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20 pages, 1912 KiB

Open AccessArticle

Cu(I)- and Pd(0)-Catalyzed Arylation of Oxadiamines with Fluorinated Halogenobenzenes: Comparison of Efficiency

by Maria S. Lyakhovich, Alexei D. Averin, Olga K. Grigorova, Vitaly A. Roznyatovsky, Olga A. Maloshitskaya and Irina P. Beletskaya

Molecules 2020, 25(5), 1084; https://doi.org/10.3390/molecules25051084 - 28 Feb 2020

Cited by 6 | Viewed by 2171

Abstract

The comparison of the possibilities of Pd- and Cu-catalyzed amination reactions using fluorine-containing aryl bromides and iodides with oxadiamines to produce their N,N′-diaryl derivatives was carried out. The dependence of the reactivity of the aryl halides on the nature of the substituents [...] Read more.

The comparison of the possibilities of Pd- and Cu-catalyzed amination reactions using fluorine-containing aryl bromides and iodides with oxadiamines to produce their N,N′-diaryl derivatives was carried out. The dependence of the reactivity of the aryl halides on the nature of the substituents and halogen atoms as well as on the structure of oxadiamines was investigated. It was found that the copper-catalyzed reactions were somewhat comparable with the palladium-mediated processes in the majority of cases, especially in the reactions with para-fluorine- and para-(trifluoromethyl)-substituted aryl halides, although the necessity to use aryl iodides in the Cu(I)-catalyzed amination was obvious. Pd catalysis was found inevitable for the successful amination of more sterically hindered ortho-(trifluoromethyl)aryl bromides. Full article

(This article belongs to the Special Issue Fabulous Fluorine in Organic and Medicinal Chemistry)

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15 pages, 3487 KiB

Open AccessFeature PaperArticle

Studies of Halogen Bonding Induced by Pentafluorosulfanyl Aryl Iodides: A Potential Group of Halogen Bond Donors in a Rational Drug Design

by Yuji Sumii, Kenta Sasaki, Seiji Tsuzuki and Norio Shibata

Molecules 2019, 24(19), 3610; https://doi.org/10.3390/molecules24193610 - 07 Oct 2019

Cited by 11 | Viewed by 4054

Abstract

The activation of halogen bonding by the substitution of the pentafluoro-λ⁶-sulfanyl (SF₅) group was studied using a series of SF₅-substituted iodobenzenes. The simulated electrostatic potential values of SF₅-substituted iodobenzenes, the ab initio molecular orbital calculations [...] Read more.

The activation of halogen bonding by the substitution of the pentafluoro-λ⁶-sulfanyl (SF₅) group was studied using a series of SF₅-substituted iodobenzenes. The simulated electrostatic potential values of SF₅-substituted iodobenzenes, the ab initio molecular orbital calculations of intermolecular interactions of SF₅-substituted iodobenzenes with pyridine, and the ¹³C-NMR titration experiments of SF₅-substituted iodobenzenes in the presence of pyridine or tetra (n-butyl) ammonium chloride (TBAC) indicated the obvious activation of halogen bonding, although this was highly dependent on the position of SF₅-substitution on the benzene ring. It was found that 3,5-bis-SF₅-iodobenzene was the most effective halogen bond donor, followed by o-SF₅-substituted iodobenzene, while the m- and p-SF₅ substitutions did not activate the halogen bonding of iodobenzenes. The similar ortho-effect was also confirmed by studies using a series of nitro (NO₂)-substituted iodobenzenes. These observations are in good agreement with the corresponding Mulliken charge of iodine. The 2:1 halogen bonding complex of 3,5-bis-SF₅-iodobenzene and 1,4-diazabicyclo[2.2.2]octane (DABCO) was also confirmed. Since SF₅-containing compounds have emerged as promising novel pharmaceutical and agrochemical candidates, the 3,5-bis-SF₅-iodobenzene unit may be an attractive fragment of rational drug design capable of halogen bonding with biomolecules. Full article

(This article belongs to the Special Issue Fabulous Fluorine in Organic and Medicinal Chemistry)

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9 pages, 1007 KiB

Open AccessCommunication

Enantioselective 5-exo-Fluorocyclization of Ene-Oximes

by Taiki Rouno, Tomoki Niwa, Kousuke Nishibashi, Nobuharu Yamamoto, Hiromichi Egami and Yoshitaka Hamashima

Molecules 2019, 24(19), 3464; https://doi.org/10.3390/molecules24193464 - 24 Sep 2019

Cited by 22 | Viewed by 2772

Abstract

The enantioselective 5-exo-fluorocyclization of ene-oxime compounds was demonstrated under phase-transfer catalysis. Although deprotonative fluorinations competed, the chemical yields and the ee values of the desired isoxazoline products were generally moderate to good. The absolute stereochemistry of the major isomer was determined [...] Read more.

The enantioselective 5-exo-fluorocyclization of ene-oxime compounds was demonstrated under phase-transfer catalysis. Although deprotonative fluorinations competed, the chemical yields and the ee values of the desired isoxazoline products were generally moderate to good. The absolute stereochemistry of the major isomer was determined to be S by comparison with the literature after transformation of the product to the corresponding iodinated isoxazoline. Full article

(This article belongs to the Special Issue Fabulous Fluorine in Organic and Medicinal Chemistry)

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8 pages, 2709 KiB

Open AccessArticle

Effects of Water Addition on a Catalytic Fluorination of Dienamine

by Daiki Kuraoku, Tsunaki Yonamine, Genta Koja, Norio Yoshida, Satoru Arimitsu and Masahiro Higashi

Molecules 2019, 24(19), 3428; https://doi.org/10.3390/molecules24193428 - 21 Sep 2019

Cited by 5 | Viewed by 2392

Abstract

We investigate the effects of water addition on a highly stereocontrolled fluorination of dienamine generated by α-branched enals and 6′-hydroxy-9-amino-9-deoxy-epi-quinidine with N-fluorobenzenesulfonimide (NFSI) in the presence of Brønsted acid both experimentally and theoretically. It is experimentally found that water addition [...] Read more.

We investigate the effects of water addition on a highly stereocontrolled fluorination of dienamine generated by α-branched enals and 6′-hydroxy-9-amino-9-deoxy-epi-quinidine with N-fluorobenzenesulfonimide (NFSI) in the presence of Brønsted acid both experimentally and theoretically. It is experimentally found that water addition to organic solvent significantly shortens the reaction time whereas excessive water addition decreases the enantiomeric excess. The results calculated with three-dimensional reference interaction site model self-consistent field (3D-RISM-SCF) method are in good agreement with the experimental ones. It is revealed that the shortness of reaction time is caused by the reactant destabilization and that the decrease in enantiomeric excess is due to the difference of hydration free energy between two transition states. Full article

(This article belongs to the Special Issue Fabulous Fluorine in Organic and Medicinal Chemistry)

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21 pages, 5057 KiB

Open AccessArticle

Synthesis and Biological Evaluation of Disubstituted Pyrimidines as Selective 5-HT_2C Agonists

by Juhyeon Kim, Yoon Jung Kim, Ashwini M. Londhe, Ae Nim Pae, Hyunah Choo, Hak Joong Kim and Sun-Joon Min

Molecules 2019, 24(18), 3234; https://doi.org/10.3390/molecules24183234 - 05 Sep 2019

Cited by 3 | Viewed by 2803

Abstract

Here, we describe the synthesis of disubstituted pyrimidine derivatives and their biological evaluation as selective 5-HT_2C agonists. To improve selectivity for 5-HT_2C over other subtypes, we synthesized two series of disubstituted pyrimidines with fluorophenylalkoxy groups at either the 5-position or 4-position [...] Read more.

Here, we describe the synthesis of disubstituted pyrimidine derivatives and their biological evaluation as selective 5-HT_2C agonists. To improve selectivity for 5-HT_2C over other subtypes, we synthesized two series of disubstituted pyrimidines with fluorophenylalkoxy groups at either the 5-position or 4-position and varying cyclic amines at the 2-position. The in vitro cell-based assay and binding assay identified compounds 10a and 10f as potent 5-HT_2C agonists. Further studies on selectivity to 5-HT subtypes and drug-like properties indicated that 2,4-disubstituted pyrimidine 10a showed a highly agonistic effect on the 5-HT_2C receptor, with excellent selectivity, as well as exceptional drug-like properties, including high plasma and microsomal stability, along with low CYP inhibition. Thus, pyrimidine 10a could be considered a viable lead compound as a 5-HT_2C selective agonist. Full article

(This article belongs to the Special Issue Fabulous Fluorine in Organic and Medicinal Chemistry)

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14 pages, 2207 KiB

Open AccessArticle

Enantioselective Benzylation and Allylation of α-Trifluoromethoxy Indanones under Phase-Transfer Catalysis

by Yumeng Liang, Mayaka Maeno, Zhengyu Zhao and Norio Shibata

Molecules 2019, 24(15), 2774; https://doi.org/10.3390/molecules24152774 - 30 Jul 2019

Cited by 6 | Viewed by 3355

Abstract

The organo-catalyzed enantioselective benzylation reaction of α-trifluoromethoxy indanones afforded α-benzyl-α-trifluoromethoxy indanones with a tetrasubstituted stereogenic carbon center in excellent yield with moderate enantioselectivity (up to 57% ee). Cinchona alkaloid-based chiral phase transfer catalysts were found to be effective for this transformation, and both [...] Read more.

The organo-catalyzed enantioselective benzylation reaction of α-trifluoromethoxy indanones afforded α-benzyl-α-trifluoromethoxy indanones with a tetrasubstituted stereogenic carbon center in excellent yield with moderate enantioselectivity (up to 57% ee). Cinchona alkaloid-based chiral phase transfer catalysts were found to be effective for this transformation, and both enantiomers of α-benzyl-α-trifluoromethoxy indanones were accessed, depended on the use of cinchonidine and cinchonine-derived catalyst. The method was extended to the enantioselective allylation reaction of α-trifluoromethoxy indanones to give the allylation products in moderate yield with good enantioselectivity (up to 76% ee). Full article

(This article belongs to the Special Issue Fabulous Fluorine in Organic and Medicinal Chemistry)

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14 pages, 1709 KiB

Open AccessCommunication

Amine-Catalyzed Decarboxylative Aldol Reaction of β-Ketocarboxylic Acids with Trifluoropyruvates

by Ryouta Kawanishi, Shinya Hattori, Seiji Iwasa and Kazutaka Shibatomi

Molecules 2019, 24(15), 2773; https://doi.org/10.3390/molecules24152773 - 30 Jul 2019

Cited by 4 | Viewed by 4326

Abstract

Decarboxylative aldol reaction of aliphatic carboxylic acids is a useful method for C–C bond formation because carboxylic acids are an easily available class of compounds. In this study, we found that the decarboxylative aldol reaction of tertiary β-ketocarboxylic acids and trifluoropyruvates proceeded smoothly [...] Read more.

Decarboxylative aldol reaction of aliphatic carboxylic acids is a useful method for C–C bond formation because carboxylic acids are an easily available class of compounds. In this study, we found that the decarboxylative aldol reaction of tertiary β-ketocarboxylic acids and trifluoropyruvates proceeded smoothly to yield the corresponding aldol products in high yields and with high diastereoselectivity in the presence of a tertiary amine catalyst. In this reaction, we efficiently constructed a quaternary carbon center and an adjacent trifluoromethylated carbon center. This protocol was also extended to an enantioselective reaction with a chiral amine catalyst, and the desired product was obtained with up to 73% enantioselectivity. Full article

(This article belongs to the Special Issue Fabulous Fluorine in Organic and Medicinal Chemistry)

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9 pages, 1134 KiB

Open AccessFeature PaperArticle

Copper-Catalyzed Regioselective Synthesis of (E)-β-Fluorovinyl Sulfones

by Raquel Román, Pablo Barrio, Natalia Mateu, Daniel M. Sedgwick and Santos Fustero

Molecules 2019, 24(8), 1569; https://doi.org/10.3390/molecules24081569 - 20 Apr 2019

Cited by 2 | Viewed by 3233

Abstract

Organofluorine compounds are finding increasing application in a variety of fields such as pharmaceutical, agrochemical, and material sciences. However, given the scarcity of fluorine-containing natural products, advancement in this area depends almost entirely on the development of new synthetic methodologies. In this article, [...] Read more.

Organofluorine compounds are finding increasing application in a variety of fields such as pharmaceutical, agrochemical, and material sciences. However, given the scarcity of fluorine-containing natural products, advancement in this area depends almost entirely on the development of new synthetic methodologies. In this article, we present the synthesis of a series of previously undescribed (E)-β-fluorovinyl sulfones via a simple copper-catalyzed addition of hydrogen fluoride to alkynyl sulfone starting materials in varying yields and E/Z selectivities. The hydrogenation of these products was also explored and compared with the hydrogenation of the related Z isomers. These new products may find interesting applications, given the versatility of vinyl sulfones in chemical synthesis and the unique properties of vinyl fluorides in biological settings. Full article

(This article belongs to the Special Issue Fabulous Fluorine in Organic and Medicinal Chemistry)

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12 pages, 17018 KiB

Open AccessArticle

General, Practical and Selective Oxidation Protocol for CF₃S into CF₃S(O) Group

by Liubov V. Sokolenko, Raisa K. Orlova, Andrey A. Filatov, Yurii L. Yagupolskii, Emmanuel Magnier, Bruce Pégot and Patrick Diter

Molecules 2019, 24(7), 1249; https://doi.org/10.3390/molecules24071249 - 30 Mar 2019

Cited by 12 | Viewed by 3663

Abstract

A simple and efficient protocol for the oxidation of trifluoromethyl, mono- and difluoromethyl sulfides to the corresponding sulfoxides without over-oxidation to sulfones, using TFPAA prepared in situ from trifluoroacetic acid and 15% H₂O₂ aqueous solution was developed. The methodology is [...] Read more.

A simple and efficient protocol for the oxidation of trifluoromethyl, mono- and difluoromethyl sulfides to the corresponding sulfoxides without over-oxidation to sulfones, using TFPAA prepared in situ from trifluoroacetic acid and 15% H₂O₂ aqueous solution was developed. The methodology is suitable for a wide range of aromatic and aliphatic substrates in milligram and multigram scales. Full article

(This article belongs to the Special Issue Fabulous Fluorine in Organic and Medicinal Chemistry)

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11 pages, 1131 KiB

Open AccessArticle

Asymmetric Electrophilic Difluoromethylthiolation of Indanone-Based β-Keto Esters Using Difluoromethanesulfonyl Hypervalent Iodonium Ylides

by Satoshi Gondo, Okiya Matsubara, Hélène Chachignon, Yuji Sumii, Dominique Cahard and Norio Shibata

Molecules 2019, 24(2), 221; https://doi.org/10.3390/molecules24020221 - 09 Jan 2019

Cited by 8 | Viewed by 3538

Abstract

The first electrophilic diastereoselective direct introduction of the difluoromethylthio group is described. We used a chiral auxiliary-based approach to illustrate the versatility of our recently developed difluoromethanesulfonyl hypervalent iodonium ylide reagents for the difluoromethylthiolation of indanone-based β-keto esters. Chiral SCF₂H-featuring compounds [...] Read more.

The first electrophilic diastereoselective direct introduction of the difluoromethylthio group is described. We used a chiral auxiliary-based approach to illustrate the versatility of our recently developed difluoromethanesulfonyl hypervalent iodonium ylide reagents for the difluoromethylthiolation of indanone-based β-keto esters. Chiral SCF₂H-featuring compounds were obtained in up to 93% ee value. Full article

(This article belongs to the Special Issue Fabulous Fluorine in Organic and Medicinal Chemistry)

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8 pages, 1309 KiB

Open AccessBrief Report

Copper-Promoted Cross-Coupling Reactions for the Synthesis of Aryl(difluoromethyl)phosphonates Using Trimethylsilyl(difluoromethyl)phosphonate

by Kazuki Komoda, Rei Iwamoto, Masakazu Kasumi and Hideki Amii

Molecules 2018, 23(12), 3292; https://doi.org/10.3390/molecules23123292 - 11 Dec 2018

Cited by 12 | Viewed by 3093

Abstract

A convenient and effective route for the synthesis of aryl(difluoromethyl)phosphonates has been developed based on cross-coupling reactions. Upon treatment with a stoichiometric amount (or a catalytic amount in some cases) of CuI and CsF, aryl iodides reacted smoothly with (silyldifluoromethyl)phosphonates to give the [...] Read more.

A convenient and effective route for the synthesis of aryl(difluoromethyl)phosphonates has been developed based on cross-coupling reactions. Upon treatment with a stoichiometric amount (or a catalytic amount in some cases) of CuI and CsF, aryl iodides reacted smoothly with (silyldifluoromethyl)phosphonates to give the corresponding aryl(difluoromethyl)phosphonates in good yields. Full article

(This article belongs to the Special Issue Fabulous Fluorine in Organic and Medicinal Chemistry)

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