A review of recent advances in electrochemical and photoelectrochemical late-stage functionalization classified by anodic oxidation, cathodic reduction, and paired electrolysis

• Nian Li,
• Ruzal Sitdikov,
• Ajit Prabhakar Kale,
• Joost Steverlynck,
• Bo Li and
• Magnus Rueping

Beilstein J. Org. Chem. 2024, 20, 2500–2566, doi:10.3762/bjoc.20.214

• agrochemical and pharmaceutical chemistry. In 2019, Jiao and colleagues reported that 1,2-dichloroethane (DCE) could be used as a chlorination reagent for the production of (hetero)aryl chlorides and vinyl chlorides [21]. The reactions were carried out in an undivided cell containing a mixture of DCE in

• products were obtained in good yields (51–81%). The reaction involves the catalytic dehydrochlorination of DCE at the cathode, simultaneously with anodic oxidative aromatic chlorination using cathodically released HCl as the chloride source (Scheme 13). Additionally, the Lei group demonstrated a double

Multicomponent syntheses of pyrazoles via (3 + 2)-cyclocondensation and (3 + 2)-cycloaddition key steps

• Ignaz Betcke,
• Alissa C. Götzinger,
• Maryna M. Kornet and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2024, 20, 2024–2077, doi:10.3762/bjoc.20.178

• 130 through chlorination and Stephens–Castro coupling [148]. With 1,4-dioxane as a solvent, chlorination yields could be increased by activation of oxalyl chloride to give glyoxyl chlorides 133. The resulting ynediones 134 were cyclized in a consecutive three-component fashion with Boc-hydrazine to

• with electrophiles, such as deuteration or electrophilic chlorination using N-chlorosuccinimide, in this consecutive three-component synthesis to give persubstituted pyrazoles 165 (Scheme 55) [162]. (3 + 2)-Cycloaddition – C2 building blocks as substrates 1,3-Dipolar cycloadditions are important

Divergent role of PIDA and PIFA in the AlX₃ (X = Cl, Br) halogenation of 2-naphthol: a mechanistic study

• Kevin A. Juárez-Ornelas,
• Manuel Solís-Hernández,
• Pedro Navarro-Santos,
• J. Oscar C. Jiménez-Halla and
• César R. Solorio-Alvarado

Beilstein J. Org. Chem. 2024, 20, 1580–1589, doi:10.3762/bjoc.20.141

• Investigaciones Químico Biológicas, Universidad Michoacana de San Nicolás de Hidalgo, Avenida Francisco J. Múgica S/N 58030, Morelia, Michoacán, México 10.3762/bjoc.20.141 Abstract The reaction mechanism for the chlorination and bromination of 2-naphthol with PIDA or PIFA and AlX3 (X = Cl, Br), previously

• reported by our group, was elucidated via quantum chemical calculations using density functional theory. The chlorination mechanism using PIFA and AlCl3 demonstrated a better experimental and theoretical yield compared to using PIDA. Additionally, the lowest-energy chlorinating species was characterized by

• halogenation via PhIX2. Keywords: aromatic bromination; aromatic chlorination; density functional theory (DFT); hypervalent iodine; iodine(III); Introduction Hypervalent iodine(III) reagents have gained attention as strong oxidants with a low toxicity [1][2][3][4][5][6][7][8] and due to the ability to mimic

Benzylic C(sp³)–H fluorination

• Alexander P. Atkins,
• Alice C. Dean and
• Alastair J. J. Lennox

Beilstein J. Org. Chem. 2024, 20, 1527–1547, doi:10.3762/bjoc.20.137

• HAT reagent. Difluorination could be achieved using excess fluoride and HAT reagent. Other nucleophiles were amenable to the reaction conditions, allowing various benzylic functionalisation reactions, including acetoxylation and chlorination. In 2023, Hamashima and co-workers disclosed an analogous

Skeletal rearrangement of 6,8-dioxabicyclo[3.2.1]octan-4-ols promoted by thionyl chloride or Appel conditions

• Martyn Jevric,
• Julian Klepp,
• Johannes Puschnig,
• Oscar Lamb,
• Christopher J. Sumby and
• Ben W. Greatrex

Beilstein J. Org. Chem. 2024, 20, 823–829, doi:10.3762/bjoc.20.74

• ]octane ring-system via the chlorosulfite intermediate. Analogous allylic alcohols with endocyclic and exocyclic unsaturations underwent chlorination without rearrangement due to formation of allylic cations. The rearrangement was also demonstrated using Appel conditions, which gave similar results via

• Diels–Alder adducts of 1, and similar results on the effect of configuration were observed [21]. During some recent attempts at the chlorination of the π-stacking chiral auxiliary 10a using SOCl2 [9], we observed the migration of O8 resulting in the formation of anomeric chlorides analogous to the

• ]. The unsubstituted derivative 11b was difficult to isolate in good yields as multiple products were formed giving complex reaction mixtures. The product 11b was consistently contaminated with a second inseparable product tentatively assigned as 14, which is the expected product of chlorination without

Advancements in hydrochlorination of alkenes

• Daniel S. Müller

Beilstein J. Org. Chem. 2024, 20, 787–814, doi:10.3762/bjoc.20.72

• hydrochlorination. Silica gel-promoted hydrochlorination of alkenes with hydrochloric acid. Hydrochlorination with hydrochloric acid promoted by acetic acid or iron trichloride. Carreira’s first report on radical hydrochlorinations of alkenes. Radical “hydrogenation” of alkenes; competing chlorination reactions

Ligand effects, solvent cooperation, and large kinetic solvent deuterium isotope effects in gold(I)-catalyzed intramolecular alkene hydroamination

• Ruichen Lan,
• Brock Yager,
• Yoonsun Jee,
• Cynthia S. Day and
• Amanda C. Jones

Beilstein J. Org. Chem. 2024, 20, 479–496, doi:10.3762/bjoc.20.43

• -workers, it was found that in chlorination reactions, activation of alkenes is not driven by the electrophilicity of the reagent being attacked by an alkene, but instead depends on nucleophile assistance: the alkene becomes more nucleophilic upon interaction with the pendant attacking nucleophile [81]. In

Pseudallenes A and B, new sulfur-containing ovalicin sesquiterpenoid derivatives with antimicrobial activity from the deep-sea cold seep sediment-derived fungus Pseudallescheria boydii CS-793

• Zhen Ying,
• Xiao-Ming Li,
• Sui-Qun Yang,
• Hong-Lei Li,
• Xin Li,
• Bin-Gui Wang and
• Ling-Hong Meng

Beilstein J. Org. Chem. 2024, 20, 470–478, doi:10.3762/bjoc.20.42

• (pathway b), while nucleophilic attack at C-14 of intermediate IV by a chloride could generate compound 5 (pathway a). In addition, compound 5 might also be derived from intermediate IV by cleavage of the ester bond at C-2 to form the intermediate VI [15], followed by chlorination (pathway c). Compounds 1

Mechanisms for radical reactions initiating from N-hydroxyphthalimide esters

• Carlos R. Azpilcueta-Nicolas and
• Jean-Philip Lumb

Beilstein J. Org. Chem. 2024, 20, 346–378, doi:10.3762/bjoc.20.35

• , sodium phenolate and thiophenolate salts give rise to products 157 and 158, respectively, while the chlorination product 159 was obtained upon the addition of tetrabutylammonium chloride (Scheme 31C). Mechanisms under electrochemical activation The electrochemical activation of NHPI esters provides

Copper-promoted C5-selective bromination of 8-aminoquinoline amides with alkyl bromides

• Changdong Shao,
• Chen Ma,
• Li Li,
• Jingyi Liu,
• Yanan Shen,
• Chen Chen,
• Qionglin Yang,
• Tianyi Xu,
• Zhengsong Hu,
• Yuhe Kan and
• Tingting Zhang

Beilstein J. Org. Chem. 2024, 20, 155–161, doi:10.3762/bjoc.20.14

• , the synthesis of important C5-halogenated products gained particular attention since Stahl et al. reported the first chlorination example using LiCl as the halogen source [10]. Following this pioneering work, elegant strategies for the C5–H bromination of the quinoline ring employing simple inorganic

• chlorination and iodination reactions using ethyl chlorodifluoroacetate (6) and 1-iodobutane (8) as the respective halogenation reagents. However, these attempts ended in failure (Scheme 4, reactions 2 and 3). Furthermore, to demonstrate the synthetic usefulness of the protocol for industrial production, a

Quinoxaline derivatives as attractive electron-transporting materials

• Zeeshan Abid,
• Liaqat Ali,
• Sughra Gulzar,
• Faiza Wahad,
• Raja Shahid Ashraf and
• Christian B. Nielsen

Beilstein J. Org. Chem. 2023, 19, 1694–1712, doi:10.3762/bjoc.19.124

• chlorination effects on the Qx20 series, resulting in four new NFAs, i.e., Qx22–Qx25 (Figure 4). The research revealed the strategic balance between molecular crystallinity, packing, and optical properties. Qx24 and Qx25, with lower steric hindrance in the alkyl side chains, showed slightly decreased

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

• complex as a catalyst and a Brønsted base were applied in the procedure. It is interesting to note that in such a method, sulfenylation of NH-oxindoles resulted in the thiolated products with excellent enantioselectivities (up to 99% ee). In 2013, sulfenylation and chlorination of β-ketoesters 93, and 95

• . Sulfenylation and chlorination of β-ketoesters. Intramolecular sulfenoamination of olefins. Plausible mechanism for intramolecular sulfenoamination of olefins. α-Sulfenylation of 5H-oxazol-4-ones. Metal-free C–H sulfenylation of electron-rich arenes. TFA-promoted C–H sulfenylation indoles. Proposed mechanism

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

• proposed to follow one of two pathways: formation of a carbocation through RPC followed by nucleophilic attack or direct RLT from a redox-active metal complex. Preliminary evidence for a radical decarboxylation/RLT cascade was reported in 1965, when Kochi demonstrated decarboxylative chlorination of

• high yields from their respective acids, a result incompatible with a carbocation RPC mechanism. This Kochi decarboxylative chlorination separated itself from other pioneering methods of decarboxylative functionalization (i.e., Barton and Hunsdiecker) because of its inclusion of RLT as a key element of

• recent work on decarboxylative functionalization involving a posited RLT pathway. I: In 1965, Kochi reported thermal and photochemical decarboxylative chlorination using stoichiometric lead(IV) acetate. LMCT on the carboxylate substrate and RLT on a Pb–Cl bond are supported by mechanistic studies. II

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

• of this heterocycle is quite challenging due to the ease of the β-fragmentation pathway of lithiated derivatives (Scheme 2). Chlorination or oxygenation of the ring sulfur atom(s) in 1, followed by Pummerer-type rearrangement and elimination, affords a straightforward access to the more useful

Functionalization of imidazole N-oxide: a recent discovery in organic transformations

• Koustav Singha,
• Imran Habib and
• Mossaraf Hossain

Beilstein J. Org. Chem. 2022, 18, 1575–1588, doi:10.3762/bjoc.18.168

• chloride and bromide where bromination occurred at higher rate, N-tosylpyridinium halide was the acylating agent in both cases. In 2017, M. Hossain and co-workers suggested a quite unique one-pot deoxygenative chlorination reaction procedure of 2-unsubstituted imidazole N-oxides using oxalyl chloride as

• tosyl halogenides. Solvent-free chlorination reaction of imidazole N-oxides. Multicomponent reaction of imidazole N-oxides 28 with Meldrum’s acid (26) and aldehydes. Multicomponent reaction of imidazole N-oxides with CH-acids and aldehydes. Reaction conditions: aThe mixture of 2-unsbstituted imidazole 1

One-pot synthesis of 2-arylated and 2-alkylated benzoxazoles and benzimidazoles based on triphenylbismuth dichloride-promoted desulfurization of thioamides

• Arisu Koyanagi,
• Yuki Murata,
• Shiori Hayakawa,
• Mio Matsumura and
• Shuji Yasuike

Beilstein J. Org. Chem. 2022, 18, 1479–1487, doi:10.3762/bjoc.18.155

• benzimidoyl chloride from thioamides by desulfurization and chlorination, as well as its application to the synthesis of 2-substituted benzazoles. Keywords: benzazole; bismuth; cyclization; desulfurization; thioamide; Introduction In the production of pharmacologically active compounds, 2-substituted

• -aminophenol with benzimidoyl chloride, which is produced by the desulfurization and chlorination of thioamides promoted by Ph3BiCl2 without a base. The developed protocol is also applied to prepare 2-substituted benzimidazoles using N-tosyl-1,2-phenylenediamines as substrates. Results and Discussion We

• aerobic conditions, and requires no bases. In this system, Ph3BiCl2 acts as a superior reagent for the desulfurization and chlorination of thioamides into benzimidoyl chloride as a reaction intermediate. On the other hand, the reaction still has the disadvantage of requiring excess amounts of Ph3BiCl2 and

Scope of tetrazolo[1,5-a]quinoxalines in CuAAC reactions for the synthesis of triazoloquinoxalines, imidazoloquinoxalines, and rhenium complexes thereof

• Laura Holzhauer,
• Chloé Liagre,
• Olaf Fuhr,
• Nicole Jung and
• Stefan Bräse

Beilstein J. Org. Chem. 2022, 18, 1088–1099, doi:10.3762/bjoc.18.111

• ). Condensation to the corresponding quinoxalinone and subsequent chlorination was followed by introduction of the tetrazole moiety into the molecule via sodium azide to yield 11a–e. Alternatively, 4-chlorotetrazolo[1,5-a]quinoxaline (11f) was obtained after reaction of 2,3-dichloroquinoxaline (10f) with

Automated grindstone chemistry: a simple and facile way for PEG-assisted stoichiometry-controlled halogenation of phenols and anilines using N-halosuccinimides

• Dharmendra Das,
• Akhil A. Bhosle,
• Amrita Chatterjee and
• Mainak Banerjee

Beilstein J. Org. Chem. 2022, 18, 999–1008, doi:10.3762/bjoc.18.100

• of NBS and NIS, the chlorination by NCS was often found sluggish and complete conversion was not observed even after vigorous grinding for 30 min. Nonetheless, the addition of a catalytic amount of H2SO4 (10 mol %) was sufficient to activate NCS and the corresponding chloro derivatives were obtained

Synthetic strategies for the preparation of γ-phostams: 1,2-azaphospholidine 2-oxides and 1,2-azaphospholine 2-oxides

• Jiaxi Xu

Beilstein J. Org. Chem. 2022, 18, 889–915, doi:10.3762/bjoc.18.90

• with excess PCl5. However, the radical chlorination of 2-methylphenyl(methyl)phosphinic chloride (9) gave the desired 2-chloromethylphenyl(methyl)phosphinic chloride (10) in 65% yield with unreacted starting 9 in 25–30%, and the dichlorinated product 11 in 5–10%. The reaction of 2-chloromethylphenyl

Mechanochemical halogenation of unsymmetrically substituted azobenzenes

• Dajana Barišić,
• Mario Pajić,
• Ivan Halasz,
• Darko Babić and
• Manda Ćurić

Beilstein J. Org. Chem. 2022, 18, 680–687, doi:10.3762/bjoc.18.69

• dichlorinated regioisomers (L5Cl-I and L5Cl-II) (Scheme 1 and Table 1, entry 4). The chlorination of L3 substrate with a primary amine as substituent gave the monochlorinated product L3Cl-I in 46% yield, while the yields of L4Cl-I and L5Cl-I were 85% and 83%, respectively (Table 1, entries 2–4). Although both

• substrates L4 and L5 contain a tertiary amine as a substituent (NMe2), the chlorination of L5 proceeded much more slowly (Table 1, entries 3 and 4). Neither NCS nor NIS yielded halogenated products with substrate L2 (Table 1, entries 1 and 9). However, the reaction of L2 with NBS gave the monobrominated

High-speed C–H chlorination of ethylene carbonate using a new photoflow setup

• Takayoshi Kasakado,
• Takahide Fukuyama,
• Tomohiro Nakagawa,
• Shinji Taguchi and
• Ilhyong Ryu

Beilstein J. Org. Chem. 2022, 18, 152–158, doi:10.3762/bjoc.18.16

• Research & Development Group, Nankai Chemical Co. Ltd., 1-1-38 Kozaika, Wakayama 641-0007, Japan Department of Applied Chemistry, National Yang Ming Chiao Tung University (NYCU), Hsinchu 30010, Taiwan 10.3762/bjoc.18.16 Abstract We report the high-speed C–H chlorination of ethylene carbonate, which gives

• ethylene carbonate was introduced to the reactor, the residence time was measured to be 15 or 30 s, depending on the slope of the reactor set at 15 or 5°, respectively. Such short time of exposition sufficed the photo C–H chlorination. The partial irradiation of the flow channels also sufficed for the C–H

• chlorination, which is consistent with the requirement of photoirradiation for the purpose of radical initiation. Near-complete selectivity for single chlorination required the low conversion of ethylene carbonate such as 9%, which was controlled by limited introduction of chlorine gas. At a higher conversion

Efficient N-arylation of 4-chloroquinazolines en route to novel 4-anilinoquinazolines as potential anticancer agents

• Rodolfo H. V. Nishimura,
• Thiago dos Santos,
• Valter E. Murie,
• Luciana C. Furtado,
• Leticia V. Costa-Lotufo and
• Giuliano C. Clososki

Beilstein J. Org. Chem. 2021, 17, 2968–2975, doi:10.3762/bjoc.17.206

• that, the cyclocondensation [29] of the halogenated anthranilamides 6a,b with benzaldehyde followed by dehydrogenation promoted by iodine gave the corresponding quinazolin-4(3H)-ones 7a,b, which we used in the next step without purification. Finally, chlorination [31] of quinazolin-4(3H)-ones 7a,b by

• was prepared by chlorination of the corresponding quinazolinone (see Supporting Information File 1), in the N-arylation reaction. N-Arylation of 16 with N-methylaniline (9l) afforded N-methyl-N-phenylquinazolin-4-amine (18) in 81% yield (Scheme 5). Subsequently, the reaction of 17 with N

Synthetic strategies toward 1,3-oxathiolane nucleoside analogues

• Umesh P. Aher,
• Dhananjai Srivastava,
• Girij P. Singh and
• Jayashree B. S

Beilstein J. Org. Chem. 2021, 17, 2680–2715, doi:10.3762/bjoc.17.182

• chlorination at the α-position of the ester. The dichloro-substituted intermediate 3k was further cyclized to produce the oxathiolane 56a by reaction with water in the presence of acetonitrile as solvent. The focus of this novel route was to access basic reagents that are useful for the synthesis of 3TC (1

• -Hydroxyoxathiolane intermediate 56a was isolated in a DKR procedure by Whitehead and co-workers (Scheme 38) [55]. Further, 5-chlorooxathiolane 56 was isolated from chlorination reaction of 5-hydroxyoxathiolane 56a using thionyl chloride in presence of catalytic DMF and dichloromethane solvent. This further reacted

A novel methodology for the efficient synthesis of 3-monohalooxindoles by acidolysis of 3-phosphate-substituted oxindoles with haloid acids

• Li Liu,
• Yue Li,
• Tiao Huang,
• Dulin Kong and
• Mingshu Wu

Beilstein J. Org. Chem. 2021, 17, 2321–2328, doi:10.3762/bjoc.17.150

• Prathima group established an expedient approach for the direct oxidative chlorination of indole-3-carboxaldehyde to 3-monochlorooxindoles using a combination of NaCl and oxone as the chlorine source and oxidant in a CH3CN/H2O 1:1 system (Scheme 1, reaction 2) [22]. Nearly at the same time, Yu and co

Base-free enantioselective S_N2 alkylation of 2-oxindoles via bifunctional phase-transfer catalysis

• Mili Litvajova,
• Emiliano Sorrentino,
• Brendan Twamley and
• Stephen J. Connon

Beilstein J. Org. Chem. 2021, 17, 2287–2294, doi:10.3762/bjoc.17.146

• -alkylated with bromo ester 13. The formed product (i.e., 14) was first amidated and then cyclised using benzylamine 11 to generate spirooxindole 15 in 54% yield and 94% ee. Chlorination with NCS, followed by tert-butyl ester cleavage in TFA/CH2Cl2 provided the final bioactive compound 6 in 93% ee