Catalytic Chan–Lam coupling using a ‘tube-in-tube’ reactor to deliver molecular oxygen as an oxidant

• Carl J. Mallia,
• Paul M. Burton,
• Alexander M. R. Smith,
• Gary C. Walter and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2016, 12, 1598–1607, doi:10.3762/bjoc.12.156

• -phenyl-1H-pyrazole (18) as the nucleophile with a number of different phenylboronic acids gave moderate to good yields (38–82% yields). In general electron-rich phenylboronic acids (19, 29–32, Scheme 2) gave better yields than electron poor ones (33–35, Scheme 2). This is probably due to the more

• -rich (65% yield) and electron-poor (38% yield) 2-substituted phenylboronic acids, most likely due to steric factors (31 and 35, Scheme 2). It is noteworthy that for all of the 3-phenyl-1H-pyrazole couplings, only the 1,3-disubsituted pyrazole products were obtained with no 1,5-disubsituted isomers

Conjugate addition–enantioselective protonation reactions

• James P. Phelan and
• Jonathan A. Ellman

Beilstein J. Org. Chem. 2016, 12, 1203–1228, doi:10.3762/bjoc.12.116

• amides into ligand 113 was crucial for achieving high enantioselectivity. A wide variety of α-aryl vinyl ketones 112 were effective substrates, and only when R1 was methyl did the enantioselectivity drop below 92:8 er to 80:20 er (Scheme 26a). The authors also investigated a number of pyrazole

Bi- and trinuclear copper(I) complexes of 1,2,3-triazole-tethered NHC ligands: synthesis, structure, and catalytic properties

• Shaojin Gu,
• Jiehao Du,
• Jingjing Huang,
• Huan Xia,
• Ling Yang,
• Weilin Xu and
• Chunxin Lu

Beilstein J. Org. Chem. 2016, 12, 863–873, doi:10.3762/bjoc.12.85

• [1][2][3][4][5][6][7][8][9][10][11][12]. A number of transition metal complexes of NHCs containing pyridine [13], pyrimidine [14], pyrazole [15][16], naphthyridine [17], pyridazine [18], and phenanthroline [19][20] donating groups have been studied in metal-catalyzed organic transformations. Recently

The aminoindanol core as a key scaffold in bifunctional organocatalysts

• Isaac G. Sonsona,
• Eugenia Marqués-López and
• Raquel P. Herrera

Beilstein J. Org. Chem. 2016, 12, 505–523, doi:10.3762/bjoc.12.50

• framework. In this case, a pyrazole moiety presents additional H-bond acceptor sites. These could play an important role in fixing the substrate to the catalyst and favoring a more rigid transition state (TS11) and thus leading to better selectivity (Scheme 12). The absolute configuration is only given for

A convenient four-component one-pot strategy toward the synthesis of pyrazolo[3,4-d]pyrimidines

• Mingxing Liu,
• Jiarong Li,
• Hongxin Chai,
• Kai Zhang,
• Deli Yang,
• Qi Zhang and
• Daxin Shi

Beilstein J. Org. Chem. 2015, 11, 2125–2131, doi:10.3762/bjoc.11.229

• -phenyl-1H-pyrazole-4-carbonitrile (6a) with benzaldehyde and ethanol, the cyclization of (E)-5-(benzylideneamino)-1-phenyl-1H-pyrazole-4-carbonitrile (7a) with ethanol or the reaction of 1,6-diphenyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (5aa) with ethanol, respectively (Scheme 2). With those

Deproto-metallation of N-arylated pyrroles and indoles using a mixed lithium–zinc base and regioselectivity-computed CH acidity relationship

• Mohamed Yacine Ameur Messaoud,
• Ghenia Bentabed-Ababsa,
• Madani Hedidi,
• Aïcha Derdour,
• Floris Chevallier,
• Yury S. Halauko,
• Oleg A. Ivashkevich,
• Vadim E. Matulis,
• Laurent Picot,
• Valérie Thiéry,
• Thierry Roisnel,
• Vincent Dorcet and
• Florence Mongin

Beilstein J. Org. Chem. 2015, 11, 1475–1485, doi:10.3762/bjoc.11.160

• antiproliferative activity, with no significant difference between the pyrrole and indole derivatives. Conclusion Unlike other azoles such as pyrazole and triazoles [37][38][40], pyrrole and indole do not possess any atom capable of coordinating metals. As a consequence, the corresponding CH acidities in THF

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

• precipitation and clogging problems, thus a pressure chamber was developed [94] that would act as a pressure regulator allowing this step to be scaled up in flow in order to provide 114 on multigram scale (134 g/h). A Knorr pyrazole formation between 114 and commercially available hydrazine 115 had previously

Diastereoselective and enantioselective conjugate addition reactions utilizing α,β-unsaturated amides and lactams

• Katherine M. Byrd

Beilstein J. Org. Chem. 2015, 11, 530–562, doi:10.3762/bjoc.11.60

• amides was reported by Sibi and co-workers [233]. In this work, they performed the 1,4-addition of O-benzylhydroxylamine to pyrazole-derived α,β-unsaturated amides using a chiral Lewis acid derived from bisoxazoline 116 (Scheme 29). The authors obtained the 1,4-addition products in optimal yields and

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

• arenes (Scheme 4). The pyridine, pyrimidine, or pyrazole moiety serves as the directing group in the oxidative ortho-alkoxylation of arenes 16 with the Cu(OAc)2/AgOTf/O2 system giving coupling products 17 (Scheme 5) [47]. It is supposed that copper is inserted into the C–H bond of arene, the resulting Cu

Three-component synthesis of C₂F₅-substituted pyrazoles from C₂F₅CH₂NH₂·HCl, NaNO₂ and electron-deficient alkynes

• Pavel K. Mykhailiuk

Beilstein J. Org. Chem. 2015, 11, 16–24, doi:10.3762/bjoc.11.3

• C2F5CHN2, that participates in a [3 + 2] cycloaddition with electron-deficient alkynes in dichloromethane. Keywords: cycloaddition; fluorine; pentafluoroethyl group; pentafluoroethyldiazomethane; pyrazole; Introduction Incorporation of fluorinated fragments into organic compounds might affect their

• reaction conversion (Table 1, entry 6). The standard work-up afforded pyrazole 1a as a white crystalline solid in 99% yield without any purification (neither recrystallization, nor column chromatography). The reaction required no inert gas atmosphere, and was performed in air. Reaction scope Having these

• encouraging results on pyrazole 1a at hand, the reaction scope was studied. First, various mono-substituted alkynes 2–14 were tested under the already optimized reaction conditions (Table 2). Substrates 2, 3, 6–9 with strong EWGs smoothly reacted with C2F5CHN2 at room temperature to afford products 2a, 3a, 6a

A novel 4-aminoantipyrine-Pd(II) complex catalyzes Suzuki–Miyaura cross-coupling reactions of aryl halides

• Claudia A. Contreras-Celedón,
• Darío Mendoza-Rayo,
• José A. Rincón-Medina and
• Luis Chacón-García

Beilstein J. Org. Chem. 2014, 10, 2821–2826, doi:10.3762/bjoc.10.299

• ppm, with its integration indicating one proton. This result suggests to us that the palladium interacts with the carbonyl and amine groups of the pyrazole ring of 4-AAP. The synthesized 4-AAP–Pd(II) complex was used to carry out all palladium-catalyzed Suzuki–Miyaura cross-coupling reactions

Facile synthesis of 1H-imidazo[1,2-b]pyrazoles via a sequential one-pot synthetic approach

• András Demjén,
• Márió Gyuris,
• János Wölfling,
• László G. Puskás and
• Iván Kanizsai

Beilstein J. Org. Chem. 2014, 10, 2338–2344, doi:10.3762/bjoc.10.243

• synthetic elaboration of a green-compatible isocyanide-based access in three-component mode, we describe an operationally simple, one-pot two-step GBB protocol for the rapid construction of a 46 membered imidazo[1,2-b]pyrazole library with yields up to 83%. Keywords: Groebke–Blackburn–Bienaymé reaction; 1H

• -imidazo[1,2-b]pyrazole; isocyanide; multicomponent reaction; N-heterocycles; Introduction For the relatively rapid design and construction of a diverse, large pharmacophore library, the basic concepts of diversity-oriented synthesis and isocyanide-based multicomponent reactions, such as the Ugi four

• (5H- or 1H-imidazo[1,2-b]pyrazole with an endo- or exocyclic double bond) of each regioisomer. As presented [7][28][29][30][31][32][33][34][35][36], the “endo” 1H- and 5H-imidazo[1,2-b]pyrazoles were synthesized by the treatment of the corresponding amino substituted pyrazoles with aldehydes and

Chiral phosphines in nucleophilic organocatalysis

• Yumei Xiao,
• Zhanhu Sun,
• Hongchao Guo and
• Ohyun Kwon

Beilstein J. Org. Chem. 2014, 10, 2089–2121, doi:10.3762/bjoc.10.218

•  23). Shortly after, the Lu group further expanded the substrate scope of asymmetric [3 + 2] annulations with allenoates to a series of 3,5-dimethyl-1H-pyrazole-derived acrylamides (Scheme 24) [55]. The dipeptide-based phosphine H10 effectively promoted the reaction in good to excellent yields, albeit

Synthesis of trifluoromethyl-substituted pyrazolo[4,3-c]pyridines – sequential versus multicomponent reaction approach

• Barbara Palka,
• Angela Di Capua,
• Maurizio Anzini,
• Gyté Vilkauskaité,
• Algirdas Šačkus and
• Wolfgang Holzer

Beilstein J. Org. Chem. 2014, 10, 1759–1764, doi:10.3762/bjoc.10.183

• . Oximes derived from (intermediate) 5-alkynyl-1-phenyl-3-trifluoromethyl-1H-pyrazole-4-carbaldehydes were transformed into the corresponding 1H-pyrazolo[4,3-c]pyridine 5-oxides by silver triflate-catalyzed cyclization. Detailed NMR spectroscopic investigations (1H, 13C, 15N and 19F) were undertaken with

• pyrazole-derived compounds the COX-2 inhibitor Celecoxib (Celebrex®) is an important representative (Figure 1) [7]. In continuation of our program regarding the synthesis of fluoro- and trifluoromethyl-substituted pyrazoles and annulated pyrazoles [8][9] we here present the synthesis of trifluoromethyl

• the pyrazolo[4,3-c]pyridine system can be mainly achieved through two different approaches. One strategy involves the annelation of a pyrazole ring onto an existing, suitable pyridine derivative [16]. Alternatively, the bicyclic system can be accessed by pyridine-ring formation with an accordant

Chemistry of polyhalogenated nitrobutadienes, 14: Efficient synthesis of functionalized (Z)-2-allylidenethiazolidin-4-ones

• Viktor A. Zapol’skii,
• Jan C. Namyslo,
• Mimoza Gjikaj and
• Dieter E. Kaufmann

Beilstein J. Org. Chem. 2014, 10, 1638–1644, doi:10.3762/bjoc.10.170

• -inhibiting and antialgal properties [49], show anticancer activity [50][51], and are inhibitors of bacterial enzyme synthetase MurD with E. coli [52]. Additional treatment of thiazolidin-4-one 8 with a fivefold excess of hydrazine hydrate resulted in the formation of a 1H-pyrazole: A total of two hydrazine

• molecules were incorporated into the final product, whereas two additional equivalents were consumed capturing hydrochloric acid. In this way, the 1H-pyrazole 27 with an exceptional substitution pattern was obtained in 64% yield. The same reaction was applied to 5-arylmethylidene-thiazolidin-4-one 25 which

• furnished the corresponding 1H-pyrazole 28 in 52% yield (Scheme 5). A plausible multistep mechanism of this conversion is shown in Scheme 6: Initially, a first molecule of the strong nucleophile hydrazine is assumed to substitute the single C–Cl group within the trichlorovinyl subunit of 8 to give the

An experimental and theoretical NMR study of NH-benzimidazoles in solution and in the solid state: proton transfer and tautomerism

• Carla I. Nieto,
• Pilar Cabildo,
• M. Ángeles García,
• Rosa M. Claramunt,
• Ibon Alkorta and
• José Elguero

Beilstein J. Org. Chem. 2014, 10, 1620–1629, doi:10.3762/bjoc.10.168

• are: TC = 277.5 K and Δν = 0.12 ppm = 48 Hz; from them and using the Eyring equation [ΔG‡TC = 19.12 × TC × (10.32 + log TC/kC)] [32], we obtained: kC = 67.88 s−1 and ΔG‡277.5 = 58.0 kJ·mol−1. This barrier is similar to that of pyrazole in the same solvent (58.6 kJ·mol−1 at 289 K) [33]. The effect of

Regioselective S_N2' Mitsunobu reaction of Morita–Baylis–Hillman alcohols: A facile and stereoselective synthesis of α-alkylidene-β-hydrazino acid derivatives

• Silong Xu,
• Jian Shang,
• Junjie Zhang and
• Yuhai Tang

Beilstein J. Org. Chem. 2014, 10, 990–995, doi:10.3762/bjoc.10.98

• nitrogen-containing heterocyclic compounds, especially pyrazole derivatives [2][3][4][5][6][7]. Although various methods detailing the synthesis of hydrazines have been established [8], the development of an efficient synthesis of hydrazines with highly structural diversity from simple starting materials

• ). To further investigate the scope, a single case using allenic MBH alcohol 6 as the substrate was studied (Scheme 3). However, under similar conditions, the reaction between alcohol 6, tert-butyl azodicarboxylate (2c), and PPh3 afforded an interesting 1H-pyrazole compound 7 in 58% yield. A possible

• silica gel (gradient eluant: petroleum ether/ethyl acetate 9:1–3:1) to afford the hydrazines 3. Synthesis of 1H-pyrazole 7 Under N2 atmosphere and at room temperature, PPh3 (157 mg, 0.6 mmol) was slowly added to a stirred solution of allenic MBH alcohol 6 (61 mg, 0.3 mmol) and di-tert-butyl

Dimerisation, rhodium complex formation and rearrangements of N-heterocyclic carbenes of indazoles

• Zong Guan,
• Jan C. Namyslo,
• Martin H. H. Drafz,
• Martin Nieger and
• Andreas Schmidt

Beilstein J. Org. Chem. 2014, 10, 832–840, doi:10.3762/bjoc.10.79

• . Keywords: E/Z isomerism; indazol-3-ylidene; mesomeric betaine; pyrazole; quinazoline; Rh complex; Introduction As a result of their biochemical and pharmacological significance, there has been a considerably growing interest in indazoles in recent years, which is reflected in several book chapters and

• organocatalysts [15][16]. The N-heterocyclic carbenes of indazole (and pyrazole [17][18]), however, have a chemistry of their own which set them apart from the NHCs of the aforementioned ring systems. Portions of that field have been covered in recent review articles [18][19]. The N-heterocyclic carbene of

• observable in NMR spectra at standard temperature conditions. The spiro compound 14c crystallized from a saturated solution in n-hexane so that we were able to perform a single crystal X-ray analysis. The compound crystallized monoclinic. As expected, neither the pyrrole ring nor the pyrazole ring is planar

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

• tautomerism and supramolecular structure. A reverse addition of the reagents led to the isolation of two novel products, namely bis-enehydrazines 6 with an unsymmetrical arrangement of the formally equivalent subunits. Keywords: bis-enehydrazines; enol ethers; NMR; pyrazole; tautomerism; Introduction Enol

• are shown in Scheme 3. It is well known that the reaction of hydrazine hydrate with alkoxymethylidenemalononitrile affords 3-amino-1H-pyrazole-4-carbonitrile (5a) [8][9][10][11][12][13]. Eight tautomeric forms of 5a could theoretically be expected (Figure 1). Five of these tauromeric forms carry an

• numbering and the fourth and fifth numbers giving the positions of two hydrogens. When dimethyl methoxymethylidenemalonate (3b) is used, methyl 3-hydroxy-1H-pyrazole-4-carboxylate (5b) is formed. Analogously, reaction of diethyl ethoxymethylenemalonate (3c) gives the corresponding ethyl 3-hydroxy-1H

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

• pyrazolones The group of Krasavin prepared both pyrazole- as well as pyrazolone-containing peptidomimetics via a sequential hydrazino-Ugi/Paal–Knorr condensation [94]. In their first approach, pyrazoles were obtained in good yields, however, with a limited scope of the condensation substrates (Scheme 32

Aminofluorination of 2-alkynylanilines: a Au-catalyzed entry to fluorinated indoles

• Antonio Arcadi,
• Emanuela Pietropaolo,
• Antonello Alvino and
• Véronique Michelet

Beilstein J. Org. Chem. 2014, 10, 449–458, doi:10.3762/bjoc.10.42

• in 75% yield (Table 1, entry 9). The addition of NaHCO3 [20][33] as a base to the reaction mixture failed to give 2a, whereas it was successful for the preparation of fluorinated pyrazole, via the gold(I)-catalyzed tandem aminofluorination of 1-phenyl-2-(4-phenylbut-3-yn-2-ylidene)hydrazine. Other

• 1/2 and comparison of 5 vs 6). The reaction conditions were compatible with a halogen substituent such as in 2e (Table 2, entries 7 and 8), which was obtained in up to 67% yield. Gratifyingly the presence of 4-substituted 1H-pyrazole allowed the clean formation of the corresponding difluoroadduct 2f

Continuous flow nitration in miniaturized devices

• Amol A. Kulkarni

Beilstein J. Org. Chem. 2014, 10, 405–424, doi:10.3762/bjoc.10.38

• by Panke et al. [27]. The nitration product of 1-methyl-3-propyl-1H-pyrazole-5-carboxylic acid is an intermediate for the “life-style drug” Sildenafil® (Scheme 1). Similarly, nitration of 2-methylindole, pyridine N-oxide and toluene (also with an acetyl nitrate Ac2O/HNO3 mixture) were conducted. The

• critical situation. It is important to note that the pyrazole was nitrated after dissolving it in the sulfuric acid. For a reactor of 10 mL volume, the temperature was maintained at 65 °C, and the hydrolysis was carried out by dropping the reaction mixture into a cold aqueous solution saturated with

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

Coupling of C-nitro-NH-azoles with arylboronic acids. A route to N-aryl-C-nitroazoles

• Marta K. Kurpet,
• Aleksandra Dąbrowska,
• Małgorzata M. Jarosz,
• Katarzyna Kajewska-Kania,
• Nikodem Kuźnik and
• Jerzy W. Suwiński

Beilstein J. Org. Chem. 2013, 9, 1517–1525, doi:10.3762/bjoc.9.173

• Materials, Polish Academy of Sciences, M. Curie-Skłodowskiej 34, Zabrze 41-819, Poland 10.3762/bjoc.9.173 Abstract A method for the synthesis of N-aryl-C-nitroazoles is presented. A coupling reaction between variously substituted arylboronic acids and 3(5)-nitro-1H-pyrazole catalyzed by copper salt has

• conditions on the yield of the product has been presented. Results and Discussion The group of products that we mainly describe is the 1-aryl derivatives of 3(5)-nitro-1H-pyrazole (1a). This is still a barely investigated group of compounds that can have attractive properties. Some recent reports describe

• ], and are described as being useful for the treatment of cognitive-deficit-associated psychiatric, neurodegenerative and neurological disorders [33]. Only four papers describe the synthesis of 3-nitro-1-phenyl-1H-pyrazole. It may be a product of oxidation of 3-amino-1-phenyl-1H-pyrazole [18], a product

Substituent effect on the energy barrier for σ-bond formation from π-single-bonded species, singlet 2,2-dialkoxycyclopentane-1,3-diyls

• Jianhuai Ye,
• Yoshihisa Fujiwara and
• Manabu Abe

Beilstein J. Org. Chem. 2013, 9, 925–933, doi:10.3762/bjoc.9.106

• method of Tiecco [32]. Pyrazole 3g was then synthesized by the reaction with hydrazine hydrate. AZg was obtained by the Diels–Alder [4 + 2]-cycloaddition with cyclopentadiene and hydrogenation using PtO2 as a catalyst. The endo-configured structure of azoalkanes AZc–g was determined by X-ray

• /z): [M + Na]+ calcd for C33H32O6N2Na, 575.21526; found, 575.21387; Rf = 0.27 (EtOAc/hexane = 30/70). 4,4-Dibenzyloxy-3,5-bis(3,5-dimethoxyphenyl)pyrazole (3e). Yellow powder (from MeOH), mp: 183–184 °C; IR (neat, cm−1): 3025, 2952, 2847, 1605, 1551, 1456, 1426, 1371, 1160, 1117, 849, 670; 1H NMR

• , phenyl), 130.47 (s, C, aryl), 136.24 (s, C, phenyl), 161.81 (s, COCH3), 167.53 (s, C); ESIMS (m/z): [M + H]+ calcd for C33H33N6O2, 553.23331; found, 553.23267; Rf = 0.13 (EtOAc/hexane = 20/80). 4,4-Bis(3,5-dimethoxybenzyloxy)-3,5-bis(3,5-dimethoxyphenyl)pyrazole (3f). IR (neat, cm−1): 3010, 2942, 1605