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

Synthesis of bis(aryloxy)fluoromethanes using a heterodihalocarbene strategy

• Carl Recsei and
• Yaniv Barda

Beilstein J. Org. Chem. 2021, 17, 813–818, doi:10.3762/bjoc.17.70

• (difluoromethoxy)arenes, while the reaction with dichlorocarbene gives salicylaldehydes via hydrolysis of an ortho-dichloromethylphenol: the Reimer–Tiemann reaction. The literature, other than this single reference with pentafluorophenol [6], is bereft of references to the capture of heterodihalocarbenes by phenol

• highly oxidizing and alkaline conditions in the synthesis of 1. We decided to probe the stability of this moiety to acidic conditions. Compound 11 proved to have considerable stability to acidic hydrolysis, suffering only 33% hydrolysis upon stirring in 2 M HCl/MeOH/1,2-dichloroethane 1:4:1 at 35 °C for

• 5 h, with 85% hydrolysis observed after 20 hours. The relative stability of 11 to acidic hydrolysis and its presumably enhanced lipophilicity with respect to a des-fluoro acetal, might presage a role for compounds possessing the acyclic bis(aryloxy)fluoromethane moiety in medicinal or agrochemical

Chiral isothiourea-catalyzed kinetic resolution of 4-hydroxy[2.2]paracyclophane

• David Weinzierl and
• Mario Waser

Beilstein J. Org. Chem. 2021, 17, 800–804, doi:10.3762/bjoc.17.68

• transformation into diastereomers by esterification with chiral acid chlorides [19][20] as well as the kinetic resolution (KR) of racemic esters of 2 via an enzymatic hydrolysis [25][26][27] were very successfully used to access enantioenriched 2. Recently, Akiyama and co-workers reported the kinetic resolution

Synthetic reactions driven by electron-donor–acceptor (EDA) complexes

• Zhonglie Yang,
• Yutong Liu,
• Kun Cao,
• Xiaobin Zhang,
• Hezhong Jiang and
• Jiahong Li

Beilstein J. Org. Chem. 2021, 17, 771–799, doi:10.3762/bjoc.17.67

• ; moreover, 53 and 54 can be mutually transformed. Excited state 53 reacts with diene 49, forming a double radical intermediate 55 that subsequently evolves to cyclobutyliminium ion 56, and then product 50 is provided after hydrolysis, along with the release of diamine 51. In 2020, Zhang and colleagues [25

Synthesis of dibenzosuberenone-based novel polycyclic π-conjugated dihydropyridazines, pyridazines and pyrroles

• Ramazan Koçak and
• Arif Daştan

Beilstein J. Org. Chem. 2021, 17, 719–729, doi:10.3762/bjoc.17.61

• pyrrole and acetate structures. The acetate is formed by reducing the carbonyl group to alcohol and then reacting this alcohol with acetic acid. After hydrolysis of the acetate group with sodium hydroxide, alcohol derivate 10bb was formed. Oxidation of alcohol 10bb with MnO2 led to the formation of the

β-Lactamase inhibition profile of new amidine-substituted diazabicyclooctanes

• Zafar Iqbal,
• Lijuan Zhai,
• Yuanyu Gao,
• Dong Tang,
• Xueqin Ma,
• Jinbo Ji,
• Jian Sun,
• Jingwen Ji,
• Yuanbai Liu,
• Rui Jiang,
• Yangxiu Mu,
• Lili He,
• Haikang Yang and
• Zhixiang Yang

Beilstein J. Org. Chem. 2021, 17, 711–718, doi:10.3762/bjoc.17.60

• compounds 11 and 12, respectively, in two steps. In the first step, the ester derivatives were N-acylated by acetic anhydride in CH2Cl2 followed by hydrolysis using aqueous NaOH in THF to afford the required intermediates 3 and 4 in overall good yields. Compound 5 was obtained by direct acylation of the

Stereoselective syntheses of 3-aminocyclooctanetriols and halocyclooctanetriols

• Emine Salamci and
• Yunus Zozik

Beilstein J. Org. Chem. 2021, 17, 705–710, doi:10.3762/bjoc.17.59

• prepared by epoxidation of the cyclooctenediol with m-chloroperbenzoic acid followed by hydrolysis with HBr(g) in methanol. Treatment of bromotriol with NaN3 and the reduction of the azide group yielded the other desired 3-aminocyclooctanetriol. Hydrolysis of the epoxides with HCl(g) in methanol gave

• cyclic sulfate 9 in 95% yield. The cyclic sulfate moiety in 9 was reacted with sodium azide in DMF at 80 °C followed by acidic hydrolysis of the resulting acyclic sulfate ester to give azidotriol 10 as a single stereoisomer in 97% yield (Scheme 2). For further structural proof, the azidotriol 10 was

[2 + 1] Cycloaddition reactions of fullerene C₆₀ based on diazo compounds

• Yuliya N. Biglova

Beilstein J. Org. Chem. 2021, 17, 630–670, doi:10.3762/bjoc.17.55

• with a covalently attached fullerene molecule [86]. To this end, adduct 13 was obtained from 4-(tert-butoxycarbonyl)phenyldiazomethane and fullerene. Subsequent acid hydrolysis of the protective ester group quantitatively gave a derivative of carboxylic acid 14, a versatile synthon for the synthesis of

• formed. In fact, a series of spirocyclopentalydenemethanofullerenes 190–193 were obtained by the reaction of C60 with lithium salts of tosylhydrazone (Scheme 34) [154]. Spiromethanofullerene 194 was prepared on the basis of monoethylene glycol tosylhydrazone. Hydrolysis of the former resulted in 6,6

Valorisation of plastic waste via metal-catalysed depolymerisation

• Francesca Liguori,
• Carmen Moreno-Marrodán and
• Pierluigi Barbaro

Beilstein J. Org. Chem. 2021, 17, 589–621, doi:10.3762/bjoc.17.53

• (a solvent is the reagent and solvolyses include hydrolysis, glycolysis, alcoholysis and aminolysis) and hydrogenolysis reactions (H2 as reagent). Hydrolysis (sometimes called hydrocracking) is in between thermochemical and chemolytic processing, basically consisting of depolymerisation by the

• developed, using a solvent or molecular hydrogen as cleaving agents [81]. The main solvolytic process include: hydrolysis (water) alcoholysis (methanol, ethanol, 1-butanol, 2-ethyl-1-hexanol, phenol) glycolysis (ethylene glycol (EG), 1,2-propanediol (PD), 1,3- and 1,4-butanediol (BD)), diethylene glycol

• (DEG), dipropylene glycol (DPG)) aminolysis (2-aminoethanol, 3-amino-1-propanol, ethylenediamine). Advantages of catalytic processes are obvious and can be witnessed in the hydrolysis and the glycolysis reactions of poly(ethylene terephthalate) (PET) [82][83]. Representative data are reported in

Breakdown of 3-(allylsulfonio)propanoates in bacteria from the Roseobacter group yields garlic oil constituents

• Anuj Kumar Chhalodia and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2021, 17, 569–580, doi:10.3762/bjoc.17.51

• from 9, followed by a series of proposed spontaneous reactions [5][8]. Through these transformations, acid 10 can undergo a dimerization with elimination of water to allicin (5). The hydrolysis of 5 results in allylsulfinic acid (12) and allyl thiol (13), the latter of which can react with another

• giving another example for the complex interactions between marine bacteria and algae. Known DMSP degradation pathways include its hydrolysis to dimethyl sulfide (DMS) and 3-hydroxypropanoic acid (15) by the enzyme DddD [19], or the lysis to DMS and acrylic acid (16) for which various enzymes including

• collapses to methanethiol (MeSH) and malonyl-CoA semialdehyde (21). This compound further degrades to acetaldehyde (22) through the thioester hydrolysis and decarboxylation [27]. Feeding of (methyl-2H6)DMSP to Phaeobacter inhibens DSM 17395 and Ruegeria pomeroyi DSM 15171 resulted in the efficient uptake of

Menthyl esterification allows chiral resolution for the synthesis of artificial glutamate analogs

• Kenji Morokuma,
• Shuntaro Tsukamoto,
• Kyosuke Mori,
• Kei Miyako,
• Ryuichi Sakai,
• Raku Irie and
• Masato Oikawa

Beilstein J. Org. Chem. 2021, 17, 540–550, doi:10.3762/bjoc.17.48

• ], the heterotricyclic framework was constructed over a five-step sequence including the domino metathesis reaction as a key step to give (rac)-7. The subsequent three steps from (rac)-7 (esterification with CH2N2, PMB removal, and ester hydrolysis) had been proven to be promising for the preparation of

• in small molecules and biomacromolecule due to intermolecular or intramolecular H-bonds and/or hydrophobic interactions [13]. Hydrolytic deprotections were finally examined to complete the synthesis. The previously employed alkaline hydrolysis (1 M aq LiOH, MeOH or THF, rt→45 °C) [4], however, gave

• hand, (2S)-MC-27 (4*) was synthesized in a reasonable yield (62%) by acidic hydrolysis (Scheme 4). The chromatographic behavior and the spectroscopic data (1H and 13C NMR) of (2S)-MC-27 (4*) thus synthesized were identical to those of the antipode 4 (see above as well as Scheme 3 and Scheme 4

Synthetic strategies of phosphonodepsipeptides

• Jiaxi Xu

Beilstein J. Org. Chem. 2021, 17, 461–484, doi:10.3762/bjoc.17.41

• and selective hydrolysis. Synthesis of α-phosphonodepsipeptides In 1987, a series of phosphonodepsidipeptides 10 was synthesized as phosphorus analogues of peptides and evaluated as inhibitors of leucine aminopeptidase from porcine kidney and two compounds, i.e., 10e and 10h (R = isobutyl, benzyl

• ) were modest inhibitors. The synthesis started from diphenyl N-Cbz-1-aminoalkylphosphonates 11 (Scheme 1). They were transformed to dimethyl esters via transesterification and further to monomethyl esters 12 via basic hydrolysis. After chlorination with thionyl chloride, the monomethyl esters 12 were

• methyl N-Cbz-protected 1-aminoethylphosphonochloridate 13b with methyl ᴅ-lactate (22a) and methyl mercaptoacetate (22b), respectively, followed by a basic hydrolysis and hydrogenolysis. The bioassay results indicated that the phosphonothiodepsidipeptide 20b did not inhibit VanX (Scheme 3) [21]. It was

Biochemistry of fluoroprolines: the prospect of making fluorine a bioelement

• Vladimir Kubyshkin,
• Rebecca Davis and
• Nediljko Budisa

Beilstein J. Org. Chem. 2021, 17, 439–460, doi:10.3762/bjoc.17.40

• (Figure 10B). If the mRNA codon matches the anticodon of the tRNAPro, GTP undergoes hydrolysis, allowing the elongation factor Tu to leave the complex. This event is followed by the peptidyl transfer reaction, which forms a new peptide bond. Subsequently, the ribosome binds the elongation factor G

• carrying a molecule of GTP, the hydrolysis of which leads to a translocation event in which the empty tRNA leaves and peptidyl-tRNA moves to the P-site. The A-site remains empty, allowing the next ternary complexes to bind in response to the next codon in the mRNA sequence [84]. The translational

Synthesis of trifluoromethyl ketones by nucleophilic trifluoromethylation of esters under a fluoroform/KHMDS/triglyme system

• Yamato Fujihira,
• Yumeng Liang,
• Makoto Ono,
• Kazuki Hirano,
• Takumi Kagawa and
• Norio Shibata

Beilstein J. Org. Chem. 2021, 17, 431–438, doi:10.3762/bjoc.17.39

• examined [46]. Trifluoromethyl ketones (TFMKs) are valuable fluorine-containing synthetic targets of bioactive compounds [55][56] that behave as mimics of the tetrahedral transition-state intermediate of enzymatic hydrolysis of esters and amides by stabilizing their hydrates (Figure 1a) [57]. In fact, the

• . Trifluoromethyl ketones. a) Hydrolysis of trifluoromethyl ketones. b) Selected examples of biologically active trifluoromethyl ketones. Chemistry of the CF3 anion generated from HCF3. a) Decomposition of the trifluoromethyl anion to difluorocarbene and fluoride. b) A hemiaminaloate adduct of CF3 anion to DMF. c

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

• mass spectra of A) unlabeled 2-(methyldisulfanyl)benzothiazole (41) and of labeled 41 after feeding of B) (methyl-2H3)methionine, C) (methyl-13C)methionine and D) (34S)DMSP. Sulfur metabolism in bacteria from the roseobacter group. A) DMSP demethylation by DmdABCD, B) DMSP hydrolysis by DddP and lysis

1,2,3-Triazoles as leaving groups: S_NAr reactions of 2,6-bistriazolylpurines with O- and C-nucleophiles

• Dace Cīrule,
• Irina Novosjolova,
• Ērika Bizdēna and
• Māris Turks

Beilstein J. Org. Chem. 2021, 17, 410–419, doi:10.3762/bjoc.17.37

• 4a. Also hydrolysis of 2c into 4b proceeded under mild conditions and only gentle warming to 50 °C was required. 2,6-Bistriazolylpurine derivatives in SNAr reactions with C-nucleophiles Next, SNAr reactions between 2,6-bistriazolylpurine 2c and C-nucleophiles offered an easy way for the C–N bond

• yield of compound 5d was obtained due to the ethyl ester hydrolysis and subsequent decarboxylation. Such side reactions were also observed for similar compounds in literature [79][80]. As a limitation of the method we have found that 2,6-bistriazolylpurine 2c was inert to SNAr reactions with