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

NORMAL CONTACT STIFFNESS OF THE ELLIPTIC AREA BETWEEN TWO ASPERITIES

A new expression for contact deformation is given, and the normal contact stiffness between single asperities is derived according to Hooke’s law. A contact model between two ellipsoidal asperities is simulated by the FE method, the result compared with the theoretical solution. It is found that the curves of the normal contact stiffness versus the included angle in the principal curvature direction show similar trends and evolve as a cosine feature. The effects of the parameters on normal contact stiffness are found to show that normal contact stiffness increases and reaches the upper limit gradually with an increase in these parameters.     

Chaotic Oscillation of Saddle Form Cable-Suspended Roofs under Vertical Excitation Action

The purpose of this paper is to investigate the dynamic behaviour of saddle form cable-suspended roofs under vertical excitation action. The governing equations of this problem are system of nonlinear partial differential and integral equations. We first establish a spectral equation, and then consider a model with one coefficient, i.e., a perturbed Duffing equation. The analytical solution is derived for the Duffing equation. Successive approximation solutions can be obtained in likely way for each time to only one new unknown function of time. Numerical results are given for our analytical solution. By using the Melnikov method, it is shown that the spectral system has chaotic solutions and subharmonic solutions under determined parametric conditions.     

大变位热弹性扁壳的一种边值模型

本文给出了正则形式基本方程及广义变分原理,并给出了关于应力函数、挠度、温度三种变量的一种边值模型。     

A study of fluorescence properties of citrinin in β-cyclodextrin aqueous solution and different solvents

Citrinin (CIT) is a nephrotoxic mycotoxin initially isolated from filamentous fungus Penicilliu citrinum. It was later isolated from several other species, such as Aspergillus and Monascus. It has a conjugated, planar structure that gives it a natural fluorescence ability, which can be used to develop sensitive methods for detecting CIT in food. In this paper, we used the spectro?uorescence technique to study the effects of pH value, β-cyclodextrin (β-CD) and organic solvents on the CIT fluorescence intensity. The results show that lower pH value, aceitc acid, β-CD and acetonitrile can induce a higher fluorescence intensity of CIT, but methanol or H₂O has a decreasing effect on the fluorescence intensity of CIT. Findings in this study provide a theoretical basis for development of a high sensitivity fluorescence-based trace analysis for CIT detection.     

Nonmonotone algorithm for minimax optimization problems

Many real life problems can be stated as a minimax optimization problem, such as the problems in economics, finance, management, engineering and other fields. In this paper, we present an algorithm with nonmonotone strategy and second-order correction technique for minimax optimization problems. Using this scheme, the new algorithm can overcome the difficulties of the Maratos effect occurred in the nonsmooth optimization, and the global and superlinear convergence of the algorithm can be achieved accordingly. Numerical experiments indicate some advantages of this scheme.     

Control of flexural waves on a beam using distributed vibration neutralisers

This paper is concerned with the use of distributed vibration neutralisers to control the transmission of flexural waves on a beam. Of particular interest is an array of beam-like neutralisers and a continuous plate-like neutraliser. General expressions for wave transmission and reflection metrics either side of the distributed neutralisers are derived. Based on transmission efficiency, the characteristics of multiple neutralisers are investigated in terms of the minimum transmission efficiency, the normalised bandwidth and the shape factor, allowing optimisation of their performance. Analytical results show that the band-stop property of the neutraliser array depends on various factors, including the neutraliser damping, mass, separation distance in the array and the moment arm of each neutraliser. Moreover, it is found that the particular attachment configuration of an uncoupled force-moment-type neutraliser can be used to improve their overall performance. It is also shown that in the limit of many neutralisers in the array, the performance tends to that of a continuous neutraliser.     

新型BrΦnsted-Lewis酸性离子液体的合成及其在松香二聚反应中的应用(英文)

合成、表征了新型 Brφnsted-Lewis 酸性离子液体 1-（3-磺酸）-丙基-3-甲基咪唑氯锌酸盐 （[HO3S-（CH2）3-mim]Cl-ZnCl2）, 并将其用于催化松香二聚反应. 结果表明, [HO3S-（CH2）3-mim]Cl-ZnCl2 （ZnCl2摩尔分数x 〉 0.5）为 Brφnsted 和 Lewis 双酸性, 且以 [HO3S-（CH2）3-mim]Cl-ZnCl2 （x = 0.64） 的催化性能较佳. 在松香 5.0 g, 甲苯15 g, 离子液体质量分数 5%, 反应温度 110℃ 和反应时间 4 h 的较佳实验条件下, 所得产物聚合松香的软化点为 118 ℃. 此外, 该催化剂的使用有利于产物的分离且分离的离子液体催化剂具有良好的重复使用性能.     

新型Br(o)nsted-Lewis酸性离子液体的合成及其在松香二聚反应中的应用

合成、表征了新型Bronsted-Lewis酸性离子液体1-(3-磺酸)-丙基-3-甲基咪唑氯锌酸盐([HO3S-(CH2)3-mim]Cl-ZnCl2),并将其用于催化松香二聚反应.结果表明,[HO3S-(CH2)3-mim]Cl-ZnCl2(ZnCl2摩尔分数x＞0.5)为Bronsted和Lewis双酸性,且以[HO3S-(CH2)3-mim]Cl-ZnCl2 (x=0.64)的催化性能较佳.在松香5.0 g,甲苯15 g,离子液体质量分数5%,反应温度110℃和反应时间4 h的较佳实验条件下,所得产物聚合松香的软化点为118 ℃.此外,该催化剂的使用有利于产物的分离且分离的离子液体催化剂具有良好的重复使用性能.