Directed Photochemically Mediated Nickel-Catalyzed (Hetero)arylation of Aliphatic C-H Bonds.

Site-selective functionalization of unactivated C(sp3)-H centers is challenging because of the ubiquity and strength of alkyl C-H bonds. Herein, we disclose a position-selective C(sp3)-C(sp2) cross-coupling reaction. This process engages C(sp3)-H bonds and aryl bromides, utilizing catalytic quantities of a photoredox-capable molecule and a nickel precatalyst. Using this technology, selective C-H functionalization arises owing to a 1,6-hydrogen atom transfer (HAT) process that is guided by a pendant alcohol-anchored sulfamate ester. These transformations proceed directly from N-H bonds, in contrast to previous directed, radical-mediated, C-H arylation processes, which have relied on prior oxidation of the reactive nitrogen center in reactions with nucleophilic arenes. Moreover, these conditions promote arylation at secondary centers in good yields with excellent selectivity.

Strategies to Generate Nitrogen-centered Radicals That May Rely on Photoredox Catalysis: Development in Reaction Methodology and Applications in Organic Synthesis.

For more than 70 years, nitrogen-centered radicals have been recognized as potent synthetic intermediates. This review is a survey designed for use by chemists engaged in target-oriented synthesis. This review summarizes the recent paradigm shift in access to and application of N-centered radicals enabled by visible-light photocatalysis. This shift broadens and streamlines approaches to many small molecules because visible-light photocatalysis conditions are mild. Explicit attention is paid to innovative advances in N-X bonds as radical precursors, where X = Cl, N, S, O, and H. For clarity, key mechanistic data is noted, where available. Synthetic applications and limitations are summarized to illuminate the tremendous utility of photocatalytically generated nitrogen-centered radicals.

Recent Advances in Photoredox-Mediated Radical Conjugate Addition Reactions: An Expanding Toolkit for the Giese Reaction.

Photomediated Giese reactions are at the forefront of radical chemistry, much like the classical tin-mediated Giese reactions were nearly forty years ago. With the global recognition of organometallic photocatalysts for the mild and tunable generation of carbon-centered radicals, chemists have developed a torrent of strategies to form previously inaccessible radical intermediates that are capable of engaging in intermolecular conjugate addition reactions. This Review summarizes advances in photoredox-mediated Giese reactions since 2013, with a focus on the breadth of methods that provide access to crucial carbon-centered radical intermediates that can engage in radical conjugate addition processes.

Photochemically Mediated Nickel-Catalyzed Synthesis of N-(Hetero)aryl Sulfamides.

A general method for the N-arylation of sulfamides with aryl bromides is described. The protocol leverages a dual-catalytic system, with [Ir(ppy)2(dtbbpy)]PF6 as a photosensitizer, NiBr2·glyme as a precatalyst, and 1,8-diazabicyclo(5.4.0)undec-7-ene (DBU) as a base, and proceeds at room temperature under visible light irradiation. Using these tactics, aryl boronic esters and aryl chlorides can be carried through the reaction untouched. The developed reactions efficiently engage simple bromoarenes and primary sulfamides in between 66% and quantitative yields. For more challenging substrates, such as secondary sulfamides, the reaction efficiency is documented. Thereby, these methods complement the known Buchwald-Hartwig coupling methods for N-arylation of sulfamides.

Modifying Positional Selectivity in C-H Functionalization Reactions with Nitrogen-Centered Radicals: Generalizable Approaches to 1,6-Hydrogen-Atom Transfer Processes.

Nitrogen-centered radicals are powerful reaction intermediates owing in part to their ability to guide position-selective C(sp3)-H functionalization reactions. Typically, these reactive species dictate the site of functionalization by preferentially engaging in 1,5-hydrogen-atom transfer (1,5-HAT) processes. Broadly relevant approaches to alter the site-selectivity of HAT pathways would be valuable because they could be paired with a variety of tactics to install diverse functional groups. Yet, until recently, there have been no generalizable strategies to modify the position-selectivity observed in these HAT processes. This Synpacts article reviews transformations in which nitrogen-centered radicals preferentially react through 1,6-HAT pathways. Specific attention will be focused on strategies that employ alcohol- and amine-anchored sulfamate esters and sulfamides as templates to achieve otherwise rare γ-selective functionalization reactions.

Photochemically-Mediated, Nickel-Catalyzed Synthesis of N-(Hetero)aryl Sulfamate Esters.

A general method is described for the coupling of (hetero)aryl bromides with O-alkyl sulfamate esters. The protocol relies on catalytic amounts of nickel and photoexcitable iridium complexes and proceeds under visible light irradiation at ambient temperature. This technology engages a broad range of simple and complex O-alkyl sulfamate ester substrates under mild conditions. Furthermore, it is possible to avoid undesirable N-alkylation, which was found to plague palladium-based protocols for N-arylation of O-alkyl sulfamate esters. These investigations represent the first use of sulfamate esters as nucleophiles in transition metal-catalyzed C-N coupling processes.

Sulfamyl Radicals Direct Photoredox-Mediated Giese Reactions at Unactivated C(3)-H Bonds.

Alcohol-anchored sulfamate esters guide the alkylation of tertiary and secondary aliphatic C(3)-H bonds. The transformation proceeds directly from N-H bonds with a catalytic oxidant, a contrast to prior methods which have required preoxidation of the reactive nitrogen center, or employed stoichiometric amounts of strong oxidants to obtain the sulfamyl radical. These sulfamyl radicals template otherwise rare 1,6-hydrogen-atom transfer (HAT) processes via seven-membered ring transition states to enable C(3)-H functionalization during Giese reactions.

A five-coordinate iron(III) porphyrin complex including a neutral axial pyridine N-oxide ligand.

While six-coordinate iron(III) porphyrin complexes with pyridine N-oxides as axial ligands have been studied as they exhibit rare spin-crossover behavior, studies of five-coordinate iron(III) porphyrin complexes including neutral axial ligands are rare. A five-coordinate pyridine N-oxide-5,10,15,20-tetraphenylporphyrinate-iron(III) complex, namely (pyridine N-oxide-κO)(5,10,15,20-tetraphenylporphinato-κ4N,N',N'',N''')iron(III) hexafluoroantimonate(V) dichloromethane disolvate, [Fe(C44H28N4)(C5H5NO)][SbF6]·2CH2Cl2, was isolated and its crystal structure determined in the space group P-1. The porphyrin core is moderately saddled and the Fe-O-N bond angle is 122.08 (13)°. The average Fe-N bond length is 2.03 Šand the Fe-ONC5H5 bond length is 1.9500 (14) Å. This complex provides a rare example of a five-coordinate iron(III) porphyrin complex that is coordinated to a neutral organic ligand through an O-monodentate binding mode.

Unified Enantioselective, Convergent Synthetic Approach toward the Furanobutenolide-Derived Polycyclic Norcembranoid Diterpenes: Synthesis of a Series of Ineleganoloids by Oxidation-State Manipulation of the Carbocyclic Core.

Late-stage synthetic efforts to advance the enatio- and diastereoselectively constructed [6,7,5,5]-fused tetracyclic scaffold toward the polycyclic norditerpenoid ineleganolide are disclosed. The described investigations focus on oxidation-state manipulation around the central cycloheptane ring. Computational evaluation of ground-state energies of dihydroineleganolide is used to rationalize empirical observations and provide insight for further synthetic development, enhancing the understanding of the conformational constraints of these compact polycyclic structures. Advanced synthetic manipulations generated a series of natural product-like compounds termed the ineleganoloids.

Correction: Enantioselective, convergent synthesis of the ineleganolide core by a tandem annulation cascade.

[This corrects the article DOI: 10.1039/C6SC03347D.].

Sulfamides direct radical-mediated chlorination of aliphatic C-H bonds.

Given the prevalence of aliphatic amines in bioactive small molecules, amine derivatives are opportune as directing groups. Herein, sulfamides serve as amine surrogates to guide intermolecular chlorine-transfer at γ-C(sp3) centers. This unusual position-selectivity arises because accessed sulfamidyl radical intermediates engage preferentially in otherwise rare 1,6-hydrogen-atom transfer (HAT) processes through seven-membered transition states. The site-selectivity of C-H abstraction can be modulated by adjusting the steric and electronic properties of the sulfamide nitrogen substituents, an ability that has not been demonstrated with other substrate classes. The disclosed reaction relies on a light-initiated radical chain-propagation mechanism to oxidize C(sp3)-H bonds efficiently.

Iron(MCP) Complexes Catalyze Aziridination with Olefins As Limiting Reagents.

Herein described are the first efficient nitrogen-atom transfer reactions mediated by iron N, N'-dimethyl- N, N'-bis(2-pyridinylmethyl)cyclohexane-1,2-diamine- (MCP-) and 2-({1-[(pyridin-2-ylmethyl)pyrrolidin-2-yl]pyrrolidin-1-yl}methyl)pyridine-type (PDP-type) complexes. These catalysts affect styrene aziridination under mild conditions based on a limiting quantity of olefin substrate.

Development of a Unified Enantioselective, Convergent Synthetic Approach Toward the Furanobutenolide-Derived Polycyclic Norcembranoid Diterpenes: Asymmetric Formation of the Polycyclic Norditerpenoid Carbocyclic Core by Tandem Annulation Cascade.

An enantioselective and diastereoselective approach toward the synthesis of the tetracyclic scaffold of the furanobutenolide-derived polycyclic norditerpenoids is described. Focusing on synthetic efforts toward ineleganolide, the synthetic approach utilizes a palladium-catalyzed enantioselective allylic alkylation for the construction of the requisite chiral tertiary ether. A diastereoselective cyclopropanation-Cope rearrangement cascade enabled the convergent assembly of the ineleganolide [6,7,5,5]-tetracyclic scaffold. Investigation of substrates for this critical tandem annulation process is discussed along with synthetic manipulations of the [6,7,5,5]-tetracyclic scaffold and the attempted interconversion of the [6,7,5,5]-tetracyclic scaffold of ineleganolide to the isomeric [7,6,5,5]-core of scabrolide A and its naturally occurring isomers. Computational evaluation of ground-state energies of late-stage synthetic intermediates was used to guide synthetic development and aid in the investigation of the conformational rigidity of these highly constrained and compact polycyclic structures.

Sulfamate Esters Guide Selective Radical-Mediated Chlorination of Aliphatic C-H Bonds.

Masked alcohols are particularly appealing as directing groups because of the ubiquity of hydroxy groups in organic small molecules. Herein, we disclose a general strategy for aliphatic γ-C(sp3 )-H functionalization guided by a masked alcohol. Specifically, we determine that sulfamate ester derived nitrogen-centered radicals mediate 1,6-hydrogen-atom transfer (HAT) processes to guide γ-C(sp3 )-H chlorination. This reaction proceeds through a light-initiated radical chain-propagation process and is capable of installing chlorine atoms at primary, secondary, and tertiary centers.

Model Studies To Access the [6,7,5,5]-Core of Ineleganolide Using Tandem Translactonization-Cope or Cyclopropanation-Cope Rearrangements as Key Steps.

Recently, we reported a convergent cyclopropanation-Cope approach to the core of ineleganolide, which was the first disclosed synthesis of the core of the norditerpene natural product ineleganolide. In this complementary work, a model system for the core of ineleganolide has been prepared through a series of tandem cyclopropanation-Cope and translactonization-Cope rearrangements. Work with this model system has enriched our understanding of the cyclopropanation-Cope rearrangement sequence. Additionally, research into this model system has driven the development of tandem translactonization-Cope rearrangements.

Synthesis of N-Substituted Sulfamate Esters from Sulfamic Acid Salts by Activation with Triphenylphosphine Ditriflate.

A general approach to access sulfamate esters through preparation of sulfamic acid salts, subsequent activation with triphenylphosphine ditriflate, and nucleophilic trapping is disclosed. The method proceeds in modest to excellent yields to incorporate nucleophiles derived from aliphatic alcohols and phenols. This approach can be employed to furnish differentially substituted sulfamides.

Exhaustive Suzuki-Miyaura reactions of polyhalogenated heteroarenes with alkyl boronic pinacol esters.

A novel Suzuki-Miyaura protocol is described that enables the exhaustive alkylation of polychlorinated pyridines. This method facilitates a formal synthesis of normuscopyridine and the rapid assembly of a dumbbell shaped portion of a [2]rotaxane.

Enantioselective, Convergent Synthesis of the Ineleganolide Core by a Tandem Annulation Cascade.

An enantioselective and diastereoselective approach toward the synthesis of the polycyclic norditerpenoid ineleganolide is disclosed. A palladium-catalyzed enantioselective allylic alkylation is employed to stereoselectively construct the requisite chiral tertiary ether and facilitate the synthesis of a 1,3-cis-cyclopentenediol building block. Careful substrate design enabled the convergent assembly of the ineleganolide [6,7,5,5]-tetracyclic scaffold by a diastereoselective cyclopropanation-Cope rearrangement cascade under unusually mild conditions. Computational evaluation of ground state energies of late-stage synthetic intermediates was used to guide synthetic development and aid in the investigation of the conformational rigidity of these highly constrained and compact polycyclic structures. This work represents the first successful synthesis of the core structure of any member of the polycyclic norcembranoid diterpene family of natural products. Advanced synthetic manipulations generated a series of natural product-like compounds that were shown to possess selective secretory antagonism of either interleukin-5 or interleukin-17. This bioactivity stands in contrast to the known antileukemic activity of ineleganolide and suggests the norcembranoid natural product core may serve as a useful scaffold for the development of diverse therapeutics.

Selective and Serial Suzuki-Miyaura Reactions of Polychlorinated Aromatics with Alkyl Pinacol Boronic Esters.

Among cross-coupling reactions, the Suzuki-Miyaura transformation stands out because of its practical advantages, including the commercial availability and low toxicity of the required reagents, mild reaction conditions, and functional group compatibility. Nevertheless, few conditions can be used to cross-couple alkyl boronic acids or esters with aryl halides, especially 2-pyridyl halides. Herein, we describe two novel Suzuki-Miyaura protocols that enable selective conversion of polychlorinated aromatics, with a focus on reactions to convert 2,6-dichloropyridines to 2-chloro-6-alkylpyridines or 2-aryl-6-alkylpyridines.