Social inequalities in children's mental health: isn't it time for action?

Maria Melchior

Sorbonne Université, INSERM, Institut Pierre Louis d'Épidémiologie et de Santé Publique (IPLESP), Equipe de Recherche en Epidémiologie Sociale (ERES), F75012, Paris, France Social inequalities with regard to children's and adolescents' mental health are documented for many years [START_REF] Costello | Relationships between poverty and psychopathology: a natural experiment[END_REF][START_REF] Mclaughlin | Socioeconomic status and adolescent mental disorders[END_REF][START_REF] Reiss | Socioeconomic status, stressful life situations and mental health problems in children and adolescents: Results of the German BELLA cohort-study[END_REF][START_REF] Hegelund | Parental socioeconomic position and risk of ADHD in offspring: a cohort study of 9648 individuals in Denmark 1976-2013[END_REF] and appear to have increased over time [START_REF] Collishaw | Brief report: a comparison of child mental health inequalities in three UK population cohorts[END_REF]. Moreover, while the relationship between family socioeconomic circumstances and children's and adolescents' risks of mental health difficulties largely reflects the role of determinants outside of the healthcare context, there is also evidence that even in universal healthcare systems, there are disparities with regard to access to care in case of psychological or neurodevelopmental disparities, which further increase socioeconomic inequalities in this area [START_REF] Chui | Inequalities in referral pathways for young people accessing secondary mental health services in south east London[END_REF].

As we enter the third academic year following the onset of the COVID-19 epidemic, it is impossible to ignore the toll the epidemic has taken on youths and associated socioeconomic inequalities in schooling and mental health. In Europe as in other parts of the world, millions of children were affected by school closures, which impacted their learning, sociability and perspectives for the future [START_REF] Unicef | Preventing a 'lockdown generation[END_REF]. For instance, in a study conducted for UNICEF in 2020 among 5000 children and adolescents, over half indicated that they learnt less since the beginning of the epidemic, 60% stated they preferred face-to-face learning, and 40% were worried about what would happen after the epidemic is over. Additionally, the epidemic has deprived children and adolescents of access to school-based healthcare and other services, leading to a reduction in the identification of cases of neglect and intra-familial violence which appear to have increased [START_REF] Chaabane | The Impact of COVID-19 School Closure on Child and Adolescent Health: A Rapid Systematic Review[END_REF][START_REF] Calvano | Families in the COVID-19 pandemic: parental stress, parent mental health and the occurrence of adverse childhood experiences-results of a representative survey in Germany[END_REF]. Lockdowns have also been related to negative changes in youths health behaviours. For example, a nationwide Italian study showed that in 2020 over 30% of primary school and over 50% of middle school students spent more than 2 hours a day using a screen for purposes other than distance learning, while their physical activity levels significantly dropped [START_REF] Scarpellini | Distance learning in Italian primary and middle school children during the COVID-19 pandemic: a national survey[END_REF]. Finally, numerous families have experienced COVID-19-related illness, sometimes death, financial difficulties and uncertainty about the future, which can also impact their children [START_REF] Calvano | Families in the COVID-19 pandemic: parental stress, parent mental health and the occurrence of adverse childhood experiences-results of a representative survey in Germany[END_REF][START_REF] Moulin | Risk and protective factors related to children's symptoms of emotional difficulties and hyperactivity/inattention during the COVID-19-related lockdown in France: results from a community sample[END_REF].

Overall, consistent evidence indicates that youths levels of sleep as well as psychological difficulties are higher recently than in previous years, with unknown perspectives as of now. A recent metaanalysis, based on twenty-three studies, reported massive and higher than expected levels of mental health difficulties in children and adolescents in the context of the COVID-19 epidemic (symptoms of depression: 29%, anxiety: 26%, sleep problems: 44%, post-traumatic stress symptoms: 48%) [START_REF] Ma | Prevalence of mental health problems among children and adolescents during the COVID-19 pandemic: A systematic review and metaanalysis[END_REF]. It is important to note that this review was mostly based on cross-sectional data exclusively from China, there is therefore need for robust data from other areas of the world, including Europe. However, existing evidence suggests that in European countries levels of mental distress among children and adolescents have also increased [START_REF] Moulin | Risk and protective factors related to children's symptoms of emotional difficulties and hyperactivity/inattention during the COVID-19-related lockdown in France: results from a community sample[END_REF][START_REF] Hu | COVID-19 and adolescent mental health in the United Kingdom[END_REF], as have levels of emergency room visits related to eating disorders and self-harm [START_REF] Ford | Mental health of children and young people during pandemic[END_REF].

All of these mental health risks related to the COVID-19 pandemic and the associated preventive measures have had greater consequences on children and adolescents growing up in families experiencing disadvantage or in deprived neighbourhoods [START_REF] Moulin | Risk and protective factors related to children's symptoms of emotional difficulties and hyperactivity/inattention during the COVID-19-related lockdown in France: results from a community sample[END_REF][START_REF] Hu | COVID-19 and adolescent mental health in the United Kingdom[END_REF][START_REF] Ford | Mental health of children and young people during pandemic[END_REF][START_REF] Li | Socioeconomic inequality in child mental health during the COVID-19 pandemic: First evidence from China[END_REF]. These children have also disproportionately been affected in terms of academic achievement [START_REF] Unicef | Preventing a 'lockdown generation[END_REF]. Hence, the COVID-19 pandemic could significantly impact the socioeconomic future of millions of children, fuelling a vicious circle of later academic, work-related and mental health difficulties.

The health crisis, which we are experiencing for the past two years, has shed light upon the extent of socioeconomic inequalities with regard to mental health in children and adolescents and their increase over time. As advocated by the WHO Commission on Social Determinants of Health 15 years ago, achieving health equity via action upon multiple determinants of health is possible [START_REF]Closing the gap in a generation: health equity through action on the social determinants of health[END_REF]. Among the overarching recommendations of this international working group, are improvements of "daily living conditions of girls, women and children" and massive investments in "early child development and education of boys and girls". These are more necessary than ever to prevent the marginalization of large parts of the population and reduce the possible impacts on the mental health of the next generation.


Laurent Marichal

Jean Philippe Renault

Jeril Degrouard

Rafael Leite Rubim

Guillaume Tresset

Serge Pin

Biophysical study of large macromolecular complexes

niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

flexible micropipette of known bending stiffness. This technique is promising for acquiring information that is currently difficult to quantify with other methods. Information such as nucleus stiffness and intracellular viscosity could be effectively evaluated.

Poster 13

The Experimental Study Of The Dynamics Of A Self-propelled Rod The self-propelled particles have two categories: Natural self-propelled particles such as bacteria, and artificial self-propelled particles made in a laboratory. It is much easier to study artificial particles because particle motion parameters can be controlled by changing laboratory conditions. In this poster, we describe the results of experiments on an artificial self-propelled rod and we show that this artificial particle has the properties of an active particle.

Yasamin Mohebi

Poster 14

Biophysical study of large macromolecular complexes

Laurent Marichal

Laurent Marichal 1,2 , Jean Philippe Renault 2 , Jéril Degrouard 1 , Rafael Rubim 1 , Guillaume Tresset 1 , Serge Pin 2 1 Laboratoire de Physique des Solides, CNRS, Université Paris-Saclay, France 2 NIMBE, CNRS, CEA Saclay, Université Paris-Saclay, France

Large macromolecular complexes are ubiquitous in biological media (e.g. protein complexes, membrane-bound complexes…). Specific biophysical techniques can be used to assess the interactions and structures of such complexes. Two independent systems were chosen as examples. The first one deals with the formation of protein coronas (protein/nanoparticle interactions) while the second system concerns virus encapsidation (protein/RNA interactions). Here, we can see how three techniques (isothermal titration calorimetry, cryoelectron microscopy, and small angle scattering) can be combined in order to answer fundamental questions.


Karen De La Vega-Hernández

Kevin Isaac

Fabrice Chemla

Franck Ferreira

Olivier Jackowski

Alejandro Perez-Luna
email: alejandro.perez_luna@sorbonne-universite.fr

Radical Silyl-and Germylzincation of Propargylic Alcohols

Keywords: Silylmetalation, Germylmetalation, Propargylic alcohols, Radical reactions, Zinc

The silyl-and germylzincation of terminal or internal propargylic alcohols by reaction with (Me3Si)3SiH/Et2Zn, [(Me3Si)3Si]2Zn/Et2Zn or Ph3GeH/Et2Zn is examined. These reactions proceed through the addition of silicon-or germanium-centered radicals across the carbon-carbon triple bond followed by the trapping by diethylzinc of the produced vinyl radical through homolytic substitution at the zinc atom. The influence of the hydroxy unit on the regio-and stereoselectivity of these reactions is discussed and compared to its role played in radical hydrosilylation and hydrogermylation reactions. Protocols developed to achieve the -regioselective silylzincation of propargyl alcohol and the -regioselective germylzincation of internal propargylic alcohols are particularly important, as they occur with trans stereoselectivity. For both procedures the C(sp 2 )-Zn bond remains available for subsequent in-situ electrophilic substitution leading overall to net alkyne trans difunctionalization.

Introduction

The prevalence of carbon-carbon double bonds in organic molecules makes the stereodefined construction of multi-substituted alkenes a central issue in organic synthesis. [START_REF] Flynn | Stereocontrolled Synthesis of Tetrasubstituted Olefins[END_REF][START_REF] Buttard | Recent advances in the stereoselective synthesis of acyclic all-carbon tetrasubstituted alkenes[END_REF] In this context, the addition of element-metal bonds across carbon-carbon triple bonds, i.e. alkyne elementometalation reactions, as coined by Negishi, [START_REF] Negishi | Alkyne Elementometalation-Pd-Catalyzed Cross-Coupling. Toward Synthesis of All Conceivable Types of Acyclic Alkenes in High Yields, Efficiently, Selectively, Economically, and Safely: "Green" Way[END_REF] is an area of intense on-going research as it offers the possibility to prepare in a single operation 1,2-difunctionalized alkenes ideally suited for the subsequent orthogonal introduction of two different substituents. [START_REF] Han | Transition metal-catalysed addition reactions of Hheteroatom and inter-heteroatom bonds to carbon-carbon unsaturated linkages via oxidative additions[END_REF][START_REF] Beletskaya | Element-Element Additions to Unsaturated Carbon-Carbon Bonds Catalyzed by Transition Metal Complexes[END_REF][START_REF] Ansell | Transition metal catalyzed elementelement additions to alkynes[END_REF][START_REF] Yoshida | Copper Catalysis for Synthesizing Main-Group Organometallics Containing B, Sn or Si[END_REF] However, the success of this approach is heavily dependent on the regio-and the stereoselectivity of the addition reaction.

In this field, as part of our interest in dialkylzinc-mediated radical reactions for the functionalization of carbon-carbon multiple bonds, [START_REF] Chemla | Radical Zinc Atom-Transfer Based Multicomponent Approaches to 3-Alkylidene Tetrahydrofurans[END_REF] we recently unveiled a radical approach to the silyl-and germylzincation of carbon-carbon triple bonds (Scheme 1). Suitable procedures relying on a combination of either (Me3Si)3SiH/Et2Zn [START_REF] Romain | Trans-Selective Radical Silylzincation of Ynamides[END_REF] or [(Me3Si)3Si]2Zn/Et2Zn [START_REF] Fopp | Stereodivergent Silylzincation of α-Heteroatom-Substituted Alkynes[END_REF][START_REF] Fopp | Stereodivergent Synthesis of β-Heteroatom-Substituted Vinylsilanes by Sequential Silylzincation-Copper(I)-Mediated Electrophilic Substitution[END_REF][START_REF] Romain | Development of a Radical Silylzincation of (Het)Aryl-Substituted Alkynes and Computational Insights into the Origin of the Trans-Stereoselectivity[END_REF] were developed to achieve the silylzincation of terminal -heteroatomor -(het)aryl-substituted alkynes, delivering the corresponding -silylated vinylzinc intermediates with excellent  regioselectivity (Scheme 1, top). The decisive feature of this approach is the uncommon transstereoselectivity. Equally, the (unprecedented) germylzincation of heteroatom substituted alkynes (terminal or internal), [START_REF] De La Vega-Hernández | Radical Germylzincation of α-Heteroatom-Substituted Alkynes[END_REF] as well as of internal aryl-or alkyl-substituted alkynes, [START_REF] De La Vega-Hernández | Radical Germylzincation of Aryl-and Alkyl-Substituted Internal Alkynes[END_REF] was achieved through the reaction with Ph3GeH/Et2Zn (Scheme 1, middle). The success of the developed radical approaches relies on the opportunity to combine two key steps: the addition of silicon-or germaniumcentered radicals across carbon-carbon triple bonds and the subsequent trapping by diethylzinc of the produced vinyl radical through homolytic substitution at the zinc atom (Scheme 1, bottom).

R 1 R 2 R 3 Y R 2 R 1 ZnEt 2 Et • • R 3 Y R 2 R 1 ZnEt [N] (Me 3 Si) 3 Si ZnEt [N] R 1 R 1 = [N], [S], [O], [P],
Ar, HetAr

(Me 3 Si) 3 Si ZnEt R 1 Ph 3 GeH Et 2 Zn w or w/o AIBN R 1 Ph 3 Ge ZnEt R 1 R 2 R 2 R 1 = [N], [S], [O], [P],
Ar, HetAr, Alkyl R 2 = H, Ar, Alkyl Silylzincation of terminal alkynes: [START_REF] Romain | Trans-Selective Radical Silylzincation of Ynamides[END_REF][START_REF] Fopp | Stereodivergent Silylzincation of α-Heteroatom-Substituted Alkynes[END_REF][START_REF] Fopp | Stereodivergent Synthesis of β-Heteroatom-Substituted Vinylsilanes by Sequential Silylzincation-Copper(I)-Mediated Electrophilic Substitution[END_REF][START_REF] Romain | Development of a Radical Silylzincation of (Het)Aryl-Substituted Alkynes and Computational Insights into the Origin of the Trans-Stereoselectivity[END_REF] Germylzincation of terminal and internal alkynes: [START_REF] De La Vega-Hernández | Radical Germylzincation of α-Heteroatom-Substituted Alkynes[END_REF][START_REF] De La Vega-Hernández | Radical Germylzincation of Aryl-and Alkyl-Substituted Internal Alkynes[END_REF] General mechanism (initiation not shown):

b a b a

During our studies, we discovered that propargylic alcohols (without need of alcohol protection) can also be well-suited substrates for this chemistry. The silylmetalation of propargylic alcohols and ethers is a synthetically relevant transformation for which a number of procedures has been developed. The most popular rely on the addition of silylcopper intermediates, either generated in catalytic amounts from silylaluminium, silylzinc, [START_REF] Wakamatsu | Transition-metal Catalyzed Silylzincation and Silylalumination of Acetylenic Compounds[END_REF][START_REF] Auer | Silylzincation of carbon-carbon multiple bonds revisited[END_REF] or silylboron [START_REF] Garcia-Rubia | Cu-Catalyzed Silylation of Alkynes: A Traceless 2-Pyridylsulfonyl controller Allows Access to Either Regioisomer on Demand[END_REF][START_REF] Yoshida | Inverse Regioselectivity in the Silylstannylation of Alkynes and Allenes: Copper-Catalyzed Three-Component Coupling with a Silylborane and a Tin Alkoxide[END_REF] reagents, or used as stoichiometric silicon anion donors. [START_REF] Lipshutz | Fine Tuning the Si-Sn Bond: Transmetalations Forming Either Trialkylstannyl or Trialkylsilyl Higher Order Cyanocuprates[END_REF][START_REF] Fleming | The Phenyldimethylsilyl Group as a Masked Hydroxy Group[END_REF][START_REF] Shi | Formal Synthesis of ()-Guanacastepene[END_REF] Direct silylalumination, [START_REF] Altnau | Syn-Addition von Tris(trimethylsilyl)aluminium an alkine: eine Neue Synthese fur Vinylsilane[END_REF] silylzincation, [START_REF] Nakamura | Chemoselective Silylzincation of Functionalized Terminal Alkynes Using Dianion-Type Zincate (SiBNOL-Zn-ate): Regiocontrolled Synthesis of Vinylsilanes[END_REF][START_REF] Bochatay | 4-Amino-1-allenylsilanes from 4-Aminopropargylic Acetates through a Silylzincation/Elimination Sequence[END_REF] dialkylzinc-catalyzed silylboration [START_REF] Nagashima | In Situ Generation of Silylzinc by Si-B Bond Activation Enabling Silylzincation and Silaboration of Terminal Alkynes[END_REF] and Pd-catalyzed silylstannylation [START_REF] Mitchell | Formation and Reactions of Olefins with Vicinal Silyl and Stannyl Substituents[END_REF] and silylboration [START_REF] Ohmura | Switch of Regioselectivity in Palladium-Catalyzed Silaboration of Terminal Alkynes by Ligand-Dependent Control of Reductive Elimination[END_REF] were also reported. With these procedures, the silicon unit is generally incorporated at the alkyne carbon distal to the oxygen group ( regioselectivity), with few exceptions. [START_REF] Nakamura | Chemoselective Silylzincation of Functionalized Terminal Alkynes Using Dianion-Type Zincate (SiBNOL-Zn-ate): Regiocontrolled Synthesis of Vinylsilanes[END_REF] Yet, regiocontrol, especially in the case of internal alkynes, is not always perfect. Regarding stereoselectivity, products arising from exclusive syn addition are customarily observed. By contrast with silylmetalation, to the best of our knowledge, there is no report on the germylmetalation of propargylic alcohols (or ethers) previous to our work. * Hereafter, we thus discuss our results regarding the implementation of the protocols developed for radical silyl-and germylzincation to this important family of alkynes. As a prelude to our work and to gain understanding about the addition of (Me3Si)3Si and Ph3Ge radicals across the carbon-carbon triple bonds of propargylic alcohols, we survey radical hydrosilylation (with (Me3Si)3SiH) and hydrogermylation (with Ph3GeH) reactions of the same substrates, combining literature precedents and new experimental results.

Results and Discussion

Radical Hydrosilylation and Hydrogermylation of Propargylic

Alcohols

Terminal Propargylic Alcohols

Propargylic alcohols having a terminal alkyne (I) react readily with (Me3Si)3SiH [START_REF] Kopping | Tris(trimethylsilyl)silane: an efficient hydrosilylating agent of alkenes and alkynes[END_REF][START_REF] Miura | Triethylborane induced stereoselective radical addition of R3SiH to acetylenes and stereoselective reduction of alkenyl iodides with tris(trimethylsilyl)silane[END_REF] or Ph3GeH [START_REF] David-Quillot | Regio-and Stereoselective Synthesis of (Z)-Vinylgermanes by Hydrogermylation of Alkynes[END_REF] to provide the corresponding vinylsilanes or vinylgermanes II through a radical chain-reaction entailing radical addition and H-atom transfer to the vinylic radical adduct (Scheme 2, top and middle). Such reactions have been reported to occur with excellent  regioselectivity related to the fact that the adding radical reacts on the terminal carbon atom of the alkyne to avoid unfavorable steric interactions. Conversely, the stereoselectivity varies with the substrate and the reaction conditions. In the case of primary or secondary alcohol derivatives, the Z-isomer is the kinetic product for both hydrosilylation [START_REF] Miura | Triethylborane induced stereoselective radical addition of R3SiH to acetylenes and stereoselective reduction of alkenyl iodides with tris(trimethylsilyl)silane[END_REF][START_REF] Wang | Air-initiated hydrosilylation of unactivated alkynes and alkenes and dehalogenation of halohydrocarbons by tris(trimethylsilyl)silane under solvent-free conditions[END_REF][START_REF] Schmohl | The Cationic Rearrangement of (3 Hydroxy-1-propenyl)tris(trimethylsilyl)silanes into (1-Trimethylsilyl-2-propenyl)bis(trimethylsilyl)silanols -Experimental and Theoretical Studies[END_REF] and hydrogermylation [START_REF] David-Quillot | Regio-and Stereoselective Synthesis of (Z)-Vinylgermanes by Hydrogermylation of Alkynes[END_REF] reactions: The reaction of the H-atom donor (R3YH) with Z-III, for which the interaction with the bulky R3Y group is avoided, is more favorable. At rt, the (Me3Si)3Si radical does not induce alkene Z-to-E isomerization [START_REF] Miura | Triethylborane induced stereoselective radical addition of R3SiH to acetylenes and stereoselective reduction of alkenyl iodides with tris(trimethylsilyl)silane[END_REF] and the Z isomer is recovered

R 3 Y YR 3 -R 3 Y • • Z-III E-III R 3 Y • -R 3 Y • R 3 Y • Z-II E-II IV R 3 YH • [In] + Z-II E-II (thermodynamic) I R 3 Y = (Me 3 Si) 3 Si, Ph 3 Ge Stereoselectivity model K eq k Z k E OR 1 R 2 R 2 R 3 Y OR 1 H R 2 R 2 R 3 Y OR 1 R 2 R 2 H R 3 Y OR 1 R 2 R 2 • H YR 3 R 3 Y OR 1 H R 2 R 2 R 2 Y OR 1 R 2 R 2 • H YR 3 R R 3 Y OR 1 R 2 R 2 H R 1 O R 2 R 2 Mechanism (initiation not shown) OR 1 R 2 R 2 R 3 Y • R 3 Y OR 1 R 2 R 2 • R 3 Y OR 1 R 2 R 2 H R 3 YH -R 3 Y • b a [In] = initiator
intact. At higher temperatures and in the case of hydrogermylation for which Ph3Ge-radical-induced isomerization leading to the thermodynamically more stable E-isomer occurs even at rt, [START_REF] Nozaki | Et3B Induced Stereoselective Radical Addition of Ph3GeH to Carbon-Carbon Multiple Bonds and Ist Application to Isomerization of Olefins[END_REF] mixtures of E and Z isomers are generally obtained. With tertiary alcohol derivatives, E-stereoselectivity was observed for hydrosilylation reactions, [START_REF] Schmohl | The Cationic Rearrangement of (3 Hydroxy-1-propenyl)tris(trimethylsilyl)silanes into (1-Trimethylsilyl-2-propenyl)bis(trimethylsilyl)silanols -Experimental and Theoretical Studies[END_REF][START_REF] Odedra | Safe, facile radical-based reduction and hydrosilylation reactions in a microreactor using tris(trimethylsilyl)silane[END_REF][START_REF] Zhu | Radical Hydrosilylation of Alkynes Catalyzed by Eosin Y and Thiol under Visible Light Irradiation[END_REF] but it was not established whether this preference for the E isomer was of kinetic or thermodynamic origin. For hydrogermylation reactions, the kinetic stereoselectivity was found to be in favor of the Z-isomer both at rt and at 100 °C. [START_REF] David-Quillot | Regio-and Stereoselective Synthesis of (Z)-Vinylgermanes by Hydrogermylation of Alkynes[END_REF] On our side, we considered the hydrosilylation and hydrogermylation reactions of propargyl alcohol (1a) in heptane at 100 °C using AIBN as radical initiator (Table 1). a] Determined by 1 H NMR analysis of the crude reaction mixture. [b] Determined by 1 H NMR spectroscopy using butadiene sulfone as internal standard. [c] Based on (Me3Si)3SiH or Ph3GeH (limiting reagent).

The yields in vinylsilane 2a or vinylgermane 3a were consistently high. Excellent regioselectivity was noted, though not perfect ( ~95:5) by contrast with the literature precedents. The stereoselectivities were in good agreement with the above-described scenario. In default of the hydride reagent, predominant formation of the kinetic Z isomer was obtained both for hydrosilylation (entry 1)

and hydrogermylation (entry 3). Conversely, using excess hydride, formation of the E isomer prevailed in the case of hydrogermylation (entry 4). For the latter, such behavior can be easily ascribed to radical induced Z-to-E isomerization. For the hydrosilylation reaction, the Z isomer remained the major product and the Z/E ratio was somewhat higher (entry 2). These results lend clear evidence that under these conditions (Me3Si)3Si-radical-promoted Z-to-E isomerization occurs minorly, if at all, and thus that the observed stereoselectivity is of kinetic origin. The reason why the ratio varies with the amount of hydride still needs to be established.

Internal Propargylic Alcohols

By contrast with derivatives bearing terminal alkynes, the radical hydrosilylation and hydrogermylation of propargylic alcohols having internal alkynes has not been reported, [START_REF] Cai | Access to Functionalized E-Allylsilanes and E-Alkenylsilanes through Visible-Light-Driven Radical Hydrosilylation of Mono-and Disubstituted Allenes[END_REF] so we decided to assess experimentally the potential of these transformations (Table 2). [a] Determined by 1 H NMR analysis of the crude reaction mixture. [b] Determined by 1 H NMR spectroscopy using butadiene sulfone as internal standard. [c] Based on (Me3Si)3SiH or Ph3GeH (limiting reagent).

Very modest reactivity was observed when alcohol 4, having an alkylsubstituted internal alkyne, was opposed to (Me3Si)3SiH under similar conditions (heptane, 100 °C) to those applied with propargyl alcohol (entry 1). On the contrary, the reaction with Ph3GeH proceeded readily with 4, as well as with phenyl-substituted propargylic alcohol

+ 1a R 3 Y OH R 3 Y OH Z-isomer H H H E-isomer R 3 YH (n equiv) AIBN (10 mol%) R 1 b a YR 3 R 1 H heptane 100 °C, 2 h OH OH n n R 3 Y R 1 + 4-6 7a 8a-10a 7b 8b-10b OH n H YR 3 H R 1 OH n H R 3 Y R 1 n Z-isomer E-isomer OH Z-isomer E-isomer R 3 YH = (Me 3 Si) 3 SiH R 3 YH = Ph 3 GeH
yields (entries 2-5). Opposite regioselectivity with respect to terminal propargylic alcohols was observed, as the  regioisomers (8 and 9)

were formed predominantly. In the absence of a strong steric bias to orient the radical addition step, this general behavior can be ascribed to an O-directing effect similar to the one observed for the betterestablished hydrostannylation reactions with Ph3SnH, wherein interaction between the oxygen and the tin atoms directs the addition at the carbon of the alkyne proximal to the oxygen atom. [START_REF] Hale | The O-Directed Free Radical Hydrostannation of Propargyloxy Dialkyl Acetylenes with Ph3SnH/cat. Et3B. A Refutal of the Stannylvinyl Cation Mechanism[END_REF] Note that in the case of 5, the vinyl radical arising from the addition of the triphenylgermyl radical at the  carbon beneficiates from stabilization by the adjacent phenyl group, and this explains the higher levels of regioselectivity (compare entries 2 and 3 with 4 and 5). Additional support for the importance of the O-directing effect came from the result of the hydrogermylation of homopropargylic alcohol 6 under similar conditions (entries 6 and 7), since an almost equimolar mixture of  and  isomers of 10 was obtained.

Regarding stereoselectivity, the obtained ratios followed a similar trend as for the hydrogermylation of propargyl alcohol, and we could again identify two different regimes depending on the amount of triphenylgermane. In default-Ph3GeH (0.8 equiv), close-to-perfect Zstereoselectivity was obtained (entries 3, 5 and 7): This corresponds to the kinetic selectivity of the H-atom transfer reaction to the vinyl radical intermediate. By contrast, with excess Ph3GeH (2.0 equiv), moderate E-stereoselectivity was obtained (entries 2, 4 and 6), as Ph3Ge-radical-promoted Z-to-E isomerization of the initially formed Z-isomer takes place. [START_REF] Nozaki | Et3B Induced Stereoselective Radical Addition of Ph3GeH to Carbon-Carbon Multiple Bonds and Ist Application to Isomerization of Olefins[END_REF] Radical Silyl-and Germylzincation of Propargylic Alcohols

Terminal Propargylic Alcohols

With this context in mind, we went on to consider silyl-and germylzincation reactions, focusing first on propargyl alcohol (1a) by reaction with respectively (Me3Si)3SiH or Ph3GeH in the presence of Et2Zn (Table 3).

Only very low amounts of product were detected for both reactions under the operating conditions previously developed for terminal ynamides (i.e., 0 °C, 3 h) (entries 1 and 2), presumably because no reaction occurred. Conversely, at a higher temperature (100 °C), and in the presence of radical initiator AIBN, the formation of vinylsilane 2a and vinylgermane 3a was observed in respectively 58% and 78% yield (entries 3 and 5). In line with the hydrosilylation and hydrogermylation reactions, the regioselectivity was in favor of the  regioisomers, but here the selectivity levels were lower, especially in the case of germylzincation, for which 18% of the  isomer (3a) was formed. Vinylsilane 2a was delivered exclusively as a Z isomer (whereas direct hydrosilylation gives Z/E = 79:21 (Table 1, entry 2)), and vinylgermane 3a was obtained as a Z/E = 67:33 mixture, unlike for direct hydrogermylation for which the E isomer is the major one (Z/E = 15:85). For both reactions, on quenching with ND4Cl/D2O, more than 90% of deuterium incorporation were detected for the  isomers (entries 4 and 6), evidencing that silyl-or germylzincation are the major reaction pathways and that direct hydrosilylation or hydrogermylation are not competitive processes in these conditions.

This result is relevant because it contrasts sharply with the case of terminal aryl-substituted acetylenes for which hydrosilylation and hydrogermylation were found to predominate under similar conditions. Note that deuterium incorporation for the very minor  isomers could not be quantified. [82(68:32):18] 77% [a] Determined by 1 H NMR analysis of the crude reaction mixture. [b] Determined by 1 H NMR spectroscopy using butadiene sulfone as internal standard. [c] The reaction was quenched with ND4Cl/D2O; the percentage of deuterium incorporation for the β isomers was estimated >90% by 1 H NMR spectroscopy.

R 3 YH (1.5-2.0 equiv) Et 2 Zn (3.0 equiv) b a heptane OH 1a 2aa, 2aa-d 1 3aa, 3aa-d 1 2ab, 2ab-d 1 3ab, 3ab-d 1 then NH 4 Cl / NH 3 or ND 4 Cl / D 2 O YR 3 OH + R 3 Y OH R 3 Y OH Z-isomer H/D H/D H/D E-isomer R 3 YH = (Me 3 Si) 3 SiH R 3 YH = Ph 3 GeH
In the present case, zinc alkoxide 11 should be the radical acceptor and vinylzinc formation can occur through intramolecular homolytic substitution at the tethered zinc atom of radical V (Scheme 3).

Scheme 3. Stereoselectivity model for the silyl-and germylzincation of propargyl alcohol by reaction with R3YH/Et2Zn (R3Y = (Me3Si)3Si, Ph3Ge).

Our hypothesis is that the zinc transfer event is thus accelerated in such a way that it prevents competitive H-atom transfer from the hydrosilane or the hydrogermane. Such acceleration may also be at the origin of the exclusive trans stereoselectivity for the silylzincation reaction, as the homolytic substitution event could become faster than Z-to-E isomerization of the primarily formed Z-V, and thus only E-VI (ultimately leading to Z-2a) would be produced, in a situation that is reminiscent of the one encountered in the radical silylzincation of terminal ynamides. [START_REF] Romain | Trans-Selective Radical Silylzincation of Ynamides[END_REF][START_REF] De La Vega-Hernández | Radical Germylzincation of α-Heteroatom-Substituted Alkynes[END_REF] For the same reasons, one would also expect trans germylzincation to be kinetically favored. Yet, under the operating conditions (excess Ph3GeH, 100 °C), Ph3Ge-radical induced isomerization of the vinylzinc intermediates should intervene [START_REF] De La Vega-Hernández | Radical Germylzincation of Aryl-and Alkyl-Substituted Internal Alkynes[END_REF] and the stereoselectivity should be rather related to the relative stability of E-VI versus Z-VI. Alas, this last speculation could not be demonstrated experimentally since the reaction was found to be very fast and the same outcome in terms of yield, regio-and stereoselectivity was already obtained after only 5 minutes of reaction time (Table 3, entry 7)!

We then turned our attention to our silylzincation method relying on [(Me3Si)3Si]2Zn as source of silyl radicals ( [a] Ratio between 2a-c/1a-c determined by 1 H NMR analysis of the crude reaction mixture. [b] Only β-silylated regioisomers were detected (β:α>98:2). [c] Combined yield of isolated diastereomers unless otherwise noted. [d] Determined by [START_REF] Flynn | Stereocontrolled Synthesis of Tetrasubstituted Olefins[END_REF] H NMR analysis of the crude reaction mixture. [e] Not determined. [f] Determined by 1 H NMR spectroscopy using butadiene sulfone as internal standard.

O ZnEt

• 11 R 3 Y O ZnEt • R 3 Y O Zn -Et R 3 Y • R 3 Y ZnEt • O Z-V E-V • R 3 Y Zn O -Et E-VI Z-VI isomerization by Ph 3 Ge • radical addition- elimination (R 3 Y = Ph 3 Ge) 1a-c Et 2 Zn (1.1 equiv) then hexane NH 4 Cl / NH 3 [(Me 3 Si) 3 Si] 2 Zn (1.1-2.2 equiv) OR 1 R 2 (Me 3 Si) 3 Si OR 1 R 2 (Me 3 Si) 3 Si R 2 OR 1 + Z-2a-c E-2a-c 6
To investigate the effect of the presence of the free hydroxy unit on the silylzincation reaction, O-PMP-protected propargyl alcohol 1b was then considered. Here, complete  regioselectivity was also noted but with lower levels of Z stereoselectivity (entry 3). Following reaction at -30 °C, vinylsilane 2b was obtained with Z/E = 83:17 in 39% yield. Performing the reaction at higher temperatures allowed for better conversion rates and thus better yields, but had no impact on the stereoselectivity (entries 4-5). Hence, alcohol protection has little impact in terms of reactivity but is deleterious for (trans)stereoselectivity.

Secondary propargylic alcohol 1c proved less reactive, but was also amenable to silylzincation, though with a preference for cis addition delivering the E vinylsilane. At -30 °C, product 2c was obtained after In the case of 12b arising from the addition of the (Me3Si)3Si radical to O-PMP-protected propargyl ether 1b (Scheme 4, top), zinc transfer occurs preferentially on the Z isomer (Z-12b  E-13b) for which the interaction between the diorganozinc reagent and the bulky (Me3Si)3Si unit is avoided. Notwithstanding (as in the case of direct hydrosilylation of propargyl alcohol -Table 1), the E isomer of 12b also reacts to some extent (E-12b  Z-13b), thereby indicating that the minimization of this (Me3Si)3Si/ZnR2 interaction does not override fully the allylic strain that destabilizes Z-12b with respect to wherein allylic strain is avoided. Importantly, by contrast with 13a, vinylzinc reagent 13c showed configurational lability (certainly not radical-induced) and it is interesting to note that there is no thermodynamic preference for either diastereomeric form.

E-12b. Vinylzinc intermediate
Configurational lability of vinylzinc species is rather uncommon, but it has been noted that the presence of a tethered zinc alkoxide can promote isomerization [START_REF] Wakamatsu | Transition-metal Catalyzed Silylzincation and Silylalumination of Acetylenic Compounds[END_REF] and this is likely the case here.

We then contemplated the use of the C(sp 2 )-Zn bond produced as handle for subsequent in-situ functionalization in order to access trisubstituted vinylsilanes, which represents a key asset of the radical alkyne silylzincation chemistry with respect to radical hydrosilylation.

For this purpose, Cu(I)-mediated electrophilic substitution has proved particularly useful in other systems, allowing for functionalization with exquisite retention of the double bond geometry. Such was the case for the Cu(I)-mediated allylation of vinylzinc E-13a arising from the silylzincation of propargyl alcohol (1a): Upon treatment with allyl bromide in the presence of THF-soluble salt CuCN•2LiCl, vinylsilane 14a was obtained in 40% yield and Z/E > 98:2 (Scheme 5). However, we quickly learned that this was not a general trend. For instance, 14b in E/Z = 61:39 ratio (i.e., overall major cis-difunctionalization). For this system, performing the electrophilic substitution step at -45 °C upon silylzincation at -30 °C led to even higher ratios of the E isomer (E/Z = 85:15). Such was also the case for the trapping of 13b with propargyl bromide, as allene 16 was produced as a single E isomer.

Z-12a (R 1 =H), Z-12c (R 1 =Ph) E-12a, E-12c E-13a, E-13c Z-13a, Z-13c K eq k Z k E (Me 3 Si) 3 Si O • (Me 3 Si) 3 Si (Me 3 Si) 3 Si • O Zn R 1 O R 1 R 1 (Me 3 Si) 3 Si Zn O R 1 ZnR ZnR R 1 = Ph Z-12b E-12b E-13b Z-13b K eq k Z k E (Me 3
Similarly, complete E-selectivity was observed for the succeeding silylzincation/allylation (14c) and silylzincation/alkynylation (17) reactions of -substituted propargylic alcohol 1c, even though in this case, the preference for cis selectivity was already noted at the silylzincation step. It is generally admitted that electrophilic substitution of vinylcopper intermediates proceeds with retention of configuration. We thus ascribe the observed behavior to the isomerization prior to electrophilic substitution of the vinylcopper reagents generated by transmetallation of the vinylzinc adducts 13a-c with CuCN. Such isomerization could be the result of a certain configurational lability, but could also occur through an elimination/syn-silylcupration process associated to a reversible silylcupration reaction. [START_REF] Cubillo De Dios | Silylcupration of a propargylsilane as a test for the reversibility of a metallometallation[END_REF] At this point, we do not have enough evidence to provide a definite conclusion, but the yields obtained for compounds 14b, 14c, 16 and 17, which are significantly higher than the yields of the silylzincation/protonolysis reactions (Table 4, entries 5 and 7) support this last hypothesis. Regardless of its origin, this preference for cis renders our approach weakly competitive against direct silylcupration chemistry in this context and we did not push it further.

Germylzincation of Internal Propargylic Alcohols

We next steered our study towards internal propargylic alcohols and focused on germylzincation given that our preliminary studies on hydrosilylation and hydrogermylation had shown that radical addition of Ph3Ge was more general for these substrates than that of (Me3Si)3Si. Application of our procedure previously developed for internal dialkyl-or aryl, alkyl-substituted alkynes proved successful. [START_REF] De La Vega-Hernández | Radical Germylzincation of Aryl-and Alkyl-Substituted Internal Alkynes[END_REF] Upon reaction with Ph3GeH and Et2Zn in heptane at 100 °C, in the The same regio-and stereochemical behavior was observed for the germylzincation of O-(tert-butyldimethylsilyl)-protected propargylic alcohol 24 which delivered 25 as a single -regioand Zstereoisomer (Scheme 6, bottom). Here however, the yield was low (34%) and the product could not be separated from the considerable amount of unreacted starting material (36%, see Supporting Information).

Scheme 6. Germylzincation of internal propargylic alcohols.

The excellent regio-and stereoselectivities observed for these reactions can be readily rationalized through the combined influence of an O-directing effect for the radical addition step and the formation of a 5-member-chelated vinylzinc species (Scheme 7).

By analogy with Hale's proposal for the hydrostannylation reactions with Ph3SnH, [START_REF] Hale | The O-Directed Free Radical Hydrostannation of Propargyloxy Dialkyl Acetylenes with Ph3SnH/cat. Et3B. A Refutal of the Stannylvinyl Cation Mechanism[END_REF] we conjecture that formation of adduct VII by interaction between the oxygen and the germanium atoms facilitates H-atom transfer from Ph3GeH and provides radical VIII poised for addition across the C-C triple bond at the proximal () carbon. The lower reactivity observed with O-silylated substrate 24 is consistent with this hypothesis, as in that case, the less favorable O-Ge interaction should prevent facilitation of the H-atom transfer step and therefore the radical chain should be less efficient. In this context, the improved regioselectivity observed for the germylzincation of 4 (Scheme 6, top) compared to hydrogermylation (Table 2, entries 2 and 3) is noteworthy, as it is coherent with a stronger O-directing effect for alkoxides than for alcohols, associated to a more favorable O-Ge interaction. Note that the same effect can account for the lower regioselectivity of germylzincation versus hydrogermylation of 1a.

Upon addition of the germanium-centered radical, intermediate IX is formed and undergoes Zn transfer to deliver ultimately vinylzinc X.

For simple alkynes, Ph3Ge-radical-induced isomerization of the vinylzinc intermediates arising from germylzincation was observed in heptane at 100 °C. For X, the formation of a 5-member chelate stabilizes the E-isomer and makes it thermodynamically more stable, so that it's not possible to conclude whether the Zn transfer step is under kinetic or thermodynamic control (and this might also be substrate-dependent). It should also be mentioned that, as previously discussed, the possibility to have a bimolecular zinc transfer followed by ligand exchange leading to chelate formation cannot be fully excluded.

GePh 3 R 1 O R 2 R 1 R 2 O ZnEt Ph 3 Ge GePh 3 R 1 Zn O R 2 H Et • R 1 R 2 O ZnEt Ph 3 Ge • • -Et EtZn VII VIII IX X b a
•

Conclusions

In conclusion, we have demonstrated that our procedures developed for radical alkyne silyl-and germylzincation can be advantageously applied with propargylic alcohols as substrates. In both reactions, the C(sp 2 )-Zn bond remains available for subsequent in-situ functionalization. The presence of the hydroxy unit has a definite impact on the reactivity and allows in most cases to obtain excellent regio-and stereocontrol. The protocols developed to achieve the regioselective silylzincation of propargyl alcohol and the regioselective germylzincation of internal propargylic alcohols are particularly relevant, as they occur with trans stereoselectivity, which remains a challenge in the field of alkyne elementometalation reactions. [39] The exquisite  regioselectivity of the germylzincation reactions of internal propargylic alcohols also merits to be emphasized as it is quite uncommon if one makes the analogy with the established silylmetalation chemistry relying on silicon nucleophiles and thus illustrates well the synthetic input of our radical elementozincation chemistry.

Experimental Section

General Procedure (GP I) for Radical Hydrosilylation with (Me3Si)3SiH or Hydrogermylation with Ph3GeH of Propargylic Alcohols (Tables 1 and2)

A dry tube under argon was charged with AIBN (6 mg, 0.03 mmol), (Me3Si)3SiH (0.8-1.5 equiv) or Ph3GeH (0.8-2.0 equiv), heptane (1.4 mL) and the appropriate propargylic alcohol (0.25 mmol). The tube was sealed with a cap and placed immediately in an oil bath preheated at 100 °C. After the given reaction time, the tube was cooled rapidly, the cap was removed and the mixture was transferred to a round-bottom flask, diluted in CH2Cl2 and concentrated under reduced pressure. The residue was dissolved in CDCl3, and butadiene sulfone (5.0 -6.5 mg) was added as internal standard for 1 H NMR analysis.

General Procedure (GP II) for Silylzincation with (Me3Si)3SiH/Et2Zn or Germylzincation with Ph3GeH/Et2Zn of Propargylic Alcohols (Table 3 and Scheme 6, top)

A dry tube under argon was charged with AIBN (10 mg, 0.06 mmol), (Me3Si)3SiH (0.12 mL, 0.39 mmol) or Ph3GeH (153 mg, 0.50 mmol), heptane (0.7 mL) and the appropriate propargylic alcohol (0.25 mmol). Et2Zn (1.0 M in hexane, 0.75 mL, 0.75 mmol) was added and the tube was sealed with a cap and placed immediately in an oil bath preheated at 100 °C. After the given reaction time, the tube was cooled down to rt, the cap was removed and the mixture was poured onto a mixture of aqueous NH4Cl/NH3 (2:1) (10 mL) and CH2Cl2 (10 mL). The layers were separated and the aqueous one was extracted with CH2Cl2 (2 x 10 mL). The combined organics were washed with brine (10 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was either purified by flash column chromatography on silica gel (Scheme 6, top) or dissolved in CDCl3, and butadiene sulfone (5.0 -6.5 mg) was added as internal standard for 1 H NMR analysis (Table 3).

General Procedure (GP III) for Silylzincation of Terminal Propargylic alcohols and Ethers with [(Me3Si)3Si]2Zn/Et2Zn

(Table 4)

A Schlenk tube was charged with the appropriate terminal propargylic alcohol (0.25 mmol) and a suspension of [(Me3Si)3Si]2Zn [START_REF] Dobrovetsky | Radical Activation of Si-H Bonds by Organozinc and Silylzinc Reagents: Synthesis of Geminal Dizinciosilanes and Zinciolithiosilanes[END_REF] (308 mg, 0.55 mmol) in n-hexane (2.0 mL) was added at -30 °C, followed by Et2Zn (1.0 M in hexane, 0.28 mL, 0.28 mmol). The turbid mixture was stirred at this temperature for the given time. The mixture was then diluted with CH2Cl2 (10 mL) and quenched with aqueous NH4Cl/NH3 (2:1) (10 mL). The layers were separated and the aqueous one was extracted with CH2Cl2 (2 x 10 mL). The combined organics were washed with brine (10 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel.

General Procedure (GP IV) for Tandem Silylzincation / Cu(I)mediated Electrophilic Substitution of Terminal Propargylic Alcohols (Scheme 5)

A Schlenk tube was charged with the appropriate terminal propargylic alcohol (0.25 mmol) and a suspension of [(Me3Si)3Si]2Zn

(308 mg, 0.55 mmol) in n-hexane (2.0 mL) was added at -30 °C, followed by Et2Zn (1.0 M in hexane, 0.28 mL, 0.28 mmol). The turbid mixture was stirred at this temperature for the given time and then CuCN•2LiCl (1.0 M in THF, 0.88 mL, 0.88 mmol) was added, followed by the appropriate electrophile (2.50 mmol). The mixture was stirred for the given temperature and time and then diluted with CH2Cl2 (15 mL) and quenched with aqueous NH4Cl/NH3 (2:1) (10 mL). The layers were separated and the aqueous one was extracted with CH2Cl2 (2 x 15 mL). The combined organics were washed with brine (10 mL), dried (Na2SO4), filtered and concentrated under reduced pressure.

The crude product was purified by flash column chromatography on silica gel.

(Z)-3-( was in good agreement with that previously reported. [START_REF] Zhu | Radical Hydrosilylation of Alkynes Catalyzed by Eosin Y and Thiol under Visible Light Irradiation[END_REF] (Z)- The Z configuration was established on the basis of the 3 J(H,H) (13.4 Hz) coupling constant between the vinylic protons. = 85:15) as a colorless oil. The spectral data of the Z isomer was in good agreement with that previously reported. [START_REF] Wang | Air-initiated hydrosilylation of unactivated alkynes and alkenes and dehalogenation of halohydrocarbons by tris(trimethylsilyl)silane under solvent-free conditions[END_REF] An analytically pure sample of the E isomer was obtained upon further purification by flash chromatography on silica gel. The Z configuration of the major isomer was established on the basis of the 3 J( 119 Sn,H) coupling constant values of the vinylic protons [START_REF] Oderinde | On the Hydrostannylation of Aryl Propargylic Alcohols and Their Derivatives: Remarkable Differences[END_REF] (171 Hz for the Z isomer and 94 Hz for the E isomer). For the sake of completeness, experimental procedures leading to compounds 8, 9, 21-23 and 25 as well as their NMR characterization data that have been published in a previous study [START_REF] De La Vega-Hernández | Radical Germylzincation of Aryl-and Alkyl-Substituted Internal Alkynes[END_REF] are reproduced hereafter.

(Z)-2-(triphenylgermyl)dec-2-en-1-ol (8): [START_REF] De La Vega-Hernández | Radical Germylzincation of Aryl-and Alkyl-Substituted Internal Alkynes[END_REF]

(Z)-3-(trimethylsilyl)-2-(triphenylgermyl)prop-2-en-1-ol (21

): [START_REF] De La Vega-Hernández | Radical Germylzincation of Aryl-and Alkyl-Substituted Internal Alkynes[END_REF] Prepared according to GP II. Purification of the crude product (Z/E > 98:2) by flash chromatography on silica gel (eluent pentane/toluene/Et2O = 50:45:5) afforded analytically pure 21 (70 mg, 65%, Z/E > 98:2) as a colorless liquid. [START_REF] De La Vega-Hernández | Radical Germylzincation of Aryl-and Alkyl-Substituted Internal Alkynes[END_REF] A dry tube under argon was charged with AIBN (10 mg, 0.06 mmol), Ph3GeH (153 mg, 0.50 mmol), heptane (0.

(Z)-4-phenyl-3-(triphenylgermyl)hepta-3,6-dien-2-ol (27):

Scheme 1 .

 1 Scheme 1. Radical silyl-and germylzincation of alkynes.

[

3Scheme 4 .

 4 Scheme 4. Stereoselectivity models for the silylzincation of 1a-c by reaction with [(Me3Si)3Si]2Zn/Et2Zn (R = (Me3Si)3Si or Et).

  13b is thus obtained as a E/Z ~85:15 mixture and no subsequent E-to-Z isomerization was noted.The situation differs in the case of non-protected propargylic alcohols, as radical addition occurs on the corresponding zinc alkoxides and afford radicals 12a and 12c (initially as Z-isomers). We have no evidence to exclude a bimolecular zinc transfer as the one discussed for 12b, but it seems reasonable to rather invoke formation of vinylzincs 13a and 13c upon intramolecular homolytic substitution at the tethered zinc atom (Scheme 4, bottom). Starting from propargyl alcohol (1a), as discussed previously for the (Me3Si)3SiH/Et2Zn protocol (see Scheme 3), primarily formed Z-12a should undergo intramolecular zinc transfer faster than Z-to-E isomerization to produce exclusively E-13a. Conversely, in the case of secondary propargylic alcohol 1c, destabilization of Z-12c reduces the efficiency of the vinylzinc formation step (Z-12c  E-13c) and isomerization (Z-12c  E-12c) becomes relevant. In this situation, zinc transfer occurs preferentially on the E isomer (E-12c  Z-13c)

  with tributyltin chloride under similar conditions delivered -stannylated vinylsilane 15 as a Z/E = 81:19 mixture resulting from predominant cis-difunctionalization! Likewise, the Cu(I)-mediated allylation of 13b arising from trans-selective silylzincation of O-PMP protected derivative 1b, yielded vinylsilane

Scheme 5 .

 5 Scheme 5. Access to trisubstituted vinylsilanes from 1a-c by sequential silylzincation / Cu-mediated electrophilic substitution.

  presence of AIBN, compounds 4 and 5 underwent germylzincation in 80-87% yield with excellent  regioselectivity and complete trans stereoselectivity, affording Z vinylgermanes 8 and 9 after protonolysis (Scheme 6, top). The protocol was similarly applied with trimethylsilyl-substituted propargylic alcohol 18 which afforded trimethylsilyl vinylgermane 21 as a single regio-and stereoisomer. Derivatives of secondary propargylic alcohols were also amenable to germylzincation with this procedure, as shown with the formation of 22 and 23 from 19 and 20.

Scheme 7 .

 7 Scheme 7. Stereoselectivity model for the germylzincation of internal propargylic alcohols.

Scheme 8 .

 8 Scheme 8. Access to tetrasubstituted vinylgermane 25 by sequential germylzincation / Cu-mediated electrophilic substitution.

  )prop-2-en-1-ol (2c): Prepared according to GP III. Purification of the crude product by flash chromatography on silica gel (eluent cyclohexane/ethyl acetate = 99/1) afforded 2c (43 mg, 45% yield, E/Z

  7 mL) and 4-phenylbut-3yn-2-ol 19 (37 mg, 0.25 mmol). Et2Zn (1.0 M in hexane, 0.75 mL, 0.75 mmol) was added and the tube was sealed with a cap and placed immediately in an oil bath preheated at 100 °C. The reaction mixture was stirred for 2 h and then progressively cooled to -30 °C. Next, CuCN•2LiCl (1.0 M in THF, 0.75 mL, 0.75 mmol) followed by allyl bromide (0.15 mL, 1.75 mmol) were added at this temperature and the reaction mixture was allowed to warm slowly to rt overnight under stirring. Then, aq NH4Cl/NH3 (2:1) (10 mL) and CH2Cl2 (10 mL) were added and after 1 h stirring the layers were separated. The aqueous layer was extracted with CH2Cl2 (3 x 10 mL), and the combined organic layers were washed with brine (2 x 10 mL), dried over Na2SO4, filtered, and concentrated under reduce pressure to afford the crude product. Purification of the crude product by flash chromatography on silica gel (eluent pentane/Et2O/toluene = 80:10:10) afforded analytically pure 27 (91 mg, 74%, Z/E > 98:2) as a white solid; mp. M.p. 109 -112 °C.

Table 1 .

 1 Radical hydrosilylation and hydrogermylation of propargyl alcohol 1a

	at 100 °C.

Entry R3YH [equiv] Product [ (Z/E)/] [a]

Yield (%)

[b]

Table 2 .

 2 Radical hydrosilylation and hydrogermylation of internal propargylic alcohols at 100 °C.

	Entry	Substrate	R3YH
			[

equiv] Products [ (Z/E)/ (Z/E)] [a] Yield (%) [b]

	1	4 (R 1 =Hept, n=1)	(Me3Si)3SiH	7/7	14
			1.5	[>98(>98:2):2]
	2	4 (R 1 =Hept, n=1)	Ph3GeH	8/8	92
			2.0	[76 (39:61):24(39:61)]
	3	4 (R 1 =Hept, n=1)	Ph3GeH	8/8	74 [c]
			0.8	[78(>95:5):22(>95:5)]
	4	5 (R 1 =Ph, n=1)	Ph3GeH	9/9	84
			2.0	[>98(14:86):2(-)]
	5	5 (R 1 =Ph, n=1)	Ph3GeH	9/9	67 [c]
			0.8	[>98(>95:5):2(-)]
	6	6 (R 1 =nHex, n=2)	Ph3GeH	10/10	84
			2.0	[57(34:66):43(33:67)]
	7	6 (R 1 =nHex, n=2)	Ph3GeH	10/10	80 [c]
			0.8	[48(>95:5):52(>95:5)]

5, delivering respectively vinylgermanes 8/8 and 9/9 in high

				R 3 YH
				(n equiv)
	b	a	OH	AIBN heptane (10 mol%)		OH
				100 °C, 2 h		YR 3
			R 3 YH = (Me 3 Si) 3 SiH	2ab	2aa
				R 3 YH = Ph 3 GeH	3ab	3aa

Table 3 .

 3 Silyl-and Germylzincation of propargyl alcohol 1a.

	Entry	R3YH	Conditions	Products

[ (Z/E)/ ] [a]

Table 4

 4

	). The reaction of 1a

according to our protocol developed for -heteroatom-substituted alkynes (i.e. hexane, -30 °C, 3 h) delivered, following work-up, vinylsilane 2a, which was isolated in 42% yield with excellent  regioand Z diastereoselectivity (entry 1). The yield in 2a could be further improved with similar levels of selectivity to a reasonable 50%, but to the expense of using a larger amount (2.2 equiv) of [(Me3Si)3Si]2Zn (entry 2).

Table 4 .

 4 Silylzincation of propargylic alcohols with terminal alkynes by reaction with [(Me3Si)3Si]2Zn/Et2Zn.

	Entry	Substrate	R 1	R 2	[(Me3Si)3Si]2Zn	Conditions	Conversion
					(equiv)		(2a-c/1a-c)

[a] Product [b] Yield (%) [c] [Z/E] [d]

	1	1a	H	H	1.1	-30 °C, 3 h	nd [e]	2a	42 [97:3]
	2	1a	H	H	2.2	-30 °C, 16 h	nd [e]	2a	50 [98:2]
	3	1b	4-MeO-Ph	H	1.1	-30 °C, 3 h	48:52	2b	39 [83:17]
	4	1b	4-MeO-Ph	H	1.1	0 °C, 16 h	63:37	2b	57 [f] [85:15]
	5	1b	4-MeO-Ph	H	2.2	-15 °C, 16 h	90:10	2b	69 [86:14]
	6	1c	H	Ph	1.1	-30 °C, 3 h	30:70	2c	29 [19:81]
	7	1c	H	Ph	2.2	-30 °C, 3 h	45:55	2c	45 [15:85]
	8	1c	H	Ph	1.1	-30 °C, 16 h	40:60	2c	40 [f] [45:55]
	9	1c	H	Ph	2.2	0 °C, 16 h	55:45	2c	55 [f] [33:67]

(trimethylsilyl)trisilan-2-yl)prop- 2-en-1-ol (2a):

  Prepared according to GP III. Purification of the crude product by flash chromatography on silica gel (eluent cyclohexane/ethyl acetate = 99/1 to 97/3) afforded 2a (38 mg, 50%,

	Z/E > 98:2) as a colorless oil.
	1 H-NMR (300 MHz, C6D6): 6.57 -6.48 (m, 1H), 5.76 (dt, 3 J(H,H) = 13.2,
	4 J(H,H)= 1.2, 1H), 4.04 (dd, 3 J(H,H) = 6.5, 4 J(H,H) = 1.2, 2H), 0.23 (s,
	27H). 13 C-NMR (75 MHz, C6D6): 147.9, 123.5, 65.0, 1.1. HR-MS (ESI):
	343.1161 ([M + K] + , C12H32KOSi4 + ; calc. 343.1162). The spectral data

-1-phenyl-2-((1,1,1,3,3,3-hexamethyl-2-(trimethylsilyl)trisilan- 2-yl)methylene)pent-4-en-1-ol (14c):

  Prepared according to GP IV

		using allyl bromide (0.22 mL, 2.50 mmol) as electrophile. Purification
	3-(1,1,1,3,3,3-hexamethyl-2-(trimethylsilyl)trisilan-2-yl)-2-	of the crude product by flash chromatography on silica gel (eluent
	(tributylstannyl)prop-2-en-1-ol (15): Prepared according to GP IV	cyclohexane/ethyl acetate = 100/0 to 99/1) afforded 14a (35 mg,
	using Bu3SnCl (0.67 mL, 2.50 mmol) as electrophile. Purification of the	40% yield, E/Z > 98:2) as a colorless oil.
	crude product by flash chromatography on silica gel (eluent	IR (neat): 2951, 2895, 2360, 2341, 1398, 1260, 1028, 830, 754, 686,
	cyclohexane/ethyl acetate = 99/1 to 98/2) afforded 15 (62 mg, 42%	622, 564. 1 H-NMR (400 MHz, C6D6) 5.82 (ddt, 3 J(H,H) = 16.9, 3 J(H,H) =
	yield, Z/E = 81:19) as a colorless oil.	10.0, 3 J(H,H) = 6.8, 1H), 5.60 (s(br), 1H), 5.06 -4.98 (m, 2H), 4.06 (s,
	IR (neat): 3418, 2953, 2921, 2872, 1679, 1457, 1376, 1243, 1048, 1019,	2H), 2.99 -2.97 (m, 2H), 0.26 (s, 27H). 13 C-NMR (100 MHz, C6D6):
	828, 745, 685, 623. 1 H-NMR (400 MHz, C6D6): (Z isomer) 6.84 (t,	156.3, 137.0, 119.2, 116.3, 66.2, 41.7, 1.2. HR-MS (ESI): 367.1731 ([M +
	4 J(H,H) = 1.6, 1H), 4.14 (d, 4 J(H,H) = 1.6, 2H), 1.69-1.63 (m, 6H), 1.49-	Na] + , C15H36NaOSi4 + ; calc. 367.1735).
	1.40 (m, 6H), 1.18 -1.06 (m, 6H), 0.99 -0.95 (m, 9H), 0.33 (s, 27H).	The Z configuration was established on the basis of NOESY
	13 C-NMR (100 MHz, C6D6): (Z isomer) 165.9, 133.6, 76.1, 29.8, 28.0,	correlations.
	14.0, 11.3, 2.0. HR-MS (ESI): 617.2500 ([M + Na] + , C24H58NaOSi4Sn + ;
	calc. 617.2480).	2-(2-((4-methoxyphenoxy)methyl)penta-1,4-dien-1-yl)-
		1,1,1,3,3,3-hexamethyl-2-(trimethylsilyl)trisilane (14b): Prepared
		according to GP IV using allyl bromide (0.22 mL, 2.50 mmol) as
		electrophile. Purification of the crude product by flash
		chromatography on silica gel (eluent cyclohexane/ethyl acetate =
		99/1) afforded 14b (101 mg, 90% yield, E/Z = 85:15) as a colorless oil.
		IR (neat): 2947, 2893, 2833, 2360, 1612, 1506, 1466, 1244, 1226, 1043,
		917, 822, 748, 686, 623. 1 H-NMR (300 MHz, C6D6): (E isomer) 6.85 -
		6.79 (m, 4H), 5.78 (ddt, 3 J(H,H) = 17.0, 3 J(H,H) = 10.1, 3 J(H,H) = 6.8,
		1H), 5.70 (s, 1H), 5.15 (d, 3 J(H,H) = 17.0, 1H), 5.11 (d, 3 J(H,H) = 10.1,
		1H), 4.49 (s, 2H), 3.76 (s, 3H), 3.00 (d, 3 J(H,H) = 6.6, 2H), 0.18 (s, 27H).
		13 C-NMR (75 MHz, C6D6): (E isomer) 154.5, 153.3, 151.3, 153.9, 119.4,
		117.5, 116.3, 114.9, 72.7, 55.3, 40.0, 1.4. HR-MS (ESI): 473.2146 ([M +
		Na] + , C22H42NaO2Si4 + ; calc. 473.2154).
		The E configuration was established on the basis of NOESY
		correlations.
		(E)using allyl bromide (0.22 mL, 2.50 mmol) as electrophile. Purification
		of the crude product by flash chromatography on silica gel (eluent
	1 H-NMR (300 MHz, C6D6) 7.35 -7.32 (m, 2H), 7.19 -7.14 (m, 2H), 7.08	cyclohexane/ethyl acetate = 99/1) afforded 14c (56 mg, 53% yield,
	-7.02 (m, 1H), 6.34 (dd, 3 J(H,H) = 18.3, 3 J(H,H) = 5.4, 1H), 6.05 (dd,	E/Z > 98:2) as a colorless oil.
	3 J(H,H) = 18.3, 4 J(H,H) = 1.3, 1H), 4.95 (d, 3 J(H,H) = 5.4, 1H), 0.22 (s,	IR (neat): 2947, 2892, 2360, 1637, 1601, 1492, 1453, 1395, 1243, 827,
	27H). 13 C-NMR (100 MHz, C6D6): 150.8, 143.8, 128.6, 127.6, 126.6,	762, 685, 621. 1 H-NMR (400 MHz, C6D6): 7.33 -7.30 (m, 2H), 7.19 -
	121.4, 77.4, 1.0. HR-MS (ESI): 381.1919 ([M + H] + , C18H37OSi4 + ; calc.	7.14 (m, 2H), 7.09 -7.05 (m, 1H), 6.10 (d, 4 J(H,H) = 1.3, 1H), 5.78
	381.1916).	(dddd, 3 J(H,H) = 17.8, 3 J(H,H) = 9.4, 3 J(H,H) = 7.7, 3 J(H,H) = 5.4, 1H),
	The E configuration was established on the basis of the 3 J(H,H) (18.3
	Hz) coupling constant between the vinylic protons.
	(Z)-2-((1,1,1,3,3,3-hexamethyl-2-(trimethylsilyl)trisilan-2-
	yl)methylene)pent-4-en-1-ol (14a): Prepared according to GP IV	443.2058).

5.10 (s(br), 1H), 5.04 -4.99 (m, 2H), 3.15 (ddt,

[START_REF] Negishi | Alkyne Elementometalation-Pd-Catalyzed Cross-Coupling. Toward Synthesis of All Conceivable Types of Acyclic Alkenes in High Yields, Efficiently, Selectively, Economically, and Safely: "Green" Way[END_REF]

J(H,H) = 14.9, 3 J(H,H) = 5.4, 4 J(H,H) = 1.9, 1H), 2.80 -2.68 (m, 1H), 0.26 (s, 27H).

[START_REF] De La Vega-Hernández | Radical Germylzincation of α-Heteroatom-Substituted Alkynes[END_REF]

C-NMR (100 MHz, C6D6): 157.4, 143.6, 137.1, 128.5, 127.8, 127.4, 117.1, 116.5, 77.1, 40.1, 1.5. HR-MS (ESI): 443.2048 ([M + Na] + , C21H40NaOSi4 + ; calc.

  J(H,H) = 7.4, 2H), 1.34 (br s, 1H), 1.26 -0.93 (m, 10H), 0.87 (t, 3 J(H,H) = 7.2, 3H). 13 C-NMR (CDCl3, 100 MHz): 145.5, 136.9, 135.8, 135.2, 129.1, 128.4, 69.2, 33.4, 31.8, 29.3, 29.2, 29.1, 22.7, 14.2.

	Prepared according to
	GP II. Purification of the crude product (α/β = 90(Z/E > 98:2):10) by
	flash chromatography on silica gel (eluent pentane/toluene/Et2O =
	80:10:10) afforded analytically pure 8 (92 mg, 80%, Z/E > 98:2) as a
	colorless liquid.
	1 H-NMR (400 MHz, CDCl3): 7.63 -7.61 (m, 6H), 7.41 -7.37 (m, 9H),
	6.55 (t, 3 J(H,H) = 7.4, 1H), 4.19 (s, 2H), 1.94 (q, 3 1 H-NMR (400 MHz, CDCl3): 7.74 (s, 1H), 7.58 -7.55 (m, 6H), 7.40 -
	7.31 (m, 9H), 7.20 -7.17 (m, 2H), 7.00 -6.95 (m, 1H), 6.93 -6.89 (m,
	2H), 4.39 (s, 2H), 1.60 (br s, 1H). 13 C-NMR (CDCl3, 100 MHz): 143.2,
	138.2, 137.3, 136.6, 135.2, 129.0, 128.8, 128.3, 127.5, 127.4, 69.9.

(Z)-3-phenyl-2-(triphenylgermyl)prop-2-en-1-ol (9):

[START_REF] De La Vega-Hernández | Radical Germylzincation of Aryl-and Alkyl-Substituted Internal Alkynes[END_REF]

Prepared according to GP II. Purification of the crude product (Z/E > 98:2) by flash chromatography on silica gel (eluent toluene/Et2O = 90:10) afforded analytically pure 9 (96 mg, 87%, Z/E > 98:2) as a colorless liquid.

phenyl-2-(triphenylgermyl)prop-2-en-1-ol (22): [14] Prepared

  H-NMR (400 MHz, CDCl3): 7.84 (s, 1H), 7.57 -7.54 (m, 6H), 7.36 -7.30 (m, 9H), 7.17 -7.15 (m, 2H), 6.94 -6.90 (m, 1H), 6.87 -6.83 (m, 2H), 4.60 (q, 3 J(H,H) = 6.4, 1H), 1.70 (br s, 1H), 1.36 (d,[START_REF] Negishi | Alkyne Elementometalation-Pd-Catalyzed Cross-Coupling. Toward Synthesis of All Conceivable Types of Acyclic Alkenes in High Yields, Efficiently, Selectively, Economically, and Safely: "Green" Way[END_REF] J(H,H) = 6.4, 3H).[START_REF] De La Vega-Hernández | Radical Germylzincation of α-Heteroatom-Substituted Alkynes[END_REF] C-NMR (100 MHz, CDCl3): 143.2, 140.6, 137.3, 137.1, 135.3, 128.9, 128.85, 128.2, 127.4, 127.2, 72.4, 24.4. H-NMR (400 MHz, CDCl3): 7.48 -7.45 (m, 6H), 7.39 -7.30 (m, 9H), 7.20 -7.17 (m, 3H), 7.10 -7.07 (m, 2H), 6.66 (qd,[START_REF] Negishi | Alkyne Elementometalation-Pd-Catalyzed Cross-Coupling. Toward Synthesis of All Conceivable Types of Acyclic Alkenes in High Yields, Efficiently, Selectively, Economically, and Safely: "Green" Way[END_REF] J(H,H) = 6.9, 4 J(H,H) 1.2, 1H), 5.33 (s, 1H), 1.87 (br s, 1H), 1.65 (dd, 3 J(H,H) = 6.9, 4 J(H,H) = 0.9, 3H).[START_REF] De La Vega-Hernández | Radical Germylzincation of α-Heteroatom-Substituted Alkynes[END_REF] C-NMR (100 MHz, CDCl3): 142.6, 140.2, 139.0, 137.0, 135.2, 128.9, 128.2, 128.1, 127.1, 126.9, 78.6, 19.5.

	1 H-NMR (400 MHz, CDCl3): 7.62 -7.59 (m, 6H), 7.43 -7.36 (m, 9H), 6.93 (s, 1H), 4.16 (s, 2H), 1.49 (br s, 1H), -0.22 (s, 9H). 13 C-NMR (100 MHz, CDCl3): 152.9, 144.1, 137.3, 135.4, 129.2, 128.3, 72.3, -0.2. (Z)-3-(Z)-1-phenyl-2-(triphenylgermyl)but-2-en-1-ol (23): [14] Prepared according to GP II. Purification of the crude product (Z/E > 98:2) by flash chromatography on silica gel (eluent pentane/Et2O/toluene = 75:15:10) afforded analytically pure 23 (58 mg, 51%, Z/E > 98:2) as a white paste.

according to GP II. Purification of the crude product (Z/E > 98:2) by flash chromatography on silica gel (eluent pentane/Et2O/toluene = 75:15:10) afforded analytically pure 22 (94 mg, 83%, Z/E > 98:2) as a colorless liquid. 1 1

in Both Regio-and Stereoselectivity in Radical-and Nonradical-Mediated Transformations', Chem. Eur. J. 2014, 20, 8579-8583.

Acknowledgements

Omar Khaled (IPCM) is gratefully acknowledged for HR-MS analyses.

Supplementary Material

Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/MS-number.

Author Contribution Statement

The project and experiments were designed by A. P.-L., F. C., F. F. and O. J. The experimental work was performed by K. V.-H., K. I., and A.

P.-L. All the authors contributed to the manuscript writing and review process.