From Renewable Levulinic Acid to a Diversity of 3‐(Azol‐3‐yl)Propanoates

Abstract

Efficient heterocyclization of methyl 7,7,7‐trifluoro‐4‐methoxy‐6‐oxo‐4‐heptenoate and methyl 7,7,7‐trichloro‐4‐methoxy‐6‐oxo‐4‐heptenoate into isoxazole and pyrazole derivatives that represent a new type of glutamate‐like 3‐(trihalomethylated‐1,2‐azol‐3‐yl)propanoate is reported. Preparation of the key methyl 7,7,7‐trihalo‐4‐methoxy‐6‐oxohept‐4‐enoate precursors from levulinic acid is also described. The synthetic potential of this synthetic protocol was indicated by the production of several methyl and ethyl 3‐(isoxazol‐3‐yl)propanoates and 3‐(1H‐pyrazol‐3‐yl)propanoates, and the respective acid derivatives, in good (70–95%) yields. The crystal structure for ethyl 5‐(3‐ethoxy‐3‐oxopropyl)‐1H‐pyrazole‐3‐carboxylate (10c) has been determined by monocrystal X‐ray diffraction analysis. The N–H…H intermolecular hydrogen bonds join the molecules into catamer.

Strategies for the Efficient Synthesis of Biheterocyclic 5-[2-(Trifluoromethylheteroaryl)-ethyl]-1,3,4-oxadiazoles from Levulinic Acid

“…19 Following the conventional route to CF 3 -containing 1H-pyrazole, the reaction of hydrazine hydrochloride with 1 in ethanol proceeded to give nearly quantitative yields of methyl 3-(5-trifluoromethyl-1H-pyrazol-3-yl)propanoate (2a). 16 For cyclocondensations between precursor 1 and amidine salts (hydrochloride or sulfate), we started the process based on a previous report on cyclocondensation [3 + 3] of 1,1,1-trifluoro-4-alkoxy-3-alken-2-ones and amidines under basic NaOH or alkoxy (methoxy, ethoxy) catalysis. 18 Initially, the cyclocondensation between 1 and 2-methyl-2-thiopseudourea sulfate was carried out in methanol via catalysis with 1 M NaOH aqueous solution at 25 °C for 1 h. This led to a good yield of 66% for pure methyl 3-(2-thiomethyl-6-trifluoromethylpyrimidin-4-yl) propanoate (2c).…”

“…This substrate has three electrophilic centers allowing its use in [4 + 1], [3 + 2], and [3 + 3] cyclocondensation processes, as shown in Scheme 1. [14][15][16][17][18] Our ongoing interest in producing and understanding the biological activities of halogenated heterocyclic systems led us to study strategies for synthesizing a diversity of biheterocyclic systems, such as 5-[2-(trifluoromethylheteroaryl)-ethyl]-1,3,4-oxadiazoles (4)(5)(6)(7), with an ethylene spacer between heterocyclic nuclei, from methyl 3-(trifluoromethylheteroaryl)propanoates, where trifluoromethylheteroaryl is 5(3)-trifluoromethyl-1H-pyrazol-3(5)-yl, 2-phenyl-6-trifluoromethyl pyrimidin-4-yl, Vol. 28, No.…”

From Levulinic Acid to Biheterocycles: Synthesis of 1-[(5-Hydroxy-5-trifluoromethyl-3-substituted-4,5-dihydro-1H-pyrazol-1-yl)-3-(5-trifluoromethyl-1H-pyrazol-3-yl)propan-1-ones

“…[16] The 1 H NMR spectra for biheterocyclic derivatives 4a-k displayed signals related to two methylenes from the propionyl chain and diastereotopic H-4 from the pyrazole ring overlapping at about d 2.9 to 3.4 ppm. The signal related to methylenes from the propionyl chain consisted of two triplets (multiplets) or an enlarged singlet.…”

“…This approach uses the versatility of the trifluoromethyl-substituted 1,3-dielectrophilic moiety for heterocycle diversification in the 3-position of the propanoic chain and the possibility of transforming the methyl ester into hydrazide; then, these new dinucleophiles are cyclocondensed with a wide range of 1,1,1-trifluoro-4-alkoxy-3-alken-2-ones (1) (Scheme 1). [14,15] In this work, we examined the synthesis of methyl (5-trifluoromethyl-1H-pyrazol-3-yl) propanoate from cyclocondensation of methyl 7,7,7-trifluoro-4-methoxy-6-oxo-4-heptenoate (1h) with hydrazine hydrochloride [16] and its conversion into the respective hydrazide derivative. We also performed cyclocondensation between propionylhydrazide derivative (3) and 1,1,1-trifluoro-4-methoxy-3-alken-2-ones (1a-k) to produce a new series of derivatives:…”

Ultrasound-Promoted Synthesis of 3-(Thiophen-2-yl)-4,5-dihydro-1H-pyrazole-1-carboximidamides and Anticancer Activity Evaluation in Leukemia Cell Lines

“…Thus, in our continuous efforts to develop sonochemically promoted reactions in environmentally benign solvents 19 and synthetic methodologies for preparation of heterocyclic compounds 20 selected on the basis of their biological activity, 21 we describe herein a rapid and efficient synthetic method for the preparation of 3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazole-1-carboximidamide hydrochlorides under ultrasonic conditions. In addition, all compounds synthetized were evaluated against the human Jurkat and RS4;11 acute lymphoblastic leukemia cell lines of T-and B-cell origin, respectively, and the K562 myelogenous leukemia cell line.…”