Copper-catalyzed deacetonative Sonogashira coupling.

A convenient Pd- and phosphine-free protocol for assembling internal alkynes from tertiary propargyl alcohols and (het)aryl halides has been developed. The proposed tandem approach includes the base-promoted retro-Favorskii fragmentation followed by Cu-catalyzed C(sp)-C(sp2) cross-coupling. The use of inexpensive reagents (e.g. a catalyst, additives, a base, and a solvent) and good functional group tolerance make the procedure practical and cost-effective. The synthetic utility of the method was demonstrated by a smooth alkynylation of vinyl iodides derived from natural steroidal hormones.

Domino assembly of dithiocarbamates via Cu-catalyzed denitrogenative thiolation of iodotriazole-based diazo precursors.

An efficient domino approach to assemble benzoxazoles and anthranilamides bearing dithiocarbamate moieties has been developed. The proposed route represents a Cu-catalyzed three-component reaction between readily available 5-iodo-1,2,3-triazoles, amines, and CS2. The cascade transformation is based on a denitrogenative coupling of in situ formed dithiocarbamic acids with diazo intermediates, generated via annulation-triggered triazole ring-opening. This method is applicable to nucleophilic secondary amines and features good functional group compatibility.

Annulation-Triggered Denitrogenative Transformations of 2-(5-Iodo-1,2,3-triazolyl)benzoic Acids.

The ability of [1,2,3]triazolobenzoxazinones to act as a source of "hidden" diazo group was discovered. These diazo precursors can be easily prepared by the intramolecular cyclization of 2-(5-iodo-1,2,3-triazolyl)benzoic acids. The Cu-catalyzed capture of the hidden diazo group allows for further functionalization through the denitrogenative pathway. The transformations proceed via the formation of either diazoimine or diazoamide intermediates. Novel routes to various anthranilamides as well as thiolated benzoxazinones were developed using the one-pot cyclization/diazo capture procedure.

Domino Construction of Benzoxazole-Derived Sulfonamides via Metal-Free Denitrogenation of 5-Iodo-1,2,3-triazoles in the Presence of SO2 and Amines.

A straightforward domino approach to assemble benzoxazole-derived sulfonamides has been developed. The method is based on annulation-induced in situ generation of diazo compounds from readily available 2-(5-iodo-1,2,3-triazolyl)phenols, followed by metal-free denitrogenative transformation upon the action of 1,4-diazabicyclo[2.2.2]octane bis(sulfur dioxide) (DABSO) and amines. The protocol is operationally simple and features a broad substrate scope, furnishing a library of target compounds in generally good yields.

Assembly of Thiosubstituted Benzoxazoles via Copper-Catalyzed Coupling of Thiols with 5-Iodotriazoles Serving as Diazo Surrogates.

An efficient cascade approach to thiosubstituted benzoxazoles has been developed. The transformation starts with in situ generation of a diazo compound via annulation-triggered electrocyclic opening of the 1,2,3-triazole ring. The subsequent Cu-catalyzed trapping of diazo intermediates by various thiols affords the desired heterocycles in generally good yields of up to 91%. The protocol features very good functional group tolerance and is applicable to substrates with different electronic properties.

A Route to Triazole-Fused Sultams via Metal-Free Base-Mediated Cyclization of Sulfonamide-Tethered 5-Iodotriazoles.

An efficient direct approach to triazole-fused sultams has been developed. The key step of the proposed strategy is base-mediated cyclization of sulfonamide-tethered 5-iodo-1,2,3-triazoles which are readily available via an improved protocol for Cu-catalyzed 1,3-dipolar cycloaddition. The annulation of the sultam fragment to the triazole ring proceeds smoothly under transition-metal-free conditions in the presence of Cs2CO3 in dioxane at 100 °C and affords fused heterocycles in high yields up to 99%. The favorability of an SNAr-like mechanism for the cyclization was supported by DFT calculations. The applicability of the developed procedure to modification of natural compounds was demonstrated by preparation of a deoxycholic acid derivative.

Annulation-Induced Cascade Transformation of 5-Iodo-1,2,3-triazoles to 2-(1-Aminoalkyl)benzoxazoles.

Base-mediated cyclization of (5-iodo-1,2,3-triazolyl)phenols was proposed as a new synthetic strategy for the in situ generation of diazoimines via electrocyclic ring opening of the fused heterocycle. Cu-catalyzed amination of the intermediate diazoalkanes was employed to develop an efficient cascade approach to functionalized benzoxazoles.

Regioselective Hydrogenolysis of Donor-Acceptor Cyclopropanes with Zn-AcOH Reductive System.

A convenient low-cost method for regioselective ring-opening of donor-acceptor cyclopropanes with the Zn-AcOH reductive system was developed. The general character of the method was displayed via efficient reduction of a representative series of 2-(het)arylcyclopropane-1,1-diesters as well as donor-acceptor cyclopropanes with other types of electron-withdrawing activating groups. This method opens a rapid access to γ-substituted propyl-1,1-diesters, ketoesters, cyanoesters, cyanoamides, dinitriles, etc., many of which are not readily accessible with alternative methods. The utility of the synthesized compounds was demonstrated by transforming them into valuable acyclic and cyclic compounds (including pharmacologically relevant carbazoles, δ-lactams, and oxindole derivatives).

Pd- and Cu-catalyzed approaches in the syntheses of new cholane aminoanthraquinone pincer-like ligands.

Cu- and Pd-catalyzed arylation of aminocholanes has been described for the first time. While this Cu-catalyzed protocol provides high yields in reactions of aminocholanes with iodoarenes, Pd catalysis was found to be preferable for the reactions of aminocholanes with dichloroanthraquinones. UV-vis titration of bis(cholanylamino)anthraquinones with a series of cations demonstrated their high binding affinity to Cu2+, Al3+, and Cr3+.

Alkynylation of steroids via Pd-free Sonogashira coupling.

Cu-catalyzed Pd-free Sonogashira coupling has been proposed as a straightforward and convenient route to valuable steroidal enynes. A biligand catalyst system based on Ph3P and TMEDA has been designed. The protocol was utilized for the efficient coupling of iodosteroids with diverse terminal alkynes and 1-trimethylsilylalkynes. A possible role of an auxiliary ligand as a phase-transfer catalyst for a sparingly soluble inorganic base (K2CO3) was revealed.

Lewis and Brønsted acid induced (3 + 2)-annulation of donor-acceptor cyclopropanes to alkynes: indene assembly.

(3 + 2)-Annulation of donor-acceptor cyclopropanes to alkynes induced by both Lewis and Brønsted acids has been developed. The reaction provides a rapid approach to functionalized indenes displaying intense visible emission (λmax = 430 nm, Φ = 0.28-0.34).

Synthesis of novel 1,2,3-triazolyl derivatives of pregnane, androstane and D-homoandrostane. Tandem "click" reaction/Cu-catalyzed D-homo rearrangement.

Copper-catalyzed 1,3-dipolar cycloaddition has been employed in the reaction of steroidal azides with various terminal alkynes. A number of novel 1,2,3-triazolyl derivatives of pregnane, androstane and D-homoandrostane were obtained in high yield (70-98%). The developed synthetic protocols allowed us to attach the triazolyl moiety to both the side chain and the steroidal backbone directly, despite the steric hindrance exerted by the polycyclic system. The presence of Cu(II) was shown to evoke d-homo rearrangement under mild conditions. A rational choice of the copper precatalyst permitted us to carry out the "click" reaction either along with tandem d-homo rearrangement or in the absence of this process. The tendency of 16-heterosubstituted steroids to undergo D-homo rearrangement under Cu(II) catalysis was studied.

Design and synthesis of bile acid-peptide conjugates linked via triazole moiety.

A conjugation of bile acids with peptides via Cu(I)-catalyzed click chemistry has been described. Novel bile acid-peptide conjugates linked via a 1,2,3-triazole moiety based on cholic, deoxycholic and lithocholic acid derivatives were synthesized using Cu(I)-catalyzed 1,3-dipolar cycloaddition ("click" reaction). It was shown that up to three peptide fragments can be attached to a central steroid core, thus forming complex three-dimensional polyconjugate structures, which can find important applications in biochemistry, medicinal chemistry, and coordination chemistry.