DOI: 10.1002/ejoc.201901181 Communication Tandem Reaction | Very Important Paper | Iron-Catalyzed Functionalization of 3-Benzylideneindoline Through Tandem Csp 2 –Csp 3 Bond Formation/Isomerization with π-Activated Alcohols Rupsa Chanda, [a] Baitan Chakraborty, [a] Gopal Rana, [a] and Umasish Jana* [a] Abstract: A new synthetic protocol was developed for the se- lective synthesis of diverse 3-substituted indoles through tan- dem carbon–carbon bond formation and isomerization of 3- benzylidene-1-tosylindoline by direct use of alcohols as alkyl- ating agents in the presence of catalytic FeCl 3 . This method is applicable to a wide range of substrates containing varieties of Introduction The indole ring is a ubiquitous structural core of a plethora of biologically active molecules and natural products. [1] This justi- fies the ongoing interests addressed to all synthetic processes concerning this heterocyclic system. Functionalization of the indole ring at the 3-position is a pivotal synthetic route to pre- pare many promising therapeutic agents embedding the indole nucleus such as antimicrobial, anti-inflammatory, anti-tumor, anti-malarial, anti-migraine, anti-estrogen and antagonist drugs. [2] In addition, C-3 substituted indole is an important syn- thetic intermediate for the construction of complex natural and unnatural polycyclic indoles derivatives. [3] Therefore, many syn- thetic methodologies for constructing 3-functionalized indoles have been developed. Among them, the classical method for the synthesis of 3-alkylated indoles involves the Friedel-Crafts reaction or S N 2 reaction of alkyl halides or other derivatives of alcohol with preformed indoles in the presence of stoichiomet- ric Lewis acids or bases. [4] While these reactions can be efficient, but their synthetic applications are inevitably hampered by the cost, harsh reaction condition and production of stoichiometric by-products. [5] In the last decade, the concept of carbon–carbon bond for- mation by the direct substitution of π-activated alcohols (R-OH) in the presence of catalytic Lewis- or Brønsted acids with vari- ous nucleophiles such as aromatic rings, alkenes and alkynes (R′–H) has generated considerable interest in the area of green chemistry, as the process is catalytic and water is the only by- product. [6] From then on, many research groups reported the synthesis of 3-substituted indoles by direct substitution of alco- [a] Department of Chemistry, Jadavpur University, Kolkata 700032, West Bengal, India E-mail: jumasish2004@yahoo.co.in umasishjana@gmail.com Supporting information and ORCID(s) from the author(s) for this article are available on the WWW under https://doi.org/10.1002/ejoc.201901181. Eur. J. Org. Chem. 0000, 0–0 © 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1 functional groups. Direct use of alcohols, such as benzylic, all- ylic, and propargylic alcohols, as electrophiles and the use of non-toxic iron catalyst makes this strategy attractive and envi- ronmentally benign. A plausible mechanism has also been pro- posed for this tandem reaction. hols using various Lewis- and Brønsted-acid catalysts, and also in metal free condition. [7] As a part of our research program of iron-catalyzed direct activation of alcohols, [8] we have also developed 3-substituted indoles by direct substitution of alco- hols using iron-catalysis. [8b] However, all these methods developed for the synthesis of 3- substituted indoles rely on the availability of preformed indole derivatives, in few cases, harsh reaction conditions, and lack of generality with respect to electrophiles and low chemical yields, which are the limitations of these strategy. In this regard, our group recently reported a new protocol for the synthesis of various 3-substituted indole derivatives via iron-catalyzed isomerization/cycloisomerization of substituted 3-methylene- indoline derivatives through π-activation of double/triple bond by iron in high yields. [9] Due to easy accessibility of 3-methyl- eneindoline derivatives through tandem Heck–Suzuki or reduc- tive Heck coupling of 2-halo-N-propargylanilide, this has been a potentially attractive intermediate for the synthesis of 3-sub- stituted indole derivatives. In continuation of our efforts for the development of C–C/ C–N bond formation with direct use of alcohols and isomeriza- tion of 3-benzylidene indole derivatives, we presumed that in situ generated carbocation from π-activated alcohol could un- dergo Csp 2 –Csp 3 bond formation, chemoselectively at the exo- cyclic double bond, and subsequent aromatization could fur- nish densely substituted 3-alkylindoles derivative (Scheme 1). Herein, we wish to disclose this new strategy for the synthesis of densely substituted 3-alkylindole derivatives in the presence of environmentally friendly and sustainable catalyst, FeCl 3 . Sev- eral π-activated alcohols, such as benzylic, allylic, and proparg- ylic alcohols were chosen as the coupling partners to furnish the complex 3-alkylated indole moieties in high yields, which are difficult to synthesize by other conventional methods. To the best of our knowledge, the present strategy for the con- struction of densely substituted 3-alkyl indoles from tandem