Visible-light-driven spirocyclization of epoxides via dual titanocene and photoredox catalysis期刊界 All Journals 搜尽天下杂志传播学术成果专业期刊搜索期刊信息化学术搜索

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

Authors:

Shuangjie Lin Yuqing Chen Fusheng Li Caizhe Shi Lei Shi

Affiliation:

Zhang Dayu School of Chemistry, State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024 China,

Abstract:

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 window Scheme 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 (39 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

Open in a separate window^aReaction conditions: 2 and 4 (100 mg, 0.1 M in THF).^bIsolated yield.^c 3c, 3e and 3f were synthesized from enantiomer pure epoxides.^dYields within parentheses are based on catalytic conditions using metal as a reductant: CpTi₂Cl₂ (5 mol%), Zn (2.0 eq.), coll·HCl (2.5 eq.), THF, 20 hours.Additive effect on Ti-catalyzed cyclization^a^,^b

Open in a separate window^aIn all cases, 2l was used as the substrate and the yield of 3l was determined with ¹H NMR.^bValues within parentheses are recovery yields of the additives determined with ¹H NMR.To examine the scalability of the reaction, gram-scale synthesis of 3a and 3c was performed under the standard conditions with 23 W CFL irradiation. Pleasingly, 92% (3a) and 89% (3c) isolated yields were obtained respectively without any deterioration. Furthermore, an additive-based investigation⁴¹ was performed and the results are summarized (†). The low-cost of 4CzIPN, broad compatibility with sensitive functional groups, and simple operation conditions are appealing for laboratory and industrial applications.Importantly, the reactions were re-subjected to metal reduction catalytic conditions for comparison with the photocatalytic conditions and the yields are shown within parentheses (

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