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Shiv Nadar University

The stereoselectivity and stereospecificity of the triflate-mediated intramolecular Schmidt reaction of substituted 3-(1-azidocyclohexyl)propanol derivatives leading to octahydro-1H-pyrrolo[1,2-a]azepine, the structural skeleton of several important families of alkaloids such as the Stemona alkaloids, has been examined. The reaction involves an initial intramolecular SN2 reaction between the azide moiety and the triflate affording an intermediate spirocyclic aminodiazonoium salt that undergoes the expected 1,2-shift/N2-elimination followed by hydride-mediated iminium salt reduction. Remarkably, chiral alcohols are converted to the azabicyclic derivative with no or limited racemization. The initial asymmetric alcohol center controls the diastereoselectivity of the whole process, leading to the formation of one out of the four possible diastereoisomers of disubstituted octahydro-1H-pyrrolo[1,2-a]azepine. The origin of the stereoselectivity is rationalized based on theoretical calculations. The concise synthesis of (−)-(cis)-3-propylindolizidine and (−)-(cis)-3-butyllehmizidine, two alkaloids found in the venom of workers of the ant Myrmicaria melanogaster, is reported.

World University root node

Chemistry

(SoNS) School of Natural Sciences

Fulltext

Angewandte Chemie - International Edition

Stereoselective and Stereospecific Triflate-Mediated Intramolecular Schmidt Reaction: Ready Access to Alkaloid Skeletons**

Stereochemical Control of the Triflate Mediated Intramolecular Schmidt Reaction

Full control over the selectivity of carbon-carbon double-bond migrations would enable access to stereochemically defined olefins that are central to the pharmaceutical, food, fragrance, materials and petrochemical arenas. The vast majority of double-bond migrations investigated over the past 60 years capitalize on precious-metal hydrides that are frequently associated with reversible equilibria, hydrogen scrambling, incomplete E/Z stereoselection and/or high cost. Here, we report a fundamentally different, radical-based approach.We showcase a nonprecious, reductant-free and atom-economical nickel (Ni)(I)-catalyzed intramolecular 1,3-hydrogen atom relocation to yield E-olefins within 3 hours at room temperature. Remote installations of E-olefins over extended distances are also demonstrated.

Science

E-Olefins through intramolecular radical relocation

A 'direct' alkynylation of isatins, which uses potassium tert-butoxide to provide the desired 3-hydroxy-3-ethynyl-2-oxindoles in good to high yields, is reported. This protocol proceeds smoothly for both electron-rich and electron-deficient alkynes in comparable reaction rates and does not require any specially design ligand or expensive transition-metal catalysts.

Synthesis (Germany)

Transition-Metal-Free Terminal Alkyne Addition to Isatins

The Cu-catalyzed oxidation of ketones with O2 has recently been extensively utilized to cleave the $\alpha$-C-C bond. This report examines the selective aerobic hydroxylation of tertiary $\alpha$-C-H bonds in ketones without C-C cleavage. We set out to understand the underlying mechanisms of these two possible reactivity modes. Using experimental, in situ IR spectroscopic and computational studies, we investigated several mechanisms. Our data suggest that both C-C cleavage and C-H hydroxylation pathways proceed via a common key intermediate, i.e., an $\alpha$-peroxo ketone. The fate of this peroxide dictates the ultimate product selectivity. Specifically, we uncovered the role of hppH [=1,3,4,6,7,8-hexahydro-2H-pyrimido[1,2-a]pyrimidine] to act not only as a base in the transformation but also as a reductant of the peroxide to the corresponding $\alpha$-hydroxy ketone. This reduction may also be accomplished through exogenous phosphine additives, therefore allowing the tuning of reduction efficiency toward higher driving forces, if required (e.g., for more-activated substrates). The likely competitive pathway is the cleavage of peroxide to the $\alpha$-oxy radical (likely catalyzed by Cu), which is computationally predicted to spontaneously trigger C-C bond cleavage. Increasing the susceptibility of this deperoxidation step via (i) the removal of reductant (use of different base, e.g., DBU) or the modulation of (ii) the substitution pattern toward greater activation (substrate control) and (iii) the nature of Cu catalyst (counterion and solvent dependence) will favor the C-C cleavage product.

Journal of the American Chemical Society

Factors That Control C-C Cleavage versus C-H Bond Hydroxylation in Copper-Catalyzed Oxidations of Ketones with O2

Potassium tert-butoxide acts as a nucleophilic oxygen source during the hydration of nitriles to give the corresponding amides under anhydrous conditions. The reaction proceeds smoothly for a broad range of substrates under mild conditions, providing an efficient and economically affordable synthetic route to the amides in excellent yields. This protocol does not need any transition-metal catalyst or any special experimental setup and is easily scalable to bulk scale synthesis. A single-electron-transfer radical mechanism as well as an ionic mechanism have been proposed for the hydration process.

Journal of Organic Chemistry

Transition-metal-free hydration of nitriles using potassium tert -butoxide under anhydrous conditions

In the presence of tert-butyl iodide, alkyl azides are converted into the corresponding iodides at room temperature, whereas, N-t-Bu anilines are obtained from aryl azides under the same experimental conditions. A mechanism is proposed to explain this unusual reactivity. {\textcopyright} 2012 Elsevier Ltd. All rights reserved.

Tetrahedron

Unexpected conversion of alkyl azides to alkyl iodides and of aryl azides to N-tert-butyl anilines

Recent advances in radical azidation using sulfonyl azides are presented. For instance, radical carboazidation using $\alpha$-iodoketones, desulfitative carboazidation and anti- Markovnikov hydroazidation of alkenes are described. These novel methods tolerate a large number of functional groups and allow the synthesis of organic azides that would be difficult to synthesize otherwise. The transformation of the azides using reductive processes as well as a Schmidt reaction under nonacidic conditions were used to synthesize alkaloids including indolizidine 167B, monomorine I, cylindricine C and lepadiformine C. {\textcopyright} 2012 IUPAC.

Pure and Applied Chemistry

Radical azidation reactions and their application in the synthesis of alkaloids

A one-pot procedure for the efficient hydroazidation of alkenes involving hydroboration with catecholborane followed by reaction with benzenesulfonyl azide in the presence of a radical initiator is described. The regioselectivity is controlled by the hydroboration step and corresponds in most cases to an anti-Markovnikov regioselectivity. This procedure is applicable to a wide range of alkenes and gives excellent results with 1,2-disubstituted and trisubstituted alkenes. {\textcopyright} 2011 American Chemical Society.

A radical procedure for the anti-markovnikov hydroazidation of alkenes

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Recent Progress in Intramolecular Schmidt Reaction and Radical Azidation

(Chemical Equation Presented) A powerful intramolecular Schmidt reaction starting from primary azidoalcohols is reported. This approach involves a nonacidic activation of the alcohol via triflation. The synthetic potential offered by the mild reaction conditions is demonstrated by a highly selective synthesis of (-)-indolizidine 167B. {\textcopyright} 2009 American Chemical Society.

Intramolecular schmidt reaction involving primary azidoalcohols under nonacidic conditions: Synthesis of indolizidine (-)-167B

A convenient approach for the synthesis of a methyl analogue of crispine A, a potent anticancer agent, through intramolecular Schmidt reaction of azido-ketone 6 is described. {\textcopyright} 2007 Elsevier Ltd. All rights reserved.

Tetrahedron Letters

An intramolecular Schmidt reaction strategy for the synthesis of a methyl analogue of crispine A

An intramolecular Schmidt reaction strategy for the synthesis of various derivatives of crispine A using azido-ketone as a key intermediate is described.