Yakovenko G. G. Synthesis of pyrazolo[4,3]pyridine systems based on N-Boc- 4-aminopyrazole-5-carbaldehyde. – The manuscript.
Dissertation for Doctor of Philosophy degree by specialty 102 “Chemistry”, specialization “Organic chemistry”. National University of ''Kyiv-Mohyla Academy'', Kyiv, 2021.
The thesis is devoted to the development of convenient and efficient preparative methods of synthesis of novel functionalized pyrazolo[4,3]pyridines and opening the synthetic access to obtain new azoheterocyclic systems.
N-Boc-4-aminopyrazole-5-carbaldehydes were chosen as basic molecular platform for the synthesis of the undescribed pyrazolo[4,3]pyridines and were obtained from N-Boc-4-aminopyrazoles, via chemoselective reaction with n-BuLi and further formylation with DMF or ethyl formate.
The synthetic potential of N-Boc-4-aminopyrazole-5- can be observed in classic Friedländer reaction, which consists of the reaction with dialkyl- or alkylarylketones in refluxing acetic acid in presence of pyrrolidine. This method allowed to obtain novel 5,6-dialkyl- or alkylaryl- substituted pyrazolo[4,3]pyridines in one preparatory stage.
Further research was focused on the interaction of N-Boc-4-aminopyrazole-5- carbaldehydes with cyclic β-diketones. As a result of such reaction the pyrazolo-[4,3- b]quinolin-8-ones were obtained, that were then treated with NH2OH to give oximes in high yields. The reaction of the latter with trifluoromethanesulfonic anhydride in Beckmann rearrangement was used to synthesize pyrazolo[3',4':5,6]pyrido[3,2- b]azepins.
Another approach was found in the reaction of N-Boc-4-aminopyrazole-5- carbaldehydes with ethyl acetoacetate derivatives and 3,3-dimethoxypropanoate that allowed obtaining 5-substituted pyrazolo[4,3-b]pyridine-6-carboxylates. The catalytic reduction of the latter gave 4,5,6,7-tetrahydropyrazolo[4,3-b]pyridine-6-carboxylates, that exhibit some bioactive properties, as analogs of nipecotinic acid. The chemical structures of the molecules have been determined using X-ray crystallography.
Reaction of malonic acid, α-cyanoacetic acid, malononitrile and α-cyanoacetic amide with N-Boc-4-aminopyrazole-5-carbaldehydes in refluxing acetic acid or acetonitrile in presence of equimolar amount of pyrrolidine was used for the synthesis of novel 5-oxo(amino)pyrazolo[4,3-b]pyridine-6-carboxylic acids, carbonitriles and carbamides, respectively.
Scientific novelty and originality of the results. As we expected, the N-Boc- 4-aminopyrazole-5-carbaldehydes have proven to be effective substrates for the synthesis of a wide range of novel substituted pyrazolo[4,3-b]pyridines.
To achieve the goals of the research the effective method of obtaining N-Boc- 4-aminopyrazole-5-carbaldehydes in multigram quantity has been developed. The latter were exanimated in reactions with methylene active compounds such as ketones, β-diketones, ethyl acetoacetate derivatives, malonic and α-cyanoacetic acids, malononitrile and α-cyanoacetic amid and creatinine.
The reaction of N-Boc-4-aminopyrazole-5-carbaldehydes with dialkyl- and arylalkylketones exhibited basic regularities of proceeding the Friedländer reaction and led to alkyl-, aryl- substituted pyrazolo[4,3-b]pyridines. Using β-diketones as reagent allowed for synthesis of the pyrazolo-[4,3-b]quinolin-8-ones, that were used for obtaining pyrazolo[3',4':5,6]pyrido[3,2-b]azepines via Beckmann rearrangement.
A new effective approach to the synthesis of potentially bioactive 4,5,6,7- tetrahydropyrazolo[4,3-b]pyridine-6-carboxylates as analogs of nipecotinic acid was proposed. The new method is based on the reaction of N-Boc-4-aminopyrazole-5-
carbaldehydes with ethyl acetoacetate derivatives or 3,3-dimethoxypropanoate to give 5- substituted pyrazolo[4,3-b]pyridines-6-carboxylates that subsequently can be successfully converted into target products by catalytic hydrogenation.
The practical significance of the results is to develop convenient preparative method of obtaining N-Boc-4-aminopyrazole-5-carbaldehydes in multigram quantities for the use in synthesis of novel pyrazolo[3,4-e]pyridines systems that proved to be valuable polyfunctional molecular platform for constructing a wide range of new promising heterocyclic systems with potentially wide range of biological activities.
Keywords: N-Boc-4-aminopyrazole-5-carbaldehydes, pyrazolo[4,3- b]pyridines, pyrazolo[3',4':5,6]pyrido[3,2-b]azepines imidazo[1,2-a]pyrazolo[3,4- e]pyridines, pyrazolo[3',4:5,6]pyrido[2,3-d]pyrimidines, Friedländer reaction, Knoevenagel reaction, Beckmann rearrangement, Curtius rearrangement, catalytic hydrogenation, heterocyclization.
