Alkene hydrofunctionalization reactions
A reductive cross coupling reaction process for functionalization of a nucleophilic alkene can be achieved. The nucleophilic alkene and a nucleophilic cross coupling partner compound can be reacted in the presence of an oxidizable alcohol and a suitable catalyst to form a reductive coupling product. Various additives can also be useful to refine the process such as by mitigating certain undesirable intermediates, facilitating specific site selectivity for various substitutions or reaction sites, etc. Chiral additives can be optionally used which act to provide asymmetric catalysis, e.g. allow for regioselective and stereoselective production of reductive coupling products. A reductive cross coupling pathway can include oxidizing the oxidizable alcohol to form a catalyst hydride. The nucleophilic alkene can be inserted into the catalyst hydride to form a catalyst-alkyl intermediate. Further, the catalyst-alkyl intermediate can be transmetallized with the nucleophilic cross coupling partner compound to form a transmetallated intermediate. The catalyst can be reductively eliminated to form the reductive coupling product and a reduced catalyst. Finally, the reduced catalyst can be oxidized under aerobic conditions, for example with oxygen, to form the oxidized catalyst and subsequent repetition through the cyclic pathway.
1. A reductive cross coupling reaction process for functionalization of a nucleophilic alkene comprising:
a) reacting the nucleophilic alkene and a nucleophilic cross coupling partner compound in the presence of an oxidizable alcohol and a catalyst to form a reductive coupling product.
2. The process of claim 1 , wherein the nucleophilic alkene is selected from the group consisting of polycyclic aromatic alkenes, monocyclic aromatic alkenes, heterocyclic aromatic alkenes, non-aromatic alkenes, conjugated dienes, and combinations thereof.
3. The process of claim 1 , wherein the nucleophilic cross coupling partner compound is selected from the group consisting of organostannanes, organosilanes, organozinc reagents, boronic acid derivatives, and combinations thereof.
4. The process of claim 3 , wherein the nucleophilic cross coupling partner is an organostannane or organoboronic acid/ester.
5. The process of claim 1 , wherein the oxidizable alcohol is selected from the group consisting of isopropyl alcohol, C1-C5 straight or branched alcohols, primary or secondary benzylic alcohols, and combinations thereof.
6. The process of claim 5 , wherein the oxidizable alcohol is isopropyl alcohol.
7. The process of claim 1 , wherein the catalyst is a palladium catalyst.
8. The process of claim 1 , wherein the palladium catalyst has the following structure:
where L is a ligand, n is any integer from 0 to 2, and X is a halogen.
9. The process of claim 8 , wherein the ligand is selected from the group consisting of heterocycle derived oxazolines, Et 2 CH—BOX ((4S,4′S)-2,2′-(propane-2,2-diyl)bis(4-(pentan-3-yl)-4,5-dihydrooxazole) chiral phosphines, chiral N-heterocyclic carbenes, chiral tertiary amines, hindered tertiary amines, carbonate bases, and combinations thereof.
10. The process of claim 8 , wherein the ligand is selected from the group consisting of IiPr (1,3-Bis(2,6-di-1-propylphenyl)imidazol-2-ylidene), SiPr (1,3-Bis(2,6-di-1-propylphenyl)-4,5-dihydroimidazol-2-ylidine), (−)-sparteine, or mixtures thereof.
11. The process of claim 1 , wherein the step of reacting further comprises an exogenous base.
12. The process of claim 11 , wherein the exogenous base is selected from the group consisting of (−)-sparteine, potassium tert-butoxide, triethylamine, Hünig's base, Tröger's base, 2,6-lutidine, 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), amine bases including tertiary, cyclic, and aromatic, inorganic bases including KOiPr, NaOiPr, KOEt, NaOEt, Cs 2 CO 3 , K 2 CO 3 , KHCO 3 , Na 2 CO 3 , CsF, CuF 2 , CuCl 2 , Cu(OAc) 2 , and mixtures thereof.
13. The process of claim 1 , wherein the step of reacting further comprises an additive which is a peroxide suppression agent or a chiral additive.
14. The process of claim 13 , wherein the additive is a chiral additive selected from the group consisting of heterocycle derived oxazolines Et 2 CH—BOX ((4S,4′S)-2,2′-(propane-2,2-diyl)bis(4-(pentan-3-yl)-4,5-dihydrooxazole), chiral phosphines, chiral N-heterocyclic carbenes, chiral tertiary amines, hindered tertiary amines, carbonate bases, and combinations thereof.
15. The process of claim 14 , wherein the chiral additive is Et 2 CH—BOX ((4S,4′S)-2,2′-(propane-2,2-diyl)bis(4-(pentan-3-yl)-4,5-dihydrooxazole).
16. The process of claim 13 , wherein the additive is a chiral additive selected to provide asymmetric catalysis.
17. The process of claim 1 , wherein the step of reacting is conducted under conditions sufficient to minimize reaction along an oxidative Heck reaction pathway by producing an oxidative Heck reaction product of less than 5% yield.
18. The process of claim 1 , wherein the step of reacting is conducted under conditions sufficient to substantially eliminate reaction along an oxidative Heck reaction pathway by producing an oxidative Heck reaction product of less than 5% yield.
19. The process of claim 18 , wherein the conditions include accelerating oxidation of the oxidizable alcohol.
20. The process of claim 1 , wherein the step of reacting substantially follows a reductive cross coupling pathway including at least the following steps:
a) oxidizing the oxidizable alcohol to form a catalyst hydride;
b) inserting the nucleophilic alkene into the catalyst hydride to form a catalyst-alkyl intermediate;
c) transmetallating of the catalyst-alkyl intermediate with the nucleophilic cross coupling partner compound to form a transmetallated intermediate; and
d) reductively eliminating the catalyst to form the reductive coupling product and a reduced catalyst.
21. The process of claim 20 , wherein the step of oxidizing the oxidizable alcohol to form a catalyst hydride is by the following reaction schematic:
where L is a ligand, n is any integer from 0 to 2, and X is a halogen.
22. The process of claim 20 , wherein the step of inserting the nucleophilic alkene into the catalyst hydride to form a catalyst-alkyl intermediate is by the following reaction schematic:
wherein the step of transmetallating of the catalyst-alkyl intermediate with the nucleophilic cross coupling partner compound to form a transmetallated intermediate is by the following reaction schematic:
wherein the step of reductively eliminating the catalyst to form the reductive coupling product and a reduced catalyst is by the following reaction schematic:
where L is a ligand, n is an integer from 0 to 2, X is a halogen, and R1 and R2 are independently any aryl or alkyl group including mixtures and substitutions thereof.
23. The process of claim 20 , further comprising oxidizing the reduced catalyst with oxygen to form the catalyst.
24. The process of claim 23 , where the step of oxidizing the reduced catalyst with oxygen to form the catalyst is by the following reaction schematic:
where L is a ligand, n is an integer from 0 to 2, and X is a halogen.
25. The process of claim 1 , wherein the reductive coupling product includes an sp 3 hybridized carbon linking the reductive coupling product, said sp 3 hybridized carbon corresponding to a carbon of the reactive alkene carbon pair in the nucleophilic alkene.
26. The process of claim 1 , wherein the nucleophilic alkene includes a terminal alkene, an internal alkene, or mixtures thereof.
27. The process of claim 1 , wherein the reacting is performed under aerobic conditions.