Studien in der Thiophenreihe. XXVIII. Über die Bromderivate des 3‐Thiotolens

Steinkopf, Wilhelm; Jacob, Hans

doi:10.1002/jlac.19355150118

Cited by 26 publications

(9 citation statements)

References 3 publications

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“…5) As for preparation of the Grignard reagent from 3, the original work of Steinkopf and Jacob [6][7][8] involved treatment of 3 with magnesium by an entrained method, followed by coupling with carbon dioxide. However, all our attempts failed when using an array of the usual activators such as iodine and 1,2-dibromoethane, which was consistent with the findings of Rieke.…”

Section: Notementioning

confidence: 99%

Practical Preparation of Ethyl 2-Methylthiophene-3-carboxylate

Kogami

Watanabe

2011

CHEMICAL & PHARMACEUTICAL BULLETIN

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NoteThiophenes serve as the central pharmacophore in drug discovery and their bioisosteric replacement of a benzene ring is widely accepted as a powerful strategy to improve biological activities and pharmacodynamic and pharmacokinetic properties.1) Therefore, use of thiophenes as building blocks undoubtedly continues to receive much attention in the pharmaceutical industry.In connection with an ongoing program, we needed kilogram quantities of 2-methylthiophene-3-carboxylic acid (1) and its esters as starting raw materials. A medicinal researchbased route was based on C-2 methylation 2-4) of dianion of commercially available 3-thiophenecarboxylic acid (2). However, because of both the expense of the reagent 2 and the use of more than 2 eq of n-butyllithium at low temperature, this route is far from ideal for large-scale preparation of these raw materials. Among several precedent methods for preparation of the corresponding acid or esters, the Grignard approach is thought to be a straightforward solution. In this note, we describe a practical synthesis of 2-methylthiophene-3-carboxylic acid ethyl ester, capitalizing on the LiCl-mediated halogen-magnesium exchange reactions.This synthesis began with 2-methylthiophene, which was converted into 3-bromo-2-methylthiophene (3) according to literature methods. 5) As for preparation of the Grignard reagent from 3, the original work of Steinkopf and Jacob [6][7][8] involved treatment of 3 with magnesium by an entrained method, followed by coupling with carbon dioxide. However, all our attempts failed when using an array of the usual activators such as iodine and 1,2-dibromoethane, which was consistent with the findings of Rieke.9,10) In recent years, there have been several publications regarding the LiCl-mediated halogen-magnesium exchange reactions (TurboGrignard reagents) of 3-bromothiophenes, and therefore we turned our attention to this technology.11) Exchange reaction of 3 with 1.5 eq of i-PrMgCl/LiCl in tetrahydrofuran (THF) reached a maximum conversion of 94% after 3 h at reflux, while reaching plateaus of 81% and 50% of the conversions after 5 h at 40°C and room temperature, respectively. The ratios were determined by quantitative HPLC analysis of reaction aliquots after quenching with an excess of aqueous ammonium chloride. Extensive survey of other inexpensive Grignard reagents including EtMgBr and i-PrMgBr provided poor conversions (20-45%), illustrating the superiority of TurboGrignard. Conveniently, similar acceleration was observed when addition of LiCl to a THF solution of 3 was followed by treatment with i-PrMgCl. 12)With the successful conversion of 3 into the corresponding Grignard reagent 4 in hand, several electrophiles were examined for installation of an ethyl ester group, and ethyl chloroformate was found to be the choice of electrophile in terms of cost and efficacy. It should be noted that the use of inexpensive diethyl carbonate gave a decreased yield (70%) accompanied by formation of symmetrical ketone 6 (3%).The initial scale-up runs indicate...

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Section: Notementioning

confidence: 99%

Practical Preparation of Ethyl 2-Methylthiophene-3-carboxylate

Kogami

Watanabe

2011

CHEMICAL & PHARMACEUTICAL BULLETIN

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“…The preparation of 5 has been reported via reaction of 3-methyl-2-thienylmagnesium halides with CO 2 . [ 8 - 11 ] The preparation of the tribromide 6 has also been reported from the bromination of 4 . [ 11 ] Our initial approach was to attempt a bromination/debromination sequence on 5 to prepare the acid precursor of 1 , a process that would give 1 from 5 in three chemical steps.…”

Section: Bromination Studies Routes To 4-bromo-3-methyl-2-thiophenecmentioning

confidence: 99%

“…[ 8 - 11 ] The preparation of the tribromide 6 has also been reported from the bromination of 4 . [ 11 ] Our initial approach was to attempt a bromination/debromination sequence on 5 to prepare the acid precursor of 1 , a process that would give 1 from 5 in three chemical steps. However, treatment of 5 with bromine gave tribromide 6 via a bromination/decarboxylation sequence, a procedure that was initially reported in 1953 and used in subsequent synthetic strategies (Scheme 1 ).…”

Section: Bromination Studies Routes To 4-bromo-3-methyl-2-thiophenecmentioning

confidence: 99%

“…The availability of dibromo intermediate 8 paved the way for insertion of the carboxylic acid functionality at the 2-thienyl position in three chemical steps from commercially available 3-methylthiophene 4 (see discussion below). Interestingly, formation of the Grignard of tribromide 6 by treatment with MeMgBr, [ 11 ] followed by treatment with CO 2 gas led to 7 in an 86% yield, identified by NMR and distinguished from isomer 18 (Scheme 2 ) by its melting point. This indicates a preferred formation of thienyl Grignard in the undesired position of 6 under these conditions (Scheme 1 ).…”

Section: Bromination Studies Routes To 4-bromo-3-methyl-2-thiophenecmentioning

confidence: 99%

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Development of potential manufacturing routes for substituted thiophenes – Preparation of halogenated 2-thiophenecarboxylic acid derivatives as building blocks for a new family of 2,6-dihaloaryl 1,2,4-triazole insecticides

Hull

Romer

Podhorez

et al. 2007

Beilstein J. Org. Chem.

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“…Zu einer Losung von 15,O g 2,5-Dibrom-3-methylthiophen [8] und 0,2 g Uibenzoylperoxid in 40 ml Tetrachlorkohlenstoff gibt man bei 75" portionenweise innerhalb von 5 Min. ein Gemisch von 10,5 g N-Bromsuccinimid und 0,2 Dibenzoylperoxid.…”

Section: 25-i~ibrom-3-brommethyl-thiaphen (Vb)unclassified