Synthesis of 4-amino-5-fluoropyrimidines and 5-amino-4-fluoropyrazoles from a β-fluoroenolate salt

• Tobias Lucas,
• Jule-Philipp Dietz and
• Till Opatz

Beilstein J. Org. Chem. 2020, 16, 445–450, doi:10.3762/bjoc.16.41

• arginine, where the desired pyrimidine 10q was also only observed in trace amounts while the majority of the starting material remained unchanged. Synthesis of fluorinated aminopyrazoles As in the cyclocondensation with amidines, the reaction of 8 with other bifunctional nucleophiles could also result in

• hydrazine on the more reactive carbon atom of the fluoroenolate in a Michael-type addition. The cyclization did not require a deprotonation of the RNH moiety. Conclusion In summary, a synthesis of fluorinated pyrimidines under mild conditions using fluoroenolate 8 and amidines in a cyclocondensation was

Facile regiodivergent synthesis of spiro pyrrole-substituted pseudothiohydantoins and thiohydantoins via reaction of [e]-fused 1H-pyrrole-2,3-diones with thiourea

• Aleksandr I. Kobelev,
• Nikita A. Tretyakov,
• Ekaterina E. Stepanova,
• Maksim V. Dmitriev,
• Michael Rubin and
• Andrey N. Maslivets

Beilstein J. Org. Chem. 2019, 15, 2864–2871, doi:10.3762/bjoc.15.280

• facile preparation of libraries of heterocyclic molecules with an emphasis on skeletal diversity from a single set of reagents [25][26][27]. One of the most intriguing chemical properties of FPDs 1 is their ability to undergo a cyclocondensation with 1,3-binucleophilic reagents to form spiro[4.4

• centers of FPDs 1, starting materials of this study. Pseudothiohydantoin–thiohydantoin rearrangement. Syntheses of regioisomeric 5-spiro-substituted thiohydantoins and pseudothiohydantoins: previous [10] and this work. Cyclocondensation of FPDs 1 with 1,3-binucleophilic reagents, resulting in pyrrole-2

Emission solvatochromic, solid-state and aggregation-induced emissive α-pyrones and emission-tuneable 1H-pyridines by Michael addition–cyclocondensation sequences

• Natascha Breuer,
• Irina Gruber,
• Christoph Janiak and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2019, 15, 2684–2703, doi:10.3762/bjoc.15.262

• Strukturchemie, Universitätsstraße 1, D-40225 Düsseldorf, Germany 10.3762/bjoc.15.262 Abstract Starting from substituted alkynones, α-pyrones and/or 1H-pyridines were generated in a Michael addition–cyclocondensation with ethyl cyanoacetate. The peculiar product formation depends on the reaction conditions as

• emission solvatochromism. Also a donor-substituted α-pyrone shows pronounced aggregation-induced emission enhancement. Keywords: cyclocondensation; DFT calculations; fluorescence; heterocycles; 1H-pyridines; α-pyrones; Introduction A high sensitivity and precise tuneability of fluorescence colors are

• alkynylation–Michael addition–cyclocondensation (AMAC) multicomponent syntheses of α-pyrones [23]. While most α-pyrones neither fluoresce in solution nor in the solid state specific substitution patterns have been identified for fluorophore design for this heterocyclic family. Tominaga and co-workers

In water multicomponent synthesis of low-molecular-mass 4,7-dihydrotetrazolo[1,5-a]pyrimidines

• Irina G. Tkachenko,
• Sergey A. Komykhov,
• Vladimir I. Musatov,
• Svitlana V. Shishkina,
• Viktoriya V. Dyakonenko,
• Vladimir N. Shvets,
• Mikhail V. Diachkov,
• Valentyn A. Chebanov and
• Sergey M. Desenko

Beilstein J. Org. Chem. 2019, 15, 2390–2397, doi:10.3762/bjoc.15.231

• starting material and subsequent dihydropyrimidine ring formation. The first approach [6][7] represents a two-component cyclocondensation of 5-aminotetrazole (1) as binucleophilic component and bielectrophilic α,β-unsaturated carbonyl compounds 2 (Scheme 1, reaction 1). The second method [8][9][10][11][12

A heteroditopic macrocycle as organocatalytic nanoreactor for pyrroloacridinone synthesis in water

• Piyali Sarkar,
• Sayan Sarkar and
• Pradyut Ghosh

Beilstein J. Org. Chem. 2019, 15, 1505–1514, doi:10.3762/bjoc.15.152

• sites along with H-bonding donor/acceptor site. So, it may also be associated to the nanoreactor to approach the enaminoketone. Then, consecutive cyclization and ring opening of isatin (translactamization) affords intermediate C which undergoes cyclocondensation to furnish the final product F

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

• directed to develop multicomponent syntheses of heterocycles by transition-metal catalysis [41][42] we conceptualized catalytic entries to alkynones and alkynediones as suitable intermediates in addition–cyclocondensation syntheses of numerous heterocycles, which can indeed be prepared by consecutive

• ][51][52], pyrimidines [48][49], and 5-acylpyrazoles [48][49]. The latter 5-acylpyrazole arose after work-up from the three-component AA–cyclocondensation synthesis employing Boc-hydrazine as a binucleophilic hydrazide substrate. Based on our attempts to isolate potential 1,5-diacylpyrazole precursors

• we discovered that 1,5-diacyl-5-hydroxypyrazolines are the intermediary products. Here, we report on the novel three-component AA–condensation–cyclization synthesis of 1,5-diacyl-5-hydroxypyrazolines. Results and Discussion In our initial study [49], the three-component AA–cyclocondensation synthesis

Steroid diversification by multicomponent reactions

• Leslie Reguera,
• Cecilia I. Attorresi,
• Javier A. Ramírez and
• Daniel G. Rivera

Beilstein J. Org. Chem. 2019, 15, 1236–1256, doi:10.3762/bjoc.15.121

• fractions; such compounds are too complex for analysis at a molecular level, so it is important to synthesize analytical standards for their study. In this context, Schulze et al. optimized a multicomponent cyclocondensation reaction [50][51] between 5α-cholestan-3-one (43), aromatic aldehydes and 2

Extending mechanochemical porphyrin synthesis to bulkier aromatics: tetramesitylporphyrin

• Qiwen Su and
• Tamara D. Hamilton

Beilstein J. Org. Chem. 2019, 15, 1149–1153, doi:10.3762/bjoc.15.111

• at room temperature, like the Lindsey synthesis, it may be that the equilibrium is reached between starting materials and cyclocondensation products before conditions are introduced to trigger the irreversible oxidation of porphyrinogen to porphyrin. Optimization of conditions could maximize the

• to cyclocondensation of pyrrole with a sterically-hindered aldehyde. After oxidation to give a porphyrin with bulky substituents, isolated yields are comparable to those obtained from high-temperature syntheses (though still lower than the 30% obtainable with added solvent at room temperature). The

Multicomponent reactions (MCRs): a useful access to the synthesis of benzo-fused γ-lactams

• Edorta Martínez de Marigorta,
• Jesús M. de Los Santos,
• Ana M. Ochoa de Retana,
• Javier Vicario and
• Francisco Palacios

Beilstein J. Org. Chem. 2019, 15, 1065–1085, doi:10.3762/bjoc.15.104

• experiments allowed the authors to propose the mechanism as follows (Scheme 20). First, cyclocondensation of 2-aminobenzamide (59) with 2-bromobenzaldehyde (62) to form intermediate 63 is followed by oxidative addition of Pd(0) to provide palladium complex 64. Then, insertion of CO (23) in the C–Pd bond

A three-component, Zn(OTf)₂-mediated entry into trisubstituted 2-aminoimidazoles

• Alexei Lukin,
• Anna Bakholdina,
• Anna Kryukova,
• Alexander Sapegin and
• Mikhail Krasavin

Beilstein J. Org. Chem. 2019, 15, 1061–1064, doi:10.3762/bjoc.15.103

• .15.103 Abstract A three-component reaction involving in situ generation of propargylureas and subsequent Zn(OTf)2-mediated cyclocondensation with a primary amine yielded trisubstituted 2-aminoimidazoles. These findings are in contrast to the previously reported base-promoted unimolecular cyclization of

• propargylureas (leading to 2-imidazolones) and extend the range of Lewis acid-catalyzed azole syntheses based on N-carbonyl propargylamines. Keywords: alkyne hydroamination; cyclocondensation; Lewis acid catalysis; multicomponent reactions; propargylurea; Introduction The pioneering publications of Beller and

Novel (2-amino-4-arylimidazolyl)propanoic acids and pyrrolo[1,2-c]imidazoles via the domino reactions of 2-amino-4-arylimidazoles with carbonyl and methylene active compounds

• Victoria V. Lipson,
• Tetiana L. Pavlovska,
• Nataliya V. Svetlichnaya,
• Anna A. Poryvai,
• Nikolay Yu. Gorobets,
• Erik V. Van der Eycken,
• Irina S. Konovalova,
• Svetlana V. Shiskina,
• Alexander V. Borisov,
• Vladimir I. Musatov and
• Alexander V. Mazepa

Beilstein J. Org. Chem. 2019, 15, 1032–1045, doi:10.3762/bjoc.15.101

• with isatins and aliphatic CH acids stable Michael adducts have not been fixed. Cyclocondensation has readily led to the formation of 6'-substituted 3',5'-diamino-1-alkyl-2-oxo-1'-arylspiro[indolin-3,7'-pyrrolo[1,2-c]imidazoles], which can be considered as the analogues of alkaloids with both pyrrolo

The LANCA three-component reaction to highly substituted β-ketoenamides – versatile intermediates for the synthesis of functionalized pyridine, pyrimidine, oxazole and quinoxaline derivatives

• Tilman Lechel,
• Roopender Kumar,
• Mrinal K. Bera,
• Reinhold Zimmer and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2019, 15, 655–678, doi:10.3762/bjoc.15.61

• - and 1,4-dicyanobenzene were also examined as second component in the three-component reaction. The obtained bis-β-ketoenamides were not isolated and purified, but directly converted into the corresponding bis-pyridin-4-ol derivatives by cyclocondensation [40]. The overall yields were only in the range

• were prepared by this largely unexplored, but very promising method. It opens a route to highly substituted heterocycles as shown by the cyclocondensation of KE78 that gave the corresponding pentasubstituted pyridin-4-ol derivative in 91% yield [22]. As mentioned above, a large number of the prepared β

• -ketoenamides KE also serve as excellent starting materials for the preparation of highly substituted pyrimidine derivatives PM [47][48][49]. Cyclocondensation reactions with ammonium salts in methanol afford these versatile heterocycles in good to excellent yields (Scheme 8). In most cases, ammonium acetate

Selectivity in multiple multicomponent reactions: types and synthetic applications

• Ouldouz Ghashghaei,
• Francesca Seghetti and
• Rodolfo Lavilla

Beilstein J. Org. Chem. 2019, 15, 521–534, doi:10.3762/bjoc.15.46

• reactions can be linked with Povarov MCRs through the intermediacy of the enamine-containing adducts from the former processes (Scheme 10C) [40]. Many additional combinations arise from the Union concept, such as Bredereck–Passerini [41], pyridone-cyclocondensation/Passerini–Ugi [42], azadiene-keteneimine

Synthesis of nonracemic hydroxyglutamic acids

• Dorota G. Piotrowska,
• Iwona E. Głowacka,
• Andrzej E. Wróblewski and
• Liwia Lubowiecka

Beilstein J. Org. Chem. 2019, 15, 236–255, doi:10.3762/bjoc.15.22

• -derived precursors When Garner’s aldehyde (R)-5 prepared from D-serine was subjected to ZnCl2-catalyzed cyclocondensation with Danishefsky's diene a (>9:1) mixture of diastereoisomeric pyranones 6 was formed with the threo isomer 6a prevailing. Oxidative removal of two carbon atoms was followed by formate

• stereoselectivity of the cyclocondensation step is best explained by the attack on a re-face of the C=O group due to chelation of Zn2+ to the carbonyl oxygen and amide nitrogen/oxygen atoms [49]. A better approach in terms of carbon atom economy relied on the addition of allylmagnesium chloride to the aldehyde (R

Green synthesis of new chiral 1-(arylamino)imidazo[2,1-a]isoindole-2,5-diones from the corresponding α-amino acid arylhydrazides in aqueous medium

• Nadia Bouzayani,
• Jamil Kraїem,
• Sylvain Marque,
• Yakdhane Kacem,
• Abel Carlin-Sinclair,
• Jérôme Marrot and
• Béchir Ben Hassine

Beilstein J. Org. Chem. 2018, 14, 2923–2930, doi:10.3762/bjoc.14.271

• -dione derivatives were obtained in good to excellent yields via the cyclocondensation of 2-formylbenzoic acid and various α-amino acid arylhydrazides using water as the solvent in the presence of sodium dodecyl sulfate as the surfactant and under simple and minimum manipulation, without purification

• -imidazo[2,1-a]isoindole-2,5(3H,9bH)-diones. Synthesis of the starting (L)-α-amino acid phenylhydrazides and 4-chlorophenylhydrazides 3a–m under solvent-free conditions. Cyclocondensation of 2-formylbenzoic acid (4) with (L)-alanine phenylhydrazide (3a). Synthesis of the nitrogenated tricyclic compounds 5a

• –m. Diastereoisomeric (dr) and enantiomeric (er) ratio were determined by chiral HPLC (see Supporting Information File 3). Proposed partial mechanism with a selectivity model. Synthesis of the α-amino acid arylhydrazides 3a–m. Optimization of the reaction conditions for the cyclocondensation of 2

Quinolines from the cyclocondensation of isatoic anhydride with ethyl acetoacetate: preparation of ethyl 4-hydroxy-2-methylquinoline-3-carboxylate and derivatives

• Nicholas G. Jentsch,
• Jared D. Hume,
• Emily B. Crull,
• Samer M. Beauti,
• Amy H. Pham,
• Julie A. Pigza,
• Jacques J. Kessl and
• Matthew G. Donahue

Beilstein J. Org. Chem. 2018, 14, 2529–2536, doi:10.3762/bjoc.14.229

• regioselectivity issues and practical challenges associated with the aniline cyclocondensation (7→8), along with the scarcity of commercially available highly substituted quinolines, we sought to employ an entirely different tactic by utilizing 2H-3,1-benzoxazine-2,4(1H)-dione (isatoic anhydride) chemistry [16][17

• cyclocondensation reaction (Scheme 4, 9→10), we hypothesized that ethyl acetopyruvate could install the desired ethyl 2-oxoacetate residue at the 3-position as in 11 that is required for the synthesis of quinolines 1 and 2 (Scheme 6). Whereas with ethyl acetoacetate as shown in Scheme 5 can only condense to form

• acids with triphosgene. Substituted 2-methyl-4-hydroxyquinolines from isatoic anhydrides and ethyl acetoacetate. Mechanistic hypothesis for the cyclocondensation reaction. Quinoline synthesis with ethyl acetylpyruvate. Elaboration of the benzoic acid ethyl ester to the acetic acid residue. Umpolung

Calixazulenes: azulene-based calixarene analogues – an overview and recent supramolecular complexation studies

• Paris E. Georghiou,
• Shofiur Rahman,
• Abdullah Alodhayb,
• Hidetaka Nishimura,
• Jaehyun Lee,
• Atsushi Wakamiya and
• Lawrence T. Scott

Beilstein J. Org. Chem. 2018, 14, 2488–2494, doi:10.3762/bjoc.14.225

• reported to date. In 2002 Lash and Colby’s reported a convenient one-step Florisil®-mediated cyclocondensation of azulene with paraformaldehyde to produce an all-hydrocarbon “calix[4]azulene” 3 [15]. Later, Lash et al. reported their synthesis of a second all-hydrocarbon tetra-6-tert-butylcalix[4]azulene

• Suzuki–Miyaura coupling reaction of bromobenzene with 5,7-di(Bpin)azulene, which in turn was formed via the exhaustive borylation of azulene with excess bis(pinacolato)diboron (B2pin2) [21]. Cyclocondensation of 5,7-diphenylazulene with formaldehyde produced 5 [22] under conditions similar to those used

Synthesis of indolo[1,2-c]quinazolines from 2-alkynylaniline derivatives through Pd-catalyzed indole formation/cyclization with N,N-dimethylformamide dimethyl acetal

• Antonio Arcadi,
• Sandro Cacchi,
• Giancarlo Fabrizi,
• Francesca Ghirga,
• Antonella Goggiamani,
• Antonia Iazzetti and
• Fabio Marinelli

Beilstein J. Org. Chem. 2018, 14, 2411–2417, doi:10.3762/bjoc.14.218

• related to hinckdentine A received increasing attention as a source of new and useful pharmaceuticals. One well-established approach is based on the elaboration of a preformed indole ring, for example through cyclocondensation of 2-(o-aminophenyl)indoles with 2-cyanobenzothiazoles [14], aldehydes [9] and

Synthesis and post-functionalization of alternate-linked-meta-para-[2ⁿ.1ⁿ]thiacyclophanes

• Wout De Leger,
• Koen Adriaensen,
• Koen Robeyns,
• Luc Van Meervelt,
• Joice Thomas,
• Björn Meijers,
• Mario Smet and
• Wim Dehaen

Beilstein J. Org. Chem. 2018, 14, 2190–2197, doi:10.3762/bjoc.14.192

• phenolic moieties was successfully performed. The 3D structure of the alternate-linked-meta-para-[22.12]thiacyclophane was further elucidated via X-ray crystallographic analysis. Keywords: alternate-linked-meta-para-bridge; cyclocondensation; heteramacrocycles; o-quinoid intermediate; thiacyclophanes

• ]. Cyclocondensation of 4 and 5 under highly diluted conditions (employing a syringe pump) resulted in the formation of a mixture of the [2 + 2] adduct 6 and the [3 + 3] adduct 7 (Scheme 2 and Table 1, entry 1). The optimization study was further conducted under diluted conditions and shorter reaction time (Table 1

• -thiacyclophane 6: (a) ball-and-stick representation, with O–H···S hydrogen bonds shown as green dashed lines, (b) space-filling representation viewed along the pseudo twofold axis. Macrocyclization towards homothiacalixarenes 3a and 3b [12]. Cyclocondensation reaction of 4 and 5 towards [2 + 2] and [3 + 3

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

• ]pyridines 32 and 34 (Scheme 5). In situ cyclocondensation of β-halovinyl aldehydes 29 with 5-aminopyrazoles (R = Ph, 16) under Heck conditions in the presence of Pd(OAc)2 with xantphos (4,5-bis(diphenylphosphino)-9,9-dimethylxanthene) gave 6-substituted pyrazolo[3,4-b]pyridines 34. On the other hand

• -aminopyrazole (R = H, 16) was condensed with 38. It was attributed to cyclocondensation between 1-NH (5-aminopyrazole) and the carbonyl carbon of the enaminone. The compounds were found to have cytotoxicity against the normal fibroblast (BHK) cell line and antitumor activity against the colon cancer cell line

• , were found to be the most active compounds showing a minimum survival of the cancer cells. Griffith et al. [96] described the synthesis of 7-hydroxypyrazolo[1,5-a]pyrimidine derivatives 137 by cyclocondensation of 5-aminopyrazole 126 (X = Me, Y = Ar) with ethyl acetoacetate 81. Pyrazolo[1,5-a

Synthesis, effect of substituents on the regiochemistry and equilibrium studies of tetrazolo[1,5-a]pyrimidine/2-azidopyrimidines

• Elisandra Scapin,
• Paulo R. S. Salbego,
• Caroline R. Bender,
• Alexandre R. Meyer,
• Anderson B. Pagliari,
• Tainára Orlando,
• Geórgia C. Zimmer,
• Clarissa P. Frizzo,
• Helio G. Bonacorso,
• Nilo Zanatta and
• Marcos A. P. Martins

Beilstein J. Org. Chem. 2017, 13, 2396–2407, doi:10.3762/bjoc.13.237

• cyclocondensation reaction [CCC + NCN] was developed. The NCN corresponds to 5-aminotetrazole and CCC to β-enaminone. Two distinct products were observed in accordance with the β-enaminone substituent. When observed in solution, the compounds can be divided into two groups: (a) precursor compounds with R = CF3 or

• atom of the enone, both soft sites of the starting materials [29]. In recent research, we developed an efficient method to obtain 1,2,4-triazolo[1,5-a]pyrimidines from the cyclocondensation reaction of 1,1,1-trifluoro-4-metoxy-3-alken-2-one or β-enaminones with 5-amino-1,2,4-triazole. The methodology

• , SCXRD, PXRD, FTIR). Therefore, this study aims to (i) propose an efficient methodology for the synthesis of tetrazolo[1,5-a]pyrimidines substituted at the 5- and 7-positions of the heterocyclic ring; (ii) observe the regiochemistry of the cyclocondensation reaction and the effect of the substituent on

Regiodivergent condensation of 5-alkoxycarbonyl-1H-pyrrol-2,3-diones with cyclic ketazinones en route to spirocyclic scaffolds

• Alexey Yu. Dubovtsev,
• Maksim V. Dmitriev,
• Аndrey N. Maslivets and
• Michael Rubin

Beilstein J. Org. Chem. 2017, 13, 2179–2185, doi:10.3762/bjoc.13.218

• cyclocondensation of six-membered cyclic enamines 1 (vinylogous secondary amides) with 5-methoxycarbonyl-1H-pyrrolediones 2 [39][40][41]. This transformation involved the Michael addition of an enamine to the α,β-unsaturated carbonyl fragment of a pyrroledione and subsequent 5-exo-trig intramolecular nucleophilic

Syntheses of 3,4- and 1,4-dihydroquinazolines from 2-aminobenzylamine

• Jimena E. Díaz,
• Silvia Ranieri,
• Nadia Gruber and
• Liliana R. Orelli

Beilstein J. Org. Chem. 2017, 13, 1470–1477, doi:10.3762/bjoc.13.145

• advantages of these reagents. Cyclocondensation is a fundamental tool in heterocycles synthesis, and microwave (MW) heating has found interesting applications in this area [55][56], overcoming limitations arising from low reactivity and side reactions typical of conventional heating [57]. We had previously

Switchable highly regioselective synthesis of 3,4-dihydroquinoxalin-2(1H)ones from o-phenylenediamines and aroylpyruvates

• Juraj Dobiaš,
• Marek Ondruš,
• Gabriela Addová and
• Andrej Boháč

Beilstein J. Org. Chem. 2017, 13, 1350–1360, doi:10.3762/bjoc.13.132

• easily prepared by cyclocondensation of o-phenylenediamines and aroylpyruvates. Unsymmetrically substituted o-phenylenediamines can be obtained form regioisomeric mixtures of 3,4-dihydroquinoxalin-2(1H)-ones. It is often quite difficult to get a pure regioisomer and determine its structure without

• controlling the reaction selectivity and exploitation of complex NMR techniques (HSQC, NOESY, HMBC). This article examines the regioselectivity of the cyclocondensation between six monosubstituted o-phenylenediamines (-OMe, -F, -Cl, -COOH, -CN, -NO2) and the derivatives of p-chlorobenzoylpyruvate (ester or

• could expand the synthetic impact of our results. Keywords: controlled regioselectivity; cyclocondensation; 3,4-dihydroquinoxaline-2(1H)one; HOBt/DIC; mechanism; Introduction The quinoxalin-2(1H)-one moiety is frequently found in compounds that exhibit biological activity, particularly antimicrobial

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

• amine component in Ugi and Groebke–Blackburn–Bienaymé multicomponent reactions. The first example of an application of aminoazoles in an Ugi four-component reaction was discovered and novel features of a Groebke–Blackburn–Bienaymé cyclocondensation are established and discussed. The heterocycles