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

Synthesis of new pyrazolo[1,2,3]triazines by cyclative cleavage of pyrazolyltriazenes

• Nicolai Wippert,
• Martin Nieger,
• Claudine Herlan,
• Nicole Jung and
• Stefan Bräse

Beilstein J. Org. Chem. 2021, 17, 2773–2780, doi:10.3762/bjoc.17.187

•  1, the alkylation protocol did not give a selective conversion in favor of one of the generated isomers. The protocol was not changed or adapted to gain a higher selectivity of one of the isomers, as both regioisomers were used in the subsequent syntheses. For the derivatives 12h and 13c, we were

• able to exemplarily determine the molecular structure by X-ray crystallography, proving the regioisomer obtained in the alkylation reaction (Figure 2). While isomer 12 was used for the synthesis of pyrazolo[3,4-d][1,2,3]-3H-triazine derivatives of general structure 5, the isomer 13 was intended to

• -triazine derivatives. Molecular structures of compounds 12h (A) and 13c (B) representing both possible regioisomers of the alkylation reaction (displacement parameters are drawn at the 50% probability level). The X-ray data corroborate the obtained NMR data. Graphical overview about selected pyrazolo[1,2,3

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

• values of up to 95% and very good yields (≈99%) in all cases (Table 11) [45]. Guo et al. synthesized a variety of benzoindolizidines (56) from α,β-unsaturated aminoketones 54 through intramolecular domino aza-Michael addition/alkylation reactions. The reactions were carried out in the presence of

• and thioureas were screened for the enantioselective N-alkylation of isoxazolin-5-ones via a 1,6-aza-Michael addition of isoxazolin-5-ones 64 to p-quinone methides (p-QMs) 65 to give isoxazolin-5-ones 67 bearing a chiral diarylmethyl moiety attached to the N atom. The best result in terms of

• aza-Michael/alkylation reaction catalyzed by cinchona alkaloid-derived quaternary ammonium salts. Asymmetric aza-Michael synthesis of isoindolinones. Asymmetric aza-Michael addition reaction catalysed by chiral bifunctional thiourea. Enantioselective 1,6-aza-Michael addition of isoxazolin-5-ones to p

Silica gel and microwave-promoted synthesis of dihydropyrrolizines and tetrahydroindolizines from enaminones

• Robin Klintworth,
• Garreth L. Morgans,
• Stefania M. Scalzullo,
• Charles B. de Koning,
• Willem A. L. van Otterlo and
• Joseph P. Michael

Beilstein J. Org. Chem. 2021, 17, 2543–2552, doi:10.3762/bjoc.17.170

• alkylation of the anion of pyrrolidin-2-one (16) with ethyl bromoacetate to afford the known compound ethyl 2-(2-oxopyrrolidin-1-yl)acetate (17) [31][32][33] in 77% yield. Thionation of 17 with Lawesson’s reagent in toluene at 80 °C gave the thione 18 as a yellow oil (86%). Reaction of 18 with phenacyl

• 19a. This enaminone-based method for constructing a pyrrole ring is similar to that in our reported routes to lamellarin alkaloids, in which N-alkylation of (Z)-configured 3,4-dihydroisoquinoline-derived enaminones with ethyl bromoacetate under either conventional [49][50] or microwave [51] heating

• such enaminones by the route shown in Scheme 4. Alkylation of piperidin-2-one (23) with ethyl bromoacetate followed by treatment of the resulting lactam [66][67] with Lawesson’s reagent in toluene at 80 °C gave the thione 24 in 83% overall yield. Reaction of 24 with phenacyl bromide and its 4-methoxy

Visible-light-mediated copper photocatalysis for organic syntheses

• Yajing Zhang,
• Qian Wang,
• Zongsheng Yan,
• Donglai Ma and
• Yuguang Zheng

Beilstein J. Org. Chem. 2021, 17, 2520–2542, doi:10.3762/bjoc.17.169

• alkylation Under mild conditions, copper salts are able to catalyze olefinic C–H functionalization or allylic alkylation, thus allow introducing alkenyl or allyl groups into organic molecules. Alkenylation and allylation reactions have been extensively investigated under thermal conditions. However, only few

• transferred electrons to organic halides, thereby achieving the cross-coupling. The detailed mechanistic studies are shown in section 3.2. In 2013, Fu and co-workers [81] reported the photoinduced copper-catalyzed alkylation of carbazoles 41 with alkyl halides 42 and completed the corresponding mechanistic

• functionalization of stable alkanes C(sp3)–H is generally difficult. In 2020, the König group [97] explored the photoinduced copperII catalyzed N–H alkylation of a broad range of nitrogen-containing compounds 61 with unactivated alkanes 62. A tert-butoxy radical abstracted a hydrogen atom from the alkane via the

Direct C(sp³)–H allylation of 2-alkylpyridines with Morita–Baylis–Hillman carbonates via a tandem nucleophilic substitution/aza-Cope rearrangement

• Siyu Wang,
• Lianyou Zheng,
• Shutao Wang,
• Shulin Ning,
• Zhuoqi Zhang and
• Jinbao Xiang

Beilstein J. Org. Chem. 2021, 17, 2505–2510, doi:10.3762/bjoc.17.167

• (sp3)–H allylic alkylation of 2-alkylpyridines with Morita–Baylis–Hillman (MBH) carbonates is described. A plausible mechanism of the reaction might involve a tandem SN2’ type nucleophilic substitution followed by an aza-Cope rearrangement. Various alkyl substituents on 2-alkylpyridines were tolerated

• in the reaction to give the allylation products in 26–91% yields. The developed method provides a straightforward and operational simple strategy for the allylic functionalization of 2-alkypyridine derivatives. Keywords: 2-alkylpyridines; allylic alkylation; aza-Cope rearrangement; catalyst-free

• synergistic catalyzed allylic alkylation between electron-deficient 2-ethyl benzoxazoles and MBH carbonates by the combination of a Lewis base and a metal salt [24]. In their studies, although pyridine derivatives were also applicable in the reaction, the presence of a strong electron-withdrawing NO2 group

Copper-catalyzed monoselective C–H amination of ferrocenes with alkylamines

• Zhen-Sheng Jia,
• Qiang Yue,
• Ya Li,
• Xue-Tao Xu,
• Kun Zhang and
• Bing-Feng Shi

Beilstein J. Org. Chem. 2021, 17, 2488–2495, doi:10.3762/bjoc.17.165

• (Scheme 1a) [17][18][19][20][21][22]. Early in 2015, the Ackermann group reported the first example of a low-valent Co-catalyzed C–H alkenylation of 2-pyridinylferrocene [23]. In 2017, the Butenschön group reported the ortho-C–H alkylation and arylation of ferrocene derivatives enabled by a combination of

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

• structural motifs to provide the functionalized pyridine and pyrrole derivatives. The functionalization reactions cover iodination, bromination, trifluoromethylation, azidation, carbonylation, arylation, alkylation, selenylation, sulfenylation, amidation, esterification, and hydroxylation. We also briefly

• functionalizations of pyrrole derivatives, such as iodination, bromination, trifluoromethylation, azidation, carbonylation, arylation, and alkylation. The proposed mechanism generally involves two kinds of intramolecular cyclizations: one is 6-endo-dig cyclization to promote the formation of pyridine ring

Efficient synthesis of polyfunctionalized carbazoles and pyrrolo[3,4-c]carbazoles via domino Diels–Alder reaction

• Ren-Jie Fang,
• Chen Yan,
• Jing Sun,
• Ying Han and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2021, 17, 2425–2432, doi:10.3762/bjoc.17.159

• scope of this domino Diels–Alder reaction, another kind of 3-vinylindoles was employed in the one-pot reaction. First, the 3-(indol-3-yl)-1,3-diphenylpropan-1-ones prepared through Friedel–Crafts alkylation of indole with chalcones, were oxidized by DDQ in acetonitrile to generate in situ the expected

Synthesis of O⁶-alkylated preQ₁ derivatives

• Laurin Flemmich,
• Sarah Moreno and
• Ronald Micura

Beilstein J. Org. Chem. 2021, 17, 2295–2301, doi:10.3762/bjoc.17.147

• (preQ1) [1]. Thus far, present-day riboswitches have only been known to bind – but not to be able to react – with their ligands [2][3]. This new finding now opens exciting avenues for the development of RNA labeling tools [4], in particular, for RNA methylation, and more generally, for RNA alkylation. To

Base-free enantioselective S_N2 alkylation of 2-oxindoles via bifunctional phase-transfer catalysis

• Mili Litvajova,
• Emiliano Sorrentino,
• Brendan Twamley and
• Stephen J. Connon

Beilstein J. Org. Chem. 2021, 17, 2287–2294, doi:10.3762/bjoc.17.146

• synthesis of a potent CRTH2 receptor antagonist. Keywords: alkylation; base-free; cinchona alkaloids; CRTH2 antagonist; hydrogen-bonding; oxindole; phase-transfer catalysis; Introduction The 2-oxindole scaffold is an important motif present in a myriad of natural products. Among 2-oxidole derivatives, 3,3

• highly valuable synthetic building blocks [5][6][7][8][9][10][11][12]. Both pyrroloindolines 1 and spirooxindoles 2 are conceivably available from key 3,3-disubstituted intermediates 3, which could be prepared via an enantioselective SN2 alkylation involving enolate 3a (Figure 1B). The versatility of

• charged intermediates, could be an excellent methodology for the enantioselective SN2 alkylation of enolates derived from the 2-oxindole core [13][14][15][16][17][18][19][20][21][22][23]. In recent years, several examples regarding the alkylation of 3-subsituted-2-oxindoles, via asymmetric phase-transfer

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

• heterolytic cleavage of HCl as displayed in Scheme 7 [55]. Moreover, other catalysts with amine functional groups were found more efficient in the enantioselective α-alkylation of aldehydes (Scheme 10b) [48] or in the asymmetric Mannich synthesis of α-amino esters using Takemoto’s bifunctional catalyst 44 [67

• catalyzed by chiral squaramide 37 by Jacobsen et al. Bis-urea-catalyzed enantioselective fluorination of a) β-bromosulfides and b) β-haloamines by Gouverneur et al. a) Bifunctional thiourea anion-binding – basic/nucleophilic catalysts. Selected applications in b) enantioselective α-alkylation of aldehydes

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

• products 39 with good regioselectivities. The authors proposed a tentative visible-light-driven radical chain mechanistic profile with nickel chain-walking as a key step to rationalize the C–H arylation process [78]. Alkylation The direct functionalization of C–H bonds in alkyl groups is a fundamental but

• nickel catalysis is also often employed to C(sp3)‒H alkylation transformations. For example, in 2017, MacMillan and co-workers reported a selective C(sp3)–H alkylation protocol via polarity-matched hydrogen atom transfer (HAT) using photoredox and nickel catalysis [85]. This method works through

• -catalyzed C–H alkylation strategy to use the readily available inexpensive organo-photocatalyst benzaldehyde as the HAT photocatalyst under UVA irradiation [68][86]. Thus, the combination of NiBr2·glyme/dtbbpy, benzaldehyde as both the photosensitizer and hydrogen abstractor, and K2HPO4 as a base under

Transition-metal-free intramolecular Friedel–Crafts reaction by alkene activation: A method for the synthesis of some novel xanthene derivatives

• Tülay Yıldız,
• İrem Baştaş and
• Hatice Başpınar Küçük

Beilstein J. Org. Chem. 2021, 17, 2203–2208, doi:10.3762/bjoc.17.142

• significance were synthesized by developing a new synthesis method. In order to obtain xanthene derivatives, the original alkene compounds to be used as the starting materials were synthesized in four steps using appropriate reactions. A cyclization reaction by intramolecular Friedel–Crafts alkylation was

• hours. As a result, an alkene compound was used for activation with TFA in the synthesis of xanthene through intramolecular Friedel–Crafts alkylation for the first time. Keywords: alkene activation; intramolecular Friedel–Crafts alkylation; trifluoroacetic acid; xanthene; Introduction The interest in

• ]. Therefore, there has been an increase in arylation methods using Friedel–Crafts alkylation (FCA) protocols without transition metals [35][36]. Environmentally friendly methods, in which metal-free catalysts are used, have come to the fore and are gaining importance because there are many disadvantages of

Preparation of mono-substituted malonic acid half oxyesters (SMAHOs)

• Tania Xavier,
• Sylvie Condon,
• Christophe Pichon,
• Erwan Le Gall and
• Marc Presset

Beilstein J. Org. Chem. 2021, 17, 2085–2094, doi:10.3762/bjoc.17.135

• describing their preparation. An evaluation of different approaches has been achieved, allowing to define the best strategies to introduce diversity on both the malonic position and the ester function. A classical alkylation step of a malonate by an alkyl halide followed by a monosaponification gave access

• intermediate Meldrum acid. Both these transformations are characterized by their simplicity and efficiency, allowing a straightforward access to SMAHOs from cheap starting materials. Keywords: alkylation; esterification; malonate; saponification; SMAHO; Introduction Malonic acid half oxyesters (MAHOs), also

• (SMAHOs) [8][9][10], or disubstituted MAHOs [11], has been only occasionally reported. Bibliographical data indicate that SMAHOs can be accessed by different routes (Scheme 1). The most classic one is the alkylation of a dialkyl malonate, followed by a monohydrolysis of one ester group. The alkylation is

Enantioenriched α-substituted glutamates/pyroglutamates via enantioselective cyclopropenimine-catalyzed Michael addition of amino ester imines

• Zara M. Seibel,
• Jeffrey S. Bandar and
• Tristan H. Lambert

Beilstein J. Org. Chem. 2021, 17, 2077–2084, doi:10.3762/bjoc.17.134

• -substituted glutamate derivatives is via the Michael addition of α-amino ester enolates to acrylate acceptors. These products can also be easily converted to pyroglutamates by lactamization [28][29][30]. Although the use of substituted amino ester derivatives for the enantioselective α-alkylation has been

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

• efficiently cyclized [42]. Friedel–Crafts alkylation of arenes with aromatic aldehydes The Lewis acid-catalyzed Friedel–Crafts alkylation of electron-rich arenes with aromatic aldehydes has proven an efficient and often direct method to prepare anthracene derivatives. Kodomari and co-workers disclosed a

• . Alkylation of arenes with aromatic aldehydes in the presence of acetyl bromide and ZnBr2/SiO2. BF3·H2O-catalyzed hydroxyalkylation of arenes with aromatic dialdehyde 44. Bi(OTf)3-promoted Friedel–Crafts alkylation of triarylmethanes and aromatic acylals and of arenes and aromatic aldehydes. Reduction of

Asymmetric organocatalyzed synthesis of coumarin derivatives

• Natália M. Moreira,
• Lorena S. R. Martelli and
• Arlene G. Corrêa

Beilstein J. Org. Chem. 2021, 17, 1952–1980, doi:10.3762/bjoc.17.128

• dihydrocinchonine 26 in combination with trifluoracetic acid (TFA) as Brønsted acid [39]. The reaction provides pyranocoumarins 25 with three vicinal stereogenic centers in high regio-, diastereo- and enantioselectivities through a tandem allylic alkylation/intramolecular oxa-Michael addition (Scheme 7). A

• described an allylic alkylation reaction between 3-cyano-4-methylcoumarins 39 and Morita–Baylis–Hillman (MBH) carbonates 40 [45]. In this case, the catalyst (DHQ)2PYR 42 activates the MBH substrate and generates the dienolate in the vinylogous coumarin moiety, acting as a base. After the nucleophilic

• -hydroxycoumarin 1 with α,β-unsaturated ketones 2 catalyzed by a chiral primary amino amide 32. Catalytic asymmetric β-C–H functionalization of ketones via enamine oxidation. Enantioselective synthesis of polycyclic coumarin derivatives 37 catalyzed by an primary amine-imine catalyst 38. Allylic alkylation

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

• alkylindazoles. Initial screening of various conditions revealed that the combination of sodium hydride (NaH) in tetrahydrofuran (THF) (in the presence of an alkyl bromide), represented a promising system for N-1 selective indazole alkylation. For example, among fourteen C-3 substituted indazoles examined, we

• 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

• 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

• and co-workers in 2018 [39]. In this work, the presence of [Sc-1] and several alkenes resulted in the successful scandium-C(sp3)–H alkylation of methyl thioethers (Scheme 4B), by which different activated internal thioethers were obtained in good yields (Scheme 4C). The transformation facilitates

• methods include V2O5 and VO(acac)2 used for the alkylation of 2-naphthol and nitrogen-containing heteroaromatic moieties containing N-methylmorpholine-N-oxide, tetrahydroisoquinolines, and N,N-dimethylacetamide [107][108][109][110][111][112][113]. The mechanisms involving oxidation of the amine mediated

Cationic oligonucleotide derivatives and conjugates: A favorable approach for enhanced DNA and RNA targeting oligonucleotides

• Mathias B. Danielsen and
• Jesper Wengel

Beilstein J. Org. Chem. 2021, 17, 1828–1848, doi:10.3762/bjoc.17.125

• effects of different amine-functionalized groups. Beginning with the 2’-O-alkylated RNA nucleotides (Table 4) it has been shown that the introduction of an aminopropyl group via 2’-O-alkylation (modification 34) leads to moderately improved hybridization properties for the modified ON against its RNA

• [117][118][119][120][121]. Rahman, Obika and co-workers investigated the properties of ONs modified with the aminoalkyl–PS linkage [117], based on the post-synthetic alkylation protocol developed earlier by Chen and Gothelf reacting PS-ONs with 2-bromoethylammonium bromide in HEPES (4-(2-hydroxyethyl

• formed by guanine alkylation prompted a switch to a 12-mer sequence containing only cytosine and thymine [117]. Conjugation of the desired aminoalkyl moieties with the stereo-pure PS-ON (Rp or Sp) gave the aminoalkyl–PS linkages shown in Table 9A, in yields between 24–55%. Extensive work has been carried

Development of N-F fluorinating agents and their fluorinations: Historical perspective

• Teruo Umemoto,
• Yuhao Yang and
• Gerald B. Hammond

Beilstein J. Org. Chem. 2021, 17, 1752–1813, doi:10.3762/bjoc.17.123

• , Banks et al. reported a new series of N-fluoro diquaternary ammonium salts, 1-alkyl-4-fluoro-1,4-diazoniabicylco[2.2.2]octane salts 16-3a–d (Scheme 33) [42]. The salts 16-3 were synthesized in high yields after alkylation of 1,4-diazabicyclo[2.2.2]octane (16-1), followed by the Umemoto’s fluorination

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

• -butynoate successfully generated the metal-bound heterocyclic complexes. The alkylation reaction of 171a led to the bond cleavage between ruthenium and nitrogen to produce several 1-alkylated 4,5-bis(ethoxycarbonyl)-1,2,3-triazoles 172 [66]. Herein, the sodium azide initially reacts with [Ru]–Cl 168 to

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

• nucleophiles, along with transition-metal catalysis, in olefin alkylation reactions [18][19][20][21]. Apart from the early examples of olefin functionalization with transition metals, such as the well-known ethylene oxidation catalyzed by Pd(II) (the Wacker reaction) [23][24], the use of carbon nucleophiles in

• of a Lewis acid (LA) to activate 1,3-dicarbonyls through the formation of metallic enolates was recently explored by Schindler’s group for the intramolecular tert-alkylation of prenylated β-keto esters 103 (Scheme 39A

Free-radical cyclization approach to polyheterocycles containing pyrrole and pyridine rings

• Ivan P. Mosiagin,
• Olesya A. Tomashenko,
• Dar’ya V. Spiridonova,
• Mikhail S. Novikov,
• Sergey P. Tunik and
• Alexander F. Khlebnikov

Beilstein J. Org. Chem. 2021, 17, 1490–1498, doi:10.3762/bjoc.17.105

• [3,4-c]isoquinolin-4-ium bromide 8. Free-radical cyclization of dihalogeno-substituted salts 9 and 12. N-alkylation of the base 6a. Isomerization of compounds 17a and 18a. N-Alkylation of compounds 18a and 19. Optimization of the reaction conditions for the cyclization of 1a with TTMSS/AIBN in MeCN