Photoredox radical conjugate addition of dithiane-2-carboxylate promoted by an iridium(iii) phenyl-tetrazole complex: a formal radical methylation of Michael acceptors

An iridium(iii) phenyl-tetrazole complex is a versatile catalyst for a new photocatalytic Michael reaction.


Table of contents:
General methods and materials S3 Optimization of radical conjugate addition of dithiane-2-carboxylate S4 Preparation of the starting Michael acceptors S5 Preparation of 2-substituted 1,3-dithiane-2-carboxylate 4b,c S7 Photoredox radical conjugate addition of carboxylates S8 Characterization data of products 5a-t, 15 and 16 S8 Reductive removal of the dithiane moiety S13 Hydrolysis of the dithiane moiety S14 Reaction in presence of TEMPO S15 Preparation of ammonium salts 17, 18, 19 S16 Photoredox radical conjugate addition of salt 17 S17 Photostability of Ir(III) complex 2 S17 Photophysical and electrochemical data S19 Determination of quantum yield S21

References S21
Copies of NMR spectra S23 Copies of IR spectra S61

Optimization of radical conjugate addition of dithiane-2-carboxylate
Compounds 3a-d were prepared following reported procedure. 5 To a solution of proline (1 mmol, 0.115 g) in DMSO (3.3 mL) aldehyde (10 mmol) was added. After 10 min. malonate (10 mmol) was slowly added and the reaction stirred overnight. The reaction mixture was diluted with Et 2 O (30 mL) and washed with water (20 mL), NaHCO 3 sat. sln. (20 mL) and brine (20 mL). The organic phase was concentrated under reduced pressure and the residue was purified by column chromatography on silica (cyclohexane:ethyl acetate from 95:5 to 90:10) to give pure 3a-d as white oils (65-84% yields). Spectroscopic data were according to the literature. 6

HOOC COOH
MeOH, reflux To a solution of itaconic acid (3.9 mmol, 0.500 g) in MeOH (10 mL Compounds 3j,k were prepared following reported procedure. 7 A mixture of ester (7.0 mmol, 1.044 g, 1 mL), paraformaldehyde (10.5 mmol, 0.313 g) and K 2 CO 3 (7.0 mmol, 0.960 g) in DMF (5 mL To a solution of 1,3-dithiane-2carboxylate (0.95 mmol, 0.183 g, 154 L) in THF (3 mL), NaH (60% suspension in mineral oil, 1.9 mmol, 0.076 g) was slowly added at 0°C. The reaction mixture was gently heated at 70°C for 20 min. and cooled at room temperature. Alkylating agent (1.4 mmol) was added and the reaction mixture was stirred overnight. After that, the reaction was cooled at 0°C, water (10 mL) and ethyl acetate (20 mL) were added and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (2 x 20 mL). The collected organic layers were washed with brine (10 mL), dried over Na 2 SO 4 and concentrated under reduced pressure to give the crude ester product.
The residue was dissolved in tBuOH (4 mL) and 1M KOH aq. (4 mL) was added. After 24 hours volatiles were evaporated under reduced pressure, water (10 mL) and Et 2 O (20 mL) were added and the organic layer was separated. The aqueous layer was extracted with Et 2 O (2 x 10 mL). 5 M HCl aq. was slowly added to aqueous layer until pH = 1, and they were extracted with DCM (4 x 20 mL). The collected organic layers were washed with brine (10 mL), dried over Na 2 SO 4 and concentrated under reduced pressure to give pure compounds as white solids, that were used in the photocatalytic reaction without further purification.   PhI(OAc) 2 method: 11 Bis(trifluoroacetoxy)iodobenzene (52 mg, 0.16 mmol) was added at 0°C to a stirred solution of 5a or 5t (0.1 mmol), water (1 mL) and CH 3 CN (9 mL). After it was stirred at room temperature for 30 min, the reaction was quenched with NaHCO 3 sat. sln. (10 ml) and the volatiles were evaporated. The residue was dissolved in ethyl acetate (20 mL) and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (3 x 10 mL). The collected organic layers were washed with brine (10 mL), dried over Na 2 SO 4 and concentrated under reduced pressure to give the crude product. Column chromatography on silica (cyclohexane:ethyl acetate from 95:5 to 80:20) afforded pure products.  Evidence of a possible radical mechanism was determinate by performing the reaction in the presence of radical scavengers like TEMPO (2,2,6,6-tetramethylpiperidine 1-oxyl).

Hydrolysis of the dithiane moiety
Two different experiments were conducted in the presence of a catalytic (20 mol%) and stoichiometric amount of TEMPO. In both cases no formation of product or adduct between TEMPO and reaction intermediates were observed.  To determinate if tetrabutylammonium salt 17 is a suitable substrate for the photoredox radical conjugate addition we tested it in the reaction using general procedure without the presence of K 2 HPO 4 as base. Product 5a was obtained in 72% of yield, demonstrating the possibility to use tetrabutylammonium carboxylate as substrate.

Photostability of Ir(III) complex 2
In order to test its photostability during the reaction, complex 2 was dissolved in degassed deuterated DMSO and was irradiated using blue light LED for 24 hours in order to replicate the reaction conditions. Any possible photolysis was monitored by 1 H NMR spectroscopy. As reported in Figure S1, less than 5% of complex 2 undergoes to photochemical decomposition after 24 hours of irradiation, revealing its good photostability under reaction conditions, differently from complex   The reaction was carried out in spectrofluorimetric grade DMSO and placed in a Suprasil® quartz cuvette with a 2.00 mm path length. The cuvette was charged with the ammonium carboxylate 17 (81 mg, 0.20 mmol, 1 equiv), the Michael acceptor 3a (80 mg, 0.40 mmol, 2 equiv), the iridium photocatalyst 2 (1.7 mg, 0.0020 mmol), and 500 µl of DMSO. Before irradiating the sample, dissolved oxygen was removed from the cuvette by argon bubbling for 15 minutes. The reaction mixture was excited at 334 nm for exactly 7 hours, using a 100 W Hg lamp equipped with an appropriate dichroic filter. During this process, the solution was stirred and kept at constant temperature.
The photon flux coming from the lamp to the sample in the cuvette was estimated using the ferrioxalate actinometer (photon flux: 1.97 nmol/s). 14 This experimental value was also confirmed by using a calibrated silicon diode (light power: 0.6 mW, corresponding to a photon flux of 2 nmol/s at 334 nm). In our experimental conditions, all the incident light is quantitatively absorbed by the iridium photocatalyst (A > 3 at 334 nm).
The product formation was determined by 1 H-NMR based on the relative conversion of the carboxylate derivative.
After irradiation, the estimated conversion was 7%, corresponding to 14 µmol of product formed.