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Reduction of Aliphatic Nitro Groups
We have been working for a little while on the aza-Henry route to PZQ. We’re going to submit a paper to an open access journal on some of this work, but I thought we should post on something we’re looking at now, since we’ve come up against an unexpectedly difficult step and need some help.
We’ve been trying to reduce an aliphatic nitro group (picture is below). The compound is a model case for PZQ that we’ve been looking at. This reduction looks to be a very simple reaction, and we did not expect problems.
Aliphatic nitro reduction
Shibasaki has reported on the reduction of aza-Henry beta-nitroamines like this.1 The literature contains few reliable procedures for aliphatic nitro reduction2 – aromatic nitro groups are no problem. We’ve tried regular hydrogenation, Raney Nickel, SmI2 and LiAlH4. Jim Anderson at Nottingham recently published a very nice paper resurrecting Al-Hg amalgam as a reagent for this transformation, and we are having luck with it.3 This post is a very overdue appeal to the community at large:
a) Does anyone know of any other good reaction conditions for this reaction?
b) Does anyone have any advice on good ways to isolate the resulting diamines?
Cheers,
Mat
1. K. Yamada, S. J. Harwood, H. Groger and M. Shibasaki, Angew. Chem. Int. Ed. 1999, 38, 3504-3506.
2. S. L. Ioffe, V. A. Tartakovskii and S. S. Novikov, Russ. Chem. Rev. 1966, 35, 19-32.
3. J. C. Anderson and H. A. Chapman, Synthesis 2006, 3309-3315.
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LiAlH4 doesn't work?
In my experience, LiAlH4 reduces aliphatic nitro groups nicely. What happens when you try that?
As for isolating the diamine, are you saying that you have difficulty separating the diamine from the starting material?
reduction of aliphatic nitrogroup
Dear Mat,I’m just wondering if in regular hydrogenation, you have tried Pd/C 10%, with hydrogen transfer conditions, like with ammonium formate or formic acid in methanol or ethers or mixture of that, at room temperature. Did you? This is a very smooth and mild reaction media for this class of compounds, that some time give surprising results.Kind regards
Stell
A few results on nitroamine reduction
Apologies for the delay in getting back to you guys – a long vacation then all my teaching in one glorious month.
Thanks for the comments. The reagents you suggest were things we considered. I’m sure we tried LAH with no luck, but having gone back to the report the relevant student wrote last year, I can’t actually find specifics. We’ll try this again and report back. We’ve actually been looking at three substrates for the reduction (1-3) below. (We ought to start using InChI in posts about molecules, put at the bottom)
We also tried:
1) Transfer hydrogenation using both formic acid and ammonium formate on substrate 1, but the chloro was lost in the process. We’d like this chloro eventually, so this procedure was not ideal. (We were following D.C. Gowda and Shankare Godwa, Indian J. Chem. 2000, 39B, 709-711 and S. Ram and R.E. Ehrenkaufer, Tetrahedron Lett. 1984, 25, 3415-3418). We could tone down the reagents a bit to see if that helps.
2) The amalgam reaction with Hg/Al followed by hydrogenation to reduce the intermediate hydroxylamine looks to go well by ESI-MS, but we cannot yet isolate the product we want from a messy NMR spectrum.
3) Samarium iodide and tin chloride both gave complex mixtures. We had a quick go with hydrzinium formate and hydrogen, both with Raney nickel, and got nothing, but we suspect the reagent in that case and will repeat.
The purification at the end of the reactions of these polar, uncolumnable nitroamines is a constant frustration, and if we had a good solution for this we would have better data to report. We’re playing around with different reaction conditions, but we could do with advice on purifying diamines like this from crude mixtures.
Benzylated nitro
InChI=1/C17H18N2O2/c20-19(21)13-17-16-9-5-4-8-15(16)10-11-18(17)12-14-6-2-1-3-7-14/h1-9,17H,10-13H2
Chloroacetylnitro
InChI=1/C12H13ClN2O3/c13-7-12(16)14-6-5-9-3-1-2-4-10(9)11(14)8-15(17)18/h1-4,11H,5-8H2
Acetylnitro
InChI=1/C12H14N2O3/c1-9(15)13-7-6-10-4-2-3-5-11(10)12(13)8-14(16)17/h2-5,12H,6-8H2,1H3
Benzylamine
InChI=1/C17H20N2/c18-12-17-16-9-5-4-8-15(16)10-11-19(17)13-14-6-2-1-3-7-14/h1-9,17H,10-13,18H2
Chloroacetylamine
InChI=1/C12H15ClN2O/c13-7-12(16)15-6-5-9-3-1-2-4-10(9)11(15)8-14/h1-4,11H,5-8,14H2
Acetylamine
InChI=1/C12H16N2O/c1-9(15)14-7-6-10-4-2-3-5-11(10)12(14)8-13/h2-5,12H,6-8,13H2,1H3
pic
Your pic is showing up broken.
Whoops
Thanks JC - fixed.
Mat
chromatography advice
I came across this advice a while back that might help for polar materials
Another approach that has worked for me in the past is to recrystallize the hydrochloride salts of amines. Take your amine up in ethanol and add a solution of conc HCl in ethanol until neutral. Evaporate off the ethanol then try to crystallize in a few solvents.
Formic acid is a no-no
Stell, We had a go at transfer hydrogenation in the presence of formic acid, and managed the beautiful conversion of our benzylnitroamine 1 to the amine 4, presumably by retro aza-Henry to 2 followed by reduction. This implies we'll need to avoid acid. However, the acylated version of 1 that we require for PZQ synthesis may be less susceptible to this, and the conditions are certainly simple and inexpensive, which is good. I'll post the conditions as well as a spectrum (where's that file, Milena?) when I get them, as an exercise in data sharing here.
Thanks for the suggestion, Mat