Formaldehyde surrogates in multicomponent reactions

• Cecilia I. Attorresi,
• Javier A. Ramírez and
• Bernhard Westermann

Beilstein J. Org. Chem. 2025, 21, 564–595, doi:10.3762/bjoc.21.45

• nucleophilic species present in the reaction medium, MMS can act as a methylene source. Under hydrolysis conditions, it can be a source of formaldehyde (Scheme 5a), but with other nucleophiles, after nucleophilic addition, the sulfide group can work as a leaving group, allowing for a sequential domino process

• presence of an excellent leaving group (methyl sulfide) which permits further transformations during the domino sequences. This dual effect of MMS makes DMSO an interesting C1 synthon that works not only as a source of a methylene unit (-CH2-) in terms of formaldehyde surrogate, but also as a promotor of

Unprecedented visible light-initiated topochemical [2 + 2] cycloaddition in a functionalized bimane dye

• Metodej Dvoracek,
• Brendan Twamley,
• Mathias O. Senge and
• Mikhail A. Filatov

Beilstein J. Org. Chem. 2025, 21, 500–509, doi:10.3762/bjoc.21.37

• reacts with hydrazine hydrate and is heated to reflux, forming a pyrazolinone 2. This product is then chlorinated at the α-carbon, introducing a leaving group, to yield 3. The parent pyrazolinone 3 is subsequently treated with a base (either K2CO3 or N,N-diisopropylethylamine) to form the bimane 4. For

Electrochemical synthesis of cyclic biaryl λ³-bromanes from 2,2’-dibromobiphenyls

• Andrejs Savkins and
• Igors Sokolovs

Beilstein J. Org. Chem. 2025, 21, 451–457, doi:10.3762/bjoc.21.32

• required thermal decomposition of the diazonium salt to effect the cyclization. In the quest for mild (room temperature) and scalable conditions toward cyclic diaryl λ3-bromanes 1 we realized that bromanyl units possess leaving group abilities comparable to the diazonium moiety [1][15]. Hence, the

The effect of neighbouring group participation and possible long range remote group participation in O-glycosylation

• Rituparna Das and
• Balaram Mukhopadhyay

Beilstein J. Org. Chem. 2025, 21, 369–406, doi:10.3762/bjoc.21.27

• glycosylation. Conventional glycosylation involves the ‘nucleophilic substitution’ of the leaving group at the sp3 anomeric centre of the donor moiety with a suitable carbohydrate or non-carbohydrate-based aglycon with the help of an electrophilic promoter to form the equatorial glycoside 7 or the axial

• as the participating group facilitating the formation of a 1,2-trans glycoside (Scheme 2). In general, the cleavage of the activated anomeric leaving group of the glycosyl donor 9 leads to the formation of an electron-deficient oxocarbenium ion 10. The participating vicinal acyl group interacts with

• -2 position to obtain 1,2-trans glycosides showing orthogonal deprotection according to the need of the compound. They introduced (2-benzyloxyphenyl)acetyl (BnPAc, 43) as a versatile leaving group showing orthogonality to both acetyl and benzyl protecting groups [127]. This group, when placed in the

Emerging trends in the optimization of organic synthesis through high-throughput tools and machine learning

• Pablo Quijano Velasco,
• Kedar Hippalgaonkar and
• Balamurugan Ramalingam

Beilstein J. Org. Chem. 2025, 21, 10–38, doi:10.3762/bjoc.21.3

Synthesis of fluorinated acid-functionalized, electron-rich nickel porphyrins

• Mike Brockmann,
• Jonas Lobbel,
• Lara Unterriker and
• Rainer Herges

Beilstein J. Org. Chem. 2024, 20, 2954–2958, doi:10.3762/bjoc.20.248

• –CH2–(CF2)n–COOCH3) with triflate as leaving group in terminal position are easily accessible and versatile building blocks for attaching long chain acids (pKa 0–1) to substrates in Williamson ether-type reactions. Keywords: acid-functionalized porphyrin; electron-rich porphyrin; nickel porphyrin

Recent advances in transition-metal-free arylation reactions involving hypervalent iodine salts

• Ritu Mamgain,
• Kokila Sakthivel and
• Fateh V. Singh

Beilstein J. Org. Chem. 2024, 20, 2891–2920, doi:10.3762/bjoc.20.243

• capability to function as radical initiators. The use of diaryliodonium salts as efficient electrophilic arylating reagents in a wide range of organic transformations is due to their unique features such as solid-state nature, excellent stability, and the presence of a robust leaving group [39][40][41][42

• of the SO2CF3 leaving group from the intermediate. For the late-stage substitution of coumarins, Han and colleagues developed a method, using hypervalent iodine reagents. At 50 °C in the presence of a base, coumarin-based aryliodonium salts are produced. These salts undergo an intramolecular aryl

• from 6 on reacting with arynophiles 14 (Scheme 5) [59]. The reaction is unique due to its ability to functionalize position 3, despite its greater steric hindrance compared to position 5. The process involves deprotonation at the 3-position of the aryl(Mes)iodonium salts, followed by exit of a leaving

Selective hydrolysis of α-oxo ketene N,S-acetals in water: switchable aqueous synthesis of β-keto thioesters and β-keto amides

• Haifeng Yu,
• Wanting Zhang,
• Xuejing Cui,
• Zida Liu,
• Xifu Zhang and
• Xiaobo Zhao

Beilstein J. Org. Chem. 2024, 20, 2225–2233, doi:10.3762/bjoc.20.190

• both β-keto thioesters and β-keto amides [40][41]. Li and co-authors achieved the synthesis of β-keto thioesters by CF3SO3H-promoted hydrolysis of α-oxo ketene N,S-acetals with an amino leaving group (Scheme 1a, path 8) [40]. Subsequently, using NaOH-promoted hydrolysis of α-oxo ketene N,S-acetals, we

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

• . The α,β-unsaturated carbonyl compounds 60 can undergo cyclization with tosylhydrazine in situ to form pyrazoles 61 under alkaline conditions, with the tosyl group acting as a leaving group. Upon deprotonation at position 1 by a base, followed by nucleophilic substitution of halides, N-functionalized

• toluene [173]. N-Vinylimidazole, an alkene with a leaving group, was used to synthesize the 3-substituted pyrazoles 169 because, unlike acetylene, it is not gaseous and, therefore, easier to handle. Instead of vinylimidazole, vinyl azides 170 can also be used as alkyne surrogates. After the 1,3-dipolar

Novel oxidative routes to N-arylpyridoindazolium salts

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

Beilstein J. Org. Chem. 2024, 20, 1906–1913, doi:10.3762/bjoc.20.166

• involvement of the amines’ lone pair in the new 14-e aromatic system (Scheme 2). One of the possible functionalities of the new compounds may be the utility of the charged aromatic fragment as an efficient leaving group in the SN(Ar) reactions, similarly to dibenzothiophenium triflates that have been recently

The Groebke–Blackburn–Bienaymé reaction in its maturity: innovation and improvements since its 21st birthday (2019–2023)

• Cristina Martini,
• Muhammad Idham Darussalam Mardjan and
• Andrea Basso

Beilstein J. Org. Chem. 2024, 20, 1839–1879, doi:10.3762/bjoc.20.162

Tetrabutylammonium iodide-catalyzed oxidative α-azidation of β-ketocarbonyl compounds using sodium azide

• Christopher Mairhofer,
• David Naderer and
• Mario Waser

Beilstein J. Org. Chem. 2024, 20, 1510–1517, doi:10.3762/bjoc.20.135

• can be accessed by different approaches [6][7][8]. Maybe the most classical way to access organic azides is based on the utilization of pre-functionalized starting materials where a suited leaving group undergoes substitution using nucleophilic azide sources such as NaN3 or TMSN3 [6][7][15]. In

Synthesis of cyclic β-1,6-oligosaccharides from glucosamine monomers by electrochemical polyglycosylation

• Md Azadur Rahman,
• Hirofumi Endo,
• Takashi Yamamoto,
• Shoma Okushiba,
• Norihiko Sasaki and
• Toshiki Nokami

Beilstein J. Org. Chem. 2024, 20, 1421–1427, doi:10.3762/bjoc.20.124

• monomers 6 with a 2-deoxy-2-phthalimido (PhthN) group (Table 1). The influence of the anomeric leaving group was not investigated in this study. However, the p-ClC6H4S (ArS) group was used to avoid the exchange of the anomeric leaving group [16]. The monomer 6a (R3 = R4 = Bz) was completely consumed with a

Oxidative hydrolysis of aliphatic bromoalkenes: scope study and reactivity insights

• Amol P. Jadhav and
• Claude Y. Legault

Beilstein J. Org. Chem. 2024, 20, 1286–1291, doi:10.3762/bjoc.20.111

• the formation of the phenyl tosyloxy iodonium intermediate A from catalytic HTIB. Dialkyl bromoalkene 1 then associates with A followed by attack of tosyloxy or water, delivering iodonium intermediate B. Being a better leaving group, the bromide anion is then expelled, which becomes a counterion for

Domino reactions of chromones with activated carbonyl compounds

• Peter Langer

Beilstein J. Org. Chem. 2024, 20, 1256–1269, doi:10.3762/bjoc.20.108

• , because the electron-withdrawing character of the CF3 group which destabilizes the formation of a cation at the neighboring position. In addition, the carbon–sulfur bond was not cleaved, due to the lower leaving group ability of sulfur as compared to oxygen. The yields of the two products were moderate. 3

• chromone. During the optimization of the conditions, the best yields were in many cases obtained when chloride was employed as the leaving group. However, for some other products the yields were slightly better in case of employment of 3-bromochromone. Most of the yields were higher than 70%, in several

• hydrate which reduces significantly its electrophilicity. In case of 3-halochromones, the halide acts as a leaving group during the reaction. For 3-cyanochromones, a nucleophilic attack of chromone-derived hydroxy group to the nitrile was observed in most cases. However, a different reaction was observed

Light on the sustainable preparation of aryl-cored dibromides

• Fabrizio Roncaglia,
• Alberto Ughetti,
• Nicola Porcelli,
• Biagio Anderlini,
• Andrea Severini and
• Luca Rigamonti

Beilstein J. Org. Chem. 2024, 20, 1076–1087, doi:10.3762/bjoc.20.95

• ) greater electrophilicity of the halo compound due to better leaving group ability of the halide ion, (iii) reduced toxicity, presumably due to faster hydrolysis [18], and (iv) easier oxidation of the halide to molecular halogen (E0 = 1.087 V (SHE) for Br2/Br−; E0 = 1.358 V (SHE) for Cl2/Cl−) [19

Synthesis and properties of 6-alkynyl-5-aryluracils

• Ruben Manuel Figueira de Abreu,
• Till Brockmann,
• Alexander Villinger,
• Peter Ehlers and
• Peter Langer

Beilstein J. Org. Chem. 2024, 20, 898–911, doi:10.3762/bjoc.20.80

• , only the double-substituted product could be found. No reaction was observed when the reaction temperature was lowered to 0 °C. This could be due to the double activation of the 5-position, despite the fact that bromine is a better leaving group than chlorine. Both positions might be influenced by the

Three-component N-alkenylation of azoles with alkynes and iodine(III) electrophile: synthesis of multisubstituted N-vinylazoles

• Jun Kikuchi,
• Roi Nakajima and
• Naohiko Yoshikai

Beilstein J. Org. Chem. 2024, 20, 891–897, doi:10.3762/bjoc.20.79

• Suzuki–Miyaura and Sonogashira couplings on 4aa or 4ba afforded the desired products 5 and 6 in 47% and 74% yields, respectively. In the former case, the C–Br bond on the pyrazole moiety remained intact, highlighting the superior leaving group ability of the BX group. Cu-catalyzed Ullmann coupling

Chemoenzymatic synthesis of macrocyclic peptides and polyketides via thioesterase-catalyzed macrocyclization

• Senze Qiao,
• Zhongyu Cheng and
• Fuzhuo Li

Beilstein J. Org. Chem. 2024, 20, 721–733, doi:10.3762/bjoc.20.66

• the resin before the SPPS, as well as a leaving group in further enzymatic cyclization (17c). Utilizing this approach, the overall yield of surugamide B (82.8%) was greater than the SNAC-based peptides with the same sequence used in the previous study (30%, Scheme 5a). In addition to investigating the

• manner catalyzed by homolog WolJ [63] and SurE G235L (Scheme 5b). Additionally, the above mentioned type I TE, TycC TE, can also tolerate ethylene glycol as a leaving group and gave tyrocidine A (1) in 70% yield, indicating that this convenient bifunctional linker may have a comparable applied range to N

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

• pyridine. A stereocontrolled synthesis of 26.4 was reported by Hajdu and Bhatia in 1988. The sequence starts from 27.1 that was prepared from ʟ-glyceric acid (Figure 27) [118]. Then, the free alcohol was converted as an efficient leaving group by reaction with 4-nitrobenzenesulfonyl chloride in the

Metal catalyst-free N-allylation/alkylation of imidazole and benzimidazole with Morita–Baylis–Hillman (MBH) alcohols and acetates

• Olfa Mhasni,
• Jalloul Bouajila and
• Farhat Rezgui

Beilstein J. Org. Chem. 2023, 19, 1251–1258, doi:10.3762/bjoc.19.93

• precursors in nucleophilic allylic substitution reactions with amines, presumably due to the perceived poor leaving group ability and low reactivity of the hydroxy group. Interestingly, the direct nucleophilic substitution of the corresponding alcohols has drawn much attention because of the availability of

• derivatives in Et3N/THF mixtures [20] (Scheme 1, reaction 1, i) and acetates in THF/water [21] (Scheme 1, reaction 1, ii), or MBH alcohols in the presence of CDI (1,1’-carbonyldiimidazole) in acetonitrile (Scheme 1, reaction 1, iii) [22]. In the last case, as the hydroxy moiety is not a good leaving group

• 5a [27] as the model substrate bearing a good leaving group, with imidazole (2a, 2 equiv) as a powerful nucleophilic reagent. The reaction was achieved with no need of a catalyst or any additive in toluene at reflux affording within 24 h the SN2-type product 6a in 82% yield (Table 1, entry 1

Cyanothioacetamides as a synthetic platform for the synthesis of aminopyrazole derivatives

• Valeriy O. Filimonov,
• Alexandra I. Topchiy,
• Vladimir G. Ilkin,
• Tetyana V. Beryozkina and
• Vasiliy A. Bakulev

Beilstein J. Org. Chem. 2023, 19, 1191–1197, doi:10.3762/bjoc.19.87

• upon addition of hydrochloric acid. This is probably due to the protonation of the dimethylamino moiety or/and that dimethylamine hydrochloride is a better leaving group than the free base. The structures of compounds 6a–f were confirmed by 1H and 13C NMR spectroscopy and HRMS, as well as X-ray

New one-pot synthesis of 4-arylpyrazolo[3,4-b]pyridin-6-ones based on 5-aminopyrazoles and azlactones

• Vladislav Yu. Shuvalov,
• Ekaterina Yu. Vlasova,
• Tatyana Yu. Zheleznova and
• Alexander S. Fisyuk

Beilstein J. Org. Chem. 2023, 19, 1155–1160, doi:10.3762/bjoc.19.83

• (Table 1). For compound 3a, the possibility of benzamide elimination was studied. The benzamide fragment is a poor leaving group; however, in a superbasic medium, we were able to eliminate this group in compound 3a. In order to select optimal synthesis conditions, we heated compound 3a in DMSO at

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

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

• formation and a hydroxyl radical (•OH). However, it is possible to transform an alcohol into a leaving group, in the radical sense, by converting it into a halide or pseudohalide derivative [104][105]. For alcohol 8, all attempts to make a better leaving group, including phenyl sulfone derivative, to have