Unexpected ortho-Heck Reaction under the Catellani Conditions

Abstract

An unexpected ortho-Heck reaction has been discovered during the study of palladium/norbornene (Pd/NBE) catalysis. Under the Catellani reaction conditions in the presence of lithium salts and olefins, Heck coupling takes place at the ortho position instead of the commonly observed ipso position; meanwhile, a norbornyl group is introduced at the arene ipso position. Systematic deuterium labeling and crossover experiments suggest an unusual 1,4-palladium migration/intramolecular hydrogen transfer pathway. The knowledge gained in this study could provide insights for the future development of the Pd/NBE catalysis.

Graphical Abstract

Palladium/norbornene (Pd/NBE) cooperative catalysis,¹ originally discovered by Catellani,² has emerged as a versatile and useful means to achieve the vicinal difunctionalization of arenes over the past two decades. In a typical Catellani reaction, through forming an aryl–norbornyl–palladacycle (ANP) intermediate, an electrophile is coupled at the arene ortho position, and a nucleophile or an olefin reacts at the ipso position.³ In particular, the use of a Heck reaction, the coupling with an olefin, for ipso-functionalization is one of the most extensively studied reaction modes in Pd/NBE catalysis (Scheme 1a). However, during our recent exploration of a potential ortho-borylation reaction, an unexpected ortho (instead of ipso) Heck product was observed as the major product under typical Catellani conditions, except when using catecholboryl chloride as the electrophile and cesium acetate as the base (eq 1). This result is unusual because olefins, such as acrylates, have not been known as electrophiles in the Pd/NBE catalysis.¹ In addition, the careful analysis of other Catellani-type reactions also revealed the formation of similar side products, although in small quantities (vide infra, Scheme 4b).⁴ The intriguing reactivity and site-selectivity “switch” motivated us to better understand this unusual reaction, which is anticipated to benefit the future development of the Pd/NBE catalysis. Herein we describe the discovery, mechanistic study, and scope of the Pd-catalyzed, NBE-mediated, ortho-Heck reaction (Scheme 1b).

Scheme 1.

ortho-Heck versus Typical Catellani Reaction

Scheme 4. Substrate Scope of the Transformation^a.

^aUnless otherwise noted, all reactions were carried out with 1 (0.2 mmol), 2 (0.24 mmol), and 3 (0.2 mmol) in 2.0 mL of DMF for 18 h; all yields are isolated yields. ^bCarried out with 1a (1.0 mmol), 2a (1.2 mmol), and 3a (1.0 mmol) in 10.0 mL of DMF for 18 h. ^cCarried out with 1a (0.1 mmol), 2h (0.12 mmol), and 3a (0.1 mmol) in 1.0 mL of DMF for 18 h; NMR yield reported. ^dSolid-state structure of 4d with thermal ellipsoids drawn at 50% probability. For clarity, the norbornyl enantiomer and hydrogen atoms have been removed.

Our study began with optimizing the reaction conditions using aryl iodide 1a as a model substrate (Table 1). A high yield of the ortho-Heck product (4a) was obtained using Pd(dba)₂ and trifurylphosphine as the metal/ligand combination (entry 1) and Li₂CO₃ as the base. The use of Bu₂BOTf and LiBr as additives significantly increased the yield of the reaction, although their roles are not essential for product formation (entries 1–4). It could be possible that bromide serves as an X ligand, thus preventing the carbonate anions, which can facilitate the formation of the ANP intermediate (vide infra, the mechanism discussion),¹ from coordinating to palladium. As expected, in the absence of the Pd catalyst, no ortho-Heck product was observed (entry 5). Using Pd(OAc)₂ instead of Pd(dba)₂ decreased the yield (entry 6). Li₂CO₃ was found to be essential for this transformation because using K₂CO₃ or Cs₂CO₃ instead resulted in significantly diminished yields under the current conditions (entries 7–9). The potassium and sodium bases were, however, found to perform somewhat better without Bu₂BOTf present in the reaction. (See the Supporting Information.) DMF proved to be a better solvent, whereas using other solvents, such as 1,4-dioxane or toluene, gave poor results (entries 10 and 11). Finally, the addition of n-BuI as an electrophile could still afford 42% of the ortho-Heck product without furnishing the regular Catellani product (entry 12).

Table 1.

Selected Optimization of the Reaction Conditions^a

^aUnless otherwise noted, all reactions were carried out with 1a (0.1 mmol), 2a (0.12 mmol), and 3a (0.1 mmol) in 1.0 mL of DMF for 18 h.

^bNMR yields determined using 1,1,2,2-tetrachloroethane as the internal standard. n.d.= not detected.

^cCatellani product 4ab was not observed, and 25% 1a was recovered.

Regarding the reaction mechanism, two pathways could be proposed for the formation of the ortho-Heck product (Scheme 2). Path a involves first forming the ANP intermediate via ortho-C–H palladation,⁵ followed by migratory insertion (or conjugate addition) of the aryl group to the olefin. The following β-hydrogen elimination and C–H reductive elimination steps could give the ortho-Heck product. Alternatively (path b), a 1,4-palladiuim shift⁶ could take place instead of forming the ANP intermediate, and the resulting aryl–palladium species could then undergo a typical Heck reaction pathway to afford the product.

Scheme 2.

Possible Reaction Pathways

To differentiate the two mechanisms, a systematic deuterium labeling study was carried out (Scheme 3). First, when deuterated acylate 2a-d₃ prepared via Ackermann’s method⁷ was used, no deuterium incorporation was observed at the C3 position of the norbornyl group (Scheme 3a). This result strongly disfavors path a, in which a hydride would be anticipated to transfer from the acrylate β position to the norbornyl C3 position. In addition, the C3 hydrogen was found to be not originating from a proton source, as the addition of deuterated methanol or acetic acid led to no deuteration on the norbornyl moiety (Scheme 3b). This excludes a pathway involving ANP formation, followed by protonation of the norbornyl group. On the contrary, using fully deuterated 1-iodonaphthalene (1i-d₇) resulted in complete deuteration at the C3 position, even in the presence of various proton sources (Scheme 3c). Additionally, both the deuterium and the aryl group were found to be located at the norbornyl exo positions, as characterized by various 2D-NMR experiments. These results indicate that the C3 hydrogen originally comes from the arene substrate and could migrate through a 1,4-metal shift.⁸

Scheme 3. Deuterium Labeling Studies^a,b.

^aUnless otherwise noted, all reactions were carried out with 1i or 1i-d₇ (0.1 mmol), 2a (0.12 mmol), and 3a (0.1 mmol) in 1.0 mL of DMF for 18 h. NMR yields were determined using 1,1,2,2-tetrachloroethane as the internal standard. ^bNMR (¹H or ²H) analysis was used to determine deuterium incorporation on the norbornyl ring.

Moreover, an isotope crossover experiment was conducted with a 1:1 ratio of deuterated 1i-d₇ and nondeuterated substrate 1a (Scheme 3d). The absence of deuterium crossover supports an intramolecular hydrogen transfer from the aryl ortho position to the norbornyl C3 position. Taken together, all of the mechanistic data obtained are consistent with the 1,4-palladium shift pathway (path b).⁹

The scope and functional group tolerance of the transformation were investigated next (Scheme 4). First, olefins with a strongly electron-withdrawing group, such as an ester, amide, ketone, nitrile, or sulfone, can all be coupled in good yield (4a–g).¹⁰ The reaction is also scalable; on a 1 mmol scale, product 4a was isolated in 75% yield. Interestingly, less electron-deficient styrene also provided the desired product (4h), albeit in 20% yield. Additionally, the structure of product 4d was unambiguously elucidated by X-ray crystallography. Both naphthalene- (4i) and quinoline-based (4j) substrates delivered the desired product smoothly. In general, electron-donating substituents para to the iodide (4a, 4k, 4l) gave higher yields, although electron-neutral (4m, 4n) and -poor (4o, 4p) arenes also delivered their corresponding ortho-Heck products. Small ortho substituents, such as –OMe (4q) and –F (4r), can also be tolerated. Interestingly, having fluoride as the ortho substituent (4r) resulted in a sequential double 1,4-migration side-product (4ra), in which two NBE insertions took place before the reaction with acrylate. Note that a similar multiple sequential NBE insertion has been previously observed in a Rh-catalyzed system.¹¹ In the absence of an ortho substituent, the ortho-Heck product (4s) can still form. Additionally, an alkenyl iodide (4t) was shown to be a competent substrate, producing a satisfying 59% yield of the desired product. Moreover, NBEs with substitutions at the five- and six-positions are suitable coupling partners (4u–v). Not surprisingly, unsymmetrical dicyclopentadiene (4u) gave an inseparable mixture of alkene regio-isomers. Under the current reaction conditions, 2,5-norbornadiene was unable to deliver the corresponding product, only producing the ipso-Heck side product (4w; see the Supporting Information for other unsuccessful substrates).

Finally, the competition between the ortho-Heck and a typical Catellani ortho-alkylation reaction was studied (Scheme 5). In the absence of LiBr and Bu₂BOTf, but with the addition of n-butyl iodide as an electrophile, carbonate bases with different metal cations were surveyed (Scheme 5a). Whereas similar yields of the ortho-Heck product were obtained in all cases, the use of Cs₂CO₃ resulted in a significantly higher yield of the Catellani product (4ab). This result indicates that Cs₂CO₃ is indeed a better base to promote the formation of the ANP intermediate, which is consistent with the fact that a majority of Catellani reactions published to date prefer using the cesium base.¹ On the contrary, when running the reaction with substrate 1a under similar conditions reported by Catellani and Cugini,^3a the ortho-Heck product (4a) was still observed and, in particular, formed in a higher yield at a higher reaction temperature (Scheme 5b).

Scheme 5. ortho-Heck versus Catellani Reaction^a.

^aUnless otherwise stated, all reactions were carried out with 1a (0.1 mmol), 2a (0.12 mmol), and 3a (0.1 mmol) in 1.0 mL of DMF for 18 h. NMR yields were determined using 1,1,2,2-tetrachloroethane as the internal standard.

In summary, a noncanonical Pd-catalyzed, NBE-mediated, ortho-Heck reaction has been identified and explored during a study of the Catellani reaction. Deuterium labeling studies suggest a 1,4-Pd migration reaction pathway, leading to olefin coupling at the arene ortho position instead of the commonly observed ipso position. Such a reaction mode appears to be quite general for diverse aryl iodides, olefins, and NBEs. The knowledge gained here should have implications on developing more efficient Pd/NBE catalytic systems or new remote C–H functionalization methods¹² by minimizing or promoting such a 1,4-metal migration process.