Preparation of imidazo[1,2-a]-N-heterocyclic derivatives with gem-difluorinated side chains

• Layal Hariss,
• Kamal Bou Hadir,
• Mirvat El-Masri,
• Thierry Roisnel,
• René Grée and
• Ali Hachem

Beilstein J. Org. Chem. 2017, 13, 2115–2121, doi:10.3762/bjoc.13.208

• (II) acetate-catalyzed aerobic oxidative amination and it proceeds through a tandem Michael addition followed by an intramolecular oxidative amination. Therefore, our target molecules A could be synthesized by the oxidative coupling of 2-aminopyridines with α,β-unsaturated ketones B, themselves easily

• demonstrate the regiochemistry of the reaction. These cascade reactions proceed first through a Michael addition of the primary amine on the enone, followed by an intramolecular cyclization by the pyridine/pyrimidine nucleus. Unfortunately, no crystal structure could be obtained for the imidazopyrimidines and

Mechanochemical synthesis of small organic molecules

• Tapas Kumar Achar,
• Anima Bose and
• Prasenjit Mal

Beilstein J. Org. Chem. 2017, 13, 1907–1931, doi:10.3762/bjoc.13.186

• -poor aromatic aldehydes and aromatic ring of the organocatalyst plays a crucial role for excellent yield and selectivity. Apparently the solvent-free system enhances the rigidity of the transition state for more selective reactions under mechanochemical activation. Michael addition Generally strong

• bases like NaOH, KOH, NaOEt etc. have been used as catalyst for the Michael addition of 1,3-dicarbonyl compounds to α,β-unsaturated ketones. In 2004, Wang and co-workers first reported a mechanochemical Michael reaction of 1,3-dicarbonyl compounds with chalcones and azachalcones using the mild base

• K2CO3 (Scheme 3). Michael adducts were isolated with good to excellent yield (76–99%) in a high-speed vibration mill (HSVM) within 10–60 min [51]. Bolm and co-workers reported an organocatalytic asymmetric version of Michael addition reaction under planetary-milling (PM) conditions. Differently

Solvent-free sonochemistry: Sonochemical organic synthesis in the absence of a liquid medium

• Deborah E. Crawford

Beilstein J. Org. Chem. 2017, 13, 1850–1856, doi:10.3762/bjoc.13.179

• that alternative products can be formed using this technique, as with ball milling. The Knoevenagel condensation [18], Michael addition [19] and Biginelli reactions [20] amongst others have been instigated by ultrasonic irradiation in the presence of solvents such as pyridine and methanol, resulting in

Chiral phase-transfer catalysis in the asymmetric α-heterofunctionalization of prochiral nucleophiles

• Johannes Schörgenhumer,
• Maximilian Tiffner and
• Mario Waser

Beilstein J. Org. Chem. 2017, 13, 1753–1769, doi:10.3762/bjoc.13.170

• -oxygenation reactions above, also the introduction of a nitrogen-based functionality alpha to a carbonyl group can be achieved by several complementary strategies. One powerful option is to carry out Michael addition-initiated aziridination reactions of α,β-unsaturated carbonyl acceptors [18][138][139][140

Bifunctional organocatalysts for the asymmetric synthesis of axially chiral benzamides

• Ryota Miyaji,
• Yuuki Wada,
• Akira Matsumoto,
• Keisuke Asano and
• Seijiro Matsubara

Beilstein J. Org. Chem. 2017, 13, 1518–1523, doi:10.3762/bjoc.13.151

• reactions to occur. Organocatalysts have also been employed in several asymmetric cyclization reactions via intramolecular hetero-Michael addition [7][8][9][10][11][12][13][14][15][16]. In these reactions, multipoint recognition by the catalysts favors the specific conformations of the substrates in the

Construction of highly enantioenriched spirocyclopentaneoxindoles containing four consecutive stereocenters via thiourea-catalyzed asymmetric Michael–Henry cascade reactions

• Yonglei Du,
• Jian Li,
• Kerong Chen,
• Chenglin Wu,
• Yu Zhou and
• Hong Liu

Beilstein J. Org. Chem. 2017, 13, 1342–1349, doi:10.3762/bjoc.13.131

• -catalyzed Michael addition/intramolecular silyl nitronate-olefin cycloaddition (ISOC)/fragmentation sequence to produce highly enantioenriched spirocyclopentaneoxindoles containing an oxime functional group from easily accessible 3-allyl-substituted oxindoles and nitroolefins, which has received wide

• addition, the electrophilicity of the reacting carbon center of nitrovinylacetamide is likely enhanced by H-bonding, thereby enabling the Michael addition to construct a unique quaternary stereogenic center complex A which would cyclize concurrently via Henry reaction to give the product 3 and regenerates

Strategies toward protecting group-free glycosylation through selective activation of the anomeric center

• A. Michael Downey and
• Michal Hocek

Beilstein J. Org. Chem. 2017, 13, 1239–1279, doi:10.3762/bjoc.13.123

• incubation with the sugar in aqueous buffer at pH 10. In all cases the Michael addition took place regioselectively at the anomeric position of the carbohydrate moiety. Each of the two surface-modification steps as well as the incubation steps was characterized using X-ray photoelectron spectroscopy (XPS) to

A strategic approach to [6,6]-bicyclic lactones: application towards the CD fragment of DHβE

• Tue Heesgaard Jepsen,
• Emil Glibstrup,
• François Crestey,
• Anders A. Jensen and
• Jesper Langgaard Kristensen

Beilstein J. Org. Chem. 2017, 13, 988–994, doi:10.3762/bjoc.13.98

• carboxylic acid 25 in these apolar solvents was the reason. However, addition of small amounts of MeOH in order to increase polarity was detrimental and led to decomposition upon heating. Since the desired cyclization could be also approached as an intramolecular Michael addition we attempted to mediate the

Automating multistep flow synthesis: approach and challenges in integrating chemistry, machines and logic

• Chinmay A. Shukla and
• Amol A. Kulkarni

Beilstein J. Org. Chem. 2017, 13, 960–987, doi:10.3762/bjoc.13.97

Sulfamide chemistry applied to the functionalization of self-assembled monolayers on gold surfaces

• Loïc Pantaine,
• Vincent Humblot,
• Vincent Coeffard and
• Anne Vallée

Beilstein J. Org. Chem. 2017, 13, 648–658, doi:10.3762/bjoc.13.64

• have been investigated for the immobilization of a target molecule through a reaction with the terminal groups of the SAMs. The most common methods to covalently functionalize these materials involve the Huisgen cycloaddition between an azide and an alkyne [8][9], Thiol-Michael addition [10][11], amide

Synthesis of new pyrrolidine-based organocatalysts and study of their use in the asymmetric Michael addition of aldehydes to nitroolefins

• Alejandro Castán,
• Ramón Badorrey,
• José A. Gálvez and
• María D. Díaz-de-Villegas

Beilstein J. Org. Chem. 2017, 13, 612–619, doi:10.3762/bjoc.13.59

• organocatalysts with a bulky substituent at C2 were synthesized from chiral imines derived from (R)-glyceraldehyde acetonide by diastereoselective allylation followed by a sequential hydrozirconation/iodination reaction. The new compounds were found to be effective organocatalysts for the Michael addition of

• aldehydes to nitroolefins and enantioselectivities up to 85% ee were achieved. Keywords: enantioselective synthesis; Michael addition; organocatalysis; pyrrolidines; synthetic methods; Introduction In the first decades of the 21st century, the enantioselective organocatalysis has witnessed a tremendous

• chiral pool, we have now focused on the synthesis of new chiral pyrrolidines capable of creating a sterically demanding environment due to the presence of a bulky 2,2-disubstituted-1,3-dioxolan-4-yl moiety at C2 from chiral imines derived from (R)-glyceraldehyde. The Michael addition of aldehydes to

Contribution of microreactor technology and flow chemistry to the development of green and sustainable synthesis

• Flavio Fanelli,
• Giovanna Parisi,
• Leonardo Degennaro and
• Renzo Luisi

Beilstein J. Org. Chem. 2017, 13, 520–542, doi:10.3762/bjoc.13.51

• synthesis and application of a recyclable immobilized analogue of benzotetramisole (BMT) used in a catalytic enantioselective Michael addition/cyclization reactions under continuous-flow conditions (Scheme 11) [60]. Resin-bound catalyst 10 was swollen with dichloromethane in a medium-pressure chromatography

Construction of bis-, tris- and tetrahydrazones by addition of azoalkenes to amines and ammonia

• Artem N. Semakin,
• Aleksandr O. Kokuev,
• Yulia V. Nelyubina,
• Alexey Yu. Sukhorukov,
• Petr A. Zhmurov,
• Sema L. Ioffe and
• Vladimir A. Tartakovsky

Beilstein J. Org. Chem. 2016, 12, 2471–2477, doi:10.3762/bjoc.12.241

• -tetraazaadamantane derivative was demonstrated. Keywords: azoalkenes; α-halogen hydrazones; heterocage compounds; hydrazone ligands; Michael addition; Introduction Hydrazones are extensively used as key structural units in the design of various functional molecular and supramolecular architectures [1][2][3][4][5

Methylenelactide: vinyl polymerization and spatial reactivity effects

• Judita Britner and
• Helmut Ritter

Beilstein J. Org. Chem. 2016, 12, 2378–2389, doi:10.3762/bjoc.12.232

• attack of the thiol takes place. This can be clearly seen in the 1H NMR spectra (Figures S18 and S19, Supporting Information File 1). Thioacetic acid was used as a potential chain-transfer agent due to its lower nucleophilicity. However, a complete thiol-Michael addition can be seen in Figure 8 (not full

• conversion of MLA due to the impurities of thioacetic acid like disulfide and acetic acid). In this context, the iodine catalyzed thiol-Michael addition was investigated [11]. Controlled radical polymerization of MLA via RAFT Since MLA acts as a vinyl monomer, it was also interesting to evaluate the

Highly chemo-, enantio-, and diastereoselective [4 + 2] cycloaddition of 5H-thiazol-4-ones with N-itaconimides

• Shuai Qiu,
• Choon-Hong Tan and
• Zhiyong Jiang

Beilstein J. Org. Chem. 2016, 12, 2293–2297, doi:10.3762/bjoc.12.222

• + 2] annulation between 5H-thiazol-4-ones and nitroalkenes [10]. In this stepwise process, the use of 3,5-dichlorophenyl as the substituent group of the urea in catalyst V would remarkably increase the free energy difference between R- and S-selection in the first Michael addition step, and also

Unusual reactions of diazocarbonyl compounds with α,β-unsaturated δ-amino esters: Rh(II)-catalyzed Wolff rearrangement and oxidative cleavage of N–H-insertion products

• Valerij A. Nikolaev,
• Jury J. Medvedev,
• Olesia S. Galkina,
• Ksenia V. Azarova and
• Christoph Schneider

Beilstein J. Org. Chem. 2016, 12, 1904–1910, doi:10.3762/bjoc.12.180

• provides a good way for the synthesis of multi-functionalized N-arylpyrrolidines by the same “metal–carbene” methodology with yields of up to 82% [15]. The reactions occur as a domino process involving an initial formation of N-ylides A followed by the intramolecular Michael addition with the conjugated

A chiral analog of the bicyclic guanidine TBD: synthesis, structure and Brønsted base catalysis

• Mariano Goldberg,
• Denis Sartakov,
• Jan W. Bats,
• Michael Bolte and
• Michael W. Göbel

Beilstein J. Org. Chem. 2016, 12, 1870–1876, doi:10.3762/bjoc.12.176

• in the field of molecular recognition, however, without being tested as catalysts [5][6][7][8][9][10]. A first example of enantioselective Michael addition has been reported for guanidine 3, albeit with low selectivity [11]. Compounds 4 and 5, inspired by the structure of ptilomycalin A and related

Practical synthetic strategies towards lipophilic 6-iodotetrahydroquinolines and -dihydroquinolines

• David R. Chisholm,
• Garr-Layy Zhou,
• Ehmke Pohl,
• Roy Valentine and
• Andrew Whiting

Beilstein J. Org. Chem. 2016, 12, 1851–1862, doi:10.3762/bjoc.12.174

• intermediate 7. Synthesis of THQ 10, by initial aza-Michael addition, followed by formation of the tertiary alcohol 9, which was then cyclised with H2SO4. Synthesis of THQ 14 by initial acylation, cyclisation with H2SO4 and reduction with borane·dimethyl sulphide complex. N-Alkylation of 13 and 14. Facile

Total synthesis of leopolic acid A, a natural 2,3-pyrrolidinedione with antimicrobial activity

• Atul A. Dhavan,
• Rahul D. Kaduskar,
• Loana Musso,
• Leonardo Scaglioni,
• Piera Anna Martino and
• Sabrina Dallavalle

Beilstein J. Org. Chem. 2016, 12, 1624–1628, doi:10.3762/bjoc.12.159

• A straightforward route to the intriguing 2,3-pyrrolidinedione system appeared to be the Michael addition of a suitable amine to ethyl acrylate, followed by a Dieckmann cyclization with diethyl oxalate [10][11]. We chose the p-methoxybenzyl (PMB) protecting group for the amine, because of its facile

Biosynthesis of oxygen and nitrogen-containing heterocycles in polyketides

• Franziska Hemmerling and
• Frank Hahn

Beilstein J. Org. Chem. 2016, 12, 1512–1550, doi:10.3762/bjoc.12.148

• precursor and thus particular ring systems [9][10][11]. Most heterocycles in polyketides are formed by specialised PKS domains and tailoring enzymes. These can be active during assembly of the nascent PKS precursor (as for example in the case of pyran/furan formation via oxa-Michael addition, see chapters

• thioester to a hydroxy group (d in Scheme 2). A Michael addition–lactonisation cascade leads to pyranones with a substituent in the 4-position 16 (e in Scheme 2). 3-Acylfuran-2-ones (19, 3-acyltetronates) are formed by acylation–Dieckmann condensation between 2-hydroxythioesters 18 and β-ketothioesters 17

• (f in Scheme 2). The oxidative cyclisation after C–H activation of alkyl carbons is known for the formation of furan rings 21 (g in Scheme 2). 1.1 Pyrans 1.1.1 oxa-Michael addition: The oxa-Michael addition on an α,β-unsaturated thioester intermediate leads to oxygen heterocycles along with the

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

• (R2 = H, Ph 71.5:28.5 to 90.5:9.5 er). In 2010, the Kobayashi group reported the calcium-catalyzed Michael addition of dibenzylmalonate (86) to N-acryloyloxazolidinones 87 followed by enantioselective protonation of a chiral calcium enolate to access 1,5-dicarbonyl compounds 90 (Scheme 21) [44]. The

Towards the total synthesis of keramaphidin B

• Pavol Jakubec,
• Alistair J. M. Farley and
• Darren J. Dixon

Beilstein J. Org. Chem. 2016, 12, 1096–1100, doi:10.3762/bjoc.12.104

• Pavol Jakubec Alistair J. M. Farley Darren J. Dixon Department of Chemistry, Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, OX1 3TA, United Kingdom 10.3762/bjoc.12.104 Abstract The enantio- and diastereoselective Michael addition of a δ-valerolactone-derived

• amine, following our well-established protocol [6][7][8][9][10][11][12]. The key quaternary stereocentre of keramaphidin B, we envisaged, would be installed through an enantio- and diastereoselective organocatalytic Michael addition [13][14][15] between pronucleophile 8 and the known substituted furanyl

• nitroolefin 9 under the control of a cinchona-derived bifunctional Brønsted base/H-bond donor organocatalyst developed in our group and others [16][17][18][19]. Bifunctional organocatalysed Michael addition studies In our previous total syntheses of nakadomarin A [5][7][20] and manzamine A [10] the

Catalytic asymmetric synthesis of biologically important 3-hydroxyoxindoles: an update

• Bin Yu,
• Hui Xing,
• De-Quan Yu and
• Hong-Min Liu

Beilstein J. Org. Chem. 2016, 12, 1000–1039, doi:10.3762/bjoc.12.98

• nucleophiles attacking the vinyliminium intermediates generated in situ from the indol-3-ylmethanols (the Michael addition) to form the intermediates. This is followed by the CPA-promoted cyclization, affording the final products bearing three continuous chiral centers. Besides, they also reported the CPA

• diastereoselectivities (all >95:5 dr) and enantioselectivities (up to >99% ee, Scheme 58) [75]. Mechanistic studies showed that this cascade reaction proceeded via a vinylogous Michael addition/Friedel–Crafts process involving a dual H-bonding activation of substrates. In 2015, Wang and co-workers reported Lewis acid

1H-Imidazol-4(5H)-ones and thiazol-4(5H)-ones as emerging pronucleophiles in asymmetric catalysis

• Antonia Mielgo and
• Claudio Palomo

Beilstein J. Org. Chem. 2016, 12, 918–936, doi:10.3762/bjoc.12.90

• )-ones 1 as pronucleophiles in organocatalyzed Michael addition reactions 2-Thio-1H-imidazol-4(5H)-ones 1 (R = SBn) have been reported to be effective equivalents of N-subtituted (alkyl, aryl, allyl) α-amino acids in conjugate addition reactions to both, nitroalkenes and α-silyloxy enones as Michael

• acceptors in reactions promoted by bifunctional Brønsted bases. 1.2.1 Nitroalkenes as acceptors. Investigation of the base-catalyzed Michael addition reaction of 2-thio-1H-imidazol-4(5H)-ones 4 to nitroalkenes 5 [55] revealed that cinchona alkaloids such as quinine, (DHQ)2Pyr or even thiourea tertiary amine

• demonstrated to be either less reactive and/or less stereoselective in their addition reaction to nitrostyrene thus affording the corresponding Michael adducts with no diastereoselectivity and/or poor enantioselectivity (Scheme 3). Useful applications of the Michael adducts coming from the Michael addition of

Muraymycin nucleoside-peptide antibiotics: uridine-derived natural products as lead structures for the development of novel antibacterial agents

• Daniel Wiegmann,
• Stefan Koppermann,
• Marius Wirth,
• Giuliana Niro,
• Kristin Leyerer and
• Christian Ducho

Beilstein J. Org. Chem. 2016, 12, 769–795, doi:10.3762/bjoc.12.77

• this producing organism, L-arginine is diastereoselectively hydroxylated to afford (3S)-3-hydroxy-L-arginine. The ring-closure reaction then occurs with formal inversion of the β-stereocenter (but quite likely through an aza-Michael addition to the α,β-unsaturated intermediate) [119][120][121]. The

• studies [123][124]. It should also be noted that a biomimetic domino guanidinylation–aza-Michael-addition reaction for the synthesis of the capreomycidine scaffold has been developed, which only furnished the target structures as stereoisomeric mixtures though [125]. The epicapreomycidine-derived