Protokol til syntese af<em> Ortho</em> -trifluoromethoxylated anilinderivater
Summary
An operationally simple procedure for the synthesis of ortho-trifluoromethoxylated aniline derivatives via a two-step sequence of O-trifluoromethylation of N-aryl-N-hydroxyacetamide followed by thermally induced intramolecular OCF3-migration is reported.
Abstract
Molekyler, der bærer trifluoromethoxy (OCF 3) gruppe ofte viser ønsket farmakologiske og biologiske egenskaber. Men facile syntese af trifluoromethoxylated aromatiske forbindelser er fortsat en enorm udfordring i organisk syntese. Konventionelle metoder ofte lider af dårligt substrat rækkevidde, eller kræver brug af meget giftige, svært at håndtere, og / eller termisk labile reagenser. Heri rapporterer vi en brugervenlig protokol for syntesen af methyl-4-acetamido-3- (trifluormethoxy) benzoat under anvendelse af 1-trifluormethyl-1,2-benziodoxol-3 (1H) -on (Togni reagens II). Behandling af methyl-4- (N -hydroxyacetamido) benzoat (1a) med Togni reagens II i nærvær af en katalytisk mængde cæsiumcarbonat (CS2 CO 3) i chloroform ved stuetemperatur gav methyl-4- (N – (trifluormethoxy) acetamido) benzoat (2a). Dette mellemprodukt blev derefter omdannet til slutproduktet methyl-4-acetamido-3- (trifluoromethoxy) benzoat (3a) i nitromethan ved 120 ° C. Denne procedure er generel og kan anvendes til syntese af et bredt spektrum af ortho -trifluoromethoxylated anilinderivater, der kunne tjene som nyttige syntetiske byggesten for opdagelsen og udvikling af nye lægemidler, landbrugskemikalier og funktionelle materialer.
Introduction
Den trifluoromethoxy (OCF 3) gruppe har lavet en dybtgående indvirkning på liv og materialevidenskab forskning siden den første syntese af trifluormethyl ether i 1935. 2 På grund af sin unikke kombination af høj elektronegativitet (χ = 3,7) 3 og fremragende lipofilitet (Π x = 1,04), 4 trifluormethoxy- gruppe har fundet bred anvendelse inden for medicin, landbrug og materialer industrien. 5-10 Men facile indførelse af OCF 3 gruppe i organiske molekyler, især aromatiske forbindelser, er fortsat en stor udfordring i syntetisk kemi.
I løbet af de seneste årtier, bestræbelser på at løse denne udfordring førte til udviklingen af en håndfuld transformationer til syntese af trifluoromethoxylated arener 5-7,9-11 Disse omfatter (i) klor / fluor udveksling på trichlorerede forstadier;. 1,12 -17 (ii) deoxyfluorination af fluoroformates; 18 </sup> (iii) oxidativ fluorodesulfurization, 19-21 (iv) elektrofil trifluoromethylation af alkoholer, 22-25 (v) nukleofil trifluoromethoxylation, 26-30, (vi) overgangsmetal-medierede trifluoromethoxylation aryl- borater og stannaner, 31 og (vii ) radikale trifluoromethoxylation. 32,33 Ikke desto mindre er mange af disse tilgange enten lider dårligt substrat omfang eller kræver brug af meget giftige og / eller termisk labile reagenser. Derfor, på grund af manglen på en generel og brugervenlig metode til at syntetisere OCF 3 holdige forbindelser, potentialet i OCF 3-gruppen er ikke blevet fuldt udnyttet i kemi.
Som en del af vores interesse i trifluoromethoxylation reaktioner, 34 beskrives heri en totrins-protokol (dvs. radikal O -trifluoromethylation og termisk induceret OCF3 -migration) til syntese af methyl-4-acetamido-3- (trifluormethoxy) benzoat (3a) ud fra methyl-4- (N -hydroxyacetamido) benzoat (1a). Strategien er let at betjene og som gælder for syntesen af en lang række ortho -trifluoromethoxylated anilinderivater.
Protocol
Representative Results
Discussion
På grund af manglen på en generel og brugervenlig fremgangsmåde til syntesen af trifluoromethoxylated arener, mange OCF3 holdige aromatiske forbindelser er ekstremt dyre. 34 Vores strategi forskyder en bred funktionel gruppe tolerance og giver en nem adgang til forskellige trifluoromethoxylated arener. Disse forbindelser kunne fungere som værdifulde byggesten til opdagelse og udvikling af nye lægemidler, landbrugskemikalier og materialer.
Hydrazin blev anvendt som …
Declarações
The authors have nothing to disclose.
Acknowledgements
Vi anerkender generøse nystartede midler fra State University of New York at Stony Brook til støtte for dette arbejde. Vi takker også TOSOH F-Tech, Inc. for at give os TMSCF 3 reagens til syntese af Togni reagens II.
Materials
| 5% Rhodium on carbon | Aspira Scientific | 300835 | 5% wt% dry loading |
| hydrazine monohydrate | Sigma-Alderich | 13696HMV | Reagent grade, 98% |
| Acetyl chloride | Alfa Aesar | 10176887 | 98% |
| Sodium bicarbonate | Fisher Scientific | 134826 | Chemical pure |
| Cesium carbonate | Alfa Aesar | 12887 | 99.9%, metals basis |
| Togni Reagent II | Prepared according to the literature procedure (ref 37). Caution: Pure Togni reagent II is impact and friction sensitive, treat it with great care (see ref. 36). | ||
| Tetrahydrofuran | BDH | BDH1149-4LG | Distilled from deep purple sodium benzophenone ketyl. |
| Diethyl Ether | Fisher Scientific | 148221 | Distilled from deep purple sodium benzophenone ketyl. |
| Chloroform | Fisher Scientific | 141739 | Dried over CaH2 and distilled |
| nitro methane | Alfa Aesar | J03z053 | Dried over CaSO4 and distilled |
| Silica gel | SILICYCLE | 60514 | 40-63 µm (230-400 mesh) |
| Cilite | EMD | 2012040674 | Not acid washed |
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