Copper-catalyzed multicomponent reactions for the efficient synthesis of diverse spirotetrahydrocarbazoles

In the presence of copper sulfate, three- or four-component reactions of 2-methylindole, aromatic aldehydes and various cyclic dienophiles in refluxing toluene afforded diverse spirotetrahydrocarbazoles. This reaction is an important development of the Levy reaction by using 2-methylindole to replace ethyl indole-2-acetate and successfully provides facile access to important polysubstituted spiro[carbazole-3,3'-indolines], spiro[carbazole-2,3'-indolines], spiro[carbazole-3,5'-pyrimidines] and spiro[carbazole-3,1'-cycloalkanes] in satisfactory yields and with high diastereoselectivity.


Results and Discussion
Initially, (E)-1-benzyl-3-(2-oxo-2-phenylethylidene)indolin-2one, benzaldehyde, and 2-methylindole served as model substrates for the optimization of reaction conditions. Inspired by our previous work [75][76][77], we first screened different catalysts ( Table 1, entries 1−5) with toluene as the solvent and found that CuSO 4 was the best choice, providing 1a in 58% isolated yield. Notably, the yield of the byproduct 1a' was also obtained in less than 5% yield, which indicated the high diastereoselectivity of this reaction. Several other solvents such as EtOH and MeCN were explored, the product 1a was formed in lower yields (Table 1, entries 6  and 7). Importantly, the reaction also proceeded smoothly when the temperature was reduced to 90 °C and with better yield at 110 °C (Table 1, entries 8 and 9). Moreover, different reaction times and the catalyst loadings were also examined ( Table 1, entries 10-12), but no better results were observed. Therefore, a mixture of 2-methylindole (0.5 mmol), benzalde- hyde (0.6 equiv), and 3-methyleneoxindole (1.0 equiv) with CuSO 4 (0.1 mmol) as the catalyst in toluene (10.0 mL) reacting at 110 °C for 3 h were selected as the optimal reaction conditions.
Having established the optimal reaction conditions, we first sought to determine the generality of the aromatic aldehydes. As illustrated in Scheme 2, the reaction usually resulted in a mixture of major isomers 1a-j and the minor isomers 1a'-j' with the molecular ratios of 6:1 to 20:1. Aromatic aldehydes with both electron-donating and electron-withdrawing groups were compatible. This reaction tolerated many kinds of functional groups, including Me (1b), OMe (1c and 1j), Cl (1d, 1e and 1f), and NO 2 (1g, 1h and 1i) groups. Besides different aromatic aldehydes, we further tested the generality of various 3-phenacylideneoxindoles. Unsurprisingly, a wide range of 3-methyleneoxindoles containing different substituents at various positions (1e-j) reacted smoothly to give the corresponding products with good to excellent diastereoselectivity. A protecting n-butyl group (1e) also could promote such a transformation with good yield and high diastereoselectivity. All major isomers 1a-j and some minor isomers 1a', 1b', 1f', 1g', 1j' were successfully isolated and fully characterized. Notably, the relative configuration of major isomer 1f (CCDC 2109575) was determined by X-ray crystallographic analysis, in which the m-chlorophenyl, benzoyl and the phenyl group in oxindole are in cis-configuration. It has been known that the benzoyl group and the phenyl group in oxindole stand in cis-position in the starting 3-phenacylideneoxindoles [75]. Therefore, a concerted Diels-Alder reaction should be involved in this three-component reaction.
On the basis of this success, we further considered whether other dienophiles could be applied in such catalytic system. Under the same reaction conditions, the three-component reaction of 2-methylindole, benzaldehyde and 2-(1-benzyl-2-oxoindolin-3-ylidene)malononitrile reacted smoothly to give the expected spiro[carbazole-2,3'indolines] in 51% yield with a diastereometric ratio (dr) value of 7:1. As shown in Scheme 3, a wide range of aromatic aldehydes with different substituents on the aromatic ring reacted smoothly to give the desired products 2a-e in good yields and with good to excellent diastereoselectivity. On the other hand, we also tested various isatylidene malononitriles, substrates with a differently substituted indole ring or with different protecting groups on the indole N-1 position (2f, 2g). All substrates reacted smoothly to give the corre- sponding products in moderate to good yields and with high stereoselectivity. It should be pointed out that the minor products 2a'-e' and 2g' were also isolated and fully characterized.
Moreover, the relative configuration of major isomer 2b (CCDC 2109576) and minor isomer 2g' (CCDC 2109577) were determined by X-ray crystallographic analysis. In the major isomer 2b, the phenyl group at C4-position is in cis-position to the aryl group in the oxindole scaffold, while these two groups exist in trans-configuration in the minor isomer 2g'.
5-Arylidene-1,3-dimethylbarbituric acids, as good dienophiles, could also react smoothly in such a catalytic system (Scheme 4a). Firstly, the three-component reaction of 2-methylindole, 5-arylidene-1,3-dimethylbarbituric acid and 4-methylbenzaldehyde under the standard reaction conditions and further oxidation with DDQ generated the final aromatized product 3a in 75% yield. Under the same reaction conditions, similar aromatized products 3b and 3c were also produced in good yields with different kinds of aromatic aldehydes and 5-arylidene-1,3-dimethylbarbituric acids. 5-Arylidene-1,3dimethylbarbituric acids could be easily generated through Knoevenagel condensation of aromatic aldehydes and 1,3dimethylbarbituric acid under the catalysis of Lewis acid. We envisioned whether the desired dienophiles, 5-arylidene-1,3dimethylbarbituric acids, could be in situ generated by aromatic aldehydes and 1,3-dimethylbarbituric acid under the standard conditions. Therefore, the four-component reaction was carried out by using two molecular aromatic aldehydes, 1,3-dimethylbarbituric acid and 2-methylindole utilizing CuSO 4 as the catalyst in toluene at 110 °C. The desired product 4a was obtained in 82% with excellent diastereoselectivity (dr > 20:1). In this reaction, both dienes (o-QDMs) and dienophiles were in situ formed from the starting material. As shown in Scheme 4b, a wide range of aromatic aldehydes that bore different substituents at the ortho-(4c), meta-(4e, 4g) and para-position (4b, 4d, 4f and 4h) of the phenyl ring reacted smoothly to give the corresponding products 4a-h in moderate to good yields with excellent diastereoselectivity (dr > 20:1  Based on the success of the four-component reaction through in situ generation of dienes and dienophiles, we further considered whether more common cyclic 1,3-diones could be applied in this catalytic system. To our delight, when cyclopentane-1,3dione was used to replace 1,3-dimethylbarbituiric acid under the same conditions, the desired product 5a was obtained in 74% yield with excellent diastereoselectivity (dr > 20:1). Furthermore, we examined the scope of aromatic aldehydes (Scheme 5), different substituents on the aromatic ring showed marginal effect on the yields. The spiro compounds 5a-g were successfully produced in moderate to excellent yields with excellent diastereoselectivity (dr > 20:1). Cyclohexane-1,3dione also reacted smoothly to produce the corresponding products 5h-k in high yields with high diastereoselectivity. The single crystal structure of compound 5b (CCDC 2109580) clearly indicated that the two aryl groups are in cis-position.
When we did not add the dienophiles to this system, 4-methylbenzaldehyde could react with two molecules of 2-methylindole under the same reaction conditions to generate the wellknown 3,3'-(p-tolylmethylene)bis(2-methylindole) (6a) in 75% yield. Subsequently, we sought to determine the generality of aromatic aldehydes. As illustrated in Scheme 6, a diversity of functional groups, which include Me (6a), OMe (6b, 6c), NMe 2 (6d), NO 2 (6e), and Cl (6f, 6g), could be well tolerated in this reaction. Importantly, the reaction is not sensitive to the elec-tronic properties of the arenes, as the substrates bearing either electron-donating (6a-d), or electron-withdrawing (6e-g) groups on the aryl ring were all transformed smoothly into the corresponding desired products 6a-g with good to excellent yields. Though 3,3'-(p-tolylmethylene)bisindoles have been previously prepared by acid-catalyzed reaction of aromatic aldehydes and various indoles. Here we also provided an alternative synthetic protocol by Lewis acid CuSO 4 catalyzed reaction. This also means that the major isomers 4 and 5 are the thermodynamically stable isomers. In the major isomer 1, the aryl group and the benzoyl group at 1,3-position also stand on the e-bonds, which indicated that the major isomer 1 is also belonging to the thermodynamically stable isomer. This result showed that this reaction is a thermodynamically controlled reaction. On the other hand, the tetrahydrospiro[carbazole-3,5'-pyrimidine] 4 can be converted to aromatized spiro[carbazole-3,5'-pyrimidine] 3 through the oxidation of DDQ. In the absence of the effective dienophile, the normal Friedel-Crafts alkylation of 2-methylindole with aromatic aldehyde gives the well-known 3,3'-(arylmethylene)bis(2-methylindoles) 6.

Conclusion
In summary, we have developed a copper-catalyzed multicomponent Diels-Alder reaction of 2-methylindole, aromatic aldehydes and cyclic 1,3-diones through in situ generated dienes and dienophiles under the same conditions. These strategies are sustainable, general and practical, which providing facile access to important polysubstituted spiro the key intermediates in these reactions. Moreover, this protocol exhibited good functional group tolerance, broad substrate scope and facile scalability. It would provide great potential for applications in organic synthesis, pharmaceutical chemistry and materials science.