One-pot Ugi-azide and Heck reactions for the synthesis of heterocyclic systems containing tetrazole and 1,2,3,4-tetrahydroisoquinoline

• Jiawei Niu,
• Yuhui Wang,
• Shenghu Yan,
• Yue Zhang,
• Xiaoming Ma,
• Qiang Zhang and
• Wei Zhang

Beilstein J. Org. Chem. 2024, 20, 912–920, doi:10.3762/bjoc.20.81

• the Ugi reaction products 5 could affect the yield of the Heck reaction. To address the issue, compounds 5 were N-alkylated to afford intermediates 7 which were used in the subsequent Heck reaction step. Thus, an alternative one-pot Ugi-azide/N-alkylation/Heck reaction procedure was developed (Scheme

• tetrazolyl-1,2,3,4-tetrahydroisoquinoline 8a in 74% isolated yield which is higher than the one-pot Ugi/Hecke reaction to give product 6b (58%). Under the alternative one-pot reaction conditions involving an N-alkylation step, the substrate scope was explored by the preparation of 10 derivatives 8a–j (Scheme

Additive-controlled chemoselective inter-/intramolecular hydroamination via electrochemical PCET process

• Kazuhiro Okamoto,
• Naoki Shida and
• Mahito Atobe

Beilstein J. Org. Chem. 2024, 20, 264–271, doi:10.3762/bjoc.20.27

• , entry 3); thus, the phosphate base plays a crucial role in N-alkylation, while its basicity is insufficient to promote aza-Michael addition (pKa of the conjugate acid of the phosphate base is 1.72 in H2O) [12]. Furthermore, N-alkylation proceeded in a divided cell (anodic chamber); thus, the possibility

• of conjugate addition of a cathodically generated carbamate anion was ruled out, prompting us to consider that N-alkylation proceeded via a radical mechanism. On the other hand, the addition of 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) led to the predominant formation of cyclized dimer 4 without N

• (Figure 2B, blue line). However, in the presence of AcOH, the N-alkylation yield was low (Table 1, entry 6) owing to the competitive Kolbe oxidation of the cathodically generated acetate anion. In fact, the oxidation potential of Bu4NOAc is lower than that of 1 (Figure 2C, orange line). A decrease in the

Facile access to pyridinium-based bent aromatic amphiphiles: nonionic surface modification of nanocarbons in water

• Lorenzo Catti,
• Shinji Aoyama and
• Michito Yoshizawa

Beilstein J. Org. Chem. 2024, 20, 32–40, doi:10.3762/bjoc.20.5

• -stacking interactions, and displayed high stability against dilution (CMC < 0.1 mM). The molecular design allowed installation of various nonionic side-chains (i.e., CH3 and CH2CH2(OCH2CH2)2–Y (Y = OCH3, OH, and imidazole)) via simple N-alkylation, enabling the nonionic surface modification of nanocarbons

Trifluoromethylated hydrazones and acylhydrazones as potent nitrogen-containing fluorinated building blocks

• Zhang Dongxu

Beilstein J. Org. Chem. 2023, 19, 1741–1754, doi:10.3762/bjoc.19.127

• -triazolines and their derivatives via tandem 1,2-addition/cyclization reactions between trifluoromethyl acylhydrazones and cyanamide [105] (Scheme 17b). Afterwards, Hu et al. developed a method for the N-arylation and N-alkylation of trifluoromethyl acylhydrazones with diaryliodonium salts and alkyl halides

• acylhydrazines. Synthesis of trifluoromethylated cyanohydrazines and 3-trifluoromethyl-1,2,4-triazolines. N-Arylation and N-alkylation of trifluoromethyl acylhydrazones. [3 + 2]-Cycladditions of trifluoromethyl acylhydrazones.

A series of perylene diimide cathode interlayer materials for green solvent processing in conventional organic photovoltaics

• Kathryn M. Wolfe,
• Shahidul Alam,
• Eva German,
• Fahad N. Alduayji,
• Maryam Alqurashi,
• Frédéric Laquai and
• Gregory C. Welch

Beilstein J. Org. Chem. 2023, 19, 1620–1629, doi:10.3762/bjoc.19.119

• cyano N-annulated ethyl propyl perylene diimide) are reported within for the first time. Starting from PDIN-H, PDIN-B and PDIN-FB can be synthesized via N-alkylation by use of a base (K2CO3) in the presence of either benzyl bromide for PDIN-B or pentafluorobenzyl bromide for PDIN-FB (Scheme 1). Starting

• from CN-PDIN-H, CN-PDIN-B and CN-PDIN-FB can be synthesized by N-alkylation by use of a base (K2CO3) in the presence of either benzyl bromide for CN-PDIN-B or pentafluorobenzyl bromide for CN-PDIN-FB (Scheme 1). The products were collected by precipitating the product out of the reaction mixtures by

Consecutive four-component synthesis of trisubstituted 3-iodoindoles by an alkynylation–cyclization–iodination–alkylation sequence

• Nadia Ledermann,
• Alae-Eddine Moubsit and
• Thomas J. J. Müller

Beilstein J. Org. Chem. 2023, 19, 1379–1385, doi:10.3762/bjoc.19.99

• transition-metal catalysis [31], we disclosed an activating group-free alkynylation–cyclization sequence to (aza)indoles [32][33] that could be readily concatenated with a concluding N-alkylation of the 7-azaindole intermediate in the sense of consecutive three-component coupling–cyclization–alkylation

• N-iodosuccinimide prior to N-alkylation to give substituted 3-iodoindoles in a concise consecutive four-component fashion in modest to good yields. These target compounds are versatile building blocks for instance for a Suzuki coupling to give 1-alkyl-2,3-diarylindoles that can be of particular

Strategies in the synthesis of dibenzo[b,f]heteropines

• David I. H. Maier,
• Barend C. B. Bezuidenhoudt and
• Charlene Marais

Beilstein J. Org. Chem. 2023, 19, 700–718, doi:10.3762/bjoc.19.51

• (Scheme 32). Yao et al. [75] reported the reaction of 1a with aryl halides 140 and 141 to afford N-aryldibenzo[b,f]azepines 142 in good to excellent yields. N-Alkylation of the 5H-dibenzo[b,f]azepine (1a) scaffold is a common point of functionalisation of 1a and the dihydro derivative, 2a. Indeed, the

• -dihydrodibenzo[b,f]heteropines via intramolecular Wurtz reaction. Phenol deprotonation and intramolecular etherification in the synthesis of bauhinoxepine J. Palladium-catalysed N-arylation of dibenzo[b,f]azepine. Cu- and Ni-catalysed N-arylation. N-Alkylation of dibenzo[b,f]azepine (1a) and dihydrodibenzo[b,f

Synthesis, α-mannosidase inhibition studies and molecular modeling of 1,4-imino-ᴅ-lyxitols and their C-5-altered N-arylalkyl derivatives

• Martin Kalník,
• Sergej Šesták,
• Juraj Kóňa,
• Maroš Bella and
• Monika Poláková

Beilstein J. Org. Chem. 2023, 19, 282–293, doi:10.3762/bjoc.19.24

• than parent DIM [15]. Also, screening of a large library of N-alkyl and N-arylalkyl DIMs revealed that they are less effective inhibitors of JBMan than DIM, indicating that N-alkylation might lead to better selectivity profiles. However, this library has not been assayed for GMII and LM, therefore the

• -benzyl group with the Cbz group, trityl ether hydrolysis, oxidation of the liberated OH group, and stereoselective addition of MeMgBr to the resulting aldehyde functionality. Hydrogenolysis of the Cbz protecting group in 13 followed by N-alkylation afforded pyrrolidines 14–16 which after acidic

• of 28 is weaker than ΔEring-E = −514.35 kcal mol−1 of 29) and the overall ΔEI-E for 28 became lower than for 29, which is in agreement with the measured inhibitory activities of these compounds. This is a surprising result because N-alkylation of 30 (structure 31 in Table 1) did not decrease

Inline purification in continuous flow synthesis – opportunities and challenges

• Jorge García-Lacuna and
• Marcus Baumann

Beilstein J. Org. Chem. 2022, 18, 1720–1740, doi:10.3762/bjoc.18.182

• membrane fouling after 1 hour. An automated fill-empty gravity separator was also used for the separation of phases in a scale up of an N-alkylation reaction reported by Eli-Lilly as an alternative to the Zaiput membranes that were better used for rapid screening of conditions [57]. The use of these

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

• ][31] and carbon dioxide (CO2) [32][33][34][35][36][37][38][39] have been developed for the N-methylation of amines. However, these N-alkylation methods often require the employment of expensive catalysts, and the N-alkylation of primary amines generally does not stop with monomethylation as expected

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

• 180 °C at 4.5 MPa for 7.5 min. These conditions allowed to suppress the decomposition of the N-alkylation product 78 by using a 1/8“-reactor. The subsequent purification was realized by a clever catch and release protocol based on a silica column, yielding iloperidone (80, 67%). The tricyclic

BINOL as a chiral element in mechanically interlocked molecules

• Matthias Krajnc and
• Jochen Niemeyer

Beilstein J. Org. Chem. 2022, 18, 508–523, doi:10.3762/bjoc.18.53

• were coupled with a benzoic acid-based stopper using N,N′-diisopropylcarbodiimide (DIC) and tributylphosphine (26–75% yield). The isolated rotaxanes were then used for subsequent reductive N-alkylation to obtain the tert-amine-type rotaxanes (R)-29a–f in yields of 67–92%. Finally, dimethyldioxirane

Regioselectivity of the S_EAr-based cyclizations and S_EAr-terminated annulations of 3,5-unsubstituted, 4-substituted indoles

• Jonali Das and
• Sajal Kumar Das

Beilstein J. Org. Chem. 2022, 18, 293–302, doi:10.3762/bjoc.18.33

• -butyloxycarbonylation and N-alkylation (Scheme 14) [25]. The C5 cyclization regioselectivity and trans-diastereoselectivity were not influenced by the electronic nature of the indole-N-substituent. Conclusion As illustrated by these studies, SEAr-based intramolecular cyclization and annulation reactions of 3,5

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

• 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

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

• 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

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

• 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

• achieve regioselective indazole N-alkylation have exploited the noted difference in reactivity between the N-1 and N-2 atom of the indazole scaffold [15], as the 1H-indazole tautomer is typically considered to be more thermodynamically stable than the corresponding 2H-tautomer [16]. Using appropriate α

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

N-tert-Butanesulfinyl imines in the asymmetric synthesis of nitrogen-containing heterocycles

• Joseane A. Mendes,
• Paulo R. R. Costa,
• Miguel Yus,
• Francisco Foubelo and
• Camilla D. Buarque

Beilstein J. Org. Chem. 2021, 17, 1096–1140, doi:10.3762/bjoc.17.86

• generated, taking place a diastereoselective nucleophilic dichloromethylation of the imine. The addition took place almost exclusively to the Re face of the imine (RS)-14, which is the less sterically hindered in the most stable s-cis conformation (see Scheme 2). The second intramolecular N-alkylation step

• ketone derivative 111, which was not isolated. After removal of the sulfinyl group under acidic conditions, and intramolecular N-alkylation upon treatment with sodium bicarbonate, (−)-pelletierine (112) was formed, and easily isolated as its hydrochloride derivative (Scheme 32) [120]. Compound 112 is a

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

• leading to poor N1/N2 selectivity, for instance, in the direct N-alkylation of triazoles [21][22][23]. Despite these challenges, a number of N1- and N2-selective alkylation methods have been developed employing transition metal catalysts which include Au-catalysed desulfonylative coupling N-tosyl-1,2,3

Synthesis of tetrafluorinated piperidines from nitrones via a visible-light-promoted annelation reaction

• Vyacheslav I. Supranovich,
• Igor A. Dmitriev and
• Alexander D. Dilman

Beilstein J. Org. Chem. 2020, 16, 3104–3108, doi:10.3762/bjoc.16.260

• likely starts from the addition of the fluorinated radical to the C=N bond followed by a conversion of the nitroxyl radical via hydrogen atom transfer [26][27] providing hydroxylamine 4. At the next stage, the intramolecular N-alkylation occurs leading to an N-oxide. This step of nucleophilic

Ultrasound-assisted Strecker synthesis of novel 2-(hetero)aryl-2-(arylamino)acetonitrile derivatives

• Emese Gal,
• Luiza Gaina,
• Hermina Petkes,
• Alexandra Pop,
• Castelia Cristea,
• Gabriel Barta,
• Dan Cristian Vodnar and
• Luminiţa Silaghi-Dumitrescu

Beilstein J. Org. Chem. 2020, 16, 2929–2936, doi:10.3762/bjoc.16.242

• lipophilic character of the metallocene [11]. However, only a limited number of reports described the application of ultrasonic irradiation for the synthesis of phenothiazine derivatives, and included the N-alkylation of 10H-phenothiazine [12], condensation of phenothiazine carbaldehyde with hydrazino

Convenient access to pyrrolidin-3-ylphosphonic acids and tetrahydro-2H-pyran-3-ylphosphonates with multiple contiguous stereocenters from nonracemic adducts of a Ni(II)-catalyzed Michael reaction

• Alexander N. Reznikov,
• Dmitry S. Nikerov,
• Anastasiya E. Sibiryakova,
• Victor B. Rybakov,
• Evgeniy V. Golovin and
• Yuri N. Klimochkin

Beilstein J. Org. Chem. 2020, 16, 2073–2079, doi:10.3762/bjoc.16.174

• presence of Pd/C. However, phosphonate 7 was unstable: already during its isolation, it was partially transformed into compounds 8 and 9. It can be assumed that N-alkylation by the phosphoryl group occurs [47][48][49]. To avoid this undesirable process, the product 7 was formylated before its isolation

Et₃N/DMSO-supported one-pot synthesis of highly fluorescent β-carboline-linked benzothiophenones via sulfur insertion and estimation of the photophysical properties

• Dharmender Singh,
• Vipin Kumar and
• Virender Singh

Beilstein J. Org. Chem. 2020, 16, 1740–1753, doi:10.3762/bjoc.16.146

• substituents at C1 (R4), compound 4eA with aromatic substituent exhibited better fluorescence due to extended conjugation. The effect of R2 substituent in these derivatives (4bA, 4dA, 4fA and 4gA) was also investigated and it was found that N-alkylation improved the photophysical properties along with higher

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

• sulfonamides 47, followed by the introduction of the fluoroallyl group via N-alkylation with previously described mesylate 38 provided fluorinated enynes 48 (Scheme 24). The enantioenriched starting materials 48 were then evaluated in the Co-mediated PKR to yield the bicyclic products 49 in moderate to good

Heterogeneous photocatalysis in flow chemical reactors

• Christopher G. Thomson,
• Ai-Lan Lee and
• Filipe Vilela

Beilstein J. Org. Chem. 2020, 16, 1495–1549, doi:10.3762/bjoc.16.125