Versatile Synthetic Building Blocks Research Articles

Cooperative Fe/Co-Catalyzed Remote Desaturation for the Synthesis of Unsaturated Amide Derivatives.

Unsaturated amides represent common functional groups found in natural products and bioactive molecules and serve as versatile synthetic building blocks. Here, we report an iron(II)/cobalt(II) dual catalytic system for the syntheses of distally unsaturated amide derivatives. The transformation proceeds through an iron nitrenoid-mediated 1,5-hydrogen atom transfer (1,5-HAT) mechanism. Subsequently, the radical intermediate undergoes hydrogen atom abstraction from vicinal methylene by a cobaloxime catalyst, efficiently yielding β,γ- or γ,δ-unsaturated amide derivatives under mild conditions. The efficiency of Co-mediated HAT can be tuned by varying different auxiliaries, highlighting the generality of this protocol. Remarkably, this desaturation protocol is also amenable to practical scalability, enabling the synthesis of unsaturated carbamates and ureas, which can be readily converted into various valuable molecules.

Asymmetric Propargylic C−C Bond Formation Using Metal–Allenylidene Species

AbstractThe alkyne group is the key component of many bioactive molecules and versatile synthetic building block, thus the introduction of which into target molecules has attracted considerable interest from scientists. Moreover, tertiary and quaternary stereocenters are common motifs in natural products and drugs, however, the asymmetric construction of such motifs is one of the challenging tasks due to the steric congestion of multiple stereospecific substituents attached to one carbon. Metal–allenylidene are an excellent type of electrophilic species. The asymmetric addition of carbon‐nucleophiles at Cγ of the metal–allenylidene provides an effective way to construct tertiary and quaternary stereocenters as well as to introduce an alkyne group. In this review, the state‐of‐the‐art asymmetric propargylic C−C bond formation via metal‐allenylidene generated in situ from propargylic alcohol derivatives are presented. Synthetic applications, mechanistic insights are addressed. The challenges and opportunities of this field are also discussed.

Design, Synthesis and Anti-Bacterial Activity Evaluation of Indole-Based Benzophenone and Their Derivatives

Indole and benzophenone moiety are of significant interest to investigators because they are found in many natural products and pharmacologically active compounds. They represent versatile synthetic building blocks. The benzophenone and indole scaffolds are special structures in medicinal chemistry because these compounds are found in several biologically active natural products, compounds containing indole and benzophenone exhibit anticancer, antiinflammatory, antimicrobial, and antiviral activities. In this study, derivatives of 2-(diphenyl methylene) hydrazine, containing both indole and benzophenone moieties were successfully synthesized. The structural elucidation of the synthesized compounds were done using spectroscopic techniques like IR, 1HNMR, and 13CNMR. The synthesized target compounds were investigated for their in vitro antibacterial activity against two bacterial strains; staphylococcus aureus (S. auras), and Escherichia coli (E. coli) using the disc diffusion method. All synthesized target compounds showed no significant activity against Staphylococcus aureus (S. aureus) but exhibited moderate activity against Escherichia coli (E. coli). Among all the synthesized compounds, 2-(diphenyl methylene)-1-((1-tosyl-1H-indol-3-yl) methylene) hydrazine (BHT) (7b) showed a good inhibition at a concentration of 50 μg/mL with a zone of inhibition of 21.7 mm against Escherichia coli (E.coli) which was comparable with standard drug Ceftriaxone with the zone of inhibition of 26 mm. Thus, this compound could be considered as a lead molecule to design and develop novel antibacterial drugs.

Chemical Upcycling of PET into a Morpholine Amide as a Versatile Synthetic Building Block

Chemical Upcycling of PET into a Morpholine Amide as a Versatile Synthetic Building Block

Vicinal Vinylation of Boron-Doped Acenes via Heck Coupling.

Silylated and halogenated benzenes 1,2-(Me3Si)2-4,5-X2-C6H2 [X = Br (3), I (4)] are versatile synthetic building blocks. 3 was prepared from known 1,2-(Me3Si)2-4,5-Cl2-C6H2 via C-Cl borylation/bromodeboronation; CuI-catalyzed Br/I exchange on 3 affords 4. 3 or 4 and BBr3 yield 9,10-dibromo-9,10-dihydro-9,10-diboraanthracenes (DBAs) 7 or 8. The B centers were protected with mesityl (Mes; 9, 10) or 2,4,6-tris(trifluoromethyl)phenyl (FMes; 11, 12) groups. Heck coupling of 9 and styrene/2,3,4,5,6-pentafluorostyrene furnishes the two tetravinyl-substituted green/blue emitters 13/14.

Chloroacetyl boronate N-tosylhydrazone as a versatile synthetic building block.

Chloroacetyl boronate N-tosylhydrazone (CABT) has been synthesized as a reagent to generate a diverse range of molecular skeletons. CABT can undergo a series of transformations involving nucleophilic substitution of the chloride and coupling of the N-tosylhydrazones, followed by boryl group functionalization. We further demonstrated that this CABT reagent could enable a diversity-oriented synthesis.

Enhanced Molecular Recognition through Substrate–Additive Complex Formation in N-Heterocyclic-Carbene-Catalyzed Kinetic Resolution of α-Hydroxythioamides

We describe a new way of understanding enhanced molecular recognition through substrate–additive complex formation and the development of the first catalytic kinetic resolution of α-hydroxythioamides, which are versatile synthetic building blocks, using chiral N-heterocyclic carbene-catalyzed enantioselective acylation assisted by a carboxylate additive. Mass spectrometry provided evidence for the role of the additive, which forms a hydrogen-bonded complex with α-hydroxythioamide, resulting in both rate and selectivity enhancements. The synthetic applications of the resolved α-hydroxythioamides highlight the usefulness of the developed method.

Electrochemical Sulfoxidation of Thiols and Alkyl Halides.

Sulfoxides are actively engaged as versatile synthetic building blocks, chiral ligands, bioactive molecules, and function materials. However, their oxidative syntheses from thioethers are inevitably impeded by overoxidation, excess oxidants, and the tedious preparation of thioethers. To address these shortcomings, we report herein a highly selective electrochemical sulfoxidation reaction featuring the use of simple starting materials, i.e., thiols and alkyl halides, in a single operation.

Synthesis and Use of Bicyclo[1.1.1]pentylaldehyde Building Blocks.

The bicyclo[1.1.1]pentane (BCP) motif is an emerging scaffold in medicinal chemistry because of its bioisosterism to 1,4-phenylene and 1,2-alkynyl functions. The current drawback of its use is the lack of stable versatile synthetic building blocks. Aldehydes are among the most useful functionalities in organic chemistry. In this paper, a simple one-pot procedure from aryl-halides and [1.1.1]propellane is described. Preparation of various BCP molecules is conducted to showcase the versatility of these stable intermediates.

Design, synthesis and evaluation of structurally diverse ortho-acylphenol-diindolylmethane hybrids as anticancer agents

A highly efficient synthesis of structurally diverse ortho-acylphenol–diindolylmethane hybrids 3 using carboxylic acid-activated chromones as versatile synthetic building blocks is reported here for the first time, through 1,4-nucleophilic addition and followed by a decarboxylation and pyrone ring opening reaction process.

Enzymatic Bromocyclization of α- and γ-Allenols by Chloroperoxidase from Curvularia inaequalis.

Vanadate‐dependent chloroperoxidase from Curvularia inaequalis catalyzes 5‐endo‐trig bromocyclizations of α‐allenols to produce valuable halofunctionalized furans as versatile synthetic building blocks. In contrast to other haloperoxidases, also the more challenging 5‐exo‐trig halocyclizations of γ‐allenols succeed with this system even though the scope still remains more narrow. Benefitting from the vanadate chloroperoxidase‘s high resiliency towards oxidative conditions, cyclization‐inducing reactive hypohalite species are generated in situ from bromide salts and hydrogen peroxide. Crucial requirements for high conversions are aqueous biphasic emulsions as reaction media, stabilized by either cationic or non‐ionic surfactants.

Copper‐Catalyzed Aza‐Sonogashira Cross‐Coupling To Form Ynimines: Development and Application to the Synthesis of Heterocycles

AbstractNitrogen‐substituted alkynes, such as ynamines and ynamides, are versatile synthetic building blocks. Ynimines bearing additional nucleophilic and electrophilic centers relative to ynamines and ynamides are expected to have high synthetic potential. However, their chemical reactivity remains unexplored owing mainly to the lack of synthetic accessibility. We report herein a versatile copper‐catalyzed synthesis of ynimines from readily available O‐acetyl ketoximes and terminal alkynes. A wide range of O‐acetyl ketoximes derived from diaryl ketones, aryl alkyl ketones and dialkyl ketones underwent cross‐coupling with a diverse set of terminal alkynes to afford the ynimines in good to excellent yields. An unprecedented [5+1] heteroannulation reaction exploiting the reactivity of the ynimine generated in situ was subsequently developed for the synthesis of medicinally important heterocycles, including isoquinolines, azaindoles, azabenzofurans, azabenzothiophenes and carbolines.

Copper-Catalyzed Aza-Sonogashira Cross-Coupling To Form Ynimines: Development and Application to the Synthesis of Heterocycles.

Nitrogen‐substituted alkynes, such as ynamines and ynamides, are versatile synthetic building blocks. Ynimines bearing additional nucleophilic and electrophilic centers relative to ynamines and ynamides are expected to have high synthetic potential. However, their chemical reactivity remains unexplored owing mainly to the lack of synthetic accessibility. We report herein a versatile copper‐catalyzed synthesis of ynimines from readily available O‐acetyl ketoximes and terminal alkynes. A wide range of O‐acetyl ketoximes derived from diaryl ketones, aryl alkyl ketones and dialkyl ketones underwent cross‐coupling with a diverse set of terminal alkynes to afford the ynimines in good to excellent yields. An unprecedented [5+1] heteroannulation reaction exploiting the reactivity of the ynimine generated in situ was subsequently developed for the synthesis of medicinally important heterocycles, including isoquinolines, azaindoles, azabenzofurans, azabenzothiophenes and carbolines.

The Versatile Reaction Chemistry of an Alpha-Boryl Diazo Compound.

The first α-boryl diazo compound that is capable of engaging in classic synthetic organic diazo reaction chemistry is described. The diazomethyl-1,2-azaborine 1, which is a BN isostere of phenyldiazomethane, is significantly more stable than phenyldiazomethane; its reaction chemistry ranges from C-H activation, O-H activation, [3+2] cycloaddition, and halogenation, to Ru-catalyzed carbonyl olefination. The demonstrated broad range of reactivity of diazomethyl-1,2-azaborine 1 makes it an exceptionally versatile synthetic building block for the 1,2-azaborine heterocyclic motif.

Haloalkenyl Imidoyl Halides as Multifacial Substrates in the Stereoselective Synthesis of N‐Alkenyl Compounds

AbstractN‐Alkenyl compounds are versatile synthetic building blocks and their stereoselective transformations are key processes in the synthesis of many prominent classes of natural products, pharmaceuticals, and agrochemicals. However, a large structural variety of known N‐alkenyl compounds and their diverse reactivity have so far precluded the development of a general method for their stereoselective synthesis. Herein we present an aluminum halide‐mediated, highly stereoselective, efficient and scalable transformation of commercially available N‐fluoroalkyl‐1,2,3‐triazoles to N‐haloalkenyl imidoyl halides, and demonstrate their use in the synthesis of stereodefined N‐alkenyl amides, amidines, imines, hydrazonoamides, imidothioates, iminophosphonates, 1,2,4‐triazoles and tetrazoles. The reaction is of wide scope on both the triazole substrate and aluminum halide, providing highly functionalized products. Mechanistic and computational investigations suggest a reaction mechanism involving the triazole ring opening, initiated by the coordination of nitrogen one of the triazole ring to the Lewis acid, N2 elimination and the formation of a vinyl cation intermediate, which reacts with nitrogen‐bound aluminum halide, followed by a series of halide exchange reactions on C−X and Al−X bonds.magnified image

α-Aminoboronates: recent advances in their preparation and synthetic applications.

α-Aminoboronic acids and their derivatives are useful as bioactive agents. Thus far, three compounds containing an α-aminoboronate motif have been approved by the Food and Drug Administration (FDA) as protease inhibitors, and more are currently undergoing clinical trials. In addition, α-aminoboronic acids and their derivatives have found applications in organic synthesis, e.g. as α-aminomethylation reagents for the synthesis of chiral nitrogen-containing molecules, as nucleophiles for preparing valuable vicinal amino alcohols, and as bis-nucleophiles in the construction of valuable small molecule scaffolds. This review summarizes new methodology for the preparation of α-aminoboronates, including highlights of asymmetric synthetic methods and mechanistic explanations of reactivity. Applications of α-aminoboronates as versatile synthetic building blocks are also discussed.

Catalytic Enantioselective Reactions with (Benzo)Pyrylium Salts.

The use of (benzo)pyrylium salts as versatile synthetic building blocks has become an attractive platform for the preparation of valuable heterocyclic compounds. Besides other numerous direct applications of (benzo)pyryliums, the intrinsic electrophilic nature of these species or the dipole character of the related oxidopyrylium derivatives have been exploited towards the development of enantioselective transformations such as nucleophilic dearomatization and cycloaddition reactions. This review aims at providing an overview on the relevant catalytic enantioselective methodologies developed in the past years, which are presented considering the involved metal- and/or organic catalytic system, as well as the type of reaction.

Chemodivergent transformations of amides using gem-diborylalkanes as pro-nucleophiles

Amides are versatile synthetic building blocks and their selective transformations into highly valuable functionalities are much desirable in the chemical world. However, the diverse structure and generally high stability of amides make their selective transformations challenging. Here we disclose a chemodivergent transformation of primary, secondary and tertiary amides by using 1,1-diborylalkanes as pro-nucleophiles. In general, selective B-O elimination occurs for primary, secondary amides and tertiary lactams to generate enamine intermediate, while tertiary amides undergo B-N elimination to generate enolate intermediate. Various in situ electrophilic trapping of those intermediates allows the chemoselective synthesis of α-functionalized ketones, β-aminoketones, enamides, β-ketoamides, γ-aminoketones, and cyclic amines from primary, secondary, tertiary amides and lactams. The key for these transformations is the enolization effect after the addition of α-boryl carbanion to amides.

The reticent tautomer: exploiting the interesting multisite and multitype reactivity of 4-pyrrolin-2-ones.

4-Pyrrolin-2-ones are a lesser known tautomeric relative of the 3-pyrrolin-2-ones. Despite their infrequent appearance in the literature, they are very interesting and useful compounds. They have highly controllable, multisite and multitype reactivities which are covered in this review. The applications of these transformations show how the 4-pyrrolin-2-ones make excellent intermediates en-route to a range of key alkaloids. Innovative, fast and adaptable syntheses of the 4-pyrrolin-2-ones and their onward use via cascade reaction sequences are also presented to complete the case for commending these compounds as highly versatile and valuable synthetic building blocks.

Copper‐Catalyzed Radical Cross‐Coupling of Oxime Esters and Sulfinates for Synthesis of Cyanoalkylated Sulfones

AbstractSulfones and alkylnitriles play a significant role in both organic and medicinal chemistry, as versatile synthetic building blocks and privileged pharmacophores in many natural products and bioactive compounds. Herein, a room‐temperature, copper‐catalyzed radical cross‐coupling of redox‐active cycloketone oxime esters and sulfinate salts is described for the first time. Key to the success of this process involves catalytic generation of a cyclic iminyl radical and ensuing ring‐opening C−C bond cleavage. The resultant cyanoalkyl radical is then engaged in cross‐coupling with nucleophilic sulfinate to form cyanoalkylated sulfones.