Synthesis of structurally diverse 3,4-dihydropyrimidin-2(1H)-ones via sequential Biginelli and Passerini reactions

• Andreas C. Boukis,
• Baptiste Monney and
• Michael A. R. Meier

Beilstein J. Org. Chem. 2017, 13, 54–62, doi:10.3762/bjoc.13.7

• modulation, α1a adrenoceptor-selective antagonists, cancer therapy, anti-HIV alkaloids) [12][13][14][15]. The mechanism of the Biginelli cyclocondensation was proposed and investigated by Kappe and is illustrated in Scheme 1a [16]. According to the generally accepted mechanism of the Biginelli reaction

Selective and eco-friendly procedures for the synthesis of benzimidazole derivatives. The role of the Er(OTf)₃ catalyst in the reaction selectivity

• Natividad Herrera Cano,
• Jorge G. Uranga,
• Mónica Nardi,
• Antonio Procopio,
• Daniel A. Wunderlin and
• Ana N. Santiago

Beilstein J. Org. Chem. 2016, 12, 2410–2419, doi:10.3762/bjoc.12.235

• , differences in reactivity were investigated by by means of theoretical calculations. Results and Discussion The benzimidazole core was obtained by air oxidative cyclocondensation of o-phenylenediamine with benzaldehyde under different conditions. In water and in the presence of Er(OTf)3, the diamine and

• between 1a and 1b observed in this work, two reaction pathways are proposed and shown in Scheme 2: (i) through bisimine rearrangement (path i) and (ii) through a monoamine cyclocondensation–aminal/immonium rearrangement (path ii). In path i, when the aldehyde approaches Er(OTf)3, the carbonyl carbon of

Microwave-assisted cyclizations promoted by polyphosphoric acid esters: a general method for 1-aryl-2-iminoazacycloalkanes

• Jimena E. Díaz,
• María C. Mollo and
• Liliana R. Orelli

Beilstein J. Org. Chem. 2016, 12, 2026–2031, doi:10.3762/bjoc.12.190

• in heterocyclic synthesis, specially in cyclocondensation reactions [39][40]. In particular, it has enabled the synthesis of the more challenging medium size (7–9 membered) heterocycles by overcoming limitations such as low reactivity and yields, harsh reaction conditions and side reactions typical

Three-component synthesis of highly functionalized aziridines containing a peptide side chain and their one-step transformation into β-functionalized α-ketoamides

• Lena Huck,
• Juan F. González,
• Elena de la Cuesta and
• J. Carlos Menéndez

Beilstein J. Org. Chem. 2016, 12, 1772–1777, doi:10.3762/bjoc.12.166

• corresponding compounds 11, which were then transformed into pyrazines 12 and quinoxalines 13 via straightforward cyclocondensation reactions with ethylenediamine and o-phenylenediamine, respectively (Scheme 6 and Table 3). The transformation of 2 into 11 can be explained by the mechanism summarized in Scheme 7

Synthesis of highly functionalized 2,2'-bipyridines by cyclocondensation of β-ketoenamides – scope and limitations

• Paul Hommes and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2016, 12, 1170–1177, doi:10.3762/bjoc.12.112

• corresponding β-ketoenamines 2a–e were converted into different β-ketoenamides 3a–g by N-acylation with 2-pyridinecarboxylic acid derivatives. These β-ketoenamides were treated with a mixture of TMSOTf and Hünig’s base to promote the cyclocondensation to 4-hydroxypyridine derivatives. Their immediate O

• couplings. Thus, a library of specifically substituted bipyridine derivatives was generated, showing the versatility of the simple 1,3-diketone-based approach to this important class of ligands. Keywords: 2,2-bipyridines; cross couplings; cyclocondensation; β-ketoenamides; nonaflates; Introduction In 2009

• we reported on a new pyridine synthesis starting from symmetrically substituted 1,3-diketones 1a and 1b, respectively, that were converted into the corresponding β-ketoenamines and subsequently by N-acylation into β-ketoenamides such as 3a or 3b [1]. Their cyclocondensation followed by O-alkylation

Antibacterial structure–activity relationship studies of several tricyclic sulfur-containing flavonoids

• Lucian G. Bahrin,
• Henning Hopf,
• Peter G. Jones,
• Laura G. Sarbu,
• Cornelia Babii,
• Alina C. Mihai,
• Marius Stefan and
• Lucian M. Birsa

Beilstein J. Org. Chem. 2016, 12, 1065–1071, doi:10.3762/bjoc.12.100

• –activity relationship study concerning the antibacterial properties of several halogen-substituted tricyclic sulfur-containing flavonoids has been performed. The compounds have been synthesized by cyclocondensation of the corresponding 3-dithiocarbamic flavanones under acidic conditions. The influence of

• and 4f crystals suitable for single crystal X-ray analysis were obtained and the results are discussed in the X-ray analysis section. The acid-catalyzed cyclocondensation of flavanones 4a–m afforded the tricyclic flavonoids 5a–m in good yields [23] (Scheme 1). The formation of the 1,3-dithiolium ring

[2.2]Paracyclophane derivatives containing tetrathiafulvalene moieties

• Laura G. Sarbu,
• Lucian G. Bahrin,
• Peter G. Jones,
• Lucian M. Birsa and
• Henning Hopf

Beilstein J. Org. Chem. 2015, 11, 1917–1921, doi:10.3762/bjoc.11.207

• salts, consists of an acid-catalyzed cyclocondensation of phenacyl carbodithioates 4. Using a concentrated sulfuric acid–glacial acetic acid mixture (1:3, v/v) [20], the cyclization of carbodithioates 4a–c takes place under mild reaction conditions. After 10 min at 80 °C the homogeneous reaction mixture

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

• small collection of 22 imidazo[1,2-a]pyridines 136 was prepared within four working days. The synthetic route consisted of an aldol condensation between various acetophenones 137 and ethyl glyoxylate (138). This was followed by an HBF4-catalysed cyclocondensation of the resulting Michael acceptor 139

The reactions of 2-ethoxymethylidene-3-oxo esters and their analogues with 5-aminotetrazole as a way to novel azaheterocycles

• Marina V. Goryaeva,
• Yanina V. Burgart,
• Marina A. Ezhikova,
• Mikhail I. Kodess and
• Viktor I. Saloutin

Beilstein J. Org. Chem. 2015, 11, 385–391, doi:10.3762/bjoc.11.44

• ], antiviral [14], antimicrobial and antioxidant activity [15] have been found among them. The known tetrazolo[1,5-a]pyrimidines were synthesized by cyclocondensation of 5-AT with 1,3-dicarbonyl compounds or their derivatives [16]. Moreover, a convenient method for obtaining this heterocyclic skeleton is the

The unexpected influence of aryl substituents in N-aryl-3-oxobutanamides on the behavior of their multicomponent reactions with 5-amino-3-methylisoxazole and salicylaldehyde

• Volodymyr V. Tkachenko,
• Elena A. Muravyova,
• Sergey M. Desenko,
• Oleg V. Shishkin,
• Svetlana V. Shishkina,
• Dmytro O. Sysoiev,
• Thomas J. J. Müller and
• Valentin A. Chebanov

Beilstein J. Org. Chem. 2014, 10, 3019–3030, doi:10.3762/bjoc.10.320

• alia, ultrasonic activation was applied to promote this multicomponent reaction. It was established that the three-component cyclocondensation of the starting compounds under ultrasonication at room temperature for 4 h led to the selective formation of the substituted chroman-3-carboxamide 4a in 58

• %) was identified as the catalyst of choice. The next step of our study was to expand the range of N-aryl-3-oxobutanamides. First, it is worth mentioning that the three-component cyclocondensation of 5-amino-3-methylisoxazole (1), salicylaldehyde (2) and N-aryl-3-oxobutanamides 3a–h under ultrasonication

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

• envisage a sequential one-pot access to 1H-imidazo[1,2-b]pyrazole species through the in situ microwave-assisted formation of 1a followed by a GBB-3CR. A comparative study for the optimum synthesis of 6 revealed that the cyclocondensation of ethoxymethylene malononitrile (4a) with hydrazine (5) under

Influence of cyclodextrin on the UCST- and LCST-behavior of poly(2-methacrylamido-caprolactam)-co-(N,N-dimethylacrylamide)

• Alexander Burkhart and
• Helmut Ritter

Beilstein J. Org. Chem. 2014, 10, 1951–1958, doi:10.3762/bjoc.10.203

• -amino-ε-caprolactam (2) was obtained according to literature via cyclocondensation of L-lysine (1) [15]. Through amidation of the primary amine (2) with methacryloyl chloride (3) the polymerizable 2-methacrylamido-caprolactam (4) was obtained (Scheme 1) [14]. Free radical copolymerization of 4 in

Syntheses of ¹⁵N-labeled pre-queuosine nucleobase derivatives

• Jasmin Levic and
• Ronald Micura

Beilstein J. Org. Chem. 2014, 10, 1914–1918, doi:10.3762/bjoc.10.199

• chromatography on SiO2 and isolated in good yields. The pyrrolo[2,3-d]pyrimidine ring system of preQ1 base was built in good yields via the cyclocondensation reaction between [15N1,15N3,H215N(C2)]-2,6-diaminopyrimidin-4-one (6) and the 2-bromo-3-phthalimidopropan-1-al (7). Finally, deprotection was performed

• compound 13, followed by cyclocondensation with 2-bromo-3-phthalimidopropan-1-al (7) to give the protected [15N9]-preQ1 base 14 for subsequent deprotection yielding the desired [15N9]-preQ1 base (2) (Scheme 3). Also for the third target, [H215N(C7')]-preQ1 base (3), our strategy turn out to be highly

• reaction with 5,5-dibromobarbituric acid [17] to obtain [15N]-2-bromo-3-phthalimidopropan-1-al (19), followed by cyclocondensation with commercially available 2,6-diaminopyrimidin-4-one (20) to give the protected [15N(C7')]-preQ1 base 21 for subsequent deprotection yielding the desired [15N(C7')]-preQ1

Stereoselective synthesis of carbocyclic analogues of the nucleoside Q precursor (PreQ₀)

• Sabin Llona-Minguez and
• Simon P. Mackay

Beilstein J. Org. Chem. 2014, 10, 1333–1338, doi:10.3762/bjoc.10.135

• formylation of chloroacetonitrile with methyl formate. The resulting volatile and unstable chloroaldehyde 6 was used without further purification. Cyclocondensation of 6 with 2,4-diamino-4-hydroxypyrimidine afforded 1 regiospecifically with no detectable formation of the undesired 6-substituted-furo[2,3-d

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

• .10.44 Abstract The cyclocondensation of enones with aminoacetonitrile furnishes 3,4-dihydro-2H-pyrrole-2-carbonitriles which can be readily converted to 2,4-disubstituted pyrroles by microwave-induced dehydrocyanation. Alternatively, oxidation of the intermediates produces 3,5-disubstituted pyrrole-2

• closure to furnish 3,4-dihydro-2H-pyrrole-2-carbonitriles 6 after reprotonation [36]. If the products are devoid of an additional substituent in 2-position, the cyclocondensation can be simply effected by refluxing a mixture of the enone 1 and aminoacetonitrile hydrochloride (2) in pyridine. The base

• pyrroles and 3,5-disubstituted pyrrole-2-carbonitriles by means of a cyclocondensation with aminoacetonitrile and a microwave-assisted dehydrocyanation or a dehydrogenation with DDQ. These methods provide a simple an efficient entry into these useful compound classes. Experimental Typical procedure for the

The Flögel-three-component reaction with dicarboxylic acids – an approach to bis(β-alkoxy-β-ketoenamides) for the synthesis of complex pyridine and pyrimidine derivatives

• Mrinal K. Bera,
• Moisés Domínguez,
• Paul Hommes and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2014, 10, 394–404, doi:10.3762/bjoc.10.37

• cyclocondensation of bis(β-ketoenamides) 13–15 to pyrimidines (Scheme 4) using ammonium acetate as ammonia source. Initially we subjected enamide 13 to conditions that had been optimized for mono-β-ketoenamides [48][49], in this case resulting in incomplete conversion: after heating 13 with 8 equiv of ammonium

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

New syntheses of 5,6- and 7,8-diaminoquinolines

• Maroš Bella and
• Viktor Milata

Beilstein J. Org. Chem. 2013, 9, 2669–2674, doi:10.3762/bjoc.9.302

• in a poor yield by application of the Skraup synthesis to 5-acetylamidoquinoxaline [16]. Notably, 7,8-diaminoquinoline dihydrochloride condensed with glyoxal bisulfite only with the amino group in position 7 and the pyrazine ring was not closed [17]. In the present case, the cyclocondensation of

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

• formed and subsequently undergoes cyclocondensation with the Michael acceptor 1.36 as the rate determining step of this sequence [30]. Other important species containing a pyridine moiety are rosiglitazone (1.40, Avandia) and pioglitazone (1.41, Actos), which are members of the so called

• chromium(VI) oxide yielded the aldehyde 1.67 required for the previously described Knoevenagel condensation. The five membered heterocycle 2,4-thiazolidinedione (1.68) is readily available commercially, but can be easily prepared at scale via a simple cyclocondensation between thiourea and chloroacetic

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

• . [47] have demonstrated that ethynyl ketones can be generated in flow by the palladium-catalysed acylation of terminal alkynes and further transformed in a continuous process to pyrazoles by cyclocondensation with hydrazines using a commercially available conductive heating modular flow reactor. Given

• that this cyclocondensation proceeds in a similar fashion and high efficiency under microwave irradiation [48], and that we have previously demonstrated that pyridines and pyrimidines can both be formed rapidly and efficiently from ethynyl ketones using microwave dielectric heating, the transfer of

• , a transformation which currently cannot be realized, it does provide a useful substrate for 3- or 4-component Hantzsch DHP synthesis that undergoes cyclocondensation with high efficiency. To conclude, continuous flow microwave-assisted reactions represent a reliable method to scale up the production

Synthesis of enones, pyrazolines and pyrrolines with gem-difluoroalkyl side chains

• Assaad Nasr El Dine,
• Ali Khalaf,
• Danielle Grée,
• Olivier Tasseau,
• Fares Fares,
• Nada Jaber,
• Philippe Lesot,
• Ali Hachem and
• René Grée

Beilstein J. Org. Chem. 2013, 9, 1943–1948, doi:10.3762/bjoc.9.230

• representative 5-membered heterocyclic systems with CF2R side chains by using cyclocondensation reactions. Furthermore, selected molecules in these series were functionalized by using appropriate palladium-catalyzed coupling reactions en route to chemical libraries. Results and Discussion The first example of a

• coupling–isomerisation process followed by a cyclocondensation [30]. Pyrroline is another noteworthy example of a heterocyclic scaffold useful in bioorganic and medicinal chemistry [31][32]. It is also well-recognized for agrochemicals, especially in combination with CF3 substituents. Recently, the group

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

• ). Claisen-Schmidt condensation of benzaldehyde with acetophenone to yield chalcone, 3a. The Biginelli cyclocondensation of benzaldehyde, ethyl acetoacetate, and urea to yield 5-ethoxycarbonyl-6-methyl-4-phenyl-3,4-dihydropyrimidin-2(1H)-one (4a). Comparison of product conversion values obtained from Raman

Asymmetric Diels–Alder reaction with >C=P– functionality of the 2-phosphaindolizine-η¹-P-aluminium(O-menthoxy) dichloride complex: experimental and theoretical results

• Rajendra K. Jangid,
• Nidhi Sogani,
• Neelima Gupta,
• Raj K. Bansal,
• Moritz von Hopffgarten and
• Gernot Frenking

Beilstein J. Org. Chem. 2013, 9, 392–400, doi:10.3762/bjoc.9.40

• -Phosphaindolizines (Scheme 2) were prepared by the [4 + 1] cyclocondensation method from the reaction of the respective 1-alkyl-2-ethylpyridinium bromide with phosphorus trichloride in the presence of triethylamine, as described in literature [56]. Analysis and characterisation of the products Melting points were

Regioselective synthesis of 7,8-dihydroimidazo[5,1-c][1,2,4]triazine-3,6(2H,4H)-dione derivatives: A new drug-like heterocyclic scaffold

• Nikolay T. Tzvetkov,
• Harald Euler and
• Christa E. Müller

Beilstein J. Org. Chem. 2012, 8, 1584–1593, doi:10.3762/bjoc.8.181

• to be introduced. Several synthetic strategies involving combinatorial and sequential approaches, in particular intramolecular cyclocondensation reactions of functionalized 1,2,4-triazole and imidazole precursors, have been developed [5][6][12]. We have been interested in expanding the medicinal

An intramolecular inverse electron demand Diels–Alder approach to annulated α-carbolines

• Zhiyuan Ma,
• Feng Ni,
• Grace H. C. Woo,
• Sie-Mun Lo,
• Philip M. Roveto,
• Scott E. Schaus and
• John K. Snyder

Beilstein J. Org. Chem. 2012, 8, 829–840, doi:10.3762/bjoc.8.93

• quantitative yield (Scheme 2). The first step in the cyclocondensation was accomplished by stirring in ethanol at rt for 12 h and heating under reflux for 20 min, after which the solvent was removed and the cyclocondensation completed by heating under reflux in bromobenzene (bp 156 °C) for 24 h. The two-step

• , toluene, methanol and acetone. Starting with other 5-substituted isatin derivatives, analogous triazines were similarly prepared in good yields (84–92%, Table 1). 5-Nitro- and 5-carboxamidoisatins also readily participated in the cyclocondensation with the oxaloamidrazonate 11 to form the corresponding