The Hydroarylation Reaction—Scope and Limitations

The synthetic potential of stereoselective, palladium-catalyzed hydro(het)arylation reactions of bi-, tri- and tetracyclic (hetero)alkenes in the presence of phospines and arsines as highly efficient ligands was studied. The mechanism of this reductive Heck reaction becomes more complex in the case of benzonorbornenes. Hydroarylation of diazabicyclo-[2.2.1]heptenes provides a stereoselective access to aryldiaminocyclopentanes. Electron-deficient arylpalladium complexes shift the reaction towards the product of a formal 1,2-hydrazidoarylation reaction of 1,3-cyclopentadiene by a stereoselective C-N cleavage. Due to steric reasons, rigid bicyclo[2.2.2]octenes react slower in hydroarylation reactions than the corresponding bicyclo[2.2.1]heptenes. The more flexible bicyclo[4.2.2]decene system already tends to undergo domino-Heck reactions, even under reductive conditions. When a tetracyclic cis-allylcyclopropane is carbopalladated in the presence of formates, the neighboring cyclopropane ring is attacked in the first reported example of a π,σ domino-Heck reaction.


Introduction
The development of new methodologies for stereoselective C-C coupling reactions in order to synthesize complex structures from easily available precursors has attracted much interest in contemporary synthetic chemistry. Among them, the transition metal-catalyzed reactions, especially the Heck and related reactions have become more and more important during the last two decades [1][2][3][4][5][6][7][8]. This palladium-catalyzed arylation provides high yields with open-chain and cyclic alkenes. In the case of rigid bicyclic alkenes a reductive variant appears feasible. The Catellani reaction uses norbornene as a template for ortho-substitution [9]. Since the first catalyzed reductive phenylation of norbornene was published in 1989 [10,11] the great synthetic potential of the hydroarylation reaction with bicyclic alkenes, including its asymmetric variant with bicyclic alkenes for the one-step construction of up to four asymmetric centers has prompted us to further investigations [12][13][14][15][16].

Results and Discussion
Starting from an open-chain alkene 2 and a halogenated arene 1 three reaction steps lead to the stereoselective formation of a styrene derivative in the presence of a stabilizing ligand L. The first step is a syn-carbopalladation of the alkene giving 4, followed by rotation around the central single bond in 5 to allow the final step, the syn-dehydropalladation giving a styrene derivative 3. In the presence of chiral ligands L 2 *, such as sugar-based, chiral phosphite-oxazolines the Heck reaction of monocyclic alkenes like cyclopentene (6) proceeds with high regio-and enantioselectivity generating one asymmetric center [17] (Scheme 1). Palladium-catalyzed C-C coupling reactions of alkenes: * Rigid bicyclic alkenes 8 cannot be arylated this way as the final syn-dehydropalladation of intermediate 9 is not feasible due to geometrical constraints; inter-or intramolecular consecutive reactions of the carbopalladation product 9 such as reduction or alkynylation (10, 11) work well [7]. Many applications for the reductive variant of the Heck reaction are known and the reductive arylation of bicyclic alkenes such as norbornene and its aza-or oxa-analogues 8 using palladium catalysts has been well studied [18] (Scheme 2). Both, the carbopalladation to yield 9 and the consecutive substitution reactions proceed with complete exo-diastereoselectivity. This was a very important finding for the stereoselective synthesis of the highly bioactive alkaloid epibatidine [19], the parent amine of 13. Epibatidine, which is a lead in the development of new analgesics, is accessible by hydroarylation of the 7-azabicyclo-[2.2.1]heptene system with 6-chloro-3-iodopyridine. In the presence of chiral ligands, three asymmetric centers can be controlled. The epibatidine enantiomers show different biological activities. For biological testing, analogues modified in the 7-position such as 12, 14 have been synthesized. The enantiomeric excesses achieved are strongly dependent on the ligands employed. The P,P-ligand (R)-BINAP (15) is well suited for the synthesis of the epibatidine derivative 13 (81% e.e.), whereas the P,N-ligand (S)-Ms-Valphos 16 proved to be the best ligand for the hydrohetarylation of the carbon analogue norbornene. Both ligands give low enantiomeric excesses in case of the oxa analogue, though (Table 1). The reductive Heck arylation can be extended to the more lipophilic benzoannelated epibatidine analogues. They are easily accessible by a Diels-Alder reaction of cyclopentadiene, furan or Nmethoxycarbonylpyrrole (17) with benzyne, generated from the diazotation product of anthranilic acid (18). Using triphenylphosphine as a ligand, the mechanism of the hydroarylation of 19 becomes more complex (Scheme 3). When triphenylphosphine is employed as a ligand in Heck reactions, a two-fold phosphinecoordinated palladium complex is known to be the catalytically active species. In the case of the hydroarylation of 19, though, the yield of product 21 increases from 18 to 49% in parallel to an increase of the ligand to palladium ratio from 2:1 to 20:1 [20]. This surprising result can only be rationalized by proposing a rather stable palladium complex between an aromatic π-bond and the nitrogen lone pair. NMR spectroscopic investigations indicate that the nitrogen inversion is already fast at room temperature. A higher amount of phosphine ligand increases the ligand pressure on the palladium, thus destabilizing the proposed complex formation on the "wrong" inner double bond of the bicycle and giving the active palladium species a fair chance to approach the free olefinic side of the azatricyclic system. Two side products are formed, a formal nitrene-extrusion product 22 of the initial carbopalladation product of the pyridylpalladium iodide to 19 and the product of a selective reduction of the chloroiodopyridine 20 giving 23. Additionally, the yield of 21 is strongly dependent on the nucleophilicity of the nitrogen: apparently, only electron-withdrawing groups such as the ester function of 19 prevent strong complexation and concomitant deactivitation of the palladium. While the parent system still gives the hydroarylation product in 28% yield, with an N-methyl-substituent the corresponding coupling product cannot be isolated even in traces. The argument of competitive N-complexation can also be applied when the unsuccessful reductive coupling of the pyridinosubstituted analogue of 19 is discussed. The better stabilizing ligand triphenylarsine leads to the best yield of 21 (75%) [18,20].
At that point we became interested in the scope and limitations of reductive Heck reactions of (bishetero)bicyclic alkenes. 2,3-Diazabicyclic alkenes are of special interest as the N-N and C-N bond represent an internal point of cleavage. The diazabicyclic alkene 26 is easily accessible by a Diels-Alder reaction of cyclopentadiene with diethyl azodicarboxylate (DEAD). Its reductive C-C coupling reaction with (het)aryl halides in the presence of an in situ generated palladium catalyst, stabilized by triphenylarsine, afforded exclusively the exo-hydroarylation products 27 and 28 in good yields [21] (Scheme 4). Encouraged by this result we tried the hydroarylation of the sterically more encumbered and more rigid tetracyclic Diels-Alder adduct 31 of 1,3-cyclopentadiene with the highly reactive azodienophile 1,4-phthalazinedione [22]. The reaction of 31 with iodobenzene in the presence of triphenylarsine as a ligand and additionally sodium fluoride at room temperature led to 3% of the expected hydroarylation product 34, only, while 67% of 35 was formed as the product of a C-N cleavage reaction. Formally, the formation of 35 is the result of a 1,2-hydrazidoarylation on the primarily employed 1,3-cyclopentadiene (Scheme 5). The yield of the hydroarylation products under standard conditions is highly dependent on the rigid tricyclic system used: the PTAD cycloadduct of 1,3-cyclopentadiene 36 is best suited, and the yield drops by a factor of almost three in the case of the diazabicyclo[2.2.2]octene system 38, due to both the lower reactivity of the less strained double bond and the steric interactions with both CH-groups. When the C=C double bond is covered by a cyclopropane ring as in compound 40, exo-attack is no longer feasible (Scheme 6).

Scheme 6.
Hydroarylation of the cycloadducts of PTAD to cyclic dienes: dependence on the ring size.
The key diazabicyclic systems become more flexible when a larger cycle is used, e.g. 1,3-cyclooctadiene (1,3-COD). As an exception, in case of the PTAD cycloadduct 41 a twofold Heck reaction takes place in good yield to give 44 with an intermediate isomerization of the remaining anti-Bredt double bond from 42 to 43. The structure of 44 was confirmed by an X-ray crystal structure analysis. Even under reductive conditions no hydroarylation product could be isolated. Therefore, in general the reductive elimination of hydridopalladium iodide to give 42 is apparently much faster than the reductive cleavage of the primarily formed carbopalladation product in the course of a hydroarylation reaction (Scheme 7). Inter-or intramolecular sequential insertion reactions of a carbopalladation product into a strained cyclopropane C-C σ-bond were unknown for a long time. The easily accessible endo,exobishomobarrelene 44 represents a cis-allylcyclopropane model compound which can be attacked from one side only, due to the shielding by the second cyclopropane ring (Scheme 8). Treatment of 45 with iodobenzene under standard hydroarylation conditions surprisingly leads to the formation of 9-phenylmonohomosemibullvalene (rac-49) in 81% yield; not even traces of a hydroarylation product was formed. In comparison, reaction of the less strained cyclobuta-annelated bicyclo [2.2.2]hexene again results in a reductive arylation. The palladium-catalyzed phenylation of an allylcyclopropane unit under sequential rearrangement is novel and may be classified as the first example of a π,σ domino-Heck reaction. We suggest the pathway outlined in Scheme 8: after an initial syn-addition of the Ph-Pd-I species to the C=C double bond, the palladium(II) substituent can interact with the Walsh-orbitals of the neighboring endo-cyclopropane ring, leading by an oxidative addition from palladium(II) to palladium(IV). This highly strained octahedral complex can be stabilized by a reductive elimination to the σ-alkylpalladium(II) complex 48 under concomitant rearrangement. Compound 48 has the structural prerequisites for a final syn-elimination of hydridopalladium iodide with formation of racemic 49. Addition of a chiral bisphosphine ligand such as (R)-BINAP allows one to control seven chiral centers within a single operation [23].

Conclusions
The palladium-catalyzed hydroarylation of bi-and oligocyclic systems has been proven a very valuable method for the stereoselective synthesis of the corresponding, frequently bioactive exoarylated products. In the presence of chiral ligands, asymmetric induction of three centers appears feasible. The hydroarylation can be extended to N-and O-analogues. Electron-deficient palladium complexes allow C-N cleavage reactions, formally creating a two-step hydrazidoarylation of the corresponding cyclic 1,3-dienes. The efficiency of the hydroarylation correlates with the ring size of the starting material: rigid bicyclo[2.2.1]heptene systems are suited best; more flexible, larger bicycles even allow twofold Heck reactions, already. Under reductive conditions the presence of a neighboring cyclopropane ring can lead to a stereoselective π,σ domino-Heck reaction which proceeds under rearrangement and arylation, creating up to seven asymmetric centers in a single operation.