Recent advances in organocatalytic atroposelective reactions

• Henrich Szabados and
• Radovan Šebesta

Beilstein J. Org. Chem. 2025, 21, 55–121, doi:10.3762/bjoc.21.6

• -Breslow-type intermediates with the chiral NHC-catalyst and subsequent deprotonation toward the nitrile product. Zhang, Wang, Ye, and co-workers utilized NHC-catalysis for the atroposelective synthesis of axially chiral diaryl ethers 59 and 61 [38]. This transformation was realized via desymmetrization of

Non-covalent organocatalyzed enantioselective cyclization reactions of α,β-unsaturated imines

• Sergio Torres-Oya and
• Mercedes Zurro

Beilstein J. Org. Chem. 2024, 20, 3221–3255, doi:10.3762/bjoc.20.268

• hydrogen bonding with the protonated tertiary amine. Then, a Michael addition of malononitrile to the azadiene takes place to obtain exclusively the (S)-intermediate A. Subsequently an intramolecular nucleophilic addition of the nitrile leads to the intermediate B, which undergoes tautomerization to

Ceratinadin G, a new psammaplysin derivative possessing a cyano group from a sponge of the genus Pseudoceratina

• Shin-ichiro Kurimoto,
• Kouta Inoue,
• Taito Ohno and
• Takaaki Kubota

Beilstein J. Org. Chem. 2024, 20, 3215–3220, doi:10.3762/bjoc.20.267

• and ECD data with those of the known psammaplysin derivative, psammaplysin F (2). Ceratinadin G (1) is a rare nitrile containing a cyano group as aminoacetonitrile, and is the first psammaplysin derivative possessing a cyano group. In vitro assays indicated that compound 1 displayed moderate

• [25][26][27][28]. It is known that natural nitrile compounds are biosynthesized through various mechanisms [29]. Rinehart and co-workers demonstrated that 2-(3,5-dibromo-4-hydroxyphenyl)acetonitrile is biosynthesized from ʟ-tyrosine via 3,5-dibromo-ʟ-tyrosine, based on experiments using 14C- and 15N

• -labeled ʟ-phenylalanine [19]. Therefore, the cyano group in bromotyrosine alkaloids containing the phenylacetonitrile moiety is derived from the α-carbon and amino group of ʟ-tyrosine. On the other hand, the biosynthesis of nitrile with a cyanoformamide moiety remains unclear. Ceratinadin G (1) represents

Synthesis of 2H-azirine-2,2-dicarboxylic acids and their derivatives

• Anastasiya V. Agafonova,
• Mikhail S. Novikov and
• Alexander F. Khlebnikov

Beilstein J. Org. Chem. 2024, 20, 3191–3197, doi:10.3762/bjoc.20.264

• azirine dicarboxylic acid 6j, oxazole-4-carboxylic acid 9 was isolated. Apparently, azirine 2j underwent ring opening at higher temperature to nitrile ylide 7, which after cyclization and hydrolysis gave acid 9 (Scheme 3) (cf., e.g. [23]). Next, given that the preparation of 2H-azirine-2-carboxamides from

• because the isomerization of 3-(tert-butyl)-5-chloroisoxazole-4-carbonyl chloride did not occur at room temperature, but at elevated temperature (82 °C) the reaction proceeded via the formation of the nitrile ylide, which cyclized to 2-(tert-butyl)-5-chlorooxazole-4-carbonyl chloride. 3-Phenyl-2H-azirine

Advances in radical peroxidation with hydroperoxides

• Oleg V. Bityukov,
• Pavel Yu. Serdyuchenko,
• Andrey S. Kirillov,
• Gennady I. Nikishin,
• Vera A. Vil’ and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2024, 20, 2959–3006, doi:10.3762/bjoc.20.249

• atom from substrate 53 to form the C-centered radical B. Copper(II) then oxidizes TBHP to form the tert-butylperoxy radical C and copper(I), closing the catalytic copper cycle. tert-Butylperoxy radical C recombines with radical B to yield the product 54. The reaction of a mono-substituted nitrile

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

• oxidized, either directly at the anode or by the TAC dication radical. The resulting intermediate undergoes the classic Ritter steps, reacting with acetonitrile to form a nitrile, which is subsequently hydrolyzed to yield the target amide product (Scheme 49). The construction of multiple C–O bonds from C–H

Evaluating the halogen bonding strength of a iodoloisoxazolium(III) salt

• Dominik L. Reinhard,
• Anna Schmidt,
• Marc Sons,
• Julian Wolf,
• Elric Engelage and
• Stefan M. Huber

Beilstein J. Org. Chem. 2024, 20, 2401–2407, doi:10.3762/bjoc.20.204

• it with our known iodonium species in the activation of Au(I)–Cl bonds. Results and Discussion As immediate precursor to the target structure 7Z, the literature-known isoxazole 10 was synthesized via a Cu(I)-catalyzed cycloaddition between (2-iodophenyl)acetylene (8) and benzyl nitrile oxide, which

Synthesis, electrochemical properties, and antioxidant activity of sterically hindered catechols with 1,3,4-oxadiazole, 1,2,4-triazole, thiazole or pyridine fragments

• Daria A. Burmistrova,
• Andrey Galustyan,
• Nadezhda P. Pomortseva,
• Kristina D. Pashaeva,
• Maxim V. Arsenyev,
• Oleg P. Demidov,
• Mikhail A. Kiskin,
• Andrey I. Poddel’sky,
• Nadezhda T. Berberova and
• Ivan V. Smolyaninov

Beilstein J. Org. Chem. 2024, 20, 2378–2391, doi:10.3762/bjoc.20.202

• nitrogen atom N3 of the nitrile group of the solvent acetonitrile molecule presenting in the cell: the corresponding distance H2B···N3 is 2.03(1) Å, the angle O2B–H2B–N3 is 169°. As a result, molecules A and B in this pair are located according to the principle of "chairs inserted into each other." The

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

• production or external purchase and have progressed along the value chain to the clinic and full approval [5]. Literature inspection reveals that an established common method to prepare deuterated benzylic isonitriles is reduction of a nitrile in the presence of a deuterium source (Scheme 1) [16][17][18

• method to prepare [D1]-formamides (D–C=O) is through a Leuckart–Wallach reaction with an amine and [D1]-methyl/ethyl formate or [D1]-dimethylformamide [19][20]. Stockmann and co-workers produced [D2]-formamides (N–D, D–C=O) via acid-catalyzed nitrile hydrolysis with HCl and D2O [21]. Thus, using the

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

• -pot two-step protocol. Several aryl-SCF3 compounds are reported by variation of the nitrile or of the trifluoroalkyl sulfoxide starting material. The variation of the perfluoroalkyl chain was also possible. Keywords: ortho functionalization; rearrangement; sulfoxide; Introduction Since decades

• under these conditions (Table 1, entry 4). The importance of the temperature was then evaluated (Table 1, entries 5–7). A too low value was deleterious to the yield, whereas −5 °C appeared as the conditions of choice. Finally, by adjusting to 5 equivalents of nitrile and base, resulted in the optimal

• -position of the nitrile is also detrimental to the reaction, resulting in less than 30% yield of the desired product 3d. Nevertheless, the reaction is compatible with halogens elsewhere in longer nitrile alkyl chains (3e,g). Finally, it was possible to obtain the terminal alkene 3f with a yield of 58

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

• )-cycloaddition of nitrile oxides 137, generated in situ from hydroxyiminoyl chloride 135 and terminal alkynes, was proposed by Kovacs and Novak. Copper supported on iron serves as a catalyst and as a reagent for the reductive ring opening and leads to β-aminoenones 139, which react in the consecutive one-pot

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

• agrochemical industries. The (3 + 2)-cycloaddition between nitrile imines and alkenes represents one of the most efficient strategies to prepare these azacycles. However, conventional methods for the generation of the nitrile imine involved the use of unstable hydrazonoyl halides or the oxidation of aldehyde

• the electrogeneration of iodine in the aqueous phase. Under high stirring, the latter would react with NH-arylhydrazones 72 in the organic phase to furnish the N-iodo hydrazonium 75 and ultimately the nitrile imine 76 under basic conditions provided by the cathodic process. The critical role of the in

• /fragmentation and extrusion of nitrogen to yield the nitrile derivative 159. The transformation proceeded neither with aldehydes nor with aromatic ketones (Scheme 32) [82]. In 2008, Okimoto et al. reported the electrochemical oxidation of ketone-derived NH-allylhydrazones 160 into the corresponding azines 161

Negishi-coupling-enabled synthesis of α-heteroaryl-α-amino acid building blocks for DNA-encoded chemical library applications

• Matteo Gasparetto,
• Balázs Fődi and
• Gellért Sipos

Beilstein J. Org. Chem. 2024, 20, 1922–1932, doi:10.3762/bjoc.20.168

• the most employed approach for producing this family of substrates [12]. Despite its effectiveness, this approach requires hazardous cyanides and harsh conditions for the subsequent hydrolysis of the nitrile or the hydantoin. Additionally, it carries significant limitations in its scope, reducing its

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

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

• have been used to effect the transformation of benzylic C(sp3)–H to C(sp3)–F bonds [22]. Shreeve and co-workers reported the use of KOH or n-BuLi to deprotonate acidic protons at benzylic positions adjacent to electron-withdrawing nitro or nitrile groups, respectively, generating benzylic anions that

• in good yield. The requirement of adjacent to nitro or nitrile groups limits the scope of this approach. Furthermore, the use of strong bases, particularly n-BuLi, prevents the application of this methodology on any substrate bearing sensitive functional groups. An analogous method for

Electrophotochemical metal-catalyzed synthesis of alkylnitriles from simple aliphatic carboxylic acids

• Yukang Wang,
• Yan Yao and
• Niankai Fu

Beilstein J. Org. Chem. 2024, 20, 1497–1503, doi:10.3762/bjoc.20.133

• esters, the so called "Barton esters", for decarboxylative cyanation of aliphatic acids with tosyl cyanide as the nitrile source under visible light irradiation at room temperature [21][22]. Although two synthetic steps are required, this is the first practical decarboxylative cyanation protocol because

• processes using cyanobenziodoxolones and tosyl cyanide as the cyanating reagents, respectively (Figure 1B, reaction 2). Recently, the Rueping group demonstrated a distinctive use of 4-cyanopyridine as nitrile source for electrochemical decarboxylative cyanation of amino acids [25]. Although these methods

• size of the alkyl side chain at the alpha position of arylacetic acids (9–16). These features offer great opportunities for the introduction of a wide range of functional groups, including bromide (9), boron (12), ether (13), nitrile (14), ester (15), and alkene (16) moieties, which are versatile

Domino reactions of chromones with activated carbonyl compounds

• Peter Langer

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

• dimethyl acetone-1,3-dicarboxylate (3) with 3-cyanochromone (16a) afforded azaxanthone 40 in 49% yield (Scheme 22) [42][43][44]. The reaction again proceeds by 1,4-addition with subsequent ring cleavage of the chromone (intermediate AD). Subsequent attack of the methylene carbon to the nitrile gave

• steric influence of the fluorine atom and of the substituent R1 might have an influence on the conformation which facilitates the intramolecular aldol reaction at the expense of the nitrile addition. In the case of formation of biphenyls 44, these products were generally obtained in good yields (63–79

• 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

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

• heterocyclic alcohols were tested and showed good functional group tolerances. However, ester and nitrile-substituted ketones were not alkylated with this protocol. The proposed mechanism showed that the Mn(CO)5Br reacted with ligand L3 to generate the active complex Mn-L3-I in the presence of a base. The

• step, the hydrogenation of the formed intermediate took place via the outer sphere mechanism to deliver the desired alkylated nitrile products (Scheme 54). In 2019, Rueping and El-Seplegy reported the well-defined manganese-PNP complex-catalyzed alkylation of nitriles with alcohols as a hydrogen donor

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

• introduced from their nitrile precursors through late-stage functionalization. In this work, we propose a novel strategy involving the use of diversely protected, unprecedented tetrazole aldehydes as building blocks. This approach facilitates the incorporation of the tetrazole group into multicomponent

• 1H-tetrazole as a bioisostere for carboxylic acid has long been recognized for its potential in enhancing drug-like properties [37]. Predominantly, tetrazoles are currently introduced by a late-stage-functionalization approach from their nitrile precursors. This work, however, takes an additional

(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

• nitrile group (to (±)-35 and (±)-37), Baeyer–Villiger oxidation (to (±)-38 and (±)-39), reduction of the nitrile group (to (±)-36) and Beckman rearrangement (to (±)-40). A mechanistically related synthesis of 1,2-BCHs was published recently by Wang and co-workers (not shown) [39]. They employed a

• (82) on multigram scale (Scheme 8) [48]. As in Camps' synthesis, their approach starts from dinitrile 83. However, while Camps and co-workers directly accessed the stellane scaffold from 83, Ryabukhin, Volochnyuk and co-workers first transformed the nitrile groups into esters before forming stellane

Advancements in hydrochlorination of alkenes

• Daniel S. Müller

Beilstein J. Org. Chem. 2024, 20, 787–814, doi:10.3762/bjoc.20.72

• broad generality and tolerates various sensitive functional groups, including aldehyde 45 and nitrile 46. However, electron-poor styrene, resulting in chloride 40, or terminal and 1,2-disubstituted alkenes forming chlorides 41–46 and cyclooctyl chloride (26) necessitated harsher reaction conditions. As

• allowed carrying out the hydrochlorination of terminal aliphatic alkenes at room temperature. Under these conditions even a nitrile group could be preserved (46). The FeCl3-promoted hydrochlorination with HCl gas was previously reported by Mayo and Scher [31][77]. This methodology is of great practical

• functional tolerance of this methodology is striking. Especially examples with sensitive aldehyde (175), nitrile (176), N-Boc (177), furan (178), thiophene (179), and even tertiary alcohols (180 and 181) are impressive. The primary drawback of this methodology lies in the synthesis of the ligand L3

Development of a chemical scaffold for inhibiting nonribosomal peptide synthetases in live bacterial cells

• Fumihiro Ishikawa,
• Sho Konno,
• Hideaki Kakeya and
• Genzoh Tanabe

Beilstein J. Org. Chem. 2024, 20, 445–451, doi:10.3762/bjoc.20.39

• µM), suggesting that these inhibitors can penetrate cells (Figure 4c). Notably, inhibitors 1 and 7 efficiently inhibited the labeling of GrsA at 10 µM. The incorporation of the nitrile group at the 2’-OH group of the adenosine skeleton is expected to provide chemical properties that would allow the

Mono or double Pd-catalyzed C–H bond functionalization for the annulative π-extension of 1,8-dibromonaphthalene: a one pot access to fluoranthene derivatives

• Nahed Ketata,
• Linhao Liu,
• Ridha Ben Salem and
• Henri Doucet

Beilstein J. Org. Chem. 2024, 20, 427–435, doi:10.3762/bjoc.20.37

• range of para-substituents on the aryl unit of the arylboronic acids was then evaluated (Scheme 4). Methyl, ester and nitrile substituents were well tolerated, giving rise to products 20, 22, and 23 in yields ranging from 71% to 77%. A 4-chloro substituent was also well tolerated, providing product 21

• , carbonyl or nitrile. Using the appropriate arenes, this synthetic route enables the desired functional groups to be introduced at positions 7 to 10 of fluoranthenes. The second method involves a Suzuki coupling followed by an intramolecular C–H bond activation step, and provides access to specific

Copper-catalyzed multicomponent reaction of β-trifluoromethyl β-diazo esters enabling the synthesis of β-trifluoromethyl N,N-diacyl-β-amino esters

• Youlong Du,
• Haibo Mei,
• Ata Makarem,
• Ramin Javahershenas,
• Vadim A. Soloshonok and
• Jianlin Han

Beilstein J. Org. Chem. 2024, 20, 212–219, doi:10.3762/bjoc.20.21

• challenging. On the other hand, several interesting transformations of nitrile ylides from diazo compounds have been developed in the past years [31][32][33][34][35][36][37][38]. In particular, acylglycine esters could be easily constructed with ester-containing diazo compounds as the starting materials. For

• example, Wan and co-workers developed a cascade reaction of α-diazo esters, nitriles, and carboxylic acids via the generation of nitrile ylides and Mumm rearrangement affording unsymmetric diacyl α-amino acid esters as products (Scheme 1a) [39]. In 2017, Zhang, Hu, and co-workers developed a Cu-catalyzed

• [42][43][44][45][46][47][48][49], we sought to develop reactions of the unexplored β-trifluoromethyl β-diazo esters. We hypothesized that nitrile ylides, in situ generated from nitriles and β-trifluoromethyl β-amino esters, could also react with carboxylic acids to give nitriliums, which then could

Using the phospha-Michael reaction for making phosphonium phenolate zwitterions

• Matthias R. Steiner,
• Max Schmallegger,
• Larissa Donner,
• Johann A. Hlina,
• Christoph Marschner,
• Judith Baumgartner and
• Christian Slugovc

Beilstein J. Org. Chem. 2024, 20, 41–51, doi:10.3762/bjoc.20.6

• intramolecular proton transfer and the methanol-mediated proton transfer, can occur. It has been described that intermediate B is more stable with enolizable electron-withdrawing groups such as esters [50] when compared to, e.g., a nitrile [49]. Accordingly, the intermolecular proton transfer pathway should be