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The deprotonative functionalization of toluenes, for their weak acidity, generally needs strong bases, thus leading to the requirement of harsh conditions and the generation of by-products. Direct nucleophilic acyl substitution reaction of amides with organometallic reagents could provide an ideal solution for ketone synthesis. However, the inert amides and highly reactive organometallic reagents bring great challenges for an efficient and selective synthetic approach. Herein, we reported an lithium diisopropylamide (LDA)-promoted benzylic aroylation of toluenes with unactivated tertiary benzamides, providing a direct and efficient synthesis of various aryl benzyl ketones. This process features a kinetic deprotonative functionalization of toluenes with a readily available base LDA. Mechanism studies revealed that the directed ortho-lithiation of the tertiary benzamide with LDA promoted the benzylic kinetic deprotonation of toluene and triggered the nucleophilic acyl substitution reaction with the amide.

New dipeptide–dihydroquinolinone derivatives were successfully synthesised by benzotriazole mediated nucleophilic acyl substitution reaction and their structures were elucidated by spectroscopic and analytic techniques. The carbonic anhydrase (CA, EC 4.2.1.1) inhibitory activity of the new compounds was determined against four human (h) isoforms, hCA I, hCA II, hCA IX and hCA XII. While all compounds showed moderate to good in vitro CA inhibitory properties against hCA IX and hCA XII with inhibition constants in the micromolar level (37.7–86.8 and 2.0–8.6 µM, respectively), they did not show inhibitory activity against hCA I and hCA II up to 100 µM concentration. The antioxidant capacity of the peptide–dihydroquinolinone conjugates was determined using 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging method. Most of the synthesised compounds showed low antioxidant activities compared to the control antioxidant compounds BHA and α-tocopherol.

A solvent-controlled protocol for the direct and transition metal-free addition of alkenyl Grignard reagents to vicinally functionalized sp3-rich morpholinones has been developed, leading to the chemo and regioselective synthesis of lactam-bearing homoallylic ketones. The addition of lithium chloride proved to be essential. In cases where a new stereocenter is generated, the doubly branched homoallylic ketones are obtained in unexpectedly high diastereoselectivities. Efforts to extend the methodology to other heterosubstituted lactams revealed some important reactivity and selectivity differences.

A tandem reaction of thioesters with vinylmagnesium bromide is reported. The initial acyl substitution provides an α,β-unsaturated ketone which further reacts with the liberated thiolate. This transition-metal-free synthesis of β-sulfanyl ketones takes place under mild reaction conditions, whereas the addition of a second Grignard molecule is almost completely suppressed. The carefully chosen parameters enabled the transformation of different substrates in moderate to good yields.

The Rh-catalyzed ortho-C(sp2 )-H functionalization of 8-aminoquinoline-derived benzamides with aliphatic acyl fluorides generated in situ from the corresponding acids has been developed. This reaction initiated with 8-aminoquinoline-directed ortho-C(sp2 )-H acylation, which was accompanied by subsequent intramolecular nucleophilic acyl substitution of amide group to produce alkylidene phthalides This approach exhibits high stereo-selectivity for Z-isomer products, and tolerates a variety of functional groups as well as aliphatic carboxylic acids with diverse structural scaffolds.

meso-Carboxyl-BODIPY responds to small electronic changes resulting from acyl substitution reactions with a marked change in fluorescence. Herein, the minute changes that accompany the thioester to amide conversion encountered in native chemical ligation (NCL) are exploited in the construction of fluorescent "turn-on" probes. Two fluorogenic probes, 1 a and 4, derived from a meso-thioester-BODIPY scaffold, were designed for the selective detection of cysteine (1 a) and aminopeptidase N (4), respectively. The aromatic (1 a) and aliphatic (4) thioesters of meso-carboxyl-BODIPY are nonfluorescent. However, specific analyte-induced conversion to the meso-amide derivative caused significant spectral changes and a dramatic fluorescence enhancement. Probe 1 a exhibited a large fluorescence "turn-on" response with high selectivity toward cysteine via a tandem NCL reaction. Probe 4 was successfully applied to the monitoring and imaging of endogenous aminopeptidase N in live cancer cells.

We report that the nucleophilic acyl substitution reaction of aliphatic and (hetero)aromatic amides by organolithium reagents proceeds quickly (20 s reaction time), efficiently, and chemoselectively with a broad substrate scope in the environmentally responsible cyclopentyl methyl ether, at ambient temperature and under air, to provide ketones in up to 93 % yield with an effective suppression of the notorious over-addition reaction. Detailed DFT calculations and NMR investigations support the experimental results. The described methodology was proven to be amenable to scale-up and recyclability protocols. Contrasting classical procedures carried out under inert atmospheres, this work lays the foundation for a profound paradigm shift of the reactivity of carboxylic acid amides with organolithiums, with ketones being straightforwardly obtained by simply combining the reagents under aerobic conditions and with no need of using previously modified or pre-activated amides, as recommended.

Directed ortho metalation (DoM) or nucleophilic acyl substitution (SNAc) can be efficiently programmed on the same aromatic carboxylic acid amide, in a choline chloride-based eutectic mixture, by simply switching the nature of the organolithium reagent. Telescoped, one-pot ortho-lithiation/Suzuki–Miyaura cross-couplings have also been demonstrated for the first time in Deep Eutectic Solvents.

This paper reports a computational study elucidating reaction mechanism for amide bond formation from esters and amines catalyzed by acetic acid. Two optional mechanisms (namely, classic stepwise and concerted acyl substitution mechanisms) have been studied. Calculation results establish the reaction energy profiles of both mechanisms and locate all the intermediates and transition states in both catalytic cycles. Our results propose that the concerted acyl substitution mechanism may be more likely wherein the formation of C N bond and the cleavage of C O bond occur concurrently without the need of rehybridization of the carbonyl carbon. This is also consistent with the fact that no significant racemization/epimerization were observed in the amide products when asymmetric esters and/or amines were used as the reactants, because concerted acyl substitution mechanism precludes the intermediacy of tetrahedral adducts and the accompanying generation/elimination of new chiral centers. Further discussion implies that the concerted acyl substitution mechanism may widely occur in related amidation reactions in the presence of different types of coupling reagents.

Pentyl 2-(1H-indole-2-carboxamido)benzoate (5) is obtained in good yield as stable crystals by reaction of pentyl 2-amino benzoate (6) with indole-2-carbonyl chloride acid (7) in the presence of pyridine. The crystal structure of 5 confirms the presence of intramolecular hydrogen bonding (N-H…O) which produces a six-membered ring, and the molecules are linked together by intermolecular hydrogen forces (N-H…O).

A new protocol has been developed for the Curtius-type rearrangement of acyl hydrazides in the presence of nucleophiles by activating acyl hydrazides with benzyne to generate aminimide intermediates. A wide variety of N'-methyl-N'-phenyl acyl hydrazides were treated with various alcohols in the presence of 2-(trimethylsilyl)phenyl triflate and CsF under mild conditions to afford structurally diverse carbamates in moderate to excellent yields. Importantly, complete retention of configuration was observed in the reaction of enantioenriched α-chiral alkanoyl hydrazides. Replacing the alcohol with water, an amine, an N'-unsubstituted acyl hydrazide, an alkoxyamine, or a thiophenol in the reaction permitted facile synthesis of ureas and analogues.

The acyl transferase from Mycobacterium smegmatis (MsAcT) catalyses transesterification reactions in aqueous media because of its hydrophobic active site. Aliphatic cyanohydrin and alkyne esters can be synthesised in water with excellent and strikingly opposite enantioselectivity [(R);E>50 and (S);E>100, respectively]. When using this enzyme, the undesired hydrolysis of the acyl donor is an important factor to take into account. Finally, the choice of acyl donor can significantly influence the obtained enantiomeric excesses.

International audience; The copper-catalyzed reaction of allenes with bis(pinacolato)diboron and acyl electrophiles is reported. In this transformation, acyl fluorides have been proven to be more efficient coupling partners than their chloride or carboxylate analogues. The optimized reaction conditions employed were shown to be compatible with a range of commonly used functional groups, thereby allowing the formation of a library of β-boryl β,γ-unsaturated ketones by varying the nature of the allene and acyl fluoride substrates.

The first palladium-catalyzed construction of ketones via Suzuki-Miyaura reaction using acid fluorides is described. In contrast to typical acyl electrophiles such as acid chlorides, acid fluorides are uncommon acyl electrophiles to use in boron-based coupling probably due to a high level of stability toward nucleophiles. This first attempt to use acid fluorides as a coupling partner with boronic acid allowed highly functional group tolerance and a wide substrate scope, and afforded various ketones in effective yields.

The catalytic activities of several uranyl complexes, such as N,N′-disalicylidene-o-phenelyenediaminato(ethanol)dioxouranium(VI) (UO2(salophen)EtOH), bis(dibenzoylmethanato)(ethanol)dioxouranium(VI) (UO2(dbm)2EtOH), pentakis(N,N-dimethylformamide)dioxouranium(VI) ([UO2(DMF)5]2+), and tetrakis(triphenylphosphine oxide)dioxouranium(VI) ([UO2(OPPh3)4]2+), were examined in the nucleophilic acyl substitution of acid anhydrides. Among them, [UO2(OPPh3)4]2+ was the most efficient to give ethyl acetate and acetic acid from acetic anhydride (Ac2O) and ethanol, and was resistant towards decomposition during the catalytic reaction. Several nucleophiles were also subjected to the catalytic acylation reaction using acetic and pivalic anhydride. Kinetic and spectroscopic studies suggested that [UO2(OPPh3)4]2+ interacts with Ac2O to form [UO2(Ac2O)(OPPh3)3]2+. Interaction of this actual catalyst with additional Ac2O determines the rate of the overall nucleophilic acyl substitution reaction.

Objective The use of the BisGMA as base monomer in dental composites has been questioned because of bisphenol A (BPA) is used as raw material in its synthesis, and BPA possess estrogenic potential associated to several health problems. This study describes the synthesis of the trimethacrylate tris(4-hydroxyphenyl)methane triglycidyl methacrylate (TTM) monomer and evaluate its effect when used as base monomer in the formulation of experimental photopolymerizable composite resins. Methods The TTM monomer was synthesized by a nucleophilic acyl substitution. Its chemical structure was confirmed via 1H and 13C NMR spectroscopy and FTIR spectroscopy. Experimental composite resins were formulated by mixing TTM, triethyleneglycol dimethacrylate (TEGDMA) and inorganic fillers. A BisGMA/TEGDMA based composite resin was prepared and used as control to compare several physicochemical properties. Cell viability assay was used for cytotoxicity evaluation. Results TTM was successfully synthesized with quantitative yields. The results showed that the TTM-based composite resin had similar values of flexural strength, elastic modulus, degree of conversion and polymerization shrinkage than the control (p > 0.05). Water sorption and solubility were statistically significantly higher than the control (p Significance TTM monomer could be potentially useful in the formulation of BisGMA free composite resins, which could mean to minimize the human exposure to BPA.

Microwave-assisted nucleophilic acyl substitution was employed to obtain thiourea derivatives (3a, 3b, 3c) from m-methoxycinnamic acid (1). This synthesis method successfully yielded 60-70% reaction product. In vivo anti-angiogenic evaluation was conducted by chick chorioallantoic membrane model, by which each of the derivative at dose 30, 60, and 90 µg induced by bFGF and compared to celecoxib 60 µg as positive control. It was found that all of the synthesized compound at the tested dose were able to inhibit neovascularization and formation of endothelial cell of new blood vessels by 51-75%. In silico analysis predicted that the anti-angiogenesis mechanism of all the synthesized compounds is through the inhibition of EGFR kinase and COX-2. N atom acts as hydrogen bonding acceptor by residue Gly526 of COX-2. While thiourea moieties of 3a-c have hydrophobic interaction by residues Ser530, Tyr385, and Leu352. In addition, the carbonyl group of thiourea of compound 3a-c inhibit EGFR kinase through the interaction with lys745. The pKCSM data revealed that 3a-c absorbed in intestine by 89-92%, and acut toxicity in rat category 4, suggesting that the compounds show good absorption, and low toxicity. In conclusion, this study successfully synthesized thiourea derivatives, which have anti-angiogenesis activity, tested by CAM model.

The crystal structures of two multidentate CMPO-containing organic ligands are described. Both compounds feature N—H⋯O hydrogen bonds in the solid state., Two bis-carbamoyl­methyl­phosphine oxide compounds, namely {[(3-{[2-(di­phen­yl­phosphino­yl)ethanamido]­meth­yl}benz­yl)carbamo­yl]meth­yl}di­phenyl­phos­phine oxide, C36H34N2O4P2, (I), and diethyl [({2-[2-(di­eth­oxy­phosphino­yl)ethanamido]­eth­yl}carbamo­yl)meth­yl]phospho­nate, C14H30N2O8P2, (II), were synthesized via nucleophilic acyl substitution reactions between an ester and a primary amine. Hydrogen-bonding inter­actions are present in both crystals, but these inter­actions are intra­molecular in the case of compound (I) and inter­molecular in compound (II). Intra­molecular π–π stacking inter­actions are also present in the crystal of compound (I) with a centroid–centroid distance of 3.9479 (12) Å and a dihedral angle of 9.56 (12)°. Inter­molecular C—H⋯π inter­actions [C⋯centroid distance of 3.622 (2) Å, C—H⋯centroid angle of 146°] give rise to supra­molecular sheets that lie in the ab plane. Key geometric features for compound (I) involve a nearly planar, trans-amide group with a C—N—C—C torsion angle of 169.12 (17)°, and a torsion angle of −108.39 (15)° between the phosphine oxide phospho­rus atom and the amide nitro­gen atom. For compound (II), the electron density corresponding to the phosphoryl group was disordered, and was modeled as two parts with a 0.7387 (19):0.2613 (19) occupancy ratio. Compound (II) also boasts a trans-amide group that approaches planarity with a C—N—C—C torsion angle of −176.50 (16)°. The hydrogen bonds in this structure are inter­molecular, with a D⋯A distance of 2.883 (2) Å and a D—H⋯A angle of 175.0 (18)° between the amide hydrogen atom and the P=O oxygen atom. These non-covalent inter­actions create ribbons that run along the b-axis direction.

A wide range of chemicals such as amides, hydrazides, amines, alcohols, carbazate, and sulfonate were reacted with acyl isocyanates generated by the reaction of primary amides with oxalyl chloride to give symmetrical and unsymmetrical diacyl urea derivatives, acyl ureas/carbamates/thiocarbamates, and related compounds. This method provides means for convenient one-pot, two-step synthesis of compounds bearing urea, carbamate, and other functional groups from cheap and commercially available starting reagents. It is expected that the results presented in this report will expand the medicinal chemist’s toolbox.

This paper reports a computational study elucidating the reaction mechanism for ynamide-mediated amide bond formation from carboxylic acids and amines. The mechanisms have been studied in detail for ynamide hydrocarboxylation and the subsequent aminolysis of the resulting adduct by an amine. Ynamide hydrocarboxylation is kinetically favorable and thermodynamically irreversible, resulting in the formation of a key low-lying intermediate CP1 featuring geminal vinylic acyloxy and sulfonamide groups. The aminolysis of CP1 by the amine is proposed to be catalyzed by the carboxylic acid itself that imparts favourable bifunctional effects. In the proposed key transition state TSaminolysis-acid-iso2, the amine undergoes direct nucleophilic substitution at the acyl of CP1 to replace the enolate group in a concerted way, which is promoted by secondary hydrogen bonding of carboxylic acid with both the amine and CP1. These secondary interactions are suggested to increase the nucleophilicity of the amine and to activate the Cacyl-O bond to be cleaved, thereby stabilizing the aminolysis transition state. The concerted aminolysis mechanism is competitive with the classic stepwise nucleophilic acyl substitution mechanism that features sequential amine addition to acyl/intramolecular proton transfer/C-O bond cleavage and a key tetrahedral intermediate. Based on the mechanistic model, the carboxylic acid substrate effect and studies of more acidic CF3SO3H as the catalyst are in good agreement with the experimental observations, lending further support for the mechanistic model. The bifunctional catalytic effect of the carboxylic acid substrate may widely play a role in related amide bond-forming reactions and peptide formation chemistry.

Amides are of fundamental interest in many fields of chemistry involving organic synthesis, chemical biology and biochemistry. Here, we report the first catalytic Buchwald-Hartwig coupling of both common esters and amides by highly selective C(acyl)-X (X = O, N) cleavage to rapidly access aryl amide functionality via a cross-coupling strategy. Reactions are promoted by versatile, easily prepared, well-defined Pd-PEPPSI type precatalysts, and proceed in good to excellent yields and with excellent chemoselectivity for the acyl bond cleavage. The method is user friendly because it employs commercially-available, moisture- and air-stable precatalysts. Notably, for the first time we demonstrate selective C(acyl)-N and C(acyl)-O cleavage/Buchwald-Hartwig amination under the same reaction conditions, which allows for streamlining amide synthesis by avoiding restriction to a particular acyl metal precursor. Of broad interest, this study opens the door to using a family of well-defined Pd(ii)-NHC precatalysts bearing pyridine "throw-away" ligands for the selective C(acyl)-amination of bench-stable carboxylic acid derivatives.

Acyl isoselenocyanates, prepared by acyl chlorides and potassium selenocyanate, are trapped by pyridin-2-amine to afford 4-substituted pyrido[1,2-a][1,3,5]triazine-2-selenone in moderate to good yields.

The use of PhSZnBr as sulfenylating agent in a solvent-free protocol to prepare thiol esters in excellent yields from acyl chlorides is reported. The products were efficiently obtained by grinding the neat reagents for 5 min in a mortar. DFT calculations showed that the coordination of solvent molecules to the metal center of PhSZnBr results in the destabilization of the frontier MOs, thus reducing the reactivity towards the acyl chloride compared with solvent-free conditions. A possible mechanism based on the coordination of the carbonyl group of the acyl chloride to the metal center of PhSZnBr is proposed.

α-(Chloromethyl)acryloyl chloride was polymerized with various bisphenols and diamines to yield poly(conjugated ester)s. The polymer prepared from bisphenol Z underwent curing by heating at 170 °C, while copolymerization with methyl methacrylate afforded a crosslinked polymer. The poly(conjugated ester)s were chemically decomposed via main-chain scission by the conjugate substitution with benzyl mercaptan. Moreover, the treatment with 5 wt% aqueous ammonia resulted in complete main-chain scission to the monomeric units by conjugate substitution and acyl substitution reaction, recovering bisphenol Z. Although curing and main-chain scission resulted in contractive changes on polymer properties, both reactions were achieved by a same skeleton, α-(aryloxymethyl)acrylate. Thus, α-(chloromethyl)acryloyl chloride is the smallest monomer to incorporate such a curable and degradable skeleton.

(Z) Enol triflates 6, 11b-d, (E) enol triflate 11e, and phenol triflate 11a, derived from β-keto esters or 2-carboalkoxy phenols, respectively, react with N-Boc 2-lithiopyrrolidine (5a), N-Boc N-methylaminomethyllithium (5b), or 2-lithio-1,3-dithiane (14) to afford 3(2H)-furanones in modest to good yields (38-81%). Product and carbanion reagent studies suggest that the 3(2H)-furanone is formed in a cascade of reactions involving nucleophilic acyl substitution, enolate formation, trifluoromethyl transfer, iminium or sulfenium ion formation, and subsequent ring closure to form the 3(2H)-furanone. The use of 2-lithio-1,3-dithiane affords a cyclic α-keto-S,S,O-orthoester in which the functionality can be selectively manipulated for synthetic applications.

The reaction of Na(OCP) with mesitoyl chloride delivers an ester functionalized 1,2,4-oxadiphosphole in a clean and P-atom economic way. The reaction mechanism has been elucidated by means of detailed NMR-spectroscopic, kinetic and computational studies. The initially formed acyl phosphaketene undergoes a pseudo-coarctate cyclization with an (OCP)− anion under the loss of carbon monoxide to yield a five-membered ring anion. Subsequently, the nucleophilic attack of the formed heterocyclic anion on a second acyl chloride molecule results in the 1,2,4-oxadiphosphole. The transient acyl phosphaketene is conserved during the reaction in the form of four-membered ring adducts, which act as a reservoir. Consequently, the phosphaethynolate anion has three different functions in these reactions: it acts as a nucleophile, as an en-component in [2 + 2] cycloadditions and as a formal P− transfer reagent., Chemical Science, 7 (9), ISSN:2041-6520, ISSN:2041-6539

Insertion of acyl cyanides into azazirconacyclopentenes derived from 1,3-azadienes has been described, which affords acyl- or non-acyl-substituted pyrroles upon acidic quenching. These reactions are initialized through C═O insertion into the azazirconacycle to afford seven-membered oxaazazirconacycles. In the cases of 1,4- or 1,2,4-substituted azadienes, addition of a second molecule of acyl cyanide followed by cyclization upon acidic quenching leads to acyl-substituted pyrroles. In the cases of 1,3,4-substituted azadienes, the addition of a second molecule of acyl cyanide cannot proceed due to the steric hindrance caused by the R3 group on the zirconium intermediate. Acidic quenching of the resulting zirconium intermediate affords non-acyl-substituted pyrroles.

The feasibility of the cyclization of γ-alkylthiobutyric acid derivatives to form previously unknown five-membered-ring acyl sulfonium cations was studied. Experimental results were in good agreement with our DFT calculations that predicted such cyclizations to be easy if starting with acyl iodides and mixed anhydrides of triflic acid. Particularly efficient were the reactions of γ-alkylthiobutyryl fluorides with trimethylsilyl triflate in CDCl3 solution, which led to cyclic acyl sulfonium triflates. In some cases, the observed acyl sulfonium salts were stable enough to be characterized by NMR spectroscopy. They were found to be both alkyl-transfer reagents and acylating agents. They react with amines to form amides. These findings lend some weight to our hypothesis that the acyl sulfonium derived from methionine may have played a major role in the prebiotic synthesis of the first peptides on the primitive Earth.

A density functional theory investigation of the PPh3-catalyzed formation of amides from benzoic acid was explored. The results confirm the involvement of a phosphonium intermediate that is crucial to activate the carboxylate for nucleophilic acyl substitution.

Soft matter nanoparticles exhibiting rich polymor- phism with reactive pentafluorophenyl methacrylate (PFPMA) units in their coronae were prepared via non-polar reversible addition-fragmentation chain transfer dispersion polymerization and polymerization-induced self-assembly. Poly(stearyl methac- rylate-stat-PFPMA) macro-CTAs, containing up to 12 mol % PFPMA, were used in n-octane and n-tetradecane for the subse- quent copolymerization of 3-phenylpropyl methacrylate. Both formulations gave the full, common family of nanoparticles (spheres, worms, and vesicles) as determined by transmission electron microscopy. Reaction of the PFP ester repeating units in the coronal layer of spherical nanoparticles with benzylamine, tetrahydrofurfurylamine, N,N-dimethylethylenediamine, and an amine functional methyl red dye yielded a new library of func- tional spherical nano-objects. The success of the nucleophilic acyl substitution reactions was confirmed using a combination of 1 H/ 19 F NMR and Fourier transform infrared spectroscopies as well as dynamic light scattering. V C 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015, 00, 000-000

The mechanistic aspects of the one-pot C-acylation of cyclic 1,3-diones are discussed. Using various substituted carboxylic acids, coupling agents and basic catalysts we aim to describe the process of direct transfer of an acyl group to the activated C-2 carbon of dimedone and 1,3-cyclohexanedione. The course of acylation was studied by high-performance liquid chromatography as well as on-line infrared spectroscopy. The results indicate that the direct acylation follows a nucleophilic acyl substitution mechanism rather than a nucleophilic attack on a ketene intermediate formed in situ from the activated carboxylic acid.

A new method including the sequence of a C N bond formation of β-keto amides with N,N-dimethylamides and subsequently another two C N bonds cleavage has been developed in the presence of hydrochloric acid. The method allows us to synthesize a wide range of R-benzyl formamides and acetamides and provides a potential strategy to construct various different acyl and aryl R-phenyl amide compounds.

Herein we report interesting reactivity of imidazole carbamate towards nucleophilic substitution with halide ions under Bronsted acidic conditions. Depending upon reaction conditions, halide ions could readily attack the carboxyl position and trigger decarboxylative alkyl halide formation. Alternatively, halide ions were also found to competitively undergo nucleophilic acyl substitution, which ultimately results in the generation of carbonate dimerization product.

A simple one-pot synthesis of highly functionalized 1,2,4-diselenazolidines is described. Treatment of an acyl chloride with potassium selenocyanate in acetone gave an acyl isoselenocyanate and propane-2-selone, which both reacted with benzylamine or its derivatives to give the required products.

A new method for cysteine–lysine cross-linking in peptides and proteins using palladium oxidative addition complexes is presented. First, a biarylphosphine-supported palladium reagent is used to transfer an aryl group bearing an O-phenyl carbamate substituent to a cysteine residue. Next, this carbamate undergoes chemoselective acyl substitution by a proximal lysine to form a cross-link. The linkage so formed is stable toward acid, base, oxygen, and external thiol nucleophiles. This method was applied to cross-link cysteine with nearby lysines in sortase A*. Furthermore, we used this method for the intermolecular cross-linking between a peptide and a protein based on the p53-MDM2 interaction. These studies demonstrate the potential for palladium-mediated methods to serve as a platform for the development of future cross-linking techniques for peptides and proteins with natural amino acid residues.

A series of benzothiazole amide derivatives were synthesized through a facile and efficient method via a nucleophilic acyl substitution reaction between 2-aminobenzothiazole and various cinnamic acid compounds. The obtained products exhibited good thermal stabilities. All compounds were evaluated for their in vitro hemostatic activities using the commercially available standard drug etamsylate as a positive control. The results showed that compound Q2 had a significant partial coagulation activity, reduced capillary permeability at 5, 10 and 50 μmol L−1, activated thrombin activity, and a more potent platelet aggregation activity than the positive control group (etamsylate, up to 1283.9 times in the nanomole range). A molecular modeling study revealed that compound Q2 was a competitive thrombin activator. Therefore, Q2 may be a potential lead for further biological screening and for the generation of drug molecules. Moreover, the structure–activity relationship of the prepared compounds is also discussed herein.

While thioesters are common intermediates in biochemical processes, they are much less appreciated in organic synthesis, also compared to other carboxylic acid derivatives. However, their chemistry and reactivity is intriguing and diversified, reaching much further than the acyl substitution and aldol chemistry. Herein, we focus on metal-catalyzed reactions for the synthesis of thioesters as well as their transformations. Reactions such as thiocarbonylation, cross-coupling, decarbonylation, allylic substitution or dual photoredox/metal catalysis are discussed. On one hand, new atom economic methods allow for convenient synthesis of thioesters from well available starting materials. On the other hand, various synthetically important compounds can by synthesized due to the multifaceted reactivity of thioesters that we aimed to depict.

The aim of this study was to synthesize and characterize fatty acid-grafted-chitosan (fatty acid-g-CS) polymer and their nanomicelles for use as carriers for gene delivery. CS was hydrophobically modified using saturated fatty acids of increasing fatty acyl chain length. Carbodiimide along with N-hydroxysuccinimide was used for coupling carboxyl group of fatty acids with amine groups of CS. Proton nuclear magnetic resonance and Fourier transform infrared spectroscopy were used to quantify fatty acyl substitution onto CS backbone. The molecular weight distribution of the synthesized polymers was determined using size exclusion high performance liquid chromatography and was found to be in range of the parent CS polymer (∼50 kDa). The critical micelle concentration (cmc) of the polymers was determined using pyrene as a fluorescent probe. The cmc was found to decrease with an increase in fatty acyl chain length. The amphiphilic fatty acid-g-CS polymers self-assembled in an aqueous environment to form nanomicelles of ∼200 nm particle size and slightly positive net charge due to the cationic nature of free primary amino groups on CS molecule. These polymeric nanomicelles exhibited excellent hemo- and cytocompatibility, as evaluated by in vitro hemolysis and MTT cell viability assay, respectively, and showed superior transfection efficiency compared to unmodified chitosan and naked DNA. The surface of these nanomicelles can be further modified with ligands allowing for selective targeting, enhanced cell binding, and internalization. These nanomicelles can thus be exploited as potential nonviral gene delivery vectors for safe and efficient gene therapy.

Macrolactonization of natural product analogs presents a significant challenge to both biosynthetic assembly and synthetic chemistry. In the preceding paper, we identified a thioesterase (TE) domain catalytic bottleneck processing unnatural substrates in the pikromycin (Pik) system, preventing the formation of epimerized macrolactones. Here, we perform molecular dynamics (MD) simulations showing the epimerized hexaketide was accommodated within the Pik TE active site; however, intrinsic conformational preferences of the substrate resulted in predominately unproductive conformations, in agreement with the observed hydrolysis. Accordingly, we engineered the stereospecific Pik TE to yield a variant (TES148C) with improved reaction kinetics and gain-of-function processing of an unnatural, epimerized hexaketide. Quantum mechanical (QM) comparison of model TES148C and TEWT reaction coordinate diagrams revealed a change in mechanism from a stepwise addition-elimination (TEWT) to a lower energy concerted acyl substitution (TES148C), accounting for the gain-of-function and improved reaction kinetics. Finally, we introduced the S148C mutation into a polyketide synthase module (PikAIII-TE) to impart increased substrate flexibility, enabling the production of diastereomeric macrolactones.

A novel three-component reaction of pyridine N-oxides, acyl chlorides, and cyclic ethers is described. Treatment of an electron-deficient pyridine N-oxide with an acyl chloride in the presence of a cyclic ether at 25–50 °C leads to a substituted pyridine as a single regioisomer in up to 58% isolated yield. Isotopic-labeling experiments and substrate scope support the reaction proceeding through a carbene intermediate.

A unique, platinum-catalyzed, direct C–H acylation of 2-(aryloxy)pyridines with acyl chlorides is discovered. The reaction requires neither an oxidant nor other additives. When both ortho positions of the aryl group are accessible, the double acylation occurs readily to produce the diacylated products. Aliphatic, aromatic, and α,β-unsaturated acyl groups can all be introduced. The acylation reaction may proceed through an analogous aromatic electrophilic substitution triggered by the nucleophilic attack of the platinum at the acyl chloride.

The first chemical study of the common species Terrazoanthus onoi, present off the coast of Ecuador, led to the identification of a new family of 2-aminoimidazole alkaloids named terrazoanthines A-C (1-3). Homologues 1 and 2 feature an unprecedented 6-(imidazol-5-yl)benzo[d]-imidazole. Acyl substitution pattern and complete configurational assignments were deduced from comparison between experimental and theoretical C-13 NMR and ECD data, respectively. These compounds may represent key derivatives in the biosynthesis of zoanthoxanthins.

The synthesis of hydantoins and dihydrouracils from ureidoacetamides has been carried out at high temperature in glycol solvents. A series of substrates were prepared and examined to determine the effect of substrate structure, N -acyl substitution (X), and solvent on the course of the reaction. A dramatic effect was observed when using ureidoacetamides (e.g., X= N -methyl- N -phenyl), which led to higher yields, faster reaction times, and lower racemization of chiral substrates. The rate of racemization of a chiral hydantoin in the presence of dibenzylamine and N -methyl aniline has also been determined. The thermal cyclization methodology has been applied to the preparation of a complex hydantoin.

In this laboratory experiment, students work in pairs to synthesize a simple aliphatic polycarbonate via ring-opening polymerization of trimethylene carbonate using 1,8-diazabicyclo[5.4.0]undec-7-ene and thiourea as organocatalysts. Following polymer isolation, students cool the material in a dry ice/acetone bath to observe its glass-transition behavior. This experiment is convenient to perform under teaching laboratory conditions and reinforces key concepts learned in second-year undergraduate organic chemistry, for example, nucleophilic acyl substitution, transesterification reactions, and Lewis acidity–basicity. Additionally, the experiment introduces students to polymer chemistry, heterocycles, materials science, and green chemistry. It also covers interesting concepts that are less frequently encountered at the undergraduate level such as biomimetic chemistry, bifunctional catalysis, and polymer–glass transitions.

Benzoyl peroxide is used as a bleaching agent for flour and whey processing, a polymerization initiator in the synthesis of plastics, and the active component of acne medication. Because of its simplicity and wide application, benzoyl peroxide is a target molecule of interest. It can be affordably synthesized in three steps from bromobenzene using procedures that can be performed in four, 4 h laboratory periods. This process includes a Grignard reaction to turn bromobenzene into benzoic acid, nucleophilic acyl substitution to transform the resulting carboxylic acid into an acid chloride, and the addition of H2O2/NaOH to the acid chloride to yield benzoyl peroxide. Most organic chemistry students are familiar with these traditional reaction mechanisms because they are covered in introductory organic chemistry courses. The starting materials for each reaction are commercially available, and the products can be readily characterized using NMR spectroscopy, IR spectroscopy, and melting point.

In this paper, we report a novel and efficient route for the synthesis of 5-nitrobenzoxazole derivatives starting from 2-fluoro-5-nitroaniline and various benzoyl chloride derivatives under solvent-free conditions at 130 °C in the presence potassium carbonate. Benzoyl chlorides easily underwent nucleophilic acyl substitution followed by intramolecular cyclization via concomitant removal of fluorine to obtain the title compounds in high yields.

Phosphinocatalysis provides a new approach toward 3-substituted-4-quinolones. A simple procedure, which uses Ph3P as an inexpensive catalyst and S-phenyl 2-(N-tosylamido)benzothioates and activated alkynes as starting materials, provides direct access to several 3-aroyl-4-quinolones and methyl 4-quinolone-3-carboxylate esters. The reaction presumably occurs through general base catalysis, with the initial addition of Ph3P to the activated alkyne generating the phosphonium enoate zwitterion, which acts as the strong base that initiates the reaction.