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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 J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 17 May 2018 Downloaded from http://pubs.acs.org on May 17, 2018
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The Journal of Organic Chemistry
Gold(III)-Catalyzed Selective Cyclization of Alkynyl Quinazolinonetethered Pyrroles: Synthesis of Fused Quinazolinone Scaffolds
Lin-Su Wei,a,# Guo-Xue He,a,# Xiang-Fei Kong,a,b Cheng-Xue Pan,a,* Dong-Liang Mo,a,* and Gui-Fa Sua,*
a
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 b
College of Chemistry and Bioengineering, Guilin University of Technology, 12 Jian
Gan Road, Guilin 541004, China O R1
O 3 N
1 N
R2 N
N
R1
R1
Me AuCl3 5 mol%
3 N
R
6-exo-dig R2
O
O
R3
1 N N
13 examples 15 - 91% yields
R3
R3 O
R2 N
N
[1,3]-rearrangement 6-exo-tr ig
Me +
N
1
R2 R3 = H
N
R3
N
N
or 7-endo-dig
N
11 examples 83 - 98% yields
Me
N
R3 H 3 examples 75 - 83% yields
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 2,3fused quinazolinones. The fused quinazolinones could be prepared at gram scale in three steps from commercial ortho-aminobenzamide. 1
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Quinazolinones are among the most important nitrogen heterocyclic compounds, not only used as powerful organic intermediates or occurred in natural products,1 but also served as pharmacophores playing important roles on the bioactivity.2 Pharmaceutical researches 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 studied well and many strategies have been developed to prepare or modify these compounds, such as rutaecarpine and (–)-circudatin B (Figure 1).4 However, 1,2-fused quinazolinones are rarely reported and only a few scaffolds were synthesized, such as isoindolo-fused quinazolinone derivatives, which have been found to be served as potent inhibitors of TNF-α (Figure 1).5 Thus, development of new efficient methods for the construction of functionalized 1,2-fused quinazolinones is desirable and valuable for the bioactive studies of these scaffolds. O O O
NH O
3
N 2
MeO
N
N 1
HN
NH
N
O N
N
N N O O
Rutaecarpine
(-)-Circudatin B
inhibitor of TNF-
inhibitor of TNF-
Figure 1. Some examples of biologically active fused quinazolinones.
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 its 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 gold-catalyzed cyclizations have widely investigated, control of regioselectivity in these reactions is 2
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still challenging.9 In 2011, Broggini and coworkers 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 1-A).10 Continued to study the mechanisms of gold-catalyzed intramolecular cyclization reactions of terminal alkyne and phenyl-substituted alkyne-tethered pyrroles, Lin and coworker 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 coworkers 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 1-B).12 It could be seen that gold-catalyzed 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 coworkers reported a basemediated prototropic isomerization of propargyamides and a sequence of AuCl3catalzyed hydroamination of 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 1-C). Herein, we reported a gold-catalyzed 3
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highly selective cyclization of N1 or N3 alkynyl quinazolinone-tethered pyrroles to access various fused quinazolinone scaffolds under mild conditions.
Scheme 1. Gold-catalyzed intramolecular cyclizations of pyrrole-ynes. 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 AuPPh3OTf or combined with 1,10-phenanthroline did not afford 4
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The Journal of Organic Chemistry
product 2a and only 1a was recovered (Table 1, entries 14-15). These results indicated that Au(I) species could not catalyze this cyclization reaction. Reducing the amount of AuCl3 to 1 mol% only afforded product 2a in 6% yield even with longer reaction time for 24 h (Table 1, entry 16). Other transition-metal catalysts were also examined. Using PdCl2 afforded product 2a in 50% yield, however, less than 15% yield of 2a was observed by using FeCl3, CuI, AgNO3, or PtCl2 even at high temperature (Table 1, entries 17-21).15 Therefore, the optimal conditions for cyclization of 1a to 2a were 5 mol% of AuCl3 in DCM at room temperature for 3 h (Table 1, entry 3). Table 1. Optimization of 6-exo-dig cyclization of N1-alkynyl quinazolinone-tethered pyrrole 1a.a O
O N
N
Me N
Catalyst
N
Solvent
N
Me N
Me 2a
1a
time (h) conversion (%)b
yield (%)c
entry
catalyst (5 mol%)
solvent
T (°C)
1
AuCl3
toluene
rt
3
10
5
2
AuCl3
CHCl3
rt
3
100
78
3
AuCl3
DCM
rt
3
100
83
4
AuCl3
THF
rt
24
8
5
5
AuCl3
MeCN
rt
24
5
-
6
AuCl3
dioxane
rt
24
6
-
7
AuCl3
MeOH
rt
24
