Methods for synthesizing rhodamine dyes

1. A method of synthesizing a rhodamine dye, the method comprising:

reacting a compound of formula (I):

wherein

R 1 and R 2 are each independently hydrogen, alkyl, or R 1a —CO—, wherein R 1a is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 4 alkoxy; or R 1 and R 2 , together with the atoms to which they are attached, form a 3-8 membered ring;

R c is selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl and halogen; and

R a and R b are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl and halogen; or

R 1 and R a , together with the atoms to which they are attached, form a 5-8 membered ring, and

R 2 and R b , together with the atoms to which they are attached, form a 5-8 membered ring;

with a compound of formula (II),

wherein

R is selected from the group consisting of halogen, alkyl, haloalkyl, cyano, carboxy, alkoxy, haloalkoxy, alkoxycarbonyl, (carboxyl)heteroalkyl, alkylcarbonyl, alkoxyalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, sulfonate, sulfonamide and amide;

n is 0, 1, 2, 3 or 4;

X is halogen or OR 3 ; and R 3 is selected from the group consisting of hydrogen, alkyl, aryl, alkylcarbonyl, alkoxycarbonyl, haloalkyl, haloalkylcarbonyl, haloalkoxycarbonyl, alkylsulfonyl, arylsulfonyl and haloalkylsulfonyl;

to form the rhodamine dye.

2. The method of claim 1 , wherein R is selected from the group consisting of hydrogen, halogen, alkyl, haloalkyl, cyano, carboxy, alkoxycarbonyl and alkylcarbonyl.

3. The method of claim 1 , wherein R is attached to the 4 or 5 position of the compound of formula (II).

4. The method of claim 1 , wherein the compound of formula (II) is selected from the group consisting of

5. The method of claim 1 , wherein X is OR 3 ;

and R 3 is hydrogen.

6. The method of claim 1 , wherein R 1 and R 2 are each independently C 1 -C 4 alkyl.

7. The method of claim 1 , wherein R c is hydrogen.

8. The method of claim 1 , wherein R 1 and R a , together with the atoms to which they are attached, form a 6- or 7-membered ring; and R 2 and R b , together with the atoms to which they are attached, form a 6- or 7-membered ring.

9. The method of claim 1 , wherein the compound of formula (I) is selected from the group consisting of:

10. The method of claim 1 , wherein the compound of formula (I) and the compound of formula (II) are reacted in at least one solvent.

11. The method of claim 10 , wherein the solvent is a halogenated solvent, water, or a combination thereof.

12. The method of claim 1 , wherein the compound of formula (I) and the compound of formula (II) are reacted in the presence of an oxidizing agent.

13. The method of claim 12 , wherein the oxidizing agent is oxygen gas.

14. The method of claim 1 , wherein oxygen is bubbled through the reaction of compound of formula (I) and the compound of formula (II).

15. The method of claim 1 , wherein the compound of formula (I) and the compound of formula (II) are reacted at a temperature greater than ambient temperature.

16. The method of claim 1 , wherein compound of formula (I) and the compound of formula (II) are heated to a temperature of about 30° C. to about 100° C.

17. The method of claim 1 , further comprising purifying the rhodamine dye.

18. The method of claim 1 , wherein the method produces a 6-substituted rhodamine dye with substantially no 5-substituted rhodamine byproduct or a 5-substituted rhodamine dye with substantially no 6-substituted rhodamine byproduct.

19. The method of claim 1 , wherein the rhodamine dye is a compound of formula (III):

wherein:

R is selected from the group consisting of halogen, alkyl, haloalkyl, cyano, carboxy, alkoxy, haloalkoxy, alkoxycarbonyl, (carboxy)heteroalkyl, alkylcarbonyl, alkoxyalkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, sulfonate, sulfonamide and amide;

n is 0, 1, 2, 3 or 4;

R 1 and R 2 are each independently hydrogen or alkyl or R 1a —CO—, wherein R 1a is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or C 1 -C 4 alkoxy; or R 1 and R 2 , together with the atoms to which they are attached, form a 3-8 membered ring;

R c is selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl and halogen; and

R a and R b are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl and halogen; or

R 1 and R a , together with the atoms to which they are attached, form a 5-8 membered ring, and

R 2 and R b , together with the atoms to which they are attached, form a 5-8 membered ring.

20. The method of claim 1 , wherein the rhodamine dye is selected from the group consisting of: