Copper-catalyzed enantioselective conjugate addition of organometallic reagents to challenging Michael acceptors

• Delphine Pichon,
• Jennifer Morvan,
• Christophe Crévisy and
• Marc Mauduit

Beilstein J. Org. Chem. 2020, 16, 212–232, doi:10.3762/bjoc.16.24

• . However, as depicted in Scheme 1, due to their stronger reactivity than that of usual esters or ketones, a competitive 1,2-addition to the carbonyl function of enals could occur, leading to the corresponding alcohol as a byproduct. Moreover, even if the 1,4-addition is favored, thanks to the copper/ligand

• enantioselective catalysis was reported by Evans and co-workers in 2005 [34]. The selected asymmetric transformation was the Friedel–Crafts 1,4-addition involving indole derivatives as nucleophiles, catalyzed by a scandium(III) triflate complex with chiral bis(oxazolinyl)pyridine ligands. As highlighted by Evans

• in Scheme 13. The successful use of α,β-unsaturated acylimidazole in Cu ECAs using organometallic reagents has been introduced very recently. Pioneering works in this field were published in 2011 by Roelfes, Liskamp, and co-workers, with the 1,4-addition of dimethyl malonate to cinnamyl 2-acyl-1

Switchable selectivity in Pd-catalyzed [3 + 2] annulations of γ-oxy-2-cycloalkenones with 3-oxoglutarates: C–C/C–C vs C–C/O–C bond formation

• Yang Liu,
• Julie Oble and
• Giovanni Poli

Beilstein J. Org. Chem. 2019, 15, 1107–1115, doi:10.3762/bjoc.15.107

• -2-cycloalkenones, simply differing on the reaction temperature, are disclosed. These domino transformations allow C–C/O–C or C–C/C–C [3 + 2] annulations at will, via an intermolecular Pd-catalyzed C-allylation/intramolecular O- or C-1,4-addition sequence, respectively. In particular, exploiting the

• reversibility of the O-1,4-addition step, in combination with the irreversible C-1,4-addition/decarboxylation path, the intramolecular conjugate addition step could be diverted from the kinetic (O-alkylation) to the thermodynamic path (C-alkylation) thanks to a simple temperature increase. Crucial for the

• -one bis-nucleophiles. Keywords: 1,4-addition; annulation; decarboxylation; palladium; Pd-catalyzed allylation reaction; Introduction The development of new strategies for the synthesis of complex carbocyclic and heterocyclic structures remains a general topic for the synthetic chemists [1]. In the

A chemically contiguous hapten approach for a heroin–fentanyl vaccine

• Yoshihiro Natori,
• Candy S. Hwang,
• Lucy Lin,
• Lauren C. Smith,
• Bin Zhou and
• Kim D. Janda

Beilstein J. Org. Chem. 2019, 15, 1020–1031, doi:10.3762/bjoc.15.100

• corresponding alkene resulted in a mixture of products. We opted to try the synthesis of HF-2 by 1,4-addition, rather than reductive amination. Thus, intermediate 5 was acylated with acryloyl chloride to give the α,β-unsaturated intermediate 10 (Scheme 1). Condensation with a tert-butyl-protected glycine

• -1 and HF-4 were obtained from reductive amination of heroin intermediate 1 to key fentanyl intermediates 7 and 25, respectively (Scheme 5). In synthesizing HF-2, the aforementioned failure to obtain the necessary aldehyde for reductive amination necessitated a strategic modification to 1,4-addition

• . After screening acid catalysts (Figure S1, Supporting Information File 1), successful 1,4-addition of heroin intermediate 1 to fentanyl intermediate 10 yielded HF-2 (Scheme 5). Heroin intermediate 16 gave access to the phenylamide-linked haptens HF-3, HF-5, HF-8 via EDC-mediated coupling to their

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

• β-ketoenamides KE. The use of α,β-unsaturated nitriles as second component did not provide reasonable results, possibly due to a competing 1,4-addition of the lithiated methoxyallene to the double bonds. On the other hand, α,β-unsaturated carboxylic acids were excellent third components as shown in

Silanediol versus chlorosilanol: hydrolyses and hydrogen-bonding catalyses with fenchole-based silanes

• Falco Fox,
• Jörg M. Neudörfl and
• Bernd Goldfuss

Beilstein J. Org. Chem. 2019, 15, 167–186, doi:10.3762/bjoc.15.17

• the yields and the enantiomeric excess. In a third reaction, the 1,4 addition of silyl keten acetals 11 to chromone 20 is investigated (Table 11, Scheme 8). Chromone 20 is first transformed to the oxonium ion pair 21. Catalyst BIFOXSi(OH)2 (9) binds the triflate anion via hydrogen bonding and leaves

Unnatural α-amino ethyl esters from diethyl malonate or ethyl β-bromo-α-hydroxyiminocarboxylate

• Eloi P. Coutant,
• Vincent Hervin,
• Glwadys Gagnot,
• Candice Ford,
• Racha Baatallah and
• Yves L. Janin

Beilstein J. Org. Chem. 2018, 14, 2853–2860, doi:10.3762/bjoc.14.264

• results, we first sought an explanation for the modest yields observed for the preparation of the 2, 3 or 4-chlorophenyl-α-hydroxyimino esters 2t–v. As depicted in Scheme 2, the 1H NMR monitoring of the ethanolic solution of the alkylidenemalonate 6u pointed out a slow but steady 1,4-addition of ethanol

• reversal of the ethanol addition and thus increased the reaction time of the reduction step, but compound 7 remained unaffected and even more side products arose. To avoid this 1,4-addition, we then resorted to use a less nucleophilic solvent, and tried isopropanol instead of ethanol. However, even if the

• using the previously reported methylmagnesium chloride 1,4-addition on diethyl furfurylidenemalonate (6ae) [6]. Quite unexpectedly, repeated attempts to obtain the α-hydroxyimino ester 35 from the resulting β-methylated derivative 34 failed. Trials were made not only with sodium ethoxide but also with

Synthesis of unnatural α-amino esters using ethyl nitroacetate and condensation or cycloaddition reactions

• Glwadys Gagnot,
• Vincent Hervin,
• Eloi P. Coutant,
• Sarah Desmons,
• Racha Baatallah,
• Victor Monnot and
• Yves L. Janin

Beilstein J. Org. Chem. 2018, 14, 2846–2852, doi:10.3762/bjoc.14.263

• 12 in 32% overall yield via the nitro compound 11. We also investigated the reported [4] 1,4-addition of a methyl on compound 2n to prepare the β-methylated derivative 13. In our hands, a rather modest 43% yield of the expected adduct 13 was achieved from purified acrylate 2n. Again, the ensuing

Hypervalent organoiodine compounds: from reagents to valuable building blocks in synthesis

• Gwendal Grelier,
• Benjamin Darses and
• Philippe Dauban

Beilstein J. Org. Chem. 2018, 14, 1508–1528, doi:10.3762/bjoc.14.128

• same syn:anti ratio while 1,4-addition products containing an (E)-olefin are selectively obtained from dienes. The authors have also shown that the reaction performed in the presence of a stoichiometric amount of p-TsOH gives β-trifluoromethylstyrene derivatives instead of the expected oxy

Investigations towards the stereoselective organocatalyzed Michael addition of dimethyl malonate to a racemic nitroalkene: possible route to the 4-methylpregabalin core structure

• Denisa Vargová,
• Rastislav Baran and
• Radovan Šebesta

Beilstein J. Org. Chem. 2018, 14, 553–559, doi:10.3762/bjoc.14.42

• reaction mixture. Nitroaldol product 5 was then dehydrated using the CuCl/DCC protocol [16] to nitroalkene 6. Overall, this sequence afforded the desired racemic Michael acceptor 6 in total 36% yield over four steps. With Michael acceptor 6 in hands, we started to investigate the 1,4-addition of dimethyl

Phosphazene-catalyzed desymmetrization of cyclohexadienones by dithiane addition

• Matthew A. Horwitz,
• Elisabetta Massolo and
• Jeffrey S. Johnson

Beilstein J. Org. Chem. 2017, 13, 762–767, doi:10.3762/bjoc.13.75

• enantioselectively delivered oxabicyclo[4.3.0]nonanes [17]; the Lautens and Lan groups have also contributed to the further development of this reaction [18][19]. The Rovis group employed cyclohexadienone hydroperoxides in a chiral phosphoric acid-catalyzed [1,2]/[1,4]-addition cascade [20]. The same group also

Synthesis of 1-indanones with a broad range of biological activity

• Marika Turek,
• Dorota Szczęsna,
• Marek Koprowski and
• Piotr Bałczewski

Beilstein J. Org. Chem. 2017, 13, 451–494, doi:10.3762/bjoc.13.48

• 55 via a formal 1,4-addition of arylboronic acids to β-aryl-α,β-unsaturated ketones and esters [39]. Thus, the α,β-unsaturated diester 52 was coupled with arylboronic acid in the presence of rhodium(I)/Chiraphos® complex as a catalyst to obtain derivative 53, which next underwent a Claisen

• (62), followed by a Knoevenagel condensation with a variety aromatic aldehydes to give chalcone derivatives 63 (Scheme 21). The reaction of the latter with hydroxylamine hydrochloride, followed by intramolecular 1,4-addition gave 1-indanone derivatives 64a–l which were further tested for in vitro

Synthesis of polyhydroxylated decalins via two consecutive one-pot reactions: 1,4-addition/aldol reaction followed by RCM/syn-dihydroxylation

• Michał Malik and
• Sławomir Jarosz

Beilstein J. Org. Chem. 2016, 12, 2602–2608, doi:10.3762/bjoc.12.255

• 1,4-addition of vinylmagnesium bromide to sugar-derived cyclohexenone, followed by an aldol reaction with a derivative of but-3-enal. The obtained diene is then subjected to an assisted tandem catalytic sequence: ring-closing metathesis with the subsequent reuse of the Ru-catalyst in the syn

• possibility of using a copper-catalyzed one-pot 1,4-addition of vinylmagnesium bromide to sugar-derived cyclic α,β-unsaturated ketones (such as 9), followed by an aldol reaction with an optically pure derivative of but-2-enal 10 to obtain a mixture of diastereomeric dienes, such as 11 (Scheme 2). As a result

• of this transformation, three new stereogenic centers are generated. A copper-catalyzed 1,4-addition of organometallic reagents to cyclic α,β-unsaturated ketones, followed by an aldol reaction has been already used in the synthesis of complex natural products [26][27][28][29][30][31][32][33

Enantioconvergent catalysis

• Justin T. Mohr,
• Jared T. Moore and
• Brian M. Stoltz

Beilstein J. Org. Chem. 2016, 12, 2038–2045, doi:10.3762/bjoc.12.192

• enantiopure phosphine catalyst 27 in order to generate the coupled product 30 with both high ee and dr (Scheme 6) [31]. Presumably, the allenyl stereochemistry is destroyed upon 1,4-addition of the phosphine catalyst, resulting in chiral phosphonium adduct 29 that further reacts with deprotonated oxazole 28

Synergistic chiral iminium and palladium catalysis: Highly regio- and enantioselective [3 + 2] annulation reaction of 2-vinylcyclopropanes with enals

• Haipan Zhu,
• Peile Du,
• Jianjun Li,
• Ziyang Liao,
• Guohua Liu,
• Hao Li and
• Wei Wang

Beilstein J. Org. Chem. 2016, 12, 1340–1347, doi:10.3762/bjoc.12.127

• acid [56]. Herein we wish to disclose the first synergistic catalytic enantioselective [3 + 2] annulation reaction between 2-vinylcyclopropanes and enals via 1,4-addition (Scheme 1, reaction 2). The process proceeds highly regio- and enantioselectively with C=C bonds in enals. Notably, a synergistic

• promote these processes (Table 1, entries 3–7). Inspired by Trost’s work of Pd(0)-catalyzed annulations of D–A cyclopropanes with C=C double bonds with Meldrum’s acid and alkylidenes or azlactone alkylidenes [45], we probed the Pd2(dba)3-dppe complex for the 1,4-addition cycloaddition reaction (Table 1

Multicomponent reactions: A simple and efficient route to heterocyclic phosphonates

• Mohammad Haji

Beilstein J. Org. Chem. 2016, 12, 1269–1301, doi:10.3762/bjoc.12.121

• diphosphorylated products [95]. The 1,5-naphthyridine 274 and phenanthrolines 276, 278 and 280 in the presence of more than 2 equiv of DMPTMS were converted to the corresponding diphosphorylated products 275, 277, 279 and 281 with a high diastereoisomeric ratio (Scheme 57). In this reaction, the 1,4-addition of

Cyclisation mechanisms in the biosynthesis of ribosomally synthesised and post-translationally modified peptides

• Andrew W. Truman

Beilstein J. Org. Chem. 2016, 12, 1250–1268, doi:10.3762/bjoc.12.120

• oxidatively decarboxylated cysteine residue onto a Dha residue derived from serine (Figure 5A). Extensive in vitro experiments indicate that decarboxylation of cysteine precedes 1,4-addition and is catalysed by a flavoprotein (EpiD) in epidermin biosynthesis [66][67], which uses flavin mononucleotide (FMN) to

• biosynthesis of labyrinthopeptin A2. S-[(Z)-2-Aminovinyl]-D-cysteine (AviCys) formation in the epidermin pathway. A) Mechanisms for decarboxylation and 1,4-addition. B) Mechanism for the E. coli Dfp-catalysed conversion of (R)-4'-phospho-N-pantothenoylcysteine into 4'-phosphopantetheine during coenzyme A

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

• utilized by the pharmaceutical and agrochemical industries as α-amino acid analogues. Darses and co-workers reported a novel approach to the synthesis of enantioenriched α-amino phosphonates 170 via a rhodium(I) catalyzed enantioselective 1,4-addition of potassium aryltrifluoroborates 168 to

Cationic Pd(II)-catalyzed C–H activation/cross-coupling reactions at room temperature: synthetic and mechanistic studies

• Takashi Nishikata,
• Alexander R. Abela,
• Shenlin Huang and
• Bruce H. Lipshutz

Beilstein J. Org. Chem. 2016, 12, 1040–1064, doi:10.3762/bjoc.12.99

• been previously observed in the coupling reactions of aryl iodides (in which even 40 mol % of MeCN was enough to almost completely shut down the reaction) [121]. In a cationic palladium(II) complex-catalyzed 1,4-addition of arylsilane, the nitrile-free cationic Pd(II) catalyst was much more effective

Rhodium, iridium and nickel complexes with a 1,3,5-triphenylbenzene tris-MIC ligand. Study of the electronic properties and catalytic activities

• Carmen Mejuto,
• Beatriz Royo,
• Gregorio Guisado-Barrios and
• Eduardo Peris

Beilstein J. Org. Chem. 2015, 11, 2584–2590, doi:10.3762/bjoc.11.278

• of ligands A and B. Synthesis of rhodium(I), iridium(I), and nickel(II) complexes of ligand B. Tolman electronic parameters (TEP) for A, B and their related monocarbenes. Schematic representation of complex 6. 1,4-Addition of arylboronic acids to 2-cyclohex-1-one.a Supporting Information Supporting

Synthesis of Xenia diterpenoids and related metabolites isolated from marine organisms

• Tatjana Huber,
• Lara Weisheit and
• Thomas Magauer

Beilstein J. Org. Chem. 2015, 11, 2521–2539, doi:10.3762/bjoc.11.273

• with acryloyl chloride gave ester 87 and a ring-closing metathesis reaction using Grubbs second generation catalyst [50] furnished an α,β-unsaturated lactone. Subsequent 1,4-addition of the cuprate derived from alkylmagnesium chloride 88 provided the trans-product with excellent diastereoselectivity

Copper-catalyzed asymmetric conjugate addition of organometallic reagents to extended Michael acceptors

• Thibault E. Schmid,
• Sammy Drissi-Amraoui,
• Christophe Crévisy,
• Olivier Baslé and
• Marc Mauduit

Beilstein J. Org. Chem. 2015, 11, 2418–2434, doi:10.3762/bjoc.11.263

• of the reaction could be achieved with a careful choice of the copper-based nucleophile. Indeed, Yamamoto’s cuprate (n-BuCu·BF3) led to the 1,4-addition product 5a, while the 1,6-adduct 5b was selectively obtained upon reaction with a Gilman reagent. Inspired by these seminal studies, the addition of

• system, a combination of Josiphos L9 as chiral ligand and copper thiophene 2-carboxylate (CuTC) afforded the desired 1,6-adducts 43 with very good regioselectivity (up to 5/95) and enantioselectivities (up to 91% ee). Enantioselective 1,4-addition to extended Michael acceptors With dialkylzinc reagents

The chemical behavior of terminally tert-butylated polyolefins

• Dagmar Klein,
• Henning Hopf,
• Peter G. Jones,
• Ina Dix and
• Ralf Hänel

Beilstein J. Org. Chem. 2015, 11, 1246–1258, doi:10.3762/bjoc.11.139

• .), the only product that we could isolate was mono-olefin 4 (Scheme 2), a formal 1,4-addition product of hydrogen to 3. Its structure was established by the usual spectroscopic and analytical data (see Supporting Information File 1). To determine the configuration of the double bond, an X-ray structural

• solvents to give mostly the 1,4-addition product (ratio 1,4-/1,2-product: 7:1) [5]. Turning to substituted dienes, 2,3-dimethylbuta-1,3-diene (11) initially also provides the 1,4-adduct 12, which subsequently is saturated to the tetrabromide 13 by reaction with a second equivalent of bromine (Scheme 4) [6

• results; and this is indeed the case (Scheme 5), as shown by diene 3. The 1,4-addition product 17, a colorless solid, is produced in near quantitative yield (93%). It is easily characterized by its spectroscopic data, which are listed in Supporting Information File 1. Unfortunately, we were unable to

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

• -unsaturated systems [13]. Most of the early work, including Michael’s, involved the use of stabilized or “soft” [14] nucleophiles such as malonates and nitroalkanes. Mechanistically, one can imagine a 1,2-addition of the nucleophile occurring versus the 1,4-addition if the EWG is a carbonyl compound, but this

• thioamide method is a useful strategy. Lewis acid activation (method D) has been used commonly for the 1,4-addition of stabilized nucleophiles, but there are some exceptions. The need to activate amides and lactams adds a level of difficulty in developing asymmetric CA (ACA) reactions. Not surprisingly, a

• 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

Photochemical approach to functionalized benzobicyclo[3.2.1]octene structures via fused oxazoline derivatives from 4- and 5-(o-vinylstyryl)oxazoles

• Ivana Šagud,
• Simona Božić,
• Željko Marinić and
• Marija Šindler-Kulyk

Beilstein J. Org. Chem. 2014, 10, 2222–2229, doi:10.3762/bjoc.10.230

• the incorporation of deuterium in the bicyclo[3.2.1]octadiene moiety and a methoxy group on the N=C oxazoline bond by 1,4-addition or more likely by addition to the N=C bond followed by keto–enol tautomerization giving 14. The adducts are spectroscopically completely identified (see Supporting

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

• phosphorus center, whereas cis confers to a R-configuration. Degradation of the adducts by ozonolysis yielded oxocycloalkane-3-carboxaldehydes 43, which are useful synthetic intermediates. Diastereomer cis-40b however gave only poor diastereofacial selection, providing the corresponding 1,4-addition adducts