Waste-minimized C(sp^(3))-H activation for the preparation of fused N-heterocycles

By exploiting the combined use of a heterogeneous recyclable palladium(II)-bis(N-heterocyclic carbene)catalyst and cyclopentyl methyl ether(CPME)as a convenient recoverable safer reaction medium,an effective wasteminimized approach has been developed for the intramolecular Pd-catalyzed C(sp3)-H activation of methyl pyrrole derivatives.This synthetic tools has allowed to access condensed N-heterocycles generally endowed with biological activities and representatively are the core motif of complex molecules such as Mitomycines and Tylophorines.The heterogeneous catalytic system could be recovered and reused up to representative five runs without any loss in efficiency.The target products(19 examples)have been obtained selectively and with excellent isolated yields up to 93%.The approach leads to the definition of a protocol with a very good E-factor(21)which is much lower(up to 98%)than those of comparable literature examples.Other green metrics have been calculated and the data collected demonstrate that our newly developed protocol is very promising in terms of its environmental impact profile.

Cp*Rh/Ag catalyzed C–H activation/cyclization sequences of NH-sulfoximines to fused aza-polyheterocycles under gentle conditions

Disclosed herein is a novel Rh/Ag co-catalyzed S=NH directed C–H activation and C–H/N–H bond functionalization protocol of free NH-sulfoximines with hypervalent iodonium ylides.With the aid of AgOTf,these C–H functionalization/cyclization sequences could be achieved at room temperature conditions.The reaction employed EtOH as a“green”solvent and low catalyst loading was required under an oxygen/water-insensitive condition.Under this mild protocol,a wide range of polyheterocyclic sulfoximines bearing fused saturated carbo(hetero)cycles are readily prepared,even toward a complex pharmaceutical Folliculin analog.

Recent advances in(4þ3)cycloaddition of allenes

Allenes are a class of unsaturated compounds containing a propadiene structural moiety,exhibiting essential physiological,pharmacological,and various reactivities.Their(4þ3)cycloaddition reaction has become an effective method for synthesizing seven-membered rings,especially for heterocycles.This method has been continuously improved and developed.Herein,we review the(4þ3)cycloaddition of allenes,focusing on the developed methodologies and the outlook in this field from 2013 to 2023.

Multicomponent cascade reaction of 3-formylchromones:Highly regioselective synthesis of functionalized pyridin-2(1H)-ones

A novel protocol was developed for the construction of highly functionalized pyridin-2(1H)-ones from 3-formylchromones,ethyl 2-(pyridin-2-yl)acetate derivatives and amines via a complex multicomponent cascade reaction involving targeted duplicated ring-opening and duplicated cyclization reactions which form skeleton-reorganized target compounds.A series of pyridin-2(1H)-ones were produced by this reaction accompanied by the formation of three bonds(one C–N and two C–C bonds)and the cleavage of one bond in one step.This protocol can be used in combinatorial and parallel syntheses of various pyridin-2(1H)-ones with potent biological activity.The advantages of this approach include simple and practical operation(multicomponent one-pot),high yields(up to 91%),and products with potential biological activity.

1,6-Conjugate addition of para-quinone methides using gem-diborylcarbanions: Practical access to gem-diborylalkanes bearing vicinal tertiary/quaternary stereocenters

A novel,efficient and pragmatic method to prepare gem-diboron products with vicinal tertiary/quaternary stereocenters using LiTMP-mediated 1,6-conjugate addition of gem-diborylalkanes to para-quinone methides was described for the first time.The results showed that various gem-diboron products with vicinal tertiary and quaternary stereocenters could be formed within 15 min at ambient temperature.This simple protocol has also been applied for the efficient synthesis of the analogue of Bedaquiline.

Flow chemistry in the multi-step synthesis of natural products

The total synthesis of natural products is constantly facing many challenges derived from the complexed chemical structures,the lengthy synthetic routes,the time-consuming workup procedures and the large environmental footprint.In the past two decades,performing chemical transformations in continuous flow using various types of microreactors and in-line auxiliary technologies have been demonstrated effectively in respects of enhanced re-action yield and selectivity,excellent reproducibility and easy scale-up,safe proceeding hazardous reaction.And the rapid synthesis of natural products,which has been enabled in continuous flow based upon the significant improvement of overall yield within a short residence time via processing intensification and systematic auto-mation,is essential to furnish sufficient quantity for the bioactivity investigation of structural diversity modifi-cation,structure-activity relationship during drug discovery and the increasing consumption of medical treatment.In this review,the multi-step continuous flow synthesis of natural products is highlighted to provide a comprehensive recognization on the intrinsic merits of flow chemistry for organic chemists to purposefully develop the flow synthetic approaches of natural products in the future.

Transition-metal-free [3+3] annulation reaction of sulfoxonium ylides with cyclopropenones for the synthesis of 2-pyrones

An efficient and practical synthetic approach was developed for the tandem synthesis of trisubstituted 2-pyrone derivatives from sulfoxonium ylides and cyclopropenones.This[3+3]annulation reaction was carried out under transition-metal-free conditions.A broad range of functional groups were tolerant under mild conditions,and a variety of 2-pyrones were obtained in moderate to good yields.

Copper-catalyzed 2,3-dihydro-1,2,4-triazoles synthesis through[3+2]-cycloaddition of nitrile ylides with azodicarboxylates

A copper-catalyzed three-component reaction of diazo compounds,nitriles,and azodicarboxylates to construct 2,3-dihydro-1,2,4-triazoles is reported.Key to the success is the utilization of azodicarboxylates to trap the in-situ formed nitrile ylides from diazo compounds by[3+2]-cycloaddition.Both the acceptor-only and donor-acceptor diazo compounds are all tolerated to the strategy.The synthetic value of this protocol is illustrated by gram-scale synthesis and valuable transformation of the obtained 2,3-dihydro-1,2,4-triazoles.

Recent advances in transition-metal-free C–H functionalization of imidazo[1,2-a]pyridines

Imidazo[1,2-a]pyridines are unique nitrogen-containing organic compounds with wide applications in pharma-ceuticals,natural products,material science and organometallics.Due to their significant biological and synthetic value,the construction of imidazo[1,2-a]pyridine scaffolds has been a highly intriguing research topic,and substantial progress had been made in the past decades.In this review,we aim to summarize the current advances in direct C–H functionalization of imidazo[1,2-a]pyridines under transition-metal-free conditions.For the selected examples,we focused on the design and catalytic cycle mechanism,as well as on representative outcomes and applications.

Polymer-supported chiral palladium-based complexes as efficient heterogeneous catalysts for asymmetric reductive Heck reaction

Heterogeneous asymmetric catalysis is an important strategy for the industrial production of chiral compounds.Herein,we reported a polymer-bound Xu-Phos-derived palladium catalyst that shows good performance in heterogeneous asymmetric reductive Heck reaction of allyl aryl ethers.This heterogeneous catalyst was easily prepared by efficient immobilization of the sulfonamide phosphine ligand(Xu-Phos)in the cross-linked polystyrene via copolymerization,and exhibits similar catalytic activity and enantioselectivity to that of the homogeneous catalyst.Moreover,the heterogeneous catalyst system is proved to be easily recovered and reused several times without losing catalytic activity obviously.

Visible-light-induced decarboxylative alkynylation of carboxylic acids in batch and continuous flow

A green efficient photoredox-catalyzed decarboxylative alkynylation of carboxylic acids with alkynyl bromides has been developed.This broadly applicable protocol is presented whereinα-amino,aliphatic andα-oxy acids are converted into useful alkynylation products.The commercially-available organic photocatalyst 4CzIPN is used as the photocatalyst,organic base DBU is utilized as the base,and DMSO serves as solvent.This strategy features mild conditions,is metal-free,and is environmentally friendly.The batch and continuous-flow protocols described were applied to obtain a broader substrate scope of functionalization(more than 50 examples).Furthermore,we demonstrate that the use of microflow technology enhanced and intensified the reaction process,achieving significantly reduced reaction times(i.e.,10 min of residence time).

Electrooxidative trifunctionalization of alkenes with N-chlorosuccinimide and ArSSAr/ArSH to α,β-dichloride arylsulfoxides

An unprecedented electrochemical oxidative trifunctionalization of olefins with diaryl disulfides/aryl thiols and N-chlorosuccinimide in an aqueous system is developed.Two C-Cl bonds,one C-S bond,and one S=O bond are produced simultaneously in one step from simple and commercially available starting materials with clean energy.This tandem methodology features as mild reaction conditions,transition metal and additional oxidant free,broad substrate scope,good functional group compatibility,and gram scale preparation.

Perspectives on green synthesis and catalysis

Despite their impressive capacity to access diverse functional groups and to synthesize structurally complex molecules,the majority of the organic reactions suffers from harsh conditions,low atom economy,and hazardous waste production.The goal of our research is geared towards developing efficient methods to minimize the adverse environmental impact and contributing to chemical sustainability.Herein,we illustrate three distinct green approaches,studying the novel reactivities with environmentally innocuous reagents to improve the synthetic efficiency,utilization of natural feedstocks,and employment of green energy to facilitate various important chemical transformations.From this perspective article,we hope to provide an overview of green synthetic chemistry and inspire the expansion of the field in the future.

Construction of highly congested quaternary carbon centers by NHC catalysis through dearomatization

A NHC-catalyzed hypervalent iodine reagents and transition-metal free redox-neutral dearomatization of phenols is reported.This protocol provides an efficient access for highly congested quaternatry carbon centers construction.It also features operationally simplicity,mild reaction conditions and good functional group tolerance.Moreover,the reported procedure can be easily emplified to 1 g scale.Mechanism study reveals the dearomative transformation possibly undergoes a single electron transfer process with NHC radical cation as a reactive intermediate.

Transition metal-free photocatalytic reductive deuteration of ketone derivatives

Deuterium labelling techniques have shown widespread applications in organic synthesis,analytic chemistry,life science and material science.The design of practical deuteration reactions which is environmentally friendly is highly desired for pharmaceutical development and industrial processes while remaining underexplored.We herein report a convenient,transition metal-free strategy for reductive deuteration of ketone derivatives toα-deuterated alcohols by employing a conjugated aryl amine-based organophotocatalyst,a dipropyl disulfide cocatalyst and an inorganic reductant.Upon irradiation with visible light and under an air atmosphere,a variety of diaryl ketones,heteroaryl ketones,cyclic ketones,α-ketoesters,benzil derivatives,aliphatic ketones and drug-like molecules were converted into correspondingα-deuterated aryl alcohols in good to excellent yields and with high deuterium incorporation(up to 99%D-incorporation).Only low toxic side-products,such as sodium salts and carbon dioxide,were generated.Consequently,the synthetic utility of this method is highlighted by the preparation of several D-labeled drug-like molecules,including orphenadrine,carbinoxamine and modafinil.

Mild construction of N-fused polycyclic compounds via Rh(Ⅲ)/EosinY co-catalyze C—H activation

The construction of N-fused polycyclic compounds at room temperature via the combination of transition-metal catalyst and photocatalyst has been reported.This novel work has successfully realized LED irradiated C—H activation of iodonium ylides.The strategy shows wide substrate scope and ideal functional group tolerance.Our work would be useful for the construction of various heterocyclic compounds.

Alternating current electrolysis:A photoredox catalysis mimic and beyond

Alternating current electrolysis(ACE)is an emerging powerful synthetic tool,which principally resembles photoredox catalysis strategies.Its periodically alternating polarity feature allows oxidation and reduction processes to take place on the same electrode surface in a well-controlled manner via the fine-tuning of current frequency along with other reaction parameters.Therefore,many challenging transformations in typical direct electrolysis,including constant current electrolysis or constant potential electrolysis,could be achieved via ACE.The recent advances in the organic synthesis using this emerging technology and its advantages over direct electrolysis are highlighted.

Efficient enzymatic synthesis of(S)-1-(30-bromo-20-methoxyphenyl)ethanol,the key building block of lusutrombopag

(S)-1-(30-Bromo-20-methoxyphenyl)ethanol((S)-1b)is the key precursor for the synthesis of Lusutrombopag.The bioreduction of 1-(30-bromo-20-methoxyphenyl)ethanone(1a)offers an attractive method to access this important compound.Through screening the available carbonyl reductases,we obtained a carbonyl reductase from Novosphingobium aromaticivorans(CBR),which could completely convert 100 g/L of 1a to(S)-1b.Furthermore,a carbonyl reductase from Novosphingobium sp.Leaf2(NoCR)was identified to completely convert 200 g/L of 1a to(S)-1b with excellent enantioselectivity(>99%ee)and 77%isolated yield using FDH/formate system for NADH regeneration.The K_(m) and k_(cat) of recombinant NoCR towards 1a were 0.66 mmol/L and 7.5 s-1,and the catalytic efficiency k_(cat)/K_(m) was 11.3 mmol/s.L.Meanwhile,NoCR showed high catalytic activity and stereoselectivity towards acetophenone derivatives with halogen or methoxy substitution on the benzene ring,indicating that NoCR is a valuable biocatalyst with potential practical applications.

Carbon-oxygen bond formation via visible-light-induced O-H insertion between acylsilanes and oximes

Visible light promoted C-O bond formation reaction through O-H insertion of acylsilanes with oximes has been developed.The reaction occurred under mild reaction conditions(sole blue LED irradiation in the absence of any catalysts or additives)with a short reaction time and afforded the corresponding oxime ethers in moderate to good yields.

Recent advances in the syntheses of pyrroles

The pyrrole moiety is an important structural motif in functional materials,natural products,and pharmaceuticals.More and more synthetic strategies toward pyrroles have emerged,where various efficient building blocks are developed and these synthons enable the syntheses of pyrroles with different numbers of components.However,no review specifically summarizes the syntheses of pyrroles according to the type and number of employed building blocks.To aid researchers to design appropriate substrates for pyrrole synthesis,herein we summarized the advances in pyrrole syntheses and classified these reactions into four categories according to the number of employed components,which may shed light on developing more efficient synthetic methods toward substituted pyrroles.