Peptide stapling by late-stage Suzuki–Miyaura cross-coupling

• Hendrik Gruß,
• Rebecca C. Feiner,
• Ridhiwan Mseya,
• David C. Schröder,
• Michał Jewgiński,
• Kristian M. Müller,
• Rafał Latajka,
• Antoine Marion and
• Norbert Sewald

Beilstein J. Org. Chem. 2022, 18, 1–12, doi:10.3762/bjoc.18.1

• phthaloyl-protected N-terminal alanine was also used for macrocyclisation in peptide stapling [51][52]. Besides addressing the indole C2, the regioselective enzymatic halogenation at C5, C6, or C7 using FAD-dependent tryptophan halogenases opens a broad area of Pd-catalysed late-stage diversifications [53

Efficient N-arylation of 4-chloroquinazolines en route to novel 4-anilinoquinazolines as potential anticancer agents

• Rodolfo H. V. Nishimura,
• Thiago dos Santos,
• Valter E. Murie,
• Luciana C. Furtado,
• Leticia V. Costa-Lotufo and
• Giuliano C. Clososki

Beilstein J. Org. Chem. 2021, 17, 2968–2975, doi:10.3762/bjoc.17.206

• of the anticancer agent verubulin. Thus, after regioselective 4-chloroquinazoline metalation by an in situ trapping metalation strategy, reaction quenching with iodine allowed us to isolate 4-chloro-8-iodoquinazoline in 83% yield. Surprisingly, further reaction of 4-chloro-8-iodoquinazoline with 4

Iron-catalyzed domino coupling reactions of π-systems

• Austin Pounder and
• William Tam

Beilstein J. Org. Chem. 2021, 17, 2848–2893, doi:10.3762/bjoc.17.196

• radical 28 (Scheme 5). Regioselective Giese addition to the π-system 21 would generate the transient 2° alkyl radical 29. Due to the high energetic barrier associated with direct cross-coupling between sterically hindered 3° alkyl radicals and aryliron complexes, it is assumed the persistent aryliron

• an Fe(II) species and S2O82−, a cascade of SET reactions between the alkylcarbazate and the Fe catalyst will lead to the formation of the alkoxycarbonyl 125. Regioselective addition of the radical across the electron-neutral olefin will generate the radical intermediate 126, followed by the 6-endo

The PIFA-initiated oxidative cyclization of 2-(3-butenyl)quinazolin-4(3H)-ones – an efficient approach to 1-(hydroxymethyl)-2,3-dihydropyrrolo[1,2-a]quinazolin-5(1H)-ones

• Alla I. Vaskevych,
• Nataliia O. Savinchuk,
• Ruslan I. Vaskevych,
• Eduard B. Rusanov,
• Oleksandr O. Grygorenko and
• Mykhailo V. Vovk

Beilstein J. Org. Chem. 2021, 17, 2787–2794, doi:10.3762/bjoc.17.189

• Shevchenko National University of Kyiv, Kyiv 01601, Ukraine 10.3762/bjoc.17.189 Abstract A regioselective method for the synthesis of 1-(hydroxymethyl)-2,3-dihydropyrrolo[1,2-a]quinazolin-5(1H)-ones – close structural analogs of naturally occurring vasicinone alkaloids – is described. The procedure is based

• formation at the two competing nucleophilic centers. Results and Discussion In this work, we propose a regioselective approach to the synthesis of 2,3-dihydropyrroloquinazolin-5(1H)-ones 6 functionalized with a hydroxymethyl group by oxidative cyclization of hereto unknown 2-(buten-3-yl)quinazolin-4(3H

Highly stereocontrolled total synthesis of racemic codonopsinol B through isoxazolidine-4,5-diol vinylation

• Lukáš Ďurina,
• Anna Ďurinová,
• František Trejtnar,
• Ľuboš Janotka,
• Lucia Messingerová,
• Jana Doháňošová,
• Ján Moncol and
• Róbert Fischer

Beilstein J. Org. Chem. 2021, 17, 2781–2786, doi:10.3762/bjoc.17.188

• methodology based on the trans-stereoselective epoxidation reaction of 2,3-dihydroisoxazoles followed by the regioselective hydrolysis of the corresponding isoxazolidinyl epoxide [15][16]. Very recently, we have reported the synthesis of γ-(hydroxyamino)-α,β-diols by the addition of Grignard reagents to

AlBr₃-Promoted stereoselective anti-hydroarylation of the acetylene bond in 3-arylpropynenitriles by electron-rich arenes: synthesis of 3,3-diarylpropenenitriles

• Yelizaveta Gorbunova,
• Dmitry S. Ryabukhin and
• Aleksander V. Vasilyev

Beilstein J. Org. Chem. 2021, 17, 2663–2667, doi:10.3762/bjoc.17.180

• ) through the regioselective hydroarylation of the carbon–carbon double bond. In TfOH, the reactions proceed further to 3-arylindanones, as products of the intramolecular aromatic acylation of the 3,3-diarylpropanenitriles by the electrophilically activated nitrile group [16][17]. Based on this study and

• -3,3-diarylpropenenitriles 2a–o as products of the regioselective hydroarylation of the acetylene bond (Scheme 1). These reactions proceeded only with an excess of AlBr3 (6 equiv). Thus, running the reaction of nitrile 1a with benzene under the action of less amount AlBr3 (1–4 equiv) resulted in an

Recent advances in the tandem annulation of 1,3-enynes to functionalized pyridine and pyrrole derivatives

• Yi Liu,
• Puying Luo,
• Yang Fu,
• Tianxin Hao,
• Xuan Liu,
• Qiuping Ding and
• Yiyuan Peng

Beilstein J. Org. Chem. 2021, 17, 2462–2476, doi:10.3762/bjoc.17.163

• corresponding plausible mechanism is shown in Scheme 19. Firstly, Au-coordinated alkyne undergoes regioselective hydration to form intermediate 48. Then, intramolecular nucleophilic attack by azide occurs to give 2-carbonyl intermediate 49. Subsequently, intermediate 49 will undergo aromatization as well as the

Synthesis of 5-arylacetylenyl-1,2,4-oxadiazoles and their transformations under superelectrophilic activation conditions

• Andrey I. Puzanov,
• Dmitry S. Ryabukhin,
• Anna S. Zalivatskaya,
• Dmitriy N. Zakusilo,
• Darya S. Mikson,
• Irina A. Boyarskaya and
• Aleksander V. Vasilyev

Beilstein J. Org. Chem. 2021, 17, 2417–2424, doi:10.3762/bjoc.17.158

• reaction of the acetylenyl-1,2,4-oxadiazoles with arenes in neat triflic acid TfOH (CF3SO3H) at room temperature for 1 h resulted in the formation of E/Z-5-(2,2-diarylethenyl)-3-aryl-1,2,4-oxadiazoles as products of regioselective hydroarylation of the acetylene bond. The addition of TfOH to the acetylene

Advances in mercury(II)-salt-mediated cyclization reactions of unsaturated bonds

• Sumana Mandal,
• Raju D. Chaudhari and
• Goutam Biswas

Beilstein J. Org. Chem. 2021, 17, 2348–2376, doi:10.3762/bjoc.17.153

• depending on the reaction conditions (Scheme 13) [53][58]. Cyclization of 4-cycloocten-1-ol (35) with Hg(OAc)2 resulted in formation of two types of fused bicyclic products, 9-oxabicyclo[3.3.1]nonane (36) and 9-oxabicyclo[4.2.1]nonane (37) (Scheme 14) [59][60]. It was observed that the regioselective

• enol ether derivative 79 forming carbocyclic compounds 81 with good yields via intermediate 80 [78]. The cyclization of compounds 79 undergo regioselective addition with the triple bond in exocyclic alkene position leading to the formation of α-mercury ketone 80, which were later functionalized by

• -metalation followed by a regioselective mercuri-cyclization reaction (Scheme 60). During the total syntheses of (±)-fastigilin C and (–)-fastigilin C (201), 2 equiv of Hg(TFA)2 were used to synthesize key intermediate tricyclic furan compounds 199, 200, and 203. Hg(TFA)2 helped in the desired ring-formation

Photoredox catalysis in nickel-catalyzed C–H functionalization

• Lusina Mantry,
• Rajaram Maayuri,
• Vikash Kumar and
• Parthasarathy Gandeepan

Beilstein J. Org. Chem. 2021, 17, 2209–2259, doi:10.3762/bjoc.17.143

• the regioselective 2-functionalization of 1,3-dioxolane (13) with aryl chlorides 8. It was found that the electron-deficient aryl chlorides resulted in better yields within shorter reaction times over the electron-rich substrates. A possible catalytic cycle was shown to account for the reaction mode

• systems 16 were arylated in moderate to good yields. This photochemical C–H arylation protocol was also suitable for functionalizing diverse primary and secondary benzylic C–H bonds. The authors proposed a mechanism for this chemo- and regioselective C‒H arylation as shown in Figure 6 [62]. The

• corresponds to the observed major isomer product (Figure 15). In a related transformation, Hong realized the exclusively α-selective hydroacylation of ynones, ynoates, and ynamides via photoredox nickel catalysis. Thus, the combination of nickel and iridium catalysts efficiently catalyzed the regioselective α

Catalyzed and uncatalyzed procedures for the syntheses of isomeric covalent multi-indolyl hetero non-metallides: an account

• Ranadeep Talukdar

Beilstein J. Org. Chem. 2021, 17, 2102–2122, doi:10.3762/bjoc.17.137

• recently found active against Parkinson’s and Alzheimer’s diseases [101][102][103]. In 2002, Jiang, while studying its synthesis, found the tris(indolyl)borane 154 instead of the desired chiral indole alcohol 155 while reacting the N-silylated 4-bromoindole 152 with n-BuLi in a failed regioselective ring

A study on selective transformation of norbornadiene into fluorinated cyclopentane-fused isoxazolines

• Zsanett Benke,
• Attila M. Remete and
• Loránd Kiss

Beilstein J. Org. Chem. 2021, 17, 2051–2066, doi:10.3762/bjoc.17.132

• mixture of monometathesized products, but some dimetathesized (±)-9c was formed too. Similar to Table 1, G-2 provided the highest combined yield of (±)-9a and (±)-9b, but it was the least regioselective (ratio of (±)-9a and (±)-9b: 3.3:1 with HG-2, 2.5:1 with G-3 and 2:1 with G-2). We continued our

• (±)-15a and (±)-15b was formed as well. Judging from the ratio of (±)-15a and (±)-15b, HG-2 catalyst was the most regioselective and G-3 was the least regioselective. The next CM partner was 2,2,2-trifluoroethyl acrylate (7e, Scheme 9 and Table 9). With HG-2 catalyst, dimetathesized product (±)-16c was

• was formed, which was separable. The main product was always (±)-17a. HG-2 was more regioselective (ratio of (±)-17a and (±)-17b: 5:1 with HG-2 and 3.3:1 with G2), but G-2 provided a higher yield. We also attempted CM reactions of (±)-5 with 8-(allyloxy)-1,1,1,2,2,3,3,4,4,5,5,6,6-tridecafluorooctane

Recent advances in the syntheses of anthracene derivatives

• Giovanni S. Baviera and
• Paulo M. Donate

Beilstein J. Org. Chem. 2021, 17, 2028–2050, doi:10.3762/bjoc.17.131

• substituted anthracenes by the regioselective oxidative benzannulation of 1-adamantyl-1-naphthylamines 10 with internal alkynes 11 (Scheme 2) [35]. To the best of our knowledge, this was the first successful example of rhodium-catalyzed benzannulation reactions of N-adamantyl-1-naphthylamines. Reactions of 10

• anthracene, tetracene, and naphtho[b]thiophene derivatives via ZnBr2-mediated regioselective annulation of asymmetric 1,2-diarylmethine dipivalates 83a (Scheme 20). On the basis of this methodology, they prepared 37 examples of different types of anthracene derivatives, such as compounds 84a–e, in very good

• yields (89–94%) and mild reaction conditions [53]. In a related approach, in 2015, Mohanakrishnan and his group reported the synthesis of anthracene derivatives and other annulated products via the regioselective cyclization of asymmetric 1,2-diarylmethine diol 83b by using a HBr/AcOH system (Scheme 20

Progress and challenges in the synthesis of sequence controlled polysaccharides

• Giulio Fittolani,
• Theodore Tyrikos-Ergas,
• Denisa Vargová,
• Manishkumar A. Chaube and
• Martina Delbianco

Beilstein J. Org. Chem. 2021, 17, 1981–2025, doi:10.3762/bjoc.17.129

• glycosidic bond formation. Control over the polysaccharide length (degree of polymerization, DP) and regioselective insertion of modifications or branches are additional challenges. Three main approaches are available (Figure 1): A) enzymatic polymerization [10][11][12][13][14][15][16][17], B) chemical

• resulting 2,3-diol as acceptor in the following glycosylation [131]. A regioselective glycosylation strategy was developed to obtain a collection of linear glucans (8mer to 16mer) (Scheme 4), as well as a branched 9mer and 17mer [137][138]. A similar strategy based on the regioselective glycosylation of a

• -mediated aglycon delivery (BMAD) with the use of a diboron catalyst allowed for regio-, as well as stereoselective glycosylation to achieve an α(1-3)-pentaglucoside [175]. Regioselective 1,2-cis-glycosylation could also be achieved by boron-catalyzed coupling via a SNi-type mechanism [176]. Hydrogen bond

Regioselective N-alkylation of the 1H-indazole scaffold; ring substituent and N-alkylating reagent effects on regioisomeric distribution

• Ryan M. Alam and
• John J. Keating

Beilstein J. Org. Chem. 2021, 17, 1939–1951, doi:10.3762/bjoc.17.127

• synthesis and isolation of the desired N-1 or N-2 alkylindazole regioisomer can often be challenging and adversely affect product yield. Thus, as part of a broader study focusing on the synthesis of bioactive indazole derivatives, we aimed to develop a regioselective protocol for the synthesis of N-1

• electrophiles, while maintaining a high degree of N-1 regioselectivity. Keywords: indazole; N-alkylation; regioselective; sodium hydride; tetrahydrofuran; Introduction Indazole (benzo[c]pyrazole) is an aromatic bicyclic heterocycle and can be viewed as a (bio)isostere of indole [1]. While only a few naturally

• indazole derivatives [9], it would be of great synthetic value to further develop regioselective methods for the preparation of N-1 or N-2 substituted indazoles. General approaches to the synthesis of N-1 or N-2 substituted indazoles involve the incorporation of the N-substituent prior to, or following

On the application of 3d metals for C–H activation toward bioactive compounds: The key step for the synthesis of silver bullets

• Renato L. Carvalho,
• Amanda S. de Miranda,
• Mateus P. Nunes,
• Roberto S. Gomes,
• Guilherme A. M. Jardim and
• Eufrânio N. da Silva Júnior

Beilstein J. Org. Chem. 2021, 17, 1849–1938, doi:10.3762/bjoc.17.126

• catalyst to perform a regioselective scandium-catalyzed alkylation of 2-phenylquinoline derivatives (Scheme 3B) [38]. It is important to highlight the biological importance of quinoline derivatives, since several quinolines are known to present valuable biological activities, such as anti-HIV (5) [48

• molecules of substrate together. In addition, the high enantiopurity was ascribed to a chiral environment that presents three elements of asymmetry. Other examples of vanadium-mediated oxidative homocouplings of phenolic substrates include regioselective and asymmetric homocoupling of phenols and 2

• heteroaromatic electrophilic substitution and a non-radical pathway. An aminomethylation of the heteroaromatic ring with N-methylmorpholine-N-oxide catalyzed by VO(aca)2 reported by Mitchell and co-workers [109], however, was found to undergo with a regioselective outcome incompatible to an electrophilic

Sustainable manganese catalysis for late-stage C–H functionalization of bioactive structural motifs

• Jongwoo Son

Beilstein J. Org. Chem. 2021, 17, 1733–1751, doi:10.3762/bjoc.17.122

• and loxoprofen underwent regioselective azidation at the secondary benzylic sites over tertiary benzylic sites (see 13d and 13e). Additional mechanistic studies support the reaction pathway depicted in Figure 4. The azide anion is oxidized to a radical species on the anodic surface, where Mn(II)/L–N3

• intramolecular KIEs of C–H cleavage are 2.5 and 3.0, respectively). Next, the benzylic radical is trapped by the Mn–imido complex to afford aminated product 19. Based on additional mechanistic experiments, it was suggested that the MnIII(ClPc) (18)-catalyzed C–H amination process is regioselective for the more

A recent overview on the synthesis of 1,4,5-trisubstituted 1,2,3-triazoles

• Pezhman Shiri,
• Ali Mohammad Amani and
• Thomas Mayer-Gall

Beilstein J. Org. Chem. 2021, 17, 1600–1628, doi:10.3762/bjoc.17.114

• materials. As such, the discovery of more effective strategies for the rapid preparation of these significant products is extremely desired. The regioselective synthesis of these compounds mainly includes (i) direct synthesis of fully decorated systems and (ii) postfunctionalization of disubstituted 1,2,3

• subsequent elimination of HBr leads to the triazole ring [39]. Another metal-free strategy to 1,4,5-trisubstituted 1,2,3-triazoles 8 was realized by regioselective reaction of aryl azides 7 with enaminones 6 in the presence of triethylamine, water, and ionic liquid (IL). This method exhibits good functional

• compounds 25 through the regioselective addition and cyclization reaction of 1,1-enediamines (EDAMs) 24 with p-methylbenzenesulfonyl azide in 1,4-dioxane as solvent at reflux was presented by Yan et al. Some substituted EDAMs (R1 = R2) were concluded to be treated with TsN3. In continuation, substituted

Methodologies for the synthesis of quaternary carbon centers via hydroalkylation of unactivated olefins: twenty years of advances

• Thiago S. Silva and
• Fernando Coelho

Beilstein J. Org. Chem. 2021, 17, 1565–1590, doi:10.3762/bjoc.17.112

• cycloisomerizations initiated by the MHAT process in all-carbon quaternary synthesis The synthetic potential of carbon-centered radicals to construct new C(sp3)–C(sp3) bonds was considerably expanded by the development of MHAT strategies involving olefins as substrates. The regioselective transfer of the hydrogen

Chemical synthesis of C6-tetrazole ᴅ-mannose building blocks and access to a bioisostere of mannuronic acid 1-phosphate

• Eleni Dimitriou and
• Gavin J. Miller

Beilstein J. Org. Chem. 2021, 17, 1527–1532, doi:10.3762/bjoc.17.110

• afforded N1-Bn and N2-Bn tetrazoles 13 and 14 in low yield (31%) and again with little regiodiscrimination (N1-Bn/N2-Bn = 1:1.2). The synthesis of appropriately protected C6-tetrazole donors 11–14 was accomplished to allow for regioselective deprotection and unveil C4-acceptor capability within a broader

Double-headed nucleosides: Synthesis and applications

• Vineet Verma,
• Jyotirmoy Maity,
• Vipin K. Maikhuri,
• Ritika Sharma,
• Himal K. Ganguly and
• Ashok K. Prasad

Beilstein J. Org. Chem. 2021, 17, 1392–1439, doi:10.3762/bjoc.17.98

• ]. Nielsen and co-workers [42] additionally synthesized 2′-(N-benzoylcytosin-1-yl)methylarabinofuranosyl-N-benzoylcytosine (7) from uridine using a similar methodology. Thus, the nucleophilic epoxide ring opening in spironucleoside 2 with uracil in DMF in a N1-regioselective manner afforded the TIPDS

Synthesis of functionalized imidazo[4,5-e]thiazolo[3,2-b]triazines by condensation of imidazo[4,5-e]triazinethiones with DMAD or DEAD and rearrangement to imidazo[4,5-e]thiazolo[2,3-c]triazines

• Alexei N. Izmest’ev,
• Dmitry B. Vinogradov,
• Natalya G. Kolotyrkina,
• Angelina N. Kravchenko and
• Galina A. Gazieva

Beilstein J. Org. Chem. 2021, 17, 1141–1148, doi:10.3762/bjoc.17.87

• 5i was additionally confirmed by X-ray diffraction analysis (Figure 3). Conclusion Thus, the conditions for the regioselective preparation of each of the regioisomeric functionalized derivatives of imidazo[4,5-e]thiazolo[3,2-b]-1,2,4-triazines 4 and imidazo[4,5-e]thiazolo[2,3-c]-1,2,4-triazines 5 in

Synthesis of multiply fluorinated N-acetyl-D-glucosamine and D-galactosamine analogs via the corresponding deoxyfluorinated glucosazide and galactosazide phenyl thioglycosides

• Vojtěch Hamala,
• Lucie Červenková Šťastná,
• Martin Kurfiřt,
• Petra Cuřínová,
• Martin Dračínský and
• Jindřich Karban

Beilstein J. Org. Chem. 2021, 17, 1086–1095, doi:10.3762/bjoc.17.85

• ). 4,6-O-Benzylidenation of diol 18 followed by regioselective opening of the benzylidene acetal produced compound 35. Subsequent DAST deoxyfluorination delivered the desired thioglycoside 36 (Scheme 3). For both compounds 18 and 35, deoxyfluorination of the C4 hydroxy group occurred with inversion of

Recent advances in palladium-catalysed asymmetric 1,4–additions of arylboronic acids to conjugated enones and chromones

• Jan Bartáček,
• Jan Svoboda,
• Martin Kocúrik,
• Jaroslav Pochobradský,
• Alexander Čegan,
• Miloš Sedlák and
• Jiří Váňa

Beilstein J. Org. Chem. 2021, 17, 1048–1085, doi:10.3762/bjoc.17.84

• -rich chalcones. The products obtained after the addition reaction with arylboronic acids were further subjected to a regioselective Bayer–Villiger oxidation (Table 5) [3]. An enhanced protocol for the synthesis of 4-aryldihydrocoumarins (Table 6) was also presented [3], which was already mentioned

Stereoselective synthesis and transformation of pinane-based 2-amino-1,3-diols

• Ákos Bajtel,
• Mounir Raji,
• Matti Haukka,
• Ferenc Fülöp and
• Zsolt Szakonyi

Beilstein J. Org. Chem. 2021, 17, 983–990, doi:10.3762/bjoc.17.80

• -amino-1,3-diols, which underwent a regioselective ring closure with formaldehyde or benzaldehyde delivering pinane-condensed oxazolidines. During the preparation of 2-phenyliminooxazolidine, an interesting ring–ring tautomerism was observed in CDCl3. Keywords: 2-amino-1,2-diol; monoterpene; oxazolidin

• regioselective ring closure resulting in 21A. The structure of 21A was determined by 1H (whereas the CH-OH gave a dublet in DMSO-d6 while the CH2-OH of 21B could be detected as triplet) and 2D NMR spectroscopic techniques (HMBC). It is important to mention that this regioselectivity is the opposite to that

• -diols underwent a regioselective ring closure with formaldehyde and benzaldehyde producing pinane-condensed oxazolidines. In the case of 2-phenyliminooxazolidine, an interesting ring–ring tautomerism was observed in CDCl3. The prepared trifunctional compounds may serve as chiral catalysts in