Regioselective halogenation of nicotine and substituted nicotines
A first aspect of the present invention is a method for of making a compound of Formula Ia or Formula Ib: wherein X is halo, by (a) metalating a precursor compound to form an organometallic intermediate, and then reacting the organometallic intermediate with a halogenating agent to produce the compound of Formula Ia or Formula Ib.
1. A method of making a compound of Formula Ib:
wherein
R 4 and R 5 are H, alkyl or aryl, or R 4 is —SiR 20 , R 21 R 22 , wherein R 20 , R 21 and R 22 are each independently alkyl or aryl;
R 6 is H, alkyl, aryl or halo;
R 7 is H, alkyl or aryl; and
X is halo; comprising the steps of:
(a) metalating a compound of Formula II:
wherein R 2 is H, with lithium tetramethylpiperidide in the presence of a compound of the formula X′SnR 30 R 31 R 32 , wherein X′ is halo and R 30 , R 31 and R 32 are each alkyl or aryl, to form an organometallic intermediate compound of Formula III:
and then
(b) reacting said organometallic intermediate compound of Formula III with a halogenating agent to produce a compound of Formula Ib.
2. The method of claim 1 , wherein said halogenating agent is selected from the group consisting of I 2 , N-bromosuccinimide, Br 2 , N-iodosuccinimide, and 1,3-dichloro-5,5-dimethylhydantoin.
3. The method of claim 1 , wherein R 6 is H.
4. The method of claim 1 , wherein R 4 and R 5 are H.
5. The method of claim 1 , wherein R 7 is methyl.
6. The method of claim 1 , wherein said compound of Formula II is (S)-nicotine.
7. The method of claim 1 , wherein X is chloro.
8. The method of claim 1 , wherein R 30 , R 31 and R 32 are each cyclohexyl.
9. The method of claim 1 , wherein said compound of the formula X′SnR 30 R 31 R 32 is tricyclohexyltin chloride.
10. A method of making a compound of Formula Ib:
wherein
R 4 and R 5 are each H, alkyl or aryl, wherein R 20 , R 21 and R 22 are each independently alkyl or aryl;
R 6 is H, alkyl or aryl;
R 7 is H, alkyl or aryl; and
X is halo; comprising the steps of:
(a) metalating a compound of Formula II:
wherein R 2 is H, with lithium tetramethylpiperidide in the presence of a compound formula X′SnR 30 R 31 R 32 , wherein X′ is halo and R 30 , R 31 and R 32 are each alkyl or aryl, to form an organometallic intermediate compound of Formula III:
and then
(b) reacting said organometallic intermediate compound of Formula III with a halogenating agent to produce said compound of Formula Ib.
11. The method of claim 10 , wherein said halogenating agent is selected from the group consisting of I 2 , N-bromosuccinimide, Br 2 , N-iodosuccinimide, and 1,3-dichloro-5,5-dimethylhydantoin.
12. The method of claim 10 , wherein R 6 is H.
13. The method of claim 10 , wherein R 4 and R 5 are H.
14. The method of claim 10 , wherein R 7 is methyl.
15. The method of claim 10 , wherein said compound of Formula II is (S)-nicotine.