5-Diazo Dihydrouracils: Preparation and Some Transformations.

An approach to a new type of diazo reagents─diazo dihydrouracils─has been developed, and various transformations of the obtained diazo heterocycles have been studied, demonstrating their high synthetic potential for obtaining structurally diverse derivatives based on the privileged dihydrouracil scaffold. The X-H insertion reactions provide high yields of a variety of 5-substituted dihydrouracils. Cyclopropanation and 1,3-dipolar cycloaddition reactions involving a carbonyl ylide intermediate have been carried out to give spiro-annulated derivatives.

Access to 2-oxoazetidine-3-carboxylic acid derivatives via thermal microwave-assisted Wolff rearrangement of 3-diazotetramic acids in the presence of nucleophiles.

In this work, we report an efficient approach to 2-oxoazetidine-3-carboxylic acid derivatives based on a thermally promoted Wolff rearrangement of diazotetramic acids in the presence of nucleophiles. The method allows easy variation of the substituent in the exocyclic acyl group by introducing different -, -, and -nucleophilic reagents into the reaction. The reaction of chiral diazotetramic acids leads exclusively to -diastereomeric β-lactams.

Discovery and characterization of potent spiro-isoxazole-based cereblon ligands with a novel binding mode.

The vast majority of current cereblon (CRBN) ligands is based on the thalidomide scaffold, relying on glutarimide as the core binding moiety. With this architecture, most of these ligands inherit the overall binding mode, interactions with neo-substrates, and thereby potentially also the cytotoxic and teratogenic properties of the parent thalidomide. In this work, by incorporating a spiro-linker to the glutarimide moiety, we have generated a new chemotype that exhibits an unprecedented binding mode for glutarimide-based CRBN ligands.

Entry to new spiroheterocycles via tandem Rh(II)-catalyzed O-H insertion/base-promoted cyclization involving diazoarylidene succinimides.

A facile approach to novel medicinally relevant spiro heterocyclic scaffolds (namely furan-2(5)-ones, tetrahydrofurans and pyrans spiro-conjugated with the succinimide ring) has been developed. The protocol consists of Rh(II)-catalyzed insertion of heterocyclic carbenes derived from diazoarylidene succinimides (DAS) into the O-H bond of propiolic/allenic acids or brominated alcohols, followed by base-promoted cyclization to afford the target spirocyclic compounds in good to high yields.

Access to Spiro Bis-β-lactams via a Metal-Free Microwave-Assisted Wolff Rearrangement/Staudinger [2+2] Cycloaddition Cascade Involving 3-Diazotetramic Acids and Imines.

Herein, we report the study of the thermally promoted reaction of 3-diazotetramic acids with imines as a rapid route to a novel spiro heterocyclic scaffold, spiro bis-β-lactams (2,6-diazaspiro[3.3]heptane-1,5-diones). The transformation proceeds via metal-free microwave-assisted Wolff rearrangement of the diazo reagent followed by Staudinger [2+2] cycloaddition of the heterocyclic ketenes with Shiff bases.

Utilizing Allenic Acids and Heterocyclic Diazo Compounds in the Synthesis of Polysubstituted Spirocyclic Butenolides and β-Methylidene 2-Furanones.

Herein, we report a novel approach for the assembly of spirocyclic Δ-butenolides and β-methylidene 2-furanones via Rh(II)-catalyzed O-H insertion of heterocyclic diazo compounds into allenic acids followed by base-promoted cyclization. Utilizing various diazo heterocycles, including α-diazo homophthalimides, 3-diazo tetramic acids, and diazo oxindoles, diverse spirocyclic scaffolds were produced. The research revealed that the allenic acid substitution pattern is decisive for the product type, enabling extraordinary target compound switching between two types of spirocyclic 2-furanones with exo- and endocyclic C═C bonds.

-Boc-α-diazo glutarimide as efficient reagent for assembling N-heterocycle-glutarimide diads via Rh(II)-catalyzed N-H insertion reaction.

A technique has been proposed for incorporating a heterocyclic component into a glutarimide framework employing a Rh(esp)-catalyzed N-H insertion with the involvement of -Boc-α-diazo glutarimide. The new diazo reagent is more stable, soluble and convenient to prepare than the previously suggested one. The approach permits the application of diverse heterocycles, including both aromatic and saturated NH-substrates.

Chemo- and Diastereoselective Entries into All-Carbon α-Quaternary Aldehydes via C-C Insertion of 4-Diazoisoquinolin-3-ones into C-CHO Bonds.

Herein, we describe a chemo- and diastereoselective formal C-C insertion reaction of 1,2-disubstituted 4-diazo-3(2)-isoquinolones and 4-diazoisochroman-3-one into C-CHO bonds of aldehydes, delivering all-carbon α-quaternary aldehydes bearing medicinally important 1,4-dihydro-3(2)-isoquinolone scaffold. Our protocol is enabled by the preferential 1,2-carbon migration over more common 1,2- shift. The corresponding reaction tolerates a wide range of functionalities in both aldehyde and diazo components, giving the target homologated aldehydes in generally high yields.

Diazo Tetramic Acids Provide Access to Natural-Like Spirocyclic Δ-Butenolides through Rh(II)-Catalyzed O-H Insertion/Base-Promoted Cyclization.

3-Diazotetramic acids were found to be valid substrates for the recently discovered approach toward natural-like Δ-spirobutenolides via Rh(II)-catalyzed O-H insertion into propiolic acids followed by base-promoted intramolecular Michael addition. The target Δ-spirobutenolides were obtained in generally high yields and, in the case of chiral 5-monosubstituted 3-diazotetramic acids, high diastereoselectivity. The synthesis of Δ-spirobutenolides that we report here was virtually insensitive to the structure of the propiolic acids though it was somewhat sensitive to the structure of the 3-diazotetramic acids, thereby demonstrating quite a large scope.

A novel spirocyclic scaffold accessed via tandem Claisen rearrangement/intramolecular oxa-Michael addition.

A straightforward access to novel spiro[benzofuran-2,3'-pyrrolidine]-2',5'-diones based on the Rh(esp)-catalyzed insertion of carbenes derived from diazo arylidene succinimides (DAS) into the O-H bond of phenols is described. The initial adducts underwent a thermally promoted Claisen rearrangement followed by DABCO-catalyzed intramolecular 5-- oxa-Michael addition.

One-Pot Sequence of Staudinger/aza-Wittig/Castagnoli-Cushman Reactions Provides Facile Access to Novel Natural-like Polycyclic Ring Systems.

Realization of the one-pot Staudinger/aza-Wittig/Castagnoli-Cushman reaction sequence for a series of azido aldehydes and homophthalic anhydrides is described. The reaction proceeded at room temperature and delivered novel polyheterocycles related to the natural product realm in high yields and high diastereoselectivity. The methodology has been extended to three other cyclic anhydrides.

Facile and diastereoselective arylation of the privileged 1,4-dihydroisoquinolin-3(2)-one scaffold.

A practically convenient and streamlined protocol for the -diastereoselective introduction of an aryl substituent at position 4 of the 1,4-dihydroisoquinol-3-one (1,4-DHIQ) scaffold is presented. The protocol involves direct Regitz diazo transfer onto readily available 3(2)-isoquinolones followed by TfOH-promoted hydroarylation by an arene molecule. Screening of the novel 1,2,4-trisubstituted 1,4-DHIQs against cancer cell lines confirmed high cytotoxicity of selected analogs, which validates this new chemotype for further investigations as anticancer cytotoxic agents.

Unexpected Ring Contraction of Homophthalic Anhydrides under Diazo Transfer Conditions.

An attempted Regitz diazo transfer onto homophthalic anhydride led to the discovery of an unexpected ring contraction, which gave -sulfonyl phthalide-3-carboxamide derivatives. The reaction is thought to proceed via a [3 + 2] cycloaddition of the substrate's enol form and the azide followed by a two-step fragmentation of the intermediate 1,2,3-triazoline with a loss of the nitrogen molecule.

Unusual highly diastereoselective Rh(II)-catalyzed dimerization of 3-diazo-2-arylidenesuccinimides provides access to a new dibenzazulene scaffold.

Formation of unusual unsymmetrical dimers or/and indenes via Rh(esp)-catalyzed decomposition of 3-diazo-2-arylidenesuccinimides has been investigated. The reaction proceeded under mild conditions, and its result was shown to strongly depend on the nature of the substituents in the diazo substrate. The new reaction provides access to dibenzoazulenodipyrrole and indenopyrrole derivatives in moderate to high yield.

Dicarboxylic Acid Monoesters in β- and δ-Lactam Synthesis.

A -(2-methoxy-2-oxoethyl)--(phenylsulfonyl)glycine monomethyl ester of the respective dicarboxylic acid was involved in a reaction with imines promoted by acetic anhydride at an elevated temperature. Instead of the initially expected δ-lactam products of the Castagnoli-Cushman-type reaction, medicinally important 3-amino-2-azetidinones were obtained as the result of cyclization, involving a methylene group adjacent to an acid moiety. In contrast, replacing alcohol residue with hexafluoroisopropyl in the same substrate made another methylene group (adjacent to the ester moiety) more reactive to furnishing the desired δ-lactam in the Castagnoli-Cushman fashion.

Metal-Free Synthesis of 1,5-Disubstituted 1,2,3-Triazoles.

A three-component synthesis of 1,5-disubstituted 1,2,3-triazoles from α-acetyl-α-diazomethane sulfonamides, primary aliphatic amines, and aromatic aldehydes is presented. The 1,2,3-triazoles can be accessed in two alternative variants, depending on the substitutions in the sulfonamide portion of the diazo reagent. In one variant, intermediate 1,2,3-triazoline-4-sulfonamides are isolated chromatographically and then subjected to thermally promoted aromatization with elimination of sulfur(IV) oxide and amine.

Diastereoselective Formal [5+2] Cycloaddition of Diazo Arylidene Succinimides-Derived Rhodium Carbenes and Aldehydes: A Route to 2-Benzoxepines.

We report on a facile method for the preparation of 2-benzoxepine derivatives as a result of Rh(II)-catalyzed decomposition of diazo arylidene succinimides in the presence of aldehydes. The process is thought to involve the formation of styryl carbonyl ylide which undergoes 1,7-electrocyclization and subsequent 1,5-hydrogen shift. In some cases, the competition of the target reaction and [3+2] dipolar cycloaddition of the intermediate carbonyl ylide to another molecule of diazo substrate was observed.

Metal-free Three-Component Synthesis of 1,2,3-Triazoline-4-sulfonamides.

A new type of diazo compounds, namely, CH-diazomethane sulfonamides (generated from readily available α-acetyl-α-diazomethane sulfonamides), was employed in a 1,3-dipolar cycloaddition reaction with imines (also formed from primary amines and aldehydes). The reaction gave hitherto undescribed 1,5-disubstituted 1,2,3-triazoline-4-sulfonamides, which were obtained in good to excellent yields with complete trans diastereoselectivity. These new sulfonamides based on the nonaromatic 1,2,3-triazoline core are rather attractive from a medicinal chemistry standpoint in light of the strong emphasis recently put on the nonflat, more saturated (higher Fsp3) scaffolds for lead-generation libraries.

Investigation of 3-sulfamoyl coumarins against cancer-related IX and XII isoforms of human carbonic anhydrase as well as cancer cells leads to the discovery of 2-oxo-2H-benzo[h]chromene-3-sulfonamide - A new caspase-activating proapoptotic agent.

Herein we report the synthesis of a set of seventeen 3-sulfonamide substituted coumarin derivatives. Prepared compounds were tested in vitro for inhibition of four physiologically relevant isoforms of the metalloenzyme human carbonic anhydrase (hCA, EC 4.2.

Tricyclic 2-benzazepines obtained an unexpected cyclization involving nitrilium ylides.

Attempted use of (E)-3-arylidene-4-diazopyrrolidine-2,5-diones in the Rh(ii)-catalyzed condensation with nitriles to form 1,3-oxazoles led to an unexpected outcome. The nitrilium ylide species thought to form on Rh(ii)-catalyzed decomposition of diazo compounds underwent a cyclization onto the nearby arylidene moiety followed by 1,5-hydride shift. This led to the formation of a 2-benzazepine core which has special significance for drug discovery and can be considered a privileged scaffold.

Unexpected formal [4 + 2]-cycloaddition of chalcone imines and homophthalic anhydrides: preparation of dihydropyridin-2(1)-ones.

A series of medicinally important dihydropyridin-2(1H)-ones have been prepared via a novel [4 + 2]-formal cycloaddition reaction of chalcone imines and homophthalic anhydrides, which is a rare example of lactam construction from an imine acting as a four-atom building block. In contrast to previous studies on the reactivity of homophthalic anhydrides towards similar substrates, N-tosyl chalcone imines, we found the possibility of switching chemoselectivity by changing substituents at the nitrogen atom, which leads to the formation of heterocycles instead of the expected carbocycles. This reaction is very similar in appearance to the classic 1,2-addition of cyclic anhydrides to imines, often referred to as the Castagnoli-Cushman reaction, but differs in mechanistic details (representing a 1,4-reaction of imine).

Diazocarbonyl and Related Compounds in the Synthesis of Azoles.

Diazocarbonyl compounds have found numerous applications in many areas of chemistry. Among the most developed fields of diazo chemistry is the preparation of azoles from diazo compounds. This approach represents a useful alternative to more conventional methods of the synthesis of azoles.

Natural-Like Spirocyclic Δ -Butenolides Obtained from Diazo Homophthalimides.

α-Diazo homophotalimides were reacted with various propiolic acids on Rh (esp) catalysis. The resulting propiolate esters were transformed into novel, heterocyclic Δ -spirobutenolides in good to excellent product yields. The approach represents a fundamentally novel entry into natural-like Δ -spirobutenolides present in many biologically active natural products as well as fully synthetic compounds endowed with diverse biological activities.

Spirocyclizations Involving Oxonium Ylides Derived from Cyclic α-Diazocarbonyl Compounds: An Entry into 6-Oxa-2-azaspiro[4.5]decane Scaffold.

New types of cyclic diazo compounds capable of Rh(II)-catalyzed spirocyclizations with tetrahydrofuran have been discovered. The formation of the spirocyclic framework is thought to proceed the formation of Rh(II) carbene species followed by interaction with the Lewis basic oxygen atom of tetrahydrofuran to give oxonium ylide species. The latter evolves predominantly the Stevens type rearrangement leading to an [ + 1] ring expansion of the tetrahydrofuran moiety, which results in the formation of a medicinally relevant 6-oxa-2-azaspiro[4.