METATHESIS CATALYSTS AND METHODS THEREOF

20160194343

14/933741

November 05, 2015

The present application provides, among other things, compounds and methods for metathesis reactions. In some embodiments, the present disclosure provides methods for preparing alkenyl halide with regioselectivity and/or stereoselectivity. In some embodiments, the present disclosure provides methods for preparing alkenyl halide with regioselectivity and Z-selectivity. In some embodiments, the present disclosure provides methods for preparing alkenyl halide with regioselectivity and E-selectivity. In some embodiments, provided technologies are particularly useful for preparing alkenyl fluorides. In some embodiments, a provided compound useful for metathesis reactions has the structure of formula II-a. In some embodiments, a provided compound useful for metathesis reactions has the structure of formula II-b.

1. A method, comprising: reacting a first species comprising an olefin with a second species comprising an olefin in the presence of a catalyst or metal complex to provide at least one product comprising an olefin, wherein: each carbon atom of the olefin in the first species is substituted with at least one halogen; and the olefin in the at least one product comprises a carbon atom from the first species and a carbon atom from the second species; and wherein the catalyst or metal complex is of formula II-a or II-b: [chemical expression included] wherein: M is molybdenum or tungsten; R1 is an optionally substituted group selected from C1-20 aliphatic, C1-20 heteroaliphatic having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, an 8-10 membered bicyclic saturated, partially unsaturated or aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or R1 is optionally substituted [chemical expression included] each of R2 and R3 is independently R′, —OR′, —SR′, —N(R′)2, —OC(O)R′, —SOR′, —SO2R′, —SO2N(R′)2, —C(O)N(R′)2, —NR′C(O)R′, or —NR′SO2R′, provided that R2 and R3 are not simultaneously hydrogen; R2′ and R3′ are taken together with their intervening metal atom to form an optionally substituted 3-8 membered saturated or partially unsaturated ring having, in addition to the intervening metal atom, 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R4 is R7, or an optionally substituted group selected from —Ar, C1-20 aliphatic, C1-20 heteroaliphatic having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, an 8-10 membered bicyclic saturated, partially unsaturated or aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-14 membered bicyclic or tricyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; Ar is of the following formula: [chemical expression included] wherein: m is 0-3; Ring B is an optionally substituted group selected from phenyl or a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; p and q are independently 0-6; each of Ring C and Ring D is independently optionally substituted groups selected from phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, an 8-10 membered bicyclic saturated, partially unsaturated or aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each of Rx, Ry, and Rz is independently Rs; R5 is halogen, —OR6, —OR7, —N(R′)2, —NR′C(O)R′, —NR′C(O)OR′, —NR′C(O)N(R′)2, —NR′SO2R′, —NR′SO2N(R′)2, or —NR′OR′, or an optionally substituted group selected from a 5-6 membered monocyclic heteroaryl ring having at least one nitrogen and 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 4-7 membered saturated or partially unsaturated heterocyclic ring having at least one nitrogen and 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having at least one nitrogen and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having at least one nitrogen and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; R6 is an optionally substituted group selected from C1-20 aliphatic, C1-20 heteroaliphatic having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, an 8-10 membered bicyclic saturated, partially unsaturated or aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-14 membered bicyclic or tricyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and each R′ is independently hydrogen or an optionally substituted group selected from C1-20 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, an 8-10 membered bicyclic saturated, partially unsaturated or aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein: two R′ groups on the same nitrogen atom are optionally taken together with the nitrogen atom to form an optionally substituted 3-8 membered, saturated, partially unsaturated, or aryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; each R7 is independently an optionally substituted group selected from —Ar′, C1-20 aliphatic, C1-20 heteroaliphatic having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, an 8-10 membered bicyclic saturated, partially unsaturated or aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-14 membered bicyclic or tricyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and two R7 are optionally taken together with the oxygen atoms they are bound to form a bidentate ligand; and Ar′ is of the following formula: [chemical expression included] wherein: t is 0-4; p is 0-6; each Ring B′ and Ring C′ is independently an optionally substituted group selected from phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, an 8-10 membered bicyclic saturated, partially unsaturated or aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 4-7 membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 7-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and each Rs is independently halogen, R′, —OR′, —SR′, —S(O)R′, —S(O)2R′, —OSi(R′)3, —N(R′)2, —NR′C(O)R′, —NR′C(O)OR′, —NR′C(O)N(R′)2, —NR′SO2R′, —NR′SO2N(R′)2, or —NR′OR′.

2. A method, comprising: reacting a first species comprising an olefin with a second species comprising an alkyne in the presence of a catalyst or metal complex to provide at least one product comprising an olefin, wherein: each carbon atom of the olefin in the first species is substituted with at least one halogen; and the olefin in the at least one product comprises a carbon atom from the first species and a carbon atom from the second species; and wherein the catalyst or metal complex is of formula II-a or II-b as described in claim 1.

3. The method of claim 1, wherein the olefin in the at least one product is formed via a metathesis reaction between the olefin in the first species and the olefin in the second species; and the halogen substituent of the first carbon atom of the double bond in the first species and the halogen substituent of the second carbon atom of the double bond in the first species is cis, and the olefin in the at least one product comprises a carbon atom from the first species and a carbon atom from the second species is produced with Z-selectivity.

4. The method of claim 3, wherein the first species has the structure of: [chemical expression included] wherein each of X and Y is independently halogen; and wherein the product is produced in a Z:E ratio greater than 80:20.

5. The method of claim 1, wherein the olefin in the at least one product is formed via a metathesis reaction between the olefin in the first species and the olefin in the second species; and the halogen substituent of the first carbon atom of the double bond in the first species and the halogen substituent of the second carbon atom of the double bond in the first species is trans, and the olefin in the at least one product comprises a carbon atom from the first species and a carbon atom from the second species is produced with E-selectivity.

6. The method of claim 5, wherein the first species has the structure of: [chemical expression included] wherein each of X and Y is independently halogen; and wherein the product is produced in a E:Z ratio greater than 80:20.

7. The method of claim 4, comprising reacting the first species with the second species via a metathesis reaction between the olefin of the first species and the olefin of the second species with regioselectivity to provide as products: CH2═CHY; and the at least one product comprising an olefin wherein the olefin comprising ═CHX, over CH2═CHX and a product comprising an olefin wherein the olefin comprising ═CHY, wherein X is smaller than Y.

8. The method of claim 7, wherein X is —F.

9. The method of claim 8, wherein the regioselectivity is greater than 80:20.

10. The method of claim 6, comprising reacting the first species with the second species via a metathesis reaction between the olefin of the first species and the olefin of the second species with regioselectivity to provide as products: CH2═CHY; and the at least one product comprising an olefin wherein the olefin comprising ═CHX, over CH2═CHX and a product comprising an olefin wherein the olefin comprising ═CHY, wherein X is smaller than Y.

11. The method of claim 10, wherein X is —F.

12. The method of claim 11, wherein the regioselectivity is greater than 80:20.

13. The method of claim 9, wherein the second species is Rt—CH═CH2, and the at least one product is (Z)Rt—CH═CHF.

14. The method of claim 12, wherein the second species is Rt—CH═CH2, and the at least one product is (Z)Rt—CH═CHF.

15. The method of claim 1, wherein R1 is optionally substituted adamantyl, or R1 is substituted phenyl comprising one or more electron-withdrawing substituents, wherein each electron-withdrawing substituent is independently halogen or substituted C1-6 alkyl comprising one or more halogen.

16. The method of claim 15, wherein R1 is [chemical expression included] R4 is optionally substituted [chemical expression included] and R5 is optionally substituted. [chemical expression included]

17. A compound of formula II-a, or a compound of formula II-b, or a fluorinated compound derived from a bioactive molecule, wherein the bioactive molecule comprises a terminal olefin, and the fluorinated derivative comprises a terminal olefin comprising —CH═CHF derived from the terminal olefin of the bioactive molecule; or a composition comprising: a first species comprising an olefin, wherein each carbon atom of the olefin in the first species is substituted with at least one halogen; and a metal complex comprising Mo or W.

18. The compound of claim 17, having the structure of [chemical expression included]

19. The compound of claim 17, having the structure of [chemical expression included]

20. The composition of claim 17, wherein: the first species has the structure of [chemical expression included] or Y, wherein each of X and Y is independently halogen; and the metal complex has the structure of formula II-a or II-b.

07; 07; 01; 07; 07; 07; 07

edspap.20160194343