Palladium-catalyzed dehydrogenative C–H cyclization for isoindolinone synthesis

In this paper Pd-catalyzed intramolecular dehydrogenative C(sp3)–H amidation for the synthesis of isoindolinones is described. This method features the use of a Pd/C catalyst and the addition of a stoichiometric amount of oxidant is not necessary. A mechanistic study suggested the possible formation of H2 gas during the reaction.

oxidant should be crucial for the successful construction of the isoindolinone ring.
Herein, we describe a catalytic system that enables cyclization of 2-benzyl-N-mesylbenzamides leading to isoindolinone derivatives, in which benzylic C(sp 3 )-H functionalization in the presence of a palladium catalyst smoothly occurs. It is particularly noteworthy to mention that any stoichiometric oxidants are not necessary for our isoindolinone synthesis. The key to success is the use of Pd/C as a catalyst. In this dehydrogenative process, an only detectable by-product was H 2 , which should also be an appealing feature of the process.
Based on our fruitful results of the heterocycles synthesis via transition metal-catalyzed C-H cyclization, 5 our investigation began by examining the conversion of N-tosyl-protected benzamide 1a to the corresponding isoindolinone 2a. During the screening studies utilizing a range of transition metal catalysts as well as various oxidants, it was found that 2a did produce even in the absence of an oxidant when Pd/C was used as a catalyst. Indeed, the use of 10 mol% of Pd/C along with Scheme 1 C-H cyclization strategies for isoindolinone synthesis. 20 mol% of KOAc enabled the desired cyclization process, providing 2a in 42% yield (Table 1). Intrigued by this unexpected oxidant-free process, the effect of the protecting group on the nitrogen atom of an amide moiety was briey evaluated. We are pleased to nd that the reaction of 1f possessing a mesyl group (-Ms) efficiently occurred and the isoindolinone 2f was obtained in fairly good yield (75%). 6 Settled in -Ms for the protecting group, further examination of the reaction parameters was performed employing 1f ( Table  2). Use of Na 2 HPO 4 gave a slightly better result (entry 2), while reactions with other bases led to lower yields (entry 3). Among a variety of solvents tested, p-xylene was found to be the best (entry 4). Varying the concentration of the reaction did not enhance the process (entry 5). Performing the reaction under an oxygen atmosphere dreadfully diminished the yield (entry 6). In contrast, use of the degassed conditions by means of Ar bubbling afforded the desired 2f with excellent yield (entry 7). In addition, it was found that the yield decreased when the reaction was carried out in the absence of a base (entry 8). 7,8 Our new method for isoindolinone synthesis can be applied to cyclization of a wide range of substrates (Table 3). Substituents such as an electron donating methyl or methoxy group as well as an electron withdrawing halogen atom on the benzene ring are well tolerated under the reaction conditions, and the corresponding products 2j-l are successfully obtained. It is also noteworthy that heterocycles such as thiophene and indoles are compatible during the process (2n-q). Remarkably, benzamides 1o-q possessing an indole nucleus that can be easily oxidable were suitable under our oxidant-free conditions. 9 An attempt to obtain 3-alkylisoindolinone 2r unfortunately failed. On the other hand, the reaction of 1f can be easily scaled up: in this case, 2f was obtained in 92% yield. 10 To further demonstrate the synthetic utility of the method we have developed, several transformations of isoindolinone 2f obtained were carried out (Scheme 2). Deprotection of a mesyl group with AIBN and Bu 3 SnH afforded the N-free isoindolinone 3 in high yield. Reduction of the carbonyl group of 2f using LiAlH 4 also successfully preceded, giving rise to isoindoline 4 in excellent yield (97%). Table 1 Effect of protecting group a,b a Reactions were run on a 0.25 mmol scale. b Isolated yields (yield determined by 1 H NMR using an internal standard in parentheses).  To gain insight into the reaction mechanism of the process, C-H cyclization of 1f in the presence of 0.5 equiv. of methyl cinnamate (5) was performed under the optimized conditions (Scheme 3). In addition to isoindolinone 2f, methyl 3-phenylpropanoate (6) was observed in 32% NMR yield, implying that the formation of H 2 gas is possibly occurring during the reaction. 11 On the basis of the nding above, a tentative reaction pathway shown in Scheme 4 is proposed. The reaction is likely initiated by the coordination of the nitrogen atom of an amide moiety to give complex A. Subsequently, the insertion of Pd(0) into the benzylic C(sp 3 )-H bond leading to the formation of sixmembered palladacycle B accompanied with the evolution of H 2 gas and the following reductive elimination process affords the desired isoindolinone 2.
In summary, we have developed intramolecular Pd-catalyzed dehydrogenative C(sp 3 )-H amidation for isoindolinone synthesis. The addition of oxidants is not necessary and the Pd/ C catalyst along with a catalytic amount (20 mol%) of base is the only reagents required for this C-H cyclization. The method developed provides a simple, facile, and efficient access to a biologically important isoindolinone nucleus. Further studies to broaden the substrate scope of the process as well as to improve the catalytic efficiency are vigorously underway in our laboratory.

Conflicts of interest
The authors declare no competing nancial interest.