Cyanation with isocyanides: recent advances and perspectives.

Cyanation has attracted considerable attention in organic synthesis because nitriles are key structural motifs in numerous important dyes, agrochemicals, natural products and drug molecules. As the fourth generation of cyanating reagents, isocyanides occupy a prominent place in the synthesis of nitriles due to their favorable stability, easy operability and high reactivity. In recent years, three types of cyanation with isocyanides have been established: the cleavage of the C-NC bond of tertiary alkyl isocyanides (Type I), the rearrangement of aryl isocyanides with azides (Type II), and the reductive cyanation of ketones with α-acidic isocyanides (Type III). This review focuses on advances in cyanation with isocyanides with an emphasis on reaction scope, limitations and mechanisms, which could reveal their remarkable value and superiority for accessing various nitriles. In addition, the future development prospects of this specific field are also introduced. We believe that this feature article will serve as a comprehensive tool to navigate cyanation with isocyanides across the vast area of synthetic chemistry.

Accessing indole-isoindole derivatives via palladium-catalyzed [3+2] cyclization of isocyanides with alkynyl imines.

A facile protocol for the preparation of indole-isoindole derivatives was developed and proceeds via a palladium-catalyzed [3+2] cyclization of isocyanides with alkynyl imines. In this transformation, the palladium catalyst has a triple role, serving simultaneously as a π acid, a transition-metal catalyst and a hydride ion donor, thus enabling the dual function of isocyanide both as a C1 synthon for cyanation and a C1N1 synthon for imidoylation. Significantly, the reaction is the sole successful example for accessing indole-isoindole derivatives, and will open up new avenues to assemble unique N-heterocycle frameworks. Furthermore, the synthetic value of this protocol is demonstrated in the late-stage modification of physiologically active molecules and in the construction of aggregation-induced emission compounds.

Rapid Access to Fused Tetracyclic N-Heterocycles via Amino-to-Alkyl 1,5-Palladium Migration Coupled with Intramolecular C(sp3)-C(sp2) Coupling.

An unprecedented route for the preparation of fused tetracyclic N-heterocycles is presented through the palladium-catalyzed cyclization of isocyanides with alkyne-tethered aryl iodides. In this transformation, a novel amino-to-alkyl 1,5-palladium migration/intramolecular C(sp3)-C(sp2) coupling sequence was observed first. More importantly, isocyanide exhibited three roles, serving simultaneously as a C1 synthon, a C1N1 synthon, and the donor of C(sp3) for C(sp3)-C(sp2) coupling, and the reaction was the sole successful example that achieved C(sp3)-H activation of isocyanide.

Halogen cation-promoted and solvent-regulated electrophilic cyclization for the regioselective synthesis of 3-haloquinolines and 3-halospirocyclohexadienones.

A novel approach for the production of halogen cations through the reaction of halogens with silver ions is described in this paper. On this basis, the regioselective synthesis of 3-haloquinolines and 3-halospirocyclohexadienones is realized through solvent regulation. The gram-scale reaction and the compatibility of complex substrates demonstrate the synthetic potential of this protocol, which will be an appealing strategy in organic synthesis.

Palladium-Catalyzed Cycloaddition of Alkynylimines, Double Isocyanides, and H2O/KOAc.

In this work, a palladium-catalyzed cyclization of alkynylimines and double isocyanides is described. This facile procedure is efficient for synthesizing various 4-amidyl-2-aminopyrroles. Mechanism investigation indicates that a four-membered ring-fused pyrrole species is a key intermediate and the reaction involves [4 + 1] cycloaddition, protonation, nucleophilic addition, 1,4-addition of isocyanide, and rearomatization. Interestingly, the linear dipyrrole derivative is found to be an appropriate fluoride ion probe with a remarkable emission change, which could serve as a potential candidate for optoelectronic conjugated materials.

External Reductant-Free Palladium-Catalyzed Reductive Insertion of Isocyanide: Synthesis of Polysubstituted Pyrroles and Its Applications as a Cysteine Probe.

In this work, an unprecedented route is described for the synthesis of 2-amino-4-cyanopyrrole derivatives via palladium-catalyzed reductive isocyanide insertion of alkynyl imines. In the reactions, no external reductant is added and isocyanide plays a dual role as both a C1 synthon for imidoylation and a cyano source for cyanation. Mechanism studies suggest a [4 + 1] cycloaddition, an isocyanide insertion, ß-carbon elimination, and palladium hydride-based reduction are involved. Moreover, the application of 2-amine-4-cyanopyrroles as a cysteine probe is realized to detect cysteine.

One-pot synthesis of polyfunctionalized quinolines via a copper-catalyzed tandem cyclization.

An efficient one-pot approach for the synthesis of polyfunctionalized quinolines was developed via a sequence of copper-catalyzed coupling reaction/propargyl-allenyl isomerization/aza-electrocyclization. Easily available starting materials, mild conditions, and a wide substrate scope make this approach potentially useful.

Construction of Polysubstituted 1,2-Dihydrocyclobuta[b]naphthalenes and 1,2-Dihydrocyclobuta[b]anthracenes with Photoluminescence.

A facile protocol for the synthesis of polysubstituted 1,2-dihydrocyclobuta[b]naphthalenes and 1,2-dihydrocyclobuta[b]anthracenes was developed via a sequence of base-promoted 1,5-H shift, intramolecular [2 + 2] cycloaddition, and aromatization. The synthesized 1,2-dihydrocyclobuta[b]anthracenes exhibited bright blue emissions in solution and strong yellow emissions in solid, which made them possible candidates for optoelectronic conjugated materials.

CuX-Activated N-Halosuccinimide: Synthesis of 3-Haloquinolines via Electrophilic Cyclization of Alkynyl Imines.

We report an electrophilic cyclization of alkynyl imines to afford polysubstituted 3-haloquinolines using CuX-activated N-halosuccinimdes (NXS) as electrophiles. Control experiments demonstrated that the NXS/CuX system might be more active than single NXS and could be applied in the electrophilic cyclization of electron- deficient substrates.