Photocatalyst-free, light-induced carbon-sulfur cross-coupling methods
In one aspect, the invention provides a method of promoting a carbon-sulfur bond forming reaction. In certain embodiments, the reaction comprises cross-coupling of a(n) (hetero)aryl halide with a thiol to form the carbon-sulfur bond, wherein the method is promoted by light irradiation in the absence of a photocatalyst. In other embodiments, the cross-coupling reaction can be promoted through visible light irradiation, including sunlight.
1. A method of generating an aryl or heteroaryl thioether, the method comprising:
irradiating a system comprising an aryl or heteroaryl halide, a thiol, dimethyl sulfoxide (DMSO) or dimethyl acetamide (DMA), and at least one base with electromagnetic radiation, and
forming a carbon-sulfur bond between the aryl or heteroaryl halide and the thiol to provide the aryl or heteroaryl thioether,
wherein the system is free of transition metal and organic photocatalyst.
2. The method of claim 1 , wherein the at least one base is selected from the group consisting of an amine, a phosphine, a carbonate salt, a hydroxide salt, an alkoxide salt, a phosphate salt, a metal hydride, and a carboxylate salt.
3. The method of claim 2 , wherein the at least one base is selected from the group consisting of Na 2 CO 3 , K 2 CO 3 , Rb 2 CO 3 , and Cs 2 CO 3 .
4. The method of claim 1 , wherein the electromagnetic radiation is selected from the group consisting of UV light, visible light, and natural sunlight.
5. The method of claim 1 , wherein the aryl or heteroaryl halide and the thiol are irradiated by a light emitting diode (LED).
6. The method of claim 1 , wherein the aryl or heteroaryl halide is at least one selected from the group consisting of fluoride chloride, bromide, and iodide.
7. The method of claim 1 , wherein the aryl or heteroaryl halide is optionally substituted with at least one additional substituent selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 2 -C 6 heteroalkenyl, C 2 -C 6 heteroalkynyl, C 3 -C 8 cycloalkyl, heterocycloalkyl, C 1 -C 6 alkoxy, aryl, heteroaryl, benzyl, heterocyclyl, cyano, halogen, hydroxy, nitro, S(C 1 -C 6 alkyl), —S(═O)(C 1 -C 6 alkyl), —S(═O) 2 (C 1 -C 6 alkyl), —S(═O) 2 NH 2 , —S(═O) 2 NH(C 1 -C 6 alkyl), —S(═O) 2 N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —NHNH 2 , —NH 2 , —NH(C 1 -C 6 alkyl optionally substituted with 1-2 OH), —N(C 1 -C 6 alkyl optionally substituted with 1-2 OH)(C 1 -C 6 alkyl optionally substituted with 1-2 OH), —NHC(═O)O(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)C(═O)O(C 1 -C 6 alkyl), —(CH 2 ) n CHO, —(CH 2 ) n C(═O)OH, —(CH 2 ) n C(═O)O(C 1 -C 6 alkyl), —C(═O)S(C 1 -C 6 alkyl), —(CH 2 ) n C(═O)NH 2 , —(CH 2 ) n C(═O)NH(C 1 -C 6 alkyl), —(CH 2 ) n C(═O)N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —(CH 2 ) n C(═O)(C 1 -C 6 alkyl), —(CH 2 ) n C(═O)(aryl), —(CH 2 ) n C(═O)(heteroaryl), —(CH 2 ) n C(═O)(heterocyclyl), —(CH 2 ) n OC(═O)O(C 1 -C 6 alkyl), —OC(═O)NH 2 , —OC(═O)NH(C 1 -C 6 alkyl), —OC(═O)N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —(CH 2 ) n NHC(═O)(C 1 -C 6 alkyl), —(CH 2 ) n N(C 1 -C 6 alkyl)C(═O)(C 1 -C 6 alkyl), wherein each occurrence of n is independently an integer ranging from 0-6, and wherein two adjacent substituents on the (hetero)aryl are taken together to form C 1 -C 6 cycloalkylene, C 1 -C 6 heterocycloalkylene, fused aryl, or fused heteroaryl;
wherein each moiety selected from the group consisting of alkyl, —CH 2 —, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, heterocyclyl, benzyl, cycloalkylene, and heterocycloalkylene is independently optionally substituted with at least one selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, aryl, heteroaryl, heterocyclyl, OH, halogen, —NH 2 , —NH(C 1 -C 6 alkyl optionally substituted with 1-2 OH), —N(C 1 -C 6 alkyl optionally substituted with 1-2 OH)(C 1 -C 6 alkyl optionally substituted with 1-2 OH), —C(═O)OH, and —C(═O)(C 1 -C 6 alkyl); or
wherein two moieties on the same N atom of the at least additional substituent, or moieties on two different atoms of the at least additional substituent, combine to form C 3 -C 8 heterocyclyl.
8. The method of claim 1 , wherein the thiol is selected from the group consisting of optionally substituted C 1 -C 6 alkylthiol, thiophenol, thionaphthol, thioanthracenol, thiophenanthrol, thiopyrenol, benzyl mercaptan, heteroaryl thiol, and heteroarylmethyl thiol.
9. The method of claim 1 , wherein the thiol is optionally substituted with at least one additional substituent selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 heteroalkyl, C 2 -C 6 heteroalkenyl, C 2 -C 6 heteroalkynyl, C 3 -C 8 cycloalkyl, heterocycloalkyl, C 1 -C 6 alkoxy, aryl, heteroaryl, benzyl, heterocyclyl, cyano, halogen, hydroxy, nitro, S(C 1 -C 6 alkyl), —S(═O)(C 1 -C 6 alkyl), —S(═O) 2 (C 1 -C 6 alkyl), —S(═O) 2 NH 2 , —S(═O) 2 NH(C 1 -C 6 alkyl), —S(═O) 2 N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —NHNH 2 , —NH 2 , —NH(C 1 -C 6 alkyl optionally substituted with 1-2 OH), —N(C 1 -C 6 alkyl optionally substituted with 1-2 OH)(C 1 -C 6 alkyl optionally substituted with 1-2 OH), —NHC(═O)O(C 1 -C 6 alkyl), —N(C 1 -C 6 alkyl)C(═O)O(C 1 -C 6 alkyl), —(CH 2 ) n CHO, —(CH 2 ) n C(═O)OH, —(CH 2 ) n C(═O)O(C 1 -C 6 alkyl), —C(═O)S(C 1 -C 6 alkyl), —(CH 2 ) n C(═O)NH 2 , —(CH 2 ) n C(═O)NH(C 1 -C 6 alkyl), —(CH 2 ) n C(═O)N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —(CH 2 ) n C(═O)(C 1 -C 6 alkyl), —(CH 2 ) n C(═O)(aryl), —(CH 2 ) n C(═O)(heteroaryl), —(CH 2 ) n C(═O)(heterocyclyl), —(CH 2 ) n OC(═O)O(C 1 -C 6 alkyl), —OC(═O)NH 2 , —OC(═O)NH(C 1 -C 6 alkyl), —OC(═O)N(C 1 -C 6 alkyl)(C 1 -C 6 alkyl), —(CH 2 ) n NHC(═O)(C 1 -C 6 alkyl), —(CH 2 ) n N(C 1 -C 6 alkyl)C(═O)(C 1 -C 6 alkyl), wherein each occurrence of n is independently an integer ranging from 0-6 , and wherein two adjacent substituents on the thiol are taken together to form C 1 -C 6 cycloalkylene, C 1 -C 6 heterocycloalkylene, fused aryl, or fused heteroaryl;
wherein each moiety selected from the group consisting of alkyl, —CH 2 —, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, heterocyclyl, benzyl, cycloalkylene, and heterocycloalkylene is independently optionally substituted with at least one selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 alkoxy, aryl, heteroaryl, heterocyclyl, OH, halogen, —NH 2 , —NH(C 1 -C 6 alkyl optionally substituted with 1-2 OH), —N(C 1 -C 6 alkyl optionally substituted with 1-2 OH)(C 1 -C 6 alkyl optionally substituted with 1-2 OH), —C(═O)OH, and —C(═O)(C 1 -C 6 alkyl); or
wherein two moieties on the same N atom of the at least additional substituent, or moieties on two different atoms of the at least additional substituent, combine to form C 3 -C 8 heterocyclyl.
10. The method of claim 1 , wherein the aryl or heteroaryl thioether comprises a first monovalent moiety and a second divalent moiety coupled to a —S— divalent group, wherein the first monovalent moiety is selected from the group consisting of phenyl and heteroaryl, and wherein the second monovalent moiety is selected from the group consisting of phenyl, benzyl, heteroaryl, and heteroarylmethyl, each of which is optionally independently substituted.
11. The method of claim 1 , wherein the system is under an inert, oxygen-free atmosphere.
12. The method of claim 1 , wherein the aryl or heteroaryl thioether comprises a polymer comprising thioether linkages.
13. The method of claim 1 , wherein the aryl or heteroaryl thioether is formed in at least 12% yield.