Regioselectivity of the S_EAr-based cyclizations and S_EAr-terminated annulations of 3,5-unsubstituted, 4-substituted indoles

• Jonali Das and
• Sajal Kumar Das

Beilstein J. Org. Chem. 2022, 18, 293–302, doi:10.3762/bjoc.18.33

• summarizing recent relevant literature reports. Keywords: annulation; cyclization; fused indoles; regioselectivity; SEAr; Introduction Over the decades, countless cyclization and annulation reactions of substituted arenes/heteroarenes involving an electrophilic aromatic substitution (SEAr) reaction as the

• published in the last decade [5][6][7], this is the first time the regioselectivity of the SEAr-based/terminated cyclization and annulation reactions of 3,5-unsubstituted, 4-substituted indolesis is sytematized as a dedicated topic. Discussion The Tsuji–Trost reaction serves as a powerful tool in

• regioselectivity in favor of the 4,5-fused indole system. Based on their experimental and computational investigations, the researchers hypothesized that Thorpe–Ingold effect could induce dispersive interactions between the indole and styrene moieties, triggering the preferential formation of the 3,4-fused indoles

Iridium-catalyzed hydroacylation reactions of C1-substituted oxabenzonorbornadienes with salicylaldehyde: an experimental and computational study

• Angel Ho,
• Austin Pounder,
• Krish Valluru,
• Leanne D. Chen and
• William Tam

Beilstein J. Org. Chem. 2022, 18, 251–261, doi:10.3762/bjoc.18.30

• regioselectivity. The mechanism and origins of selectivity in the iridium-catalyzed hydroacylation reaction has been examined at the M06/Def2TZVP level of theory. The catalytic cycle consists of three key steps including oxidative addition into the aldehyde C–H bond, insertion of the olefin into the iridium

• hydride, and C–C bond-forming reductive elimination. Computational results indicate the origin of regioselectivity is involved in the reductive elimination step. Keywords: C–H activation; density functional theory; hydroacylation; iridium catalysis; regioselectivity; Introduction Organic synthesis is

• , the regioselectivity of such reactions is still undefined (Scheme 1) [58]. While the chemistry of symmetric OBD derivatives is well established, their unsymmetrically substituted counterparts 5 have remained underexplored (Scheme 1). Upon C1-substitution, the reactivity of C1-substituted OBDs 5 can

Synthesis of novel [1,2,4]triazolo[1,5-b][1,2,4,5]tetrazines and investigation of their fungistatic activity

• Anna V. Korotina,
• Svetlana G. Tolshchina,
• Rashida I. Ishmetova,
• Natalya P. Evstigneeva,
• Natalya A. Gerasimova,
• Natalya V. Zilberberg,
• Nikolay V. Kungurov,
• Gennady L. Rusinov,
• Oleg N. Chupakhin and
• Valery N. Charushin

Beilstein J. Org. Chem. 2022, 18, 243–250, doi:10.3762/bjoc.18.29

• inherent in the known triazolo[4,3-b][1,2,4,5]tetrazine system. However, their reactions have a low regioselectivity, thus leading to a large number of byproducts, thus making it difficult to separate the reaction mixture. All synthesized [1,2,4]triazolo[1,5-b][1,2,4,5]tetrazines 3–5 were screened in vitro

Organocatalytic asymmetric nitroso aldol reaction of α-substituted malonamates

• Ekta Gupta,
• Narendra Kumar Vaishanv,
• Sandeep Kumar,
• Raja Krishnan Purshottam,
• Ruchir Kant and
• Kishor Mohanan

Beilstein J. Org. Chem. 2022, 18, 217–224, doi:10.3762/bjoc.18.25

• using a silver-BINAP catalyst combination [25]. Later, the same group could successfully tune the catalytic system to control the regioselectivity in the addition of metal enolate to nitrosoarenes to achieve an α-hydroxyamination [26]. Since then, several groups have shown the use of metal-catalyzed

Diametric calix[6]arene-based phosphine gold(I) cavitands

• Gabriele Giovanardi,
• Andrea Secchi,
• Arturo Arduini and
• Gianpiero Cera

Beilstein J. Org. Chem. 2022, 18, 190–196, doi:10.3762/bjoc.18.21

• catalytic activity was demonstrated in promoting gold(I)-catalyzed cycloisomerization of 1,6-enynes, with ample scope and high regioselectivity. However, preliminary studies suggested that the catalytic event occurs outside the macrocyclic cavity. In order to get more insights on the role of the cavity to

Chemical and chemoenzymatic routes to bridged homoarabinofuranosylpyrimidines: Bicyclic AZT analogues

• Sandeep Kumar,
• Jyotirmoy Maity,
• Banty Kumar,
• Sumit Kumar and
• Ashok K. Prasad

Beilstein J. Org. Chem. 2022, 18, 95–101, doi:10.3762/bjoc.18.10

• reusability of the recovered Lipozyme® TL IM was also checked and it was found that the lipase could be used up to seven cycles of selective acetylation of 3′-azido-3′-deoxy-β-ᴅ-allofuranosyl nucleosides 14a,b without noticeable loss of regioselectivity and efficiency. Thus, trihydroxy nucleosides 14a,b were

Efficient and regioselective synthesis of dihydroxy-substituted 2-aminocyclooctane-1-carboxylic acid and its bicyclic derivatives

• İlknur Polat,
• Selçuk Eşsiz,
• Uğur Bozkaya and
• Emine Salamci

Beilstein J. Org. Chem. 2022, 18, 77–85, doi:10.3762/bjoc.18.7

• cyclic β-amino acid derivative, was achieved by oxirane ring opening in epoxide 7 with HCl(g)–MeOH, NaHSO4, or NH4Cl–DMF. The regioselectivity of oxirane ring-opening in 7 was attributed to the conformational effects. The mechanism for the formation of compound 10 was elucidated with DFT computations

Recent advances and perspectives in ruthenium-catalyzed cyanation reactions

• Thaipparambil Aneeja,
• Cheriya Mukkolakkal Abdulla Afsina,
• Padinjare Veetil Saranya and
• Gopinathan Anilkumar

Beilstein J. Org. Chem. 2022, 18, 37–52, doi:10.3762/bjoc.18.4

• essential for promoting this reaction (Scheme 12). Both electron-rich and electron-deficient indoles afforded the desired products in good yields. The major advantages of this method include high regioselectivity, mild reaction conditions, and reusability of the catalyst. Two years later, in 2014, Ackermann

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

• heteroarenes were all well-tolerated; however, monosubstituted aryl rings suffered from low regioselectivity which is in accordance with HAS-type reactions [138]. In 2020, the Wu group expanded on the radical cyclization chemistry of γ,δ-unsaturated oxime esters, describing a carbonylative cyclization with

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

• (see Scheme 1C) [10]. Appropriately 2-functionalized quinazolinones of type 5 might be good starting materials for the intramolecular cyclization providing the target compounds (see Scheme 1D); however, this approach was rarely used [33][34][35][36], possibly due to low regioselectivity of the ring

• reaction proceeded with high regioselectivity as 5-exo-trig cyclization. The substituent in the quinazoline ring had virtually no effect at the yield or selectivity of the heterocyclization. Two pathways seem to be possible for the oxidative heterocyclization of quinazolinones 7 (see Scheme 2). The first

• )-ones was found. The reaction proceeds with high regioselectivity when 2.5 equivalents of PIFA are used in 2,2,2-trifluoroethanol solution at 0 °С over 24 h. The synthesized compounds represent a new class of functionalized pyrroloquinazolinones – close analogs of naturally occurring vasicinone

Recent advances in the asymmetric phosphoric acid-catalyzed synthesis of axially chiral compounds

• Alemayehu Gashaw Woldegiorgis and
• Xufeng Lin

Beilstein J. Org. Chem. 2021, 17, 2729–2764, doi:10.3762/bjoc.17.185

• substrates and the chiral phosphoric acid, with the substituent at the 1-position of the 2-naphthol playing a key role in controlling the regioselectivity [107]. Conclusion In recent decades, chiral phosphoric acids have been recognized as privileged chiral catalysts and ligands and have therefore become an

Recent advances in organocatalytic asymmetric aza-Michael reactions of amines and amides

• Pratibha Sharma,
• Raakhi Gupta and
• Raj K. Bansal

Beilstein J. Org. Chem. 2021, 17, 2585–2610, doi:10.3762/bjoc.17.173

• yields ranged 57–89% with ee 70–97% [52]. A similar chiral multifunctional thiourea/boronic acid was used as an organocatalyst by Michigami et al. for the enantioselective synthesis of N-hydroxyaspartic acid derivatives 76 with perfect regioselectivity and high enantioselectivity (Table 17) [53

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

• performed well in the reaction with 1,3-enynes 54, providing moderate yield and regioselectivity. The CuH-catalyzed intramolecular coupling of enyne containing a nitrile group worked smoothly and gave a moderate yield under standard conditions at a decreased concentration. A plausible mechanism according to

Synthesis and investigation on optical and electrochemical properties of 2,4-diaryl-9-chloro-5,6,7,8-tetrahydroacridines

• Najeh Tka,
• Mohamed Adnene Hadj Ayed,
• Mourad Ben Braiek,
• Mahjoub Jabli and
• Peter Langer

Beilstein J. Org. Chem. 2021, 17, 2450–2461, doi:10.3762/bjoc.17.162

• -5,6,7,8-tetrahydroacridine (4a) (Table 1, entries 1–6). Towards a better understanding of the regioselectivity of the coupling, we carried out a series of experiments with decreased amounts of phenylboronic acid. In all cases, the cross-coupling took place at both bromine atoms of 4a and we could never

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

• electrophilic addition (Scheme 26). Schwartz et al. developed a new route for the synthesis of exocyclic enol ether 83 and endocyclic enol ether 85 involving a Hg(II)-induced cyclization of acetylenic alcohols 82 and 84, respectively [79]. This work revealed that the regioselectivity of the Hg(II) addition to

• group (101), chromone derivatives 102 were formed. On the introduction of the methylene moiety in between the aryl and methoxy group, 103 yielded isofuran derivatives 104 due to the change in regioselectivity during the cyclization. Dihydronapthalenes 106 were synthesized by cyclization of the

A visible-light-induced, metal-free bis-arylation of 2,5-dichlorobenzoquinone

• Pieterjan Winant and
• Wim Dehaen

Beilstein J. Org. Chem. 2021, 17, 2315–2320, doi:10.3762/bjoc.17.149

• multistep procedures requiring large amounts of toxic metal complexes [12][33][34]. Later improvements still demand prefunctionalization of the quinone substrate [35][36][37]. While effectively eliminating this requirement, CH bis-arylation using palladium complexes still suffers from regioselectivity

• combining photoredox and diazonium chemistry. By starting from the commercially available 2,5-dichlorobenzoquinone (1), we eliminate the issue of regioselectivity and effectively create a green synthesis pathway towards a versatile bis-electrophile. Results and Discussion We initiated our investigation by

Halides as versatile anions in asymmetric anion-binding organocatalysis

• Lukas Schifferer,
• Martin Stinglhamer,
• Kirandeep Kaur and
• Olga García Macheño

Beilstein J. Org. Chem. 2021, 17, 2270–2286, doi:10.3762/bjoc.17.145

• enantioselectivity, but this system also allowed the control over regioselectivity (C2 vs C4 cyclization) through alteration of the N-substituent of the pyrrole substrate and the acylating reagent (Scheme 4a) [34]. This example showcases that next to the counterion, the acylating group can have a major influence on

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

• nickel catalysis enables these protocols at room temperature with ample substrate scope (Scheme 8). Unsymmetrical amine substrates favored arylation at the methylene C‒H over methyl C‒H with good regioselectivity [59]. In 2017, Doyle utilized the photoredox nickel catalysis approach for the formylation

• arylated with moderate to good yields. When both primary and secondary C(sp3)‒H bonds are present in the substrate, regioselectivity favors the secondary position. The catalytic reaction conditions were compatible with the C(sp3)‒H arylation of tetrahydrothiophene (28a) as well [68]. The enantioselective C

• reaction, TIPS-protected ynones, ynoates, and ynamides smoothly transformed into the corresponding trisubstituted alkenes 63 in high regio- and stereoselectivities. A possible mechanism was proposed similar to the one shown in Figure 15 to account for the observed high regioselectivity. Allylation The

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. Similar to Table 1, HG-2 provided the lowest combined yield of monocoupled products, but it had the highest regioselectivity (ratio of (±)-10a and (±)-10b: 3.3:1 with HG-2 and 1.66:1 with G-2 and G-3, respectively). The highest yield for the (±)-10a and (±)-10b mixture (23%) was achieved with G-2

• monometathesized products were separable. Interestingly, regioselectivity was reversed compared to those in Tables 1–3: the main product was (±)-11b (26% with HG-2, 25% with G-2), while isomeric product (±)-11a was formed in lower yield (15% with HG-2 and 10% with G-2). G2 catalyst showed better regioselectivity

• ) accompanied by some (±)-13c. Interestingly, regioselectivity of all three catalysts was the same, with a 1.4:1 ratio of (±)-13a and (±)-13b. We continued our work with the study of CM reactions of compound (±)-5, which has a slightly longer alkyl chain on the heteroring compared to that of (±)-4. Similar to

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

• ]anthracene [62]. Sakaguchi, Nakae, and co-workers synthesized halogenated dibenzo[a,h]anthracenes 126a–c and 5,8-diiodopicenes from dibromo- or diiodoethynylterphenyl compounds 125 via a AuCl-catalyzed intramolecular double cyclization (Scheme 29) [63]. The authors investigated the regioselectivity of the

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

• 2,3-diol 4,6-O-benzylidene acceptor permitted to access various β(1–3)-glucans, ranging from trimer to 13mer [126]. Regioselectivity was also achieved using a gold-catalyzed glycosylation, to give a linear β(1–3)-linked 11mer and a branched 14mer in a convergent manner [139]. Collection of linear as

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

• observed > 99% N-1 regioselectivity for 3-carboxymethyl, 3-tert-butyl, 3-COMe, and 3-carboxamide indazoles. Further extension of this optimized (NaH in THF) protocol to various C-3, -4, -5, -6, and -7 substituted indazoles has highlighted the impact of steric and electronic effects on N-1/N-2 regioisomeric

• distribution. For example, employing C-7 NO2 or CO2Me substituted indazoles conferred excellent N-2 regioselectivity (≥ 96%). Importantly, we show that this optimized N-alkylation procedure tolerates a wide structural variety of alkylating reagents, including primary alkyl halide and secondary alkyl tosylate

• 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

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

• authors used a bulky titanium catalyst, by which a desirable regioselectivity could be achieved (Scheme 7B and C). The obtained N-substituted anilines resemble some important compounds already known for their biological activities, such as antimalarial (17) [69] and anticancer (18) [70][71] properties

• by vanadium to give iminium ions, followed by a nucleophilic attack of the heteroaromatic ring, have been suggested for most reactions. Evidence comes from the observed regioselectivity and the tolerance of the reactions to radical scavengers, which are in accordance with the occurrence of a

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

• (see 2b), respectively. Therein, C2 fluorination was favored, and 2a was observed as the major product due to the sterically congested environment at C3 created by the adjacent gem-dimethyl groups. The regioselectivity at the C2 position was observed similarly in a study on Mn-catalyzed chlorination

• solution obtained by the nuclear reaction using a cyclotron, and manganese–salen complex 7 was used as a fluoride transfer catalyst, which facilitated late-stage C–H radiofluorination, affording the corresponding radiofluorinated bioactive molecules 8a–h. In general, the regioselectivity of fluorination

• source to execute facile C–H azidation of pharmaceutical-like complex molecules (Scheme 3) [38]. In this study, the regioselectivity is governed not only by electronic and steric effects of the manganese catalysts 5 and 10 but also by the electronic properties of the substrates. Pregabalin is an

2,4-Bis(arylethynyl)-9-chloro-5,6,7,8-tetrahydroacridines: synthesis and photophysical properties

• Najeh Tka,
• Mohamed Adnene Hadj Ayed,
• Mourad Ben Braiek,
• Mahjoub Jabli,
• Noureddine Chaaben,
• Kamel Alimi,
• Stefan Jopp and
• Peter Langer

Beilstein J. Org. Chem. 2021, 17, 1629–1640, doi:10.3762/bjoc.17.115

• and prolonging the reaction time. In order to study the regioselectivity of the reaction, a series of experiments were carried out with decreasing amounts of phenylacetylene. Although we used one equivalent of phenylacetylene, we were not able to isolate the mono coupling product. Concerning the