Trimethylamine N-oxide as a precursor of azomethine ylides

Beugelmans, R.; Negron, G.; Roussi, G.

doi:10.1039/c39830000031

Cited by 28 publications

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“…Unfortunately, there has been little follow-up exploration since Roussi’s initial evaluation of the tertiary amine N -oxide route . His initial work was on a limited set of substrates including trimethylamine, dibenzylmethylamine, benzyldimethylamine, and β-amino alcohols. − These experiments resulted in modest yields, none higher than 66%, and lacked significant levels of regio- and/or stereoselectivity, with 36% de obtained under optimal conditions. , However, the fundamental reaction remains attractive and shows significant promise as an efficient route to biologically relevant structures from simple precursors.…”

Section: Introductionmentioning

confidence: 99%

“…Roussi et al originally reported the N -oxide route to 1,3-dipoles in 1982, starting with dibenzylmethylamine N -oxide 7 and benzyldimethylamine N -oxide 10 (Figure ). , The work was eventually expanded to include trimethylamine N -oxide . Treatment of these tertiary amine N -oxides with strong bases resulted in either dimerization or a [3 + 2] cycloaddition when in the presence of alkene dipolarophiles. − Given the importance of the pyrrolidine motif and the need to synthesize the requisite compounds, it is surprising that the mechanism for conversion of N -oxides into azomethine ylide has yet to receive thorough attention.…”

Section: Introductionmentioning

confidence: 99%

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Multi-Ion Bridged Pathway of N-Oxides to 1,3-Dipole Dilithium Oxide Complexes

et al. 2021

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Roussi's landmark work on the generation of 1,3dipoles from tertiary amine N-oxides has not reached its full potential since its underlying mechanism is neither well explored nor understood. Two competing mechanisms were previously proposed to explain the transformation involving either an iminium ion or a diradical intermediate. Our investigation has revealed an alternative mechanistic pathway that explains experimental results and provides significant insights to guide the creation of new Noxide reagents beyond tertiary alkylamines for direct synthetic transformations. Truhlar's M06-2x functional and Møller−Plesset second-order perturbation theory with Dunning's [jul,aug]-cc-pv[D,T]z basis sets and discrete-continuum solvation models were employed to determine activation enthalpies and structures. During these mechanistic explorations, we discovered a unique multiion bridged pathway resulting from the rate-determining step, which was energetically more favorable than other alternate mechanisms. This newly proposed mechanism contains no electrophilic intermediates, strengthening the reaction potential by broadening the reagent scope and limiting the possible side reactions. This thoroughly defined general mechanism supports a more direct route for improving the use of N-oxides in generating azomethine ylide−dilithium oxide complexes with expanded functional group tolerance and breadth of chemistry.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Multi-Ion Bridged Pathway of N-Oxides to 1,3-Dipole Dilithium Oxide Complexes

et al. 2021

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“…This reaction is an important method for the formation of pyrrolidines [ 26 ] and has been used in the synthesis of natural products [ 27 , 28 ]. Among the vast number of procedures for making azomethine ylides [ 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 ], the decarboxylative condensation of α-amino acids with aldehydes, typically heated in toluene or DMF, was chosen [ 42 ]. Thus, the reaction of paraformaldehyde and sarcosine ( N -methylglycine) in refluxing toluene in the presence of the 2-cyanoacrylates 8 cleanly provided the desired pyrrolidines 7 , containing the 2-arylethyl amine motif ( Table 2 ).…”

Section: Resultsmentioning

confidence: 99%

Synthesis of Dihydrouracils Spiro-Fused to Pyrrolidines: Druglike Molecules Based on the 2-Arylethyl Amine Scaffold

et al. 2010

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The synthesis of a small library of dihydrouracils spiro-fused to pyrrolidines is described. These compounds are synthesized from β-aryl pyrrolidines, providing products with the 2-arylethyl amine moiety, a structural feature often encountered in compounds active in the central nervous system. The β-aryl pyrrolidines are synthesized through a three-step methodology that includes a Knoevenagel condensation reaction, a 1,3-dipolar cycloaddition reaction, and a nitrile reduction.

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“…A survey of the chemical literature unearthed a little used, but powerful method wherein a reactive unstabilized azomethine ylide can be generated by treating trimethylamine N-oxide 4 with lithium diisopropylamide at low temperature. 7 Under these strongly basic conditions, ylide formation is thought to proceed by deoxygenation of the N-oxide. The resultant intermediate is extremely reactive and can be trapped by simple alkenes such as hex-1-ene, cyclopentene, styrene, and stilbene.…”

Section: Scheme 1 Acid-catalyzed [3+2]-cycloaddition Reactionmentioning

confidence: 99%

Remarkable [3+2] Annulations of Electron-Rich Olefins with Unstabilized Azomethine Ylides

Davoren¹,

Gray²,

Harris³

et al. 2010

Synlett

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Herein we would like to communicate that an unstabilized azomethine ylide generated from commercial trimethylamine N-oxide will undergo a remarkable 1,3-dipolar cycloaddition in good yield with electron-rich and unpolarized olefins. A broad range of substituents on the alkenes are tolerated provided they are compatible with excess LDA. This demonstration of novel reaction scope should encourage others to try trimethylamine N-oxide as an azomethine ylide precursor in the synthesis of challenging 3,4-disubstituted pyrrolidines.Substituted pyrrolidines are common structural motifs present in a wide variety of natural products, 1 chiral ligands, 2 and biologically active compounds. 3 One of the most prevalent and reliable methods for the diastereoselective construction of 3,4-substituted architecture is the 1,3-dipolar cycloaddition reaction of an azomethine ylide and an appropriately substituted alkene. 4During the course of our research we became interested in constructing novel 3,4-disubstituted pyrrolidine ring systems. Since we did not require substitution on the 2-and 5-positions of the pyrrolidine ring, the azomethine ylide derived from the acid-catalyzed decomposition of commercial N-methoxymethyl-N-trimethylsilyl methyl phenyl methanamine (1) 5 was deemed a suitable choice (Scheme 1). Scheme 1 Acid-catalyzed [3+2]-cycloaddition reactionIn general, with compatible substrates, we found this wellprecedented chemistry to be operationally simple and scalable. In several cases we obtained multigram quantities of the corresponding N-benzyl pyrrolidine. A welldocumented drawback of this method is that this type of unstabilized azomethine ylide does not readily undergo cycloaddition with unactivated dipolarophiles. 6Pyrrolidines whose requisite alkenes were unreactive under the acid-catalyzed conditions required a different preparation. A survey of the chemical literature unearthed a little used, but powerful method wherein a reactive unstabilized azomethine ylide can be generated by treating trimethylamine N-oxide 4 with lithium diisopropylamide at low temperature. 7 Under these strongly basic conditions, ylide formation is thought to proceed by deoxygenation of the N-oxide. The resultant intermediate is extremely reactive and can be trapped by simple alkenes such as hex-1-ene, cyclopentene, styrene, and stilbene. 8 Scheme 2 Basic [3+2]-cycloaddition reactionHerein we would like to report that this cycloaddition reaction furnished targeted N-methyl pyrrolidines in yields ranging from good to excellent in nearly all cases examined. 9 A broad range of substituents on the alkenes were tolerated in this transformation provided that functionalities were compatible with excess LDA. Among the successful dipolarophiles were several examples of electronrich olefins including those that failed under the acid conditions (specifically products 8-10, Table 1). We found this reaction to be operationally straightforward with cycloadditions generally reaching completion in less than one hour.

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Trimethylamine N-oxide as a precursor of azomethine ylides

Cited by 28 publications

References 0 publications

Multi-Ion Bridged Pathway of N-Oxides to 1,3-Dipole Dilithium Oxide Complexes

Multi-Ion Bridged Pathway of N-Oxides to 1,3-Dipole Dilithium Oxide Complexes

Synthesis of Dihydrouracils Spiro-Fused to Pyrrolidines: Druglike Molecules Based on the 2-Arylethyl Amine Scaffold

Remarkable [3+2] Annulations of Electron-Rich Olefins with Unstabilized Azomethine Ylides

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