Catalysing (organo-)catalysis: Trends in the application of machine learning to enantioselective organocatalysis

• Stefan P. Schmid,
• Leon Schlosser,
• Frank Glorius and
• Kjell Jorner

Beilstein J. Org. Chem. 2024, 20, 2280–2304, doi:10.3762/bjoc.20.196

• enantioselectivities of a kinetic resolution of benzyl alcohols and an enantiodivergent fluorination of allylic alcohols, observing good correlations for both reactions. Since then, the proposed NCI descriptors have been successfully applied to multiple different reactions, such as an allenoate Claisen rearrangement

• , Chen and Pollice proposed Pint as a descriptor of the London dispersion potential that is universal and can be calculated without a probe system [94]. Although Pint has not been utilised for organocatalysis, the authors applied it to a Pd-metal-catalysed enantioselective 1,1-diarylation of benzyl

Deuterated reagents in multicomponent reactions to afford deuterium-labeled products

• Kevin Schofield,
• Shayna Maddern,
• Yueteng Zhang,
• Grace E. Mastin,
• Rachel Knight,
• Wei Wang,
• James Galligan and
• Christopher Hulme

Beilstein J. Org. Chem. 2024, 20, 2270–2279, doi:10.3762/bjoc.20.195

• [D3]-formamide. The ability to deuterate at benzylic positions is particularly relevant as benzylic C–H bonds are common in biologically relevant chemotypes and moreover appear in approximately 25% of the top selling 200 pharmaceuticals [23]. Benzyl cation stability is a driver of metabolism at these

Metal-free double azide addition to strained alkynes of an octadehydrodibenzo[12]annulene derivative with electron-withdrawing substituents

• Naoki Takeda,
• Shuichi Akasaka,
• Susumu Kawauchi and
• Tsuyoshi Michinobu

Beilstein J. Org. Chem. 2024, 20, 2234–2241, doi:10.3762/bjoc.20.191

• was outside the scope of this study. Next, DBA 5 was subjected to the SpAAC with benzyl azide. When two equivalents of benzyl azide were added to a solution of 5 in CDCl3 at a controlled temperature of 30 °C, the reaction slowly proceeded (Figure 2). After 22 h, the original peak ascribed to starting

• followed a second-order reaction. Since no monoadducts were formed, the rate-determining step is the first azide addition. Based on this fact, the activation energy (Ea) of the reaction between 5 and benzyl azide in CDCl3, determined by the Arrhenius plots, was 60.9 kJ mol−1 (Figure 3). This value was

• apparently smaller than those previously reported for the reaction between DBA-OHex and benzyl azide (Table S1 in Supporting Information File 1). However, the Ea values were previously measured in DMSO-d6 and C6D6, and it is known that there is a solvent polarity effect on the reactivity of SpAACs. In order

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

• well as electron-withdrawing substituents on the two phenyl rings in compounds 1, such as methyl, methoxy, halogen atoms (F, Cl, Br, I), CF3 and SO2CH3, were well tolerated, and their electronic effects insignificantly impacted the formation of 3. Similarly, N-benzyl-3-oxo-3-phenylpropanamide (3w

Electrochemical allylations in a deep eutectic solvent

• Sophia Taylor and
• Scott T. Handy

Beilstein J. Org. Chem. 2024, 20, 2217–2224, doi:10.3762/bjoc.20.189

• more substituted end (gamma addition) was the major product in both cases, although alpha addition was also observed. In the case of crotyl bromide, no diastereoselectivity was noted for the gamma product. Non-allylic halides such as benzyl bromide, propargyl bromide, and ethyl bromoacetate (Table 3

• , entries 5–7) did not result in carbonyl addition. The benzyl bromide was recovered intact, while for the other two, they are both sufficiently volatile that they would have been lost during the work-up. For all three, the aldehyde was recovered unreacted. While the use of DES as solvent and electrolyte

Efficacy of radical reactions of isocyanides with heteroatom radicals in organic synthesis

• Akiya Ogawa and
• Yuki Yamamoto

Beilstein J. Org. Chem. 2024, 20, 2114–2128, doi:10.3762/bjoc.20.182

• yields. In the case of tert-butyl and benzyl isocyanides, the substituents on the nitrogen of imidoyl radical 2 (R = t-Bu or PhCH2, E = Et2P or Ph2P) were eliminated to give cyanophosphines (R’2P–CN, Scheme 7) [38]. On the other hand, we attempted a photoinduced addition of phosphorus–phosphorus

From perfluoroalkyl aryl sulfoxides to ortho thioethers

• Yang Li,
• Guillaume Dagousset,
• Emmanuel Magnier and
• Bruce Pégot

Beilstein J. Org. Chem. 2024, 20, 2108–2113, doi:10.3762/bjoc.20.181

• using a series of nitriles with the sulfoxide 1a (Scheme 3). We noticed that the length of the alkyl chain has no impact on the yield (3a,b). However, the use of benzyl cyanide is completely deleterious for the reaction as no product was observed (3c). The presence of a chlorine atom at the alpha

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

Electrochemical radical cation aza-Wacker cyclizations

• Sota Adachi and
• Yohei Okada

Beilstein J. Org. Chem. 2024, 20, 1900–1905, doi:10.3762/bjoc.20.165

• compatible to give the respective five-membered pyrrolidines, except for that possessing a 2-nitro group 7. As discussed later with cyclic voltammetric studies, the electron density in the aryl rings does not seem to have a significant impact on the reaction. While benzyl sulfonamide 8 was productive under

Access to 2-oxoazetidine-3-carboxylic acid derivatives via thermal microwave-assisted Wolff rearrangement of 3-diazotetramic acids in the presence of nucleophiles

• Ivan Lyutin,
• Vasilisa Krivovicheva,
• Grigory Kantin and
• Dmitry Dar’in

Beilstein J. Org. Chem. 2024, 20, 1894–1899, doi:10.3762/bjoc.20.164

• -generated ketene, previously described using carbocyclic diazodiketones [35] were also unsuccessful. Of the diazotetramic acids, only the spiro adamantane derivative 1m was not able to form the desired β-lactam. These reactions gave complex mixtures of unidentified products. The benzyl esters 3k and 3n were

• -diastereomeric β-lactam products. The use of variously substituted diazotetramic acids, including their spirocyclic derivatives, provides access to a new structural diversity of medically relevant β-lactam derivatives. The possibility of transforming the obtained benzyl esters into 2-oxoazetidine-3-carboxylic

• ; reaction scale – 0.25 mmol; ascaled-up (1.5 mmol) yield. Negative results with several N-, O-, and C-nucleophiles and with diazo reagent 1m. Preparation of acids 4 by hydrogenolysis of benzyl esters and examples of acid 4a amidation. Supporting Information Deposition Number CCDC 2323689 (for 3t) contains

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

• aldehydic component has been generated in situ through Fe3O4-mediated aerobic oxidation of benzyl alcohols. Magnetic nanoparticles were supported by Shaabani and Farhid on spent coffee ground and served also as catalyst for the GBB reaction, although the role of coffee ground was not clearly explained [33

• diversification points. The scope of the reaction was limited: alkyl aldehydes and aryl/benzyl isocyanides could not be used, and 4 distinct compounds were obtained in yields of 23–40%. Nevertheless, these results represent an improvement compared to previous studies where substitution on C4 of the 2

Ugi bisamides based on pyrrolyl-β-chlorovinylaldehyde and their unusual transformations

• Alexander V. Tsygankov,
• Vladyslav O. Vereshchak,
• Tetiana O. Savluk,
• Serhiy M. Desenko,
• Valeriia V. Ananieva,
• Oleksandr V. Buravov,
• Yana I. Sakhno,
• Svitlana V. Shishkina and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2024, 20, 1773–1784, doi:10.3762/bjoc.20.156

• chlorine atom in the chlorovinyl fragment to the hydroxy group, probably under the influence of water (Figure 4). It is worth noting that the synthesis of Ugi bisamides 5–8 (Table 1) yielded compounds 10 and ketobisamide 12 in some cases. For example, in the Ugi reaction involving benzyl isocyanide (4b

• Ugi bisamide 5d in the presence of HCl. Conditions: (A) 5 equiv HCl, MeOH, 80 °C, 3 h; (B) 5 equiv HCl, EtOH, MW 120 °C, 15 min; (C) 5 equiv HCl, MeCN, MW 100 °C, 20 min. The Ugi-4CR with the participation of p-anisidine and benzyl isocyanide. Successful attempt at tandem one-pot coupling of the Ugi

Oxidation of benzylic alcohols to carbonyls using N-heterocyclic stabilized λ³-iodanes

• Thomas J. Kuczmera,
• Pim Puylaert and
• Boris J. Nachtsheim

Beilstein J. Org. Chem. 2024, 20, 1677–1683, doi:10.3762/bjoc.20.149

• tetrazine salt 1c. Based on these results, the reaction conditions were further optimized using NHI 1a with the benzyl alcohols 3a (electron-rich) and 3b (electron-poor) as the model substrates. First, the reaction temperature was increased, finding 60 °C to be the optimal value in EtOAc (Table 1, entry 1

Ring opening of photogenerated azetidinols as a strategy for the synthesis of aminodioxolanes

• Henning Maag,
• Daniel J. Lemcke and
• Johannes M. Wahl

Beilstein J. Org. Chem. 2024, 20, 1671–1676, doi:10.3762/bjoc.20.148

• extending the reaction time to reach full conversion, significant amounts of Norrish type II cleavage were obtained and product 3b was isolated in only 16% yield. This substrate was therefore abandoned. Interestingly, ethyl (1c) and benzyl (1d) substitution was detrimental to the cyclization, indicated by

• (Table 1, entry 9). The notable influence of steric and electronic parameters of the PG prompted us to investigate a range of sterically diverse alkyl substituents. Interestingly, while only fragmentation products were obtained for methyl and benzyl groups (Table 1, entries 10 and 11), the sterically

• of substrates 1a and 1e. On the other hand, increasing steric demand at the α-aminocarbon has a detrimental effect on the cyclization, as indicated by the poor performances of ethyl and benzyl substitution (1c and 1d). In contrast, sterically demanding groups at the nitrogen can have a positive

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

• ]. Furthermore, alternative alkyl groups such as ethyl, propargyl, allyl, benzyl, and nitrobenzyl groups can be transferred [31][138][139][140][141][142]. Such alkylation strategies have been successfully applied to small molecules such as coumarin [141], anthranilate [21], and pyrazole [24], as well as larger

• used for biocatalytic methylation reactions. If RiPP MTs, like many other MTs, also accept SAM-derivatives with larger alkyl groups as substrates, they can transfer various groups such as ethyl, allyl, propyl, and benzyl moieties. In vitro systems can be used to install specific modifications in

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

• predominately considered to be stable to isolation conditions, secondary and tertiary suffer from the elimination of HF, especially in the presence of silica gel or glass vessels. Therefore, benzyl fluorides have been derivatised, for example in C–O, C–N and C–C bond-forming reactions [18][19][20], thereby also

• subsequently attack electrophilic Selectfluor to afford the benzyl fluoride (Figure 2) [34]. The methodology was demonstrated on eight para-substituted benzylic substrates. The authors noted that resubjecting the monofluorinated compound 1 to the same reaction conditions afforded the difluorinated compound 2

• authors displayed the stability of the secondary benzyl fluoride 9 to various SNAr conditions. While these methods demonstrate excellent application of palladium catalysts to perform benzylic fluorinations, the need to install a directing group can limit substrate scope. Therefore, methods that can

Synthesis of 2-benzyl N-substituted anilines via imine condensation–isoaromatization of (E)-2-arylidene-3-cyclohexenones and primary amines

• Lu Li,
• Na Li,
• Xiao-Tian Mo,
• Ming-Wei Yuan,
• Lin Jiang and
• Ming-Long Yuan

Beilstein J. Org. Chem. 2024, 20, 1468–1475, doi:10.3762/bjoc.20.130

• additive-free synthesis of 2-benzyl N-substituted anilines from (E)-2-arylidene-3-cyclohexenones and primary amines has been reported. The reaction proceeds smoothly through a sequential imine condensation–isoaromatization pathway, affording a series of synthetically useful aniline derivatives in

• -benzyl-N-substituted anilines. In this work, (E)-2-arylidene-3-cyclohexenones firstly react with primary amines to form cyclohexenylimine intermediates I. Afterward, isoaromatization resulting from imine–enamine tautomerization and exocyclic double bond shift occurs to give rise to stable aniline

• % yields. Finally, when we switched our attention to the generality of primary aromatic amines such as aniline or secondary amines such as dibenzylamine, it was found that only the starting materials were recovered after work-up of the reaction mixture. The structure of 2-benzyl N-substituted anilines 4

Rapid construction of tricyclic tetrahydrocyclopenta[4,5]pyrrolo[2,3-b]pyridine via isocyanide-based multicomponent reaction

• Xiu-Yu Chen,
• Ying Han,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2024, 20, 1436–1443, doi:10.3762/bjoc.20.126

• . Under the optimized reaction conditions, the scope of the reaction was developed by using various substrates. The results are summarized in Table 2. At first, several alkyl isocyanides such as cyclohexyl, tert-butyl and benzyl isocyanide have been successfully employed in the reaction. Dimethyl but-2

• one hour. After removing the solvent by rotatory evaporation at reduced pressure, the residue was subjected to column chromatography with a mixture of ethyl acetate and petroleum ether (v/v = 1:4) as eluent to give the pure product for analysis. Pentamethyl rel-(4R,4aR,4bS,8aS)-1-benzyl-8-cyclohexyl-4

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

• (R3 = Ac, R4 = Bn) were obtained in 13% and 6% yield, respectively. The protecting group R3 of 3-OH was changed from an acetyl to a benzyl group. However, conversion and yield of linear oligosaccharides 9c and 10c decreased, and the corresponding cyclic disaccharide 8c was not obtained at all (Table 1

• , entry 4). The reasons for the lower conversion and yield are unclear. However, the lower yield may stem from the lower stability of glycosylation intermediates with a benzyl protecting group at C-3. In all cases, the major product was 1,6-anhydrosugar 7, which was the intramolecular glycosylation

• linear trisaccharide 20b were produced with monomer 17b with a 3,4-di-O-benzyl group (Table 2, entry 2). Although the 3-hydroxy protecting group R3 also affected the product distribution, formation of the corresponding 1,6-anhydrosugars was not observed in both cases. NMR data suggested that cyclic

Challenge N- versus O-six-membered annulation: FeCl₃-catalyzed synthesis of heterocyclic N,O-aminals

• Giacomo Mari,
• Lucia De Crescentini,
• Gianfranco Favi,
• Fabio Mantellini,
• Diego Olivieri and
• Stefania Santeusanio

Beilstein J. Org. Chem. 2024, 20, 1412–1420, doi:10.3762/bjoc.20.123

• more encumbered alcohol, such as benzyl alcohol, which is not sequestered by MS 4 Å. As a matter of fact, the new benzylated N,O-aminal 7 was successfully obtained in 70% isolated yield as the sole product (experiment D, Scheme 5). In this latter case, the benzyl alcohol presumably reacts with the

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

• alcohols and benzylic alcohols delivered fruitful results. However, the reaction of benzyl alcohols was found to proceed within shorter reaction times and much higher yields compared to aliphatic alcohols. This process presumably involves a Cannizzaro reaction during the conversion of the benzyl alcohols

Generation of alkyl and acyl radicals by visible-light photoredox catalysis: direct activation of C–O bonds in organic transformations

• Mithu Roy,
• Bitan Sardar,
• Itu Mallick and
• Dipankar Srimani

Beilstein J. Org. Chem. 2024, 20, 1348–1375, doi:10.3762/bjoc.20.119

• success of the reaction. The reaction was well compatible with various N-phthalimidoyl oxalates (i.e., 31h–k) as well as electron-deficient alkenes (i.e., 31l–o). Xanthates: In 2017, Molander and co-workers [51] introduced a C(sp3)–C(sp2) cross-coupling reaction of benzyl radicals generated from o-benzyl

• xanthate esters with aryl bromides via dual photoredox and nickel catalysis (Scheme 14). sec-BuBF3K was found to be the best radical precursor for generating the alkyl radicals that initiated the C–O bond cleavage of O-benzyl xanthate esters to provide benzyl radicals. Next, the benzyl radicals underwent

• -butyl arenes were generated. This underpinned the formation of sec-butyl radicals in the system that rapidly reacted with O-benzyl xanthates before participating in the nickel-catalyzed cross-coupling reactions. Precatalyst [Ni(dtbbpy)(H2O)4]Cl2 (50) and photosensitizer [Ir(dF(CF3)ppy)2(bpy)]PF6 (49

Rhodium-catalyzed homo-coupling reaction of aryl Grignard reagents and its application for the synthesis of an integrin inhibitor

• Kazuyuki Sato,
• Satoki Teranishi,
• Atsushi Sakaue,
• Yukiko Karuo,
• Atsushi Tarui,
• Kentaro Kawai,
• Hiroyuki Takeda,
• Tatsuo Kinashi and
• Masaaki Omote

Beilstein J. Org. Chem. 2024, 20, 1341–1347, doi:10.3762/bjoc.20.118

• benign synthetic applications [14][15][16][17][18]. We have successfully achieved various reactions using a Rh complex easily derived from dialkylzinc (R2Zn) and RhCl(PPh3)3 [19][20]. Additionally, in the related study, we also reported a new Rh-catalyzed C(sp3)–C(sp3) homo-coupling reaction of benzyl

• halides, which involved a rhodium-bis(benzyl) complex (Scheme 2) [21]. Following these outcomes, as part of a research program aimed at a wide range of Rh-catalyzed C–C bond-formation reactions, in this paper, we report a Rh-catalyzed Ullmann-type homo-coupling reaction of aryl Grignard reagents. Results

• and Discussion Methodology development In our work towards Rh-catalyzed homo-coupling reactions of benzyl halides, we observed that a similar rhodium–bis(benzyl) complex can also be formed from benzyl halide by using a Grignard reagent instead R2Zn in the presence of RhCl(PPh3)3 to subsequently give

Sustainable tandem acylation/Diels–Alder reaction toward versatile tricyclic epoxyisoindole-7-carboxylic acids in renewable green solvents

• Ayhan Yıldırım

Beilstein J. Org. Chem. 2024, 20, 1308–1319, doi:10.3762/bjoc.20.114

• optimum reaction conditions, a series of reactions between N-benzyl-1-(furan-2-yl)methanamine (1a) and maleic anhydride were carried out and the results obtained are shown in Table 1. As can be seen from the table, SSO, OO, OA and LM are all excellent solvents for the IMDAF reaction and allow the

• moiety in N-furfuryl-N-benzylmaleamic acid, formed by acylation of N-benzyl-N-furfurylamine with maleic anhydride, adopts a favorable conformational structure thanks to two activating electron-withdrawing groups and participates in the formation of the corresponding IMDAF product in oil medium rapidly

• a 50 mL round bottom flask, N-benzyl-1-(furan-2-yl)methanamine (1a, 0.30 g, 1.60 mmol) was dissolved in 2 mL of SSO and heated in an oil bath to 50 °C. Then, into the observed solution, maleic anhydride (0.16 g, 1.63 mmol) was added and the resulted mixture was heated at 50 °C for 30 min. Thereafter

Domino reactions of chromones with activated carbonyl compounds

• Peter Langer

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

• the chromone and at carbon C-4 of the diene. However, in case of a benzyl and a benzyloxy group located at carbon C-4 of the diene, the overall yields were rather low (20%). This might be explained by steric effects. One of the best yields was obtained for the reaction of diene 6a with unsubstituted