Pyridine C(sp²)–H bond functionalization under transition-metal and rare earth metal catalysis

• Haritha Sindhe,
• Malladi Mounika Reddy,
• Karthikeyan Rajkumar,
• Akshay Kamble,
• Amardeep Singh,
• Anand Kumar and
• Satyasheel Sharma

Beilstein J. Org. Chem. 2023, 19, 820–863, doi:10.3762/bjoc.19.62

• materials [1][2][3][4][5][6][7][8][9][10]. Due to its different characteristics such as basicity, stability, water solubility, small molecular size, and ability to form hydrogen bonds, pyridine continues to be a suitable moiety in organic synthesis. In addition, it has been observed that pyridine rings

Eschenmoser coupling reactions starting from primary thioamides. When do they work and when not?

• Lukáš Marek,
• Jiří Váňa,
• Jan Svoboda and
• Jiří Hanusek

Beilstein J. Org. Chem. 2023, 19, 808–819, doi:10.3762/bjoc.19.61

• reactions involve the imidothioate IV formed via deprotonation from nitrogen (pKaN in Scheme 2). The imidothioate IV can undergo cyclization to give an energetically favorable five-membered thiazoline ring VII which then either eliminates a leaving group Y− (when Y: alkoxy, amino) or a water molecule (when

• 70–95%). The presence of a base and the type of solvent seems to be an important factor for the reaction course. In toluene, ionic liquid or in refluxing ethanol without a base [16][19][20] or in the presence of weakly basic pyridine [17][18][21] (pKa = 5.23 in water, 3.4 in DMSO, 3.3 in DMF, and

• water) tend to the formation [5][6] of the ECR product (XIV). A similar tendency to produce either ECR or thiazole products depending on the solvent was observed already by Eschenmoser and his co-workers for the reaction of α-bromoketones with thiolactams [23]. On the other hand, Bergman et al

Synthesis of substituted 8H-benzo[h]pyrano[2,3-f]quinazolin-8-ones via photochemical 6π-electrocyclization of pyrimidines containing an allomaltol fragment

• Constantine V. Milyutin,
• Andrey N. Komogortsev,
• Boris V. Lichitsky,
• Mikhail E. Minyaev and
• Valeriya G. Melekhina

Beilstein J. Org. Chem. 2023, 19, 778–788, doi:10.3762/bjoc.19.58

• (Scheme 6). However, the key difference is the regioselectivity of the process and the absence of a pathway associated with the direct elimination of a water molecule and the formation of the polyaromatic compound 12. It can be assumed that for the considered system a [1,9]-H sigmatropic shift is a much

Honeycomb reactor: a promising device for streamlining aerobic oxidation under continuous-flow conditions

• Masahiro Hosoya,
• Yusuke Saito and
• Yousuke Horiuchi

Beilstein J. Org. Chem. 2023, 19, 752–763, doi:10.3762/bjoc.19.55

• , which diminishes the atom economy [2]. To overcome this limitation, the use of molecular oxygen (O2) present in air as an oxidant is one of the ideal solutions [10][11]. The reduction of O2 generates only water as a byproduct, leading to high atom-economy processes. However, the use of O2 as an oxidant

• to handle aerobic oxidation. Therefore, passive mixing should be more suitable for aerobic oxidation. The whole flow reactor with passive mixing can be immersed in incombustible medium such as water, leading to the improvement of the process safety. Passive mixing is commonly realized using slug-flow

Synthesis of imidazo[1,2-a]pyridine-containing peptidomimetics by tandem of Groebke–Blackburn–Bienaymé and Ugi reactions

• Oleksandr V. Kolomiiets,
• Alexander V. Tsygankov,
• Maryna N. Kornet,
• Aleksander A. Brazhko,
• Vladimir I. Musatov and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2023, 19, 727–735, doi:10.3762/bjoc.19.53

• -chlorobenzaldehyde (5b), 4-methoxyaniline (6a) and tert-butyl isocyanide (3a). It should be especially noted that the solubility of compound 8a is very low (soluble in DMSO and N-methyl-2-pyrrolidone (NMP), slightly soluble in methanol, 1- and 2-propanol, acetone, DMF and insoluble in water, ethanol, acetonitrile

Photocatalytic sequential C–H functionalization expediting acetoxymalonylation of imidazo heterocycles

• Deepak Singh,
• Shyamal Pramanik and
• Soumitra Maity

Beilstein J. Org. Chem. 2023, 19, 666–673, doi:10.3762/bjoc.19.48

• chemodivergent formation of C-3 ethoxycarbonylmethylated and hydroxyalkylated IPs under visible light using water or alcohol as the source of the oxygenated group under degassed conditions [22]. However, all these photochemical methods require the usage of a substantial amount of base, the preactivation with a

• degassed conditions with or without water only delivered a trace amount (<5%) of the desired products, indicating that aerial oxygen plays a crucial role in the second catalytic cycle for the conversion of 5 to 3a or 4a (Scheme 3C). To determine the role of zinc acetate, a standard reaction of 1a and 2a in

Nucleophile-induced ring contraction in pyrrolo[2,1-c][1,4]benzothiazines: access to pyrrolo[2,1-b][1,3]benzothiazoles

• Ekaterina A. Lystsova,
• Maksim V. Dmitriev,
• Andrey N. Maslivets and
• Ekaterina E. Khramtsova

Beilstein J. Org. Chem. 2023, 19, 646–657, doi:10.3762/bjoc.19.46

• (toluene, acetonitrile, DMSO-d6) at room temperature, or when these solutions were slightly heated, the compounds 5a,b,e dissociated to form APBTTs 1 (the solutions got violet color, characteristic of compounds 1) (Scheme 10). In the presence of water (including the atmospheric moisture), hydration

pH-Responsive fluorescent supramolecular nanoparticles based on tetraphenylethylene-labelled chitosan and a six-fold carboxylated tribenzotriquinacene

• Nan Yang,
• Yi-Yan Zhu,
• Wei-Xiu Lin,
• Yi-Long Lu and
• Wen-Rong Xu

Beilstein J. Org. Chem. 2023, 19, 635–645, doi:10.3762/bjoc.19.45

• , PR China 10.3762/bjoc.19.45 Abstract We synthesized a new tetraphenylethylene-modified chitosan bioconjugate, CS-TPE, that shows the aggregation-induced emission effect. It can self-assemble into fluorescent polymeric nanoparticles in an aqueous solution at pH 5.3 either alone or with the water

• supramolecular systems derived from water-soluble macrocycles, including cyclodextrins (CDs), calix[n]arenes (CXs), cucurbiturils (CBs), and pillararenes have been widely studied [2][6][7][8]. Similar to those macrocyclic acceptors, tribenzotriquinacene (TBTQ) derivatives, a class of versatile host molecules

• with a bowl-shaped C3v-symmetric skeleton, are capable of effectively encapsulating guest molecules [9][10][11][12][13][14][15]. In recently published studies [16][17], we have successfully synthesized two water-soluble hexacarboxylated tribenzotriquinacene derivatives, 2,2',2'',2''',2'''',2'''''-((12d

Phenanthridine–pyrene conjugates as fluorescent probes for DNA/RNA and an inactive mutant of dipeptidyl peptidase enzyme

• Josipa Matić,
• Tana Tandarić,
• Marijana Radić Stojković,
• Filip Šupljika,
• Zrinka Karačić,
• Ana Tomašić Paić,
• Lucija Horvat,
• Robert Vianello and
• Lidija-Marija Tumir

Beilstein J. Org. Chem. 2023, 19, 550–565, doi:10.3762/bjoc.19.40

• modelling combined with spectrophotometric experiments revealed that in neutral and acidic buffered water solutions conjugates predominantly exist in intramolecularly stacked conformations because of the π–π stacking interaction between pyrene and phenanthridine moieties. The investigated systems exhibited

• solvents, including water. The exciplex was formed by the intramolecular interaction of guanine and pyrene, linked by a flexible methylene chain [10]. Our lab has conducted considerable research on phenanthridine derivatives, and earlier research has demonstrated that two phenanthridine units can also

• chromophores enabled intramolecular contacts between the phenanthridine and pyrene chromophore. This stacking interaction minimized the surface area that was exposed to water. As a result, mutual shielding of chromophores and coulombic interaction between induced dipoles could cause hypochromism and consequent

Transition-metal-catalyzed domino reactions of strained bicyclic alkenes

• Austin Pounder,
• Eric Neufeld,
• Peter Myler and
• William Tam

Beilstein J. Org. Chem. 2023, 19, 487–540, doi:10.3762/bjoc.19.38

• equivalents of water interrupted the cyclization step and led entirely to reductively coupled alkenylated ring-opened products. Interestingly, when this methodology was applied to the ester-bearing oxabicyclic 1a, the anticipated reductive coupling product was not detected; instead, bicyclic γ-lactone 4 was

• phenanthridinones produced, the authors were able to quickly afford novel fagaronine 117j and nitidine 117k derivatives. Rhodium-catalyzed reactions In 2002, the Lautens laboratory reported a tandem cyclization of arylboronate esters 118 with a variety of bicyclic alkenes 15 using a water-soluble Rh-catalytic

• with the bicyclic substrate to produce 123. A 5-exo-trig ring closure of 123 produces 124 followed by a rapid protodemetalation with water releasing the final indane product 119a and regenerating the active Rh(I) species. The authors proposed that the origin of the diastereoselectivity is due to

Dipeptide analogues of fluorinated aminophosphonic acid sodium salts as moderate competitive inhibitors of cathepsin C

• Karolina Wątroba,
• Małgorzata Pawełczak and
• Marcin Kaźmierczak

Beilstein J. Org. Chem. 2023, 19, 434–439, doi:10.3762/bjoc.19.33

• result of the reactions carried out, the dipeptide analogues of α- and β-fluorinated aminophosphonic acids 8 and 10 were obtained. All the samples were solids, with very poor solubility in water and organic solvents such as DMSO and MeOH. The final step of the synthesis was the reaction of the resulting

Combretastatins D series and analogues: from isolation, synthetic challenges and biological activities

• Jorge de Lima Neto and
• Paulo Henrique Menezes

Beilstein J. Org. Chem. 2023, 19, 399–427, doi:10.3762/bjoc.19.31

• bond of 28 leads to compounds of increasing activity, being the more polar hydroxy-substituted derivatives the most active (Table 2) [73]. One of the major obstacles in the development of highly potent drugs is the water solubility. Pettit and co-workers [55] conducted an extensive study in an attempt

• to improve the water solubility of combretastatin D-2 (2) by converting it into a series of phosphate salts and other prodrugs. Thus, phosphorylation of combretastatin D-2 (2) using dibenzyl phosphite gave derivative 183. Further cleavage of the benzyl groups using TMSBr followed by the reaction of

• the obtained phosphoric acid derivative with a series of bases led to the formation of different phosphate salts 184–187 (Scheme 35) [55]. The authors observed that the prodrug salts had substantially improved solubility in water, an important feature for transport to metastatic cancer (Table 3) [75

Discrimination of β-cyclodextrin/hazelnut (Corylus avellana L.) oil/flavonoid glycoside and flavonolignan ternary complexes by Fourier-transform infrared spectroscopy coupled with principal component analysis

• Nicoleta G. Hădărugă,
• Gabriela Popescu,
• Dina Gligor (Pane),
• Cristina L. Mitroi,
• Sorin M. Stanciu and
• Daniel Ioan Hădărugă

Beilstein J. Org. Chem. 2023, 19, 380–398, doi:10.3762/bjoc.19.30

• principal component analysis (FTIR–PCA). These innovative complexes combine the characteristics of the three components and improve the properties of the resulting material such as the onsite protection against oxidative degradation of hazelnut oil unsaturated fatty acid glycerides. Also, the apparent water

• , leading to high water solubility. On the other hand, the tetrahydropyran moieties of the Glcp units provide the hydrophobic property of the CD cavity [4]. As a consequence of their unique structure, CDs can encapsulate hydrophobic molecules or hydrophobic moieties of geometrically compatible bioactive

• compounds [5]. The resulting supramolecular inclusion complexes provide enhanced water solubility and bioavailability/bioaccessibility of the nanoencapsulated bioactive compounds, higher oxidative and thermal stability or photostability of labile compounds, and their controlled release [6][7]. Vegetable oil

CuAAC-inspired synthesis of 1,2,3-triazole-bridged porphyrin conjugates: an overview

• Dileep Kumar Singh

Beilstein J. Org. Chem. 2023, 19, 349–379, doi:10.3762/bjoc.19.29

• triazoloporphyrins 32a–c and triazole-bridged bisporphyrins 34 in good yields. The “click reaction” of azidoporphyrin 30 with the terminal alkynes 31a–c and 33 in a THF/water (3:1) mixture was investigated by using different catalytic systems. Among these, copper carbene (SIMes)CuBr proved to be a better catalyst

• -porphyrin and copper-corrole moieties upon photoexcitation. Moreover, the theoretical calculations suggested that the porphyrin moiety acted as a donor while the corrole unit acted as an acceptor in dimer 60. Recently S. Y. Yap and co-workers [38] used “click chemistry” to link a water-soluble porphyrin

• with a histidine like group for the development of theranostic agents. Firstly, zinc triazole-porphyrins 63 and 66a were synthesized by the click reaction between water-soluble azidoporphyrin 61 and ᴅ-propargylglycine 62 or trifunctional-propargyllysine 65 in 83.6% and 77% yield, respectively, under

Recommendations for performing measurements of apparent equilibrium constants of enzyme-catalyzed reactions and for reporting the results of these measurements

• Robert N. Goldberg,
• Robert T. Giessmann,
• Peter J. Halling,
• Carsten Kettner and
• Hans V. Westerhoff

Beilstein J. Org. Chem. 2023, 19, 303–316, doi:10.3762/bjoc.19.26

• , disodium salt hydrate, CAS number 34369-07-8) along with the concentrations at which it was used. The sources of all substances used, their batch numbers, and estimated purities, as well as the methods of analysis used by the manufacturer and by the investigators should be reported. Also, since water is

• standard states must be paid when water is a reactant. One generally takes the activity (or concentration) of water to be unity [19] when calculating the equilibrium constant for a reaction that occurs when water is the solvent and is present in vast excess. However, biochemical reactions can also take

• place in non-aqueous solvents and with water as a reactant. In such cases, one must measure the concentration of water in the non-aqueous phase in order to be able to calculate rigorously a value for the equilibrium constant. And, per section 2, the equilibrium constant must always be clearly defined

Continuous flow synthesis of 6-monoamino-6-monodeoxy-β-cyclodextrin

• János Máté Orosz,
• Dóra Ujj,
• Petr Kasal,
• Gábor Benkovics and
• Erika Bálint

Beilstein J. Org. Chem. 2023, 19, 294–302, doi:10.3762/bjoc.19.25

• complexation can lead to a significant solubility enhancement of poorly water-soluble molecules, and therefore it can enable the biological testing of drugs, which would otherwise not be possible by any other means [2][3]. Monosubstituted CDs contain only one hydroxy group modified with a functional group. In

• monosulfonated compound is separated by recrystallization from hot water in the case of the β-CD derivative, and by chromatography in the case of α- and γ-CDs. The larger cavity size of γ-CD is the reason of polysubstitution when TsCl is used [9]. To ensure a better yield of the monosubstituted product, bulkier

• sulfonyl chloride reagents are used. 2-Naphthalenesulfonyl chloride in pyridine is one common method. However, the concentration of γ-CD must be lower than 20 mM to favor monosubstitution and to ensure the optimal yield (around 30%) after recrystallization from hot water [9]. Sometimes purification using

Strategies to access the [5-8] bicyclic core encountered in the sesquiterpene, diterpene and sesterterpene series

• Cécile Alleman,
• Charlène Gadais,
• Laurent Legentil and
• François-Hugues Porée

Beilstein J. Org. Chem. 2023, 19, 245–281, doi:10.3762/bjoc.19.23

An efficient metal-free and catalyst-free C–S/C–O bond-formation strategy: synthesis of pyrazole-conjugated thioamides and amides

• Shubham Sharma,
• Dharmender Singh,
• Sunit Kumar,
• Vaishali,
• Rahul Jamra,
• Naveen Banyal,
• Deepika,
• Chandi C. Malakar and
• Virender Singh

Beilstein J. Org. Chem. 2023, 19, 231–244, doi:10.3762/bjoc.19.22

• -aminopyridine. Thereafter, a nucleophilic attack of H2O2 on the imine carbon may afford the intermediate 17. Finally, the loss of a water molecule from the intermediate 17 may generate the pyrazole-pyridine conjugate with amide linkage 1F. Conclusion In summary, a simple, straightforward and efficient approach

• TLC, cold water was added to the reaction mixture at room temperature which resulted in precipitation of the product. The product was collected by filtration under reduced pressure using a Büchner funnel and further purified by silica gel column chromatography (60–120 mesh silica gel) using hexane and

• mmol), morpholine (C, 0.36 g, 4.14 mmol), and elemental sulfur (0.48 g, 15 mmol) in dry DMF (10 mL) followed by heating of the reaction mixture at 70 °C for 2.5 h. On completion of the reaction, as determined by TLC, the reaction content was cooled to room temperature and poured into ice-cold water

Investigation of cationic ring-opening polymerization of 2-oxazolines in the “green” solvent dihydrolevoglucosenone

• Solomiia Borova and
• Robert Luxenhofer

Beilstein J. Org. Chem. 2023, 19, 217–230, doi:10.3762/bjoc.19.21

• , environmentally friendly, highly stable towards oxidation, yet degrades into water and carbon dioxide [27][38]. Therefore, DLG is an interesting candidate to investigate as solvent for the CROP of 2-oxazolines. Accordingly, in this work, we present the first examples of the successful CROP of POx and discuss the

• full monomer conversion. Monomer conversion was monitored by 1H NMR spectroscopy. After complete monomer consumption, the reaction was terminated by adding 3.0 equiv of water and left to react overnight at 45 °C. The polymer was purified by precipitation from cold diethyl ether (Et2O) or direct

• dialysis against water overnight, followed by lyophilization. The resulting polymer was obtained as a slightly yellow powder. The synthesis of 2-ethyl-3-methyloxazolinium triflate was carried out as follows: 30 mL of dry diethyl ether were placed in a dry round-bottomed flask and methyl

Friedel–Crafts acylation of benzene derivatives in tunable aryl alkyl ionic liquids (TAAILs)

• Swantje Lerch,
• Stefan Fritsch and
• Thomas Strassner

Beilstein J. Org. Chem. 2023, 19, 212–216, doi:10.3762/bjoc.19.20

• presented by Wilke and colleagues in 1986 [17]. At that time, chloroaluminate ionic liquids were used both as a solvent and catalyst [18][19], but these systems proved to be unstable under ambient air conditions and prone to decompose in the presence of water [20]. In the following years, ionic liquids

• cost-efficient metal salts in a water and air stable ionic liquid is still hard to find [50][51]. In this contribution, we present the use of imidazolium-based tunable aryl alkyl ionic liquids (TAAILs) in a catalytic Friedel–Crafts acylation. This relatively new class of ionic liquids [52] previously

• (Ac2O) to acetanisole 7 was chosen as the model reaction (Scheme 2) [36]. As different metal salts are known to be effective catalysts for this reaction [58][59][60], several metal chlorides were tested for their capability to catalyze the acylation in TAAILs. To our surprise, neither water-free AlCl3

Germacrene B – a central intermediate in sesquiterpene biosynthesis

• Houchao Xu and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2023, 19, 186–203, doi:10.3762/bjoc.19.18

• is terminated by deprotonation to yield a terpene hydrocarbon or by nucleophilic attack of water to generate a terpene alcohol. For the precursor of sesquiterpenes FPP six initial cyclisation modes are possible (Scheme 1). After ionisation to A either a 1,10-cyclisation to the (E,E)-germacradienyl

• acetone and water to a hemiacetal that can decompose to 11 (Scheme 4B) [43]. Furthermore, 1 shows an interesting photochemistry (Scheme 4C). A [2 + 2] cycloaddition of the endocyclic double bonds yields 12 whose formation is understandable from conformers 1c and 1d. The all-cis stereoisomer 14 requires a

• discussed in the following sections. Eudesmanes from I1 The eudesmane sesquiterpenes derived from cation I1 are summarised in Scheme 7. Cation I1 can either be deprotonated to yield selina-3,7(11)-diene (9), (+)-γ-selinene (10) or (+)-selina-4,7(11)-diene (18), or captured by water resulting in juniper

Identification and determination of the absolute configuration of amorph-4-en-10β-ol, a cadinol-type sesquiterpene from the scent glands of the African reed frog Hyperolius cinnamomeoventris

• Angelique Ladwig,
• Markus Kroll and
• Stefan Schulz

Beilstein J. Org. Chem. 2023, 19, 167–175, doi:10.3762/bjoc.19.16

• slow reaction, but a 37% solution of formaldehyde in water/methanol proved to be successful (Table 1, entries 5–10). Nevertheless, two problems were encountered. First, the Diels–Alder products 9–11 proved to be also active Mannich acceptors, leading to the unwanted unsaturated ketone 20, a double

Insight into oral amphiphilic cyclodextrin nanoparticles for colorectal cancer: comprehensive mathematical model of drug release kinetic studies and antitumoral efficacy in 3D spheroid colon tumors

• Sedat Ünal,
• Gamze Varan,
• Juan M. Benito,
• Yeşim Aktaş and
• Erem Bilensoy

Beilstein J. Org. Chem. 2023, 19, 139–157, doi:10.3762/bjoc.19.14

• % penicillin/streptomycin (P4333, Sigma-Aldrich, USA) was used for 2D and 3D cell culture studies. Ultrapure water was obtained from a Millipore Simplicity 185 Ultrapure Water System (Millipore, France). All other chemicals were purchased from Sigma-Aldrich and were of analytical purity. Release kinetic

• hours, respectively. In this context, the dialysis bag was transferred to the previously prepared release media, respectively [9]. The dialysis membrane method at 37 °C in a shaking water bath (100 rpm) was used. The closed dialysis membrane bag (average flat width 25 mm, MWCO: 14,000 Da) containing the

Nostochopcerol, a new antibacterial monoacylglycerol from the edible cyanobacterium Nostochopsis lobatus

• Naoya Oku,
• Saki Hayashi,
• Yuji Yamaguchi,
• Hiroyuki Takenaka and
• Yasuhiro Igarashi

Beilstein J. Org. Chem. 2023, 19, 133–138, doi:10.3762/bjoc.19.13

• described in a patent [15]. Results and Discussion A water-thawed algal mass of strain MAC0804NAN (374.6 g) was repeatedly extracted with EtOH. The combined extract was partitioned between 60% aqueous MeOH and CH2Cl2, and the latter lipophilic layer was further partitioned between 90% aqueous MeOH and n

• on a Bruker micrOTOF mass spectrometer. Optical rotation and UV spectra were recorded on a JASCO P-1030 polarimeter and a Shimadzu UV-1800 spectrophotometer, respectively. Biological material N. lobatus MAC0804NAN was cultured as described in [13]. Extraction and isolation A water-thawed specimen

• , which were left standing until completely dried. A loop of the test organism, suspended in a small amount of water, was mixed with liquefied agar medium precooled to nearly body temperature, and the inoculated medium was quickly poured into a sterile plastic dish. The composition of the medium is 0.5

1,4-Dithianes: attractive C2-building blocks for the synthesis of complex molecular architectures

• Bram Ryckaert,
• Ellen Demeyere,
• Frederick Degroote,
• Hilde Janssens and
• Johan M. Winne

Beilstein J. Org. Chem. 2023, 19, 115–132, doi:10.3762/bjoc.19.12

• ) and the dimethylacetal derived from chloroacetaldehyde 11 affords the dithiolane 12. This 1,3-dithiolane spontaneously rearranges to the 1,4-dithiane with an elimination of hydrochloric acid by refluxing in a mixture of water and toluene. This two-step procedure constitutes a scalable and simple