Copper-catalysed alkylation of heterocyclic acceptors with organometallic reagents

• Yafei Guo and
• Syuzanna R. Harutyunyan

Beilstein J. Org. Chem. 2020, 16, 1006–1021, doi:10.3762/bjoc.16.90

• chiral natural products and bioactive molecules. Hence, this review focuses on the progress made over the past 20 years for heterocyclic acceptors. Keywords: conjugate addition; copper catalysis; heterocyclic Michael acceptor; organometallics; Introduction The copper-catalysed asymmetric addition of

• enantioselective methods for the synthesis of these compounds resulting in high yield and enantioselectivity has proven challenging. As a result, significant effort has been invested into copper-catalysed asymmetric conjugate addition reactions using organometallics. In 2005, Feringa and co-workers reported on the

• copper-catalysed asymmetric conjugate addition (ACA) of dialkylzinc reagents to N-substituted 2,3-dehydro-4-piperidones 1 in order to access useful chiral piperidine derivatives (Scheme 1A) [15]. They found the catalytic system based on the chiral phosphoramidite L1 and a copper salt to be the most

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

• Delphine Pichon Jennifer Morvan Christophe Crevisy Marc Mauduit Université de Rennes, Ecole Nationale Supérieure de Chimie de Rennes, CNRS, ISCR – UMR 6226, F-35000 Rennes, France 10.3762/bjoc.16.24 Abstract The copper-catalyzed enantioselective conjugate addition (ECA) of organometallic

• -deficient functions (i.e., aldehydes, thioesters, acylimidazoles, N-acyloxazolidinones, N-acylpyrrolidinones, amides, N-acylpyrroles) were recently investigated. Remarkably, only a few chiral copper-based catalytic systems have successfully achieved the conjugate addition of different organometallic

• accomplished in this stimulating field. Keywords: acylimidazole; N-acyloxazolidinone; N-acylpyrrole; N-acylpyrrolidinone; aldehyde; amide; copper catalysis; electron-deficient alkenes; enantioselective conjugate addition; Michael acceptor; thioester; Introduction Generating high molecular complexity and

Rapid, two-pot procedure for the synthesis of dihydropyridinones; total synthesis of aza-goniothalamin

• Thomas J. Cogswell,
• Craig S. Donald and
• Rodolfo Marquez

Beilstein J. Org. Chem. 2020, 16, 135–139, doi:10.3762/bjoc.16.15

• described above. Rewardingly, Hosomi–Sakurai allylation of the conjugated imine intermediate proceeded to afford the desired diene 10 in working yield (35%). The formation of diene 10 is significant as the corresponding α,β-enones and α,β-enals undergo exclusive conjugate addition under Hosomi–Sakurai

A review of asymmetric synthetic organic electrochemistry and electrocatalysis: concepts, applications, recent developments and future directions

• Munmun Ghosh,
• Valmik S. Shinde and
• Magnus Rueping

Beilstein J. Org. Chem. 2019, 15, 2710–2746, doi:10.3762/bjoc.15.264

1,5-Phosphonium betaines from N-triflylpropiolamides, triphenylphosphane, and active methylene compounds

• Vito A. Fiore,
• Chiara Freisler and
• Gerhard Maas

Beilstein J. Org. Chem. 2019, 15, 2603–2611, doi:10.3762/bjoc.15.253

• reactions. We propose two mechanistic pathways for the synthesis of betaines 3 from N-triflylpropiolamides 1 (Scheme 6). Both of them begin with the conjugate addition of PPh3 at the C–C-triple bond, leading to the vinyl anion intermediate 5. On pathway A, 5 is protonated by the active methylene compound to

Synthesis of pyrrolo[1,2-a]quinolines by formal 1,3-dipolar cycloaddition reactions of quinolinium salts

• Anthony Choi,
• Rebecca M. Morley and
• Iain Coldham

Beilstein J. Org. Chem. 2019, 15, 1480–1484, doi:10.3762/bjoc.15.149

• with triethylamine promoted the reaction of the resulting quinolinium ylides (formally azomethine ylides) with electron-poor alkenes by conjugate addition followed by cyclization or by [3 + 2] dipolar cycloaddition. The pyrroloquinoline products were formed as single regio- and stereoisomers. These

• with electron-poor alkenes occurs through a stepwise conjugate addition–cyclization process [23]. We were interested in the related quinolinium ylides that, on (formal) cycloaddition would provide pyrrolo[1,2-a]quinolines as products. These are tricyclic compounds consisting of a pyrrole ring fused

Synthesis of non-racemic 4-nitro-2-sulfonylbutan-1-ones via Ni(II)-catalyzed asymmetric Michael reaction of β-ketosulfones

• Alexander N. Reznikov,
• Anastasiya E. Sibiryakova,
• Marat R. Baimuratov,
• Eugene V. Golovin,
• Victor B. Rybakov and
• Yuri N. Klimochkin

Beilstein J. Org. Chem. 2019, 15, 1289–1297, doi:10.3762/bjoc.15.127

• reaction with their participation. Asymmetric conjugate addition of activated methylene compounds (such as diketones, keto esters and malonates) to nitroalkenes in the presence of Mg [43], Co [44][45], Mn [45] and Ru [46] complexes was performed. The most remarkable results were obtained with Ni(II

• coordination to Ni. The complex B regenerates after the conjugate addition via transition state C and coordination of a new β-ketosulfone molecule to Ni. TS1 and TS2 are proposed by analogy with 1,3-dicarbonyl compounds [47] to rationalize the asymmetric induction. As illustrated in Scheme 2, β-ketosulfone is

Ugi reaction-derived prolyl peptide catalysts grafted on the renewable polymer polyfurfuryl alcohol for applications in heterogeneous enamine catalysis

• Alexander F. de la Torre,
• Gabriel S. Scatena,
• Oscar Valdés,
• Daniel G. Rivera and
• Márcio W. Paixão

Beilstein J. Org. Chem. 2019, 15, 1210–1216, doi:10.3762/bjoc.15.118

• employ a three-component, diastereoselective variant of the Ugi reaction for the synthesis of a prolyl pseudo-peptide catalyst, which proved effective in an organocatalytic conjugate addition reaction [6]. Later, our groups developed an Ugi reaction-based multicomponent approach enabling the structure

• the peptide moieties into the PFA matrix, while proving the good stability of the PFA-supported catalysts under classic working temperatures (i.e., up to 100 °C). To assess the catalytic performance of the PFA-supported catalysts, the model system consisting in organocatalytic conjugate addition of n

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

• 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

• ]nonane-3,8-dione (5a) with 50% and 69% yield, respectively (Table 1, entries 8 and 9). This product plausibly arises from a C-allylation step followed by an intramolecular C-conjugate addition/decarboxylation sequence, although throughout this study the putative intermediate 3a proved always elusive

• d). Pd(0) decoordination closes the catalytic cycle delivering intermediate E(keto) (step e) (Scheme 7). The following spontaneous intramolecular O-conjugate addition of one of the two possible enol tautomers of E(keto) affords the kinetic C–C/O–C adduct 4a through steps (f, g), or (h, i, j) (Scheme

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

• conjugate addition of benzamide nitrogen onto the 2-ynamide generates the final cyclization product 24 through allene intermediate 28. Taking into account that the reaction does not take place with internal alkynes, the authors conclude that a terminal alkyne is necessary for the formation of the first

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

• pyrrolidine-2-one (3S,4S,5R)-123 [111]. Oxidation of the hydroxymethyl group and acid hydrolysis gave (2S,3S,4S)-4 [112]. By enantioselective conjugate addition and asymmetric dihydroxylation An orthogonally protected 3,4-dihydroxy-L-glutamic acid was envisioned as an intermediate in the projected synthesis

• O-benzyl-L-serine. Reagents and conditions: a) (CF3CH2O)2P(O)CH2COOMe, KHMDS, 18-crown-6; b) I2, MeCN; c) Bu3SnH, AIBN, benzene, reflux; d) H2, 10% Pd/C, ethanol; e) CrO3, acetone, then CH2N2, ether; f) 3 M HCl, 80 °C. Synthesis of (2S,3R)-2 employing a one-pot cis-olefination–conjugate addition

• ; j) 6 M HCl, 80 °C. Synthesis of (2S,3S,4R)-127 by enantioselective conjugate addition and asymmetric dihydroxylation. Reagents and conditions: a) ethyl 1-phenylselenylacrylate, chiral PTC, 50% KOH, CH2Cl2; b) 1 M HCl, THF; c) 9-bromo-9-phenylfluorene, K2PO4, PbNO2, MeCN; d) NaIO4, NaHCO3, MeOH/H2O

Synthesis and biological evaluation of 1,2-disubstituted 4-quinolone analogues of Pseudonocardia sp. natural products

• Stephen M. Geddis,
• Teodora Coroama,
• Suzanne Forrest,
• James T. Hodgkinson,
• Martin Welch and
• David R. Spring

Beilstein J. Org. Chem. 2018, 14, 2680–2688, doi:10.3762/bjoc.14.245

• natural products. The chemistry developed towards the allylic alcohols 5 and 6, outlined in Scheme 1, seemed ideal to this end. A range of alkynes 10 could undergo Sonogashira coupling with the commercially available acid chloride 9. The resultant ynones 11 could then undergo conjugate addition with

• resulted for 11b, which was attributed to difficulties in obtaining its precursor 10b with high purity which stemmed from its volatility. These ynones were then subjected to a conjugate addition with an assortment of primary amines 12a–f (Scheme 3). The reactions proceeded with excellent yield in all cases

• -quinolone Pseudonocardia sp. natural products, which encompassed variation of both the side chain and N-substituent. This represented an extension of the chemistry which we employed towards the natural products, utilising sequential Sonogashira coupling, high-yielding conjugate addition, and metal-catalysed

A survey of chiral hypervalent iodine reagents in asymmetric synthesis

• Soumen Ghosh,
• Suman Pradhan and
• Indranil Chatterjee

Beilstein J. Org. Chem. 2018, 14, 1244–1262, doi:10.3762/bjoc.14.107

• the enolate intermediate 111 followed by the generation of a C–C bond via conjugate addition delivered intermediate carbene 113. A 1,2-hydrogen shift led to the formation of products 108 with enantioselectivities up to 79% (Scheme 24). Later, Maruoka et al. improved the enantioselectivity up to 95% ee

One hundred years of benzotropone chemistry

• Arif Dastan,
• Haydar Kilic and
• Nurullah Saracoglu

Beilstein J. Org. Chem. 2018, 14, 1120–1180, doi:10.3762/bjoc.14.98

• as a fairly air-stable red-brown solid. b. Nucleophilic addition to 4,5-benzotropone (11): Ried’s group realized the reaction of 4,5-benzotropone (11) and its derivatives with lithium acetylide as a nucleophile between −50 and −32 °C [130]. While the possible 1,4-conjugate addition product 149 was

Gram-scale preparation of negative-type liquid crystals with a CF₂CF₂-carbocycle unit via an improved short-step synthetic protocol

• Tatsuya Kumon,
• Shohei Hashishita,
• Takumi Kida,
• Shigeyuki Yamada,
• Takashi Ishihara and
• Tsutomu Konno

Beilstein J. Org. Chem. 2018, 14, 148–154, doi:10.3762/bjoc.14.10

• the 1,2-addition reaction of Int-I proceeds in preference to the conjugate addition reaction, the desired octa-1,7-diene 5a should be produced in higher yield. However, no significant improvement was observed after various attempts such as employing a more nucleophilic lithium reagent instead of the

• the other hand, the β-carbon at the α,β-unsaturated carbonyl moiety of Int-I may be susceptible to attack by the vinylic Grignard reagent, as shown by the purple arrow in Scheme 3, because of the high electrophilicity and lack of steric hindrance. As a consequence, Int-I also undergoes conjugate

• addition reaction, a Michael addition reaction, giving rise to the corresponding magnesium enolate Int-L. The subsequent hydrolysis of Int-L then leads to the γ-hydroxyketone 8a', which easily tautomerizes into the more stable 5-membered hemiacetal 8a. From the above insight into the reaction mechanism, if

Conjugated nitrosoalkenes as Michael acceptors in carbon–carbon bond forming reactions: a review and perspective

• Yaroslav D. Boyko,
• Valentin S. Dorokhov,
• Alexey Yu. Sukhorukov and
• Sema L. Ioffe

Beilstein J. Org. Chem. 2017, 13, 2214–2234, doi:10.3762/bjoc.13.220

• acceptors in organic synthesis [1][2][3][4][5]. Unlike the parent α-nitroalkenes, α-nitrosoalkenes are unstable species usually generated in situ, and their synthetic potential has been studied in significantly less detail [6][7]. Because of relatively short lifetimes of α-nitrosoalkenes, conjugate addition

• years, there has been a considerable growth of interest to the conjugate addition of carbon-centered nucleophiles to α-nitrosoalkenes. This is mainly due to the development of new precursors, from which nitrosoalkenes are generated at low stationary concentrations under very mild conditions that allows

• the potential use of this strategy in the synthesis of natural products. Weinreb and co-workers performed a comprehensive investigation of the stereoselectivity of the conjugate addition to α-nitrosoalkenes using both cyclic [29] and acyclic substrates [30]. They have demonstrated that the

The chemistry and biology of mycolactones

• Matthias Gehringer and
• Karl-Heinz Altmann

Beilstein J. Org. Chem. 2017, 13, 1596–1660, doi:10.3762/bjoc.13.159

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

• intramolecular conjugate addition to an α,β-unsaturated ester [12][13][14][15] or copper-catalyzed annulation of N-arylamidines [41], among others [42]. Most of the already mentioned methods have been applied to the synthesis of 3,4-dihydroquinazolines. Among them, only a few were used for the preparation of 1,4

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

• Matthew A. Horwitz Elisabetta Massolo Jeffrey S. Johnson Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-3290, USA 10.3762/bjoc.13.75 Abstract We report a desymmetrization of cyclohexadienones by intramolecular conjugate addition of a tethered dithiane

• nucleophile. Mild reaction conditions allow the formation of diversely functionalized fused bicyclic lactones. The products participate in facially selective additions from the convex surface, leading to allylic alcohol derivatives. Keywords: conjugate addition; cyclohexadienones; dearomatization

• ] nucleophiles using bifunctional cinchona alkaloid catalysts. The Sasai and Enders groups used a phosphinothiourea to enable a Rauhut–Currier reaction to form bicyclic enones [16]. The Tian and Lin group used alkyne-tethered cyclohexadienones in an arylrhodation/conjugate addition sequence that

Solid-phase enrichment and analysis of electrophilic natural products

• Frank Wesche,
• Yue He and
• Helge B. Bode

Beilstein J. Org. Chem. 2017, 13, 405–409, doi:10.3762/bjoc.13.43

• calculated mass of 3 (Figure 1) derived from the derivatization of epoxystilbene 1, an oxidized isopropylstilbene derivative from this strain. Since only a single peak could be seen within the chromatogram, we assume that the conjugate addition took place only on the less hindered position in epoxide 1

The reductive decyanation reaction: an overview and recent developments

• Jean-Marc R. Mattalia

Beilstein J. Org. Chem. 2017, 13, 267–284, doi:10.3762/bjoc.13.30

• substituted carbocycles [119][120]. An example in described in Scheme 22. The 5-membered ring is formed via a K2CO3 mediated SN2 – conjugate addition sequence between malononitrile and 6-bromo-2-hexenoate derivatives 67a,b. Dicyanocyclopentanes 68a,b are treated with tributyltin hydride/AIBN giving the

First DMAP-mediated direct conversion of Morita–Baylis–Hillman alcohols into γ-ketoallylphosphonates: Synthesis of γ-aminoallylphosphonates

• Marwa Ayadi,
• Haitham Elleuch,
• Emmanuel Vrancken and
• Farhat Rezgui

Beilstein J. Org. Chem. 2016, 12, 2906–2915, doi:10.3762/bjoc.12.290

• were prepared by reductive amination of γ-aminophosphonyl ketones using sodium borohydride [41], or by conjugate addition of diethyl methylphosphonite to 2-cyclohexenone followed by Bucherer–Bergs amino acid synthesis [42]. Another synthetic approach for a series of α-fluorinated-γ-aminophosphonates

• , entries 1–5), as well as five-membered cyclic MBH alcohol 1f (Table 2, entry 6). A putative reaction pathway could start from a first β-conjugate addition of DMAP onto the allylic alcohol 1a (i), followed by the elimination of the hydroxide ion that would afford the intermediate I (ii). Similarly, a

• second β’-conjugate addition of triethyl phosphite onto I (iii), followed by the release of DMAP would provide the phosphonium intermediate II (iv). Finally, the hydroxide ion is expected to react with II via an Arbuzov rearrangement to provide the desired γ-ketoallylphosphonate 2a (v) (Scheme 3). We

New approaches to organocatalysis based on C–H and C–X bonding for electrophilic substrate activation

• Pavel Nagorny and
• Zhankui Sun

Beilstein J. Org. Chem. 2016, 12, 2834–2848, doi:10.3762/bjoc.12.283

• directionality that might make these interactions of a great value to the field of organocatalysis [71][72][73]. Molecular iodine has been used for many decades as a mild catalyst or promoter of various organic transformations such as conjugate addition, imine formation or aldolate dehydration reactions [74][75

• -workers have re-evaluated the molecular iodine-catalyzed conjugate addition to α,β-unsaturated carbonyls or nitrostyrenes (Scheme 14) [80]. Based on their computational studies, they proposed that iodine activates the enone moiety by forming a halogen bond with the carbonyl and thus forming a more

Et₃B-mediated and palladium-catalyzed direct allylation of β-dicarbonyl compounds with Morita–Baylis–Hillman alcohols

• Ahlem Abidi,
• Yosra Oueslati and
• Farhat Rezgui

Beilstein J. Org. Chem. 2016, 12, 2402–2409, doi:10.3762/bjoc.12.234

• -allylated product 3j in 12% yield, along with the tricyclic compound 6j, in good yield, which is resulting from the intramolecular conjugate addition of 3j carbanion on the enone moiety (Table 3, entry 2). Under the same conditions, the keto ester 2j reacted with alcohol 1a, in DMF at 80 °C for 6 h longer

• conjugate addition of the β-keto ester carbanion onto the enone moiety (Scheme 2) [50][51]. The structure of the tricyclic compound 6j was elucidated on the basis of X-ray diffraction analysis (Figure 2). In a previous report, Alexakis and co-workers have demonstrated that copper-catalyzed conjugate

• addition of Grignard reagents onto α-methyl cyclic enones, affording mainly the trans-2,3-disubstituted cyclohexanones as being the thermodynamic products [52]. Similarly, we believe that the intramolecular conjugate addition of carbanion 3j onto α-substituted enone moiety is under thermodynamic control

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

• class of sulfur-containing pro-nucleophiles in a highly enantio- and diastereoselective conjugate addition to nitroalkenes, providing α,α-disubstituted α-mercapto carboxylic acids [5]. Since then, several asymmetric variants using 5H-thiazol-4-ones as nucleophiles have been disclosed; such as amination

• [6], allylation [7], conjugate addition to enones [8], and γ-addition with allenoates [9]. All these examples focused on nucleophilic addition reactions of the C5 atom of 5H-thiazol-4-ones. Recently, we described an organocatalytic asymmetric [4 + 2] cyclization of 5H-thiazol-4-ones with a series of

• excellent catalytic efficacy as demonstrated in a series of asymmetric reactions [18]. It was found that the reaction was completed after 48 hours, affording the desired [4 + 2] annulation adduct 3a in 55% yield with 64% ee. A significant amount of conjugate addition adduct led to the unsatisfactory