Reagent-controlled regiodivergent intermolecular cyclization of 2-aminobenzothiazoles with β-ketoesters and β-ketoamides

• Irwan Iskandar Roslan,
• Kian-Hong Ng,
• Gaik-Khuan Chuah and
• Stephan Jaenicke

Beilstein J. Org. Chem. 2017, 13, 2739–2750, doi:10.3762/bjoc.13.270

• . coupled various 1,2-dihaloarenes with 2-mercaptobenzimidazole in a nucleophilic aromatic substitution reaction [53]. Zhu’s group used Cu salts as a promoter for the cycloaddition of isocyanides with benzothiazoles [54]. Benzo[d]imidazo[2,1-b]thiazoles have also been synthesized via coupling of 2

Photocatalyzed synthesis of isochromanones and isobenzofuranones under batch and flow conditions

• Manuel Anselmo,
• Lisa Moni,
• Hossny Ismail,
• Davide Comoretto,
• Renata Riva and
• Andrea Basso

Beilstein J. Org. Chem. 2017, 13, 1456–1462, doi:10.3762/bjoc.13.143

• intercepted by other nucleophiles (such as isocyanides, carboxylates, etc.), in the case the attack by the solvent could be prevented. Unfortunately, reactions performed in inert solvents with isocyanides, carboxylic acids, and mixtures of both, alcohols or amines never succeeded in affording the desired

New tricks of well-known aminoazoles in isocyanide-based multicomponent reactions and antibacterial activity of the compounds synthesized

• Maryna V. Murlykina,
• Maryna N. Kornet,
• Sergey M. Desenko,
• Svetlana V. Shishkina,
• Oleg V. Shishkin,
• Aleksander A. Brazhko,
• Vladimir I. Musatov,
• Erik V. Van der Eycken and
• Valentin A. Chebanov

Beilstein J. Org. Chem. 2017, 13, 1050–1063, doi:10.3762/bjoc.13.104

• exocyclic NH2 group and an endocyclic nucleophilic center, they can act both as primary amines and as 1,3-binucleophiles, therefore, their treatments with isocyanides, aldehydes and carboxylic acids may proceed either as Ugi-4CR (aminoazole – primary amine, acid – reagent) or as GBB-3CR (aminoazole – 1,3

Catalytic Wittig and aza-Wittig reactions

• Zhiqi Lao and
• Patrick H. Toy

Beilstein J. Org. Chem. 2016, 12, 2577–2587, doi:10.3762/bjoc.12.253

• catalytic aza-Wittig reactions (Scheme 16) [33]. It was reported that mixing 2-aminobenzoyl azides 55, carboxylic acids 56, isocyanides 57 with aldehydes 6 in methanol generated intermediates 58, which underwent rearrangement to isocyanates 59 in refluxing toluene. Finally, catalytic aza-Wittig reactions

One-pot synthesis of tetracyclic fused imidazo[1,2-a]pyridines via a three-component reaction

• Bo Yang,
• Chuanye Tao,
• Taofeng Shao,
• Jianxian Gong and
• Chao Che

Beilstein J. Org. Chem. 2016, 12, 1487–1492, doi:10.3762/bjoc.12.145

• -component reaction has been developed to assemble biologically and pharmaceutically important tetracyclic fused imidazo[1,2-a]pyridines in a one-pot fashion utilizing readily available 2-aminopyridines, isatins and isocyanides. The three-component coupling proceeds through the Groebke–Blackburn–Bienaymé

• scaffolds can be constructed in great diversity by a multicomponent reaction of amidines, aldehydes and isocyanides. This MCR, a variant of the Ugi reaction [24][25], was discovered independently by three groups and is known as the Groebke–Blackburn–Bienaymé (GBB) reaction [26][27][28][29]. The reaction

• involves a formal [4 + 1] cycloaddition of isocyanides [30] and imines, generated from the amidines and aldehydes, allowing straightforward access to diverse imidazo[1,2-x]azines [31][32][33]. In view of the significance of the GBB reaction and the imidazo[1,2-a]pyridine core structure, the further

Multicomponent reactions: A simple and efficient route to heterocyclic phosphonates

• Mohammad Haji

Beilstein J. Org. Chem. 2016, 12, 1269–1301, doi:10.3762/bjoc.12.121

• acyl chlorides 191, isocyanides 193 and dialkyl acetylenedicarboxylates 194 to afford 2-phosphonofuran derivatives 196 has been reported by our group (Scheme 41) [79]. The desired furanylphosphonates were isolated in 52–67% yield at rt in CH2Cl2. In this transformation the zwitterionic intermediate 195

• -component reaction of acylphosphonates, isocyanides and dialkyl acetylenedicarboxylate to afford 2-phosphonofuran derivatives. Synthesis of (4-imino-3,4-dihydroquinazolin-2-yl)phosphonates via an isocyanide-based three-component reaction. Silver-catalyzed three-component synthesis of (2-imidazolin-4-yl

Diastereoselective Ugi reaction of chiral 1,3-aminoalcohols derived from an organocatalytic Mannich reaction

• Samantha Caputo,
• Andrea Basso,
• Lisa Moni,
• Renata Riva,
• Valeria Rocca and
• Luca Banfi

Beilstein J. Org. Chem. 2016, 12, 139–143, doi:10.3762/bjoc.12.15

• , allowing the introduction of five diversity inputs. Keywords: aminoalcohols; isocyanides; multicomponent reactions; peptidomimetics; Ugi reaction; Findings Isocyanide-based multicomponent reactions [1][2][3], such as the Ugi reaction, were demonstrated to be very useful in the rapid assembly of complex

• simpler variants) [10][11][12]. On the other hand, diastereoselective reactions using at least one chiral component are troublesome. Chiral isocyanides and chiral carboxylic acids invariably afford nearly 1:1 mixtures. α-Chiral aldehydes have a high tendency to racemize/epimerize [13][14] and additionally

• is considered excellent for isocyanide-based multicomponent reactions, due to the very low steric biases of isocyanides. We then moved on to establish the scope of the method, varying the Boc-protected aminoalcohol, the carboxylic acid and the isocyanide (see Table 2). For a comparison, we performed

Recent applications of ring-rearrangement metathesis in organic synthesis

• Sambasivarao Kotha,
• Milind Meshram,
• Priti Khedkar,
• Shaibal Banerjee and
• Deepak Deodhar

Beilstein J. Org. Chem. 2015, 11, 1833–1864, doi:10.3762/bjoc.11.199

• -centre-4-component reaction (U-5C-4CR) with a wide variety of aldehydes and isocyanides. Subsequently, the products obtained (e.g., 278) were subjected to a RRM protocol with catalyst 2 to generate the required 2-aza-7-oxabicyclo systems such as 279 (Scheme 57). The advantage of this approach is to

Synthesis of antibacterial 1,3-diyne-linked peptoids from an Ugi-4CR/Glaser coupling approach

• Martin C. N. Brauer,
• Ricardo A. W. Neves Filho,
• Bernhard Westermann,
• Ramona Heinke and
• Ludger A. Wessjohann

Beilstein J. Org. Chem. 2015, 11, 25–30, doi:10.3762/bjoc.11.4

• monomers eligible for dimerizations by Glaser coupling, equimolar amounts of propargylamine (3), aldehyde 4, carboxylic acid 5, and isocyanides 6 were reacted in methanol at room temperature over 24 h following well established Ugi protocols [12]. After flash column chromatography N-propargyl peptoids 7a–j

Come-back of phenanthridine and phenanthridinium derivatives in the 21st century

• Lidija-Marija Tumir,
• Marijana Radić Stojković and
• Ivo Piantanida

Beilstein J. Org. Chem. 2014, 10, 2930–2954, doi:10.3762/bjoc.10.312

Facile synthesis of 1H-imidazo[1,2-b]pyrazoles via a sequential one-pot synthetic approach

• András Demjén,
• Márió Gyuris,
• János Wölfling,
• László G. Puskás and
• Iván Kanizsai

Beilstein J. Org. Chem. 2014, 10, 2338–2344, doi:10.3762/bjoc.10.243

• -component reaction (U-4CR), can be adopted. The sequential combination of four species (amines, aldehydes, isocyanides and carboxylic acids) in a single-pot synthetic operation permits access to bisamide peptidomimetics through a highly electrophilic nitrilium intermediate [1][2][3][4]. Modification of the

• isocyanides in the presence (5–30 mol %) of Lewis or Brønsted acid at ambient temperature or under heating (50–140 °C). The main disadvantages of this protocol involve long reaction times (3–18 hours) and requisite purification protocols (column chromatography and/or recrystallisation) besides limited

• [1,2-b]pyrazole library in sequential one-pot protocol utilizing four components such as hydrazine hydrate, ethoxymethylene substituted malononitrile or ethyl cyanoacetate derivatives, isocyanides and aldehydes. Results and Discussion In the initial stage, a model GBB-3CR was performed between 5

Synthesis of α-amino amidines through molecular iodine-catalyzed three-component coupling of isocyanides, aldehydes and amines

• Praveen Reddy Adiyala,
• D. Chandrasekhar,
• Jeevak Sopanrao Kapure,
• Chada Narsimha Reddy and
• Ram Awatar Maurya

Beilstein J. Org. Chem. 2014, 10, 2065–2070, doi:10.3762/bjoc.10.214

• the synthesis of α-amino amidines has been developed using a molecular iodine-catalyzed three-component coupling reaction of isocyanides, amines, and aldehydes. The presented strategy offers the advantages of mild reaction conditions, low environmental impact, clean and simple methodology, high atom

• reaction worked well with a variety of isocyanides such as tert-butyl isocyanide, cyclohexyl isocyanide, and more importantly with functional groups bearing isocyanides such as ethyl isocyanoacetate and p-toluenesulfonylmethyl isocyanide (p-TosMIC) (Table 2, entries 19 and 20). Thus, the diversification of

Multicomponent reactions in nucleoside chemistry

• Mariola Koszytkowska-Stawińska and
• Włodzimierz Buchowicz

Beilstein J. Org. Chem. 2014, 10, 1706–1732, doi:10.3762/bjoc.10.179

• amide resin, one of 15 isocyanides and one of 59 carboxylic acids per reaction; (ii) treatment of the reaction mixtures with methanolic HCl. Products 46 were obtained as 1:1 mixtures of diastereoisomers. Within the library, 246 compounds showed higher than 50% inhibitory activity against Candida

Asymmetric Ugi 3CR on isatin-derived ketimine: synthesis of chiral 3,3-disubstituted 3-aminooxindole derivatives

• Giordano Lesma,
• Fiorella Meneghetti,
• Alessandro Sacchetti,
• Mattia Stucchi and
• Alessandra Silvani

Beilstein J. Org. Chem. 2014, 10, 1383–1389, doi:10.3762/bjoc.10.141

• , thus letting us foresee the application of this approach to isocyanides prepared from natural amino acids. If compared with tert-butylisocyanide (2a), benzylisocyanide (2c) (Table 2, entries 5, 6 and 13) seems to be less effective in terms of an acceptable dr, while the yields were still good. Of

Isocyanide-based multicomponent reactions towards cyclic constrained peptidomimetics

• Gijs Koopmanschap,
• Eelco Ruijter and
• Romano V.A. Orru

Beilstein J. Org. Chem. 2014, 10, 544–598, doi:10.3762/bjoc.10.50

• cyclic constrained peptidomimetics, the acyclic products have to be cyclized via additional cyclization strategies. This is possible via incorporation of bifunctional substrates into the initial IMCR. Examples of such bifunctional groups are N-protected amino acids, convertible isocyanides or MCR

• and macrocyclic peptidomimetics. Keywords: heterocycles; isocyanides; macrocycles; multicomponent reaction; medicinal chemistry; organic synthesis; peptidomimetics; Introduction Peptides and proteins fulfill a key role in many biological and physiological functions of living organisms. Therefore

• provides α-acyloxy carboxamides by reacting carbonyl compounds, carboxylic acids and isocyanides. The reaction is usually performed with high concentrations of starting materials using aprotic solvents. A wide range of all three components is tolerated in the Passerini 3-CR, which makes this reaction

Silver and gold-catalyzed multicomponent reactions

• Giorgio Abbiati and
• Elisabetta Rossi

Beilstein J. Org. Chem. 2014, 10, 481–513, doi:10.3762/bjoc.10.46

• reactivity, silver(I) salts and complexes have been used to activate either the nucleophile or the imine. Isocyanides have been found to be versatile reagents in heterocyclic synthesis [82][83]. In particular, the α-metallation of isocyanides was accomplished by Schöllkopf [84] and Van Leusen [85] for the

• -protons and thus allowing for an easy α-deprotonation with weak bases (Scheme 32) [86][87]. Recently, Orru’s group successfully translated the stepwise Schöllkopf–Van Leusen synthesis of dihydroimidazoles 65 in a MCR involving isocyanides 61, aldehydes 62 and primary amines 63 [88]. Initial results

• , obtained in the presence of a simple dehydrating agent, were limited to the use of simple aldehydes, amines and α-acidic α,α-disubstituted isocyanides such as methyl isocyano(phenyl)acetate and 9-isocyano-9H-fluorene [89]. The scope of these reactions could be extended to isocyanides with other

Diversity-oriented synthesis of dihydrobenzoxazepinones by coupling the Ugi multicomponent reaction with a Mitsunobu cyclization

• Lisa Moni,
• Luca Banfi,
• Andrea Basso,
• Alice Brambilla and
• Renata Riva

Beilstein J. Org. Chem. 2014, 10, 209–212, doi:10.3762/bjoc.10.16

• chromatography at the level of 9. With these optimized conditions in hand, we performed a series of Ugi reactions using azides 2a–d, glycolic acid, various aldehydes and isocyanides (Scheme 2). After a fast purification through a short silica gel column, the Ugi adducts 9a–n were submitted to hydrogenolysis and

• /imines [13][14][15] and isocyanides [16][17]. Experimental Typical procedure for the synthesis of dihydrobenzoxazepinones 10a–n. A solution of benzyl azide 2 (1 mmol) in dry THF (3 mL) was treated with trimethylphosphine (1 M solution in toluene, 1.1 mmol) and stirred for 2 h at room temperature. Then

Studies on the interaction of isocyanides with imines: reaction scope and mechanistic variations

• Ouldouz Ghashghaei,
• Consiglia Annamaria Manna,
• Esther Vicente-García,
• Marc Revés and
• Rodolfo Lavilla

Beilstein J. Org. Chem. 2014, 10, 12–17, doi:10.3762/bjoc.10.3

• Barcelona, Spain 10.3762/bjoc.10.3 Abstract The interaction of imines with isocyanides has been studied. The main product results from a sequential process involving the attack of two units of isocyanide, under Lewis acid catalysis, upon the carbon–nitrogen double bond of the imine to form the 4-membered

• ring system. The scope of the reaction regarding the imine and isocyanide ranges has been determined, and also some mechanistic variations and structural features have been described. Keywords: azetidines; heterocycles; imines; isocyanides; multicomponent reactions; Introduction The interaction of

• imines with isocyanides is mainly focused on to the well-known Ugi multicomponent reaction (MCR) [1]. This fundamental process features the participation of a carboxylic acid group which attacks the intermediate nitrilium ion thus leading, after the Mumm rearrangement, to α-amidoamides. However, the

The rapid generation of isothiocyanates in flow

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2013, 9, 1613–1619, doi:10.3762/bjoc.9.184

• isocyanides [30][31], guanidines [32][33] and thiosemicarbazides [34]. Due to the limited commercial availability of diversely functionalised isothiocyanates chemists normally pursue a de novo synthesis, which most commonly involves the condensation of an amine with thiophosgene or carbon disulfide [35][36

Novel synthesis of pseudopeptides bearing a difluoromethyl group by Ugi reaction and desulfanylation

• Jingjing Wu,
• Hui Li and
• Song Cao

Beilstein J. Org. Chem. 2011, 7, 1070–1074, doi:10.3762/bjoc.7.123

• group (PhS) with Bu3SnH/AIBN according to our previous research, and the desired difluoromethyl-containing pseudopeptide was successfully obtained [27]. To demonstrate the scope of the method, several different substituted anilines, substituted benzaldehydes, isocyanides and this novel difluorinated

• difluoromethyl-containing pseudopeptides (3a–m and 4a–m) in good yields (Table 1). Conclusion In summary, we have developed a novel and efficient protocol for the synthesis of CF2H-containing pseudopeptides by Ugi reaction of substituted anilines, benzaldehyde, isocyanides and the novel building block 2,2

Long-range diastereoselectivity in Ugi reactions of 2-substituted dihydrobenzoxazepines

• Luca Banfi,
• Andrea Basso,
• Valentina Cerulli,
• Valeria Rocca and
• Renata Riva

Beilstein J. Org. Chem. 2011, 7, 976–979, doi:10.3762/bjoc.7.109

• venerable reaction is the poor diastereoselectivity typically experienced when using chiral inputs. It is well known that chiral isocyanides, aldehydes/ketones and carboxylic acids always bring about no or very little diastereoselectivity, whereas some relative asymmetric induction has been reported only

• noting that the Mitsunobu reaction is not effective on unprotected salicylaldehyde. 2,3-Dihydrobenzo[f][1,4]oxazepines similar to 5a,b have been previously prepared, but through less general routes [22][23][24]. Compounds 5a,b were reacted with a series of isocyanides and carboxylic acids to give, in

• diastereoselectivity (from 5.25:1 up to 9:1) is completely unprecedented for an isocyanide based multicomponent reaction. A slight increase in the dr was observed on passing from R1 = Me to bulkier R1 = iBu. On the other hand the structure and the nature of both isocyanides and carboxylic acids seem to have little

(Pseudo)amide-linked oligosaccharide mimetics: molecular recognition and supramolecular properties

• José L. Jiménez Blanco,
• Fernando Ortega-Caballero,
• Carmen Ortiz Mellet and
• José M. García Fernández

Beilstein J. Org. Chem. 2010, 6, No. 20, doi:10.3762/bjoc.6.20

• followed by treatment with yellow mercury (II) oxide [68]. There are two general strategies to access pseudoamide-type oligosaccharide mimics: i) nucleophilic addition of sugar derivatives to carbohydrate isocyanates, isothiocyanates or isocyanides; and ii) conversion of sugar azides into glycosyl

• or sugars, respectively, and glycosyl-isocyanates [73][74] or isocyanides [75]. However, the experimental difficulties in handling isocyanates has led to the preferential use of sugar carbodiimides as key intermediates for the preparation of glycosylureido sugars [76][77][78][79]. From the large

Synthesis of dihydrophenanthridines by a sequence of Ugi-4CR and palladium- catalyzed intramolecular C-H functionalization

• Florence Bonnaterre,
• Michèle Bois-Choussy and
• Jieping Zhu

Beilstein J. Org. Chem. 2008, 4, No. 10, doi:10.3762/bjoc.4.10

• heterocycles is evidently valuable in diversity oriented synthesis. The scope of this cyclization was next examined. From three aldehydes, eight amines, five carboxylic acids, and three isocyanides, Ugi-adducts were prepared and their subsequent palladium-catalyzed cyclization was investigated. The results are

Aroylketene dithioacetal chemistry: facile synthesis of 4-aroyl- 3-methylsulfanyl- 2-tosylpyrroles from aroylketene dithioacetals and TosMIC

• H. Surya Prakash Rao and
• S. Sivakumar

Beilstein J. Org. Chem. 2007, 3, No. 31, doi:10.1186/1860-5397-3-31

• use of some isocyanides for the syntheses of trisubstituted pyrroles prompts us to disclose our efforts in this area. [16] Results and Discussion The cycloaddition of TosMIC 2 to 3,3-di(methylsulfanyl)-1-phenyl-2-propen-1-one 1a was taken as a test case to evaluate the cycloaddition and to arrive at