Catalyst-Free Photoredox Addition–Cyclisations: Exploitation of Natural Synergy between Aryl Acetic Acids and Maleimide

Suitably functionalised carboxylic acids undergo a previously unknown photoredox reaction when irradiated with UVA in the presence of maleimide. Maleimide was found to synergistically act as a radical generating photoxidant and as a radical acceptor, negating the need for an extrinsic photoredox catalyst. Modest to excellent yields of the product chromenopyrroledione, thiochromenopyrroledione and pyrroloquinolinedione derivatives were obtained in thirteen preparative photolyses. In situ NMR spectroscopy was used to study each reaction. Reactant decay and product build-up were monitored, enabling reaction profiles to be plotted. A plausible mechanism, whereby photo-excited maleimide acts as an oxidant to generate a radical ion pair, has been postulated and is supported by UV/Vis. spectroscopy and DFT computations. The radical-cation reactive intermediates were also characterised in solution by EPR spectroscopy.


General Experimental Section
All reagents and solvents were purchased from either Sigma Aldrich, Alfa Aesar or TCI Europe and used without further purification. Tetrahydrofuran was distilled over sodium and dichloromethane was distilled over calcium hydride. Column chromatography was carried out using Silica 60A (particle size 40-63 µm, Silicycle, Canada) as the stationary phase, and TLC was performed on precoated silica gel plates (0.20 mm thick, Sil G UV 254 , Macherey-Nagel, Germany) and observed under UV light. 1 H and 13 C NMR spectra were recorded on Bruker AV III 500, Bruker AV II 400 and Bruker AV 300 instruments.
Chemical shifts are reported in parts per million (ppm) from low to high frequency and referenced to the residual solvent resonance. Coupling constants (J) are reported in hertz (Hz). Standard abbreviations indicating multiplicity were used as follows: s = singlet, d = doublet, t = triplet, dd = double doublet, q = quartet, m = multiplet, b = broad. Melting points (M.p.) were determined using a Sanyo Gallenkamp apparatus and are reported uncorrected. Mass spectrometry was carried out at the EPSRC National Mass Spectrometry Service Centre, Swansea, UK. UV/Vis spectrometry was carried out using a Cary 50 spectrophotometer (Varian Inc.).

General Procedure for the Preparation of Phenoxy-and Phenylthio-Acetic Acids
To a solution of the phenol/thiol (1 equiv.) in anhydrous THF was added methyl bromo acetate (2 equiv.) and potassium carbonate (5 equiv.) at room temperature. The resultant mixture was refluxed at 80°C for 48-72 hours. The mixture was concentrated under reduced pressure, dissolved in 100 mL CH 2 Cl 2 , washed with H 2 O (3 x 100 mL), dried over MgSO 4 and the solvent removed under reduced pressure. To a solution of the resultant ester (1 equiv.) in MeOH/H 2 O (3:1 v/v) was added LiOH (5 equiv.) at room temperature and allowed to stir overnight. The reaction mixture was concentrated under reduced pressure, dissolved in 100 mL saturated (NH 4 ) 2 SO 4 , adjusted to ca. pH3 and extracted with EtOAc (3 x 100 mL).
The combined extracts were dried over MgSO 4 and the solvent removed under reduced pressure.

Optimisation Studies
The reaction between 4-methoxyphenoxyacetic acid 4d and maleimide 1a was used as a test reaction to determine the optimum reaction conditions. Early work indicated that the reaction generally needed to be run overnight. However, for the purposes of optimisation a reaction time of 5 hours was adopted.
Scheme S2. Test reaction for optimisation studies.

Reaction Stoichiometry
4-Methoxyphenoxyacetic acid 4d (47.4 mg, 0.26 mmol) was dissolved in 10 mL anhydrous MeCN along with various equivalents of maleimide 1. The resultant mixture was degassed for 15 minutes by argon bubbling before being irradiated for 5 hours by two hemispherical banks of six Philips Cleo 15W tubes.

Attempted Synthesis of 9
Maleimide (732 mg, 7.5 mmol) and hydroquinone-O,O'-diacetic acid (169.7 mg, 0.75 mmol) were dissolved in 26 mL CH 3 CN and 7 mL H 2 O and irradiated though pyrex for 18 hours. Following irradiation the reaction mixture was concentrated under reduced pressure. 1

H NMR and GC-MS analyses
revealed that the desired product 9 had not been formed.

X-ray Crystallography
Fig. S1. The X-ray crystal structure of 5g.  S2. The X-ray crystal structure of 5i.

In-situ NMR Monitoring
A 5 mL stock solution of 37.5 mM of the acid 4 and 187.5 mM of maleimide 1a was prepared in a 65 : 35 mixture of CD 3 CN and D 2 O. The solution was purged with argon for 5 minutes before transferring 1 mL to an NMR tube. The tube was irradiated using a 12 x 8 W BLB photoreactor (λ max = 365 nm).

Figure S3.
Irradiation setup for in-situ NMR monitoring.
EPR parameters in table 4 of the main text. Figure S21. EPR spectrum obtained on UV photolysis of methyl (4-methylthiophenoxy) acetate 15 in PhH at 300K. Table 4 of the main text.

EPR parameters in
Computational Methods. The ground-state geometries and energies of the precursor acids and their ions were investigated using the Gaussian 09 program package. The standard UB3LYP functional with the split-valence and with the aug-cc-pvtz basis sets was employed. Geometries were fully optimized with both basis sets without any symmetry constraints for all model compounds. Optimized structures were characterized as minima or saddle points by frequency calculations at the 6-311+G(2d,p) level. The experimental EPR data was all obtained in the non-polar hydrocarbon solvents tert-butylbenzene or benzene. Solvent effects, particularly differences in solvation between the neutral reactants and neutral transition states, are therefore expected to be minimal for the EPR work. However, the addition/cyclisation reactions were carried out in acetonitrile/water. In an attempt to model the effect of solvent the CPCM polarizable conductor calculation model was then applied, with acetonitrile as the solvent, and with the aug-cc-pvtz basis set and geometry.

Dihedral vs rel E 4-MeOPhOCH2cat
Center Atomic Atomic Coordinates (Angstroms) Number Number