Allylic C(sp3)–H alkylation via synergistic organo- and photoredox catalyzed radical addition to imines

A new catalytic method for the direct alkylation of allylic C(sp³)–H bonds from unactivated alkenes via synergistic organo- and photoredox catalysis is described. The transformation achieves an efficient, redox-neutral synthesis of homoallylamines with broad functional group tolerance, under very mild reaction conditions. Mechanistic investigations indicate that the reaction proceeds through the N-centered radical intermediate which is generated by the allylic radical addition to the imine.

A new catalytic method for the direct alkylation of allylic C(sp³)–H bonds from unactivated alkenes via synergistic organo- and photoredox catalysis is described.     

Radical chain monoalkylation of pyridines

The monoalkylation of N-methoxypyridinium salts with alkyl radicals generated from alkenes (via hydroboration with catecholborane), alkyl iodides (via iodine atom transfer) and xanthates is reported. The reaction proceeds under neutral conditions since no acid is needed to activate the heterocycle and no external oxidant is required. A rate constant for the addition of a primary radical to N-methoxylepidinium >10⁷ M⁻¹ s⁻¹ was experimentally determined. This rate constant is more than one order of magnitude larger than the one measured for the addition of primary alkyl radicals to protonated lepidine demonstrating the remarkable reactivity of methoxypyridinium salts towards radicals. The reaction has been used for the preparation of unique pyridinylated terpenoids and was extended to a three-component carbopyridinylation of electron-rich alkenes including enol esters, enol ethers and enamides.

N-Methoxypyridinium salts are exceptionally reactive radical traps that can be used in efficient radical chain reactions with organoboranes.     

Radical α-addition involved electrooxidative [3 + 2] annulation of phenols and electron-deficient alkenes

An electrooxidative [3 + 2] annulation of phenols and electron-deficient alkenes for the synthesis of C3-functionalized 2-aryl-2,3-dihydrobenzofuran derivatives was achieved. The ring construction starts by a unique α-addition of carbon radicals derived from anodic oxidation of phenols to electron-deficient alkenes. The subsequent anodic oxidation of the resulting alkyl radical intermediates followed by trapping with the phenolic hydroxy group assembles the 2,3-dihydrobenzofuran core. Such a pathway enables the installation of various electrophilic functionalities including alkoxycarbonyl, alkylaminocarbonyl, trifluoromethyl, and cyano groups at the C-3 of the 2,3-dihydrobenzofuran framework, which is unattainable by other intermolecular reactions. The application of this method for a rapid synthesis of a bioactive natural product is demonstrated.

An electrooxidative [3 + 2] annulation between phenols and electron-deficient alkenes for the synthesis of C3-functionalized 2-aryl-2,3-dihydrobenzofuran derivatives is described.     

Heterocyclic group transfer reactions with I(iii) N-HVI reagents: access to N-alkyl(heteroaryl)onium salts via olefin aminolactonization

Pyridinium and related N-alkyl(heteroaryl)onium salts are versatile synthetic intermediates in organic chemistry, with applications ranging from ring functionalizations to provide diverse piperidine scaffolds to their recent emergence as radical precursors in deaminative cross couplings. Despite their ever-expanding applications, methods for their synthesis have seen little innovation, continuing to rely on a limited set of decades old transformations and a limited subset of coupling partners. Herein, we leverage (bis)cationic nitrogen-ligated I(iii) hypervalent iodine reagents, or N-HVIs, as “heterocyclic group transfer reagents” to provide access to a broad scope of N-alkyl(heteroaryl)onium salts via the aminolactonization of alkenoic acids, the first example of engaging an olefin to directly generate these salts. The reactions proceed in excellent yields, under mild conditions, and are capable of incorporating a broad scope of sterically and electronically diverse aromatic heterocycles. The N-HVI reagents can be generated in situ, the products isolated via simple trituration, and subsequent derivatizations demonstrate the power of this platform for diversity-oriented synthesis of 6-membered nitrogen heterocycles.

Complex N-alkyl (heteroaryl)onium salts are accessed via heterocyclic group transfer reactions of N-ligated I(iii) reagents with alkenoic acids. The reactions proceed in excellent yields, under mild conditions, and with broad substrate scope.     

Regiodivergent synthesis of pyrazino-indolines vs. triazocines via α-imino carbenes addition to imidazolidines

Hexahydropyrazinoindoles were prepared in a single step from N-sulfonyl triazoles and imidazolidines. Under dirhodium catalysis, α-imino carbenes were generated and formed nitrogen ylide intermediates that, after subsequent aminal opening, afforded the pyrazinoindoles predominantly via formal [1,2]-Stevens and tandem Friedel–Crafts cyclizations. Of mechanistic importance, a regiodivergent reactivity was engineered through the use of a specific unsymmetrically substituted imidazolidine that promoted the exclusive formation of 8-membered ring 1,3,6-triazocines. Based on DFT calculations, an original Curtin–Hammett-like situation was demonstrated for the mechanism. Further derivatizations led to functionalized tetrahydropyrazinoindoles in high yields.

Hexahydropyrazinoindoles are prepared in a single step from N-sulfonyl triazoles and imidazolidines. Of mechanistic importance, a regiodivergent reactivity can be engineered towards the exclusive formation of 8-membered ring 1,3,6-triazocines.     

Rhodium-catalysed tetradehydro-Diels–Alder reactions of enediynes via a rhodium-stabilized cyclic allene

Efficient methods for the synthesis of fused-aromatic rings is a critical endeavour in the creation of new pharmaceuticals and materials. A direct method for preparing these systems is the tetradehydro-Diels–Alder reaction, however this is limited by the need for harsh reaction conditions. A potential, but underdeveloped, route to these systems is via transition metal-catalysed cycloaromatisation of ene-diynes. Herein, tethered unconjugated enediynes have been shown to undergo a facile room-temperature Rh^I-catalysed intramolecular tetradehydro-Diels–Alder reaction to produce highly substituted isobenzofurans, isoindolines and an indane. Furthermore, experimental and computational studies suggest a novel mechanism involving an unprecedented and complex Rh^I/Rh^III/Rh^I/Rh^III redox cycle involving the formation of an unusual strained 7-membered rhodacyclic allene intermediate and a Rh^III-stabilized 6-membered ring allene complex.

Room temperature Rh-catalysed tetradehydro-Diels–Alder reaction via an unusual Rh-stabilised allene.     

Divergent reactivity of sulfinates with pyridinium salts based on one- versus two-electron pathways

One of the main goals of modern synthesis is to develop distinct reaction pathways from identical starting materials for the efficient synthesis of diverse compounds. Herein, we disclose the unique divergent reactivity of the combination sets of pyridinium salts and sulfinates to achieve sulfonative pyridylation of alkenes and direct C4-sulfonylation of pyridines by controlling the one- versus two-electron reaction manifolds for the selective formation of each product. Base-catalyzed cross-coupling between sulfinates and N-amidopyridinium salts led to the direct introduction of a sulfonyl group into the C4 position of pyridines. Remarkably, the reactivity of this set of compounds is completely altered upon exposure to visible light: electron donor–acceptor complexes of N-amidopyridinium salts and sulfinates are formed to enable access to sulfonyl radicals. In this catalyst-free radical pathway, both sulfonyl and pyridyl groups could be incorporated into alkenes via a three-component reaction, which provides facile access to a variety of β-pyridyl alkyl sulfones. These two reactions are orthogonal and complementary, achieving a broad substrate scope in a late-stage fashion under mild reaction conditions.

Divergent reactions of sulfinates with pyridinium salts were developed by controlling the one- versus two-electron reaction manifolds.     

Harnessing sulfur and nitrogen in the cobalt(iii)-catalyzed unsymmetrical double annulation of thioamides: probing the origin of chemo- and regio-selectivity

An unconventional cobalt(iii)-catalyzed one-pot domino double annulation of aryl thioamides with unactivated alkynes is presented. Sulfur (S), nitrogen (N), and o,o′-C–H bonds of aryl thioamides are involved in this reaction, enabling access to rare 6,6-fused thiopyrano-isoquinoline derivatives. A reverse ‘S’ coordination over a more conventional ‘N’ coordination of thioamides to the Co-catalyst specifically regulates the formation of four [C–C and C–S at first and then C–N and C–C] bonds in a single operation, a concept which is uncovered for the first time. The power of the N-masked methyl phenyl sulfoximine (MPS) directing group in this annulation sequence is established. The transformation is successfully developed, building a novel chemical space of structural diversity (56 examples). In addition, the late-stage annulation of biologically relevant motifs and drug candidates is disclosed (17 examples). The preliminary photophysical properties of thiopyrano-isoquinoline derivatives are discussed. Density functional theory (DFT) studies authenticate the participation of a unique 6π-electrocyclization of a 7-membered S-chelated cobaltacycle in the annulation process.

A Co-catalyzed one-pot double annulation of sulfoximine bearing thioamides with alkynes for the synthesis of [6,6]-fused thiopyrano-isoquinolines is disclosed. The annulation involves a 6π-electrocyclization of 7-membered S-chelated cobaltacycle.     

Catalytic enantioselective synthesis of macrodiolides and their application in chiral recognition

New types of C₂-symmetric chiral macrodiolides are readily obtained via chiral N,N′-dioxide-scandium(iii) complex-promoted asymmetric tandem Friedel–Crafts alkylation/intermolecular macrolactonization of ortho-quinone methides with C3-substituted indoles. This protocol provides an array of enantioenriched macrodiolides with 16, 18 or 20-membered rings in moderate to good yields with high diastereoselectivities and excellent enantioselectivities through adjusting the length of the tether at the C3 position of indoles. Density functional theory calculations indicate that the formation of macrocycles is more favorable than that of 9-membered-ring lactones in terms of kinetics and thermodynamics. The potential utility of these intriguing chiral macrodiolide molecules is demonstrated in the enantiomeric recognition of aminols and chemical recognition of metal ions.

An asymmetric tandem Friedel–Crafts alkylation/intermolecular macrolactonization of ortho-quinone methides with C3-substituted indoles was achieved by using a chiral N,N′-dioxide-scandium(iii) complex.     

Switching between mono and doubly reduced odd alternant hydrocarbon: designing a redox catalyst

Since the early Hückel molecular orbital (HMO) calculations in 1950, it has been well known that the odd alternant hydrocarbon (OAH), the phenalenyl (PLY) system, can exist in three redox states: closed shell cation (12π e⁻), mono-reduced open shell neutral radical (13π e⁻) and doubly reduced closed shell anion (14π e⁻). Switching from one redox state of PLY to another leads to a slight structural change owing to its low energy of disproportionation making the electron addition or removal process facile. To date, mono-reduced PLY based radicals have been extensively studied. However, the reactivity and application of doubly reduced PLY species have not been explored so far. In this work, we report the synthesis of the doubly reduced PLY species (14π e⁻) and its application towards the development of redox catalysis via switching with the mono-reduced form (13π e⁻) for aryl halide activation and functionalization under transition metal free conditions without any external stimuli such as heat, light or cathodic current supply.

A doubly reduced redox non-innocent phenalenyl based transition metal free catalyst has been designed and utilized in the development of the C–C cross coupling reaction through the activation of aryl halides at room temperature.     

Metal-free tandem carbene N–H insertions and C–C bond cleavages

A metal-free C–H [5 + 1] annulation reaction of 2-arylanilines with diazo compounds has been achieved, giving rise to two types of prevalent phenanthridines via highly selective C–C cleavage. Compared to the simple N–H insertion manipulation of diazo, this method elegantly accomplishes a tandem N–H insertion/S_EAr/C–C cleavage/aromatization reaction, and the synthetic utility of this new transformation is exemplified by the succinct syntheses of trisphaeridine and bicolorine alkaloids.

A metal-free C–H [5 + 1] annulation reaction of 2-arylanilines with diazo compounds has been achieved, giving rise to two types of prevalent phenanthridines via highly selective C–C cleavage.     

Ruthenium-catalyzed cascade C–H activation/annulation of N-alkoxybenzamides: reaction development and mechanistic insight

A highly selective ruthenium-catalyzed C–H activation/annulation of alkyne-tethered N-alkoxybenzamides has been developed. In this reaction, diverse products from inverse annulation can be obtained in moderate to good yields with high functional group compatibility. Insightful experimental and theoretical studies indicate that the reaction to the inverse annulation follows the Ru(ii)–Ru(iv)–Ru(ii) pathway involving N–O bond cleavage prior to alkyne insertion. This is highly different compared to the conventional mechanism of transition metal-catalyzed C–H activation/annulation with alkynes, involving alkyne insertion prior to N–O bond cleavage. Via this pathway, the in situ generated acetic acid from the N–H/C–H activation step facilitates the N–O bond cleavage to give the Ru-nitrene species. Besides the conventional mechanism forming the products via standard annulation, an alternative and novel Ru(ii)–Ru(iv)–Ru(ii) mechanism featuring N–O cleavage preceding alkyne insertion has been proposed, affording a new understanding of transition metal-catalyzed C–H activation/annulation.

A highly selective ruthenium-catalyzed C–H activation/annulation through a pathway involving N–O bond cleavage prior to alkyne insertion is developed.     

Palladium-catalyzed hydroalkylation of methylenecyclopropanes with simple hydrazones

A palladium-catalyzed hydroalkylation reaction of methylenecyclopropanes via highly selective C–C σ-bond scission was achieved under mild conditions, in which simple hydrazones served as carbanion equivalents. This method featured good functional group compatibility, affording high yields of C-alkylated terminal alkenes.

A palladium-catalyzed hydroalkylation of methylenecyclopropanes via selective C–C σ-bond scission was achieved, in which simple hydrazones served as carbanion equivalents. This method affords high yields of C-alkylated terminal alkenes with good functional group compatibility.     

A Giese reaction for electron-rich alkenes

A general method for the hydroalkylation of electron-rich terminal and non-terminal alkenes such as enol esters, alkenyl sulfides, enol ethers, silyl enol ethers, enamides and enecarbamates has been developed. The reactions are carried out at room temperature under air initiation in the presence of triethylborane acting as a chain transfer reagent and 4-tert-butylcatechol (TBC) as a source of hydrogen atom. The efficacy of the reaction is best explained by very favorable polar effects supporting the chain process and minimizing undesired polar reactions. The stereoselective hydroalkylation of chiral N-(alk-1-en-1-yl)oxazolidin-2-ones takes place with good to excellent diastereocontrol.

Giese reaction not anymore limited to electron poor alkenes! A general method for the radical mediated hydroalkylation of electron rich alkenes including enol ethers, silylenolethers, enamides, and enecarbamates has been developed.     

Investigation of some biologically relevant redox reactions using electrochemical mass spectrometry interfaced by desorption electrospray ionization

Recently we have shown that, as a versatile ionization technique, desorption electrospray ionization (DESI) can serve as a useful interface to combine electrochemistry (EC) with mass spectrometry (MS). In this study, the EC/DESI-MS method has been further applied to investigate some aqueous phase redox reactions of biological significance, including the reduction of peptide disulfide bonds and nitroaromatics as well as the oxidation of phenothiazines. It was found that knotted/enclosed disulfide bonds in the peptides apamin and endothelin could be electrochemically cleaved. Subsequent tandem MS analysis of the resulting reduced peptide ions using collision-induced dissociation (CID) and electron-capture dissociation (ECD) gave rise to extensive fragment ions, providing a fast protocol for sequencing peptides with complicated disulfide bond linkages. Flunitrazepam and clonazepam, a class of nitroaromatic drugs, are known to undergo reduction into amines which was proposed to involve nitroso and N-hydroxyl intermediates. Now in this study, these corresponding intermediate ions were successfully intercepted and their structures were confirmed by CID. This provides mass spectrometric evidence for the mechanism of the nitro to amine conversion process during nitroreduction, an important redox reaction involved in carcinogenesis. In addition, the well-known oxidation reaction of chlorpromazine was also examined. The putative transient one-electron transfer product, the chlorpromazine radical cation (m/z 318), was captured by MS, for the first time, and its structure was also verified by CID. In addition to these observations, some features of the DESI-interfaced electrochemical mass spectrometry were discussed, such as simple instrumentation and the lack of background signal. These results further demonstrate the feasibility of EC/DESI-MS for the study of the biology-relevant redox chemistry and would find applications in proteomics and drug development research.     

Synthesis of N-aryl amines enabled by photocatalytic dehydrogenation

Catalytic dehydrogenation (CD) via visible-light photoredox catalysis provides an efficient route for the synthesis of aromatic compounds. However, access to N-aryl amines, which are widely utilized synthetic moieties, via visible-light-induced CD remains a significant challenge, because of the difficulty in controlling the reactivity of amines under photocatalytic conditions. Here, the visible-light-induced photocatalytic synthesis of N-aryl amines was achieved by the CD of allylic amines. The unusual strategy using C₆F₅I as an hydrogen-atom acceptor enables the mild and controlled CD of amines bearing various functional groups and activated C–H bonds, suppressing side-reaction of the reactive N-aryl amine products. Thorough mechanistic studies suggest the involvement of single-electron and hydrogen-atom transfers in a well-defined order to provide a synergistic effect in the control of the reactivity. Notably, the back-electron transfer process prevents the desired product from further reacting under oxidative conditions.

The synergy of SET, HAT, and BET enables a visible-light induced catalytic dehydrogenation for the synthesis of N-aryl amines.     

Fe-catalyzed three-component dicarbofunctionalization of unactivated alkenes with alkyl halides and Grignard reagents

A highly chemoselective iron-catalyzed three-component dicarbofunctionalization of unactivated olefins with alkyl halides (iodides and bromides) and sp²-hybridized Grignard reagents is reported. The reaction operates under fast turnover frequency and tolerates a diverse range of sp²-hybridized nucleophiles (electron-rich and electron-deficient (hetero)aryl and alkenyl Grignard reagents), alkyl halides (tertiary alkyl iodides/bromides and perfluorinated bromides), and unactivated olefins bearing diverse functional groups including tethered alkenes, ethers, protected alcohols, aldehydes, and amines to yield the desired 1,2-alkylarylated products with high regiocontrol. Further, we demonstrate that this protocol is amenable for the synthesis of new (hetero)carbocycles including tetrahydrofurans and pyrrolidines via a three-component radical cascade cyclization/arylation that forges three new C–C bonds.

A highly selective iron-catalyzed three-component dicarbofunctionalization of unactivated alkenes with alkyl halides and sp²-hybridized Grignard reagents is reported.     

Persistent,highly localized,and tunable [4]helicene radicals

Persistent organic radicals have gained considerable attention in the fields of catalysis and materials science. In particular, helical molecules are of great interest for the development and application of novel organic radicals in optoelectronic and spintronic materials. Here we report the syntheses of easily tunable and stable neutral quinolinoacridine radicals under anaerobic conditions by chemical reduction of their quinolinoacridinium cation analogs. The structures of these [4]helicene radicals were determined by X-ray crystallography. Density functional theory (DFT) calculations, supported by electron paramagnetic resonance (EPR) measurements, indicate that over 40% of spin density is located at the central carbon of our [4]helicene radicals regardless of their structural modifications. The localization of the charge promotes a reversible oxidation to the cation upon exposure to air. This unusual reactivity toward molecular oxygen was monitored via UV-Vis spectroscopy.

We report a series of tunable and persistent [4]-helicene neutral radicals by chemical reduction of the [4]-helicenium cation analogue. EPR spectroscopy and DFT calculations indicate that the unpaired electron is localized at the central carbon atom.     

Carbene-catalyzed enantioselective annulation of dinucleophilic hydrazones and bromoenals for access to aryl-dihydropyridazinones and related drugs

4,5-Dihydropyridazinones bearing an aryl substituent at the C6-position are important motifs in drug molecules. Herein, we developed an efficient protocol to access aryl-dihydropyridazinone molecules via carbene-catalyzed asymmetric annulation between dinucleophilic arylidene hydrazones and bromoenals. Key steps in this reaction include polarity-inversion of aryl aldehyde-derived hydrazones followed by chemo-selective reaction with enal-derived α,β-unsaturated acyl azolium intermediates. The aryl-dihydropyridazinone products accessed by our protocol can be readily transformed into drugs and bioactive molecules.

Polarity inversion of arylidene hydrazones to react with bromoenals via carbene organic catalysis is disclosed. The reaction enantioselectively affords 6-aryl-4,5-dihydropyridazinones and related drugs with proven commercial applications.     

A pyrone remodeling strategy to access diverse heterocycles: application to the synthesis of fascaplysin natural products

The synthesis of diverse N-fused heterocycles, including the pyrido[1,2-a]indole scaffold, using an efficient pyrone remodeling strategy is described. The pyrido[1,2-a]indole core was demonstrated to be a versatile scaffold that can be site-selectively functionalized. The utility of this novel annulation strategy was showcased in a concise formal synthesis of three fascaplysin congeners.

The synthesis of diverse N-fused heterocycles, including the pyrido[1,2-a]indole scaffold, using an efficient pyrone remodeling strategy is described.