anti-Markovnikov Hydroamination Research Articles

Programmable Piperazine Synthesis via Organic Photoredox Catalysis.

Piperazine cores have long been identified as privileged scaffolds in the development of pharmaceutical compounds. Despite this, the facile synthesis of diverse C-substituted piperazines remains a challenge without prefunctionalized substrates/cores. Herein, we describe a programmable approach to highly diversifiable piperazine cores, which circumvents the typical need for radical precursors. The use of organic photoredox catalysis renders this method operationally simple, as direct substrate oxidation followed by 6-endo-trig radical cyclization with in situ generated imines may furnish the product. Additionally, the photoredox-catalyzed anti-Markovnikov hydroamination of readily accessible ene-carbamates provides a modular approach to functionalized diamine starting materials which are shown to generate more complex piperazine cores. A wide range of both carbonyl and amine condensation partners were shown to be compatible with this system in good to excellent yield.

Intermolecular Anti-Markovnikov Hydroamination of Alkenes with Sulfonamides, Sulfamides, and Sulfamates

Intermolecular Anti-Markovnikov Hydroamination of Alkenes with Sulfonamides, Sulfamides, and Sulfamates

Organic Synthesis Away from Equilibrium: Contrathermodynamic Transformations Enabled by Excited-State Electron Transfer.

ConspectusChemists have long been inspired by biological photosynthesis, wherein a series of excited-state electron transfer (ET) events facilitate the conversion of low energy starting materials such as H2O and CO2 into higher energy products in the form of carbohydrates and O2. While this model for utilizing light-driven charge transfer to drive catalytic reactions thermodynamically "uphill" has been extensively adapted for small molecule activation, molecular machines, photoswitches, and solar fuel chemistry, its application in organic synthesis has been less systematically developed. However, the potential benefits of these approaches are significant, both in enabling transformations that cannot be readily achieved using conventional thermal chemistry and in accessing distinct selectivity regimes that are uniquely enabled by excited-state mechanisms. In this Account, we present work from our group that highlights the ability of visible light photoredox catalysis to drive useful organic transformations away from their equilibrium positions, addressing a number of long-standing synthetic challenges.We first discuss how excited-state ET enabled the first general methods for the catalytic anti-Markovnikov hydroamination of unactivated alkenes with alkyl amines. In these reactions, an excited-state iridium(III) photocatalyst reversibly oxidizes secondary amine substrates to their corresponding aminium radical cations (ARCs). These electrophilic N-centered radicals can then react with olefins to furnish valuable tertiary amine products with complete anti-Markovnikov regioselectivity. Notably, some of these products are less thermodynamically stable than their corresponding amine and alkene starting materials. We next present a strategy for light-driven C-C bond cleavage within various aliphatic alcohols mediated by homolytic activation of alcohol O-H bonds by excited-state proton-coupled electron transfer (PCET). The resulting alkoxy radical intermediates then undergo C-C β-scission to ultimately provide isomeric linear carbonyl products that are often higher in energy than their cyclic alcohol precursors. Applications of this chemistry for the light-driven depolymerization of lignin biomass, commercial phenoxy resin, hydroxylated polyolefin derivatives, and thermoset polymers are presented as well. We then describe a method for the contrathermodynamic positional isomerization of highly substituted olefins by means of cooperative photoredox and chromium(II) catalysis. In this work, generation of an allylchromium(III) species that can undergo highly regioselective in situ protodemetalation enables access to a less substituted and thermodynamically less stable positional isomer. Product selectivity in this reaction is determined by the large differential in oxidation potentials between differently substituted olefin isomers. Lastly, we discuss a light-driven deracemization reaction developed in collaboration with the Miller group, wherein a racemic urea substrate undergoes spontaneous optical enrichment upon visible light irradiation in the presence of an iridium(III) chromophore, a chiral Brønsted base, and a chiral peptide thiol. Excellent levels of enantioselectivity are achieved via sequential and synergistic proton transfer (PT) and H atom transfer (HAT) steps. Taken together, these examples highlight the ability of excited-state ET events to enable access to nonequilibrium product distributions across a wide range of catalytic, redox-neutral transformations in which photons are the only stoichiometric reagents.

A Type of Chiral C2-Symmetric Arylthiol Catalyst for Highly Enantioselective Anti-Markovnikov Hydroamination.

The development of chiral hydrogen donor catalysts is fundamental in the expansion and innovation of asymmetric organocatalyzed reactions via an enantioselective hydrogen atom transfer (HAT) process. Herein, an unprecedented type of chiral C2-symmetric arylthiol catalysts derived from readily available enantiomeric lactate ester was developed. With these catalysts, an asymmetric anti-Markovnikov alkene hydroamination-cyclization reaction was established, affording a variety of pharmaceutically interesting 3-substituted piperidines with moderate to high enantioselectivity. Results of the designed control experiments and theoretical computation rationalized the origin of stereocontrol and disclosed the spatial effect of the moiety of chiral thiols on the enantioselectivity. We believed the facile synthesis, flexible tunability, and effective enantioselectivity-controlling capability of these catalysts would shed light on the development of versatile chiral HAT catalysts and related asymmetric reactions.

Catalyst-free anti-Markovnikov hydroamination and hydrothiolation of vinyl heteroarenes in aqueous medium: an improved process towards centhaquine.

Catalyst-free hydroamination and hydrothiolation of alkenes have been achieved in an aqueous medium. The anti-Markovnikov addition works efficiently in suspended water at room temperature and allows straightforward access to centhaquine, a drug used for the management of hypovolemic shocks in critically ill patients, and its derivatives. Various primary and secondary amines, thiols, and hydrazides were successfully reacted with a number of heteroaryl/aryl-alkenes. The scalability of the process has been demonstrated by synthesizing centhaquine at a 19.65 g scale. A comparative analysis of the present process with previous approaches has been provided on the basis of green chemistry metrics.

Photocatalytic N-Alkylation of NH-Diaryl Sulfondiimines via Anti-Markovnikov Hydroamination with Styrenes.

Sulfondiimines, which are isoelectronic with sulfones and sulfoximines, represent a neglected yet intriguing pharmacophore in the discovery program. Herein, we present a facile and mild photocatalytic anti-Markovnikov hydroamination of styrenes for the construction of N-alkylated sulfondiimines with primary, secondary, and tertiary alkyl substituents. A sulfondiimine-derived analogue of the marketed drug Vioxx was synthesized using this method as the key step.

Photocatalytic Anti-Markovnikov Hydroamination of Alkenes with Primary Heteroaryl Amines.

We report a light-driven method for the intermolecular anti-Markovnikov hydroamination of alkenes with primary heteroaryl amines. In this protocol, electron transfer between an amine substrate and an excited-state iridium photocatalyst affords an aminium radical cation (ARC) intermediate that undergoes C-N bond formation with a nucleophilic alkene. Integral to reaction success is the electronic character of the amine, wherein increasingly electron-deficient heteroaryl amines generate increasingly reactive ARCs. Counteranion-dependent reactivity is observed, and iridium triflate photocatalysts are employed in place of conventional iridium hexafluorophosphate complexes. This method exhibits broad functional group tolerance across 55 examples of N-alkylated products derived from pharmaceutically relevant heteroaryl amines.

Progression of Hydroamination Catalyzed by Late Transition-Metal Complexes from Activated to Unactivated Alkenes.

ConspectusCatalytic intermolecular hydroamination of alkenes is an atom- and step-economical method for the synthesis of amines, which have important applications as pharmaceuticals, agrochemicals, catalysts, and materials. However, hydroaminations of alkenes in high yield with high selectivity are challenging to achieve because these reactions often lack a thermodynamic driving force and often are accompanied by side reactions, such as alkene isomerization, telomerization, and oxidative amination. Consequently, early examples of hydroamination were generally limited to the additions of N-H bonds to conjugated alkenes or strained alkenes, and the catalytic hydroamination of unactivated alkenes with late transition metals has only been disclosed recently. Many classes of catalysts, including early transition metals, late transition metals, rare-earth metals, acids, and photocatalysts, have been reported for catalytic hydroamination. Among them, late transition-metal complexes possess several advantages, including their relative ease of handling and their high compatibility of substrates containing polar or sensitive functional groups.This Account describes the progression in our laboratory of hydroaminations catalyzed by late transition-metal complexes from the initial additions of N-H bonds to activated alkenes to the more recent additions to unactivated alkenes. Our developments include the Markovnikov and anti-Markovnikov hydroamination of vinylarenes with palladium, rhodium, and ruthenium, the hydroamination of dienes and trienes with nickel and palladium, the hydroanimation of bicyclic strained alkenes with neutral iridium, and the hydroamination of unactivated terminal and internal alkenes with cationic iridium and ruthenium. Enantioselective hydroaminations of these classes of alkenes to form enantioenriched, chiral amines also have been developed.Mechanistic studies have elucidated the elementary steps and the turnover-limiting steps of these catalytic reactions. The hydroamination of conjugated alkenes catalyzed by palladium, rhodium, nickel, and ruthenium occurs by turnover-limiting nucleophilic attack of the amine on a coordinated benzyl, allyl, alkene, or arene ligand. On the other hand, the hydroamination of unconjugated alkenes catalyzed by ruthenium and iridium occurs by turnover-limiting migratory insertion of the alkene into a metal-nitrogen bond. In addition, pathways for the formation of side products, including isomeric alkenes and enamines, have been identified during our studies. During studies on enantioselective hydroamination, the reversibility of the hydroamination has been shown to erode the enantiopurity of the products. Based on our mechanistic understandings, new generations of catalysts that promote catalytic hydroaminations with higher rates, chemoselectivity, and enantioselectivity have been developed. We hope that our discoveries and mechanistic insights will facilitate the further development of catalysts that promote selective, practical, and efficient hydroamination of alkenes.

Cope-Type Hydroamination of Vinylboronates.

Aminoboronic acid derivatives can serve as versatile synthetic intermediates and pharmacophores but remain difficult to synthesize. Herein we report a synthesis of the β-aminoboronic acid motif via anti-Markovnikov hydroamination of vinylboronates. This reaction benefits from the activating effect of the boronate substituent and forms novel BON-containing heterocycles, oxazaborolidine zwitterions. A computational study is included to help determine the effects of alkene boron substitution. Derivatization reactions also support the synthetic utility of the oxazaborolidine adducts.

Photoinduced Disulfide-Catalyzed Intramolecular Anti-Markovnikov Hydroamination through in Situ N-S Species.

The photoinduced anti-Markovnikov hydroamination of olefins typically required photocatalysts with a high oxidative ability to initiate the single-electron process. Herein, we alternatively utilize bis(2,4,6-triisopropylphenyl) disulfide, an inexpensive reagent with relatively low oxidative ability, as a photo and hydrogen atom transfer catalyst to achieve intramolecular hydroamination. The mechanistic studies as well as the DFT calculations are consistent with a novel process involving N-centered radical generation through the homolysis of the in situ formed N-S species and subsequent cyclization. An array of diverse nitrogen-containing cycles could be obtained.

Hydroamination of Unactivated Alkenes with Aliphatic Azides.

We report here an efficient and highly diastereoselective intermolecular anti-Markovnikov hydroamination of unactivated alkenes with aliphatic azides in the presence of silane. The system tolerates a wide range of azides and alkenes and operates with alkene as limiting reagent. Mechanistic studies suggest a radical chain pathway that involves aminium radical formation, radical addition to alkenes and HAT from silane to β-aminium alkyl radical. The use of sterically bulky silane is proposed to contribute to the excellent diastereoselectivity for HAT. Computational analysis uncovers the reaction pathway of aliphatic azide activation with silyl radical for aminyl radical formation.

Manganese-Catalyzed Asymmetric Formal Hydroamination of Allylic Alcohols: A Remarkable Macrocyclic Ligand Effect.

A unique family of chiral peraza N6 -macrocyclic ligands, which are conformationally rigid and have a tunable saddle-shaped cavity, is described. Utilizing their manganese(I) complexes, the first example of earth-abundant transition metal-catalyzed asymmetric formal anti-Markovnikov hydroamination of allylic alcohols was realized, providing a practical access to synthetically important chiral γ-amino alcohols in excellent yields and enantioselectivities (up to 99 % yield and 98 % ee). The single-crystal structure of a MnI complex indicates that the manganese atom coordinates with the chiral dialkylamine moiety in a bidentate fashion. Further DFT calculations revealed that five of the six nitrogen atoms in the ligand were engaged in multiple noncovalent interactions with Mn, an isopropanol molecule, and a β-amino ketone intermediate via coordination, hydrogen bonding, and/or CH⋅⋅⋅π interactions in the transition state, showing a remarkable role of the macrocyclic framework.

Transition-metal-free regioselective hydroamination of styrenes with amino-heteroarenes.

The base-mediated anti-Markovnikov hydroamination of functionally varied styrenes with amino-substituted pyridine, quinoline, pyrimidine, pyrazine, and phenanthridine with excellent regioselectivity has been described. Double hydroamination was observed chemoselectively on the secondary amine, leaving the primary amine intact. Experimental evidence suggests that the proposed reaction involves the nucleophilic addition of the aminopyridyl radical onto vinyl arenes via a single electron transfer.

Anti-Markovnikov Hydroamination of Alkenes Enabled by Dual Phospine/Photoredox Catalysis

Anti-Markovnikov Hydroamination of Alkenes Enabled by Dual Phospine/Photoredox Catalysis

Cobalt-catalyzed Divergent Markovnikov and Anti-Markovnikov Hydroamination.

Catalytic hydroamination of the readily available alkenes is among the most straightforward means to construct diverse alkyl amines. To this end, the facile access to both regioselectivity, i.e., Markovnikov or anti-Markovnikov hydroamination, with minimum reaction-parameter alternation, remains challenging. Herein, we report a cobalt-catalyzed highly selective and divergent Markovnikov and anti-Markovnikov hydroamination of alkenes, in which the switch of regioselectivity is achieved simply by the variation of the addition sequence of 9-BBN.

Phosphine/Photoredox Catalyzed Anti-Markovnikov Hydroamination of Olefins with Primary Sulfonamides via α-Scission from Phosphoranyl Radicals.

New strategies to access radicals from common feedstock chemicals hold the potential to broadly impact synthetic chemistry. We report a dual phosphine and photoredox catalytic system that enables direct formation of sulfonamidyl radicals from primary sulfonamides. Mechanistic investigations support that the N-centered radical is generated via α-scission of the P-N bond of a phosphoranyl radical intermediate, formed by sulfonamide nucleophilic addition to a phosphine radical cation. As compared to the recently well-explored β-scission chemistry of phosphoranyl radicals, this strategy is applicable to activation of N-based nucleophiles and is catalytic in phosphine. We highlight application of this activation strategy to an intermolecular anti-Markovnikov hydroamination of unactivated olefins with primary sulfonamides. A range of structurally diverse secondary sulfonamides can be prepared in good to excellent yields under mild conditions.

Rhodium-Catalyzed Anti-Markovnikov Hydroamination of Aliphatic and Aromatic Terminal Alkynes with Aliphatic Primary Amines.

Anti-Markovnikov hydroamination of both aliphatic and aromatic terminal alkynes with primary amines was achieved using an 8-quinolinolato rhodium catalyst to form aldimines and enamines in high yields. This catalytic system realized high functional group tolerance including hydroxy, bromo, cyano, and thioester groups.

Mechanistic Investigation and Optimization of Photoredox Anti-Markovnikov Hydroamination.

The reaction mechanism and the origin of the selectivity for the photocatalytic intermolecular anti-Markovnikov hydroamination of unactivated alkenes with primary amines to furnish secondary amines have been revealed by time-resolved laser kinetics measurements of the key reaction intermediates. We show that back-electron transfer (BET) between the photogenerated aminium radical cation (ARC) and reduced photocatalyst complex (Ir(II)) is nearly absent due to rapid deprotonation of the ARC on the sub-100 ns time scale. The selectivity for primary amine alkylation is derived from the faster addition of the primary ARCs (as compared to secondary ARCs) to alkenes. The turnover of the photocatalyst occurs via the reaction between Ir(II) and a thiyl radical; the in situ formation of an off-cycle disulfide from thiyl radicals suppresses this turnover, diminishing the efficiency of the reaction. With these detailed mechanistic insights, the turnover of the photocatalyst has been optimized, resulting in a >10-fold improvement in the quantum yield. These improvements enabled the development of a scalable flow protocol, demonstrating a potential strategy for practical applications with improved energy efficiency and cost-effectiveness.

2:1 versus 1:1 Coupling of Alkylacetylenes with Secondary Amines: Selectivity Switching in 8-Quinolinolato Rhodium Catalysis.

Both 2:1 and 1:1 couplings of alkylacetylenes with secondary amines were achieved using 8-quinolinolato rhodium catalysts and CsF. The 2:1/1:1 selectivity was switched by choosing the reaction solvent. In DMA, an unprecedented 2:1 coupling reaction of alkylacetylenes with amines proceeded to give 2-aminodiene products. One-pot 2:1 coupling/reduction provided rapid access to various allylamines, while one-pot coupling/hydrolysis gave enones as products. In toluene, anti-Markovnikov hydroamination occurred under relatively mild conditions to give 1:1 coupling products.

Photocatalytic intermolecular anti-Markovnikov hydroamination of unactivated alkenes with N-hydroxyphthalimide

A visible-light-induced/phosphite-promoted anti-Markovnikov hydroamination of alkenes with N-hydroxyphthalimide was successfully realized, which was initiated by a proton-coupled electron transfer to enable direct cleavage of its N–O bond.