Showing papers on "Intramolecular force published in 2010"

Crystallization-Induced Phosphorescence of Pure Organic Luminogens at Room Temperature

Abstract: Phosphorescence has rarely been observed in pure organic chromophore systems at room temperature. We herein report efficient phosphorescence from the crystals of benzophenone and its derivatives with a general formula of (X-C6H4)2C═O (X = F, Cl, Br) as well as methyl 4-bromobenzoate and 4,4′-dibromobiphenyl under ambient conditions. These luminogens are all nonemissive when they are dissolved in good solvents, adsorbed on TLC plates, and doped into polymer films, because active intramolecular motions such as rotations and vibrations under these conditions effectively annihilate their triplet excitons via nonradiative relaxation channels. In the crystalline state, the intramolecular motions are restricted by the crystal lattices and intermolecular interactions, particularly C−H···O, N−H···O, C−H···X (X = F, Cl, Br), C−Br···Br−C, and C−H···π hydrogen bonding. The physical constraints and multiple intermolecular interactions collectively lock the conformations of the luminogen molecules. This structural rigi...

Intramolecular Hydrogen Bonding in Medicinal Chemistry

Abstract: The formation of intramolecular hydrogen bonds has a very pronounced effect on molecular structure and properties. We study both aspects in detail with the aim of enabling a more rational use of this class of interactions in medicinal chemistry. On the basis of exhaustive searches in crystal structure databases, we derive propensities for intramolecular hydrogen bond formation of five- to eight-membered ring systems of relevance in drug discovery. A number of motifs, several of which are clearly underutilized in drug discovery, are analyzed in more detail by comparing small molecule and protein-ligand X-ray structures. To investigate effects on physicochemical properties, sets of closely related structures with and without the ability to form intramolecular hydrogen bonds were designed, synthesized, and characterized with respect to membrane permeability, water solubility, and lipophilicity. We find that changes in these properties depend on a subtle balance between the strength of the hydrogen bond interaction, geometry of the newly formed ring system, and the relative energies of the open and closed conformations in polar and unpolar environments. A number of general guidelines for medicinal chemists emerge from this study.

Palladium‐Catalyzed C3 or C4 Direct Arylation of Heteroaromatic Compounds with Aryl Halides by C ? H Bond Activation

Abstract: In recent years, palladium-catalyzed direct C2 or C5 arylation of heteroaromatic compounds with aryl halides by C-H bond activation has become a popular method for generating carbon-carbon bonds For this reaction, a wide variety of heteroaromatics, such as furans, thiophenes, pyrroles, thiazoles, oxazoles, imidazoles, pyrazoles, indoles, triazoles, or even pyridines, can be employed C3 and C4 arylations of heteroaromatics by C-H bond activation have also been described Such reactions initially attracted much less attention than the C2 or C5 arylations due to the lower reactivity of the C3 and C4 positions However, in more recent years, several results from using modified and improved catalysts and reaction conditions have been reported, which permit C3 and C4 arylations in synthetically useful yields Several intramolecular cyclizations of 2-substituted heterocycles have been described, with formation of a C—C bond on C3 resulting in the formation of five- to nine-membered rings incorporating pyrroles, indoles, thiophenes, furans, isoxazoles, or pyridines Intermolecular C3 or C4 direct arylations are still quite rare for some heteroaromatics and are in several cases not highly regioselective For such reactions, the best results have been obtained using pyrroles, thiophenes, or furans For selected substrates, regioselective arylation at C3 or C4 of the heteroaromatic compounds took place under appropriate reaction conditions Only a few examples of intermolecular couplings using oxazoles, thiazoles, imidazoles, isoxazoles, pyrazoles, triazoles, or pyridines have been reported For most of these reactions, aryl iodides or bromides have been used as coupling partners, although a few examples with aryl chlorides are also known This method allows the synthesis of complex molecules in only a few steps, and will provide access to a very wide variety of new heteroaryl derivatives in the next years

A Direct Intramolecular C−H Amination Reaction Cocatalyzed by Copper(II) and Iron(III) as Part of an Efficient Route for the Synthesis of Pyrido[1,2-a]benzimidazoles from N-Aryl-2-aminopyridines

Abstract: A novel and efficient synthesis of pyrido[1,2-a]benzimidazoles through direct intramolecular aromatic C-H amination of N-aryl-2-aminopyridines has been developed. The reaction, cocatalyzed by Cu(OAc)(2) and Fe(NO(3))(3)·9H(2)O, is carried out in DMF under a dioxygen atmosphere. Diversified pyrido[1,2-a]benzimidazoles containing various substitution patterns are obtained in moderate to excellent yields by using this procedure. The results of mechanistic studies suggest that a Cu(III)-catalyzed electrophilic aromatic substitution (S(E)Ar) pathway is operating in this process. The unique role of iron(III) is believed to lie in its ability to facilitate formation of the more electrophilic Cu(III) species. In the absence of iron(III), a much less efficient and reversible Cu(II)-mediated S(E)Ar process takes place.

Enantioselective organocatalytic C-H bond functionalization via tandem 1,5-hydride transfer/ring closure: asymmetric synthesis of tetrahydroquinolines.

Abstract: The first organocatalytic enantioselective intramolecular 1,5-hydride transfer/ring closure reaction is described. This redox neutral reaction cascade allows for the efficient formation of ring-fused tetrahydroquinolines in high enantioselectivities.

Pd(II)-Catalyzed Carbonylation of C(sp3)−H Bonds: A New Entry to 1,4-Dicarbonyl Compounds

Abstract: Pd(II)-catalyzed β-C(sp3)−H carbonylation of N-arylamides under CO (1 atm) has been achieved. Following amide-directed C(sp3)−H cleavage and insertion of CO into the resulting [Pd(II)−C(sp3)] bond, intramolecular C−N reductive elimination gave the corresponding succinimides, which could be readily converted to 1,4-dicarbonyl compounds. This method was found to be effective with substrates containing α-hydrogen atoms and could be applied to effect methylene C(sp3)−H carbonylation of cyclopropanes.

Spin- and energy-dependent tunneling through a single molecule with intramolecular spatial resolution.

Abstract: We investigate the spin- and energy-dependent tunneling through a single organic molecule (CoPc) adsorbed on a ferromagnetic Fe thin film, spatially resolved by low-temperature spin-polarized scanning tunneling microscopy. Interestingly, the metal ion as well as the organic ligand show a significant spin dependence of tunneling current flow. State-of-the-art ab initio calculations including also van der Waals interactions reveal a strong hybridization of molecular orbitals and substrate $3d$ states. The molecule is anionic due to a transfer of one electron, resulting in a nonmagnetic ($S=0$) state. Nevertheless, tunneling through the molecule exhibits a pronounced spin dependence due to spin-split molecule-surface hybrid states.

Investigation of the Mechanism of C(sp3)−H Bond Cleavage in Pd(0)-Catalyzed Intramolecular Alkane Arylation Adjacent to Amides and Sulfonamides

Abstract: The reactivity of C(sp3)−H bonds adjacent to a nitrogen atom can be tuned to allow intramolecular alkane arylation under Pd(0) catalysis. Diminishing the Lewis basicity of the nitrogen lone pair is crucial for this catalytic activity. A range of N-methylamides and sulfonamides react exclusively at primary C(sp3)−H bonds to afford the products of alkane arylation in good yields. The isolation of a Pd(II) reaction intermediate has enabled an evaluation of the reaction mechanism with a focus on the role of the bases in the C(sp3)−H bond cleaving step. The results of these stoichiometric studies, together with kinetic isotope effect experiments, provide rare experimental support for a concerted metalation−deprotonation (CMD) transition state, which has previously been proposed in alkane C(sp3)−H arylation. Moreover, DFT calculations have uncovered the additional role of the pivalate additive as a promoter of phosphine dissociation from the Pd(II) intermediate, enabling the CMD transition state. Finally, kinet...

Intramolecular hydrogen migration in alkylperoxy and hydroperoxyalkylperoxy radicals: accurate treatment of hindered rotors.

Abstract: We have calculated the thermochemistry and rate coefficients for stable molecules and reactions in the title reaction families using CBS-QB3 and B3LYP/CBSB7 methods. The accurate treatment of hindered rotors for molecules having multiple internal rotors with potentials that are not independent of each other can be problematic, and a simplified scheme is suggested to treat them. This is particularly important for hydroperoxyalkylperoxy radicals (HOOQOO). Two new thermochemical group values are suggested in this paper, and with these values, the group additivity method for calculation of enthalpy as implemented in reaction mechanism generator (RMG) gives good agreement with CBS-QB3 predictions. The barrier heights follow the Evans−Polanyi relationship for each type of intramolecular hydrogen migration reaction studied.

The Effect of Intermolecular Hydrogen Bonding on the Fluorescence of a Bimetallic Platinum Complex

Abstract: The bimetallic platinum complexes are known as unique building blocks and arewidely utilized in the coordination-driven self-assembly of functionalized supramolecular metallacycles Hence, photophysical study of the bimetallic platinum complexes will be very helpful for the understanding on the optical properties and further applications of coordination-driven self-assembled supramolecular metallacycles Herein, we report steady-state and time-resolved spectroscopic experiments as well as quantum chemistry calculations to investigate the significant intermolecular hydrogen bonding effects on the intramolecular charge transfer (ICT) fluorescence of a bimetallic platinum compound 4,4'-bis(trans-Pt(PEt(3))(2)OTf)benzophenone 3 in solution We demonstrated that the fluorescent state of compound 3 can be assigned as a metal-to-ligand charge transfer (MLCT) state Moreover, it was observed that the formation of intermolecular hydrogen bonds can effectively lengthen the fluorescence lifetime of 3 in alcoholic solvents compared with that in hexane solvent At the same time, the electronically excited states of 3 in solution are definitely changed by intermolecular hydrogen bonding interactions As a consequence, we propose a new fluorescence modulation mechanism by hydrogen bonding to explain different fluorescence emissions of 3 in hydrogen-bonding solvents and nonhydrogen-bonding solvents

Gold-catalyzed intramolecular aminoarylation of alkenes: C-C bond formation through bimolecular reductive elimination.

Abstract: Gold-ilocks and the 3 mol % catalyst: Bimetallic gold bromides allow the room temperature aminoarylation of unactivated terminal olefins with aryl boronic acids using Selectfluor as an oxidant. A catalytic cycle involving gold(I)/gold(III) and a bimolecular reductive elimination for the key CC bond-forming step is proposed. dppm= bis(diphenylphosphanyl)methane.

Tuning the Optoelectronic Properties of Carbazole/Oxadiazole Hybrids through Linkage Modes: Hosts for Highly Efficient Green Electrophosphorescence

Abstract: A series of bipolar transport host materials: 2,5-bis(2-(9H-carbazol-9-yl)phenyl)-1,3,4-oxadiazole (o-CzOXD) (1), 2,5-bis(4-(9H-carbazol-9-yl)phenyl)-1,3,4-oxadiazole (p-CzOXD) (2), 2,5-bis(3-(9H-carbazol-9-yl)phenyl)-1,3,4-oxadiazole (m-CzOXD) (3) and 2-(2-(9H-carbazol-9-yl)phenyl)-5-(4-(9H-carbazol-9-yl)phenyl)-1,3,4-oxadiazole (op-CzOXD) (4) are synthesized through simple aromatic nucleophilic substitution reactions. The incorporation of the oxadiazole moiety greatly improves their morphological stability, with T-d and T-g in the range of 428-464 degrees C and 97-133 degrees C, respectively. The ortho and meta positions of the 2,5-diphenyl-1,3,4-oxadiazole linked hybrids (1 and 3) show less intramolecular charge transfer and a higher triplet energy compared to the para-position linked analogue (2). The four compounds exhibit similar LUMO levels (2.55-2.59 eV) to other oxadiazole derivatives, whereas the HOMO levels vary in a range from 5.55 eV to 5.69 eV, depending on the linkage modes. DFT-calculation results indicate that 1, 3, and 4 have almost complete separation of their HOMO and LUMO levels at the hole- and electron-transporting moieties, while 2 exhibits only partial separation of the HOMO and LUMO levels possibly due to intramolecular charge transfer. Phosphorescent organic light-emitting devices fabricated using 1-4 as hosts and a green emitter, Ir(ppy)(3) or (ppy)(2)Ir(acac), as the guest exhibit good to excellent performance. Devices hosted by o-CzOXD (1) achieve maximum current efficiencies (eta(c)) as high as 77.9 cd A(-1) for Ir(ppy)(3) and 64.2 cd A(-1) for (ppy)(2)Ir(acac). The excellent device performance may be attributed to the well-matched energy levels between the host and hole-transport layers, the high triplet energy of the host and the complete spatial separation of HOMO and LUMO energy levels.

Intramolecular palladium-catalyzed alkane C-H arylation from aryl chlorides.

Abstract: The first examples of efficient and general palladium-catalyzed intramolecular C(sp(3))-H arylation of (hetero)aryl chlorides, giving rise to a variety of valuable cyclobutarenes, indanes, indolines, dihydrobenzofurans, and indanones, are described. The use of aryl and heteroaryl chlorides significantly improves the scope of C(sp(3))-H arylation by facilitating the preparation of reaction substrates. Careful optimization studies have shown that the palladium ligand and the base/solvent combination are crucial to obtaining the desired class of product in high yields. Overall, three sets of reaction conditions employing P(t)Bu(3), PCyp(3), or PCy(3) as the palladium ligand and K(2)CO(3)/DMF or Cs(2)CO(3)/pivalic acid/mesitylene as the base/solvent combination allowed five different classes of products to be accessed using this methodology. In total, more than 40 examples of C-H arylation have been performed successfully. When several types of C(sp(3))-H bond were present in the substrate, the arylation was found to occur regioselectively at primary C-H bonds vs secondary or tertiary positions. In addition, in the presence of several primary C-H bonds, selectivity trends correlate with the size of the palladacyclic intermediate, with five-membered rings being favored over six- and seven-membered rings. Regio- and diastereoselectivity issues were studied computationally in the prototypal case of indane formation. DFT(B3PW91) calculations demonstrated that C-H activation is the rate-determining step and that the creation of a C-H agostic interaction, increasing the acidity of a geminal C-H bond, is a critical factor for the regiochemistry control.

Time-Resolved Fluorescence Study of Aggregation-Induced Emission Enhancement by Restriction of Intramolecular Charge Transfer State

Abstract: Cyano-substituted oligo (α-phenylenevinylene)-1,4-bis(R-cyano-4-diphenylaminostyryl)-2,5-diphenylbenzene (CNDPASDB) molecules are studied in solution and aggregate state by time-resolved fluorescence techniques. CNDPASDB exhibits a strong solvent polarity dependent characteristic of aggregation-induced emission (AIE). By time-dependent spectra, the gradual transition from local excited state to intramolecular charge transfer state with the increasing solvent polarity is clearly resolved. The transition time in high polarity solvent DMF is very fast, around 0.5 ps, resulting in a low fluorescence quantum yield. While in aggregate state, the intramolecular torsion is restricted and the local environment becomes less polar. Thus, the intramolecular charge transfer state is eliminated and efficient AIE occurs.

Transition-Metal-CatalyzedOxidative Heck Reactions

Abstract: Oxidative Heck reactions provide a facile and efficient routeto carbon-carbon bond formations. This review is dividedinto two main sections, the first consisting of oxidative Heck reactions oforganometallic compounds such as organoboranes, organosilanols andarylstannanes, and the second covering oxidative Heck reactionsvia C-H activation, a topic which has become an attractive themein organic synthesis. 1 Introduction 2 Oxidative Heck Reactions of Organometallic Compounds 2.1 With Palladium(II) Catalysts 2.1.1 Ligand-Free Reactions 2.1.1.1 Anaerobic 2.1.1.2 Aerobic 2.1.2 Ligand-Based Reactions 2.1.2.1 Aerobic 2.1.2.2 Anaerobic 2.1.3 Asymmetric Reactions 2.1.3.1 Aerobic 2.1.3.2 Anaerobic 2.1.4 With Polymer-Supported Palladium(II) Catalysts 2.2 With Other Transition-Metal Catalysts 2.3 With Other Organometallic Compounds 3 Oxidative Heck Reactions of C-H Compounds 3.1 Catalytic Reactions 3.1.1 Intermolecular Reactions 3.1.1.1 Anaerobic 3.1.1.2 Aerobic 3.1.2 Intramolecular Reactions 3.1.2.1 Anaerobic 3.1.2.2 Aerobic 4 Conclusions and Outlook

Serendipitous Discovery of the Catalytic Hydroammoniumation and Methylamination of Alkynes

Abstract: The transition-metal-catalyzed hydroamination reaction, that is, the addition of an N—H bond across a carbon-carbon multiple bond, has been widely studied.[1,2] We have recently reported that cationic gold(I) complexes,[3,4] supported by cyclic (alkyl)(amino)carbene (CAAC) ligands,[5] readily catalyze the intermolecular hydroamination of alkynes with a variety of amines,[6] including ammonia.[6c] Based on preliminary mechanistic studies, we postulated that the key step of the catalytic cycle was the formation of a tricoordinate gold complex (I), which was followed by inner-sphere C—N bond formation, as first postulated by Tanaka et al.,[7a] and Nishina and Yamamoto[7b,c] (Scheme 1). However, for other gold catalysts,[8] Che et al.[9a] and Li et al.[9b] hypothesized an outer-sphere nucleophilic attack to the alkyne complex II, a mechanism widely accepted for palladium[10] and platinum complexes.[11] Herein, our attempts to isolate a gold(I) complex of type I have led to the structural characterization of two (CAAC)(η1-alkene)AuI complexes, and to the discovery of two catalytic reactions: the intramolecular hydroammoniumation using tertiary ammonium salts, and the aminomethylation of carbon–carbon triple bonds. Scheme 1 Possible intermediates I and II in the gold-catalyzed hydroamination of alkynes, and the gold complexes A and B used in this study. For obvious entropic reasons, intramolecular hydroamination reactions occur under much milder conditions than their intermolecular analogues, and therefore are better suited for characterizing reaction intermediates. We first chose N-methyl-2-(2-phenylethynyl)aniline (1), as the rigidity of the phenyl spacer group places both the amino and the alkyne moieties in the ideal positions to coordinate to the metal center. The reaction of 1 with a stoichiometric amount of cationic gold(I) complex B at room temperature was monitored by multinuclear NMR spectroscopy. The instantaneous disappearance of both 1 and B was observed, along with the formation of a new complex, which was isolated in near quantitative yield. However, the spectroscopic data suggested that it was not the desired tricoordinate gold(I) complex of type I, but rather complex 2, presumably formed from the coordination of the hydroamination product 3 to the metal (Scheme 2). Even by monitoring the reaction at −70°C, no trace of starting material 1 could be observed, the conversion into 2 being complete in a few seconds. The high catalytic activity was confirmed using 5 mol% of B; at room temperature, heterocycle 3 formed instantaneously in almost quantitative yield. As expected, addition of one equivalent of B to heterocycle 3 led cleanly to complex 2. Scheme 2 Stoichiometric and catalytic gold(I)-catalyzed intramolecular hydroamination of 1. To prevent the hydroamination process, and thereby possibly characterize a putative tricoordinate gold(I) complex, we prepared the corresponding tertiary amine 4a. A stoichiometric amount of cationic gold(I) complex B was added at room temperature to a solution of 4a in CDCl3, and the reaction was monitored by NMR spectroscopy (Scheme 3). Once again, we observed the instantaneous disappearance of both 4a and B, and the clean formation of a new complex 5, which was isolated in 98% yield. Surprisingly, single-crystal X-ray diffraction[12] revealed that 5 was a gold(I) η1-alkene complex resulting from the addition of the tertiary amino group to the coordinated alkyne (Figure 1, left). Complex 5 is structurally reminiscent of complexes recently isolated by Hammond et al,[13] and Gagne et al.,[14] from the gold-promoted cyclization of allenoates, and the intramolecular hydroarylation of allenes, respectively.[15] Interestingly, the formation of gold(I) η1-alkene complexes of type 5 is not limited to the rigid 2-alkynyl-benzenamine 4a. A mixture of (CAAC)AuCl(A)/AgOTf (1:1) instantaneously reacted stoichiometrically at room temperature with aliphatic N,N-diethylamino alkyne 6 to afford complex 7, which was isolated in 95% yield and fully characterized (Figure 1, right). Figure 1 ORTEP of gold complexes 5 (left) and 7 (right); ellipsoids set at 50% probability. Hydrogen atoms, solvent molecules, and the corresponding counterions are omitted for clarity. Scheme 3 Synthesis of complexes 5 and 7. Not surprisingly, treatment of complex 5 with one equivalent of trifluoromethanesulfonic acid induced immediate proto-deauration,[2,16] affording the corresponding gold-free cyclic ammonium salt 8a (Scheme 4). The stoichiometric two-step transformation of 4a into 8a (through 5) led to the question of whether this process could be catalytic for gold, or if the presence of triflic acid would preferentially protonate the basic tertiary amine,[7a,17] preventing the cyclization process. Addition of one equivalent of triflic acid to solution of alkynyl amine 4a in chloroform readily gave rise to the corresponding acyclic ammonium salt 9. In the absence of the gold catalyst, no cyclization occurred, even under heating a CDCl3 solution of 9 in a sealed tube at 120 °C for three days[18] (Table 1, entry 1). In contrast, we were pleased to observe that in the presence of 5 mol% of a 1:1 mixture of (CAAC)AuCl(A)/AgOTf, derivative 9 underwent the desired cyclization to form 8a in 98% yield after only 3 h at 70°C (Table 1, entry 2). Scheme 4 Stoichiometric and catalytic syntheses of 8a. X=TfO. Table 1 Gold(I)-catalyzed intramolecular hydroammoniumation of 4 with HOTf.[a] Following a brief investigation into the scope of this hydroammoniumation reaction, we found that aryl or alkyl substituents were tolerated on the alkyne, and that the cyclization process occurred under milder conditions when a more weakly basic amine was used. For example, the hydroammoniumation of 4 f readily occurred in a few minutes at room temperature (Table 1, entry 7). Examples in the literature of the direct carboamination of alkynes (the addition of a carbon–nitrogen bond to a carbon–carbon triple bond) are very rare. Yamamoto et al.[19] have reported the platinum- and palladium-catalyzed intramolecular C—N bond addition of amides and N,O-acetals, and Cacchi et al.[20] reported the palladium-catalyzed cyclization of 2-alkynyl-N-allyl-N′-trifluoroacetyl benzenamine. Although the cleavage of a relatively weak carbon–nitrogen bond was involved in both cases, these results prompted us to investigate the related methylamination reaction: in the presence of 10 mol% of a 1:1 mixture of (CAAC)AuCl(A)/KB(C6F5)4, 2-alkynyl-N,N′-dimethyl-benzenamines 4a–d was transformed into 2,3-disubstituted indoles 10a–d in good to excellent yields after 20 h at 160°C (Scheme 5). This rearrangement tolerates aryl or alkyl substituents on the alkyne. However, in the case of the N-ethyl-N′-methyl-benzenamine 4e, loss of ethylene was observed, and the 3-unsubstituted indole 3 was cleanly formed. Scheme 5 First examples of catalytic methylamination of alkyne. These results suggest that, at least for the intramolecular variant, the gold-catalyzed hydroamination of alkynes does not involve a tricoordinate gold complex of type I. Importantly, cationic gold(I) complexes supported by CAAC ligands promote the intramolecular hydroammoniumation and methylamination reactions of alkynes. The scope of these catalytic reactions is under investigation.

Copper-promoted and copper-catalyzed intermolecular alkene diamination.

Abstract: Olefin diamination methods provide powerful access to vicinal diamines useful in drug discovery, materials and catalysis.[1] A number of impressive diastereoselective, enantioselective and catalytic olefin diamination methods have been recently reported.[2–7] The intramolecular olefin diamination forms nitrogen heterocycles directly and has predominantly been accomplished by using tethered amine nucleophiles wherein both amine additions occur in intramolecular fashion (cf. Scheme 1). This olefin diamination strategy has been reduced to practice by using palladium,[4a] nickel[4b] and gold[4c] catalysts and stoichiometric copper reagents[3] and has resulted in the synthesis of a number of interesting compounds such as bicyclic sulfamides, ureas and guanidines. An intra/intermolecular alkene diamination would result in the convergent formation of one new nitrogen heterocycle along with the installation of a differently functionalized amine substituent. In a recent report, Michael and co-workers found that the use of a palladium catalyst, in combination with N-fluorobenzenesulfonimide led to the formation of nitrogen heterocycles with –CH2N(SO2Ph)2 substitution.[5] Herein we report a new copper(II)-promoted and catalyzed intra/intermolecular diamination of alkenes that engages a wide range of internal and external amine sources for the formation of differently functionalized and various nitrogen heterocycles. Importantly, this communication reports the first intramolecular diamination protocol where catalyst-based asymmetric induction has been observed (vide infra). Impressive catalytic enantioselective intermolecular olefin diaminations have been reported,[2] but no enantioselective intramolecular variant has been reported.[8] Herein is reported our progress towards this elusive transformation. Scheme 1 Previous work: Copper-promoted doubly intramolecular alkene diamination. ND = neodecanoate. The copper(II)-promoted and catalyzed intra/intermolecular alkene diamination protocols disclosed herein are an advance on earlier studies by our lab which involved the synthesis of bicyclic sulfamides and ureas via a tethered olefin diamination approach (Scheme 1).[3] We have recently found that we can expand this process to involve the participation of an external amine source in the second C-N bond-forming step (Table 1). Table 1 Copper(II)-promoted intra/intermolecular diamination of N-allyl ureas. Thus, heating 1-allyl-1-benzyl-2-phenyl urea (1a) in the presence of copper(II) 2-ethylhexanoate, Cu(EH)2 (3 equiv), Cs2CO3 and aniline (1.5 equiv) in PhCF3 for 24 h provides imidazolidin-2-one 2a in 92% yield (Table 1, Conditions A). Other copper-promoted processes such as intramolecular carboamination,[9] aminoacetoxylation[9e] and hydroamination[9b] can occur with the substrates used in this study (see Supporting Information), but the intra/intermolecular diamination process appears to be most favorable when the reaction is run in the presence of an external amine nucleophile. A number of substituted anilines (substitutents = Cl, CF3, Me, F, OMe, i-Pr, NO2) also participated as the external amine in this diamination process, providing 2b–2i in good to excellent yield (Table 1). The amount of substituted aniline had to be increased to 3 equiv (Conditions B) in order to minimize competititve formation of 2a, a product that can originate from the creation of PhNH2 from partial decomposition of 1a under the reaction conditions. In addition, at least 2 equiv of Cu(EH)2 is necessary to minimize formation of a hydroamination side product (see Supporting Information for optimization tables). Sodium azide,[10] benzamide and p-toluene sulfonamide were also competent nucleophiles in this diamination reaction (entries 10–12, Table 1). The 4,4-disubstituted imidazolidin-2-one 4 was formed efficiently from diamination/cyclization of the corresponding 1,1-disubstituted alkenyl urea 3 (Scheme 2). Gratifyingly, chiral imidazolidin-2-ones 6 were formed with high 4,5-trans selectivity from the corresponding alkenyl urea substrate 5 (Scheme 3). Formation of the trans diastereomer can be rationalized via cyclic transition state A, where the substituent adopts a pseudo-equatorial position. Scheme 2 Diaminations of a 1,1-disubstituted alkenyl urea. Scheme 3 High diastereoselectivity for allylic substituted ureas. N-aryl-γ-pentenyl amides, and sulfonamides with different γ-alkenyl backbones, were also good substrates in this intra/intermolecular diamination reaction (Table 2). Both 2,5-cis and 2,5-trans pyrrolidines can be formed with high diastereoselectivity (Table 2, entries 10–12). Table 2 Copper(II)-promoted intra/intermolecular diamination of γ-alkenyl amides and sulfonamides.[a] In general it appears that electron-deficient anilines are better coupling partners than electron-rich anilines in this reaction. For example, the electron-deficient p-trifluoromethylaniline provided the highest yield with 1a, giving 97% of 2f (Table 1, entry 6), while only the product of substrate decomposition, 2a, was observed in the attempted diamination with p-methoxyaniline with 1a. p-Methoxyaniline was marginally competent in the diamination reaction with N-tosyl-orthoallylaniline (which cannot undergo the same decomposition), giving 12d in 42% yield (Table 2, entry 7). Electron-rich amines may bind too tightly to the copper promoter, thereby inhibiting either or both of the C-N bond forming steps. To gain insight into the formation of the second C-N bond, we subjected the trans-deuterated alkene d-13[9b] to the diamination reaction (Scheme 4). Partial conversion led to isolation of a 1:1 ratio of diamination diastereomers d-14a (64%) and 25% of d-13, recovered without alkene isomerization. We interpret this to indicate the irreversible formation of a transient primary carbon radical (as in Scheme 5), the result of C-Cu(II) bond homolysis.[3,9b] The radical can then recombine with Cu(II) to generate a C-Cu(III) intermediate which may then undergo RNH2 and reductive elimination to produce the observed diamine product (Scheme 5). Scheme 4 Isotopic labeling experiment. Scheme 5 Origin of 2,5-cis-pyrrolidine diastereoselectivity. We interpret the 2,5-cis-pyrrolidine selectivity shown in products 16 and 18 to be the result of the first C-N bond formation occurring through either the chair-like or boat-like transition states in Scheme 5, where the dominant stereochemistry-determining interaction is avoidance of steric hindrance between the alpha-substituent and the N-substituent.[9] This diastereoselectivity can be switched to favor the 2,5-trans-pyrrolidine (cf. 20) by connecting these two substituents directly to one another.[11] Our initial attempts to render this diamination reaction catalytic in copper(II) using MnO2 as stoichiometric oxidant with either N-allyl urea 1a or N-sulfonyl ortho-allylaniline 11a and aniline or NaN3 as nucleophiles led to no reaction. MnO2 is a competent oxidant in our previously reported copper-catalyzed carboamination reaction.[9c,e] Sulfamide and urea substrates such as those shown in Scheme 1 also failed to undergo copper-catalyzed doubly intramolecular alkene diamination. To our delight, however, when p-TolSO2NH2 was used as the nucleophile with substrates 1a and 11a, the catalytic intra/intermolecular alkene diamination reactions occurred efficiently (Table 3). Superior yields (87% vs 72%, entry 1) were obtained when 2,6-di-tert-butyl-4-methyl pyridine was used as base instead of Cs2CO3. Table 3 Copper(II)-catalyzed intra/intermolecular diamination of alkenes.[a] We next challenged the reaction in the catalytic enantioselective manifold. When copper(II) triflate (30 mol%) complexed with (R)-Ph-bis(oxazoline) ligand (37.5 mol%) was used, diamination adduct 12e was obtained in 51% yield and 71% ee (Scheme 6). The major enantiomer is tentatively assigned S by analogy.[9c] This is a promising lead for development of the elusive catalytic enantioselective intramolecular alkene diamination reaction. Mechanistically, this reaction clearly demonstrates copper is present in the C-N bond-forming step (as indicated in Schemes 3 and ​and5).5). Further optimization of the catalytic enantioselective process is underway in our labs. Scheme 6 Enantioselective copper(II)-catalyzed intra/intermolecular alkene diamination (%ee determined by chiral HPLC).

Copper-catalyzed intramolecular C-H oxidation/acylation of formyl-N-arylformamides leading to indoline-2,3-diones.

Abstract: A new, efficient Cu-catalyzed intramolecular C-H oxidation/acylation method has been developed for the synthesis of substituted indoline-2,3-diones (isatins). In the presence of CuCl(2) and O(2), a variety of formyl-N-arylformamides underwent the tandem reaction to afford the corresponding indoline-2,3-diones in moderate to good yields. It is noteworthy that the reaction serves as the first example of transition-metal-catalyzed transformation for the preparation of indoline-2,3-diones.

Total synthesis and absolute stereochemical assignment of (-)-communesin F.

Abstract: A concise asymmetric total synthesis of (-)-communesin F (∼6% overall yield in the longest linear sequence of 19 steps) is described. It features an unprecedented intramolecular oxidative coupling strategy for the elaboration of the requisite spiro-fused indoline moiety. Other notable elements are the use of TBS-protected (S)-phenylglycinol as a chiral auxiliary to induce the asymmetric formation of the spiro-fused indoline part, the mesylate-mediated formation of its G ring, and the introduction of the A ring at the final stage via intramolecular Staudinger reaction. This intramolecular Staudinger reaction proceeded smoothly at 80 °C, providing an additional example illustrating that twisted amides are more reactive than simple amides. Along with the total synthesis, we were able to assign the absolute configuration of natural communesin F as 6R,7R,8R,9S,11R.

Copper-Catalyzed Synthesis of Azaspirocyclohexadienones from α-Azido-N-arylamides under an Oxygen Atmosphere

Abstract: A copper-catalyzed reaction of α-azido-N-arylamides was found to proceed under an oxygen atmosphere to afford azaspirocyclohexadienones. The present transformation is carried out by a sequence of denitrogenative formation of iminyl copper species from α-azido-N-arylamides and their imino-cupration with an intramolecular benzene ring on the amido nitrogen followed by consecutive formation of C═O bonds. The preliminary investigation revealed that molecular oxygen is a prerequisite for achieving the present catalytic cyclization and that one of the oxygen atoms of O2 was found to be incorporated into the cyclohexadienone moiety.

Selective Intramolecular C ? H Amination through the Metalloradical Activation of Azides: Synthesis of 1,3‐Diamines under Neutral and Nonoxidative Conditions

Abstract: A wide range of sulfamoyl azides smoothly undergoes Co-catalyzed intramolecular C—H amination to give thiadiazine derivatives, e.g. (II), (IV) or (VI), in excellent yields.

The role of reversible oxidative addition in selective palladium(0)-catalyzed intramolecular cross-couplings of polyhalogenated substrates: synthesis of brominated indoles.

Abstract: A Pd(0)-catalyzed C−N bond-forming reaction leading to the synthesis of brominated indoles is described. The use of the phosphine ligand PtBu3 is necessary for reactivity. It is proposed that the bulky ligand serves to prevent inhibition of the catalyst by facilitating reversible oxidative addition into the product C−Br bond. Intramolecular coupling of a vinyl bromide in the presence of an aryl iodide can take place, demonstrating unprecedented levels of selectivity.

CHARMM Additive All-Atom Force Field for Glycosidic Linkages in Carbohydrates Involving Furanoses

Abstract: Presented is an extension of the CHARMM additive carbohydrate all-atom force field to enable modeling of polysaccharides containing furanose sugars. The new force field parameters encompass 1 ↔ 2, 1 → 3, 1 → 4, and 1 → 6 pyranose-furanose linkages and 2 → 1 and 2 → 6 furanose-furanose linkages, building on existing hexopyranose and furanose monosaccharide parameters. The model compounds were chosen to be monomers or glycosidic-linked dimers of tetrahydropyran (THP) and tetrahydrofuran (THF) as to contain the key atoms in full carbohydrates. Target data for optimization included two-dimensional quantum mechanical (QM) potential energy scans of the Φ/Ψ glycosidic dihedral angles, with geometry optimization at the MP2/6-31G(d) level followed by MP2/cc-pVTZ single-point energies. All possible chiralities of the model compounds at the linkage carbons were considered, and for each geometry, the THF ring was constrained to the favorable south or north conformations. Target data also included QM vibrational frequencies and pair interaction energies and distances with water molecules. Force field validation included comparison of computed crystal properties, aqueous solution densities, and NMR J-coupling constants to experimental reference values. Simulations of infinite crystals showed good agreement with experimental values for intramolecular geometries as well as for crystal unit cell parameters. Additionally, aqueous solution densities and available NMR data were reproduced to a high degree of accuracy, thus validating the hierarchically optimized parameters in both crystalline and aqueous condensed phases. The newly developed parameters allow for the modeling of linear, branched, and cyclic pyranose/furanose polysaccharides both alone and in heterogeneous systems including proteins, nucleic acids, and/or lipids when combined with existing additive CHARMM biomolecular force fields.

Enantioselective Intramolecular Aza‐Michael Additions of Indoles Catalyzed by Chiral Phosphoric Acids

Abstract: The asymmetric N-alkylation of indoles proceeds in the absence of electron-withdrawing groups under acidic conditions

Alkylgold complexes by the intramolecular aminoauration of unactivated alkenes

Abstract: Alkylgold(I) complexes were formed from the gold(I)-promoted intramolecular addition of various amine nucleophiles to alkenes. These experiments provide the first direct experimental evidence for the elementary step of gold-promoted nucleophilic addition to an alkene. Deuterium-labeling studies and X-ray crystal structures provide support for a mechanism involving anti-addition of the nucleophile to a gold-activated alkene, which is verified by DFT analysis of the mechanism. Ligand studies indicate that the rate of aminoauration can be drastically increased by use of electron-poor arylphosphines, which are also shown to be favored in ligand exchange experiments. Attempts at protodeauration lead only to recovery of the starting olefins, though the gold can be removed under reducing conditions to provide the purported hydroamination products.