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

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

• process displayed good regioselectivity (Scheme 10) [23]. The authors proposed that the reaction may proceed through the mechanism illustrated in Scheme 11. Initially, EDAM 24 is treated with an azide source and subsequently, the intermediate 26 is formed through 1,2-addition reaction. The intermediate 26

• a [3 + 2]-cycloaddition between alkynes 73 and 76 and alkylthiotosyl azides 74 using MeOLi in the presence of a copper(I) catalyst in dioxane at room temperature. This Click/intramolecular sulfenylation reaction displayed an extensive scope, complete regioselectivity, and good to high yield of

Copper-mediated oxidative C−H/N−H activations with alkynes by removable hydrazides

• Feng Xiong,
• Bo Li,
• Chenrui Yang,
• Liang Zou,
• Wenbo Ma,
• Linghui Gu,
• Ruhuai Mei and
• Lutz Ackermann

Beilstein J. Org. Chem. 2021, 17, 1591–1599, doi:10.3762/bjoc.17.113

• hydrazide 1n was also amenable to this protocol and delivered the desired product 3na with high regioselectivity. We further investigated the viable scope of differently substituted terminal alkynes 2 as the general coupling partners for this transformation. As shown in Scheme 2, a variety of valuable

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

• patterns and electronic features were measured previously by the rate of deuterium/hydrogen exchange [77], and the observed constants served as a guide to the regioselectivity prediction of the HAT processes in substrates with different olefins. In substrate 40, for example, the hydrogen atom was

• olefins that are less reactive, such as the non-terminal ones, to be effectively functionalized. Eventually, the repair chain step could lead to an isomerized olefin. However, in most cases, it proceeds with almost perfect regioselectivity toward the regeneration of the starting material. Another example

• methylcycloalkanes (94a and 94b) and the terminal olefin 93 (Scheme 37A). Both examples showed perfect regioselectivity for the functionalization of the tertiary C(sp3)–H bond. Mechanistic studies carried out by the authors revealed a strong kinetic isotope effect (KIE = 11.5:1) when a competitive reaction was

A comprehensive review of flow chemistry techniques tailored to the flavours and fragrances industries

• Guido Gambacorta,
• James S. Sharley and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2021, 17, 1181–1312, doi:10.3762/bjoc.17.90

Heterogeneous photocatalytic cyanomethylarylation of alkenes with acetonitrile: synthesis of diverse nitrogenous heterocyclic compounds

• Guanglong Pan,
• Qian Yang,
• Wentao Wang,
• Yurong Tang and
• Yunfei Cai

Beilstein J. Org. Chem. 2021, 17, 1171–1180, doi:10.3762/bjoc.17.89

• phenyl ring (Scheme 3) were smoothly converted to the corresponding isoquinolinones 6a–e in moderate to good yields (51–69%, Scheme 3). The regioselectivity of this reaction was studied using the meta-substituted substrate 5f. The results indicated that the cyclization occurred at the less crowded

• regioselectivity to afford the six-membered product 8t in 22% yield. Regarding the scope of N-benzoyl acrylamides, the electronic property of a substituent on the phenyl ring also had little influence on the reaction, furnishing the desired isoquinolinediones 10a–c in moderate to high yields (Scheme 5, 60–70%). To

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

• with asymmetric substrates is the high regioselectivity of the cyclizations of intermediate Michael adducts at one of several reactive nitrogen atoms. For example, reported by Giannola et al. [21], the reaction of 3-thioxo-1,2,4-triazin-5-ones 1 with dimethyl acetylenedicarboxylate (DMAD) leads to the

• started by examining the regioselectivity of the condensation of imidazo[4,5-e]triazine-3-thiones 3 with DEAD. The effects of temperature, the nature of the solvent, and the structure of the starting substrates on the total yields and ratios of isomeric products 4 and 5 were investigated (Table 1, see

• also Supporting Information File 1 for details). The reaction of 5,7-dimethylimidazo[4,5-e]triazine-3-thione (3a) with DEAD proceeded in alcohols with moderate regioselectivity and isomer 5 predominated in the filtered precipitates (Table 1, entries 1–3). The use of absolute or 95% ethanol as a solvent

Synthesis of 10-O-aryl-substituted berberine derivatives by Chan–Evans–Lam coupling and investigation of their DNA-binding properties

• Peter Jonas Wickhorst,
• Mathilda Blachnik,
• Denisa Lagumdzija and
• Heiko Ihmels

Beilstein J. Org. Chem. 2021, 17, 991–1000, doi:10.3762/bjoc.17.81

• the Cu2+-catalyzed coupling reaction with the boronic acid (Scheme 2). The regioselectivity of the latter reaction step is most likely determined by a stronger nucleophilicity of the oxyanion in the 10-position of 6 that is caused by the particular electron distribution in the intermediate 6