Synthesis of new bile acid-fused tetrazoles using the Schmidt reaction

• Dušan Đ. Škorić,
• Olivera R. Klisurić,
• Dimitar S. Jakimov,
• Marija N. Sakač and
• János J. Csanádi

Beilstein J. Org. Chem. 2021, 17, 2611–2620, doi:10.3762/bjoc.17.174

• different ketone and enone precursors from cholic acid, deoxycholic acid, and chenodeoxycholic acid was established. Newly obtained tetrazole derivatives were characterized by NMR and X-ray diffraction spectroscopy. In a number of cases, preliminary antiproliferative tests of new compounds showed strong and

• . Results and Discussion In order to investigate possibilities for the synthesis of bile acid B-ring- and bile acid C-ring-fused tetrazoles by a variation of the Schmidt reaction, the appropriate ketone and enone derivatives were prepared firstly. This was achieved using cholic acid, deoxycholic acid (1

• noticeably, while the yield was preserved. Ketone 3 and enone 4 were used for the optimization of reaction conditions. Firstly, the ketone 3 was reacted with hydrazoic acid in the presence of boron trifluoride etherate as a Lewis acid (Table 1, entry 1). The desired tetrazole 13 was obtained after

Recent advances in organocatalytic asymmetric aza-Michael reactions of amines and amides

• Pratibha Sharma,
• Raakhi Gupta and
• Raj K. Bansal

Beilstein J. Org. Chem. 2021, 17, 2585–2610, doi:10.3762/bjoc.17.173

• subsequently deprotonates pyrrole to provide the stronger nucleophilic pyrrolide anion [27]. Similarly, Liu et al. accomplished an asymmetric intramolecular aza-Michael addition of various enone carbamates 10 using a chiral cinchona-based primary-tertiary diamine as catalyst to obtain 2-substituted piperidines

• -catalysts and trifluoroacetic acid and diphenyl hydrogenphosphate (DPP) were found to give the best results [30]. Cheng et al. reported an intramolecular 6-exo-trig aza-MR of hydroxylamine-derived enone 15 for the synthesis of chiral 3-substituted 1,2-oxazinanes 16. The catalyst 11 was used in this case

α-Ketol and α-iminol rearrangements in synthetic organic and biosynthetic reactions

• Scott Benz and
• Andrew S. Murkin

Beilstein J. Org. Chem. 2021, 17, 2570–2584, doi:10.3762/bjoc.17.172

• used to shift a four-carbon chain one position on the bicyclic molecule 32 using the base calcium methoxide with a yield of 70% of 33 and a diastereomeric ratio of 3:1 (14:1 after separation) (Figure 8) [11]. Note that 33 bears an enone moiety, and therefore, this reaction is apparently the first

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

• addition of 4-hydroxycoumarin (1) by the Re face of the enones 2 through a bifunctional modified binaphthyl organocatalyst 18 with primary amine [37]. The reaction occurs through the activation of the enone substrate by formation of an iminium ion intermediate and, in the presence of an acid additive

• gram-scale experiment, affording the desired product 21a with excellent yield and ee (Scheme 6b). Ren et al. reported an enantioselective reaction of cyclopent-2-enone-derived Morita–Baylis–Hillman (MBH) alcohols 24 with 4-hydroxycoumarins 1 catalyzed by a chiral primary amine derived from

• amines enables both the formation of an imine ion with the enone and activation of the hydroxycoumarin by hydrogen bonding [41]. Despite the long reaction time (3 days), the desired products 3 were obtained with good to excellent yields and moderate enantiomeric excesses (Scheme 9). A new organocatalyst

A recent overview on the synthesis of 1,4,5-trisubstituted 1,2,3-triazoles

• Pezhman Shiri,
• Ali Mohammad Amani and
• Thomas Mayer-Gall

Beilstein J. Org. Chem. 2021, 17, 1600–1628, doi:10.3762/bjoc.17.114

• also applicable in the reaction. In continuation of the study, various alkyl- and aryl-substituted unmodified cyclic enones were explored, and the result was a moderate to good yield of the corresponding products. The reaction was performed well using alkyl-substituted cyclic enone. Finally, acyclic

• enone 46 reacted with aryl and vinyl azides to afford a moderate to high yield of the triazole products (Scheme 16) [46]. A simple one-pot two-stage strategy for the synthesis of disubstituted 4-chloro-, 4-bromo-, and 4-iodo-1,2,3-triazoles 50 from the reaction of the corresponding nonactivated alkynes

Breaking paracyclophane: the unexpected formation of non-symmetric disubstituted nitro[2.2]metaparacyclophanes

• Suraj Patel,
• Tyson N. Dais,
• Paul G. Plieger and
• Gareth J. Rowlands

Beilstein J. Org. Chem. 2021, 17, 1518–1526, doi:10.3762/bjoc.17.109

• compound 6. It is unclear how the denitration product 15 forms. Elimination of the ether 14 to regenerate the enone 6 is straightforward, but reductive denitration is a taxing reaction that normally requires strongly reducing conditions or a single electron donor. There are examples of milder denitrations

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

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

• the conclusion that in this catalytic system, much better results were obtained when aryltrifluoroborates are used. The system also worked well for linear enone electrophiles (entries 12–20, Table 1). The main disadvantage of this approach is the necessity of sub-zero temperatures [32][33]. A follow

• the addition of the boronic acid to the β-(2-hydroxyaryl)enone could be oxidized to afford optically pure 4-phenylchroman-2-one (Scheme 1). Also in 2007, Miyaura and co-workers presented the synthesis of enantioenriched 1-aryl-1H-indenes by a tandem 1,4-addition of arylboronic acids to enones and

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

• products 143b. The proposed mechanism in Scheme 58 depicts the formation of intermediate A from condensation of arylglyoxal and pyrazolylamine protonated by p-TsOH with subsequent dehydration. An enone intermediate generated from the carbonyl addition reaction of intermediate A with imine B transforms into

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

• anion III on the enone intermediate 4 (path A), followed by elimination of OTs affords the corresponding β-triazolylenone 3 (Scheme 4) [52]. The β-O-tosylcyclopentenone intermediate 4b can also undergo intramolecular tosyl migration to form a stable C-tosylated product 4b’ (see also Scheme 3b and c

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

• imines 115, which led to alkylideneazetidines 116 (Scheme 52) [102]. The MgI2 acted as a Lewis acid and reducing agent, effecting the distal C–C bond cleavage in 113a to form an allenyl ketone, or an equivalent fluoro,iodo-enone species, either of which could then have added to the imine 115 and led to

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

• –dehydration reactions, via intermediate anti-aldol (−)-67 (Scheme 8). The addition of Grignard reagent to the enone (E)-(−)-68 occurred anti to the group TpMo(CO)2 to give adduct (E)-69, which was used in the next step without purification. The treatment of this adduct with HCl in dioxane promoted

• potassium enolate to neutral η3-allylmolibdenum. The crude anionic intermediate 72 was treated with nitrosonium hexafluorophosphate in DME to provide bicyclic enone (−)-73 with 80% yield over two steps. Protection of the non-conjugated ketone (−)-73 as an acetal derivative occurred selectively to provide

• enone (−)-74, which was subjected to Luche reduction followed by removing the resulting alcohol under Barton–McCombie conditions, providing alkene (−)-75 in 55% yield from (−)-73. Finally, the acetal group of (+)-75 was hydrolyzed in the presence of catalytic Pd(MeCN)2Cl2. The intermediate ketone was

Pentannulation of N-heterocycles by a tandem gold-catalyzed [3,3]-rearrangement/Nazarov reaction of propargyl ester derivatives: a computational study on the crucial role of the nitrogen atom

• Giovanna Zanella,
• Martina Petrović,
• Dina Scarpi,
• Ernesto G. Occhiato and
• Enrique Gómez-Bengoa

Beilstein J. Org. Chem. 2020, 16, 3059–3068, doi:10.3762/bjoc.16.255

• protonation/deprotonation sequence. Finally, although we did not study in detail the acetate hydrolysis from XV to 15, we could confirm the higher stability (by more than 6 kcal⋅mol−1) of 15 relative to the enone isomer arising from XII, in agreement again with the experimental results. Experimental

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

• tetracyclic compound 56. Dihydroxylation of freshly prepared 56 with OsO4 and then selective tosylation afforded 57 in 39% yield over two steps. Exposure of 57 to DBU upon heating gave the elimination product 58, which was subjected to an oxidative rearrangement with PDC to give enone 59 in 68% yield. Copper

• -mediated conjugated addition of methyllithium to enone 59 in the presence of boron trifluoride ether [34][35] produced desired ketone 60 in 75% yield. The resultant ketone 60 was converted to waihoensene (16) in two steps. Palladium-catalyzed carboxylative trimethylenemethane cycloaddition In 1986, Trost

• -catalyzed intermolecular carboxylatve TMM [3 + 2] cycloaddition [36] of enone 65 and TMM donor 62 to forge the highly-substituted spirocyclic cyclopentane 66a [38] (Scheme 4A). Methylation of the resultant cyclopentane 66a gave methyl ester 66b in 93% yield over two steps. A six-step synthesis from ester

Recent developments in enantioselective photocatalysis

• Callum Prentice,
• James Morrisson,
• Andrew D. Smith and
• Eli Zysman-Colman

Beilstein J. Org. Chem. 2020, 16, 2363–2441, doi:10.3762/bjoc.16.197

• begins with the condensation of 49 with enone 50 to form the iminium ion intermediate 51. Concomitantly, the excited-state photocatalyst generates an alkyl radical R• from R–H, either through HAT ([W] with a benzodioxole derivative) or SET ([Ir] with a tertiary amine). This radical then adds to the β

• likely operates via a radical chain mechanism. Initiation begins with the reductive quenching of the photocatalyst using iPr2NEt as a sacrificial reductant to give [Ru]•−, which then reduces the Lewis acid-coordinated enone 271 to give alkyl radical 271•. In the presence of a second enone 270 and chiral

Formation of an exceptionally stable ketene during phototransformations of bicyclo[2.2.2]oct-5-en-2-ones having mixed chromophores

• Asitanga Ghosh

Beilstein J. Org. Chem. 2020, 16, 2297–2303, doi:10.3762/bjoc.16.190

• interesting reactions. Indeed, this type of mixed enone photochemistry is also an attractive field [7][8] for chemists because the photochemistry of such substrates can feature the intramolecular competition of different photochemical rearrangements. For several years, our laboratory (S. Lahiri et al.) is

• enones like D to minimize this route. Interestingly such rigid systems may either be considered as α,β- or β,γ-enone with δ-keto conjugation. However, in one of our previous works [16], we have established that the system should be considered as α,β-enone with δ-keto homoconjugation. Simple β,γ-enone

• systems show an absorption band at about 210–250 nm characteristic for (π,π*) transition and at around 280–300 nm characteristic for (n,π*) transition. However, enone D shows enhanced intensity of an (n,π*) absorption band near 300 nm (log ε ≈ 3.5), along with an additional weak (n,π*) absorption band

Photosensitized direct C–H fluorination and trifluoromethylation in organic synthesis

• Shahboz Yakubov and
• Joshua P. Barham

Beilstein J. Org. Chem. 2020, 16, 2151–2192, doi:10.3762/bjoc.16.183

• and co-workers reported that enones also served as directing groups for PS TTET fluorinations [206]. C(sp3)–H bonds that were proximal (5 or 6 carbon atoms away) or distal (5 or 6 carbon atoms away) from the enone underwent C(sp3)–H fluorination to afford the products 56–59 in modest to very good

• through small-diameter (μm–mm) channels. Lectka and co-workers reported the processing of their benzil-photosensitized enone-directed C(sp3)–H fluorination in a custom-built flow reactor, comprised of a syringe pump, a coil of fluorinated ethylene propylene (FEP) tubing (7.5 m; inner diameter 1.6 mm

Syntheses of spliceostatins and thailanstatins: a review

• William A. Donaldson

Beilstein J. Org. Chem. 2020, 16, 1991–2006, doi:10.3762/bjoc.16.166

• (−)-51 (Scheme 6) [16]. An Achmatowicz oxidation [29] with tert-butyl hydroperoxide catalyzed by VO(acac)2 afforded the hemiketal 52, and the ionic reduction [22] of 52 gave the enone (−)-53. The enone transposition of 53 was effected by the addition of methyl-Grignard, followed by the oxidation with PCC

• yield and high enantioselectivity (Scheme 7) [15][16]. The Achmatowicz oxidation and ionic reduction generated the enone 58, which is regioisomeric with 53. The 1,4-addition of lithium dimethylcopper gave the desired cis-55 with high a diastereoselectivity (25:1). The cross-metathesis of 55 with 3

Pauson–Khand reaction of fluorinated compounds

• Jorge Escorihuela,
• Daniel M. Sedgwick,
• Alberto Llobat,
• Mercedes Medio-Simón,
• Pablo Barrio and
• Santos Fustero

Beilstein J. Org. Chem. 2020, 16, 1662–1682, doi:10.3762/bjoc.16.138

• , predictable for unsymmetrical alkynes (things are more complex regarding the olefin). Generally, the most sterically encumbered substituent of the alkyne occupies the proximal position in the enone system. This is dictated by the migratory insertion of the olefin into the most accessible Co–C bond (Scheme 3

• ). This trend is strictly followed by terminal alkynes, for which exclusive formation of the α-substituted enone is observed, while mixtures are usually obtained with internal dissymmetric alkynes, although the major product follows the aforementioned trend [41]. On the other hand, for alkynes bearing

• )8 followed by the addition of NMO), and starting from the pure anti diastereoisomer of 1,7-enyne 20, the expected bicyclic enone was obtained in good yield and high diastereoselectivity (de > 95%). An attempt to extend the PKR to the formation of a fused tricyclic structure, starting from 1,7-enyne

An overview on disulfide-catalyzed and -cocatalyzed photoreactions

• Yeersen Patehebieke

Beilstein J. Org. Chem. 2020, 16, 1418–1435, doi:10.3762/bjoc.16.118

• subsequent SET from the radical 60 to the thiyl radical yields the allylic cation 61 and a thiolate anion. The following proton abstraction by this thiolate anion from the intermediate 62 gives the enone 63 and thiophenol to complete the oxidation. In the hydrogenation step, the addition of a thiyl radical

• to the enone 63 and posterior hydrogen transfer from thiol to the intermediate 64 forms the ketone intermediate 65 (pathway 1). This ketone intermediate 65 is also accessible by an ionic addition in the dark (pathway 2). The tautomerization of the ketone 65 yields the enol form 66, which reacts with

Recent synthesis of thietanes

• Jiaxi Xu

Beilstein J. Org. Chem. 2020, 16, 1357–1410, doi:10.3762/bjoc.16.116

Recent applications of porphyrins as photocatalysts in organic synthesis: batch and continuous flow approaches

• Rodrigo Costa e Silva,
• Luely Oliveira da Silva,
• Aloisio de Andrade Bartolomeu,
• Timothy John Brocksom and
• Kleber Thiago de Oliveira

Beilstein J. Org. Chem. 2020, 16, 917–955, doi:10.3762/bjoc.16.83

• steps an electrochemical cyclization and an endoperoxidation photocatalyzed by TPP in an almost gram-scale (Scheme 38) [88]. In 2020, Burchill and George reported a 0.5 g-scale ene-reaction with singlet oxygen and a cromene derivative, thus giving a conjugated enone after a Kornblum–DeLaMare

Combining enyne metathesis with long-established organic transformations: a powerful strategy for the sustainable synthesis of bioactive molecules

• Valerian Dragutan,
• Ileana Dragutan,
• Albert Demonceau and
• Lionel Delaude

Beilstein J. Org. Chem. 2020, 16, 738–755, doi:10.3762/bjoc.16.68

• metathesis (RCM) [67][68]. Starting from 3-cyanocyclohex-2-enone, the authors obtained a versatile intermediate able to provide the appropriate dienyne precursors (A–C, Scheme 4) by multicomponent Grignard addition-alkylations. Through divergent cyclizations involving a chemoselective enyne metathesis

Combination of multicomponent KA² and Pauson–Khand reactions: short synthesis of spirocyclic pyrrolocyclopentenones

• Riccardo Innocenti,
• Elena Lenci,
• Gloria Menchi and
• Andrea Trabocchi

Beilstein J. Org. Chem. 2020, 16, 200–211, doi:10.3762/bjoc.16.23

• cyclopentenone ring [37], as this heterocycle is a powerful synthon for the synthesis of a variety of bioactive target molecules, due to the broad diversity of chemical modifications available for the enone structural motif [38]. The most common approach to access such chemotype is the Pauson–Khand (PK) reaction

• Pauson–Khand conditions (Table 1,entry 14). The synthetic utility of the spiro derivatives resulting from the combined KA2/Pauson–Khand process to generate second-generation molecular scaffolds was tested on compound 5 by applying representative reactions on the enone structural motif (Scheme 3). The

• imposed by the adjacent phenyl and cyclohexyl rings [59]. The treatment of compound 5 under Schmidt reaction conditions with sodium azide in TFA [60] resulted in the conversion to the corresponding six-membered ring lactam 39 in 41% yield, demonstrating the reactivity of the enone 5 at the carbonyl group