One-pot Reductive Nitromethylation of Aldehydes

[Rhodium]

One-pot Reductive Nitromethylation of Aldehydes

R-CHO -> R-CH₂CH₂NO₂ (One Pot, 70-90% yield)

Fluoride ion catalyzed condensation of aldehydes with nitromethane to form the beta-nitroalcohol, followed by acetylation and reduction of the beta-nitroacetate with sodium borohydride to form the nitroalkane in 70-90% overall yield.

Tet. Lett. 3219-3222 (1978)

(https://www.thevespiary.org/rhodium/Rhodium/pdf/aldehyde.reductive.nitromethylation.pdf)

(The reference originally found here:

Post 371253

(Barium: "Hey Ritter old chap!", Novel Discourse))

[Kinetic]

This will make a welcome addition to

Post 367468

(Regis: "The most interesting CTH reaction ever documented?", Novel Discourse); in fact, I've just noticed Barium refers to it in that same thread:

Post 371253

(Barium: "Hey Ritter old chap!", Novel Discourse). This route seems very promising indeed. I wonder if it'll work on acetophenones?  

It may also be worth trying CsF as the catalyst - from the Synthesis article cited by GC_MS in the above thread, both CsF and RbF are more active than KF as catalysts - RbF slightly more so, but it's cost probably outweighs the increase in yield.

[Aurelius]

Hey Rhodium, don't you already have a pretty impressive list of references regarding this reaction?  If so, please include this one in that list.

[Rhodium]

Yup. I will - and I must say that I totally missed the connection betwen this article and the excerpt in Barium's post as I found this independent of that. I must have been tired when reading Barium's post.

[hest]

Made an eksp. with 3,4,5-trimethoxy-benzaldehyde, 2 mole nitromethane, in 2-propanol and some KF. Yeald under 50%, the rest was starting material.

[Rhodium]

Nice that you tried it out! As you got the remaining 50% back as unreacted starting material, then at least it is selective for the nitroalcohol and does not give the alkene under these conditions. By avoiding the nitrostyrene, the borohydride reduction will not cause the formation of any dimers through michael addition.

3,4,5-TMB is a notoriously bad substrate in the Henry reaction with many catalysts, EDDA gives 15-30% yield if I remember correctly. If you try another substrate I'm sure it will go much better.

[hest]

I'm sure you right Rhodium, but as you know3,4,5-TMBA is one of the reaction's I would love to gain betteher yeald from. I'll give 2,5-dimethoxybensaldehyde a shot tomorrow.

[hest]

And the resul't was the same as last time. Approx. 50% of the 2,5-DMBA reacted with the nitromethane after 12 houers.