Attempting to react 2,2-difluorocyclopropylamine HCl with 4-fluorobenzaldehyde in order to synthesize a secondary amine. Have tried this reaction about 3 different times and each time the aldehyde doesn't react which is unusual as it should be fairly reactive. I even tried free basing the amine starting material but to no avail. Would appreciate any insight in troubleshooting this reaction. Thank you.
Hi Sina, which reaction protocol are you using? You can try different reducing agents (NaBH3CN, NaBH4, etc.). Also you can consider to use additives (AcOH). Helpful information could be found in these papers:
Article ChemInform Abstract: Protecting-Group-Free Synthesis of Amin...
Article Reductive Amination of Aldehydes and Ketones with Sodium Tri...
Hi Maksim, thanks for your response. I normally allow the aldehyde and amine to react to form the imine for 10 min at 60C before adding NaBH3CN. For this current reaction I haven't added any base yet as the aldehyde hasn't reacted.
Hi,
The aldehyde reactivity is lowered by the fluorine substituent.
As Maksim mentioned you can add an acid in order to activate the carbonyl group, see the attached procedure they used H2SO4 with a reaction time of 1-2 h.
Good luck!
The fluorine (from your second reagent) has also an effect on the basicity of the amino group (see attached a comparison for CF3(CH3)2NH2 and CF3CH2NH2).
Hi
sina, take amine in methanol and cool it by ice. then add aldehyde by dissolving in minimum amount of methanol dropwise. after 30 minutes keep reaction mixture at room temperature for 2-3 hours.
i believe it will work.
I would liberate 2,2-difluorocyclopropylamine HCl with Et3N in absolute Ethanol. Maybe catalytic addition of AcOH or TFA. Wait until the formation of the imine is finished an then add NaBH4 or NaCNBH3.
If this doesnot work maybe you try the following procedures:
Reductive amination of aldehydes and ketones with the InCl3/Et3SiH/MeOH system is highly chemoselective and can be applied to various cyclic, acyclic, aromatic, and aliphatic amines. Functionalities including ester, hydroxyl, carboxylic acid, and olefin are tolerated. O.-Y. Lee, K.-L. Law, C.-Y. Ho, D. Yang, J. Org. Chem., 2008, 73, 8829-8837.
J. Chem. Soc., Perkin Trans. 1, (16), 2527-2532 : Facile preparation of N-methyl secondary amines by titanium(IV) isopropoxide-mediated reductive amination of carbonyl compounds
You can try and activate such synthesis by using titanium isopropoxide. This method was made for secondary amines, at metaloorganics are generally more reactive, so it should overcome deactivation of amine by fluorine.
Article Titanium(IV) Isopropoxide and Sodium Borohydride: A Reagent ...
http://www.eurekaselect.com/76767/article
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