Catalytic efficiency of β-cyclodextrin hydrate-chemoselective reaction of indoles with aldehydes in aqueous medium
Graphical abstract
Introduction
Cyclodextrins (CDs) are a family of macrocyclic oligosaccharides linked together by α-1,4 glucopyranose subunits and produced enzymatically from starch. β-Cyclodextrin (β-CD) consists of seven d-glucopyranose units forming a cyclic, hollow cone-shaped cavity and possessing hydrophilic exterior due to upper and lower rims decorated with hydroxyl groups as well as hydrophobic internal pocket that embrace substrates selectively [1] through inclusion complexes. But, β-Cyclodextrin hydrate (β-CDH) contains exchangeable hydrogen atoms [2] associated with protonic conductivity which is similar to that of hydrated proteins. The water molecules are present inside and outside of β-CD hydrate (β-CDH) provides an efficient path for the extended movement of protons which is also responsible for the protonic conductivity via a concerted and co-operative translocation of protons through the so-called flip-flop hydrogen bond [3]. The catalytic applications [4] of CDs for the synthesis of biologically important compounds have been reported. But surprisingly the catalytic attributes of β-cyclodextrin hydrate, which behaves differently from β-cyclodextrin, have not been explored much after the maiden report from our group [5].
Friedel-Crafts reaction is one of the cornerstone reactions for fundamental carbon–carbon (CC) bond formation and construction of important classes of building blocks [6]. Bis-(indolyl)methanes (BIMs) are prominent and privileged structural motif in bioactive metabolites as well as compounds of both terrestrial and marine origin [7]. A broad range of biologically and pharmacologically active compounds, such as anticancer [8a], antitumor [8b], antifungal [8c], and HIV-1 integrase inhibitor [8d] also carry this structural unit. Therefore, various synthetic strategies such as solid acids [9a,9b], Lewis acids [9](c), [9](d), [9](e), [9](f), hetero-polyacids [9g], ionic liquids [9](h), [9](i), and many other transition metal-free protocols [9](j), [9](k), [9](l), [9](m), [9](n), [9](o), [9](p), [9](q) have been developed during the last few years. Several homogeneous and heterogeneous systems, such as Fe [10a], Cu [10b], Zn [10c], Ag [10d], Sc [10e], Mo [10f], Pd [10g], Nb [10h], Ni-Dy complex [10i], and Dy(OTf)3-ILs [10j], were also reported for the similar transformations. Even though these reported protocols are satisfactory, but they also suffer from certain disadvantages such as high temperature [[9], [9](a), [10](g)], long reaction time [9](p), [9](q), [10](c), [10](g), [10](i), [10](j), harsh reaction condition [10g], use of expensive metal catalysts [10](e), [10](f), [10](g), [10](h), [10](i), [10](j), limitation in gram scale production [9](a), [10](a), [10](d), [10](h), [10](i), [10](j), insufficient recovery of catalyst [10](b), [10](d), [10](e), [10](g), [10](i), lack of chemoselectivity [9](a), [9](h), [9](m), [9](n), [10](a), [10](d), [10](f), [10](j), [10](k), and involvement of organic solvents [9](e), [9](g), [10](b), [10](d), [10](e), [10](g), [10](k) having poor scope to recover and recycle. Therefore, an operationally simple, catalytically efficient, and eco-compatible protocol for the chemoselective synthesis of bis-(indolyl)methanes through the three component reaction [11] involving indoles [12] is of great demand from the standpoint of sustainability. The use of β-cyclodextrin hydrate (β- CD hydrate) as a mildly acidic, efficient and recyclable catalyst during an organic reaction in aqueous medium has been reported [5] for the first time from our group. In continuation of our investigations in this direction we report herein the synthesis of bis-(indolyl)methanes using β-CD hydrate as an eco-friendly catalyst through chemoselective Friedel-Crafts alkylation of substituted indoles with differently substituted aromatic and aliphatic aldehydes in aqueous medium where the assistive role of water molecules present inside the cavity of β-CD hydrate was established.
Section snippets
Results and discussion
We initiated our experiments by investigating the Friedel-Crafts alkylation reaction between 2-methylindole 1a (1 mmol) with 4-methoxybenzaldehyde 2a (0.5 mmol) in water at 60 °C in the presence of different catalysts with the variation of reaction time and catalyst loading to obtain the corresponding bis-(indolyl)methanes 3a (Table 1).
As shown in Table 1, the reaction did not occur at all in the absence of any catalyst (Entry 1), the unreacted substrates were isolated intact. The reaction was
Conclusion
Catalytic efficiency of β-cyclodextrin hydrate has been investigated towards the synthesis of bis-(indol-3-yl)-methanes through the Friedel-Crafts alkylation reaction of indoles with aryl, heteroaryl as well as alkyl aldehydes under mild reaction condition. This newly developed atom-economical protocol shows good chemoselectivity which has been substantiated through intermolecular as well as intramolecular competition experiments. Practical synthetic utility was also demonstrated by gram scale
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
Financial assistance from RUSA 2-Programme and UGC-CAS-II programme in Chemistry at Jadavpur University are gratefully acknowledged. S. N. thanks DST, INSPIRE, New Delhi for senior research fellowship. Thanks to Mr. N. Dutta of IACS and Mr. R. Biswas of JU for necessary assistance.
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