Pyridinoacridine alkaloids of marine origin: NMR and MS spectral data, synthesis, biosynthesis and biological activity

• Louis P. Sandjo,
• Victor Kuete and
• Maique W. Biavatti

Beilstein J. Org. Chem. 2015, 11, 1667–1699, doi:10.3762/bjoc.11.183

• function by first hydrolyzing the amide function to the corresponding amine following by the preparation of the diazonium and substitution of the diazonium function with a nitrile group. The latter was then converted to a carboxylic group under strongly acidic conditions. The acid derivative was treated

Development of variously functionalized nitrile oxides

• Haruyasu Asahara,
• Keita Arikiyo and
• Nagatoshi Nishiwaki

Beilstein J. Org. Chem. 2015, 11, 1241–1245, doi:10.3762/bjoc.11.138

• -functionalized isoxazole derivatives. Since the amide was prepared by the cycloaddition reaction of ethynylbenzene and N-methylcarbamoylnitrile oxide, the nitrile oxide served as the equivalent of the nitrile oxides bearing a variety of functional groups such as carboxy, alkoxycarbonyl, carbamoyl, acyl and

• formyl moieties. Keywords: acylnitrile oxide; amide; formylnitrile oxide; functionalized nitrile oxide; Weinreb amide; Introduction Nitrile oxides are valuable synthetic synthons for the construction of heterocyclic compounds by cycloaddition reactions, which lead to the formation of two bonds in a

• single experimental step [1][2]. In addition, cycloadducts serve as precursors of polyfunctionalized compounds by ring opening reaction followed by N–O bond fission [2][3]. Hence, functionalized nitrile oxides are clearly useful for the preparation of more complex systems. However, because the precursors

The synthesis of active pharmaceutical ingredients (APIs) using continuous flow chemistry

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2015, 11, 1194–1219, doi:10.3762/bjoc.11.134

• and chloroacetyl chloride. The crude nitrile product 81 was then collected in a batch vessel and isolated in pure form after crystallisation and washing with n-heptane. Alkylation of 81 with the corresponding amino-adamantane derivate in the presence of excess K2CO3 following an existing batch

Thiazole formation through a modified Gewald reaction

• Carl J. Mallia,
• Lukas Englert,
• Gary C. Walter and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2015, 11, 875–883, doi:10.3762/bjoc.11.98

• general, substrates which have an α-methylene adjacent to the nitrile group gave 2-aminothiophene (Scheme 1) whilst those that possessed an α-methine yielded the corresponding 2-substituted thiazole. Originally, reactions were performed using conventional heating, however, to allow for a wider temperature

• conversion and isolated yield (58%) with tetramethylethylenediamine (TMEDA) also giving a respectable yield of 50% (Table 1, entries 1 and 10). The stronger guanidine bases 1,1,3,3-tetramethylguanidine (TMG) and 1,8-diazabicycloundec-7-ene (DBU) both gave full consumption of the nitrile starting material

• its condensation with the aldehyde component (generated from 10), which inhibits the transformation. In addition, a sulfonic acid bound resin (QP-SA) was also trialled as an additive but showed no conversion allowing full recovery of the starting nitrile (see later discussion on mechanism). These

Trifluoromethyl-substituted tetrathiafulvalenes

• Olivier Jeannin,
• Frédéric Barrière and
• Marc Fourmigué

Beilstein J. Org. Chem. 2015, 11, 647–658, doi:10.3762/bjoc.11.73

• the deformation of the unsymmetrically substituted dithiole rings, when bearing one, or two different EWG, and attributed to the mesomeric effect of ester or nitrile groups, is not notably modified or counter-balanced by the introduction of a neighboring trifluoromethyl group. DFT calculations confirm

• these observations and also show that the low energy HOMO–LUMO absorption band found in nitrile or ester-substituted TTFs is not found in TTF-CF3, where, as in TTF itself, the low energy absorption band is essentially attributable to a HOMO→LUMO + 1 transition. Despite relatively high oxidation

• tetrathiafulvalenes functionalized by electron-withdrawing groups (EWG) are less documented, essentially because the presence of such substituents as halogen, acyl, ester, amide or nitrile on the TTF redox core dramatically increases its oxidation potential and destabilizes the radical cation form. This strong anodic

TTFs nonsymmetrically fused with alkylthiophenic moieties

• Rafaela A. L. Silva,
• Bruno J. C. Vieira,
• Marta M. Andrade,
• Isabel C. Santos,
• Sandra Rabaça,
• Dulce Belo and
• Manuel Almeida

Beilstein J. Org. Chem. 2015, 11, 628–637, doi:10.3762/bjoc.11.71

• cyanoethyl groups, by C–H…N hydrogen bonds and S…N short contacts. There are no interactions between A and D molecules and the stacks are out-of-registry; 2) on the other side the stacking interaction is between the nitrile groups of A and the methyl groups of D, and is mediated by a weak C–H…N hydrogen bond

Cross-dehydrogenative coupling for the intermolecular C–O bond formation

• Igor B. Krylov,
• Vera A. Vil’ and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2015, 11, 92–146, doi:10.3762/bjoc.11.13

Highly selective electrochemical fluorination of dithioacetal derivatives bearing electron-withdrawing substituents at the position α to the sulfur atom using poly(HF) salts

• Bin Yin,
• Shinsuke Inagi and
• Toshio Fuchigami

Beilstein J. Org. Chem. 2015, 11, 85–91, doi:10.3762/bjoc.11.12

• Bin Yin Shinsuke Inagi Toshio Fuchigami Department of Electronic Chemistry, Tokyo Institute of Technology, Nagatsuta, Midori-ku, Yokohama 226-8502, Japan 10.3762/bjoc.11.12 Abstract Anodic fluorination of dithioacetals bearing electron-withdrawing ester, acetyl, amide, and nitrile groups at their

• having a strongly electron-withdrawing nitrile group gave the α-fluorination product predominantly regardless of the poly(HF) salts used. Keywords: anodic fluorination; anodic fluorodesulfurization; electrosynthesis; fluorination product selectivity; poly(HF) salt; Introduction The introduction of

A carbohydrate approach for the formal total synthesis of (−)-aspergillide C

• Pabbaraja Srihari,
• Namballa Hari Krishna,
• Ydhyam Sridhar and
• Ahmed Kamal

Beilstein J. Org. Chem. 2014, 10, 3122–3126, doi:10.3762/bjoc.10.329

• deprotecting the acetyl groups (without affecting the benzoate functionality) by employing acetyl chloride in anhydrous methanol to afford diol 13 [33]. A two-fold silylation and selective mono desilylation afforded primary alcohol 14 which was converted to its corresponding nitrile via the triflate. The

• nitrile functionality was hydrolysed with 8 N NaOH in ethanol to yield the seco acid 4. The seco acid 4 was already utilized for the total synthesis of (−)-aspergillide C through macrolactonization and TBS deprotection as reported earlier by Kuwahara (Table 1) [23]. Thus, by synthesizing 4, we have

The Shono-type electroorganic oxidation of unfunctionalised amides. Carbon–carbon bond formation via electrogenerated N-acyliminium ions

• Alan M. Jones and
• Craig E. Banks

Beilstein J. Org. Chem. 2014, 10, 3056–3072, doi:10.3762/bjoc.10.323

• α-amino nitrile, reinstalled the N-acyliminium ion. Reduction of the N-acyliminium afforded the major diastereoisomer as shown in Scheme 14 in 79% after column chromatography. Further synthetic modification of this key intermediate afforded the total synthesis of (+)-myrtine (66) in a further 5

Synthesis of nanodiamond derivatives carrying amino functions and quantification by a modified Kaiser test

• Gerald Jarre,
• Steffen Heyer,
• Elisabeth Memmel,
• Thomas Meinhardt and
• Anke Krueger

Beilstein J. Org. Chem. 2014, 10, 2729–2737, doi:10.3762/bjoc.10.288

• combustion analysis is not suitable for this type of nanodiamond derivatives. The dicyanopyrazine conjugate 4 can be submitted to a reduction of the nitrile groups using borane solution in THF. This mild yet efficient reaction leads to the complete transformation of the nitriles to amino groups as evidenced

• (0.60 mmol g−1) is corroborated by the value obtained in the modified Kaiser test (see below). The reduction of the nitrile groups has an important influence on the colloidal stability of the ND conjugate. Whereas the nitrile derivate 4 is soluble in rather nonpolar organic solvents, the amino derivate

• mmol g−1 (calculated from corrected TGA); zetapotential: +12.2 mV (measured in aqueous dispersion). FTIR-spectra of annealed nanodiamond 2 (a), nitrile 4 (b) and amine 5 (c). As can be seen from the disappearance of the CN signal after the reduction of 4 the nitrile is fully converted into the

Indium-mediated allylation in carbohydrate synthesis: A short and efficient approach towards higher 2-acetamido-2-deoxy sugars

• Christopher Albler,
• Ralph Hollaus,
• Hanspeter Kählig and
• Walther Schmid

Beilstein J. Org. Chem. 2014, 10, 2230–2234, doi:10.3762/bjoc.10.231

• chemistry as tracers for tumor detection, myocardial ischemia or infarct diagnostics [10]. The group of Perez et al has taken a particular interest in the chemistry of 2-aminoheptoses [11][12][13][14] which they prepared via an amino-nitrile synthesis [15]. This method, first described by Kuhn and

Application of cyclic phosphonamide reagents in the total synthesis of natural products and biologically active molecules

• Thilo Focken and
• Stephen Hanessian

Beilstein J. Org. Chem. 2014, 10, 1848–1877, doi:10.3762/bjoc.10.195

• addition of trimethylsilylcyanide to the formed Schiff-base provided aminonitrile 168 as the major diastereomer (dr 95:5). Oxidative cleavage of the phenylglycinol moiety with Pb(OAc)4 liberated the amino-functionality and hydrolysis of the amide and nitrile under acidic conditions finally gave DCG-IV (162

• )4 liberated the amino functionality and hydrolysis of both the phosphonamide and nitrile groups under acidic conditions finally provided phosphonocyclopropylamino acid 21. This compound showed to be a group III mGluRs selective ligand with moderate potency as mGluR4 and mGluR6 agonist (EC50 59 µM

Proton transfers in the Strecker reaction revealed by DFT calculations

• Shinichi Yamabe,
• Guixiang Zeng,
• Wei Guan and
• Shigeyoshi Sakaki

Beilstein J. Org. Chem. 2014, 10, 1765–1774, doi:10.3762/bjoc.10.184

• reaction have not been elucidated. As shown in Scheme 1, the Strecker reaction includes two reaction stages. The first reaction stage is the condensation of aldehydes with ammonia and hydrogen cyanide leading to α-aminonitriles . The second reaction stage is the hydrolysis of the nitrile group. In these

• )-CNH+ R-CH(NH2)-CNH+ + OH2 → R-CH(NH2)-C(OH)=NH + H+ However, the proton affinity (PA) of the nitrile is much smaller than that of the amino group, for example, the PAs of the cyano and amino groups of 2-amino-propanonitrile (Me-CH(NH2)-CN) are 190.7 and 199.6 kcal/mol, respectively. Thus, in the

• -aminopropanonitrile 8. Starting from 4, a concerted SN2-type pathway was also examined, which directly leads to the nitrile compound 8; see Scheme 6. In this pathway, the proton is transferred from the NH3+ group to the hydroxy group via a two-water-molecule bridge. At the same time, the H2O elimination and the

Atherton–Todd reaction: mechanism, scope and applications

• Stéphanie S. Le Corre,
• Mathieu Berchel,
• Hélène Couthon-Gourvès,
• Jean-Pierre Haelters and
• Paul-Alain Jaffrès

Beilstein J. Org. Chem. 2014, 10, 1166–1196, doi:10.3762/bjoc.10.117

• and purification on silica gel finally afforded the β-alkynyl-enolphosphate in 61–75% yield [58]. Azide, nitrile and thiocyanate were three other nucleophilic species used to produce pseudohalogenated phosphorus species by the AT reaction. Among them, the commercially available diphenyl

Preparation of phosphines through C–P bond formation

• Iris Wauters,
• Wouter Debrouwer and
• Christian V. Stevens

Beilstein J. Org. Chem. 2014, 10, 1064–1096, doi:10.3762/bjoc.10.106

• hydrophosphination of vinyl nitriles catalyzed by a dicationic nickel complex (Table 3). The method is based on the activation of the electrophile. It was suggested that complexation of the nitrile 50 to the chiral nickel Lewis acid activates the double bond towards 1,4-addition of the phosphine 25b. A final proton

Domino reactions of 2H-azirines with acylketenes from furan-2,3-diones: Competition between the formation of ortho-fused and bridged heterocyclic systems

• Alexander F. Khlebnikov,
• Mikhail S. Novikov,
• Viktoriia V. Pakalnis,
• Roman O. Iakovenko and
• Dmitry S. Yufit

Beilstein J. Org. Chem. 2014, 10, 784–793, doi:10.3762/bjoc.10.74

• into pyrazines, even when stored in a fridge. Different mechanisms of dimerization were assumed, such as formation and dimerization of nitrile ylides [37][40], hydrolysis to α-aminoketenes followed by condensation [37][41], intermediate formation of metal complexes in the reaction mediated by metals

• [41][43][46]. It was found that water [37], Brønsted [44][48] and Lewis acids [40][41][43] facilitate the formation of pyrazine derivatives. 2H-Azirines undergo ring opening on electronic excitation to give nitrile ylides [50]. Nitrile ylide formation under thermal conditions even from such strained

• compounds as 2H-azirines needs to overcome a quite high energy barrier. According to calculations at the DFT B3LYP/6-31G(d) level the free energy barriers to formation of nitrile ylides 13a–c from azirines 2a–c are 48.4, 47.6, 47.9 kcal·mol−1 (353 K, benzene (PCM)), respectively. Therefore the process of

Use of activated enol ethers in the synthesis of pyrazoles: reactions with hydrazine and a study of pyrazole tautomerism

• Denisa Tarabová,
• Stanislava Šoralová,
• Martin Breza,
• Marek Fronc,
• Wolfgang Holzer and
• Viktor Milata

Beilstein J. Org. Chem. 2014, 10, 752–760, doi:10.3762/bjoc.10.70

• ]. Electron-accepting groups can include ester, cyano, acetyl, nitro and trifluoroacetyl moieties. Thus, the simplest way to obtain activated enol ethers 3 is the condensation of active methylene components 2 such as malonic acid derivatives (esters, nitrile), (trifluoro)acetoacetic acid derivatives (esters

• , nitrile), acetylacetone, and nitroacetates with trialkyl orthoformate 1 (Scheme 1). Transesterification can be avoided if 1 bears the same alkyl group as 2. The reaction can be carried out with or without Lewis acid catalysis [2]. Pyrazoles constitute a large group of pharmacologically active compounds

Integration of enabling methods for the automated flow preparation of piperazine-2-carboxamide

• Richard J. Ingham,
• Claudio Battilocchio,
• Joel M. Hawkins and
• Steven V. Ley

Beilstein J. Org. Chem. 2014, 10, 641–652, doi:10.3762/bjoc.10.56

• explored the possibility of developing a machine-automated synthesis of this compound which might later be extended to analogous structures. For the facile machine-assisted synthesis of 1 we devised and optimised the fully continuous sequential hydration of nitrile 3 to amide 2 and hydrogenation of

• pyrazine 2 to piperazine 1 (Figure 2b). Both of these steps involve flowing through heterogeneous catalysts, a metal oxide for the hydration of the nitrile and a supported precious metal for the hydrogenation of the heteroaromatic ring. Furthermore, both steps involve the addition of a volatile small

• molecule to the substrate with no byproducts: the addition of water for the nitrile hydration, and the addition of hydrogen to the heteroarene for the reduction. Thus, this sequence is ideal for a fully continuous multi-step process. Results and Discussion Nitrile hydration Primary amides can be prepared

Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics

• Gijs Koopmanschap,
• Eelco Ruijter and
• Romano V.A. Orru

Beilstein J. Org. Chem. 2014, 10, 544–598, doi:10.3762/bjoc.10.50

• Ugi-adduct 180 with acid both cleaved the N-Boc-protecting group and activated the nitrile amide. Subsequent addition of a base induced cyclization and resulted in the DKP-scaffolds (182, Scheme 55). In total seven compounds were synthesized based on this UDAC-protocol with yields varying from 56 to

Simple two-step synthesis of 2,4-disubstituted pyrroles and 3,5-disubstituted pyrrole-2-carbonitriles from enones

• Murat Kucukdisli,
• Dorota Ferenc,
• Marcel Heinz,
• Christine Wiebe and
• Till Opatz

Beilstein J. Org. Chem. 2014, 10, 466–470, doi:10.3762/bjoc.10.44

• -dicarbonyl [44]. Compared to this elegant strategy, our two-step protocol provides a higher overall yield of compound 7a and uses less expensive reagents. In addition to the thermal elimination of HCN, intermediates 6 can also be aromatized by dehydrogenation. In this case, the nitrile group remains in the

The Flögel-three-component reaction with dicarboxylic acids – an approach to bis(β-alkoxy-β-ketoenamides) for the synthesis of complex pyridine and pyrimidine derivatives

• Mrinal K. Bera,
• Moisés Domínguez,
• Paul Hommes and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2014, 10, 394–404, doi:10.3762/bjoc.10.37

• – discovered and mechanistically elucidated by Oliver Flögel – features a three-component reaction that employs alkoxyallenes, nitriles and carboxylic acids: upon treatment with n-butyllithium the allene is lithiated in α-position to the alkoxy moiety; the addition of a nitrile as electrophile to this highly

Recent applications of the divinylcyclopropane–cycloheptadiene rearrangement in organic synthesis

• Sebastian Krüger and
• Tanja Gaich

Beilstein J. Org. Chem. 2014, 10, 163–193, doi:10.3762/bjoc.10.14

• achieved by the conjugate addition of cyanide [78]. Reduction of the newly introduced nitrile yielded the unexpected stable pentacycle 77. Formation of the missing methyl group (compound 78) could be achieved using forcing Wolff–Kishner-conditions. Benzoate formation and global oxidation [79][80] finally

• conditions [216] to obtain 285. This compound underwent smooth cyclopropanation with the adjacent benzene moiety to give cis-vinylcyclopropane cyanide 286. Conversion of the ketone to the corresponding triflate followed by mono-reduction of the nitrile furnished cis-vinylcyclopropane carbaldehyde 287, which

New developments in gold-catalyzed manipulation of inactivated alkenes

• Michel Chiarucci and
• Marco Bandini

Beilstein J. Org. Chem. 2013, 9, 2586–2614, doi:10.3762/bjoc.9.294

• equivalents of water, a nucleophilic attack of the nitrile itself on the hydroamination intermediate took place, affording the corresponding aminoamidation product 127 in moderate to good yields (Scheme 32b). In absence of external nucleophiles, the phenyl rings of the substrate backbone could intercept the

Cu-catalyzed trifluoromethylation of aryl iodides with trifluoromethylzinc reagent prepared in situ from trifluoromethyl iodide

• Yuzo Nakamura,
• Motohiro Fujiu,
• Tatsuya Murase,
• Yoshimitsu Itoh,
• Hiroki Serizawa,
• Kohsuke Aikawa and
• Koichi Mikami

Beilstein J. Org. Chem. 2013, 9, 2404–2409, doi:10.3762/bjoc.9.277

• established in DMPU at 50 °C in the presence of a catalytic amount of CuI and phen, the scope and limitation of this method were evaluated. The results are shown in Figure 1. The use of the electron-deficient aryl iodides 1b–f bearing nitrile, nitro, formyl, and trifluoromethyl groups led to the corresponding