Staudinger ligation towards cyclodextrin dimers in aqueous/organic media. Synthesis, conformations and guest-encapsulation ability

• Malamatenia D. Manouilidou,
• Yannis G. Lazarou,
• Irene M. Mavridis and
• Konstantina Yannakopoulou

Beilstein J. Org. Chem. 2014, 10, 774–783, doi:10.3762/bjoc.10.73

• couplings [16][23], the classical formation of ester [12][17], amide [25][26] or imide [27] bonds between CDs or amino CDs and acid- or anhydride-linkers, and finally urea/thiourea bonds [28][29]. However, the obvious advantages of the Staudinger ligation (high reaction rates, absence of a catalyst, aqueous

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

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

• p-TsNCO 18 to generate the acyclic urea IV, and the alkyne moiety of IV coordinates to gold to form a new alkyne π-complex V. A 5-exo-dig cyclization by nucleophilic attack of the urea oxygen forms the vinylgold carbamimidinium ion VI (the minor 6-endo-dig 19 product is not shown), which undergoes

Continuous flow nitration in miniaturized devices

• Amol A. Kulkarni

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

• and industrial explosive. Nitro derivatives of glycerine, urea and naphthalene also exhibit explosive properties. Some of the aniline based dyes were used for medical applications, too. The extension of the aniline based medicines led to hundreds of drugs [11], which were used for medication during

Secondary amine-initiated three-component synthesis of 3,4-dihydropyrimidinones and thiones involving alkynes, aldehydes and thiourea/urea

• Jie-Ping Wan,
• Yunfang Lin,
• Kaikai Hu and
• Yunyun Liu

Beilstein J. Org. Chem. 2014, 10, 287–292, doi:10.3762/bjoc.10.25

• ] and enaminones [34]. On the other hand, as frequently utilized building blocks in organic synthesis, alkynes have been known to possess versatile reactivity in the synthesis of small molecules. For example, a previous protocol employing aryl alkynes, aldehydes and urea/thiourea has been found to

• scope. Various aldehydes of different properties have been subjected to react with thioureas/N-substituted thioureas/urea as well as different propiolates. Typical results were listed in Table 2. It can be seen from these reactions that aldehydes containing various functional groups tolerate the

• thiourea and alkyne were not successful. On the other hand, benzaldehydes with ortho- and meta-substitution could also react with thioureas and propiolates to give the corresponding DHPMs 5l–5p. However, compared with thiourea, urea has been found to undergo a similar transformation more toughly, and DHPMs

New hydrogen-bonding organocatalysts: Chiral cyclophosphazanes and phosphorus amides as catalysts for asymmetric Michael additions

• Helge Klare,
• Jörg M. Neudörfl and
• Bernd Goldfuss

Beilstein J. Org. Chem. 2014, 10, 224–236, doi:10.3762/bjoc.10.18

• . DFT computations reveal high hydrogen-bonding strengths of cyclodiphosphazane PV-amides compared to urea-based catalysts. Experimental results and computations on the enantiodetermining step with cis-cyclodiphosphazane 14a suggest a strong bidentate H-bond activation of the nitrostyrene substrate by

• ) catalysts represent an ever growing class [6][7][8]. The majority of non-specific hydrogen-bonding catalysts are based on the (thio)urea motif (I, Figure 1) [9][10]. More recently squaramides (II, Figure 1) have emerged as complementing motif in HB catalysis [11]. Other H-bonding motifs are less established

• , e.g. sulfonamides [12], urea-N-sulfoxides [13], guanines [14] as well as protonated catalysts such as ammonium [15], 2-aminopyridinium [16] and guanidinium [17] motifs. Most catalysts can form two hydrogen bonds to a reactant, which further enhances their ability to activate and constrain it to a

Synthesis of five- and six-membered cyclic organic peroxides: Key transformations into peroxide ring-retaining products

• Alexander O. Terent'ev,
• Dmitry A. Borisov,
• Vera A. Vil’ and
• Valery M. Dembitsky

Beilstein J. Org. Chem. 2014, 10, 34–114, doi:10.3762/bjoc.10.6

• -fused 7,8,10,11-tetraoxatrispiro[5.2.2.5.2.2]henicosane 227 (Scheme 64) [252]. 3.5. Synthesis of 1,2-dioxanes by the Kobayashi method The synthesis is based on the peroxidation of the carbonyl group of unsaturated ketones 228 with the urea–hydrogen peroxide complex followed by a Michael cyclization of

Efficient synthesis of dihydropyrimidinones via a three-component Biginelli-type reaction of urea, alkylaldehyde and arylaldehyde

• Haijun Qu,
• Xuejian Li,
• Fan Mo and
• Xufeng Lin

Beilstein J. Org. Chem. 2013, 9, 2846–2851, doi:10.3762/bjoc.9.320

• Haijun Qu Xuejian Li Fan Mo Xufeng Lin Department of Chemistry, Zhejiang University, Hangzhou 310027, China 10.3762/bjoc.9.320 Abstract A one-pot three-component synthesis of dihydropyrimidinones via a molecular iodine-catalyzed tandem reaction of simple readily available mono-substituted urea

• Biginelli [3][4]. Among them, the Biginelli multicomponent reaction, involving a multicomponent condensation of aldehyde, β-ketoester, and urea, provides an easy access to the preparation of DHPMs, because multicomponent reactions (MCRs) are considered with high facileness, efficiency and economy in organic

• Biginelli-type synthesis of DHPMs from simple readily available mono-substituted urea, alkylaldehyde, and arylaldehyde under mild reaction conditions [22][23][24]. The present method is suitable for a wide range of substrates, and especially for functionalized arylaldehydes. The first catalytic

New developments in gold-catalyzed manipulation of inactivated alkenes

• Michel Chiarucci and
• Marco Bandini

Beilstein J. Org. Chem. 2013, 9, 2586–2614, doi:10.3762/bjoc.9.294

• type 11 were isolated by Toste in the intramolecular hydroamination of alkenyl urea 14 with a stoichiometric amount of phosphine–gold complex [(PPh3Au)3O]BF4 (Scheme 5a) [2]. The reaction proceeded at room temperature and was found being favoured by electron-withdrawing ligands. Finally, the use of the

One-pot sequential synthesis of isocyanates and urea derivatives via a microwave-assisted Staudinger–aza-Wittig reaction

• Diego Carnaroglio,
• Katia Martina,
• Giovanni Palmisano,
• Andrea Penoni,
• Claudia Domini and
• Giancarlo Cravotto

Beilstein J. Org. Chem. 2013, 9, 2378–2386, doi:10.3762/bjoc.9.274

• , University of Insubria, Via Valleggio 11, 22100 Como, Italy Department of Chemistry, Universidad Nacional del Sur, Av. Alem 1253, B8000CPB, Bahía Blanca, Buenos Aires, Argentina 10.3762/bjoc.9.274 Abstract A fast and efficient protocol for the synthesis of N,N'-disubstituted urea derivatives from alkyl

• : isocyanates; microwave-assisted reaction; one-pot reaction; tandem Staudinger–aza-Wittig reaction; urea derivatives; Introduction The industrial and commercial impact of isocyanates (R–NCO) is steadily growing. In particular, the polyurethane output has undergone yearly increases of 5% over the last decade

• [1]. Isocyanates play a relevant role as chemical intermediates in the manufacturing of thermoplastic foams, elastomers, adhesives, agrochemicals and pharmaceuticals. The isocyanate group is also widely used as a precursor to several bioactive compounds and drugs that contain urea and carbamate

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

• various robust routes (Scheme 31) [84][85]. Most of these transformations use condensation reactions between urea (3.6) and a bis-electrophile to generate the desired structures. For instance, ester 3.7 furnishes uracil (3.5), which in turn can be converted into cytosine (3.4) by selective amination with

• ammonia/ammonium chloride (Scheme 31). Alternatively, thymine (3.3) may be accessed by reacting methyl formylpropionate (3.8) which acts as a bis-electrophile with urea. Following construction of the pyrimidone core the linkage to the anomeric position of a ribose is best achieved using the Vorbrüggen

Creating Complexity

• Donald Craig

Beilstein J. Org. Chem. 2013, 9, 1881–1882, doi:10.3762/bjoc.9.220

• cyanate could be converted into urea [2]. Since that seminal finding, chemical synthesis has advanced to extents which must have been unimaginable to its early practitioners. The numerous paradigm-shifts which have taken place throughout the history of synthesis have been driven largely by a single

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

• product conversions of 66−98% depending on how electron rich or deficient the aromatic ring of the aldehyde was (Table 3). The Biginelli reaction As our final reaction for study, we turned to the Biginelli reaction (Scheme 4) [43][44][45][46][47][48]. This acid-catalyzed cyclocondensation of urea, β

• reaction of benzaldehyde, ethyl acetoacetate and urea catalyzed by sulfuric acid (Figure 8). The calculated Raman spectrum of the product, 4a, shows a strong signal at 1598 cm−1 which was selected for monitoring. Using a catalyst loading of 10 mol % and a flow rate of 1 mL/min, we monitored the reaction

• volumetric flask was dissolved urea (3.003 g, 50 mmol, 1 equiv.) in methanol (~30 mL). Into the flask was then added benzaldehyde (1.306 g, 50 mmol, 1 equiv) and ethyl acetoacetate (6.507 g, 50 mmol, 1 equiv). Methanol was added to bring the total volume to 50 (1 M) and the reagents were thoroughly mixed. An

Organocatalyzed enantioselective desymmetrization of aziridines and epoxides

• Ping-An Wang

Beilstein J. Org. Chem. 2013, 9, 1677–1695, doi:10.3762/bjoc.9.192

• desirable products (Scheme 2, 13 to 18, up to 97% ee) with 50% aqueous K2HPO4 as base. However, under the same conditions, the PTCs with a free 9-OH (OC-17) led to 13 in low yields and enantioselectivities (21% ee). The urea catalyst OC-19 proved to be very inefficient and afforded 13 in 10% yield with 6

The rapid generation of isothiocyanates in flow

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2013, 9, 1613–1619, doi:10.3762/bjoc.9.184

• -oxathiazoline intermediate that readily rearranges into urea and eliminates the desired isothiocyanate product [37][38] (Scheme 1b). Whilst this approach appears on initial inspection to be very attractive it is somewhat hampered by the requirement to access the reactive nitrile oxide species, which once formed

Structures of the reaction products of the AZADO radical with TCNQF₄ or thiourea

• Hideto Suzuki,
• Yuta Kawahara,
• Hiroki Akutsu,
• Jun-ichi Yamada and
• Shin’ichi Nakatsuji

Beilstein J. Org. Chem. 2013, 9, 1487–1491, doi:10.3762/bjoc.9.169

• the reaction product of AZADO and thiourea We next tried to perform the reaction of AZADO (2) with thiourea (4) to see if some intriguing complexes would be formed, since a lot of inclusion compounds derived from urea or thiourea are known [13]. The reaction between 2 and 4 was first tried by mixing

Aqueous reductive amination using a dendritic metal catalyst in a dialysis bag

• Jorgen S. Willemsen,
• Jan C. M. van Hest and
• Floris P. J. T. Rutjes

Beilstein J. Org. Chem. 2013, 9, 960–965, doi:10.3762/bjoc.9.110

• signals at 1580 and 1640 cm−1 derived from the newly formed urea functionalities. The next reaction, coordination of iridium to the dendritic ligands in methanol, afforded the corresponding iridium complexes 14 and 15 in quantitative yield. In the final step, the complex was converted into the water

Carbolithiation of N-alkenyl ureas and N-alkenyl carbamates

• Julien Lefranc,
• Alberto Minassi and
• Jonathan Clayden

Beilstein J. Org. Chem. 2013, 9, 628–632, doi:10.3762/bjoc.9.70

• products that may be deprotected in situ to provide a new connective route to hindered amines. Keywords: carbamate; carbolithiation; carbometallation; organolithium; stereospecificity; styrene; urea; Introduction Enamines and N-acyl enamines are in general nucleophiles, reacting with electrophiles at the

• -alkenyl carbamates. Results and Discussion Simple N-alkenyl ureas 1 were prepared by a reported method [2] entailing N-acylation of an acetophenimine with an isocyanate, followed by N-alkylation of the resulting urea. When urea 1a was treated with t-BuLi or s-BuLi in THF at −78 °C for one hour, followed

• by protonation, carbolithiated products 2a and 2b were isolated in good yield (Scheme 1 and Table 1, entries 1 and 2). Similar reactivity was observed between urea 1a and less hindered organolithiums such as iPrLi or n-BuLi [3], but in THF even at −78 °C a rearrangement [14][15][16][17][18] of the

Facile synthesis of benzothiadiazine 1,1-dioxides, a precursor of RSV inhibitors, by tandem amidation/intramolecular aza-Wittig reaction

• Krishna C. Majumdar and
• Sintu Ganai

Beilstein J. Org. Chem. 2013, 9, 503–509, doi:10.3762/bjoc.9.54

• -dioxides are generally synthesized either by condensation of o-aminobenzenesulfonamides with urea at elevated temperature [23] or by the reaction of o-aminobenzenesulfonamide with isocyanates in DMF under reflux [24]. Although various approaches to the preparation of 1,2,4-benzothiadiazine 1,1-dioxide

Design and synthesis of a photoswitchable guanidine catalyst

• Philipp Viehmann and
• Stefan Hecht

Beilstein J. Org. Chem. 2012, 8, 1825–1830, doi:10.3762/bjoc.8.209

• 2E. The therefore necessary urea 4 can be obtained from the addition of pyrrolidine to phenylisocyanate (3). The structure of guanidine 2E was proven by NMR spectroscopy, HRMS, as well as by single-crystal X-ray structure analysis (Figure 1). To our knowledge, this is the first example of an X-ray

Organocatalytic asymmetric addition of malonates to unsaturated 1,4-diketones

• Sergei Žari,
• Tiiu Kailas,
• Marina Kudrjashova,
• Mario Öeren,
• Ivar Järving,
• Toomas Tamm,
• Margus Lopp and
• Tõnis Kanger

Beilstein J. Org. Chem. 2012, 8, 1452–1457, doi:10.3762/bjoc.8.165

• bicyclic guanidines [7][9][12]. Xiao et al. reported the addition of nitroalkanes to 4-oxo-enoates, using chiral urea derivatives [7]. Miura et al. achieved an asymmetric addition of α,α-disubstituted aldehydes to maleimides catalyzed by primary amine thiourea organocatalyst [13]. Wang et al. reported the

Synthesis of chiral sulfoximine-based thioureas and their application in asymmetric organocatalysis

• Marcus Frings,
• Isabelle Thomé and
• Carsten Bolm

Beilstein J. Org. Chem. 2012, 8, 1443–1451, doi:10.3762/bjoc.8.164

• by three-component condensations of aldehydes, urea-type substrates and enolisable carbonyl compounds. Because of the pharmacological relevance of the products, considerable research has been directed towards asymmetric approaches of these inherently chiral heterocycles [61][62][63]. Until recently

• condensation reaction in an asymmetric fashion. Using a slightly modified procedure of the thiourea-catalyzed Biginelli reaction developed by Miao and Chen [69], we chose the condensation between urea, benzaldehyde (1.5 equiv), and ethyl acetoacetate (3 equiv) to give dihydropyrimidine 20 (Table 1) as test

• (urea) concentration from 0.25 mol/L to 0.025 mol/L caused a distinct improvement of the enantiomeric excess and the enantiomer ratio of the product 20 raised from 58:42 to 72:28 (Table 1, entry 6 vs entry 10). In addition, product 20 was isolated in a slightly better yield (92%). The attempt to reduce

Cation affinity numbers of Lewis bases

• Christoph Lindner,
• Raman Tandon,
• Boris Maryasin,
• Evgeny Larionov and
• Hendrik Zipse

Beilstein J. Org. Chem. 2012, 8, 1406–1442, doi:10.3762/bjoc.8.163

• pivaloylamido group (α, β, γ). The resulting MCA values vary by about 18 kJ/mol. Besides these amide-containing phosphanes (thio-)urea-containing phosphanes were also investigated. They possess lower MCA values than the previously discussed ones. In general, the ‘thiourea-phosphanes’ (258, 263) show even lower

• MCA values than the ‘urea-phosphanes’ (262, 265, 272). Can MCA values be increased through integration of the P-atom into a ring system? With respect to the results obtained for a small set of cyclic phosphanes (Table 7) it appears that there is at least no general trend for cyclic and acyclic

• respective ACA values (Table 14). Most of the 3,4-diaminopyridines (58, 59, 63, 399–408) show ACA values which are roughly between 235 and 243 kJ/mol. However, the introduction of a (thio)urea moiety as in 383–387, 389–394, and 397 lowers the ACA value by 10 to 25 kJ/mol. Annelation of an additional six

Restructuring polymers via nanoconfinement and subsequent release

• Alan E. Tonelli

Beilstein J. Org. Chem. 2012, 8, 1318–1332, doi:10.3762/bjoc.8.151

• ; inclusion compounds; nanoconfinement; organization; polymers; properties; release; urea; Introduction The behaviors and properties of polymer materials are closely related to the organizations, structures, and morphologies of their constituent chains, which can be significantly altered during their

• coalesced bulk polymer sample. This process is illustrated in Figure 1, in which the cyclic starches, cyclodextrins (CDs), are the host molecules used to form ICs with guest polymers [1][2]. In polymer ICs formed with CDs and other small-molecule hosts, such as urea, thiourea, cyclotriphosphazenes, and

• distinguished [20]. Finally, examination by DSC can determine whether the guest polymer has been included in the columnar CD lattice or not, by the absence or presence, respectively, of the thermal signature(s) characteristic of the polymer, i.e., Tg and/or Tm. The formation of polymer ICs with host urea (U

Synthesis and biological evaluation of nojirimycin- and pyrrolidine-based trehalase inhibitors

• Davide Bini,
• Francesca Cardona,
• Matilde Forcella,
• Camilla Parmeggiani,
• Paolo Parenti,
• Francesco Nicotra and
• Laura Cipolla

Beilstein J. Org. Chem. 2012, 8, 514–521, doi:10.3762/bjoc.8.58

• their preliminary biological evaluation as inhibitors against porcine and insect trehalase from C. riparius. Results and Discussion In previous studies by us and other research groups it was reported that 1-deoxynojirimycin (7) and its benzyl urea derivative 8 (Figure 2) [17][18] are trehalase

• possibility to synthesize a few nojirimycin and pyrrolidine derivatives bearing a benzyl urea moiety and a different alkyl substituent on the adjacent carbon (10, 11, 15 and 18, Figure 3). Thus the presence of a benzyl urea moiety was expected to be a common feature of the majority of the iminosugar

• derivatives (piperidines and pyrrolidines). However, during the final deprotection step by hydrogenolysis, the reaction resulted in the formation of the disubstituted urea 10 or, unexpectedly, monosubstituted ureas 12, 16 and 19 (Figure 3), depending on the starting material. Pyrrolidine derivatives were