Trans-Concerted Addition to Alkynes: the case of Ynamide Silylzincation.

An original concerted antarafacial mechanism for the addition of diorganosilyl-zinc reagents across the C-C triple bond in ynamides is computationally investigated using DFT calculations. This concerted mechanism, leading to a trans-product in only one step, results in the formation of a Si-C and a Zn-C σ-bonds on opposite sides of the π-system. We demonstrate that the mechanism going through a η2-vinyl intermediate and the proposal of a radical chain pathway are energetically unsustainable. The retained concerted antarafacial pathway is tested on experimental selectivities: the regioselectivity, in favor of the silyl ß-addition in ynamide, and stereoselectivity, which is cis- with (Me2PhSi)2Zn but trans- with [(Me3Si)3Si]2Zn, are well reproduced by DFT calculations. The regio- and stereoselectivity are discussed using the activation strain model and a chemical bonding analysis.

α-(Aminomethyl)acrylates as acceptors in radical-polar crossover 1,4-additions of dialkylzincs: insights into enolate formation and trapping.

We demonstrate that α-(aminomethyl)acrylates are suitable acceptors for 1,4-additions of dialkylzincs in aerobic conditions. The air-promoted radical-polar crossover process involves the 1,4-addition of an alkyl radical followed by homolytic substitution at the zinc atom of dialkylzinc. Coordination of the nitrogen atom to zinc enables this SH2 process which represents a rare example of alkylzinc-group transfer to a tertiary α-carbonyl radical. The zinc enolate thus formed readily undergoes ß-fragmentation unless it is trapped by electrophiles in situ. Enolates of substrates having free N-H bonds undergo protodemetalation to provide ultimately the 1,4-addition adduct. In the presence of carbonyl acceptors, aldol condensation occurs providing overall a tandem 1,4-addition-aldol process. When a tert-butanesulfinyl moiety is present on the nitrogen atom, these electrophilic substitution reactions occur with good levels of chiral induction, paving the way to enantioenriched ß2-amino acids and ß2,2-amino acids.

Enantioselective Sequential Catalytic Arylation-Fukuyama Cross-coupling of 1,1-Biszincioalkane Linchpins.

1,1-Bis(iodozincio)alkanes are used as dinucleophilic linchpins in an enantioselective double cross-coupling reaction sequence involving aryl iodides and then thioesters. The two catalytic C-C bond-forming reactions are achieved in the same pot through two distinct palladium-based catalytic systems: a first non-enantioselective one delivering configurationally labile secondary benzylzinc species from an achiral precursor, and a second enantioconvergent one that operates a highly efficient dynamic kinetic resolution of the racemic intermediates. This strategy, new in the area of asymmetric synthesis through two consecutive electrophilic substitution reactions of geminated C(sp3 )-organodimetallics, provides useful methodology to access in a modular fashion acyclic α-disubstituted ketone products with very high enantiomeric purity.

Modular synthesis of 2-furyl carbinols from 3-benzyldimethylsilylfurfural platforms relying on oxygen-assisted C-Si bond functionalization.

3-Silylated furfurals, readily prepared in three steps from biomass-derived furfural and 5-methylfurfural, are converted into 3-silylated 2-furyl carbinols upon condensation with organomagnesium or organolithium reagents. The hydroxy unit of the carbinol adducts can be exploited to promote C3(sp2)-Si bond functionalization through intramolecular activation. Two approaches were contemplated for this purpose. Activation by alkoxides of the C3-SiEt3 or C3-SiMe2 t-Bu bonds was ineffective. Conversely, treatment of the C3-benzyldimethylsilyl-appended derivatives with tetrabutylammonium fluoride led to cyclic siloxanes, which revealed to be competent donors for copper-catalyzed cross-coupling reactions, such as arylation reactions catalyzed by Pd2(dba)3/CuI, as well as allylation and methylation reactions catalyzed by CuI⋅PPh3. C3-Benzyldimethylsilyl-appended furfurals are thus introduced as versatile platforms, providing a modular access to 3-substituted 2-furyl carbinols from renewable feedstock.

Modular access to substituted germoles by intramolecular germylzincation.

Intramolecular alkyne germylzincation giving access to a wide range of germoles is achieved from triarylhydrogermanes in the presence of diethylzinc and AIBN as radical initiator. The reaction proceeds through activation of the Ge-H bond, leading to a heteroarylzinc intermediate after cyclisation, which can then be involved in a post-functionalisation reaction. Our results show that only 5-endo-dig cyclizations occur, with benzogermoles being exclusively obtained.

Radical Germylzincation of Aryl- and Alkyl-Substituted Internal Alkynes.

The stereoselective germylzincation of internal alkynes delivering trisubstituted vinylgermanes is achieved via a radical chain process involving Ph3GeH and Et2Zn with AIBN as the initiator. Excellent levels of regiocontrol are observed for nonsymmetric (aryl, alkyl)-substituted alkynes and for propargylic alcohols with aryl-, alkyl-, or silyl-substituted alkynes. The germylzincation reaction can be combined in one pot with the Cu(I)-mediated electrophilic substitution of the C(sp2)-Zn bond to obtain synthetically challenging tetrasubstituted vinylgermanes.

Catalytic Chemoselective and Stereoselective Semihydrogenation of Alkynes to E-Alkenes Using the Combination of Pd Catalyst and ZnI2.

An efficient E-selective semihydrogenation of internal alkynes was developed under low dihydrogen pressure and low reaction temperature from commercially available reagents: Cl2Pd(PPh3)2, Zn0, and ZnI2. Kinetic studies and control experiments underline the significant role of ZnI2 in this process under H2 atmosphere, establishing that the transformation involves syn-hydrogenation followed by isomerization. This simple and easy-to-handle system provides a route to E-alkenes under mild conditions.

Radical Germylzincation of α-Heteroatom-Substituted Alkynes.

The regio- and stereoselective addition of germanium and zinc across the C-C triple bond of nitrogen-, sulfur-, oxygen-, and phosphorus-substituted terminal and internal alkynes is achieved by reaction with a combination of R3GeH and Et2Zn. Diagnostic experiments support a radical-chain mechanism and the ß-zincated vinylgermanes that show exceptional stability are characterized by NMR spectroscopy and X-ray crystallography. The unique feature of this new radical germylzincation reaction is that the C(sp2)-Zn bond formed remains available for subsequent in situ Cu(I)- or Pd(0)-mediated C-C or C-heteroatom bond formation with retention of the double bond geometry. These protocols offer modular access to elaborated tri- and tetrasubstituted vinylgermanes decorated with heteroatom substituents ß to germanium that are useful for the preparation of stereodefined alkenes.

Revealing the electrophilicity of N-Ac indoles with FeCl3: a mechanistic study.

Herein, we report a mechanistic exploration of the unusual FeCl3-mediated hydroarylation of N-Ac indoles. Electron density topology analysis of a crystal, in situ IR monitoring, Hammett and Taft studies as well as DFT computations allowed us to determine that activation of acetyl with FeCl3 and of the C2[double bond, length as m-dash]C3 bond with a proton is involved.

Harnessing the Lewis Acidity of HFIP through its Cooperation with a Calcium(II) Salt: Application to the Aza-Piancatelli Reaction.

A method to extend the scope of the aza-Piancatelli reaction between 2-furylcarbinols and anilines is depicted. We found that 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) is the solvent of choice for this transformation, as it outcompetes the usual solvents in terms of rate and yield. Side reactions and other issues raised by the title reaction are prevented, thereby providing an avenue to complex molecules that were previously inaccessible. Lewis acidity studies and computations were carried out to unveil the role of HFIP. Based on these results, we propose that HFIP is, in fact, acting as a Lewis acid and that its acidity can be enhanced when combined with a calcium(II) salt.

C2-Alkylation and Alkenylation of Indoles Catalyzed by a Low-Valent Cobalt Complex in the Absence of Reductant.

Herein an extremely versatile, well-defined, low-valent cobalt catalyst [Co(PMe3)4] capable of intermolecular and intramolecular imine-directed C2-alkylation and alkenylation of indoles is reported. The reaction proceeds in the absence of reducing agents or additives, affording a range of substituted indoles and dihydropyrroloindoles in high yields and regioselectivities. With the aid of deuterium labeling studies and DFT (Density Functional Theory) calculations, a mechanism is proposed that is based on a Ligand-to-Ligand Hydrogen Transfer pathway.

Stereodivergent Silylzincation of α-Heteroatom-Substituted Alkynes.

Zinc reagents (Me2PhSi)2Zn and [(Me3Si)3Si]2Zn undergo highly regio- and stereoselective addition across the carbon-carbon triple bond of nitrogen-, sulfur-, oxygen-, and phosphorus-substituted terminal alkynes in the absence of copper or any other catalyst. Both reagents yield exclusively ß-isomers, and the stereoselectivity is determined by the silyl group: Me2PhSi for cis or (Me3Si)3Si for trans. These stereodivergent silylzincation protocols offer an efficient access to heteroatom-substituted vinylsilanes with either double bond geometry, including trisubstituted vinylsilanes by one-pot electrophilic substitution of the intermediate C(sp(2))-Zn bond by copper(I)-mediated carbon-carbon bond formation.

tert-Butanesulfinamides as Nitrogen Nucleophiles in Carbon-Nitrogen Bond Forming Reactions.

The use of tert-butanesulfinamides as nitrogen nucleophiles in carbon-nitrogen bond forming reactions is reviewed. This field has grown in the shadow of the general interest in N-tert-butanesulfinyl imines for asymmetric synthesis and occupies now an important place in its own right in the chemistry of the chiral amine reagent tert-butanesulfinamide. This article provides an overview of the area and emphasizes recent contributions wherein the tert-butanesulfinamides act as chiral auxiliaries or perform as nitrogen donors in metal-catalyzed amination reactions.

C-H activation/functionalization catalyzed by simple, well-defined low-valent cobalt complexes.

A facile C-H activation and functionalization of aromatic imines is presented using low-valent cobalt catalysts. Using Co(PMe3)4 as catalyst we have developed an efficient and simple protocol for the C-H/hydroarylation of alkynes with an anti selectivity. Deuterium-labeling experiments, DFT calculations coupled with the use of a well-defined catalyst have for the first time shed light on the elusive black box of cobalt catalyzed C-H functionalization.

Trans-selective radical silylzincation of ynamides.

The silylzincation of terminal ynamides is achieved through a radical-chain process involving (Me3Si)3SiH and R2Zn. A potentially competing polar mechanism is excluded on the basis of diagnostic control experiments. The unique feature of this addition across the C≡C bond is its trans selectivity. One-pot electrophilic substitution of the C(sp2)-Zn bond by Cu(I)-mediated C-C bond formation and subsequent manipulation of the C(sp2)-Si bond provides a modular access to Z-α,ß-disubstituted enamides.

Radical zinc-atom-transfer-based carbozincation of haloalkynes with dialkylzincs.

The formation of alkylidenezinc carbenoids by 1,4-addition/carbozincation of dialkylzincs or alkyl iodides based on zinc atom radical transfer, in the presence of dimethylzinc with ß-(propargyloxy)enoates having pendant iodo- and bromoalkynes, is disclosed. Formation of the carbenoid intermediate is fully stereoselective at -30 °C and arises from a formal anti-selective carbozincation reaction. Upon warming, the zinc carbenoid is stereochemically labile and isomerizes to its more stable form.

Three-carbon homologation of diorganozincs with lithiated acetylenic epoxides.

Reaction of dialkylzincs with lithiated acetylenic epoxides is described to give zincates that undergo a 1,2-metallate rearrangement by an anti-S(N)2' pathway. This rearrangement occurs with the transfer of an alkyl or a silyl group affording allenylzinc intermediates. Allenic and/or homopropargylic alcohols are obtained upon hydrolysis. Quenching the reaction mixture with aldehydes or ketones is shown to give access to 2-alkynyl-1,3-diols in a stereoselective manner.

Synthesis of (-)-swainsonine and (-)-8-epi-swainsonine by the addition of allenylmetals to chiral α,ß-alkoxy sulfinylimines.

The asymmetric synthesis of (-)-swainsonine and (-)-8-epi-swainsonine is reported through the addition of either the allenylzinc or the allenyl lithio cyanocuprate reagents derived from [3-(methoxymethoxy)prop-1-ynyl]trimethylsilane to enantiopure α,ß-dialkoxy N-tert-butanesulfinylimines derived from d-erythronolactone.

Cyclization of zincated α-N-homoallylamino nitriles: a new entry to enantiopure 2,3-methanopyrrolidines.

Stereoselective cyclization of zincated α-N-homoallylamino nitriles has been developed. Following treatment with lithium diisopropylamide (LDA) and transmetalation with zinc bromide, α-N-(1-phenylethyl)-N-homoallylamino nitriles lead to 2,3-methanopyrrolidines in moderate to good yields (up to 66 %) and excellent selectivities (up to >98:2). With substrates derived from α-branched homoallylic amines, a stereospecific inversion of the homoallylic stereogenic center was observed. To account for this, a mechanistic rationale involving the formation of zincioiminium ions from zincated α-amino nitriles is put forward. 2,3-Methanopyrrolidines should then arise from a sequence involving an aza-Cope rearrangement providing a configurationally stable (2-azoniaallyl)zinc species that then undergoes a [3+2] cycloaddition reaction.