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In this short review, we summarize the recent developments on thermo-driven C(sp3)–O bond radical scission methods and their applications in the construction of C(sp3)–C bonds via conjugate addition with activated double bonds and reductive coupling mediated by economic 3d metals, in particular nickel. We have arranged the review based on three approaches for C(sp3)–O bond radical scission (vide infra). After generating the radical intermediates, their subsequent transformation into C(sp3)–C bonds enabled by C(sp3)–O cross-electrophile coupling with carbon electrophiles is discussed in detail.1 Introduction2 Direct Single-Electron Transfer to a C(sp3)–O Bond3 Radical Scission of Activated C(sp3)–O Bonds via Single-Electron Transfer to Protecting Groups4 In Situ Activation of Alcohols5 Summary and Outlook

Ni-catalyzed asymmetric arylation/vinylation of racemic 1-chloro-1-alkanol esters with aryl/vinyl electrophiles has been developed for the synthesis of aryl/vinyl alkyl carbinol esters with a high level of enantioselectivity.

A Ni-catalyzed reductive cross-coupling between α-C-tosyl peptides and Csp2 triflates/halides has been developed. This protocol enables the formation of various unnatural di- and tripeptides containing vinyl and aryl side chains, and it expands the applications of Ni-catalyzed reductive cross-coupling in late-stage diversification of peptides.

An efficient kinetic resolution of N-aryl β-amino alcohols has been developed via asymmetric para-aminations of anilines with azodicarboxylates enabled by chiral phosphoric acid catalysis. Broad substrate scope and high kinetic resolution performances were afforded with this method. Control experiments supported the critical roles of the NH and OH group in these reactions.

An efficient radical conjugate addition/enantioselective protonation process was developed for N-aryl glycines and alkenyl oxazolines enabled by the cooperative photoredox catalysis and chiral phosphoric acid catalysis, which generated a series of chiral oxazolines bearing an α-stereocenter with high enantioselectivities. The facile transformations of the chiral oxazoline products into enantioenriched lactams and γ-amino esters bearing α-stereocenters demonstrate the value of this method.

An efficient approach for asymmetric synthesis of planar-chiral macrocycles (paracyclophanes) has been disclosed through enantioselective electrophilic aromatic aminations with azodicarboxylates enabled by chiral phosphoric acid catalysis. A wide range of chiral macrocycles bearing varied ring sizes (16 to 23-membered) and functional group-containing ansa chains were readily afforded using this method, with excellent yields and high enantioselectivities (23 examples, up to 99.5 : 0.5 er). Experimental studies and DFT calculations were performed to elucidate the mechanism and origin of stereoselectivities of these reactions. Preliminary utilization of the planar-chiral macrocycle as chiral organocatalyst showcased the potential applications of these novel chiral skeletons.

An efficient kinetic resolution of

A novel kinetic resolution of 2,2-disubstituted dihydroquinolines was achieved by regioselective asymmetric halogenations enabled by chiral phosphoric acid catalysis. A series of dihydroquinolines bearing 2,2-disubstitutions were well-tolerated in these reactions, generating both the recovered dihydroquinolines and C-6-brominated products with high enantioselectivities, with s-factors up to 149. In addition, this kinetic resolution protocol is also applicable for 2,2-disubstituted tetrahydroquinoline and asymmetric iodonation reaction.

The first kinetic resolution of hydroquinoline derivatives with α,α-disubstitution has been achieved through asymmetric remote aminations with azodicarboxylates enabled by chiral phosphoric acid catalysis. Mechanistic studies suggest a monomeric catalyst pathway proceeding through rate- and enantio-determining electrophilic attack promoted by a network of attractive non-covalent interactions between the substrate and catalyst. Facile subsequent removal and transformations of the newly introduced hydrazine moiety enable these protocols to serve as powerful tools for asymmetric synthesis of N-heterocycles with α,α-disubstitution.

An AgI-mediated ethoxycarbonyldifluoromethylation of isocyanides has been developed. This radical cascade reaction involves the addition of difluoromethylene radical to the isocyanide functionality, and subsequent homolytic aromatic substitution to give difluoromethylated phenanthridines with a good functional-group tolerance.

Copper-catalyzed gem-difluoromethylenation of the C(sp2)–H bonds of alkenes has been developed. This protocol is the first to efficiently achieve gem-difluoromethylenation of C(sp2)–H bonds of unactivated aliphatic terminal olefins and is applied in gem-difluoromethylenation/cyclization of alkenes.

Manganese-mediated/-catalyzed oxidative carboazidation of acrylamides was developed for the synthesis of various azido oxindoles in 32% to 99% yields. tert-Butyl peroxybenzoate (TBPB) was used as an oxidant for the Mn-catalyzed method. And a Mn(II)/Mn(IV)/Mn(III) catalysis cycle via a stepwise or concerted regeneration of high-valent manganese was proposed for this protocol. This reaction system exhibits great functional group tolerance.

Summary Chiral 1,3-propanediamine moieties are present in a range of bioactive small molecules, chiral catalysts, and ligands. The enantioselective desymmetrization of 2-substituted 1,3-propanediamines is a straightforward and efficient method to give access to these types of enantioenriched compounds. However, the state of the art of this strategy is limited to enzymatic catalysis and 2-monosubstituted substrates. Herein, we report the nonenzymatic desymmetrization of C-2-substituted 1,3-propanediamines through chiral phosphoric-acid-catalyzed asymmetric para-aminations of anilines with azodicarboxylates. Both C-2-monosubstituted and C-2-disubstituted 1,3-propanediamine substrates are compatible with this method, providing chiral 1,3-propanediamines bearing C-2 tertiary and quaternary stereocenters with high enantioselectivities. Preliminary mechanistic studies are performed to shed light on the reaction mechanism and the key asymmetric induction transition state.

The first AgI-mediated C–H ethoxycarbonyl difluoromethylation with TMSCF2COOEt (TMS = trimethylsilyl) has been developed. The radical difluoromethylation proceeds smoothly to give the difluoromethylated arenes in moderate to high yields with Friedel–Crafts-type regioselectivity. Mechanistic studies indicate that the innate C–H difluoromethylation proceeds through an electrophilic radical-type pathway.

A simple AgI-mediated direct difluoromethylation reaction of activated alkenes by using TMSCF2COOEt (TMS = trimethylsilyl) under mild reaction conditions has been described. This reaction tolerates a variety of functional groups and allows for a highly efficient synthesis of various difluoro-containing oxindoles. Mechanistic investigations indicate that a difluoromethyl radical initiated the cascade sequence by undergoing an addition reaction to the alkene.

Efficient direct gem-difluoromethylenation of an sp(3)-hybridized carbon center in benzyl bromides using benzo-1,3-azolic (oxa-, thia- or aza-) difluoromethyl bromides for construction of a CH2-CF2 linkage has been developed through radical/radical C-C cross-coupling via two separate single electron transfer processes (SET) under the promotion of different copper sources.

We report the first example of a novel two-photon active, biocompatible, and macrophage cell-membrane permeable carbazole-based cyanine fluorophore for the detection of three biologically important ROS, namely, ˙OH, O2(-) and OCl(-) in solution. This versatile probe shows cellular protection not only in stimulated macrophages from phorbol-12-myristate-13-acetate-induced morphological changes but also lipopolysaccharide-induced cytotoxicity by quenching with the O2(-) and OCl(-) production, respectively. Such protection could be visualized by a distinct change in the fluorescence intensity of the probe.

An efficient method for the synthesis of the thermally stable and pharmaceutically important gem-difluoromethylene azo compounds is developed. This protocol achieved gem-difluoromethylenation of the nitrogen center of arenediazonium salts through in situ generated benzo-1,3-diazolic difluoromethylene radical addition to arenediazonium salts under mild Ag-initiated conditions.

In this new Ag(I)-promoted reaction between N-arylacrylamides and ethyl trimethylsilyldifluoroacetate, the corresponding 3-(2-ethoxycarbonyl-2,2-difluoroethyl)-2-oxo-2,3-dihydro-1H-indoles have been prepared in good yields.

A mild, versatile and efficient method for the silver(I)-catalyzed oxidative decarboxylative gem-difluoromethylenation has been developed. The radical cascade reaction comprises the addition of an oxidatively generated difluoromethylene radical to the isonitrile functionality and subsequent homolytic aromatic substitution. It provides a novel and efficient access to the C-CF2 bond formation.

Efficient direct gem-difluoromethylenation of an sp3-hybridized carbon center in benzyl bromides using benzo-1,3-azolic (oxa-, thia- or aza-) difluoromethyl bromides for construction of a CH2–CF2 linkage has been developed through radical/radical C–C cross-coupling via two separate single electron transfer processes (SET) under the promotion of different copper sources.

To explore the regulatory mechanism of Siahl in the pathogenesis of hypoxic pulmonary hypertension (HPH) in rats.According to the random number table, 40 adult male Wistar rats were randomly divided into 5 groups (n = 8 each). And the animals were exposed to normoxia or hypoxia for 3, 7, 14 or 21 days respectively. The HPH model was established by normobaric intermittent hypoxia. Mean pulmonary arterial pressure (mPAP), ratio of vascular wall area to total vascular area (WA%), ratio of vascular lumen area to total vascular area (LA%) and right ventricle hypertrophy index (RVHI) were measured. The mRNA and protein relative levels of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) were detected by in situ hybridization and immunohistochemistry respectively. Reverse transcriptase-polymerase chain reaction ( RT-PCR) and in situ hybridization were used to determine the relative expressions of mRNA of hypoxia-inducible factor-1 (FIH) and Siahl. Immunohistochemistry and Western blot were employed to determine the relative expressions of proteins of FIH and Siahl.The levels of mPAP, WA% and LA% were significantly higher after 7-day hypoxia than those in normoxic control (21. 3 1. 6) vs (15. 9 ± 1. 3) mmHg (1 mmHg = 0. 133 kPa), (41.4 ± 2.8)% vs (35.0 ± 2.2)%, (58.6 ± 2.8)% vs (65.0 ± 2.2)%, all P0.05). The level of RVHI was significantly higher after 14-day hypoxia than that in normoxic control ((27. 0 ± 1. 8) % vs (3. 2 ± 2. 1) %, P0. 05). The relative expression of HIF-1α mRNA was significantly higher after 14-day hypoxia than that in normoxic control (0. 188 ± 0. 014 vs 0. 150 ± 0. 014, P0. 05). The relative expression of HIF-1α protein was significantly higher after 3-day hypoxia than that in normoxic control (0. 186 ± 0.014 vs 0. 067 ± 0.008, P0.05). The relative levels of VEGF mRNA and protein were significantly higher after 7-day hypoxia than those in normoxic control (0. 152 ± 0. 019 vs 0. 057 ± 0. 007, 0. 176 ± 0. 017 vs 0. 083 ± 0. 010, both P0. 05). The relative expression of FIH mRNA had little changes after exposure to hypoxia compared with normoxia. However the related expression of FIH protein was markedly lower after 7-day hypoxia than that in normoxic control (0. 166 ± 0. 015 vs 0. 200 ± 0. 017, P0. 05). The relative levels of Siahl mRNA and protein were markedly higher after 7-day hypoxia than those in normoxic control (0. 144 ± 0. 014 vs 0. 067 ± 0. 010, 0. 136 ± 0. 017 vs 0. 084 ± 0. 019, both P0. 05). Linear correlation analysis showed that HIF-1α protein was positively correlated with the relative levels of VEGF mRNA and VEGF protein (r = 0. 545, 0. 523, both P0. 01) while FIH protein was negatively correlated with the relative levels of VEGF mRNA and VEGF protein (r = -0. 785, -0. 788, both P0. 01). There was a positive correlation between the relative levels of Siahi mRNA and Siahl protein (r = 0. 823, P0. 01) while a negative correlation existed between the relative levels of Siahl protein and FIH protein (r = -0. 671, P0. 01).Under chronic hypoxia, Siahl is transcriptionally induced in pulmonary arterioles and it facilitates the degradation and decline of FIR in rats. And deceased FIH protein in pulmonary arterioles under hypoxia may attenuate its inhibitory effect on the transactivational activity of HIF-l a and promote the transactivation of such HIF-1α target gene as VEGF. Thus it is probably implicated in the pathogenesis of HPH.

A mild, versatile and efficient method for the silver(I)-catalyzed oxidative decarboxylative gem-difluoromethylenation has been developed. The radical cascade reaction comprises the addition of an oxidatively generated difluoromethylene radical to the isonitrile functionality and subsequent homolytic aromatic substitution. It provides a novel and efficient access to the C-CF2 bond formation.

Extended 2 dimensional MMR Code is a kind of facsimile signal source code. Vertical relativity is utilized when MMR code is coded. In addition, there is no line synchronized code in MMR code. So when an error occurs, the bitstream cannot be decoded after the error point. To prevent error diffusion in MMR coding, this paper introduces a method: moving window error-correcting arithmetic which can partly correct some random and outburst errors