Nucleophilic Addition Research Articles

Horner–Wadsworth–Emmons olefination of proteins and glycoproteins

Chemo-selective modifications of proteins are fundamental to the advancement of biological and pharmaceutical sciences. The search for biocompatible chemical reactions has prompted us to investigate Horner–Wadsworth–Emmons (HWE) olefinations, iconic reactions in organic synthesis that would give rise to new selective protein olefinations. Our choice of HWE olefinations was inspired by the growing number of methods for generating aldehydes as transient reactive groups in proteins and the potential for mild and simple reaction conditions. Here we show that HWE olefination reactions on aldehydes, produced by both chemical and enzymatic methods, are compatible with physiological conditions and highly selective in small and large proteins, including therapeutic antibodies and stable recombinant proteins exemplified by green fluorescent protein. Reaction kinetics can be fine-tuned over orders of magnitude both by judicious use of substituents and pH regulation. The electrophilic nature of the HWE olefination products can be tuned to allow for subsequent nucleophilic additions, including thiol- and phospha-Michael additions. Our results demonstrate that HWE olefination of aldehydes in proteins provides efficient and selective bioconjugation chemistries that are orthogonal to existing methods.

Organocatalytic Enantioselective 1,12-Addition of Alkynyl Biphenyl Quinone Methides Formed In Situ.

The chemistry of quinone methides formed in situ has been flourishing in recent years. In sharp contrast, the development and utilization of biphenyl quinone methides are rare. In this study, we achieved a remote stereocontrolled 1,12-conjugate addition of biphenyl quinone methides formed in situ for the first time. In the presence of a suitable chiral phosphoric acid, alkynyl biphenyl quinone methides were generated from α-[4-(4-hydroxyphenyl)phenyl]propargyl alcohols, followed by enantioselective 1,12-conjugate addition with indole-2-carboxylates. The strategy enabled the alcohols to serve as efficient allenylation reagents, providing practical access to a broad range of axially chiral allenes bearing a (1,1'-biphenyl)-4-ol unit, which were previously less accessible. Combined with control experiments, density functional theory calculations shed light on the reaction mechanism, indicating that enantioselectivity originates from the nucleophilic addition of alkynyl biphenyl quinone methides. Notably, not only the presence of biphenyl quinone methides as versatile intermediates was confirmed but also organocatalytic enantioselective 1,12-addition was established.

Organocatalytic Enantioselective 1,12‐Addition of Alkynyl Biphenyl Quinone Methides Formed In Situ

AbstractThe chemistry of quinone methides formed in situ has been flourishing in recent years. In sharp contrast, the development and utilization of biphenyl quinone methides are rare. In this study, we achieved a remote stereocontrolled 1,12‐conjugate addition of biphenyl quinone methides formed in situ for the first time. In the presence of a suitable chiral phosphoric acid, alkynyl biphenyl quinone methides were generated from α‐[4‐(4‐hydroxyphenyl)phenyl]propargyl alcohols, followed by enantioselective 1,12‐conjugate addition with indole‐2‐carboxylates. The strategy enabled the alcohols to serve as efficient allenylation reagents, providing practical access to a broad range of axially chiral allenes bearing a (1,1′‐biphenyl)‐4‐ol unit, which were previously less accessible. Combined with control experiments, density functional theory calculations shed light on the reaction mechanism, indicating that enantioselectivity originates from the nucleophilic addition of alkynyl biphenyl quinone methides. Notably, not only the presence of biphenyl quinone methides as versatile intermediates was confirmed but also organocatalytic enantioselective 1,12‐addition was established.

Accurate control on nucleophilic addition of H2O to internal alkynes: Ag catalyzed regiospecific hydration strategy

In the absence of directing auxiliaries, catalytic addition of nucleophiles to unactivated alkynes with accurate control of regioselectivity remains an ongoing challenge in organic chemistry. Herein, we realized a Ag‐catalysed regiospecific hydration process of unactivated alkynes. Computational investigations offered insights into the origin of the regiochemical outcome. The practicability and efficacy of the protocol was exemplified by its simple reaction conditions without incorporation of acidic additives, as well as the toler‐ance of a wide range of alkynes equipped with various functional groups, leading to the ketone products in up to 98% yield. Direct modification of bioactive organic molecules and gram‐scale experiments further showcased the application potential of the strategy. The catalyst control principles are expected to advance efforts towards the development of general site‐selective addition of nucleophile to unsaturated substrates, removing the requirement for neighboring activating groups.

Fusion of Cyclohepta[def]fluorene Units: Toward Synthesis of High‐Spin Non‐Benzenoid Nanographenes

AbstractNon‐benzenoid diradicaloids possessing high‐spin ground states are attractive synthetic targets given their high potential for spintronics and quantum computing. Nevertheless, the synthesis of such compounds remains highly challenging due to their inherent instability. In this work, we present the synthetic attempt towards creating a non‐benzenoid diradicaloid (1) with a triplet ground state by fusing two cyclohepta[def]fluorene units onto a benzene ring. Our synthetic approach involves both oxidation and reduction pathways. In the oxidation path, we obtained the partially dehydrogenated products 1+H and 1+2H containing an indeno[1,2‐b]fluorene core from the tetrahydro precursor (2). However, further dehydrogenation to afford the target molecule (1) did not proceed. On the other hand, with the reduction pathway, a novel tetraketone precursor (9) with two pairs of pentagons and heptagons was successfully synthesized. The subsequent nucleophilic attack however was proved to be difficult probably due to the unselective nucleophilic addition on the zigzag nanographene ketones. Furthermore, UV‐vis absorption, cyclic voltammetry, and theoretical calculations were conducted to explore the optical, electrochemical properties, and aromaticity of all the obtained molecules (1+H, 1+2H and 9). Although the desired target 1 is not achieved, our work provides insight into designing novel high‐spin non‐benzenoid NGs based on nonalternant cyclohepta[def]fluorene system.

Divergent synthesis of pyrrolizine derivatives through C-H bond functionalization of pyrroles.

Presented herein is the synthesis of diversely functionalized pyrrolizines from the reaction of N-alkoxycarbamoyl pyrroles with CF3-ynones. The formation of the product is based on a C-H bond activation-initiated cascade process including N-alkoxycarbamoyl group-directed alkenylation of the pyrrole scaffold followed by simultaneous intramolecular nucleophilic addition along with cleavage and transfer of the directing group. By taking advantage of the rich chemistry of the transferred alkoxycarbamoyl moiety, the products could be transformed into a series of structurally and biologically interesting pyrrolizine derivatives. To our knowledge, this is the first example in which the N-alkoxycarbamoyl unit acted as a transferable and transformable directing group for the divergent synthesis of pyrrolizines.

Gold-catalyzed Reactions of Substituted 1,5-diynes: Recent Advances and their Chemistry

Abstract: Diynes are identified as exceptionally potent and superior substrates in gold-catalyzed organic transformations. Gold (I) and gold (III) complexes exhibit unique activity towards diynes, encouraging the nucleophilic addition of different functional groups both inter and intra- molecularly. In this review, particularly, we focused on recent advances in gold-catalyzed reactions of 1,5-diynes along with their mechanistic aspects. These reactions are interesting for constructing molecular complexity, medicinal chemistry, and material science.

Activation/Cyclization of 2H‐Azirines and 3‐Amino‐2‐fluoropyridines Towards 2‐Aryl‐Pyrido[2,3‐b]pyrazines

AbstractThe electrophilic activation of 2H‐azirines with triflic anhydride (Tf2O) for an addition/cyclization reaction producing 2‐aryl‐pyrido[2,3‐b]pyrazines regioselectively is described. This reaction proceeds via nucleophilic addition of 3‐amino‐2‐fluoropyridines onto 1‐trifloyl‐aziridin‐2‐yl triflates and subsequent cyclization via SNAr. Desulfonylation and oxidation provides a single regioisomer of the aza‐bicyclic heterocycle after treatment with Et3N. Optimization of the reaction conditions lead to a range of 2‐aryl‐pyrido[2,3‐b]pyrazines in isolated yields of 20 % to 60 %.

Synthesis of Benzo[a]carbazoles and Dibenzo[c,g]carbazoles via Sequential Gold Catalysis and Photomediated Cyclization.

Herein, we report a reaction protocol for the construction of benzo[a]carbazole and dibenzo[c,g]carbazole frameworks. The detailed gold catalytic reaction conditions developed for the challenging intermolecular carbon nucleophilic addition to internal alkynes are realized, giving the desired alkyne hydroarylation products in good yields. The resulting trisubstituted alkenes are able to undergo photomediated cyclization, furnishing the desired carbazole molecules with excellent yields and high efficiency.

Electrochemical Deconstructive and Ring-Expansion Functionalization of Unstrained Cycloalkanols.

An efficient and sustainable electrochemical method for the synthesis of cyclic ethers and acyclic aldehydes from alkanols has been reported. This strategy has been successfully applied to cycloalkanols bearing different ring sizes and different types of nucleophiles. In addition, mechanistic investigations show that the reactions undergo sequential processes, including anodic oxidation, β-scission, and nucleophilic addition. This method provides a new synthetic approach to constructing cyclic ethers and terminal aldehydes from cycloalkanols and nucleophiles.

Synthesis of a Family of Pd(II) Complexes Using Pyridyl-Ketone Ligands: Crystal Structure, Thermal, Physicochemical, XRD/HSA, Docking, and Heck Reaction Application.

Four Pd(II) complexes, (dpk)PdCl2 (complex-1), and (dpk)Pd(OAc)2 (complex-2) have been prepared using di(2-pyridyl) ketone as the chelate ligand (dpk). The (dpk·EtOH)PdCl2 (complex-3) and (dpk·EtOH)Pd(OAc)2 (complex-4) were synthesized by selectively introducing complex-1 and complex-2 to an EtOH in situ nucleophilic addition reaction on the O=C of the dpk ligand, respectively. All complexes were characterized using CHN-EA, UV-vis, FT-IR, FAB-MS, EDX, TGA, and NMR physicochemical tools. The XRD-crystallography technique was employed to ascertain the structure of complex-3. The analysis revealed a monoclinic/P21/c crystal system characterized by a square planar structure oriented in the cis direction around the Pd center. Several C-H···Cl and O-H···O H-bonds constructing 2D-S12 and S7 synthons were confirmed via XRD/HSA interactions. The influence of EtOH addition to the O=C group of dpk in (dpk)PdCl2 was documented by using UV-vis/FT-IR spectra and TGA analysis. As catalysts, all complexes have demonstrated a notable catalytic function in the Heck reaction, resulting in a high yield under gentle conditions using iodobenzene and methyl acrylate as model reactions. Moreover, the complex-1 and complex-3 docking activity was evaluated against 1BNA-DNA.

Total Synthesis of Carbazomycins E and F.

Total synthesis of carbazomycins E and F was achieved by double functionalization of an aryne intermediate generated from a 2-aminobiphenyl derivative. The tethered amino group underwent nucleophilic addition to the aryne intermediate to construct the carbazole skeleton. The resulting carbanion was formylated to give the multiply substituted carbazole. This formyl group caused several problems. For example, it was difficult to perform regioselective demethylation of the methoxy group proximal to the formyl group without protecting the carbazole nitrogen. In addition, the formyl group was unexpectedly reduced to give a methoxymethyl group under heating conditions with copper iodide and sodium methoxide. Oxidation of this compound in the presence of water was effective for obtaining the formylated carbazole, leading to the first total synthesis of carbazomycin F.

CuH-Catalyzed Reductive Coupling of Nitroarenes with Phosphine Oxides for the Direct Synthesis of Phosphamides.

A CuH-catalyzed reductive coupling of nitroarenes with phosphine oxides is developed, which produces a series of phosphamides in moderate to excellent yields with good functional group tolerance. Gram-scale synthesis and late-stage modification of nitro-aromatic functional molecule niclosamide are also successfully conducted. The mechanism study shows that the nitro group is transformed after being reduced to nitroso and a nucleophilic addition procedure is involved during the reaction.

Spontaneous α‐C−H Carboxylation of Ketones by Gaseous CO2 at the Air‐water Interface of Aqueous Microdroplets

AbstractWe present a catalyst‐free route for the reduction of carbon dioxide integrated with the formation of a carbon‐carbon bond at the air/water interface of negatively charged aqueous microdroplets, at ambient temperature. The reactions proceed through carbanion generation at the α‐carbon of a ketone followed by nucleophilic addition to CO2. Online mass spectrometry reveals that the product is an α‐ketoacid. Several factors, such as the concentration of the reagents, pressure of CO2 gas, and distance traveled by the droplets, control the kinetics of the reaction. Theoretical calculations suggest that water in the microdroplets facilitates this unusual chemistry. Furthermore, such a microdroplet strategy has been extended to seven different ketones. This work demonstrates a green pathway for the reduction of CO2 to useful carboxylated organic products.

Electrophilic Hydrosilylation of Electron-Rich Alkenes Derived from Enamines.

The low-electron count, air-stable, platinum complexes [Pt(ItBu')(ItBu)][BArF] (C1) (ItBu=1,3-di-tert-butylimidazol-2-ylidene), [Pt(SiPh)3(ItBuiPr)2][BArF] (C2) (ItBuiPr=1-tert-butyl-3-iso-propylimidazol-2-ylidene), [Pt(SiPh)3(ItBuMe)2][BArF] (C3), [Pt(GePh3)(ItBuiPr)2][BArF] (C4), [Pt(GePh)3(ItBuMe)2][BArF] (C5) and [Pt(GeEt)3(ItBuMe)2][BArF] (C6) (ItBuMe=1-tert-butyl-3-methylimidazol-2-ylidene) are efficient catalysts (particularly the germyl derivatives) in both the silylative dehydrocoupling and hydrosilylation of electron rich alkenes derived from enamines. The steric hindrance exerted by the NHC ligand plays an important role in the selectivity of the reaction. Thus, bulky ligands are selective towards the silylative dehydrocoupling process whereas less sterically hindered promote the selective hydrosilylation reaction. The latter is, in addition, regioselective towards the β-carbon atom of both internal and terminal enamines, leading to β-aminosilanes. Moreover, the syn stereochemistry of the amino and silyl groups implies an anti Si-H bond addition across the double bond. All these facts point to a mechanistic picture that, according to experimental and computational studies, involves a non-classical hydrosilylation process through an outer-sphere mechanism in which a formal nucleophilic addition of the enamine to the silicon atom of a platinum σ-SiH complex is the key step. This is in sharp contrast with the classical Chalk-Harrod mechanism prevalent in platinum chemistry.

Synthesis of 2‐Trifluoromethyl Pyridines through Multicomponent Kröhnke Reaction

AbstractA multicomponent Kröhnke reaction route toward 2‐trifluoromethyl pyridines from reaction of chalcones with easily available and stable 1‐(3,3,3‐trifluoro‐2‐oxopropyl)pyridin‐1‐ium bromide and ammonium acetate is reported. The reaction is found to be general with a range of substituted chalcones, and the applicability of the methodology in gram scale is demonstrated. Preliminary results suggest that this transformation is initiated by 1,4‐Michael addition, followed by inter‐ and intramolecular nucleophilic addition, and elimination.

Electrophilic Hydrosilylation of Electron‐Rich Alkenes Derived from Enamines

AbstractThe low‐electron count, air‐stable, platinum complexes [Pt(ItBu’)(ItBu)][BArF] (C1) (ItBu=1,3‐di‐tert‐butylimidazol‐2‐ylidene), [Pt(SiPh)3(ItBuiPr)2][BArF] (C2) (ItBuiPr=1‐tert‐butyl‐3‐iso‐propylimidazol‐2‐ylidene), [Pt(SiPh)3(ItBuMe)2][BArF] (C3), [Pt(GePh3)(ItBuiPr)2][BArF] (C4), [Pt(GePh)3(ItBuMe)2][BArF] (C5) and [Pt(GeEt)3(ItBuMe)2][BArF] (C6) (ItBuMe=1‐tert‐butyl‐3‐methylimidazol‐2‐ylidene) are efficient catalysts (particularly the germyl derivatives) in both the silylative dehydrocoupling and hydrosilylation of electron rich alkenes derived from enamines. The steric hindrance exerted by the NHC ligand plays an important role in the selectivity of the reaction. Thus, bulky ligands are selective towards the silylative dehydrocoupling process whereas less sterically hindered promote the selective hydrosilylation reaction. The latter is, in addition, regioselective towards the β‐carbon atom of both internal and terminal enamines, leading to β‐aminosilanes. Moreover, the syn stereochemistry of the amino and silyl groups implies an anti Si−H bond addition across the double bond. All these facts point to a mechanistic picture that, according to experimental and computational studies, involves a non‐classical hydrosilylation process through an outer‐sphere mechanism in which a formal nucleophilic addition of the enamine to the silicon atom of a platinum σ‐SiH complex is the key step. This is in sharp contrast with the classical Chalk–Harrod mechanism prevalent in platinum chemistry.

Mechanism, Chemoselectivity, and Stereoselectivity of an NHC-Catalyzed Reaction of Aldehydes and Hydrazones: A DFT Study.

To elucidate the mechanism and origins of chemo- and enantioselectivities of the reaction between aliphatic aldehydes and hydrazones catalyzed by triazolium-derived NHC, density functional theory computations have been performed. According to our calculated results, the whole catalytic cycle for the formation of dihydropyridazinones proceeds via the initial nucleophilic addition of NHC to an aliphatic aldehyde, followed by the concerted intramolecular proton transfer and C-Cl bond cleavage. Subsequent deprotonation generates an enolate intermediate. The enolate intermediate then undergoes 1,4-addition to hydrazone to construct a new carbon-carbon bond. The following ring-closure would lead to a six-membered ring intermediate, which, upon the release of NHC, affords the final product dihydropyridazinone. The computation results reveal that intramolecular proton transfer is significantly promoted by the Brønsted acid DIPEA·H+. The carbon-carbon bond formation step could determine not only the chemoselectivity but also the stereoselectivity and lead to the S-isomer product. It was found that the stereoselectivity arises from a combination of weak interactions, including C-H···O, C-H···N, C-H···π, and LP···π. NHC could enhance the nucleophilicity of the aliphatic aldehyde and facilitate further reaction with hydrazone. This work could be beneficial for the development of new catalytic strategies in the future.

Metal-Free Enantioselective 1,4-Addition of Diarylphosphine Oxides to α,β-Unsaturated Carboxylic Esters.

The catalytic asymmetric conjugate addition of phosphorus nucleophiles to unsaturated compounds, catalyzed by metallic or nonmetallic catalysts, has been extensively developed. However, the enantioselective transformations involving α,β-unsaturated carboxylic esters for constructing chiral c-p bonds have been rarely reported, particularly in metal-free processes. In this study, we present a novel metal-free methodology for enantioselective 1,4-addition of diarylphosphine oxides to α,β-unsaturated carboxylic esters using classical chiral oxazaborolidine catalysts. Remarkably high yields and enantioselectivities were obtained for most of the products. Furthermore, these valuable chiral phosphorus esters serve as crucial intermediates that can be transformed into various derivatives including amides, acids, and alcohols in a single step.

Palladium-Catalyzed anti-Michael-Type (Hetero)arylation of Acrylamides.

This paper reports a direct α-(hetero)arylation of acrylamides through an inverse electron-demand nucleophilic addition, specifically an anti-Michael-type addition. The introduction of a quinolyl directing group facilitates the nucleophilic addition of (hetero)arenes to the α-position of acrylamides. The quinolyl directing group effectively suppresses undesired β-hydrogen elimination and is removable for subsequent derivatization. The presented method provides an atom economical synthesis of α-(hetero)arylamide with a high degree of functional group tolerance.