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

• , amides, aldehyde, and ketone upon treatment with hydroxide, alkoxide, amine, diisobutylaluminium hydride and Grignard reagent, respectively. In these transformations, N-methyl-N-tosylcarboxamides behave like a Weinreb amide. Similarly, N-methyl-5-phenylisoxazole-3-carboxamide was converted into 3

• aromatic and aliphatic amides, and a similar conversion of N-methyl-5-phenylisoxazole-3-carboxamide (3), which is equal to the generation of variously functionalized nitrile oxides. Results and Discussion At the outset, methanesulfonylation (mesylation) of amides was studied. To a suspension of N,4

• alcohol 11j were also detected (Table 2, entries 18 and 19). In contrast to tosylated amides 8Ab and 8Bb, tosylated N-methyl-5-phenylisoxazole-3-carboxamide 12 exhibited higher reactivity. Upon tosylation under similar conditions 3 did not afford product 12, and isoxazole-3-carboxylic acid 5a, a

The unexpected influence of aryl substituents in N-aryl-3-oxobutanamides on the behavior of their multicomponent reactions with 5-amino-3-methylisoxazole and salicylaldehyde

• Volodymyr V. Tkachenko,
• Elena A. Muravyova,
• Sergey M. Desenko,
• Oleg V. Shishkin,
• Svetlana V. Shishkina,
• Dmytro O. Sysoiev,
• Thomas J. J. Müller and
• Valentin A. Chebanov

Beilstein J. Org. Chem. 2014, 10, 3019–3030, doi:10.3762/bjoc.10.320

• hydroxyaryl group as well as tricyclic nitrogen-containing heterocycles derived from salicylaldehyde have been reported as anticancer [1], antihypertensive agents [2], neuropeptide Y antagonists [3], and calcium channel blockers [4]. Fused azoloazines containing carboxamide substituents also exhibit a broad

• 48 h the reaction proceeded to form mainly two compounds – Knoevenagel adduct 7 and Schiff base 8 (Scheme 3). Trace amounts of 2-hydroxy-N-(2-methoxyphenyl)-2-methyl-4-(3-methylisoxazol-5-ylamino)chroman-3-carboxamide (4a) were detected in the reaction mixture as well. Furthermore, both conventional

• alia, ultrasonic activation was applied to promote this multicomponent reaction. It was established that the three-component cyclocondensation of the starting compounds under ultrasonication at room temperature for 4 h led to the selective formation of the substituted chroman-3-carboxamide 4a in 58

Synthesis and characterization of a new photoinduced switchable β-cyclodextrin dimer

• Florian Hamon,
• Claire Blaszkiewicz,
• Marie Buchotte,
• Estelle Banaszak-Léonard,
• Hervé Bricout,
• Sébastien Tilloy,
• Eric Monflier,
• Christine Cézard,
• Laurent Bouteiller,
• Christophe Len and
• Florence Djedaini-Pilard

Beilstein J. Org. Chem. 2014, 10, 2874–2885, doi:10.3762/bjoc.10.304

• ’-Bis[6I-deoxy-β-cyclodextrin-6I-yl]carboxamide-4,4’-azobenzene, AZO-CDim (1): β-CD-NH2 (2.02 g, 1.78 mmol, 2 equiv) and 3 (404 mg, 0.87 mmol, 1 equiv) were dissolved in 5 mL of dried distilled DMF. After 16 h of stirring at room temperature, the mixture was concentrated and the product precipitated by

Asymmetric Ugi 3CR on isatin-derived ketimine: synthesis of chiral 3,3-disubstituted 3-aminooxindole derivatives

• Giordano Lesma,
• Fiorella Meneghetti,
• Alessandro Sacchetti,
• Mattia Stucchi and
• Alessandra Silvani

Beilstein J. Org. Chem. 2014, 10, 1383–1389, doi:10.3762/bjoc.10.141

• amine and the isonitrile-derived primary carboxamide functional groups (Scheme 1). Also, this chemical correlation of the major diastereoisomer 10a allowed us to further confirm the prevailing S-configuration at the tetrasubstituted stereocenter C3 of the Ugi products. Compound 15a was submitted to a

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

• Abstract Here we describe the use of a new open-source software package and a Raspberry Pi® computer for the simultaneous control of multiple flow chemistry devices and its application to a machine-assisted, multi-step flow preparation of pyrazine-2-carboxamide – a component of Rifater®, used in the

• treatment of tuberculosis – and its reduced derivative piperazine-2-carboxamide. Keywords: automation; flow chemistry; hydration; hydrogenation; sustainable processing; Introduction Enabling synthesis technologies such as flow chemistry are becoming commonplace in modern laboratories (for recent reviews

• database for medicinal chemistry. For example, piperazine-2-carboxamide (1, Figure 2a) is an amino acid derivative with interesting biological properties [17]. At the time of writing, racemic 1 was identified as a notably expensive building block [18] and thus a good target for this transformation. We have

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

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

• . 2'-(4-tert-Butyl-5-methoxy-6-methylpyrimidin-2-yl)-N-(4-methoxy-2,2-dimethyl-5-oxohex-3-en-3-yl)biphenyl-2-carboxamide (24b): IR (ATR) ν: 3325 (N-H), 3065–2865 (=C-H, C-H), 1700, 1665 (C=O), 1550–1445 (C=C) cm−1; 1H NMR (CDCl3, 500 MHz) δ 0.71 (s, 9H, t-Bu), 1.26 (s, 9H, t-Bu), 2.31, 2.33 (2 s, 3H

An efficient method for the construction of polysubstituted 4-pyridones via self-condensation of β-keto amides mediated by P₂O₅ and catalyzed by zinc bromide

• Liquan Tan,
• Peng Zhou,
• Cui Chen and
• Weibing Liu

Beilstein J. Org. Chem. 2013, 9, 2681–2687, doi:10.3762/bjoc.9.304

• -diphenylpyridine-3-carboxamide (2a) in 94% GC yield (Table 1, entries 2, 4–6). Results of the screening study of the amount of ZnBr2 and P2O5 (Table 1, entries 6–8 and 12) indicated that 0.2 equiv of ZnBr2 and 1.5 equiv of P2O5 was sufficient for the completion of this transformation. In order to improve the

An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2013, 9, 2265–2319, doi:10.3762/bjoc.9.265

Synthesis and antibacterial activity of monocyclic 3-carboxamide tetramic acids

• Yong-Chul Jeong and
• Mark G. Moloney

Beilstein J. Org. Chem. 2013, 9, 1899–1906, doi:10.3762/bjoc.9.224

• Yong-Chul Jeong Mark G. Moloney Chemistry Research Laboratory, University of Oxford, Mansfield Rd, University of Oxford, OX1 3TA, UK 10.3762/bjoc.9.224 Abstract A chemical library of carboxamide-substituted tetramates designed by analogy with antibacterial natural products, a method for their

• inhibitory activity) [7] and unnatural systems, such as 3-carboxamide tetramic acid 1c and 3-carboxamide piperidine-2,4-dione 1d (undecaprenyl pyrophosphate synthase (UPPS) inhibitory activity) [8] exhibit high levels of antibacterial activity (Figure 1). All these systems share a β-dicarbonyl core. A drug

• discovery programme inspired by these natural products, as promoted by Waldmann [9], was of interest to us. We have recently focused on the construction and evaluation of libraries derived from tetramic acid scaffolds and discovered that bicyclic 3-carboxamide 1e, bicyclic 3-acyl 1f and monocyclic 3-acyl 1g

A Lewis acid-promoted Pinner reaction

• Dominik Pfaff,
• Gregor Nemecek and
• Joachim Podlech

Beilstein J. Org. Chem. 2013, 9, 1572–1577, doi:10.3762/bjoc.9.179

• used. A possible mechanism of this reaction is given in Scheme 7. Double silylation leads to the formation of a good leaving group and the highly electrophilic benzylic carbon is attacked by the nitrile yielding a nitrilium cation. The reaction is finalized by hydrolysis furnishing the carboxamide

• acid-promoted Pinner reaction. Synthesis of monaspilosin. Proposed mechanism of the trimethylsilyl triflate-promoted Ritter reaction. Selection of optimization experiments. Variation of nitriles and alcohols.a Carboxamide formation in a Pinner-type reaction.a Supporting Information Supporting

Gold-catalyzed intermolecular hydroamination of allenes with sulfonamides

• Chen Zhang,
• Shao-Qiao Zhang,
• Hua-Jun Cai and
• Dong-Mei Cui

Beilstein J. Org. Chem. 2013, 9, 1045–1050, doi:10.3762/bjoc.9.117

• [7][8][9][10][11][12][13][14][15]. More recently, Au(I), Au(III), Pt(II) and Rh(I) have been used for the intermolecular hydroamination of allenes with secondary alkylamines, ammonia, or carboxamide [7][16][17][18][19][20][21][22][23][24]. Although some of these advances have been efficiently made in

Development of peptidomimetic ligands of Pro-Leu-Gly-NH₂ as allosteric modulators of the dopamine D₂ receptor

• Swapna Bhagwanth,
• Ram K. Mishra and
• Rodney L. Johnson

Beilstein J. Org. Chem. 2013, 9, 204–214, doi:10.3762/bjoc.9.24

• able to modulate dopamine receptors because of their ability to place the carboxamide NH2 pharmacophore in the same topological space as that seen in the type II β-turn. Extensive studies with the spiro-bicyclic PLG peptidomimetics also established that both positive and negative modes of modulation

• hexafluorophosphate (HATU) as the coupling reagent in order to provide the primary carboxamide intermediate, which could be deprotected to give 48. The lithium enolate of Seebach’s oxazolidinone 30 served as the starting material for the stereoselective synthesis of ethylene-linked biproline derivative 50. The nature

• the Φ, ψ, and ω torsion angles of the type II β-turn, the type VI β-turn, and the polyproline II helix conformational types indicates that they each possess similar torsion angles at their N-termini, but they differ at their C-termini. However, they all place the carboxamide NH2 pharmacophore in the

Chemical–biological characterization of a cruzain inhibitor reveals a second target and a mammalian off-target

• Jonathan W. Choy,
• Clifford Bryant,
• Claudia M. Calvet,
• Patricia S. Doyle,
• Shamila S. Gunatilleke,
• Siegfried S. F. Leung,
• Kenny K. H. Ang,
• Steven Chen,
• Jiri Gut,
• Juan A. Oses-Prieto,
• Jonathan B. Johnston,
• Michelle R. Arkin,
• Alma L. Burlingame,
• Jack Taunton,
• Matthew P. Jacobson,
• James M. McKerrow,
• Larissa M. Podust and
• Adam R. Renslo

Beilstein J. Org. Chem. 2013, 9, 15–25, doi:10.3762/bjoc.9.3

• )-1-(benzenesulfonyl)-5-phenylpent-1-en-3-yl]amino]-3-(4-methylphenyl)-1-oxopropan-2-yl]pyridine-4-carboxamide (4), which is trypanocidal at ten-fold lower concentrations than for 1. We now find that the trypanocidal activity of 4 derives primarily from the inhibition of T. cruzi 14-α-demethylase

Features of the behavior of 4-amino-5-carboxamido-1,2,3-triazole in multicomponent heterocyclizations with carbonyl compounds

• Eugene S. Gladkov,
• Katerina A. Gura,
• Svetlana M. Sirko,
• Sergey M. Desenko,
• Ulrich Groth and
• Valentin A. Chebanov

Beilstein J. Org. Chem. 2012, 8, 2100–2105, doi:10.3762/bjoc.8.236

• of the NH2-group and endocyclic NH (Figure 2, compound VII or its position isomer VIII), or an alternative pathway involving the NH2-group and carboxamide fragment [25][26] (compound IX). Thus, there are several alternative directions for reactions between 4-amino-5-carboxamido-1,2,3-triazole

• '-cyclopentane}-3-carboxamide (4a) or 5,6,7,8-tetrahydro-4H-spiro{[1,2,3]triazolo[5,1-b]quinazoline-9,1'-cyclohexane}-3-carboxamide (4b) under all the conditions tested. The best results were observed in the case of microwave-assisted synthesis in methanol at 120 °C. Spirocompound 4c may be obtained by a

Total synthesis and biological evaluation of fluorinated cryptophycins

• Christine Weiß,
• Tobias Bogner,
• Benedikt Sammet and
• Norbert Sewald

Beilstein J. Org. Chem. 2012, 8, 2060–2066, doi:10.3762/bjoc.8.231

• homoallyl alcohol 16. The magnesium bromide diethyl etherate mediated allylation proceeded under substrate control and with complete diastereoselectivity [23][32]. Cross-metathesis of homoallyl alcohol 16 with the unit B derived acrylamide 17 provided the α,β-unsaturated δ-hydroxy carboxamide 18 (Scheme 2

• B was synthesized by the same convergent route as described for derivative 22. Homoallyl alcohol 27 [23] was reacted with the D-pentafluorophenylalanine derivative 26 in a cross-metathesis reaction in the presence of Grubbs II catalyst (Scheme 4). The resulting α,β-unsaturated δ-hydroxy carboxamide

Palladium-catalyzed dual C–H or N–H functionalization of unfunctionalized indole derivatives with alkenes and arenes

• Gianluigi Broggini,
• Egle M. Beccalli,
• Andrea Fasana and
• Silvia Gazzola

Beilstein J. Org. Chem. 2012, 8, 1730–1746, doi:10.3762/bjoc.8.198

• -methyl-2-butene. Proposed mechanism of the N-indolyl prenylation. Regioselective arylation of indoles by dual C–H functionalization. Plausible mechanism of the selective indole arylation. Chemoselective cyclization of N-allyl-1H-indole-2-carboxamide derivatives. Intramolecular annulations of

An intramolecular inverse electron demand Diels–Alder approach to annulated α-carbolines

• Zhiyuan Ma,
• Feng Ni,
• Grace H. C. Woo,
• Sie-Mun Lo,
• Philip M. Roveto,
• Scott E. Schaus and
• John K. Snyder

Beilstein J. Org. Chem. 2012, 8, 829–840, doi:10.3762/bjoc.8.93

• dried over sodium sulfate, and then the solvent was removed in vacuo. The residue was purified by flash chromatography to yield the desired amide 13. Representative example: N-Methyl-5-[(4-methylbenzene)sulfonyl]-N-(prop-2-yn-1-yl)-5H-[1,2,4]triazino[5,6-b]indole-3-carboxamide (13a). According to

Aryl nitrile oxide cycloaddition reactions in the presence of pinacol boronic acid ester

• Sarah L. Harding,
• Sebastian M. Marcuccio and
• G. Paul Savage

Beilstein J. Org. Chem. 2012, 8, 606–612, doi:10.3762/bjoc.8.67

• -3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4,5-dihydroisoxazole-5-carboxamide (7d): Isolated as a colourless oil (85 mg, 49%) after purification by column chromatography (80% Et2O in petroleum ether, Rf 0.43, 50% Et2O in petroleum ether); 1H NMR (CDCl3, 400 MHz) δ 7.82 (d, J = 8.3 Hz

Synthesis and characterization of new diiodocoumarin derivatives with promising antimicrobial activities

• Hany M. Mohamed,
• Ashraf H. F. Abd EL-Wahab,
• Ahmed M. EL-Agrody,
• Ahmed H. Bedair,
• Fathy A. Eid,
• Mostafa M. Khafagy and
• Kamal A. Abd-EL-Rehem

Beilstein J. Org. Chem. 2011, 7, 1688–1696, doi:10.3762/bjoc.7.199

• with p-phenylenediamine in boiling AcOH afforded the 6,8-diiodocoumarin-3-carboxamide derivatives 4 and 5, respectively. Interaction of 3 with glycine in dry benzene under reflux gave the new 6,8-diiodocoumarin-3-N,N-dimethylcarboxamide (7) instead of 6,8-diiodocoumarin-3-ylcarbonylglycine (6). The

• and p-aminophenylacetic acid), was successful, and the corresponding 6,8-diiodocoumarin-3-carboxamide derivatives 8–11 were obtained (Scheme 3). The structures of compounds 8–11 were established by IR, 1H NMR, 13C NMR and MS. The IR spectra of compound 8 showed 3287 cm–1 (OH, NH) and 1719 cm–1 (CO

• that the activity is considerably affected by the presence of the diiodocoumarino[3,4-c]pyridine, 2-methyl-8,10-diiodobenzo[2,1-g]-2H-1,3-oxazocine, diiodocoumarin-3-carboxamide or 2,3-dimethyl-8,10-diiodobenzo[2,1-g]-2H-1,3-oxazocine, and slightly decreases with the presence of different amide groups

Recent advances in direct C–H arylation: Methodology, selectivity and mechanism in oxazole series

• Cécile Verrier,
• Pierrik Lassalas,
• Laure Théveau,
• Guy Quéguiner,
• François Trécourt,
• Francis Marsais and
• Christophe Hoarau

Beilstein J. Org. Chem. 2011, 7, 1584–1601, doi:10.3762/bjoc.7.187

• in favour of the C5 position (Scheme 16) [64]. Miura first highlighted the reactivity of the C4 position of the oxazole ring in a direct substitutive-coupling methodology by reacting N-phenyl-2-phenyloxazole-5-carboxamide with phenylbromide (Scheme 17) [65]. Nevertheless, the introduction of a phenyl

Access to pyrrolo-pyridines by gold-catalyzed hydroarylation of pyrroles tethered to terminal alkynes

• Elena Borsini,
• Gianluigi Broggini,
• Andrea Fasana,
• Chiara Baldassarri,
• Angelo M. Manzo and
• Alcide D. Perboni

Beilstein J. Org. Chem. 2011, 7, 1468–1474, doi:10.3762/bjoc.7.170

• either from direct cyclization or from a formal rearrangement of the carboxamide group. Terminal alkynes are essential to achieve bicyclic pyrrolo-fused pyridinones by a 6-exo-dig process, while the presence of a phenyl group at the C–C triple bond promotes the 7-endo-dig cyclization giving pyrrolo

• . Cyclization reactions of pyrrole-carboxamides A solution of the appropriate pyrrole-carboxamide (2 mmol) was stirred, under an argon atmosphere, with AuCl3 (0.01 mmol) in 30 mL of an appropriate solvent (see Table 3 and Table 4 for solvents, temperatures and times). At the end of the reaction, the solvent was

NMR studies of anion-induced conformational changes in diindolylureas and diindolylthioureas

• Damjan Makuc,
• Jennifer R. Hiscock,
• Mark E. Light,
• Philip A. Gale and
• Janez Plavec

Beilstein J. Org. Chem. 2011, 7, 1205–1214, doi:10.3762/bjoc.7.140

• -indole-2-carboxamide (0.27 g, 1.07 mM) with 7-isothiocyanato-N-phenyl-1H-indole-2-carboxamide (0.31 g, 1.07 mM) in pyridine in 27% yield (see Supporting Information File 1 for details). Structural features and NMR chemical shifts The conformational properties of diindolylureas and diindolylthioureas 1–4

• are spatially close and the C2α carbonyl group is oriented towards the indole H1 proton. NOE enhancements between H2β and H3 protons were observed also in the 3·AcO− and 3·BzO− complexes, which suggests that the orientation of the carboxamide group along the C2–C2α bond is retained in 3 upon addition

An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals

• Marcus Baumann,
• Ian R. Baxendale,
• Steven V. Ley and
• Nikzad Nikbin

Beilstein J. Org. Chem. 2011, 7, 442–495, doi:10.3762/bjoc.7.57

• as T-cells and macrophages followed by viral fusion and entry into white blood cells. Maraviroc blocks this pathway by acting as an antagonist for the CCR-5 receptor hence disrupting HIV life cycle. The structural features of this molecule are a geminal difluorocyclohexyl carboxamide which is linked

Approaches towards the synthesis of 5-aminopyrazoles

• Ranjana Aggarwal,
• Vinod Kumar,
• Rajiv Kumar and
• Shiv P. Singh

Beilstein J. Org. Chem. 2011, 7, 179–197, doi:10.3762/bjoc.7.25

• reviewed in two books published in 1964 [5] and in 1967 [6]. Structurally simple 5-amino-1-tert-butylpyrazole-4-carboxamide I was found to inhibit p56 Lck [7] (Figure 1). 5-Amino-1-(4-methylphenyl) pyrazole II has been tested as an NPY5 antagonist [8]. 5-Amino-4-benzoyl-3-methylthio-1-(2,4,6

• al. [71] have reported that the reaction of α-cyano-β-dimethylaminocrotonamide (103) with hydrazine hydrate yields 5-amino-3-methylpyrazole-4-carboxamide (104). The reaction proceeds by loss of dimethylamine in first step followed by cyclization via nucleophilic attack on cyano group (Scheme 29). 3

• -heteroaryl-3-methyl/aryl-4-cyanopyrazoles. Synthesis of 5-amino-3-methylpyrazole-4-carboxamide. Synthesis of 4-acylamino-3(5)-amino-5(3)-arylsulfanylpyrazoles. Synthesis of 5-amino-1-aryl-4-diethoxyphosphoryl-3-halomethylpyrazoles. Synthesis of substituted 5-amino-3-trifluoromethylpyrazoles 114 and 118