Org Prep Daily

November 17, 2006

Diazaindole cyclization

Filed under: procedures — milkshake @ 4:46 pm

diazaindoles2.gif

The acetylene compound 92.5mg (0.3 mmol) and CuI 114.5mg (0.6mmol) was suspended in anh. dimethylacetamide 0.8mL in a 25mL14/20 round flask equipped with a straight stopcock. The mixture was degassed by highvac/Ar purge. Barton base 0.15mL (0.75mmol, Fluka) was added through the stopcock and the mixture was stirred at 135-140C oil bath under Ar in a closed flask for 3 hours. The mixture was cooled to RT, methanol 1mL was added followed by TMS-CN 0.25mL. The mixture  was diluted with dichloromethane 10mL, sonicated for 10 min and then stirred at RT for 1 hour. The precipitated CuCN was removed by filtration through a pad of silica. The silica was washed with 50mL of a 10:1 mixture of dichloromethane with methanol. The filtrates were evaporated and the residue was dried on highvac. The crude product was purified on a column of silica (35g) in EtOAc gradient in dichloromethane, 10 to 30% of EtOAc (in 45 min, 20mL/min). Y= 77mg(83%) of a light tan solid

1H(CDCl3, 400MHz):8.330(br s, 1H), 7.393(m, 2H), 7.298(m, 2H), 7.223(m, 1H), 6.025(s, 1H), 5.707(br s, 1H), 4.677(s, 2H), 4.071(q, 7.0Hz, 2H), 2.635(t, 7.8Hz, 2H), 1.686(m, 2H), 1.453(m, 2H), 1.280(t, 7.0Hz, 3H), 0.973(t, 7.4Hz, 3H)

The above procedure was succesfully used to cyclize a large number of diaminopyrimidine acetylenes with excellent yields (82 to 96%Y). Various substituent groups on amines and Phe, Bu, H on acetylene were tolerated. Only TMS-protected acetylene compounds failed to provide diazaindoles but the deprotected acetylenes (R=H) cyclized smoothly.

Barton base is a low-boiling strong base. It serves here both as a copper ligand and a base – it keeps things soluble and it deprotonates the aminopyrimidine NH. (I have not tried other bases like DBU but the reaction works even without base – the reaction was slower and formation of voluminous precipitate was a complication). Since the product binds strongly to Cu, cyanide excess was used in the workup to break the complex. Trimethylsilyl cyanide is very poisonous, it has to be handled with gloves in the hood.

End of daily updates darek_rakeff.jpg

8 Comments »

  1. Could Iodine be added to break up the copper complexes, or perhaps fluoride (TBAF for instance)?

    Comment by Luke — November 18, 2006 @ 4:48 pm

  2. I am a firm believer in washing Cu reactions with EDTA solution. And the aqueous will be blue no doubt. I have always used DBU for any reaction that the guanidine base of Barton was used in and not yet been disappointed.

    Comment by TMS — November 18, 2006 @ 7:33 pm

  3. Right you are, TMS on both counts I think. I used Barton base the first time and it worked – so I did not look further. I thought of EDTA but have used cyanide here to avoid aqueous workup because it takes more time and I was running a bunch of these reactions in parallel on a small scale. But this would probably be the first thing to replace if one would do a scale-up. I did have a good experience with EDTA workup of Ar-Br to ArCN exchange with CuCN.
    Luke: I dont think I- or F- would work here. Iodide was in already, from CuI. I tried H2S gas and it worked to some degree but cyanide was better and less messy.

    Comment by milkshake — November 18, 2006 @ 10:00 pm

  4. Very sad that daily procedures have ended… too bad I can’t send you some of my own preps…
    Good luck

    Comment by transitionstate — November 19, 2006 @ 12:26 pm

  5. How can you make an aqueous EDTA solution? The solubility is less than 50 mg/100 mL of water!

    Comment by Christiane — January 22, 2007 @ 12:19 pm

  6. Use the disodium salt. Or start with the free acid and adjust the pH with NaOH to pH=8.

    Sigma sells 0.5M solution of the disodium salt.

    Comment by milkshake — January 22, 2007 @ 3:41 pm

  7. Could anyone help me to find a method to get 6-amino-7-azaindole? Thanks.

    Comment by landery — April 20, 2007 @ 12:57 pm

  8. 6-amino-7-azaindole is commercially available form some company called Sinova. I guess you can take 2,6-diamino-3-bromopyridine, do Sonogashira with TMS-acetylene, cleave TMS with potassium carbonate in MeOH and do the copper-promoted cyclization. 2,6-diaminobromopyridine is expensive but I guess one can make it from 2,6-diaminopyridine. (That was result from brief search in ACD/ISIS databaze of commercial chemicals)

    Comment by milkshake — April 20, 2007 @ 5:05 pm


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