Nucleophilic Acyl Substitution Research Articles

Divergent Transformations of Aromatic Esters: Decarbonylative Coupling, Ester Dance, Aryl Exchange, and Deoxygenative Coupling.

ConspectusAromatic esters are cost-effective, versatile, and commonly used scaffolds that are readily synthesized or encountered as synthetic intermediates. While most conventional reactions involving these esters are nucleophilic acyl substitutions or 1,2-nucleophilic additions─where a nucleophile attacks the carbonyl group, decarbonylative transformations offer an alternative pathway by using the carbonyl group as a leaving group. This transition-metal-catalyzed process typically begins with oxidative addition of the C(acyl)-O bond to the metal. Subsequently, the reaction involves the migration of CO to the metal center, the reaction with a nucleophile, and reductive elimination to yield the final product. Pioneering work by Yamamoto on nickel complexes and the development of decarbonylative reactions (such as Mizoroki-Heck-type olefination) using aromatic carboxylic anhydrides catalyzed by palladium were conducted by de Vries and Stephan. Furthermore, reports have surfaced of decarbonylative hydrogenation of pyridyl methyl esters by Murai using ruthenium catalysts as well as Mizoroki-Heck-type reactions of nitro phenyl esters by Gooßen under palladium catalysis. Our group has been at the forefront of developing decarbonylative C-H arylations of phenyl esters with 1,3-azoles and aryl boronic acids using nickel catalysts. The key to this reaction is the use of phenyl esters, which are easy to synthesize, stabilize, and handle, allowing oxidative addition of the C(acyl)-O bond; nickel, which facilitates oxidative addition of the C(acyl)-O bond; and suitable bidentate phosphine ligands that can stabilize the intermediate. By modification of the nucleophiles, esters have been effectively utilized as electrophiles in cross-coupling reactions, encouraging the development of these nucleophiles among researchers. This Account summarizes our advancements in nucleophile development for decarbonylative coupling reactions, particularly highlighting the utilization of aromatic esters in diverse reactions such as alkenylation, intramolecular etherification, α-arylation of ketones, C-H arylation, methylation, and intramolecular C-H arylation for dibenzofuran synthesis, along with cyanation and reductive coupling. We also delve into reaction types that are distinct from typical decarbonylative reactions, including ester dance reactions, aromatic ring exchanges, and deoxygenative transformations, by focusing on the oxidative addition of the C(acyl)-O bond of the aromatic esters to the metal complex. For example, the ester dance reaction is hypothesized to undergo 1,2-translocation starting with oxidative addition to a palladium complex, leading to a sequence of ortho-deprotonation/decarbonylation, followed by protonation, carbonylation, and reductive elimination. The aromatic exchange reaction likely involves oxidative addition of complexes of different aryl electrophiles with a nickel complex. In deoxygenative coupling, an oxidative addition complex with palladium engages with a nucleophile, forming an acyl intermediate that undergoes reductive elimination in the presence of an appropriate reducing agent. These methodologies are poised to captivate the interest of synthetic chemists by offering unconventional and emerging approaches for transforming aromatic esters. Moreover, we demonstrated the potential to transform readily available basic chemicals into new compounds through organic synthesis.

Amine-Carbamate Self-Immolative Spacers Counterintuitively Release 3° Alcohol at Much Faster Rates than 1° Alcohol Payloads.

Self-immolative (SI) spacers are degradable chemical connectors widely used in prodrugs and drug conjugates to release pharmaceutical ingredients in response to specific stimuli. Amine-carbamate SI spacers are particularly versatile, as they have been used to release different hydroxy cargos, ranging from 2° and 3° alcohols to phenols and oximes. In this work, we describe the ability of three amine-carbamate SI spacers to release three structurally similar imidazoquinoline payloads, bearing either a 1°, a 2° or a 3° alcohol as the leaving group. While the spacers showed comparable efficacy at releasing the 2° and 3° alcohols, the liberation of the 1° alcohol was much slower, unveiling a counterintuitive trend in nucleophilic acyl substitutions. The release of the 1° alcohol payload was only possible using a SI spacer bearing a pyrrolidine ring and a tertiary amine handle, which opens the way to future applications in drug delivery systems.

Transition‐Metal Free, One Pot Synthesis of Selenoesters via Reaction of Alkyl Selenides and Acyl Chlorides

AbstractHerein, we report a new and efficient method for the synthesis of selenoesters by a direct coupling reaction of alkyl selenides with acyl chlorides in ethanol under transition metal‐free conditions. This nucleophilic acyl substitution afforded selenoesters in good yields. Traditionally, synthesis of selenoesters involve the reaction of acyl chlorides with an organoselenium anions generated in situ through the reductive cleavage of previously prepared diselenides. Our one‐pot approach avoids the pre‐preparation of diselenides and operated in atom‐economical and environmentally friendly conditions. The synthetic utility of these selenoesters was studied using Se‐butyl benzoselenoate as substrate in a Sonogashira‐type cross‐coupling reaction.

Synthesis of 1,2,3-Triazole-Containing Methoxylated Cinnamides and Their Antileishmanial Activity against the Leishmania braziliensis Species.

Leishmaniasis is a group of infectious diseases caused by protozoan parasites that belong to the genus Leishmania. Currently, there is no human vaccine, and the available treatments are associated with toxicity, high cost, and the emergence of resistant strains. These factors highlight the need to identify new antileishmanial candidates. In this study, we synthesized twenty-four methoxylated cinnamides containing 1,2,3-triazole fragments and evaluated their antileishmanial activity against the Leishmania braziliensis species, which is the main etiological agent responsible for American Tegumentary Leishmaniasis (ATL). The cinnamides were synthetically prepared using nucleophilic acyl substitution and copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reactions. The compounds were characterized using infrared, nuclear magnetic resonance, and high-resolution mass spectrometry techniques. We performed preliminary studies to evaluate the biological activity of these compounds against L. braziliensis promastigotes and axenic amastigotes. Compound 28, N-((1-(7-(diethylamino)-2-oxo-2H-chromen-3-yl)-1H-1,2,3-triazole-4-yl) methyl)-3,4-dimethoxy cinnamide, demonstrated relevant antileishmanial activity with low toxicity in murine cells. The selectivity index values for this compound were superior compared with data obtained using amphotericin B. Furthermore, this cinnamide derivative reduced the infection percentage and number of recovered amastigotes in L. braziliensis-infected macrophages. It also induced an increase in reactive oxygen species production, depolarization of the mitochondrial potential, and disruption of the parasite membrane. Taken together, these findings suggest that this synthetic compound holds potential as an antileishmanial candidate and should be considered for future studies in the treatment of ATL.

Real-Time Monitoring of Reactions by Headspace Sampling under Ambient Mass Spectrometric Conditions

The helium-plasma (HePI) ionization mass spectrometry method was used to track the formation of reaction products and consumption of reactants by continually monitoring the vapors in the reaction headspace in real time. Two examples of the application procedure are presented here: a nucleophilic acyl substitution reaction and a 1,4-nucleophilic addition process. For the purposes of the work, a specially constructed helium-plasma ionization (HePI) source was mounted on a single-quadrupole benchtop mass spectrometer. However, any electrospray source is easily convertible to an ambient HePI source. This setup has the potential to be used in the teaching of organic and analytical chemistry laboratories, as well as for demonstrations. Because the procedure requires only the headspace of the reaction vessel to be sampled by an easily prepared Venturi suction device (pump), the experiments can be quickly set up and adapted for any available mass spectrometer equipped with an electrospray source. For sampling, students can be shown how to prepare their own Venturi pumps and conduct reactions at different temperatures.

Synthesis and preliminary pharmacological profile of some new 3,5-dihydro-4H-imidazol-4-one and α,β-dehydroamino acid derivatives

A new series of 3,5-dihydro-4H-imidazol-4-one derivatives incorporating thiazole moiety have been readily prepared through the nucleophilic acyl substitution reactions of 5(4H)-oxazolones derivatives (2A-2J) with 4-(benzo[d]thiazol-2-yl) aniline (3) using a simple synthetic strategy under mild condition. Furthermore, the ring opening reaction of same components were examined to afford a new series of α,β-dehydroamino acid derivatives (4A-4J) in good yield. The preliminary pharmacological profile of all newly synthesized compounds were evaluated in vitro for their antibacterial and antifungal activities using micro broth dilution assay method, and it was revealed that most of the synthesized derivatives were exhibiting promising pharmacological activities against both strains. The structures of the newly synthesized 3,5- dihydro-4H-imidazol-4-one (5A-5J)) and α,β-dehydroamino acid derivatives (4A-4J) were expounded and elucidated on the bases of their FT-IR, 1H- and 13C –NMR spectral data.

Synthesis and evaluation of newly E-octadec-9-enoic acid derivatives as sustainable corrosion inhibitors for mild steel in 1.0 M HCl

Several new amide derivatives having varied aromatic characteristics prepared efficiently via nucleophilic acyl substitution reactions are tested for corrosion inhibition of mild steel in 1 M HCl at 20, 40, and 60 °C range by gravimetric methods. All compounds have shown very good inhibition efficiency (IE%) in acidic solutions. Increasing the temperature (in the presence of the inhibitor in the higher concentration (100–1000 μM) are found to increase the inhibition efficiency of the amide’s derivatives. Results from gravimetric measurements further revealed that Inh. 4 shows excellently at 60 °C giving IE% of 91.88 at 1000 μM. Thermodynamic parameters (ΔG º ads, ΔH º ads, and ΔS º ads) for the adsorption process and kinetic parameters for the metal dissolution (or hydrogen evolution) reaction in the presence of the new derivatives were determined. Experimental results agree with the Temkin adsorption isotherm. The inhibition of corrosion in 1 M HCl, influenced by both physi- and chemisorption, was found to be under mixed control but predominantly under cathodic control as revealed by the potentiodynamic polarization measurements for Inh. 4. Frontier molecular orbital calculations predicted that the newly synthesized inhibitors with aromatic characteristics serve as donor-centers to the empty d-orbital of the metal atoms and would exhibit higher corrosion IE%.

Synthesis and characterization of 2-Benzamido-NBenzylbenzamide Derivative

Anthranilamide derivatives exhibit anti-inflammatory, antipyretic, antibacterial, antiangiogenic, and anticoagulant properties. With an early in silico examination of its analgesic capabilities, this study aimed to generate a novel anthranilamide molecule by altering 2-Benzamido-N-Benzylbenzamide. Modification of anthranilamide with 1/2/3-chloro benzoyl chloride by acylation resulted in the design, synthesis, characterization, and research of the analgesic effects of 2-benzamido-N-benzoylbenzamide derivatives. 2-(2-chlorobenzamido)-N-(2-chlorobenzoyl)benzamide, 2-(3-chlorobenzamido)-N-(3-chlorobenzoyl)benzamide, and 2-(4-chlorobenzamido)-N-(4-chlorobenzoyl)benzamide were prepared. The nucleophilic acyl substitution reaction method was used to prepare these three chemicals by interaction with anthranylamide and benzoyl chloride molecules. Melting point and thin-layer chromatography were used to check the purity of the synthesis fi ndings. The structure was confi rmed by UV-Vis and infrared spectrophotometry.

Catalytic Enantioselective Entry to Triflones Featuring a Quaternary Stereocenter.

A highly enantioselective one-pot synthesis of functionalized triflones, bearing a quaternary stereocenter, has been developed, exploiting the Michael reaction of α-(trifluoromethylsulfonyl) aryl acetic acid esters with N-acryloyl-1H-pyrazole catalyzed by commercially available Takemoto’s catalyst, followed by nucleophilic acyl substitution with alcohols. Preliminary investigations highlighted the attractive potential of the triflinate anion as the leaving group for stereocontrolled postfunctionalizations.

Thionyl Fluoride-Mediated One-Pot Substitutions and Reductions of Carboxylic Acids.

Thionyl fluoride (SOF2) is an underutilized reagent that is yet to be extensively studied for its synthetic applications. We previously reported that it is a powerful reagent for both the rapid syntheses of acyl fluorides and for one-pot peptide couplings, but the full scope of these nucleophilic acyl substitutions had not been explored. Herein, we report one-pot thionyl fluoride-mediated syntheses of peptides and amides (35 examples, 45-99% yields) that were not explored in our previous study. The scope of thionyl fluoride-mediated nucleophilic acyl substitutions was also expanded to encompass esters (24 examples, 64-99% yields) and thioesters (11 examples, 24-96% yields). In addition, we demonstrate that the scope of thionyl fluoride-mediated one-pot reactions can be extended beyond nucleophilic acyl substitutions to mild reductions of carboxylic acids using NaBH4 (13 examples, 33-80% yields).

Protein Synthesis via Activated Cysteine-Directed Protein Ligation.

Proteins with a functionalized C-terminus are critical to synthesizing large proteins via expressed protein ligation. To overcome the limitations of currently available C-terminus functionalization strategies, we established an approach based on a small molecule cyanylating reagent that chemically activates a cysteine in a recombinant protein at its N-side amide for undergoing nucleophilic acyl substitution with amines. We demonstrated the versatility of this approach by successfully synthesizing RNAse H with its RNA hydrolyzing activity restored and in vitro nucleosome build with a C-terminal posttranslational modified histone H2A. This technique will expand the landscape of protein chemical synthesis and its application in new research fields significantly.

Maleated soybean oil derivatives as versatile reactive diluents: Synthesis, characterization, and evaluation

AbstractFour maleated soybean oil (SBO) derivatives were synthesized and used as bio‐based reactive diluents (RDs) for alkyd coating systems. The RDs were prepared in a two‐step fashion: (a) Maleation of SBO with maleic anhydride (MA) via an ene reaction followed by (b) a nucleophilic acyl substitution of the grafted succinic anhydride with allyl‐ or methacrylate‐functional molecules. The structures were characterized using 1H NMR, 13C NMR, 13C‐1H heteronuclear single quantum coherence NMR, 13C‐1H heteronuclear multiple bond correlation NMR spectroscopy, FT‐IR (ATR) spectroscopy, and MALDI‐ToF‐MS. The 2D NMR spectroscopy techniques helped confirm that MA was successfully grafted onto SBO. FT‐IR spectroscopy identified new absorption bands at 1780 and 1850 cm−1, following the maleation reaction, corresponding to the anhydride functionality. Alkyd coating formulations were prepared with either 0, 10, 20, or 30 wt% of the different RDs. Brookfield viscosity measurements were conducted on the formulations to measure the efficiency of the SBO‐based RDs. At 20 wt% loading level, the RDs typically reduced the viscosity of the base alkyd resin by 50%–60%. Coatings tests and gel content measurements were also conducted in order to understand the effects that these RDs had on the performance of the alkyd coatings.

Facile Synthesis of Alkylidene Phthalides by Rhodium-Catalyzed Domino C-H Acylation/Annulation of Benzamides with Aliphatic Carboxylic Acids.

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.

Synthesis and characterization of a benzoyl modified Pebax materials for gas separation applications

Pebax copolymers produced by Arkema are widely employed for different applications, including active molecular carriers and membranes for gas separation. In the present work, a new modification approach for Pebax®2533 is presented, along with the characterization of the newly obtained materials.Pebax was modified by grafting, through a nucleophilic acyl substitution, a benzoyl group on Polyamide12 block. The yield of the reaction was confirmed by FTIR and NMR analysis, while thermal DSC and TGA characterizations were then carried out on the polymeric products characterized by different degrees of substitution to understand their properties. Finally, self-standing films were obtained by casting and gas permeation tests were conducted at 35 °C using CO2, N2, CH4, O2 and He, in order to understand the potentiality of the new material as membrane for gas separation.DSC showed that in the modified Pebax, named “Benzoyl-P2533” (BP2533), the crystalline phase of the Nylon block was canceled, as expected, but at the same time the degree of crystallinity of the block of Polytetramethyleneoxide increased from 19%, measured for the unmodified Pebax, to a max of 35% for the fully substituted material. For this reason, gas permeability showed small but consistent increment, in the order of 10–11% for most of the gas tested, with the only exception being helium, where the increment resulted to be around 48%. As a consequence, the overall selectivity of CO2 against helium dropped with respect to pristine Pebax. For all the other gases, on the other hand the selectivity with respect to CO2 remained substantially constant, resulting in slight but neat improvement of the ability of the new material to separate this gas.

A Fast and General Route to Ketones from Amides and Organolithium Compounds under Aerobic Conditions: Synthetic and Mechanistic Aspects.

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.

Stereoselective Synthesis of Multisubstituted α-fluoro-β-lactams

β-Lactams, found in β-lactam antibiotics, are the structurally distorted cyclic compounds being subjected to nucleophilic acyl substitution reaction. α-Fluorination of β -lactams is a simple and expedient approach to control the reactivity of β-lactam ring toward nucleophilic attack, which would hopefully lead to the new design of future antibiotics. From the viewpoint of obtaining multisubstituted α-fluoro-β-lactams, α-bromo-α- fluoro-β-lactams are considered as key compounds for structure functionalization, including nucleophilic substitution reaction, aldol-type reaction and metal-catalyzed crosscoupling reaction. All the reactions can be conducted smoothly to afford a variety of multisubstituted α-fluoro-β-lactams. During the course of the examination, chiral α,α-difluoro- β-lactams and α -bromo-β-fluoro-α-lactams are successfully obtained, which are considered potent precursors for making stereocontrolled multisubstituted α-fluoro-β-lactams.

Halide-Accelerated Acyl Fluoride Formation Using Sulfuryl Fluoride

Herein, we report a new one-pot sequential method for SO2F2-mediated nucleophilic acyl substitution reactions starting from carboxylic acids. A mechanistic study revealed that SO2F2-mediated acid activation proceeds via the anhydride, which is then converted to the corresponding acyl fluoride. Tetrabutylammonium chloride or bromide accelerate the formation of acyl fluoride. Optimized halide-accelerated conditions were used to synthesize acyl fluorides in 30-80% yields, and esters, amides, and thioesters in 72-96% yields without reoptimization for each nucleophile.

Expressed Protein Ligation without Intein.

Proteins with a functionalized C-terminus such as a C-terminal thioester are key to the synthesis of larger proteins via expressed protein ligation. They are usually made by recombinant fusion to intein. Although powerful, the intein fusion approach suffers from premature hydrolysis and low compatibility with denatured conditions. To totally bypass the involvement of an enzyme for expressed protein ligation, here we showed that a cysteine in a recombinant protein was chemically activated by a small molecule cyanylating reagent at its N-side amide for undergoing nucleophilic acyl substitution with amines including a number of l- and d-amino acids and hydrazine. The afforded protein hydrazides could be used further for expressed protein ligation. We demonstrated the versatility of this activated cysteine-directed protein ligation (ACPL) approach with the successful synthesis of ubiquitin conjugates, ubiquitin-like protein conjugates, histone H2A with a C-terminal posttranslational modification, RNase H that actively hydrolyzed RNA, and exenatide that is a commercial therapeutic peptide. The technique, which is exceedingly simple but highly useful, expands to a great extent the synthetic capacity of protein chemistry and will therefore make a large avenue of new research possible.

Preparation and evaluation of a BisGMA-free dental composite resin based on a novel trimethacrylate monomer

ObjectiveThe 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. MethodsThe 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. ResultsTTM 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 < 0.05), however they complied the requirements stablished by the ISO 4049. Finally, this study shows there were no statistically significant differences for the biocompatibility outcomes (p = 0.345). SignificanceTTM monomer could be potentially useful in the formulation of BisGMA free composite resins, which could mean to minimize the human exposure to BPA.

Preparation, carbonic anhydrase enzyme inhibition and antioxidant activity of novel 7-amino-3,4-dihydroquinolin-2(1H)-one derivatives incorporating mono or dipeptide moiety

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.