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

• due to its preeminent synthetic efficiency, also in the construction of heterocyclic and condensed heterocyclic systems [23][24][25][26][27]. After testing different reaction conditions we found that microwave heating of the chloroaldehyde 2 with tert-butylamine in the presence of 6 mol % of Pd(PPh3

Automated solid-phase peptide synthesis to obtain therapeutic peptides

• Veronika Mäde,
• Sylvia Els-Heindl and
• Annette G. Beck-Sickinger

Beilstein J. Org. Chem. 2014, 10, 1197–1212, doi:10.3762/bjoc.10.118

• special features such as automated monitoring (e.g., via chromophors [67] or conductivity [68]), microwave heating, capability for inert atmosphere and automated peptide cleavage [65]. The systems are mostly based on filtration by vacuum or pressure application [69], or centrifugation [70] and can work in

Rapid pseudo five-component synthesis of intensively blue luminescent 2,5-di(hetero)arylfurans via a Sonogashira–Glaser cyclization sequence

• Fabian Klukas,
• Alexander Grunwald,
• Franziska Menschel and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2014, 10, 672–679, doi:10.3762/bjoc.10.60

• under microwave heating (the temperature optimum of 130 °C was quickly identified by screening experiments), the water/KOH ratio, and the concentrations were varied. In the course of our studies a related work using copper catalysts with the electronrich DMEDA (N,N’-dimethylethylenediamine) or the

• electronpoor 1,10-phenanthroline as ligands was published [32], however, in our hands no favorable effect on the isolated yields of 2a was found (Table 1, entries 4–8). The cyclization works equally well with conductive heating in an oil bath instead of microwave heating (Table 1, entry 8). At higher

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

• 79%. Recently, another UDC-based synthesis of DKP scaffolds using the cheaper and commercial available n-butylisocyanide as convertible component was reported [149]. The scaffolds were obtained in good yields in a 1:1 diastereomeric ratio. However, microwave heating was required to induce cyclization

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

• ) under acidic conditions. Several strong and weak acids were screened at temperatures ranging from 0–150 °C. The formation of pyrrole 7a was observed in acetic acid under microwave heating but many byproducts were formed under these conditions, presumably due to oligo- and polymerization of the product

Synthesis of 3,4-dihydro-1,8-naphthyridin-2(1H)-ones via microwave-activated inverse electron-demand Diels–Alder reactions

• Salah Fadel,
• Youssef Hajbi,
• Mostafa Khouili,
• Said Lazar,
• Franck Suzenet and
• Gérald Guillaumet

Beilstein J. Org. Chem. 2014, 10, 282–286, doi:10.3762/bjoc.10.24

• ynamides 2–5 [22][23][24][53] afforded triazinylpent-4-ynamides 6–9 in moderate to good yields (Scheme 3, Table 2). Intramolecular inverse electron-demand Diels–Alder reactions With the tethered triazines 6–9 in hand, we were able to study the cycloaddition reaction under microwave heating following the

Microwave-assisted synthesis of 5,6-dihydroindolo[1,2-a]quinoxaline derivatives through copper-catalyzed intramolecular N-arylation

• Fei Zhao,
• Lei Zhang,
• Hailong Liu,
• Shengbin Zhou and
• Hong Liu

Beilstein J. Org. Chem. 2013, 9, 2463–2469, doi:10.3762/bjoc.9.285

• technology to conduct the intramolecular N-arylation. As a result, a similar yield was obtained under the same catalytic conditions when 1a was subjected to microwave irradiation for just one hour (Table 1, entry 2). Then, we tried to optimize the reaction conditions under microwave heating. At first

Temperature measurements with two different IR sensors in a continuous-flow microwave heated system

• Jonas Rydfjord,
• Fredrik Svensson,
• Magnus Fagrell,
• Jonas Sävmarker,
• Måns Thulin and
• Mats Larhed

Beilstein J. Org. Chem. 2013, 9, 2079–2087, doi:10.3762/bjoc.9.244

• ; dipolar polarization and ionic conduction [11][12][13]. Compared to conventional heating this reverses the situation; in conventional heating the walls of the reaction vessel will be hotter than the reaction mixture whilst when using microwave heating the reaction mixture will have a higher temperature

• ][15][16]. In contrast, microwave transparent fiber optic probes can be used for correct temperature measurements. In a recent tutorial review Kappe highlighted the difficulties of temperature monitoring under microwave heating [16]. We recently described the concept of a nonresonant microwave

• temperature under the influence of an electromagnetic field is not a trivial problem. In this evaluation we have used a fiber optic probe which allows the measurement of temperatures inside a reactor in a continuous-flow system using a nonresonant microwave heating device, and investigated two IR sensors as

Acid, silver, and solvent-free gold-catalyzed hydrophenoxylation of internal alkynes

• Marcia E. Richard,
• Daniel V. Fraccica,
• Kevin J. Garcia,
• Erica J. Miller,
• Rosa M. Ciccarelli,
• Erin C. Holahan,
• Victoria L. Resh,
• Aakash Shah,
• Peter M. Findeis and
• Robert A. Stockland Jr.

Beilstein J. Org. Chem. 2013, 9, 2002–2008, doi:10.3762/bjoc.9.235

• column chromatography, dried using molecular sieves (hexane/EtOAc solution), and isolated as oils or powders following removal of the volatiles. Preparation of 4-[[(1Z)-1-butyl-1-hexen-1-yl]oxy]nitrobenzene (16): General procedure B was followed (microwave heating) with 1 (0.0088 g, 0.014 mmol), 5-decyne

• solvent. Microwave heating with 1 or 7 as the catalyst (14.0 μmol, 5%). The yield of the addition product and ratio of regioisomers was determined by 1H NMR spectroscopy using anisole as an internal standard. Hydrophenoxylation of unactivated internal alkynes.a Supporting Information Supporting

One-step synthesis of pyridines and dihydropyridines in a continuous flow microwave reactor

• Mark C. Bagley,
• Vincenzo Fusillo,
• Robert L. Jenkins,
• M. Caterina Lubinu and
• Christopher Mason

Beilstein J. Org. Chem. 2013, 9, 1957–1968, doi:10.3762/bjoc.9.232

• . Strauss first demonstrated in 1994 that by combining microwave-heating technology with continuous flow processing, problems with the limited penetration depth of microwave irradiation and the physical restrictions of a standing wave cavity could be overcome [14]. A continuous flow reactor has the

• combination of microwave heating and continuous flow or stop-flow processing [16][17]. Continuous flow microwave reactors have been used in transition metal-mediated cross-coupling reactions by Organ et al. in a Pd-coated capillary [18][19][20], over a solid-supported Pd catalyst using a thin layer of gold as

• recent advent of new technology for mesoscale microwave-assisted continuous flow reactions [30], we set out to establish if readily-available ethynyl carbonyl precursors were capable of delivering diverse heterocyclic targets under a continuous flow regime under microwave heating. Ley and Baxendale et al

Raman spectroscopy as a tool for monitoring mesoscale continuous-flow organic synthesis: Equipment interface and assessment in four medicinally-relevant reactions

• Trevor A. Hamlin and
• Nicholas E. Leadbeater

Beilstein J. Org. Chem. 2013, 9, 1843–1852, doi:10.3762/bjoc.9.215

• to the flow unit In interfacing our Raman spectrometer with a continuous-flow reactor, our objective was to use a similar approach to that which proved successful when using microwave heating. Borosilicate glass is essentially “Raman transparent”. Therefore reactions could be monitored by placing a

• ). We had extensive experience of monitoring this reaction both qualitatively [32] and quantitatively [36] when using microwave heating so believed it would be a good starting point for our present study. The reaction works well when using ethyl acetate as the solvent. However, 1 is not completely

Synthesis and physicochemical characterization of novel phenotypic probes targeting the nuclear factor-kappa B signaling pathway

• Paul M. Hershberger,
• Satyamaheshwar Peddibhotla,
• E. Hampton Sessions,
• Daniela B. Divlianska,
• Ricardo G. Correa,
• Anthony B. Pinkerton,
• John C. Reed and
• Gregory P. Roth

Beilstein J. Org. Chem. 2013, 9, 900–907, doi:10.3762/bjoc.9.103

• against TNFα mediated NF-κB activation as measured in our reporter gene assay format. Probe 8 was synthesized as shown in Scheme 2 [12]. Reaction of 4-tert-butyl-cyanobenzene with hydroxylamine hydrochloride under microwave heating conditions resulted in the hydroxyamidine 6. This intermediate was

• purification with crotylamine under microwave heating conditions to provide 15. Reaction of 15 with potassium ethyl xanthogenate, again under microwave heating conditions, led to the bicyclic thiol 16. Without purification, 16 was added to 1-bromo-3-phenylpropane in the presence of potassium carbonate to

Efficient Cu-catalyzed base-free C–S coupling under conventional and microwave heating. A simple access to S-heterocycles and sulfides

• Silvia M. Soria-Castro and
• Alicia B. Peñéñory

Beilstein J. Org. Chem. 2013, 9, 467–475, doi:10.3762/bjoc.9.50

• . More recently, S-aryl thioacetates have been obtained by the catalyst system [Pd2(dba)3-Xantphos] in 1,4-dioxane under microwave heating at 160 °C in good yields [51]. The synthesis of arylthiobenzoates by a CuI/1,10-phenanthroline, starting from thiobenzoic acid and iPr2NEt (DIPEA) in toluene after 24

• conversion times and yields (Table 3, Method B). These reactions occur in only 2 h with yields comparable to those under conventional heating, for EWGs and EDGs (Table 3, entries 1, 3, 5, 7, 9 and 12). Bromobenzene was unreactive towards 1 under both conventional and microwave heating (Table 3, entry 13

Multivalent display of the antimicrobial peptides BP100 and BP143

• Imma Güell,
• Rafael Ferre,
• Kasper K. Sørensen,
• Esther Badosa,
• Iteng Ng-Choi,
• Emilio Montesinos,
• Eduard Bardají,
• Lidia Feliu,
• Knud J. Jensen and
• Marta Planas

Beilstein J. Org. Chem. 2012, 8, 2106–2117, doi:10.3762/bjoc.8.237

• , acylation of the secondary nitrogen with Fmoc-Leu-OH was mediated by N,N’-diisopropylcarbodiimide (DIPCDI) with microwave heating at 60 °C. Peptide chain elongation followed standard 9-fluorenylmethoxycarbonyl (Fmoc) solid-phase chemistry. After chain assembly was completed, peptides were released from the

• , Fluka, NovaBiochem (Schwalbach, Germany) or Iris Biotech GmbH (Marktredwitz, Germany) and used without further purification. Microwave heating was performed in a Biotage Initiator instrument (Biotage, Uppsala, Sweden). An acetate buffer (0.1 M, pH 4.76) was prepared by dissolving an equal amount of

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

• the viewpoint of yields and purity of the target compounds were observed when ultrasound-assisted method C was applied. Sequential reaction via synthesis of arylidenecyclohexanone 10 also gave as sole reaction product compound 7 under all the methods of activation applied. However, microwave heating

The multicomponent approach to N-methyl peptides: total synthesis of antibacterial (–)-viridic acid and analogues

• Ricardo A. W. Neves Filho,
• Sebastian Stark,
• Bernhard Westermann and
• Ludger A. Wessjohann

Beilstein J. Org. Chem. 2012, 8, 2085–2090, doi:10.3762/bjoc.8.234

• , with imine preformation in methanol, to give 13a in 51% yield. Finally, saponification of 13a afforded the racemic viridic acid (±)-1 in 83% yield. Attempts to improve the MCR yield with conventional or microwave heating, or by employing trifluoroethanol or DMF as solvents resulted in poor conversions

Antifreeze glycopeptide diastereomers

• Lilly Nagel,
• Carsten Budke,
• Axel Dreyer,
• Thomas Koop and
• Norbert Sewald

Beilstein J. Org. Chem. 2012, 8, 1657–1667, doi:10.3762/bjoc.8.190

• subsequent step the pure α-product 3A/3B was subjected to tert-butyl ester cleavage with TFA. Peptide synthesis was accomplished under microwave heating in a semi-automated fashion, as previously published by us [16][23], by employing 2-chlorotrityl resin loaded with Fmoc-L-Ala-OH or Fmoc-D-Ala-OH. After

Regioselectivity in the multicomponent reaction of 5-aminopyrazoles, cyclic 1,3-diketones and dimethylformamide dimethylacetal under controlled microwave heating

• Kamal Usef Sadek,
• Ramadan Ahmed Mekheimer,
• Tahany Mahmoud Mohamed,
• Moustafa Sherief Moustafa and
• Mohamed Hilmy Elnagdi

Beilstein J. Org. Chem. 2012, 8, 18–24, doi:10.3762/bjoc.8.3

• (DMFDMA) in DMF at 150 °C under controlled microwave heating afforded regioselectively 8,9-dihydropyrazolo[1,5-a]quinazolin-6(7H)-ones 6 rather than the corresponding dihydropyrazolo[5,1-b]quinazolin-8(5H)-ones 4. Keywords: aminopyrazoles; dimedone; DMFDMA; regioselectivity; Introduction Several

• tricyclic reaction products, no general basis on which to determine the preferred tautomeric form of the final product has been established. In continuation of our studies in which we performed multicomponent reactions using controlled microwave heating [22][23][24], we report herein the results of our

• investigation concerning the regioselectivity in multicomponent reactions of 5-aminopyrazoles, cyclic 1,3-diketones and dimethylformamide dimethylacetal (DMFDMA) under controlled microwave heating. We began this study by treating 5-amino-3-methylpyrazole (1a) and dimedone (2a) with DMFDMA (3) in DMF under

Continuous-flow hydration–condensation reaction: Synthesis of α,β-unsaturated ketones from alkynes and aldehydes by using a heterogeneous solid acid catalyst

• Magnus Rueping,
• Teerawut Bootwicha,
• Hannah Baars and
• Erli Sugiono

Beilstein J. Org. Chem. 2011, 7, 1680–1687, doi:10.3762/bjoc.7.198

• and microwave heating offers advantages such as a cleaner reaction profile, reduction of reaction times, higher yields and better selectivity [41][42][43][44][45][46][47][48][49][50][51][52][53][54]. Results and Discussion α,β-Unsaturated ketones are a common motif found in the principal core of a

• ). However, the best result was achieved when the reaction was conducted under solvent-free conditions (Table 1, entry 4). To probe the influence of microwave heating on this transformation, we examined the same transformation under batch conditions and without microwave irradiation. As shown in Table 1

Pseudo five-component synthesis of 2,5-di(hetero)arylthiophenes via a one-pot Sonogashira–Glaser cyclization sequence

• Dominik Urselmann,
• Dragutin Antovic and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2011, 7, 1499–1503, doi:10.3762/bjoc.7.174

• taking advantage of the high yield Sonogashira–Glaser coupling synthesis [15] of 1,4-diphenylbutadiyne starting from iodobenzene (1a) (Table 1). In addition, the final cyclization step to give 2,5-diphenylthiophene (2a) was performed under microwave heating at 120 °C for a hold time of 2 h. The solvent

Continuous preparation of carbon-nanotube-supported platinum catalysts in a flow reactor directly heated by electric current

• Alicja Schlange,
• Antonio Rodolfo dos Santos,
• Ulrich Kunz and
• Thomas Turek

Beilstein J. Org. Chem. 2011, 7, 1412–1420, doi:10.3762/bjoc.7.165

• experimental setup it is possible to produce a Pt/CNT catalyst in a continuous polyol process. Heating rates generated during the reaction are comparable to a microwave oven. The apparatus does not require expensive temperature sensors as used in microwave heating systems. The costs for the described

Amines as key building blocks in Pd-assisted multicomponent processes

• Didier Bouyssi,
• Nuno Monteiro and
• Geneviève Balme

Beilstein J. Org. Chem. 2011, 7, 1387–1406, doi:10.3762/bjoc.7.163

• presence of Et3N and catalytic amounts of PdCl2(PPh3)2 and CuI. The resulting ynones 27 were then treated in situ with diversely substituted hydrazine derivatives to produce, upon microwave heating, a series of pyrazoles 28–30 (Scheme 15). As previously established for this type of cycloaddition, one of

Translation of microwave methodology to continuous flow for the efficient synthesis of diaryl ethers via a base-mediated S_NAr reaction

• Charlotte Wiles and
• Paul Watts

Beilstein J. Org. Chem. 2011, 7, 1360–1371, doi:10.3762/bjoc.7.160

• Charlotte Wiles Paul Watts Chemtrix BV, Burgemeester Lemmensstraat 358, 6163 JT, Geleen, The Netherlands Department of Chemistry, The University of Hull, Cottingham Road, Hull, HU6 7RX, UK 10.3762/bjoc.7.160 Abstract Whilst microwave heating has been widely demonstrated as a synthetically useful

• microwave reactors have been found to be more energy efficient than small single-mode systems, but not more efficient than conventional heating, due to their minimal penetration depth [19]. Coupled with the fact that microwave heating is eight times more expensive than conventional heating [20], techniques

Synthesis of diverse dihydropyrimidine-related scaffolds by fluorous benzaldehyde-based Biginelli reaction and post-condensation modifications

• Bruno Piqani and
• Wei Zhang

Beilstein J. Org. Chem. 2011, 7, 1294–1298, doi:10.3762/bjoc.7.150

• achieved by conducting a multicomponent reaction for improved atom economy, under microwave heating for fast reaction, and with fluorous solid-phase extractions (F-SPE) for ease of purification. Keywords: Biginelli reaction; dihydropyrimidine; diversity-oriented synthesis; fluorous; Suzuki coupling

• leads for AIDS therapies [2]. The Biginelli reaction of a β-keto ester, an aldehyde, and urea is considered as one of the most efficient ways to synthesize dihydropyrimidinones [3]. This acid-catalyzed reaction can be conducted under conventional or microwave heating [4][5]. Reported in this paper is a

• products 4a–e were used for Suzuki coupling reactions to remove the fluorous linker and introduce the biaryl functional group. The coupling reactions were promoted by microwave heating at 140 °C for 30 min with Pd(pddf)Cl2 as a catalyst, Cs2CO3 as a base, and 4:4:1 acetone/toluene/H2O as a solvent [13

Scaling up of continuous-flow, microwave-assisted, organic reactions by varying the size of Pd-functionalized catalytic monoliths

• Ping He,
• Stephen J. Haswell,
• Paul D. I. Fletcher,
• Stephen M. Kelly and
• Andrew Mansfield

Beilstein J. Org. Chem. 2011, 7, 1150–1157, doi:10.3762/bjoc.7.133

• been developed to perform Suzuki–Miyaura reactions under a microwave heating regime, in which the volumetric throughput of a Pd-supported silica monolith can be used to increase the quantity of the product without changing the optimal operating conditions. Two silica monoliths (both 3 cm long), with

• , respectively. Under optimal reaction conditions the quantity of product could be increased from 31 mg per hour to 340 mg per hour simply by changing the volumetric capacity of the monolith. Keywords: continuous flow; microwave heating; monolith; scaling-up; Suzuki–Miyaura reaction; Introduction Interest in

• [12][13]. To this end, the use of microwave heating in conjunction with microporous monolithic reactors has attracted some interest for small-scale synthesis under continuous-flow conditions [14][15][16]. One obvious problem, however, when using microwaves to heat solvents/reagents and surface