One-pot preparation of hexahydroisoquinolines from dihydroisoquinolines
View Patent ↗The present invention provides an efficient process for the preparation of hexahydroisoquinolines from dihydroisoquinolines. In particular, the invention provides a good yielding, one-pot process for the synthesis of hexahydroisoquinolines.
1. A one-pot process for the preparation of a compound having Formula (IV) from a mixture of compounds having Formulas (II) and (II′), the process comprising:
(a) contacting the compounds having Formulas (II) and (II′) with an asymmetric catalyst and a hydrogen donor comprising a formate ion to form a mixture of compounds having Formulas (III) and (III′); and
(b) contacting the compounds having Formulas (III) and (III′) with an alkali metal and an electron source to form the compound having Formula (IV) according to the following reaction scheme:
wherein:
R 1 , R 5 , and R 7 are independently chosen from hydrogen, hydrocarbyl, substituted hydrocarbyl, and —OR 111 ;
R 2 and R 6 are independently chosen from hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, and —OR 211 ;
R 3 is chosen from hydrogen, hydrocarbyl, substituted hydrocarbyl, and —OR 211 ;
R 4 is chosen from —C(O)R 212 , —C(O)C(R 212 ) 3 , —C(O)NHR 212 , and —SO 2 R 212 ;
R 12 and R 13 are independently chosen from hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, and —OR 111 ;
R 111 is chosen from hydrogen, hydrocarbyl, and substituted hydrocarbyl;
R 211 is chosen from hydrogen, hydrocarbyl, —C(O)R 212 , —C(O)C(R 212 ) 3 , —C(O)NHR 212 , and —SO 2 R 212 ; and
R 212 is chosen from hydrocarbyl and substituted hydrocarbyl,
and further wherein the compounds haying Formulas (III) and (III′) are not crystallized prior to step (b).
2. The process of claim 1 , wherein a compound chosen from Formulas (IV′), (IV″), and a combination thereof is also formed during step (b):
wherein:
R 1 , R 5 , and R 7 are independently chosen from hydrogen, hydrocarbyl, substituted hydrocarbyl, and —OR 111 ;
R 2 and R 6 are independently chosen from hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, and —OR 211 ;
R 3 is chosen from hydrogen, hydrocarbyl, substituted hydrocarbyl, and —OR 211 ;
R 12 and R 13 are independently chosen from hydrogen, hydrocarbyl, substituted hydrocarbyl, halo, and —OR 111 ;
R 111 is chosen from hydrogen, hydrocarbyl, and substituted hydrocarbyl;
R 211 is chosen from hydrogen, hydrocarbyl, —C(O)R 212 , —C(O)C(R 212 ) 3 , —C(O)NHR 212 , and —SO 2 R 212 ; and
R 212 is chosen from hydrocarbyl and substituted hydrocarbyl.
3. The process of claim 1 , wherein:
R 3 is —OR 211 ; R 211 is chosen from hydrogen, alkyl, —C(O)R 212 , —C(O)C(R 212 ) 3 , —C(O)NHR 212 , and —SO 2 R 212 ; and
R 212 is chosen from alkyl and aryl.
4. The process of claim 1 , wherein:
R 5 is —OR 211 ;
R 211 is chosen from hydrogen, alkyl, —C(O)R 212 , —C(O)C(R 212 ) 3 , —C(O)NHR 212 , and —SO 2 R 212 ; and
R 212 is chosen from alkyl and aryl.
5. The process of claim 1 , wherein R 1 , R 2 , R 5 , R 7 , R 12 , and R 13 are hydrogen; R 3 and R 6 are methoxy; R 4 is —C(O)R 212 ; and R 212 is chosen from methyl, t-butyl, and phenyl.
6. The process of claim 1 , wherein:
R 3 and R 5 are —OR 211 ;
R 211 is chosen from hydrogen, alkyl, —C(O)R 212 , —C(O)C(R 212 ) 3 , —C(O)NHR 212 , and —SO 2 R 212 ; and
R 212 is chosen from alkyl and aryl.
7. The process of claim 1 , wherein the asymmetric catalyst comprises a metal or a metal source and a chiral ligand.
8. The process of claim 7 , wherein the metal or metal source is chosen from ruthenium, a ruthenium complex, osmium, an osmium complex, rhodium, a rhodium complex, iridium, an iridium complex, palladium, a palladium complex, platinum, a platinum complex, and combinations thereof.
9. The process of claim 7 , wherein the chiral ligand is a compound chosen from Formula 670, Formula 680, Formula 690, and Formula 700:
wherein:
R 671 , R 672 , R 673 , R 681 , R 691 , R 692 , R 701 , and R 702 are independently alkyl or aryl; and further wherein
R 691 and R 692 of Formula (690) and R 701 and R 702 of Formula (700), and the carbon atoms to which they are attached, may optionally form a cyclic or bicyclic compound.
10. The process of claim 7 , wherein the metal source is dichloro(p-cymene)ruthenium(II) dimer and the chiral ligand is (1S,2S)-(+)-N-4-tolylsulfonyl-1,2-diphenylethylene-1,2-diamine.
11. The process of claim 1 , wherein the weight ratio of the asymmetric catalyst to the compounds having Formulas (II) and (II′) is about 0.001:1 to about 0.1:1.
12. The process of claim 1 , wherein the hydrogen donor is chosen from formic acid, a salt of formic acid, and a mixture of formic acid and an organic base.
13. The process of claim 1 , wherein the hydrogen donor comprises formic acid and triethylamine.
14. The process of claim 1 , wherein the molar ratio of the compounds having Formulas (II) and (II′) to the hydrogen donor is about 1:1 to about 1:20.
15. The process of claim 1 , wherein the alkali metal is chosen from lithium, sodium, and potassium; and the electron source is chosen from liquid ammonia, methylamine, ethylamine, ethylenediamine, and combinations thereof.
16. The process of claim 1 , wherein the alkali metal is lithium and the electron source is liquid ammonia.
17. The process of claim 1 , wherein the molar ratio of the compounds having Formulas (III) and (III′) to the alkali metal is from about 1:2: to about 1:20, and the weight to volume ratio of the compounds having Formulas (III) and (III′) to the electron source is from about 1:2 to about 1:50 (g/mL).
18. The process of claim 1 , wherein step (a) is conducted at a temperature from about 20° C. to about 100° C., and step (b) is conducted at a temperature from about −80° C. to about 10° C.
19. The process of claim 1 , wherein the compound having Formula (IV) has a yield of at least about 60%.
20. The process of claim 1 , wherein the asymmetric catalyst comprises dichloro(p-cymene)ruthenium(II) dimer and either (1S,2S)-(+)-N-4-tolylsulfonyl-1,2-diphenylethylene-1,2-diamine or (1R,2SR)-(+)-N-4-tolylsulfonyl-1,2-diphenylethylene-1,2-diamine; the weight ratio of the asymmetric catalyst to the compounds having Formulas (II) and (II′) is about 0.01:1; the hydrogen donor comprises formic acid and triethylamine; the molar ratio of the compounds having Formulas (II) and (II′) to formic acid to triethylamine is from about 1:4:2 to about 1:6:3; the alkali metal is lithium and the electron source is liquid ammonia; the molar ratio of the compounds having Formulas (III) and (III′) to lithium is from about 1:3 to about 1:10; the weight to volume ratio of the compounds having Formulas (III) and (III′) to liquid ammonia is from about 1:3 to about 1:10 (g/mL); step (a) is conducted at a temperature from about 22° C. to about 25° C.; step (b) is conducted at a temperature from about −70° C. to about −60° C.; and the compound having Formula (IV) has a yield of at least about 60%.