Asymmetric Ruthenium Catalysis Enables Fluorophores with Point Chirality Displaying CPL Properties.

A novel enantiopure π-allylruthenium(IV) precatalyst allowed the enantioselective and stereospecific allylations of indoles and gave access to indolin-3-ones, containing vicinal stereogenic centers. Facile separation of diastereoisomers exhibiting opposite circularly polarized luminescence (CPL) activities in diverse solvents, including water, demonstrated the potential of these sustainable transformations and of the newly prepared molecules.

Access to 3-Oxindoles from Allylic Alcohols and Indoles.

The site-selective and regioselective allylation of 2-substituted indoles was performed by using a ruthenium(IV) precatalyst containing a phosphine-sulfonate chelate. Mono-, di-, and triallylated indoles were selectively obtained depending on the reaction conditions with the formation of water as the only byproduct. The preparation of 3-oxindole derivatives was then successfully performed owing to air oxidation of the corresponding allylated indoles. Diallylated pseudoindoxyls were proven to be good synthons to perform cyclization through a ring-closing metathesis reaction to afford the corresponding tricyclic adducts. The photophysical properties of the 3-oxindoles were measured, and some of the compounds showed strong fluorescence in water.

Selective ruthenium-catalyzed hydrochlorination of alkynes: one-step synthesis of vinylchlorides.

An unprecedented ruthenium-catalyzed direct and selective alkyne hydrochlorination is reported and leads to vinylchlorides in excellent yields with atom economy. The reaction proceeds at room temperature from terminal alkynes and provides a variety of chloroalkenes. Only the regioisomer resulting from the formal Markovnikov addition is selectively formed. Mechanistic studies show the stereoselective syn addition of HCl to alkynes at room temperature and suggest a chloro hydrido Ru(IV) species as a key intermediate of the reaction.

Ruthenium-catalysed synthesis of functional conjugated dienes from propargylic carbonates and silyl diazo compounds.

Ru being served? The reactions of propargylic carbonates with silyl diazo compounds in the presence of [Cp*RuCl(cod)] as a catalyst precursor led to the formation of dienyl carbonates in excellent yields under mild conditions (see scheme; Y = SiMe(3)).

One-step synthesis of 1-halo-1,3-butadienes via ruthenium-catalysed hydrohalogenative dimerisation of alkynes.

An efficient, novel and direct access to 1-halo-1,3-butadienes is developed. This stereoselective ruthenium-catalysed reaction proceeds under mild conditions via the head-to-head oxidative coupling of two alkynes and a concomitant hydrohalogenation.

Regio- and stereoselective syntheses of piperidine derivatives via ruthenium-catalyzed coupling of propargylic amides and allylic alcohols.

Intermolecular selective coupling of linear allylic alcohols and propargylic amides occurs in the presence of a catalytic amount of the cationic ruthenium complex [Cp*Ru(NCCH(3))(3)]PF(6) followed by condensation to generate six-membered cyclic enamides or hemiaminal ethers with water as the only side product.

Ruthenium-catalysed synthesis of fluorinated bicyclic amino esters through tandem carbene addition/cyclopropanation of enynes.

The reaction of fluorinated 1,6- and 1,7-enynes, containing the moiety N(PG)C(CF(3))(CO(2)R), with diazo compounds in the presence of [RuCl(cod)(Cp*)] (cod=cycloocta-1,5-diene, Cp*=C(5)Me(5) , PG=protecting group) as the catalyst precursor leads to the formation of fluorinated 3-azabicyclo[3.1.0]hexane-2-carboxylates and 4-azabicyclo-[4.1.0]heptane-3-carboxylates. This catalytic transformation was applied to various protecting groups and has proved to be a selective and a general synthetic tool to form constrained proline or homoproline derivatives in good yields. Z stereoselectivity of the created alkenyl group is obtained with N(2)CHSiMe(3), whereas N(2)CHCO(2)Et favours selectively the E configuration for the same double bond. The diastereoselectivity exo/endo depends on the size of the created ring. The X-ray structures of two products have been determined, showing the stereochemistry of the compounds. The reaction can be understood by initial [2+2] addition of the Ru=CHY bond, generated from diazoalkane, with the C≡CH bond of the enyne leading to a key bicyclic ruthenacyclobutane, which promotes the cyclopropanation, rather than metathesis. This selective formation of bicyclic [n.1.0] compounds results from the ruthenium-catalysed creation of three carbon-carbon bonds in a single step under mild conditions.

Ruthenium-catalyzed synthesis of functional conjugated dienes via addition of two carbene units to alkynes.

The reaction of a variety of alkynes with N(2)CHSiMe(3), in the presence of Cp*RuCl(cod) as the catalyst precursor, leads to the general formation of functional conjugated dienes. This selective formation results from the ruthenium-catalyzed creation of two carbon-carbon double bonds in a single step under mild conditions. Terminal alkynes produce 1,4-bistrimethylsilylbuta-1,3-dienes with Z stereoselectivity for the less hindered double bond whereas disubstituted alkynes favor E-configuration for the same double bond. Diynes react also as monoalkynes, and only one triple bond is transformed to give disilylated dienynes. The reaction can be applied to the in situ desilylation in methanol and formation of monosilylated dienes. The catalytic formation of 1,4-bisfunctional buta-1,3-dienes can also take place with N(2)CHCO(2)Et and N(2)CHPh. The reaction can be understood by addition of two carbene units to triple bonds. An initial [2 + 2] addition of the Ru=CHSiMe(3) bond with the alkyne triple bond leads to an alkenyl ruthenium-carbene species capable of coordinating a second carbene unit to produce conjugated dienes.

Ruthenium-catalyzed synthesis of functionalized dienes from propargylic esters: formal cross-coupling of two carbenes.

Cross-coupling carbenes: The coupling of a propargylic ester with a diazoalkane in the presence of [RuCl(cod)Cp*] catalyst leads to the formation of functionalized conjugated dienes with high stereoselectivity. The reaction involves the cross-coupling of a vinylcarbene fragment, arising from a ruthenium-catalyzed propargylic ester rearrangement, with a diazoalkane carbene.

Selective ruthenium-catalyzed transformations of enynes with diazoalkanes into alkenylbicyclo[3.1.0]hexanes.

Reaction of a variety of CCH bond-containing 1,6-enynes with N2CHSiMe3 in the presence of RuCl(COD)Cp* as catalyst precursor leads, at room temperature, to the general formation of alkenylbicyclo[3.1.0]hexanes with high Z-stereoselectivity of the alkenyl group and cis arrangement of the alkenyl group and an initial double-bond substituent, for an E-configuration of this double bond. The stereochemistry is established by determining the X-ray structures of three bicyclic products. The same reaction with 1,6-enynes bearing an R substituent on the C1 carbon of the triple bond results in either cyclopropanation of the double bond with bulky R groups (SiMe3, Ph) or formation of alkylidene-alkenyl five-membered heterocycles, resulting from a beta elimination process, with less bulky R groups (R = Me, CH2CH=CH2). The reaction can be applied to in situ desilylation in methanol and direct formation of vinylbicyclo[3.1.0]hexanes and to the formation of some alkenylbicyclo[4.1.0]heptanes from 1,7-enynes. The catalytic formation of alkenylbicyclo[3.1.0]hexanes also takes place with enynes and N2CHCO2Et or N2CHPh. The reaction can be understood to proceed by an initial [2+2] addition of the Ru=CHSiMe3 bond with the enyne CCH bond, successively leading to an alkenylruthenium-carbene and a key alkenyl bicyclic ruthenacyclobutane, which promotes the cyclopropanation, rather than metathesis, into bicyclo[3.1.0]hexanes. Density functional theory calculations performed starting from the model system Ru(HCCH)(CH2=CH2)Cl(C5H5) show that the transformation into a ruthenacyclobutane intermediate occurs with a temporary eta3-coordination of the cyclopentadienyl ligand. This step is followed by coordination of the alkenyl group, which leads to a mixed alkyl-allyl ligand. Because of the non-equivalence of the terminal allylic carbon atoms, their coupling favors cyclopropanation rather than the expected metathesis process. A direct comparison of the energy profiles with respect to those involving the Grubbs catalyst is presented, showing that cyclopropanation is favored with respect to enyne metathesis.

Tandem catalytic carbene addition/bicyclization of enynes. One-step synthesis of fluorinated bicyclic amino esters by ruthenium catalysis.

The reaction of diazo compounds with enynes, containing a fluorinated amino acid moiety, in the presence of the precatalyst Cp(Cl)Ru(COD) leads to fluorinated alkenyl bicyclo[3.1.0]hexane and [4.1.0]heptane amino acid derivatives. It is remarkable that the catalyst, in situ generated from ruthenium complex and diazo compound, completely inhibits the ring closing metathesis of enyne to the profit of tandem alkenylation/cyclopropanation with high stereoselectivity. The study shows that the Cp(Cl)Ru moiety in ruthenacyclobutane favors reductive elimination versus expected alkene metathesis. [reaction: see text]

Ruthenium-catalyzed synthesis of alkylidenecyclobutenes via head-to-head dimerization of propargylic alcohols and cyclobutadiene-ruthenium intermediates.

The reaction of propargylic alcohols with carboxylic acid, or phenol derivatives, in the presence of the precatalyst [RuCl(cod)(C5Me5)] leads selectively to a variety of alkylidenecyclobutenes through head-to-head dimerization of propargylic alcohol. The first step is the formation of a cyclobutadiene-ruthenium intermediate resulting from the head-to-head coupling of two molecules of propargylic alcohol. On protonation with strong acids (HPF6, HBF4) dehydration of the cyclobutadiene complex leads to formation of an alkylidenecyclobutenyl-ruthenium complex. The X-ray structure of one such complex, [RuCl(C5Me5)(eta4-R'CCH--CH--C=CR2)] (R'=cyclohexen-1-yl, CR2 = cyclohexylidene) has been determined. Carboxylate is added at the less substituted carbon of the cyclic allylic ligand. DFT/B3 LYP calculations confirm that the intermediate arising from head-to-head coupling of alkyne to the RuClCp* species yields the cyclobutadiene-ruthenium complex more easily with propargylic alcohol than with acetylene.

Biscarbene-ruthenium complexes in catalysis: novel stereoselective synthesis of (1E,3E)-1,4-disubstituted-1,3-dienes via head-to-head coupling of terminal alkynes and addition of carboxylic acids.

The reaction of a variety of alkynes RCtbd1;CH with a variety of carboxylic acids R(1)CO(2)H, in the presence of 5% of RuCl(COD)C(5)Me(5), selectively leads to the dienylesters (1E,3E)-RCH(1)=CH(2)-CH(3)=C(R)(O(2)CR(1)). The reaction also applies to amino acid and dicarboxylic acid derivatives. It is shown that the first step of the reaction consists of the head-to-head alkyne coupling and of the formation of the metallacyclic biscarbene-ruthenium complex isolated for R = Ph and catalyzing the formation of dienylester. D-labeled reactions show that the alkyne protons remain at the alkyne terminal carbon atoms and carboxylic acid protonates the C(1) carbon atom. QM/MM (ONIOM) calculations, supporting a mixed Fischer-Schrock-type biscarbene complex, show that protonation occurs preferentially at the carbene carbon C(1) adjacent to Ru, in the relative cis position with respect to the Ru-Cl bond, to give a mixed C(1)alkyl-C(4)carbene complex in which the C(4) carbene is conjugated with the noncoordinated C(2)=C(3) double bond. This 16-electron intermediate has a weak stabilizing alpha agostic C-H bond. This most stable isomer appears to have a C(4) center more accessible to the nucleophilic addition which accounts for the experimentally observed product.

Ruthenium catalyzed regioselective hydrophosphination of propargyl alcohols.

Catalytic hydrophosphination of propargyl alcohols by ruthenium complexes RuCl(cod)(C5Me5) and RuCl(PPh3)2(C5Me5) leads to the formation of functionalized vinylphosphines, with linkage of the phosphorus atom to the terminal alkyne carbon, via a ruthenium vinylidene intermediate.

Ruthenium-Catalyzed One-Step Transformation of Propargylic Alcohols into Alkylidene Cyclobutenes: X-ray Characterization of an Ru(η3 -cyclobutenyl) Intermediate.

The precatalyst [Cp*RuCl(cod)] promotes the head-to-head cyclodimerization of propargylic alcohols and the formation of novel alkylidene cyclobutenes (see scheme; Cp*=C5 Me5 , cod=1,5-cyclooctadiene) by addition of carboxylic acid to the Ru(η4 -cyclobutadiene) intermediate and dehydration.

Synthesis of 2-Alkoxy-5-methylenetetrahydropyrans: A Regioselective Ruthenium-Catalyzed C-C Coupling Reaction of Prop-2-yn-1-ols with Allyl Alcohol.

The carbon-carbon coupling of prop-2-yn-1-ols with allyl alcohol is achieved in the presence of the ruthenium(II) catalyst RuCl(cod)(C(5)Me(5)). The coupling reaction is highly regioselective and leads to the HOCR(2)C(=CH(2))CH(2)CH(2)CHO isomer and, after cyclization, to either 2-hydroxy- or 2-alkoxy-5-methylenetetrahydropyrans, at room temperature or at 80 degrees C, respectively. It is used for the synthesis of molecules containing two and three tetrahydropyran moieties. The study of a variety of prop-2-yn-1-ols has shown the influence of the substituent at the propargyl carbon on the regioselectivity of the C-C coupling. In the case of tertiary alcohols, the reaction leads to only one cyclic isomer, the 2-alkoxytetrahydropyran whereas with secondary alcohols, a linear isomer is also obtained. The tetrahydropyranols are easily oxidized into lactones.