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Iridium(III)-Catalyzed Tandem Annulation Synthesis of Pyrazolo [1,2-#] Cinnolines from Pyrazolones and Sulfoxonium Ylides Chen-Fei Liu, Man Liu, and Lin Dong J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02582 • Publication Date (Web): 06 Dec 2018 Downloaded from http://pubs.acs.org on December 7, 2018
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The Journal of Organic Chemistry
Iridium(III)-Catalyzed Tandem Annulation Synthesis of Pyrazolo [1,2-α] Cinnolines from Pyrazolones and Sulfoxonium Ylides Chen-Fei Liu,+ Man Liu,+ and Lin Dong* Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, West China School of Pharmacy, Sichuan University, Chengdu 610041,China [+] These authors contribute equally to the work.
Corresponding author: Lin Dong E-mail:
[email protected] Graphic Abstract
Abstract: A highly efficient iridium-catalyzed cascade annulation of pyrazolones and sulfoxonium ylides to access various pyrazolo [1,2-α] cinnoline derivatives has been achieved. This novel approach expanded the application scope of coupling partners to ylides. The control experiments were performed to give insight to the mechanism of this reaction.
Cinnolines represent an important class of nitrogen-containing heterocycles with diverse biological and pharmacological activities.1 Due to their challenging frameworks and appealing properties, both synthetic and medicinal chemists have been devoted to constructing such heterocycles, but most of the approaches suffer from multistep synthetic processes and the harsh reaction conditions.2 Thus, to fully disclose the pharmacological potential of cinnoline derivatives, efficient and simple synthetic strategies are highly desirable.
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In view of the advances in transition-metal-catalyzed C–H activation, especially the achievements to construct intricate organic molecules and many natural products, C−H functionalization has emerged as versatile methods in the past few decades.3 Cinnolines have also been studied by many groups via C−H activation.4 However, to our knowledge, there are only a few examples of synthesizing pyrazolo [1,2-α] cinnoline skeleton.5-7 Huang and Lin et al utilized pyrazolidinones to construct such a unit (Scheme 1, eqs 1 and 2).6a,7b Very recently, Zhang et al reported an alternative synthesis of cinnoline complex through rhodium-catalyzed oxidative coupling of N-aryl-1H-pyrazol5(4H)-ones with various alkynes (Scheme 1, eq 3).5 It is generally known that 3-methyl-1-phenyl-1H-pyrazol5(4H)-one as a new pyrazolin compound namely Edaravone also known as MCI-186 is the first novel neuroprotective, antioxidant medical drug. In addition, pyrazole units have also been widely implicated in pharmaceutical molecules (Figure 1).8,9
Figure 1. Drugs Bearing Pyrazole Units
Therefore, this unique unit of pyrazolo [1,2-α]cinnoline derivatives has aroused our great interest, which might have more potential application value and activities. Herein, we described a novel approach to access wider pyrazolo [1,2-α] cinnoline derivatives via iridium(III)-catalyzed tandem annulation between 3-methyl-1-phenyl-1H-pyrazol5(4H)-ones and sulfoxonium ylides (Scheme 1, eq 4).10
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The Journal of Organic Chemistry
Scheme 1. Synthesis of Cinnolines via C−H Activation
We commenced our investigation with the screening of reaction parameters for the coupling of 3-methyl-1phenyl-1H-pyrazol-5(4H)-one (1a) and sulfoxonium ylide (2a) (Table 1). In the presence of a catalytic amount of [IrCp*Cl2]2 (5 mol %) and Zn(OTf)2 (0.5 equiv) in TFE at 120 °C for 12 h, the desired product 3aa was obtained, although albeit in a low yield (entries 1-4). To our delight, the addition of silver salts could effectively enhance the reaction activity and AgSbF6 turned out to be the optimal one (entries 5–8). It is noteworthy to mention, the reaction afforded negative efficiency in the absence of Zn(OTf)2 (entries 9 and 10). However, other solvents including DCE and several proton solvents were less active giving 3aa in lower yields (entries 11–14). Satisfyingly, further introduction of TsOH into the reaction system intensively improved the yield of 3aa to 92% (entries 15-17). Decreasing the loading of Zn(OTf)2 resulted in a higher yield (entry 18). In contrast, an inferior yield was observed by reducing the amount of TsOH (entry 19). In addition, 67% yield was obtained by using polar aprotic solvent CH3CN (entry 20). Moreover, decreasing the temperature gave inferior result (entry 21). In addition, different material ratio gave relatively low yield (entry 22). In addition, to evaluate the synthetic potential of this methodology, a gram scale reaction of 3aa was carried out: 1a (6 mmol) smoothly reacted with sulfoxonium ylide 2a (4 mmol), affording the desired product 3aa still in good yield (entries 23 and 24). Table 1. Optimization of the Reaction Conditionsa
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entry
catalyst
additive/[equiv.]
acid/[equiv.]
solvent
yield b (%)
1
[Cp*IrCl2]2
Zn(OTf)2/0.5
-
TFE
26
2
[Cp*RhCl2]2
Zn(OTf)2/0.5
-
TFE
15
3
[Cp*CoCl2]2
Zn(OTf)2/0.5
-
TFE
ND
4
Ru(PPh3)3Cl2
Zn(OTf)2/0.5
-
TFE
ND
5
[Cp*IrCl2]2
AgBF4/0.2 + Zn(OTf)2/0.5
-
TFE
ND
6
[Cp*IrCl2]2
AgSbF6/0.2 + ZnOTf)2/0.5
-
TFE
70
7
[Cp*IrCl2]2
AgNTf2/0.2 + Zn(OTf)2/0.5
-
TFE
43
8
[Cp*IrCl2]2
AgOTf /0.5 + Zn(OTf)2/0.5
-
TFE
63
9
[Cp*IrCl2]2
AgSbF6/0.2 + Zn(OAc)22H2O/0.5
-
TFE
ND
10
[Cp*IrCl2]2
AgSbF6/0.2 + AgOTf/0.5
-
TFE
42
11
[Cp*IrCl2]2
AgSbF6/0.2 + Zn(OTf)2/0.5
-
DCE
37
12
[Cp*IrCl2]2
AgSbF6/0.2 + Zn(OTf)2/0.5
-
HFIP
54
13
[Cp*IrCl2]2
AgSbF6/0.2 + Zn(OTf)2/0.5
-
MeOH
ND
14
[Cp*IrCl2]2
AgSbF6/0.2 + Zn(OTf)2/0.5
-
t-BtOH
