Synthesis of new N -norbornylimide substituted amide derivatives, their reductive Heck and domino Heck reactions

Palladium-catalyzed, regioselective hydroarylation reactions of N -norbornenylimide substituted amides were studied to synthesize pentanamide derivatives containing exo -aryl-substituted norbornyl imide groups in excellent yields. All newly synthesized derivatives have been characterized by FTIR, 1 H, 13 C NMR, GC/MS and TOF/Qtof analyses .


Introduction
Carboxamide functions are widely found in various molecules such as drugs, polymers, pharmaceutical agents, peptides, natural molecules, proteins, alkaloids, etc. 1 Compounds containing an amide bond play an important role in biological processes such as enzymatic catalysis, transportation and immune protection.Amide bonds have been a main topic of scientific interest to medicinal and organic chemists for a long period due to their biological properties of amides. 2 Functional groups, especially carboxamides, are important for the activity and pharmacokinetic properties of a drug.There are many drugs containing amide groups and they are still widely used today, e.g.Penicilins 1, Paracetamol 2 and Oxicams 3 (Scheme 1).Penicilin was the first broadspectrum antibiotic to be used against many bacterial infections 3 , Paracetamol is a widely used pharmaceutical to treat fever and pain 4 , and Oxicams are anti-inflammatory drugs. 5All of these important drugs contain an amide group and have a large share in the worldwide pharmaceutical market.Scheme 1.Some drugs including an amide group.
Additionally, anti-cancer agents containing amides have become a focus in the improvement of new treatments of cancer.An increasing number of amide antitumor agents is now becoming effective; for example, Fidarestat 4 (Scheme 2) and Sorbinil 5 are anti-cancer and anti-diabetic agents 6 , and Leflunomide 6 is also a well-known anti-cancer agent. 7Scheme 2. Some anti-cancer drugs containing an amide group.
The carbon-carbon bond formation is a crucial transformation in synthetic organic chemistry.][10] N-Substituted tricyclic imides are Scheme 3. Application of the Heck reaction on some drugs' total synthesis.
][26] Having this information in mind, we focused on the synthesis of a new class of compounds including exoaryl(hetaryl)-substituted norbornylimide derivatives of N-4-azabicyclo [2.2.1]

Results and Discussion
Initially, we prepared the endocyclic anhydride 1 using freshly distilled cyclopentadiene and maleic anhydride in ethyl acetate at 0 °C using a known procedure. 27Thereafter, compound 2 was obtained from the reaction of hydrazonium chloride and compound 1 in toluene at room temperature. 28We continued to prepare the optically active norbornenylimide substituted acid 3 from 1 using Amos' procedure. 29As the last step of this part, we synthesized a new norbornenylimide acyl chloride derivative 4 from 3 in an excellent yield.(Scheme 4).© ARKAT USA, Inc Scheme 4. Preparation of compunds 1 -4.
As the second step of our starting material preparation, we synthesized the new amide 5 from 2 and 4 in dry dichloromethane at room temperature in a good yield (Scheme 5).Scheme 5. Synthesis of compound 5.
Compound 5 was then reacted with various aryl iodides (Table 1) under reductive Heck reaction conditions to afford newly synthesized amide derivatives (6a -e, 7a and 8) in good yields (Scheme 6).Table 1 shows the angles of specific rotation for all new products we obtained.
It was expected that during the reaction a mixture of diastereomers would be formed as 5 has two alkene subunits (Scheme 6).In each case an excess of the arylating agent was used.From the results presented in Scheme 6 it is apparent that the more reactive alkene is the one in the norbornene system proximal to the N,N-succinoylhydrazide functionality since the product composition 6a and 7a indicates that the bis-arylation succeeds the mono-arylation at the more reactive double bond.At this time, and without computational work, it would be speculative to assess the relative reactivities at the two double bonds.However, the origin is most likely an electronic one, i.e., it would not be unreasonable to argue that the norbornene system carrying the N,N-succinoylhydrazide moiety is somewhat more electron-rich than the other nornbornene double bond.Computational modeling studies are under way to address this interesting aspect of regioselectivity.The structure of the N-N-cleavage product 8, which was obtained during the course of the attempted hydroarylation reaction of 5 with difluoroiodobenzene, helped us to determine where the first aryl group was located (Scheme 6).A structural proof by X-ray crystallography was not yet possible due to a missing single crystal.The exo-stereochemistry for each hydroarylation product was inferred from the 1 H NMR spectra including diagnostic spin-spin interactions.The exo-position of the C-8 substituent was confirmed by the fact that H8n showed no significant interaction with H1.The geminal protons on C-9 were identified by vicinal coupling to H1.Additionally, 1 H-1 H-COSY spectra showed cross peaks between H2 and H6 and between H8 and H9, respectively.The presence of alkenic hydrogens in the 1 H NMR spectrum of compound 7a shows that it undergoes hydroarylation on one side.In addition to the 13 C NMR and FTIR spectral data which were in agreement with the proposed structures, LC-MSMS (Qtof) results of all new compounds showed the expected accurate mass with hydrogen additions.Domino-Heck arylation conditions were also successfully applied to the reaction of 5 with 1-iodobenzene and 4-chloro-1-iodobenzene together with phenylacetylene to give the new exo-alkynylated norbornyl substituted amide derivatives (9a and 9b) in good yields, respectively (Scheme 8).The reactions were repeated many times, obtaining the same results.It was determined that during the determination of structures of these products, the arylation reagents were attached from the single alkenic side as compound 7a.The absence of H9x hydrogens in the proton NMR spectrum of the compounds indicates that phenyl acetylene is also bound from the exo-position.In addition, the structures are confirmed with the observation of alkyne carbons in the carbon NMR spectrum at the expected site.

Conclusions
New bistricyclic amide derivatives (5, 6a -e, 7a) and acyl chloride derivative 4 have been synthesized and extensively characterized by the use of spectroscopic studies such as 1 H NMR, 13 C NMR, GC-MS and LC-MSMS/QTOF analyses.Regioselective (Domino) Heck reactions of compound 5 were also studied, leading to the two new alkyne substituted derivatives 9a and 9b.These compounds should have the potential to show various microbiological activities due to their substructures aryl groups, the leucine chain, amide and imide groups.