Development of Scalable Manufacturing Routes to AZD1981. Application of the Semmler–Wolff Aromatisation for Synthesis of the Indole-4-amide Core

Sulur, Manjunatha; Sharma, Parhalad; Ramakrishnan, Ravi; Naidu, R. Seshadri; Merifield, Eric; Gill, D M; Clarke, Adrian; Thomson, Colin; Butters, Michael; Bachu, Sreekanth; Benison, Colin H.; Dokka, Nagaraju; Fong, Emily R.; Hose, David R. J.; Howell, Gareth P.; Mobberley, Siobhan; Morton, Simon C.; Mullen, A.; Rapai, Jayan; Tejas, Bharathi

doi:10.1021/op300173z

Cited by 15 publications

(2 citation statements)

References 26 publications

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“…To circumvent this problem, we designed the second generation route featuring formation of bromo-2-tetralone 4 using a Friedel–Crafts reaction with ethylene gas and conversion of tetralone 4 to bromonaphthylamine 6 via oxime 5 using the Semmler–Wolff aromatization reaction (Scheme ). Although the Semmler–Wolff reaction has been known for more than 100 years, it mostly has been used in synthesizing acetamido arenes . Direct application of the Semmler–Wolff aromatization in preparation of arylamines is less known and often requires high reaction temperatures and suffers low yields. , In this communication, we report our work on developing optimized aromatization conditions for 6 and its application in the large-scale preparation of sulfonamide 1 .…”

Section: Introductionmentioning

confidence: 99%

Practical Large-Scale Synthesis of 6-Bromo-2-naphthylmethanesulfonamide Using Semmler–Wolff Reaction

Towne

Liang

et al. 2014

Org. Process Res. Dev.

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A practical, scalable synthetic process for a sulfonamide was developed featuring a Semmler–Wolff aromatization as the key step. The optimized reaction conditions using HCl in HOAc give directly the desired naphthylamine in high yield as opposed to a naphthylacetamide commonly formed in the Semmler–Wolff reactions. One little known byproduct of anomalous rearrangement, ketoamine, was observed and a mechanism proposed to explain its formation. Employing the optimized process, 360 kg was prepared to support drug development.

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Section: Introductionmentioning

confidence: 99%

Practical Large-Scale Synthesis of 6-Bromo-2-naphthylmethanesulfonamide Using Semmler–Wolff Reaction

Towne

Liang

et al. 2014

Org. Process Res. Dev.

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“…As these materials are easily accessed by classic condensation chemistry, their implementation would provide a valuable alternative for the preparation of aminated heterocycles, which are a known synthetic challenge both in terms of aryl halide/boronic acid starting material synthesis and following crosscoupling. 39 Pleasingly, using 1 as the amine we efficiently prepared 5-and 8morpholino-quinolines (67 and 68) and -benzothiophenes (69 and 70), as well as 5morpholino-benzofuran (71), -indole (72) and -indazole (73). An interesting application of this reactivity would be the use of ammonia to access free anilines, an important class of building blocks.…”

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confidence: 99%

A photochemical dehydrogenative strategy for aniline synthesis

Dighe

Juliá

Luridiana

et al. 2020

Nature

156

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Chemical reactions that reliably join two molecular fragments together (crosscouplings) are essential to the discovery and following manufacture of high-value materials like pharmaceuticals and agrochemicals. 1,2 In this area, the introduction of amines onto functionalised aromatics at specific and pre-determined positions (ortho vs meta vs para) is currently a prerogative of transition metal-catalysed processes and requires halogen/boron-containing substrates. 3-6 The introduction of these groups around the aromatic unit is dictated by the intrinsic reactivity profile of the method (e.g. electrophilic halogenation, C-H borylation) so selective targeting of all possible positions is often not possible. Here we report a noncanonical cross-coupling approach for the programmable construction of anilines on demand, exploiting saturated cyclohexanones as aryl electrophile surrogates. The condensation between amines and carbonyls, a process extensively used by Nature and (bio)organic chemists, 7 is the enabling feature that ensures a predetermined and site-selective carbon-nitrogen bond formation, while a synergistic photoredox and cobalt catalytic system is simultaneously employed to progressively desaturate the cyclohexene ring en route to the aniline. As functionalised cyclohexanones are readily accessible with complete regiocontrol by well-established carbonyl chemistry, this approach offers a solution to bypass some of the frequent selectivity issues of aromatic chemistry. The utility of this novel C-N coupling protocol was demonstrated by the preparation of commercial medicines and the late-stage amination-aromatization of natural products, steroids and terpene feedstocks.Innovations in synthetic chemistry are integral to the discovery and production of highvalue materials and medicines, and as a result, the well-being of society. In particular, chemical transformations able to couple together complex and functionalized building blocks in a site-selective and programmable manner are fundamental to downstream access to increasingly complex molecules. Within the realm of cross-coupling reactions, processes leading to the construction of C-N bonds across aromatic systems have played a fundamental role in assembling anilines, key structural elements of drugs, agrochemicals and materials. [8][9][10] Currently, the most reliable way to selectively introduce amines into specific positions on functionalised aromatics (ortho vs meta vs para), is to use palladium-or coppercatalysed strategies. 11 For these processes to work, the aromatic coupling partner needs to be pre-equipped with a (pseudo)halide (Buchwald-Hartwig 4,12 and Ullmann 6 crosscouplings) or a boronic acid (Chan-Lam cross-coupling 5 ) in order to generate arylpalladium/copper species that, after amine coordination and reductive elimination,

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Nucleophilic Substitution of Hydrogen in Arenes and Heteroarenes

Mąkosza

Wojciechowski

2013

Topics in Heterocyclic Chemistry

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Development of Scalable Manufacturing Routes to AZD1981. Application of the Semmler–Wolff Aromatisation for Synthesis of the Indole-4-amide Core

Cited by 15 publications

References 26 publications

Practical Large-Scale Synthesis of 6-Bromo-2-naphthylmethanesulfonamide Using Semmler–Wolff Reaction

Practical Large-Scale Synthesis of 6-Bromo-2-naphthylmethanesulfonamide Using Semmler–Wolff Reaction

A photochemical dehydrogenative strategy for aniline synthesis

Nucleophilic Substitution of Hydrogen in Arenes and Heteroarenes

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