Letter pubs.acs.org/OrgLett
One-Pot Regiospecific Synthesis of Imidazo[1,2‑a]pyridines: A Novel, Metal-Free, Three-Component Reaction for the Formation of C−N, C−O, and C−S Bonds Hua Cao,*,† Xiaohang Liu,‡ Limin Zhao,† Jinghe Cen,† Jingxin Lin,† Qiuxia Zhu,† and Minling Fu† †
School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Guangzhou 510006, P.R. of China BASF Catalyst, 23800 Mercantile Road, Beachwood, Ohio 44124, United States
‡
S Supporting Information *
ABSTRACT: A novel transition-metal-free three-component reaction for the construction of imidazo[1,2-a]pyridines has been developed. It represents a facile approach for the formation of C−N, C−O, and C−S bonds from ynals, pyridin-2-amines, and alcohols or thiols.
T
adding catalysts. As shown in Table 1, the reaction could be catalyzed by AcOH (entry 10). But, the product 4a was formed with low yield or not detected in the presence of DABCO, DBU, THT, PPh3, K2CO3, Na2CO3, NaHCO3, or L-proline (entries 2−9, 11). Lewis acids, such as ZnCl2, FeCl3, and AlCl3, were also examined, which failed to produce the desired products (entries 12−14). The addition of Lewis acid also led to zero recovery of substrates. Interestingly, the corresponding product 4a was obtained in 76% and 83% yields when the reactions were carried out at 50 and 80 °C, respectively (entries 15−17). The result clearly indicated that the transformation was sensitive to temperature variations. The effects of solvents were next examined (entries 18−21). Among the solvents, we were delighted to find that the product 4a was readily formed in 87% or 89% yields in CH3CN or C2H5OH, respectively. Other solvents, such as DMF, DMSO, and toluene, were also afforded in moderate to good yields. Finally, the optimization of reaction time showed that 8 h was optimal (entries 22 and 23). In order to explore the scope of this transformation, a variety of pyridin-2-amines, ynals, and alcohols, or thiols were evaluated under the optimized reaction conditions. First, 1a and 3a were fixed as substrates to test various substituted pyridin-2-amines. The results are described in Scheme 1. Various substituted pyridin-2-amines reacted well with 1a, 3a and led to the desired product 4a−l in good to high yields. Different substituents on the pyridine ring, such as CH3, F, Cl, Br, I, and CF3, led to a beneficial effect on the reaction outcome. For the reaction of 1a, 2, and 3a, pyridin-2-amines substituted with both electron-rich groups and electron-poor groups were suitable partners and gave the desired products in good yields. It is also worth noting that multisubstituted pyridin-2-amine, 5-chloro-3-iodopyridin-2-amine, and 3,5-dibromo-4-chloropyridin-2-amine reacted with 1a and 3a more smoothly under the optimized conditions. However, when 2-
he imidazo[1,2-a]pyridines are an important target in organic synthetic chemistry1 and have attracted critical attention of chemists for their application value. They are found in a large number of natural products and bioactive molecules, many of which exhibit a broad range of biological activities, such as antiviral,2 antiprotozoal,3 antiherpes,4 and antiapoptotic.5 The core structure of imidazo[1,2-a]pyridines has also been found in many drugs such as zolpidem, alpidem, zolimidine, olprinone, saripidem, and necopidem.6 It is not surprising, therefore, that great efforts have been directed toward developing synthetic approaches for the construction of this privileged structure.7 Recently, a variety of significant and elegant metal-catalyzed methods8 have been developed for the synthesis of imidazo[1,2-a]pyridine derivatives. However, most of the metal catalysts are costly and toxic to some degree, which limit their applications. Therefore, the development of a metalfree strategy9 to form C−N, C−O, and C−S bonds represents an attractive area of research for the construction of those heterocycles.10 On the other hand, metal-free, three-component reactions (MCRs) represent powerful tools for the rapid preparation of diverse and complex molecules with an optimal number of new bonds and functionalities from readily accessible starting materials in a single operation under mild conditions.11 Very recently, we have developed an efficient transformation to construct functionalized furans and imidazo[1,2-a]pyridine.12 In this context, we described a novel transformation to prepare3- heteroatom substituted (O, N, S)-substituted imidazo[1,2-a]pyridines which appeared as key structural units in many important bioactive compounds.13 Initially, 3-phenylpropiolaldehyde 1a, pyridin-2-amine 2a, and ethanol 3a were chosen as model substrates. The results of the optimization study for the MCRs synthesis of 4a are summarized in Table 1. A variety of catalysts in conjunction with different temperatures, solvents, and time were screened. First, the desired product 4a was formed in 7% yield without any catalysts in DMF at room temperature (entry 1). The result encouraged us to improve the yield of this novel MCRs by © 2013 American Chemical Society
Received: October 31, 2013 Published: December 9, 2013 146
dx.doi.org/10.1021/ol4031414 | Org. Lett. 2014, 16, 146−149
Organic Letters
Letter
Table 1. Optimization of Reaction Conditions.a
Scheme 2. Construction of Imidazo[1,2-a]pyridinesa
entry
catalyst
temp (°C)
solvent
time (h)
yieldb (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
DABCO DBU Py THT PPh3 K2CO3 Na2CO3 NaHCO3 AcOH L-proline ZnCl2 FeCl3 AlCl3 AcOH AcOH AcOH AcOH AcOH AcOH AcOH AcOH AcOH
rt rt rt rt rt rt rt rt rt rt rt rt rt rt 50 80 100 80 80 80 80 80 80
DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMSO CH3CN C2H5OH toluene CH3CN CH3CN
8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 12 4
7
