Reductive Heck Reactions of N-Methyl-substituted Tricyclic Imides

The palladium-catalyzed hydroarylation of N-methyl-substituted tricyclic imides was studied in order to find a new stereoselective access to a series of new exo-aryl(hetaryl)-substituted tricyclic N-methylimides.


Introduction
The imide moiety is an integral structural part of various important bioactive molecules such as fumaramidmycin, granulatimide, isogranulatimide and rebeccamycin. These molecules are reported to exhibit antitumor, anti-inflammatory and antimicrobial activities [1][2][3]. A literature search reveals that certain compounds with antitumor activity, and in particular molecules able to interact with DNA, are characterized by the presence of both an extended π-system and an imide function.
On the other hand, derivatives of the tricyclic anhydride exo-5,6-dehydronorcantharidin (2, Figure 1) are also pharmacologically active [4]. Norcantharidin shows a comparable activity with cantharidin (1, Figure 1) which is the major effective ingredient in pharmaceuticals for the treatment of certain malignant tumors in China. Compound 2 has been widely employed in clinical practice, as it is less toxic and much easier to synthesize [5,6]. Furthermore, in connection with an additional imide unit OPEN ACCESS this type of structure has recently become an intense research topic in heterocyclic chemistry because of its anti-tumor, anti-virus, analgesic, sedative and fungicidal activities. Therefore, we became interested in bioactive cantharidin analogues that represent aryl-modified bicyclic imide systems. We first synthesized endo-N-phenylbicyclo [2.2.1]hept-5-ene-2,3dicarboximide as the starting material for reductive Heck reactions. In the presence of triphenylarsine as a ligand [7] the palladium-catalyzed hydroarylation of the easily accessible, unsaturated tricyclic N-phenyl (or phenyl-substituted) imides has been proven to be a stereoselective, versatile and highyield approach for the synthesis of the corresponding aryl and heteroaryl derivatives [8,9]. In this paper, we synthesized various N-methyl derivatives of the unsaturated imides by a hydroarylation procedure to check the effect on both, the reactivity of the starting materials as well as the bioactivity of the products.

Scheme 3. Synthesis of 12-14.
The new structures were assigned by their 1 H-NMR data. The stereochemistry was inferred from their NMR spectra including diagnostic spin-spin interactions. The exo-position of the C-8 substituent was confirmed by the fact that H 8 showed no significant interaction with H 1. The geminal protons at C-9 were identified by vicinal coupling to H 1 . Additionally, H-H COSY spectra showed cross peaks between H 2 and H 6 and between H 8 and H 9 , respectively. In addition to the 13 C-NMR, DEPT and FTIR spectral data which were in agreement with the proposed structures, the mass spectra of all new compounds showed the expected molecular ion peaks. The data show that independently from the stereochemistry of the starting imide moiety, hydroarylation leads to the formation of the exo-arylated products, exclusively.

General
All the reactions were carried out under nitrogen atmosphere unless otherwise indicated. Reactions were monitored by thin-layer chromatography (TLC). Visualization of the developed chromatograms were performed either with UV light or KMnO 4 stain. Products were purified by silica gel chromatography with a solvent gradient of ethyl acetate/n-hexane to afford the title compounds. IR spectra were obtained with a Perkin Elmer FT-IR instrument and absorption frequencies are reported in cm -1 . Melting points were determined with a Gallenkamp digital thermometer. NMR spectra were determined with a Varian-INOVA-500 MHz NMR. 2D NMR experimental studies were measured with a Bruker Ac-400 MHz NMR. TMS (tetramethylsilane) was used as an internal standard and CDCl 3 was used as the solvent. Signal multiplicities in the NMR spectra are reported as follows: ssinglet, brs-broad singlet, d-doublet, dd-doublet of doublets, m-multiplet. Mass spectra were measured with Agilent 6890N GC-System-5973 IMSD.

Conclusions
In summary, in the presence of triphenylarsine as a ligand the palladium-catalyzed hydroarylation of the readily accessible N-substituted tricyclic imides 3, 4 and 5 was shown to be a stereoselective, versatile and high yield approach to the synthesis of aryl and heteroaryl derivatives of tricyclic imides 6-14. The above approach has been proved very useful for the construction of novel heterocycles of potential pharmacological interest.