Search

A general, convenient, and friendly route for preparing a versatile building block of isocyanides from primary amines is developed. Difluorocarbene, generated in situ from decarboxylation of chlorodifluoroacetate, reacts efficiently with primary amines to produce isocyanides. Various primary amines are well tolerated, including aryl, heteroaryl, benzyl, and alkyl amines, as well as amine residues in amino acids and peptides. Late-stage functionalization of biologically active amines is demonstrated, showing its practical capacity in drug design and peptide modification.

We report herein a strategy of ammonium hydrogen-bonding-assisted α-F elimination from Cu–CF3 compounds that generates R3N·HF reagents in situ. Combining this strategy and Cu(III)–CF3 chemistry with alkynes, dual fluorination and trifluoromethylation of terminal alkynes is enabled by a single Cu(III)–CF3 compound assisted by a tertiary amine with excellent regio- and stereoselectivity. This strategy also enables the development of other reaction types involving trapping of the in situ-formed R3N·HF reagents by other electrophilic groups and can be used for the late-stage functionalization of estrone derivatives.

The formation conditions of the Amadori compound (ARP) N-(1-deoxy-d-xylulos-1-yl)-alanine were determined in an aqueous Maillard reaction between l-alanine and d-xylose under a two-step temperature rising process with (-)-epigallocatechin gallate (EGCG) as an indicator followed by browning intensity detection of the final Maillard reaction products (MRPs). To clarify the mechanism of EGCG indication on the ARP formation, the change in the concentration of some key products generated during the Maillard reaction with EGCG addition was investigated. Results showed an inhibition effect of EGCG on the browning precursor formation through the generation of ARP-EGCG adducts and deoxyosone-EGCG adducts, which was proposed as an important pathway to inhibit browning during the Maillard reaction and to indicate ARP formation.

An efficient and selective hydro-trifluoromethylation of terminal alkynes is developed to enable the synthesis of 1,2-disubstituted trifluoromethylated Z-alkenes from terminal alkynes, a silane and a Cu(III)–CF3 complex in DMF. The unusual Z-selectivity and the compatibility of various functional groups make this reaction complementary to previous vinyl–CF3 bond-forming methods producing dominantly E-products or a mixture of E,Z-isomers. Extensive mechanistic studies indicate that this reaction may involve a key step of migratory insertion of initially formed Ar–C≡C–CF3 into LCu(I)-H intermediate and subsequent hydrogenation of the vinyl-copper species to give finally the Z-trifluoromethylated styrenes. Deuterium labeling experiments show that DMF acts not merely as the solvent but also as the source of α-H in the Z-trifluoromethylated styrene products. Given the novel syn-difunctionalization of alkynes using Cu(III)–CF3 complexes/a nucleophilic reagent we developed recently that are also in contrast to t...

One-step concurrent fluoro-trifluoromethylation across the triple bond of arylacetylenes in a syn mode is enabled by the collaboration of (phen)CuIII(CF3)3 and CsF that produces chemo-, regio-, and stereoselectively (Z)-α-fluoro-β-CF3 styrenes. This method can be extended to achieve syn-oxy-trifluoromethylation and syn-aryl-trifluoromethylation of alkynes using phenoxides, alkoxides, or phenylboronic acid in place of CsF. It opens up new opportunities for preparing various functionalized trifluoromethylated Z-alkenes and demonstrates the potential of Cu(III)–CF3 complexes in organic synthesis.

Chemoselective access to either γ-ketoesters with a quaternary all-carbon α-stereogenic center or γ-keto nitriles is described by copper-catalyzed aerobic reaction of styrenes with α-cyanoesters. Formal oxo-enolation or oxo-cyanomethylation of styrenes is achieved via a sequence of addition of enolate (or cyanomethyl) radical to olefin and oxidation of the resulting radical adduct. This method starts from abundant and cheap feedstock under aerobic conditions, without any prefunctionalization or the production of stoichiometric metal salts waste, making it very attractive for practical use.

The novel cascade photoredox/iodide catalytic system enables the alkene to serve as a radical acceptor capable of achieving aminodifluoroalkylation of alkenes. Cheap iodide salts play a vital role in this reaction, which could tune carbocation reactivity through reversible C-I bond formation for controlling reaction selectivity, and a series of competitive reactions are completely eliminated in the presence of multiple reactivity pathways. The present dual catalytic protocol affords a very convenient method for direct synthesis of various difluoro-γ-lactams from simple and readily available starting materials under mild reaction conditions.

A theoretical study on reaction mechanisms for copper-catalyzed Ullmann-type C–P coupling of diphenylphosphine with aryl halides is reported herein. The equilibria and consequent relative concentrations of possible copper species in the reaction solution were evaluated to determine probable active catalytic species in the presence of several typical ancillary ligands in toluene and DMSO solvents. Subsequently, reactivity of these key copper species with aryl halides were studied in the context of commonly proposed mechanisms for copper(I)-catalyzed Ullmann reactions, including oxidative addition/reductive elimination, σ-bond metathesis, single electron transfer (SET), and halogen atom transfer (HAT) mechanisms. On the basis of these studies, we propose that for phenanthroline and 1,2-ethylenediamine types of bidentate ligands, the active catalyst should be the neutral form LCu(I)-PPh2 in nonpolar toluene, while the Cu(PPh2)2– anion should be significant in highly polar DMSO. In contrast, for phosphine typ...

A theoretical study of reaction mechanisms for C–CN bond activation of nitriles by a RhIII–silyl complex is reported. Various mechanisms including direct oxidative addition, insertion of the cyanide C≡N triple bond into the RhIII–silyl bond followed by β-carbon elimination, insertion of the cyanide C≡N triple bond into the RhIII–silyl bond followed by α-carbon elimination (deisocyanide), radical mechanisms, and other possible alternatives have been evaluated. Our results provide strong evidence for the sequential mechanism of cyano insertion/α-C elimination (deisocyanide). The cyanide insertion step should be the rate-limiting step, while the deisocyanide step is facile. The intermediate from cyanide insertion, i.e., the Rh(III) η2-iminoacyl complex, has been identified and is in good agreement with the experimentally characterized X-ray crystal structure. The oxidative addition and cyanide insertion/β-C elimination mechanisms are kinetically inhibited due to extremely high activation barriers. Radical me...

A systematic theoretical study on reaction mechanisms for copper-catalyzed Ullmann S-arylation reactions of thiophenols with aryl halides is reported herein. The equilibriums and consequent relative concentrations of possible copper species in the reaction solution were carefully evaluated to determine the most probable active catalytic forms. Subsequently, reactivity studies of these copper species with aryl halides were performed in the context of several commonly proposed mechanisms for copper(I)-catalyzed Ullmann reactions, such as oxidative addition/reductive elimination, σ-bond metathesis, single electron transfer (SET), and halogen atom transfer (HAT) mechanisms. On the basis of these intensive studies, we propose for the first time that the active copper catalyst should be neutral (L)Cu(I)-SAr species (L denotes a neutral ancillary ligand; SAr denotes a thiophenolato type ligand) in nonpolar or less polar solvent and anionic Cu(SAr)2— species in highly polar solvent. These two kinds of species are...

Density functional theory method B3LYP was used to study the mechanism of amination reactions between aryl bromides and alkylamines catalyzed by Cu(I) species with 1,3-diketone ligands. Through systematic evaluation of the relative concentrations of possible copper species in solution and oxidative addition of these species with aryl bromide, we propose that the active catalyst is a neutral three-coordinate 1,3-diketonate-ligated Cu(I)(amine) complex. Oxidative addition of aryl bromide to this species is the rate-limiting step of the catalytic cycle. These results explain why for basic alkylamine substrates, diamine ligands are ineffective, because for diamine ligands, formation of such a neutral Cu(I) complex containing both ligand and nucleophile is thermodynamically unfavorable. Interestingly, the active catalyst Cu(I)(diketonate)(amine) complex is essentially akin to the active catalyst Cu(I)(diamine)(amidate) proposed in copper-catalyzed coupling of amides with aryl halides. Therefore, this implies t...

Transition-metal-catalyzed decarboxylative coupling presents a new and important direction in synthetic chemistry. Mechanistic studies on decarboxylative coupling not only improve the understanding of the newly discovered transformations, but also may have valuable implications for the development of more effective catalyst systems. In this work, a comprehensive theoretical study was conducted on the mechanism of Myers' Pd-catalyzed decarboxylative Heck reaction. The catalytic cycle was found to comprise four steps: decarboxylation, olefin insertion, beta-hydride elimination, and catalyst regeneration. Decarboxylation was the rate-limiting step, and it proceeded through a dissociative pathway in which Pd(II) mediated the extrusion of CO(2) from an aromatic carboxylic acid to form a Pd(II)-aryl intermediate. Further analysis was conducted on the factors that might control the efficiency of Myers' decarboxylative Heck reaction. These factors included Pd salts, ligands, acid substrates, and metals. (1) Regarding Pd salts, PdCl(2) and PdBr(2) were worse catalysts than Pd(TFA)(2), because the exchange of Cl or Br by a carboxylate from Pd was thermodynamically unfavorable. (2) Regarding ligands, DMSO provided the best compromise between carboxyl exchange and decarboxylation. Phosphines and N-heterocarbenes disfavored decarboxylation because of their electron richness, whereas pyridine ligands disfavored carboxyl exchange. (3) Regarding acid substrates, a good correlation was observed between the energy barrier of R-COOH decarboxylation and the R-H acidity. Substituted benzoic acids showed deviation from the correlation because of the involvement of pi(substituent)-sigma(C(ipso)-Pd) interaction. (4) Regarding metals, Ni and Pt were worse catalysts than Pd because of the less favorable carboxyl exchange and/or DMSO removal steps in Ni and Pt catalysis.

Ni-catalyzed selective C-O bond activation opens a door for the cross-coupling of aryl esters. The present study reports a thorough theoretical analysis of Ni-catalyzed cross-coupling between aryl esters and arylboronic acids, with an emphasis on explaining the cause for the surprising selectivity in C-O activation. The overall catalytic cycle is found to include three basic steps: oxidative addition, transmetalation, and reductive elimination. Oxidative addition of Ar-OAc to Ni(0) in the presence of PCy(3) ligand proceeds through the monophosphine pathway (instead of the alternative two-phosphine pathway) with a relatively low barrier of +22.9 kcal/mol. Transmetalation proceeds via a base-assisted mechanism with a barrier of +31.2 kcal/mol. Reductive elimination is the most facile step in the whole catalytic cycle. Comparatively, oxidative addition of ArO-Ac to Ni(0) is a more facile process (barrier = +14.2 kcal/mol) than oxidative addition of Ar-OAc to Ni(0). However, the former process is associated with a fairly low reverse barrier, and its product does not transmetalate easily (barrier = +33.1 kcal/mol). By comparison, the latter process is an irreversible reaction, and its product transmetalates more readily. These results explain why only the cross-coupling products from the Ar-OAc activation (but not from the ArO-Ac activation) were observed in experiments.

The manganese-catalyzed dehydrative [2 + 2 + 2] annulation reaction of a 1,3-dicarbonyl compound and a terminal alkyne provides an efficient and regioselective synthesis of a substituted benzene derivative, highlighted by the exclusive formation of a p-terphenyl derivative from an aryl acetylene. The mechanism and the origin of the regioselectivity of the reaction were explored by experiments and density functional theory (DFT) calculations. Experimental data revealed the cis stereochemistry of a cyclohexadienol precursor to the benzene product and suggested that two reaction pathways may operate competitively sequential carbometalation reactions of a manganese enolate and formation of a manganacyclopentadiene intermediate. The DFT study supported the first possibility, namely that the reaction involves three steps: (1) addition of a manganese enolate of a 1,3-dicarbonyl compound to a terminal alkyne to give a vinylmanganese complex, (2) insertion of a second alkyne into the vinyl-Mn bond to give a dienylmanganese complex, and (3) intramolecular nucleophilic addition of the dienylmanganese to the carbonyl group. This mechanism is consistent with the experimental facts such as the perfect regioselectivity of the reaction of an aryl acetylene, the moderate regioselectivity of the reaction of an alkyl acetylene, and the stereochemistry of the annulation product. An alternative mechanism involving a manganacyclopentadiene intermediate failed to account for the experimental regioselectivity, although it may be occurring as a very minor competitive pathway.

The density functional theory method augmented with the CPCM solvation model was used to study the mechanism of Cu(I)-catalyzed aryl amidation. On the basis of the comparison of multiple reaction pathways, it was determined that diamine-ligated copper(I) amidate was the most reactive intermediate in the reaction mixture for the oxidative addition to aryl halide. Cationic diamine-ligated Cu(I) was calculated to have a lower free energy barrier for oxidative addition, but its concentration in the reaction mixture was too low to represent a useful catalyst. On the other hand, multiple ligation of the amide to Cu(I) at low diamine concentration led to the least reactive intermediate and, thereby, retarded the oxidative addition. Further calculations showed that oxidative addition was the rate-limiting step in Cu-catalyzed aryl amidation. Unlike the transformation from Pd(0) to Pd(II), the Cu(I) → Cu(III) oxidative addition product was pentacoordinated and, thereby, more sensitive to the steric hindrance. A ma...

Pd-catalyzed decarboxylative cross-couplings of 2-(2-azaaryl)acetates with aryl halides and triflates have been discovered. This reaction is potentially useful for the synthesis of some functionalized pyridines, quinolines, pyrazines, benzoxazoles, and benzothiazoles. Theoretical analysis shows that the nitrogen atom at the 2-position of the heteroaromatics directly coordinates to Pd(II) in the decarboxylation transition state.

The origin of the contrasting regioselectivities in allylic substitution found for a heterocuprate MeCu(CN)Li and a homocuprate Me2CuLi was studied using density functional calculations. The gamma-selectivity of MeCu(CN)Li is determined at the oxidative addition stage of the reaction, where the different degree of trans effect of the Me and the CN groups dictates the relative orientation of the methyl group and the leaving acetate group. As the result, the transition state where the acetate group leaves trans to the Me group on the copper atom is favored, and the gamma-selectivity results. The homocuprate Me2CuLi is symmetrical by nature and does not show such regioselectivity.