Deciphering the Origin of Regioselectivity in Ru(II)-Catalyzed C-H Annulation of N-Chlorobenzamides with 1,3-Diynes.

Understanding the reaction mechanism and origin of regioselectivity in transition metal-catalyzed C-H activation/annulation reactions with 1,3-diynes has remained an intriguing challenge. In this article, to establish the mechanism and decipher the origin of regioselectivity, we report a detailed computational density functional theory-based mechanistic investigation on the recently developed Ru(II)-catalyzed [4 + 2] annulation of N-chlorobenzamides with 1,3-diynes for the synthesis of 3-alkynylated isoquinolone derivatives. Our calculations reveal a redox-neutral pathway for the annulation reaction. The stepwise analysis of the reaction channels indicates the migratory insertion step and the concerted reductive elimination/oxidative addition of the Ru(p-cymene) moiety to form the N-C bond leading to the 3-alkynylated product to be the selectivity- and rate-determining steps, respectively. Finally, the distortion/interaction analysis using the activation-strain model suggests the steric effect as the determining factor for the observed regioselectivity for the formation of the 3-alkynylated product. Overall, the computationally obtained key insights into the catalytic mechanism and the origin of regioselectivity in the C-H activation/annulation reaction can be used as a guide to rationally design and develop novel transformation strategies for heterocycle synthesis.

Advances in transition metal-catalyzed C-H amination strategies using anthranils.

Modern times have witnessed an uprise in the synthesis and derivatization of nitrogen-containing fused heterocycles. Amination reactions involving nitrene chemistry have always been the most convenient choice for the incorporation of a nitrogen atom in a molecule. The utilization of an open nitrene species harnesses harsh conditions. Hence, transition metal-catalyzed C-H amination reactions using aminating agents have been an attractive choice. Electrophilic aminating agents for C-H amination reactions are well exploited due to their desirable reaction conditions. Out of all, anthranils have paved the way forward due to their utility in simultaneously forming two new functional groups (amine and carbonyl). Amination using anthranils follows a metal-nitrenoid pathway. Often, the amination has been followed by a Lewis acid or transition metal-mediated intramolecular cyclization to directly produce fused heterocycles. This review broadly demonstrates the utilization of anthranils as an aminating agent for transition metal-catalyzed C-H amination reactions. The focus has been given to the scope, limitations, and mechanistic understanding of using such an electrophilic aminating agent, anthranil, with transition metals.

Reverse Regioselective Cp*Co(III)-Catalyzed [4 + 2] C-H Annulation of N-Chloroamides with Vinylsilanes: Synthesis of 4-Silylated Isoquinolones and Their Synthetic Utilities.

We have developed a Cp*Co(III)-catalyzed reverse regioselective [4 + 2] annulation of N-chlorobenzamides/acrylamides with vinylsilanes for the synthesis of 4-silylated isoquinolones. The reaction was performed at ambient temperature under redox-neutral conditions. The reaction utilized the N-Cl bond as an internal oxidant, furnished the required products with excellent regioselectivities, and demonstrated high functional group tolerance. The synthetic utility of 4-silylated isoquinolones has been demonstrated for the preparation of 4-heteroarylated and 4-alkylated isoquinolones via metal-free C-C couplings. Additionally, 3,4-dihydroisoquinolones were synthesized via protodesilylation of 4-silylated isoquinolones, thus making vinylsilane an ethylene surrogate.

Harnessing Vinyl Acetate as an Acetylene Equivalent in Redox-Neutral Cp*Co(III)-Catalyzed C-H Activation/Annulation for the Synthesis of Isoquinolones and Pyridones.

We have developed Cp*Co(III)-catalyzed redox-neutral synthesis of 3,4-unsubstituted isoquinoline 1(2H)-ones at ambient temperature using N-chloroamides as a starting material. The reaction utilizes vinyl acetate as an inexpensive and benign acetylene surrogate. The N-Cl bond of the N-chlorobenzamides plays the role of an internal oxidant and hence precludes the need for an external oxidant. The reaction works with a wide range of substrates having various functional groups and a substrate containing a heterocyclic ring. Notably, the reaction is extended to the N-chloroacrylamides in which vinylic C-H activation occurs to furnish the 2-pyridone derivatives. Preliminary mechanistic studies were also conducted to shed light on the mechanism of this reaction.

Redox-neutral C-H annulation strategies for the synthesis of heterocycles via high-valent Cp*Co(III) catalysis.

A variety of biologically active molecules, pharmaceuticals, and natural products consist of a nitrogen-containing heterocyclic backbone. The majority of them are isoquinolones, indoles, isoquinolines, etc.; thereby the synthesis and derivatization of such heterocycles are synthetically very relevant. Also, certain naphthol derivatives have high synthetic utility as agrochemicals and in dye industries. Previous approaches have utilized ruthenium, rhodium, or iridium which may not be desirable due to the high toxicity, low abundance, and high cost of such 4d and 5d metals. Moreover, the need for an external oxidant during the reaction also adds by-products to the system. A high-valent cobalt-catalyzed redox-neutral C-H functionalization strategy has emerged to be a far better alternative in this regard. The use of the non-noble metal cobalt allows for selectivity and specificity in product formation. Also, the redox-neutral concept avoids the use of an external oxidant either due to the presence of a metal in a non-variable oxidation state throughout the catalytic cycle or due to the presence of an oxidizing directing group or an oxidizing coupling partner. Such an oxidizing directing group not only directs the catalyst to a specific reaction site by chelation but also regenerates the catalyst at the end of the cycle. Certain bonds such as N-O, N-N, N-Cl, N-S, and C-S are the main game-players behind the oxidizing property of such directing groups. In the other case, the directing group only chelates the catalyst to a reaction center, whereas the oxidation is carried out by the upcoming group/coupling partner. Overall, merging the redox-neutral concept with the high-valent cobalt catalysis is paving the way forward toward a sustainable and environmentally friendly approach. This review critically describes the mechanistic understanding, scope, limitations, and synthesis of various biologically relevant heterocycles via the redox-neutral concept in the high-valent Cp*Co(III)-catalyzed C-H functionalization chemistry domain.

Ru(II)-Catalyzed Regioselective Redox-Neutral [4 + 2] Annulation of N-Chlorobenzamides with 1,3-Diynes at Room Temperature for the Synthesis of Isoquinolones.

Herein, we report Ru(II)-catalyzed C-H/N-H bond functionalization of N-chlorobenzamides with 1,3-diynes via regioselective (4 + 2) annulation for the synthesis of isoquinolones under redox-neutral conditions at room temperature. This represents the first example of C-H functionalization of N-chlorobenzamides using an inexpensive and commercially available [Ru(p-cymene)Cl2]2 catalyst. The reaction is operationally simple, works in the absence of any silver additives, and is also applicable to a broad range of substrates with good functional group tolerance. The synthetic utility of the isoquinolone is demonstrated for the synthesis of bis-heterocycles consisting of isoquinolone-pyrrole and isoquinolone-isocoumarin scaffolds.

Free Amine-Directed Ru(II)-Catalyzed Redox-Neutral [4 + 2] C-H Activation/Annulation of Benzylamines with Sulfoxonium Ylides.

An external oxidant free Ru(II)-catalyzed C-H functionalization/annulation of primary benzylamines with sulfoxonium ylides has been developed for the synthesis of isoquinolines. The reaction utilizes free amine as a directing group, which is generally considered to be a poor directing group. This work presents the first example of Ru-catalyzed C-H functionalization of benzylamines under redox-neutral conditions. The detection of the amine-directed ruthenacyclic intermediate using high-resolution mass spectrometry corroborated the involvement of free amine as a directing group.

Cp*Co(III)-catalyzed C-H amination/annulation cascade of sulfoxonium ylides with anthranils for the synthesis of indoloindolones.

Cp*Co(iii)-catalyzed [4+1] annulation of sulfoxonium ylides with anthranils has been developed for the synthesis of indole-indolone scaffolds. The dual functionality of anthranils was exploited, wherein the nitrogen has been used for C-H amination and the aldehyde group was utilized in the subsequent intramolecular aldol condensation to furnish the corresponding annulated products.

Catalyst- and reagent-free 1,6-hydrophosphonylation of p-quinone methides: a practical approach for the synthesis of diarylmethyl phosphine oxides.

We developed a catalyst-, reagent-, and additive-free protocol with 100% atom economy for the synthesis of diarylmethyl phosphine oxides via 1,6-hydrophosphonylation of p-quinone methides using water as a green solvent. The reaction showed broad scope with excellent functional group tolerance. The practicability of this method was demonstrated by carrying out the reaction on the gram scale whereby product was obtained in high yield by the filtration technique avoiding chromatographic purification.

Cp*Ir(III)-Catalyzed C-H/O-H Functionalization of Salicylaldehydes for the Synthesis of Chromones at Room Temperature.

Herein, we report Cp*Ir(III)-catalyzed C-H/O-H-bond functionalization of salicylaldehydes with α-diazocarbonyl compounds for the synthesis of chromones under redox-neutral conditions. The reaction proceeds at room temperature and displays excellent functional group tolerance along with high yields of the corresponding products. The developed reaction protocol was successfully applied for the late-stage functionalization of estrone derivative.

Cp*Ir(iii)-catalyzed C-H/N-H functionalization of sulfoximines for the synthesis of 1,2-benzothiazines at room temperature.

The first Cp*Ir(iii)-catalyzed C-H/N-H bond functionalization of sulfoximines with α-diazocarbonyl compounds has been developed for the synthesis of 1,2-benzothiazines under redox-neutral conditions. The reactions proceed at room temperature with excellent functional group tolerance and high yields without the requirement of any silver additive.

Cp*Co(III)-Catalyzed C-H Functionalization Cascade of N-Methoxyamides with Alkynedione for the Synthesis of Indolizidines.

Cp*Co(III)-catalyzed C-H functionalization cascade of N-methoxyamides with alkynedione has been reported for the synthesis of indolizidine scaffolds under redox-neutral conditions. The reaction displays broad functional group tolerance along with excellent yield. The reaction proceeds with kinetically relevant C-H bond activation through carboxylate assistance with excellent diastereoselectivity and complete opposite selectivity with respect to alkyne insertion.

Total Synthesis of Lamellarin D Trimethyl Ether, Lamellarin D, and Lamellarin H.

Total syntheses of three different lamellarins have been accomplished using a Ru(II)-catalyzed (3 + 2) annulation strategy to construct the central pyrrole ring. The striking features of this synthesis are the use of PEG-400 as a green solvent for the (3 + 2) annulation reaction and multiple catalytic reactions with excellent overall yield. The present route also enables the synthesis of various lamellarin analogues devoid of a B ring.

Cp*Co(III)-Catalyzed C-H/N-N Functionalization of Arylhydrazones for the Synthesis of Isoquinolines.

Cationic Co(III)-catalyzed C-H/N-N bond functionalization of arylhydrazones with internal alkynes has been developed for the synthesis of isoquinoline derivatives. The arylhydrazones are easy to prepare and require inexpensive and commercially available hydrazine hydrate. The reaction works well with a variety of internal alkynes and arylhydrazones and offers broad scope, good functional group tolerance, and high yields under redox-neutral conditions in the presence of air.

Cobalt(III)-catalyzed C-H halogenation of 6-arylpurines: facile entry into arylated, sulfenylated and alkoxylated 6-arylpurines.

Cobalt-catalyzed C-H halogenation of biologically important 6-arylpurines has been reported under mild conditions with good functional group tolerance. The regioselective halogenation of thiophenes, as well as the synthetic applicability of the present protocol for the synthesis of arylated, sulfenylated and alkoxylated purine analogues was also demonstrated.

Cobalt-catalyzed C-H cyanation of (hetero)arenes and 6-arylpurines with N-cyanosuccinimide as a new cyanating agent.

A cobalt-catalyzed C-H cyanation reaction of arenes has been developed using N-cyanosuccinimide as a new electrophilic cyanating agent. The reaction proceeds with high selectivity to afford monocyanated products with excellent functional group tolerance. Substrate scope was found to be broad enough to include a wide range of heterocycles including 6-arylpurines.

Catalytic cyanation of aryl iodides using DMF and ammonium bicarbonate as the combined source of cyanide: a dual role of copper catalysts.

Cu(II)-catalyzed cyanation of aryl iodides has been developed using DMF and ammonium bicarbonate as the combined source of cyanide. It is assumed that copper is involved both in the generation of "CN" units from DMF-ammonia and in the cyanation of aryl halides. A range of electron-rich and fused (hetero)aryl iodides underwent cyanation resulting in moderate to good yields.

Formal total synthesis of palmerolide†A.

A formal total synthesis of the 20-membered marine macrolide, palmerolide A from chiral pool tartaric acid is described. Elaboration of a γ-hydroxy amide, which is derived from the desymmetrization of tartaric acid amide, and Boord olefination are the pivotal reactions employed for the synthesis of the chiral building blocks, and Stille coupling and ring-closing metathesis (RCM) are used to assemble the macrolactone.

Enantioselective formal synthesis of palmerolide A.

Enantioselective formal synthesis of macrolactone palmerolide A, a polyketide marine natural product, is described. Key strategies in the synthesis include the oxidative furan ring-opening of a chiral furyl carbinol for the installation of the 1,4-dienol core and a Jung nonaldol-aldol reaction for the dienamide core.