Icilio Guareschi and his amazing “1897 reaction”

• Gian Cesare Tron,
• Alberto Minassi,
• Giovanni Sorba,
• Mara Fausone and
• Giovanni Appendino

Beilstein J. Org. Chem. 2021, 17, 1335–1351, doi:10.3762/bjoc.17.93

• , inorganic, and analytical branches and systematically crosses the divide between pure and applied science as well as between the history of chemistry and the personal contributions to its development. Keywords: Guareschi; history of chemistry; hydrocarbons; name reactions; pyridine; Introduction Modern

• eponymous reactions. His synthesis of cyanopyridones was at the basis of the first industrial synthesis of pyridoxine (vitamin B6, 1, Scheme 1) by Merck [2], is used for the preparation of the blockbuster drug gabapentin (2) [3], and features in countless medicinal chemistry projects based on the pyridine

• Guareschi pyridine synthesis is a modified two-component version, mechanistically similar to the Biginelli pyrimidine synthesis [33] and based on the condensation of cyanoacetamide and a β-dicarbonyl derivative [45][46]. This is the most famous Guareschi pyridine synthesis, both in textbooks and in other

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

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

• thioacetic acid [54][55]. Hence, the hemiacetals were reacted with thioacetic acid in pyridine to give acetamides 49–58 (Scheme 5) and the target trifluoro analogs 59 and 60. Reversing the order of hemiacetal and acetamide formation was not an option because NBS-promoted hydrolysis of 2-acetamido

• degree upon reaction with AcSH in pyridine and traces of O1 acetates were removed by chromatography or recrystallization. Palladium-catalyzed hydrogenolytic debenzylation of 49–58 then yielded the target fluoro analogs 61–70. To complete the series of fluorinated analogs for the purpose of comparing

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

• (phosphines, NHC-carbenes, bisoxazolines, pyridine-oxazolines, and miscellaneous) is used. Review Catalytic systems based on phosphine ligands A pioneering work on the enantioselective addition of boron-derived carbon nucleophiles to cyclic enones was published by the group of Miyaura et al. in 2005 [32

• [46]. Catalytic systems based on pyridine-oxazolines ligands Currently, the most studied ligand class is focused on pyridine-oxazolines (PyOx). The first report for the use of this type of ligand for the asymmetric addition of arylboronic acids to cyclic enones was published by the Stoltz group in

• not estimated after each cycle [58]. In 2019, Lee et al. focused on the enantioselective desymmetrisation of polycyclic cyclohexenediones [59]. The variously substituted pyridine-oxazolines L9 and L12a,b were tested as ligands in combination with Pd(OAc)2 or Pd(TFA)2 (Table 31). As a suitable solvent

Synthetic accesses to biguanide compounds

• Oleksandr Grytsai,
• Cyril Ronco and
• Rachid Benhida

Beilstein J. Org. Chem. 2021, 17, 1001–1040, doi:10.3762/bjoc.17.82

• corresponding bisamidinohydrazide product with a moderate 48% yield using the same conditions. Recently, the scope of the transformation was extended to other aminated nucleophiles such as hydroxylamine and methoxyamine. By using methoxyamine hydrochloride as a reactant along with 1 equivalent of pyridine, the

• addition of pyridine to cyanoguanidine was reported by Petersen et al. [50]. This resulted from an unexpected cyclization under acidic conditions, of different pyridylcyanoguanidines to 4-imino-4H-pyrido[1,2-a][1,3,5]triazin-2-amines (Scheme 20). In conclusion, the preparation of biguanides from

• -amidinopyrazole hydrochloride from cyanoguanidine, by the addition of pyrazole hydrochloride in refluxing pyridine, refluxing 3 M aqueous HCl or by a direct fusion at 140–200 °C (no yields disclosed) [66]. Later in 1992, Bernatowicz et al., in an attempt to produce guanidine derivatives of ornithine-containing

Application of the Meerwein reaction of 1,4-benzoquinone to a metal-free synthesis of benzofuropyridine analogues

• Rashmi Singh,
• Tomas Horsten,
• Rashmi Prakash,
• Swapan Dey and
• Wim Dehaen

Beilstein J. Org. Chem. 2021, 17, 977–982, doi:10.3762/bjoc.17.79

• , Belgium 10.3762/bjoc.17.79 Abstract Several new heterocyclic systems based on a hydroxybenzofuro[2,3-b]pyridine building block were prepared. This benzofuropyridine is easily available from the Meerwein reaction of benzoquinone and a heterocyclic diazonium salt, followed by reduction and cyclization

• to hydroquinone 12 with N,N-diethylhydroxylamine (N,N-DEHA) and cyclized via intramolecular nucleophilic aromatic substitution to isolate 6-hydroxybenzofuro[2,3-b]pyridine (13) with 82% yield. Conveniently, the synthesis of 13 was achieved in a one-pot reaction from 11 with no significant differences

• in the yield. To the best of our knowledge, this is the first procedure toward compound 13, without additional substituents on the pyridine ring. Furthermore, this method is complementary to the most common routes towards the biologically active 1-aza-9-oxafluorenes [20][21][22][23][24][25][26]. To

Beyond ribose and phosphate: Selected nucleic acid modifications for structure–function investigations and therapeutic applications

• Christopher Liczner,
• Kieran Duke,
• Gabrielle Juneau,
• Martin Egli and
• Christopher J. Wilds

Beilstein J. Org. Chem. 2021, 17, 908–931, doi:10.3762/bjoc.17.76

Microwave-assisted multicomponent reactions in heterocyclic chemistry and mechanistic aspects

• Shivani Gulati,
• Stephy Elza John and
• Nagula Shankaraiah

Beilstein J. Org. Chem. 2021, 17, 819–865, doi:10.3762/bjoc.17.71

• yields the desired products 127 (Scheme 50). 8.2 Fused pyridines Fused pyridines have been profoundly known for various pharmacological activities. Moreover, the imidazo[1,2-a]pyridine core is found in various drugs like zolpidem (128), alpidem (129), olprinone (130). They are also promising antiviral

• , antiulcer, anxiolytic, antiherpes agents [115][116][117][118][119]. Similarly, pyrazolo-pyridines are found to be potent antibacterial (131), cytotoxic (132), antiproliferative (133) and antimalarial (134) agents (Figure 10) [120][121]. 8.2.1 Imidazo[1,2-a]pyridine: Sun and co-workers [122] accomplished the

• between benzimidazole-linked aminopyridine and Lewis acid activated aldehyde which further on nucleophilic addition with substituted isocyanide leads to intermediate B. A 5-exo-dig intramolecular cyclization with isocyanide aids in the formation of the imidazo[1,2-a]pyridine intermediate C. The final

A chromatography-free and aqueous waste-free process for thioamide preparation with Lawesson’s reagent

• Ke Wu,
• Yichen Ling,
• An Ding,
• Liqun Jin,
• Nan Sun,
• Baoxiang Hu,
• Zhenlu Shen and
• Xinquan Hu

Beilstein J. Org. Chem. 2021, 17, 805–812, doi:10.3762/bjoc.17.69

• simplify the work-up of the reaction with LR, this newly developed method was extended to synthesize two pincer ligands, N2,N6-di(n-butyl)pyridine-2,6-bis(carbothioamide) (4, Scheme 1) and N2,N6-bis(2,4,6-trimethylphenyl)pyridine-2,6-bis(carbothioamide) (6, Scheme 2) [34][35][43][44]. With a slight excess

• . The solvent was removed under reduced pressure. The reside was purified by silica gel column chromatography using petroleum ether/ethyl acetate as the eluent to afford the desired thioamide 2. Synthesis of N2,N6-di(n-butyl)pyridine-2,6-(carbothioamide) (3) [34] To a 500 mL four-necked flask were added

• 50.1 g of pyridine-2,6-dicarboxylic acid (0.3 mol), 1 mL of DMF and 55 mL of SOCl2. The mixture was heated to 80 °C to get a clear solution and stirred for 30 min. Then, SOCl2 was removed in vacuum and the crude acyl chloride was dissolved in 50 mL of toluene. To a 1 L flask were added 48 g of n

Synthetic reactions driven by electron-donor–acceptor (EDA) complexes

• Zhonglie Yang,
• Yutong Liu,
• Kun Cao,
• Xiaobin Zhang,
• Hezhong Jiang and
• Jiahong Li

Beilstein J. Org. Chem. 2021, 17, 771–799, doi:10.3762/bjoc.17.67

• an EDA complex. First, the N-hydroxyphthalimide (NHPI) ester 142 is excited to electron acceptor 142* through visible-light intersystem crossing (ISC); diborate 143 combining with pyridine results in electron donor 145. Upon the formation of the EDA complex between 145 and 142*, electron transfer

Synthesis of β-triazolylenones via metal-free desulfonylative alkylation of N-tosyl-1,2,3-triazoles

• Soumyaranjan Pati,
• Renata G. Almeida,
• Eufrânio N. da Silva Júnior and
• Irishi N. N. Namboothiri

Beilstein J. Org. Chem. 2021, 17, 762–770, doi:10.3762/bjoc.17.66

• functionalization of triazoles under metal-free conditions has been reported. These include the Broensted acid-catalysed N2 alkylation [27], organocatalytic N1 alkylation [28][29], N2-arylation using hypervalent iodine (Scheme 1c) [30], N2-alkylation involving radical intermediate [31], pyridine-N-oxide-mediated N1

DNA with zwitterionic and negatively charged phosphate modifications: Formation of DNA triplexes, duplexes and cell uptake studies

• Yongdong Su,
• Maitsetseg Bayarjargal,
• Tracy K. Hale and
• Vyacheslav V. Filichev

Beilstein J. Org. Chem. 2021, 17, 749–761, doi:10.3762/bjoc.17.65

• TsN3 in MeCN or 0.7 M 4-(azidosulfonyl)-N,N,N-trimethylbutan-1-aminium iodide in DMF) was introduced as replacement of a standard iodine/pyridine oxidation step to react with 3',5'-dinucleoside β-cyanoethyl phosphites (Scheme 1, I), forming the N-modified iminophosphorane (Scheme 1, II). ONs bearing

Total synthesis of pyrrolo[2,3-c]quinoline alkaloid: trigonoine B

• Takashi Nishiyama,
• Erina Hamada,
• Daishi Ishii,
• Yuuto Kihara,
• Nanase Choshi,
• Natsumi Nakanishi,
• Mari Murakami,
• Kimiko Taninaka,
• Noriyuki Hatae and
• Tominari Choshi

Beilstein J. Org. Chem. 2021, 17, 730–736, doi:10.3762/bjoc.17.62

• heterocyclic compounds by constructing fused pyridine ring systems based on a thermal electrocyclization of an azahexatriene moiety [14][15]. It has been hoped that the development of compounds with enhanced biological activity would be possible using these natural products and their derivatives [16][17][18

• ]. We have previously reported the total syntheses of indolo[3,2-c]quinoline (isocryptolepine) [19], azaanthracenones (kalasinamide, marcanine A, and geovanine) [20], imidazo[4',5':4,5]pyrido[2,3-b]indole (grossularine-1 and -2) [21][22], imidazo[4,5-b]pyridine (2-amino-1-methyl-6-phenylimidazo[4,5-b

• ]pyridine and 2-amino-1,6-dimethylimidazo[4,5-b]pyridine) [23], and imidazo[4,5-c]quinoline (imiquimod) [24] based on the electrocyclization of 2-azahexatriene involving an isocyanate moiety as the key intermediate. In addition, we recently reported the total syntheses of marinoquinolines A (3a), B (3b

β-Lactamase inhibition profile of new amidine-substituted diazabicyclooctanes

• Zafar Iqbal,
• Lijuan Zhai,
• Yuanyu Gao,
• Dong Tang,
• Xueqin Ma,
• Jinbo Ji,
• Jian Sun,
• Jingwen Ji,
• Yuanbai Liu,
• Rui Jiang,
• Yangxiu Mu,
• Lili He,
• Haikang Yang and
• Zhixiang Yang

Beilstein J. Org. Chem. 2021, 17, 711–718, doi:10.3762/bjoc.17.60

• reacted with SO3·pyridine to form sulfonic acid derivatives A1–21 after purification by preparative HPLC. The sodium salts of these compounds were obtained by ion exchange using a column filled with Dowex-50wx Na+ resin using water as the eluent, followed by lyophilization. In case of compound A18, Boc

• %; (iii) SO3·pyridine, pyridine, or SO3·pyridine, TEA, THF/water, rt, 16 h, or then Dowex-50wx Na+, 8–99%. Synthesis of compounds A22 and A23. Reagents and conditions: (i) HATU, DIPEA or DCC, DMAP, DMF or THF, rt, 16 h, 62% (B22), 80% (B23); (ii) TBAF, THF, 80% (C22), 92% (C23); (iii) SO3·pyridine

• , pyridine, or SO3·pyridine, TEA, THF/water, rt, 16 h, then Dowex-50wx Na+, 83% (A22), 35% (A23). In vitro antibacterial activity of avibactam and compounds A1-23 alone as well as in combination with meropenem (MER). Supporting Information Supporting Information File 106: Detailed experimental protocols, 1H

Stereoselective syntheses of 3-aminocyclooctanetriols and halocyclooctanetriols

• Emine Salamci and
• Yunus Zozik

Beilstein J. Org. Chem. 2021, 17, 705–710, doi:10.3762/bjoc.17.59

• oxidation of the double bond gave diacetatediol 7 [33]. Treatment of diacetatediol 7 with thionyl chloride in pyridine gave the corresponding cyclic sulfite 8 in 95% yield (Scheme 1). Oxidation of the cyclic sulfite 8 with sodium periodate in the presence of ruthenium trichloride provided the corresponding

• converted into the corresponding triacetate 11 with acetic anhydride in pyridine and 4-(dimethylamino)pyridine (DMAP) (yield 76%). To determine the exact configurations of the substituents in 11, we made full assignments for the H-3 and the acetoxy protons with the help of the 1D and 2D NMR experiments

• ] (79% yield) as the sole product (Scheme 3). Ring opening of trans-epoxide 13 by HBr(g)–MeOH gave bromotriol 14, which is an ideal substrate for the synthesis of the aminocyclooctanetriol 18. For structural proof, bromotriol 14 was converted into the corresponding acetate 15 using Ac2O in pyridine and

[2 + 1] Cycloaddition reactions of fullerene C₆₀ based on diazo compounds

• Yuliya N. Biglova

Beilstein J. Org. Chem. 2021, 17, 630–670, doi:10.3762/bjoc.17.55

• reaction of 4,4'-bis(N-acetyl-2-aminoethyl)diphenyldiazomethane with C60 in toluene gave adduct 25 that was isolated in 38% yield in the first stage. After that, it was quantitatively converted into primary diamine compound 26 in an acid medium. Upon addition of succinic anhydride in dry pyridine

• heating, or photochemically in a nitrogen atmosphere (Scheme 23) [109]. The reaction of spiro[10-anthron-9,61'-methanofullerene] (79) [110] with bis(trimethylsilyl)carbodiimide and malononitrile in pyridine in the presence of TiCl4 resulted in spirocyclic blocks 80 and 81, respectively (Scheme 24) [111

• solar cells, [60]PCBM, as an example (Scheme 26). The mechanism of fullerene cyclopropanation is presented in Scheme 27. Using a similar procedure, the reaction of C60 and alkyl-4-benzoyl butyrate p-tosylhydrazone in the presence of sodium methoxide and pyridine, the following [6,6]-phenyl-C61-butyric

Designed whole-cell-catalysis-assisted synthesis of 9,11-secosterols

• Marek Kõllo,
• Marje Kasari,
• Villu Kasari,
• Tõnis Pehk,
• Ivar Järving,
• Margus Lopp,
• Arvi Jõers and
• Tõnis Kanger

Beilstein J. Org. Chem. 2021, 17, 581–588, doi:10.3762/bjoc.17.52

• , 303.1961. 11β-Acetoxyandrost-4-ene-3,17-dione (3) Starting steroid 2 (202 mg, 0.67 mmol, 1 equiv) was dissolved in dry dichloromethane (9.8 mL), and after that 4-(dimethylamino)pyridine (8.2 mg, 0.067 mmol, 0.1 equiv), triethylamine (373 μL, 2.67 mmol, 4 equiv) and acetic anhydride (316 μL, 3.34 mmol, 5

Synthesis of (Z)-3-[amino(phenyl)methylidene]-1,3-dihydro-2H-indol-2-ones using an Eschenmoser coupling reaction

• Lukáš Marek,
• Lukáš Kolman,
• Jiří Váňa,
• Jan Svoboda and
• Jiří Hanusek

Beilstein J. Org. Chem. 2021, 17, 527–539, doi:10.3762/bjoc.17.47

• pyridine–P4S10 as sulfurization agent. The tertiary thiobenzamides 4a–c were synthetized by a one-pot acylation/thionation from the corresponding acid chlorides and dimethylamine [55]. Other chemicals and solvents were purchased from Acros Organics, Sigma-Aldrich, or Fluorochem and were used as received

Deoxygenative C2-heteroarylation of quinoline N-oxides: facile access to α-triazolylquinolines

• Geetanjali S. Sontakke,
• Rahul K. Shukla and
• Chandra M. R. Volla

Beilstein J. Org. Chem. 2021, 17, 485–493, doi:10.3762/bjoc.17.42

• ][37][38][39][40][41][42][43][44][45]. For example, Yin and co-workers developed a protocol for the deoxygenative C2-amination of pyridine/quinoline N-oxides using t-BuNH2 and Ts2O/TFA in 2007 (Scheme 1a) [48]. Later, Londregan and co-workers were successful in achieving C2-amination employing

• to amination and amidation, there are few reports on metal-free C2-heteroarylation of pyridine N-oxides. In 1984, Rogers demonstrated the synthesis of 2-triazolylpyridines from 2-azidopyridines and phenylacetylene [51]. Along the same lines, Keith reported methodologies for the C2-imidazolylation and

• pyridine N-oxides [54]. Despite the versatility of these methods, the above reports involve the use of external additives for activating the N-oxides and suffer from other disadvantages, including prolonged reaction time, high temperature and limited substrate scope. At the same time, with the advent of Cu

Synthesis of trifluoromethyl ketones by nucleophilic trifluoromethylation of esters under a fluoroform/KHMDS/triglyme system

• Yamato Fujihira,
• Yumeng Liang,
• Makoto Ono,
• Kazuki Hirano,
• Takumi Kagawa and
• Norio Shibata

Beilstein J. Org. Chem. 2021, 17, 431–438, doi:10.3762/bjoc.17.39

• common nitrogen-containing compounds such as pyridine, pyrazine, 1H-pyrazole, 1H-indole, 1-methyl-1H-indole, piperidine, and piperazine were subjected to screening. Pyridine and piperidine slightly hamper the reaction of 1g (Table 2, entries 2 and 7, 80–82%). Other nitrogen-containing compounds have more

Unexpected rearrangements and a novel synthesis of 1,1-dichloro-1-alkenones from 1,1,1-trifluoroalkanones with aluminium trichloride

• Beatrice Lansbergen,
• Catherine S. Meister and
• Michael C. McLeod

Beilstein J. Org. Chem. 2021, 17, 404–409, doi:10.3762/bjoc.17.36

• %. Naphthalene 6h and 2-pyridine 6i were also successfully obtained, however, the reactions with the 3- and 4-pyridines 5j and 5k resulted in complex mixtures from which no desired product, nor starting material, could be observed. The scope of this chemistry also extends to substrates with a shorter

CF₃-substituted carbocations: underexploited intermediates with great potential in modern synthetic chemistry

• Anthony J. Fernandes,
• Armen Panossian,
• Bastien Michelet,
• Agnès Martin-Mingot,
• Frédéric R. Leroux and
• Sébastien Thibaudeau

Beilstein J. Org. Chem. 2021, 17, 343–378, doi:10.3762/bjoc.17.32

• electrophiles [101]) generated in superacid media [102]. Hence, when trifluoroacetyl pyridine 156 was treated with benzene in triflic acid, alcohol derivative 157 was obtained. In a superacid, 156 generates a dication 158 in which the electrophilicity is enhanced through a strong charge repulsion (Scheme 39

Synthesis of legonmycins A and B, C(7a)-hydroxylated bacterial pyrrolizidines

• Wilfred J. M. Lewis,
• David M. Shaw and
• Jeremy Robertson

Beilstein J. Org. Chem. 2021, 17, 334–342, doi:10.3762/bjoc.17.31

• pyridine as a scavenger for the liberated HCl, gave solutions of crude diacylated product 18 in acceptable purity after simple filtration as work-up. It was reasoned that the activation of the electron-rich pyrrole (with generic electrophile X2 as shown) would hasten cleavage of the ester and that

• which a −78 °C solution of the crude diacylated species 18 in methanol-d4 was treated sequentially with a solution of I2 (1.0 equiv) in methanol-d4 and pyridine-d5 (≈4.5 equiv). The 1H NMR spectrum acquired after 20 min showed loss of the triplet at 3.76 ppm arising from the enantiotopic CH2N protons in

• work-up and chromatography options. To a mixture of 3-aminopyrrolizine hydrochloride derivative 17 (2.0 g, 10.6 mmol), distilled pyridine (3.42 mL, 42.4 mmol), and acetonitrile (21 mL) at rt was added isovaleryl chloride (2.58 mL, 21.2 mmol). The mixture was stirred for 1 h, then half of the reaction

Hydrazides in the reaction with hydroxypyrrolines: less nucleophilicity – more diversity

• Dmitrii A. Shabalin,
• Evgeniya E. Ivanova,
• Igor A. Ushakov,
• Elena Yu. Schmidt and
• Boris A. Trofimov

Beilstein J. Org. Chem. 2021, 17, 319–324, doi:10.3762/bjoc.17.29

• traces of the 1,4-dihydropyridazine 4af were detected following the two-step, one-pot protocol (Scheme 3). Apparently, the basic pyridine nitrogen atoms of intermediate 3af deactivate the acid catalyst, whilst the use of 3.4 equiv of TFA causes the full protonation of the pyridine rings thus making them

Decarboxylative trifluoromethylthiolation of pyridylacetates

• Ryouta Kawanishi,
• Kosuke Nakada and
• Kazutaka Shibatomi

Beilstein J. Org. Chem. 2021, 17, 229–233, doi:10.3762/bjoc.17.23

• subsequent decarboxylative trifluoromethylthiolation were performed in a one-pot fashion. Keywords: decarboxylation; fluorinated compounds; pyridine compounds; trifluoromethylthiolation; Introduction The pyridine ring is found in numerous biologically active compounds. Therefore, efficient methods for

• mechanism for this reaction, as outlined in Scheme 5. An electrophilic sulfur atom of 6 approaches the nitrogen atom on the pyridine ring to promote decarboxylation via the formation of N-trifluoromethylthio-2-alkylidene-1,2-dihydropyridine intermediate I, which immediately isomerizes to afford 2 (Scheme 5

• trifluoromethylthiolated product at all, despite complete saponification of the methyl ester. Conclusion In conclusion, we demonstrated the decarboxylative trifluoromethylthiolation of lithium 2- and 4-pyridylacetates to synthesize pyridine derivatives with a trifluoromethylthio group at a tertiary carbon center adjacent