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21 pages, 2101 KiB

Open AccessArticle

Straightforward Superbase-Mediated Reductive O-Phosphorylation of Aromatic and Heteroaromatic Ketones with Red Phosphorus in the Superbase Suspension KOH/DMSO(H₂O)

by Vladimir A. Kuimov, Svetlana F. Malysheva, Natalia A. Belogorlova, Ruslan I. Fattakhov, Alexander I. Albanov, Irina Yu. Bagryanskaya, Nikolay I. Tikhonov and Boris A. Trofimov

Molecules 2025, 30(6), 1367; https://doi.org/10.3390/molecules30061367 - 18 Mar 2025

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Abstract

It was shown for the first time that diaryl(hetaryl)ketones are capable of directly phosphorylating with red phosphorus in the superbase suspension KOH/DMSO(H₂O) at 85 °C for 1.5 h to afford potassium bis(diaryl(hetaryl)methyl)phosphates that were earlier inaccessible in a yield of up [...] Read more.

It was shown for the first time that diaryl(hetaryl)ketones are capable of directly phosphorylating with red phosphorus in the superbase suspension KOH/DMSO(H₂O) at 85 °C for 1.5 h to afford potassium bis(diaryl(hetaryl)methyl)phosphates that were earlier inaccessible in a yield of up to 45%. The ESR data demonstrate that unlike previously published phosphorylation with elemental phosphorus, this new phosphorylation reaction proceeds via a single electron transfer from polyphospide anions to diaryl(hetaryl)ketones. This is the first example of the C-O-P bond generation during the phosphorylation with elemental phosphorus in strongly basic media, which usually provides C-P bond formation. Full article

(This article belongs to the Special Issue Exclusive Contributions by the Editorial Board Members (EBMs) of the Organic Chemistry Section of Molecules)

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24 pages, 2465 KiB

Open AccessArticle

Enantiopure Turbo Chirality Targets in Tri-Propeller Blades: Design, Asymmetric Synthesis, and Computational Analysis

by Yu Wang, Ting Xu, Ankit Pandey, Shengzhou Jin, Jasmine X. Yan, Qingkai Yuan, Sai Zhang, Jia-Yin Wang, Ruibin Liang and Guigen Li

Molecules 2025, 30(3), 603; https://doi.org/10.3390/molecules30030603 - 29 Jan 2025

Viewed by 663

Abstract

Enantiopure turbo chirality in small organic molecules, without other chiral elements, is a fascinating topic that has garnered significant interest within the chemical and materials science community. However, further research into and application of this concept have been severely limited by the lack [...] Read more.

Enantiopure turbo chirality in small organic molecules, without other chiral elements, is a fascinating topic that has garnered significant interest within the chemical and materials science community. However, further research into and application of this concept have been severely limited by the lack of effective asymmetric tools. To date, only a few enantiomers of turbo chiral targets have been isolated, and these were obtained through physical separation using chiral HPLC, typically on milligram scales. In this work, we report the first asymmetric approach to enantiopure turbo chirality in the absence of other chiral elements such as central and axial chirality. This is demonstrated by assembling aromatic phosphine oxides, where three propeller-like groups are anchored to a P(O) center via three axes. Asymmetric induction was successfully carried out using a chiral sulfonimine auxiliary, with absolute configurations and conformations unambiguously determined by X-ray diffraction analysis. The resulting turbo frameworks exhibit three propellers arranged in either a clockwise (P,P,P) or counterclockwise (M,M,M) configuration. In these arrangements, the bulkier sides of the aromatic rings are oriented toward the oxygen atom of the P=O bond rather than in the opposite direction. Additionally, the orientational configuration is controlled by the sulfonimine auxiliary as well, showing that one of the Naph rings is pushed away from the auxiliary group (-CH₂-NHSO₂-tBu) of the phenyl ring. Computational studies were conducted on relative energies for the rotational barriers of a turbo target along the P=O axis and the transition pathway between two enantiomers, meeting our expectations. This work is expected to have a significant impact on the fields of chemistry, biomedicine, and materials science in the future. Full article

(This article belongs to the Special Issue Exclusive Contributions by the Editorial Board Members (EBMs) of the Organic Chemistry Section of Molecules)

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13 pages, 926 KiB

Open AccessArticle

Synthesis of Alkyl α-Amino-benzylphosphinates by the Aza-Pudovik Reaction; The Preparation of the Butyl Phenyl-H-phosphinate Starting P-Reagent

by Bence Bajusz, Dorka Nagy, Regina Tóth, Zsuzsanna Szalai, Ágnes Gömöry, Angéla Takács, László Kőhidai and György Keglevich

Molecules 2025, 30(2), 339; https://doi.org/10.3390/molecules30020339 - 16 Jan 2025

Viewed by 701

Abstract

Butyl phenyl-H-phosphinate that is not available commercially was prepared from phenyl-H-phosphinic acid by three methods: by alkylating esterification (i), by microwave-assisted direct esterification (ii), and unexpectedly, by thermal esterification (iii). Considering the green aspects, selectivity and scalability, the thermal [...] Read more.

Butyl phenyl-H-phosphinate that is not available commercially was prepared from phenyl-H-phosphinic acid by three methods: by alkylating esterification (i), by microwave-assisted direct esterification (ii), and unexpectedly, by thermal esterification (iii). Considering the green aspects, selectivity and scalability, the thermal variation seemed to be optimal. However, there was need for prolonged heating. The butyl phenyl-H-phosphinate, along with the ethyl analogue, was utilized in the synthesis of alkyl (α-alkylamino-arylmethyl-)phenyl phosphinates in the aza-Pudovik reaction with imines obtained from primary amines and substituted benzaldehydes. The aminophosphinates were obtained as diastereomeric mixtures in 65–92% yields. The aza-Pudovik approach was more efficient than the Kabachnik–Fields condensation. Interestingly, one aminophosphinate, the butyl (α-butylamino-benzyl-)phenylphosphinate, was of significant cytotoxic activity on the PANC-1 pancreas cell line. Another derivative, ethyl (α-benzylamino-benzyl-)phenylphosphinate, revealed a selective toxic activity on U266 myeloma cells. Full article

(This article belongs to the Special Issue Exclusive Contributions by the Editorial Board Members (EBMs) of the Organic Chemistry Section of Molecules)

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20 pages, 976 KiB

Open AccessArticle

Benzo[d]oxazoles from Anilides by N-Deprotonation–O-S_NAr Cyclization

by Nash E. Nevels, Luke Subera and Richard A. Bunce

Molecules 2024, 29(18), 4322; https://doi.org/10.3390/molecules29184322 - 12 Sep 2024

Viewed by 932

Abstract

A synthesis of benzo[d]oxazoles by an N-deprotonation–O-S_NAr cyclization sequence from anilide precursors is reported. Anilides derived from 2-fluorobenzaldehydes, activated toward S_NAr ring closure by C5 electron-withdrawing groups, were prepared and subjected to deprotonation–cyclization using [...] Read more.

A synthesis of benzo[d]oxazoles by an N-deprotonation–O-S_NAr cyclization sequence from anilide precursors is reported. Anilides derived from 2-fluorobenzaldehydes, activated toward S_NAr ring closure by C5 electron-withdrawing groups, were prepared and subjected to deprotonation–cyclization using 2 equiv. of K₂CO₃ in anhydrous DMF. Following deprotonation at nitrogen, the delocalized anion cyclized from the amide oxygen to give high yields of benzo[d]oxazoles. The temperature required for the cyclization of benzanilides correlated with the potency of the C5 activating group on the S_NAr acceptor ring with nitro (most potent) reacting at 90 °C (1 h), cyano reacting at 115 °C (1 h), methoxycarbonyl reacting at 120 °C (2 h), and trifluoromethyl (least potent) reacting at 130 °C (3 h). Acetanilides were more difficult to cyclize but generally required 4–6 h at these same temperatures for completion. Product purification was accomplished by recrystallization or chromatography. Full article

(This article belongs to the Special Issue Exclusive Contributions by the Editorial Board Members (EBMs) of the Organic Chemistry Section of Molecules)

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14 pages, 4895 KiB

Open AccessArticle

Deep-Cavity Calix[4]naphth[4]arene Macrocycles: Synthesis, Conformational Features, and Solid-State Structures

by Paolo Della Sala, Veronica Iuliano, Margherita De Rosa, Carmen Talotta, Rocco Del Regno, Placido Neri, Silvano Geremia, Neal Hickey and Carmine Gaeta

Molecules 2024, 29(17), 4142; https://doi.org/10.3390/molecules29174142 - 31 Aug 2024

Cited by 2 | Viewed by 1575

Abstract

We recently introduced calix[n]naphth[m]arenes as a novel class of deep-cavity hybrid macrocycles constituted by phenol (n) and naphthalene (m) units. In this study, we report the synthesis, conformational analysis, spectroscopic properties, and solid-state structures of calix[4]naphth[4]arene (C₄ [...] Read more.

We recently introduced calix[n]naphth[m]arenes as a novel class of deep-cavity hybrid macrocycles constituted by phenol (n) and naphthalene (m) units. In this study, we report the synthesis, conformational analysis, spectroscopic properties, and solid-state structures of calix[4]naphth[4]arene (C₄N₄) and its permethylated analog (C₄N₄-Me), thereby expanding the calix[n]naphth[m]arene family. C₄N₄ was synthesized through a 2 + 2 fragment coupling macrocyclization under acidic conditions, where the solvent played a crucial role in selectively forming the C₄N₄ derivative. The X-ray structure of C₄N₄ reveals a chair-like 1,2,3,4-alternate conformation characterized by two opposing 3/4-cone moieties stabilized by intramolecular hydrogen bonds. In contrast, the X-ray structure of C₄N₄-Me exhibits a 1,3,5,7-alternate conformation. Full article

(This article belongs to the Special Issue Exclusive Contributions by the Editorial Board Members (EBMs) of the Organic Chemistry Section of Molecules)

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15 pages, 1636 KiB

Open AccessArticle

Selective Oxidation of Benzo[d]isothiazol-3(2H)-Ones Enabled by Selectfluor

by Qin Li, Dan Yuan, Chong Liu, Faith Herington, Ke Yang and Haibo Ge

Molecules 2024, 29(16), 3899; https://doi.org/10.3390/molecules29163899 - 17 Aug 2024

Viewed by 1038

Abstract

A metal-free and Selectfluor-mediated selective oxidation reaction of benzo[d]isothiazol-3(2H)-ones in aqueous media is presented. This novel strategy provides a facile, green, and efficient approach to access important benzo[d]isothiazol-3(2H)-one-1-oxides with excellent yields and high tolerance to [...] Read more.

A metal-free and Selectfluor-mediated selective oxidation reaction of benzo[d]isothiazol-3(2H)-ones in aqueous media is presented. This novel strategy provides a facile, green, and efficient approach to access important benzo[d]isothiazol-3(2H)-one-1-oxides with excellent yields and high tolerance to various functional groups. Furthermore, the purification of benzoisothiazol-3-one-1-oxides does not rely on column chromatography. Moreover, the preparation of saccharine derivatives has been achieved through sequential, double oxidation reactions in a one-pot aqueous media. Full article

(This article belongs to the Special Issue Exclusive Contributions by the Editorial Board Members (EBMs) of the Organic Chemistry Section of Molecules)

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17 pages, 6715 KiB

Open AccessArticle

A [3+3] Aldol-S_NAr-Dehydration Approach to 2-Naphthol and 7-Hydroxyquinoline Derivatives

by Kwabena Fobi, Ebenezer Ametsetor and Richard A. Bunce

Molecules 2024, 29(14), 3406; https://doi.org/10.3390/molecules29143406 - 20 Jul 2024

Viewed by 1031

Abstract

A one-pot [3+3] aldol-S_NAr-dehydration annulation sequence was utilized to fuse hindered phenols onto aromatic substrates. The transformation joins doubly activated 1,3-disubstituted acetone derivatives (dinucleophiles) with C5-activated 2-fluorobenzaldehyde S_NAr acceptors (dielectrophiles) in the presence of K₂CO₃ in [...] Read more.

A one-pot [3+3] aldol-S_NAr-dehydration annulation sequence was utilized to fuse hindered phenols onto aromatic substrates. The transformation joins doubly activated 1,3-disubstituted acetone derivatives (dinucleophiles) with C5-activated 2-fluorobenzaldehyde S_NAr acceptors (dielectrophiles) in the presence of K₂CO₃ in DMF at 65–70 °C to form polysubstituted 2-naphthols and 7-hydroxyquinolines. The reaction is regioselective in adding the most stable anionic center to the aldehyde followed by S_NAr closure of the less stabilized anion to the electron-deficient aromatic ring. Twenty-seven examples are reported, and a probable mechanism is presented. In two cases where S_NAr activation on the acceptor ring was lower (a C5 trifluoromethyl group on the aromatic ring or a 2-fluoropyridine), diethyl 1,3-acetonedicarboxylate initiated an interesting Grob-type fragmentation to give cinnamate esters as the products. Full article

(This article belongs to the Special Issue Exclusive Contributions by the Editorial Board Members (EBMs) of the Organic Chemistry Section of Molecules)

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14 pages, 1436 KiB

Open AccessArticle

Enzymatic Desymmetrisation of Prochiral meso-1,2-Disubstituted-1,2-Diaminoethane for the Synthesis of Key Enantioenriched (−)-Nutlin-3 Precursor

by Virginia Cristofori, Davide Illuminati, Chiara Bisquoli, Martina Catani, Greta Compagnin, Giulia Turrin, Claudio Trapella and Anna Fantinati

Molecules 2024, 29(14), 3267; https://doi.org/10.3390/molecules29143267 - 10 Jul 2024

Cited by 1 | Viewed by 972

Abstract

Herein we present the biocatalysed preparation of a mono-N-carbamate-protected precursor of antitumoral Nutlin-3a through enantioselective alkoxycarbonylation of meso-1,2-disubstituted-1,2-diaminoethane using enzyme lipases and dialkyl carbonates as acylating agents. A series of supported or free lipase enzymes were screened in combination with [...] Read more.

Herein we present the biocatalysed preparation of a mono-N-carbamate-protected precursor of antitumoral Nutlin-3a through enantioselective alkoxycarbonylation of meso-1,2-disubstituted-1,2-diaminoethane using enzyme lipases and dialkyl carbonates as acylating agents. A series of supported or free lipase enzymes were screened in combination with commercially available diallyl, diethyl and dimethyl carbonates. The reactions were conducted at different temperatures, for different reaction times and with variable co-solvent systems to evaluate the effects on the enzyme catalytic activity. The best results in terms of conversion, enantiomeric excess and yield were obtained when lipase from Candida antarctica B (CAL-B) was used with diallyl carbonate (DAC) when conducting the reaction solventless at 75 °C. Full article

(This article belongs to the Special Issue Exclusive Contributions by the Editorial Board Members (EBMs) of the Organic Chemistry Section of Molecules)

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Review

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61 pages, 23396 KiB

Open AccessReview

Porphyrins as Chiroptical Conformational Probes for Biomolecules

by Gabriele Travagliante, Massimiliano Gaeta, Roberto Purrello and Alessandro D’Urso

Molecules 2025, 30(7), 1512; https://doi.org/10.3390/molecules30071512 - 28 Mar 2025

Viewed by 230

Abstract

Porphyrins are highly conjugated macrocyclic compounds that possess exceptional photophysical and chemical properties, progressively establishing themselves as versatile tools in the structural investigation of biomolecules. This review explores their role as chiroptical conformational probes, focusing on their interactions with DNA and RNA. The [...] Read more.

Porphyrins are highly conjugated macrocyclic compounds that possess exceptional photophysical and chemical properties, progressively establishing themselves as versatile tools in the structural investigation of biomolecules. This review explores their role as chiroptical conformational probes, focusing on their interactions with DNA and RNA. The planar electron rich structure of porphyrin macrocycle that promote π–π interactions, their easy functionalization at the meso positions, and their capacity to coordinate metal ions enable their use in probing nucleic acid structures with high sensitivity. Emphasis is placed on their induced circular dichroism (ICD) signals in the Soret region, which provide precise diagnostic insights into binding mechanisms and molecular interactions. The review examines the interactions of porphyrins with various DNA structures, including B-, Z-, and A-DNA, single-stranded DNA, and G-quadruplex DNA, as well as less common structures like I-motif and E-motif DNA. The last part highlights recent advancements in the use of porphyrins to probe RNA structures, emphasizing binding behaviors and chiroptical signals observed with RNA G-quadruplexes, as well as the challenges in interpreting ICD signals with other RNA motifs due to their inherent structural complexity. Full article

(This article belongs to the Special Issue Exclusive Contributions by the Editorial Board Members (EBMs) of the Organic Chemistry Section of Molecules)

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12 pages, 1532 KiB

Open AccessReview

Aromaticity and Chirality: New Facets of Old Concepts

by Bagrat A. Shainyan

Molecules 2024, 29(22), 5394; https://doi.org/10.3390/molecules29225394 - 15 Nov 2024

Viewed by 952

Abstract

The review summarizes the results of previous and the latest studies on aromaticity and related concepts. The electron counting rule for 3D-aromatic systems 2(n + 1)² is shown to be a generalization of the 4n + 2 rule for planar molecules, and, [...] Read more.

The review summarizes the results of previous and the latest studies on aromaticity and related concepts. The electron counting rule for 3D-aromatic systems 2(n + 1)² is shown to be a generalization of the 4n + 2 rule for planar molecules, and, vice versa, the latter can be derived from the former. The relative stability of the push–pull and captodative aromatic systems is shown to depend on the nature of the groups separated by the C=C bond in geminal or vicinal positions. The fully symmetrical molecules of hexamethylbenzene and hexacyanobenzene were studied using structural, energetic, and NMR criteria, and the donor substituents were shown to increase the aromaticity. Taking into account the coincidence of the number of π-electrons in aromatic systems with the number of electrons on the filled electron subshells (s, p, d, and f) and considering electrons as objects in a space of states allowed to conclude that no g-elements can exist and that the extension of the Periodic Table is possible only by filling 6f, 7d, or 8s subshells. The dimensionality of space also affects the chirality of molecules, making planar or even linear molecules chiral on oriented surfaces, which can be used for the preparation of enantiomerically pure drugs, resolution of prochiral compounds, etc. Full article

(This article belongs to the Special Issue Exclusive Contributions by the Editorial Board Members (EBMs) of the Organic Chemistry Section of Molecules)

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