Synthetic methodology for the reductive alkylation at the C-3 position of indoles

1. A method for the reductive alkylation at the C-3 position of an indole, said method comprising treating the indole with an aldehyde in the presence of a silicon hydride reducing agent selected from the group consisting of tri(C 1 -C 4 alkyl)silane, triphenylsilane, diphenylsilane and phenylmethylsilane, and a Lewis acid selected from the group consisting of salts of boron, aluminium, antimony or a rare earth metal and a halogen or triflate anion, and pentafluorophenylmetallic acids in which the metal is boron, aluminium, antimony or a rare earth metal; and subsequently adding an organic acid to the reaction mixture after the reaction has begun, wherein the organic acid is selected from the group consisting of trifluoroacetic acid, CCl X H 3-X CO 2 H where X is 0-3, p-toluenesulfonic acid, and benzenesulfonic acid.

2. The method of claim 1 wherein the organic acid is added approximately 30-60 minutes after the reaction has begun.

3. The method according to claim 1 or 2 , wherein the indole comprises an acid-sensitive substituent bonded to the N-1 nitrogen.

4. The method claim 3 wherein the acid-sensitive substituent is selected from the group consisting of benzhydryl, 2,4-dimethoxybenzyl, 2-hydroxybenzyl, 5-dibenzosuberyl, and triphenylmethyl, and is optionally substituted with 1 to 3 substituents selected independently from the group consisting of halogen, —CN, —CHO, —CF 3 , —OCF 3 , —OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —NH 2 , —N(C 1 -C 6 alkyl) 2 , —NH(C 1 -C 6 alkyl), —NH—C(O)—(C 1 -C 6 alkyl), and —NO 2 .

5. The method according to claim 1 wherein the Lewis acid is selected from the group consisting of a flouride, chloride, or triflate salt of boron, aluminium, antimony or a rare earth metal, and pentafluorophenylboronic acid.

6. The method of claim 5 wherein the Lewis acid is selected from the group consisting of BF 3 , boron tris(trifluoromethanesulfonate), and pentafluorophenylboronic acid.

7. The method according to claim 1 wherein the silicon hydride reducing agent is triethylsilane.

8. The method according to claim 1 wherein the reaction takes place at a temperature in the range of from about −30° C. to about +25° C.

9. A method for the reductive alkylation at the C-3 position of an indole, wherein the indole comprises a compound of the formula

wherein

R is selected from the group consisting of —(CH 2 ) n3 -A, —(CH 2 ) n3 —S-A, and —(CH 2 ) n3 —O-A, wherein A is selected from the group consisting of:

wherein

E is selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —CF 3 , and —(CH 2 ) n4 —CF 3 ; and

D and G independently are selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, furyl, thienyl and pyrrolyl, each optionally substituted by from 1 to 3 substituents selected independently from halogen, —CN, —CHO, —CF 3 , —OCF 3 , —OH, C 1 -C 6 alkoxy, —NH 2 , —N(C 1 -C 6 alkyl) 2 , —NH(C 1 -C 6 alkyl), —NH—C(O)—(C 1 -C 6 alkyl), NO 2 , and a 5- or 6-membered heterocyclic or heteroaromatic ring containing 1 or 2 heteroatoms selected from O, N and S;

X 1 is selected from the group consisting of a chemical bond, —S—, —O—, —S(O)—, —S(O) 2 —, —NH—, —NHC(O)—, —C═C—,

R 1 is selected from the group consisting of C 1 -C 6 alkyl, C 1 -C 6 fluorinated alkyl, C 3 -C 6 cycloalkyl, tetrahydropyranyl, camphoryl, adamantyl, —CN, —N(C 1 -C 6 alkyl) 2 , phenyl, pyridinyl, pyrimidinyl, furyl, thienyl, naphthyl, morpholinyl, triazolyl, pyrazolyl, piperidinyl, pyrrolidinyl, imidazolyl, piperazinyl, thiazolidinyl, thiomorpholinyl, tetrazolyl, indolyl, benzoxazolyl, benzofuryl, imidazolidinyl-2-thione, 7,7-dimethyl-bicyclo[2.2.1]heptyl-2-one, benzo[1.2.5]oxadiazolyl, 2-oxa-5-aza-bicyclo[2.2.1]heptyl, piperazinyl-2-one and pyrrolyl, each optionally substituted with 1 to 3 substituents independently selected from the group consisting of halogen, —CN, —CHO, —CF 3 , —OCF 3 , —OH, C 1 -C 6 alkyl, —(C 1 -C 6 alkyl)-R 7 , C 1 -C 6 alkoxy, —(C 1 -C 6 alkoxy)-R 7 , —C(O)—(C 1 -C 6 alkyl), —NH 2 , —N(C 1 -C 6 alkyl) 2 , —NH(C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)—NH 2 , —(C 1 -C -C 6 alkyl)-N(C 1 -C 6 alkyl) 2 , —(C 1 -C 6 alkyl)-NH(C 1 -C 6 alkyl), —NH—C(O)—(C 1 -C 6 alkyl), —NO 2 , —SO 2 (C 1 -C 6 alkyl), —SO 2 NH 2 , —SO 2 NH(C 1 -C 6 alkyl), —SO 2 N(C 1 -C 6 alkyl) 2 , —COOH, —C(O)O—(C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)-COOH, 1-chloro-2-methyl-propyl, —C 1 -C 6 thioalkyl, —(C 1 -C 6 alkyl)C(O)CH 3 , —(C 1 -C 6 alkyl)OCH 3 , C(O)NH 2 , phenyl, benzyl, benzyloxy, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, furyl, thienyl, imidazolyl, tetrazolyl, pyrazinyl, pyrazolonyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 2-methyl-thiazolyl,

R 3 is selected from the group consisting of H, halogen, —CN, —CHO, —CF 3 , —OCF 3 , —OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 thioalkyl, —NH 2 , —N(C 1 -C 6 alkyl) 2 , —NH(C 1 -C 6 alkyl), —NH—C(O)—(C 1 -C 6 alkyl), and —NO 2 ;

R 4 is selected from the group consisting of H, halogen, —CN, —CHO, —CF 3 , —OCF 3 , —OH, —C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 thioalkyl, —NH 2 , —N(C 1 -C 6 alkyl) 2 , —NH(C 1 -C 6 alkyl), —NHC(O)—(C 1 -C 6 alkyl), —NO 2 , —NH—C(O)—NH(C 1 -C 6 alkyl) 2 , —NH—C(O)—NH(C 1 -C 6 alkyl), —NH—C(O)—O—(C 1 -C 6 alkyl), —SO 2 —(C 1 -C 6 alkyl), —S—(C 3 -C 6 cycloalkyl), —S—CH 2 —(C 3 -C 6 cycloalkyl), —SO 2 —(C 3 -C 6 cycloalkyl), —SO 2 —CH 2 —(C 3 -C 6 cycloalkyl), C 3 -C 6 cycloalkyl, —CH 2 —(C 3 -C 6 cycloalkyl), —O—(C 3 -C 6 cycloalkyl), —O—CH 2 —(C 3 -C 6 cycloalkyl), phenyl, benzyl, benzyloxy, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl furyl, thienyl, imidazolyl, tetrazolyl, pyrazinyl, pyrazolonyl, pyrazolyl, oxazolyl and isoxazolyl, the rings of each of these R 4 groups each being optionally substituted by from 1 to 3 substituents selected from the group consisting of halogen, —CN, —CHO, —CF 3 , —OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —NH 2 , —N(C 1 -C 6 alkyl) 2 , —NH(C 1 -C 6 alkyl), —NH—C(O)—(C 1 -C 6 alkyl), —NO 2 , —SO 2 (C 1 -C 6 alkyl), —SO 2 NH(C 1 -C 6 alkyl), —SO 2 N(C 1 -C 6 alkyl) 2 , and —OCF 3 ;

R 5 and R 6 independently are selected from the group consisting of H and C 1 -C 6 alkyl; or

R 5 and R 6 together with the atom to which they are bonded form C 3 -C 6 cycloalkyl;

R 7 is selected from the group consisting of phenyl, benzyl, benzyloxy, morphlinyl, pyrrolidinyl, piperidinyl, piperazinyl, furyl, thienyl, imidazolyl, tetrazolyl, pyrazinyl, pyrazolonyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, 2-methyl-thiazolyl, each being optionally substituted by from 1 to 3 substituents selected from the group consisting of halogen, —CN, —CHO, —CF 3 , —OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —C(O)—(C 1 -C 6 alkyl), —C(O)O—(C 1 -C 6 alkyl), —NH 2 , —N(C 1 -C 6 alkyl) 2 , —NH(C 1 -C 6 alkyl), —NH—C(O)—(C 1 -C 6 alkyl), —NO 2 , —SO 2 (C 1 -C 6 alkyl), —SO 2 NH(C 1 -C 6 alkyl), —SO 2 N(C 1 -C 6 alkyl) 2 , and —OCF 3 ;

n 1 is an integer selected from 1, 2, or 3;

n 2 is an integer selected from 0, 1, 2, 3, or 4;

n 3 is an integer selected from 0, 1, 2, or 3; and

n 4 is an integer selected from 1, 2, or 3; the method comprising treating the indole with an aldehyde in the presence of a silicon hydride reducing agent selected from the group consisting of tri(C 1 -C 4 alkyl)silane, triphenylsilane, diphenylsilane and phenylmethylsilane, and a Lewis acid selected from the group consisting of salts of boron, aluminium, antimony or a rare earth metal and a halogen or triflate anion, and pentafluorophenylmetallic acids in which the metal is boron, aluminum, antimony or a rare earth metal.

10. The method of claim 9 , wherein R has the formula

wherein X 3 and X 4 independently are selected form the group consisting of H, halogen, —CN, —CHO, —CF 3 , —OCF 3 , —OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —NH 2 , —N(C 1 -C 6 alkyl) 2 , —NH(C 1 -C 6 alkyl), —NH—C(O)—(C 1 -C 6 alkyl), and —NO 2 .

11. The method of claim 10 , wherein

X 3 is H; and

X 4 is H.

12. The method of claim 9 , wherein the indole comprises a compound of the formula

wherein

X 3 and X 4 independently are selected from the group consisting of H, halogen, —CN, —CHO, —CF 3 , —OCF 3 , —OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —NH 2 , —N(C 1 -C 6 alkyl) 2 , —NH(C 1 -C 6 alkyl), —NH—C(O)—(C 1 -C 6 alkyl), and —NO 2 ; and

X 5 , X 6 , X 7 , and X 8 independently are selected from the group consisting of H, halogen, —CN, —CHO, —CF 3 , —OCF 3 , —OH, C 1 -C 6 alkyl, —(C 1 -C 6 alkyl)-R 7 , C 1 -C 6 alkoxy, —(C 1 -C 6 alkoxy)-R 7 , —C(O)—(C 1 -C 6 alkyl), —NH 2 , —N(C 1 -C 6 alkyl) 2 , —NH(C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)-NH 2 , —(C 1 -C 6 alkyl)-N(C 1 -C 6 alkyl) 2 , —(C 1 -C 6 alkyl)-NH(C 1 -C 6 alkyl), —NH—C(O)—(C 1 -C 6 alkyl), —NO 2 , —SO 2 (C 1 -C 6 alkyl), —SO 2 NH 2 , —SO 2 NH(C 1 -C 6 alkyl), —SO 2 N(C 1 -C 6 alkyl) 2 , —COOH, —C(O)O—(C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)-COOH, 1-chloro-2-methyl-propyl, C 1 -C 6 thioalkyl, —(C 1 -C 6 alkyl)C(O)CH 3 , —(C 1 -C 6 alkyl)OCH 3 , —C(O)NH 2 , phenyl, benzyl, benzyloxy, morpholinyl, pyrrolidinyl, piperidinyl, piperazinyl, furyl, thienyl, imidazolyl, tetrazolyl, pyrazinyl, pyrazolonyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 2-methyl-thiazolyl,

 the rings of each of these X 5 , X 6 , X 7 , and X 8 groups each being optionally substituted by from 1 to 3 substituents selected from the group consisting of halogen, —CN, —CHO, —CF 3 , —OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, —C(O)—(C 1 -C 6 alkyl), —NH 2 , —N(C 1 -C 6 alkyl) 2 , —NH(C 1 -C 6 alkyl), —NH—C(O)—(C 1 -C 6 alkyl), —NO 2 , —SO 2 (C 1 -C 6 alkyl), —SO 2 NH(C 1 -C 6 alkyl), —SO 2 N(C 1 -C 6 alkyl) 2 , and —OCF 3 .

13. The method of claim 12 , wherein

X 3 is H; and

X 4 is H.

14. The method according to any of claims 12 or 13 , wherein

X 5 is —CF 3 ;

X 6 is H;

X 7 is H; and

X 8 is H.

15. The method according to any of claims 12 or 13 , wherein

X 5 is —CH 3 ;

X 6 is H;

X 7 is H; and

X 8 is —CH 3 .

16. The method according to any of claims 12 or 13 , wherein

X 5 is H;

X 6 is Cl;

X 7 is Cl; and

X 8 is H.

17. The method of claim 9 wherein the aldehyde is a compound of the formula

wherein

X 2 is selected from the group consisting of —O—, —CH 2 —, —S—, —SO—, —SO 2 —, —NH—, —C(O)—, —NHSO 2 —,

R 2 is a ring moiety selected from the group consisting of phenyl, pyridinyl, pyrimidinyl, furyl, thienyl and pyrrolyl, the ring moiety being substituted by a group of the formula —(CH 2 ) n6 —CO 2 R 8 or a pharmaceutically acceptable bioisostere, and optionally further substituted by 1 or 2 substituents independently selected from the group consisting of halogen, —CN, —CHO, —CF 3 , —OCF 3 , —OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 thioalkyl, —NH 2 , —N(C 1 -C 6 alkyl) 2 , —NH(C 1 -C 6 alkyl), —NH—C(O)—(C 1 -C 6 alkyl), and —NO 2 ;

R 8 is selected from the group consisting of H and C 1 -C 6 alkyl;

n 5 is an integer selected from 0, 1, 2, or 3; and

n 6 is an integer selected from 0, 1, or 2.

18. The method of claim 17 , wherein the aldehyde is a compound of the formula

wherein R 8 comprises a C 1 -C 6 alkyl group.

19. The method according to claim 18 , further comprising the step of removing the R 8 group to form a carboxylic acid.

20. The method according to any of claims 17 - 19 wherein

R is benzhydryl; and

the Lewis acid is BF 3 .

21. The method according to claim 20 , wherein the silicon hydride reducing agent is triethylsilane.

22. The method of claim 10 , further comprising subsequently adding an organic acid to the reaction mixture after the reaction has begun, wherein the organic acid is selected from the group consisting of trifluoroacetic acid, CCl X H 3-X CO 2 H where X is 0-3, p-toluenesulfonic acid, and benzenesulfonic acid.

23. The method according to claim 22 , wherein the organic acid is added approximately 30-60 minutes after the reaction has begun.

24. The method of claim 22 , wherein the organic acid is trifluoroacetic acid.

25. The method of claim 9 , wherein the Lewis acid is selected from the group consisting of a fluoride, chloride, or triflate salt of boron, aluminium, antimony or a rare earth metal, and pentafluorophenylboronic acid.

26. The method of claim 25 wherein the Lewis acid is selected from the group consisting of BF 3 , boron tris(trifluoromethanesulfonate), and pentafluorophenylboronic acid.

27. The method of claim 9 , wherein the reaction takes place at a temperature in the range of from about −30° C. to about +25° C.

28. The method claim 9 , wherein the silicon hydride reducing agent is triethylsilane.