Nickel fluorinating complexes and uses thereof

Patent metadata

Field	Value
Publication number	US-9273083-B2
Application number	US-201314431371-A
Country	US
Kind code	B2
Filing date	Sep 26, 2013
Priority date	Sep 26, 2012
Publication date	Mar 1, 2016
Grant date	Mar 1, 2016

Abstract

The present invention provides novel nickel complexes. These complexes are in providing fluorinating organic compounds. The invention is particularly useful for fluorinating compounds with 18 F for PET imaging.

First claim

The invention claimed is:

1. A method of producing a fluorinated organic compound, the method comprising mixing a nickel comprising complex of formula (I):

wherein:
Ar 1 is aryl or heteroaryl substituted with n occurrences of R 1 ;
Ar 2 is aryl or heteroaryl substituted with m occurrences of R 2 ;
A 1 is C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, C 2-6 alkenyl, C(O)—R 6 , C(O)OR 6 , —NH 2 , —NHR 7 , —N(R 7 ) 2 , NO 2 , —OH, —OR 6 , aryl, heteroaryl or heterocyclyl, wherein each alkyl, alkoxy, cycloalkyl, alkenyl, aryl, heteroaryl or heterocyclyl can be further substituted with o occurrences of R 3 ;
A 2 is an N-heterocyclic carbene, phosphine, phosphate or heteroaryl substituted with p occurrences of R 4 ;
S is a substrate wherein the substrate is linked through an aryl, heteroaryl or alkenyl moiety present in the substrate;
each R 1 , R 2 , R 3 and R 4 is independently halo, C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, C 2-6 alkenyl, C(O)—R 6 , C(O)OR 6 , —NH 2 , —NHR 7 , —N(R 7 ) 2 , NO 2 , —OH, —OR 6 , aryl, heteroaryl or heterocyclyl, wherein each alkyl, alkoxy, cycloalkyl, alkenyl, aryl, heteroaryl or heterocyclyl can be further substituted with 0-3 occurrences of R 8 ;
R 6 is C 1-6 alkyl, C 1-6 alkenyl, C 3-7 cycloalkyl, —C(O)O—C 1-6 alkyl, aryl, heteroaryl or heterocyclyl;
each R 7 is independently C 1-6 alkyl, C 1-6 alkenyl, C 3-7 cycloalkyl, —C(O)—C 1-6 alkyl, —C(O)O—C 1-6 alkyl, aryl, heteroaryl or heterocyclyl;
each R 8 is independently halo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkenyl, C 3-7 cycloalkyl, C 1-6 alkyl-amine, —C(O)—C 1-6 alkyl, —C(O)O—C 1-6 alkyl, C 0-6 alkyl—NHR 7 , aryl, aryloxy, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl or heterocyclylalkyl or wherein two adjacent R 8 moieties, taken together with the atoms to which they are attached, form a C 3-7 cycloalkyl, aryl, heteroaryl or heterocyclyl group, wherein each alkyl, alkoxy, alkenyl, cycloalkyl, aryl; and
m, n, o and p are each independently an integer from 0-5;

with a source of fluorine and an organic compound under conditions sufficient to fluorinate the organic compound, thereby providing a fluorinated organic compound.

2. The method of claim 1 , wherein the source of fluorine is a fluoride source comprising water or a fluorinating agent.

3. The method of claim 1 , wherein source of fluorine comprises 18 F or 19 F.

4. The method of claim 1 , wherein the nickel complex of formula (I) is a complex of formula (II):

5. The method of claim 4 , wherein A 1 is aryl substituted with o occurrences of R 3 .

6. The method of claim 1 , wherein the nickel complex of formula (I) is a complex of formula (III):

7. The method of claim 6 , wherein A 2 is heteroaryl substituted with p occurrences of R 4 .

8. The method of claim 1 , wherein the nickel complex of formula (I) is a complex of formula (IV):

9. The method of claim 1 , wherein the nickel complex of formula (I) is a complex of formula (V):

10. The method of claim 1 , wherein S is an optionally substituted aryl comprising substrate an optionally substituted heteoaryl or an optionally substituted C 2-6 alkenyl.

11. The method of claim 10 , wherein S is selected from one of the following:

12. The method of claim 1 , wherein the complex of formula (I) is selected from the following:

13. The method of claim 1 , further comprising an oxidant, wherein the oxidant is a compound of formula (IX):

wherein
X is a halogen
A 3 is an aryl or heteroaryl group;
Cy taken together with the nitrogen atom to which it is attached forms a heterocyclyl or heteroaryl ring;
each occurrence of R F is independently halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; —OR″; —C(═O)R″; —CO 2 R″; —CN; —SCN; —SR″; —SOR″; —SO 2 R″; —NO 2 ; —N(R″) 2 ; —NHC(O)R″; or —C(R″) 3 ; wherein each occurrence of R″ is independently a hydrogen, a protecting group, an aliphatic moiety, a heteroaliphatic moiety, an aryl moiety; a heteroaryl moiety; alkoxy; aryloxy; alkylthio; arylthio; amino, alkylamino, dialkylamino, heteroaryloxy; or heteroarylthio moiety; and
Z is an anion.

14. The method of claim 13 , wherein the oxidant is selected from the following:

15. The method of claim 1 , wherein the fluorinated organic compound is selected from the following:

16. The method of claim 1 , wherein the method further comprises adding a salt to the source of fluorine.

17. The method of claim 1 , wherein the method further comprises adding a salt to the nickel comprising complex.

18. The method of claim 1 , wherein the method further comprises including a salt in the mixture containing the nickel comprising complex and source of fluorine.

19. A method of making a nickel complex of formula (I), the method comprising treating an organic compound of formula (VI):
S—X   (VI),

with tetramethylethylenediamine and bis( 1 , 5 -cyclooctadiene)nickel to provide a nickel complex of formula (VII):

the method further comprising, treating a nickel complex of formula (VII) with a silver compound of formula (VIII) and A 2 :

to provide a nickel complex of formula (I), wherein
X is a leaving group; and
Ar 1 , Ar 2 , A 1 , A 2 , A 3 , R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8 , m, n, o and p are as defined for formula (I).

20. A nickel complex of formula (I):

wherein:
Ar 1 is aryl or heteroaryl substituted with n occurrences of R 1 ;
Ar 2 is aryl or heteroaryl substituted with m occurrences of R 2 ;
A 1 is C 1-6 alkyl, C 1-6 alkoxy, C 3-7 cycloalkyl, C 2-6 alkenyl, C(O)—R 6 , C(O)O—R 6 ,

Assignees

• Harvard College

Inventors

• Ritter Tobias
• Lee Eunsung

Classifications

• C07C67/287

  by introduction of halogen; by substitution of halogen atoms by other halogen atoms · CPC title

• C07C271/22

  to carbon atoms of hydrocarbon radicals substituted by carboxyl groups · CPC title

• C07C69/78

  Benzoic acid esters · CPC title

• C07C67/293

  by isomerisation; by change of size of the carbon skeleton · CPC title

• C07C2101/14

  Chemistry & Metallurgy · mapped topic