Intramolecular Addition Reactions Research Articles

The synthesis of novel unnatural amino acid by intramolecular aza-Michael addition reaction as multitarget enzyme inhibitors.

Synthesis of novel unnatural amino acids (UAAs) from 4-oxo-4-phenylbut-2-enoic acid derivatives with intramolecular aza-Michael addition reaction in the presence of chlorosulfonyl isocyanate (CSI) was reported in soft conditions without any metal catalyst. Acids and base as a catalyst, and solvents effects were investigated for the synthesis of novel UAAs. This novel method provides inexpensive, practicable, and efficient approach to generate UAAs. The use of UAAs has attracted great interest in the development of therapeutic agents and drug discovery to improve their properties. In this context, in addition to the synthesis of new UAAs, their inhibition effects on important metabolic enzymes of acetylcholinesterase (AChE) and carbonic anhydrases I and II (hCA I and II) enzymes were investigated. The compound 2g showed the best inhibition for CA I and AChE enzymes, while compound 2i exhibited the best inhibition profile against CA II isoenzyme. The inhibition values of these compounds were found as 1.85 ± 0.64 for AChE, 0.53 ± 0.07 for hCA I, 0.44 ± 0.15 µM for hCA II, respectively, and they showed a stronger inhibitory property than acetazolamide (standard inhibitor for hCA I and II) and tacrine (standard inhibitor for AChE) molecules. The activity of the studied molecule against different proteins that are hCA I (PDB ID: 2CAB), hCA II (PDB ID: 5AML), and AChE (PDB ID: 1OCE) was examined. Finally, the drug properties of the studied molecule were examined by performing absorption, distribution, metabolism, excretion, and toxicity analysis.

Synthesis of polycyclic fused oxazolidin-2-ones by catalytic Boron(III)-Promoted oxo-Michael addition reaction and evaluation on their cytotoxicity

Oxazolidin-2-one served as a class of highly important nitrogen-containing five-membered heterocycles has been found in a wide range of biologically active molecules and chiral ligands. Consequently, its synthesis has attracted significant attention from chemists, leading to extensive investigations in this area. In this study, we developed a novel and more sustainable synthetic approach, using BF3·Et2O as the catalyst to facilitate intramolecular oxo-Michael addition reactions of Boc-protected p-quinoamines. This approach allowed for the efficient construction of diverse polycyclic fused oxazolidin-2-one compounds and yields up to 98 %. Furthermore, the anti-tumor activity of these structurally unique oxazolidin-2-one derivatives was reported.

Naphthalimide-based probe as an in situ indicator of photochemical reaction for self-reporting imidazole ring formation

Fluorescent probes were promising ultrasensitive candidates in the sensing area. Herein, a fluorescent indicator bearing an active photochemical reactive site based on naphthalimide was designed and synthesized. Under UV irradiation, the photocyclization reaction to form imidazole occurred through the intramolecular addition reaction between α-amine and imine. This photochemical reaction was dynamically monitored in real time by significant fluorescence and UV spectrum changes. The reaction mechanism was further verified by NMR, MS, IR and free radical quenching reaction. The photocyclization reactions of analogous substrates based on this mechanism were also monitored by self-reporting spectrum changes.

Acid/Base-Steered Cascade Cyclization: An Efficient One-Pot Access to Diverse Isobenzofuranone and Isoindolobenzoxazinone Derivatives.

We herein report the acid/base-steered two distinct reaction pathways of 2-acylbenzoic acids with isatoic anhydrides. In the presence of Na2CO3, the cascade process consists of the cyclization of 2-acetylbenzoic acid and nucleophilic ring-opening reaction of isatoic anhydride to furnish isobenzofuranone derivatives with high efficiency. However, p-toluenesulfonic acid can promote the product isobenzofuranones to undergo sequential intramolecular rearrangment, nucleophilic addition and cyclization reaction to produce diverse isoindolobenzoxazinones in good yields. The synthetic utility of this method was further demonstrated by the gram-scale preparation of the desired products and the facile transformations of the resulting products.

Mechanistic Insights into Multisilver-Mediated Synergistic Activation of Terminal Alkynes.

Synergistic effect extensively exists in multimetal-involved catalytic or mediated processes of group 11 metals due to their remarkable metallophilic interactions. Herein, we present a multiple synergism model for alkynyl substrates and conduct theoretical investigations on various multimetallic bonding modes and the corresponding synergistic activations. We computationally screen nine alkynyl multisilver coordination modes and sequence their reactivity shown in an intramolecular nucleophilic addition reaction by the trend of active μ4-η1η1η2η2 and μ3-η1η1η2 to the relatively inert μ2-η1η2. The transition-state (TS) stabilization of the high-nuclearity mode mainly comes from the significant negative interaction energies between Agn and the substrate based on the distortion/interaction analysis. Energy decomposition analysis-natural orbitals for chemical valence (EDA-NOCV) analysis further reveals the charge-accepting reservoir effect of the polysilver moiety and the orbital match between the alkynyl group and specific spatial arrangement of silver atoms to account for this efficient activation. In addition, tests on different ligands coordinated to silver atoms show a correlation of the ligand conformation adjustability with the reactivity of the alkynyl unit, and the accommodable η2 activation unit embodies a lower deformation energy than the other homonuclear synergistic modes. Privileged multiple synergistic models have been further evidenced based on on-bench experiments by isolating trisilver and tetrasilver alkynyl complexes. This study not only systematically evaluates the multimetallic synergism of different coordination modes in alkyne activation but also provides a guidance for the future design of multimetallic catalysts.

Ambiphilic Behavior of Ge(II)-Pseudohalides in Inter- and Intramolecular Frustrated Lewis Pair Alkyne Addition Reactions.

The reaction of the germylene chloride (NacNac)GeCl (1, NacNac = CH{(CMe)(2,6-iPr2C6H3N)}2), phenylacetylene, and B(C6F5)3 gives the intermolecular frustrated Lewis pair (FLP) addition product 2. In this case, the Ge(II) center acts as a base. In contrast, the analogous reaction of germylene thiocyanate 3 reacts independently with B(C6F5)3 to give the germylene cation salt [(NacNac)Ge][SCNB(C6F5)3] 4. Subsequent in the presence of alkynes, the Ge(II) cation and γ-C of 4 act as a Lewis acidic and basic center, respectively, to affect the addition of alkynes, affording products [(NacNac)Ge(RCCR')][SCNB(C6F5)3] 5 and 6. Compound 4 also reacts with Me3SiCN to give the cyanide-bridged Ge/B species 7, which also reacts with phenylacetylene to give CN abstraction and intramolecular addition yielding the salt [(NacNac)Ge(PhCCH)][NCB(C6F5)3] 8. Despite the similarity of 1 and 3, DFT calculations show that the highest occupied molecular orbital (HOMO) of 1 is mainly located at the more sterically hindered germylene center, while the HOMO of 3 is located on the less sterically hindered NCS group, prompting markedly different FLP addition products.

Phytophenol Dimerization Reaction: From Basic Rules to Diastereoselectivity and Beyond.

Phytophenol dimerization, which is a radical-mediated coupling reaction, plays a critical role in many fields, including lignin biosynthesis. To understand the reaction, 2,2-diphenyl-1-picrylhydrazyl radical was used to initiate a series of phytophenol dimerization reactions in methanol. The products were identified using ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (UHPLC-ESI-Q-TOF-MS/MS) analysis in situ. The identified products mainly included biphenols, magnolol, honokiol, gingerol 6,6′-dimers, 3,6-dimethoxylcatechol β,β′ dimer, euphorbetin, bis-eugenol, dehydrodiisoeugenol, trans-ε-viniferin, (+) pinoresinol, and (−) pinoresinol. Structure–function relationship analysis allowed four basic rules to be defined: meta-excluded, C–C bonding domination, ortho-diOH co-activation, and exocyclic C=C involvement. The exocyclic C=C involvement, however, required conjugation with the phenolic core and the para-site of the -OH group, to yield a furan-fused dimer with two chiral centers. Computational chemistry indicated that the entire process was completed via a radical coupling reaction and an intramolecular conjugate addition reaction. Similar results were also found for the horseradish peroxidase (HRP)-catalyzed coniferyl alcohol dimerization, which produced (+) and (−) pinoresinols (but no (−) epipinoresinol), suggesting that the HRP-catalyzed process was essentially an exocyclic C=C-involved phytophenol dimerization reaction. The reaction was highly diastereoselective. This was attributed to the intramolecular reaction, which prohibited Re-attack. The four basic rules and diastereoselectivity can explain and even predict the main products in various chemical and biological events, especially oxidase-catalyzed lignin cyclization.

Stereoselective Synthesis of Cyclohexane Derivatives: Tandem Lithium Iodide Mediated Intramolecular Conjugate Addition of Thiols to α,β-Bisenones

AbstractA tandem intramolecular conjugate addition reaction was conducted with α,β-bisenones as selected Michael acceptors which were converted into 1,2,3-trisubstituted six-membered rings in the presence of activated sulfur nucleophiles. The products were obtained in good to excellent yields (maximum yield: 99%). Various substituted α,β-bisenones and sulfur nucleophiles were examined to understand the substrate scope of the reaction. Only one diastereomer was isolated, as lithium iodide mediated enolate trapping reactions improve the stereoselectivity of reactions involving 1,2,3-trisubstituted cyclohexanes.

Preparation of 5-methyl-3,5-dipropyl-2-pyrazoline catalyzed by chloroaluminate ionic liquids

5-methyl-3,5-dipropyl-2-pyrazoline is an intermediate for the preparation of new high energy fuels. In this paper, chloroaluminate ionic liquids ([Bmim]Cl-xAlCl3, x = 1, 1.2, 1.4, 1.6, 1.8, 2.0) were applied as green catalysts for the synthesis of 5-methyl-3,5-dipropyl-2-pyrazoline through the intramolecular cyclization reaction of 2-pentyl ketazine. The effects of temperature, acidity and dosage of ionic liquids on the cyclization reaction were studied in detail and the highest catalytic performance was under the conditions as 110 °C, [Bmim]Cl-1.6AlCl3 and 10% of 2-pentyl ketazine. With the theoretical simulations, the possible catalytic mechanism was proposed as the hydrogen-like interaction between Al ([Bmim]+AlCl4−) and N1 atoms, which increases the charge of N2 atoms, thereby improving its nucleophilicity and further making it undergo intramolecular addition reaction with methyl. This study will provide guidance for the green preparation of 5-methyl-3,5-dipropyl-2-pyrazoline.

Rapid synthesis of polyester based single-chain polymeric nanoparticles via an intra-molecular aza-Michael addition reaction

An alternative method to produce single-chain polymeric nanoparticles using the aza-Michael addition reaction of a linear polyester containing in-chain reactive triple bonds is introduced.

Synthesis of sp3-rich chiral bicyclo[3.3.1]nonanes for chemical space expansion and study of biological activities

Chiral sp3-rich bicyclo[3.3.1]nonane scaffolds 10–12 were synthesized as single diastereomers from aldehyde 9, which was prepared from 4,4-dimethoxycyclohexa-2,5-dienone through a copper-catalyzed enantioselective reduction. Three different types of intramolecular addition reactions were studied: SmI2-mediated reductive cyclization, base-promoted aldol reaction, and one-pot Mannich reaction. We succeeded in introducing three side-chains to scaffold 11 and construct an sp3-rich compound library in both enantiomeric variants by simply changing the chirality of the ligands. The biological evaluation revealed that all synthesized compounds exhibited a concentration-dependent inhibition of hypoxia-inducible factor-1 (HIF-1) transcriptional activity, with IC50 values in the range of 17.2–31.7 µM, whereas their effects on cell viability were varied (IC50 = 3.5 to > 100 µM). The most active compound 16f inhibits the accumulation of HIF-1α protein and mRNA in hypoxia, indicating that it has a mechanism of action distinctly different from other known compounds bearing the common bicyclo[3.3.1]nonane skeleton.

An intramolecular oxa-Michael addition on prebuilt β-lactam tethered α, β-unsaturated ester: A remarkable synthesis of a unique scaffold of 2,3-fused β-lactam-1,4-dioxepane

An expeditious base assisted highly diastereoselective intramolecular oxy-Michael addition reaction in the synthesis of enantiomerically pure 1,4-dioxepane fused β-lactam has been described. This present study has been portrayed a rapid intramolecular 7-exo-trig oxy-Michael reaction involving chemoselective nucleophilic addition of 20 alcohol of the vic-diols to an α β-unsaturated ester. Furthermore, the developed methodology elaborates an extremely atom-economical approach in constructing the C–O bond in stereoselective fashion under mild reaction conditions.

Nickel-Catalyzed Intramolecular Nucleophilic Addition of Aryl Halides to Aryl Ketones for the Synthesis of Benzofuran Derivatives

AbstractA nickel-catalyzed intramolecular nucleophilic addition reaction of aryl halides to aryl ketones for the formation of benzofuran derivatives has been developed. A number of substrates bearing electron-donating or electron-withdrawing groups were subjected to the standard reaction conditions, giving the corresponding products in moderate to good yields.

Sequential N‐Arylation and Intramolecular Imine Addition Reaction of Indoloazomethine Ylides with Arynes for the Synthesis of Thiadiazepine Derivatives

AbstractMetal‐free reaction of indoloazomethine ylides with 2‐(trimethylsilyl)aryl triflates in the presence of TMAF and MeOH provided 1,4‐thiadiazepines through sequential N‐arylation and intramolecular imine addition reaction, which is fully oxidized with p‐chloranil. These compounds are smoothly isomerized to indoloindolizines in quantitative yield. Moreover, formation of indoloindolizine was accessed from indoloazomethine ylide and 2‐(trimethylsilyl)aryl triflate in semi‐one‐pot.magnified image

Design and synthesis of dual active neovibsanin derivatives based on a chemical structure merging method

A hybrid compound consisting of neovibsanin and trans-banglene was designed according to a structure merging method and synthesized via a sequence of key steps including a Diels–Alder cycloaddition, stereoselective alkynylation, and intramolecular oxa-Michael addition reaction. The biological activity of the synthetized acetal compound and its hemiacetal analogue was investigated in PC12 cells. These studies revealed that the designed hybrid compounds displayed neuritogenic activity. Furthermore, a relatively strong neurite outgrowth promoting activity was observed in the presence of NGF. These results suggest that the designed hybrid compound exhibited a dual activity.

A common strategy towards the synthesis of 1,4-dideoxy-1,4-imino-l-xylitol, deacetyl (+)-anisomycin and amino-substituted piperidine iminosugars

A strategy towards the synthesis of three different target molecules, namely 1,4-dideoxy-1,4-imino-l-xylitol, deacetyl (+)-anisomycin and amino-substituted piperidine iminosugars, molecules of potential biological and medicinal significance, is reported from a common amino-vicinal diol intermediate derived from tri-O-benzyl-d-glucal. Construction of the key pyrrolidine ring present in 1,4-dideoxy-1,4-imino-l-xylitol and (+)-anisomycin was a consequence of thermodynamically driven concomitant intramolecular nucleophilic addition reaction of the amino group to the resultant aldehyde obtained by oxidative cleavage of the amino-vicinal diol. Alternatively, double nucleophilic substitution on an amino-diol, after mesylation, with various amines delivered amino-substituted piperidine iminosugars in good yields.

Regiodivergent Intramolecular Nucleophilic Addition of Ketimines for the Diverse Synthesis of Azacycles.

Azacycles such as indoles and tetrahydroquinolines are privileged structures in drug development. Reported here is an unprecedented regiodivergent intramolecular nucleophilic addition reaction of imines as a flexible approach to access N-functionalized indoles and tetrahydroquinolines, by the control of reaction at the N-terminus and C-terminus, respectively. Using ketimines derived from 2-(2-nitroethyl)anilines with isatins or α-ketoesters, the regioselective N-attack reaction gives N-functionalized indoles, while the catalytic enantioselective C-attack reaction affords chiral tetrahydroquinolines featuring an α-tetrasubstituted stereocenter. Mechanistic studies reveal that hydrogen-bonding interactions may greatly facilitate such unusual N-attack reactions of imines. The utility of this protocol is highlighted by the catalytic enantioselective formal synthesis of (-)-psychotrimine, and the construction of various fused aza-heterocycles.

Grob-Fragmentation-Enabled Approach to Clavulactone Analogues.

The novel synthetic strategy for dolabellane skeleton was realized, which allowed the synthesis of clavulactone analogues 26 and 27 in a concise and efficient manner. Salient transformations include a diastereoselective Mukaiyama aldol reaction, an intramolecular nucleophilic addition reaction, a Grob fragmentation reaction, and an efficient Mukaiyama-Michael addition reaction.

Synthesis of Substituted Cyclopentenol Derivatives via Intramolecular Addition Reaction of Vinylcopper Species

A new method for the synthesis of substituted cyclopentenes is developed, based on an intramolecular 1,2-addition reaction of vinylcopper species generated from 1,1-dibromoalkene derivatives. The substrates are prepared from ketones through the aldol reaction with 3,3-dibromoacrolein followed by silylation of the hydroxyl group. Treatment of the substrate with excess Me2CuLi results in the formation of 3-methyl-2-cyclopenten-1-ol derivatives with good yields.

Catalytic Enantioselective Synthesis of 4-Amino-1,2,3,4-tetrahydropyridine Derivatives from Intramolecular Nucleophilic Addition Reaction of Tertiary Enamides

A general and efficient method for the synthesis of highly enantiopure 4-amino-1,2,3,4-tetradydropyridine derivatives based on chiral phosphoric acid catalyzed intramolecular nucleophilic addition of tertiary enamides to imines has been developed. We have also demonstrated a substrate engineering strategy to significantly improve the enantioselectivity of asymmetric catalysis