A recent overview on the synthesis of 1,4,5-trisubstituted 1,2,3-triazoles

• Pezhman Shiri,
• Ali Mohammad Amani and
• Thomas Mayer-Gall

Beilstein J. Org. Chem. 2021, 17, 1600–1628, doi:10.3762/bjoc.17.114

• compounds 9, and tosyl azide through a cycloaddition process in DCM as solvent and HOAc as additive at 90 °C in moderate to excellent yield (Scheme 6) [41]. As illustrated in Scheme 7, imine intermediate 12 was generated via the reaction between amine 10 and 1,3-dicarbonyl compound 9. Then, tautomerization

• of the imine intermediate produces the intermediate enamine 13. The 1,3-dipolar cycloaddition of enamine 13 with azide produces intermediate 1,2,3-triazoline 14. In continuation, a ring-opening process is promoted by acetic acid to afford the intermediate 16. Afterward, triazene intermediate 17 was

• is imine–enamine-tautomerized to afford the intermediate 27. Then, the final triazole compound, as major isomer, is achieved through an intermolecular cyclization process and elimination of one unit of TsNH2 [23]. A general strategy was described for the synthesis of 1,4,5-trisubstituted glycosyl

Methodologies for the synthesis of quaternary carbon centers via hydroalkylation of unactivated olefins: twenty years of advances

• Thiago S. Silva and
• Fernando Coelho

Beilstein J. Org. Chem. 2021, 17, 1565–1590, doi:10.3762/bjoc.17.112

• ]. This approach allowed the synthesis of alkylated benzofurans and benzothiophenes (Scheme 27). Investigations of the substrate scope revealed that both electron-donating and electron-withdrawing group substituents at the aromatic portions of the imine substrate could afford the aromatic heterocycle in

A straightforward conversion of 1,4-quinones into polycyclic pyrazoles via [3 + 2]-cycloaddition with fluorinated nitrile imines

• Greta Utecht-Jarzyńska,
• Karolina Nagła,
• Grzegorz Mlostoń,
• Heinz Heimgartner,
• Marcin Palusiak and
• Marcin Jasiński

Beilstein J. Org. Chem. 2021, 17, 1509–1517, doi:10.3762/bjoc.17.108

• exclusively [16]. Noteworthy, [3 + 2]-cycloadditions of nitrile imines to the C=O group of 1,4-quinones have not yet been reported. In a historical work by Rolf Huisgen et al., the first [3 + 2]-cycloadditions of some 1,4-quinones, e.g., 1,4-naphthoquinone (1a), with C,N-diphenyl nitrile imine (2) were

• ]. Results and Discussion In a preliminary experiment, the reaction of 1,4-naphthoquinone (1a) with N-phenyltrifluoroacetohydrazonoyl bromide (8a), used as an easy-to-handle precursor of nitrile imine 7a, was examined. The reaction was performed in selected aprotic organic solvents by using organic and

• reported by Huisgen [17], who in the reaction of nitrile imine 2 with the same dipolarophile obtained the expected [3 + 2]-cycloadduct to the C=C bond as a single regioisomer, which was isolated in 33% yield. The observed outcome suggests that the thermally generated nitrile imine 2 undergoes [3 + 2

One-step synthesis of imidazoles from Asmic (anisylsulfanylmethyl isocyanide)

• Louis G. Mueller,
• Allen Chao,
• Embarek AlWedi and
• Fraser F. Fleming

Beilstein J. Org. Chem. 2021, 17, 1499–1502, doi:10.3762/bjoc.17.106

• Substituted imidazoles are readily prepared by condensing the versatile isocyanide Asmic, anisylsulfanylmethylisocyanide, with nitrogenous π-electrophiles. Deprotonating Asmic with lithium hexamethyldisilazide effectively generates a potent nucleophile that efficiently intercepts nitrile and imine

• to imidazoles [11][12], the condensation of metalated isocyanides with nitrogenous π-electrophiles is distinguished by excellent efficiency and modularity. Deprotonating an isocyanide 1 affords an isocyanide-stabilized anion 2 whose condensation with an imidate or nitrile generates a transient imine

Synthesis of 1-indolyl-3,5,8-substituted γ-carbolines: one-pot solvent-free protocol and biological evaluation

• Premansh Dudhe,
• Mena Asha Krishnan,
• Kratika Yadav,
• Diptendu Roy,
• Krishnan Venkatasubbaiah,
• Biswarup Pathak and
• Venkatesh Chelvam

Beilstein J. Org. Chem. 2021, 17, 1453–1463, doi:10.3762/bjoc.17.101

• base) at room temperature in a non-polar solvent such as toluene, only marginal amounts of the corresponding imine were observed, that could not be isolated (Table 1, entry 1). When the reaction mixture was further heated to reflux for 16 h, only traces of 1-indolyl 3,5,8-substituted γ-carboline 3aa

• 5, which undergoes nucleophilic addition with another molecule of aldehyde 1 to furnish the iminoalcohol intermediate 6. The iminoalcohol 6 undergoes dehydration under the reaction conditions to give E-imine/Z-enamine 7a or Z-imine/E-enamine 7c intermediates irreversibly, which plays a decisive role

• in determining ring closure either via path a or path b. In path a, the protonation of the imine nitrogen in 7a by the conjugate acid (+ BH) leads to an electrophilic aromatic substitution at the 3-position of the indole unit to form a carbon–carbon bond in the intermediate 8. A further proton

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

• less active than the primary amine. The authors suggest the reaction occurs through an imine/iminium intermediate as they confirmed a first order relationship between the reaction rate and the catalyst concentration. After washing with nitromethane, the catalyst could be reused a second time, obtaining

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

• -butanesulfinyl imines as reaction intermediates, including the synthesis of several natural products. The synthesis of nitrogen-containing heterocycles in which the nitrogen atom is not provided by the chiral imine will not be considered in this review. The sections are organized according to the size of the

• or in the carbonyl component of the starting imine (Scheme 1). Synthesis of tert-butane N-sulfinyl imines The first method developed for the synthesis of enantiomerically pure N-tert-butanesulfonamide 1 was reported by Ellman and co-workers [14][15]. In 1999, they described the synthesis of imines

• -bromoenolates to enantiopure p-toluenesulfinamide 5. cis-aziridine 7a was formed as the major diastereoisomer in 89% yield and the trans-isomer in 8% yield in a one-step procedure using lithium enolates of methyl bromoacetate 6a and sulfinyl imine 5. Lithium enolates of methyl α-bromopropionate gave trans

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

• plausible mechanism shown in Scheme 14 explains the formation of azomethine ylide B by condensation of isatin with amino acid followed by release of a molecule of CO2 via A. The imine B undergoes 1,3-dipolar cycloaddition with the dipolarophiles 39. The cyclization yields the desired product 40 of the three

• consecutive ring closure yields the desired product 75 aided by the attack of nitrogen lone pair in Michael’s adduct C via a sequential ethanol elimination (E) from D followed by aerial oxidation of intermediate F. Another proposed mechanism follows the formation of imine derivative G produced by the reaction

• between aldehyde and amidine. The imine G thereby reacts with ethyl cyanoacetate to result in intermediate I, which on intramolecular cyclization leads to D. The remaining pathway pursues same mechanism as the first one (Scheme 27). Later in 2016, Gopalakrishnan and co-workers [74] demonstrated the

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

• the fact that diamine can condense with the enol substrate, forming an imine-ion intermediate absorbing in the visible region. The direct excitation of the intermediate leads to a charge-transfer excited state, completing the stereocontrolled intermolecular cycloaddition reaction with a good ratio of

• to convert α,β-unsaturated aldehydes selectively into 4-ketoaldehydes (Scheme 38). The imine salt (electron acceptor) that forms EDA complex 112 with electron donor α-keto acid 109 is synthesized by secondary amine catalyst and α,β-unsaturated aldehyde 110. Compound 112 turns to excited state 112

• , which can be considered an effective method for the generation of alkyl radicals without catalyst. In 2019, Yu and Zhang [15] reported a radical acylation reaction initiated by an EDA complex promoted by visible light. Imine 122 was employed as electron acceptor with α-keto acid 109 as electron donor to

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

• the equilibrium concentration) of the intermediary α-thioiminium salt which is much more reactive towards an internal nucleophilic attack than the free thioimidate group. Although an electron-withdrawing substituent R4 also enhances the internal nucleophilic attack to both α-thioiminium and imine

Mesoionic tetrazolium-5-aminides: Synthesis, molecular and crystal structures, UV–vis spectra, and DFT calculations

• Vladislav A. Budevich,
• Sergei V. Voitekhovich,
• Alexander V. Zuraev,
• Vadim E. Matulis,
• Vitaly E. Matulis,
• Alexander S. Lyakhov,
• Ludmila S. Ivashkevich and
• Oleg A. Ivashkevich

Beilstein J. Org. Chem. 2021, 17, 385–395, doi:10.3762/bjoc.17.34

• thermal stability of the tetrazolium-5-aminides (see Supporting Information File 1 for more details). Some nucleophilic displacement reactions were carried out in order to show the higher reactivity of the aminides in comparison to the parent aminotetrazoles. The high nucleophilicity of the imine group in

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

• to give an imine in the first step, which is protonated by (S)-TRIP to generate the corresponding chiral CF3-substituted iminium ion. The latter subsequently reacts via the most accessible Re-face with indole 149 to afford the resulting Friedel–Crafts product 177. Worthy of note is the fact that the

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

• imines 115, which led to alkylideneazetidines 116 (Scheme 52) [102]. The MgI2 acted as a Lewis acid and reducing agent, effecting the distal C–C bond cleavage in 113a to form an allenyl ketone, or an equivalent fluoro,iodo-enone species, either of which could then have added to the imine 115 and led to

Direct synthesis of anomeric tetrazolyl iminosugars from sugar-derived lactams

• Michał M. Więcław and
• Bartłomiej Furman

Beilstein J. Org. Chem. 2021, 17, 115–123, doi:10.3762/bjoc.17.12

• hydride, known as Schwartz’s reagent [8]. This reduces the amide moiety, giving a complex that can be readily transformed into an imine or iminium cation [9]. It may perhaps be observed without straying too far afield from our primary focus that reduction of amides is actually not a leading use case of

• to the aforementioned method’s limitation to tertiary amides. Our previous work shows that Charette’s methodology is also not applicable in this case, as it does not lead to the formation of an imine [23]. Luckily, we were able to use a formerly established strategy based on Georg’s procedure with

• highest yield and diastereoselectivity, thus were chosen as optimal (Table 1, entry 9.). We also tried to isolate the imine after the reduction step and carry out the second step in a solvent commonly used for the Ugi–azide reaction alone. For this, we observed a significant decrease in overall yield and

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

• synthesis of (±)-hirsutene (14) used an alkylidene carbene as source of TMM diyl in the intramolecular [3 + 2] cycloaddition [24] (Scheme 1D). Heating of epoxyaziridinyl imine 32 produced tricyclic compound 36 in 57% yield as a single product. The authors proposed that heating of epoxyaziridinyl imine 32

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

• nucleophile to an imine C–N bond. Among the various cyanide transferring agents, which were largely documented in the search for advantageous synthetic procedures of these synthetic intermediates [17], trimethylsilyl cyanide (TMSCN) gave the possibility of accomplishing Strecker reactions using a wide variety

• (hetero)aromatic units and either electron-donating (methyl, methoxy) or electron-withdrawing groups (carboxy, nitro, etc.) pending on the imine substrate. The molecular structures of all synthesized α-(arylamino)acetonitriles 2a–j were fully characterized by spectroscopic methods. The MS spectra

Three-component reactions of aromatic amines, 1,3-dicarbonyl compounds, and α-bromoacetaldehyde acetal to access N-(hetero)aryl-4,5-unsubstituted pyrroles

• Wenbo Huang,
• Kaimei Wang,
• Ping Liu,
• Minghao Li,
• Shaoyong Ke and
• Yanlong Gu

Beilstein J. Org. Chem. 2020, 16, 2920–2928, doi:10.3762/bjoc.16.241

• proposed and is depicted in Scheme 5. Initially, a reaction of 1a and 3a occurred, providing an imine intermediate I, which tautomerized to the corresponding enamine form. Meanwhile, the activation of 2a with AlCl3 allowed the formation of a carbocation intermediate II, which was then trapped by the

• , affording the polysubstituted pyrazolo[3,4-b]pyridine 5a in 53% yield. The formation of an imine intermediate V may be involved in the reaction mechanism, and the enamine form of V contained two nucleophilic sites to react with a molecule of 3a, which generated the intermediate VI. Finally, VI underwent an

Synthesis of imidazo[1,5-a]pyridines via cyclocondensation of 2-(aminomethyl)pyridines with electrophilically activated nitroalkanes

• Dmitrii A. Aksenov,
• Nikolai A. Arutiunov,
• Vladimir V. Maliuga,
• Alexander V. Aksenov and
• Michael Rubin

Beilstein J. Org. Chem. 2020, 16, 2903–2910, doi:10.3762/bjoc.16.239

• highly important imidazo[1,5-a]pyridines. It was imagined that the initial nucleophilic attack of the 2-(aminomethyl)pyridine (12) on the nitronate 2 would provide an amidinium species 13, which is very well suited for a 5-exo-trig cyclization involving the masked imine moiety of the pyridine ring

A heterobimetallic tetrahedron from a linear platinum(II)-bis(acetylide) metalloligand

• Matthias Hardy,
• Marianne Engeser and
• Arne Lützen

Beilstein J. Org. Chem. 2020, 16, 2701–2708, doi:10.3762/bjoc.16.220

• ligand syntheses is the subcomponent self-assembly strategy [18][19][20][21][22][23]. Following this strategy, the actual ligand is generated in situ during the self-assembly process via reversible formation of covalent bonds, in most cases imine bonds. Despite this achievement, addressing even higher

• (II) triflate hexahydrate in acetonitrile giving rise to the desired heterobimetallic [Fe4Pt6] complex as a mixture of diastereomers (Scheme 1). Despite the introduced imine functionalities, which are prone to hydrolysis, we did not observe any hydrolysis under the reaction conditions with at least 3

• equivalents of water per imine function that originate from the hydrate salt and imine condensations. Following this approach, the heterobimetallic cage 4 was obtained as a dark purple solid in 87% yield. Interestingly, complex 4 turned out to be rather stable as a solid under ambient conditions for several

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

• cycloaddition of in situ-generated azomethine imine under microwave conditions is described. The reaction of 6-aryl-1,5-diazabicyclo[3.1.0]hexanes with 1,3-diphenylprop-2-en-1-ones proceeds regio- and stereoselectively giving mostly good yields of the corresponding perhydropyrazolopyrazoles. The products of the

• the hexahydropyrazolo[1,2-a]pyrazole ring, respectively, apparently through zwitterionic intermediates [28][29]. At the same time, the cycloaddition of azomethine imine to 1,3-diphenylprop-2-en-1-ones (chalcones) in IL proceeds stereo- and regioselectively giving two diastereomeric bicyclic anti

• formation of adduct 3m and pyrazoline 4b (Scheme 3). Thus, the azomethine imine A, formed by heating of DABCH 1a, either reacts with propenone 2f giving the adduct 3m or undergoes isomerization affording pyrazoline 4a. On the basis of this observation we suppose that the reaction products undergo

Asymmetric Mannich reactions of (S)-N-tert-butylsulfinyl-3,3,3-trifluoroacetaldimines with yne nucleophiles

• Ziyi Li,
• Li Wang,
• Yunqi Huang,
• Haibo Mei,
• Hiroyuki Konno,
• Hiroki Moriwaki,
• Vadim A. Soloshonok and
• Jianlin Han

Beilstein J. Org. Chem. 2020, 16, 2671–2678, doi:10.3762/bjoc.16.217

• (Scheme 1b) [35]. Based on our experience in the preparation of trifluoromethylated amino compounds [36][37][38][39][40] and the chemistry of N-tert-butylsulfinyl-3,3,3-trifluoroacetaldimine (1) [41][42][43][44][45][46][47][48][49][50][51][52][53][54], we noticed that the reactions of chiral imine 1 with

• mode of nucleophilic attack on the imine double bond in 1. As presented in Figure 3, imine 1 might react in the most stable conformation with the bulky tert-butyl group pointing away from the imine double bond. In this case the only stereocontrolling factor in play is the difference between the

• sulfinyl oxygen and the oxygen electron lone pair. The latter presents a lesser steric obstacle rendering the corresponding nucleophilic attack the more probable event. These ever-unexpected results strongly suggest that the origin of the stereocontrol in the reactions of imine 1 is not just the bulk of

Synthesis of novel fluorinated building blocks via halofluorination and related reactions

• Attila Márió Remete,
• Tamás T. Novák,
• Melinda Nonn,
• Matti Haukka,
• Ferenc Fülöp and
• Loránd Kiss

Beilstein J. Org. Chem. 2020, 16, 2562–2575, doi:10.3762/bjoc.16.208

• halolactons (rac)-17a,b. The initial attack of the halogen cation occurs at the sterically more accessible side of the C=C bond; (rac)-17a: X = Br; (rac)-2a: X = I. Unsuccessful halofluorination of the bicyclic diester 18. Halofluorination reactions of the rigid tricyclic imine 19. The relevant NOESY

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

• then reduce 3-nitrobenzoic acid to the corresponding aniline 25 to turn over the cobalt cycle. Simultaneously, 23 condenses with the chiral primary amine catalyst 26 to give enamine intermediate 27, which can be intercepted by 24 to generate imine intermediate 28, which is finally hydrolysed to turn

• ketones 29 with 2-substituted indoles 30 as a precursor to imine 31, for the synthesis of indolin-3-ones 32 in good yields and excellent enantioselectivities (21 examples, up to >99:1 er) (Scheme 4a) [29]. Zhang et al. recently added to the scope of this family of reactions with their use of aldehydes

• -position of the iminium ion generating an unstable iminyl radical 52•+ that is quickly quenched by the nearby carbazole to form a more stable carbazole centred radical 53•+. Rapid tautomerisation to imine 54•+ precludes the undesired back electron transfer. Single electron reduction of 54•+ by PC•– and

Synthetic approaches to bowl-shaped π-conjugated sumanene and its congeners

• Shakeel Alvi and
• Rashid Ali

Beilstein J. Org. Chem. 2020, 16, 2212–2259, doi:10.3762/bjoc.16.186

• worldwide. To this context, Hirao’s team has reported the synthesis of sumanenemonoone imine compounds 134 and 135 along with the Pd(II) complex 136 formed in a stepwise coordination manner investigated by a titration experiment (Scheme 35) [67]. As can be inspected from Scheme 35, compound 134 was prepared

Controlling the stereochemistry in 2-oxo-aldehyde-derived Ugi adducts through the cinchona alkaloid-promoted electrophilic fluorination

• Yuqing Wang,
• Gaigai Wang,
• Anatoly A. Peshkov,
• Ruwei Yao,
• Muhammad Hasan,
• Manzoor Zaman,
• Chao Liu,
• Stepan Kashtanov,
• Olga P. Pereshivko and
• Vsevolod A. Peshkov

Beilstein J. Org. Chem. 2020, 16, 1963–1973, doi:10.3762/bjoc.16.163

• -component Passerini [19][20][21][22] and four-component Ugi [23][24] reactions that rely on the ability of organic isocyanides to participate in the nucleophilic attack onto the carbonyl or imine group are among the most studied MCRs. Accordingly, a wide range of post-MCR transformations have been