Cationic Gold(I)-Catalyzed Cascade Bicyclizations for

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Jun 11, 2018 - containing a disubstituted alkene in a single operation through ..... Yang, W.; Liu, H. Palladium-Catalyzed Difunctionalization of Alkynes.

Letter Cite This: ACS Catal. 2018, 8, 6388−6393

Cationic Gold(I)-Catalyzed Cascade Bicyclizations for Divergent Synthesis of (Spiro)polyheterocycles Zhenghua Li,†,¶ Liangliang Song,†,¶ Luc Van Meervelt,‡ Guilong Tian,*,† and Erik V. Van der Eycken*,†,§ †

Laboratory for Organic and Microwave-Assisted Chemistry (LOMAC) and ‡Biomolecular Architecture, Department of Chemistry, KU Leuven, Celestijnenlaan 200F, Heverlee, Leuven 3001, Belgium § Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya Street, Moscow 117198, Russia S Supporting Information *

ABSTRACT: We herein report an expeditious synthetic strategy to access diverse (spiro)polyheterocycles from easily available starting materials in two operational steps including an Ugi four-component reaction and a cationic gold(I)catalyzed cascade bicyclization. Divergent synthesis of these structurally complex pyrido[2,1-a]isoindol-4(6H)-ones and spiroisoquinoline-pyrrole-3,5′-diones via a cascade nucleophilic cyclization/intramolecular 1,3-migration/1,5-enyne cycloisomerization process and a tandem hydroamination/ Michael addition sequence, respectively, was controlled by substituents, where the electronic effect on the migrating groups and steric effect of the secondary amide moieties play crucial roles. KEYWORDS: gold catalysis, heterocycles, cascade cyclization, 1,3-migration, substrate control and divergent synthesis


Scheme 1. Construction of Heterocyclic Scaffolds by Transition-Metal Catalysis

iven the importance of heterocycles in biologically active natural products, pharmaceuticals, and organic materials, organic chemists have invested significant efforts in exploring effective strategies for their synthesis.1 In this regard, the intramolecular addition of various nucleophiles, such as alcohols, thiols, and amines, to transition metal-activated alkynes has served as a powerful tool for constructing innumerable heterocycles in an efficient and atom-economic manner (Scheme 1a, R2 = H).2 Meanwhile, employing weaker nucleophiles, such as ethers, sulfides, tertiary amines, and amides, has resulted in the formation of heterocycles containing a disubstituted alkene in a single operation through rearrangement of the allyl,3 propargyl,4 acyl,5 α-alkoxy alkyl,6 sulfonyl,7 silane,8 or benzyl group9 (Scheme 1a, R2 ≠ H). Furthermore, various fragment migrations have been involved as the key step in many homogeneous gold-catalyzed cascade processes for the effective synthesis of highly complex heterocycles and natural products.10 However, to the best of our knowledge, there are no reports11 where a latent nucleophilic enamine, generated via fragment migration from 2-alkynylphenyl-N,N-disubstituted ethanamine, is subsequently trapped by an extra electrophile to achieve one more heterocyclic ring. Moreover, the highly investigated Ugi four-component reaction (Ugi-4CR)12 has been widely employed to generate multifunctionalized acyclic adducts for a myriad of intramolecular cyclizations enabled by various transition-metal catalysts.13 This strategy provides an access to rapidly assemble diverse N-heterocyclic scaffolds from readily available building © XXXX American Chemical Society

blocks in two operational steps, which is highly useful for highthroughput screenings in drug discovery. Among them, the cooperation of Ugi-4CR and tandem gold catalysis has gained striking achievements for synthesizing complex heterocycles Received: May 8, 2018 Revised: June 7, 2018 Published: June 11, 2018 6388

DOI: 10.1021/acscatal.8b01789 ACS Catal. 2018, 8, 6388−6393


ACS Catalysis Table 1. Optimization of the Reaction Conditionsa

with high structural variability.13b−d Inspired by these results, we envisaged that a post-Ugi gold-catalyzed nucleophilic cyclization/1,3-migration/1,5-enyne cycloisomerization process would be quite promising to expeditiously construct diverse pyrido[2,1-a]isoindol-4(6H)-one 2 (Scheme 1b, a → b→ c route). This skeleton is often encountered in various biologically active natural products such as the antitumor alkaloid camptothecin and nothapodytines A and B (Figure. 1).14




IPrAuCl/ AgOTf IPrAuCl/ AgOTf IPrAuCl/ AgOTf IPrAuCl/ AgOTf IPrAuCl/ AgOTf IPrAuCl/ AgBF4 IPrAuCl/ AgSbF6 IPrAuCl/ AgNTf2 Au(PPh3)Cl/ AgOTf AuCl AuCl3 IPrAuCl/ AgOTf IPrAuCl/ AgOTf IPrAuCl AgOTf [email protected]

2 3 4 5d

Figure 1. Representative bioactive (spiro)polyheterocycles. 6

On the other hand, considering the presence of the nucleophilic secondary amide introducing from Ugi-4CR, we assumed that the hydroamination of gold-activated alkyne with the nitrogen atom of the secondary amide could occur first, followed by Michael addition to the tertiary propiolamide moiety producing the spiroisoquinoline-pyrrolone 3 (Scheme 1b, d → e route), which is also interesting as similar skeletons could be found in lots of natural products as well as pharmaceutical compounds like the insecticide spiropidion (Figure 1).15 We speculated that the stabilization of the migrating group, as well as steric effect of the secondary amide moieties might play crucial roles in determining the possible reaction route, providing a steering handle. To test the feasibility of our hypothesis, the acyclic precursor 1a obtained via Ugi-4CR of 2-ethynylbenzaldehyde, 4methoxybenzylamine, tert-butyl isocyanide and phenylpropiolic acid, was chosen as a model substrate (Table 1). Employment of the in situ formed cationic gold(I) catalyst [IPrAu]+[OTf]− from IPrAuCl/AgOTf (5 mol %) in DCE at 60 °C for 16 h gave the expected pyrido[2,1-a]isoindol-4(6H)-one 2a in 43% yield along with 22% of the spiroisoquinoline-pyrrole-3,5′dione 3a (entry 1). Further gradually increasing the reaction temperature to 120 °C selectively delivered the polyheterocycle 2a in the highest yield of 81% along with traces of spiroheterocycle 3a (entries 2−4). A reduced reaction time led to a lower yield of 2a (8 h, entry 5). Employing IPrAuCl with other chloride scavengers such as AgBF4, AgSbF6, or AgNTf2 failled to ameliorate the yield of 2a (entries 6−8). No product 2a was observed in the case of Au(PPh3)Cl/AgOTf, AuCl, and AuCl3 (entries 9−11). A diminished yield of 2a was detected while changing the solvent to MeCN or toluene (entries 12 and 13). Treating with IPrAuCl or AgOTf separately resulted in almost no conversion (entries14 and 15). No target product 2a was detected when employing the heterogeneous nanogold catalyst [[email protected]] (entry 16).16 With the optimal conditions in hand, various Ugi adducts 1, synthesized from 2-ethynylbenzaldehydes, were subjected to this cascade nucleophilic cyclization/1,3-migration/1,5-enyne cycloisomerization process to examine the scope and limitations (Table 2). First, the tolerance of R1-substituent on the tertiary propiolamide was investigated. The reaction worked well with hydrogen (2b), various alkyls (2c−g), as well as the heteroaromatic thiophene groups (2h). Second, the

7 8 9 10 11 12 13 14 15 16


T/ °C

yield of 2ab/%

yield of 3a/%