Adenosine derivatives, Dimroth rearrangement

Figure 1.54 Alkylation reactions can occur at the N-l position of adenosine, resulting in a Fischer-Dimroth rearrangement to yield an Ng derivative.

Advances in the Dimroth rearrangement in the adenine series have been reviewed. A-l-Methoxy derivatives of adenosine and 2 -deoxyadenosine have been found to... 

Based on the experience mentioned previously, the Dimroth rearrangement was succesfully applied for the preparation of water-soluble macro-molecular adenosine derivatives of the redox enzymes 72 (NAD(H), NADP(H), and FAD) (Scheme IV.31) (86MI1 87MI3, 87MI2 88H1623 89MI1 90M11). 

The reaction of adenosine, and some other derivatives, with DMAD has been shown to yield a mixture of different pyrimido[2, l-/]purines depending on the reaction conditions. The kinetically favoured products (80) usually crystallise from the reaction medium, but if they are soluble then the thermodynamically favoured products (81) result via a Dimroth rearrangement 95H(41)1197],... 

In the laboratory of R.A. Jones, A/ -methoxy derivatives of adenosine and 2 -deoxyadenosine were found to undergo a facile Dimroth rearrangement The high-yielding process allowed the efficient synthesis of [1,7- N2]- and [1,7, NH2- N3] adenosine and 2 -deoxyadenosine that are important tools in the NMR studies of nucleic acid structure and interactions. The rearrangement was carried out in weakly acidic refluxing methanol. 

Treatment of the 5 -phosphate of cytidine or adenosine with methyl sulfate at pH 5 yields iV -methylcytidine 5 -phosphate and iV -methyl-adenosine 5 -phosphate (244), along with their (methyl phosphate) derivatives. When the methylated adenylic acid (244) is treated with a mild alkali, a Dimroth rearrangement occurs, with formation of A -methyladenosine 5 -phosphate (245). Methylation of the synthetic homopolymer poly (adenylic acid) with methyl sulfate, followed by adjustment of the pH of the reaction mixture to pH 11, gave a polymer that contained an appreciable percentage of iV -methyladenylic acid residues in the polynucleotide chain. 

Kinetic studies have shown that the substituent at position 1 and pH also play an important role in the Dimroth rearrangement of adenine and adenosine derivatives. For adenine derivatives substituted at position 1, the individual rates for methyl, ethyl and propyl derivatives were comparable, while the benzyl derivative rearranged faster (not shown). Above pH 10, methyl-substituted adenine derivatives rearranged fastest, while the benzyl-substituted derivatives rearranged the slowest. Subsequently, the authors found that adenosine 130 rearranged faster at pH values below 10, whereas adenoside 128 rearranged faster at pH values above 10, and in both cases the reaction rates were enhanced by the presence of ribose. The authors attributed these observations to the electronic effects of the substituents, which play a greater role at pH values less than 10 where the nucleoside remains protonated. At pH values above pH 10, the adenine/adenosine derivatives are neutral and sterics plays a more important role. 

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