Synthesis of alpha fluoroalkyl amines
View Patent ↗This invention describes the reaction of an alpha fluoroalkyl ketone with a bis(trialkylsilyl)amide to give a stable N-trialkylsilyl imine. Treatment of the N-trialkylsilyl imine with an alcohol leads to solvolysis of the trialkylsilyl group and yields a stable mixture of an aminal and an imine in high yield. Catalytic reduction of this mixture, or of the individual components, in the presence of a chiral catalyst leads to a fluoroalkyl amine with high enantioselectivity and high yield.
1. A process for preparing a compound of formula IA or IB:
comprising the steps of:
a. Combining an alpha fluoroalkyl ketone of formula II in the presence of a bistrialkylsilylamide to form an N-trialkylsilyl imine of formula III,
b. Reducing the N-trialkylsilyl imine of formula III to produce a compound of formula IA or IB;
wherein R 1 is aryl or heteroaryl;
R 2 is C 1-5 haloalkyl; and
R 3 is C 1-6 alkyl.
2. The process of claim 1 wherein the bistrialkylsilylamide is lithium bistrimethylsilylamide, sodium bistrimethylsilylamide or potassium bistrimethylsilylamide.
3. The process of claim 2 wherein an N-trialkylsilyl imine of formula III is treated with an alcohol of formula R 4 OH to yield a mixture of an aminal of formula IV and an imine of formula V,
wherein R 4 is C 1-5 alkyl.
4. The process of claim 3 wherein the alcohol is methanol, ethanol, n-propanol, 2-propanol or a mixture thereof.
5. The process of claim 3 wherein the aminal of formula IV and the imine of formula V are reduced with a reducing agent in the presence of a chiral catalyst to yield the compound of formula IA or IB.
6. The process of claim 5 wherein the chiral catalyst is of general structure
wherein R 5 is hydrogen or aryl;
R 6 is hydrogen or aryl;
R 7 is hydrogen or C 1-5 alkyl;
R 8 is hydrogen or C 1-5 alkyl;
R 9 is hydrogen or C 1-5 alkyl;
or R 8 and R 9 can be taken together with the carbon and nitrogen atom to which they are attached and form a 5 or 6 membered nitrogen containing ring; and
R 10 is hydrogen or C 1-5 alkyl or aryl.
7. The process of claim 5 wherein the reducing agent is a boron hydride.
8. The process of claim 7 wherein the boron hydride is borane dimethylsulfide, borane tetrahydrofuran or catechol borane.