[Seanlet]

I have been tasked with converting the top compound bearing an N-cyclobutylmethyl with an N-methyl. My initial thought was to follow the general route outlined by Grewe (amongst others):

1-protect the phenol group with benzoyl chloride
2-oxidise the amine with mCPBA in methanol (or H2O2 or other suitable oxidizing agent)
3-reduce with FeCl2.4H2O in H2O to produce secondary amine.
4-deprotect phenol.

I know chloroformate esters are a more modern general approach & have seen examples of Pd or Ru catalysed methods but I've actually seen an outline of an N-cyclobutylmethyl being removed using the above route in 60% yield. Not bad - but the amount of precursor available is very limited so the learning curve is going to have to be steep

One left-field idea that occured to me was that quaternization with a methyl halide followed by dequaternization. As a general rule, small tert alkyl first, then methyl then ethyl or isopropyl. leaving a dealkylated amine, it is usually driven by the stability of the resulting cation and frequently by the volatility of the resulting alkyl halide. I've noted sodium thipohenoxide & ethanolamine being used for this.

Another interesting one was the N-deallylation of a tertiary amine in which Wilkinson's catalyst (10& mol weight) isomerized the N-allyl to an enamine facilitating quantitative results.

Any and all suggestions & references would be gratefully received. I've been out of the synthetic chemistry arena for close on a decade so please forgive my clunky thought-processes.

[Seanlet]

Hi,
    I know that N-demethylation is much more common so was pleased to find a 2-step (1 pot) route in which the amine is oxidised to the amine oxide & the amine oxide is reductively dealkylated to the secondary amine and cyclobutanecarbaldehyde. The phenol should be protected (benzoyl chloride) for better yields but 82% overall isn't too shabby!

No loss of chiral purity that I could detect, either.

770 Communications            synthesis

'Secondary amines from Iron(II) Ion-catalysed Reaction of Amine Oxides: A general Method for the Dealkylation of Tertiary Amines'
Ivo Monković, Henry Wong & Carol Bachand
Bristol-Myers Company, Pharmaceutical Research and Development Division, Candiac P.Q. Canada J5R 1J1
and Bristol-Myers Company, Pharmaceutical Research and Development Division, P.O. Box 4755, Syracuse, New York 13221-4755, USA

[Dan]

Thanks for the follow up. For the benefit of others, the reference is:

Ivo Monković, Henry Wong & Carol Bachand Synthesis 1985, 8, 770-773 Link

[Seanlet]

Of course, the reference simply removes the N-alkyl forming the secondary amine (traditionally 'the hard part). To N-methylate, there are a few routes - maybe someone could help provide a bigger list?

1) The Eschweiler–Clarke reaction. this name-reaction most often used my first thought.

2) Hunig's Base + alkyl halide¹ - allows CH3I so I pondered in another thread that this could N & O methylate at the same time.

3) Methylating agents (Dimethyl Sulfate, Trimethyl Phosphate/Trimethyl Carbonate?). Rarely mentioned (dimethyl is an 'also possible' in the Hunig'sbase-type schemes so maybe the others?



[1]An Efficient & operationally general synthesis of tertiary amines by direct alkylation of secondary amines with alkul halides in the presence of Huenig's base
Jason L. Moore, Stephen M. Taylor and Vadim A SoloShonok
ARKIVOK 2005 (vi) 287-292

[Dan]

1) The Eschweiler–Clarke reaction. this name-reaction most often used my first thought.

On this theme, there are many ways to do the reductive amination of formaldehyde.