Org Prep Daily

September 26, 2006


Filed under: procedures — milkshake @ 2:13 pm

4-Fluoro-2-methylaniline 6.258g (50 mmol) was dissolved in anhydrous acetic acid 20mL and acetic anhydride 5.00mL (53 mmol) was added without cooling (exothermic reaction). After 10 minutes, the mixture was heated to 90 C on oil bath and a solution of tBuOCl 9.0mL (81.8mmol) in acetic acid 60mL was slowly added (using an addition funnel) over a 3 hour period and the reaction was then  continued for additional 1 hour at 90C. The mixture was cooled and evaporated to dryness. The solid residue was re-crystallized from a mixture of ethanol 20mL and water 20mL (5 hours at ambient temperature). The precipitated product (6.305g) was collected by filtration, dried on highvac and re-crystallized from benzene (100mL, overnight), to obtain 5.484g of the chloroacetanilide intermediate as a white crystalline solid (96% pure by HPLC). 1H(d6-DMSO, 400MHz): 9.476 (br s, 1H), 7.316(dd, 8.4Hz, 2.9Hz, 1H), 7.158(dd, 9.3Hz, 2.8Hz, 1H), 2.174(s, 3H), 2.042(s, 3H).

The chloroacetanilide 5.484g was dissolved in conc. HCl 120mL. Water 120mL was added and the resulting slurry was refluxed for 3 hours (oil bath 130-140C). The resulting homogenous mixture was evaporated to dryness, the residue was dissolved in water 100mL, the solution was made basic with concentrated ammonia (pH approx 9.5 to 10) and the mixture was extracted with dichloromethane (2x100mL). The combined extracts were dried (MgSO4) and evaporated. The residue was dried on higvac with cooling on ice bath. Y=4.259g (53.5% overall) of a light-tan liquid that solidifies upon cooling to 0C.

1H(d6-DMSO, 400MHz): 7.022(dd, 8.5Hz, 2.9Hz, 1H), 6.866(dd, 9.3Hz, 2.8Hz, 1H), 4.880(br s, 2H), 2.139(s, 3H); 19F(d6-DMSO, 376.5MHz): -128.10(m, 1F)


  1. Hi MS,

    I need to introduce chloro adjacent to 2-amino pyridine. Remaining positions of pyridine systems are alky groups. I was able to synthesize 3-Iodo 2-amino pyridine from 2- amino pyridine. But similar reaction with NCS gave SM and I also tried this reaction with 2-N-Ac/2-N-Pyrrole pyridine but the reaction gave only about 10% chlorinated product. I am wondering whether I can apply this method for my compound synthesis.

    I am confident that 3-position of our pyridyl systems are e-rich for electrophilic substiution.

    Please suggest me what conditions need to be tried for the chloro intoruction at 3- position for 2-amino pyridines (subtsiuted with alkyl/EDG groups).



    Comment by marto — March 22, 2011 @ 1:49 am

    • I think this should work. Here is a similar example on a substrate that is closer to yours:

      The first product of chlorination is N-acetyl-N-chloro compound and that one is quite resistant to further ring chlorination, no matter how many extra equivalents of tBuOCl you use. I have actually isolated this N-chloro compound by accident (it forms quickly even at room temperature, and is quite nicely behaved).

      But the N-chlorination is reversible so if there is some material around with free NH it will keep exchanging the N-chlorine until something eventually gets ring chlorinated.

      So the idea is that one should add tBuOCl solution gradually, over a period of time, into a heated solution of the N-acetyl compound so that the N-acetyl and N-acetyl-N-chloro compound get enough time to play together and that the ring chlorination has had a chance to consume enough N-chloro before you add more tBuOCl. If you add tBuOCl too fast, or if the temperature is too low, you would get most of the material N-chlorinated and with no free NH around this greatly slows down the ring chlorination and heating it more only makes the reaction more messy.

      Maybe you should try a small-scale pilot experiment first: Add a half equivalent of tBuOCl at room temperature, take HPLC sample from the reaction and you should be able to see 1:1 mix of the starting N-acetyl material and N-chloro-N-acetyl (N-Cl it is actually quite stable on HPLC) . When you heat up, the N-chloro will gradually turn into ring chlorinated product, which should be more polar than the N-chloro-N-acetyl but less polar than the starting material. Then you add another half equivalent tBuOCl and repeat. Then another half equivalent, etc. At the end you will see more and more ring-chloro-N-chloro product that is even less polar. Evaporating the mix and working up the material with Na2SO3 will remove the N-chloro.

      Comment by milkshake — March 22, 2011 @ 5:15 am

  2. Hi MS,

    Thanks very much for the procedure


    Comment by marto — March 22, 2011 @ 6:37 am

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