This paper deals with a novel, efficient and environmentally friendly synthesis of dialkyl haloalkylphosphonates via a microwave-assisted Michaelis–Arbuzov reaction. The approach is solventless, requires only one equivalent of each of the starting compounds, and provides high yields of pure products from which the impurities are easy to remove. The process has been optimised for batch and flow reactors and is especially profitable for the production of key intermediates in synthesis of Ethephon or acyclic nucleoside phosphonates such as adefovir, tenofovir, and cidofovir.

A new highly efficient method for the hydrolysis of acyclic nucleoside phosphonate diesters (or generally of any organophosphonates) to the corresponding phosphonic acids has been developed. This novel methodology employs inexpensive hydrochloric acid in equimolar amounts to the number of ester groups present in the molecule and thus, avoids using trimethylsilyl halogenides, the standard reagents for these types of transformations. Moreover, simple and easy work-up of the reaction mixture affords very clean products in high yields (usually 77–93%). Another advantage of the described hydrolysis of phosphonate diesters is the fact that the course of the reaction can be instantly monitored through pressure changes in the reaction vessel. This ‘green’ method has also been successfully used for the preparation of otherwise synthetically difficult to access (phosphonomethoxy)ethyl (PME) derivatives of guanine (PMEG) and hypoxanthine (PMEHx), and furthermore, the method gains access to important novel acyclic nucleoside phosphonates derived from 2-chlorohypoxanthine and from xanthine (e.g. PMEX).

Reaction of 8-bromoadenine derivatives2with sodium acetate in acetic acid and cleavage of (S)-7-[(trityloxy)methyl]-7,8-dihydro[1,3]oxazolo[3,2-e]purin-4-amine (12) and diisopropyl (S)-{[(4-amino-8,9-dihydro-7H-[1,3]oxazino[3,2-e]purin-8-yl)oxy]methyl}phosphonate (13a) were used for the synthesis of the corresponding N⁹-substituted derivatives of 6-amino- 7H-purin-8(9H)-one3a-3cand7. Alkylation of 6-amino-7H-purin-8(9H)-one (3a) with diverse alkylation agents afforded the title N⁹-monosubstituted3b,3dand7aand N⁷,N⁹-disub- stituted acyclic nucleoside and nucleotide analogs6b,6dand8a.