Scalable and Straightforward Synthesis of All Isomeric (Cyclo)alkylpiperidines

Subota, Andrii I.; Lutsenko, Anton O.; Vashchenko, Bohdan V.; Volochnyuk, Dmitriy M.; Levchenko, V. M.; Dmytriv, Yurii V.; Русанов, Эдуард Б.; Gorlova, Alina O.; Grygorenko, Oleksandr O.

doi:10.1002/ejoc.201900450

Cited by 11 publications

(10 citation statements)

References 65 publications

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“…First, we tested the lithiation of 1-methyl-3-(trifluoromethyl)-1 H -pyrazole leading to 3 -CF 3 - 5 -FG derivatives of type 12 . To develop the scale-up protocol, we studied the lithiation of compound 1a in a flow variant using our in-house developed flow systems . An in-house flow apparatus trim is shown in Figure .…”

Section: Resultsmentioning

confidence: 99%

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Practical Synthetic Method for Functionalized 1-Methyl-3/5-(trifluoromethyl)-1H-pyrazoles

Tairov

Levchenko

Stadniy

et al. 2020

Org. Process Res. Dev.

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A new, high-yielding, and practical method for synthesis of 1-methyl-3-(trifluoromethyl)-1H-pyrazole and 1-methyl-5-(trifluoromethyl)-1H-pyrazole, key intermediates for important building blocks relevant to medicinal and agrochemistry, is developed. A one-step procedure for synthesis of the regioisomeric mixture of target pyrazoles was proposed starting from 4-ethoxy-1,1,1-trifluoro-3-buten-2-one. The procedure for separation of this mixture was elaborated on the basis of the boiling point vs pressure diagram analysis. The efficient synthetic strategies for regioisomeric building blocks bearing CF3 groups at the 3rd and 5th positions were demonstrated. A set of 1-methyl-3-(trifluoromethyl)-1H-pyrazoles containing such a functional group as aldehyde, acid, boron pinacolate, lithium sulfinate, and sulfonyl chloride was synthesized based on lithiation of 1-methyl-3-(trifluoromethyl)-1H-pyrazole in a flow reactor. Bromination of both 1-methyl-3-(trifluoromethyl)-1H-pyrazole and 1-methyl-5-(trifluoromethyl)-1H-pyrazole by NBS in mild conditions was performed. The introduction of the functional group at the 4th position of 1-methyl-5-(trifluoromethyl)-1H-pyrazole was illustrated by the optimized synthesis of the corresponding aldehyde and acid based on the Br–Li exchange in an appropriate bromide. Alternatively, the introduction of the functional group (acid and boron pinacolate) at the 5th position of 1-methyl-5-(trifluoromethyl)-1H-pyrazole was performed based on the direct ortho-metalation (DoM) reaction of 4-bromo-1-methyl-5-(trifluoromethyl)pyrazole followed by catalytic reductive debromination.

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Section: Resultsmentioning

confidence: 99%

“…This atom was then removed by hydrogenation. We recently used a similar approach for the synthesis of pyridine derivatives …”

Section: Introductionmentioning

confidence: 99%

Practical Synthetic Method for Functionalized 1-Methyl-3/5-(trifluoromethyl)-1H-pyrazoles

Tairov

Levchenko

Stadniy

et al. 2020

Org. Process Res. Dev.

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“…13 1 H NMR (500 MHz, dimethyl sulfoxide (DMSO)-d 6 ) δ 8.64 (dd, J = 4.8, 2.0 Hz, 1H), 8.23 (dd, J = 7.9, 1.9 Hz, 1H), 7.25 (dd, J = 8.0, 4.9 Hz, 1H), 3.13 (t, J = 6.3 Hz, 2H), 2.66 (t, J = 6.5 Hz, 2H), 2.17 (p, J = 6.5 Hz, 2H). 13 (24). A solution of NaOH (8.80 g, 0.22 mol) in H 2 O (200 mL) was added to a stirred solution of ethyl 5,6,7,8-tetrahydroquinoline-6-carboxylate (30.0 g, 0.146 mol) in MeOH (300 mL).…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

Cu-Catalyzed Pyridine Synthesis via Oxidative Annulation of Cyclic Ketones with Propargylamine

et al. 2021

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A Cu-catalyzed, easily scalable one-pot synthesis of fused pyridines by the reaction of cyclic ketones with propargylamine is described. The protocol was optimized based on the results of more than 30 experiments. The highest product yields were achieved in i-PrOH as a solvent in the presence of 5.0 mol % CuCl 2 in air. In contrast to the wellknown Au-catalyzed protocol, our procedure is "laboratory friendly", costeffective, and suitable for preparing dozens of grams of fused pyridine-based building blocks and does not require a high-pressure autoclave technique. Decreasing the catalyst amount in the reaction to 1.25 mol % CuCl 2 provided a yield comparable to that achieved with 5 mol % catalyst, though a longer reaction time was required. A plausible reaction mechanism was proposed. The scope and limitation of the reaction were studied using 24 different cyclic ketones as starting materials. The fused pyridine yield decreased among cyclic ketones in the following order: six-membered ≫ eight-membered > five-membered ∼ seven-membered. The elaborated reaction conditions demonstrated tolerance to a number of protective functional groups in ketone such as ester, tertbutoxycarbonyl (Boc)-protected amine, and acetal moieties.

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“…This well‐established approach is convergent and powerful, but it is limited by the incompatibility of the organometallic reagents with many polar entities and by the difficulty of implementing such methods for the late‐stage modification of advanced candidates in medicinal chemistry programs. References [18–21] give academic examples of additions of pyridine derived organolithiums and Grignard reagents to cyclobutanones; many more can be found in the patent literature, reflecting the importance of such compounds for the pharmaceutical industry. We herein describe a radical based strategy that complements conventional ionic and organometallic methods and allows access to structures not readily available by more established approaches.…”

Section: Figurementioning

confidence: 99%

A Practical Route to Cyclobutanols and Fluorocyclobutanes

Revil-Baudard

Zard

2021

Helvetica Chimica Acta

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1‐[(Ethoxycarbonothioyl)sulfanyl]cyclobutyl acetate (xanthate 7) was found to add to electronically unbiased alkenes and to certain heteroarenes. In the latter case, this corresponds to a variant of the Minisci reaction and allows the late‐stage modification of biologically active substances. Saponification of the acetate furnishes the corresponding cyclobutanols, which, in the case of the nicotine adduct, can be converted into fluorocyclobutanes by the action of DAST. Fluorocyclobutyl substituted aromatics and heteroaromatics are increasingly present in drug candidates. Heating of the acetoxycyclobutyl derivative of caffeine with TFA gives rise to the cyclobutene analogue. Finally, O‐ethyl S‐[1‐(2,2,2‐trifluoroethoxy)cyclobutyl] carbonodithioate, obtained unexpectedly while optimizing the synthesis of xanthate 7, is a very promising reagent for the introduction of the very rare 2,2,2‐trifluoroethoxycyclobutyl motif.

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Scalable and Straightforward Synthesis of All Isomeric (Cyclo)alkylpiperidines

Cited by 11 publications

References 65 publications

Practical Synthetic Method for Functionalized 1-Methyl-3/5-(trifluoromethyl)-1H-pyrazoles

Practical Synthetic Method for Functionalized 1-Methyl-3/5-(trifluoromethyl)-1H-pyrazoles

Cu-Catalyzed Pyridine Synthesis via Oxidative Annulation of Cyclic Ketones with Propargylamine

A Practical Route to Cyclobutanols and Fluorocyclobutanes

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