One-pot multistep mechanochemical synthesis of fluorinated pyrazolones

• Joseph L. Howard,
• William Nicholson,
• Yerbol Sagatov and
• Duncan L. Browne

Beilstein J. Org. Chem. 2017, 13, 1950–1956, doi:10.3762/bjoc.13.189

• be obtained on introduction of fluorine to a molecule [18][19][20][21][22][23][24][25]. However, there have been limited reports on the synthesis of fluorinated pyrazoles, but fluorinated pyrazolones remain poorly studied [26][27][28][29][30]. Results and Discussion Initially the mechanochemical

Oxidative dehydrogenation of C–C and C–N bonds: A convenient approach to access diverse (dihydro)heteroaromatic compounds

• Santanu Hati,
• Ulrike Holzgrabe and
• Subhabrata Sen

Beilstein J. Org. Chem. 2017, 13, 1670–1692, doi:10.3762/bjoc.13.162

• oxidation. One of the early examples of such reaction was demonstrated by Han et al. in 2006 [84]. Here in pyridines 71 and pyrazoles 72 were synthesized in excellent yield by the oxidation of 4-substituted Hantzsch 1,4-dihydropyridines 69 and 1,3,5-trisubstituted pyrazolines 70 via molecular oxygen. The

New tricks of well-known aminoazoles in isocyanide-based multicomponent reactions and antibacterial activity of the compounds synthesized

• Maryna V. Murlykina,
• Maryna N. Kornet,
• Sergey M. Desenko,
• Svetlana V. Shishkina,
• Oleg V. Shishkin,
• Aleksander A. Brazhko,
• Vladimir I. Musatov,
• Erik V. Van der Eycken and
• Valentin A. Chebanov

Beilstein J. Org. Chem. 2017, 13, 1050–1063, doi:10.3762/bjoc.13.104

• with 2-amino-1,3,4-thiadiazoles [71][83][84][89][90], 2-aminoimidazoles [71][72][91][92], 2-aminoxazoles [71] and 1,2,5-oxadiazole-3,4-diamine [93] with the formation of imidazoazoles. Among the pyrazoles only 5-amino-3-methylpyrazole, 5-aminopyrazole-4-carbonitrile and ethyl 5-aminopyrazole-4

Synthesis of tetrasubstituted pyrazoles containing pyridinyl substituents

• Josef Jansa,
• Ramona Schmidt,
• Ashenafi Damtew Mamuye,
• Laura Castoldi,
• Alexander Roller,
• Vittorio Pace and
• Wolfgang Holzer

Beilstein J. Org. Chem. 2017, 13, 895–902, doi:10.3762/bjoc.13.90

• 42, A-1090 Vienna, Austria 10.3762/bjoc.13.90 Abstract A synthesis of tetrasubstituted pyrazoles containing two, three or four pyridinyl substituents is described. Hence, the reaction of 1,3-dipyridinyl-1,3-propanediones with 2-hydrazinopyridine or phenylhydrazine, respectively, affords the

• corresponding 1,3,5-trisubstituted pyrazoles. Iodination at the 4-position of the pyrazole nucleus by treatment with I2/HIO3 gives the appropriate 4-iodopyrazoles which served as starting materials for different cross-coupling reactions. Finally, Negishi cross-coupling employing organozinc halides and Pd

• catalysts turned out to be the method of choice to obtain the desired tetrasubstituted pyrazoles. The formation of different unexpected reaction products is described. Detailed NMR spectroscopic investigations (1H, 13C, 15N) were undertaken with all products prepared. Moreover, the structure of a

Sydnone C-4 heteroarylation with an indolizine ring via Chichibabin indolizine synthesis

• Florin Albota,
• Mino R. Caira,
• Constantin Draghici,
• Florea Dumitrascu and
• Denisa E. Dumitrescu

Beilstein J. Org. Chem. 2016, 12, 2503–2510, doi:10.3762/bjoc.12.245

• interesting chemical reactions of sydnones are their electrophilic substitution at C-4 and their participation in 1,3-dipolar cycloaddition reactions with olefinic and acetylenic dipolarophiles to form pyrazoles and functional transformation at C-4 [20][21][22][23][24][25][26]. Herein we present the synthesis

A new paradigm for designing ring construction strategies for green organic synthesis: implications for the discovery of multicomponent reactions to build molecules containing a single ring

• John Andraos

Beilstein J. Org. Chem. 2016, 12, 2420–2442, doi:10.3762/bjoc.12.236

• showed that benzimidazoles, Biginelli adducts, dihydropyridines, furans, pyrans, pyridinones, and thiophenes had a high representation of intrinsic greenness; whereas, a high proportion of MCRs producing chromene-4-ones, coumarins, indoles, and pyrazoles had low probabilities of achieving intrinsic

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

• being detected. The regioselectivity of the 1,3-disubsituted pyrazoles was confirmed by NOESY NMR experiments (30, 33 and 35, Figures 4–6) as well as comparison to known published data. In addition, an X-ray crystal structure for compound 33 was obtained and the connectivity confirmed. It was noted that

• conditions allowed for a scalable and efficient way for the continuous synthesis of a number of functionalised aromatic and aliphatic amines including a number of 1,3-disubstituted pyrazoles which were selectively obtained over the regioisomeric 1,5-disubstituted products. When compared to other published

Multicomponent reactions: A simple and efficient route to heterocyclic phosphonates

• Mohammad Haji

Beilstein J. Org. Chem. 2016, 12, 1269–1301, doi:10.3762/bjoc.12.121

• adduct 214, resulting from condensation of aldehydes 211 and nitrile derivatives 212, lead to cyclo-adduct intermediates 216 which cyclize to phosphorylated pyrazoles 217. In this way, a one-pot three-component reaction of aldehydes 218, methyl ketones 219 and the Bestmann–Ohira reagent has been

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

• Feng group has reported the conjugate addition of pyrazoles to α-substituted aromatic vinyl ketones followed by enantioselective protonation of the enolate intermediate using an N,N’-dioxide–Sc(III) catalyst system (Scheme 26) [51]. During optimization, the authors found that incorporation of bulky

• thiols to N-arylitaconimides. Enantioselective addition of thiols to α-substituted N-acryloylamides. Kobayashi’s enantioselective addition of thiols to α,β-unsaturated ketones. Feng’s enantioselective addition of pyrazoles to α-substituted vinyl ketones. Luo and Cheng’s addition of indoles to vinyl

A convenient route to symmetrically and unsymmetrically substituted 3,5-diaryl-2,4,6-trimethylpyridines via Suzuki–Miyaura cross-coupling reaction

• Dariusz Błachut,
• Joanna Szawkało and
• Zbigniew Czarnocki

Beilstein J. Org. Chem. 2016, 12, 835–845, doi:10.3762/bjoc.12.82

• teams in the construction of polyarylated benzenes [56], pyridines [57][58][59][60], thiophenes [61][62], quinoxalines [63], pyrazoles [64] pyrroles [65], pyrimidines [66][67], benzofuranes [68], imidazo[1,2-a]pyridines [69], diaryl/heteroaryl methanes [70], and indoles [71], bearing differently

Beyond catalyst deactivation: cross-metathesis involving olefins containing N-heteroaromatics

• Kevin Lafaye,
• Cyril Bosset,
• Lionel Nicolas,
• Amandine Guérinot and
• Janine Cossy

Beilstein J. Org. Chem. 2015, 11, 2223–2241, doi:10.3762/bjoc.11.241

• moieties such as pyridines, pyrimidines, imidazoles and pyrazoles (Scheme 37). From the selected examples discussed above, we tried to delineate some trends regarding to the use of alkenes possessing N-heteroaromatics in RCM and CM. In RCM, GI and GII are usually preferred and diluted conditions are

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

• solution, which were calculated using a continuum solvation model, better help in rationalizing the outcome of the deproto-metallation reactions. In addition, whereas N-(4-substituted phenyl)pyrazoles and -triazoles (e.g., with methoxy as substituent, Figure 7) can be deprotonated at C2’ for the same

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

• -deficient alkynes gives C2F5-substituted pyrazoles in excellent yields. The transformation smoothly proceeds in dichloromethane/water, tolerates the presence of air, and requires no purification of products by column chromatography. Mechanistically, C2F5CH2NH2·HCl and NaNO2 react first in water to generate

• physicochemical and biological properties [1][2][3][4][5][6][7][8]. It is not surprising, therefore, that up to 20% of all modern drugs contain at least one fluorine atom [9][10][11]. Fluorinated pyrazoles, for example, do play a role in medicinal chemistry: among them are inhibitors of the measles virus RNA

• drugs and agrochemicals – Bixafen, Fipronyl, Celecoxib, Pyroxasulfone and Penflufen – are also pyrazoles with diverse fluorine-containing substituents (Figure 1) [22][23]. Moreover, fluorinated NH-pyrazoles have also found an application as ligands in coordinational chemistry [24][25][26][27]. While the

Palladium-catalyzed 2,5-diheteroarylation of 2,5-dibromothiophene derivatives

• Fatma Belkessam,
• Aidene Mohand,
• Jean-François Soulé,
• Abdelhamid Elias and
• Henri Doucet

Beilstein J. Org. Chem. 2014, 10, 2912–2919, doi:10.3762/bjoc.10.309

• –2 mol % palladium catalysts, the target 2,5-diheteroarylated thiophenes were obtained in moderate to good yields and with a wide variety of heteroarenes such as thiazoles, thiophenes, furans, pyrroles, pyrazoles or isoxazoles. Moreover, sequential heteroarylation reactions allow the access to 2,5

• promotes the 2,5-diheteroarylation of 2,5-dibromothiophene in the presence of a variety of heteroarenes such as thiophenes, furans, pyrroles, pyrazoles or isoxazoles as the coupling partners. The sequential diheteroarylation of 2,5-dibromothiophene was also found to be possible to afford 2,5

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

• -free catalysts for SM coupling reactions. Transition metal complexes that have shown a wide range of biological activity are those containing the pyrazolone derivative 4-aminoantipyrine (4-amino-1,5-dimethyl-2-phenyl-1H-pyrazol-3(2H)-one, or simply “4-AAP”) [18]. Pyrazoles, in general, are one of the

One-pot four-component reaction for convenient synthesis of functionalized 1-benzamidospiro[indoline-3,4'-pyridines]

• Chao Wang,
• Yan-Hong Jiang and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2014, 10, 2671–2676, doi:10.3762/bjoc.10.281

• [indoline-3,4'-pyrano[2,3-c]pyrazoles] have been developed very recently by several groups [25][26][27]. Against this background and in continuation of our efforts toward the development of practical multicomponent reactions based on the reactivity of isatin and its derivatives [28][29][30][31][32][33][34

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

• Abstract 5-Aminopyrazole-4-carbonitrile and ethyl 5-aminopyrazole-4-carboxylate, as potential trifunctional building blocks are introduced in a facile, chemo- and regioselective multicomponent assembly of imidazo[1,2-b]pyrazoles via the Groebke–Blackburn–Bienaymé reaction (GBB reaction). Besides the

• have predominantly been described as 5H-imidazo[1,2-b]pyrazoles with an endo double bond (and not as 1H-imidazo[1,2-b]pyrazoles), but without 2D NMR-based support. However, the GBB-3CR of functionalized pyrazoles might lead to the formation of two regioisomers [24] and four different tautomeric forms

• (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

(CF₃CO)₂O/CF₃SO₃H-mediated synthesis of 1,3-diketones from carboxylic acids and aromatic ketones

• JungKeun Kim,
• Elvira Shokova,
• Victor Tafeenko and
• Vladimir Kovalev

Beilstein J. Org. Chem. 2014, 10, 2270–2278, doi:10.3762/bjoc.10.236

• application of the proposed protocol allowed for the synthesis of selected polysubstituted pyrazoles in a one-pot procedure directly from acids and ketones. Keywords: Claisen condensation; 1,3-diketones; heterocycles; triflic acid; trifluoroacetic acid anhydride; Introduction 1,3-Diketones represent one of

• hydroxydiketone 3x, which could be hydrolyzed to the corresponding alcohol 3y (reaction 3 in Scheme 2). The acylation of 1-indanone (2а) with 2,2’-(adamantane-1,3-diyl)diacetic acid (1l) gave the tetraketone 3z. Finally, we used our method in a two-stage one-pot syntheses of pyrazoles, which find extensive use in

• the pharmaceutical industry [8][28]. Diketones 3a–c,f, essential for synthesis of the pyrazoles 6a–d, were obtained by one of the three routes (Scheme 3). The one-pot intra- and intermolecular acylation of β-phenylpropionic acids 1а,b gave 3а,b. The acylation of the 1-indanone (2а) by acetic acid (1g

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

• the field of pyrazoles, pyridines and condensed systems thereof trifluoromethyl-substituted congeners can be found as partial structures in several pharmacologically active compounds. In the pyridine series the HIV protease inhibitor Tipranavir (Aptivus®) [6] may serve as an example, within the

• 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

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

• cyclization step, a series of (Z)-2-allylidenethiazolidin-4-ones was obtained in yields up to 81%. Some subsequent reactions have been examined too, such as the formation of perfunctionalized 1H-pyrazoles upon treatment with hydrazine. Thiazolidinones are as well known for their physiological activities as

• for their application in optoelectronics. Keywords: atropisomers; cyclization; 2-nitroperchlorobutadiene; 1H-pyrazoles; thiazolidin-4-ones; Introduction Preliminary studies in the field of polyhalogenated nitrobutadienes have already shown the enormous potential of pentachloro-2-nitro-1,3-butadiene

• condensation of the heterocyclic rings with aromatic aldehydes, and an unusual formation of persubstituted pyrazoles demonstrate the chemical versatility of these heterocyclic systems. The newly formed thiazolidinones deserve additional synthetic interest as starting materials, also due to their trichlorovinyl

Allenylphosphine oxides as simple scaffolds for phosphinoylindoles and phosphinoylisocoumarins

• G. Gangadhararao,
• Ramesh Kotikalapudi,
• M. Nagarjuna Reddy and
• K. C. Kumara Swamy

Beilstein J. Org. Chem. 2014, 10, 996–1005, doi:10.3762/bjoc.10.99

• series include phosphonobenzofurans/indenones [21][22], -pyrazoles [23], -chromenes/thiochromenes [24][25], -pyrroles [26], multiply substituted furans [27], indolopyran-1-ones [28], N-hydroxyindolinones [29], and oxindoles [30]. In the reaction shown in Scheme 1a, for the formation of the

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

• University, Althanstrasse 14, A-1090 Vienna, Austria 10.3762/bjoc.10.70 Abstract Activated enol ethers derived from esters or the dinitrile of malonic acid, or from pentane-2,4-dione were treated with hydrazine hydrate. The structures of the obtained products – pyrazoles 5 – were studied with a focus on

• trifunctional electrophiles and are useful building blocks for the introduction of a three carbon fragment into the resulting molecule. Thus, the reaction of enol ethers with hydrazines produces pyrazoles, with amidines pyrimidines, with hydroxylamine isoxazoles, and with anilines quinolines/ones are formed [2

• , 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

One-pot three-component synthesis and photophysical characteristics of novel triene merocyanines

• Christian Muschelknautz,
• Robin Visse,
• Jan Nordmann and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2014, 10, 599–612, doi:10.3762/bjoc.10.51

• convergent strategies paved the way to luminescent push–pull dienes 1–4 with conformationally flexible and fixed acceptor units (Figure 1) [30][31][32], pyrazoles [33][34], benzodiazepines [35], furans and pyrroles [36][37] by consecutive multicomponent reactions and to highly emissive spirocycles [38][39

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

• also explored with several aliphatic and aromatic amines, in which the more electron-rich inputs gave the higher yields. In a variation, first the triazole-unit was formed followed by the Ugi MCR. However this resulted in lower yields compared to the initial sequence (33–39% vs. 31–61%). Pyrazoles and

• 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

Silver and gold-catalyzed multicomponent reactions

• Giorgio Abbiati and
• Elisabetta Rossi

Beilstein J. Org. Chem. 2014, 10, 481–513, doi:10.3762/bjoc.10.46

• corresponding tricyclic naphthalene fused pyrazoles 15 (Scheme 12, path A). Moreover, in a subsequent work, the authors applied the same strategy to obtain pyrazolo[4,3-b]indoles 16, a new class of CK2 inhibitors [42]. These products were obtained starting from properly substituted dihydropyrazoles 13 in which