Investigation of the one-pot synthesis of quinolin-2-(1H)-ones and the discovery of a variation of the three-component Ugi reaction

Rapid access to the quinolin-2-(1H)-one scaffold is afforded by a sequential 4 component Ugi–Knoevenagel condensation of an aminophenylketone, an aromatic aldehyde possessing electron donating moieties, cyanoacetic acid and an aliphatic isocyanide, in moderate to good yields (49–71%). Interestingly, when the reaction is performed using aromatic aldehydes bearing electron withdrawing moieties or isocyanides containing aromatic or ester units, a mixture of a quinolin-2-(1H)-one and an α-amino amide (Ugi three-component adduct) is afforded in varying ratios. Further when the reaction is performed utilizing a combination of an isocyanide-containing aromatic or carbonyl unit, and an aldehyde possessing an electron withdrawing functionality, the Ugi three-component adduct is exclusively afforded. In our hands this new variation of the Ugi 3CR proved to be efficient and robust affording analogues in good yields (51–70%).     

Microchip-based synthesis and analysis: control of multicomponent reaction products and intermediates

A miniaturised-SYNthesis and Total Analysis System (mu SYNTAS) was used for the solution-phase synthesis and on-line analysis (TOF-MS) of Ugi multicomponent reaction (MCR) products. This approach provides an unusually high degree of control of the MCR and delivers detailed, novel information on reaction intermediates in real-time. Specifically, the Ugi 4 component condensation (4CC) involving the reaction of an amine, acid, aldehyde and isocyanide species was performed at room temperature in a controllable fashion. Furthermore, observation of the nitrilium intermediate, cyclohexyl(2-piperidin-1-ylethylidyne)ammonium chloride, is presented for the first time.     

Heterocycles from substituted amides. VIII Oxazole derivatives from reaction of isocyanates with 2-isocyanoacetamides

A facile reaction of 2-isocyanoacetamides 1 with reactive aryl and sulfonyl isocyanates is shown to give 5-amino-2-oxazolecarboxamides 3 in a reaction arising from electrophilic attack of isocyanate with the nucleophilic isocyanide carbon. This reaction, perhaps proceeding through an unstable nitrile ylid intermediate reminiscent of the Cornforth rearrangement, is a first example of ring closure via acylation, involving the activated methylene of an organic isocyanide, without recourse to added base. Isomeric 5-amino-4-oxazolecarboxamides 4 are formed when 5-aminooxazoles 2 react with isocyanates. Since 2 has previously been shown to easily form by thermal isomerization of 1 , methods now exist for the preparation of both 5-amino- 2- and 4-oxazolecarboxamides from the single starting material 1 . In contrast, 1 with acyl isocyanates is shown to give a variety of products, including iminooxazolinediones, 5-amino-2-oxazolecarbox-amide 3 and 2 (1) pyrazinones (tentatively identified), depending on the structure of the isocyanates.     

Solid-supported synthesis of putative peptide beta-turn mimetics via Ugi reaction for diketopiperazine formation

The scope and limitations of the solid-supported synthesis of a bicyclic diketopiperazine, an internal, putative peptide beta-turn mimetic, are presented. The 4CC multicomponent Ugi reaction of alpha-N-Boc-diaminopropionic acid resin ester (an amine input), optically active alpha-bromoacid, aldehyde, and isocyanide is the key step in the proposed synthetic protocol. Application of cyclitive cleavage as the final step led to desired products in high purity.     

Synthesis of novel heterocyclic structures via reaction of isocyanides with S-trans-enones

The reaction of enone 1, bearing an internal nucleophilic moiety, i.e., furan or pyrrole (X = O, NR'), with isocyanides is presented. The formation of products resulting from the reaction of the zwitterionic intermediate 2 with a second equivalent of isocyanide prior to cyclization to give 3, as well as the direct formation of 4 from 2, is described.     

One-pot synthesis of oxoisoindoline-1,2,3-triazole hybrid by a Ugi–click reaction

1,2,3-Triazole-3-oxoisoindoline-1-carboxamide system was successfully synthesized by using a combination of Ugi and click reactions. This two-step, one-pot synthesis was started by the reaction of 2-formyl benzoic acid, propargyl amine, and cyclohexyl isocyanide in ethanol. The resultant Ugi adduct underwent a copper-catalyzed click reaction, producing the desired products in good yields.     

Trityl Isocyanide as a Mechanistic Probe in Multicomponent Chemistry: Walking the Line between Ugi‐ and Strecker‐type Reactions

Herein, we describe the versatile application of triphenylmethyl (trityl) isocyanide in multicomponent chemistry. This reagent can be employed as a cyanide source in the Strecker reaction and as convertible isocyanide in the preparation of N‐acyl amino acids by Ugi 4CR/detritylation and free imidazo[1,2‐a]pyridin‐3‐amines by a Groebke–Blackburn–Bienaymé 3CR condensation/deprotection protocol. The mechanisms of these three classical MCRs intersect at the common N‐trityl nitrilium ion intermediate, whose predictable reactivity can be exploited towards chemoselective transformations.     

Optically active helical polyisocyanides bearing chiral phosphine pendants: Facile synthesis and application in enantioselective Rauhut-Currier reaction

Three novel enantiopure phenyl isocyanide monomers with BH3-protected phosphine functional group were designed and synthesized.Polymerization of these monomers using a alkyne-Pd(Ⅱ) complex as a catalyst led to the formation of respective helical polyisocyanides in high yields with controlled molecular weights (Mns) and narrow molecular weight distributions (Mw/Mns).Removing the protecting BH3 groups afforded helical poly(phenyl isocyanide)s bearing phosphine pendants.Thanks to the chiral induction of monomer,the isolated helical polyisocyanides showed high optical activity,as revealed by circular dichroism (CD) and absorption spectroscopies and polarimetry.The helical structures of these polymers were quite stable in various organic solvents with different polarities and in a wide temperature range.Moreover,these helical polymers could be used as organocatalysts and showed good performance in enantioselective cross Rauhut-Currier reaction.The enantiomeric excess (ee) values of the isolated products of cross Rauhut-Currier reaction could be up to 90％.The polymer organocatalysts could be easily recovered from the reaction mixtures and reused at least five times in the reaction without significant loss of their enantioselectivities and catalytic activities.     

Template Synthesis of Peptidomimetics Composed of Aspartic Acid Moiety by Ugi Four‐Component Condensation Reaction

Abstract

Caspase‐3 inhibitors were supposed to be of benefit to both acute and chronic neurodegenerative conditions. In this work, a CPP32‐peptidomimetic‐inhibitor library was designed. The necessary aspartate moiety was reserved at the C terminal. A facile and versatile method based on Ugi‐4CR was developed to build up the library. The aspartic acid–derived isocyanide 3, the most important component of the four, was effectively synthesized from protected aspartic acid. This Ugi procedure was tested by synthesizing a small library.     

Facile,efficient and diastereoselective synthesis of α-hydrazine tetrazoles through a novel one-pot four-component reaction

A novel and efficient method for the diastereoselective synthesis of α-hydrazine tetrazoles via an isocyanide-based multicomponent reaction is reported in good yields. The α-hydrazine tetrazoles were obtained by a facile azide Ugi four-component reaction (U-4CR) using cyclic ketones, trimethylsilyl azide, hydrazides, and corresponding isocyanide without any catalyst and with high bond forming efficiency at room temperature.     

Propylphosphonic anhydride (T3P®) mediated synthesis of 3-oxoisoindoline-1-carboxamides from 2-formylbenzoic acid,amines, and isocyanides. Preparation of isoindolinone alkaloids

Propylphosphonic anhydride (T3P®) was successfully applied to the synthesis of an isoindolinone library by the utilization of an Ugi four-center, three-component reaction (Ugi-4C-3CR). The use of T3P® significantly shortened the required reaction time and the corresponding products were obtained in good to high yields. Moreover, a side-reaction was observed when phenylethylamine derivatives and tryptamine were used as the amine component. The latter reaction was applied to the microwave-assisted, one-pot synthesis of the isoquinoline alkaloid (±)-nuevamine. Surprisingly, the traditional Ugi four-component reaction (Ugi-4CR) was unsuccessful in the presence of T3P®. In this case an α-amino amide was produced excluding the carboxylic acid from the multicomponent reaction.     

One-pot synthesis of 5-(furo[3,4-b]chromenyl)-5-hydroxybarbiturates via a three-component cascade reaction

A three-component domino reaction between a 3-formylchromone, an isocyanide, and 1,3-dimethylalloxan which affords novel 5-(furo[3,4-b]chromenyl)-5-hydroxybarbiturate derivatives is reported. The reaction sequence consists of an initial [4+1] cycloaddition followed by an activated electrophilic heteroaromatic substitution on the furan ring to afford the products. This novel cascade reaction sequence represents an atom-economic route to biologically interesting molecules.     

One-step synthesis of N-acetylcysteine and glutathione derivatives using the Ugi reaction

Fully protected natural and unnatural N-acetylcysteine, dipeptide Cys-Gly, glutathione, and homoglutathione derivatives were synthesized by the Ugi four-component reaction using various benzylthio aldehydes and ketones as carbonyl building blocks. The scope and limitations of the method were investigated. Formation of imidazoline by-products in the Ugi reaction was discussed. 2,2,2-Trifluoroethanol was shown to be a superior reaction media than methanol in some reactions. Also, the 4-methyl-2,6,7-trioxabicyclo[2.2.2]octyl derivative (OBO-ester) of isocyanoacetic acid was shown to be superior to use than ethyl isocyanoacetate as a peptide synthesis precursor in cases when higher reactivity of an isocyanide is required.     

α,α-Dialkylglycines obtained by solid phase Ugi reaction performed over isocyanide functionalized resins

The multicomponent Ugi reaction is a straightforward method that can be used for the synthesis of highly hindered C-tetrasubstituted amino acids by reacting an amine, a ketone or aldehyde, a carboxylic acid and an isocyanide. In the present work, the synthesis of several α,α-dialkylglycines (α,α-diethylglycine, Deg; α,α-dipropylglycine, Dpg; 1-amino-1-cyclohexanecarboxylic acid, Ac₆c) was achieved by solid phase Ugi reaction using resins functionalized with the isocyanide group. Since no resins with these features were available commercially, the functionalization of an aminomethylated resin started by the use of glycine (Gly), β-alanine (β-Ala) and γ-aminobutyric acid (GABA) as spacers. After spacer N-formylation, followed by dehydration, isocyanide functionalised resins were obtained. The resins were then used in solid phase Ugi reaction, using phenylacetic acid as the acid component, 4-methoxybenzylamine as the amine component and different ketones, to afford the desired N-acylated α,α-dialkylglycines in good overall yields (60–80%), after acidolytic cleavage from the resin, thus proving the feasibility of this approach.     

A palladium-catalyzed three-component reaction for the preparation of quinazolin-4(3H)-imines

A novel and efficient route for the preparation of quinazolin-4(3H)-imines via a palladium-catalyzed three-component reaction of carbodiimide, isocyanide, and nucleophile is described. The palladium-catalyzed isocyanide insertion is believed to be the key step during the reaction process.     

α-Amino acids as acid components in the Passerini reaction: influence of N-protection on the yield and stereoselectivity

The Passerini reaction offers an easy access to depsipeptides, when both acid and isocyanide are derived from α-amino acids. However, racemisation of isocyanides derived from α-amino acid esters severely limits their use in the Passerini reaction. In order to overcome this limitation, a study on the influence of the α-amino acid N-protecting group on the yield and diastereoisomeric ratio of the product of the Passerini reaction was performed. Six different protecting groups were tested. Their influence turns out to be crucial and is not constant when the amino acid is changed. After optimisation, the Passerini reaction products with cyclohexanone as the carbonyl component were obtained with 99% yield and >98% de.     

Acid Catalyzed Reaction of Isocyanide with Epoxide

We have reported the acid–catalyzed cycloadditions of isocyanide with carbonyl compounds^1,2) and with Schiff bases,³⁾ in which the isocyanide component is incorporated as an imine group into the heterocyclic products. The cycloaddition of isocyanide with oxetane, four–membered cyclic ether, has also been realized with the aid of BF₃.Et₂o, which produces 1:1 cyclic adduct of 2–iminoterrahydrofuran.⁴⁾.     

A novel one-pot pseudo-four-component isocyanide-based reaction: an unexpected approach for the synthesis of tetrahydrodiisoindoloquinoxalines and tetrahydrobenzodiisoindoloquinoxalines

A novel isocyanide based one-pot pseudo-four-component strategy for the synthesis of tetrahydrodiisoindoloquinoxaline and tetrahydrobenzodiisoindoloquinoxaline derivatives via the reaction of 1,2-diamines, 2-formylbenzoic acid, and an isocyanide at room temperature in good yields without using any catalyst and activation, is described.     

Synthesis of novel furo-pyran derivatives via reaction between an isocyanide and alkylidene-substituted Meldrum’s acid

An unexpected four-component (3+1) reaction of an alkyl isocyanide with alkylidene-substituted Meldrum’s acid in CH₂Cl₂ at room temperature produces imino-furopyranones in good yields. The structures of the products are deduced from their IR, ¹H NMR, and ¹³C NMR spectra and by X-ray analysis. The products are structurally similar to 2H-furo[2,3-c]pyran-2-one natural products.     

A novel three-component reaction for the synthesis of 1,2-dihydroisoquinolines via the reaction of isoquinoline and isocyanides with strong CH-acids in water

A straightforward and efficient method for the synthesis of 1,2-dihydroisoquinolines via the one-pot, three-component reaction of an isocyanide, isoquinoline and a strong CH-acid in water without using any catalyst at 70 °C is reported. The method offers several advantages including high yields of products and an easy work-up procedure.