Regioselectively Nucleus and/or Side-Chain Fluorinated 2-(Phenanthryl)propionic Acids by an Effective Combination of Radical and Organometallic Chemistry

Abstract

Regioselectively nucleus and/or side-chain fluorinated 2-(phenanthr-1-yl)- and 2-(phenanthr-2-yl)propionic acids 1-5 were prepared using phenanthren-1(2H)-ones 6a-c as key intermediates. Thus, ethyl 2-(fluorophenanthryl)propionates 11 were obtained in good yields by Reformatsky reaction of 6a-c with ethyl 2-bromopropionate followed by dehydratation and DDQ-promoted aromatization of the resulting beta-hydroxyesters. Side-chain alkyl 2-hydroxy-2-(phenanthr-1-yl)propionates 14 were obtained by bromine/lithium permutation of dihydrophenanthryl bromides 12a-c with butyllithium followed by quenching of the lithiated intermediates with methyl pyruvate or ethyl 3,3,3-trifluoropyruvate and subsequent DDQ-promoted aromatization. The alkyl 2-hydroxy-2-(phenanthr-1-yl)propionates 25 were prepared by reacting 8-bromo-1,3-difluorophenanthrene 24 with butyllithium for 10 seconds at -110 degrees C and subsequent addition of the suitable pyruvate to the lithiated intermediates. Alkyl 2-hydroxy-2-(phenanthr-2-yl)propionates 26 and 29 were suitably obtained by site-selective metalation of 1,3-difluorophenanthrene 28 and the bromophenanthrene 24, respectively, with LDA followed by quenching of the metalated intermediates with the suitable alkyl pyruvate. Fluorination of the above alpha-hydroxypropionates with DAST, followed by the alkaline hydrolysis, allowed the expected 2-(phenanthryl)propionic acids 1-5 to be obtained in satisfactory overall yields.

Design, Synthesis, and Biological Evaluation of a Series of Benzo[de][1,7]naphthyridin-7(8H)-ones Bearing a Functionalized Longer Chain Appendage as Novel PARP1 Inhibitors

“…Further, reduction of 41 with NaBH 4 provided alcohol 42 in 91% yield, which was then treated with DAST at 0 °C, afforded fluoride 43 in 73% yield (Scheme 5). 46 Reductive amination of 41 with NH 4 OAc and NaBH 3 CN under microwave irradiation (5 min, 130 °C) 47 yielded amine 44 in 72% yield.…”

“…Meanwhile, the precursor 34 used for Schmidt rearrangement was also treated with acid 25a led to amide 41 lacking the lactam function in 54% yield. Further, reduction of 41 with NaBH 4 provided alcohol 42 in 91% yield, which was then treated with DAST at 0 °C, afforded fluoride 43 in 73% yield (Scheme ) . Reductive amination of 41 with NH 4 OAc and NaBH 3 CN under microwave irradiation (5 min, 130 °C) yielded amine 44 in 72% yield.…”

Are carboxylic esters really refractory to DAST? On the fluorination of α-hydroxyesters with DAST

“…Therefore, since esters are refractory to this kind of fluorinating reagents, their conversion into a,a-difluoroalkyl/aryl ethers is made possible only after being transformed into the corresponding thioesters. In a previous research aimed at synthesizing some regioselectively fluorinated profens, we found that 2-aryl-2-fluoropropionic acid can be easily obtained from the corresponding 2-hydroxyesters by DAST-promoted OH/F permutation followed by alkaline hydrolysis of the resulting 2-fluoroester [22]. At the same time, we noticed that dialkyl 2-alkyl-2-fluoromalonates were prepared by exhaustive alcoholysis of hexafluoropropene followed by base-promoted alkylation of the resulting 2-fluoromalonates with alkyl halogenides [23] or, alternatively, by fluorination of dialkyl 2-alkylsodiomalonates with either Xenon difluoride [24] or electrophilic NF fluorinating reagents [25][26][27].…”

New Synthesis of 2‐Heteroarylperfluoropropionic Acids Derivatives by Reaction of Azine N‐Oxides with Hexafluoropropene

“…Their potentially interesting properties were first pointed out by Ricci and Ruzziconi, who elaborated a general approach to the synthesis of 2-phenanthryl-2-fluoropropionic and 2-phenanthrylperfluoropropionic esters and acids. [7] Apart from their contribution, there are currently no general methods to access 2-arylperfluoropropionic Abstract: Hexafluoropropene reacts with aromatic azine N-oxides under mild conditions to produce fluorides of 2-heteroarylperfluoropropionic acids. The reaction proceeds as 1,3-dipolar cycloaddition followed by spontaneous scission of the NÀO bond in the isoxazolidine ring and elimination of HF.…”