Diethoxymethyl acetate

Reactions of 3-hydrazino-l,2,4-triazine 1-oxide 31 or 3-hydrazinopyrido [2,3-c]-l,2,4-triazine 1-oxide 32 with diethoxymethyl acetate or triethyl orthoformate proceed as cyclization reactions at the N(4) atom and the amino group to form the corresponding pyrazolo[3,4-c]-l,2,4-triazine 6-oxides 33 and 34 (74MI, 80JOC5421, 80MI). 

This ring system is represented by tricyclic ring system 533 (76JHC1249). Reaction of 3-hydrazino[l,2,4]triazin-5-ones 531 with 3-imi-nobutyronitrile afforded 6-methyl- (or phenyl-) 3-[3-methyl-5-aminopyra-zolyl]-2,5-dihydro[l,2,4]triazin-5-ones 532A, which may exist in tautomeric form 532B. Its reaction with diethoxymethyl acetate (DEMA) or ortho-esters afforded the tricyclic compounds 533. 

Scheme 7.49). The requisite activated double bond is generated in situ from the 1,3-dicarbonyl compound and a one-carbon synthon such as a trialkyl orthoformate, diethoxymethyl acetate or Al,Al-dimethylformamide dimethyl acetal. 

Tartaric acid, dibenzoate, (-)-Orthoformate or diethoxymethyl acetate Cyclopropylamine... 

Treatment of 2-hydroxy-2-(polyhaloalkyl)chroman-4-ones with diethoxymethyl acetate affords 3-(polyhaloacyl)-chromones in modest to high yield (Equation 314) <2005SL1164>. 

The product from Step 3 (0.19 mmol) and diethoxymethyl acetate (0.97 mmol) were dissolved in 1ml HOAc and heated to 110°C 1 hour. The reaction was cooled and the product precipitated by the addition of diethyl ether. The mixture was filtered and the product isolated. H-NMR data supplied. 

The thiourea (180) rapidly cyclizes with diethoxymethyl acetate to the thione (181) from which derivatives can be made via nucleophilic displacement of methanethiol e.g. 182 Scheme 57) (74JHC991). 

Triethyl orthoformate has proved to be a useful cyclizing agent, especially when mixed with acetic anhydride which produces diethoxymethyl acetate (56JA1928,56JOC599, B-78MI40903, p. 995). 

Tetrazolopyrimidines can also act as a source of a diaminopyrimidine and hence of purines. Thus 8-amino-7-chlorotetrazolo[l,5-c]pyrimidine (362) when heated with diethoxymethyl acetate furnished 6-chloro-8-ethoxypurine (Scheme 153) (62JOCl67i) via a nitrene intermediate and concomitant loss of nitrogen. 

Purine is probably best prepared by the Traube route from 4,5-diaminopyrimidine and formic acid in an atmosphere of carbon dioxide (83% yield) (54JA6073), or, better, using diethoxymethyl acetate as the cyclizing agent (82% yield) (60JOC395). 

Purine (6) itself is a colorless crystalline weak base which was first prepared by Fischer " the first synthesis using the Traubc condensation was reported by Isay. The Traube protocol is probably the best method to prepare purine, using pyrimidine-4,5-diamine as precursor and formic acid in an atmosphere of carbon dioxide or diethoxymethyl acetate as cyclizing reagents. 

Thus, facile conversion of acetylated AICN-riboside into 7-ribosyl-6-sulfanylpurine 1 has been accomplished with diethoxymethyl acetate and hydrogen sulfide in pyridine. " ... 

Amino-1-(2. 3. 5 -tri-(3-acetyl-/8-D-ribofuranosyl)iraidazole-5-carbonttrile (1.2 g, 3.2 mmol) was heated at reflux temperature in diethoxymethyl acetate (20 mL) for 6 h and the orange solution was then evaporated in vacuo to a syrup. This syrup was dissolved in pyridine (200 mL) and heated at reflux while H S gas was slowly bubbled through for 1 h. The solution was then refluxed without the addition of H S for an additional 10 h. The dark solution was evaporated in vacuo, and then treated with MeOH (100 mL) which had been previously saturated with NHj. This mixture was allowed to stand for 18h at rt and then evaporated in vacuo to give a semisolid. The semisolid was dissolved in HjO (50 mL), the pH adjusted to 5 with coned HCl, and the solution allowed to stand at rt for 2 d. The precipitate was filtered yield 1.2 g (73%) mp 204-206 =C. 

The isomeric 5-aminoimidazole-4-carbonitrile 2 -deoxyribofuranosides have been condensed with diethoxymethyl acetate in the synthesis of 2 -deoxyadenosine and its N7 glycosylated isomer 6. " ... 

A solution of 4-amino-l-[2-deoxy-3,5-di-0-(4-toluoyl)-/J-D-ribofuranosyl]-l/f-imidazole-5-carbonitrile (400 mg, 0.87 mmol) in diethoxymethyl acetate (10 mL) was heated under reflux for 4 h. The solution was evaporated, the resulting syrup dissolved in toluene, and again evaporated. Methanolic NH, (60 mL, previously saturated at 0 C) was added and the solution stirred at rt for 24 h. After evaporation (he residue was purified by flash chromatography (silica gel 60H, CH CL/MeOH 4 1). After crystallization (MeOH), colorless crystals were obtained yield ISOmg (69%) mp 187 C. 

In this context, a polyfluorinated imidazopyridine system 21 has been prepared by a multistep synthetic route (see Figure 11.7) beginning from 3-chlorotetrafluoropyridine 22, via the formation and subsequent condensation of 3,4-diamino-2,5,6-trifluoropyridine with diethoxymethyl acetate [45], Subsequent reaction of the ring-fused system with ammonia demonstrated the potential of such systems as polyfunctional scaffolds, if much shorter... 

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