Aromatic C–H bond functionalization through organocatalyzed asymmetric intermolecular aza-Friedel–Crafts reaction: a recent update

• Anup Biswas

Beilstein J. Org. Chem. 2023, 19, 956–981, doi:10.3762/bjoc.19.72

• different types of C–H bonds, an aromatic C–H bond is even more inert rendering this type of bond functionalization more difficult. Herewith the term “bond functionalization” is defined as the cleavage of an existing bond with substitution by another bond. Aromatic C–H bond functionalizations have gained

• considerable attention by organic chemists because of the strategic importance of this process as well as the ability to synthesize functionalized aromatic molecules in a straightforward way. Many organic name reactions have been discovered utilizing the C–H bond functionalization concept [1]. Metals were

• ], amidines [11], isothioureas [12][13], whereas thioureas [14][15], ureas [16], phosphoric acids [17][18], and squaramides [19][20] fall into the second category. The Friedel–Crafts reaction, discovered by Charles Friedel and James Crafts in 1877 allows the aromatic C–H bond functionalization through the

Clauson–Kaas pyrrole synthesis using diverse catalysts: a transition from conventional to greener approach

• Dileep Kumar Singh and
• Rajesh Kumar

Beilstein J. Org. Chem. 2023, 19, 928–955, doi:10.3762/bjoc.19.71

• –Kaas synthesis [37][38], Piloty–Robinson synthesis [39][40][41], and Barton–Zard reaction [42][43][44] (Scheme 1). Among these, the Clauson–Kaas pyrrole synthesis has received much attention because the synthesized pyrrole contains unsubstituted carbons that can be used for further functionalization

• functionalization. The formation of the desired products depends on the amount of triflic acid used in the reaction. Using 0.05 equivalents triflic acid gives N-sulfonylpyrroles 15 in 80–92% yields, 1.0 equivalent of triflic acid provides N-sulfonylindole 16 in 75–91% yields and 3.5 equivalents of triflic acid

• -functionalization method using a benign and naturally occurring glutathione and magnetic ferrite nanoparticles by sonication in water at room temperature. Furthermore, using this organocatalyst, various N-substituted pyrroles were prepared by reacting various amines 56 with 2,5-DMTHF (2) in water at 140 °C under

Photoredox catalysis enabling decarboxylative radical cyclization of γ,γ-dimethylallyltryptophan (DMAT) derivatives: formal synthesis of 6,7-secoagroclavine

• Alessio Regni,
• Francesca Bartoccini and
• Giovanni Piersanti

Beilstein J. Org. Chem. 2023, 19, 918–927, doi:10.3762/bjoc.19.70

• ground state catalyst [21][22][23][24][25][26]. While early research has focused on methods for the functionalization of relatively simple hydrocarbons [27][28][29][30], developments in photoredox catalysis have gained traction recently as a viable strategy for the total synthesis of natural products [31

• Hz, 1H)], strongly indicating that this product is not the desired structure 6’ but the eight-membered cycloalkene structure 6, shown in Scheme 2. Based on these results and previous reports on the benzylic and allylic C–H bond functionalization enabled by metallaphotoredox catalysis [86], we propose

Light-responsive rotaxane-based materials: inducing motion in the solid state

• Adrian Saura-Sanmartin

Beilstein J. Org. Chem. 2023, 19, 873–880, doi:10.3762/bjoc.19.64

• is the functionalization of mesoporous silica nanoparticles with light-responsive rotaxane-based molecular shuttles to control the uptake and release of target molecules [31][32][33][34]. This perspective is focused on recent examples of light-responsive rotaxane-based solid-state materials in which

• focused on the integration of new photoswitchable scaffolds which allow both the formation of the intertwined species and the arrangement of the solid materials. In this regard, the functionalization of different templates already tested in solution chemistry is envisioned as the main strategy

Pyridine C(sp²)–H bond functionalization under transition-metal and rare earth metal catalysis

• Haritha Sindhe,
• Malladi Mounika Reddy,
• Karthikeyan Rajkumar,
• Akshay Kamble,
• Amardeep Singh,
• Anand Kumar and
• Satyasheel Sharma

Beilstein J. Org. Chem. 2023, 19, 820–863, doi:10.3762/bjoc.19.62

• of several methods for the synthesis of functionalized pyridines or their integration into an organic molecule, new methodologies for the direct functionalization of pyridine scaffolds have been developed during the past two decades. In addition, transition-metal-catalyzed C–H functionalization and

• rare earth metal-catalyzed reactions have flourished over the past two decades in the development of functionalized organic molecules of concern. In this review, we discuss recent achievements in the transition-metal and rare earth metal-catalyzed C–H bond functionalization of pyridine and look into

• the mechanisms involved. Keywords: C–H functionalization; heterocycles; pyridine; rare earth metal; transition-metal-catalyzed; Introduction Pyridine, one of the most important azaheterocyclic scaffolds, is found in a diverse range of bioactive natural products, pharmaceuticals, and functional

Facile access to 3-sulfonylquinolines via Knoevenagel condensation/aza-Wittig reaction cascade involving ortho-azidobenzaldehydes and β-ketosulfonamides and sulfones

• Ksenia Malkova,
• Andrey Bubyrev,
• Stanislav Kalinin and
• Dmitry Dar’in

Beilstein J. Org. Chem. 2023, 19, 800–807, doi:10.3762/bjoc.19.60

• novel quinoline construction and functionalization techniques resulting in new or rare derivatives [17][18][19][20][21][22][23][24][25][26] is an important mission in the field of drug discovery and medicinal chemistry. The sulfonamide group is a known privileged motif in drug design often serving as a

Construction of hexabenzocoronene-based chiral nanographenes

• Ranran Li,
• Di Wang,
• Shengtao Li and
• Peng An

Beilstein J. Org. Chem. 2023, 19, 736–751, doi:10.3762/bjoc.19.54

• introduction of different main group elements beyond nitrogen summarized above would provide more diverse structures and properties. Meanwhile, the methodologies for further functionalization of the existing nanographene molecules are still needed for application purposes. Construction of HBC by Scholl

Strategies in the synthesis of dibenzo[b,f]heteropines

• David I. H. Maier,
• Barend C. B. Bezuidenhoudt and
• Charlene Marais

Beilstein J. Org. Chem. 2023, 19, 700–718, doi:10.3762/bjoc.19.51

• ) [77][78]. The allyl moiety in 144 allows for facile further functionalization. Amidation of the dihydrodibenzo[b,f]azepine (2a) derivatives with acyl halides 145 allowed for the introduction of variable length amide linkers by Kastrinsky et al. [3] (Scheme 33B). An industrial synthesis of opipramol (5

Photocatalytic sequential C–H functionalization expediting acetoxymalonylation of imidazo heterocycles

• Deepak Singh,
• Shyamal Pramanik and
• Soumitra Maity

Beilstein J. Org. Chem. 2023, 19, 666–673, doi:10.3762/bjoc.19.48

• from academia and industry. Herein, we report a direct C-3 acetoxymalonylation of imidazo heterocycles using relay C–H functionalization enabled by organophotocatalysis starring zinc acetate in the triple role of an activator, ion scavenger as well as an acetylating reagent. The mechanistic

• investigation revealed a sequential sp2 and sp3 C–H activation, followed by functionalization driven by zinc acetate coupled with the photocatalyst PTH. A variety of imidazo[1,2-a]pyridines and related heterocycles were explored as substrates along with several active methylene reagents, all generating the

• products with excellent yields and regioselectivity, thus confirming excellent functional group tolerability. Keywords: C–H functionalization; imidazo heterocycles; photoredox; regioselective; relay catalysis; Introduction Among all N-fused heterocycles, imidazo[1,2-a]pyridines (IPs) are the prevalent

Enolates ambushed – asymmetric tandem conjugate addition and subsequent enolate trapping with conventional and less traditional electrophiles

• Péter Kisszékelyi and
• Radovan Šebesta

Beilstein J. Org. Chem. 2023, 19, 593–634, doi:10.3762/bjoc.19.44

C3-Alkylation of furfural derivatives by continuous flow homogeneous catalysis

• Grédy Kiala Kinkutu,
• Catherine Louis,
• Myriam Roy,
• Juliette Blanchard and
• Julie Oble

Beilstein J. Org. Chem. 2023, 19, 582–592, doi:10.3762/bjoc.19.43

• .19.43 Abstract The C3-functionalization of furfural using homogeneous ruthenium catalysts requires the preinstallation of an ortho-directing imine group, as well as high temperatures, which did not allow scaling up, at least under batch conditions. In order to design a safer process, we set out to

• formation of the imine directing group and the C3-functionalization with some vinylsilanes and norbonene. Keywords: biomass; C–H activation; flow; furfural; homogeneous catalysis; Introduction The conversion of biomass derivatives into value-added products is one of the key branches of green chemistry and

• well as monomers for materials science [9][10][11][12][13][14][15]. In this context, their functionalization is fundamental to further improve their inclusion in fine organic synthesis and industrial processes. For this reason, in recent years, innovative protocols for the formation of new bonds on

Direct C2–H alkylation of indoles driven by the photochemical activity of halogen-bonded complexes

• Martina Mamone,
• Giuseppe Gentile,
• Jacopo Dosso,
• Maurizio Prato and
• Giacomo Filippini

Beilstein J. Org. Chem. 2023, 19, 575–581, doi:10.3762/bjoc.19.42

• ) and carbon–heteroatom (C–X) bonds has been and still is a central topic in organic synthesis [1][2]. Historically, organic chemists have extensively relied on the use of noble-metal-based catalysts (e.g., Pd, Rh, Ir, among others) to achieve such type of functionalization [3][4][5]. However, reliance

• tool to guide the development of greener and more convenient synthetic protocols [7][8][9][10][11][12]. In this context, photochemical approaches based on electron donor–acceptor (EDA) complexes have been successfully exploited to drive the direct C–H functionalization of a large number of organic

• to photochemically generate electrophilic radicals that can drive the functionalization of suitable electron-rich substrates [23]. Exploiting this strategy, here we report a novel metal-free methodology for the direct homolytic aromatic substitution (HAS) reaction of indoles 1 with α-iodosulfones 2

A new oxidatively stable ligand for the chiral functionalization of amino acids in Ni(II)–Schiff base complexes

• Alena V. Dmitrieva,
• Oleg A. Levitskiy,
• Yuri K. Grishin and
• Tatiana V. Magdesieva

Beilstein J. Org. Chem. 2023, 19, 566–574, doi:10.3762/bjoc.19.41

• thermodynamically controlled stereoselectivity as compared to the parent Belokon complex. Additionally, functionalization with the tert-butyl group significantly enhances the reactivity of the deprotonated glycine complex towards electrophiles as compared to the anionic species formed from the original Belokon

• ]. Functionalization of the phenyl ring in the benzophenone gives rise to an additional axial chirality (L3), thus improving stereoselectivity observed at the removed stereocenter [24][25]. Replacing N-benzylproline for 2,7-dihydro-1H-azepine (L5) allowed obtaining a new tridentate ligand with chemically stable axial

• base chiral template is a fairly versatile “tool” that can be adapted to a specific task. A relatively new approach to functionalization of amino acids is a combination of a stereoselective synthesis in a metal-coordination environment with electrochemical activation [31]. It increases the reactivity

Transition-metal-catalyzed domino reactions of strained bicyclic alkenes

• Austin Pounder,
• Eric Neufeld,
• Peter Myler and
• William Tam

Beilstein J. Org. Chem. 2023, 19, 487–540, doi:10.3762/bjoc.19.38

• bridging heteroatom increases the ring-strain energy of the system, conceptualized by the decrease in bond distances. Typically, there are two modes for ring-strain release. First, functionalization of the double bond mildly alleviates the ring strain by relieving nonoptimal bond angles enforced by the

• metal catalysts towards coordination on the exo face biases the reaction outcome towards exo-selective functionalization. Upon exo coordination of a metal catalyst with the π system and subsequent migratory insertion, the resulting alkyl metal intermediate is quite limited in how it can propagate. In

• on the functionalization of the bicyclic framework itself rather than its use as a transient mediator for domino reactions [13][14][15][16][17]; however, we point the reader to several excellent reviews. The “trapped” alkyl metal intermediate can undergo subsequent migratory insertion steps with

Transition-metal-catalyzed C–H bond activation as a sustainable strategy for the synthesis of fluorinated molecules: an overview

• Louis Monsigny,
• Floriane Doche and
• Tatiana Besset

Beilstein J. Org. Chem. 2023, 19, 448–473, doi:10.3762/bjoc.19.35

• approaches, the transition-metal-catalyzed functionalization of various scaffolds with a panel of fluorinated groups (XRF, X = S, Se, O) offered straightforward access to high value-added compounds. This review will highlight the main advances made in the field with the transition-metal-catalyzed

• functionalization of C(sp2) and C(sp3) centers with SCF3, SeCF3, or OCH2CF3 groups among others, by C–H bond activation. The scope and limitations of these transformations are discussed in this review. Keywords: C–H bond activation; emergent fluorinated groups; homogeneous catalysis; organofluorine chemistry

• [6][7][8][9][10][11]. Among them [2][5][12][13][14][15][16][17][18], the direct functionalization of a simple C–H bond by transition-metal catalysis [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43] became an important tool offering new

Asymmetric synthesis of a stereopentade fragment toward latrunculins

• Benjamin Joyeux,
• Antoine Gamet,
• Nicolas Casaretto and
• Bastien Nay

Beilstein J. Org. Chem. 2023, 19, 428–433, doi:10.3762/bjoc.19.32

• secured by the NMR analysis of Mosher's esters made from (R)-(+)- and (S)-(−)-α-methoxy-α-trifluoromethylphenylacetic acid (MTPA) (see Supporting Information File 1) [23][24][25], confirming the installation of the C-11 stereocenter of latrunculins. The next steps consisted in the functionalization of 12

CuAAC-inspired synthesis of 1,2,3-triazole-bridged porphyrin conjugates: an overview

• Dileep Kumar Singh

Beilstein J. Org. Chem. 2023, 19, 349–379, doi:10.3762/bjoc.19.29

• carbohydrate sequences suitable for tumor-binding-associated lectins on the porphyrin periphery. Continuing our work on the functionalization of porphyrin at the meso-position [32][33], we used the CuAAC click protocol to synthesize meso-phenyltriazole-linked porphyrin-coumarin dyads 44–48 in good to excellent

Synthesis and reactivity of azole-based iodazinium salts

• Thomas J. Kuczmera,
• Annalena Dietz,
• Andreas Boelke and
• Boris J. Nachtsheim

Beilstein J. Org. Chem. 2023, 19, 317–324, doi:10.3762/bjoc.19.27

• compounds based on azol-based iodazinium as reactive intermediates. Most interestingly, functionalization of the heteroarene salts was achieved without an undesired attack of the delicate C–I bond at the hypervalent iodine center. Experimental General procedure for the synthesis of azoiodazinium salts

• ; c) I: PhNH2, Cu(OAc)2·H2O, Na2CO3, iPrOH, 40 °C, 17 h, II: CuI, Cs2CO3, DMF, 120 °C, 40 h; d) TsNH2, (CH2OH)2, iPrOH, Na2CO3, 100 °C, 24 h, e) KX, H2O, EtOH, reflux; f) CuI, DMEDA, 1,4-dioxane, TBAI, rt, 24 h; g) MeOTf, DMF, 40 °C, 24 h. Post-functionalization of mono- and dicationic iodonium salts

Strategies to access the [5-8] bicyclic core encountered in the sesquiterpene, diterpene and sesterterpene series

• Cécile Alleman,
• Charlène Gadais,
• Laurent Legentil and
• François-Hugues Porée

Beilstein J. Org. Chem. 2023, 19, 245–281, doi:10.3762/bjoc.19.23

• iterative addition of geranyl (C10) or farnesyl (C15) building blocks derived from isoprene as starting unit and further structure rearrangement and functionalization [1]. This ubiquitous distribution highlights their pivotal role in living systems such as cell wall structural agent or ecological mediator

• following criteria: position/stage of the key cyclooctane ring formation in the synthesis plan, the selectivity, and the opportunity for late-stage functionalization. Review 1 Metathesis: ring-closing metathesis and related methods The metathesis reaction, first discovered by serendipity in the 1950s, has

• . Further functionalization steps finally furnished (+)-ophiobolin A (8). In the fusicoccanes family, cotylenol (50), the aglycon of cotylenin A (131) (see section 3.1), is a fungal metabolite which displays various interesting biological activities [28]. For example, it expresses a moderate cytotoxicity

Total synthesis of insect sex pheromones: recent improvements based on iron-mediated cross-coupling chemistry

• Eric Gayon,
• Guillaume Lefèvre,
• Olivier Guerret,
• Adrien Tintar and
• Pablo Chourreu

Beilstein J. Org. Chem. 2023, 19, 158–166, doi:10.3762/bjoc.19.15

• transmetallation step, and not in the coordination of the iron-containing intermediates [36][37]. The use of magnesium alkoxide salts, either as an ω-functionalization of the nucleophilic partner (Scheme 4) or as an external molecular additive such as EtOMgCl (Scheme 5), also likely proceeds similarly to the NMP

1,4-Dithianes: attractive C2-building blocks for the synthesis of complex molecular architectures

• Bram Ryckaert,
• Ellen Demeyere,
• Frederick Degroote,
• Hilde Janssens and
• Johan M. Winne

Beilstein J. Org. Chem. 2023, 19, 115–132, doi:10.3762/bjoc.19.12

• derivatives are relatively limited (see Scheme 4, top frame), but many of these heterocycles can be easily prepared from simple and widely available organic building blocks. The parent fully saturated 1,4-dithiane (1) is commercially available, but has limited synthetic application, as the functionalization

• Downstream chemistry and further applications: deprotection, cleavage or further functionalization of 1,4-dithianes In organic synthesis, the deprotection of 1,3-dithianes has a reputation of being a troublesome reaction. In the chemical literature, there are probably well over a hundred distinct procedures

• ][57]. Stereoselective 5,6-dihydro-1,4-dithiin-based synthesis of cis-olefins [42][58]. Addition to aldehydes and applications in stereoselective synthesis. Direct C–H functionalization methods for 1,4-dithianes [82][83]. Known cycloaddition reactivity modes of allyl cations [84][85][86][87][88][89][90

Practical synthesis of isocoumarins via Rh(III)-catalyzed C–H activation/annulation cascade

• Qian-Ci Gao,
• Yi-Fei Li,
• Jun Xuan and
• Xiao-Qiang Hu

Beilstein J. Org. Chem. 2023, 19, 100–106, doi:10.3762/bjoc.19.10

• . The success of gram-scale reaction and diverse functionalization of isocoumarins demonstrated the synthetic utility of this protocol. Keywords: C–H activation; enaminone; iodonium ylide; isocoumarin; rhodium catalysis; Introduction Isocoumarins are an important structural motif in many naturally

• easily available, which have been established as versatile synthetic building blocks for the synthesis of cyclic scaffolds [25]. In 2016, Zhu et al. reported the first example of a Rh-catalyzed C–H functionalization of enaminones with alkynes and α-diazo-β-ketoesters to access naphthalenes [26]. Very

• and diverse functionalization of the isocoumarin products highlight the tremendous synthetic potential of this methodology in chemical synthesis and drug discovery. Experimental A 10 mL screw-cap vial was charged with enaminone 1 (0.2 mmol), iodonium ylide 2 (0.6 mmol), [Cp*RhCl2]2 (6.2 mg, 5 mol

NaI/PPh₃-catalyzed visible-light-mediated decarboxylative radical cascade cyclization of N-arylacrylamides for the efficient synthesis of quaternary oxindoles

• Dan Liu,
• Yue Zhao and
• Frederic W. Patureau

Beilstein J. Org. Chem. 2023, 19, 57–65, doi:10.3762/bjoc.19.5

• future synthetic developments [61][62][63][64][65][66][67]. The NaI/PPh3 system has been further broadly applied to the functionalization of alkenes [68][69][70], as well as to decarboxylative C(sp3)–X bond formation [71], cyclization of 1,7-enynes [72][73] and other reactions [74][75][76][77]. Inspired

• -active ester derived from methionine could be converted effectively to α-aminoalkylation product 3al in overall 70% yield, which thus provides a mild method for the functionalization and derivation of abundant natural or unnatural amino acids. Some functional groups such as a terminal alkene in 3am, a

Modern flow chemistry – prospect and advantage

• Philipp Heretsch

Beilstein J. Org. Chem. 2023, 19, 33–35, doi:10.3762/bjoc.19.3

• diameter can both accelerate the transformations as well as lead to significantly less side products by continuously removing the products from the irradiation source. As an example, Noël and co-workers performed efficient irradiation in flow for the C(sp3)–H functionalization of gaseous hydrocarbons [8

Redox-active molecules as organocatalysts for selective oxidative transformations – an unperceived organocatalysis field

• Elena R. Lopat’eva,
• Igor B. Krylov,
• Dmitry A. Lapshin and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2022, 18, 1672–1695, doi:10.3762/bjoc.18.179

• aimed at overviewing the current state-of-art and perspectives of oxidative organocatalysis by redox-active molecules with the emphasis on challenging chemo-, regio- and stereoselective CH-functionalization processes. The catalytic systems based on N-oxyl radicals, amines, thiols, oxaziridines, ketone

• /peroxide, quinones, and iodine(I/III) compounds are the most developed catalyst types which are covered here. Keywords: CH-functionalization; free radicals; hypervalent iodine; N-oxyl radicals; redox-active molecules; Introduction Organocatalysis can be defined as catalysis by small organic molecules

• organic syntheses [5][6][7][8][9] and offer rich opportunities for the adaptation of organocatalysis. The diversity of such transformations spans from the functionalization of hydrocarbon raw materials to the fine organic synthesis, including functional group transformations, oxidative cyclizations, and