Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
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Pd(II)/Cu(II)-Catalyzed Regio- and Stereoselective Synthesis of (E)‑3Arylmethyleneisoindolin-1-ones Using Air as the Terminal Oxidant So Won Youn,* Tae Yun Ko, Young Ho Kim, and Yun Ah Kim Center for New Directions in Organic Synthesis, Department of Chemistry and Research Institute for Natural Sciences, Hanyang University, Seoul 04763, Korea
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ABSTRACT: Regio- and stereoselective synthesis of (E)-3-arylmethyleneisoindolin-1-ones via Pd(II)/Cu(II)-catalyzed onepot C−C/C−N bond forming sequence between amides and styrenes is reported. This method provides facile and rapid access to a diverse range of such compounds using readily available starting materials under mild aerobic conditions with good functional group tolerance and high selectivity and efficiency. Further elaboration of the products obtained from this process enabled very short and efficient syntheses of aristolactam and indoloisoquinolinone alkaloids.
substrate preparation and byproduct formation from the reagents and halide salts. In this regard, a direct reaction between two simple and readily available starting materials, i.e., amides9 and styrenes, via both C− C and C−N bond formation, would be a more efficient atom-/ step-economic route to this scaffold. Wang and Booker-Milburn independently reported a Pd-catalyzed oxidative annulation of Nmethoxybenzamides with activated alkenes (e.g., acrylates), and only one example using styrene was reported to afford the corresponding (E)-isomer (Ar = Ph) in moderate 46−50% yields (Scheme 1d, upper).10a,b Although these chemical yields and stereoselectivities were not reproducible, the substrate scope could be successfully broadened with the slightly modified catalytic protocol by Hii’s group (Scheme 1d, upper).10c However, limitations such as poor stereoselectivity (E-/Z- = ∼2:1), competitive formation of side products (via 6-endo cyclization) resulting in moderate yields (mostly 55−65%) of the desired products and requirement of strongly acidic conditions still remain. Furthermore, despite significant advances in transition metal-catalyzed oxidative annulation of amides with activated alkenes (e.g., acrylates) for the synthesis of 3methyleneisoindolin-1-ones,10a,b,11 the use of styrenes as a substrate is challenging, leading to no conversion11a−d or formation of undesired side products such as 2-alkenylated benzamides11e,g,12 or 3,4-dihydroisoquinolinone.12b,13 Therefore, a simple and efficient protocol under mild conditions for regio- and stereoselective formation of such compounds, which overcomes the drawbacks of previous methods such as need for
3-Methyleneisoindolin-1-ones are frequently found as a key structural motif in a wide range of natural products and pharmaceuticals.1 Among them, 3-arylmethyleneisoindolin-1ones exhibit various biological activities and are useful intermediates for the synthesis of numerous alkaloids (Scheme 1, bottom).2,3a−c In particular, stereoselective synthesis of 3arylmethyleneisoindolin-1-ones with (E)-stereochemistry is highly desirable.3 Classical methods to produce such compounds involve preliminary construction of highly functionalized parent isoindolin-1-ones for subsequent Horner reaction or hydroxyalkylation/dehydration.2,3b−e Due to their synthetic inefficiency, such as multistep manipulations for substrate preparation and poor functional group tolerance, alternative protocols including transition metal-catalyzed intramolecular cyclization of 2-alkenyl-4 or 2-alkynylbenzamides5 through C−N bond formation (Scheme 1a) or intermolecular alkynylation/annulation of benzamides with alkynes through dual C−C and C−N bond formation (Scheme 1b)6,7 have been developed. With incomplete regioselectivity (e.g., 5-exo vs 6-endo, C−N vs C−O bond formation) in some cases, however, these processes lead to formation of only (Z)-isomers or a mixture of (Z)- and (E)isomers. Stereoselective synthesis of (E)-isomers can be achieved by Heck−Suzuki−Miyaura domino reactions of 2-halo-substituted ynamides with arylboronic acids (Scheme 1c, left).8 Recently, Wang and co-workers reported a bimetallic Rh(III)/ Ag(I) relay catalysis for heteroannulation of benzamides with 2,2difluorovinyl tosylate to afford OTs-substituted 3-alkylideneisoindolin-1-ones, which can undergo Suzuki−Miyaura coupling with an arylboronic acid, leading to successful synthesis of (E)isomers (Scheme 1c, right).3a In spite of their potential utility, these methods suffer from intrinsic drawbacks, such as tedious © XXXX American Chemical Society
Received: October 24, 2018
A
DOI: 10.1021/acs.orglett.8b03409 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
It should be noted that a catalytic amount of Cu(OAc)2 in air proved to be comparable to 2 equiv of Cu(OAc)2 (entries 15 vs 2) and was more effective than the combination of Cu(OAc)2 and O2 (entries 17 vs 18). Reactions run with either air or O2 in the absence of Cu(OAc)2 resulted in low conversion (entries 8−9), while the use of a catalytic amount of Cu(OAc)2 under argon atmosphere gave a 36% yield of 3aa (entry 19). When a stoichiometric amount of Pd(OAc)2 was employed, the desired product 3aa was formed in only moderate yield (entry 23), whereas the reaction did not proceed in the presence of only Cu(OAc)2 without Pd(OAc)2 (entry 24). These results indicate that all of the reaction parameters (Pd catalyst, Cu salt, air) were crucial for the reaction to occur, and that ambient air as an effective source of O2 serves as the terminal oxidant for recycling of a substoichiometric amount of Cu(OAc)2 co-oxidant, which efficiently regenerates the active Pd(II) catalyst during the catalytic cycle.16 Next, the effect of NH acidity was examined. As expected on the basis of literature precedent regarding the influence of NH acidity of the amide directing group on reactivity (i.e., effect of Nprotecting groups) in related C−H functionalization reactions,14 weaker NH acidic benzamides rather than 1a were unsuitable substrates, and the Ts group was revealed as the protecting group of choice for this transformation (below Table 1). Both carbonyl and tosyl substituents on the N atom were essential for the reaction to take place, alluding to involvement of Pd−N bond formation facilitated by the acidity of the NH, followed by cyclopalladation. Having determined the optimized conditions as entry 15 in Table 1, we set out to explore the scope of this process (Scheme 2). First, we examined the reaction of various styrenes with 1a (Scheme 2a). Irrespective of the electronic properties and positions of substituents, a wide range of styrenes (2) smoothly underwent intermolecular oxidative annulation to afford the corresponding (E)-3-arylmethyleneisoindolin-1-ones (3) in good to high yields. Unfortunately, the reaction failed with heteroaryl- and alkyl-substituted alkenes, while α-methylstyrene resulted in only low conversion (
