Formal Hydroamination Research Articles

Copper‐Catalyzed Dearomative 1,2‐Hydroamination

AbstractCatalytic olefin hydroamination reactions are some of the most atom‐economical transformations that bridge readily available starting materials–olefins and high‐value‐added amines. Despite significant advances in this field over the last two decades, the formal hydroamination of nonactivated aromatic compounds remains an unsolved challenge. Herein, we report the extension of olefin hydroamination to aromatic π‐systems by using arenophile‐mediated dearomatization and Cu‐catalysis to perform 1,2‐hydroamination on nonactivated arenes. This strategy was applied to a variety of substituted arenes and heteroarenes to provide general access to structurally complex amines. We conducted DFT calculations to inform mechanistic understanding and rationalize unexpected selectivity trends. Furthermore, we developed a practical, scalable desymmetrization to deliver enantioenriched dearomatized products and enable downstream synthetic applications. We ultimately used this dearomative strategy to efficiently synthesize a collection of densely functionalized small molecules.

Copper-Catalyzed Dearomative 1,2-Hydroamination.

Catalytic olefin hydroamination reactions are some of the most atom-economical transformations that bridge readily available starting materials-olefins and high-value-added amines. Despite significant advances in this field over the last two decades, the formal hydroamination of nonactivated aromatic compounds remains an unsolved challenge. Herein, we report the extension of olefin hydroamination to aromatic π-systems by using arenophile-mediated dearomatization and Cu-catalysis to perform 1,2-hydroamination on nonactivated arenes. This strategy was applied to a variety of substituted arenes and heteroarenes to provide general access to structurally complex amines. We conducted DFT calculations to inform mechanistic understanding and rationalize unexpected selectivity trends. Furthermore, we developed a practical, scalable desymmetrization to deliver enantioenriched dearomatized products and enable downstream synthetic applications. We ultimately used this dearomative strategy to efficiently synthesize a collection of densely functionalized small molecules.

Regio- and Enantioselective Synthesis of 1,2-Diamines by Formal Hydroamination of Enamines: Scope, Mechanism, and Asymmetric Synthesis of Orthogonally Protected Bis-Piperazines as a Privileged Scaffold.

We have previously reported the first formal hydroamination of enamines for the synthesis of chiral 1,2-diamines. Here, we describe: (i) the discovery, optimization, and substrate expansion of this reaction; (ii) a novel and straightforward protocol for the "click-type" synthesis of enamines in quantitative yield utilizing sodium sulfate in a dual role as an ancillary and dehydrating agent without the need for workup or purification; (iii) the application of this methodology to the first enantioselective synthesis of orthogonally protected 1,1'-(1-(4-fluorophenyl)ethane-1,2-diyl) piperazines, a scaffold for rapid lead optimization in drug discovery; (iv) a computational investigation into the mechanism and rationalization of the enantioselectivities of the reaction.

Ru(η1-BH4)(daipena)(diphosphine): Ruthenabicyclic borohydride complexes for asymmetric hydrogenation of ketones and asymmetric formal hydroamination of allylic alcohols under base-free conditions

Ruthenabicyclic complexes bearing a η1-BH4 ligand and exhibiting notable stability under air were developed. These novel Ru complexes were efficient catalyst precursors for asymmetric hydrogenation of simple ketones under base-free conditions or with a small amount of DABCO to afford the corresponding alcohols with high enantioselectivity (>99 % ee in the best cases). Asymmetric formal hydroamination of allylic alcohols without an addition of base, via a borrowing hydrogenation strategy, was also achieved. A variety of allylic alcohols and amines were applicable to the reaction (>99 % ee in the best cases).

Anti-Markovnikov Intermolecular Hydroamination of Alkenes and Alkynes: A Mechanistic View.

Hydroamination, the addition of an N-H bond across a C-C multiple bond, is a reaction with a great synthetic potential. Important advances have been made in the last decades concerning catalysis of these reactions. However, controlling the regioselectivity in the amine addition toward the formation of anti-Markovnikov products (addition to the less substituted carbon) still remains a challenge, particularly in intermolecular hydroaminations of alkenes and alkynes. The goal of this review is to collect the systems in which intermolecular hydroamination of terminal alkynes and alkenes with anti-Markovnikov regioselectivity has been achieved. The focus will be placed on the mechanistic aspects of such reactions, to discern the step at which regioselectivity is decided and to unravel the factors that favor the anti-Markovnikov regioselectivity. In addition to the processes entailing direct addition of the amine to the C-C multiple bond, alternative pathways, involving several reactions to accomplish anti-Markovnikov regioselectivity (formal hydroamination processes), will also be discussed in this review. The catalysts gathered embrace most of the metal groups of the Periodic Table. Finally, a section discussing radical-mediated and metal-free approaches, as well as heterogeneous catalyzed processes, is also included.

Catalyst‐Controlled Regiodivergent and Enantioselective Formal Hydroamination of N,N‐Disubstituted Acrylamides to α‐Tertiary‐α‐Aminolactam and β‐Aminoamide Derivatives

AbstractEnantioenriched α‐tertiary‐α‐aminoacid and α‐chiral‐β‐aminoacid derivatives play an important role in biological science and pharmaceutical chemistry. Thus, the development of methods for their synthesis is highly valuable and yet remains challenging. Herein, an unprecedented catalyst‐controlled regiodivergent and enantioselective formal hydroamination of N,N‐disubstituted acrylamides with aminating agents has been developed, accessing enantioenriched α‐tertiary‐α‐aminolactam and α‐chiral‐β‐aminoamide derivatives. Sterically‐disfavored and electronically‐disfavored enantioselective hydroamination of electron‐deficient alkenes have been successfully tuned using different transition metals and chiral ligands. Notably, extremely hindered aliphatic α‐tertiary‐α‐aminolactam derivatives were synthesized by Cu−H catalyzed asymmetric C−N bond forming with tertiary alkyl species. Enantioenriched α‐chiral‐β‐aminoamide derivatives have been accessed by Ni−H catalyzed anti‐Markovnikov‐selective formal hydroaminations of alkenes. This set of reactions tolerates a wide range of functional groups to deliver diverse α‐tertiary‐α‐aminolactam and α‐chiral‐β‐aminoamide derivatives in good yields with high levels of enantioselectivity.

Catalyst-Tuned Regiodivergent and Enantioselective Formal Hydroaminations of Acryamides to α-Tertiary-α-Aminolactam and β-Aminoamide Derivatives.

Enantioenriched α-tertiary-α-aminoacid and α-chiral-β-aminoacid derivatives play an important role in biological science and pharmaceutical chemistry. Thus, the development of methods for their synthesis is highly valuable yet remains challenging. Herein, an unprecedented catalyst-controlled regiodivergent and enantioselective formal hydroamination of 1,1-disubstituted acrylamides with aminating agents has been developed, accessing enantioenriched α-tertiary-α-aminolactam and α-chiral-β-aminoamide derivatives. Conceptually, sterically-disfavoured and electronically-disfavoured enantioselective hydroamination of electron-deficient alkenes have been successfully tuned using different transition metals and chiral ligands. Notably, extremely steric congested aliphatic α-tertiary-α-aminolactam derivatives were synthesized by Cu-H catalyzed asymmetric forge of C-N bond with tertiary alkyl species for the first time. Enantioenriched α-chiral-β-aminoamide derivatives have been accessed by Ni-H catalyzed anti-Markovnikov-selective formal hydroaminations of alkenes. This set of reactions tolerates a wide range of functional groups to deliver diverse α-tertiary-α-aminolactam and α-chiral-β-aminoamide derivatives in good yields with high levels of enantioselectivity.

Iridium-Catalyzed Hydroiodination and Formal Hydroamination with N-Iodo Reagents and Hydrogen

Iridium-Catalyzed Hydroiodination and Formal Hydroamination with N-Iodo Reagents and Hydrogen

Manganese-Catalyzed Asymmetric Formal Hydroamination of Allylic Alcohols Enabled by a Remarkable Macrocyclic Ligand Effect

Manganese-Catalyzed Asymmetric Formal Hydroamination of Allylic Alcohols Enabled by a Remarkable Macrocyclic Ligand Effect

\u03b3-Selective C(sp3)\u2013H amination via controlled migratory hydroamination

Remote functionalization of alkenes via chain walking has generally been limited to C(sp3)–H bonds α and β to polar-functional units, while γ-C(sp3)–H functionalization through controlled alkene transposition is a longstanding challenge. Herein, we describe NiH-catalyzed migratory formal hydroamination of alkenyl amides achieved via chelation-assisted control, whereby various amino groups are installed at the γ-position of aliphatic chains. By tuning olefin isomerization and migratory hydroamination through ligand and directing group optimization, γ-selective amination can be achieved via stabilization of a 6-membered nickellacycle by an 8-aminoquinoline directing group and subsequent interception by an aminating reagent. A range of amines can be installed at the γ-C(sp3)–H bond of unactivated alkenes with varying alkyl chain lengths, enabling late-stage access to value-added γ-aminated products. Moreover, by employing picolinamide-coupled alkene substrates, this approach is further extended to δ-selective amination. The chain-walking mechanism and pathway selectivity are investigated by experimental and computational methods.

Front Cover Picture: Catalytic Formal Hydroamination of Allylic Alcohols Using Manganese PNP‐Pincer Complexes (Adv. Synth. Catal. 17/2021)

The front cover picture, designed by L. Duarte de Almeida et al. illustrates the successful application of a well-defined manganese PNP pincer complex in the formal hydroamination of allylic alcohols with primary and secondary amines as well as with N-heterocycles. The corresponding γ-amino alcohols were obtained in up to 94% yield in a tandem reaction combining dehydrogenation/Michael addition/hydrogenation sequence. The properties of these non-innocent pincer ligands allowed application of this non-noble metal catalyst in organic synthesis with a broad substrate scope. Details can be found in the communication by M. Beller, K. Junge and co-workers (L. Duarte de Almeida, F. Bourriquen, K. Junge, M. Beller, Adv. Synth. Catal. 2021, 363, 4177–4181; DOI: 10.1002/adsc.202100081).

Catalytic Formal Hydroamination of Allylic Alcohols Using Manganese PNP-Pincer Complexes.

Several manganese‐PNP pincer catalysts for the formal hydroamination of allylic alcohols are presented. The resulting γ‐amino alcohols are selectively obtained in high yields applying Mn‐1 in a tandem process under mild conditions.

Regio- and Enantioselective Formal Hydroamination of Enamines for the Synthesis of 1,2-Diamines.

The asymmetric formal hydroamination of enamines using a CuH catalyst is reported. The method provides a straightforward and efficient approach to the synthesis of chiral 1,2-dialkyl amines in good yields with high levels of enantioselectivities for a broad range of substrates, and should have significant value for the preparation of molecules bearing a 1,2-diamine motif.

Regio‐ and Enantioselective Formal Hydroamination of Enamines for the Synthesis of 1,2‐Diamines

AbstractThe asymmetric formal hydroamination of enamines using a CuH catalyst is reported. The method provides a straightforward and efficient approach to the synthesis of chiral 1,2‐dialkyl amines in good yields with high levels of enantioselectivities for a broad range of substrates, and should have significant value for the preparation of molecules bearing a 1,2‐diamine motif.

A Practical Electrophilic Nitrogen Source for the Synthesis of Chiral Primary Amines by Copper-Catalyzed Hydroamination.

A mild and practical method for the catalytic installation of the amino group across alkenes and alkynes has long been recognized as a significant challenge in synthetic chemistry. As the direct hydroamination of olefins using ammonia requires harsh conditions, the development of suitable electrophilic aminating reagents for formal hydroamination methods is of importance. Herein, we describe the use of 1,2-benzisoxazole as a practical electrophilic primary amine source. Using this heterocycle as a new amino group delivery agent, a mild and general protocol for the copper-hydride-catalyzed hydroamination of alkenes and alkynes to form primary amines was developed. This method provides access to a broad range of chiral α-branched primary amines and linear primary amines, as demonstrated by the efficient synthesis of the antiretroviral drug maraviroc and the formal synthesis of several other pharmaceutical agents.

Mechanistic Insights into First-row Late Transition Metal-catalysed (formal) Hydroamination of Unactivated Alkenes.

This short review provides a mechanistic overview of the most relevant developments into the area of intra- and intermolecular hydroamination and formal hydroamination of unactivated alkenes (excluding allenes and 1,3-dienes) promoted by first-row late transition metal catalysts involving zinc, copper, iron and cobalt. The different activation strategies and mechanistic disparities encountered with these systems will be highlighted. The relevant literature from 2012 until early 2018 has been covered.

Formal Enantioselective Hydroamination of Non‐Activated Alkenes: Transformation of Styrenes into Enantiomerically Pure 1‐Phenylethylamines in Chemoenzymatic One‐Pot Synthesis

AbstractAs a complementary approach to current asymmetric synthetic methods, a direct transformation of styrenes into 1‐phenylethylamines was developed. The one‐pot process represents a formal hydroamination of a non‐activated alkene with ammonia and is based on the combination of a Pd/Cu‐catalyzed Wacker‐oxidation with an enzymatic transamination. A key feature of this process is the compartmentation of the catalytic systems, which turned out to be essential to avoid deactivation of the transaminase by the Cu‐component. This one‐pot synthesis can be applied to a broad substrate range, which leads to the chiral amines with high conversions and excellent enantioselectivities of >99 % ee.

ChemInform Abstract: Chemoselective Nitro Reduction and Hydroamination Using a Single Iron Catalyst.

AbstractThe reduction and reductive addition (formal hydroamination) of functionalized nitroarenes is carried out in the presence of a silane and a bench‐stable iron catalyst.

ChemInform Abstract: Amine‐Bis(phenolate) Iron(III)‐Catalyzed Formal Hydroamination of Olefins.

AbstractThe reaction tolerates 1,1‐disubstituted, tri‐ as well as well tetra‐substituted olefins which are efficiently hydroaminated with various nitroarenes using phenylsilane as the reducing agent.

ChemInform Abstract: Regioselective, Asymmetric Formal Hydroamination of Unactivated Internal Alkenes.

We report the regioselective and enantioselective formal hydroamination of unsymmetrical internal alkenes catalyzed by a copper catalyst ligated by DTBM-SEGPHOS. The regioselectivity of the reaction is controlled by the electronic effects of ether, ester, and sulfonamide groups in the homoallylic position. The observed selectivity underscores the influence of inductive effects of remote substituents on the selectivity of catalytic processes occurring at hydrocarbyl groups, and the method provides direct access to various 1,3-aminoalcohol derivatives with high enantioselectivity.