Fluorination of organic compounds
Methods for fluorinating organic compounds utilizing a novel organic reagent are described herein. The invention further discloses the utility of this reagent for incorporation of the 18 F isotope into hydroxyl group-containing organic molecules for PET imaging studies. Preparation of the reagents is described along with isolable intermediate structures from reaction of the reagent with a hydroxyl group-containing organic molecule.
1. A compound of Formula (I):
wherein
D is oxygen;
A is hydrogen, LiX, MgX 2 , ScX 3 , ScR 6 3 YX 3 , YR 6 3 , BR 6 3 , BX 3 , TiX 4 , TiR 6 4 , ZrX 4 , ZrR 6 4 , FeX 3 , FeR 6 3 , ZnX 2 , ZnR 6 2 , AlX 3 , AlR 6 3 , InX 3 , InR 6 3 , SiX 4 , SiR 6 4 , SnX 2 , SnR 6 2 , SnX 4 , SnR 6 4 , BiX 3 , or BiR 6 3 ;
each occurrence of R 6 is independently C 1-6 alkyl, —OR 7 , C 6-10 aryl, C 6-10 aralkyl, 5-10 membered heteroaryl, 5-10 membered heteroaralkyl, 4-10 membered heterocyclyl, 4-10 membered heterocyclylalkyl, 3-10 membered carbocyclyl, or 3-10 membered carbocyclylalkyl, wherein each of C 1-6 alkyl, C 6-10 aryl, C 6-10 aralkyl, 5-10 membered heteroaryl, 5-10 membered heteroaralkyl, 4-10 membered heterocyclyl, 4-10 membered heterocyclylalkyl, 3-10 membered carbocyclyl, and 3-10 membered carbocyclylalkyl is independently optionally substituted with 0 to 5 occurrences of R 5 ; each occurrence of X is independently halogen or Q −t ;
Q −t is an anion;
R 1 and R 2 are independently selected from the group consisting of C 1-6 alkyl, C 6-10 aryl, C 6-10 aralkyl, 5-10 membered heteroaryl, 5-10 membered heteroaralkyl, 4-10 membered heterocyclyl, 4-10 membered heterocyclylalkyl, 3-10 membered carbocyclyl, and 3-10 membered carbocyclylalkyl, each of which is independently optionally substituted with 0 to 5 occurrences of R 5 ;
R 3 and R 4 are independently selected from the group consisting of hydrogen, unsubstituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, nitro, cyano, halo, C 1-6 haloalkyl, C 1-6 alkoxy, optionally substituted C 6-10 aryl, optionally substituted C 6-10 aralkyl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-10 membered heterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclylalkyl, acyl, —NH 2 , —NHR 7 , —N(R 7 ) 2 , —OH, —SH, —SO 2 R 7 , —SOR 7 , —SO 2 N(R 7 ) 2 , and —SR 7 ;
each occurrence of R 7 is independently selected from the group consisting of hydrogen, acyl, optionally substituted aliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R 7 groups are taken together with their intervening atoms to form an optionally substituted heterocyclic ring;
each occurrence of R 5 is independently selected from the group consisting of halo, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, optionally substituted C 6-10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-10 membered heterocyclyl, optionally substituted 3-10 membered carbocyclyl, nitro, cyano, acyl, —NH 2 , —NHR 7 , —N(R 7 ) 2 , —OH, —SH, —SO 2 R 7 , —SOR 7 , —SO 2 N(R 7 ) 2 , and —SR 7 ;
t is the anion charge number and is 1, 2, or 3;
v is 0, 1, 2, or 3; and
m is 1, 2, 3, 4, or 5;
provided that the compound is electrically neutral.
2. The compound of claim 1 , wherein R 1 and R 2 are independently C 6-10 aryl, optionally substituted with 0 to 5 occurrences of R 5 .
3. The compound of claim 1 , wherein the compound is of Formula (I-a):
4. The compound of claim 1 , wherein the compound is of Formula (I-b):
5. The compound of claim 3 , wherein A is hydrogen, m is 1, t is 1, and v is 1.
6. The compound of claim 1 , wherein both R 3 and R 4 are hydrogen.
7. The compound of claim 1 , wherein the compound is of Formula (I-c):
8. The compound of claim 1 , wherein Q −t is a halide, trifluoroacetate, trichloroacetate, NO 2 − , NO 3 − , H 2 PO 4 − , PF 6 − , HF 2− , HSO 4 − , SbF 6 − , ClO 4 − , SO 4 −2 , (R 6 )SO 3 − , OTf − , OTs − , ONf − , ONs − , BF 4 − , or B(R 6 ) 4 − .
9. The compound of claim 1 , wherein A is LiX, MgX 2 , ScX 3 , ScR 6 3 YR 6 3 , BR 6 3 , BX 3 , TiX 4 , TiR 6 4 , ZrX 4 , ZrR 6 4 , FeX 3 , FeR 6 3 , ZnX 2 , ZnR 6 2 , AlX 3 , AlR 6 3 , InX 3 , InR 6 3 , SiX 4 , SiR 6 4 , SnX 2 , SnR 6 2 , SnX 4 , SnR 6 4 , BiX 3 , or BiR 6 3 .
10. A compound of Formula (II) or (II′):
wherein:
S is an organic substrate;
Q ⊖ is Cl − , Br − , or NO 3 − ;
Q 2⊖ is SO 4 2− ;
R 1 and R 2 are independently selected from the group consisting of C 1-6 alkyl, C 6-10 aryl, C 6-10 aralkyl, 5-10 membered heteroaryl, 5-10 membered heteroaralkyl, 4-10 membered heterocyclyl, 4-10 membered heterocyclylalkyl, 3-10 membered carbocyclyl, and 3-10 membered carbocyclylalkyl, each of which is independently optionally substituted with 0 to 5 occurrences of R 5 ;
R 3 and R 4 are independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, nitro, cyano, halo, C 1-6 haloalkyl, C 1-6 alkoxy, optionally substituted C 6-10 aryl, optionally substituted C 6-10 aralkyl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-10 membered heterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclylalkyl, acyl, —NH 2 , —NHR 7 , —N(R 7 ) 2 , —OH, —SH, —SO 2 R 7 , —SOR 7 , —SO 2 N(R 7 ) 2 , and —SR 7 ;
each occurrence of R 7 is independently selected from the group consisting of hydrogen, acyl, optionally substituted aliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R 7 groups are taken together with their intervening atoms to form an optionally substituted heterocyclic ring; and
each occurrence of R 5 is independently selected from the group consisting of halo, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, optionally substituted C 6-10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-10 membered heterocyclyl, optionally substituted 3-10 membered carbocyclyl, nitro, cyano, acyl, —NH 2 , —NHR 7 , —N(R 7 ) 2 , —OH, —SH, —SO 2 R 7 , —SOR 7 , —SO 2 N(R 7 ) 2 , and —SR 7 .
11. A compound of Formula (V):
wherein:
S is an organic substrate;
R 1 and R 2 are independently selected from the group consisting of C 1-6 alkyl, C 6-10 aryl, C 6-10 aralkyl, 5-10 membered heteroaryl, 5-10 membered heteroaralkyl, 4-10 membered heterocyclyl, 4-10 membered heterocyclylalkyl, 3-10 membered carbocyclyl, and 3-10 membered carbocyclylalkyl, each of which is independently optionally substituted with 0 to 5 occurrences of R 5 ;
R 3 and R 4 are independently selected from the group consisting of hydrogen, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, nitro, cyano, halo, C 1-6 haloalkyl, C 1-6 alkoxy, optionally substituted C 6-10 aryl, optionally substituted C 6-10 aralkyl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-10 membered heterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclylalkyl, acyl, —NH 2 , —NHR 7 , —N(R 7 ) 2 , —OH, —SH, —SO 2 R 7 , —SOR 7 , —SO 2 N(R 7 ) 2 , and —SR 7 ;
each occurrence of R 7 is independently selected from the group consisting of hydrogen, acyl, optionally substituted aliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R 7 groups are taken together with their intervening atoms to form an optionally substituted heterocyclic ring; and
R 5 is independently selected from the group consisting of halo, optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 alkoxy, optionally substituted C 6-10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-10 membered heterocyclyl, optionally substituted 3-10 membered carbocyclyl, nitro, cyano, acyl, —NH 2 , —NHR 7 , —N(R 7 ) 2 , —OH, —SH, —SO 2 R 7 , —SOR 7 , —SO 2 N(R 7 ) 2 , and —SR 7 .
12. The compound of claim 10 , wherein the compound is of Formula (VI):
wherein:
each occurrence of R 8 is independently selected from the group consisting of optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, nitro, cyano, halo, C 1-6 haloalkyl, C 1-6 alkoxy, optionally substituted C 6-10 aryl, optionally substituted C 6-10 aralkyl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-10 membered heterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclylalkyl, acyl, —N(R 8a ) 2 , —OR 8 a, —CO 2 R 8a , —SO 2 R 8a , —SOR 8a , —SO 2 N(R 8a ) 2 , and —SR 8a ;
each occurrence of R 9 is independently selected from the group consisting of optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, nitro, cyano, halo, C 1-6 haloalkyl, C 1-6 alkoxy, optionally substituted C 6-10 aryl, optionally substituted C 6-10 aralkyl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-10 membered heterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclylalkyl, acyl, —N(R 9a ) 2 , —OR 9a , —CO 2 R 9a , —SO 2 R 9a , —SOR 9a , —SO 2 N(R 9a ) 2 , and —SR 9a ;
each occurrence of R 8a or R 9a is independently selected from the group consisting of hydrogen, acyl, optionally substituted aliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R 8a or R 9a groups are taken together with their intervening atoms to form an optionally substituted heterocyclic ring; and
p is 0, 1, 2, or 3.
13. A reaction mixture comprising a compound of Formula (I) of claim 1 and a fluorine source.
14. The compound of claim 10 , wherein S is optionally substituted aryl or optionally substituted heteroaryl.
15. The compound of claim 10 , wherein compound is of Formula (II):
wherein Q ⊖ is Cl − .
16. The compound of claim 10 , wherein R 1 and R 2 are independently C 6-10 aryl, optionally substituted with 0 to 5 occurrences of R 5 .
17. The compound of claim 10 , wherein R 3 and R 4 are hydrogen.
18. The compound of claim 10 , wherein the compound is of Formula (II-a):
19. The compound of claim 10 , wherein the compound is of Formula (II-b):
20. The compound of claim 10 , wherein the compound is of Formula (II-h):
21. The compound of claim 10 , wherein the compound is of Formula (II-e):
22. The compound of claim 10 , wherein:
the compound is of Formula (II-e):
and
S is optionally substituted aryl or optionally substituted heteroaryl.
23. The compound of claim 10 , wherein:
the compound is of Formula (II-e):
and
S is:
24. The compound of claim 11 , wherein S is optionally substituted aryl or optionally substituted heteroaryl.
25. The compound of claim 11 , wherein R 1 and R 2 are independently C 6-10 aryl, optionally substituted with 0 to 5 occurrences of R 5 .
26. The compound of claim 11 , wherein R 3 and R 4 are hydrogen.
27. A method of replacing a hydroxyl group on an organic compound with a fluorine atom, the method comprising contacting a compound of Formula (I) of claim 1 :
with an organic compound under conditions sufficient to replace the hydroxyl group of the organic compound with a fluorine atom, wherein D, A, Q −t , R 1 , R 2 , R 3 , R 4 , t, v, and m are as defined in claim 1 .
28. A method of replacing a hydroxyl group on an organic compound with a fluorine atom, the method comprising exchanging Q ⊖ of a compound of Formula (II) of claim 10 or exchanging Q 2⊖ of Formula (II′) of claim 10 :
with a fluoride or HF 2 anion, wherein S, Q ⊖ , Q 2⊖ , R 1 , R 2 , R 3 , and R 4 are as defined in claim 10 .
29. A method of producing a compound of Formula (II) or (II′) of claim 10 :
the method comprising contacting a compound of Formula (VI) or (VI′):
with a hydroxyl group-containing organic substrate and exchanging
wherein:
S, Q ⊖ , Q 2⊖ , R 1 , R 2 , R 3 , and R 4 are as defined in claim 10 ;
each occurrence of R 8 is independently selected from the group consisting of optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, nitro, cyano, halo, C 1-6 haloalkyl, C 1-6 alkoxy, optionally substituted C 6-10 aryl, optionally substituted C 6-10 aralkyl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-10 membered heterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclylalkyl, acyl, —N(R 8a ) 2 , —OR 8a , —CO 2 R 8a , —SO 2 R 8a , —SOR 8a , —SO 2 N(R 8a ) 2 , and —SR 8a ;
each occurrence of R 9 is independently selected from the group consisting of optionally substituted C 1-6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, nitro, cyano, halo, C 1-6 haloalkyl, C 1-6 alkoxy, optionally substituted C 6-10 aryl, optionally substituted C 6-10 aralkyl, optionally substituted 5-10 membered heteroaryl, optionally substituted 4-10 membered heterocyclyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclylalkyl, acyl, —N(R 9a ) 2 , —OR 9a , —CO 2 R 9a , —SO 2 R 9a , —SOR 9a , —SO 2 N(R 9a ) 2 , and —SR 9a ;
each occurrence of R 8a and R 9a is independently selected from the group consisting of hydrogen, acyl, optionally substituted aliphatic, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R 8a or R 9a groups are taken together with their intervening atoms to form an optionally substituted heterocyclic ring; and
p is 0, 1, 2, or 3.
30. A method of producing a compound of Formula (I) of claim 1 , the method comprising reacting a compound of Formula (I-e):
with a Brønsted acid, a Lewis acid, or an acid anhydride to produce the compound of Formula (I), wherein the Lewis acid is LiX, MgX 2 , ScX 3 , ScR 6 3 YX 3 , YR 6 3 , BR 6 3 , BX 3 , TiX 4 , TiR 6 4 , ZrX 4 , ZrR 6 4 , FeX 3 , FeR 6 3 , ZnX 2 , ZnR 6 2 , AlX 3 , AlR 6 3 , InX 3 , InR 6 3 , SiX 4 , SiR 6 4 , SnX 2 , SnR 6 2 , SnX 4 , SnR 6 4 , BiX 3 , or BiR 6 3 ; and X, R 6 , D, R 1 , R 2 , R 3 , and R 4 are as defined in claim 1 .