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

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

• , Lakhdar and colleagues [10] obtained the target product 3 with LED (5 W) irradiation of a solution containing arylphosphine oxide 2, alkynes 1, eosin Y (EY, 4 mol %), N-ethoxy-2-methylpyridinium (4), and sodium bicarbonate in DMF (Scheme 2). As a distinct example of EDA complexes, the process efficiency

• depends on the association of eosin Y and oxidant 4 to a donor–acceptor EY–4 ground-system complex (high reactivity). Due to the ability of aryl groups to stabilize the formed alkenyl radical, this protocol could control regioselectivity efficiently with unsymmetrical alkynes. In addition, EPR

• unactivated olefins and alkynes. This approach employed 68 and Togni reagent 69 (electron acceptor) as substrates, NMM as electron donor, and pyrrolidin-2-one as solvent to give hydrotrifluoromethylated product 70 at room temperature (Scheme 24). CF3 was added to a variety of terminal alkenes, leading to

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

• azides and alkynes [14][15]. However, the formation of the nitrogenated azoles by the classical Huisgen methodology is slow due to its high activation energies and also lack of regiochemical control, in general, leading to a mixture of 1,4- and 1,5-regioisomers of 1,2,3-triazoles. Later, Sharpless and

• -triazoles with alkynes and Rh catalysed N1 and N2 selective alkylations [24][25]. As for metal-free approaches, besides synthesizing N-alkylated triazoles via 1,3-dipolar cycloaddition of alkyl azide with enols generated from carbonyl compounds under transition metal-free conditions [26], a direct

• alternative approach for the synthesis of such triazole moiety 3a is the [3 + 2] cycloaddition between alkynes and the corresponding azides. However, the major disadvantage of such a strategy is the use of 3-azidoenone which is difficult to handle owing to its explosive nature. Therefore, our method provides

Effective microwave-assisted approach to 1,2,3-triazolobenzodiazepinones via tandem Ugi reaction/catalyst-free intramolecular azide–alkyne cycloaddition

• Maryna O. Mazur,
• Oleksii S. Zhelavskyi,
• Eugene M. Zviagin,
• Svitlana V. Shishkina,
• Vladimir I. Musatov,
• Maksim A. Kolosov,
• Elena H. Shvets,
• Anna Yu. Andryushchenko and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2021, 17, 678–687, doi:10.3762/bjoc.17.57

• harder while the microwave-assisted catalyst-free conditions were effective for both terminal and non-terminal alkynes. Keywords: click chemistry; microwave chemistry; multicomponent reactions; triazolobenzodiazepines; Ugi reaction; Introduction Benzannulated heterocycles are among the most important

• and yield. Quantitative yields were also observed when N-phenyl (6abb) and N-benzyl (6aeb) propiolamides were subjected to the cyclization (see results on Scheme 5). Performing the IAAC for internal alkynes under non-catalyzed conditions is more challenging due to the reduced reactivity of the triple

• bond. Usually, AAC reactions on non-terminal alkynes are performed with ruthenium catalysis [21] that determined our decision to start screening conditions using the chloro(cyclopentadienyl)bis(triphenylphosphine)ruthenium(II) complex ((Cp)Ru(PPh3)2Cl) as catalyst. However, carrying out the reaction

Synthesis of N-perfluoroalkyl-3,4-disubstituted pyrroles by rhodium-catalyzed transannulation of N-fluoroalkyl-1,2,3-triazoles with terminal alkynes

• Olga Bakhanovich,
• Viktor Khutorianskyi,
• Vladimir Motornov and
• Petr Beier

Beilstein J. Org. Chem. 2021, 17, 504–510, doi:10.3762/bjoc.17.44

• Prague, Czech Republic 10.3762/bjoc.17.44 Abstract The rhodium-catalyzed transannulation of N-perfluoroalkyl-1,2,3-triazoles with aromatic and aliphatic terminal alkynes under microwave heating conditions afforded N-perfluoroalkyl-3,4-disubstituted pyrroles (major products) and N-fluoroalkyl-2,4

• -disubstituted pyrroles (minor products). The observed selectivities in the case of the reactions with aliphatic alkynes were high. Keywords: pyrrole; transannulation; rhodium carbene; triazole; Introduction Pyrroles are known to be important structural moieties appearing in natural products, synthetic drugs

• , conveniently prepared by [3 + 2] cycloadditions of terminal alkynes with sulfonyl azides, have been used as the precursors to N-sulfonylindoles by transition-metal-catalyzed transannulation reactions. In the presence of Rh(II) or Ni(0) catalysts the triazole ring-opening takes place and intermediate highly

The preparation and properties of 1,1-difluorocyclopropane derivatives

• Kymbat S. Adekenova,
• Peter B. Wyatt and
• Sergazy M. Adekenov

Beilstein J. Org. Chem. 2021, 17, 245–272, doi:10.3762/bjoc.17.25

• reaction of 54 with AlCl3 and an alkene at −20 °C (Scheme 22). The difluorocyclopropane 55 was obtained in 75% yield [63]. A bis(trifluoromethyl)zinc reagent was employed as the difluorocarbene source for the gem-difluorocyclopropanation of alkenes or alkynes via thermal decomposition [64]. The reagent was

• alkynylation of cyclopropanes 161 with terminal alkynes that led to the formation of the isomeric fluorinated enynes 164 and 165. Shortly before, a Pd-catalyzed ring-opening sulfonylation of gem-difluorocyclopropanes with the formation of 2-fluoroallylic sulfones 166 has been reported (Scheme 71) [122]. The

Selective synthesis of α-organylthio esters and α-organylthio ketones from β-keto esters and sodium S-organyl sulfurothioates under basic conditions

• Jean C. Kazmierczak,
• Roberta Cargnelutti,
• Thiago Barcellos,
• Claudio C. Silveira and
• Ricardo F. Schumacher

Beilstein J. Org. Chem. 2021, 17, 234–244, doi:10.3762/bjoc.17.24

• synthesis and medicinal chemistry. In the last years, different methods have been developed to prepare these classes of molecules, which includes the reaction of alkynes [39][40][41][42][43] as well as α-halogenated [44][45] and α-diazo carbonyl compounds [46][47][48][49] with thiols, diorganyl disulfides

1,2,3-Triazoles as leaving groups in S_NAr–Arbuzov reactions: synthesis of C6-phosphonated purine derivatives

• Kārlis-Ēriks Kriķis,
• Irina Novosjolova,
• Anatoly Mishnev and
• Māris Turks

Beilstein J. Org. Chem. 2021, 17, 193–202, doi:10.3762/bjoc.17.19

• chlorine at the purine C2 position by azide, and 3) copper-catalyzed azide–alkyne 1,3-dipolar cycloaddition (CuAAC) with different alkynes. Pathway B included: 1) the two-step synthesis of 2,6-bistriazolylpurine derivatives 6 from 2,6-dichloropurine derivative 1 [22] and 2) the SNAr–Arbuzov reaction with

• (OEt)3 Next, we switched to pathway B (Scheme 2) and prepared 2,6-diazidopurine derivative 5 from 2,6-dichloropurine (11) via a Mitsunobu alkylation and SNAr reaction with NaN3 (Scheme 5) [22]. 2,6-Bistriazolylpurine derivatives 6a–i were obtained in CuAAC reactions with various alkynes in 35–76% yield

Synthesis, crystal structures and properties of carbazole-based [6]helicenes fused with an azine ring

• Daria I. Tonkoglazova,
• Anna V. Gulevskaya,
• Konstantin A. Chistyakov and
• Olga I. Askalepova

Beilstein J. Org. Chem. 2021, 17, 11–21, doi:10.3762/bjoc.17.2

• acid as a cyclizing agent [72]. Unfortunately, only in the case of compound 9c, heating in trifluoroacetic acid led to isomerization into the required carbazole-based [6]helicene 10c (Table 5, entry 3). Under these conditions, alkynes 9a and 9b produced an unseparable mixture of some products. To our

Silver-catalyzed synthesis of β-fluorovinylphosphonates by phosphonofluorination of aromatic alkynes

• Yajing Zhang,
• Qingshan Tian,
• Guozhu Zhang and
• Dayong Zhang

Beilstein J. Org. Chem. 2020, 16, 3086–3092, doi:10.3762/bjoc.16.258

• 200032, P. R. China 10.3762/bjoc.16.258 Abstract A silver-catalyzed three-component reaction involving alkynes, Selectfluor®, and diethyl phosphite was employed for the one-pot formation of C(sp2)–F and C(sp2)–P bonds to provide an efficient access to β-fluorovinylphosphonates in a highly regio- and

• stereoselective manner under mild reaction conditions. This reaction is operationally simple and offers an excellent functional group tolerance as well as a broad substrate scope that includes both terminal and internal alkynes. The reaction proceeded through the oxidative generation of a P-centered radical and

• . Among the strategies for constructing diverse alkenes containing two-heteroatom bonds, such as disulfonylation [14][15][16], heterohalogenation [17][18][19][20], bis(trifluoromethyl)thiolation [21], and phosphorylation [22], the direct heterodifunctionalization of alkynes using three-component reactions

Amine–borane complex-initiated SF₅Cl radical addition on alkenes and alkynes

• Audrey Gilbert,
• Pauline Langowski,
• Marine Delgado,
• Laurent Chabaud,
• Mathieu Pucheault and
• Jean-François Paquin

Beilstein J. Org. Chem. 2020, 16, 3069–3077, doi:10.3762/bjoc.16.256

• , France 10.3762/bjoc.16.256 Abstract The SF5Cl radical addition on unsaturated compounds was performed using an air-stable amine–borane complex as the radical initiator. This method showed to be complementary to the classic Et3B-mediated SF5Cl addition on alkenes and alkynes. A total of seven alkene and

• addition of SF5Cl on alkenes and alkynes (Scheme 1) [29][30]. This strategy represented a tremendous step forward in the pentafluorosulfanyl aliphatic chemistry, since it addressed the drawbacks that were previously reported with the use of SF5Cl as a reagent. It allows the SF5Cl addition to occur in the

• SF5Cl to produce a chloroalkane as well as the key SF5• radical. The propagation steps would occur exactly as reported by Dolbier and co-workers for the Et3B-mediated radical addition of SF5Cl on alkenes and alkynes [29][30]. Overall, while similar mechanistically, the use of an amine–borane complex as

Regioselective synthesis of heterocyclic N-sulfonyl amidines from heteroaromatic thioamides and sulfonyl azides

• Vladimir Ilkin,
• Vera Berseneva,
• Tetyana Beryozkina,
• Tatiana Glukhareva,
• Lidia Dianova,
• Wim Dehaen,
• Eugenia Seliverstova and
• Vasiliy Bakulev

Beilstein J. Org. Chem. 2020, 16, 2937–2947, doi:10.3762/bjoc.16.243

• commonly used methods to prepare these compounds include the Cu-catalyzed multicomponent reaction of alkynes, sulfonyl azides and amines [23][24][25][26][27][28][29][30][31], the reaction of thioacetamide derivatives and cyclic thioamides with sulfonyl azides [22][32][33], the chlorophosphite-mediated

A novel and robust heterogeneous Cu catalyst using modified lignosulfonate as support for the synthesis of nitrogen-containing heterocycles

• Bingbing Lai,
• Meng Ye,
• Ping Liu,
• Minghao Li,
• Rongxian Bai and
• Yanlong Gu

Beilstein J. Org. Chem. 2020, 16, 2888–2902, doi:10.3762/bjoc.16.238

• -Cu-promoted conditions as well, and gave the product 4o in 65% yield. The successful attempts in the three-component reaction of 4-aminoindoles (1a), alkynes and aldehydes indicate that the heterogeneous catalyst LS-FAS-Cu is competent for catalyzing nitrogen-containing heterocyclic compounds without

• ). Recyclability of LS-FAS-Cu, LS-FM-Cu and Resin-Cu in the reaction between compounds 1a, 2a and 3a. Substrate scope of LS-FAS-Cu catalyzed three-component reactions of 4-aminoindoles, alkynes and aldehydes. Three-component reaction of 1a, 2a, and 3a to synthesis of 4aa. Optimizing the reaction condition of

Synthesis and investigation of quadruplex-DNA-binding, 9-O-substituted berberine derivatives

• Jonas Becher,
• Daria V. Berdnikova,
• Heiko Ihmels and
• Christopher Stremmel

Beilstein J. Org. Chem. 2020, 16, 2795–2806, doi:10.3762/bjoc.16.230

• -forming repeat unit from the “insulin-linked polymorphic region” (ILPR) [50], that was also shown to bind quadruplex ligands [51]. Results Synthesis As the Cu-catalyzed click reaction between azides and alkynes is a well-established method for the variable functionalization of G4-DNA ligands [52], the

Easy access to a carbohydrate-based template for stimuli-responsive surfactants

• Thomas Holmstrøm,
• Daniel Raydan and
• Christian Marcus Pedersen

Beilstein J. Org. Chem. 2020, 16, 2788–2794, doi:10.3762/bjoc.16.229

• ]. Furthermore, starting from the azide 8, it was possible to achieve ester functionalities by a CuAAC reaction [23][24] in the presence of the two different alkynes 14 and 15, giving rise to the diester derivative 12 and the tetraester derivative 13 (Scheme 2). Subsequently, the esters could be hydrolyzed by

• functionalization. The azido groups also can undergo a CuAAC reaction with alkynes substituted with ester functionalities, which can subsequently be hydrolyzed to either the di- or tetra acids. Using the CuAAC reaction, it was also possible to install aliphatic chains. Introducing picoline residues on the 3,6

Ring-closing metathesis of prochiral oxaenediynes to racemic 4-alkenyl-2-alkynyl-3,6-dihydro-2H-pyrans

• Viola Kolaříková,
• Markéta Rybáčková,
• Martin Svoboda and
• Jaroslav Kvíčala

Beilstein J. Org. Chem. 2020, 16, 2757–2768, doi:10.3762/bjoc.16.226

• intermediate to undergo subsequent metathesis reactions leading to catalyst deactivation [23]. In both cases, the effect of ethene was especially productive for the Grubbs 1st generation precatalyst and is typically applied for terminal alkynes or alkynes with little steric hindrance of the triple bond. In

Selective and reversible 1,3-dipolar cycloaddition of 6-aryl-1,5-diazabicyclo[3.1.0]hexanes with 1,3-diphenylprop-2-en-1-ones under microwave irradiation

• Alexander P. Molchanov,
• Mariia M. Efremova,
• Mariya A. Kryukova and
• Mikhail A. Kuznetsov

Beilstein J. Org. Chem. 2020, 16, 2679–2686, doi:10.3762/bjoc.16.218

• ]. A wide range of pharmaceuticals, agrochemicals, and other biologically active compounds are prepared using different types of (3 + n) cycloadditions, mainly with alkenes and alkynes [3][4][5][6][7]. For example, N,N'-cyclic azomethine imines are precursors of biologically active bicyclic

Recent developments in enantioselective photocatalysis

• Callum Prentice,
• James Morrisson,
• Andrew D. Smith and
• Eli Zysman-Colman

Beilstein J. Org. Chem. 2020, 16, 2363–2441, doi:10.3762/bjoc.16.197

Design and synthesis of a bis-macrocyclic host and guests as building blocks for small molecular knots

• Elizabeth A. Margolis,
• Rebecca J. Keyes,
• Stephen D. Lockey IV and
• Edward E. Fenlon

Beilstein J. Org. Chem. 2020, 16, 2314–2321, doi:10.3762/bjoc.16.192

• . Keywords: alkynes; azides; host–guest; macrocycles; molecular knots; Introduction Macrocycles have played a central role in the development of molecular recognition, self-assembled molecular devices, and molecular topology [1][2][3][4][5][6]. For example, early work by Pedersen on crown ethers [1], Lehn

Regioselective cobalt(II)-catalyzed [2 + 3] cycloaddition reaction of fluoroalkylated alkynes with 2-formylphenylboronic acids: easy access to 2-fluoroalkylated indenols

• Tatsuya Kumon,
• Miroku Shimada,
• Jianyan Wu,
• Shigeyuki Yamada and
• Tsutomu Konno

Beilstein J. Org. Chem. 2020, 16, 2193–2200, doi:10.3762/bjoc.16.184

• Tatsuya Kumon Miroku Shimada Jianyan Wu Shigeyuki Yamada Tsutomu Konno Faculty of Molecular Chemistry and Engineering, Kyoto Institute of Technology, Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan 10.3762/bjoc.16.184 Abstract [2 + 3] cycloaddition reactions of fluorinated alkynes with 2

• best of our knowledge, there are no reports on the practical synthesis of disubstituted 2-fluoroalkylated indenols so far. Transition-metal-catalyzed carbocyclization reactions of alkynes with benzene derivatives having a leaving group X (X = Br, I, OTs, B(OH)2) have been widely considered as one of

• the most efficient and convenient protocols for the construction of various 2,3-disubstituted indene derivatives, such as indenols and indenamines (Scheme 1b) [23][24][25]. There have been numerous studies on the reaction with nonfluorinated alkynes under the influence of various transition metals

Efficient [(NHC)Au(NTf₂)]-catalyzed hydrohydrazidation of terminal and internal alkynes

• Maximillian Heidrich and
• Herbert Plenio

Beilstein J. Org. Chem. 2020, 16, 2080–2086, doi:10.3762/bjoc.16.175

• alkynes (7a–j, 10 examples, 0.2–0.5 mol % [(NHC)Au(NTf2)], T = 60–80 °C) utilizing a complex with a sterically demanding bispentiptycenyl-substituted NHC ligand and the benign reaction solvent anisole, is reported. Keywords: alkyne; gold; homogeneous catalysis; hydrohydrazidation; NHC ligand

• ; Introduction Cationic gold complexes with weakly coordinating counterions (which are often considered to be solvent-separated ions) [1][2][3], render powerful catalysts for the transformation of organic substrates [4][5][6], specifically the reactions of alkynes with a variety of heteroatom nucleophiles

• % at 60 °C were required to obtain the respective addition product in yields of 66–93%. Internal alkynes were much less reactive and even at 12 mol % catalyst loading the reaction of 3-hexyne and PhCONHNH2 yielded the respective addition product in only 32% yield, with diphenylacetylene only 12% of the

Reactions of 3-aryl-1-(trifluoromethyl)prop-2-yn-1-iminium salts with 1,3-dienes and styrenes

• Thomas Schneider,
• Michael Keim,
• Bianca Seitz and
• Gerhard Maas

Beilstein J. Org. Chem. 2020, 16, 2064–2072, doi:10.3762/bjoc.16.173

• cyclobutene and several cationic intermediates and mainly yield 2-(1-phenylvinyl)indenes. In a similar reaction cascade, a fulvene derivative was obtained with 1,4-diphenylbutadiene as the substrate. Keywords: alkynes; aromatic substitution; cyclization; cycloaddition; iminium salts; Introduction In recent

• presumably renders an ionic [2 + 2] cycloaddition pathway competitive with the Diels–Alder reaction. The few reported examples of cyclobutene formation from alkynes and unactivated 1,3-dienes include the sensitized photocycloaddition of phenylacetylene and DMBD [30] and the gold(I)-catalyzed reaction of

• concerted conrotatory process [47][48] would create a strained cis,trans-dihydrobenzo[8]annulene ring system. Cyclobutenes resulting from a [2 + 2] cycloaddition of electrophilic alkynes and alkenes under moderate thermal conditions have been isolated also from the reaction of CF3-free propyniminium salts

When metal-catalyzed C–H functionalization meets visible-light photocatalysis

• Lucas Guillemard and
• Joanna Wencel-Delord

Beilstein J. Org. Chem. 2020, 16, 1754–1804, doi:10.3762/bjoc.16.147

• photocatalyst. The strategy was utilized for the C–H bond annulation of benzamides with alkynes, furnishing isoquinolones, an important moiety in various natural products (Figure 15) [78]. The C–H activation step was assisted by an 8-quinolyl DG and occurred under an oxygen atmosphere at room temperature. A

• , pyrimidyl, and 7-azaindolyl were found to be compatible with this transformation. While symmetrical alkynes led to the desired products in moderate to good yields, the unsymmetrical ones afforded a mixture of products with very high regioselectivity, with the favored formation of cyclized compounds bearing

• performed under air at high temperatures. The coupling exhibited a broad substrate scope and the procedure tolerated a variety of even sensitive functional groups, including trifluoromethyl, ketone, or ester motifs. Unsymmetrical alkynes were also compatible, although the cyclization provided the desired

Clickable azide-functionalized bromoarylaldehydes – synthesis and photophysical characterization

• Dominik Göbel,
• Marius Friedrich,
• Enno Lork and
• Boris J. Nachtsheim

Beilstein J. Org. Chem. 2020, 16, 1683–1692, doi:10.3762/bjoc.16.139

• cycloadditions with model alkynes. Besides two ortho- and para-bromo-substituted benzaldehydes, the azide functionalization of a fluorene-based structure will be presented. The copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC) of the so-synthesized azide-functionalized bromocarbaldehydes with terminal

• alkynes, exhibiting different degrees of steric demand, was performed in high efficiency. Finally, we investigated the photophysical properties of the azide-functionalized arenes and their covalently linked triazole derivatives to gain deeper insight towards the effect of these covalent linkers on the

• reactions (CuAAC). For this, we treated the azide-functionalized luminophores with alkynes exhibiting different degrees of steric demand, including 1-decyne (29), phenylacetylene (30), 1-ethynyladamantane (31) and 1,3-di-tert-butyl-5-ethynylbenzene (32, see Scheme 5). All triazoles 33–44, based on the

Pauson–Khand reaction of fluorinated compounds

• Jorge Escorihuela,
• Daniel M. Sedgwick,
• Alberto Llobat,
• Mercedes Medio-Simón,
• Pablo Barrio and
• Santos Fustero

Beilstein J. Org. Chem. 2020, 16, 1662–1682, doi:10.3762/bjoc.16.138

• that will be discussed in this review belongs to the fluorinated building blocks category. More specifically, the participation of fluorine-containing olefins and alkynes in the Pauson–Khand cyclization, with a special focus on the intramolecular version using fluorinated enynes, which will be

• the intramolecular version, the fluorine atom or fluorinated group can also form a part of the linker. The reaction yields are dependent on the degree of substitution, bulkiness, and electronic effects of the substituents of both the alkyne and alkene moieties. In general, electron-deficient alkynes

• are poor substrates for the PKR as they are deactivated in the cobalt-complexation step, and the highest yields are usually obtained with terminal alkynes. The scenario is similar in the case of fluorinated substrates, with the intramolecular version being much more developed than the intermolecular