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

• usually achieved by a nucleophilic substitution of an alkyl halide by the deprotonated malonate [12][13][14][15][16][17][18][19], but other strategies could be envisioned: Cu-catalyzed arylation reactions for aryl-substituted MAHOs [20][21][22][23]; Knoevenagel/reduction sequences for benzyl-substituted

• . SMAHOs bearing classical ester groups could be obtained in moderate yields (iPr: 51%; Bn: 53%; allyl: 52%) and the use of less nucleophilic alcohols such as t-BuOH, 2,2,2-trifluoroethanol, (−)-menthol, and phenol led to decreased yields (37%, 34%, 28%, and 17%, respectively). More functionalized alcohols

Progress and challenges in the synthesis of sequence controlled polysaccharides

• Giulio Fittolani,
• Theodore Tyrikos-Ergas,
• Denisa Vargová,
• Manishkumar A. Chaube and
• Martina Delbianco

Beilstein J. Org. Chem. 2021, 17, 1981–2025, doi:10.3762/bjoc.17.129

• for new strategies to provide anchimeric assistance, without affecting the nucleophilicity of the hydroxy group at C-3. β(1–6)-Glucans The formation of the β(1–6)-glycosidic bond poses less synthetic challenges than the β(1–3) bond. The primary C-6 hydroxy group is more nucleophilic than the secondary

• reported, the construction of multiple α-linkages remains challenging, in particular with the increasing size of the acceptor. The nucleophilic additive glycosylation-based approach (Scheme 5A) offers the opportunity to install multiple 1,2-cis glycosidic bonds by converting the glycosyl donor 30 into a

• diminished with the increasing length of the oligosaccharide, possibly due to steric hindrance [180]. The nucleophilic modulation strategy in combination with the O-6-Lev remote anchimeric assistance could further improve the stereoselectivity of the 1,2-cis glycosylations, leading to the synthesis of long

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

• electrophilic and nucleophilic α-functionalizations are possible, whereas with the use of α,β-unsaturated aldehydes the β-position is functionalized with nucleophiles and the γ-position with electrophiles. In this sense, Jørgensen and colleagues have developed the first organocatalytic asymmetric Michael

• nucleophilic addition of the hydroxycoumarin. The procedure allowed obtaining products 34 with excellent yields and enantiomeric excesses (Scheme 11). Zhu et al. described the asymmetric Michael addition of substituted 4-hydroxycoumarins (1) to cyclic enones 36, using an in situ formed organocatalyst [44]. The

• described an allylic alkylation reaction between 3-cyano-4-methylcoumarins 39 and Morita–Baylis–Hillman (MBH) carbonates 40 [45]. In this case, the catalyst (DHQ)2PYR 42 activates the MBH substrate and generates the dienolate in the vinylogous coumarin moiety, acting as a base. After the nucleophilic

Regioselective N-alkylation of the 1H-indazole scaffold; ring substituent and N-alkylating reagent effects on regioisomeric distribution

• Ryan M. Alam and
• John J. Keating

Beilstein J. Org. Chem. 2021, 17, 1939–1951, doi:10.3762/bjoc.17.127

• followed by the nucleophilic substitution of alkylating reagent R2–X to selectively give the desired N-1 regioisomer 68. It is likely that a mixture of the solvent-separated ion pairs 65 and 66 predominate, when using polar solvents such as DMF [24]. Furthermore, precluding tight ion pair formation through

On the application of 3d metals for C–H activation toward bioactive compounds: The key step for the synthesis of silver bullets

• Renato L. Carvalho,
• Amanda S. de Miranda,
• Mateus P. Nunes,
• Roberto S. Gomes,
• Guilherme A. M. Jardim and
• Eufrânio N. da Silva Júnior

Beilstein J. Org. Chem. 2021, 17, 1849–1938, doi:10.3762/bjoc.17.126

• by vanadium to give iminium ions, followed by a nucleophilic attack of the heteroaromatic ring, have been suggested for most reactions. Evidence comes from the observed regioselectivity and the tolerance of the reactions to radical scavengers, which are in accordance with the occurrence of a

• ′-bipyrrolidine) controls the site- and chemoselectivity in the hydroxylating step of the methylene C(sp3)–H bond while milder oxidation conditions help to increase the chemoselectivity. The methylation step is accomplished using a modestly nucleophilic organoaluminium reagent (AlMe3) to activate the hemiaminal

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

• useful electrophilic or radical fluorinating agents by virtue of their easy handling, efficiency, and selectivity. These non-hygroscopic nature and stability make them easier to handle than nucleophilic fluoride reagents. Potassium fluoride (KF) and naked fluoride anion salts are extremely sensitive to

• that the fluorinations with 1-1 were suppressed by the formation of perfluoro-3,4,5,6-tetrahydropyridine (1-5), which was reactive to the nucleophilic substrates existing in the reaction mixture. In 1986, Banks and co-worker reported the preparation of polymeric analogues of perfluoro-N

• pyridine (10% F2/N2) at low temperature in a freon solvent, could undergo straightforward counteranion replacement with a non-nucleophilic anion. Therefore, exchange with salts such as sodium triflate in acetonitrile generated non-hygroscopic N-fluoropyridinium triflate salts as highly thermally stable

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

• demanding the exclusion of oxygen. This issue can be mitigated by using triarylphosphines that are by far less prone to oxidation. Both, the rate of oxidation and the reactivity in nucleophilic additions correlate with the electron density residing on the phosphorous center [11][12][13]. Accordingly

• 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

• prepared with nucleophilic catalysis using 10 mol % N-heterocyclic carbenes such as 1,3,4-triphenyl-4,5-dihydro-1H-1,2,4-triazol-5-ylidene or 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene. The polymerization was carried out at room temperature for 24 h and no solvent was used. The resulting reaction

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

• corresponding triazole products in moderate yield (Scheme 8) [42]. The authors proposed a reaction mechanism in which the β-thioenaminone 18 tolerates deprotonation to afford anionic intermediate 21 through the tautomer 20 in the presence of a base. In the next step, the nucleophilic addition of 21 to the azide

• attacks the Cu(III) intermediate 87, formed via the reaction between diaryl diselenide 84 and the bimetallic complex [L2Cu]2I2. Next, the produced intermediate 88 undergoes a reductive elimination to achieve intermediate 89 with regeneration of the Cu complex [L2Cu]2I2. Then, nucleophilic attack of the

• -carboxamides. The reaction includes oxidative addition of 5-iodo-1,2,3-triazole 117 to a Pd center to achieve the intermediate 120. The intermediate 121 is formed via coordination and insertion of CO to intermediate 120. Then, the intermediate 122 is obtained via a nucleophilic attack of amine 118. Finally, a

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

• as precursors of nucleophilic radical species in metal hydride hydrogen atom transfer reactions. This unique reactivity, combined with the wide availability of olefins as starting materials and the success reported in the construction of all-carbon C(sp3) quaternary centers, makes hydroalkylation

• expense of the olefin double bond. Review Olefin activation by transition metals Transition metals can act as π-acid catalysts in olefin double bond activation, as they weaken the alkene double bond through coordination to allow a nucleophilic attack on the sp2 carbon to form an alkylmetal intermediate

• than Pd(II)-catalytic types have also been explored. Pd(II)-catalyzed hydroalkylation reactions The σ-alkylpalladium species formed after a carbon nucleophilic attack on an alkene double bond (Scheme 1) have a marked tendency to undergo a hydride β-elimination process that leads to oxidative coupling

One-step synthesis of imidazoles from Asmic (anisylsulfanylmethyl isocyanide)

• Louis G. Mueller,
• Allen Chao,
• Embarek AlWedi and
• Fraser F. Fleming

Beilstein J. Org. Chem. 2021, 17, 1499–1502, doi:10.3762/bjoc.17.106

• contain an adjacent electron withdrawing group (1, R1 = EWG) [13]. Installation of an electron withdrawing group adjacent to an isocyanide facilitates the deprotonation but creates weak nucleophiles 2 that are insufficiently nucleophilic to react with nitriles [14]. Described below is the use of Asmic

Cascade intramolecular Prins/Friedel–Crafts cyclization for the synthesis of 4-aryltetralin-2-ols and 5-aryltetrahydro-5H-benzo[7]annulen-7-ols

• Jie Zheng,
• Shuyu Meng and
• Quanrui Wang

Beilstein J. Org. Chem. 2021, 17, 1481–1489, doi:10.3762/bjoc.17.104

• ratio = 79:21) in 70% yield (Scheme 9). With regard to the partial epimerization of product 21, it may be due to the action of pyridine. In the preparation of compound 21, pyridine is used both as solvent and the acid acceptor. Because pyridine itself can show nucleophilic reactivity in addition to

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

• substituted pyrrole-2-aldehydes to 5-azaindole transformation during a base-catalyzed imination reaction [31]. However, we envisioned that our methodology might be strategically applied towards the synthesis of substituted γ-carbolines as a C-3 nucleophilic attack is more favored in indoles than in pyrroles

• were formed that were still insufficient for complete characterization. Intending to improve the yield of 3aa, we screened various solvents, non-nucleophilic organic bases such as triethylamine and DBU, and several inorganic bases like K2CO3, Cs2CO3, and NaH (Table 1, entries 2–6). After systematic

• 5, which undergoes nucleophilic addition with another molecule of aldehyde 1 to furnish the iminoalcohol intermediate 6. The iminoalcohol 6 undergoes dehydration under the reaction conditions to give E-imine/Z-enamine 7a or Z-imine/E-enamine 7c intermediates irreversibly, which plays a decisive role

Organocatalytic asymmetric Michael/acyl transfer reaction between α-nitroketones and 4-arylidenepyrrolidine-2,3-diones

• Chandrakanta Parida and
• Subhas Chandra Pan

Beilstein J. Org. Chem. 2021, 17, 1447–1452, doi:10.3762/bjoc.17.100

• -nitroketones have been found to be a popular nucleophilic acyl transfer reagent. In 2011, three research groups namely Wang, Yan and Kwong independently revealed the organocatalytic asymmetric conjugate addition of α-nitroketones to β,γ-unsaturated α-keto esters with the concomitant acyl transfer reaction to

Double-headed nucleosides: Synthesis and applications

• Vineet Verma,
• Jyotirmoy Maity,
• Vipin K. Maikhuri,
• Ritika Sharma,
• Himal K. Ganguly and
• Ashok K. Prasad

Beilstein J. Org. Chem. 2021, 17, 1392–1439, doi:10.3762/bjoc.17.98

• ′-ketonucloside 1 with trimethylsulfoxonium iodide in DMSO afforded the spironucleoside 2, which in turn was converted to the TIPDS-protected 2′-(pyrimidin-1-yl)methyl-/2′-(purin-9-yl)methylarabinofuranosyluracil derivatives 3a–f by nucleophilic epoxide ring opening with thymine, N-benzoyladenine, 6-O-allyl-N

• ]. Nielsen and co-workers [42] additionally synthesized 2′-(N-benzoylcytosin-1-yl)methylarabinofuranosyl-N-benzoylcytosine (7) from uridine using a similar methodology. Thus, the nucleophilic epoxide ring opening in spironucleoside 2 with uracil in DMF in a N1-regioselective manner afforded the TIPDS

• the nucleophilic opening of O-2,2′-anhydrouridine [44]. The azido nucleoside 12 was reacted with N6-benzoyl-N9-propargyladenine (13a) and N1-propargylthymine (13b) via a CuAAC reaction where the triazole-containing linker connected the additional thymine or adenine to the 2′-position of 2

Fritsch–Buttenberg–Wiechell rearrangement of magnesium alkylidene carbenoids leading to the formation of alkynes

• Tsutomu Kimura,
• Koto Sekiguchi,
• Akane Ando and
• Aki Imafuji

Beilstein J. Org. Chem. 2021, 17, 1352–1359, doi:10.3762/bjoc.17.94

• -tolyl sulfoxides 2, 5–7 and 1-unsubstituted sulfoxide 8 were prepared from carbonyl compounds 1 (Scheme 3). The 2,2-bis(4-methoxyphenyl)-substituted sulfoxides 2a, 5, and 8 were prepared via the nucleophilic addition of [(p-tolylsulfinyl)methyl]lithiums to 4,4'-dimethoxybenzophenone, acylation of the

• ethylmagnesium bromide (Scheme 7c) [16]. The nucleophilic substitution of the halide on the magnesium atom with the carbenoid carbon atom having a halogen substituent is a plausible mechanism for the isomerization. The FBW rearrangement of magnesium alkylidene carbenoids was studied by using DFT calculations

Structural effects of meso-halogenation on porphyrins

• Keith J. Flanagan,
• Maximilian Paradiz Dominguez,
• Zoi Melissari,
• Hans-Georg Eckhardt,
• René M. Williams,
• Dáire Gibbons,
• Caroline Prior,
• Gemma M. Locke,
• Alina Meindl,
• Aoife A. Ryan and
• Mathias O. Senge

Beilstein J. Org. Chem. 2021, 17, 1149–1170, doi:10.3762/bjoc.17.88

• product has been previously reported [56], this appears to be the first instance of the free base counterpart. One such study, using (5,15-bis(4-methylphenyl)porphyrinato)zinc(II), alludes to nucleophilic substitution by Cl to form the chlorinated product, with the only possible source of the exogenous Cl

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

• is, probably, a result of a transamidation reaction upon the treatment with a base, for example, alkoxide anion. The nucleophilic attack of the alkoxide anion leads to the cleavage of the C(7)–N(8) bond to form intermediates B and C followed by the recyclization of the thiazolidine ring involving the

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

• imines derived from tert-butanesulfinamide. These imines are versatile chiral auxiliaries and have been extensively used as eletrophiles in a wide range of reactions. The electron-withdrawing sulfinyl group facilitates the nucleophilic addition of organometallic compounds to the iminic carbon with high

• -containing heterocycles; N-tert-butanesulfinyl imines; Intoduction Chiral imines derived from tert-butanesulfinamide have been extensively used as electrophiles in a wide range of reactions. The presence of the chiral electron-withdrawing sulfinyl group facilitates the nucleophilic addition of

• Re-face of the imine (Scheme 4) [1][36]. The nucleophilic addition reactions to N-tert-butanesulfinyl imines were also described by Ellman and co-workers who reported the addition of allylmagnesium bromide to ketimines. The employment of Grignard reagents showed greater diastereoselectivity than

Synthesis of multiply fluorinated N-acetyl-D-glucosamine and D-galactosamine analogs via the corresponding deoxyfluorinated glucosazide and galactosazide phenyl thioglycosides

• Vojtěch Hamala,
• Lucie Červenková Šťastná,
• Martin Kurfiřt,
• Petra Cuřínová,
• Martin Dračínský and
• Jindřich Karban

Beilstein J. Org. Chem. 2021, 17, 1086–1095, doi:10.3762/bjoc.17.85

• thioglycosides prepared from deoxyfluorinated 1,6-anhydro-2-azido-β-ᴅ-hexopyranose precursors by ring-opening reaction with phenyl trimethylsilyl sulfide. Nucleophilic deoxyfluorination at C4 and C6 by reaction with DAST, thioglycoside hydrolysis and azide/acetamide transformation completed the synthesis

• biomedical applications due to their ability to inhibit the glycan and glycosaminoglycan biosynthesis [34][35][36][37]. The fluorine substituent has typically been introduced into these GlcNAc and GalNAc analogues using nucleophilic fluorination. The primary position (C6 hydroxy group) was fluorinated by

• DAST [22][25][26][30][35], or reaction of C3/C4 methanesulfonate or trifluoromethanesulfonate esters with a source of nucleophilic fluorine, such as TBAF or KF [22][25][34]. Although these fluorinations usually proceeded with inversion of configuration, the acetylated 3-fluoro-GlcNAc analogue was most

Synthetic accesses to biguanide compounds

• Oleksandr Grytsai,
• Cyril Ronco and
• Rachid Benhida

Beilstein J. Org. Chem. 2021, 17, 1001–1040, doi:10.3762/bjoc.17.82

• nucleophilic amines, which led to undesired side reactions on the terminal amine of the cyanoguanidine. This issue was partly solved by using TMSCl to activate the nitrile function of the cyanoguanidine, along with shortening the reaction times to 10 min. Recently, this approach was used under classical

• , Mayer et al., did not observe the condensation and reported the formation of the corresponding N1-arylbiguanide with 74% yield (Scheme 13B) [24]. Similarly to anthranilic acid, Shestakov et al. reported the reaction of 2-mercaptobenzoic acid, which was nucleophilic enough to undergo the

Synthesis of 10-O-aryl-substituted berberine derivatives by Chan–Evans–Lam coupling and investigation of their DNA-binding properties

• Peter Jonas Wickhorst,
• Mathilda Blachnik,
• Denisa Lagumdzija and
• Heiko Ihmels

Beilstein J. Org. Chem. 2021, 17, 991–1000, doi:10.3762/bjoc.17.81

• strands [30]. Due to their straightforward synthetic accessibility by substitution at the 9-hydroxy functionality of berberrubine (1b), 9-O-substituted berberine derivatives are particularly attractive. But so far, only functionalization at this position by alkylation [23][24][25][26] and nucleophilic

Application of the Meerwein reaction of 1,4-benzoquinone to a metal-free synthesis of benzofuropyridine analogues

• Rashmi Singh,
• Tomas Horsten,
• Rashmi Prakash,
• Swapan Dey and
• Wim Dehaen

Beilstein J. Org. Chem. 2021, 17, 977–982, doi:10.3762/bjoc.17.79

• to hydroquinone 12 with N,N-diethylhydroxylamine (N,N-DEHA) and cyclized via intramolecular nucleophilic aromatic substitution to isolate 6-hydroxybenzofuro[2,3-b]pyridine (13) with 82% yield. Conveniently, the synthesis of 13 was achieved in a one-pot reaction from 11 with no significant differences

Metal-free glycosylation with glycosyl fluorides in liquid SO₂

• Krista Gulbe,
• Jevgeņija Lugiņina,
• Edijs Jansons,
• Artis Kinens and
• Māris Turks

Beilstein J. Org. Chem. 2021, 17, 964–976, doi:10.3762/bjoc.17.78

• conclusion that the Lewis basic carbonyl oxygen of the acetyl group is more coordinated and less nucleophilic in liquid SO2 than the carbonyl oxygen of the pivaloyl group. The profile of side-products in this glucose series was similar to that observed for fluoride β-9 (see Supporting Information File 1

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

• an intimate ion pair 51. The proximal addition of a bromide ion to 51 produces axial adduct 56 exclusively. However, when SnBr4 is used as a Lewis acid, oxocarbenium ion 52 is formed via 50. The counterion SnBr4− being much less nucleophilic than the Br− ion allows the formation of a solvent

• . Formation of the oxocarbenium ion 289, followed by an intramolecular nucleophilic attack by the alkynyl bond on the cyclopropane unit gave cyclic oxocarbenium intermediate 290. Further, the attack of a halide anion (from TiX4) leads to the Prins cyclization to give bishalogenated bicyclic THP with all-cis

• activation via DDQ oxidation, followed by nucleophilic attack of an unactivated olefin to obtain all-cis-trisubstituted Prins products with high stereochemical precision [111]. A single-electron transfer (SET) mechanism was proposed for the above transformation (Scheme 69). A SET from an arene or alkene to

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 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

• electrostatic interaction between carboxylate and iminium moieties undergoes a nucleophilic attack by isocyanide to generate nitrilium ion B. The intramolecular acylation of B forms C followed by Mumm rearrangement results in the formation of the desired products 22. The intermediate D may exist in equilibrium

• -methyl-2H-pyran-2-one and arylglyoxal to form intermediate A. Michael addition of amine to intermediate A gives B which further undergoes an intramolecular nucleophilic addition reaction to yield C which on cyclization and with subsequent loss of water from D produce the desired products 34. Meshram and