Process for preparing 7-(acryloyl)indoles

1. A process for preparing a compound of formula I:

wherein

R 1 is chosen from:

hydrogen;

C 1 -C 10 alkyl;

C 1 -C 10 alkyl substituted with one or more of halogen, hydroxy, alkoxy, phenoxy, nitro, cyano, carboxyl, —C(═O)O(C 1 -C 4 )alkyl, —CONH 2 , aryl, or heteroaryl; said aryl or heteroaryl substituted with one or more of (C 1 -C 4 )alkyl, halogen, hydroxy, alkoxy, phenoxy, nitro, cyano, carboxyl, —C(═O)O(C 1 -C 4 )alkyl, and —CONH 2 ;

aryl and aryl substituted with one or more of (C 1 -C 4 )alkyl, halogen, hydroxy, alkoxy, phenoxy, nitro, cyano, carboxyl, —C(═O)O(C 1 -C 4 )alkyl, and —CONH 2 ; and

heteroaryl and heteroaryl substituted with one or more of (C 1 -C 4 )alkyl, halogen, hydroxy, alkoxy, phenoxy, nitro, cyano, carboxyl, —C(═O)O(C 1 -C 4 )alkyl, and —CONH 2 ;

R 2 is chosen from:

hydrogen;

C 1 -C 10 alkyl and C 1 -C 10 alkyl substituted with one or more of halogen, hydroxyl, alkoxy, aryloxy, nitro, cyano, carboxyl, —C(═O)Oalkyl, —C(═O)Oaryl, —CONH 2 , aryl, or heteroaryl;

aryl and aryl substituted with one or more of (C 1 -C 4 )alkyl, halogen, hydroxy, alkoxy, phenoxy, nitro, cyano, carboxyl, —C(═O)O(C 1 -C 4 )alkyl, and —CONH 2 ; and

heteroaryl and heteroaryl substituted with one or more of (C 1 -C 4 )alkyl, halogen, hydroxy, alkoxy, phenoxy, nitro, cyano, carboxyl, —C(═O)O(C 1 -C 4 )alkyl, and —CONH 2 ;

R 3 is chosen from:

hydrogen, chlorine, fluorine, hydroxy, cyano, nitro, alkoxy, aryloxy, thioalkyl, amino, aminoalkyl, aminoaryl, fluoroalkyl, C 1 -C 10 alkyl, C 1 -C 10 alkyl substituted with one or more of fluorine, hydroxyl, alkoxy, aryloxy, aryl or heteroaryl;

R 4 is chosen from:

hydroxyl;

C 1 -C 10 alkoxy;

C 1 -C 10 alkoxy substituted with one or more of fluorine, alkoxy, aryloxy, aryl, or heteroaryl;

NR 5 R 6 , where R 5 and R 6 are the same or different and are chosen from hydrogen;

C 1 -C 6 alkyl substituted with one or more of halogen, hydroxyl, alkoxy, aryloxy, nitro, cyano, carboxyl, carboxyalkyl, carboxyaryl, or carbonylamino; and

SO 2 R 7 in which R 7 is chosen from alkyl, aryl and heteroaryl, said aryl and heteroaryl substituted with one or more of halogen, hydroxy, amino, nitrile, nitro or C 1 -C 6 alkyl; or

R 5 and R 6 taken together form a monocylic 4-7 membered ring or bicyclic 8-12 membered ring;

said process comprising the steps of:

a) rearranging a compound of formula II

wherein

X and Y are independently chosen from bromine, chlorine, iodine, and triflate;

in the presence of a transition metal catalyst to form a compound of formula III

b) followed by reacting said compound of formula III with a compound of formula IV

R 4 —C(═O)—CH═CH 2   (IV)

in the presence of a transition metal catalyst.

2. A process for preparing a compound of formula Ia:

wherein

R 1a and R 2a are chosen from hydrogen, alkyl, benzyl and substituted benzyl;

R 3a is chosen from hydrogen, chlorine, fluorine, hydroxyl, cyano, nitro, alkoxy, aryloxy, thioalkyl, amino, aminoalkyl, aminoaryl, fluoroalkyl, and alkyl; and

R 4a is chosen from hydroxyl and alkoxy;

comprising the steps of:

a) rearranging a compound of formula IIa

wherein

X and Y are chosen from bromine, chlorine, iodine, and triflate;

in the presence of a transition metal catalyst to form a compound of formula IIIa

b) followed by reacting said compound of formula IIIa with a compound of formula IVa

R 4a —C(═O)CH═CH 2   (IVa)

in the presence of a transition metal catalyst.

3. A process according to claim 1 wherein the transition metal in said transition metal catalyst is palladium, nickel, platinum, iron, cobalt, chromium, copper, or zirconium.

4. A process according to claim 3 wherein said transition metal is palladium.

5. A process according to claim 1 wherein said transition metal catalyst is Pd(PPh 3 ) 4 , PdCl 2 , or Pd(OAc) 2 .

6. A process according to claim 1 wherein said rearrangement of said compound of formula II is carried out in the presence of a base.

7. A process according to claim 1 wherein said reaction of said compound of formula III with said compound of formula IV is carried out in the presence of a base.

8. A process according to claim 6 wherein said base is chosen from a trialkylamine, an alkali metal hydroxide, and an alkali metal carbonate.

9. A process according to claim 7 wherein said base is chosen from a trialkylamine, an alkali metal hydroxide, and an alkali metal carbonate.

10. A process according to claim 6 wherein said base is chosen from triethylamine, potassium carbonate, cesium carbonate, diisopropylethylamine, potassium hydroxide, and sodium hydroxide.

11. A process according to claim 7 wherein said base is chosen from triethylamine, potassium carbonate, cesium carbonate, diisopropylethylamine, potassium hydroxide, and sodium hydroxide.

12. A process according to claim 1 wherein said compound of formula II is produced by a process of reacting a compound of formula V:

wherein W is chosen from bromine, chlorine, iodine, toluensulfonate, methanesulfonate, trifluoromethanesulfonate and methyl phosphate, with an aniline of formula VI:

in the presence of a base.

13. A process according to claim 2 wherein said compound of formula ha is produced by a process of reacting a compound of formula Va:

wherein W is chosen from bromine, chlorine, iodine, and triflate; with an aniline of formula VIa

in the presence of a base.

14. A process according to claim 12 wherein said base is chosen from potassium t-butoxide, lithium dialkylamide and sodium or potassium hydride.

15. A process according to claim 12 wherein W is bromine.

16. A process for preparing DTSI:

comprising the steps of:

a) rearranging a compound of formula IIb

in the presence of a transition metal catalyst to form formula IIIb

b) followed by reacting said compound of formula IIIb with methyl acrylate in the presence of a transition metal catalyst to provide a compound of formula Ib

c) transforming said compound of formula Ib to DTSI via a series of further process steps.

17. A process for preparing DTSI:

comprising the steps of:

a) rearranging a compound of formula IIc

in the presence of a transition metal catalyst to form formula IIIc

b) followed by reacting the compound of formula IIIc with methyl acrylate in the presence of a transition metal catalyst to provide a compound of formula Ic

c) transforming the compound of formula Ic to DTSI via a series of further process steps.

18. A process for preparing DTSI:

comprising the steps of:

a) rearranging a compound of formula IIb

in the presence of a transition metal catalyst to form formula IIIb

b) followed by reacting said compound of formula IIIb with acrylic acid in the presence of a transition metal catalyst to provide a compound of formula Id

c) transforming said compound of formula Id to DTSI via a series of further process steps.

19. A process according to claim 16 wherein the transition metal in said transition metal catalyst is palladium, nickel, platinum, iron, cobalt, chromium, copper, or zirconium.

20. A process according to claim 19 wherein said transition metal is palladium.

21. A process according to claim 16 wherein said transition metal catalyst is Pd(PPh 3 ) 4 , PdCl 2 , or Pd(OAc) 2 .

22. A process according to claim 16 wherein said rearrangement of said compound of formula IIb and formula IIc is carried out in the presence of a base.

23. A process according to claim 22 wherein said base is chosen from a trialkylamine, an alkali metal hydroxide, and an alkali metal carbonate.

24. A process according to claim 22 wherein said base is chosen from triethylamine, potassium carbonate, cesium carbonate, diisopropylethylamine, potassium hydroxide, and sodium hydroxide.

25. A process according to claim 16 wherein said compound of formula IIb is produced by a process of reacting a compound of formula VIb:

with allyl halide in the presence of a base.

26. A process according to claim 18 wherein said compound of formula IIb is produced by a process of reacting a compound of formula VIb:

with allyl halide in the presence of a base.

27. A process according to claim 17 wherein said compound of formula IIc is produced by a process of reacting a compound of formula VIb:

with allyl halide in the presence of a base followed by alkylation with 2,4-dichlorobenzyl halide in the presence of base.

28. A process according to claim 17 wherein said compound of formula IIc is produced by a process comprising

(a) reacting a compound of formula VIb:

with 2,4-dichlorobenzyl halide in the presence of a base; and

(b) alkylating a product of step (a) with an allyl halide in the presence of base.

29. A process for preparing DTSI:

comprising the steps of:

(a) bringing together a compound of formula IIb

in the presence of a palladium catalyst with acrylic acid to form a compound of formula Id

(b) transforming said compound of formula Id to DTSI via a series of further process steps.

30. A process according to claim 29 wherein said further process steps include:

(a) reacting said compound of formula Id with 2,4-dichlorobenzyl chloride to provide an N-benzyl indole of formula:

(b) reacting said N-benzyl indole with 4,5-dichlorothiophene-2-sulfonamide to provide DTSI.