Synthesis of spiroindolenines through a one-pot multistep process mediated by visible light

• Francesco Gambuti,
• Jacopo Pizzorno,
• Chiara Lambruschini,
• Renata Riva and
• Lisa Moni

Beilstein J. Org. Chem. 2024, 20, 2722–2731, doi:10.3762/bjoc.20.230

• overall yield resulted even better (76% starting from 1 g of N-Ph-THIQ), a slight decrease of the conversion of α-aminoamidine 2d into the spiro[indole-THIQ] 3d was observed. As expected, the use of a larger-diameter reactor caused a low penetration of the irradiation, thus leading to lower efficiency

Efficient modification of peroxydisulfate oxidation reactions of nitrogen-containing heterocycles 6-methyluracil and pyridine

• Alfiya R. Gimadieva,
• Yuliya Z. Khazimullina,
• Aigiza A. Gilimkhanova and
• Akhat G. Mustafin

Beilstein J. Org. Chem. 2024, 20, 2599–2607, doi:10.3762/bjoc.20.219

• dihydroxylation product – was only obtained after the oxidation of the previously synthesized HPy (9, Scheme 2). The overall yield of the 2,5-dihydroxy derivative 11 with PcCo, PcFe(II), and PcFe(III) ranged from 37–72%, with the highest yield (72%) obtained at 0.15 wt % PcCo. Increasing the catalyst quantity did

Machine learning-guided strategies for reaction conditions design and optimization

• Lung-Yi Chen and
• Yi-Pei Li

Beilstein J. Org. Chem. 2024, 20, 2476–2492, doi:10.3762/bjoc.20.212

• interdependencies between different reaction sequences, such as additional separation and purification steps, could reduce the overall yield [202]. This indicates that the suboptimal combination of each reaction does not necessarily represent the global optimum for multistep synthesis [203][204][205]. In contrast

Asymmetric organocatalytic synthesis of chiral homoallylic amines

• Nikolay S. Kondratyev and
• Andrei V. Malkov

Beilstein J. Org. Chem. 2024, 20, 2349–2377, doi:10.3762/bjoc.20.201

• cleavage of the methoxyphenyl group in aqueous methanol using excess of ceric ammonium nitrate (CAN) as a soft oxidant (Scheme 14). The sequence afforded the target (S)-homoallylic amine 69 in 64% overall yield with a complete retention of chirality. To gain a mechanistic insight into the formation of the

• practical potential of the methodology was illustrated by constructing the medicinal chemistry-relevant highly fused spiro compound 140 featuring 5 stereocentres (3 quaternary) in 99% ee and 76% overall yield from achiral 136 and racemic 137 in just 2 steps. Selected substrates were converted to the

Deuterated reagents in multicomponent reactions to afford deuterium-labeled products

• Kevin Schofield,
• Shayna Maddern,
• Yueteng Zhang,
• Grace E. Mastin,
• Rachel Knight,
• Wei Wang,
• James Galligan and
• Christopher Hulme

Beilstein J. Org. Chem. 2024, 20, 2270–2279, doi:10.3762/bjoc.20.195

• increased the overall yield of the reaction (Table 1, entry 5). In summary, minimal formamide (1–2 equiv), excess [D2]-formic acid, and heating to 170 °C in a microwave reactor for 5 minutes is expected to give excellent yields in good deuteration %. A tentative mechanism to [D3]-formamides is shown in

O,S,Se-containing Biginelli products based on cyclic β-ketosulfone and their postfunctionalization

• Kateryna V. Dil and
• Vitalii A. Palchykov

Beilstein J. Org. Chem. 2024, 20, 2143–2151, doi:10.3762/bjoc.20.184

• (Table 1, entry 7). Reflux in alcoholic media in the presence of p-toluenesulfonic acid or CAN (ceric ammonium nitrate) was also not particularly successful (Table 1, entries 8 and 9, yield 32–35%). We subsequently explored a range of reaction conditions to improve overall yield and selectivity. We

• ). However, increasing acidity and using trifluoroacetic acid (Table 1, entry 17) did not improve the overall yield. We also tried microwave activation conditions since this is a known technique for reactions of this type [32], but unfortunately, we did not find any improvement in the yield (Table 1, entry

Negishi-coupling-enabled synthesis of α-heteroaryl-α-amino acid building blocks for DNA-encoded chemical library applications

• Matteo Gasparetto,
• Balázs Fődi and
• Gellért Sipos

Beilstein J. Org. Chem. 2024, 20, 1922–1932, doi:10.3762/bjoc.20.168

• unaffected by the presence of light (see pages 5 and 6 in Supporting Information File 1). In the case of indazoles, increased reaction rates were observed in the presence of light, but the overall yield was the same for the dark and irradiated experiments. Although these reactions are typically complete

• on gram scale starting from 2.1 g of 2-bromobenzothiazole (1i). The gram scale production showed comparable results to those obtained in the small-scale procedure, leading to the formation of 1.8 g (67% overall yield) of the final product 6i (Scheme 7, bottom). On-DNA validation Due to the large

• scheme, scope and gram scale experiment. The numbers in brackets represent the overall yield for the synthesis of the amino esters from the Negishi coupling till the reduction/protection step. Reactions scheme and results for the on-DNA experiments. The reported values represent the normalized yield for

The Groebke–Blackburn–Bienaymé reaction in its maturity: innovation and improvements since its 21st birthday (2019–2023)

• Cristina Martini,
• Muhammad Idham Darussalam Mardjan and
• Andrea Basso

Beilstein J. Org. Chem. 2024, 20, 1839–1879, doi:10.3762/bjoc.20.162

• yield of 83–95%. The second strategy, based on the deacetylation of 29 followed by the GBB-3CR, led to a lower overall yield of 21–23%. The reaction with different 2-aminopyridines and alkyl/aryl isocyanides afforded the intermediates 30 in 86 to 96% yield, and the subsequent deacetylation with

• potassium carbonate was almost quantitative (97–99% yield). It is worth mentioning that the GBB reaction starting from the deacetylated substrate also leads to good results (83–91% of yield), but the overall yield is lowered due to a sluggish deacetylation reaction of 29. Sugar-based aldehydes were employed

• get 43 in an overall yield of 40–80% (Scheme 17). In this study, 14 distinct products were obtained, and the only limitation was observed using aliphatic aldehydes, due to the instability of the deprotected GBB adducts. Imidazopirimidines are a privileged scaffold incorporated in many bioactive

Synthesis of polycyclic aromatic quinones by continuous flow electrochemical oxidation: anodic methoxylation of polycyclic aromatic phenols (PAPs)

• Hiwot M. Tiruye,
• Solon Economopoulos and
• Kåre B. Jørgensen

Beilstein J. Org. Chem. 2024, 20, 1746–1757, doi:10.3762/bjoc.20.153

• multiple products were formed. The lability of the acetals prompted us to submit the crude intermediate directly to hydrolysis without prior isolation (Table 4). As mentioned above, having an aqueous reaction mixture in the electrochemical oxidation will give reduced yields. The overall yield of 9b from 6b

Syntheses and medicinal chemistry of spiro heterocyclic steroids

• Laura L. Romero-Hernández,
• Ana Isabel Ahuja-Casarín,
• Penélope Merino-Montiel,
• Sara Montiel-Smith,
• José Luis Vega-Báez and
• Jesús Sandoval-Ramírez

Beilstein J. Org. Chem. 2024, 20, 1713–1745, doi:10.3762/bjoc.20.152

• of these compounds against various diseases. Review Spiro steroids with four-membered heterocycles Spirooxetane steroids In 2003 Wüst et al. reported the synthesis of the oxetan-3-one derivative 2 in an overall yield of 4.2% from hydrocortisone, in six steps. A key intermediate for oxetan-3-one 2 was

• . The oxetane compound 6 was further derivatized to incorporate a pyrrolidine moiety in presence of ammonia. Upon debenzylation at C-3, the target compound 7 was obtained in an 18% overall yield from 3. The pyrrolidino-oxetane derivative exhibited potent inhibition of Hedgehog signaling, comparable to

• of 10% Pd/C and 5% Pd/CaCO3 yielded reduced compound 19. Cleavage of the THP group with Amberlist-15® resin and a final Jones oxidation of the primary alcohol to the carboxylic acid, led to cyclization with the 17β-OH group affording the lactone 20 in a moderate overall yield (Scheme 6). Biological

Chemo-enzymatic total synthesis: current approaches toward the integration of chemical and enzymatic transformations

• Ryo Tanifuji and
• Hiroki Oguri

Beilstein J. Org. Chem. 2024, 20, 1693–1712, doi:10.3762/bjoc.20.151

• chemo-enzymatic total synthesis of jorunnamycin A (103). SfmC-catalyzed enzymatic conversion followed by cyanation and N-methylation also converted substrate analog 101 to the corresponding pentacyclic tertiary amine 102 in 18% overall yield based on peptidyl aldehyde 101. Subsequent simple chemical

New triazinephosphonate dopants for Nafion proton exchange membranes (PEM)

• Fátima C. Teixeira,
• António P. S. Teixeira and
• C. M. Rangel

Beilstein J. Org. Chem. 2024, 20, 1623–1634, doi:10.3762/bjoc.20.145

• ]methylphosphonate (10). The following hydrogenolysis under H2/Pd/C conditions in ethanol, afforded the desired diethyl (4-hydroxyphenyl)methylphosphonate (7), in an overall yield of 80%. The synthesis of diethyl [hydroxy(4-hydroxyphenyl)methyl]phosphonate (11) [55] started with the reaction of 4-hydroxybenzaldehyde

Challenge N- versus O-six-membered annulation: FeCl₃-catalyzed synthesis of heterocyclic N,O-aminals

• Giacomo Mari,
• Lucia De Crescentini,
• Gianfranco Favi,
• Fabio Mantellini,
• Diego Olivieri and
• Stefania Santeusanio

Beilstein J. Org. Chem. 2024, 20, 1412–1420, doi:10.3762/bjoc.20.123

• (entries 1–7, Table 1). Similarly to what was observed by Yu and co-workers for the intramolecular cyclization of alkynyl aldehyde acetals [28][29], it was found that the use of FeCl3 provided the better result in terms of overall yield (entry 3, Table 1). Moreover, the choice of iron(III) seemed to have

Computation-guided scaffold exploration of 2E,6E-1,10-trans/cis-eunicellanes

• Zining Li,
• Sana Jindani,
• Volga Kojasoy,
• Teresa Ortega,
• Erin M. Marshall,
• Khalil A. Abboud,
• Sandra Loesgen,
• Dean J. Tantillo and
• Jeffrey D. Rudolf

Beilstein J. Org. Chem. 2024, 20, 1320–1326, doi:10.3762/bjoc.20.115

• derivatives (16 and 17), in a ratio of 3:1 in 82% overall yield, with a phenylselenyl groups at C6 were obtained when 2 was reacted with PhSeBr in acetonitrile overnight (Figure 4 and Figures S24–S36 in Supporting Information File 1). A similar reaction with PhSCl was also tested but yielded only several

Light on the sustainable preparation of aryl-cored dibromides

• Fabrizio Roncaglia,
• Alberto Ughetti,
• Nicola Porcelli,
• Biagio Anderlini,
• Andrea Severini and
• Luca Rigamonti

Beilstein J. Org. Chem. 2024, 20, 1076–1087, doi:10.3762/bjoc.20.95

• developed method was finally successfully scaled up to 10 g scale, giving 3a in excellent isolated yield (87%), with only small amounts of polybrominated byproducts as contaminants (<2%). The pure product was obtained through (unoptimised) crystallisation from toluene, giving 3a in 80% overall yield, and

Enantioselective synthesis of β-aryl-γ-lactam derivatives via Heck–Matsuda desymmetrization of N-protected 2,5-dihydro-1H-pyrroles

• Arnaldo G. de Oliveira Jr.,
• Martí F. Wang,
• Rafaela C. Carmona,
• Danilo M. Lustosa,
• Sergei A. Gorbatov and
• Carlos R. D. Correia

Beilstein J. Org. Chem. 2024, 20, 940–949, doi:10.3762/bjoc.20.84

• previous works [18], the oxidation step is practical and high-yielding, and the overall yield can be reported based on the isolated lactams. By evaluating the electronics of the diazonium salt, we observed that the electron-donating p-OMe substituent performed better (4aa, 68% yield) when compared to

• 93:7. The methodology was shown to be robust, allowing the use of different protecting groups at the nitrogen of the 4-pyrroline substrate. We also report straightforward synthetic routes to obtain (R)-rolipram (5b, 61% overall yield, 3 steps, 82:18 er) and (R)-baclofen hydrochloride (6, 49% overall

• yield, 4 steps, 90:10 er) using the Heck–Matsuda reaction as a key step for constructing the stereogenic center. N,N-Ligands evaluated in this work. Rationalization of the enantioselectivity obtained in the Heck–Matsuda reaction of protected 2,5-dihydro-1H-pyrrole with aryldiazonium salts catalyzed by

Direct synthesis of acyl fluorides from carboxylic acids using benzothiazolium reagents

• Lilian M. Maas,
• Alex Haswell,
• Rory Hughes and
• Matthew N. Hopkinson

Beilstein J. Org. Chem. 2024, 20, 921–930, doi:10.3762/bjoc.20.82

• product resulting from addition of 1 to thiocarbonyl difluoride. After a further 30 minutes at rt, 19F NMR analysis of the crude mixture indeed indicated the formation of 2a in an overall yield of 74%, implying both pathways are feasible and that sub-stoichiometric amounts of BT-SCF3 relative to the

Three-component N-alkenylation of azoles with alkynes and iodine(III) electrophile: synthesis of multisubstituted N-vinylazoles

• Jun Kikuchi,
• Roi Nakajima and
• Naohiko Yoshikai

Beilstein J. Org. Chem. 2024, 20, 891–897, doi:10.3762/bjoc.20.79

• reaction using alkyne 3a and BXT (1). 4-Bromo and 4-methylpyrazoles afforded the desired products 4ba and 4ca in 92% and 38% yields, respectively. 3-Phenylpyrazole underwent competitive alkenylation at the N1 and N2 positions, affording the N2-alkenylated product 4da and its N1-regioisomer in 84% overall

• yield in a ratio of 7:3. Indazole and its 4-bromo and 6-methoxycarbonyl analogues afforded the expected N1-alkenylated products 4ea–4ga in 43–68% yields. 1,2,3-Triazole and benzotriazole both smoothly participated in the reaction to give their respective products 4ha and 4ia in 60% and 81% yields

(Bio)isosteres of ortho- and meta-substituted benzenes

• H. Erik Diepers and
• Johannes C. L. Walker

Beilstein J. Org. Chem. 2024, 20, 859–890, doi:10.3762/bjoc.20.78

• [1.1.1]propellanes (Scheme 13B) [27]. These new syntheses increased the overall yield of the [3.1.1]propellane synthesis from Gassman’s original 6% to 23% (Uchiyama) and up to 35% (Anderson) in 5 steps. Iodine-substituted 1,5-BCHeps 134a–g were shown to be accessible from [3.1.1]propellane via

Substrate specificity of a ketosynthase domain involved in bacillaene biosynthesis

• Zhiyong Yin and
• Jeroen S. Dickschat

Beilstein J. Org. Chem. 2024, 20, 734–740, doi:10.3762/bjoc.20.67

• SNAC ester (S)-11, with a yield of 32% over 5 steps starting from 13C-labelled 3. Analogous reactions were performed to obtain (R)-11 from ᴅ-leucine ((R)-6) with a comparable overall yield of 35% from labelled 3. BaeJ-KS2 activity assay The substrate specificities of ketosynthases in trans-AT PKSs hold

Chemoenzymatic synthesis of macrocyclic peptides and polyketides via thioesterase-catalyzed macrocyclization

• Senze Qiao,
• Zhongyu Cheng and
• Fuzhuo Li

Beilstein J. Org. Chem. 2024, 20, 721–733, doi:10.3762/bjoc.20.66

• sequential NRPS genes. However, none of them contain the thioesterase domain, which is essential for late-stage cyclization [59]. In 2018, Wakimoto, Kuranaga and co-workers reported the first total synthesis of surugamide B (16) in 34% overall yield through the general SPPS process and the macrocyclization

• the resin before the SPPS, as well as a leaving group in further enzymatic cyclization (17c). Utilizing this approach, the overall yield of surugamide B (82.8%) was greater than the SNAC-based peptides with the same sequence used in the previous study (30%, Scheme 5a). In addition to investigating the

• overall yield. According to the biosynthetic approach, these macrolides are produced by the type I PKS system, including thioesterase (TE)-catalyzed cyclization of the linear hexa- and heptaketide intermediates, post-PKS oxidation, and glycosylation [67]. Cane and co-workers reported that Pik TE, the TE

Regioselective quinazoline C2 modifications through the azide–tetrazole tautomeric equilibrium

• Dāgs Dāvis Līpiņš,
• Andris Jeminejs,
• Una Ušacka,
• Anatoly Mishnev,
• Māris Turks and
• Irina Novosjolova

Beilstein J. Org. Chem. 2024, 20, 675–683, doi:10.3762/bjoc.20.61

• product. Compounds 12 did not tolerate aqueous conditions or high temperatures and have also been observed to degrade under direct sunlight. Next, a stepwise one-pot approach was investigated to increase the overall yield (Scheme 6). The reaction in anhydrous DMF yielded a mixture of the desired product

Synthesis of π-conjugated polycyclic compounds by late-stage extrusion of chalcogen fragments

• Aissam Okba,
• Pablo Simón Marqués,
• Kyohei Matsuo,
• Naoki Aratani,
• Hiroko Yamada,
• Gwénaël Rapenne and
• Claire Kammerer

Beilstein J. Org. Chem. 2024, 20, 287–305, doi:10.3762/bjoc.20.30

• of devices and in situ generation of the active material by late stage S-extrusion. Nevertheless, the synthetic route towards dinaphthothiepine bisimides initially reported suffered from several drawbacks: it had limited efficiency (1.2% overall yield over 8 steps for the synthesis of thiepine 3a

• -substituted soluble precursors 3a–f owing to increased modularity (Scheme 5) [62]. To this aim, acenaphthene was selected as key building block and it underwent two successive regioselective halogenations to give bromochloroacenaphthene 8 in 64% overall yield. The latter was next converted into the

• temperature required for the imide formation, as high temperature (>130 °C) induced undesired thermally-activated S-extrusion as side-reaction. According to this new synthetic route, compound 3a carrying octyl substituents was obtained on a gram-scale in 7 steps from acenaphthene, in 14% overall yield. The

Substitution reactions in the acenaphthene analog of quino[7,8-h]quinoline and an unusual synthesis of the corresponding acenaphthylenes by tele-elimination

• Ekaterina V. Kolupaeva,
• Narek A. Dzhangiryan,
• Alexander F. Pozharskii,
• Oleg P. Demidov and
• Valery A. Ozeryanskii

Beilstein J. Org. Chem. 2024, 20, 243–253, doi:10.3762/bjoc.20.24

• positions 5 and 8 already at room temperature (Scheme 3). The overall yield of the main product 10 turned out to be high, but the substance contained a hard-to-separate impurity in an amount of up to 12%, to which, judged by the high-field position of the signals in the corresponding proton spectrum, was

Optimizations of lipid II synthesis: an essential glycolipid precursor in bacterial cell wall synthesis and a validated antibiotic target

• Milandip Karak,
• Cian R. Cloonan,
• Brad R. Baker,
• Rachel V. K. Cochrane and
• Stephen A. Cochrane

Beilstein J. Org. Chem. 2024, 20, 220–227, doi:10.3762/bjoc.20.22

• -phosphite intermediate was then oxidized with hydrogen peroxide to yield dibenzyl α-phosphate 6, achieving an overall yield of 89% for these two steps. Removal of the 2-(phenylsulfonyl)ethanol protecting group in compound 6 was successfully achieved through treatment with 1,8-diazabicyclo[5.4.0]undec-7-ene

• mixture underwent a cross-coupling reaction with prenyl monophosphates [46] in DMF/THF over a four-day period, yielding fully protected versions of lipid II and its analogues. Subsequent global deprotection reactions, using aqueous NaOH, led to the formation of lipid II (11), with an overall yield of 16