Alkyne–Alkene [2 + 2] cycloaddition based on visible light photocatalysis

UV-activated alkyne–alkene [2 + 2] cycloaddition has served as an important tool to access cyclobutenes. Although broadly adopted, the limitations with UV light as an energy source prompted us to explore an alternative method. Here we report alkyne–alkene [2 + 2] cycloaddition based on visible light photocatalysis allowing the synthesis of diverse cyclobutenes and 1,3-dienes via inter- and intramolecular reactions. Extensive mechanistic studies suggest that the localized spin densities at sp2 carbons of alkenes account for the productive sensitization of alkenes despite their similar triplet levels of alkenes and alkynes. Moreover, the efficient formation of 1,3-dienes via tandem triplet activation of the resulting cyclobutenes is observed when intramolecular enyne cycloaddition is performed, which may serve as a complementary means to the Ru(II)-catalyzed enyne metathesis. In addition, the utility of the [2 + 2] cycloaddition has been demonstrated by several synthetic transformations including synthesis of various extended π-systems.


Optimization of reaction conditions
Optimization procedure : Di(p-tolyl)acetylene 1a (0.05 mmol, 1.0 equiv.), N-methylmaleimide 2a (1.5 equiv.), and photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (PC I) were added to an oven-dried 4 mL vial equipped with a stir bar. The combined materials were dissolved in solvent under argon atmosphere in glovebox. The reaction mixture was then irradiated by 12 W blue LED strip at room temperature (maintained with a cooling fan). After completion of the reaction as indicated by TLC, the solution was concentrated under reduced pressure. The yield was determined by 1 H NMR analysis (CDCl3) of the crude reaction mixture using trichloroethylene as the internal standard.

General procedure A (for the synthesis of cyclobutenes)
Alkyne (0.1 mmol, 1.0 equiv.), alkene (1.5 equiv.), and photocatalyst Ir[dF(CF3)ppy]2(dtbbpy)PF6 (2.5 mol%) were added to an oven-dried 4 mL vial equipped with a stir bar. The combined materials were dissolved in CH2Cl2 (2 mL) under argon atmosphere in glovebox. The reaction mixture was then irradiated by 12 W blue LED strip at room temperature (maintained with a cooling fan). After completion of the reaction as indicated by TLC, the solution was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give the desired product.
Then the reaction mixture was cooled to 0 ºC and Trifluoromethanesulfonic anhydride (1.1 equiv.) was added dropwise. The reaction mixture was slowly warmed up to room temperature. and stirred at room temperature for 4 hours. The reaction mixture was washed with water and extracted with CH2Cl2. The combined organic layer was dried over Na2SO4, filtered and concentrated.
The combined organic layer was dried over Na2SO4, filtered and concentrated.

1-phenylbut-3-yn-1-ol (1u)
To a suspension of benzaldehyde (5 mmol, 1.0 equiv.) and propargyl bromide (3.0 equiv.) in THF (17 mL, 0.3 M) was added iron chloride (3.0 equiv.) at 0 °C. After stirring the mixture for 10 min, zinc dust (3.0 equiv.) was added in a few portions over a period. The reaction mixture was slowly warmed up to room temperature and stirred at room temperature for overnight. Hz, 1H); The structure was further confirmed by spectral comparison with literature data. 16
Then, the solvent was removed under reduced pressure. The residue was dissolved in dry CH2Cl2 and slowly added dropwise to a solution of amine (2.5 equiv.) and Et3N (2.5 equiv.) in dry CH2Cl2 (25 mL, 0.2 M) at 0°C.
The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with CH2Cl2. The combined organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by flash chromatography on silica gel.
The reaction mixture was diluted in EtOAc, washed with water and extracted with EtOAc. The combined organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography on silica gel to afford the desired product. 79% yield; pale brown solid; 1 H NMR (400 MHz, CDCl3) δ 6.88 (s, 1H), 3.08 (s, 3H); The structure was further confirmed by spectral comparison with literature data. 24
The resulting crude product was purified by flash column chromatography on silica gel to afford the desired product.

nd step :
To a solution of 3-methylenepyrrolidine-2,5-dione (2.79 mmol, 1.0 equiv.) in THF (3 mL) was added Et3N (3 mL). The solution was refluxed for overnight, and then the mixture was concentrated in vacuo. The reaction mixture was washed with water and extracted with EtOAc. The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography on silica gel to afford the desired product.

3,4-dimethylfuran-2,5-dione (2′s)
A solution of 2-aminopyridine (12.0 mmol, 1.0 equiv.) in acetic acid (3 mL, 4 M) was refluxed for 1 h, then a solution of maleic anhydride (2.0 equiv.) in acetic acid (3 mL, 4 M) was added. The reaction mixture was refluxed for 3 hours. The solvent was evaporated under reduced pressure, aqueous 2 M sulfuric acid was added. Reaction mixture was refluxed for 2 hours. The reaction mixture was washed with 1 N aqueous HCl solution and extracted with CH2Cl2. The combined organic layer was dried over Na2SO4, filtered and concentrated. The crude is used without further purification. 60% yield; white solid; 1 H NMR (400 MHz, CDCl3) δ 2.08 (s, 6H); The structure was further confirmed by spectral comparison with literature data. 30

General procedure D (for ethylation on aniline)
Corresponding aniline (1.0 equiv.) was dissolved in THF (0.2 M) under nitrogen atmosphere and cooled to -78°C.
n-BuLi solution (2.5 M in hexane, 1.1 equiv.) was added dropwise, and the mixture was stirred for 1h. Iodoethane (1.0 equiv.) was added dropwise at -78 °C, and the reaction mixture was stirred for 1h at room temperature. The reaction mixture was quenched by addition of saturated solution of NH4Cl and extracted with ethyl acetate. The combined organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by flash chromatography on silica gel.

General Procedure E (for ester and amide synthesis via acid chloride)
To a suspension of the corresponding acid (1.2 equiv.), DMF (3 mol%) in dry CH2Cl2 (0.5 M) was added dropwise oxalyl chloride (1.1 equiv., per acid) at 0°C. The reaction mixture was stirred at room temperature for 1h. Then, the solvent was removed under reduced pressure. The residue was dissolved in dry THF (0.3 M) and slowly added dropwise to a solution of the appropriate phenol or aniline (1.0 equiv.) and Et3N (1.2 equiv.) at 0°C. The mixture was stirred at room temperature until TLC indicated complete consumption of the starting material. The reaction mixture was diluted with water and extracted with CH2Cl2. The combined organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by flash chromatography on silica gel.

General Procedure F (for amide synthesis via mixed anhydride)
To a solution of the corresponding acid (1.0 equiv.), and Et3N (1.2 equiv.) was dissolved in THF (0.15 M) under nitrogen atmosphere and cooled to 0°C. Isobutyl chloroformate (1.0 equiv.) was added dropwise, and the mixture was stirred for 30 min at 0°C. The appropriate amine (1.0 equiv.) in solvent was added dropwise at 0°C, and the reaction mixture was stirred at room temperature. The solvent was evaporated under reduced pressure. The crude material was purified by flash chromatography on silica gel.

General Procedure G (for ethylation of amide)
To solution of the corresponding amide (1.0 equiv.) in THF (0.3 M) was added sodium hydride (1.5 equiv.) at 0°C.
The reaction mixture was stirred at room temperature for 1 hour. Then iodoethane (2.9 equiv.) was added dropwise.
The reaction mixture was monitored by TLC. The reaction mixture was washed with a saturated solution of NH4Cl and extracted with EtOAc. The combined organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by flash chromatography on silica gel.

Synthetic applications
To a solution of cyclobutene 3qa (0.1 mmol, 1.0 equiv.) in triethyl orthoacetate (0.5 mL, 0.2 M) was added a catalytic quantity of trimethylacetic acid (0.1 equiv.) at room temperature. The reaction mixture was stirred at 110 °C for 24 hours. The reaction mixture was washed with saturated aqueous NaHCO3 and extracted with CH2Cl2.

Radical Clock Experiments a)
See Supplementary Methods for experimental details.

Visible light irradiation on/off experiments.
Both reactions were conducted under irradiation of 12 W blue LED strip and Ar atmosphere. Light was switched off during the "off" periods. Ratio determined by 1 H NMR spectroscopic analysis.

Quantum yield measurement and UV-Vis absorption spectra of substrates
Quantum yields were measured following a procedure by Yoon and coworkers. 53 The reaction yield can be converted to its quantum yield using the pre-determined photon flux of the system.

Determination of the light intensity at 436 nm
The effective photon flux of the used fluorometer was determined using standard ferrioxalate actinometry. A 0.15 M ferrioxalate solution was prepared by dissolving potassium ferrioxalate hydrate (221 mg, 0.45 mmol) in 0.05 M H2SO4 (3 mL). A buffer solution of 1,10-phenanthroline was prepared by dissolving 1,10-phenanthroline (10 mg, 0.055 mmol) and sodium acetate (2.25 g) in 0.5 M H2SO4 (10 mL). The ferrioxalate solution (0.4 mL) was added to cuvette and was irradiated at 436 nm for 90 s in the fluorometer. After irradiation, the phenanthroline solution (0.07 mL) was added to the cuvette and the mixture was allowed in the absence of light for 1 h to achieve full phenanthroline coordination to the ferrous ions. In addition, a non-irradiated sample was prepared similarly.
The absorbance of both samples was measured at 510 nm. From these values, conversion could be determined using Lambert-Beer's law : Where V is the total volume (0.47 mL) of the solution after addition of phenanthroline, l is the optical path length of the cuvette (1.00 cm), ε is the molar absorptivity of the ferrioxalate actinometer (11,100 L mol -1 cm -1 ) and ΔA is the absorbance difference between the irradiated at 436 nm and non-irradiated sample (1.305).
From this value, the photon flux Φq in the system can be calculated as : . .

(2)
Where ΦF is the quantum yield of the ferrioxalate system ( Where A in Supplementary Equation 3 is the measured absorbance of ferrioxalate solution at 436 nm. It was measured to be 2.873. The photon flux Φq was calculated (average of two experiments) to be 6.09×10 -10 einstein s -1 .

Determination of quantum yield
A cuvette was charged with alkyne 1a (0.025 mmol, 1 equiv.), alkene 2a ( The absorbance of photocatalyst in CH2Cl2 was measured at the reaction concentration of 1.

Computational details
All DFT calculations were carried out in the Gaussian 09 software (Rev D.01) 54 using the M06 functional 55 .
Geometry optimization was performed with the 6-311+g(d,p) basis set 56,57 for H, C, N, O atoms, which were obtained from the EMSL Basis Set Exchange 58,59 . Frequency calculations were performed for every optimized geometry with the same level of theory to obtain vibrational frequencies and thermochemical data at 298.15K.
The SMD solvation model 60 with the solvent of dichloromethane (ε= 8.930) was used for all calculations. The transition states were identified by having one imaginary frequency, and intrinsic reaction coordinate 61,62 (IRC) calculations were performed to connect transition states with corresponding intermediates. Each intermediate was verified as minima by having no imaginary frequency, and the geometries of intermediates with possibility of multiple conformations were optimized with several different starting geometries to find the lowest energy conformation. Triplet energies were calculated by the previously reported method [63][64][65]