Epibatidine Alkaloid Chemistry: 5. Domino-heck Reactions of Azabicyclic and Tricyclic Systems †

Palladium-catalyzed hydroarylations and additional domino reactions of aza-bicyclic and tricyclic norbornene derivatives were investigated and a series of new epibatidine analogues were synthesized.


Introduction
Epibatidine (1), a novel class of amphibian alkaloid, was first isolated by Daly in trace amounts from the skin of the Ecuadorian poison frog Epipedobates tricolor [1].The very high analgesic activity of 1 is a consequence of its high potency as an agonist towards nicotinic acetylcholine receptors (nAChRs) in the central and autonomic nervous systems [2].The exciting biological properties and unique structure of 1, combined with its scarcity in Nature (ca. 1 mg were obtained from some 750 frogs) have aroused the interest of synthetic chemists [3].Despite the large number of syntheses of epibatidine published to date [4,5], only a few analogues with modified pyridine rings have been prepared by reductive Heck reactions [6,7].In conjuction with this work we became interested in the possibility of synthesizing epibatidine analogues with modified bicyclic ring systems in a single synthetic operation via reductive Heck and additional domino-Heck reactions employing aryl(heteroaryl) iodides.

Results and Discussion
Our synthesis started with the Hetero-Diels-Alder reaction of cyclopentadiene and the iminium ion generated from formaldehyde and ammonium chloride [8].The reaction occurred smoothly in aqueous methanol at room temperature to give the bicyclic amine 2. Because of its unstable nature, this secondary amine was protected with benzoyl chloride to provide 3 in good yield (Scheme 1).

Scheme 1
Due to the presence of rotamers, all the signals in the NMR spectra of 3 appear in pairs.Malpass and co-workers have previously prepared and protected compound 2 using both the benzyloxycarbonyl-(Cbz) and t-butoxycarbonyl (BOC) groups.They only worked with 2-chloro-5iodopyridine under reductive Heck conditions using triphenylphosphine (PPh 3 ) as the ligand [6].In our work excellent yields were obtained using triphenylarsine (AsPh 3 ) instead of PPh 3 .Treatment of 3 with iodobenzene, 2-iodothiophene, 2-iodonaphthalene and 2-chloro-5-iodopyridine under reductive Heck conditions gave new compounds 4a-d and 5b, 5d as regioisomers after chromatographic separation.The reactions with iodobenzene and 2-iodonaphthalene gave only 5-exoproducts.The use of trimethylsilylacetylene under domino-Heck conditions provided alkynic bicyclic systems 6e and 6f (Scheme 2).The reactivity of the bicyclic double bond in 3 is dependent on the nature of the Nprotecting group.The regiochemistry of new compounds was inferred from their 1 H-NMR and HH-COSY spectra.For example, observation of the H 1 proton at 4.15 ppm in the 1 H-NMR spectra of 4b (red spectrum in Figure 1), while it appeared at 4.04 ppm for 5b (blue spectrum in Figure 1) was the first evidence for determining both exo-regioisomers.In the HH-COSY spectra of 4b, an interaction between H 6x and H 1 was seen clearly, but the spectrum of 5b did not show the same coupling due to the 6-exosubstituent.

Figure 1
The structures of the regioisomers 6e and 6f resulting from the domino-Heck reactions were also identified from the HMBC spectra.In the spectrum of 6f, the interaction of the acetylene carbon (at 103.5 ppm) with the H 1 proton (at 4.24 ppm) was obvious; in the isomer 6e, an interaction between the phenyl group quaternary carbon (at 139.0 ppm) with the H 1 proton (at 4.40 ppm) was apparent, but in both cases similar effects were not seen in the other isomers.This provided good evidence for the assignment of the positions of the phenyl and trimethlysilylacetylene substituents on the bicyclic ring.
In the second part of this work we prepared compound 7 by the reaction of N-carbomethoxypyrrole with N-phenylmaleimide, using the literature procedure [9], to explore tricyclic epibatidine analogues in order to find the most active members of the class (Scheme 3).

Scheme 3
Due to the strain in substituted norbornenes and their derivatives such as 7, the C=C double bond reacts readily with many transition metal catalysts.Under typical reductive Heck coupling reaction conditions, and using aryl(heteroaryl) iodides such as iodobenzene, 2-iodothiophene and 4chloroiodobenzene, we obtained a series of bicyclic imides 8a-c as single regioisomers due to the symmetry of 7. We also synthesized a new diazatricylic compound 9 using domino-Heck conditions.Not surprisingly, the attachments of phenyl and silylethynyl groups was observed to have taken place exclusively from the exo-side of the bicylic alkene 7 (Scheme 4).The structures of 8a-c and 9 were also assigned by analysis of their HH-COSY and HMBC spectra in CDCl 3 .

Conclusions
The palladium-catalyzed hydroarylation of the easily accessible N-benzoylated 2-azabicyclo[2.2.1]heptene (3) in the presence of triphenylarsine as a ligand has been proven to be an excellent, versatile and high-yield approach to aryl-and heteroaryl analogues 4 and 5 of the bioactive alkaloid epibatidine (1); in case of aryl groups the reaction proceeds regioselectively.Reductive arylations of a diazatricyclic alkene 7, synthesized by cycloaddition of a pyrrole carboxylic ester with N-phenylmaleimide, also succeeded under comparable reaction conditions.Domino-Heck sequential C-C couplings with aryl halides have been shown to be feasible in the presence of trimethylsilylacetylene.All Heck-type reactions proceed exo-selectively, leading to the same stereochemistry as found in 1.

General
NMR spectra (CDCl 3 solvent) were recorded on Bruker Digital FT-NMR Avance 400 and Varian Inova 500 MHz NMR spectrometers, with TMS as internal reference.In the 13 C-NMR spectra quaternary, methylene and methyl carbons were identified using DEPT experiments.FTIR spectra (KBr) were recorded on a Perkin Elmer FT-IR spectrometer.GC-EIMS spectra were measured on a Varian SAT2100T/GC3900 spectrometer using ionisation by FAB.Reactions were performed under dry nitrogen.Melting points were measured on a Gallenkamp melting point apparatus.Silicagel 60 (Merck) was used for column chromatography separations.TLC was conducted on standard aluminium sheets pre-coated with a 0.2 mm layer of silica gel.

Domino-Heck Reactions -General Procedure
Pd(OAc) 2 (5.6 mg, 25 µmol) and the arsine ligand (55 µmol) were dissolved in dry DMF (3 mL) and the solution was stirred at 40 o C for 15 min.Then, 3 or 7 (1.0 mmol), the aryl compound (1.5 mmol), triethylamine (488 µL, 3.50 mmol) and trimethylsilylacetylene (3.00 mmol) were added rapidly in one portion.The mixture was heated at the same temperature for 24 h.After cooling down to r.t.brine (50 mL) was added, the reaction mixture was extracted with ethyl acetate and dried over MgSO 4 .The solvent was evaporated and the residue purified by column chromatography.