Constrained thermoresponsive polymers – new insights into fundamentals and applications

• Patricia Flemming,
• Alexander S. Münch,
• Andreas Fery and
• Petra Uhlmann

Beilstein J. Org. Chem. 2021, 17, 2123–2163, doi:10.3762/bjoc.17.138

• , the developed GA-polyHMPA initially exhibits UCST responsiveness, but can subsequently be slowly biodegraded to a fully water-soluble polymer (polyHMPA) via hydrolysis. Initial in vivo studies of a sustained release of either a hydrophilic model protein or a hydrophobic dye entrapped within the

Catalyzed and uncatalyzed procedures for the syntheses of isomeric covalent multi-indolyl hetero non-metallides: an account

• Ranadeep Talukdar

Beilstein J. Org. Chem. 2021, 17, 2102–2122, doi:10.3762/bjoc.17.137

• Buchwald amination led to the 4-amino-substituted compounds 158 or acids 159 after basic hydrolysis (Scheme 21) [108]. Compound 159c had the maximum potency against IDO1 and TDO with IC50 values of 2.72 mM and 3.48 mM, respectively compared to 159a and 159b, which is 15 and 28.5 times higher than that of

• -mediated coupling of N-silylated 6-hydroxyindole 174 with the corresponding boronic acid 173 (Scheme 24) [114]. For further synthetic transformations of 175, N-protection with bromo esters 176 followed by hydrolysis towards acids 177a and 177b were performed. The products 177a and 177b are potent anti-HIV

An initiator- and catalyst-free hydrogel coating process for 3D printed medical-grade poly(ε-caprolactone)

• Jochen Löblein,
• Thomas Lorson,
• Miriam Komma,
• Tobias Kielholz,
• Maike Windbergs,
• Paul D. Dalton and
• Robert Luxenhofer

Beilstein J. Org. Chem. 2021, 17, 2095–2101, doi:10.3762/bjoc.17.136

• improved by a variety of methods like plasma treatment, NaOH hydrolysis treatment or a micro deposition system. This study outlines a potential approach to coat medical-grade PCL with a thin hydrogel that requires no initiator or catalyst – just a deoxygenated aqueous monomer solution and UV light. We

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

• led to lower but still useful yields (3ak, 41%; 3bl, 44%; 3bm, 51%). In all these cases, the hydrolysis step delivered the expected SMAHOs in good to excellent yields. However, this reaction should be performed in a water/alcohol mixture, this latter being the same as the ester substituent to avoid

• efficiency, this second strategy required an additional step of hydrolysis of a substituted malonate to prepare the requisite substituted malonic acid. Monoesterification route In order to take advantage of the preparation of substituted malonates 3, we decided to explore a more straightforward strategy, the

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

• only small modifications, hampering the formation of unnatural polymers. Low glycosylation yields and product hydrolysis represent additional hurdles associated with enzymatic synthesis of polysaccharides [23]. With this approach, homopolymers are often obtained as non-uniform samples, because the

• yields (2–5%). This approach circumvented the precipitation of the water-insoluble oligomers and allowed for chain elongation [72][73]. This methodology was improved employing a protic co-catalyst system to yield DP > 120 in a 26% conversion [74]. Generally, an acid catalyst would promote the hydrolysis

• differences in the conformational behavior of the two analogues (β(1–3) vs β(1–4) oligomers), it was observed that the β(1–3)-mimetic was still recognized by wheat germ agglutinin and a chitinase enzyme, and could act as a moderate inhibitor of chitin hydrolysis [268]. Mannose- and rhamnose-based

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

• -methoxybenzaldehyde imine derivatives with phenyl Grignard reagents as coupling partners. As the catalyst CrCl2 is used and either 2,3-dichlorobutane (DCB) or 1,2-dichloropropane (DCP) are used as oxidant to give 2,5-diarylbenzaldehyde after imine hydrolysis (Scheme 16B). Although benzaldehyde is a basic structure

Cationic oligonucleotide derivatives and conjugates: A favorable approach for enhanced DNA and RNA targeting oligonucleotides

• Mathias B. Danielsen and
• Jesper Wengel

Beilstein J. Org. Chem. 2021, 17, 1828–1848, doi:10.3762/bjoc.17.125

• stability was observed relative to their unmodified ON [113][114]. Interestingly, a difference in hydrolysis rate was noticed: the aminomethyl (69) modification was readily hydrolysed at pH 7 whereas the aminoethyl (70) modification was completely stable under the same conditions [114]. A preliminary cell

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

• the faster hydrolysis of the in situ generated imine intermediates, aromatic aldehydes containing electron-withdrawing substituents afforded no product in the reaction. It was proved that a variety of aliphatic primary amines can efficiently produce the triazole products (Scheme 14) [45]. This one-pot

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

• hydroalkylation reactions of less activated substrates [31]. Later studies demonstrated that the true reason for the reaction success was not the putative in situ formation of silyl enol ethers but the HCl formation due to TMSCl hydrolysis. The HCl catalyzed the formation of the enolic form responsible for the

• nucleophilic attack on the metal-complexed olefin (see Scheme 3, intermediate A). Taking advantage of HCl as an additive (or generated in situ by silyl chloride hydrolysis), Widenhoefer described the intramolecular hydroalkylation of even less reactive alkenyl ketones 4 under Pd(II) catalysis, with minor

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

• pathway involves electrophilic addition para to the phenol to form the ipso-substituted nitro 12 compound. Subsequent rearrangement of the nitro species 12 to the nitrito dienone 13, by homolysis and recombination of the radical pair, is followed by hydrolysis to furnish alcohol 6 [70]. Addition of the

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

• hydrolysis using 18% aq HCl furnishing the corresponding aldehyde [21]. Without purification, the resultant aldehyde intermediate was then directly reduced using potassium borohydride to the corresponding primary alcohol 11a in 74% yield starting from 9a. Pd-catalyzed cross-coupling of 11a with pinacol

Total synthesis of ent-pavettamine

• Memory Zimuwandeyi,
• Manuel A. Fernandes,
• Amanda L. Rousseau and
• Moira L. Bode

Beilstein J. Org. Chem. 2021, 17, 1440–1446, doi:10.3762/bjoc.17.99

• , followed by hydrolysis with solid K2CO3 and water for 30 min (Scheme 5). The desired aldehyde 18 was recovered in an excellent yield of 99%, and product epimerization was not detected based on 13C NMR spectroscopic analysis. This was confirmed by analysis of the 13C chemical shifts of the acetonide group

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

• reaction of 3,5-di-tert-butyl-1,2-benzoquinone with 5′-amino-5′-deoxy-2′,3′-O-isopropylideneuridine (67) and 5′-amino-2′,5′-dideoxyadenosine (70). The unprotected double-headed nucleoside (R)-N1-(4-(4,6-di-tert-butylbenzoxazol-2-yl)-β-ᴅ-erythrofuranosyl)uracil (69) was obtained by acidic hydrolysis of the

• nucleoside 5′-(R)-C-(thymin-1-ylmethyl)-3′-O-(tert-butyldimethylsilyl)thymidine (108) was synthesized by treating the double-headed nucleoside 107 with triflic anhydride followed by basic hydrolysis (Scheme 24) [31]. Subsequently, the double-headed nucleoside 107 was incorporated into oligonucleotides [31

Icilio Guareschi and his amazing “1897 reaction”

• Gian Cesare Tron,
• Alberto Minassi,
• Giovanni Sorba,
• Mara Fausone and
• Giovanni Appendino

Beilstein J. Org. Chem. 2021, 17, 1335–1351, doi:10.3762/bjoc.17.93

• amine, affording a 6-aminopyridone, which, after acidic treatment, is turned into the same β,β-disubstituted glutarate formed by hydrolysis of the pyridone from the type-IV Guareschi reaction. This modification of the type-IV Guareschi reaction is the “real” Guareschi–Thorpe reaction, which in many

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

• as a chiral auxiliary which was then removed by hydrolysis in the final step of the overall seven-step synthesis. Deprotonation of 41 using LiHMDS in THF in a primary reactor was performed at −40 °C and telescoped into a second reactor along with a stream containing the trityl-protected aldehyde, 42

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

• 40% KOH aqueous solution resulted in a skeletal rearrangement of the tricyclic system, which, however, was accompanied by reesterification with methanol and partial hydrolysis of the ester group. As a result, the methyl ester 5a was obtained in 66% yield (Scheme 3). Rearrangement of 1,3-dimethyl- and

• 1,3-diethylimidazo[4,5-e]thiazolo[3,2-b]triazines 4a,b,h,i upon treatment with an equivalent amount of triethylamine in corresponding alcohols proceeded without hydrolysis of ester groups and led to the formation of the corresponding regioisomeric derivatives 5a,b,h,i (Scheme 4). The isomerization of

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

• trimethylsilyl cyanide (TMSCN) in THF at −10 °C. The reaction product 142 was obtained in quantitative yield and good diastereomeric ratio. Further hydrolysis of the cyclic acetal, and subsequent epoxidation of the resulting diol under typical Mitsunobu conditions led to epoxide derivative 143. The piperidine

• ring was formed through a 6-endo-tet cyclization by treatment of the epoxide 143 with sodium carbonate in toluene at 80 °C. Hydrolysis of the cyano group under acidic conditions of compound 144 led to expected ʟ-hydroxypipecolic acid hydrochloride 145 in high yield (Scheme 39) [129]. In 2018, Wei and

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

• convenient because thioglucosides 15 and 18 (vide infra) were available for deoxyfluorination only as enriched anomeric mixtures α/β ≥ 3.3:1 and any traces of the migration products were removed in the subsequent thioaglycone hydrolysis. Thioglycosides 14–17 and 19 were also O6-benzylated [40] to

• thioacetic acid [54][55]. Hence, the hemiacetals were reacted with thioacetic acid in pyridine to give acetamides 49–58 (Scheme 5) and the target trifluoro analogs 59 and 60. Reversing the order of hemiacetal and acetamide formation was not an option because NBS-promoted hydrolysis of 2-acetamido

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

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

• presence of strong aqueous acids (>1 M) or alkali (>1 M), is required to observe an appreciable degradation accompanied in many cases by urea or biuret as the hydrolysis products. The compounds are also relatively resistant to many classical reducing and oxidizing agents [2]. However, very strong oxidants

• benzoxazoles might be explained by the subsequent hydrolysis of this relatively fragile ring under the strongly acidic aqueous conditions. Recently, a protocol using a Lewis acid (AlCl3) as an activating agent of the cyanoguanidine in dry THF allowed improving the yields up to 70% (Scheme 11B) [32]. Related

• efficiency for simple substrates, like the synthesis of 1-mexyl-5-phenylbiguanides described by Lebel et al. (Scheme 16A) [46]. However, the presence of hydrolysis sensitive functions like esters usually leads to an understandable drop in yields (Scheme 16B) [47]. A microwave-assisted version of this

Stereoselective synthesis and transformation of pinane-based 2-amino-1,3-diols

• Ákos Bajtel,
• Mounir Raji,
• Matti Haukka,
• Ferenc Fülöp and
• Zsolt Szakonyi

Beilstein J. Org. Chem. 2021, 17, 983–990, doi:10.3762/bjoc.17.80

• NMR and X-ray spectroscopic techniques. The regioisomeric spiro-oxazolidin-2-one was prepared in a similar way starting from the commercially available (1R)-(−)-myrtenol (10). The reduction or alkaline hydrolysis of the oxazolidines, followed by reductive alkylation resulted in primary and secondary 2

• transformations of pinane-based 2-amino-1,3-diols To obtain a library of pinane-based 2-amino-1,3-diols, the oxazolidine-2-ones 9 and 12 were applied as starting materials. The alkaline hydrolysis of both 9 and 12 resulted in the same primary aminodiol 13 [38]. According to the NMR spectra and other physical and

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

• mannosyl fluoride α-1a was achieved and the desired O-mannoside 3a was isolated in a high yield and α-selectivity. Hemiacetal α-4 was isolated as the only side-product formed via glycosyl donor hydrolysis with the water present in commercial SO2 [62]. To note, at lower temperatures (Table 1, entry 1) no

• various side-reactions. A series of side-products formed by hydrolysis and protecting group migrations were detected and their structures are proposed (see Supporting Information File 1). Next, glycosyl fluorides α-11 and α-12 containing more acid-sensitive acetyl protecting groups were applied for the

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

• presence of the mild Lewis acid InCl3 and benzaldehyde (88), which produced all-cis-tetrahydropyran-4-one 90 in excellent yield. The transformation proceeded through cyclization of a diequatorial chair-like conformation of the oxocarbenium ion 89 to provide an N-acyliminium ion, which upon hydrolysis

Kinetics of enzyme-catalysed desymmetrisation of prochiral substrates: product enantiomeric excess is not always constant

• Peter J. Halling

Beilstein J. Org. Chem. 2021, 17, 873–884, doi:10.3762/bjoc.17.73

• -pong second (ketone amination, diol esterification, desymmetrisation in the second half reaction); ping-pong first (diol ester hydrolysis) and ping-pong both (prochiral diacids). For plausible values of enzyme kinetic parameters, the product enantiomeric excess (ee) can decline substantially as the

• are the reduction of prochiral ketones to chiral secondary alcohols, transamination of prochiral ketones to chiral amines, hydrolysis of symmetrical diesters to a chiral monoester, and esterification of prochiral diacids or diols. In desymmetrisation reactions, the enzyme initially produces the two

• prochiral diol esters. The enzyme reacts enantiospecifically with the ester to release a chiral product, leaving the acyl group attached to the active site. In a second stage the achiral acyl group undergoes hydrolysis by water. In the desymmetrisation of diols (and diacids, below) kinetic amplification can

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

• solvent to successfully furnish 5,6-disubstituted pyrrolo[2,3-d]pyrimidine-2,4-diones 89. Similarly, excellent yields were obtained when the thiol was replaced by malononitrile (51) even in the absence of catalyst or any promoter. The malononitrile undergoes hydrolysis forming an amide, thus giving rise