Article pubs.acs.org/joc
Cite This: J. Org. Chem. 2019, 84, 9257−9269
Visible-Light-Triggered Selective Intermolecular [2+2] Cycloaddition of Extended Enones: 2‑Oxo-3-enoates and 2,4-Dien-1-ones with Olefins Lei-Min Zhao,†,‡,⊥ Tao Lei,†,‡,⊥ Rong-Zhen Liao,§ Hongyan Xiao,†,‡ Bin Chen,†,‡ Vaidhyanathan Ramamurthy,∥ Chen-Ho Tung,†,‡ and Li-Zhu Wu*,†,‡
Downloaded via IDAHO STATE UNIV on July 19, 2019 at 12:02:23 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.
†
Key Laboratory of Photochemical Conversion and Optoelectronic Materials, Technical Institute of Physics and Chemistry, The Chinese Academy of Sciences, Beijing 100190, P. R. China ‡ School of Future Technology, University of Chinese Academy of Sciences, Beijing 100049, P. R. China § School of Chemistry and Chemical Engineering, Huazhong University of Science and Technology, Wuhan 430074, P. R. China ∥ Department of Chemistry, University of Miami, Coral Gables, Miami, Florida 33146, United States S Supporting Information *
ABSTRACT: Photosensitization has recently re-emerged owing to the current interest in visible-light catalysis. One of the photoreactions investigated in this context, namely, photo[2+2]cycloaddition of olefins, is established to show high selectivity and wide generality. Here, we describe the results of our studies on selective intermolecular cycloaddition between extended enones (2,4-dien-1-ones and 2-oxo-3-enoates) and olefins under visible-light sensitization. With Ru(bpy)3Cl2 as the triplet energy sensitizer, [2+2] addition of 2,4-dien-1-ones to olefins resulted in the addition to the “ene” part of enones with high efficiency. Generality and functional group tolerance were established by examining a number of enones. 2-Oxo-3-enoates also underwent addition to olefins in the presence of Ru(phen)3(PF6)2. Both additions were more efficient in the presence of the triplet sensitizer than upon direct irradiation. No Paternò−Büchi product was detected. Density functional theory calculations revealed the origin of high selectivity in the two extended enone systems. Together with spectroscopic studies and control experiments, the cycloaddition has been demonstrated to occur from the excited triplet state of these extended enones, which were generated via the energy transfer process.
■
INTRODUCTION Cyclobutanes and their derivatives play a predominant role in the synthesis of pharmaceutical products and commercialvalued materials.1 One convenient and extensively employed method to build a cyclobutane skeleton is the [2+2] cycloaddition between an excited- and a ground-state olefin.2 Use of visible light in initiating photoreactions,3 a topic of current interest, is particularly appealing in building cyclobutanes because of the following advantages: (a) the low cost and decreased energy demand of the visible-light source, (b) feasibility to conduct a photoreaction without the need of specific photoreactors or quartz-wares, and (c) ability to selectively excite a photosensitizer without directly exciting the reactant molecules. © 2019 American Chemical Society
Among the various photocycloaddition reactions, addition of excited enones4 to olefins has been extensively investigated. It is well known that under visible-light photocatalysis (VLPC), olefins and α,β-enones undergo intra-5,6 and intermolecular7,8 [2+2] cycloaddition to form cyclobutanes via single-electron transfer (SET)5,7 and energy transfer (ET)6,8 pathways. Given the usefulness of above cycloaddition reactions in synthesis, we thought it is important to examine the behavior of α,β-enones with extended conjugation (extended CC and CO bonds). It was anticipated that such an extended conjugation will shift the absorption to longer wavelengths and lower the Received: May 12, 2019 Published: June 18, 2019 9257
DOI: 10.1021/acs.joc.9b01273 J. Org. Chem. 2019, 84, 9257−9269
Article
The Journal of Organic Chemistry Scheme 1. Intermolecular Cycloadditions of Extended Enones
excited singlet and triplet state energies. Thus, these systems would be ideally suited for VLPC. However, one problem we foresaw with such systems behaving like a diene would offer an additional site for photoaddition. Thus-far reported studies on cyclic dienones focused on direct irradiation, and the products were formed with poor selectivity.9 An example of interest is the addition of a diene-incorporated acyl imidazole to an olefin reported by Meggers.8c This addition is facilitated by coordination with an asymmetric Lewis acid. Extended enones like enediones/eneketoesters are known to undergo Paternò− Büchi reaction to yield oxetanes.10 This prompted us to probe whether π-extended conjugated enone molecules would react at the CO or CC end of the molecule. Here, we disclose our recent results on the intermolecular [2+2] reaction of excited 2,4-dien-1-ones (enones involving additional CC bonds; dienones) and excited 2-oxo-3-enones (enediones or eneketoesters involving additional CO bonds) with groundstate olefins such as 1,1-diphenylethylene (Scheme 1). When a mixture of 2,4-dien-1-ones, terminal olefins, and a visible-lightabsorbing photocatalyst was irradiated, cyclobutanes were obtained via intermolecular [2+2] addition to the α,β- CC bond of the dienone. Similar addition also occurs when 2-oxo3-enoates and olefins were photocatalyzed by visible-lightabsorbing catalysts. Thus, in these two cases, extension of the enone with either CC or CO functionality did not alter the reactivity of the parent system. Results presented here for the two classes of molecules derived from α,β-enones under visible-light photocatalysis (VLPC) conditions, we believe, are valuable in building complex organic molecules.
Table 1. Optimizations of the [2+2] Conditions of 2,4-Dien1-onea
entry
catalyst
solvent
yield (%)b
d.r.
1 2 3 4 5 6 7 8c 9
Ir(ppy)3 Ru(bpz)3Cl2 Ru(bpy)3Cl2 Ru(bpy)3Cl2 Ru(bpy)3Cl2 Ru(bpy)3Cl2 Ru(bpy)3Cl2 Ru(bpy)3Cl2 no PC
MeCN MeCN MeCN MeOH EtOH i-PrOH HFIP HFIP HFIP
52 26 59 69 63 56 93 N.D N.D
5:1 3:1 5:1 5:1 5:1 5:1 5:1
a
The reactions were carried out in 2.5 mL of the solvent with 0.1 mmol 1a, indicated 2a, and 2 mol % PC (0.8 mM) under the irradiation of blue LEDs (λ = 455 nm) for 10 h. bYields and d.r. (anti:syn) were determined by 1H NMR using biphenylacetonitrile as the internal standard. cDark conditions, N.D = not detected.
yield; Table 1, entries 3−7). Further control experiments confirmed the necessity of visible light and the photocatalyst. Omitting any one of the two components (photocatalyst or visible light) yielded no addition product (Table 1, entries 8 and 9). Having identified the optimum reaction condition, we proceeded to explore the scope of the [2+2] reaction between 2,4-dien-1-ones and various olefins (Scheme 2). Products and their yields are summarized in Scheme 2. From the data, it is clear that (a) the electronic nature of the para-aryl group substitution on the dienone including methyl, methoxyl, halogen atom, and CF3 had a little influence on the conversion efficiency (3aa−3ia). Even strongly withdrawing group NO2 gave 31% isolated product (3ja). (b) The position of the methoxyl substituent on the phenyl ring showed a little difference in the conversion [p-OCH3, 97% (3ca); o-OCH3, 96% (3da); and 98% m-OCH3, (3ea)], indicating the absence of the steric effect caused by the substitution of an aryl group. (c) Introduction of a naphthalene ring led to a single isomer with a moderate yield. (d) More importantly, less conjugated 2,4-dienoates (nonaryl systems) were also smoothly converted
■
RESULTS AND DISCUSSION Intermolecular [2+2] Reaction of 2,4-Dien-1-one under VLPC Condition. To avoid complications caused by geometric isomerization of the terminal double bond, we initiated the study with 2,4-dien-1-one 1a and olefin 2a as substrates and Ir(ppy)3 as the photocatalyst. When a mixture of 0.1 mmol 1a, 0.5 mmol 2a, and 2 mol % Ir(ppy)3 in acetonitrile (MeCN) was irradiated with blue LEDs (λ = 455 nm) for 10 h, a cyclobutane product derived from the CC bond adjacent to the carbonyl group was obtained in 52 % yield and 5:1 d.r. (Table 1, entry 1). Screening of several photocatalysts revealed that Ru(bpy)3Cl2 was the best (Table 1, entries 1−3). Optimization of the solvents suggested that hexafluoro-iso-propanol (HFIP) was the most suitable (93% 9258
DOI: 10.1021/acs.joc.9b01273 J. Org. Chem. 2019, 84, 9257−9269
Article
The Journal of Organic Chemistry Scheme 2. Generality of the Cycloaddition of 2,4-Dien-1-ones with Terminal Olefina
a Reaction conditions: the reactions were carried out in 2.5 mL of HFIP with 0.1 mmol 1, 5 equiv 2, and 2 mol % Ru(bpy)3Cl2 (0.8 mM) under the irradiation of blue LEDs (λ = 455 nm) for 10 h. Yields and d.r. (anti:syn) were determined by 1H NMR using biphenylacetonitrile as the internal standard; the ones in parenthesis are isolated yields.
to anti-products (3la, 3ma, 3na, and 3oa). (e) The structure of the photoproduct 3ha was confirmed to have anti-configuration by X-ray diffraction. In all other cases, 1H and 13C NMR spectra were employed to confirm the structure of the products (see the Supporting Information). (f) To probe the generality of the participating olefin, the structure of the diphenylethylene was modified. Different substitutions like methyl (3ab), F (3ad), and Br (3af) showed good tolerance. Methoxyl (3ac) and Cl (3ae) led to moderate results due to the lower solubility in HFIP. From the above discussion, it is clear that the cycloaddition is specific and occurred only at the α, β bond of the dienones. The reaction proceeded smoothly with the dienone containing different electronic features. Similarly, the reaction was also general from the perspective of the 1,1-diaryl ethylene. Intermolecular [2+2] Cycloaddition of 2-Oxo-3enoates with Olefins under VLPC Condition. Recently, Luo’s group11 has reported the cycloaddition of the methyl ester of 2-oxo-3-enoate 4a to yield the [2+2] adduct with styrenes via direct irradiation. Given the compound has virtually no absorption at 455 nm, we believed that a better approach to conduct the cycloaddition was to use a visiblelight-absorbing catalyst, that is, a triplet sensitizer. With this in
mind, we performed the photocycloaddition of 2-oxo-3enoates using Ru(bpy)3Cl2 as the visible light-absorbing catalyst. A mixture of 0.1 mmol 2-oxo-3-enoate 4a, 0.5 mmol 2a, and 2 mol % Ru(bpy)3Cl2 in 1,2-dichloroethane (DCE) was irradiated with blue LEDs (λ = 455 nm) for 10 h (see the Supporting Information, Table S1). Isolation of the product gave a cyclobutane in moderate yield (57%, Table S1, entry 1) and with high diastereoselectivity (d.r. > 20:1). To identify the optimum condition for this reaction, several catalysts and solvents were examined. Ru(phen)3(PF6)2 and acetone were found to be the best catalyst and the solvent, respectively (for details, see the Supporting Information, Table S1). Experiments with varying concentrations of the olefin revealed that excess olefin was not required for this selective cross [2+2] cycloaddition under VPLC conditions. This is different from the direct irradiation conditions wherein 5-fold excess amount was required.11 To prove the role of VLPC, additional reactions were carried out in different solvents with and without Ru(phen)3(PF6)2. Under the optimum condition of 1.2 equiv olefin 2a in acetone, direct irradiation without the photocatalyst led to 56% yield and 9:1 diastereoselectivity (Table 2, entry 1). Results in other solvents like DCE, dioxane, dimethyl sulfoxide, and 9259
DOI: 10.1021/acs.joc.9b01273 J. Org. Chem. 2019, 84, 9257−9269
Article
The Journal of Organic Chemistry
acetonitrile gave similar low yields. On the contrary, the presence of Ru(phen)3(PF6)2 enhanced the yield of adduct to 98% and >20:1 d.r. in acetone. Apparent enhancement was also obtained in other tested media. These results confirmed the positive influence of VLPC on this reaction. Keeping the above solution in dark did not result in a reaction (Table S1 in SI, entry 10), confirming the necessity of visible light. More importantly, we established the synthetic value of the reaction by isolating the cyclobutane product in 82% yield upon irradiating 4a and 2a in gram scales in the presence of Ru(phen)3(PF6)2 (2 mol %) (Table S1, entry 13). The generality of Ru(phen)3(PF6)2 photocatalyzed cycloaddition was established by examining the behavior of more than two dozen substituted 2-oxo-3-enoates toward different terminal olefins, which included substituted diphenylalkenes, styrenes, and dialkylated alkenes (Scheme 3). Perusal of the product yields listed in Scheme 3 leads to the following conclusions: (a) Highly efficient cycloaddition occurred between 2-oxo-3-enoates and diphenyl alkene, with different electron-donating (5ea, 5fa, and 5ka) and electron-withdrawing (5ba, 5ca, 5da, 5ia, and 5ja) groups on the phenyl ring of 2-oxo-3-enoates. This suggested that the cycloaddition
Table 2. Importance of PC in the [2+2] Reactions of 2-Oxo3-enoates with Olefins under VLPC Conditiona
with PC
without PC
entry
solvent
yield (%)
d.r.
yield (%)
d.r.
1 2 3 4 5
acetone DCE dioxane DMSO MeCN
98 89 56 44 85
>20:1 15:1 15:1 10:1 15:1
56 25 40 20 45
9:1 8:1 4:1 3:1 1.2:1
a
The reactions were carried out in 2.5 mL of the solvent with 0.1 mmol 4a, 1.2 equiv 2a, and 2 mol % PC (0.8 mM) (or not) under the irradiation of blue LEDs (λ = 455 nm) for 10 h. Yields and d.r. (anti:syn) were determined by 1H NMR using biphenylacetonitrile as the internal standard. The structure of the product was the same with or without PC.
Scheme 3. Generality of the Cycloaddition of 2-Oxo-3-enoates with Terminal Olefinsa,b
a Reaction conditions: the reactions were carried out in 2.5 mL of acetone with 0.1 mmol 4, 1.2 equiv 2, and 2 mol % Ru(phen)3(PF6)2 (0.8 mM) under the irradiation of blue LEDs (λ = 455 nm) for 10 h. Unless noted, yields are isolated yields; the yields in parenthesis and d.r. were determined by 1H NMR using biphenylacetonitrile as the internal standard. The configuration of the aryl group and the carbonyl group is anti (anti:syn > 20:1). With regard to the product 5af, the 2:1 d.r. was introduced by another chiral center from the asymmetric olefin. bAliphatic olefins were added in 5 equiv and irradiated for 20 h.
9260
DOI: 10.1021/acs.joc.9b01273 J. Org. Chem. 2019, 84, 9257−9269
Article
The Journal of Organic Chemistry
energy transfer have been established in visible-light-induced intermolecular [2+2] cycloaddition of enones. Oftentimes, the same catalyst could act both as an electron7a and an energy transfer8d,8f catalyst. The former process was established for 1phenylalkyl-2-en-1-one derivatives7a,d and the latter for chalcone and cinnamic acid esters.8 Since the extension of enones with an additional CC or CO bond would lead to changes in both electronic and excited-state properties, consequent changes in the mechanism were likely. To probe the mechanism involved in this study, we undertook a detailed mechanistic study. First, we studied the spectroscopic and electrochemical properties of these two extended enones. As illustrated in the Supporting Information, 2,4-dien-1-one 1a does not absorb the blue light and only the photocatalyst absorbs the visible light. At room temperature, upon excitation, Ru(bpy)3Cl2 showed an emission with a maximal wavelength (λmax) of 573 nm (Figure S1).13 The above emission was quenched by 1a with a rate constant of 9.70 × 108 M−1·s−1 (Figure S2).14 Based on electrochemical data [ERu(III/II*) = −1.14 V vs SCE, E(1a/1a)−· < −1.2 V vs SCE, ΔG > 0.06 eV; ERu(II*/I) = 1.17 V vs SCE, E(2a/2a)+· = 1.44 V vs SCE, ΔG = 0.27 eV] (Table 3, Figure S5),
was independent of the electronic effect on the aryl group substituted on the enone moiety. (b) Phenyl and other alkylmodified substrates (5ma, 5na, and 5oa) at the ester moiety showed equal efficiency as 5a. (c) Bulkiness of o- and mmethyl groups on the aryl ring had a moderate effect on the conversion (5ga and 5ha). (d) 2-Oxo-3-enoates with a larger aromatic group like naphthalene (5la) gave the cycloadduct in 95% yield. (e) With regard to styrene reactants, 1,1diphenylalkenes bearing electron-donating and electron-withdrawing groups reacted with 4a in good yields (5ab, 5ac, 5ae, and 5af). Monosubstituted terminal styrenes gave adduct (5ag) in moderate yield with 2:1 d.r. (f) Dialkylated alkenes such as methylidene-cyclopentane gave moderate yields of the cycloadducts 5ah. In the absence of our ability to obtain crystals of the product 5, we relied on 1H NMR to characterize the structure of adducts, which could be either head-to-head or head-to-tail. To ascertain the regiochemistry of the products isolated in this part, enolization and H−D exchange of 5aa were performed in DMSO-d6 with Cs2CO3 as the base.12 It was anticipated that replacement of H by D would help confirm the structure of the cycloadduct (Figure 1). According to the 1H NMR spectrum
Table 3. Redox Potentials of Each Componenta entry
compound
E1/2 (M+/M)
E1/2 (M/ M−)
1b 2b 3b 4c 5c 6c
1a 2a Ru(bpy)32+ 4a 2a Ru(phen)32+
>1.6 1.44 1.23 0.84 >1.6 1.35
