The LANCA three-component reaction to highly substituted β-ketoenamides – versatile intermediates for the synthesis of functionalized pyridine, pyrimidine, oxazole and quinoxaline derivatives

• Tilman Lechel,
• Roopender Kumar,
• Mrinal K. Bera,
• Reinhold Zimmer and
• Hans-Ulrich Reissig

Beilstein J. Org. Chem. 2019, 15, 655–678, doi:10.3762/bjoc.15.61

• are not directly accessible [44]. In contrast, products that are formally derived from 3-aryl-substituted alkoxyallenes can smoothly be prepared from the corresponding alkyl propargyl ethers E (Scheme 7). Their deprotonation with n-butyllithium proceeds with a proton shift delivering the intermediate

• purified and characterized or, for further transformations, the crude products are directly converted into the corresponding nonaflates by deprotonation with sodium hydride and treatment with 1-nonafluorobutanesulfonyl fluoride (NfF). Scheme 13 shows two examples, PM52 and PM54 that are ready for palladium

Intramolecular cascade annulation triggered by rhodium(III)-catalyzed sequential C(sp²)–H activation and C(sp³)–H amination

• Liangliang Song,
• Guilong Tian,
• Johan Van der Eycken and
• Erik V. Van der Eycken

Beilstein J. Org. Chem. 2019, 15, 571–576, doi:10.3762/bjoc.15.52

• intermediate G, which could be oxidized by O2 to regenerate the catalyst. In the minor pathway (path b), intermediate D undergoes protonation by acetic acid to give product 2a, which undergoes deprotonation to form intermediate D again, then following the main pathway to give product 3a. Conclusion In summary

Synthesis and selected transformations of 2-unsubstituted 1-(adamantyloxy)imidazole 3-oxides: straightforward access to non-symmetric 1,3-dialkoxyimidazolium salts

• Grzegorz Mlostoń,
• Małgorzata Celeda,
• Katarzyna Urbaniak,
• Marcin Jasiński,
• Vladyslav Bakhonsky,
• Peter R. Schreiner and
• Heinz Heimgartner

Beilstein J. Org. Chem. 2019, 15, 497–505, doi:10.3762/bjoc.15.43

• . Deprotonation of the latter with triethylamine in the presence of elemental sulfur allows the in situ generation of the corresponding imidazol-2-ylidene, which traps elemental sulfur yielding a 1,3-dihydro-2H-imidazole-2-thione as the final product. Keywords: alkoxyamines; imidazole N-oxides; imidazolium salts

• -tetramethylcyclobutane-1,3-dione. Imidazolium salts are of special importance as they are widely used as ionic liquids or precursors of imidazole-based nucleophilic carbenes (imidazol-2-ylidenes). For example, deprotonation of 1,3-diadamantylimidazolium chloride led to the first stable imidazol-2-ylidene (the so-called

• (5) atoms appeared at 6.69 ppm, and in the 13C NMR spectrum, the C(4) and C(5) atoms gave only one signal localized at 114.6 ppm. Apparently, deprotonation of the imidazolium cation results in the formation of the nucleophilic imidazol-2-ylidene 16, which in situ reacts with elemental sulfur

Study on the regioselectivity of the N-ethylation reaction of N-benzyl-4-oxo-1,4-dihydroquinoline-3-carboxamide

• Pedro N. Batalha,
• Luana da S. M. Forezi,
• Maria Clara R. Freitas,
• Nathalia M. de C. Tolentino,
• Ednilsom Orestes,
• José Walkimar de M. Carneiro,
• Fernanda da C. S. Boechat and
• Maria Cecília B. V. de Souza

Beilstein J. Org. Chem. 2019, 15, 388–400, doi:10.3762/bjoc.15.35

• comparative analysis of the possible reaction paths. Acidity of the N–H units A first possibility to rationalize the reactivity of carboxamide 5 was its deprotonation to produce a nucleophilic species which would then attack the bromoethane to produce the derivatives 7 or 11. Therefore, we considered the

• deprotonation of both the oxoquinoline core and the carboxamide N–H sites, followed by the alkylation of the respective anion 8a and 8b, providing two possible products 7 and 11, from which the results obtained could be compared (Scheme 3). The acidity of both carboxamide and oxoquinoline N–H sites were

• results, only equilibrium I, referring to the deprotonation of the oxoquinoline N–H presented negative values of ΔH and ΔG in all cases, characterizing the reaction as an exothermic one and favorable to the formation of the respective conjugate base, under such conditions. Deprotonation of the carboxamide

Sigmatropic rearrangements of cyclopropenylcarbinol derivatives. Access to diversely substituted alkylidenecyclopropanes

• Guillaume Ernouf,
• Jean-Louis Brayer,
• Christophe Meyer and
• Janine Cossy

Beilstein J. Org. Chem. 2019, 15, 333–350, doi:10.3762/bjoc.15.29

• , presumably because of competitive deprotonation at C4. A phenyl substituent was incompatible at C4 as the corresponding substrate 65j decomposed upon treatment with KHMDS/Me3SiCl. This was explained by a competitive abstraction of the hydrogen at C4 by the base thereby resulting in side reactions. However

Oxidative radical ring-opening/cyclization of cyclopropane derivatives

• Yu Liu,
• Qiao-Lin Wang,
• Zan Chen,
• Cong-Shan Zhou,
• Bi-Quan Xiong,
• Pan-Liang Zhang,
• Chang-An Yang and
• Quan Zhou

Beilstein J. Org. Chem. 2019, 15, 256–278, doi:10.3762/bjoc.15.23

• of MCPs 1 formed the more stable benzyl radical intermediate 5 [45][46], which underwent a ring-opening to generate the alkyl radical 6 [47]. Finally, the desired product 3 was generated through intramolecular cyclization of radical intermediate 6 with an aryl ring and oxidation deprotonation by

• . Finally, the intermediate 136 underwent oxidation and deprotonation to give the desired product 132. In this year, Melchiorre’s group reported the ring-opening and [3 + 2]-annulation of cyclopropanols 91 with α,β-unsaturated aldehydes 138 for the synthesis of stereochemically dense cyclopentanols 139 with

Computational characterization of enzyme-bound thiamin diphosphate reveals a surprisingly stable tricyclic state: implications for catalysis

• Ferran Planas,
• Michael J. McLeish and
• Fahmi Himo

Beilstein J. Org. Chem. 2019, 15, 145–159, doi:10.3762/bjoc.15.15

• + state. With only one known exception [7], the protonation/deprotonation of the N1′ position is performed by a highly conserved glutamic acid residue that is thought to stabilize the imino tautomer IP [6]. The subsequent loss of a proton from N4′ of APH+ gives the IP state. Deprotonation of the C2

• position results in the ylide form which can be either protonated (YIH+) or deprotonated (YI) at the N1′ position. The C2 deprotonation is believed to be performed by the N4′ nitrogen [2][8][9], and is assisted by the cofactor being held in a “V” conformation in which the imino group is located within a

• formation of ylide was dependent on deprotonation of N1′ and, consistent with experimental findings, deprotonation was, in turn, likely dependent on conformational changes induced by the presence of substrate [22]. More recently, the relative stabilities of a number of the ThDP states (AP, APH+, IP and YI

N-Arylphenothiazines as strong donors for photoredox catalysis – pushing the frontiers of nucleophilic addition of alcohols to alkenes

• Fabienne Speck,
• David Rombach and
• Hans-Achim Wagenknecht

Beilstein J. Org. Chem. 2019, 15, 52–59, doi:10.3762/bjoc.15.5

• attacked by methanol as nucleophile and finally deprotonation gives rise to the product 17 (see Figure 4). The principal problem of this type of photoredox catalytic cycle is that the back-electron transfer cannot compete with the initial electron transfer because both components, 1+· and 13−·, are formed

A simple and effective preparation of quercetin pentamethyl ether from quercetin

• Jin Tatsuzaki,
• Tomohiko Ohwada,
• Yuko Otani,
• Reiko Inagi and
• Tsutomu Ishikawa

Beilstein J. Org. Chem. 2018, 14, 3112–3121, doi:10.3762/bjoc.14.291

• by deprotonation of a single OH group of quercetin (2) were calculated. The deprotonation is an endothermic process in this calculation model. The most stable anion was derived from the OH group at 7 position (7-anion 2A), which is stabilized by the conjugation with the carbonyl group at 4 position

• Although we focused on the deprotonation energy of quercetin (2), the deprotonation energy of each OH group may change with the progress of methylation. Figure 5 compares the deprotonation energies during generation of 5-anion 2A from neutral quercetin 2A, and 5-anion 4A from neutral 3,7,3',4

• deprotonation energy in the case of neutral 3,7,3',4'-tetramethylquercetin (4). This result is consistent with the experimental observation of the difficulty of methylation of the OH group at 5 position, as exemplified by the formation of 4 in some of the per-O-methylation trials (see Table 2). On C-methylation

Mn-mediated sequential three-component domino Knoevenagel/cyclization/Michael addition/oxidative cyclization reaction towards annulated imidazo[1,2-a]pyridines

• Olga A. Storozhenko,
• Alexey A. Festa,
• Delphine R. Bella Ndoutoume,
• Alexander V. Aksenov,
• Alexey V. Varlamov and
• Leonid G. Voskressensky

Beilstein J. Org. Chem. 2018, 14, 3078–3087, doi:10.3762/bjoc.14.287

• . Subsequent treatment of the reaction mixture with nucleophile, oxidant and a base leads to the Michael addition on C(4) of the chromene ring to produce 2-aminochromene B with incorporated nucleophilic moiety. Further cyclization and deprotonation furnishes anion C, which is easily oxidized to final product 5

Nucleofugal behavior of a β-shielded α-cyanovinyl carbanion

• Rudolf Knorr and
• Barbara Schmidt

Beilstein J. Org. Chem. 2018, 14, 3018–3024, doi:10.3762/bjoc.14.281

• carbonyl addition; shielded acrylonitrile; Introduction A carbanionic fragment shows nucleofugal behavior on breaking its single-bond connection with a developing electrophilic center. Apart from deprotonation reactions or formation of a separated ion pair and other trivial examples, the (at least

• Scheme 1). For this purpose, A1M1 should be demetalated through work-up to give, for instance, the alcohol A1H; the subsequent deprotonation of A1H by an M2-containing base BM2 must be complete before the generated alkoxide A1M2 begins to release C–M2 that would otherwise be protonated by any unconsumed

• ) and (c) with the focus on some nucleofugal traits of the carbanion unit of the stable [4], β-shielded α-metalated acrylonitriles. Results and Discussion The α-cyanoalkenyllithium 2Li (top line of Scheme 2) may be prepared [4] either by LDA-mediated deprotonation (LDA = iPr2NLi) of the β-shielded

Reactions of 3-(p-substituted-phenyl)-5-chloromethyl-1,2,4-oxadiazoles with KCN leading to acetonitriles and alkanes via a non-reductive decyanation pathway

• Akın Sağırlı and
• Yaşar Dürüst

Beilstein J. Org. Chem. 2018, 14, 3011–3017, doi:10.3762/bjoc.14.280

• that are generally obtained by the reaction of benzyl halides with appropriate cyanating agents such as KCN [14], TMSCN [15], K4(Fe(CN)6 [16]. Deprotonation of the α-carbon (adjacent to nitrile) by strong bases, especially lithiated ones, resulted in an anionic species that easily undergoes a

Generation of 1,2-oxathiolium ions from (arysulfonyl)- and (arylsulfinyl)allenes in Brønsted acids. NMR and DFT study of these cations and their reactions

• Stanislav V. Lozovskiy,
• Alexander Yu. Ivanov,
• Olesya V. Khoroshilova and
• Aleksander V. Vasilyev

Beilstein J. Org. Chem. 2018, 14, 2897–2906, doi:10.3762/bjoc.14.268

• , leads to their deprotonation with a stereoselective formation of (arysulfonyl)butadienes (for instance, ArSO2–CR1=C–C(Me)=CH2, for R2 = R3 = Me, yields of 87–98%). Reactions of (arysulfonyl)allenes in the system TfOH (0.1 equiv)–HFIP (hexafluoropropan-2-ol) followed by hydrolysis give rise to allyl

• strongly depends on the nucleophilicity of the quenching medium. Under the conditions of low nucleophilic work-up with aqueous HCl (Table 3, entry 4), the deprotonation takes place leading to butadiene Z-3a. The predominant formation of the Z-isomer of 3a may reveal that cation Ba undergoes deprotonation

Synthesis of unnatural α-amino esters using ethyl nitroacetate and condensation or cycloaddition reactions

• Glwadys Gagnot,
• Vincent Hervin,
• Eloi P. Coutant,
• Sarah Desmons,
• Racha Baatallah,
• Victor Monnot and
• Yves L. Janin

Beilstein J. Org. Chem. 2018, 14, 2846–2852, doi:10.3762/bjoc.14.263

• improve this transformation (trials with manganese(III) acetate were not successful either). We then resorted to a different approach to prepare the oxazole-bearing α-amino ester 36 from 2,4,5-trimethyloxazole (33). Deprotonation of this compound was achieved using lithium diisopropylamide (LDA) and this

Synthesis of functionalised β-keto amides by aminoacylation/domino fragmentation of β-enamino amides

• Pavel Yanev and
• Plamen Angelov

Beilstein J. Org. Chem. 2018, 14, 2602–2606, doi:10.3762/bjoc.14.238

• necessitates either a double deprotonation to ambident 1,3-dianions [10] or proper masking of the amide functionality prior to deprotonation [11][12]. Consequently, there are very few published reagents that are synthetically equivalent to primary or secondary amide enolate synthons. With regard to acylation

Synthesis of aryl sulfides via radical–radical cross coupling of electron-rich arenes using visible light photoredox catalysis

• Amrita Das,
• Mitasree Maity,
• Simon Malcherek,
• Burkhard König and
• Julia Rehbein

Beilstein J. Org. Chem. 2018, 14, 2520–2528, doi:10.3762/bjoc.14.228

• photocatalyst and complete the catalytic cycle forming the sulfate dianion 5 and sulfate radical anion 6. The phenyl sulfide radical 2 formed upon homolytic cleavage of diphenyl disulfide adds to the radical cation of the arene to form the unstable cationic intermediate 3. Aromatization by deprotonation leads

Synthesis of a leopolic acid-inspired tetramic acid with antimicrobial activity against multidrug-resistant bacteria

• Luce Mattio,
• Loana Musso,
• Leonardo Scaglioni,
• Andrea Pinto,
• Piera Anna Martino and
• Sabrina Dallavalle

Beilstein J. Org. Chem. 2018, 14, 2482–2487, doi:10.3762/bjoc.14.224

• -alkylation. Moreover, we selected a base containing potassium as a metal cation, which provides a greater electron density to the nucleophilic enolate, thus favouring O-alkylation. Satisfyingly, O-selective alkylation of compound 10 was achieved by deprotonation with KHMDS followed by alkylation with benzyl

Synthesis of eunicellane-type bicycles embedding a 1,3-cyclohexadiene moiety

• Alex Frichert,
• Peter G. Jones and
• Thomas Lindel

Beilstein J. Org. Chem. 2018, 14, 2461–2467, doi:10.3762/bjoc.14.222

• cyanoformate in the presence of DMPU affording an inconsequential 5.6:1 mixture of diastereomers favoring 10 (3J3H-4H 12.2 Hz vs 4.8 Hz, Scheme 1). The cyclohexadiene system of 11 was formed after deprotonation of 10 (LiHMDS) and quenching with triflic anhydride. All compounds carrying the 1,3-cyclohexadiene

One-pot synthesis of epoxides from benzyl alcohols and aldehydes

• Edwin Alfonzo,
• Jesse W. L. Mendoza and
• Aaron B. Beeler

Beilstein J. Org. Chem. 2018, 14, 2308–2312, doi:10.3762/bjoc.14.205

• through in situ generation of sulfonium salts from benzyl alcohols and their subsequent deprotonation for use in Corey–Chaykovsky epoxidation of aldehydes. The generality of the method is exemplified by the synthesis of 34 epoxides that were made from an array of electronically and sterically varied

• essential to control the exotherm caused by the deprotonation. Having established a robust method, we then turned our attention to evaluating the scope of the reaction using three electronically varied benzyl alcohols 1, 4, and 5 (Figure 1) on a preparative scale (3 mmol, 5 mmol, 10 mmol). A range of aryl

The enzymes of microbial nicotine metabolism

• Paul F. Fitzpatrick

Beilstein J. Org. Chem. 2018, 14, 2295–2307, doi:10.3762/bjoc.14.204

• intermediate. Attack of the substrate, activated by deprotonation of a substrate hydroxy group, on the peroxyflavin yields the hydroxylated product after a tautomerization. Two histidyl residues have been proposed to be involved in accepting the substrate proton. The details of further catabolism of 2,3,6

Hydroarylations by cobalt-catalyzed C–H activation

• Rajagopal Santhoshkumar and
• Chien-Hong Cheng

Beilstein J. Org. Chem. 2018, 14, 2266–2288, doi:10.3762/bjoc.14.202

• or a C–H activation with high-valent cobalt to give A2 via deprotonation, followed by migratory insertion and reductive elimination or protonation (Scheme 3). We believe that this review will be helpful to the researchers for their future research on hydroarylation using earth-abundant metal

• tolerance toward a variety of functionalities on arenes as well as alkynes. The isolated cationic cobalt intermediate (C3) and the mechanistic studies strongly indicate that the reaction proceeds through C–H activation via concerted metallation-deprotonation (CMD) to form cobaltacycle C1. Subsequently

Investigation of the electrophilic reactivity of the biologically active marine sesquiterpenoid onchidal and model compounds

• Melissa M. Cadelis and
• Brent R. Copp

Beilstein J. Org. Chem. 2018, 14, 2229–2235, doi:10.3762/bjoc.14.197

• H2O and methanol, respectively. The +198 mu adduct could have arisen via elimination of H2O or methanol from the corresponding adducts, or alternatively, from deprotonation of the anticipated lysozyme-onchidal azafulvenium intermediate. The adduct product distributions were calculated from the

Dynamic light scattering studies of the effects of salts on the diffusivity of cationic and anionic cavitands

• Anthony Wishard and
• Bruce C. Gibb

Beilstein J. Org. Chem. 2018, 14, 2212–2219, doi:10.3762/bjoc.14.195

• -solubilizing group. Although its pKa may not be optimal for deprotonation at neutral or physiological pH, its small size and relatively high free energy of hydration (−373 kJ mol−1) ensure that ion-pairing effects are not strong. This was further confirmed by 1H NMR spectroscopy (Supporting Information File 1

Synthesis and post-functionalization of alternate-linked-meta-para-[2ⁿ.1ⁿ]thiacyclophanes

• Wout De Leger,
• Koen Adriaensen,
• Koen Robeyns,
• Luc Van Meervelt,
• Joice Thomas,
• Björn Meijers,
• Mario Smet and
• Wim Dehaen

Beilstein J. Org. Chem. 2018, 14, 2190–2197, doi:10.3762/bjoc.14.192

• deprotonation of the OH group and subsequent chloride loss of 4 an o-quinoid structure 9 is formed in situ, that quickly reacts with the deprotonated thiol 10 via Michael addition (Scheme 3, route A) [28][29][30]. However, as aromatic thiols at the benzylic position are good leaving groups, conversely β

Cobalt-catalyzed peri-selective alkoxylation of 1-naphthylamine derivatives

• Jiao-Na Han,
• Cong Du,
• Xinju Zhu,
• Zheng-Long Wang,
• Yue Zhu,
• Zhao-Yang Chu,
• Jun-Long Niu and
• Mao-Ping Song

Beilstein J. Org. Chem. 2018, 14, 2090–2097, doi:10.3762/bjoc.14.183

• calculations (DFT) [30][31], the C–H activation most possibly proceeded via a single-electron transfer (SET) path compared to a concerted metalation-deprotonation (CMD) path. Followed by an intermolecular SET process, the cation-radical intermediate A was generated, which coordinates with a CoIII species to

• provide the intermediate B. Subsequently, the transfer of ligand OR from the coordinated CoIII to the naphthalene ring led to the formation of intermediate C. Finally, the alkoxylated product 3aa was released accompanied with the deprotonation and the CoII species was transformed into the CoIII species by