Organocatalytic asymmetric nitroso aldol reaction of α-substituted malonamates

• Ekta Gupta,
• Narendra Kumar Vaishanv,
• Sandeep Kumar,
• Raja Krishnan Purshottam,
• Ruchir Kant and
• Kishor Mohanan

Beilstein J. Org. Chem. 2022, 18, 217–224, doi:10.3762/bjoc.18.25

• using a silver-BINAP catalyst combination [25]. Later, the same group could successfully tune the catalytic system to control the regioselectivity in the addition of metal enolate to nitrosoarenes to achieve an α-hydroxyamination [26]. Since then, several groups have shown the use of metal-catalyzed

• thiourea moiety with the oxygen of the nitrosobenzene. The tertiary amine, present in the catalyst acts as a base in assisting the deprotonation of the highly acidic malonamate to generate the corresponding enolate. Subsequently, a face-selective nucleophilic addition of the enolate to nitroso selective

Synthesis and late stage modifications of Cyl derivatives

• Phil Servatius and
• Uli Kazmaier

Beilstein J. Org. Chem. 2022, 18, 174–181, doi:10.3762/bjoc.18.19

• , such as histone deacetylases. Keywords: chelated enolate; Claisen rearrangement; HDAC inhibitor; peptide; late stage modification; Introduction Among natural products, peptidic structures have entered the limelight due to their extraordinary biological activities [1]. Often found as secondary

• decided to take advantage of an asymmetric chelate enolate Claisen rearrangement, which should allow the stereoselective generation of the unusual amino acid, depending on the configuration of the chiral allylic alcohol used [41][42]. If a peptide Claisen rearrangement [43][44][45] is carried out with a

• usual conditions of an ester enolate Claisen rearrangement with zinc chloride as chelating metal gave the rearranged product in only 33% yield and a diastereomeric ratio of 93:7 (Table 1, entry 1). The reaction was kept at −45 °C overnight to suppress potential epimerization of the peptide. Generally

A two-phase bromination process using tetraalkylammonium hydroxide for the practical synthesis of α-bromolactones from lactones

• Yuki Yamamoto,
• Akihiro Tabuchi,
• Kazumi Hosono,
• Takanori Ochi,
• Kento Yamazaki,
• Shintaro Kodama,
• Akihiro Nomoto and
• Akiya Ogawa

Beilstein J. Org. Chem. 2021, 17, 2906–2914, doi:10.3762/bjoc.17.198

• -valerolactone (1a), has been limited. The main process for the bromination of δ-valerolactone (1a) was treating the lactone with lithium diisopropylamide (LDA) at −78 °C to first generate the corresponding enolate, trapping it with trimethylsilyl chloride (TMSCl) to form the enol silyl ether, followed by

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

• -promoted steps, beginning with a vinylogous α-ketol rearrangement to 46. Following protonation of the enolate and addition of hydroxide to the carbonyl on the D ring, 47 rearranges with loss of chloride to give enedione 48. Base-catalyzed isomerization yields 44, which is apparently more stable despite the

Advances in mercury(II)-salt-mediated cyclization reactions of unsaturated bonds

• Sumana Mandal,
• Raju D. Chaudhari and
• Goutam Biswas

Beilstein J. Org. Chem. 2021, 17, 2348–2376, doi:10.3762/bjoc.17.153

• temperature. It was an example of cycloisomerization of 2-ethynylaniline derivatives utilizing mild reaction conditions (Scheme 50) [110]. Rong et al. had demonstrated the Hg(II)-salt-catalyzed enolate umpolung reaction for the efficient synthesis of various 3-indolinones and 3-coumaranones 174. They had

• Petasis–Ferrier-type cyclization, and finally nucleophilic addition of mercuric enolate to iminium results in the formation of azaspiro structure. Conclusion In conclusion, this review summarizes Hg(II)-salt-mediated cyclization reactions either for direct synthesis of cyclized products or as a part of

Base-free enantioselective S_N2 alkylation of 2-oxindoles via bifunctional phase-transfer catalysis

• Mili Litvajova,
• Emiliano Sorrentino,
• Brendan Twamley and
• Stephen J. Connon

Beilstein J. Org. Chem. 2021, 17, 2287–2294, doi:10.3762/bjoc.17.146

• ester moieties at C-3 have been shown to participate in enantioselective phase-transfer-catalysed alkylations promoted by ad-hoc designed quaternary ammonium salts derived from quinine bearing hydrogen-bond donating substituents. For the first time in such phase-transfer-catalysed enolate alkylations

• highly valuable synthetic building blocks [5][6][7][8][9][10][11][12]. Both pyrroloindolines 1 and spirooxindoles 2 are conceivably available from key 3,3-disubstituted intermediates 3, which could be prepared via an enantioselective SN2 alkylation involving enolate 3a (Figure 1B). The versatility of

• other hand, such electron-withdrawing groups, α to the reactive centre, dramatically changes the acidity of the substrate (and thus the reactivity of the enolate conjugate base) and as consequence its reactivity which can drastically impact the enantioselectivity in SN2 alkylation processes. In this

Halides as versatile anions in asymmetric anion-binding organocatalysis

• Lukas Schifferer,
• Martin Stinglhamer,
• Kirandeep Kaur and
• Olga García Macheño

Beilstein J. Org. Chem. 2021, 17, 2270–2286, doi:10.3762/bjoc.17.145

• proton of the enolizable β-ketoester 49 and thus activating the nucleophilic species. This enolate then adds to the cationic substrate from in situ upon halide abstraction of α-chloro amino acid derivatives 48 by the thiourea moiety of the bifunctional catalyst (Scheme 10c, key intermediate), leading to

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

• reported [45], for which a detailed transition state model was developed. In that study, it was determined that the reaction proceeds via several competing low-energy transition states involving both O–H and N–H enolate binding modes, E and Z enolate isomers, and a range of H-bonding and other noncovalent

• enolate geometry and N–H vs O–H binding). From this transition state, addition of the enolate to the acrylate followed by rapid proton transfer would lead to the glutamate derivative 10 (path a, red dashed line). A competing pathway involving bond formation between the acrylate α-carbon and the imine

• carbon, either in a concerted fashion or via subsequent addition of a putative acrylate enolate intermediate, would lead to the cycloaddition byproduct 11 (path b, red and blue dashed lines). It should be noted that cyclopropenimine catalysts do not promote the cyclization of 10 to 11. From this model

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

• deprotonated by a base, affording an ammonium ylide/enolate. Meanwhile, the Re-face attack is favored after interaction of squaramide portion of the catalyst with coumarin. Then, a Michael addition followed by intramolecular cyclization affords the desired product 75, as shown in Scheme 23. An enantioselective

• catalyst provides the formation of an ionic pair with coumarin enolate and activation of the imine by hydrogen bonding with the secondary amine, resulting in products 113 with excellent yields and high enantioselectivity [75]. This transformation draws attention because it uses only 0.1 mol % of catalyst

Development of N-F fluorinating agents and their fluorinations: Historical perspective

• Teruo Umemoto,
• Yuhao Yang and
• Gerald B. Hammond

Beilstein J. Org. Chem. 2021, 17, 1752–1813, doi:10.3762/bjoc.17.123

• reagents, a match process which minimizes side reactions. Thus, these N-fluoropyridinium salts made possible the fluorination of a diversity of nucleophilic organic compounds with different reactivities ranging across aromatics, carbanions (Grignard reagents, enolate anions), active methylene compounds

• no α-proton to the N-F site proved to be a good choice for fluorinating enolate anions (Scheme 24). The side reaction, involving HF elimination, and which was a problem in reactions with the Barnette’s reagents 4-1 having the α-proton(s) except for 4-1b [26], was avoided here. The HF elimination is a

•  30). NFSI is a stable and non-hygroscopic crystalline solid with a mp of 114–116 °C. NFSI was shown to fluorinate a variety of nucleophiles. As seen in Scheme 31, trimethylsilyl enol ethers, enolate anions of ketones and esters, and aryl- and vinyllithiums were fluorinated with NFSI in moderate to

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

• ) [45]. In 2020, Ramachary et al. reported the 1,3-dipolar cycloaddition of various enones 43 and 46 with less reactive vinyl/alkyl/aryl azides 44 via an enolate-mediated organocatalyst. This protocol provides diverse double C- and N-vinylated 1,2,3-triazole derivatives and C-vinylated 1,2,3-triazole

• derivatives from azidophilic substrates and different azide derivatives. A short reaction time, good to high yield of products, high diversity, high selectivity, and ease of operation were some benefits of this methodology. The enolate reactivity with azides was compared to enamines. The best conditions were

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

• the protonation of a Pd(II) enolate intermediate by a proton source (HCl) generated at the cyclization step. The catalytic cycle begins with the enolic carbon of A attacking the complexed metal–olefin double bond in a turnover-limiting 6-endo-trig cyclization step (Scheme 3). The formed alkylpalladium

• (II) intermediate (B) then undergoes a sequence of reversible hydride β-eliminations [30] until the formation of the Pd(II) enolate (F), which, after protonation, irreversibly furnishes the product 2 and regenerates the Pd(II) catalyst. The lack of the usually kinetically favored 5-exo-trig

• Markovnikov-type addition to generate a carbon-centered radical (B) that attacks the electron-deficient olefin (Scheme 22A). The newly formed alkyl radical (C) is then reduced by a Fe(II) species to an enolate (D) in an electron transfer (ET) step; a proton abstraction then delivers the hydroalkylated product

Synthesis of 1-indolyl-3,5,8-substituted γ-carbolines: one-pot solvent-free protocol and biological evaluation

• Premansh Dudhe,
• Mena Asha Krishnan,
• Kratika Yadav,
• Diptendu Roy,
• Krishnan Venkatasubbaiah,
• Biswarup Pathak and
• Venkatesh Chelvam

Beilstein J. Org. Chem. 2021, 17, 1453–1463, doi:10.3762/bjoc.17.101

• formation of γ-carboline derivatives 3aa–ac and 3ba–ea involves the initial formation of trans-iminoester 4 from the N-protected indole-2-carboxaldehydes 1a–e and 1g, and glycine alkyl esters 2a–c. The Hünig’s base, DIPEA, helps abstract the active methylene proton from iminoester 4 to generate enolate ion

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

• ., benzaldehydes) and low-molecular-weight enolate nucleophiles, therefore, temperature regulation is vital for selectivity. This requirement for strict temperature control makes aldol reactions highly suited to flow processing conditions. In 2008, Tanaka et al. [96] disclosed several examples of aldol reaction in

• was evident (Scheme 3). Within the microreactor acetone was first deprotonated by merging with a 2.5 M sodium hydroxide stream at room temperature, then, after a residence time of just 45 seconds, the resultant enolate was introduced to a stream containing the aldehyde as a 5.5 M solution also in

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

• -aziridine in 50% yield under the same conditions. The transition state is proposed with a six-membered chair-like transition containing a four-membered metallocycle. In cis-aziridine the enolate of methyl α-bromoacetate has E-geometry and the trans-aziridine 8a has Z-geometry [32][33]. In the transition

• state, the metal cation of the enolate is being coordinated with both nitrogen and oxygen atoms of the sulfinimine [25][26] (Scheme 3). In 1999, Ellman and co-workers described the reduction of sulfinyl imines using sodium borohydride (NaBH4) [34] or o ʟ-selectride [35]. Davis–Ellman transition state

• consequence of the E stereochemistry of both the imine 14 and the enolate derived from bromoester 26 (Scheme 9). A two-step protocol carried out in a single synthetic operation was developed by Chen and Zhang to synthesize 3-substituted 2-chloroaziridines with relative cis configuration [71]. The reaction of

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

• progresses under neutral conditions. The authors postulated that the vacancy on the square-planar Pd(II) species allows a faster alkene insertion in comparison to Pd(0). The cationic Pd(II) enolate exists as a dynamic mixture of C- and O-bound enolate and is highly susceptible to hydrolysis. This means that

• protonolysis of the O-bound enolate in the presence of PPh3 that leads to the regeneration of the catalytically active hydroxopalladium species and the addition product (Scheme 8) [43]. The presence of PPh3 ensures the preference of hydrolysis instead of a β-hydride elimination, which would lead to an

Prins cyclization-mediated stereoselective synthesis of tetrahydropyrans and dihydropyrans: an inspection of twenty years

• Asha Budakoti,
• Pradip Kumar Mondal,
• Prachi Verma and
• Jagadish Khamrai

Beilstein J. Org. Chem. 2021, 17, 932–963, doi:10.3762/bjoc.17.77

•  18). A sequence of reactions involving elimination of a proton from 83, treatment of 84 with an alkoxide, and protonation of the resulting enolate delivered thermodynamically favored equatorial ester 80 and 81. The highly diastereoselective Brønsted superacid-catalyzed Prins cyclization of

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

• . The postulated mechanism indicates the formation of acylimine A from the lanthanum oxide-catalyzed reaction of aldehyde and 77. Further, addition of acyclic 1,3-diketone ester enolate to acylamine A form B which upon subsequent cyclization and dehydration resulted in the formation of desired products

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

• to exist in twist-boat conformation. When R = H, the pseudoaxial approach of the nucleophile towards the β-position leading to the enolate intermediate VI (R = H) bearing pseudoequatorially oriented OTs group or the pseudoequatorial approach of the nucleophile leading to the intermediate VII (R = H

α,γ-Dioxygenated amides via tandem Brook rearrangement/radical oxygenation reactions and their application to syntheses of γ-lactams

• Mikhail K. Klychnikov,
• Radek Pohl,
• Ivana Císařová and
• Ullrich Jahn

Beilstein J. Org. Chem. 2021, 17, 688–704, doi:10.3762/bjoc.17.58

• corresponding acyclic or cyclic allylic amines in very good yields (see Supporting Information File 1 for details). Their subsequent α-deprotonation by LDA followed by treatment with chlorotrimethylsilane at −78 °C [81] resulted in clean C-silylation of the corresponding enolate providing silylacetamides 8a–m

• enolate formation from 8h,i with s-BuLi, a deuterium quenching experiment with D2O was performed. Analysis by 1H NMR spectroscopy revealed 87 and 91% deuterium incorporation, respectively, indicating that a deprotonation occurred, but the epoxide opening was hampered by the combination of a sterically

• diastereomeric ratios. To confirm enolate formation, lactam 12f was deprotonated by LDA at −78 °C and quenched with D2O, resulting in lactam 12f with 86% deuterium incorporation, but no change in the diastereomeric ratio. Spirolactams 12m,n were also subjected to epimerization (Scheme 4). The change of the

Progress in the total synthesis of inthomycins

• Bidyut Kumar Senapati

Beilstein J. Org. Chem. 2021, 17, 58–82, doi:10.3762/bjoc.17.7

• followed by subsequent oxidation produced aldehyde (Z,Z)-61. After extensive unsuccessful efforts to produce enantiopure aldol fragment (Z,Z)-62 using the N-tosyl-ʟ-valine-derived oxazaborolidinone, the racemic synthesis of (Z,Z)-(rac)-62 was achieved by utilizing the lithium enolate of methyl isobutyrate

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

• 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

• -sulfinimes (+)-95 and (+)-96 were added to a −78 °C solution of the N-methoxy-N-methylacetamide enolate 102, leading to Weinreb amides (+)-97 and (+)-98, respectively, with good yields and high diastereoisomeric excesses (Scheme 11). The reaction of (+)-97 and (+)-98 with five equivalents of methylmagnesium

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

• [52][53] with the allenyl rhodium to the enal and gives the allenyl rhodium species C. A Conia-ene-type reaction [54] between the Rhoda-enolate species and the allene of complex C produces the desired [3.3.0] bicycle D. Protonolysis [55][56][57] of complex D with the alcohol 110 gives bicyclic product

• cation, which is intercepted by the titanium enolate and results in the new C–C bond formation to give the five-membered carbocycle 169. Conclusion The all-carbon [3 + 2] cycloaddition, together with the [3 + 2] annulation, continue to be an attractive class of reactions for the synthesis of highly

Synthesis of novel fluorinated building blocks via halofluorination and related reactions

• Attila Márió Remete,
• Tamás T. Novák,
• Melinda Nonn,
• Matti Haukka,
• Ferenc Fülöp and
• Loránd Kiss

Beilstein J. Org. Chem. 2020, 16, 2562–2575, doi:10.3762/bjoc.16.208

• epimerization is required. The requirement of additional reaction steps may explain the lower yield (31%) of this reaction. Note, that from the other three substrates, the product (rac)-27 was obtained in a yield of 52–54%. Since the enolate (rac)-T9 is all-equatorial, and consequently, the energy is lower than

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

• trapped by enolate 160 in a chiral environment, provided by the PTC, to form a α-hydroperoxyl intermediate 161. Subsequent deoxygenation by another molecule of 160 forms two molecules of the α-hydroxylated products 162 in excellent yields and moderate enantioselectivities (11 examples, up to 88:12 er

•  24) [77]. Interestingly, this takes place without the need for an external photocatalyst and is proposed to proceed via an intermediate EDA complex 164, which, upon excitation, forms perfluoroalkyl radicals 163• that add to the enolate substrate that is coordinated to a chiral counterion 165 to give

• to generate diradical 177 that then adds to the alkene to form diradical 178. A SET between the ketyl radical and the α-carbonyl radical generates enolate intermediate 179, which after proton transfer regenerates the catalyst and releases the desired cyclisation product 180 in a moderate yield and