Photoinduced Multicomponent Reactions

The combination of multicomponent approaches with light‐driven processes opens up new scenarios in the area of synthetic organic chemistry, where the need for sustainable, atom‐ and energy‐efficient reactions is increasingly urgent. Photoinduced multicomponent reactions are still in their infancy, but significant developments in this area are expected in the near future.     

Pd/Light‐Accelerated Atom‐Transfer Carbonylation of Alkyl Iodides: Applications in Multicomponent Coupling Processes Leading to Functionalized Carboxylic Acid Derivatives

The atom‐transfer carbonylation reaction of various alkyl iodides thereby leading to carboxylic acid esters was effectively accelerated by the addition of transition‐metal catalysts under photoirradiation conditions. By using a combined Pd/hν reaction system, vicinal C‐functionalization of alkenes was attained in which α‐substituted iodoalkanes, alkenes, carbon monoxide, and alcohols were coupled to give functionalized esters. When alkenyl alcohols were used as acceptor alkenes, three‐component coupling reactions, which were accompanied by intramolecular esterification, proceeded to give lactones. Pd‐dimer complex [Pd₂(CNMe)₆][PF₆]₂, which is known to undergo homolysis under photoirradiation conditions, worked quite well as a catalyst in these three‐ or four‐component coupling reactions. In this metal/radical hybrid system, both Pd radicals and acyl radicals are key players and a stereochemical study confirmed the carbonylation step proceeded through a radical carbonylation mechanism.     

Enantioselective Multicomponent Synthesis of Fused 6–5 Bicyclic 2‐Butenolides by a Cascade Heterobicyclisation Process

The successive coupling of an alkoxy(aryl/heteroaryl)carbene complex of chromium with either a ketone or an imide lithium enolate and then a 3‐substituted (H, TMS, PhCH₂, PhCH₂CH₂, Me) propargylic organomagnesium reagent has afforded novel hydroxy‐substituted bicyclic [4.3.0]‐γ‐alkylidene‐2‐butenolides with three modular points that has allowed the efficient introduction of molecular complexity, including a homopropargylic alcohol core. The selective formation of these five‐ or six‐component heterobicyclisation products is the result of the regioselective integration of the Grignard reagent as a propargyl fragment followed by a cascade CO/alkyne/CO insertion, ketene trapping and elimination sequence. By using lithium enolates of chiral N‐acetyl‐2‐oxazolidinones and the corresponding propargylic organocerium reagents, both enantiomers of these bicyclic heterocycles were efficiently prepared with very high enantiomeric purity. Architecturally, these fused bicyclic butenolides are characterised by a highly unsaturated and oxygenated core and they exhibit strong blue fluorescence in solution.     

Transition‐Metal‐Free Multicomponent Approach to Stereoenriched Cyclopentyl‐isoxazoles through C−C Bond Cleavage

An efficient multicomponent reaction for the synthesis of stereoenriched cyclopentyl‐isoxazoles from camphor‐derived α‐oximes, alkynes, and MeOH is reported. Our method involved a series of cascade transformations, including the in situ generation of an I^III catalyst, which catalyzed the addition of MeOH to a sterically hindered ketone. Oxidation of the oxime, and rearrangement of the α‐hydroxyiminium ion generated a nitrile oxide in situ, which, upon [3+2] cycloaddition reaction with an alkyne, delivered the regioselective product. This reaction was very selective for the syn‐oxime. This multicomponent approach was also extended to the synthesis of a new glycoconjugate, camphoric ester‐isoxazole C‐galactoside.     

Multicomponent Diene‐Transmissive Diels–Alder Sequences Featuring Aminodendralenes

1‐Aminodecalins were prepared from acyclic precursors by combining the powerful twofold diene‐transmissive Diels–Alder chemistry of [3]dendralenes with the simplicity of enamine formation. On mixing at ambient temperature, a simple dienal condenses with a primary or secondary amine to generate the enamine, a 1‐amino‐[3]dendralene in situ, and this participates as a double diene in a sequence of two Diels–Alder events with separate dienophiles. Overall, four C?C bonds and one C?N bond are formed. Mechanistic insights into these reactions are provided by means of density functional theory calculations.     

Mild and Low‐Pressure fac‐Ir(ppy)3‐Mediated Radical Aminocarbonylation of Unactivated Alkyl Iodides through Visible‐Light Photoredox Catalysis

A novel, mild and facile preparation of alkyl amides from unactivated alkyl iodides employing a fac‐Ir(ppy)₃‐catalyzed radical aminocarbonylation protocol has been developed. Using a two‐chambered system, alkyl iodides, fac‐Ir(ppy)₃, amines, reductants, and CO gas (released ex situ from Mo(CO)₆), were combined and subjected to an initial radical reductive dehalogenation generating alkyl radicals, and a subsequent aminocarbonylation with amines affording a wide range of alkyl amides in moderate to excellent yields.     

二芳基脯氨醇衍生物催化的硝基烯参与的多组分不对称串联合成研究进展

硝基烯是一类重要的有机合成子,以硝基烯烃为原料,二芳基脯氨醇衍生物催化的多组分不对称串联反应是构建复杂手性化合物的重要方法,被广泛应用于有机合成和新药开发领域.根据构建的目标化合物类型,较全面地总结了基于二芳基脯氨醇衍生物催化、硝基烯为合成子的多组分不对称串联反应的合成研究,从反应的催化剂体系、反应机理、实验结果、反应优点、存在的问题和局限性等方面进行介绍,并对今后的发展做出展望.     

Monofluoroalkenylation of Dimethylamino Compounds through Radical–Radical Cross‐Coupling

An unprecedented and challenging radical–radical cross‐coupling of α‐aminoalkyl radicals with monofluoroalkenyl radicals derived from gem‐difluoroalkenes was achieved. This first example of tandem C(sp³)?H and C(sp²)?F bond functionalization through visible‐light photoredox catalysis offers a facile and flexible access to privileged tetrasubstituted monofluoroalkenes under very mild reaction conditions. The striking features of this redox‐neutral method in terms of scope, functional‐group tolerance, and regioselectivity are illustrated by the late‐stage fluoroalkenylation of complex molecular architectures such as bioactive (+)‐diltiazem, rosiglitazone, dihydroartemisinin, oleanic acid, and androsterone derivatives, which represent important new α‐amino C?H monofluoroalkenylations.     

A Multiple Multicomponent Approach to Chimeric Peptide–Peptoid Podands

The success of multi‐armed, peptide‐based receptors in supramolecular chemistry traditionally is not only based on the sequence but equally on an appropriate positioning of various peptidic chains to create a multivalent array of binding elements. As a faster, more versatile and alternative access toward (pseudo)peptidic receptors, a new approach based on multiple Ugi four‐component reactions (Ugi‐4CR) is proposed as a means of simultaneously incorporating several binding and catalytic elements into organizing scaffolds. By employing α‐amino acids either as the amino or acid components of the Ugi‐4CRs, this multiple multicomponent process allows for the one‐pot assembly of podands bearing chimeric peptide–peptoid chains as appended arms. Tripodal, bowl‐shaped, and concave polyfunctional skeletons are employed as topologically varied platforms for positioning the multiple peptidic chains formed by Ugi‐4CRs. In a similar approach, steroidal building blocks with several axially‐oriented isocyano groups are synthesized and utilized to align the chimeric chains with conformational constrains, thus providing an alternative to the classical peptido‐steroidal receptors. The branched and hybrid peptide–peptoid appendages allow new possibilities for both rational design and combinatorial production of synthetic receptors. The concept is also expandable to other multicomponent reactions.     

Radical‐Mediated Fluoroalkylations

Recently, the development of eco‐friendly radical processes has become of great interest in synthetic chemistry. In particular, visible‐light photocatalysis has drawn tremendous attention for its environmental compatibility and versatility in promoting many synthetically important reactions. In addition, inorganic electrides as electron donors have emerged as new eco‐friendly tools for radical transformations since they consist of non‐toxic and naturally abundant main metals such as calcium. The design of new fluoroalkylation reactions has benefited greatly from recent advances in visible‐light photocatalysis and the chemistry of inorganic electrides. Since adding fluoroalkyl groups can dramatically change the physical and chemical properties of organic compounds, using these processes to promote eco‐friendly radical fluoroalkylations will have a major impact in areas such as pharmaceuticals, agrochemicals, and material sciences. This Personal Account reviews radical‐mediated fluoroalkylations, such as trifluoromethylations and difluoroalkylations, recently developed in our laboratory.

     

Programming Organic Molecules: Design and Management of Organic Syntheses through Free‐Radical Cascade Processes

Cascade, domino, or tandem processes, that link together two or more transformations in one pot, are increasing in popularity because they lead to improvements in synthetic efficiency and decreases in environmental impact. Not only do these cascades contain choice mechanistic gems but they also deliver compact and elegant syntheses of complex natural products. Longer cascades require more functional groups precisely configured within carefully designed initial molecular architectures. Such “purposeful” molecules can be thought of as chemical algorithms.This article surveys the phenomenal range of unimolecular free‐radical cascades. A convenient system for classifying free‐radical cascades is described that is useful for evaluating and comparing cascades and aids the design of synthetic routes to polycyclic structures.Double cyclization cascades lead to cyclopentylcyclopentane or bicyclo[3.3.0]octane derivatives. Precursors that contain a ring as a template have been used to control stereochemistry in syntheses of triquinanes and many related compounds. Of the cascades containing ring‐cleavage steps, the most useful are the ring expansions which have opened up new synthetic routes to medium ring polycycles.The key design features of three‐stage unimolecular free‐radical cascades that yielded steroid structures, are linear arrays of radical acceptor units associated with methyl groups distributed every fifth C‐atom in the precursor polyenes. Ring cleavage is the reverse of cyclization. In special, symmetrical structures, therefore, this led to sequences that were reversible, thus launching endlessly repeating cascades supported by delightfully fluxional structures. The science of “programming” organic molecules to achieve particular target structures is maturing rapidly. Coordination and classification of the welter of information in this area is intended to facilitate design and hence to extend the range and complexity of attainable structures.     

Construction of Cyclobutanes by Multicomponent Cascade Reactions in Homogeneous Solution through Visible-Light Catalysis

[2+2] Photocycloaddition of two olefins is a general method to assemble the core scaffold, cyclobutane, found in numerous bioactive molecules. A new approach to synthesize cyclobutanes through multicomponent cascade reactions by merging aldol reaction and Witting reaction with visible-light-induced [2+2] cycloaddition is reported. An array of cyclobutanes with high selectivity has been achieved from commercially available aldehydes, ketones (or phosphorus ylide), and olefins with visible-light irradiation of a catalytic amount of (fac-tris(2-phenylpyridinato-C₂,N)iridium) ([Ir(ppy)₃]) at room temperature. Control experiments and spectroscopic studies revealed that the triplet–triplet energy transfer from the excited [Ir(ppy)₃]* to enones, generated in situ from aldehyde and ketone or aldehyde and phosphorus ylide, is responsible for these simple and efficient muticomponent transformations.     

Aminobisphosphonate Polymers via RAFT and a Multicomponent Kabachnik–Fields Reaction

Polyacrylamides containing pendant aminobisphosphonate groups are synthesized via reversible addition‐fragmentation chain transfer (RAFT) polymerization and a multicomponent postpolymerization functionalization reaction. A Moedritzer–Irani reaction installs the phosphonic acid groups on well‐defined, RAFT‐generated polymers bearing a pendant amine. An alternate route to the same materials is developed utilizing a three‐component Kabachnik–Fields reaction and subsequent dealkylation. Kinetics of the RAFT polymerization of the polymer precursor are studied. Successful functionalization is demonstrated by NMR and FTIR spectroscopy and elemental analysis of the final polymers.

     

Analysis of Nascent Rotational Energy Distributions and Reaction Mechanisms of the Gas‐Phase Radical–Radical Reaction O(3P)+(CH3)2CH→C3H6+OH

This paper reports on the gas‐phase radical–radical dynamics of the reaction of ground‐state atomic oxygen [O(³P), from the photodissociation of NO₂] with secondary isopropyl radicals [(CH₃)₂CH, from the supersonic flash pyrolysis of isopropyl bromide]. The major reaction channel, O(³P)+(CH₃)₂CH→C₃H₆ (propene)+OH, is examined by high‐resolution laser‐induced fluorescence spectroscopy in crossed‐beam configuration. Population analysis shows bimodal nascent rotational distributions of OH (X²Π) products with low‐ and high‐N′′ components in a ratio of 1.25:1. No significant spin–orbit or Λ‐doublet propensities are exhibited in the ground vibrational state. Ab initio computations at the CBS‐QB3 theory level and comparison with prior theory show that the statistical method is not suitable for describing the main reaction channel at the molecular level. Two competing mechanisms are predicted to exist on the lowest doublet potential‐energy surface: direct abstraction, giving the dominant low‐N′′ components, and formation of short‐lived addition complexes that result in hot rotational distributions, giving the high‐N′′ components. The observed competing mechanisms contrast with previous bulk kinetic experiments conducted in a fast‐flow system with photoionization mass spectrometry, which suggested a single abstraction pathway. In addition, comparison of the reactions of O(³P) with primary and tertiary hydrocarbon radicals allows molecular‐level discussion of the reactivity and mechanism of the title reaction.