Fluorinated enol ethers: their synthesis and reactivity

Decostanzi, Mélanie; Campagne, Jean‐Marc; Leclerc, E.

doi:10.1039/c5ob00855g

Cited by 98 publications

(62 citation statements)

References 215 publications

(165 reference statements)

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“…However, the use of reactive, partially fluorinated building blocks often offers interesting alternatives with a higher flexibility and a greater molecular diversity. Fluorinated enol ethers and enolates are representative of this strategy since they allow the introduction of a fluorinated carbonyl moiety through an aldol reaction 6. The efficiency of aldol or Reformatsky reactions to provide monofluorinated aldols has been demonstrated 7.…”

Section: Methodsmentioning

confidence: 99%

Brook/Elimination/Aldol Reaction (BEAR) Sequence for the Direct Preparation of Fluorinated Aldols from β,β‐Difluoro‐α‐(trimethylsilyl)alcohols

et al. 2015

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Am ethodology allowing the preparation of aldols featuring af luorinated stereogenic center is reported. Thec orresponding fluoroenolates are formed in situ from stable b,b-difluoro-a-(trimethylsilyl)alcohols,t hrough ab ase-mediated process involving aB rook rearrangement followed by af luoride elimination, and are directly added to aromatic aldehydes.T wo different sets of conditions were disclosed. Thef irst one involves the stoichiometric addition of potassium tert-butoxide (t-BuOK) while the second is based on the use of ac atalytic amount of an ammonium phenoxide.T he latter opens the way for ac atalytic and asymmetric version of this Brook/elimination/aldol reaction( BEAR) sequence.Keywords: aldol reaction; Brook rearrangement; fluorine;organocatalysis;s tereogenic centers Since the disclosure of fluorouracila nd of fluorinated corticosteroids in the 1950s,t he presence of fluorine atoms in bioactive molecules has considerably increased, with as trong acceleration during the last twenty years. [1,2] Up to 20% of the drugs and 30% of the agrochemicals launched every yearsince 2000f eature af luorinated group in their structure, and the proportion is evenh igher for top-selling drugs.[3] The singular properties of the fluorine atom and of the C À Fb ond often allow interesting modulations of the behaviouro ft hese molecules,w hich go from ah igher metabolic stability to an increased activity.[4] Thed evelopment of synthetic methodologies for the preparation of fluorinated organic molecules hast hus become am ajor goal in modern organic chemistry. Thei nvestigation of direct electrophilic or nucleophilic fluorination as well as difluoromethylation and trifluoromethylation reactions is stillaprivileged research field.[5] However, the use of reactive, partially fluorinated building blocks often offersi nteresting alternatives with ah igher flexibility and ag reater moleculard iversity.F luorinated enol ethers ande nolates are representativeo ft his strategy since they allow the introduction of af luorinated carbonyl moiety through an aldol reaction.[6] Thee fficiency of aldolo rR eformatsky reactions to provide monofluorinated aldols has been demonstrated. [7] However, there are only few examples of aldol reactions providing monofluorinated adducts featuring at etrasubstituted stereogenic center. [8,9] Moreover, among all these examples,d irect aldol reactions often require the use of strong bases while Mukaiyama aldol reactions involve poorly stable fluorinated silyl enol ethers.W ew ish to present herein an ew methodologya llowing the preparation of new aldols featuring af luorinated tetrasubstituted stereogenic center, and proceeding throught he mild in situ generation of the enolate from as table precursor. [10,11] While studying for other purposes the addition of difluoromethyllithium compounds onto electrophiles, we were intriguedb yt he results obtained in the reaction between 1 and acetyltrimethylsilane 2a.[12]Indeed, we expected that such an addition wouldl ead directlyt ot he corresponding m...

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Section: Methodsmentioning

confidence: 99%

Brook/Elimination/Aldol Reaction (BEAR) Sequence for the Direct Preparation of Fluorinated Aldols from β,β‐Difluoro‐α‐(trimethylsilyl)alcohols

et al. 2015

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“…One of the most common approaches of accessing gem-difluorinated molecules with adjacent functional groups such as alcohols or amines, other than the bis-fluorination of 1,3-dicarbonyl compounds, [3] relies on the use of gem-difluorinated pronucleophiles (Scheme 1 a). [4] Indeed, by taking advantage of the electronic properties conferred by the presence of the CF 2 substituent, nucleophilic additions of various difluorinated pronucleophiles to imines, aldehydes or ketones were performed. [5] Quite surprisingly, excluding the nucleophilic aldolization of electronically biased aldehydes containing a perfluoroalkyl chain, [6] the alternative direct aldolization to gem-difluorinated aldehydes is to the best of our knowledge unprecedented.…”

Section: Introductionmentioning

confidence: 99%

Organo‐ and Copper‐Multi‐Catalyzed Pseudo Four‐Component Access to gem‐Difluorohydrins

2018

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A new efficient multi‐catalytic pseudo four‐component strategy combining an aldehyde, a β‐keto‐acid and two equivalents of a fluorinating agent has been designed. Thanks to the combined effects of a secondary amine as organocatalyst and a copper catalyst, highly volatile gem‐difluorinated intermediates can be produced and trapped in situ by a chemo‐compatible decarboxylative aldolization providing a rapid access to original gem‐difluorinated β‐aldol building blocks.

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“…Consequently, the preparation of difluorinated aldol and Mannich products, either through direct aldol, Reformatsky‐type or Mukaiyama‐type reactions, has known considerable developments ,. However, most of these approaches either suffer from the use of strong bases or overstoichiometric amounts of metallic salts, or imply the sometimes delicate preparation of difluorinated silyl enol ethers . Alternatives to these classical approaches have been recently devised, such as the elegant trifluoroacetate release strategy pioneered by Colby and Wolf, or a one‐pot one‐catalyst procedure relying on a Brook rearrangement/fluoride elimination sequence recently reported by us ,.…”

Section: Introductionmentioning

confidence: 99%

α,α‐Difluoro‐α‐(trimethylsilyl)acetamides as Versatile Reagents for the Preparation of Difluorinated Aldol and Mannich Adducts

et al. 2017

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Thev ery efficient addition of a,a-difluoroa-(trimethylsilyl)acetamides to aldehydes,k etones and N-(tert-butanesulfinyl)imines is described. The reactioni sp romoted by ac atalytic amount of tetran-butylammonium diphenyltrifluorosilicate (TBAT) and high yields,a sw ell as very high stereoselectivities in the case of N-(tert-butanesulfinyl)imines,a re achieved. Thes ynthetic potentialo ft his method is il-lustrated by the conversion of the resulting products to b-hydroxy ketones,d iols and b-amino alcohols by addition of various Grignard reagents or reduction of the amide moiety.

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Fluorinated enol ethers: their synthesis and reactivity

Cited by 98 publications

References 215 publications

Brook/Elimination/Aldol Reaction (BEAR) Sequence for the Direct Preparation of Fluorinated Aldols from β,β‐Difluoro‐α‐(trimethylsilyl)alcohols

Brook/Elimination/Aldol Reaction (BEAR) Sequence for the Direct Preparation of Fluorinated Aldols from β,β‐Difluoro‐α‐(trimethylsilyl)alcohols

Organo‐ and Copper‐Multi‐Catalyzed Pseudo Four‐Component Access to gem‐Difluorohydrins

α,α‐Difluoro‐α‐(trimethylsilyl)acetamides as Versatile Reagents for the Preparation of Difluorinated Aldol and Mannich Adducts

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