Benzo-fused Nitrogen Heterocycles by Asymmetric Ring Expansion and Stereochemically Retentive Re-contraction of Cyclic Ureas.

Benzo-fused nitrogen heterocycles are common features of bioactive molecules, and the enantioselective synthesis of their substituted analogues is an important goal. In this paper we demonstrate a practical and mechanistically intriguing approach to the enantioselective synthesis of 1-arylbenzazepines and their analogues. The reaction sequence starts with an asymmetric migratory ring expansion of indoline, tetrahydroquinoline, or tetrahydrobenzazepine ureas on treatment with a chiral lithium amide base. Treatment of the ring-expanded ureas with acid triggers a two-atom ring contraction-an 'azatropic shift' in which one urea nitrogen displaces the other-with almost complete retention of stereochemistry. Aminolysis of the urea products provides enantioenriched 1-aryl-tetrahydrobenzazepine derivatives and their congeners, including an analogue of an intermediate in the synthesis of the drug solifenacin. Deuteration, in situ IR, and DFT studies provide evidence for the mechanisms of the reaction steps.

Regioselective Difunctionalization and Annulation of Ynamide.

The use of ynamides in organic synthesis has gained significant attention due to their ability to provide access to complex molecular structures through transformations such as 1,2-difunctionalization and annulation reactions. These reactions enable the formation of highly functionalized N-bearing olefins and unusual N-bearing heterocycles. In this minireview, we present a systematic overview of the regioselective difunctionalization and annulation reactions of ynamides. We discuss the multi-component reactions, and radical-triggered functionalizations across the ynamides carbon-carbon multiple bonds and the use of bifunctional reagents in annulation of ynamides, highlighting their potential in expanding the substrate scope. Furthermore, we provide insights into the mechanistic breakthroughs that have been achieved in recent years in the development of these reactions. Finally, we emphasize the promising future prospects of ynamides as versatile building blocks for the synthesis of complex molecular architectures.

Enantioselective Intramolecular α-Arylation of Benzylamine Derivatives: Synthesis of a Precursor to Levocetirizine.

A practical, transition metal-free method allows the enantioselective synthesis of α,α-diarylmethylamines by asymmetric α-arylation of benzylamines. Enantioselective lithiation of N'-aryl-N-benzyl-N-isopropyl ureas using a chiral lithium amide base generates a benzyllithium that undergoes an unactivated stereospecific intramolecular nucleophilic aromatic substitution to generate an α,α-diarylmethylamine in the form of its urea derivative, in up to >99 % ee. Treatment with acid induces an "azatropic shift" with retention of configuration, the product of which may be hydrolysed to the target amine.

Yb(iii)-catalysed syn-thioallylation of ynamides.

Reported herein is a syn-thioallylation of ynamides incorporating a sulfide moiety at the α-position and an allyl group at the ß-position of the ynamide. The transformation is successful under ytterbium(iii)-catalysis, providing access to highly substituted thioamino-skipped-dienes with broad substrate scope. Thus, tetrasubstituted olefins (with four different functional groups: amide, phenyl, thioaryl/alkyl, and allyl on the carbon centers) are made in a single step from readily accessible ynamides, preserving complete atom economy. The reaction can be extended to the synthesis of selenoamino dienes by ynamide syn-selenoallylation. DFT studies and control experiments provide insight into the reaction mechanism.

Lewis Acid-Driven Meyer-Schuster-Type Rearrangement of Yne-Dienone.

Developed herein is a Cu(II)-catalyzed Meyer-Schuster-type rearrangement of alkyne-tethered cyclohexadienone for the construction of m-enone-substituted phenols. The reaction involves an uncommon 5-exo-trig 1,6-enyne cyclization of alkyne-tethered-cyclohexadienone, aromatization-triggered C-O bond cleavage, and an electrocyclic 4π-ring-opening of oxetene intermediate. This atom-efficient transformation provides access to a wide range of synthetically important α-(m-substituted phenol)-α,ß-unsaturated ketones, featuring a broad scope with labile functional group tolerance. The gram-scale demonstration makes this transformation synthetically viable. The synthetic application of α,ß-unsaturated ketones is also showcased.

Keteniminium-Driven Umpolung Difunctionalization of Ynamides.

A three-component Pd-catalyzed coupling of ynamides, aryl diazonium salts, and aryl boronic acids for the synthesis of novel triaryl-substituted enamides is described. This transformation represents the first example of an umpolung regioselective unsymmetrical syn-1,2-diarylation/aryl-olefination of ynamides. The aryl moieties of the diazonium salt (electrophile) and boronic acid (nucleophile) are explicitly incorporated in the electrophilic α- and nucleophilic ß-position, respectively, of the ynamide, resulting in a single isomer of the N-bearing tetrasubstituted olefin. The scope is broad (68 examples), showing excellent functional-group tolerance. DFT calculations substantiate the rationale of the mechanistic cycle and the regioselectivity. The chemoselectivity and synthetic potential of the enamide products were also studied.

Thioarylative Radical Cyclization of Yne-Dienone.

We herein demonstrated a N-hydroxyphthalimide (NHPI)-mediated chemo- and regioselective radical cyclization of yne-dienone with thiols to construct 3-thioaryl bearing [6,6]-fused dihydrochromenone derivatives. This transformation tolerates common functional groups and has broad scope. The reaction proceeds via the attack of a thioaryl radical to alkyne over the activated Michael acceptor. The TEMPO quenching experiment suggests the involvement of a radical intermediate. Synthetic versatility of 3-thioaryldihydrochromenones is also showcased.

Umpolung Reactivity of Ynamides: An Unconventional [1,3]-Sulfonyl and [1,5]-Sulfinyl Migration Cascade.

A regioselective sulfonyl/sulfinyl migration cycloisomerization cascade of alkyne-tethered ynamides is developed in the presence of XPhosgold catalyst. This reaction is the first example of a general [1,3]-sulfonyl migration from the nitrogen center to the ß-carbon atom of ynamides, followed by umpolung 5-endo-dig cyclization of the ynamide α-carbon atom to the gold-activated alkyne, and final deaurative [1,5]-sulfinylation. This process allows the synthesis of peripherally decorated unconventional 4-sulfinylated pyrroles with broad scope from N-propargyl-tethered ynamides. In contrast, N-homopropargyl-tethered ynamides undergo intramolecular tetradehydro Diels-Alder reaction to provide 2,3-dihydro-benzo[f]indole derivatives. Control experiments and density-functional theory studies were used to study the reaction pathways.

Alkyne Versus Ynamide Reactivity: Regioselective Radical Cyclization of Yne-Ynamides.

Ynamides are typically more reactive than simple alkynes and olefins. However, a serendipitous observation revealed a rare case where the reactivity of simple alkynes exceeds that of ynamides. This led to the development of a unique sulfur-radical-triggered cyclization of yne-tethered ynamides, which involves attack of the alkyne by a thiyl radical followed by cyclization with the ynamide. A wide range of novel 4-thioaryl pyrroles that could tolerate common functional moieties and N-protecting groups were expediently constructed by this strategy. The current method contrasts with the typical cyclization of yne-ynamides, which involves the attack of the alkyne moiety by the ynamide core. Control experiments and DFT calculations supported the participation of the sulfur radical in the reaction and the regioselective cyclization. The synthetic potential of the substituted pyrroles is also discussed.

Regioselective Synthesis of 2,4,5-Trisubstituted Oxazoles and Ketene Aminals via Hydroamidation and Iodo-Imidation of Ynamides.

A novel and straightforward protocol is demonstrated for the synthesis of highly substituted oxazoles from readily accessible ynamides in the presence of ytterbium(III) trifluoromethanesulfonate [Yb(OTf)3], N-iodosuccinimide (NIS), and acetonitrile. Multiple oxazole skeletons in the aryl periphery are constructed in a single operation for the first time. The hydroamidation and iodo-imidation of ynamides to trisubstituted and tetrasubstituted ketene aminals is exemplified. An isotope labeling experiment is used to identify the oxygen source in this transformation. The reactions are scalable to the gram scale, testifying the robustness of the transformations.