Applied to the Buchwald-Hartwig Reaction

Entry Aryl Compound Amine Condition Ligand % yield of Product 

We applied the improved conditions (Condition E) to the macrocycle substrate. The reaction of 38 with the d/1 isomer of 17 using Condition E showed some formation of product in the crude NMR, but recovery of pure product was not achieved (entry 10). The reaction condition was then applied to the meso isomer of 17 and 21 % of the diarylated compound 41a and 19 % of the mono-arylated compound 41b were isolated (entry 11). Several other attempts gave no improvement in the yield. 

The synthesis of macrocycle 17 was optimized to 46 % overall yield of both isomers and 22 % overall yield of the meso isomer in nine steps. During this synthesis a method was developed to separate the pro-meso isomer from the pro-d/1 isomer of the amides. This method was very reproducible and there was good recovery of compound from the column. A method was also developed to separate the meso isomer from the d/1 isomer that resulted from isomerization of the meso isomer to a 1 1 mixture of meso and d/1 during the reduction of pro-meso to the meso isomer. However, this method was tedious and not very reproducible therefore care must be taken to prevent isomerization during the reduction of the amide. With an optimized synthesis of the macrocycle 17 at hand, enough macrocycle was made available to explore synthesis of the attachment of the side arm. 

The side arms were introduced via a Buchwald-Hartwig reaction. While the yield of the reaction was low and the reaction was not reproducible, this was the first example of a Buchwald-Hartwig reaction on a macrocyclic system of this kind. In addition, this was the first example of a Buchwald-Hartwig reaction to di-arylate a diamine system. 

To a solution of 4-nitrophenylacetic acid (3.62 g, 20.0 mmol) in methanol (30.0 mL, 0.670 M) was added concentrated sulfuric acid (0.500 mL) and the reaction was refluxed at 70 °C overnight. The volatile components were removed under reduced pressure and the residue was taken up in EtOAc (100 mL), washed with sat d NaHC03 (3 x 50.0 mL), washed with brine, dried over MgSCL and filtered. The volatile components were removed under reduced pressure to give 3.78 g of crude 24 as a white solid in 97.0 % yield, which was carried on to the next step without further purification. 

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Table 3. Conditions Applied to the Buchwald-Hartwig Reaction.

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