Chemistry in the Ambient Field of the Alkaloid Epibatidine, 2: Triphenylarsine as an Efficient Ligand in the Pd-Catalyzed Synthesis of Epibatidine and Analogs

Abstract

The key-step in the original synthesis of the N-protected form 4 of the highly analgetic, but also toxic alkaloid epibatidine (1) via Pd-catalyzed Heck-type hydroarylation gave only a moderate yield. With triphenylarsine as a ligand we obtained 4 in 81% yield and some partly new analogs 5 -8 in racemic form in 75 to 100% yield. Further attempts to optimize the ligand properties led to the combination of As and N donor centers. The N-protected pyrrolidine derivative 10 bearing a diphenylarsino substituent provided 4 in 92% yield.Epibatidine (1) 1 was isolated from an Ecuadorian poison frog and characterized by Daly in 1992. 2 From a synthetical viewpoint we have focused on a convergent synthesis using the Pd-catalyzed Heck-type hydro(het)arylation of an appropriate bicyclic alkene 2. Scheme 1After we had shown that a broad variety of both aryl and hetaryl components 3 can be attached to the bicyclic alkene norbornene by this reaction type we published recently the high-yielding synthesis of the N-protected epibatidine 4 and of some analogs 1 applying a modified hydroarylation procedure of Clayton and Regan. 4 For example, with triphenylphosphine as a ligand in the key-step we obtained N-methoxycarbonyl protected epibatidine 4 in up to 77% yield. Herein, we report the synthesis of 4 in yields up to 92% using ligands with arsine donor centers in the hydroarylation procedure. To the best of our knowledge, this synthetic pathway is hitherto the shortest route to the novel alkaloid 1 and together with our preliminary published synthesis of the azabicyclic alkene 2 1 , epibatidine 1 is now obtainable in 59% overall yield starting from bis(trimethylsilyl)acetylene.Apart from a few exceptions the use of arsine ligands in Pd-catalyzed reactions is a new synthetic procedure. An early application, for example, was published in 1989 by Trost and co-workers who used triphenylarsine in a Pdmediated cyclization of an allylic enyne. 5 Farina et al. 6 found an acceleration of the Stille-coupling and other recent examples also deal with Stille-7 and Suzuki-type 8 coupling reactions. The Pd-catalyzed cross-coupling reaction between organozinc halides and vinyl or aryl halides has been investigated by Rossi et al. 9 During our investigations Shibasaki documented Heck reactions performed with arsine ligands. 10 Using triphenylarsine as a ligand, the C-C coupling step of 2-chloro-5-iodopyridine (3) with 2 was completed within 2 hours. 11 We were very pleased to note that the undesired reduction of the aryl derivative 3 was driven back in favour of the reductive hetarylation. With different carbo-, azaand oxabicyclic alkenes we obtained the corresponding racemic hydroarylation products 5 -8 12 in yields ranging from 75 to 100% 13 (Scheme 2, Table 1). Scheme 2Thus, triphenylarsine is a soft ligand, suitable for Hecktype hydro-arylations, which enables high yields and short reaction times. We should emphasize that in the case of the benzo-anellated azabicyclic compound 7 the prelimiDownloaded by: Nanyang Technological University NTU. C...

The Heck Reaction as a Sharpening Stone of Palladium Catalysis

“…Thus, it proved to be a better ligand for the arylation of norbornene and related bicyclic structures in the presence of formate hydride donor for reductive trapping of organopalladium intermediate. The procedure was applied to the synthesis of the alkaloid epibatidine in 92% yield (Scheme ) 36 …”

The Heck Reaction in Ionic Liquids: A Multiphasic Catalyst System

“…It is often used to functionalize aromatic rings and as an alternate to the Friedel−Crafts reaction . The Heck reaction usually involves the interaction of an aromatic halide or anhydride with an alkene, in the presence of a palladium catalyst at typically a 1−2 mol % concentration, to give an aryl alkene. The reaction normally requires a base to be present, , particularly in the reactions of aryl halides (but not anhydrides) .…”

The Hydroarylation Reaction—Scope and Limitations

“…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).…”

“…The argument of competitive N -complexation can also be applied when the unsuccessful reductive coupling of the pyridino-substituted analogue of 19 is discussed. The better stabilizing ligand triphenylarsine leads to the best yield of 21 (75%) [18,20].…”