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Highly Regioselective, Acid Catalyzed, Three-Component Cascade Reaction for the Synthesis of 2-aminopyridine-Decorated Imidazo[1,2-a]pyridine Qiu-Xing He, Yao-Feng Liang, Chang Xu, Xiao-Kun Yao, Hua Cao, and Hua-Gang Yao ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/acscombsci.8b00149 • Publication Date (Web): 17 Jan 2019 Downloaded from http://pubs.acs.org on January 21, 2019
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ACS Combinatorial Science
Highly Regioselective, Acid Catalyzed, Three-Component Cascade Reaction
for
the
Synthesis
of
2-aminopyridine-Decorated
Imidazo[1,2-a]pyridine Qiu-Xing He,a, * Yao-Feng Liang,a Chang Xu,a Xiao-Kun Yao,a Hua Cao a and Hua-Gang Yao,a, * a
School of Chemistry and Chemical Engineering and Guangdong Cosmetics Engineering &
Technology Research Center, Guangdong Pharmaceutical University, Zhongshan 528458, China
ABSTRACT: A highly regioselective acid-catalyzed three-component reaction of 2-aminopyridine and 3-phenylpropiolaldehyde for the construction of imidazo[1,2-a]pyridine has been developed. This strategy provides a broad range of substrates and represents an efficient approach to give various 2-aminopyridine-decorated imidazo[1,2-a]pyridine in good yields. KEYWORDS: Pivalic acid, 2-aminopyridine, three-component reaction, imidazo[1,2-a] pyridine
Considerable efforts have been devoted to developing new Imidazo[1,2-a]pyridine-based heterocycles compounds1-4, that is, a single compound that displays the coexistence or synergism of two or more properties including obvious inhibitory effects on many target enzymes5-7 and good bioactivity in the aspect of anti-tumor8-12, anti-virus13-15, anti-bacterial16-18, anti-tuberculosis19,20, anti-inflammatory21, antiulcer22, anti-diabetic23, antipsychotic24,25, etc. 3-Substituted imidazo[1,2-a]pyridines are of particular interest, because of their potential applications in many commercially available drugs such as necopidem, alpidem, saripidem, minodronic acid. The versatility and value of these Imidazo[1,2-a]pyridine derivatives for a wide range of applications feeds the continuous synthetic drive for novel and better synthetic strategies, including oxidative cross-coupling, multi-component reaction26-34. Despite the fact that much progress has been made in the synthesis of these derivatives, there still remains great challenges for synthetic organic chemists in developing a facile approach for the direct synthesis of 3-2-aminopyridine-decorated imidazo[1,2-a]pyridines. For example, Mareev35 et al. first reported the synthesis of 3-[2-pyridylamino(phenyl) methyl]imidazo[1,2-a]pyridine by employing phenylpropynal and 2-aminopyridine (Scheme 1, a). Unfortunately, only one product has been synthesized under their protocol. Subsequently, we disclosed an efficient one-pot methodology for the synthesis of these compounds via AcOH catalysis (Scheme
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1, b) and a series of imidazo[1,2-α]pyridines were obtained in high to excellent yields36. However ， there are still some limitations and inconveniences of this protocol. The substituted pyridine-2-amine used to undergo a Michael type addition to finish the transformation should be the same as the one reacted with the aldehyde to form the imine intermediate during the first step of the reaction. This seriously restricted the further application of a diversity oriented synthesis. Therefore, the development of new catalytic systems to achieve two different 2-aminopyridine reactions for the direct construction of multifunctional imidazo[1,2-a]pyridines is still of great importance. In this context, our group envisions to construct 2-aminopyridine-decorated imidazo[1,2-a]pyridine derivatives via a three-component reaction of 2-aminopyridines and 3-phenylpropionaldehyde.
Scheme 1
Syntheses of N-(imidazo[1,2-a]pyridin-3-yl(phenyl) methyl)2-aminopyridine
(a) Mareev et al. work:
N
Ph
CHO
NH2
5 mol% HCl MeCN 25 oC
+
H N
N
N N only one example
Ph (b) Our previous work: R1
R
CHO AcOH CH3CN
+ N
NH2
1
N
o
80 C 8 h
R1
N N
R1
R
H N
R = Cl, CF3 (c) This work: R
CHO R
1
+ N
NH2
R + NH2 2
N
R1 R
N
H N
R2
N N
In the beginning, the model reaction of 2-amino-3-methylpyridin 1{1}, 5-(trifluoromethyl)-2-aminopyridine 1{5} and 3-phenylpropiolaldehyde 2{1} were conducted to determine the suitable reaction conditions37. The results are described in Table 1. The desired product 3{1,5,1} was not obtained without any catalysts in dioxane at room temperature (entry 1). We then attempted to increase the yield of product 3{1,5,1} by adding variety of catalysts. Using 5 mol % PivOH in dioxane at room temperature afforded a yield of 42% (entry 2), but the addition of benzoic acid,
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ACS Combinatorial Science
AcOH, TsOH, TFA, ZnCl2, FeCl3, FeCl2, showed that the product 3{1,5,1} was formed in relatively lower yield or not detected (entries 3-10). It is interesting to note that the temperature changes significantly affect the yield. The results indicated that the reaction at 60 °C was the most suitable (entry 2, 9-13). In order to improve the reaction efficiency, we evaluated the influence of various solvents. Among the solvents, we were delighted to find that the product 3{1,6,1} was readily formed in 92 % yield in CH2Cl2. Other solvents, such as DMSO, DMF, or toluene, did not lead to any improved result (entries 14-19). Table 1.
Optimization of the reaction conditionsa
NH2 F3C N 1{1}
Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
+
NH2 N
CHO
+ Ph 2{1}
1{5}
Catalyst PivOH Benzoic Acid AlCl3 AcOH TsOH TFA ZnCl2 FeCl3 FeCl2 PivOH PivOH PivOH PivOH PivOH PivOH PivOH PivOH PivOH
N
solvent, N2, 8 h
N
Solvent 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane 1,4-dioxane DMSO DMF CH2Cl2 toluene DCE THF
N
Ph
catalyst, temp
T (oC) rt rt rt rt rt rt rt rt rt rt 60 80 100 60 60 60 60 60 60
a Reaction
CF3
N H 3{1,5,1}
Yield b (%) N.P. 42 28 30 14 17 14 trace trace N.P. 67 65 64 23
