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

• N-oxide 119b was formed during benzylation of 2-ethylpyridine N-oxide. A possible mechanism has also been reported (Scheme 23b). Electrophilic palladation at the C2-position of pyridine N-oxide 9 provides intermediate 120. The radical intermediate 121 is generated in situ by H-atom abstraction from

• , facilitating the C–H arylation of pyridine. Dimethyl sulfate was used as a good N-methylating agent, which acts as transient activator. The group performed HRMS and KIE studies and proposed a catalytic cycle (Scheme 25b). The oxidative addition of ArBr 130 to the in situ-formed Pd(0) species gives species 132

Sulfate radical anion-induced benzylic oxidation of N-(arylsulfonyl)benzylamines to N-arylsulfonylimines

• Joydev K. Laha,
• Pankaj Gupta and
• Amitava Hazra

Beilstein J. Org. Chem. 2023, 19, 771–777, doi:10.3762/bjoc.19.57

• synthesis of synthetically useful N-arylsulfonylimines from N-(arylsulfonyl)benzylamines using K2S2O8 in the presence of pyridine as a base is reported herein. In addition, a “one-pot” tandem synthesis of pharmaceutically relevant N-heterocycles by the reaction of N-arylsulfonylimines, generated in situ

• approach, a gram-scale synthesis and a “one-pot” tandem synthesis of pharmaceutically relevant N-heterocycles by the reaction of in situ-generated N-arylsulfonylimines with various ortho-substituted anilines were also developed. The mechanism of the oxidation is believed to occur via hydrogen atom

• nucleophilic addition and as a result the corresponding cyclized product is not formed. The synthesis of these nitrogen heterocycles signifies the innate ability of in situ-generated N-arylsulfonylimines in a variety of reactions with various ortho-substituted anilines without the need for pre-isolation or

Palladium-catalyzed enantioselective three-component synthesis of α-arylglycine derivatives from glyoxylic acid, sulfonamides and aryltrifluoroborates

• Bastian Jakob,
• Nico Schneider,
• Luca Gengenbach and
• Georg Manolikakes

Beilstein J. Org. Chem. 2023, 19, 719–726, doi:10.3762/bjoc.19.52

• , e.g., the antiplatelet drug clopidogrel [7] or the β-lactam antibiotic amoxicillin [8] (Figure 1). Therefore, the chemical synthesis of α-aryglycines has received considerable attention. Among the different methods introduced over time, multicomponent reactions utilizing an in situ generated reactive

• electrophilic iminium carbon, leading to the amine product as racemic mixture. Consequently, examples for asymmetric Petasis borono-Mannich reactions are rare [13] and usually rely on the utilization of chiral amine components in stoichiometric amounts [10][11]. As part of our research program utilizing the in

• situ generation of reactive imine species, we have disclosed iron- and bismuth-catalyzed three-component reactions for the synthesis of α-arylglycines [14][15][16], in which the arylboronic acid could be replaced with an electron-rich (hetero)arene as nucleophile. In parallel, we have developed

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

• . through a multicomponent reaction system [57]. The authors provided a series of substituted derivatives through Pd/Rh-catalysed domino coupling. The reaction proceeded via a Suzuki coupling, followed by an in situ Buchwald–Hartwig amination. The authors reported moderate to good yields in a series with

• , whereafter Buchwald–Hartwig amination afford the various diarylazepines. A three-component one-pot process allowed for a second in situ Buchwald–Hartwig amination of the diarylazepine with aryl or benzyl halides to give the respective N-aryl and N-benzylazepine derivatives 83 and 84 (Scheme 16). 3.2 Mizoroki

• bromides and electron-withdrawing groups. The authors found that the addition of potassium iodide, and thus in situ palladium-catalysed halogen exchange, improved the yield of dibenzo[b,f]azepine 110. Unsymmetrical derivatives of 110 containing -CO2Me, -CF3, -NO2 and -CN substituents were synthesised in

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

• conversion into ZnBr2 (confirmed by HRMS). These in situ-generated free acetate ions function as a base, deprotonating carbocation III to produce the intermediate IV and AcOH. The first step of cycle-2 involves the oxidation of the excited photocatalyst by aerial oxygen to generate superoxide anion and PC

Nucleophile-induced ring contraction in pyrrolo[2,1-c][1,4]benzothiazines: access to pyrrolo[2,1-b][1,3]benzothiazoles

• Ekaterina A. Lystsova,
• Maksim V. Dmitriev,
• Andrey N. Maslivets and
• Ekaterina E. Khramtsova

Beilstein J. Org. Chem. 2023, 19, 646–657, doi:10.3762/bjoc.19.46

• to the plausible pathway shown in Scheme 6. As we expected, the nucleophile 2a attacked on the position C4 of the substrate 1a, which resulted in the cleavage of the S5–C4 bond and the formation of a thiol intermediate A (1-(2-thiophenyl)pyrrole derivative generated in situ as a precursor analog for

• the cleavage of the S–C bond of the 1,4-benzothiazine moiety under the action of the nucleophile to form in situ a 1-(2-thiophenyl)pyrrole derivative that undergoes an intramolecular cyclization to give the target pyrrolobenzothiazoles 3, 7, and 12. The developed approach works well with alkanols 2

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

• developed a copper/Rev-Josiphos-catalyzed asymmetric conjugate addition of Grignard reagents to 2-methylcyclopentenone (78), which provided 2,3-disubstituted cyclopentanones in high yields and enantiomeric purities [53]. The one-pot alkylation reaction of the in situ formed magnesium enolate with alkylating

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

• steps, and thus to consider the direct functionalization of furfural via the in-situ formation of furfurylimine. Furthermore, as the [Ru3(CO)11(PPh3)] comp4 catalyst showed an activity and a solubility in batch similar to comp1, we continued the optimization with the latter, triphenylphosphine being

• imine in situ. Furthermore, the optimized conditions with the pulsed-flow device proved to be effective, as an NMR yield of 62% of the C3-alkylated imine I2a was obtained by preheating at 130 °C for 5 min in reactor 1 (after introduction of mixture B), followed by heating at 180 °C for 45 min in reactor

• reaction conditions while providing products in shorter reaction times. In addition, the ability to couple multiple reactors with a flow apparatus could also enable us to perform these functionalizations directly from furfural by forming the imine in a first reactor. It should be noted that, in batch, 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

• initiates with the in situ reduction of Ni(II) to Ni(0) followed by the side-on coordination of the alkene and alkyne substrates to the metal center with subsequent oxidative cyclometallation to form a nickel metallacycle, similar to several reported Ni-catalyzed [2 + 2] cycloadditions [29][30]. Rather than

• arnottianum Maxim which possesses some antibiotic properties [34]. Mechanistically, the authors proposed the reaction begins with the in situ reduction of Ni(II) to Ni(0) by zinc to generate Ni(0) which undergoes oxidative addition with the organo iodide to yield Ni(II) intermediate 11. Coordination of 11 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

• ) (Scheme 1d). In some cases, this transmetallation step is carried out in situ [14][15][29][30][31][32]. Notably, these generally successful synthetic routes produce a considerable amount of transition metal waste (next to the inherent use of solvents) and are therefore in misalignment with the principles

• of green chemistry. Syntheses via mechanochemical methods offer elegant and atom-economic alternatives to liquid state synthesis approaches [33][34][35][36][37][38][39][40][41][42][43]. In accordance with the in situ transmetallation route in liquid state synthesis, a one-pot two-step procedure in a

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

• oxidation in presence of DMP. The assembly of aldehyde 8 and methyl ketone 15 was envisaged through a stereoselective aldol reaction. After unsuccessful attempts of Mukaiyama aldol reactions with silyl enol ethers [28], we found that dicyclohexylboron enolate 20, made in situ from ketone 15 and Cy2BCl in

Combretastatins D series and analogues: from isolation, synthetic challenges and biological activities

• Jorge de Lima Neto and
• Paulo Henrique Menezes

Beilstein J. Org. Chem. 2023, 19, 399–427, doi:10.3762/bjoc.19.31

• hydroxybenzaldehyde 80 into the corresponding acetal followed by Ullmann-type coupling with 52, led to the formation of diaryl ether 83. Subsequent Corey–Fuchs reaction [49] and in situ alkylation led to formation of the propargylic alcohol 85. Deprotection of the aldehyde followed by chain elongation through the

Group 13 exchange and transborylation in catalysis

• Dominic R. Willcox and
• Stephen P. Thomas

Beilstein J. Org. Chem. 2023, 19, 325–348, doi:10.3762/bjoc.19.28

• catalyse the hydroboration of alkynes with HBcat [50]. Hoshi later reported that Cy2BH [51] and in situ generated bis(pentafluorophenyl)borane, Piers’ borane [52], catalysed the hydroboration of alkynes with HBpin, to give alkenyl pinacol boronic esters. Tris(2,4,6-trifluorophenyl)borane [53], tris(3,4,5

• ‒H borylation, with an initial B‒Y/B‒H transborylation activating the precatalyst [62][63][64][65]. Zhang showed that benzoic acid decomposed HBpin to BH3 in situ to catalyse the C2‒H borylation of indoles (Scheme 4b) [66][67]. Gellrich reported the bis(pentafluorophenyl)borane-catalysed dimerisation

• transborylation in catalysis (Scheme 6) [69]. Reactive intermediates were characterised and BH3 was observed to be generated in situ by the decomposition of HBpin. The proposed catalytic cycle involved nucleophile-promoted decomposition of HBpin to various borohydride species 19, which reacted with the BH3

Recommendations for performing measurements of apparent equilibrium constants of enzyme-catalyzed reactions and for reporting the results of these measurements

• Robert N. Goldberg,
• Robert T. Giessmann,
• Peter J. Halling,
• Carsten Kettner and
• Hans V. Westerhoff

Beilstein J. Org. Chem. 2023, 19, 303–316, doi:10.3762/bjoc.19.26

• opposite directions of reaction. If the necessary substances are not readily available, it is necessary to prepare them in order to perform a rigorous measurement of the equilibrium constant. Labile or difficult to obtain substances may be prepared in situ [29]. For reactions that proceed without the need

• demonstrate the approach to equilibrium from different directions of reaction. Thus, as mentioned in section 3.9, some investigators have used very small quantities of a substrate that required substantial synthetic efforts [25] or have prepared the needed substrate in situ [27]. 3.14. Importance of careful

Continuous flow synthesis of 6-monoamino-6-monodeoxy-β-cyclodextrin

• János Máté Orosz,
• Dóra Ujj,
• Petr Kasal,
• Gábor Benkovics and
• Erika Bálint

Beilstein J. Org. Chem. 2023, 19, 294–302, doi:10.3762/bjoc.19.25

• , these two drawbacks are not a problem for large-scale flow synthesis when using an H-Cube system with an incorporated electrolytic cell producing H2 in situ from ultrapure water [47]. The Pd/C catalyst is placed in a stainless steel cartridge, so it is not necessary to separate it from the solution

• prepared in situ in the flow tube reactor, as the aqueous solution containing β-CD (1) and NaOH (1.5 equiv) was introduced into the reactor at twice the flow rate as the solution of TsCl in THF (Scheme 1). In this way, twice as many equivalents of TsCl were required compared to the general 1.3 equivalents

Sequential hydrozirconation/Pd-catalyzed cross coupling of acyl chlorides towards conjugated (2E,4E)-dienones

• Benedikt Kolb,
• Daniela Silva dos Santos,
• Sanja Krause,
• Anna Zens and
• Sabine Laschat

Beilstein J. Org. Chem. 2023, 19, 176–185, doi:10.3762/bjoc.19.17

• of 20 h at 50 °C led only to 8% yield (Table 2, entry 8). Trapping experiments of the in situ-formed (E)-alkenylzirconocene 24 revealed quantitative conversion of the starting material 25a and only traces of chain walking (less than 4%) (for details see Supporting Information File 1, chapter 2.1). To

• (dba) were catalytically inactive (Table 3, entries 6 and 7). Furthermore, in situ-formed Schwartz reagent was found to be less effective as compared to the use of isolated Cp2Zr(H)Cl and thus further experiments in this direction were abandoned. In order to explore the substrate scope of the

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

• , phosphate leaving groups, etc.) is still an unclear question, even if the latter species proved to have an unambiguous beneficial effect on the cross-coupling yields and selectivities. Several recent literature results which enlighten the role of those additives, either brought by external reagents or by in

• situ-formed intermediates, are gathered in Table 2. The beneficial role of the NMP co-solvent on the alkyl–alkenyl cross-coupling yield reported by Cahiez (Scheme 2b) and considerably used ever since was explained at a molecular level by Neidig in 2018. It was demonstrated that NMP did not act as a

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

• the relative stereochemistry (Scheme 17) [108][109]. 6 Synthetic equivalents of vinyl carbenes in (2 + 1) cycloadditions: Au(I)-catalyzed generation of 1,4-dithiane-fused vinylcarbene species In 2007, Wang and co-workers reported a gold-catalyzed Parham-type 1,2-sulfur migration to generate in situ a

Catalytic aza-Nazarov cyclization reactions to access α-methylene-γ-lactam heterocycles

• Bilge Banu Yagci,
• Selin Ezgi Donmez,
• Onur Şahin and
• Yunus Emre Türkmen

Beilstein J. Org. Chem. 2023, 19, 66–77, doi:10.3762/bjoc.19.6

• Research Center, Institute of Materials Science and Nanotechnology, Bilkent University, Ankara 06800, Turkey 10.3762/bjoc.19.6 Abstract We have developed a catalytic aza-Nazarov reaction of N-acyliminium salts generated in situ from the reaction of a variety of cyclic and acyclic imines with α,β

• acetal group could be used as substrates in an aza-Nazarov cyclization with the intermediacy of in situ-generated N-acyliminium ions (Scheme 1b) [21]. The first catalytic aza-Nazarov reaction was reported by Tius and co-workers in 2010, which involved the kinetic resolution of azirine derivatives via an

• cyclization of an in situ-formed iminium intermediate is not efficient under certain reaction conditions, then its hydrolysis with adventitious water, which might be present in the reaction medium, would lead to the formation of an aldehyde side product. Unfortunately, our attempts to isolate such a side

Total synthesis of grayanane natural products

• Nicolas Fay,
• Rémi Blieck,
• Cyrille Kouklovsky and
• Aurélien de la Torre

Beilstein J. Org. Chem. 2022, 18, 1707–1719, doi:10.3762/bjoc.18.181

• reagent and DMDO could induce an epoxidation on the strained olefin. From intermediate 40, the key reductive epoxide opening/Dowd–Beckwith rearrangement cascade could be performed in the presence of an in situ-generated Ti(III) catalyst. The main side-product of this reaction was due to a simple reductive

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

• instead of corresponding C-nucleophiles or C-electrophiles in redox-neutral organocatalyzed reactions. Organocatalysis by redox-active organic molecules N-Oxyl radical catalysis Reactive N-oxyl radicals generated in situ from the corresponding N-hydroxy compounds have found numerous applications in CH

• improved stability and tunable reactivity by structure modification. Amine-N-oxyl radical/oxoammonium cation catalysis Compared to the N-oxyl radical catalysis discussed above, where reactive N-oxyl radicals represent an active organocatalyst form generated in situ, in oxoammonium cation catalysis [74][76

• be selectively oxidized in the presence of secondary alcohols. In the case of co-catalysts Fe(NO3)3 or NOx species (NaNO2, HNO3, t-BuONO), an aminoxyl is oxidized in situ to an oxoammonium cation, which oxidizes alcohols. Fe and NOx-based methods demonstrate lower functional group compatibility and

Navigating and expanding the roadmap of natural product genome mining tools

• Friederike Biermann,
• Sebastian L. Wenski and
• Eric J. N. Helfrich

Beilstein J. Org. Chem. 2022, 18, 1656–1671, doi:10.3762/bjoc.18.178

• (non-targeted, e.g., modifying culturing conditions) and pathway-specific (e.g., heterologous expression or in situ pathway activation) approaches have been developed to awaken silent biosynthetic pathways [16]. Most importantly, however, genome mining can prevent the time-consuming re-discovery of

A new route for the synthesis of 1-deazaguanine and 1-deazahypoxanthine

• Raphael Bereiter,
• Marco Oberlechner and
• Ronald Micura

Beilstein J. Org. Chem. 2022, 18, 1617–1624, doi:10.3762/bjoc.18.172

• . Subsequent reduction with sodium dithionite then afforded triamine 9. Another way comprised the installation of a nitroso group in compound 6 through reaction with in situ-generated nitrous acid giving nitroso compound 8. The subsequent reduction to the corresponding amine with hydrogen sulfide afforded the

One-pot double annulations to confer diastereoselective spirooxindolepyrrolothiazoles

• Juan Lu,
• Bin Yao,
• Desheng Zhan,
• Zhuo Sun,
• Yun Ji and
• Xiaofeng Zhang

Beilstein J. Org. Chem. 2022, 18, 1607–1616, doi:10.3762/bjoc.18.171

• introduced in this study. Subsequently one equivalent of aldehyde and olefinic oxindole in situ were followed by decarboxylative 1,3-dipolar cycloaddition for diastereoselective synthesis of spirooxindolepyrrolothiazoles with generating 5 new bonds, 5 stereocenters and two heterocycles (Scheme 1C and Scheme

• purification from N,S-acetalation with 1.0:1.15 of 1a/2 at 25 °C for 6 h with EtOH as solvent, in situ followed by addition of 1.1:1.0 of 1a/4a for [3 + 2] cycloaddition at 90 °C for 9 h gave compound 5a with the 81% of LC yield. Next, the stepwise process was also carried out by using the thioproline 3a (1

Preparation of β-cyclodextrin-based dimers with selectively methylated rims and their use for solubilization of tetracene

• Konstantin Lebedinskiy,
• Volodymyr Lobaz and
• Jindřich Jindřich

Beilstein J. Org. Chem. 2022, 18, 1596–1606, doi:10.3762/bjoc.18.170

• propargyl-containing compounds, including other CDs, to form a dimer [12]. Usually, such reactions proceed with a Cu(I) catalyst [27]; however, Cu(I) can be generated in situ by the reduction of Cu(II) [12][28] or by the dissolution of metal copper [29]. Moreover, the load of the catalyst varies from