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This work describes the application of pentafluoropyridine (PFP), a cheap commercially available reagent, in the deoxyfluorination of carboxylic acids to acyl fluorides. The acyl fluorides can be formed from a range of acids under mild conditions. We also demonstrate that PFP can be utilized in a one-pot amide bond formation via in situ generation of acyl fluorides. This one-pot deoxyfluorination amide bond-forming reaction gives ready access to amides in yields of ≤94%.

The synthesis of symmetrical 3,3′-bisoxindoles from simple acyclic β-oxoanilides is reported. The described method forges three new C-C bonds in a single step via a sequential Mn(OAc)3·2H2O mediated oxidative radical cyclization-fragmentation-dimerization process. The scope of this reaction is demonstrated in the preparation of a variety of 3,3′-bisoxindoles, as well as its application toward the formal synthesis of the Calycanthaceae alkaloid, (±)-folicanthine.

A novel methodology for the construction of various secondary (4 examples), tertiary amides (31 examples), and imides (16 examples) by a Cobalt(II) catalyzed oxidative amide coupling in aqueous media. The Co(III)-TMC was reacted with N-Heteroatom Carbene to form active catalyst Co(II)NHC-TMC in situ which involves in the coordination with Breslow's intermediate and SET for the activation of aldehyde and amides. The mechanism for activation of amide and amine differs on the basis of SET based nucleophilic addition and ligand exchange respectively. The regeneration of the catalyst was achieved using Fe(III)(EDTA)-H2O2 as oxidant. The use of Co(II)TMC-O2 was also found equally efficient in the process. The method is found regioselective for N?H activation in the presence of equally susceptible ortho-C?H bond activation. And amines were found more susceptible then the corresponding amide for the reaction.

The construction of amide bonds and peptide linkages is one of the most fundamental transformations in all life processes and organic synthesis. The synthesis of structurally ubiquitous amide motifs is essential in the assembly of numerous important molecules such as peptides, proteins, alkaloids, pharmaceutical agents, polymers, ligands and agrochemicals. A method of SO2F2-mediated direct clickable coupling of carboxylic acids with amines was developed for the synthesis of a broad scope of amides in a simple, mild, highly efficient, robust and practical manner (>110 examples, >90% yields in most cases). The direct click reactions of acids and amines on a gram scale are also demonstrated using an extremely easy work-up and purification process of washing with 1 M aqueous HCl to provide the desired amides in greater than 99% purity and excellent yields.

An efficient and mild protocol has been developed for the synthesis of 2-substituted benzothiazole under solvent- and metal-free conditions using CBr4 as the catalyst. This process involves the activation of a thioamide through halogen bond formation between the sulphur atom of the thioamide and bromine atom of the CBr4 molecule. The presence of halogen-bonding interaction between N-methylthioamides and tetrabromomethane has been demonstrated with several control experiments, spectroscopic analysis and density functional theory (DFT). This methodology has a wide substrate scope for the synthesis of both 2-alkyl and 2-aryl substituted benzothiazoles.

A series of catalysts based on supported copper nanoparticles have been prepared and tested in the amide bond formation from tertiary amines and acid anhydrides, in the presence of tert-butyl hydroperoxide as an oxidant. Copper nanoparticles on zeolite Y (CuNPs/ZY) was found to be the most efficient catalyst for the synthesis of amides, working in acetonitrile as solvent, under ligand- and base-free conditions in air. The products were obtained in good to excellent yields and in short reaction times. The CuNPs/ZY system also exhibited higher catalytic activity than some commercially available copper and iron sources and it was reused in ten reaction cycles without any further pre-treatment. This methodology has been successfully scaled-up to a gram scale with no detriment to the yield.

A simple and efficient Ru(II)-catalyzed transfer hydro-dehalogenation of organic halides using 2-propanol solvent as the hydride source was reported. This methodology is applicable for hydro-dehalogenation of a variety of aromatic halides and α-haloesters and amides without additional ligand, and quantitative yields were achieved in many cases. The potential synthetic application of this method was demonstrated by efficient gram-scale transformation with catalyst loading as low as 0.5 mol %.

A simple extension of the carbamoyl Baker-Venkataraman rearrangement has been developed. If residual water in the reaction is not strictly excluded a Baker-Venkataraman retro-Claisen cascade takes place, giving amide products, in which an alkyl group apparently migrates between two functionalities of the substrate.

Abstract The synthesis of bis-oxindoles via the copper(II)-mediated double cyclisation of linear bis-anilides is described. Cu(OAc)2·H2O was identified as an efficient and inexpensive catalyst for this process. In contrast to previous methods, which rely on the synthesis of the central core from existing oxindole building blocks, this new approach focusses on concurrent formation of both oxindole rings from a simple linear precursor, allowing the formation of bis-oxindoles containing a diverse range of cyclic and acyclic linkers using a single synthetic method.

A double C-H, Ar-H coupling process for the conversion of bis-anilides into spirocyclic bis-oxindoles, enabling the concomitant formation of two all-carbon quaternary centers at oxindole 3-positions in a diastereoselective manner, is described. The optimum cyclization conditions utilize stoichiometric Cu(OAc)2·H2O/KOtBu in DMF at 110 °C and have been applied to prepare a range of structurally diverse bis-spirooxindoles in fair to good yields (28-77%); the method has also been extended to prepare bis-oxindoles linked by a functionalized acyclic carbon chain.

A general and efficient method for amide bond synthesis has been developed. The method allows for synthesis of tertiary amides from readily available tertiary amines and anhydrides in the presence of FeCl2 as catalyst and tert-butyl hydroperoxide in water (T-Hydro) as oxidant. Mechanistic studies indicated that the in situ-generated α-amino peroxide of tertiary amine and iminium ion act as key intermediates in this oxidative transformation.

Hydrazine hydrate with acetic and propionic acids was an efficient reagent for acylation of primary and secondary amines at reflux temperatures. The reported one-pot method is high-yielding, simple, mild, and inexpensive. Copyright Taylor & Francis Group, LLC.

The role of single electron transfer (SET) in P450-catalyzed N-dealkylation reactions has been studied using the probe substrates N-cyclopropyl-N-methylaniline (2a) and N-(1′-methylcyclopropyl)-N-methylaniline (2b). In earlier work, we showed that SET oxidation of 2a by horseadish peroxidase leads exclusively to products arising via fragmentation of the cyclopropane ring [Shaffer, C. L.; Morton, M. D.; Hanzlik, R. P. J. Am. Chem. Soc. 2001, 123, 8502-8508]. In the present study, we found that liver microsomes from phenobarbital pretreated rats (which contain CYP2B1 as the predominant isozyme) oxidize [1′-13C, 1′-14C]-2a efficiently (80% consumption in 90 min). Disappearance of 2a follows first-order kinetics throughout, indicating a lack of P450 inactivation by 2a. HPLC examination of incubation mixtures revealed three UV-absorbing metabolites: N-methylaniline (4), N-cyclopropylaniline (6a), and a metabolite (M1) tentatively identified as p-hydroxy-2a, in a 2:5:2 mole ratio, respectively. 2,4-Dinitrophenylhydrazine trapping indicated formation of formaldehyde equimolar with 6a; 3-hydroxypropionaldehyde and acrolein were not detected. Examination of incubations of 2a by 13C NMR revealed four 13C-enriched signals, three of which were identified by comparison to authentic standards as N-cyclopropylaniline (6a, 33.6 ppm), cyclopropanone hydrate (11, 79.2 ppm), and propionic acid (12, 179.9 ppm); the fourth signal (42.2 ppm) was tentatively determined to be p-hydroxy-2a. Incubation of 2a with purified reconstituted CYP2B1 also afforded 4, 6a, and M1 in a 2:5:2 mole ratio (by HPLC), indicating that all metabolites are formed at a single active site. Incubation of 2b with PB microsomes resulted in p-hydroxylation and N-demethylation only; no loss or ring-opening of the cyclopropyl group occurred. These results effectively rule out the participation of a SET mechanism in the P450-catalyzed N-dealkylation of cyclopropylamines 2a and 2b, and argue strongly for the N-dealkylation of 2a via a carbinolamine intermediate formed by a conventional C-hydroxylation mechanism.

By the combined use of Co(acac)2 with DIBAL, various α,β-unsaturated carbonyl compounds such as enones, α,β-unsaturated carboxylates and carboxamides were selectively reduced in a 1,4-manner to obtain the corresponding 1,4-reduced products in good-to-high yields. Thieme.

The use of certain types of atropisomeric amides, incorporating an N-MEM-ortho-tert-bityariume group, for stereoselective reactions, has been explored. Enolate reactions of these systems are highly diastereocontrolled, and enantiomerically enriched starting materials can be obtained, starting from lactic acid, via a new SmI2 mediated reduction process.

SmI2 or SmI2-LiCl mixtures can be used to reduce α-functionalised amides in yields of up to 85% depending upon the amide structure. The method has been applied to the synthesis of an atropisomeric anilide system in highly enantioenriched form, starting with (S)-O-acetyl lactic acid.

2A palladium-catalyzed α-arylation of amides is reported. Intermolecular arylation of N,N-dimethylamides and lactams occurs using aryl halides, silylamide base, and a palladium catalyst. Intramolecular arylation of N-(2-halophenyl)amides occurs using alkoxide base and a palladium catalyst. The palladium catalyst was formed in situ from Pd(dba)2 (dba = trans,trans-dibenzylidene acetone) and BINAP (2,2′-bis(diphenylphosphino)-1,1′-binaphthalene). Although the intermolecular arylation of amides is less general than that reported previously for ketones, unfunctionalized and electron-rich aryl halides gave α-arylamides in 48-75% yield and N-methyl-α-phenylpyrrolidinone in 49% yield. These reactions provided the highest yields yet reported for regioselective amide arylations. Intramolecular amide arylation of 2-bromoanilides gave oxindoles in 52-82% yield. Mono- and disubstituted acetanilides gave 1,3-di- and 1,3,3-trisubstituted oxindoles. The use of dioxane, rather than THF, solvent was important for some of the amide arylations.

The reactions of α-anilino alkenenitriles with iodobenzene catalyzed by palladium gave amides and benzonitrile. A general mechanism is proposed to explain the chemoselective arylation at the cyano group.

Diphenyl phosphorazidate (DPPA) was used as the azide source in a one-pot synthesis of 2,2-disubstituted 3-amino-2H-azirines 1 (Scheme 1).The reaction with lithium enolates of amides of type 2, bearing two substituents at C(2), proceeded smoothly in THF at 0 degree C; keteniminium azides C and azidoenamines D are likely intermediates.Under analogous reaction conditions, DPPA and amides of type 3 with only one substituent at C(2) gave 2-diazoamides 5 in fair-to-good yield (Scheme 2).The corresponding 2-diazo derivatives 6-8 were formed in low yield by treatment of the lithium enolates of N,N-dimethyl-2-phenylacetamide, methyl 2-phenylacetate, and benzyl phenyl ketone, respectively, with DPPA.Thermolysis of 2-diazo-N-methyl-N-phenylcarboxamides 5a and 5b yielded 3-subdtituted 1,3-dihydro-N-methyl-2H-indol-2-ones 9a and 9b, respectively (Scheme 3).The diazo compounds 5-8 reacted with 1,3-thiazole-5(4H)-thiones 10 and thiobenzophenone (13) to give 6-oxa-1,9-dithia-3-azaspironona-2,7-dienes 11 (Scheme 4) and thiirane-2-carboxylic acid derivatives 14 (Scheme 5), respectively.In analogy to previously described reactions, a mechanism via 1,3-dipolar cycloaddition, leading to 2,5-dihydro-1,3,4-thiadiazoles, and elimination of N2 to give the 'thiocarbonyl ylides' of type H or K is proposed.These dipolar intermediates with a conjugated C=O group then undergo either a 1,5-dipolar electrocyclization to give spiroheterocycles 11 or a 1,3-dipolar electrocyclization to thiiranes 14.

Suitable o-bromo-N-methylanilides are efficiently converted into oxindoles by treatment with tributylstannane at 160 degC via tandem translocation of the initially formed aryl radical and intramolecular homolytic substitution.

Dibromo- and dichloro(1,2-bis(di-2-propylphosphino)benzene)nickel(II) is compared with tetrakis(triphenylphosphino)nickel(II) as an electrocatalyst for the reductive coupling of aryl halides.In many of the reactions examined, dehalogenation of the substrate predominated over coupling; however, preparative yields of biphenyls as high as 96percent can be obtained with aryl chlorides and 2 mol percent of the title catalyst in polar, coordinating solvents.Experimental factors governing the efficiency of these reactions are discussed, and possible mechanisms for coupling and catalyst deactivation are considered.Much better selectivity for aryl chlorides is attained in electroreductive couplings catalyzed by the title compound, whereas electrocatalysis with (Ph3P)4NiCl2 allows for selective intra- and intermolecular coupling at aryl bromide and vinyl chloride sites.Modest yields of cyclization products can be attained with either electrocatalyst in the presence of appropriately functionalized aryl or vinyl halides.

Various α,β-unsaturated carbonyl compounds, such as α,β-unsaturated esters, α,β-unsaturated ketones, α,β-unsaturated nitriles, and α,β-unsaturated amides, were directly converted to the corresponding α-hydroxyimino carbonyl compounds in high yields on treatment with butyl nitrite and phenylsilane in the presence of a catalytic amount of N,N'-bis(2-ethoxycarbonyl-3-oxobutylidene)ethylenediaminatocobalt(II) complex under mild conditions.

(Trimethylsilyl)ethoxyacetylene, a stable and easy-handling reagent, serves as an excellent dehydrating agent for the synthesis of carboxylic anhydrides and amides from the corresponding carboxylic acids.By means of this reagent, various types of acid-sensitive carboxylic anhydrides and amides were obtained almost in quantative yields.Twenty-two examples of carboxylic anhydrides and 12 examples of amides were presented.

The rate constants of hydrolysis of series of 4-substituted phenyl propionates, catalysed by bile-salt-stimulated human milk lipase in the absence and presence of cholate or taurocholate stimulation, have been measured at pH 7.3, 310.5 K.There is little evidence for an alkyl site electronic interaction in the rate-determining step of the esterolytic reaction.However, a negatively charged substrate or an amido-substituent caused an inhibition of unstimulated esterase activity.In the presence of the bile-salt cofactors, esterolytic activity against charged substrates may be stimulated or inhibited, depending on the proximity of the charge to the steroidal side chain and the subsequent substrate-interaction within the surrounding environment of the active site.It has been confirmed that bile-salt-stimulated lipase is not an amidase, but that an amide, of the correct geometry, may occupy the active site and restrict esterase activity.

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