New Advances in the Synthesis of Emerging Cyclic Amidrazones to Foster Bioisosterism of Azaheterocycles

Abstract

The pace and the scope of new molecules design is often constrained by limitations in synthetic chemistry. The azaheterocyclic amidrazones are of particular interest for bioisosteric considerations in drug discovery. However, the lack of efficient synthetic access has undoubtedly hampered their occurrence in the drug chemical space. Our current results describe a robust synthetic access relying on cyclization of aminohydrazine in presence of various orthoesters by either metal free‐ or metal‐catalyzed condensations. This optimized synthetic access to cyclic amidrazones as original scaffold should inspire the chemist community and further drive innovation in the design of molecular structure for many applications (for example, drugs, materials, dyes).

A new synthetic route towards multifunctionalized cyclic amidrazones for feeding chemical space

“…Following our initial synthetic strategy, 7 we evaluated our 5-step sequence starting from N -benzylethylenediamine 1a to introduce an alkyl chain at the N -1 position of the amidrazone (Scheme 1). Unfortunately, the regioselectivity of the Boc protection was altered and the expected compound 2a was isolated with a modest yield of 45%.…”

“…It is worth noting that this double sequence of reductive amination starting from Boc-hydrazide 5 can lead efficiently to a variety of DiBoc-aminohydrazines 7 (exemplified here with only benzylic and methylic groups, 7aa and 7ab , respectively), which can be considered as very convenient start of synthesis to obtain cyclic amidrazones bearing any functional groups at the N -1 position depending on the nature of versatile aldehydic partners. Based on our previous work, 7 we validated the cyclization of DiBoc-aminohydrazines 7aa and 7ab into the corresponding N 1 -alkyl-cyclic amidrazones in the presence of orthoformate reagents (Table 2). After clean removal of the Boc-protective group under acidic conditions, the thermal-mediated condensation of the corresponding diammonium salts 11aa or 11ab in the presence of various orthoformate reagents afforded successfully the cyclic amidrazones 12 , 13 and 14 differently substituted at the C-3 position.…”

“…No more occurrence of this scaffold appeared in the literature until our recent publication reporting a novel synthetic access to C-3 functionalized amidrazones either by thermal- or transition metal-assisted condensation reactions. 7 Our results were limited to only the synthesis of amidrazone derivatives featuring a phenyl group at the N 1 position of the heterocycle (Fig. 1a, R 2 = Ph).…”