Unexpected formation of dinaphthoaza-17-crown-5 ether containing γ-aminopiperidine subunit

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Visible-light-driven spirocyclization of epoxides via dual titanocene and photoredox catalysis

We describe the synergistic utilization of titanocene/photoredox dual catalysis driven by visible light for the radical opening/spirocyclization of easily accessible epoxyalkynes. This environmentally benign process uses the organic donor–acceptor fluorophore 2,4,5,6-tetra(9H-carbazol-9-yl)isophthalonitrile (4CzIPN) as a photocatalyst and Hantzsch ester (HE) as an electron donor instead of stoichiometric metallic reductants. The photocatalytic conditions showed exceptionally high reactivity for the synthesis of privileged and synthetically challenging spirocycles featuring a spiro all-carbon quaternary stereocenter. Cyclic voltammetry (CV) studies suggest that Cp₂Ti^IIICl is the catalytically active species.

We describe the synergistic utilization of titanocene/photoredox dual catalysis driven by visible light for radical opening/spirocyclization of easily accessible epoxyalkynes.

Over the last few decades, radical-based transformations have been increasingly used in organic synthesis due to their salient features, such as ease of generation, mild reaction conditions, and broad functional group compatibility.^1,2 As a mild single-electron-transfer (SET) reagent, titanocene monochloride (Cp₂Ti^IIICl) is considered a formidable tool in contemporary radical chemistry due to its ability to promote various fundamental radical-based transformations.^3–7 Cp₂Ti^IIICl was first introduced by Nugent and RajanBabu as a very mild stoichiometric reagent for the reductive opening of epoxides.^8–11 Later, the catalytic conditions developed by Gansäuer et al. (Scheme 1a)¹² employing stoichiometric amounts of active metals in combination with 2,4,6-collidine·HCl further expanded its applications and led to the discovery of a number of novel transformations.^13–16 The key to success was the formation of a stable complex A in reactions while decreasing the concentration of active Cp₂Ti^IIICl.^17,18 We were interested in the radical opening/cyclization reaction of epoxides which has attracted considerable attention from the synthetic community and has been used numerous times in the synthesis of natural products.^19,20 Nevertheless, this reaction required stoichiometric metallic reductants and proceeded slowly particularly with sterically hindered substrates even with high catalyst loading.²¹ Therefore, the development of an eco-friendly and efficient catalytic system with an expanded substrate scope is highly desirable.Open in a separate windowScheme 1Cp₂Ti^IIICl mediated radical opening/spirocyclization of epoxides; (a) generation of Ti^IIIvia a metal reduction approach; (b) dual titanocene/photoredox catalysis; (c) examples of drugs and natural products containing heterospirocycles.In recent years metallaphotoredox catalysis has been a new and rapidly growing research subject.^22–29 Photoredox processes can directly modulate the oxidation state of metals by electron transfer (ET).^30–33 Given that the generation of Ti^III is a SET process, we envisioned that the reduction could be facilitated by a photoredox-controlled process while overcoming the aforementioned limitations. On the other hand, spirocycles bearing a chiral spiro all-carbon quaternary carbon are particularly attractive synthetic targets in pharmaceutical development (Scheme 1c).^34–36 Such privileged rigid 3D structures offer the concomitant ability to project functionalities in all three-dimensional orientations and led to enhanced pharmacological activities of molecules. Thus significant attention has been paid to their synthesis.^37,38 Against this backdrop, here we describe our efforts on the synthesis of various heterospirocycles with the aid of photoredox catalysis.We chose epoxyalkyne 2a as a model substrate for optimization of reaction conditions. After a systematic variation of different reaction parameters, we were pleased to identify the optimal reaction conditions in which a mixture of Cp₂TiCl₂ (5.0 mol%), [Ir(dtbbpy)(ppy)₂]PF₆ (1a, 1.0 mol%, E^III/II_1/2 = −1.51 V vs. SCE in MeCN), HE (1.2 equiv.) and 2a (1.0 equiv.) in THF at room temperature under the irradiation of a 10 W 450 nm light emitting diode (LED) lamp for 12 hours afforded the desired product 3a in an excellent yield of 96% (13 : 1 d.r.) upon isolation (entry 1). Using a commercial 23 W compact fluorescent lamp (CFL) instead of the 10 W 450 nm LED did not compromise the overall yield of the reaction (entry 2). Notably, when the loading of Cp₂TiCl₂ was decreased to as low as only 2.0 mol%, the reaction still led to full conversion and produced 3a in 95% yield (entry 3). Further screening of other photosensitizers revealed that the cheap and readily obtained organic dye 4CzIPN 1b is a competent alternative, which led to full conversion with 94% isolated yield (entry 4). Importantly, the reaction did not proceed in the absence of Cp₂TiCl₂, HE, the photocatalyst, or visible light (entries 5–8). Various solvents, including DMF, MeOH, DMSO, and MeCN, were screened, and they all resulted in poor conversion. The use of other organic electron donors, such as triethylamine, triethanolamine, and ascorbic acid, afforded the product in poor yield.With satisfactory reaction conditions established, we then explored the scope of the cyclization reaction using 4CzIPN as the photosensitizer. Positively, the cyclization reaction worked well and afforded the desired variably heterospirocyclic products in good to excellent yield (Tables 2 and ​and3).3). The reaction allows the rapid construction of various 5/5, 5/6, 5/7 and 5/8 spiro-ring fused systems (3a–3k) bearing tetrahydrofuran or pyrrolidine motifs via the 5-exo cyclization pathway. Interesting, the diastereoselectivity of the cyclization reaction is highly correlated with the ring size in the substrates. Heterospirocycles containing a 5/5 spiro-ring fused system (3a–3f) were obtained with surprisingly high diastereoselectivity. In some cases (3b, 3c, and 3e) only a single isomer was obtained. The product 3d with a sterically hindered t-butyloxy carbonyl (Boc) protecting group on the N atom was obtained with reduced diastereoselectivity (5 : 1 d.r.). The diastereoselectivities dropped in 5/6, 5/7 and 5/8 spiro-ring fused systems. Given that enantioenriched epoxides could be easily obtained (e.g. via sharpless asymmetric epoxidation), this strategy provides access to optically active spirocycles featuring an all-carbon quaternary stereocenter with the transfer of stereochemical information from epoxides (3c, 3e and 3f). Bis-heterospirocyclic scaffolds were frequently employed in pharmaceutical chemistry. For example, bis-heterospirocyclic 3d is the core structure of DLK inhibitors³⁹ and XEN402 (ref. 40) (scheme 1c), which are used for treating neurodegeneration and congenital erythromelalgia respectively. Furthermore, 6-exo cyclization was also investigated under the standard conditions and smoothly produced a serious of drug-like 6-(trifluoromethyl)-3-pyridinesulfonyl piperidine derivatives including 6/5, 6/6 and 6/7 spiro-ring fused systems (5a–5k) in generally excellent yields. Moreover, cyclization reactions with epoxy-alkynes afforded products containing exocyclic-alkenes and free alcohols which were suitable for further functionalization. This approach provides access to a broad range of novel spirocyclic piperidine and pyrrolidine spirocycles which could be of interest to synthetic and medicinal chemists.Scope of 5-exo and 6-exo cyclization^a,b,c,d

Application of polymethyl methacrylate in cathode materials of lithium-ion batteries

A study of the Li₂FeSiO₄/C cathode material doped with Mn demonstrated that introduction of polymethyl methacrylate results in a substantial decrease in the particle size and increase in the specific surface area of the cathode material. Polymethyl methacrylate strongly improves the cyclic stability of the cathode material. The discharge capacity after the first cycle was 218 mA h g^–1, and that upon stabilization of the structure of the cathode material, 170 mA h g^–1.     

Self-penetrating and interpenetrating 3D metal-organic frameworks constructed from 4-(4-carboxyphenoxy)-phthalic acid and <Emphasis Type="Italic">N</Emphasis>-donor auxiliary ligands

Two new interesting entangled structures, namely, [Ni_1.5(L)(bpy)₂(H₂O)₃] _n · 3nH₂O (I) and [Cd₃(L)₂(bbi)₂]n · nH₂O (II)(where H₃L is 4-(4-carboxyphenoxy)-phthalic acid, bpy is 4,4′-bipyridine, and bbi is 1,1′-(1,4-butanediyl)bis(imidazole)) have been synthesized and characterized by elemental analysis (EA), infrared spectra (IR), X-ray powder diffraction (XRPD), solid fluorescence and thermogravimetric analysis (TGA). Single-crystal X-ray diffraction analysis revealed that complex I possesses a 3D self-penetrating framework constructed from ladder-like and fishbone-like subunits. Complex II shows a 3D framework of two-fold interpenetration assembled from trinuclear Cd(II) clusters bridged by bbi and L^3? ligands.     

Improvements to CO<Subscript>2</Subscript> headspace biodegradability test

This study proposes changes to the design and evaluation of the CO₂ headspace test, which is used as a simple method for assessment of the complete biodegradability of surfactants. It presents a modified equation for the calculation of biodegradation. It is proposed that the solution of 7 mol L^?1 sodium hydroxide commonly used in the process involving alkalinisation of the vial contents be replaced with 15 mol L^?1 sodium hydroxide. The use of the higher hydroxide concentration leads to a significant reduction in the value of the blank CO₂ headspace test.     

Synthesis of potential inhibitors of glycosyltransferases representing UDP-GlcNAc

Based on rational design of the transition state analog inhibitors of glycosyltransferases, four model glycomimetics of this type, viz. benzyl 2-thio-α-dfructofuranoside 1-diethylphosphate (XIa), its β-anomer (XIb), and their ethyl 2-thio analogs — α-anomer (XIIa) and β-anomer (XIIb), were synthesized. In addition, fourteen precursors arising during the synthesis of the desired final model compounds (XI and XII), partially or fully acetylated benzyl and/or ethyl 2-thiofructofuranoside 1-diethyl phosphates, were isolated and characterized with the aim to prepare complete series of glycomimetics, representing donor UDP-GlcNAc designated for biological assays on human GnT’s, viz. GnT-I, Core2GnT, and GnT-V.     

Antioxidative properties of <Emphasis Type="Italic">Sambucus nigra</Emphasis> extracts

Potential protective effects of elderberry (Sambucus nigra) extracts against oxidative degradation of hyaluronan (HA) were detected in vitro. To induce free-radical-mediated HA degradation, Weissberger’s biogenic oxidative system, which mimics the situation of acute inflammation, was applied. Time- and dose-dependent changes of dynamic viscosity of the HA solutions in the presence and absence of two elderberry extracts produced in 2006 and 2012 were recorded by rotational viscometry (RV). Radical scavenging capacity of both extracts was investigated by the spectrocolorimetric ABTS [2,2′-azinobis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt] assay and the “inverted” ABTS assay. Oxygen consumption of the system oxidizing HA either in the absence or presence of the elderberry extracts was determined. The results of RV revealed that an addition of the newer extract (2012) promoted the inhibition of HA degradation more markedly compared to the older extract (2006). The same effect of both extracts on ABTS^·+ scavenging was observed. Inverted ABTS assay demonstrated that colorful substances were not responsible for the radical-scavenging activity. Results of oximetry demonstrated that the effect of the extract from 2006 was more significant than that of the extract from 2012.     

Preparation of Lewis acid ionic liquids for one-pot synthesis of benzofuranol from pyrocatechol and 3-chloro-2-methylpropene

Several Lewis acid ionic liquids (LAILs) with different acidic scales were synthesised and used as catalysts for the synthesis of benzofuranol by condensation of pyrocatechol and 3-chloro-2-methylpropene in one pot. The catalytic activity of these ionic liquids was correlated with their Lewis acidity. Low to moderate conversion with excellent selectivity to benzofuranol was obtained in the presence of the appropriate LAILs. Compared to the two-step synthetic method currently used in industry, a higher yield plateau (81.1%) of benzofuranol was achieved in the presence of [BMIm][AlCl₄] IL as catalyst at 418 K after 4 h. Furthermore, the catalyst is readily separated from the resultant products via decantation and could be reused after treatment in vacuum.     

Robust model-based predictive control of exothermic chemical reactor

A case study of the robust model-based predictive control (MPC) of an exothermic continuous stirred tank reactor (CSTR) with uncertain parameters is presented. Three robust MPC approaches are considered and the simulation results are compared in terms of quality of control performance and total consumption of coolant. The results reveal the main benefits of the considered approaches and confirm that the robust MPC can bring about a reduction in consumption of the coolant.