Recent advances on the transition-metal-catalyzed synthesis of imidazopyridines: an updated coverage

• Gagandeep Kour Reen,
• Ashok Kumar and
• Pratibha Sharma

Beilstein J. Org. Chem. 2019, 15, 1612–1704, doi:10.3762/bjoc.15.165

One-pot activation–alkynylation–cyclization synthesis of 1,5-diacyl-5-hydroxypyrazolines in a consecutive three-component fashion

• Christina Görgen,
• Katharina Boden,
• Guido J. Reiss,
• Walter Frank and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2019, 15, 1360–1370, doi:10.3762/bjoc.15.136

• -hydroxypyrazolines in moderate to good yields. The structures were unambiguously corroborated by comprehensive NMR spectroscopy and X-ray structure analyses of selected derivatives. Keywords: activation; alkynylation; C–C coupling; copper; cyclization; multicomponent reactions; Introduction Pyrazoles [1][2] and

• –cyclization sequence of (hetero)arylglyoxylic acids, oxalyl chloride, arylacetylenes, and hydrazides does not form aromatic pyrazoles, but rather 1,5-diacyl-5-hydroxypyrazolines, i.e., the aromatizing elimination of water does not occur under these neutral conditions. This novel one-pot synthesis of 1,5

Synthesis of 2H-furo[2,3-c]pyrazole ring systems through silver(I) ion-mediated ring-closure reaction

• Vaida Milišiūnaitė,
• Rūta Paulavičiūtė,
• Eglė Arbačiauskienė,
• Vytas Martynaitis,
• Wolfgang Holzer and
• Algirdas Šačkus

Beilstein J. Org. Chem. 2019, 15, 679–684, doi:10.3762/bjoc.15.62

• and efficient procedure to access the 2H-furo[2,3-c]pyrazole ring system was developed by employing the silver(I) ion-mediated ring-closure reaction of 4-alkynyl-3-hydroxy-1-phenyl-1H-pyrazoles as a key step. The required intermediate hydroxyalkynyl substrates for this reaction were prepared by a Pd

• cyclization of readily available 4-alkynyl-3-hydroxy-1H-pyrazoles can be used as an efficient method to access many novel 2,5-disubstituted 2H-furo[2,3-c]pyrazoles. Keywords: 5-endo-dig cyclization; 2H-furo[2,3-c]pyrazole; pyrazole; silver(I) catalyst; Sonogashira coupling; Introduction Heterocyclic ring

• -c]pyrazoles, where both the fused pyrazole and furan moieties are aromatic, are still quite limited, and their chemistry and functional properties remain largely underexplored. Huang et al. have reported the synthesis and the evaluation of antiplatelet and anti-allergic activities of 2,3,4

Molecular iodine-catalyzed one-pot multicomponent synthesis of 5-amino-4-(arylselanyl)-1H-pyrazoles

• Camila S. Pires,
• Daniela H. de Oliveira,
• Maria R. B. Pontel,
• Jean C. Kazmierczak,
• Roberta Cargnelutti,
• Diego Alves,
• Raquel G. Jacob and
• Ricardo F. Schumacher

Beilstein J. Org. Chem. 2018, 14, 2789–2798, doi:10.3762/bjoc.14.256

• de Santa Maria – UFSM, 97105-900, Santa Maria, RS, Brazil 10.3762/bjoc.14.256 Abstract A one-pot iodine-catalyzed multicomponent reaction has been developed for the selective preparation of 5-amino-4-(arylselanyl)-1H-pyrazoles from a diverse array of benzoylacetonitriles, arylhydrazines and diaryl

• imidazopyridines, for example, is widely found in literature [6][7]. However, the preparation of 4-arylselanyl-1H-pyrazoles is quite scarce. Tiecco and co-workers described the preparation of phenylseleno substituted pyrazolidines by reacting allylhydrazines with phenylselanenyl sulfate generated in situ (Scheme 1

• the 3-methyl-5-methylsulfanyl-4-phenylselanyl-1H-pyrazole [10]. Our research group described the multicomponent synthesis of 3,5-dimethyl-4-arylselanyl-1H-pyrazoles catalyzed by copper iodide using DMSO as solvent [4]. More recently, Zora and co-workers reported the one-pot preparation of 4

Hydroarylations by cobalt-catalyzed C–H activation

• Rajagopal Santhoshkumar and
• Chien-Hong Cheng

Beilstein J. Org. Chem. 2018, 14, 2266–2288, doi:10.3762/bjoc.14.202

• a similar C–H amidation reaction of aryl pyrazoles 64 with isocyanates in the presence of [CoCp*(C6H6)](PF6)2 and KOAc [101]. Conclusion Hydroarylation is an emerging methodology in organic synthesis, because it is a highly atom-, step-, and redox-economical and simple reaction compared to

Applications of organocatalysed visible-light photoredox reactions for medicinal chemistry

• Michael K. Bogdos,
• Emmanuel Pinard and
• John A. Murphy

Beilstein J. Org. Chem. 2018, 14, 2035–2064, doi:10.3762/bjoc.14.179

• potential to be of interest if explored further. The good physical chemical properties of thiazoles, as well as their ability to act as isosteres to thiophenes, carbonyls and pyrazoles [49][50] make this scaffold an intriguing novel motif. 2.3 C(sp2)–X bond formation The obvious extension after considering

[3 + 2]-Cycloaddition reaction of sydnones with alkynes

• Veronika Hladíková,
• Jiří Váňa and
• Jiří Hanusek

Beilstein J. Org. Chem. 2018, 14, 1317–1348, doi:10.3762/bjoc.14.113

• this synthetic approach for the synthesis of polysubstituted 1,2-diazoles (pyrazoles, indazoles). However, until 2013 when Taran’s group introduced the regioselective Cu(I)-phenanthroline catalysis [3] this method was of limited value due to the harsh reaction conditions and sometimes also due to low

• of substituted 1,3,4-tri- or 1,3,4,5-tetrasubstituted pyrazoles [1][2][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39] or indazoles. Dimethyl acetylenedicarboxylate (DMAD, R3 = COOMe) or its analogues (diethyl; R3

• acids – potent xanthine oxidoreductase inhibitors [40] or even 3,4-unsubstituted pyrazoles [16]. Both pyrazole carboxylic groups can be also modified to hydrazides and oxazole rings [26] or a new condensed pyridazine ring [27]. Less reactive dipolarophiles such as dibenzoylacetylenes (1,4-diphenylbut-2

An unusual thionyl chloride-promoted C−C bond formation to obtain 4,4'-bipyrazolones

• Gernot A. Eller,
• Gytė Vilkauskaitė,
• Algirdas Šačkus,
• Vytas Martynaitis,
• Ashenafi Damtew Mamuye,
• Vittorio Pace and
• Wolfgang Holzer

Beilstein J. Org. Chem. 2018, 14, 1287–1292, doi:10.3762/bjoc.14.110

• , therein several drug molecules, agrochemicals, dyestuffs, compounds for optoelectronic purposes, complexing ligands and more contain a pyrazole nucleus [1][2][3][4][5][6][7][8]. Condensed pyrazoles are of special interest, as a commonly used example the phosphodiesterase 5 (PDE5) inhibitor sildenafil

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

• atom-economical biphenylation of N-heterocycles was developed [33]. This method involved a direct N-arylation of pyrazoles or triazoles 12 under basic conditions, followed by a ruthenium-catalysed C–H arylation with the emerging aryl iodide (Scheme 8). Due to the fact that the first step of this

An overview of recent advances in duplex DNA recognition by small molecules

• Sayantan Bhaduri,
• Nihar Ranjan and
• Dev P. Arya

Beilstein J. Org. Chem. 2018, 14, 1051–1086, doi:10.3762/bjoc.14.93

• significant antibacterial activity against Gram-positive bacterial strains [50]. Several other distamycin analogs were synthesized by replacing one or more pyrrole rings with other heterocycles such as pyrazoles [51], benzofurans [52], thiazoles, thiophenes, imidazole and oxazoles [53] in order to establish a

5-Aminopyrazole as precursor in design and synthesis of fused pyrazoloazines

• Ranjana Aggarwal and
• Suresh Kumar

Beilstein J. Org. Chem. 2018, 14, 203–242, doi:10.3762/bjoc.14.15

• resemblance. In addition to the immense biological potential related to fused pyrazoles, their synthetic potential needs to be reviewed for further improvements and extension of interests. Various efforts have been developed for the synthesis of pyrazole-based fused heterocycles. 5-Aminopyrazoles have been

• -aminopyrazoles 16, cyclic β-diketones 58 and heteroaryl aldehydes 47 (Scheme 17). The reaction under conventional heating in DMF provided best results with high yields of the corresponding pyrazolo[3,4-b]pyridines 74. The multicomponent reactions of 5-(4-substituted-benzylamino)pyrazoles 75, cyclic-β-diketones

Progress in copper-catalyzed trifluoromethylation

• Guan-bao Li,
• Chao Zhang,
• Chun Song and
• Yu-dao Ma

Beilstein J. Org. Chem. 2018, 14, 155–181, doi:10.3762/bjoc.14.11

• good tolerance to many functional groups, such as unsaturated double bonds, triple bonds and even unprotected OH group. Different heteroaromatic amines were also amenable to this conversion, including pyridines and pyrazoles. A mechanistic study indicated that an aryl radical and CuCF3 were involved in

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