Org Prep Daily

November 16, 2006

Sonogashira on 2,4-diamino-5-bromopyrimidine

Filed under: procedures — milkshake @ 10:41 pm


A solution of 5-bromo-2,4-dichloropyrimidine 4.989g (21.89mmol, Aldrich) in anh THF 20 mL was cooled to 0C. With vigorous stirring, a solution of 2M ethyl amine in THF 24 mL (48 mmol, Aldrich) was added dropwise over 15min (a voluminous precipitate formed). The cooling bath was removed and the mixture was stirred at RT for 45 min. The reaction mixture was filtered through a 40g plug of silica and silica was washed with 5:1 mixture dichloromethane-ethyl acetate 240mL. The filtrates were evaporated and the residue was dried on highvac overnight. The obtained oily residue was dissolved in neat benzylamine 14.4mL (132 mmol) and the mixture was stirred under argon at 60C for 11 hours (overnight).  The reaction mixture was concentrated on highvac to dryness. The residue was dissolved in a mixture 4:1 dichloromethane-ethyl acetate, filtered through a pad of silica (40g) and silica was washed with 250mL of the same mixture. The filtrates were evaporated and dried on highvac. The solidified residue was re-crystallized from hexane. Y=5.631g (84%) of a white crystalline solid. (The minor regioisomer remained in the supernatants). 1H(CDCl3, 400MHz): 7.710(br s, 1H), 7.333-7.221(m, 5H), 5.852(br s, 1H), 5.098(s, 1H), 4.542(d, 6Hz, 2H), 3.416(m, 2H), 1.174(t, 7.4Hz, 3H); 13C(CDCl3, 100MHz): 161.05, 158.16, 155.66, 139.65, 128.44, 127.533, 127.01, 45.72, 35.78, 14.74

5-bromo-2-benzylamino-4-ethylaminopyrimidine 276.5mg (0.90 mmol) from the previous step was combined with 15 mg of PdCl2(dppf).CH2Cl2 (2 mol%) and 2.5mL of anh. THF in a 4mL vial. Triethylamine 0.19mL(1.35mmol) and 1-hexyne 0.155mL (1.35 mmol) was added and the mixture was stirred in a closed vial for 10 min. Solid CuI 2.9mg (1.7mol%) was added, the vial was briefly flushed with Ar, capped and placed on oil bath. The mixture was stirred at 60C for 20h. (The progres of reaction was monitored by observing formation of Et3N.HBr precipitate). The reaction mixture was filtered through a plug of silica (2g, washed with 5:1 DCM-EtOAc mix 45mL). The filtrates were evaporated and the residue was purified on a column of silica 10g  using a ethyl acetate gradient in dichloromethane, 0 to 15% EtOAc. Y=249mg (90%) of a pale-yellow solid.

1H(CDCl3, 400MHz): 7.880(br s, 1H), 7.331-7.258(m, 5H), 5.387(br s, 1H), 5.274(br s, 1H), 4.598(d, 5.5Hz, 2H), 3.437(m, 2H), 2.442(t, 7.3Hz, 2H), 1.575(m, 2H), 1.465(m, 2H), 1.188(t, 7.2Hz, 3H), 0.950(t, 7.4Hz, 3H); 13C(CDCl3, 100MHz): 162.14, 160.64, 157.73, 139.72, 128.45, 127.52, 127.01, 96.50, 73.77, 45.45, 35.39, 31.03, 22.06, 19.44, 14.85, 13.63

Coordinating properties of diaminopyrimidine make these bromides a relatively troublesome substrate class in the Sonogashira coupling. By comparison with various frequently-used sonogashira systems, the above conditions – THF, NEt3, PdCl2(dppf), CuI – were far superior to many other systems for these diaminopyrimidine bromides. Phenyacetylene and TMS-acetylene also coupled with high yields (>80%). With less electron rich alkynes like phenylacetylene, 5mol% of the catalyst was usualy applied to make the reaction complete within one day at 60C. Degassing is not essential. It is important that CuI is added very last. Small quantities of CuI can be difficult to weight (a cut tip of Pasteur pippet was used for weighing) but it is important not to overload the reaction with Cu salt - Cu is not rate-controlling and its excess promotes side-reactions. CuBr can be used in place of CuI.  The products have tendency to tail on silica therefore the gradient elution was used. Since the stating material is usualy close to the product, it is important to ensure a complete conversion of the starting material.

The analogous diaminopyrimidine iodides had faster initial rate but curiously failed to provide a complete conversion of the starting material under these reaction conditions. It is possible that the reaction progress was in this case inhibited by accumulation of NEt3.HI together with coordinating properties of the pyrimidines.


  1. Hey Milkshake,

    your Sonogashira conditions screem “Use microwaves” at me !?! Any thoughts on that

    Comment by BeenThereBefore — January 31, 2007 @ 6:21 am

  2. Yeah, we have been using microwave for Suzuki but this one was a bit touchy reaction and I did not feel like over-heating it. I had 4 stirplates placed in a cheap Fisher incubator thermostated to 60C and I could run there a bunch of reaction in parallel, in 4mL teflon-capped vials. Since all reactions were done on the same scale and the progress could be observed just by watching the NEt3.HBr precipitate level increasing, one could tell which reaction was close to completion. Overnight experiment in this kind of setup is not too long… Most of the time, weighing out the reagents and precursors and then working up the reaction and purifying the product is much more time consuming. (Besides, even chemists have to sleep sometimes, too.)

    Comment by milkshake — January 31, 2007 @ 1:46 pm

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