Methods for the preparation of thiazolidinethione indene-based chiral auxiliaries

1. A method for preparing a compound comprising contacting a compound of formula (I),

wherein

R 1 -R 6 are each independently hydrogen, cyano, halo, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are each optionally substituted with one or more groups which are each independently cyano, halo, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl;

R 7 and R 8 are each independently hydrogen, C 1-6 alkyl, or phenyl, wherein the alkyl and phenyl groups are each optionally substituted with one or more groups which are each independently halo or C 1-6 alkyl;

or one or more of

(a) R 1 and R 2 taken together with the carbon atoms to which they are bonded;

(b) R 2 and R 3 taken together with the carbon atoms to which they are bonded;

(c) R 3 and R 4 taken together with the carbon atoms to which they are bonded; and

(d) R 5 and R 6 taken together with the carbon atoms to which they are bonded, form a fused C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl ring wherein the fused ring is optionally substituted with one or more groups which are each independently halo or C 1-6 alkyl;

with sulfuric acid, phosphoric acid, or trifluorosulfonic acid, under suitable reaction conditions to provide a first intermediate; and

contacting the first intermediate with a compound of formula (II),

in the presence of an alkali hydroxide, wherein

M + is lithium, sodium, potassium, or ammonium; and

R 10 is C 1-20 alkyl, C 2-20 alkenyl, C 2-20 alkynyl, C 3-8 cycloalkylC 1-6 alkyl, heterocyclylC 1-6 alkyl, arylC 1-6 alkyl, heteroarylC 1-6 alkyl, C 3-8 cycloalkyl, heterocyclyl, heteroaryl, or aryl, wherein

R 10 is optionally substituted with one or more groups which are each independently nitro, cyano, halo, hydroxy, C 1-6 alkoxy, C 1-6 alkyl, or C 1-6 haloalkyl;

under suitable reaction conditions to provide a compound of formula (III),

2. The method of claim 1 , wherein the compound of formula (I) is of formula (Ia),

3. The method of claim 1 , wherein the compound of formula (I) is of formula (Ib),

4. The method of claim 1 , wherein the compound of formula (I) is of formula (Ic),

5. The method of claim 1 , wherein the compound of formula (I) is of formula (Id),

6. The method of claim 1 , wherein the compound of formula (I) is of formula (Ie),

7. The method of claim 1 , wherein the compound of formula (I) is of formula (If),

8. The method of claim 1 , wherein the compound of formula (I) is of formula (Ig),

9. The method of claim 1 , wherein the compound of formula (I) is of formula (Ih),

10. The method of claim 1 , wherein R 10 is C 1 -C 20 alkyl or phenyl, wherein R 10 is optionally substituted with one or more groups which are each independently nitro, cyano, halo, hydroxy, C 1-6 alkoxy, C 1-6 alkyl, or C 1-6 haloalkyl.

11. The method of claim 10 , wherein R 10 is C 1-20 alkyl.

12. The method of claim 10 , wherein R 10 is phenyl optionally substituted with one or more groups which are each independently nitro, cyano, halo, hydroxy, C 1-6 alkoxy, C 1-6 alkyl, or C 1-6 haloalkyl.

13. The method of claim 1 , wherein the alkali hydroxide is sodium or potassium hydroxide.

14. The method of claims 1 , wherein M + is sodium or potassium.

15. The method of claim 14 , wherein M + is potassium.

16. The method of claim 1 , wherein the acid is sulfuric acid.

17. The method of claim 1 , further comprising contacting the compound of formula (III) with

(a) a compound of the formula R N —X or R N —O—R N , wherein

X is halo, and

each R N is independently —C(O)CH(R 21 )R 20 or —C(O)C(R 21 )═CH(R 20 ), wherein R 20 is hydrogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, arylC 1-6 alkyl, aryl C 2-6 alkenyl, heteroarylC 1-6 alkyl, heteroarylC 2-6 alkenyl, C 3-8 cycloalkylC 1-6 alkyl, C 3-8 cycloalkylC 2-6 alkenyl heterocyclylC 1-6 alkyl, heterocyclylC 2-6 alkenyl, aryl, heteroaryl, C 3-8 cycloalkyl, or heterocyclyl; and R 21 is hydrogen or C 1-6 alkyl;

or

(b) a compound of the formula R N —OH in the presence of an amide coupling reagent, under suitable reaction conditions to provide a compound of formula (IV),

18. The method of claim 17 , wherein R N is —C(O)C 1-6 alkyl or —C(O)C(R 21 )═CH(R 20 ),

wherein R 20 and R 21 are independently hydrogen or C 1-6 alkyl.

19. The method of claim 17 , comprising contacting the compound of formula (III) with a compound of the formula R N —X.

20. The method of claim 17 , comprising contacting the compound of formula (III) with a compound of the formula R N —O—R N .

21. The method of claim 17 , comprising contacting the compound of formula (III) with a compound of the formula R N —OH and an amide coupling agent.

22. The method of claim 21 , wherein the amide coupling agent is a carbodiimide, a N,N′-carbonyldiimizadole, or a benzotriazol-1-yloxyphosphonium salt.

23. A method for preparing a compound comprising contacting a compound of formula (I),

wherein

R 1 -R 6 are each independently hydrogen, cyano, halo, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 1-6 alkynyl, C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl groups are each optionally substituted with one or more groups which are each independently cyano, halo, nitro, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl;

R 7 and R 8 are each independently hydrogen, C 1-6 alkyl, or phenyl, wherein the alkyl and phenyl groups are each optionally substituted with one or more groups which are each independently halo or C 1-6 alkyl;

or one or more of

(a) R 1 and R 2 taken together with the carbon atoms to which they are bonded;

(b) R 2 and R 3 taken together with the carbon atoms to which they are bonded;

(c) R 3 and R 4 taken together with the carbon atoms to which they are bonded; and

(d) R 5 and R 6 taken together with the carbon atoms to which they are bonded, form a fused C 3-8 cycloalkyl, heterocyclyl, aryl, or heteroaryl ring wherein the fused ring is optionally substituted with one or more groups which are each independently halo or C 1-6 alkyl;

with either

(i) sulfuric acid under suitable reaction conditions to provide a compound of the formula,

(ii) trifluoromethylsulfonic acid under suitable reaction conditions to provide a compound of the formula,

wherein R A is —CF 3 and A − is R A SO 2 O − ; or

(iii) phosphoric acid under suitable reaction conditions to provide a compound of the formula,

24. The method of claim 23 , wherein the acid is sulfuric acid.