N-Sulfenylsuccinimide/phthalimide: an alternative sulfenylating reagent in organic transformations

• Fatemeh Doraghi,
• Seyedeh Pegah Aledavoud,
• Mehdi Ghanbarlou,
• Bagher Larijani and
• Mohammad Mahdavi

Beilstein J. Org. Chem. 2023, 19, 1471–1502, doi:10.3762/bjoc.19.106

• and acetic acid (AcOH) as a Brønsted acid, whereas i(a)midation was achieved by using Pd(OAc)2 as catalyst and Cu(OAc)2 as a Lewis acid. A possible mechanism for this chemodivergent C–H activation is depicted in Scheme 16. First, Pd catalyzed the formation of palladacycle I. Oxidative addition of AcOH

• acid organocatalysts were evaluated for sulfenylation on C3, or C2 position of N-heterocycles 115, including indoles, peptides, pyrrole, and 1-methyl-1H-pyrrolo[2,3-b]pyridine. The authors hypothesized a mechanism for the activation of N-sulfanylsuccinimides 1 or 14 by conjugate Lewis base Brønsted

• Lewis base organocatalysts (Scheme 56) [88]. In this procedure, the cyclized products were obtained via the activation of the sulfur electrophile by a Lewis base to generate the thiiranium ion intermediate from the β,γ-unsaturated sulfonyl carboxamide. The attack of the sulfonamide nitrogen atom on this

Cyclization of 1-aryl-4,4,4-trichlorobut-2-en-1-ones into 3-trichloromethylindan-1-ones in triflic acid

• Vladislav A. Sokolov,
• Andrei A. Golushko,
• Irina A. Boyarskaya and
• Aleksander V. Vasilyev

Beilstein J. Org. Chem. 2023, 19, 1460–1470, doi:10.3762/bjoc.19.105

• ; indanones; trichloromethyl group; triflic acid; Introduction Superelectrophilic activation of organic compounds under the action of strong Brønsted and Lewis acids is an effective method for the synthesis of various carbocycles and heterocycles, and polyfunctional compounds (see books [1][2] and reviews [3

• conjugated enones afford O,C-diprotonated forms under superelectrophilic activation conditions. These dications can participate in electrophilic aromatic substitution reactions with arenes ([11] and references therein). Recently, we have shown that the reaction of (E)-5,5,5-trichloropent-3-en-2-one [Cl3CCH

• ). The second protonation of the C=C bond is hampered due to a strong acceptor character of the substituents, contrary to other more donating enones. As a continuation of the research on the electrophilic activation of electron-poor alkenes bearing two electron-withdrawing substituents at the C=C bond

Application of N-heterocyclic carbene–Cu(I) complexes as catalysts in organic synthesis: a review

• Nosheen Beig,
• Varsha Goyal and
• Raj K. Bansal

Beilstein J. Org. Chem. 2023, 19, 1408–1442, doi:10.3762/bjoc.19.102

• activation to generate an aryl–Cu–NHC species. This is followed by the reaction with NHC–Pd to produce an Ar–Pd(NHC)Cl intermediate through the oxidative addition to Pd(0)NHC. Finally, transmetallation of [(It-Bu)Cu(Ar)] with [(SIPr)Pd(Ar)Cl] followed by reductive elimination leads to biaryl product. No

Consecutive four-component synthesis of trisubstituted 3-iodoindoles by an alkynylation–cyclization–iodination–alkylation sequence

• Nadia Ledermann,
• Alae-Eddine Moubsit and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2023, 19, 1379–1385, doi:10.3762/bjoc.19.99

• nitrogen protection or activation using KOt-Bu in DMSO as a base. Under these conditions, the formation of the terminal (aza)indole anion is the driving force (Scheme 1) [34]. As a consequence, the electrophilic trapping of this intermediate with alkyl halides provides as concise access to N-substituted

Synthesis of ether lipids: natural compounds and analogues

• Marco Antônio G. B. Gomes,
• Alicia Bauduin,
• Chloé Le Roux,
• Romain Fouinneteau,
• Wilfried Berthe,
• Mathieu Berchel,
• Hélène Couthon and
• Paul-Alain Jaffrès

Beilstein J. Org. Chem. 2023, 19, 1299–1369, doi:10.3762/bjoc.19.96

• cesium cation with the halogen atom and the activation of the Sn–O bond of the stannylene acetal via a pentacoordinated intermediate with the fluoride anion [110]. The acetylation of the secondary alcohol and the deprotection of the primary alcohol with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ

Non-noble metal-catalyzed cross-dehydrogenation coupling (CDC) involving ether α-C(sp³)–H to construct C–C bonds

• Hui Yu and
• Feng Xu

Beilstein J. Org. Chem. 2023, 19, 1259–1288, doi:10.3762/bjoc.19.94

• overcome the shortcomings of the above coupling reactions, organic chemists have envisaged the construction of C–C bonds directly through C–H bond activation [5]. Fortunately, scientists have used various transition metals as catalysts to realize the activation of various types of C–H bonds, and have

• involved in the activation of DDQ by coordinating the carbonyl oxygen atom which leads to an increase in the oxidation activity of DDQ. Subsequently, Li et al. improved the above method, using a mixture of indium and copper salts as a catalyst, NHPI (N-hydroxyphthalimide) as a co-catalyst to achieve the

• . Due to the challenges associated with the activation of C(sp3)–H bonds, this kind of activation strategy has received extensive attention. Huang et al. developed a Cu-catalyzed CDC of unactivated C(sp3)–H ethers with simple ketones under the synergistic effect of CuBr2 and pyrrolidine. By this route

Acetaldehyde in the Enders triple cascade reaction via acetaldehyde dimethyl acetal

• Alessandro Brusa,
• Debora Iapadre,
• Maria Edith Casacchia,
• Alessio Carioscia,
• Giuliana Giorgianni,
• Giandomenico Magagnano,
• Fabio Pesciaioli and
• Armando Carlone

Beilstein J. Org. Chem. 2023, 19, 1243–1250, doi:10.3762/bjoc.19.92

• self-aldol condensations, polymerization and Tishchenko-type processes) and stereoselectivity [20]; the activation of acetaldehyde via aminocatalysis, furthermore, suffers from a lack of proper steric hindrance for the enantio-discrimination process. However, some methodologies enabling the use of

Radical ligand transfer: a general strategy for radical functionalization

• David T. Nemoto Jr,
• Kang-Jie Bian,
• Shih-Chieh Kao and
• Julian G. West

Beilstein J. Org. Chem. 2023, 19, 1225–1233, doi:10.3762/bjoc.19.90

• addition to alkenes and radical decarboxylation, with many of these being driven by light energy. RLT in alkene functionalization Outside of the realm of C–H activation, RLT has been leveraged to afford complex medicinal scaffolds in alkene difunctionalization. A recent example can be found in the merger

Exploring the role of halogen bonding in iodonium ylides: insights into unexpected reactivity and reaction control

• Carlee A. Montgomery and
• Graham K. Murphy

Beilstein J. Org. Chem. 2023, 19, 1171–1190, doi:10.3762/bjoc.19.86

• ). Control experiments showed that the reaction failed in the dark at room temperature, and they concluded that blue light activation of the initially-formed EDA complex (analogous to 36) promoted the onset of SET events. As this latter protocol also required two equivalents of ylide 39, the authors proposed

• ]. Computational investigations were conducted to better understand these reactions, and it was determined that the changing alkyl motif (e.g., dimethyl, cyclopentyl, adamantyl) had minimal impact on the activation energy of the fluorination reactions. The reaction coordinate was calculated for Meldrum’s acid

• hard fluoride interacts with the stronger σ-hole. Structural modification of the β-dicarbonyl auxiliary has led to improved outcomes, due to increased ylide stability rather than decreasing activation energies of the fluorination reaction. There are, however, other conflicting pieces of evidence that

Photoredox catalysis harvesting multiple photon or electrochemical energies

• Mattia Lepori,
• Simon Schmid and
• Joshua P. Barham

Beilstein J. Org. Chem. 2023, 19, 1055–1145, doi:10.3762/bjoc.19.81

• generation of reactive intermediates for both oxidative and reductive processes via photon activation of a catalyst. Although this represents a significant step towards chemoselective and, more generally, sustainable chemistry, its efficacy is limited by the energy of visible light photons. Nowadays

• remain inert to direct photoredox activation powered by visible light [12]. Irradiation with UV photons that intrinsically possess higher energy, however, is generally unfavorable due to the high expense and thermal footprint of the reactors. Although most organic molecules directly absorb photons in the

• photoredox catalysts and ii) energy that parallels the energy of UV-driven transformations, but under cheaper, safer conditions and in a more selective manner by indirect substrate activation via a catalyst. These are: a) multi-photon processes that accumulate visible light photon energies for electron

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

• activation of the reaction components through H-bonding engagement with free hydroxy groups of the catalysts also favoring stereoselective addition (see structure 28 in Scheme 8a) [32]. Two years later, the same research group utilized the C1-symmetric catalyst P10 for the functionalization of the C3–H bond

• developed an aza-Friedel–Crafts reaction involving β-naphthols 119 as π-nucleophiles and benzothiazolimines 118 as electrophiles. Chiral squaramide S1-assisted this process affording enantioenriched 1-((benzothiazol-2-ylamino)methyl)naphthalen-2-ols 120 with high chemical yields. The activation of the

• ) [59]. Other catalysts In 2019, Vila, Pedro and co-workers reported a functional group-directed activation of the carbocyclic ring of indoles utilizing cyclic imines as electrophiles. The quinine-derived compound O1 was the catalytic reagent to functionalize the ortho-C–H bond of 4-, 5-, and 6

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

• ][64][65][66][67], we became fascinated in exploring whether photoredox catalysis could be applied for the activation of such unnatural amino acids to expedite the development of completely new synthetic pathways. In particular, 4-dimethylallyltryptophan (DMAT) is of interest for the following reasons

• cyclization event would be triggered using their innate functionality, namely the α-amino carboxylate, through photoredox-mediated oxidative activation and CO2 extrusion, without the need for acid prefunctionalization to the redox-activated ester. Consequently, a technique involving direct generation of α

Synthesis of aliphatic nitriles from cyclobutanone oxime mediated by sulfuryl fluoride (SO₂F₂)

• Xian-Lin Chen and
• Hua-Li Qin

Beilstein J. Org. Chem. 2023, 19, 901–908, doi:10.3762/bjoc.19.68

• the construction of a range of δ-olefin-containing aliphatic nitriles with (E)-configuration selectivity. This new method features wide substrate scope, mild conditions, and direct N–O activation. Keywords: direct N–O activation; E-selectivity; nitrile synthesis; ring-opening cross-coupling; sulfuryl

• ) carbon, which leads to side reactions of the alkyl intermediates [14][19][20]. Besides, most of the C(sp2)–C(sp3) reactions employ organic halides or organometallic reagents [21][22][23], which are not environmentally friendly. Recently, based on the activation effect of O-acyloximes on N–O bonds [24][25

• esters and adopted the pre-acylation activation strategies [39][40][41]. Up to now, only one report employed an oxime for the generation of iminyl radicals to obtain the similar products, in which, substrates were limited to the electron-rich alkenes (Scheme 2b) [42]. On the other hand, sulfuryl fluoride

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

• , diversely functionalized pyridines have been synthesized via C–H activation under transition-metal and rare earth metal catalysis, including C–H alkylation, alkenylation, arylation, heteroarylation, borylation, etc. Recently, metal-free approaches have also been developed for the C–H functionalization of N

• also found to have a higher catalytic activity for the ortho-alkylation of pyridines with styrenes to give the linear alkylated products (5b,c, Scheme 2). Further, the authors proposed that the C–H bond activation could be the rate limiting step based on kinetic isotope experiments (KIE). The proposed

• mechanism involves the coordination of pyridine to the metal center of the cationic catalyst and B(C6F5)3 promotes the ortho-C–H activation (deprotonation) of pyridine to afford pyridyl species 6. Next, the 2,1-migratory insertion of alkene 2 into the metal–pyridyl bond in 6 gives the intermediate 7, which

Eschenmoser coupling reactions starting from primary thioamides. When do they work and when not?

• Lukáš Marek,
• Jiří Váňa,
• Jan Svoboda and
• Jiří Hanusek

Beilstein J. Org. Chem. 2023, 19, 808–819, doi:10.3762/bjoc.19.61

• ) with activation free energies 47 and 59 kJ·mol−1 than from 4-bromo-1,1-dimethyl-1,4-dihydroisoquinolin-3(2H)-one (2b) and N-phenyl-2-bromo(phenyl)acetamide (4a) with activation free energies 78 and 88 kJ·mol−1. These trends fully correspond to a combination of electronic effects (bridging C=O has an

• the ring strain involved in the enthalpy term disfavors it) shows the opposite trend. This means that the activation free energies are decreasing from 47 to 23 kJ·mol−1, respectively. Spontaneous co-catenation (or thiophile-assisted when a P(III) compound is added) extrusion of sulfur from thiirane

• of these isomeric salts have the highest contributions to the overall barrier for Hantzsch reaction pathways because their cyclization through TS4 is very fast (activation free energies 5–15 kJ·mol−1). The overall (relative) energy barriers now decrease in the order 6a > 10a > 15 > 12a, which is

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

• Gibbs activation energy of enantiomer 53 for the racemization process was determined as 33.0 kcal mol−1 at 298 K. The CPL spectra of M-53 and P-53 showed an emission maximum at 560 nm with glum value of 2.3 × 10−4. Instead of helicene formation in the final Scholl-type ring formation step, Martín and co

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

• 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

• activation and functionalization of sp2 and sp3 C–H bonds via relay catalysis (Scheme 4). The relay can be divided into two cycles; the first cycle (cycle-1) deals with the C(sp2)–H functionalization at the C-3 position of the imidazo heterocycles, while the second cycle (cycle-2) is all about the C(sp3)–H

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

• activation of the Michael acceptor and the formation of intermediate organocuprates from stoichiometric organometallic reagents [18]. Metal enolates formed in this way can react in many transformations (Scheme 1) [19][20]. It has been documented that metal enolates from conjugate additions engaged in aldol

• . Entrapping of the Zn enolate directly with acetyl chloride was found inefficient and led to a mixture of C-, O-, and diacylated products as described by Murphy and co-workers [37]. Encouraged by the work of Noyori on the activation of Li enolates using Me2Zn [38], they have tried to facilitate the enolate

• diastereomers were detected (Scheme 9A). Furthermore, the authors have also demonstrated a four-component coupling reaction: by simply increasing the amount of the organolithium reagent (2.05 equiv) used for the activation of the Zn enolate, β-hydroxyketones 40 were gained via 1,2-addition of the zincate

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

• 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

• furfural derivatives have been developed. In particular, their direct functionalization by transition-metal-catalyzed C–H activation processes [16][17][18] has become a major area of interest where only a few methods have been reported so far. Most examples concern functionalization at C5, which is the

• furfural derivatives by C–H activation, a) in batch: previous works, and b) in continuous flow: this work. C3-alkylation of bidentate imine 1 performed in batch. Optimization of the heating for the alkylation reaction on the homemade pulsed-flow setup. Proposed reaction mechanism for the alkylation

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

• 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

Access to cyclopropanes with geminal trifluoromethyl and difluoromethylphosphonate groups

• Ita Hajdin,
• Romana Pajkert,
• Mira Keßler,
• Jianlin Han,
• Haibo Mei and
• Gerd-Volker Röschenthaler

Beilstein J. Org. Chem. 2023, 19, 541–549, doi:10.3762/bjoc.19.39

• adds to the diazo compound 5 under formation of zwitterionic Int1 (ΔG = 5.2 kcal/mol). Afterwards, copper carbene complex Int2 is formed after extrusion of nitrogen. The transition state of this metal carbene formation TS1 was calculated with an activation free energy of 16.4 kcal/mol (Scheme 5). Int2

• adds to styrene to the carbon atom in 2-position of the ethenyl group. At this point, four different orientations of the phenyl group are conceivable (Scheme 6 and Scheme 7, TS2_1 to TS2_4). After an early transition state with hardly any activation barrier, the addition of styrene to Int2 proceeds in

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

• norbornene derivatives 15 using imides 27 and tetraarylborates 28 (Scheme 5) [37]. The method utilizes C–N bond activation to trigger the reaction. The authors demonstrated a broad reaction scope. Electron-deficient amides were shown to perform worse than their electron-rich counterparts with the p

• proceeds similarly to Nakamura’s Fe-catalyzed methodology (Scheme 13) [48]. In 2017, the Cheng laboratory investigated the Co-catalyzed ring-opening/dehydration of oxabicyclic alkenes via the C–H activation of arenes (Scheme 15) [50]. First, the group explored the ortho-naphthylation of N-pyrimidinylindole

• 5.0 equivalents of Cs2CO3 provided the naphthalene core via sequential dehydration. Based on preliminary mechanistic experiments, the authors proposed the reaction begins with the oxidation of Co(II) to Co(III) by O2. MHP-directed C–H activation of the ortho-C–H position generates 90 which can

Computational studies of Brønsted acid-catalyzed transannular cycloadditions of cycloalkenone hydrazones

• Manuel Pedrón,
• Jana Sendra,
• Irene Ginés,
• Tomás Tejero,
• Jose L. Vicario and
• Pedro Merino

Beilstein J. Org. Chem. 2023, 19, 477–486, doi:10.3762/bjoc.19.37

• (3+ + 2) reaction in which distortion effects are crucial for achieving the required ion-pair geometry in the transition state. Following this precedent, we proceeded to calculate the energy barriers and the corresponding activation parameters for all the reactions illustrated in Scheme 1 (series a–k

• yields. Similarly, data of Table 1 predict that the reaction of 1g and 1h leading to 5-5 and 5-6 systems (not tested experimentally, yet), respectively could also be observed experimentally. On the other hand, the higher activation barrier of compounds 1c, 1d, and 1k makes the cyclization way more energy

• model [30] the distortion energy (ΔE≠d) corresponds to the difference between the single point corresponding to interacting 3 and 4, and the sum of single-point calculations for TS2-a and TS2b. The apparent activation energy (ΔE≠app) refers to the energy difference between TS2 and the interacting

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

• 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

• retrosynthetic disconnections. In this context, a strong interest from the scientific community was shown towards the challenging synthesis of fluorinated molecules by transition-metal-catalyzed C–H bond activation [44][45][46][47][48][49][50], allowing the functionalization of complex molecules and even for

• (e.g., SCF3, SeCF3, SCF2CO2Et, OCH2CF3) by transition-metal-catalyzed C–H bond activation (Scheme 1). The review will be organized in two main parts, dedicated to the construction of a C–SCF2R/SeCF3 and C–OCH2CF3 bond. This review does not aim to be exhaustive and key examples were carefully chosen to

Mechanochemical solid state synthesis of copper(I)/NHC complexes with K₃PO₄

• Ina Remy-Speckmann,
• Birte M. Zimmermann,
• Mahadeb Gorai,
• Martin Lerch and
• Johannes F. Teichert

Beilstein J. Org. Chem. 2023, 19, 440–447, doi:10.3762/bjoc.19.34

• an ester reduction with H2 as terminal reducing agent utilizing bifunctional copper(I)/NHC complex 5 bearing a guanidine moiety as additional catalytic unit [48]. This catalyst acts by employing the copper(I)/NHC complex for H2 activation on the one hand and by using the guanidine subunit for

• simultaneous organocatalytic activation of the ester on the other hand. Following a previously established synthetic pathway [49], we have found that transmetallation via silver(I)/NHC complex 4 was the only viable synthetic entry point to this sophisticated bifunctional catalyst (Scheme 2) [10][12][14][50