Multicomponent formation route to a new class of oxygen-based 1,3-dipoles and the modular synthesis of furans

A new class of phosphorus-containing 1,3-dipoles can be generated by the multicomponent reaction of aldehydes, acid chlorides and the phosphonite PhP(catechyl). These 1,3-dipoles are formally cyclic tautomers of simple Wittig-type ylides, where the angle strain and moderate nucleophilicity in the catechyl-phosphonite favor their cyclization and also direct 1,3-dipolar cycloaddition to afford single regioisomers of substituted products. Coupling the generation of the dipoles with 1,3-dipolar cycloaddition offers a unique, modular route to furans from combinations of available aldehydes, acid chlorides and alkynes with independent control of all four substituents.

A new class of phosphorus-containing 1,3-dipoles has been developed, which, when coupled with cycloaddition, offers modular synthesis of furans with independent control of all four substituents.     

Regiodivergent sulfonylarylation of 1,3-enynes via nickel/photoredox dual catalysis

Catalytic difunctionalization of 1,3-enynes represents an efficient and versatile approach to rapidly assemble multifunctional propargylic compounds, allenes and 1,3-dienes. Controlling selectivity in such addition reactions has been a long-standing challenging task due to multiple reactive centers resulting from the conjugated structure of 1,3-enynes. Herein, we present a straightforward method for regiodivergent sulfonylarylation of 1,3-enynes via dual nickel and photoredox catalysis. Hinging on the nature of 1,3-enynes, diverse reaction pathways are feasible: synthesis of α-allenyl sulfones via 1,4-sulfonylarylation, or preparation of (E)-1,3-dienyl sulfones with high chemo-, regio- and stereoselectivity through 3,4-sulfonylarylation. Notably, this is the first example that nickel and photoredox catalysis are merged to achieve efficient and versatile difunctionalization of 1,3-enynes.

A mild reaction protocol for regiodivergent sulfonylarylation of 1,3-enynes via dual nickel and photoredox catalysis has been developed, which led to efficient synthesis of α-allenyl sulfones or 1,3-dienyl sulfones.     

Palladium-catalyzed remote para-C–H activation of arenes assisted by a recyclable pyridine-based template

Direct para-selective C–H functionalization of arenes remains a daunting challenge and is still significantly restricted to a few scaffolds. Herein, we report an unprecedented pyridine-based para-directing template (DT) assisted, Pd-catalyzed para-C–H alkenylation of three classes of arenes, i.e. phenylpropanoic acids, 2-phenyl benzoic acids and benzyl alcohols, with a series of alkenes including perfluoroalkenes. Notably, the pyridine-based para-DT could be easily synthesized and readily recycled under mild conditions. These results may find application in rapid construction of para-substituted arenes and stimulate the exploration of novel methods for para-C–H functionalization of arenes.

An unprecedented pyridine-based para-directing template (DT) assisted, Pd-catalyzed remote para-C–H alkenylation of three classes of arenes is reported herein.     

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.     

Kinetic resolution of racemic allylic alcohols via iridium-catalyzed asymmetric hydrogenation: scope,synthetic applications and insight into the origin of selectivity

Asymmetric hydrogenation is one of the most commonly used tools in organic synthesis, whereas, kinetic resolution via asymmetric hydrogenation is less developed. Herein, we describe the first iridium catalyzed kinetic resolution of a wide range of trisubstituted secondary and tertiary allylic alcohols. Large selectivity factors were observed in most cases (s up to 211), providing the unreacted starting materials in good yield with high levels of enantiopurity (ee up to >99%). The utility of this method is highlighted in the enantioselective formal synthesis of some bioactive natural products including pumiliotoxin A, inthomycin A and B. DFT studies and a selectivity model concerning the origin of selectivity are presented.

Asymmetric hydrogenation is one of the most commonly used tools in organic synthesis, whereas, kinetic resolution via asymmetric hydrogenation was less developed.     

Prebiotic access to enantioenriched glyceraldehyde mediated by peptides

A prebiotically plausible route to enantioenriched glyceraldehyde is reported via a kinetic resolution mediated by peptides. The reaction proceeds via a selective reaction between the l-peptide and the l-sugar producing an Amadori rearrangement byproduct and leaving d-glyceraldehyde in excess. Solubility considerations in the synthesis of proline–valine (pro–val) peptides allow nearly enantiopure pro–val to be formed starting from racemic pro and nearly racemic (10%) ee val. (ee = enantiomeric excess = (|d − l|)/(d + l)) Thus enantioenrichment of glyceraldehyde is achieved in a system with minimal initial chiral bias. This work demonstrates synergy between amino acids and sugars in the emergence of biological homochirality.

A prebiotically plausible route to enantioenriched glyceraldehyde is reported via a kinetic resolution mediated by peptides.     

The synthesis of brominated-boron-doped PAHs by alkyne 1,1-bromoboration: mechanistic and functionalisation studies

The synthesis of a range of brominated-B_n-containing (n = 1, 2) polycyclic aromatic hydrocarbons (PAHs) is achieved simply by reacting BBr₃ with appropriately substituted alkynes via a bromoboration/electrophilic C–H borylation sequence. The brominated-B_n-PAHs were isolated as either the borinic acids or B-mesityl-protected derivatives, with the latter having extremely deep LUMOs for the B₂-doped PAHs (with one example having a reduction potential of E_1/2 = −0.96 V versus Fc⁺/Fc, Fc = ferrocene). Mechanistic studies revealed the reaction sequence proceeds by initial alkyne 1,1-bromoboration. 1,1-Bromoboration also was applied to access a number of unprecedented 1-bromo-2,2-diaryl substituted vinylboronate esters directly from internal alkynes. Bromoboration/C–H borylation installs useful C–Br units onto the B_n-PAHs, which were utilised in Negishi coupling reactions, including for the installation of two triarylamine donor (D) groups onto a B₂-PAH. The resultant D–A–D molecule has a low optical gap with an absorption onset at 750 nm and emission centered at 810 nm in the solid state.

The synthesis of a range of brominated-B_n-containing (n = 1, 2) polycyclic aromatic hydrocarbons (PAHs) is achieved simply by reacting BBr₃ with appropriately substituted alkynes via a bromoboration/electrophilic C–H borylation sequence.     

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.     

C4-arylation and domino C4-arylation/3,2-carbonyl migration of indoles by tuning Pd catalytic modes: Pd(i)–Pd(ii) catalysis vs. Pd(ii) catalysis

Efficient C4-arylation and domino C4-arylation/3,2-carbonyl migration of indoles have been developed. The former route enables C4-arylation in a highly efficient and mild manner and the latter route provides an alternative straightforward protocol for synthesis of C2/C4 disubstituted indoles. The mechanism studies imply that the different reaction pathways were tuned by the distinct acid additives, which led to either the Pd(i)–Pd(ii) pathway or Pd(ii) catalysis.

C4-arylation via Pd(i)–Pd(ii) catalysis and domino C4-arylation/3,2-carbonyl migration of indoles via Pd(ii) catalysis tuning by acids have been developed.     

Acceptorless dehydrogenative synthesis of primary amides from alcohols and ammonia

The highly desirable synthesis of the widely-used primary amides directly from alcohols and ammonia via acceptorless dehydrogenative coupling represents a clean, atom-economical, sustainable process. Nevertheless, such a reaction has not been previously reported, and the existing catalytic systems instead generate other N-containing products, e.g., amines, imines and nitriles. Herein, we demonstrate an efficient and selective ruthenium-catalyzed synthesis of primary amides from alcohols and ammonia gas, accompanied by H₂ liberation. Various aliphatic and aromatic primary amides were synthesized in high yields, with no observable N-containing byproducts. The selectivity of this system toward primary amide formation is rationalized through density functional theory (DFT) calculations, which show that dehydrogenation of the hemiaminal intermediate into primary amide is energetically favored over its dehydration into imine.

An efficient and selective synthesis of primary amides from alcohols and ammonia, with H₂ evolution, has been achieved by an unprecedented acceptorless dehydrogenative process catalyzed by a pyridine-based PNN–ruthenium pincer complex.     

Asymmetric hydroalkylation of alkynes and allenes with imidazolidinone derivatives: α-alkenylation of α-amino acids

This work reports a new method for the synthesis of quaternary α-alkenyl substituted amino acids by the enantio- and diastereoselective addition of imidazolidinone derivatives to alkynes and allenes. Further hydrolysis of the imidazolidinone products under acidic conditions afforded biologically relevant amino acid derivatives. This method is geometry-selective (E-isomer), enantio- and diastereoselective, and products were obtained in good to excellent yields. The utility of this new methodology is proved by its operational simplicity and the successful accomplishment of gram-scale reactions. Experimental and computational studies suggest the key role of Li in terms of selectivity and support the proposed reaction mechanism.

Enantio-, diastereoselective, geometry-selective addition of imidazolidinone derivatives to alkynes and allenes in the presence of LiHMDS in order to obtain quaternary α-alkenyl substituted amino acids in high isolated yields.     

Ritter-type iodo(iii)amidation of unactivated alkynes for the stereoselective synthesis of multisubstituted enamides

The Ritter reaction, Brønsted- or Lewis acid-mediated amidation of alkene or alcohol with nitrile via a carbocation, represents a classical method for the synthesis of tertiary amides. Although analogous reactions through a vinyl cation or a species alike may offer a route to enamide, an important synthetic building block as well as a common functionality in bioactive compounds, such transformations remain largely elusive. Herein, we report a Ritter-type trans-difunctionalization of alkynes with a trivalent iodine electrophile and nitrile, which affords β-iodanyl enamides in moderate to good yields. Mediated by benziodoxole triflate (BXT), the reaction proves applicable to a variety of internal alkynes as well as to various alkyl- and arylnitriles. The benziodoxole group in the product serves as a versatile handle for further transformations, thus allowing for the preparation of various tri- and tetrasubstituted enamides that are not readily accessible by other means.

Ritter-type trans-selective iodo(iii)amidation of internal alkynes with benziodoxole triflate and various nitriles has been achieved for the stereocontrolled synthesis of multisubstituted enamides.     

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.     

Generation of organo-alkaline earth metal complexes from non-polar unsaturated molecules and their synthetic applications

Organomagnesium compounds, represented by the Grignard reagents, are one of the most classical yet versatile carbanion species which have widely been utilized in synthetic chemistry. These reagents are typically prepared via oxidative addition of organic halides to magnesium metals, via halogen–magnesium exchange between halo(hetero)arenes and organomagnesium reagents or via deprotonative magnesiation of prefunctionalized (hetero)arenes. On the other hand, recent studies have demonstrated that the organo-alkaline earth metal complexes including those based on heavier alkaline earth metals such as calcium, strontium and barium could be generated from readily available non-polar unsaturated molecules such as alkenes, alkynes, 1,3-enynes and arenes through unique metallation processes. Nonetheless, the resulting organo-alkaline earth metal complexes could be further functionalized with a variety of electrophiles in various reaction modes. In particular, organocalcium, strontium and barium species have shown unprecedented reactivity in the downstream functionalization, which could not be observed in the reactivity of organomagnesium complexes. This perspective will focus on the newly emerging protocols for the generation of organo-alkaline earth metal complexes from non-polar unsaturated molecules and their applications in chemical synthesis and catalysis.

In this perspective, we highlight the recent development of metallation protocols of non-polar unsaturated molecules for the generation of organo-alkaline earth metal compounds and their applications in chemical synthesis and catalysis.     

Radical boron migration of allylboronic esters

A photocatalyzed 1,3-boron shift of allylboronic esters is reported. The boron atom migration through the allylic carbon skeleton proceeds via consecutive 1,2-boron migrations and Smiles-type rearrangement to furnish a variety of terminally functionalized alkyl boronates. Several types of migrating variations of heteronuclei radicals and dearomatization processes are also tolerated, allowing for further elaboration of highly functionalized boron-containing frameworks.

A photocatalyzed 1,3-boron shift of allylboronic esters is reported. The atom-switch acrobatics proceeds via cascade 1,2-boron migrations and Smiles type rearrangement to furnish a variety of terminally functionalized alkyl boronates.     

Efficient access to materials-oriented aromatic alkynes via the mechanochemical Sonogashira coupling of solid aryl halides with large polycyclic conjugated systems

Sonogashira coupling represents an indispensable tool for the preparation of organic materials that contain C(sp)–C(sp²) bonds. Improving the efficiency and generality of this methodology has long been an important research subject in materials science. Here, we show that a high-temperature ball-milling technique enables the highly efficient palladium-catalyzed Sonogashira coupling of solid aryl halides that bear large polyaromatic structures including sparingly soluble substrates and unactivated aryl chlorides. In fact, this new protocol provides various materials-oriented polyaromatic alkynes in excellent yield within short reaction times in the absence of bulk reaction solvents. Notably, we synthesized a new luminescent material via the mechanochemical Sonogashira coupling of poorly soluble Vat Red 1 in a much higher yield compared to those obtained using solution-based conditions. The utility of this method was further demonstrated by the rapid synthesis of a fluorescent metal–organic framework (MOF) precursor via two sequential mechanochemical Sonogashira cross-coupling reactions. The present study illustrates the great potential of Sonogashira coupling using ball milling for the preparation of materials-oriented alkynes and for the discovery of novel functional materials.

Using a high-temperature ball-milling technique, a practical mechanochemical protocol for the Sonogashira cross-coupling of polyaromatic halides was achieved, which provides efficient access to materials-oriented aromatic alkynes.     

Spontaneous emergence of membrane-forming protoamphiphiles from a lipid–amino acid mixture under wet–dry cycles

Dynamic interplay between peptide synthesis and membrane assembly would have been crucial for the emergence of protocells on the prebiotic Earth. However, the effect of membrane-forming amphiphiles on peptide synthesis, under prebiotically plausible conditions, remains relatively unexplored. Here we discern the effect of a phospholipid on peptide synthesis using a non-activated amino acid, under wet–dry cycles. We report two competing processes simultaneously forming peptides and N-acyl amino acids (NAAs) in a single-pot reaction from a common set of reactants. NAA synthesis occurs via an ester–amide exchange, which is the first demonstration of this phenomenon in a lipid–amino acid system. Furthermore, NAAs self-assemble into vesicles at acidic pH, signifying their ability to form protocellular membranes under acidic geothermal conditions. Our work highlights the importance of exploring the co-evolutionary interactions between membrane assembly and peptide synthesis, having implications for the emergence of hitherto uncharacterized compounds of unknown prebiotic relevance.

Synthesis of lipoamino acids via ester–amide exchange under prebiotically plausible wet-dry cycling conditions that results in vesicles at acidic pH.     

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.     

BNN-1,3-dipoles: isolation and intramolecular cycloaddition with unactivated arenes

The mono-base-stabilized 1,2-diboranylidenehydrazine derivatives featuring a 1,3-dipolar BNN skeleton are obtained by dehydrobromination of [ArB(Br)NH]₂ (Ar = 2,6-diphenylphenyl (Dpp), Ar = 2,6-bis(2,4,6-trimethylphenyl)phenyl (Dmp) or Ar = 2,4,6-tri-tert-butylphenyl (Mes*)) with N-heterocyclic carbenes (NHCs). Depending on the Ar substituents, such species can be isolated as a crystalline solid (Ar = Mes*) or generated as reactive intermediates undergoing spontaneous intramolecular aminoboration of the proximal arene rings via [3 + 2] cycloaddition (Ar = Dpp or Dmp). The latter reactions showcase the 1,3-dipolar reactivity toward unactivated arenes at ambient temperature. In addition, double cycloaddition of the isolable BNN species with two CO₂ molecules affords a bicyclic species consisting of two fused five-membered BN₂CO rings. The electronic structures of these BNN species and the mechanisms of these cascade reactions are interrogated through density functional theory (DFT) calculations.

The mono-base-coordinated 1,2-diboranylidenehydrazine derivatives exhibiting the BNN-1,3-dipolar reactivity toward unactivated arenes and CO₂ are reported.     

A modular and divergent approach to spirocyclic pyrrolidines

An efficient three-step sequence to afford a valuable class of spirocyclic pyrrolidines is reported. A reductive cleavage/Horner–Wadsworth–Emmons cascade facilitates the spirocyclisation of a range of isoxazolines bearing a distal β-ketophosphonate. The spirocyclisation precursors are elaborated in a facile and modular fashion, via a [3 + 2]-cycloaddition followed by the condensation of a phosphonate ester, introducing multiple points of divergence. The synthetic utility of this protocol has been demonstrated in the synthesis of a broad family of 1-azaspiro[4,4]nonanes and in a concise formal synthesis of the natural product (±)-cephalotaxine.

A three-step, modular and divergent sequence accessing challenging spirocyclic pyrrolidines has been developed, featuring a novel reductive spirocyclization cascade.