Reconocemos fondos iniciales generosas de la Universidad Estatal de Nueva York en Stony Brook en apoyo de este trabajo. También agradecemos a TOSOH F-Tech, Inc. por proporcionarnos TMSCF 3 reactivo para la síntesis de Togni reactivo II.

1. Preparación Precursor: Síntesis de 4- (N -hydroxyacetamido) benzoato de metilo (1a) <ol><li> Reducción de metil 4-nitrobenzoato. <ol><li> Añadir 5,00 g de metil 4-nitrobenzoato de metilo (27,6 mmol, 1,00 equiv), 159 mg de rodio al 5% sobre carbono (Rh / C, 0,300% en moles Rh), y una varilla de agitación magnética en un secado en horno 250 ml de dos cuello del matraz de fondo redondo (secado a 150 ° C durante 18 h). NOTA: Los reactivos se pueden pesar a cabo bajo atmósfera ambiente. Sin embargo, la reacción debe llevarse a cabo bajo atmósfera de nitrógeno. </li><li> Conecte un cuello del matraz a un nitrógeno / colector de vacío y la tapa del otro cuello con un tabique. Realizar tres ciclos de vacío-recarga (es decir, bombeando el aire del matraz y reemplazando el vacío resultante con gas nitrógeno) para reemplazar el aire en el matraz con gas nitrógeno. </li><li> Añadir 138 ml de tetrahidrofurano anhidro (THF, 0,200 M) al matraz de reacción usando una jeringa hermética al aire. Dejar enfriar y remover las mixto de reacciónure a 0 ° C durante 15 minutos. </li><li> Añadir 1,47 ml de monohidrato de hidrazina (1,52 g, 30,4 mmol, 1,20 equiv) gota a gota a la mezcla de reacción a 0 ° C usando una jeringa hermética al aire. Supervisar la reacción utilizando una cromatografía en capa fina (TLC). Utilice hexanos: acetato de etilo (EtOAc) (4: 1 v / v, Rf = 0,23) como eluyente para desarrollar el TLC. </li><li> Cuando metil 4-nitrobenzoato de metilo se consume completamente, filtrar la mezcla de reacción a través de un lecho corto de tierra de diatomeas (es decir, Celite, 5 g) en una frita de 60 ml embudo Buchner utilizando filtración a vacío. Lavar el filtro con EtOAc (20 ml x 3 veces). Se concentra el filtrado a vacío usando un evaporador rotatorio para dar el benzoato de metilo crudo 4- (N -hydroxyamino), que se utiliza directamente sin purificación adicional. </li></ol></li><li> Protección Acetil de 4- (N -hydroxyamino) benzoato de metilo <ol><li> Añadir 2,55 g de bicarbonato de sodio (NaHCO 3, 30,4 mmol, 1,20 equiv), todo el crudometil 4- (N -hydroxyamino) benzoato de metilo obtenido de la etapa anterior, y una varilla de agitación en un 500 ml matraz de fondo redondo de dos bocas secado en horno. </li><li> Cap de un cuello con un tabique y conectar otro cuello a un colector de nitrógeno / vacío. Realizar tres ciclos de vacío-de recarga para reemplazar el aire en el matraz con gas nitrógeno. </li><li> Añadir 138 ml de éter dietílico anhidro (Et 2 O, 0,200 M) al matraz de reacción usando una jeringa hermética al aire. Enfriar y se agita la mezcla de reacción a 0 ° C durante 15 min. </li><li> Preparar una solución de cloruro de acetilo (2,17 ml, 2,39 g, 30,4 mmol, 1,20 equiv) en Et2O anhidro (138 ml, 0,220 M). Añadir la solución de la mezcla de reacción a 0 ° C utilizando una bomba de jeringa a una velocidad de 10,0 ml / hr. </li><li> Al final de la adición, se filtra la mezcla de reacción a través de un lecho corto de tierra de diatomeas (es decir, Celite, 5 g) en 60 ml de frita embudo Buchner utilizando filtración a vacío. Lavar el filtro con EtOAc (20 ml x 3 veces). Se concentra lafiltrado a vacío usando un evaporador rotatorio. </li><li> Se purifica el producto en bruto con cromatografía en columna ultrarrápida 35 eluyendo con hexanos: EtOAc (4: 1 a 1: 1 (v / v)) (R f = 0,13, hexanos: EtOAc (4: 1 (v / v)) para dar 5,31 g de 4- (N -hydroxyacetamido) benzoato como un sólido amarillo claro (25,4 mmol, 92% de rendimiento). </li></ol></li></ol> 2. Síntesis de 4- (N - (trifluorometoxi) acetamido) benzoato de metilo (2a) <ol><li> Añadir 2,00 g de 4- (N -hydroxyacetamido) benzoato de metilo (1a) (9,56 mmol, 1,00 equiv), 311 mg de Cs 2 CO 3 (0,956 mmol, 10,0% en moles), 3,63 g de Togni reactivo II (11,5 mmol, 1,20 equiv), y una varilla de agitación magnética en un matraz de 250 ml de fondo redondo secado al horno dentro de un (atmósfera de nitrógeno guantera). NOTA: Esta reacción también se puede realizar utilizando técnicas de Schlenk fuera de la guantera. Precaución: Pure reactivo Togni II es el impacto y la fricción sensible, llama abiertas, chispas y / o molienda debe ser evitado. Herramientas suaves y pulidas se deben utilizar para la manipulación. Además, la mezcla de reacción debe agitarse detrás de un escudo de seguridad. 36 </li><li> Añadir 95,6 ml de cloroformo se seca y desgasificada (CHCl3, 0,100 M) al matraz de reacción. </li><li> Se tapa el matraz con tabique y se agita la mezcla de reacción a 23 ° C bajo atmósfera de N2, ya sea dentro o fuera de la caja de guantes durante 16 horas. </li><li> Se filtra la mezcla de reacción a través de un embudo de filtración para eliminar cualquier residuo sólido. Se concentra el filtrado a vacío usando un evaporador rotatorio. </li><li> Se purifica el producto en bruto por cromatografía en columna ultrarrápida eluyendo con hexanos: diclorometano (CH 2 Cl 2) (7: 3 a 0: 1 (v / v)) (R f = 0,44 (CH 2 Cl 2) para dar 2,51 g de 4- (N - (trifluorometoxi) acetamido) benzoato de metilo (9,05 mmol, rendimiento del 95%). NOTA: Togni reactivo II es el acuerdo preparadoing a los procedimientos de la literatura 37 y almacenados en el congelador a -35 guantera ° C para mantener su calidad durante un largo período de tiempo. Esta reacción es sensible al oxígeno. Aunque todos los reactivos se pueden pesar a cabo bajo atmósfera ambiente a TA, la eliminación de todo el oxígeno del matraz de reacción es crítico. Secos y desgasificado CHCl3 se prepara destilando desde CaH2 bajo atmósfera de nitrógeno, seguido de la realización de un período de tres ciclos del procedimiento de congelación-bombeo-descongelación. </li></ol> 3. Síntesis de metil 4-acetamido-3- (trifluorometoxi) benzoato de metilo a través OCF 3 -migración (3a) <ol><li> Añadir 2,51 g de 4- (N - (trifluorometoxi) acetamido) benzoato de metilo (9,05 mmol, 1,0 equiv), una varilla de agitación magnética, y 9,05 ml de MeNO 2 (1,00 M) en un recipiente a presión 50 ml. Tapar el recipiente con un tapón de rosca. </li><li> Se agita la mezcla de reacción a 120 ° C tras el escudo de seguridad para 20 hr. Precaución: nitrometano Impuroes explosivo, por lo que la mezcla de reacción debe agitarse detrás del escudo de seguridad. </li><li> Se enfría la mezcla de reacción a RT. </li><li> Transferir la mezcla de reacción a un matraz de fondo redondo de 100 ml. </li><li> Se concentra la mezcla de reacción a vacío usando un evaporador rotatorio. </li><li> Se purifica el producto en bruto por cromatografía en columna ultrarrápida eluyendo con hexanos: EtOAc (9: 1 a 7: 3 (v / v)) (R f = 0,51 hexanos: EtOAc (4: 1 (v / v)) para dar 2,13 g de metil (trifluorometoxi) benzoato de metilo-3- 4-acetamido (7,69 mmol, 85%). NOTA: Esta reacción puede llevarse a cabo bajo atmósfera ambiente. No se requiere una atmósfera de nitrógeno. Un matraz de fondo redondo equipado con un condensador de agua se puede utilizar como un aparato de reacción alternativa. </li></ol> 4. Caracterización de Nuevos Productos <ol><li> Caracterizar todos los nuevos compuestos por 1 H, 13 C RMN espectroscopía y espectroscopia de masas de alta resolución y el uso de la espectroscopia de 19 F RMNpara caracterizar compuestos que contienen átomos de flúor. 34 </li></ol>

<ol>
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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.

Debido a la falta de un procedimiento general y fácil de usar para la síntesis de arenos trifluoromethoxylated, muchos OCF compuestos aromáticos 3 -containing son extremadamente caros. 34 Nuestra estrategia desplaza una amplia tolerancia grupo funcional y ofrece un fácil acceso a varios arenos trifluoromethoxylated. Estos compuestos podrían servir como bloques de construcción valiosos para el descubrimiento y desarrollo de nuevos productos farmacéuticos, agroquímicos, y materiales. La hidrazina se utilizó como una fuente de hidrógeno para la reducción catalizada por rodio de nitroarenos. Su calidad es una de las claves en la obtención de los productos de reducción en altos rendimientos. Los rendimientos de reducción se redujo cuando se utilizó un viejo hidrazina pocos meses. Para asegurar la reproducibilidad, transferimos parte de la hidracina de una botella comercial grande a una más pequeña 20 ml frasco y lo usamos desde el vial de 20 ml. Además, nos guardaron en el refrigerador (4 ° C) para disminuir la velocidadde descomposición. Por otra parte, la adición lenta de hidrazina es crucial en conseguir hidroxilaminas limpias con buenos rendimientos. La trifluorometilación O- es un proceso mediado por radicales, por lo que la exclusión de oxígeno de la mezcla de reacción es crítico. El uso de cloroformo-un desgasificado como disolvente o la realización de la reacción bajo atmósfera ambiente resultó en un menor rendimiento. Nuestros estudios mecanísticos preliminares muestran que el 3 -migración proceso OCF involucrados inducida térmicamente de escisión heterolítica del enlace N-OCF 3 para generar un par de iones ajustado de ion nitrenium y trifluoromethoxide. 34 Trifluoromethoxide ataca el orto -Posición del ion nitrenium seguido por la tautomerización para producir los derivados de anilina trifluoromethoxylated deseados orto. Formación del ion nitrenium en sustratos deficientes de electrones es energéticamente desfavorecido y por lo tanto requiere una mayor temperatura de reacción. En sumamary, nos informó un protocolo sintético escala general y de laboratorio para la síntesis regioselectiva de orto -OCF 3 derivados de anilina. Esta estrategia tiene varias características únicas: (i) una amplia gama de grupos funcionales y patrones de sustitución son toleradas; (ii) la simplicidad operativa de nuestro protocolo haría trifluoromethoxylation a disposición de la comunidad más amplia sintético; y (iii) los productos finales son nuevos y se podrían utilizar como bloques de construcción sintéticos útiles para la investigación en ciencias biológicas y los materiales. Algunos de los procedimientos de solución de problemas se resumen en: (i) almacenar el producto de reducción, hidroxilamina arilo, en el congelador o inmediatamente lo uso para el siguiente paso; (ii) controlar las reacciones de reducción / protección estrechamente con TLC para evitar el exceso de reducción de nitroarenos o protección de hidroxiaminas N-; (iii) la exclusión de oxígeno de las mezclas de reacción es crítica para la reducción de nitroarenos y O -trifluoromethylation; (iv) mayor reactioSe necesita temperatura n de electrones arenos deficientes en el OCF intramolecular 3 -migración paso.

El trifluorometoxi (OCF 3) grupo ha tenido un impacto profundo en la investigación en ciencias biológicas y los materiales desde la primera síntesis de éter trifluorometilo en 1935. 2 Debido a su combinación única de alta electronegatividad (χ = 3.7) 3 y excelente lipofilia (Π x = 1,04), 4 del grupo trifluorometoxi ha encontrado amplias aplicaciones en la medicina, la agricultura y la industria de materiales. 5-10 Sin embargo, la introducción fácil del grupo OCF 3 en moléculas orgánicas, especialmente los compuestos aromáticos, sigue siendo un reto importante en la química sintética. Durante las últimas décadas, los esfuerzos para hacer frente a este desafío condujeron al desarrollo de un puñado de transformaciones para la síntesis de arenos trifluoromethoxylated 5-7,9-11 Estos incluyen (i) el intercambio de cloro / flúor sobre los precursores triclorado;. 1,12 -17 (ii) deoxyfluorination de fluoroformiatos; 18 </sup&gt; (iii) fluorodesulfurization oxidativo; 19 hasta 21 (iv) trifluorometilación electrófila de alcoholes; 22-25 de (v) trifluoromethoxylation nucleófila; 26-30 (vi) de metal de transición trifluoromethoxylation mediada de los boratos arilo y estannanos; 31 y (vii ) trifluoromethoxylation radical. 32,33 Sin embargo, muchos de estos enfoques ya sea sufren de alcance sustrato pobre o requiere el uso de reactivos altamente tóxicos y / o térmicamente lábiles. Por lo tanto, debido a la falta de un método general y fácil de usar para sintetizar compuestos OCF 3 -containing el potencial del grupo OCF 3 no se ha explotado completamente en química. Como parte de nuestro interés en reacciones trifluoromethoxylation, 34 describimos aquí un protocolo de dos pasos (es decir, -trifluoromethylation O radical y OCF inducida térmicamente 3 -migración) para la síntesis de 4-acetamido-3- (trifluorometoxi) benzoato de metilo (3a) a partir de metil 4- (N -hydroxyacetamido) benzoato de metilo (1a). La estrategia es fácil de operar y aplicable a la síntesis de una amplia gama de derivados de la anilina orto -trifluoromethoxylated.

<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

Las moléculas que llevan trifluorometoxi grupo (OCF 3) a menudo muestran desean propiedades farmacológicas y biológicas. Sin embargo, la síntesis fácil de compuestos aromáticos trifluoromethoxylated sigue siendo un reto formidable en la síntesis orgánica. Los enfoques convencionales a menudo sufren de alcance sustrato pobre, o requieren el uso de, mango difíciles de altamente tóxico, y / o reactivos térmicamente lábiles. En este documento, se presenta un protocolo de fácil manejo para la síntesis de 4-acetamido-3- (trifluorometoxi) benzoato utilizando 1-trifluorometil-1,2-benciodoxol-3 (1H) -ona (Togni reactivo II). El tratamiento de 4- (N -hydroxyacetamido) benzoato de metilo (1a) con Togni reactivo II en presencia de una cantidad catalítica de carbonato de cesio (Cs 2 CO 3) en cloroformo a temperatura ambiente proporcionó metil 4- (N - (trifluorometoxi) acetamido) benzoato de metilo (2a). Después, este intermedio se convierte en el producto final de metilo 4-acetamido-3- (trifluoromethoxy) benzoato de (3a) en nitrometano a 120 ° C. Este procedimiento es general y puede aplicarse a la síntesis de un amplio espectro de derivados de anilina orto -trifluoromethoxylated, que podría servir como bloques de construcción sintéticos útiles para el descubrimiento y desarrollo de nuevos productos farmacéuticos, agroquímicos, y materiales funcionales.

4- (N -hydroxyacetamido) benzoato de metilo (1a) se sintetizó en 92% de rendimiento aislado a través de un procedimiento de dos pasos (es decir, la reducción de metil 4-nitrobenzoato con hidrazina usando 5% Rh / C como catalizador para formar 4- ( N -hydroxyamino) benzoato de metilo, seguido por la protección de acetilo de la hidroxilamina resultante). O- trifluorometilación de 1a con Togni reactivo II en presencia de una cantidad catalítica de carbonato de cesio (Cs 2 CO 3) en cloroformo a temperatura ambiente proporcionó el 4- ( N - (trifluorometoxi) acetamido) benzoato de (2a) en el 95% de rendimiento aislado. Este compuesto fue sometida inducida térmicamente OCF 3 -migración en MeNO 2 a 120 ° C para dar el metil 4-acetamido-3- (trifluorometoxi) benzoato de metilo (3a) deseado en 85% de rendimiento aislado. El 1 H, <sup&gt; 13 C, y 19 F espectro de RMN del producto final 3a se representan en la Figura 1, Figura 2, y la Figura 3, respectivamente. Un distinguir pico cuarteto en 120,6 ppm con una gran constante de acoplamiento (258.9 Hz) en 13 espectros de RMN de C corresponde al carbono CF 3. Cuando el OCF 3 -migración tiene lugar, un cambio brusco en el 19 F RMN de -65 ppm (2a) para -58.1ppm se observa (3a). Los datos de caracterización de detalle 3a se reporta como sigue: Rf = 0,51 (hexanos / EtOAc 4: 1 (v / v)). NMR Spectroscopy: 1 H RMN (700 MHz, CDCl3, 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 RMN (175 MHz, CDCl3, 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 RMN (376 MHz, CDCl3, 25 ° C, δ): -58,1 (s). La espectrometría de masa: HRMS (ESI-TOF) (m / z): calculado para C 11 H 11 NO 4 F 3 ([M + H] +) 278,0640, encontrado 278,0643. Este protocolo es general y aplicable a una amplia gama de compuestos aromáticos (Tabla 1). La reacción tolera un amplio espectro de grupos funcionales que incluyen éster (3a, 3d), cetona (3b), nitrilo (3c), éteres (3e, 3m), halógenos (3g - 3L), CF grupo 3 (3m, 3n), amida (3o) y heterociclo sustituyente (3o). Los sustituyentes halógeno, especialmente Br y I, son particularmente útiles debido a que proporcionan asas sintéticas para funcionalización adicional. Además, los altos niveles de orto - más de selec para-tividad se observan (3f, 3k - 3l). En la presencia de dos posiciones orto no idénticos, bajos niveles de regiocontrol se obtienen (3d, 3e, 3k, 3m). Además, la temperatura de reacción para la etapa OCF 3 -migración depende de la naturaleza electrónica de arenos. Generalmente, arenos deficientes más electrones requieren una mayor temperatura de reacción. <img alt="Figura 1" src="/files/ftp_upload/53789/53789fig1.jpg" /> Figura 1. Espectro de RMN 1H de 3a. Desplazamiento químico y la integración relativa de protones característicos están etiquetados. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/53789/53789fig1large.jpg" target="_blank">Haga clic aquí para ver una versión más grande de esta figura.</a> Figura 2. 13 espectro de RMN de C 3a. Desplazamiento químico de carbonos característicos se etiqueta. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/53789/53789fig2large.jpg" target="_blank">Por favor haga clic aquí para ver una versión más grande de esta figura.</a> <img alt="figura 3" src="/files/ftp_upload/53789/53789fig3.jpg" /> Figura 3. 19 F espectro de RMN de 3a. Desplazamiento químico del flúor característica está marcada usando trifluorotolueno (-63,3 ppm) como referencia interna. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/53789/53789fig3large.jpg" target="_blank">Haga clic aquí para ver una versión más grande de esta f</a>igura. <img alt="Mesa 1" src="/files/ftp_upload/53789/53789table1highres.jpg" width="700" /> Tabla 1. Ejemplos seleccionados de trifluoromethoxylation de arenos Tiempo de reacción:. 11-48 h. Rendimientos citados y proporciones de isómeros son para OCF 3 -migración paso (2-3) y de material aislado por cromatografía en columna flash. [a] 50 ° C. [b] 120 ° C. [c] 140 ° C. [d] se detectó producto apartado Menos del 5%. THF = tetrahidrofurano; AcCl = cloruro de acetilo. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/53789/53789table1highres.jpg" target="_blank">Por favor haga clic aquí para ver una versión más grande de esta tabla.</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

Protocolo para la Síntesis de<em&gt; Ortho</em&gt; derivados de anilina -trifluoromethoxylated

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

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Protocol for the Synthesis of Ortho-trifluoromethoxylated Aniline Derivatives

Aromatic Compounds

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9.8K vistas.  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.

Video: 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.

Síntesis de hipervalente iodonio Alquinilo triflatos para la Aplicación de Generación Cyanocarbenes

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

Investigación

Química

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.

Síntesis de derivados Antiviral tetrahidrocarbazol por fotoquímica y catalizada por ácido CH funcionalización a través de intermedios peróxidos (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.

Un directa, Protocolo Guanidinylation Etapa Temprana para la Síntesis de complejos productos naturales que contiene aminoguanidina-

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 como un catalizador heterogéneo para la Síntesis de la vainillina

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.

Un protocolo para la producción de nanopartículas gliadina-cianoacrilato para el recubrimiento hidrofílico

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.

Síntesis de Proteínas bioconjugados<em&gt; vía</em&gt; Química cisteína-maleimida

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.

Síntesis Facile de micelas similares a gusanos de luz visible mediada por dispersión Polimerización con catalizador Photoredox

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.

Protocolo para la síntesis en fase sólida de oligómeros de ARN que contiene un 2&#39;-<emO</em&gt; -tiofenilmetilo Modificación y caracterización mediante dicroísmo circular

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.

Síntesis y análisis de espectrometría de masas de peptoides Oligo

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.

El protocolo MPLEx para Multi-omic análisis de muestras de suelo

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