Synthesis of O⁶-alkylated preQ₁ derivatives

• Laurin Flemmich,
• Sarah Moreno and
• Ronald Micura

Beilstein J. Org. Chem. 2021, 17, 2295–2301, doi:10.3762/bjoc.17.147

• dibenzylamine–formaldehyde and 2-acylaminopyrrolo[2,3-d]pyrimidin-4(3H)-one as key step, thereby selectively installing a dibenzylaminomethyl moiety [22]. Exchange of the dibenzylamine group in the Mannich base with NH3 provided preQ1 [22]. Alternatively, Klebe demonstrated a Michael addition of 2,6

Preparation of mono-substituted malonic acid half oxyesters (SMAHOs)

• Tania Xavier,
• Sylvie Condon,
• Christophe Pichon,
• Erwan Le Gall and
• Marc Presset

Beilstein J. Org. Chem. 2021, 17, 2085–2094, doi:10.3762/bjoc.17.135

• MAHOs [24][25][26][27]; and a Michael addition for 3'-oxoalkyl-substituted MAHOs [28]. As studied by Niwayama [29], the hydrolysis step is generally achieved by saponification using alcoholic KOH (or NaOH) [30][31][32][33][34][35][36], but other selective cleavages of one ester group are possible [37

Enantioenriched α-substituted glutamates/pyroglutamates via enantioselective cyclopropenimine-catalyzed Michael addition of amino ester imines

• Zara M. Seibel,
• Jeffrey S. Bandar and
• Tristan H. Lambert

Beilstein J. Org. Chem. 2021, 17, 2077–2084, doi:10.3762/bjoc.17.134

• of α-substituted glutamates and pyroglutamates via a cyclopropenimine-catalyzed Michael addition of amino ester imines is described. Enantioselectivities of up to 94% have been achieved, and a variety of functional groups were found to be compatible. The impact of the catalyst structure and imine

• substitution is discussed. Compared to other methods, this protocol allows for a broader and more enantioselective access to pyroglutamate derivatives. Keywords: Brønsted base; cyclopropenimine; enantioselective catalysis; Michael addition; pyroglutamate; Introduction α-Substituted glutamates have value as

• -substituted glutamate derivatives is via the Michael addition of α-amino ester enolates to acrylate acceptors. These products can also be easily converted to pyroglutamates by lactamization [28][29][30]. Although the use of substituted amino ester derivatives for the enantioselective α-alkylation has been

Asymmetric organocatalyzed synthesis of coumarin derivatives

• Natália M. Moreira,
• Lorena S. R. Martelli and
• Arlene G. Corrêa

Beilstein J. Org. Chem. 2021, 17, 1952–1980, doi:10.3762/bjoc.17.128

• enantioselective Michael addition of ketones 20 to 3-aroylcoumarins 19 [38]. For this transformation, the authors used a cinchona alkaloid-derived primary amine catalyst 22 (Scheme 6a). The study was performed with cyclic and acyclic ketones 20 and various 3-aroylcoumarins 19 and the desired products 21 were

• obtained with good to excellent yields and enantiomeric excesses. Besides, the one-pot synthesis of coumarins followed by the Michael addition step was proven to be a good alternative, affording the desired product with excellent yield and ee. The applicability of the methodology was also demonstrated by a

• dihydrocinchonine 26 in combination with trifluoracetic acid (TFA) as Brønsted acid [39]. The reaction provides pyranocoumarins 25 with three vicinal stereogenic centers in high regio-, diastereo- and enantioselectivities through a tandem allylic alkylation/intramolecular oxa-Michael addition (Scheme 7). A

Electron-rich triarylphosphines as nucleophilic catalysts for oxa-Michael reactions

• Susanne M. Fischer,
• Simon Renner,
• A. Daniel Boese and
• Christian Slugovc

Beilstein J. Org. Chem. 2021, 17, 1689–1697, doi:10.3762/bjoc.17.117

• masses of about 1200 g/mol at room temperature are accessible. Polymerizations carried out at 80 °C resulted in macromolecules containing a considerable share of Rauhut–Currier-type repeat units and consequently lower molar masses were obtained. Keywords: Michael acceptor affinity; Michael addition

• -Michael addition. Triphenylphosphine (TPP), (4-methoxyphenyl)diphenylphosphine (MMTPP) and tris(4-trimethoxyphenyl)phosphine (TMTPP). The catalysts were investigated in the reaction of four different Michael acceptors with four different alcohols. In the oxa-Michael addition, the zwitterion i, initially

• generating the ion pair iii. In the final step, the α-carbanionic species in iii gets protonated by an alcohol generating the oxa-Michael addition product (iv) and regenerating ii (Scheme 1). Additionally, the ion par ii might directly react via a nucleophilic substitution of the phosphonium group by the

Chemical approaches to discover the full potential of peptide nucleic acids in biomedical applications

• Nikita Brodyagin,
• Martins Katkevics,
• Venubabu Kotikam,
• Christopher A. Ryan and
• Eriks Rozners

Beilstein J. Org. Chem. 2021, 17, 1641–1688, doi:10.3762/bjoc.17.116

Methodologies for the synthesis of quaternary carbon centers via hydroalkylation of unactivated olefins: twenty years of advances

• Thiago S. Silva and
• Fernando Coelho

Beilstein J. Org. Chem. 2021, 17, 1565–1590, doi:10.3762/bjoc.17.112

• cascade aza-Michael addition/olefin hydroalkylation reaction between N-tosylallylamines and α,β-unsaturated ketones using a catalytic system of a gold(I) complex and a silver salt [45]. The spiro compound 25, which was obtained in moderate yield and with poor diastereoselectivity after a 20 h reaction

• the aza-Michael addition and that only the cationic gold(I) complex was associated with the intramolecular hydroalkylation reaction. These observations justified the use of a three-fold excess of AgOCl in relation to the gold complex since the silver salt participated both as a source of a non

A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries

• Guido Gambacorta,
• James S. Sharley and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2021, 17, 1181–1312, doi:10.3762/bjoc.17.90

Synthesis of functionalized imidazo[4,5-e]thiazolo[3,2-b]triazines by condensation of imidazo[4,5-e]triazinethiones with DMAD or DEAD and rearrangement to imidazo[4,5-e]thiazolo[2,3-c]triazines

• Alexei N. Izmest’ev,
• Dmitry B. Vinogradov,
• Natalya G. Kolotyrkina,
• Angelina N. Kravchenko and
• Galina A. Gazieva

Beilstein J. Org. Chem. 2021, 17, 1141–1148, doi:10.3762/bjoc.17.87

• mechanism of the formation of compounds 4 and 5 is detailed in Scheme 6. The reaction of imidazothiazolotriazines 3 with esters of acetylenedicarboxylic acid affords the Michael addition product A, which undergoes cyclization involving the nitrogen atom N(2) to give compound 4. Rearrangement of the latter

N-tert-Butanesulfinyl imines in the asymmetric synthesis of nitrogen-containing heterocycles

• Joseane A. Mendes,
• Paulo R. R. Costa,
• Miguel Yus,
• Francisco Foubelo and
• Camilla D. Buarque

Beilstein J. Org. Chem. 2021, 17, 1096–1140, doi:10.3762/bjoc.17.86

Recent advances in palladium-catalysed asymmetric 1,4–additions of arylboronic acids to conjugated enones and chromones

• Jan Bartáček,
• Jan Svoboda,
• Martin Kocúrik,
• Jaroslav Pochobradský,
• Alexander Čegan,
• Miloš Sedlák and
• Jiří Váňa

Beilstein J. Org. Chem. 2021, 17, 1048–1085, doi:10.3762/bjoc.17.84

• given combination of enone and arylboronic acid. Keywords: asymmetric reaction; boronic acid; conjugated enones; chromones; enantioselective catalysis; Michael addition; Pd complexes; Introduction The asymmetric 1,4-addition of arylboronic acids to conjugated cyclic enones and chromones is a very

• system for the synthesis of intermediates of biologically active compounds [4]. Usage of a Michael addition catalysed by L9/Pd(TFA)2 in the total synthesis of (–)-ar-tenuifolene [12]. Synthesis of terpenoids by Michael addition to 3-methyl-2-cyclopentenone [13]. Rh-catalysed isomerisation of 3-alkyl-3

Microwave-assisted multicomponent reactions in heterocyclic chemistry and mechanistic aspects

• Shivani Gulati,
• Stephy Elza John and
• Nagula Shankaraiah

Beilstein J. Org. Chem. 2021, 17, 819–865, doi:10.3762/bjoc.17.71

• -MCRs and their mechanistic insights over the past decade and shed light on its advantage over the conventional approach. Keywords: cycloaddition; Knoevenagel condensation; Michael addition; microwave; multicomponent reactions; Introduction Recently, organic chemists are focussed to develop

• enaminone B. Later, the successive Michael addition of A and enaminone B followed by an intramolecular cycloaddition with concomitant dehydration delivered the final product 7 (Scheme 2). In 2018, our research group [39] contemplated and developed an expeditious process for the synthesis of phenanthrene

• the involvement of an elementary formation of Knoevenagel adduct A from the reaction between the aldehyde and 11. This adduct undergoes an intermolecular Michael addition to naphthylamine resulting in the formation of B. A subsequent intramolecular nucleophilic cyclization leads C followed by

Synthesis of β-triazolylenones via metal-free desulfonylative alkylation of N-tosyl-1,2,3-triazoles

• Soumyaranjan Pati,
• Renata G. Almeida,
• Eufrânio N. da Silva Júnior and
• Irishi N. N. Namboothiri

Beilstein J. Org. Chem. 2021, 17, 762–770, doi:10.3762/bjoc.17.66

• triazole 1b' did not afford the expected product 3f (Scheme 3d). This suggests that triazole 1b' is not the active nucleophile in this transformation. However, when the O-tosyl intermediate 4b was treated with a more nucleophilic amine, namely benzyl amine 5a, it indeed afforded the Michael addition

• , triazoles 1b and 1c containing electron donating 4-tolyl and 4-methoxyphenyl groups did not deliver the products 3b and 3c, respectively, even after prolonged reaction time. This is attributable to the greater reactivity of their corresponding triazolyl anion which preferred protonation over Michael

• addition (see mechanism, Scheme 4, vide infra). On the other hand, 4-tert-butyl analog 1d underwent the reaction smoothly to form the corresponding product 3d in 70% yield. However, due to the inconsistent results with cyclohexanedione 2a, further scope was investigated by employing cyclopentane-1,3-dione

The synthesis of chiral β-naphthyl-β-sulfanyl ketones via enantioselective sulfa-Michael reaction in the presence of a bifunctional cinchona/sulfonamide organocatalyst

• Deniz Tözendemir and
• Cihangir Tanyeli

Beilstein J. Org. Chem. 2021, 17, 494–503, doi:10.3762/bjoc.17.43

• %) catalyst loading. Selected enantiomerically enriched sulfa-Michael addition products were subjected to oxidation to obtain the corresponding sulfones. Keywords: asymmetric synthesis; bifunctional catalysis; cinchona alkaloids; organocatalysis; sulfa-Michael reaction; Introduction Derivatives of the

• -Michael addition (SMA) reactions remain a rather less explored reaction among asymmetric organocatalytic transformations, mainly because of the high nucleophilicity of thiols causing difficulties in controlling the stereoselectivity [21], despite C–S bond-forming reactions are of great interest in

• nucleophiles [27][28][29][30]. Thionaphthols, however, are overlooked in sulfa-Michael addition reactions. And to our best knowledge, no study is present concerned with SMAs with naphthalene-1-thiol as the nucleophile for the addition to enones. Encouraged by the good results obtained with enantioselective

Identification of volatiles from six marine Celeribacter strains

• Anuj Kumar Chhalodia,
• Jan Rinkel,
• Dorota Konvalinkova,
• Jörn Petersen and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2021, 17, 420–430, doi:10.3762/bjoc.17.38

• were obtained by the Michael addition of NaSMe to ethyl propiolate (45), yielding a mixture of stereoisomers inseparable by silica gel column chromatography (92%). The major stereoisomer was found to be (Z)-42 (dr 94:6), whose preferred formation may be a result of a chalcogen–chalcogen interaction

Coupling biocatalysis with high-energy flow reactions for the synthesis of carbamates and β-amino acid derivatives

• Alexander Leslie,
• Thomas S. Moody,
• Megan Smyth,
• Scott Wharry and
• Marcus Baumann

Beilstein J. Org. Chem. 2021, 17, 379–384, doi:10.3762/bjoc.17.33

• resulting telescoped flow process was effectively applied across a series of acid substrates rendering the desired carbamate structures in high yield and purity. The derivatization of these products via complementary flow-based Michael addition reactions furthermore demonstrated the creation of β-amino acid

• utilizing electron-poor alkenes as the reaction partners that would undergo aza-Michael addition reactions on the Cbz-carbamates (Scheme 4). Driven by the desire to develop readily scalable routes towards the target products 8, continuous flow processing was again exploited. In a first approach the use of

• -based aza-Michael addition reactions. This novel approach allows for the creation of important chemical building blocks whilst demonstrating a new use of biocatalysts in continuous flow processes. Scope of Cbz-carbamate products obtained via flow process (*tRes = 60 min, **T = 80 °C; isolated yields

Annulation of a 1,3-dithiole ring to a sterically hindered o-quinone core. Novel ditopic redox-active ligands

• Sergey V. Norkov,
• Anton V. Cherkasov,
• Andrey S. Shavyrin,
• Maxim V. Arsenyev,
• Viacheslav A. Kuropatov and
• Vladimir K. Cherkasov

Beilstein J. Org. Chem. 2021, 17, 273–282, doi:10.3762/bjoc.17.26

• bulky sulfur-containing group. The possible pathway for the following cyclization is the Michael addition of the sulfide atom to the central carbon of the acetylacetonate group [38][39][40][41]. The X-ray diffraction study as well as IR and NMR spectroscopy data reveal that in all synthesized compounds

The preparation and properties of 1,1-difluorocyclopropane derivatives

• Kymbat S. Adekenova,
• Peter B. Wyatt and
• Sergazy M. Adekenov

Beilstein J. Org. Chem. 2021, 17, 245–272, doi:10.3762/bjoc.17.25

• -difluorocyclopropanecarboxylic acid derivatives 58 by the Michael addition of ester and amide enolates to 2,4,6-trimethylphenyl 4-bromo-4,4-difluorocrotonate (57) followed by an Et3B-initiated radical cyclization (Scheme 24) [68]. Furthermore, when the sodium salt of dimethyl malonate was used as the Michael donor the

Selective synthesis of α-organylthio esters and α-organylthio ketones from β-keto esters and sodium S-organyl sulfurothioates under basic conditions

• Jean C. Kazmierczak,
• Roberta Cargnelutti,
• Thiago Barcellos,
• Claudio C. Silveira and
• Ricardo F. Schumacher

Beilstein J. Org. Chem. 2021, 17, 234–244, doi:10.3762/bjoc.17.24

• -rich N-heterocycles [2][3][4], decarboxylative cross-coupling reactions with propiolic acid derivatives [5], Michael addition reaction [6], cross-couplings catalyzed by Pd [7] and Cu salts [8][9], the preparation of symmetrical and nonsymmetrical disulfides [10][11], and the synthesis of β-acetamido

Facile preparation and conversion of 4,4,4-trifluorobut-2-yn-1-ones to aromatic and heteroaromatic compounds

• Takashi Yamazaki,
• Yoh Nakajima,
• Minato Iida and
• Tomoko Kawasaki-Takasuka

Beilstein J. Org. Chem. 2021, 17, 132–138, doi:10.3762/bjoc.17.14

• ][19], we decided to employ them without further purification. The Michael addition reactions were then carried out under basic conditions for the ynone 2a thus obtained, which, to our astonishment, was found to be relatively rare even for the nonfluorinated counterparts (Table 2) [24][25][26][27][28

• slowdown of the reaction rate when tert-butylamine was employed, which was considered to be a reflection of the sensitivity of ynones 2 towards steric hindrance. Because appropriate conditions for the initial Michael addition reactions were thus determined, further conversion to the benzene derivative 4aa

• seemed to be an important factor, and the corresponding lithium and sodium salts did not aid the reaction satisfactory. Moreover, EtONa was found to be inappropriate for this protocol (Table 3, entries 10 and 11). Determination of the appropriate conditions both for Michael addition as well as

Direct synthesis of anomeric tetrazolyl iminosugars from sugar-derived lactams

• Michał M. Więcław and
• Bartłomiej Furman

Beilstein J. Org. Chem. 2021, 17, 115–123, doi:10.3762/bjoc.17.12

• as the aldol reaction [30], Michael addition [31], Mannich reaction [32], and hydrogenation [33]. Results and Discussion Quite recently Xie and Dixon showed that it is possible to synthesize α-tetrazolylamines from simple and linear tertiary amides using an iridium-based catalytic protocol [19]. They

• widely used as organocatalysts. Such moieties are employed in a number of important synthetic transformations, including the aldol reaction [30], Michael addition [31], Mannich reaction [32], and hydrogenation [33]. We plan to test these possibilities in the near future. Stereochemistry and configuration

Recent progress in the synthesis of homotropane alkaloids adaline, euphococcinine and N-methyleuphococcinine

• Dimas J. P. Lima,
• Antonio E. G. Santana,
• Michael A. Birkett and
• Ricardo S. Porto

Beilstein J. Org. Chem. 2021, 17, 28–41, doi:10.3762/bjoc.17.4

• forms. Key (homotropane construction) steps included: i) inter and intramolecular Mannich reaction; ii) double Michael addition in the cyclooctadienone derivative; and iii) intramolecular 1,3-dipolar cycloaddition. As shown in Scheme 1, the azabicyclononane ring is an interesting target for strategies

All-carbon [3 + 2] cycloaddition in natural product synthesis

• Zhuo Wang and
• Junyang Liu

Beilstein J. Org. Chem. 2020, 16, 3015–3031, doi:10.3762/bjoc.16.251

• 66b gave α,β-unsaturated amide 67, which was treated with KHMDS to facilitate an intramolecular Michael addition to give lactam 68 in quantitative yield. The conversion of freshly prepared lactam 68 to xanthante ester 69 was achieved in three steps. Exposure of xanthante ester 69 to AIBN and a

• underwent successive intramolecular Michael addition and hydrolytic nitrile reduction to give 79 in 46% yield in two steps. Extensive studies of the nitrile reduction eventually identified that Et3Al and DIBAL-H could effectively reduce the nitrile group to the corresponding aldehyde and treatment with

• intramolecular [3 + 2] cycloaddition begins with the reaction between the rhodium catalyst Rh(I)LCl and alcohol 110 to give complex A through alcoholysis [50][51] (Scheme 8B). Rh(I)-mediated retro-propargylation of the homopropargyl alcohol A afforded complex B. It undergoes an intramolecular Michael addition

Convenient access to pyrrolidin-3-ylphosphonic acids and tetrahydro-2H-pyran-3-ylphosphonates with multiple contiguous stereocenters from nonracemic adducts of a Ni(II)-catalyzed Michael reaction

• Alexander N. Reznikov,
• Dmitry S. Nikerov,
• Anastasiya E. Sibiryakova,
• Victor B. Rybakov,
• Evgeniy V. Golovin and
• Yuri N. Klimochkin

Beilstein J. Org. Chem. 2020, 16, 2073–2079, doi:10.3762/bjoc.16.174

• reactions with aldehydes yielding tetrahydropyranylphosphonates as individual stereoisomers. These nonracemic heterocycles containing phosphoryl moieties are useful for designing new pharmacologically active compounds. Keywords: asymmetric catalysis; Michael addition; phosphonates; pyrrolidines

• heterocycles. The present work reports on the synthesis of nonracemic phosphoryl-substituted pyrrolidines and tetrahydropyranes via Ni(II)-catalyzed asymmetric Michael addition of β-keto phosphonates to conjugated nitroolefins. Results and Discussion For the synthesis of nonracemic polysubstituted pyrrolidin-3

• -ylphosphonic acids and tetrahydropyranylphosphonates, we assumed that the 4-nitro-2-oxophosphonates – the Michael adducts of β-keto phosphonates and nitroolefins – are suitable precursors, considering that the Ni(II)-catalyzed Michael addition was carried out not only enantioselectively, but also

Reactions of 3-aryl-1-(trifluoromethyl)prop-2-yn-1-iminium salts with 1,3-dienes and styrenes

• Thomas Schneider,
• Michael Keim,
• Bianca Seitz and
• Gerhard Maas

Beilstein J. Org. Chem. 2020, 16, 2064–2072, doi:10.3762/bjoc.16.173

• -iminium triflates R‒C≡C‒C(CF3)=N+Me2 TfO− [27]. As a first synthetic application, we have reported the phospha-Michael addition providing 3-(triphenylphosphonio)-1-(trifluoromethyl)-1-(dimethylamino)allenes, which were subsequently transformed into α-(trifluoromethyl)pyrroles. In the present paper, we