Selected synthetic strategies to cyclophanes

• Sambasivarao Kotha,
• Mukesh E. Shirbhate and
• Gopalkrushna T. Waghule

Beilstein J. Org. Chem. 2015, 11, 1274–1331, doi:10.3762/bjoc.11.142

• 26, which was subsequently converted to the cyclophane 28 by a Mannich-type condensation reaction (40%) (Scheme 1). Michael addition: In 1999, Reißig and co-workers [85] have synthesized a functionalized cyclophane by a cascade reaction, which proceeds with desilylation, ring opening, proton transfer

• , and finally, an intramolecular Michael addition to provide benzannulated large ring compounds 31 and 33. In this regard, substituted methyl 2-alkenyl-2-siloxycyclopropanecarboxylate 29 was converted into the alkylation product and further react with the ester enolate dibromide to yield vinyl

• cyclopropane derivatives 30 (62%) and 32 (44%). Later, Michael addition in the presence of caesium fluoride and benzyltriethylammonium chloride in DMF gave the benzannulated cyclodecanone derivatives 31 (11%) and 33 (10%) (Scheme 2). Oxymercuration – Hantzsch pyridine synthesis: Kondo and Miyake [86] have

One-pot odourless synthesis of thioesters via in situ generation of thiobenzoic acids using benzoic anhydrides and thiourea

• Mohammad Abbasi and
• Reza Khalifeh

Beilstein J. Org. Chem. 2015, 11, 1265–1273, doi:10.3762/bjoc.11.141

• reaction of thiourea with benzoic anhydrides, which were subjected to conjugate addition with electron-deficient alkenes or a nucleophilic displacement reaction with alkyl halides. Keywords: benzoic anhydride; Michael addition; nucleophilic displacement; thioester; thiourea; Introduction Thioesters have

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

• syntheses of two lead compounds reported earlier by AstraZeneca. The first one details the flow synthesis of a potent 5HT1B antagonist (28) that was assembled through a five step continuous synthesis including a SNAr reaction, heterogeneous hydrogenation, Michael addition–cyclisation and final amide

Cathodic hydrodimerization of nitroolefins

• Michael Weßling and
• Hans J. Schäfer

Beilstein J. Org. Chem. 2015, 11, 1163–1174, doi:10.3762/bjoc.11.131

• anion b formed by one electron reduction of the substrate a, has three pathways for dimerization [1][2]. In path (I) protonation followed by one-electron reduction leads to anion c, which in a Michael addition with substrate a forms the anion d, which is protonated to hydrodimer f. In path (II) b

• reasons, which can explain the absence of the dimer. This can favour the further reaction of the radical anion of 14 to the oxime 24 and the Michael addition of hydroxy ions to form the nitro alcohol 25. The smaller space filling of the fluorine atom compared to the chlorine atom should lead to a

• trimer (3, n = 2). The trimer could arise by a Michael addition of the intermediate dimer radical anion or dimer dianion of 4 to olefin 4. Indications to greater portions of 3 (n = 1) and 3 (n = 3) were not found in the LDI–MS. Support for this assumption comes from coulometry for 4 in [17], which

Peptide–polymer ligands for a tandem WW-domain, an adaptive multivalent protein–protein interaction: lessons on the thermodynamic fitness of flexible ligands

• Katharina Koschek,
• Vedat Durmaz,
• Oxana Krylova,
• Marek Wieczorek,
• Shilpi Gupta,
• Martin Richter,
• Alexander Bujotzek,
• Christina Fischer,
• Rainer Haag,
• Christian Freund,
• Marcus Weber and
• Jörg Rademann

Beilstein J. Org. Chem. 2015, 11, 837–847, doi:10.3762/bjoc.11.93

• ) was selected and synthesized on Rink amide polystyrene resin. For attachment to the polymer carriers the N-cysteinylated peptide CGPPPRGPPPR-NH2 (P2) was prepared, containing a free N-terminus in order to enable the attachment to polymers via native chemical ligation or Michael addition to maleimide

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

• ; Michael addition; Introduction Conjugate (or 1,4- or Michael) additions [1][2][3][4][5] are some of the most powerful carbon–carbon bond forming reactions in the synthetic chemist’s toolbox. These reactions have been the key step in the syntheses of numerous natural products and pharmaceutically relevant

• this topic has recently been reviewed [26]. In terms of the mechanisms of the CA reactions, only those mechanisms that differ from the generally accepted ones will be discussed [4][27]. Finally, the terms conjugate addition, Michael addition and 1,4-addition will be used interchangeably throughout this

• environment for the reaction to occur. The first part of this section will focus on the asymmetric 1,4-addition of carbon nucleophiles and the next two parts will discuss the addition of amines (aza-Michael addition) and phosphorous compounds. 2.4.1 Asymmetric 1,4-addition of carbon nucleophiles: Since its

Come-back of phenanthridine and phenanthridinium derivatives in the 21st century

• Lidija-Marija Tumir,
• Marijana Radić Stojković and
• Ivo Piantanida

Beilstein J. Org. Chem. 2014, 10, 2930–2954, doi:10.3762/bjoc.10.312

• reaction. Ghosh, Dhara et al. also reported a synthesis of substituted phenanthridines based on palladium-mediated Suzuki coupling (Scheme 14) [34][35]. Aerobic ligand-free domino Suzuki coupling–Michael addition reaction in the presence of Pd(OAc)2 and K3PO4 as a catalytic system in H2O was catalysed 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

• Michael addition/ring closure with in situ generated quinones (section 2.2) and sequential cyclizations involving acyliminium species and alkoxycarbenium ions (section 2.3) represent the majority of recently reported intermolecular electrochemical cyclizations. Cases which do not fall into any of these

• generated 1,2-benzoquinones via sequential Michael addition/ring closure An electrochemical method for the synthesis of benzofuran and indol derivatives is based on the oxidation of catechol in presence of 1,3-dicarbonyl compounds or analogous C,H-acidic compounds 62 (Scheme 24) [69][70][71][72]. The

• 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

Stereoselective synthesis of perillaldehyde-based chiral β-amino acid derivatives through conjugate addition of lithium amides

• Zsolt Szakonyi,
• Reijo Sillanpää and
• Ferenc Fülöp

Beilstein J. Org. Chem. 2014, 10, 2738–2742, doi:10.3762/bjoc.10.289

• -6720 Szeged, Eötvös u. 6, Hungary 10.3762/bjoc.10.289 Abstract The Michael addition of dibenzylamine to (+)-tert-butyl perillate (3) and to (+)-tert-butyl phellandrate (6), derived from (S)-(−)-perillaldehyde (1), resulted in diastereomeric β-amino esters 7A–D in a moderately stereospecific reaction

• addition was observed. Amino ester 11 was obtained as a single product and transformed to the corresponding amino acids 10A and 10D in good yields on the gram scale. Keywords: asymmetric synthesis; β-amino acid; chiral; Michael addition; monoterpene; Introduction In the past decade, cyclic β-amino acids

• achiral anhydrides followed by Curtius degradation [18][19][20]. The highly stereoselective Michael addition of lithium amide-type nucleophiles to α,β-unsaturated esters also proved to be a very efficient and useful method for the preparation of alicyclic β-amino acids in homochiral form [21][22

End group functionalization of poly(ethylene glycol) with phenolphthalein: towards star-shaped polymers based on supramolecular interactions

• Carolin Fleischmann,
• Hendrik Wöhlk and
• Helmut Ritter

Beilstein J. Org. Chem. 2014, 10, 2263–2269, doi:10.3762/bjoc.10.235

• (PP-NH2) was obtained through a Michael addition reaction of PP-AAm and cysteamine hydrochloride. The hydrochloride was chosen in order to disable the competing nucleophilic addition of the amine and therefore, to prevent the formation of side products. The purified PP-NH2 was then converted into the

Indium-mediated allylation in carbohydrate synthesis: A short and efficient approach towards higher 2-acetamido-2-deoxy sugars

• Christopher Albler,
• Ralph Hollaus,
• Hanspeter Kählig and
• Walther Schmid

Beilstein J. Org. Chem. 2014, 10, 2230–2234, doi:10.3762/bjoc.10.231

• intramolecular Michael addition, leading to the formation of highly substituted tetrahydrofuran derivatives of the C-glycoside type [31]. Next, we investigated the azide reduction of compounds 6a–c under different reaction conditions. Unfortunately DTT/DIPA, thioacetic acid, tributylphosphine/H2O and H2/Pd

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

• groups, could undergo further transformations, such as Diels–Alder reactions, reduction, and hydrolysis, to afford nitrogen-containing heterocyclic compounds. In contrast to the intermolecular aza-RC reaction/Michael addition sequence described above, the mechanism was assumed to involve an initial aza

• -RC reaction between the α,β-unsaturated imine and the enolate, followed by an SN2 reaction. 2.14 Annulations through double-Michael additions The bisphosphine-catalyzed double-Michael addition of dinucleophiles to electron-deficient alkynes provides an efficient approach for the synthesis of

• 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

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

• base. More recently, Carell and coworkers developed a straightforward pathway based on the key reaction of in situ α-brominated 3-phthalimidopropanal with 2,6-diaminopyrimidin-4-one [11], inspired by Grubb’s synthesis of the Q base (queuine) [12]. Alternatively, Klebe and coworkers employed a Michael

• addition of the same pyrimidinone to the nitroolefin 2-[(2E)-3-nitroprop-2-en-1-yl]-1H-isoindole-1,3(2H)-dione [13], however, this route seemed inconvenient for our purposes because access to the nitroolefin requires several additional steps. Results and Discussion Our aim was to develop a robust synthetic

Application of cyclic phosphonamide reagents in the total synthesis of natural products and biologically active molecules

• Thilo Focken and
• Stephen Hanessian

Beilstein J. Org. Chem. 2014, 10, 1848–1877, doi:10.3762/bjoc.10.195

• was dependent on the stereocontrolled Michael addition of the anion generated from crotyl phosphonamide 28f, which set three contiguous stereocenters in one step. Thus, addition of the Li anion of 28f to cyclopentenone 153 gave adduct 154 as a single diastereomer on a gram scale. Cleavage of the

Multicomponent reactions in nucleoside chemistry

• Mariola Koszytkowska-Stawińska and
• Włodzimierz Buchowicz

Beilstein J. Org. Chem. 2014, 10, 1706–1732, doi:10.3762/bjoc.10.179

• three-component process involving the Knoevenagel condensation, the Michael addition and the Thorpe–Ziegler heterocyclization (Scheme 23). Malonitrile acted as the Knoevenagel donor in all cases. The subsequent Michael addition steps involved: cyanothioacetamide [91], 4-hydroxy-6-methylpyridin-2(1H)-one

• Knoevenagel condensation, the Michael addition, and the N-nucleophilic cyclization (Scheme 24) [94]. Whereas 5,5-dimethylcyclohexane-1,3-dione (66) or Meldrum’s acid (67) acted as the Knoevenagel donor, 3-methyl-1-phenyl-1H-pyrazol-5-amine (68) played the role of the Michael donor in these reactions. The

A tandem Mannich addition–palladium catalyzed ring-closing route toward 4-substituted-3(2H)-furanones

• Jubi John,
• Eliza Târcoveanu,
• Peter G. Jones and
• Henning Hopf

Beilstein J. Org. Chem. 2014, 10, 1462–1470, doi:10.3762/bjoc.10.150

• )-furanones from activated alkenes and 4-chloroacetoacetates (Scheme 1) [40]. The reaction was found to be general for a wide range of alkenes derived from aromatic and aliphatic aldehydes. The reaction proceeded via Michael addition of the acetoacetate to the alkene with a subsequent palladium-catalyzed ring

Cyclization–endoperoxidation cascade reactions of dienes mediated by a pyrylium photoredox catalyst

• Nathan J. Gesmundo and
• David A. Nicewicz

Beilstein J. Org. Chem. 2014, 10, 1272–1281, doi:10.3762/bjoc.10.128

• hydroperoxides with pendant alkenes or alkynes have been developed. Selected examples include Pd(II)-catalyzed hydroalkoxylation reactions of unsaturated hydroperoxides [9], Au(I)-catalyzed endoperoxidation of alkynes [10] and Brønsted acid-catalyzed enantioselective acetalization/oxa-Michael addition cascade

Syntheses of fluorooxindole and 2-fluoro-2-arylacetic acid derivatives from diethyl 2-fluoromalonate ester

• Antal Harsanyi,
• Graham Sandford,
• Dmitri S. Yufit and
• Judith A.K. Howard

Beilstein J. Org. Chem. 2014, 10, 1213–1219, doi:10.3762/bjoc.10.119

• structurally sophisticated selectively fluorinated systems. For example, 2-fluoromalonate esters have been used for the preparation of various α-fluorocarboxylic acids [28][29][30][31][32], heterocycles, such as fluoropyrimidine [33] and quinolone [34] derivatives, alkylated [35] and Michael addition [36][37

Atherton–Todd reaction: mechanism, scope and applications

• Stéphanie S. Le Corre,
• Mathieu Berchel,
• Hélène Couthon-Gourvès,
• Jean-Pierre Haelters and
• Paul-Alain Jaffrès

Beilstein J. Org. Chem. 2014, 10, 1166–1196, doi:10.3762/bjoc.10.117

• reaction [102], Michael addition [103], Diels–Alder reaction [104], Friedel–Crafts alkylation [105]) illustrate the use of phosphoramidates as organocatalysts. These phosphoramidates were not synthesized by an AT reaction. Instead, the reaction of an amine with an electrophilic phosphorus species (P–Cl

4-Hydroxy-6-alkyl-2-pyrones as nucleophilic coupling partners in Mitsunobu reactions and oxa-Michael additions

• Michael J. Burns,
• Thomas O. Ronson,
• Richard J. K. Taylor and
• Ian J. S. Fairlamb

Beilstein J. Org. Chem. 2014, 10, 1159–1165, doi:10.3762/bjoc.10.116

• , which are found embedded in a number of natural products. Keywords: heterocycles; Mitsunobu reaction; oxa-Michael addition; 2-pyrone; vinyl ethers; Introduction The 2-pyrone motif is a prevalent structural feature of many complex natural products and biologically active compounds [1][2]. Various

• part of our extensive studies on reactions involving 2-pyrone derivatives, we report herein a significant expansion of the Mitsunobu protocol to a variety of different coupling partners, along with an alternative route to the formation of 2-pyronyl enol ethers using an oxa-Michael addition to

• extensively delocalised. To the best of our ability we could not find a single previous published example of a Michael addition employing 4-hydroxy-2-pyrones. Initial experiments reacting 4-hydroxy-2-pyrone 3a with methyl propiolate (6a) in the presence of an amine base afforded only moderate yields of

Molecular architecture with carbohydrate functionalized β-peptides adopting 3₁₄-helical conformation

• Nitin J. Pawar,
• Navdeep S. Sidhu,
• George M. Sheldrick,
• Dilip D. Dhavale and
• Ulf Diederichsen

Beilstein J. Org. Chem. 2014, 10, 948–955, doi:10.3762/bjoc.10.93

• -peptide incorporation of sugar-β-amino acids are described providing the saccharide units as amino acid side chain. The respective sugar-β-amino acids are accessible by Michael addition of ammonia to sugar units derivatized as α,β-unsaturated esters. Three sugar units were incorporated in β-peptide

• attracted interest due to their use as structural elements as peptidomimetics [38][39], oligosaccharide mimetics [40][41] and induction of secondary structures [42][43][44][45][46]. Carbohydrate-derived β-amino acids used in this study were obtained by conjugate addition (Michael addition) of ammonia to a

• conformation, thereby organizing the D-glucose, D-galactose or D-xylose carbohydrate epitopes on one face of the helix. Results and Discussion Synthesis of carbohydrate-β3-amino acids Key step for the synthesis of β3-sugar amino acids is the Michael addition of ammonia to α,β-unsaturated esters [47][48][49][50

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

• used to catalyze the Michael addition of ketones with isatylidenemalononitrile derivatives. Diamine 1a in combination with D-CSA as an additive provided Michael adducts in high yield (up to 94%) and excellent enantioselectivity (up to 99%). The catalyst 1a was successfully used to catalyze the three

• attention as novel substrates for the enantioselective synthesis of 3,3'-disubstituted oxindoles [18][19][20][21][22]. The organocatalytic Michael addition of ketones to isatylidenemalononitriles via enamine-catalysis has emerged as a useful tool for the synthesis of 3,3'-disubstituted oxindoles, which

• in Michael addition reactions via an iminium–enamine catalysis [31][32][33][34][35][36][37]. A few applications of primary-tertiary diamine in aldol reactions have been published [39][40][41][42][43]. To the best of our knowledge, however, the catalytic potential of amino acids derived primary

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

• . Tandem Kabacknik–Fields/C–N cross-coupling reaction. Tandem Kabacknik–Fields/C-P cross-coupling reaction. Heterocyclization via amide formation. Cyclization via reductive amination. H-Phosphinate alkylation. Cyclization through intramolecular Michael addition. Double Arbuzov reaction of bis

One-pot three-component synthesis and photophysical characteristics of novel triene merocyanines

• Christian Muschelknautz,
• Robin Visse,
• Jan Nordmann and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2014, 10, 599–612, doi:10.3762/bjoc.10.51

• case of amine additions to ynylideneindolone intermediates 11 we recently could show by experimental and computational studies that the terminal Michael addition proceeds in a stepwise fashion with the intermediacy of an allenyl enol that undergoes a rapid, irreversible 1,5-sigmatropic hydride shift

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

• -[4,5]deca-6,9-diene-3,8-diones (171) via a 5-exo-Michael addition, whereas DCM as solvent induced an intramolecular thiophene Diels–Alder reaction yielding tricyclic lactam 173. In an alternative approach an Ugi-protocol employing a resin-bound carbonate-based convertible isocyanide 174 (CCI) was