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

• (Scheme 6). The study explored a broad range of p-methoxyphenyl (PMP)imines derived from aryl, heteroaryl and alkyl aldehydes (including ethyl glyoxylate), demonstrating yields of 57–98% and high enantioselectivity of 90–98%. Screening of aldehyde and amine components indicated that the method is

• slightly more efficient with electron-poor substrates. On the other hand, high enantioselectivity was maintained over the aldehyde scope regardless of steric size and position of the substituents. A few years later, Wulff and co-workers [42] further elaborated the aza-Cope rearrangement methodology by

• crystal XRD of the corresponding hydrochloride salt. Microwave-induced one-pot asymmetric allylation of in situ-formed arylimines, catalysed by (R)-3,3’-diphenyl-BINOL. Aldehyde and amine scope [26]. aThe reaction was conventionally heated at 50 °C for 24 hours instead of microwave irradiation. b1.0 equiv

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

• aldehyde [10]. Latterly, Yamamoto utilized a 90% deuterated [D2]-isocyanide in a copper catalyzed [3 + 2] cycloaddition to afford a 60% deuterated [D2]-pyrrole [11]. The utility of the Leuckart–Wallach reaction towards the generation of isocyanides was first explored by Dömling [12], yet the use of such

• deuteration of formamide product while increasing formamide equivalents increases the yield at the cost of deuterated %. Excess reaction time increases side product formation and thermal degradation of the aldehyde starting material. To combat this, microwave irradiation was employed which dramatically

• Scheme 2 but is open to debate. Thus, formamide adds to the [D1]-aldehyde A to form hemiaminal B which eliminates D2O to give imine D. Deprotonation of formamide D forms the resonance and zwitterrion-stabilized isocyanate E [22]. We then hypothesize that zwitterion E rearranges with loss of CO2 to form

Synthesis and reactivity of the di(9-anthryl)methyl radical

• Tomohiko Nishiuchi,
• Kazuma Takahashi,
• Yuta Makihara and
• Takashi Kubo

Beilstein J. Org. Chem. 2024, 20, 2254–2260, doi:10.3762/bjoc.20.193

• dimerization in solution, the radical still remains even at 190 K due to the bulky nature of the two anthryl groups. Interestingly, upon exposure to air, the purple color of the radical solution quickly fades to orange, resulting in decomposition to give 9-anthryl aldehyde and anthroxyl radical derivatives

• radical. The unpaired electron is primarily located at the central sp2 carbon, a highly reactive site. The DAntM radical readily reacts with oxygen, leading to 1,2-dioxetane intermediate and decomposition to give anthryl aldehyde and a stable anthroxyl radical. Results and Discussion The synthetic route

• formation of a 1,2-dioxetane (DOT) intermediate and decomposition to aldehyde 1 and anthroxyl radical 5 via C–C and O–O bond cleavage. This reactivity is attributed to the predominant localization of an unpaired electron at the central sp2 carbon of the DAntM radical. These findings provide variable

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

• constant current of 20 mA. With this promising start, several other aldehydes and two ketones were explored under the same reaction conditions (Table 2). A range of aromatic aldehydes worked well as well as one aliphatic aldehyde (Table 2, entry 13) and one alkenyl aldehyde (Table 2, entry 10), although

• , 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

• the allylation product. Only in the case of the cyclohexanecarboxaldehyde (Table 6, entry 3) was the yield lower and in this case this lower yield was the result of incomplete conversion of the aldehyde. For as successful as the TBAB/EG conditions were, TBAB is not inexpensive. Choline chloride is

O,S,Se-containing Biginelli products based on cyclic β-ketosulfone and their postfunctionalization

• Kateryna V. Dil and
• Vitalii A. Palchykov

Beilstein J. Org. Chem. 2024, 20, 2143–2151, doi:10.3762/bjoc.20.184

• ) are the key methodology to access valuable heterocycles for medicinal chemistry projects. The classical Biginelli reaction (1893) is an acid-catalyzed, three-component reaction between an aldehyde, β-ketoester, and urea that produces 3,4-dihydropyrimidin-2(1H)-ones, also known as DHPMs (Scheme 1A

• -alkyl/aryl-substituted analogues, and aldehyde component switch to heteroaromatic (2-pyridinaldehyde) and aliphatic (iPrCHO, cinnamaldehyde). Unfortunately, we failed in both replacements and were unable to obtain any reasonable products. The list of unsuccessful reagents is shown in Figure S7 (see

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

• hydrolactite catalysts (C-Mg-Al HAT-3) [90]. With β-ketoesters, the method can be extended to a four-component synthesis. Initially, β-ketoesters react with hydrazine to form pyrazolones, while a Knoevenagel reaction between malononitrile and aldehyde simultaneously generates a Michael system. Both

Harnessing the versatility of hydrazones through electrosynthetic oxidative transformations

• Aurélie Claraz

Beilstein J. Org. Chem. 2024, 20, 1988–2004, doi:10.3762/bjoc.20.175

• readily available hydrazones under mild, safe and oxidant-free reaction conditions. This review presents a comprehensive overview of oxidative electrosynthetic transformations of hydrazones. It includes the construction of azacycles, the C(sp2)−H functionalization of aldehyde-derived hydrazones and the

• asymmetric preparation of chiral amines through the addition of nucleophilic partners [21][22] while the azaenamine character of some aldehyde-derived hydrazones has been demonstrated in the coupling with suitable electrophiles such as Michael acceptors [23][24]. Last but not least, the C=N bond of

• the electrochemical oxidative transformations of hydrazones. It is organized in four main parts: (i) synthesis of azacycles, (ii) synthesis of functionalized hydrazones through C(sp2)–H functionalization of aldehyde-derived hydrazones, (iii) access to diazo compounds, and (iv) synthesis of

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