anti-Markovnikov Hydroamination Research Articles

Catalytic Anti-Markovnikov Transformations of Hindered Terminal Alkenes Enabled by Aldehyde-Selective Wacker-Type Oxidation.

A new strategy for the functionalization of sterically hindered terminal olefins is reported. Alkenes bearing quaternary carbons at the allylic or homoallylic position are readily oxidized to the corresponding aldehydes by palladium/copper/nitrite catalysis. A broad range of functional groups including esters, nitriles, silyl ethers, vinylogous esters, ketones, lactones, and β-ketoesters are tolerated under the reaction conditions. The crude aldehyde products can be transformed further, enabling direct conversion of hindered terminal alkenes to various other synthetically useful functional groups, resulting in formal anti-Markovnikov hydroamination, among other transformations.

A General Approach to Catalytic Alkene Anti-Markovnikov Hydrofunctionalization Reactions via Acridinium Photoredox Catalysis

The development of methods for anti-Markovnikov alkene hydrofunctionalization has been a focal point of catalysis research for several decades. The vast majority of work on the control of regioselectivity for this reaction class has hinged on transition metal catalyst activation of olefin substrates. While progress has been realized, there are significant limitations to this approach, and a general solution for catalysis of anti-Markovnikov hydrofunctionalization reactions of olefins does not presently exist. In the past several years, this research lab has focused on alkene activation by single electron oxidation using organic photoredox catalysts to facilitate anti-Markovnikov hydrofunctionalization. By accessing reactive cation radical intermediates, we have realized a truly general approach to anti-Markovnikov olefin hydrofunctionalization reactions. We have identified a dual organic catalyst system consisting of an acridinium photooxidant, first reported by Fukuzumi, and a redox-active hydrogen atom donor that accomplishes a wide range of hydrofunctionalization reactions with complete anti-Markovnikov regiocontrol. This method relies on single electron oxidation of the alkene to reverse its polarity and results in the opposite regioselectivity for hydrofunctionalization. In 2012, we disclosed the anti-Markovnikov hydroetherification of alkenols employing an acridinium photocatalyst and a hydrogen atom donor that proceeds via interwoven polar and radical steps. This general catalyst system has enabled several important reactions in this area, including anti-Markovnikov alkene hydroacetoxylation, hydrolactonization, hydroamination, and hydrotrifluoromethylation reactions. More recently, we have also delineated conditions for intermolecular anti-Markovnikov hydroamination reactions of alkenes using either triflamide or nitrogen-containing heteroaromatic compounds such as pyrazole, indazole, imidazole, and 1,2,3-triazole. Further development led to a method for the anti-Markovnikov addition of mineral acids to olefins using lutidinium halide salts as convenient reagents to deliver the mineral acids. Acids including HCl, HF, H3PO4, and MeSO3H all participate in the hydrofunctionalization reactions, even with alkenes that are highly prone to polymerization. A combination of transient and steady-state absorption spectroscopy tools were employed to observe alkene cation radicals and the resultant acridine radical, lending support for an electron transfer mechanism. The origin of the anti-Markovnikov selectivity in these reactions is likely the result of a reversible addition of the nucleophile to the alkene cation radical resulting in a greater population of the more stable radical. Loss of a proton followed by reaction of the radical intermediate with the hydrogen atom donor completes the transformations. Again, by means of transient absorption spectroscopy, oxidative turnover of the acridine radical was observed to complete the dual catalytic cycle mechanistic picture.

Acceleration of Anti‐Markovnikov Hydroamination in the Synthesis of an Active Pharmaceutical Ingredient

AbstractSlow chemical reactions are a big challenge in the modern pharmaceutical industry. Their accelerations together with the introduction of continuous manufacturing modes are major drivers for future development. One example reaction is hydroamination, a reaction between unsaturated hydrocarbons and amines. Such a reaction type is the main focus of this work. More precisely, the anti‐Markovnikov hydroamination reaction between cis/trans 9H‐thioxanthene‐2‐chloro‐9‐(2‐propenylidene)‐(9CI) and 1‐(2‐hydroxyethyl)piperazine (HEP) is investigated in detail. It has been traditionally performed in toluene with a huge excess of HEP and reaction times of up to 24 h. Acceleration of the reaction from 24 down to 4 h is achieved by switching from batch operation mode in toluene to either solvent‐free batch mode or microwave‐assisted hydroamination with tetrahydrofuran as a solvent.

The Origin of Anti-Markovnikov Regioselectivity in Alkene Hydroamination Reactions Catalyzed by [Rh(DPEphos)](.).

The development of regioselective anti-Markovnikov alkene's hydroamination is a long-standing goal in catalysis. The [Rh(COD)(DPEphos)](+) complex is the most general and regioselective group 9 catalyst for such a process. The reaction mechanism for intermolecular hydroamination of alkenes catalyzed by [Rh(DPEphos)](+) complex is analyzed by means of DFT calculations. Hydroamination (alkene vs. amine activation routes) as well as oxidative amination pathways are analyzed. According to the computational results the operating mechanism can be generally described by alkene coordination, amine nucleophilic addition, proton transfer through the metal center and reductive elimination steps. The mechanism for the formation of the oxidative amination side product goes via a β-elimination after the nucleophilic addition and metal center protonation steps. The origin of the regioselectivity for the addition process (Markovnikov vs. anti-Markovnikov additions) is shown to be not charge but orbitally driven. Remarkably, η(2) to η(1) slippage degree on the alkene coordination mode is directly related to the regioselective outcome.

ChemInform Abstract: Gold‐Catalyzed Intermolecular anti‐Markovnikov Hydroamination of Methylenecyclopropanes with 2‐Pyridones.

The cationic gold phosphine complex [(o-biphenylPCy2)Au(NCMe)]+ SbF6− catalyzes the intermolecular, anti-Markovnikov hydroamination of methylenecyclopropanes (MCPs) with 2-pyridones at 80 °C. The transformation was effective for a range of pyridones and for monosubstituted and cis- and trans-disubstituted MCPs to form 1-cyclopropylmethyl-2-pyridones with excellent regio- and diastereoselectivity in moderate to good yields.

Anti-Markovnikov Hydroamination of Homoallylic Amines.

The development of an anti-Markovnikov-selective hydroamination of unactivated alkenes is a significant challenge in organometallic chemistry. Herein, we present the rhodium-catalyzed anti-Markovnikov-selective hydroamination of homoallylic amines. The proximal Lewis basic amine serves to promote reactivity and enforce regioselectivity through the formation of the favored metallacycle, thus over-riding the inherent reactivity of the alkene. The scope of both the amine nucleophiles and homoallylic amines that participate in the reaction is demonstrated.

ChemInform Abstract: A Formal anti‐Markovnikov Hydroamination of Allylic Alcohols via Tandem Oxidation/1,4‐Conjugate Addition/1,2‐Reduction Using a Ru Catalyst

Abstract24 examples

ChemInform Abstract: Enantioselective CuH‐Catalyzed anti‐Markovnikov Hydroamination of 1,1‐Disubstituted Alkenes.

AbstractThis mild catalytic asymmetric anti‐Markovnikov hydroamination of 1,1‐disubstituted alkenes with o‐benzoyl‐N,N‐disubstituted hydroxylamines offers a convenient route to β‐chiral amines.

ChemInform Abstract: Catalytic Olefin Hydroamination with Aminium Radical Cations: A Photoredox Method for Direct C—N Bond Formation.

While olefin amination with aminium radical cations is a classical method for C–N bond formation, catalytic variants that utilize simple 2° amine precursors remain largely undeveloped. Herein we report a new visible-light photoredox protocol for the intramolecular anti-Markovnikov hydroamination of aryl olefins that proceeds through catalytically generated aminium radical intermediates. Mechanistic studies are consistent with a process involving amine oxidation via electron transfer, turnover-limiting C–N bond formation, and a second electron transfer step to reduce a carbon-centered radical, rendering the overall process redox-neutral. A range of structurally diverse N-aryl heterocycles can be prepared in good to excellent yields under conditions significantly milder than those required by conventional aminium-based protocols.

A formal anti-Markovnikov hydroamination of allylic alcohols via tandem oxidation/1,4-conjugate addition/1,2-reduction using a Ru catalyst

A formal anti-Markovnikov hydroamination of allylic alcohols using a Ru catalyst via tandem oxidation/1,4-conjugate addition/1,2-reduction was developed. Thus, the reaction of allylic alcohols with amines was performed in the presence of the catalyst generated from RuClH(CO)(PPh3)3 and 2,6-bis(n-butyliminomethyl)pyridine in situ to afford the corresponding γ-amino alcohols efficiently.

Efficient and practical synthesis of enantioenriched 2,3-dihydropyrroles through gold-catalyzed anti-Markovnikov hydroamination of chiral homopropargyl sulfonamides.

A direct gold-catalyzed 5-endo-dig cycloisomerization of chiral homopropargyl sulfonamides has been developed. A range of enantioenriched 2,3-dihydropyrroles are readily accessed by utilizing this approach. Importantly, this gold-catalyzed cycloisomerization reaction proceeds through an anti-Markovnikov addition by using a catalytic base as the additive, which completely suppresses the undesired dimerization.

Gold-catalyzed intermolecular anti-markovnikov hydroamination of alkylidenecyclopropanes.

The cationic gold phosphine complex [{PCy2 (o-biphenyl)}Au(NCMe)](+) SbF6 (-) (Cy=cyclohexyl) catalyzes the intermolecular, anti-Markovnikov hydroamination reaction of monosubstituted and cis- and trans-disubstituted alkylidenecyclopropanes (ACPs) with imidazolidin-2-ones and other nucleophiles. This reaction forms 1-cyclopropyl alkylamine derivatives in high yield and with high regio- and diastereoselectivity. NMR spectroscopic analysis of gold π-ACP complexes and control experiments point to the sp hybridization of the ACP internal alkene carbon atom as controlling the regiochemistry of the ACP hydroamination reaction.

Enantioselective CuH-catalyzed anti-Markovnikov hydroamination of 1,1-disubstituted alkenes.

Enantioselective synthesis of β-chiral amines has been achieved via copper-catalyzed hydroamination of 1,1-disubstituted alkenes with hydroxylamine esters in the presence of a hydrosilane. This mild process affords a range of structurally diverse β-chiral amines, including β-deuterated amines, in excellent yields with high enantioselectivities. Furthermore, catalyst loading as low as 0.4 mol% could be employed to deliver product in undiminished yield and selectivity, demonstrating the practicality of this method for large-scale synthesis.

Catalytic olefin hydroamination with aminium radical cations: a photoredox method for direct C-N bond formation.

While olefin amination with aminium radical cations is a classical method for C-N bond formation, catalytic variants that utilize simple 2° amine precursors remain largely undeveloped. Herein we report a new visible-light photoredox protocol for the intramolecular anti-Markovnikov hydroamination of aryl olefins that proceeds through catalytically generated aminium radical intermediates. Mechanistic studies are consistent with a process involving amine oxidation via electron transfer, turnover-limiting C-N bond formation, and a second electron transfer step to reduce a carbon-centered radical, rendering the overall process redox-neutral. A range of structurally diverse N-aryl heterocycles can be prepared in good to excellent yields under conditions significantly milder than those required by conventional aminium-based protocols.

Photoredox Organocatalytic Anti-Markovnikov Hydroamination of Alkenes

Key words hydroamination - alkenes - photoredox catalysis - phenethylamines

Anti-Markovnikov hydroamination of alkenes catalyzed by a two-component organic photoredox system: direct access to phenethylamine derivatives.

Disclosed herein is a general catalytic system for the intermolecular anti-Markovnikov hydroamination of alkenes. By using an organocatalytic photoredox system, α- and β-substituted styrenes as well as aliphatic alkenes undergo anti-Markovnikov hydroamination. Heterocyclic amines were also successfully employed as nitrogen nucleophiles, thus providing a direct route to heterocyclic motifs common in medicinal agents.

Bis(amidate)bis(amido) Titanium Complex: A Regioselective Intermolecular Alkyne Hydroamination Catalyst

An efficient and selective bis(amidate)bis(amido) titanium precatalyst for the anti-Markovnikov hydroamination of alkynes is reported. Hydroamination of terminal and internal alkynes with primary alkylamines, arylamines, and hydrazines is promoted by 5-10 mol % of Ti catalyst. Various functional groups are tolerated including esters, protected alcohols, and imines. The in situ generated complex shows comparable catalytic activity, demonstrating its synthetic versatility for benchtop application. Applications of this catalyst for the synthesis of amino alcohols and a one-pot procedure for indole synthesis are described. A mechanistic proposal that invokes turnover-limiting protonolysis is presented to rationalize the observed regioselectivities.

Intermolecular hydroamination versus stereoregular polymerization of phenylacetylene by rhodium catalysts based on N–O bidentate ligands

N–O bidentate ligands, such as 8-quinolinol and aminoacids, in combination with the dinuclear precursor [{Rh(μ-OMe)(COD)}2] are versatile catalytic systems. Thus, stereoregular polymerization of phenylacetylene (PA) is observed in the presence of secondary amines. Interestingly, the outcome of the catalysis changes drastically on addition of strong coordinating phosphines, giving the product of the intermolecular anti-Markovnikov hydroamination of phenylacetylene.

Enantio- and Regioselective CuH-Catalyzed Hydroamination of Alkenes

A highly enantio- and regioselective copper-catalyzed hydroamination reaction of alkenes has been developed using diethoxymethylsilane and esters of hydroxylamines. The process tolerates a wide variety of substituted styrenes, including trans-, cis-, and β,β-disubstituted styrenes, to yield α-branched amines. In addition, aliphatic alkenes coupled to generate exclusively the anti-Markovnikov hydroamination products.

One-Pot Anti-Markovnikov Hydroamination of Unactivated Alkenes by Hydrozirconation and Amination

A one-pot anti-Markovnikov hydroamination of alkenes is reported. The synthesis of primary and secondary amines from unactivated olefins was accomplished in the presence of a variety of functional groups. Hydrozirconation, followed by amination with nitrogen electrophiles, provides exclusive anti-Markovnikov selectivity. Most products are isolated in high yields without the use of column chromatography.