Synthesis and Cyclization Reaction of Pyrazolin-5-one Derivatives

Abstract

A versatile synthetic method for preparing 3-pyrazolin-5-ones and 5,8dihydro-1H-pyrazolo[1,2-a]pyridazines from simple β-keto esters is demonstrated.The synthetic strategies involve the acylation of β-keto esters, cyclocondensation with hydrazine followed by trapping with a diene under oxidative conditions. RESULTS AND DISCUSSIONThe necessary α-acylated esters (3a-n) could easily be obtained, in high yields, by treatment of ethyl acetoacetate (1a), ethyl cyanoacetate (1b) or diethyl malonate (1c) with the appropriate acyl chlorides (2) in the presence of magnesium/ethanol in anhydrous toluene (Table 1).Table 1.Acylation of ethyl acetoacetate (1a), ethyl cyanoacetate (1b) and diethyl malonate (1c).Entry Compound R 1 R 2 Yield (%) a Products (K/E) b 1 1a COMe Me 91 3a 12a (nd) c 2 COMe (CH 2 ) 4 CH 3 98 3b 12b (nd) 3 COMe Bz 94 3c 12c (nd) 4 1b CN Me 90 3d 12d (0/100) 5 CN c-C 3 H 5 84 3e (nd) 6 CN c-C 5 H 9 81 3f (nd) 7 CN 2-Thienyl 86 3g 12e (0/100) 8 CN Ph 88 3h 12d (0/100) 9 CN 4-MeOC 6 H 4 85 3i 12f (0/100) 10 1c CO 2 Et Me 82 3j 12g (29/71) 11 CO 2 Et Et 88 3k h (50/50) 12 CO 2 Et (CH 2 ) 4 CH 3 87 3l 12i (39/61) 13 CO 2 Et (CH 2 ) 8 CH 3 89 3m 12j (37/63) 14 CO 2 Et CH 2 -Bz 84 3n 12k (42/58) aIsolated yields: in the case of ethyl cyanoacetate (Entries 4-9), the yields were calculated based on recovered starting material.b Keto-enol ratios based on integration of 1 H-NMR.c nd=not determined.The α-acylated ethyl acetoacetates were ring cyclized by treatment with hydrazine (80%) in ethanol;while the α-acylated diethyl malonates were treated with hydrazine (pH 7), 13 hydrazine (55%) in acetic acid or hydrazine monohydrochloride to give the desired pyrazolin-5-ones in good yields.We have shown previously that, in general, under these conditions ring cyclization proceeds smoothly for those α-acylated esters or diesters that exist primarily in the enol form.Compounds with aromatic substituents that exist predominately in the keto form rapidly undergo β-cleavage (retro aldol) to give either low yield or no yield of the desired pyrazolin-5-one.On the other hand, ethyl cyanoacetate (1b) underwent acylation with several acyl chlorides to afford α-acylated products, which exist completely in the enol form (Table 1, Entries 4 and7-9). 14