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7 pages, 1600 KiB

Open AccessShort Note

by Guido Gambacorta, Qin Han Teo and Ian R. Baxendale

Molbank 2025, 2025(1), M1969; https://doi.org/10.3390/M1969 - 19 Feb 2025

Viewed by 922

A continuous flow process was optimised for the perchlorination of p-cresol to the corresponding 2,4,6-trichloro-cyclohexa-2,5-dienone derivative employing trichloroisocyanuric acid as a green and safer-to-handle chlorinating agent. The system could furnish 200 g of pure material within 5 h of operation (throughput = [...] Read more.

A continuous flow process was optimised for the perchlorination of p-cresol to the corresponding 2,4,6-trichloro-cyclohexa-2,5-dienone derivative employing trichloroisocyanuric acid as a green and safer-to-handle chlorinating agent. The system could furnish 200 g of pure material within 5 h of operation (throughput = 40 g h⁻¹). The compound was easily isolated by filtration and obtained in 95% purity as determined by GC analysis; it could be further purified by crystallisation from a 20:1 Hexane/AcOEt mixture left at −20 °C overnight. The resultant product was characterised by ¹H & ¹³C NMR, MS, IR analyses, with melting point and X-ray single-crystal data being obtained, confirming the structure. Full article

(This article belongs to the Section Organic Synthesis and Biosynthesis)

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8 pages, 1493 KiB

Open AccessShort Note

6-Chloro-3H-benzo[d][1,2,3]dithiazol-2-ium Chloride

by Alexander J. Nicholls and Ian R. Baxendale

Molbank 2022, 2022(1), M1339; https://doi.org/10.3390/M1339 - 11 Feb 2022

Cited by 1 | Viewed by 2461

Abstract

This short note describes the synthesis of an amorphous benzo[1,2,3]dithiazole chloride salt (commonly known as a ‘Herz salt’) by use of the Herz reaction. Hetero- and homolytic transformations of this species to a variety of useful adducts in medicinal and materials chemistry are [...] Read more.

This short note describes the synthesis of an amorphous benzo[1,2,3]dithiazole chloride salt (commonly known as a ‘Herz salt’) by use of the Herz reaction. Hetero- and homolytic transformations of this species to a variety of useful adducts in medicinal and materials chemistry are well established, although there are limited examples of isolation in the literature, and characterisation data is even harder find. While several studies have confirmed the structure of the benzodithiazole ring beyond doubt, (having generated suitably crystalline salts with large counterions for XRD-analysis), there remains value in understanding and optimising the synthesis of the simple, amorphous polymorphs. For the first time, MS data is provided for this compound and a new mechanism of its formation is proposed based upon new experimental observations and data. Full article

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5 pages, 970 KiB

Open AccessCommunication

4,4’-(Pyridin-4-ylmethylene)dibenzonitrile

by Ben M. J. Lancaster, Alexander J. Nicholls and Ian R. Baxendale

Molbank 2021, 2021(4), M1302; https://doi.org/10.3390/M1302 - 30 Nov 2021

Viewed by 3085

Abstract

This communication describes an unprecedented substitution cascade, in which 4-methylpyridine, following deprotonation with LDA, twice acts as a carbon nucleophile in an unusual S_NAr process, to form a novel triarylmethane structure. A proposed mechanism for this sequence is presented that is [...] Read more.

This communication describes an unprecedented substitution cascade, in which 4-methylpyridine, following deprotonation with LDA, twice acts as a carbon nucleophile in an unusual S_NAr process, to form a novel triarylmethane structure. A proposed mechanism for this sequence is presented that is supported by single crystal X-ray analysis of the resulting product. We believe this unique transformation is of note as it highlights a neat and efficient entry as a single step to complex triarylmethane architectures containing both substituted phenyl and pyridyl aromatics. Full article

(This article belongs to the Section Organic Synthesis and Biosynthesis)

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34 pages, 13479 KiB

Open AccessReview

Benzo[1,2,3]dithiazole Compounds: A History of Synthesis and Their Renewed Applicability in Materials and Synthetic Chemistry, Originating from the Herz Reaction

by Alexander J. Nicholls and Ian R. Baxendale

Reactions 2021, 2(3), 175-208; https://doi.org/10.3390/reactions2030013 - 29 Jun 2021

Cited by 8 | Viewed by 6135

Abstract

The benzo[1,2,3]dithiazole is a unique heteroaromatic functionality whose conjugated profile instils some fascinating electronic properties. This has been historically recognized in the design and manufacture of organic dyes early last century. Although, with the benefit of increased diagnostic techniques and improved understanding, these [...] Read more.

The benzo[1,2,3]dithiazole is a unique heteroaromatic functionality whose conjugated profile instils some fascinating electronic properties. This has been historically recognized in the design and manufacture of organic dyes early last century. Although, with the benefit of increased diagnostic techniques and improved understanding, these structures are attracting greater attention in additional research settings, including applications as organic radicals and semiconductors. In addition, the benzodithiazole functionality has been shown to be a valuable synthetic intermediate in the preparation of a variety of other privileged aromatic and heteroaromatic targets, many of which are important APIs. In this review, the authors aim to critically analyse the potential applicability of these compounds to the fields of not only small-scale laboratory synthetic and medicinal chemistry but also commercial-scale processes and increasingly materials chemistry. Full article

(This article belongs to the Special Issue Feature Papers in Reactions in 2021)

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14 pages, 2632 KiB

Open AccessArticle

A One-Pot Divergent Sequence to Pyrazole and Quinoline Derivatives

by Guido Gambacorta, David C. Apperley and Ian R. Baxendale

Molecules 2020, 25(9), 2160; https://doi.org/10.3390/molecules25092160 - 5 May 2020

Cited by 4 | Viewed by 3456

Abstract

The hydroxy-pyrazole and 3-hydroxy-oxindole motifs have been utilised in several pharma and agrochemical leads but are distinctly underrepresented in the scientific literature due to the limited routes of preparation. We have developed a one-pot procedure for their synthesis starting from simple isatins. The [...] Read more.

The hydroxy-pyrazole and 3-hydroxy-oxindole motifs have been utilised in several pharma and agrochemical leads but are distinctly underrepresented in the scientific literature due to the limited routes of preparation. We have developed a one-pot procedure for their synthesis starting from simple isatins. The method employs cheap and easy-to-handle building blocks and allows easy isolation. Full article

(This article belongs to the Special Issue Enabling Chemical Technologies in Medicinal Chemistry)

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19 pages, 3437 KiB

Open AccessFeature PaperArticle

Copper-Mediated Nitrosation: 2-Nitrosophenolato Complexes and Their Use in the Synthesis of Heterocycles

by Alexander J. Nicholls, Andrei S. Batsanov and Ian R. Baxendale

Molecules 2019, 24(22), 4154; https://doi.org/10.3390/molecules24224154 - 16 Nov 2019

Cited by 3 | Viewed by 3673

Abstract

A simple protocol yielding ortho-substituted nitrosophenols from phenols is demonstrated, in the form of copper(II) bis(nitrosophenolato) complexes. The developed methodology was applied to a range of substrates, confirming the role of the copper in both the formation and protection of the [...] Read more.

A simple protocol yielding ortho-substituted nitrosophenols from phenols is demonstrated, in the form of copper(II) bis(nitrosophenolato) complexes. The developed methodology was applied to a range of substrates, confirming the role of the copper in both the formation and protection of the challenging 1, 2-substitution pattern. Using polymer supported thiourea, the Cu could be stripped from the complexes and thus enabled the isolation or identification of the uncoordinated ligands and their decomposition products, in yields generally low in line with the intrinsic high reactivity of 2-nitrosophenols. The product complexes are useful intermediates as demonstrated in revisiting a formal [4 + 2] cycloaddition with dimethylacetylene dicarboxylate to synthesise bicyclic products in variable yields, revealing the product has a novel structure different from those previously reported in the literature. Full article

(This article belongs to the Special Issue Recent Synthetic Aspects on the Chemistry of Nitro, Nitroso and Amino Compounds II)

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31 pages, 9578 KiB

Open AccessReview

The Synthesis and Utility of Metal-Nitrosophenolato Compounds—Highlighting the Baudisch Reaction

by Alexander J. Nicholls, Thomas Barber and Ian R. Baxendale

Molecules 2019, 24(22), 4018; https://doi.org/10.3390/molecules24224018 - 6 Nov 2019

Cited by 9 | Viewed by 6427

Abstract

The syntheses of the title compounds demonstrate a privileged introduction of a nitroso (and a hydroxyl via the Baudisch reaction) group to an aromatic ring. These complexes first appeared in the literature as early as 1939, and a range of applications has subsequently [...] Read more.

The syntheses of the title compounds demonstrate a privileged introduction of a nitroso (and a hydroxyl via the Baudisch reaction) group to an aromatic ring. These complexes first appeared in the literature as early as 1939, and a range of applications has subsequently been published. However, optimisations of the preparative sequences were not considered, and as such, the reactions have seldom been utilised in recent years; indeed, there remains confusion in the literature as to how such complexes form. In this review, we aim to demystify the misunderstanding surrounding these remarkable complexes and consider their renewed application in the 21st century. Full article

(This article belongs to the Special Issue Recent Synthetic Aspects on the Chemistry of Nitro, Nitroso and Amino Compounds II)

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18 pages, 3253 KiB

Open AccessArticle

Flow Hydrodediazoniation of Aromatic Heterocycles

by Liesa Röder, Alexander J. Nicholls and Ian R. Baxendale

Molecules 2019, 24(10), 1996; https://doi.org/10.3390/molecules24101996 - 24 May 2019

Cited by 12 | Viewed by 6255

Abstract

Continuous flow processing was applied for the rapid replacement of an aromatic amino group with a hydride. The approach was applied to a range of aromatic heterocycles, confirming the wide scope and substituent-tolerance of the processes. Flow equipment was utilized and the process [...] Read more.

Continuous flow processing was applied for the rapid replacement of an aromatic amino group with a hydride. The approach was applied to a range of aromatic heterocycles, confirming the wide scope and substituent-tolerance of the processes. Flow equipment was utilized and the process optimised to overcome the problematically-unstable intermediates that have restricted yields in previous studies relying on batch procedures. Various common organic solvents were investigated as potential hydride sources. The approach has allowed key structures, such as amino-pyrazoles and aminopyridines, to be deaminated in good yield using a purely organic-soluble system. Full article

(This article belongs to the Special Issue Flow Chemistry in Organic Synthesis)

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4 pages, 1422 KiB

Open AccessShort Note

Ethyl 5-(4-Bromophenyl)-4-methyl-1H-pyrrole-2-carboxylate

by Marcus Baumann and Ian R. Baxendale

Molbank 2017, 2017(3), M951; https://doi.org/10.3390/M951 - 4 Aug 2017

Viewed by 3690

Abstract

This note describes a sequence converting an oxime-substituted pyrrolidine into a trisubstituted pyrrole structure. The synthetic route is based on a double chlorination of the pyrrolidine substrate followed by the base induced formation of both an imine and a nitrile oxide functionality. The [...] Read more.

This note describes a sequence converting an oxime-substituted pyrrolidine into a trisubstituted pyrrole structure. The synthetic route is based on a double chlorination of the pyrrolidine substrate followed by the base induced formation of both an imine and a nitrile oxide functionality. The latter reacts with an immobilized thiourea to yield an isothiocyanate which upon elimination generates the final pyrrole in an unprecedented cascade of events. Full article

(This article belongs to the Section Organic Synthesis and Biosynthesis)

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4 pages, 1083 KiB

Open AccessCommunication

Rac-2′,3a,6,6,6′,6′-Hexamethyl-3a,3b,6,7-tetra-hydrospiro-[benzo[2,3]cyclopropa[1,2-c]pyrazole-1,1′-cyclo-hepta[2,4]diene]

by Marcus Baumann, Sophie Lapraille and Ian R. Baxendale

Molbank 2017, 2017(3), M948; https://doi.org/10.3390/M948 - 1 Aug 2017

Cited by 1 | Viewed by 3920

Abstract

This note describes a novel reaction cascade in which a tosylhydrazone derivative of eucarvone undergoes a non-classical dimerization process under basic conditions. The key step in this sequence is a dipolar cycloaddition between a diazo species and a transient cyclopropene. A proposed mechanism [...] Read more.

This note describes a novel reaction cascade in which a tosylhydrazone derivative of eucarvone undergoes a non-classical dimerization process under basic conditions. The key step in this sequence is a dipolar cycloaddition between a diazo species and a transient cyclopropene. A proposed mechanism for this sequence is presented that is supported by single crystal X-ray analysis of the resulting dimer. We believe this unique transformation is of note as it highlights a neat and efficient entry to complex polycyclic architectures containing an embedded pyrazoline moiety. Full article

(This article belongs to the Section Organic Synthesis and Biosynthesis)

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23 pages, 1744 KiB

Open AccessArticle

Exploring Flow Procedures for Diazonium Formation

by Te Hu, Ian R. Baxendale and Marcus Baumann

Molecules 2016, 21(7), 918; https://doi.org/10.3390/molecules21070918 - 14 Jul 2016

Cited by 33 | Viewed by 11978

Abstract

The synthesis of diazonium salts is historically an important transformation extensively utilized in dye manufacture. However the highly reactive nature of the diazonium functionality has additionally led to the development of many new reactions including several carbon-carbon bond forming processes. It is therefore [...] Read more.

The synthesis of diazonium salts is historically an important transformation extensively utilized in dye manufacture. However the highly reactive nature of the diazonium functionality has additionally led to the development of many new reactions including several carbon-carbon bond forming processes. It is therefore highly desirable to determine optimum conditions for the formation of diazonium compounds utilizing the latest processing tools such as flow chemistry to take advantage of the increased safety and continuous manufacturing capabilities. Herein we report a series of flow-based procedures to prepare diazonium salts for subsequent in-situ consumption. Full article

(This article belongs to the Special Issue Recent Synthetic Aspects on the Chemistry of Nitro, Nitroso and Amino Compounds)

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5 pages, 723 KiB

Open AccessShort Note

Ethyl 2-hydroxy-2-phenyl-2-(thiazol-2-yl)acetate

by Carl J. Mallia, Lukas Englert, Gary C. Walter and Ian R. Baxendale

Molbank 2015, 2015(2), M857; https://doi.org/10.3390/M857 - 6 May 2015

Viewed by 3989

Abstract

This short note describes the synthesis of the title compound through spontaneous aerobic oxidation of ethyl 2-phenyl-2-(thiazol-2-yl)acetate. Due to the prevalence of such functional motifs in biologically active substances, we believe the oxidation encountered highlights an important degradation pathway worthy of note. Full article

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4 pages, 373 KiB

Open AccessShort Note

Syn-Ethyl 1-hydroxy-7-methoxy-2,3-dihydro-1H-pyrrolo[3,4-b]quinolone-3-carboxylate HCl Salt

by Marcus Baumann and Ian R. Baxendale

Molbank 2015, 2015(1), M846; https://doi.org/10.3390/M846 - 3 Mar 2015

Cited by 2 | Viewed by 3293

Abstract

This short note describes a one-step synthesis of the title compound from commercially available starting materials and reports its full spectroscopic characterization data. Full article

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24 pages, 708 KiB

Open AccessArticle

Synthesis of Riboflavines, Quinoxalinones and Benzodiazepines through Chemoselective Flow Based Hydrogenations

by Marcus Baumann, Ian R. Baxendale, Christian H. Hornung, Steven V. Ley, Maria Victoria Rojo and Kimberley A. Roper

Molecules 2014, 19(7), 9736-9759; https://doi.org/10.3390/molecules19079736 - 8 Jul 2014

Cited by 28 | Viewed by 10974

Abstract

Robust chemical routes towards valuable bioactive entities such as riboflavines, quinoxalinones and benzodiazepines are described. These make use of modern flow hydrogenation protocols enabling the chemoselective reduction of nitro group containing building blocks in order to rapidly generate the desired amine intermediates in [...] Read more.

Robust chemical routes towards valuable bioactive entities such as riboflavines, quinoxalinones and benzodiazepines are described. These make use of modern flow hydrogenation protocols enabling the chemoselective reduction of nitro group containing building blocks in order to rapidly generate the desired amine intermediates in situ. In order to exploit the benefits of continuous processing the individual steps were transformed into a telescoped flow process delivering selected benzodiazepine products on scales of 50 mmol and 120 mmol respectively. Full article

(This article belongs to the Special Issue Heterocycles in Supramolecular Chemistry)

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