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Cite This: J. Org. Chem. 2018, 83, 6719−6727
Gold(III)-Catalyzed Selective Cyclization of Alkynyl QuinazolinoneTethered Pyrroles: Synthesis of Fused Quinazolinone Scaffolds Lin-Su Wei,†,# Guo-Xue He,†,# Xiang-Fei Kong,†,‡ Cheng-Xue Pan,*,† Dong-Liang Mo,*,† and Gui-Fa Su*,† †
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State Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources, Ministry of Science and Technology of China, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, 15 Yu Cai Road, Guilin 541004, China ‡ College of Chemistry and Bioengineering, Guilin University of Technology, 12 Jian Gan Road, Guilin 541004, China S Supporting Information *
ABSTRACT: A series of 1,2- and 2,3-fused quinazolinones have been synthesized in good to excellent yields through gold-catalyzed selective hydroarylations of alkynyl quinazolinone-tethered pyrroles. The studies revealed that 1,2-fused quinazolinones were obtained through a 1,3-rearrangement and sequential 6-exo-trig cyclization of N1-alkynyl quinazolinone-tethered pyrroles, while N3-alkynyl quinazolinone-tethered pyrroles went through 6-exo-dig or 7-endo-dig cyclizations directly to afford 2,3-fused quinazolinones. The fused quinazolinones could be prepared at gram scale in three steps from commercial ortho-aminobenzamide.
Q
efficiency and easy operations.6,7 In particular, cyclizations of alkyne-tethered pyrroles have attracted considerable interest due to the importance of nitrogen-containing heterocycles in biological and pharmaceutical technologies.8 Although goldcatalyzed cyclizations have widely investigated, control of regioselectivity in these reactions is still challenging.9 In 2011, Broggini and co-workers developed a AuCl3-catalzyed intramolecular 6-exo-dig and 5-exo-dig cyclizations of alkyne-tethered pyrroles to form two types of pyrrolopyridines, and further found the regioselectivity of cyclizations was influenced by the phenyl substituent on the alkyne; however, mixture of the cyclization products was obtained (Scheme 1A).10 Continuing to study the mechanisms of gold-catalyzed intramolecular cyclization reactions of terminal alkyne and phenyl-substituted alkyne-tethered pyrroles, Lin and co-worker have explained the regioselectivity and rationalized the major/minor products observed by Broggini’s group based on the detailed density functional theory calculations.11 In 2012, Van der Eycken and co-workers reported an excellent approach for the synthesis of pyrrolopyridinones by gold(I) and platinum(II) catalyzed intramolecular cyclizations of alkyne-tethered pyrroles with high regioselectivity (Scheme 1B).12 It could be seen that goldcatalyzed cyclizations of alkyne-tethered pyrroles have been studied, but the regioselectivity of cyclization is still unresolved for more complex molecules. More importantly, the mechanism proposed in these cyclizations was usually a direct cyclization under gold catalyst. In 2012, Broggini and co-workers reported a base-mediated prototropic isomerization of propargyamides and a sequence of AuCl3-catalzyed hydroamination of
uinazolinones are among the most important nitrogen heterocyclic compounds, not only used as powerful organic intermediates or occurring in natural products,1 but also serving as pharmacophores playing important roles on the bioactivity.2 Pharmaceutical research has demonstrated that most of the compounds containing quinazolinones possess antiinflammatory, antibacterial, antidiabetic, and anticancer activities.3 In particular, 2,3-fused quinazolinones with diverse heterocycles have been well studied, and many strategies have been developed to prepare or modify these compounds, such as rutaecarpine and (−)-circudatin B (Figure 1).4 However, 1,2-
Figure 1. Some examples of biologically active fused quinazolinones.
fused quinazolinones are rarely reported and only a few scaffolds were synthesized, such as isoindolo-fused quinazolinone derivatives, which have been found to serve as potent inhibitors of TNF-α (Figure 1).5 Thus, development of new efficient methods for the construction of functionalized 1,2fused quinazolinones is desirable and valuable for the bioactive studies of these scaffolds. Gold-catalyzed intramolecular cyclizations of alkyne-tethered indoles, furans and pyrroles have proven to be appealing methods to form C−O, C−N and C−C bonds to afford various N-heterocycles in modern synthetic chemistry due to their © 2018 American Chemical Society
Received: January 18, 2018 Published: May 17, 2018 6719
DOI: 10.1021/acs.joc.8b00168 J. Org. Chem. 2018, 83, 6719−6727
Note
The Journal of Organic Chemistry Scheme 1. Gold-Catalyzed Intramolecular Cyclizations of Pyrrole-Ynes
Table 1. Optimization of 6-exo-dig Cyclization of N1-Alkynyl Quinazolinone-Tethered Pyrrole 1aa
entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15d 16e 17 18 19 20 21
anthranilic allenamides to afford quinazoline derivatives.13 During studies of the bioactivity of quinazolinone scaffolds in our group,14 we surmised that intramolecular cyclizations of N1 or N3 alkynyl quinazolinone-tethered pyrroles will conveniently furnished 1,2- or 2,3-fused quinazolinones and the rigidity of the 1,2- or 2,3-fused quinazolinones will selectively facilitate the 6-exo-dig cyclization. However, we found the mechanism of cyclization of N1 or N3 alkynyl quinazolinone-tethered pyrroles under gold catalyst is completely different by the substrate control (Scheme 1C). Herein, we reported a goldcatalyzed highly selective cyclization of N1 or N3 alkynyl quinazolinone-tethered pyrroles to access various fused quinazolinone scaffolds under mild conditions. Initially, alkynyl quinazolinone-tethered pyrrole 1a was conducted under AuCl3 in toluene at room temperature to test the efficiency of cyclization. As shown in Table 1, only 5% yield of 6-exo-dig cyclization product 2a was observed and the starting material 1a was recovered (Table 1, entry 1). 78% and 83% yields of product 2a were obtained when the reaction ran in CHCl3 and DCM for 3 h, respectively (Table 1, entries 2 and 3). However, almost no desired product 2a was observed and the conversion of 1a was low in other solvents such as THF, MeCN, dioxane, MeOH, and DMF (Table 1, entries 4−8). Addition of AgSbF6 did not improve the yield of product 2a (Table 1, entry 9). Other Au(I) catalysts were also investigated. No desired product 2a was observed when AuCl and Au(PPh3) Cl were used (Table 1, entries 10−11). Addition of AgOTf or AgSbF6 did not promote the reaction (Table 1, entries 12−13). Moreover, using AuPPh 3 OTf or combined with 1,10phenanthroline did not afford product 2a and only 1a was
catalyst (5 mol %) AuCl3 AuCl3 AuCl3 AuCl3 AuCl3 AuCl3 AuCl3 AuCl3 AuCl3/AgSbF6 AuCl AuPPh3Cl AuPPh3Cl/ AgOTf AuPPh3Cl/ AgSbF6 AuPPh3OTf AuPPh3OTf AuCl3 FeCl3 CuI AgNO3 PdCl2 PtCl2/AgOTf
solvent
T (°C)
time (h)
conversion (%)b
yield (%)c
toluene CHCl3 DCM THF MeCN dioxane MeOH DMF DCM DCM DCM DCM
rt rt rt rt rt rt rt rt rt rt rt rt
3 3 3 24 24 24 24 24 3 3 3 24
10 100 100 8 5 6
