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

• the predictions of enantioselectivities for Pd(TFA)2 complexes of 27 new PyOx-type ligands (for the reaction of 3-methyl-2-cyclohexenone with phenylboronic acid) and 59 new enones (in reactions with phenylboronic acid catalysed by L9/Pd(TFA)2). The calculation performed was related to a transition

• state and included steric and inductive effects. Although this approach may be suitable for predicting theoretically achievable enantioselectivity and is very promising, it is not engineered to predict reactivity. Besides, the reactivity (conversion or yield) depends on the reaction medium which is not

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

• performed on the model reaction α-11 + MeOH → α-13c to elucidate the influence of SO2 on the dissociation of the glycosidic C–F bond [78] (Figure 2). Indeed, it was found that the coordination of the Lewis acidic SO2 to the fluoride (transition state TS-A≠ versus TS-A(SO2)≠) decreases the C–F bond

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

• to give oxocarbenium ion 15, wherefrom two competing transition states, 15a and 15b, can possibly form. In the 6-membered chair-like transition state 15a, there is a 1,3-diaxial interaction between “H” and the substituent R2, while for the other five-membered transition state 15b, there is no such

• cyclization, Scheidt and co-workers introduced a new method to access highly functionalized chiral THP efficiently (Scheme 17) [52]. Furthermore, the possible reaction pathway indicates the formation of oxocarbenium ion 82, followed by C–C bond formation via a chair-like transition state to afford 83 (Scheme

• methyl ricinoleate (127) with various aldehydes to produce 2,3,6-trialkyl-substituted 4-chlorotetrahydropyran 128 with excellent stereocontrol in all-cis-configuration (Scheme 30) [66]. The stereochemical outcome of this cyclization was rationalized by a chair-like transition state to produce

The synthesis of chiral β-naphthyl-β-sulfanyl ketones via enantioselective sulfa-Michael reaction in the presence of a bifunctional cinchona/sulfonamide organocatalyst

• Deniz Tözendemir and
• Cihangir Tanyeli

Beilstein J. Org. Chem. 2021, 17, 494–503, doi:10.3762/bjoc.17.43

• transition state model to explain the origin of the stereoinduction was proposed (Scheme 2), according to the Houk’s Brønsted acid hydrogen bonding model. Guo’s computational work in 2017 on the sulfa-Michael addition of thiols to enones in the presence of cinchona alkaloid-type organocatalysts showed that

• ). The solvent effects on the SMA of the chalcone derivatives and naphthalene-1-thiol are summarized in Figure 2. This behavior might be related to the better stabilization of the transition state of the substrates containing electron-withdrawing substituents or halogen atoms with THF, or vice versa. In

• . Structures of the screened organocatalysts. Comparison of the ee values of SMA in the presence of THF and DCM as solvent. Synthesis of organocatalyst 5. Proposed transition state for the SMA of 1-thionaphthol to trans-chalcones. Catalyst and solvent screening. Further screening results of the model reaction

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

CF₃-substituted carbocations: underexploited intermediates with great potential in modern synthetic chemistry

• Anthony J. Fernandes,
• Armen Panossian,
• Bastien Michelet,
• Agnès Martin-Mingot,
• Frédéric R. Leroux and
• Sébastien Thibaudeau

Beilstein J. Org. Chem. 2021, 17, 343–378, doi:10.3762/bjoc.17.32

• much faster than that of 45f by at least a factor of 10, encouraging the authors to suggest “a transition state resembling 48f in the rate-limiting step”. Sulfurane 53, bearing OC(CF3)3 groups, was also treated with triflic acid, affording dialkylsulfonium species 54 in 91% yield along with perfluoro

• kCH3/kCF3 = 5.4 × 105 was observed, while 85 promoted the Finkelstein reaction (SN2) about 11 times faster than 84 (kCH3/kCF3 = 8.9 × 10−2, Scheme 23). This is the result of a destabilized cationic intermediate in the first case and a stabilized negatively charged transition state in the second. When

Diels–Alder reaction of β-fluoro-β-nitrostyrenes with cyclic dienes

• Savva A. Ponomarev,
• Roman V. Larkovich,
• Alexander S. Aldoshin,
• Andrey A. Tabolin,
• Sema L. Ioffe,
• Jonathan Groß,
• Till Opatz and
• Valentine G. Nenajdenko

Beilstein J. Org. Chem. 2021, 17, 283–292, doi:10.3762/bjoc.17.27

• File 1. The predicted reaction pathways for the formation of the exo- and endo-isomeric norbornene 2h using M062X are displayed in Figure 3. For each isomer one transition state exo-TS and endo-TS was identified. The former transition state is higher in energy and leads to the less exergonic product

• transition state and is more exergonic than the path resulting in the exo-2h isomer. Energies are given in kJ mol−1 and were calculated with M062X/6-311+G(d,p) at 383.15 K in o-xylene (the corresponding B3LYP reaction pathway is not shown). Kinetic curves for the reactions of nitrostyrene 1h with CPD (50–130

Insight into functionalized-macrocycles-guided supramolecular photocatalysis

• Minzan Zuo,
• Krishnasamy Velmurugan,
• Kaiya Wang,
• Xueqi Tian and
• Xiao-Yu Hu

Beilstein J. Org. Chem. 2021, 17, 139–155, doi:10.3762/bjoc.17.15

• advantages of the macrocycles in photocatalysis including: i) substrate selectivity, ii) controllability of the rate of photochemical reactions, iii) the close proximity to substrates in a confined space, iv) the generation of a stabilized high-energy transition state, and v) macrocyclic-cavity-size

Direct synthesis of anomeric tetrazolyl iminosugars from sugar-derived lactams

• Michał M. Więcław and
• Bartłomiej Furman

Beilstein J. Org. Chem. 2021, 17, 115–123, doi:10.3762/bjoc.17.12

• of the product as a chair (1C4, 4C1) or a skew-boat (1S3, 3S1) conformer, of which the former is favored, as it proceeds via the lower-energetic chair-like transition state. The favored path of action will result in addition syn or anti to the substituent in position 5, depending on the starting

• spontaneous decomposition of the zirconium complex INT-1-A to the free imine species INT-3. This process is much more likely to occur via the 5-membered cyclic transition state TS-1-A than the alternative TS-1-B, as the energy barrier of 60.1 kcal·mol−1 is definitely too high for the reaction to take place

Deoxyfluorination of acyl fluorides to trifluoromethyl compounds by FLUOLEAD^®/Olah’s reagent under solvent-free conditions

• Yumeng Liang,
• Akihito Taya,
• Zhengyu Zhao,
• Norimichi Saito and
• Norio Shibata

Beilstein J. Org. Chem. 2020, 16, 3052–3058, doi:10.3762/bjoc.16.254

• an intermediate III via transition state II. The intermediate III is further activated by (HF)n to form IV, which finally induces the deoxyfluorination via V furnishing the trifluoromethylated products 2 with the release of ArS(O)F and (HF)n. Conclusion We have reported an efficient protocol for the

Recent developments in enantioselective photocatalysis

• Callum Prentice,
• James Morrisson,
• Andrew D. Smith and
• Eli Zysman-Colman

Beilstein J. Org. Chem. 2020, 16, 2363–2441, doi:10.3762/bjoc.16.197

• al. [94] it is suggested that this reaction uses 1O2 for the oxidation, and proceeds through transition state 219‡ for the hydrogen-bonded catalysed nucleophilic addition step. Jiang et al. recently applied a similar dual catalytic system to the dehalogenative protonation of α,α-chlorofluoro ketones

• •−, which adds to the nitrone via a proposed 6-membered transition state to afford radical cation 286•+. Subsequent hydrogen atom abstraction from TEEDA•+ generates complex 286−. Protonation and displacement by other substrate molecules releases the desired 1,2-amino alcohol products 287 in excellent yields

Photosensitized direct C–H fluorination and trifluoromethylation in organic synthesis

• Shahboz Yakubov and
• Joshua P. Barham

Beilstein J. Org. Chem. 2020, 16, 2151–2192, doi:10.3762/bjoc.16.183

• parameters of para substituents [197], and therefore the reaction success could relate to the transition state of the benzylic radical’s fluorination step. Given later studies [147][198][199], it cannot be ruled out that this reaction could be interpreted as a photosensitized C–H fluorination involving the

• fluorination [46][205]. The selectivity for β- or γ-fluorination could be attributed to an interaction of the breaking C(sp3)–H bond and the neighboring ketone, which is part of the proposed 5- and 6-membered transition state, respectively. When the 5- and the 6-membered transition state is possible, the free

• . The authors demonstrated that the transition state for Selectfluor® undergoing HAT at this position (see TS1) was more kinetically accessible, despite the bond dissociate free energies (BDFEs) suggesting C3 functionalization (Scheme 27). 3.4 Directing-group-guided benzylic C–H fluorination In another

Reactions of 3-aryl-1-(trifluoromethyl)prop-2-yn-1-iminium salts with 1,3-dienes and styrenes

• Thomas Schneider,
• Michael Keim,
• Bianca Seitz and
• Gerhard Maas

Beilstein J. Org. Chem. 2020, 16, 2064–2072, doi:10.3762/bjoc.16.173

• of 1a and 2,3-dimethylbutadiene (DMBD), the regioselectivity of which is as expected for a highly asynchronous transition state with effective stabilization of the positive charge or a two-step ionic process (vide infra). The high electrophilic power of the 1-CF3-substituted propyn-1-iminium ion

Natural dolomitic limestone-catalyzed synthesis of benzimidazoles, dihydropyrimidinones, and highly substituted pyridines under ultrasound irradiation

• Kumar Godugu,
• Venkata Divya Sri Yadala,
• Mohammad Khaja Mohinuddin Pinjari,
• Trivikram Reddy Gundala,
• Lakshmi Reddy Sanapareddy and
• Chinna Gangi Reddy Nallagondu

Beilstein J. Org. Chem. 2020, 16, 1881–1900, doi:10.3762/bjoc.16.156

• confirmed that the reaction stopped at the bisimine I stage. This was due to the intramolecular hydrogen bonding between the hydrogen atom of the ortho-hydroxy group and the nitrogen atom of the imine group in a six-membered ring transition state [87]. Similarly, the reaction between 3-ethoxysalicylaldehyde

Stereoselective Biginelli-like reaction catalyzed by a chiral phosphoric acid bearing two hydroxy groups

• Xiaoyun Hu,
• Jianxin Guo,
• Cui Wang,
• Rui Zhang and
• Victor Borovkov

Beilstein J. Org. Chem. 2020, 16, 1875–1880, doi:10.3762/bjoc.16.155

• yield and enantioselectivity of the reaction dropped dramatically, hence confirming our initial proposal that the free hydroxy groups in the chiral phosphoric acid 3 played an important role in this enantioselective transformation. Based on these results, a plausible transition-state structure was

• ) H bondings with the enolizable ketone, respectively. This rigid chiral transition-state structure favored the stereoselective attack of the enol on the imine. Once the two hydroxy groups were etherified, the loss of the rigid structure would lead to low enantioselectivity. Additionally, this

• solvent, the residue was purified by column chromatography using petroleum ether/ethyl acetate 6:1–3:1. A plausible chiral transition-state structure in the Biginelli-like reaction catalyzed by phosphoric acid 3. Synthesis of chiral phosphoric acid 3. Synthesis of methylated chiral phosphoric acid 7

Synthesis, docking study and biological evaluation of ᴅ-fructofuranosyl and ᴅ-tagatofuranosyl sulfones as potential inhibitors of the mycobacterial galactan synthesis targeting the galactofuranosyltransferase GlfT2

• Marek Baráth,
• Jana Jakubčinová,
• Zuzana Konyariková,
• Stanislav Kozmon,
• Katarína Mikušová and
• Maroš Bella

Beilstein J. Org. Chem. 2020, 16, 1853–1862, doi:10.3762/bjoc.16.152

• substrate of mycobacterial galactofuranosyltransferase GlfT2 in the transition state, we evaluated these compounds by computational methods, as well as in an enzyme assay for the possible inhibition of the mycobacterial galactan biosynthesis. Our data show that despite favorable docking scores to the active

• site of GlfT2, none of these compounds serve as efficient inhibitors of the enzymes involved in the mycobacterial galactan biosynthesis. Keywords: GlfT2; molecular modeling; mycobacterium tuberculosis; synthesis; transition state inhibitors; Introduction Tuberculosis (TB) is one of the most prevalent

• mechanism studies using computational chemistry methods. The probable reaction mechanisms were studied by hybrid DFT QM/MM molecular dynamics simulations [11] where the possible transition state (TS) structures were localized. The observation of the possible TS structure opens the opportunities for the in

Polarity effects in 4-fluoro- and 4-(trifluoromethyl)prolines

• Vladimir Kubyshkin

Beilstein J. Org. Chem. 2020, 16, 1837–1852, doi:10.3762/bjoc.16.151

• trifluoromethyl- or a difluoromethylene group. This orientation of the substituents explains the observed trends in the pKa values, lipophilicity, and the kinetics of the amide bond rotation. The study also provides a set of evidences that the transition state of the amide-bond rotation in peptidyl-prolyl favors

• water). At the same time, the amide rotation is a simple process with only one (prevalent) transition state and two ground states [93]. The high level of the energetic barrier implies that there is only a negligible subpopulation of molecules that may be involved in the transition, and therefore the

• rotation velocity. The difference was especially prominent in the trifluoromethylated species, 3 and 4 (see Table 3). Curiously, it is not possible to explain this finding by considering the ground state, thus the so-called syn/exo transition state [96] should be analyzed instead. The data make sense, if

One-pot synthesis of oxazolidinones and five-membered cyclic carbonates from epoxides and chlorosulfonyl isocyanate: theoretical evidence for an asynchronous concerted pathway

• Esra Demir,
• Ozlem Sari,
• Yasin Çetinkaya,
• Ufuk Atmaca,
• Safiye Sağ Erdem and
• Murat Çelik

Beilstein J. Org. Chem. 2020, 16, 1805–1819, doi:10.3762/bjoc.16.148

• onto C1 or C2 and an attack of O3 on C5 occur in an asynchronous concerted manner. The first transition state (TS1) corresponds to the nucleophilic attack of N4 onto the C2 of 7f leading to oxazolidinone intermediate 10. The alternative transition state (TS1′) corresponds to the nucleophilic attack of

• the transition state and so lowering the activation energy barrier (Figure 3a). On the other hand, stabilization of the benzylic cation is not possible along the IRC path for TS1′ (Figure 3b), since the bond distance C2–C(Ph) is found as around 1.50 Å showing a single bond character. This can be the

• main reason for the predominant formation of intermediate 10 which results in the regioselective formation of oxazolidinone 9f Optimized geometries for reactant complex RC1 (7f+CSI), transition state TS1 and 10 for the selected path are depicted in Figure 4. This step is common for all paths studied

Pauson–Khand reaction of fluorinated compounds

• Jorge Escorihuela,
• Daniel M. Sedgwick,
• Alberto Llobat,
• Mercedes Medio-Simón,
• Pablo Barrio and
• Santos Fustero

Beilstein J. Org. Chem. 2020, 16, 1662–1682, doi:10.3762/bjoc.16.138

• repulsions that occur in the equatorial position. Consequently, in the most favorable transition state there is no steric hindrance between the CF3 group and the ethylenic hydrogen, leading to the observed diastereoisomer. On the other hand, the use of 1,9-enyne 18c (n = 3) did not afford the corresponding

Fluorohydration of alkynes via I(I)/I(III) catalysis

• Jessica Neufeld,
• Constantin G. Daniliuc and
• Ryan Gilmour

Beilstein J. Org. Chem. 2020, 16, 1627–1635, doi:10.3762/bjoc.16.135

• and 9, respectively, Figure 3A). Deletion of the ester carbonyl (10) and replacement of the phenyl group by methyl (11) was also detrimental. From these data it is tempting to speculate upon the involvement of a chair-like transition state in which the intramolecular interaction of the phenyl π-system

In silico rationalisation of selectivity and reactivity in Pd-catalysed C–H activation reactions

• Liwei Cao,
• Mikhail Kabeshov,
• Steven V. Ley and
• Alexei A. Lapkin

Beilstein J. Org. Chem. 2020, 16, 1465–1475, doi:10.3762/bjoc.16.122

• a relatively unstable intermediate (Figure 1) [26], the Hammond postulate can be applied to the electrophilic substitution reactions. The Hammond postulate states that a transition state will be structurally and energetically similar to the species (reactant, intermediate or product) nearest to it

Highly selective Diels–Alder and Heck arylation reactions in a divergent synthesis of isoindolo- and pyrrolo-fused polycyclic indoles from 2-formylpyrrole

• Carlos H. Escalante,
• Eder I. Martínez-Mora,
• Carlos Espinoza-Hicks,
• Alejandro A. Camacho-Dávila,
• Fernando R. Ramos-Morales,
• Francisco Delgado and
• Joaquín Tamariz

Beilstein J. Org. Chem. 2020, 16, 1320–1334, doi:10.3762/bjoc.16.113

• . Accordingly, the R2 substituent in the diene would play an important role in directing the endo/exo orientation of the approach to the maleimide at the transition state (TS). Therefore, the endo diastereoselectivity is apparently not controlled by the presence or the absence of the substituent bonded to the

Fluorinated phenylalanines: synthesis and pharmaceutical applications

• Laila F. Awad and
• Mohammed Salah Ayoup

Beilstein J. Org. Chem. 2020, 16, 1022–1050, doi:10.3762/bjoc.16.91

• -protected acid 120 in good yield. Finally, removal of the Boc group then generated the free amino acid (3R)-3-fluoro-ʟ-phenylalanine (121) [64] (Scheme 27). Okuda’s group used 121 in the synthesis of a nucleoside that could be used to assess the transition state of a ribosome-catalyzed peptide-bond

Aldehydes as powerful initiators for photochemical transformations

• Maria A. Theodoropoulou,
• Nikolaos F. Nikitas and
• Christoforos G. Kokotos

Beilstein J. Org. Chem. 2020, 16, 833–857, doi:10.3762/bjoc.16.76

• compound 44 and a triplet state olefin molecule 17 in a nonplanar configuration. Both processes, oxetane formation and isomerization, were thought to proceed via the triplet state of benzaldehyde. The alternative pathway includes a polarization of the π-system of the olefin, forming a transition state

Preparation of 2-phospholene oxides by the isomerization of 3-phospholene oxides

• Péter Bagi,
• Réka Herbay,
• Nikolett Péczka,
• Zoltán Mucsi,
• István Timári and
• György Keglevich

Beilstein J. Org. Chem. 2020, 16, 818–832, doi:10.3762/bjoc.16.75

• rearrangement, involving zwitterionic structure 11 via high energy and a four-membered ring transition state [TS(1→11)]. This stressed structure has a rigid, entropically unbeneficial transition. The second transition state [TS(11→4)] represents a significantly lower energy gap with a more comfortable five

• atom can be easily protonated via a high enthalpy transition state [TS(17→18)], which is the rate determining step of this reaction sequence. We suppose that this rather high enthalpy is much lower due to the tunneling effect of the proton, whose energy gap is estimated to be reduced to about 130 kJ

• mol−1 in an optimal arrangement of the proton [73][74]. After the transition state, the mesylate anion attacks consecutively the position C(3), forming a neutral, relatively low-enthalpy intermediate 18. The departure of the mesylate anion from position C(3) attracts the proton from C(2) via a lower