Domino‐Heck Reactions of Carba‐ and Oxabicyclic, Unsaturated Dicarboximides: Synthesis of Aryl‐Substituted, Bridged Perhydroisoindole Derivatives

Abstract

The CÀC coupling of the two bicyclic, unsaturated dicarboximides 5 and 6 with aryl and heteroaryl halides gave, under reductive Heck conditions, the C-aryl-N-phenyl-substituted oxabicyclic imides 7a -c and 8a -c (Scheme 3). Domino-Heck CÀC coupling reactions of 5, 6, and 1b with aryl or heteroaryl iodides and phenyl-or (trimethylsilyl)acetylene also proved feasible giving 8, 9, and 10a -c, respectively (Scheme 4). Reduction of 1b with LiAlH 4 (! 11) followed by Heck arylation and reduction of 5 with NaBH 4 (! 13) followed by Heck arylation open a new access to the bridged perhydroisoindole derivatives 12a,b and 14a,b with prospective pharmaceutical activity (Schemes 5 and 6).Introduction. -Due to its broad synthetic potential as a stereoselective CÀC coupling method, the Heck reaction has been the subject of several synthetic and mechanistic studies over the last 30 years [1 -5]. Originally developed to arylate acyclic alkenes, the reaction scope has been extended to cyclic compounds later, too. Rigid biand multicyclic systems make the catalytic oxidative Heck-coupling reaction impossible. To circumvent this problem, domino-Heck reactions were introduced with a hydroarylation reaction as its simplest variant [6 -8], leading to a reductive CÀC coupling reaction. Kaufmann and co-workers have been carrying out new examples of reductive Heck reactions using bicyclic systems aiming at the synthesis of new biologically active compounds [9 -15].In our previous works, we have accomplished Pd-catalyzed domino-Heck applications of bi-and tricyclic precursors of epibatidine analogs [16]. We then focused on reductive Heck reactions of polyfunctional tricyclic molecules with a strained C¼C bond and an N-(acylamino)imide group [17].Later, we became interested in the synthesis of bioactive norcantharidin analogues 3 and 4b that represent aryl-modified bicyclic imide systems, too. We had first synthesized N-phenylbicyclo[2.2.1]hept-5-ene-2-endo,3-endo-dicarboximide (1a) and N-phenyl-7-oxabicyclo[2.2.1]hept-5-ene-2-exo,3-exo-dicarboximide (1b) as starting compounds according to [18] [19]. We then investigated their hydroarylation reactions with aryl-and heteroaryl iodides (ArI) in the presence of Ph 3 As giving 2a,b and subsequent reduction reactions by LiAlH 4 to open a new access to perhydroisoindole derivatives 4a,b [20] (Scheme 1). In reductive arylation reactions, Ph 3 As has proved to be superior to Ph 3 P and carbenes as ligands in both selectivity and yield [21].

Reductive Heck reactions of N-arylamino-substituted tricyclic imides

“…[9][10][11] Reductive Heck reactions of unsaturated N-substituted tricyclic imides, which have possible biological activities, were studied previously. [12][13][14][15][16][17][18] The palladium-catalyzed hydroarylations of several N-substituted tricyclic imides were studied in order to find a new stereoselective access to a series of new exo-aryl(hetaryl)-substituted tricyclic imides in the presence of triphenylarsine using the Kaufmann reductive Heck procedure. [19][20][21] In this study, the endic anhydride (1) 22 was combined with 3-chloro-4-fluorophenylhydrazine (2), which was chosen for the active groups on the aromatic ring, and 2,4-dinitrophenylhydrazine (5), which was chosen for many applications of this group in medicinal chemistry, using the Kas'yan method.…”

Evaluation of the Antioxidative Properties of N‐Acylamino‐Substituted Tricyclic Imides

“…As an extension of the Heck reaction, Pd-catalyzed hydroarylation of alkynes and alkenes continues to attract researchers' interest in simple coupling processes and cyclization reactions [19,20]. In the presence of triphenylarsine as a ligand [21,22] the palladium-catalyzed hydroarylation of the easily accessible, unsaturated tricyclic N-substituted imides such as aryl-and methyl-substituted, epibatidine, epiboxidine, and tandospirone analogs have been proven to be a stereoselective, versatile, and high-yield approach for the synthesis of the corresponding aryl and heteroaryl derivatives [23][24][25][26][27][28][29][30][31].…”

Reductive Heck Reactions of N-Methyl-substituted Tricyclic Imides

“…We first synthesized endo - N -phenylbicyclo[2.2.1]hept-5-ene-2,3-dicarboximide 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 high-yield 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.…”