Environmentally Benign and User-Friendly In Situ Generation of Nitrile Imines from Hydrazones for 1,3-Dipolar Cycloaddition

Abstract

Nitrile imines are highly reactive and versatile dipoles and conventionally generated in situ from unstable hydrazonyl halides under basic conditions. Herein, we report the first green and userfriendly protocol for in situ generation of nitrile imines from Oxone− KBr oxidation of hydrazones and base-promoted dehydrobromination. The nitrile imines were demonstrated for 1,3-dipolar cycloaddition with various dipolarophiles, including alkene and alkyne groups. With its green nature, ease of operation, and air and moisture tolerance, we expect our method will find wide applications in organic synthesis.

Achmatowicz Rearrangement-Inspired Development of Green Chemistry, Organic Methodology, and Total Synthesis of Natural Products

“…This substitution is important because it not only eliminates the potential risk of carrying out the reactions but also reduces the cost and environmental damage to a minimal level at the source. The oxone-halide system was successfully applied to alkene dichlorination, oxidative halogenation of aldoximes/hydrazones to generate in situ nitrile oxides/imines for 1,3-dipolar cycloaddition, oxidative halocyclization of tryptamines/tryptophols, oxidative cleavage of indoles (Witkop oxidation), and oxidative rearrangement of tetrahydro-β-carbolines (tryptolines) (Scheme a), all of which previously employed toxic halogenating agents or stoichiometric heavy transition metals. Although oxone as a terminal oxidant contributes to poor green metrics, it has admirable bench stability and distinct selectivity toward halide oxidation over other electron-rich substrates (arenes, alkenes, indoles, and furans).…”

“…Aza-AchR of readily available, enantiomerically pure known furfuryl amide 89 using our green oxone-KBr (cat) protocol gave a 70% yield of 90 in a decagram scale, which was allylated to provide 2,6- cis -dihydropyridin-one 91 in a 90% yield. Luche reduction of 91 followed by rhodium-catalyzed hydroformylation afforded the aldehyde 92 , which underwent oxidative [3 + 2] dipolar cycloaddition with hydroxyamine using our green oxone-halide condition (Scheme ) to provide the tricyclic isooxazoline 93 . Thus, the construction of the DHQ core was accomplished in only five steps on gram scales.…”

Two Green Protocols for Halogenative Semipinacol Rearrangement

“…Our laboratory has a continuous interest in developing green protocols for various halogenation/oxidation reactions. As shown in Scheme a, we have exploited the reactive halogenating species (RHS) in situ generated from oxone/halide and Fenton halide (FeBr 2 –H 2 O 2 or CeBr 3 –H 2 O 2 ) for Achmatowicz rearrangement, oxidative rearrangement of indoles, dihalogenation of alkenes/alkynes, oxidative halocyclization of tryptamines/tryptophols, oxidative halogenation of hydrazones/aldoximes, halogenation of arenes/alkenes/alkynes, desulfurization of thioacetals/thioketals, and oxidation of alcohols . We envisioned that the in situ generated RHS from both oxone/halide and Fenton halide might be used for HSPR of allyl alcohols (Scheme b).…”

Elektrochemische Synthese von Pyrazolinen und Pyrazolen via [3+2] dipolarer Cycloaddition

“…[17,18] Konventionell können Pyrazole und Pyrazoline durch Kondensation von 1,3-Diketonen oder α,β-ungesättigten Ketonen [19] mit Hydrazinen synthetisiert werden. [3+2]-Dipolare Cycloadditionen von Nitriliminen und Alkenen oder Alkinen ermöglichen ebenfalls den Zugang zu diesen Verbindungen, [20,21] wobei die Nitrilimine meist durch Abspaltung von Chlorwasserstoff aus Hydrazonoylchloriden gebildet werden (Schema 1, oben). [22] Bei der Synthese von Hydrazonoylhalogeniden müssen jedoch gefährliche Chemikalien wie N-Chlorsuccinimid (NCS), N-Bromsuccinimid (NBS) [21,23] oder phosphorhaltige Reagenzien [24] zur Oxidation der entsprechenden Hydrazone eingesetzt werden.…”

“…[3+2]-Dipolare Cycloadditionen von Nitriliminen und Alkenen oder Alkinen ermöglichen ebenfalls den Zugang zu diesen Verbindungen, [20,21] wobei die Nitrilimine meist durch Abspaltung von Chlorwasserstoff aus Hydrazonoylchloriden gebildet werden (Schema 1, oben). [22] Bei der Synthese von Hydrazonoylhalogeniden müssen jedoch gefährliche Chemikalien wie N-Chlorsuccinimid (NCS), N-Bromsuccinimid (NBS) [21,23] oder phosphorhaltige Reagenzien [24] zur Oxidation der entsprechenden Hydrazone eingesetzt werden. Erst vor kurzem wurde von Lam et al [25] eine nachhaltige elektrochemische Oxidation von Hydrazonen vorgestellt, die den Zugang zu Diazoverbindungen ermöglicht.…”