Stefano Marcaccini: a pioneer in isocyanide chemistry.

Stefano Marcaccini was one of the pioneers in the use of isocyanide-based multicomponent reactions in organic synthesis. Throughout his career at the University of Florence he explored many different faces of isocyanide chemistry, especially those geared towards the synthesis of biologically relevant heterocycles. His work inspired many researchers who contributed to other important developments in the field of multicomponent reactions and created a school of synthetic chemists that continues today. In this manuscript we intend to review the articles on isocyanide multicomponent reactions published by Dr. Marcaccini and analyse their influence on the following works by other researchers. With this, we hope to highlight the immense contribution of Stefano Marcaccini to the development of isocyanide chemistry and modern organic synthesis as well as the influence of his research on future generations. We believe that this review will not only be a well-deserved tribute to the figure of Stefano Marcaccini, but will also serve as a useful inspiration for chemists working in this field.

The Castagnoli-Cushman Reaction.

Since the first reports of the reaction of imines and cyclic anhydrides by Castagnoli and Cushman, this procedure has been applied to the synthesis of a variety of lactams, some of them with important synthetic or biological interest. The scope of the reaction has been extended to the use of various Schiff bases and anhydrides as well as to different types of precursors for these reagents. In recent years, important advances have been made in understanding the mechanism of the reaction, which has historically been quite controversial. This has helped to develop reaction conditions that lead to pure diastereomers and even homochiral products. In addition, these mechanistic studies have also led to the development of new multicomponent versions of the Castagnoli-Cushman reaction that allow products with more diverse and complex molecular structures to be easily obtained.

Synthesis of imidazolocoumarins by the amide-directed oxidative cyclisation of enol-Ugi derivatives.

The oxidative C(sp3)-H intramolecular imination of hydroxycoumarin enol-Ugi adduct derivatives affords selectively diversely substituted imidazolocoumarins in one pot. The amide group derived from the enol-Ugi isocyanide component directs the functionalisation of the adjacent C(sp3)-H and then is lost as an isocyanate molecule in an unprecedented transformation. This strategy was applied for the synthesis of potential modulators of innate immune system receptor TLR7, which showed high binding affinities in the molecular docking studies.

Synthesis of Chromeno[3,4-b]piperazines by an Enol-Ugi/Reduction/Cyclization Sequence.

Keto piperazines and aminocoumarins are privileged building blocks for the construction of geometrically constrained peptides and therefore valuable structures in drug discovery. Combining these two heterocycles provides unique rigid polycyclic peptidomimetics with drug-like properties including many points of diversity that could be modulated to interact with different biological receptors. This work describes an efficient multicomponent approach to condensed chromenopiperazines based on the novel enol-Ugi reaction. Importantly, this strategy involves the first reported post-condensation transformation of an enol-Ugi adduct.

Tandem Synthesis of Polycyclic Isoindoles.

We report an easy multicomponent synthesis of polycyclic isoindoles from cyclic 1,3-dicarbonyls, aldehydes, isocyanides, and maleimides. The key step consists of the one-pot Diels-Alder trapping of a reactive 2-aminofuran intermediate, formed by a sequence of a Knoevenagel condensation and a [4+1] cycloaddition. Moreover, a further microwave-promoted dehydrogenative N-C bond forming reaction allows the straightforward synthesis of a natural product like isoindolocarbazole, validating the utility of our methodology to obtain isoindoles as useful intermediates for the synthesis of complex polycyclic molecules.

Tandem synthesis of 4-aminoxanthones is controlled by a water-assisted tautomerization: a general straightforward reaction.

Aminoxanthones constitute a group of therapeutically promising compounds that so far have been synthetically challenging. Here, we report the synthesis of both aminodihydroxanthones and fully aromatized aminoxanthones by an easy to perform, one-step multicomponent reaction of isocyanides, 3-carbonylchromones and dienophiles. The mechanism of the reaction involves a sequence of a [4 + 1] cycloaddition, iminolactone-aminofuran tautomerization, [4 + 2] cycloaddition, oxygen ring opening and aromatization. Remarkably, DFT quantum chemical computations revealed that the iminolactone-aminofuran tautomerization requires the assistance of a water molecule and, contrary to intuition, it is the rate-determining step. Conversely, both the [4 + 1] and the [4 + 2] cycloadditions have relatively low calculated energy barriers, regardless the substituents on the starting materials. Thus, we have stablished a straightforward and a wide-ranging synthesis of diversely substituted xanthones. This highly convergent process has also been applied to the synthesis of biologically important chromenophenantridines and secalonic acid related xanthone dimers.

Regioselective Tandem [4 + 1]-[4 + 2] Synthesis of Amino-Substituted Dihydroxanthones and Xanthones.

A highly convergent and operationally simple approach to mycotoxin-related 4-amino-substituted 1-hydroxydihydroxanthones is described. The target compounds are obtained in one pot by the multicomponent reaction of 3-carbonylchromones, isocyanides, and nonsymmetric dienophiles. The reaction, which involves a tandem [4 + 1]-[4 + 2] cycloaddition, efficiently affords a variety of both monomeric and dimeric polysubstituted dihydroxanthones structurally similar to bioactive ergochromes. Further aromatization to the corresponding xanthones is readily achieved by treatment with DBU under microwave irradiation.

Elusive 2-aminofuran Diels-Alder substrates for a straightforward synthesis of polysubstituted anilines.

The first multicomponent coupling of isocyanides, α,ß-unsaturated carbonylic compounds and dienophiles, based on the trapping of unstable intermediate 2-aminofurans, is described. This novel tandem [4 + 1]-[4 + 2] cycloaddition is efficiently catalysed by yttrium triflate and constitutes an operationally simple and highly convergent approach to a variety of polysubstituted anilines. Moreover, this methodology permits the use of tert-butylisocyanide as a convertible isocyanide to yield directly N-unprotected anilines in the same pot.

Conjugate addition of isocyanides to chromone 3-carboxylic acid: an efficient one-pot synthesis of chroman-4-one 2-carboxamides.

We report a novel Lewis acid catalysed tandem reaction of isocyanides, chromone 3-carboxylic acid and nucleophiles. An experimentally very simple procedure, involving the use of microwave irradiation in the presence of a Lewis acid catalyst, affords a representative collection of chromone-2-carboxamides and chromone-2-carboxamido-3-esters in high yields, in just a few minutes. Such an unprecedented strategy is formally equivalent to a conjugate addition of isocyanides to Michael acceptors.

1H NMR to analyse the lipid profile in the glyceride fraction of different categories of Iberian dry-cured hams.

The extraordinary organoleptic qualities of Iberian ham derive from the singular producing pig breed and from the traditional rearing conditions, both of which define its lipid content and composition. In this work 1H NMR spectroscopy is used for the first time to analyse the lipid profile of Iberian hams as determinant of quality. Quantification of fatty acids is readily obtained from the spectra, with the monounsaturated fatty acids standing out, especially in the higher quality hams. Unprecedently, triacylglyceride hydrolysis products formed during the curing process can also be directly detected and quantified. Furthermore, chemometric analysis of the NMR data allows to classify Iberian hams according to the pig's crossbreed and feeding regime. Principal component analysis shows fatty acid unsaturation and triacylglyceride hydrolysis as discriminating variables. 1H NMR spectroscopy has thus revealed as a convenient and powerful tool for the lipid analysis and classification of Iberian hams and for detection of fraud.

A straightforward synthesis of 2-aminobenzothiazoles from Herz compounds.

2-Aminobenzothiazoles are readily synthesised from anilines, sulfur monochloride and isocyanides. The key step consists of an iodine-catalysed insertion of isocyanides into the S-S bond of hydrolysed Herz salts, with concomitant extrusion of sulfur monoxide.

A multicomponent approach to the synthesis of 1,3-dicarbonylic compounds.

A general synthesis of 1,3-dicarbonylic compounds using multicomponent reactions of isocyanides is described. The process involves a Passerini three-component condensation of glyoxal derivatives, isocyanides and acetic acid, followed by metal mediated reductive or solvolytic removal of the acid component. Noteworthy, reductive deacetoxylation of Passerini glyoxylamide adducts was successfully achieved using photochemically activated SmI(2). This procedure constitutes a novel convenient method for the direct synthesis of malonic retro-peptidic subunits.

Sequential five-component synthesis of spiropyrrolidinochromanones.

Herein we report a novel, diastereoselective, one-pot, two-step, sequential synthesis of highly functionalized natural product-like spiropyrrolidinochromanones. The process consists of an Ugi four-component condensation of 3-formylchromones with amines, isocyanides, and glyoxylic acids followed by a nucleophilic conjugate addition and intramolecular cyclization. The experimental simplicity and tolerance to a wide variety of substituents makes this method suitable for combinatorial synthesis.

Synthesis of Bis[1,2]dithiolo[1,4]thiazines and a [1,2]Dithiolo[1,4]thiazine from Tertiary Diisopropylamines.

The reaction of N-(2-chloroethyl)diisopropylamine 1a with S2Cl2 allows the selective one-pot preparation of the tricyclic 4-(2-chloroethyl) bisdithiolothiazines 2-4 or, by addition of phosphorus pentasulfide at a late stage in the reaction, of the dithiolothiazine 5. The chloroethyl derivative 2 is also obtained from (2-diisopropylamino)ethanethiol 1b, or its disulfide 1c, with S2Cl2, in a rare conversion of a thiol or disulfide into the corresponding chloro compound. Compounds 2 and 5 are also obtained from N-(2-hydroxyethyl)diisopropylamine 1d, though in much lower yields. The reaction of N-(2-phenylthioethyl) (1e) or N-(2-phthalimidoethyl)diisopropylamines 1f,g affords bisdithiolothiazines 7, 8, 9, and 11 and the dithiolopyrrole 10. A coherent set of reaction pathways for the formation of these products is proposed. X-ray crystallography shows that the bisdithiolothiazine ring system of 2 is folded out of planarity about the thiazine N-S vector, with the N-chloroethyl group folded back over the thiazine ring with the chlorine atom lying above the thiazine sulfur atom; the dithiolothiazine ring system of 5 has the thiazine ring in a "sofa" conformation.

Enols as feasible acid components in the Ugi condensation.

Heterocyclic enols are used for the first time as acid components in an Ugi-type multicomponent condensation. For that purpose, we have chosen enols containing a Michael acceptor, in order to facilitate an irreversible rearrangement of the primary Ugi adduct. The new four-component process leads readily and efficiently to heterocyclic enamines containing at least six elements of diversity.

Indene and pseudoazulene discotic liquid crystals: a synthetic and structural study.

Several new liquid-crystalline indene and pseudoazulene systems are reported. These molecules give rise to either columnar hexagonal mesophases and/or columnar plastic phases. The unique nature of these compounds stems from their non-classical discotic structure. Although the molecules have rigid aromatic cores, they lack terminal tails and instead the polarizable atoms (S, halogens) or polar groups (CN, CO) act as unusual soft parts. On the basis of many structurally related materials, we conclude that for this type of compound molecular stacking in the solid state is a prerequisite for the appearance of a columnar mesophase, although other intermolecular interactions within the layers are also important in establishing liquid-crystalline order. The behavior reported for these mesomorphic molecules opens up new possibilities in the search for related molecular interactions that might be useful for the construction of supramolecular architectures with particular properties.

Synthesis of highly branched sulfur-nitrogen heterocycles by cascade cycloadditions of [1,2]dithiolo[1,4]thiazines and [1,2]dithiolopyrroles.

We report the synthesis of some new polysulfur-nitrogen heterocycles by cascade cycloadditions to readily available polycyclic 1,2-dithiole-3-thiones. Thus, treatment of bis[1,2]dithiolopyrrole dithione 1 with dimethyl acetylenedicarboxylate (DMAD) or dibenzoylacetylene (DBA) gave the 1:4 adducts 2a,b and 3a. On the other hand, cycloaddition of bis[1,2]dithiolo[1,4]thiazine dithiones 4a-d with the same dipolarophiles gave the 1:2, 1:3, or 1:4 adducts 5a-c, 6a, 7a, 8a, 9a, and 10a,c,d selectively in fair to high yields. Reaction conditions were crucial for achievement of selectivity in thermal reactions. Catalysis by scandium triflate was used in the reaction of 4a and 2 equiv of DMAD. Treatment of the [1,2]dithiolo[1,4]thiazine dithione 11 with DBA gave the 1:2, 1:3 (two isomers), and 1:4 adducts 12-14 and 15a-d selectively. Cyclic voltammetry of selected examples showed irreversible processes that were not influenced by peripheral groups bonded to the heterocyclic system.

Synthesis of [1,3]dithiole and spiro[1,3]dithiole thiopyran derivatives of the [1,2]dithiolo[1,4]thiazine ring system.

We report the synthesis of some new polysulfur-nitrogen heterocycles by cycloaddition reactions to readily available tricyclic condensed 1,2-dithiole-3-thiones. Thus, treatment of bis[1,2]dithiolopyrrole ketothione 1 with diacyl acetylenes gave the bis-aducts 2a-d. On the other hand, cycloaddition of bis[1,2]dithiolo[1,4]thiazine ketothione 3 with 1 equiv of acyl or diacyl acetylenes gave [1,3]dithiolylidenyl[1,2]dithiolo[1,4]thiazines 4a-f in fair to high yields. Catalysis by scandium triflate was used in the reactions that implied the less reactive dipolarophiles. Treatment of 3 with 2 equiv of DBA gave the bis-aduct 5a, and reaction of 4c with DMAD gave the mixed bis-adduct 5b. Cyclic voltammetry of selected examples showed irreversible processes that were influenced by the electrochemical activity of peripheral groups bonded to the heterocyclic system.