Rapid construction of tricyclic tetrahydrocyclopenta[4,5]pyrrolo[2,3-b]pyridine via isocyanide-based multicomponent reaction

An efficient protocol for the synthesis of polyfunctionalized tetrahydrocyclopenta[4,5]pyrrolo[2,3-b]pyridine-3,4b,5,6,7(1H)-pentacarboxylates was developed by a three-component reaction. In the absence of any catalyst, the three-component reaction of alkyl isocyanides, dialkyl but-2-ynedioates and 5,6-unsubstituted 1,4-dihydropyridines in refluxing acetonitrile afforded polyfunctionalized tetrahydrocyclopenta[4,5]pyrrolo[2,3-b]pyridine-3,4b,5,6,7(1H)-pentacarboxylates in high yields and with high diastereoselectivity. The reaction was finished by in situ generation of activated 5-(alkylimino)cyclopenta-1,3-dienes from addition of alkyl isocyanide to two molecules of but-2-ynedioates and sequential formal [3 + 2] cycloaddition reaction with 5,6-unsubstituted 1,4-dihydropyridine.


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). 1 H 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 ( ).Other common bases such as Et 3 N 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.
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-un- substituted 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 1 H 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.
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 threecomponent reaction of methyl propiolate, cinnamaldehyde and arylamines.The results are summarized in Table 3.It should be pointed out that TLC analysis and 1 H 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-po-Scheme 1: Proposed reaction mechanism.
sition 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.In consideration of the high diastereoselectivity of the reaction, the concerted addition process is much more likely.However, it is difficult to distinguish between these two reaction processes at present.

Conclusion
In summary, we investigated the three-component reaction of alkyl isocyanides, dialkyl but-2-ynedioates and 5,6-unsubstituted 1,4-dihydropyridines in refluxing acetonitrile.This reaction provided an efficient synthetic protocol for the polyfunctionalized tetrahydrocyclopenta [4,5]pyrrolo[2,3-b]pyridine-3,4b,5,6,7(1H)-pentacarboxylates in high yields and with high diastereoselectivity.A novel example of an activated intermediate derived from the reaction of alkyl isocyanide and two molecules of but-2-ynedioate was successfully explored in the reaction.This reaction has the advantages of using readily available reagents, simple reaction conditions, high atomic convergence and atomic economy, which might be found potential applications in heterocyclic chemistry.

Experimental General procedure for the multicomponent reaction
To a round flask was added alkyl isocyanide (0.1 mmol), dialkyl but-2-ynedioate (0.5 mmol), 5,6-unsubstitued 1,4-dihydropyridine (0.1 mmol) and acetonitrile (5.0 mL).The solution was stirred at reflux temperature for nearly one hour.After removing the solvent by rotatory evaporation at reduced pressure, the residue was subjected to column chromatography with a mixture of ethyl acetate and petroleum ether (v/v = 1:4) as eluent to give the pure product for analysis.

Table 1 :
Optimizing reaction conditions a .

Table 2 :
The synthesis of the tricyclic compounds 4a-t a .

Table 1 ,
16tries 7-10).When the reaction was carried out in refluxing acetonitrile, the tricyclic compound 4a can be obtained in 47% yield (Table1, entry 11).Then, the stoichiometry of dimethyl but-2ynedioate was examined (Table1, entries 12-15).The highest yield of 4a (89%) was obtained by employing five equiv of dimethyl but-2-ynedioate in the reaction (Table1, 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% (Table1, entry16

Table 3 :
The synthesis of the tricyclic compounds 6a-k a .