Divergent Strategies for the π-Extension of Heteroaryl Halides Using Norbornadiene as an Acetylene Synthon

Jeong, Siyeon; Kim, Eunmin; Kim, Minkyu; Hwang, Ye Ji; Padhi, Birakishore; Choi, Jonghoon; Lee, Yunho; Joo, Jung Min

doi:10.1021/acs.orglett.0c03732

Cited by 12 publications

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“…Recently, we demonstrated that the incorporation of NBD as an acetylene synthon led to the benzannulation of five‐membered heteroarenes through a Pd‐catalyzed cyclization followed by a retro‐Diels‐Alder reaction (Figure 2B, top) [12] . In addition to the Pd‐catalyzed 1:2 coupling reaction between heteroaryl halides and NBD, a 2:1 coupling reaction was developed to synthesize polycyclic heteroaromatic systems (Figure 2B, middle) [13] . Consequently, it was considered that C4(C7)‐substituted benzofused heteroarenes could arise from alkynyl norbornene derivatives, through a simultaneous retro‐Diels‐Alder reaction of the norbornene ring, which results in π‐conjugated structures (Figure 2B, bottom).…”

Section: Figurementioning

confidence: 99%

“…[12] In addition to the Pd-catalyzed 1:2 coupling reaction between heteroaryl halides and NBD, a 2:1 coupling reaction was developed to synthesize polycyclic heteroaromatic systems (Figure 2B, middle). [13] Consequently, it was considered that C4(C7)-substituted benzofused heteroarenes could arise from alkynyl norbornene derivatives, through a simultaneous retro-Diels-Alder reaction of the norbornene ring, which results in π-conjugated structures (Figure 2B, bottom). This approach provides increased accessibility to the cyclization precursors prepared by Pd-catalyzed three-component reactions, using readily available heteroaryl halides, NBD, and terminal alkynes in one step (Scheme 1).…”

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Pd‐Catalyzed Cyclization of Alkynyl Norbornene Derivatives for the Synthesis of Benzofused Heteroarenes

et al. 2021

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Modular approaches, which allow a systematic variation of heteroaromatic cores and substituents, are crucial for the development of heteroaromatic drug candidates and organic functional materials. A new strategy involving the cyclization of heteroarenes tethered with alkynes through a norbornene bridge was developed. The precursors were readily prepared by a three‐component coupling process of heteroaryl halides, norbornadiene, and terminal alkynes. The Pd catalytic system derived from Pd(OAc)2 and 2‐(pyrazol‐1‐yl)pyridine transformed a variety of five‐membered heteroarenes to the corresponding benzofused products, including (di)benzothiophene, indazole, carbazole, indole, and benzofuran, with aryl and alkyl substituents at the C4(C7) position. During the cyclization process, the norbornene ring underwent a retro‐Diels‐Alder reaction, serving as an acetylene synthon. This approach was used to synthesize naphthalene derivatives from electron‐rich arenes, demonstrating its versatility in the annulation of (hetero)aromatic rings.

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Pd‐Catalyzed Cyclization of Alkynyl Norbornene Derivatives for the Synthesis of Benzofused Heteroarenes

et al. 2021

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“…75 The use of bromopyrazoles and TBAI was optimal for the three-component reaction with 1,3-azoles (Scheme 20). 3 Similar to the 1:2 coupling, the addition of two heteroarenes to NBD was exo-and syn-selective. Therefore, the presence of two heteroarene rings on the same side creates a steric effect, and epimerization readily occurs to afford the corresponding trans-isomer in N,N-dimethylacetamide (DMA).…”

Section: Three-component Couplingmentioning

confidence: 95%

“…M. Jeong, S. Kim, E. Kim, M. Hwang, Y. J. Padhi, B. Choi, J. Lee, Y. Joo, J. M. Org. Lett.20202296709676 …”

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“…The effect of the position of the halide was also evident in the three-component reaction (Scheme 19). 3 Although the Pd− NBE adduct should be coupled with 1,3-azoles for the successful three-component reaction, the formation of the palladacycle inhibits this pathway. Instead, it leads to the oxidative addition of the iodopyrazole that eventually generates a tricyclic fused ring with two pyrazole units.…”

Section: Three-component Couplingmentioning

confidence: 99%

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Transition-Metal-Catalyzed Divergent C–H Functionalization of Five-Membered Heteroarenes

Jeong

Joo

2021

Acc. Chem. Res.

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Metrics & MoreArticle Recommendations CONSPECTUS: Conversion of common reactants to diverse products is a key objective of organic syntheses. Recent developments in transition-metal-catalyzed C−H functionalization have increased the interest in such conversions. Both the position of functionalization and the type of the substituent can be varied, allowing systematic diversification of common structural cores. Because five-membered heteroarenes (pyrazole, imidazole, thiazole, pyrrole, and thiophene) are ubiquitous in pharmaceuticals and organic functional materials, the selective C−H functionalization of these heterocyclic cores facilitates both the optimization of their physicochemical properties and streamlining of their preparation. In addition, the parent forms of these heterocycles are more readily available and inexpensive than any other derivatives of their families. Hence, their nondirected C−H functionalization is highly desirable. Although various regioselective reactions have been developed, many of them target the most reactive site; hence, except for some extensively studied arylation reactions, regiodivergent functionalization of two or more sites has been limited. This Account summarizes our work on the regiodivergent, nondirected C−H functionalization of five-membered heteroarenes with alkenes and alkynes. These unsaturated hydrocarbons are readily available, and all the composing atoms can be incorporated into products with high atom efficiency. Furthermore, the installed alkenyl groups can be transformed to other useful functional groups.To achieve comparable selectivity to that observed in the traditional reactions of these heteroarenes with highly electrophilic reagents and strong bases, a transition metal catalytic system was carefully devised with a more streamlined synthesis. A judicious choice of metals, ligands, acid and base additives, and solvents orchestrates divergent transformations using electronic and steric effects of the heteroarenes. Although C−H cleavage is a rate-and site-selectivity-determining step in most cases, the subsequent steps involving the formation of C−C bonds are often more critical than the other steps. For the C−H cleavage step, modulating the electronic properties of catalysts to make them electrophilic allows preferential alkenylation at the nucleophilic position. In addition, the presence of an internal base that can be exploited for concerted metalation−deprotonation of the acidic C−H bond offers alternative regioselectivity. Furthermore, we developed our own ligand system based on a conformationally rigid pyrazolonaphthyridine scaffold that enables aerobic C−H alkenylation reactions with steric control. We showed that the electronic and steric effects of heteroarenes can be further extended to chemodivergent reactions with norbornene derivatives. Depending on whether the palladacycle is formed, heteroarenes selectively undergo 1:2 annulation with norbornene derivatives and threecomponent reactions with other azoles through the Pd−norbornene adducts or Catell...

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C–H Functionalization as an Imperative Tool Toward Multicomponent Synthesis and Modification of Heterocycles

Festa

Voskressensky

2021

Multicomponent Reactions Towards Heterocycles

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Divergent Strategies for the π-Extension of Heteroaryl Halides Using Norbornadiene as an Acetylene Synthon

Cited by 12 publications

References 59 publications

Pd‐Catalyzed Cyclization of Alkynyl Norbornene Derivatives for the Synthesis of Benzofused Heteroarenes

Pd‐Catalyzed Cyclization of Alkynyl Norbornene Derivatives for the Synthesis of Benzofused Heteroarenes

Transition-Metal-Catalyzed Divergent C–H Functionalization of Five-Membered Heteroarenes

C–H Functionalization as an Imperative Tool Toward Multicomponent Synthesis and Modification of Heterocycles

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