Two Approaches to a Trifluoromethyl Triazole: A Fit-for-Purpose Trifluoromethylation in Flow-Mode and a Long-Term Decarboxylative Click Approach

Ayothiraman, Rajaram; Gangu, Aravind S.; Bandaru, Durgarao; Guturi, Siva Krishna; Lakshminarasimhan, Thirumalai; Jaleel, Mohamed; Kanagavel, Kishorekumar; Rangaswamy, Sundaramurthy; Cuniere, Nicolas; Zaretsky, Serge; Eastgate, Martin D.; Vaidyanathan, Rajappa

doi:10.1021/acs.oprd.9b00492

Cited by 8 publications

(11 citation statements)

References 23 publications

(28 reference statements)

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“…[38] A 1-aryl-4-CF 3 -1,2,3-triazole was prepared either by a late-stage trifluoromethylation of the corresponding 1-aryl-4-iodo-1,2,3-triazole or by decarboxylative Cu(I)-catalyzed [3 + 2] cycloaddition from ethyl 4,4,4-trifluorobut-2-ynoate/LiOH and an aryl azide. [39] Characteristic features of our method are: mild reaction conditions of the 1,3-dipolar cycloaddition, complete regioselectivity, and introduction of an aldiminium or ketiminium functional group at the C-4 position of the triazole ring, followed by in situ transformation of the iminium group into a variety of other substituents.…”

Section: Trapping Reactions With Organoazidesmentioning

confidence: 99%

3‐Trifloxy‐3‐(trifluoromethyl)prop‐2‐ene 1‐Iminium Salts as Precursors for Elusive 3‐(Trifluoromethyl)prop‐2‐yne 1‐Iminium Salts

et al. 2021

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prop-2-yne 1-iminium triflate salts were generated from 3-trifloxy-3-(trifluoromethyl)prop-2-ene 1iminium salts by triethylamine-assisted elimination of triflic acid and trapped in situ in various cycloaddition reactions. These included Diels-Alder reactions with 1,3-dienes, [2 + 2] cyclo-addition with 1,4-diphenylbuta-1,3-diene, and [3 + 2] cycloaddition with organoazides. All these reactions revealed the excellent dienophilic and dipolarophilic reactivity of the electrophilic C,C triple bond of the novel 3-CF 3 -propyniminium salts.

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Section: Trapping Reactions With Organoazidesmentioning

confidence: 99%

3‐Trifloxy‐3‐(trifluoromethyl)prop‐2‐ene 1‐Iminium Salts as Precursors for Elusive 3‐(Trifluoromethyl)prop‐2‐yne 1‐Iminium Salts

et al. 2021

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“…It must be ensured that there are no interactions between the matrix-deactivating agent and the analyte. 30 As reported by Ayothiraman et al, 31 in one of our recent internal programs, the synthesis of an arylated trifluoromethyl triazole from an amine using TBN as a reagent (Scheme S1 of Supporting Information) was performed. It was imperative to check for trace levels of residual TBN in the reaction mixture before the next step, and a reliable method was required.…”

Section: ■ Introductionmentioning

confidence: 99%

“…The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.oprd.1c00158. Pharmaceutical intermediate synthetic scheme reproduced from Ayothiraman et al, preliminary experimental data for method selection (LC–MS, GC–FID, and GC–MS data), the correlation between TBN degradation and solvent parameters, TBN degradation profile in various solvents, and TBN stability profile in basicified diluents (PDF) …”

mentioning

confidence: 99%

Low-Level Quantification of tert-Butyl Nitrite in a Pharmaceutical Intermediate

Patel

Chokkalingam

Das

et al. 2021

Org. Process Res. Dev.

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A sensitive, reliable, and reproducible headspace gas chromatography-flame ionization detection method was developed and validated to detect and quantify low levels of tert-butyl nitrite (TBN). TBN is a reagent commonly used by synthetic chemists for nitrogen insertion reactions and is also a potential mutagenic impurity due to a structurally alerting nitrite group. However, there is an inherent analytical challenge in the quantification of TBN due to its chemical instability in solution (e.g., degradation of TBN to tert-butyl alcohol, TBA, in protic solvents). The proposed methodology is based on stabilizing TBN in solution by adding imidazole to a sample diluent before static headspace gas chromatographic analysis. The gas chromatography method utilizes a high-polarity poly(ethylene glycol) stationary phase that provides the resolution of TBN from an interference peak in the sample matrix and facilitates the attainment of the required sensitivity of the TBN peak. The limit of detection (LOD) and limit of quantitation (LOQ) of this method were established as 0.05 μg mL −1 (0.05 ppm) and 0.15 μg mL −1 (0.15 ppm), respectively. Method validation experiments indicated excellent analytical performance of the method with respect to specificity (resolution of ∼2.2 from a matrix interference peak), linearity (range: 16.7−1000% of the working concentration), precision (relative standard deviation, RSD, of 1.0% for n = 6 at LOQ level), and recovery (94% at LOQ level). This is the first report of a practical strategy to stabilize TBN for its trace-level quantification.

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“…1a ). As part of an ongoing development program, we sought a straightforward access to N -aryl-1,2,3-triazole 1a 5 . An attractive and efficient approach to access such heterocyclic motif is the C–H functionalization of 1-aryl-1 H -1,2,3-triazoles such as 2a (Fig.…”

Section: Introductionmentioning

confidence: 99%

Regioselective functionalization of aryl azoles as powerful tool for the synthesis of pharmaceutically relevant targets

et al. 2020

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Aryl azole scaffolds are present in a wide range of pharmaceutically relevant molecules. Their ortho-selective metalation at the aryl ring is challenging, due to the competitive metalation of the more acidic heterocycle. Seeking a practical access to a key Active Pharmaceutical Ingredient (API) intermediate currently in development, we investigated the metalation of 1-aryl-1H-1,2,3-triazoles and other related heterocycles with sterically hindered metal-amide bases. We report here a room temperature and highly regioselective ortho-magnesiation of several aryl azoles using a tailored magnesium amide, TMPMgBu (TMP = 2,2,6,6-tetramethylpiperidyl) in hydrocarbon solvents followed by an efficient Pd-catalyzed arylation. This scalable and selective reaction allows variation of the initial substitution pattern of the aryl ring, the nature of the azole moiety, as well as the nature of the electrophile. This versatile method can be applied to the synthesis of bioactive azole derivatives and complements existing metal-mediated ortho-functionalizations.

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Two Approaches to a Trifluoromethyl Triazole: A Fit-for-Purpose Trifluoromethylation in Flow-Mode and a Long-Term Decarboxylative Click Approach

Cited by 8 publications

References 23 publications

3‐Trifloxy‐3‐(trifluoromethyl)prop‐2‐ene 1‐Iminium Salts as Precursors for Elusive 3‐(Trifluoromethyl)prop‐2‐yne 1‐Iminium Salts

3‐Trifloxy‐3‐(trifluoromethyl)prop‐2‐ene 1‐Iminium Salts as Precursors for Elusive 3‐(Trifluoromethyl)prop‐2‐yne 1‐Iminium Salts

Low-Level Quantification of tert-Butyl Nitrite in a Pharmaceutical Intermediate

Regioselective functionalization of aryl azoles as powerful tool for the synthesis of pharmaceutically relevant targets

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