Radical Clock Research Articles

O-Heterocycle Synthesis via Intramolecular C-H Alkoxylation Catalyzed by Iron Acetylacetonate.

Intramolecular alkoxylation of C-H bonds can rapidly introduce structural and functional group complexities into seemingly simple or inert precursors. The transformation is particularly important due to the ubiquitous presence of tetrahydrofuran (THF) motifs as fundamental building blocks in a wide range of pharmaceuticals, agrochemicals, and natural products. Despite the various synthetic methodologies known for generating functionalized THFs, most show limited functional group tolerance and lack demonstration for the preparation of spiro or fused bi- and tricyclic ether units prevalent in molecules for pharmacological purposes. Herein we report an intramolecular C-H alkoxylation to furnish oxacycles from easily prepared α-diazo-β-ketoesters using commercially available iron acetylacetonate (Fe(acac)2) as a catalyst. The reaction is proposed to proceed through the formation of a vinylic carboradical arising from N2 extrusion, which mediates a proximal H-atom abstraction followed by a rapid C-O bond forming radical recombination step. The radical mechanism is probed using an isotopic labeling study (vinyl C-D incorporation), ring opening of a radical clock substrate, and Hammett analysis and is further corroborated by density functional theory (DFT) calculations. Heightened reactivity is observed for electron-rich C-H bonds (tertiary, ethereal), while greater catalyst loadings or elevated reaction temperatures are required to fully convert substrates with benzylic, secondary, and primary C-H bonds. The transformation is highly functional group tolerant and operates under mild reaction conditions to provide rapid access to complex structures such as spiro and fused bi-/tricyclic O-heterocycles from readily available precursors.

Oxidative Addition of Aryl and Alkyl Halides to a Reduced Iron Pincer Complex.

The two-electron oxidative addition of aryl and alkyl halides to a reduced iron dinitrogen complex with a strong-field tridentate pincer ligand has been demonstrated. Addition of iodobenzene or bromobenzene to (3,5-Me2MesCNC)Fe(N2)2 (3,5-Me2MesCNC = 2,6-(2,4,6-Me-C6H2-imidazol-2-ylidene)2-3,5-Me2-pyridine) resulted in rapid oxidative addition and formation of the diamagnetic, octahedral Fe(II) products (3,5-Me2MesCNC)Fe(Ph)(N2)(X), where X = I or Br. Competition experiments established the relative rate of oxidative addition of aryl halides as I > Br > Cl. A linear free energy of relative reaction rates of electronically differentiated aryl bromides (ρ = 1.5) was consistent with a concerted-type pathway. The oxidative addition of alkyl halides such as methyl-, isobutyl-, or neopentyl halides was also rapid at room temperature, but substrates with more accessible β-hydrogen positions (e.g., 1-bromobutane) underwent subsequent β-hydride elimination. Cyclization of an alkyl halide containing a radical clock and epimerization of neohexyl iodide-d2 upon oxidative addition to (3,5-Me2MesCNC)Fe(N2)2 are consistent with radical intermediates during C(sp3)-X bond cleavage. Importantly, while C(sp2)-X and C(sp3)-X oxidative addition produces net two-electron chemistry, the preferred pathway for obtaining the products is concerted and stepwise, respectively.

Visible-Light-Enhanced Cobalt-Catalyzed Hydrogenation: Switchable Catalysis Enabled by Divergence between Thermal and Photochemical Pathways

The catalytic hydrogenation activity of the readily prepared, coordinatively saturated cobalt(I) precatalyst, (R,R)-(iPrDuPhos)Co(CO)2H ((R,R)-iPrDuPhos = (+)-1,2-bis[(2R,5R)-2,5-diisopropylphospholano]benzene), is described. While efficient turnover was observed with a range of alkenes upon heating to 100 °C, the catalytic performance of the cobalt catalyst was markedly enhanced upon irradiation with blue light at 35 °C. This improved reactivity enabled hydrogenation of terminal, di-, and trisubstituted alkenes, alkynes, and carbonyl compounds. A combination of deuterium labeling studies, hydrogenation of alkenes containing radical clocks, and experiments probing relative rates supports a hydrogen atom transfer pathway under thermal conditions that is enabled by a relatively weak cobalt–hydrogen bond of 54 kcal/mol. In contrast, data for the photocatalytic reactions support light-induced dissociation of a carbonyl ligand followed by a coordination-insertion sequence where the product is released by combination of a cobalt alkyl intermediate with the starting hydride, (R,R)-(iPrDuPhos)Co(CO)2H. These results demonstrate the versatility of catalysis with Earth-abundant metals as pathways involving open- versus closed-shell intermediates can be switched by the energy source.

Ag-Catalyzed Remote Unactivated C(sp3)-H Heteroarylation of Free Alcohols in Water.

Catalyzed by silver salt, the unactivated C(sp3)-H heteroarylation of free alcohol at the δ position is realized under gentle thermal conditions in water through a radical procedure. Both protonic acids and Lewis acids are found to be efficient for activating pyridines for this Minisci-type reaction. The reaction enjoys a good functional group tolerance and substrate scope. Terminal secondary and tertiary alcohols are suitable substrates. With either electron-donating or -withdrawing groups, the electron-deficient heteroarene substrates generate the target products in moderate to good yields. A gram-scale experiment can be successfully operated. A radical blocking experiment and a radical clock experiment are studied to support the radical mechanism.

Transition-Metal-Free Reductive Cross-Coupling Employing Metabisulfite as a Connector: General Construction of Alkyl–Alkyl Sulfones

Transition-Metal-Free Reductive Cross-Coupling Employing Metabisulfite as a Connector: General Construction of Alkyl–Alkyl Sulfones

A visible-light mediated ring opening reaction of alkylidenecyclopropanes for the generation of homopropargyl radicals.

Classical cyclopropylcarbinyl radical clock reactions have been widely applied to conduct mechanistic studies for probing radical processes for a long time; however, alkylidenecyclopropanes, which have a similar molecular structure to methylcyclopropanes, surprisingly have not yet attracted researcher's attention for similar ring opening radical clock processes. In recent years, photocatalytic NHPI ester activation chemistry has witnessed significant blooming developments and provided new synthetic routes for cross-coupling reactions. Herein, we wish to report a non-classical ring opening radical clock reaction using innovative NHPI esters bearing alkylidenecyclopropanes upon photoredox catalysis, providing a brand-new synthetic approach for the direct preparation of a variety of alkynyl derivatives. The potential synthetic utility of this protocol is demonstrated in the diverse transformations and facile synthesis of bioactive molecules or their derivatives and medicinal substances.

Synthesis of maleimide-based enediynes with cyclopropane moieties for enhanced cytotoxicity under normoxic and hypoxic conditions.

Myers-Saito cycloaromatization (MSC) is the working mechanism of many natural enediyne antibiotics with high antitumor potency. However, the presence of the equilibrium between diradical and zwitterionic intermediates in MSC severely hinders further improvement in cytotoxicity toward tumor cells. To this end, a series of maleimide-based enediynes with cyclopropane moieties were synthesized for enhanced cytotoxicity toward tumor cells. By taking advantage of radical clock reactions, the diradical intermediates generated from MSC would rearrange to new diradicals with much longer separation and weaker interactions between two radical centers. The computational study suggested a low energy barrier (4.4 kcal mol-1) for the radical rearrangement through the cyclopropane ring-opening process. Thermolysis experiments confirmed that this radical rearrangement results in the formation of a new diradical intermediate, followed by abstracting hydrogen atoms from 1,4-cyclohexadiene. Interestingly, the DNA cleavage ability and cytotoxicity of enediynes were significantly enhanced after the introduction of cyclopropane moieties. In addition, these maleimide-based enediynes exhibited a similar cytotoxicity under hypoxic conditions to that under normoxic conditions, which is beneficial for treating solid tumors where hypoxic environments frequently lead to deteriorated efficiency of many antitumor drugs. Docking studies indicated that the diradical intermediate was located between the minor groove of DNA with a binding energy of -7.40 kcal mol-1, which is in favor of intracellular DNA damage, and thereby inducing cell death via an apoptosis pathway as suggested by immunofluorescence analysis.

(o-Phenylenediamino)borylstannanes: Efficient Reagents for Borylation of Various Alkyl Radical Precursors.

(o-Phenylenediamino)borylstannanes were newly synthesized to achieve radical boryl substitutions of a variety of alkyl radical precursors. Dehalogenative, deaminative, decharcogenative, and decarboxylative borylations proceeded in the presence of a radical initiator to give the corresponding organic boron compounds. Radical clock experiments and computational studies have provided insights into the mechanism of the homolytic substitution (SH 2) of the borylstannanes with alkyl radical intermediates. DFT calculation disclosed that the phenylenediamino structure lowered the LUMO level including the vacant p-orbital on the boron atom to enhance the reactivity to alkyl radicals in SH 2. Moreover, C(sp3 )-H borylation of THF was accomplished using the triplet state of xanthone.

Development and Application of a Peroxyl Radical Clock Approach for Measuring Both Hydrogen-Atom Transfer and Peroxyl Radical Addition Rate Constants.

The rate-determining step in free radical lipid peroxidation is the propagation of the peroxyl radical, where generally two types of reactions occur: (a) hydrogen-atom transfer (HAT) from a donor to the peroxyl radical; (b) peroxyl radical addition (PRA) to a "C═C" double bond. Peroxyl radical clocks have been used to determine the rate constants of HAT reactions (kH), but no radical clock is available to measure the rate constants of PRA reactions (kadd). In this work, we modified the analytical approach on the linoleate-based peroxyl radical clock to enable the simultaneous measurement of both kH and kadd. Compared to the original approach, this new approach involves the use of a strong reducing agent, LiAlH4, to completely reduce both HAT and PRA-derived products and the relative quantitation of total linoleate oxidation products with or without reduction. The new approach was then applied to measuring the kH and kadd values for several series of organic substrates, including para- and meta-substituted styrenes, substituted conjugated dienes, and cyclic alkenes. Furthermore, the kH and kadd values for a variety of biologically important lipids were determined for the first time, including conjugated fatty acids, sterols, coenzyme Q10, and lipophilic vitamins, such as vitamins D3 and A.

Mn(OAc)3-Mediated Addition Reactions of NaSO2CF3 and Perhalogenated Carboxylic Acids with Unactivated Alkenes Conjectured by a Single Electron Transfer and Halogen Abstraction Mechanism

A free-radical halotrifluoromethylation of olefins by using Mn(OAc)3·2H2O, CF3SO2Na, and perhalogenated carboxylic acids has been achieved. Perhalogenated carboxylic acids act as a halogen source and CF3SO2Na acts as a CF3 source. The reaction displayed good tolerance of functional groups in the substrates under mild conditions. The radical clock experiment and TEMPO inhibition experiment support a radical process. The halogen reagent competition experiment shows that the last step of halogenation process is mainly through a halogen abstraction mechanism.

Visible-Light-Driven Anti-Markovnikov Hydrocarboxylation of Acrylates and Styrenes with CO 2

Light-driven carbon dioxide (CO2) capture and utilization is one of the most fundamental reactions in Nature. Herein, we report the first visible-light-driven photocatalyst-free hydrocarboxylation ...

Carboalumination of Seven-Membered-Ring trans-Alkenes.

Seven-membered-ring trans-alkenes undergo rapid hydro- and carboalumination reactions in the absence of a catalyst with complete regio- and diastereoselectivity. Control experiments, including deuterium labeling, adding radical inhibitors, and using a radical clock, suggest that these reactions proceed by a concerted mechanism. The products of the reaction possess a new carbon-aluminum bond that can then undergo subsequent transformations, particularly oxidation, providing functionalized products as single stereoisomers.

Reversible Formation of Alkyl Radicals at [Fe4S4] Clusters and Its Implications for Selectivity in Radical SAM Enzymes.

All kingdoms of life use the transient 5'-deoxyadenosyl radical (5'-dAdo•) to initiate a wide range of difficult chemical reactions. Because of its high reactivity, the 5'-dAdo• must be generated in a controlled manner to abstract a specific H atom and avoid unproductive reactions. In radical S-adenosylmethionine (SAM) enzymes, the 5'-dAdo• is formed upon reduction of SAM by an [Fe4S4] cluster. An organometallic precursor featuring an Fe-C bond between the [Fe4S4] cluster and the 5'-dAdo group was recently characterized and shown to be competent for substrate radical generation, presumably via Fe-C bond homolysis. Such reactivity is without precedent for Fe-S clusters. Here, we show that synthetic [Fe4S4]-alkyl clusters undergo Fe-C bond homolysis when the alkylated Fe site has a suitable coordination number, thereby providing support for the intermediacy of organometallic species in radical SAM enzymes. Addition of pyridine donors to [(IMes)3Fe4S4-R]+ clusters (R = alkyl or benzyl; IMes = 1,3-dimesitylimidazol-2-ylidene) generates R•, ultimately forming R-R coupled hydrocarbons. This process is facile at room temperature and allows for the generation of highly reactive radicals including primary carbon radicals. Mechanistic studies, including use of the 5-hexenyl radical clock, demonstrate that Fe-C bond homolysis occurs reversibly. Using these experimental insights and kinetic simulations, we evaluate the circumstances in which an organometallic intermediate can direct the 5'-dAdo• toward productive H-atom abstraction. Our findings demonstrate that reversible homolysis of even weak M-C bonds is a feasible protective mechanism for the 5'-dAdo• that can allow selective X-H bond activation in both radical SAM and adenosylcobalamin enzymes.

Radical Pentafluoroethylation of Unactivated Alkenes Using CuCF2CF3.

We have found that the CuCF2CF3 complex generated from low-cost pentafluoroethane is a convenient and practical source for the CF2CF3 radical under aerobic conditions at room temperature. Using this system, readily available unactivated alkenes can be pentafluoroethylated to provide novel allylic CF2CF3 compounds with excellent E-selectivity and functional group tolerability. Mechanistic studies including TEMPO-CF2CF3 trapping and radical clock experiments provided strong evidence for radical pathways, offering a new opportunity for copper-mediated radical perfluoroalkylation.

Cobalt-Bisoxazoline-Catalyzed Enantioselective Cross-Coupling of α-Bromo Esters with Alkenyl Grignard Reagents.

The first catalytic asymmetric Kumada cross-coupling of organic halides with alkenyl Grignard reagents has been developed. The reaction was promoted by the cobalt-bisoxazoline catalyst and afforded various α-alkyl-β,γ-unsaturated esters with excellent enantioselectivities and moderate to good yields (≤95% ee and ≤82% yields). The formal synthesis of the California red scale pheromone using this method was investigated, and radical clock experiments were performed.

Evidence against Single-Electron Transfer in the Additions of Most Organomagnesium Reagents to Carbonyl Compounds.

A radical clock system was developed to investigate single-electron transfer (SET) in the reactions of organomagnesium reagents with carbonyl compounds. The fluorenylcyclopropyl radical clock was selected because it is the fastest known radical clock. Additions of Grignard reagents to aldehydes or methyl ketones provided no evidence for ring-opened products that would indicate reaction through SET. Additions of some Grignard reagents to aromatic ketones, however, resulted in the formation of ring-opened products, suggesting SET.

Kinetically Controlled Radical Addition/Elimination Cascade: From Alkynyl Aziridine to Fluorinated Allenes.

A kinetically controlled radical addition/elimination reaction generating fluorinated allenes was developed. This strategy offers a route to a facile synthesis of diverse trifluoromethyl, difluoromethylene, and perfluoroalkyl functionalized allenes from readily available fluoroalkyl halides and alkynyl aziridines under visible-light irradiation. Density functional theory calculation of this radical clock type of reaction revealed a kinetically controlled C-N bond cleavage overcoming the alternative thermodynamically controlled C-C bond cleavage process.

Radical Clock Probes to Determine Carbohydrate Radical Stabilities.

Carbohydrate radical stabilities in the 1- and 2-position have been determined by a radical clock approach, starting from cyclopropanated sugars with xanthates as precursors. Various hexoses and pentoses afforded 1-deoxy sugars as main products, indicating that anomeric radicals are more stable than radicals in the 2-position. An additional influence of the configurations on radical stabilities has been observed. Our results should be interesting for the understanding of 1,2-radical rearrangements in carbohydrate chemistry and offer an easy access to deoxy-vinyl sugars.

Oxidative Addition of C–X Bonds and H–H Activation Using PNNP‐Iron Complexes

AbstractIron(0) complex bearing a phenanthroline‐based meridional PNNP ligand [{Fe(PNNP)}2(μ‐N2)] (1) (PNNP=2,9‐bis((diphenylphosphino)methyl)‐1,10‐phenanthroline) smoothly reacted with CH3I at ambient temperature to cleave C–I bond, resulting in the formation of the corresponding oxidative addition product, [Fe(CH3)(I)(PNNP)] (2). Complex 2 was fully identified by NMR and its structure was determined by a single crystal X‐ray diffraction study. Mechanistic study using cyclopropylmethyl bromide as a radical clock supported a radical pathway for the C–I bond cleavage of CH3I. Complex 2 underwent deprotonation on treatment with NaOtBu to form 4, which possessed a dearomatized phenanthroline backbone. Complex 4 further reacted with H2 to cleave H–H bond. The reaction was mediated by metal‐ligand cooperation process that involves re‐aromatization of the phenanthroline backbone of the PNNP ligand.

Au Nanoparticle‐Catalyzed Silaboration of Aryl‐Substituted Cyclopropyl Aldehydes Forming Rearranged β‐Boronate Silyl Enol Ethers

2‐Aryl‐substituted cyclopropyl aldehydes undergo an unprecedented Au nanoparticle‐catalyzed silaboration leading to rearranged linear β‐boronate‐bearing silyl enol ethers. Formation of these products is attributed to the ring opening radical clock rearrangement of the intermediate α‐cyclopropyl radical into a benzyl radical.