Siladifluoromethylation and Deoxo-trifluoromethylation of PV–H Compounds with TMSCF3: Route to PV–CF2– Transfer Reagents and P–CF3 Compounds

Krishnamurti, Vinayak; Barrett, Colby; Prakash, G. K. Surya

doi:10.1021/acs.orglett.9b00381

Cited by 26 publications

(19 citation statements)

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“…Common to most proposals for the mechanism of the Prakash–Hu difluorocyclopropanation , is the assumption that (i) the process involves generation of free CF 2 from 1 , which then adds to the alkene, , and (ii) the CF 2 arises from direct loss of fluoride ( k α ) from a transient CF 3 anionoid , (Mechanisms I and II; Scheme ). In the absence of alkene, the CF 2 is suggested to spontaneously dimerize to give TFE .…”

Section: Resultsmentioning

confidence: 99%

Difluorocarbene Generation from TMSCF₃: Kinetics and Mechanism of NaI-Mediated and Si-Induced Anionic Chain Reactions

et al. 2020

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The mechanism of CF2-transfer from TMSCF3 (1), mediated by TBAT (2-12 mol%) or by NaI (5-20 mol%), has been investigated by in situ / stopped-flow 19 F NMR spectroscopic analysis of the kinetics of alkene difluorocyclopropanation, and competing TFE / c-C3F6 / homologous perfluoroanion generation, 13 C/ 2 H KIEs, LFERs, CF2-transfer efficiency and selectivity, the effect of inhibitors, and density functional theory (DFT) calculations. The reactions evolve with profoundly different kinetics, undergoing auto-inhibition (TBAT) or stochastic auto-acceleration (NaI), and co-generating perfluoroalkene side products. An overarching mechanism involving direct and indirect fluoride transfer from a CF3-anionoid to TMSCF3 (1) has been elucidated. It allows rationalization of why the NaI-mediated process is more effective for less-reactive alkenes and alkynes, why a large excess of TMSCF3 ( 1) is required in all cases, and why slow-addition protocols can be of benefit. Issues relating to exothermicity, toxicity, and scale-up are also noted.a Relative rates (krel) are for competitive first-order CF2 capture by the alkene/yne, not to overall rates of reaction. b Values in parenthesis by DFT. 26 See sections S3.7, S3.8 and S6.2 in the SI. Singlet CF2 as the ReactiveIntermediate. We began by studying the reaction of TMSCF3 (1) with alkenes 3i, and E/Z-4 and alkyne 5, Table 1. All underwent difluorocyclopropanation, to varying degrees of conversion, in the presence of TMSCF3 (1, 1.5 M) and 1-5 mol % TBAT, or NaI. Reactions of E/Z-4 proceeded stereospecifically, and with >98 % retention. The difluorocyclopropene 8, generated in low yield (12%) from alkyne 5, under the TBATmediated conditions, underwent partial decomposition to unidentified products. In contrast, 8 was quantitatively-generated, and stable, under NaI-mediated conditions, see section S3.3 in the SI. The same difluorocyclopropane products (6, 7) were obtained from 3i and E/Z-4 on thermalization with the zwitterionic CF2-source Ph3PCF2CO2. 22 The relative reactivities (krel) of alkenes 3i, E-4, and Z-4, and the LFER correlation for a-methylstyrenes (3i-vii, r + = -0.6), 23 were independent of the reagent (1 / Ph3PCF2CO2), and initiator (TBAT / NaI), Table 1, 24 within experimental error. Scheme 3. Experimental a and calculated b KIEs for rapid addition of transient singlet CF2 to 3i, at 300 K. 25 a Experimental (exp.) values in THF; and in PhCl, as solvent. 25 b Calculated (calc.) values by DFT, at the M06/6-31+G* level in Gauss-ian09 employing IEF-PCM single points to account for solvation, and goodvibes, kinisot and PyQuiver to compute free energy corrections and KIEs, see sections S1.6 and S6.2 in the SI. 26Kinetic isotope effects for the reaction of p-F-a-methylstyrene 3i with TMSCF3 (1) initiated by TBAT were obtained by a series of competitions of 13 C-and 2 H-labelled a-methylstyrenes 3i against aryl-D4-3i, monitored by 19 F NMR spectroscopy (aryl-DdF = 0.5 ppm). 25 The resulting primary and secondary kinetic isotope effects, Scheme 3, were consistent with thos...

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Section: Resultsmentioning

confidence: 99%

Difluorocarbene Generation from TMSCF₃: Kinetics and Mechanism of NaI-Mediated and Si-Induced Anionic Chain Reactions

et al. 2020

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“…In this light, the work by Prakash and co‐workers reported in 2019 looks particularly encouraging [227] . The group has developed a direct method for the preparation of Me 3 SiCF 2 P(O)(OAlk) 2 compounds by a formal Michaelis‐Becker reaction of lithio dialkyl phosphonates with Me 3 SiCF 3 [228] .…”

Section: Synthetic Methodsmentioning

confidence: 99%

Recent Advances in Synthesis of Difluoromethylene Phosphonates for Biological Applications

et al. 2021

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For almost 40 years, difluoromethylene phosphonates have proven to be versatile molecular tools in biochemical studies owing to their close resemblance to naturally occurring phosphates and phosphonates. As bioisosteric, non‐hydrolyzable analogs of these essential molecules, difluoromethylene phosphonates can target the critical parts of the cellular machinery and therefore exhibit a diverse spectrum of biological activity. In the past ten years, there have appeared many new methods for the synthesis of difluoromethylene phosphonates. Most notably, photoredox catalysis has firmly entered the field, while cross‐coupling and nucleophilic strategies have met considerable elaboration and refinement, entirely in accord with the current trends in synthetic organic chemistry. Herein, we introduce difluoromethylene phosphonates as a distinct, high‐tech subclass of synthetic phosphonates resulting from the research efforts on the cross‐section of organophosphorus, organofluorine, and bioorganic chemistry. We then proceed to the discussion of general methods for the preparation of difluoromethylene phosphonates, comprehensively reviewing reactions developed in the past 15 years while providing the context of earlier works where appropriate. Finally, we present selected examples of molecules with high biological activity, their biological targets, and the synthetic steps employed for their preparation.

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“…Consequently, nucleophilic, − electrophilic, − and radical − difluoromethylations have been developed. Electrophilic difluoromethylation using difluorocarbene is a popular method for insertion of −CF 2 – into alkenes/alkynes, , as well as C–H, , O–H, S–H, N–H, and P–H bonds. Numerous reagents have been developed to generate difluorocarbene.…”

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confidence: 99%

Chemoselective N- and O-Difluoromethylation of 2-Pyridones, Isoquinolinones, and Quinolinones with TMSCF₂Br

et al. 2021

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An operationally simple protocol for direct N- and O-difluoromethylation of 2-pyridones, quinolinones, and isoquinolinones using commercially available TMSCF2Br is disclosed. The chemoselectivity is modulated by simple variations in temperature, solvent, and strength of the base. Diverse, synthetically relevant functional groups are tolerated, including functional groups that have reported reactivity with TMSCF2Br. Gram-scale reactions to prepare both N- and O-difluoromethyl compounds are included.

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Siladifluoromethylation and Deoxo-trifluoromethylation of P^V–H Compounds with TMSCF₃: Route to P^V–CF₂^– Transfer Reagents and P–CF₃ Compounds

Cited by 26 publications

References 69 publications

Difluorocarbene Generation from TMSCF₃: Kinetics and Mechanism of NaI-Mediated and Si-Induced Anionic Chain Reactions

Difluorocarbene Generation from TMSCF₃: Kinetics and Mechanism of NaI-Mediated and Si-Induced Anionic Chain Reactions

Recent Advances in Synthesis of Difluoromethylene Phosphonates for Biological Applications

Chemoselective N- and O-Difluoromethylation of 2-Pyridones, Isoquinolinones, and Quinolinones with TMSCF₂Br

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Siladifluoromethylation and Deoxo-trifluoromethylation of PV–H Compounds with TMSCF3: Route to PV–CF2– Transfer Reagents and P–CF3 Compounds

Cited by 26 publications

References 69 publications

Difluorocarbene Generation from TMSCF3: Kinetics and Mechanism of NaI-Mediated and Si-Induced Anionic Chain Reactions

Difluorocarbene Generation from TMSCF3: Kinetics and Mechanism of NaI-Mediated and Si-Induced Anionic Chain Reactions

Recent Advances in Synthesis of Difluoromethylene Phosphonates for Biological Applications

Chemoselective N- and O-Difluoromethylation of 2-Pyridones, Isoquinolinones, and Quinolinones with TMSCF2Br

Contact Info

Product

Resources

About

Siladifluoromethylation and Deoxo-trifluoromethylation of P^V–H Compounds with TMSCF₃: Route to P^V–CF₂^– Transfer Reagents and P–CF₃ Compounds

Difluorocarbene Generation from TMSCF₃: Kinetics and Mechanism of NaI-Mediated and Si-Induced Anionic Chain Reactions

Difluorocarbene Generation from TMSCF₃: Kinetics and Mechanism of NaI-Mediated and Si-Induced Anionic Chain Reactions

Chemoselective N- and O-Difluoromethylation of 2-Pyridones, Isoquinolinones, and Quinolinones with TMSCF₂Br