Copper(I)-Catalyzed Formal [4 + 2] Cyclocondensation of ortho-Hydroxybenzyl Alcohol, Aromatic Terminal Alkynes, and Sulfonyl Azides: An Alternative Approach to 2-Sulfonyliminocoumarins

In this paper, an alternative and efficient copper(I)-catalyzed synthesis of 2-sulfonyliminocoumarins is developed through a three-component reaction of ortho-hydroxybenzyl alcohol, alkynes, and p-toluenesulfonyl azide. The proposed route for access to the 2-iminocoumarin ring involves a [4 + 2] hetero-Diels-Alder reaction between ortho-quinone methide and ketenimine intermediates generated in situ.

Scheme 1.Recent reports on the synthesis of 2-sulfonyliminocoumarins using phenols.

Results and Discussion
Based on the above-mentioned formation of ketenimine in the presence of copper ( salts [12,[27][28][29], we examined reactions using various copper (I) salts as catalysts and sim ple bases in different solvents under an air atmosphere.As summarized in Table 1, in TH solvent with triethylamine (TEA) as the base, CuCl, CuBr, and CuI showed a similar an effective catalytic activity, catalyzing cyclocondensation of 2-(hydroxymethyl)phenol (1 phenyl acetylene (2a), and p-toluenesulfonyl azide (3) at 80 °C, affording the desired pro uct 4a in 65%, 70%, and 65% isolated yields, respectively (entries 1-3).The structure of 4 was confirmed unambiguously through X-ray diffraction studies [30 and see suppleme tary materials].When 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and K2CO3 were used bases, the 4a yield decreased greatly (entries 4-5).The screening of solvents using TE showed that 1,2-dichloroethane (DCE) was a better solvent for CuI-catalyzed formation 4a (entry 6).DCE was the best solvent when compared with THF, dioxane, DMF (N,N dimethylformamide), and toluene, with the use of CuTC (copper(I)-thiophene-2-carbo ylate) as catalyst to afford 4a in 82% yield (entries 7-11).When 5.0 mol% of CuTC w used, the yield of 4a decreased to 51% (entry 12), and in the absence of a catalyst, no d sired product formed at all (entry 13).In addition, under a nitrogen atmosphere, the yie of 4a decreased to 11%. a Reactions were carried out using 1.0 mmol of 1, 1.0 mmol of 2a, 1.0 mmol of 3, 1.0 mmol of bas and 0.1 mmol of copper (I) salts in 4.0 mL of solvent under an air atmosphere.b Isolated yields.c 5 mol% of CuTC was used.d Under a nitrogen atmosphere.
Then, we examined the reactions of 2-(hydroxymethyl)phenol (1) and p-toluenesu fonyl azide (3) with various aromatic terminal alkynes under the optimized reaction co dition (indicated in entry 11 of Table 1) to explore the functional group tolerance.A shown in Table 2, compared with 2a, 1-naphthyl acetylene (2b) and 2-naphthyl acetylen (2c) underwent the cyclocondensation to provide slightly lower yields of 4b and 4c.Bo electron-rich and electron-poor aromatic terminal alkynes showed a good reactivity, r sulting in yields of 62-81% for the corresponding products, and the reactions of the ele tron-rich aromatic terminal alkynes resulted in improved yields for the products.For e ample, the reactions of aromatic terminal alkynes bearing electron-donating groups, suc as Me (2d-2f), Et (2g), n-Pr (2h), t-Bu (2i), and MeO (2j-2k), produced the desired produc  Then, we examined the reactions of 2-(hydroxymethyl)phenol (1) and p-toluenesulfonyl azide (3) with various aromatic terminal alkynes under the optimized reaction condition (indicated in entry 11 of Table 1) to explore the functional group tolerance.As shown in Table 2, compared with 2a, 1-naphthyl acetylene (2b) and 2-naphthyl acetylene (2c) underwent the cyclocondensation to provide slightly lower yields of 4b and 4c.Both electron-rich and electron-poor aromatic terminal alkynes showed a good reactivity, resulting in yields of 62-81% for the corresponding products, and the reactions of the electron-rich aromatic terminal alkynes resulted in improved yields for the products.For example, the reactions of aromatic terminal alkynes bearing electron-donating groups, such as Me (2d-2f), Et (2g), n-Pr (2h), t-Bu (2i), and MeO (2j-2k), produced the desired products with yields of 65-81% (4d-4k).Because of the steric hindrance, orthoand meta-substituents resulted in a slightly lower yield (4d vs. 4e, 4j vs. 4k).The reactions of electron-poor aromatic terminal alkynes with F (2l-2m), Cl (2n), and Br (2o) groups afforded the products (4l-4o) in 62-73% yields, and these products could easily further derivate with the possible activation of the carbon-halogen bond.In addition, heteroaromatic terminal alkynes (2p) could be tolerated in this reaction, resulting in a yield of 76% for the desired product (4p).Moreover, the reaction of 1, 2a, and benzenesulfonyl azide resulted in a yield of 55% for the corresponding product 4q, while the reaction of 1, 2a, and methanesulfonyl azide did not afford the expected product at all.Note that when aliphatic terminal alkynes were used, none of the expected products formed either.with yields of 65-81% (4d-4k).Because of the steric hindrance, ortho-and meta-substituents resulted in a slightly lower yield (4d vs. 4e, 4j vs. 4k).The reactions of electron-poor aromatic terminal alkynes with F (2l-2m), Cl (2n), and Br (2o) groups afforded the products (4l-4o) in 62-73% yields, and these products could easily further derivate with the possible activation of the carbon-halogen bond.In addition, heteroaromatic terminal alkynes (2p) could be tolerated in this reaction, resulting in a yield of 76% for the desired product (4p).Moreover, the reaction of 1, 2a, and benzenesulfonyl azide resulted in a yield of 55% for the corresponding product 4q, while the reaction of 1, 2a, and methanesulfonyl azide did not afford the expected product at all.Note that when aliphatic terminal alkynes were used, none of the expected products formed either.a Reactions were carried out using 1.0 mmol of 1, 1.0 mmol of 2, 1.0 mmol of 3, 1.0 mmol of TEA, and 0.1 mmol of CuTC in 4.0 mL of DCE under an air atmosphere.
Caution! p-Toluenesulfonyl azide (TsN3, 3) can undergo explosive decomposition at 120°.Although it is safe at 80 °C in a sealed vessel under standard reaction conditions, it with yields of 65-81% (4d-4k).Because of the steric hindrance, ortho-and meta-substituents resulted in a slightly lower yield (4d vs. 4e, 4j vs. 4k).The reactions of electron-poor aromatic terminal alkynes with F (2l-2m), Cl (2n), and Br (2o) groups afforded the products (4l-4o) in 62-73% yields, and these products could easily further derivate with the possible activation of the carbon-halogen bond.In addition, heteroaromatic terminal alkynes (2p) could be tolerated in this reaction, resulting in a yield of 76% for the desired product (4p).Moreover, the reaction of 1, 2a, and benzenesulfonyl azide resulted in a yield of 55% for the corresponding product 4q, while the reaction of 1, 2a, and methanesulfonyl azide did not afford the expected product at all.Note that when aliphatic terminal alkynes were used, none of the expected products formed either.a Reactions were carried out using 1.0 mmol of 1, 1.0 mmol of 2, 1.0 mmol of 3, 1.0 mmol of TEA, and 0.1 mmol of CuTC in 4.0 mL of DCE under an air atmosphere.
Caution! p-Toluenesulfonyl azide (TsN3, 3) can undergo explosive decomposition at 120°.Although it is safe at 80 °C in a sealed vessel under standard reaction conditions, it
Caution! p-Toluenesulfonyl azide (TsN 3 , 3) can undergo explosive decomposition at 120 • .Although it is safe at 80 • C in a sealed vessel under standard reaction conditions, it is potentially explosive.Therefore, all of the reactions were carried out behind a safety shield in a hood.

Typical Experimental Procedure for the Synthesis of 4-Methyl-N-(3-phenyl-2H-chromen-2ylidene)benzenesulfonamide (4a)
A mixture of 2-(hydroxymethyl)phenol (1, 124.1 mg, 1.0 mmol), phenyl acetylene (2a, 102.0 mg, 1.0 mmol), sulfonyl azide (3,197.0mg, 1.0 mmol), TEA (102.0 mg, 1.0 mmol), CuTC (19.0 mg, 0.1 mmol), and DCE (4.0 mL) under an air atmosphere in a 25 mL screwcapped thick-walled Pyrex tube was stirred at 80 • C for 18 h in an oil bath.After the reaction mixture was cooled to room temperature, it was poured into a solvent mixture of water (50.0 mL) and ethyl acetate (20.0 mL), and the two phases were then separated.The aqueous layer was extracted with ethyl acetate (3 × 20.0 mL).The combined organic solvent was dried over anhydrous Na 2 SO 4 .After removal of the organic solvent under reduced pressure, the residue was purified by column chromatography on silica gel with petroleum ether/ethyl acetate (gradient mixture ratio from 100:0 to 80:20) as the eluent to afford 4a as a pale yellow solid (255.2 mg, 0.82 mmol, 82%).The single crystals of 4a were obtained by slow evaporation of its solution in a mixture solvent of petroleum ether and CH 2 Cl 2 at room temperature.

a
Reactions were carried out using 1.0 mmol of 1, 1.0 mmol of 2a, 1.0 mmol of 3, 1.0 mmol of base, and 0.1 mmol of copper (I) salts in 4.0 mL of solvent under an air atmosphere.b Isolated yields.c 5.0 mol% of CuTC was used.d Under a nitrogen atmosphere.

4q 55 a
Reactions were carried out using 1.0 mmol of 1, 1.0 mmol of 2, 1.0 mmol of 3, 1.0 mmol of TEA, and 0.1 mmol of CuTC in 4.0 mL of DCE under an air atmosphere.

Table 1 .
Optimization of the reaction conditions a .

Table 1 .
Optimization of the reaction conditions a

Table 2 .
Scope for the formation of 2-sulfonyliminocoumarins a .

Table 2 .
Scope for the formation of 2-sulfonyliminocoumarins a

Table 2 .
Scope for the formation of 2-sulfonyliminocoumarins a