Intramolecular Amination Research Articles

Synthesis of 1,2-Benzothiazine via Nickel-Catalyzed Electrochemical Intramolecular Amination.

Constructing a C-N bond by merging electrochemistry and nickel catalysis is considered a powerful strategy. Herein, we investigate highly efficient intramolecular amination at room temperature with excellent functional group tolerance. Mechanistic studies suggest that the rapid ligand exchange may lead to the NiI/NiIII catalytic cycle. This method not only provides a new perspective for intramolecular amination but also offers a novel approach for constructing the benzothiazine scaffold.

Bifunctional Imine Reductase Cascades for the Synthesis of Saturated N-Heterocycles.

Saturated N-heterocycles constitute a vital scaffold for pharmaceutical chemistry but are challenging to access synthetically, particularly asymmetrically. Here, we demonstrate how imine reductases can achieve annulation through tandem inter- and intramolecular reductive amination processes. Imine reductases were used in combination with further enzymes to access unsubstituted, α-substituted, and α,α'-disubstituted N-heterocycles from simple starting materials in one pot and under benign conditions. This work shows the remarkable flexibility of these enzymes to have broad activity against numerous substrates derived from singlular starting materials.

Copper-Catalyzed, Intramolecular Amination of Unactivated C(sp3)-H Bonds through Radical Relay.

Although copper-catalyzed amination of activated C(sp3)-H bonds through radical relay has been developed, amination of unactivated C(sp3)-H bonds is rare. Herein, copper-catalyzed intramolecular amination of remote unactivated C(sp3)-H bonds is reported. The reaction is conducted in a mild and effective manner with moderate to good yields, demonstrating broad tolerance toward various functional groups and exhibiting complete regio- and chemoselectivities. This innovation supplies novel synthetic pathways for the construction of saturated nitrogenated heterocycles.

One-Pot Multienzyme Cascades for Stereodivergent Synthesis of Tetrahydroquinolines.

The tetrahydroquinoline (THQ) framework is commonly found in natural products and pharmaceutically relevant molecules. Apart from the use of transition metal catalysts and chiral phosphoric acids, the chiral 2-substituted 1,2,3,4-THQs are synthesized using amine oxidase biocatalysts. However, the use of imine reductases (IREDs) in their asymmetric synthesis remained unexplored. In the current work, IREDs are employed in telescopic multienzyme cascades to catalyze the intramolecular reductive amination leading to chiral 2-alkyl and 2-aryl substituted-1,2,3,4-tetrahydroquinolines starting from inexpensive nitroalkenones. The cascades containing NtDBR (an ene reductase), NfsB (a nitro reductase) with either Na2S2O4 or V2O5, various IREDs, and glucose dehydrogenase (for NADPH regeneration) are used to synthesize a broad range of (R)/(S)-2-alkyl-substituted (THQs) (26 examples) with high yield (up to 93%) and excellent ee (up to 99%) in one-pot. The method further facilitates the one-pot biocatalytic synthesis of chiral 2-aryl substituted THQs (26 examples) from amino chalcones. Lastly, the asymmetric synthesis of several (R)- and (S)-THQ based intermediates of Hancock alkaloids showed the practical application of the newly developed biocatalytic cascades.

Iron Corrole-Catalyzed Intramolecular Amination Reactions of Alkyl Azides. Spectroscopic Characterization and Reactivity of [FeV(Cor)(NAd)

As nitrogen analogues of iron-oxo species, high-valent iron-imido species have attracted great interest in the past decades. FeV-alkylimido species are generally considered to be key reaction intermediates in Fe(III)-catalyzed C(sp3)─H bond aminations of alkyl azides but remain underexplored. Here, it is reported that iron-corrole (Cor) complexes can catalyze a wide range of intramolecular C─H amination reactions of alkyl azides to afford a variety of 5-, 6- and 7-membered N-heterocycles, including alkaloids and natural product derivatives, with up to 3880 turnover numbers (TONs) and excellent diastereoselectivity (>99:1d.r.). Mechanistic studies including density functional theory (DFT) calculations and intermolecular hydrogen atom abstraction (HAA) reactions reveal key reactive FeV-alkylimido intermediates. The [FeV(Cor)(NAd)] (Ad = adamantyl) complex is independently prepared and characterized through electron paramagnetic resonance (EPR), resonance Raman (rR) measurement, and X-ray photoelectron spectroscopy (XPS). This complex is reactive toward HAA reactions with kinetic isotope effects (KIEs) similar to [Fe(Cor)]-catalyzed intramolecular C─H amination of alkyl azides.

Gold(I)−Catalyzed Synthesis of Cyclic Sulfamides via an Intramolecular Dehydrative Amination of Allylic Alcohols: A Strategy for 1,3‐Diamine Synthesis

AbstractA gold(I)‐catalyzed intramolecular dehydrative amination method has been developed to synthesize diverse cyclic sulfamides efficiently. Reactions proceed smoothly at room temperature using a combination of (IPr)AuCl (5 mol%) and AgBF4 (5 mol%). This method showcases a broad substrate scope, encompassing challenging seven‐membered ring structures, and exhibits functional group compatibility. Moreover, the reaction demonstrates high stereoselectivity, allowing the synthesis of enantiomerically enriched cyclic sulfamides from chiral secondary allylic alcohols. The synthesized cyclic sulfamides serve as valuable intermediates for generating 1,3‐diamines. This approach provides an improved route for cyclic sulfamide synthesis and a strategic entry point for obtaining essential 1,3‐diamine derivatives.

Asymmetric Intramolecular Amination Catalyzed with Cp*Ir-SPDO via Nitrene Transfer for Synthesis of Spiro-Quaternary Indolinone.

An asymmetric intramolecular spiro-amination to high steric hindering α-C-H bond of 1,3-dicarbonyl via nitrene transfer using inactive aryl azides has been carried out by developing a novel Cp*Ir(III)-SPDO (spiro-pyrrolidine oxazoline) catalyst, thereby enabling the first successful construction of structurally rigid spiro-quaternary indolinone cores with moderate to high yields and excellent enantioselectivities. DFT computations support the presence of double bridging H-F bonds between [SbF6]- and both the ligand and substrate, which favors the plane-differentiation of the enol π-bond for nitrenoid attacking. These findings open up numerous opportunities for the development of new asymmetric nitrene transfer systems.

Hexafluoroisopropanol-assisted selective intramolecular synthesis of heterocycles by single-electron transfer

Intramolecular amination of remote aliphatic C–H bonds via hydrogen-atom transfer reactions has become a powerful tool for accessing saturated nitrogen-containing heterocycles. However, the formation of six-membered rings or oxa-heterocycles remains a formidable challenge for Hofmann–Löffler–Freytag reactions. Here we show how by simply combining bench-stable (bis(trifluoroacetoxy)iodo)benzene and hexafluoroisopropanol (HFIP) we can switch from the well-established Hofmann–Löffler–Freytag mechanism to a different versatile reaction pathway that enables selective C(sp3)–H bond functionalization. We have exploited the facile formation of radical cations via single-electron transfer, in the presence or absence of light, to synthesize pyrrolidines and piperidines, including drug-type molecules, along with O-heterocycles. Experimental and computational mechanistic studies support two distinct mechanistic pathways, depending on the electron density of the substrate, in which the HFIP plays a multifunctional role.

Construction of the Akuammiline Alkaloid Core Structure via Stereoselective E-Ring Formation.

Construction of the core structure of akuammiline alkaloids with three-dimensional cage-like structures for their diversity-oriented synthesis was investigated. Extensive exploration centered around the introduction of nitrogen functional groups and construction of the E-ring in an intramolecular or intermolecular manner revealed that a Claisen rearrangement approach involving intramolecular amination provided a common precursor, potentially facilitating divergent access to various types of akuammiline alkaloids.

(5S)-5-Benzylswainsonines as potent and selective inhibitors of Golgi α-mannosidase II: synthesis, enzyme evaluation and molecular modelling

Development of novel anti-cancer therapeutics based on Golgi α-mannosidase II (GMII) inhibition is considerably impeded by an undesired co-inhibition of lysosomal α-mannosidase leading to severe side-effects. In this contribution, we describe a fully stereoselective synthesis of (5S)-5-[4-(halo)benzyl]swainsonines as highly potent and selective inhibitors of GMII. The synthesis starts from a previously reported aldehyde readily available from l-ribose, and the key features include an intramolecular reductive amination with substrate-controlled stereoselectivity and a late-stage derivatisation of the benzyl group via ipso-substitution. These novel swainsonine analogues were found to be nanomolar inhibitors of the Golgi-type α-mannosidase AMAN-2 (Ki = 23–75 nM) with excellent selectivity (selectivity index = 205–870) over the lysosomal-type Jack bean α-mannosidase. Finally, molecular docking and pKa calculations were performed to provide more insight into the structure of the inhibitor:enzyme complexes, and a pair interaction energy analysis (FMO-PIEDA) was carried out to rationalise the observed potency and selectivity of the inhibitors.

Enantioselective iron-catalysed transformations. An update

This review updates the field of enantioselective iron-catalysed transformations of all types since the beginning of 2020. It shows that asymmetric iron catalysis, that suits the growing demand for greener processes, offers a real opportunity to replace toxic and expensive metals in the near future. The review includes enantioselective iron-catalysed domino reactions; reductions of ketones and imines; cycloadditions; additions to alkenes; coupling reactions; Michael-type reactions; α-functionalisations of carbonyl compounds; sulfoxidations; alkylations of indoles; rearrangement reactions; intramolecular aminations; and miscellaneous reactions.

The synthesis and characterization of an iron(VII) nitrido complex

Complexes of iron in high oxidation states are captivating research subjects due to their pivotal role as active intermediates in numerous catalytic processes. Structural and spectroscopic studies of well-defined model complexes often provide evidence of these intermediates. In addition to the fundamental molecular and electronic structure insights gained by these complexes, their reactivity also affects our understanding of catalytic reaction mechanisms for small molecule and bond-activation chemistry. Here, we report the synthesis, structural and spectroscopic characterization of a stable, octahedral Fe(VI) nitrido complex and an authenticated, unique Fe(VII) species, prepared by one-electron oxidation. The super-oxidized Fe(VII) nitride rearranges to an Fe(V) imide through an intramolecular amination mechanism and ligand exchange, which is characterized spectroscopically and computationally. This enables combined reactivity and stability studies on a single molecular system of a rare high-valent complex redox pair. Quantum chemical calculations complement the spectroscopic parameters and provide evidence for a diamagnetic (S = 0) d2 Fe(VI) and a genuine S = 1/2, d1 Fe(VII) configuration of these super-oxidized nitrido complexes.

Copper-catalyzed intramolecular dearomative aza-Wacker reaction of indole.

Herein, we describe a copper-catalyzed intramolecular dearomative amination of indoles via a formal aza-Wacker reaction. This protocol provides an efficient method to access aza-polycyclic indoline molecules bearing exocyclic CC bonds in moderate to excellent yields in the presence of molecular oxygen as an oxidant. It is worth noting that indolin-3-ones are achieved when employing C3-non-substituted indoles as substrates.

Conjugate Aminocyclization Catalyzed by a Bismuthinidene

AbstractWe disclose how an N,C,N‐bismuthinidene is able to promote an intramolecular conjugate amination that affords cyclic carbamates in 91–97% yields. The reaction proceeds at room temperature in short reaction times, requiring a remarkably low loading of a bismuth(I) complex (0.1 mol%) without the need of an additional Brønsted base. Preliminary mechanistic studies suggest that the reaction takes place through a polar pathway involving the conjugate addition of the nucleophilic bismuthinidene, followed by an intramolecular aza‐Michael reaction.

Rh2(II)-Catalyzed Selective C(sp3)-H Bond Electrophilic Amination of Aryl Azide-Tethered 1,3-Dicarbonyl Compounds.

Herein, we report the accomplishment of Rh2(II)-catalyzed intramolecular amination of aryl azide-tethered 1,3-dicarbonyls to access privileged heterocyclic scaffolds with exclusive diastereoselectivity under simple reaction conditions. This method also allows an unconventional direct α-amination at electron-deficient C(sp3)-H bonds of aryl azide-tethered 1,3-diketones to afford fused 2-azatricyclo[4.4.0.02,8]decanones and 2,2-disubstituted indolines, which are present in several biologically active alkaloids. Kinetic isotope experiments revealed that the nucleophilic addition of enol π-bonds on the transient electrophilic rhodium-nitrenoid intermediate enables C-N bond formation.

Stereoselective Synthesis of Heavily Hydroxylated Azepane Iminosugars via Osmium-Catalyzed Tethered Aminohydroxylation.

A novel stereoselective synthetic approach to pentahydroxyazepane iminosugars is described. The strategy relies on a key osmium-catalyzed aminohydroxylation reaction of allylic alcohols obtained via addition of vinylmagnesium bromide to a d-mannose-derived aldehyde, which forms the new C-N bond with complete regio- and stereocontrol according to the tethering approach. Subsequent intramolecular reductive amination afforded the desired azepanes. This method represents the first application of the osmium-catalyzed tethered aminohydroxylation reaction to the synthesis of iminosugars.

Electrostatic Interactions in Asymmetric Organocatalysis.

ConspectusElectrostatic interactions are ubiquitous in catalytic systems and can be decisive in determining the reactivity and stereoselectivity. However, difficulties quantifying the role of electrostatic interactions in transition state (TS) structures have long stymied our ability to fully harness the power of these interactions. Fortunately, advances in affordable computing power, together with new quantum chemistry methods, have increasingly enabled a detailed atomic-level view. Empowered by this more nuanced perspective, synthetic practitioners are now adopting these techniques with growing enthusiasm.In this Account, we narrate our recent results rooted in state-of-the-art quantum chemical computations, describing pivotal roles for electrostatic interactions in the organization of TS structures to direct the reactivity and selectivity in the realm of asymmetric organocatalysis. To provide readers with a fundamental foundation in electrostatics, we first introduce a few guiding principles, beginning with a brief discussion of how electrostatic interactions can be harnessed to tune the strength of noncovalent interactions. We then describe computational approaches to capture these effects followed by examples in which electrostatic effects impact structure and reactivity. We then cover some of our recent computational investigations in three specific branches of asymmetric organocatalysis, beginning with chiral phosphoric acid (CPA) catalysis. We disclose how CPA-catalyzed asymmetric ring openings of meso-epoxides are driven by stabilization of a transient partial positive charge in the SN2-like TS by the chiral electrostatic environment of the catalyst. We also report on substrate-dependent electrostatic effects from our study of CPA-catalyzed intramolecular oxetane desymmetrizations. For nonchelating oxetane substrates, electrostatic interactions with the catalyst confer stereoselectivity, whereas oxetanes with chelating groups adopt a different binding mode that leads to electrostatic effects that erode selectivity. In another example, computations revealed a pivotal role of CH···O and NH···O hydrogen bonding in the CPA-catalyzed asymmetric synthesis of 2,3-dihydroquinazolinones. These interactions control selectivity during the enantiodetermining intramolecular amine addition step, and their strength is modulated by electrostatic effects, allowing us to rationalize the effect of introducing o-substituents. Next, we describe our efforts to understand selectivity in a series of NHC-catalyzed kinetic resolutions, where we discovered that the electrostatic stabilization of key proton(s) is the common driver of selectivity. Finally, we discuss our breakthrough in understanding asymmetric silylium ion-catalyzed Diels-Alder cycloaddition of cinnamate esters to cyclopentadienes. The endo:exo of these transformations is guided by electrostatic interactions that selectively stabilize the endo-transition state.We conclude with a brief overview of the outstanding challenges and potential roles of computational chemistry in enabling the exploitation of electrostatic interactions in asymmetric organocatalysis.

Sulfamidate-Based Stereoselective Total Synthesis of (+)-Preussin Using Gold(I)-Catalyzed Intramolecular Dehydrative Amination: Dead End and Detour.

A sulfamidate-based stereoselective total synthesis of (+)-preussin has been developed. The key step involves a gold(I)-catalyzed intramolecular dehydrative amination of sulfamate esters tethered to allylic alcohols, which allows for the construction of the cyclic sulfamidate with high stereoselectivity. Further manipulation to highly constrained bicyclic sulfamidate and the following ring-opening process afford 3-hydroxypyrrolidine motif stereoselectively. The energy of the constrained bicyclic ring system is relieved by the subsequent ring-opening process, which leads to a stereoselective formation of the 3-hydroxypyrrolidine motif under mild reaction conditions. The success of this approach not only provides a new method for the total synthesis of enantiomerically pure (+)-preussin but also highlights the synthetic utility of sulfamidates in constructing valuable natural product architectures.

Construction of 2‐Azabicyclo[2.2.1]heptenes via Selenium‐Catalyzed Intramolecular Oxidative Amination of Cyclopentenes

AbstractA selenium‐catalyzed intramolecular oxidative amination of cyclopentenes has been described. A variety of 2‐azabicyclo[2.2.1]heptenes were obtained with 58%–96% yields. This protocol was featured with mild reaction conditions and broad substrate scope. The subsequent modification of the bicyclic backbone and amino group further demonstrated the application value of this aza‐bridged ring.

Metal-Free Construction of Multisubstituted Indolizines via Intramolecular Amination of Allylic Alcohols.

An intramolecular amination of allylic alcohols is developed as an efficient and general access to biologically important multisubstituted indolizines and their variants. Two metal-free synthetic platforms including using aqueous hydrochloric acid solution as the solvent and p-toluenesulfonic acid as the catalyst have been established, enabling the divergent synthesis of these valuable compounds in high yields.