Synthesis of Tetrahydropyrazolo[1,5-c]pyrimidine-2,7(1H,3H)-diones

Abstract

on the occasion of his 70th birthday.Abstract: A series of tetrahydropyrazolo[1,5-c]pyrimidine-2,7(1H,3H)-diones 3a-h as the first representatives of the so far unexplored saturated heterocyclic system have been synthesized, formally in 12 steps from methyl acrylate (4). The synthesis comprises a four-step preparation of methyl N-Cbz-5-alkylamino-3-oxopentanoates 9a-c, their three-step transformation into 5-{2-[(alkyl)(benzyloxycarbonyl)amino]ethyl}pyrazolidin-3-ones 12a-c, three-step selective alkylation of the amidic N-2 to give 2-alkyl-5-{2-[(alkyl)(benzyloxycarbonyl)amino]ethyl}pyrazolidin-3-ones 16b-h, followed by hydrogenolytic Cbz-deprotection and subsequent cyclization of the intermediate 1,4-diamine with CDI to furnish the title compounds 3. Most of the synthetic steps were performed as a one-pot transformation.

Synthesis of Novel 3D-Rich α-Amino Acid-Derived 3-Pyrazolidinones

“…[35][36][37][38][39] Masamune-Claisen condensation of amino acid 1a, i.e. activation of 1a with 1,1'-carbonyldiimidazole (CDI) followed by treatment of the intermediate imidazolide with a mixture of potassium monomethyl malonate and magnesium chloride gave the corresponding β-keto ester 2a in 93% yield.…”

“…Scheme 1), N-Cbz-sarcosine (1c) and N-benzyl-N-Cbz-glycine (1d) were transformed in four steps into the corresponding pyrazolidinones 5c and 5d. In a subsequent one-pot procedure, 35 compounds 5c and 5d were Boc-protected at N(1), methylated at N(2), and Boc-deprotected to give the N(1)-unsubstituted intermediates 12a and 12b in good yields over seven steps. Somewhat expectedly, 38 cyclizations of 12a,b into imidazo [1,5-b]pyrazole derivatives 14a,b proceeded well.…”

“…The 5-substituted pyrazolidinone was obtained by cyclization of the corresponding β-mesyloxy ester, which in turn was obtained in three steps from a suitably functionalized carboxylic acid. 31 Pyrazolidinones with 2-hydroxyethyl 36 and 2-aminoethyl 35,37 functional groups at position 5 were used as key intermediates in the synthesis of novel saturated heterocyclic systems, while 5-[(S)-1-aminoalkyl] derivatives prepared from N-protected α-amino acids were used as scaffolds for potential organocatalysts 38 and as key-intermediates in the synthesis of 3-pyrrolinones. 40 In addition to previously published 5-aminoethyl and 5-hydroxymethyl-3-pyrazolidinones, we also tried to prepare the 5-aminomethyl analogues, because they could be useful intermediates in the synthesis of novel saturated heterocycles in the imidazo [1,5-b]pyrazole and pyrazolo[1,5-a]pyrazine series.…”

“…Compounds 5a, 5b, and 5'b were prepared in a one-pot procedure following the combined slightly modified general literature procedures for the preparation of analogous compounds. 35,38,39 …”

“…In the context of our ongoing work on the synthesis of chiral heterocycles with emphasis on pyrazole 33,34 and pyrazolidinone derivatives, 31,32 we reported the synthesis of tetrahydropyrazolo [1,5-c]pyrimidine-2,7-diones as the first representatives of a novel saturated heterocyclic system, 35,36 followed by preparation of closely related tetrahydropyrazolo [1,5-c]pyrimidine-3-carboxamides 37 and tetrahydro-1H-imidazo [1,5-b]pyrazole-2,6-diones. 38 In ex-…”