H -furo[3‘,2’:3,4]cyclobuta-[1,2-b]chromen-4-one: A Flavone-Based [2 + 2]-Photocycloadduct

: The intermolecular [2 + 2]-photocycloaddition of the parent ﬂavone molecule ( 4 ) as the triplet energy-accepting species and the electron-rich alkene 2, 3-dihydrofuran ( 5 ) was performed by visible-light-mediated triplet-sensitization with an iridium-based organometallic sensitizer. The reaction proceeds with high diastereo- and regioselectivity (>98:2 for the regiochemical orientation and with 95% d.s.). In contrast to numerous other ene/enone combinations that are described in the literature and were also performed by us, the reaction between 4 and 5 almost solely afforded the cis - syn - cis cyclobutane 6, whereas analogous conjugated six- and ﬁve-membered cycloalkenones preferentially react to cis - anti - cis cyclobutanes or a mixture of both diastereoisomers (e.g., for the cyclohexanone-derived example 9 ).


Introduction
The [π 2 + π 2 ]-photocycloaddition of two alkene (ene/ene, enone/enone or enone/ene combinations) components with the formation of cyclobutanes is the prime example for a basic photochemical reaction that has been studied extensively-and periodically reviewed-over the last 60 years [1][2][3][4]. These cyclobutanes are interesting molecular scaffolds that find application in natural product synthesis and as precursors for organic synthesis. They are well suited for fragmentation or ring-enlargement reactions facilitated by their high ring strain [5][6][7][8][9][10]. While earlier examples were mainly focused on direct excitation of the substrates with highly energetic UV light [11][12][13][14], recent advances derived milder approaches by irradiation with visible light [15][16][17][18]. Over the last two decades, tremendous improvements on the field of enantioselective [2 + 2]-photocycloaddition reactions emerged from the pioneering work of the research groups of Bach [19,20], Meggers [21], Yoon [22,23] and others. The spin state of the electronically excited component in these bimolecular processes is predominantly triplet, either from fast ISC out of the initially formed singlet excited state or via triplet-triplet energy transfer. Our interest in spin-selective processes and the consequences of spin state on the regio-and diastereoselectvity initiated a systematic study on the donor/acceptor enone/ene (1/2) -combinations in intermolecular photocycloadditions [24] (Scheme 1). The non-symmetric enone/ene substrates 1 and 2 can combine in a 1,2-or 1,3-regioisomeric fashion and with formation of four stereogenic centers, resulting in a maximum of 16 possible cyclobutane isomers with eight diastereoisomers of 31,2 and 31,3. Due to the fact that the triplet [2+2]-photocycloaddition cannot proceed in a concerted fashion, the two carbon-carbon bond-forming steps are separated in time and the selectivity-deter-Scheme 1. Intermolecular enone/ene photocycloaddition: 16 possible products. The non-symmetric enone/ene substrates 1 and 2 can combine in a 1,2-or 1,3regioisomeric fashion and with formation of four stereogenic centers, resulting in a maximum of 16 possible cyclobutane isomers with eight diastereoisomers of 3 1,2 and 3 1,3 . Due to the fact that the triplet [2 + 2]-photocycloaddition cannot proceed in a concerted fashion, the two carbon-carbon bond-forming steps are separated in time and the selectivitydetermining steps are also separated: (a) the regioselectivity is determined by the triplet biradical stability; at least numerous examples imply this relationship, (b) the diastereoselectivity of the first C-C-bond formation is determined by Csp 2 -Csp 2 -overlap geometry and often follows well-known ground-state rules, (c) the diastereoselectivity for the second C-C-bond (finishing the cyclobutane formation) is determined by optimal triplet biradical intersystem-crossing geometries, mostly the best geometries for large spin-orbit-couplings (SOC-geometries) [25].
One specific naturally occurring cyclic enone structure is 2-phenylchromen-4-one, the basic flavone molecule. Flavonoids are important biomaterials that are commonly found in nature as pigments in plants. The field of application is broad, from nutrition, pharmaceuticals to the application in cosmetics. Their medicinal properties include antioxidative, anti-inflammatory, anti-mutagenic and anti-carcinogenic activity [26][27][28][29]. Due to their highly conjugated π-system, these molecules are well suited chromophores that have been investigated in several photophysical and -chemical studies and assimilate cyclic chalcone derivatives [30][31][32]. Flavone (4) is such an example from which excitation occurs at λ max = 365 nm with quantum yields for ISC close to unity (Φ ISC = 0.9) to its triplet state by a π,π*-transition (E T = 2.69 eV, 3 τ = 4.5 µs) [33,34]. Thus, direct excitation is possible with UV-A radiation or purple light. On the other hand, triplet sensitization appears feasible with diverse triplet sensitizers that absorb in the visible region and can be excited with blue LEDs as the cheap and versatile state-of-the-art light sources.

Discussion
Based on the photophysical and electrochemical properties of the photocatalyst (ET = 2.58 eV) as well as the substrates, a photosensitized energy-transfer mechanism can be anticipated. The triplet energy of flavone was reported between 2.7 and 2.8 eV [33,34], a recent TT absorption study and computational investigation reported a value of 2.59 eV for the lowest (ππ*) T1-state [36]. The energy difference between 4 and the photocatalyst is thus approximately 0 to 4 kcal/mol and thus, isoenergetic or slightly endergonic energy transfer can be expected. As already established for the well-known triplet-triplet energy transfer processes with cis-and trans-stilbene, slightly endergonic energy transfer happens with still high-rate constants between 10 8 and 10 9 M-s −1 [37]. The flavone / Ir(F) pair is one of these examples that is expected to generate a vibrationally cold T1 state of the energy acceptor.
In contrast to the parent flavone, similar [2+2]-photocycloaddition reactions [24] only resulted in the anti-isomer 9 from cyclohexanone 7 with high diastereo-and regioselectivity (Scheme 3). Based on theories proposed in the literature [14,38], the syn-isomer should be favored over the anti-isomer due to stronger orbital interaction in the succeeding electronically excited π-complex (exciplex). However, steric interactions were proposed to inhibit or reduce the formation of syn-isomer, which were shown to result in an increased anti-fusion.
In case of the parent flavone, the rigid structure would reduce these steric interactions with the alkene and may, therefore, be responsible for the selectivity shift (Scheme 4). However, a different explanation may derive from the electronic contribution of the additional oxygen of flavone in comparison to cyclohexanone 7. Hence, electrostatic interactions could also be responsible for the preferred orientation of the substrates. Either way, these observations may more likely indicate that the diastereoselectivity of the cycloaddition is determined prior to the formation of the 1,4-biradical intermediate, i.e., in the initial

Discussion
Based on the photophysical and electrochemical properties of the photocatalyst (E T = 2.58 eV) as well as the substrates, a photosensitized energy-transfer mechanism can be anticipated. The triplet energy of flavone was reported between 2.7 and 2.8 eV [33,34], a recent TT absorption study and computational investigation reported a value of 2.59 eV for the lowest (ππ*) T 1 -state [36]. The energy difference between 4 and the photocatalyst is thus approximately 0 to 4 kcal/mol and thus, isoenergetic or slightly endergonic energy transfer can be expected. As already established for the well-known triplet-triplet energy transfer processes with cisand trans-stilbene, slightly endergonic energy transfer happens with still high-rate constants between 10 8 and 10 9 M-s −1 [37]. The flavone/Ir(F) pair is one of these examples that is expected to generate a vibrationally cold T 1 state of the energy acceptor.
In contrast to the parent flavone, similar [2 + 2]-photocycloaddition reactions [24] only resulted in the anti-isomer 9 from cyclohexanone 7 with high diastereo-and regioselectivity (Scheme 3). Based on theories proposed in the literature [14,38], the syn-isomer should be favored over the anti-isomer due to stronger orbital interaction in the succeeding electronically excited π-complex (exciplex). However, steric interactions were proposed to inhibit or reduce the formation of syn-isomer, which were shown to result in an increased anti-fusion. triplet exciplex. In summary, the reported reaction adds a new stereochemical feature to the broad field of visible-light-induced 2+2-cycloadditions [39].
In case of the parent flavone, the rigid structure would reduce these steric interactions with the alkene and may, therefore, be responsible for the selectivity shift (Scheme 4). However, a different explanation may derive from the electronic contribution of the additional oxygen of flavone in comparison to cyclohexanone 7. Hence, electrostatic interactions could also be responsible for the preferred orientation of the substrates. Either way, these observations may more likely indicate that the diastereoselectivity of the cycloaddition is determined prior to the formation of the 1,4-biradical intermediate, i.e., in the initial triplet exciplex. In summary, the reported reaction adds a new stereochemical feature to the broad field of visible-light-induced [2 + 2]-cycloadditions [39]. Scheme 3. A comparable energy-transfer sensitized photocycloaddition of 3-phenylcyclohexenone with 2,3-dihydrofuran [24].

Materials and Methods
1 H-NMR spectra were recorded on a Bruker Avance 500 spectrometer (Bruker, Ettlingen, Germany) instruments operating at 500 MHz. Chemical shifts are reported as δ in ppm and the coupling constants J in Hz units. In all spectra, the solvent peaks were used as the internal standard. Solvents used were CDCl3 (δ = 7.26 ppm). Splitting patterns are designated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; the 13 C-NMR spectra were recorded on a Bruker Avance 500 spectrometer instrument operating at 125 MHz. High-resolution mass spectra (HR-MS) were recorded on a LC/MS LTW Orbitrap LX (Thermo Fischer Scientific, Waltham, MA, USA) and measured for the molecular ion peak (M + H + and M + Na + ). GC-MS measurements were performed with a Varian 4000 device (now Agilent) with helium as the carrier gas and a silica fused WCOT column with a standardized method [50 °C (5 min), 20 °C/min→280 °C (18 min)]. IR spectra were obtained on a Si crystal Fourier Transform spectrometer by Thermo Scientific (Nicolet 380 FT-IR). Solvents for column chromatography were distilled prior to use (c-Hex, EtOAc); acetonitrile was used in HPLC grade or higher. For photolysis, an LED Pow-erBar (Osram, Munich, Germany) with 12 blue LEDs (Ptotal = 14 W, λ em max = 455 nm) was placed horizontally to the middle of the reaction tube in a distance of 4 cm (±1 cm) to the sample.

Materials and Methods
1 H-NMR spectra were recorded on a Bruker Avance 500 spectrometer (Bruker, Ettlingen, Germany) instruments operating at 500 MHz. Chemical shifts are reported as δ in ppm and the coupling constants J in Hz units. In all spectra, the solvent peaks were used as the internal standard. Solvents used were CDCl 3 (δ = 7.26 ppm). Splitting patterns are designated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad; the 13 C-NMR spectra were recorded on a Bruker Avance 500 spectrometer instrument operating at 125 MHz. High-resolution mass spectra (HR-MS) were recorded on a LC/MS LTW Orbitrap LX (Thermo Fischer Scientific, Waltham, MA, USA) and measured for the molecular ion peak (M + H + and M + Na + ). GC-MS measurements were performed with a Varian 4000 device (now Agilent) with helium as the carrier gas and a silica fused WCOT column with a standardized method [50 • C (5 min), 20 • C/min→280 • C (18 min)]. IR spectra were obtained on a Si crystal Fourier Transform spectrometer by Thermo Scientific (Nicolet 380 FT-IR). Solvents for column chromatography were distilled prior to use (c-Hex, EtOAc); acetonitrile was used in HPLC grade or higher. For photolysis, an LED PowerBar (Osram, Munich, Germany) with 12 blue LEDs (P total = 14 W, λ em max = 455 nm) was placed horizontally to the middle of the reaction tube in a distance of 4 cm (±1 cm) to the sample.