Electron-deficient pyridinium salts/thiourea cooperative catalyzed O-glycosylation via activation of O-glycosyl trichloroacetimidate donors

• Mukta Shaw,
• Yogesh Kumar,
• Rima Thakur and
• Amit Kumar

Beilstein J. Org. Chem. 2017, 13, 2385–2395, doi:10.3762/bjoc.13.236

• presence of Schreiner′s thiourea in the reaction medium enhances the acidity of the ammonium salt due to doubling their dual hydrogen bonding ability with the carboxylate and the alkoxy group of the ammonium salt. A thiourea derivative also enhances the nucleophilicity of the glycosyl acceptor by imparting

• -CO2Me of 3a (Figure 3d). Also, the magnification of the nucleophilicity of the glycosyl acceptor by the thiourea derivative results in shifting of the -OH peak from δ 2.70 to δ 3.62 (Figure 3d). Once this understanding was gained from 1H NMR studies, aryl thiourea cocatalyst 4 (10 mol %) was added with

Dialkyl dicyanofumarates and dicyanomaleates as versatile building blocks for synthetic organic chemistry and mechanistic studies

• Grzegorz Mlostoń and
• Heinz Heimgartner

Beilstein J. Org. Chem. 2017, 13, 2235–2251, doi:10.3762/bjoc.13.221

• β-aminoalcohols. The different nucleophilicity of the NH2 and OH groups determines the sequence of the reaction steps. In the reported cases, the initially formed N-(β-hydroxyalkyl)enamines 79 undergo spontaneous lactonization with the geminal alkoxycarbonyl group leading to the six-membered

Regiodivergent condensation of 5-alkoxycarbonyl-1H-pyrrol-2,3-diones with cyclic ketazinones en route to spirocyclic scaffolds

• Alexey Yu. Dubovtsev,
• Maksim V. Dmitriev,
• Аndrey N. Maslivets and
• Michael Rubin

Beilstein J. Org. Chem. 2017, 13, 2179–2185, doi:10.3762/bjoc.13.218

• -membered ring of intermediate 11 (Scheme 3). Although the reasons for such divergence in the reactivity are not completely understood, one could argue that the lower nucleophilicity of enolates derived from 8 as compared to that of enamine 1a could be responsible for this effect. Indeed in this case, the

• formation of the indoline ring was unambiguously confirmed by the crystal structure of compound 21ab (CCDC 1546063, Figure 2). It seems that the nucleophilicity of the hydrazine moiety prevailed, and the formation of the thermodynamically more favorable amide bond governed the overall direction of this

• transformation. It should be also taken into account that, unlike the aforementioned hydrazone structures 15 and 16, ketazinones appear to be more stable in keto-enamine form 17. We reasoned that the nucleophilicity of the ketazinone moiety can be substantially reduced via incorporation of excessive steric bulk

Preactivation-based chemoselective glycosylations: A powerful strategy for oligosaccharide assembly

• Weizhun Yang,
• Bo Yang,
• Sherif Ramadan and
• Xuefei Huang

Beilstein J. Org. Chem. 2017, 13, 2094–2114, doi:10.3762/bjoc.13.207

• glycosyl hemiacetal 33 with one of its hydroxy groups free available as the acceptor producing disaccharide 34. The regioselectivity is presumably due to the higher nucleophilicity of the alkyl hydroxy group than that of the hemiacetal hydroxy group. This process can be repeated for chain elongation

• utilized to glycosylate iduronic acid 55, disaccharide 56 was obtained only in 31% yield along with aglycon transfer products, 57 (19%) and 58 (24%). The modest yield of the desired glycoside product resulted from the lower nucleophilicity of 4-OH as compared to the thioethyl moiety, which could compete

• nucleophilicity of the thiophenyl moiety due to the steric as well as electronegative effects of the phenyl group. The hemiacetal donor 49 glycosylated the thiophenyl glucuronate acceptor 50 in an excellent 91% yield using the preactivation protocol (Scheme 11c). The successful preparation of disaccharides 61 and

High-speed vibration-milling-promoted synthesis of symmetrical frameworks containing two or three pyrrole units

• Marco Leonardi,
• Mercedes Villacampa and
• J. Carlos Menéndez

Beilstein J. Org. Chem. 2017, 13, 1957–1962, doi:10.3762/bjoc.13.190

• ), piperazine (1i,j) or tetramethyldisiloxane (1k–o) fragments, was also feasible. Interestingly, the use of N1-(2-aminoethyl)ethane-1,2-diamine as the starting material was also possible, without interference from the secondary amino group in spite of its nucleophilicity, to give compound 1h. This kind of

One-pot multistep mechanochemical synthesis of fluorinated pyrazolones

• Joseph L. Howard,
• William Nicholson,
• Yerbol Sagatov and
• Duncan L. Browne

Beilstein J. Org. Chem. 2017, 13, 1950–1956, doi:10.3762/bjoc.13.189

• the hydrazine is slow, meaning that the nucleophilicity is greatly retarded compared to lower acid loadings. Nonetheless, considering that the subsequent fluorination step should proceed optimally under basic conditions [17], the lowest amount of acid which also provided a good yield was thus chosen

Influence of the milling parameters on the nucleophilic substitution reaction of activated β-cyclodextrins

• László Jicsinszky,
• Kata Tuza,
• Giancarlo Cravotto,
• Andrea Porcheddu,
• Francesco Delogu and
• Evelina Colacino

Beilstein J. Org. Chem. 2017, 13, 1893–1899, doi:10.3762/bjoc.13.184

• , ZrO2 gave the best performances in reactions involving TU (Supporting Information File 1, Table S1, entries 16 and 17). Thus, NaN3 seemingly displayed stronger nucleophilicity than TU when stainless steel milling tools were utilized and vice versa for ZrO2 milling tools. In another set of experiments

Enzymatic synthesis of glycosides: from natural O- and N-glycosides to rare C- and S-glycosides

• Jihen Ati,
• Pierre Lafite and
• Richard Daniellou

Beilstein J. Org. Chem. 2017, 13, 1857–1865, doi:10.3762/bjoc.13.180

• sugar during GT-catalysed reactions, GTs are also classified as inverting or retaining (Figure 1). Inverting GTs operate via a SN2 mechanism in a single displacement step where an acid/base residue enhances the nucleophilicity of the acceptor, via an oxocarbenium-like transition state. Unlike inverting

Mechanochemical synthesis of thioureas, ureas and guanidines

• Vjekoslav Štrukil

Beilstein J. Org. Chem. 2017, 13, 1828–1849, doi:10.3762/bjoc.13.178

• -withdrawing group in the amine (lower nucleophilicity) and an electron-donating group in the isothiocyanate component (lower electrophilicity) led to prolonged grinding times necessary to achieve quantitative conversion. The reaction time in these cases was successfully reduced by LAG, providing N,N

• under ball-milling conditions by using two equivalents of sodium hydroxide. Deprotonation of the N–H group increased the nucleophilicity of the nitrogen atoms, enabling the nucleophilic displacement reaction with two equivalents of 4-bromobenzyl bromide to yield di(4-bromobenzyl)urea 34 in 41%, after a

• total of 34 hours of milling (Scheme 13b). This transformation showed that ball milling could potentially be applied to increase the nucleophilicity of an otherwise poorly reactive compound. In the course of our studies on mechanochemical desymmetrization, we also investigated the reaction of o-pda and

NHC-catalyzed cleavage of vicinal diketones and triketones followed by insertion of enones and ynones

• Ken Takaki,
• Makoto Hino,
• Akira Ohno,
• Kimihiro Komeyama,
• Hiroto Yoshida and
• Hiroshi Fukuoka

Beilstein J. Org. Chem. 2017, 13, 1816–1822, doi:10.3762/bjoc.13.176

• to 83% in the equimolar reaction of 9 with 3. In addition, the product 10 was recovered unchanged after treatment with 6a irrespective of DIPEA. The nucleophilicity of 10 may be canceled by the two benzoyl groups. The product 10 was fairly stable to air and moisture, and thus E-structure was

• -triketones reacted with NHCs to afford bisacylated Breslow intermediates in high yield. However, their nucleophilicity was so weak that they were recovered unchanged in the reaction with enones. It was also found that the monoacylated Breslow intermediates changed reversibly to the resting state of acid

Syntheses of 3,4- and 1,4-dihydroquinazolines from 2-aminobenzylamine

• Jimena E. Díaz,
• Silvia Ranieri,
• Nadia Gruber and
• Liliana R. Orelli

Beilstein J. Org. Chem. 2017, 13, 1470–1477, doi:10.3762/bjoc.13.145

• different nucleophilicity of both amino groups, the predictable formation of a hydrogen bond between the aromatic amino group (hydrogen bond donor) and the aliphatic NHR (hydrogen bond acceptor) could increase the nucleophilicity of the former and decrease the reactivity of the latter, favoring the chance

Switchable highly regioselective synthesis of 3,4-dihydroquinoxalin-2(1H)ones from o-phenylenediamines and aroylpyruvates

• Juraj Dobiaš,
• Marek Ondruš,
• Gabriela Addová and
• Andrej Boháč

Beilstein J. Org. Chem. 2017, 13, 1350–1360, doi:10.3762/bjoc.13.132

• consumption of 11a–c (Table 1, entries 1–3, column 6) was good (75–100%), but insufficient for 11d–f (22–50%, Table 1, entries 4–6, column 6). Our explanation for the low conversions is a diminished amine nucleophilicity in the EWG-substituted dianilines 11d–f and reduced electrophilicity of the 12a due to a

• cycloadditions performed by p-TsOH (Table 1, column 4). From the above experimental results, we have proved that the regioselectivity of the cyclocondensation depends on both (a) the different nucleophilicity of the two amines from o-phenylenediamines 11a–f and (b) the electrophilicity of the α-carbonyl in 12a

• shifted H-N(1) and H-C(8), whereby coupling of HC(5 and 8) depends on type of the regioisomer). It was proved that observed regioselectivity of performed cyclocondensations depends on both a/ the different nucleophilicity of amine groups in diamine 11 (with two clusters of substituents: EDGs + halogens

Strategies toward protecting group-free glycosylation through selective activation of the anomeric center

• A. Michael Downey and
• Michal Hocek

Beilstein J. Org. Chem. 2017, 13, 1239–1279, doi:10.3762/bjoc.13.123

• reaction. Removal of the OH groups at positions C2 of Glc, C1′and C3′-Fru resulted in no conversion at all. The authors demonstrated that not only these deoxygenations change the hydrogen-bonding network but also have a very large effect on the overall nucleophilicity of the disaccharide and its

Substitution of fluorine in M[C₆F₅BF₃] with organolithium compounds: distinctions between O- and N-nucleophiles

• Anton Yu. Shabalin,
• Nicolay Yu. Adonin and
• Vadim V. Bardin

Beilstein J. Org. Chem. 2017, 13, 703–713, doi:10.3762/bjoc.13.69

• PhC≡CLi is a consequence of the low nucleophilicity of PhC≡CLi. For instance, C6F6 and C6F5C6F5 do not react with PhC≡CLi in ether, although the addition of a coordinating solvent (DME, diglyme [39], THF [40]) accelerates nucleophilic substitution. C6F5CH3 bearing the non-electron-withdrawing

Transition-metal-catalyzed synthesis of phenols and aryl thiols

• Yajun Liu,
• Shasha Liu and
• Yan Xiao

Beilstein J. Org. Chem. 2017, 13, 589–611, doi:10.3762/bjoc.13.58

• chemical properties, such as acidity and nucleophilicity, and thus to some extent, the synthetic methods could be developed analogously to each other. In this context, it is valuable to compare their existing synthetic methods for better understanding, so as to inspire organic chemists to invent new

Studies directed toward the exploitation of vicinal diols in the synthesis of (+)-nebivolol intermediates

• Runjun Devi and
• Sajal Kumar Das

Beilstein J. Org. Chem. 2017, 13, 571–578, doi:10.3762/bjoc.13.56

• nucleophilic attack of the phenolic hydroxy group; instead it reacted with water during the work-up process. This different outcome of this reaction compared to Borhan’s results might be attributed to the lower nucleophilicity of phenols compared to alcohols. Previously, Panda and co-worker converted

Continuous N-alkylation reactions of amino alcohols using γ-Al₂O₃ and supercritical CO₂: unexpected formation of cyclic ureas and urethanes by reaction with CO₂

• Emilia S. Streng,
• Darren S. Lee,
• Michael W. George and
• Martyn Poliakoff

Beilstein J. Org. Chem. 2017, 13, 329–337, doi:10.3762/bjoc.13.36

• expected to produce high selectivity for the corresponding imidazolidinone 16 via the incorporation of CO2. The competing oxazolidinone formation should be limited as the nucleophilicity of nitrogen is more than that of the oxygen. Furthermore, the formation of dimers were expected to be supressed as 16

Regiochemistry of cyclocondensation reactions in the synthesis of polyazaheterocycles

• Patrick T. Campos,
• Leticia V. Rodrigues,
• Andrei L. Belladona,
• Caroline R. Bender,
• Juliana S. Bitencurt,
• Fernanda A. Rosa,
• Davi F. Back,
• Helio G. Bonacorso,
• Nilo Zanatta,
• Clarissa P. Frizzo and
• Marcos A. P. Martins

Beilstein J. Org. Chem. 2017, 13, 257–266, doi:10.3762/bjoc.13.29

• be a reason for the decrease in the N1 nucleophilicity. Nevertheless, the HOMO coefficient values found for the substituted 1,2-phenylenediamine were lower than those found for 1,2-phenylenediamine (8d) without a substituent. Similarly, for 8b smaller HOMO coefficients are obtained than for the

Total synthesis of a Streptococcus pneumoniae serotype 12F CPS repeating unit hexasaccharide

• Peter H. Seeberger,
• Claney L. Pereira and
• Subramanian Govindan

Beilstein J. Org. Chem. 2017, 13, 164–173, doi:10.3762/bjoc.13.19

• the repeating unit hexasaccharide 1 was envisioned. The union of trisaccharides 2 and 3 (Scheme 1, route A) was identified as the key step. The outcome of this late-stage block coupling was deemed risky considering the poor nucleophilicity of the C4 hydroxy group of the β-mannosazide in 3 combined

• ether protecting group 38 was recovered. The undesired outcome of this coupling step likely resulted from the poor nucleophilicity of 3 rather than a lack of reactivity of trisaccharide glycosylating agent 2, as demonstrated by an experiment in which model monosaccharide 37 [29] also failed to react

• protected mannosazide 4 was successfully glycosylated using building blocks 5 or 37 to yield the corresponding disaccharide in 21% and 37% yield, respectively. The failure of the [3 + 3] coupling to produce hexasaccharide 36 was apparently a result of the poor nucleophilicity of the C4 hydroxy group in 3

Chemical probes for competitive profiling of the quorum sensing signal synthase PqsD of Pseudomonas aeruginosa

• Michaela Prothiwa,
• Dávid Szamosvári,
• Sandra Glasmacher and
• Thomas Böttcher

Beilstein J. Org. Chem. 2016, 12, 2784–2792, doi:10.3762/bjoc.12.277

• findings are surprising, as all three reactive groups are known to bind to cysteines which indicate a fine-tuned nucleophilic reactivity of the active site cysteine Cys112. The fine-tuned nucleophilicity towards our probes is supported by calculations of a mechanistic model where Cys112 is activated by

Enzymatic synthesis and phosphorolysis of 4(2)-thioxo- and 6(5)-azapyrimidine nucleosides by E. coli nucleoside phosphorylases

• Vladimir A. Stepchenko,
• Anatoly I. Miroshnikov,
• Frank Seela and
• Igor A. Mikhailopulo

Beilstein J. Org. Chem. 2016, 12, 2588–2601, doi:10.3762/bjoc.12.254

• possible to overcome the barrier of 9 kcal/mol required to activate the substrate. At the same time, the corresponding sp2 structures 8b and 8c are characterized by the highest partial charges of the N-1 atoms (−0.202/−0.214 e) reflecting the nucleophilicity of these atoms that attack the electrophilic C-1

• satisfactorily. On the contrary, UP is not able to catalyze the nucleophilic attack of the structure 8c of 2SaThy owing probably to the lower nucleophilicity of the N-1 nitrogen atom (−0.109 e) compared to 2SUra for which the partial charge of −0.146 e of the N-1 atom was calculated (Table 1). With respect to E

Thiazol-4-one derivatives from the reaction of monosubstituted thioureas with maleimides: structures and factors determining the selectivity and tautomeric equilibrium in solution

• Alena S. Pankova,
• Pavel R. Golubev,
• Alexander F. Khlebnikov,
• Alexander Yu. Ivanov and
• Mikhail A. Kuznetsov

Beilstein J. Org. Chem. 2016, 12, 2563–2569, doi:10.3762/bjoc.12.251

• sets of insufficiently resolved signals of other protons. The presence of two forms follows from the 13C NMR spectra as well. Taking into account the differences in nucleophilicity between the unsubstituted and phenyl-substituted nitrogen atoms of thiourea 1a, the phenyl group in compounds 3a,b is more

• had no effect on the regioselectivity of the addition to maleimide 2 forming thiazolidines 3h–k (Table 1). Although alkyl groups generally increase the nucleophilicity of the adjacent nitrogen atom as compared to the unsubstituted one, the methyl-substituted thiazoldine 3k having the methyl group

• (ratio 4k:3k after 2 h was 1:0.9, after 4 h it changed to 1:2.4). Whereas the formation of the isomer 4k corresponds to the relative nucleophilicity of the nitrogen atoms of thiourea 1f, the isomer 3k seems to be more thermodynamically stable. The choice of the solvent turned out to be crucial for the

Methylenelactide: vinyl polymerization and spatial reactivity effects

• Judita Britner and
• Helmut Ritter

Beilstein J. Org. Chem. 2016, 12, 2378–2389, doi:10.3762/bjoc.12.232

• attack of the thiol takes place. This can be clearly seen in the 1H NMR spectra (Figures S18 and S19, Supporting Information File 1). Thioacetic acid was used as a potential chain-transfer agent due to its lower nucleophilicity. However, a complete thiol-Michael addition can be seen in Figure 8 (not full

Efficient mechanochemical synthesis of regioselective persubstituted cyclodextrins

• Laszlo Jicsinszky,
• Marina Caporaso,
• Katia Martina,
• Emanuela Calcio Gaudino and
• Giancarlo Cravotto

Beilstein J. Org. Chem. 2016, 12, 2364–2371, doi:10.3762/bjoc.12.230

• per-6-halogenated CDs. The preparation is also carried out in a polar aprotic solvent, as in case of the azide exchange, while byproducts may also be similar despite the higher nucleophilicity of sulfur. The reaction under classic conditions usually requires large TU excess. Various per-6-alkylthio-β

Isosorbide and dimethyl carbonate: a green match

• Fabio Aricò and
• Pietro Tundo

Beilstein J. Org. Chem. 2016, 12, 2256–2266, doi:10.3762/bjoc.12.218

• with the presence of four oxygen atoms all in β position to each other that enhance the nucleophilicity of the hydroxy groups. Conclusion Among the top chemical opportunities from biorefinery carbohydrates D-sorbitol is a platform chemical of considerable interest that has led to intensive research in

• base. This result was ascribed to the neighbouring effect of the oxygen situated all in β-position to each other that most probably enhances the nucleophilicity of the corresponding hydroxy group. Furthermore the amphoteric catalyst hydrotalcite was extremely efficient in the synthesis of DMI when