Post-condensation Modifications Research Articles

Decarboxylative 1,3-dipolar cycloaddition of amino acids for the synthesis of heterocyclic compounds.

The [3 + 2] cycloadditions of stabilized azomethine ylides (AMYs) derived from amino esters are well-established. However, the reactions of semi-stabilized AMYs generated from decarboxylative condensation of α-amino acids with arylaldehydes are much less explored. The [3 + 2] adducts of α-amino acids could be used for a second [3 + 2] cycloaddition as well as for other post-condensation modifications. This article highlights our recent work on the development of α-amino acid-based [3 + 2] cycloaddition reactions of N-H-type AMYs in multicomponent, one-pot, and stepwise reactions for the synthesis of diverse heterocycles related to some bioactive compounds and natural products.

Synthesis of Nβ-Substituted 1,2-Diazetidin-3-ones by the Ugi Reaction Comprising Chiral α-Hydrazino Acids.

We report the synthesis of a structurally diverse library of chiral Nβ-substituted 1,2-diazetidin-3-ones by a 4-center 3-component Ugi reaction comprising unprotected α-hydrazino acids. Various isocyanides and carbonyl compounds and both aldehydes and ketones were utilized. In addition, postcondensation modifications at three different sites have been demonstrated.

3-Substituted 2-isocyanopyridines as versatile convertible isocyanides for peptidomimetic design.

We report the use of 3-substituted 2-isocyanopyridines as convertible isocyanides in Ugi four-component reactions. The N-(3-substituted pyridin-2-yl)amide Ugi products can be cleaved by amines, alcohols, and water with Zn(OAc)2 as a catalyst. In addition, the applicability of the method was demonstrated in constrained di-/tripeptides bearing acid and base sensitive protective groups obtained via Ugi-4CR post-condensation modifications.

Enediyne-Comprising Amino Aldehydes in the Passerini Reaction.

Multicomponent reactions represent a highly efficient approach to a broad spectrum of structurally diverse compounds starting from simple and affordable compounds. A focused library of tweezers-like compounds is prepared by employing the multicomponent Passerini reaction comprising enediyne-derived amino aldehydes. The reaction proceeds under mild conditions yielding Passerini products in good to excellent yields. Postcondensation modifications of Passerini products are demonstrated through a simple deprotection/coupling approach comprising amino functionality, furnishing enediyne cores with highly decorated arms.

Synthesis of Monofunctionalized Calix[5]arenes

Seven OH-free and O-permethylated monofunctionalized calix[5]arenes carrying either additional methyl or tert-butyl groups are prepared following fragment condensation protocols. This strategy proves to be superior to previous approaches. Calix[5]arenes with free OH groups all adopt a cone conformation stabilized by a seam of hydrogen bonds at the lower rim. Post-condensation modifications, i.e., methylation of phenolic OH groups or functional group interconversions can also be achieved. Bulky tert-butyl groups are also found to stabilize the cone conformations of O-methylated compounds. These compounds offer versatile functional groups that make these concave molecules interesting building blocks for the synthesis of more sophisticated molecular architectures.

Synthesis of quinoxalines and pyrido[2,3-b]pyrazines by Suzuki–Miyaura cross-coupling reaction

Bromo-substituted quinoxalines and pyrido[2,3-b]pyrazines were synthesized by condensation reactions of aromatic 1,2-diamino and 1,2-diketone compounds. These compounds were used as common intermediates for postcondensation modification by Suzuki–Miyaura coupling reaction to form aryl-substituted quinoxalines and pyrido[2,3-b]pyrazines. High-efficiency with improved product yield of aryl-substituted quinoxalines and pyrido[2,3-b]pyrazine derivatives was achieved by conducting a coupling reaction in presence of Pd(dppf)Cl2·CH2Cl2 in tetrahydrofuran (THF) using K2CO3 as base at reflux temperature.

A facile and concise route toward the synthesis of novel imidazo-tetrazolodiazepinones via post-condensation modifications of the Ugi-azide adduct

This Letter describes novel methodology for the rapid assembly of unprecedented and likely biologically relevant imidazo-tetrazolodiazepinones. The product of a TMSN3-Ugi multi-component reaction is treated with an excess of isocyanate to generate 1,5-disubstituted tetrazolo-hydantoins functionalized with an internal-masked amino nucleophile previously introduced by the isocyanide input. Final products are obtained in good overall yields after microwave irradiation of the tetrazolo-hydantoin in acidic media. This methodology allows the production of complex polycyclic compounds in a mere three synthetic steps.

1,3-Dipolar Cycloaddition-based Synthesis of Diverse Heterocyclic Scaffolds

Abstract 1,3-Dipolar cycloaddition reaction-based diversity-oriented synthesis developed from our research lab is highlighted. The initial [3 + 2] cycloaddition products are subjected to postcondensation modifications to afford heterocyclic scaffolds with substitutional, skeletal, and stereochemical variations. Multicomponent reactions and fluorous linker-facilitated separation are integrated to increase the efficiency of compound library synthesis.

Synthesis of diverse dihydropyrimidine-related scaffolds by fluorous benzaldehyde-based Biginelli reaction and post-condensation modifications.

Dihydropyrimidinones and dihydropyrimidinethiones generated from the Biginelli reactions of perfluorooctanesulfonyl-attached benzaldehydes are used as common intermediates for post-condensation modifications such as cycloaddition, Liebeskind–Srogl reaction and Suzuki coupling to form biaryl-substituted dihydropyrimidinone, dihydropyrimidine, and thiazolopyrimidine compounds. The high efficiency of the diversity-oriented synthesis is achieved by conducting a multicomponent reaction for improved atom economy, under microwave heating for fast reaction, and with fluorous solid-phase extractions (F-SPE) for ease of purification.

Application of iminophosphorane in heterocyclic synthesis

Recent work of our group on the synthesis of heterocycles via aza-Wittig reaction of iminophosphorane was reviewed. We have developed a new efficient synthesis of various imidazolones or oxazoles by utilizing a consecutive cyclization of α-ethoxycarbonyl iminophosphorane, isocynate (or carbon disulfide) and various nucleophilic reagents. New derivatives of (fused) quinazolinones and pyrimidinones were prepared from the tandem reaction of β-ethoxycarbonyl iminophosphorane, isocynate (or carbon disulfide) and various nucleophilic reagents. Indole derivatives were also obtained in good yields from the sequential reaction of β-phenylethynyl iminophosphorane, isocynate and various nucleophilic reagents in the presence of a catalytic amount of Ag+. Recently the iminophosphorane was applied in post-condensation modifications of Ugi and Passerini reactions to prepare multisubstituted benzoxazines and quinazolines.

Ugi Reactions with Ammonia Offer Rapid Access to a Wide Range of 5-Aminothiazole and Oxazole Derivatives

A series of Ugi reactions has been successfully performed using ammonia as the amine component, employing 2,2,2-trifluoroethanol as a non-nucleophilic solvent in order to suppress known side reactions. Utilizing concentrated aqueous ammonia as a convenient source, this approach offered a simple, one-step assembly of Ugi adducts suitable for elaboration into a variety of 5-aminoazole compounds through postcondensation modifications. Free or N-substituted 5-aminothiazoles and 5-(trifluoroacetamido)oxazoles were all prepared by this improved methodology. The scope of the synthetic route developed and application of the different products are discussed.

Studies on isocyanides. A facile synthesis of 4,5-dihydro-1,4-benzothiazepin-3(2 H)-ones via post-condensation modifications of the Ugi reaction

A series of 4,5-dihydro-1,4-benzothiazepin-3(2 H)-ones 9 was prepared via Ugi 4-CC, S N aliph, and S N arom. This procedure, which resembles the well-known Hulme’s and Zhu’s protocols, allows a facile access to the above heterocyclic system. Further transformations of the cyclized products appear to be feasible.

Library Generation via Postcondensation Modifications of Isocyanide‐Based Multicomponent Reactions

AbstractFor Abstract see ChemInform Abstract in Full Text.

Library Generation via Postcondensation Modifications of Isocyanide-Based Multicomponent Reactions

Publisher Summary This chapter focuses on a particular branch of multicomponent condensation reaction (MCR) methodologies— namely, the postcondensation modifications (or secondary reactions) of isocyanide-based multicomponent reactions (IMCRs). One attractive feature of the multicomponent reaction is the relative ease of its automation. Discrete reactions may be run in parallel by either solution- or solid-phase protocols in a standard 96-well format. One of the methodologies discussed in the chapter is the UDC (Ugi/De-Boc/Cyclize) methodology. The biological utility of 1,4-benzodiazepine-2,5-diones (BDPs) appears in many areas, including the applications as antagonists of the platelet glycoprotein IIb-IIIa, anticonvulsant agents, antihypnotic agents, reverse transcriptase inhibitors, and selective cholecystokinin (CCK) receptor subtype A or B antagonists. The chapter presents three miscellaneous postcondensation modification reactions: (1) TMSN 3 modified Ugi Reactions, (2) postcondensation Passerini reactions, and (3) TMSN 3 -modified Passerini reaction. The TMSN 3 -modified Ugi reaction involves the condensation of an appropriately substituted aldehyde or ketone with a primary or secondary amine.

Novel applications of convertible isonitriles for the synthesis of mono and bicyclic γ-lactams via a UDC strategy

This communication reveals a novel application of the so-called convertible isonitriles for the solution/solid phase generation of γ-lactam analogues. Use of tethered N-BOC aldehydes in the Ugi multi-component reaction (MCR), followed by BOC removal and base treatment (a ‘3-step, 1-pot procedure’) affords γ-lactams in good yield. The UDC (Ugi/De-BOC/Cyclize) strategy, coupled with a convertible isonitrile, is now feasible from all three substitution sites of the Ugi product. A conceptually novel approach, combining a bi-functional precursor with a post-condensation modification to give fused lactam-ketopiperazines, is also revealed.

ChemInform Abstract: Postcondensation Modifications of Ugi Four‐Component Condensation Products: 1‐Isocyanocyclohexene as a Convertible Isocyanide. Mechanism of Conversion, Synthesis of Diverse Structures, and Demonstration of Resin Capture.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Postcondensation Modifications of Ugi Four-Component Condensation Products: 1-Isocyanocyclohexene as a Convertible Isocyanide. Mechanism of Conversion, Synthesis of Diverse Structures, and Demonstration of Resin Capture

The concept of a “universal isocyanide” that enables postcondensation modification of Ugi four-component condensation products is introduced. This strategy is suited for the synthesis of libraries. By using 1-isocyanocyclohexene as the isocyanide input in the Ugi reaction, the product cyclohexenamides can be converted to a variety of products. From the original α-(acylamino) amides, new carboxylic acids, esters, and thioesters are produced from acid-activated conversion of the cyclohexenamide moiety. It has been determined that the intermediate in conversion of this type is an oxazolinium-5-one (munchnone) that reacts with many nucleophiles to yield the products above. The munchnone can also undergo cycloaddition with acetylenic dipolarophiles to form pyrroles. Through internal nucleophilic attack, Ugi products are shown to convert to a protected monosaccharide derivative and to 1,4-benzodiazepine-2,5-diones. All of the conversions described consist of a single step. Resin capture of Ugi products is demon...