Development of a flow photochemical process for a π-Lewis acidic metal-catalyzed cyclization/radical addition sequence: in situ-generated 2-benzopyrylium as photoredox catalyst and reactive intermediate

• Masahiro Terada,
• Zen Iwasaki,
• Ryohei Yazaki,
• Shigenobu Umemiya and
• Jun Kikuchi

Beilstein J. Org. Chem. 2024, 20, 1973–1980, doi:10.3762/bjoc.20.173

• time was extended from 2.5 min to 10 min), it did not exceed the yield of the batch reaction. In contrast, aldehyde 1n having a simple phenyl group gave product 3n in good yield (Table 3, entry 3: 72%). Because the yield of this flow reaction was better than that of the batch reaction (65%), the

• , respectively, in high yields (Table 3, entries 4 and 5). The aldehyde 1q bearing a strong electron-withdrawing trifluoromethyl group at the para-position gave product 3q in moderate yield (Table 3, entry 6: 63%), with the recovery of substrate 1q (18%). The reaction of ortho-methyl-substituted aldehyde 1r

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

• significantly more active than 9, owing to higher rigidity and the correct position of the ortho H atoms in close proximity to the σ-holes on the I atom. The authors demonstrated that hydrogen bonding between H in ortho position of 8 and both O atom of aldehyde and N atom of imine significantly increased the

• the tolerability of a wide range of aldehydes, starting from one of the most used, benzaldehyde, passing through heteroaromatic and aliphatic structures with different substituents. In this context, some examples where the aldehyde functionality is incorporated into sugar derivatives, natural

• , the use of 5-HMF (23) [36], a renewable carbon source derived from biomass, responds to these requirements. This aldehyde displays additional functionalities useful for further modifications of the GBB adducts, but some optimization was necessary due to its intolerance to high temperatures and

A facile three-component route to powerful 5-aryldeazaalloxazine photocatalysts

• Ivana Weisheitelová,
• Radek Cibulka,
• Marek Sikorski and
• Tetiana Pavlovska

Beilstein J. Org. Chem. 2024, 20, 1831–1838, doi:10.3762/bjoc.20.161

• have been successfully synthesised through a one-pot, three-component reaction involving N,N-dimethylbarbituric acid, an aromatic aldehyde and aniline. By utilizing readily available reagents, this approach opens up the opportunity for the efficient formation of a variety of 5-aryldeazaalloxazines

• derivatives 2i–k, we changed the solvent to DMF/AlCl3, which increased the yields to 41–45%. However, the 7-methoxy derivative 2l with o-methyl substituent in the aldehyde moiety precipitated in DMSO after two days of reaction time. Interestingly, we observed only traces of another possible regioisomer 2m

• the described conditions. The halogen groups on the anilines slightly decreased their reactivity, leading to the formation of products 2q–w with lower yields. However, the 8-chlorine derivative 2u with a o-tolyl aldehyde moiety was prepared with a yield of 37%. Aromatic aldehydes bearing bromine and

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

• . [15][18]. Further, the application of reagents with additional functional groups in the Ugi reaction makes it possible to further increase the complexity of the product structures, also due to possible post-transformation reactions. For example, if an unsaturated bond is present in the aldehyde

• presence of several alternative reaction centers in the structure of our substances, we sometimes encountered unexpected and intriguing results. Results and Discussion Synthesis of Ugi bisamides Four-component and three-component Ugi reactions The combination of pyrrole-containing α,β-unsaturated aldehyde

Chemo-enzymatic total synthesis: current approaches toward the integration of chemical and enzymatic transformations

• Ryo Tanifuji and
• Hiroki Oguri

Beilstein J. Org. Chem. 2024, 20, 1693–1712, doi:10.3762/bjoc.20.151

• biosynthetic intermediate 8 to its analogs 21, enabling the chemo-enzymatic total synthesis of 1. The chemical synthesis commenced with the preparation of two fragments and their subsequent coupling to assemble the core 5/8/5 tricyclic scaffold (Scheme 3A). The left-half fragment, aldehyde 14, was synthesized

• and subsequent oxidation yielded aldehyde 18, a precursor for the intramolecular ring closure of the eight-membered ring. Upon treatment of 18 with BF3·Et2O, diastereoselective Prins cyclization of 18 proceeded to generate secondary alcohol 19. Subsequent one-pot treatment with (n-Bu)4NF·HF resulted

• -terminus of SorbB catalyzes conversion of thioester 31 using NADPH to liberate aldehyde 32, and subsequent Knoevenagel condensation-type cyclization leads to sorbicillin (33). The FAD-dependent monooxygenase SorbC, utilized in the chemo-enzymatic total synthesis of 2, catalyzes the oxidative

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

• with common iodine(III) reagents by 1H NMR spectroscopy (Figure 4). After 60 h the measurements revealed a higher yield of aldehyde 4a using 1a (68%) compared to 1c (30%) under the influence of AlCl3. As a comparison, the use of PIDA (5b) and IBA (5c) with the additive resulted in a significantly lower

• (75%). The ortho-phenyl-substituted aldehyde 4h was isolated in 85% yield, while the ortho-methoxy substrate did not convert to 4i. The ortho-, meta- and para-permutation of a CF3 group showed lower reactivity for the ortho-substituted 4j (53%), while the meta- and para-derivatives 4k and 4l gave

• higher yields of 84% and 71%, respectively. The steric inhibition of a doubly substituted phenyl ring was observed in a diminished formation of 2,6-dichlorobenzaldehyde (4m) in 39% yield. Naphthalen-2-ylmethanol gave aldehyde 4n in 44% yield. Pyridines 4o and 4p were also compatible and gave good yields

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

• [34]. In reductive amination, the substrate is usually an aldehyde or amine. After the formation of the iminium ion, it is reduced with the appropriate reagent to form the N-methylated amino acid. Different methods have been established using for example benzaldehyde as a protection group, sodium

• cyanoborohydride as a mild reducing agent, and paraformaldehyde as a methylating agent [36]. Methanol can be used as the methylating reagent in other methods. Here, a palladium on carbon (Pd/C) catalyst processes the dehydrogenation of the alcohol to form the corresponding aldehyde. The subsequently formed imine

New triazinephosphonate dopants for Nafion proton exchange membranes (PEM)

• Fátima C. Teixeira,
• António P. S. Teixeira and
• C. M. Rangel

Beilstein J. Org. Chem. 2024, 20, 1623–1634, doi:10.3762/bjoc.20.145

• phosphonation of the aldehyde group. To implement this strategy, a reaction between 4-hydroxybenzaldehyde (12) and cyanuric chloride (1) was performed, in toluene with Na2CO3 as base, to obtain compound 19 [58] in very good yield (87%) (Scheme 7). Compound 19 was subjected to similar reaction conditions that

Generation of multimillion chemical space based on the parallel Groebke–Blackburn–Bienaymé reaction

• Evgen V. Govor,
• Vasyl Naumchyk,
• Ihor Nestorak,
• Dmytro S. Radchenko,
• Dmytro Dudenko,
• Yurii S. Moroz,
• Olexiy D. Kachkovsky and
• Oleksandr O. Grygorenko

Beilstein J. Org. Chem. 2024, 20, 1604–1613, doi:10.3762/bjoc.20.143

• reaction is a three-component condensation of an α-amino heterocycle (e.g., 2-aminopyridine) 1, an aldehyde 2, and an isonitrile 3 providing the corresponding fused imidazoles (e.g., imidazo[1,2-a]pyridines) of general formula 4 (Scheme 1) [18][19][20][21]. Imidazo[1,2-a]pyridines and related heterocycles

• components of the reaction, the aldehyde and isonitrile, while the steric factor was found to be not significant. The protocol was used to prepare a 790-member compound library with 85% synthesis success rate. Furthermore, a readily available (REAL) chemical space comprising 271 Mln. members was generated

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

• was effective for the stereoselective fluorination of benzylic positions ortho to aldehyde substituents (Figure 9). The choice of a bulky amino, transient, directing group dictated the stereochemical outcome and promoted the C–F reductive elimination through an inner-sphere pathway. A competitive C–O

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

• keto function of the hydrazone moiety and the open-chain hemiacetal or aldehyde hydrate in Brønsted acid medium to access 1H-imidazo[5,1-c][1,4]oxazine derivatives (Scheme 1) [21]. Considering that the hydrazone function at C-4 of 4a–r may exist in a tautomeric equilibrium with the corresponding ene

• (entries 1–7, Table 1). Similarly to what was observed by Yu and co-workers for the intramolecular cyclization of alkynyl aldehyde acetals [28][29], it was found that the use of FeCl3 provided the better result in terms of overall yield (entry 3, Table 1). Moreover, the choice of iron(III) seemed to have

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

• simplified form, focuses on the base-induced disproportionation of two molecules of a non-enolizable aromatic and/or aliphatic aldehyde (without an α-hydrogen atom). These aldehydes undergo in the presence of concentrated alkali or other strong bases, a simultaneous oxidation and reduction sequence of two

• aldehyde molecules, forming an alcohol and an acid [1][2][3][4]. Since its discovery in 1853, the Cannizzaro reaction has emerged as an important reaction in synthetic organic chemistry with intermolecular, crossed, and intramolecular versions as demonstrated by numerous applications. Notably, the

• Cannizzaro reaction has come across with subtle developments and changes in base modifications leading to compounds of potential interest [5][6]. The intermolecular Cannizzaro reaction is a chemical process in which two molecules of a non-enolizable aldehyde (2R1CHO) are disproportionated by a base to

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

•  21). Styrenes selectively reacted with vinyl ethers in the presence of an acridinium photocatalyst and a diphenyl disulfide HAT catalyst to produce the aldehyde product when exposed to blue LED light. Differently substituted styrenes were examined using this protocol, which produced the aldehyde

• products in good yield (i.e., 80a–d, 48–80%). Cyclic olefins also performed well under these conditions and generated products with a β-ring moiety (i.e., 80e–g, 60–64%), which would have been challenging to synthesize otherwise. 2-Substituted ethyl vinyl ethers also provided α-branched aldehyde products

• in decent yield (i.e., 80h–k, 49–66%). An α,β,γ-trisubstituted aldehyde (i.e., 80l, 65%) was synthesized using an α,β-disubstituted styrene, which could not be produced using the conventional method. The excited photocatalyst *Mes–Acr+ oxidized the styrene to produce the extremely electrophilic

Domino reactions of chromones with activated carbonyl compounds

• Peter Langer

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

• ) [32]. The formation of the products can be explained by Michael reaction (1,4-addition) of 3 to the chromone and ring cleavage to give intermediate G. Subsequent Knoevenagel reaction by attack of the methylene carbon to the aldehyde resulted in the formation of the final products. The regioselective

• cyclization can be explained by the higher electrophilicity of the aldehyde as compared to the ketone. The yields were in general quite good (51–65%). Relatively low yields (51–52%) were obtained for chromones containing methyl substituents, presumably due to the lower electrophilicity of the chromone based

The Ugi4CR as effective tool to access promising anticancer isatin-based α-acetamide carboxamide oxindole hybrids

• Carolina S. Marques,
• Aday González-Bakker and
• José M. Padrón

Beilstein J. Org. Chem. 2024, 20, 1213–1220, doi:10.3762/bjoc.20.104

• , aliphatic chain on the acid component and small aliphatic chain on the aldehyde component to increase the antiproliferative activity. Also, benzyl isocyanide was favored over the aliphatic one (Scheme 1A) [16]. Considering the value of amide groups in drug discovery [19], the feasibility of running the

• efficient Ugi4CR approach. Easy access to isatin from the 3-protected oxindole scaffold was demonstrated using mild reaction conditions. Flexibility of the carboxylic acid component and also the carbonyl one (ketone/aldehyde) was exhibited in the library of Ugi adducts obtained in moderate to good yields

Cofactor-independent C–C bond cleavage reactions catalyzed by the AlpJ family of oxygenases in atypical angucycline biosynthesis

• Jinmin Gao,
• Liyuan Li,
• Shijie Shen,
• Guomin Ai,
• Bin Wang,
• Fang Guo,
• Tongjian Yang,
• Hui Han,
• Zhengren Xu,
• Guohui Pan and
• Keqiang Fan

Beilstein J. Org. Chem. 2024, 20, 1198–1206, doi:10.3762/bjoc.20.102

• 2 via Baeyer–Villiger oxidation, followed by hydrolysis to yield another crucial aldehyde/acid intermediate 3 [11][15]. Commencing from 3, diverse ring rearrangement reactions can occur, leading to the formation of distinct products. In the AlpJ-catalyzed reaction, compound 3 undergoes ring

• aldehyde–acid intermediate 11. In JadG-catalyzed reactions, compound 11 participated in a reaction with ʟ-isoleucine to yield 6. In contrast, in AlpJ- or Flu17-catalyzed reactions, 11 underwent decarboxylation and an aldol reaction, giving rise to intermediate 12. Subsequent dehydration of 12 led to the

Bismuth(III) triflate: an economical and environmentally friendly catalyst for the Nazarov reaction

• Manoel T. Rodrigues Jr.,
• Aline S. B. de Oliveira,
• Ralph C. Gomes,
• Amanda Soares Hirata,
• Lucas A. Zeoly,
• Hugo Santos,
• João Arantes,
• Catarina Sofia Mateus Reis-Silva,
• João Agostinho Machado-Neto,
• Leticia Veras Costa-Lotufo and
• Fernando Coelho

Beilstein J. Org. Chem. 2024, 20, 1167–1178, doi:10.3762/bjoc.20.99

• in moderate to good yields. With the β-ketoesters prepared, we began the synthesis of the Knoevenagel derivatives. To do so, we employed an adapted protocol from the literature. Using 1.00 equiv of β-ketoester, 1.50 equiv of aldehyde, 0.60 equiv of acetic acid, and 0.25 equiv of piperidine, the

Manganese-catalyzed C–C and C–N bond formation with alcohols via borrowing hydrogen or hydrogen auto-transfer

• Mohd Farhan Ansari,
• Atul Kumar Maurya,
• Abhishek Kumar and
• Saravanakumar Elangovan

Beilstein J. Org. Chem. 2024, 20, 1111–1166, doi:10.3762/bjoc.20.98

• , respectively. The proposed mechanism suggested that the active amido species (Mn5-a) was formed by treating Mn5 with the base. Then, the alkoxy intermediate Mn5-b is formed by reaction with the alcohol followed by release of an aldehyde and formation of the manganese hydride Mn5-c. The released aldehyde

• condenses with hydrazine followed by reduction and condensation with another aldehyde to afford the N-substituted hydrazones (Scheme 8). Balaraman and co-workers established a phosphine-free manganese catalyst generated in situ from a manganese precursor and a ligand for the N-alkylation of anilines with

• homogeneous nature of the catalytic system. The mechanistic investigation suggested that the reaction proceeds via a dehydrogenative pathway confirmed by forming an aldehyde product and H2 gas which was detected by GC. In 2019, Morrill’s group reported the N-alkylation of sulfonamides using Mn1. The reaction

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

• -cored halides can be broadened by converting C–Hal functions into different functional groups. For example, aldehyde and amine functionalities can be readily derived from C(sp3)–Hal functions through hydrolysis–oxidation [13] or substitution [14], respectively. This is of significant interest in the

A Diels–Alder probe for discovery of natural products containing furan moieties

• Alyssa S. Eggly,
• Namuunzul Otgontseren,
• Carson B. Roberts,
• Amir Y. Alwali,
• Haylie E. Hennigan and
• Elizabeth I. Parkinson

Beilstein J. Org. Chem. 2024, 20, 1001–1010, doi:10.3762/bjoc.20.88

• for 18 was more complicated, showing many more side products compared to other tested substrates (see Figure S7 in Supporting Information File 1). We hypothesize this is due to 18 undergoing a reaction in aqueous solutions to generate a geminal diol in place of an aldehyde, as has been previously

Carbonylative synthesis and functionalization of indoles

• Alex De Salvo,
• Raffaella Mancuso and
• Xiao-Feng Wu

Beilstein J. Org. Chem. 2024, 20, 973–1000, doi:10.3762/bjoc.20.87

• 1883 and involves its synthesis from phenylhydrazine and an aldehyde or ketone using an appropriate acid catalyst [8]. In the following years, new processes were developed for the synthesis of indole such as the Castro, Bischler, and Larock synthesis etc. [2][9][10]. Carbonylation reactions represent a

Innovative synthesis of drug-like molecules using tetrazole as core building blocks

• Jingyao Li,
• Ajay L. Chandgude,
• Qiang Zheng and
• Alexander Dömling

Beilstein J. Org. Chem. 2024, 20, 950–958, doi:10.3762/bjoc.20.85

• of tetrazole building blocks which provides the handle of alcohol functionality and further oxidation serves as an oxo component in subsequent MCRs (Figure 1d). The synthesis of oxo-tetrazoles was targeted because of the prevalence of the aldehyde substrate in MCRs and their use in medicinal

• chemistry literature. Results and Discussion First, we planned to provide a number of orthogonally protected tetrazole carbaldehyde building blocks. This should be accomplished by synthesizing the hydroxymethyl precursors by a Passerini-tetrazole synthesis, followed by oxidation to the aldehyde (Figure 1d

• smoothly and provided moderate to excellent yields of 58–83%. Among this, the tert-octyl-substituted aldehyde exhibited excellent product transformation with a yield of 83% of 3e. Various isocyanides such as benzyl, phenylethyl, tert-octyl and tert-butyl isocyanides participated in the reaction with

One-pot Ugi-azide and Heck reactions for the synthesis of heterocyclic systems containing tetrazole and 1,2,3,4-tetrahydroisoquinoline

• Jiawei Niu,
• Yuhui Wang,
• Shenghu Yan,
• Yue Zhang,
• Xiaoming Ma,
• Qiang Zhang and
• Wei Zhang

Beilstein J. Org. Chem. 2024, 20, 912–920, doi:10.3762/bjoc.20.81

• schistosomiasis [22][23][24][25]. The combination of the privileged heterocycles tetrazole and tetrahydroisoquinoline in one molecule generates new molecules which could have biological activities. A standard Ugi four-component reaction (Ugi-4CR) of an aldehyde, amine, isocyanide, and a carboxylic acid produces

• highly diverse peptidic structures A with up to four points of substitution (Scheme 1) [26][27]. By replacing the carboxylic acid with a nucleophilic azide reagent XN3 (generally TMSN3), the Ugi-azide four-component reaction (UA-4CR) of an aldehyde, amine, isocyanide, and azide gives 1,5-disubstituted 1H

(Bio)isosteres of ortho- and meta-substituted benzenes

• H. Erik Diepers and
• Johannes C. L. Walker

Beilstein J. Org. Chem. 2024, 20, 859–890, doi:10.3762/bjoc.20.78

• and aldehyde protecting groups. Recently, Lebold, Sarpong, and co-workers showed that 1,2-BCPs (±)-14a–e are also accessible from 1,5-disubstituted 2-azabicyclo[2.1.1]hexanes 13 (2-aza-1,5-BCHs) through a skeletal editing strategy utilising commercially available Levin’s reagent [30][31] (Scheme 1D

• homologation and hydrolysis led to aldehyde (±)-46 which could then be oxidised to acid (±)-47 using a Pinnick oxidation. BCH 42b also led to ester (±)-48 via a Horner–Wadsworth–Emmons reaction followed by hydrogenation of the formed alkene. 1,2-BCH 44 could be turned into amine (±)-49 by oxime formation and

• conditions in the transformation of alcohol 153 to aldehyde 154. All of these transformations could be performed without reduction in diastereomeric ratio. Additionally, the authors showed that acid 152 can undergo nickel-catalysed decarboxylative cross coupling reactions via redox active ester 156 to afford

Ortho-ester-substituted diaryliodonium salts enabled regioselective arylocyclization of naphthols toward 3,4-benzocoumarins

• Ke Jiang,
• Cheng Pan,
• Limin Wang,
• Hao-Yang Wang and
• Jianwei Han

Beilstein J. Org. Chem. 2024, 20, 841–851, doi:10.3762/bjoc.20.76

• generally moderate to good yields of 22–83% (Table 2, entries 1–17). These substituents included halogen (Br), methyl, phenyl, aldehyde, ester, and methoxy groups, all of which were compatible with the reaction conditions. Notably, compounds 3ab, 3ah, 3aj, 3am and 3ap bearing bromine are very useful modules