We acknowledge generous start-up funds from the State University of New York at Stony Brook in support of this work. We also thank TOSOH F-Tech, Inc. for providing us TMSCF3 reagent for the synthesis of Togni reagent II.

1. Vorläuferherstellung: Synthese von Methyl-4- (N -hydroxyacetamido) benzoat (1a) <ol><li> Reduktion von Methyl-4-nitrobenzoesäuremethylester. <ol><li> Hinzufügen 5,00 g Methyl-4-nitrobenzoesäuremethylester (27,6 mmol, 1,00 Äquivalente), 159 mg 5% Rhodium auf Kohlenstoff (Rh / C, 0,300 Mol-% Rh), und einen magnetischen Rührstab in einen im Ofen getrockneten 250 ml Zwei Halsrundkolben (bei 150 ° C für 18 Stunden getrocknet). HINWEIS: Die Reagenzien kann unter Umgebungsatmosphäre abgewogen werden. Allerdings muss die Reaktion unter Stickstoffatmosphäre durchgeführt werden. </li><li> Verbinden Sie ein Hals des Kolbens, um eine Stickstoff / Vakuumverteiler und die Kappe der andere Hals mit einem Septum. Haben drei vakuum Nachfüllzyklen (dh Pumpen der Luft aus der Flasche und Ersetzen des resultierenden Vakuums mit Stickstoffgas), um die Luft in dem Kolben durch Stickstoffgas zu ersetzen. </li><li> Add 138 ml wasserfreiem Tetrahydrofuran (THF, 0,200 M) in den Reaktionskolben mit luftdichten Spritze. Kühlen und rühren Sie die Reaktions mixture bei 0 ° C für 15 min. </li><li> Hinzufügen 1,47 ml Hydrazinmonohydrat (1,52 g, 30,4 mmol, 1,20 Äquivalente) tropfenweise zu dem Reaktionsgemisch bei 0 ° C unter Verwendung eines luftdichten Spritze. Überwachen Sie die Reaktion unter Verwendung eines Dünnschicht-Chromatographie (TLC). Verwenden Hexan: Ethylacetat (EtOAc) (4: 1 v / v, Rf = 0,23) als Elutionsmittel gereinigt, um die TLC entwickeln. </li><li> Wenn Methyl-4-nitrobenzoesäuremethylester vollständig verbraucht ist, filtern das Reaktionsgemisch durch ein kurzes Kissen aus Diatomeenerde (dh Celite, 5 g) in einer 60 ml frit Büchner-Trichter unter Verwendung von Vakuumfiltration. Das Filter mit EtOAc (20 ml x 3 Mal) waschen. Das Filtrat wird im Vakuum unter Verwendung eines Rotationsverdampfers entfernt, um das rohe Methyl-4- (N -hydroxyamino) benzoat, welches direkt ohne weitere Reinigung verwendet wird. </li></ol></li><li> Acetyl Schutz von Methyl-4- (N -hydroxyamino) benzoat <ol><li> Hinzufügen 2,55 g Natriumhydrogencarbonat (NaHCO 3, 30,4 mmol, 1,20 equiv), die alle das roheMethyl-4- (N -hydroxyamino) benzoat aus dem vorherigen Schritt erhalten wird, und einem Rührstab in einen im Ofen getrockneten 500 ml Zweihalsrundkolben. </li><li> Cap One Hals mit einem Septum und schließen Sie einen anderen Ansatz zu einer Stickstoff / Vakuumverteiler. Haben drei vakuum Nachfüllzyklen, um die Luft in dem Kolben durch Stickstoffgas zu ersetzen. </li><li> Add 138 ml wasserfreiem Diethylether (Et 2 O, 0,200 M) in den Reaktionskolben unter Verwendung eines luftdichten Spritze. Kühlen und rühren Sie die Reaktionsmischung bei 0 ° C für 15 min. </li><li> Eine Lösung aus Acetylchlorid (2,17 ml, 2,39 g, 30,4 mmol, 1,20 Äquivalente) in wasserfreiem Et 2 O (138 ml, 0,220 M). Zugeben der Lösung zu dem Reaktionsgemisch bei 0 ° C unter Verwendung einer Spritzenpumpe mit einer Rate von 10,0 ml / Std. </li><li> Am Ende der Zugabe filtriert man das Reaktionsgemisch durch ein kurzes Kissen aus Diatomeenerde (dh Celite, 5 g) in 60 ml frit Büchner-Trichter unter Verwendung von Vakuumfiltration. Das Filter mit EtOAc (20 ml x 3 Mal) waschen. Konzentrieren sich dieFiltrat im Vakuum am Rotationsverdampfer. </li><li> Das Rohprodukt wird mit Flash-Säulenchromatographie unter 35 unter Eluieren mit Hexan: EtOAc (4: 1 bis 1: 1 (v / v)) (R f = 0,13, Hexane: EtOAc (4: 1 (v / v)), um 5,31 leisten g Methyl-4- (N -hydroxyacetamido) -benzoat als hellgelben Feststoff (25,4 mmol, 92% Ausbeute). </li></ol></li></ol> 2. Synthese von Methyl-4- (N - (Trifluormethoxy) acetamido) benzoat (2a) <ol><li> Hinzufügen von 2,00 g Methyl-4- (N -hydroxyacetamido) benzoat (1a) (9,56 mmol, 1,00 Äquivalente), 311 mg Cs 2 CO 3 (0,956 mmol, 10,0 mol%), 3,63 g Togni Reagenz II (11,5 mmol, 1,20 equiv) und einem Magnetrührstab in einen ofengetrockneten 250 ml-Rundkolben in einer Glovebox (Stickstoffatmosphäre). ANMERKUNG: Diese Reaktion kann auch unter Verwendung von Schlenk-Techniken außerhalb der Glovebox erfolgen. Achtung: Reine Togni-Reagens II ist Schlag und Reibung empfindlich, offene Flammens sollte Funken und / oder Schleifen zu vermeiden. Weich und poliert Werkzeuge sollten für Manipulationen verwendet werden. Darüber hinaus sollte das Reaktionsgemisch hinter einem Sicherheitsschild gerührt werden. 36 </li><li> Hinzufügen 95,6 ml getrocknetem und entgastem Chloroform (CHCl 3, 0,100 M) in den Reaktionskolben. </li><li> Kappe der Flasche mit Septum gegeben und das Reaktionsgemisch bei 23 ° C unter N 2 -Atmosphäre innerhalb oder außerhalb des Handschuhfachs 16 Stunden. </li><li> Filtern der Reaktionsmischung durch ein Filtertrichter jede feste Rückstände zu entfernen. Das Filtrat wird im Vakuum unter Verwendung eines Rotationsverdampfers. </li><li> Das Rohprodukt wird mit Flash-Säulenchromatographie unter Elution mit Hexan: Dichlormethan (CH 2 Cl 2) (7: 3 auf 0: 1 (v / v)) (R f = 0,44 (CH 2 Cl 2) gereinigt, 2,51 g Methyl-4- (N - (Trifluormethoxy) acetamido) -benzoat (9,05 mmol, 95% Ausbeute). HINWEIS: Togni-Reagens II ist bereit according zu den Literaturverfahren 37 und in der Glovebox Gefrierapparat bei -35 ° C gelagert, um seine Qualität über einen langen Zeitraum aufrechtzuerhalten. Diese Reaktion ist sauerstoffempfindlich. Obwohl alle Reagenzien können unter Umgebungsatmosphäre bei RT gewogen werden, ist die Entfernung von allem Sauerstoff aus dem Reaktionskolben kritisch. Getrocknet und entgast CHCl 3 wird durch Destillation aus CaH 2 unter Stickstoffatmosphäre, gefolgt von Ausführen einer drei Zyklen von dem Gefrier-Pump-Tau-Verfahren hergestellt. </li></ol> 3. Synthese von 4-Acetamido-3- (trifluormethoxy) benzoat über OCF 3 -Migration (3a) <ol><li> Hinzufügen 2,51 g Methyl-4- (N - (Trifluormethoxy) acetamido) -benzoat (9,05 mmol, 1,0 Äquivalente), einem Magnetrührstab und 9,05 ml MeNO 2 (1,00 M) in einem 50 ml Druckgefäß. Kappe der Behälter mit einem Schraubdeckel. </li><li> Das Reaktionsgemisch wird bei 120 ° C hinter dem Sicherheitsschild 20 Std. Achtung: Unreine Nitromethanexplosiv, so sollte das Reaktionsgemisch hinter dem Sicherheitsschild gerührt werden. </li><li> Kühle das Reaktionsgemisch auf RT. </li><li> Übertragen der Reaktionsmischung in einen 100 ml Rundkolben. </li><li> Konzentriere das Reaktionsgemisch im Vakuum am Rotationsverdampfer. </li><li> Das Rohprodukt wird mit Flash-Säulenchromatographie unter Elution mit Hexan: EtOAc (9: 1 bis 7: 3 (v / v)) (R f = 0,51 Hexan: EtOAc (4: 1 (v / v)) gereinigt, 2,13 g Methyl-4-acetamido-3- (trifluormethoxy) benzoat (7,69 mmol, 85%). ANMERKUNG: Diese Reaktion kann unter Umgebungsatmosphäre durchgeführt werden. Stickstoffatmosphäre nicht erforderlich ist. Ein Rundkolben, der mit einem Wasserabscheider ausgestattet ist als Alternative Reaktionsvorrichtung verwendet werden. </li></ol> 4. Charakterisierung Neue Artikel <ol><li> Charakterisieren Sie alle neuen Verbindungen, die durch 1 H, 13 C-NMR-Spektroskopie und hochauflösende Massenspektroskopie und verwenden 19 F-NMR-Spektroskopiezur Charakterisierung von Verbindungen, die Fluoratome enthält. 34 </li></ol>

<ol>
	<li>Yagupolskii, L. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Sintez+proizvodnykh+feniltriftormetilovogo+efira.">Sintez proizvodnykh feniltriftormetilovogo efira.</a> Dokl. Akad. Nauk SSSR. 105, 100-102 (1955).</li><li>Booth, H. S., Burchfield, P. E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Fluorination+of+halogeno+methyl+ethers.+I.+Fluorination+of+trichlorodimethyl+ether.">Fluorination of halogeno methyl ethers. I. Fluorination of trichlorodimethyl ether.</a> J. Am. Chem. Soc. 57, 2070 (1935).</li><li>McClinton, M. A., McClinton, D. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Trifluoromethylations+and+related+reactions+in+organic-chemistry.">Trifluoromethylations and related reactions in organic-chemistry.</a> Tetrahedron. 48, 6555-6666 (1992).</li><li>Hansch, C., Leo, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=.">.</a> Substituent Constants for Correlation Analysis in Chemistry and Biology. , (1979).</li><li>Leroux, F., Jeschke, P., Schlosser, M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Alpha-fluorinated+ethers,+thioethers,+and+amines:+Anomerically+biased+species.">Alpha-fluorinated ethers, thioethers, and amines: Anomerically biased species.</a> Chem. Rev. 105, 827-856 (2005).</li><li>Jeschke, P., Baston, E., Leroux, F. R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Alpha-fluorinated+ethers+as+'exotic'+entity+in+medicinal+chemistry.">Alpha-fluorinated ethers as 'exotic' entity in medicinal chemistry.</a> Mini-Rev. Med. Chem. 7, 1027-1034 (2007).</li><li>Leroux, F. R., Manteau, B., Vors, J. P., Pazenok, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Trifluoromethyl+ethers+-+synthesis+and+properties+of+an+unusual+substituent.">Trifluoromethyl ethers - synthesis and properties of an unusual substituent.</a> Beilstein J. Org. Chem. 4, (2008).</li><li>Fantasia, S., Welch, J. M., Togni, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Reactivity+of+a+hypervalent+iodine+trifluoromethylating+reagent+toward+THF:+ring+opening+and+formation+of+trifluoromethyl+ethers.">Reactivity of a hypervalent iodine trifluoromethylating reagent toward THF: ring opening and formation of trifluoromethyl ethers.</a> J. Org. Chem. 75, 1779-1782 (2010).</li><li>Manteau, B., Pazenok, S., Vors, J. P., Leroux, F. R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=New+trends+in+the+chemistry+of+alpha-fluorinated+ethers,+thioethers,+amines+and+phosphines.">New trends in the chemistry of alpha-fluorinated ethers, thioethers, amines and phosphines.</a> J. Fluorine Chem. 131, 140-158 (2010).</li><li>Landelle, G., Panossian, A., Leroux, F. R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Trifluoromethyl+ethers+and+-thioethers+as+tools+for+medicinal+chemistry+and+drug+discovery.">Trifluoromethyl ethers and -thioethers as tools for medicinal chemistry and drug discovery.</a> Curr. Top. Med. Chem. 14, 941-951 (2014).</li><li>Liang, T., Neumann, C. N., Ritter, T. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Introduction+of+fluorine+and+fluorine-containing+functional+groups.">Introduction of fluorine and fluorine-containing functional groups.</a> Angew. Chem. Int. Ed. 52, 8214-8264 (2013).</li><li>Yarovenko, N. N., Vasileva, A. S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+new+method+for+the+introduction+of+trihalomethyl+groups+into+organic+molecules.">A new method for the introduction of trihalomethyl groups into organic molecules.</a> Zh. Obshch. Khim. 28, 2502-2504 (1958).</li><li>Yagupols, L., Troitskaya, V. I. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Synthesis+of+phenyl+trifluoromethyl+ether+derivatives.">Synthesis of phenyl trifluoromethyl ether derivatives.</a> Zh. Obshch. Khim. 31, 915-924 (1961).</li><li>Yagupolskii, L. M., Orda, V. V. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Bis(triftormetoksi+I+triftormetilmerkapto)-proizvodnye+benzola.">Bis(triftormetoksi I triftormetilmerkapto)-proizvodnye benzola.</a> Zh. Obshch. Khim. 34, 1979-1984 (1964).</li><li>Louw, R., Franken, P. W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Selective+side-chain+chlorination+of+methoxybenzenes.">Selective side-chain chlorination of methoxybenzenes.</a> Chem Ind-London. , 127-128 (1977).</li><li>Feiring, A. E. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Chemistry+in+hydrogen-fluoride.+7.+Novel+synthesis+of+aryl+trifluoromethyl+ethers.">Chemistry in hydrogen-fluoride. 7. Novel synthesis of aryl trifluoromethyl ethers.</a> J. Org. Chem. 44, 2907-2910 (1979).</li><li>Salome, J., Mauger, C., Brunet, S., Schanen, V. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Synthesis+conditions+and+activity+of+various+Lewis+acids+for+the+fluorination+of+trichloromethoxy-benzene+by+HF+in+liquid+phase.">Synthesis conditions and activity of various Lewis acids for the fluorination of trichloromethoxy-benzene by HF in liquid phase.</a> J. Fluorine Chem. 125, 1947-1950 (2004).</li><li>Sheppard, W. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Alpha-Fluorinated+Ethers.+I.+Aryl+Fluoroalkyl+Ethers.">Alpha-Fluorinated Ethers. I. Aryl Fluoroalkyl Ethers.</a> J. Org. Chem. 29, 1-11 (1964).</li><li>Kuroboshi, M., Suzuki, K., Hiyama, T. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Oxidative+desulfurization-fluorination+of+xanthates+-+a+convenient+synthesis+of+trifluoromethyl+ethers+and+difluoro(methylthio)methyl+ethers.">Oxidative desulfurization-fluorination of xanthates - a convenient synthesis of trifluoromethyl ethers and difluoro(methylthio)methyl ethers.</a> Tetrahedron Lett. 33, 4173-4176 (1992).</li><li>Kanie, K., Tanaka, Y., Suzuki, K., Kuroboshi, M., Hiyama, T. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+convenient+synthesis+of+trifluoromethyl+ethers+by+oxidative+desulfurization-fluorination+of+dithio+carbonates.">A convenient synthesis of trifluoromethyl ethers by oxidative desulfurization-fluorination of dithio carbonates.</a> Bull. Chem. Soc. Jpn. 73, 471-484 (2000).</li><li>Kuroboshi, M., Kanie, K., Hiyama, T. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Oxidative+desulfurization-fluorination:+A+facile+entry+to+a+wide+variety+of+organofluorine+compounds+leading+to+novel+liquid-crystalline+materials.">Oxidative desulfurization-fluorination: A facile entry to a wide variety of organofluorine compounds leading to novel liquid-crystalline materials.</a> Adv. Synth. Catal. 343, 235-250 (2001).</li><li>Umemoto, T. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Electrophilic+perfluoroalkylating+agents.">Electrophilic perfluoroalkylating agents.</a> Chem. Rev. 96, 1757-1777 (1996).</li><li>Umemoto, T., Adachi, K., Ishihara, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=CF3+oxonium+salts,+O-(trifluoromethyl)dibenzofuranium+salts:+in+situ+synthesis,+properties,+and+application+as+a+real+CF3++species+reagent.">CF3 oxonium salts, O-(trifluoromethyl)dibenzofuranium salts: in situ synthesis, properties, and application as a real CF3+ species reagent.</a> J. Org. Chem. 72, 6905-6917 (2007).</li><li>Stanek, K., Koller, R., Togni, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Reactivity+of+a+10-I-3+hypervalent+iodine+trifluoromethylation+reagent+with+phenols.">Reactivity of a 10-I-3 hypervalent iodine trifluoromethylation reagent with phenols.</a> J. Org. Chem. 73, 7678-7685 (2008).</li><li>Koller, R., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Zinc-mediated+formation+of+trifluoromethyl+ethers+from+alcohols+and+hypervalent+iodine+trifluoromethylation+reagents.">Zinc-mediated formation of trifluoromethyl ethers from alcohols and hypervalent iodine trifluoromethylation reagents.</a> Angew. Chem. Int. Ed. 48, 4332-4336 (2009).</li><li>Trainor, G. L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+preparation+of+O-trifluoromethyl+carbohydrates.">The preparation of O-trifluoromethyl carbohydrates.</a> J. Carbohydr. Chem. 4, 545-563 (1985).</li><li>Nishida, M., Vij, A., Kirchmeier, R. L., Shreeve, J. M. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Synthesis+of+polyfluoro+aromatic+ethers+-+a+facile+route+using+polyfluoroalkoxides+generated+from+carbonyl+and+trimethysilyl+compounds.">Synthesis of polyfluoro aromatic ethers - a facile route using polyfluoroalkoxides generated from carbonyl and trimethysilyl compounds.</a> Inorg. Chem. 34, 6085-6092 (1995).</li><li>Kolomeitsev, A. A., Vorobyev, M., Gillandt, H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Versatile+application+of+trifluoromethyl+triflate.">Versatile application of trifluoromethyl triflate.</a> Tetrahedron Lett. 49, 449-454 (2008).</li><li>Marrec, O., Billard, T., Vors, J. P., Pazenok, S., Langlois, B. R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+deeper+insight+into+direct+trifluoromethoxylation+with+trifluoromethyl+triflate.">A deeper insight into direct trifluoromethoxylation with trifluoromethyl triflate.</a> J. Fluorine Chem. 131, 200-207 (2010).</li><li>Marrec, O., Billard, T., Vors, J. P., Pazenok, S., Langlois, B. R. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+new+and+direct+trifluoromethoxylation+of+aliphatic+substrates+with+2,4-dinitro(trifluoromethoxy)benzene.">A new and direct trifluoromethoxylation of aliphatic substrates with 2,4-dinitro(trifluoromethoxy)benzene.</a> Adv. Synth. Catal. 352, 2831-2837 (2010).</li><li>Huang, C. H., Liang, T., Harada, S., Lee, E., Ritter, T. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Silver-mediated+trifluoromethoxylation+of+aryl+stannanes+and+arylboronic+acids.">Silver-mediated trifluoromethoxylation of aryl stannanes and arylboronic acids.</a> J. Am. Chem. Soc. 133, 13308-13310 (2011).</li><li>Rozen, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Selective+fluorinations+by+reagents+containing+the+OF+group.">Selective fluorinations by reagents containing the OF group.</a> Chem. Rev. 96, 1717-1736 (1996).</li><li>Venturini, F., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Direct+trifluoro-methoxylation+of+aromatics+with+perfluoro-methyl-hypofluorite.">Direct trifluoro-methoxylation of aromatics with perfluoro-methyl-hypofluorite.</a> J. Fluorine Chem. 140, 43-48 (2012).</li><li>Hojczyk, K. N., Feng, P., Zhan, C., Ngai, M. -. Y. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Trifluoromethoxylation+of+arenes:+synthesis+of+ortho-trifluoromethoxylated+aniline+derivatives+by+OCF3+migration.">Trifluoromethoxylation of arenes: synthesis of ortho-trifluoromethoxylated aniline derivatives by OCF3 migration.</a> Angew. Chem. Int. Ed. 53, 14559-14563 (2014).</li><li>Still, W. C., Kahn, M., Mitra, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Rapid+chromatographic+technique+for+preparative+separations+with+moderate+Resolution.">Rapid chromatographic technique for preparative separations with moderate Resolution.</a> J. Org. Chem. 43, 2923-2925 (1978).</li><li>Fiederling, N., Haller, J., Schramm, H. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Notification+about+the+Explosive+Properties+of+Togni's+Reagent+II+and+One+of+Its+Precursors.">Notification about the Explosive Properties of Togni's Reagent II and One of Its Precursors.</a> Org. Process Res. Dev. 17, 318-319 (2013).</li><li>Matousek, V., Pietrasiak, E., Schwenk, R., Togni, A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=One-pot+synthesis+of+hypervalent+iodine+reagents+for+electrophilic+trifluoromethylation.">One-pot synthesis of hypervalent iodine reagents for electrophilic trifluoromethylation.</a> J. Org. Chem. 78, 6763-6768 (2013).</li></ol>

The authors declare no competing financial interests.

Due to the lack of a general and user-friendly procedure for the synthesis of trifluoromethoxylated arenes, many OCF3-containing aromatic compounds are extremely expensive.34 Our strategy displaces a broad functional group tolerance and provides an easy access to various trifluoromethoxylated arenes. These compounds could serve as valuable building blocks for the discovery and development of new pharmaceuticals, agrochemicals, and materials.
Hydrazine was used as a hydrogen source for the rhodium-catalyzed reduction of nitroarenes. Its quality is one of the keys in obtaining the reduction products in high yields. The reduction yields dropped when a few-month old hydrazine was used. To ensure the reproducibility, we transferred some of the hydrazine from a large commercial bottle to a smaller 20 ml vial and used it from the 20 ml vial. In addition, we stored it in the refrigerator (4 &#176;C) to slow down the rate of decomposition. Moreover, slow addition of hydrazine is crucial in getting clean hydroxylamines in good yields.
The O-trifluoromethylation is a radical mediated process, so exclusion of oxygen from the reaction mixture is critical. Using un-degassed chloroform as the solvent or performing the reaction under ambient atmosphere resulted in lower yield. Our preliminary mechanistic studies shown that the OCF3-migration process involved thermally induced heterolytic cleavage of the N-OCF3 bond to generate a tight ion pair of nitrenium ion and trifluoromethoxide.34 Trifluoromethoxide attacks the ortho-position of the nitrenium ion followed by the tautomerization to afford the desired ortho-trifluoromethoxylated aniline derivatives. Formation of the nitrenium ion in electron deficient substrates is energetically disfavored and thus requires higher reaction temperature.
In summary, we reported a general and laboratory scale synthetic protocol for the regioselective synthesis of ortho-OCF3 aniline derivatives. This strategy has several unique features: (i) a wide range of functional groups and substitution patterns are tolerated; (ii) the operational simplicity of our protocol would render trifluoromethoxylation available to broader synthetic community; and (iii) the final products are novel and could be used as useful synthetic building blocks for life and materials science research. Some troubleshooting procedures are outlined here: (i) store the reduction product, aryl hydroxyl amine, in the freezer or immediately use it for the next step; (ii) monitor the reduction/protection reactions closely with TLC to avoid over reduction of nitroarenes or protection of N-hydroxyamines; (iii) exclusion of oxygen from the reaction mixtures is critical for the reduction of nitroarenes and O-trifluoromethylation; (iv) higher reaction temperature is needed for electron deficient arenes in the intramolecular OCF3-migration step.

Die Trifluormethoxy (OCF 3) Gruppe hat eine tief greifende Auswirkungen auf das Leben und den Materialwissenschaften Forschung seit der ersten Synthese von Trifluormethyl Ether 1935 2 Aufgrund seiner einzigartigen Kombination aus hoher Elektronegativität gemacht (χ = 3,7) 3 und ausgezeichnete Lipophilie (Π x = 1.04), 4 die Trifluormethoxygruppe hat breite Anwendungen in der Medizin, der Landwirtschaft und Materialien der Industrie gefunden. 5-10, einfache Einführung des OCF 3 -Gruppe in organische Moleküle, insbesondere aromatische Verbindungen, bleibt eine der größten Herausforderungen in der Synthesechemie. Im Laufe der letzten Jahrzehnte, die Bemühungen um dieser Herausforderung zu begegnen, führte zur Entwicklung von einer Handvoll von Transformationen für die Synthese von trifluoromethoxylated Arenen 5-7,9-11 Diese umfassen (i) Chlor / Fluor-Austausch am trichlorierte Vorläufern;. 1,12 17 (ii) deoxyfluorination von Fluorformiate; 18 </sup&gt; (iii) oxidative fluorodesulfurization; 19-21 (iv) elektro Trifluormethylierung von Alkoholen; 22-25 (v) nucleophile trifluoromethoxylation; 26-30, (vi) Übergangsmetall-vermittelte trifluoromethoxylation Aryl Borate und Stannane; 31 und (vii aus armen Substratspektrum) radikale trifluoromethoxylation. 32,33 Dennoch sind viele dieser Ansätze entweder leiden oder erfordern den Einsatz von hochgiftigen und / oder thermisch labil Reagenzien. Daher wird aufgrund des Fehlens einer allgemeinen und benutzerfreundliches Verfahren zur OCF 3 -haltigen Verbindungen zu synthetisieren, wird das Potential des OCF 3 -Gruppe ist noch nicht vollständig in der Chemie genutzt. Als Teil unserer Interesse trifluoromethoxylation Reaktionen, 34 beschreiben wir hier die ein zweistufiges Protokoll (dh Rest O -trifluoromethylation und thermisch induzierte OCF 3 -Migration) für die Synthese von Methyl-4-acetamido-3- (trifluormethoxy) benzoat (3a) aus Methyl-4- (N -hydroxyacetamido) benzoat (1a). Die Strategie ist einfach zu bedienen und für die Synthese einer breiten Palette von ortho -trifluoromethoxylated Anilinderivate.

<table border="0" cellpadding="0" cellspacing="0" width="573">
	<tbody>
		<tr height="43">
			<td height="43" style="height:43px;width:216px;">5% Rhodium on carbon</td>
			<td style="width:71px;">Aspira Scientific</td>
			<td style="width:119px;">300835</td>
			<td style="width:167px;">5% wt% dry loading</td>
		</tr>
		<tr height="43">
			<td height="43" style="height:43px;width:216px;">hydrazine monohydrate</td>
			<td style="width:71px;">Sigma-Alderich</td>
			<td style="width:119px;">13696HMV</td>
			<td style="width:167px;">Reagent grade, 98%</td>
		</tr>
		<tr height="43">
			<td height="43" style="height:43px;width:216px;">Acetyl chloride</td>
			<td style="width:71px;">Alfa Aesar</td>
			<td style="width:119px;">10176887</td>
			<td style="width:167px;">98%</td>
		</tr>
		<tr height="43">
			<td height="43" style="height:43px;width:216px;">Sodium bicarbonate</td>
			<td style="width:71px;">Fisher Scientific</td>
			<td style="width:119px;">134826</td>
			<td style="width:167px;">Chemical pure</td>
		</tr>
		<tr height="43">
			<td height="43" style="height:43px;width:216px;">Cesium carbonate</td>
			<td style="width:71px;">Alfa Aesar</td>
			<td style="width:119px;">12887</td>
			<td style="width:167px;">99.9%, metals basis</td>
		</tr>
		<tr height="148">
			<td height="148" style="height:148px;width:216px;">Togni Reagent II</td>
			<td style="width:71px;"></td>
			<td style="width:119px;"></td>
			<td style="width:167px;">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).</td>
		</tr>
		<tr height="64">
			<td height="64" style="height:64px;width:216px;">Tetrahydrofuran</td>
			<td style="width:71px;">BDH</td>
			<td style="width:119px;">BDH1149-4LG</td>
			<td style="width:167px;">Distilled from deep purple sodium benzophenone ketyl.</td>
		</tr>
		<tr height="64">
			<td height="64" style="height:64px;width:216px;">Diethyl Ether</td>
			<td style="width:71px;">Fisher Scientific</td>
			<td style="width:119px;">148221</td>
			<td style="width:167px;">Distilled from deep purple sodium benzophenone ketyl.</td>
		</tr>
		<tr height="47">
			<td height="47" style="height:47px;width:216px;">Chloroform</td>
			<td style="width:71px;">Fisher Scientific</td>
			<td style="width:119px;">141739</td>
			<td style="width:167px;">Dried over CaH2 and distilled</td>
		</tr>
		<tr height="47">
			<td height="47" style="height:47px;width:216px;">nitro methane</td>
			<td style="width:71px;">Alfa Aesar</td>
			<td style="width:119px;">J03z053</td>
			<td style="width:167px;">Dried over CaSO4 and distilled</td>
		</tr>
		<tr height="43">
			<td height="43" style="height:43px;width:216px;">Silica gel</td>
			<td style="width:71px;">SILICYCLE</td>
			<td style="width:119px;">60514</td>
			<td style="width:167px;">40-63 &#181;m (230-400 mesh)</td>
		</tr>
		<tr height="22">
			<td height="22" style="height:22px;width:216px;">Cilite</td>
			<td style="width:71px;">EMD</td>
			<td style="width:119px;">2012040674</td>
			<td style="width:167px;">Not acid washed</td>
		</tr>
	</tbody>
</table>

protocol for the synthesis of ortho-trifluoromethoxylated aniline derivatives

Moleküle, die Trifluormethoxy (OCF 3) Gruppenausstellung oft gewünschten pharmakologischen und biologischen Eigenschaften. , Einfache Synthese von trifluoromethoxylated Aromaten bleibt jedoch eine große Herausforderung in der organischen Synthese. Herkömmliche Ansätze leiden häufig unter schlechten Substratbreite oder erfordern den Einsatz von hochgiftigen, schwierig zu handhabenden und / oder thermisch labil Reagenzien. Hier haben wir ein benutzerfreundliches Protokoll für die Synthese von Methyl-4-Acetamido-3- (Trifluormethoxy) benzoat mit dem Report 1-Trifluormethyl-1,2-benziodoxol-3 (1 H) -on (Togni-Reagens II). Behandlung von Methyl-4- (N -hydroxyacetamido) benzoat (1a) mit Togni Reagenz II in Gegenwart einer katalytischen Menge von Cäsiumcarbonat (Cs 2 CO 3) in Chloroform bei Raumtemperatur, die Methyl-4- (N - (Trifluormethoxy) acetamido) -benzoat (2a). Dieses Zwischenprodukt wurde dann in das Endprodukt Methyl-4-acetamido-3- (trifluorome umgewandeltthoxy) benzoat (3a) in Nitromethan bei 120 ° C. Dieses Verfahren ist allgemein und kann zur Synthese eines breiten Spektrums von ortho -trifluoromethoxylated Anilin-Derivate, die als nützliche Synthesebausteine ​​für die Entdeckung und Entwicklung neuer Pharmazeutika, Agrochemikalien und funktionellen Materialien dienen könnte angewendet werden.

Methyl-4- (N -hydroxyacetamido) benzoat (1a) wurde in 92% isolierter Ausbeute durch ein Zwei-Schritt-Verfahren synthetisiert (das heißt, die Verringerung Methyl-4-nitrobenzoat mit Hydrazin unter Verwendung von 5% Rh / C als Katalysator, um Methyl-4- (bilden N -hydroxyamino) benzoat, gefolgt von Acetyl Schutz des resultierenden Hydroxylamin). O- Trifluormethylierung von 1a mit Togni Reagenz II in Gegenwart einer katalytischen Menge von Cäsiumcarbonat (Cs 2 CO 3) in Chloroform bei RT ergab das gewünschte 4- ( N - (Trifluormethoxy) acetamido) benzoat (2a) in 95% isolierter Ausbeute. Diese Verbindung unterzog thermisch bei 120 ° C induziert OCF 3 -Migration in MeNO 2, um den gewünschten Methyl-4-acetamido-3- (trifluormethoxy) benzoat (3a) in 85% isolierter Ausbeute zu ergeben. Das 1 H, <sup&gt; 13 C und 19 F-NMR-Spektrum des Endprodukts 3a sind in Figur 1, Figur 2 und 3 dargestellt sind. Eine Unterscheidung Quartett Peak bei 120,6 ppm mit einem großen Kopplungskonstante (258,9 Hz) in 13 C-NMR-Spektren entspricht der CF 3 C. Wenn die OCF 3 -Migration stattfindet, um eine scharfe Änderung in der 19 F-NMR von -65 ppm (2a) -58.1ppm (3a) wird beobachtet. Die Detailcharakterisierungsdaten 3a wird wie folgt angegeben: R f = 0,51 (Hexan / EtOAc 4: 1 (v / v)). NMR-Spektroskopie: 1 H-NMR (700 MHz, CDCl 3, 25 ° C, δ): 8,56 (d, J = 8,6 Hz, 1H), 7,97 (d, J = 8,6 Hz, 1H), 7,93 (s, 1H) 7,56 (br. s, 1H), 3,92 (s, 3H), 2,27 (s, 3H) 13 C-NMR (175 MHz, CDCl 3, 25 ° C, δ):. 168.5, 165.6, 137.2, 134.7, 129.3 , 125,8, 121,5, 120,8, 120,6 (q, J = 258,9 Hz), 52. 0,5, 25,2 19 F-NMR (376 MHz, CDCl 3, 25 ° C, δ): -58,1 (s). Massenspektrometrie: HRMS (ESI-TOF) (m / z): Berechnet für C 11 H 11 NO 4 F 3 ([M + H] +): 278,0640, gefunden 278,0643. Dieses Protokoll ist allgemein und für eine breite Palette von aromatischen Verbindungen (Tabelle 1). Die Reaktion toleriert ein breites Spektrum von funktionalen Gruppen einschließlich Ester (3a, 3d), Keton (3b), Nitril (3c), Ether (3e, 3m), Halogene (3G - 3l), CF 3 -Gruppe (3m, 3n), amid (3o) und Heterocyclus-Substituenten (3o). Die Halogensubstituenten, insbesondere Br und I, sind besonders nützlich, da sie Kunststoffgriff für eine weitere Funktionalisierung. Darüber hinaus ein hohes Maß an ortho - über Para- Selecvität beobachtet (3f, 3k - 3l). In Anwesenheit von zwei nicht identische ortho-Positionen sind geringe Regioselektivität erhalten (3d, 3e, 3k, 3m). Ferner kann die Reaktionstemperatur für die OCF3 -Migration Schrittes hängt von der elektronischen Natur von Arenen. Im Allgemeinen elektronenarme Arene erfordert höhere Reaktionstemperatur. <img alt="Abbildung 1" src="/files/ftp_upload/53789/53789fig1.jpg" /> Abbildung 1. 1 H-NMR-Spektrums von 3a. Chemische Verschiebung und die relative Integration der charakteristischen Protonen sind beschriftet. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/53789/53789fig1large.jpg" target="_blank">Bitte klicken Sie hier, um eine größere Version dieser Figur zu sehen.</a> Abbildung 2. 13 C-NMR-Spektrum von 3a. Chemische Verschiebung der charakteristischen Kohlenstoffen markiert ist. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/53789/53789fig2large.jpg" target="_blank">Bitte klicken Sie hier, um eine größere Version dieser Figur zu sehen.</a> <img alt="Figur 3" src="/files/ftp_upload/53789/53789fig3.jpg" /> Abbildung 3. 19 F-NMR-Spektrum von 3a. Chemische Verschiebung der charakteristischen Fluor ist beschriftet mit Trifluortoluol (-63,3 ppm) als interne Referenz. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/53789/53789fig3large.jpg" target="_blank">Bitte klicken Sie hier, um eine größere Version dieses f ansehen</a>ild. <img alt="Tabelle 1" src="/files/ftp_upload/53789/53789table1highres.jpg" width="700" /> Tabelle 1. Ausgewählte Beispiele trifluoromethoxylation von Arenen Reaktionszeit:. 11 bis 48 h. Angeführten Ausbeuten und isomeren Verhältnisse sind für OCF 3 -Migration Schritt (2-3) und des isolierten Materials durch Flash-Säulenchromatographie. [a] 50 ° C. [b] 120 ° C. [c] 140ºC. [d] Weniger als 5% Para- Produkt haben wir erkannt. THF = Tetrahydrofuran; AcCl = Acetylchlorid. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/53789/53789table1highres.jpg" target="_blank">Bitte klicken Sie hier, um eine größere Version dieser Tabelle anzuzeigen.</a>

Watch this Scientific Journal Video about Protocol for the Synthesis of Ortho-trifluoromethoxylated Aniline Derivatives at JoVE.com

Protocol for the Synthesis of Ortho-trifluoromethoxylated Aniline Derivatives

Protokoll für die Synthese von<em&gt; Ortho</em&gt; -trifluoromethoxylated Anilin-Derivate

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.

Molecules bearing trifluoromethoxy (OCF3) group often show desired pharmacological and biological properties. However, facile synthesis of ...

protocol-for-synthesis-ortho-trifluoromethoxylated-aniline

Nanyang Technological University

Research

Education

JoVE Core

JoVE Journal

Organic Chemistry

Chemistry

Unit 1

Protocol for the Synthesis of Ortho-trifluoromethoxylated Aniline Derivatives

Aromatic Compounds

SCIENTISTS IN ACTION

9.8K Aufrufe.  State University of New York at Stony Brook. 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.

Serie: Protocol for the Synthesis of Ortho-trifluoromethoxylated Aniline Derivatives

Synthesis of Hypervalent Iodonium Alkynyl Triflates for the Application of Generating Cyanocarbenes

The procedures described in this article involve the synthesis and isolation of hypervalent iodonium alkynyl triflates (HIATs) and their subsequent reactions with azides to form cyanocarbene intermediates. The synthesis of hypervalent iodonium alkynyl triflates can be facile, but difficulties stem from their isolation and reactivity. In particular, the necessity to use filtration under inert atmosphere at -45 &deg;C for some HIATs requires special care and equipment. Once isolated, the compounds can be stored and used in reactions with azides to form cyanocarbene intermediates. 
The evidence for cyanocarbene generation is shown by visible extrusion of dinitrogen as well as the characterization of products that occur from O-H insertion, sulfoxide complexation, and cyclopropanation. A side reaction of the cyanocarbene formation is the generation of a vinylidene-carbene and the conditions to control this process are discussed. There is also potential to form a hypervalent iodonium alkenyl triflate and the means of isolation and control of its generation are provided. The O-H insertion reaction involves using a HIAT, sodium azide or tetrabutylammonium azide, and methanol as solvent/substrate. The sulfoxide complexation reaction uses a HIAT, sodium azide or tetrabutylammonium azide, and dimethyl sulfoxide as solvent. The cyclopropanations can be performed with or without the use of solvent. The azide source must be tetrabutylammonium azide and the substrate shown is styrene.

Herein is described the synthesis, isolation, and reactions of hypervalent iodonium alkynyl triflates (HIATs) with azides to generate cyanocarbenes. The procedures will involve air-sensitive and cryogen techniques, including cold filtration under an inert atmosphere. Handling and safety of the synthesized compounds will also be discussed.

Synthese von hypervalenten Iodonium Alkinyl triflaten für die Anwendung der Gene Cyanocarbenes

The procedures described in this article involve the synthesis and isolation of hypervalent iodonium alkynyl triflates (HIATs) and their subsequent ...

Forschung

Chemie

Synthesis of Antiviral Tetrahydrocarbazole Derivatives by Photochemical and Acid-catalyzed C-H Functionalization via Intermediate Peroxides (CHIPS)

The direct functionalization of C-H bonds is an important and long standing goal in organic chemistry. Such transformations can be very powerful in order to streamline synthesis by saving steps, time and material compared to conventional methods that require the introduction and removal of activating or directing groups. Therefore, the functionalization of C-H bonds is also attractive for green chemistry. Under oxidative conditions, two C-H bonds or one C-H and one heteroatom-H bond can be transformed to C-C and C-heteroatom bonds, respectively. Often these oxidative coupling reactions require synthetic oxidants, expensive catalysts or high temperatures. Here, we describe a two-step procedure to functionalize indole derivatives, more specifically tetrahydrocarbazoles, by C-H amination using only elemental oxygen as oxidant. The reaction uses the principle of C-H functionalization via Intermediate PeroxideS (CHIPS). In the first step, a hydroperoxide is generated oxidatively using visible light, a photosensitizer and elemental oxygen. In the second step, the N-nucleophile, an aniline, is introduced by Br&#248;nsted-acid catalyzed activation of the hydroperoxide leaving group. The products of the first and second step often precipitate and can be conveniently filtered off. The synthesis of a biologically active compound is shown.

Synthesis of Antiviral Tetrahydrocarbazole Derivatives by Photochemical and Acid-catalyzed C-H Functionalization via Intermediate Peroxides CHIPS

A two-step procedure for the synthesis of pharmaceutically active indole-derivatives by C-H functionalization with anilines is described, using photo- and Br&#248;nsted acid catalysis.

Synthese von Antivirale Tetrahydrocarbazolderivate durch photochemische und Säure-katalysierten CH-Funktionalisierung über Zwischen Peroxide (CHIPS)

The direct functionalization of C-H bonds is an important and long standing goal in organic chemistry. Such transformations can be very powerful in order ...

A Direct, Early Stage Guanidinylation Protocol for the Synthesis of Complex Aminoguanidine-containing Natural Products

The guanidine functional group, displayed most prominently in the amino acid arginine, one of the fundamental building blocks of life, is an important structural element found in many complex natural products and pharmaceuticals. Owing to the continual discovery of new guanidine-containing natural products and designed small molecules, rapid and efficient guanidinylation methods are of keen interest to synthetic and medicinal organic chemists. Because the nucleophilicity and basicity of guanidines can affect subsequent chemical transformations, traditional, indirect guanidinylation is typically pursued. Indirect methods commonly employ multiple protection steps involving a latent amine precursor, such as an azide, phthalimide, or carbamate. By circumventing these circuitous methods and employing a direct guanidinylation reaction early in the synthetic sequence, it was possible to forge the linear terminal guanidine containing backbone of clavatadine A to realize a short and streamlined synthesis of this potent factor XIa inhibitor. In practice, guanidine hydrochloride is elaborated with a carefully constructed protecting array that is optimized to survive the synthetic steps to come. In the preparation of clavatadine A, direct guanidinylation of a commercially available diamine eliminated two unnecessary steps from its synthesis. Coupled with the wide variety of known guanidine protecting groups, direct guanidinylation evinces a succinct and efficient practicality inherent to methods that find a home in a synthetic chemist&#39;s toolbox.

Here, we present a protocol for direct, early stage guanidinylation that enables rapid total synthesis of aminoguanidine-containing small organic molecules. An advanced synthetic intermediate used in the synthesis of a blood coagulation factor XIa inhibitor was prepared using this protocol.

Eine direkte, Early Stage Guanidinylierung Protokoll zur Synthese von komplexen Aminoguanidin haltige Naturprodukte

The guanidine functional group, displayed most prominently in the amino acid arginine, one of the fundamental building blocks of life, is an important ...

HKUST-1 as a Heterogeneous Catalyst for the Synthesis of Vanillin

Vanillin (4-hydoxy-3-methoxybenzaldehyde) is the main component of the extract of vanilla bean. The natural vanilla scent is a mixture of approximately 200 different odorant compounds in addition to vanillin. The natural extraction of vanillin (from the orchid Vanilla planifolia, Vanilla tahitiensis and Vanilla pompon) represents only 1% of the worldwide production and since this process is expensive and very long, the rest of the production of vanillin is synthesized. Many biotechnological approaches can be used for the synthesis of vanillin from lignin, phenolic stilbenes, isoeugenol, eugenol, guaicol, etc., with the disadvantage of harming the environment since these processes use strong oxidizing agents and toxic solvents. Thus, eco-friendly alternatives on the production of vanillin are very desirable and thus, under current investigation. Porous coordination polymers (PCPs) are a new class of highly crystalline materials that recently have been used for catalysis. HKUST-1 (Cu3(BTC)2(H2O)3, BTC = 1,3,5-benzene-tricarboxylate) is a very well known PCP which has been extensively studied as a heterogeneous catalyst. Here, we report a synthetic strategy for the production of vanillin by the oxidation of trans-ferulic acid using HKUST-1 as a catalyst.

The conversion of trans-ferulic acid to vanillin was achieved by heterogeneous catalysis. HKUST-1 was employed in this synthesis and the essential step in the catalytic process was the generation of unsaturated metal sites. Thus, when the catalyst was activated under vacuum, full vanillin conversion (yield of 95%) was obtained.

HKUST-1 als heterogener Katalysator für die Synthese von Vanillin

Vanillin (4-hydoxy-3-methoxybenzaldehyde) is the main component of the extract of vanilla bean. The natural vanilla scent is a mixture of approximately ...

A Protocol for the Production of Gliadin-cyanoacrylate Nanoparticles for Hydrophilic Coating

This article presents a protocol for the production of protein-based nanoparticles that changes the hydrophobic surface to hydrophilic by a simple spray coating. These nanoparticles are produced by the polymerization reaction of alkyl cyanoacrylate on the surface of cereal protein (gliadin) molecules. Alkyl cyanoacrylate is a monomer that instantly polymerizes at RT when it is applied to the surface of materials. Its polymerization reaction is initiated by the trace amounts of weakly basic or nucleophilic species on the surface, including moisture. Once polymerized, the polymerized alkyl cyanoacrylates show a strong affinity with the object materials because nitrile groups are in the backbone of poly (alkyl cyanoacrylate). Proteins also work as initiator for this polymerization because they contain amine groups that can initiate the polymerization of cyanoacrylate. If aggregated protein is used as an initiator, protein aggregate is surrounded by the hydrophobic poly(alkyl cyanoacrylate) chains after the polymerization reaction of alkyl cyanoacrylate. By controlling the experimental condition, particles in the nanometer range are produced. The produced nanoparticles readily adsorb to the surface of most materials including glass, metals, plastics, wood, leather, and fabrics. When the surface of a material is sprayed with the produced nanoparticle suspension and rinsed with water, the micellar structure of nanoparticle changes its conformation, and the hydrophilic proteins are exposed to the air. As a result, the nanoparticle-coated surface changes to hydrophilic.

This article presents a protocol for the production of protein-based nanoparticles that changes the hydrophobic surface to hydrophilic. The produced nanoparticle is an assembly of gliadin-cyanoacrylate diblock copolymers. Spray coating with the produced nanoparticle changes the surface of target material to a hydrophilic surface.

Ein Protokoll zur Herstellung von Gliadin-cyanacrylat Nanopartikel für die hydrophile Beschichtung

This article presents a protocol for the production of protein-based nanoparticles that changes the hydrophobic surface to hydrophilic by a simple spray ...

Synthesis of Protein Bioconjugates via Cysteine-maleimide Chemistry

The chemical linking or bioconjugation of proteins to fluorescent dyes, drugs, polymers and other proteins has a broad range of applications, such as the development of antibody drug conjugates (ADCs) and nanomedicine, fluorescent microscopy and systems chemistry. For many of these applications, specificity of the bioconjugation method used is of prime concern. The Michael addition of maleimides with cysteine(s) on the target proteins is highly selective and proceeds rapidly under mild conditions, making it one of the most popular methods for protein bioconjugation.
We demonstrate here the modification of the only surface-accessible cysteine residue on yeast cytochrome c with a ruthenium(II) bisterpyridine maleimide. The protein bioconjugation is verified by gel electrophoresis and purified by aqueous-based fast protein liquid chromatography in 27% yield of isolated protein material. Structural characterization with MALDI-TOF MS and UV-Vis is then used to verify that the bioconjugation is successful. The protocol shown here is easily applicable to other cysteine - maleimide coupling of proteins to other proteins, dyes, drugs or polymers.

Synthesis of Protein Bioconjugates via Cysteine-maleimide Chemistry

This protocol details the important steps required for the bioconjugation of a cysteine containing protein to a maleimide, including reagent purification, reaction conditions, bioconjugate purification and bioconjugate characterization.

Synthese von Protein Biokonjugate<em&gt; über</em&gt; Cystein-maleimid Chemie

The chemical linking or bioconjugation of proteins to fluorescent dyes, drugs, polymers and other proteins has a broad range of applications, such as the ...

Facile Synthesis of Worm-like Micelles by Visible Light Mediated Dispersion Polymerization Using Photoredox Catalyst

Presented herein is a protocol for the facile synthesis of worm-like micelles by visible light mediated dispersion polymerization. This approach begins with the synthesis of a hydrophilic poly(oligo(ethylene glycol) methyl ether methacrylate) (POEGMA) homopolymer using reversible addition-fragmentation chain-transfer (RAFT) polymerization. Under mild visible light irradiation (&#955; = 460 nm, 0.7 mW/cm2), this macro-chain transfer agent (macro-CTA) in the presence of a ruthenium based photoredox catalyst, Ru(bpy)3Cl2 can be chain extended with a second monomer to form a well-defined block copolymer in a process known as Photoinduced Electron Transfer RAFT (PET-RAFT). When PET-RAFT is used to chain extend POEGMA with benzyl methacrylate (BzMA) in ethanol (EtOH), polymeric nanoparticles with different morphologies are formed in situ according to a polymerization-induced self-assembly (PISA) mechanism. Self-assembly into nanoparticles presenting POEGMA chains at the corona and poly(benzyl methacrylate) (PBzMA) chains in the core occurs in situ due to the growing insolubility of the PBzMA block in ethanol. Interestingly, the formation of highly pure worm-like micelles can be readily monitored by observing the onset of a highly viscous gel in situ due to nanoparticle entanglements occurring during the polymerization. This process thereby allows for a more reproducible synthesis of worm-like micelles simply by monitoring the solution viscosity during the course of the polymerization. In addition, the light stimulus can be intermittently applied in an ON/OFF manner demonstrating temporal control over the nanoparticle morphology.

This article describes a process for producing polymeric self-assembled nanoparticles using visible light mediated dispersion polymerization. Using low energy visible light to control the polymerization allows for the reproducible formation of self-assembled worm-like micelles at high solids content.

Einfache Synthese von wurmartigen Mizellen durch sichtbares Licht Mediated Dispersion Polymerisation mit Photoredox Katalysator

Presented herein is a protocol for the facile synthesis of worm-like micelles by visible light mediated dispersion polymerization. This approach begins ...

Protocol for the Solid-phase Synthesis of Oligomers of RNA Containing a 2'-O-thiophenylmethyl Modification and Characterization via Circular Dichroism

Solid-phase synthesis has been used to obtain canonical and modified polymers of nucleic acids, specifically of DNA or RNA, which has made it a popular methodology for applications in various fields and for different research purposes. The procedure described herein focuses on the synthesis, purification, and characterization of dodecamers of RNA 5&#39;-[CUA CGG AAU CAU]-3&#39; containing zero, one, or two modifications located at the C2&#39;-O-position. The probes are based on 2-thiophenylmethyl groups, incorporated into RNA nucleotides via standard organic synthesis and introduced into the corresponding oligonucleotides via their respective phosphoramidites. This report makes use of phosphoramidite chemistry via the four canonical nucleobases (Uridine (U), Cytosine (C), Guanosine (G), Adenosine (A)), as well as 2-thiophenylmethyl functionalized nucleotides modified at the 2&#39;-O-position; however, the methodology is amenable for a large variety of modifications that have been developed over the years. The oligonucleotides were synthesized on a controlled-pore glass (CPG) support followed by cleavage from the resin and deprotection under standard conditions, i.e., a mixture of ammonia and methylamine (AMA) followed by hydrogen fluoride/triethylamine/N-methylpyrrolidinone. The corresponding oligonucleotides were purified via polyacrylamide electrophoresis (20% denaturing) followed by elution, desalting, and isolation via reversed-phase chromatography (Sep-pak, C18-column). Quantification and structural parameters were assessed via ultraviolet-visible (UV-vis) and circular dichroism (CD) photometric analysis, respectively. This report aims to serve as a resource and guide for beginner and expert researchers interested in embarking in this field. It is expected to serve as a work-in-progress as new technologies and methodologies are developed. The description of the methodologies and techniques within this document correspond to a DNA/RNA synthesizer (refurbished and purchased in 2013) that uses phosphoramidite chemistry.

Protocol for the Solid-phase Synthesis of Oligomers of RNA Containing a 2'-O-thiophenylmethyl Modification and Characterization via Circular Dichroism

This article provides a detailed procedure on the solid-phase synthesis, purification, and characterization of dodecamers of RNA modified at the C2&#39;-O-position. UV-vis and circular dichroism photometric analyses are used to quantify and characterize structural aspects, i.e., single-strands or double-strands.

Protokoll für die Festphasensynthese von Oligomeren der RNA mit einem 2&#39;-<em&gt; O</em&gt; -thiophenylmethyl-Modifikation und Charakterisierung über Kreisdichroismus

Solid-phase synthesis has been used to obtain canonical and modified polymers of nucleic acids, specifically of DNA or RNA, which has made it a popular ...

Synthesis and Mass Spectrometry Analysis of Oligo-peptoids

Peptoids are sequence-controlled peptide-mimicking oligomers consisting of N-alkylated glycine units. Among many potential applications, peptoids have been thought of as a type of molecular information storage. Mass spectrometry analysis has been considered the method of choice for sequencing peptoids. Peptoids can be synthesized via solid phase chemistry using a repeating two-step reaction cycle. Here we present a method to manually synthesize oligo-peptoids and to analyze the sequence of the peptoids using tandem mass spectrometry (MS/MS) techniques. The sample peptoid is a nonamer consisting of alternating N-(2-methyloxyethyl)glycine (Nme) and N-(2-phenylethyl)glycine (Npe), as well as an N-(2-aminoethyl)glycine (Nae) at the N-terminus. The sequence formula of the peptoid is Ac-Nae-(Npe-Nme)4-NH2, where Ac is the acetyl group. The synthesis takes place in a commercially available solid-phase reaction vessel. The rink amide resin is used as the solid support to yield the peptoid with an amide group at the C-terminus. The resulting peptoid product is subjected to sequence analysis using a triple-quadrupole mass spectrometer coupled to an electrospray ionization source. The MS/MS measurement produces a spectrum of fragment ions resulting from the dissociation of charged peptoid. The fragment ions are sorted out based on the values of their mass-to-charge ratio (m/z). The m/z values of the fragment ions are compared against the nominal masses of theoretically predicted fragment ions, according to the scheme of peptoid fragmentation. The analysis generates a fragmentation pattern of the charged peptoid. The fragmentation pattern is correlated to the monomer sequence of the neutral peptoid. In this regard, MS analysis reads out the sequence information of the peptoids.

A protocol is described for the manual synthesis of oligo-peptoids followed by sequence analysis by mass spectrometry.

Synthese- und Massenspektrometrie der Oligo-peptoids

Peptoids are sequence-controlled peptide-mimicking oligomers consisting of N-alkylated glycine units. Among many potential applications, peptoids have ...

The MPLEx Protocol for Multi-omic Analyses of Soil Samples

Mass spectrometry (MS)-based integrated metaproteomic, metabolomic, and lipidomic (multi-omic) studies are transforming our ability to understand and characterize microbial communities in environmental and biological systems. These measurements are even enabling enhanced analyses of complex soil microbial communities, which are the most complex microbial systems known to date. Multi-omic analyses, however, do have sample preparation challenges, since separate extractions are typically needed for each omic study, thereby greatly amplifying the preparation time and amount of sample required. To address this limitation, a 3-in-1 method for the simultaneous extraction of metabolites, proteins, and lipids (MPLEx) from the same soil sample was created by adapting a solvent-based approach. This MPLEx protocol has proven to be both simple and robust for many sample types, even when utilized for limited quantities of complex soil samples. The MPLEx method also greatly enabled the rapid multi-omic measurements needed to gain a better understanding of the members of each microbial community, while evaluating the changes taking place upon biological and environmental perturbations.

A protocol is presented for simultaneously extracting metabolites, proteins, and lipids from a single soil sample, allowing reduced sample preparation times and enabling multi-omic mass spectrometry analyses of samples with limited quantities.

Das MPLEx-Protokoll für Multi-Omic Analysen von Bodenproben

Mass spectrometry (MS)-based integrated metaproteomic, metabolomic, and lipidomic (multi-omic) studies are transforming our ability to understand and ...