Introduction

Isocyanide is a unique and attractive functional group in organic chemistry. The carbon atom of isocyanide has both a lone electron pair and empty orbitals, so it has outstanding electrophilic and nucleophilic reactivity. At the same time, isocyanide also has good coordination ability to coordinate with metals to form diverse metal complexes . Therefore, isocyanides have been known as indispensable building blocks in modern organic chemistry. Many isocyanide-based carbon–carbon and carbon–heteroatom bond forming reactions have been developed in fascinating ways over the past decades . The famous multicomponent reactions such as Passerini reaction, Ugi reaction, Orru reaction and Van Leusen reaction, in which isocyanides were employed as key substrates have become the most powerful tools for rapid construction of various nitrogen-containing organic compounds . On the other hand, the reactive Huisgen’ 1,4-dipoles can be in situ generated by addition reaction of isocyanides to electron-deficient alkynes, which were sequentially trapped by various electrophiles and nucleophiles to give versatile acyclic and heterocyclic compounds . In recent years, many multicomponent reactions based on alkyl isocyanides, electron-deficient alkynes and other reagents have been successfully developed for the synthesis of various carbocyclic and heterocyclic compounds .

The 5,6-unsubstituted 1,4-dihydropyridine is one of special kinds of 1,4-dihydropyridines. It can act as an activated enamino unit and electron-rich dienophile to take part in some synthetic reactions . In recent years, 5,6-unsubstituted 1,4-dihydropyridines have been recognized as the reactive electron-rich dienophiles, which proceeded several Povarov reactions with various 1-aza-1,3-butadienes . Recently, we have found that the three-component reaction of isoquinolines, dialkyl but-2-ynediaotes and 5,6-unsubstituted 1,4-dihydropyridines afforded functionalized isoquinolino[1,2-f][1,6]naphthyridines in good yields and with high diastereoselectivity via a [4 + 2] cycloaddition process . Very recently, we also found that base-promoted [4 + 2] cycloaddition of salicyl N-tosylimines and 5,6-unsubstituted 1,4-dihydropyridines resulted in novel tetrahydrochromeno[3,2-b]pyridine derivatives in satisfactory yields . Inspired by these efficient synthetic protocols and in continuation of our aim to develop isocyanide-based multicomponent reactions for construction of diverse nitrogen-containing heterocyclic compounds , herein we wish to report the mutlicomponent reaction of alkyl isocyanides, dialkyl but-2-ynedioates and 5,6-unsubstituted dihydropyridines for the efficient synthesis of polyfunctionalized tetrahydrocyclopenta[4,5]pyrrolo[2,3-b]pyridine-3,4b,5,6,7(1H)-pentacarboxylates.

Results and Discussion

Initially, the reaction conditions were examined by employing cyclohexyl isocyanide (1a), dimethyl but-2-ynedioate (2a) and 5,6-unsubstituted dihydropyridine 3a as standard reaction. The main results are summarized in Table 1. The expected product was not observed when the three-component reaction was carried out in methanol, ethanol or tetrahydrofuran at room temperature (Table 1, entries 1–3). The reaction in toluene, methylene dichloride or acetonitrile at room temperature afforded an unexpected tricyclic compound 4a in 12–18% yields (Table 1, entries 4–6). 1H NMR spectra clearly indicated that two molecules of dimethyl but-2-ynedioates took part in the reaction. The yields of the product 4a slightly increased to 29–45% yields when the reaction was carried out at elevated temperature in toluene, methylene dichloride or acetonitrile (Table 1, entries 7–10). When the reaction was carried out in refluxing acetonitrile, the tricyclic compound 4a can be obtained in 47% yield (Table 1, entry 11). Then, the stoichiometry of dimethyl but-2-ynedioate was examined (Table 1, entries 12–15). The highest yield of 4a (89%) was obtained by employing five equiv of dimethyl but-2-ynedioate in the reaction (Table 1, entry 15). It can be found that the reaction can be finished in less than one hour. In the presence of DABCO as base catalyst, the yield of 4a decreased to 27% (Table 1, entry 16). Other common bases such as Et3N and DMAP were also employed in the reaction, they did no gave the product 4a in higher yields than that in the absence of any base, which showed that the reaction does not need any base promotor (Table 1, entry 17 and 18). It was also found that the yield of product 4a cannot be increased when the reaction time was prolonged to three hours (Table 1, entry 19). Thus, the optimized reaction conditions for this multicomponent reaction were successfully established.

Table 1: Optimizing reaction conditionsa.

Entry Base Ratio of
1a/2a/3a Solvent Temp (°C) Time (h) Yield (%)b 1   1.5:3:1 MeOH rt 6 – 2   1.5:3:1 EtOH rt 6 – 3   1.5:3:1 THF rt 6 – 4   1.5:3:1 PhMe rt 1 12 5   1.5:3:1 CH2Cl2 rt 1 13 6   1.5:3:1 MeCN rt 1 18 7   1.5:3:1 CH2Cl2 reflux 1 29 8   1.5:3:1 PhMe reflux 1 45 9   1.5:3:1 MeCN 40 °C 1 27 10   1.5:3:1 MeCN 60 °C 1 40 11   1.5:3:1 MeCN reflux 1 47 12   1:2:1 MeCN reflux 1 52 13   1:3:1 MeCN reflux 1 62 14   1:4:1 MeCN reflux 1 71 15   1:5:1 MeCN reflux 1 89 16 DABCO 1:5:1 MeCN reflux 1 27 17 Et3N 1:5:1 MeCN reflux 1 70 18 DMAP 1:5:1 MeCN reflux 1 39 19   1:5:1 MeCN reflux 3 87

aReaction conditions: cyclohexyl isocyanide (0.1 mmol), dialkyl but-2-ynedioate, 1,4-dihydropyridine, acetonitrile (5.0 mL); bisolated yields.

Under the optimized reaction conditions, the scope of the reaction was developed by using various substrates. The results are summarized in Table 2. At first, several alkyl isocyanides such as cyclohexyl, tert-butyl and benzyl isocyanide have been successfully employed in the reaction. Dimethyl but-2-ynedioate usually gave the expected tricyclic products in good yields. However, the reaction with diethyl but-2-ynedioate afforded products 4p, 4r and 4t in moderate to lower yields. The 5,6- unsubstituted dihydropyridines with various substituents showed marginal effects on the yields. These results clearly showed that this reaction has a wide scope of substrates. The obtained compounds 4a–t have four chiral carbon atoms. The multicomponent reaction might result in several diastereomers. On the basis of TLC analysis and 1H NMR spectra of the crude products, only one relative stereochemistry was produced in the reaction, while the other diastereomers were not detected. In order to elucidate the relative configuration of the obtained compounds, the molecular structure of the compound 4a was determined by single crystal X-ray diffraction (Figure 1). From Figure 1, it can be seen that the fused dihydropyridine ring connects with the pyrrolidine ring in cis-position. The 4-aryl group exists on the trans-position to the 2,3-pyrrolidine ring. The methoxycarbonyl group in the ring of the cyclopentadiene stretches to the cis-position of the 4-aryl group in the dihydropyridine ring. Thus, it can be assigned that all tricyclic compounds have this kind of relative configuration on the basis of NMR spectra and single crystal structure.

Table 2: The synthesis of the tricyclic compounds 4a–ta.

Entry Compound R1 R2 Ar R3 R4 Yield (%)b 1 4a cyclohexyl CH3 o-CH3OC6H4 Bn CH3 89 2 4b cyclohexyl CH3 p-NO2C6H4 Bn CH3 84 3 4c cyclohexyl CH3 p-CH3C6H4 Bn CH3 81 4 4d cyclohexyl CH3 o-CH3OC6H4 p-CH3OC6H4CH2 CH3 84 5 4e cyclohexyl CH3 C6H5 p-ClC6H4CH2 CH3 82 6 4f cyclohexyl CH3 C6H5 Bn CH3 90 7 4g cyclohexyl CH3 C6H5 o-CH3C6H4CH2 CH3 81 8 4h cyclohexyl CH3 C6H5 o-ClC6H4CH2 CH3 80 9 4i cyclohexyl CH3 C6H5 m-CH3OC6H4CH2 CH3 80 10 4j cyclohexyl CH3 C6H5 p-CH3OC6H4 CH3 87 11 4k cyclohexyl CH3 C6H5 p-BrC6H4 CH3 93 12 4l cyclohexyl CH3 C6H5 m-ClC6H4 CH3 92 13 4m cyclohexyl CH3 o-CH3OC6H4 o-CH3C6H4 CH3 93 14 4n cyclohexyl CH3 C6H5 n-Bu CH3 80 15 4o cyclohexyl CH3 C6H5 Bn CH2CH3 79 16 4p cyclohexyl CH2CH3 C6H5 Bn CH3 72 17 4q t-Bu CH3 C6H5 Bn CH3 66 18 4r t-Bu CH2CH3 C6H5 Bn CH3 58 19 4s Bn CH3 C6H5 Bn CH3 54 20 4t Bn CH2CH3 C6H5 Bn CH3 30

aReaction conditions: cyclohexyl isocyanide (0.1 mmol), dialkyl but-2-ynedioate (0.5 mmol), 1,4-dihydropyridine (0.1 mmol), acetonitrile (5.0 mL), reflux, 1 h; bisolated yields.

Figure 1: Molecular structure of compound 4a.

In order to develop the scope of the reaction, another kind of 5,6-unsubstituted 1,4-dihydropyridines 5 were also employed in the reaction, which were previously prepared from the three-component reaction of methyl propiolate, cinnamaldehyde and arylamines. The results are summarized in Table 3. It should be pointed out that TLC analysis and 1H NMR spectra of the crude products usually indicated that only one diastereomer was predominately produced in the reaction even though there are four chiral carbon atoms in the products. It can be found that all reactions proceeded smoothly to give the expected polycyclic compounds 6a–k in satisfactory yields. The substituents on the three components showed very little effect on the yields. These results showed that this reaction can be performed with a wide variety of substrates. The molecular structure of the compound 6g was determined by single crystal X-ray diffraction method (Figure 2). The o-methoxyphenyl group exists on the trans-position of the fused pyrrolidine unit. The methoxycarbonyl group also exists on the cis-position of the o-methoxyphenyl group. Therefore, compound 6g has the same relative configuration to that of the above mentioned product 3a, which also indicated that this reaction has same steric controlling effect.

Table 3: The synthesis of the tricyclic compounds 6a–ka.

Entry Compd R1 R2 Ar R3 Yield (%)b 1 6a cyclohexyl CH3 C6H5 Bn 92 2 6b cyclohexyl CH3 C6H5 m-CH3OC6H4CH2 82 3 6c cyclohexyl CH3 C6H5 o-CH3C6H4CH2 83 4 6d cyclohexyl CH3 C6H5 p-CH3C6H4 83 5 6e cyclohexyl CH3 C6H5 m-ClC6H4 84 6 6f cyclohexyl CH3 C6H5 o-CH3C6H4 81 7 6g cyclohexyl CH3 o-CH3OC6H4 p-BrC6H4 88 8 6h cyclohexyl CH3 p-NO2C6H4 p-BrC6H4 82 9 6i cyclohexyl CH2CH3 C6H5 Bn 77 10 6j t-Bu CH3 C6H5 Bn