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

Herein, we report a novel approach for the assembly of spirocyclic Δα,ß-butenolides and ß-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.

Access to Spiro Bis-ß-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-ß-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. This methodology enables the preparation of diastereomerically pure spiro bis-ß-lactams in high yields and provides an avenue for exploring new versions of the privileged ß-lactam core for drug design.

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 N-, O-, and S-nucleophilic reagents into the reaction. The reaction of chiral diazotetramic acids leads exclusively to trans-diastereomeric ß-lactams. The use of variously substituted diazotetramic acids, including spirocyclic derivatives, as well as a wide range of nucleophiles provides access to a structural diversity of medically relevant 2-oxoazetidine-3-carboxylic acid amides and esters.

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(5H)-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.

Diazo Tetramic Acids Provide Access to Natural-Like Spirocyclic Δα,ß-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 Δα,ß-spirobutenolides via Rh(II)-catalyzed O-H insertion into propiolic acids followed by base-promoted intramolecular Michael addition. The target Δα,ß-spirobutenolides were obtained in generally high yields and, in the case of chiral 5-monosubstituted 3-diazotetramic acids, high diastereoselectivity. The synthesis of Δα,ß-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. Thus, a new class of α-diazocarbonyl compounds suitable for the realization of the approach outlined above was identified.

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(2H)-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(2H)-isoquinolone scaffold. Our protocol is enabled by the preferential 1,2-carbon migration over more common 1,2-H 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. The synthetic utility of this method has been further showcased by some transformations of the formyl moiety.

N-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 Rh2(esp)2-catalyzed N-H insertion with the involvement of N-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. This yields structures that are appealing for generating cereblon ubiquitin-ligase ligands and for potential use in crafting PROTAC molecules.

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. These further unravel the potential of the Castagnoli-Cushman reaction in generating polyheterocyclic molecular scaffolds.

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

A N-(2-methoxy-2-oxoethyl)-N-(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.

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 Rh2(esp)2-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-exo-trig oxa-Michael addition.

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

A practically convenient and streamlined protocol for the trans-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(2H)-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.

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 Rh2(esp)2-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. Dibenzoazulenodipyrroles bearing alkyl substituents at the nitrogen atom showed pronounced cytotoxocity against the A549 human lung adenocarcinoma cell line while N-aryl analogs were non-cytotoxic.

Natural-Like Spirocyclic Δα,ß -Butenolides Obtained from Diazo Homophthalimides.

α-Diazo homophotalimides were reacted with various propiolic acids on Rh2 (esp)2 catalysis. The resulting propiolate esters were transformed into novel, heterocyclic Δα,ß -spirobutenolides in good to excellent product yields. The approach represents a fundamentally novel entry into natural-like Δα,ß -spirobutenolides present in many biologically active natural products as well as fully synthetic compounds endowed with diverse biological activities. The Δα,ß -spirobutenolides thus obtained were shown to inhibit thioredoxin reductase, a selenocysteine enzyme target for cancer. Moreover, for the best compound in the series (TrxR IC50 1.49±0.08 µM), by using MALDI-TOF mass-spectrometry it was shown that it selectively binds selenocysteine in the presence of a 10-fold excess of cysteine. This validates the new compound as a promising lead for anticancer therapy development.

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

A new type of diazo compounds, namely, CH-diazomethane sulfonamides (generated in situ from readily available α-acetyl-α-diazomethane sulfonamides), was employed in a 1,3-dipolar cycloaddition reaction with imines (also formed in situ 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. The oxidative aromatization of 1,2,3-triazoline-4-sulfonamides by manganese(IV) oxide gave nearly quantitative yields of 1,2,3-triazole-4-sulfonamides, of which only two examples have been reported in the literature.

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. Generally, the desired 2-benzoxepines were isolated in good to high yields and high diastereoselectivity. The developed original approach toward a 2-benzoxepine core via formal [5+2] cycloaddition of styryl carbenoids and aldehydes significantly expands the arsenal of synthetic methods for producing this scaffold.

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. In the other variant, both chemical transformations take place in a single step conducted at room temperature.

Tricyclic 2-benzazepines obtained via 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(1H)-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). The developed atom-economical, stereoselective and catalyst- and chromatography-free protocol provided facile access to 28 structurally diverse heterocyclic products (in up to 88% yield) including synthetically challenging annelated tricyclic and previously unreported pentaaryl-substituted dihydropyridin-2(1H)-ones.

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. A comprehensive review on the preparation of various azoles (oxazoles, thiazoles, imidazoles, pyrazoles, triazoles, and tetrazoles) from diazocarbonyl and related compounds is presented for the first time along with discussion of advantages and disadvantages of «diazo¼ approaches to azoles.

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 via 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 via the Stevens type rearrangement leading to an [n + 1] ring expansion of the tetrahydrofuran moiety, which results in the formation of a medicinally relevant 6-oxa-2-azaspiro[4.5]decane scaffold. The spirocyclization process was often observed in competition with mechanistically distinct C-H insertion into a tetrahydrofuran molecule. This competing process gave compounds based on the 3-(tetrahydrofur-2-yl)pyrrolidine scaffold, which are also relevant from the medicinal chemistry standpoint. These findings enrich the available arsenal of metal-catalyzed spirocyclization methods based on the use of cyclic diazo compounds.