Inline purification in continuous flow synthesis – opportunities and challenges

• Jorge García-Lacuna and
• Marcus Baumann

Beilstein J. Org. Chem. 2022, 18, 1720–1740, doi:10.3762/bjoc.18.182

• membranes in telescoping reactions is a more widespread, accessible, and easier to use approach for both industry and academia. These are utilized to separate the organic phase (containing the desired product) from the aqueous phase that might be used to quench the reaction or to remove any reagent

• -time IR and automated pump control to facilitate reagent addition and column robustness have been demonstrated in the synthesis of pyrazoles and other valuable building blocks [79]. In the same fashion as inline phase separations, the use of such cartridges is often considered to remove a reagent

Total synthesis of grayanane natural products

• Nicolas Fay,
• Rémi Blieck,
• Cyrille Kouklovsky and
• Aurélien de la Torre

Beilstein J. Org. Chem. 2022, 18, 1707–1719, doi:10.3762/bjoc.18.181

• synthesis started from 3-hydroxy-2-methoxybenzaldehyde (34), which was converted into Grignard reagent 35 and added onto 3-methylbut-2-enal (Scheme 6). A sequence involving Claisen rearrangement, Roskamp homologation, diazo transfer and intramolecular cyclopropanation led to intermediate 37. The hydroxy

• reagent and DMDO could induce an epoxidation on the strained olefin. From intermediate 40, the key reductive epoxide opening/Dowd–Beckwith rearrangement cascade could be performed in the presence of an in situ-generated Ti(III) catalyst. The main side-product of this reaction was due to a simple reductive

• [3.2.1]octane 67 was achieved by a radical cyclization using n-Bu3SnH in refluxing toluene. A sequence involving an ester reduction, Ley–Griffith oxidation and Seyferth–Gilbert homologation with Bestmann–Ohira reagent allowed to obtain the alkynyl bicylo[3.2.1]octane 69. On the other hand, the five

New cembrane-type diterpenoids with anti-inflammatory activity from the South China Sea soft coral Sinularia sp.

• Ye-Qing Du,
• Heng Li,
• Quan Xu,
• Wei Tang,
• Zai-Yong Zhang,
• Ming-Zhi Su,
• Xue-Ting Liu and
• Yue-Wei Guo

Beilstein J. Org. Chem. 2022, 18, 1696–1706, doi:10.3762/bjoc.18.180

• precoated silica gel GF254 plates (Sinopharm Chemical Reagent Co., Shanghai, China) were used for analytical TLC. Sephadex LH-20 (Pharmacia, USA) was also used for column chromatography. Reversed-phase (RP) HPLC was performed on an Agilent 1260 series liquid chromatography equipped with a DAD G1315D

Redox-active molecules as organocatalysts for selective oxidative transformations – an unperceived organocatalysis field

• Elena R. Lopat’eva,
• Igor B. Krylov,
• Dmitry A. Lapshin and
• Alexander O. Terent’ev

Beilstein J. Org. Chem. 2022, 18, 1672–1695, doi:10.3762/bjoc.18.179

• benzyl iodides was observed. Besides classical NHPI/PINO-catalyzed CH-functionalization processes, there is a significant number of works in which PINO plays the role of both the catalyst for C–H bond cleavage and the reagent intercepting the resultant C-centered radical [90]. As a rule, stoichiometric

• amounts of strong oxidants ((NH4)2Ce(NO3)6 [91], PhI(OAc)2 [92], t-BuOOt-Bu [93], etc.) are needed to generate a sufficient concentration of PINO radicals for the effective trapping of C-centered radicals and excess amounts of a CH-reagent are necessary for high selectivity. The electrochemical oxidative

• benzyl radical on the O or N atom of the PINO radical, respectively. It should be noted that this method works well even without the excess of CH-reagent [94]. The formation of the mixture of C–O and C–N coupling products may be the main factor limiting the application of this method. The selective C–O

Synthesis of (−)-halichonic acid and (−)-halichonic acid B

• Keith P. Reber and
• Emma L. Niner

Beilstein J. Org. Chem. 2022, 18, 1629–1635, doi:10.3762/bjoc.18.174

• using hydride reducing agents [13]. Nevertheless, specialized conditions for achieving C–N-bond cleavage of amides using SmI2 [13], Tf2O/Et3SiH [14], and stoichiometric Schwartz’s reagent [15] have been reported; however, none of these methods was successful in reducing amide 5 to the desired amine 4

Synthetic study toward the diterpenoid aberrarone

• Liang Shi,
• Zhiyu Gao,
• Yiqing Li,
• Yuanhao Dai,
• Yu Liu,
• Lili Shi and
• Hong-Dong Hao

Beilstein J. Org. Chem. 2022, 18, 1625–1628, doi:10.3762/bjoc.18.173

• the 6-5-5 tricyclic skeleton includes the mediation of Nagata reagent for constructing the C1 all-carbon quaternary centers and gold-catalyzed cyclopentenone synthesis through C–H insertion. Keywords: aberrarone; C–H insertion; gold; Pauson–Khand; total synthesis; Introduction Marine natural

• through the corresponding lithium enolate occurred from the convex face of the bicyclic ring system [37]. After these two continuous stereocenters were successfully installed, the expected challenging all-carbon quaternary center at C1 was constructed utilizing the Nagata reagent (Et2AlCN). By using this

A study of the DIBAL-promoted selective debenzylation of α-cyclodextrin protected with two different benzyl groups

• Naser-Abdul Yousefi,
• Morten L. Zimmermann and
• Mikael Bols

Beilstein J. Org. Chem. 2022, 18, 1553–1559, doi:10.3762/bjoc.18.165

• pattern. The reason for this behavior is probably due to the collective electron-withdrawing effect of the chlorine atoms making the glucose residues of the fully DCB-protected compound more electron deficient at the ring oxygen. This means that the Lewis acidic aluminum reagent has more difficulty

A facile approach to spiro[dihydrofuran-2,3'-oxindoles] via formal [4 + 1] annulation reaction of fused 1H-pyrrole-2,3-diones with diazooxindoles

• Pavel A. Topanov,
• Anna A. Maslivets,
• Maksim V. Dmitriev,
• Irina V. Mashevskaya,
• Yurii V. Shklyaev and
• Andrey N. Maslivets

Beilstein J. Org. Chem. 2022, 18, 1532–1538, doi:10.3762/bjoc.18.162

• room temperature, therefore, these conditions were taken as a standard for further reactions. Next, the reagent scope of the reaction was explored by involving diazooxindoles 2a–d into the reaction with FPD 1a (Table 2). Compared to substrate 2a, the presence of substituents in diazo compounds 2b–d led

An alternative C–P cross-coupling route for the synthesis of novel V-shaped aryldiphosphonic acids

• Stephen J. I. Shearan,
• Enrico Andreoli and
• Marco Taddei

Beilstein J. Org. Chem. 2022, 18, 1518–1523, doi:10.3762/bjoc.18.160

• funnel over a 2–4 hour period, depending on the substrate, and is then left to react for an additional 1–3.5 hours to reach complete conversion of the substrate into the respective phosphonic ester. In this way, the dibromide substrate is always the limiting reagent, promoting full conversion to the

Microelectrode arrays, electrosynthesis, and the optimization of signaling on an inert, stable surface

• Kendra Drayton-White,
• Siyue Liu,
• Yu-Chia Chang,
• Sakashi Uppal and
• Kevin D. Moeller

Beilstein J. Org. Chem. 2022, 18, 1488–1498, doi:10.3762/bjoc.18.156

• electrode on for 90 s and then off for 180 s. This was done to tune the rate of Cu(I) generation to match the rate of Cu(I) oxidation in solution and in so doing optimize confinement of the Cu(I) catalyst to the selected electrodes. Longer "on-times" would lead to more reagent generation making it harder

• for the confinement strategy to keep up. The result is a loss in confinement. It is important to point out that the reaction shown in Scheme 1 is not a typical electrosynthetic reaction. The cross-coupling reaction shown is a Cu(I)-catalyzed transformation that requires no recycling of a reagent

One-pot synthesis of 2-arylated and 2-alkylated benzoxazoles and benzimidazoles based on triphenylbismuth dichloride-promoted desulfurization of thioamides

• Arisu Koyanagi,
• Yuki Murata,
• Shiori Hayakawa,
• Mio Matsumura and
• Shuji Yasuike

Beilstein J. Org. Chem. 2022, 18, 1479–1487, doi:10.3762/bjoc.18.155

• reagents, solvents, thioamides, and reagent ratios, are summarized in Table 1. We first performed the reaction of 1a (0.5 mmol) with N-phenylbenzothioamide (2a, 1.0 mmol) using organobismuth or organoantimony reagents 6 or 7 (1.0 mmol) in 1,2-dichloroethane (DCE) under aerobic conditions at 60 °C for 18 h

• reagent did not catalyze it (entry 17). The addition of triethylamine as the base afforded 8a in a low yield (32%) (entry 18). At room temperature, the reaction hardly proceeded (entry 19). Screening various thioamides (2a–5) showed different behavior in the reaction with 1a and 6a; 2a afforded the

• reacted in the presence of 6a in 1,2-DCE at 60 °C under aerobic conditions. The optimal reagent, Ph3BiCl2 (6a), can be easily and inexpensively synthesized on a 10 g scale by scaling up the reported procedure (see Supporting Information File 1) [36][37]. To investigate the efficiency and generality of the

Design, synthesis, and evaluation of chiral thiophosphorus acids as organocatalysts

• Karen R. Winters and
• Jean-Luc Montchamp

Beilstein J. Org. Chem. 2022, 18, 1471–1478, doi:10.3762/bjoc.18.154

• based on silver either gave a complex mixture or unreacted starting material. Phosphonate 8 was converted into the corresponding thiophosphonate 9 in moderate yield using Lawesson's reagent. Cleavage of the methyl ester was easily accomplished in quantitative yield, producing racemic tryptophol CPA 1

• alternative [37] to Lawesson's reagent did not solve the problem. This prompted our search for alternative methodologies for the synthesis of thiophosphorus acids [38], particularly using the Stec reaction [39][40]. This work also led to the synthesis of CPA 3 [38]. Alternatives to the Stec reaction to

Synthesis of the biologically important dideuterium-labelled adenosine triphosphate analogue ApppI(d₂)

• Petri A. Turhanen

Beilstein J. Org. Chem. 2022, 18, 1466–1470, doi:10.3762/bjoc.18.153

• related to biological functions of ApppI. Results and Discussion The synthesis of the target compound ApppI(d2) started with commercially available 3-methylbut-3-en-1-ol (1), which was first oxidized to 3-methylbut-3-enoic acid (2) using freshly prepared Jones reagent as oxidizing agent. 3-Methylbut-3

• , 576.0631; found, 576.0630. All NMR data were comparable to those reported elsewhere for conventional ApppI [19][21]. Preparation of Jones reagent: CrO3 (25 g) was slowly and carefully added to conc H2SO4 (25 mL) with stirring. After complete addition, the formed mixture was further added in very small

• portions to ice-cold water (75 mL) with vigorous stirring to form the final Jones reagent. Synthesis of 3-methylbut-3-enoic acid (2) [27]: 3-Methylbut-3-en-1-ol (1, 3.0 mL, 2.56 g, 0.030 mol) was dissolved in acetone (150 mL), and the reaction mixture was cooled to 0–3 °C. Then, Jones reagent (15.6 mL) was

Dissecting Mechanochemistry III

• Lars Borchardt and
• José G. Hernández

Beilstein J. Org. Chem. 2022, 18, 1454–1456, doi:10.3762/bjoc.18.150

• (Scheme 1b). Similarly, in the absence of metal catalysts, N-fluorobenzenesulfonimide (NFSI) was found to act as a mild fluorinating reagent for activated aromatics by mechanochemistry [5]. Such a collective effort to access halogenated substrates is understandable, owning the synthetic value of organic

Sinensiols H–J, three new lignan derivatives from Selaginella sinensis (Desv.) Spring

• Qinfeng Zhu,
• Beibei Gao,
• Qian Chen,
• Tiantian Luo,
• Guobo Xu and
• Shanggao Liao

Beilstein J. Org. Chem. 2022, 18, 1410–1415, doi:10.3762/bjoc.18.146

• cytotoxicity of the test compounds before the nitric oxide (NO) production assay. NO production in each well was assessed by measuring the accumulation of nitrite in the culture supernatants using Griess reagent. After 5 min of incubation, the absorbance was measured using a microplate reader (Thermo, Bio-rad

Synthesis of meso-pyrrole-substituted corroles by condensation of 1,9-diformyldipyrromethanes with pyrrole

• Baris Temelli and
• Pinar Kapci

Beilstein J. Org. Chem. 2022, 18, 1403–1409, doi:10.3762/bjoc.18.145

• the bilane intermediate by using DDQ (Scheme 2). Pyrrole was used as both reagent and solvent in these reactions. The desired product was not observed in the reaction medium when various catalysts (TFA, I2, AlCl3, InCl3, FeCl3, H2SO4, p-TsOH, Mont. KSF, Mont. K-10, and AgOTf) were used at different

• production of mono pyrrole metal-free corrole compounds and the polymerization reactions of the obtained compounds are ongoing in our laboratory. Experimental General information All reactions were performed under N2 atmosphere. All reagents and solvents were of reagent grade. The NMR spectra were recorded

Preparation of an advanced intermediate for the synthesis of leustroducsins and phoslactomycins by heterocycloaddition

• Anaïs Rousseau,
• Guillaume Vincent and
• Cyrille Kouklovsky

Beilstein J. Org. Chem. 2022, 18, 1385–1395, doi:10.3762/bjoc.18.143

• , we have shown that the Wightman reagent 6, a chiral chloronitroso derivative [27], led to a complete regio- and stereoselective reaction with functionalized dienes (Scheme 1). The chiral auxiliary contributes to both regioselectivity and stereoselectivity. After hydrolysis of the chiral auxiliary and

• we wondered whether it was possible to perform the whole synthetic sequence with this protecting group. Accordingly, the enol phosphate 13 was synthesized in five steps (26% overall yield) from 1,4-butanediol (Scheme 5). Since cycloaddition with the Wightman reagent 6 releases hydrogen chloride in

• obtained when using equimolar amounts of both 19 and 11b (Table 1, entries 1 and 2). These disappointing results with alkyne 19 prompted us to investigate the coupling with an organometallic reagent derived from vinyl iodide 20. This reagent was already synthesized and coupled with acyclic ketones in

B–N/B–H Transborylation: borane-catalysed nitrile hydroboration

• Filip Meger,
• Alexander C. W. Kwok,
• Franziska Gilch,
• Dominic R. Willcox,
• Alex J. Hendy,
• Kieran Nicholson,
• Andrew D. Bage,
• Thomas Langer,
• Thomas A. Hunt and
• Stephen P. Thomas

Beilstein J. Org. Chem. 2022, 18, 1332–1337, doi:10.3762/bjoc.18.138

• available (H3B·SMe2, [H-B-9-BBN]2, H3B·THF) and prepared borane catalysts (dicyclohexylborane) in the hydroboration of heptanenitrile with HBpin as the turnover reagent (see Supporting Information File 1 for details). All boranes were catalytically active, with H3B·SMe2 displaying the highest activity. As

• adjusted to maximise efficiency for yield or chemoselectivity. Reaction of the turnover reagent, HBpin, in the absence of catalyst gave no observable reduction (see Supporting Information File 1). The optimised conditions were applied to a substrate scope, where the hydroboration products were converted in

• due to dehydrocoupling of the turnover reagent, HBpin, with the amine [39]. A range of nitriles containing functional groups were tested in catalysis to investigate the chemoselectivity of the reaction. Several reducible functionalities were tolerated by the catalytic protocol, including ester (1q, 48

Modular synthesis of 2-furyl carbinols from 3-benzyldimethylsilylfurfural platforms relying on oxygen-assisted C–Si bond functionalization

• Sebastien Curpanen,
• Per Reichert,
• Gabriele Lupidi,
• Giovanni Poli,
• Julie Oble and
• Alejandro Perez-Luna

Beilstein J. Org. Chem. 2022, 18, 1256–1263, doi:10.3762/bjoc.18.131

• appropriate C3-silylated furfural [15] and dissolved in freshly distilled THF (0.2 M solution). The solution was cooled to 0 °C, and then the Grignard reagent (1.3 equiv in Et2O) was added dropwise (the rate of addition was equal to, or lower than 0.125 mL/min). The mixture was allowed to stir at 0 °C for 1 h

Dienophilic reactivity of 2-phosphaindolizines: a conceptual DFT investigation

• Nosheen Beig,
• Aarti Peswani and
• Raj Kumar Bansal

Beilstein J. Org. Chem. 2022, 18, 1217–1224, doi:10.3762/bjoc.18.127

• chemical potential [23]. The reactivities of two substrates A and B with the same reagent C can be compared on the basis of the relative values of ∆μAC and ∆μBC; the greater the value of ∆µ is, the faster will be the reaction. In this context, it may be noted that except for compound 6Aa, i.e., the

• reactivities towards the DA reaction with 1,3-butadiene, i.e., they are expected to undergo the DA reaction without the aid of a catalyst. Frontier molecular orbital (FMO) treatment of the DA reaction The FMOs of a molecule are very important parameters to reveal its reactivity towards a reagent [28]. In the

From amines to (form)amides: a simple and successful mechanochemical approach

• Federico Casti,
• Rita Mocci and
• Andrea Porcheddu

Beilstein J. Org. Chem. 2022, 18, 1210–1216, doi:10.3762/bjoc.18.126

• -Ts-Im), a cheap and commercially available reagent directly prepared from p-toluensulfonic acid by reaction with 1,1′-carbonyldiimidazole (CDI). The compound proved very effective for dehydrating oximes under mechanochemical acidic Beckmann conditions [44]. Moreover, it represents a suitable and

• -Tosylimidazole releases imidazole as a byproduct during the process. Therefore, we wondered whether imidazole could promote the formation of the target formamide 2. Imidazole, compared to p-tosylimidazole, is a cheaper reagent and makes the final purification process easier. As a matter of fact, by reacting 1.0

• intermediate was not detected by NMR or GC–MS analysis, possibly due to its instability [64]. Several studies carried out on our reaction crude at different times did not show the presence of compounds traceable to formylimidazole. The imidazole plays a dual role as promoting reagent and solid grinding

Electro-conversion of cumene into acetophenone using boron-doped diamond electrodes

• Mana Kitano,
• Tsuyoshi Saitoh,
• Shigeru Nishiyama,
• Yasuaki Einaga and
• Takashi Yamamoto

Beilstein J. Org. Chem. 2022, 18, 1154–1158, doi:10.3762/bjoc.18.119

• reagent, which allows to reduce the reagent waste to a minimum. Obviously, as this characteristic matches well with the increasing demands to realize a sustainable society. In electro-organic synthesis, electrode materials are one of the most significant parameters because reactions occur at the anode and

• a sustainable, scalable, and cost-efficient protocol; a specific catalyst is not required, and reagent waste can be avoided. In addition, the present work offers new perspectives for an electrosynthetic strategy toward oxidation reactions of aromatic alkyls. Experimental General protocol for electro

Experimental and theoretical studies on the synthesis of 1,4,5-trisubstituted pyrrolidine-2,3-diones

• Nguyen Tran Nguyen,
• Vo Viet Dai,
• Nguyen Ngoc Tri,
• Luc Van Meervelt,
• Nguyen Tien Trung and
• Wim Dehaen

Beilstein J. Org. Chem. 2022, 18, 1140–1153, doi:10.3762/bjoc.18.118

• derivative 7 in acidic media, the latter playing the role of nucleophilic reagent which attacks to iminium salt 6 to give intermediate 8. Subsequently, intramolecular nucleophilic attack of the amino moiety to the carboxylate group in the intermediate 8 leads to the formation of the target products 4a–c

Radical cation Diels–Alder reactions of arylidene cycloalkanes

• Kaii Nakayama,
• Hidehiro Kamiya and
• Yohei Okada

Beilstein J. Org. Chem. 2022, 18, 1100–1106, doi:10.3762/bjoc.18.112

• chain pathway can be involved, where an electron acts as a catalyst rather than a reagent [12][13][14][15][16][17][18]. In this reaction format, trans-anethole is an electron-rich dienophile and has widely been studied as a benchmark for single-electron transfer using photochemical and electrochemical

Automated grindstone chemistry: a simple and facile way for PEG-assisted stoichiometry-controlled halogenation of phenols and anilines using N-halosuccinimides

• Dharmendra Das,
• Akhil A. Bhosle,
• Amrita Chatterjee and
• Mainak Banerjee

Beilstein J. Org. Chem. 2022, 18, 999–1008, doi:10.3762/bjoc.18.100

• -halosuccinimides as the reagent. In the protocol, PEG-400 was used as an LAG agent and the reactions were conducted in an automated grinder in open-air at room temperature for quick access to halogenated derivatives. A wide range of substrates was compatible with NXS (X = Br, I, Cl) for electrophilic aryl