Phosphorus oxychloride → 5-Iodo-2,4-dimethoxypyrimidine

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Reaction Steps

As illustrated in Scheme 2, 5-iodouracil was converted to 2,4-dichloro-5-iodopyrimidine with phosphorus oxychloride, which on treatment with sodium methoxide yielded 2,4-dimethoxy-5-iodopyrimidine (2a). The latter was coupled with trimethylsilylacetylene in the presence of (Ph3P)2PdCl2 /CuI, Et3N in CH2Cl2 to give 3a, followed by deprotection of the trimethylsilyl group with n-Bu4NF to give 2,4-dimethoxy-5-ethynylpyrimidine (4a). The coupling of decaborane with the alkyne was first conducted at 110° C. in toluene in the presence of propriononitrile as an activating agent for the decaborane, which is known to give very good yields (>70%) with a variety of terminal alkynes. Unfortunately, when these conditions were applied to the compound 4a, the formation of two products in equal proportion was observed by TLC. The less polar component corresponded to a product which had the two methoxy groups, but no signal for the B-C-H proton by 1H NMR, whereas the second more polar product corresponded to the desired compound 5a. A kinetics study of this reaction monitored by TLC showed the initial exclusive formation of the desired product. However, when the reaction was maintained at 110° C., the formation of the less polar product occurred and increased if the reaction was maintained at the same temperature. These observations were confirmed by 1H-NMR after quenching the reaction with MeOH at different times. The temperature at which the reaction was performed appeared critical since it had been reported by Heying, T. L. et al. , "A new series of organoboranes. (I) Carboranes from the reaction of decaborane with acetylenic compounds," Inorg. Chem. 1963, 2, 1089-1092, that formation of the decaborane-propriononitrile complex occurs only at high temperature. Surprisingly, when the coupling reaction was conducted in the absence of propriononitrile, the formation of the only desired compound 5a was obtained in 60% yield. Demethylation of the methoxy groups using iodotrimethylsilane gave after crystallization in MeOH the desired pure 5-carboranyluracil (6a) exclusively in the closo-form. The absence of the nido-compound [(nido-7,8-C2B9H11)- ] was confirmed by mass spectroscopy and a stain test (spraying the TLC plate with 0.1% PdCl2 in concentrated HCl and heating, produces a gray color for the closo-form and a black color for the nido-form of carboranes) as a white crystalline solid. The availability of 5-carboranyluracil (6a) provided a versatile intermediate for the synthesis of a number of nucleoside analogues described below.

Provenance & Evidence