Org Prep Daily

June 22, 2007

Direct preparation of 2-Aminopyridines from pyridine N-oxides

Filed under: lit highlights — milkshake @ 6:54 pm

There is a lovely JOC note from Merck Process group:

pyridines1.gif

The N-oxide is transformed to N-tert-butylamino intermediate and then deprotected in situ with TFA in a one-pot operation. The procedure works well with a wide variety of substrates: pyridines, quinolines, isoquinolines. The few examples of unsymmetrically-substituted pyridine-oxides that had both the 2 and 6 positions free provided a mix of the two ortho amino regioisomers. [This is an improved version of the amination procedure with TsCl, NH3 that was useful for 2-aminoquinoline scale-up: Couturier et al, Org Process R & D, 10 (2006), 534-8.]

Another related simple procedure for acylamidation of N-oxides from Pfizer process group uses RCONCO that is generated generated in situ from RCONH2 and oxalyl chloride:

quinolines.gif 

This acylamination procedure is however limited to quinolines, isoquinolines and phenanthrolines; pyridine N-oxides fail in the acylamidation. 

10 Comments »

  1. Merck’s new prep appears to be a nice improvement of their earlier process, which used a rather fancy cyclic imidoyl chloride reagent (see Hagmann et al Bioorg. Med. Chem. Lett. 2000, 10, 1975) that takes a few steps to make. In that prep, the imidoyl chloride serves to activate the pyridine N-oxide and deliver the nitrogen.

    Since I was actually planning to make the fancy imidoyl chloride for a 2-aminopyridine synthesis, I’ll have to read up on their new prep first. – Thanks Milkshake!

    Comment by cjdquest — June 23, 2007 @ 5:09 pm

  2. I couldn’t help but notice that you’re putting the ref in the gif! This means that the information on what paper you’re talking about cannot be automatically extracted.

    It would be great if you could put the DOI of the papers into the text, as it will then be extracted and aggregrated by Chemical Blogspace.

    Comment by baoilleach — June 27, 2007 @ 12:37 pm

  3. sorry but I was lazy. I will adhere to good habits next time.

    Comment by milkshake — June 27, 2007 @ 2:03 pm

  4. Sweet, something else besides the Chichibabin amination for those pesky pyridines. That’s the way I aminate my pyridines, but it takes quite a while for those electron rich ones in refluxing toluene and the reaction was done in the 1900s, so I’m feeling like trying something new. Besides, the Chichibabin amination requires no N-oxide first, so these new fangled syntheses would be new territory for me. (Mild sarcasm alert)

    Comment by blatnoi — July 6, 2007 @ 9:47 pm

  5. an undergrad in our group has had a tough time reproducing that Merck amination protocol. Her technique seems to be bang on and we even tried exact entries from the Merck paper’s table with no luck. Just kept isolating TsHNtBu.

    Comment by ... — July 19, 2007 @ 5:55 pm

  6. i want more information about those papers so please send to my mail

    Comment by sivasankari.R — August 8, 2008 @ 2:36 am

  7. dear Sir! Please I want you to ask somebody else to copy those papers for ya

    Comment by milkshake — August 8, 2008 @ 6:20 am

  8. Hi MS,

    I would like to introduce methyl to 3-Bromo functionalized pyridones by organometallic coupling. Do I need to protect the ring nitrogen for this? There are reports for the introduction of aryl group (Suzuki reaction) without protection. Is there any good methods for methyl introduction by coupling reaction? (Methods known with Sn(Me3)4 and B(OH)2OMe Reagents).

    Thanks for your help.

    Marto

    Comment by marto — November 19, 2010 @ 3:39 am

    • I would recommend to introduce pyridones in a protected form, perhaps as alkoxy-pyridines. Methyl from 2-methoxy pyridine falls off easily by heating in aqueous HCl…

      Comment by milkshake — November 19, 2010 @ 4:53 pm

  9. Thanks very much..

    Marto

    Comment by marto — November 20, 2010 @ 3:53 am


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