Intramolecular amidation intermolecular amination

Abstract Direct sp C-H bond functionalization is an efficient, straightforward, and powerful method to construct new C-X (X=C, N, F, S) bonds from nonfunctionalized aliphatic motif of organic molecules, which has been used in late-stage modification of complex molecules. In this chapter, the recent developments of silver-mediated direct sp C-H functionalizations are reviewed, categorized by C-C bond formation (C-H insertion), C-N bond formation (intramolecular and intermolecular amination/amidation), C-F bond formation, and C-S bond formation. 

Nitrogen-containing functional groups are basic and important structural motifs, exiting in biologically active compounds and natural products [27]. The development of new and efficient methods to construct C-N bonds through C-H activation attracted much attention in medicinal chemistry and organic chemistry. Usually, there are two ways to introduce C-N bonds via C-H activation, intramolecular and intermolecular amination/amidation. 

Sargeson and his coworkers have developed an area of cobalt(III) coordination chemistry which has enabled the synthesis of complicated multidentate ligands directly around the metal. The basis for all of this chemistry is the high stability of cobalt(III) ammine complexes towards dissociation. Consequently, a coordinated ammonia molecule can be deprotonated with base to produce a coordinated amine anion (or amide anion) which functions as a powerful nucleophile. Such a species can attack carbonyl groups, either in intramolecular or intermolecular processes. Similar reactions can be performed by coordinated primary or secondary amines after deprotonation. The resulting imines coordinated to cobalt(III) show unusually high stability towards hydrolysis, but are reactive towards carbon nucleophiles. While the cobalt(III) ion produces some iminium character, it occupies the normal site of protonation and is attached to the nitrogen atom by a kinetically inert bond, and thus resists hydrolysis. 

The aziridination of olefins, which forms a three-membered nitrogen heterocycle, is one important nitrene transfer reaction. Aziridination shows an advantage over the more classic olefin hydroamination reaction in some syntheses because the three-membered ring that is formed can be further modified. More recently, intramolecular amidation and intermolecular amination of C-H bonds into new C-N bonds has been developed with various metal catalysts. When compared with conventional substitution or nucleophilic addition routes, the direct formation of C-N bonds from C-H bonds reduces the number of synthetic steps and improves overall efficiency.2 After early work on iron, manganese, and copper,6 Muller, Dauban, Dodd, Du Bois, and others developed different dirhodium carboxylate catalyst systems that catalyze C-N bond formation starting from nitrene precursors,7 while Che studied a ruthenium porphyrin catalyst system extensively.8 The rhodium and ruthenium systems are... 

This new disilver system was found to be more active in intramolecular amidation reactivity compared to the original [Ag2(t-Bu3tpy)2] catalyst, showing both increased yields and decreased temperature (from 82 to 50°C). More importantly, this system was able to catalyze the intermolecular amination reaction of both benzylic and inert aliphatic C—Hbonds.Asimilar copper system reported similar activity however, it was only able to aminate benzylic C—H bonds (Table I). In the silver case, it was found that substitutions on the 2 and 9 positions of the phenanthroline shut down the reactivity of the catalyst, suggesting the importance of keeping a disilver core structure. 

Typically, the last domain in the final module of modular PKS and NRPS systems is a thioesterase (TE) domain. This domain catalyzes the release of the assembled polyketide or peptide chain from carrier protein domain within the last module of the PKS or NRPS. Separately encoded, stand-alone TE enzymes are also found in some systems, such as the coelichelin biosynthetic system. TE domains catalyze two related types of chain release reactions. The first type is the hydrolysis or intermolecular condensation with a soluble amine and the second is intramolecular amide or ester bond formation. These chain release reactions result in distinct metabolic products. The intermolecular reactions lead to linear products with a carboxyl-terminus, whereas the intramolecular reactions lead to cyclic products. Sequence comparisons of TE domains from various modular PKSs that assemble known metabolic products have established a correlation between the phylogenetic relatedness of the domains and the type of chain release reaction catalyzed. " However, this predictive tool, which has been developed by Ecopia BioSciences, is not yet publicly accessible. 

In comparison, intermolecular reaction met high challenges due to both enthalpy and entropy reasons. In 2007, He and coworkers developed a disilver-based new catalyst 11 which showed high efficiency for intramolecular C-H amination reaction (Scheme 10) [32]. Such an intermolecular C-H amination/amidation ran at mild condition. The new catalyst set has successfully been applied to intermolecular amination reaction for the first time (Scheme 11). In the reaction, the catalyst was added in two portions in order to increase the yield. Under typical reaction condition, AgOTf (2 mol%) and ligand (2.4 mol%) were mixed in DCM in a tube for 20 min. Then the substrate (5.0 or 10.0 eqmv.), PhI=NNs (1.0 equiv.) and 4 A molecular sieves (2 g/mmol) were added under N2 atmosphere. The tube was sealed and heated to 50°C for 2 h before another AgOTf (2 mol%) and ligand (2.4 mol%) mixed in DCM were added. The reaction was carried out at 50°C... 

Organolanthanide complexes are known to be highly active catalysts for a variety of organic transformations, which can be either intramolecular or intermolecular in character. Successful intramolecular transformations include hydroelementation processes, which is the addition of a H-E (E = N, O, P, Si, S, H) bond across unsaturated C-C bonds, such as hydroamination, hydroalkoxylation, and hydrophosphination. Intermolecular transformations include a series of asymmetric syntheses, the amidation of aldehydes with amines, Tishchenko reaction, addition of amines to nitriles, aUcyne dimerization, and guanylation of terminal aUcynes, amines, and phosphines with carbodiimides. 

Azetidones (p-lactams) are generally obtained in high yield from (3-halopropion-amides (Table 5.18) and the low yield from the reaction of N-phenyl (3-chloropropi-onamide can be reconciled with the isolation of A-phenyl acrylamide in 58% yield [34]. The unwanted elimination reaction can be obviated by conducting the cyclization in a soliddiquid system under high dilution [35, 36]. Azetidones are also formed by a predominant intramolecular cyclization of intermolecular dimerization to yield piperazine-2,5-diones, or intramolecular alkylation to yield aziridones. Aone-pot formation of azetidones in 45-58% yield from the amine and P-bromocarboxylic acid chloride has also been reported [38]. 

Apart from the increased catalytic efficiency, this structure design produced two positive side effects. In contrast to monofunctional (thio)ureas, which exhibit low solubility in nonpolar solvents due to intermolecular hydrogen-bonding association, tertiary amine thioureas of type 12 revealed intramolecular hydrogen bonding between the amine group and the amide protons making these (thio)ureas soluble in nonpolar reaction media such as toluene. The analysis of the X-ray crystal-... 

The design of polydentate ligands containing imines has exercised many minds over many years, and imine formation is probably one of the commonest reactions in the synthetic co-ordination chemist s arsenal. Once again, the chelate effect plays an important role in stabilising the co-ordinated products and the majority of imine ligands contain other donor atoms that are also co-ordinated to the metal centre. The above brief discussion of imine formation will have shown that the formation of the imine from amine and carbonyl may be an intra- or intermolecular process. In many cases, the detailed mechanism of the imine formation reaction is not fully understood. In particular, it is not always clear whether the nucleophile is metal-co-ordinated amine or amide. Some intramolecular imine formation reactions at cobalt(m) are known to proceed through amido intermediates. A particularly useful intermediate (5.24) in metal-directed amino acid chemistry is... 

The scope aromatic C-N bond formation extends beyond simple amine substrates. For example, selected imines, sulfoximines, hydrazines, lactams, azoles, and carbamates give useful products from intermolecular aromatic C-N bond formation. Intramolecular formation of aryl amides has been reported. In addition, allylamine undergoes arylation, providing a readily cleaved amine alternative to the ammonia surrogates benzylamine, t-butylcarbamate, or benzophenone imine. Although it is an amine substrate, the reaction of this reagent is included here because of its special purpose. 

Antimony(m) ethoxide (Sb(OEt)3) promotes the intermolecular amidation of esters and carboxylic acids with amines under azeotropic conditions.47,48 When tetramino esters are used, the antimony(in)-templated intramolecular macrolactamization provides macrocyclic spermine alkaloids in good yields (Equation (14)). Under the same... 

---