Visible-light-induced transition metal and photosensitizer free decarbonylative addition of amino-arylaldehydes to ketones

The decarbonylative-coupling reaction is generally promoted by transition metals (via organometallic complexes) or peroxides (via radical intermediates), often at high temperatures to facilitate the CO release. Herein, a visible-light-induced, transition metal and external photosensitizer free decarbonylative addition of benzaldehydes to ketones/aldehydes at room temperature is reported. Tertiary/secondary alcohols were obtained in moderate to excellent yields promoted by using CsF under mild conditions. The detailed mechanistic investigation showed that the reaction proceeded through photoexcitation–decarbonylation of the aldehyde to generate an aromatic anion, followed by its addition to ketones/aldehydes. The reaction mechanism was verified by the density functional theory (DFT) calculations.

A visible-light-induced, transition-metal and external photosensitizer free decarbonylative addition of benzaldehydes to ketones/aldehydes via anion intermediates at room temperature is developed.     

Easily accessible non-aromatic heterocycles with handles: 4-bromo-2,3-dihydrofurans from 1,2-dibromohomoallylic alcohols

The first general preparation of 4-bromo-2,3-dihydrofurans is reported. These non-aromatic heterocycles containing a useful coupling handle are accessed via Cu-catalyzed intramolecular cyclization of 1,2-dibromohomoallylic alcohols, which are themselves available in just two steps from aromatic and aliphatic aldehydes and ketones. Molecular dynamics simulations using the simple substrates and key geometric parameters provide a rationale for the selectivities observed. The synthetic utility of the 4-bromodihydrofurans is also demonstrated.

The first general preparation of 4-bromo-2,3-dihydrofurans is reported.     

Photocatalytic redox-neutral hydroxyalkylation of N-heteroaromatics with aldehydes

Hydroxyalkylation of N-heteroaromatics with aldehydes was achieved using a binary hybrid catalyst system comprising an acridinium photoredox catalyst and a thiophosphoric acid organocatalyst. The reaction proceeded through the following sequence: (1) photoredox-catalyzed single-electron oxidation of a thiophosphoric acid catalyst to generate a thiyl radical, (2) cleavage of the formyl C–H bond of the aldehyde substrates by a thiyl radical acting as a hydrogen atom transfer catalyst to generate acyl radicals, (3) Minisci-type addition of the resulting acyl radicals to N-heteroaromatics, and (4) a spin-center shift, photoredox-catalyzed single-electron reduction, and protonation to produce secondary alcohol products. This metal-free hybrid catalysis proceeded under mild conditions for a wide range of substrates, including isoquinolines, quinolines, and pyridines as N-heteroaromatics, as well as both aromatic and aliphatic aldehydes, and tolerated various functional groups. The reaction was applicable to late-stage derivatization of drugs and their leads.

Hydroxyalkylation of N-heteroaromatics with aldehydes was achieved using a binary hybrid catalyst system comprising an acridinium photoredox catalyst and a thiophosphoric acid organocatalyst.     

Formyl-selective deuteration of aldehydes with D2O via synergistic organic and photoredox catalysis

Formyl-selective deuteration of aldehydes is of high interest for labeling purposes and for optimizing properties of drug candidates. Herein, we report a mild general method for formyl-selective deuterium labeling of aldehydes with D₂O, an inexpensive deuterium source, via a synergistic combination of light-driven, polyoxometalate-facilitated hydrogen atom transfer and thiol catalysis. This highly efficient, scalable reaction showed excellent deuterium incorporation, a broad substrate scope, and excellent functional group tolerance and selectivity and is therefore a practical method for late-stage modification of synthetic intermediates in medicinal chemistry and for generating libraries of deuterated compounds.

Formyl-selective deuteration of aldehydes with D₂O mediated by the synergistic combination of light-driven, polyoxometalate-facilitated HAT and thiol catalysis is reported.     

Organoborohydride-catalyzed Chichibabin-type C4-position alkylation of pyridines with alkenes assisted by organoboranes

The first NaBEt₃H-catalyzed intermolecular Chichibabin-type alkylation of pyridine and its derivatives with alkenes as the latent nucleophiles is presented with the assistance of BEt₃, and a series of branched C4-alkylation pyridines, even highly congested all-carbon quaternary center-containing triarylmethanes can be obtained in a regiospecific manner. Therefore, the conventional reliance on high cost and low availability transition metal catalysts, prior formation of N-activated pyridines, organometallic reagents, and extra oxidation operation for the construction of a C–C bond at the C4-position of the pyridines in previous methods are not required. The corresponding mechanism and the key roles of the organoborane were elaborated by the combination of H/D scrambling experiments, ¹¹B NMR studies, intermediate trapping experiments and computational studies. This straightforward and mechanistically distinct organocatalytic technology not only opens a new door for the classical but still far less well-developed Chichibabin-type reaction, but also sets up a new platform for the development of novel C–C bond-forming methods.

The first NaBEt₃H-catalyzed intermolecular Chichibabin-type alkylation of pyridines with alkenes as the latent nucleophiles is presented in the presence of BEt₃, and a series of branched C4-alkylated pyridines were obtained in a regiospecific manner.     

A palladium-catalyzed C–H functionalization route to ketones via the oxidative coupling of arenes with carbon monoxide

We describe the development of a new palladium-catalyzed method to generate ketones via the oxidative coupling of two arenes and CO. This transformation is catalyzed by simple palladium salts, and is postulated to proceed via the conversion of arenes into high energy aroyl triflate electrophiles. Exploiting the latter can also allow the synthesis of unsymmetrical ketones from two different arenes.

A palladium catalyzed route to prepare aryl ketones from their two fundamental building blocks, two arenes and carbon monoxide, is described.     

Pd-catalyzed cross-electrophile Coupling/C–H alkylation reaction enabled by a mediator generated via C(sp3)–H activation

Transition-metal-catalyzed cross-electrophile C(sp²)–(sp³) coupling and C–H alkylation reactions represent two efficient methods for the incorporation of an alkyl group into aromatic rings. Herein, we report a Pd-catalyzed cascade cross-electrophile coupling and C–H alkylation reaction of 2-iodo-alkoxylarenes with alkyl chlorides. Methoxy and benzyloxy groups, which are ubiquitous functional groups and common protecting groups, were utilized as crucial mediators via primary or secondary C(sp³)–H activation. The reaction provides an innovative and convenient access for the synthesis of alkylated phenol derivatives, which are widely found in bioactive compounds and organic functional materials.

A cascade Pd-catalyzed cross-electrophile coupling and C–H alkylation reaction of 2-iodo-alkoxylarenes with alkyl chlorides has been developed by using an ortho-methoxy or benzyloxy group as a mediator via C(sp³)–H activation.     

Base-catalyzed aryl halide isomerization enables the 4-selective substitution of 3-bromopyridines

The base-catalyzed isomerization of simple aryl halides is presented and utilized to achieve the 4-selective etherification, hydroxylation and amination of 3-bromopyridines. Mechanistic studies support isomerization of 3-bromopyridines to 4-bromopyridines proceeds via pyridyne intermediates and that 4-substitution selectivity is driven by a facile aromatic substitution reaction. Useful features of a tandem aryl halide isomerization/selective interception approach to aromatic functionalization are demonstrated. Example benefits include the use of readily available and stable 3-bromopyridines in place of less available and stable 4-halogenated congeners and the ability to converge mixtures of 3- and 5-bromopyridines to a single 4-substituted product.

The base-catalyzed isomerization of aryl halides is described and applied to the tandem isomerization/4-substitution of 3-bromopyridines as a strategy for achieving unconventional selectivity in nucleophilic aromatic substitution reactions.     

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.     

Deoxygenative α-alkylation and α-arylation of 1,2-dicarbonyls

Construction of C–C bonds at the α-carbon is a challenging but synthetically indispensable approach to α-branched carbonyl motifs that are widely represented among drugs, natural products, and synthetic intermediates. Here, we describe a simple approach to generation of boron enolates in the absence of strong bases that allows for introduction of both α-alkyl and α-aryl groups in a reaction of readily accessible 1,2-dicarbonyls and organoboranes. Obviation of unselective, strongly basic and nucleophilic reagents permits carrying out the reaction in the presence of electrophiles that intercept the intermediate boron enolates, resulting in two new α-C–C bonds in a tricomponent process.

α-Branched carboxylic acids and other carbonyls are readily accessed by a metal- and base-free deoxygenative α-alkylation and α-arylation of 1,2-dicarbonyls via boron enolates, resulting in a tricomponent coupling with unconventional electrophiles.     

A bifunctional iminophosphorane squaramide catalyzed enantioselective synthesis of hydroquinazolines via intramolecular aza-Michael reaction to α,β-unsaturated esters

An efficient synthesis of enantioenriched hydroquinazoline cores via a novel bifunctional iminophosphorane squaramide catalyzed intramolecular aza-Michael reaction of urea-linked α,β-unsaturated esters is described. The methodology exhibits a high degree of functional group tolerance around the forming hydroquinazoline aryl core and wide structural variance on the nucleophilic N atom of the urea moiety. Excellent yields (up to 99%) and high enantioselectivities (up to 97 : 3 er) using both aromatic and less acidic aliphatic ureas were realized. The potential industrial applicability of the transformation was demonstrated in a 20 mmol scale-up experiment using an adjusted catalyst loading of 2 mol%. The origin of enantioselectivity and reactivity enhancement provided by the squaramide motif has been uncovered computationally using density functional theory (DFT) calculations, combined with the activation strain model (ASM) and energy decomposition analysis (EDA).

The activation of both aromatic and aliphatic ureas as N-centered nucleophiles in intramolecular Michael addition reactions to α,β-unsaturated esters was achieved under bifunctional iminophosphorane squaramide superbase catalysis.     

Directed regioselective ortho,ortho′-magnesiations of aromatics and heterocycles using sBu2Mg in toluene

Aryl azoles are ubiquitous as bioactive compounds and their regioselective functionalization is of utmost synthetic importance. Here, we report the development of a toluene-soluble dialkylmagnesium base sBu₂Mg. This new reagent allows mild and regioselective ortho-magnesiations of various N-arylated pyrazoles and 1,2,3-triazoles as well as arenes bearing oxazoline, phosphorodiamidate or amide directing groups. The resulting diarylmagnesium reagents were further functionalized either by Pd-catalyzed arylation or by trapping reactions with a broad range of electrophiles (aldehydes, ketones, allylic halides, acyl chlorides, Weinreb amides, aryl halides, hydroxylamine benzoates, terminal alkynes). Furthermore, several double ortho,ortho′-magnesiations were realized in the case of aryl oxazolines, N-aryl pyrazoles as well as 2-aryl-2H-1,2,3-triazoles by simply repeating the magnesiation/electrophile trapping sequence allowing the preparation of valuable 1,2,3-functionalized arenes.

A toluene solution of sBu₂Mg allowed a regioselective ortho-magnesiation of aromatic and heterocyclic systems. A second ortho,ortho′-functionalization was achieved in the case of aryl oxazolines, N-aryl pyrazoles as well as N-aryl triazoles.     

Selective aldehyde reductions in neutral water catalysed by encapsulation in a supramolecular cage

The enhancement of reactivity inside supramolecular coordination cages has many analogies to the mode of action of enzymes, and continues to inspire the design of new catalysts for a range of reactions. However, despite being a near-ubiquitous class of reactions in organic chemistry, enhancement of the reduction of carbonyls to their corresponding alcohols remains very much underexplored in supramolecular coordination cages. Herein, we show that encapsulation of small aromatic aldehydes inside a supramolecular coordination cage allows the reduction of these aldehydes with the mild reducing agent sodium cyanoborohydride to proceed with high selectivity (ketones and esters are not reduced) and in good yields. In the absence of the cage, low pH conditions are essential for any appreciable conversion of the aldehydes to the alcohols. In contrast, the specific microenvironment inside the cage allows this reaction to proceed in bulk solution that is pH-neutral, or even basic. We propose that the cage acts to stabilise the protonated oxocarbenium ion reaction intermediates (enhancing aldehyde reactivity) whilst simultaneously favouring the encapsulation and reduction of smaller aldehydes (which fit more easily inside the cage). Such dual action (enhancement of reactivity and size-selectivity) is reminiscent of the mode of operation of natural enzymes and highlights the tremendous promise of cage architectures as selective catalysts.

Herein, we use a supramolecular coordination cage as a catalyst for the reduction of aldehydes to the corresponding alcohols using a weak hydride donor in neutral water, with a mode of action reminiscent of natural enzymes.     

Chiral Lewis acid-bonded picolinaldehyde enables enantiodivergent carbonyl catalysis in the Mannich/condensation reaction of glycine ester

A new strategy of asymmetric carbonyl catalysis via a chiral Lewis acid-bonded aldehyde has been developed for the direct Mannich/condensation cascade reaction of glycine ester with aromatic aldimines. The co-catalytic system of 2-picolinaldehyde and chiral Yb^III-N,N′-dioxides was identified to be efficient under mild conditions, providing a series of trisubstituted imidazolidines in moderate to good yields with high diastereo- and enantioselectivities. Enantiodivergent synthesis was achieved via changing the sub-structures of the chiral ligands. The reaction could be carried out in a three-component version involving glycine ester, aldehydes, and anilines with equally good results. Based on control experiments, the X-ray crystal structure study and theoretical calculations, a possible dual-activation mechanism and stereo-control modes were provided to elucidate carbonyl catalysis and enantiodivergence.

The catalytic asymmetric Mannich/condensation of glycine ester with aldimines was achieved by merging chiral N,N′-dioxide/Yb^III complex Lewis acid catalysis/carbonyl catalysis under mild condition.     

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.     

Barbier coupling in water: SnCl2-mediated and Co(acac)2-catalyzed allylation of carbonyls

Co(acac)₂·2H₂O efficiently catalyzes SnCl₂-mediated Barbier coupling in water between carbonyls, including aromatic, aliphatic and α,β-unsaturated aldehydes, ketones, sugars and allyl bromide to afford the corresponding homoallylic alcohols in high yields. The catalyst was reused for several cycles with consistent activity.     

Palladium catalyzed carbonylative generation of potent,pyridine-based acylating electrophiles for the functionalization of arenes to ketones

We describe here the design of a palladium catalyzed route to generate aryl ketones via the carbonylative coupling of (hetero)arenes and aryl- or vinyl-triflates. In this, the use of the large bite angle Xantphos ligand on palladium provides a unique avenue to balance the activation of the relatively strong C(sp²)–OTf bond with the ultimate elimination of a new class of potent Friedel–Crafts acylating agent: N-acyl pyridinium salts. The latter can be exploited to modulate reactivity and selectivity in carbonylative arene functionalization chemistry, and allow the efficient synthesis of ketones with a diverse array of (hetero)arenes.

A palladium catalyzed approach to the overall carbonylative functionalization of arenes to form ketones with aryl- and vinyl-triflates is described.     

Anodic oxidation triggered divergent 1,2- and 1,4-group transfer reactions of β-hydroxycarboxylic acids enabled by electrochemical regulation

We report a set of electrochemically regulated protocols for the divergent synthesis of ketones and β-keto esters from the same β-hydroxycarboxylic acid starting materials. Enabled by electrochemical control, the anodic oxidation of carboxylic acids proceeded in either a one-electron or a two-electron pathway, leading to a 1,4-aryl transfer or a semipinacol-type 1,2-group transfer product with excellent chemoselectivity. The 1,4-aryl transfer represents an unprecedented example of carbon-to-oxygen group transfer proceeding via a radical mechanism. In contrast to previously reported radical group transfer reactions, this 1,4-group transfer process features the migration of electron-rich aryl substituents. Furthermore, with these chemoselective electrochemical oxidation protocols, a range of ketones and β-keto esters including those possessing a challenging-to-access medium-sized ring could be synthesized in excellent yields.

We report a set of electrochemically regulated protocols for the divergent synthesis of ketones and β-keto esters from the same β-hydroxycarboxylic acid starting materials.     

Tubularenes

We report the synthesis and characterization of conjugated, conformationally rigid, and electroactive carbon-based nanotubes that we term tubularenes. These structures are constructed from a resorcin[n_b]arene base. Cyclization of the conjugated aromatic nanotube is achieved in one-pot eight-fold C–C bond formation via Suzuki–Miyaura cross-coupling. DFT calculations indicate a buildup of strain energy in excess of 90 kcal mol⁻¹. The resulting architectures contain large internal void spaces >260 ų, are fluorescent, and able to accept up to 4 electrons. This represents the first scaffolding approach that provides conjugated nanotube architectures.

First scaffolding approach to obtain tubular-shaped contorted aromatic architectures.     

Regioselective difunctionalization of pyridines via 3,4-pyridynes

A new regioselective 3,4-difunctionalization of 3-chloropyridines via 3,4-pyridyne intermediates is reported. Regioselective lithiation of 3-chloro-2-ethoxypyridine and a related 2-thio-derivative followed by treatment with aryl- and alkylmagnesium halides as well as magnesium thiolates at −78 °C produced 3,4-pyridynes during heating to 75 °C. Regioselective addition of the Grignard moiety in position 4 followed by an electrophilic quench in position 3 led to various 2,3,4-trisubstituted pyridines. This method was adapted into a continuous flow set-up. As an application, we have prepared a key intermediate for (±)-paroxetine.

A regioselective 3,4-difunctionalization of pyridines was performed. Lithiation and transmetalation with arylmagnesiums gave 3,4-pyridyne intermediates. Addition of magnesium species led to 3-pyridylmagnesiums which were quenched with electrophiles.