Processes for preparing indoles

Patent metadata

Field	Value
Publication number	US-9334275-B2
Application number	US-201214360250-A
Country	US
Kind code	B2
Filing date	Dec 19, 2012
Priority date	Dec 19, 2011
Publication date	May 10, 2016
Grant date	May 10, 2016

Abstract

Methods for the synthesis of an indole in provided. Methods comprise oxidizing a N-aryl imine in the presence of a palladium-based catalyst, an oxidant, and a solvent.

First claim

The invention claimed is:

1. A method for the synthesis of an indole of Formula (I) or a salt thereof,

the method comprising oxidizing a N-aryl imine of Formula (II)

in the presence of a palladium-based catalyst, an oxidant selected from the group consisting of copper (II) acetate, benzoquinone, tert-butylhydroperoxide, di-tert-butyl peroxide (tBuOOtBu), tert-butyl benzoyl peroxide (BzOOtBu), molecular oxygen (O 2 ), and air, or combinations thereof and a solvent comprising of dimethylsulfoxide, wherein the amount of oxidant is about 0.5 equivalence to about 5 equivalence of N-aryl amine;
wherein
R 1 at each occurrence is independently selected from the group consisting of hydrogen, optionally substituted C 1 -C 20 alkyl, optionally substituted C 3 -C 20 mono-, or poly-cycloalkyl, optionally substituted 2-20-membered heteroalkyl, optionally substituted 3-20-membered mono-, or poly-heterocycloalkyl, halogen, and —OR; wherein R is optionally substituted C 1 -C 20 alkyl; wherein R 2 is selected from the group consisting of optionally substituted C 2 -C 20 alkenyl, optionally substituted 2-20-membered heteroalkenyl, optionally substituted monocyclic, condensed polycyclic or bridged polycyclic C 5 -C 20 aryl, and optionally substituted 5-20-membered monocyclic, condensed polycyclic or bridged polycyclic heteroaryl; wherein R 3 is selected from the group consisting of hydrogen, C 1 -C 20 alkyl, C 2 -C 20 alkenyl; monocyclic, condensed polycyclic or bridged polycyclic C 5 -C 20 aryl; C 3 -C 20 mono-, or poly-cycloalkyl; and C 3 -C 20 mono-, or poly-cycloalkenyl;
m is 0, 1, 2, 3, or 4;

wherein
R 1 at each occurrence is positioned on the phenyl ring in 3-, 4-, 5-, or 6-position with respect to the bond linking the phenyl to the —N—H group according to Formula (I) or the —N═C group according to Formula (II).

2. The method according to claim 1 , wherein R 1 at each occurrence is independently selected from the group consisting of hydrogen, alkyl, —O-alkyl, and halogen.

3. The method according to claim 1 , wherein R 1 at each occurrence is independently selected from the group consisting of —H, —OCH 3 , and —Cl.

4. The method according to claim 1 , wherein R 1 is positioned on the phenyl ring in 4-position with respect to the bond linking the phenyl to the —N—H group according to Formula (I) or the —N═C group according to Formula (II).

5. The method according to claim 1 , wherein R 2 is

wherein * denotes the point in which R 2 is connected to the parent molecular moiety.

6. The method according to claim 1 , wherein R 3 is hydrogen or phenyl.

7. The method according to claim 1 , wherein the indole is 2-aryl indole, 2-alkenyl indole, 2,3-diaryl indole, 2-aryl-3-alkenyl indole, 2-alkenyl-3-aryl indole, 2,3-dialkenyl indole, 2-aryl-3-alkyl indole, or 2-alkenyl-3-alkyl indole.

8. The method according to claim 1 , wherein the indole is

9. The method according to claim 1 , wherein the palladium-based catalyst is selected from the group consisting of palladium metal, palladium (II) acetate, sodium palladium (II) chloride, palladium (II) acetylacetonate, palladium(II) trifluoroacetate, palladium hydroxide, palladium(II) bromide, palladium (II) chloride, palladium(II) cyanide, palladium(II) hexafluoroacetylacetonate, palladium(II) iodide, palladium(II) nitrate dehydrate, palladium(II) nitrate hydrate, palladium(II) oxide, palladium (II) propionate, palladium (II) sulfate, and palladium (II) sulfide, or mixtures thereof.

10. The method according to claim 9 , wherein the palladium-based catalyst comprises of palladium (II) acetate.

11. The method according to claim 1 , wherein the amount of palladium-based catalyst is in the range of about 0.1 mol % to about 20 mol %, with respect to the amount of N-aryl imine.

12. The method according to claim 1 , wherein the oxidant comprises of copper (II) acetate.

13. The method according to claim 1 , wherein the oxidant comprises of molecular oxygen (O 2 ).

14. The method according to claim 1 , wherein the amount of oxidant is about 2 equivalence to about 3 equivalence, of the amount of N-aryl imine.

15. The method according to claim 1 , further comprising reacting in the presence of an additive, wherein the additive comprises a quaternary ammonium salt of Formula (III)
(R 4 ) n N—X  Formula (III)

wherein
R 4 at each occurrence is independently selected from C 1 -C 20 alkyl;
n is 1, 2, 3 or 4; and
X is selected from the group consisting of a halogen and —OCOCH 3 .

16. The method according to claim 15 , wherein the additive is selected from the group consisting of Bu 4 NBr, Bu 4 NCl, Bu 4 NI, and Bu 4 NOCOCH 3 .

17. The method according to claim 15 , wherein the amount of additive is about 1 equivalence to about 3 equivalence of the amount of N-aryl imine.

18. The method according to claim 15 , wherein the additive comprises a ligand for the palladium-based catalyst, wherein the ligand is selected from the group consisting of pyridine, 2,2′-bipyridine, 1,10-phenanthroline, PPh 3 , dppm, dppe, dppp, dcpe, P(c-hex) 3 , P(tBu) 3 , P(C 6 F 5 ) 3 , and P(2,4,6-Me 3 C 6 H 2 ) 3 , or mixtures thereof.

19. The method according to claim 18 , wherein the amount of ligand is about 1 equivalence to about 2 equivalence of the amount of palladium present in the palladium-based catalyst.

20. The method according to claim 1 , wherein the method is carried out at a temperature in the range of about 0° C. to about 150° C.

Assignees

• Univ Nanyang Tech

Inventors

• Yoshikai Naohiko
• Wei Ye

Classifications

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07D209/12

  Radicals substituted by oxygen atoms · CPC title

• C07D209/10

  with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring · CPC title

• C07D209/42

  Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals · CPC title

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title