Tandem aza-Claisen rearrangement and ring-closing metathesis reactions: the stereoselective synthesis of functionalised carbocyclic amides

Abstract

Abstract-A one-pot, tandem process has been developed for the efficient synthesis of functionalised carbocyclic amides. A substituted cyclopentenyl trichloroacetamide was synthesised using a tandem thermal aza-Claisen rearrangement and RCM process, while an analogous cyclohexenyl trichloroacetamide was generated with high diastereoselectivity using a tandem MOM-ether directed metal-catalysed aza-Claisen rearrangement and RCM process.Tandem and cascade reactions have emerged as powerful tools to perform several transformations in one synthetic operation rapidly increasing molecular complexity. In an effort to synthesise functionalised carbocyclic amides stereoselectively using a tandem process, it was proposed that this could be achieved by combining the etherdirected Overman rearrangement with a RCM reaction (Scheme 2). This communication describes the highly efficient synthesis of substrates 1 and 2 and the subsequent studies on the development of a tandem Overman rearrangement and RCM reaction for the one-pot synthesis of functionalised 5-and 6-membered carbocyclic amides.The allylic alcohol substrates 11 and 12, required for this study were synthesised in seven steps as shown in Scheme 3. (S)-Glycidol 3 was protected under standard conditions as the tert-butyldimethylsilyl ether. Regioselective ring opening of the epoxide using a copper-catalysed Grignard reaction with either vinylmagnesium bromide or allylmagnesium bromide gave adducts 5 and 6, respectively, both in high yields. Compounds 5 and 6 were converted to primary alcohols 7 and 8 by protection of the secondary alcohol with bromomethyl methyl ether followed by deprotection of the primary alcohol using TBAF. This allowed the one-pot Swern oxidation/HornerWadsworth-Emmons reaction of 7 and 8 to give α,β-unsaturated esters 9 and 10 in 99% and 94% yields, respectively. 14 Finally, DIBAL-H reduction of the esters completed the synthesis of allylic alcohols 11 and 12 in 68% and 78% overall yields, respectively.Development of a tandem ether-directed Overman rearrangement and RCM reaction was initially attempted using allylic trichloroacetimidate 1 which was prepared from allylic alcohol 11 using trichloroacetonitrile and DBU (Scheme 4). Surprisingly, treatment of 1 with bis(acetonitrile)palladium(II) chloride under standard conditions returned only starting material. Several other palladium(II) catalysts were also investigated giving the same result. 12b During the development of our original tandem process, the allylic acetimidate formed from (2E)-hepta-2,6-dien-1-ol was shown to rearrange in the presence of bis(acetonitrile)palladium(II) chloride in under 3 hours. 10The only difference in structure between this substrate and allylic trichloroacetimidate 1 is the MOM-ether group. This suggests that the MOM-ether may be coordinating to the palladium catalyst and directing it to the terminal alkene rather than the adjacent alkene 2 of the allylic trichloroacetimidate functional group. Such an intermediate would prevent the rearrangement from proceeding. A ta...

Toward a Symphony of Reactivity: Cascades Involving Catalysis and Sigmatropic Rearrangements

“…Specifically, Sutherland and co-workers combined the asymmetric Overman rearrangement, a hetero-Claisen variant involving trichloroacetimidate 237 , with a ring-closing metathesis to synthesize the cyclic allylic trichloroacetamide 239 (Scheme 54). [82,104] The Overman rearrangement has wide appeal since the trichloroacetamide handle has utility for a number of subsequent transforma tions, and use of the enantiopure palladium complex (S)-COP-Cl makes it catalytic and asymmetric. [83] Trichloracet-amide 239 was used in a synthesis of the tropane alkaloid (+)-physoperuvine.…”

“…[83] Trichloracet-amide 239 was used in a synthesis of the tropane alkaloid (+)-physoperuvine. [82a] …”

Recentes aplicações sintéticas de compostos orgânicos tricloro(bromo)metila substituídos

“…Essa reação, conhecida como rearranjo de Overman, envolve a adição nucleofílica de um álcool alílico 65 à tricloroacetonitrila para formar tricloroacetoimidato 66, que sofre um rearranjo pericíclico para formar uma tricloroacetamida, 67 (Esquema 21). [104][105][106][107][108] Esse rearranjo tem sido objeto central de diversos trabalhos de síntese orgânica, especialmente, envolvendo a obtenção de produtos naturais nitrogenados. 104 Algumas virtudes do rearranjo de Overman são as suaves condições empregadas nas reações, a transferência de quiralidade de alcoóis quirais e a enantiosseletividade a partir de misturas racêmicas utilizando-se catalisadores quirais.…”

“…As reações de HCA com diaminas, ditióis, sob energia de ultrassom, [107][108][109] e com dióis, com diferentes catalisadores hidrossilicatos, 126,127 levaram à obtenção de ureias, ditiocarbonatos e carbonatos, todos cíclicos, conforme exemplificado pelos compostos 87, 88 e 89, obtidos com 61, 50 e 98% de rendimento, respectivamente (Esquema 30). Esses exemplos indicam que a HCA é um reagente alternativo ao tóxico fosgênio na preparação de vários heterociclos.…”

“…Esses exemplos indicam que a HCA é um reagente alternativo ao tóxico fosgênio na preparação de vários heterociclos. 107,108 A HCA reage com excesso (10 vezes) de diferentes di-e polinucleófilos para formar heterociclos "sem carbonila", sob energia de ultrassom, conforme exemplos apresentados no Esquema 31, relatados por Zucco e colaboradores. [83][84][85][128][129][130] As reações de HCA com etilenodiamina e 1,2-diaminociclo-hexano, utilizando a própria diamina como solvente, produziram compostos 90 e 91, com rendimentos de 60 e 52%, respectivamente.…”