Mechanistic Studies on the Synthesis of Pyrrolidines and Piperidines via Copper-Catalyzed Intramolecular C–H Amination

We have recently developed a method for the synthesis of pyrrolidines and piperidines via intramolecular C–H amination of N-fluoride amides using [TpxCuL] complexes as precatalysts [Tpx = tris(pyrazolyl)borate ligand and L = THF or CH3CN]. Herein, we report mechanistic studies on this transformation, which includes the isolation and structural characterization of a fluorinated copper(II) complex, [(TpiPr2OH)CuF] [TpiPr = hydrotris(3,5-diisopropylpyrazolyl)borate], pertinent to the mechanistic pathway. The effects of the nature of the Tpx ligand in the copper catalyst as well as of the halide in the N–X amides employed as reactants have been investigated both from experimental and computational perspectives.We thank the Ministerio de Ciencia e Innovación (PID2020- 113797RB-C21, PID2020-112825RB-I00, CTQ2017-88496-R, and CEX2019-000925-S), COST Action CA15106 “C−H Activation in Organic Synthesis (CHAOS)”and Red Intecat (CTQ2016-81923-REDC), and Universidad de Huelva (P.O.Feder 2014-2020 UHU-1254043). We thank Universidad de Huelva/CBUA for funding for open access charge

Comparison of Free Energy Surfaces Calculations from Ab Initio Molecular Dynamic Simulations at the Example of Two Transition Metal Catalyzed Reactions

We carried out ab initio molecular dynamic simulations in order to determine the free energy surfaces of two selected reactions including solvents, namely a rearrangement of a ruthenium oxoester in water and a carbon dioxide addition to a palladium complex in carbon dioxide. For the latter reaction we also investigated the gas phase reaction in order to take solvent effects into account. We used two techniques to reconstruct the free energy surfaces: thermodynamic integration and metadynamics. Furthermore, we gave a reasonable error estimation of the computed free energy surface. We calculated a reaction barrier of ΔF = 59.5 ± 8.5 kJ mol−1 for the rearrangement of a ruthenium oxoester in water from thermodynamic integration. For the carbon dioxide addition to the palladium complex in carbon dioxide we found a ΔF = 44.9 ± 3.3 kJ mol−1 from metadynamics simulations with one collective variable. The investigation of the same reactions in the gas phase resulted in ΔF = 24.9 ± 6.7 kJ mol−1 from thermodynamic integration, in ΔF = 26.7 ± 2.3 kJ mol−1 from metadynamics simulations with one collective variable, and in ΔF = 27.1 ± 5.9 kJ mol−1 from metadynamics simulations with two collective variables

Enantioselective 4-Hydroxylation of Phenols under Chiral Organoiodine(I/III) Catalysis

A procedure for the intermolecular enantioselective dearomatization of phenols under chiral (I/III) catalysis is reported. This protocol employs mCPBA as the terminal oxidant together with a defined C2-symmetric aryl iodide as the effective organocatalyst. This enantioselective reaction proceeds with complete selectivity under mild conditions and enables the hydroxylative dearomatization of a number of phenols into the corresponding para-quinol products with up to 50

Selective Piperidine Synthesis Exploiting Iodine-Catalyzed Csp3-H Amination under Visible Light

A route to selective piperidine formation through intramolecular catalytic Csp3-H amination is described. This hydro- carbon amination reaction employs a homogeneous iodine catalyst derived from halogen coordination between molecular iodine and a terminal oxidant. It relies on visible light initiation and proceeds within two catalytic cycles that comprise a radical C-H func- tionalization and an iodine-catalyzed C-N bond formation. Under these conditions, the commonly observed preference for pyrroli- dine synthesis based on halogenated nitrogen intermediates within the Hofmann-Löffler domain is effectively altered in favor of a free radical promoted piperidine formation. The protocol is demonstrated for a total of 30 applications

Indole Synthesis via Sequential Electrophilic N-H and C-H Bond Activation using Iodine(III) Reactivity

An intramolecular approach towards the regioselective construction of 2,3-diarylated indoles is reported. The reaction follows an intramolecular approach of an electrophilic N-H and C-H bond functionalization between an aniline and an acetylene. It employs the concept of a traceless tether to provide access to the free 2,2-diarylated indole products comprising a total of 18 examples. Hypervalent iodine reagents were identified as suitable promoters and four different protocols are provided including stoichiometric and catalytic transformations.</p

Enantioselective Vicinal Diacetoxylation of Alkenes under Chiral Iodine(III) Catalysis

Abstract: A procedure for the intermolecular enantioselective dioxygenation of alkenes under iodine(III) catalysis has been developed. This protocol employs Selectfluor as the terminal oxidant together with a defined C2-symmetric aryl iodide as the organocatalyst. This enantioselective reaction proceeds under mild conditions and converts a series of terminal and internal styrenes into the corresponding vicinal diacetoxylation products with up to 96% ee.</p

Dioxoiodane Compounds as Versatile Sources for Iodine(I) Chemistry

The general synthesis, isolation and characterization of electrophilic iodine reagents of the general formula R4N[I(O2CAr)2] is reported. These compounds are air‐ and moisture‐stable iodine(I) reagents, which were characterized including X‐ray analysis. They represent conceptually new iodine(I) reagents with anions as stabilizers. These compounds display the expected performance as electrophilic reagents upon interaction with electron‐rich substrates. The performance of these compounds in a total of 47 different reactions of vicinal iodooxygenation of alkenes is studied and some key features on the reagents are revealed

An Improved Catalyst for Iodine(I/III)-Catalysed Intermolecular C-H Amination

1,2-Diiodobenzene is presented as an efficient catalyst precursor for the intermolecular amination of arenes under homogeneous conditions. N-Troc and N-phthalimido-substituted methoxyamines serve as suitable nitrogen sources providing the corresponding aniline derivatives in up to 99% yield and with up to 66:1 regioselectivity. Key for this successful C-N coupling protocol is the strained m-oxo-bridged conformation of the bisiodine(III) catalyst, which induces unparalleled high reactivity.</p

Designing Homogeneous Bromine Redox Catalysis for Selective Aliphatic C-H Bond Functionalization

Das Potential der homogenen Oxidationskatalyse unter Verwendung von Brom ist weitgehend unerforscht. Wir zeigen hier, dass die Kombination von Tetraalkylammoniumbromid und 3‐Chlorperbenzoesäure ein einzigartiges Katalysatorsystem für die bequeme und selektive Oxidation gesättigter C(sp3)‐H‐Bindungen unter photochemischer Initiierung mit Tageslicht bietet. Es ermöglicht eine positionsselektive intramolekulare Aminierung, wie anhand von 20 verschiedenen Beispielen gezeigt wurde. Zum ersten Mal konnte ein N‐halogeniertes Intermediat in einer katalytischen Hofmann‐Löffler‐Reaktion isoliert werden. Darüber hinaus wurde eine neuartige schnelle Eintopfsynthese von N‐Sulfonyloxaziridinen aus N‐Sulfonamiden entwickelt und für 15 Transformationen beispielhaft dargestellt. Diese bahnbrechenden Beispiele bieten ein neuartiges Konzept für die molekulare Katalyse mit Brom