One-pot preparation of hexahydroisoquinolines from amides
View Patent ↗The present invention provides an efficient process for the preparation of hexahydroisoquinolines from amides. 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 (III′), the process comprising:
(a) contacting a compound having Formula (I) with POCl 3 to form a compound having Formula (II); and
(b) contacting the compound having Formula (II) with an asymmetric catalyst and a hydrogen donor comprising a formate ion to form a compound having Formula (III′)
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 , R 4 , 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 , —O(O)C(R 212 ) 3 , —C(O)NHR 212 , and —SO 2 R 212 ;
R 212 is chosen from hydrocarbyl and substituted hydrocarbyl; and
the compound having Formula (II) is not isolated as a solid prior to step (b).
2. The process of claim 1 , wherein a compound having Formula (III) 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 , R 4 , 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 , —O(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 4 is —OR 211 ;
R 211 is chosen from hydrogen, alkyl, —C(O)R 212 , —C(O)O(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 6 is —OR 211 ;
R 211 is chosen from hydrogen, alkyl, —C(O)R 212 , —C(O)O(R 212 ) 3 , —C(O)NHR 212 , and —SO 2 R 212 ; and
R 212 is chosen from alkyl and aryl.
6. 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 chosen from hydroxyl, —OC(O)CH 3 , —C(O)C(CH 3 ) 3 , —OC(O)Ph, and —OSO 2 CH 3 ; R 12 is chosen from alkyl, allyl, benzyl, and halo; and R 212 is methyl.
7. The process of claim 1 , wherein:
R 3 , R 4 , and R 6 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.
8. The process of claim 1 , wherein the molar ratio of the compound comprising Formula (I) to POCl 3 is from about 1:0.5 to about 1:5.
9. The process of claim 1 , wherein the asymmetric catalyst comprises a metal or a metal source and a chiral ligand.
10. The process of claim 9 , 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; and 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
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.
11. The process of claim 9 , 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.
12. The process of claim 1 , wherein the weight ratio of the asymmetric catalyst to the compound having Formula (II) is about 0.001:1 to about 0.1:1; the molar ratio of the compound having Formula (II) to the hydrogen donor is about 1:1 to about 1:20.
13. 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.
14. The process of claim 1 , wherein the hydrogen donor comprises formic acid and triethylamine.
15. The process of claim 2 , wherein steps (a) and (b) are conducted at a temperature from about 20° C. to about 100° C.; and the compound having Formula (III) has a yield of at least about 60%.
16. The process of claim 1 , wherein the molar ratio of the compound having Formula (I) to POCl 3 is about 1:1; 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,2R)-(+)-N-4-tolylsulfonyl-1,2-diphenylethylene-1,2-diamine; the weight ratio of the asymmetric catalyst to the compound having Formula (II) is about 0.01:1; the hydrogen donor comprises formic acid and triethylamine; the molar ratio of the compound having Formula (II) to formic acid to triethylamine is from about 1:4:2 to about 1:6:3; and steps (a) and (b) are conducted at a temperature from about 22° C. to about 25° C.