Exclusive 5-exo-dig Hydroarylation of o-Alkynyl Biaryls Proceeding via C–H Activation Pathway

Intramolecular palladium-catalyzed hydroarylation of alkynes was first reported by Fujiwara in 2000.^1a–c Shortly after, other transition-metal-^2,3 and Lewis acid-catalyzed⁴ versions of this transformation emerged, and the method quickly became a powerful tool for the construction of carbo- and heterocycles. This transformation is most efficient with electron-rich aromatic rings, hence, not surprisingly, a Friedel–Crafts-type electrophilic aromatic substitution path has been generally accepted as the most probable mechanism for this reaction.^3,5 Thus, one of the representative examples reported by Fürstner^3b shows that o-alkynyl biaryls possessing an electron-rich aryl ring in the presence of transition metals undergo a facile intramolecular hydroarylation reaction. Reaction proceeds via electrophilic activation of the triple bond followed by exclusive or predominant 6-endo-dig⁶ carbocyclization, leading to the phenanthrene frameworks (eq 1). Herein, we wish to report the first example of the Pd-catalyzed exclusive 5-exo-dig hydroarylation of electron-neutral and electron-deficient o-alkynyl biaryls proceeding via a C–H activation path (eq 2).

(1)

(2)

We turned our attention to the palladium-catalyzed intramolecular hydroarylation of alkynes, which proceeds under ligandfree acidic conditions and produces the 6-endo-dig cyclization products.^1,2 Although a C–H activation motif was initially proposed,¹ an electrophilic aromatic substitution path has been suggested later as the most probable path for this transformation.^3,5 We hypothesized that switching from acidic to neutral reaction conditions may affect the reaction mechanism. To this end, cyclization of o-alkynyl biaryls 1 in the presence of a palladium catalyst/phosphine ligand combination has been investigated. We were pleased to find that 2-(phenylethynyl)biphenyl (1a) in the presence of the Pd(OAc)₂/dppf system in toluene at 120 °C underwent smooth 5-exo-dig carbocyclization to produce fluorene 2a in 70% GC yield! Moreover, switching to bulkier 1,1′-bis(diisopropylphosphino)ferrocene allowed us to obtain 2a in nearly quantitative yield (Table 1, entry 1).

Table 1. Pd-Catalyzed Hydroarylation of o-Alkynyl Biaryls^a.

#	Product	Time, h Yield, %b	#	Product	Time, h Yield, %b
1		2.5	10		3.0
		98			93
2		3.0	11		3.0
		95			94
3		1.5	12		4.0
		96			89
4		2.0	13		5.0
		96			87
5		0.5	14		1.0
		79			85
6		3.0	15		1.5
		92			77
7		4.0	16		24
		95			47
8		1.0	17		48
		93			30
9		0.5	18		6.0
		98			86

^aReaction conditions: 0.5 mmol of 1, 0.025 mmol of Pd(OAc)₂, 0.035 mmol of 1,1′-bis(diisopropylphosphino)ferrocene, 1 mL of toluene, 120 °C.

^bIsolated yields.

With these conditions in hand, the generality of the cyclization has been studied. It was found that a variety of o-alkynyl biaryls bearing electron-neutral, and even more surprisingly electron-deficient aryl rings, underwent highly effective 5-exo-dig carbocyclization to give 9-benzylidene-9H-fluorene derivatives 2a–2j in good to excellent yields (Table 1). Various groups, such as F, NO₂, CO₂Me, and OMe, were perfectly tolerated under these reaction conditions. Importantly, in contrast to the previously reported intramolecular hydroarylation of alkynes,^1–5o-alkynyl biaryls, possessing electron-deficient substituents (R² = F, CF₃, CO₂Me), underwent substantially faster cyclization compared to that for the o-alkynyl biaryls bearing electron-neutral aryl rings. Substrates with electron-deficient groups at the alkyne moiety (R¹) reacted slightly faster, though no significant effect of the nature of R¹ on the reaction yield has been observed (Table 1, entries 5, 7, 8, and 11). Remarkably, cyclizations of all compounds 1a–r proceeded with high cis-selectivity, providing geometrically pure fluorenes 2a–r (Table 1).⁷

In order to better understand this transformation, we performed kinetic isotope effect studies. Experiment demonstrated that this cyclization exhibits significant intermolecular (k_H/k_D = 2.6) and intramolecular (k_H/k_D = 3.5) hydrogen/deuterium kinetic isotope effect (Scheme 1).⁸ These data are in a range of the isotope effects observed for the reactions proceeding via the Pd-catalyzed aromatic C–H activation pathways.^9,10 Accordingly, we envision that this reaction proceeds via orthopalladation of intermediate 1 to give 8 (Scheme 2), which, upon migratory insertion to a triple bond, gives vinylpalladium species 9. Protiodepalladation of 9 produces 2 and regenerates the catalyst. An alternative path may involve palladium hydride species 10, which, via consecutive carbopalladation of the triple bond and reductive elimination, would furnish the reaction product. However, on the basis of the substantial loss of deuterium observed in the cyclization of 4,¹¹ this pathway was considered to be less likely. Possible involvement of the Friedel–Crafts mechanism (Scheme 3) was ruled out based on the higher propensity of the electron-deficient alkynes toward this hydroarylation reaction, as well as on the high values of the kinetic isotope effects (Scheme 1).¹² The stereochemistry of the obtained products 2 also contradicts with the electrophilic pathway. Indeed, based on the literature reports,^1–5 Friedel-–Crafts cyclization of 1 is expected to proceed in the trans-fashion to produce (Z)-fluorene 2′ (Scheme 3). In contrast, the Pd-catalyzed hydroarylation, described herein, produces fluorine 2¹³ with alternative geometry of the double bond apparently, via a cis-cyclization path (Table 1, Scheme 2).

Scheme 1. Kinetic Isotope Effect Studies.

Scheme 2. Proposed Mechanism.

Scheme 3. Electrophilic Path for Cyclization of 1.

In conclusion, we have demonstrated the first example of the palladium-catalyzed exclusive 5-exo-dig hydroarylation. This method allows for efficient cyclization of a variety of o-alkynyl biaryls possessing electron-neutral and electron-deficient aryl rings into the corresponding fluorenes. On the basis of the high efficiency of the cyclization of substrates bearing electron-deficient aryl rings, the observed high values of kinetic isotope effects, as well as on the exclusive cis-selectivity of cyclization, a mechanism involving the C–H activation motif has been proposed for this transformation.