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

• unreliable isolation of acyl fluoride intermediates, we next considered whether BT-SCF3-mediated deoxyfluorination of carboxylic acids could be coupled with a subsequent acylation in an overall one-pot process. Selecting amines as nucleophilic coupling partners, a short optimisation study was carried out to

• , reacting BT-SCF3 with carboxylic acids 1 under similar conditions provides (trifluoromethyl)thioesters 3 via a concerted deoxytrifluoromethylthiolation process from tetrahedral intermediate A affording thiocarbamate by-product B [31]. To test whether thioester species could act as intermediates in the

One-pot Ugi-azide and Heck reactions for the synthesis of heterocyclic systems containing tetrazole and 1,2,3,4-tetrahydroisoquinoline

• Jiawei Niu,
• Yuhui Wang,
• Shenghu Yan,
• Yue Zhang,
• Xiaoming Ma,
• Qiang Zhang and
• Wei Zhang

Beilstein J. Org. Chem. 2024, 20, 912–920, doi:10.3762/bjoc.20.81

• the Ugi reaction products 5 could affect the yield of the Heck reaction. To address the issue, compounds 5 were N-alkylated to afford intermediates 7 which were used in the subsequent Heck reaction step. Thus, an alternative one-pot Ugi-azide/N-alkylation/Heck reaction procedure was developed (Scheme

(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

• , respectively (Scheme 12B) [58]. Saponification of the ester moieties in these species followed by Curtius rearrangements then led to amines 114 and 116. Non-natural amino acid derivatives 113 and 117 are intermediates prepared using these methods that could be of interest to medicinal chemistry. Alcohol 111

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

• 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

• either IM-9 or IM-11 cations. A direct dyotropic rearrangement, or two stepwise 1,2-alkyl migrations of IM-9, are possible pathways en route to cation IM-10. The presence of these intermediates IM-9, -10, -11 could be inferred by the identification of GJ1012B/D (5/6, Scheme 1D) [11], cattleyene (7) [19

Skeletal rearrangement of 6,8-dioxabicyclo[3.2.1]octan-4-ols promoted by thionyl chloride or Appel conditions

• Martyn Jevric,
• Julian Klepp,
• Johannes Puschnig,
• Oscar Lamb,
• Christopher J. Sumby and
• Ben W. Greatrex

Beilstein J. Org. Chem. 2024, 20, 823–829, doi:10.3762/bjoc.20.74

• ]octane, while O6 migrated when the C4–OH was axial leading to 2,4-dioxabicyclo[2.2.2]octanes. The formation of both anomers from the non-selective addition of fluoride suggested intermediates with oxocarbenium character. This work has recently been extended by Banwell and co-workers to include a set of

• sulfites were not intermediates in the reaction manifold. Furthermore, the isolation of some starting alcohols in the reactions of 10b and 10d following chromatography was attributed to hydrolysis of the corresponding dialkyl sulfite 13b and 13d on silica, a process that can be acid or base-catalysed [26

• skeletal rearrangement (vide infra). Inclusion of the soft-nucleophile allyltrimethylsilane in the reaction of 10b to trap potential oxocarbenium ion intermediates also resulted in a complex mixture. During the isolation of the chloroalkyl ether products 11a–f, it was apparent that hydrolysis occurred

Advancements in hydrochlorination of alkenes

• Daniel S. Müller

Beilstein J. Org. Chem. 2024, 20, 787–814, doi:10.3762/bjoc.20.72

• the alkene in the first step, providing a carbocation that subsequently reacts with a chloride anion to yield the Markovnikov product. While this ionic mechanism is commonly illustrated in textbooks by showing “naked” cations as intermediates, several recent studies suggest a molecular concerted or

• ) could be prevented when switching to BCl3 (10 mol %). Interestingly, toluene (94), which is generated as a byproduct of the Grob fragmentation, must react more sluggishly with the generated cationic intermediates compared to chloride, as no alkylations of toluene were reported. In 2017, the Snyder group

• concerning the polar hydrochlorinations the activation energy for an anti-Markovnikov addition is at least by 30 kJ mol−1 higher than for normal addition. Therefore, the formation of the anti-Markovnikov product via purely cationic intermediates is never observed. The only report for the formation of the

Synthesis and characterization of water-soluble C₆₀–peptide conjugates

• Yue Ma,
• Lorenzo Persi and
• Yoko Yamakoshi

Beilstein J. Org. Chem. 2024, 20, 777–786, doi:10.3762/bjoc.20.71

• s, number of scans: 1. b) Scheme for the photoinduced 1O2 generation by C60 and reaction with spin trapping reagent 4-oxo-TEMP to form 4-oxo-TEMPO. Supporting Information Supporting Information File 4: Details for the synthesis of 5a–c and intermediates as well as spectral data. Acknowledgements

Research progress on the pharmacological activity, biosynthetic pathways, and biosynthesis of crocins

• Zhongwei Hua,
• Nan Liu and
• Xiaohui Yan

Beilstein J. Org. Chem. 2024, 20, 741–752, doi:10.3762/bjoc.20.68

• cell suspension culture, heterologous biosynthesis, and total synthesis [16][17]. Crocins can be obtained from plant cell culture, but the production is prone to epigenetic silencing and toxic intermediates. The chemical synthesis of crocins is challenging due to the presence of numerous chiral centers

• activity. Screening of novel enzymes for crocin biosynthesis and the directed evolution of known enzymes should facilitate the high-titer production of the key intermediates 5–7 etc. and the efficient conversion of these precursors into crocetin (1) and crocins. In conclusion, crocins are high-value plant

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

• agreement with the presence of a double bond between C22 and C23 in 1. A contrasting picture was obtained through deletion of the TE domain that resulted in off-loading of all premature intermediates from the PKS [16], possibly catalysed by a proofreading AT-like enzyme encoded in the bae cluster [17

• ]. These intermediates consistently showed masses two Da higher than expected, in agreement with a fully saturated intermediate at module 3 [16]. Subsequent investigations demonstrated that the C22=C23 double bond in 1 is incorporated in a post-PKS step through the action of BaeS (highlighted in blue) [18

• by the preceding modules (highlighted in purple) [14][16]. Furthermore, the structures of 1 and 2 show a shifted triene portion that is not in conjugation with the carboxylic acid function. NMR studies of off-loaded intermediates with the TE deletion mutant revealed that these double bond shifts are

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

• 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

SOMOphilic alkyne vs radical-polar crossover approaches: The full story of the azido-alkynylation of alkenes

• Julien Borrel and
• Jerome Waser

Beilstein J. Org. Chem. 2024, 20, 701–713, doi:10.3762/bjoc.20.64

• building blocks bearing two of the most versatile functional groups, allowing a rich panel of functionalization. They have been used as intermediates in numerous syntheses to access bioactive compounds [1][2][3][4] or materials [5][6][7]. In addition, azide reduction affords homopropargylic amines, which

• reduced yields (Table 3, entry 5). We were pleased to see that running the reaction in DME afforded 36% of 4a (Table 3, entry 6). A mixture of DME with HFIP, known to stabilize carbocationic intermediates [56], slightly increased the yield (Table 3, entry 7). DME was selected for further optimization as

Evaluation of the enantioselectivity of new chiral ligands based on imidazolidin-4-one derivatives

• Jan Bartáček,
• Karel Chlumský,
• Jan Mrkvička,
• Lucie Paloušová,
• Miloš Sedlák and
• Pavel Drabina

Beilstein J. Org. Chem. 2024, 20, 684–691, doi:10.3762/bjoc.20.62

• enhanced economic efficiency, eco-friendly practices, and reduced waste. Catalysts with the highest enantioselectivity have been employed in the synthesis of essential chiral intermediates for drug production, such as amprenavir [12], rivaroxaban [13][14], linezolid [13] and salmeterol [7]. Therefore

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

• selectivity was reached only in polar solvents such as DMF, DMSO, and MeCN. In other solvents, no reactivity was observed at the C2 or C4 positions. Selective modification of the C2 position of 6,7-dimethoxyquinazoline Products 12 are useful intermediates to achieve selective modification at the C2 position

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

• cationic intermediates, leading to the terpenoid structure of each product [6][7]. Particular attention has been paid to the biosynthesis of the compounds derived from farnesyl-DMOA (5) composed of 3,5-dimethylorsellinic acid (DMOA, 4) and the C15 terpenoid moiety due to their structural diversity (Figure

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

• also in the alpha position of the furanone ring. Reactions with allenic acids 11 were carried out according to a similar scheme, in the one-pot mode, without isolation of OH-insertion intermediates 12 (Scheme 4). In order to accelerate the cyclization step in this case, moderate heating was used after

• attack of the oxygen atom of the ester group on the benzyl bromide residue prevails, with the cleavage of the arylidene succinimide fragment involved in further non-selective processes. The causes of the failed cyclizations in the last two cases can be summarized as follows. The intermediates obtained

• multiple bonds (10 and 12). However, in the case of shorter (from 2-bromoethanol) and longer (compound 24) chain intermediates, the cyclization is retarded due to the disadvantage of forming a strained four-membered ring in the former case and a significant loss of entropy during the formation of a seven

Synthesis and biological profile of 2,3-dihydro[1,3]thiazolo[4,5-b]pyridines, a novel class of acyl-ACP thioesterase inhibitors

• Jens Frackenpohl,
• David M. Barber,
• Guido Bojack,
• Birgit Bollenbach-Wahl,
• Ralf Braun,
• Rahel Getachew,
• Sabine Hohmann,
• Kwang-Yoon Ko,
• Karoline Kurowski,
• Bernd Laber,
• Rebecca L. Mattison,
• Thomas Müller,
• Anna M. Reingruber,
• Dirk Schmutzler and
• Andrea Svejda

Beilstein J. Org. Chem. 2024, 20, 540–551, doi:10.3762/bjoc.20.46

• quantities of the most active compounds for advanced biological testing. Pleasingly, our four-step approach using a potassium O-ethyl dithiocarbonate-mediated formation of thio intermediates 11a–c (thiol–thione tautomers) with subsequent sulfur removal using iron powder in acetic acid [19] proceeded smoothly

• synthetic route, which enabled us to introduce a methyl substituent in this position. Likewise, methyl-substituted thiazolo[4,5-b]pyridines 5, 15a, and 15c were synthesized using an optimized Suzuki coupling and served together with compounds 12a–c as key intermediates to explore different reagents and

Ligand effects, solvent cooperation, and large kinetic solvent deuterium isotope effects in gold(I)-catalyzed intramolecular alkene hydroamination

• Ruichen Lan,
• Brock Yager,
• Yoonsun Jee,
• Cynthia S. Day and
• Amanda C. Jones

Beilstein J. Org. Chem. 2024, 20, 479–496, doi:10.3762/bjoc.20.43

• intermediates (expected from allene/alkyne addition) are more reactive than the C(sp3)-alkylgold intermediates expected from alkene addition [29]. Another study demonstrated the inefficiency of protodeauration in the presence of (albeit more basic) alkylamines [30]. These studies cast doubt on protodeauration

• ]. Protic additives are widely accepted to “facilitate proton transfer,” but they can also influence the aggregation of charged intermediates. Most mechanistic discussions incorporate protodeauration of alkylgold intermediates and consider a continuum from rate or enantio-determining nucleophilic attack

• molecule of amine delivers a proton to the alkylgold intermediate (for protodeauration). In a platinum-catalyzed hydroamination, a protodemetalation pathway is supported by kinetics and reactivity studies on generated platinum alkyl intermediates [46]. In a palladium-catalyzed hydroamination, a

Synthesis of 2,2-difluoro-1,3-diketone and 2,2-difluoro-1,3-ketoester derivatives using fluorine gas

• Alexander S. Hampton,
• David R. W. Hodgson,
• Graham McDougald,
• Linhua Wang and
• Graham Sandford

Beilstein J. Org. Chem. 2024, 20, 460–469, doi:10.3762/bjoc.20.41

• enolization of the monofluoro-diketone intermediates. In addition, imines and α-diboryl ketone derivatives can also be transformed to 2,2-difluoroketones using an N–F electrophilic fluorinating reagent [18]. Alternatively, building blocks containing CF2 units such as ethyl bromodifluoroacetate and

• ][31][32]. Since profit margins in the life science industries are always under constant pressure, less expensive methods of introducing fluorine selectively into active intermediates for manufacture on the industrial scale are required and, as a relatively inexpensive strategy, direct fluorination of

• of the enolization processes of residual 1a–i-keto or, more critically, the 2-fluoro-keto intermediates 2a–i-keto that are formed after monofluorination [50][53][54]. Consequently, we believe a stronger base must be formed during the fluorination process in the presence of quinuclidine, and it is

Mechanisms for radical reactions initiating from N-hydroxyphthalimide esters

• Carlos R. Azpilcueta-Nicolas and
• Jean-Philip Lumb

Beilstein J. Org. Chem. 2024, 20, 346–378, doi:10.3762/bjoc.20.35

• years and in the past, they were perceived as fleeting reaction intermediates. Recent progress in photoredox catalysis [6][7][8], electrochemistry [9][10], and the use of transition-metal (TM) catalysts in radical cross-coupling reactions [11] have dramatically expanded the use of radicals in synthesis

• the fragmentation step can be considered. Importantly, the diverse mechanisms in which RAEs engage in radical reactions can be exploited to modulate the reactivity of the resulting substrate radicals. For example, under net-reductive conditions, the radical intermediates are typically terminated via

• , fragmentation of 90 yields tert-butyl radical 64, which then adds to styrene 91 affording radical intermediate 92. At this stage, recombination of intermediates 89 and 92 may occur via SET followed by addition or through radical–radical coupling, affording benzylsulfonium intermediate 93. Finally, nucleophilic

Discovery of unguisin J, a new cyclic peptide from Aspergillus heteromorphus CBS 117.55, and phylogeny-based bioinformatic analysis of UngA NRPS domains

• Sharmila Neupane,
• Marcelo Rodrigues de Amorim and
• Elizabeth Skellam

Beilstein J. Org. Chem. 2024, 20, 321–330, doi:10.3762/bjoc.20.32

• of several catalytic domains organized into modules. Typically, a module possesses an adenylation (A) domain for selecting and activating amino- or keto acids, a thiolation (T) domain for shuttling intermediates between catalytic domains, and a condensation (C) domain that catalyzes amide or ester

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

• , with heavier chalcogens, only partially cyclized backbones, namely seco-HBCs 28, were obtained (Scheme 8, bottom). The synthesis of these helical compounds was based on S-, Se- or Te-dibenzo[b,f]heteropines 23b–d as key intermediates, which were engaged in a Diels–Alder reaction with

• under light activation thus prompted the investigation of 1,2-dithia-3,5-cyclohexadienes as synthetic photoprecursors of thiophene-based π-CPCs. In this sense, Schroth et al. reported the synthesis of thienothiophene and benzothienothiophene 40 from dithiin key intermediates (Scheme 11, top) [71]. Benzo

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

• transformation (debromination of 15 under the action of hydroxides or alkoxides) at early stages to catch possible intermediates, but without success (for example, in the 1H NMR spectrum of the mixture there are no signals of methoxy groups when using MeONa). Additional experiments show that under the reaction

Photochromic derivatives of indigo: historical overview of development, challenges and applications

• Gökhan Kaplan,
• Zeynel Seferoğlu and
• Daria V. Berdnikova

Beilstein J. Org. Chem. 2024, 20, 228–242, doi:10.3762/bjoc.20.23

• the Z-isomer with metal cations. Schematic representation of indigo-type (left) and amide-type (right) resonances in N,N'-acetylindigo (9a). Suggested intermediates for the double bond cleavage for the thermal relaxation of N,N'-diacylindigos: (A) a biradical transient species, (B) a dipolar transient

Copper-catalyzed multicomponent reaction of β-trifluoromethyl β-diazo esters enabling the synthesis of β-trifluoromethyl N,N-diacyl-β-amino esters

• Youlong Du,
• Haibo Mei,
• Ata Makarem,
• Ramin Javahershenas,
• Vadim A. Soloshonok and
• Jianlin Han

Beilstein J. Org. Chem. 2024, 20, 212–219, doi:10.3762/bjoc.20.21

• organic synthesis, as they can be used as diazo intermediates or carbene precursors for the rapid construction of complex molecules along with the introduction of fluoroalkyl groups [14][15][16]. Although the reaction of trifluorodiazoethane [17][18][19][20][21][22][23][24][25][26][27] as well as α-diazo

• . Conclusion In summary, a series of new β-trifluoromethyl β-diazo esters have been designed, which are applied for the first time in a cascade reaction through an interrupted esterification with nitrile ylides as the key intermediates under copper-catalysis conditions. Varieties of unsymmetric trifluoromethyl

Metal-catalyzed coupling/carbonylative cyclizations for accessing dibenzodiazepinones: an expedient route to clozapine and other drugs

• Amina Moutayakine and
• Anthony J. Burke

Beilstein J. Org. Chem. 2024, 20, 193–204, doi:10.3762/bjoc.20.19

• step-wise counterparts. Although the one-pot method worked for one example in both cases (but in one case it gave the DBDAP enol form), it failed to work for other substrates, and for that reason we had to rely on the step-wise approach. The more efficient method to access the diamine intermediates 3