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

• scaffolds. During the reaction, the arylcyclopropane is oxidized at the anode to form a radical cation, causing the weakening of the Cα–Cβ bond. The radical cation then undergoes a three-electron SN2 reaction to generate a benzylic radical, which loses an electron at the anode to form a benzylic carbocation

Hypervalent iodine-mediated cyclization of bishomoallylamides to prolinols

• Smaher E. Butt,
• Konrad Kepski,
• Jean-Marc Sotiropoulos and
• Wesley J. Moran

Beilstein J. Org. Chem. 2024, 20, 2455–2460, doi:10.3762/bjoc.20.209

• , the iodane moiety in 12 is eliminated by an intramolecular attack by the amide nitrogen to form the aziridinium 13. Finally, ring-opening by SN2 attack of trifluoroacetate leads to the final product 14 [20]. In this case, the kinetic pyrrolidine product is obtained due to the electron-withdrawing

Facile preparation of fluorine-containing 2,3-epoxypropanoates and their epoxy ring-opening reactions with various nucleophiles

• Yutaro Miyashita,
• Sae Someya,
• Tomoko Kawasaki-Takasuka,
• Tomohiro Agou and
• Takashi Yamazaki

Beilstein J. Org. Chem. 2024, 20, 2421–2433, doi:10.3762/bjoc.20.206

• -to-handle reagent, NaOCl·5H2O. Because very little has been disclosed about the reactivity of such 2,3-epoxyesters, their epoxy ring opening by a variety of nucleophiles was carried out and we succeeded in clarifying these chemo- as well as regioselective processes proceeding via the SN2 mechanism to

• is the high regio- and stereoselectivities of its epoxy ring opening specifically occurring at the 2 position in an SN2 manner, when it is treated with appropriate nucleophiles (Nu), leading to the formation of the 2-substituted 3-hydroxyesters with 2,3-anti stereochemistry. These characteristic

• outcomes would stem from a result of the electronically repulsive interaction between the incoming nucleophiles and an electronically strongly negative CF3 group, and the anticipated clean SN2 mechanism of epoxides in general, respectively. This is interestingly compared with the case of 2a with

Asymmetric organocatalytic synthesis of chiral homoallylic amines

• Nikolay S. Kondratyev and
• Andrei V. Malkov

Beilstein J. Org. Chem. 2024, 20, 2349–2377, doi:10.3762/bjoc.20.201

• concerted SN2 mechanism or SN1 mechanism with the allyl nucleophile addition step as rate-determining. Interestingly, the authors observed a 0.55 order in the catalyst, which indicates that a substantial part of the catalyst forms a hydrogen-bonded dimer with Kdiss ≈ 1000 M−1 when not in the catalytic cycle

• , an observation that is in good agreement with previously obtained data on bisurea catalysts [36]. To further distinguish between the SN1 and SN2 mechanisms, the authors performed an in silico simulation of the non-catalysed reaction to determine the possible potential energy surface and found that

• concerted SN2-key intermediate 60 must be at least 18.9 kcal/mol more favoured than a separated imine–chloride ion pair 61 attacked by the free allylsilane (Figure 3). Altogether, the developed methodology can be formally viewed as a useful tool for the enantioselective synthesis of chiral α-carboxyl-2,3

Methyltransferases from RiPP pathways: shaping the landscape of natural product chemistry

• Maria-Paula Schröder,
• Isabel P.-M. Pfeiffer and
• Silja Mordhorst

Beilstein J. Org. Chem. 2024, 20, 1652–1670, doi:10.3762/bjoc.20.147

• (Mg2+-dependent, metal-independent, cobalamin-dependent), common structural folds (class I–V, with class I being the largest group, characterised by the Rossmann fold) [58], or catalytic mechanism (SN2 mechanism, radical mechanism, Figure 3) [59]. This review categorises RiPP MTs based on the acceptor

• broad range of reactions [60]. There are different rSAM MT classes, description of the classes follows below in the C-MT section. Unlike conventional MTs, which follow an SN2 mechanism, rSAM MTs can methylate non-activated carbons. O-Methyltransferases The predominant group of MTs are O-MTs, which

• binding domain (CBD) at the N-terminus and an rSAM domain at the C-terminus (Figure 9) [119]. In addition to its different enzyme structure, a distinct mechanism of methylation than the classical SN2 mechanism is employed. Reductive cleavage of SAM generates a 5'-deoxyadenosyl (dAdo) radical, which

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

• reference. At this stage, the PIDA–AlBr3 adduct undergoes ionization, giving rise to the corresponding ion pair I-1–Br (ΔG = −31.3 kcal/mol) in a highly exergonic and energetically favorable process. Next, an intramolecular SN2 reaction of the formed aluminum anion transfers a bromine atom to the

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

• bond formation to afford the acyloxylation product was observed, and favoured when using directing groups with less steric bulk. This product had the opposite stereochemistry to the fluorination product suggesting it occurred via a competitive SN2 pathway. This is supported by the selectivity for C–O

• bond formation for substrates bearing primary benzylic positions, attributed to the faster rate of SN2 at the less hindered carbon. The scope was limited to substrates bearing secondary benzylic sites, with various functional groups tolerated. However, substrates bearing electron-donating substituents

Photoswitchable glycoligands targeting Pseudomonas aeruginosa LecA

• Yu Fan,
• Ahmed El Rhaz,
• Stéphane Maisonneuve,
• Emilie Gillon,
• Maha Fatthalla,
• Franck Le Bideau,
• Guillaume Laurent,
• Samir Messaoudi,
• Anne Imberty and
• Juan Xie

Beilstein J. Org. Chem. 2024, 20, 1486–1496, doi:10.3762/bjoc.20.132

• formation of the 1,2-anhydro sugar through intramolecular attack of the 2-hydroxy group of the DMC-activated β-intermediate, followed by dihydroxyazobenzene attacking the anomeric center in an SN2 manner, or by direct nucleophilic SN2 attack on the DMC-activated α-intermediate, to produce the corresponding

Synthetic applications of the Cannizzaro reaction

• Bhaskar Chatterjee,
• Dhananjoy Mondal and
• Smritilekha Bera

Beilstein J. Org. Chem. 2024, 20, 1376–1395, doi:10.3762/bjoc.20.120

• exchange and transmetalation to the organocuprate 83. The latter undergoes an SN2’ addition to the propargyl chloride 84 and the resulting allene intermediate 85 undergoes an intramolecular Cannizzaro-type hydride transfer via 86 to produce the 8-membered cyclized target 87 in good yield (70%) (Scheme 24

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

• (Scheme 3). No α-tosyloxy ketone products were observed in the crude reaction mixtures, either with catalytic or stoichiometric use of TsOH·H2O, even when the reactions were incomplete. These observations ruled out the possibility of double SN2 attack by tosylate followed by bromide. TsOH·H2O accelerates

• the iodonium intermediate C. Liberation of PhI serves as the driving force for subsequent SN2 attack by the bromide anion to give the dialkyl α-bromoketone 2. m-CPBA then regenerates the hypervalent iodine (HTIB) catalyst by oxidizing PhI in the presence of TsOH·H2O. The formation of the Ritter-type

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

• desired reactivity. Substitution of a hydrogen atom with a halogen atom within an organic skeleton significantly increases the electrophilicity of the linked carbon centre, enhancing concerted (SN2) as well as carbenium ion-mediated (SN1) substitutions, common – for instance – on benzylic positions

Comparison of glycosyl donors: a supramer approach

• Anna V. Orlova,
• Nelly N. Malysheva,
• Maria V. Panova,
• Nikita M. Podvalnyy,
• Michael G. Medvedev and
• Leonid O. Kononov

Beilstein J. Org. Chem. 2024, 20, 181–192, doi:10.3762/bjoc.20.18

• the presentation [39] (i.e., microenvironment) of glycosyl donor molecules, which are incorporated in supramers, hence their chemical properties [35], thus making possible a shift of a fragile and not well-understood borderline between different reaction pathways at the SN1–SN2 interface [22][24][25

• concentration on stereoselectivity achieved with different glycosyl donors are currently missing. A putative cross-over from one reaction pathway to another one within the SN1–SN2 continuum [22][24][25] would require a sensible explanation why this happens differently for the two glycosyl donors under study

• the SN1-like mechanism to a more SN2-like mechanism occurs only (or mainly) for sialyl donor 2. Although this hypothesis can explain why the glycosylation with sialyl donor 2 exhibits substantial concentration dependence, it does not allow one even to guess why such SN1-to-SN2 cross-over did not occur

Controlling the reactivity of La@C₈₂ by reduction: reaction of the La@C₈₂ anion with alkyl halide with high regioselectivity

• Yutaka Maeda,
• Saeka Akita,
• Mitsuaki Suzuki,
• Michio Yamada,
• Takeshi Akasaka,
• Kaoru Kobayashi and
• Shigeru Nagase

Beilstein J. Org. Chem. 2023, 19, 1858–1866, doi:10.3762/bjoc.19.138

• transfer, followed by bimolecular nucleophilic substitution (SN2) reaction [8]. Endohedral metallofullerenes, wherein one or more metal atoms are encapsulated inside a fullerene cage, have garnered research interest [12][13][14][15]. The encapsulation of metal atoms can result in electron transfer from the

• derivatives followed by the radical coupling reaction is more plausible for the formation of the corresponding adducts rather than the SN2 reaction mechanism of the La@C2v-C82 anion with benzyl bromide derivatives. Conclusion The reaction of La@C2v-C82 anion with benzyl bromide derivatives 1 at 110 °C

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

• chromatography. Because 4.6 was obtained in better yields and in only 3 steps, the epimerization of 4.6 to 4.10 was also reported (Figure 4B). This epimerization is achieved in three-step sequence that starts with the double tosylation of 4.6 to produce 4.11. Then, the SN2 reaction with potassium acetate in DMSO

• mesylation produced 17.3. Then, the nucleophilic substitution (SN2) reaction of benzoate with 17.3 produced the benzoate ester 17.4 with an inversion of configuration. Then, the two protecting groups (ester and trityl) were removed to produce (S)-17.6. The modification of the sn-2 position is illustrated in

• Figure 17B starting from the mesylate derivative (S)-17.3. Its reaction with sodium azide produced, following a SN2 reaction, the azido derivative 17.7. The deprotection of the alcohol function produced 17.8 that subsequently reacted with 2-chloro-2-oxo-1,3,2-dioxaphospholane (17.9) in the presence of

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

• , such alcohols were in situ converted into the corresponding O-allyl carbamates as leaving groups, followed by their reaction with imidazoles, affording the SN2’ products 3 (Scheme 1, reaction 1, iii). Correlatively, we have previously reported a direct amination of cyclic MBH alcohols 4 with morpholine

• 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

• reaction of the primary five-membered alcohol 4b [29] with imidazole (2a) as well as to that of alcohols 4a,b with benzimidazole (2b), leading to the SN2-type products 6b and 7b,c, respectively, in 55–80% yields (Table 1, entries 7–9). In addition, we have shown that the direct amination of the available

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

• indicative of a carbocationic pathway are not observed, suggesting that RPC does not occur. Further, the inability of ATRA products to undergo SN2 with the added nucleophiles under our reaction conditions is inconsistent with a tandem ARTA/nucleophilic displacement alternative mechanism. Finally, a

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

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

• cross-coupling of pyridine N-oxides with nonactivated secondary (2°) alkyl bromides [51]. The cross-coupling is difficult to achieve as the Pd-catalyzed SN2 process is sensitive towards the steric bulk of the secondary or tertiary alkyl electrophiles. The optimized conditions for the ortho-alkylation of

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

• applied to a substrate with a pending bromo substituent (93), the formed enolate 94 underwent a spontaneous cyclization via an SN2 displacement (Scheme 24). The Harutyunyan team showed that this methodology also applies to aza-enolates that are generated by the conjugate addition of Grignard reagents to

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

• stereoselectivity level. Additionally, Schiff base derivatives of L7 have a considerably higher solubility in acetonitrile as compared to the L4-based complexes (see Table 3 and Supporting Information File 1); this makes it easier to scale-up the synthesis (e.g., for the SN2 alkylations or nucleophilic addition

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

• ]-sigmatropic rearrangement of the diazabicycle 47 to form the allylic carbazate intermediate 51. Nucleophilic attack of an organomagnesium, or organocuprate, in an anti SN2’ fashion on 52 furnish the final ring-opened product 49. The authors note the use of a carbamate protecting group was crucial for the

• then nucleophillically attacks the alkene in an SN2’ fashion producing the trans-isocyanate 149. Subsequently, insertion of the Rh–O bond into the isocyanate results in 150. Finally, protonolysis produces the oxazolidinone product 147e as well as regenerates the active Rh(I) catalyst. In 2013, the

• to other ARO reactions, the catalytic cycle is proposed to begin with the oxidative insertion of the Rh(I) catalyst into the bridgehead C–O bond producing 204. The phosphorus ylide attacks 204 in an SN2’ fashion on the endo face giving the ring-opened 205 as well as regenerating the Rh(I) catalyst

Revisiting the bromination of 3β-hydroxycholest-5-ene with CBr₄/PPh₃ and the subsequent azidolysis of the resulting bromide, disparity in stereochemical behavior

• Christian Schumacher,
• Jas S. Ward,
• Kari Rissanen,
• Carsten Bolm and
• Mohamed Ramadan El Sayed Aly

Beilstein J. Org. Chem. 2023, 19, 91–99, doi:10.3762/bjoc.19.9

• from the stereochemistry of the standard Appel mechanism due to participation of the Δ5 π-electrons. In contrast, the subsequent azidolysis (NaN3/DMF) of 3β-bromocholest-5-ene proceeds predominantly by Walden inversion (SN2) affording 3α-azidocholest-5-ene. The structures of all relevant products were

Combining the best of both worlds: radical-based divergent total synthesis

• Kyriaki Gennaiou,
• Antonios Kelesidis,
• Maria Kourgiantaki and
• Alexandros L. Zografos

Beilstein J. Org. Chem. 2023, 19, 1–26, doi:10.3762/bjoc.19.1

• 167 at 390 nm in the presence of NaHCO3 in CH3CN/t-BuOH, 5:1 to provide 168 in 55% yield (Scheme 14) [91]. Alkylation of the tetracycle, followed by epimerization of the C2 center and radical deoxygenation, or alternatively SN2 etherification, provided the common scaffold 170. The latter can serve as

Efficient synthesis of aziridinecyclooctanediol and 3-aminocyclooctanetriol

• Emine Salamci and
• Ayse Kilic Lafzi

Beilstein J. Org. Chem. 2022, 18, 1539–1543, doi:10.3762/bjoc.18.163

• group in compound 10 was converted to the corresponding alcohol 11 as the sole isomer via SN2 substitution by hydrolysis. In the azidolysis reaction of compound 8, we propose that because the azide group is bulkier than the water molecule, it could not substitute the second mesylate group, and therefore

A facile approach to spiro[dihydrofuran-2,3'-oxindoles] via formal [4 + 1] annulation reaction of fused 1H-pyrrole-2,3-diones with diazooxindoles

• Pavel A. Topanov,
• Anna A. Maslivets,
• Maksim V. Dmitriev,
• Irina V. Mashevskaya,
• Yurii V. Shklyaev and
• Andrey N. Maslivets

Beilstein J. Org. Chem. 2022, 18, 1532–1538, doi:10.3762/bjoc.18.162

• negatively charged [38] C(3) atom of diazooxindoles 2 at the C(3a) atom of FPDs 1 (Scheme 5), and (b) further intramolecular SN2 attack by the oxygen of the aroyl group with ensuing elimination of a nitrogen molecule. To verify our assumption, 3-bromooxindole (4) was involved in the reaction with FPD 1i in

• the presence of 1.1 equiv of TEA. In this case, the base-promoted deprotonation of 3-bromooxindole (4) affords a highly nucleophilic intermediate, which undergoes Michael addition to FPD 1i, followed by intramolecular SN2 attack [39][40][41][42][43] by the oxygen of the aroyl group (Scheme 5) to give