Highly regioselective gold-catalyzed formal hydration of propargylic <i>gem</i>-difluorides

Hamel, Jean‐Denys; Hayashi, T; Cloutier, Mélissa; Savoie, Paul R.; Thibeault, Olivier; Beaudoin, Meggan; Paquin, Jean‐François

doi:10.1039/c7ob02406a

Cited by 30 publications

(34 citation statements)

References 81 publications

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“…In the course of synthesizing 17, we isolated the 3,3-difluoroketones 14 and 23, which are potentially useful building blocks for a variety of applications, but are notoriously difficult to prepare. 42 By combining deoxofluorination and desulfurative fluorination strategies, we installed the (gem-CF 2 ) fragment in the presence of the ketone rather than hydrating a propargylic gem-difluoride to form a ketone. Thus, our synthetic strategy expands the scope of the double di-fluorination of 1,3-diketones and provides an alternative route to the synthesis of 3,3-difluoroketones using accessible and scalable chemistry.…”

Section: Resultsmentioning

confidence: 99%

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Synthesis of a Hominal Bis(difluoromethyl) Fragments

Ivasyshyn¹,

Smit²,

Chiechi

2019

Preprint

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<div> <div> <p>This paper describes the synthesis of discrete units of hominal bis(gem-CF2). The controlled introduction of fluorine atoms is a powerful synthetic tool to introduce dipole moments with minimal impact to sterics. Polyvinylidene fluoride (PVDF) is a striking example of the influence of fluorine atoms, which impart ferroelectric behavior from the alignment of the dipole moments of CF2 units, however, it is prepared via direct polymerization of vinylidene difluoride. Thus, a different synthetic pathway is required to produce synthons containing discrete numbers of CF2 groups in a hominal relation to each other. We found out that, in the case of short chains, the consecutive deoxofluorination of sequentially-introduced keto groups is very inefficient, as it requires harsh conditions and sharply decreasing yields at each step. To solve this problem, we combined the selective desulfurative fluorination of dithiolanes with pyridinium fluoride and the deoxofluorination of keto groups with morpholinosulfur trifluoride. This strategy is highly reproducible and scalable, allowing the synthesis of the hominal bis(gem-CF2) fragment as a shelf-stable tosylate, which can be used to install discrete chains of hominal bis(gem-CF2) on a variety of synthons and monomers.</p> </div> </div>

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Section: Resultsmentioning

confidence: 99%

“…In both works by Stepanov et al 36 and Wang et al, 40 propargylic gem-difluorides. 42 This approach installs the (gem-CF 2 ) fragment before the ketone, suggesting that β-ketones deactivate deoxofluorinations.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of a Hominal Bis(difluoromethyl) Fragments

Ivasyshyn¹,

Smit²,

Chiechi

2019

Preprint

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“…In the course of synthesizing 17 , we isolated the 3,3-difluoroketones 8 , 14 , and 23 , which are potentially useful building blocks for a variety of applications. 43 By combining deoxofluorination and desulfurative fluorination strategies, we installed the hominal bis( gem -CF 2 ) fragment in the presence of the ketone rather than hydrating a propargylic gem -difluoride to form a ketone. Thus, our synthetic strategy expands the scope of the double difluorination of 1,3-diketones and provides an alternative route to the synthesis of 3,3-difluoroketones using accessible and scalable chemistry.…”

Section: Discussionmentioning

confidence: 99%

“…3,3-Difluoroketones themselves are attractive building blocks but are difficult to synthesize; however, recent work by Hamel et al demonstrated the synthesis of 3,3-difluoroketones via a regioselective gold-catalyzed formal hydration of propargylic gem-difluorides. 43…”

Section: Introductionmentioning

confidence: 99%

Synthesis of a Hominal Bis(difluoromethyl) Fragment

2019

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This paper describes the synthesis of a discrete unit of hominal bis( gem -CF 2 ). The controlled introduction of fluorine atoms is a powerful synthetic tool to introduce dipole moments with minimal impact to sterics. Poly(vinylidene difluoride) is a striking example of the influence of fluorine atoms, which impart ferroelectric behavior from the alignment of the dipole moments of CF 2 units; however, it is prepared via direct polymerization of vinylidene difluoride. Thus, a different synthetic pathway is required to produce synthons containing discrete numbers of CF 2 groups in a hominal relation to each other. We found out that, in the case of short chains, the consecutive deoxofluorination of sequentially introduced keto groups is inefficient, as it requires harsh conditions and decreasing yields at each step. To solve this problem, we combined the selective desulfurative fluorination of dithiolanes with pyridinium fluoride and the deoxofluorination of keto groups with morpholinosulfur trifluoride. This strategy is highly reproducible and scalable, allowing the synthesis of the hominal bis( gem -CF 2 ) fragment as a shelf-stable tosylate, which can be used to install discrete chains of hominal bis( gem -CF 2 ) on a variety of synthons and monomers.

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“…The treatment of compound 15 with a gold catalyst in the presence of MeOH, followed by hydrolysis, provided ketone 35 in 91% yield (Scheme 3a). 35 The construction of indole 36 through Larock's approach 36 by a reaction of the alkyne 15 with 2-iodoaniline proceeded smoothly (Scheme 3a). Besides, the alkyne could be employed to generate difluoromethylated isoxazole 37 through [3+2] cyclization (Scheme 3b).…”

Section: Synthetic Utilitymentioning

confidence: 99%

Palladium Difluorocarbene Involved Catalytic Coupling with Terminal Alkynes

Zhang

et al. 2020

CCS Chem

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Cite this: CCS Chem. 2020, 2, 293-304Difluoromethylated alkynes are a versatile synthon for the diversity-oriented synthesis of difluoromethyl compounds that are of great interest in life and materials sciences. However, the catalytic cross-coupling for the synthesis of difluoromethylated alkynes remains challenging, despite impressive achievements made in the cross-coupling reactions for alkynes, including the Sonogashira reaction. Here, we report a palladium difluorocarbene involvement in catalytic coupling with terminal alkynes, representing a new mode of conjugation reaction, which circumvents the radical pathway usually encountered during the coupling of alkynes with fluoroalkyl electrophiles. The reaction uses inexpensive and abundant industrial raw material chlorodifluoromethane (ClCF 2 H) as the difluorocarbene precursor, and features cost-effectiveness, excellent functional group tolerance, and broad substrate scope, including synthesis of drug-like complex molecules. Our mechanistic studies showed a unique catalytic pathway of this process, in which additive hydroquinone plays a pivotal role in promoting the reaction. + [Pd] (2.5 mol %) Xantphos (2.5 or 7.5 mol %) Hydroquinone, K 2 CO 3 dioxane/DMA (w/wo), 80 o C CF 2 H R Het R Het [Pd 0 ]=CF 2 via cat. [Pd] nucleophilic 32 examples, yield up to 95% alkyne hydroquinone hydroquinone F F Cl H RESEARCH ARTICLE

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Highly regioselective gold-catalyzed formal hydration of propargylic gem-difluorides

Cited by 30 publications

References 81 publications

Synthesis of a Hominal Bis(difluoromethyl) Fragments

Synthesis of a Hominal Bis(difluoromethyl) Fragments

Synthesis of a Hominal Bis(difluoromethyl) Fragment

Palladium Difluorocarbene Involved Catalytic Coupling with Terminal Alkynes

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