Ugi-azide Reaction Research Articles

Ultrasound-assisted diastereoselective green synthesis of spiro-fused-γ-lactams functionalized with an amide bond heterocyclic bioisostere via the Ugi azide/domino process coupled strategy.

A series of linked-type 1,5-disubstituted tetrazoles (1,5-DS-Ts) were synthesised via an isocyanide-based multicomponent reaction (IMCR) and used as synthetic platforms to access bound-type polyheterocycles containing an epoxyisoindol-1(6H)-one scaffold under green conditions. This rapid sonochemical synthetic strategy includes a double domino process using an orthogonal heterocyclic input in the Ugi-azide (UA) reaction. DFT calculations and NBO analysis were performed to understand the pseudopericyclic reaction involved in the 1,5-electrocyclization of the UA mechanism.

Green Methodologies for Tetrazole Synthesis from Different Starting Materials: A Recent Update

Abstract: Tetrazole is a most versatile pharmacophore of which more than twenty FDAapproved drugs have been marketed globally for the management of various diseases. In spite of many remarkable and consistent efforts having been made by the chemists towards the development of greener and sustainable strategies for the synthesis of tetrazole derivatives, this approach still needs more attention. The present review focuses on the green synthetic approach for the preparation of tetrazole derivatives from different starting materials such as nitrile, isonitrile, carbonyl, amine, amide, oxime and terminal alkyne functions. The mechanism of tetrazole synthesis from different substrates is discussed. In addition to this, a four component Ugi-azide reaction to the tetrazole synthesis is also described. Of note, the present articles exploited several water-mediated and solvent-free methodologies for tetrazole synthesis. The important key features of tetrazole synthesis were pinpointing in each synthetic scheme which provides excellent guide to those searching for selective procedure to achieve the desired transformation. This review seeks to present a timely account (2011-2023) on the splendid array of ecofriendly procedures of synthesis known today for the preparation of tetrazole derivatives from different starting materials. The rational of this review is to enlighten recent advancements in the synthesis of tetrazole derivatives from different substrates.

Enantioselective Ugi and Ugi-azide reactions catalyzed by anionic stereogenic-at-cobalt(III) complexes

Ugi reactions and related variations are proven to be atom and step-economic strategies for construction of highly valuable peptide-like skeletons and nitrogenous heterocycles. The development of structurally diverse range of novel catalytic systems and the discovery of new approaches to accommodate a broader scope of terminating reagents for asymmetric Ugi four-component reaction is still in high demand. Here, we report a strategy that enables enantioselective Ugi four-component and Ugi-azide reactions employing anionic stereogenic-at-cobalt(III) complexes as catalysts. The key nitrilium intermediates, generated through the nucleophilic addition of isocyanides to the chiral ion-pair which consists of stereogenic-at-cobalt(III) complexes counteranion and a protonated iminium, are trapped by either carboxylic acids or in situ-generated hydrazoic acid, delivering α-acylamino amides and α-aminotetrazoles in good to excellent enantioselectivities (up to 99:1 e.r.).

Synthesis of 4-Tetrazolyl-Substituted 3,4-Dihydroquinazoline Derivatives with Anticancer Activity via a One-Pot Sequential Ugi-Azide/Palladium-Catalyzed Azide-Isocyanide Cross-Coupling/Cyclization Reaction.

A new one-pot preparation of 4-tetrazolyl-3,4-dihydroquinazolines has been reported. The Ugi-azide reactions of 2-azidobenzaldehydes, amines, trimethylsilyl azide, and isocyanides produced azide intermediates without separation, which were treated with isocyanides to give 4-tetrazolyl-3,4-dihydroquinazoline derivatives through a sequential Palladium-catalyzed azide-isocyanide cross-coupling/cyclization reaction in moderate to good yields. The biological evaluation demonstrated that compound 6c inhibited breast cancer cells well and displayed broad applications for synthesis and medicinal chemistry.

8-Amino-6-Methoxyquinoline-Tetrazole Hybrids: Impact of Linkers on Antiplasmodial Activity.

A new series of compounds was prepared from 6-methoxyquinolin-8-amine or its N-(2-aminoethyl) analogue via Ugi-azide reaction. Their linkers between the quinoline and the tert-butyltetrazole moieties differ in chain length, basicity and substitution. Compounds were tested for their antiplasmodial activity against Plasmodium falciparum NF54 as well as their cytotoxicity against L-6-cells. The activity and the cytotoxicity were strongly influenced by the linker and its substitution. The most active compounds showed good activity and promising selectivity.

Cytoprotective organoselenium compounds for oligodendrocytes

Herein we report the synthesis of peptide-like and tetrazole-based organoselenium compounds via Ugi and Ugi-azide reactions, respectively. The organoselenium compounds' intrinsic cytoprotective and antioxidant capacities were evaluated in 158 N and 158JP murine oligodendrocytes. Furthermore, their redox properties were theoretically evaluated using Molecular Operating Environment-docking studies. Most of the compounds did not exhibit any cytotoxicity against the 158JP and 158 N cells. Among the tested compounds, the tetrazole- (e.g., 6, 7, and 9) and the pseudopeptide-based organoselenium compounds (e.g., 11, 15, and 17) displayed antioxidant properties. On the other hand, the quinones- (e.g., 4c and 18) and the pseudopeptides-based (e.g., 12, 14, and 17) organoselenium compounds exhibited prooxidant activities. Furthermore, the tetrazole-based organoselenium compounds 5 and 9 and the selenopeptide 11 and 15 showed good GPx-like activity. Some of the newly synthesized organoselenium compounds presented interesting antioxidant and cytoprotective activities and are therefore considered potential myelin diseases drug candidates.

Iron- or copper-catalyzed aerobic oxidative Ugi-azide reactions with tertiary amines: Efficient access to α-aminotetrazoles

An efficient and versatile Fe- or Cu-catalyzed aerobic oxidative Ugi-azide multicomponent reaction (MCR) with tertiary amines has been developed for the synthesis of α-aminotetrazoles. The reaction proceeds through formal C(sp3)-H activation of the tertiary amines and occurred in one-pot under mild conditions.

Combining the Ugi-azide multicomponent reaction and rhodium(III)-catalyzed annulation for the synthesis of tetrazole-isoquinolone/pyridone hybrids.

An efficient sequence based on the Ugi-azide reaction and rhodium(III)-catalyzed intermolecular annulation has been established for the preparation of tetrazole-isoquinolone/pyridone hybrids. Several N-acylaminomethyltetrazoles were reacted with arylacetylenes to form the hybrid products in moderate to very good yields. The method relies on the capacity of the rhodium catalyst to promote C(sp2)–H activation in the presence of a suitable directing group. The Ugi-azide reaction provides broad molecular diversity and enables the introduction of the tetrazole moiety, which may further assist the catalytic reaction by coordinating the metal center. The scope of the isoquinolones is very wide and may be extended to the preparation of complex compounds having heterocyclic moieties such as pyridone, furan, thiophene and pyrrole, as well as the corresponding benzo-fused derivatives. The developed procedure is simple, reproducible and does not require inert conditions.

Synthesis of 1,5-disubstituted tetrazole-1,2,3 triazoles hybrids via Ugi-azide/CuAAC

A new synthetic strategy to obtain new linked 1,5-disubstituted tetrazole-1,2,3-triazoles via the Ugi-azide reaction followed by a copper-catalyzed alkyne-azide reaction (CuAAC) was developed. This strategy used solvent-free conditions for the Ugi-azide reaction. This two-step strategy affords the products in moderate to good yields. To the best of our knowledge, this is the first report using the CuAAC reaction as a post-condensation process in an Ugi-azide reaction and therefore, the first describing the synthesis of 1,5-disubstituted tetrazole (1,5-DS-T) linked to the 1,2,3-triazole moiety, which are molecules that may have potential applications in medicinal chemistry.

New Facile Synthesis of 3,4-Dihydroquinazoline-2(1H)-thiones by a Sequential Ugi-Azide/Staudinger/Aza-Wittig/Cyclization Reaction

A new facile synthesis of 3,4-dihydroquinazoline-2(1H)-thiones by an Ugi-azide/Staudinger/aza-Wittig/cyclization sequence has been developed. The Ugi-azide reactions of 2-azidobenzaldehydes, amines, trimethylsilyl azide, and isocyanides produced tetrazoles, which, when treated with methyldiphenylphosphane and CS2, produced 3,4-dihydroquinazoline-2(1H)-thiones in good overall yields via a sequential Staudinger/aza-Wittig/cyclization reaction.

Anticancer Evaluation of 1,5-Disubstituted Tetrazoles using Ugi-Azide Four-Component Reactions (UA-4CRs)

Azide isocyanide-based multicomponent reactions allow the formation of relatively complex molecules through a one-pot synthesis. The proposed reactions have been coupled of four classes of compounds including 3-phenoxybenzaldehyde, various aromatic amines, TMS-N3 and tertiary butylisocyanide, which is known as Ugi-azide four-component reactions (UA-4CRs). It generated a diverse class of 1,5-disubstituted tetrazoles which are an important drug-like scaffold known for their ability to mimic the carcinogenic conformers used in medicinal chemistry. This work presents a concise, novel, general strategy to access a surplus of new heterocyclic scaffolds through the Ugi-azide reaction. Frequency in anticancer drug design can be partly attributed to their being extremely common in nature and there are multiple metabolic pathways and cellular processes within cancer pathology that can be susceptible to heterocycles-based drugs. The anticancer screening of derived molecules were carried out using one dose response study using NCI-60 cell-lines and found most active in breast cancer cell-lines.

Synthesis, biological evaluation and molecular dynamic simulations of novel Benzofuran-tetrazole derivatives as potential agents against Alzheimer’s disease

A series of novel Benzofuran-tetrazole derivatives were successfully synthesised by integrating multicomponent Ugi-azide reaction with the molecular hybridization approach. Interestingly, a number of synthesized derivatives (5c, 5d, 5i, 5l, 5q and 5s) exhibited significant reduction of aggregation of “human” amyloid beta peptide, expressing on transgenic Caenorhabditis elegans (C. elegans) strain CL4176. Further, in silico docking results have evidenced the exquisite interaction of active compounds with the help of TcAChE–E2020 complex. These findings underscore the potential of these hybrids as lead molecules against Alzheimers’s disease.

C–H functionalization enabled stereoselective Ugi-azide reaction to α-tetrazolyl alicyclic amines

An unprecedented stereoselective C–H functionalization enabled Ugi-azide (CH-Ugi-azide) reaction to access α-tetrazolyl alicyclic amines directly from N-heterocycles is reported.

One-pot synthesis of novel 1-(1H-tetrazol-5-yl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine derivatives via an Ugi-azide 4CR process.

A facile one-pot method has been developed for the synthesis of novel pyrrolo[2,1-a]pyrazine scaffolds. A variety of 1-(1H-tetrazol-5-yl)-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine derivatives were obtained in moderate to high yields in methanol using a one-pot four-component condensation of 1-(2-bromoethyl)-1H-pyrrole-2-carbaldehyde, amine, isocyanide and sodium azide at room temperature. These reactions presumably proceed via a domino imine formation, intramolecular annulation and Ugi-azide reaction. Unambiguous assignment of the molecular structures was carried out by single-crystal X-ray diffraction.

Efficient Synthesis of 1,5-disubstituted-1H-tetrazoles by an Ugi-azide Process

A series of eighteen novel 1,5-disubstituted-1H-tetrazoles has been prepared with moderate to good overall yields using an Ugi-azide reaction as key step under mild conditions. Tetrazoles are heterocyclic systems present in several synthetic products which have privileged biological activity. Therefore, in this paper we describe the synthesis of novel compounds containing the tetrazole moiety, which could present biological activity.

Synthesis of 1, 5‐ Disubstituted Tetrazole via Ugi Azide Reaction: An Asymmetric Induction Approach

AbstractThe Ugi‐azide reaction of an enantiopure amino acid derived isocyanides, amino acid esters, aldehydes and TMS‐N3 in MeOH:THF solvent system at 50 °C yielded peptidomimetics comprising tetrazole as amide bond isostere. Both N‐terminal (α‐isocyanoesters) and C‐terminal isocyanides (Nβ‐Cbz‐protected amino alkyl isocyanides) have been employed to yield diversified tetrazole peptidomimetics, having the possibility of further derivatization through either N‐ or C‐terminal chain elongation. Ugi‐azide reaction is a isocyanide based multi‐component reaction (IMCR), as a result, change in amino acid derived isocyanides had given structurally diverse products of biological interest. Good yields of products were obtained after column purification and were stable for shelf storage. The products are novel and were well characterized by Mass, 1H NMR and 13C NMR spectral studies. The present method offers several advantages such as one‐pot simple procedure, high yields and easy purification of products.

Copper(i) catalyzed oxidative hydrolysis of Ugi 3-component and Ugi-azide reaction products towards 2° α-ketoamides and α-ketotetrazoles.

Herein, a two-step MCR-oxidation methodology accessing decorated 2° α-ketoamides and α-ketotetrazoles is described via a catalytic copper(i)-mediated C-N oxidation/acidic hydrolysis of Ugi-three-component and Ugi-azide reaction products. The ability to install diversity from aldehyde and isocyanide synthons allows rapid complexity generation. Of note, (1) 2° α-ketoamides are traditionally difficult to access and more so reminiscent of the endogenous peptide bonds. (2) The route to α-keto-tetrazoles is significantly shorter than that in previous reports.

Endogenous water-triggered and ultrasound accelerated synthesis of 1,5-disubstituted tetrazoles via a solvent and catalyst-free Ugi-azide reaction

An ultrasound accelerated, environmentally benign Ugi-azide based method was developed for the synthesis of 1,5-disubstituted tetrazoles under solvent and catalyst-free conditions.

Two-Step Route to Diverse N-Functionalized Peptidomimetic-like Isatins through an Oxidation/Intramolecular Oxidative-Amidation Cascade of Ugi Azide and Ugi Three-Component Reaction Products.

Two-step methodology described herein showcases the first example of an oxidation/oxidative amidation cyclization cascade of MCR products toward diverse N-functionalized isatins. Products of both the Ugi 3CR and the Ugi azide reactions are oxidatively cyclized through a postcondensation process utilizing selenium dioxide. This methodology was found to be applicable for the generation of bis-peptidomimetic-like isatins containing multiple points of diversification.

Synthesis of 1,5-disubstituted tetrazoles containing a fragment of the anticancer drug imatinib via a microwave-assisted Ugi-azide reaction

Thirty novel N 1-[(1-alkyl-1H-tetrazol-5-yl)(aryl)methyl]-4-methyl-N 3-[4-(pyridine-3-yl)pyrimidin-2-yl]benzene-1,3-diamines were synthesized in moderate to good yields (50–85 %) via a microwave-assisted Ugi-azide reaction. These products may exhibit cytotoxicity and/or tyrosine-kinase inhibitory properties because of their structural similarities with potent anticancer drugs such as imatinib. Finally, in order to visualize the stereoelectronic nature of Schiff bases having various basic sites involved in the Ugi-azide reaction mechanism, we analyzed a molecular electrostatic potential surface, which was plotted by means of density functional theory at the UB3LYP/6-311G(d) level.