Causes and global, regional, and national burdens of traumatic brain injury from 1990 to 2019.

PURPOSE: Traumatic brain injury (TBI), currently a major global public health problem, imposes a significant economic burden on society and families. We aimed to quantify and predict the incidence and severity of TBI by analyzing its incidence, prevalence, and years lived with disability (YLDs). The epidemiological changes in TBI from 1990 to 2019 were described and updated to provide a reference for developing prevention, treatment, and incidence-reducing measures for TBI. METHODS: A secondary analysis was performed on the incidence, prevalence, and YLDs of TBI by sex, age group, and region (n = 21,204 countries and territories) between 1990 and 2019 using the Global Burden of Diseases, Injuries, and Risk Factors Study 2019. Proportions in the age-standardized incidence rate due to underlying causes of TBI and proportions of minor and moderate or severe TBI were also reported. RESULTS: In 2019, there were 27.16 million (95% uncertainty intervals (UI): 23.36 - 31.42) new cases of TBI worldwide, with age-standardized incidence and prevalence rates of 346 per 100,000 population (95% UI: 298-401) and 599 per 100,000 population (95% UI: 573-627), respectively. From 1990 to 2019, there were no significant trends in global age-standardized incidence (estimated annual percentage changes: -0.11%, 95% UI: -0.18% - -0.04%) or prevalence (estimated annual percentage changes: 0.01%, 95% UI: -0.04% - 0.06%). TBI caused 7.08 million (95% UI: 5.00 - 9.59) YLDs in 2019, with age-standardized rates of 86.5 per 100,000 population (95% UI: 61.1 - 117.2). In 2019, the countries with higher incidence rates were mainly distributed in Central Europe, Eastern Europe, and Australia. The 2019 global age-standardized incidence rate was higher in males than in females. The 2019 global incidence of moderate and severe TBI was 182.7 per 100,000 population, accounting for 52.8% of all TBI, with falls and road traffic injuries being the main causes in most regions. CONCLUSIONS: The incidence of moderate and severe TBI was slightly higher in 2019, and TBI still accounts for a significant portion of the global injury burden. The likelihood of moderate to severe TBI and the trend of major injury under each injury cause from 1990 to 2019 and the characteristics of injury mechanisms in each age group are presented, providing a basis for further research on injury causes in each age group and the future establishment of corresponding policies and protective measures.

Intermolecular 1,2-Difunctionalization of Alkenes Enabled by Fluoroamide-Directed Remote Benzyl C(sp3)-H Functionalization.

A copper-catalyzed remote benzylic C-H functionalization strategy enabling 1,2-difunctionalization of alkenes with 2-methylbenzeneamides and nucleophiles, including alcohols, indoles, pyrroles, and the intrinsic amino groups, is reported, which is characterized by its redox-neutral conditions, exquisite site-selectivity, broad substrate scope, and wide utilizations of late-stage modifying bioactive molecules. This reaction proceeds through nitrogen-centered radical generation, hydrogen atom transfer, benzylic radical addition across the alkenes, single-electron oxidation, and carbocation electrophilic course cascades. While using external nucleophiles manipulates three-component alkene alkylalkoxylation and alkyl-heteroarylation with 2-methylbenzeneamides to access dialkyl ethers, 3-alkylindoles, and 3-alkylpyrroles, omitting the external nucleophiles results in two-component alkylamidation ([5+2] annulation) of alkenes with 2-methylbenzeneamides to benzo-[f][1,2]thiazepine 1,1-dioxides.

Copper-catalyzed C-H [3 + 2] annulation of N-substituted anilines with α-carbonyl alkyl bromides via C(sp3)-Br/C(sp2)-H functionalization.

A copper-catalyzed C-H [3 + 2] annulation of N-substituted anilines with α-carbonyl alkyl bromides for the synthesis of 3,3'-disubstituted oxindoles is developed. Tandem C-H cycloamidation reactions of various α-carbonyl alkyl bromide derivatives including tertiary-α-bromoalkyl ketone esters, malonic esters and cycloalkanes, with N-aryl or alkyl substituted anilines, can be performed using this system, affording a vast array of valuable 3,3'-disubstituted oxindoles in moderate to good yields.

Manganese(iii)-promoted tandem phosphinoylation/cyclization of 2-arylindoles/2-arylbenzimidazoles with disubstituted phosphine oxides.

A simple and practical method for the synthesis of phosphoryl-substituted indolo[2,1-a]isoquinolin-6(5H)-ones and benzimidazo[2,1-a]isoquinolin-6(5H)-ones through manganese(iii)-promoted tandem phosphinoylation/cyclization of 2-arylindoles or 2-arylbenzimidazoles with disubstituted phosphine oxides was developed. In this transformation, new C-P bond and C-C bond were constructed simultaneously under silver-free conditions, exhibiting a broad substrate scope. It was noted that not only diarylphosphine oxides but also dialkyl and arylalkyl-phosphine oxides were compatible with the conditions.

Recent Advances in the Intermolecular Oxidative Difunctionalization of Alkenes.

Functionalization of alkenes has been well investigated by chemists, thus it has been extensively applied in organic synthesis and industries. In the past few decades, transition-metal, such as palladium, rhodium, gold, iridium, copper and iron, catalyzed functionalization reactions of alkenes have been significantly developed and played vital roles in synthesis. The difunctionalization of alkenes are appealing as an important alternative to the traditional approaches for the construction of useful carbon centers, particularly carbon quaternary centers, which commonly existed as structural motifs in numerous natural products, pharmaceuticals, and biologically active molecules. This account will summarize our recent advances in the intermolecular difunctionalization of alkenes, and also highlight the scope and limitations as well as the mechanisms of these difunctionalization reactions. In general, in this account the difunctionalization of alkenes starting from dicarbofunctionalization will be discussed. Then carboheterofunctionalization of alkenes will be intensively reviewed, and diheterofunctionalization will also be highlighted.

Palladium-Catalyzed Reductive [5+1] Cycloaddition of 3-Acetoxy-1,4-enynes with CO: Access to Phenols Enabled by Hydrosilanes.

A new palladium-catalyzed reductive [5+1] cycloaddition of 3-acetoxy-1,4-enynes with CO, enabled by hydrosilanes, has been developed for delivering valuable functionalized phenols. This methodology employs hydrosilanes as the external reagent to facilitate the [5+1] carbonylative benzannulation. The reaction is a conceptually and mechanistically novel carbonylative cycloaddition route for the construction of substituted phenols, through the formation of four new chemical bonds, with excellent functional-group tolerance.

Iron-Catalyzed Intermolecular 1,2-Difunctionalization of Styrenes and Conjugated Alkenes with Silanes and Nucleophiles.

The first iron-catalyzed 1,2-difunctionalization of styrenes and conjugated alkenes with silanes and either N or C, using an oxidative radical strategy, is described. Employing FeCl2 and di-tert-butyl peroxide allows divergent alkene 1,2-difunctionalizations, including 1,2-aminosilylation, 1,2-arylsilylation, and 1,2-alkylsilylation, which rely on a wide range of nucleophiles, namely, amines, amides, indoles, pyrroles, and 1,3-dicarbonyls, thus providing a powerful platform for producing diverse silicon-containing alkanes.

1,2-Alkylarylation of Styrenes with α-Carbonyl Alkyl Bromides and Indoles Using Visible-Light Catalysis.

A new intermolecular 1,2-alkylarylation of styrenes with α-carbonyl alkyl bromides and indoles using fac-[Ir(ppy)3] as the photoredox catalyst has been developed. The method allows the simultaneous formation of two new carbon-carbon bonds through three component reaction, and represents a new single-electron transfer (SET) strategy for the 1,2-alkylarylation of the styrenes with broad substrate scope and excellent functional group tolerance.

Silver-Mediated Intermolecular 1,2-Alkylarylation of Styrenes with α-Carbonyl Alkyl Bromides and Indoles.

A new iron-facilitated silver-mediated radical 1,2-alkylarylation of styrenes with α-carbonyl alkyl bromides and indoles is described, and two new C-C bonds were generated in a single step through a sequence of intermolecular C(sp(3)-Br functionalization and C(sp(2))-H functionalization across the alkenes. This method provides an efficient access to alkylated indoles with broad substrate scope and excellent selectivity.

[5+2] Cycloaddition of 2-(2-Aminoethyl)oxiranes with Alkynes via Epoxide Ring-Opening: A Facile Access to Azepines.

A new FeCl3 and BF3 ⋅OEt2 co-catalyzed tandem hetero-[5+2] cycloaddition of 2-(2-aminoethyl)oxiranes with a wide range of alkynes, including terminal alkynes and alkyl-substituted internal alkynes is presented. This is the first example of rapid and facile production of diverse 2,3-dihydro-1H-azepines through a sequence of epoxide ring-opening, annulation, and dehydroxylation with broad substrate scope and exquisite selectivity control.

Metal-free radical 5-exo-dig cyclizations of phenol-linked 1,6-enynes for the synthesis of carbonylated benzofurans.

A new metal-free radical 5-exo-dig cyclization of phenol-linked 1,6-enynes with O2, 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), and tBuONO is described. With this general method, carbonylated benzofurans can be accessed through incorporation of two oxygen atoms into the product from O2 and TEMPO through dioxygen activation and oxidative cleavage of the N-O bond, respectively.

Metal-Free Radical [2+2+1] Carbocyclization of Benzene-Linked 1,n-Enynes: Dual C(sp(3))-H Functionalization Adjacent to a Heteroatom.

A new metal-free oxidative radical [2+2+1] carbocyclization of benzene-linked 1,n-enynes with two C(sp(3))-H bonds adjacent to the same heteroatom is described. This method achieves two C(sp(3))-H oxidative functionalizations and an annulation, thus providing efficient and general access to a variety of fused five-membered carbocyclic hydrocarbons.

Rhodium(III)-Catalyzed [3+2]/[5+2] Annulation of 4-Aryl 1,2,3-Triazoles with Internal Alkynes through Dual C(sp2)-H Functionalization.

A rhodium(III)-catalyzed [3+2]/[5+2] annulation of 4-aryl 1-tosyl-1,2,3-triazoles with internal alkynes is presented. This transformation provides straightforward access to indeno[1,7-cd]azepine architectures through a sequence involving the formation of a rhodium(III) azavinyl carbene, dual C(sp(2))-H functionalization, and [3+2]/[5+2] annulation.

Alkylation of terminal alkynes with transient σ-alkylpalladium(II) complexes: a carboalkynylation route to alkyl-substituted alkynes.

A mild and general alkylation of terminal alkynes with transient σ-alkylpalladium(II) complexes for assembling alkyl-substituted alkynes is described. This method represents a new way to the use of transient σ-alkylpalladium(II) complexes in organic synthesis through 1,2-carboalkynylation of alkenes.

Rhodium-catalyzed synthesis of isoquinolines and indenes from benzylidenehydrazones and internal alkynes.

A new route is presented for the selective assembly of isoquinolines and indenes by rhodium-catalyzed tandem cyclization of benzylidenehydrazones with internal alkynes. This method involves the selective cleavage of the N-N bond and the C═N bonds and is dependent on the substituents of the benzylidenehydrazone.

Synthesis of benzocyclohepta[b]indoles by Lewis acid catalyzed annulation of two 3-(1H-isochromen-1-yl)-1H-indoles.

A novel Lewis acid catalyzed annulation reaction has been established for the synthesis of benzocyclohepta[b]indoles. This method represents a new annulation strategy to a seven-membered carbocyclic ring system from two 3-(1H-isochromen-1-yl)-1H-indole molecules using Cu(OTf)2 catalyst; moreover, the products, benzocyclohepta[b]indoles, can be used as the rapid mercuric ion colorimetric detection reagents.

Metal-free oxidative ipso-carboacylation of alkynes: synthesis of 3-acylspiro[4,5]trienones from N-arylpropiolamides and aldehydes.

A general and metal-free radical route to synthesis of 3-acylspiro[4,5]trienones is established that utilizes TBHP (tert-butyl hydrogenperoxide) as an oxidation and a reaction partner to trigger the oxidative ipso-carboacylation of N-arylpropiolamides with aldehydes. This method offers a new difunctionalization of alkynes through oxidative cross coupling of the aldehyde C(sp(2))-H bond with an ipso-aromatic carbon.

Hexafluoroantimonic acid catalysis: formal [3+2+2] cycloaddition of aziridines with two alkynes.

A practical method for the synthesis of azepine derivatives, a typical seven-membered heterocyclic ring system, was developed and involves the use of hexafluoroantimonic acid to catalyze a formal [3+2+2] cycloaddition of aziridines with two alkynes. This method was applicable to two of the same or different terminal alkynes for the [3+2+2] cycloaddition with unactivated aziridines, and furnished the corresponding azepine derivatives in good yields with good levels of chemo- and regioselectivity. The mechanism was also discussed according to the results of the in situ HRMS and (1)H NMR analysis.

Palladium-catalyzed oxidative difunctionalization of alkenes with α-carbonyl alkyl bromides initiated through a Heck-type insertion: a route to indolin-2-ones.

The oxidative interception of various σ-alkyl palladium(II) intermediates with additional reagents for the difunctionalization of alkenes is an important research area. A new palladium-catalyzed oxidative difunctionalization reaction of alkenes with α-carbonyl alkyl bromides is described, in which the σ-alkyl palladium(II) intermediate is generated through a Heck insertion and trapped using an aryl C(sp(2))-H bond. This method can be applied to various α-carbonyl alkyl bromides, including primary, secondary, and tertiary α-bromoalkyl esters, ketones, and amides.

Rhodium(III)-catalyzed [3+2] annulation of 5-aryl-2,3-dihydro-1H-pyrroles with internal alkynes through C(sp²)-H/alkene functionalization.

This study describes a new rhodium(III)-catalyzed [3+2] annulation of 5-aryl-2,3-dihydro-1H-pyrroles with internal alkynes using a Cu(OAc)2 oxidant for building a spirocyclic ring system, which includes the functionalization of an aryl C(sp(2))-H bond and addition/protonolysis of an alkene C=C bond. This method is applicable to a wide range of 5-aryl-2,3-dihydro-1H-pyrroles and internal alkynes, and results in the assembly of the spiro[indene-1,2'-pyrrolidine] architectures in good yields with excellent regioselectivities.