Catalytic asymmetric formal synthesis of beraprost

• Yusuke Kobayashi,
• Ryuta Kuramoto and
• Yoshiji Takemoto

Beilstein J. Org. Chem. 2015, 11, 2654–2660, doi:10.3762/bjoc.11.285

• enantioselective intramolecular oxa-Michael reaction of an α,β-unsaturated amide mediated by a newly developed benzothiadiazine catalyst. The Weinreb amide moiety and bromo substituent of the Michael adduct were utilized for the C–C bond formations to construct the scaffold. All four contiguous stereocenters of

• few asymmetric syntheses relying on the optical resolution of racemic intermediates [16][17][18][23]. Herein we report the first catalytic asymmetric synthesis of the key intermediate 2 through organocatalyzed-enantioselective intramolecular oxa-Michael reaction [24][25][26]. Results and Discussion

• condensation followed by diazo-transfer reaction. The chiral dihydrobenzofuran scaffold (5 or 6) could be synthesized by asymmetric intramolecular oxa-Michael reaction (AIOM) of α,β-unsaturated amides 7 or 8. Such reactions are generally considered to be challenging due to low nucleophilicity of the oxygen

Organocatalytic and enantioselective Michael reaction between α-nitroesters and nitroalkenes. Syn/anti-selectivity control using catalysts with the same absolute backbone chirality

• Jose I. Martínez,
• Uxue Uria,
• Maria Muñiz,
• Efraím Reyes,
• Luisa Carrillo and
• Jose L. Vicario

Beilstein J. Org. Chem. 2015, 11, 2577–2583, doi:10.3762/bjoc.11.277

• Jose I. Martinez Uxue Uria Maria Muniz Efraim Reyes Luisa Carrillo Jose L. Vicario Department of Organic Chemistry II, University of the Basque Country (UPV/EHU), P.O. Box 644, 48080 Bilbao, Spain 10.3762/bjoc.11.277 Abstract The asymmetric and catalytic Michael reaction between α-nitroesters and

• extension of this behaviour to the Michael reaction between α-substituted nitroacetates and nitroalkenes. The Michael reaction is regarded as a fundamental tool for the formation of C–C bonds during the synthesis of complex molecules [33][34][35], in particular, being able to control both the simple and the

• , isolating the other possible diastereoisomer anti-3a in good yield, 88:12 dr and 90% ee. Once we had confirmed the good performance of the reaction in this intermolecular Michael reaction, we proceeded to evaluate the scope of this transformation in order to establish whether this method could be useful and

Diastereoselective and enantioselective conjugate addition reactions utilizing α,β-unsaturated amides and lactams

• Katherine M. Byrd

Beilstein J. Org. Chem. 2015, 11, 530–562, doi:10.3762/bjoc.11.60

• development of asymmetric variants of the Michael reaction. In early studies, chemists relied on chiral auxiliaries [5], heterocuprates [15][16], or natural product-based [17] ligands to induce high to modest stereoselectivity. In 1991, Alexandre Alexakis and co-workers reported the first asymmetric conjugate

• initial discovery [176][177], the Mukaiyama–Michael reaction has emerged as a reliable alternative to the use of metal enolates as nucleophiles in Michael reactions. Katsuki and co-workers reported the first application of this reaction to α,β-unsaturated amides [178]. Their reactions were promoted by

Recent advances in the electrochemical construction of heterocycles

• Robert Francke

Beilstein J. Org. Chem. 2014, 10, 2858–2873, doi:10.3762/bjoc.10.303

• anodically generated 1,2-benzoquinone undergoes a Michael reaction with 62 under formation of adduct 63, which is further oxidized to give benzoquinone 64. Finally, anellation proceeds in a second Michael addition step under formation of heterocyclic compound 65. In the reported cases, both the generation of

Chiral phosphines in nucleophilic organocatalysis

• Yumei Xiao,
• Zhanhu Sun,
• Hongchao Guo and
• Ohyun Kwon

Beilstein J. Org. Chem. 2014, 10, 2089–2121, doi:10.3762/bjoc.10.218

• enantioselectivity. In a relatively successful example, the chiral aminophosphine G9 catalyzed the asymmetric double-Michael reaction between o-tosylamidophenyl malonate and 3-butyn-2-one to give the indoline derivative in 69% yield and up to 10% ee (Scheme 53). 2.15 Annulation through tandem Michael addition/Wittig

Primary-tertiary diamine-catalyzed Michael addition of ketones to isatylidenemalononitrile derivatives

• Akshay Kumar and
• Swapandeep Singh Chimni

Beilstein J. Org. Chem. 2014, 10, 929–935, doi:10.3762/bjoc.10.91

• -component version of the reaction by a domino Knoevenagel–Michael sequence. The Michael adduct 4a was transformed into spirooxindole 6 by a reduction with sodium borohydride in a highly enantioselective manner. Keywords: 3,3'-disubstituted oxindoles; Michael reaction; organocatalysis; primary-tertiary

• diamine; spirooxindoles; Introduction The Michael reaction is one of the fundamental carbon–carbon bond forming reactions in organic synthesis, since a plethora of carbon nucleophiles and activated olefins could be expected to give versatile arrangements [1][2][3][4][5][6][7][8]. Among the various

• -tertiary diamine organocatalysts for Michael reaction via enamine activation has not been investigated so far [38]. With readily available and inexpensive natural amino acids as a chiral source, we developed very simple primary-tertiary diamine organocatalysts (Figure 2) for asymmetric aldol reactions [44

Phosphinate-containing heterocycles: A mini-review

• Olivier Berger and
• Jean-Luc Montchamp

Beilstein J. Org. Chem. 2014, 10, 732–740, doi:10.3762/bjoc.10.67

• synthesis of chiral bicyclic phosphinates 23a–k by domino hydrophosphinylation/Michael/Michael reaction was realized by Fourgeaud et al. (Scheme 10) [25]. Several 1-oxa-3-aza-6-phosphabicyclo[3.3.0]octanes derivatives 23a–k were obtained in yields around 70% by reacting allenes 21 with imines 22 derived

• malonate anion. Tandem hydrophosphinylation/Michael/Michael reaction of allenyl-H-phosphinates. 5-Membered “cyclo-PALA” via intramolecular Mitsunobu reaction. 6-Membered “cyclo-PALA” via intramolecular Mitsunobu reaction. Intramolecular Kabachnik–Fields reaction. Tandem Kabachnik–Fields/alkylation reaction

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

• tautomerizes, the authors proposed a plausible mechanism, in which tautomer 113 undergoes cyclization via an intramolecular Michael reaction to give intermediate 114. The next step involves cleavage of the dimethylamine group to afford the thiazole structures 115. In 2003, the same group also described a solid

Boron-substituted 1,3-dienes and heterodienes as key elements in multicomponent processes

• Ludovic Eberlin,
• Fabien Tripoteau,
• François Carreaux,
• Andrew Whiting and
• Bertrand Carboni

Beilstein J. Org. Chem. 2014, 10, 237–250, doi:10.3762/bjoc.10.19

• based on a first Diels–Alder cycloaddition, as shown above. However, a recent report of Norsikian, Beau and co-workers described a novel sequence of tandem transformations which combined the Petasis reaction, intramolecular [4 + 2]-cycloaddition, cross metathesis and Michael reaction. This process gave

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

• 1,2-dioxolanes represents an intramolecular version of the Michael reaction, in which the hydroperoxide group acts as the nucleophile. Generally, the reaction is performed in fluorinated alcohols (CF3CH2OH or (CF3)2CHOH) in the presence of diethylamine or, in some cases, of cesium hydroxide. Initially

Total synthesis of (−)-epimyrtine by a gold-catalyzed hydroamination approach

• Thi Thanh Huyen Trinh,
• Khanh Hung Nguyen,
• Patricia de Aguiar Amaral and
• Nicolas Gouault

Beilstein J. Org. Chem. 2013, 9, 2042–2047, doi:10.3762/bjoc.9.242

• of (−)-epimyrtine have been described to date including the intramolecular allylsilane N-acyliminium ion cyclization [6], the organocatalytic aza-Michael reaction [7], the intramolecular Mannich reaction [8], and the iminium ion cascade reaction [9][10]. More efficient, convenient and highly

The chemistry of amine radical cations produced by visible light photoredox catalysis

• Jie Hu,
• Jiang Wang,
• Theresa H. Nguyen and
• Nan Zheng

Beilstein J. Org. Chem. 2013, 9, 1977–2001, doi:10.3762/bjoc.9.234

• 15 by abstraction of a hydrogen atom directly. The addition of the enol form of α-ketoester 59 to 15 furnishes the Mannich adduct 60. A retro-aza-Michael reaction via enol 61 allows cleavage of the C–N bond to yield secondary aniline 62. Aniline 62 is first oxidized to imine 63, which is further

• independently discovered that the efficiency of the same Michael reaction was greatly improved in the presence of a Brønsted acid (Scheme 23) [90]. Some of the improvements included shorter reaction time, higher yields, and use of a weaker light source (CFL). The most effective acid catalysts, of which TFA was

Efficient synthesis of β’-amino-α,β-unsaturated ketones

• Isabelle Abrunhosa-Thomas,
• Aurélie Plas,
• Nishanth Kandepedu,
• Pierre Chalard and
• Yves Troin

Beilstein J. Org. Chem. 2013, 9, 486–495, doi:10.3762/bjoc.9.52

• devised for the asymmetric synthesis of β’-amino-protected-α,β enones, a valuable intermediate for the synthesis of trans 2,6-disubstituted piperidines. The scope and limitation of the aza-Michael reaction were studied with a range of substrates. We are currently working on the application of this

Reactions of salicylaldehyde and enolates or their equivalents: versatile synthetic routes to chromane derivatives

• Ishmael B. Masesane and
• Zelalem Yibralign Desta

Beilstein J. Org. Chem. 2012, 8, 2166–2175, doi:10.3762/bjoc.8.244

• 60. However, the reaction suffered from very poor yields (15–21%). The reaction is thought to proceed through the condensation of aldehyde 60 and prolinol 61 to give a chiral iminium-ion intermediate. This intermediate then undergoes a domino reaction involving a Michael reaction with salicylaldehyde

Mechanochemistry assisted asymmetric organocatalysis: A sustainable approach

• Pankaj Chauhan and
• Swapandeep Singh Chimni

Beilstein J. Org. Chem. 2012, 8, 2132–2141, doi:10.3762/bjoc.8.240

• enantioselectivity (56–86% ee). The reactions carried out under HSBM afford (S)-3-hydroxyindole with higher enantioselectivity, relative to the reaction performed under traditional stirring in solvent. Michael reaction The asymmetric organocatalytic Michael addition to various unsaturated acceptors is one of the

• ball-milling conditions. O-Lauroyl-trans-4-hydroxyproline (VII) was identified as the best catalyst in aqueous media, whilst α,α-diphenylprolinol trimethylsilyl ether (VIII) turned out to be the best catalyst under ball-milling conditions. Michael reaction of aliphatic aldehydes 6 with nitroalkenes 7

• with conventional stirring, because when the reaction was carried out by conventional stirring, the product yield and stereoselectivity deteriorated significantly. Xu and co-workers reported a highly enantioselective organocatalytic Michael reaction of 1,2-carbonyl compounds to nitro-olefins under

Organocatalytic tandem Michael addition reactions: A powerful access to the enantioselective synthesis of functionalized chromenes, thiochromenes and 1,2-dihydroquinolines

• Chittaranjan Bhanja,
• Satyaban Jena,
• Sabita Nayak and
• Seetaram Mohapatra

Beilstein J. Org. Chem. 2012, 8, 1668–1694, doi:10.3762/bjoc.8.191

• high yield (up to 90%) and enantioselectivity (up to 99%), whereas compound 2 having electron-withdrawing groups provided poor results. Very recently, Xu et al. [46] reported an improved protocol for the domino-oxa-Michael reaction of salicylaldehydes 1 with α,β-unsaturated aldehydes 2 employing

• ).The protocol involved a tandem oxa-Michael–Michael reaction of 3-methyl-but-2-enal (22) and (E)-2-(2-nitrovinyl)-benzene-1,4-diol (21) followed by a domino Michael–aldol condensation with aldehyde 24 in the presence of TMS-protected diphenylprolinol Ib/AcOH as catalyst, affording the hexahydro-6H

• %) (Scheme 31). In this cascade reaction, the installation of electron-withdrawing groups on the amino moiety of 2-aminobenzaldehydes is anticipated to increase the aniline N–H acidity, the abstraction of which by the tertiary amine leads to an aza-Michael reaction. The thiourea group in the chiral catalyst

Synthesis and evaluation of new guanidine-thiourea organocatalyst for the nitro-Michael reaction: Theoretical studies on mechanism and enantioselectivity

• Tatyana E. Shubina,
• Matthias Freund,
• Sebastian Schenker,
• Timothy Clark and
• Svetlana B. Tsogoeva

Beilstein J. Org. Chem. 2012, 8, 1485–1498, doi:10.3762/bjoc.8.168

• produces the Michael product 15 with 66% yield in only 2 h. We therefore decided to study the solvent effects on the reaction outcome in the nitro-Michael reaction of diethylmalonate with trans-β-nitrostyrene further. The results are shown in Table 1. Whereas Michael reactions performed in dichloromethane

• systems, we decided to carry out a computational investigation of this guanidine-thiourea catalysed nitro-Michael reaction employing density functional calculations. Theoretical studies: DFT calculations The main goal of our calculations was to gain insight into the mechanism of the nitro-Michael addition

• not considered for the further studies. A similar Michael reaction of 1,3-dicarbonyl compounds with nitroolefins has been studied in some detail before [57][59]. It is generally proposed that the reaction proceeds first by deprotonation of the acidic proton of malonate 14 followed by formation of a

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

• calculated VCD spectra of the reaction product 3a. Keywords: Michael addition; non-covalent catalysis; organocatalysis; squaramide; thiourea; Introduction The asymmetric 1,4-conjugated addition (Michael reaction) of C-nucleophiles to enones is a powerful tool for obtaining a significant variety of

Stereoselective, nitro-Mannich/lactamisation cascades for the direct synthesis of heavily decorated 5-nitropiperidin-2-ones and related heterocycles

• Pavol Jakubec,
• Dane M. Cockfield,
• Madeleine Helliwell,
• James Raftery and
• Darren J. Dixon

Beilstein J. Org. Chem. 2012, 8, 567–578, doi:10.3762/bjoc.8.64

• with the generally high diastereocontrol in the formation of piperidinones 1a–j and 2a–l is interesting and worthy of further commentary. With the knowledge that the retro-Michael reaction does not occur under standard reaction conditions (Scheme 4) and assuming that the final step of the cascade (the

Catalyst-free and solvent-free Michael addition of 1,3-dicarbonyl compounds to nitroalkenes by a grinding method

• Zong-Bo Xie,
• Na Wang,
• Ming-Yu Wu,
• Ting He,
• Zhang-Gao Le and
• Xiao-Qi Yu

Beilstein J. Org. Chem. 2012, 8, 534–538, doi:10.3762/bjoc.8.61

• ). Some aromatic 1,3-dicarbonyl compounds were also successfully used as donors in this Michael reaction in moderate to good yields (Table 1, entries 18–21). In addition, furylnitrostyrene (1m) reacted with 1,3-cyclopentanedione (2a) as well as furan-2,4(3H,5H)-dione (2b) to give the corresponding

Synthesis and characterization of new diiodocoumarin derivatives with promising antimicrobial activities

• Hany M. Mohamed,
• Ashraf H. F. Abd EL-Wahab,
• Ahmed M. EL-Agrody,
• Ahmed H. Bedair,
• Fathy A. Eid,
• Mostafa M. Khafagy and
• Kamal A. Abd-EL-Rehem

Beilstein J. Org. Chem. 2011, 7, 1688–1696, doi:10.3762/bjoc.7.199

• -diiodosalicylaldehyde; diethyl malonate; ethyl cyanoacetate; coumarins; Michael reaction; Introduction Coumarins and their derivatives are biologically and pharmaceutically interesting compounds known for their use as additives in food, perfumes, cosmetics, pharmaceuticals, platelet aggregation and agrochemicals [1][2

• -withdrawing carbonyl groups, the behavior of 1 towards activated methylene compounds under Michael reaction conditions was investigated. Thus, treatment of 1 with ethyl cyanoacetate/NH4OAc in boiling ethanol afforded two reaction products. The insoluble reaction product was identified as ethyl 2-(3-carbamoyl

• Michael reaction conditions to yield a cyclic Michael adduct, which underwent hydrolysis by NH3 or MeNH2 and cyclization through the elimination of H2O (Scheme 5). The structure of compound 14a was established by 13C NMR, which showed δ at 42.5 (CH2(c)), 168.4 cm–1 (CONH), and 170 cm–1 (CO). The

Efficient gold(I)/silver(I)-cocatalyzed cascade intermolecular N-Michael addition/intramolecular hydroalkylation of unactivated alkenes with α-ketones

• Ya-Ping Xiao,
• Xin-Yuan Liu and
• Chi-Ming Che

Beilstein J. Org. Chem. 2011, 7, 1100–1107, doi:10.3762/bjoc.7.126

• simple starting materials [41]. We initially envisioned that the gold(I)-catalyzed cascade process could be established starting from the intermolecular N-Michael reaction of α,β-unsaturated ketone 1 and substituted allylamine 2 to furnish an α-ketone intermediate I [42][43][44] (for gold-catalyzed

• intramolecular N-Michael reaction see [42][43]), which further undergoes a subsequent gold(I)-catalyzed hydroalkylation to give pyrrolidine compounds 3 (Scheme 1); these compounds are versatile synthetic building blocks for organic synthesis and are important structural elements of many therapeutic drug

• of the intermolecular N-Michael reaction. Upon subsequent treatment of phenyl vinyl ketone (1a) with N-tosylallylamine (2a) in the presence of 10 mol % of AgClO4 at 90 °C for 3 h, the α-ketone intermediate 4 was formed in 85% yield, however, no product 3a was observed. Even after a longer reaction

Single enantiomer synthesis of α-(trifluoromethyl)-β-lactam

• Václav Jurčík,
• Alexandra M. Z. Slawin and
• David O'Hagan

Beilstein J. Org. Chem. 2011, 7, 759–766, doi:10.3762/bjoc.7.86

• explored for the hydrogenolysis of 5a, however cleavage of the C–N bond proved very difficult and a satisfactory method could not be found. Therefore, (S)-α-(p-methoxyphenyl)ethylamine (3b) was explored as an alternative amine for the aza-Michael reaction, as removal of this amine using ceric ammonium

• nitrate (CAN) oxidation offered a milder deprotection method [15]. The aza-Michael reaction proved straightforward to generate 4b and then cyclisation again using thionyl chloride and triethylamine gave β-lactams 5b in a 40% de, presumably again a thermodynamically biased isomer ratio. The

Michael-type addition of azoles of broad-scale acidity to methyl acrylate

• Sławomir Boncel,
• Kinga Saletra,
• Barbara Hefczyc and
• Krzysztof Z. Walczak

Beilstein J. Org. Chem. 2011, 7, 173–178, doi:10.3762/bjoc.7.24

• retro-Michael reaction – in equilibrium with Michael-type addition. By contrast, DIPEA, with a lower pKa gave the same adducts 3a and 3b in excellent yields. For 1b (the azole with the lowest acidity) a similar yield to 1a was achieved only after a significantly prolonged reaction time due to its lower

• acrylate was observed. Nevertheless, decreased yields for azole adducts when DBU or NaH were used as catalysts at elevated temperature could originate from a reversibility of the Michael reaction since unreacted azoles were isolated. This observation is in a good agreement with our recent findings for

• Michael-type addition of uracils to acrylic acceptors [27][42], where a a strongly basic catalyst (DBU) enabled control of regioselectivity via a retro-Michael reaction. Conclusion We have developed and optimised a simple and effective synthetic protocol for Michael-type addition of azoles of broad-scale

A short synthesis of (±)-cherylline dimethyl ether

• Bhima Y. Kale,
• Ananta D. Shinde,
• Swapnil S. Sonar,
• Bapurao B. Shingate,
• Sanjeev Kumar,
• Samir Ghosh,
• Soodamani Venugopal and
• Murlidhar S. Shingare

Beilstein J. Org. Chem. 2009, 5, No. 80, doi:10.3762/bjoc.5.80

• followed by Pictet–Spengler cyclization. Keywords: Curtius rearrangement; Michael reaction; Pictet–Spengler cyclization; radical azidonation; Introduction Aryl-1,2,3,4-tetrahydroisoquinolines have attracted much attention from the synthetic community owing to the potential biological activities of this