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

• Chemistry and Center for Green Chemistry, University of Massachusetts Boston, 100 Morrissey Blvd, Boston, MA 02125, USA 10.3762/bjoc.20.81 Abstract A new method for the synthesis of heterocyclic systems containing tetrazole and tetrahydroisoquinoline is developed via the performance of one-pot Ugi-azide

• and Heck cyclization reactions. The integration of the multicomponent and post-condensation reactions in one-pot maximizes the pot-, atom-, and step-economy (PASE). Keywords: Heck reaction; one-pot; tetrahydroisoquinoline; tetrazolo-pyrazino[2,1-a]isoquinolin-6(5H)-ones; tetrazole; Ugi-azide reaction

• schistosomiasis [22][23][24][25]. The combination of the privileged heterocycles tetrazole and tetrahydroisoquinoline in one molecule generates new molecules which could have biological activities. A standard Ugi four-component reaction (Ugi-4CR) of an aldehyde, amine, isocyanide, and a carboxylic acid produces

Synthesis of imidazo[1,2-a]pyridine-containing peptidomimetics by tandem of Groebke–Blackburn–Bienaymé and Ugi reactions

• Oleksandr V. Kolomiiets,
• Alexander V. Tsygankov,
• Maryna N. Kornet,
• Aleksander A. Brazhko,
• Vladimir I. Musatov and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2023, 19, 727–735, doi:10.3762/bjoc.19.53

• , Zaporizhzhya National University, Zhukovsky str., 66, Zaporizhzhya, 69600, Ukraine 10.3762/bjoc.19.53 Abstract Peptidomimetics with a substituted imidazo[1,2-a]pyridine fragment were synthesized by a tandem of Groebke–Blackburn–Bienaymé and Ugi reactions. The target products contain substituted imidazo[1,2-a

• ]pyridine and peptidomimetic moieties as pharmacophores with four diversity points introduced from readily available starting materials, including scaffold diversity. A small focused compound library of 20 Ugi products was prepared and screened for antibacterial activity. Keywords: Groebke–Blackburn

• –Bienaymé reaction; imidazo[1,2-a]pyridine; isocyanide; multicomponent reaction; peptidomimetic; Ugi reaction; Introduction The use of isocyanide multicomponent reactions (IMCR) to prepare biologically active compounds is one of the most promising tools in modern organic and medicinal chemistry. Therefore

A trustworthy mechanochemical route to isocyanides

• Francesco Basoccu,
• Federico Cuccu,
• Federico Casti,
• Rita Mocci,
• Claudia Fattuoni and
• Andrea Porcheddu

Beilstein J. Org. Chem. 2022, 18, 732–737, doi:10.3762/bjoc.18.73

• first synthetic approaches were reported by Ugi and Hofmann (Scheme 1) [3][4], who described their characteristic odour as “horrible” and “extremely distressing”. With such a breakthrough, isonitriles gained wide popularity in organic synthesis due to their extreme versatility [5][6][7]. Especially

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

• -cd]indoles 21 from the intramolecular cyclization of Ugi adducts 20 in moderate to good yields and excellent chemo-, regio-, and diastereoselectivity (Scheme 7) [17]. Mechanistically, the reaction involves a tandem gold(I)-catalyzed dearomatization/ipso-cyclization/Michael addition sequence to

Peptide stapling by late-stage Suzuki–Miyaura cross-coupling

• Hendrik Gruß,
• Rebecca C. Feiner,
• Ridhiwan Mseya,
• David C. Schröder,
• Michał Jewgiński,
• Kristian M. Müller,
• Rafał Latajka,
• Antoine Marion and
• Norbert Sewald

Beilstein J. Org. Chem. 2022, 18, 1–12, doi:10.3762/bjoc.18.1

• ], disulfide- [13], thioether- [14][15][16][17][18][19][20], triazole- [21][22], oxime- [23] and hydrazone formation [24] as well as multicomponent reactions such as the Ugi- or Petasis reaction [25][26][27][28][29][30][31][32]. The content of helicity can moreover be changed by the introduction of a photo

Recent advances in the tandem annulation of 1,3-enynes to functionalized pyridine and pyrrole derivatives

• Yi Liu,
• Puying Luo,
• Yang Fu,
• Tianxin Hao,
• Xuan Liu,
• Qiuping Ding and
• Yiyuan Peng

Beilstein J. Org. Chem. 2021, 17, 2462–2476, doi:10.3762/bjoc.17.163

• release of a nitrogen molecule to form the desired product 46. In 2018, Ding and co-workers reported the synthesis of 2-tetrazolyl-substituted 3-acylpyrroles 53 via sequential Ugi-azide/Ag-catalyzed oxidative cycloisomerization reactions in good yield (Scheme 20) [64]. Firstly, The Ugi-azide reaction

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

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

• of the useful tools in the synthesis of biologically relevant heterocycles. These reactions are strategically employed for the generation of a variety of heterocycles along with multiple point diversifications. Over the last few decades classical MCRs such as Ugi, Biginelli, etc. have witnessed

• atorvastatin, a potent HMG-CoA reductase inhibitor. Dömling and co-workers efficiently demonstrated an Ugi-based MCR approach towards the synthesis of atorvastatin in four steps ruling out the lengthy seven step protocol, and paving a rapid entry to the drug discovery market [12]. Alternatively, microwave

• azepinone 22 and exemplified a modified Ugi reaction (four-component reaction). The aldehyde and acid component of the Ugi reaction was functionalized on the same biaryl ring employing a Suzuki–Miyaura coupling. The authors advocated the use of microwave as it consistently increased the yield from 49% to 82

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

• Chemistry, University of Nebraska – Lincoln, 639 N 12th St, Lincoln, NE 68588, USA 10.3762/bjoc.17.57 Abstract A novel catalyst-free synthetic approach to 1,2,3-triazolobenzodiazepinones has been developed and optimized. The Ugi reaction of 2-azidobenzaldehyde, various amines, isocyanides, and acids

• harder while the microwave-assisted catalyst-free conditions were effective for both terminal and non-terminal alkynes. Keywords: click chemistry; microwave chemistry; multicomponent reactions; triazolobenzodiazepines; Ugi reaction; Introduction Benzannulated heterocycles are among the most important

• a few steps and constitutes one of the most actual and promising synthetic routes of modern organic chemistry. Among a wide variety of tandem strategies combination of an isocyanide-based multicomponent Ugi reaction with secondary transformations is one of the most powerful tools and provides access

Menthyl esterification allows chiral resolution for the synthesis of artificial glutamate analogs

• Kenji Morokuma,
• Shuntaro Tsukamoto,
• Kyosuke Mori,
• Kei Miyako,
• Ryuichi Sakai,
• Raku Irie and
• Masato Oikawa

Beilstein J. Org. Chem. 2021, 17, 540–550, doi:10.3762/bjoc.17.48

• studies will straightforwardly focus on the enantioselective synthesis of only the (2R)-isomer. The asymmetric Ugi reaction recently developed [29] is of interest for the selective preparation of (2R)-6 (Scheme 1 and Scheme 5) [6][8]. Studies are in progress to develop an asymmetric Ugi/Diels–Alder

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

• Schwartz’s reagent-mediated reductive amide functionalization followed by a variant of the Ugi–azide multicomponent reaction. The anomeric configurations of two products were unambiguously confirmed by X-ray analysis. This work also describes examples of interesting further transformations of the title

• one-pot Mannich/Michael sequence leading to oligocyclic compounds [24], and employment in subsequent Joulié–Ugi multicomponent reactions [25]. This work is an extension of these efforts and seeks to investigate the possibility of incorporating the Ugi–azide multicomponent reaction in this workflow. A

• standard Ugi–azide reaction conditions [35][36][37][38][39] in a one-pot, tandem process. Subjecting glucose-derived lactam 1 to such a procedure gave the desired product in good yield, but with virtually no diastereoselectivity, as shown in Scheme 2. Optimization and scope An initial optimization study

One-pot multicomponent green Hantzsch synthesis of 1,2-dihydropyridine derivatives with antiproliferative activity

• Giovanna Bosica,
• Kaylie Demanuele,
• José M. Padrón and
• Adrián Puerta

Beilstein J. Org. Chem. 2020, 16, 2862–2869, doi:10.3762/bjoc.16.235

• not new to research. The pioneer multicomponent reactions are the Hantzsch (1882), Biginelli (1891), Mannich (1912), Passerini (1921), and Ugi (1959) reactions [3]. The significance of such a phenomenal approach for the synthesis of novel compounds first began as a way of increasing the chemical

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

• . China The Environment and Resource Efficiency Cluster (EREC), Nazarbayev University, Nur-Sultan, Republic of Kazakhstan 10.3762/bjoc.16.163 Abstract In this report, we introduce a new strategy for controlling the stereochemistry in Ugi adducts. Instead of controlling stereochemistry directly during the

• Ugi reaction we have attempted to stereodefine the chiral center at the peptidyl position through the post-Ugi functionalization. In order to achieve this, we chose to study 2-oxo-aldehyde-derived Ugi adducts many of which partially or fully exist in the enol form that lacks the aforementioned chiral

• center. This in turn led to their increased nucleophilicity as compared to the standard Ugi adducts. As such, the stereocenter at the peptidyl position could be installed and stereodefined through the reaction with a suitable electrophile. Towards this end, we were able to deploy an asymmetric cinchona

Palladium-catalyzed regio- and stereoselective synthesis of aryl and 3-indolyl-substituted 4-methylene-3,4-dihydroisoquinolin-1(2H)-ones

• Valeria Nori,
• Antonio Arcadi,
• Armando Carlone,
• Fabio Marinelli and
• Marco Chiarini

Beilstein J. Org. Chem. 2020, 16, 1084–1091, doi:10.3762/bjoc.16.95

• palladium-catalyzed regioselective cascade cyclization of propargylamides/coupling with ArB(OH)2 in dioxane/water, to give trisubstituted arylidene-isoquinolinones [44] was published. However, the Ugi four-component reaction used to construct the starting building blocks was limited to the preparation of

Recent applications of porphyrins as photocatalysts in organic synthesis: batch and continuous flow approaches

• Rodrigo Costa e Silva,
• Luely Oliveira da Silva,
• Aloisio de Andrade Bartolomeu,
• Timothy John Brocksom and
• Kleber Thiago de Oliveira

Beilstein J. Org. Chem. 2020, 16, 917–955, doi:10.3762/bjoc.16.83

• biologically active compounds [104]. These compounds can be trapped with nucleophiles to produce the α-amino-substituted compounds, and be employed as substrates for a variety of chemical transformations such as Ugi- and Mannich-type reactions. In this regard, Seeberger and co-workers reported the primary

• –84% yields (Scheme 59) [97]. The Ugi-type multicomponent reactions between imines, carboxylic acids, and isocyanides, and Mannich-type reactions between iminium and carbonyl groups have found many applications in organic synthesis [108]. Che’s group employed the methodology of oxidation of an amine

• with singlet oxygen to produce an imine, which was used as a substrate in the Ugi-type reaction. Thus, the oxidations of both 1,2,3,4-tetrahydroisoquinoline and dibenzylamine using TPP were carried out with high yield and selectivity, and the Ugi products were obtained after removal of the solvent and

Microwave-assisted efficient and facile synthesis of tetramic acid derivatives via a one-pot post-Ugi cascade reaction

• Yong Li,
• Zheng Huang,
• Jia Xu,
• Yong Ding,
• Dian-Yong Tang,
• Jie Lei,
• Hong-yu Li,
• Zhong-Zhu Chen and
• Zhi-Gang Xu

Beilstein J. Org. Chem. 2020, 16, 663–669, doi:10.3762/bjoc.16.63

• developed through an Ugi/Dieckmann cyclization strategy with DBU. This two-step one-pot procedure afforded the targeted tetramic acid analogues in good yields. With commercially available Ugi starting materials, microwave irradiation, a simple operation, excellent yields, and a broad scope, this reaction

• has the potential to produce a large number of tetramic acid analogues, which cannot be easily accessed by the classic synthetic methods. Keywords: Dieckmann cyclization; multicomponent reactions; nitrogen heterocycles; one-pot reaction; Ugi reaction; Introduction Nitrogen-containing heterocycles

• medicinal chemistry. Multicomponent reactions (MCRs) [22][23][24] are emerging tools for assembling complex molecules in a rapid and efficient manner. The four-component Ugi reaction followed by a suitable post modification of [25][26] has become a popular research field for diversity-oriented synthesis [27

A systematic review on silica-, carbon-, and magnetic materials-supported copper species as efficient heterogeneous nanocatalysts in “click” reactions

• Pezhman Shiri and
• Jasem Aboonajmi

Beilstein J. Org. Chem. 2020, 16, 551–586, doi:10.3762/bjoc.16.52

• reactions, Ugi–Smiles reactions, Mizoroki–Heck reactions, aldol reactions, oxidation and dehydration reactions, Mannich reactions, and multicomponent reactions. Because of the mentioned reasons as well as due to the low toxicity of silica nanoparticles, they are often a good option [24]. For this review

Combination of multicomponent KA² and Pauson–Khand reactions: short synthesis of spirocyclic pyrrolocyclopentenones

• Riccardo Innocenti,
• Elena Lenci,
• Gloria Menchi and
• Andrea Trabocchi

Beilstein J. Org. Chem. 2020, 16, 200–211, doi:10.3762/bjoc.16.23

• in DOS [19][20][21][22], such as the exploitation of the Petasis three-component [23][24][25][26][27][28][29] and the Ugi four-component reactions [30][31][32][33], showing interesting properties for the generation of compounds characterized by high stereochemical and skeletal diversity. Although not

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

• Gerardo M. Ojeda,
• Prabhat Ranjan,
• Pavel Fedoseev,
• Lisandra Amable,
• Upendra K. Sharma,
• Daniel G. Rivera and
• Erik V. Van der Eycken

Beilstein J. Org. Chem. 2019, 15, 2447–2457, doi:10.3762/bjoc.15.237

• Natural Product Research, Faculty of Chemistry, University of Havana, Zapata y G, 10400, La Habana, Cuba Peoples´ Friendship University of Russia (RUDN University) Miklukho-Maklaya Street 6, 117198 Moscow, Russia 10.3762/bjoc.15.237 Abstract An efficient sequence based on the Ugi-azide reaction and

• 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

• prospect of the tetrazole hybridization strategy in drug discovery. Among the most versatile methods for obtaining tetrazoles are the Ugi-azide four-component reaction (Ugi-azide-4CR) [14][15][16] and the 1,3-dipolar cycloaddition of azides with (acyl)cyanides [17][18]. The Ugi-azide-4CR enables the

1,2,3-Triazolium macrocycles in supramolecular chemistry

• Mastaneh Safarnejad Shad,
• Pulikkal Veettil Santhini and
• Wim Dehaen

Beilstein J. Org. Chem. 2019, 15, 2142–2155, doi:10.3762/bjoc.15.211

• developed for the synthesis of bile acid-based macrocycles, using macrolactamization, ring-closing metathesis and Ugi-multicomponent macrocyclization. Developing more efficacious and economical methods for the construction of these macrocycles is still in demand due to the disadvantages of the

Recent advances on the transition-metal-catalyzed synthesis of imidazopyridines: an updated coverage

• Gagandeep Kour Reen,
• Ashok Kumar and
• Pratibha Sharma

Beilstein J. Org. Chem. 2019, 15, 1612–1704, doi:10.3762/bjoc.15.165

Efficiency Eff_syn of complex syntheses as multicomponent reactions, its algorithm and calculations based on concrete criteria

• Heiner Eckert

Beilstein J. Org. Chem. 2019, 15, 1425–1433, doi:10.3762/bjoc.15.142

• applied without limitations to other syntheses of this type. MCR Strategy: Ugi-4CR in ecteinascidin-743 total synthesis As described above, yields can be significantly increased by using the fragment strategy. However, the fragment strategy is limited to 2 components, while an MCR provides multiple

• components for linking, and also generates its own structure which is capable of extensions like the domino reaction types [5]. An Ugi reaction is used in the total synthesis of the extremely potent antitumor agent ecteinascidin-743 (Et-743, 1) by Fukuyama to form a large part of the skeleton 2 (Scheme 5

• ). All data for the U-4CR are available in the literature [14]. The precursors of the Ugi reaction consist of 3 reaction chains of 6, 6 and 2 links, respectively. Calculation by means of the algorithm The calculation of the overall yield yoa of 2 is based on the data basis for the total synthesis of

Doebner-type pyrazolopyridine carboxylic acids in an Ugi four-component reaction

• Maryna V. Murlykina,
• Oleksandr V. Kolomiets,
• Maryna M. Kornet,
• Yana I. Sakhno,
• Sergey M. Desenko,
• Victoriya V. Dyakonenko,
• Svetlana V. Shishkina,
• Oleksandr A. Brazhko,
• Vladimir I. Musatov,
• Alexander V. Tsygankov,
• Erik V. Van der Eycken and
• Valentyn A. Chebanov

Beilstein J. Org. Chem. 2019, 15, 1281–1288, doi:10.3762/bjoc.15.126

• , Kharkiv, Ukraine Peoples' Friendship University of Russia, Miklukho-Maklya str., 6, 117198, Moscow, Russia 10.3762/bjoc.15.126 Abstract Substituted 1H-pyrazolo[3,4-b]pyridine-4- and 1H-pyrazolo[3,4-b]pyridine-6-carboxamides have been synthetized through a Doebner–Ugi multicomponent reaction sequence in a

• available starting materials including scaffold diversity. A small focused compound library of 23 Ugi products was created and screened for antibacterial activity. Keywords: antibacterial activity; Doebner reaction; pyrazolo[3,4-b]pyridine carboxylic acids; Ugi reaction; Introduction Modern medicinal

• virus infections [20], etc. Among the variety of heterocyclic acids used in Ugi-4CR [15][16][17][18][19][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42] only a few of them in addition to bearing a simple pharmacophore core (group I, Scheme 1) are also

Steroid diversification by multicomponent reactions

• Leslie Reguera,
• Cecilia I. Attorresi,
• Javier A. Ramírez and
• Daniel G. Rivera

Beilstein J. Org. Chem. 2019, 15, 1236–1256, doi:10.3762/bjoc.15.121

• steroid derivatization methods using MCRs was reported by the Ugi laboratory in 1995 (Scheme 1) [14]. The occurrence of pachystermin A, an unusual natural steroid isolated from the boxaceous plant Pachysandra terminalis and having a β-lactam moiety in ring A, inspired these authors to obtain a steroidal β

• -lactam, albeit functionalized in the side chain. The one-pot synthesis of the β-lactam steroid was achieved via the Ugi 3-component-4-center reaction using the dehydrocholic aldehyde 1 as carbonyl component. This variation of the Ugi reaction including a β-amino acid component allows the formation of the

• intermediate was far away from the chiral steroidal nucleus. A better stereoselectivity was reported by Bruttomesso et al. in their work on the Ugi four-component reaction (Ugi-4CR) with a steroidal aldehyde, in which the carbonyl group was directly linked at the steroidal framework [16]. As shown in Scheme 2

Ugi reaction-derived prolyl peptide catalysts grafted on the renewable polymer polyfurfuryl alcohol for applications in heterogeneous enamine catalysis

• Alexander F. de la Torre,
• Gabriel S. Scatena,
• Oscar Valdés,
• Daniel G. Rivera and
• Márcio W. Paixão

Beilstein J. Org. Chem. 2019, 15, 1210–1216, doi:10.3762/bjoc.15.118

• Abstract The multicomponent synthesis of prolyl pseudo-peptide catalysts using the Ugi reaction with furfurylamines or isocyanides is described. The incorporation of such a polymerizable furan handle enabled the subsequent polymerization of the peptide catalyst with furfuryl alcohol, thus rendering

• employ a three-component, diastereoselective variant of the Ugi reaction for the synthesis of a prolyl pseudo-peptide catalyst, which proved effective in an organocatalytic conjugate addition reaction [6]. Later, our groups developed an Ugi reaction-based multicomponent approach enabling the structure

• synthesis of prolyl pseudo-peptides having a furan ring handle, which could be subsequently incorporated into PFA during the polymerization process. Results and Discussion To this end, a solution-phase multicomponent procedure based on the Ugi four-component reaction (Ugi-4CR) [14], was employed to