135351-20-1Relevant articles and documents
Synthesis and [3,3]-sigmatropic rearrangements of 5-(pentafluorosulfanyl)-pent-3-en-2-ol, its homologues, and trifluoromethyl analogues
Haufe, Günter,Husstedt, Wibke S.,dudziński, piotr,matsnev, Andrej V.,thrasher, Joseph S.
, p. 5607 - 5623 (2021/07/02)
The synthesis of aliphatic (pentafluoro-λ6-sulfanyl)(SF5)-substituted compounds is more challenging than that of the related CF3-substituted analogues. Previous investigations of [3,3]-sigmatropic rearrangements of γ-SF5-substituted allylic alcohols failed to yield 3-SF5-substituted carboxylic acid derivatives. Herein, we present the synthesis of a series of 1-SF5-alk-1-en-3-ols and our efforts to apply them in Johnson-Claisen, ester enolate-Claisen, and Ireland-Claisen rearrangements. Unfortunately, these reactions failed to include the 1-SF5-substituted 1,2-double bond, although successful reactions of analogous CF3-allylic alcohols were reported. Further experiments revealed that bulkiness rather than electronic properties of the SF5group prevented [3,3]-sigmatropic rearrangements. Indeed, the introduction of a competing second vinyl group into the system (1-SF5-penta-1,4-dien-3-ol) confirmed that a Johnson-Claisen rearrangement was successful (92% yield of methyl 7-SF5-hepta-4,6-dienoate) with incorporation of the unsubstituted 4,5-double bond while the 1-SF5-substituted 1,2-double bond remained unchanged. Efforts to apply 1-(SF5CF2)-substituted 1,2-double bond systems, which are similar to CF3analogues in steric requirements, in Johnson-Claisen or ester enolate-Claisen rearrangements failed because of the instability of the SF5CF2substituent under various reaction conditions. On the other hand, when the SF5group was separated from the reaction center by a CH2group instead (5-SF5-pent-3-en-2-ol), Johnson-Claisen rearrangements using six orthoesters provided the target 2-substituted 3-(CH2SF5)-hex-4-enoates in 55-76% yields as ～1?:?1 mixtures of diastereomers. As an example to demonstrate the utility of these products, methyl 3-(CH2SF5)-hex-4-enoate was reduced, and the formed alcohol was oxidized to the aldehyde. Finally, initial experiments showed that the synthetic sequence developed for SF5compounds is also applicable for analogous CF3-substituted allylic alcohols (5-CF3-pent-3-en-2-ol) and their Johnson-Claisen rearrangement.
Convergent synthesis and cytotoxicity of novel trifluoromethyl-substituted (1H-pyrazol-1-yl)(quinolin-4-yl) methanones
Bonacorso, Helio G.,Nogara, Pablo A.,Silva, Fernanda D'A.,Rosa, Wilian C.,Wiethan, Carson W.,Zanatta, Nilo,Martins, Marcos A.P.,Rocha, Jo?o B.T.
, p. 31 - 40 (2016/09/02)
A convergent synthesis of a series of 16 new polysubstituted (5-hydroxy-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-1-yl)(quinolin-4-yl)methanones, starting from isatin and alky(aryl/heteroaryl) ketones, is described. The diheteroaryl methanones were achieved at yields of up to 95% by a [3?+?2] cyclocondensation reaction involving 4-alkyl(aryl/heteroaryl)-4-methoxy-1,1,1-trifluorobut-3-en-2-ones (by two-step reaction) and 2-alkyl(aryl/heteroaryl)-4-carbohydrazides (by three-step reaction). Subsequently, representative dehydrated heterocyclic derivatives were obtained from the respective 5-hydroxy-2-pyrazoline moieties by classical dehydration reactions, which resulted in the corresponding (5-(trifluoromethyl)-1H-pyrazol-1-yl)(quinolin-4-yl)methanones (three examples) at yields of 69–82%. The subsequent cytotoxicity evaluation showed that compounds with aromatic groups at the 2-position of the quinoline and a methyl moiety at the 3-position of the pyrazole have significant cytotoxicity in human leukocytes at high concentrations (200?μM).
Identification of N-acyl 4-(3-pyridonyl)phenylalanine derivatives and their orally active prodrug esters as dual acting α4β1 and α4β7 receptor antagonists
Tilley, Jefferson W.,Sidduri, Achyutharao,Lou, Jianping,Kaplan, Gerry,Tare, Nadine,Cavallo, Gary,Frank, Karl,Pamidimukkala, Anjula,Choi, Duk Soon,Gerber, Louise,Railkar, Aruna,Renzetti, Louis
, p. 1036 - 1040 (2013/03/13)
From a series of N-acyl 4-(3-pyridonyl)phenylalanine derivatives of 4, the trifluoromethyl derivative 28 was identified as a potent, dual acting alpha4 integrin antagonist with activity in primate models of allergic asthma. Investigation of a series of prodrug esters led to the discovery of the morpholinopropyl derivative 48 that demonstrated good intestinal fluid stability, solubility and permeability. Compound 48 gave high blood levels of 28 when dosed orally in cynomolgus monkeys. Surprisingly, hydrolysis of 48 was rapid in liver microsomes from the pharmacological species, mouse, rat and monkey, but slow in dog and human; in vivo studies also indicated there was prolonged exposure to unchanged prodrug in dogs.
