Selective hydrolysis of α-oxo ketene N,S-acetals in water: switchable aqueous synthesis of β-keto thioesters and β-keto amides

• Haifeng Yu,
• Wanting Zhang,
• Xuejing Cui,
• Zida Liu,
• Xifu Zhang and
• Xiaobo Zhao

Beilstein J. Org. Chem. 2024, 20, 2225–2233, doi:10.3762/bjoc.20.190

• carbocation of I produces intermediate II, which converts into intermediate III through a deprotonation–protonation process. Finally, the elimination of PhNH2 from intermediate III occurs to afford the desired product 2a. In the presence of NaOH, the Michael addition between 1a and base initially occurs to

Natural resorcylic lactones derived from alternariol

• Joachim Podlech

Beilstein J. Org. Chem. 2024, 20, 2171–2207, doi:10.3762/bjoc.20.187

Multicomponent syntheses of pyrazoles via (3 + 2)-cyclocondensation and (3 + 2)-cycloaddition key steps

• Ignaz Betcke,
• Alissa C. Götzinger,
• Maryna M. Kornet and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2024, 20, 2024–2077, doi:10.3762/bjoc.20.178

• acetylacetonate 20. Extension of the sequence by cyclization with hydrazine leads to the pyrazole products 21 (Scheme 5) [53]. The method works best with acetylacetonates, since deprotonation of other diketones with NaOEt leads to deactivation of the isothiocyanates. A limitation of the method is the formation of

• . The α,β-unsaturated carbonyl compounds 60 can undergo cyclization with tosylhydrazine in situ to form pyrazoles 61 under alkaline conditions, with the tosyl group acting as a leaving group. Upon deprotonation at position 1 by a base, followed by nucleophilic substitution of halides, N-functionalized

Diastereoselective synthesis of highly substituted cyclohexanones and tetrahydrochromene-4-ones via conjugate addition of curcumins to arylidenemalonates

• Deepa Nair,
• Abhishek Tiwari,
• Banamali Laha and
• Irishi N. N. Namboothiri

Beilstein J. Org. Chem. 2024, 20, 2016–2023, doi:10.3762/bjoc.20.177

• , our methodology involves a biphasic reaction medium where the starting material, viz. arylidenemalonate, remains in the organic layer and prevents itself from undergoing saponification because it requires either aqueous or alcoholic (MeOH or EtOH) medium. Furthermore, deprotonation of curcumin

• ). Unfortunately, no reaction occurred with aliphatic valeryl derivate 2h, presumably due to the competitive deprotonation of the active methylene group of curcumin and the allylic γ-position of the diester and/or the +I effect of the alkyl group which deactivates the β-position of the diester (Table 2, entry 8

Harnessing the versatility of hydrazones through electrosynthetic oxidative transformations

• Aurélie Claraz

Beilstein J. Org. Chem. 2024, 20, 1988–2004, doi:10.3762/bjoc.20.175

• formation of dimeric side products. Cyclic voltammetry analysis suggested an initial anodic single electron transfer (SET) to radical cation 5, cyclization and deprotonation. Subsequent SET oxidation in solution by 5 led to cation 7. Final deprotonation furnished aromatic cycle 4. In 2022, Zhang et al

• hydrazones initiated with the SET anodic oxidation of the hydrazone and deprotonation to form the N-centered radical 10. After aza-cyclization on the aromatic ring, a second SET oxidation and deprotonation delivered the heterocycle 9. This mechanism was supported by cyclic voltammetry analysis of a model

• point of view, the authors proposed the formation of N-pyridyl radical 18 through the anodic oxidation of in situ-generated anion 17. Subsequent radical cyclization, second anodic cyclization and deprotonation yielded the fused heterocycle 16. Similarly, Youssef and Alajimi disclosed the electrochemical

Regioselective alkylation of a versatile indazole: Electrophile scope and mechanistic insights from density functional theory calculations

• Pengcheng Lu,
• Luis Juarez,
• Paul A. Wiget,
• Weihe Zhang,
• Krishnan Raman and
• Pravin L. Kotian

Beilstein J. Org. Chem. 2024, 20, 1940–1954, doi:10.3762/bjoc.20.170

• negligible. These data suggest that deprotonation occurs prior to alkylation and that deprotonation of either indazole tautomer leads to anions of identical or highly similar energy. Furthermore, as seen in Figure 4, a total, five coordinated complexes were found to be at least 4.5 kcal/mol more stable than

• system (Figure 10). Under conditions A, deprotonation and cesium coordination were heavily favored by 11.1 kcal/mol (18(N-H)). Transition states 18-N2-Cs and 18-N1-Cs were found leading to N1- and N2-products, respectively. NCIs between the cesium cation with the ester and sulfonate oxygens, and

• molecules. Tautomerism of indazole. DFT-calculated deprotonation of 6 with Cs2CO3 in implicit THF with the temperature of the calculation set to 90 °C to simulate the dioxane conditions (top) and energy differences of four enolate resonance structures of 6 calculated as discrete structures. The hybrid is

Solvent-dependent chemoselective synthesis of different isoquinolinones mediated by the hypervalent iodine(III) reagent PISA

• Ze-Nan Hu,
• Yan-Hui Wang,
• Jia-Bing Wu,
• Ze Chen,
• Dou Hong and
• Chi Zhang

Beilstein J. Org. Chem. 2024, 20, 1914–1921, doi:10.3762/bjoc.20.167

• deprotonation with sulfamate, gives the 4-substituted isoquinolinone derivative 2a (Scheme 6). Looking into the formation of 2c' from 1c (Scheme 2), two other resonance structures for the initially formed intermediate 1CC, namely 1CC' and 1CC'', are shown in Scheme 7. The oxygen atom in the amide motif of the

Novel oxidative routes to N-arylpyridoindazolium salts

• Oleg A. Levitskiy,
• Yuri K. Grishin and
• Tatiana V. Magdesieva

Beilstein J. Org. Chem. 2024, 20, 1906–1913, doi:10.3762/bjoc.20.166

• make oxidation of amines less anodic (due to the H-bonding and facilitation of deprotonation of the radical cations), thus narrowing the potential gap. Preparative experiments were performed under the same conditions as described above: A one-compartment cell, DMF, 0.25 mol equiv of a mediator was

• contained some other compounds, which have not been identified. Among the amines studied, amine A3 is less prone to oxidation (due to the electron-withdrawing effect of the trifluoromethyl group) and is the less basic; the presence of a lutidine base even more fastens deprotonation of the radical cation

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

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

• skeletal rearrangement, providing the distinct skeleton of 11 via carbocation C. This rearrangement involves the preferential migration of an alkenyl group in C to the carbocation, followed by deprotonation at C18 to form an exo-olefin. β-face-selective hydroxylation at C12 in 11 by the P450 enzyme BscG

• deprotonation to form exomethylene. Subsequent in situ removal of the silyl protecting groups led to the total synthesis of brassicicene K (27). Thus, the biosynthetic proposal featuring the Wagner–Meerwein-type skeletal rearrangement (9→11) through the catalysis of P450 enzyme BscF was successfully emulated by

Methyltransferases from RiPP pathways: shaping the landscape of natural product chemistry

• Maria-Paula Schröder,
• Isabel P.-M. Pfeiffer and
• Silja Mordhorst

Beilstein J. Org. Chem. 2024, 20, 1652–1670, doi:10.3762/bjoc.20.147

• . Additionally, stereoselectivity can be achieved by using potassium bis(trimethylsilyl)amide for deprotonation and methylation with MeI [33][39]. Any of these routes would yield methylated amino acids that can then be incorporated into an oligopeptide in solid-phase peptide synthesis (SPPS). Additionally, N

pKalculator: A pK_a predictor for C–H bonds

• Rasmus M. Borup,
• Nicolai Ree and
• Jan H. Jensen

Beilstein J. Org. Chem. 2024, 20, 1614–1622, doi:10.3762/bjoc.20.144

• at 298.15 K. Following the approach of the Grzybowski group [3], we compute the heterolytic dissociation energy through the direct deprotonation reaction, ; see Equation 1. For each set of deprotonated C–H sites in a molecule, we determine the minimum heterolytic dissociation energy (). Hereafter, we

• use an out-of-sample dataset of 1043 pKa-dependent reactions from Reaxys, containing 584 aldol, 408 Claisen, and 51 Michael reactions. These reactions are chosen because they all involve a deprotonation step, and the C–H site with the lowest pKa value is most likely the site of the reaction. We also

• ML models predict the site of reaction using the lowest ML-predicted pKa value. To understand the result for the out-of-sample set, we show three different reactions in Scheme 1. The first step of the reaction shown in Scheme 1a is an aldol reaction where the deprotonation occurs at the least

Supramolecular assemblies of amphiphilic donor–acceptor Stenhouse adducts as macroscopic soft scaffolds

• Ka-Lung Hung,
• Leong-Hung Cheung,
• Yikun Ren,
• Ming-Hin Chau,
• Yan-Yi Lam,
• Takashi Kajitani and
• Franco King-Chi Leung

Beilstein J. Org. Chem. 2024, 20, 1590–1603, doi:10.3762/bjoc.20.142

• were investigated in aqueous medium. An aqueous solution of 5.0 wt % DA11 in Milli-Q water was prepared, followed by deprotonation with 1.0 equivalent of NaOH, showing excellent solubility up to 93 mM, giving a deep purple solution. An aqueous 43 µM solution DA11, diluted from the 5.0 wt % stock

Divergent role of PIDA and PIFA in the AlX₃ (X = Cl, Br) halogenation of 2-naphthol: a mechanistic study

• Kevin A. Juárez-Ornelas,
• Manuel Solís-Hernández,
• Pedro Navarro-Santos,
• J. Oscar C. Jiménez-Halla and
• César R. Solorio-Alvarado

Beilstein J. Org. Chem. 2024, 20, 1580–1589, doi:10.3762/bjoc.20.141

• -4–Br. The next step is a deprotonation assisted by the released Br3Al–OAc species. This allows the formation of the AcO–AlBr2 salt via TS3–Br and the trans intermediate I-5–Br, which contains a Br–I(Ph)–O–naphthyl bond of 2.14 Å length. The last step is the bromination of I-5–Br by isomerization to

Benzylic C(sp³)–H fluorination

• Alexander P. Atkins,
• Alice C. Dean and
• Alastair J. J. Lennox

Beilstein J. Org. Chem. 2024, 20, 1527–1547, doi:10.3762/bjoc.20.137

• for the efficient monofluorination of 4- and 2-alkylpyridines (Figure 4 – conditions [A]) [36]. The transformation relied on the polarisation of the heterobenzylic C–H bond, via the intermediate formation of an N-sulphonylpyridinium salt, to promote deprotonation. Following a polar mechanism with

Selectfluor and alcohol-mediated synthesis of bicyclic oxyfluorination compounds by Wagner–Meerwein rearrangement

• Ziya Dağalan,
• Muhammed Hanifi Çelikoğlu,
• Saffet Çelik,
• Ramazan Koçak and
• Bilal Nişancı

Beilstein J. Org. Chem. 2024, 20, 1462–1467, doi:10.3762/bjoc.20.129

• selectfluor and a carbocation is formed by bonding with fluorine. Subsequently, fluoroalkoxy compound 4 is formed by Wagner–Meerwein rearrangement followed by alcohol addition and deprotonation. Conclusion New bicyclic fluoroalkoxy compounds were synthesized by a molecular fluorine and metal-free methodology

Generation of alkyl and acyl radicals by visible-light photoredox catalysis: direct activation of C–O bonds in organic transformations

• Mithu Roy,
• Bitan Sardar,
• Itu Mallick and
• Dipankar Srimani

Beilstein J. Org. Chem. 2024, 20, 1348–1375, doi:10.3762/bjoc.20.119

• iridium photocatalyst [Ir(dF(CF3)ppy)2(dtbbpy)]PF6 leads to excited-state *[Ir(III)], Ered (*[Ir(III)]/[Ir(II)]) = +1.21 V, possessing sufficient energy to oxidize PPh3, forming the triphenylphosphine radical cation. Subsequently, benzoic acid undergoes deprotonation facilitated by a base, producing

• converted rather selectively in the order tertiary alcohol< secondary alcohol < primary alcohol. They also proposed a mechanism, which is outlined in Scheme 16. The first step involves deprotonation of alcohol in the presence of base and nucleophilic attack of CS2 to generate a xanthate salt intermediate

• -state *[Ir(III)] complex can effectively oxidize the nitrogen atom of activated NHC–alcohol adduct 66 via SET. The resulting nitrogen radical cation intermediate 67 weakens the adjacent C–H bond, making it more acidic and susceptible to deprotonation by a suitable base, ultimately yielding an α-amino

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

• rearrangement (27.7 kcal mol−1; Figure S12, Supporting Information File 1) of uncharged 11 compared to that of 2 (Figure 3B). The free energy barrier value for 11 is likely too high to be non-enzymatic at 28 °C and may at least require deprotonation of the hydroxy group or at least H-bonding with solvent [23

Cofactor-independent C–C bond cleavage reactions catalyzed by the AlpJ family of oxygenases in atypical angucycline biosynthesis

• Jinmin Gao,
• Liyuan Li,
• Shijie Shen,
• Guomin Ai,
• Bin Wang,
• Fang Guo,
• Tongjian Yang,
• Hui Han,
• Zhengren Xu,
• Guohui Pan and
• Keqiang Fan

Beilstein J. Org. Chem. 2024, 20, 1198–1206, doi:10.3762/bjoc.20.102

• deprotonation of 8 to form a substrate anion, which activated molecular oxygen to generate a substrate radical and the superoxide anion O2•−. The ensuing radical rebound reaction led to the formation of a peroxide intermediate, which in turn underwent a ring opening reaction to generate the hydroquinone

Stability trends in carbocation intermediates stemming from germacrene A and hedycaryol

• Naziha Tarannam,
• Prashant Kumar Gupta,
• Shani Zev and
• Dan Thomas Major

Beilstein J. Org. Chem. 2024, 20, 1189–1197, doi:10.3762/bjoc.20.101

• isoprenoid allylic carbocation has the capability to engage in standard carbocation reactions, including cyclization via intramolecular olefin attack at the positively charged center, Wagner–Meerwein rearrangements, and hydride or proton shifts. This sequence concludes either through deprotonation, resulting

• germacradienyl cation, and 1,11-cyclization resulting in the humulyl cation [14][15]. Deprotonation of the intermediate germacradienyl cation yields germacrene A, a doorway towards the synthesis of many eudesmane and guaiane sesquiterpene hydrocarbons through its reprotonation-induced transannular reactions

• (Scheme 1) [16]. As an alternative to deprotonation, the germacradienyl cation can be captured by water to yield the sesquiterpene alcohol hedycaryol, which is an important intermediate towards the synthesis of sesquiterpene alcohols [17]. The reprotonation of (R)-(+)-1 germacrene A or hedycaryol at 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

• this conjecture, the present reaction is proposed to involve reversible complexation between the alkyne and the cationic iodine(III) electrophile and subsequent trans-addition of the azole nucleophile, the latter step being coupled with concomitant deprotonation of the N–H bond by the triflate anion

Confirmation of the stereochemistry of spiroviolene

• Yao Kong,
• Yuanning Liu,
• Kaibiao Wang,
• Tao Wang,
• Chen Wang,
• Ben Ai,
• Hongli Jia,
• Guohui Pan,
• Min Yin and
• Zhengren Xu

Beilstein J. Org. Chem. 2024, 20, 852–858, doi:10.3762/bjoc.20.77

• isotope labeling experiments [6], followed by a 2,7-cyclization, afforded C6 cationic intermediate IM-3 with cyclopiane skeleton. Quench of the cation IM-3 with water would give 4, while upon two 1,2-alkyl shifts of IM-3, followed by deprotonation of cation IM-4, would give spiroviolene (1). On the other

• IM-7. A key 1,3-hydride shift of IM-7 from the β-face, followed by deprotonation of the formed C2-cation IM-8, would deliver the originally proposed structure 1' [6]. However, no related natural products that would be derived from the intermediates of this pathway have been found so far. A third

• ][20], and fusaterpenol (8, GJ1012E) [17]. A similar 1,2-alkyl shift of IM-10, followed by deprotonation of the formed spirocyclic cation IM-12, afforded 3. Although previous isotope labeling experiments did not support this pathway for spiroviolene cyclization, it should be noted that a subtle

Activity assays of NnlA homologs suggest the natural product N-nitroglycine is degraded by diverse bacteria

• Kara A. Strickland,
• Brenda Martinez Rodriguez,
• Ashley A. Holland,
• Shelby Wagner,
• Michelle Luna-Alva,
• David E. Graham and
• Jonathan D. Caranto

Beilstein J. Org. Chem. 2024, 20, 830–840, doi:10.3762/bjoc.20.75

• metabolic enzymes. In addition, it has been shown to irreversibly inhibit isocitrate lyase 1 (ICL1) from Mycobacterium tuberculosis [40], and key metabolic protein for these pathogens [41]. Isocitrate lyases convert isocitrate to glyoxylate and succinate. Deprotonation of 3NP (pKa = 9.0) results in the

• transition analog of carboxylate groups, resulting in nitro compounds also acting as tight-binding reversible inhibitors [42]. Deprotonation of NNG also results in formation of the corresponding nitronate, albeit with a pKa of 6.6 [24], far lower than that for 3-NP (Scheme 2). Therefore, a much larger

Recent developments in the engineered biosynthesis of fungal meroterpenoids

• Zhiyang Quan and
• Takayoshi Awakawa

Beilstein J. Org. Chem. 2024, 20, 578–588, doi:10.3762/bjoc.20.50

• led to the production of preterretonin A (7) (Figure 2) [9]. These data indicated that Trt1 protonates the epoxide of (10'R)-epoxyfarnesyl-DMOA-3,5-methyl ester (6), leading to the cyclization of the terpenoid moiety in the chair–chair conformation, and catalyzes the deprotonation of H-9' of the

• meroterpenoids: insuetusin A1 (12) and insuetusin B1 (10), respectively (Figure 2) [9]. Like other Trt1-type enzymes, InsB2 catalyzes the protonation of the epoxide, the formation of two six-membered rings in a chair–chair conformation, but the reaction finishes with the deprotonation of the hydroxy group at C-3

• to produce compound 10. In contrast, InsA7 commonly initiates and terminates the reaction with the protonation of the epoxide and the deprotonation of OH-3, respectively, but it produces product 12 via a boat–chair conformation. Since all of the other Trt1-like cyclases catalyze the reaction with

Entry to new spiroheterocycles via tandem Rh(II)-catalyzed O–H insertion/base-promoted cyclization involving diazoarylidene succinimides

• Alexander Yanovich,
• Anastasia Vepreva,
• Ksenia Malkova,
• Grigory Kantin and
• Dmitry Dar’in

Beilstein J. Org. Chem. 2024, 20, 561–569, doi:10.3762/bjoc.20.48

• -membered cycle in the latter case. The main direction of the reaction in these examples becomes isomerization (migration of a proton when it is captured by an intermediate anion) or other side processes. In the conjugated anion formed as a result of deprotonation (Scheme 8), one would also expect