Abstract
Double difunctionalization of a vinyl ether tethered hydroxy or carbamoyl group with electron-deficient alkenes such as acrylonitrile or acrylic esters was achieved by visible-light irradiation in a two-molecule photoredox system. Use of anhydrous acetonitrile solution as a solvent promoted both dimerization of the radical cation of electron-rich alkene with electron-rich alkene and intramolecular nucleophilic addition to generate an electron-rich radical that was added to electron-deficient alkene to furnish the double difunctionalized product. A variety of electronically differentiated rich and deficient alkenes were used in the photoreaction; a simple construction of a complex carbon framework containing acetal from simple alkenes was successful under mild conditions.
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Difunctionalization of alkenes simultaneously incorporates two functional groups, representing a powerful and effective synthetic technology, because alkenes are commercially available, inexpensive, and easily prepared materials from renewable resources and petrochemical feedstocks [1]. Mild and environmentally friendly difunctionalization reactions of alkenes using a photoredox catalyst (PC) have been developed [2,3,4]. For example, generation of a radical cation of electron-rich alkene via photoinduced electron transfer (PET) by PC is captured by nucleophiles such as alcohol and amine derivatives (Nu-H); the resulting radical reacts with radical acceptors such as a hydrogen donor (thiol) and oxygen or is further oxidized to form a corresponding cation that is captured by another nucleophile (Nu’-H) to provide the difunctionalized product (Scheme 1a).
Difunctionalization of alkene in photoredox catalysis
We recently reported an efficient photoinduced difunctionalization reaction assisted by intermolecular nucleophilic addition between electron-rich and electron-deficient alkenes [5] in a two-molecule photoredox system with featured reactivities [6, 7] compared to a one-molecule photoredox system using Ir or the Fukuzumi catalyst (Scheme 1b). PET between biphenyl (BP) and the excited state of 1,4-dicyanonaphthalene (DCN) or 9,10-dicyanoanthracene (DCA) by UV (mainly 313 nm) or visible light (405 nm) generates the radical cation of BP and the radical anion of DCN or DCA. Oxidation of vinyl ether 1 by the radical cation of BP forms the radical cation of 1 and BP. With a high concentration of the nucleophile R’OH (Path A), a high rate of nucleophilic addition to the radical cation of 1 leads to formation of the electron-rich radical 2; addition of radical 2 to an electron-deficient alkene such as acrylonitrile 3A forms electron-deficient radical 4. Back-electron transfer (BET) from the radical anion of DCN or DCA to radical 4 generates the carbanion, followed by protonation to yield 1:1 adducts. In the absence of BP, the direct PET between the excited state of DCN (the oxidation potential of the excited state of DCN = + 2.24 V vs. SCE in CH3CN) [8] and 1 significantly decreased the yield of the corresponding product (2%), because the efficient BET between the radical cation of 1 and the radical anion of DCN prevented the sequential reaction to recover the starting material 1 [5]. Thus, this transformation required two-molecule photoredox system. When the concentration of R’OH is low (Path B), the low rate of nucleophilic addition to the radical cation results in dimerization of 1, as reported in the similar PET-promoted addition of vinyl ethers to generate the radical cation of dimer 5 [9]. Nucleophilic addition of R’OH to 5 forms electron-rich radical 6; the same radical addition and BET process provides 2:1 adducts, leading to double difunctionalization of 1. Thus, successful control of the formation of two types of difunctionalization or double difunctionalization products (1:1 or 2:1 adducts) by varying the concentration of a nucleophile (R’OH) was achieved. This type of coupling reaction between electronically differentiated rich and deficient alkenes is rare because copolymerization between the alkenes is common. The results encouraged us to investigate a new process of visible-light-induced double difunctionalization through intramolecular nucleophilic addition of the radical cation [4]. Herein, we report that double difunctionalization of vinyl ether tethered nucleophile 7 provided unique 2:1 adducts through intramolecular nucleophilic addition and intermolecular radical addition in the two-molecule photoredox system (Scheme 1c). This double difunctionalization forms two C–C bonds between electronically differentiated rich and deficient alkenes and one C-heteroatom bond at another site, and is not possible in a one-molecule photoredox system.
Initially, we attempted to optimize the PCs in the visible-light-induced reaction using a blue LED (18 W, 405 nm) of anhydrous acetonitrile containing 2 equiv. of vinyl ether tethered hydroxy group 7a (20 mM) as an electron-rich alkene and acrylonitrile 3A (10 mM) as an electron-deficient alkene in an Ar atmosphere at room temperature to provide the 5-membered acetal product 8aA as a racemic mixture (Scheme 2). BP is an essential PC because oxidation of vinyl ether with a high oxidation potential (+ 1.99 V vs. SCE in CH3CN) [10] requires the radical cation of BP (the oxidation potential of BP = + 1.95 V vs. SCE in CH3CN) [11], as reported in our previous study [5]. As we recently reported, the higher solubility of 9-cyano-10-methoxycarbonylanthracene (CMA) significantly improved the reaction efficiency and yield via visible-light-induced decarboxylation [12]. Photoreaction of 2 equiv. of 7a, 3A, BP (8 mM), and CMA (8 mM) for 1 h resulted in a high yield of 8aA (86%) via intramolecular nucleophilic addition, and BP and CMA were almost completely recovered. The two molecule photoredox system required the high concentrations of PCs due to the low efficiency of electron transfer processes (PET and BET), but they can work as PCs [6]. DCA instead of CMA had low solubility in the acetonitrile solution, which decreased the photoreaction efficiency and the yield of 8aA (27%). Use of a typical visible one-molecule photoredox catalyst such as Ir[dF(CF3)ppy]2(dtbbpy)+ (+ 1.21 V vs. SCE in CH3CN) [13] or the Fukuzumi catalyst (+ 2.06 V vs. SCE in CH3CN) [14] did not provide any 8aA, because the low oxidation ability of the Ir catalyst could not oxidize vinyl ether 7a. In addition, the high BET rate between the radical cation of 7a and reductant part of the Fukuzumi catalyst regenerated starting materials 7a. A similar successful trend was observed for the photoinduced decarboxylation of benzoic acids [7a] and primary carboxylic acids [7b] due to the low efficiency of BET in the two-molecule photoredox system [6]. This combination of BP and CMA was effective in formation of 1:1 or 2:1 adducts in the corresponding conditions with visible-light irradiation of vinyl ethers (1a,b and 7a) and tetrasubstituted alkene 1c with 3A, as shown in Table 1 [3, 4]. For aqueous acetonitrile solution (CH3CN/H2O = 9:1) as a solvent, intermolecular nucleophilic adducts 9aA–cA and 10aA (1:1 adduct) were only obtained in the photoreaction of 1a–c and 7a with 3A. When a mixture solution of acetonitrile and methanol was used, selective formation of 1:1 and 2:1 adducts (11aA and 12aA) was observed by varying the methanol concentration. Thus, the low efficiency of BET in the two-molecule photoredox system using BP and CMA resulted in successful double functionalization of 7a with 3A in anhydrous acetonitrile via the intramolecular nucleophilic addition. This system can be applied to formation of 1:1 or 2:1 adducts via intermolecular nucleophilic addition.
Photoreaction of 7a with 3A using BP and CMA
Next, the scopes of vinyl ether tethered nucleophile 7 and electron-deficient alkene 3 were explored in the same photochemical conditions (Table 2). Similar photoreactions of one-carbon expanded vinyl ether 7b between vinyl ether and hydroxy group moieties led to formation of 6-membered acetal product 8bA with the same yield (86%); two-carbon expanded vinyl ether 6c decreased the yield of 7-membered acetal product 8cA (68%). When 7d,e with methyl groups between vinyl ether and hydroxy group moieties were reacted, slightly decreased yields of products 8dA,eA were observed due to a steric hindrance. Use of relatively poorly electron-deficient alkenes 3B–G instead of 3A resulted in formation of corresponding acetal products 8aB–aG in lower yields because radical oligomerization of the relatively poorly electron-deficient alkenes occurred [15]. It was observed that use of dehydroamino acid 3G as an electron-deficient alkene provided the unique α-amino acid derivatives 8aG as a racemic and diastereomeric mixture. Similar photoreactions of vinyl ether tethered amine 7f,g replacing the hydroxy group with a carbamoyl group provided corresponding double-functionalized products 8fA,gA as racemic and diastereomeric mixtures in moderate yields. Furthermore, vinyl ethers 7h,i derived from bioactive alcohols such as L-serine and L-threonine were converted to a diastereomeric mixture of α-amino acid derivatives 8hA,iA in the same photochemical conditions, even with low yields (Scheme 3). Thus, a variety of electron-rich and electron-deficient alkenes can be used in the photoreaction to provide unique adducts in mild conditions.
Photoreaction of vinyl ethers 7 h,i prepared from L-serine or L-threonine with 3A
Based on the previous [5] and current results, the proposed mechanism is shown in Scheme 4. The radical cation of BP via PET can oxidize 7a to form 7a.+. Use of anhydrous acetonitrile solution as a solvent promoted both dimerization of 7a.+ with 7a and intramolecular nucleophilic addition to generate an electron-rich radical that was added to electron-deficient alkene 3A to provide 2:1 adduct 8aA via BET and protonation. The low efficiency of BET to 7a.+ in the two-molecule photoredox system likely led to successful double difunctionalization of 7a.
Proposed mechanism
In conclusion, we developed a new general method for preparation of double difunctionalized products of vinyl ether tethered nucleophiles such as a hydroxy or carbamoyl group with electron-deficient alkenes using visible-light irradiation in a two-molecule photoredox system (BP/CMA). This process can be used with a variety of alkenes, and can lead to construction of a fundamental framework of complex molecules from simple alkenes.
Data availability
The data that supports the findings of this study are available in the supplementary material of this article.
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Acknowledgements
This work was partially supported by the Japan Society for the Promotion of Science (JSPS), Grant-in-Aid nos. 23K04750 (Y.Y.) and 22K18199 (M.Y.) for scientific research, the Asahi Glass Foundation, Continuation Grants for Outstanding Projects (Y.Y.), and Iketani Science and Technology Foundation (M.Y.).
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Open Access funding provided by University of Fukui. Asahi Glass Foundation, Continuation Grants for Outstanding Projects, Yasuharu Yoshimi, Japan Society for the Promotion of Science, 23K04750, Yasuharu Yoshimi, 22K18199, Mugen Yamawaki, Iketani Science and Technology Foundation
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Ikeda, T., Tanaka, Y., Hashimoto, R. et al. Double difunctionalization of vinyl ether tethered nucleophile with electron-deficient alkene in two-molecule photoredox system. Photochem Photobiol Sci 23, 1417–1423 (2024). https://doi.org/10.1007/s43630-024-00588-5
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DOI: https://doi.org/10.1007/s43630-024-00588-5