Metal-free tandem carbene N–H insertions and C–C bond cleavages

A metal-free C–H [5 + 1] annulation reaction of 2-arylanilines with diazo compounds has been achieved, giving rise to two types of prevalent phenanthridines via highly selective C–C cleavage. Compared to the simple N–H insertion manipulation of diazo, this method elegantly accomplishes a tandem N–H insertion/S_EAr/C–C cleavage/aromatization reaction, and the synthetic utility of this new transformation is exemplified by the succinct syntheses of trisphaeridine and bicolorine alkaloids.

A metal-free C–H [5 + 1] annulation reaction of 2-arylanilines with diazo compounds has been achieved, giving rise to two types of prevalent phenanthridines via highly selective C–C cleavage.     

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.     

Nickel-catalyzed C–O/N–H,C–S/N–H,and C–CN/N–H annulation of aromatic amides with alkynes: C–O,C–S,and C–CN activation

The Ni-catalyzed reaction of ortho-phenoxy-substituted aromatic amides with alkynes in the presence of LiO^tBu as a base results in C–O/N–H annulation with the formation of 1(2H)-isoquinolinones. The use of a base is essential for the reaction to proceed. The reaction proceeds, even in the absence of a ligand, and under mild reaction conditions (40 °C). An electron-donating group on the aromatic ring facilitates the reaction. The reaction was also applicable to carbamate (C–O bond activation), methylthio (C–S bond activation), and cyano (C–CN bond activation) groups as leaving groups.

The Ni-catalyzed reaction of ortho-phenoxy-substituted aromatic amides with alkynes in the presence of LiO^tBu as a base results in C–O/N–H annulation with the formation of 1(2H)-isoquinolinones.     

The impact of protonation and deprotonation of 3-methyl-2'-deoxyadenosine on N-glycosidic bond cleavage

The enzyme-substrate contacts that are believed to be involved in depurination by proton transfer have been modelled by protonation and deprotonation of 3-methyl-2'-deoxyadenosine (3-MDA) using quantum mechanical calculations in the gas-phase and solution media. The change in the charge distribution on the sugar ring and nucleobase that is introduced by the protonation and deprotonation strongly affects the N-glycosidic bond length. The unimolecular cleavage and hydrolysis of the N-glycosidic bond, involving D(N)*A(N) and A(N)D(N) pathways, have been considered at several levels of theory. The trend in the energy barriers is A(N)D(N) > cleavage > D(N)*A(N). All probable proton transfer reactions resulting from enzyme-substrate contacts do not facilitate the N-glycosidic bond cleavage of 3-MDA. The deprotonation of 3-MDA that may result from the interaction between H6 and enzyme do not facilitate bond cleavage. The protonation at N7 induces more positive charge on the sugar ring and further facilitates the depurination relative to the protonation at N1. The changes in the charges calculated on the ribose and nucleobase are in good relationship with the C1'-C2', C1'-O4', and N-glycosidic bond lengths along the cleavage. The change in energy barrier ΔE of glycosidic bond cleavage from the gas-phase to solution media strongly depends on the charge of the species.     

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.     

Thioether-enabled palladium-catalyzed atroposelective C–H olefination for N–C and C–C axial chirality

Thioethers allowed for highly atroposelective C–H olefinations by a palladium/chiral phosphoric acid catalytic system under ambient air. Both N–C and C–C axial chiral (hetero)biaryls were successfully constructed, leading to a broad range of axially chiral N-aryl indoles and biaryls with excellent enantioselectivities up to 99% ee. Experimental and computational studies were conducted to unravel the walking mode for the atroposelective C–H olefination. A plausible chiral induction model for the enantioselectivity-determining step was established by detailed DFT calculations.

Thioethers allowed for highly atroposelective C–H olefinations by a palladium/chiral phosphoric acid catalytic system under ambient air.     

Enantioselective palladaelectro-catalyzed C–H olefinations and allylations for N–C axial chirality

Enantioselective palladaelectro-catalyzed C–H alkenylations and allylations were achieved with easily-accessible amino acids as transient directing groups. This strategy provided access to highly enantiomerically-enriched N–C axially chiral scaffolds under exceedingly mild conditions. The synthetic utility of our strategy was demonstrated by a variety of alkenes, while the versatility of our approach was reflected by atroposelective C–H allylations. Computational studies provided insights into a facile C–H activation by a seven-membered palladacycle.

Enantioselective palladaelectro-catalyzed C–H alkenylations and allylations were achieved by the means of an easily-accessible amino acid for the synthesis of N–C axially chiral indole biaryls.     

N−H Bond Formation at a Diiron Bridging Nitride

Despite their connection to ammonia synthesis, little is known about the ability of iron‐bound, bridging nitrides to form N?H bonds. Herein we report a linear diiron bridging nitride complex supported by a redox‐active macrocycle. The unique ability of the ligand scaffold to adapt to the geometric preference of the bridging species was found to facilitate the formation of N?H bonds via proton‐coupled electron transfer to generate a μ‐amide product. The structurally analogous μ‐silyl‐ and μ‐borylamide complexes were shown to form from the net insertion of the nitride into the E?H bonds (E=B, Si). Protonation of the parent bridging amide produced ammonia in high yield, and treatment of the nitride with PhSH was found to liberate NH₃ in high yield through a reaction that engages the redox‐activity of the ligand during PCET.     

Electrochemical oxidative N–H/P–H cross-coupling with H2 evolution towards the synthesis of tertiary phosphines

Tertiary phosphines(iii) find widespread use in many aspects of synthetic organic chemistry. Herein, we developed a facile and novel electrochemical oxidative N–H/P–H cross-coupling method, leading to a series of expected tertiary phosphines(iii) under mild conditions with excellent yields. It is worth noting that this electrochemical protocol features very good reaction selectivity, where only a 1 : 1 ratio of amine and phosphine was required in the reaction. Moreover, this electrochemical protocol proved to be practical and scalable. Mechanistic insights suggested that the P radical was involved in this reaction.

A facile and novel electrochemical oxidative N–H/P–H cross-coupling method for obtaining tertiary phosphines(iii) was developed.     

Implications of protonation and substituent effects for C-O and O-P bond cleavage in phosphate monoesters

A recent study of phosphate monoesters that broke down exclusively through C-O bond cleavage and whose reactivity was unaffected by protonation of the nonbridging oxygens (Byczynski et al. J. Am. Chem. Soc. 2003, 125, 12541) raised several questions about the reactivity of phosphate monoesters, R-O-P(i). Potential catalytic strategies, particularly with regard to selectively promoting C-O or O-P bond cleavage, were investigated computationally through simple alkyl and aryl phosphate monoesters. Both C-O and O-P bonds lengthened upon protonating the bridging oxygen, R-O(H(+))-P(i), and heterolytic bond dissociation energies, DeltaH(C)(-)(O) and DeltaH(O)(-)(P), decreased. Which bond will break depends on the protonation state of the phosphoryl moiety, P(i), and the identity of the organosubstituent, R. Protonating the bridging oxygen when the nonbridging oxygens were already protonated favored C-O cleavage, while protonating the bridging oxygen of the dianion form, R-O-PO(3)(2)(-), favored O-P cleavage. Alkyl R groups capable of forming stable cations were more prone to C-O bond cleavage, with tBu > iPr > F(2)iPr > Me. The lack of effect on the C-O cleavage rate from protonating nonbridging oxygens could arise from two precisely offsetting effects: Protonating nonbridging oxygens lengthens the C-O bond, making it more reactive, but also decreases the bridging oxygen proton affinity, making it less likely to be protonated and, therefore, less reactive. The lack of effect could also arise without bridging oxygen protonation if the ratio of rate constants with different protonation states precisely matched the ratio of acidity constants, K(a). Calculations used hybrid density functional theory (B3PW91/6-31++G) methods with a conductor-like polarizable continuum model (CPCM) of solvation. Calculations on Me-phosphate using MP2/aug-cc-pVDZ and PBE0/aug-cc-pVDZ levels of theory, and variations on the solvation model, confirmed the reproducibility with different computational models.     

Reagent‐Free C−H/N−H Cross‐Coupling: Regioselective Synthesis of N‐Heteroaromatics from Biaryl Aldehydes and NH3

An unprecedented synthesis of N‐heteroaromatics from biaryl aldehydes and NH₃ through reagent‐free C−H/N−H cross‐coupling has been developed. The electrosynthesis uses NH₃ as an inexpensive and atom‐economic nitrogen donor, requires no oxidizing agents, and allows efficient and regioselective access to a wide range of phenanthridines and structurally related polycyclic N‐heteroaromatic products.     

Nickel-mediated N–N bond formation and N2O liberation via nitrogen oxyanion reduction

The syntheses of (DIM)Ni(NO₃)₂ and (DIM)Ni(NO₂)₂, where DIM is a 1,4-diazadiene bidentate donor, are reported to enable testing of bis boryl reduced N-heterocycles for their ability to carry out stepwise deoxygenation of coordinated nitrate and nitrite, forming O(Bpin)₂. Single deoxygenation of (DIM)Ni(NO₂)₂ yields the tetrahedral complex (DIM)Ni(NO)(ONO), with a linear nitrosyl and κ¹-ONO. Further deoxygenation of (DIM)Ni(NO)(ONO) results in the formation of dimeric [(DIM)Ni(NO)]₂, where the dimer is linked through a Ni–Ni bond. The lost reduced nitrogen byproduct is shown to be N₂O, indicating N–N bond formation in the course of the reaction. Isotopic labelling studies establish that the N–N bond of N₂O is formed in a bimetallic Ni₂ intermediate and that the two nitrogen atoms of (DIM)Ni(NO)(ONO) become symmetry equivalent prior to N–N bond formation. The [(DIM)Ni(NO)]₂ dimer is susceptible to oxidation by AgX (X = NO₃⁻, NO₂⁻, and OTf⁻) as well as nitric oxide, the latter of which undergoes nitric oxide disproportionation to yield N₂O and (DIM)Ni(NO)(ONO). We show that the first step in the deoxygenation of (DIM)Ni(NO)(ONO) to liberate N₂O is outer sphere electron transfer, providing insight into the organic reductants employed for deoxygenation. Lastly, we show that at elevated temperatures, deoxygenation is accompanied by loss of DIM to form either pyrazine or bipyridine bridged polymers, with retention of a BpinO⁻ bridging ligand.

Deoxygenation of nitrogen oxyanions coordinated to nickel using reduced borylated heterocycles leads to N–N bond formation and N₂O liberation. The nickel dimer product facilitates NO disproportionation, leading to a synthetic cycle.     

Aufbau und Abbau von (NH4)[BF4] und H3N‐BF3

Production and Decomposition of (NH₄)[BF₄] and H₃N‐BF₃ (NH₄)[BF₄] is produced as single crystals during the reaction of elemental boron and NH₄HF₂ (B : NH₄HF₂ = 1 : 2) and NH₄F (B : NH₄F = 1 : 4), respectively, in sealed copper ampoules at 300 °C. The crystal structure (baryte type, orthorhombic, Pnma, Z = 4) was redetermined at ambient temperature (a = 909.73(18), b = 569.77(10), c = 729.47(11) pm, R_all = 0.0361) and at 140 K (a = 887.3(2), b = 574.59(12), c = 717.10(12) pm, R_all = 0.0321). Isolated (NH₄)⁺ and [BF₄]^— tetrahedra are the important building units. The thermal behaviour of (NH₄)[BF₄] was investigated under inert (Ar, N₂) and reactive conditions (NH₃) with the aid of DTA/TG and DSC measurements and with in‐situ X‐ray powder diffraction as well. Finally, (NH₄)[BF₄] is decomposed yielding NH₃ and BF₃, BN is not produced under the current conditions. Colourless single crystals of H₃N‐BF₃ were prepared directly from the components NH₃ and BF₃. The crystal structure was determined anew at 293 and 170 K (orthorhombic, Pbca, Z = 8, a = 815.12(10), b = 805.91(14), c = 929.03(12) pm, R_all = 0.0367; a = 807.26(13), b = 800.48(10), c = 924.31(11) pm, R_all = 0.0292, T = 170 K). The crystal structure contains isolated molecules H₃N‐BF₃ in staggered conformation with a B‐N distance of 158 pm. The thermal behaviour of H₃N‐BF₃ was studied likewise.     

Cation assisted binding and cleavage of dinitrogen by uranium complexes

The role of alkali promoters in N₂ cleavage by metal complexes remains poorly understood despite its relevance to the industrial production of ammonia from N₂. Here we report a series of alkali bound-oxo-bridged diuranium(iii) complexes that provide a unique example of decreasing N₂ binding affinity with increasing cation size (from K to Cs). N₂ binding was found to be irreversible in the presence of K. A N₂ complex could be isolated in the solid state in the presence of the Rb cation and crystallographically characterized, but N₂ binding was found to be reversible under vacuum. In the presence of the Cs cation N₂ binding could not be detected at 1 atm. Electrochemical and Computational studies suggest that the decrease in N₂ binding affinity is due to steric rather than electronic effects. We also find that weak N₂ binding in ambient conditions does not prevent alkali assisted N₂ cleavage to nitride from occurring. More importantly, we present the first example of cesium assisted N₂ cleavage leading to the isolation of a N₂ derived multimetallic U/Cs bis-nitride. The nitrides readily react with protons and CO to yield ammonia, cyanate and cyanide.

N₂ binding affinity decreases markedly in a series of isostructural U(iii)–alkali ions complexes with increasing cation size. N₂ binding is undetectable in the Cs analogue, but the first example of cesium-assisted N₂ cleavage to bis-nitride was observed at ambient condition.     

Estimation of peptide N–Cα bond cleavage efficiency during MALDI‐ISD using a cyclic peptide

Matrix‐assisted laser desorption/ionization in‐source decay (MALDI‐ISD) induces N–C_α bond cleavage via hydrogen transfer from the matrix to the peptide backbone, which produces a c′/z? fragment pair. Subsequently, the z? generates z′ and [z + matrix] fragments via further radical reactions because of the low stability of the z?. In the present study, we investigated MALDI‐ISD of a cyclic peptide. The N–C_α bond cleavage in the cyclic peptide by MALDI‐ISD produced the hydrogen‐abundant peptide radical [M + 2H]⁺? with a radical site on the α‐carbon atom, which then reacted with the matrix to give [M + 3H]⁺ and [M + H + matrix]⁺. For 1,5‐diaminonaphthalene (1,5‐DAN) adducts with z fragments, post‐source decay of [M + H + 1,5‐DAN]⁺ generated from the cyclic peptide showed predominant loss of an amino acid with 1,5‐DAN. Additionally, MALDI‐ISD with Fourier transform‐ion cyclotron resonance mass spectrometry allowed for the detection of both [M + 3H]⁺ and [M + H]⁺ with two ¹³C atoms. These results strongly suggested that [M + 3H]⁺ and [M + H + 1,5‐DAN]⁺ were formed by N–C_α bond cleavage with further radical reactions. As a consequence, the cleavage efficiency of the N–C_α bond during MALDI‐ISD could be estimated by the ratio of the intensity of [M + H]⁺ and [M + 3H]⁺ in the Fourier transform‐ion cyclotron resonance spectrum. Because the reduction efficiency of a matrix for the cyclic peptide cyclo(Arg‐Gly‐Asp‐D‐Phe‐Val) was correlated to its tendency to cleave the N–C_α bond in linear peptides, the present method could allow the evaluation of the efficiency of N–C_α bond cleavage for MALDI matrix development. Copyright © 2016 John Wiley & Sons, Ltd.     

Functionalisation of ethereal-based saturated heterocycles with concomitant aerobic C–H activation and C–C bond formation

With an ever-growing emphasis on sustainable synthesis, aerobic C–H activation (the use of oxygen in air to activate C–H bonds) represents a highly attractive conduit for the development of novel synthetic methodologies. Herein, we report the air mediated functionalisation of various saturated heterocycles and ethers via aerobically generated radical intermediates to form new C–C bonds using acetylenic and vinyl triflones as radical acceptors. This enables access to a variety of acetylenic and vinyl substituted saturated heterocycles that are rich in synthetic value. Mechanistic studies and control reactions support an aerobic radical-based C–H activation mechanism.

Herein we disclose a novel method for the aerobic C–H activation of ethereal-based heterocycles to generate various α-functionalised building blocks.     

Synthesis and hydrogenation of polycyclic aromatic hydrocarbon-substituted diborenes via uncatalysed hydrogenative B–C bond cleavage

The classical route to the PMe₃-stabilised polycyclic aromatic hydrocarbon (PAH)-substituted diborenes B₂Ar₂(PMe₃)₂ (Ar = 9-phenanthryl 7-Phen; Ar = 1-pyrenyl 7-Pyr) via the corresponding 1,2-diaryl-1,2-dimethoxydiborane(4) precursors, B₂Ar₂(OMe)₂, is marred by the systematic decomposition of the latter to BAr(OMe)₂ during reaction workup. Calculations suggest this results from the absence of a second ortho-substituent on the boron-bound aryl rings, which enables their free rotation and exposes the B–B bond to nucleophilic attack. 7-Phen and 7-Pyr are obtained by the reduction of the corresponding 1,2-diaryl-1,2-dichlorodiborane precursors, B₂Ar₂Cl₂(PMe₃)₂, obtained from the SMe₂ adducts, which are synthesised by direct NMe₂–Cl exchange at B₂Ar₂(NMe₂)₂ with (Me₂S)BCl₃. The low-lying π* molecular orbitals (MOs) located on the PAH substituents of 7-Phen and 7-Pyr intercalate between the B–B-based π and π* MOs, leading to a relatively small HOMO–LUMO gap of 3.20 and 2.72 eV, respectively. Under vacuum or at high temperature 7-Phen and 7-Pyr undergo intramolecular hydroarylation of the B B bond to yield 1,2-dihydronaphtho[1,8-cd][1,2]diborole derivatives. Hydrogenation of 7-Phen, 7-Pyr and their 9-anthryl and mesityl analogues III and II, respectively, results in all cases in splitting of the B–B bond and isolation of the monoboranes (Me₃P)BArH₂. NMR-spectroscopic monitoring of the reactions, solid-state structures of isolated reaction intermediates and computational mechanistic analyses show that the hydrogenation of the three PAH-substituted diborenes proceeds via a different pathway to that of the dimesityldiborene. Rather than occurring exclusively at the B–B bond, hydrogenation of 7-Ar and III proceeds via a hydroarylated intermediate, which undergoes one B–B bond-centered H₂ addition, followed by hydrogenation of the endocyclic B–C bond resulting from hydroarylation, making the latter effectively reversible.

In contrast to classical B–B bond-centred diborene hydrogenation, polycyclic aromatic hydrocarbon-substituted diborenes first undergo thermal intramolecular hydroarylation, followed by hydrogenation of the remaining B–B and endocyclic B–C bonds.     

An economical approach for peptide synthesis via regioselective C–N bond cleavage of lactams

An economical, solvent-free, and metal-free method for peptide synthesis via C–N bond cleavage using lactams has been developed. The method not only eliminates the need for condensation agents and their auxiliaries, which are essential for conventional peptide synthesis, but also exhibits high atom economy. The reaction is versatile because it can tolerate side chains bearing a range of functional groups, affording up to >99% yields of the corresponding peptides without racemisation or polymerisation. Moreover, the developed strategy enables peptide segment coupling, providing access to a hexapeptide that occurs as a repeat sequence in spider silk proteins.

An economical, solvent-free, and metal-free method for peptide synthesis via C–N bond cleavage using lactams has been developed.