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 for of making a compound of Formula Ia:
wherein:
R 2 is H, alkyl, aryl, alkoxy or halo;
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 7 is H, alkyl or aryl; and
X is halo; comprising the steps of:
(a) metalating a compound of Formula II:
wherein R 6 is H, with a metal base complex to form an organometallic intermediate compound; and then
(b) reacting said organometallic intermediate compound with a halogenating agent to produce a compound of Formula Ia.
2. The method of claim 1 , wherein said base is an alkyllithium base.
3. The method of claim 1 , wherein said base is n-BuLi-LiDMAE.
4. The method of claim 1 , wherein said base is TMP-Zincate.
5. The method of claim 1 , wherein said halogenating agent is selected from the group consisting of I 2 , C 2 Cl 6 , N-bromosuccinimide, Br 2 , N-iodosuccinimide, CCl 4 , and 1,3-dichloro-5,5-dimethylhydantoin.
6. The method of claim 1 , wherein R 2 is H.
7. The method of claim 1 , wherein R 4 and R 5 are H.
8. The method of claim 1 , wherein R 7 is methyl.
9. The method of claim 1 , wherein said compound of Formula II is (S)-nicotine.