From amines to (form)amides: a simple and successful mechanochemical approach

• Federico Casti,
• Rita Mocci and
• Andrea Porcheddu

Beilstein J. Org. Chem. 2022, 18, 1210–1216, doi:10.3762/bjoc.18.126

• Federico Casti Rita Mocci Andrea Porcheddu Dipartimento di Scienze Chimiche e Geologiche, Università degli Studi di Cagliari, Cittadella Universitaria, 09042 Cagliari, Italy 10.3762/bjoc.18.126 Abstract Two easily accessible routes for preparing an array of formylated and acetylated amines under

• mechanochemical conditions are presented. The two methodologies exhibit complementary features as they enable the derivatization of aliphatic and aromatic amines. Keywords: acetamides; formamides; mechanochemistry; N-formylation; p-tosylimidazole; Introduction The preparation of N-formylated and N-acetylated

• amines plays a crucial role in organic synthesis [1][2][3][4][5][6]. In one respect, it is relevant to protect the amine group straightforwardly and under mild conditions [7][8]. On the other hand, the formamide and acetamide moieties are found in many active pharmaceutical ingredients (APIs) and natural

Derivatives of benzo-1,4-thiazine-3-carboxylic acid and the corresponding amino acid conjugates

• Péter Kisszékelyi,
• Tibor Peňaška,
• Klára Stankovianska,
• Mária Mečiarová and
• Radovan Šebesta

Beilstein J. Org. Chem. 2022, 18, 1195–1202, doi:10.3762/bjoc.18.124

• , three-component procedure was also explored for the preparation of 3-aryl-4H-benzo-1,4-thiazin-2-amines [18]. 3-Aryl- and 3-alkyl-4H-benzo[b][1,4]thiazine-4-carbonitriles 2 (Figure 1) were synthesized in high yield from the corresponding 2-aminobenzothiazoles using the copper–organic framework Cu–MOF-74

Experimental and theoretical studies on the synthesis of 1,4,5-trisubstituted pyrrolidine-2,3-diones

• Nguyen Tran Nguyen,
• Vo Viet Dai,
• Nguyen Ngoc Tri,
• Luc Van Meervelt,
• Nguyen Tien Trung and
• Wim Dehaen

Beilstein J. Org. Chem. 2022, 18, 1140–1153, doi:10.3762/bjoc.18.118

• -Trisubstituted pyrrolidine-2,3-dione derivatives were prepared from the above mentioned 2-pyrrolidinone derivatives and aliphatic amines, which exist in enamine form and are stabilized by an intramolecular hydrogen bond. A possible reaction mechanism between 3-pyrroline-2-one and aliphatic amine (CH3NH2) was

• to obtain structurally complicated and biologically active products containing substantial portions of all starting materials [27]. Recently, polysubstituted 3-hydroxy-1,5-dihydro-2H-pyrrol-2-ones have been synthesized via eco-friendly multicomponent reactions of aromatic aldehydes, amines, and

• dialkyl acetylenedicarboxylate or sodium diethyl oxalacetate [28][29][30][31][32][33][34]. The resulting products have the 4-position locked by the alkoxycarbonyl (–COOR) group and these 2-pyrrolidinone derivatives can be functionalized with amines as nucleophiles via the 3-position [10][35][36][37][38

Scope of tetrazolo[1,5-a]quinoxalines in CuAAC reactions for the synthesis of triazoloquinoxalines, imidazoloquinoxalines, and rhenium complexes thereof

• Laura Holzhauer,
• Chloé Liagre,
• Olaf Fuhr,
• Nicole Jung and
• Stefan Bräse

Beilstein J. Org. Chem. 2022, 18, 1088–1099, doi:10.3762/bjoc.18.111

• denitrogenative reduction to quinoxaline-2-amines 17 was noticed as a side reaction. Depending on the residue in 4-position (R, Table 1) on the pyrazine ring of the tetrazolo[1,5-a]quinoxaline, the formation of either the triazole or the imidazole product or both products occurred. For groups with electron

A versatile way for the synthesis of monomethylamines by reduction of N-substituted carbonylimidazoles with the NaBH₄/I₂ system

• Lin Chen,
• Xuan Zhou,
• Zhiyong Chen,
• Changxu Wang,
• Shunjie Wang and
• Hanbing Teng

Beilstein J. Org. Chem. 2022, 18, 1032–1039, doi:10.3762/bjoc.18.104

• monomethylamines by reduction of N-substituted carbonylimidazoles with NaBH4/I2 in THF at reflux temperature is described. This method used no special catalyst and various monomethylamines can be easily obtained in moderate to good yields from a wide range of raw materials including amines (primary amines and

• secondary amines), carboxylic acids and isocyanates. Besides, an interesting reduction selectivity was observed. Exploration of the reaction process shows that it undergoes a two-step pathway via a formamide intermediate and the reduction of the formamide intermediate to monomethylamine as the rate

• -determining step. This work can contribute significantly expanding the applications of N-substituted carbonylimidazoles. Keywords: amines; carboxylic acids; isocyanates; monomethylamines; N-substituted carbonylimidazoles; reduction; Introduction N-Methylamines are widely found in natural products, fine

First example of organocatalysis by cathodic N-heterocyclic carbene generation and accumulation using a divided electrochemical flow cell

• Daniele Rocco,
• Ana A. Folgueiras-Amador,
• Richard C. D. Brown and
• Marta Feroci

Beilstein J. Org. Chem. 2022, 18, 979–990, doi:10.3762/bjoc.18.98

• [33]. Flow electrochemistry was applied to oxidize the Breslow intermediate to the corresponding electrophilic acylthiazolium intermediate, which then functioned as an acyl-transfer reagent, reacting with alcohols or amines. To the best of our knowledge, only one research group reported the cathodic

Synthetic strategies for the preparation of γ-phostams: 1,2-azaphospholidine 2-oxides and 1,2-azaphospholine 2-oxides

• Jiaxi Xu

Beilstein J. Org. Chem. 2022, 18, 889–915, doi:10.3762/bjoc.18.90

• (methyl)phosphinic chloride (10) with amines generated N-aryl-2-chloromethylphenyl(methyl)phosphinamides 12 in 52–99% yields, which were further treated with DBU in refluxing THF, affording 2-aryl-1-methyl-2,3-dihydrobenzo[c][1,2]azaphosphole 1-oxides 13 in 40–100% yield (Scheme 3) [23]. This is a general

• synthetic method showed very limited substrate scope. Only less bulky primary amines underwent the first aza-Michael addition and then intramolecular nucleophilic substitution. However, aromatic amines, aniline, 2,3-dihydro-1H-inden-4-amine, and the bulky aliphatic primary amine adamantylamine did not

• bis(hydroxymethyl-derived cyclohexadiene-fused γ-phosphinolactam)s from tetramethylene-linked bis(diphenyl-N-benzylphosphinamide). Synthesis of 2-aryl/dimethylamino-1-ethoxy-2-hydrobenzo[c][1,2]azaphosphol-3-one 1-oxides from ethyl (2-(chlorocarbonyl)phenyl)phosphonochloridate 200 with amines and N,N

Synthesis and HDAC inhibitory activity of pyrimidine-based hydroxamic acids

• Virginija Jakubkiene,
• Gabrielius Ernis Valiulis,
• Markus Schweipert,
• Asta Zubriene,
• Daumantas Matulis,
• Franz-Josef Meyer-Almes and
• Sigitas Tumkevicius

Beilstein J. Org. Chem. 2022, 18, 837–844, doi:10.3762/bjoc.18.84

• followed by aminolysis of the obtained esters with hydroxylamine. Oxidation of the 2-methylthio group to the methylsulfonyl group and following treatment with amines resulted in the formation of the corresponding 2-amino-substituted derivatives, the ester group of which reacted with hydroxylamine to give

• shifted by 0.8 ppm and 24.8 ppm in the 1H and 13C NMR spectra, respectively, in comparison with the signals of the methylthio group of compound 3 (see Supporting Information File 1, Figures S1, S2 and S5, S6). Heating compound 5 with primary and secondary amines in dimethyl sulfoxide at 50–70 °C for 0.5 h

An isoxazole strategy for the synthesis of 4-oxo-1,4-dihydropyridine-3-carboxylates

• Timur O. Zanakhov,
• Ekaterina E. Galenko,
• Mikhail S. Novikov and
• Alexander F. Khlebnikov

Beilstein J. Org. Chem. 2022, 18, 738–745, doi:10.3762/bjoc.18.74

• due to their specific characteristics such as basicity, hydrogen bond forming ability, water solubility, and especially because of pyridine rings are bioisosteres of amines, amides, N-heterocyclic rings and benzene rings [1][2][3][4][5]. A special type of pyridine, the 4-pyridones, is also fairly well

Inductive heating and flow chemistry – a perfect synergy of emerging enabling technologies

• Conrad Kuhwald,
• Sibel Türkhan and
• Andreas Kirschning

Beilstein J. Org. Chem. 2022, 18, 688–706, doi:10.3762/bjoc.18.70

• applications. NiO2, on the other hand, was used to achieve the dehydrogenation of amines (to nitriles) and to perform the α,β dehydrogenation of ketones 61. 3.2.3 Using chemically active fixed beds (catalysts): Copper metal in the form of wires or turnings can also be inductively heated when placed inside flow

• three-component reaction (reaction 2) to propargyl amines 8 under continuous flow conditions with microwave assistance. Claisen rearrangement in flow: A. comparison between conventional heating (external oil bath), microwave irradiation, and inductive heating; and B. coupled flow-through protocol

Tri(n-butyl)phosphine-promoted domino reaction for the efficient construction of spiro[cyclohexane-1,3'-indolines] and spiro[indoline-3,2'-furan-3',3''-indolines]

• Hui Zheng,
• Ying Han,
• Jing Sun and
• Chao-Guo Yan

Beilstein J. Org. Chem. 2022, 18, 669–679, doi:10.3762/bjoc.18.68

• functionalized various spiro[cyclohexane-1,3'-indolines] and related reactions. Results and Discussion Initially, the reaction conditions were optimized by using isatylidene malononitrile 1a and bis-chalcone 2a as standard reaction. Tertiary amines such as DMAP and DABCO did not catalyze this reaction (entries 1

Direct C–H amination reactions of arenes with N-hydroxyphthalimides catalyzed by cuprous bromide

• Dongming Zhang,
• Bin Lv,
• Pan Gao,
• Xiaodong Jia and
• Yu Yuan

Beilstein J. Org. Chem. 2022, 18, 647–652, doi:10.3762/bjoc.18.65

• constructing C–N bonds are in high demand in organic synthesis since nitrogen-containing organic compounds are widely used in biologically active substances [1], multifunctional materials [2][3], and metal ligands [4][5]. Among them, the synthesis of aromatic amines has been important to researchers in recent

• (reaction 3) [27]. Herein, we report a method for the construction of aromatic amines via the copper-catalyzed intermolecular radical amination of arenes with N-hydroxyphthalimide (NHPI) under air. Results and Discussion Initially, N-hydroxyphthalimide (NHPI, 2a) was reacted with benzene, catalyzed by CuBr

• envisaged that this work will provide a simple amination strategy for synthesizing aromatic amines. Experimental All new compounds were fully characterized. 1H NMR and 13C NMR spectra were obtained with Agilent Technologies AVANCE-400 MHz or 600 MHz spectrometers in CDCl3 as the solvent with TMS as an

Cholyl 1,3,4-oxadiazole hybrid compounds: design, synthesis and antimicrobial assessment

• Anas J. Rasras,
• Mohamed El-Naggar,
• Nesreen A. Safwat and
• Raed A. Al-Qawasmeh

Beilstein J. Org. Chem. 2022, 18, 631–638, doi:10.3762/bjoc.18.63

• products derived from piperazine derivatives with aromatic electron-donating (4d), electron-withdrawing (4b, 4c, and 4f), and aliphatic groups (4g, 4i, and 4j) were obtained. Moreover, the reaction with secondary aliphatic amines with various alkyl chains afforded products 4r–u, whereas products 4o and 4p

• MIC values piperazines with a methyl group (4i) and compounds with cyclic amines (4o and 4p) were the most active against B. subtilis. Compounds 4a, 4e, 4h, 4k, 4m, 4u, and 4v showed no activities against the tested Gram-negative bacteria under these screening conditions (Table 2). Conclusion A new

Chemistry of polyhalogenated nitrobutadienes, 17: Efficient synthesis of persubstituted chloroquinolinyl-1H-pyrazoles and evaluation of their antimalarial, anti-SARS-CoV-2, antibacterial, and cytotoxic activities

• Viktor A. Zapol’skii,
• Isabell Berneburg,
• Ursula Bilitewski,
• Melissa Dillenberger,
• Katja Becker,
• Stefan Jungwirth,
• Aditya Shekhar,
• Bastian Krueger and
• Dieter E. Kaufmann

Beilstein J. Org. Chem. 2022, 18, 524–532, doi:10.3762/bjoc.18.54

• acid. The next step of our investigation was the two-step synthesis of persubstituted aminopyrazoles 5 upon reaction of the benzotriazolyl derivative 2c with primary, secondary, aliphatic, or (het)aromatic amines (first step) and successive reaction of the obtained dienes 4 with 7-chloro-4

• strongly varying yields (5–72%) and dual orientation (either 3,5- or 5,3-positions) of an amino and dichloromethyl unit in the pyrazole (Scheme 3). We suggest that dienes 4a,l–o, obtained from 2c and primary amines are stabilized by formation of intramolecular hydrogen bonds between the NH and the NO2

• , obtained from reaction of 2c and secondary amines, are obviously stabilized by the effective conjugation between the amino and nitro groups and react with 7-chloro-4-hydrazinylquinoline to give 3-aminopyrazoles 5b–k. In this case, the nucleophilic attack of the NH2 group of ArNHNH2 on the C1 position of

Menadione: a platform and a target to valuable compounds synthesis

• Acácio S. de Souza,
• Ruan Carlos B. Ribeiro,
• Dora C. S. Costa,
• Fernanda P. Pauli,
• David R. Pinho,
• Matheus G. de Moraes,
• Fernando de C. da Silva,
• Luana da S. M. Forezi and
• Vitor F. Ferreira

Beilstein J. Org. Chem. 2022, 18, 381–419, doi:10.3762/bjoc.18.43

Synthesis of piperidine and pyrrolidine derivatives by electroreductive cyclization of imine with terminal dihaloalkanes in a flow microreactor

• Yuki Naito,
• Naoki Shida and
• Mahito Atobe

Beilstein J. Org. Chem. 2022, 18, 350–359, doi:10.3762/bjoc.18.39

• . Furthermore, piperidine and pyrrolidine derivatives could be obtained on preparative scale by continuous electrolysis for approximately 1 hour. Keywords: electrochemical synthesis; electrocyclization; flow microreactor; heterocyclic amines; imine; Introduction Heterocycles are a very important class of

• compounds and make up more than half of all known organic chemicals [1]. Among them, heterocyclic amines, particularly pyrrolidine and piperidine derivatives, have attracted considerable attention because these are important structural motifs in a wide variety of applications including pharmaceuticals

• ]. Conventional synthetic methods for piperidine derivatives include nucleophilic substitution (route (1) in Scheme 1), reductive amination (route (2)), intramolecular cyclization of amines and alkenes (route (3)), the Diels–Alder reaction and subsequent reduction (route (4)), and the radical cyclization reaction

Unexpected chiral vicinal tetrasubstituted diamines via borylcopper-mediated homocoupling of isatin imines

• Marco Manenti,
• Leonardo Lo Presti,
• Giorgio Molteni and
• Alessandra Silvani

Beilstein J. Org. Chem. 2022, 18, 303–308, doi:10.3762/bjoc.18.34

•  1), evaluating firstly different amines (Table 1, entries 1–5), in place of benzylamine. Using DIPEA, the new product 2a was obtained in 31% yield, even if together with 1-methylisatin and other impurities. Aiming to improve the fruitful conversion of substrate 1a, we considered to reduce the amount

New efficient synthesis of polysubstituted 3,4-dihydroquinazolines and 4H-3,1-benzothiazines through a Passerini/Staudinger/aza-Wittig/addition/nucleophilic substitution sequence

• Long Zhao,
• Mao-Lin Yang,
• Min Liu and
• Ming-Wu Ding

Beilstein J. Org. Chem. 2022, 18, 286–292, doi:10.3762/bjoc.18.32

• isocyanides 3 produced the azide intermediates 4, which were treated sequentially with triphenylphosphine, isocyanates (or CS2), and secondary amines to give polysubstituted 3,4-dihydroquinazolines 8 and 4H-3,1-benzothiazines 11 in good overall yields through consecutive Passerini/Staudinger/aza-Wittig

• of their derivatives [12][13][14][15][16][17][18][19][20][21][22]. For example (Scheme 1), a one-pot Tf2O-mediated assembly of amides, amines, and ketones provided 3,4-dihydroquinazolines in good yields via successive triflic anhydride-mediated amide dehydration, ketimine addition, and Pictet

• product 8a was 53%. Therefore, the reaction conditions of entry 1 in Table 1 were optimal for the above transformation. The optimal reaction conditions were then utilized for the sequential reactions of different 2-azidobenzaldehydes 1, benzoic acid (2a), isocyanides 3, isocyanates and secondary amines

Recent developments and trends in the iron- and cobalt-catalyzed Sonogashira reactions

• Surendran Amrutha,
• Sankaran Radhika and
• Gopinathan Anilkumar

Beilstein J. Org. Chem. 2022, 18, 262–285, doi:10.3762/bjoc.18.31

• products, pharmaceuticals of biological activity, and materials science [3]. In a Sonogashira reaction, the reaction conditions are mild and many reactions can be performed at room temperature [4]. However, the reaction is usually carried out in organic solvents like amines, benzene, THF, and DMF along

Synthesis of novel [1,2,4]triazolo[1,5-b][1,2,4,5]tetrazines and investigation of their fungistatic activity

• Anna V. Korotina,
• Svetlana G. Tolshchina,
• Rashida I. Ishmetova,
• Natalya P. Evstigneeva,
• Natalya A. Gerasimova,
• Natalya V. Zilberberg,
• Nikolay V. Kungurov,
• Gennady L. Rusinov,
• Oleg N. Chupakhin and
• Valery N. Charushin

Beilstein J. Org. Chem. 2022, 18, 243–250, doi:10.3762/bjoc.18.29

• -disubstituted 1,2,4,5-tetrazines bearing amidine fragments. It is shown that the heterocyclic systems obtained can be modified easily at C(3) position in the reactions with aliphatic alcohols and amines. Also, the reactivity of [1,2,4]triazolo[1,5-b][1,2,4,5]tetrazines towards CH-active compounds has been

New advances in asymmetric organocatalysis

• Radovan Šebesta

Beilstein J. Org. Chem. 2022, 18, 240–242, doi:10.3762/bjoc.18.28

• by a review article devoted to aza-Michael reactions of amines and amides [17]. The evolution of the understanding of noncovalent activation modes led to the realization that anion-binding is a critical feature in many transformations. Halide anions are highly relevant and widely occurring within

Trichloroacetic acid fueled practical amine purifications

• Aleena Thomas,
• Baptiste Gasch,
• Enzo Olivieri and
• Adrien Quintard

Beilstein J. Org. Chem. 2022, 18, 225–231, doi:10.3762/bjoc.18.26

• . Inspired by recent work on out of equilibrium molecular machinery, using trichloroacetic acid (TCA), we disclose a purification technique considerably decreasing the number of operations and the waste generation required for such purifications. At first, TCA triggers the precipitation of the amines through

• their protonated salt formation, enabling the separation with the impurities. From these amine salts, simple decarboxylation of TCA liberates volatile CO2 and chloroform affording directly the pure amines. Through this approach, a broad range of diversely substituted amines could be isolated with

• success. Keywords: amines; decarboxylation; eco-compatible; out of equilibrium; purification; Introduction Isolation of pure amines from reaction mixtures or natural extracts is crucial in modern organic chemistry. However, the most widely applied methods for these purifications have remained unchanged

Organocatalytic asymmetric nitroso aldol reaction of α-substituted malonamates

• Ekta Gupta,
• Narendra Kumar Vaishanv,
• Sandeep Kumar,
• Raja Krishnan Purshottam,
• Ruchir Kant and
• Kishor Mohanan

Beilstein J. Org. Chem. 2022, 18, 217–224, doi:10.3762/bjoc.18.25

• metal-catalyzed reactions [31][32][33][34][35][36]. The most successful among them are the ʟ-proline-catalyzed reactions of enolizable aldehydes with nitrosoarenes [37][38][39][40][41][42][43]. Besides ʟ-proline and its derivatives, various secondary amines derived from BINOL and cinchona alkaloids were

Ready access to 7,8-dihydroindolo[2,3-d][1]benzazepine-6(5H)-one scaffold and analogues via early-stage Fischer ring-closure reaction

• Irina Kuznetcova,
• Felix Bacher,
• Daniel Vegh,
• Hsiang-Yu Chuang and
• Vladimir B. Arion

Beilstein J. Org. Chem. 2022, 18, 143–151, doi:10.3762/bjoc.18.15

• [2,3-d][1]benzazepin-6(5H)-one (3a). This procedure delivered analytically pure 3a in 80% yield as also confirmed by SC-XRD (Figure 3). The final step to structure C required removal of the benzyl group. Debenzylation of amines is commonly performed by palladium-catalyzed hydrogenation [40]. However

Green synthesis of C5–C6-unsubstituted 1,4-DHP scaffolds using an efficient Ni–chitosan nanocatalyst under ultrasonic conditions

• Soumyadip Basu,
• Sauvik Chatterjee,
• Suman Ray,
• Suvendu Maity,
• Prasanta Ghosh,
• Asim Bhaumik and
• Chhanda Mukhopadhyay

Beilstein J. Org. Chem. 2022, 18, 133–142, doi:10.3762/bjoc.18.14

• same time, namely that of an aldehyde and that of one multiple bond. Generally, aldehydes and multiple bonds are very reactive in the presence of primary amines. However, since we used cinnamaldehyde derivatives 3, which are conjugated systems of a double bond and an aldehyde, the reactivity was rather

• The substrate scope and the generality of the reaction under the optimized conditions were explored through the synthesis of various products using differently substituted primary amines 1, cinnamaldehydes 3, and dialkyl but-2-ynedioates 2. Aromatic, aliphatic, benzylic, and various other types of

• primary amines 1 afford an excellent yield. Ortho-, meta-, and para-substituted aromatic amines with both electron-donating and -withdrawing groups were used in this protocol. Aromatic amines with electron-donating groups offered a slightly higher yield compared to those with electron-withdrawing groups