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

• perfluoroalkyl iodide form a halogen-bond adduct, and then light-induced electron transfer happens in order to give a perfluoroalkyl radical. The protocol can realize alkene- and alkyne iodide perfluoroalkylation and C–H perfluoroalkylation of electron-rich heteroaromatic hydrocarbons, providing a novel protocol

• corresponding hydrotrifluoromethylation products with moderate to good yield. In 2017, Yu and colleagues [30] proposed an EDA-complex-induced alkyne trifluoromethylation reaction. The EDA complex formed by a catalytic quantity of Togni reagent 69 and NMM initiated the chain propagation, causing the final alkyne

• phenol anion is first added to the alkyne group of an EBX, forming electron acceptor 169, which causes the destabilization of the C–I bond. Then, electron acceptor 169 forms an EDA complex with phenol anion, along with light-promoted electron transfer occurring. Thereby, the C–I bond and the I–O bond

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

• Meldal have independently developed a copper-catalysed azide–alkyne cycloaddition that accelerated the rate of the reaction and allowed the selective preparation of 1,5-disubstituted 1,2,3-triazoles [16][17][18][19]. As noted above, a wide range of methods are available in the literature for the

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

• followed by microwave-assisted intramolecular azide–alkyne cycloaddition (IAAC) gave a series of target heterocyclic compounds in moderate to excellent yields. Surprisingly, the normally required ruthenium-based catalysts were found to not affect the IAAC, only making isolation of the target compounds

• to a large number of diverse heterocyclic compounds [10][11]. Over the past decade, several cases of using an Ugi four-component reaction (Ugi-4CR) in combination with intramolecular azide–alkyne cycloaddition (IAAC) for the synthesis of 1,2,3-triazolobenzodiazepines were reported [3][7][12][13][14

• availability of previously described methods for the synthesis of 1,2,3-triazolobenzodiazepines represented in Scheme 1, they have such drawbacks as long reaction time, use of toxic solvents, additional catalysts, etc. In this article, we present a novel tandem Ugi/catalyst-free intramolecular azide–alkyne

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

• general trend in the efficiency of the reaction or product selectivity was observed. Hex-5-ynenitrile was used in the transannulation with 1a with the aim to assess the relative propensity of nitrile and alkyne groups in the reaction. The triple bond reacted in the transannulation about two times faster

• of the rhodium-catalyzed transannulation to pyrroles has recently been investigated computationally with N-sulfonyltriazoles [31]. It seems that the formed rhodium carbenoid B reacts with the alkyne in a concerted process and even in the presence of Ag+ salts, a nucleophilic addition of silver

1,2,3-Triazoles as leaving groups: S_NAr reactions of 2,6-bistriazolylpurines with O- and C-nucleophiles

• Dace Cīrule,
• Irina Novosjolova,
• Ērika Bizdēna and
• Māris Turks

Beilstein J. Org. Chem. 2021, 17, 410–419, doi:10.3762/bjoc.17.37

• of purine [73][74][75][76] or alkylation of inosine or guanosine derivatives (Ib→II, Scheme 1) [30][36]. In the next step, azide can be introduced either by a second SNAr reaction on the C2-halo derivative or by diazotization/azidation at C2. Then, the Cu(I)-catalyzed azide–alkyne cycloaddition

Helicene synthesis by Brønsted acid-catalyzed cycloaromatization in HFIP [(CF₃)₂CHOH]

• Takeshi Fujita,
• Noriaki Shoji,
• Nao Yoshikawa and
• Junji Ichikawa

Beilstein J. Org. Chem. 2021, 17, 396–403, doi:10.3762/bjoc.17.35

• reactions (Scheme 1a). Diels–Alder (Scheme 1b) [15] and radical reactions (Scheme 1c) [16] directed toward helicene synthesis require high temperature conditions even for low to moderate yields. Olefin metathesis (Scheme 1d) [17] and alkyne trimerization (Scheme 1e) [18][19] require the use of expensive

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

Au(III) complexes with tetradentate-cyclam-based ligands

• Ann Christin Reiersølmoen,
• Thomas N. Solvi and
• Anne Fiksdahl

Beilstein J. Org. Chem. 2021, 17, 186–192, doi:10.3762/bjoc.17.18

• , due to sample decomposition. Attempts to obtain crystals for X-ray analysis by slow diffusion of n-pentane into a DCM solution of the complexes were unsuccessful. Catalytic activity For evaluation of the catalytic ability of the new Au(III) complexes, alkyne carboalkoxylation [47][48] and

• activity was observed for cyclam–gold complex 6a-Au(III) versus the open cyclam analogues 5a-Au(III). Complex 5a-Au(III) afforded a full conversion in the alkyne carboalkoxylation in 5.5 hours, compared to in 24 hours for complex 6a-Au(III) (Table 1, entries 1 and 2). The same trend was observed for Au(III

• . A high catalytic ability was shown for novel N,N,N,N-Au(III) complexes 5a and 6a in alkyne carboalkoxylation and propargyl ester cyclopropanation (full conversion in 1–24 h, 62–97% product yields). No enantioselectivity was observed in the test reactions. The activity and stability of the Au(III

Supramolecular polymerization of sulfated dendritic peptide amphiphiles into multivalent L-selectin binders

• David Straßburger,
• Svenja Herziger,
• Katharina Huth,
• Moritz Urschbach,
• Rainer Haag and
• Pol Besenius

Beilstein J. Org. Chem. 2021, 17, 97–104, doi:10.3762/bjoc.17.10

• structures modified with sulfate groups, and their capability to interact with biological components has been demonstrated recently [31][32]. In this work, we therefore coupled dPGS to C2-symmetrical discotic peptide amphiphiles using copper-catalyzed azide alkyne cycloaddition chemistry. The evaluation of

• , post-functionalization using a subsequent copper-catalyzed azide–alkyne cycloaddition reaction became accessible [35][36]. At the same time the other two unmodified side arms of the dendritic amphiphile make sure that the fidelity of the β-sheet motifs and directed supramolecular polymerization remains

• copper-catalyzed azide–alkyne cycloaddition (Scheme 2). The reaction took place in degassed DMSO at 50 °C with CuSO4 pentahydrate, sodium ascorbate and tris(benzyltriazolylmethyl)amine (TBTA) as chelating species. HPLC-monitoring of the reaction showed a full conversion after three days and the crude

Progress in the total synthesis of inthomycins

• Bidyut Kumar Senapati

Beilstein J. Org. Chem. 2021, 17, 58–82, doi:10.3762/bjoc.17.7

• evidence [60]. The synthetic route was designed in such a way that intercept both Ryu’s intermediate (+)-69 [50] and Hatakeyama’s intermediate (+)-82b [22] (Scheme 12 and Scheme 13). In this approach, the asymmetric alkylation of 96 with alkyne 95 under Carreira’s conditions [61][62][63] afforded (−)-98 in

• using a four-step sequence such as Negishi’s (Z) and (E)-stereoselective isomerization of the terminal alkyne followed by iodinolysis [19][70][71], oxidation to the corresponding aldehydes and enantioselective Kiyooka–Mukaiyama aldol reaction followed by TES protection of the resulting alcohols (Scheme

• -catalyzed nucleophilic alkyne addition of methyl propiolate, provided ynone 139 in 86% yield over two steps. When, compound 139 was treated with (+)-diisopinocampheylchloroborane (DIPCl) [75][76] at room temperature and the resulting mixture was processed as in the usual manner using diethanolamine, the

Recent progress in the synthesis of homotropane alkaloids adaline, euphococcinine and N-methyleuphococcinine

• Dimas J. P. Lima,
• Antonio E. G. Santana,
• Michael A. Birkett and
• Ricardo S. Porto

Beilstein J. Org. Chem. 2021, 17, 28–41, doi:10.3762/bjoc.17.4

• (2) was synthesized from terminal alkyne 76 (Scheme 9). This alkyne was prepared from 5-bromopentene, according to the procedure described by Negishi [54]. Zr-catalyzed carboalumination furnished vinylalane, treated with p-menthane-3-carboxaldehyde providing the allylic alcohols (−)-77a and (−)-77b

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

• without THF solvent producing alkyne 9b in 82% yield (Table 4, entry 2). The structure of 9c was unambiguously proved by X-ray structural analysis (see Supporting Information File 1, Figure S34). Earlier, at the final step of a similar synthesis of the azine-fused [5]helicenes, we used trifluoroacetic

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

• is the most rapid and convenient one (Scheme 1). Although studies on alkyne difunctionalization are ongoing [23], the successful attachment of a fluorine atom to the resulting alkene through transition metal catalysis remains a challenge. In particular, the phosphonofluorination of alkynes for the

• -rich and electron-deficient moieties at the para- and meta-positions generally reacted smoothly to afford the desired products 2a–o in moderate to good yield. An aromatic alkyne possessing a Cl substituent at the ortho-position also reacted smoothly to provide the corresponding product 2k in 56% yield

• determine whether diethyl fluorophosphonate is a key intermediate in the reaction with aromatic alkynes. Based on a method by Gupta et al. [29], we obtained diethyl fluorophosphonate. Subsequently, the diethyl fluorophosphonate did not react with an aromatic alkyne in the desired phosphonofluorination so

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

• three alkyne derivatives were tested in the reaction, with yields ranging from 3% to 85%. Keywords: amine-borane complex; pentafluorosulfanyl chloride; pentafluorosulfanyl substituent; radical addition; radical initiation; Introduction The pentafluorosulfanyl (SF5) substituent has been attracting its

• was performed on the internal alkyne 6-dodecyne, and the Dolbier’s protocol led to the moderate yield of 65% of the desired compound 2l, while only a 17% NMR yield was obtained in the reaction using DICAB as the radical initiator. Conclusion In conclusion, we have shown that amine–borane complexes can

• total of 7 examples of alkene derivatives and 3 examples of alkyne derivatives were evaluated in the reaction, with yields ranging from 3% to 85%. Overall, this reaction represents a complementary method to the Et3B-mediated SF5Cl addition on unsaturated compounds. Structures and acronyms of the amine

Pentannulation of N-heterocycles by a tandem gold-catalyzed [3,3]-rearrangement/Nazarov reaction of propargyl ester derivatives: a computational study on the crucial role of the nitrogen atom

• Giovanna Zanella,
• Martina Petrović,
• Dina Scarpi,
• Ernesto G. Occhiato and
• Enrique Gómez-Bengoa

Beilstein J. Org. Chem. 2020, 16, 3059–3068, doi:10.3762/bjoc.16.255

• species to the alkyne 5, as in I (Figure 2). The first step TS1 has a low activation energy (ΔG‡ = 12.2 kcal⋅mol−1) to form the unstable cyclic intermediate II. This short-lived species rapidly reopens through TS2 (ΔΔG‡ = 8.1 kcal⋅mol−1) to give the pentadienyl cation III, which presents a high stability

All-carbon [3 + 2] cycloaddition in natural product synthesis

• Zhuo Wang and
• Junyang Liu

Beilstein J. Org. Chem. 2020, 16, 3015–3031, doi:10.3762/bjoc.16.251

• subsequent treatment with Waser’s reagent 116 [61] afforded alkyne 117 in 62% yield over two steps. Enyne 118, which was prepared in two steps from 117, was subjected to rhodium-catalyzed intramolecular [3 + 2] cycloaddition in the presence of carbon monoxide to give tricycle 119 bearing the desired vicinal

• carbene complex intermediate and a mechanism was proposed (Scheme 10B). An nucleophilic attack of the amine nitrogen onto the alkyne 139 under the effect of activated Pt(II) A produces zwitterionic intermediate B. Elimination of the methoxy group from zwitterion B generates the α,β-unsaturated carbene

Changed reactivity of secondary hydroxy groups in C8-modified adenosine – lessons learned from silylation

• Jennifer Frommer and
• Sabine Müller

Beilstein J. Org. Chem. 2020, 16, 2854–2861, doi:10.3762/bjoc.16.234

• RNA in a highly selective and efficient way. The more traditional strategies rely on reaction of isothiocyanates or NHS esters with aliphatic amines [13][14], or on addition of thiols to the α,β-unsaturated carbonyl face of maleimides [15]. Over the past years, the copper catalyzed alkyne–azide

• cycloaddition (CuAAC) became very popular [16]. A variant of this, the strain-promoted alkyne–azide cycloaddition (SPAAC) even offers the possibility of in cell application, as applies also to the inverse electron-demand Diels–Alder reaction (IEDDA) [17][18]. In vitro, often a combination of orthogonal methods

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

• alkenyl dialkynylphosphinates (Scheme 4) [31]. Thus, the possibility to perform a desymmetrizing RCEYM of oxaenediynes, which should lead to chiral compounds bearing both alkyne and conjugated diene systems, seemed highly appealing to us. Before addressing the enantioselective RCEYM, we report in this

• article the scope and limitations of the racemic metathesis with the emphasis on catalysts used, optional application of Mori conditions, and substitution in both the alkyne and the allyloxy part of the enediynes studied. Results and Discussion Choice and synthesis of starting substrates In our research

• (Scheme 9). With the aim to enable the further functionalization of the products of the oxaenediyne metathesis, we also synthesized substrates modified at the terminal alkyne positions with silyl or ester groups. Because these substrates were inaccessible by the above described methods, we obtained the

Palladium nanoparticles supported on chitin-based nanomaterials as heterogeneous catalysts for the Heck coupling reaction

• Tony Jin,
• Malickah Hicks,
• Davis Kurdyla,
• Sabahudin Hrapovic,
• Edmond Lam and
• Audrey Moores

Beilstein J. Org. Chem. 2020, 16, 2477–2483, doi:10.3762/bjoc.16.201

• and aldehyde–amine–alkyne (A3) coupling reactions [16]. Off this discovery, in this letter, we further expand the scope of using both ChNCs and ChsNCs as a catalyst support for Pd NPs to allow access towards other highly relevant C–C bond-forming reactions. A one-pot fabrication method is used to

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

• alkyne–azide click cycloaddition as the linking step, and ester saponification as the cutting step [13][21] (Supporting Information File 1). The target trefoil knot using host 1 and guest 2 is shown in Figure 2c. The binding event during the double-threading step was modeled after previous literature

• more than twice as high and this route is more amenable to multigram scale reactions. Azido-bromide 6 can undergo both alkyne–azide click cycloaddition and etherification and the effect of the reaction order on the overall yield was explored next. The click cycloaddition was pursued first and reaction

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

• corresponding trimer of the fluoroalkylated alkyne, as reported by our group [27]. Finally, only 2-iodoaryl ketones (R3 = Me, Cy, Ph) were applicable in this catalytic reaction, whereas the cycloaddition using 2-iodobenzaldehyde (R3 = H) did not work at all. Therefore, the development of practical protocols for

• cobalt(II) species as a catalyst to suppress the trimerization products (Scheme 1d). Results and Discussion Initially, we carried out the screening of the reaction conditions for the cobalt-catalyzed [2 + 3] cycloaddition using fluoroalkylated alkyne 1a and 2-formylphenylboronic acid (2A) [28]. The

• results are summarized in Table 1. The cycloaddition of the fluoroalkylated alkyne 1a with 2.0 equiv of 2-formylphenylboronic acid (2A) in the presence of 10 mol % each of Co(acac)2·2H2O and 1,2- bis(diphenylphosphino)ethane (dppe) in CH3CN at 80 °C for 18 h proceeded to afford the corresponding cyclic

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

• oxygen and nitrogen-containing molecules, which tend to be more difficult for catalytic transformations utilizing other transition metals [32][33][34][35][36]. The [LAu(NTf2)]-catalyzed reaction can be described by a general mechanism (Scheme 1), in which the coordination of LAu+ by the alkyne [37][38

• activating the alkyne. Consequently, even at 0.05 mol % catalyst loading virtually quantitative substrate conversion was observed after extending the reaction time to 96 h (Table 2, entry 3). In the absence of the Au catalyst, no product was formed. Hydrohydrazidation reactions of terminal alkynes: Following

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

• effect of the iminium activation. The Diels–Alder reaction of alkyne 1a with 2,3-dimethylbutadiene also occurred under very mild conditions and yielded the iminium-substituted 1,4-cyclohexadiene 4-Ch (Scheme 2), which, due to its high sensitivity toward moisture, was not purified but was further

• , 22 h; 3. o-chloranil, CH2Cl2, rt, 12 h. Diels–Alder reaction of 1a and anthracene followed by an intramolecular SE(Ar) reaction. Reactions of propyn-1-iminium salt 1a with styrenes. A mechanistic proposal for the reaction of alkyne 1a with styrenes. Reaction of alkyne 1a with 1,2-dihydronaphthalene

Syntheses of spliceostatins and thailanstatins: a review

• William A. Donaldson

Beilstein J. Org. Chem. 2020, 16, 1991–2006, doi:10.3762/bjoc.16.166

• in a high yield and enantioselectivity (Scheme 5) [17][18]. The Rubottom oxidation [28] of 43 gave a separable mixture of the desired 44 and its C-14 epimer (≈7:1 ratio). The reductive deoxygenation of 44 proceeded via the tosylhydrazone to afford 45, which upon desilylation and alkyne isomerization