Alkyne Insertion Step Research Articles

Nickel-catalyzed defluorinative asymmetric cyclization of Trifluoromethyl-substituted 1,6-Enynes: Insights from DFT calculations on the reaction mechanism and selectivity

Density functional theory (DFT) calculations were employed to elucidate the mechanism and selectivity of nickel-catalyzed defluorinative asymmetric cyclization reactions of trifluoromethyl-substituted 1,6-enynes. The results indicate that the product is formed via a stepwise addition cyclization mechanism, including sequential steps of ligand coordination, transmetalation, ligand exchange, alkyne insertion, olefin insertion, β-F elimination, another transmetalation, and a final ligand exchange. The regioselectivity is primarily governed by the alkyne insertion step, where electrostatic interactions strongly favor 1,2-insertion of the carbon-carbon triple bond over 2,1-insertion. The enantioselectivity is largely determined during the insertion step of the olefin insertion step, with the (S)-product forming preferentially over the (R)-product due to stronger non-covalent interactions between the ligand and the substrate, minimal catalyst conformational distortion, and enhanced electronic interactions between the catalyst and the substrate.

Tailor-made poly(vinylidene sulfide)s by Rh(I)–NHC catalyzed regioselective thiol-yne click polymerization

The [Rh(μ-Cl)(IPr)(η2-coe)]2/pyridine system efficiently catalyzes the polyhydrothiolation of a series of dialkynes with dithiols, producing sulfur-rich poly(vinylidene sulfide)s with a typical Mw in the range 20.000–124.000 and vinylidene content of 75–87%. A combination of flexible aliphatic dithiols, including 1,6-hexanedithiol and 2,2′-(ethylendioxy)diethanethiol, and the rigid aromatic dithiol 4,4′-thiobisbenzenethiol, with rigid aromatic dialkynes, 1,3-diethynylbenzene and 1,4-diethynylbenzene, and flexible dialkynes, including propargyl ether and 1,7-octadiyne, have been used to prepare poly(vinylidene sulfide)s. The copolymerization of flexible dithiols with rigid aromatic dialkynes or vice versa results in high molecular weight polymers, Mw up to 259.000, with low polydispersities. However, polyhidrothiolation of flexible dialkynes with flexible dithiols is much less efficient and usually results in the formation of oligomers. The interplay of the IPr and pyridine ligands on the RhCl(IPr)(py)(η2-coe) catalyst, which controls the regioselectivity of the alkyne insertion step towards the branched vinyl sulfide, is key in the preparation of these poly(vinylidene sulfide)s.

Theoretical Investigation on the Mechanistic Pathways of Cp*Cobalt(III)- Catalyzed Transformation of N-Substituted Carbamoyl Indoles to Pyrroloindolone Derivatives

Aim: A theoretical study on the Cp*cobalt(III) catalyzed C-H functionalization transformation of N-substituted carbamoyl indoles with alkyne derivatives to pyrroloindolone derivatives has been performed using DFT method. Background: Indole skeleton is an important part for developing regioselective C-H bond functionalisation reactions. Pyrrolo[1,2-a]indole bearing a 6-5-5 tricyclic skeleton (Scheme-1) is an important structural component found in many biologically active natural products and pharmaceuticals, (such as antitumor mitomycin C, antimalarial flinderole B etc.).Thus C−H activation process has great demand methods for efficiently synthesizing a pyrrolo[1,2-a]indole unit from readily available starting materials. One such attractive report was published by Matsunaga & Kanai et.al., Which shows pyrroloindolone derivatives can be synthesized (Scheme-2) through Cp*Co(III) catalysed C-H alkenylation and annulations from N-substituted carbamoyl indoles. Objective: Our current project deals with the determination of the rate determining step of the reaction, to determine the energetically favourable pathway. Investigation of the actual reason behind the regioselectivity of the products whether it is steric or electronic effects of the substituents. Method: The geometry optimization and energy calculations of all the systems were carried out with the Gaussian 09 software. Construction of trial geometries, monitoring the progress of calculations and visualization of the final output were done by several graphical user interface softwares like Gauss View, Molden etc. Geometry optimization of all species is performed using M06-2X functional in DFT method as a method for performing optimization of structures. 6-31G (d, p) basis set was employed for all non-metal atoms and the LANL2DZ basis set was employed for cobalt. To find out the geometries of several transition structures on the potential energy surface (PES) of the reaction pathway, relaxed scan method was used. Result: DFT study on a reaction of carbamoyl indoles with alkyne derivatives by activate Co(III)Cp* catalytic condition is done here. The target scheme followed the energetics of two possible pathways. The initial step of the reaction is the alkyne insertion step which needs 21.27 kcal mol-1 amount of energy. In the first case the final annulated product has been generated through a carbon-carbon bond formation, proton transfer and demetallation processes in path-a. The global activation barrier has been found to be quite high (30.17 kcal mol-1). However the study of the second pathway, which generated the simple alkenylated product through the proto-demetalation process in path-b, reveals a more reliable activation barrier (21.27 kcal mol-1). Conclusion: Comparison of the energy requirement clearly reveals that the formation of the final product should go through favourable simple alkenylation process that is path-b for dimethyl amine. Due to lower energy barrier the simple alkenylation pathway (i.e Path-b) is more favourable one. Initial alkyne addition step is the rate determining step. The regioselectivity of the alkyne addition is purely governed by the steric crowding around the substrate. Thus the favourable mode of alkyne addition has lower energy barrier due to lesser steric interactions. This theoretical investigation may guide the future researchers for developing some other economical route for generating similar derivatives.

Pd-Catalyzed Synthesis of Densely Functionalized Cyclopropyl Vinyl Sulfides Reveals the Origin of High Selectivity in a Fundamental Alkyne Insertion Step

Catalytic atom-economic hydrothiolation of cyclopropyl acetylenes was developed. Using Pd/NHC complex as a precatalyst, regioselective addition of thiols to cyclopropyl acetylenes was successfully ...

Mechanistic Insights into Manganese (I)‐Catalyzed Chemoselective Hydroarylations of Alkynes: A Theoretical Study

AbstractDensity functional theory calculations were employed to elucidate the mechanism of Mn‐catalyzed chemoselective hydroarylation reactions. The Mn‐catalyzed [4+2] annulation undergoes a reaction pathway involving sequential imine‐directed C−H bond cleavage, alkyne insertion into the Mn−C bond, β‐oxygen elimination and outer catalytic cycle annulation–aromatization. Computational results demonstrated that the previously proposed chelation‐assisted alkyne insertion process was unfavorable owing to the weak coordination ability of the β‐oxygen leaving group compared with that of CO. Further noncovalent interactions analysis indicated that the origin of the high regioselectivity was contributed to the steric repulsion resulting from significant nonbonding overlap between the reacting aryl moiety and the quaternary carbon group of the reactant in the alkyne insertion step. In addition, in the Brønsted‐acid‐mediated chemoselective alkenylation reaction, the used terminal alkynes had relatively enhanced reactivity in the alkyne insertion step owing to its reduced steric repulsion. From the active alkenyl‐Mn intermediate, the activation free energy of protonation and β‐oxygen elimination are approximate, thus the alkenylated product is obtained after protonation in an acidic system. We expect that this detailed mechanistic study will significantly enhance our ability to develop Mn‐catalyzed arene C−H bond functionalization reactions.

Computational Characterization of the Mechanism for the Oxidative Coupling of Benzoic Acid and Alkynes by Rhodium/Copper and Rhodium/Silver Systems.

DFT calculations were applied to study the oxidative coupling between benzoic acid and 1-phenyl-1-propyne catalyzed by [CpRhCl2 ]2 (Cp=cyclopentadienyl) by using either Cu(OAc)2 (H2 O) or Ag(OAc) as the terminal oxidant, a process that has been experimentally shown to have subtleties related to regioselectivity (placement of the phenyl substituent of the alkyne in the isocoumarin product) and chemoselectivity (isocoumarin or naphthalene derivatives). Calculations reproduced the experimental results and showed the involvement of the oxidant throughout the catalytic cycle. The regioselectivity was found to be decided in the alkyne insertion step, in particular by the relative arrangement of the two phenyl groups. The high chemoselectivity towards isocoumarin associated to Cu(OAc)2 (H2 O) could be explained by the fact that the copper moiety blocks the CO2 extrusion pathway, which would lead to naphthalene derivatives, something that does not happen if Ag(OAc) is used.

Mechanistic insights into the ligand-controlled regioselectivity in Cu-catalyzed terminal alkynes alkylboration

The recent Cu-catalyzed alkylboration of unactivated terminal alkynes shows intriguing ligand-controlled regioselectivity. The anti-Markovnikov alkylboration products were obtained with dppbz as ligand, while the Markovnikov products were obtained with DMAP as ligand. In the present study, the theoretical calculation was carried out to investigate the detailed mechanism of the alkylboration process and the mechanistic origin for the ligand-regulated regioselectivity. For both dppbz and DMAP, it was found that the alkylboration undergoes alkyne insertion and sigma-complex-assisted metathesis processes. In the concerted process, the carbon atom of the alkyl iodides directly bonded with the alkenyl carbon which is generated from alkyne insertion step. The anti-Markovnikov and Markovnikov alkylboration is, respectively, favorable for dppbz and DMAP ligand, which is consistent with the regioselectivity in experiment. What's more, the alkyne insertion step is the regioselectivity determining step for both of dppbz and DMAP ligands. The bulky dppbz-coordinated situation makes steric hindrance the main determinant factor of selectivity, therefore the less steric hindrance makes the anti-Markovnikov selectivity more favorable. For DMAP ligands, the electronic effect becomes the main factor due to the strong complexation of DMAP with Cu metal center. Therefore the better FMO interaction between Cu-B bond and alkyne favors the Markovnikov selectivity in the DMAP-coordinated situation.

Mechanistic study on the Rh(III)-catalyzed synthesis of indolines via selective O-atom transfer of arylnitrones: Origins of the regioselectivity and the improved yield with pivalic acid additive

Recent development on Rh(III)-catalyzed synthesis of indolines from arylnitrones and alkynes provides an efficient redox-neutral method integrating C–H activation with O-atom transfer. Here density functional theory calculations were performed on the mechanism of a representative model system: [Cp*Rh]2+-catalyzed reaction of phenylnitrone with 1-phenylpropyne. The results suggest that the catalytic cycle involves a Rh(III)–Rh(I)–Rh(III) transformation and consists of C–H activation, alkyne insertion/O-atom transfer, and cyclization-protonation. The C–H activation, the rate-determining step, proceeds via a self-assisted deprotonation mechanism. The alkyne prefers the insertion into Rh–C(sp2) bond rather than Rh–O bond. The calculations locate an intermediate containing an enol unit, which plays a crucial role in facilitating the cyclization process. The theoretical results provide an explanation for the puzzling experimental observations. The regioselectivity of the reaction is stemmed from the electronic effect rather than steric effect and controlled by the alkyne insertion step. The improved yield with the addition of pivalic acid is attributed to the strong deprotonation capability of pivalate, which significantly facilitates the C–H activation via the concerted metalation–deprotonation (CMD) mechanism.

Cobalt-Catalyzed Oxidase C-H/N-H Alkyne Annulation: Mechanistic Insights and Access to Anticancer Agents.

Cp*-free cobalt-catalyzed alkyne annulations by C-H/N-H functionalizations were accomplished with molecular O2 as the sole oxidant. The user-friendly oxidase strategy proved viable with various internal and terminal alkynes through kinetically relevant C-H cobaltation, providing among others step-economical access to the anticancer topoisomerase-I inhibitor 21,22-dimethoxyrosettacin. DFT calculations suggest that electronic effects control the regioselectivity of the alkyne insertion step.

Ruthenium-Catalyzed Formal Dehydrative [4 + 2] Cycloaddition of Enamides and Alkynes for the Synthesis of Highly Substituted Pyridines: Reaction Development and Mechanistic Study.

Reported herein is a ruthenium-catalyzed formal dehydrative [4 + 2] cycloaddition of enamides and alkynes, representing a mild and economic protocol for the construction of highly substituted pyridines. Notably, the features of broad substrate scope, high efficiency, good functional group tolerance, and excellent regioselectivities were observed for this reaction. Density functional theory (DFT) calculations and experiments have been carried out to understand the mechanism and regiochemistry. DFT calculations suggested that this formal dehydrative [4 + 2] reaction starts with a concerted metalation deprotonation of the enamide by the acetate group in the Ru catalyst, which generates a six-membered ruthenacycle intermediate. Then alkyne inserts into the Ru-C bond of the six-membered ruthenacycle, giving rise to an eight-membered ruthenacycle intermediate. The carbonyl group (which comes originally from the enamide substrate and is coordinated to the Ru center in the eight-membered ruthenacycle intermediate) then inserts into the Ru-C bond to give an intermediate, which produces the final pyridine product through further dehydration. Alkyne insertion step is a regio-determining step and prefers to have the aryl groups of the used alkynes stay away from the catalyst in order to avoid repulsion of aryl group with the enamide moiety in the six-membered ruthenacycle and to keep the conjugation between the aryl group and the triple C-C bond of the alkynes. Consequently, the aryl groups of the used alkynes are in the β-position of the final pyridines, and the present reaction has high regioselectivity.

ChemInform Abstract: Synthesis of Indolo[2,1‐a]isoquinolines via a Triazene‐Directed C—H Annulation Cascade.

Indole-containing polyaromatic scaffolds are widely found in natural products, pharmaceutical agents, and π-conjugated functional materials. Often, the synthesis of these highly valuable molecules requires a multistep sequence. Therefore, a simple, one-step protocol to access libraries of polyaromatic indole scaffolds is highly desirable. Herein we describe the direct synthesis of polysubstituted indolo[2,1-a]isoquinoline analogues via a double C–H annulation cascade using triazene as an internally cleavable directing group. Evidence from HRMS and theoretical calculations suggests that an unprecedented 1,2-alkyl migration might be responsible for the in situ cleavage of the directing group. Both kinetic isotope effects and DFT calculations suggested that the alkyne insertion step is rate-limiting for the second C,N annulation reaction.

Reaction Mechanism and Regioselectivity of Cu(I)-Catalyzed Hydrocarboxylation of 1-Phenyl-propyne with Carbon Dioxide

Density functional theory (DFT) calculations have been used to conduct a detailed study of the mechanism involved the copper(1)-catalyzed hydrocarboxylation of 1-phenyl-propyne using CO2 and hydrosilane. Theoretical calculations suggested that the activated catalyst Cl2IPrCuH is initially generated in situ by the reaction of Cl2IPrCuF with (EtO)(3)SiH, and that the entire catalytic reaction involves three steps, including (1) the addition of Cl2IPrCuH to 1-phenyl-propyne to afford two isomeric copper alkenyl intermediates, which lead to the formation of the corresponding final alpha,beta-unsaturated carboxylic acid derivatives; (2) CO2 insertion to give the corresponding copper carboxylate intermediate; and (3) sigma-bond metathesis of the copper carboxylate intermediate with a hydrosilane to provide the corresponding silyl ester with the regeneration of the active catalyst. The results of our calculations show that the rate-limiting steps for the two paths leading to the two alpha,beta-unsaturated carboxylic acid derivatives are different. In Path a, the alkyne and CO2 insertion steps were both identified as possible rate-limiting steps, with free energy barriers of 68.6 and 67.8 kJ.mo1(-1), respectively. However, in Path b, the alkyne insertion step was identified as the only possible rate-limiting step with an energy barrier of 78.7 kJ.mol(-1). These results were in agreement with the experimental observations. It was also found that the alkyne insertion step controlled the regioselectivity of the products, and that electronic effects were responsible for the experimentally observed regioselectivity.

Synthesis of indolo[2,1-a]isoquinolines via a triazene-directed C-H annulation cascade.

Indole-containing polyaromatic scaffolds are widely found in natural products, pharmaceutical agents, and π-conjugated functional materials. Often, the synthesis of these highly valuable molecules requires a multistep sequence. Therefore, a simple, one-step protocol to access libraries of polyaromatic indole scaffolds is highly desirable. Herein we describe the direct synthesis of polysubstituted indolo[2,1-a]isoquinoline analogues via a double C-H annulation cascade using triazene as an internally cleavable directing group. Evidence from HRMS and theoretical calculations suggests that an unprecedented 1,2-alkyl migration might be responsible for the in situ cleavage of the directing group. Both kinetic isotope effects and DFT calculations suggested that the alkyne insertion step is rate-limiting for the second C,N annulation reaction.

Mechanistic Study of the Rhodium‐Catalyzed [3+2+2] Carbocyclization of Alkenylidenecyclopropanes with Alkynes

A systematic theoretical study has been performed on the recently reported Rh(I)-catalyzed [3+2+2] carbocyclization reactions between alkenylidenecyclopropanes (ACPs) and alkynes. With the aid of theoretical calculations, two possible mechanisms, that is, alkene-carbometalation-first and alkyne-carbometalation-first mechanisms, are examined in this study. In the oxidative addition step, the possibility of reaction on either the distal or proximal C-C bond of the cyclopropane group has been evaluated. The calculations indicate that the alkene-activation-first mechanism is more favored for the overall catalytic cycle. This mechanism involves four steps, that is, oxidative addition of the distal (rather than the proximal) C-C bond of cyclopropane group, alkene carbometalation, alkyne carbometalation, and reductive elimination. The rate-determining step in the overall catalytic cycle is the carbometalation of the alkyne (i.e., the alkyne-insertion step) and this step also determines the regioselectivity. Finally, the origin of the regioselectivity is determined by the steric effect (i.e., the steric crowding between the electron-withdrawing group on alkyne and other ligands on the rhodium center) in the alkyne-insertion step.

Rh-catalyzed (5+2) cycloadditions of 3-acyloxy-1,4-enynes and alkynes: computational study of mechanism, reactivity, and regioselectivity.

The mechanism of Rh-catalyzed (5+2) cycloadditions of 3-acyloxy-1,4-enyne (ACE) and alkynes is investigated using density functional theory calculations. The catalytic cycle involves 1,2-acyloxy migration, alkyne insertion, and reductive elimination to form the cycloheptatriene product. In contrast to the (5+2) cycloadditions with vinylcyclopropanes (VCPs), in which alkyne inserts into a rhodium-allyl bond, alkyne insertion into a Rh-C(sp(2)) bond is preferred. The 1,2-acyloxy migration is found to be the rate-determining step of the catalytic cycle. The electron-rich p-dimethylaminobenzoate substrate promotes 1,2-acyloxy migration and significantly increases the reactivity. In the regioselectivity-determining alkyne insertion step, the alkyne substituent prefers to be distal to the forming C-C bond and thus distal to the OAc group in the product.

ChemInform Abstract: Asymmetric Rh(I)‐Catalyzed Intramolecular [3 + 2] Cycloaddition of 1‐Yne‐vinylcyclopropanes for Bicyclo[3.3.0] Compounds with a Chiral Quaternary Carbon Stereocenter and Density Functional Theory Study of the Origins of Enantioselectivity.

A highly enantioselective Rh(I)-catalyzed intramolecular [3 + 2] cycloaddition of 1-yne-VCPs to bicyclo[3.3.0] compounds with an all-carbon chiral quaternary stereocenter at the bridgehead carbon was developed. DFT calculations of the energy surface of the catalytic cycle (complexation, cyclopropane cleavage, alkyne insertion, and reductive elimination) of the asymmetric [3 + 2] cycloaddition reaction indicated that the rate- and stereo-determining step is the alkyne-insertion step. Analysis of the alkyne-insertion transition states revealed that the serious steric repulsion between the substituents in the alkyne moiety of the substrates and the rigid H(8)-BINAP backbone is responsible for not generating the disfavored [3 + 2] cycloadducts.

Asymmetric Rh(I)-Catalyzed Intramolecular [3 + 2] Cycloaddition of 1-Yne-vinylcyclopropanes for Bicyclo[3.3.0] Compounds with a Chiral Quaternary Carbon Stereocenter and Density Functional Theory Study of the Origins of Enantioselectivity

A highly enantioselective Rh(I)-catalyzed intramolecular [3 + 2] cycloaddition of 1-yne-VCPs to bicyclo[3.3.0] compounds with an all-carbon chiral quaternary stereocenter at the bridgehead carbon was developed. DFT calculations of the energy surface of the catalytic cycle (complexation, cyclopropane cleavage, alkyne insertion, and reductive elimination) of the asymmetric [3 + 2] cycloaddition reaction indicated that the rate- and stereo-determining step is the alkyne-insertion step. Analysis of the alkyne-insertion transition states revealed that the serious steric repulsion between the substituents in the alkyne moiety of the substrates and the rigid H(8)-BINAP backbone is responsible for not generating the disfavored [3 + 2] cycloadducts.

Understanding the Highly Regioselective Cyanothiolation of 1-Alkynes Catalyzed by Palladium Phosphine Complexes

A computational study with the Becke3LYP DFT functional was carried out on the palladium-catalyzed regioselective cyanothiolation of 1-alkynes with thiocyanates. The full catalytic cycle was computed, starting from the oxidative addition and finishing with the reductive elimination. The two most important issues, namely, the regioselective bond cleavage of thiocyanates and the nature of insertion of 1-alkynes into a Pd−S bond, are discussed. The calculations indicate that the sulfur−cyano (PhS−CN) bond cleavage on Pd(0) is kinetically and thermodynamiclly more favorable than the carbon−sulfur (Ph−SCN) bond cleavage. The kinetic preference of 1,2-insertion over 2,1-insertion in the alkyne insertion step leads to the cyanothiolation products with the SPh group attached to the substituted carbon atom of 1-alkynes.

Mechanism of Enyne Metathesis Catalyzed by Grubbs Ruthenium−Carbene Complexes: A DFT Study

The complete catalytic cycle of the reaction of alkenes and alkynes to dienes by Grubbs ruthenium carbene complexes has been modeled at the B3LYP/LACV3P**+//B3LYP/LACVP level of theory. The core structures of the substrates and the catalyst were used as models, namely, ethene, ethyne, hept-1-en-6-yne, (Me(3)P)(2)Cl(2)Ru=CH(2), and [C(2)H(4)(NMe)(2)C](Me(3)P)Cl(2)Ru=CH(2). Insight into the electronically most preferred mechanistic pathways was gained for both intermolecular as well as for intramolecular enyne metathesis. Alkene metathesis is predicted to proceed fast and reversible, while the insertion of the alkyne substrate is slower, irreversible, and kinetically regioselectivity determining. Ruthenacyclobut-2-ene structures do not exist as local minima in the catalytic cycle. Instead, vinylcarbene complexes are formed directly. The alkyne insertion step and the cycloreversion of 2-vinyl ruthenacyclobutanes feature comparable predicted overall barriers in intermolecular enyne metathesis. For intramolecular enyne metathesis, a noncyclic alkene fragment of the enyne substrate is first incorporated into the Grubbs catalyst by an alkene metathesis reaction. The subsequent insertion of the alkyne fragment then proceeds intramolecularly. Alkene association, cycloaddition, and cycloreversion to the diene product complex close the catalytic cycle. Rate enhancement by an ethene atmosphere (Mori's conditions) originates from a constantly higher overall alkene concentration that is necessary for the rate-limiting [2 + 2] cycloreversion step to the diene product complex.