Multicomponent reactions (MCRs): a useful access to the synthesis of benzo-fused γ-lactams

• Edorta Martínez de Marigorta,
• Jesús M. de Los Santos,
• Ana M. Ochoa de Retana,
• Javier Vicario and
• Francisco Palacios

Beilstein J. Org. Chem. 2019, 15, 1065–1085, doi:10.3762/bjoc.15.104

• -component reaction, to afford isoindolinones 53 substituted with nitrile or carboxamide groups (Scheme 15, method A) [93]. Trimethylsilylcyanide (52), and benzyl-, alkyl- and allylamines 2 were reacted with 2-formylbenzoic acid (33) in the presence of OSU-6, a mesoporous silica performing as a green Lewis

• acid catalyst for this transformation. At room temperature, the product of this environmentally friendly Strecker reaction is nitrile derivative 53 (R2 = CN, Scheme 15, method A), while at reflux carboxamide 53 (R2 = CONH2, Scheme 15, method A) is obtained. Notoriously, aromatic amines 2 did not work

• oxidation of this radical would give rise to the corresponding cation 74, which would add to the nucleophilic nitrile 70. Intramolecular nucleophilic attack of the carboxy group in 75 followed by rearrangement of intermediate 76 delivered isoindolinone derivatives 71. Ortho-functionalized benzoic acids have

Novel (2-amino-4-arylimidazolyl)propanoic acids and pyrrolo[1,2-c]imidazoles via the domino reactions of 2-amino-4-arylimidazoles with carbonyl and methylene active compounds

• Victoria V. Lipson,
• Tetiana L. Pavlovska,
• Nataliya V. Svetlichnaya,
• Anna A. Poryvai,
• Nikolay Yu. Gorobets,
• Erik V. Van der Eycken,
• Irina S. Konovalova,
• Svetlana V. Shiskina,
• Alexander V. Borisov,
• Vladimir I. Musatov and
• Alexander V. Mazepa

Beilstein J. Org. Chem. 2019, 15, 1032–1045, doi:10.3762/bjoc.15.101

• CN at 2250 cm−1. In addition, there are characteristic bands at 1664–1668 cm−1, which may include both C=C bond and the exocyclic C=N bond. Fluctuations of endocyclic C=N fragments are observed at 1584 cm−1. Thus, at least one nitrile and one NH2 group are present in the obtained compounds. The 1H

Heck- and Suzuki-coupling approaches to novel hydroquinone inhibitors of calcium ATPase

• Robert J. Kempton,
• Taylor A. Kidd-Kautz,
• Soizic Laurenceau and
• Stefan Paula

Beilstein J. Org. Chem. 2019, 15, 971–975, doi:10.3762/bjoc.15.94

• -step sequence of oxidation employing ammonium cerium(IV) nitrate (CAN) [20] to afford the corresponding quinone (not shown), followed by reduction with sodium hydrosulfite [21]. With the nitrile in hand, we next attempted to reduce that functional group to an amine to which a leucine moiety could be

• , followed by addition of bromide 5a, potassium phosphate and PdCl2(dppf)2 in DMF at 85 °C for 3.5 h gave the coupled product 10 in 47–63% yields (Scheme 3). In contrast to the case of the Heck coupling products (6 and 8, Scheme 2), nitrile 10 underwent facile reduction with lithium aluminium hydride. The

Efficient synthesis of pyrazolopyridines containing a chromane backbone through domino reaction

• Razieh Navari,
• Saeed Balalaie,
• Saber Mehrparvar,
• Fatemeh Darvish,
• Frank Rominger,
• Fatima Hamdan and
• Sattar Mirzaie

Beilstein J. Org. Chem. 2019, 15, 874–880, doi:10.3762/bjoc.15.85

• hydrogen in intermediate B, it is possible to form chromonyl-malononitrile conjugated system C and to eliminate the phenylhydrazine. Intermediate C is a highly potent Michael acceptor that may allow the addition of hydrazine to the nitrile group resulting in intermediate D that after elimination of water

• products 5a–d were not formed. The reaction mechanism is shown in Scheme 2. The chemical structures of the products 5a–d are shown in Figure 4. Usually, to activate the nitrile group for cyclization reaction, the existence of Lewis acid, the addition of organolithium reagents or metal

• hexamethylenedisalazane is necessary. However, in this approach, the nucleophilic addition on the nitrile group and the cyclization was achieved without the addition of a catalyst [44]. This reaction possesses a highly atom economical character and requires only triethylamine (40 mol %) as a base in EtOH and provides

The LANCA three-component reaction to highly substituted β-ketoenamides – versatile intermediates for the synthesis of functionalized pyridine, pyrimidine, oxazole and quinoxaline derivatives

• Tilman Lechel,
• Roopender Kumar,
• Mrinal K. Bera,
• Reinhold Zimmer and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2019, 15, 655–678, doi:10.3762/bjoc.15.61

• to β-ketoenamides that are uniquely functionalized alkenes and suitable for a variety of subsequent reactions, in particular in heterocyclic synthesis. This LANCA three-component reaction (LA = lithiated alkoxyallene, N = nitrile, CA = carboxylic acid) was observed for the first time by Oliver Flögel

• in the three-component reaction. The products KE36–39 are derived from the O-protected nitrile obtained from (S)-lactic acid [35][36]. This chiral acid itself was incorporated as third component resulting in β-ketoenamides KE39–41. There is no indication of an erosion of the enantiopurity and the

• reasonable overall yields (Scheme 20) [30]. This pathway via the pyrimidine N-oxides represents a good alternative to the direct oxidation of the 4-methyl group by selenium dioxide (see Scheme 11). The subsequent transformation of the aldehyde PM71 to the oxime followed by dehydration afforded nitrile PM72

Cross metathesis-mediated synthesis of hydroxamic acid derivatives

• Shital Kumar Chattopadhyay,
• Subhankar Ghosh and
• Suman Sil

Beilstein J. Org. Chem. 2018, 14, 3070–3075, doi:10.3762/bjoc.14.285

• nitrile functionalities [19][20] have been shown to yield shorter routes to compounds of interest as well as for green chemical applications [21][22]. Hydroxamates belong to a class of valuable biologically relevant compounds of proven record of utility. For example, the hydroxamate SAHA (1, Figure 1) [23

Nucleofugal behavior of a β-shielded α-cyanovinyl carbanion

• Rudolf Knorr and
• Barbara Schmidt

Beilstein J. Org. Chem. 2018, 14, 3018–3024, doi:10.3762/bjoc.14.281

• –30 °C under argon gas cover during the addition of n-BuLi (1.05 mmol) in hexane (0.47 mL). The created LDA (up to 1.05 mmol) solution was treated with the solid nitrile 1 (200 mg, 0.95 mmol) and stirred further at rt till 1 was completely dissolved, whereupon the carbonyl compound (1.24 mmol, neat or

Reactions of 3-(p-substituted-phenyl)-5-chloromethyl-1,2,4-oxadiazoles with KCN leading to acetonitriles and alkanes via a non-reductive decyanation pathway

• Akın Sağırlı and
• Yaşar Dürüst

Beilstein J. Org. Chem. 2018, 14, 3011–3017, doi:10.3762/bjoc.14.280

• that are generally obtained by the reaction of benzyl halides with appropriate cyanating agents such as KCN [14], TMSCN [15], K4(Fe(CN)6 [16]. Deprotonation of the α-carbon (adjacent to nitrile) by strong bases, especially lithiated ones, resulted in an anionic species that easily undergoes a

• products 4f and 4g, respectively, in a shorter reaction time (Table 2, entries 6 and 7). However, due to the replacement of the nitrile group with hydrogen after decyanation in product 4, the methylenic protons and the methinic proton resonates at around 4–5 ppm as doublets and 5 ppm as pentet

• . Then, the acidic hydrogen adjacent to the nitrile group in the intermediate product is sequentially abstracted by a CN− anion with the extrusion of an HCN molecule and a carbanion alpha to the nitrile group bearing a 1,2,4-oxadiazole ring is formed. The resulted carbanion undergoes a substitution

1,8-Bis(dimethylamino)naphthyl-2-ketimines: Inside vs outside protonation

• A. S. Antonov,
• A. F. Pozharskii,
• P. M. Tolstoy,
• A. Filarowski and
• O. V. Khoroshilova

Beilstein J. Org. Chem. 2018, 14, 2940–2948, doi:10.3762/bjoc.14.273

• Synthesis of DMAN-ortho-ketimines and their cations Target compounds 4a–7a were synthesised by techniques previously developed in our laboratory (Scheme 4) [7][8]. Compounds 4a–6a were obtained by the treatment of the ortho-lithium derivative 8 with the corresponding nitrile (path a). Unfortunately, the

Synthesis of indole–cycloalkyl[b]pyridine hybrids via a four-component six-step tandem process

• Muthumani Muthu,
• Rakkappan Vishnu Priya,
• Abdulrahman I. Almansour,
• Raju Suresh Kumar and
• Raju Ranjith Kumar

Beilstein J. Org. Chem. 2018, 14, 2907–2915, doi:10.3762/bjoc.14.269

• [b]pyridine-3-carbonitrile hybrid heterocycles 7 with an ortho/ortho-para/ortho-meta substituted phenyl ring at C-4 may be attributed to the axial chirality induced in these molecules due to the restricted rotation of the C–C single bond. The steric hindrance exerted between the nitrile group at C-3

Olefin metathesis catalysts embedded in β-barrel proteins: creating artificial metalloproteins for olefin metathesis

• Daniel F. Sauer,
• Johannes Schiffels,
• Takashi Hayashi,
• Ulrich Schwaneberg and
• Jun Okuda

Beilstein J. Org. Chem. 2018, 14, 2861–2871, doi:10.3762/bjoc.14.265

• catalyst or redox catalyst. Various metalloenzymes have been applied in laboratory-scale reactions and a few metalloenzymes such as nitrile hydratase (cobalt(III) in the active site) for the production of acrylamide have found application in industry [25]. Notably, however, the reaction scope of natural

Oxidative and reductive cyclization in stiff dithienylethenes

• Michael Kleinwächter,
• Ellen Teichmann,
• Lutz Grubert,
• Martin Herder and
• Stefan Hecht

Beilstein J. Org. Chem. 2018, 14, 2812–2821, doi:10.3762/bjoc.14.259

• found, giving rise to an oxidation wave corresponding to the closed isomer (Figure S23, Supporting Information File 1). Once formed, the closed isomers of both nitrile-substituted compounds, i.e., sDTE66-PhCN and DTE-PhCN, can be reversibly reduced and oxidized (Figure S20 and Figure S23, Supporting

Synthesis of α-D-GalpN₃-(1-3)-D-GalpN₃: α- and 3-O-selectivity using 3,4-diol acceptors

• Emil Glibstrup and
• Christian Marcus Pedersen

Beilstein J. Org. Chem. 2018, 14, 2805–2811, doi:10.3762/bjoc.14.258

• terminal part of the LTA from S. pneumoniae. The deprotection of disaccharide 22 to give 27 followed by formation of the trichloroacetimidate 28 proceeded smoothly, as shown in Scheme 6. The following glycosylation using MeCN as solvent relied on the nitrile effect to afford the desired β-anomer 29 in 74

DABCO- and DBU-promoted one-pot reaction of N-sulfonyl ketimines with Morita–Baylis–Hillman carbonates: a sequential approach to (2-hydroxyaryl)nicotinate derivatives

• Soumitra Guin,
• Raman Gupta,
• Debashis Majee and
• Sampak Samanta

Beilstein J. Org. Chem. 2018, 14, 2771–2778, doi:10.3762/bjoc.14.254

• -hydroxyaryl)pyridine derivatives bearing a carboxylate or a nitrile group suitably placed at C3 position of the aza-ring has been achieved in acceptable chemical yields with a broad functional group tolerance. This sequential C–C/C–N bond making process proceeds through a regioselective allylic alkylation/aza

Ring-opening metathesis of some strained bicyclic systems; stereocontrolled access to diolefinated saturated heterocycles with multiple stereogenic centers

• Zsanett Benke,
• Melinda Nonn,
• Márton Kardos,
• Santos Fustero and
• Loránd Kiss

Beilstein J. Org. Chem. 2018, 14, 2698–2707, doi:10.3762/bjoc.14.247

• (5 mol %), leading at 20 °C to δ-lactone derivative (±)-15 although with low yield (Scheme 6, Table 4). In continuation, we selected a cyclooctene-fused system, namely isoxazoline (±)-16 which, in turn, was accessed through nitrile–oxide dipolar cycloaddition, by using nitroethane, DMAP and Boc2O

• vacuum and the residue was purified by column chromatography on silica gel (n-hexane/EtOAc). General procedure for the nitrile–oxide cycloaddition To a solution of 1,5-cyclooctadiene (1.5 mmol) in THF (20 mL), EtNO2 (5 equiv), DMAP (0.3 mmol, 20 mol %) and Boc2O (4.5 mmol, 3 equiv) were added and the

Assembly of fully substituted triazolochromenes via a novel multicomponent reaction or mechanochemical synthesis

• Robby Vroemans,
• Yenthel Verhaegen,
• My Tran Thi Dieu and
• Wim Dehaen

Beilstein J. Org. Chem. 2018, 14, 2689–2697, doi:10.3762/bjoc.14.246

• ], via intramolecular cyclization of a diazomethane group and a nitrile [23], or via our recently reported NH-triazole synthesis starting from 6-methoxyflavanone [24]. Furthermore, 1,4,5-trisubstituted 1,2,3-triazole annulated chromenes have been reported via an intramolecular arylation reaction of 1,2,3

Carbonylonium ions: the onium ions of the carbonyl group

• Daniel Blanco-Ania and
• Floris P. J. T. Rutjes

Beilstein J. Org. Chem. 2018, 14, 2568–2571, doi:10.3762/bjoc.14.233

• followed by a suffix indicating the positively-charged groups has made nomenclature richer and more fluent. IUPAC has given name to several functional groups as protonated species and organyl derivatives thereof: imine–iminium, amide–amidium, nitrile–nitrilium, amine–aminium [34]. In this sense, we propose

Cobalt- and rhodium-catalyzed carboxylation using carbon dioxide as the C1 source

• Tetsuaki Fujihara and
• Yasushi Tsuji

Beilstein J. Org. Chem. 2018, 14, 2435–2460, doi:10.3762/bjoc.14.221

• the corresponding products, which were isolated as methyl esters (Scheme 8). Thus, compound 7 bearing alkyl, ether, ester, and halide substituents exhibited good reactivity. Cinnamonitrile afforded 8f-Me in 81% yield using 10 mol % of catalyst. α-Phenyl-substituted α,β-unsaturated nitrile also reacted

• conditions, the desired carboxylated product 26a was obtained in 75% yield. A variety of arylboronic esters (25b–i) were converted into the corresponding carboxylic acids 26b–i in good-to-high yields. It is noteworthy that ketone, ester, and nitrile functionalities in 26d, 26e, and 26f, respectively, were

Tetrathiafulvalene – a redox-switchable building block to control motion in mechanically interlocked molecules

• Hendrik V. Schröder and
• Christoph A. Schalley

Beilstein J. Org. Chem. 2018, 14, 2163–2185, doi:10.3762/bjoc.14.190

• . Very recently, our group reported on a crown/ammonium rotaxane 17 in which a TTF unit is implemented in the crown-ether wheel (Figure 15) [82]. The rotaxane was synthesized by a catalyst-free nitrile oxide capping strategy in 67% yield. In the neutral state, the wheel is strongly bound to the ammonium

D-Fructose-based spiro-fused PHOX ligands: synthesis and application in enantioselective allylic alkylation

• Michael R. Imrich,
• Jochen Kraft,
• Cäcilia Maichle-Mössmer and
• Thomas Ziegler

Beilstein J. Org. Chem. 2018, 14, 2082–2089, doi:10.3762/bjoc.14.182

• solvent) the reaction proceeded smoothly in good to high yields. We chose 2-bromobenzonitrile (8) as a nucleophile because we planned to modify the aryl bromide by transition metal-catalyzed cross-coupling reactions afterwards. Unfortunately, the nitrile must be used in a high excess of 15 equiv because

• nitrile according to the Fürst–Plattner rule provides 10 in a high excess (Table 1, entries 1–3). With the smaller substituent R1 = CH3 conformer 9b gets more important and more 11 is produced (Table 1, entries 4 and 5). By comparing entries 2 and 3 as well as 4 and 5 we noticed that the size of R2 has an

• is such a substituent the oxocarbenium ion 9a is stabilized as indicated in Scheme 6. In the stabilized species 9c the formerly favored nucleophilic attack from the top is blocked so that the addition of the nitrile has to occur from the bottom and higher amounts of 11 are generated. Neighboring

Assessing the possibilities of designing a unified multistep continuous flow synthesis platform

• Mrityunjay K. Sharma,
• Roopashri B. Acharya,
• Chinmay A. Shukla and
• Amol A. Kulkarni

Beilstein J. Org. Chem. 2018, 14, 1917–1936, doi:10.3762/bjoc.14.166

• ) condensation b) aromatic nucleophilic substitution reaction, c) deprotection and d) formation of lactate salt. Details of the same are given below: Condensation: Condensation takes place in a first reactor TR1 between the nitrile and hydrazine at high temperature and under pressure. Here, the nitrile was

• dissolved in a THF and hydrazine was dissolved in a mixture of solvents such as methanol, acetone, and water. The nitrile was pumped using pump P1 and hydrazine was pumped through P2 into the tubular reactor TR1 maintained at a temperature of 130 °C at residence time of 60 minutes to obtain the pyrazole

Synthesis of new tricyclic 5,6-dihydro-4H-benzo[b][1,2,4]triazolo[1,5-d][1,4]diazepine derivatives by [3⁺ + 2]-cycloaddition/rearrangement reactions

• Lin-bo Luan,
• Zi-jie Song,
• Zhi-ming Li and
• Quan-rui Wang

Beilstein J. Org. Chem. 2018, 14, 1826–1833, doi:10.3762/bjoc.14.155

• + + 2]-cycloaddition, α-acetoxyazo intermediates are initially transformed into an azocarbenium ion. Subsequently, it takes part in a cationic cycloaddition reaction with the triple bond of a nitrile followed by a rearrangement reaction [35][36][37][38][39]. This type of ionic cycloaddition

• that various electron-donating and electron-withdrawing groups on the benzene ring were compatible with the reaction conditions furnishing the desired products 10i–r in good yields. This indicated that the nucleophilicity of the nitrogen atom of nitrile 9 is strong enough to override the electronic

• give the desired product 10y. This result could be attributed to the increased steric hindrance in nitrile moiety. As can be seen from Scheme 3, equally satisfactory results could be obtained from the reaction of other acetoxyazo compounds 8 with several different substituents on the benzene ring, as

Glycosylation reactions mediated by hypervalent iodine: application to the synthesis of nucleosides and carbohydrates

• Yuichi Yoshimura,
• Hideaki Wakamatsu,
• Yoshihiro Natori,
• Yukako Saito and
• Noriaki Minakawa

Beilstein J. Org. Chem. 2018, 14, 1595–1618, doi:10.3762/bjoc.14.137

• donors [83]. Since the reactions often were unselective in the absence of C2 acetate-directing groups, Bennett et al. investigated the compatibility of the above-mentioned reaction in nitrile solvents documented to have a β-directing effect, with the aim of developing a glycosylation that can be

• provided the optimal reaction outcome. However, they also encountered a problem: the reduced solubility of substrate in the solvent system resulted in lower yields. They therefore examined mixed nitrile solvents again, and eventually found that a quaternary solvent mixture composed of 6:1:1:1 CH2Cl2

Atom-economical group-transfer reactions with hypervalent iodine compounds

• Andreas Boelke,
• Peter Finkbeiner and
• Boris J. Nachtsheim

Beilstein J. Org. Chem. 2018, 14, 1263–1280, doi:10.3762/bjoc.14.108

• [31]. Under copper-catalysis diarylated isoindolin-1-ones 9 were formed starting from 2-formylbenzonitriles 8 upon treatment with mesityl(aryl)iodonium salts 1a (Scheme 6). A plausible reaction mechanism starts with the selective terminal arylation of the nitrile, forming the arylnitrilium cation A

Rhodium-catalyzed C–H functionalization of heteroarenes using indoleBX hypervalent iodine reagents

• Erwann Grenet,
• Ashis Das,
• Paola Caramenti and
• Jérôme Waser

Beilstein J. Org. Chem. 2018, 14, 1208–1214, doi:10.3762/bjoc.14.102

• introduction of further heterocyclic rings, such as indoles, is particularly attractive. Most of the methods for indolylpyridinone synthesis involve a condensation cascade process to generate the pyridinone ring [4][5][6]. These methods usually require an electron-withdrawing group (nitrile, nitro, carbonyl