Iodonium Cyclophanes for SECURE arene functionalization
This disclosure relates to compounds, reagents, and methods useful in the synthesis of aryl fluorides, for example, in the preparation of 18 F labeled radiotracers. For example, this disclosure provides universal “locked” aryl substituents that result in StereoElectronic Control of Unidirectional Reductive Elimination (SECURE) from diaryliodonium salts. The reagents and methods provided herein may be used to access a broad range of compounds, including aromatic compounds, heteroaromatic compounds, amino acids, nucleotides, and synthetic compounds.
1. A compound of Formula (1):
wherein:
Ar is a substituted or unsubstituted aryl or heteroaryl ring system;
X is either a moiety wherein the pKa of the acid H—X is less than 12 or a leaving group;
R 1 is hydrogen or a substituent having a Hammett σ p value of less than zero; and
R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are independently selected from the group consisting of: H, CF 3 , OCF 3 , CN, hydroxyl, amino, aminoalkyl, (CH 2 ) n N(CH 2 ) m , —SR 8 , —SOR 8 , halo, SO 2 R 8 , (CH 2 ) n OR 8 , C(═O)NR 8 R 9 , SO 2 NR 8 R 9 , NR 8 SO 2 R 9 , COOR 8 , NR 8 C(═O)R 9 , NR 8 C(═O)NR 9 , SO 2 R 8 , (CH 2 ) n C(═O)NR 8 R 9 , (CH 2 ) n SO 2 NR 8 R 9 , (CH 2 ) n NR 8 SO 2 R 9 , (CH 2 ) n COOR 8 , (CH 2 ) n NR 8 C(═O)R 9 , (CH 2 ) n NR 8 C(═O)NR 9 , alkoxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
each m and n is independently an integer from 0 to 10; and
each R 8 and R 9 are independently chosen from H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
2. The compound of claim 1 , wherein X comprises a radioactive isotope.
3. The compound of claim 1 , wherein X is selected from the group consisting of halide, aryl carboxylate, alkyl carboxylate, phosphate, phosphonate, phosphonite, azide, thiocyanate, cyanate, phenoxide, triflate, trifluoroethoxide, thiolates, and stabilized enolates.
4. The compound of claim 1 , wherein X is selected from the group consisting of: fluoride, chloride, bromide, iodide, triflate, trifluoroacetate, benzoate, acetate, phenoxide, trifluoroethoxide, cyanate, azide, thiocyanate, thiolates, phosphates, and stabilized enolates.
5. The compound of claim 4 , wherein X is fluoride.
6. The compound of claim 5 , wherein X is 18 F.
7. The compound of claim 1 , wherein X is selected from the group consisting of: triflate, mesylate, nonaflate, hexaflate, tosylate, nosylate, brosylate, perfluoroalkyl sulfonate, tetraphenylborate, hexafluorophosphate, trifluoroacetate, tetrafluoroborate, perchlorate, perfluoroalkylcarboxylate, chloride, bromide, and iodide.
8. The compound of claim 1 , wherein R 1 is selected from the group consisting of: —(C 1 -C 10 )alkyl, —(C 1 -C 10 )haloalkyl, (C 2 -C 10 )alkenyl, (C 2 -C 10 )alkynyl, —O—(C 1 -C 10 )alkyl, —C(O)—O—(C 1 -C 10 )alkyl, aryl, and heteroaryl.
9. The compound of claim 8 , wherein R 1 is —O-(C 1 -C 10 )alkyl.
10. The compound of claim 9 , wherein R 1 is OCH 3 .
11. The compound of claim 1 , wherein Ar is an electron rich aryl or heteroaryl ring system.
12. The compound of claim 11 , wherein Ar—H is more easily oxidized than benzene.
13. The compound of claim 1 , wherein Ar is chosen from a phenylalanine derivative, tyrosine derivative, tryptophan derivative, histidine derivative, and estradiol derivative.
14. The compound of claim 1 , wherein the compound of Formula (1) is a compound of Formula (1A):
15. The compound of claim 1 , wherein Ar is selected from the group consisting of:
wherein:
each of P 1 , P 2 and P 6 are independently a nitrogen protecting group, or P 1 and P 2 come together to form a single nitrogen protecting group;
each of P 3 , P 4 , and P 7 are independently an alcohol protecting group, or P 3 and P 4 come together to form a single oxygen protecting group; and
P 5 is a carboxylic acid protecting group.
16. The compound of claim 1 , wherein the compound of Formula (1) is selected from the group consisting of:
wherein:
each of P 1 and P 2 are independently a nitrogen protecting group, or P 1 and P 2 come together to form a single nitrogen protecting group;
each of P 3 , and P 4 are independently an alcohol protecting group, or P 3 and P 4 come together to form a single oxygen protecting group; and
P 5 is a carboxylic acid protecting group.
17. The compound of claim 1 , wherein the compound of Formula (1) is selected from the group consisting of:
18. The compound of claim 1 , wherein the compound of Formula (1) is selected from the group consisting of:
wherein:
each of P 3 and P 4 are independently an alcohol protecting group.
19. The compound of claim 1 , wherein the Ar moiety is enantiomerically enriched.
20. The compound of claim 19 , wherein the Ar moiety is present in an enantiomeric excess of at least 75%.
21. The compound of claim 19 , wherein the Ar moiety is present in an enantiomeric excess of at least 95%.
22. The compound of claim 19 , wherein the Ar moiety is present in an enantiomeric excess of at least 98%.
23. A method of making a compound of Formula (2):
Ar—X
wherein:
Ar is a substituted or unsubstituted aryl or heteroaryl ring system; and
X is a moiety wherein the pKa of the acid H—X is less than 12;
the method comprising heating a solution comprising a compound MX, wherein M is a counter ion, and a compound of Formula (3):
wherein:
Ar is a substituted or unsubstituted aryl or heteroaryl ring system;
Y is a leaving group;
R 1 is hydrogen or a substituent having a Hammett σ p value of less than zero; and
R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are independently selected from the group consisting of: H, CF 3 , OCF 3 , CN, hydroxyl, amino, aminoalkyl, (CH 2 ) n N(CH 2 ) m , —SR 8 , —SOR 8 , halo, SO 2 R 8 , (CH 2 ) n OR 8 , C(═O)NR 8 R 9 , SO 2 NR 8 R 9 , NR 8 SO 2 R 9 , COOR 8 , NR 8 C(═O)R 9 , NR 8 C(═O)NR 9 , SO 2 R 8 , (CH 2 ) n C(═O)NR 8 R 9 , (CH 2 ) n SO 2 NR 8 R 9 , (CH 2 ) n NR 8 SO 2 R 9 , (CH 2 ) n COOR 8 , (CH 2 ) n NR 8 C(═O)R 9 , (CH 2 ) n NR 8 C(═O)NR 9 , alkoxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
each m and n is independently an integer from 0 to 10; and
each R 8 and R 9 are independently chosen from H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
24. The method of claim 23 , wherein M is selected from the group consisting of: potassium; sodium; cesium; complexes of lithium, sodium, potassium, or cesium with cryptands or crown ethers; tetrasubstituted ammonium cations; and phosphonium cations.
25. The method of claim 23 , wherein the solution further comprises a non-polar solvent.
26. The method of claim 25 , wherein the nonpolar solvent is selected from the group consisting of: benzene, toluene, o-xylene, m-xylene, p-xylene, ethyl benzene, carbon tetrachloride, hexane, cyclohexane, fluorobenzene, chlorobenzene, nitrobenzene, and mixtures thereof.
27. The method of claim 25 , wherein the method further comprises filtering the solution to remove insoluble material prior to heating.
28. The method of claim 27 , wherein the solvent is removed from the filtrate prior to heating.
29. The method of claim 23 , wherein the solution further comprises a polar solvent.
30. The method of claim 29 , wherein the polar solvent is chosen from: acetonitrile, acetone, dichloromethane, ethyl acetate, tetrahydrofuran, dimethylformamide, 1,2-difluorobenzene, benzotrifluoride and mixtures thereof.
31. The method of claim 29 , wherein the method further comprises filtering the solution to remove insoluble material prior to heating.
32. The method of claim 31 , wherein the solvent is removed from the filtrate prior to heating.
33. The method of claim 29 , wherein the method further comprises removing salt by chromatography.
34. The method of claim 33 , wherein the chromatography is gel permeation chromatography.
35. The method of claim 23 , wherein the heating comprises heating at a temperature ranging from about 25° C. to about 250° C.
36. The method of claim 23 , wherein the heating occurs for from about 1 second to about 25 minutes.
37. The method of claim 36 , wherein the heating is accomplished by a flash pyrolysis method, a conventional heating method, or by a microwave method.
38. The method of claim 23 , wherein the compound of Formula (2) is chosen from:
39. The method of claim 23 , wherein the compound of Formula (2) is chosen from:
wherein:
each of P 3 and P 4 are independently an alcohol protecting group.
40. The method of claim 23 , wherein the compound of Formula (2) is:
wherein:
each of P 1 and P 2 are independently a nitrogen protecting group, or P 1 and P 2 come together to form a single nitrogen protecting group;
each of P 3 , and P 4 are independently an alcohol protecting group, or P 3 and P 4 come together to form a single oxygen protecting group; and
P 5 is a carboxylic acid protecting group.
41. The method of claim 40 , wherein the compound of Formula (2) is:
42. The method of claim 23 , wherein the compound of Formula (2) is:
43. A compound of Formula (4):
wherein:
Ar is a substituted or unsubstituted aryl or heteroaryl ring system;
R 1 is hydrogen or a substituent having a Hammett σ p value of less than zero; and
R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are independently selected from the group consisting of: H, CF 3 , OCF 3 , CN, hydroxyl, amino, aminoalkyl, (CH 2 ) n N(CH 2 ) m, —SR 8 , —SOR 8 , halo, SO 2 R 8 , (CH 2 ) n OR 8 , C(═O)NR 8 R 9 , SO 2 NR 8 R 9 , NR 8 SO 2 R 9 , COOR 8 , NR 8 C(═O)R 9 , NR 8 C(═O)NR 9 , SO 2 R 8 , (CH 2 ) n C(═O)NR 8 R 9 , (CH 2 ) n SO 2 NR 8 R 9 , (CH 2 ) n NR 8 SO 2 R 9 , (CH 2 ) n COOR 8 , (CH 2 ) n NR 8 C(═O)R 9 , (CH 2 ) n NR 8 C(═O)NR 9 , alkoxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
each m and n is independently an integer from 0 to 10; and
each R 8 and R 9 are independently chosen from H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
44. A method of making a compound of Formula (5):
Ar—F
wherein:
Ar is a substituted or unsubstituted aryl or heteroaryl ring system;
the method comprising heating a solution comprising a compound MF, wherein M is a counter ion, and a compound of Formula (3):
wherein:
Ar is a substituted or unsubstituted aryl or heteroaryl ring system;
Y is a leaving group;
R 1 is hydrogen or a substituent having a Hammett σ p value of less than zero; and
R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 are independently selected from the group consisting of: H, CF 3 , OCF 3 , CN, hydroxyl, amino, aminoalkyl, (CH 2 ) n N(CH 2 ) m , —SR 8 , —SOR 8 , halo, SO 2 R 8 , (CH 2 ) n OR 8 , C(═O)NR 8 R 9 , SO 2 NR 8 R 9 , NR 8 SO 2 R 9 , COOR 8 , NR 8 C(═O)R 9 , NR 8 C(═O)NR 9 , SO 2 R 8 , (CH 2 ) n C(═O)NR 8 R 9 , (CH 2 ) n SO 2 NR 8 R 9 , (CH 2 ) n NR 8 SO 2 R 9 , (CH 2 ) n COOR 8 , (CH 2 ) n NR 8 C(═O)R 9 , (CH 2 ) n NR 8 C(═O)NR 9 , alkoxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;
each m and n is independently an integer from 0 to 10; and
each R 8 and R 9 are independently chosen from H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
45. The compound of claim 43 , wherein F is 18 F.
46. The compound of claim 43 , wherein R 1 is selected from the group consisting of: —(C 1 -C 10 )alkyl, —(C 1 -C 10 )halo alkyl, (C 2 -C 10 )alkenyl, (C 2 -C 10 )alkynyl, —O—(C 1 -C 10 )alkyl, —C(O)—O—(C 1 -C 10 )alkyl, aryl, and heteroaryl.
47. The compound of claim 46 , wherein R 1 is —O—(C 1 -C 10 )alkyl.
48. The compound of claim 47 , wherein R 1 is OCH 3 .
49. The compound of claim 43 , wherein Ar is an electron rich aryl or heteroaryl ring system.
50. The compound of claim 49 , wherein Ar—H is more easily oxidized than benzene.
51. The compound of claim 43 , wherein Ar is chosen from a phenylalanine derivative, tyrosine derivative, tryptophan derivative, histidine derivative, and estradiol derivative.
52. The compound of claim 43 , wherein the compound of Formula (4) is a compound of Formula (4A):
53. The compound of claim 43 , wherein the compound of Formula (4) is a compound of Formula (4B):
54. The compound of claim 43 , wherein Ar is selected from the group consisting of:
wherein:
each of P 1 , P 2 and P 6 are independently a nitrogen protecting group, or P 1 and P 2 come together to form a single nitrogen protecting group;
each of P 3 , P 4 , and P 7 are independently an alcohol protecting group, or P 3 and P 4 come together to form a single oxygen protecting group; and
P 5 is a carboxylic acid protecting group.
55. The compound of claim 43 , wherein the compound of Formula (4) is selected from the group consisting of:
wherein:
each of P 1 and P 2 are independently a nitrogen protecting group, or P 1 and P 2 come together to form a single nitrogen protecting group;
each of P 3 , and P 4 are independently an alcohol protecting group, or P 3 and P 4 come together to form a single oxygen protecting group; and
P 5 is a carboxylic acid protecting group.
56. The compound of claim 43 , wherein the compound of Formula (4) is selected from the group consisting of:
57. The compound of claim 43 , wherein the compound of Formula (4) is selected from the group consisting of:
wherein:
each of P 3 and P 4 are independently an alcohol protecting group.
58. The compound of claim 43 , wherein the Ar moiety is enantiomerically enriched.
59. The compound of claim 58 , wherein the Ar moiety is present in an enantiomeric excess of at least 75%.
60. The compound of claim 58 , wherein the Ar moiety is present in an enantiomeric excess of at least 95%.
61. The compound of claim 58 , wherein the Ar moiety is present in an enantiomeric excess of at least 98%.
62. The method of claim 44 , wherein M is selected from the group consisting of: potassium; sodium; cesium; complexes of lithium, sodium, potassium, or cesium with cryptands or crown ethers; tetrasubstituted ammonium cations; and phosphonium cations.
63. The method of claim 44 , wherein the solution further comprises a non-polar solvent.
64. The method of claim 44 , wherein the nonpolar solvent is selected from the group consisting of: benzene, toluene, o-xylene, m-xylene, p-xylene, ethyl benzene, carbon tetrachloride, hexane, cyclohexane, fluorobenzene, chlorobenzene, nitrobenzene, and mixtures thereof.
65. The method of claim 44 , wherein the method further comprises filtering the solution to remove insoluble material prior to heating.
66. The method of claim 44 , wherein the solvent is removed from the filtrate prior to heating.
67. The method of claim 44 , wherein the solution further comprises a polar solvent.
68. The method of claim 67 , wherein the polar solvent is chosen from: acetonitrile, acetone, dichloromethane, ethyl acetate, tetrahydrofuran, dimethylformamide, 1,2-difluorobenzene, benzotrifluoride and mixtures thereof.
69. The method of claim 67 , wherein the method further comprises filtering the solution to remove insoluble material prior to heating.
70. The method of claim 69 , wherein the solvent is removed from the filtrate prior to heating.
71. The method of claim 67 , wherein the method further comprises removing salt by chromatography.
72. The method of claim 71 , wherein the chromatography is gel permeation chromatography.
73. The method of claim 44 , wherein the heating comprises heating at a temperature ranging from about 25° C. to about 250° C.
74. The method of claim 44 , wherein the heating occurs for from about 1 second to about 25 minutes.
75. The method of claim 73 , wherein the heating is accomplished by a flash pyrolysis method, a conventional heating method, or by a microwave method.
76. The method of claim 44 , wherein the compound of Formula (5) is chosen from:
77. The method of claim 44 , wherein the compound of Formula (5) is chosen from:
wherein:
each of P 3 and P 4 are independently an alcohol protecting group.
78. The method of claim 44 , wherein the compound of Formula (5) is:
wherein:
each of P 1 and P 2 are independently a nitrogen protecting group, or P 1 and P 2 come together to form a single nitrogen protecting group;
each of P 3 , and P 4 are independently an alcohol protecting group, or P 3 and P 4 come together to form a single oxygen protecting group; and
P 5 is a carboxylic acid protecting group.
79. The method of claim 78 , wherein the compound of Formula (5) is:
80. The method of claim 44 , wherein the compound of Formula (5) is:
81. The method of claim 44 , wherein F is 18 F.
82. The method of claim 44 , wherein the compound of Formula (3) is a compound of Formula (3A):
83. The method of claim 44 , wherein the compound of Formula (3) is a compound of Formula (3B):