One-Pot Highly Regioselective Synthesis of α-Ketoamide N-Arylpyrazoles from Secondary β-Enamino Diketones

Abstract

An efficient one-pot method is described for the highly regioselective synthesis of α-ketoamide N-arylpyrazoles from secondary β-enamino diketones. For this, the key intermediate, 4-acyl 3,5-dihydroxypyrrolone, was generated in situ and underwent bimolecular nucleophilic substitution at C-5 by arylhydrazine, with subsequent heterocyclization at the carbonyl carbon of the acyl group. This strategy allowed for regiochemical control of α-ketoamide N-arylpyrazoles from β-enamino diketones and arylhydrazines.

Regiodivergent Synthesis of 3,4- and 4,5-Disubstituted N-Methylpyrazoles from 4-Acyl-1H-pyrrole-2,3-dione and Methylhydrazine

“…As shown in Table , both methodologies previously reported by us afforded a mixture of three regioisomers (A, B, and C) with poor regioselectivity (Table , entries 1 and 2). Then, we further explored the reactivity of the 4-acyl-1 H -pyrrole-2,3-dione Ia , which was generated in situ from BED 2a . Gratifyingly, the reaction gave only one product which was characterized as 4,5-disubstituted N -methylpyrazole 4a on the basis of HSQC and HMBC experiments.…”

The Wonderful World of β‐Enamino Diketones Chemistry

“…A very interesting approach to the regioselective synthesis of α‐ketoamide N ‐arylpyrazoles has recently been reported (Scheme 13). [ 56 ] The reaction is based upon the transformation of starting β‐enamino diketones 3 into their corresponding secondary β‐enamino diketones 31 , which, under DBU action (in CH 2 Cl 2 , at r. t., for 3 min), furnish the lactam 32 , which, in turn, undergoes 1,4‐addition of OH – , to finally furnish the 4‐acyl‐3,5‐dihydroxypyrrolone 33 – a great advance in the synthesis of 5‐hydroxypyrrolidin‐2‐ones (Scheme 13). [ 57 ] Compound 33 was treated with phenylhydrazine in CH 2 Cl 2 at r. t. for 40 min, which furnished pyrazole 34 at 87 % yield.…”

“…To overcome this, p ‐toluenesulfonic acid (PTSA) was added, and pyrazoles 34 were subsequently obtained at yields of 60–90 % (Scheme 13). [ 56 ]…”

“…A plausible mechanism for this interesting transformation was proposed by the authors. [ 56 ] It is based upon the nucleophilic substitution with phenylhydrazine at the C5 of 33 , [ 58 ] followed by heterocyclization at the adjacent carbonyl, thus furnishing a fused intermediate (pyrrolo‐pyrazole), which undergoes ring opening (pyrrole) to furnish the aromatic pyrazoles 34 .…”

Divergent and Regioselective Synthesis of (Trifluoromethyl/carboxyethyl)benzo[4,5]imidazo[1,2‐a]pyrimidines from β‐Enamino Diketones

“…[ 18 ] To overcome the selectivity issue, β‐enamino diketones (see Scheme 1) have emerged as suitable starting materials for the synthesis of several heterocyclic scaffolds, due to presenting high selectivity in most of the cyclocondensation reactions performed. [ 19–21 ] Even though the chemistry of carboxyethyl β‐enamino diketones 1 has been explored, [ 22–29 ] trifluoromethyl 2 ones have been far less used in heterocyclic synthesis. [ 21,30–34 ] Thus, this work aims to study the cyclocondensation reaction between β‐enamino diketones ( CCC building blocks) and 2‐aminobenzimidazole ( NCN ‐dinucleophile), observing the regioselectivity of the obtained products.…”