the tert-butyl radical addition was the most efficient of the simple alkyl fragments (90%, 4a), followed by isopropyl addition (50%, 4b), ethyl addition (48%, 4c), and finally methyl addition (43%, 4d) (Fig. 4). Simple carbocyclic radical fragments such as cyclohexyl (4e), cyclobutyl (4f), and cyclopropyl (4g) provided the corresponding alkylation products in 88%, 57%, and 34% yield, respectively. Interestingly, Minisci alkylation products from more complex carbocyclic radical fragments were also accessible under-developed reaction conditions as 1-phenylcyclopropyl (4h), adamantyl (4i), 4-(methoxycarbonyl)-[2.2.2]-bicycloctyl (4j), and 3-(methoxycarbonyl)-[1.1.1]-bicyclopentyl (4k) fragments gave the corresponding radical addition products in 37–80% yield. Application of tetrahydropyran-4-carbonyl chloride (4l), N-Boc azetidine 3-carbonyl chloride (4m), N-Boc piperidine 4-carbonyl chloride (4n), and N-Boc piperidine 3-carbonyl chloride (4o) provided the desired coupling products in 41–61% yield, respectively.Assessment of the heterocyclic coupling partners revealed that substituted pyridine and quinoline derivatives performed well in the Minisci alkylation, however, over-alkylation of the heteroarene was often observed (4p–4t). Notably, 4-cyanopyridine (4p) and lepidine (4s) performed well under the developed intermolecular reaction conditions; these substrates were either low yielding or inaccessible under our previously reported fragment coupling conditions.⁸ Modestly complex heteroaromatic scaffolds such as quinoxaline (4u), and 3-chloro-6-phenylpyridazine (4v) also performed well under the tert-butylation reaciton conditions. Biologically active scaffolds such as the 4-chloroquinazoline core of erlotinib (4w) and the imidazopyrazine core structure of gandotinib (4x) each provided a single regioisomer of the tert-butyl addition product in high yield. Finally, nicotine (4y) was observed to undergo tert-butyl addition in 37% yield with retention of the configuration at the benzylic stereocenter.During the exploration of the Minisci alkylation reaction, it was realized that the deoxygenated quinoline could be recovered in high yields (87% recovery). Resubjecting the recovered quinoline to oxidation conditions, PQCNO could be re-generated in 71% yield. Regenerated PQCNO was observed to show no decrease in reactivity when recycled through three consecutive reactions (see ESI^†).To probe the mechanism of the photoinduced Minisci alkylation reaction, we monitored the reaction by employing an in situ LED NMR device equipped with a 430 nm LED source. Investigation of the N–O bond fragmentation revealed that the rate of deoxygenation was not dependent on the rate of decarboxylation for the acyloxy group. Benzoyloxy and pivaloyloxy substituted N-oxides provided similar rates of deoxygenation (k_obs = −5.8 × 10⁻⁵ M s⁻¹ (BzO–) vs. k_obs = −6.3 × 10⁻⁵ M s⁻¹ (PivO–); see ESI^†), a result that is interesting given the difference in rates of decarboxylation form the respective carboxylic acids.^17,18 Alteration of the aryl substituent in the 2-position of the PQCNO auxiliary was observed to impact the rate of deoxygenation, as ortho substituted 2,6-dimethylphenyl substituent provided an increased rate of deoxygenation (k_obs = −7.9 × 10⁻⁵ M s⁻¹), whereas electron rich para-methoxyphenyl substituent led to a substantial decrease in the observed rate for deoxygenation (k_obs = −2.2 × 10⁻⁵ M s⁻¹).Monitoring the deoxygenation of Piv-PQCNO under reaction conditions revealed an increase in the observed rate of deoxygenation in the presence of 4-chloroquinoline (Fig. 5A). We hypothesize that the change in rate for deoxygenation is indicative of a propagative reaction mechanism in which electron transfer from the radical addition product (III) to acylated PQCNO (I) leads to formation of the final C–H alkylated product as well as generating a second equivalent of R˙ through a reductive decarboxylation of acylated PQCNO (I). Determination of the quantum yield (Φ) for the decomposition of Piv-PQCNO supported the proposed propagative chain mechanism, in the presence of 4-chloroquinoling Φ = 0.983 whereas in the absence of a substrate Φ = 0.218 for Piv-PQCNO decomposition. The increase in observed quantum yield is indicative of chain mechanism promoting Piv-PQCNO decomposition in the presence of a substrate. Further support was found when subjecting 2-phenylpropionyl chloride to the reaction conditions in the absence of a heteroaromatic substrate, 1-chloro-1-phenylethane was observed (see ESI^†), demonstrating the ability of acyl PQCNO to oxidize stabilized radical intermediates.Open in a separate windowFig. 5(A) Reaction profile in the presence (blue) and absence (yellow) of substrate, monitored using 430 nm LED NMR apparatus. (B) Proposed mechanism for photomediated Minisci reaction.¹⁹On the basis of these findings, we propose the following mechanism (Fig. 5B). Initiation of the Minisci alkylation occurs by the photoinduced decomposition of acyl-PQCNO (I) to generate an equivalent of a reactive radical intermediate (R˙). Addition of R˙ to an equivalent of the protonated heteroaromatic substrate provides intermediate (II). Deprotonation of (II) generates radical intermediate (III) that is in turn oxidized by a second equivalent of acyl-PQCNO (I), providing the desired C–H alkylated product while generating a second equivalent of R˙ through the decomposition of reduced acyl-PQCNO (IV), thereby propagating the reaction.Finally, we sought to explore alternate radical transformations that can be promoted by PQCNO-based esters (Scheme 1). Lactonization of 2-phenylbenzoyl chloride was carried out, providing moderate yield for the 3,4-benzocoumarin product.²⁰ By employing trifluoroacetic anhydride (TFAA) as an acyl equivalent in the presence of tert-butyl anisole, radical trifluoromethylation of the electron-rich arene was achieved in moderate yields.⁸ Further assessments of reactivity are currently ongoing within our laboratory.Open in a separate windowScheme 1Alternate radical transformations.In conclusion, we have developed a photoactive ester based upon the quinoline N-oxide core which delivers a strong oxidant in its excited state. The designed photocleavable ester enabled the development of a photochemical Minisci alkylation, providing a reaction platform that leveraged both the photochemical dissociation and the oxidizing characteristics of the photoactive esters. The photochemical reactivity of the PQCNO ester was also demonstrated to effect radical lactonization and trifluoromethylation reactions.     

Chelation-assisted C–C bond activation of biphenylene by gold(i) halides

A chelation-assisted oxidative addition of gold(i) into the C–C bond of biphenylene is reported here. The presence of a coordinating group (pyridine, phosphine) in the biphenylene unit enabled the use of readily available gold(i) halide precursors providing a new, straightforward entry towards cyclometalated (N^C^C)- and (P^C)-gold(iii) complexes. Our study, combining spectroscopic and crystallographic data with DFT calculations, showcases the importance of neighboring, weakly coordinating groups towards the successful activation of strained C–C bonds by gold.

Pyridine and phosphine directing groups promote the C–C activation of biphenylene by readily available gold(i) halides rendering a new entry to (N^C^C)- and (P^C)-gold(iii) species.

Activation of C–C bonds by transition metals is challenging given their inertness and ubiquitous presence alongside competing C–H bonds.¹ Both the intrinsic steric hindrance as well as the highly directional character of the p orbitals involved in the σ_C–C bond impose a high kinetic barrier for this type of processes.^2,3 Biphenylene, a stable antiaromatic system featuring two benzene rings connected via a four-membered cycle, has found widespread application in the study of C–C bond activation. Since the seminal report from Eisch et al. on the oxidative addition of a nickel(0) complex into the C–C bond of biphenylene,⁴ several other late transition metals have been successfully applied in this context.⁵ Interestingly, despite the general reluctance of gold(i) to undergo oxidative addition,⁶ its oxidative insertion into the C–C bond of biphenylene was demonstrated in two consecutive reports by the groups of Toste^7a and Bourissou,^7b respectively. The high energy barrier associated with the oxidation of gold could be overcome by the utilization of gold(i) precursors bearing ligands that exhibit either a strongly electron-donating character (e.g. IPr = [1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene])^7a or small bite angles (e.g. DPCb = diphosphino-carborane).^7b,8 In line with these two approaches, more sophisticated bidentate (N^C)- and (P^N)-ligated gold(i) complexes have also been shown to aid the activation of biphenylene at ambient temperature (Scheme 1a).^7c,dOpen in a separate windowScheme 1(a) Previous reports on oxidative addition of ligated gold(i) precursors onto biphenylene. (b) This work: pyridine- and phosphine-directed C–C bond activation of biphenylene by commercially available gold(i) halides.In this context, we hypothesized that the oxidative insertion of gold(i) into the C–C bond of biphenylene could be facilitated by the presence of a neighboring chelating group.⁹ This approach would not only circumvent the need for gold(i) precursors featuring strong σ-donor or highly tailored bidentate ligands but also offer a de novo entry towards interesting, less explored ligand templates. However, recent work by Breher and co-workers showcased the difficulty of achieving such a transformation.¹⁰Herein, we report the oxidative insertion of readily available gold(i) halide precursors into the C–C bond of biphenylene. The appendage of both pyridine and phosphine donors in close proximity to the σ_C–C bond bridging the two aromatic rings provides additional stabilization to the metal center and results in a de novo entry to cyclometalated (N^C^C)- and (P^C)gold(iii) complexes (Scheme 1b).Our study commenced with the preparation of 5-chloro-1-pyridino-biphenylene system 2via Pd-catalyzed Suzuki cross coupling reaction between 2-bromo-3-methylpyridine and 2-(5-chlorobiphenylen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 1 (Scheme 2).¹¹ To our delight, the reaction of 2 with gold(i) iodide in toluene at 130 °C furnished complex κ³-(N^C^C)Au(iii)–I 3 in 60% yield.^12,13 Complex 3 was isolated as yellow plate-type crystals from the reaction mixture and its molecular structure was unambiguously assigned by NMR spectroscopy, high-resolution mass spectrometry (HR-MS) and crystallographic analysis. Complex 3 exhibits the expected square-planar geometry around the metal center, with a Au–I bond length of 2.6558(3) Å.¹⁴ The choice of a neutral weakly bound gold(i)-iodide precursor is key for a successful reaction outcome: similar reactions in the presence of [(NHC)AuCl + AgSbF₆] failed to deliver the desired biscyclometalation adducts, as reported by Breher et al. in ref. 10. The oxidative insertion of gold(i) iodide into the four-membered ring of pyridino-substituted biphenylene provides a novel and synthetically efficient entry to κ³-(N^C^C)gold(iii) halides. These species have recently found widespread application as precursors for the characterization of highly labile, catalytically relevant gold(iii) intermediates,^15a–d as well as for the preparation of highly efficient emitters in OLEDs.^15e–g Previous synthetic routes towards these attractive biscyclometalated gold(iii) systems involved microwave-assisted double C–H functionalization reactions that typically proceed with low to moderate yields.^15aOpen in a separate windowScheme 2Synthesis of complex 3via oxidative addition of Au(i) into the C–C bond of pyridine-substituted biphenylene. X-ray structures of complex 3 with atoms drawn using 50% probability ellipsoids. Hydrogen atoms have been omitted for clarity. Additional selected bond distances [Å]: N–Au = 2.126(2), C1–Au = 1.973(2), C2–Au = 2.025(2), Au–I = 2.6558(3) and bond angles [deg]: N–Au–I = 99.25(6), N–Au–C1 = 79.82(9), C1–Au–C2 = 81.2(1), C2–Au–I = 99.73(8). For experimental details, see ESI.^†Encouraged by the successful results obtained with the pyridine-substituted biphenylene and considering the prominent use of phosphines in gold chemistry,^6,16 we wondered whether the same reactivity would be observed for a P-containing system. To this end, both adamantyl- and tert-butyl-substituted phosphines were appended in C1 position of the biphenylene motif. Starting from 5-chlorobiphenylene-1-carbaldehyde 4, phosphine-substituted biphenylenes 5a and 5b could be accessed in 3 steps (aldehyde reduction to the corresponding alcohol, Appel reaction and nucleophilic displacement of the corresponding benzylic halide) in 64 and 57% overall yields, respectively.¹³ The reactions of 5a and 5b with commercially available gold(i) halides (Me₂SAuCl and AuI) furnished the corresponding mononuclear complexes 7a–b and 8a–b, respectively (Scheme 3).¹³ All these complexes were fully characterized and the structures of 7a, 7b and 8a were unambiguously characterized by X-ray diffraction analysis.¹³ Interestingly, the nature of the halide has a clear effect on the chemical shift of the phosphine ligand so that a Δδ of ca. 5 ppm can be observed in the ³¹P NMR spectra of 7a–b (Au–Cl) compared to 8a–b (Au–I), the latter being the more deshielded. The Au–X bond length is also impacted, with a longer Au–I distance (2.5608(1) Å for 8a) compared to that measured in the Au–Cl analogue (2.2941(7) Å for 7a) (Δd = 0.27 Å).¹³Open in a separate windowScheme 3Synthesis and reactivity of complexes 7a–b, 8a–b, 9 and 10. X-ray structure of complexes 11b, 12 and 14 with atoms drawn using 50% probability ellipsoids. Hydrogen atoms have been omitted for clarity. For experimental details and X-ray structures see ESI.^†Despite numerous attempts to promote the C–C activation in these complexes,^10,13 all reactions resulted in the formation of highly stable cationic species 11a–b and 12, which could be easily isolated from the reaction media. In the case of cationic mononuclear-gold(i) complexes 11, a ligand scrambling reaction in which the chloride ligand is replaced by a phosphine in the absence of a scavenger, a process previously described for gold(i) species, can be used to justify the reaction outcome.¹⁷ The formation of dinuclear gold complex 12 can be ascribed to the combination of a strong aurophilic interaction between the two gold centers (Au–Au = 2.8874(4) Å) and the stabilizing η²-coordination of the metal center to the aromatic ring of biphenylene. Similar η²-coordinated gold(i) complexes have been reported but, to the best of our knowledge, only as mononuclear species.¹⁸Taking into consideration the observed geometry of complexes 7a–b in the solid state,¹³ the facile formation of stable cationic species 11 and 12 and the lack of reactivity of the gold(i) iodides 8a–b, we hypothesized that the free rotation around the C–P bond was probably restricted, placing the gold(i) center away from the biphenylene system and thus preventing the desired oxidative insertion reaction. To overcome this problem, we set out to elongate the arm bearing the phosphine unit with an additional methylene group, introduced via a Wittig reaction from compound 4 to yield ligand 6, prepared in 4 steps in 27% overall yield. Coordination with Me₂SAuCl and AuI resulted in gold(i) complexes 9 and 10, respectively (Scheme 3). The structure of 9 was unambiguously assigned by X-ray diffraction analysis and a similar environment around the metal center to that determined for complex 7a was observed for this complex.¹³With complexes 9 and 10 in hand, we explored their reactivity towards C–C activation of the four-membered ring of biphenylene.¹⁹ After chloride abstraction and upon heating at 100 °C for 5 hours, ring opening of the biphenylene system was observed for complex 9. Interestingly, formation of mono-cyclometalated adduct 13 was exclusively observed (the structure of 13 was confirmed by ¹H, ¹³C, ³¹P, ¹⁹F, ¹¹B and 2D NMR spectroscopy and HR-MS).¹³ The solvent appears to play a major role in this process, as performing the reaction in non-chlorinated solvents resulted in stable cationic complexes similar to 11.^13,20,21 The presence of adventitious water is likely responsible for the formation of the monocyclometalated (P^C)gold(iii) complex 13 as when the reaction was carried out in C₂H₄Cl₂ previously treated with D₂O, the corresponding deuterated adduct 13-d could be detected in the reaction media. These results showcase the difficulties associated with the biscyclometalation for P-based complexes as well as the labile nature of the expected biscyclometalated adducts. Interestingly though, these processes can be seen as a de novo entry towards relatively underexplored (P^C)gold(iii) species.²²The C–C activation was further confirmed by X-ray diffraction analysis of the phosphonium salt 14, which arise from the reductive elimination at the gold(iii) center in 13 upon exchange of the BF₄⁻ counter-anion with the weakly coordinating sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (NaBAr^F).^13,23 The phosphorus atom is four-coordinate, with weak bonding observed to the distant counter-anion and a distorted tetrahedral geometry (C1–P–C2 = 95.05(17), C2–P–C3 = 112.1(1), C3–P–C4 = 116.6(1), C4–P–C1 = 107.4(2) deg). These results represent the third example in which the C(sp²)–P bond reductive elimination at gold(iii) has been reported.²⁴Further, it is important to note that, in contrast to the reactivity observed for the pyridine-substituted biphenylene, neither P-coordinated gold(i) iodo complexes 8a, 8b nor 10 reacted to give cyclometalated products despite prolonged heating, which highlights the need for highly reactive cationized gold(i) species to undergo oxidative addition when phosphine ligands are flanking the C–C bond.¹³To get a deeper understanding on the observed differences in reactivity for the N- vs. P-based directing groups, ground- and transition-state structures for the oxidative insertion of gold(i) halides in C1-substituted biphenylenes were computed by DFT calculations. The reactions of Py-substituted 2 with AuI to give 3 (I) and those of P-substituted 7a (II) and 9 (III) featuring the cationization of the gold(i) species were chosen as models for comparative purposes with the experimental conditions (Fig. 1 and S1–S10 in the ESI^†).^25–27 The computed activation energies for the three processes are in good agreement with the experimental data. The pyridine-substituted biphenylene I exhibits the lowest activation barrier for the oxidative insertion process (ΔG^‡ = 34.4 kcal mol⁻¹). The reaction on the phosphine-substituted derivatives II and III proved to be, after cationization of the corresponding gold(i) halide complexes (II-BF₄, III-BF₄) higher in energy (ΔG^‡ = 39.6 and 46.3 kcal mol⁻¹ respectively), although the obtained values do not rule out the feasibility of the C–C activation process. The transition state between I and I′ exhibits several interesting geometrical features: (a) the biphenylene is significantly bent, (b) the cleavage of the C–C bond is well advanced (d_C–C = 1.898 Å in TSIvs. d_C–C = 1.504 Å in I), and (c) the two C and the I atoms form a Y-shape around gold with minimal coordination from the pyridine (d_N–Au = 2.742 Å in TSIvs. d_N–Au = 2.093 Å in I and 2.157 Å in I′, respectively). The transition-state structures found for the P-based ligands (TSII and TSIII) also show an elongation of the C–C bond and display a bent biphenylene. However, much shorter P–Au distances (d_P–Au = 2.330 Å for TSII and 2.314 Å for TSIII) can be observed compared to the pyridine-based system, as expected due to the steric and electronic differences between these two coordinating groups. Analogously, longer C–Au distances were also found for the P-based systems (d_C1–Au = 2.152 Å for TSIvs. 2.235 Å and 2.204 Å for TSII and TSIII; d_C2–Au = 2.143 Å for TSIvs. 2.219 Å and 2.162 Å for TSII and TSIII), with a larger deviation of square planarity for Au in TSIII compared to TSII.^28,29 These results suggest that, provided the appropriate distance to the C–C bond is in place, the strong coordination of phosphorous to the gold(i) center does not prevent the C–C activation of biphenylene but other reactions (i.e. formation of diphosphine gold(i) cationic species, protodemetalation) can outcompete the expected biscyclometalation process. In contrast, a weaker donor such as pyridine offers a suitable balance bringing the gold in close proximity to the C–C bond and enables both the oxidative cleavage as well as the formation of the double metalation product.Open in a separate windowFig. 1Energy profile (ΔG and ΔG^‡ in kcal mol⁻¹), optimized structures, transition states computed at the IEFPCM (toluene/1,2-dichloroethane)-B3PW91/DEF2QZVPP(Au,I)/6-31++G(d,p)(other atoms) level of theory for the C–C activation of biphenylene with gold(i) iodide from I and gold(i) cationic from II and III. Computed structures of the transition states (TSI, TSII and TSIII) and table summarizing relevant distances.     

Enantioselective palladium-catalyzed C(sp2)–C(sp2) σ bond activation of cyclopropenones by merging desymmetrization and (3 + 2) spiroannulation with cyclic 1,3-diketones

Catalytic asymmetric variants for functional group transformations based on carbon–carbon bond activation still remain elusive. Herein we present an unprecedented palladium-catalyzed (3 + 2) spiro-annulation merging C(sp²)–C(sp²) σ bond activation and click desymmetrization to form synthetically versatile and value-added oxaspiro products. The operationally straightforward and enantioselective palladium-catalyzed atom-economic annulation process exploits a TADDOL-derived bulky P-ligand bearing a large cavity to control enantioselective spiro-annulation that converts cyclopropenones and cyclic 1,3-diketones into chiral oxaspiro cyclopentenone–lactone scaffolds with good diastereo- and enantio-selectivity. The click-like reaction is a successful methodology with a facile construction of two vicinal carbon quaternary stereocenters and can be used to deliver additional stereocenters during late-state functionalization for the synthesis of highly functionalized or more complex molecules.

An unprecedented palladium-catalyzed (3 + 2) spiro-annulation merging C–C bond activation and desymmetrization was developed for the enantioselective construction of synthetically versatile and value-added oxaspiro products with up to 95% ee.     

Photoactive electron donor–acceptor complex platform for Ni-mediated C(sp3)–C(sp2) bond formation

A dual photochemical/nickel-mediated decarboxylative strategy for the assembly of C(sp³)–C(sp²) linkages is disclosed. Under light irradiation at 390 nm, commercially available and inexpensive Hantzsch ester (HE) functions as a potent organic photoreductant to deliver catalytically active Ni(0) species through single-electron transfer (SET) manifolds. As part of its dual role, the Hantzsch ester effects a decarboxylative-based radical generation through electron donor–acceptor (EDA) complex activation. This homogeneous, net-reductive platform bypasses the need for exogenous photocatalysts, stoichiometric metal reductants, and additives. Under this cross-electrophile paradigm, the coupling of diverse C(sp³)-centered radical architectures (including primary, secondary, stabilized benzylic, α-oxy, and α-amino systems) with (hetero)aryl bromides has been accomplished. The protocol proceeds under mild reaction conditions in the presence of sensitive functional groups and pharmaceutically relevant cores.

This works demonstrates the implementation of an electron donor–acceptor (EDA) complex platform toward Ni-catalyzed C(sp³)–C(sp²) bond formation, circumventing the need for exogenous photocatalysts, additives, and stoichiometric metal reductants.     

Synergistic effects of CH3CO2H and Ca2+ on C–H bond activation by MnO4−

The activation of metal-oxo species with Lewis acids is of current interest. In this work, the effects of a weak Brønsted acid such as CH₃CO₂H and a weak Lewis acid such as Ca²⁺ on C–H bond activation by KMnO₄ have been investigated. Although MnO₄⁻ is rather non-basic (pK_a of MnO₃(OH) = −2.25), it can be activated by AcOH or Ca²⁺ to oxidize cyclohexane at room temperature to give cyclohexanone as the major product. A synergistic effect occurs when both AcOH and Ca²⁺ are present; the relative rates for the oxidation of cyclohexane by MnO₄⁻/AcOH, MnO₄⁻/Ca²⁺ and MnO₄⁻/AcOH/Ca²⁺ are 1 : 73 : 198. DFT calculations show that in the active intermediate of MnO₄⁻/AcOH/Ca²⁺, MnO₄⁻ is H-bonded to 3 AcOH molecules, while Ca²⁺ is bonded to 3 AcOH molecules as well as to an oxo ligand of MnO₄⁻. Our results also suggest that these synergistic activating effects of a weak Brønsted acid and a weak Lewis acid should be applicable to a variety of metal-oxo species.

The activation of metal-oxo species with Lewis acids is of current interest.     

Activation of perfluoroalkyl iodides by anions: extending the scope of halogen bond activation to C(sp3)–H amidation,C(sp2)–H iodination,and perfluoroalkylation reactions

A simple, efficient, and convenient activation of perfluoroalkyl iodides by tBuONa or KOH, without expensive photo- or transition metal catalysts, allows the promotion of versatile α-sp³ C–H amidation reactions of alkyl ethers and benzylic hydrocarbons, C–H iodination of heteroaryl compounds, and perfluoroalkylations of electron-rich π bonds. Mechanistic studies show that these novel protocols are based on the halogen bond interaction between perfluoroalkyl iodides and tBuONa or KOH, which promote homolysis of perfluoroalkyl iodides under mild conditions.

A simple activation of perfluoroalkyl iodides by tBuONa or KOH allows the promotion of α-sp³ C–H amidation reactions of alkyl ethers and benzylic hydrocarbons, C–H iodination of heteroaryl compounds, and perfluoroalkylations of electron-rich π bonds.     

Pd-catalyzed cross-electrophile Coupling/C–H alkylation reaction enabled by a mediator generated via C(sp3)–H activation

Transition-metal-catalyzed cross-electrophile C(sp²)–(sp³) coupling and C–H alkylation reactions represent two efficient methods for the incorporation of an alkyl group into aromatic rings. Herein, we report a Pd-catalyzed cascade cross-electrophile coupling and C–H alkylation reaction of 2-iodo-alkoxylarenes with alkyl chlorides. Methoxy and benzyloxy groups, which are ubiquitous functional groups and common protecting groups, were utilized as crucial mediators via primary or secondary C(sp³)–H activation. The reaction provides an innovative and convenient access for the synthesis of alkylated phenol derivatives, which are widely found in bioactive compounds and organic functional materials.

A cascade Pd-catalyzed cross-electrophile coupling and C–H alkylation reaction of 2-iodo-alkoxylarenes with alkyl chlorides has been developed by using an ortho-methoxy or benzyloxy group as a mediator via C(sp³)–H activation.     

Unexpected fragmentation of β-substituted meso-tetraphenylporphyrins induced by high-energy collisional activation

The protonated molecules and radical cations of meso-tetraphenylporphyrins with β-pyrrolic substituents, when formed by fast atom bombardment (FAB) and subjected to high-energy collisions, give rise to unexpected fragment ions. The reaction involves hydrogen migration from the ortho position of the phenyl ring to the atom of the substituent, with formation of an intramolecular, six-membered ring. The process is analogous to condensed-phase cyclizations described for the same type of compounds. The fragmentation requires the presence of a double bond in the substituent group attached to the pyrrolic ring. A rearrangement process involving anchimeric assistance by the phenyl group (analogous to an ortho effect) is proposed for the formation of these ions.     

NiCl2(PMe3)(2)-catalyzed borylation of aryl chlorides

The cross-coupling of aryl chlorides and bis(pinacolato)diboron was achieved using NiCl(2)(PMe(3))(2) catalyst in the presence of metal 2,2,2-trifluoroethoxide. The catalyst smoothly provided the desired products regardless of a variety of functional groups and substituted positions.     

Organometallic condensation polymerization: Carbon–carbon bond formation by coupling of 1-phenylcyclohexenyl chromophores

Diolefins XV and XVII have been successfully polymerized with metallic lithium in tetrahydrofuran by a radical-anion, carbon–carbon coupling reaction. The coupling takes place in the mode known for the dimerization of α-methylstyrene and 1,1-diphenylethylene and shown herein for 1-phenylcyclohexene.     

Merging C(sp3)–H activation with DNA-encoding

DNA-encoded library (DEL) technology has the potential to dramatically expedite hit identification in drug discovery owing to its ability to perform protein affinity selection with millions or billions of molecules in a few experiments. To expand the molecular diversity of DEL, it is critical to develop different types of DNA-encoded transformations that produce billions of molecules with distinct molecular scaffolds. Sequential functionalization of multiple C–H bonds provides a unique avenue for creating diversity and complexity from simple starting materials. However, the use of water as solvent, the presence of DNA, and the extremely low concentration of DNA-encoded coupling partners (0.001 M) have hampered the development of DNA-encoded C(sp³)–H activation reactions. Herein, we report the realization of palladium-catalyzed C(sp³)–H arylation of aliphatic carboxylic acids, amides and ketones with DNA-encoded aryl iodides in water. Notably, the present method enables the use of alternative sets of monofunctional building blocks, providing a linchpin to facilitate further setup for DELs. Furthermore, the C–H arylation chemistry enabled the on-DNA synthesis of structurally-diverse scaffolds containing enriched C(sp³) character, chiral centers, cyclopropane, cyclobutane, and heterocycles.

DNA-compatible C(sp³)–H activation reactions of aliphatic carboxylic acids, amides, and ketones were developed for efficient access to DEL synthesis.     

Photocatalytic C(sp3) radical generation via C–H,C–C,and C–X bond cleavage

C(sp³) radicals (R˙) are of broad research interest and synthetic utility. This review collects some of the most recent advancements in photocatalytic R˙ generation and highlights representative examples in this field. Based on the key bond cleavages that generate R˙, these contributions are divided into C–H, C–C, and C–X bond cleavages. A general mechanistic scenario and key R˙-forming steps are presented and discussed in each section.

C(sp³) radicals (R˙) are of broad research interest and synthetic utility.     

Carbon‐iodide bond activation by cyclometalated Pt (II) complexes bearing tricyclohexylphosphine ligand: A comparative kinetic study and theoretical elucidation

Cyclometalated Pt (II) complexes [PtMe(C^N)(L)], in which C^N = deprotonated 2,2′‐bipyridine N‐oxide (Obpy), 1 , deprotonated 2‐phenylpyridine (ppy), 2 , deprotonated benzo [h] quinolone (bzq), 3 , and L = tricyclohexylphosphine (PCy₃) were prepared and fully characterized. By treatment of 1–3 with excess MeI, the thermodynamically favored Pt (IV) complexes cis‐[PtMe₂I(C^N)(PCy₃)] (C^N = Obpy, 1a ; ppy, 2a ; and bzq, 3a ) were obtained as the major products in which the incoming methyl and iodine groups adopted cis positions relative to each other. All the complexes were characterized by means of NMR spectroscopy while the absolute configuration of 1a was further determined by X‐ray crystal structure analysis. The reaction of methyl iodide with 1–3 were kinetically explored using UV–vis spectroscopy. On the basis of the kinetic data together with the time‐resolved NMR investigation, it was established that the oxidative addition reaction occurred through the classical S_N2 attack of Pt (II) center on the MeI reagent. Moreover, comparative kinetic studies demonstrated that the electronic and steric nature of either the cyclometalating ligands or the phosphine ligand influence the rate of reaction. Surprisingly, by extending the oxidative addition reaction time, very stable iodine‐bridged Pt (IV)‐Pt (IV) complexes [Pt₂Me₄(C^N)₂(μ‐I)₂] (C^N = Obpy, 1b ; ppy, 2b ; and bzq, 3b ) were obtained and isolated. In order to find a reasonable explanation for the observation, a DFT (density functional theory) computational analysis was undertaken and it was found that the results were consistent with the experimental findings.     

Ni(0)-promoted activation of Csp2–H and Csp2–O bonds

A dinickel(0)–N₂ complex, stabilized with a rigid acridane-based PNP pincer ligand, was studied for its ability to activate C(sp²)–H and C(sp²)–O bonds. Stabilized by a Ni–μ–N₂–Na⁺ interaction, it activates C–H bonds of unfunctionalized arenes, affording nickel–aryl and nickel–hydride products. Concomitantly, two sodium cations get reduced to Na(0), which was identified and quantified by several methods. Our experimental results, including product analysis and kinetic measurements, strongly suggest that this C(sp²)–H activation does not follow the typical oxidative addition mechanism occurring at a low-valent single metal centre. Instead, via a bimolecular pathway, two powerfully reducing nickel ions cooperatively activate an arene C–H bond and concomitantly reduce two Lewis acidic alkali metals under ambient conditions. As a novel synthetic protocol, nickel(ii)–aryl species were directly synthesized from nickel(ii) precursors in benzene or toluene with excess Na under ambient conditions. Furthermore, when the dinickel(0)–N₂ complex is accessed via reduction of the nickel(ii)–phenyl species, the resulting phenyl anion deprotonates a C–H bond of glyme or 15-crown-5 leading to C–O bond cleavage, which produces vinyl ether. The dinickel(0)–N₂ species then cleaves the C(sp²)–O bond of vinyl ether to produce a nickel(ii)–vinyl complex. These results may provide a new strategy for the activation of C–H and C–O bonds mediated by a low valent nickel ion supported by a structurally rigidified ligand scaffold.

A structurally rigidified nickel(0) complex was found to be capable of cleaving both C(sp²)–H and C(sp²)–O bonds.     

Cooperative B–H bond activation: dual site borane activation by redox active κ2-N,S-chelated complexes

Cooperative dual site activation of boranes by redox-active 1,3-N,S-chelated ruthenium species, mer-[PR₃{κ²-N,S-(L)}₂Ru{κ¹-S-(L)}], (mer-2a: R = Cy, mer-2b: R = Ph; L = NC₇H₄S₂), generated from the aerial oxidation of borate complexes, [PR₃{κ²-N,S-(L)}Ru{κ³-H,S,S′-BH₂(L)₂}] (trans–mer-1a: R = Cy, trans–mer-1b: R = Ph; L = NC₇H₄S₂), has been investigated. Utilizing the rich electronic behaviour of these 1,3-N,S-chelated ruthenium species, we have established that a combination of redox-active ligands and metal–ligand cooperativity has a big influence on the multisite borane activation. For example, treatment of mer-2a–b with BH₃·THF led to the isolation of fac-[PR₃Ru{κ³-H,S,S′-(NH₂BSBH₂N)(S₂C₇H₄)₂}] (fac-3a: R = Cy and fac-3b: R = Ph) that captured boranes at both sites of the κ²-N,S-chelated ruthenacycles. The core structure of fac-3a and fac-3b consists of two five-membered ruthenacycles [RuBNCS] which are fused by one butterfly moiety [RuB₂S]. Analogous fac-3c, [PPh₃Ru{κ³-H,S,S′-(NH₂BSBH₂N)(SC₅H₄)₂}], can also be synthesized from the reaction of BH₃·THF with [PPh₃{κ²-N,S-(SNC₅H₄)}{κ³-H,S,S′-BH₂(SNH₄C₅)₂}Ru], cis–fac-1c. In stark contrast, when mer-2b was treated with BH₂Mes (Mes = 2,4,6-trimethyl phenyl) it led to the formation of trans- and cis-bis(dihydroborate) complexes [{κ³-S,H,H-(NH₂BMes)Ru(S₂C₇H₄)}₂], (trans-4 and cis-4). Both the complexes have two five-membered [Ru–(H)₂–B–NCS] ruthenacycles with κ²-H–H coordination modes. Density functional theory (DFT) calculations suggest that the activation of boranes across the dual Ru–N site is more facile than the Ru–S one.

Redox-active ruthenium complexes supported by hemilabile κ²-N,S-chelated ruthenacycles undergo unusual dual site B–H bond activation through metal–ligand cooperation with free and bulky boranes.