Microwave-assisted synthesis of isoindolinones via Pd-mediated tandem coupling reactions

The use of palladium (Pd) to catalyze the formation of C-C bonds has matured to become an indispensable tool in modern synthetic organic chemistry [1]. Using Pd chemistry, simple organic molecules and structurally complex targets, such as natural products, have been constructed. Undoubtedly, heterocyclic chemistry has benefited from the growing repertoire of transformations that can be accomplished using Pd chemistry [2]. Besides its reproducibility and the use of sub-stoichiometric amounts of catalyst, a pursued feature of Pd chemistry is the possibility of performing tandem reactions, allowing the generation of complexity from simple and readily available starting materials, ideally in a one-pot operation [3].

Isoindolinones are present in pharmaceuticals and natural products, such as compounds isolated from the endophytic fungus Emericella sp. showing antiviral activity against influenza A virus [4]. These heterocyclic motifs have also been used for the synthesis of several bioactive alkaloids, such as lennoxamine which is an isoindolobenzazepine isolated from the Chilean plant Berberis darwinii [5, 6]. Several approaches have evolved over the years to synthesize isoindolinones. In 1996, Campbell reported the preparation of isoindolinones using a directed ortho-metallation [7]. A closely related strategy has afforded 2,3-dihydroisoindolinones in excellent yields [8]. 3,3-Diallylisoindolinones have been synthesized via an indium-mediated Barbier-type allylation reaction of ortho-cyanobenzoates in good yields [9]. The diallylisoindolinones thus obtained have been transformed into spiroisoindolinones via a ring closing metathesis. Isoindolinones have also been prepared via a Pd-catalyzed intramolecular aminocarbonylation of 2-iodobenzylamine to give 1-isoindolinone, a basic skeleton of an atypical antipsychotic agent [10]. Starting from a furan, an intramolecular Diels-Alder approach has been used to construct the isoindolinone ring of a drug indicated for schizophrenia [11]. Isoindolinones bearing a quaternary carbon have been prepared by Rovis et al. [12] by coupling of O-pivaloyl-substituted benzohydroxamic acids with diazo compounds. In a closely related process, isoindolinones have been constructed by a Rh(III)-catalyzed oxidative [4+1] cycloaddition of benzohydroxamic acids and α-diazoesters [13] and by Rh(III)-catalyzed one-pot reaction of benzamides, ketones and hydrazines [14]. An asymmetric version of this process has been recently developed by Cramer [15]. A Pd-catalyzed C-H activation/annulation approach has been employed for the fast and convenient synthesis of hydroxyisoindolones [16]. Single isoindolinones have been used for the preparation of structurally elaborated spirocyclic isoindoles using a metathesis strategy [17]. Spiroisoindolinones have also been prepared by a regiospecific 1,3-dipolar cycloaddition of 3-methylene-N-substituted isoindolones [18]. Herein, we report a simple and efficient procedure to obtain isoindolones using a Pd-mediated tandem protocol [19]. Originally, we aimed to obtain isoquinolones using an intramolecular 6-endo-trig Heck reaction on the substituted methyl acrylate 3 (Scheme 1).

Scheme 1

 

N-Boc-protected methyl 2-(2-iodobenzamido)acrylate 3 was easily obtained starting with condensation of DL-serine methyl ester hydrochloride (2) with acid chloride 1. The intermediate product was subjected to elimination in the presence of MsCl and Et₃N and a subsequent N-Boc protection to afford 3 in 73% yield over three steps (Scheme 1). With compound 3 in hand, an intramolecular Heck reaction was attempted. Unfortunately, all the attempted experiments to obtain isoquinolone 4 from 3 had failed (Scheme 1). A thin-layer chromatography (TLC) analysis showed the formation of a complex mixture that could not be resolved.

It was envisioned that the intermediate product 5 is generated during the Heck reaction as discussed above (Scheme 2). According to Baldwin’s rules, the formation of isoindolinone 5 is allowed via a 5-exo-trig process [20, 21]. To substantiate this hypothesis, an experiment to trap intermediate 5 by heating a mixture of N-Boc-protected substrate 3, phenylboronic acid (6a), Pd(OAc)₂, and Ph₃P in a mixture of tetrahydrofuran (THF)/1N NaOH was designed. We were delighted to observe the formation of isoindolinone 7a via a Suzuki coupling, albeit in low yield of 15%. Suzuki couplings are performed using a two-phase solvent system of aqueous NaOH and an organic solvent [22]. When toluene was used instead of THF, the yield of 7a increased to 45%. Attempts to further increase the yield, included the use of triton B (benzyltrimethylammonium hydroxide) instead of aqueous NaOH in a 2:1 mixture of toluene and water at 100°C and the use of P(t-Bu)₃ as the ligand [23]. Under these conditions, compound 7a was obtained in 40% yield.

Scheme 2

 

Preparation of additional isoindolinones 7 in the system of toluene and aqueous NaOH is shown in Scheme 2. These products were obtained by the reaction of 3 with various boronic acids substituted with an electron-donating or electron-withdrawing group using two sources of heating (A: oil bath, B: microwave oven). As can be seen, for the successful reactions, the yields of products 7 are invariably greater under microwave-induced heating and the reaction times are greatly reduced. The optimized conditions are 110°C, 100 W, 15 min. However, product 7f could not be obtained under either condition, and the conventional heating failed to produce 7g.

To investigate the scope of the tandem process, it was decided to study the use of methyl propiolate 8 (Scheme 3). In the initial experiment, a mixture of N-Boc-protected compound 3 and alkyne 8 was heated in THF at reflux temperature either under conventional heating (Method A: reflux, 36 h) or microwave irradiation (Method B: 100 W, 110°C, 15 min, sealed vial), in the presence of Pd(OAc)₂, P(Ph)₃ and K₂CO₃. After monitoring the course of the reaction for an extended period, in both cases only the unreacted starting material was recovered. However, when tris(o-tolyl)phosphine was used instead of P(Ph)₃ under microwave irradiation, desired product 9 was obtained in 43% yield. A switch to a bidentate ligand, [1,2-bis(diphenylphosphino)ethane or 1,3-bis(diphenylphosphino)propane], had a positive effect on the outcome and resulted in the increase of the yield to 67%. The effect of the base was also explored. The use of Cs₂CO₃ instead of K₂CO₃ did not have any effect on the yield. The use of either 4-methylmorpholine or triethylamine resulted in a decrease in the yield to 33% compared with the use of K₂CO₃. The use of other solvents commonly employed in this type of coupling including toluene, dioxane and acetonitrile resulted in diminished yields to 0%, 31% and 25%, respectively. Thus, under the optimized conditions, this reaction is conducted in THF in the presence of Pd(OAc)₂, 1,3-bis(diphenylphosphino)propane and K₂CO₃ at 110°C in a sealed vial under microwave heating (Scheme 3).

Scheme 3

 

In summary, a new Pd-mediated one-pot tandem synthetic procedure for isoindolinones bearing a quaternary C-atom was developed. This synthetic protocol is amenable to the synthesis of more complex organic structures. Further applications of our proposed protocol for the synthesis of natural products are currently underway, and the results will be published in due course.